VOLUME 22 䡠 NUMBER 16 䡠 AUGUST 15 2004

JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T

Phase I Study of an Immunomodulatory Thalidomide

Analog, CC-4047, in Relapsed or Refractory
Multiple Myeloma
S.A. Schey, P. Fields, J.B. Bartlett, I.A. Clarke, G. Ashan, R.D. Knight, M. Streetly, and A.G. Dalgleish
From the Guy’s and St Thomas’ Trust,
A B S T R A C T
Department of Haematology, Thomas
Guy House; Department of Cellular and
Molecular Medicine, St George’s Hospi- Purpose
tal, London, United Kingdom; and
To assess the safety, efficacy, and immunomodulatory effects of CC-4047 (Actimid; Celgene, San Diego,
Celgene Corp, San Diego, CA.
CA) in patients with relapsed or refractory myeloma.

Submitted October 9, 2003; accepted Patients and Methods

March 19, 2004.
Support for this study was provided by
Celgene Corp, Warren, NJ.
Preliminary data presented at the 31st
International Society of Haematology,
Montreal, Canada, July 2002.
Authors’ disclosures of potential con-
flicts of interest are found at the end of
this article.
Address reprint requests to S.A. Schey,
MD, Guy’s and St Thomas’ Trust, De-
partment of Haematology, Thomas Guy
House, London SE1 9RT, United
Kingdom; e-mail: steve.schey@
gstt.sthames.nhs.uk.
© 2004 by American Society of Clinical
Oncology
0732-183X/04/2216-3269/$20.00
DOI: 10.1200/JCO.2004.10.052
Twenty-four relapsed or refractory patients were treated with a dose-escalating regimen of oral
CC-4047. Clinical responses and adverse effects were identified, and peripheral T-cell subsets, serum
cytokines, and proangiogenic factors were evaluated.
Results
CC-4047 was tolerated with no serious nonhematologic adverse events. All patients were eligible for
analysis. Toxicity criteria during the initial 4 weeks of study were used to define the maximum-tolerated
dose (MTD). During this period, one patient withdrew with a deep vein thrombosis (DVT) probably
caused by an undiagnosed primary melanoma with lymphadenopathy in the groin, one patient withdrew
because of progressive disease (PD), and three patients discontinued with neutropenia. Nineteen of 24
patients continued on treatment beyond 4 weeks to PD or development of a serious adverse event.
Three further patients developed a DVT at 4, 9, and 11 months. Treatment resulted in a greater than
25% reduction in paraprotein in 67% of patients, 13 patients (54%) experienced a greater than 50%
reduction in paraprotein, and four (17%) of 24 patients entered complete remission. The MTD was
2 mg/d. All patients showed increased CD45RO expression on CD4⫹ and CD8⫹ cells, with a
concomitant decrease in CD45RA⫹ cells. CC-4047 treatment was associated with significantly
increased serum interleukin (IL)-2 receptor and IL-12 levels, which is consistent with activation of T
cells and monocytes and macrophages.
Conclusion
This study demonstrates the safety and efficacy of CC-4047. The MTD of CC-4047 orally was 2 mg/d.
This is the first report demonstrating in vivo T-cell costimulation by this class of compound, supporting
a potential role for CC-4047 as an immunostimulatory adjuvant treatment.

J Clin Oncol 22:3269-3276. © 2004 by American Society of Clinical Oncology

growth factor (VEGF) and basic fibroblast

INTRODUCTION
Multiple myeloma (MM) is incurable with
conventional chemotherapy and has a me-
dian survival time of 2.5 to 3.5 years. Much
knowledge has accrued about the mecha-
nisms whereby MM cells home and adhere
to the bone marrow stromal cells and extra
cellular matrix proteins. Interleukin (IL)-6
has been shown to be important in aug-
menting myeloma cell growth, inhibiting
apoptosis, and enhancing drug resistance in
the MM cell. Similarly, vascular endothelial
growth factor (bFGF) stimulate angiogenesis,
inhibit myeloma cell transendothelial migra-
tion, and reduce dendritic cell formation.
These insights have resulted in a plethora
of new agents being developed, including tha-
lidomide analogs1,2 and proteasome inhibi-
tors.3 Thalidomide was initially given because
of its antiangiogenic properties.4,5 However,
thalidomide also exerts other effects including
modulation of adhesion of MM cells to bone
marrow stromal cells,6 decreasing secretion
and bioreactivity of cytokines in the bone mar-

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Copyright © 2020 American Society of Clinical Oncology. All rights reserved.
 Schey et al
row environment,7,8 and immunomodulatory properties.9,10
The initial encouraging results in advanced relapsed and
refractory disease11 led to the development of thalidomide-
derived immunomodulatory drugs (IMiDs), which demon-
strated improved potency and reduced toxicity. CC-4047 is
one of two small molecule derivatives of thalidomide
used in patients with MM. We present data from a phase
I study addressing the tolerability, efficacy, and immu-
nologic effects of CC-4047 in the treatment of patients
with relapsed or refractory MM.
PATIENTS AND METHODS
Study Objectives
The primary objective of this study was to evaluate the safety
of CC-4047 and determine the maximum-tolerated dose (MTD)
of CC-4047 given daily by mouth, at doses of 1 to 10 mg/d, to
patients with relapsed or progressive disease. The secondary ob-
jectives were to evaluate disease response and the effect of CC-
4047 on T-cell activation and serologic levels of IL-6, IL-12, IL-8,
IL-10, tumor necrosis factor alpha (TNF-␣), VEGF, and bFGF
over the initial 4-week study period.
Study Design
The study was an open, single-center, phase I, dose-
escalation study, with 1, 2, 5, and 10 mg given daily by mouth 2
hours before any food. Patients were entered onto cohorts of three
subjects at doses of 1, 2, 5, and 10 mg/d. Each cohort was entered
after the safety and tolerability of the prior lower-dose cohort had
been established after a minimum of 28 days of treatment. If no
dose-limiting toxicity (DLT) was observed, the next cohort of
three patients was entered at the next highest dose level. If one of
three patients at any dose level developed DLT during the first 4
weeks of treatment, a further three patients were enrolled at that
dose level, up to a maximum of six patients. If no further DLT was
observed, the subsequent cohort was enrolled at the next dose level. If
two or more patients developed DLT, the following cohort was en-
rolled at the previous dose level. An additional six patients were
entered at the MTD to gain experience and define the toxicity rate.
Pharmacokinetic analysis was performed on days 1 to 3 and
day 28. Patients were evaluated for adverse events at each visit
using the National Cancer Institute Common Toxicity Criteria,
and treatment was discontinued if they experienced a DLT. Pa-
tients who discontinued treatment because of an adverse event
were followed-up to document resolution or stabilization of the
event. Patients who showed disease response or stability continued
on treatment past 28 days until they developed a DLT or disease
progression. In the event of a hematologic DLT, patients were
allowed to reduce dose and continue on treatment at the next dose
level down if recovery occurred within 4 weeks.
Patient Selection
Patients diagnosed with MM and who were considered re-
fractory to treatment after at least two cycles of treatment or who
relapsed after previous treatment were eligible for entry. Bisphos-
phonates were allowed, but corticosteroids or other chemother-
apy, including investigational agents, had to be discontinued for at
least 30 days before entry onto study. Patients were not eligible if
they had serum creatinine levels greater than 1.5 mg/dL or grade 3
peripheral neuropathy as assessed by the clinician-assessed Neu-
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Copyright © 2020 American Society of Clinical Oncology. All rights reserved.
ropathy Targeted Symptom Questionnaire, were unable to main-
tain a platelet count ⱖ 20,000 cells/␮L, or had an absolute
neutrophil count of less than 1,000 cells/␮L. Patients were also
excluded if they had a history of malignancy within the last 3 years
or had other clinically relevant active comorbid medical condi-
tions within 6 months or less that were uncontrolled by appropri-
ate medication. All patients gave written informed consent.
Laboratory Investigations
Cytokine enzyme-linked immunosorbent assay analysis. Blood
was collected into serum separator tubes, left to clot for approxi-
mately 30 minutes, and then spun at 950 ⫻ g for 10 minutes, and
the serum was collected. Sera were frozen in aliquots at ⫺70°C
until assayed for serum IL-2 receptor (sIL-2r), IL-2, IL-12, TNF-␣,
interferon gamma (IFN-␥), granulocyte-macrophage colony-
stimulating factor, VEGF, IL-8, and bFGF by enzyme-linked im-
munosorbent assay (R&D Systems, Abingdon, United Kingdom).
Standard absorbance (405 nm) of duplicate wells was used to
calculate the concentration of cytokine and receptor levels.
Phenotypic analysis of T cells. Heparinized venous blood
was collected into sodium heparin vacutainers and surface
stained (for 15 minutes at room temperature) with the follow-
ing fluorochrome-conjugated monoclonal antibodies: anti-CD4
PerCP (Clone SK7; Becton Dickinson Immunocytometry Sys-
tems, Oxford, United Kingdom) or anti-CD8 PerCP (SK1; Becton
Dickinson Immunocytometry Systems) with anti-CD45RA fluo-
rescein isothiocyanate (L48; Becton Dickinson Immunocytometry
Systems) and anti-CD45RO PE (UCHL-1; Becton Dickinson Im-
munocytometry Systems) plus appropriate isotype-matched and
compensation controls. RBCs were lysed with 2 mL of 1⫻ FACS
Lysing Solution (Becton Dickinson Immunocytometry Systems;
for 10 minutes at room temperature) and spun down (500 ⫻ g for
5 minutes), and the cell pellet was resuspended in 200 ␮L of
CellFix (Becton Dickinson Immunocytometry Systems) for anal-
ysis. Peripheral-blood mononuclear cells were surface stained (30
minutes at 4°C) with anti-CD4 or anti-CD8 PerCP with anti-
CD45RO PE plus the appropriate isotype-matched and compen-
sation controls.
Lymphocytes were gated on flow cytometric analysis for for-
ward scatter versus side scatter properties, and positive T-cell
subsets were displayed as two-color dot plots. For each sample,
10,000 lymphocytes were acquired on a Becton Dickinson FACScan
(Becton Dickinson Immunocytometry Systems) using CellQuest
software (BD Biosciences, San Jose, CA) and analyzed using EXPO32
(Beckman Coulter, Fullerton, CA).
Pharmacokinetic analysis. Pharmacokinetic analysis was
performed on days 1 and 28, before dose and 0.25, 0.5, 0.75, 1, 1.5,
2, 2.5, 3, 4, 6, 8, 10, 12, 18, and 24 hours after dose. In addition, a
blood sample was collected at each weekly clinic visit for CC-4047
level determination. Urine was collected and pooled according to
the following time intervals after dose: 0 to 4, 4 to 8, 8 to 12, and 12
to 24 hours.
Response Assessment
Response was assessed by Ig paraprotein quantitation using
immunoelectrophoresis of serum and 24-hour urine collection.
Samples were taken weekly for the first 4 weeks and monthly
thereafter. Bone marrow analysis was performed before entry and
repeated if the patient was thought to have achieved a complete
response or developed myelosuppression to distinguish between
disease progression or drug-induced toxicity. Radiologic investi-
gations were performed as clinically indicated.
JOURNAL OF CLINICAL ONCOLOGY
 Phase I Study of CC-4047 in MM

Definitions of Response to Therapy

Complete remission (CR) was defined as the disappearance Table 1. Patient Characteristics

of serum and urine M-components on electrophoresis as well as by No. of

immunofixation studies. Very good partial response was defined Characteristic Patients %
as a 75% to 99% reduction in quantitative Ig, and if urinary Sex
M-component (Bence Jones protein) was present, either a 90% to Male 13 54
99% reduction in this protein or a urine M-component of less than Female 11 46
0.2 g/d. Partial response was defined as a 50% to 74% reduction in Age, years
the quantitative Ig, and if present, a 50% to 89% reduction in the Mean 66
urinary M-component (BJP). Minimal response was defined as a SD 9
25% to 49% reduction in the quantitative Ig or the urinary BJP. M-component
Stable disease or no response was defined as a less than 25% IgG 20 83
IgA 4 17
reduction in either the quantitative Ig or the urinary BJP. Refrac-
Prior lines of therapy
tory disease or progression was defined as an increase to more than
Median 3
25% of the baseline protein level or reappearance of any
Range 1-6
M-component that had disappeared with treatment. Relapse after
Previous stem-cell transplantation 5 21
remission was defined as any of the following: (1) a more than 25% Previous thalidomide 7 29
increase in M-component from the baseline levels; (2) a reappearance Hemoglobin, g/dL
of the M paraprotein that had disappeared; or (3) a definite increase in Mean 9.3
the size and number of lytic bone lesions recognized on radiographs SD 1.8
(compression fractures per se did not constitute a relapse). Total white cell count, ⫻109/L
Mean 4.1
Adverse Events
SD 1.9
Patients were monitored before enrollment and at weekly
Neutrophil count, ⫻109/L
and monthly intervals thereafter until completion of or with-
Mean 2.3
drawal from study. Patients were evaluated by direct questioning, SD 1.3
physical examination, and laboratory investigation of full blood Platelets, ⫻109/L
count and film, biochemistry, and liver function tests and urinal- Mean 193
ysis every 3 months. Patients had a baseline ECG and skeletal SD 101
survey performed within 4 weeks of study entry and as indicated Serum creatinine, mmol/L
thereafter. DLT was defined as grade 3 or 4 nonhematologic or Mean 107
grade 4 hematologic toxicity. SD 64
Serum calcium, mmol/L
Statistical Analysis
Mean 2.49
The MTD was defined using a standard, phase I, dose- SD 0.22
escalation study design. The model predicts that if the true DLT is Serum albumin, g/L
5%, then the probability of dose escalation will be 0.97. All patients Mean 30
were analyzed for progression-free and overall survival on an SD 6
intent-to-treat basis using Kaplan-Meier survival estimations.12 Serum LDH, U/L
Correlation of responses was assessed using linear regression. Mean 462
Comparison of cytokine levels before and 4 weeks after the start of SD 165
treatment was analyzed using the Student’s t test. Data were ana- Serum beta2-microglobulin, n ⫽ 16
lyzed using GB Stat version 10 (Dynamic Microsystems, Silver Mean 4.9
Spring, MD). SD 3.3
Performance status, ECOG
0-1 17 70
RESULTS
2-3 7 30

NOTE. Absolute values given are means and SD.

Twenty-four patients were entered onto the study. All pa-
tients had evidence of disease progression on study entry,
and five patients were refractory to treatment. The median
age at entry was 66 years (range, 49 to 82 years), and the
male to female ratio was 13:11. Twenty patients (83%) had
IgG paraprotein, and four (17%) had IgA. There was a
median of three prior courses of chemotherapy (range, one
to six courses). Five patients (21%) had undergone a previ-
ous autologous stem-cell transplantation, and seven pa-
tients (29%) had received prior thalidomide therapy (Table
1). The median duration of study treatment for all patients
was 28 weeks (range, 3 to 132 weeks), and three patients
currently continue on treatment.
Abbreviations: SD, standard deviation; Ig, immunoglobulin; LDH, lactate
dehydrogenase; ECOG, Eastern Cooperative Oncology Group.
Adverse Events
The MTD was defined by the DLT that occurred in
the first 4 weeks of treatment. All 24 patients were assess-
able for toxicity.
Nonhematologic toxicity. One patient who was receiv-
ing 1 mg of CC-4047 developed a deep vein thrombosis
(DVT) that was proven on Doppler ultrasound at week 3;
the DVT required anticoagulation and discontinuation of

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Copyright © 2020 American Society of Clinical Oncology. All rights reserved.
 Schey et al
Fig 1. Nonhematologic grade 1 (G1) and 2 (G2) adverse events.
treatment (grade 3 cardiovascular event). Subsequent in-
vestigations identified a malignant melanoma with inguinal
lymphadenopathy on the side of the previously diagnosed
DVT. The patient died of progressive melanoma with stable
MM disease. Three further patients developed DVT after
the initial 28-day study period at 4, 9, and 11 months. The
patients were receiving 2, 2, and 5 mg CC-4047 daily at the
time of the event and were discontinued from treatment.
No other grade 3 or 4 nonhematologic DLT was observed.
Grade 1 gastrointestinal toxicity was reported in four pa-
tients (18%), and grade 2 gastrointestinal toxicity was re-
ported in four patients (18%). Grade 1 skin toxicity was
reported in five patients (21%). Grade 1 neuropathy oc-
curred in three patients (16%); none of these patients had
previously received thalidomide. Transient grade 1 ortho-
static hypotension occurred in two patients receiving 5 and
10 mg of CC-4047; and grades 1 and 2 self-limiting edema
occurred in three patients receiving 5, 5, and 2 mg and one
patient receiving 1 mg of CC-4047, respectively. Only three
of these events occurred after week 4 (Fig 1). All patients
were treated with supportive care only, and the toxicities
resolved without evidence of deterioration.
Hematologic toxicity. Dose-limiting grade 4 neutrope-
nia occurred in a total of six patients at a median of 3 weeks
after starting therapy (Table 2). Two events occurred on 10
mg daily at 2 and 3 weeks, two occurred on 5 mg at 3 weeks,
and two occurred on 2 mg at 3 weeks. All of these patients
Table 2. Hematologic Dose-Limiting Toxicity: Neutropenia
No. of Patients
No. of
Dose (mg) Patients Grade 3 Grade 4
1 6 1 0
2 9 2 2
5 6 4 2
10 3 1 2 to 71 weeks). These responses occurred despite dose reduc-
Overall 24 8 6
Median time to onset, weeks — 3 3 (Table 3). The median duration of therapy was 28 weeks
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Copyright © 2020 American Society of Clinical Oncology. All rights reserved.
discontinued treatment according to protocol and recov-
ered their neutrophil counts spontaneously without the
need to resort to the use of growth factors. Three of the
patients with grade 4 neutropenia were able to restart treat-
ment with CC-4047 at a lower dose. Two of the three
patients developed recurrent grade 4 neutropenia, and one
of these patients recovered within 4 weeks and was able to
restart treatment after a further dose reduction. This patient
continued on the reduced dose for a further 6 months and
has subsequently relapsed from his myeloma. Grade 3 neu-
tropenia occurred in a further eight patients at a median of
3 weeks from starting treatment (Table 2). One patient had
progressive disease and discontinued treatment; two pa-
tients continued on treatment with no worsening of the
neutropenia; and in five patients, the neutropenia resolved
after discontinuing CC-4047 within 4 weeks, and they re-
started therapy at a lower dose. Two of these five patients
experienced recurrence of neutropenia at the lower dose,
and one of the patients was able to continue therapy after a
further dose reduction (Table 2). After the initial 4-week
period, only one new patient developed neutropenia, and
this occurred after a dose escalation to 5 mg. Three patients
experienced grade 3 thrombocytopenia during the study
period; one of the patients had progressive disease and
discontinued treatment, and the other two patients discon-
tinued treatment, and the thrombocytopenia resolved
spontaneously with no adverse clinical effect.
In total, five patients did not continue CC-4047 beyond
28 days (one patient with thrombosis, three patients with
neutropenia, and one patient with progressive disease). The
DLT was neutropenia, and the MTD was 2 mg/d.
Clinical Response
Response was analyzed on an intent-to-treat basis, and
all 24 patients were assessable. Four (17%) of 24 patients
achieved CR at 12, 26, 31, and 43 weeks. The patient who
achieved CR at 43 weeks subsequently developed a DVT
and discontinued treatment. She has continued to be off all
antimyeloma therapy for 15 months and remains in CR.
Three (13%) of 24 patients achieved very good partial re-
sponses at 32, 40, and 97 weeks, and six (25%) of 24 patients
achieved a partial response at 4 to 71 weeks. An additional
four (17%) of 24 patients achieved a minimal response, and
six (25%) of 24 patients had stable disease. Therefore, a total
of 13 (54%) of 24 patients had a greater than 50% decrease
in paraprotein, and 17 (71%) of 24 patients had a greater
than 25% decrease in paraprotein. One (4%) of 24 patients
had progressive disease during the first 4 weeks of therapy
(Table 3). Initial responses were seen at all dose levels, with
a median time to maximum response of 21 weeks (range, 4
tions, and two of four CR occurred after dose de-escalation
(range, 3 to 132 weeks). Responses were observed regardless
JOURNAL OF CLINICAL ONCOLOGY
 Phase I Study of CC-4047 in MM

Table 3. Maximum Response According to Starting Dose and Dose at Time of Maximum Response
Maximum Response (No. of patients)
No. of
Dose Patients CR VGPR PR MR SD PD

Overall 24 4 3 6 4 6 1
Starting dose, mg
1 6 1 1 1 1 2 0
2 9 1 0 4 1 3 0
5 6 2 1 0 1 1 1
10 3 0 1 1 1 0 0
Dose at maximum response, mg
1 6 0 1 1 2ⴱ 2 0
2 14 4† 2‡ 4 1 3 0
5 3 0 0 1§ 0 1 1
10 1 0 0 0 1 0 0

Abbreviations: CR, complete response; VGPR, very good partial response; PR, partial response; MR, minimal response; SD, stable disease; PD,
progressive disease.
ⴱ
One patient decreased to 2 mg at 6 weeks and 1 mg at 10 weeks.
†One patient increased from 1 mg at 27 weeks; two patients decreased from 5 mg at 8 weeks.
‡One patient decreased from 5 mg at 4 weeks; one patient decreased from 10 mg to 5 mg at 8 weeks and 2 mg at 14 weeks.
§Patient decreased dose at 8 weeks.

of the number of lines of previous therapy or modality At all dose levels, after maximum serum concentration,
(Table 4). There was a correlation between the paraprotein plasma concentrations of CC-4047 declined in a predomi-
response seen at week 4 and the maximum response nantly monophasic manner, with the start of the elimina-
achieved (r ⫽ 0.71; P ⬍ .0001). tion phase occurring between 3 and 10 hours after dose on
The median event-free survival time was 28 weeks, the day 1 and week 4. The mean terminal elimination half-lives
median progression-free survival time was 39 weeks, and were similar on both day 1 and week 4, with geometric mean
the median overall survival time was 90 weeks (Fig 2). values ranging from 6.8 to 7.9 hours and 6.2 to 7.8 hours,
Eighteen (75%) of 24 patients continued on study treat- respectively. By week 4, there was only a small degree of
ment beyond 12 weeks, with a median dose of 2 mg/d accumulation of CC-4047, with mean accumulation ratios
(range, 1 to 5 mg/d). of CC-4047 in plasma being approximately 1.06 to 1.52 and
Pharmacokinetics 1.01 to 1.62 for maximum serum concentration and area
CC-4047 was steadily absorbed at the 1-, 2-, 5-, and under the curve (0-␶), respectively. At the 10-mg dose level,
10-mg dose levels, with time to maximum plasma concen- trough concentrations at the end of weeks 1, 2, and 3 indi-
trations occurring at a median of between 2.5 and 2.75 cated that CC-4047 was accumulating in plasma to a greater
hours after dose on day 1 and between 3 and 4 hours after extent than that seen at the lower dose levels. Two thirds of
dose in week 4. For individual patients, the time to maxi- the drug was excreted in the urine.
mum plasma concentration ranged from 0.5 to 8 hours after
dose and showed no obvious trend with increasing dose or Cytokine and T-Cell Profiles
multiple dosing. Serum IL-12 and soluble sIL-2r levels increased signif-
icantly during the first 4 weeks of treatment (P ⬍ .01 and
P ⬍ .001, respectively; Fig 2). There was a correlation be-
tween the percentage change in IL-12 and sIL-2r (before
Table 4. Maximum Response According to Prior Treatment and 4 weeks after treatment) and percentage decrease in
Maximum Response (No.) paraprotein levels over the same period (r ⫽ 0.469, P ⬍ .05;
Prior Treatment CR VGPR PR MR SD PD and r ⫽ 0.639, P ⬍ .05, respectively). There were no signif-
⬍ 3 lines (n ⫽ 11) 3 1 3 0 4 0 icant changes and no correlation was found in IL-6, TNF-␣,
ⱖ 3 lines (n ⫽ 13) 1 2 3 3 3 1 IL-10, VEGF, or bFGF levels between paraprotein response
Previous thalidomide (n ⫽ 7) 0 1 1 2 2 1 (data not shown). In 17 of 18 patients, the peripheral-blood
Previous SCT (n ⫽ 5) 1 0 1 1 2 0
CD4⫹/45RO⫹ and CD8⫹/45RO⫹ cells increased signifi-
Abbreviations: CR, complete response; VGPR, very good partial cantly (P ⬍ .009 and P ⬍ .002, respectively), with a con-
response; PR, partial response; MR, minimal response; SD, stable
disease; PD, progressive disease; SCT, stem-cell transplantation. comitant decrease in both CD4⫹/45RA⫹ and CD8⫹/
45RA⫹ cells (P ⬍ .007 and P ⬍ .002, respectively; Fig 3).

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Copyright © 2020 American Society of Clinical Oncology. All rights reserved.
 Schey et al
Fig 2. Serum interleukin-2 receptor (sIL-2r) and interleukin-12 (IL-12) before and 4 weeks after commencing treatment with CC-4047 (P ⬍ .001 and
P ⬍ .01, respectively).
DISCUSSION
Thalidomide has been clearly shown to be active in relapsed
and refractory myeloma, but its role in conjunction with
other treatment modalities and optimal timing of the intro-
duction of this novel agent in the natural history of the
disease currently remains under investigation.13 However,
the use of thalidomide is associated with significant nonhe-
matologic toxicity, particularly peripheral neuropathy,
somnolence, skin rashes, and constipation. The IMiD tha-
lidomide analog CC-5013 has been shown in recent phase I
and II studies to have marked antitumor activity.14,15 In
vitro studies suggest markedly increased stimulation of
T-cell proliferation, IL-2 secretion, and IFN-␥ production
compared with thalidomide.16 Furthermore, CC-4047 pos-
sesses antiangiogenic activity17 and augments antitumor
responses in vivo after autologous tumor cell vaccination in
a murine colorectal cancer model.18 Thalidomide was
withdrawn in the United Kingdom in the early 1960s
because of its observed teratogenic effects. No evidence
of mutagenic or clastogenic potential for CC-4047 on the
basis of evaluation of reverse mutation in bacteria, in-
duction of chromosome aberrations in human
peripheral-blood lymphocytes, or induction of muta-
tions in mouse lymphoma L5178Y cells has been identi-
fied. In a screening reproductive toxicity study, CC-4047
was without embryotoxic effect. However, the glycolipopro-
tein teratogenicity studies for CC-4047 in two species, includ-
ing the New Zealand rabbit, a species that is highly susceptible
to the teratogenic effects of thalidomide, have not yet been
conducted; and therefore, evidence for the potential teratoge-
nicity of CC-4047 is still pending.
The first clinically available analog, CC-5013 (Revimid;
Celgene Corp, San Diego, CA), was reported by Richardson et
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Copyright © 2020 American Society of Clinical Oncology. All rights reserved.
al19 in a phase I study of relapsed MM. Our study reports the
first use of another IMiD, CC-4047 (Actimid; Celgene Corp),
in patients with advanced cancer.
This study shows that CC-4047 is well tolerated orally
in patients in the outpatient setting. Thrombosis was re-
ported in four patients, but in one patient, this was most
likely secondary to the development of malignant mela-
noma. Therefore, the treatment-related incidence of
thrombosis was 12.5%, which is comparable to the inci-
dence reported by others in myeloma treated with chemo-
therapy or thalidomide as a single agent.20,21 No other grade
3 or 4 nonhematologic DLTs were observed. Dose-
limiting hematologic neutropenia was observed in six
patients. Neutropenia resolved in all except one patient
with progressive disease, and most patients were able to
restart treatment at a lower dose. There was no grade 4
dose-limiting thrombocytopenia observed. The oral
MTD of CC-4047 was 2 mg/d as defined by the toxicity
criteria outlined in Patients and Methods.
The responses noted in this study are encouraging, and
this early data seems to offer improved outcomes compared
with currently available therapeutic options. Only one pa-
tient progressed during the first 4 weeks of treatment, and
response durations were also encouraging. It is of interest to
note that the patient who discontinued treatment because
of a DVT while in CR remained in CR 15 months after
stopping CC-4047. The correlation seen between the re-
sponse at 4 weeks and the maximum response achieved
supports the addition of dexamethasone in those patients
with stable or suboptimal responses at 4 weeks. Pharmaco-
kinetic data showed CC-4047 to be well absorbed by mouth
at all dose levels from 1 to 10 mg/d, with a median half-life
of 7 hours.
JOURNAL OF CLINICAL ONCOLOGY
 Phase I Study of CC-4047 in MM

Fig 3. Circulating CD45 RO and CD45 RA CD4⫹ and CD8⫹ cells before and 4 weeks after commencing treatment with CC-4047.

Thalidomide’s antiangiogenic activity originally led to
its use in MM. However, its rapid onset of action and the
failure to identify an inhibitory effect on angiogenic cyto-
kines in vivo22 suggests that its activity may be the result of
another mechanism of action. However, other antiangio-
genic factors, such as the angiopoietins, may also be impor-
tant in disease control.23
IMiDs are able to potently costimulate CD4⫹ and
CD8⫹ T cells.24 Evidence from in vitro data suggests that
this leads to enhanced T-cell– dependent IL-12 production
in association with increased CD40L expression. IL-12 is
derived from monocytes and macrophages and has a key
role in amplifying a Th1 type response.25 In murine tumor
models, IL-12 has been shown to exhibit potent antitumor
activity through a variety of mechanisms including the
stimulation of natural killer cells, CD8⫹ cytotoxic T cells,
and IFN-␥–mediated antiangiogenesis.25-27 In vitro studies
suggest that stimulated T lymphocytes from MM patients
are able to differentiate toward a Th1 subset in the presence
of recombinant IL-12.28,29 Our results support a significant
in vivo effect of CC-4047 on serum IL-12 and sIL-2r levels
during the first 4 weeks of treatment, which correlated
significantly with the percentage decrease in paraprotein.
The highly consistent elevation of sIL-2r provides indirect
evidence of IMiD-induced T-cell activation because surface
IL-2 receptor is shed on activation of IL-2–mediated activa-
tion pathways. The decrease in CD4⫹/CD45RA⫹ (P ⬍
.001) and CD8⫹/CD45RA⫹ cells (P ⬍ .002) during the
first 4 weeks of study was accompanied by a correspond-
ing increase in CD4⫹/CD45RO⫹ (P ⬍ .009) and CD8⫹/
CD45RO⫹ cells (P ⬍ .002), suggesting a switch from
resting memory or naive cells to activated effector T cells.
Naturally occurring, major histocompatibility com-
plex—restricted, myeloma idiotype-specific T cells have
previously been identified circulating in patients with
myeloma.30 Although we did not demonstrate a tumor-
specific response in this study, our findings provide
strong evidence for a switch to a Th1 immune response
induced by the use of CC-4047.
In conclusion, CC-4047 was well tolerated. Responses
in this heavily pretreated group of patients were excellent,
with only one patient having progressive disease during the
initial treatment period. Although there was no evidence of
an in vivo effect on angiogenic factors, TNF-␣, or IL-6

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Copyright © 2020 American Society of Clinical Oncology. All rights reserved.
 Schey et al

serum levels, significant increases in serum levels of the
immunomodulatory cytokine IL-12 and CD4⫹ and CD8⫹
T-cell activation status provide the first evidence of an in
vivo effect of CC-4047 acting as a potent immunomodula-
tor. These encouraging data further support the use of
CC-4047 as an immune adjuvant in the postvaccination
setting by boosting antitumor immunity.31,32 These results
support the further study of CC-4047 in a larger phase II
trial at a dose of 2 mg/d.
■ ■ ■
Authors’ Disclosures of Potential
Conflicts of Interest
The following authors or their immediate family mem-
bers have indicated a financial interest. No conflict exists for
drugs or devices used in a study if they are not being evaluated
as part of the investigation. Owns stock (not including shares
held through a public mutual fund): Steve A. Schey, Celgene;
Angus G. Dalgleish, Celgene. Acted as a consultant within the
last 2 years: Angus G. Dalgleish, Celgene. Performed contract
work within the last 2 years: Steve A. Schey, Celgene; Angus G.
Dalgleish, Celgene.

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