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Phase I Trial of a Monoclonal Antibody Specific for _vß₃ Integrin (MEDI-522) in Patients with Advanced Malignancies, Including an Assessment of Effect on Tumor Perfusion

Authors' Affiliations:¹ University of Wisconsin Comprehensive Cancer Center; Departments of ² Medicine, ³ Biostatistics, ⁴ Radiology, and ⁵ Pathology; ⁶ School of Pharmacy, University of Wisconsin, Madison, Wisconsin; ⁷ MedImmune Oncology, Inc., Gaithersburg, Maryland; and ⁸ Investigational Drug Branch, Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland

Requests for reprints: Douglas G. McNeel, Department of Medicine/Medical Oncology, University of Wisconsin Comprehensive Cancer Center, K4/518 Clinical Science Center, 600 Highland Avenue, Madison, WI 53792. Phone: 608-265-8131; Fax: 608-265-8133; E-mail: dm3{at}medicine.wisc.edu.

At present, a variety of agents targeting tumor angiogenesis are under clinical investigation as new therapies for patients with cancer. Overexpression of the _vß₃ integrin on tumor vasculature has been associated with an aggressive phenotype of several solid tumor types. Murine models have shown that antibodies targeting the _vß₃ integrin can affect tumor vasculature and block tumor formation and metastasis. These findings suggest that antibodies directed at _vß₃ could be investigated in the treatment of human malignancies. The current phase I dose escalation study evaluated the safety of MEDI-522, a monoclonal antibody specific for the _vß₃ integrin, in patients with advanced malignancies. Twenty-five patients with a variety of metastatic solid tumors were treated with MEDI-522 on a weekly basis with doses ranging from 2 to 10 mg/kg/wk. Adverse events were assessed weekly; pharmacokinetic studies were done; and radiographic staging was done every 8 weeks. In addition, dynamic computed tomography imaging was done at baseline and at 8 weeks in patients with suitable target lesions amenable to analysis, to potentially identify the effect of MEDI-522 on tumor perfusion. Treatment was well tolerated, and a maximum tolerated dose was not identified by traditional dose-limiting toxicities. The major adverse events observed were grade 1 and 2 infusion-related reactions (fever, rigors, flushing, injection site reactions, and tachycardia), low-grade constitutional and gastrointestinal symptoms (fatigue, myalgias, and nausea), and asymptomatic hypophosphatemia. Dynamic computed tomography imaging suggested a possible effect on tumor perfusion with an increase in contrast mean transit time from baseline to the 8-week evaluation with increasing doses of MEDI-522. No complete or partial responses were observed. Three patients with metastatic renal cell cancer experienced prolonged stable disease (34 weeks, >1 and >2 years) on treatment. With this weekly schedule of administration, and in the doses studied, MEDI-522 seems to be without significant toxicity, may have effects on tumor perfusion, and may have clinical activity in renal cell cancer. These findings suggest the MEDI-522 could be further investigated as an antiangiogenic agent for the treatment of cancer.

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