Details

Autor(en) / Beteiligte

• TON, N. C
• PARKER, G. J. M
• POWER, F
• LAWRANCE, J
• VALLE, J
• SAUNDERS, M
• FELIX, R
• SORANSON, J. A
• ROLFE, L
• ZINKEWICH-PEOTTI, K
• JAYSON, G. C
• JACKSON, A
• MULLAMITHA, S
• BUONACCORSI, G. A
• ROBERTS, C
• WATSON, Y
• DAVIES, K
• CHEUNG, S
• HOPE, L

Titel

Phase I Evaluation of CDP791, a PEGylated Di-Fab′ Conjugate that Binds Vascular Endothelial Growth Factor Receptor 2

Ist Teil von

• Clinical cancer research, 2007-12, Vol.13 (23), p.7113-7118

Ort / Verlag

Philadelphia, PA: American Association for Cancer Research

Erscheinungsjahr

2007

Quelle

MEDLINE

Beschreibungen/Notizen

• Purpose: 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.