A phase 1/2 first-in-human study of TH9619 in patients with advanced refractory solid tumors (ODIN).

Abstract

TPS3165 Background: TH9619 is a first-in-class, potent, small-molecule, and dual inhibitor of methylene-tetrahydrofolate dehydrogenase (MTHFD)1 and MTHFD2, both highly overexpressed in solid tumors and cancer-specific key enzymes within the one-carbon metabolic pathway. TH9619 kills cancer cells via a dual mechanism of action (1) inhibition of MTHFD1 traps folate leading to thymidine depletion, and (2) inhibition of nuclear MTHFD2 disrupts DNA damage response and repair pathways. With its unique characteristics, in preclinical models, TH9619 kills tumour cells, while sparing healthy tissues. The results from pre-clinical models, the novel mechanism of action, and the high unmet medical need in advanced refractory solid tumours support this investigation. Methods: ODIN (NCT07151040; EudraCT No. 2024-519639-40-00) is a first-in-human, multicentre, open-label, Phase 1/2 study. Eligible patients include adults with histologically confirmed advanced colorectal cancer, non–small cell lung cancer, head and neck squamous cell carcinoma, gastric cancer, or gastroesophageal junction cancer who have exhausted the institutional standard of care and have progressive and measurable disease per RECIST 1.1. Patients will receive TH9619 monotherapy via an intravenous infusion, weekly for 3 weeks, followed by one week without infusion, of a 28-day cycle, for up to 2 years. The Phase 1a dose-escalation, planning to recruit up to 80 patients, will assess the overall safety and tolerability profile and determine the maximum tolerated dose (MTD) and recommended Phase 2 dose(s) (RP2D(s)). Phase 1b is cohort expansion and plans to recruit up to 60 patients. Assessments include adverse events, pharmacokinetic (PK) and pharmacodynamic (PD) parameters, and preliminary anti-tumor activity per RECIST v1.1. Additionally, predictive biomarkers and metabolites related to the one-carbon metabolism and potential correlation with efficacy of TH9619 will be explored. The Phase 2 will further characterize safety, PK, PD, and efficacy at the RP2D(s). The ODIN phase 1/2 study is actively enrolling across leading academic and clinical research centres in the United Kingdom, France, and Spain, with expansion planned across additional European sites in the coming months. As of this submission, dose escalation is ongoing. Clinical trial information: NCT07151040 .