CCL2/CCR2 plays a key role in immunosuppressive properties of the pancreatic adenocarcinoma tumor microenvironment (TME), patients’ (pts) prognosis and chemoresistance. PF-04136309 (oral CCR2 inhibitor) blocks recruitment and migration of inflammatory monocytes (IM) from bone marrow (BM) to TME.
This ongoing multicentre phase Ib study is investigating PF-04136309 in combination with nab-paclitaxel and gemcitabine (nab-P+Gem) in pts with previously untreated metastatic pancreatic ductal adenocarcinoma (mPDAC). Objectives; primary: safety, tolerability, maximum tolerated dose, recommended dose; secondary: pharmacokinetics (PK), pharmacodynamics of PF-04136309; exploratory: efficacy, proof of mechanism (POM), as CCR2 inhibition trapped IMs in BM and decreased IMs in peripheral blood and metastatic tumor tissue with paired tumor biopsies and bone marrow aspirates at baseline and after 1 or 2 cycles.
From May 1, 2016–March 17, 2017, 21 pts (ECOG PS 0-1; mean age 61.8 yrs; range 46-79) received PF-04136309. Cohort 1, starting dose level: 1 grade 3 drug-related DLT (cognitive disorder), 1 grade 2 and 2 grade 1 rashes. Cohort 2 (1 dose level reduction): 4 (23.5%) grade 3 drug-related DLT (1 scalp dysesthesia, 1 ALT-AST, 1 pneumonia, 1 pneumonitis). Recommended total daily dose 1000mg. With median duration of treatment of 4 mo (1–9), grade ≥3 drug-related AEs: neutropenia 3 (17.6%), fatigue 4 (23.5%), diarrhea 1 (5.9%), lung toxicities 3 (17.6%); % pts with dose-reduction: nab-P 47%, Gem 53%, PF-04136309 41%; median relative dose intensity: nab-P 84%, Gem 67%, PF-04136309 80%. Early objective response in 10 evaluable pts: PR 6 (60%), SD 1 (10%), PD 3 (30%). Disease control rate at 4 mo: 70%. Median PFS not reached (8 pts on treatment). PF-04136309 PK was consistent with previous single agent studies. Almost all had a drop in peripheral blood CD14+CCR2+ monocytes (baseline-Day 15). IMs decreased and CD4+ and CD8+ T cells increased (5–8 fold) in paired biopsy samples. One of 2 pts had increased tumor associated PD1+CD4+ and PD-1+CD8+ T cells.
Encouraging safety, favorable PK, clinical responses and POM with CCR2 inhibition plus nab-P+Gem in mPDAC pts.
Clinical trial identification
Legal entity responsible for the study
M. Noel: Speaker’s bureau for Taiho Oncology. M. Lowery: Advisory board: Agios Pharmaceuticals, Celgene. D. Ryan: MPM Capital. C. Britten: Research paid to institution: Pfizer. B. Jin, C.T. Taylor, B.J. Ganguly, D. Yin, E.C. Gamelin, D.A. Wunderlich: Employee and stockholder of Pfizer Inc. All other authors have declared no conflicts of interest.