Phase I Dose-Escalation Study of Venetoclax Plus BEAM Followed By Autologous Stem Cell Transplant (ASCT) for Chemoresistant or High-Risk Relapsed/Refractory Non-Hodgkin Lymphoma (NHL)
Authors: Maakaron Joseph , Zhao Qiuhong , Puto Marcin , Verfurth Quinn , Penza Sam , Brammer Jonathan E , Efebera Yvonne A. , Rosko Ashley E. , Saad Ayman , Jaglowski Samantha , William Basem M. 
Published: November 2019

Introduction:
High dose therapy with carmustine, etoposide, cytarabine, and melphalan (BEAM) followed by ASCT is standard treatment for patients with chemosensitive, relapsed/refractory (r/r) NHL. Rational approaches to patients who relapse post-ASCT remains an unmet need. We present a phase I trial of dose-escalation venetoclax combined with BEAM conditioning regimen for the treatment of r/r or high-risk NHL.
Venetoclax is an oral BCL-2 inhibitor that has significant single-agent and combination activity in r/r NHL. It also has anti-tumor activity in T-cell lymphoma cell lines. Preclinical observations showed that venetoclax potentiates the cytotoxicity of chemotherapy, increases synergistic cell kill, and can overcome chemoresistance even in highly aggressive lymphomas. In this trial, we aim to test the safety of the combination of venetoclax plus BEAM followed by ASCT. We hypothesize that venetoclax will help overcome the chemoresistance of these tumors and decrease post-ASCT relapse.
Methods:
This is an open-label, single-center, phase I trial (NCT03583424) with a dose expansion cohort of venetoclax in combination with BEAM and ASCT for patients with r/r or high-risk NHL. Venetoclax is given for 10 days, starting at D-10 before ASCT, in three dosing cohorts (400, 800, 1200 mg) using a quick ramp-up schedule (Table 1). Accrual occurred in a standard 3+3 fashion to establish the maximum tolerated dose (MTD) of venetoclax in combination with BEAM. An expansion cohort of 10 additional patients using the MTD is planned. Eligible participants include adult, fit patients with B and T-cell NHL refractory after upfront induction therapy, in partial remission or progressed after salvage, requiring ≥ 3 lines of therapy, relapsed within 1 year of induction, or at a high risk of relapse after ASCT (in first complete or partial remission) including mantle cell or peripheral T-cell lymphoma. Patients with small lymphocytic lymphomas, with primary, or uncontrolled secondary, CNS lymphoma patients are excluded. Primary outcome is safety and determination of MTD. Adverse events (AEs) were recorded using CTCAE v 4.1 between days -10 to -6 then the Bearman scale was used from day -6 until engraftment.
Results:
Dose-escalation proceeded with no dose-limiting toxicities (DLTs) and 9 patients were accrued across three cohorts. Baseline characteristics and safety data for all three cohorts are presented in Table 2. The majority were male (67%) and had stage IV disease (66%). The media age was 64 (range 49-72) years. Histologies were diverse including aggressive, indolent, transformed indolent B-NHL, and T-NHL. No unusual toxicities were encountered beyond what is expected with BEAM. No serious AEs were observed between days -10 to -6. No tumor lysis syndrome or other toxicities attributable to venetoclax were observed. Toxicities are summarized in table 2. The MTD was not reached and the recommended phase 2 dose was determined to be 1200 mg.
Discussion:
The addition of venetoclax to BEAM appears to be safe and well-tolerated in a typical, elderly population with high-risk disease. CD19 chimeric antigen receptor (CAR-T) T-cells are an attractive option for many patients with r/r B-NHL. Unfortunately, many patients don't have access to them because of coverage or financial reasons. Venetoclax in combination with BEAM can represent another option for patients with relapsed and refractory NHL. The expansion cohort is currently accruing.

Disclosures
Brammer: Bioniz Therapeutics, Inc.: Research Funding; Viracta Therapeutics, Inc.: Research Funding; Verastem, Inc: Research Funding. Efebera:Takeda: Honoraria; Akcea: Other: Advisory board, Speakers Bureau; Janssen: Speakers Bureau. Rosko:Vyxeos: Other: Travel support. Saad:OrcaBio: Other: Research Support; Kadmon: Other: Research Support; Amgen: Other: Research Support; Actinium Pharma Inc: Consultancy. Jaglowski:Novartis: Consultancy, Other: advisory board, Research Funding; Kite: Consultancy, Other: advisory board, Research Funding; Juno: Consultancy, Other: advisory board; Unum Therapeutics Inc.: Research Funding.