Phase I/II study of 9-ING-41, a small molecule selective glycogen synthase kinase-3 beta (GSK-3β) inhibitor, as a single agent and combined with chemotherapy, in patients with refractory haematological malignancies or solid tumours

Abstract

Abstract Background 9-ING-41 is a first-in-class, intravenously (IV) administered, small molecule potent selective GSK-3β inhibitor with significant pre-clinical antitumor activity in a broad spectrum of malignancies, both as a single agent and in combination with cytotoxic agents. GSK-3β is a serine/threonine kinase important in tumor progression and modulation of oncogenes, cell cycle regulators and mediators of epithelial-mesenchymal transition. Aberrant overexpression of GSK-3β is associated with advanced stage and aggressive tumor growth as well as chemotherapy resistance. Trial design This Phase 1/2 study is designed to evaluate the safety and efficacy of 9-ING-41 as a single agent and in combination with cytotoxic agents, in patients with refractory cancers. Treatment consists of twice-weekly IV infusion of 9-ING-41 as a single agent (21-day-cycle) or combined with chemotherapeutic agents including gemcitabine, doxorubicin, lomustine, carboplatin, nab-paclitaxel, or paclitaxel. Study parts 1 and 2 will evaluate the safety and tolerability, describe any dose-limiting toxicity (DLT), determine the maximum tolerated dose (MTD) and the recommended Phase 2 study dose (RP2D) for 9-ING-41 as monotherapy (Part 1) and in combination with chemotherapies (Part 2). Part 3 (Simon 2-Stage Phase 2 at the RP2D) will assess clinical benefit in patients with relapsed or refractory malignancies treated with 9-ING-41-based combinations at the RP2D established in Part 2. Safety will be assessed by recording and monitoring adverse events (CTCAE). For solid tumors, response will be defined by response evaluation criteria in solid tumors (RECIST) 1.1 criteria in the evaluable lesion(s). For lymphoma, response will be assessed per the International Working Group Response Criteria. For CNS tumors, response will be followed by the RANO and the MacDonald criteria. The study is opening in 25 sites globally and will accrue approximately 250 patients. Clinical trial identification NCT03678883. Legal entity responsible for the study Actuate Therapeutics Inc. Funding Actuate Therapeutics Inc. Disclosure B. Carneiro: Research grant / Funding (institution): Actuate Therapeutics Inc; Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Bayer. L. Cavalcante: Research grant / Funding (institution): Actuate Therapeutics Inc. P. Munster: Research grant / Funding (institution): Actuate Therapeutics Inc. F. Giles: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Actuate Therapeutics Inc. All other authors have declared no conflicts of interest.