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, 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, 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

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.

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

References

    1. Ryan DP, Hong TS, Bardeesy N. Pancreatic adenocarcinoma. N Engl J Med. 2014;371:2140–2141. doi: 10.1056/NEJMc1412266.
    1. Hidalgo M. Pancreatic cancer. N Engl J Med. 2010;362:1605–1617. doi: 10.1056/NEJMra0901557.
    1. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369:1691–1703. doi: 10.1056/NEJMoa1304369.
    1. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364:1817–1825. doi: 10.1056/NEJMoa1011923.
    1. Adamska A, Domenichini A, Falasca M (2017) Pancreatic ductal adenocarcinoma: current and evolving therapies. Int J Mol Sci 18. 10.3390/ijms18071338
    1. Rodriguez D, Silvera R, Carrio R, et al. Tumor microenvironment profoundly modifies functional status of macrophages: peritoneal and tumor-associated macrophages are two very different subpopulations. Cell Immunol. 2013;283:51–60. doi: 10.1016/j.cellimm.2013.06.008.
    1. Rolinski J, Hus I. Breaking immunotolerance of tumors: a new perspective for dendritic cell therapy. J Immunotoxicol. 2014;11:311–318. doi: 10.3109/1547691X.2013.865094.
    1. Sanford DE, Belt BA, Panni RZ, et al. Inflammatory monocyte mobilization decreases patient survival in pancreatic cancer: a role for targeting the CCL2/CCR2 axis. Clin Cancer Res. 2013;19:3404–3415. doi: 10.1158/1078-0432.CCR-13-0525.
    1. Diaz-Montero CM, Salem ML, Nishimura MI, Garrett-Mayer E, Cole DJ, Montero AJ. Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy. Cancer Immunol Immunother. 2009;58:49–59. doi: 10.1007/s00262-008-0523-4.
    1. Melani C, Sangaletti S, Barazzetta FM, Werb Z, Colombo MP. Amino-biphosphonate-mediated MMP-9 inhibition breaks the tumor-bone marrow axis responsible for myeloid-derived suppressor cell expansion and macrophage infiltration in tumor stroma. Cancer Res. 2007;67:11438–11446. doi: 10.1158/0008-5472.CAN-07-1882.
    1. Yang L, DeBusk LM, Fukuda K, et al. Expansion of myeloid immune suppressor gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell. 2004;6:409–421. doi: 10.1016/j.ccr.2004.08.031.
    1. Bunt SK, Yang L, Sinha P, Clements VK, Leips J, Ostrand-Rosenberg S. Reduced inflammation in the tumor microenvironment delays the accumulation of myeloid-derived suppressor cells and limits tumor progression. Cancer Res. 2007;67:10019–10026. doi: 10.1158/0008-5472.CAN-07-2354.
    1. Sinha P, Clements VK, Bunt SK, Albelda SM, Ostrand-Rosenberg S. Cross-talk between myeloid-derived suppressor cells and macrophages subverts tumor immunity toward a type 2 response. J Immunol. 2007;179:977–983. doi: 10.4049/jimmunol.179.2.977.
    1. Srivastava MK, Sinha P, Clements VK, Rodriguez P, Ostrand-Rosenberg S. Myeloid-derived suppressor cells inhibit T-cell activation by depleting cystine and cysteine. Cancer Res. 2010;70:68–77. doi: 10.1158/0008-5472.CAN-09-2587.
    1. Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 2009;9:162–174. doi: 10.1038/nri2506.
    1. Marx J. Cancer immunology. Cancer's bulwark against immune attack: MDS cells. Science. 2008;319:154–156. doi: 10.1126/science.319.5860.154.
    1. Ostrand-Rosenberg S, Sinha P. Myeloid-derived suppressor cells: linking inflammation and cancer. J Immunol. 2009;182:4499–4506. doi: 10.4049/jimmunol.0802740.
    1. Ostrand-Rosenberg S. Myeloid-derived suppressor cells: more mechanisms for inhibiting antitumor immunity. Cancer Immunol Immunother. 2010;59:1593–1600. doi: 10.1007/s00262-010-0855-8.
    1. Huang B, Lei Z, Zhao J, et al. CCL2/CCR2 pathway mediates recruitment of myeloid suppressor cells to cancers. Cancer Lett. 2007;252:86–92. doi: 10.1016/j.canlet.2006.12.012.
    1. Huang B, Pan PY, Li Q, et al. Gr-1+CD115+ immature myeloid suppressor cells mediate the development of tumor-induced T regulatory cells and T-cell anergy in tumor-bearing host. Cancer Res. 2006;66:1123–1131. doi: 10.1158/0008-5472.CAN-05-1299.
    1. Koga M, Kai H, Egami K, et al. Mutant MCP-1 therapy inhibits tumor angiogenesis and growth of malignant melanoma in mice. Biochem Biophys Res Commun. 2008;365:279–284. doi: 10.1016/j.bbrc.2007.10.182.
    1. Nywening TM, Wang-Gillam A, Sanford DE et al (2016) Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: a single-centre, open-label, dose-finding, non-randomised, phase 1b trial. Lancet Oncol 17:651–662. 10.1016/S1470-2045(16)00078-4
    1. Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014;74:2913–2921. doi: 10.1158/0008-5472.CAN-14-0155.
    1. Pokorny AMJ, Chin VT, Nagrial AM, Yip D, Chantrill LA. Metastatic pancreatic ductal adenocarcinoma: diagnosis and treatment with a view to the future. Intern Med J. 2018;48:637–644. doi: 10.1111/imj.13810.
    1. Mitchem JB, Brennan DJ, Knolhoff BL, et al. Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses. Cancer Res. 2013;73:1128–1141. doi: 10.1158/0008-5472.CAN-12-2731.
    1. Chiorean EG, Coveler AL. Pancreatic cancer: optimizing treatment options, new, and emerging targeted therapies. Drug Des Devel Ther. 2015;9:3529–3545. doi: 10.2147/DDDT.S60328.
    1. Von Hoff DD, Ramanathan RK, Borad MJ, et al. Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol. 2011;29:4548–4554. doi: 10.1200/JCO.2011.36.5742.
    1. Sahin IH, Geyer AI, Kelly DW, O'Reilly EM. Gemcitabine-related pneumonitis in pancreas adenocarcinoma–an infrequent event: elucidation of risk factors and management implications. Clin Colorectal Cancer. 2016;15:24–31. doi: 10.1016/j.clcc.2015.08.003.
    1. Nywening TM, Belt BA, Cullinan DR, et al. Targeting both tumour-associated CXCR2(+) neutrophils and CCR2(+) macrophages disrupts myeloid recruitment and improves chemotherapeutic responses in pancreatic ductal adenocarcinoma. Gut. 2018;67:1112–1123. doi: 10.1136/gutjnl-2017-313738.

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