Phase I Study of Rogocekib in Patients with Relapsed or Refractory Hematologic Malignancies.

Rogocekib (development name CTX-712) is a first-in-class, orally available, highly potent, and selective small molecule inhibitor of CDC2-like kinase (CLK), a key regulator of the RNA splicing process. Preclinical studies demonstrated anti-proliferative activity on various in-vitro and in-vivo models of hematologic malignancies. Based on these findings, a phase I study of rogocekib was conducted to evaluate the safety and preliminary efficacy in patients with relapsed or refractory acute myeloid leukemia (AML) and higher-risk myelodysplastic syndrome (MDS). Using a 3+3 design informed by prior solid tumor safety data, patients received 70 mg or 105 mg twice a week (TW) in capsule form. One dose limiting toxicity (DLT) of Grade 4 Pneumonia was observed in the 105 mg TW cohort. Among 12 AML patients, complete remission (CR) was observed in 3 patients (25.0%), and CR with incomplete hematologic recovery (CRi) was observed in 1 patient (8.3%). In MDS patients (n=2), CR was observed in 1 patient (50.0%). Pharmacokinetics (PK) analyses showed higher mean Cmax and AUC0-24 of rogocekib at 105 mg compared to 70 mg. Pharmacodynamics (PD) analysis showed that the relative magnitude of exon skipping in peripheral blood cells increased with exposure of rogocekib. Rogocekib demonstrated a manageable and tolerable safety profile in patients with hematologic malignancies. This study was registered on the Japan Registry of Clinical Trials under jRCT2080224127. Currently, a Phase I/II Study of rogocekib in relapsed/refractory AML and higher risk MDS is ongoing in the United States (NCT05732103).