Abstract CT195: First-in-human phase 1 study of WEE1 inhibitor APR-1051 in patients with advanced solid tumors harboring cancer-associated gene alterations
Authors: Yap Timothy A. , Miller Crystal , Stenehjem David , Brown Eric J. , Carleton Mike , Mirza Nadeem Q. 
Published: April 2024

Abstract
Background: WEE1 tyrosine kinase plays a key role in cell cycle regulation and DNA damage responses, acting as a principal gatekeeper of the G1-S and G2-M cell cycle checkpoints. Thus, inhibition of WEE1 can result in high cyclin-dependent kinase 1 and 2 activities, leading to aberrant cell cycle progression. Increasing premature entry into mitosis and subsequent apoptosis via WEE1 inhibition is one potential approach to killing cancer cells effectively. APR-1051 is an orally bioavailable, highly potent, small molecule inhibitor of WEE1 that has demonstrated in vivo anti-proliferative activity in multiple cancer cell lines and high selectivity for WEE1 versus polo-like kinases 1, 2, and 3. Increased selectivity for WEE1 may reduce the myelosuppressive toxicity (e.g., limiting Grade 3 toxicities) reported with other WEE1 inhibitors.
Methods: The primary aim of this multi-center, open-label Phase I study is to characterize the safety, dose-limiting toxicities (DLTs), maximum tolerated dose (MTD)/maximum administered dose (MAD) and recommended Phase 2 dose (RP2D) of APR-1051 in patients with advanced solid tumors harboring cancer-associated gene alterations. Secondary objectives include evaluating the pharmacokinetic (PK) properties of APR-1051, assessing the effect of food on its PK, and its preliminary efficacy per RECIST version 1.1. The exploratory objective is to assess the pharmacodynamic effects of APR-1051. For dose escalation, an accelerated titration followed by a BOIN design will be utilized to determine the MAD/MTD. Upon completion of the dose escalation, two suitable doses and schedules of single-agent APR-1051 will be determined for further investigation in dose selection optimization. Key inclusion criteria are age at least 18 years with advanced solid tumor and cancer-associated gene alterations (e.g., amplification/overexpression of CCNE1 or CCNE2, deleterious mutations in FBXW7 or PPP2R1A), ECOG PS 0 or 1, and adequate organ function. Key exclusion criteria are cancer therapy within 3 weeks or at least 5 half-lives, prior radiation therapy at the target lesion except if evidence of disease progression, unresolved therapy-related AEs, investigational agent within 5 half-lives or 30 days of study drug, prior WEE1 inhibitor, CNS metastases or unstable involvement, secondary malignancies that are active and/or require therapy, and concomitant moderate/strong inhibitors/inducers of CYP3A4/5, MDR1, or BCRP. Up to 79 patients will be enrolled at 3 to 5 sites in the United States.
Citation Format: Timothy A. Yap, Crystal Miller, David Stenehjem, Eric J. Brown, Mike Carleton, Nadeem Q. Mirza. First-in-human phase 1 study of WEE1 inhibitor APR-1051 in patients with advanced solid tumors harboring cancer-associated gene alterations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT195.