Abstract A050: A Phase 1 dose escalation study of TACH101, a first-in-class KDM4 inhibitor for advanced solid tumors
Authors: Tsimberidou Apostolia , Vandross Andrae L , Sommerhalder David , Joseph Charmaine , Chandhasin Chandtip , Perabo Frank , Clarke Michael F 
Published: December 2023

Abstract
The KDM4 family of histone demethylases (KDM4A, B, C, D) have been identified as key oncogenic drivers in various cancers. KDM4 proteins control transitions between transcriptionally silent and active chromatin states via removal of methyl marks on histones H3K9 and H3K36 and have been shown to play an important role in epigenetic dysregulation during tumorigenesis. Functional redundancy and cross-activity have been observed across KDM4 family members, thus, selective inhibition of one isoform is not effective. TACH101 is a novel, first-in-class small molecule KDM4 inhibitor that targets isoforms A-D. In vitro and in vivo studies have shown potent anti-proliferative activity and strong tumor growth inhibition across multiple xenograft models. Preclinical studies demonstrated favorable pharmacokinetics (PK) and safety profiles. Initial clinical development of TACH101 will target advanced or metastatic solid tumors. TACH101-CS-0001 is an open-label, single-arm, phase 1 dose escalation study evaluating the safety and tolerability of orally administered TACH101 in subjects with solid tumors. Patients receive TACH101 in a single-dose lead-in period followed by repeated dosing on a weekly schedule. Using a Bayesian optimal interval (BOIN) design, the trial will evaluate up to 8 dose levels following a 3-days on/4-days off dosing schedule. Escalation across 2 dose cohorts (5 and 10mg) has been completed and enrollment into cohort 3 (25 mg) has begun. The planned enrollment is up to 33 patients including dose escalation and dose expansion (highest safe dose level) cohorts. Inclusion criteria include advanced or metastatic solid tumor that has progressed or was non-responsive or intolerant to available therapies and for which no standard or available curative therapy exists. Patients must have disease that is measurable according to RECIST (v1.1) and an ECOG performance status score of 0 to 1. Exclusion criteria include severe hematologic, hepatic, or renal insufficiency. Primary endpoints will assess safety and tolerability to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D). Secondary endpoints will evaluate PK and preliminary anti-tumor activity as assessed by objective response rate (ORR), duration of response (DOR), and clinical benefit rate (CBR). Exploratory endpoints include evaluation of circulating tumor DNA (ctDNA)-based genetic markers as well as molecular characterization of optional tissue biopsies. This trial will be the first to evaluate the full potential of KDM4 inhibition in solid tumors with the novel epigenetic-targeting drug candidate TACH101 in subjects with advanced or metastatic cancers. (NCT05076552).
Citation Format: Apostolia Tsimberidou, Andrae L Vandross, David Sommerhalder, Charmaine Joseph, Chandtip Chandhasin, Frank Perabo, Michael F Clarke. A Phase 1 dose escalation study of TACH101, a first-in-class KDM4 inhibitor for advanced solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A050.