LV5FU2-cisplatin followed by gemcitabine or the reverse sequence in metastatic pancreatic cancer: Preliminary results of a randomized phase III trial (FFCD 0301). E. Mitry, L. Dahan, M. Ychou, J. Arthaud, M. Gasmi, J. Raoul, C. Mariette, J. M. Phelip, L. Bedenne, J.F. Seitz, Fédération Francophone de Cancérologie Digestive

Abstract Background: Pts with metastatic pancreatic adenocarcinoma (MPA) have a poor prognosis with no major survival improvement since the introduction of gemcitabine (Burris 1997). The LV5FU2-P regimen was reported as safe and active with a 9 months median overall survival (OS) in a phase II trial (Taïeb 2002). This randomized multicenter phase III trial compared LV5FU2-P followed by gemcitabine in arm A versus gemcitabine followed by LV5FU2-P in arm B to evaluate the best sequence. Methods: Pts with measurable MPA, PS 0-2, non prior CT, were randomly assigned to receive either LV5FU2-P (2-hour infusion of LV 200 mg/m2 followed by a FU bolus 400 mg/m2 and 46-hour infusion 2,400 mg/m2 every 2 weeks, with cisplatin 50 mg/m2 as a 2-hour infusion on D1 or 2, followed by gemcitabine (1,000 mg/m2 for 7 weeks out of 8 and then 3 weeks out of 4) at progression or toxicity (arm A) or the opposite sequence (arm B). Randomization was done using minimization with stratification according to center, PS tumoral localization and infusion duration. Primary endpoint was OS. It was required to include 202 pts and observe 170 deaths to detect an expected improvement in median OS from 6.5 to 10 months in arm A (bilateral α = 5% and β = 20%). Secondary endpoints included progression free-survival (PFS) after first and second line, toxicity, quality of life (QLQ-C30) and percentage of second line in each arm. Results: From 08/2003 to 05/2006, 202 pts were included in 33 centers, 102 in arm A and 100 in arm B. Median age (62 [40 - 84] vs 64 [39 - 81] years), male/female ratio (1.7 vs 1.7), PS 0-1 (76.5% vs 83%), previous surgery (22.5% vs 27%). After a median follow-up of 33,6 months [min 17; max 48], 185 pts had died. Median OS for arm A was 6.6 months [95% CI- 5.2 to 8.4] versus 8.2 months [95% CI- 6.1 to 9.7] for arm B (HR B vs A 0.95 [95% CI 0.71 - 1.27], Log Rank p = 0.72). 1- year and 2-year survival rates were 29.5% and 8% for arm A versus 34.5% and 3.5% for arm B, respectively. Conclusions: This trial failed to reach its primary endpoint and both sequences achieved a similar efficacy with no significant differences between the two arms in median OS. Updated results (including response, PFS and toxicity analyses) will be presented at the meeting.

Introduction Pts with metastatic pancreatic adenocarcinoma (MPA) have a poor prognosis with no major survival improvement since the introduction of gemcitabine (Burris 1997). The LV5FU2-P regimen was reported as safe and active with a 9 months median overall survival (OS) in a phase II trial (Taïeb 2002).

Gemcitabine followed by LV5FU2-P at progression or toxicity Study design Multicentre phase III study To compare the best sequence of chemotherapy Stratification: Centre WHO PS (0,1 vs 2) Location (head vs other) GEM infusion rate Arm A: LV5FU2-P followed by Gemcitabine at progression or toxicity Arm B: Gemcitabine followed by LV5FU2-P at progression or toxicity R (Minimization) Gemcitabine: 1000 mg/m² on D1 as a 30 mn infusion or with an infusion rate of 10 mg/m2/min* , weekly 7 weeks /8, then 3 weeks / 4 LV5FU2-P: 2-hour infusion of LV 200 mg/m2 followed by a FU bolus 400 mg/m2 and 46-hour infusion 2,400 mg/m2 every 2 weeks, with cisplatin 50 mg/m2 as a 2-hour infusion on D1 or D2 (* Each participating centre had to always use the same administration method)

Primary endpoint : overall survival Secondary endpoints (Time interval between randomization and death from all causes) Secondary endpoints Progression Free survival (Time interval between randomization and first progression or death from all causes) Progression free survival after 1st and 2nd line Proportion of patients receiving a second line Tolerance Quality of life (EORTC QLQ-C30)

Statistical analyses : Sample Size : inclusion of 202 pts with 170 deaths required to detect an expected improvement in median OS from 6.5 to 10 months in arm A (bilateral α = 5% and β = 20%) Strict intent to treat analyses Fischer exact test or Chi2 to compare qualitative variables Wilcoxon test to compare continuous variables Survival calculated using Kaplan Meier estimation Log Rank and stratified Log Rank to compare survival curves Univariate Cox analyses to calculate Hazard Ratio and its 95% CI Median Follow-up calculated using Reverse Kaplan Meier method

Inclusion criteria Pathologically-proven pancreatic adenocarcinoma Metastatic disease (locally advanced patients excluded) Measurable disease No previous chemotherapy WHO performance status 0-2 Age ≥18 years Life expectancy > 2 months Adequate biologic parameters Written informed consent

Enrollment Period of inclusion: 08-2003 to 05-2006 33 participating centres 202 patients randomized (Arm A: 102, arm B: 100) 5 untreated patients (Arm A: 1, Arm B: 4) Date of point: October, 1st 2007 Number of death : 188 pts Arm A: 93 (91.2%) Arm B: 95 (95.0%) Median follow-up time: 44 months Intent to treat popultation: 202 pts Evaluable for tolerance: 197 pts 5 untreated patients : raison = inconnue pour le moment

Baseline characteristics ARM A n (%) ARM B n (%) n 102 100 Median age years [range] 62 [40-84] 64.5 [39-81] WHO PS 28 (27.4) 30 (30.0) 1 51 (50.0) 53 (53.0) 2 22 (21.6) 14 (14.0) unknown 1 (1.0) 3 (3.0) Male 65 (63.7) 65 (64.0) Primary tumor location Head 57 (55.9) 49 (49.0) Other 44 (43.1) 50 (50.0) Unknown Stage Metastatic 100 (99.0) 99 (99.0) Metastatic sites Liver 87 (85.3) 90 (90.0) Peritoneum 11 (10.8) 17 (17.0) Lymph nodes 18 (17.6) 24 (24.0) Lung 15 (14.7) 12 (12.0) CA 19.9 (n, median value UI/ml) 95, 565 95, 560 No statistically significant difference between treatment groups

Treatment administration ARM A n=102 ARM B n=100 p Pts receiving a 2nd line 69 (67.7%) 55 (55%) 0.127 LV5FU2-P Line of treatment First line Second line N of pts with at least 1 administration 101 (99.0 %) 55 (55 %) <0.001 Median number of cycles [range] (1 cycle = 1 month) 3 [1-16] 2 [1-9] 0.8 Median dose (mg) [range] Bolus 5FU 1248 [0-3440] 1285 [0-1764] Continuous 5FU 7236 [970-10480] 7628 [2000-9800] 0.055 Cisplatin 155 [0-440] 160 [0-200] 0.2 GEMCITABINE 69 (67.7 %) 96 (96 %) Median number of cycles [range] 1[1-14] 3 [1-13] 0.0024 Gemcitabine 4525.5 [1178-18025] 5100 [0-15120] 0.159

Tolerance (grade 3-4 toxicity per patient) ARM A (%) ARM B (%) p LV5FU2-P Line of treatment First Second Safety population N With available Toxicity reports 101 99 55 All toxicities 79.8 70.91 0.2 Hematological toxicity 49.5 34.5 0.1 Non-hematological toxicity 54.5 50.9 0.7 GEMCITABINE 69 68 96 94 75.0 64.9 58.8 35.1 0.002 51.5 46.8 0.084 Overall toxicity (1st + 2nd line) 87.0 81.1 0.256 60.0 43.2 0.018 70.0 63.2 0.311

Tumor response (Best observed overall response, RECIST criteria) ARM A n=102 n (%) ARM B n=100 n (%) p Complete response 3 (2.9) 4 (4.0) 0.78 Partial response 16 (15.7) 18 (18.0) Stable disease 39 (38.2) 37 (37.0) Progression 24 (23.5) 17 (17.0) Non evaluable 2 (1.9) 1 (1.0) Unknown 18 (17.6) 23 (23.0)

Overall survival ARM A ARM B 6.63 [5.27 – 8.07] 8.03 [5.93 – 9.97] Primary endpoint of the study ARM A ARM B P (log-rank) Median survival months [95% CI] 6.63 [5.27 – 8.07] 8.03 [5.93 – 9.97] 0.77

Progression free-survival ARM A ARM B P (log-rank) Median PFS months [95% CI] 3.83 [2.36 – 7.03] 4.73 [2.43-8.23] 0.90 PFS 1st line, PFS 2nd line : not yet available

Conclusion The primary endpoint of the study is not reached : there is no significant difference in overall survival between arm A and B More patients received a second-line when treated with LV5FU2-P in first-line (non significant) Gemcitabine appears to be more toxic when given in second line. While the overall toxicity was not different between arms we observe an increase of overall hematological toxicities for arm A. => Gemcitabine remains the first choice in the front-line treatment of advanced pancreatic adenocarcinoma