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dc.contributor.authorTon, Nhuan C
dc.contributor.authorParker, Geoff J M
dc.contributor.authorJackson, Alan
dc.contributor.authorMullamitha, Saifee A
dc.contributor.authorBuonaccorsi, Giovanni A
dc.contributor.authorRoberts, Caleb
dc.contributor.authorWatson, Yvonne
dc.contributor.authorDavies, Karen
dc.contributor.authorCheung, Susan
dc.contributor.authorHope, Lynn
dc.contributor.authorPower, Fiona
dc.contributor.authorLawrance, Jeremy A L
dc.contributor.authorValle, Juan W
dc.contributor.authorSaunders, Mark P
dc.contributor.authorFelix, R
dc.contributor.authorSoranson, J A
dc.contributor.authorRolfe, L
dc.contributor.authorZinkewich-Peotti, K
dc.contributor.authorJayson, Gordon C
dc.date.accessioned2009-07-07T16:31:45Z
dc.date.available2009-07-07T16:31:45Z
dc.date.issued2007-12-01
dc.identifier.citationPhase I evaluation of CDP791, a PEGylated di-Fab' conjugate that binds vascular endothelial growth factor receptor 2. 2007, 13 (23):7113-8 Clin. Cancer Res.en
dc.identifier.issn1078-0432
dc.identifier.pmid18056191
dc.identifier.doi10.1158/1078-0432.CCR-07-1550
dc.identifier.urihttp://hdl.handle.net/10541/72888
dc.description.abstractPURPOSE: Specific blocking of vascular endothelial growth factor receptor 2 (VEGFR-2) is a novel therapeutic approach. Here, we report the first phase I clinical trial evaluation of CDP791, a PEGylated di-Fab' conjugate that binds VEGFR-2. EXPERIMENTAL DESIGN: Cohorts of patients received CDP791 at doses between 0.3 and 30 mg/kg every 3 weeks for the initial two doses. RESULTS: The compound was well tolerated with no dose-limiting toxicity. Dose-related hypertension was observed in patients receiving CDP791 10 mg/kg or more and several patients on the higher doses developed infusion-related cutaneous hemangiomata arising 28 to 106 days after the first drug administration and resolving 3 weeks after cessation. Biopsy and histologic evaluation showed that CDP791-bound VEGFR-2 is non-phosphorylated, suggesting that the drug is biologically active. Concentrations of CDP791 considered biologically relevant were sustained for 3 weeks when doses of 10 mg/kg or more were administered. Although no reductions in vascular permeability were recorded using dynamic contrast enhanced magnetic resonance imaging (DCE-MRI), there was a significant dose level-related reduction in tumor growth. While challenging the recent dogma that active VEGF inhibitors should modulate DCE-MRI measurements of vascular permeability, this highlights the potential of serial three-dimensional tumor measurements to detect tumor growth arrest. Twelve patients received drug for more than two treatments, although no partial or complete responses were seen. CONCLUSION: The data show that CDP791 is biologically active and well tolerated, achieving appropriate plasma concentrations when administered at 10 mg/kg or more every 3 weeks.
dc.language.isoenen
dc.subjectCanceren
dc.subject.meshAdolescent
dc.subject.meshAdult
dc.subject.meshAged
dc.subject.meshAged, 80 and over
dc.subject.meshAngiogenesis Inhibitors
dc.subject.meshCohort Studies
dc.subject.meshDose-Response Relationship, Drug
dc.subject.meshDrug Administration Schedule
dc.subject.meshFemale
dc.subject.meshHumans
dc.subject.meshImmunoconjugates
dc.subject.meshImmunoglobulin Fab Fragments
dc.subject.meshMagnetic Resonance Imaging
dc.subject.meshMale
dc.subject.meshMiddle Aged
dc.subject.meshNeoplasms
dc.subject.meshPolyethylene Glycols
dc.subject.meshVascular Endothelial Growth Factor Receptor-2
dc.titlePhase I evaluation of CDP791, a PEGylated di-Fab' conjugate that binds vascular endothelial growth factor receptor 2.en
dc.typeArticleen
dc.contributor.departmentCancer Research UK and University of Manchester Department of Medical Oncology, Christie Hospital, Withington, United Kingdom.en
dc.identifier.journalClinical Cancer Researchen
html.description.abstractPURPOSE: Specific blocking of vascular endothelial growth factor receptor 2 (VEGFR-2) is a novel therapeutic approach. Here, we report the first phase I clinical trial evaluation of CDP791, a PEGylated di-Fab' conjugate that binds VEGFR-2. EXPERIMENTAL DESIGN: Cohorts of patients received CDP791 at doses between 0.3 and 30 mg/kg every 3 weeks for the initial two doses. RESULTS: The compound was well tolerated with no dose-limiting toxicity. Dose-related hypertension was observed in patients receiving CDP791 10 mg/kg or more and several patients on the higher doses developed infusion-related cutaneous hemangiomata arising 28 to 106 days after the first drug administration and resolving 3 weeks after cessation. Biopsy and histologic evaluation showed that CDP791-bound VEGFR-2 is non-phosphorylated, suggesting that the drug is biologically active. Concentrations of CDP791 considered biologically relevant were sustained for 3 weeks when doses of 10 mg/kg or more were administered. Although no reductions in vascular permeability were recorded using dynamic contrast enhanced magnetic resonance imaging (DCE-MRI), there was a significant dose level-related reduction in tumor growth. While challenging the recent dogma that active VEGF inhibitors should modulate DCE-MRI measurements of vascular permeability, this highlights the potential of serial three-dimensional tumor measurements to detect tumor growth arrest. Twelve patients received drug for more than two treatments, although no partial or complete responses were seen. CONCLUSION: The data show that CDP791 is biologically active and well tolerated, achieving appropriate plasma concentrations when administered at 10 mg/kg or more every 3 weeks.


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