James R. Berenson, MD
Administering carfilzomib once weekly in combination with dexamethasone is safe, with few ≥3 adverse events, and has significant antitumor activity in the treatment of patients with relapsed or refractory multiple myeloma.
In 27 patients who were evaluated for response in the phase I dose-escalation portion of the CHAMPION study, the objective response rate (ORR) was 81% and the clinical benefit rate was 93% with once weekly carfilzomib in all dose cohorts, reported lead investigator James R. Berenson, MD, at the 2014 ASCO Annual Meeting.
The findings suggest that carfilzomib may be administered in a convenient once weekly schedule in combination with dexamethasone. The maximum tolerated dose (MTD) was 70 mg/m2
, at which dose carfilzomib “certainly looks as active giving it once a week if not more active [than the approved dosage],” Berenson said. The approved dose and schedule for single-agent carfilzomib is 20/27 mg/m2
administered intravenously (IV) over 2 to 10 minutes on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle.
“The goal of the study was to modify the dose of carfilzomib to see if we could make it more convenient and possibly more active,” said Berenson, founder, President and Medical and Scientific Director of the Institute for Myeloma and Bone Cancer Research, and President of Oncotherapeutics.
In the study, 27 patients with relapsed or refractory multiple myeloma who received 1 to 3 prior regimens were treated with carfilzomib as a 30-minute IV infusion on days 1, 8, and 15 of each 28-day cycle in a 3+3 dose escalation scheme. All patients received carfilzomib, 20 mg/m2
, on day 1 of cycle 1. Subsequent doses started at 45 mg/m2
and were escalated to 56, 70, or 88 mg/m2
in successive cohorts until the MTD was determined.
An expansion cohort of 9 additional patients was also enrolled to confirm the MTD before moving to the phase II portion of the study. Patients received dexamethasone, 40 mg IV or per orally, on days 1, 8, 15, and 22 of cycles 1 through 8. Administration of dexamethasone on day 22 was omitted from cycle 9 and beyond.
Prior to enrolling in the study, patients had received prior treatment with bortezomib (85%), with 63% becoming refractory to this treatment. Forty-one percent had received 2 prior regimens. The median treatment duration was 8.3 months in the overall population, and 13 patients (48%) were still receiving treatment at data cut-off (May 5, 2014).
In the response evaluation, the ORR was 81% and the clinical benefit rate was 93%. At 70 mg/m2
of carfilzomib, there were 3 complete responses in the 6 patients treated in the dose-escalation cohort, and 1 complete response in the 9 treated in the expansion cohort. The ORR with 70 mg/m2
in the dose-expansion cohort was 100% (9 of 9).
During dose-escalation, no dose-limiting toxicities were reported up to 70 mg/m2
. At the 88 mg/m2
, dose-limiting toxicities were observed: grade 3 dyspnea and grade 3 vomiting. Therefore, MTD of weekly carfilzomib in combination with weekly dexamethasone was 70 mg/m2
. Per study protocol, an expansion cohort of 9 patients was enrolled at 70 mg/m2
, and there was 1 dose-limiting toxicity in the expansion cohort: grade 3 dyspnea at days 16 to 18.
In the 70-mg/m2
dose escalation cohort, 1 patient discontinued treatment for an increased blood creatinine level and 1 for general weakness. Five of 6 patients in the 88-mg/m2
cohort required 1 or more carfilzomib dose reductions due to adverse events or dose-limiting toxicities. In the 45-mg/m2
, and 70-mg/m2
dose escalation cohorts, no patients had a dose reduction. Two of the 9 patients in the 70-mg/m2
expansion cohort had dose reductions due to adverse events.
There was a dose-proportional increase in mean Cmax
and area under the curve for carfilzomib, 20 mg/m2
to 88 mg/m2
. Weekly carfilzomib at 70 mg/m2
had a mean terminal half-life similar to the currently approved twice-weekly carfilzomib-dosing regimen, but achieved a lower Cmax
than the approved twice-weekly dosage regimen.
“The trial has now moved rapidly to phase II,” said Berenson. “We hope to present those data sometime within the next 6 to 12 months.”