Phase 1 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, a key regulator of the RNA splicing process. Preclinical studies demonstrated antiproliferative activity on various in vitro and in vivo models of hematologic malignancies. Based on these findings, a phase 1 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 previous solid tumor safety data, patients received 70 mg or 105 mg twice a week in capsule form. One dose-limiting toxicity of grade 4 pneumonia was observed in the 105 mg twice a week cohort. Among 12 patients with AML, complete remission (CR) was observed in 3 patients (25.0%), and CR with incomplete hematologic recovery was observed in 1 patient (8.3%). In patients with MDS (n = 2), CR was observed in 1 patient (50.0%). Pharmacokinetics analyses showed higher mean maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time 0 to 24 hours post dose (AUC0-24) of rogocekib at 105 mg compared with 70 mg. Pharmacodynamics analysis showed that the relative magnitude of exon skipping in peripheral blood cells increased with exposure to rogocekib. Rogocekib demonstrated a manageable and tolerable safety profile in patients with hematologic malignancies. Currently, a phase 1/2 study of rogocekib in relapsed/refractory AML and higher risk MDS is ongoing in the United States (ClinicalTrials.gov identifier: NCT05732103). This trial was registered at the Japan Registry of Clinical Trials as jRCT2080224127.