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

Abstract

3113 CNTO 95 is a fully human anti-αvintegrin antibody that inhibits the growth of human melanoma xenografts in nude mice and rats by ∼80% and >99%, respectively. The objective of this phase I dose-escalating study was to assess the safety and pharmacokinetics of CNTO 95 in patients with advanced refractory solid tumors. CNTO 95 was infused on days 0, 28, 35 and 42 and standard clinical assessments, DCE-MRI, and FDG-PET were performed. Twenty four patients were enrolled at 0.1, 0.3, 1, 3 and 10 mg/kg. Tumor types included ovarian (6), colorectal (9), angiosarcoma (2), ureteric (1), PNET (1), pseudomyxoma peritonei (1), endometrial (1), metastatic melanoma (1), renal cell carcinoma (1), and carcinosarcoma (1). CNTO95 was associated with one episode of grade III and several episodes of grade II infusion-related fever, which were controllable with acetaminophen. One patient with cutaneous angiosarcoma dosed at 10 mg/kg had a partial response that is ongoing after 2 months on extended treatment (10 mg/kg). A lesion in a patient with ovarian carcinosarcoma and stable disease (10mg/kg) was undetectable on FDG-PET at day 49. Exploratory DCE-MRI analysis indicated a non-dose dependent decrease in area under the gadolinium curve in some patients. Preliminary PK data indicated that drug exposure increased in a greater than dose propor tional manner with dose dependent half-life ranging from 0.19 to 11.81 days over the doses 0.1–10 mg/kg. The initial rapid clearance is probably due to tissue binding at low doses (< 3 mg/kg). At higher doses slower drug clearance could indicate saturation of tissue sites. In conclusion, CNTO 95, a fully human mAb to αv integrins, is well tolerated up to weekly doses of 10 mg/kg. Six patients had extended therapy including one with angiosarcoma who has a partial response. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Centocor Centocor Centocor