Journal of Clinical Oncology, 2009 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 27, No 15S (May 20 Supplement), 2009: e13500 © 2009 American Society of Clinical Oncology
Abstract
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
S. K. Sandhu, Dr, P. C. Fong, Dr, S. Frentzas, Dr, A. Patnaik, K. Papadopoulos, B. Tromp, T. Puchalski, B. Berns, A. W. Tolcher and J. S. De-Bono, Dr Royal Marsden Hospital, London, United Kingdom; START, San Antonio, TX; Ortho Biotech Oncology, London, United Kingdom; Ortho Biotech Oncology, London, United Kingdom; Ortho Biotech Oncology Research and Development, London, United Kingdom; South Texas Accelerated Research Therapeutics, San Antonio, TX; Institute of Cancer Research, London, United Kingdom
e13500
Background: The chemokine CCL2 promotes angiogenesis, tumor proliferation, migration and metastasis through PI3K and NFkB signaling. CNTO 888 is a human IgG1 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. http://meeting.ascopubs.org/cgi/content/abstract/27/15S/e135… xxxxxxxxxxxxxx Eine Vorstufe zum proof of concept. :-)
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