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.
Swinnen LJ, Flowers CR, Wang D, Reid E, Fowler N, Cordero J, Dunbar M, Enschede S, Nolan C, Petrich AM, Ross J, Salem AH, Verdugo M, Wong S, Zhou L, Kozloff M, Nastoupil L, and De Vos S. 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. Hematol Oncol 2017; 35:90.
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(FN) and AEs related to disease progression (8%) the most frequent. 29 pts discontinued the study (PD, n = 16; withdrawn consent, n = 4; AEs, n = 3; other, n = 6); 5 pts died from either disease progression (n = 4) or respiratory failure (n = 1).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.