PMID- 30060083 OWN - NLM STAT- MEDLINE DCOM- 20191223 LR - 20210109 IS - 1569-8041 (Electronic) IS - 0923-7534 (Print) IS - 0923-7534 (Linking) VI - 29 IP - 9 DP - 2018 Sep 1 TI - Venetoclax, bendamustine, and rituximab in patients with relapsed or refractory NHL: a phase Ib dose-finding study. PG - 1932-1938 LID - S0923-7534(19)34175-4 [pii] LID - 10.1093/annonc/mdy256 [doi] 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. FAU - de Vos, S AU - de Vos S AD - David Geffen School of Medicine at UCLA, Los Angeles. Electronic address: deVos@mednet.ucla.edu. FAU - Swinnen, L J AU - Swinnen LJ AD - Division of Hematologic Malignancies, Department of Oncology, Johns Hopkins University, Baltimore. FAU - Wang, D AU - Wang D AD - Division of Hematology/Oncology, Department of Medicine, Henry Ford Hospital, Detroit. FAU - Reid, E AU - Reid E AD - Division of Hematology-Oncology, Moores Cancer Center, University of California San Diego, La Jolla. FAU - Fowler, N AU - Fowler N AD - Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston. FAU - Cordero, J AU - Cordero J AD - AbbVie Inc., North Chicago, USA. FAU - Dunbar, M AU - Dunbar M AD - AbbVie Inc., North Chicago, USA. FAU - Enschede, S H AU - Enschede SH AD - AbbVie Inc., North Chicago, USA. FAU - Nolan, C AU - Nolan C AD - AbbVie Inc., North Chicago, USA. FAU - Petrich, A M AU - Petrich AM AD - AbbVie Inc., North Chicago, USA. FAU - Ross, J A AU - Ross JA AD - AbbVie Inc., North Chicago, USA. FAU - Salem, A H AU - Salem AH AD - AbbVie Inc., North Chicago, USA; Ain Shams University, Cairo, Egypt. FAU - Verdugo, M AU - Verdugo M AD - AbbVie Inc., North Chicago, USA. FAU - Agarwal, S AU - Agarwal S AD - AbbVie Inc., North Chicago, USA. FAU - Zhou, L AU - Zhou L AD - AbbVie Inc., North Chicago, USA. FAU - Kozloff, M AU - Kozloff M AD - Department of Oncology, Cancer Research Center, Ingalls Memorial Hospital, Harvey. FAU - Nastoupil, L J AU - Nastoupil LJ AD - Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston. FAU - Flowers, C R AU - Flowers CR AD - Division of Hematology and Oncology, Winship Cancer Institute, Emory University-School of Medicine, Atlanta, USA. LA - eng SI - ClinicalTrials.gov/NCT01594229 PT - Clinical Trial, Phase I PT - Journal Article PT - Multicenter Study PT - Research Support, Non-U.S. Gov't PL - England TA - Ann Oncol JT - Annals of oncology : official journal of the European Society for Medical Oncology JID - 9007735 RN - 0 (Bridged Bicyclo Compounds, Heterocyclic) RN - 0 (Sulfonamides) RN - 4F4X42SYQ6 (Rituximab) RN - 981Y8SX18M (Bendamustine Hydrochloride) RN - N54AIC43PW (venetoclax) SB - IM MH - Adult MH - Aged MH - Aged, 80 and over MH - Antineoplastic Combined Chemotherapy Protocols/*administration & dosage/adverse effects/pharmacokinetics MH - Bendamustine Hydrochloride/administration & dosage/adverse effects/pharmacokinetics MH - Bridged Bicyclo Compounds, Heterocyclic/administration & dosage/adverse effects/pharmacokinetics MH - Chemotherapy-Induced Febrile Neutropenia/epidemiology/etiology MH - Disease Progression MH - Drug Administration Schedule MH - Drug Resistance, Neoplasm/drug effects MH - Female MH - Humans MH - Lymphoma, Non-Hodgkin/*drug therapy/mortality/pathology MH - Male MH - Maximum Tolerated Dose MH - Middle Aged MH - Neoplasm Recurrence, Local/*drug therapy/pathology MH - Progression-Free Survival MH - Rituximab/administration & dosage/adverse effects/pharmacokinetics MH - Salvage Therapy/adverse effects/*methods MH - Sulfonamides/administration & dosage/adverse effects/pharmacokinetics PMC - PMC6158762 EDAT- 2018/07/31 06:00 MHDA- 2019/12/24 06:00 PMCR- 2018/07/28 CRDT- 2018/07/31 06:00 PHST- 2018/07/31 06:00 [pubmed] PHST- 2019/12/24 06:00 [medline] PHST- 2018/07/31 06:00 [entrez] PHST- 2018/07/28 00:00 [pmc-release] AID - S0923-7534(19)34175-4 [pii] AID - mdy256 [pii] AID - 10.1093/annonc/mdy256 [doi] PST - ppublish SO - Ann Oncol. 2018 Sep 1;29(9):1932-1938. doi: 10.1093/annonc/mdy256.