VENETOCLAX (VEN), BENDAMUSTINE (B) AND RITUXIMAB (R) IN PATIENTS (PTS) WITH RELAPSED OR REFRACTORY (R/R) NON‐HODGKIN LYMPHOMA (NHL): FINAL RESULTS OF a PHASE I STUDY

Abstract

Introduction: VEN is a potent, selective BCL-2 inhibitor with clinical activity in R/R NHL pts. Preclinical data suggest synergy between VEN and both B and R; together BR is one of the most commonly used regimens in NHL. Final results of a dose finding study of VEN + BR (NCT01594229) are reported. Methods: This was a Phase 1 dose finding study of VEN + BR in pts ≥18 years with R/R NHL and ECOG PS of 0-1. Diffuse large B-cell lymphoma (DLBCL) pts who progressed during/within 2 months (mo) of most recent therapy, and pts with mantle cell lymphoma, were excluded. Dose escalation followed a 3 + 3 design. Oral VEN (50-1200 mg) was given for 3, 7 or 28 consecutive days (d) of each 28d cycle. BR regimen was 6 cycles: B (90 mg/m2 , IV, 2d/cycle) and R (375 mg/m2 IV, 1d/cycle). After completing VEN + BR, pts could continue VEN alone for ≤2 years after the date of last subject enrolled (maintenance) in the absence of progression and/or unacceptable toxicity. Primary endpoints included safety, pharmacokinetics, maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D); secondary endpoint was preliminary efficacy. Adverse events (AE) were graded per NCI CTCAE v4.0 and efficacy per 2007 IWG criteria. Data cut-off was Feb 15, 2017. Results: Between Jun 2012 and Oct 2015 60 pts were enrolled. Median age was 62 (range, 29-90) years; 53% (n = 32) had follicular lymphoma (FL), 37% (n = 22) had DLBCL and 10% (n = 6) had marginal zone lymphoma (MZL). Pts had a median of 3 (1-8) prior therapies. Median time on study was 7.7 (0.13-51.3) mo.Overall, 98% pts had an AE; most frequent (any grade) were nausea, neutropenia (68% each), diarrhea (55%) and thrombocytopenia (52%). Most common Grade 3/4 AEs were neutropenia (60%), and lymphopenia (38%). 24 pts reported serious AEs, with febrile neutropenia (FN) and AEs related to disease progression (8%) the most frequent. 29 pts discontinued the study (PD, n = 16; withdrawn consent, n = 4; AEs, n = 3; other, n = 6); 5 pts died from either disease progression (n = 4) or respiratory failure (n = 1). After early incidents of FN the protocol was revised to incorporate use of G-CSF. MTD was not reached; RP2D for VEN + BR was declared 800 mg continuously. VEN exposure with and without BR was comparable. The table presents efficacy data. Conclusions: VEN + BR demonstrated tolerable safety profile at up to 1200 mg continuously, and significant clinical activity; 800 mg VEN continuously is being used in the randomized CONTRALTO study. In pts with indolent lymphoma who received maintenance VEN, durable responses were observed.