Zentalis Pharmaceuticals, Inc. announced the presentation of final results from a Phase 1 trial of azenosertib and gemcitabine in relapsed or refractory (R/R) osteosarcoma at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago. 31 patients were enrolled in the study, of which 31 were evaluable for safety, 29 were evaluable for dose-limiting toxicities and 28 were evaluable for efficacy. The median age was 27 (range 12-76) and 21 patients (68%) were =39 years old.

Patients received a median of 3 (range 1-9) prior therapies, including 10 patients (32%) who had previous treatment with gemcitabine. The 18-week event-free survival rate (EFS; time from treatment initiation until disease progression or death due to any cause) was 39% (11/28) across all dose levels. The EFS observed in the study compares favorably to historical cohorts with a similar patient population where a 16-week EFS of ~12% has been reported.

The maximum tolerated dose (MTD) of azenosertib was determined to be 150 mg daily on a 5:2 schedule (5 days on, 2 days off) + gemcitabine 800 mg/m2. At the MTD, the most frequent grade =3 adverse events (=20%) included thrombocytopenia and lymphopenia (33% each); there were no grade 4 thrombocytopenia events or instances of febrile neutropenia at the MTD. Data support further investigation of azenosertib administered in combination with gemcitabine in patients with R/R osteosarcoma in an upcoming investigator-initiated Phase 2 trial.

Phase 1 dose-finding study (NCT04833582) assessed azenosertib administered in combination with gemcitabine in patients =12 years of age. The primary endpoint was the incidence and severity of dose-limiting toxicities. Secondary endpoints included the incidence and severity of adverse events and EFS at 18 weeks per RECIST v1.1. Azenosertib is a novel, selective, and orally bioavailable inhibitor of WEE1 currently being evaluated as a monotherapy and combination clinical studies in ovarian cancer and additional tumor types.

WEE1 acts as a master regulator of the G1-S and G2-M cell cycle checkpoints, through negative regulation of both CDK1 and CDK2, to prevent replication of cells with damaged DNA. By inhibiting WEE1, azenosertib enables cell cycle progression, despite high levels of DNA damage, thereby resulting in the accumulation of DNA damage and leading to mitotic catastrophe and cancer cell death.