Experimental and Clinical Therapeutics

Monday, October 17, 2005 3:00 PM-5:00 PM Exhibit Hall

(PP189) Improvement of fractionated radiation therapy by combination with a VEGF blocker, VEGF Trap.

Wachsberger, Phyllis *,1, Burd, Randy1, Marrero, Nichol1, Rossetti, Dianne1, Strickler, Tara 1, Yancopoulos, George2, Holash, Jocelyn2, Dicker, Adam1, 1 Department of Radiation Oncology, Philadelphia, PA, USA2 Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA

ABSTRACT- Background: Recent studies have suggested that radiotherapy in combination with VEGF targeting agents can enhance the therapeutic ratio of ionizing radiation. VEGF Trap is a soluble decoy receptor created by fusing the ligand-binding immunoglobulin domains of VEGF receptor 1 (VEGFR1) and VEGF receptor 2 (VEGFR2) to the constant region (Fc) of human IgG1. The objective of the present study was to evaluate the effect of VEGF Trap (Regeneron) on tumor growth delay in response to fractionated radiotherapy in the clinically relevant U87 human glioblastoma model, which is known to express high levels of VEGF. Methods: U-87 cells were injected subcutaneously into the right hind limb of athymic NCR NUM mice. and allowed to grow until reaching a diameter of 4-5 mm before treatment. VEGF Trap was administered at two doses (high (10 mg/kg) and low (2.5 mg/kg), every third day starting on day 0 for up to three weeks. Radiation was administered on days 7,8 and 9 (3 x 5 Gy). Analysis of data was performed by using mixed-effects linear regression to model the base-10 logarithm of tumor volume as a function of time and treatment. Results: Average tumor growth in the untreated group corresponded to a doubling time of 3.1 days. Radiation alone when administered to tumors that were size matched to correspond to the smaller VEGF Trap treated tumors, slowed tumor doubling time to 6.5 days(p<0.001). The low dose VEGF Trap group (2.5 mg/kg) had a doubling time of 4.7 days while the high dose VEGF Trap group (10 mg/kg) lengthened doubling time (9.5 days; p < 0.001 vs. control). Combination of low dose VEGF Trap and radiotherapy slowed the mean doubling time to 10.4 days, a stronger effect than that seen by a comparable regimen of VEGF Trap alone (p <0.001), or radiation alone (p = 0.059). The combination of high dose VEGF Trap with radiation slowed the mean tumor doubling time to 17.0 days, a stronger effect than that of either high dose VEGF trap alone or radiation alone (p = 0.060 and 0.003), respectively Conclusions: In summary, adding low dose VEGF Trap (2.5 mg/kg) or high dose VEGF Trap (10mg/kg) to fractionated radiation (3 x 5 Gy) was better than radiation alone. It is concluded that VEGF Trap may be of benefit in a fractionated radiotherapy regimen. (This work was supported by grants from the Radiation Therapy Oncology Group and Regeneron Pharmaceuticals, Inc.)

Key words: fractionated radiotherapy, VEGF Trap, U87 glioblastoma

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2005 RRS