Targeted antiangiogenic therapy for cancer using Vitaxin: a humanized monoclonal antibody to the integrin alphavbeta3.
Angiogenesis plays a central role in the growth and metastasis of cancers. Strategies aimed at interfering with tumor blood supply offer promise for new cancer therapies. Vitaxin (an anti-alphavbeta3 antibody) interferes with blood vessel formation by inducing apoptosis in newly generated endothelial cells. This Phase I study evaluates the safety and pharmacokinetics of Vitaxin in humans with cancer. Eligible patients demonstrated progressive tumors with stage IV disease and an Eastern Cooperative Oncology Group performance status < or =2. Treatment consisted of six weekly infusions of Vitaxin. Escalating doses from 0.1 and 4.0 mg/kg/week were evaluated based on the expectation that plasma levels would bracket the effective in vitro concentration. Escalation beyond 4 mg/kg/week was limited by drug availability. Adverse events were assessed weekly. Pharmacokinetics were 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 infusion-related fever, which could be controlled with prophylactic antipyretics. Doses > or =1 mg/kg/week produced plasma concentrations sufficient to saturate the alphavbeta3 receptor in vitro (25 microg/ml). Vitaxin demonstrated a half-life in excess of 5 days at higher doses with no accumulation over 6 weeks of therapy. One patient demonstrated a partial 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 active, suggesting that vascular integrin alphavbeta3 represents a clinically relevant antiangiogenic target for prolonged cancer therapy.
Gutheil
J C
JC
Department of Clinical Oncology Research, Sidney Kimmel Cancer Center, San Diego, California 92121, USA. Jgutheil@vical.com
Campbell
T N
TN
Pierce
P R
PR
Watkins
J D
JD
Huse
W D
WD
Bodkin
D J
DJ
Cheresh
D A
DA
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D004306:Dose-Response Relationship, Immunologic; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism*; D019030:Receptors, Vitronectin / Q000276:immunology
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D019030:Receptors, Vitronectin; C112567:etaracizumab