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

摘要: Summary Background In pancreatic ductal adenocarcinoma, the CCL2–CCR2 chemokine axis is used to recruit tumour-associated macrophages for construction of an immunosuppressive tumour microenvironment. This pathway has prognostic implications in cancer, and blockade CCR2 restores anti-tumour immunity preclinical models. We aimed establish safety, tolerability, recommended phase 2 oral dose inhibitor PF-04136309 combination with FOLFIRINOX chemotherapy (oxaliplatin irinotecan plus leucovorin fluorouracil). Methods did this open-label, dose-finding, non-randomised, 1b study at one centre USA. enrolled treatment-naive patients aged 18 years or older borderline resectable locally advanced biopsy-proven Eastern Cooperative Oncology Group performance status 1 less, measurable disease as defined by Response Evaluation Criteria Solid Tumors version 1.1, normal end-organ function. Patients were allocated receive either alone 85 mg/m , 180 400 bolus fluorouracil followed 2400 46-h continuous infusion), administered every weeks a total six treatment cycles, PF-04136309, starting 500 mg twice daily standard 3 + 3 de-escalation design. Both simultaneously initiated duration 12 weeks. The primary endpoints FOLFIRINOX, expansion planned dose. analysed outcome intention treat. trial registered ClinicalTrials.gov, number NCT01413022. Results Between April 19, 2012, Nov 12, 2014, we treated 47 (n=8) (n=39). One patient had dose-limiting toxic effect group receiving (n=6); was established pooled expansion-phase (n=33) those that received assessment treatment-related toxicity. Six (75%) eight assessed toxicity, after exclusion two (25%) due insurance coverage issues. median follow-up toxicity 72·0 days (IQR 49·5–89·0) 77·0 (70·0–90·5) group. No deaths occurred. Two (5%) stopped earlier than effects. Grade 3 higher adverse events reported least 10% included neutropenia (n=27), febrile (n=7), lymphopenia (n=4), diarrhoea (n=6), hypokalaemia (n=7). (n=1), anaemia (n=2), hypoalbuminaemia (n=3). Therapy terminated because (17%) alone. 16 (49%) 33 who undergone repeat imaging achieved objective response, local control 32 (97%) patients. group, none five although four (80%) stable disease. Interpretation CCR2-targeted therapy safe tolerable. Funding Washington University–Pfizer Biomedical Collaborative.