NOVEL TARGETING DRUGS AND RADIOTHERAPY 2012 PROGRAMME AND ABSTRACT BOOK - 23- the blood vessels and for Ki67. To assess the changes in circulating VEGF ligands during treatment with bevacizumab, we have performed Lumfnex analysis on the blood samples collected at 6 time points during treatment with the human angiogenesis multianalyte profiling kit (Endostatin, Angiopoietin-1, PDGF-AA, POGF·BB, PIGF, VEGF, Thrombospondin-2, VEGF·D). Results: Sixty five patients are registered to date and 52 (80%) have completed the full treatment scheme. A complete pathological response was seen in 30% (8/26) and 12% (3/26) of the patients in arm A and B respectively (p;0.08). Th ere were more good responders (Dworak 3 ft 4) in arm A (69%) in comparison with arm B (38%) (p;0.05). Toxicity was geileratty mild and manageable. The most common grade 3/4 toxicities reported were peri-operative complications (9/31). Grade 3 and 4 toxicities reported during preoperative treatment were more frequent in arm A (n=20) than arm B (n=11 ). Immunohistochemistry showed a decrease after one dose of bevacizumab fn the number of pericyt covered blood vessels, with a continued decrease during chemoradiati on wi th bevacizumab. The proliferation of the tumour was not affected by bevacizumab, but decreased clearly during the combined treatment. A Luminex analysis of the first group of 32 patients showed treatment-induced changes for PDGF·AA and PDGF-BB in patients with complete pathological response and for VEGF fn ail patients. Conclusions: These preliminary results suggest that the combined treatment vlith bevacizumab, capecitabine and radiation therapy with or without oxaliplatin seems feasible. Addition of oxalipla ti n to the treatment scheme showed an acceptable i ncrease in toxicity and might increase the percentage of responders. The fir st translational data suggest a possible role for PDGF for the early prediction of response to chemoradiation vlith bevacizumab in rectal cancer. OC-08 PHASE I TRIAL OF SORAFENIB AND RADIATION: ACUTE TOXICITY REPORT FOR A NEW CONSERVATI VE APPROACH IN BLADDER CANCER. F. Ferrer Gonzalez', G. Sancho 2 , A. Rovirosa 1 , J.P. 1\\aroto\ B. Mellado 5 , F. Vigues 6 , J. Palou 7 , 1\\.J. Ribal ', A. Boladeras 1 , X. Garcia del Muro 9 1 1nstitut Catalil d'Oncologla, Radiation Oncology, L'Hospitqlet de Uobregat, Spain 1 Hospital de Sant Pau, Radiation Oncology, Barcelona, Spain 1 Hospital Clinic, Radiation Oncology, Barcelona, Spain 4 Hospi tal de Sant Pau, IAedical Oncology, Barcelona, Spain 5 Hospital Clinic, Medical Oncology, Barcelona, Spain 6 Hospital de Bellvitge, Urology, L'Hospi talet de Uobregat, Spain 7 Fundaci6 Pulgvert, Urology, Barcelona, Spain 8 Hospital Clinic, Urology, Barcelona, Spain 9 /nst/tut Catalil d'Oncolagia, IMdical Oncology, L'Hospitalet de Llobregat, Spain Purpose/Obj ec tive: Bladder cancer like other solid t umors requires an acti ve angiogenesis to support growth and progression. Preclinical sorafenib studies suggest enhanced radiation-induced cell death wh en VEGFR inhibitor therapies are combined vlith RT. A phase I study was undertaken to assess dose limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended dose (RD) of sorafenib as continuous oral administration combined with pelvic radiation in bladder cancer patients vlith conservative bladder management. To describe any related radiation grade 3-4 toxicity to dosimetric parameters. Mater ials and Methods: SOGUC 07-01 phase I multicentric tri al (approved by ethical board) wa s offered to patients vlith localized carcinoma of the bladder in stage pT2-3 NO MO, who were not eligible or rejected radical cystectomy. Treatment consisted of TUR, followed by normofractionated (2 Gy/day) external-beam RT with high-energy photons, 46 Gy to minor pelvis and 64Gy to bladder, combined with sorafenib given po cont inuously. Sorafenib was started two weeks before RT and was administered for 12 weeks, fin ishi ng 4 weeks aft er RT. A 3+3 sorafenib dose escalation design vlith cohorts of 3-6 patients was used. Dose levels 1, 2 and 3 corre sponded to sorafenfb 200 mg qd, 200 mg bid and 400 mg bid. Pathological response was assessed by post- treatment TUR. Dosimetr ic parameters V40, V60 for rectum, V40 for bowel, VSO for femoral heads were recorded in order to asses any relationship with grade 3-4 acute toxicities. For this purpose a model of binary logisti c r egre ssion vlith significance level of O.OSbilateralfor all tests. The selecti on of associ ated factors was carried out by backward stepvlise method, using the conditional approach. Results: Ten patients (7 M, 3 F)vlith median age of 71 years (44 - 84) were included. The MTD was reached at level 3 and the RD was: sorafenib 200 mg bid vlith RT. Two DL Ts occurred, both at the third dose level: diarrhea grade 3 and digestive bleeding grade 3 vlith secondary anaemia and hemodynamic angor in a patient vlith previous small bowel angiodysplasfa. The most frequent toxicity was diarrhea. Pathological complete response was achieved in 8 of 9 patients evaluated. Salvage cystectomy has been performed in two patients due to recurrent superficial bladder tumor one and two years after combined therapy. One patient showed a distant node progression which respond to chemotherapy with cis-platin, One patient developed late radiation cystitis. After a median follow up of 36 months, 7 patients remain disease-free vlith intact bladder. None significant relationship was found between dosimetric parameters and acute grade 3·4 toxicities. Conclusions: The combination of sorafenfb and RT seems to be feasible and sa fe allowing long-term bladder preservation in selected patients. None of the dosimetric parameters showed significant contribution to grade 3-4 acute toxicity. OC-09 TAT-RASGAP317-326 ABOLISHES IN VIVO RADIO-RESISTANCE OF P53 DEFECTIVE TUMOR D. Viertl 1 , A. Annibaldi\ Ill. tizsahin 1 , C. Widmann 2 , 0. ,\\atzinger' 'Centre Hospitalier Univ. Vaudois, Radiation Oncology, Lausanne, Switzerland 1 Un/versity of Lausanne, Department of Physiology, Lausanne, Switzerland Purpose/Objective: Despite progress in dose delivery, damage to healthy tissues remains a limi ti ng factor in radiotherapy (RT). A RasGAP-derived peptide, call ed TAT-RasGAP 117 • 326 , has been shown to sensi tize tumor cells to genotoxin-induced death but whether thi s compound is beneficial in the context of RT is unknown. Th erefore, we studied whether TAT-RasGAP 117 • 326 can improve the therapeutic index of RT in vitro and in vivo. Materials and Methods: Clonogenfc assays on 4 human cancer cell lines (Hel a, PANC- 1, HCT116 p53' 1 ', HCT116 p53·'·J and a non-tumor cell line (HaCaT) were per formed follovling treatment vlith TAT-RasGAP111-JZ6 and irradiation with 0, 1, 2 and 4 Gy. Mice bearing xenograft tumors were treated with 1.65 mg/kg TAT- RasGAPJ17.m and locally irradiated wi th 3 Gy during 10 days. Tumor growth was then monitored. Results: In vitro, adjunction of TAT-RasGAPm. 116 to irradiation significantly decreased survival in all cancer cell lines tested. In contrast, TAT-RasGAP 117 • 316 did not modulate survival of irradiated non-tumor HaCaT cells. In non-irradiated cells, TAT-RasGAP 317 .m had no effect on clone viability. In vivo, mice treated with TAT- RasGAPl17-Jzo Improved the capacity of RT to reduce tumor growth of p53-positive cancer cells. Tumors lacking p53 displayed an increased resistance to RT. Remarkably, TAT-RasGAP 117 .m rendered p53 -negative tumors as sensitive to RT as the p53 - posi tive tumors. Conclusions: TAT-Ra sGAP117.n6 sensitizes tumors to RT without increasing toxicity to healthy cells or ti ssues. Importantly, the peptide alleviates the RT resistance of p53-negative tumors. Since human tumors often display mutations in p53 or in p53- regulatory pathways, TAT-RasGAP 117 • 126 may be beneficial for patients treated vlith RT. OC-10 BLOCKADE OF TGF·B SIGNALLING RESTORES NEUROGENESIS IN THE IRRADIATED ADULT BRAIN M.A. Mouthon', J.R. Pineda', M. Daynac 1 , A. Chicheporliche 1 , F.D. Boussi n 1 1 1nstltut de Radiologie Cellullaire et Ma/liculalre, CfAiiNSfRIMUI.1R967, Fontenay-aux-Roses, France Purpose/Objective: Cranial radiotherapy provokes progressive cognitive decline that is poorly understood and currently untreatable. Increasing evidence has revealed that collapse of neurogenesis after irradiation contributes to cognitive decline. Neurogenesis persists in restricted regions of the adult brain, and is insured by neural stem cells which proliferate and differentiate into young neurons in specialized neurogenic niches. This work explores whether t he decline in neurogenesis is merely a function of neural stem cell depletion or reflects more profound changes in the stem cell niche. V) 1--- u 0:: 1--- Vl CD <(