title: Phase I trial of a monoclonal antibody specific for alphavbeta3 integrin (MEDI-522) in patients with advanced malignancies, including an assessment of effect on tumor perfusion.
abstract: At present, a variety of agents targeting tumor angiogenesis are under clinical investigation as new therapies for patients with cancer. Overexpression of the alpha(v)beta(3) integrin on tumor vasculature has been associated with an aggressive phenotype of several solid tumor types. Murine models have shown that antibodies targeting the alpha(v)beta(3) integrin can affect tumor vasculature and block tumor formation and metastasis. These findings suggest that antibodies directed at alpha(v)beta(3) 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 alpha(v)beta(3) 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.
authors.affiliation: University of Wisconsin Comprehensive Cancer Center, Madison, 53792, USA. dm3@medicine.wisc.edu
authors.forename: Douglas G
authors.initials: DG
authors.lastname: McNeel
authors.forename: Jens
authors.initials: J
authors.lastname: Eickhoff
authors.forename: Fred T
authors.initials: FT
authors.lastname: Lee
authors.forename: David M
authors.initials: DM
authors.lastname: King
authors.forename: Dona
authors.initials: D
authors.lastname: Alberti
authors.forename: James P
authors.initials: JP
authors.lastname: Thomas
authors.forename: Andreas
authors.initials: A
authors.lastname: Friedl
authors.forename: Jill
authors.initials: J
authors.lastname: Kolesar
authors.forename: Rebecca
authors.initials: R
authors.lastname: Marnocha
authors.forename: Jennifer
authors.initials: J
authors.lastname: Volkman
authors.forename: Jianliang
authors.initials: J
authors.lastname: Zhang
authors.forename: Luz
authors.initials: L
authors.lastname: Hammershaimb
authors.forename: James A
authors.initials: JA
authors.lastname: Zwiebel
authors.forename: George
authors.initials: G
authors.lastname: Wilding
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019540:Area Under Curve; D002292:Carcinoma, Renal Cell / Q000473:pathology; D002986:Clinical Trials as Topic; D015331:Cohort Studies; D003287:Contrast Media; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000737:chemistry / Q000276:immunology*; D007680:Kidney Neoplasms / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism*; D009389:Neovascularization, Pathologic; D010477:Perfusion; D016016:Proportional Hazards Models; D013997:Time Factors; D014057:Tomography, X-Ray Computed
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D003287:Contrast Media; D039302:Integrin alphaVbeta3