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

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.

Annals of oncology, 2018-09, Vol.29 (9), p.1932-1938 [Periódico revisado por pares]

England: Elsevier Ltd

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Título:
Venetoclax, bendamustine, and rituximab in patients with relapsed or refractory NHL: a phase Ib dose-finding study
Autor: 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.
Assuntos: 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
É parte de: Annals of oncology, 2018-09, Vol.29 (9), p.1932-1938
Descrição: 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.
Editor: England: Elsevier Ltd
Idioma: Inglês

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

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.

England: Elsevier Ltd

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