Background
Methylthioadenosine phosphorylase (MTAP) homozygous deletion is present in many human malignancies. The metabolic enzyme methionine adenosyltransferase 2α (MAT2A) is considered as a synthetic lethal target in MTAP deleted tumors. S095035 is an oral potent reversible inhibitor of MAT2A.
Preclinical pharmacology studies in MTAP-/- or null cell line-derived human tumor xenografts in mice demonstrated a dose-dependent reduction of SAM levels in plasma and tumor, correlating with tumor growth inhibition.
Methods
This Phase 1, open-label, multicenter clinical trial is investigating safety, tolerability and preliminary antitumor activity of S095035 administered as a single agent in patients with advanced or metastatic solid tumors with documented homozygous deletion of MTAP.
Approximately 27 eligible patients who have failed to respond to or have progressed after prior treatment, and for whom additional effective standard-of-care treatment is not available, will be enrolled in the dose finding study. S95035 will be administered orally once daily in a 28-day cycle dose escalation phase starting at 50 mg with a maximum dose of 600mg to be tested.
Time-to-event Bayesian optimal interval (TITE-BOIN) with adaptive dose modification (ADM) design will be used to guide the dose escalation process and the determination of the recommended dose for expansion (RD) and/or the maximum tolerated dose (MTD).
The primary objective of the Phase 1 study is to assess the safety and tolerability and identify the recommended dose (RD) and/or maximum tolerated dose (MTD).
Key secondary objectives include characterization of pharmacokinetics (PK), pharmacodynamics (PD) and preliminary antitumor activity using RECIST v1.1. Identification of predictive biomarkers and changes from baseline in intra-tumoral concentrations of SAM and MTA are key exploratory endpoints of the study.
Clinical trial information (NCT06188702)