A phase 1/2 dose escalation study of the BCL-2 inhibitor ZN-d5 and the WEE1 inhibitor azenosertib (ZN-c3) in patients (Pts) with acute myeloid leukemia (AML).
Authors: Smith Catherine Choy , Vachhani Pankit , Garcia-Manero Guillermo , Grieselhuber Nicole Renee , Guru Murthy Guru Subramanian , Bhatia Astha , Arora Jatinder , Izadi Hooman , Fiorino Anthony , Rampal Raajit 
Published: June 2023

TPS7077 Background: B-cell lymphoma 2 (BCL-2) is an anti-apoptotic protein and pathway inhibition combined with chemotherapy and/or targeted therapeutics has led to significant clinical benefit in pts with AML. Disruption of cell cycle regulation may complement BCL-2 inhibition as many malignant cells are dependent on proteins that regulate cell cycle progression. The cell cycle checkpoint protein, WEE1, is highly expressed in genomically unstable malignancies and inhibition of WEE1 induces tumor cell apoptosis. It has been previously reported that the combination of ZN-d5 (an oral, selective BCL-2 inhibitor) and azenosertib (an oral, highly potent WEE1 inhibitor) synergistically enhance killing of AML cells both in vitro and in vivo, as well as in TP53-mutated models (Izadi, AACR 2022). Based on this strong pre-clinical rationale, a Phase 1/2 study was designed to evaluate the novel combination of ZN-d5 and azenosertib in pts with relapsed/refractory (R/R) AML. Methods: This phase 1/2 open-label study (ZN-d5-004C, NCT05682170) is determining the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), pharmacokinetics (PK), and clinical activity of ZN-d5 + azenosertib in pts with AML. The phase 1 dose-escalation stage is based on a Bayesian Optimal Interval design. Phase 2 is an open-label expansion to be conducted if supported by safety and efficacy data from the dose-escalation stage. Prior to initiating dose-escalation for the ZN-d5 + azenosertib combination, an azenosertib monotherapy cohort is being enrolled, as it has not been previously administered to pts with hematologic malignancies. For the dose-escalation azenosertib monotherapy (n≈15) and ZN-d5 combination (n≈40) cohorts, pts must have relapsed/refractory (R/R) disease after ≥1 line of AML therapy that may include the BCL-2 inhibitor, venetoclax. In phase 1, an azenosertib monotherapy cohort will be opened prior to investigation of ZN-d5 + azenosertib in combination. In phase 2, ZN-d5 + azenosertib will be given at the RP2D. Alternative dosing schedules may also be investigated based on emerging clinical data. The primary endpoints are adverse events and dose-limiting toxicities. Secondary endpoints include the rate and duration of remission according to the European LeukemiaNet 2017 criteria, including complete remission (CR), CR with incomplete hematologic recovery (CRi), morphologic leukemia-free state (MLFS), partial remission (PR), stable disease, progressive disease, relapse after remission (including molecular relapse), remission rate (CR + CRi), overall response rate (CR + CRi + MLFS + PR), and rate of and time to relapse. Pts will remain on study until disease progression, failure to respond, remission if additional therapy is clinically indicated, withdrawal of consent, loss to follow-up, or death. Clinical trial information: NCT05682170 .