Safety and Efficacy of Venetoclax (VEN) in Combination with Bendamustine (B) Plus Rituximab (R) or Obinutuzumab (G) in Patients (pts) with Previously Untreated Chronic Lymphocytic Leukemia (CLL): Results from a Phase Ib Study (GO28440)
Authors: Stilgenbauer Stephan , Morschhauser Franck , Wendtner Clemens-Martin , Cartron Guillaume , Hallek Michael , Eichhorst Barbara , Kozloff Mark F. , Giever Thomas , Lozanski Gerard , Jiang Yanwen , Huang Huang , Pignataro Daniela Soriano , Schary William , Humphrey Kathryn , Mobasher Mehrdad , Salles Gilles 
Published: October 2019

Abstract
Introduction
Anti-apoptotic protein BCL2 is overexpressed in hematologic malignancies such as CLL. BCL2 inhibitor VEN has shown profound efficacy when combined with B and anti-CD20 antibodies G and R, all of which are established components of CLL therapy. Pre-clinical and early clinical data in R/R CLL suggest addition of VEN to BR or BG may improve efficacy. Here we present data from a Phase Ib study of VEN in combination with BR/BG evaluated for first line (1L) CLL patients (pts).
Methods
This single-arm, open-label study had dose-finding (3 + 3 design) and subsequent safety-expansion stages. 1L CLL pts with ECOG PS ≤1, adequate marrow and organ function, who were in need of treatment, were first enrolled to BR-VEN, then safety data were reviewed before initiation of the BG-VEN cohort and expansions. In dose finding, 2 dosing schedules were assessed: a) Cycle 1: VEN ramp up introduced before BR/BG or b) Cycle 1: BR/BG loading dose introduced before VEN ramp up, with 1 schedule to be chosen for expansion. Pts were to receive 6 (28-day) cycles of BR/BG-VEN followed by 6 mo of VEN single agent for an overall treatment duration of 1 yr. VEN single agent could be extended upon request of the treating physician if pts were bone marrow (BM) minimal residual disease (MRD) positive and/or had partial response. Objectives were maximum tolerated dose of BR/BG-VEN, safety/tolerability of the combinations and efficacy, including undetectable MRD (<1 CLL cell/104 leukocytes) rate by 5-color flow cytometry. Disease response was assessed by investigators per iwCLL 2008. Pooled data from dose finding and safety expansion for each combination are presented.
Results
During dose finding, no dose-limiting toxicities were observed; schedule b (BR/BG before VEN) and VEN 400mg were recommended for safety expansion. As of June 1 2018, 50 pts were enrolled overall (baseline characteristics in Table 1): 49 pts received ≥1 dose of any study drug (27 BR-VEN, 22 BG-VEN), and 45 (26 BR-VEN, 19 BG-VEN) were evaluable for efficacy.
41% pts (11/27 BR-VEN, 9/22 BG-VEN) completed 6 combination cycles. Median B cycles: 5 (1-6) in both cohorts. Median VEN duration: 371 days (4-1082) BR-VEN, 336 days (11-543) BG-VEN. 8 pts in each cohort had VEN beyond planned 1 yr (14 still on VEN, 2 stopped as of cut-off date). Median time on study: 26 mo (3-43) BR-VEN and 18 mo (1-33) BG-VEN. VEN dose reductions/interruptions occurred in 82% pts (22/27 BR-VEN, 18/22 BG-VEN). 14 pts (8 BR-VEN, 6 BG-VEN) discontinued VEN due to AEs.
All pts experienced ≥1 AE. Most common Gr 3-4 AEs: neutropenia (85% BR-VEN, 55% BG-VEN) and thrombocytopenia (37% BR-VEN, 50% BG-VEN; Table 2). No clinical tumor lysis syndrome (TLS) was observed; laboratory TLS was seen in 1 pt with BG before any VEN was given. 1 fatal AE occurred (hemorrhagic transformation after stroke in BR-VEN cohort, onset on Day 82). Infections (all-Gr/Gr 3-4) were observed in 70/0% with BR-VEN and 73/27% with BG-VEN.
All pts responded to treatment; objective rates were consistent among pts with del(17p) and/or TP53 mutation (mut) and IGHV unmut status or number of B cycles received (6 vs <6; Table 3). Half of pts achieved a complete response (CR) with each combination. Undetectable MRD was seen in most pts; full data on peripheral blood and BM MRD will be presented at the meeting. As of the cut-off date, only 1 pt experienced PD (in BR cohort), there was no Richter transformation in either cohort. Estimated 18-mo PFS was 96% with BR-VEN and 100% with BG-VEN.
Conclusion
VEN 400mg daily combined with BR or BG in 1L CLL treatment was associated with toxicity leading to treatment interruptions and discontinuations; the most frequently reported toxicities were hematologic. However, despite dose modifications, all pts responded to treatment, independently of subgroups. 50% of pts achieved a CR/CRi; higher than previously reported with BG or BR alone (Brown et al. Blood 2015; Michallet et al. Haematologica 2018). Responses were durable and preliminary PFS data are encouraging. Response rates were similar, irrespective of whether pts received planned 6 or fewer cycles of B; the optimal number of B cycles and general benefit of B in combination with R-VEN or G-VEN should be examined further with longer follow-up. No marked differences in quality of clinical responses were observed when VEN was combined with BR or BG. Updated MRD data will provide a better understanding of the efficacy of these combination regimens compared with backbone chemo-free regimens.

Disclosures
Stilgenbauer: GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Hoffmann La-Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmcyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Morschhauser:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy; Servier: Membership on an entity's Board of Directors or advisory committees. Wendtner:Pharmacyclics: Consultancy, Honoraria, Other: travel support, Research Funding; Janssen: Consultancy, Honoraria, Other: travel support, Research Funding; Roche: Consultancy, Honoraria, Other: travel support, Research Funding; MorphoSys: Consultancy, Honoraria, Other: travel support, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Other: travel support, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; Genetech: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Research Funding. Cartron:Roche: Consultancy, Honoraria; Gilead Sciences: Honoraria; Celgene: Consultancy, Honoraria; Janssen: Honoraria; Sanofi: Honoraria. Hallek:Abbvie: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding. Eichhorst:AbbVie, Celgene, Gilead, Janssen, Mundipharma, Novartis, Roche: Honoraria, Other: Travel support, Research Funding. Kozloff:Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Lozanski:Novartis: Research Funding; BI: Research Funding; Stem Line: Research Funding; Beckman: Research Funding; Coulter: Research Funding; Genentech: Research Funding. Jiang:Genentech Inc: Employment, Equity Ownership. Huang:F. Hoffmann La Roche: Employment. Pignataro:Roche Products Limited: Employment. Schary:AbbVie: Employment. Humphrey:Roche Products Limited: Employment. Mobasher:F. Hoffmann-La Roche Ltd: Other: Ownership interests non-PLC; Genentech Inc: Employment. Salles:Gilead: Honoraria, Other: Advisory Board; Epizyme: Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; BMS: Honoraria, Other: Advisory Board; Merck: Honoraria; Pfizer: Honoraria; Takeda: Honoraria; Morphosys: Honoraria; Acerta: Honoraria; Janssen: Honoraria, Other: Advisory Board; Abbvie: Honoraria; Celgene: Honoraria, Other: Advisory Board, Research Funding; Novartis: Consultancy, Honoraria; Amgen: Honoraria; Servier: Honoraria, Other: Advisory Board; Servier: Honoraria.