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/m 2) and gemcitabine (1000 mg/m 2) 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.

Whole-blood expression of inflammasome- and glucocorticoid-related mRNAs correctly separates treatment-resistant depressed patients from drug-free and responsive patients in the BIODEP study

“…If replicated in larger, longitudinal samples, this signature might be helpful in identifying patients that should be fast-tracked into augmentation regimes-potentially a step toward overcoming the classic 'trial and error' approach in treating depression. In terms of novel targets, antagonists of P2RX7 72 , JAK 73 , CCR2 74 and FKBP5 16 are all novel antidepressant tools supported by our findings. Future studies will need to examine if these new treatments work, and whether responses to such new treatments can be improved by selecting patients with abnormal levels of relevant mRNAs 75 .…”

Tumor-Associated Macrophage Status in Cancer Treatment

“…In the FOLFIRINOX group none objective response was observed [41]. On the contrary, the combination of PF-04136309 with paclitaxel and gemcitabine in metastatic pancreatic cancer displayed safety issues and had no therapeutic advantage with respect to the standard treatment [42]. The partial response to CCL2/CCR2 targeting strategies highlights that other chemokines, cytokines and growth factors contribute to the process, or may compensate the absence of CCL2/CCR2, with differences depending on the stage and the type of tumor, that hence need to be carefully evaluated for the development of effective strategies.…”

The emerging role of myeloid-derived suppressor cells in radiotherapy

“…In a phase Ib clinical trial, a CCR2 antagonist (PF-04136309) was tested in combination with nab-paclitaxel plus gemcitabine in patients with pancreatic ductal adenocarcinoma. However, the results showed that PF-04136309 did not improve the efficacy compared to nab-paclitaxel plus gemcitabine [58].…”