Phase 1b study targeting tumour associated macrophages with CCR2 inhibition plus FOLFIRINOX in locally advanced and borderline resectable pancreatic cancer

By T. Nywening, A. Wang-Gillam, Dominic E. Sanford, B. Belt, R. Panni, Brian M Cusworth, A. Toriola, Rebecca Nieman, Lori A Worley, M. Yano and 11 more. The Lancet Oncology, 2016

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Background Pancreatic ductal adenocarcinoma utilizes the CCL2/CCR2 chemokine axis to facilitate recruitment of tumor associated macrophages to sculpt an immunosuppressive tumor microenvironment. This pathway has prognostic implications in pancreas cancer, and blockade of CCR2 restores anti-tumor immunity in pre-clinical models. This provided the rationale for a clinical study in pancreatic adenocarcinoma to determine the safety and recommended phase 2 oral dosage of the CCR2 inhibitor PF-04136309 in combination with chemotherapy (FOLFIRINOX). Methods In this single-center, open label, phase Ib clinical trial patients age ≥ 18 years with treatment naïve borderline resectable or locally advanced, biopsy-proven pancreatic ductal adenocarcinoma, Eastern Cooperative Oncology Group performance status <2, measurable disease by Response Evaluation Criteria in Solid Tumors Version 1.1, and normal end organ function were eligible for enrollment. FOLFIRINOX (oxaliplatin, 85 mg/m2; irinotecan, 180 mg/m2; leucovorin, 400 mg/m2, and bolus fluorouracil 400 mg/m2 followed by 2,400 mg/m2 46 hour continuous infusion) was administered every 2 weeks for a total of six treatment cycles. To determine the recommended phase 2 dose, PF-04136309 was orally administered at a starting dose of 500 mg twice daily in a standard 3+3 dose de-escalation design with an expansion phase planned at the recommended phase 2 dose. Both FOLFIRINOX and PF-04136309 were simultaneously initiated with a total treatment duration of 3 months. The primary endpoints were to determine the recommended phase 2 dose and toxicity of PF-04136309 in combination with FOLFIRINOX. All patients in the dose de-escalation and expansion phase received the recommended phase 2 dose of PF-04136309 were combined for assessment of treatment toxicity by an intention to treat analysis. For tissue specimen comparison in corollary studies, a group of patients receiving FOLFIRINOX alone were enrolled and evaluated for treatment related toxicity. This study has been completed and is registered at ClinicalTrials.gov; number NCT01413022. Results From April 19th, 2012 through November 12th, 2014 a total of 47 patients were enrolled. The dose de-escalation group (n=6) received PF-04136309 at 500 mg administered orally twice daily. No dose-limiting toxicities were observed and this was established as the recommended phase 2 dose. The expansion phase cohort (n=33) and patients in the dose de-escalation arm receiving PF-04136309 at the recommended phase 2 dose (n=6) were combined for assessment of treatment related toxicity. No therapy related deaths occurring during the study interval. Early termination as the result of treatment related toxicity occurred in 2 of the 39 patients (5%) in the FOLFIRINOX plus PF-04136309 arm. Grade ≥3 adverse events reported in ≥10% of the patients receiving PF-04136309 included neutropenia in 27 patients (69%), febrile neutropenia in 7 patients (18%), lymphopenia in 4 patients (10%), diarrhea in 6 patients (15%), and hypokalemia in 7 patients (18%). Among patients receiving FOLFIRINOX alone (n=8), a total of 6 patients were evaluated for treatment toxicity, with 2 patients receiving the intended therapy but not monitored for adverse events due to insurance coverage issues and excluded. Therapy was terminated due treatment related toxicity in 1 of the 6 patients (17%) receiving FOLFIRINOX alone. Grade ≥3 adverse events reported in ≥10% of patients receiving FOLFIRINOX alone were neutropenia in 6 cases (100%), febrile neutropenia in 1 case (17%), anemia in 2 cases (33%), lymphopenia in 1 cases (17%), diarrhea in 2 cases (33%), hypoalbuminemia in 1 case (17%), and hypokalemia in 3 cases (50%). An objective tumor response was seen in 16 of 33 patients (49%) receiving FOLFIRINOX plus PF-04136309 that had repeat imaging available, with local tumor control achieved in 32 of 33 patients (97%). In the FOLFIRINOX alone arm there were no objective responses among 5 patients with repeat imaging, with 4 out of 5 patients (80%) demonstrating stable disease. Interpretation CCR2 targeted therapy with PF-04136309 in combination with FOLFIRINOX is safe and tolerable. Corollary studies suggest that CCR2 blockade reduces TAM and alters the TME, providing rationale for future clinical studies of this promising treatment modality.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/cef3473f78354c5817d829b45e0aa8da7ea1523f

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