Phase I Trial of a Monoclonal Antibody Specific for αvβ3 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 a v h 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 a v h 3 integrin can affect tumor vasculature and block tumor formation and metastasis.These findings suggest that antibodies directed at a v h 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 a v h 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 1and 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, >1and >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.

α7 Helix Region of αI Domain Is Crucial for Integrin Binding to Endoplasmic Reticulum Chaperone gp96

“…However, these inhibitors only showed promising results in some preclinical studies, phase I/II clinical trials but largely failed during clinical phase III trials (11)(12)(13)(14)(15)(16)(17). The failure of these phase III trials can be ascribed to three causes.…”

Cilengitide: An RGD Pentapeptide ανβ3 and ανβ5 Integrin Inhibitor in Development for Glioblastoma and Other Malignancies

“…Of note, phase I studies in advanced solid tumor patients with each of these MAbs confirmed their overall safety and lack of "class-associated" toxicities; in fact, a maximal tolerated dose (MTD) could not be identified in any of these dose-escalation trials. In addition, evidence of anti-tumor activity was observed despite the dose escalation study design [76][77][78].…”

Integrins in prostate cancer progression

“…The second trial utilizes MEDI-522, a humanized monoclonal IgG1 antibody directed against the a v b 3 integrin. MEDI-522 blocks the binding of ligands, such as vitronectin, to a v b 3 integrin (McNeel et al 2005). A Phase II, randomized, open-label, twoarm, multicenter study of MEDI-522, in combination with docetaxel, prednisone, and zoledronic acid in the treatment of patients with metastatic androgen-independent prostate cancer (NCT00072930) is ongoing.…”