ASCO - Gastrointestinal Cancers Symposium Orlando (FL), January 2008 First-line Irinotecan, Oxaliplatin and Infusional 5FU/LV (FOLFOXIRI) in combination with Bevacizumab (BV) in Metastatic Colorectal Cancer (mCRC) Patients (pts): a Phase II Study by the G.O.N.O. Group Masi G 1, Loupakis F 1,6, Baldi G 1, Fornaro L 1, Di Leo A 2, Ciarlo A 2, Amoroso D 3, Granetto C 4, Di Donato S 5, Falcone A 1,6. 1 Division of Medical Oncology, Azienda USL 6 - Istituto Toscano Tumori Livorno, Italy, 2 Division of Medical Oncology, Misericordia e Dolce Hospital, Prato, Italy, 3 Division of Medical Oncology, Versilia Hospital, Lido di Camaiore, Italy, 4 Division of Medical Oncology, S. Croce e Carle Hospital, Cuneo, Italy, 5 Division of Medical Oncology, S. Chiara Hospital, Pisa, Italy, 6 Department of Oncology, Transplantation and New Technologies in Medicine, University of Pisa, Italy

ABSTRACT (updated) Background : A phase III study demonstrated that the GONO-FOLFOXIRI regimen significantly improved response-rate (RR), progression-free survival (PFS), overall survival (OS) and post-CT surgical resections of metastases vs FOLFIRI. The combination of BV with fluoropyrimidines/oxaliplatin/irinotecan-based doublets is safe and associated with promising activity and efficacy. Methods: We are conducting a phase II study to evaluate the bi-weekly combination of bevacizumab 5 mg/kg on d1 with the GONO-FOLFOXIRI regimen (irinotecan 165 mg/sqm d1, oxaliplatin 85 mg/sqm d1, l-LV 200 mg/sqm d1 and 5FU 3200 mg/sqm 48-h flat continuous infusion starting on d1) (FOIB regimen) in initially unresectable mCRC pts. Results : Up today 40 pts have been enrolled. Main pts characteristic are: M/F = 65%/35%, median age (range) = 61 (41-75) years, ECOG-PS 0/1 = 68%/32%, primary colon/rectum = 72%/28%, primary on site = 10 pts (25%), sites of disease single/multiple = 52%/48%, liver only mts = 50%. Among the 38 pts so far assessable for toxicity the G3-4 maximum observed toxicities were: neutropenia 34% (febrile neutropenia 3%), diarrhea 8%, nausea 5%, stomatitis 3%, neurotoxicity 3%, deep venous thrombosis 5% and hypertension 8%; G1 bleeding occurred in 12 pts (32%). No toxic deaths have occurred. Up today 29 pts have been evaluated for response and we observed 2 CR, 20 PR (ORR = 76%) and 7 SD (disease control rate = 100%). So far 5 pts (17%) have undergone to secondary surgery on liver mts and 4 R0 resections have been performed. After a median follow up of 6.5 months, median PFS and OS have not yet been reached. Conclusions : The addiction of BV to the GONO-FOLFOXIRI regimen is feasible with manageable toxicities; the characteristic toxicity of BV and FOLFOXIRI occurs with the expected incidence and there were not unexpected adverse events. Preliminary data on activity are promising. The study is still ongoing. Partially supported by ARCO Foundation.

BACKGROUND The best outcome of mCRC is achieved in pts receiving 5FU, irinotecan, and oxaliplatin in the course of their disease, but in a sequential strategy 25-50% of pts does not receive II line CT and therefore is not exposed to all the 3 agents. A way to expose 100% of pts to all the 3 agents is to incorporate them in first-line therapy. The “GONO” FOLFOXIRI regimen is the first triple-drug combination demonstrated to be superior to an infusional 5FU containing doublet as FOLFIRI in terms of RR, R0 resections, PFS and OS in metastatic colorectal cancer patients (Falcone A, J Clin Oncol 2007). Bevacizumab associated with IFL is feasible and significantly improves response rate, progression free and overall survival compared to IFL alone in first-line treatment of MCRC pts. Bevacizumab associated with oxaliplatin-based chemotherapy (FOLFOX or XELOX) is feasible and significantly increases progression free survival compared to chemotherapy alone in first- and second-line treatment of MCRC pts. Two large phase IV trials evaluating a total of about 4000 MCRC pts show that the combination of Bevacizumab with any first-line chemotherapy is safe and effective.

OBJECTIVES PRIMARY  Percentage of patients free of progression at 10 months SECONDARY  Response rate  Progression free survival  Overall survival  Safety profile  Evaluation of potential surrogate markers predictive of bevacizumab activity

SELECTION CRITERIA INCLUSION CRITERIA Histologically confirmed colorectal adenocarcinoma Unresectable and measurable metastatic disease (RECIST criteria) Age > 18 years and ≤ 75 years ECOG PS < 2 if aged < 71 years; ECOG PS = 0 if aged years Previous adjuvant chemotherapy allowed if more than 12 months have elapsed between the end of adjuvant therapy and first relapse Adeguate liver, renal and bone marrow functions Urine dipstick for proteinuria < 2+ EXCLUSION CRITERIA Prior palliative chemotherapy of bevacizumab treatment Bowel obstruction, inflammatory enteropathy, extensive intestinal resection Presence or history of CNS metastasis Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to treatment Clinically significant cardiovascular disease, uncontrolled hypertension, thromboembolic or hemorrhagic events within 6 months prior to treatment, bleeding diathesis or coagulopathy

TREATMENT So far, 289 cycles of “induction” treatment with FOLFOXIRI plus Bevacizumab were administered and the median number of cycles FOLFOXIRI plus Bevacizumab was 8 (range 1-16) 5FU flat continuous infusion 3200 mg/sqm L-LV 200 mg/sqm Oxaliplatin 85 mg/sqm 2 hours Repeated every 14 days CPT mg/sqm 48 hours Day 1 Day 2 Day 3 1 hour BV 5 mg/Kg 30 min

PATIENTS’ CHARACTERISTICS N% Patients40- Age, median (range)60 (41-75)- Sex (M/F)26/1465/35 ECOG PS 0/127/1367.5/32.5 Primary site (colon/rectum)29/1172.5/27.5 Surgery for primary tumor (y/n)30/1075/25 Previous adjuvant CT (y/n)2/385/95 Sites of disease (single/multiple)21/1952.5/47.5 Liver only mts2050 Lung only mts12.5

TOXICITY (% per cycle; N=289) ToxicityG1G2G3G4 Nausea24810 Vomiting7500 Diarrhea22710 Stomatitis27310 Neutropenia12962 Thrombocytopenia14000 Anemia Neurotoxicity Hypertension3120 Deep venous thrombosis0010 Bleeding6000 Cardiac ischemia0010 Febrile neutropenia 1%. No toxic death has so far occurred.

TOXICITY (% per patient; N=38) ToxicityG1G2G3G4 Nausea Vomiting Diarrhea24 80 Stomatitis Neutropenia Thrombocytopenia26000 Anemia Neurotoxicity Hypertension18380 Deep venous thrombosis0050 Bleeding32000 Cardiac ischemia0050 Febrile neutropenia 3% (1 patient). No toxic death has so far occurred.

RESPONSE RATE (RECIST CRITERIA) Total evaluable patientsN=29 Complete Response (CR)27% Partial Response (PR)2069% Overall Response Rate2276% Stable Disease (SD)724% Progressive Disease00 Disease Control Rate (CR + PR + SD) 29100%

R0-SURGERY, PFS, OS So far 5 pts (17%) have undergone to secondary surgery on liver mts; 4 R0 and 1 R1 resections have been performed After a median follow up of 6.5 months, median PFS and OS have not yet been reached

CONCLUSIONS The addiction of BV to the GONO-FOLFOXIRI regimen is feasible with manageable toxicities The characteristic toxicity of BV and FOLFOXIRI occurs with the expected incidence and there were not unexpected adverse events Preliminary data on activity are promising. The study is still ongoing to complete the planned accrual and to better determine the activity and safety profile of the combination.

ACKNOWLEDGEMENTS Livorno Masi G, Loupakis F, Baldi G, Fornaro L, Antonuzzo A, Di Marsico R, Stasi I, Cupini S, Fontana A, Vasile E, Andreuccetti M, Falcone A. PratoCiarlo A, Cavaciocchi D, Di Leo A. VersiliaDonati S, Rondini M, Puccetti C, Amoroso D. CuneoGranetto C, Fea E, Merlano M. Pisa Di Donato S, Brunetti I, Lencioni M, Pfanner E, Petrini I, Ricci S. GenovaSonaglio C, Chiara S. RomaFerraldeschi R, Puglisi M, Cortesi E.