Abstract A102: First-in-man, first-in-class, pharmacokinetic and pharmacodynamic phase I clinical trial of a human monoclonal antibody CNTO888 to CC-chemokine ligand 2 (CCL2) / monocyte chemoattractant protein (MCP-1) in patients with advanced solid tumors

Abstract

Abstract Background: The chemokine CCL2 / MCP-1 is highly expressed in multiple tumor types. Overexpression of CCL2 is associated with more advanced disease and a worse prognosis in some cancers. CCL2 plays a pivotal role in recruitment of tumor-associated macrophages and osteoclastic differentiation resulting in enhanced tumorigenesis and promotion of skeletal metastasis. CCL2 fosters angiogenesis, tumor proliferation, migration and metastasis through PI3K and NFkB signalling. CNTO888 is a human IgG1k monoclonal antibody with high CCL2 binding affinity and promising preclinical antitumor activity. Methods: CNTO888 was administered as a 90-minute infusion on days 1, 29 of cycle 1 and subsequently on a two-weekly schedule to patients with advanced solid tumors. Pharmacodynamic assessments included free and bound CCL2 levels, circulating tumor and endothelial cell enumeration, C-telopeptide levels and other markers of bone turnover. Paired tumor biopsies were mandatory in the 2nd expansion cohort to define pharmacodynamic effects in tumor. Pre- and post-treatment diffusion contrast-enhanced computed tomography studies were carried out to explore the potential antiangiogenic effects of CNTO888. Results: A total of 43 patients were treated with CNTO888: 21 patients during the dose escalation (0.3mg/kg, 1mg/kg, 3mg/kg, 10mg/kg, 15 mg/kg doses) and 22 patients in 2 dose expansion cohorts (10mg/kg and 15mg/kg doses). CNTO888 was well tolerated with mild toxicities namely fatigue, nausea, vomiting, headaches and one case of vasculitic rash. No dose limiting toxicities (DLTs) were observed. Preliminary pharmacokinetic data for CNTO888 doses ≥ 10mg/kg demonstrated dose proportional kinetics with a bi-exponential decline and t1/2 of 4.4–6.9 days. The 10mg/kg dose level achieved more than the steady-state concentrations required to inhibit chemotaxis and calcium mobilization as defined by preclinical studies. Dosedependent increases in bound CCL2 levels of > 1000-fold were demonstrated, confirming target modulation. An advanced ovarian cancer patient treated at 0.3mg/kg CNTO888 achieved a CA125 response by Gynaecologic Cancer Intergroup criteria with meaningful RECIST disease stabilisation for 10 months. A further two patients demonstrated RECIST stable disease > 6 months at 15mg/kg CNTO888 (ocular melanoma and neuroendocrine tumor). Conclusions: CNTO888 is well tolerated with no DLT. Pharmacokinetics are dose proportional, with evidence of pharmacodynamic target inhibition. The recommended phase II dose for single agent CNTO888 is 15mg/kg, every two weeks. Preliminary evidence of antitumor activity has been observed. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A102.