Abstract 561TiP
Background
Anti-apoptotic proteins such as B-cell lymphoma 2 (BCL-2) are commonly utilized by malignant cells to evade signals that would typically induce programmed cell death. High BCL-2 expression is correlated with poor prognosis and poor responses to conventional therapies in patients with a broad range of malignancies, and dependence on BCL-2 can render cancer cells susceptible to therapy targeting this pathway. ZN-d5 is a novel, oral, once-daily BH3 mimetic with improved selectivity for BCL-2 over BCL-xL compared to the commercially available BCL-2 inhibitor venetoclax, which could reduce the rate of thrombocytopenia. ZN-d5 inhibits tumor cell growth in vitro and exhibits significant anti-tumor activity in multiple xenograft models of hematologic malignancies as a single agent and in combinations with other anti-tumor drugs.
Trial design
This phase 1, open-label, global multicenter study is evaluating the safety, pharmacokinetics, pharmacodynamics, and anti-tumor activity of ZN-d5 in adult subjects with relapsed or refractory NHL and AML. The primary objectives are to determine maximum tolerated doses and recommended phase 2 doses for each disease cohort using a modified Bayesian continual reassessment method dose-escalation design. NHL subjects (including diffuse large B-cell lymphoma, follicular lymphoma, marginal zone lymphoma, mantle cell lymphoma, large cell lymphoma, or peripheral T-cell lymphoma) must have failed at least 2 prior lines of therapy; AML subjects must have failed at least 1 prior line of therapy. The study initiated enrollment in November 2020 with NHL subjects, with enrollment of the AML group to start after a biologically active dose is identified in subjects with NHL. AML dose escalation will start at that dose and proceed in a similar manner as for NHL. In both disease cohorts, subjects will be treated until disease progression, development of unacceptable toxicity, withdrawal of consent or death. Clinical activity is assessed in the NHL disease cohort according to the 2014 Lugano classification and for AML according to the European LeukemiaNet 2017 recommendations. Subject recruitment is ongoing.
Clinical trial identification
NCT04500587.
Editorial acknowledgement
Legal entity responsible for the study
Zentalis Pharmaceuticals.
Funding
Zentalis Pharmaceuticals.
Disclosure
J.M. Zaucha: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker: Abbvie; Financial Interests, Personal, Invited Speaker: Takeda; Financial Interests, Personal, Invited Speaker: Janssen; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: Bristol-Myers Squibb. T. Fiorino: Financial Interests, Personal, Full or part-time Employment: Zentalis Parmaceuticals; Financial Interests, Personal, Stocks/Shares: Zentalis Parmaceuticals. N. Viiala: Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Sandoz; Financial Interests, Institutional, Principal Investigator: Zentalis. G. Gordon: Financial Interests, Personal, Advisory Role: Zentalis Parmaceuticals. R. Kirshoff: Financial Interests, Personal, Full or part-time Employment: Zentalis Parmaceuticals; Financial Interests, Personal, Stocks/Shares: Zentalis Parmaceuticals. S. Lopez: Financial Interests, Personal, Full or part-time Employment: Zentalis Parmaceuticals; Financial Interests, Personal, Stocks/Shares: Zentalis Parmaceuticals. L. Makris: Financial Interests, Personal, Advisory Role: Zentalis Parmaceuticals. C. Miller: Financial Interests, Personal, Full or part-time Employment: Zentalis Parmaceuticals; Financial Interests, Personal, Stocks/Shares: Zentalis Parmaceuticals. S. Park: Financial Interests, Personal, Full or part-time Employment: Zentalis Parmaceuticals; Financial Interests, Personal, Stocks/Shares: Zentalis Parmaceuticals. D. Voliotis: Financial Interests, Personal, Full or part-time Employment: Zentalis Parmaceuticals; Financial Interests, Personal, Stocks/Shares: Zentalis Parmaceuticals. All other authors have declared no conflicts of interest.