RANDOMIZED PHASE II TRIAL COMPARING FOLFIRINOX (5FU/LEUCOVORIN, IRINOTECAN AND OXALIPLATIN) VS GEMCITABINE AS FIRST-LINE TREATMENT FOR METASTATIC PANCREATIC ADENOCARCINOMA FIRST RESULTS OF THE ACCORD 11/0402 TRIAL M. Ychou 1, F. Desseigne 2, R. Guimbaud 3, M. Ducreux 4, O. Bouché 5, Y. Bécouarn 6, A. Adenis 7, C. Montoto-Grillot 8, E. Luporsi 9, T. Conroy 9 1. Centre Val d'Aurelle, Montpellier 2. Centre Léon Bérard, Lyon 3. Institut Claudius Regaud, Toulouse 4. Institut Gustave Roussy, Villejuif 5. Centre Hospitalier R. Debré, Reims 6. Institut Bergonié, Bordeaux 7. Centre Oscar Lambret, Lille 8. Fédération Nationale des Centres de Lutte Contre le Cancer- BECT, Paris 9. Centre Alexis Vautrin, Nancy, FRANCE

Abstract # 4516 RANDOMIZED PHASE II TRIAL COMPARING FOLFIRINOX (5FU/LEUCOVORIN, IRINOTECAN AND OXALIPLATIN) VS GEMCITABINE AS FIRST-LINE TREATMENT FOR METASTATIC PANCREATIC ADENOCARCINOMA FIRST RESULTS OF THE ACCORD 11/0402 TRIAL M. Ychou 1, F. Desseigne 2, R. Guimbaud 3, M. Ducreux 4, O. Bouché 5, Y. Bécouarn 6, A. Adenis 7, C. Montoto-Grillot 8, E. Luporsi 9, T. Conroy 9 Background: In a phase II trial of Folfirinox (F) in 35 MPA patients (pts), we reported a 26% response rate and median survival of 9.5 months (mo) with quality of life improvement (Conroy, JCO 2005). The aim of this phase II trial was to compare the response rate and safety of F vs G in patients with MPA.

Methods: Chemotherapy-naïve patients aged years with histologically or cytologically confirmed measurable MPA were randomized to receive G (1000 mg/m2 IV weekly x 7 for 8 weeks [wks] then weekly x 3 out of 4 wks) or F (O 85mg/m2 d1 + I 180mg/m2 d1 + LV 400mg/m2 d1 followed by 5FU 400mg/m2 bolus d1 and 2400 mg/m2 46h continuous infusion biweekly). Patients were stratified by centre, performance status (ECOG 0 versus 1), and primary tumor location (head vs other). Primary endpoint was response rate.

Results: From 01/05 to 11/06, all planned 88 pts (44 per arm) were enrolled. Median age was 56 yrs [35-76]. Currently, safety data for 81 pts (41F/40G) and efficacy data for 65 pts (31F/34G) are available (17 too early). One pt was ineligible in arm F. Two pts, one in each arm, did not receive protocol therapy. Median number of wks on treatment was 18 (F) and 7 (G). No toxic death occurred. Main grade 3-4 toxicities (arm F vs G) were G3 neutropenia (32%/17.5), G4 neutropenia (19.5%/0), G3-4 thrombocytopenia (12%/0), G3 vomiting (17%/2.5), G3 transaminases (0%/15) and G3-4 fatigue (27%/15).Confirmed partial responses (PR) rates (F/G) were 38.7% (12/31) and 11.7 % (4/34) according to the investigators and median duration of response was 6,3 and 4,6 mo. PR and stable disease (SD) were documented for 21/31 evaluable pts in arm F and expert review confirmed 13 PR (41.9 %) and 6 SD (19.3%). Conclusions: Folfirinox induces a response rate > 30% with manageable toxicity in ECOG 0-1 pts with MPA. According to these interim results, this trial will continue as a phase III study. Updated results will be presented at the meeting. Supported by a PHRC 2004 grant from the French Ministry of Health.

Background Advanced pancreatic adenocarcinoma remains an incurable disease with few good treatment options. Weekly gemcitabine has been widely adopted as the standard of care, with median survival of 4.6 to 7.3 months in phase III randomized studies.

Background Folfirinox regimen (oxaliplatin, irinotecan, bolus and continuous infusion 5-FU plus leucovorin) was assessed in a phase II study and seems promising in good performance status patients (Conroy T et al. J Clin Oncol 2005;23: ). A confirmed response rate of 25.7 % and a median overall survival of 9.5 months was described in 35 patients with metastatic disease. Quality of life (assessed with EORTC QLQ-C30) was improved.

Background Therefore, we launched a phase II-III randomized study comparing Folfirinox regimen to gemcitabine alone. We report here the first results of the randomized phase II step.

Objectives Primary objective (for the phase II step) : to assess the response rate in both arms Secondary objective to assess the toxicity profile of each arm using NCI-CTC version 3.0, especially grade 3-4 toxicities

Study design Multicenter (n=17) randomized phase II trial Randomization between the 2 arms with stratification according to : center performance status : 0 versus 1 location of the tumor : head versus other location of pancreatic tumors

Treatments Arm A: FOLFIRINOX Oxaliplatin 85 mg/m 2 in 2 hours infusion, Folinic acid 400 mg/m 2 in 2 hours infusion, Irinotecan 180 mg/m 2 in 90mn infusion, Bolus 5-FU 400 mg/m 2, Continuous infusion 5-FU 2.4 g/m 2 on 46 hours. 1 cycle = 14 days 1 h 30 2 h 46 h L-OHP 85 mg/m2 CPT mg/m2 Leucovorin 400 mg/m2 Continuous 5-FU mg/m 2 Bolus 5-FU 400 mg/m 2

Treatments Arm B: Gemcitabine Gemcitabine 1000 mg/m2 over 30 minutes given weekly X 7/8 and then weekly X 3/4 1 cycle = 28 days A 6 months duration of chemotherapy was advised for both arms

Statistical considerations The sample size calculation was calculated to reject a 10% response rate in favor of a target response rate of 24% for the experimental arm, with a significance level of 0.05 and a power of 92% by using Fleming's method: - In the initial stage, a total of 20 evaluable patients were to be entered and evaluated for response. If there was less than 3 responses, accrual was to be terminated. - If more than 3 responses were observed in the first stage, then 10 additional patients were to be entered in the second stage to achieve a target sample size of 30 evaluable patients. - Further accrual of 10 patients was planned if more than 4 responses were observed in the first 30 patients in the Folfirinox arm. A sample size of 80 patients (40 patients per study arm) was needed. Taking into consideration the estimate of approximately 5% of patients which will not be evaluable, a total number of 88 patients had to be randomized.

Inclusion criteria Histologically or cytologically proven adenocarcinoma of the pancreas ECOG performance status of 0 or 1 Measurable metastases (outside a radiotherapy field) No prior cytotoxic chemotherapy No prior abdominal radiotherapy Age years Adequate hematopoietic, hepatic and renal function No unstable angina or myocardial infarction within 12 months before the study Written informed consent

Non inclusion criteria Other pancreatic tumor (endocrine, acinar cell…) Central nervous system metastases Chronic diarrhea Previous or concomitant other malignant disease Locally advanced pancreatic cancer without distant metastases (stage III)

Efficacy assessment Tumor Response investigator assessment every 8 weeks according RECIST criteria independent blinded review of Objective Response (OR) and Stable Disease (SD) Quality of life assessment with EORTC QLQ-C30 (results not shown)

RESULTS Inclusion period from January 2005 to October PS (WHO) [35-71] 58 [38-76] Median age (years) [range] 26/1829/15Sex ratio M / F Gemcitabine (B) n = 44 FOLFIRINOX (A) n = 44 Patients characteristics (1)

RESULTS Measurable Site Liver Pancreas Nodes Peritoneal Lung Other 26 Pancreatic Tumor Resected Tumor Location Head Other Gemcitabine (B) n = 44 FOLFIRINOX (A) n = 44 Patients characteristics (2)

RESULTS 0 2 (4%) 7 (16%) 6 (14%) Anemia 0 1 (2%) Febrile neutropenia 16 (37%)38 (88%) Neutropenia Gemcitabine (B) n = 43 Number of patients (%) FOLFIRINOX (A) n = 43 Number of patients (%) Main grade 3-4 hematological toxicities Thrombopenia

RESULTS 2 (4%) 6 (14%) 2 (4%) 3 (7%) 0 (0%) 15 (35%) 10 (23%) 6 (14%) 1 (2%) 2 (4%) 10 (23%) 15 (35%) Vomiting Gemcitabine (B) n = 43 Number of patients (%) FOLFIRINOX (A) n = 43 Number of patients (%) Main grade 3-4 non hematological toxicities Nausea Diarrhea Abdominal cramps Neuropathy Fatigue

RESULTS – EFFICACY 9 (20.4 %) 27 (61.4 %) 3 (6.8 %) 12 (27.3 %) 15 (34.1 %) 3 (6.8 %) Stable Disease (SD) 5 (11.4 %) [ %] 14 (31.8 %) [ %] Partial Response (PR) [ 95 % IC ] 00Complete Response (CR) Gemcitabine (B) n = 44 FOLFIRINOX (A) n = 44 Investigators Response Rate* (ITT Population) Progressive Disease (PD) Non Evaluable (NE)** * Panel confirmed 15 PR in arm A and 4 in arm B ** 2 non treated and 4 ineligible

Conclusions Folfirinox induces a response rate > 30% with manageable toxicity in ECOG 0-1 pts with metastatic pancreatic adenocarcinoma. According to these interim results, this trial will continue as a phase III study to demonstrate an improvement in overall survival.

Acknowledgments  Patients  Co-investigators  Sponsor : J. Genève, M. Torres, F. Do Nascimento, AC. Le Gall (FNCLCC, BECT, Paris)  Data center : C. Kadouci (Centre Alexis Vautrin, Nancy)  Supported by a Clinical Research Hospital Program grant (PHRC 2004) grant from the French Ministry of Health  Grants from Pfizer and sanofi-aventis