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Abstract Background: Narmafotinib (AMP945) is a selective and orally bioavailable inhibitor of Focal Adhesion Kinase (FAK). FAK plays a key role in tumour growth, particularly in immunosuppression, cancer cell invasion and metastasis, and contributes to multiple mechanisms underlying fibrosis. In the Phase 1 study (healthy volunteers) narmafotinib was safe and well tolerated across single ascending dose (15 to 125 mg) and multiple ascending doses for 7 days (25 to 100 mg), with PK/PD data demonstrating wide tissue distribution and target engagement. Methods: ACCENT trial (NCT05355298) is a Phase 1b/2a, open label study of the pharmacokinetics, safety and efficacy of narmafotinib in combination with gemcitabine and nab-paclitaxel (Abraxane) standard of care as first-line therapy in patients with advanced pancreatic cancer. The trial is a single-arm open label study conducted in two stages. In Part A, patients were enrolled in a 3+3 design to determine the narmafotinib recommended Phase 2 dose (RP2D), with narmafotinib dose-escalation (100, 200 and 400 mg). Part B is a Simon’s two stage design, with the primary objectives of assessing safety, tolerability, and efficacy of the combination using RECIST v1. 1 (centrally by independent reviewers). Narmafotinib plasma PK samples were collected on Days -8, -7, 1, 3, 8, and 10 of Run-In/Cycle 1. Safety and tolerability were assessed according to incidence and severity of adverse events. Imaging was conducted every 2 months. Results: Preliminary analysis across all doses (14 patients) showed narmafotinib to be generally safe and well-tolerated and showed promising signs of efficacy. At first on study imaging (Day 56), 86% of patients had stable disease and 12% had a partial response (PR). Subsequent RECIST assessments conducted locally at sites showed PR in 47% of patients. A single DLT was reported: uncontrolled grade 3 nausea (400 mg cohort). Fatigue, grade 3 or below was related to narmafotinib occurred in more than one participant. All patients who completed their first 28-day cycle of treatment elected to stay on narmafotinib, with 7 patients receiving narmafotinib in combination with chemotherapy for 5 months or more. The PK for narmafotinib is dose-proportional across the dose range tested, and the half-life supports once a day dosing. The chemotherapy regimen used in this study did not impact narmafotinib PK. Conclusions: Based on this promising Phase 1b data, 400 mg of narmafotinib has been selected for RP2D and the trial will proceed through Simon’s Two Stage design and enrol up to 50 patients as part of the Phase 2 expansion cohort. Citation Format: Terrie-Anne Cock, Anthony Bishop, Nicole Kruger, Sarah McCormack, Marion Harris, Sumitra Ananda, Lara Lipton, Adnan Nagrial, Nick Pavlakis, Warren Joubert, Laura Donato, Jason Lickliter, Christopher Burns. Phase 1b/2a of narmafotinib (AMP945) in combination with gemcitabine and nab-paclitaxel (Abraxane) standard of care as first-line therapy in patients with advanced pancreatic cancer (ACCENT trial): interim analysis abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (7Suppl): Abstract nr CT220.
Cock et al. (Fri,) studied this question.