Phase 1 study of zavondemstat (TACH101), a first-in-class KDM4 inhibitor, in patients with advanced solid tumors: Results on safety, pharmacokinetics, and anti-tumor activity.
Year: 2025
Type: conference-abstract
Abstract: 3124 Background: Zavondemstat is an epigenetic targeting inhibitor of KDM4 histone demethylase. Dysregulation of KDM4 enzymes (isoforms A-D) has been implicated in various cancers where they drive oncogenesis and resistance pathways by regulating gene transcription. Preclinical studies of zavondemstat demonstrated robust anti-proliferative effects and significant inhibition of tumor growth across numerous xenograft and PDX models. Targeting KDM4 offers the potential to reprogram the epigenetic dysfunction of cancer cells and inhibit drivers of tumor dedifferentiation and proliferation leading to apoptotic cell death. This is the first clinical evaluation of a pan-isoform KDM4 inhibitor. Methods: TACH101-CS-0001 (NCT05076552) was an open-label Phase 1 study assessing zavondemstat's safety, tolerability, pharmacokinetics (PK), and recommended Phase 2 dose (RP2D) in patients (pts) with advanced solid tumors. Pts received zavondemstat orally on a weekly schedule in 28-day cycles. Dose escalation followed a Bayesian optimal interval (BOIN) design and explored both intermittent and continuous dosing. Inclusion criteria included heavily pre-treated advanced/metastatic solid tumors that progressed or were non-responsive to available therapies and for which no standard therapy exists. Pts must have measurable disease according to RECIST (v1.1) and ECOG score of 0 to 1. Exclusion criteria included severe hematologic, hepatic, or renal insufficiency. Primary endpoints included safety/tolerability, MTD and RP2D. Secondary endpoints included PK and radiographic response per RECIST v1.1. Results: Thirty patients were enrolled across 6 dose cohorts. MTD was not reached; RP2D was not determined. 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 TRAEs ≥ Grade 3 were reported). No treatment-related serious adverse events (SAEs) or dose limiting toxicities (DLTs) were reported. In 23 response-evaluable patients, 10 patients (44%) achieved stable disease (SD) across dosing cohorts. Two patients (9%) had SD ≥ 6 months, including a patient with castration-resistant prostate cancer (CRPC) and a patient with leiomyosarcoma. Another patient with leiomyosarcoma is continuing to receive zavondemstat under compassionate use, demonstrating SD for a total of 6 months at time of abstract submission. Zavondemstat demonstrated a dose-proportional exposure profile with a short 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 signals of clinical benefit in very heavily pre-treated metastatic cancer patients. Continued evaluation of zavondemstat is warranted. Clinical trial information: NCT05076552 .
Source: Journal of Clinical Oncology
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W4410822832