Venetoclax, bendamustine, and rituximab in patients with relapsed or refractory NHL: A phase Ib dose-finding study

S. De Vos*, L. J. Swinnen, D. Wang, E. Reid, N. Fowler, J. Cordero, M. Dunbar, S. H. Enschede, C. Nolan, A. M. Petrich, J. A. Ross, A. H. Salem, M. Verdugo, S. Agarwal, L. Zhou, M. Kozloff, L. J. Nastoupil, C. R. Flowers

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

58 Scopus citations

Abstract

Background Venetoclax is a selective, potent inhibitor of the anti-apoptotic B-cell leukemia/lymphoma-2 protein approved for treatment of chronic lymphocytic leukemia. We conducted a dose-finding study of venetoclax in combination with bendamustine-rituximab (BR) in patients with relapsed/refractory non-Hodgkin's lymphoma (NHL). Patients and methods BR was given for six cycles at standard doses. Intermittent and continuous oral venetoclax administration was explored at 50-1200 mg daily doses. Co-primary objectives included safety, pharmacokinetics (PKs), maximum-tolerated dose (MTD), and recommended phase II dose (RP2D); secondary objective was preliminary efficacy. Results Sixty patients were enrolled: 32 with follicular lymphoma, 22 with diffuse large B-cell lymphoma, and 6 with marginal zone lymphoma. Nausea (70%), neutropenia (68%), diarrhea (55%), and thrombocytopenia (52%) were the most frequent adverse events (AEs). Most common grade 3/4 AEs were neutropenia (60%) and lymphopenia (38%). Serious AEs were reported in 24 patients; the most frequent were febrile neutropenia and disease progression (8% each). Five patients died from either disease progression (n = 4) or respiratory failure (n = 1). MTD was not reached; RP2D for venetoclax-BR combination was established as 800 mg daily continuously. Venetoclax PK exposure with and without BR was comparable. For all patients, overall response rate was 65%. Median duration of overall response, overall survival, and progression-free survival was 38.3 months [95% confidence interval (CI) 10.4-NR], not yet reached, and 10.7 months (95% CI 4.3-21.0), respectively. Conclusions This study established the safety profile of venetoclax in combination with BR, and results demonstrated tolerability and preliminary efficacy of the combination. Additional follow-up is needed to better determine the future role of BR plus venetoclax in the treatment of relapsed/refractory B-cell NHL. Trial registered Clinicaltrials.gov, NCT01594229.

Original languageEnglish
Pages (from-to)1932-1938
Number of pages7
JournalAnnals of Oncology
Volume29
Issue number9
DOIs
StatePublished - 1 Sep 2018
Externally publishedYes

Keywords

  • bendamustine-rituximab
  • phase Ib
  • relapsed/refractory NHL
  • venetoclax

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