Dose-finding study of ibrutinib and venetoclax in relapsed or refractory mantle cell lymphoma

Abstract

Relapsed Mantle cell lymphoma (MCL) is often treated with Bruton's tyrosine kinase inhibitors (BTKi); however, post-BTKi relapse can be challenging. Adding venetoclax (VEN) to ibrutinib (IBR) has shown synergy in preclinical MCL models. Prior MCL studies of the combination show promising efficacy but have conducted limited dose finding. We sought to identify the optimal dosing combination, based on efficacy and toxicity, utilizing a continual reassessment method of 6 combinations of IBR (280 mg, 420 mg, and 560 mg by mouth daily) and VEN (max dose of 200 mg and 400 mg by mouth daily). Eligible participants were not previously exposed to BTKi and not high risk for tumor lysis syndrome (TLS). VEN, initiated first at 100 mg, then at 20 mg by mouth daily after a TLS event, was started prior to adding IBR and ramped-up based on the dose level assigned. Combination treatment continued for six 28-day cycles. Thirty-five participants were enrolled and treated. One TLS event occurred with starting dose of 100 mg VEN; no TLS was seen with 20 mg. The optimal dosing combination was considered to be VEN 200 mg and IBR 420 mg with an overall response rate (ORR) of 93.8% (95% CI: 73.6% to 99.7%) and DLT incidence of 6.2% (95% CI: 0.3% to 26.4%). ORR for all arms was 82.3% (28/34; 95% CI: 65.5% to 93.2%) with a complete response (CR) rate of 42.4% (14/33; 95% CI: 25.5% to 60.8%). A participant was not allocated to IBR 560 mg and VEN 400 mg. ORR benefit was not seen with higher dosing combinations and toxicity was higher; a comparison made within the limitations of small cohorts. Resistance was seen in nearly all arms. This trial was registered at www.clinicaltrials.gov #NCT02419560.

© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.

Figures

Graphical abstract

Figure 1.

Treatment schema. Participants were initially treated with VEN, starting at 20 mg by mouth daily and increasing to 50 mg by mouth daily and 100 mg by mouth daily over 2 weeks (cycle 0*). Participants must have had at least 2 but no more than 4 days of 20 mg, and 3 but no more than 5 days of 50 mg before moving to 100 mg by mouth daily for 7 days. Ibrutinib (IBR), at the allocated dose, was added to venetoclax (VEN) at 100 mg by mouth daily for an additional 7 days (cycle 1, week 1). Weekly VEN dose titration was continued to the allocated dose as shown.

Figure 2.

PFS and OS. (A) PFS for all participants. (B) PFS for the optimal dose, arm B (IBR 420 mg daily and VEN 200 mg daily). (C) OS for all participants. (D) OS for the optimal dose, arm B (IBR 420 mg daily and VEN 200 mg daily).

Figure 3.

PFS in those finishing study therapy. PFS starts at the end of therapy and compares those that were treated with IBR (red) to those that were not (blue).