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Open Access 01-06-2020 | Pancreatic Cancer | PHASE I STUDIES

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

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

Published in: Investigational New Drugs | Issue 3/2020

Summary

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

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Title: 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
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
Publication date: 01-06-2020
Publisher: Springer US
Keywords: Pancreatic Cancer
Pancreatic Cancer
Published in: Investigational New Drugs / Issue 3/2020
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI: https://doi.org/10.1007/s10637-019-00830-3

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