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

Investigational New Drugs - Tập 38 Số 3 - Trang 800-811 - 2020
Marcus Smith Noel1, Eileen M. O’Reilly2, Brian M. Wolpin3, David P. Ryan4, Andrea J. Bullock5, Carolyn D. Britten6, David C. Linehan7, Brian A. Belt8, Éric Gamelin9, Bishu Ganguly9, Dong Yin9, Tenshang Joh9, Ira Jacobs9, Carrie Turich Taylor9, Maeve A. Lowery10
1Department of Medicine, Division of Hematology/Oncology, University of Rochester Medical Center School of Medicine & Dentistry, Rochester, NY, USA
2Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY, USA
3Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
4MGH Cancer Center, Division of Hematogy-Oncology, Massachusetts General Hospital, Boston, MA, USA
5Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA
6Division of Hematology/ Oncology, Medical University of South Carolina, Charleston, SC, USA
7Department of Surgery, University of Rochester Medical Center School of Medicine & Dentistry, Rochester, NY, USA
8Department of Surgery, University of Rochester, Rochester, NY, USA
9Early Oncology Development and Clinical Research, Pfizer Inc, 219 East 42nd Street, New York, NY, 10017, USA
10Trinity St James’s Cancer Institute, Trinity College Dublin, Dublin, Ireland

Tóm tắt

SummaryBackground 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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Investigational New Drugs

Tập 38 Số 3

800-811

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