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.

Viswatej Avutu Memorial Sloan Kettering Cancer Center, New York, NY info_outline Viswatej Avutu, J. Andrew Livingston, Noah Federman, Lee D. Cranmer, Nathalie Gaspar, Maud Toulmonde, Joseph Gerald Pressey, Mehdi Brahmi, Andrew Stewart Poklepovic, Qing Shi, Nathan Jameson, Adrian Michael Jubb, Chrystal Ursula Louis, Sant P. Chawla, William D. Tap

Authors Viswatej Avutu Memorial Sloan Kettering Cancer Center, New York, NY info_outline Viswatej Avutu, J. Andrew Livingston, Noah Federman, Lee D. Cranmer, Nathalie Gaspar, Maud Toulmonde, Joseph Gerald Pressey, Mehdi Brahmi, Andrew Stewart Poklepovic, Qing Shi, Nathan Jameson, Adrian Michael Jubb, Chrystal Ursula Louis, Sant P. Chawla, William D. Tap Organizations Memorial Sloan Kettering Cancer Center, New York, NY, The University of Texas MD Anderson Cancer Center, Houston, TX, UCLA David Geffen School of Medicine, Los Angeles, CA, University of Washington, Fred Hutchinson Cancer Center, Seattle, WA, Gustave Roussy Cancer Centre, Villejuif, France, Institut Bergonié, Bordeaux, France, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, Centre Léon Bérard, Lyon, France, Virginia Commonwealth University Health System, Richmond, VA, Zentalis Pharmaceuticals, New York, NY, Sarcoma Oncology Center, Santa Monica, CA, Sarcoma Medical Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY Abstract Disclosures Research Funding No funding sources reported 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.

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