Phase 1 results of the WEE1 inhibitor, azenosertib, in combination with gemcitabine (gem) in adult and pediatric patients (pts) with relapsed or refractory (R/R) osteosarcoma.

11525 Background: Patients with R/R osteosarcoma have poor outcomes with a historical 16-week event-free survival (EFS) of ~12% after treatment with salvage therapy (Lagmay et al, 2016). Azenosertib is a highly selective WEE1 inhibitor that induces cancer cells to accelerate through the G1/S and G2/M checkpoints without repairing damaged DNA, causing mitotic catastrophe and cell death. Azenosertib has demonstrated significant synergy with gem in non-clinical models. The purpose of this study was to evaluate the safety and tolerability, determine the maximum tolerated dose (MTD), and assess for anti-tumor activity in pts with R/R osteosarcoma receiving C and gem. Methods: This dose-finding study (NCT04833582) assessed azenosertib + gem in pts ≥12 years of age using a standard 3+3 design. The MTD was defined as the dose level with prespecified adverse events (dose-limiting toxicities DLTs) occurring at a rate <33%. The primary endpoint was the incidence and severity of DLTs in cycle 1. Secondary endpoints included the incidence and severity of adverse events and EFS at 18-weeks per RECIST v1.1 (time from treatment initiation until disease progression or death due to any cause). Pts were treated across 5 dose-finding cohorts, receiving azenosertib (starting dose 200 mg QD PO on a continuous schedule) and gem (starting dose 1000 mg/m 2 IV on D1 and D8 of a 21D cycle) until disease progression or unacceptable toxicity. Results: As of Nov 30, 2023, 31 pts had been treated. The median age was 27y (range 12-76); 21 (68%) pts were ≤39y. Pts received a median of 3 (1-9) prior therapies. At tolerated doses, 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. DLTs included thrombocytopenia and gastrointestinal toxicity. The MTD was determined to be azenosertib 150 mg daily on a 5:2 schedule (5 days on, 2 days off) + gem 800 mg/m 2 . None of the pts treated at the MTD (n=6) required dose reductions of azenosertib due to AEs and only 1 required a dose interruption. The 18-week EFS was 39% (11/28) across all dose levels. Conclusions: Azenosertib + gem was well tolerated at the MTD and provided a greater EFS than historical control cohorts of salvage therapy in pts with R/R osteosarcoma. The MTD of the combination was well tolerated and these data support further investigation of azenosertib with gem in pts with R/R osteosarcoma in an upcoming Investigator-Initiated Phase 2 trial. Clinical trial information: NCT04833582 .