Abstract B011: Early safety and efficacy of APR-1051, a novel WEE1 inhibitor, in patients with cancer-associated gene alterations: Updated data from ACESOT-1051 phase 1 trial

Abstract Background: WEE1 tyrosine kinase regulates G1-S and G2-M cell cycle checkpoints and DNA damage responses. WEE1 inhibition can kill cancer cells by forcing premature mitotic entry and subsequent apoptosis. APR-1051 is an orally bioavailable, highly potent WEE1 inhibitor with demonstrated in vivo anti-proliferative activity in cancer models. APR-1051 exhibits high selectivity for WEE1, potentially mitigating the hematologic toxicities observed with other WEE1 inhibitors. Material and Methods: This first-in-human, open-label dose escalation (accelerated titration and BOIN) and dose selection optimization evaluates APR-1051 at three U.S. sites (NCT06260514). APR-1051 is being evaluated at once-daily (QD) dose levels (10 to 150 mg). The primary objective is to characterize the safety, dose-limiting toxicity, maximum tolerated dose/maximum administered dose, and recommended phase 2 dose of APR-1051. Secondary objectives will evaluate pharmacokinetic (PK) properties of APR-1051, and preliminary efficacy per RECIST v1.1 (PCWG3 criteria for patients with mCRPC). Key inclusion criteria are age > 18 years with advanced solid tumor and cancer-associated gene alterations, prior standard-of-care systemic treatment, and ECOG PS 0 or 1. Key exclusion criteria are unresolved therapy-related adverse events (AEs), prior WEE1 inhibitor use, CNS metastases or unstable involvement, active secondary malignancies requiring therapy, and concomitant moderate/strong inhibitors/inducers of CYP3A4/5, MDR1, or BCRP. Results: As of July 7, 2025, 15 patients have been enrolled at doses up to 100 mg QD (median age 58 years [range: 40-86]; 53% Male; 47% White, 13% Black, 13% Asian, 7% American Indian, 20% Not reported/ Unknown). Colorectal malignancies comprised the majority (n=10, 67%) of cases, including colon cancer (n=9, 60%) and rectal cancer (n=1, 7%). Pancreatic cancer accounted for 13% of cases (n=2). Single cases were observed for gastric, uterine, and oropharyngeal cancer (each n=1, 7%). The median prior lines of treatments was 2. All (100%) patients experienced any grade adverse events (AEs). A total of 8 (53.3%) patients had 11 unique serious AEs, with one event probably related to APR-1051. Eight patients had treatment-related AEs (TRAEs), mostly non-serious gastrointestinal events. One patient experienced grade 3 elevated liver enzymes (AST, ALT). Preliminary PK demonstrates a median half-life of ∼17 hours supporting once-daily dosing, and exposure (AUC0-24 and Cmax) is increasing in a dose proportional manner. Preliminary antitumor activity includes one patient with HPV+ oropharyngeal cancer who achieved stable disease on the first two scans at the 70 mg QD dose level. Conclusion: Continuous once-daily oral APR-1051 shows a manageable safety profile with preliminary signals of antitumor activity in this ongoing trial. Study progress will be updated at the congress. Citation Format: Anthony Tolcher, David Sommerhalder, Shiraj Sen, Crystal Miller, David Stenehjem, Mike Carleton, Philippe Pultar, Timothy A. Yap. Early safety and efficacy of APR-1051, a novel WEE1 inhibitor, in patients with cancer-associated gene alterations: Updated data from ACESOT-1051 phase 1 trial [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B011.