Targeted antiangiogenic therapy for cancer using vitaxin: A humanized monoclonal antibody to the integrin alpha(nu)beta(3)

Angiogenesis plays a central role in the growth and metastasis of cancers. Strategies aimed at interfering with tumor blood supply offer promise for n ew cancer therapies. Vitaxin (an anti-alpha(nu)beta(3) antibody) interferes with blood vessel formation by inducing apoptosis in newly generated endot helial cells. This Phase I study evaluates the safety and pharmacokinetics of Vitaxin in humans with cancer. Eligible patients demonstrated progressiv e tumors with stage IV disease and an Eastern Cooperative Oncology Group pe rformance status less than or equal to 2. Treatment consisted of six weekly infusions of Vitaxin. Escalating doses from 0.1 and 4.0 mg/kg/week were ev aluated based on the expectation that plasma levels would bracket the effec tive in vitro concentration. Escalation beyond 4 mg/kg/week was limited by drug availability. Adverse events were assessed weekly. Pharmacokinetics we re performed weekly through week 9. Clinical response was assessed at week 9. Of 17 patients treated, 14 were evaluable for response. Treatment was well tolerated with little or no toxicity, The most common side effect was infus ion-related fever, which could be controlled with prophylactic antipyretics . Doses greater than or equal to 1 mg/kg/week produced plasma concentration s sufficient to saturate the alpha(nu)beta(3) receptor in vitro (25 mu g/ml ). Vitaxin demonstrated a half-life in excess of 5 days at higher doses wit h no accumulation over 6 weeks of therapy. One patient demonstrated a parti al response, and seven patients demonstrated stable disease. Three patients received Vitaxin beyond the first cycle of therapy. Each of these patients demonstrated disease stabilization that in one case lasted 22 months. At the doses and schedule studied, Vitaxin appears safe and potentially act ive, suggesting that vascular integrin alpha(nu)beta(3) represents a clinic ally relevant antiangiogenic target for prolonged cancer therapy.