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

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.