On July 20, 2012, the U. S. Food and Drug Administration granted accelerated approval to carfilzomib injection (Kyprolis, Onyx Pharmaceuticals), for the treatment of patients with multiple myeloma who have received at least two prior therapies, including bortezomib and an immunomodulatory agent, and have demonstrated disease progression on or within 60 days of the completion of the last therapy.
The approval was based on the results of a single-arm, multicenter clinical trial enrolling 266 patients with relapsed multiple myeloma who had received at least two prior therapies, including bortezomib and an immunomodulatory agent (thalidomide or lenalidomide). Carfilzomib was administered intravenously over 2 to 10 minutes on 2 consecutive days weekly for 3 weeks, followed by a 12-day rest period (28 day treatment cycle). Treatment was continued until disease progression, unacceptable toxicity, or completion of a maximum of 12 cycles. Patients received 20 mg/m2 at each dose in cycle 1, and 27 mg/m2 in subsequent cycles.
To reduce the incidence and severity of infusion reactions associated with carfilzomib administration, dexamethasone (4 mg orally or intravenously) was administered prior to all carfilzomib doses during the first cycle and prior to all carfilzomib doses during the first dose-escalation (27 mg/m2) cycle. Dexamethasone premedication was re-instated if these symptoms reappeared during subsequent cycles.
The primary efficacy endpoint was overall response rate (ORR), determined by Independent Review Committee assessment using International Myeloma Working Group criteria. The ORR was 22.9% (95% CI: 18.0, 28.5), consisting of 1 complete response, 13 very good partial responses and 47 partial responses. The median response duration was 7.8 months (95% CI: 5.6, 9.2).
Safety data was evaluated in 526 patients with relapsed multiple myeloma who received carfilzomib as monotherapy. Patients received a median of 4 treatment cycles with a median cumulative carfilzomib dose of 993.4 mg. The most common adverse reactions (incidence of 30% or greater) observed in clinical trials of patients with multiple myeloma were fatigue, anemia, nausea, thrombocytopenia, dyspnea, diarrhea, and pyrexia. Serious adverse reactions were reported in 45% of patients. The most common serious adverse reactions were pneumonia, acute renal failure, pyrexia, and congestive heart failure. There were 37/526 (7%) deaths on study. The most common causes of death, other than underlying disease, were cardiac (5 patients), end-organ failure (4 patients), and infection (4 patients).
As a condition of accelerated approval, Onyx will submit the complete analysis of an ongoing randomized phase 3 trial comparing lenalidomide plus low-dose dexamethasone to lenalidomide plus low-dose dexamethasone plus carfilzomib. The primary endpoint of this trial is progression-free survival, with enrollment of patients with relapsed or refractory multiple myeloma after 1-3 prior therapies.
Carfilzomib should be administered intravenously over 2 to 10 minutes, on two consecutive days weekly (for 3 weeks (days 1, 2, 8, 9, 15, and 16), followed by a 12 day rest period (days 17 to 28). Recommended cycle one dose is 20 mg/m2/day, and, if tolerated, the recommended dose for the second and succeeding cycles is 27 mg/ m2/day.
Full prescribing information, including clinical trial information, safety, dosing, drug-drug interactions and contraindications is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202714lbl.pdf
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).