in locally advanced rectal carcinoma (LARC): The phase II TRUST trial Induction treatment with FOLFOXIRI + bevacizumab (BV) followed by chemo-radiotherapy (CRT) + BV and surgery in locally advanced rectal carcinoma (LARC): The phase II TRUST trial Caterina Vivaldi1, Aldo Sainato2, Sara Lonardi3, Piero Buccianti4, Lorenzo Marcucci5, Francesco Di Clemente6, Gianna Musettini1, Sabrina Montrone2, Francesca Bergamo 3, Matteo Franceschi4, Laura Ginocchi5, Angelo Martignetti6, Concetta La Liscia2, Francesca Battaglin3, Lucio Urbani4, Bruno Manfredi2, Laura Rumano’3, Francesco Sidoti4, Alfredo Falcone1,7, Gianluca Masi7.  1Università di Pisa, Pisa, Italy; 2 U.O. Radioterapia, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy ; 3 Dipartimento di Oncologia Clinica e Sperimentale, UOC Oncologia Medica I, Istituto Oncologico Veneto-IRCCS, Padova, Italy; 4 U.O. Chirurgia Generale, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy; 5Division of Medical Oncology, USL 5 Pontedera, Pontedera, Italy; 6 Dipartimento Oncologico, Siena, Italy; 7Oncology Unit II, University Hospital of Pisa, Pisa, Italy Abstr 673 Poster J12 Background Matherials and Methods Main inclusion criteria: Rectal adenocarcinoma at <12 cm from the anal verge Stage N+ or cT4 or high risk cT3 (MRI criteria) Patients were treated with 6 cycles of biweekly FOLFOXIRI (irinotecan 165mg/m2 day 1; oxaliplatin 85 mg/m2 day1; folinate 200 mg/m2 day 1; 5FU 3200 mg/m2 48h continuous infusion starting on day 1) and BV (5mg/kg day 1). After 3 weeks patients underwent concomitant CRT (50.4 Gy in 28 fractions over 5.5 weeks + 5FU 225 mg/m2/day continuous infusion or capecitabine 825 mg/m2/bid continuously plus BV 5mg/kg on day 1,15,28) After amendment dose of concomitant capecitabine was modified as follow: 800 mg/m2/bid 5 days/week Surgery is planned 7-9 weeks after the end of CRT (Figure 1). Primary endpoint is 2-year disease-free survival (DFS) Neoadjuvant fluoropyrimidine-based CRT in LARC does not achieve effective control of distant micrometastases Induction CT before CRT is promising option in LARC BV improves the results of fluoropyrimidine-based CT FOLFOXIRI plus BV is an effective treatment option in metastatic colorectal cancer Figure 1, Study Schedule Results Patients’ characteristics Induction Chemotherapy Concomitant Chemo-radiotherapy Surgical Procedures Forty-five patients started CRT (1 patient underwent surgery after induction CT because of SAE - pneumonia ) All patients received 50.4 Gy After the first 13 patients, protocol was amended due to an excessive rate of G3 toxicities during CRT: hand-foot syndrome (HFS) (23%), proctalgia (23%), proctitis (23%) and diarrhea (15%). After amendment all patients completed CRT with acceptable toxicities (Table 3). RR after CRT was 78% 44 patients underwent surgery: one patient experienced disease progression after the end of CRT and died Surgery was low anterior resection in 86% of pts, abdomino- perineal resection 7%, other 7%. Radical resection was achieved in 98% Early post-surgical complication rate was 30% This is a multicentric study (4 centers) From April 2012 to April 2015 48 patients were enrolled Main patients’ characteristics are summerized in Table 1 Toxicities observed during induction treatment are summarized in Table 2. As expected main grade (G) 3/4 toxicities were neutropenia (42%) and diarrhea (12,5%) Two patients did not completed induction CT: the first died due to bowel perforation and febrile neutropenia with sepsis after the first cycle, the second one had acute renal injury without sequelae and decided to stop chemotherapy Response rate (RR) after induction CT was 77% Characteristic No (%) Number of patients enrolled 48 100 Sex , Male/Female 31/17 64,6/35,4 Median Age, years (range) 53 (30-74) ECOG PS, 0 / 1-2 47/1 97,/2,1 Clinical Tumor Category, T2/T3/T4 2/29/17 4,2/60,4/35,4 Clinical Nodal Category, N0/N1-2 8/40 16,7/83,3 Activity Histopathological results are available for 43 patients Pathologic complete response was reached in 15/43 patients (35%) Pathological downstaging was obtained in 56% of patients No. of patients = 32 (%) Adverse Event Grade 1 Grade 2 Grade 3 Grade 4 Total Anemia 15 (46,9) - 15(46,9) Neutropenia 13(40,6) 5(15,6) 18(56,2) Thrombocytopenia 9(28,1) Hand Foot Syndrome 7(21,9) 2(6,2) Neurotoxicity 11(34,4) Stomatitis 1(3,1) Hypertension Nausea Vomiting Cystitis Radiation dermatitis 16(50) 6(18,7) 32(68,7) Diarrhea 20(62,4) Rectal Bleeding Proctalgia 3(9,4) Proctitis 24(74,8) No. of patients = 48 (%) Adverse Event Grade 1 Grade 2 Grade 3 Grade 4 Total Anemia 32(66,6) 3(6,3) - 35 (72,9) Thrombocytopenia 9(18,7) 1(2,1) 10(20,8) Neutropenia 5(10,4) 13(27,1) 11(22,9) 38(79,1) Febrile neutropenia 2 (4,2) 2(4,2) Nausea 23(47,9) 36(75) Vomiting 8(16,6) 4(8,3) 12(24,9) Diarrhea 17(35,4) 32(66,7) Hand Foot Syndrome Stomatitis 8(16,2) 27(56,8) Rectal Bleeding Asthenia 28(58,3) Hypertension 6(12,5) Neurotoxicity 25(52,1) 7(14,6) At a median follow up of 22 months, 7 patients had PD: 1 experienced locoregional recurrence and 6 distant metastases Estimated 2year-DFS is 78% Table 1, Patients characteristics Flow chart Enrolled patients: 48 Patients evaluable for induction CT: 48 (100%) Patients who have completed induction CT: 46 (96%) Patients evaluable for CRT: 45 (94%) Patients who have completed CRT: 45 (94%) Patients evaluable for surgery: 44 (92%) Available histopathological report: 43 (90%), 1 ongoing Conclusions Induction CT with FOLFOXIRI and BV is feasible and highly active A protocol amendment was needed due to toxicities during CRT The rate of early post-surgical complications is not negligible A longer follow up is needed for DFS Table 2, Induction toxicities Table 3, Chemo-radiotherapy toxicities after protocol amendment ca caterinavivaldi@gmail.com