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Phase II study of volociximab (M200), an α5β1 anti-integrin antibody in metastatic melanoma
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2006
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Endothelial CellsImmunologyPhase Ii StudyImmunotherapeuticsImmunotherapyTumor BiologyTumor AngiogenesisAngiogenesisOncologyTumor ImmunityFibroblast Growth FactorRadiation OncologyCancer Researchα5β1 Anti-integrin AntibodyMelanomaMetastatic MelanomaImmune SurveillanceVascular BiologyNeovascularizationImmune Checkpoint InhibitorIntegrin α5β1MedicineCancer Growth
8011 Background: Integrin α5β1 has been reported to be unregulated in metastatic melanoma and in tumor angiogenesis. A critical survival step in angiogenesis is the ligation of fibronectin in the extracellular matrix to α5β1 on endothelial cells. M200 is an IgG4 chimeric monoclonal antibody targeting α5β1, inducing apoptosis of proliferating endothelial cells. M200 activity is independent of growth factor stimulus, suggesting that binding of fibronectin to α5β1 occurs downstream of growth factor signalling, and is possibly a final common pathway for the development of neovasculature. Methods: This is a multicenter, open label, single cohort, pilot phase II study of 40 patients (pts) in metastatic melanoma. Pts received M200 10 mg/kg IV every 2 weeks with DTIC 1g/m 2 monthly until disease progression. Pts were evaluated for efficacy every 8 weeks by objective response using RECIST criteria. Additional evaluations included pharmacokinetics and immunogenicity profile. An independent data safety monitoring board was utilized to review safety data. Results: A total of 40 pts have been enrolled to date. All pts were evaluable for safety and 30 pts for objective response using ITT population. Median age was 58.8 years, with 26 (65%) male. ECOG score was 0–1 in 37 (92%) pts. Up to 14 doses of M200 (median 4 doses) and 7 doses of DTIC (median 2) have currently been administered, with dosing continuing. Thirty-one (77.5%) pts have had at least 1 AE with 8 (20%) pts at least 1 SAE. The most frequent adverse events for M200 were nausea 17.5%, constipation 10% and vomiting 10% and for DTIC were nausea 35%, vomiting 20% and pyrexia 15%. Fifteen SAE’s with 2 possibly related to M200 including hypertension and deep vein thrombosis. Four pts died in the study, all with progressive disease (PD). Best overall response at 8 weeks was stable disease (SD) in 16/30 pts and PD in 14/30 pts. Median time to progression was 72 days. Conclusions: M200 appears to be well tolerated at 10 mg/kg Q2W in combination with DTIC. [Table: see text]