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

Abstract

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...

Pancreatic Cancer Genomes: Implications for Clinical Management and Therapeutic Development

“…Inhibiting the CCR2-CCL2 axis modulates both T and non-T cell immune mechanisms, potentially leading to enhanced response in combination with cytotoxic chemotherapy (74). Intriguingly, it appears that myeloid cell depletion is crucial to inducing durable anti-tumor immune responses (73,74,77).…”

“…Inhibiting the CCR2-CCL2 axis modulates both T and non-T cell immune mechanisms, potentially leading to enhanced response in combination with cytotoxic chemotherapy (74). Intriguingly, it appears that myeloid cell depletion is crucial to inducing durable anti-tumor immune responses (73,74,77). With increasing immunotherapies becoming available and entering clinical trials, there is an urgent need to identify biomarkers of response to stratify patients to effective immunotherapy combinations at appropriate time-points in the tumor life-span.…”

Immunotherapy in gastrointestinal cancers

“…In a phase 1b trial of borderline resectable and locally advanced PDAC, the small molecule CCR2 inhibitor PF-04136309, in combination with FOLFIRINOX, was safe and tolerable, and displayed an objective tumor response of 49% (16/33 patients), compared to zero of five patients treated with FOLFIRINOX alone. As expected, the addition of PF-04136309 resulted in a re-distribution of CCR2-positive monocytes from the peripheral blood to the bone marrow compartment (the opposite of that seen with FOLFIRINOX alone) and an approximate 4-fold decrease in the number of tumor-associated macrophages (TAM), a 2-fold increase in the number of CD4 + and CD8 + T cells, and nearly a 6-fold decrease in the number of Tregs in tumors compared to FOLFIRINOX alone (48). This work lays the foundation for further investigation into CCR2 modulation in pancreatic cancer.…”

Small Molecules Drive Big Improvements in Immuno‐Oncology Therapies

“…The CCL2‐CCR2 axis is important for the recruitment of tumor‐associated macrophages in pancreatic ductal adenocarcinoma and leads to an immunosuppressive tumor microenvironment. Further preclinical models also demonstrated that blockade of CCR2 can lead to recovery of antitumor immunity 78. The orally bioavailable CCR2 inhibitor PF‐4136309 ( 34 , Pfizer, Figure 19) was investigated in a phase I study in combination with the FOLFIRINOX chemotherapy regimen in patients with borderline resectable and locally advanced pancreatic adenocarcinoma.…”

“…The orally bioavailable CCR2 inhibitor PF‐4136309 ( 34 , Pfizer, Figure 19) was investigated in a phase I study in combination with the FOLFIRINOX chemotherapy regimen in patients with borderline resectable and locally advanced pancreatic adenocarcinoma. The compound was reported to be safe, and an improvement in tumor response could be observed 78, 79. PF‐413609 is also being tested in a phase Ib/II study in combination with Gemcitabine and Nab‐Paclitaxel in first‐line metastatic pancreatic patients 80.…”