CHAMPION-1: a phase 1/2 study of once-weekly carfilzomib and dexamethasone for relapsed or refractory multiple myeloma

Abstract

Carfilzomib, a proteasome inhibitor, is approved in the United States as a single agent, and in combination with dexamethasone or lenalidomide/dexamethasone (KRd) for relapsed or refractory multiple myeloma (MM). Under the single-agent and KRd approvals, carfilzomib is administered as a 10-minute IV infusion on days 1, 2, 8, 9, 15, and 16 of 28-day cycles (20 mg/m(2) [cycle 1, days 1-2]; 27 mg/m(2) thereafter). This multicenter, single-arm, phase 1/2 study, Community Harmonized Assessment of Myeloma Patients via an Integrated Oncology Network-1 (CHAMPION-1), evaluated once-weekly carfilzomib with dexamethasone in relapsed, or relapsed and refractory MM (1-3 prior therapies). Patients received carfilzomib (30-minute IV infusion) on days 1, 8, and 15 of 28-day cycles. The phase 1 portion used a 3 + 3 dose-escalation scheme to determine the maximum tolerated dose (MTD) of carfilzomib. During phase 2, patients received carfilzomib on the same schedule at the MTD. Patients received dexamethasone (40 mg) on days 1, 8, 15, and 22; dexamethasone was omitted on day 22 for cycles 9+. A total of 116 patients were enrolled. The MTD was 70 mg/m(2), and 104 patients (phase 1/2) received carfilzomib 70 mg/m(2) At 70 mg/m(2), the median number of prior regimens was 1; and 52% were bortezomib-refractory. At 70 mg/m(2), the most common grade ≥3 adverse events were fatigue (11%) and hypertension (7%). Overall response rate at 70 mg/m(2) was 77%. Median progression-free survival was 12.6 months. These findings merit additional evaluation of the once-weekly dosing regimen. This trial was registered at www.clinicaltrials.gov as #NCT01677858.

Figure 1

Kaplan–Meier estimate of PFS. Kaplan–Meier estimated median PFS was 12.6 months (95% CI, 9.0-not estimable); median follow-up for PFS was 10.7 months (95% CI, 9.2-12.5).

Figure 2

Carfilzomib plasma concentration-time profile following a 30-minute IV infusion of carfilzomib, and proteasome activity and active-site binding probe subunit occupancy in PBMCs. (A) Mean (standard deviation) carfilzomib plasma concentration time profile after administration via a 30-minute IV infusion of 20, 70, or 88 mg/m² carfilzomib. (B) Dose-dependent proteasome activity and active-site binding probe subunit occupancy in PBMCs at 1 hour post-dose on C2D1 (unless otherwise noted) in CHAMPION-1 and PX-171-007; 20 mg/m² (C1D1), n = 10-11; 20 mg/m², n = 3; 27 mg/m², n = 3; 36 mg/m², n = 20-24; 45 mg/m², n = 3-8; 56 mg/m², n = 5-13; and 70 mg/m², n = 7. Data for 20, 27, 36, 45, and 56 mg/m² doses are from the PX-171-007 study (twice-weekly dosing); 20 mg/m² (C1D1 only) and 70 mg/m² data are from the CHAMPION-1 study (once-weekly dosing). Values (relative to C1D1 pre-dose) are presented as mean (± standard error of the mean). CT-L activity was measured by the fluorescent enzymatic cleavage LLVY-AMC assay,^, whereas subunit occupancy was measured by the ProCISE assay. The ProCISE assay employs a proteasome active-site binding probe that generates a signal from catalytic sites that are not already bound by inhibitor (ie, carfilzomib); subunit (probe) occupancy is thus proportional to the presence of active subunit. (C) Time-course of inhibition, and recovery of proteasome activity and active-site binding probe subunit occupancy in peripheral blood at 1 hour post-dose on C2D1; 20 mg/m², n = 3-48; 36 mg/m², n = 4-24; and 70 mg/m²; n = 7-11. LMP2, low molecular mass polypeptide 2; LMP7, low molecular mass polypeptide 7; MECL-1, multi-catalytic endopeptidase complex-like 1.