Wear, Sandra

Abstract Abstract 813FN2 Introduction: Carfilzomib is 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. Carfilzomib has demonstrated durable anti-tumor activity and an acceptable tolerability profile in patients with multiple myeloma (MM). Final results will be presented for the bortezomib-naïve group of PX-171-004, a phase 2 study of single-agent carfilzomib in patients with relapsed and/or refractory MM. Herein we report the most recent data analysis available at time of abstract submission. Updated final results for the bortezomib-naïve group of PX-171-004, including OS data, will be presented at the meeting. Methods: Patients received either 20 mg/m2 for all treatment cycles (Cohort 1) or a stepped-up dose-escalating regimen of 20 mg/m2 for Cycle 1 and 27 mg/m2 for all treatment cycles thereafter (Cohort 2). Carfilzomib was administered over 2–10 minutes on Days 1, 2, 8, 9, 15, and 16 of every 28-day cycle, for a maximum of 12 cycles. The primary endpoint was the best overall response rate (ORR; [CR + VGPR + PR]) determined according to the IMWG Uniform Response Criteria. Secondary endpoints included the clinical benefit response rate (CBR; [ORR + MR per EBMT criteria]), progression-free survival (PFS), time to progression (TTP), duration of response (DOR), OS, and safety. The result of efficacy analysis from disease assessment by the Independent Review Committee is presented in this abstract. Results: 127 of 129 enrolled bortezomib-naïve patients were evaluable for response. Prior therapies included thalidomide (59%), lenalidomide (59%), alkylating agents (81%), and stem cell transplant (73%). Patients had received a median of 2 prior regimens (1 in 54 patients, 2 in 40 patients, 3 in 28 patients, and ≥4 in 7 patients). 84 patients (65%) were disease refractory to their most recent therapy, defined as ≤25% response or progression during or within 60 days after completion of therapy. The median duration of carfilzomib treatment is 7 cycles (range 1−12) in Cohort 1; 8 patients were receiving drug as of February 2011 in Cohort 2 with a median treatment of 6.5 cycles (range 1−13) at that time. Best ORR was 42% in Cohort 1 and 52% in Cohort 2. Median TTP was 8.3 months and median DOR was 13.1 months in Cohort 1. The median TTP and DOR for Cohort 2 have not been reached at the time of this interim analysis; the lower bound of the 95% CI for the median TTP was 10.2 months, and 84% were estimated to have DOR ≥1 year at the time of data cutoff. Higher response rates for Cohort 2 compared with Cohort 1 do not appear to be associated with higher toxicities. Patients with unfavorable cytogenetic characteristics (≥1 abnormality) per mSMART criteria had an ORR of 37% and CBR of 42% compared with 50% and 65%, respectively, for patients with no abnormality. The most common treatment-emergent adverse events (AEs), regardless of relationship to carfilzomib in Cohorts 1 and 2, respectively, were fatigue (71%, 54%), nausea (54%, 43%), anemia (46%, 37%), and dyspnea (49%, 33%). These were primarily ≤Grade 2 in severity. The most common Grade 3/4 AEs were anemia (15%), lymphopenia (15%), thrombocytopenia (13%), pneumonia (12%) and neutropenia (12%). Treatment-emergent peripheral neuropathy (PN) was mild and infrequent (16%). Only 1 case of Grade 3 PN (0.8%) was observed. Overall, 38 patients (30%) completed 12 cycles and 22 of these patients continued to receive carfilzomib therapy under a safety extension protocol (PX-171-010), an ongoing, multicenter, open-label phase 2 study to monitor long-term use of single-agent carfilzomib. Conclusions: To date we have seen robust and durable single-agent activity for carfilzomib in bortezomib-naïve patients with relapsed and often refractory MM with an ORR of 42−52% and a CBR of 59−63% from 2 separate dose cohorts in a population wherein 92% received an immunomodulatry drug and 73% had undergone an autologous stem cell transplant previously. These data are suggestive of a dose–response relationship and are being further evaluated in the exploratory phase 1b/2 study PX-171-007. Carfilzomib was associated with minimal PN and excellent long-term tolerability, with nearly one-third of patients completing 12 cycles and 22 of these continuing treatment beyond 1 year in the extension protocol PX-171-010. Disclosures: Vij: Onyx Pharmaceuticals: Consultancy, Research Funding; Celgene: Research Funding, Speakers Bureau; Millennium: Speakers Bureau. Kaufman:Millenium: Consultancy; Onyx Pharmaceuticals: Consultancy; Novartis: Consultancy; Keryx: Consultancy; Merck: Research Funding; Celgene: Research Funding. Jakubowiak:Ortho Biotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Millennium Pharmaceuticals, Inc.: 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. Wang:Onyx Pharmaceuticals: Research Funding. 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. Kukreti:Celgene: Honoraria. Alsina:Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Allergan: Research Funding. Belch:Celgene: Research Funding; Onyx: Research Funding. Gabrail:Millennium: Research Funding. Matous:Celgene: Speakers Bureau; Millenium: Speakers Bureau; Cephalon: Speakers Bureau. Vesole:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Speakers Bureau. Orlowski:Onyx Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kunkel:VLST biothech: Consultancy; Threshold: Consultancy; Onyx Pharmaceuticals: Consultancy. Wong:Onyx Pharmaceuticals: Employment, Equity Ownership. Stewart:Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding.

Abstract Abstract 1024 Background: The MMRC is a non-profit, disease-focused consortium founded in 2004. Sixteen North American member institutions with expertise in multiple myeloma (MM) work collaboratively with the MMRC Inc. (Norwalk, CT) and numerous pharmaceutical partners to speed development of new treatment options to MM patients. In December 2007, MMRC Inc. implemented business solutions to address barriers to rapid activation of phase I-II trials and established benchmarks for initiating and conducting these studies. In December 2010, we reported significantly faster trial start up and accrual data from previous years1,2. Today, we update and expand on MMRC performance data and analysis of progress. Methods: Twenty-five (25) trials conducted within the Consortium from May 2006 to July 2011 had sufficient start up trial data for review. FPFD was defined as the time from the member institutions' receipt of the final protocol (FP) from the trial sponsor, to the time the first patient was dosed on the trial at any participating MMRC member institution. With respect to enrollment, pre-study enrollment commitment (EC) established between MMRC and the study sponsor was defined as the total number of subjects committed to receive at least one dose of study drug across all participating MMRC centers on a trial; baseline enrollment timeline (BET) was prospectively defined as the target time period to attain EC. Results: Mean time to FPFD in the recent group of trials (RG; n=18; Sept 08-Jul 11) held steady at 131 calendar days from receipt of FP as compared to 181 days for the early group of trials (EG; n=7; Jun06-Sept08) representing a 28% reduction in time to FPFD. More importantly, there was a 20% decrease in time to FPFD by all participating MMRC centers on any MMRC trial from 189 days in the RG compared to 236 days in the EG representing an important achievement especially in the Phase I/II arena. MMRC trial accrual data was available for 17/25 trials (2 EG trials were missing data and 6 RG trials continue enrolling). The pre-study mean MMRC EC was 44 subjects per trial (n=19 trials; 849 patients); the mean actual MMRC enrollment was 49 subjects per trial (n=19; 935 patients through July 11) representing a 10% over enrollment versus committed enrollment. A total of 17/19 evaluable trials (89%) met their EC; 12/19 trials met EC within BET (71%) of which 8/12 trials (67%) reached EC 34% faster than their BET (representing a mean reduction of 4.5 months). The overall pre-study mean BET for 19 trials was 13.6 months. MMRC's actual mean enrollment timeline was 12.8 months for the group of 17 evaluable trials representing improvement over the original BET by a mean of 10%. Discussion: MMRC's acceleration of clinical trials provides physicians and patients with rapid access to novel compounds; industry with data for important drug development decisions; and academic institutions with more trials of high scientific interest. Even so, our data uncovered opportunities for improvement. The submission time from receipt of the final protocol from the trial sponsor to Scientific Review Committee (SRC) took an average 30 calendar days across all trials. A reduction to half this time could make a difference to patients and therefore warrants further exploration. Conclusion: Today, drug development in multiple myeloma is fast-paced and highly competitive. MMRC's frequent review of trial metrics provides valuable insight to continually speed answers to physicians, patients and industry. Disclosures: Richardson: Multiple Myeloma Research Consortium: Annual grant in support Clinical Trial Project Management. Vij:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Lonial:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Siegel:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Jakubowiak:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Reece:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Jagannath:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Hofmeister:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Stewart:Multiple Myeloma Research Consortium: Annual Grant in support of clinical trial Project Management. Wolf:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Krishnan:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Zimmerman:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Kumar:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Roy:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Fay:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Anderson:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management.

Abstract Abstract 1875 Introduction: Carfilzomib (CFZ) is a next-generation proteasome inhibitor that has demonstrated durable single-agent antitumor activity in patients (pts) with relapsed and/or refractory multiple myeloma (R/R MM). Previously we have shown that unfavorable cytogenetic features, defined as presence of any of del 13 or hypodiploidy by metaphase cytogenetic analysis and/or del 17p13, t(4;14), t (14;16) by fluorescence in situ hybridization (FISH), did not appreciably affect overall (≥PR) and clinical benefit (≥MR) response rates (ORR and CBR) in PX-171-003-A1, a large phase 2 study of single-agent CFZ in pts with R/R MM (Jakubowiak et al. Ann Oncol. 2011;22(S4): Abstract 117). The objectives of the present analysis were to evaluate the impact of specific cytogenetic abnormalities on efficacy and treatment outcomes. Methods: Pts with unfavorable cytogenetic abnormalities (defined above) were eligible for inclusion in this analysis. All pts received CFZ at 20 mg/m2 IV on days 1, 2, 8, 9, 15, and 16 of 28-day cycles (C) and were dose-escalated to 27 mg/m2 at C2. Pts were treated for up to 12 C. Responses were assessed by International Myeloma Working Group criteria, with minimal response (MR) by European Group for Blood and Marrow Transplantation criteria. Assessments were confirmed by an Independent Review Committee (IRC). Results: A total of 234 pts were included in this analysis. Metaphase cytogenetic data were available for 203 pts (87%), and FISH data were available for 210 pts (90%); 178 pts had both (76%). Seventy-five of 234 pts (32%) had ≥1 abnormality and represented the unfavorable group in this analysis. Of these, 49 (65%) had abnormalities detected via metaphase cytogenetics, 47 (63%) by FISH, and 21 (28%) by both methods. Characteristics of pts in the unfavorable and normal/favorable groups were comparable overall, with the exception of a higher proportion of pts with International Staging System stage II/III in the unfavorable group (83% vs 64%). Response rates per the IRC, presented previously, included an ORR of 30% for pts with ≥1 abnormality compared with 23% for pts with none. The corresponding CBRs were 34% and 40%, respectively. Duration of response (DOR) and time to progression (TTP) values were 7 months (mo) (95% CI 4–9) and 4 mo (95% CI 3–6), respectively, for pts with ≥1 abnormality and 8 mo (95% CI 6–12) and 5 mo (95% CI 3–6), respectively, for pts with none. The ORRs, CBRs, and disease control rates (DCRs) according to specific cytogenetic abnormalities are presented below. Response rates were largely unaffected by the presence of specific unfavorable cytogenetic abnormalities, with the possible exceptions of trends toward a higher response rate for t(4;14) and a lower rate for t(14;16), although the latter abnormality was only noted in 3 pts. The trend for better response rates in pts with t(4;14) corresponded to a DOR of 5.6 mo (95% CI 2.8–10.2). In contrast, the DOR appeared shorter for the subgroup of pts with del 17p13 (4.6 mo, 95% CI: 3.7–Not reached). Time-to-event endpoints including TTP are being analyzed for these and the other subpopulations, and data on these will be presented, along with overall survival stratified by cytogenetic abnormality. Conclusions: CFZ demonstrated comparable response rates in pts with relapsed/refractory MM in both the absence and presence of unfavorable cytogenetic abnormalities in the 003-A1 study. Similarly, in the phase 2 PX-171-004 study, no significant difference in response rates between unfavorable and normal/favorable groups has been observed in a population of less heavily-pretreated pts with relapsed or R/R MM. Taken together, the results of these and other analyses to date suggest that responses to single-agent CFZ can be achieved in heavily pretreated pts and that overall, these responses appear not to be significantly influenced by poor prognostic cytogenetic features. Further analyses from studies with CFZ in newly diagnosed MM and in less heavily-pretreated pts are needed to determine whether a trend toward lower response rates and DOR for pts with del 17p13 is consistently observed in other populations. Disclosures: Jakubowiak: Ortho Biotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Millennium Pharmaceuticals, Inc.: 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. Off Label Use: Use of the investigational agent carfilzomib, proteasome inhibitor, in the treatment of relapsed and/or refractory multiple myeloma. 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. Singhal:Celgene: Speakers Bureau; Millennium: Speakers Bureau; Onyx Pharmaceuticals: Research Funding. Martin:Celgene: Honoraria; Onyx Pharmaceuticals: Consultancy. Lonial:Onyx: Consultancy; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Millennium Pharmaceuticals, Inc.: Consultancy; Merck: Consultancy. Kukreti:Celgene: Honoraria. Bahlis:Celgene: Honoraria, Speakers Bureau. Alsina:Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Allergan: Research Funding. Kunkel:Onyx Pharmaceuticals: Consultancy; Threshold: Consultancy; VLST biothech: Consultancy. Wong:Onyx Pharmaceuticals: Employment, Equity Ownership. Orlowski:Onyx Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Stewart:Celgene Corporation: Consultancy, Research Funding; Millenium: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. 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. Wang:Onyx Pharmaceuticals: Research Funding.

Abstract Abstract 3803 Background: The MMRC is a non-profit, disease-focused consortium founded in 2004 comprised of 13 North American centers with expertise in multiple myeloma (MM). The MMRC Inc. (Norwalk, CT), MMRC's member institutions, and several pharmaceutical partners work closely to speed early development of new treatment options for MM patients. In December 2007, MMRC headquarters staff implemented multiple project management (PM) business solutions to address trial barriers that delay activation of our phase I-II clinical trials and established trial metric benchmarks considered attainable at our member institutions. In November 2009, we reported initial data1 on trial activation: MMRC trials initiated between Sep08-Jul09 (n=5) demonstrated a 38% decrease in mean time to first patient dosed (FPFD), compared with the Early Group trials (EG) initiated before PM solutions (Jun06-Sept08; n=7 trials). These results also confirmed improvement over published metrics from Dilts et al 2,3. We present additional data on time to FPFD and now enrollment, to assess impact of the MMRC PM resources and processes on trial efficiency. Methods: Twenty-one (21) trials conducted within the MMRC from May 2006 to June 2010 had sufficient trial data for review. Data were collected by MMRC-funded project managers at the clinical centers using a web-based clinical trial management system (CTMS). FPFD was defined as the time from the member institutions' receipt of the final protocol (FP) from the trial sponsor, to the time the first patient was dosed on the trial at any participating MMRC member institution. With respect to enrollment, pre-study enrollment commitment (EC) established between MMRC and the study sponsor was defined as the total number of subjects committed to receive at least one dose of study drug across all participating MMRC centers on a trial; baseline enrollment timeline (BET) was prospectively defined as the target time period to attain EC. Results: Mean time to FPFD was 181 calendar days for the early group trials (EG, n=7) and 122 days for the recent group (RG) trials (n=14, Sep08 – Jun10), representing a 32% reduction of time to FPFD in the RG. Additionally, time from final protocol to first patient dosed at all MMRC centers on a trial decreased 18% from a mean of 7.7 months (EG) to 6.3 months (RG). With respect to MMRC trial enrollment, data was available for 16/21 trials (5 EG and 11 RG). 2 EG trials were missing data and 3 RG trials were still enrolling as of June 2010. The mean MMRC pre-study EC was 39 subjects per trial (n=16 trials; 626 enrollment target); the mean actual MMRC enrollment was 49 subjects per trial (n=16; 783 enrolled through Jun 29, 2010) representing a 25% increase in actual versus committed enrollment. Two trials did not meet MMRC EC: MMRC investigators discontinued their involvement in these trials at approximately 30% target EC due to trial complexity or low patient enrollment. 14/16 evaluable trials (88%) met their EC; 11/16 trials met EC within BET (69%) of which 8/16 trials (50%) reached EC 34% faster than their BET (representing a mean reduction of 4.5 months). The overall pre-study mean BET for 16 trials was 13.1 months. MMRC's actual mean enrollment timeline was 11.3 months for the group of 14 evaluable trials representing improvement over the original BET by a mean of 1.9 months (14%). We believe FP to FPFD is a more meaningful metric beyond that of first patient consented. Moreover, we believe that if all participating trial centers focus their efforts on dosing the first patient and within a targeted timeframe, it may improve our research efforts overall. Conclusion: Development of drugs in the clinical setting has become time and resource intensive. Activating and enrolling trials promptly is a priority for drug development. The MMRC's standardization of processes and support for site-based PM resources results in improved trial metrics. MMRC member centers met or exceeded pre-specified enrollment targets in 88% of the trials analyzed to date. Ongoing monitoring of trial conduct continues to reveal areas where increased focus is needed to realize further trial efficiencies. These trial metrics and measures to improve efficiency may be applied with similar expected benefit in all oncology disciplines. Disclosures: Wear: Multiple Myeloma Research Consortium (MMRC): Employment. Richardson:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC; Millennium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees. Revta:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Vij:Multiple Myeloma Research Consortium (MMRC): Research Funding; Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Fiala:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Lonial:Bristo-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium Pharmaceuticals Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Francis:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Siegel:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC; Celgene: Speakers Bureau; Millennium: Speakers Bureau. Schramm:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Jakubowiak:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC, Research Funding; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Centocor Ortho-Biotech: Honoraria, Speakers Bureau; Exelixis: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Harvey:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Reece:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC; Celgene: Honoraria, Research Funding; Ortho Biotech: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Facet: Research Funding; Otsuka: Honoraria, Research Funding. Gul:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Jagannath:Celgene: Honoraria; Millenium: Honoraria; Orthobiotec: Honoraria; Onyx Pharma: Honoraria; Merck: Honoraria; Proteolix: Honoraria; Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. La:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Hofmeister:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Jansak:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Stewart:Millennium: Consultancy; Celgene: Honoraria; Multiple Myeloma Research Consortium: Member Institution of the MMRC. Hagerty:Mayo Clinic: Employment; Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Wolf:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC; Celgene: Speakers Bureau; Millennium: Speakers Bureau; Novartis: Speakers Bureau; Orthobiotech: Speakers Bureau. Davis:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Krishnan:Celgene: Speakers Bureau; Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Duarte:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Zimmerman:Millennium, Celgene: Speakers Bureau. Cisneros:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Kumar:Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding; Bayer: Research Funding; Multiple Myeloma Research Consortium: Member Institution of the MMRC. Birgin:Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC. Ott:Multiple Myeloma Research Consortium (MMRC): Employment. Tasca:Multiple Myeloma Research Consortium (MMRC): Employment. Kelley:Multiple Myeloma Research Consortium (MMRC): Employment. Anderson:Millennium: Consultancy; Multiple Myeloma Research Consortium (MMRC): Member Institution of the MMRC; Celgene: Consultancy; Novartis: Consultancy; Onyx: Consultancy; Merck: Consultancy; Bristol-Myers Squibb: Consultancy; Acetylon: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Giusti:Multiple Myeloma Research Consortium (MMRC): Employment.

SummaryCarfilzomib is a next‐generation proteasome inhibitor that selectively and irreversibly binds to its target. In clinical studies, carfilzomib has shown efficacy in patients with relapsed and/or refractory multiple myeloma (MM) and has demonstrated a tolerable safety profile. In this phase 2, open‐label, multicentre clinical trial, 35 patients with relapsed and/or refractory MM following 1–3 prior therapies, including at least one bortezomib‐based regimen, received carfilzomib 20 mg/m2 in a twice‐weekly, consecutive‐day dosing schedule for ≤12 monthly cycles. The best overall response rate (ORR) was 17·1% and the clinical benefit response rate (ORR + minimal response) was 31·4%. The median duration of response was >10·6 months and the median time to progression was 4·6 months. The most common adverse events were fatigue (62·9%), nausea (60·0%), and vomiting (42·9%). No exacerbation of baseline peripheral neuropathy was observed. Single‐agent carfilzomib was generally well tolerated for up to 12 treatment cycles and showed activity in patients with relapsed and/or refractory MM who had received prior treatment with bortezomib. These data, combined with an acceptable toxicity profile, support the potential use of carfilzomib in patients with relapsed and/or refractory MM and warrant continued investigation of carfilzomib as single agent or in combination with other agents.

AbstractCarfilzomib is a next-generation, selective proteasome inhibitor being evaluated for the treatment of relapsed and refractory multiple myeloma. In this open-label, single-arm phase 2 study (PX-171-003-A1), patients received single-agent carfilzomib 20 mg/m2 intravenously twice weekly for 3 of 4 weeks in cycle 1, then 27 mg/m2 for ≤ 12 cycles. The primary endpoint was overall response rate (≥ partial response). Secondary endpoints included clinical benefit response rate (≥ minimal response), duration of response, progression-free survival, overall survival, and safety. A total of 266 patients were evaluable for safety, 257 for efficacy; 95% were refractory to their last therapy; 80% were refractory or intolerant to both bortezomib and lenalidomide. Patients had median of 5 prior lines of therapy, including bortezomib, lenalidomide, and thalidomide. Overall response rate was 23.7% with median duration of response of 7.8 months. Median overall survival was 15.6 months. Adverse events (AEs) were manageable without cumulative toxicities. Common AEs were fatigue (49%), anemia (46%), nausea (45%), and thrombocytopenia (39%). Thirty-three patients (12.4%) experienced peripheral neuropathy, primarily grades 1 or 2. Thirty-three patients (12.4%) withdrew because of an AE. Durable responses and an acceptable tolerability profile in this heavily pretreated population demonstrate the potential of carfilzomib to offer meaningful clinical benefit. This trial was registered at www.clinicaltrials.gov as #NCT00511238.

Abstract Background: Activation of oncology trials is a lengthy and complex process. Recent literature has identified numerous opportunities to improve activation timelines1, 2. The Multiple Myeloma Research Consortium (MMRC) has implemented several processes to identify and overcome myeloma clinical trial activation barriers within the consortium network of 14 North American cancer centers. We examined the impact of these processes preand post- implementation and also compared activation times with published clinical trial metrics data. Methods/Results: 12 MMRC-facilitated trials had sufficient trial data available for review within the study period of May 2006 to March 2009. Activation time was defined as the time from a center's receipt of the final clinical trial protocol from the sponsor, to the time the first patient was enrolled into a trial at any MMRC participating center. The earlier group (EG) of MMRC trials (n=7) required a mean of 257 calendar days for activation, comparable to the mean published data of 251 calendar days1. The more recent group (RG) of MMRC trials (n=5) required a mean of 158 calendar days for activation, representing a 38% shortening of activation time. Additionally, implementation of standardized processes and rigorous project management resulted in a reduction in activation times for all MMRC centers in a given trial from a mean of 7.5 months to a mean of 5.1 months. Improving the mean time of several several specific steps in the process including time to initial protocol review submission from receipt (EG=37 vs. RG=19 days), scientific review committee time (EG=98 vs. RG=55 days), and the time from trial opening to first patient dosed (EG=74 vs. RG=27 days) contributed to the overall decrease in activation times. The EG metrics data are comparable to published data1 for each process step. Conclusion: The MMRC member institutions have seen substantial improvements in trial activation times and are in the process of implementing additional processes to further improve protocol development and trial conduct metrics. The efficiencies and process improvements realized from application of rigorous MMRC project management resources and the standardization of contracting and other key activities may be applied in other areas of oncology clinical trials beyond multiple myeloma. With increasing numbers of new oncology agents to be evaluated and greater pressure on trial sponsors to introduce efficiencies into trial timelines, overcoming such barriers is of critical importance. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B58.

Abstract Carfilzomib is a selective proteasome inhibitor that binds irreversibly to its target. In phase 1 studies, carfilzomib elicited promising responses and an acceptable toxicity profile in patients with relapsed and/or refractory multiple myeloma (R/R MM). In the present phase 2, multicenter, open-label study, 129 bortezomib-naive patients with R/R MM (median of 2 prior therapies) were separated into Cohort 1, scheduled to receive intravenous carfilzomib 20 mg/m2 for all treatment cycles, and Cohort 2, scheduled to receive 20 mg/m2 for cycle 1 and then 27 mg/m2 for all subsequent cycles. The primary end point was an overall response rate (≥ partial response) of 42.4% in Cohort 1 and 52.2% in Cohort 2. The clinical benefit response (overall response rate + minimal response) was 59.3% and 64.2% in Cohorts 1 and 2, respectively. Median duration of response was 13.1 months and not reached, and median time to progression was 8.3 months and not reached, respectively. The most common treatment-emergent adverse events were fatigue (62.0%) and nausea (48.8%). Single-agent carfilzomib elicited a low incidence of peripheral neuropathy—17.1% overall (1 grade 3; no grade 4)—in these pretreated bortezomib-naive patients. The results of the present study support the use of carfilzomib in R/R MM patients. This trial is registered at www.clinicaltrials.gov as NCT00530816.