Abstract B241: Extended follow-up from a phase I study of AS1409, a novel antibody-cytokine fusion protein, suggests efficacy in malignant melanoma (MM)

Abstract

Abstract Introduction: AS1409 (huBC1-huIL-12) is a fusion protein comprising the humanized antibody, BC1, specific for the ED-B splice variant of fibronectin, and the human cytokine, IL-12. ED-B-fibronectin is expressed in tumor vasculature but has restricted distribution in normal tissue. IL-12 has immunostimulatory, anti-metastatic and anti-angiogenic properties. Responses to IL-12 occur in MM and RCC but with high systemic toxicity. AS1409 is designed to target IL-12 to tumor vasculature. We report extended follow-up from a phase I study to assess the tolerability, safety, pharmacokinetics and activity of AS1409 in patients with MM or renal cell carcinoma (RCC). Methods: Patients with MM or RCC were treated in a dose-escalating trial of weekly i.v. AS1409 for 6 weeks at a starting dose of 15mcg/kg. Patients without unacceptable toxicity or disease progression could continue therapy. IFN-gamma and IP-10 were measured as markers of immune response. Results: 13 patients (11 MM, 2 RCC) were treated (7 at 15mcg/kg, 6 at 25mcg/kg). DLTs observed at 25mcg/kg were transaminase elevation, fatigue and hemolytic anemia. Most common drug-related adverse events were Grade 1 or 2 and related to flu-like syndrome. Four patients continued to receive AS1409 beyond 6 weeks and one received 30 cycles of treatment. All patients showed elevation of IFN-gamma and IP-10 following the first dose. Tumor shrinkage was demonstrated in 5/9 evaluable MM patients - a partial response was confirmed in a patient with MM metastatic to lymph nodes and a further four patients achieved stable disease. One MM patient with previously rapidly progressive disease exhibited prolonged tumor shrinkage 12 months after discontinuing treatment. Anti-drug antibody (ADA) responses were seen in all patients. ADAs were shown not to neutralize the effect of AS1409 in vitro. Conclusions: At 15mcg/kg, AS1409 was associated with manageable toxicity. Biomarker activation and objective radiological evidence of anticancer activity was observed at this dose in patients with MM, including one partial response and one patient with prolonged clinical benefit beyond 12 months from treatment. Further development of AS1409 in MM is warranted. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B241.