A Dose-Escalation Study of Venetoclax (ABT-199/GDC-0199) in Combination with Bendamustine and Rituximab in Patients with Relapsed or Refractory Non-Hodgkin's Lymphoma
Authors: de Vos Sven , Swinnen Lode , Kozloff Mark , Wang Ding , Reid Erin , Nastoupil Loretta , Fowler Nathan , Cordero Jaclyn , D'Amico Diane , Diehl Susan , Dunbar Martin , Zhu Ming , Wong Shekman , Heitner Enschede Sari , Chien David , Humerickhouse Rod A. , Flowers Christopher 
Published: October 2019

Abstract
Introduction: Bcl-2 is an antiapoptotic protein commonly overexpressed in hematologic malignancies, including non-Hodgkin's lymphoma (NHL). Venetoclax (VEN) is a selective, potent, orally bioavailable BCL-2 inhibitor that has demonstrated single-agent activity in patients with relapsed or refractory (R/R) NHL. Data in NHL xenograft models indicate that VEN enhances the efficacy of bendamustine (B) and rituximab (R).
Methods: This ongoing phase 1, open-label, dose-escalation study with a safety expansion portion evaluates VEN in combination with BR in patients with R/R NHL (NCT01594229). Patients (≥18 years) with ECOG PS ≤1 are treated with oral VEN (50-800 mg) for 3, 7, or 28 consecutive days of each 28-day cycle. Patients with refractory diffuse large B-cell lymphoma (DLBCL) who progressed during or within 2 months of completion of their last planned course of chemotherapy were excluded. Dose escalation follows a 3+3 design. The BR regimen is administrated for 6 cycles: B (90 mg/m2; 2 days/cycle) and R (375 mg/m2; 1 day/cycle). Patients who complete VEN + BR treatment can continue VEN monotherapy for up to 2 years following the date of the last subject enrolled, in the absence of disease progression or toxicity. Primary objectives are to assess safety, pharmacokinetics (PK) profile, and to determine the maximum tolerated dose (MTD) and the recommended phase 2 dose of VEN in combination with BR. Secondary objectives include preliminary efficacy evaluations. Dose-limiting toxicities (DLTs) are assessed during cycle 1. Disease responses were evaluated on day 1 of cycles 3, 5, 7, 11, 14, 17, 23, and every 6 cycles thereafter.
Results: As of June 17, 2015, 47 patients (64% male; median age 63 years) have been enrolled in 10 escalation cohorts. Twenty-seven patients (57%) had been diagnosed with follicular lymphoma, 15 (32%) with DLBCL, and 5 (11%) with marginal zone lymphoma. Patients had a median of 3 (range: 1-8) prior therapies. All patients had prior R or R-combination, of whom 44 (94%) had R-based chemotherapy. Eleven patients (23%) had prior B or BR therapy. Median time on study is 128 days (range: 3-1066). As of June 2015, 25 patients (53%) are active and 22 (47%) discontinued (13 progressive disease, 4 adverse events [AEs; Table 1], 3 consent withdrawal, 1 noncompliance, and 1 completion of BR regimen per protocol). For the 17 patients who completed 6 cycles of combination therapy, 14 have continued to monotherapy and 11 active patients have not reached 6 cycles. Most common AEs (≥25%) in the combination therapy portion of the study (≤6 cycles) were nausea (51%), thrombocytopenia (45%), neutropenia (40%), constipation (36%), anemia (34%), diarrhea (30%), fatigue (30%), hyperglycemia (30%), lymphocyte count decrease (28%), and hypokalemia (28%). Most common grade 3/4 AEs (≥10%) during combination therapy were neutropenia (32%), lymphocyte count decrease (26%), thrombocytopenia (21%), anemia (15%), and leukopenia (13%). The most frequent serious AE was febrile neutropenia (9%). Three deaths occurred; none were drug-related AEs. Four patients experienced a DLT during cycle 1 (Table 1). Following 2 DLTs (febrile neutropenia and thrombocytopenia) in Cohort 5 (200 mg; 28/28d), a protocol amendment was filed in order to strongly encourage granulocyte colony-stimulating factor prophylaxis during VEN administration, particularly in heavily pretreated patients, and to refine the DLT definition in the context of known BR toxicities. Escalation continues with only 2 observed DLTs: Stevens-Johnson syndrome (400 mg 28/28d; primary reasonable possibility due to allopurinol; patient discontinued) and thrombocytopenia (600 mg 28/28d). Coadministration of BR did not significantly impact the PK of VEN. A total of 38 patients were evaluable for disease response. Overall, 29 patients had an objective response: 10 complete responses, 19 partial responses, and 4 patients had stable disease. Objective responses were observed across dose cohorts. Responses by NHL histology subgroups are shown in Table 1. Enrolling in Cohort 11 (1200 mg 28/28d) is currently ongoing.
Conclusions: Combination therapy with VEN and BR demonstrated a tolerable safety profile. Responses were observed across dose cohorts in this heavily pretreated population. The MTD has not been reached and dose escalation is ongoing.

Disclosures
Off Label Use: Venetoclax is an investigational drug that is not yet approved in this indication.. Kozloff:Genentech: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; AbbVie: Consultancy. Nastoupil:AbbVie: Research Funding; Celgene: Honoraria; TG Therapeutics: Research Funding; Janssen: Research Funding; Genentech: Honoraria. Cordero:AbbVie: Employment, Equity Ownership. D'Amico:AbbVie: Employment, Equity Ownership. Diehl:AbbVie: Employment, Equity Ownership. Dunbar:AbbVie: Employment, Equity Ownership. Zhu:AbbVie: Employment, Equity Ownership. Wong:AbbVie: Employment, Equity Ownership. Heitner Enschede:AbbVie: Employment, Equity Ownership. Chien:AbbVie: Employment, Equity Ownership. Humerickhouse:AbbVie: Employment, Equity Ownership. Flowers:Millennium/Takeda: Research Funding; Gilead Sciences: Research Funding; AbbVie: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding; Millennium/Takeda: Research Funding; Onyx Pharmaceuticals: Research Funding; OptumRx: Consultancy; Janssen: Research Funding; AbbVie: Research Funding; Seattle Genetics: Consultancy; Gilead Sciences: Research Funding; Janssen: Research Funding; Onyx Pharmaceuticals: Research Funding; Spectrum: Research Funding; Spectrum: Research Funding; Acerta: Research Funding; Celegene: Other: Unpaid consultant, Research Funding; Acerta: Research Funding; Infinity Pharmaceuticals: Research Funding; OptumRx: Consultancy; Seattle Genetics: Consultancy; Pharmacyclics: Research Funding; Infinity Pharmaceuticals: Research Funding; Genentech: Research Funding; Celegene: Other: Unpaid consultant, Research Funding.