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3249 Phase 1/2 Multicenter, Open-Label Study of CTX-712 in Patients with Relapsed/Refractory Acute Myeloid Leukemia and Higher Risk Myelodysplastic Syndromes

Program: Oral and Poster Abstracts
Session: 637. Myelodysplastic Syndromes – Clinical and Epidemiological: Poster II
Hematology Disease Topics & Pathways:
Research, clinical trials, Non-Biological therapies, Clinical Research, Chemotherapy, Therapies
Sunday, December 10, 2023, 6:00 PM-8:00 PM

Aref Al-Kali, MD1, Antoine Saliba, MD1, Cecilia Y. Arana Yi, MD2, James M. Foran, MD3, Yasushi Tanoue, MD, PhD4*, Maki Yamamoto, MS5*, Joachim Gullbo, MD, PhD6,7* and Guillermo Garcia-Manero, MD8

1Division of Hematology, Mayo Clinic, Rochester, MN
2Hematology/Oncology, Mayo Clinic, Scottsdale, AZ
3Hematology/Oncology, Mayo Clinic, Jacksonville, FL
4Chordia Therapeutics, Chuo-Ku, Japan
5Chordia Thaerapeutics, Chuo-Ku, Japan
6Theradex Oncology, Princeton, NJ
7Uppsala University, Uppsala, Sweden
8University of Texas MD Anderson Cancer Center, Houston, TX

Background and Significance
Dysregulation of alternative splicing, caused by abnormal expression or mutation of splicing factors, has been identified as an important contributor to the genesis and progression of cancer, and suggested as a novel target for anticancer treatment.

CDC2-like kinases (CLK) represent a family of dual-specificity tyrosine and serine-threonine kinases that are involved in the regulation of splicing by phosphorylation of serine/arginine-rich splicing factors (SRSFs) which play a central role in exon recognition.

CTX-712 is an orally available, potent, selective, and a first-in-class pan-CLK inhibitor (CLK 1-4), that inhibits phosphorylation of SRSFs resulting in significant antitumor activity in vitro and multiple xenograft models in vivo. CTX-712 formulated in capsules is currently being evaluated in an ongoing first-in-man study in Japan, evaluating tolerability and early efficacy in patients with solid tumors or hematologic malignancies (JapicCTI-184188). Preliminary data from the Japanese study were presented during ASCO 2022 and ASH 2022, and showed an acceptable safety profile (doses up to 175 mg (MTD 140 mg) twice a week in 28-day cycles, observed DLTs included dehydration, decreased platelets, hypokalemia, and pneumonia) with early signs of clinical antitumor activity (2 partial responses / 26 treated solid tumor patients, 5 complete remissions and complete remission with incomplete hematologic recovery/ 8 treated patients with AML or MDS), warranting further clinical investigations.. (J Clin Oncol (2022) 40(16_suppl):3080. Blood (2022) 140(Supplement 1):6211–2.). This abstract details a second study with CTX-712 that has just been initiated.

Study Design and Methods
A new film-coated tablet formulation will be evaluated in this phase 1/2 multicenter, open-label study of CTX-712 in patients with (mutated or wild type spliceosomes genes) relapsed/refractory AML, higher risk MDS (IPSS-R intermediate, high, or very high), or high marrow blast (≥5 %) MDS/MPN (including

CMML). The phase 1 part of the study will be conducted at 4 US sites, and all sites are currently open for enrolment. The study allows patients with performance status 0, 1, or 2, adequate organ function, and up to four prior lines of therapy. Due to potential risk of interactions (in vitro studies suggest CYP3A4 as main metabolic pathway for CTX-712), concomitant use of strong CYP3A4 inhibitors is prohibited. Use of azole antifungals that are not strong CYP3A4 inhibitors (e.g., isavuconazole) is permitted.

The phase 1 part of the study consists of dose-escalation (sequential standard 3 + 3 design), where cohorts of 3 (or 6) patients will receive ascending doses of CTX-712 once weekly in a 28-day cycle with continuous monitoring of emerging clinical PK, PD, safety, and efficacy data, to determine the recommended phase 2 dose (RP2D) based on the suggestion by the Safety Review Committee (SRC). The protocol defines five different dose levels (20-140 mg, once weekly) but also authorizes the SRC to suggest up to two interim dose levels or alternate schedules (e.g., dosing two times a week) if supported by emerging data. The suggested RP2D will be used in a confirmatory phase 1 expansion cohort where an additional 10 patients (total n = 16; 8 patients with AML and 8 patients with MDS) will be treated to gain further confidence in the selected dose level.

The phase 2 part of the study will commence after the RP2D has been identified and confirmed and aims at evaluating therapeutic activity in R/R AML (Cohort 2a) or R/R HR-MDS (Cohort 2b), in addition to confirmation of the safety profile.

Clinical trial registry number: NCT05732103

Disclosures: Foran: Sellas: Research Funding; Novartis: Research Funding; Roivant: Research Funding; Astellas: Research Funding; NCI: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Actinium: Research Funding; Kura: Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees; CTI: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Tanoue: Chordia Therapeutics Inc.: Current Employment. Yamamoto: Chordia Therapeutics: Current Employment. Garcia-Manero: Bristol Myers Squibb: Other: Medical writing support, Research Funding; Genentech: Research Funding; AbbVie: Research Funding.

OffLabel Disclosure: CTX-712, an inhibitor of CDC2-like kinase (CLK), is being evaluated as an anticancer drug.

*signifies non-member of ASH