A Phase I Trial of Venetoclax in Combination with BEAM Conditioning Chemotherapy (V-BEAM) with Autologous Stem Cell Transplantation in Non-Hodgkin Lymphoma

Background: High-dose chemotherapy (HDCT) followed by autologous stem cell transplantation (ASCT) is a standard treatment both as consolidation after induction chemotherapy and as second-line therapy depending on the histologic subtype of NHL. BEAM (BCNU, etoposide, cytarabine, and melphalan) is a commonly used conditioning regimen for NHL but often fails to produce durable remission, likely due to inherent chemoresistance. Many B-cell NHL subtypes including diffuse large B-cell lymphoma and double-hit lymphoma are resistant to chemotherapy-induced apoptosis by overexpression of Bcl-2. Venetoclax is an orally administered selective Bcl-2 inhibitor with significant single agent activity in CLL and mantle cell lymphoma. In addition, the efficacy of venetoclax is potentiated by combination with rituximab [Seymour 2018, Kater 2018] and multiple lines of preclinical data show synergistic efficacy with a range of both novel and conventional antineoplastic agents [Johnson-Farley 2015, Li 2015].

Study Design and Methods: This is a single arm, open-label, dose-escalation phase I trial to evaluate the safety of venetoclax in combination with BEAM (V-BEAM) conditioning chemotherapy. Key inclusion criteria include patients with pathologically confirmed NHL, regardless of specific histology, who have received one prior systemic therapy and are eligible for and proceeding with HDCT followed by ASCT. The trial employs a standard 3+3 cohort-based dose escalation design of venetoclax (800 mg daily days -7 through -6 on dose level 1, 800 mg daily days -7 through -5 on dose level 2, 800 mg daily days -7 through -4 on dose level 3, 800 mg daily days -7 through -3 on dose level 4, and 800 mg daily days -7 through -2 on dose level 5) with standard doses of BEAM followed by ASCT. The primary objectives are to assess safety, describe dose-limiting toxicities, engraftment of stem cells and to identify the recommended phase II dose. Secondary objectives include evaluation of progression-free survival (PFS) and overall survival (OS) compared to historical controls treated with BEAM as part of ASCT. Neutrophil and platelet engraftment will be estimated with cumulative incidence and compared to controls with Gray test. OS and PFS will be estimated with Kaplan-Meier and compared to controls with the log-rank test. As of 8/1/2019, the first dosing cohort of 3 patients have been enrolled and successfully completed study treatment. There are 3 patients in screening to be enrolled in dose level 2. Additional accrual will be presented at the time of the meeting. Clinical trial information: NCT03713580.