TY - JOUR
T1 - Venetoclax, bendamustine, and rituximab in patients with relapsed or refractory NHL
T2 - A phase Ib dose-finding study
AU - De Vos, S.
AU - Swinnen, L. J.
AU - Wang, D.
AU - Reid, E.
AU - Fowler, N.
AU - Cordero, J.
AU - Dunbar, M.
AU - Enschede, S. H.
AU - Nolan, C.
AU - Petrich, A. M.
AU - Ross, J. A.
AU - Salem, A. H.
AU - Verdugo, M.
AU - Agarwal, S.
AU - Zhou, L.
AU - Kozloff, M.
AU - Nastoupil, L. J.
AU - Flowers, C. R.
N1 - Publisher Copyright:
© 2018 The Author(s).
PY - 2018/9/1
Y1 - 2018/9/1
N2 - 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.
AB - 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.
KW - bendamustine-rituximab
KW - phase Ib
KW - relapsed/refractory NHL
KW - venetoclax
UR - http://www.scopus.com/inward/record.url?scp=85054167614&partnerID=8YFLogxK
U2 - 10.1093/annonc/mdy256
DO - 10.1093/annonc/mdy256
M3 - Article
C2 - 30060083
AN - SCOPUS:85054167614
SN - 0923-7534
VL - 29
SP - 1932
EP - 1938
JO - Annals of Oncology
JF - Annals of Oncology
IS - 9
ER -