Ccx872: Pharmacodynamic Study Of A Potent And Selective Ccr2 Antagonist In Human Volunteers And Plans For Phase Ib Trial In Patients With Pancreatic Cancer

Recent clinical results have highlighted the importance of myeloid-derived suppressor cells in enhancing the ability of the host immune system to limit the growth of tumors. Chemokine receptors control the directed trafficking and persistence of peripheral blood mononuclear cells, including effector and suppressor cells, to the tumor microenvironment. Myeloid derived suppressor cells in particular express high levels of the chemokine receptor CCR2, and pre-clinical data suggests that CCR2 plays an important role in the recruitment of these suppressor cells to tumors. Here we report pharmacodynamic details of a potent and selective small molecule antagonist of CCR2, CCX872, and our plans for a phase Ib trial in patients with pancreatic cancer. CCX872 has been successfully evaluated in a phase I single and multiple ascending dose study (3 to 300 mg) in 40 healthy volunteers. All dose levels were well tolerated and safe. CCX872-B showed a dose-linear PK profile. Ex vivo CCR2 occupancy and internalization assays revealed that blood monocytes from CCX872, but not placebo-treated subjects, were impaired in their ability to bind to or internalize exogenously added CCL2, indicating that CCX872 blocked CCR2 in the treated subjects. The 300 mg daily dose of CCX872 exhibited 104 ± 3% blockade at 2 hours and 93 ± 7% blockade at 24 hours. We calculated that 150 mg twice a day would provide over 90% CCR2 inhibition at all times. Analysis of data from the Tumor Cancer Genome Atlas revealed high levels of expression of CCL2 in pancreatic tumors, and co-expression of CCR2 with monocyte/macrophage markers such as CD68 and CSF1R. In pre-clinical studies, we found that a CCR2 antagonist reduced the growth of the pancreatic tumor cell line, PancO2, in rodent xenograft models. Based in part on these data we have initiated a phase Ib single arm, open label, multicenter study of CCX872 in patients with un-resectable pancreatic cancer. In Part A, subjects will receive a single dose of CCX872 for pharmacokinetic and pharmacodynamics analyses. In Part B, up to 50 subjects will be treated for at least 12 weeks with CCX872 in addition to FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin). Responders and those with stable disease after 12 weeks will continue treatment until disease progression, unacceptable toxicity or death. The primary endpoints are safety/tolerability and efficacy (progression-free rate at 6 months based on RECIST criteria). Other endpoints include overall survival, and effect on the tumor microenvironment and immunological biomarkers in the blood. This trial will test the hypothesis that CCR2 plays an important role in enabling the myeloid suppressor cell response to pancreatic cancer, and will determine if addition of a CCR2 antagonist can enhance the standard of care for these patients Citation Format: Anne-Marie Duliege, Stefan Sleijfer, Ashley Bischof, Joanne Tan, Penglie Zhang, Lisa Seitz, Daniel Dairaghi, Pirow Bekker, Israel Charo, Thomas Schall. CCX872: Pharmacodynamic study of a potent and selective CCR2 antagonist in human volunteers and plans for phase Ib trial in patients with pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT223. doi:10.1158/1538-7445.AM2015-CT223