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Originally published as JCO Early Release 10.1200/JCO.2004.10.052 on July 12 2004 © 2004 American Society of Clinical Oncology. Phase I Study of an Immunomodulatory Thalidomide Analog, CC-4047, in Relapsed or Refractory Multiple MyelomaFrom the Guy’s and St Thomas’ Trust, Department of Haematology, Thomas Guy House; Department of Cellular and Molecular Medicine, St George’s Hospital, London, United Kingdom; and Celgene Corp, San Diego, CA Address reprint requests to S.A. Schey, MD, Guy’s and St Thomas’ Trust, Department of Haematology, Thomas Guy House, London SE1 9RT, United Kingdom; e-mail: steve.schey{at}gstt.sthames.nhs.uk
PURPOSE: To assess the safety, efficacy, and immunomodulatory effects of CC-4047 (Actimid; Celgene, San Diego, CA) in patients with relapsed or refractory myeloma. PATIENTS AND METHODS: 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.
Multiple myeloma (MM) is incurable with conventional chemotherapy and has a median survival time of 2.5 to 3.5 years. Much knowledge has accrued about the mechanisms 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 augmenting myeloma cell growth, inhibiting apoptosis, and enhancing drug resistance in the MM cell. Similarly, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) stimulate angiogenesis, inhibit myeloma cell transendothelial migration, and reduce dendritic cell formation. These insights have resulted in a plethora of new agents being developed, including thalidomide analogs1,2 and proteasome inhibitors.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 marrow 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 demonstrated 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 immunologic effects of CC-4047 in the treatment of patients with relapsed or refractory MM.
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 objectives 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 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. Patients 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
Laboratory Investigations 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 following fluorochrome-conjugated monoclonal antibodies: anti-CD4 PerCP (Clone SK7; Becton Dickinson Immunocytometry Systems, Oxford, United Kingdom) or anti-CD8 PerCP (SK1; Becton Dickinson Immunocytometry Systems) with anti-CD45RA fluorescein isothiocyanate (L48; Becton Dickinson Immunocytometry Systems) and anti-CD45RO PE (UCHL-1; Becton Dickinson Immunocytometry Systems) plus appropriate isotype-matched and compensation controls. RBCs were lysed with 2 mL of 1x FACS Lysing Solution (Becton Dickinson Immunocytometry Systems; for 10 minutes at room temperature) and spun down (500 x g for 5 minutes), and the cell pellet was resuspended in 200 µL of CellFix (Becton Dickinson Immunocytometry Systems) for analysis. 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 compensation controls. Lymphocytes were gated on flow cytometric analysis for forward 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
Definitions of Response to Therapy
Adverse Events
Statistical Analysis
Twenty-four patients were entered onto the study. All patients 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 previous autologous stem-cell transplantation, and seven patients (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.
Adverse Events The MTD was defined by the DLT that occurred in the first 4 weeks of treatment. All 24 patients were assessable for toxicity. Nonhematologic toxicity. One patient who was receiving 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 treatment (grade 3 cardiovascular event). Subsequent investigations 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 patients (18%), and grade 2 gastrointestinal toxicity was reported in four patients (18%). Grade 1 skin toxicity was reported in five patients (21%). Grade 1 neuropathy occurred in three patients (16%); none of these patients had previously received thalidomide. Transient grade 1 orthostatic 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 neutropenia 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 discontinued treatment according to protocol and recovered 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 treatment 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 neutropenia 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 patients 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 restarted 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 discontinued 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
The median event-free survival time was 28 weeks, the median progression-free survival time was 39 weeks, and the median overall survival time was 90 weeks (Fig 2). Eighteen (75%) of 24 patients continued on study treatment beyond 12 weeks, with a median dose of 2 mg/d (range, 1 to 5 mg/d).
Pharmacokinetics CC-4047 was steadily absorbed at the 1-, 2-, 5-, and 10-mg dose levels, with time to maximum plasma concentrations occurring at a median of between 2.5 and 2.75 hours after dose on day 1 and between 3 and 4 hours after dose in week 4. For individual patients, the time to maximum plasma concentration ranged from 0.5 to 8 hours after dose and showed no obvious trend with increasing dose or multiple dosing.
At all dose levels, after maximum serum concentration, plasma concentrations of CC-4047 declined in a predominantly monophasic manner, with the start of the elimination phase occurring between 3 and 10 hours after dose on day 1 and week 4. The mean terminal elimination half-lives were similar on both day 1 and week 4, with geometric mean values ranging from 6.8 to 7.9 hours and 6.2 to 7.8 hours, respectively. By week 4, there was only a small degree of accumulation of CC-4047, with mean accumulation ratios of CC-4047 in plasma being approximately 1.06 to 1.52 and 1.01 to 1.62 for maximum serum concentration and area under the curve (0-
Cytokine and T-Cell Profiles
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 introduction 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 nonhematologic toxicity, particularly peripheral neuropathy, somnolence, skin rashes, and constipation. The IMiD thalidomide 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 possesses 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, induction of chromosome aberrations in human peripheral-blood lymphocytes, or induction of mutations in mouse lymphoma L5178Y cells has been identified. In a screening reproductive toxicity study, CC-4047 was without embryotoxic effect. However, the glycolipoprotein teratogenicity studies for CC-4047 in two species, including 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 teratogenicity of CC-4047 is still pending. The first clinically available analog, CC-5013 (Revimid; Celgene Corp, San Diego, CA), was reported by Richardson et 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 reported in four patients, but in one patient, this was most likely secondary to the development of malignant melanoma. Therefore, the treatment-related incidence of thrombosis was 12.5%, which is comparable to the incidence reported by others in myeloma treated with chemotherapy 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 patient 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 response at 4 weeks and the maximum response achieved supports the addition of dexamethasone in those patients with stable or suboptimal responses at 4 weeks. Pharmacokinetic 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. 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 cytokines in vivo22 suggests that its activity may be the result of another mechanism of action. However, other antiangiogenic factors, such as the angiopoietins, may also be important 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-
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-
The following authors or their immediate family members 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.
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 conflicts of interest are found at the end of this article.
1. Raje N, Anderson KC: Thalidomide and immunomodulatory drugs as cancer therapy. Curr Opin Oncol 14:635-640, 2002[CrossRef][Medline] 2. Schey SA: Thalidomide in the management of multiple myeloma. Hematology 7:291-299, 2002[CrossRef][Medline]
3. Richardson PG, Barlogie B, Berenson, et al: A phase 2 study of bortezomib in relapsed refractory myeloma. N Engl J Med 348:2609-2617, 2003
4. D’Amato RJ, Loughman MS, Flynn E, et al: Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci U S A 91:4082-4085, 1994
5. Singhal S, Mehta J, Desikan R, et al: Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 341:1565-1571, 1999 6. Geitz H, Handt S, Zwingenberger K: Thalidomide selectively modulates the density of cell surface molecules involved in the adhesion cascade. Immunopharmacology 31:213-221, 1996[CrossRef][Medline]
7. Moreira AL, Sumpaio EP, Zmuidizinas A, et al: Thalidomide exerts its inhibitory action in tumor necrosis factor alpha by enhancing mRNA degradation. J Exp Med 177:1675-1680, 1993 8. Hideshima T, Chauhan D, Schlossman R, et al: The role of tumor necrosis factor in the pathophysiology of human multiple myeloma: Therapeutic applications. Oncogene 20:4519-4527, 2001[CrossRef][Medline] 9. McHugh SM, Rifkin IR, Deighton J, et al: The immunosuppressive drug thalidomide induces T helper cell type 2 (Th2) and concomitantly inhibits Th1 cytokine production in mitogen and antigen-stimulated human peripheral blood mononuclear cell cultures. Clin Exp Immunol 99:160-167, 1995[Medline]
10. Haslett PA, Corral LG, Albert M, et al: Thalidomide co-stimulates primary human T lymphocytes, preferentially inducing proliferation, cytokine production and cytotoxic responses in the CD8 + subsets. J Exp Med 187:1885-1892, 1998 11. Schey SA, Cavenagh J, Jones RW, et al: An UK myeloma forum phase II study of thalidomide: Long-term follow-up and recommendations for treatment. Leuk Res 27:909-914, 2003[CrossRef][Medline] 12. Kaplan EL, Meier P: Non-parametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958[CrossRef] 13. Schey SA: Myeloma: New insights. Eur J Cancer 1:35-41, 2004 14. Marriott JB, Muller GW, Stirling D, et al: Immunotherapeutic and antitumour potential of thalidomide analogues. Expert Opin Biol Ther 1:675-682, 2001[CrossRef][Medline] 15. Dredge K, Dalgleish AG, Marriott JB: Thalidomide analogs as emerging anti-cancer drugs. Anticancer Drugs 14:331-335, 2003[CrossRef][Medline]
16. Corral LG, Haslett PAJ, Muller GW, et al: Differential cytokine modulation and T cell activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF- 17. Dredge K, Marriott JB, Macdonald CD, et al: Novel thalidomide analogues display anti-angiogenic activity independently of immunomodulatory effects. Br J Cancer 87:1166-1172, 2002[CrossRef][Medline]
18. Dredge K, Marriott JB, Todryk SM, et al: Protective anti-tumor immunity induced by a costimulatory thalidomide analog in conjunction with whole tumour cell vaccination is mediated by increased Th1-type immunity. J Immunol 168:4914-4919, 2002
19. Richardson PG, Schlossman RL, Weller E, et al: Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood 100:3063-3067, 2002
20. Urbauer E, Kaufmann H, Nösslinger T, et al: Thromboembolic events during treatment with thalidomide. Blood 99:4247-4248, 2002 21. Zangari M, Barlogie B, Thertulien R, et al: Thalidomide and deep vein thrombosis in multiple myeloma: Risk factors and effect on survival. Clin Lymphoma 4:32-35, 2003[Medline] 22. Neben K, Moehler T, Kraemer A, et al: Response to thalidomide in progressive multiple myeloma is not mediated by inhibition of angiogenic cytokine secretion. Br J Haematol 115:605-608, 2001[CrossRef][Medline]
23. Giuliani N, Colla S, Lazzaretti M, et al: Proangiogenic properties of human myeloma cells: Production of angiopoietin-1 and its potential relationship to myeloma-induced angiogenesis. Blood 102:638-645, 2003 24. Marriott JB, Clarke IA, Dredge K, et al: Thalidomide and its analogues have distinct and opposing effects on TNF-alpha and TNFR2 during co-stimulation of both CD4(+) and CD8(+) T cells. Clin Exp Immunol 130:75-84, 2002[CrossRef][Medline]
25. Osterborg A, Yi Q, Henriksson L, et al: Idiotype immunization combined with granulocyte-macrophage colony-stimulating factor in myeloma patients induced type I, major histocompatibility complex-restricted, CD8- and CD4-specific T-cell responses. Blood 91:2459-2466, 1998
26. Brunda MJ, Luistro L, Warrier RR, et al: Antitumor and antimetastatic activity of interleukin 12 against murine tumors. J Exp Med 178:1223-1230, 1993
27. Nakajima A, Kodama T, Morimoto S, et al: Antitumor effect of CD40 ligand: Elicitation of local and systemic antitumor responses by IL-12 and B7. J Immunol 161:1901-1907, 1998 28. Coughlin CM, Salhany KE, Wysocka M, et al: Interleukin-12 and interleukin-18 synergistically induce murine tumor regression which involves inhibition of angiogenesis. J Clin Invest 101:1441-1452, 1998[Medline] 29. Frassanito MA, Cusmai A, Dammacco F: Deregulated cytokine network and defective Th1 immune response in multiple myeloma. Clin Exp Immunol 125:190-197, 2001[CrossRef][Medline]
30. Yi Q, Osterborg A, Bergenbrant S, et al: Idiotype-reactive T-cell subsets and tumor load in monoclonal gammopathies. Blood 86:3043-3049, 1995 31. Gollob JA, Schniper CP, Orsini E, et al: Characterization of a novel subset of CD8(+) T cells that expand in patients receiving interleukin-12. J Clin Invest 102:561-575, 1998[Medline]
32. Rasmussen T, Hansson L, Österborg A, et al: Idiotype vaccination in multiple myeloma induced a reduction of circulating clonal tumor B cells. Blood 101:4607-4610, 2003 Submitted October 9, 2003; accepted March 19, 2004.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
20,000 cells/µL, or had an absolute neutrophil count of less than 1,000 cells/µL. Patients were also excluded if they had a history of malignancy within the last 3 years or had other clinically relevant active comorbid medical conditions within 6 months or less that were uncontrolled by appropriate medication. All patients gave written informed consent. 
), respectively. At the 10-mg dose level, trough concentrations at the end of weeks 1, 2, and 3 indicated that CC-4047 was accumulating in plasma to a greater extent than that seen at the lower dose levels. Two thirds of the drug was excreted in the urine. 
