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

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

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;23:1228-36

Ychou M et al. J Clin Oncol 2007;25:18S:201s

Prodige 4 - ACCORD 11 trial design

Stratification :

center performance status: 0 versus 1 location of the tumor: head versus other location of the primary

Metastaticpancreaticcancer

RANDOMIZE

Folfirinox

Gemcitabine

6 months of chemotherapy recommended

CT scans: obtained

every 2 months

for both arms:

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 18-75 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

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

Experimental Arm: FOLFIRINOX

Oxaliplatin 85 mg/m2 over 2 hours,Leucovorin 400 mg/m2 over 2 hours,Irinotecan 180 mg/m2 in 90 mn infusion,5-FU 400 mg/m2 bolus, 5-FU 2400 mg/m2 on 46-h infusion.

1 cycle = 14 days

1 h 30

2 h

2 h 46 h

Oxaliplatin85 mg/m2

Irinotecan180 mg/m2

Leucovorin400 mg/m2

Continuous 5-FU 2.400 mg/m2

Bolus 5-FU 400 mg/m2

q2wks

Reference Arm: Gemcitabine

Gemcitabine 1000 mg/m2 over 30 minutes

given weekly x 7/8and then weekly x 3/4

1 cycle = 14 days

Burris AH et al. J Clin Oncol 1997;15:2403-13

Endpoints

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)

Primary: overall survival

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)

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)

Flow Chart

Folfirinox Gemcitabine Total

Total randomized 171 171 342

Did not fulfill all eligibility criteria

8* 7* 15 (4%)

Untreated patients 4 2 6 (2%)

ITT population 171 171 342 (100%)

Safety population 167 169 336 (98%)

*Folfirinox arm : 2 patients > 76 years; one patient PS=2; 5 patients with high bilirubin, high creatinine or low platelets

*Gemcitabine arm: 7 patients with high bilirubin, high creatinine or low platelets

Patients characteristics

CharacteristicFolfirinox

N=171

GemcitabineN=171

p

Median age (yrs)

[range]

61

[25-76]

61

[34-75]NS

Sex Male

Female

106 (62%)

65 (38%)

105 (61.4%)

66 (38.6%) NS

Baseline PS 0

1

2

64 (37.4%)

106 (62.0%)

1 (0.6%)

66 (38.6%)

105 (61.4%)

0 (0.0%)NS

Location of primary Head

Other

62 (36.3%)

109 (63.7%)

60 (35.1%)

111 (64.9%) NS

Disease characteristics

CharacteristicFolfirinox

N=171

GemcitabineN=171

p

Synchronous metastases

Metachronous metastases

156 (91.2%)

15 (8.8%)

161 (94.2%)

10 (5.8%)

NS

NS

Median nr. of involved sites

CA19-9 59 ULN

2 (1-6)

68 (41.5%)

2 (1-6)

77 (46.7%)

NS

NS

Measurable site

Liver

Pancreas

Nodes

Lungs

Peritoneal

149 (88.2%)

89 (52.7%)

48 (28.4%)

33 (19.5%)

33 (19.5%)

150 (87.7%)

91 (53.2%)

39 (22.8%)

49 (28.7%)

32 (18.7%)

NS

NS

NS

0.049

NS

Safety: hematological AEs

AE, % per patient

FolfirinoxN=167

GemcitabineN=169

p

All Grade 3/4 All Grade 3/4 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 54.8 2.4 0.008

5.4

42.5 % of the pts received G-CSF in the F arm vs 5.3% in the G armOne toxic death occurred in each armAE, adverse event

Safety: main non-hematological AEs

AE, % per patientFolfirinox N=167 Gemcitabine N=169

pAll Grade 3/4 All Grade 3/4

Infection without neutropenia

6 1.2 7.1 1.8 NS

Peripheral neuropathy 70.5 9 0.6 0 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 1.2 0.0001

Alopecia (grade 2) 32.5 (11.4) 3.0 (0.6) 0.0001

ALT 64.8 7.3 83.8 0.002218.618.6

Objective Response Rate

FolfirinoxN=171

GemcitabineN=171

p

Complete response 0.6% 0%

Partial response 31% 9.4% 0.0001

CR/PR 95% CI [24.7-39.1] [5.9-15.4]

Stable disease 38.6% 41.5%

Disease control

CR+PR+SD70.2% 50.9% 0.0003

Progression 15.2% 34.5%

Not assessed 14.6% 14.6%

Median durationof response

5.9 mo. 4 mo. ns

Progression-Free Survival

0.00

0.25

0.50

0.75

1.00

Pro

babi

lity

171 121 85 42 17 7 4 1 1 0 0 0 0Folfirinox171 88 26 8 5 2 0 0 0 0 0 0 0Gemcitabine

Number at risk

0 3 6 9 12 15 18 21 24 27 30 33 36Months

Gemcitabine Folfirinox

p<0.0001

HR=0.47 : 95%CI [0.37-0.59]

Median PFS Folfirinox: 6.4 mo. Median PFS Gemcitabine: 3.3 mo

Overall Survival

Folfirinox

N=171

Gemcitabine

N=171 p HR

Median survival[CI 95%]

11.1 mo.[ 9 - 13.1]

6.8 mo.[ 5.5 - 7.6]

<0.0001 0.57

1-yr. survival 48.4% 20.6%

18-mo. survival 18.6% 6%

Median follow up: 26.6 months [95% CI: 20.5 – 44.9]

Overall Survival

0.00

0.25

0.50

0.75

1.00

Pro

babi

lity

171146116 81 62 34 20 13 9 5 3 2 2Folfirinox171134 89 48 28 14 7 6 3 3 2 2 2Gemcitabine

Number at risk

0 3 6 9 12 15 18 21 24 27 30 33 36Months

Gemcitabine Folfirinox

Stratified Log-rank test, p<0.0001

HR=0.57 : 95%CI [0.45-0.73]

Time to definitive QoL degradation

0.00

0.25

0.50

0.75

1.00

Pro

babi

lity

163 89 35 13 4 1 1Folfirinox157 53 9 1 0 0 0Gemcitabine

Number at risk

0 3 6 9 12 15 18Months

Gemcitabine Folfirinox

p=.001

Kaplan-Meier estimation for TUDD ofGlobal health status/QoL (MCID 10 points)

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

Thank you !

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.

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.

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