Abstract CT240: A first-in-human study of the dual A2A/A2B adenosine receptor antagonist M1069 in patients with advanced solid tumors

Abstract

Abstract A2A and A2B adenosine receptors have been shown to mediate immunosuppressive and tumor-promoting signals in the tumor microenvironment and their inhibition may be a promising treatment strategy for patients with advanced solid tumors. Dual A2A/A2B inhibition has shown an acceptable safety profile as monotherapy and early signs of clinical activity in combination with chemotherapy in patients with advanced solid tumors. M1069 is a novel, orally administered, highly selective dual antagonist of the A2A and A2B adenosine receptors that has recently demonstrated significant anti-tumor activity in vivo as monotherapy and in combination with chemotherapeutic agents in adenosine-rich tumor models. The aim of this Phase Ia First in Human noncontrolled, open-label, multicentre, dose escalation clinical study (NCT05198349) is to investigate the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary activity of M1069 in patients with metastatic or locally advanced unresectable solid tumors. Study Design: Patients aged ≥18 years, with an Eastern Cooperative Oncology Group performance status ≤1, adequate baseline hematological, renal and hepatic function, and with locally advanced or metastatic disease refractory to, or who have progressed with, standard therapy are eligible. Patients who have had prior treatment with another agent targeting the adenosine signalling pathway or prior anticancer treatment within 4 weeks or 5 half-lives are excluded. The study includes a 28-day screening period, a study intervention period of 21-day cycles, a 21-day dose-limiting toxicity observation period, an end of study intervention visit and a safety follow-up period of 30±7 days. Patients (approximately 21-30) will receive M1069 monotherapy twice daily in 21-day cycles until disease progression, unacceptable toxicity, withdrawal of consent or any criterion for withdrawal from study intervention. The starting dose is M1069 150 mg twice daily, with dose escalation decisions (300, 450, 600 and 700 mg twice daily) made by the safety monitoring committee and supported by results of a Bayesian Logistic Regression Model (BLRM). The primary objectives of the study are to determine the dose toxicity relationship and maximum tolerated dose (MTD), if reached, of M1069 and to determine the recommended dose for expansion of M1069 for further exploratory clinical development. These will be measured by the occurrence of dose-limiting toxicities, adverse events and treatment-related adverse events, and, through analysis of the safety, tolerability, pharmacokinetics, pharmacodynamics and post-treatment changes in the tumor microenvironment in available paired tumor biopsies, respectively. The target dose-limiting toxicity probability for the MTD is 30% which will be estimated by the BLRM. Pharmacokinetic parameters will be calculated using noncompartmental analysis. The study is open and patients are being treated at the first dose level. Citation Format: Lillian L. Siu, Martin E. Gutierrez, Guelseren Guezel, Katia Ruth, Ping Hu, Thomas Kitzing, Christina Habermehl, Meredith McKean. A first-in-human study of the dual A2A/A2B adenosine receptor antagonist M1069 in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT240.