CCR2-targeted therapy with investigational PF-04136309 in combination with FOLFIRINOX (fluorouracil, leucovorin, irinotecan, oxaliplatin) chemotherapy is safe and tolerable in patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma.1
Preclinical models have demonstrated that blockade of CCR2, which plays a role in the recruitment of tumor-associated macrophages for construction of an immunosuppressive tumor microenvironment, restores anti-tumor immunity in pancreatic cancer.
Therefore, researchers sought to establish the safety, tolerability, and recommended phase 2 oral dose of the CCR2 inhibitor PF-04136309 in combination with FOLFIRINOX.
For the single-center, open-label, dose-finding, phase 1b study, researchers enrolled 47 treatment-naïve patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma.
Patients were assigned to receive either FOLFIRINOX alone (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2, and bolus fluorouracil 400 mg/m2, followed by 2400 mg/m2 46-hour continuous infusion), administered every 2 weeks for 6 cycles, or in combination with oral PF-04136309, given at a starting dose of 500 mg twice daily, both for 12 weeks.
Researchers determined that the 500 mg twice daily dose would be the recommended phase 2 dose for PF-04136309.
Results showed that the most common grade 3 or worse adverse events in the CCR2 inhibitor group were neutropenia, febrile neutropenia, lymphopenia, diarrhea, and hypokalemia.
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Two patients discontinued combination therapy due to treatment-related toxicities compared with 1 patient in the FOLFIRINOX alone group. Of note, no treatment-related death occurred.
In regard to activity, 49% of the 33 receiving FOLFIRINOX plus PF-04136309 who had undergone repeat imaging achieved an objective response, with 97% of the 33 patients achieving local tumor control. No patients in the chemotherapy alone group achieved an objective response, but 80% had stable disease.
- Nywening TM, Wang-Gillam A, Sanford DE, et al. 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 [published online ahead of print April 4, 2016]. Lancet Oncol. doi: 10.1016/S1470-2045(16)00078-4.