Phase I And Dce-Mri Evaluation Of Cdp791, A Di-Fab Peg Conjugate That Inhibits Vegfr2

3523 Background: VEGF inhibitors are of proven clinical value. However, very few drugs specifically inhibit VEGFR2. CDP791 is a di-Fab PEG conjugate that binds VEGFR2 with a Kd of 49pM. Methods: We performed a single site, open label, dose-escalation study of CDP791. Cohorts of patients received between 0.3 and 30 mg/kg every 3 weeks until disease progression. DCE-MRI was performed at each dose level. Results: Thirty-one patients with colorectal, ovarian or renal cancer or other tumors were treated. There was no observed dose limiting toxicity or maximum tolerated dose. At doses of 10mg/kg or above, 7/16 patients developed cutaneous hemangiomata that regressed upon drug withdrawal. Biopsy of these confirmed that CDP791 was co-located with unphosphorylated VEGFR2. DCE-MRI revealed a dose- dependent inhibition of tumor growth over 20 days post-treatment, although there was no measurable change in Ktrans, an indicator of blood flow and capillary permeability. Fourteen patients received extended treatment and 5 (with renal (x2), colorectal, endometrial cancer and melanoma) had stable disease after 6 cycles. Plasma concentrations of CDP791 >10mcg/mL were sustained across the 21-day cycle for doses 10mg/kg and above. Conclusions: CDP791 is a pure VEGFR2 antagonist that is well tolerated up to doses of 30mg/kg. The drug is mechanistically active, associated with hemangiomata and dose-level dependent inhibition of tumor growth but not with reduction in vascular permeability or blood flow on DCE-MRI. These data imply that the drug is active in patients but challenge our understanding of the regulation of tumor vascular permeability. In addition, they suggest that serial 3-dimensional measurements of short-term tumor growth patterns are a sensitive method to detect biological therapy-related tumor growth inhibition. [Table: see text]