A phase I/IIa trial of Aurora-A inhibitor (JAB-2485) in adult patients with advanced solid tumors

BackgroundAurora kinase A (AURKA), a crucial mitotic regulator, is frequently dysregulated in a wide range of cancers, which contributes to clinical aggressiveness and poor patient survival, making it an attractive therapeutic target. Prior studies with pan-Aurora kinase inhibitors have shown limited success, largely owing to the narrow therapeutic window associated with bone marrow toxicity caused by targeting Aurora B. The development of highly selective AURKA inhibitors, with improved efficacy and tolerability, is highly warranted. We have developed JAB-2485, a potent, small-molecule AURKA inhibitor with greater than 1500-fold selectivity over AURKB and AURKC. JAB-2485 efficiently induced G2/M phase cell cycle arrest and apoptosis of cancer cells in vitro. Furthermore, it showed impressive anti-tumor efficacy both as a single agent and in synergy with chemotherapies in multiple animal models.Trial designThis global first-in-human, open-label, multi-center phase 1/2a trial evaluates the safety and tolerability of JAB-2485 in adult patients with advanced solid tumors. In the dose escalation phase (phase 1), six dose levels of daily JAB-2485 (5, 10, 20, 40, 60, and 80mg) will be explored to determine the maximum tolerated dose (MTD) using a modified toxicity probability interval 2 (mTPI-2) method. After determining the recommended phase 2 dose (RP2D), the dose-expansion phase (Phase 2a) will explore the preliminary anti-tumor activity of JAB-2485 as a single agent in patients with ER+ breast cancer, triple-negative breast cancer, small cell lung cancer, and tumors harboring ARID1A mutations. The inclusion criteria for the phase 1 portion include progressive refractory advanced solid malignancy, ≥18 years of age, ECOG performance status ≤ 1, and adequate organ function. The primary endpoint is the incidence of dose-limiting toxicity (DLT) and the safety and tolerability of JAB-2485. The secondary endpoints include pharmacokinetics, overall response rate, time to, and duration, of response. Exploratory endpoints include correlative pharmacodynamic markers.Enrollment in this trial started in January 2023 in the US and April 2024 in China.Clinical trial identificationNCT05490472; CTR20223395.Legal entity responsible for the studyJacobio Pharmaceuticals Co., Ltd.FundingJacobio Pharmaceuticals Co., Ltd.DisclosureV. Florou: Financial Interests, Personal, Advisory Board, Consultant: Deciphera; Financial Interests, Personal, Advisory Board: Incyte. A. Morton: Financial Interests, Institutional, Full or part-time Employment, Employer: Jacobio Pharmaceuticals Inc. S. Liu: Financial Interests, Personal, Full or part-time Employment: Jacobio Pharmaceuticals Co., Ltd. S. Gadgeel: Financial Interests, Personal, Advisory Board: AstraZeneca, Amgen, Genentech/Roche, Bristol Myers Squibb, Pfizer, Daiichi, Mirati, Lilly, Merck, Eisai, Gilead, Regeneron, Takeda, Bayer; Financial Interests, Personal, Other, Data Safety Monitoring Board: AstraZeneca; Financial Interests, Personal, Other, Travel support to attend WCLC 2023 for oral presentation: Mirati, Merck; Financial Interests, Institutional, Local PI: AstraZeneca, Nuvalent, Tango Pharmaceuticals, Genentech/Roche, Genmab, Nimbus, Daiichi, Janssen, Amgen, Bayer, Mirati, BioAtla, Pfizer, D3 Bio, Debio Pharma, Arrivent, Grail, Iovance, Jacobio, Kymera, Keza Pharmaceuticals, AbbVie, Amgen, Novita, Regeneron, Turning Point, Verastem; Financial Interests, Institutional, Steering Committee Member: Genmab; Financial Interests, Personal, Local PI: Arcus, Effector. All other authors have declared no conflicts of interest.