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947 Phase II Study of Infusional Carfilzomib in Patients with Relapsed or Refractory Multiple Myeloma

Program: Oral and Poster Abstracts
Type: Oral
Session: 653. Myeloma - Therapy, excluding Transplantation: Clinical issues in myeloma and amyloidosis patients: novel agent and novel agent-based combinations
Tuesday, December 11, 2012: 8:30 AM
Thomas Murphy Ballroom 2-3, Level 5, Building B (Georgia World Congress Center)

Nikoletta Lendvai, MD PhD1,2, Heather Landau, MD3, Alexander Lesokhin, MD4, Ioanna Tsakos, BS5*, Guenther Koehne, MD, PhD6, David Chung, MD PhD3, Sean Devlin, PhD7*, Hani Hassoun, MD1 and Sergio A Giralt, MD8

1Myeloma/Lymphoma Service, Memorial Sloan-Kettering Cancer Center, New York, NY
2Weill Medical College of Cornell University, New York, NY
3Adult Bone Marrow Transplantation Service, Memorial Sloan-Kettering Cancer Center, New York, NY
4Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY
5Medicine, MSKCC, New York, NY
6Department of Medicine, Adult Allogeneic Bone Marrow Transplant Service, Memorial Sloan-Kettering Cancer Center, New York, NY
7Epidemiology and Biostatistics, MSKCC, New York, NY
8Allogeneic Bone Marrow Transplantation - Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY

Background: Carfilzomib (CFZ) is a selective, irreversible epoxyketone inhibitor of the chymotrypsin-like activity of both the constitutive proteasome and the immunoproteasome. In patients with multiple myeloma single-agent CFZ is active and well tolerated at doses up to 27 mg/m2 when administered intravenously over 2–10 minutes. Based on preclinical safety data showing that a slower infusion was better tolerated and permitted administration of higher doses than a 2–10 minute infusion, the phase1b/2 PX-171-007 (NCT00531284) study evaluated the administration of CFZ as a 30-minute infusion. That study found the maximally tolerated dose of CFZ given as a 30 minutes infusion to be 56mg/m2. We designed a single institution, phase 2 study of high dose, infusional CFZ in patients with relapsed and/or refractory multiple myeloma.

Methods: CFZ was given as a 30-minute IV infusion on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. Cycle1 Day1–2 doses were 20 mg/m2, followed by escalation to 56mg/m2. Dexamethasone 8 mg was given prior to infusion as premedication to mitigate infusion-related reactions. Patients who did not achieve a partial response (PR) after two cycles of CFZ or initially responded to single agent CFZ, but later showed evidence of progression of disease (POD) had dexamethasone (40mg/week) added to their regimen. Overall response rate (ORR; [sCR + CR + VGPR + PR]) was determined according to International Myeloma Working Group Uniform Response Criteria. Subjects were evaluated for adverse events according to the Common Terminology Criteria for Adverse Events v 4.0.

Results: Thirty-four patients have been enrolled. Patients had received a median of 5 (range 1-11) prior treatment regimens and included 7 patients who relapsed following allogeneic stem cell transplant. Seventy eight percent of patients were bortezomib-refractory. ORR among patients who completed 4 cycles of therapy or experienced POD prior to completing 4 cycles of therapy was 58% with 1 CR, 7 VGPRs, and 6 PRs. ORR after 4 cycles of therapy was 57% in bortezomib-refractory patients. By intention to treat analysis the ORR in all comers was 50%. Median progression free survival was 4.6 months, median overall survival has not been reached with a median follow-up among survivors of 9.6 months (range: 0.3-14.3 months). The average time to best response was two cycles. Three out of the 11 patients that had dexamethasone 40mg/week added to their regimen obtained an improved response. Twelve patients (35%) were dose reduced. Treatment emergent, non-hematologic Grade 3/4 adverse events for which contribution of CFZ cannot be excluded were: HTN (n = 7), lung infection (n = 6), pulmonary edema (n = 3), reduced ejection fraction (n=1), sepsis (n=2), febrile neutropenia (n=1), bacteremia (n = 1), protothecosis (n = 1), fatigue (n=1), neuropathy (n=1), microangiopathic hemolytic anemia(n=1), nausea/vomiting/+/- diarrhea (n = 2), gastrointestinal bleed in the setting of Grade 4 thrombocytopenia (n = 1), hyperkalemia (n = 1).

Conclusions: The 20/56 mg/m2 dose for CFZ administered as a 30-minute IV infusion was associated with 58% ORR, in a heavily pretreated patient population, including 21% of patients w/ prior allogeneic transplant, where the majority of patients were bortezomib-refractory. The ORR from this study is consistent with the one previously reported at the similar dose. Higher doses of carfilzomib continue to be explored in ongoing Phase 2 and Phase 3 studies.

Disclosures: Landau: Onyx: Research Funding; Milleneum: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Hassoun: Millenium: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Giralt: Onyx: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Milleneum: Membership on an entity’s Board of Directors or advisory committees.

*signifies non-member of ASH