Orally administered CCR2 selective inhibitor CCX872-b clinical trial in pancreatic cancer.

Abstract

276 Background: CCR2 inhibition decreases tumor-associated macrophages and Treg cells, and increases CD8+ and CD4+ T cells in pancreatic tumors. Single oral doses of 150 mg CCX872-B were well tolerated in patients with pancreatic cancer. The first stage results of the multiple dose part of this study are presented. Methods: Patients with locally advanced or metastatic pancreatic cancer, ECOG score ≤ 2 were studied. Patients received FOLFIRINOX (fluorouracil [5-FU], leucovorin, irinotecan, oxaliplatin) q2weeks for up to 24 wks plus 150 mg CCX872-B once or twice daily until disease progression or intolerance to CCX872-B. The primary efficacy endpoint is progression-free survival (PFS) at 24 wks. Tumor control rate (TCR) and the objective response rate (ORR), a secondary endpoint, are presented. Results: Fifty patients were enrolled. Baseline: Mean ± SD age: 60 ± 8.6 years, male 52%; primary tumor location: head 57%, body/tail 41%, local recurrence 2%; metastatic disease 78%, ECOG score 0: 62%, ECOG score 1: 38%. Thirty five of 50 patients completed week 12. Most common reasons for early withdrawal were subject request (5 pts) and adverse events typically associated with FOLFIRINOX (4 pts). In the pre-specified analysis population, i.e., those with ≥ 1 post baseline CT scan, tumor control at wk 12 was achieved in 32 of 41 (78%) patients, with 15 of 41 (37%) partial responders, and 17 of 41 (41%) with stable disease. The ORR was 37% (all partial responders) in the primary analysis population (30% when all enrolled patients were included). Thirteen of 21 patients with available CT scan results at week 24 were progression-free. Mean trough CCX872 plasma level was ~8 μg/mL. CCR2 was covered 88% on average by CCX872-B based on receptor occupancy assays. CCX872-B appeared to be well tolerated and the incidence of ≥ Gr 3 AEs was not increased with CCX872-B plus FOLFIRINOX vs historical data with FOLFIRINOX alone. The complete set of PFS data will be available by the end of 2016. Conclusions: CCX872-B plus FOLFIRINOX resulted in a TCR of 78% and an ORR of 30 to 37% with no safety issues ascribed to CCX872-B use. Clinical trial information: NCT02345408.

Dectin-2–induced CCL2 production in tissue-resident macrophages ignites cardiac arteritis

“…Our findings demonstrate that Candida PAMPs initiate arteritis by activating TRMs in the aortic root and inducing chemokine and cytokine production in a mouse model of vasculitis resembling KD. Several case reports have shown promising results using the IL-1R antagonist Anakinra to treat KD (57,58) and new therapeutics that target the CCL2/CCR2 chemokine axis are currently in clinical trials for cancer (59,60). Finally, Syk inhibitors are available and have been in clinical trials for the treatment of rheumatoid arthritis (61).…”

Tumor-associated macrophages in tumor metastasis: biological roles and clinical therapeutic applications

“…Encouragingly, preliminary clinical benefit has been observed in a phase Ib trial evaluating the safety and effectiveness of CCX872, an orally administered CCR2 inhibitor, in patients with advanced pancreatic cancer. According to the data announced in January 2018, 29% patients receiving CCX872 and FOLFIRINOX combination therapy survived at the 18th month, more favorable than previously published OS rates of 18.6% at 18th month using FOLFIRINOX alone [132, 133]. Furthermore, a number of agents, such as CCL2 inhibitor bindarit, anti-CCL2 mAb carlumab, CSF1 inhibitor GW2580, and dequalinium-14, have been confirmed of potent and sustained anti-tumor activities via declining macrophages infiltration in a battery of cell lines and xenograft models [156–160].…”

“…It was reported that both small molecular inhibitors and antibodies targeting either CCL2/CCR2 or CSF-1/CSF-1R signaling axis obviously inhibited the mobilization of monocytes and macrophages accumulation in tumor sites. As a matter of fact, several inhibitors and antibodies targeting the TAM recruiting factors are being evaluated in early clinical trials across various types of tumor [132, 133, 154, 155]. For example, emactuzumab (RG7155) is a novel humanized antibody targeting CSF-1R in both ligand-dependent and ligand-independent manners [154].…”

Tuning the Tumor Myeloid Microenvironment to Fight Cancer

“…NOX-E36 therapy in a mouse tumor model inhibited the infiltration of tumor-associated macrophages leading to significant changes of the TME and a reduction in liver tumor burden (126). The small molecule inhibitor CCX-872, which targets CCR2, is currently in the clinic for the treatment of patients with advanced and metastatic pancreatic cancer (NCT02345408), and data from the ongoing Phase Ib trial demonstrated promising safety and overall survival with the CCX872 and FOLFIRINOX combination therapy compared to FOLFIRINOX alone (127, 128).…”