Phase 1b study of a small molecule antagonist of human chemokine (C-C motif) receptor 2 (PF-04136309) in combination with nab-paclitaxel/gemcitabine in first-line treatment of metastatic pancreatic ductal adenocarcinoma

• DOI: 10.1007/s10637-019-00830-3
• Publication Date: 2019-07-12T01:02:56Z
• Authors: Marcus Noel; Eileen M. O’Reilly; Brian M. Wolpin; David P. Ryan; Andrea J. Bullock; Carolyn D. Britten; David C. Linehan; Brian A. Belt; Eric C. Gamelin; Bishu Ganguly; Donghua Yin; Tenshang Joh; Ira A. Jacobs; Carrie T. Taylor; Maeve A. Lowery
• Keywords: Tolerability

Background In pancreatic ductal adenocarcinoma (PDAC), the chemokine (C-C motif) ligand 2 (CCL2)/chemokine receptor (CCR2) axis plays a key role in immunosuppressive properties of tumor microenvironment, patient prognosis, and chemoresistance. This phase Ib study assessed effects orally administered CCR2 inhibitor PF-04136309 combination with nab-paclitaxel gemcitabine patients previously untreated metastatic PDAC. Methods Patients received twice daily (BID) continuously plus (125 mg/m2) (1000 on days 1, 8, 15 each 28-day cycle. The primary objectives were to evaluate safety tolerability, characterize dose-limiting toxicities (DLTs), determine recommended II dose (RP2D) PF-04136309. Results all, 21 at starting 500 mg or 750 BID. RP2D was identified be Of 17 treated BID dose, three (17.6%) experienced total four DLTs, including grade 3 dysesthesia, diarrhea, hypokalemia one event 4 hypoxia. Relative small number (n = 21), high incidence (24%) pulmonary toxicity observed this study. objective response rate for 23.8% (95% confidence interval: 8.2-47.2%). Levels CD14 + CCR2+ inflammatory monocytes (IM) decreased peripheral blood, but did not accumulate bone marrow. Conclusions had profile that raises concern synergistic show an efficacy signal above gemcitabine. ClinicalTrials.gov identifier: NCT02732938.