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 Journal Article
| Authors: | Noel, M.; O’Reilly, E. M.; Wolpin, B. M.; Ryan, D. P.; Bullock, A. J.; Britten, C. D.; Linehan, D. C.; Belt, B. A.; Gamelin, E. C.; Ganguly, B.; Yin, D.; Joh, T.; Jacobs, I. A.; Taylor, C. T.; Lowery, M. A. |
| Article 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 |
| Abstract: | 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. © 2019, The Author(s). |
| Keywords: | adult; clinical article; controlled study; human tissue; treatment response; aged; unclassified drug; human cell; constipation; drug tolerability; fatigue; neutropenia; diarrhea; drug efficacy; drug potentiation; drug safety; gemcitabine; paclitaxel; cancer incidence; cancer grading; controlled clinical trial; lung toxicity; multiple cycle treatment; pain; anemia; leukopenia; nausea; thrombocytopenia; vomiting; peripheral neuropathy; cohort analysis; continuous infusion; abdominal pain; chill; fever; hyperglycemia; lymphocytopenia; rash; hypoxia; hypokalemia; insomnia; malaise; blood sampling; peripheral edema; pancreas adenocarcinoma; liver disease; headache; pancreatic cancer; phase 1 clinical trial; drug cytotoxicity; monocyte; alopecia; chemokine receptor ccr2; cd14 antigen; primary health care; cellulitis; dysesthesia; body weight disorder; immuno-oncology; chemokine receptor ccr2 antagonist; human; male; female; priority journal; article; loss of appetite; tumor-infiltrating macrophages; ccr2 inhibitor; tumor-infiltrating cells; pf 04136309 |
| Journal Title: | Investigational New Drugs |
| Volume: | 38 |
| Issue: | 3 |
| ISSN: | 0167-6997 |
| Publisher: | Springer |
| Date Published: | 2020-06-01 |
| Start Page: | 800 |
| End Page: | 811 |
| Language: | English |
| DOI: | 10.1007/s10637-019-00830-3 |
| PUBMED: | 31297636 |
| PROVIDER: | scopus |
| PMCID: | PMC7211198 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 June 2020 -- Source: Scopus |
