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Abstract 132: A phase I and pharmacokinetic clinical trial of subcutaneous (sc) VEGF Trap in advanced solid tumor patients
Citation: European Journal of Cancer Supplements Volume 2, No.8, September 2004, page 43
J. Dupont1, L. Schwartz1, J. Koutcher1, D.R. Spriggs1, M.S. Gordon2, D. Mendelson2, J. Murren3, A. Lucarelli4, J.M. Cedarbaum4
1Memorial Sloan-Kettering Cancer Center, Medicine, New York, USA
2Arizona Cancer Center, Medicine, Scottsdale, USA
3Yale University, Medicine, New Haven, USA
4Regeneron Pharmaceuticals Inc, Medicine, Tarrytown, USA
Background: VEGF Trap is a potent angiogenesis inhibitor comprised of portions of the human VEGF receptor VEGFR1 (Flt-1) and VEGFR2 (KDR) extracellular domains fused to the Fc portion of human IgG. VEGF Trap binds VEGF-A 100- to 1000-fold more tightly than monoclonal antibodies (Kd <1 pM) and neutralizes all circulating and tissue VEGF-A isoforms plus placental growth factor.
Methods: In this phase I trial, successive cohorts of pts with relapsed or refractory solid tumors received 1 (or 2) doses of sc VEGF Trap, followed 4 weeks later by 6 weekly (or twice weekly) doses. Pts without disease progression subsequently entered a long-term extension study. Study endpoints included safety, pharmacokinetics, and immunogenicity. Antitumor activity was assessed by CT scan.
Results: A total of 38 pts were treated across 7 dose levels: 0.025, 0.05, 0.1, 0.2, 0.4, and 0.8 mg/kg weekly, and 0.8 mg/kg twice weekly. Potentially drug-related grade 3 or 4 adverse events (AEs) encountered included hypertension (n=2), proteinuria (n=1), afebrile neutropenia (n=1), and pulmonary embolism (n=1). Other than HTN, no dose-related pattern of AEs emerged. The maximum tolerated dose was not reached. No pts have developed anti-VEGF Trap antibodies, including those pts treated for ³6 mos. Plasma VEGF Trap levels associated with antitumor activity in animal models were approached in the 0.8 mg/kg once and twice weekly dose groups. Objective partial or complete responses were not achieved, but 17 of 35 evaluable pts, including 8 of 12 pts treated with ³0.8 mg/kg/week, maintained stable disease (SD) for at least 10 weeks and entered the extension study.
Conclusions: VEGF Trap has a favorable safety and tolerability profile. Consistent with previous findings with an anti-VEGF antibody, VEGF Trap may be associated with dose-dependent hypertension. Eight of 12 (67%) of evaluable pts treated with 0.8 mg/kg once or twice weekly, compared with 9 of 23 (39%) who received lower doses, maintained SD at the end of the 10-week study. Final results of the study will be presented. |
