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Volociximab, a Chimeric Monoclonal Antibody that Specifically Binds ₅β₁ Integrin: A Phase I, Pharmacokinetic, and Biological Correlative Study

Authors' Affiliations: ¹ Institute for Drug Development, Cancer Therapy and Research Center and The University of Texas Health Science Center at San Antonio and ² Brooke Army Medical Center, San Antonio, Texas; ³ University of Wisconsin, Paul P. Carbone Comprehensive Cancer Center, Madison, Wisconsin; and ⁴ PDL Biopharma, Inc., Fremont, California

Requests for reprints: Anthony W. Tolcher, START Institute (South Texas Accelerated Research Therapeutics), 4319 Medical Drive, Suite 205, San Antonio, TX 78229. Phone: 210-593-5255; Fax: 210-615-1121; E-mail: atolcher{at}start.stoh.com.

Purpose: This study aimed to assess the safety and feasibility of administering volociximab, a chimeric monoclonal antibody that specifically binds to ₅β₁ integrin, and to determine the pharmacokinetics, pharmacodynamics, and preliminary evidence of antitumor activity.

Experimental Design: Patients with advanced solid malignancies were treated with escalating doses of volociximab i.v. administered over 60 minutes. Blood samples were assayed to determine plasma pharmacokinetic parameters, detect human antichimeric antibody formation, and determine the saturation of ₅β₁ sites on peripheral blood monocytes.

Results: Twenty-one patients received 223 infusions of volociximab at doses ranging from 0.5 to 15 mg/kg i.v. on days 1, 15, 22, 29, and 36; and weekly thereafter. Treatment was well tolerated, and dose-limiting toxicity was not identified over the range examined. Mild (grade 1 or 2), reversible fatigue was the principal toxicity of volociximab at the highest dose levels of 10 and 15 mg/kg. Nausea, fever, anorexia, headache, vomiting, and myalgias were mild and infrequent, and there was no hematologic toxicity. Volociximab had biexponential distribution; clearance was inversely related to increasing dose, and the half-life at 15 mg/kg was estimated as being 30 days. Three patients tested positive for anti-volociximab antibodies. Saturation of monocyte ₅β₁ integrin sites was dose-dependent up to 15 mg/kg. There was one minor response (renal, 7 months) and one durable stable disease (melanoma, 14 months).

Conclusions: Volociximab can be safely administered at 15 mg/kg i.v. per week. The absence of severe toxicities and preliminary activity at the highest dose level warrants further disease-directed studies.

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