A First-in-Human Phase I Study of CTX-712 in Patients with Advanced, Relapsed or Refractory Malignant Tumors - Hematologic Malignancies Dose Escalation Cohort

Background: Mutations of RNA splicing factors, including SF3B1, SRSF2, U2AF1, and ZRSR2, are implicated in the pathogenesis of various cancers, such as acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), most likely via abnormal RNA splicing. CTX-712 is a first-in-class, orally available, highly potent, and selective small-molecular inhibitor of CDC2-like kinase (CLK), a key regulator of the RNA splicing process. Preclinical data show that CTX-712 demonstrated anti-proliferative activity on various in vitro and in vivo models derived from not only solid tumors but also hematologic malignancies. Based on these results, a phase I study of CTX-712 was conducted to determine the recommended dose (RD) in solid tumors and hematologic malignancies. While therapeutic agents have been developed to target RNA splicing factor abnormalities, no such agents have been developed to be standard care until now. We report the interim data from the dose escalation cohort of relapsed or refractory AML and MDS, including preliminary efficacy results of CTX-712.

Methods: The objectives of this cohort are to evaluate the maximum tolerated dose, dose- limiting toxicity (DLT), safety, pharmacokinetic/pharmacodynamic profiles, and preliminary efficacy of CTX-712 and to determine the RD for the next phase in patients with hematologic malignancies. A 3+3 design is used for finding the RD. An initial CTX-712 dose of 105 mg twice a week was used based on the safety information of the preceding solid tumor dose escalation cohort.

Results: As of April 28, 2022, a total of 6 patients (5 AML and 1 MDS) were enrolled in the initial 105 mg twice-a-week dosing cohort. Three of the 6 patients were considered non-evaluable for DLT analysis (2 patients received less than 75% of the dose in cycle 1 due to tumor lysis syndrome, 1 patient discontinued treatment due to disease progression before completing cycle 1). A DLT of Grade 4 pneumonia was observed in 1 of 3 DLT-evaluable patients. Based on these safety profiles, the safety monitoring committee recommended to suspend the 105 mg twice-a-week dosing cohort and to initiate a 70 mg twice-a-week dosing cohort.

Among the safety analysis population (N=6), with a median treatment duration of 114 days (Range 15-609 days), the common any-grade adverse events (AEs) (≥30%) were nausea (100%), diarrhea, hypotension (66.7%), vomiting, blood creatinine increased, pyrexia, insomnia (50.0%), fatigue, malaise, amylase increased, tumour lysis syndrome, dysgeusia, nail discoloration, dry skin, rash, and oedema (33.3%). The most common Grade 3 or higher AE was tumour lysis syndrome (33.3%).

In the AML patients (N=5), complete remission (CR) was observed in two patients (40.0%), and CR with incomplete hematologic recovery (CRi) was observed in one patient (20.0%). The median time to remission is 56 days (Range 29-57 days), and the median duration of response is 56 days (Range 49+-532 days). In the MDS patient (N=1), CR was observed. Pharmacokinetic/pharmacodynamic profiles of the hematologic malignancies cohort were comparable with those of the solid tumor cohort in the same dosage.

Conclusions: Assessment of CTX-712 safety profile for hematologic malignancies is ongoing. CTX-712 showed preliminary anti-tumor efficacy for both AML and MDS.

Clinical trial information: JapicCTI-184188