1. RANDOMIZED PHASE III TRIAL COMPARING FOLFIRINOX (5FU/leucovorin, irinotecan and oxaliplatin) VS GEMCITABINE AS FIRST-LINE TREATMENT FOR METASTATIC PANCREATIC ADENOCARCINOMA Prodige 4 - ACCORD 11/0402 trial: final results
T. Conroy, F. Desseigne, M. Ychou, M. Ducreux, O. Bouché, R. Guimbaud, Y. Bécouarn, C. Montoto-Grillot, S. Gourgou-Bourgade, A. Adenis, FNCLCC-FFCD Prodige group
Centre Alexis Vautrin, Nancy; Centre Léon Bérard, Lyon; Centre Val d'Aurelle, Montpellier; Institut Gustave Roussy, Villejuif; Centre Hospitalier R. Debré, Reims; Institut Claudius Regaud, Toulouse; Institut Bergonié, Bordeaux; Fédération Nationale des Centres de Lutte Contre le Cancer - BECT, Paris; Centre Oscar Lambret, Lille; FRANCE

2. Background Metastatic pancreatic ductal adenocarcinoma:
incurable disease
few good treatment options
Gemcitabine as single agent:
cornerstone of treatment
median survival: 6 to 7 mo.
Gemcitabine-based combinations generally failed to increase survival
Some trials suggested a possible benefit from combination chemotherapy in good performance status patients

3. Background Folfirinox regimen assessed in a phase II study (n=35)
promising regimen in good PS patients with M1 disease
median survival of 9.5 months
A phase II-III randomized study comparing Folfirinox regimen to gemcitabine alone was launched
Results of phase II randomized study step (n=88) were presented during ASCO 2007:
31.8% RR in the Folfirinox arm vs
11.4% in the gemcitabine arm
Due to these encouraging interim results, the trial continued as a phase III study.
Conroy T et al. J Clin Oncol 2005;23:
Ychou M et al. J Clin Oncol 2007;25:18S:201s

4. Prodige 4 - ACCORD 11 trial design
6 months of chemotherapy recommended
CT scans: obtained every 2 months
for both arms: R A N D O M I Z E
Folfirinox
Metastatic
pancreatic
cancer
Gemcitabine
Stratification :
center
performance status: 0 versus 1
location of the tumor: head versus other location of the primary

5. Inclusion Criteria
Histologically/cytologically confirmed pancreatic adenocarcinoma
ECOG performance status of 0 or 1
Measurable metastases
No prior cytotoxic chemotherapy
No prior abdominal radiotherapy
Age years
Adequate hematopoietic, hepatic and renal function
Bilirubin < 1.5 UNL
No unstable angina or myocardial infarction within 12 months before entry
Written informed consent

6. Non Inclusion Criteria
Non ductal pancreatic cancer (endocrine, acinar cell…)
Adenocarcinoma of the ampulla of Vater
Unresectable locally advanced pancreatic cancer without distant metastases (stage III)
Central Nervous System metastases
Chronic diarrhea
Other previous or concomitant malignant disease

7. Experimental Arm: FOLFIRINOX
Oxaliplatin mg/m2 over 2 hours,
Leucovorin 400 mg/m2 over 2 hours,
Irinotecan mg/m2 in 90 mn infusion,
5-FU mg/m2 bolus,
5-FU mg/m2 on 46-h infusion cycle = 14 days
Bolus 5-FU 400 mg/m2
2 h
Oxaliplatin
85 mg/m2
Leucovorin
400 mg/m2
Continuous 5-FU
2.400 mg/m2
Irinotecan
180 mg/m2
2 h
46 h
1 h 30
q2wks

8. Reference Arm: Gemcitabine
1000 mg/m2 over 30 minutes
given weekly x 7/8
and then weekly x 3/4
1 cycle = 14 days
Burris AH et al. J Clin Oncol 1997;15:

9. Endpoints Primary: overall survival Secondary:
objective response rate (RECIST)
toxicity (NCI-CTC version 3.0 grading)
progression-free survival (PFS)
quality of life (EORTC QLQ-C30 v 3.0)

10. Statistical considerations
Hypothesis: Study designed to have 80% power to detect an increase in median overall survival from 7 to 10 months (HR 0.70)
Sample size:
360 patients required to reach 250 events for final analysis, based on the use of the log-rank test with a two-sided significance level of 5%
Planned interim analysis after observation of 167 events
Intent to treat analysis (ITT)

11. Trial progress Recruitment: January 2005-October 2009
IDMC meeting, 30 September, 2009: Preplanned interim analysis after 192 events
Recommendation to stop accrual: preplanned primary objective met (p <0.001)
Final accrual of 342 patients
Current analysis database frozen: 16 April, 2010
Number of deaths observed: 273 (73.4% of the sample size)

12. Flow Chart Folfirinox Gemcitabine Total Total randomized 171 342
Did not fulfill all eligibility criteria 8* 7*
15 (4%)
Untreated patients 4 2
6 (2%)
ITT population
342 (100%)
Safety population
167
169
336 (98%)
*Folfirinox arm : 2 patients > 76 years; one patient PS=2; patients with high bilirubin, high creatinine or low platelets
*Gemcitabine arm: 7 patients with high bilirubin, high creatinine or low platelets

13. Patients characteristics
Folfirinox
N=171
Gemcitabine p
Median age (yrs)
[range] 61
[25-76]
[34-75] NS
Sex
Male
Female
106 (62%)
65 (38%)
105 (61.4%)
66 (38.6%)
Baseline PS 1 2
64 (37.4%)
106 (62.0%)
1 (0.6%)
0 (0.0%)
Location of primary
Head
Other
62 (36.3%)
109 (63.7%)
60 (35.1%)
111 (64.9%)

14. Disease characteristics
Folfirinox
N=171
Gemcitabine p
Synchronous metastases
Metachronous metastases
156 (91.2%)
15 (8.8%)
161 (94.2%)
10 (5.8%) NS
Median nr. of involved sites
CA19-9  59 ULN
2 (1-6)
68 (41.5%)
77 (46.7%)
Measurable site
Liver
Pancreas
Nodes
Lungs
Peritoneal
149 (88.2%)
89 (52.7%)
48 (28.4%)
33 (19.5%)
150 (87.7%)
91 (53.2%)
39 (22.8%)
49 (28.7%)
32 (18.7%)
0.049

15. Safety: hematological AEs
AE, % per patient
Folfirinox
N=167
Gemcitabine
N=169 p
All
Grade 3/4
Neutropenia
79.9
45.7
54.8
18.7
0.0001
Febrile Neutropenia
7.2
2.4
0.6
0.009
Anemia
90.4
7.8
94.6
5.4 NS
Thrombocytopenia
75.2
9.1
0.008
5.4
42.5 % of the pts received G-CSF in the F arm vs 5.3% in the G arm
One toxic death occurred in each arm
AE, adverse event

16. Safety: main non-hematological AEs
AE, % per patient
Folfirinox N=167
Gemcitabine N=169 p
All
Grade 3/4
Infection without neutropenia 6
1.2
7.1
1.8 NS
Peripheral neuropathy
70.5 9
0.6
0.0001
Vomiting
61.4
14.5
43.2
4.7
0.002
Fatigue
87.3
23.2
78.7
14.2
0.036
Diarrhea
73.3
12.7
30.8
Alopecia (grade 2)
32.5
(11.4)
3.0
(0.6)
ALT
64.8
7.3
83.8
0.0022
18.6

17. Objective Response Rate
Folfirinox
N=171
Gemcitabine p
Complete response
0.6% 0%
Partial response
31%
9.4%
0.0001
CR/PR 95% CI
[ ]
[ ]
Stable disease
38.6%
41.5%
Disease control
CR+PR+SD
70.2%
50.9%
0.0003
Progression
15.2%
34.5%
Not assessed
14.6%
Median duration of response
5.9 mo.
4 mo. ns

18. Progression-Free Survival
Median PFS Folfirinox: 6.4 mo. Median PFS Gemcitabine: 3.3 mo

19. Overall Survival Median survival 11.1 mo. 6.8 mo. <0.0001 0.57
Median follow up: 26.6 months [95% CI: 20.5 – 44.9]
Folfirinox
N=171
Gemcitabine p HR
Median survival
[CI 95%]
11.1 mo.
[ ]
6.8 mo.
[ ]
<0.0001
0.57
1-yr. survival
48.4%
20.6%
18-mo. survival
18.6% 6%

20. Overall Survival

21. Time to definitive QoL degradation

22. Conclusions
Folfirinox treatment resulted in a higher frequency of gr. 3/4 febrile neutropenia (5.4%), emphasizing the need for vigilant patient selection, education, monitoring, and active management
Folfirinox regimen:
is more toxic but has manageable toxicity
Significantly improves PFS: reduced risk of disease progression by 53%
Delays QoL degradation
Significantly improves overall survival (HR 0.57, p<0.0001) : median survival 11.1 mo.
Folfirinox recommended as new worldwide standard of care for patients with metastatic pancreatic cancer, bilirubin <1.5 UNL and PS 0-1
This combination will be tested in adjuvant setting

23. Thank you !
To our very brave and wonderful patients and their families who trust us.
To enthusiastic CRA (M. Torres-Macque, F. Nait-Atmane, S. Prigent, S. Levêque), Anne-Chantal Le Gall, and safety department (J. Genève, MD, and collaborators) who also trust us... but check everything!
To our remarkably efficient data-managers (A. Pommier and S. Louveau)
To all investigators of the 48 active centers, their pharmacists and research staff for quick accrual and excellent quality of the data
To very talented physicians and statisticians who helped to plan and execute this trial
To IDMC members (B. Asselain, MD; E. François, MD; Pr E. Gamelin, MD; Pr C. Louvet, MD) for their sound advice.
Trial supported by two Clinical Research Hospital Program grants (PHRC 2004 and 2007) from the French Ministry of Health.
sanofi-aventis and Pfizer for oxaliplatin and irinotecan supply.
Grants from Amgen and from the French National League Against Cancer.

24. Acknowledgements
All investigators : Dr Françoise DESSEIGNE, Dr Christelle de la FOUCHARDIERE Centre Léon Bérard LYON ; Pr. Marc YCHOU Centre Val d'Aurelle MONTPELLIER ; Pr. Michel DUCREUX Institut Gustave Roussy VILLEJUIF ; Pr Olivier BOUCHE Centre Hospitalier R. Debré REIMS ; Pr Rosine GUIMBAUD Institut Claudius Regaud TOULOUSE ; Dr Yves BECOUARN Institut Bergonié BORDEAUX ; Pr. Antoine ADENIS Centre Oscar Lambret LILLE; Pr. Jean-Luc RAOUL Centre Eugène Marquis RENNES ; Pr Philippe ROUGIER Hôpital Ambroise Paré BOULOGNE-BILLANCOURT ; Dr Jaafar BENNOUNA Centre René Gauducheau NANTES - St HERBLAIN ; Dr Marie-Christine KAMINSKY, Dr Ivan KRAKOWSKI, Centre Alexis Vautrin, NANCY; Dr Faiza KHEMISSA-AKOUZ Centre hospitalier M. Joffre PERPIGNAN ; Dr Denis PÈRE-VERGÉ Hôpital de la Croix-Rousse LYON ; Dr Catherine DELBALDO CHU Henri Mondor CRETEIL ; Pr Bruno CHAUFFERT Centre François Leclerc DIJON; Pr Pierre MICHEL CHU ROUEN ; Dr Thierry N'GUYEN CHU Jean Minjoz BESANCON ; Dr Jean-Louis JOUVE CHU du Bocage DIJON ; Dr Gilles PIOT CMC Les Ormeaux Vauban LE HAVRE ; Dr Mohammed GASMI Hôpital Nord MARSEILLE ; Dr Patrick TEXEREAU Centre Hospitalier Général MONT DE MARSAN ; Dr Christian BOREL Centre Paul Strauss STRASBOURG ; Dr Frédérique CVITKOVIC Centre René Huguenin SAINT-CLOUD ; Dr Marie-Pierre GALAIS Centre François Baclesse CAEN ; Dr Thierry LECOMTE Centre hospitalier TOURS ; Dr Jean-Paul LAGASSE CHR ORLEANS ; Pr Françoise MORNEX Centre Hospitalier Lyon Sud PIERRE-BENITE ; Dr Dominique ARSENE Centre hospitalier universitaire CAEN ; Dr Yves RINALDI Hôpital Ambroise Paré MARSEILLE ; Dr Gaël DEPLANQUE Hôpital Saint Joseph PARIS  ; Pr Thomas APARICIO Hopital Bichat-Claude Bernard PARIS; Dr Vanessa PALASCAK-JUIF Hôpital Hautepierre STRASBOURG ; Dr Gaëtan DES GUETZ Hôpital Avicenne BOBIGNY ; Dr Cédric LECAILLE Polyclinique Bordeaux Nord Aquitaine BORDEAUX ; Dr Catherine LOMBARD-BOHAS Hôpital Edouard Herriot LYON; Dr Pierre-Luc ETIENNE Clinique Armoricaine de Radiologie SAINT-BRIEUC ; Dr Laurent CHARNEAU Hôpital Duchenne BOULOGNE sur MER ; Dr Serge FRATTE CH de Belfort-Montbéliard BELFORT ; Dr Gilles BREYSACHER Hôpitaux Civils de Colmar COLMAR ; Dr Ahmed AZZEDINE Centre Hospitalier Henri Duffaut AVIGNON ; Dr Jean-Paul JOLY CHU Amiens Picardie AMIENS ; Dr Laurent POINCLOUX CHU Hôtel Dieu CLERMONT-FERRAND ; Dr Anne-Marie QUEUNIET CHI Elbeuf-Louviers-Val de Reuil St AUBIN lès ELBEUF ; Dr Jean-Frédéric BLANC Hôpital Saint André BORDEAUX ; Dr Olivier DUBROEUCQ Institut Jean Godinot REIMS ; Dr Christophe DESAUW Hôpital Saint Vincent de Paul LILLE ; Pr Jean-François SEITZ CHU de la Timone MARSEILLE; Dr Christian PLATINI Hôpital Bon Secours METZ. FRANCE