684TiP - A phase I, open-label, multicenter, dose escalation and expansion study of HM97662 (EZH1/2 dual inhibitor) as a single agent in patients with advanced or metastatic solid tumors

Background

Enhancer of zeste homolog 2 (EZH2) and its close homolog EZH1 are the enzymatic core subunits of polycomb repressive complex 2 (PRC2). EZH1/2 repress the transcription of target genes by triggering tri-methylation of the lysine 27 residue of histone H3 (H3K27me3). H3K27me3 plays a critical role in cancer progression and is associated with poor prognosis. EZH2 gain-of-function (GOF) mutations or overexpression lead to hyper tri-methylation of H3K27 when loss-of-function mutation of major components of regulatory protein complexes promote cancer pathogenesis by losing its ability to oppose PRC2. Given that EZH1 compensates the activity of EZH2 in EZH2-depleted cells, dual inhibition of EZH1/2 is expected to have a greater anti-tumor activity through suppressing PRC2 function. In preclinical studies, HM97662, a novel EZH1/2 dual inhibitor have demonstrated simultaneous inhibition of the methyltransferase activity of wild-type EZH1/2 as well as GOF mutant EZH2. Given the promising preclinical results, first-in-human phase I study of HM97662 was designed.

Trial design

This is a phase I, open-label, multicenter study of HM97662 as a single agent in patients with advanced or metastatic solid tumors who have failed or are intolerant to standard therapy. Dose escalation part is planned with a 3+3 design to establish the maximum tolerated dose or recommended dose for the randomized dose ranging part. The starting dose is 50 mg once daily (QD) and may proceed to subsequent cohorts increased by 50 mg from the preceding cohort until the maximum dose of 350 mg QD. Randomized dose ranging part is mainly designed with the purpose of dose optimization by evaluating the safety and preliminary efficacy of HM97662 in patients with genomic alterations for more than one feasible doses selected from the dose escalation part. Dose expansion part is designed to assess and confirm the efficacy, safety, pharmacokinetics, and pharmacodynamics of HM97662 with specific target disease determined by available preclinical study results and clinical outcomes. The final analysis will be performed once or separately for each part based on study progression.

Clinical trial identification

NCT05598151.

Editorial acknowledgement

Legal entity responsible for the study

Hanmi Pharmaceutical Co. Ltd.

Funding

Hanmi Pharmaceutical Co. Ltd.

Disclosure

B. Keam: Financial Interests, Personal, Invited Speaker: Merck, Lilly, MSD, LG Chem; Financial Interests, Personal, Advisory Board: Handok, TrialInformatics, ImmunOncia, NeoImmunetech, Beigen; Financial Interests, Personal, Coordinating PI: MSD Oncology, AstraZeneca, Ono Pharmaceutical, Bayer. V. Ganju: Financial Interests, Personal, Other, Honoraria: Roche/Genentech, AstraZeneca. V. Kwatra: Financial Interests, Personal, Advisory Board: Roche. A. Body: Financial Interests, Institutional, Local PI: BeiGene, DayOne, Innovent, Gilead, Hanmi Pharmaceutical, Stingray Therapeutics, Vivace Therapeutics; Financial Interests, Institutional, Research Grant: Cancer Australia (Australian Government). P.D. Rhee, S. Jung, J. Yoon, E. Baek, Y.S. Noh: Financial Interests, Personal, Full or part-time Employment: Hanmi Pharmaceutical Co., Ltd. All other authors have declared no conflicts of interest.