A phase I study of AS1409, a novel antibody-cytokine fusion protein, in patients with malignant melanoma (MM) or renal cell carcinoma (RCC)

Abstract

3024 Background: AS1409 (huBC1-huIL-12) is a fusion protein combining a humanized antibody specific for the ED-B splice variant of fibronectin with human IL-12. ED-B-fibronectin is expressed in tumor vasculature. IL-12 stimulates T and NK cell activity. Responses to IL12 occur in MM and RCC, but with high systemic toxicity. AS1409 is designed to target IL-12 to tumor vasculature. Methods: Patients with MM or RCC were treated in a dose-escalating trial of weekly i.v. AS1409 for 6 weeks with a starting dose of 15mcg/kg. Patients without unacceptable toxicity or disease progression could continue therapy. IFN-gamma and IP-10 were measured as biomarkers of activation of cellular immunity. Results: 13 patients (9 males; median age 53 years; 11 MM, 2 RCC) were treated (7 at 15mcg/kg, 6 at 25mcg/kg). DLTs observed at 25 mcg/kg were transaminase elevation and fatigue. Other toxicities included flu-like syndrome, fever, myalgia, and mucositis. Three patients continued to receive AS1409 beyond 6 weeks and 1 patient remained on treatment beyond 30 weeks. All patients showed elevation of IFN-gamma and IP10 following the first dose, although subsequently attenuated; prominent anti-drug antibody (ADA) responses were seen. A partial response was seen in a patient with MM metastatic to lymph nodes treated at 15mcg/kg, and a best response of stable disease was seen in 4 patients. Mean AS1409 half-life was 19.3 ±5.3h, mean distribution volume was 0.25 ± 0.098L/kg and clearance was 9.8 ± 6.5mL/hr/kg. Conclusions: At 15mcg/kg AS1409 was well tolerated. Biomarker activation and objective radiological evidence of anticancer activity was observed at this dose. Further study of AS1409 is focussed on optimizing dosing and scheduling, characterizing the ADA response, and antibody biodistribution. [Table: see text]