First-in-human, first-in-class, phase I study of a human monoclonal antibody CNTO 888 to the CC-chemokine ligand 2 (CCL2/MCP-1) in patients with solid tumors

Abstract

e13500 Background: The chemokine CCL2 promotes angiogenesis, tumor proliferation, migration and metastasis through PI3K and NFkB signaling. CNTO 888 is a human IgG1κ monoclonal antibody with high binding affinity for CCL2 and documented preclinical antitumor activity. Methods: Patients were administered a 90 minute infusion of CNTO 888 on day 1, day 28 and subsequently on a q14 schedule. Exploratory PD assessments include diffusion contrast enhanced CT, circulating tumor and endothelial cells, free and bound CCL2 levels, bone markers and paired tumor biopsies. Results: 21 patients in cohorts of 3–6 patients received repeated CNTO 888 infusions at 5 dose levels (0.3mg/kg, 1mg/kg, 3mg/kg, 10mg/kg, 15 mg/kg). A further 23 patients are currently being evaluated in 2 expansion cohorts; 10mg/kg (n=12) and 15mg/kg (n=11). No dose limiting toxicities were seen up to 15 mg/kg q14. Preliminary pharmacokinetic (PK) data for doses ≤ 10 mg/kg showed linear kinetics with a bi-exponential decline and a t1/2 of 4.4 - 8.7 days. The 10 mg/kg dose level resulted in steady-state minimum concentrations above that needed to inhibit chemotaxis and calcium mobilization in preclinical studies. Dose-dependent increase in bound CCL2 levels of > 1000-fold seen following treatment, supports target modulation. 2 patients demonstrated stable disease (SD) > 6 months at 15mg/kg CNTO 888 (ocular melanoma and neuroendocrine tumor). Another patient at 0.3mg/kg CNTO 888 with ovarian cancer had 50% CA125 decline and SD for 10 months. Conclusions: CNTO 888 is well tolerated with no DLTs when administered up to 15mg/kg q14. Preliminary evidence of antitumor activity is reported. [Table: see text]