Trial in Progress: Once-Weekly vs Twice-Weekly Dosing of Carfilzomib-Lenalidomide-Dexamethasone in Patients w/ Relapsed or Refractory Multiple Myeloma

Purpose of the Study: Carfilzomib (K), an irreversible proteasome inhibitor, is approved for the treatment of patients (pts) with relapsed or refractory  multiple  myeloma  (RRMM).  In  the  randomized  phase 3 ASPIRE trial, twice-weekly K (27 mg/m2) in combination with lenalidomide-dexamethasone (Rd) (KRd27) led to significant improve- ment over Rd in progression-free survival (PFS) (median PFS, 26.3 mos for KRd27 vs 17.6 mos for Rd; hazard ratio [HR], 0.69) and overall survival (OS) (median OS, 48.3 mos for KRd27 vs 40.4 mos for Rd; HR, 0.79). However, the demands of twice-weekly dosing of K may be bur- densome for pts and caregivers, compromising adherence to the cor- rect K-dosing schedule. The randomized phase 3 A.R.R.O.W. trial demonstrated that once-weekly Kd70 significantly reduced the risk of progression by 30% compared with twice-weekly Kd27 and increased the overall response rate (ORR) to 62.9% from 40.8% in twice-weekly Kd27 with comparable overall safety between the two groups. The U.S. has approved this more convenient once-weekly K (70 mg/m2) in combination with dexamethasone (Kd70) for the treatment of RRMM pts (Moreau Lancet Oncol 2018). Given the favorable outcomes of the once-weekly Kd70, a more convenient once-weekly dosing of K at 56 or 70 mg/m2 was explored in combination with Rd (KRd56 or KRd70) for pts with RRMM in a phase 1b study (Biran Am J Hematol 2019), which demonstrated efficacy and acceptable safety for once- weekly KRd56. Based on the results of the phase 1b trial, a randomized, open-label, non-inferiority phase 3 A.R.R.O.W.2 trial has been initiated to evaluate the clinical outcomes of once-weekly KRd56 vs twice- weekly KRd27 dosing using the ASPIRE trial as a historical reference.

Summarized Description of the Project: In A.R.R.O.W.2 trial, pts with RRMM and 1 to 3 prior lines of therapy will be randomized 1:1 to once-weekly or twice-weekly dosing of KRd. Approximately 460 pts will be enrolled in 14 countries. Pts will receive KRd up to twelve 28-day cycles (C) or until discontinuation of treatment, disease progression, or death. No crossover between the once-weekly and twice- weekly arms is permitted. In the once-weekly group, K will be administered  intravenously  (IV)  for  30  mins  on  days  (D)  1,  8,  and  15 (20 mg/m2: C1D1; 56 mg/m2 thereafter). In the twice-weekly group, K will be administered IV for 10 mins on D1, 2, 8, 9, 15 and 16 (20 mg/m2: C1D1 and C1D2; 27 mg/m2 thereafter). Pts in both arms will take 25 mg of R orally on D1 to D21, and 40 mg of d orally or intravenously on D1, 8, and 15 of each cycle with d on D22 for C1 to C9 only. The primary endpoint is ORR. The secondary endpoints include one-year PFS, patient-reported convenience with K-dosing schedule, minimal residual disease negativity rate for patients with complete response or better, and safety. The first subject was enrolled on May 8, 2019.