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Clinical Trial
. 2020 Jun;38(3):800-811.
doi: 10.1007/s10637-019-00830-3. Epub 2019 Jul 12.

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

Marcus Noel  1 , Eileen M O'Reilly  2 , Brian M Wolpin  3 , David P Ryan  4 , Andrea J Bullock  5 , Carolyn D Britten  6 , David C Linehan  7 , Brian A Belt  8 , Eric C Gamelin  9 , Bishu Ganguly  9   10 , Donghua Yin  9 , Tenshang Joh  9 , Ira A Jacobs  11 , Carrie T Taylor  9 , Maeve A Lowery  12
Affiliations
Clinical Trial

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

Marcus Noel et al. Invest New Drugs. 2020 Jun.

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.

Keywords: CCR2 inhibitor; Immuno-oncology; Pancreatic cancer; Tumor-infiltrating cells; Tumor-infiltrating macrophages.

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Conflict of interest statement

MN is a consultant of Celgene and Taiho Oncology. CDB has received research funding to her institution from Pfizer, Eli Lilly, Celgene, EMD Serono, Five Prime, Regeneron, Tesaro, and Halozyme, and travel paid for by Five Prime, Genentech, and Amgen. EOR has received research funding to her institution from Pfizer, Celgene, Mabvax, Actabiologica, and Halozyme, and is a consultant and member of advisory panels for Celgene, Targovax, and Roche. BMW has received research funding from Celgene, and is a consultant of G1 Therapeutics, BioLineRx, and GRAIL. DR is an advisor of MPM Capital. DR is an advisor and stockholder of MPM Capital, an advisor for Oncorus and Gritsone Oncology, received royalties from Johns Hopkins University Press, Uptodate, and McGraw Hill and funding from Pfizer. DCL has received research funding to his institution from Pfizer. AJB is an advisor for Bayer, Halozyme, Taiho, and Exelixis. ML is a consultant and member of advisory boards for Celgene and Agios pharmaceuticals. ECG, DY, TH, IAJ, and CTT are employees of and hold shares in Pfizer. BG holds shares in Pfizer and is an employee of, and holds stock options in Lyell Immunopharma.

Figures

Fig. 1
Fig. 1
Clinical response. a Bar plot for duration of treatment by dose level (including response, dose reduction, and DLT). mITT population was analyzed. Only the first time of dose reduction is presented. Each bar represents one patient in the study. Duration was calculated as follows: (last dose date – first dose date +1) / 7. b Waterfall plot of tumor size percent change data. mITT population was analyzed. Largest decrease or smallest increase represents best response to treatment. Only patients with target lesions at baseline and at least one post-baseline target lesion based on investigator assessment per RECIST version 1.1 are included (n = 18). Abbreviations: BID twice daily, DLT dose-limiting toxicity, DR dose reduction, In indeterminate, mITT modified intent-to-treat, PD progressive disease, PR partial response, RECIST Response Evaluation Criteria in Solid Tumors, SD stable/no response, Un PR unconfirmed partial response
Fig. 2
Fig. 2
Effect of PF-04136309 in combination with nab-paclitaxel/gemcitabine on the CCL2 pathway. a and b Plasma CCL2 levels of individuals were examined by an immunoassay using a luminex-based method. c and d Individual plots of CCL2-induced pERK by treatment group. Target engagement was measured by an ex vivo CCL2-induced pERK assay. a and c treatment group: 750 mg BID PF-04136309 + nab-paclitaxel/gemcitabine. b and d treatment group: 500 mg BID PF-04136309 + nab-paclitaxel/gemcitabine. Each symbol represents individual patient. Abbreviations: BID twice daily, C cycle, CCL2 the chemokine (C-C motif) ligand 2, D day, EOT end of treatment, Fl fluorescence intensity, F-U follow-up, H hour, nab-P/gem nab-paclitaxel/gemcitabine, pERK phosphorylated extracellular signal regulated kinase phosphorylation, PRE before treatment
Fig. 3
Fig. 3
Changes of immune cell levels in the peripheral blood, bone marrow, or tumor after dosing with PF-04136309 in combination with nab-paclitaxel/gemcitabine. Changes of CD14+ CCR2+ monocytes in patients with (a) best response of stable disease or partial response or (b) patients with progressive disease, serious adverse event, or withdrawn from study. c Percentage change of CCR2+ monocytes in the bone marrow. Bar represents SEM. d Percentage of CD8+, CD4+, and CD4 + FoxP3+ T cells in biopsy samples at baseline and week 6. Each symbol represents individual patient. Abbreviations: AE adverse event, CCR2 chemokine (C-C motif) receptor 2, EOT end of treatment, nab-P/gem nab-paclitaxel/gemcitabine, SEM standard error of mean; Treg regulatory T cell
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