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

• Type of Material: Article
• Authors: Craig A Portell, University of Virginia; Nolan A Wages, University of Virginia; Brad S Kahl, Washington University; Lihua E Budde, City of Hope National Medical Center; Robert W Chen, City of Hope National Medical Center; Jonathon Cohen, Emory University; Nikole E Varhegyi, University of Virginia; Gina R Petroni, University of Virginia; Michael E Williams, University of Virginia
• Language: English
• Date: 2022-03-08
• Publisher: ELSEVIER
• Publication Version: Final Published Version
• Copyright Statement: © 2022 by The American Society of Hematology
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1182/bloodadvances.2021005357
• Title of Journal or Parent Work: BLOOD ADVANCES
• Volume: 6
• Issue: 5
• Start Page: 1490
• End Page: 1498
• Grant/Funding Information: This publication was supported by the University of Virginia Cancer Center (P30CA044579).; This work was supported by a grant from AbbVie Inc. to the University of Virginia. The design, execution, results, and findings were made by the authors independent from AbbVie Inc. The findings were reviewed by AbbVie prior to submission for publication.
• Keywords: RESISTANCE; Hematology; BRUTONS TYROSINE KINASE; Life Sciences & Biomedicine; FOLLOW-UP; PLUS VENETOCLAX; RITUXIMAB; Science & Technology; INHIBITOR; IMMUNOCHEMOTHERAPY; TRANSPLANTATION; NON-HODGKIN-LYMPHOMA; SURVIVAL
• Research Categories: Health Sciences, Public Health; Health Sciences, Oncology

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.