Phase II trial of chemotherapy with high-dose FOLFIRI plus bevacizumab in the front-line treatment of patients with metastatic colorectal cancer (mCRC) and genotype UGT1A1*1/ UGT1A1*1 or UGT1A1*1/ UGT1A1*28 (FFCD 0504 trial) Results of a planned interim analysis. E Mitry 1, O Bouché 2, L Dahan 3, F Bonnetain 4, P Laurent-Puig 5, T Aparicio 6, PL Etienne 7, C Lecaille 8, JP Lafargue 9, JL Jouve 4, Fédération Francophone de Cancérologie Digestive 1 CHU A Paré, Boulogne 2 CHU Reims 3 CHU La Timone, Marseille 4 FFCD, Dijon 5 Hôpital Européen G Pompidou, Paris 6 CHU Bichat, Paris 7 Clinique Armoricaine, St Brieuc 8 Polyclinique Bordeaux Nord Aquitaine, Bordeaux 9 CHD, La Roche/Yon INTRODUCTION INTERIM ANALYSIS RESULTS (among 17 patients with UGT1A1*1/ UGT1A1*1 genotype) # 4065 REFERENCES CONCLUSION STUDY DESIGN Main inclusion criteria ‣ Age ‣ WHO performance status ≤2 ‣ Genotype UGT1A1*1/*1 or UGT1A1*1/*28 ‣ Non resectable metastatic colorectal cancer ‣ No prior chemotherapy ‣ Measurable disease (RECIST) ‣ No brain metastases ‣ Adequate bone marrow, liver and renal functions Primary endpoint ‣ Objective response (OR) at 6 months (RECIST criteria, independent review) ‣ Tolerability (NCI CTC v. 2.0 criteria) Secondary endpoints ‣ Progression-free survival and overall survival. ‣ Time to treatment failure. ‣ Quality of life (EuroQOL EQ5D questionnaire).  Ducreux M, Raoul JL, Marti P, Merrouche Y, Tigaud JM, Rebischung C, et al. High-dose irinotecan plus LV5FU2 or simplified LV5FU (HD-FOLFIRI) for patients with untreated metastatic colorectal cancer: a new way to allow resection of liver metastases? Oncology 2008;74:  O'Dwyer PJ, Catalano RB. Uridine diphosphate glucuronosyltransferase (UGT) 1A1 and irinotecan: practical pharmacogenomics arrives in cancer therapy. J Clin Oncol 2006;24: Baseline characteristics ‣ High-dose FOLFIRI plus bevacizumab, although effective, was associated with a high toxicity rate among patients with UGT1A1 *1/*1 genotype ‣ 7 patients presented toxic events when interim analysis stopping rules required ≤ 3 patients ‣ According to interim analysis rules, the trial was closed to inclusion (for both groups) on December 16th 2008 for toxicity ‣ Toxicity however was manageable. There was no toxic death and no grade 4 diarrhea. ‣ Interim analysis for patients with UGT1A1 *1/*28 genotype is ongoing ‣ FOLFIRI-bevacizumab is a standard front line treatment of advanced colorectal cancer. ‣ The combination of high-dose irinotecan (260 mg/m²) with LV5FU2 regimen was feasible with an acceptable safety profile and promising efficacy data ‣ Genotype UGT1A1*28/ UGT1A1*28 is associated with an increased toxicity of irinotecan ABSTRACT Statistical Analyses ‣ Bryant & Day design, intent to treat analysis ‣ Primary endpoint : objective response rate (H0 ≤ 40%; H1 : ≥ 60%) and toxicity (gr 4 neutropenia or febrile neutropenia or gr 3-4 diarrhea; H0 ≥ 20%; H1≤ 5% ) ‣ 108 pts required (54 in each group) (alpha 5% and power 80%) ‣ Planned interim analysis after the inclusion of 17 pts with 6- months follow-up by group. ‣ The trial will be stopped at interim analysis if ≤ 7 pts had an OR and/or ≥ 3 pts had a severe toxicity. Enrollment ‣ Date of point for interim analysis : May, 2 nd 2008 (6-months follow-up for the 17th patient) ‣ 96/108 patients included (arm 1: 40, arm 2 : 46) Interim analysis for the first 17 patients in arm 1 ‣ Period of inclusion: to ‣ 9 participating centres n (%) n17 Median age years [range] 58 [52-74] ECOG Performance status 05 (29.4) 111 (64.7) 21 (5.9) Male11 (64.7) Genotype UGT1A1*1/*117 (100) Primary tumor location Colon10 (58.8) Rectum7 (41.2) Metastatic sites Liver9 (53) Peritoneum10 (58.8) Lung4 (23.5) Background: The antitumor efficacy of irinotecan may be dose dependent. In a recent phase II trial, the combination of high-dose irinotecan (260 mg/m²) with LV5FU2 regimen was feasible with an acceptable safety profile and promising efficacy data. The aim of this study was to evaluate the association of the high-dose FOLFIRI plus bevacizumab in patients (pts) selected on the UGT1A1 polymorphism, which could be predictive of the irinotecan toxicity. Methods: Pts with UGT1A1 *1/*1 (group 1) or *1/*28 (group 2) genotypes and previously untreated mCRC were treated with bevacizumab 5 mg/kg D1, irinotecan 260 mg/m² D1, LV 400 mg/m² D1, 5FU 400 mg/m² IV bolus D1 and 5FU 2400 mg/m² 46h infusion D1-2 every 2 weeks. Using Bryant & Day design with OR (independent review, H0 ≤ 40%; H1 : ≥ 60%) and toxicity (gr 4 neutropenia or febrile neutropenia or gr3-4 diarrhea; H0 ≥ 20%; H1≤ 5% ) as primary endpoints; a total of 108 pts, 54 in each group, was required (alpha 5% and power 80%) with a planned interim analysis after the inclusion of 17 pts by group. The trial will be stopped at interim analysis if ≤ 7 pts had an OR and/or ≥ 3 pts had a severe toxicity. All analyses were performed in ITT. Results: At the time of interim analysis, done for group 1 when the 17th pt had a 6-months follow- up, 96 pts have been included (group 1: 40 pts, group 2: 46 pts). An objective response rate was observed in 9/17 pts but 7/17 pts had a severe toxicity (gr 4 neutropenia: 2 pts, febrile neutropenia: 2 pts, gr 3 diarrhea: 4 pts). Overall, 14/17 pts had a gr3-4 toxicity. There was no toxic death. According to interim analysis rules, the trial was closed to inclusion (for both groups) on December 16th 2008 for toxicity. The interim analysis for pts of group 2 is planned for February 2009 when the 17th patient will have a 6-months follow- up. Conclusions: High-dose FOLFIRI plus bevacizumab, although effective, was associated with a high toxicity rate among pts with UGT1A1 *1/*1 genotype. Multicenter phase II study 2 arms according to genotype ‣ Arm 1 (54 patients) : UGT1A1*1/ UGT1A1*1 ‣ Arm 2 (54 patients) : UGT1A1*1/ UGT1A1*28 Treatment ‣ Bevacizumab 5 mg/kg IV day 1 ‣ High dose FOLFIRI ‣ irinotecan 260 mg/m 2 IV day 1 ‣ calcium folinate 400 mg/m 2 day 1 ‣ 5FU 400 mg/m 2 IV bolus day 1 ‣ 5FU 2400 mg/m 2 IV46 hours day1-2 ‣ Treatment every 2 weeks Confirmed objective responses ‣ 9 patients ‣ Response rate 53% interim analysis stopping rules required > 7 pts Toxic events considered for interim analysis ‣ 7 patients ‣ gr 4 neutropenia : 2 patients ‣ febrile neutropenia : 2 patients ‣ gr 3 diarrhea : 4 patients 1 patient with gr 4 neutropenia and grade 3 diarrhea no grade 4 diarrhea interim analysis stopping rules required ≤ 3 pts n (%) Any14 (83.5) Non hematologic Diarrhea4 (23.5) Venous thromboembolic event4 (23.6) Nausea1 (5.9) Vomiting1 (5.9) Epistaxis1 (5.9) Hypertension1 (5.9) Hematologic Neutropenia5 (29.4) Febrile neutropenia2 (11.8) Anemia2 (11.8) Thrombocytopenia0 Severe toxicity (grade 3-4) No toxic death