Phase I study of CNTO 95, a fully human monoclonal antibody (mAb) to αv integrins, in patients with solid tumors

Abstract

3119 Background: Integrins of the αv family are implicated in tumor angiogenesis and growth. CNTO 95 is a fully human mAb that binds to cellular αv integrins with a KD of ∼5 nM. In a rat aortic ring angiogenesis assay CNTO 95 (∼70 nM) completely inhibited microvessel growth. In human melanoma xenograft models in nude mice and rats CNTO 95 inhibited tumor growth by ∼80% and >99%, respectively (P< 0.0005). Methods: A Phase I dose-escalating study of CNTO 95 in patients with advanced solid tumors refractory to standard therapy is ongoing. CNTO 95 was infused on days 0, 28, 35 and 42, and standard clinical assessments as well as DCE-MRI and FDG-PET were also performed. Results: Thirteen patients, with a median number of two prior systemic therapies (range 1–5), have been enrolled at 0.1, 0.3 and 1.0 mg/kg, n=7, 3 and 3, respectively. Tumor types included ovarian (6), colorectal (4), ureteric (1), PNET (1), and pseudomyxoma peritonei (1). An ileo-femoral DVT was seen in the first cohort, although this was confounded by tumor blockage of the blood supply to that patient's extremity. This cohort was expanded to 6 evaluable patients without additional DLTs. There were no other CNTO 95-related SAEs or Grade 3/4 adverse events. Three ovarian cancer patients (2 at 0.3 mg/kg, and 1 at 1 mg/kg) had stable disease (per RECIST criteria) at day 42 and remain on extended dosing. Dose escalation to a planned study maximum of 10 mg/kg continues. Single dose PK analysis showed that Cmax and AUC appeared to increase in a greater than dose proportional manner on days 1 and 42, perhaps due to a tissue or tumor binding mechanism. No accumulation was observed upon repeat dosing. Conclusions: CNTO 95 is a fully human mAb to αv integrins with anti-tumor and anti-angiogenic properties in rodents. In an ongoing Phase I trial CNTO 95 appears to be well tolerated and 3 patients are on extended therapy. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Centocor Centocor; Johnson & Johnson Centocor; Johnson & Johnson Centocor Centocor Centocor Centocor