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

Abstract

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 bindsVEGFR-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 CDP79110 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 threedimensional 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.

Biomarkers of angiogenesis and their role in the development of VEGF inhibitors

“…This was coupled with a marked increase in tumour cell apoptosis, but no significant change in proliferation (Wedam et al, 2006). In a phase I trial of a VEGFR-2-binding di-Fab fragment, biopsy data were compatible with the proposed mechanism of action (Ton et al, 2007). However, such reports are very infrequent for at least two reasons: processing tissues from patients to detect phospho-proteins requires extremely rapid tissue preservation to avoid de-phosphorylation of receptors.…”

Advanced targeted therapies in cancer: Drug nanocarriers, the future of chemotherapy

“…From these approvals, twenty years ago, numerous clinical trials of polymer-proteins conjugates have been or are being performed. Those include enzymes (arginase [104,105], arginine deiminase [104,106,107], glutaminase [108,109]) and biological response modifiers (interleukin 2 [110][111][112], interferonalpha [113][114][115][116][117][118][119], antibody fragment angiogenesis inhibitor [120,121]) bound to PEG [93,[122][123][124][125], but to the best of our knowledge there are no new FDA approvals for cancer treatment [126][127][128].…”

Vegfrs in Neoplastic Angiogenesis and Prospects for Therapy Оf Brain Tumors

“…СDP791 -ПЭГилированный бивалент-ный Fab-фрагмент, высокоаффинно связывающий VEGFR2. В I фазе исследований показано, что СDP791 при взаи-модействии с рецептором препятствует его фосфорилиро-ванию и блокирует проведение клеточного сигнала [62].…”

“…Анти-VEGFR2-терапия приводит к регрессии сосудистой сети, снижению плотности и диа-метра сосудов в опухоли, увеличению числа перицитов на стенках капилляров, к нормализации структуры базаль-ной мембраны, повышению уровня экспрессии коллагена IV типа, а также к снижению проницаемости сосудов и интерстициального давления [9,[58][59][60][61][62][63][64][65][66][67], таким образом замедляя рост опухоли.…”