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

Yokoyama:Astellas: Honoraria; BMS: Honoraria; Janssen: Honoraria; Sanofi: Honoraria. Fukuhara:Abbvie: Consultancy; Nippon Shinyaku: Honoraria; Kyowa kirin: Honoraria; Janssen: Honoraria; Eisai: Honoraria; Dainippon Sumitomo: Honoraria; Incyte: Research Funding; Genmab: Research Funding; BMS: Honoraria, Research Funding; Chugai pharma: Honoraria, Research Funding; Bayer: Research Funding; Novartis: Consultancy, Honoraria; HUYA: Consultancy; Eli Lilly: Consultancy; AstraZeneca: Consultancy, Honoraria; Sanofi: Honoraria; Ono pharma: Honoraria; Celgene: Honoraria, Research Funding; Symbio: Honoraria; Takeda: Honoraria. Iida:Chugai: Research Funding; Astellas: Honoraria; Novartis: Honoraria; Janssen: Honoraria; bristol myers squibb: Honoraria. Miyake:Takeda Pharmaceutical Company Ltd.: Current equity holder in publicly-traded company, Patents & Royalties: Chordia has royalty bearing rights to execute Takeda's CLK inhibitor etc. patent., Research Funding; Chordia Therapeutics Inc.: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees. Tanoue:Chordia Therapeutics Inc.: Current Employment; Eisai Inc.: Ended employment in the past 24 months. Tozaki:Honda Motor Co., Ltd.: Current equity holder in publicly-traded company; Kyowa Kirin Co., Ltd.: Current Employment, Patents & Royalties: Japanese Patent Application No.2002-078819; Chordia Therapeutics inc.: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company, Patents & Royalties. Mizutani:Chordia Therapeutics inc.: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company, Patents & Royalties. Morishita:Chordia Therapeutics lnc: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company, Patents & Royalties. Takeyama:Chordia Therapeutics Inc: Consultancy, Current equity holder in private company, Ended employment in the past 24 months. Shimizu:Eli Lilly: Honoraria, Research Funding, Speakers Bureau; LOXO Oncology: Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi-Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Chordia Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Eisai: Research Funding; AstraZeneca: Research Funding; Takeda Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; 3D-Medicine: Research Funding; Symbio Pharmaceuticals: Research Funding; Pfizer: Research Funding; Astellas Pharma: Research Funding; Chugai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Honoraria, Speakers Bureau. Yamamoto:Astellas: Research Funding; Chugai: Research Funding; Eisai: Research Funding; Taiho: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Eli Lilly: Research Funding; AbbVie: Research Funding; Daiichi-Sankyo: Research Funding; Bayer: Research Funding; Boehringer Ingelheim: Research Funding; Kyowa Kirin: Research Funding; Takeda: Research Funding; ONO: Research Funding; Janssen Pharma: Research Funding; MSD: Research Funding; MERCK: Research Funding; GSK: Research Funding; Sumitomo Dainippon: Research Funding; Chiome Bioscience: Research Funding; Otsuka: Research Funding; Ciome Biosciences: Research Funding; Genmab: Research Funding; Shionogi: Research Funding; TORAY: Research Funding; Eisai: Consultancy; Takeda: Consultancy; Otsuka: Consultancy; Boehringer Ingelheim: Consultancy; Cimic: Consultancy; Chugai: Consultancy; AstraZeneca: Speakers Bureau; Eli Lilly: Speakers Bureau; ONO: Speakers Bureau; Chugai: Speakers Bureau; Sysmex: Speakers Bureau; Daiichi-Sankyo: Speakers Bureau; Eisai: Speakers Bureau.

CTX-712 clinical trial compound

Author notes

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Asterisk with author names denotes non-ASH members.

© 2022 by The American Society of Hematology
2022
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