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

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-Hodgki...

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Bibliographic Details
Published in:	Annals of oncology Vol. 29; no. 9; pp. 1932 - 1938
Main Authors:	de Vos, S., Swinnen, L.J., Wang, D., Reid, E., Fowler, N., Cordero, J., Dunbar, M., Enschede, S.H., Nolan, C., Petrich, A.M., Ross, J.A., Salem, A.H., Verdugo, M., Agarwal, S., Zhou, L., Kozloff, M., Nastoupil, L.J., Flowers, C.R.
Format:	Journal Article
Language:	English
Published:	England Elsevier Ltd 01-09-2018 Oxford University Press
Subjects:	Adult Aged Aged, 80 and over Antineoplastic Combined Chemotherapy Protocols - administration & dosage Antineoplastic Combined Chemotherapy Protocols - adverse effects Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics Bendamustine Hydrochloride - administration & dosage Bendamustine Hydrochloride - adverse effects Bendamustine Hydrochloride - pharmacokinetics bendamustine–rituximab Bridged Bicyclo Compounds, Heterocyclic - administration & dosage Bridged Bicyclo Compounds, Heterocyclic - adverse effects Bridged Bicyclo Compounds, Heterocyclic - pharmacokinetics Chemotherapy-Induced Febrile Neutropenia - epidemiology Chemotherapy-Induced Febrile Neutropenia - etiology Disease Progression Drug Administration Schedule Drug Resistance, Neoplasm - drug effects Female Humans Lymphoma, Non-Hodgkin - drug therapy Lymphoma, Non-Hodgkin - mortality Lymphoma, Non-Hodgkin - pathology Male Maximum Tolerated Dose Middle Aged Neoplasm Recurrence, Local - drug therapy Neoplasm Recurrence, Local - pathology Original phase Ib Progression-Free Survival relapsed/refractory NHL Rituximab - administration & dosage Rituximab - adverse effects Rituximab - pharmacokinetics Salvage Therapy - adverse effects Salvage Therapy - methods Sulfonamides - administration & dosage Sulfonamides - adverse effects Sulfonamides - pharmacokinetics venetoclax relapsed/refractory NHL phase Ib venetoclax bendamustine–rituximab bendamustine-rituximab
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Summary:	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). BR was given for six cycles at standard doses. Intermittent and continuous oral venetoclax administration was explored at 50–1200mg daily doses. Co-primary objectives included safety, pharmacokinetics (PKs), maximum-tolerated dose (MTD), and recommended phase II dose (RP2D); secondary objective was preliminary efficacy. 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 800mg 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 38.3months [95% confidence interval (CI) 10.4–NR], not yet reached, and 10.7months (95% CI 4.3–21.0), respectively. 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. Clinicaltrials.gov, NCT01594229.
ISSN:	0923-7534 1569-8041
DOI:	10.1093/annonc/mdy256