Abstract B24: Pharmacokinetic and pharmacodynamic profile of the novel, oral and selective CCR2 inhibitor CCX872-B in a Phase 1B pancreatic cancer trial
Authors: Hezel Aram , Eskens Ferry , Sleijfer Stefan , Noel Marcus , Wang-Gillam Andrea , Cheng Sabrina , Potarca Antonia , Zhao Bin , Lohr Lisa , Miao Shichang , Charo Israel , Bekker Pirow , Schall Thomas J. 
Published: May 2016

Abstract
Introduction: The monocyte chemoattractant protein-1/ chemokine receptor 2 (CCR2) axis regulates the recruitment of inflammatory monocytes to sites of inflammation and cancer. CCR2 inhibition in preclinical models has resulted in diminished numbers of tumor-infiltrating immuno-suppressive macrophages and decreased pancreatic tumor size. Recently, a clinical trial with a different CCR2 inhibitor, PF-4136309, reported increased response rate from 28% historically (FOLFIRINOX alone, fluorouracil [5-FU], leucovorin, irinotecan, oxaliplatin) to 48% (FOLFIRINOX plus CCR2 inhibitor) at 12 weeks. CCX872-B is a potent, oral CCR2 inhibitor with a favorable PK profile compared to PF-4136309. In a Phase 1 healthy volunteer study, single and multiple doses of CCX872-B ranging from 3 to 300 mg were explored. CCX872-B was well-tolerated, with a dose-linear pharmacokinetic (PK) profile and dose-dependent blockade of CCR2 on circulating monocytes in receptor occupancy (RO) and internalization (RI) assays.
Experimental Procedures: This ongoing clinical trial consists of a single-dose CCX872-B regimen in Part A which has been completed in 4 patients with pancreatic adenocarcinoma, followed by a multiple dose Part B regimen in up to 50 additional patients, in combination with FOLFIRINOX therapy for up to 12 cycles. Each patient in Part A received one dose of 150 mg CCX872-B. PK, pharmacodynamics (PD), and safety were evaluated on Days 1, 4, and 8. PD was assessed via blockade of CCR2 by CCX872-B. Patient plasma obtained pre-dose, 2 hr, and 12 hr post dose was mixed with human CD14+ monocytes, and was used to measure monocyte migration at EC50 and EC90 of MCP-1, the principal ligand for CCR2, in a chemotaxis assay. Patient plasma obtained as above and mixed with human monocytes was used to measure Alexa Fluor ®-labeled MCP-1 in RO (4°C) and RI (37 °C) assays via flow cytometry.
Results: CCX872-B was well tolerated by all subjects. Mean Cmax was 8580 ng/mL, AUClast was 164,000 hr*ng/mL, and terminal t1/2 was 35h. Mean% CCR2 coverage, based on migration, RO, and RI assays, respectively, was 95%, 98%, and 95% at 2h post dose, and 86%, 84%, and 73% at 12h post dose. With an expected 4-5 fold accumulation at steady state dosing, CCR2 coverage of ≥90% is anticipated with a twice daily (BID) dosing regimen.
Conclusions: The safety, PK, and PD data of CCX872-B in pancreatic cancer patients, consistent with healthy volunteer data, support BID dosing of 150 mg CCX872-B to provide excellent CCR2 blockade in Part B of this ongoing trial. Currently, 4 patients with non-resectable pancreatic cancer have been enrolled in Part B. All patients will receive either 150 mg CCX872-B once daily or BID for at least 12 weeks combined with FOLFIRINOX for up to 12 cycles. Patients with stable disease may continue treatment beyond 12 weeks. The primary endpoint of this study is the progression free survival at week 24, aiming to improve this rate from 50% with FOLFIRINOX alone historically to at least 60%.
Citation Format: Aram Hezel, Ferry Eskens, Stefan Sleijfer, Marcus Noel, Andrea Wang-Gillam, Sabrina Cheng, Antonia Potarca, Bin Zhao, Lisa Lohr, Shichang Miao, Israel Charo, Pirow Bekker, Thomas J. Schall. Pharmacokinetic and pharmacodynamic profile of the novel, oral and selective CCR2 inhibitor CCX872-B in a Phase 1B pancreatic cancer trial. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B24.