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

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 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.

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.

Zavondemstat was very well tolerated and showed encouraging preliminary clinical benefit in heavily pretreated patients with advanced cancer. Continued evaluation of zavondemstat is warranted.