Kim - Lancet Oncol - 2018 (MAVORIC) - Appendix

Appendix
Contents
Study Investigators ........................................................................................................................................................2
Methods ....................................................................................................................................................................... 10
TNMB staging classification ................................................................................................................................... 10
Table S1. TNMB staging .................................................................................................................................... 10
Table S2. Clinical staging/Classification of MF and SS ..................................................................................... 12
Tools/methods for assessment of disease in each compartment .............................................................................. 13
Modified severity-weighted assessment tool (mSWAT) .................................................................................... 13
Table S3. Modified severity-weighted assessment tool score ............................................................................. 13
Response criteria for skin.................................................................................................................................... 14
Table S4. Response criteria for skin, as assessed by mSWAT scoresa ............................................................... 14
Response criteria in blood ................................................................................................................................... 15
Table S5. Blood response criteriaa ...................................................................................................................... 15
Evaluation of disease in lymph nodes and viscera .............................................................................................. 16
Table S6 Response in lymph nodesa ................................................................................................................... 17
Table S7. Response in viscera............................................................................................................................. 18
Primary endpoint definition .................................................................................................................................... 19
Results ......................................................................................................................................................................... 20
Table S8. Summary of PRO measures from baseline through 6-month assessment ............................................... 20
Table S9. Exploratory analyses of overall survival ................................................................................................. 20
Table S10. Treatment-emergent adverse events (comprehensive listing) ............................................................... 21
Table S11. Serious adverse reactions by body system ............................................................................................ 27
Figure S1. Scatterplot of CCR4 expression percentage and global overall response rate based on Investigator’s
assessment* ............................................................................................................................................................. 30
References .................................................................................................................................................................. 31
Protocol....................................................................................................................................................................... 32
Page 1
Study Investigators
Institution/ Principal Patient

Country Investigator Accrual Additional Key Contributors
Hôpital Saint Louis Martine Bagot, 24 Caroline Ram-Wolff, MD; Jennifer Roux, MD; Jean-David Bouaziz,
France Professor MD; Barouyr Baroudjian, MD; Cécile Pages, MD; Touda Bounfour,
MD; Pauline Laly, MD; Camille Salle De Chou, MD; Jérémy
Gottlieb, MD; Steve Mathieu, MD; Julie Delyon, MD
H. Lee Moffitt Cancer Lubomir Sokol, MD, 20 Bijal Shah, MD; Celeste Bello, MD; Pedro Horna, MD; Julio Chavez,
Center and Research PhD MD; Farrah Farquharson, PA-C; Christopher Salamanca, PA-C; Elyce
Institute Turba, CTC
United States
Istituto de Ematologia e Pier Luigi Zinzani, 18 Vittorio Stefoni, MD; Alessandro Broccoli, MD; Letizia Gandolfi,
Oncologia Medica “L. e A. MD MD; Cinzia Pellegrini, MD; Beatrice Casadei, MD; Federica Quirini,
Seràgnoli” MD
Italy
Stanford Cancer Center Youn Kim, MD 17 Michael Krathen, MD; Analuisa Lares, NP; Timothy H. Almazan,
United States MD; Amelia Komp, NP; Jenna Strelo, NP; Ziba Rahbar; Richard
Hoppe, MD; Ranjana Advani, MD; Sunil Reddy, MD; Sameer
Freidenerich Center for Bashey, MD; Jenna Strelo, NP; Rochelle Reyes, PA-C; Annie
Translation Research Nguyen-Lin, MD; Kokil Bakshi, CCRP; Illisha Rajasansi, BS; Sima
United States Rozati, MD; Michael Khodadoust, MD; Julia Dai, MD
General Clinical Research

Center / Clinical and
Translational Research Unit
United States
The University of Texas Ronald Peter Rapini, 15 Pamela Ganger, MD; Sangeetha Venkatarajan, MD; Casey Wang,
M.D. Anderson Cancer MD MD; Juri Bassuner, MD; Auris Onn-Lay Huen, PharmD, MD; Ana
Center (Replaced Auris Mercedes Ciurea, MD
United States Huen, MD, PharmD)
(Replaced Madeleine
Duvic, MD)
Guy’s and St. Thomas’ Stephen Lloyd 15 Fiona Child, MD; Sean Whittaker, MD; Ajay Aggarwal, MD; Thomas
NHS Foundation Trust Morris, MD Bird, MD; Blaithin Moriarty, MD; Mary Wain, MD; Anastasia
Guy’s Hospital Therianou, MD; Delali Adjogatse, MD; Aleksandra Kuciejewska,
UK MD; Magnus Lynch, MD; Clare Kiely, MD; Elizabeth Orrin, MD;
Gemma McCormick, MD; Dr. Vanessa Priscilla Martins da Silva;
Dr. Jennifer Turner
Washington University Amy Musiek, MD 13 Camille Abboud, MD; Nancy Bartlett, MD; Amanda Cashen, MD;
School of Medicine (Replaced Kenneth Todd Fehniger, MD, PhD; Timothy J. Pluard, MD; Keith Stockerl-
Siteman Cancer Center Carson, MD) Goldstein, MD; Geoffrey Uy, MD; Ravi Vij, MD; Nina Wagner-
United States Johnston, MD; Peter Westervelt, MD, PhD; Stephanie Bauer, NP;
Holly Comer, NP; Stephanie Thompson, NP; Jeane Kuensting, NP;
Barnes-Jewish Hospital, Katy Thomas, NP; Kimbra Cardwell, NP; Alex Politsmakher, MD;
South Campus Karen Hampel, NP; John F. DiPersio, MD, PhD; Amy Musiek, MD;
United States Ashley Frith, MD
Perelman Center for Ellen Kim, MD 13 Alain Rook, MD; Jennifer Villasenor-Park, MD; Natalie Spaccarelli,
Advanced Medicine MD
Hospital of the University of
Pennsylvania
United States
Clinical and Translational

Research Center
Hospital of the University of
Pennsylvania
United States
Hospital Universitario 12 de Pablo L. Ortiz- 13 Concepción Postigo, MD; Lidia Maroñas, MD; Vanessa Gargallo, MD
Octubre Romero, MD, PhD
Spain
Page 2
UCLA Herbert Eradat, MD 12 Sven de Vos, MD, PhD; Sarah Larson, MD; Herbert Eradat, MD; John
Hematology/Oncology (Replaced Lauren Timmerman, MD; Lee Rosen, MD; Cynthia Carsten, NP
Clinical Research Unit Pinter-Brown, MD)
United States
Ronald Reagan UCLA

Medical Center
United States
Santa Monica UCLA

Medical Center and
Orthopaedic Hospital
United States
UCLA Santa Monica

Hematology Oncology
United States
Westwood Bowyer Clinic

United States
University of Alabama at Craig Elmets, MD 12 Wendy Cantrell, RN, MSN, CRNP, DNP; Casey Wang, MD; Theresa
Birmingham (Replaced Lauren Canavan, MD; Lucia Seminario, MD, PhD; Tiffany Mayo, MD;
United States Hughey, MD) Annette Nicole Sullivan, MD
Wilhelms Universität Nina Magnolo, MD 11 Carsten Weishaupt, MD; Rose Moritz, MD; Sabine Steinke; Antonia
Münster (replaced Athanasios Jeskowiak, MD; Nina Magnolo, MD; Eva Thriyani Tjandra, MD;
Germany Tsianakas, MD) Patricia Convalexius, MD; Thuy-Anh Mai; Claudia Riepe, MD;
Manuel Pereira, MD
University Hospitals Julia Scarisbrick, MD 11 Farida Shah, MD; Simon Tso, MD; Jinah Yoo, MD; Seow Foo, MD;
Birmingham NHS Manisha Panchal, MD; Alexa Shipman, MD; Manju Paul; Rengau
Foundation Trust Ramesh Raghavendran, MD; Paul Gazzani, MD; Sue Ann Chan, MD;
Queen Elizabeth Hospital James Carr, MD; Weronika Szczecinska, MD; Saibal Sanyal, MD
UK
Seattle Cancer Care Andrei Shustov, MD 10 Karen Schiavo, ARNP; Michi Shinohara, MD; Edward Libby, MD;
Alliance Stephen Smith, MD
(University of Washington)
United States
Centre Hospitalier Lyon Sud Stéphane Dalle, MD 10 Mona Amini-Adle, MD; Marie Perier-Muzet, MD; Sébastien
France Debarbieux, MD; Anne-Laure Breton, MD; Laura Weiler, MD
Dana-Farber Cancer David C. Fisher, MD 10 Thomas S. Kupper, MD; Nicole Leboeuf, MD; Allison Goddard, MD;
Institute Eric Jacobsen, MD; Marianne Tawa, NP; Michele Walsh, DNP;
United States Suzanne MacRae, RN; John O’Malley, MD, PhD; Jeffrey Barnes,
MD; Joi Carter, MD; Amanda Crawford, NP; Brianne McGree, NP;
Brigham and Woman’s Patricia Renaudie, RN; Colleen Chin, RN; Cecilia Larocca, MD;
Hospital (BWH) Ashleigh Eberly Puleo, PAC
United States
Massachusetts General
Hospital (MGH)
United States
Page 3
University of Rochester Brian Poligone, MD, 8 Elaine Gilmore, MD, PhD; Christopher Richardson, MD, PhD;
Medical Center PhD Kathryn Somers, MD; Amy Strikwerda, MD; Michael Bax, MD; Mary
United States Gail Mercurio, MD; Lisa Beck, MD; Francisco Tausk, MD; Amanda
Moon, MD; Rachel Garner, MD; Kimberly Brady, MD; Franki
Rochester Skin Lymphoma Lambert-Smith, MD; Ilya Lim, MD; Matthew Lewis, MD; Virginia
Medical Group, PLLC Hanchett, CNP; Kristen Ahern, MD; Neal Varughese, MD; Kira
United States Mayo, MD; Harjot Maan, MD; Alice Pentland, MD; Carla Casulo,
MD; Laurel Mallory, RN; Tia Albro (DeRosa), RN, MSN, ACNP;
Universal Dermatology, Elise DeLuke, MD; Carolina Alexander-Saviono, BS, CCRC
PLLC
United States
Rochester General Hospital

United States
Northwestern Medical Barbara Pro, MD 8 Leo I. Gordon, MD; Jane Norma Winter, MD; Adam Matthew Petrich,
Faculty Foundation (Replaced Timothy MD; Shuo Ma, MD, PhD; Katie M. Habersbrunner, PA-C; Betsy
United States M. Kuzel, MD) Mitchell, RN, BSN, MSN, ANP-BC; Brenda Martone, MSN, ANP-
(Replaced Steven T. BC, OCN; Joan Guitart, MD; Elizabeth Hamilton; Jason B. Kaplan,
Northwest Memorial Rosen, MD, FACP) MD; Ellen Dammrich, APN; Amanda J. Williams, PA-C
Hospital
United States
A.O. Città della Salute e Maria Teresa Fierro, 8 Pietro Quaglino, MD; Paola Savoia, MD; Paolo Fava, MD; Giovanni
della Scienza di Torino (San MD Cavaliere, MD; Matteo Brizio, MD; Elisa Faure, MD; Caterina Cariti,
Lazzaro) MD
Italy
Vanderbilt University John P. Greer, MD 7 Brian Engelhardt, MD; David Morgan, MD; Nishitha Reddy, MD;
Medical Center Jeremy Warner, MD; Leslie Goebel, ANP; Madan Jagasia, MD;
United States Meera Srinivas Kumar, PA; Meghan E. Caldwell, ANP; Olalekan
Oluwole, MD; Sanjay Ram Mohan, MD; Stephan Strickland, Jr., MD;
Henry-Joyce Cancer Clinic John Alan Zic, MD; Jeffrey Paul Zwerner, MD; Laura Young McGirt,
United States MD; Shelton L. Harrell (Lacy), APN
University of Utah Ahmad Sami 7 Michael Deininger, MD, PhD; Martha Glenn, MD; Paul Shami, MD;
Huntsman Cancer Institute Halwani, MD Gerhard Hildebrandt, MD; Amie Clark, APRN; Renee Vadeboncoeur,
United States APRN; Mary Lowe, RN; Tibor Kovacsovics, MD; Glen M. Bowen,
MD; Mark Hyde, PA; David A. Wada, MD; Deborah Stephens, DO
CHU de Nantes Brigitte Dreno, 7 Gaëlle Quéreux, MD; Anabelle Brocard, MD; Lucie Peuvrel, MD;
France Professor Mélanie Saint-Jean, MD; Marie Le Moigne, MD; Justine Daguzé
Peter MacCallum Cancer Amit Khot, MD 7 Kate Burbury, FRACP, FRCPA, DPhil, MBBS; Michael Dickinson,
Centre FRCPA, FRACP, MBBS; Simon Harrison, PhD, FRACP, MBBS;
Australia Elchanan Henry Januszewicz, FRACP; Henry Miles Prince, MD
MBBS; Constantine Tam, MD, MBBS; Max Wolf, MBBS; Kah-Lok
Parkville Cancer Clinical Chan, MBBS; Chun Yew Fong, MBBS, FRACP; Paul Sung-Hao Yeh,
Trials Unit MBBS; Carrie Van Der Weyden, MBBS; Kylee MacLachlan, MB,
Australia ChB; Anna Piggin, MBBS; Marzia Rahman, MBBS; Myles Wright,
MBBS; Sasanka Handunnetti, MBBS; Barnali Srivastava, MBBS;
Gaurav Srivastava, MBBS; Khai-Li Chai, MBBS; John Seymour,
MBBS, PhD, FRACP; Liesl Butler, MBBS
Dartmouth-Hitchcock Frederick Lansigan, 6 Elizabeth Bengtson, MD; Kenneth Meehan, MD; John M. Hill, Jr.,
Medical Center MD MD; Christopher Lowrey, MD; Marc Gautier, MD; Alexey Danilov,
United States MD; Kathryn Zug, MD; Sara Metzler, RN; Julie Schettino; Deborah
Lindberg, RN; Kara Brandariz; Darcie Findley
CHU de Bordeaux Marie Beylot Barry, 6 Antoine Fauconneau, MD; Anne Liên Pham-Ledard, MD; Anne-
Hôpital Saint-André Professor Sophie Dutkiewicz, MD; Caroline Dutriaux, MD; Aurélia Gey, MD;
France Stéphanie Guillet, MD; Emilie Gerard, MD; Léa Dousset
CHU de Bordeaux
Hôpital Haut Lévêque
France
Page 4
University Hospitals Neil Korman, MD, 6 Fuad Muakkassa, MD; Luisa Christensen, MD; Joselin Tacastacas,
Cleveland Medical Center PhD MD; MaryAnn Smith, RN; Heather Tribout, BS, CCRP; Kristen
United States Doud, PhD; Amanda Suggs, MD; Ritva Vyas, MD; Jacqueline Selph,
MD; Luke Lennox, MD
University Hospitals Case
Medical Center
United States
Memorial Sloan-Kettering Alison J. Moskowitz, 5 Steven M. Horwitz, MD; Andrew Zelenetz, MD, PhD; John
Cancer Center MD Gerecitano, MD, PhD; Ariela Noy, MD; Craig Moskowitz, MD;
United States Matthew Matasar, MD; Carol Portlock, fisMD; David Straus, MD;
Paul Hamlin, MD; Maria Lia Palomba, MD; Anas Younes, MD;
Christiane Querfeld, MD; Patricia Myskowski, MD
Westmead Hospital Jillian Wells, MD 5 Marina Ali, PhD; Ian Bilmon, MD; Giuliana Carlos, MD; Deepal
Australia Jayant Deshpande, MD; Pablo Fernández-Peñas, Associate Professor;
Shelly Ji Eun Hwang, MD
Wake Forest Baptist Health Zanetta Lamar, MD 5 David Hurd, MD; Elizabeth Holland, PA-C; Scarlett Hutchens, RN,
United States BSN; Zachariah McIver, DO; Mary Lynch, PA-C; Jennifer MacLean,
BS, RN; Rakhee Vaidya, MD; Melanie Brooke Kennedy, NP; Kathryn
Satterfield Mercer, PA-C
Emory University Hospital Mary Jo Lechowicz, 4 Ajay Nooka, MD; Leonard T. Heffner, Jr., MD; Christopher Flowers,
United States MD MD; Nassoma King-Bumpers, PA; Amelia Langston, MD; Daniela
Casbourne, NP; Danielle Roberts, PA; Karen Young, LPN, CCRC;
Emory Clinic Hannah Collins, NP; Zaid Al-Kadhimi, MD; Jonathon Cohen, MD;
United States Amanda Colbert; Amanda Hutchison-Rzepka; Melissa Kives; Vanessa
Smith; Soonja Sawyer, PA; Ryan Handy; Cecilia Rosand, PA;
Winship Cancer Institute Alexandra Palmer, NP
United States
University of Pittsburgh Oleg Akilov, MD, 4 Lisa Grandinetti, MD; Sara Story, MD; Einat Rabinovich, MD;
Medical Center-Presbyterian PhD (Replaced William Johnson, DO; Oleg Akilov, MD, PhD; Charles Vainder, MD;
Shadyside Timothy Patton, DO) Matthew Heller, MD; J. Desiree Douglas, PA-C; Sue McCann, RN
United States (Replaced Lisa
Grandinetti, MD)
(Replaced Larisa
Geskin, MD)
Hospital Clinico Dolores Caballero, 4 Belén Vidriales, MD; Alejandro Martín, MD; Marcos González, MD;
Universitario de Salamanca MD, PhD Concepción Román, MD; Emilia Fernández, MD; Javier Cañueto-
Spain Álvarez, MD
The Christie NHS Richard Cowan, 4 Professor Tim Illidge; Christina Hague, MD; Stephen Kennedy, MD;
Foundation Trust Professor Shazril Imran Shaukat, MD; Clara Chan, MD; Valerie Goode; Victoria
UK Lavin, MD; Anthea Cree, MD
UniversitätsSpital Zürich Reinhard Georg 4 Antonio Pius Martin Cozzio; Michael Kunz; Anna Lisa Frauchiger;
Switzerland Dummer, MD Nicoletta F. Jaberg-Bentele; Simone M. Goldinger; Thi Dan Linh
Nguyen; Fabrice Kaufmann; Samuel Conrad; Selina Thurneysen;
Florentina Dimitriou; Lukas Kraehenbuehl; Alexandra Valeska Matter
Yale University School of Francine Foss, MD 3 Scott Huntington, MD; Lisa Rivera, APRN; Rachel Pransky, APRN;
Medicine Gottfried Von Keudell, MD; Dennis Cooper, MD; Stuart Seropian,
United States MD; Daniel Persky, MD; Terri Parker, MD; Erikka Baehring, APRN
Smilow Cancer Center at

Yale New Haven Hospital
United States
Columbia University Larisa Geskin, MD 3 John Gregory Mears, MD; Genet Finnegan, PA; Lauren Levy, RN;
Medical Center- New York- (Replaced Adrienne Ahmed Sawas, MD; Owen O’Connor, MD; Jasmine Zain, MD;
Presbyterian Hospital Phillips, MD) Adrienne Phillips, MD; David Diuguld, MD; Jordan Schecter, MD;
United States Rita Gazivoda, RN; David Leung, MD; Frances Brogan, RN; Julia
Forman, NP
Columbia University
Medical Center
United States
Aarhus University Hospital Lars Iversen, MD 3 Dorte Moller Lybaek; Anne Bregnhoej
Denmark
Page 5
The University of Tokyo Tomomitsu 3 Tomomitsu Miyagaki, MD, PhD; Makiko Kawaguchi, MD; Naomi
Hospital Miyagaki, MD, PhD Takahashi, MD; Tomonori Oka, MD; Taro Akatsuka, MD
Japan (Replaced Makoto
Sugaya, MD)
Royal Adelaide Hospital Pratyush Kumar Giri, 3 Pratyush Kumar Giri, MBBS, FRACP, FRCPA; Agnes Siew Mee
Haematology and Bone MD (Replaced Ian Yong, MB BCh, FRACPA, PhD; Michelle Damin, MBBS; Chandrika
Marrow Transplant Unit Lewis, Associate Rajapaksha, MBBS, FRCPA
Australia Professor)
The Ohio State University Basem William, MD 2 Alejandro Gru, MD; Benjamin H. Kaffenberger, MD; Henry Wong,
Wexner Medical Center (Replaced Pierluigi MD; Kelly H. Tyler, MD
James Cancer Hospital Porcu, MD)
United States
University of Colorado Theresa Pacheco, 2 Paul Bunn, MD; Karl Lewis, MD; Bradley Haverkos, MD; Vu
Anschutz Cancer Pavilion MD Nguyen, MD
United States
University of Michigan Ryan A. Wilcox, 2 Sumana Devata, MD; Mark Kaminski, MD; Thomas F. Anderson,
Medical Center MD, PhD MD Michael Goldfarb, MD; Tera Mayer, NP
United States
Leiden University Medical Maarten H. Vermeer, 2 Rein Willemze; Stéphanie Eveline Boonk; Constantijn Jozef Marie
Centre MD Halkes; Koen D. Quint; Marjolein Donker; W.A.F. Marijt
Netherlands
The University of Kansas Sunil Abhyankar, 2 Joseph McGurik, DO; Tara Lin, MD; Daniel Aires, MD; Siddhartha
Hospital MD Ganguly, MD; Anurag Singh, MD; Mary Luder, APRN/NP; Omar
United States Aljitawi, MD; Leyla Shune, MD; Keely LaNoue, APRN/NP; May Lou
Wieliczka, APRN/NP; Joanne Wilson, APRN/NP; Liza Rodriguez,
The University of Kansas APRN/NP; Alison Coats, APRN/NP; Christina Schmidt, APRN/NP;
Cancer Center and Medical Sabita Pokhrel, APRN/NP; Sarah Fitzmaurice, APRN/NP; Jordan
Pavilion Leal, APRN/NP; Kristina Delaney, APRN/NP; Cherie Morey,
United States APRN/NP; Heather Male, MD; Allan Fleming, MD; Ruben Reyes,
MD; Suman Kambhampati, MD; Brea Lipe, MD; Olajire Kilanko,
APRN/NP; Abdulraheem Yacoub, MD; Abigail Raynolds, APRN/NP;
Kayla Pfannenstiel, APRN/NP; Marc Hoffmann, MD; Sepideh
Nikbakht, APRN/NP; Christine Smith, APRN/NP; Christopher
Sirridge, MD; Lee Jackson, APRN/NP; Lisa Stewart, APRN/NP; Neil
Dunavin, MD; Anusha Vallurupalli, MD; Ajoy Dias, MD; Zora
Bingham, APRN/NP
Kochi Medical School Shigetoshi Sano, MD 2 Hideki Nakajima, MD; Takeo Shiga, MD; Mika Teraishi, MD; Yumi
Hospital Honda, MD; Tomoko Matsumoto, MD; Tatsushi Ishimoto, MD;
Japan Hiroyuki Morisaka, MD; Risa Nakazawa, MD; Yukiko Tsuji, MD
Tokyo Metropolitan Tama Kaoru Nishiwaki, 2 Ayano Kanzaki, MD; Takayuki Kariya, MD; Yukihiko Kato, MD;
Medical Center MD (Replaced Hiroko Wakimoto, MD
Japan Yukihiko Kato, MD)
Froedtert Hospital and the Timothy Fenske, MD 1 Ehab Atallah, MD; Timothy Fenske, MD; Parameswaran Hari, MD;
Medical College of (Replaced Samuel Jeanne Palmer, MD; Stefan Schieke, MD; James Thomas, MD; Mehdi
Wisconsin Hwang, MD, PhD) Hamadani, MD
United States
Boston Medical Center Adam Lerner, MD 1 Debjani Sahni, MD; J. Mark Sloan, MD
United States
Tohoku University Hospital Noriko Fukuhara, 1 Hideo Harigae, MD; Yasushi Onishi, MD; Noriko Fukuhara, MD;
Japan MD (Replaced Yoko Okitsu, MD; Masahito Himuro, MD; Kei Saito, MD; Takuma
Kenichi Ishizawa, Suzuki, MD; Taku Fujimura, MD, PhD; Setsuya Aiba, MD, PhD;
MD) Makiko Tsukita, MD; Masahiro Kobayashi, MD; Yumi Kambayashi,
MD; Sadanori Furudate, MD; Koichi Onodera, MD; Mai Watanabe,
MD; Satoshi Ichikawa, MD; Shunsuke Hatta, MD
Mie University Hospital Koji Habe, MD 1 Keiichi Yamanaka, MD, PhD; Hitoshi Mizutani, MD; Jin Mizutani,
Japan (Replaced Kenichi MD; Youichi Omoto, MD; Tomoya Yokoyama, MD; Koji Habe, MD;
Isoda, MD) Masato Kakeda, MD; Yasuo Nakai, MD; Kenshiro Tuda, MD; Akisa
Yamagiwa, MD; Makoto Kondo, MD; Mariko Miyazaki, MD;
Masaaki Gyobu, MD; Ayaka Higashiyama, MD; Ai Umaoka, MD;
Tomoko Akeda, MD; Chie Nakai, MD; Ryoko Hidaka, MD; Kento
Mizutani, MD; Yoshiaki Matsushima, MD; Karin Okada, MD
Page 6
Osaka University Hospital Eiji Kiyohara 1 Toshifumi Yamaoka, MD, PhD; Hiroyuki Murota, MD, PhD; Atsushi
Japan (Replaced Mamori Tanemura, MD; Hiroaki Azukizawa, MD, PhD; Misa Hayashi, MD;
Tani, MD) Hideki Higashihara, MD, PhD; Eiji Kiyohara, MD; Yukinobu
Nakagawa, MD
Kansai Medical University Hiroyuki Okamoto, 1 Hiroyuki Okamoto, MD; Shuichi Ohe, MD; Fumikazu Yamazaki,
Hirakata Hospital MD MD; Taro Kusuyama, MD; Takahiro Kiyohara, MD; Toshiaki
Japan (Replaced Taiki Isei, Kogame, MD; Yoshigi Kobayashi, MD
MD)
Imamura Bun-in Hospital Kentaro Yonekura, 1 Yoshifusa Takatsuka, MD; Tamotsu Kanzaki, MD; Nobuyo
Japan MD Kawakami, MD; Shogo Takeuchi, MD; Koichiro Takeda, MD
Flinders Medical Centre Bryone Jean Kuss, 1 Ashanka Beligaswatte, MBBS, MD, FRACP, FRCPA; Jir-Ping Boey,
Australia Associate Professor BA, MBBS, MMedSC, MRCP (UK); Douglas Coghlan, MBBS,
FRACP, FRCPA; Alexander Gallus, MBBS, FRACP, FRCPA, FRCP;
Hui-Peng Lee, BHB, MBChB, FRACP, FRCPA; David Ross, MBBS,
PhD, FRACP, FRCPA; Magdalena Sobieraj-Teague. MBBS, FRACP,
FRCPA; Candice Thomson, MBBS, BMSc; Danielle Blunt, MBBS;
Kate Newland, MBBS, FACD; Sunayana Pema Patel, MBBS; Hisashi
Tsuji, MBBS; Anya Hotinski, BSc (Hons), BMBS; Thomas Day,
MBBS, BMedSc
Shinshu University Hospital Hiroshi Koga 1 Yukiko Kiniwa, MD, PhD; Koichi Hayashi, MD; Atsuko Ashida, MD;
Japan (replaced Hisashi Hiroshi Koga, MD; Ryuhei Uchiyama, MD; Atsuko Ohashi, MD;
Uhara, MD) Tomomi Miyake, MD; Fuminao Kamijyo, MD; Yasutomo Mikoshiba,
MD; Tasuku Sano, MD; Asuka Tsuji, MD; Asuka Mikoshiba, MD;
Aya Kobayashi, MD; Eisaku Ogawa, MD; Takushi Shirai, MD; Kaori
Sakaizawa, MD; Yuko Takazawa, MD; Nana Saito, MD
Okayama University Toshihisa Hamada, 1 Hiroko Fukamatsu, MD; Tatsuya Kaji, MD
Hospital MD
Japan
Asahikawa Medical Jiro Uehara, MD 1 Masaru Honma, MD; Yashushi Ohishi, MD; Kazuhiro Kaneta, MD;
University Hospital Haruki Doi, MD; Taisuke Matsuya, MD; Takeshi Iwasaki, MD
Japan
City of Hope Christiane Querfeld, 1 Ahmed Aribi, MD; Steven Rosen, MD; Jasmine Zain, MD; William
United States MD Boswell, MD; Belen Rubio-Gonzalez, MD; Leslie Popplewell, MD
Banner MD Anderson Javier Munoz, MD 1 Horst Uwe Klueppelberg, MD; Matthew Ulrickson, MD; Kristen
Cancer Center Dearing, DNP, FNP, BC; Gale Barr, NP; Kim O’Riley, NP
United States
IU Dermatology Lawrence A. Mark, 1 Kristin Hoffmann, MD; Jose Azar, MD; Michael Robertson, MD
United States MD
IU Health University
Hospital
United States
Indiana Clinical Research

Center
United States
Indiana University Simon

Cancer Center (IUSCC)
United States
Page 7
Thomas Jefferson S. Onder Alpdogan, 0 Manish Sharma, MD; Neal Flomenberg, MD; Margaret Kasner, MD;
University MD (Replaced Matthew Carabasi, MD; Mark Weiss, MD; John Wagner, MD; Joanne
United States Barbara Pro, MD) Filicko-O’Hara, MD; Ubaldo Martinez, MD; Thomas Klumpp, MD;
Joya Sahu, MD; S. Onder Alpdogan, MD
Thomas Jefferson
University, Sidney Kimmel
Cancer Center -
United States
Bodine Center, Gibbon

Building - Thomas Jefferson
University
United States
Tulane University Health Erin Boh, MD, PhD 0 Azeen Sadeghian, MD; William Claiborne, MD; Christi Baker, MD
Sciences Center
United States
Rush University Medical Michael D. Tharp, 0 Warren Piette, MD
Center MD
Chicago, IL 60612
Universitätsmedizin Jan Peter Nicolay, 0 Jan Peter Nicolay, MD; Mortiz Felcht, MD; Thomas Henzler, MD;
Mannheim MD Erika Anna Hernekamp (nee Pawlik), MD; Nolwenn Esther Maurier,
Germany (Replaced Claus- MD
Detlev Klemke, MD)
National Cancer Center Kensei Tobinai, MD, 0 Yukio Kobayashi, MD; Dai Maruyama, MD; Tatsuya Suzuki, MD;
Hospital PhD Wataru Munakata, MD; Hideaki Kitahara, MD; Shinichi Makita, MD;
Japan Akihiro Oomoto, MD; Ryoko Fukushima, MD; Akihisa Kawajiri,
MD; Yosuke Tanaka, MD; Sayako Yuda, MD; Tadahiro Honda, MD;
Hideaki Saitou, MD; Naoya Yamazaki, MD; Wataru Omata, MD;
Suguru Fukuhara, MD; Kosuke Toyoda, MD; Nobuhiko Yamauchi,
MD; Otake Yohei, MD; Hiroyuki Kubo, MD; Yukiko Kubo, MD
Japanese Foundation of Kiyohiko Hatake, 0 Masahiro Yokoyama, MD; Hideaki Nitta, MD; Noriko Nishimura,
Cancer Research MD MD; Kyoko Ueda, MD; Yasuhito Terui, MD; Yoshiharu Kusano, MD;
Japan Yuko Mishima, MD; Tadahiro Gunji, MD
Nagoya City University Shinsuke Iida, MD 0 Hirokazu Komatsu, MD, PhD; Takashi Ishida, MD, PhD; Shigeru
Hospital Kusumoto, MD, PhD; Masaki Ri, MD, PhD; Asahi Ito, MD, PhD;
Japan Haruhito Totani, MD; Shiori Kinoshita, MD; Akimichi Morita, MD,
PhD; Emi Nishida, MD, PhD; Ryouji Kubo, MD; Shinnosuke
Muramatsu, MD; Satsuki Murakami, MD; Takashi Kanamori, MD;
Tomoko Narita, MD
Fukushima Medical Mikio Ohtsuka, MD 0 Masataka Sato, MD; Yasunobu Kato, MD; Yuka Hanami, MD;
University Hospital Nobuyuki Kikuchi, MD; Takenobu Ohashi, MD;
Japan
Gunma University Hospital Osamu Ishikawa, 0 Masayoshi Yamanaka, MD; Masahito Yasuda, MD
Japan MD
Yokohama City University Hidefumi Wada, MD 0 Syuichi Ishida, MD; Tomoko Okawa, MD; Kayoko Oda, MD; Yusuke
Hospital Inoue, MD, PhD; Tomohiko Tanegashima, MD; Isoda Yuji, MD
Japan
Hamamatsu Medical Yoshiki Tokura, MD, 0 Toshiharu Fujiyama, MD; Shigeki Ikeya, MD; Kazuki Tatsuno, MD;
University Hospital PhD Masahiro Aoshima, MD; Akira Kasuya, MD
Japan
Hiroshima University Maiko Tanaka, MD 0 Akio Tanaka, MD; Makiko Hiragun, MD; Sugiyama Kazuhiko, MD
Hospital
Japan
Oregon Health and Science Craig Yoshitsugu N/A
University Okada, Assistant
United States Professor
(Independent
Reviewer); Jessica
Taft Leonard,
Instructor
(Independent
Reviewer)
Page 8
Page 9
Methods
TNMB staging classification
Classification of MF/SS was performed via the modified International Society of Cutaneous Lymphomas/European
Organization for Research and Treatment of Cancer (ISCL/EORTC) revisions to TNMB staging (Tables S1 and
S2).
Table S1. TNMB staging

TNMB stages Description of TNMB
Skin*
T1 Limited patches, papules, and/or plaques covering <10% of the skin surface. May further stratify into T1a
(patch only) vs. T1b (plaque +/- patch).
T2 Patches, papules, or plaques covering ≥10% of the skin surface. May further stratify into T2a (patch only) vs.
T2b (plaque+/- patch).
T3 One or more tumors (≥1 cm in diameter)
T4 Confluence of erythema covering ≥80% BSAa
Node†
N0 No clinically abnormal lymph nodes; biopsy not required
N1 Clinically abnormal lymph nodes; histopathology Dutch Grade 1 or NCI LN 0-2
N1a Clone negative
N1b Clone positive
N2 Clinically abnormal lymph nodes; histopathology Dutch Grade 2 or NCI LN 3
N2a Clone negative
N2b Clone positive
N3 Clinically abnormal lymph nodes; histopathology Dutch Grade 3-4 or NCI LN4; clone positive or negative
Nx Clinically abnormal lymph nodes without histologic confirmation or inability to fully characterize the
histological subcategories
Visceral
M0 No visceral organ involvement
M1 Visceral involvement (must have pathology confirmation and organ involved should be specified)
Blood
B0 Absence of significant blood involvement: ≤5% (based on morphology) of peripheral blood lymphocytes are
atypical (Sézary) cellsb
B0a Clone negative
B0b Clone positive
B1 Low blood tumor burden: >5% (based on morphology) of peripheral blood lymphocytes are atypical (Sézary)
cells, but does not meet the criteria of B2c
B1a Clone negative
Page 10
TNMB stages Description of TNMB
B1b Clone positive
B2 High blood tumor burden: ≥1000/µL Sézary cells with positive clone.‡ One of the following can be
substituted for Sézary cells: CD4/CD8 ≥10, CD4+CD7- cells ≥40%, or CD4+CD26- cells ≥ 30%
BSA=body surface area; ISCL/EORTC=International Society of Cutaneous Lymphomas/European Organization for Research and Treatment of
Cancer; mSWAT=modified Severity Weighted Assessment Tool; NCI=National Cancer Institute.
*Patch=any size lesion without induration or significant elevation above the surrounding uninvolved skin: poikiloderma may be present.
Plaque=any size lesion that is elevated or indurated: crusting or poikiloderma may be present. Tumor=any solid or nodular lesion ≥1 cm in
diameter with evidence of deep infiltration in the skin and/or vertical growth.
†
Lymph node classification was modified from 2007 ISCL/EORTC (Olsen, 2007)1 consensus revisions to include central nodes. Lymph nodes
were qualified as abnormal if >1.5 cm in diameter.
‡
The clones in the blood should match that of the skin. The relevance of an isolated clones in the blood or a clone in the blood that does not match
the clone in the skin remains to be determined.
a
If the mSWAT at the time of screening is <80% but the patient has a history of T4 disease, a comment was to be added to the General Comments
electronic case report form indicating that the patient had historical T4 disease.
b
In the present study, flow cytometry (not morphology) was used to assess blood. According to the 2011 ISCL/EORTC recommendations (Olsen,
2011),2 patients with <15% of CD4+CD26- or CD4+CD7- cells were considered to have B0 blood disease.
c
In the present study, flow cytometry (not morphology) was used to assess blood. According to the 2011 ISCL/EORTC recommendations (Olsen,
2011),2 patients with 15% or more of CD4+CD26- or CD4+CD7- cells were considered to have at least B1 blood disease.
Reprinted with permission. © (2007) American Society of Hematology from Olsen E, Vonderheid E, Pimpinelli N, et al. Blood 2007;110:1713-
22. All rights reserved.1
Page 11
Table S2. Clinical staging/Classification of MF and SS
Clinical Stage T N M B
IA 1 0 0 0,1
IB 2 0 0 0,1
IIA 1,2 1,2, X 0 0,1
IIB 3 0-2, X 0 0,1
IIIA 4 0-2, X 0 0
IIIB 4 0-2, X 0 1
IVA1 1-4 0-2, X 0 2
IVA2 1-4 3 0 0-2
IVB 1-4 0-3, X 1 0-2

MF=mycosis fungoides; SS=Sézary Syndrome. X=clinically abnormal lymph nodes without histologic confirmation or inability to fully
characterize histologic subcategories.
Reprinted with permission. © (2007) American Society of Hematology from Olsen E, Vonderheid E, Pimpinelli N, et al. Blood 2007;110:1713-
22. All rights reserved.1
Page 12
Tools/methods for assessment of disease in each compartment
Modified severity-weighted assessment tool (mSWAT)
Skin lesions and erythema were evaluated using the mSWAT. An mSWAT score was derived by measuring each
lesion as a percentage of total body surface area (%TBSA) and multiplying it by a severity-weighting factor (1 =
patch, 2 = plaque, 4 = tumor). All individual numbers were then added to produce a total score. Areas of skin
involvement identified as patch, plaque, or tumor and erythema were defined (Table S3).
Table S3. Modified severity-weighted assessment tool score

Body region (%BSA) Patch* Plaque* Tumor*
Head (7%)
Neck (2%)
Anterior trunk (13%)
Arms (8%)
Forearms (6%)
Hands (5%)
Posterior trunk (13%)
Buttocks (5%)
Thighs (19%)
Legs (14%)
Feet (7%)
Groin (1%)
Subtotal of lesion BSA
Weighting factor x1 x2 x4
Subtotal lesion BSA x weighting factor
mSWAT score = summation of each column line above
BSA=body surface area.
Patch = any size lesion without induration or significant elevation above the surrounding uninvolved skin: poikiloderma may be present.
Plaque = any size lesion that is elevated or indurated; crusting, ulceration, or poikiloderma may be present.
Tumor = any solid or nodular lesion ≥1 cm in diameter with evidence of deep infiltration in the skin and/or vertical growth.
Reprinted with permission. © (2011) American Society of Clinical Oncology from Olsen EA, Whittaker S, Kim YH, et al: J Clin Oncol 29(18),
2011: 2598- 2607. All rights reserved.2
Page 13
Response criteria for skin
Response in skin was determined by changes in mSWAT score (Table S4). Responses (complete response [CR] and
partial response [PR]) had to be confirmed for a minimum of 4 weeks.
Table S4. Response criteria for skin, as assessed by mSWAT scoresa

Response Definition
CR 100% clearance of skin lesionsb
PR 50% to 99% clearance of skin disease from baseline without new tumors (T3) in patients with T1, T2, or T4 only skin disease
SD <25% increase to <50% clearance in skin disease from baseline without new tumors (T3) in patients with T 1, T2, or T4 only
skin disease
PDc (1) ≥25% increase in skin disease from baseline or
(2) New tumors (T3) in patients with T1, T2, or T4 only skin disease or
(3) Loss of response: in those with CR or PR, increase of skin score of greater than the sum of nadir plus 50% baseline
score
Relapsed Any disease recurrence in those with CR
CR=complete response; MF=mycosis fungoides; mSWAT=modified severity-weighted assessment tool; PD=progressive disease; PR=partial
response; SD=stable disease; SS=Sézary Syndrome.
a
Based on mSWAT score.
b
A biopsy of normal appearing skin is unnecessary to assign a CR. However, a skin biopsy should be performed of a representative area of the
skin if there is any question of residual disease where otherwise a CR would exist. If histologic features are suspicious or suggestive of MF/SS,
the response should be considered a PR only.
c
Whichever criterion occurs first.
d
For purposes of the study, relapse should be defined as loss of response (as defined for PD) in those with CR, ie, increase of skin score of greater
than the sum of nadir plus 50% baseline score. Patients may remain on treatment until subsequent measurement to confirm progression.
Page 14
Response criteria in blood
In the present study, flow cytometry (not morphology) was used to assess blood. Abnormal T-lymphocyte
populations, CD4+CD7- and CD4+CD26-, cells were identified and followed over time. All blood responses (CR
and PR) had to be confirmed for a minimum of 4 weeks (Table S5).
Table S5. Blood response criteriaa

b B0
CR
c >50% decrease in quantitative measurements of blood tumor burden from baseline in those with high tumor burden at
PR
baseline (B2)
SD Fails to attain criteria for CR, PR or PD
d (1) B0 to B2 or
PD
(2) >50% increase from baseline and at least 5,000 neoplastic cells/μL or
(3) Loss of response: in those with PR who were originally B2 at baseline, >50% increase from nadir and at least 5,000
neoplastic cells/μL
Relapse Increase of neoplastic blood lymphocytes to ≥ B1 in those with CR
CR=complete response; PD=progressive disease; PR=partial response; SD=stable disease.

Note: Parameters assessed and reported to investigators for them to use in making their assessment of blood response were; white blood cell
count, absolute lymphocyte count, absolute CD3+ T lymphocyte count, CD4+ CD7 % and absolute lymphocyte count, CD4+CD26- % and
absolute lymphocyte count, CD4/CD8 ratio, CD3+CD4+CD7- % and absolute lymphocyte count, CD3+CD4-CD26- % and absolute lymphocyte
count
a
As determined by absolute numbers of neoplastic cells/L.
b
If a bone marrow biopsy was performed at baseline and determined to unequivocally be indicative of lymphomatous involvement, then to
confirm a global CR where blood assessment now meets criteria for B0, a repeat bone marrow biopsy must show no residual disease or the
response should be considered a PR only.
c
There is no PR in those with B1 disease at baseline as the difference within the range of neoplastic cells that define B1 is not considered
significant and should not affect determination of global objective response.
d
Whichever occurs first.
Page 15
Evaluation of disease in lymph nodes and viscera
The baseline tumor burden was assessed by computed tomography of the neck, chest, abdomen, and pelvis within 30
days prior to the first dose of study drug. The Investigator was to identify, prospectively, the lesions to be followed
to evaluate the patient’s response to therapy. Lymph nodes must have been >15 mm in the long axis (greatest
transverse diameter [GTD]) or >10 mm in the short axis if the GTD was >10 to ≤15 mm. Lymph node biopsies were
to be performed at the discretion of the Investigator to rule out inflammation or to confirm disease. Analysis of these
biopsies was to be done by the pathologist at the study site. The same method of assessment and the same technique
were to be used to characterize each identified and reported lesion at Screening and at reassessment during
treatment.
In patients with lymph node and/or visceral involvement, responses (CR and PR) had to be confirmed for a
minimum of 4 weeks (Tables S6 and S7).
Page 16
Table S6 Response in lymph nodesa
CR All lymph nodes are now ≤15 mm in GTD by the method used to assess lymph nodes at baseline. In addition, lymph nodes
that were ≤15 mm in GTD and >10 mm in the short axis at baseline must now be ≤10 mm in the short axis.
PR Cumulative reduction ≥50% of the SPD as compared to baseline and no new lymph node (>15 mm in the GTD or >10 mm in
the short axis if the GTD is >10 mm to ≤15 mm)
SD Fails to attain the criteria for CR, PR, or PD
PD Must meet any of the following:
(1) ≥50% increase in SPD from baseline of lymph nodes, or
(2) Loss of response, which is >50% increase from nadir SPD of lymph nodes in patients previously assessed as PR,
or
(3) >50% increase compared to nadir, but which does not meet the criteria for PR (ie, up to a 50% reduction compared to
baseline),
or
(4) Any new nodal lesion >15 mm in the GTD or >10 mm in short axis diameter if the GTD is >10 mm to ≤15 mm
Relapse (1) Any new lymph node >15 mm in GTD or >10 mm in short axis if the GTD is > 10 mm to ≤15 mm
(2) Recurrence of any lymph node previously selected at baseline, which was previously assessed as a CR, but which has
recurred and measures >15 mm in the GTD or >10 mm in the short axis if the GTD is >10 mm to ≤15 mm
Unable to A lymph node present at baseline, but which was not measured or which subsequently became unevaluable, leading to an
evaluate inability to determine the status of that particular node for the time point in question
CR=complete response; GTD=greatest transverse diameter; PD=progressive disease; PR=partial response; SD=stable disease; SPD=sum of the
products of the diameters.
a
Peripheral and central lymph nodes.
Page 17
Table S7. Response in viscera
(1) 100% reduction in the SPD of all lesions selected at baseline
CR (2) Liver or spleen or any organ considered involved at baseline should be considered normal by imaging
(3) No nodules should be present on any imaging of liver or spleen
(1) ≥50% regression in all splenic or liver nodules, or in measurable disease (SPD) in all organs abnormal at baseline
PR (2) No increase in the size of liver or spleen consistent with disease progression and no new sites of involvement
Must meet any of the following:
PD (1) >50% increase in SPD of organs involved at baseline, or
(2) New organ involvement, or
(3) Loss of response, which is >50% increase from nadir in the SPD of previous organ involvement in patients previously
assessed as PR, or
(4) >50% increase compared to nadir, but which does not meet the criteria for PR (ie, up to a 50% reduction compared to
baseline)
(1) New organ involvement in patients previously assessed as CR
Relapse (2) Recurrence of any lesion previously selected at baseline, which was previously assessed as a CR, but which has recurred
and meets the measurement criteria (≥10 mm and/or 2x the reconstruction interval in the GTD)
Unable to An area of visceral disease present at baseline, but which was not measured or which subsequently became unevaluable, leading
evaluate to an inability to determine the status of that particular area for the time point in question
CR=complete response; GTD=greatest transverse diameter; PD=progressive disease; PR=partial response; SD=stable disease; SPD=sum of the
products of the diameters.
Page 18
Primary endpoint definition
Progression-free survival (PFS), which was analyzed using Kaplan-Meier survival analysis methods, was defined as
the time from the day of randomization to a treatment arm until documented progression or death. For patients who
exhibited conditions of disease progression, but continued on the study due to a questionable clinical impression, the
patient was not considered to have progressed unless disease progression was confirmed at least 4 weeks after the
date of the initial questionable disease progression. In this case, the initial date was used as the date of disease
progression.
For PFS events, all deaths were to be attributed to progression, and hence, the time to progression equaled the time
to death and was to be uncensored. Patients who died without a reported prior progression were still to be considered
to have progressed on the day of their death. In the event that a randomized patient withdrew from the study for any
reason before documented progression, the time from the day of randomization to the last tumor assessment (from
any compartment) was to be used as a censored time point. For all patients randomized to a treatment arm but
withdrawing prior to first tumor assessment for any reason other than disease progression, the PFS time was to be
censored at the last documented assessment.
Page 19
Results
Table S8. Summary of PRO measures from baseline through 6-month assessment
Change From Baseline
Treatment Difference (Mogamulizumab vs. Vorinostat)
Timepoint Adjusted
Treatment Na LS Mean (SE) 95% CI LS Mean (SE) 95% CI p-value p-value
Scale - Skindex-29
Overall Across 6 Months -6.7 (1.77) (-10.14, -3.19) 0.0002 0.0008
Vorinostat 171 -6.0 (1.75) (-9.39, -2.52)
Mogamulizumab 162 -12.6 (1.69) (-15.94, -9.29)
Scale - FACT-G
Overall Across 6 Months 6.9 (1.31) (4.33, 9.47) <0.0001 <0.0001
Vorinostat 177 -2.3 (1.28) (-4.84, 0.21)
Mogamulizumab 167 4.6 (1.24) (2.14, 7.04)
Scale - 3-Level EQ-5D
Overall Across 6 Months 0.03 (0.015) (0.005, 0.064) 0.0210 0.0814
Vorinostat 174 0.02 (0.015) (-0.008, 0.052)
Mogamulizumab 169 0.06 (0.015) ( 0.028, 0.085)
Scale - ItchyQoL
Overall Across 6 Months -0.1 (0.07) (-0.29, -0.01) 0.0342
Vorinostat 175 -0.4 (0.07) (-0.52, -0.24)
Mogamulizumab 166 -0.5 (0.07) (-0.66, -0.39)
CI=confidence interval; FACT-G=Functional Assessment of Cancer Therapy-General; LS=least square; MMRM=mixed-effect model repeated
measures; PRO=patient-reported outcome; SE=standard error.
Note: LS means, SEs, 95% CIs, and p-values are from MMRM, with treatment, disease type, disease stage, and region as fixed effects and
baseline score as a covariate. Adjusted p-values are calculated using the Sidak method for the overall difference across timepoints through 6-
month assessment (including end of cycles 1, 3, and 5 timepoints only).
a
N is the number of subjects with values at baseline and post-baseline.
Table S9. Exploratory analyses of overall survival

Adjustment for Crossover Hazard Ratio 95% Confidence Interval
As randomizeda 0.93 (0.61, 1.43)
Censoring at crossoverb 0.709 (0.405, 1.242)
Rank Preserving Structural Failure Time
(RPSFT) Modelingc 0.739 (0.479, 1.141)
Inverse Probability Censoring Weighting
(IPCW) Methodd 0.508 (0.172, 2.905)
a
Crossover analyzed as randomized with no adjustment (P-value, CI by log-rank and Cox model with covariates Stage, Type, and Region).
b
Crossover censored at time crossover occurred (P-value, CI by log-rank and Cox model with covariates Stage, Type, and Region).
c
P-value and 95% CI by log-rank and Cox model with covariates Stage and Type.3-6
d
95% CI was based on 10000 bootstrap samples with logistic model, including terms of baseline ECOG score, age, sex, Stage, Type, Region,
time-dependent disease progression status, and number of adverse events.7,8
Page 20
Table S10. Treatment-emergent adverse events (comprehensive listing)
Mogamulizumab Vorinostat Crossover to Mogamulizumab
N=184 N=186 N=136
Grade 1-2 Grade 3 Grade 4 Grade 5 Grade 1-2 Grade 3 Grade 4 Grade 5 Grade 1-2 Grade 3 Grade 4 Grade 5
Blood and Lymphatic System Disorders
Anaemia 17 (9.2) 2 (1.1) 0 0 17 (9.1) 1 (0.5) 1 (0.5) 0 6 (4.4) 1 (0.7) 0 0

Eosinophilia 4 (2.2) 0 0 0 0 1 (0.5) 0 0 1 (0.7) 0 0 0
Febrile neutropenia 0 0 0 0 0 1 (0.5) 0 0 0 0 0 0
Leukocytosis 0 0 0 0 1 (0.5) 2 (1.1) 0 0 0 2 (1.5) 0 0
Leukopenia 1 (0.5) 0 0 0 3 (1.6) 1 (0.5) 0 0 5 (3.7) 1 (0.7) 0 0
Neutropenia 4 (2.2) 1 (0.5) 0 0 7 (3.8) 2 (1.1) 1 (0.5) 0 5 (3.7) 2 (1.5) 0 0
Thrombocytopenia 21 (11.4) 0 0 0 44 (23.7) 11 (5.9) 2 (1.1) 0 9 (6.6) 1 (0.7) 0 0
Cardiac Disorders
Acute myocardial infarction 0 1 (0.5) 0 0 0 0 0 0 0 1 (0.7) 0 0
Angina unstable 0 0 0 0 0 1 (0.5) 0 0 0 0 0 0
Atrial tachycardia 1 (0.5) 1 (0.5) 0 0 0 0 0 0 0 0 0 0
Cardiac failure 0 1 (0.5) 0 0 0 0 0 0 0 0 0 0
Coronary artery disease 0 1 (0.5) 0 0 0 0 0 0 0 0 0 0
Left ventricular hypertrophy 0 0 0 0 0 0 0 1 (0.5) 0 0 0 0
Myocarditis 0 1 (0.5) 0 0 0 0 0 0 0 0 0 0
Ventricular tachycardia 0 1 (0.5) 0 0 0 0 0 0 0 0 0 0
Eye Disorders
Lagophthalmos 0 1 (0.5) 0 0 0 0 0 0 0 0 0 0
Lens dislocation 0 1 (0.5) 0 0 0 0 0 0 0 0 0 0
Retinal vein occlusion 0 1 (0.5) 0 0 0 0 0 0 0 0 0 0
Gastrointestinal Disorders
Abdominal pain 7 (3.8) 0 0 0 21 (11.3) 0 0 0 5 (3.7) 0 0 0
Abdominal pain upper 1 (0.5) 0 0 0 10 (5.4) 1 (0.5) 0 0 3 (2.2) 0 0 0
Anal fistula 0 0 0 0 0 1 (0.5) 0 0 0 0 0 0
Constipation 20 (10.9) 1 (0.5) 0 0 32 (17.2) 2 (1.1) 0 0 11 (8.1) 0 0 0
Diarrhoea 42 (22.8) 1 (0.5) 0 0 106 (57.0) 9 (4.8) 0 0 18 (13.2) 1 (0.7) 0 0
Gastric haemorrhage 0 1 (0.5) 0 0 0 0 0 0 0 0 0 0
Ileitis 0 0 0 0 0 1 (0.5) 0 0 0 0 0 0
Intestinal obstruction 0 0 0 0 0 0 0 1 (0.5) 0 0 0 0
Mouth ulceration 1 (0.5) 1 (0.5) 0 0 0 0 0 0 2 (1.5) 0 0 0
Nausea 27 (14.7) 1 (0.5) 0 0 76 (40.9) 3 (1.6) 0 0 9 (6.6) 0 0 0
Vomiting 11 (6.0) 0 0 0 23 (12.4) 1 (0.5) 0 0 4 (2.9) 0 0 0
General Disorders and Administration Site Conditions
Asthenia 10 (5.4) 0 0 0 23 (12.4) 4 (2.2) 0 0 9 (6.6) 1 (0.7) 0 0
Disease progression 2 (1.1) 1 (0.5) 0 1 (0.5) 0 0 0 1 (0.5) 0 0 0 0
Fatigue 40 (21.7) 3 (1.6) 0 0 59 (31.7) 11 (5.9) 0 0 12 (8.8) 0 0 0
General physical health deterioration 0 1 (0.5) 0 0 0 1 (0.5) 0 0 1 (0.7) 0 0 0
Page 21
N=184 N=186 N=136
Generalised oedema 1 (0.5) 1 (0.5) 0 0 1 (0.5) 0 0 0 0 0 0 0

Oedema 0 1 (0.5) 0 0 1 (0.5) 0 0 0 0 0 0 0
Oedema peripheral 27 (14.7) 0 0 0 26 (14.0) 1 (0.5) 0 0 12 (8.8) 1 (0.7) 0 0
Pain 5 (2.7) 1 (0.5) 0 0 1 (0.5) 0 0 0 1 (0.7) 0 0 0
Pyrexia 30 (16.3) 1 (0.5) 0 0 11 (5.9) 0 0 0 15 (11.0) 0 0 0
Hepatobilary Disorders
Cholangitis 0 0 0 0 0 0 1 (0.5) 0 0 0 0 0
Cholecystitis 0 0 0 0 1 (0.5) 1 (0.5) 0 0 0 0 0 0
Hepatitis acute 0 1 (0.5) 0 0 0 0 0 0 0 1 (0.7) 0 0
Hepatocellular injury 0 0 1 (0.5) 0 1 (0.5) 0 0 0 0 0 0 0
Immune System Disorders
Contrast media allergy 3 (1.6) 1 (0.5) 0 0 1 (0.5) 0 0 0 3 (2.2) 0 0 0
Drug hypersensitivity 2 (1.1) 1 (0.5) 0 0 1 (0.5) 0 0 0 0 0 0 0
Hypersensitivity 0 1 (0.5) 0 0 0 0 0 0 0 0 0 0
Infections and Infestations
Abscess limb 0 1 (0.5) 0 0 0 0 0 0 0 0 0 0
Atypical pneumonia 0 1 (0.5) 0 0 0 0 0 0 0 0 0 0
Bacteraemia 0 2 (1.1) 0 0 0 0 0 0 0 0 0 0
Bronchitis 4 (2.2) 0 1 (0.5) 0 4 (2.2) 0 0 0 6 (4.4) 0 0 0
Bronchopneumonia 0 0 0 0 0 0 0 1 (0.5) 0 0 0 0
Cellulitis 2 (1.1) 3 (1.6) 1 (0.5) 0 6 (3.2) 4 (2.2) 0 0 6 (4.4) 0 0 0
Cytomegalovirus infection 1 (0.5) 1 (0.5) 0 0 0 0 0 0 0 0 0 0
Endocarditis 0 0 0 0 0 0 0 1 (0.5) 0 0 0 0
Folliculitis 13 (7.1) 0 0 0 3 (1.6) 1 (0.5) 0 0 13 (9.6) 0 0 0
Gastroenteritis 3 (1.6) 0 0 0 3 (1.6) 1 (0.5) 0 0 1 (0.7) 0 0 0
Herpes simplex 2 (1.1) 2 (1.1) 0 0 0 0 0 0 0 0 0 0
Infection 0 1 (0.5) 0 0 0 0 0 0 0 0 0 0
Influenza 5 (2.7) 1 (0.5) 0 0 3 (1.6) 1 (0.5) 0 0 4 (2.9) 0 0 0
Lower respiratory tract infection 1 (0.5) 1 (0.5) 0 0 2 (1.1) 1 (0.5) 0 0 0 0 0 0
Meningitis 0 1 (0.5) 0 0 0 0 0 0 0 0 0 0
Oral herpes 2 (1.1) 1 (0.5) 0 0 2 (1.1) 0 0 0 2 (1.5) 0 0 0
Osteomyelitis 0 2 (1.1) 0 0 0 0 0 0 0 0 0 0
Periorbital cellulitis 0 1 (0.5) 0 0 0 0 0 0 0 0 0 0
Pneumocystis jiroveci pneumonia 0 1 (0.5) 0 0 0 0 0 0 0 0 0 0
Pneumonia 2 (1.1) 3 (1.6) 1 (0.5) 0 0 1 (0.5) 0 1 (0.5) 1 (0.7) 2 (1.5) 0 0
Pneumonia influenzal 0 1 (0.5) 0 0 0 0 0 0 0 0 0 0
Pneumonia legionella 0 1 (0.5) 0 0 0 0 0 0 0 0 0 0
Pneumonia pneumococcal 0 0 0 1 (0.5) 0 0 0 0 0 0 0 0
Respiratory tract infection 0 1 (0.5) 0 0 0 0 0 0 0 0 0 0
Sepsis 1 (0.5) 2 (1.1) 0 1 (0.5) 1 (0.5) 0 4 (2.2) 1 (0.5) 0 0 0 1 (0.7)
Page 22
N=184 N=186 N=136
Sepsis syndrome 0 0 0 0 0 0 1 (0.5) 0 0 0 0 0

Septic embolus 0 1 (0.5) 0 0 0 0 0 0 0 0 0 0
Septic shock 0 0 0 0 0 0 0 1 (0.5) 0 0 0 0
Skin infection 17 (9.2) 0 0 0 10 (5.4) 3 (1.6) 0 0 4 (2.9) 0 0 0
Staphylococcal abscess 1 (0.5) 1 (0.5) 0 0 0 0 0 0 0 0 0 0
Staphylococcal bacteraemia 0 1 (0.5) 0 0 0 1 (0.5) 0 0 0 0 0 0
Staphylococcal infection 2 (1.1) 1 (0.5) 0 0 2 (1.1) 0 0 0 0 0 0 0
Staphylococcal sepsis 0 1 (0.5) 0 0 0 0 1 (0.5) 0 0 0 0 0
Superinfection 0 1 (0.5) 0 0 1 (0.5) 0 0 0 0 0 0 0
Tooth abscess 1 (0.5) 0 0 0 0 1 (0.5) 0 0 0 0 0 0
Tooth infection 0 1 (0.5) 0 0 0 0 0 0 2 (1.5) 0 0 0
Upper respiratory tract infection 19 (10.3) 0 0 0 7 (3.8) 2 (1.1) 0 0 12 (8.8) 0 0 0
Wound infection 2 (1.1) 1 (0.5) 0 0 0 0 0 0 0 0 0 0
Injury, Poisoning, and Procedural Complications
Ankle fracture 0 1 (0.5) 0 0 0 0 0 0 0 0 0 0
Fall 10 (5.4) 1 (0.5) 0 0 3 (1.6) 0 0 0 6 (4.4) 0 0 0
Infusion related reaction 58 (31.5) 3 (1.6) 0 0 1 (0.5)a 0 0 0 44 (32.4) 6 (4.4) 0 0
Laceration 2 (1.1) 1 (0.5) 0 0 4 (2.2) 0 0 0 1 (0.7) 0 0 0
Pelvic fracture 0 0 0 0 0 1 (0.5) 0 0 0 0 0 0
Subdural haematoma 0 0 0 0 0 1 (0.5) 0 0 0 0 0 0
Vascular access complication 0 1 (0.5) 0 0 0 0 0 0 0 0 0 0
Investigations
Alanine aminotransferase increased 10 (5.4) 0 0 0 8 (4.3) 1 (0.5) 0 0 8 (5.9) 2 (1.5) 0 0
Aspartate aminotransferase increased 6 (3.3) 2 (1.1) 0 0 11 (5.9) 1 (0.5) 0 0 8 (5.9) 3 (2.2) 0 0
Blood bilirubin increased 0 1 (0.5) 0 0 8 (4.3) 1 (0.5) 0 0 0 0 0 0
Blood creatine phosphokinase increased 2 (1.1) 1 (0.5) 0 0 2 (1.1) 0 0 0 0 0 0 0
Blood creatinine increased 6 (3.3) 0 0 0 52 (28.0) 0 0 0 3 (2.2) 0 0 0
Blood glucose increased 1 (0.5) 1 (0.5) 0 0 6 (3.2) 0 0 0 0 0 0 0
Blood lactate dehydrogenase increased 3 (1.6) 0 0 0 2 (1.1) 1 (0.5) 0 0 1 (0.7) 0 0 0
Blood pressure increased 0 0 0 0 0 2 (1.1) 0 0 0 0 0 0
Electrocardiogram QT prolonged 1 (0.5) 0 0 0 0 1 (0.5) 0 0 0 1 (0.7) 0 0
Hepatic enzyme increased 0 0 0 0 2 (1.1) 1 (0.5) 0 0 2 (1.5) 0 0 0
International normalised ratio increased 0 1 (0.5) 0 0 1 (0.5) 0 0 0 1 (0.7) 0 0 0
Neutrophil count decreased 3 (1.6) 0 0 0 1 (0.5) 1 (0.5) 0 0 2 (1.5) 0 0 0
Platelet count decreased 4 (2.2) 0 0 0 19 (10.2) 0 0 0 5 (3.7) 0 0 0
Protein total decreased 0 0 0 0 1 (0.5) 1 (0.5) 0 0 1 (0.7) 0 0 0
Weight decreased 10 (5.4) 1 (0.5) 0 0 31 (16.7) 2 (1.1) 0 0 8 (5.9) 1 (0.7) 0 0
Weight increased 13 (7.1) 1 (0.5) 0 0 2 (1.1) 0 0 0 5 (3.7) 0 0 0
White blood cell count increased 1 (0.5) 1 (0.5) 0 0 1 (0.5) 0 0 0 1 (0.7) 0 0 0
Page 23
N=184 N=186 N=136
Metabolism and Nutrition Disorders

Decreased Appetite 12 (6.5) 2 (1.1) 0 0 44 (23.7) 2 (1.1) 0 0 6 (4.4) 0 0 0
Dehydration 2 (1.1) 1 (0.5) 0 0 7 (3.8) 2 (1.1) 0 0 2 (1.5) 0 0 0
Diabetes mellitus 1 (0.5) 1 (0.5) 0 0 2 (1.1) 0 0 0 0 0 0 0
Gout 5 (2.7) 1 (0.5) 0 0 1 (0.5) 0 0 0 0 0 0 0
Hypercalcaemia 2 (1.1) 1 (0.5) 1 (0.5) 0 1 (0.5) 0 0 0 0 0 0 0
Hyperglycaemia 13 (7.1) 2 (1.1) 0 0 12 (6.5) 1 (0.5) 1 (0.5) 0 4 (2.9) 0 0 0
Hyperkalaemia 5 (2.7) 0 1 (0.5) 0 7 (3.8) 1 (0.5) 0 0 2 (1.5) 1 (0.7) 0 0
Hyperuricaemia 8 (4.3) 0 0 0 3 (1.6) 1 (0.5) 0 0 4 (2.9) 0 0 0
Hypoalbuminaemia 3 (1.6) 0 1 (0.5) 0 3 (1.6) 1 (0.5) 0 0 2 (1.5) 1 (0.7) 0 0
Hypokalaemia 10 (5.4) 0 0 0 10 (5.4) 1 (0.5) 1 (0.5) 0 0 1 (0.7) 0 0
Hypophosphataemia 5 (2.7) 3 (1.6) 0 0 3 (1.6) 3 (1.6) 0 0 0 2 (1.5) 0 0
Metabolic acidosis 0 0 0 0 0 1 (0.5) 0 0 0 0 0 0
Tumour lysis syndrome 1 (0.5) 1 (0.5) 0 0 0 0 0 0 0 0 0 0
Type 2 diabetes mellitus 0 0 0 0 0 1 (0.5) 0 0 0 0 0 0
Musculoskeletal and Connective Tissue Disorders
Arthralgia 12 (6.5) 1 (0.5) 0 0 11 (5.9) 0 0 0 10 (7.4) 0 0 0
Back pain 17 (9.2) 1 (0.5) 0 0 8 (4.3) 1 (0.5) 0 0 9 (6.6) 0 0 0
Muscle spasms 9 (4.9) 0 0 0 27 (14.5) 2 (1.1) 0 0 2 (1.5) 0 0 0
Muscular weakness 7 (3.8) 1 (0.5) 0 0 9 (4.8) 0 0 0 6 (4.4) 0 0 0
Myalgia 11 (6.0) 0 0 0 6 (3.2) 2 (1.1) 0 0 4 (2.9) 1 (0.7) 0 0
Myositis 1 (0.5) 1 (0.5) 0 0 0 0 0 0 0 0 0 0
Pain in extremity 12 (6.5) 0 0 0 8 (4.3) 1 (0.5) 0 0 9 (6.6) 0 0 0
Polymyositis 0 0 0 1 (0.5) 0 0 0 0 0 0 0 0
Neoplasms Benign, Malignant, and Unspecified (Incl. Cysts and Polyps)
Adenocarcinoma 0 1 (0.5) 0 0 0 0 0 0 0 0 0 0
Colon cancer 0 0 0 0 0 1 (0.5) 0 0 0 0 0 0
Malignant melanoma 0 0 1 (0.5) 0 0 0 0 0 0 0 0 0
Malignant pleural effusion 0 0 1 (0.5) 0 0 0 0 0 0 0 0 0
Mycosis fungoides 0 0 0 0 0 0 0 1 (0.5) 0 0 0 0
Ovarian cancer 0 0 1 (0.5) 0 0 0 0 0 0 0 0 0
Squamous cell carcinoma 6 (3.3) 1 (0.5) 0 0 2 (1.1) 1 (0.5) 0 0 2 (1.5) 1 (0.7) 0 0
Nervous System Disorders
Depressed level of consciousness 0 0 0 0 1 (0.5) 0 0 1 (0.5) 0 0 0 0
Dizziness 12 (6.5) 0 0 0 19 (10.2) 0 0 0 8 (5.9) 0 0 0
Dysgeusia 6 (3.3) 0 0 0 53 (28.5) 1 (0.5) 0 0 2 (1.5) 0 0 0
Headache 23 (12.5) 0 0 0 28 (15.1) 1 (0.5) 0 0 15 (11.0) 0 0 0
Miller fisher syndrome 0 1 (0.5) 0 0 0 0 0 0 0 0 0 0
Monoparesis 0 0 0 0 0 1 (0.5) 0 0 0 0 0 0
Neuropathy peripheral 7 (3.8) 0 0 0 4 (2.2) 1 (0.5) 0 0 5 (3.7) 0 0 0
Page 24
N=184 N=186 N=136
Polyneuropathy 0 0 0 0 0 1 (0.5) 0 0 0 0 0 0
Presyncope 2 (1.1) 1 (0.5) 0 0 0 0 0 0 0 0 0 0
Syncope 0 0 0 0 1 (0.5) 1 (0.5) 0 0 1 (0.7) 1 (0.7) 0 0
Psychiatric Disorders
Confusional state 0 0 0 0 1 (0.5) 1 (0.5) 0 0 0 0 0 0
Depression 9 (4.9) 1 (0.5) 1 (0.5) 0 6 (3.2) 0 0 0 1 (0.7) 0 1 (0.7) 0
Emotional distress 0 0 0 0 0 1 (0.5) 0 0 0 0 0 0
Renal and Urinary Disorders
Haematuria 4 (2.2) 1 (0.5) 0 0 2 (1.1) 0 0 0 1 (0.7) 0 0 0
Proteinuria 4 (2.2) 1 (0.5) 0 0 1 (0.5) 0 0 0 1 (0.7) 0 0 0
Renal failure 0 1 (0.5) 0 0 9 (4.8) 0 0 0 1 (0.7) 0 0 0
Renal failure acute 6 (3.3) 1 (0.5) 0 0 7 (3.8) 0 0 0 2 (1.5) 0 0 0
Renal impairment 1 (0.5) 0 0 0 4 (2.2) 1 (0.5) 0 0 0 0 0 0
Urinary retention 1 (0.5) 1 (0.5) 0 0 2 (1.1) 0 1 (0.5) 0 1 (0.7) 0 0 0
Reproductive System and Breast Disorders
Prostatitis 0 0 0 0 0 1 (0.5) 0 0 0 0 0 0
Uterine prolapse 0 0 0 0 0 1 (0.5) 0 0 0 0 0 0
Respiratory, Thoracic, and Mediastinal Disorders
Acute respiratory distress syndrome 0 1 (0.5) 0 0 0 0 0 0 0 0 0 0
Bronchitis chronic 0 1 (0.5) 0 0 0 0 0 0 0 0 0 0
Chronic obstructive pulmonary disease 1 (0.5) 2 (1.1) 0 0 0 0 0 0 1 (0.7) 0 0 0
Haemoptysis 0 1 (0.5) 0 0 2 (1.1) 0 0 0 0 0 0 0
Oropharyngeal pain 9 (4.9) 1 (0.5) 0 0 5 (2.7) 0 0 0 6 (4.4) 0 0 0
Pulmonary embolism 0 0 0 0 0 4 (2.2) 1 (0.5) 2 (1.1) 0 0 0 1 (0.7)
Respiratory failure 0 0 2 (1.1) 0 0 0 0 0 0 0 0 0
Skin and Subcutaneous Tissue Disorders
Alopecia 13 (7.1) 0 0 0 36 (19.4) 0 0 0 9 (6.6) 0 0 0
Dermatitis exfoliative 3 (1.6) 0 0 0 2 (1.1) 0 1 (0.5) 0 1 (0.7) 1 (0.7) 0 0
Drug eruptionb 36 (19.6) 8 (4.3) 0 0 1 (0.5) 0 0 0 29 (21.3) 5 (3.7) 0 0
Pain of skin 5 (2.7) 1 (0.5) 0 0 5 (2.7) 3 (1.6) 0 0 3 (2.2) 0 0 0
Photosensitivity reaction 1 (0.5) 1 (0.5) 0 0 0 0 0 0 1 (0.7) 0 0 0
Pruritus generalised 0 0 0 0 0 1 (0.5) 0 0 0 0 0 0
Rash 6 (3.3) 0 0 0 8 (4.3) 1 (0.5) 0 0 9 (6.6) 0 0 0
Rash generalised 2 (1.1) 0 0 0 0 1 (0.5) 0 0 0 0 0 0
Skin disorder 0 0 0 0 1 (0.5) 0 0 1 (0.5) 0 0 0 0
Skin fissures 6 (3.3) 0 0 0 2 (1.1) 1 (0.5) 0 0 0 0 0 0
Skin ulcer 4 (2.2) 1 (0.5) 0 0 2 (1.1) 0 0 0 1 (0.7) 0 0 0
Surgical and Medical Procedures
Hysterectomy 0 0 0 0 0 1 (0.5) 0 0 0 0 0 0
Page 25
N=184 N=186 N=136
Vascular Disorders
Air embolism 0 0 0 0 0 0 1 (0.5) 0 0 0 0 0
Embolism 0 2 (1.1) 0 0 0 0 0 0 0 0 0 0
Essential hypertension 0 1 (0.5) 0 0 0 0 0 0 0 0 0 0
Hypertension 9 (4.9) 8 (4.3) 0 0 13 (7.0) 12 (6.5) 0 0 2 (1.5) 1 (0.7) 0 0
Jugular vein thrombosis 0 0 0 0 0 1 (0.5) 0 0 0 0 0 0
Peripheral arterial occlusive disease 0 1 (0.5) 0 0 0 0 0 0 0 0 0 0
Data are n (%). Events that occurred as grade 1-2 in at least 10% of patients in either treatment group, and any grade 3, 4, or 5 event.
a
One patient had an infusion reaction on Day 1 of crossover to mogamulizumab treatment (17 days after the last dose of vorinostat) that was indicated as possibly related to vorinostat (and
mogamulizumab).
b
Skin rashes that were assessed by Investigator or sponsor as possibly, probably, or definitely related to study drug.
Page 26
Table S11. Serious adverse reactions by body system
System Organ Class Mogamulizumab Vorinostat
Preferred Term* N=184 N=186
n (%) n (%)
Patients With Any Treatment-Emergent SAEs 69 (37.5) 46 (24.7)
Infections and Infestations 30 (16.3) 20 (10.8)
Cellulitis 5 (2.7) 6 (3.2)
Sepsis 3 (1.6) 5 (2.7)
Pneumonia 4 (2.2) 2 (1.1)
Skin infection 0 3 (1.6)
Bacteraemia 2 (1.1) 0
Bronchitis 2 (1.1) 0
Herpes simplex 2 (1.1) 0
Lower respiratory tract infection 1 (0.5) 1 (0.5)
Osteomyelitis 2 (1.1) 0
Staphylococcal bacteraemia 1 (0.5) 1 (0.5)
Staphylococcal sepsis 1 (0.5) 1 (0.5)
Upper respiratory tract infection 0 2 (1.1)
Abscess limb 1 (0.5) 0
Arthritis bacterial 1 (0.5) 0
Atypical pneumonia 1 (0.5) 0
Bronchopneumonia 0 1 (0.5)
Cytomegalovirus infection 1 (0.5) 0
Diverticulitis 0 1 (0.5)
Endocarditis 0 1 (0.5)
Gastroenteritis 0 1 (0.5)
Influenza 0 1 (0.5)
Meningitis 1 (0.5) 0
Periorbital cellulitis 1 (0.5) 0
Pneumocystis jiroveci pneumonia 1 (0.5) 0
Pneumonia influenzal 1 (0.5) 0
Pneumonia legionella 1 (0.5) 0
Pneumonia pneumococcal 1 (0.5) 0
Respiratory tract infection 1 (0.5) 0
Sepsis syndrome 0 1 (0.5)
Septic embolus 1 (0.5) 0
Septic shock 0 1 (0.5)
Staphylococcal abscess 1 (0.5) 0
Staphylococcal infection 1 (0.5) 0
Superinfection 1 (0.5) 0
Urinary tract infection 1 (0.5) 0
Wound infection 1 (0.5) 0
General Disorders and Administration Site Conditions 15 (8.2) 8 (4.3)
Pyrexia 8 (4.3) 1 (0.5)
Disease progression 4 (2.2) 1 (0.5)
Asthenia 0 2 (1.1)
General physical health deterioration 1 (0.5) 1 (0.5)
Hypothermia 1 (0.5) 1 (0.5)
Facial pain 0 1 (0.5)
Fatigue 0 1 (0.5)
Oedema 1 (0.5) 0
Oedema peripheral 0 1 (0.5)
Respiratory, Thoracic, and Mediastinal Disorders 9 (4.9) 6 (3.2)
Pulmonary embolism 0 6 (3.2)
Respiratory failure 2 (1.1) 0
Acute respiratory distress syndrome 1 (0.5) 0
Bronchitis chronic 1 (0.5) 0
Chronic obstructive pulmonary disease 1 (0.5) 0
Dyspnoea exertional 1 (0.5) 0
Haemoptysis 1 (0.5) 0
Interstitial lung disease 1 (0.5) 0
Pleural effusion 1 (0.5) 0
Page 27
n (%) n (%)
Pneumonitis 1 (0.5) 0
Gastrointestinal Disorders 3 (1.6) 8 (4.3)
Constipation 1 (0.5) 1 (0.5)
Diarrhoea 1 (0.5) 1 (0.5)
Abdominal pain 0 1 (0.5)
Abdominal pain upper 0 1 (0.5)
Anal fistula 0 1 (0.5)
Gastric haemorrhage 1 (0.5) 0
Ileitis 0 1 (0.5)
Intestinal obstruction 0 1 (0.5)
Nausea 0 1 (0.5)
Vomiting 0 1 (0.5)
Metabolism qnd Nutrition Disorders 6 (3.3) 4 (2.2)
Hypercalcaemia 3 (1.6) 0
Decreased appetite 1 (0.5) 1 (0.5)
Dehydration 1 (0.5) 0
Gout 1 (0.5) 0
Hyperglycaemia 0 1 (0.5)
Hypoalbuminaemia 1 (0.5) 0
Hypokalaemia 0 1 (0.5)
Metabolic acidosis 0 1 (0.5)
Injury, Poisoning, and Procedural Complications 6 (3.3) 2 (1.1)
Infusion related reaction 3 (1.6) 0
Fall 2 (1.1) 0
Laceration 1 (0.5) 0
Pelvic fracture 0 1 (0.5)
Subdural haemorrhage 0 1 (0.5)
Vascular access complication 1 (0.5) 0
Musculoskeletal and Connective Tissue Disorders 6 (3.3) 2 (1.1)
Arthralgia 2 (1.1) 1 (0.5)
Back pain 1 (0.5) 0
Muscular weakness 1 (0.5) 0
Musculoskeletal chest pain 0 1 (0.5)
Myalgia 0 1 (0.5)
Myositis 1 (0.5) 0
Polymyositis 1 (0.5) 0
Neoplasms Benign, Malignant, and Unspecified (Incl. Cysts and 5 (2.7) 3 (1.6)
Polyps)
Adenocarcinoma 1 (0.5) 0
Basal cell carcinoma 1 (0.5) 0
Colon cancer 0 1 (0.5)
Malignant melanoma 1 (0.5) 0
Malignant pleural effusion 1 (0.5) 0
Mycosis fungoides 0 1 (0.5)
Ovarian cancer 1 (0.5) 0
Squamous cell carcinoma 0 1 (0.5)
Cardiac Disorders 5 (2.7) 2 (1.1)
Acute myocardial infarction 1 (0.5) 0
Angina unstable 0 1 (0.5)
Cardiac failure 1 (0.5) 0
Left ventricular hypertrophy 0 1 (0.5)
Myocarditis 1 (0.5) 0
Supraventricular tachycardia 1 (0.5) 0
Ventricular tachycardia 1 (0.5) 0
Skin and Subcutaneous Tissue Disorders 4 (2.2) 3 (1.6)
Dermatitis exfoliative 1 (0.5) 1 (0.5)
Drug eruption 2 (1.1) 0
Photosensitivity reaction 1 (0.5) 0
Pruritus 0 1 (0.5)
Page 28
n (%) n (%)
Skin disorder 0 1 (0.5)
Blood and Lymphatic System Disorders 1 (0.5) 5 (2.7)
Thrombocytopenia 0 3 (1.6)
Anaemia 1 (0.5) 1 (0.5)
Neutropenia 0 2 (1.1)
Febrile neutropenia 0 1 (0.5)
Renal and Urinary Disorders 3 (1.6) 3 (1.6)
Renal failure acute 2 (1.1) 1 (0.5)
Haematuria 1 (0.5) 0
Renal failure 1 (0.5) 0
Renal impairment 0 1 (0.5)
Urinary retention 0 1 (0.5)
Vascular Disorders 4 (2.2) 1 (0.5)
Embolism 2 (1.1) 0
Air embolism 0 1 (0.5)
Peripheral arterial occlusive disease 1 (0.5) 0
Phlebitis 1 (0.5) 0
Nervous System Disorders 2 (1.1) 2 (1.1)
Depressed level of consciousness 0 1 (0.5)
Miller fisher syndrome 1 (0.5) 0
Monoparesis 0 1 (0.5)
Motor dysfunction 1 (0.5) 0
Hepatobiliary Disorders 2 (1.1) 1 (0.5)
Cholangitis 0 1 (0.5)
Hepatitis acute 1 (0.5) 0
Hepatocellular injury 1 (0.5) 0
Investigations 2 (1.1) 1 (0.5)
Alanine aminotransferase increased 2 (1.1) 0
Aspartate aminotransferase increased 2 (1.1) 0
Blood alkaline phosphatase increased 1 (0.5) 0
Blood creatinine increased 0 1 (0.5)
Eye Disorders 2 (1.1) 0
Lens dislocation 1 (0.5) 0
Retinal vein occlusion 1 (0.5) 0
Immune System Disorders 2 (1.1) 0
Contrast media allergy 1 (0.5) 0
Drug hypersensitivity 1 (0.5) 0
Hypersensitivity 1 (0.5) 0
Psychiatric Disorders 1 (0.5) 1 (0.5)
Confusional state 0 1 (0.5)
Depression 1 (0.5) 0
Social Circumstances 1 (0.5) 0
Social stay hospitalisation 1 (0.5) 0
Surgical and Medical Procedures 1 (0.5) 0
Cardiac pacemaker replacement 1 (0.5) 0
*MedDRA Version 15.1 was used for coding.
Page 29
Figure S1. Scatterplot of CCR4 expression percentage and global overall response rate based on
Investigator’s assessment*
Mogamulizumab Vorinostat
*Of the 290 patients with CCR4 expression data, 110 mogamulizumab patients and 105 vorinostat patients had
response data.
The red lines indicate median % of CCR4 expression.
Page 30
References
1. Olsen E, Vonderheid E, Pimpinelli N, et al. Revisions to the staging and classification of mycosis
fungoides and Sezary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL)
and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer
(EORTC). Blood 2007; 110: 1713-22.
2. Olsen EA, Whittaker S, Kim YH, et al. Clinical end points and response criteria in mycosis fungoides and
Sezary syndrome: a consensus statement of the International Society for Cutaneous Lymphomas, the
United States Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the
European Organisation for Research and Treatment of Cancer. J Clin Oncol 2011; 29: 2598-607.
3. Robins JM. Information recovery and bias adjustment in proportional hazards regression analysis of
randomized trials using surrogate markers. 1993. https://cdn1.sph.harvard.edu/wp-
content/uploads/sites/343/2013/03/biopharm.pdf (accessed February 16, 2018).
4. Robins JM, Finkelstein DM. Correcting for noncompliance and dependent censoring in an AIDS Clinical
Trial with inverse probability of censoring weighted (IPCW) log-rank tests. Biometrics 2000; 56(3): 779-
88.
5. Hernan MA, Brumback B, Robins JM. Marginal structural models to estimate the causal effect of
zidovudine on the survival of HIV-positive men. Epidemiology 2000; 11(5): 561-70.
6. Hernan MA, Hernandez-Diaz S, Werler MM, Mitchell AA. Causal knowledge as a prerequisite for
confounding evaluation: an application to birth defects epidemiology. Am J Epidemiol 2002; 155(2): 176-
84.
7. Robins JM, Tsiatis AA. Correcting for non-compliance in randomized trials using rank preserving structure
failure time models. Commun Statist Theory Meth 1991; 20(8): 2609-31.
8. Robins JM. Correction for non-compliance in equivalence trials. Stat Med 1998; 17(3): 269-302; discussion
387-9.
Page 31
Protocol
The copy of the clinical trial protocol in this supplement has been made available by the authors to provide
additional information about their work.
Page 32
PROTOCOL 0761-010
Open-Label, Multi-Center, Randomized Study of Anti-CCR4 Monoclonal Antibody KW-0761
(mogamulizumab) Versus Vorinostat in Subjects with Previously Treated Cutaneous T-Cell
Lymphoma
REVISED TO INCORPORATE AMENDMENT 8
Protocol Number: 0761-010
Replaces
Amendment 7: 09 Mar 2016
Amendment 8: 20 Jan 2017
Phase: 3
IND Number:
EudraCT Number:
Sponsor: Kyowa Kirin Pharmaceutical Development, Inc.
212 Carnegie Center, Suite 101
Princeton, NJ 08540
1 609 919-1100
Study Monitors:
Medical Monitors:
Confidentiality Statement
The information contained in this document is the property of or under the control of Kyowa Kirin Pharmaceutical
Development, Inc. and its affiliated companies. This information is provided to you in confidence as an investigator,
potential investigator or consultant, for review by you, your staff and applicable Institutional Review Board/Ethics
Committee. You shall not disclose this information to others without prior written authorization from Kyowa Kirin
Pharmaceutical Development, Inc., except to the extent necessary to obtain informed consent from those persons to whom
the drug may be administered, and except as may be required by federal, state, or local laws or regulations.
CONFIDENTIAL 1
Page 33
Page 34
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Protocol 0761-010, Amendment 8
Table of Contents
TABLE OF CONTENTS ..................................................................................................... 6

LIST OF IN-TEXT TABLES ............................................................................................ 11
LIST OF APPENDICES.................................................................................................... 11
PROTOCOL SYNOPSIS .................................................................................................. 12
LIST OF ABBREVIATIONS ............................................................................................ 27
1 BACKGROUND AND RATIONALE .................................................................... 30
1.1 Cutaneous T-Cell Lymphomas ............................................................................... 30
1.2 Treatment of Cutaneous T-cell Lymphomas ........................................................... 31
1.3 Chemokine Receptor 4 and T-Cell Malignancies .................................................... 31
1.4 KW-0761 (mogamulizumab) .................................................................................. 33
1.5 Safety and Efficacy of KW-0761 ............................................................................ 33
1.6 Vorinostat (ZOLINZA®) ........................................................................................ 34
1.7 Rationale ................................................................................................................ 36
2 OBJECTIVES .......................................................................................................... 37
2.1 Primary Objectives ................................................................................................. 37
2.2 Secondary Objectives ............................................................................................. 37
2.3 Exploratory Objectives ........................................................................................... 38
3 STUDY POPULATION .......................................................................................... 38
3.1 Subject Selection .................................................................................................... 38
3.2 Inclusion Criteria .................................................................................................... 38
3.3 Exclusion Criteria ................................................................................................... 40
3.4 Eligibility for Cross-over to KW-0761.................................................................... 41
4 INVESTIGATIONAL PLAN .................................................................................. 42
4.1 Overview of Study Design...................................................................................... 42
4.2 Number of Subjects ................................................................................................ 42
4.3 Investigational Centers ........................................................................................... 42
CONFIDENTIAL 6
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5 TREATMENT PLAN .............................................................................................. 42

5.1 Assignment to Study............................................................................................... 42
5.2 Study Treatments.................................................................................................... 42
5.2.1 Study Drug: KW-0761 (mogamulizumab) ........................................................... 43
5.2.1.1 Premedication Prior to KW-0761 Infusion ....................................................... 43
5.2.1.2 Definition of Treatment Cycle ......................................................................... 43
5.2.1.3 Delays in Dosing ............................................................................................. 43
5.2.1.4 Duration of Treatment ..................................................................................... 43
5.2.1.5 Replacement of Subjects .................................................................................. 44
5.2.1.6 Dose Modifications .......................................................................................... 44
5.2.1.7 Treatment of Hypersensitivity-Like Reactions ................................................. 44
5.2.1.8 Treatment Emergent Skin Rash ........................................................................ 46
5.2.2 Study Drug: Vorinostat (ZOLINZA®) ................................................................. 48
5.2.2.1 Definition of Treatment Cycle ......................................................................... 49
5.2.2.2 Delays in Dosing ............................................................................................. 49
5.2.2.3 Duration of Treatment ..................................................................................... 49
5.2.2.4 Replacement of Subjects .................................................................................. 50
5.2.2.5 Dose Modifications .......................................................................................... 50
5.3 Cross-over to Study Drug KW-0761 ....................................................................... 50
5.4 Concomitant Therapy ............................................................................................. 51
5.4.1 Permitted Treatment ............................................................................................ 51
5.4.2 Prohibited Treatment........................................................................................... 52
5.5 Criteria for Removal from Study ............................................................................ 52
6 STUDY PROCEDURES.......................................................................................... 54
7 STUDY MEASUREMENTS ................................................................................... 54
7.1 Safety Evaluations .................................................................................................. 54
7.1.1 Clinical Laboratory Evaluations .......................................................................... 55
7.1.2 Vital Signs and Body Weight .............................................................................. 56
7.1.3 Physical Examination .......................................................................................... 57
7.1.4 Electrocardiograms ............................................................................................. 57
7.1.5 Blood Sample for Determination of Natural Ligands ........................................... 57
CONFIDENTIAL 7
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7.1.6 Genomic Sampling (For subjects receiving KW-0761 as first assigned

therapy only) ....................................................................................................... 58
7.1.7 Immunogenicity (For subjects receiving KW-0761) ............................................ 58
7.2 Efficacy Evaluations ............................................................................................... 58
7.2.1 Evaluation of Skin Disease.................................................................................. 59
7.2.1.1 Skin Biopsy ..................................................................................................... 59
7.2.1.2 Skin Photographs ............................................................................................. 60
7.2.1.3 Modified Severity Weighted Assessment Tool (mSWAT) ............................... 60
7.2.1.4 Response Criteria for Skin ............................................................................... 62
7.2.1.5 Pruritus Evaluation .......................................................................................... 63
7.2.2 Evaluation of Blood Disease ............................................................................... 63
7.2.2.1 Flow Cytometric Analysis ............................................................................... 63
7.2.2.2 Response Criteria in Blood .............................................................................. 63
7.2.3 Evaluation of Disease in Lymph Nodes and Viscera............................................ 64
7.2.3.1 Baseline Tumor Assessments ........................................................................... 64
7.2.3.2 Method of Tumor Response Assessment .......................................................... 64
7.2.3.3 Determination of Response in Lymph Nodes and Viscera ................................ 65
7.2.4 Global Composite Response Score ...................................................................... 66
7.2.4.1 Independent Review of Progression ................................................................. 67
7.3 Pharmacokinetics (for subjects receiving KW-0761) .............................................. 68
7.4 Quality of Life Assessments ................................................................................... 68
7.5 Follow-Up .............................................................................................................. 68
7.6 Follow-Up for Subjects Achieving a Complete Response ....................................... 69
7.7 Study Procedures for Subjects Continuing Study Treatment at the Time
of Primary Efficacy Analysis .................................................................................. 70
8 STUDY AGENTS .................................................................................................... 71
8.1 KW-0761 (mogamulizumab) .................................................................................. 71
8.1.1 Description ......................................................................................................... 71
8.1.2 Preparation of Dose............................................................................................. 71
8.1.3 Study Drug Administration ................................................................................. 71
8.1.4 KW-0761 Formulation and Storage ..................................................................... 72
8.1.5 Packaging and Labeling of KW-0761 .................................................................. 72
CONFIDENTIAL 8
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8.1.5.1 Labeling .......................................................................................................... 72

8.1.6 Drug Accountability............................................................................................ 72
8.1.7 Return and Destruction ....................................................................................... 73
8.2 Vorinostat (ZOLINZA®) Capsules.......................................................................... 73
8.2.1 Description ......................................................................................................... 73
8.2.2 Administration .................................................................................................... 74
8.2.3 Vorinostat Adverse Events .................................................................................. 74
8.2.4 Return and Destruction ....................................................................................... 74
9 ADVERSE EVENT REPORTING IN CLINICAL TRIALS ................................ 74
9.1 Definitions ............................................................................................................. 74
9.1.1 Adverse Events ................................................................................................... 74
9.1.2 Adverse Event Severity ....................................................................................... 75
9.1.3 Adverse Event Relationship to Study Drug ......................................................... 75
9.2 Serious Adverse Events .......................................................................................... 76
9.3 Other Safety Considerations ................................................................................... 78
9.5 Data Safety Monitoring Board ................................................................................ 78

10 DATA ANALYSIS AND STATISTICAL CONSIDERATIONS........................... 79
10.1 Populations to be Analyzed .................................................................................... 79
10.2 Analyses of Safety Data.......................................................................................... 79
10.3 Analyses of Efficacy Data ...................................................................................... 80
10.4 Exposure-Response Analysis .................................................................................. 84
11 ETHICAL ASPECTS .............................................................................................. 84
11.1 Ethics and Good Clinical Practice ........................................................................... 84
11.2 Ethics Committee/Institutional Review Board ........................................................ 85
11.3 Informed Consent ................................................................................................... 85
12 INVESTIGATOR OBLIGATIONS AND STUDY MANAGEMENT .................. 87
12.1 Administrative ........................................................................................................ 87
12.2 Changes in Protocol................................................................................................ 87
12.3 Protocol Deviations ................................................................................................ 87
12.4 Monitoring and Quality Assurance ......................................................................... 87
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12.5 Electronic Case Report Forms (eCRFs) and Source Documentation ....................... 88
12.6 Record Retention .................................................................................................... 89
12.7 Confidentiality ....................................................................................................... 89
12.8 Disclosure .............................................................................................................. 89
12.9 Termination of Study.............................................................................................. 90
12.10 Final Report/Publications ....................................................................................... 90
13 REFERENCES ........................................................................................................ 91
CONFIDENTIAL 10
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List of In-text Tables

Table 1 Study Procedures: First Treatment Cycle ....................................20
Table 2 Study Procedures: Subsequent Cycles in Year 1 .........................22
Table 3 Study Procedures: Subsequent Cycles in Year 2 and Beyonda ....24
Table 5.2.1-1 Guidelines for Treatment of Skin Rash ........................................48
Table 7.1.1-1 Clinical Laboratory Assessments .................................................56
Table 7.2.1-1 Modified Severity Weighted Assessment Tool ............................61
Table 7.2.1-2 Modified Severity Weighted Assessment Tool Score ..................62
Table 7.2.1-3 Response Criteria for Skin, as assessed by mSWAT scoresa ........63
Table 7.2.2-1 Blood Response Criteriaa.............................................................64
Table 7.2.3-1 Response in Lymph Nodesa .........................................................65
Table 7.2.3-2 Response in Viscera ....................................................................66
Table 7.2.4-1 Global Composite Scoring System ..............................................67
Table 10.3-1 Required PFS Events and Power for Comparison of PFS Kaplan-
Maier Curves Between the Vorinostat and KW-0761 Arms at the
0.025 Level .................................................................................84
CONFIDENTIAL 11
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PROTOCOL SYNOPSIS
Name and Address of Individual Study Table Referring (For National Authority Use
Sponsor/Company: to Part of the Dossier. only)
Kyowa Kirin Pharmaceutical Volume:
Development, Inc.
212 Carnegie Center, Suite 101 Page:
Princeton, NJ 08540
Name of Finished Product:
Name of Active Ingredient:

KW-0761 (mogamulizumab)
Study Title:
(mogamulizumab) Versus Vorinostat in Subjects with Previously Treated Cutaneous T-Cell Lymphoma
Protocol No.
0761-010
Study Location:
United States, Europe, Japan, and Australia
Clinical Phase:
3
Study Period:
Planned enrollment period: 24 months
Planned study period: 36 months
Study Drug:
KW-0761
Comparator Drug:
Vorinostat (ZOLINZA®)
Population Size:
It is anticipated that approximately 317 subjects may be required to enroll in this study in order to achieve the
necessary 255 progression-free survival (PFS) events for analysis.
Study Design:
This is an open-label, multi-center randomized, Phase 3 study with 1:1 randomization of study drug, KW-0761
versus the comparator, vorinostat.
Study Population:
This study will enroll subjects with Stage IB, II-A, II-B, III and IV mycosis fungoides (MF) or Sézary syndrome
(SS) who have failed at least one prior course of systemic therapy.
Study Objectives:
Primary Objective
• To compare the progression free survival of KW-0761 versus vorinostat for subjects with relapsed or
refractory Cutaneous T-Cell Lymphoma (CTCL).
Secondary Objectives
• To compare the overall response rate of KW-0761 versus vorinostat in subjects with relapsed or refractory
CTCL;
• To evaluate and compare improvements in Quality of Life (QoL) measurements, Skindex-29, FACT-G, and
EQ-5D-3L for subjects receiving KW-0761 versus vorinostat;
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Study Title:
Protocol No.
0761-010
• To evaluate and compare improvements in the Pruritus Evaluation (Likert scale & Itchy QoL) for subjects
receiving KW-0761 versus vorinostat;
• To estimate the duration of response for both the KW-0761 and vorinostat arms for those subjects with
relapsed or refractory CTCL responding to treatment;
• To determine if subjects who relapse on vorinostat can achieve response upon cross over to treatment with
KW-0761;
• To further assess the safety of KW-0761;
• To describe the immunogenicity of KW-0761;
Exploratory Objectives
• To compare the overall survival of KW-0761 versus vorinostat for subjects with relapsed or refractory
CTCL.
• To conduct exploratory evaluation of KW-0761 exposure-response relationships.
Inclusion Criteria:
1) Voluntarily signed and dated Institutional Review Board / Ethics Committee approved informed
consent form in accordance with regulatory and institutional guidelines. Written informed consent must
be obtained prior to performing any study-related procedure;
Age and Sex
2) Males and female subjects ≥ 18 years of age at the Pre-treatment Visit, i.e., at the time that written
informed consent is obtained, except in Japan where subjects must be ≥ 20 years of age;
Target Population
3) Histologically confirmed diagnosis of MF or SS;
a. For SS (defined as meeting T4 plus B2 criteria), where the biopsy of erythrodermic skin may only
reveal suggestive but not diagnostic histopathologic features, the diagnosis may be based on either
a node biopsy or fulfillment of B2 criteria including a clone in the blood that matches that of the
skin.
4) Stage IB, II-A, II-B, III and IV;
5) Subjects who have failed at least one prior course of systemic therapy (e.g., interferon, denileukin
diftitox, bexarotene, photopheresis, anti-neoplastic chemotherapy, etc.). Psoralen plus ultraviolet light
therapy (PUVA) is not considered to be a systemic therapy;
6) Eastern Cooperative Oncology Group (ECOG) performance status score of ≤ 1;
7) The subject has resolution of all clinically significant toxic effects of prior cancer therapy to Grade ≤ 1
by the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0
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Development, Inc.
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Study Title:
Protocol No.
0761-010
(NCI-CTCAE, v.4.0) excluding the specifications required in 8, 9 and 10 below.
8) Adequate hematological function:
a. absolute neutrophil count (ANC) ≥ 1,500 cells/μL (≥ 1,500/mm3);
b. platelets ≥ 100,000 cells/μL; (≥ 100,000/mm3);
c. in subjects with known bone marrow involvement, ANC must be ≥ 1,000 cells/μL (≥ 1,000/mm3)
and platelets ≥ 75,000 cells/μL. (≥ 75,000/mm3).
9) Adequate hepatic function:
a. bilirubin ≤ 1.5 times the specific institutional upper limit of normal (ULN), except for subjects
with Gilbert’s syndrome;
b. aspartate transaminase (AST) and alanine transaminase (ALT) each ≤ 2.5 x ULN or ≤ 5.0 x ULN
in the presence of known hepatic involvement by CTCL.
10) Adequate renal function:
a. serum creatinine ≤ 1.5 x ULN;
or
b. calculated creatinine clearance > 50 mL/min using the Cockcroft-Gault formula.
11) Subjects previously treated with anti-CD4 antibody or alemtuzumab are eligible provided their CD4+
cell counts are ≥ 200/mm3.
12) Subjects with MF and a known history of non-complicated staphylococcus infection/colonization are
eligible provided they continue to receive stable doses of prophylactic antibiotics.
13) Women of childbearing potential (WOCBP) must have a negative pregnancy test within 7 days of
receiving study medication.
14) WOCBP must agree to use effective contraception, defined as oral contraceptives, double barrier
method (condom plus spermicide or diaphragm plus spermicide) or practice true abstinence from
sexual intercourse (periodic abstinence, e.g., calendar, ovulation, symptothermal, post-ovulation
methods and withdrawal are not acceptable methods of contraception) during the study and for
3 months after the last dose. WOCBP includes any female who has experienced menarche and who has
not undergone successful surgical sterilization or is not postmenopausal (defined as amenorrhea
≥ 12 consecutive months without an alternative medical cause);
15) Male subjects and their female partners of child bearing potential must be willing to use an appropriate
method of contraception defined as oral contraceptives, double barrier method (condom plus
spermicide or diaphragm plus spermicide) or practice true abstinence from sexual intercourse (periodic
abstinence, e.g., calendar, ovulation, symptothermal, post-ovulation methods and withdrawal are not
acceptable methods of contraception) during the study and for 3 months after the last dose.
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Study Title:
Protocol No.
0761-010
NOTE: For subjects continuing to receive study treatment as of protocol Amendment 8, the period of
contraceptive use should be extended to 6 months after the last dose of KW-0761.
Exclusion Criteria:
Medical History and Concurrent Diseases
1) Current evidence of large cell transformation (LCT). Subjects with clinical features suggestive of LCT
must have a biopsy performed within 4 months prior to Cycle 1 Day 1 to rule out transformed disease.
Subjects with a history of LCT but without current aggressive disease and no current evidence of LCT
on pathology in skin or lymph nodes would be eligible;
2) Diagnosed with a malignancy in the past 2 years. However, subjects with non-melanoma skin cancers,
melanoma in situ, localized cancer of the prostate with current prostate-specific antigen of
< 0.1 ng/mL, treated thyroid cancer or cervical carcinoma in situ or ductal/lobular carcinoma in situ of
the breast with in the past 2 years may enroll as long as there is no current evidence of disease.
3) Clinical evidence of central nervous system (CNS) metastasis.
4) Psychiatric illness, disability or social situation that would compromise the subject’s safety or ability to
provide consent, or limit compliance with study requirements.
5) Significant uncontrolled intercurrent illness including, but not limited to:
a. uncontrolled infection requiring antibiotics;
b. clinically significant cardiac disease (class III or IV of the New York Heart Association
classification);
c. unstable angina pectoris;
d. angioplasty, stenting, or myocardial infarction within 6 months;
e. uncontrolled hypertension (systolic blood pressure (BP) > 160 mm Hg or diastolic BP
> 100 mm Hg, found on 2 consecutive measurements separated by a 1-week period) despite 2 anti-
hypertensive medications;
f. clinically significant cardiac arrhythmia; or
g. uncontrolled diabetes.
6) Known or tests positive for human immunodeficiency virus, human T-cell leukemia virus, hepatitis B
or hepatitis C disease.
7) Active herpes simplex or herpes zoster. Subjects on prophylaxis for herpes who started taking
medication at least 30 days prior to the Pre-treatment Visit, and have no active signs of active infection,
and whose last active infection was more than 6 months ago, may enter the study, and should continue
to take the prescribed medication for the duration of the study.
8) Experienced allergic reactions to monoclonal antibodies or other therapeutic proteins.
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Study Title:
Protocol No.
0761-010
9) Known active autoimmune disease will be excluded. (For example, Graves’ disease; systemic lupus
erythematosus; rheumatoid arthritis; Crohn’s disease; psoriasis).
10) Is pregnant (confirmed by beta human chorionic gonadotrophin [β-HCG]) or lactating.
Prohibited Therapies and/or Medications
11) Prior treatment with KW-0761.
12) Prior treatment with vorinostat. Patients who were exposed to vorinostat for a short time, did not
progress while on treatment, and did not have intolerable toxicity but were discontinued for another
reason (e.g., comorbidity) may be permitted to enter the study after discussion with the Medical
Monitor.
13) Have had any therapy directed against the subject’s underlying cancer or any investigational
medications within four weeks of randomization (skin directed treatments, including topicals and
radiation within 2 weeks of randomization). However, subjects with rapidly progressive malignant
disease may be enrolled prior to this period after discussion with the Medical Monitor.
14) Subjects on a stable dose of a low dose systemic corticosteroid (≤ 20 mg prednisone equivalent) for at
least 4 weeks prior to the Pre-treatment Visit may continue use although the investigator should attempt
to taper the use to the lowest dosage tolerable while on study. Initiation of treatment with systemic
corticosteroids or increase in dose while on study is not permitted except to treat an infusion reaction
(see Section 5.2.1.7). Subjects may receive intra-articular corticosteroid injections, intraocular
corticosteroid drops, inhalation or nasal corticosteroids and replacement doses of systemic
corticosteroids as needed.
15) Subjects on a stable dose of medium or low potency topical corticosteroids for at least 4 weeks prior to
the Pre-treatment Visit may continue use at the same dose, although the investigator should attempt to
taper the use to the lowest dosage tolerable while on study. Initiation of treatment with topical
corticosteroids while on study is not permitted except to treat an acute rash.
16) History of allogeneic transplant.
17) Autologous hematopoietic stem cell transplant within 90 days of the Pre-treatment Visit.
18) Subjects on any immunomodulatory drug for concomitant or intercurrent conditions other than T-cell
lymphoma or who have received any of these agents within 4 weeks of treatment, including but not
limited to the following, will be excluded: low dose or oral methotrexate; azathioprine; intravenous
(iv) immunoglobulin; low dose or oral cyclophosphamide; cyclosporine; mycophenolate; infliximab;
etanercept; leflunomide; adalimumab; lenalidomide; abatacept; rituximab; anakinra; interferon-β; IL-2
and natalizumab.
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Study Title:
Protocol No.
0761-010
Methods:
Subjects will be randomized 1:1 to receive either KW-0761 or vorinostat. Treatment will be administered on an
outpatient basis. The dose of KW-0761 will be 1.0 mg/kg. The dose of vorinostat will be the recommended dose
of 400 mg (once daily with food).
Each treatment cycle is 28 days. Subjects will receive KW-0761 as an iv infusion over at least 1 hour on Days 1,
8, 15 and 22 of the first cycle and on Days 1 and 15 of subsequent cycles. Vorinostat will be administered orally
daily beginning on Day 1.
Duration of Treatment
Subjects may remain in the treatment phase up until progressive disease (PD), drug intolerance, or unacceptable
toxicity, or until any of the other criteria for study removal are met. If the subject experiences an overall CR, the
subject may continue treatment for up to 12 months or until progression, whichever comes first.
Cross-over to Study Drug KW-0761
Subjects who have received at least 2 full treatment cycles and demonstrate progression of disease on treatment
with vorinostat at the 8 week (Cycle 2, Day 26-28) assessment, or anytime thereafter, may cross over to
treatment with KW-0761 after discussion with Medical Monitor or designee and receipt of approval for cross
over from KKD. Investigators should strive to maintain subjects on treatment for at least the 8 week period,
adjusting the dose of vorinostat as needed for toxicities in order to allow sufficient time to see effect. In cases
where a subject’s disease progresses rapidly (i.e., prior to 8 weeks), the Medical Monitor or designee should be
contacted and may consider the possibility of early crossover, if appropriate for that subject. All subjects must
undergo the full extent of disease evaluations (including computed tomography scanning) to document PD prior
to crossover.
Study Procedures for Subjects Continuing Study Treatment at the Time of Primary Efficacy Analysis
For subjects who are continuing to receive study treatment at the time of the primary efficacy analysis,
procedures and assessments are described in Section 7.7.
Replacement of Subjects
Subjects will not be replaced.
Criteria for Evaluation:
Safety: The safety of KW-0761 and vorinostat will be determined by reported AEs, changes in physical
examinations, vital sign measurements, ECGs and laboratory analyses. Safety evaluations will be performed
throughout the study.
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Study Title:
Protocol No.
0761-010
Efficacy: Efficacy evaluations will be based on response to treatment (partial response [PR] or better), time to
PD, duration of overall response, and quality of life.
Statistical Analysis:
The following analysis sets will be used in the study:
• Intent-to-Treat (ITT) Set: Includes all subjects randomized to a therapy and assigned a study number.
• Safety Analysis Set: Includes all subjects who received at least one dose of the assigned study agent (even
a partial dose).
• Efficacy Evaluable Set: Includes all subjects who receive the first cycle of treatment and who have baseline
and the Day 26-28 on-study assessment for response.
• Pharmacokinetic (PK) Analysis Set: All subjects who provide at least one post-dose KW-0761
concentration measurement will be included in the PK analysis dataset.
Evaluation of the data for this study will consist primarily of data listings and summary displays. Demographic
and other baseline characteristic information will be summarized for the ITT Set. All summaries for the Safety
Analysis Set will be prepared for each treatment arm. Adverse events will be tabulated by body system, severity,
and relation to treatment. Similar presentations will be provided for serious adverse events, AEs leading to
withdrawal from study, and AEs leading to death. The tabulation of laboratory parameters will indicate the
normal range for each parameter. Each value will be classified as falling above, below, or within the normal
range.
Subjects will be evaluated for response in each compartment. Progression-free-survival, overall response,
duration of response, and QoL will be analyzed. For any time-to-event endpoints, the date of disease progression
will be determined by both the on-site investigator’s assessment and by independent review (IR). All efficacy
analyses will be conducted on both the ITT and Efficacy Evaluable sets.
The primary comparison of PFS between both arms will be performed on the ITT set based upon the results of
the on-site investigator’s assessment using a stratified Log-rank test at the one-sided 2.5% significance level.
Stratification is done by disease type, either SS or MF, and disease stage, either IB/II or III/ IV. A similar
secondary analysis will be performed on the results based on the IR. An IR will review each subject to make a
determination regarding progression and the date of progression in each compartment.
Each analysis will also be conducted for the Efficacy Evaluable Set. PFS, which will be analyzed using Kaplan-
Meier survival analysis methods, is defined as the time from the first day of randomization to a treatment arm
until documented progression or death.
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Study Title:
Protocol No.
0761-010
For PFS events, all deaths will be attributed to progression and, hence, the time to progression will equal the
time to death and will be uncensored. Subjects who die without a reported prior progression will still be
considered to have progressed on the day of their death. In the event that a randomized subject withdraws from
the study for any reason before documented progression, the time from the day of randomization to the last
tumor assessment (from any compartment) will be used as a censored time point. For all subjects randomized to
a treatment arm but withdrawing prior to first tumor assessment for any reason other than disease progression,
the PFS time will be censored at last documented visit.
ORR will be calculated as the proportion of subjects who are responders (complete response, and PR) and the
95% exact confidence interval for response will be calculated.
Since the primary endpoint is PFS, the reference median PFS for vorinostat is assumed to be 169 days. The
median PFS for KW-0761 therapy is targeted for 254 days, a 50% improvement over this reference median. The
ITT set is used for this primary analysis. The same analysis conducted using the Efficacy Evaluable set is
considered secondary.
Under these assumptions, for the ITT population, a total of 255 PFS events will give 90% power. In the event
that the study is stopped prior to 255 PFS events are observed, the primary test will be performed at less than
90% power under the current assumptions.
A total sample size of 288 may be necessary for 255 PFS events to occur within the projected 36 months of the
trial. A 10% inflation factor is applied to this total (about 29 subjects) to take into account those subjects that
may be lost to follow-up prior to documented progression, for a total of 317 enrolled subjects to observe
255 PFS events. If the 255 PFS events are not observed within 36 months from the start of enrollment the study
will be stopped at approximately 24 months after the last randomized subject’s first dose.
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Table 1 Study Procedures: First Treatment Cycle

Pre- First Treatment Cycle
treatment
Procedures Visit D1 D8 D 15 D 22 D 26-28a
Up to
Visit Window Day -30 ±2 days ±2 days ±2 days + 2 days
Informed consent X
Review of subject eligibility X
Medical history X
Physical examinationb X X X X
ECOG performance status (PS) X X X X
Vital signs, Weight X Xc Xc Xc Xc X
ECG X
Pregnancy test (within 7 days) X
Urinalysis X X
Hematology profile X Xd Xd Xd Xd X
Chemistry profile X Xd Xd Xd Xd X
Coagulation profile X Xd
Thyroid function tests (Free T4, TSH) X X
Hepatitis B & C, HIV, HTLV-1 X
Flow Cytometric Analysis X X
Blood sample for determination of X X
natural ligands
Serum sample for KW-0761 X X X X X
concentration assessmente
Saliva sample for genetic analysis Xf
KW-0761 Administrationg X Xh Xh Xh
Vorinostat Administration Xi
Adverse event assessmentj X X X X X X
Concomitant medication assessmentk X X X X X X
CT (diagnostic quality) X X
Bone marrow aspiration & biopsyl X X
Skin biopsy for assessment of disease Xm Xn
Skin biopsy or archival tissue for CCR4 X
expressiono
Skin photographs X X
Modified Severity Weighted X X
Assessment Tool (mSWAT)
Pruritus Evaluation (Likert Scale & X X
Itchy QoL)
Skindex-29 , FACT-G & EQ-5D-3L X X
Immunogenicityp X X
Disease Progressionq
Survival statusr
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Footnotes to Table 1
a: If progression is noted at Day 26-28, visit should take place before initiation of new therapy. In cases where the definition
of PD or relapse is met but the clinical impression is questionable, subjects may remain on study until the next evaluation
(4 weeks later if questionable finding in skin or blood; 8 weeks later in first year and 16 weeks later after Year 1 if
questionable finding in lymph nodes or viscera, with at least stable disease in other compartments) to avoid a subject
being removed prematurely from the study. For subjects receiving a subsequent treatment course, procedures performed
at this time can also be used to satisfy the Day 1 requirements for the subsequent course, provided they are performed
within ± 2 days of next KW-0761 administration. For subjects who will not receive subsequent treatment, this visit will be
considered the final treatment visit and subjects should undergo testing/procedures specified for End-of-treatment visit
(See Table 3).
b: Complete physical examination including height at Pre-treatment Visit; brief physical examination of pertinent systems at
other times. Responses to questions for surveillance of autoimmune type symptoms (See Appendix 4) should be
documented at time of physical exam.
c: For subjects receiving KW-0761, vital signs will be checked and recorded prior to the start of each infusion, at the end of
each infusion and 1 hour after the completion of the infusion. For subjects taking vorinostat, vital signs can be taken
irrespective of dosing. Weight will be checked with vitals.
d: Blood can be drawn 1 day prior to visit, if needed, to ensure results are available. In subjects receiving KW-0761, results
must be reviewed prior to infusion. The platelet count must be ≥ 100,000 / mm3 and the ANC must be ≥ 1,500/mm3
before a subject can receive study drug.
e: Serum samples will be collected for subjects treated with KW-0761 pre-dose on days indicated (sample collection will
still be needed even if dosing is not performed at a visit), as applicable. On Day 1, an additional sample should be
obtained from the arm contralateral to that of study drug administration at the end of infusion (10-15 minutes after
completion of the infusion) as well. At selected sites, 4 additional samples will be drawn between 6 and 8 hours, and at
24, 48, and 72 - 96 hours after the first infusion on Day 1.
f: Samples to be obtained for subjects assigned to KW-0761 as first assigned therapy only.
g: KW-0761 is to be administered over at least one hour.
h: If the study visit does not occur within ± 2 days of the scheduled visits, KW-0761 should not be administered at the visit
and the next dose should be administered at the next timepoint.
i: Vorinostat is administered orally daily beginning on Day 1 with food.
j: If a subject who is receiving KW-0761 develops a skin rash, notify KKD and refer to Section 5.2.1.8 to treat and
document the rash.
k: Medication taken within 30 days prior to the first dose of study drug, and at any time after the start of treatment until
30 days after the final study drug administration will be recorded.
l: To be performed in subjects with cytopenia or other clinical suspicions of bone marrow involvement, at the discretion of
the investigator.
m: Subjects with clinical features suggestive of LCT must have a biopsy performed within 4 months prior to Cycle 1/Day 1
to rule out transformed disease.
n: Biopsy at the end of the cycle is optional and can be performed at the discretion of the investigator. Analysis of the biopsy
will be done by a pathologist at the study site.
o: To be performed for CCR4 expression as determined by IHC. IHC analysis will be performed by central laboratory
designated by the Sponsor. The paraffin block or a fresh sample, if the study site is unable to process the tissue on the day
obtained, may be submitted. Submission of unstained slides, while not recommended due to stability concerns with the
sample, will be accepted. In the event, it is not possible to obtain a skin biopsy, use of an archived sample (taken within
6 months prior to treatment) may be allowed with prior authorization from the Sponsor. For subjects receiving vorinostat
who cross over to treatment with KW-0761, investigators are strongly encouraged to perform another biopsy for
determination of CCR4 expression prior to treatment with KW-0761.
p: KW-0761 subjects only for determination of anti-KW-0761 antibodies.
q: Subjects who terminate for reasons other than disease progression or their referring physicians will be contacted every
3 months (± 14 days) until documented disease progression or death or initiation of alternative therapy.
r: All subjects or their referring physician will be contacted every 3 months (± 14 days) to ascertain survival status
following discontinuation of treatment.
CONFIDENTIAL 21
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Table 2 Study Procedures: Subsequent Cycles in Year 1

Subsequent Cycles 2 through 13a
D 26-28 D 26-28
(Cycles 2, 4, 6, (Cycles 3, 5, 7,
Procedures D1 D 15 8, 10, 12)b 9, 11, 13)b
Visit Window ± 2 days + 2 days + 2 days
Physical examinationc X X X X
ECOG PS X X X X
Vital signs, Weight Xd Xd X X
ECG
Urinalysis X
Hematology profile Xe Xe X X
Chemistry profile Xe Xe X X
Coagulation profile Xe
Thyroid function tests (Free T4, TSH) X
Flow Cytometric Analysisf X X
Blood sample for determination of X
natural ligands
Serum sample for KW-0761 Xg Xg
concentration assessment
KW-0761 Administration Xh Xh
Vorinostat Administration Xi
Adverse event assessmentj X X X X
Concomitant medication assessmentk X X X X
CT (diagnostic quality)f X
Bone marrow aspiration & biopsyl X
Skin biopsy Xm
Skin photographsf X X
Modified Severity Weighted X X
Assessment Tool (mSWAT)f
Pruritus Evaluation (Likert scale & X X
Itchy QoL)
Skindex-29, FACT-G & EQ-5D-3L X
Immunogenicityn X
Disease Progressiono
Survival Statusp
a: Subject may remain in treatment phase up until progressive disease, drug intolerance, or unacceptable toxicity, or until
any of the other criteria for removal (See Section 5.5) are met. At each cycle, the Investigator must minimally have
reviewed the mSWAT to determine if progression of skin disease has occurred prior to subsequent dosing (see Section
5.2.1.4). For subjects who are continuing to receive study treatment at the time of the primary efficacy analysis,
procedures and assessments are described in Section 7.7.
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Footnotes to Table 2 (continued).

b: For subjects receiving a subsequent treatment course, procedures performed at this time can also be used to satisfy the
Day 1 requirements for the subsequent course, provided they are performed within ± 2 days of next KW-0761
administration. For subjects who will not receive subsequent treatment, this visit will be considered the final treatment
visit and subjects should undergo testing/procedures specified for End-of-treatment visit (See Table 3). If progression is
noted at Day 26-28, visit should take place before initiation of new therapy. In cases where the definition of PD or relapse
is met but the clinical impression is questionable, subjects may remain on study until the next evaluation (4 weeks later if
questionable finding in skin or blood; 8 weeks later in first year and 16 weeks later after Year 1 if questionable finding in
lymph nodes or viscera, with at least stable disease in other compartments) to avoid a subject being removed prematurely
from the study.
c: Brief physical examination of pertinent systems to be performed during subsequent treatment cycles. Complete physical
exam to be performed at End of Treatment visit. Responses to questions for surveillance of autoimmune type symptoms
(See Appendix 4) should be documented at time of physical exam.
d: For subjects receiving KW-0761, vital signs will be checked and recorded prior to the start of each infusion, at the end of
e: Blood can be drawn 1 day prior to visit, if needed, to ensure results are available. In subjects receiving KW-0761, results
f: If clinical progression is noted at any time prior to the scheduled assessments for efficacy, CT, mSWAT, skin
photographs and flow cytometry assessments should be done at that time to fully document disease progression, i.e.,
Global Composite Response Score. CT must be performed even if previously negative at baseline.
g: Serum samples for PK assessment should be collected for subjects treated with KW-0761 prior to infusion of KW-0761 in
Cycles 2 and 3 (sample collection will still be needed even if dosing is not performed at a visit).
h: KW-0761 is to be administered over at least one hour.
document the rash.
k: Medication taken at any time after the start of treatment until 30 days after the final study drug administration will be
recorded.
l: To be performed in subjects with cytopenia or other clinical suspicions of bone marrow involvement, at the discretion of
the investigator. If a bone marrow biopsy was performed at baseline and determined to unequivocally be indicative of
lymphomatous involvement, then to confirm a global CR where blood assessment now meets criteria for B0, a repeat
bone marrow biopsy must show no residual disease or the response should be considered a PR only (See Table 7.2.2-1).
m: Biopsies at the end of the cycle and to confirm a CR (See Table 7.2.1-3) are optional and can be performed at the
discretion of the investigator. Analysis of these biopsies will be done by a pathologist at the study site.
n: KW-0761 subjects only for determination of anti-KW-0761 antibodies and concentration of KW-0761.
o: Subjects who terminate for reasons other than disease progression or their referring physicians will be contacted every
p: All subjects or their referring physician will be contacted every 3 months (± 14 days) to ascertain survival status
following discontinuation of treatment.
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Table 3 Study Procedures: Subsequent Cycles in Year 2 and Beyonda

D 26-28
D 26-28 Q 16
(Cycles D 26-28 wks
14, 16, (Cycles 15, (Cycles End-of-
18, 20, 17, 19, 21, 17, 21, treatment Follow-
Procedures D1 D 15 etc)b etc)b etc) visit upc
Within 30
days of last
Visit Window ± 2 days + 2 days + 2 days + 5 days dose
Physical examinationd X X X X X
ECOG PS X X X X X
Vital signs, Weight Xe Xe X X X
ECG X
Urinalysis X X
Hematology profile Xf Xf X X X
Chemistry profile Xf Xf X X X
Coagulation profile Xf
Thyroid function tests X X
(Free T4, TSH)
Flow Cytometric X X
Analysisg
Blood sample for X
determination of
natural ligands
Serum sample for X
KW-0761
concentration
assessment
KW-0761 Xh Xh
Administration
Vorinostat Xi
Administration
Adverse event X X X X X Xk
assessmentj
Concomitant X X X X X X
medication assessmentl
CT (diagnostic quality)g X
Bone marrow X
aspiration & biopsym
Skin biopsy Xn
Skin photographsg X X
Modified Severity X X
Weighted Assessment
Tool (mSWAT)g
Pruritus Evaluation X X
(Likert scale & Itchy
QoL)
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D 26-28
D 26-28 Q 16
(Cycles D 26-28 wks
Within 30
days of last
Skindex-29, FACT-G X X
& EQ-5D-3L
Immunogenicityo X
CD4, CD8 (for Xp Xp
KW-0761 subjects)
Disease Progressionq
Survival Statusr
a: Subject may remain in treatment phase up until progressive disease, drug intolerance or unacceptable toxicity, or until any
of the other criteria for removal (See Section 5.5) are met. At each cycle, the investigator must minimally have reviewed
the mSWAT to determine if progression of skin disease has occurred prior to subsequent dosing (see Section 5.2.1.4). For
subjects who are continuing to receive study treatment at the time of the primary efficacy analysis, pending notification
by the Sponsor, subjects may be followed according to institutional standard of care for subsequent assessments of
treatment efficacy as described in Section 7.7.
b: For subjects receiving a subsequent treatment course, procedures performed at this time can also be used to satisfy the
Day 1 requirements for the subsequent course, provided they are performed within ± 2 days of next KW-0761
administration. For subjects who will not receive subsequent treatment, this visit will be considered the final treatment
visit and subjects should undergo testing/procedures specified for End-of-treatment visit. If progression is noted at Day
26-28, visit should take place before initiation of new therapy. In cases where the definition of PD or relapse is met but
the clinical impression is questionable, subjects may remain on study until the next evaluation (4 weeks later if
questionable finding in skin or blood; 8 weeks later in first year and 16 weeks later after Year 1 if questionable finding in
lymph nodes or viscera, with at least stable disease in other compartments) to avoid a subject being removed prematurely
from the study.
c: For subjects going off treatment after achieving a CR, refer to Section 7.6 for study procedures and timing.
d: Brief physical examination of pertinent systems to be performed during subsequent treatment cycles. Complete physical
exam to be performed at End of Treatment visit. Responses to questions for surveillance of autoimmune type symptoms
(See Appendix 4) should be documented at time of physical exam.
e: For subjects receiving KW-0761, vital signs will be checked and recorded prior to the start of each infusion, at the end of
f: Blood can be drawn 1 day prior to visit, if needed, to ensure results are available. In subjects receiving KW-0761, results
g: If clinical progression is noted at any time prior to the scheduled assessments for efficacy, CT, mSWAT, skin
photographs and flow cytometry assessments should be done at that time to fully document disease progression, i.e.,
Global Composite Response Score. CT must be performed even if previously negative at baseline.
h: KW-0761 is to be administered over at least one hour.
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D 26-28
D 26-28 Q 16
(Cycles D 26-28 wks
Within 30
days of last
Footnotes to Table 3 continued.
document the rash.
k: Adverse events will be collected every 30 days (± 7 days) for up to 90 days after the last dose of study drug or initiation
of alternative therapy. In all subjects who cross over from vorinostat to KW-0761, the causality should be assessed for
both drugs for 30 days after vorinostat was stopped (or later if the event is considered to be related to vorinostat).
l: Medication taken at any time after the start of treatment until 30 days after the final study drug administration will be
recorded. A medication taken during follow-up will also be recorded if it is used to treat an AE or is temporally associated
with an AE and may have a causal relationship.
m: To be performed in subjects with cytopenia or other clinical suspicions of bone marrow involvement, at the discretion of
the investigator. If a bone marrow biopsy was performed at baseline and determined to unequivocally be indicative of
lymphomatous involvement, then to confirm a global CR where blood assessment now meets criteria for B0, a repeat
bone marrow biopsy must show no residual disease or the response should be considered a PR only (See Table 7.2.2-1)
n: Biopsies at the end of the cycle and to confirm a CR (See Table 7.2.1-3) are optional and can be performed at the
discretion of the investigator. Analysis of these biopsies will be done by pathologist at the study site.
o: KW-0761 subjects only for determination of anti-KW-0761 antibodies.
p: If CD4 and CD8 counts are less than 200/mm3 at the End-of-treatment visit, they will be followed every 3 months
(±14 days) until they return to at least 200/mm3, initiation of alternative therapy or 1 year, whichever comes first.
Assessments will be performed at the study site.
q: Subjects who terminate for reasons other than disease progression or their referring physicians will be contacted every
r: All subjects or their referring physician will be contacted every 3 months (± 14 days) to ascertain survival status following
discontinuation of treatment.
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List of Abbreviations
Abbreviations
Ab antibody
ADCC antibody dependent cellular cytotoxicity
AE adverse event
Ag antigen
ALT Alanine transaminase
ANC absolute neutrophil count
ASCO American Society of Clinical Oncology
ASH American Society of Hematology
AST aspartate transaminase
ATL adult T-cell leukemia-lymphoma
β-HCG beta-human chorionic gonadotrophin
BUN blood urea nitrogen
CBC complete blood count
CCR4 CC chemokine receptor 4, chemokine (C-C motif) receptor 4
CNS central nervous system
CR complete response
CS clinically significant
CT computed tomography
CTA Clinical Trial Authorization
CTCAE Common Terminology Criteria for Adverse Events
CTCL cutaneous T-cell lymphoma
CTIVRS ClinTrak Interactive Voice/Web Response System
DOR duration of response
DSMB Data Safety Monitoring Board
EC Ethics Committee
ECG electrocardiogram
ECOG Eastern Cooperative Oncology Group
eCRF electronic case report form
EDC electronic data capture
EMA European Medicines Agency
EORTC European Organization for Research and Treatment of Cancer
FDA Food and Drug Administration
GCP Good Clinical Practice
GMP Good Manufacturing Practice
HDAC histone deacetylase
HEENT head, eyes, ears, nose and throat
HIV human immunodeficiency virus
HSCT hematopoetic stem cell transplantation
HTLV-1 human T-cell lymphotropic virus type-1
IB Investigator’s Brochure
ICH International Conference on Harmonization
IHC immunohistochemistry
IND Investigational New Drug Application
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Abbreviations
INR International Normalized Ratio
IRB Institutional Review Board
IR Independent Review/Reviewer
ISCL International Society of Cutaneous Lymphomas
ITT Intent-to-Treat
iv intravenous
KKD Kyowa Kirin Pharmaceutical Development, Inc.
KW-0761 humanized monoclonal antibody against CCR4
LDH lactate dehydrogenase
Mab monoclonal antibody
MDC macrophage derived chemokine
MedDRA Medical Dictionary for Regulatory Activities
MF mycosis fungoides
mSWAT modified Severity Weighted Assessment Tool
NCCN National Comprehensive Cancer Network
NCI National Cancer Institute
NCS not clinically significant
NHL non-Hodgkin’s Lymphoma
NYHA New York Heart Association
ORR objective response rate
OS overall survival
PD progressive disease
PDF Portable Document Format
PFS progression-free survival
PK pharmacokinetic
PR partial response
PS performance status
PT prothrombin time
PTCL peripheral T-cell lymphoma
PTT partial thromboplastin time
QoL Quality of Life
SAE serious adverse event
SD stable disease
SEER Surveillance Epidemiology and End Results
SGOT serum glutamic oxaloacetic-transaminase
SGPT serum glutamic pyruvic-transaminase
SPD sum of the product of the diameters
SS Sézary Syndrome
TARC thymus- and activation-regulated chemokine
TBSA total body surface area
TEAE treatment-emergent adverse event
TTP time to progression
ULN upper limit of normal
US United States
USCLC United States Cutaneous Lymphoma Consortium
WHO World Health Organization
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Abbreviations
WOCBP women of childbearing potential
Definition of Terms
pH hydrogen ion concentration; negative logarithm of hydrogen ion activity
p.r.n. as needed
QT interval in electrocardiography, the time from the beginning of the QRS complex to the end of the T
wave.
QTc interval QT interval corrected for heart rate
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1 BACKGROUND AND RATIONALE

1.1 Cutaneous T-Cell Lymphomas
T-cell non-Hodgkin’s lymphoma (NHL) comprises approximately 10–15% of all adult NHL
(Vose, 2008). The T-cell lymphomas are a highly heterogeneous group of disorders with a
highly variable prognosis, response to therapy and geographic distribution, of which the 2
most common forms of Cutaneous T-cell Lymphoma (CTCL) are mycosis fungoides (MF)
and Sézary syndrome (SS).
The estimated incidence of CTCL in the U.S. based on the Surveillance Epidemiology and
End Results (SEER) data from 2001–2007 is 0.5/100,000 or about 2,400 new cases per year,
which represents about 25% of all T-cell lymphomas (SEER Data, 2001-2007). From 1973 to
2002, there appears to have been at least a three-fold rise in the incidence of CTCL
(Criscione, 2007), although this may partially represent a greater degree of awareness and
reporting of the disease.
Unlike other forms of NHL, CTCL mainly affects the skin. It can present as patches, plaques,
tumors or erythroderma and may be associated with severe pruritus (Horwitz, 2008; Meyer,
2010). The type and extent of skin involvement as well as the presence of extracutaneous
disease are significant prognostic factors in this subject population (Kim, 2003). Cutaneous
T-cell Lymphoma can cause significant morbidity and adversely affect the subject’s quality
of life (QoL) (Demierre, 2003; Demierre, 2005; Demierre, 2006).
Cutaneous T-cell lymphoma is staged according to four anatomical compartments:
involvement of skin (T), nodes (N), visceral metastases (M) and peripheral blood (B). Blood
involvement is further divided into three categories, B0 (absence of significant blood
involvement where ≤ 5% of peripheral blood lymphocytes are atypical [Sézary] cells), B1
(low blood tumor burden where >5% of peripheral blood lymphocytes are atypical [Sézary]
cells without meeting the criteria of B2) and B2 (high blood tumor burden with > 1,000/µl
Sézary cells) (Olsen, 2011).
At presentation, up to 50% of subjects with MF will have limited disease, while only 10-20%
present with erythrodermic involvement (Diamendidou, 1996). Survival, as would be
expected, is related to stage. Subjects with early stage MF have median survivals in excess of
25 years; median survival of advanced disease is very variable, with some reporting median
survival as little as 1.5 years (Kim, 2003).
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1.2 Treatment of Cutaneous T-cell Lymphomas
Subjects with early stage disease are treated topically. As the disease progresses, systemic
therapy may become necessary. There is no standard therapy for subjects with later stage
disease. Both approved and unapproved agents are used in these subjects including immune
modulators, single agent or combination chemotherapy or other investigational agents.
Current National Comprehensive Cancer Network (NCCN) guidelines (National
Comprehensive Cancer Network, Inc., 2013) recommend these agents or a clinical trial as
first line therapy.
There are four approved agents in the United States (US) for the treatment of CTCL,
bexarotene, vorinostat, denileukin diftitox and most recently, romidepsin. All of these agents,
except for denileukin diftitox are indicated only after subjects have failed at least one other
systemic therapy. The overall response rates (ORRs) of 32% (Duvic, 2001; Targretin
capsules, 2011), 30% (Olsen, 2007; Mann, 2007; ZOLINZA, 2011), 30% (Olsen, 2001;
Ontak, 2011) and 35% (Demierre, 2009; Istodax, 2011), respectively for these agents are
relatively modest and their duration of response fairly short. The European Medicines
Agency (EMA) granted a marketing authorization for bexarotene in refractory CTCL.
Denileukin diftitox and romidepsin have been granted orphan drug status for the treatment of
CTCL by the EMA. Vorinostat is not currently approved by the EMA for the treatment of
CTCL and would be considered an investigational medicinal product within Europe. In
Japan, vorinostat is approved for the treatment of CTCL. Romidepsin and vorinostat have
been granted orphan drug status for the treatment of CTCL by Australia’s Therapeutic Goods
Administration. Of the approved therapies, vorinostat (US approval) and bexarotene (US,
Europe and Japan approval) are indicated only for the cutaneous manifestations of CTCL. In
these subjects, the presence of extracutaneous disease, lymphadenopathy and peripheral
blood involvement are all poor prognostic factors (Agar, 2010). There is a great unmet need
to develop other agents that can target all disease compartments (skin, blood, lymph nodes,
and viscera) and provide a more durable response.
1.3 Chemokine Receptor 4 and T-Cell Malignancies
CC Chemokine receptor 4 (CCR4), the receptor for macrophage derived chemokine (MDC)
and thymus- and activation-regulated chemokine (TARC) is over expressed on the surfaces of
the cells comprising several T-cell malignancies. Macrophage derived chemokine and TARC
share 37% homology, both are highly expressed in the thymus, but barely at all in any other
tissues, and both are encoded on chromosome 16. In subjects with most forms of CTCL,
CCR4 expression has been identified on peripheral blood or tissue infiltrating neoplastic
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T cells. Although the degree of CCR4 expression can differ substantially between published
studies due to differences in disease severity, subject demographics and detection methods
employed may all play a role.
In one study using a combination of immunohistochemistry (IHC) and flow cytometry, CCR4
was expressed on 5 of 15 samples of plaque stage MF and 9 of 9 samples of Tumor stage and
Folliculotropic MF. CC Chemokine receptor 4 was not detected in subjects with patch stage
MF (0/2 samples) and the authors suggested the differential CCR4 expression mirrored
disease severity. In the same study, all subjects with Sézary Syndrome (5/5), CD30+ ALK−
ALCL (5/5) and 3 of 4 subjects with LyP also expressed CCR4 on the neoplastic T cells. No
CCR4 was detected in the subject’s with CD8+ CTL (0/5) or T/NK lymphomas (0/5) (Yagi,
2006). In a separate study by Jones et al. CCR4 expression also mirrored disease severity in
MF subjects with 5 of 5 subjects with transformed MF exhibiting expression of CCR4 versus
1 of 7 with non-transformed MF (Jones, 2000). Both ALK+ (5/5) and ALK− (3/6) CD30+
ALCL expressed CCR4. Other forms of CTCL including unspecified T cell lymphomas and
angioblastic T cell lymphomas did not show a predication for CCR4 expression on subject
samples (5/24 combined) (Jones, 2000). A similar distribution of the various subtypes of
CTCL that expressed CCR4 to some degree was also observed by Ishida and colleagues.
Subjects with transformed MF (7/17) and ALK- ALCL (8/12) expressed high levels of
CCR4. In contrast to other published reports, few ALK+ ALCL subjects (1/24) expressed
CCR4 in this study whilst 5 of 12 T/NK cell lymphomas showed expression. Unspecified
T cell lymphoma subject samples exhibited CCR4 expression (19/50) which was a slightly
larger proportion than other published data (Ishida, 2004).
In CTCL subjects with peripheral blood involvement, increased expression of CCR4 has been
demonstrated in several studies. In a study conducted on 12 SS subject samples, it was shown
that CCR4 expression on circulating TCR-Vβ-positive population was significantly higher
(mean = 80 ± 25%; median = 90%; range 31-100%) when compared with healthy donor
controls (mean = 27 ± 5.1%) (Narducci, 2006). In a separate study, Fierro et al. (2006)
demonstrated that CCR4 expression on circulating CD4+CD26- lymphocytes is significantly
higher in SS subjects (59.1 ± 18.6%, n = 20) when compared with inflammatory
erythroderma (11.5 ± 7.4%, n = 25) and healthy controls (3.9 ± 2.4%). The CCR4 expression
in peripheral blood lymphocytes was also significantly higher in SS subjects (67.6 ± 16%,
n = 20) compared to inflammatory erythroderma (39.6 ± 15.9%, n = 25) and healthy controls
(16.6 ± 4.5%). In the same study, it was also shown that CCR4 expression in skin-infiltrating
CD4+CD26- lymphocytes was higher in SS (42.3 ± 18%) versus inflammatory erythroderma
(17.6 ± 12.3%).
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In another study in CTCL subjects with peripheral blood involvement (Ferenczi, 2002), there
was a significant increase in T cells displaying the putative skin-homing phenotype
(CCR4+CLA+) when compared with healthy controls (62% versus 20%). This study also
demonstrated that while the expression of CCR4 is similar on T cells from normal skin and
CTCL lesions, the expression of CCR4 ligands TARC/CCL17 and MDC/CCL22 is strongly
enhanced; suggesting the importance of CCR4 mediated recruitment of T-cells in the skin.
More recently (Campbell, 2010), demonstrated that L-CTCL and MF arise from distinctive
T-cell subsets and that in a T-cell migration assay, L-CTCL clones migrated more efficiently
to CCR4 ligand when compared to skin tropic (CLA+) T cells from blood.
Based on multiple studies suggesting the significance of CCR4 in CTCL, a targeted
therapeutic against this molecule may be a good approach for treatment of CTCL subjects.
1.4 KW-0761 (mogamulizumab)
KW-0761 is a defucosylated, humanized, monoclonal antibody (Mab) with enhanced

antibody dependent cellular cytotoxicity (ADCC; Potelligent®) that binds to CCR4. The lack
of fucose results in the antibody eliciting more potent ADCC than conventionally produced
antibodies. KW-0761 is devoid of complement dependent cytotoxicity.
CC Chemokine receptor 4 is over expressed on the surfaces of cells comprising several T-cell
malignancies such as peripheral T-cell lymphoma (PTCL) and CTCL, and is a potential target
for anti-neoplastic therapy in these disorders.
1.5 Safety and Efficacy of KW-0761
In preliminary human clinical trials, doses of up to 1.0 mg/kg have been well tolerated. As of
31 December 2013, approximately 340 subjects have received at least one dose of KW-0761.
Efficacy has been demonstrated in subjects with T-cell lymphoma including ATL, CTCL,
and PTCL, with ORRs ranging from 31% to 50%. Adverse events have generally been mild
to moderate in severity. In the clinical trials sponsored by KKD with similar dosing regimens
(i.e., 1.0 mg/kg administered weekly for 4 weeks in a completed Phase 1/2 study [Study
KW-0761-001] or weekly for 5 weeks in ongoing studies [Studies 0761-007, 0761-009,
0761-010], and then every other week until disease progression), the most frequent treatment-
emergent adverse events (TEAEs) that were considered at least possibly related to study drug
in > 10% of subjects included infusion related reaction, nausea, pyrexia, fatigue, and drug
eruption.
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Exploratory testing of CCR4 expression was performed using IHC and flow cytometry. The
assays were conducted at an academic research center and have not been validated.
Thirty-five (35) subject samples from a Phase 1/2 study in subjects with CTCL
(Study KW-0761-001) were tested for CCR4 expression by IHC (skin samples) and/or flow
cytometry (blood samples). Data for subjects that had detectable tumor cells in the blood
(n = 28) demonstrated that 100% were positive for CCR4 expression by flow cytometry and
thirty one (31) subjects were positive for CCR4 expression by at least one method. Four
subjects had no or background staining by IHC (< 5% tumor cells positive for CCR4) and no
detectable tumor cells in blood; 2 of these 4 subjects had a partial response (Duvic, 2015).
Given the small sample size and investigative nature of the above, inclusion of all subjects in
this current proposed study, 0761-010, is warranted to further characterize the role of CCR4
in predicting response. CC Chemokine receptor 4 expression in the 0761-010 study will be
determined in skin biopsy samples using a validated IHC assay. Exploratory analysis will be
performed to determine if there is any correlation of CCR4 expression with global overall
response.
POTELIGEO® (mogamulizumab) was approved by the Ministry of Health, Labor and
Welfare in Japan for the treatment of CCR4-positive ATL, and relapsed or refractory
CCR4-positive CTCL and PTCL.
Further information is provided in the Investigator’s Brochure (IB).
1.6 Vorinostat (ZOLINZA®)
Vorinostat ZOLINZA® (Merck & Co., Inc.) also called suberoylanilide hydroxamic acid
(SAHA) is a small molecule inhibitor of class I and II histone deacetylase (HDAC) enzymes
(IC50<86 nmol/L) (ZOLINZA, 2011). Vorinostat has been demonstrated to induce cell-cycle
arrest and apoptosis in a variety of human cancer cell lines including CTCL and in peripheral
blood lymphocytes (PBL) of CTCL patients with high percentage of circulating malignant
T cells (Zhang, 2005). The antineoplastic effect of vorinostat has not been fully
characterized; (ZOLINZA, 2011) however, it is known that cancers of hematologic origin
(e.g., CTCL) are associated with hypoacetylation, which induces decreased expression of
genes responsible for cell-cycle control, apoptosis, and tumor suppression (Kavanaugh,
2010). By inhibiting HDAC activity, vorinostat has been shown to induce the accumulation
of acetylated histones (among other proteins) (Duvic, 2007; O’Connor, 2006) and the
transcription of tumor-repressing genes (Kavanaugh, 2010). Vorinostat has also demonstrated
antitumor activity in in vivo leukemia and solid tumor animal models (He, 2001; Richon,
2006).
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Phase 1 trials were conducted to assess vorinostat pharmacokinetics, safety, and antitumor
activity in subjects with hematologic malignancies, including CTCL, and solid tumors
(O’Connor, 2006; Kelly, 2003; Kelly, 2005; Rubin, 2006). Both intravenous (iv) and oral
formulations of vorinostat were generally well tolerated (Duvic, 2007; O’Connor, 2006;
Kelly, 2003). Dose-limiting toxicities included gastrointestinal AEs (nausea, vomiting, or
diarrhea), anorexia, and dehydration observed mostly with oral formulations, while
myelosuppression (thrombocytopenia, neutropenia, or leukopenia) was more prominent with
the use of iv formulations (Duvic, 2007; Kelly, 2003). In these Phase 1 trials, antitumor
activity (complete response [CR] or partial response [PR]) was observed in subjects with
refractory solid tumors and hematologic malignancies, including CTCL (O’Connor, 2006;
Kelly, 2005). In the O’Connor 2006 study, one MF subject in the oral formulation group
(n = 2 CTCL/PTCL subjects) achieved partial response for more than 4 months (after which
he developed progressive disease [PD]) (O’Connor, 2006).
Vorinostat was subsequently evaluated in two single-arm Phase 2 clinical trials (Olsen, 2007;
Duvic, 2007). The first Phase 2 trial, an open-label, single site, single group, nonrandomized
study, was conducted to assess the safety and efficacy of vorinostat in 33 subjects with CTCL
(MF and SS) who were intolerant or refractory to conventional topical or systemic treatments
(Duvic, 2007). Subjects were divided in 3 groups and vorinostat was administered orally as
follows:
• Group 1 - 400 mg daily (n=13)
• Group 2 - 300 mg twice daily for 3 days with 4 days rest (n=11)
• Group 3 - 300 mg twice daily for 14 days with 7 days rest followed by 200 mg twice
daily (n=9).
The overall response rate was 24.2% (8/33) with responses in Groups 1, 2, and 3 of 31%, 9%,
and 33%, respectively. All responses were partial. The median time to progression (TTP) for
the overall population was 12.1 weeks (84.7 days) and for the responders (n = 8) 30.2 weeks
(211.4 days). This study provided the basis for the selection of 400 mg once daily dose for
the second Phase 2 trial. This second pivotal, Phase 2b, single-group, multicenter,
nonrandomized study was conducted to assess the safety and activity of vorinostat
monotherapy, in 74 subjects with refractory CTCL (MF and SS) (Olsen, 2007). The overall
response rate was 29.7%, similarly to the 31% ORR reported for the 400 mg group in the first
Phase 2 study. One subject achieved a CR. The median TTP was 148 days for the overall
population and was ≥ 299 days (range, 85 to 470+ days) for responders with ≥ Stage IIB
CTCL.
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These results led to Food and Drug Administration (FDA) approval of vorinostat for the
treatment of CTCL in subjects with progressive, persistent, or recurrent disease on or
following 2 prior systemic therapies. Pruritus relief was substantial in both first and second
trials (45% [Duvic, 2007] and 32.3% [Olsen, 2007] of evaluable subjects, respectively),
however, this effect was not included in the FDA-approved indication due to the lack of a
control group and blinding in these studies.
Vorinostat has not been approved in Europe and would be considered an investigational
medicinal product. Merck Sharp & Dohme withdrew its application for a centralized
marketing authorization for vorinostat based on the Committee For Medicinal Products For
Human Use (CHMP) view that the data provided at that time were not sufficient to allow the
committee to conclude on a positive benefit-risk balance as the clinical trial design did not
compare vorinostat with other active treatments or placebo and the single pivotal study did
not demonstrate compelling clinical benefit.
Use of vorinostat has been associated with serious adverse events (SAEs) including
pulmonary embolism, thrombocytopenia, squamous cell carcinoma, anemia, deep vein
thrombosis, gastrointestinal disturbances, and hyperglycemia (ZOLINZA, 2011). Of the
subjects who received 400 mg once daily, 9.3% (8/86) of subjects discontinued participation
due to drug-related adverse experiences and 10.5% (9/86) of subjects required a dose
reduction due to AEs (ZOLINZA, 2011).
1.7 Rationale
Current treatment options for CTCL are limited. Although responses have been
demonstrated, their duration is often short, regardless of disease stage. Additional treatment
options are needed which demonstrate activity in cutaneous and extracutaneous sites.
Preliminary data from a Phase 1/2 study in CTCL (KW-0761-001) demonstrated that
KW-0761 has a significant effect on disease in blood, 18 of 19 subjects had a response in the
blood, including 11 CRs. Response in skin disease and lymph nodes has also been observed
with rates of 42% and 25% respectively with an overall response rate of 37% (Duvic, 2015).
The vorinostat clinical program also evaluated response in lymph node size or blood tumor
burden (Olsen, 2007). Response for vorinostat has been reported to be ≥ 51.8% in blood
(14 of 27 evaluable SS subjects had blood tumor reduction of ≥ 25%) and 41.7% in lymph
nodes (10 of 24 evaluable subjects with clinically abnormal lymph nodes had a ≥ 50%
reduction in size, including 4 of 10 with an objective cutaneous response) (Olsen, 2007).
Clinical experience since the advent of immune-based anti-neoplastic therapy, recently well
documented in the trials of ipilimumab in subjects with advanced melanoma, has shown that
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the time required to demonstrate a response to immune-based therapies may be more

prolonged than that seen following cytotoxic chemotherapy (Wolchok, 2009). In fact, actual
signs of objective progression may precede subsequent demonstration of an objective
response (Weber, 2012). For this reason, responses to KW-0761, a monoclonal antibody
dependent on inducing antibody-dependent, cell mediated cytotoxicity, may be delayed. In
addition, several investigators who have treated advanced CTCL subjects with KW-0761,
have noticed what they consider a “flare” in skin lesions, which may be indicative of early
immune-based damage, but which may mimic progression clinically. Therefore, the protocol
specifies that Investigators may keep subjects on until the next evaluation in cases where the
definition of PD or relapse is met but the clinical impression is questionable (Sections 5.2.1.4
and 5.2.2.3).
Both KW-0761 and vorinostat demonstrate activity in all disease compartments. Given the
ongoing medical need for new therapies in CTCL, the manageable safety profile of KW-0761
and its high degree of demonstrated activity, further development of KW-0761 is warranted.
2 OBJECTIVES
2.1 Primary Objectives
The primary objective of this study will be:

• To compare the progression free survival of KW-0761 versus vorinostat for subjects with
relapsed or refractory CTCL.
2.2 Secondary Objectives
The secondary objectives will be:

• To compare the overall response rate of KW-0761 versus vorinostat in subjects with
relapsed or refractory CTCL;
• To evaluate and compare improvements in QoL measurements, Skindex-29, FACT-G and
EQ-5D-3L for subjects receiving KW-0761 versus vorinostat;
• To evaluate and compare improvements in the Pruritus Evaluation (Likert scale & Itchy
QoL) for subjects receiving KW-0761 versus vorinostat;
• To estimate the duration of response for both the KW-0761 and vorinostat arms for those
subjects with relapsed or refractory CTCL responding to treatment;
• To determine if subjects who relapse on vorinostat can achieve response upon cross over
to treatment with KW-0761;
• To further assess the safety of KW-0761;
• To describe the immunogenicity of KW-0761.
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2.3 Exploratory Objectives
• To compare the overall survival of KW-0761 versus vorinostat for subjects with relapsed
or refractory CTCL;
• To conduct exploratory evaluation of KW-0761 exposure-response relationships.
3 STUDY POPULATION
3.1 Subject Selection
This study will enroll subjects with CTCL who have failed at least one prior course of
systemic therapy. This should be adequately documented in the subject’s medical record.
3.2 Inclusion Criteria
Subject must meet the following criteria for inclusion in this study:
Signed Written Informed Consent
1) Voluntarily signed and dated Institutional Review Board (IRB)/ Ethics Committee
approved informed consent form in accordance with regulatory and institutional
guidelines. Written informed consent must be obtained prior to performing any
study-related procedure;
Age and Sex
2) Males and female subjects ≥ 18 years of age at the Pre-treatment Visit, i.e., at the
time that written informed consent is obtained, except in Japan where subjects must
be ≥ 20 years of age;
Target Population
3) Histologically confirmed diagnosis of MF or SS;
a. For SS (defined as meeting T4 plus B2 criteria), where the biopsy of
erythrodermic skin may only reveal suggestive but not diagnostic
histopathologic features, the diagnosis may be based on either a node biopsy or
fulfillment of B2 criteria including a clone in the blood that matches that of the
skin (Olsen, 2011).
4) Stage IB, II-A, II-B, III and IV (Olsen, 2011) (see Appendix 1);
5) Subjects who have failed at least one prior course of systemic therapy (e.g.,
interferon, denileukin diftitox, bexarotene, photopheresis, anti-neoplastic
chemotherapy, etc.). Psoralen plus ultraviolet light therapy (PUVA) is not
considered to be a systemic therapy;
6) Eastern Cooperative Oncology Group (ECOG) performance status score (Oken,
1982) of ≤ 1 (see Appendix 2).
7) The subject has resolution of all clinically significant toxic effects of prior cancer
therapy to Grade ≤ 1 by the National Cancer Institute Common Terminology
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Criteria for Adverse Events, version 4.0 (NCI-CTCAE, v.4.0) excluding the
specifications required in 8, 9 and 10 below.
8) Adequate hematological function:
a. absolute neutrophil count (ANC) ≥ 1,500 cells/μL (≥ 1,500/mm3);
b. platelets ≥ 100,000 cells/μL (≥ 100,000/mm3);
c. in subjects with known bone marrow involvement, ANC must be
≥ 1,000 cells/μL (≥ 1,000/mm3) and platelets ≥ 75,000 cells/μL (≥ 75,000/mm3).
9) Adequate hepatic function:
a. bilirubin ≤ 1.5 times the specific institutional upper limit of normal (ULN),
except for subjects with Gilbert’s syndrome;
b. aspartate transaminase (AST) and alanine transaminase (ALT) each
≤ 2.5 x ULN or ≤ 5.0 x ULN in the presence of known hepatic involvement by
CTCL.
10) Adequate renal function:
a. serum creatinine ≤ 1.5 x ULN
or
b. calculated creatinine clearance > 50 mL/min using the Cockcroft-Gault formula.
11) Subjects previously treated with anti-CD4 antibody or alemtuzumab are eligible
provided their CD4+ cell counts are ≥ 200/mm3.
12) Subjects with MF and a known history of non-complicated staphylococcus
colonization/infection are eligible provided they continue to receive stable doses of
prophylactic antibiotics.
13) Women of childbearing potential (WOCBP) must have a negative pregnancy test
within 7 days of receiving study medication.
14) WOCBP must agree to use effective contraception, defined as oral contraceptives,
double barrier method (condom plus spermicide or diaphragm plus spermicide) or
practice true abstinence from sexual intercourse (periodic abstinence, e.g., calendar,
ovulation, symptothermal, post-ovulation methods and withdrawal are not
acceptable methods of contraception) during the study and for 3 months after the
last dose. WOCBP includes any female who has experienced menarche and who has
not undergone successful surgical sterilization or is not postmenopausal (defined as
amenorrhea ≥ 12 consecutive months without an alternative medical cause).
15) Male subjects and their female partners of child bearing potential must be willing to
use an appropriate method of contraception defined as oral contraceptives, double
barrier method (condom plus spermicide or diaphragm plus spermicide) or practice
true abstinence from sexual intercourse (periodic abstinence, e.g., calendar,
ovulation, symptothermal, post-ovulation methods and withdrawal are not
acceptable methods of contraception) during the study and for 3 months after the
last dose.
NOTE: For subjects continuing to receive study treatment as of protocol Amendment 8, the
period of contraceptive use should be extended to 6 months after the last dose of KW-0761.
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3.3 Exclusion Criteria

Subjects with any of the following will be excluded from the study:
Medical History and Concurrent Diseases
1) Current evidence of large cell transformation (LCT). Subjects with clinical features
suggestive of LCT must have a biopsy performed within 4 months prior to Cycle 1
Day 1 to rule out transformed disease. Subjects with a history of LCT but without
current aggressive disease and no current evidence of LCT on pathology in skin or
lymph nodes would be eligible.
2) Diagnosed with a malignancy in the past 2 years. However, subjects with non-
melanoma skin cancers, melanoma in situ, localized cancer of the prostate with
current prostate-specific antigen of < 0.1 ng/mL, treated thyroid cancer or cervical
carcinoma in situ or ductal/lobular carcinoma in situ of the breast with in the past
2 years may enroll as long as there is no current evidence of disease.
3) Clinical evidence of central nervous system (CNS) metastasis.
4) Psychiatric illness, disability or social situation that would compromise the subject’s
safety or ability to provide consent, or limit compliance with study requirements.
5) Significant uncontrolled intercurrent illness including, but not limited to:
a. uncontrolled infection requiring antibiotics;
b. clinically significant cardiac disease (class III or IV of the New York Heart
Association [NYHA] classification, see Appendix 3);
c. unstable angina pectoris;
d. angioplasty, stenting, or myocardial infarction within 6 months;
e. uncontrolled hypertension (systolic blood pressure (BP) > 160 mm Hg or diastolic
BP > 100 mm Hg, found on 2 consecutive measurements separated by a 1-week
period) despite 2 anti-hypertensive medications;
f. clinically significant cardiac arrhythmia or
g. uncontrolled diabetes.
6) Known or tests positive for human immunodeficiency virus (HIV), human T-cell
lymphotropic virus (HTLV-1), hepatitis B or hepatitis C disease.
7) Active herpes simplex or herpes zoster. Subjects on prophylaxis for herpes who
started taking medication at least 30 days prior to the Pre-treatment Visit, and have no
active signs of active infection, and whose last active infection was more than
6 months ago, may enter the study, and should continue to take the prescribed
medication for the duration of the study.
8) Experienced allergic reactions to monoclonal antibodies or other therapeutic proteins.
9) Known active autoimmune disease will be excluded. (For example, Graves’ disease;
systemic lupus erythematosus; rheumatoid arthritis; Crohn’s disease; psoriasis).
10) Is pregnant (confirmed by beta human chorionic gonadotrophin [β-HCG]) or
lactating.
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Prohibited Therapies and/or Medications

11) Prior treatment with KW-0761.
12) Prior treatment with vorinostat. Patients who were exposed to vorinostat for a short
time, did not progress while on treatment, and did not have intolerable toxicity but
were discontinued for another reason (e.g., comorbidity) may be permitted to enter the
study after discussion with the Medical Monitor.
13) Have had any therapy directed against the subject’s underlying cancer or any
investigational medications within four weeks of randomization (skin directed
treatments, including topicals and radiation within 2 weeks of randomization).
However, subjects with rapidly progressive malignant disease may be enrolled prior
to this period after discussion with the Medical Monitor.
14) Subjects on a stable dose of a low dose systemic corticosteroid (≤ 20 mg prednisone
equivalent) for at least 4 weeks prior to the Pre-treatment Visit may continue use
although the investigator should attempt to taper the use to the lowest dosage tolerable
while on study. Initiation of treatment with systemic corticosteroids or increase in
dose while on study is not permitted except to treat an infusion reaction (see Section
5.2.1.7). Subjects may receive intra-articular corticosteroid injections, intraocular
corticosteroid drops, inhalation or nasal corticosteroids and replacement doses of
systemic corticosteroids as needed.
15) Subjects on a stable dose of medium or low potency topical corticosteroids for at least
4 weeks prior to the Pre-treatment Visit may continue use at the same dose, although
the investigator should attempt to taper the use to the lowest dosage tolerable while on
study. Initiation of treatment with topical corticosteroids while on study is not
permitted except to treat an acute rash.
16) History of allogeneic transplant.
17) Autologous hematopoietic stem cell transplant within 90 days of the Pre-treatment
Visit.
18) Subjects on any immunomodulatory drug for concomitant or intercurrent conditions
other than T-cell lymphoma or who have received any of these agents within 4 weeks
of treatment, including but not limited to the following, will be excluded: low dose or
oral methotrexate; azathioprine; iv immunoglobulin; low dose or oral
cyclophosphamide; cyclosporine; mycophenolate; infliximab; etanercept;
leflunomide; adalimumab; lenalidomide; abatacept; rituximab; anakinra; interferon-β;
IL-2 and natalizumab.
3.4 Eligibility for Cross-over to KW-0761
Subjects who are randomized to the vorinostat arm may cross over to KW-0761 upon
progression or in the event of intolerable toxicity (see Section 5.3). Crossover may take place
following discussion with the Medical Monitor or designee and receipt of approval for cross
over from Kyowa Kirin Pharmaceutical Development, Inc. (KKD). However, they must
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continue to fulfill inclusion criteria 6 through 15, and will be excluded if they fulfill the
exclusion criteria, except for exclusion criteria 1, 12 and 13 (refer to Section 3.3).
4 INVESTIGATIONAL PLAN
4.1 Overview of Study Design
This is an open-label, multi-center randomized, Phase 3 study with 1:1 randomization of

study drug, KW-0761 versus the comparator, vorinostat.
4.2 Number of Subjects
Approximately 317 subjects may enroll in this study over a period of 24 months. The primary
analysis will be conducted when 255 total progression-free survival (PFS) events have been
observed or 24 months after the last randomized subject’s first dose, whichever comes first.
4.3 Investigational Centers
It is anticipated that approximately 75 investigational centers in the US, Europe, Japan and
Australia will participate in this study.
5 TREATMENT PLAN
5.1 Assignment to Study
After a subject signs consent, screening numbers should be assigned by the investigator (or
designee) using ClinTrak Interactive Voice/Web Response System (CTIVRS). Once
assigned, numbers for any screen failures or non-treated, non-evaluable, or discontinued
subjects will not be re-used.
A subject who meets all entry criteria will be randomized in a 1:1 ratio to receive KW-0761
or vorinostat. The randomization to treatment groups will be stratified by disease type (MF or
SS) and disease stage (IB/II or III/IV). When a subject is determined to be eligible for
randomization the investigator (or designee) will contact CTIVRS to obtain the
randomization assignment for the subject. If a subject is randomized in error, or a dosing
error occurs, KKD (or designee) should be notified as soon as the error is discovered.
5.2 Study Treatments
In this protocol, study treatments are KW-0761 and vorinostat. Subjects will be randomized
to the study drug, KW-0761 or comparator, vorinostat, in a 1:1 ratio.
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5.2.1 Study Drug: KW-0761 (mogamulizumab)
Treatment can be administered on an outpatient basis. Subjects will receive 1.0 mg/kg of
KW-0761 as an iv infusion over at least 1 hour on Days 1, 8, 15, and 22 of the first cycle and
on Days 1 and 15 of subsequent cycles. No other investigational or commercial agents or
therapies other than the study treatment and those described in Section 5.4.1 may be
administered with the intent to treat the subject’s malignancy.
5.2.1.1 Premedication Prior to KW-0761 Infusion

It is recommended that subjects be premedicated with acetaminophen or paracetamol orally
and diphenhydramine 50 mg iv (or equivalent anti-histamine) before the first KW-0761
infusion. For subjects who experience an infusion related reaction, premedication is
recommended prior to every subsequent infusion.
5.2.1.2 Definition of Treatment Cycle

Each treatment cycle is 28 days.
5.2.1.3 Delays in Dosing

During the first treatment cycle, KW-0761 should be administered beginning on Day 1 and
within ± 2 days of the other scheduled visits (i.e., Days 8, 15 and 22 during Cycle 1; Day 15
during subsequent cycles). If the study visit does not occur within this visit window,
KW-0761 should not be administered at the visit and the next dose should be administered at
the next timepoint.
A subject’s next cycle should begin within 2 weeks of the completion of the prior cycle. The
start of a new cycle may be delayed to allow resolution of treatment-related toxicities or for
non-medical reasons (holidays, vacations, etc.). Delay of the start of a new cycle greater than
2 weeks must be discussed with the Medical Monitor or designee.
5.2.1.4 Duration of Treatment

Subjects may remain in the treatment phase up until PD, drug intolerance or unacceptable
toxicity, or until any of the other criteria for study removal are met, as defined in Section 5.5.
Except in cases of unacceptable toxicity or drug intolerance, every effort should be made to
ensure the subject remains in the study until disease progression (See Section 7.2.4, regarding
definition of disease progression).
At each cycle, the investigator must minimally have reviewed the modified Severity
Weighted Assessment Tool (mSWAT) to determine if progression of skin disease has
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occurred prior to subsequent dosing. Ideally, results of flow cytometry and CT assessment, as
applicable, should be reviewed at this visit as well. However, it is understood that these
results may not be reported for several days and may not be available. Once those results are
obtained evidence of progression in all compartments should be determined.
In cases where the definition of PD or relapse is met but the clinical impression is
questionable, subjects may remain on study until the next evaluation (4 weeks later if
questionable finding in skin or blood; 8 weeks later in first year and 16 weeks later after
Year 1 if questionable finding in lymph nodes or viscera, with at least stable disease in other
compartments) to avoid a subject being removed prematurely from the study. If PD is
confirmed at this subsequent evaluation, subject should be discontinued from treatment. If PD
is not confirmed at this subsequent evaluation, the subject may remain on study.
This course of action only applies to cases where the clinical impression is questionable;
subjects in frank or obvious PD in any compartment should be discontinued from protocol
therapy.
If clinical progression is noted at any time prior to the scheduled assessments for efficacy, the
assessments (computed tomography [CT], mSWAT, skin photographs and flow cytometry)
should be done at that time to fully document disease progression. CT must be performed
even if previously negative at baseline.
If the subject experiences an overall CR, the subject may continue treatment for up to
12 months or until progression, whichever comes first.
For subjects who are continuing to receive study treatment at the time of the primary efficacy
analysis, procedures and assessments are described in Section 7.7.
5.2.1.5 Replacement of Subjects

5.2.1.6 Dose Modifications

No dose modifications of the KW-0761 will be permitted in this study.
5.2.1.7 Treatment of Hypersensitivity-Like Reactions

It may be difficult to differentiate an infusion reaction from a true hypersensitivity (i.e.,
allergic) reaction. If a reaction occurs during infusion of KW-0761, investigators may use the
following guidelines to best treat the subject’s symptoms:
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Grade 1/2:
• Stop the infusion for 15–30 minutes;
• Acetaminophen or paracetamol orally and diphenhydramine 50 mg iv or equivalent
anti-histamine may be administered;
• If symptoms abate, re-start the infusion at one-half the previous rate;
• If symptoms do not abate after 30 minutes, discontinue that day’s treatment. Additional
medical measures, such as administration of corticosteroids (see below) may be
considered for reactions that do not abate after 30 minutes.
Grade 3
• Stop the infusion for 15–30 minutes;
• Consider administering the following:
– Acetaminophen or paracetamol orally;
– Diphenhydramine 50 mg iv or an equivalent anti-histamine;
– Dexamethasone 20 mg iv or an equivalent corticosteroid;
– Albuterol or salbutamol inhaler 2 puffs p.r.n. for bronchospasm or an equivalent
bronchodilator;
– O2 by nasal cannula.
• Additional agents may be administered per institutional guidelines for the treatment of
infusion reactions;
• If symptoms abate, re-start the infusion at one-half the previous rate;
• If symptoms do not abate after 30 minutes, discontinue the subject from the study.
Grade 4
• Administration of the agents specified for a Grade 3 infusion reaction above should be
considered.
• Any subject who experiences a Grade 4 infusion reaction is to be discontinued from the
study.
If a reaction with severity of Grade 2 or higher occurs upon re-challenge with KW-0761, or if
in the opinion of the investigator the reaction represents a true hypersensitivity (i.e., allergic)
reaction of Grade 2 or higher, KW-0761 should be stopped and not restarted and the subject
should be discontinued from the study.
If an infusion reaction occurs, a serum sample should be obtained and sent to the designated
central laboratory for analysis of anti-KW-0761 antibodies.
If an infusion reaction occurs, the duration of administration of KW-0761 should be increased
to 2 hours for the next 2 infusions. Subsequent infusion duration may be 1 to 2 hours, as
tolerated.
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For infusion reactions occurring after completion of the infusion, administration of the agents
specified for a Grade 3 infusion reaction above should be considered, along with any other
medical intervention stipulated in institutional guidelines for the treatment of infusion
reactions.
Any subject who experiences an infusion reaction requiring the administration of systemic
vasopressors or that results in hospitalization (directly due to infusion reaction symptoms) of
the subject is to be removed from the study.
5.2.1.8 Treatment Emergent Skin Rash

In the event a subject develops a treatment emergent skin rash, the following measures must
be taken to appropriately document the event:
Initial Work-up of All Skin Rashes (new and re-challenge)
1) Notify KKD of the skin rash.
2) Photograph the rash.
3) If the rash is ≥ Grade 2 or if the affected area cannot be differentiated from a new area
of lymphoma, a biopsy must be performed. Biopsy the rash as well as an area of skin
unaffected by the rash in order to compare possible drug eruption to background
lymphoma involved skin. If the rash is Grade 1 and topical steroids are to be applied,
the rash must be biopsied prior to steroid treatment.
4) Confer with Medical Monitor or designee after completion of one week of treatment
with topical corticosteroids to assess response to treatment.
5) Forward all results to Medical Monitor and discuss with Medical Monitor or designee
a treatment plan and medical follow up.
6) Biopsy should be read by the dermatopathologist at the study center. Additional
sample should be sent to the laboratory designated by the Sponsor for central review
as well. Specific instructions for sample preparation and handling for central
laboratory will be provided in the Laboratory Manual.
7) If biopsy indicates that rash is a drug eruption record appropriately as AE/SAE. If
biopsy indicates that rash is lymphoma, do not record as an AE.
Rash Treatment Guidelines (after initial work-up):
Grade 1 Rash (drug related or non-drug related)
1) Treatment with KW-0761 may continue.
2) Treat rash with topical corticosteroids as needed.
Grade 2 or above Rash (drug related)
1) Treatment with KW-0761 must be stopped.
2) Treat rash with 2-week course of topical corticosteroids.
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3) After 2-week course, re-assess rash per the steps outlined in initial assessment; if
resolved completely or to Grade 1, KW-0761 treatment may be resumed. If not
resolved, contact the Medical Monitor for further discussion.
Grade 2 or above rash on Re-challenge
1) If rash recurs and becomes a Grade 3, the subject must be discontinued from the trial
and the rash work up above must be completed.
2) If the rash recurs at a Grade 2, follow the steps above for Grade 2 Rash.
3) If the rash recurs at Grade 2 or higher for a third time, the rash work up must be
performed and the subject must be discontinued from the trial.
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Table 5.2.1-1 Guidelines for Treatment of Skin Rash

Medical
Monitor
or
Rash designee Treatment Study
Grade Photographs Biopsy Consult Regimen KW-0761 Participation
Initial Drug Rash
1 Yes Required if Yes Topical Continue Continue
topical corticosteroids
steroids will as needed
be used
2 Yes Yes Yes 2-week Temporarily If rash does not
topical steroid Stop; re-start resolve to ≤ Grade
if ≤ Grade1 1 within 2 weeks
within 2 consult with
weeks medical monitor
3 Yes Yes Yes 2-week Temporarily If rash does not
topical steroid Stop: re-start resolve to
if ≤ Grade 1 ≤ Grade 1 within
within 2 2 weeks consult
weeks with medical
monitor
Subsequent Drug Rash/Rechallenge
1 Yes Yes Yes Topical Continue Continue
corticosteroids
as needed
2 Yes Yes Yes 2-week Temporarily D/C if rash does
topical steroid Stop: re-start not resolve to
if ≤ Grade 1 ≤ Grade 1 within
within 2 2 weeks
weeks
3 Yes Yes Yes 2-week Discontinue Discontinue
topical steroid
Subjects who require systemic steroid therapy to treat a severe skin rash should be
discontinued from the study.
5.2.2 Study Drug: Vorinostat (ZOLINZA®)
Treatment can be administered on an outpatient basis. Subjects will take 400 mg orally once
daily with food.
Vorinostat is approved for marketing in the US, Japan and Australia and is indicated for the
treatment of progressive, persistent or recurrent CTCL. Investigators will administer
according to the currently approved US prescribing information (e.g. dosage and
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administration, warnings, precautions, adverse reactions, dose modifications and omissions

and storage information). No other investigational or commercial agents or therapies other
than the study treatments and those described in Section 5.4.1 may be administered with the
intent to treat the subject’s malignancy.
5.2.2.1 Definition of Treatment Cycle

Each treatment cycle is 28 days.
5.2.2.2 Delays in Dosing

Refer to Section 5.2.2.5.
5.2.2.3 Duration of Treatment

Subjects may remain in the treatment phase up until PD, drug intolerance or unacceptable
toxicity, or until any of the other criteria for study removal are met, as defined in Section 5.5.
Except in cases of unacceptable toxicity or drug intolerance, every effort should be made to
ensure the subject remains in the study until disease progression (See Section 7.2.4, regarding
definition of disease progression).
At each cycle, the investigator must minimally have reviewed the mSWAT to determine if
progression of skin disease has occurred prior to subsequent dosing. Ideally, results of flow
cytometry and CT assessment, as applicable, should be reviewed at this visit as well.
However, it is understood that these results may not be reported for several days and may not
be available. Once those results are obtained evidence of progression in all compartments
should be determined.
In cases where the definition of PD or relapse is met but the clinical impression is
questionable, subjects may remain on study until the next evaluation (4 weeks later if
questionable finding in skin or blood; 8 weeks later in first year and 16 weeks later after
Year 1 if questionable finding in lymph nodes or viscera, with at least stable disease in other
compartments) to avoid a subject being removed prematurely from the study. If PD is
confirmed at this subsequent evaluation, subject should be discontinued from treatment. If PD
is not confirmed at this subsequent evaluation, the subject may remain on study.
This course of action only applies to cases where the clinical impression is questionable;
subjects in frank or obvious PD in any compartment should be discontinued from protocol
therapy.
assessments (CT, mSWAT, skin photographs and flow cytometry) should be done at that
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time to fully document disease progression. CT must be performed even if previously

negative at baseline.
If the subject experiences an overall CR, the subject may continue treatment for up to
12 months or until progression, whichever comes first.
5.2.2.4 Replacement of Subjects

5.2.2.5 Dose Modifications

Management of severe or intolerable adverse reactions may require dose omission, reduction
or interruption of vorinostat therapy. Refer to US prescribing information for complete
recommendations regarding dose modifications.
5.3 Cross-over to Study Drug KW-0761
Subjects who have received 2 full treatment cycles and demonstrate progression of disease on
treatment with vorinostat at the 8 week (Cycle 2, Day 26-28) assessment, or anytime
thereafter, may cross over to treatment with KW-0761 after discussion with Medical Monitor
or designee and receipt of approval for cross over from KKD. Investigators should strive to
maintain subjects on treatment for at least the 8 week period, adjusting the dose of vorinostat
as needed for toxicities in order to allow sufficient time to see effect. In cases where a
subject’s disease progresses rapidly (i.e., prior to 8 weeks), the Medical Monitor or designee
should be contacted and may consider the possibility of early crossover, if appropriate for
that subject. All subjects must undergo the full extent of disease evaluations (including CT
scanning) to document PD prior to crossover.
There must be at least 2 weeks between the last dose of vorinostat and first dose of KW-0761.
Subject must continue to meet eligibility criteria outlined in Section 3.4 and all toxicity must
have resolved to Grade ≤ 1 or to baseline in order to receive KW-0761. Treatment with
KW-0761 should commence with procedures outlined for Day 1 in Table 1 of Study
Procedures for the first treatment cycle. In cases where a subject’s disease progresses rapidly,
the Medical Monitor or designee should be contacted and may consider initiation of treatment
with KW-0761 prior to the 2-week washout period.
For subjects who are unable to tolerate the toxicities associated with vorinostat treatment,
dose reduction should be initiated in an attempt to have the subject complete 2 full cycles of
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treatment. If the subject is unable to tolerate treatment with vorinostat despite attempts at
dose reduction and has not had documented disease progression, the subject may receive
KW-0761 after consultation with the Medical Monitor or designee and subsequent approval
documentation from the Sponsor.
Drug intolerance is defined as:
• A serious AE attributed to the drug;
• ≥ Grade 3 AEs excluding inadequately treated nausea, vomiting and diarrhea and
alopecia.
5.4 Concomitant Therapy
Subjects should receive appropriate medical care for all intercurrent medical conditions
consistent with community standards of medical care. Subjects are to receive vigorous
supportive care for study medication-related toxicities and appropriate palliation for tumor
symptoms, such as pain and anorexia.
All concomitant treatments whether for treatment of concurrent medical conditions, toxicity,
management of pain, infections or other complications of the malignancy, must be recorded
on the relevant electronic case report form (eCRF) page along with the reason for use.
Medication taken within 30 days prior to the first dose of study drug, and at any time after the
start of treatment until 30 days after the final study drug administration will be recorded. A
medication taken during follow-up will also be recorded if it is used to treat an AE or is
temporally associated with an AE and may have a causal relationship.
While on study treatment, subjects are not permitted to receive any experimental therapy or
anticancer therapy other than the study medication. Any subject requiring other anticancer
therapy is to be removed from study treatment.
5.4.1 Permitted Treatment
• Hematopoietic growth factors and erythropoiesis-stimulating agents (based on threshold

and target hemoglobin levels in the American Society of Hematology (ASH)/American
Society of Clinical Oncology (ASCO) guidelines) (Rizzo, 2010) are allowed, if consistent
with regional approved prescribing information, after completing Cycle 1.
• Subjects on a stable dose of a low dose systemic corticosteroid (≤ 20 mg prednisone
equivalent) for at least 4 weeks prior to the Pre-treatment Visit may continue use.
Subjects may receive intra-articular corticosteroid injections, intraocular corticosteroids
drops, inhalation or nasal corticosteroids and replacement doses of systemic
corticosteroids as needed.
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• Subjects on a stable dose of medium or low potency topical corticosteroids for at least
4 weeks prior to the Pre-treatment Visit may continue use at the same dose, although the
investigator should attempt to taper the use to the lowest dosage tolerable while on study.
• Prophylactic treatment for the infectious complications of T-cell lymphoma is permitted
at the discretion of the investigator.
• For subjects receiving vorinostat, prolongation of prothrombin time (PT) and
International Normalized Ratio (INR) have been observed in subject receiving
concomitant therapy with coumarin-derivative anticoagulants, carefully monitor PT and
INR in these subjects.
• Influenza vaccination consisting of killed virus or viral particles may be administered to
subjects on study. Subjects should not receive an influenza vaccine containing live
attenuated virus. It should also be understood that because KW-0761, as well as CTCL,
can affect the immune system, immunity to influenza may not be achieved despite
vaccination.
5.4.2 Prohibited Treatment
• Initiation of treatment with systemic steroids or increase in dose while on study is not
permitted except to treat an infusion reaction (see Section 5.2.1.7). Subjects who require
systemic steroid therapy to treat a severe skin rash should be discontinued from the study
(see Section 5.2.1.8).
• Initiation of treatment with topical corticosteroids while on study is not permitted except
to treat an acute rash.
• Any experimental therapy or anticancer therapy including radiation and phototherapy
other than the study medications.
• Any live or live attenuated vaccine.
• Alternative medicines, particularly use of St. John’s Wort.
• Immunomodulatory agents such as methotrexate; azathioprine; iv immunoglobulin;
cyclophosphamide; cyclosporine; mycophenolate; infliximab; etanercept; leflunomide;
adalimumab; lenalidomide; abatacept; rituximab; anakinra; interferon-α; interferon-β;
IL-2 and natalizumab.
• Other concurrent HDAC inhibitors including valproic acid.
• Whenever possible, concomitant use of drugs which may cause a prolongation of the QTc
interval should be avoided. If such a drug is necessary (e.g., anti-emetics), monitor the
QTc interval closely.
5.5 Criteria for Removal from Study
In the absence of a medical contraindication or significant protocol violation, every effort will
be made by the Principal Investigator to keep the subject in the study. However, should the
subject decide to discontinue treatment, all efforts will be made to complete and report the
observations as thoroughly as possible, including a complete final evaluation at the time of
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the subject’s withdrawal with an explanation of why the subject is withdrawing from the
study.
Study treatment will be stopped if any of the following events occur:
• Disease progression (as defined in Section 7.2.4);
• An infusion-related reaction (see Section 5.2.1.7);
– with a severity of ≥ Grade 2 upon re-challenge with KW-0761,
– with a severity of Grade 3 with symptoms that do not abate after 30 minutes,
– with a severity of Grade 4,
– requiring the administration of systemic vasopressors,
– that results in hospitalization (directly due to infusion reaction symptoms),
• Initiation of treatment with systemic corticosteroids, except when initiated to treat an
infusion reaction (see Section 5.2.1.7);
• A true hypersensitivity (i.e., allergic) reaction to KW-0761 with a severity of ≥ Grade 2;
• A rash which recurs and becomes Grade 3 on re-challenge (see Section 5.2.1.8);
• A rash which recurs at Grade 2 or higher for a third time on re-challenge (see Section
5.2.1.8);
• A rash which requires systemic steroid therapy (see Section 5.2.1.8);
• The subject has any clinical AE, laboratory abnormality, intercurrent illness, or other
medical condition that indicates to the Investigator that continued participation is not in
the best interest of the subject. The Investigator should make a distinction between AEs
that may require only interruption of study medication and those that require
discontinuation;
• The subject wishes to withdraw consent from the study in the absence of a medical need
to withdraw as determined by the Investigator;
• The Investigator concludes that it is in the best interest of the subject to discontinue study
treatment including subjects who have not benefited from treatment;
• Subject is willingly or inadvertently noncompliant in the opinion of the Investigator;
• Administrative reasons determined by the Sponsor; or
• If pregnancy is suspected while the subject is receiving study treatment, the study
medication must immediately be withheld until the result of pregnancy testing is known.
If pregnancy is confirmed, the study medication will be permanently discontinued and the
subject withdrawn from treatment.
In the case of pregnancy that occurs while the subject is receiving study medication through
6 months after the last dose of study medication, the Investigator must immediately notify the
Sponsor of this event and record the pregnancy on the Pregnancy Surveillance Form. The
Sponsor must also be notified if a partner of a study subject becomes pregnant while the
subject was receiving study medication through 6 months after the last dose of study
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medication. Reasonable attempts will be made to follow the pregnancy to conclusion in order
to obtain information regarding the outcome.
The Investigator must complete all applicable End-of-treatment visit procedures (i.e., safety
laboratory parameters, electrocardiogram (ECG), physical examination, vital signs) and
eCRF pages for subjects who discontinue treatment, and include the reason for
discontinuation of treatment.
6 STUDY PROCEDURES
The key study procedures and the frequency of their occurrences are outlined in the Study
Procedures Tables (Table 1, Table 2, and Table 3). Labs, ECG, and physical exams on day of
treatment should be obtained prior to study treatment.
7 STUDY MEASUREMENTS
Screening evaluations used to determine the subject’s study eligibility must be completed
within 30 days prior to starting treatment unless otherwise specified.
Written informed consent must be obtained prior to any study-specific procedures.
Results of all screening evaluations must be reviewed by the Investigator or his/her designee
to ensure that all eligibility criteria have been satisfied prior to registering the subject with the
Sponsor. All pathology reports relevant to confirmation of the diagnosis of CTCL (mycosis
fungoides or Sezary syndrome) for all enrolled subjects should be de-identified and provided
to the Sponsor. For subjects with SS, this would include results confirming fulfillment of B2
criteria including a clone in the blood that matches that of the skin per Section 3.2.
An End-of-treatment visit must be conducted for all subjects who discontinue from study
treatment. This visit must occur within 30 days after the last dose of study medication. All
End-of-treatment assessments must be conducted prior to the initiation of new therapy.
7.1 Safety Evaluations
The safety of KW-0761 and vorinostat will be determined by reported AEs, changes in
physical examinations, vital sign measurements, ECGs and laboratory analyses. Safety
evaluations will be performed throughout the study. All subjects who received at least one
dose, including a partial dose, of study drug will be evaluated for safety. The NCI-CTCAE
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v4.0 system will be used to grade AEs, both clinical and laboratory. AEs will be grouped and
tabulated by Medical Dictionary for Regulatory Activities (MedDRA) preferred terms by
system organ class. All subjects will be assessed regularly for potential occurrence of AEs
from the time of signing the informed consent until 90 days after the last dose or initiation of
alternative therapy whichever comes first. In all subjects who cross over from vorinostat to
KW-0761, the causality of any reported AEs should be assessed for both drugs for 30 days
after vorinostat was stopped (or later if the event is considered to be related to vorinostat).
7.1.1 Clinical Laboratory Evaluations
Clinical laboratory assessments will be performed at the visits specified in the Study
Procedures. A pregnancy test (serum or urine) is to be performed for all women of
childbearing potential prior to administration of study medication.
Any clinically important abnormal laboratory values noted at the screening visit will be
recorded as medical history. In addition, in order for KKD to collect additional information
about clinically important laboratory abnormalities, at minimum, the following laboratory
abnormalities should be captured on the non-serious or serious AE pages of the eCRF as
appropriate:
• Any laboratory test result that meets the criteria for a SAE;
• Any laboratory abnormality that requires the subject to have study medication
discontinued or interrupted;
• Any laboratory abnormality that requires the subject to receive specific corrective
therapy.
All clinically important abnormal laboratory tests occurring during the study will be repeated
at appropriate intervals until (1) the value returns to baseline, (2) the value is judged to be
clinically acceptable by the Investigator and the Sponsor, or (3) a diagnosis that explains the
abnormal laboratory value is made. When possible, the Investigator should report the clinical
rather than the laboratory term (e.g., anemia versus low hemoglobin).
Clinical laboratory assessments will include the following:
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Table 7.1.1-1 Clinical Laboratory Assessments

Serum Chemistry Sodium Albumin Calcium
Potassium SGPT (ALT) Phosphorus
Glucose SGOT (AST) Chloride
Blood urea nitrogen Alkaline phosphatase Bicarbonate (serum or blood)
(BUN)
Creatinine Total bilirubin Uric acid
Total protein Lactate dehydrogenase Magnesium
(LDH)
Thyroid function T4 (free) TSH
Coagulation Panel International normalized ratio (INR) Partial thromboplastin time
(PTT) or
Activated Partial
thromboplastin time (aPTT)
Hematology Complete blood count Platelet count
(CBC) and
differential
Absolute neutrophil
count
T-cell counts Absolute CD4 count Absolute CD8 count
CD4 and CD8 counts will be reported based on the flow cytometric sample sent to
Quest while the subject is on study. On site counts need only be obtained at End-of-
treatment visit with appropriate follow up if less than 200/mm3.
Urinalysis routine urinalysis or dipstick measurements and, if clinically indicated, microscopic
analysis. Parameters should include:
Color WBC
Specific Gravity RBC or hemoglobin
pH Protein
Glucose Ketones
Pregnancy Test A serum or urine pregnancy test will be performed for all women of childbearing
potential at screening.
Virus Testing hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), hepatitis
C antibodies (HC Ab)
HIV
HTLV-1
7.1.2 Vital Signs and Body Weight
Vital signs (pulse, respiration rate, temperature, and blood pressure) will be measured, with
the subject in the seated position, at the visits specified in the Study Procedures (Table 1,
Table 2, and Table 3). Additional vital signs will be obtained if clinically significant signs or
symptoms occur.
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Weight will be included in vital sign assessments. The subject’s height will be measured at
the Pre-Treatment visit.
7.1.3 Physical Examination
The Investigator will perform a full physical examination at the Pre-treatment (including
height at only this visit) and End-of-treatment visits and brief physical examinations at other
visits specified in the Study Procedures (Table 1, Table 2, and Table 3). The full physical
examination requires assessment of the following categories: head, eyes, ears, nose, and
throat (HEENT), heart, lungs, abdomen, skin, musculoskeletal, extremities, neurological,
lymph nodes and ‘other.’ Brief physical examination consists of examination of pertinent
systems, i.e., those in which abnormalities were noted previously as well as those likely to be
affected during the course of therapy and those suggested by reported adverse experiences.
Attention should be paid to those body systems referable to possible autoimmune disorders,
such as the joints, the eyes, the GI tract as well as signs and symptoms of hypothyroidism. To
assist in this surveillance, a list of directed questions and suggested actions is provided in
Appendix 4.
ECOG Performance Status (PS) will be assessed at each exam according to the ECOG PS
criteria (Appendix 2).
7.1.4 Electrocardiograms
A baseline 12-lead ECG is to be obtained at the Pre-treatment Visit. Follow up ECGs should
be performed during the study if clinically indicated and then at the End of Treatment visit.
The Investigator will have the responsibility for evaluating the ECG interpretation in
relationship to clinical signs and symptoms and for reaching a medical decision regarding the
subject’s medical status. If not within normal limits, the ECG findings should be marked
“clinically significant” or “not clinically significant” (i.e., “CS” or “NCS”) and the ECG
should be initialed and dated by the Investigator.
7.1.5 Blood Sample for Determination of Natural Ligands
Blood samples will be drawn to measure the concentration of natural ligands such as
CCL17/TARC and CCL22/MDC at the visits specified in the Study Procedures. Analysis of
samples will be performed by a central laboratory designated by the Sponsor. Instructions for
preparation and shipment of samples will be provided in the Laboratory Manual.
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7.1.6 Genomic Sampling (For subjects receiving KW-0761 as first assigned

therapy only)
A saliva sample will be collected to obtain baseline germline DNA sample to assess
Fc-gamma receptor polymorphisms. Exploratory analysis of the effect of this genetic
determinant on safety parameters may be performed.
Analysis will be performed by a central laboratory designated by the Sponsor. Instructions for
7.1.7 Immunogenicity (For subjects receiving KW-0761)
Serum samples will be drawn for the determination of anti-KW-0761 antibodies and
concentration of KW-0761 at the visits specified in the Study Procedures. Analysis of
samples will be performed by a central laboratory designated by the Sponsor. Instructions for
7.2 Efficacy Evaluations
Response in skin and blood will be evaluated every 4 weeks during treatment. In the first year
of treatment, response in lymph nodes and viscera will be documented at 4 weeks after the
start of study treatment (end of Cycle 1) and every 8 weeks thereafter. After the first year,
response in the lymph nodes and viscera will be documented every 16 weeks. In the first year
of treatment, the global composite response (including skin, blood, lymph nodes and viscera)
will be assessed at 4 weeks (end of Cycle 1) and every 8 weeks thereafter (Cycle 3, 5, etc.);
after the first year, global composite response will be assessed every 16 weeks (Cycle 17, 21,
etc.).
For those subjects who cross over from the vorinostat arm to KW-0761 treatment, response
within the second arm of the study will be measured from the first day of dosing with
KW-0761. Baseline measurements for this arm are considered to be those taken at the last
assessment which documented progression on vorinostat or if repeated, assessment
completed closest to and before the first KW-0761 infusion (i.e., mSWAT done on Cycle 1,
Day 1 is the new baseline).
Prior to starting study treatment, visual inspection of the skin with photographs and
measurements (mSWAT), assessment of CT images and hematological examinations will be
done to document extent of disease. Skin disease will be evaluated using a modification of
the SWAT (Olsen, 2007; Stevens, 2002). Response for skin will be based on mSWAT scores.
In addition, pruritus will be evaluated using a Likert scale and Itchy QoL. Lymph nodes and
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visceral disease will be evaluated by CT. The response in blood will be assessed by flow
cytometry.
The response in all compartments (skin, blood, lymph nodes and viscera, as applicable) and
overall response will be assessed, except as otherwise noted, in accordance with the response
criteria determined by consensus of the International Society of Cutaneous Lymphomas
(ISCL), the United States Cutaneous Lymphoma Consortium (USCLC) and the Cutaneous
Lymphoma Task Force of the European Organization for Research and Treatment of Cancer
(EORTC) (Olsen, 2011).
assessments (CT, mSWAT, skin photographs and flow cytometry) should be done at that
time to fully document disease progression. CT must be performed even if previously
negative at baseline.
7.2.1 Evaluation of Skin Disease
7.2.1.1 Skin Biopsy

7.2.1.1.1 CCR4 Expression
A skin biopsy will be taken at baseline for determination of CCR4 expression by IHC. In the
event it is not possible to obtain a skin biopsy, use of an archived sample (taken within
6 months prior to treatment) may be allowed with prior authorization from the Sponsor. To
determine if vorinostat alters CCR4 expression, investigators are strongly encouraged to
obtain an additional skin biopsy for the determination of CCR4 expression, prior to treatment
with KW-0761, in subjects who cross over from treatment with vorinostat.
Tissue is typically expected to have been prepared for standard histopathological examination
following formalin or other fixation and embedding in paraffin. The paraffin block is to be
submitted to a Central Laboratory designated by the Sponsor. If the study site is unable to
process the tissue, a fresh sample may be sent to the Central Laboratory on the day obtained.
Submission of unstained slides, while not recommended due to stability concerns with the
sample, will be accepted. Specific instructions for sample preparation and handling will be
provided in the Laboratory Manual.
With the consent of the subject, the remainder of the skin or lymph node biopsy specimens,
i.e., the tissue that is left over after the study-specific tests are conducted, will be archived
and the remainders of the specimens will be used in the development of an
immunohistochemical assay for the semi-quantitative detection of CCR4. All specimens
submitted for the purpose of the development of this assay should be managed by the
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investigator and his/her staff with adequate precautions to ensure subject confidentiality, in
accordance with applicable national and/or local laws and regulations on personal data
protection.
7.2.1.1.2 Disease Status/Other Biopsy Recommendations

Subjects with clinical features suggestive of LCT must have a biopsy performed within
4 months prior to Cycle 1 Day 1 to rule out transformed disease.
Skin biopsies at the end of the cycle and to confirm a CR are optional and can be performed
at the discretion of the investigator. Analysis of these biopsies will be done by the pathologist
at the study site.
Additional translational assessments may be performed to further characterize the response in
skin on any biopsy samples obtained.
7.2.1.2 Skin Photographs

Cameras will be supplied to the study site by Canfield Scientific, Inc. for use in this study.
All involved areas that are representative of the subject’s extent of disease, will be selected at
baseline and measured and photographed using the digital camera provided by Canfield. In
addition, half-body global photos (waist to feet, waist to top of head and sides) will also be
obtained. Photos should be taken against a blue backdrop.
Skin photographs should be obtained prior to administration of study drug on Day 1 of the
first treatment cycle and then as specified in the Study Procedures tables.
Special care should be taken to shield the subject’s identity in accordance with local
guidelines on data privacy.
Photos must be labeled with only the subject identification number and initials. Digital photos
will then be submitted on an ongoing basis to Canfield Scientific, Inc. for quality review.
Canfield Scientific, Inc. will review photographs on an ongoing basis for assessment of
image quality and provide feedback to sites to ensure the photographs are appropriately
representative of extent of skin disease.
More detailed instructions regarding photographing of skin lesions will be provided in the
Photography User Manual.
7.2.1.3 Modified Severity Weighted Assessment Tool (mSWAT)

Skin lesions and erythema will be evaluated using the mSWAT.
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The mSWAT is an objective, quantitative, severity-weighted method to assess the extent of

skin lesions. An mSWAT score is derived by measuring each lesion as a percentage of total
body surface area (%TBSA) and multiplying it by a severity-weighting factor (1 = patch,
2 = plaque, 4 = tumor). All individual numbers are then added to produce a total score.
Areas of skin involvement identified as patch, plaque, or tumor and erythema are defined in
Table 7.2.1-1 and Table 7.2.1-2:
Table 7.2.1-1 Modified Severity Weighted Assessment Tool

Skin Lesion Definitions
Lesion Type Abnormal Skin Erythema
Patch Abnormal skin not elevated from Flat erythema or erythema with mild
normal skin infiltration
Plaque Abnormal skin elevated from normal Elevated erythema or erythema with moderate
skin by < 5 mm infiltration
Tumor Abnormal skin elevated from normal Erythema with fissuring, ulceration, or tumor
skin by ≥ 5 mm
mSWAT Score Calculation
Sum of %TBSA from all body regions affected by patches x severity-weighting factor of 1
+ Sum of %TBSA from all body regions affected by plaques x severity-weighting factor of 2
+ Sum of %TBSA from all body regions affected by tumors x severity-weighting factor of 4
= Total mSWAT (maximum score = 400).
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Table 7.2.1-2 Modified Severity Weighted Assessment Tool Score

Body region (%BSA) Patch* Plaque* Tumor*
Head (7 %)
Neck (2%)
Anterior trunk (13%)
Arms (8%)
Forearms (6%)
Hands (5%)
Posterior trunk (13%)
Buttocks (5%)
Thighs (19%)
Legs (14%)
Feet (7%)
Groin (1%)
Subtotal of lesion BSA
Weighting factor x1 x2 x4
Subtotal lesion BSA x weighting factor
mSWAT score = summation of each column line above =
patch = any size lesion without induration or significant elevation above the surrounding uninvolved skin: poikiloderma may
be present.
plaque = any size lesion that is elevated or indurated; crusting, ulceration or poikiloderma may be present.
tumor = any solid or nodular lesion ≥ 1 cm in diameter with evidence of deep infiltration in the skin and/or vertical growth.
7.2.1.4 Response Criteria for Skin

Response in skin will be determined by changes in mSWAT score as specified in Table
7.2.1-3. Responses (CR and PR) must be confirmed for a minimum of 4 weeks.
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Table 7.2.1-3 Response Criteria for Skin, as assessed by mSWAT scoresa

Response Definition
b
CR 100% clearance of skin lesions
PR 50 to 99% clearance of skin disease from baseline without new tumors (T3) in subjects with T1,
T2 or T4 only skin disease
SD < 25% increase to <50% clearance in skin disease from baseline without new tumors (T3) in
subjects with T1, T2 or T4 only skin disease
PDc (1) ≥ 25% increase in skin disease from baseline or
(2) New tumors (T3) in subjects with T1, T2 or T4 only skin disease or
(3) Loss of response: in those with CR or PR, increase of skin score of greater than the sum of
nadir plus 50% baseline score
Relapsed Any disease recurrence in those with CR
a: Based on mSWAT score.
b: A biopsy of normal appearing skin is unnecessary to assign a CR. However, a skin biopsy should be performed of a
representative area of the skin if there is any question of residual disease where otherwise a CR would exist. If histologic
features are suspicious or suggestive of MF/SS (see histologic criteria for early MF7), the response should be considered
a PR only.
c: Whichever criterion occurs first.
d: For purposes of the study, relapse should be defined as loss of response (as defined for PD) in those with CR, ie, increase
of skin score of greater than the sum of nadir plus 50% baseline score. Subjects may remain on treatment until subsequent
measurement to confirm progression.
7.2.1.5 Pruritus Evaluation

The extent of pruritus can have a significant impact on the subject’s QoL. A Likert scale
(Appendix 9) will be completed by each subject to assess their degree of pruritus at the visits
specified in the Study Procedures. The Itchy Quality of Life questionnaire (Desai, 2008) (see
Appendix 5) will also be completed at these visits to further evaluate the impact of pruritus
on their QoL. Medications taken to treat pruritus will be documented.
7.2.2 Evaluation of Blood Disease
7.2.2.1 Flow Cytometric Analysis

A peripheral blood sample will be used to evaluate circulating malignant T-cells and further
assess immune cells in the blood.
Samples will be sent to a central laboratory designated by the Sponsor. Specific directions for
sample preparation and packaging will be provided in the Laboratory Manual.
7.2.2.2 Response Criteria in Blood

In subjects with blood involvement, all blood responses (CR and PR) must be confirmed for
a minimum of 4 weeks.
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Response criteria are specified in Table 7.2.2-1.
Table 7.2.2-1 Blood Response Criteriaa

CRb B0
PRc > 50% decrease in quantitative measurements of blood tumor burden from baseline in those with
high tumor burden at baseline (B2)
SD Fails to attain criteria for CR, PR or PD
PDd (1) B0 to B2 or
(2) > 50% increase from baseline and at least 5,000 neoplastic cells/μL or
(3) Loss of response: in those with PR who were originally B2 at baseline, > 50% increase from
nadir and at least 5,000 neoplastic cells/μL
Relapse Increase of neoplastic blood lymphocytes to ≥ B1 in those with CR
a: As determined by absolute numbers of neoplastic cells/uL.
b: If a bone marrow biopsy was performed at baseline and determined to unequivocally be indicative of lymphomatous
involvement, then to confirm a global CR where blood assessment now meets criteria for B0, a repeat bone marrow
biopsy must show no residual disease or the response should be considered a PR only.
c: There is no PR in those with B1 disease at baseline as the difference within the range of neoplastic cells that define B1 is
not considered significant and should not affect determination of global objective response.
d: Whichever occurs first.
7.2.3 Evaluation of Disease in Lymph Nodes and Viscera
7.2.3.1 Baseline Tumor Assessments

The baseline tumor burden will be assessed by CT of the neck, chest, abdomen and pelvis
within 30 days prior to the first dose of study drug. The Investigator will identify,
prospectively, the lesions to be followed to evaluate the subject’s response to therapy. Lymph
nodes must be > 15 mm in the long axis (greatest transverse diameter, GTD) or > 10 mm in
the short axis if the GTD is > 10 to ≤ 15 mm.
Lymph node biopsies may be performed, at the discretion of the Investigator, to rule out
inflammation or to confirm disease. Analysis of these biopsies will be done by the pathologist
at the study site.
7.2.3.2 Method of Tumor Response Assessment

The same method of assessment and the same technique should be used to characterize each
identified and reported lesion at Screening and at reassessment during treatment.
Imaging-based evaluation is preferred to evaluation by clinical examination when both
methods have been used to assess the anti-tumor effect of a treatment. Lesions evaluated
clinically will only be considered measurable when they are superficial (e.g., skin nodules,
palpable lymph nodes). In the case of skin lesions, documentation by color photography,
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including a ruler to estimate the size of the lesion, is recommended. Contrast enhanced CT
will be considered the best currently available and reproducible method to measure target
lesions selected for response assessment. For subjects who are allergic to contrast agents,
non-contrast CT can be performed. The allergy must be documented on the Medical History
eCRF. Ultrasound is not an acceptable method to measure disease. Central review of
radiology may be performed to confirm the date of disease progression. Images should be
transmitted to the central radiology group as described in the Imaging Manual.
7.2.3.3 Determination of Response in Lymph Nodes and Viscera

The Investigator will make a determination of response based on criteria as specified in Table
7.2.3-1 and Table 7.2.3-2. In subjects with lymph node and/or visceral involvement,
responses (CR and PR) must be confirmed for a minimum of 4 weeks.
Table 7.2.3-1 Response in Lymph Nodesa

CR All lymph nodes are now ≤ 15 mm in GTD by the method used to assess lymph nodes at baseline.
In addition, lymph nodes that were ≤ 15 mm in GTD and > 10 mm in the short axis at baseline
must now be ≤ 10 mm in the short axis.
PR Cumulative reduction ≥ 50% of the SPD as compared to baseline and no new lymph node
(> 15 mm in the GTD or > 10 mm in the short axis if the GTD is > 10 mm to ≤ 15 mm).
PD Must meet any of the following:
(1) ≥ 50% increase in SPD from baseline of lymph nodes, or
(2) Loss of response, which is > 50% increase from nadir SPD of lymph nodes in subjects
previously assessed as PR, or
(3) > 50% increase compared to nadir, but which does not meet the criteria for PR (i.e., up to a
50% reduction compared to baseline), or
(4) Any new nodal lesion > 15 mm in the GTD or >10 mm in short axis diameter if the GTD is
> 10 mm to ≤ 15 mm)
Relapse (1) Any new lymph node > 15 mm in GTD or >10 mm in short axis if the GTD is > 10 mm to
≤ 15 mm
(2) Recurrence of any lymph node previously selected at baseline, which was previously assessed
as a CR, but which has recurred and measures > 15 mm in the GTD or > 10 mm in the short axis
if the GTD is > 10 mm to ≤ 15 mm.
Unable to A lymph node present at baseline, but which was not measured or which subsequently became
Evaluate unevaluable, leading to an inability to determine the status of that particular node for the time
point in question.
a: Peripheral and central lymph nodes
GTD=greatest transverse diameter; SPD=sum of the products of the diameters
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Table 7.2.3-2 Response in Viscera

(1) 100% reduction in the SPD of all lesions selected at baseline.
(2) Liver or spleen or any organ considered involved at baseline should be considered normal by
imaging.
CR (3) No nodules should be present on any imaging of liver or spleen.
(1) ≥ 50% regression in all splenic or liver nodules, or in measurable disease (SPD) in all organs
abnormal at baseline.
(2) No increase in the size of liver or spleen consistent with disease progression and no new sites of
PR involvement.
Must meet any of the following:
(1) > 50% increase in SPD of organs involved at baseline, or
(2) New organ involvement, or
(3) Loss of response, which is > 50% increase from nadir in the SPD of previous organ involvement
in subjects previously assessed as PR, or
(4) > 50% increase compared to nadir, but which does not meet the criteria for PR (i.e., up to a 50%
PD reduction compared to baseline).
(1) New organ involvement in subjects previously assessed as CR.
(2) Recurrence of any lesion previously selected at baseline, which was previously assessed as a CR,
but which has recurred and meets the measurement criteria (≥ 10 mm and/or 2× the reconstruction
Relapse interval in the GTD).
Unable An area of visceral disease present at baseline, but which was not measured or which subsequently
to became unevaluable, leading to an inability to determine the status of that particular area for the time
Evaluate point in question.
GTD=greatest transverse diameter; SPD=sum of the products of the diameters
7.2.4 Global Composite Response Score
Overall response will be based on response in each compartment (skin, blood, lymph nodes
and viscera) as specified in Table 7.2.4-1.
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Table 7.2.4-1 Global Composite Scoring System

Global
Score Definition Skin Nodes Viscera Blood
CR Complete disappearance of all CR All categories have CR/NI
clinical evidence of disease
PR Regression of measurable CR All categories do not have a CR/NI and no
disease category has a PD
PR No category has a PD and if any other category
involved at baseline, at least one has a CR or
PR
SD Failure to attain CR, PR or PD PR No category has a PD and if any other category
involved at baseline, no CR or PR in any
SD CR/NI,PR,SD in any category and no category
has a PD
PD Progressive disease PD in any category
Relapse Recurrence of disease in prior Relapse in any category
CR
NI=non-involved
Node, viscera and blood response contributes towards global response only if disease present
at baseline, unless defining global PD which is met by new disease in previously uninvolved
compartment. However, subjects who meet PD criteria in any compartment, or relapse in
blood, lymph nodes or viscera, confirmed at 2 consecutive visits must be discontinued from
study treatment due to disease progression/relapse. If subsequent assessment does not
confirm PD in any compartment, or relapse in blood, lymph nodes or viscera, subject may
continue on treatment. An unconfirmed PD/relapse would not preclude future responses (CR
or PR).
If PD is documented in any compartment at any point leading to subject’s discontinuation
from treatment, the overall global composite score should be completed at that time even if
all compartments have not been assessed.
7.2.4.1 Independent Review of Progression

A blinded independent review of response data for each subject will be performed to make a
determination regarding progression and the date of progression. The nodal and visceral
compartments evaluation will be based upon radiologic data. The independent radiology
review of radiographic exams will provide an assessment of tumor response and progression
for all subjects. A separate radiology charter will detail the roles and responsibilities of the
radiology reviewers and how the reads will be performed. An independent reviewer (IR) will
assess PFS based on date of progression or death, whichever comes first. For this assessment
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the independent reviewer will be supplied the results of the independent radiology review, the
mSWAT score for each subject, as assessed by the investigator, and the results of central
flow cytometry in order to assess blood response, and date of death for subjects who died
before progression.
Secondarily, the IR will review the date of any objective responses (CR or PR).
7.3 Pharmacokinetics (for subjects receiving KW-0761)
Serum samples will be drawn in subjects who receive KW-0761 (as first assigned therapy or
crossover) at the timepoints specified in the Study Procedures Tables (Table 1, Table 2, and
Table 3) for determination of KW-0761 concentration, through Cycle 3 and at the
End-of-treatment Visit. At selected sites, 4 additional samples will be drawn between 6 and
8 hours, and at 24, 48, and 72 - 96 hours after the first infusion on Day 1/Cycle 1 in
approximately 10 subjects, including crossover subjects. Blood samples obtained
post-infusion should be obtained from the arm contralateral to that of study drug
administration. The exact time of sample draw must be recorded in the eCRF.
All samples will be sent to a central laboratory designated by the Sponsor. Specific directions
for sample preparation and packaging will be provided in the Laboratory Manual.
7.4 Quality of Life Assessments
Subjects with CTCL often suffer from the symptoms related to their disease (pain, sleep
disturbance, etc.), the social and psychological problems related to sometimes unsightly skin
lesions and the burden of living with a chronic disease. In an effort to assess some of these
QoL issues, the Skindex-29 (see Appendix 6), FACT-G (see Appendix 7) and EQ-5D-3L (see
Appendix 8) will be administered.
7.5 Follow-Up
All subjects will be contacted by telephone every 30 days (± 7 days) up to 90 days after the
last dose of study medication or initiation of alternative therapy, whichever comes first, to
confirm any new onset AEs or toxicities. If a subject who has received KW-0761 undergoes a
stem cell transplant at any time during or after the 90-day follow-up period, AEs/SAEs
should be documented from the transplant procedure through 180 days post-transplant.
During follow-up, medications used to treat an AE and those that are temporally associated
with the AE and may have a causal relationship will be recorded. In all subjects who cross
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over from vorinostat to KW-0761, the causality should be assessed for both drugs for 30 days
• After a subject who receives KW-0761 goes off study, if CD4 and CD8 counts are less
than 200/mm3 at the End-of-treatment visit, they will be followed every 3 months
(± 14 days) until they return to at least 200/mm3, initiation of alternative therapy or
1 year, whichever comes first.
• In the absence of disease progression, all subjects or their referring physicians will be
contacted every 3 months (± 14 days) until documented disease progression or death, or
initiation of alternative therapy.
• All subjects or their referring physician will be contacted every 3 months (± 14 days) to
ascertain survival status.
• For all subjects who have received KW-0761, subsequent stem cell transplant information
should be recorded in a separate CRF provided by the Sponsor. For subjects who undergo
transplant, concomitant medications and AEs/SAEs should be documented through
180 days post-transplant on the CRFs provided.
• All follow up information and attempts to obtain follow up information should be
documented in the subject’s source record.
7.6 Follow-Up for Subjects Achieving a Complete Response
Those subjects who do not continue treatment after achieving a CR will undergo the
following assessments every 8 weeks (± 14 days) for the first 6 months (if CR achieved prior
to one year on study) and then every 16 weeks (± 14 days) thereafter until progression:
• Chemistry/Hematology profile;
• Skin photographs;
• mSWAT;
• Pruritus evaluation;
• Blood sample for flow cytometric analysis;
• CT;
• Overall Disease Response;
• Immunogenicity (for subjects receiving KW-0761).
After progression of disease, subjects will be followed as applicable according to the
procedures for post-treatment follow-up described in Section 7.5 including collection of
transplant information for subjects who have received KW-0761.
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7.7 Study Procedures for Subjects Continuing Study Treatment at the Time
of Primary Efficacy Analysis
Subjects receiving study treatment at the time of the primary efficacy analysis may continue
on study. For these subjects, administration of study drug(s) and data collection should
continue as described below. Note: Initiation of disease evaluation assessments per
institution/Investigator standard of care should not occur until notification by the Sponsor.
Study Drug Administration
• KW-0761 administration: KW-0761 may continue to be administered according to the
protocol (as specified in Section 8.1) on Day 1 and Day 15 of each cycle until PD, drug
intolerance or unacceptable toxicity, or until any of the other criteria for study removal
are met (as defined in Section 5.5) or until KW-0761 is approved/not approved for
marketing for the indication and regimen under study in the geographic region of study.
• Vorinostat treatment will continue to be administered as described in Section 5.2.2.
Vorinostat will be supplied by the Sponsor for a period of up to 1 year after the data
cutoff for the primary efficacy analysis. During this year all study subjects are eligible to
cross over to mogamulizumab as described in Sections 3.4 and 5.3.
Safety: Safety data will continue to be collected as described in the protocol for as long as the
subject receives study drug through 90 days after the last dose or initiation of alternative
therapy whichever comes first (as described in Section 7.1).
If a subject who has received KW-0761 undergoes a stem cell transplant at any time during or
after the 90-day follow-up period, transplant information should be documented as described
in Section 7.5 including recording of concomitant medications and AEs/SAEs from the
transplant procedure through 180 days post-transplant.
Efficacy: Efficacy data will be collected for 1 year after the time of the primary efficacy
analysis. During that 1-year period, pending notification by the Sponsor, Investigators should
follow study subjects in accordance with the standard of care at their Institution in order to
assess subjects’ disease status. Required data collection will be limited to the following
(additional data may be collected at the discretion of the Investigator):
• At the time of disease progression or discontinuation from treatment for any other reason,
sites are to perform the disease evaluation assessments per institution/Investigator
standard of care. The method of assessment of PD, if applicable, should be recorded;
• PRO - Itchy QoL, Skindex-29, EQ-SD-3L, Likert, and FACT-G will be collected every
4 mos. (16 weeks) for as long as the subject receives study drug.
In addition, all subjects or their referring physician will continue to be contacted every
3 months (± 14 days) to ascertain survival status.
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8 STUDY AGENTS
8.1 KW-0761 (mogamulizumab)
8.1.1 Description
KW-0761 drug product was manufactured by Toyobo Co., Ltd., the contracted manufacturer,
under Good Manufacturing Practice (GMP) conditions as an injectable solution, contained in
single-use, ready-to-use 10 mL vials. Each vial contains 5 mL of a 4 mg/mL solution of
KW-0761 drug substance in a colorless glass vial with fluoropolymer coated butyl rubber
stoppers and polypropylene flip-off cap with aluminum over seal.
8.1.2 Preparation of Dose
Subjects will receive KW-0761 at a dose of 1.0 mg/kg. The total dose and volume of the
study drug to be administered will be dependent upon the subject’s weight. If the subject’s
body weight changes by > 10% at any time during study relative to Day 1, subsequent doses
of study drug should be adjusted relative to the new weight.
The appropriate volume of KW-0761 based on weight will be withdrawn and diluted into
250 ml normal saline (0.9% sodium chloride). KW-0761 will then be filtered through a
0.22 μm protein-sparing/low-protein binding in-line filter.
Once KW-0761 drug product (DP) has been reconstituted with normal saline, the solution can
be stored at room temperature for up to 24 hours in the infusion bag. However, since there are
no preservatives, it is recommended the product be used within 8 hours. Once constituted, it
is not necessary to shield the infusion bag from light. Refer to the Pharmacy Manual for
additional information.
8.1.3 Study Drug Administration
Subjects will receive KW-0761 as an iv infusion over at least 1 hour for all infusions.
Subjects will be observed closely for 1 hour following each administration of KW-0761 for
any potential AEs in an area with resuscitation equipment. Vital signs will be checked and
recorded prior to start of infusion, at the end of the infusion and at 1 hour after completion of
infusion.
Hematology results should be reviewed before each subsequent dose. Laboratory assessments
may be performed the day prior to dosing to ensure results are available prior to dosing. The
platelet count must be ≥ 100,000 / mm3 and the ANC must be ≥ 1,500/mm3 before a subject
can receive study drug. If a scheduled dose cannot be given within the allowed window, the
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dose should be skipped and the subject should resume dosing with the next scheduled dose
assuming the platelet count and ANC are within the parameters described above. If a subject
misses 2 consecutive doses, contact the Medical Monitor or designee to determine if the
subject should be withdrawn from the trial.
Should a hypersensitivity reaction to KW-0761 occur, the subject must be treated according
to the best available medical practices. Subjects should be instructed to report any delayed
reactions to the investigator immediately. See Section 5.2.1.7 for additional information
regarding the treatment of infusion reactions.
8.1.4 KW-0761 Formulation and Storage
KW-0761 is available as a 4 mg/mL clear to slightly opalescent, preservative-free, sterile

solution for dilution for iv infusion. Each 10-mL clear, single-use Type 1 glass vial contains
20 mg of KW-0761 in 5.0 mL of 2.1 mmol/L citric acid monohydrate, 300 mmol/L glycine,
and 0.2 mg/mL polysorbate 80 (Tween 80), pH 5.5.
KW-0761 should be stored at a temperature of 2°C to 8°C and protected from light. The
diluted product for subject administration does not require protection from light.
Drug supplies must be kept in a secure, limited-access storage area under the recommended
storage conditions.
8.1.5 Packaging and Labeling of KW-0761
Almac Clinical Services, Inc. (Souderton, PA) will distribute the study drug to the
pharmacies at the study sites in the US. AndersonBrecon (UK) Limited, now doing business
as Packaging Coordinators, Inc. (PCI), will distribute the study drug to the pharmacies at the
study sites in Europe and Australia. DHL Supply Chain Ltd. will distribute the study drug to
the pharmacies at the study sites in Japan.
8.1.5.1 Labeling
Vial and carton labels will bear the appropriate text as required by each country’s regulatory
agency requirements.
8.1.6 Drug Accountability
The Principal Investigator and pharmacy at the study site are responsible for maintaining
accurate records of the receipt, dispensing, and return of all investigational materials. The
Investigator may dispense study drug only to subjects enrolled in the study. Under no
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circumstance will the Investigator allow study drug to be used other than as directed by the
protocol.
The pharmacy designated by the Investigator, must maintain an inventory of drug supplies
received, dispensed, and destroyed. All used and unused study drug must be accounted for.
When a shipment is received, the Investigator or pharmacist must verify the quantities
received and return the acknowledgement to the study monitor or designee. The study drug
accountability record includes the identification of the person to whom the drug is dispensed,
the lot number on the vial, the date of dispensing, and any returned or unused drug. An
account must be given of any discrepancies. This record is in addition to information
regarding dose recorded on the eCRF. These records must be readily available for inspection
by KKD monitor or designee and are open to FDA or other regulatory authority inspection at
any time. Copies of this record will be provided to the sponsor by the Investigator at the
conclusion of the study.
8.1.7 Return and Destruction
Upon completion or termination of the study, all unopened vials of KW-0761 must be
destroyed at the study site according to local regulations, unless other arrangements have
been approved by KKD.
8.2 Vorinostat (ZOLINZA®) Capsules
8.2.1 Description
Vorinostat will be supplied by the Sponsor for a period of up to 1 year after 255 PFS events
are observed. Vorinostat is a white to light orange powder. Each 100 mg capsule for oral
administration contains 100 mg vorinostat and the following inactive ingredients:
microcrystalline cellulose, sodium croscarmellose and magnesium stearate. The capsule shell
excipients are titanium dioxide, gelatin and sodium lauryl sulfate. This agent is approved for
marketing in the US, Japan and Australia and is indicated for the treatment of progressive,
persistent or recurrent CTCL. Since vorinostat is not approved in the EU, it will be labeled as
an investigational drug according to applicable regulations. Investigators will use the supplies
provided and will follow the FDA approved US prescribing information (e.g., dosage and
administration, warnings, precautions, adverse reactions, dose modifications and omissions
and storage information).
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8.2.2 Administration
Subjects will receive 400 mg daily of vorinostat orally with food commencing on Day 1.
8.2.3 Vorinostat Adverse Events
The most common AEs (≥ 20%) are diarrhea, fatigue, nausea, thrombocytopenia, anorexia
and dysgeusia. Please refer to the US prescribing information for more complete information.
8.2.4 Return and Destruction
Upon completion or termination of the study, all unopened containers of vorinostat must be
destroyed at the study site according to local regulations, unless other arrangements have
been approved by KKD.
9 ADVERSE EVENT REPORTING IN CLINICAL TRIALS

The Investigator will inquire about AEs at all subject visits by asking the subject a question
such as: “How have you been feeling since your last visit?” All AEs, whether observed by the
Investigator or reported by the subject, must be collected and recorded on the appropriate AE
page of the eCRF and as appropriate on the SAE form (see Section 9.2). The collection of AE
information commences following the subject’s written Informed Consent to participate in
the study. If a subject experiences an AE, the subject will receive appropriate treatment and
supportive care as necessary, and the Investigator will continue to follow up until there is a
return to the subject’s baseline condition, or until a clinically satisfactory resolution is
achieved.
Timely and complete reporting of all AEs assists the Sponsor in identifying any untoward
medical occurrence, thereby allowing: (1) protection of safety of study subjects; (2) a greater
understanding of the overall safety profile of the study drug; (3) recognition of dose-related
study drug toxicity; (4) appropriate modification of study protocols; (5) improvements in
study design or procedures; and (6) adherence to worldwide regulatory requirements. Every
effort should be made to enter the AE information in the eCRF within 7 days of when the
information becomes available in order to ensure timely reporting to the Sponsor.
9.1 Definitions
9.1.1 Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered an

investigational product and which does not necessarily have to have a causal relationship
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with this treatment. An AE can therefore be any unfavorable and unintended sign (including
an abnormal laboratory finding, for example), symptom or disease temporally associated with
the use of an investigational product, whether or not considered related to the investigational
product.
The description of each AE will identify the subject, date of onset, the date of resolution, the
severity of the event, the action taken regarding study drug, the outcome of the event, and the
relationship of the event to study drug. A medical condition present at screening that has
increased in frequency or severity must be recorded on the AE page of the eCRF.
Standard medical terminology should be used to document AEs on the eCRF. The subject’s
exact description of the event will be recorded in the source documentation. In the case of
signs and symptoms, the underlying illness or diagnosis will be recorded as the event when
known.
For this study, disease progression will not be considered as an AE. Lymphopenia is the
pharmacologic effect of the drug and will also not be considered an AE for this study.
Lymphocytes will be monitored and evaluated with the laboratory data.
9.1.2 Adverse Event Severity
All AEs will be graded using CTCAE Version 4.0 as:

Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not
indicated
Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate
instrumental ADLa
Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or
prolongation of hospitalization indicated; disabling; limiting self-care ADLb
Grade 4 Life-threatening consequences; urgent intervention indicated
Grade 5 Death related to AE
a: Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc.
b: Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not
bedridden.
ADL=Activities of Daily Living
For AEs not contained within CTCAE, Version 4.0, the Investigator will assess the
severity/grade of an AE according to the five grades above.
9.1.3 Adverse Event Relationship to Study Drug
The relationship of each AE to the study drug will be evaluated using the following
guidelines:
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Definitely Related
An AE that follows a reasonable temporal sequence from administration of the drug
(including the course after withdrawal of the drug) and that satisfies any of the following:
(1) reappearance of a similar reaction upon re-administration (positive re-challenge);
(2) positive results in a drug sensitivity test (skin test, etc.); (3) toxic level of the drug as
evidenced by measurement of drug concentrations in blood or other bodily fluid.
Probably Related
(including the course after withdrawal of the drug) and for which involvement of factors
other than the drug, such as underlying diseases, complications, concomitant drugs and
concurrent treatments, can reasonably be excluded. This may also include positive
dechallenge (event abates upon discontinuation of the investigational agent).
Possibly Related
(including the course after withdrawal of the drug) and for which possible involvement of the
drug can be suggested (for example previous similar reports or pharmacologic actions of the
drug) although factors other than the drug, such as underlying diseases, complications,
concomitant drugs and concurrent treatments may also be responsible.
Unlikely
An AE that, while relationship to the drug cannot be definitively excluded, does not appear to
follow a reasonable temporal sequence from administration of the drug or that appears to be
reasonably explained by other factors, such as underlying diseases, complications,
concomitant drugs and concurrent treatments.
Not Related
An AE that does not follow a reasonable temporal sequence from administration of the drug
or that can reasonably be explained by other factors, such as underlying diseases,
complications, concomitant drugs and concurrent treatments.
9.2 Serious Adverse Events
Any AE that is initially considered serious or becomes serious should be reported on the SAE
form.
A SAE is any untoward medical occurrence which:
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• Results in death;
• Is immediately life threatening;
– The term “life-threatening” in the definition of “serious” refers to an event in which
the subject was at risk of death at the time of the event; it does not refer to an event
that hypothetically might have caused death if it were more severe.
– If an event is Grade 4 by CTCAE version 4.0, it does not necessarily meet the
definition for life-threatening.
• Requires in-patient hospitalization/admission or prolongation of existing hospitalization;
• Results in persistent or significant disability/incapacity;
• Is a congenital anomaly/birth defect; or
• Is an important medical event:
– Those events that may not be immediately life-threatening or result in death or
hospitalization but based upon appropriate medical and scientific judgment may
jeopardize the subject or may require intervention to prevent one of the serious
outcomes listed above. Examples include intensive treatment in an emergency room
or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not
result in hospitalization; development of drug dependency or drug abuse.
All AEs, whether non-serious or serious, must be recorded on the AE page of the eCRF. In
addition, any AE that is initially considered serious or becomes serious must be reported on
the SAE form. The SAE information entered on the eCRF must be consistent with the
information entered on the SAE form.
Serious adverse events require expeditious handling to comply with regulatory requirements.
Any SAE occurring in a clinical study subject must be reported to the Sponsor or designee
within 24 hours of the Investigator having knowledge of the SAE.
The Investigator or other qualified individual at the investigative site must complete the SAE
form and fax it to the Sponsor or designee. All telephone communication regarding an SAE
must be followed by a written report. In addition, SAE reports may require subsequent
notification of the IRB and/or Ethics Committee (EC), if appropriate.
The Investigator is obligated to immediately report to the Sponsor or designee any SAE
occurring at any time after the subject signs the Informed Consent Form and within 90 days
after the last dose of study drug or initiation of alternative therapy whichever comes first,
independent of the circumstances or suspected cause. In all subjects who cross over from
vorinostat to KW-0761, the causality should be assessed for both drugs for 30 days after
vorinostat was stopped (or later if the event is considered to be related to vorinostat). In
addition, the Investigator must promptly report to the Sponsor any SAE occurring at any
other time after completion of the study if a causal relationship to study drug is suspected.
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For all SAEs, the Investigator is obligated to pursue and provide information as requested by
the Sponsor in addition to that requested on the SAE form. Information must include a
description of the SAE in sufficient detail to allow for a complete medical assessment of the
case and independent determination of causality. In the case of a subject death, a summary of
autopsy findings, if available, must be submitted as soon as possible to the Sponsor. The
Investigator will ensure that information reported immediately by telephone or other means
and information entered on the SAE form is accurate and consistent.
9.3 Other Safety Considerations
Any clinically important changes noted during interim or final physical examinations, ECGs,
x-rays, or any other potential safety assessments, whether or not these procedures are
required by the protocol, must also be recorded on the appropriate eCRF page and SAE form,
as appropriate, in order for the Sponsor to collect additional information about that
abnormality, including information regarding relationship to study drug, any action taken,
and resolution.
9.4
9.5 Data Safety Monitoring Board
A Data Safety Monitoring Board (DSMB), whose composition, roles and responsibilities are
described in a separate DSMB charter, will oversee subject safety in the trial. The DSMB
consists of at least 2 medical doctors and a statistician.
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10 DATA ANALYSIS AND STATISTICAL CONSIDERATIONS

The number of subjects enrolled and discontinued will be presented. A summary of reasons
for discontinuation will be provided. The number of subjects in the Intent-to-Treat (ITT),
Safety Analysis, and Efficacy Evaluable Sets (see Section 10.1) will be presented by
treatment arm and combined.
Demographic and other baseline subject characteristics will be summarized by treatment arm
for the ITT Set. These summaries will include demographics (including age, race, sex, height,
weight, and body surface area) and baseline values for disease information.
Descriptive statistics (mean, standard deviation, median, minimum, and maximum) for
continuous variables and frequency distributions and percentages for discrete variables will
be utilized.
10.1 Populations to be Analyzed
The following analysis sets will be used in the study:

• Intent-to-Treat Set: Includes all subjects randomized to a therapy and assigned a study
number.
• Safety Analysis Set: Includes all subjects who received at least one dose of the assigned
study agent (even a partial dose).
• Efficacy Evaluable Set: Includes all subjects who receive the first cycle of treatment and
who have baseline and the Day 26-28 on-study assessment for response.
• Pharmacokinetic (PK) Analysis Set: All subjects who provide at least one post-dose
KW-0761 concentration measurement will be included in the PK analysis dataset.
10.2 Analyses of Safety Data
The safety and tolerability of KW-0761 and vorinostat is determined by reported AEs,
physical examinations, ECGS, vital signs, and laboratory tests. All summaries for the Safety
Analysis Set will be prepared for each treatment arm. For those subjects in the vorinostat arm
who cross over to KW-0761 treatment arm, AEs with an onset date/time after the first dose of
KW-0761 will be summarized separately within that KW-0761 crossover group.
The World Health Organization (WHO) Drug Dictionary will be used to classify prior and
concomitant medications by therapeutic class and Preferred Term. Prior medications include
medications that were taken within 30 days prior to the Pre-treatment Visit. Concomitant
medications include medications that started at any time and were taken at any time after the
start of treatment until the end of the entire treatment period.
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Adverse events are collected from the time the subject signs the ICF until 90 days after the
last dose or initiation of alternative therapy, whichever comes first. In all subjects who cross
over from vorinostat to KW-0761, the causality should be assessed for both drugs for 30 days
The NCI-CTCAE v4.0 system will be used to grade AEs. Treatment-emergent AEs will be
grouped and tabulated by MedDRA preferred terms and system organ class. AEs will be
classified by body system, incidence, severity, and causality. All treatment-emergent AEs
will be summarized showing the number and percent of subjects for each outcome.
The results from physical examination will be presented in the subject data listings. Vital sign
measurements will be summarized at each time point. The incidence of clinically significant
laboratory abnormalities will be presented, and laboratory data will be summarized at each
time point by the NCI-CTCAE v4.0 toxicity grade. Laboratory data will be presented for
subjects having Grade 3 or 4 changes from baseline by treatment arm.
Pre- and post-treatment serum samples will be assayed for development of human antibodies
to KW-0761 (anti-KW-0761).
10.3 Analyses of Efficacy Data
Disease status will be assessed every 4 weeks in skin and blood. In the first year of treatment,
response in lymph nodes and viscera and the overall global composite score will be
documented every 8 weeks. After the first year, response in the lymph nodes and viscera and
the overall global composite score will be documented every 16 weeks. Additionally, if
clinical progression is noted, efficacy assessments are performed to fully document disease
progression.
These assessments will be compared with the baseline assessment to determine response.
Subjects will be evaluated for response in each compartment. Progressive-free survival,
overall response, duration of response, and QoL will be analyzed. For any time-to-event
endpoints, the date of disease progression will be determined by both the on-site
investigator’s assessment and the IR. All efficacy analyses will be conducted on both the ITT
and Efficacy Evaluable sets.
The primary comparison of PFS between both arms will be performed on the ITT set based
upon the results of the on-site investigator’s assessment using a stratified Log-rank test at the
one-sided 2.5% significance level. Stratification is done by disease type, either SS or MF, and
disease stage, either IB/II or III/ IV. A similar secondary analysis will be performed on the
results based on the IR. Each analysis will also be conducted for the Efficacy Evaluable Set.
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Progressive-free survival, which will be analyzed using Kaplan-Meier survival analysis

methods, is defined as the time from the day of randomization to a treatment arm until
documented progression or death. For subjects who exhibit conditions of disease progression,
but continue on the study due to a questionable clinical impression as described in Sections
5.2.1.4 and 5.2.2.3, the subject is not considered to have progressed unless disease
progression is confirmed at least 4 weeks after the date of the initial questionable disease
progression. In this case, the initial date will be used as the date of disease progression.
For PFS events, all deaths will be attributed to progression and, hence, the TTP will equal the
time to death and will be uncensored. Subjects who die without a reported prior progression
will still be considered to have progressed on the day of their death. In the event that a
randomized subject withdraws from the study for any reason before documented progression,
the time from the day of randomization to the last tumor assessment (from any compartment)
will be used as a censored time point. For all subjects randomized to a treatment arm but
withdrawing prior to first tumor assessment for any reason other than disease progression, the
PFS time will be censored at the last documented visit. Sensitivity analyses for PFS will be
performed, with the details specified in the Statistical Analysis Plan.
Frequency tables will be used to display best response. Best response will be presented for all
subjects by treatment arm. The best overall response is the best response from the start of
treatment until disease progression/recurrence. The subject’s best response assignment will
depend on the achievement of both measurement and confirmation criteria. Response data
will be analyzed for both the ITT and the Efficacy Evaluable Set for each treatment arm.
Exact 95% confidence intervals for response rate will be calculated for each of these groups
along with the difference in response rates between the 2 treatment arms. All 95% confidence
intervals on individual rates will be computed using exact computational methods. Any
confidence interval on the difference of proportions will be computed using exact
unconditional confidence limits for the risk difference. These confidence intervals can be
constructed using SAS version 9.2 with the FREQ procedure specifying the RISKDIFF
option in the EXACT statement (Santner, 1980). ORR will be calculated as the proportion of
subjects who are responders (CR and PR) and the 95% exact confidence interval for response
will be calculated.
The duration of response (DOR), which will be estimated using survival analysis methods, is
measured from the time measurement criteria are met for CR/PR (whichever is first recorded)
until the first date that PD or death is objectively documented (taking as a reference for PD
that smallest measurement recorded since the treatment started). Subjects who do not relapse
will be censored at the day of their last tumor assessment. The DOR will be estimated
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separately for each treatment arm. Because the DOR is a conditional estimate (conditional on
having a response), comparison between KW-0761 and vorinostat would not be based on
randomized groups and therefore will not be made.
The Pruritus Evaluation (Likert scale & Itchy QoL) and Skindex-29, FACT-G and EQ-5D-3L
assessments will be summarized at baseline and at the timepoints specified in the study
procedures tables for each arm. The improvement (change from baseline) for each of these
measures will also be summarized and analyzed using repeated measures ANCOVA utilizing
time points through the 6-month assessment.
For those subjects who crossover from the vorinostat arm to the KW-0761 arm, these
assessments within the second arm of the study will be measured at the end of the first cycle
after the first day of dosing for KW-0761. Baseline measurements for crossover subjects are
those documented closest to and before the first KW-0761 infusion. No statistical
comparisons will be made for information gathered in the crossover from the vorinostat arm
to the KW-0761 arm. All summaries for this arm will be purely descriptive.
Progression-free survival is the primary endpoint in this study. There are four key secondary
endpoints in this study that require a comparison between treatment arms: ORR, Skindex-29,
FACT-G, and EQ-5D-3L. Comparisons of these four secondary endpoints between the
2 treatment arms will be conducted using p-values that are adjusted to control the overall
study-wise Type 1 error rate to be less than 0.05. Since these tests are not independent, the
four secondary tests will be conducted using the Sidak adjusted p-value method defined as
Adjusted p-value = 1-(1-p)4 where p is the original p-value of the individual test
These adjusted p-values will then be compared to .05 for each test.
Comparisons between treatment arms for all other secondary endpoints such as Likert scale,
and Itchy QoL will be conducted with no adjustment for multiple comparisons used for those
statistical tests. Exploratory subset analyses for PFS and any of the secondary endpoints by
region, study site, compartment involvement, CCR4 expression status, disease subtypes, and
medical history may be conducted. Details of such subset analyses will be provided in the
Statistical Analysis Plan. Although overall survival (OS) is not a secondary endpoint, each
subject will be followed in this study for a minimum of 2 years to generate information on
OS. Using this follow-up information, a comparison between treatment arms for OS will also
be conducted and considered exploratory. Statistical analyses on OS using follow-up data
may take place after database lock for the study and will be reported as supplemental to the
Clinical Study Report.
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Randomization will be stratified within the 2 disease types, SS and MF and 2 disease stages
IB or II and III or IV. The efficacy analyses described in this section will be conducted as
stratified tests but may also be conducted as a subset analysis within each of these
disease-type groups and disease stages. Comparison of endpoints between these 2 groups and
stages will be conducted for each treatment assuming adequate sample sizes in the respective
groups.
Exploratory analyses based on other subject groupings and with other parameters may also be
conducted.
Since the primary endpoint is PFS, the reference median PFS for vorinostat is assumed to be
169 days. The median PFS for KW-0761 therapy is targeted for 254 days, a 50%
improvement over this reference median. For a 24-month accrual and 12 month follow-up on
the last subject dosed, Table 10.3-1 gives the power and the number of PFS events required to
show superior PFS for KW-0761 therapy over vorinostat at the one-sided 0.025 significance
level. The ITT set is used for this primary analysis. The same analysis conducted using the
Efficacy Evaluable set is considered secondary.
Under these assumptions, for the ITT population, a total of 255 PFS events will give 90%
power (row is in bold in Table 10.3-1). For this study, the final primary analysis comparing
PFS between treatment groups will not be conducted until 255 PFS events occur or until a
maximum of 24 months after the last randomized subject’s first dose, whichever comes first.
In the event that the study is stopped prior to 255 PFS events are observed, the primary test
will be performed at less than 90% power under the current assumptions according to
Table 10.3-1.
Each of these calculations uses a log-rank test to compare the 2 survival curves. Sample size
calculations were computed using SAS software version 9.3 using PROC POWER,
Twosamplesurvival test = logrank.
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Table 10.3-1 Required PFS Events and Power for Comparison of PFS Kaplan-Maier
Curves Between the Vorinostat and KW-0761 Arms at the 0.025 Level
Vorinostat Median PFS = 169 Days, KW-0761 Median PFS = 254 Days
Total Required PFS Expected Total Sample Size to Achieve The Required
Power Events Events
90 255 288
89 247 280
88 239 270
87 231 262
86 225 254
85 218 248
84 212 240
83 206 234
82 201 228
81 196 222
80 191 216
The total sample size of 288 represents the approximate number of subjects that may be
necessary for 255 PFS events to occur within the projected 36 months of the trial. If a 10%
inflation factor is applied to this total (about 29 subjects) to take into account those subjects
that may be lost to follow-up prior to documented progression, a total of 317 enrolled
subjects may be necessary in order to observe 255 PFS events.
The observed rates of PFS events, recruitment, and drop-outs will be monitored throughout
the study and may be used to alter the number of sites, the accrual period, and the follow-up
period to achieve the required 255 PFS events in a timely manner. If the 255 PFS events are
not observed within 36 months from the start of enrollment the study will be stopped at
approximately 24 months after the last randomized subject’s first dose.
10.4 Exposure-Response Analysis
Values for individual drug concentrations and descriptive statistics for each blood sample for
PK assessment will be provided at each scheduled time point of collection.
Exposure-response analysis using population-based methods will be presented in a separate
report.
11 ETHICAL ASPECTS
11.1 Ethics and Good Clinical Practice
This study will be conducted in compliance with the International Conference on

Harmonization (ICH) E6 Good Clinical Practice (GCP) guidance, and the most recent version
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of the Declaration of Helsinki as amended in 2008. In addition, all applicable local laws and
regulatory requirements relevant to the use of new therapeutic agents in the countries
involved will be adhered to.
11.2 Ethics Committee/Institutional Review Board
Prior to implementation of the study, the protocol and the proposed informed consent form
must be reviewed and approved by a properly constituted EC/IRB. A dated statement that the
protocol and informed consent have been approved by the EC/IRB must be provided to the
Sponsor prior to study initiation. Any amendments to the protocol will also require EC/IRB
approval, except in the case of changes made to protect subject safety, which may be
implemented immediately. The name and occupation of the chairperson and the members of
the EC/IRB will be provided.
The Investigator will provide progress reports to the EC/IRB as required by the EC/IRB. The
Investigator will provide a final report to the EC/IRB within three months after completion of
participation in the study.
The Investigator will not start this study, nor will study drug be shipped to the Investigator’s
site, before providing the Sponsor or designee with evidence of EC/IRB approval.
11.3 Informed Consent
The Investigator must explain to each subject the research nature of the study, its purpose,
procedures, expected duration and the potential risks and benefits involved in study
participation. Each subject must be informed that participation in the study is voluntary and
that he/she may withdraw from the study at any time and that withdrawal of consent will not
affect his/her right to the most appropriate medical treatment or affect the doctor/subject
relationship.
The informed consent should be given by means of a standard written statement. The
informed consent document should be written so as to be easily understood by the subject or
the subject’s legal representative. The subject or the subject’s legal representative should be
given time to read and understand the information before signing the informed consent
document. The subject should receive a copy of the written informed consent document once
he/she has signed.
If signed consent is not possible, then it is also possible to obtain consent orally, in which
case, the act of informed consent should be established by an additional signed statement
from an independent witness. The Investigator should explain in the chart why direct-signed
CONFIDENTIAL 85
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consent was not possible. Each investigator must provide a copy of the signed informed
consent form to the subject. A subject may not be admitted to the study unless informed
consent of the subject (or his/her legally authorized representative) has been obtained.
Subjects will be asked to consent to allow the sponsor, sponsor representative or regulatory
auditor to review their medical records to confirm compliance with GCP and the protocol.
The standard written informed consent statement forms a part of the protocol that is
submitted to the EC/IRB for approval. The Investigator must submit a specimen copy of the
EC/IRB-approved informed consent document to be used in the study before the study is
initiated.
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12 INVESTIGATOR OBLIGATIONS AND STUDY MANAGEMENT

12.1 Administrative
All references to KKD in this section include all designees e.g., Contract Research
Organizations or Consultants acting on behalf of KKD.
12.2 Changes in Protocol
Any change to the protocol will be made by written amendment to the Investigational New
Drug Application (IND) and Clinical Trial Authorization (CTA) (if required) and approved
by KKD and the Principal Investigator(s) before the change is implemented. All amendments
to the protocol and informed consent form, which require regulatory and/or EC/IRB
approval/favorable opinion, must be reviewed and approved by KKD, the EC/IRB and/or
local authorities before being implemented. Amendments should not be implemented until all
necessary approvals have been obtained, except when necessary to eliminate an immediate
hazard(s) to study subjects.
12.3 Protocol Deviations
KKD, as the protocol sponsor, is responsible for implementing and maintaining quality
assurance and quality control to ensure that studies are conducted according to the protocol,
GCPs and all applicable regulatory requirements. A protocol deviation is any noncompliance
with the protocol. Noncompliance can be on the part of the study participant, the Investigator
or the study site staff. Deviations to the protocol are not permitted except when necessary to
eliminate an immediate hazard(s) to study subjects.
12.4 Monitoring and Quality Assurance
The Sponsor of this study, KKD, has responsibilities to health authorities to take all
reasonable steps to ensure the proper conduct of the study as regards to ethics, protocol
adherence, integrity, validity of the data recorded on the eCRF and adherence to regulations
regarding GCP and the protection of human subjects.
If the study site has not participated in a KKD sponsored trial within the past year, KKD or
its designee will assess the study site prior to study initiation to verify the qualifications of the
Investigator, inspect the study site’s facilities and inform the Investigator of his/her
responsibilities and the procedures for ensuring adequate and correct documentation.
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During the course of the study, the study monitor will make routine site visits to review
protocol compliance, compare eCRFs with individual subject’s original source documents,
assess drug accountability and ensure that the study is being conducted according to the
pertinent regulatory requirements. The review of the subject’s medical record will be
performed in a manner to ensure that the subject’s confidentiality is maintained. Monitoring
visits will occur approximately every 6-8 weeks. Frequency of visits may be modified based
on the rate of enrollment or as otherwise necessary to ensure GCP compliance. The
Investigator agrees to cooperate with the monitor to ensure that any problems detected in the
course of these monitoring visits, including delays in completing case report forms, are
resolved.
Regulatory authorities and/or the KKD staff may carry out source document verification
visits and/or site inspections/audits. Direct access to original source data will be required for
inspections/audits, which will be carried out giving due consideration to data protection and
subject confidentiality.
12.5 Electronic Case Report Forms (eCRFs) and Source Documentation
The investigator is required to prepare and maintain adequate and accurate case histories (i.e.,
medical records) designed to record all observations and other data pertinent to the study for
each study participant.
It is the responsibility of the Principal Investigator to prepare and maintain adequate and
accurate eCRFs that have been designed by the Sponsor to record all observations and other
data pertinent to the clinical investigation.
Electronic Case Report Forms are used to record information collected in the performance of
this study and to transfer the data into the study database. These eCRFs are organized as an
ordered series of electronic data entry modules specific for each scheduled and unscheduled
study visit.
The electronic data capture (EDC) users at the study site will exercise due diligence in
ensuring that study subject data are entered accurately and in their entirety from the
investigative site’s source documents and flow sheets into the appropriate data entry fields.
Only staff listed on the “Delegation of Authority” page in the study file notebook and who
have been appropriately trained will be issued a user ID enabling them to make entries and
edits to the electronic trial database and to respond to queries. Only the Principal Investigator
will be issued a user ID allowing the application of an electronic signature to a completed
CONFIDENTIAL 88
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study subject record signifying the data has been reviewed and verified as complete and
accurate.
Upon completion of the study, validated study subject records will be published
electronically along with the Principal Investigator’s electronic signature in a Portable
Document Format (PDF) file and transferred to a CD-ROM. The compact disc(s) will then be
distributed to the Study Site to be retained by the Principal Investigator as a component of the
required records for this study.
12.6 Record Retention
Study data and other essential documents should be retained by the study site for a minimum
of 2 years after the last approval of a marketing application in an ICH region and until there
are no pending or contemplated marketing applications in an ICH region or until at least
2 years have elapsed since the formal discontinuation of clinical development of the
investigational product. However, these documents should be retained for a longer period if
required by the applicable legal requirements. KKD or its designee will inform the
investigator, in writing, as to when these documents no longer need to be maintained.
12.7 Confidentiality
All personal data collected and processed for the purposes of this study should be managed
by the investigator and his/her staff with adequate precautions to ensure the confidentiality of
those data, and in accordance with applicable national and/or local laws and regulations on
personal data protection.
Monitors, auditors, and other authorized agents of KKD and/or its designee, the EC/IRBs
approving this research, and the regulatory authorities, as well as that of any other applicable
government agency(ies), will be granted direct access to the study subjects’ original medical
records for verification of clinical trial procedures and/or data, without violating the
confidentiality of the subjects, to the extent permitted by the law and regulations. In any
presentations of the results of this study or in publications, the subjects’ identity will remain
confidential.
12.8 Disclosure
By conducting this study, the Investigator agrees that all information provided will be
maintained by the Investigator and his/her staff in strict confidence. Such information may be
communicated to the Scientific Committee and/or EC/IRB under a similar, appropriate
understanding of the confidential nature of the information. Study documents provided
CONFIDENTIAL 89
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(protocols, IBs, case report forms and other material) will be stored appropriately to ensure
their confidentiality. It is understood that the confidential information provided to the
Investigator will not be disclosed to others without written authorization from KKD, except
to the extent necessary to obtain informed consent from those subjects who are eligible and
choose to participate in the study.
Such information will not be provided to potential subjects by telephone or to any other
individual.
12.9 Termination of Study
The Sponsor reserves the right to terminate the study or individual study sites at any time.
Reasons for study termination include, but may not be limited to, manufacturing problems, a
request to discontinue the study from a regulatory authority, a corporate decision to
discontinue development of KW-0761, AE incidence or severity not consistent with the
potential benefit of the drug, poor enrollment or inadequate adherence to GCP guidances. In
terminating the study, the Sponsor and the Principal Investigator will assure that adequate
consideration is given to the protection of the subjects’ interest. If the trial is terminated
prematurely, the EC/IRB and regulatory authorities (if required) will be notified.
12.10 Final Report/Publications
The study is part of a multicenter study; accordingly, the Institution and Principal Investigator
of the study agree that the first publication of the results of the study shall be made in
conjunction with the presentation of a joint, multicenter publication of the study results with
the Investigators and the Institutions from all appropriate sites contributing data, analyses and
comments. However, if such a multicenter publication is not submitted within 12 months
after the database has been locked, abandonment or termination of the study at all sites, or
after Sponsor confirms there will be no multicenter study publication, the Institution and/or
such Principal Investigator may publish the results from the institution site individually in
accordance with the following requirements. Prior to submission of any materials for
publication or presentation, the Institution will provide such materials or manuscript to the
Sponsor for review. Details of the Sponsor’s publication policy can be found in the Clinical
Trial Agreement.
CONFIDENTIAL 90
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Appendix

Institution/ Principal Patient

General Clinical Research

Clinical and Translational

Ronald Reagan UCLA

Santa Monica UCLA

UCLA Santa Monica

Westwood Bowyer Clinic

Rochester General Hospital

Smilow Cancer Center at

Indiana Clinical Research

Indiana University Simon

Bodine Center, Gibbon

Table S1. TNMB staging

T4 Confluence of erythema covering ≥80% BSAa

N1 Clinically abnormal lymph nodes; histopathology Dutch Grade 1 or NCI LN 0-2

N1a Clone negative

N1b Clone positive

N2 Clinically abnormal lymph nodes; histopathology Dutch Grade 2 or NCI LN 3

N2a Clone negative

N2b Clone positive

B0b Clone positive

IIA 1,2 1,2, X 0 0,1

IIB 3 0-2, X 0 0,1

IVA1 1-4 0-2, X 0 2

IVA2 1-4 3 0 0-2

IVB 1-4 0-3, X 1 0-2

Table S3. Modified severity-weighted assessment tool score

BSA=body surface area.

Table S4. Response criteria for skin, as assessed by mSWAT scoresa

Relapsed Any disease recurrence in those with CR

Table S5. Blood response criteriaa

Relapse Increase of neoplastic blood lymphocytes to ≥ B1 in those with CR

CR=complete response; PD=progressive disease; PR=partial response; SD=stable disease.

Table S9. Exploratory analyses of overall survival

Blood and Lymphatic System Disorders

Anaemia 17 (9.2) 2 (1.1) 0 0 17 (9.1) 1 (0.5) 1 (0.5) 0 6 (4.4) 1 (0.7) 0 0

Generalised oedema 1 (0.5) 1 (0.5) 0 0 1 (0.5) 0 0 0 0 0 0 0

Sepsis syndrome 0 0 0 0 0 0 1 (0.5) 0 0 0 0 0

Metabolism and Nutrition Disorders

TABLE OF CONTENTS ..................................................................................................... 6

5 TREATMENT PLAN .............................................................................................. 42

7.1.6 Genomic Sampling (For subjects receiving KW-0761 as first assigned

8.1.5.1 Labeling .......................................................................................................... 72

9.5 Data Safety Monitoring Board ................................................................................ 78

List of In-text Tables

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Table 1 Study Procedures: First Treatment Cycle

Table 2 Study Procedures: Subsequent Cycles in Year 1

Footnotes to Table 2 (continued).

Table 3 Study Procedures: Subsequent Cycles in Year 2 and Beyonda

Table 3 Study Procedures: Subsequent Cycles in Year 2 and Beyonda

Table 3 Study Procedures: Subsequent Cycles in Year 2 and Beyonda

1 BACKGROUND AND RATIONALE

1.2 Treatment of Cutaneous T-cell Lymphomas

1.3 Chemokine Receptor 4 and T-Cell Malignancies

1.4 KW-0761 (mogamulizumab)

KW-0761 is a defucosylated, humanized, monoclonal antibody (Mab) with enhanced

1.5 Safety and Efficacy of KW-0761