A planned interim analysis has shown that the phase 3 head-to-head clinical trial ENDEAVOR evaluating Carfilzomib ( Kyprolis ) for injection in combination with low-dose Dexamethasone versus Bortezomib ( Velcade ) and low-dose Dexamethasone met the primary endpoint of progression-free survival ( PFS ).
Patients with relapsed multiple myeloma treated with Carfilzomib lived twice as long without their disease worsening, demonstrating statistically and clinically significant superiority over Bortezomib ( median PFS 18.7 months versus 9.4 months; hazard ratio, HR=0.53, 95% CI, 0.44 – 0.65 ).
The Carfilzomib combination has demonstrated superiority over Bortexomib combination for secondary objectives of higher overall response rate and lower neuropathy events. Overall survival data are not yet mature and continue to be monitored.
Treatment discontinuation due to adverse events and on-study deaths were comparable between the two arms. The rates of cardiac failure and renal failure for Carfilzomib were comparable to those observed in the phase 3 ASPIRE study.
In ENDEAVOR, the rates for cardiac and renal failure were higher in the Carfilzomib arm versus the Bortezomib arm. There was an increase in the incidence of hypertension and dyspnea in the Carfilzomib arm compared to Bortezomib and that observed in the ASPIRE study.
The ENDEAVOR study is the first of two head-to-head studies for Kyprolis versus Velcade, an established proteasome inhibitor, currently approved to treat multiple myeloma.
The randomized ENDEAVOR ( RandomizEd, OpeN Label, Phase 3 Study of Carfilzomib Plus DExamethAsone Vs Bortezomib Plus DexamethasOne in Patients With Relapsed Multiple Myeloma ) trial of 929 patients evaluated Carfilzomib in combination with low-dose Dexamethasone, versus Bortezomib with low-dose Dexamethasone in patients whose multiple myeloma has relapsed after at least one, but not more than three prior therapeutic regimens.
The primary endpoint of the trial was progression-free survival, defined as the time from treatment initiation to disease progression or death.
Patients received Carfilzomib as a 30 minute infusion along with low-dose Dexamethasone ( 20 mg ). For cycle 1 only, Carfilzomib was administered at 20 mg/m2 on days 1 and 2, followed by escalation to 56 mg/m2 on days 8, 9, 15, and 16. Patients who tolerated 56 mg/m2 in cycle 1 were kept at this dose for subsequent cycles on days 1, 2, 8, 9, 15, and 16 on a 28 day cycle.
Patients who received Bortezomib ( 1.3 mg/m2 ) with low-dose Dexamethasone ( 20 mg ) were administered Bortezomib subcutaneously or intravenously at the discretion of the investigator and in accordance with regulatory approval of Velcade. More than 75% of the patients in the control arm received Velcade subcutaneously.
On July 20, 2012, the FDA ( Food and Drug Administration ) granted accelerated approval of Kyprolis for the treatment of patients with multiple myeloma who have received at least two prior therapies including Bortezomib and an immunomodulatory agent ( IMiD ) and have demonstrated disease progression on or within 60 days of completion of the last therapy.
Approval was based on response rate. Clinical benefit, such as improvement in survival or symptoms, has not been verified. Kyprolis is administered intravenously over 2 to 10 minutes, on two consecutive days each week for three weeks ( days 1, 2, 8, 9, 15, and 16 ), followed by a 12-day rest period ( days 17 to 28 ) at a recommended cycle 1 dose of 20 mg/m2/day and if tolerated increased cycle 2 dose and subsequent cycles doses of 27 mg/m2/day.
Multiple myeloma is the second most common hematologic cancer and results from an abnormality of plasma cells, usually in the bone marrow.
Worldwide, nearly 230,000 people are living with multiple myeloma, approximately 114,000 new cases were diagnosed and 80,000 people died in 2012.
In the U.S., approximately 83,000 people are living with multiple myeloma and more than 22,000 new cases were diagnosed and more than 10,000 people died in 2013.
In Europe, approximately 89,000 people are living with multiple myeloma, approximately 42,000 new cases were diagnosed and approximately 26,000 people died in 2012. ( Xagena )
Source: Amgen, 2015