A multicenter, open-label phase II study to evaluate the efficacy and safety of pimicotinib (CSF-1R inhibitor) in combination with chemotherapy with or without toripalimab in patients (pts) with advanced pancreatic ductal adenocarcinoma (aPDAC)

BackgroundThe persistent low overall survival (OS) rate of aPDAC underscores an urgent need for therapeutic breakthroughs. PDAC is distinguished by a desmoplastic stroma and significant infiltration by tumor-associated macrophages (TAM). PDAC overexpresses colony-stimulating factor 1 (CSF-1) and recruits CSF-1 receptor (CSF-1R) positive macrophages, which indicates poor prognosis. Targeting CSF-1R can inhibit TAM, thereby potentially reactivating anti-tumor immunity, influencing stromal density, therefore enhancing efficacy of chemotherapy and immunotherapy. Building on the above hypothesis, this phase II study (NCT06111274) marks as the first use of an oral, highly selective, and potent CSF-1R inhibitor Pimicotinib (Pimi) in combination with chemotherapy with(out) immunotherapy as a first-line treatment in aPDAC.Trial designPts aged 18 to 75 years, diagnosed aPDAC without known BRCA mutation and received no prior systemic treatment are eligible. The study comprises two parts and two cohorts. In Part A (dose-escalation), the Bayesian optimal interval design is employed to establish recommended dose/regimen (RDE) for Part B (expansion). Cohort 1 involves Pimi starting from 25mg QD, combined with nab-paclitaxel at 125mg/m2 and gemcitabine at 1000mg/m2 on day 1 and 8, within a 21-day cycle (Q3W). Cohort 2 follows the same regimen, with additional toripalimab 240mg Q3W. Following tolerability assessment, escalation to higher doses of Pimi is feasible with additional pts. Upon establishing RDEs for both cohorts in Part A, Part B will enroll additional 20 pts per cohort. The primary endpoint, objective response rate (RECIST 1.1), will be evaluated every 6 weeks, with secondary endpoints of duration of response, progression-free survival, OS, and pharmacokinetics, to assess the impact of CSF-1R blockade on enhancing anti-tumor activities of chemotherapy and immunotherapy. The exploratory endpoints include on-target pharmacodynamics effects and the investigation of tissue biomarkers correlating with efficacy. The baseline tumor microenvironment also will be analyzed.Clinical trial identificationNCT06111274.Legal entity responsible for the studyAbbisko Therapeutics Co., Ltd.FundingAbbisko Therapeutics Co., Ltd.DisclosureAll authors have declared no conflicts of interest.