RANDOMIZED PHASE III TRIAL COMPARING FOLFIRINOX (5FU/leucovorin, irinotecan and oxaliplatin) VS...
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Transcript of RANDOMIZED PHASE III TRIAL COMPARING FOLFIRINOX (5FU/leucovorin, irinotecan and oxaliplatin) VS...
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