Phase 1 study of zavondemstat (TACH101), a first-in-class KDM4 inhibitor, in patients with advanced solid tumors - Abstract

Sep 23, 2026

First-in-human phase I dose-escalation study assessed safety, pharmacokinetics, and preliminary efficacy of zavondemstat (TACH101), a KDM4 histone demethylase epigenetic inhibitor, in heavily pre-treated advanced/metastatic solid tumors. Weekly oral dosing used 28-day cycles with Bayesian optimal interval design exploring intermittent and continuous schedules. Primary endpoints evaluated safety, dose-limiting toxicities, maximum tolerated dose, and RP2D; secondary endpoints included pharmacokinetics and radiographic response by RECIST v1.1. Thirty patients in six cohorts were enrolled; MTD was not reached, and TRAEs were grade 1–2 only, with stable disease in 44%.

LanguageEnglish

CategoryHealthcare

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Pages10

Reading Time25 min

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Abstract

Background

Patients and Methods

Results

Conclusions

Implications for Practice

Introduction

Phase 1 study of zavondemstat (TACH101), a first-in-class KDM4 inhibitor, in patients with advanced solid tumors Apostolia M. Tsimberidou*, 1,, Farshid Dayyani2,, David Sommerhalder3, Andrae L. Vandross4, Meredith S. Pelster5, Jason T. Henry6, CesarA. Perez7, Abhijit Chakraborty1, Mehmet A. Baysal1,, Chandtip Chandhasin8, Yiyun Dai7, Shirley Tu8, Ivan King8, Frank Perabo8 1Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 2Chao Family Comprehensive Cancer Center, University of California at Irvine, Orange, CA, USA 3 NEXT Oncology, San Antonio, TX, USA 4 NEXT Oncology, Austin, TX, USA 5Sarah Cannon Research Institute, Nashville, TN, USA 6Sarah Cannon Research Institute at HealthONE, Denver, CO, USA 7Sarah Cannon Research Institute at Florida Cancer Specialists, Orlando, FL, USA 8Tachyon Therapeutics Inc., San Francisco, CA, USA * Corresponding author: Apostolia-Maria Tsimberidou, MD, PhD, FASCO, FAAAS, Professor, The University of Texas MD Anderson Cancer Center, Department of Investigational Cancer Therapeutics, Unit 455, 1515 Holcombe Boulevard, Houston, TX 77030, USA ([atsimber@mdanderson.org](atsimber@mdanderson.org)) . Abstract Background: This was a first-in-human, phase I, dose-escalation study evaluating the safety, pharmacokinetics, and preliminary efficacy of zavondemstat (TACH101), an epigenetic targeting inhibitor of KDM4 histone demethylase, in patients with heavily pre-treated advanced/metastatic cancers. Patients and Methods: Patients received zavondemstat orally on a weekly schedule in 28-day cycles. Dose escalation followed a Bayesian optimal interval design and explored both intermittent and continuous dosing. The primary objectives were to assess safety, dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and recommended phase II dose (RP2D) . Secondary objectives included pharmacokinetics and radiographic response per Response Evaluation Criteria in Solid Tumors, version 1.1. Results: Thirty patients were enrolled across 6 dose cohorts. MTD was not reached at the maximum dose tested. The most common treatment-related adverse events (TRAEs) were diarrhea (12%), fatigue (7%), decreased appetite (7%), nausea (7%), and hyponatremia (7%) . All TRAEs were grade 1 or 2. No serious TRAEs or DLTs were reported. Of 23 response-evaluable patients, 10 (44%) achieved stable disease (SD) . Two patients (9%) had SD ≥ 6 months, including a patient with castration-resistant prostate cancer and a patient with leiomyosarcoma . A third patient (leiomyosarcoma) receiving ongoing treatment with zavondemstat under compassionate use has had SD for 6+ months. Zavondemstat demonstrated a dose-proportional exposure profile with a half-life of about 1.5 hours. There was no to minimal drug accumulation observed. Conclusions: Zavondemstat was very well tolerated and showed encouraging preliminary clinical benefit in heavily pretreated patients with advanced cancer. Continued evaluation of zavondemstat is warranted. Key words: histone lysine demethylase; KDM4; epigenetic; zavondemstat; TACH101 . Implications for Practice This is the first evaluation of KDM4 inhibition in a clinical setting. In this phase I study, zavondemstat, a pan-isoform KDM4 inhibitor, demonstrated a favorable benefit/risk profile in patients with heavily pretreated advanced cancers. The safety profile for zavondemstat was excellent, with only grade 1 and 2 adverse events reported, including at the highest dose evaluated. No serious adverse events were observed. Preliminary antitumor activity showed a stable disease rate of 44%, with SD ≥ 6 months in 3 patients. These findings suggest that KDM4 inhibition is a promising novel therapeutic strategy in heavily pre-treated patients with advanced cancer. Introduction KDM4 (histone lysine demethylase 4) is part of the Jumonji C (JmjC) family of epigenetic regulators that play a crucial role in embryonic developm

FAQs

What was the purpose of the phase I dose-escalation study of zavondemstat (TACH101)?

To evaluate safety, pharmacokinetics, and preliminary efficacy of zavondemstat in heavily pre-treated advanced/metastatic cancers.

How was zavondemstat administered in the trial?

Patients received zavondemstat orally on a weekly schedule in 28-day cycles, with Bayesian dose-escalation exploring intermittent and continuous dosing.

What safety outcomes and adverse event severity were reported?

Thirty patients were enrolled across six dose cohorts; the maximum tolerated dose was not reached, and treatment-related adverse events were grade 1–2 only, with no serious treatment-related adverse events or DLTs reported.

Sep 23, 2026

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