McCulloch, Leanne

Abstract Abstract 1876 Carfilzomib (CFZ), a next-generation proteasome inhibitor that selectively and irreversibly binds to its target, resulting in sustained inhibition absent of off-target effects relative to bortezomib, is being evaluated in MM patients. The selectivity of CFZ for the proteasome may explain the low rates of peripheral neuropathy (PN) relative to historical data for bortezomib (BTZ). Safety data have been compiled for >700 patients who received CFZ in 9 Phase (Ph) 1 or 2 trials, 4 of which are completed. The majority of patients had relapsed and refractory (R/R) MM, and many had comorbidities including baseline PN and renal insufficiency. This abstract updates and summarizes mature safety data for single-agent CFZ in 526 patients with R/R MM who took part in 1 of 3 Ph 2 studies and is a follow-up with more mature data compared with those presented at ASH 2010. Patients enrolled and treated with CFZ in the following trials are included in this analysis: PX-171-003 (conducted in 2 parts, a pilot study, PX-171-003-A0 [R/R MM], followed by PX-171-003-A1 [R/R MM]), PX-171-004 (relapsed MM), and PX-171-005 (R/R MM with varying degrees of renal function). In all studies, CFZ was dosed on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle (C). Doses were 20 mg/m2 in C1, escalating to 27 mg/m2 in C2 for all studies with the exception of 005 (15 mg/m2 in C1, 20 mg/m2 in C2, and 27 mg/m2 in C3). Overall, CFZ had a favorable safety profile in these studies. The most frequently reported adverse events (AEs) occurring in ≥30% of patients included fatigue (55%), anemia (47%), nausea (45%), thrombocytopenia (36%), dyspnea (35%), diarrhea (33%), and pyrexia (30%). The most common (≥10% of patients overall) ≥G3 AEs were thrombocytopenia (23%), anemia (22%), lymphopenia (18%), pneumonia (11%), and neutropenia (10%). The assessment of PN was based on a pooled aggregate of PN preferred terms, including neuropathy peripheral, neuropathy, peripheral sensory neuropathy, and peripheral motor neuropathy. PN was reported infrequently (14% overall) across all studies. Although 378 (72%) patients had baseline PN (≤G 2), only 13% reported treatment-emergent symptoms during the study. PN was generally mild to moderate in severity (1.3% G3 PN with no G4 PN), and only 5 patients (1%) required dose modification or discontinuation due to PN. Renal AEs (mainly ≤G2) were reported in 174 (33%) patients, and CFZ was discontinued because of a renal AE in only 21 patients (4%). A summary of CFZ exposure and discontinuation rates is reported in the table. There were a total of 37 (7%) deaths on study, including within 30 days of the last dose of study drug. The primary cause of death was due to disease progression in 22/37 patients (4.2%); however, AEs, including in order of frequency, cardiac events, hepatic failure, and infection, contributed to 14 of these deaths.No. of Patients (%) in Ph 2 MM Studies Who Received Carfilzomib003-A0 (N = 46)003-A1 (N = 266)004 (N = 164)005 (N = 50)All Patients (N = 526)Cycles, mean, n (SD)4.4 (3.4)5.3 (4.1)7.0 (4.4)5.5 (3.7)5.7 (4.2)Completed ≥12 cycles4 (8.7)40 (15.0)47 (28.7)3 (6.0)94 (17.9)Reason for not completing 12 cycles Progressive Disease23 (50.0)157 (59.0)64 (39.0)24 (48.0)268 (51.0) Adverse Event13 (28.3)33 (12.4)26 (15.9)6 (12.0)78 (14.8) Withdrew Consent2 (4.3)22 (8.3)9 (5.5)4 (8.0)37 (7.0) Other4 (8.7)14 (5.3)10 (6.1)028 (5.3) Of the 526 patients included in these analyses, >50% were treated on the 003-A1 dose and schedule (20/27 mg/m2), and fewer than 10% required dose reduction. 18% of patients completed ≥12 cycles (∼1 y) and were eligible to participate in an ongoing, multicenter, open-label Ph 2 study (PX-171-010) to monitor long-term single-agent CFZ safety. To date, patients in this extension trial have not shown evidence of cumulative toxicity. In summary, these data confirm and extend results that were previously presented, namely that single-agent CFZ has an acceptable safety profile in heavily pretreated patients with R/R MM, including those with pre-existing renal dysfunction and PN. Disclosures: Singhal: Onyx Pharmaceuticals: Research Funding, Speakers Bureau; Millennium: Speakers Bureau; Celgene: Speakers Bureau. Siegel:Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Martin:Celgene: Honoraria; Onyx Pharmaceuticals: Consultancy. Vij:Onyx Pharmaceuticals: Consultancy, Research Funding; Celgene: Research Funding, Speakers Bureau; Millennium: Speakers Bureau. Wang:Onyx Pharmaceuticals: Research Funding. Jakubowiak:Ortho Biotech: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Exelixis: Consultancy, Honoraria. Lonial:Millennium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy; Onyx Pharmaceuticals: Consultancy; Merck: Consultancy. Kukreti:Celgene: Honoraria. Zonder:Millennium: Consultancy, Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Medtronics: Honoraria; Amgen: Consultancy. Wong:Onyx Pharmaceuticals: Employment, Equity Ownership. McCulloch:Onyx Pharmaceuticals: Employment. Niesvizky:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Research Funding; Seattle Genetics Inc: Research Funding, Speakers Bureau. Orlowski:Onyx Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Stewart:Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Kotlovker:Onyx Pharmaceuticals: Employment. Jagannath:Millennium: Honoraria; Celgene: Honoraria; Onyx Pharmaceuticals: Honoraria; Merck: Honoraria; OrthoBiotec. Imedex: Membership on an entity's Board of Directors or advisory committees; Medicom World Wide: Membership on an entity's Board of Directors or advisory committees; Optum Health Education: Membership on an entity's Board of Directors or advisory committees; PER Group: Membership on an entity's Board of Directors or advisory committees.

Abstract Abstract 1954 Background: Carfilzomib (CFZ) is a novel, highly selective epoxyketone proteasome inhibitor that produces potent and sustained proteasome inhibition both in vitro and in vivo. CFZ appears to lack many of the off-target activities frequently associated with bortezomib (BTZ). This lack of off-target activity may account for observed differences in tolerability seen with CFZ including lack of significant neuropathy and minimal neutropenia and diarrhea. To date, single agent CFZ has been evaluated in Ph 1 and 2 studies in >600 patients, and the vast majority of patients treated had relapsed and/or refractory (R/R) MM. In these settings, CFZ has demonstrated durable single-agent activity and was well-tolerated in patients with advanced stage disease with co-morbidities including baseline neuropathy or renal insufficiency. Here we present the results of parallel safety analyses of patients from four Ph 1 and 2 studies with CFZ. Materials and Methods: The present safety analyses were based on data accumulated from patients enrolled in the following trials: PX-171-003 A0 (R/R MM), PX-171-003 A1 (R/R MM), PX-171-004 (relapsed MM), and PX-171-005 (R/R MM with varying degrees of renal function). In all studies, the treatment schedule was based on a 28-day cycle, dosing CFZ QDx2 each week for 3 weeks (Days 1, 2, 8, 9, 15, 16) with 12 days of rest. Doses of CFZ ranged from 15–20 mg/m2 in cycle 1 (005 [15 mg/m2], 003 A0 and A1, 004 [20 mg/m2]). In three studies CFZ was escalated to 27 mg/m2 after the first cycle, as tolerated (003- A1, 004-BTZ naïve subset and 005). In PX-171-005, low-dose dexamethasone was added in the majority of patients. Results: CFZ was well-tolerated by patients across the 4 studies analyzed. The most common treatment-emergent adverse events (AEs) included fatigue, anemia, nausea, dyspnea, and thrombocytopenia. Detailed descriptions of the incidence of treatment-related AEs (all Grades (G) in ≥25% of pts; ≥G3 in ≥5% of pts) across studies are presented in the table. Peripheral neuropathy (PN) occurred infrequently across all 4 studies (N= 517), with only 20 patients (3.9%) experiencing PN of any G and only 2 patients (0.4%) with G3 PN. Febrile neutropenia was likewise uncommon, occurring in only 3 patients (0.6%). Serious treatment emergent AEs (SAEs) occurring in ≥1% of patients and considered possibly/probably related to study drug across all 4 studies included: pneumonia (3.5%), congestive cardiac failure (2.5%), acute renal failure (1.7%), pyrexia (1.2%), and dyspnea (1%). Conclusions: Despite a substantial disease burden present in the patient populations described here, CFZ was well-tolerated by patients with MM across all studies examined. The excellent safety/tolerability profile of CFZ has permitted prolonged administration (in some cases over 24 mos of continuous therapy including extension study) with minimal dose modifications or discontinuations due to toxicity. The low levels of neuropathy seen with CFZ make this agent a potentially important treatment option for patients with pre-existing neuropathy from either underlying disease or prior neuropathic anti-myeloma therapy. Disclosures: Singhal: Celgene: Speakers Bureau; Takeda/Millenium: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Onyx: Research Funding. Siegel:Millenium: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Martin:Celgene: Honoraria; Onyx: Consultancy. Vij:Onyx: Honoraria. Wang:Celgene: Research Funding; Onyx: Research Funding; Millenium: Research Funding; Novartis: Research Funding. Jakubowiak:Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene: Consultancy, Honoraria; Centocor Ortho Biotec: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Exelixis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Lonial:Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Kukreti:Celgene: Honoraria; Roche: Honoraria; Ortho Biotech: Honoraria. Zonder:Millenium: Consultancy, Honoraria, Research Funding; Cephalon: Research Funding; Celgene: Honoraria. Wong:Onyx Pharmaceuticals: Employment. McCulloch:Onyx Pharmaceuticals: Employment. Kauffman:Onyx Pharmaceuticals: Employment. Niesvizky:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millenium: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Consultancy, Research Funding. Stewart:Millennium: Consultancy; Celgene: Honoraria. Jagannath:Millenium, OrthoBiotec, Celgene, Merck, Onyx: Honoraria; Imedex, Medicom World Wide, Optum Health Education, PER Group: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau.