717TiP - An open-label, multicentre, dose-escalation, first-in-human phase I study to evaluate safety, tolerability and antineoplastic activity of OATD-02 (dual arginase 1 and arginase 2 inhibitor) in patients with selected advanced and/or metastatic solid tumors

Background

Despite recent therapeutic progress, patients with advanced/metastatic solid tumors have limited options after standard of care therapies and high unmet medical needs. The arginine metabolism pathway is hyperreactive in several cancers and overexpression of arginases, arginase 1 (ARG1) and arginase 2 (ARG2), is considered as a poor prognostic factor and major contributor to the immunosuppressive tumor microenvironment. OATD-02 is the only small molecule with dual activity against intracellular ARG1 and ARG2. Data from non-clinical studies showed dose-dependent tumor growth inhibition with an associated increase in arginine levels in monotherapy setting. Prediction of human pharmacokinetics (PK) of OATD-02 resulted in a moderate oral bioavailability of 35% and the half-life of approx. 33 h.

Trial design

This phase I, open-label First-In-Human clinical study aims to determine if OATD-02 administration as a monotherapy is safe and results in immune activation effects through increased arginine levels and/or intrinsic anti-tumor activity. OATD-02 will be administered in patients with advanced and/or metastatic colorectal cancer, ovarian cancer, pancreatic ductal adenocarcinoma, or renal cell carcinoma. Up to 40 patients will be enrolled to receive OATD-02 orally q.d. until disease progression. The study will follow Bayesian Optimal Interval (BOIN) dose escalation/de-escalation design with overdose control based on dose-limiting toxicities (DLTs) during the evaluation period (first cycle). Six pre-defined dose levels are planned to be explored ranging from 2.5 mg to 30 mg. Primary endpoints include nature, frequency and severity of adverse events (AEs), and occurrence of DLTs. Secondary endpoints: PK and arginine assessments, anti-tumor activity parameters. Exploratory endpoints for safety and biologic effects include pharmacodynamic biomarkers (e.g. arginase, ornithine, microRNA), orotic acid and metabolites characterisation. As of May 2023, two patients have been enrolled. The study is ongoing. Clinical trial information: NCT05759923.

Clinical trial identification

EudraCT 2022-000697-25. Study Protocol No: OATD-02-C-01. Protocol version and date: Final version 2.0, 13 December 2022. NCT05759923.

Editorial acknowledgement

Legal entity responsible for the study

Molecure SA.

Funding

Molecure SA.

Disclosure

M.A. Dudek, Z. Zasłona, R. Błaszczyk, M.M. Grzybowski, T. Rejczak, A. Cabaj, P. Dera, K. Lisiecki, P. Iwanowski, T. Charitos, S. Fung: Financial Interests, Personal, Full or part-time Employment: Molecure SA.