Abstract 3631: Preclinical and clinical pharmacodynamic characterization of BBI-355, a novel, orally bioavailable, and selective CHK1 inhibitor being evaluated in the first-in-human Phase 1/2 POTENTIATE clinical trial of patients with cancer harboring oncogene amplifications

Abstract

Abstract Pharmacodynamic (PD) biomarkers play an integral role in the rational development of novel therapeutic agents. Critically, PD biomarkers enable the measurement and confirmation of a drug’s intended effect in early clinical trials. Integration of PD biomarker assessments in early therapeutic development can inform the relationship between drug dose and regimen, target modulation, and biological tumor response, which are fundamental to determining the efficacy and safety of novel therapeutic agents. Boundless Bio is evaluating a novel, orally available, and selective Checkpoint Kinase 1 (CHK1) inhibitor, BBI-355, in the Phase 1/2 clinical trial, POTENTIATE (NCT05827614), in patients with solid tumors harboring oncogene amplification including those on extrachromosomal DNA (ecDNA). ecDNA-enabled oncogene amplification endows cancers with significant genomic plasticity, which can facilitate resistance to targeted therapy (Nathanson et al., 2014), and which is also associated with significantly shorter survival (Kim et al., 2020). While ecDNA provides a fitness advantage to cancer cells, its unique features also confer certain liabilities, including elevated DNA replication stress (RS). Elevated RS results in DNA damage and makes ecDNA+ cancers hyper-reliant on the master regulator of RS, CHK1, which manages DNA replication and repair to maintain cell viability (Chowdhry, 2022). Due to their elevated RS and hyper-reliance on CHK1, ecDNA+ cancer cells are rendered more susceptible to CHK1 inhibition than cancer cells that lack ecDNA. Prior clinical CHK1 inhibitor programs have lacked effective clinical PD biomarker assays. Here, we present preclinical data supporting the use of phosphorylated-CHK1 Ser345 (pCHK1-S345), a proximal marker of RS, as a PD biomarker for CHK1 inhibition by BBI-355. In preclinical studies, BBI-355 treatment induced pCHK1-S345 protein expression by immunoblotting in tumor cell lines in vitro and in xenograft tumors in vivo, which corresponded with tumor cell cytotoxicity. We went on to demonstrate in rats the utility of skin as a tumor surrogate tissue to detect CHK1 inhibitor PD effect through induction of pCHK1-S345 expression by immunohistochemistry. Finally, and for the first time, PD activity of a CHK1 inhibitor in humans was demonstrated by increased pCHK1-S345 expression by immunohistochemistry in skin biopsies from patients enrolled on the POTENTIATE study and treated with BBI-355. In conclusion, pCHK1-S345 is a useful PD biomarker for confirming clinical on-target activity of BBI-355 and may be useful to inform the pharmacologically active range of BBI-355 to support clinical development. Citation Format: Debbie Liao, Ryan Hansen, Sudhir Chowdhry, Evan Holmes, Julie Wiese, Auzon Steffy, AnneMarie Pferdekamper, Edison Tse, Salvador Garcia, Rebecca Reynolds, Sara Weymer, Klaus Wagner, Chris Hassig, Shailaja Kasibhatla. Preclinical and clinical pharmacodynamic characterization of BBI-355, a novel, orally bioavailable, and selective CHK1 inhibitor being evaluated in the first-in-human Phase 1/2 POTENTIATE clinical trial of patients with cancer harboring oncogene amplifications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3631.