Abstract CT112: Initial results from a Phase 1 trial of a first-in-class pan-CDC-like kinase inhibitor (SM08502) with proof of mechanism in subjects with advanced solid tumors
Authors: Tolcher Anthony , Babiker Hani M. , Chung Vincent , Kim Edward , Moser Justin , Karim Raghad , Vandross Andre , Sommerhalder David , Scott Aaron J. , Fakih Marwan , Massarelli Erminia , Adams Jeffrey , Stewart Joshua , Bossard Carine , Do Long , White Michael , Beaupre Darrin M. , Borazanci Erkut 
Published: July 2021

Abstract
Dysregulation of alternative pre-mRNA splicing has been identified as a common mechanistic driver of tumor initiation, disease progression, and emergence of therapy resistance. An iterative screening campaign identified SM08502, a potent pan-inhibitor of CDC-like kinases (CLKs), which are known to regulate alternative splicing. In preclinical studies, SM08502 inhibited growth and induced apoptosis in a broad array of tumor models. Study NCT03355066 is a two-part Phase 1 first-in-human study that evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of orally administered SM08502 in subjects with advanced solid tumors. In Part 1A of the study, which utilized an accelerated-titration/3 + 3 dose-escalation design, 19 subjects were administered SM08502 at doses ranging from 10 mg to 80 mg; a maximum tolerated dose has not yet been identified. Systemic exposures showed dose-dependent increases from 10 mg to 80 mg and the mean time to maximal concentration (tmax) ranged from 3.3 to 5.9 hours on Cycle 1 Day 1 and from 1 to 24.6 hours on Cycle 2 Day 1. SM08502 had low-to-moderate clearance and a high volume of distribution, which resulted in a long terminal half-life (t½ &gt; 24 hours) and accumulation of approximately 2- to 3.9-fold. Based on preclinical tumor xenograft models, exposures (AUC and Cmax) in the expected therapeutic range were attained. The most commonly reported adverse events (AEs) included nausea (12/19 [63.2%]), diarrhea (10/19 [52.6%]), fatigue (8/19 [42.1%]), and vomiting (7/19 [36.8%]), with the most common grade 3 or greater AEs being diarrhea (3/19 [15.8%]), anemia (2/19 [10.5%]), and decreased lymphocyte count (2/19 [10.5%]). The most common possibly or probably related serious AE (SAE) was diarrhea (2/19 [10.5%]). Two subjects experienced dose-limiting toxicity: one at the 40 mg dose level (elevated liver function tests [ALT and AST]) and a second at the 80 mg dose level (diarrhea). In peripheral blood mononuclear cells, evidence for disruption of alternative splicing was detected through expression changes associated with mRNA splicing and nonsense-mediated decay. Further, direct evidence for CLK1 inhibition was observed at tolerated doses, which provided proof of mechanism. Radiological assessment demonstrated tumor shrinkage in two subjects with endometrial cancer. In addition, stable disease lasting longer than 6 months was observed in four subjects. Further dose finding is planned prior to the Part 2 expansion.
Conclusion: In this first-in-human study, PK and PD data demonstrate proof of mechanism for the pan-CLK inhibitor SM08502 at tolerated doses.
Citation Format: Anthony Tolcher, Hani M. Babiker, Vincent Chung, Edward Kim, Justin Moser, Raghad Karim, Andre Vandross, David Sommerhalder, Aaron J. Scott, Marwan Fakih, Erminia Massarelli, Jeffrey Adams, Joshua Stewart, Carine Bossard, Long Do, Michael White, Darrin M. Beaupre, Erkut Borazanci. Initial results from a Phase 1 trial of a first-in-class pan-CDC-like kinase inhibitor (SM08502) with proof of mechanism in subjects with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT112.