A Phase 1b Study of 30-Minute Infusion Carfilzomib 20/45 and 20/56 Mg/m² Plus 40 Mg Weekly Dexamethasone in Patients with Relapsed and/or Refractory (R/R) Multiple Myeloma

Carfilzomib, a next-generation proteasome inhibitor, has shown a favorable efficacy and safety profile in phase 1 and 2 trials in patients with multiple myeloma (MM) with doses up to 27 mg/m² administered intravenously (IV) over 2–10 minutes on 2 consecutive days for 3 weeks of a 4-week cycle. In patients with relapsed and/or refractory MM, durable responses were noted in 24% of patients from the pivotal trial PX-171-003-A1 (Siegel DS, et al. Blood. 2012) and in 48% of bortezomib-naïve patients from PX-171-004 (Vij R, et al. Blood. 2012). Based on preclinical safety data showing that a slower infusion rate of carfilzomib was better tolerated and permitted administration of higher doses than a 2- to 10-minute infusion, a phase 1b/2 study (PX-171-007, NCT00531284) was undertaken to evaluate a 30-minute infusion of escalated doses of carfilzomib. As previously reported, the MTD was 56 mg/m² with an ORR of 60% and >50% of patients treated at this dose reporting fatigue, nausea, dyspnea, and pyrexia (Papadopoulos KP, et al. Blood. 2011). To assess the tolerability and efficacy of higher doses of carfilzomib in combination with dexamethasone 40 mg weekly, we expanded a MM cohort of the 007 study and administered carfilzomib at 45 mg/m² (n=14) and 56 mg/m² (n=8) as a 30-minute IV infusion. An interim analysis of the results is reported herein.

Carfilzomib was administered as a 30-minute IV infusion on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. Cycle 1, Day 1–2 doses were 20 mg/m², followed by escalation to either 45 or 56 mg/m². Dexamethasone 20 mg was administered prior to carfilzomib dosing on Days 1, 2, 8, 9, 15, and 16; 40 mg was administered on Day 22 during the carfilzomib “rest” week of the cycle. Safety assessments included incidence, severity, and duration of adverse events (AEs), which were evaluated according to the Common Terminology Criteria for Adverse Events v 3.0. Responses were determined according to International Myeloma Working Group Uniform Response Criteria. The response-evaluable population required 2 consecutive assessments made at any time before classification as relapse or disease progression.

A total of 22 patients were treated; the median age was 59.5 years (range 41 − 72); 17 were men and 7 were African American. The median number of prior chemotherapies was 4 lines (range 1−9), and median number of transplants was 2 (range 0−4); 96% of patients received prior bortezomib. As of May 2012, patients had received a median of 4 cycles (range 1−6), with no dose reductions reported. Thirty-minute infusion of carfilzomib at 45 mg/m² or 56 mg/m² in combination with dexamethasone was well tolerated. The most common AEs, irrespective of relationship to carfilzomib, were fatigue (36.4%), headache (36.4%), thrombocytopenia (36.4%), anemia (31.8%), cough (31.8%), dyspnea (31.8%), insomnia (27.3%), upper respiratory tract infection (27.3%), nausea (22.7%), and hypertension (18.2%). Non-hematologic AEs were mostly Grade 1 or 2. Grade 3 or higher AEs reported in >10% of patients were anemia (27.3%) and thrombocytopenia (27.3%). SAEs were reported in 4 (18.2%) patients, and there were no deaths on study. Seven patients discontinued therapy due to PD (n=6, all on 45 mg/m²) or SAE (n=1, on 56 mg/m²for Grade 4 increased aspartate aminotransferase). Preliminary responses in patients who completed at least 2 cycles (n=20) included VGPR (n=2) and PR (n=9), for an ORR of 55% with SD in 6 patients and PD in 3. The remaining 2 patients discontinued prior to cycle 2 (unrelated AE=1, patient decision=1).

Thirty-minute infusion of carfilzomib combined with dexamethasone was well tolerated with a trend toward fewer AEs related to fatigue, nausea, dyspnea, and pyrexia relative to single-agent carfilzomib. In addition, preliminary reports of efficacy are compelling. This combination regimen with carfilzomib at 56 mg/m² is currently being evaluated in the phase 3 trial ENDEAVOR comparing carfilzomib plus dexamethasone vs bortezomib plus dexamethasone in patients with relapsed MM (NCT01568866).

Off Label Use: Carfilzomib for the treatment of Multiple Myeloma. Papadopoulos:Onyx Pharmaceuticals: Honoraria, Research Funding. Zojwalla:Onyx Pharmaceuticals: Employment. Lee:Onyx Pharmaceuticals: Employment. Siegel:Millennium: Advisory Boards, Advisory Boards Other, Honoraria, Speakers Bureau; Merck: Advisory Boards, Advisory Boards Other, Honoraria, Speakers Bureau; Celgene: Advisory Boards, Advisory Boards Other, Honoraria, Speakers Bureau; Onyx Pharmaceuticals: Advisory Boards Other, Honoraria, Speakers Bureau.