Phase I Study of Rogocekib in Patients with Advanced, Relapsed, or Refractory Malignant Solid Tumors

PURPOSE: Aberrant splicing plays a significant role in cancer progression, yet targeted treatments are lacking. Rogocekib (developmental name CTX-712) is a potent oral inhibitor of CDC2-like kinase (CLK) that targets RNA splicing. This Phase I study aimed to evaluate the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), safety, tolerability, pharmacokinetics (PK)/pharmacodynamics (PD) profiles, preliminary efficacy, and the recommended dose (RD) of rogocekib in patients with advanced solid tumors. PATIENTS AND METHODS: The dose escalation started with an accelerated titration phase and then transitioned to a 3+3 design at doses ranging from 10 mg to 175 mg, administered twice weekly (BIW). For dose expansion,105 mg BIW, 70 mg BIW, and 105 mg once weekly (QW) were investigated. RESULTS: In total, 46 patients with solid tumors were administered rogocekib. The MTD was determined to be 140 mg BIW. DLTs were observed in 1 patient at 140 mg BIW (platelet count decreased, hypokalemia) and 1 patient at 175 mg BIW (dehydration). Common related adverse events included nausea, vomiting, and diarrhea. Two treatment related deaths were observed. PK analysis showed a dose-dependent increase in systemic exposure to rogocekib. PD analysis of two markers (THAP9-AS1 and S6K) showed target engagement of rogocekib. Partial response (PR) was observed in 6.5% of patients, all with ovarian cancer (n=3). CONCLUSIONS: Although most toxicities were manageable, two treatment related deaths were observed, underscoring the need for vigilant safety monitoring. Overall, rogocekib demonstrated evidence of target engagement in most patients with solid tumors and preliminary antitumor activity, warranting further clinical investigation.