Plenary paper
`
`Iin1nun01nodulatory drug CC-5013 overc01nes drug resistance and is well
`tolerated in patients with relapsed multiple myel01na
`
`Paul G. Richardson , Robert L. Schlossman , Edie Weller, Teru Hideshima , Constantine Mitsiades , Faith Davies , Richard LeBlanc,
`Laurence P. Calley, Deborah Doss, Kathleen Kelly, Mary McKenney, Julie Mechlowicz, Andrea Freeman, Reggie Deocampo,
`Rebecca Rich , Joan J . Ryoo, Dharminder Chauhan, Kathe Balinski, Jerome Zeldis, and Kenn eth C. Anderson
`
`Thalidomide (Thal) can overcome drug
`resistance in multiple rnyelorna (MM) but
`is associated with somnolence, constipa(cid:173)
`tion, and neuropathy. In previous in vitro
`studies, we have shown that the potent
`irnrnunornodulatory derivative of thalido(cid:173)
`mide (IMiD) CC-5013 induces apoptosis
`or growth arrest even in resistant MM cell
`lines and patient cells, decreases binding
`of MM cells to bone marrow strornal cells
`(BMSCs), inhibits the production in the
`BM milieu of cytokines (interleukin-6 [IL-
`6), vascular endothelial growth factor
`[VEGFJ, tumor necrosis factor-a [TNF-a))
`mediating growth and survival of MM
`cells, blocks angiogenesis, and stimu(cid:173)
`lates host anti-MM natural killer (NK) cell
`immunity. Moreover, CC-5013 also inhib(cid:173)
`its tumor growth, decreases angiogen-
`esis, and prolongs host survival in a
`
`human plasmacytoma mouse model. In
`the present study, we carried out a phase 1
`CC-5013 dose~scalation (5 mg/d, 10 mg/d,
`25 mg/d, and 50 mg/d) study in 27 patients
`(median age 57 years; range, 40-71 years)
`with relapsed and refractory relapsed MM.
`They received a median of 3 prior regi(cid:173)
`mens (range, 2-6 regimens), including
`autologous stern cell transplantation and
`Thal in 15 and 16 patients, respectively. In
`24 evaluable patients, no dose-limiting
`toxicity (DLT) was observed in patients
`treated at any dose level within the first 28
`days; however, grade 3 myelosuppres(cid:173)
`sion developed after day 28 in all 13
`patients treated with 50 mg/d CC-5013. In
`12 patients, dose reduction to 25 mg/d
`was well tolerated and therefore consid(cid:173)
`ered the maximal tolerated dose (MTD).
`Importantly, no significant somnolence,
`
`Introduction
`
`constipation, or neuropathy has been
`seen in any cohort. Best responses of at
`least 25% reduction in paraprotein oc(cid:173)
`curred in 17 (71 %) of 24 patients (90%
`confidence interval [Cl], 52%-85%), includ(cid:173)
`ing 11 (46%) patients who had received
`prior Thal. Stable disease (less than 25%
`reduction in paraprotein) was observed in
`an additional 2 (8%) patients. Therefore,
`17 (71 %) of 24 patients (90% Cl, 52%-85%)
`demonstrated benefit from treatment. Our
`study therefore provides the basis for the
`evaluation of CC-5013, either alone or in
`combination, to treat patients with MM at
`earlier stages of disease. (Blood. 2002;
`100:3063-3067)
`
`Multiple myeloma (MM) is the second most common hemato(cid:173)
`logic malignancy, affecting 14 400 new and 50 000 total patients
`in the United States in 200 I, 1 and remains incurable despite
`conventional and high-dose chemotherapy. To overcome resis(cid:173)
`tance lo current therapies and improve patient outcome, novel
`biologically based treatment approaches are needed that target
`mechanisms whereby MM cells grow and survive in the bone
`marrow (BM). Thalidomide (Thal), used empirically to treat
`MM based upon its antiangiogenic activity and the increased
`angiogenesis observed in MM BM, ach ieves responses even in
`refractory, relapsed discase. 1 Importantly, our in vitro and in
`vivo preclinical studies both define a role for MM-host interac(cid:173)
`tions in regulating MM cell growth, survival, drug resistance,
`and migration in the BM 3• 12 and demonstrate that Thal targets
`the MM cell in its BM milieu to overcome classical drug
`resistance both in vitro and in vivo in animal models. 1J- Ir,
`However, Thal has significant and dose-limiting side effects,
`including somnolence, constipation, and neuropathy, which has
`
`prompted the search for more potent and less toxic Thal
`derivatives.
`Tmmunomodulatory drugs (!MiDs) are potent Thal derivatives
`that markedly stimulate T-cell proliferation, as well as interleukin-2
`(IL-2) and interferon--y (IFN--y) production, but do not inhibit
`phosphodiesterase-4 (PDE-4). 17 CC-5013 (REVIMID) is 50 to
`2000 times more potent than Thal in stimulating T-cell proliferation
`triggered via the T-ccll receptor (TCR) and 50 to I 00 times more
`potent lhan Thal in augmenting IL-2 and IFN--y production. In
`addition, CC-5013 triggers dose-dependent decreased secretion of
`tumor necrosis factor-a (TNF-a), IL-I 13, and IL-6 and triggers
`increased secretion of IL- I 0. The CC-5013 concentration for 50%
`inhibition (TC50) of lipopolysaccharide (LPS)-induccd TNF-a
`secretion by peripheral blood mononuclear cells (PBMCs) is about
`I 00 nM (25.9 ng/mL), whereas Thal has an IC50 of about 194 µM
`(50.2 µg/mL). 1x Based upon these more potent effects of !MiDs
`than Thal on normal cells, we compared their relative anti-MM
`activitit:s. Our in vitro studies show an IC50 of 0.4 µM (I 03.6 ng/mL)
`
`From the Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer
`Institute, Harvard Medical School, Boston , MA; and Celgene, Warren, NJ.
`
`Submitted April 2, 2002; accepted May 1, 2002. Prepublished online as Blood
`First Edition Paper, July 12, 2002; DOI 10.1182/blood-2002-03-0996.
`
`Supported by National Institutes of Health grants R0-1 50947 and P0-78378,
`the Multiple Myeloma Research Foundation (T.H., C.M., R.L.), the Myeloma
`Research Fund (K C.A.), and the Doris Duke Distinguished Clinical Research
`
`Scientist Award (K.C.A.).
`
`Reprints: Kenneth C. Anderson, Dana-Farber Cancer Institute, Mayer 557, 44
`Binney St, Boston, MA 02115; e-mail: kenneth_anderson@dfci.harvard.edu.
`
`The publication costs of this article were defrayed in part by page charge
`payment. Therefore, and solely to indicate this fact, this article is hereby
`marked "advertisement" in accordance with 18 U.S.C. section 1734.
`
`BLOOD, 1 NOVEMBER 2002 • VOLUME 100, NUMBER 9
`
`3063
`
`DR. REDDY’S LABS., INC. EX. 1044 PAGE 1
`
`

`

`3064
`
`RICHARDSON el al
`
`BLOOD, 1 NOVEMBER 2002 • VOLUME 100, NUMBER 9
`
`Figure 1. Mechanisms of action of CC-5013 targeting
`MM cells and the BM microenvironment. (A) MM cell
`G1 growlh arrest and apoplosis. (B) Decreased MM cell
`lo BMSC binding. (C) Decreased cylokine activity. (D)
`Decreased cylokine production in BM. (E) Decreased
`angiogenesis. (F) Induced host anti-MM immune re(cid:173)
`sponse.
`
`I C. CC-5013 I
`MM cells ~ tt.' D. CC-5013 ]
`~Ge;) I B. CC-5013 1~~~:tt
`I A. CC-5013 j...
`.,
`Bone Marrow
`J
`ICAM-1 ~ StrornaJ Cells
`-~ Bone Marrow
`{
`e ~
`VEGFt
`• @~'\IL-2t
`«:>Vessels
`bF~ -@~
`~ @~
`
`PBMC
`
`CDS+ cells
`NK cells
`
`IFNyt
`
`t
`IF. CC-5013 [
`
`for CC-5013 against MM cell lines and patient cells that are
`resistant to conventional therapy; in contrast, even at concentra(cid:173)
`tions up to 100 µM (25.8 µg/mL), Thal decreases MM cell
`proliferation by only 15% or 20%. 13 Our studies further demon(cid:173)
`strate that CC-5013 decreases binding of MM cells to bone marrow
`stromal cells (BMSCs), inhibits the production in the BM milieu of
`cytokines (IL-6, vascular endothelial growth factor [VEGF], TNF-a)
`mediating growth and survival of MM cells, blocks angiogenesis,
`and stimulates host anti-MM natural killer (NK) cell immunity 13·15
`(Figure I). In addition, we detennined that CC-5013 inhibits tumor
`growth, decreases angiogenesis, and prolongs host survival in a
`human plasmacytoma mouse model. 16 These preclinical studies
`suggest that CC-5013 may overcome drug resistance, even to Thal,
`in MM cells.
`The remarkable in vitro and in vivo activity ofCC-5013 against
`resistant MM cells in preclinical studies provided the framework
`for this phase I dose-escalation trial of CC-5013 in patients with
`relapsed and refractory MM. Importantly, CC-5013 achieved either
`response or stabilization of disease in 17 (71 %) of 24 evaluable
`patients (90% confidence interval [CI], 52%-85%) and demon(cid:173)
`strated a favorable toxicity profile. Our study therefore provides the
`basis for the evaluation of CC-5013, either alone or in combination,
`to treat patients with MM at earlier stages of disease.
`
`Patients, materials, and methods
`
`Study objectives
`
`The primaiy objectives of this study were to identify the maximum
`tolerated dose (MTD) and to evaluate the safety of CC-5013 when given at
`doses of 5 mg/d to 50 mg/din patients with rcfractmy and/or relapsed MM.
`A seconda1y objective was to evaluate the response to CC-5013.
`
`Study design
`
`A standard dose escalation of CC-50 J3 (5, I 0, 25, and 50 mg/d) was
`pe1to1med to identify the MTD under the auspices ofan institutional review
`board (!RB) protocol and after obtaining infonned consent. Three patients
`were enrolled at each dose level, with up to 6 patients assigned to each dose
`level, depending on dose-limiting toxicity (DLT). DLT is defined to be at
`least grade 2 cardiac a1i-hythmia, at least grade 3 nonhematologic toxicity,
`or grade 4 hematologic toxicity using National Cancer Institute (NCI)
`common toxicity criteria during the first 4 weeks of treatment. Following
`
`the standard design, if no DLTs were observed among the first cohort of 3
`patients at each dose level, the next set of3 patients was entered on the next
`highest dose. lf2 or more DLTs were observed, the previous dose level was
`identified as the MTD. If I DLT was observed among the initial 3 patients,
`an additional 3 patients would be entered. If none of !he additional 3
`patients experienced a DLT, the dose was escalated; othe1wise, the lower
`dose was identified as the MTD. Ten additional patients were enrolled at the
`MTD to better define the toxicity rate (Figure 2).
`Patients were assessed before and weekly for the first month after
`treatment. Patients were hospitalized in the clinical research unit for at least
`72 hours after the first dose of CC-5013 and overnight on day 28. Patients
`who did not have either disease progression or DLT at day 28 continued on
`treatment until disease relapse or progression, with monthly follow-up.
`Safety and efficacy assessments were pe1formed at each visit, with blood
`and urine samples collected for phannacokinetics on days I to 4 and day 28.
`
`Patient selection
`
`Patients with relapsed and/or refractory MM were eligible and must have
`foiled to respond to at least 2 prior regimens of treatment. Patients were
`considered refracto1y if they had progressive disease by Southwest
`Oncology Group (SWOG) criteria (an increase by more than I 00% of the
`lowest level of protein production). Relapse following a remission was
`defined by SWOG criteria as any of !he following: (I) more than 25%
`increase in M protein from baseline levels, (2) reappearance of M
`paraprotcin, or (3) a definite increase in the size and number of lytic bone
`lesions recognized on radiographs (compression fractures per se did not
`constitute a relapse). Prior therapy with Thal was allowed, provided that it
`was tolerated. Exclusion criteria included a prolonged QT interval (> 430
`ms); predisposition to cardiac anythmias; concomitant medications known
`to prolong the QT segment; at least grade 3 peripheral ncuropathy;
`inadequate renal function (serum creatinine > 1.5 mg/dL); evidence of
`
`N=3
`
`5 mg/day
`
`N=3
`
`10 mg/day -
`
`N=J
`25 mg/day
`
`-
`
`N=3
`50 mg/day
`
`DLT:2: grade 2 cardiac arrythmia, 2: grade 3 nonhematologic
`toxicity, 2: grade 4 hematologic toxicity. If 1 DLT, add 3 p ati<mtsl<-(cid:173)
`at that dose level: If 2:2 DLT, stop : MTD=dose lcliol below DLT
`At MTD add 10 patients
`
`Figure 2. Schema of CC-5013 phase 1 trial in myeloma.
`
`DR. REDDY’S LABS., INC. EX. 1044 PAGE 2
`
`

`

`BLOOD, 1 NOVEMBER 2002 • VOLUME 100, NUMBER 9
`
`CC-5013 IN MYELOMA
`
`3065
`
`mucosa! or internal bleeding; thrombocytopenia (platelets < 50 X I 09/L
`[50 0001µ.L]); neutropcnia (absolute ncutrophil count< I X 109/L [10001 Results
`µ.L]); pregnant or lactating women; and women of childbearing potential
`who were not using adequate contraception.
`
`Patients treated
`
`Treatment
`
`Each patient received CC-5013 as a single daily oral dose. Depending on
`the order of study entiy and the tolerability of prior dose levels, patients
`received CC-5013 at 5, I 0, 25, or 50 mgld for the first 4 weeks. Accrual to
`the next higher dose level did not occur until the safety and tolerability of
`CC-5013 at prior dose level(s), when given for at least 4 weeks, had been
`established. Patients experiencing DLT during the first 28 days had therapy
`discontinued. After the first 4 weeks of treatment, dose reduction was
`permitted to manage any toxicity.
`
`Safety parameters
`
`Prior to enrollment, at each weekly and monthly visit, and either at the
`completion of the study or at premature discontinuation, evaluation of each
`patient included medical history and physical examination (to include
`assessment of peripheral neuropathy and measurement of vital signs), query
`for adverse events and concomitant medication use, and clinical laboratory
`testing (blood chemistry, hematology, urinalysis, and thyroid function
`testing [every 3 months]). Electrocardiograms (ECGs) were recorded at the
`first 4 weekly visits and monthly thereafter for the first 12 months of
`treatment. During the 72-hour inpatient period following the first dose
`administration, vital signs, ECGs, and adverse events were monitored and
`recorded at I, 2, 4, and 8 hours. Adverse events and vital sign measurements
`were recorded evety 8 hours thereafter, and ECGs were perfonned on days
`2, 3, and 4. Severity of adverse experiences, including any clinical
`laboratory and vital sign abnormalities, were evaluated using common
`toxicity criteria. No drug-related renal compromise was observed.
`
`Response
`
`Response to treatment was assessed by using M-protein quantification (by
`protein electrophoresis) in serum and a 24-hour urine collection at
`screening, start of therapy, day 14 and day 28, as well as monthly thereafter
`( or upon early termination). Bone marrow aspirations and biopsies were
`petformed at baseline, 3, 6, and 12 months, and/or at completion of therapy.
`A skeletal survey was also pe1formed in patients who had abnonnal
`pretreatment studies or as clinically indicated.
`
`Pharmacokinetics
`
`Blood and urine samples were collected for analysis of phannacokinetic
`parameters on days I and 28. Specifically, blood samples were collected
`before dose as well as at 0.25, 0.5, 0.75, I, 1.5, 2, 2.5, 3, 4, 6, 8, I 0, 12, 18,
`and 24 hours after dose. In addition, blood samples were collected weekly
`for CC-5013 level detenninations. Total urine was collected and assayed at
`0 to 4, 4 to 8, 8 to 12, and 12 to 24 hours after drug administration.
`Appropriate noncompartmental phannacokinetic parameters were esti(cid:173)
`mated using the actual blood sampling times for each patient on day I and
`day 28. Values for noncompartmental pharmacokinetic parameters were
`calculated based on CC-5013 plasma concentration-time data obtained
`during each dosing period.
`
`Twenty-seven patients with a median age of 57 years (range, 40-71
`years) were enrolled. Two patients were removed from study on the
`first day of treatment due to rapid disease progression resulting in
`renal dysfunction, a known complication of MM, which rendered
`them ineligible. Of the 25 patients who received therapy, 19 were
`men and 6 were women. Immunoglobulin G (IgG) MM was
`present in 15 (60%), IgA in 7 (28%), and light-chain-only disease
`in 3 (12%) patients. Fifteen (60%) patients had undergone prior
`autologous stem cell transplantation (SCT), and 16 (64%) had
`received prior Thal. Patients received a median of 3 prior regimens
`(range, 2-6 regimens); all patients had relapsed MM, and 18 (72%)
`were refractory to salvage therapy.
`
`Toxicity profile
`
`The first 3 patients were treated for 28 days with CC-5013 5 mg/d
`without DLT. In the second cohort of3 patients treated at 10 mg/d,
`I patient had DLT characterized by grade 3 leukopenia and
`neutropenia, resulting in her removal from study before day 28; 2
`other patients tolerated the drug without complication, and an
`additional 3 patients treated at IO mg/d also demonstrated no DLT.
`The patient who had the DLT previously experienced a similar
`reaction to Thal and to dexamethasone (Dex). CC-5013 was well
`tolerated within the first 28 days in all 3 patients treated at 25 mg/d;
`however, grade 3 thrombocytopenia and grade 4 neutropenia
`developed during the second month, resulting in 2 patients being
`removed from study. All 3 patients treated with CC-5013 at 50
`mg/d tolerated therapy without DLT in the first 28 days, and an
`additional IO patients were treated at 50 mg/d to better define
`toxicity and outcome. None of the patients (0 of 13) treated at 50
`mg/d had DLT in the first 28 days (90% CI, 0%-21 %).
`Overall, the median duration ofCC-5013 therapy was 6 months
`(range, 2 weeks to 16 months), and 10 patients continued on
`treatment (4 patients at 25 mg/d, 3 patients at 10 mg/d, and 3
`patients at 5 mg/d). Importantly, no significant somnolence,
`constipation, or neuropathy has been seen in any cohort. Grade 3
`and 4 myelosuppression developed in 12 of 13 patients treated with
`50 mg/d CC-5013 beyond 28 days, eventually prompting dose
`reduction and granulocyte colony-stimulating factor (G-CSF) sup(cid:173)
`port in all 12 patients, with a median duration of 3 months (range,
`2-4 months) of CC-5013 therapy at 50 mg/d. All 12 patients who
`were reduced to 25 mg/d of CC-5013 tolerated the lower dose, and
`in aggregate 13 patients remained on therapy at this dose for a
`median of 4 months (range, 2-8 months). Based on greater
`exposures to CC-5013 for more than 28 days, we therefore
`conclude that 25 mg/d is the MTD. The most common adverse
`events for treated patients (n = 25), including those observed after
`day 28, are presented in Figure 3. Grade 3 neutropenia occurred in 15
`(60%) of25 patients (90% CI, 42%-76%) and grade 4 neutropenia in 4
`(16%) of 25 patients (90% CI, 6%-33%). Grade 3 thrombocytopenia
`occurred in 5 (20%) of25 patients (90% CI, 8%-38%).
`
`Biostatistical analysis
`
`Response
`
`The MTD was identified using a standard phase I design (Figure 2). With
`this design, the probability of dose escalation was 0.97 if the trne DLT rate
`was 5%. The 90% confidence intervals are repmted on the percentage of
`patients who experience toxicity at the MTD and the percentage of patients
`who achieved reduction in their paraprotein.
`
`Maximal paraprotein reductions observed in 24 patients who
`received at least 28 days of treatment are summarized in Table I.
`Best responses of at least 25% reduction in paraprotein occurred in
`17 (71 %) of 24 evaluable patients (90% CI, 52%-85%), including
`at least 50% reduction in paraprotein in 7 (29%) of 24 patients
`
`DR. REDDY’S LABS., INC. EX. 1044 PAGE 3
`
`

`

`3066
`
`RICHARDSON et al
`
`BLOOD, 1 NOVEMBER 2002 • VOLUME 100, NUMBER 9
`
`Llghlheadedness
`
`t=:::J
`
`• Grade4
`llilGrade3
`0Grad&2
`DGrade 1
`
`Raoh ~
`
`Leg cramps
`
`Thrombocytopenla -
`
`0
`
`10
`
`20
`
`30
`
`40
`
`50
`
`60
`
`70
`
`BO
`
`90 100
`
`% of Patients
`Figure 3. Profile of adverse events. Severity of adverse events was assessed using
`common toxicity criteria for the entire duration of therapy (n = 25 patients).
`
`(90% CI, 15%-48%). Stable disease (25% or less reduction in
`paraprotein) was noted in an additional 2 (8%) patients. Therefore,
`17 (71%) of24 patients (90% CI, 52%-85%) demonstrated benefit
`from treatment, including 11 (46%) patients who had received prior
`Thal. Eleven (85%) of 13 patients treated at 50 mg/d had at least
`25% paraprotein reductions (90% CI, 59%-97%), and 5 (38%) of
`13 patients (90% CI, 17%-65%) had at least 50% declines. Most
`responses have been at 25 mg/d (2 of 3 patients) and 50 mg/d
`CC-5013 (12 of 13 patients), although clinical activity was also
`seen in patients treated at both 5 mg/d (3 of3 patients) and IO mg/d
`(1 of 5 patients) dose levels. Median time to best response was 2
`months (range, 1-11 months), and median duration of response was
`6 months (range, 2-18 months).
`
`Pharmacokinetic analysis
`
`CC-5013 was rapidly absorbed, with maximum plasma concentrations
`at a median T max (time of maximum concentration) of I hour or 1.5
`hours on day 1 and day 28 in patients treated at each dose level. No trend
`in T max was noted with either increasing dose level or multiple <losings.
`Following Cmox (maximum concentration), plasma concentrations of
`CC-5013 declined in a predominantly monophasic manner, with elimi(cid:173)
`nation phase starting at I to 8 hours after dose on day I and day 28. The
`mean terminal elimination half-lives were 3.1 to 4.2 hours on both day I
`and day 28. There was little orno accumulation ofCC-5013: The mean
`accumulation ratio ofCC-5013 in plasma was 0.7 to 1.0, with a Cmax and
`area under the curve (AUC) (0-) of0.8 to 1.2 on day 28 compared with
`day 1. Intersubject variability was generally low to moderate for AUC
`and Cmax, with values ranging from 10.6% to 51.8% and 3% to 33% on
`day 1 and day 28, respectively.
`
`Bone marrow examination
`
`Of the 13 patients treated with CC-5013 at 50 mg/d, 12 patients and
`a single patient developed grades 3 and 4 neutropenia, respectively;
`BM hemopoiesis was nonnal or improved in IO and reduced in just
`2 of these patients. In the 5 patients treated with 50 mg/d CC-5013
`who developed grade 2 or 3 thrombocytopenia, megakaryocyte
`numbers were nonnal in 3 and mildly reduced in 2 cases. In
`aggregate, the BM findings were therefore most remarkable for the
`absence ofhypoplasia despite low circulating peripheral counts.
`
`Discussion
`
`Our long-tenn studies, both in vitro and in animal models, have
`shown the importance of host BM-MM cell interactions in
`promoting MM cell growth, survival, drug resistance, and migra(cid:173)
`tion in the BM microenvironment.3·t 2 Importantly, our studies have
`also shown that CC-5013 can target the MM cell in its BM milieu
`to overcome drug resistance in vitro as well as decrease tumor
`growth and extend survival in vivo in a murine model. 13-t 6 The
`present clinical study now demonstrates both the safety and
`efficacy of CC-5013 in patients with refractory and relapsed MM.
`In aggregate, these studies therefore provide the framework for
`development of a new treatment paradigm using CC-5013 to target
`both the MM cell and its microenvironment, overcome drug
`resistance, and improve patient outcome.
`The choice of dose levels in this phase 1 clinical trial (5-50
`mg/d) was targeted to achieve CC-5013 concentrations of approxi(cid:173)
`mately 25.9 to 259 ng/mL, levels that modulate the production of
`cytokines and inhibit MM cell proliferation in vitro. Importantly,
`except for an idiosyncratic reaction to CC-5013 that had also
`occurred to Thal, no DLT occurred within the first 28 days in any
`dose cohort; remarkably, no sedation, constipation, or neuropathy
`was seen. Twenty-five percent or greater reductions in paraprotein
`were observed in 17 (71 %) of 24 evaluable patients. This anti-MM
`activity was remarkable given that 15 patients (60%) had under(cid:173)
`gone prior SCT and 16 patients (64%) had progressive disease
`despite Thal treatment. In addition, less than 25% paraprotein
`reductions were observed in an additional 2 patients. These data,
`coupled with the absence of somnolence, constipation, and neurop(cid:173)
`athy, support future phase 2 studies of CC-5013 for MM patients
`earlier in the course of their disease.
`Pharmacokinetic studies completed in 24 subjects reveal rapid
`absorption (Tmax 1-1.5 hours), monophasic elimination (half-life
`[T 112 ] 3. 1-4.2 hours), and low to moderate intersubject variability
`for AUC (11 %-52%) and Cmax (3%-33%). In addition, there was no
`significant accumulation by day 28. The myelosuppression after
`day 28 seen in the patients treated with 50 mg/d CC-5013 is
`considered to be DLT. Furthermore, 13 of 15 patients treated at 25
`mg/d remained on therapy at this dose for a median of 4 months
`(range, 2-8 months); therefore, 25 mg/d is considered MTD. The
`
`Table 1. Maximal changes In paraproteln after CC-5013 treatment
`
`Decrease
`
`Dose, mg/d
`
`No. of patients
`
`<25%
`
`2: 25% < 50%
`
`2: 50% < 75%
`
`2: 75% < 99%
`
`5
`10
`25
`50
`Subtotal
`
`3
`5
`3
`13
`24
`
`0
`0
`
`2(8%)
`
`2
`0
`2
`6
`10 (42%)
`
`0
`2
`4(17%)
`
`0
`0
`0
`3
`3 (13%)
`
`Increase
`
`2: 25%
`
`0
`4
`0
`
`5(21%)
`
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`

`BLOOD, 1 NOVEMBER 2002 • VOLUME 100, NUMBER 9
`
`CC-5013 IN MYELOMA
`
`3067
`
`absence of significant marrow hypoplasia observed in most patients
`with cytopenias suggests etiologies other than BM suppression,
`which will be evaluated in future studies.
`Based upon the current study showing efficacy and tolerability of
`CC-5013, several future clinical phase 2 trials are planned in patients
`with refractory relapsed disease. First, because some patients treated
`with CC-5013 at 25 mgid developed granulocytopenia and thrombocy(cid:173)
`topenia, a dosing regimen that cycles drug exposure, with time for
`granulocyte and platelet recovery, will attempt to achieve clinical benefit
`while avoiding myelosuppression. Second, given the activity of the drug
`seen at lower dose levels and the T 112 of3 to 4 hours, a comparative trial
`of2 cycling regimens will be undertaken: 30 mgid as a single daily dose
`versus 30 mgid in divided doses. Third, because laboratory and clinical
`data have suggested at least additive effects of dexamethasone in
`
`combination with Thal, 13•19,20 and our preclinical data suggest that Dex
`also enhances anti-MM activity ofCC-5013, 13,21 clinical trials will also
`determine whether the addition of dexamethasone to CC-5013 enhances
`its clinical efficacy in MM.
`Thal has achieved response rates of 30% in patients with refractory,
`relapsed MM and, when combined with dexamethasone, response rates
`of 64% in patients with newly diagnosed disease. 2•20 However, somno(cid:173)
`lence, constipation, and neuropathy preclude its use in some patients.
`Because our study now shows that oral CC-5013 has antitumor activity,
`favorable pharmacokinetics, and acceptable toxicity in patients with
`relapsed and refractory MM, we will carry out clinical protocols of
`CC-5013, alone and in combination with dexamethasone, for the
`treatment of MM earlier in the disease course, including as initial
`treatment, therapy for first relapse, and maintenance therapy.
`
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