Conditions: Metastatic Pancreatic Cancer
Keywords: cancer pancreatic cancer metastatic pancreatic cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 276
Healthy volunteers: no

Brief summary:
The pancreas cancer is the 4th cause of death. All stage confused, the survival at 5 years is note over 5 %. At metastatic stage, the pancreatic adenocarcinoma is an incurable disease with the survival median of 2-4 months without chemotherapy.

Up to 2011, gemcitabine was the only reference treatment of this type of cancer. But until, the FOLFIRINOX could permitted to improve significantly the overall survival (6,8 months with gemcitabine vs 11,1 months with FOLFIRINOX) and the progression free survival (3,3 months with gemcitabine vs 6,4 months with FOLFIRINOX) for patients under 76 years. Main toxicities of this treatment are hematological, gastrointestinal and neuropathy with apparition of sensitive neuropathy, reversible, related to oxaliplatin.

These results are on a population under 76 years old. In this study, the median age of patients at inclusion was 61 years old and FOLFIRINOX was still beneficial for patients more than 65 years old. Given the increase of proportion of patients than more of 65 years old with pancreatic cancer and given the increase of life expected, it is important to know the effectiveness and tolerance of such treatment for patient older than 65 years and 76 years.

FIRGEM is an original strategic sequential treatment witch alternates, every 2 month, 4 cycles of FOLFIRI.3 and 2 cycles of 3 injections of gemcitabine. There is no cross resistance known between this 2 treatments witch limit toxicities and preserve quality of life of patients. A Phase II trial testing this treatment regimen to classical regimen of gemecitabine, showed an overall survival of 11 months in the FIRGEM regimen and an overall survival of 8,2 months in the gemcitabine regimen. The rate of progression was 45% near of progression rate with FOLFIRINOX. Tolerance is close to that FOLFIRINOX regimen but this strategic doesn't induce limiting neurotoxicities and allow to use oxaliplatin in 2de line of treatment.

The trial propose to evaluate the effectiveness and tolerance of FOLFIRINOX regimen (8 cycles) with LV5FU2 in maintenance (that could increase the FOLFIRINOX tolerable without decrease efficiency), to FIRGEM regimen and to FOLFIRINOX (12 cycles) which is the reference regimen.

Detailed description:

Arms:
arm 1: Every two weeks (maximum of 12 cycles) : Oxaliplatin 85 mg / m2 Day1 in 2 hours - then Irinotecan 180 mg / m2 Day1 in 90 minutes - Folinic acid 400 mg / m2 Day1 in 2 h (during the irinotecan infusion) - 5-FU bolus 400 mg / m² Day1 followed by continuous 5-FU 2400 mg / m2 total over 46 hours arm 2: Folfirinox during 4 months followed by LV5FU2 maintenance until progression:

Folfirinox (as described in arm FOLFIRINOX) LV5FU2 : Folinic acid 400 mg/m² (200 mg/m² if Elvorine), in perfusion over 2 hours the 5FU 400 mg/m² in bolus over 10 mn followed by 5FU 2400 mg/m² in perfusion over 46 hours. arm 3: Alternance of 2 months of FOLFIRI.3 with 2 months of GEMCITABINE:

Folfiri.3: Irinotécan 90 mg/m² at day 1 in perfusion over 60 minutes in parralel of folinic acid Folinic acid 400 mg/m² (or 200 mg/m² Elvorine) at day 1 in perfusion over 2 hours 5FU continue 2000 mg/m² over 46 heures then irinotécan at 90 mg/m² (1h) at day 3 when 5U perfusion is over

Gemcitabine: 1000 mg/m² in perfusion over 30 mn at day 1,8,15,29,36 and 43 over (1 injection per week during 3 weeks followed with 7 days of rest )

Interventions: intervention 1: FOLFIRINOX intervention 2: LV5FU2 intervention 3: FOLFIRI.3 intervention 4: Gemcitabine
Intervention descriptions: intervention 1: Perfusion :oxaliplatine, Irinotecan ,folinic acid, 5FU bolus and continue intervention 2: Perfusion: Folinic Acid,5FU Bolus,5FU continue intervention 3: Perfusion :Irinotecan,Acide folinique ,5FU continue intervention 4: Gemcitabine perfusion

Protocol document:
Prot_000.pdf: 
 
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PRODIGE 35 - FFCD 1403 – PANOPTIMOX  
RANDOMISED PHASE II STUDY IN METASTATIC PANCREATIC CANCER 
EVALUATING FOLFIRINOX +/- LV5FU2 IN MAINTENANCE VERSUS FIRGEM IN 
FIRST-LINE 
 
 
Randomised Phase II - multi-centre 
EudraCT No. 2014-002574-36 
 
FFCD Intergroup Trial - UNICANCER GI  
 
COORDINATOR (FFCD): 
Dr Laetitia Dahan  
Digestive Oncology Department 
Hôpital de la Timone, 264 rue Saint Pierre 
13005 MARSEILLES, FRANCE 
Tel. +33 (0)4 91 38 60 23 
Email: Laetitia.DAHAN@ap-hm.fr 
 
CO-COORDINATOR (UNICANCER-GI):  
Dr Eric François  
Centre Antoine Lacassagne  
33 avenue de Valombrose 
06189 NICE Cedex 2 
Tel. +33 (0) 4 92 03 16 13 
Email: eric.francois@nice.unicancer.fr 
 
EDITORIAL COMMITTEE 
 E CRETEL (Marseilles), L DAHAN (Marseilles), E FRANCOIS (Nice), K LE MALICOT (Dijon), M MOREAU 
(Dijon), JF SEITZ (Marseilles), J TAIEB (Paris), I TROUILLOUD (Paris)  
 
SPONSOR AND CENTRE DE RANDOMISATION-GESTION-ANALYSE (CRGA): 
Fédération Francophone de Cancérologie Digestive (FFCD), Faculté de Médecine, 7, Boulevard Jeanne d’Arc, 
BP 87900, 21079 Dijon Cedex, France 
 
Administrative Director: 
Cécile Girault 
 
Tel.: +33 (0)3 80 66 80 13 – Fax: +33 (0)3 80 38 18 41 
 
Email: cecile.girault@u-bourgogne.fr 
 
 
Statistician: 
Karine Le Malicot 
 
Tel.: +33 (0)3 80 39 34 71 - Fax: +33 (0)3 80 38 18 41 
 
Email: karine.le-malicot@u-bourgogne.fr 
 
Project manager: 
Marie Moreau 
 
Tel.: +33 (0)3 80 39 34 04 - Fax: +33 (0)3 80 38 18 41 
 
Email: marie.moreau@u-bourgogne.fr 
 


 
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Confidential 
This document is the property of the Fédération Francophone de Cancérologie Digestive [Francophone Digestive Cancer Federation] and may not - in 
whole or in part - be transmitted, reproduced, published or used without the express authorisation of the Fédération Francophone de Cancérologie 
Digestive. 
 
 
TABLE OF CONTENTS 
STUDY ENDPOINTS ........................................................................................................................... 11 
Primary endpoint............................................................................................................................................. 11 
Secondary endpoints ....................................................................................................................................... 11 
PATIENT SELECTION AT ENROLEMENT .................................................................................. 12 
Inclusion criteria .............................................................................................................................................. 12 
Non-inclusion criteria ...................................................................................................................................... 13 
BASELINE ASSESSMENT ................................................................................................................. 13 
RANDOMISATION ............................................................................................................................. 15 
STUDY DESIGN  ............................................................................................................................... 15 
TREATMENTS ..................................................................................................................................... 17 
FOLFIRINOX (Arm A) .................................................................................................................................. 17 
FOLFIRINOX with maintenance via simplified LV5FU2 (Arm B) ........................................................... 18 
FIRGEM (Arm C) ........................................................................................................................................... 18 
DOSE ADJUSTMENT ACCORDING TO TOXICITY ................................................................... 20 
Arm A and B FOLFIRINOX +/- LV5FU2: ................................................................................................... 20 
Arm C FIRGEM (FOLFIRI 3 and GEMCITABINE) ................................................................................. 22 
Adjustment of Irinotecan doses for elevation of bilirubinaemia ................................................................. 23 
Pre-medication, concomitant treatments and contraindicated treatments ................................................ 23 
MONITORING OF PATIENTS ......................................................................................................... 24 
Before each course: .......................................................................................................................................... 24 
Arms A and B: FOLFIRINOX and FOLFIRINOX with LV5FU2 as maintenance ...................................... 24 
Arm C: FIRGEM ........................................................................................................................................... 25 
Evaluation every 8 weeks (for the three treatment arms)  and/or within 30 following the final CT 
course 25 
Follow-up after discontinuation of treatment (for the three treatment arms) ........................................... 26 
EARLY DISCONTINUATION OF THE TREATMENT AND SUBSEQUENT TREATMENTS
 
26 
ANCILLARY STUDY LOGISTICS ................................................................................................... 27 
MANAGEMENT OF SERIOUS ADVERSE EVENTS (SAE) ......................................................... 27 
STATISTICAL ANALYSIS ................................................................................................................ 30 
Planned study schedule ................................................................................................................................... 30 
Calculation of the number of patients, statistical assumptions ................................................................... 30 
Endpoint criteria ............................................................................................................................................. 32 
Primary efficacy outcome measure ............................................................................................................... 32 


 
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Secondary outcome measures ........................................................................................................................ 32 
STUDY COMMITTEES ...................................................................................................................... 33 
Independent committee ................................................................................................................................... 33 
Steering committee .......................................................................................................................................... 33 
Medical review ................................................................................................................................................. 34 
Biological research committee ........................................................................................................................ 34 
BASIS AND RATIONALE OF THE STUDY .................................................................................... 34 
BIBLIOGRAPHY ................................................................................................................................. 35 
ADMINISTRATIVE CONSIDERATIONS ....................................................................................... 38 
PUBLICATION RULES ...................................................................................................................... 40 
APPENDICES ....................................................................................................................................... 40 
 
 
 


 
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LIST OF ABBREVIATIONS 
 
 
CEA 
Carcinoembryonic Antigen 
ALT  
Alanine aminotransferase (or SGPT: serum glutamic pyruvic transaminase) 
ANSM 
Agence nationale de sécurité du médicament et des produits de santé (French National Agency for 
Medicines and Health Products Safety) 
CRA 
Clinical Research Associate 
AST 
Aspartate-aminotransferase (or SGOT: serum glutamic-oxaloacetic transaminase) 
EC 
Ethics Committee 
CRF 
Case Report Form 
CT 
Chemotherapy 
CTC  
Common Toxicity Criteria 
EDTA 
Ethylene diamine tetracetic acid 
EGF  
Epidermal Growth Factor 
EGFR 
Epidermal Growth Factor Receptor 
AE 
Adverse event 
SAE 
Serious adverse event 
5FU 
5-fluorouracil 
FFCD 
Fédération Francophone de Cancérologie Digestive [Francophone Digestive Cancer Federation] 
FOLFIRI 
Folinic acid - Fluorouracil - IRInotecan 
GDS 
Geriatric depression scale 
GGT 
Gamma glutamyl transpeptidase 
Hb 
Haemoglobin 
HR 
Hazard ratio  
AHT 
Arterial hypertension 
INR 
International Normalized Ratio 
MRI 
Magnetic Resonance Imaging 
ITT 
Intention to treat 
IV 
Intravenous 
D 
Day 
KM 
Kaplan Meier 
LDH 
Lactate dehydrogenase 
ULN 
Upper Limit of Normal 
MMSE 
Mini Mental State Examination 
N 
Normal  
NCI-CTCAE 
National Cancer Institute - Common Terminology Criteria for Adverse Events 
CBC 
Complete blood count 
WHO 
World Health Organisation 
ALP 
Alkaline phosphatase 
PNN 
Polynuclear neutrophil 
Q1-Q3 
Quartiles 
RECIST 
Response Evaluation Criteria In Solid Tumors 
CR 
Complete Response 
PR 
Partial Response 
OR 
Objective Response 
PNN 
Polymorphonuclear neutrophils 
OS 
Overall survival 
PFS 
Progression-free survival 
SD 
Stable Disease 
TAP 
Thoracic-Abdominal-Pelvic 
CT 
Computerized tomography 
PT 
Prothrombin Time 
UICC 
Union for International Cancer Control 


 
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PROTOCOL ACCEPTANCE FORM 
 
PRODIGE 35 STUDY - FFCD 1403 – PANOPTIMOX  
Randomised Phase II Randomised in Metastatic Pancreatic Cancer Evaluating FOLFIRINOX +/- 
LV5FU2 in Maintenance Versus FIRGEM In First-Line 
 
Randomised Phase II - multi-centre 
EudraCT No. 2014-002574-36 
Version 2.2 – 18/08/2014 
This version of the protocol has been approved by: 
The Sponsor:  
Ms Cécile Girault 
Date: 18/08/2014 Signature:    
The Coordinator: Dr Laetitia Dahan 
Date: 18/08/2014 Signature:   
 
I, the undersigned, Doctor:  
 
 .................................................................................................................................. 
 
After having read the prerequisites for this research, the protocol and its appendices, agree to conduct this trial in 
accordance with Good Clinical Practice and in accordance with the applicable provisions of the French Public 
Health Code. 
In particular, I agree to: 
- 
comply with the protocol as well as all changes notified to me by the Sponsor 
- 
supervise the research at the centre and provide training to my colleagues on how to conduct the research 
and provide a list of named colleagues 
- 
ensure that each patient signs a written consent form after reading the patient information leaflet, before 
carrying out any research procedures 
- 
report serious adverse events or new information within 24 hours of becoming aware of their occurrence, 
in compliance with the indications set out in the research protocol 
- 
comply with the inclusion and exclusion criteria, as well as the study start and end dates 
- 
participate in the biological part of the study, subject to the patient signing the specific consent form, and 
to send the samples in accordance with recommendations 
- 
complete all items on the case report form, oversee the quality of the data collection, and manage products 
correctly 
- 
retain research-related data and documents for a period of 15 years after the end of the study 


 
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- 
notify the Sponsor of any conflicts of interest likely to jeopardise my scientific independence under the 
scope of the research 
- 
notify the Sponsor immediately of any amicable or contentious proceedings brought by any person involved 
in the research or his/her beneficiaries, likely to implicate the liability of the sponsor 
- 
accept regular visits from the sponsor's representatives, and make available to them all source documents 
and materials related to the research, to check the quality of data recorded on the case report form. I agree 
to a review in the form of an audit carried out by the Sponsor and/or an inspection by the heath authorities 
- 
answer by phone or mail any requests for corrections or clarifications relating to the case report form 
- 
provide sufficient time to allow the FFCD CRA to sign the forms, answer any questions and take the 
required actions. 
Date: 
Signature: 
 
STAMP OF THE CENTRE: 
 
 
 
Send the original document to CRGA at the FFCD – 7 bd Jeanne d’Arc – BP 87900 – 21079 Dijon Cedex, France 


 
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SYNOPSIS 
Title  
PRODIGE 35 - PANOPTIMOX 
Randomised Phase II Randomised in Metastatic Pancreatic Cancer Evaluating 
FOLFIRINOX +/- LV5FU2 in Maintenance Versus FIRGEM In First-Line 
 
Sponsor  
Fédération Francophone de Cancérologie Digestive (FFCD) 
Study design 
Arm A: FOLFIRINOX  
FOLFIRINOX every 2 weeks until progression or occurrence of unacceptable 
toxicity (a maximum of 12 courses is recommended). 
 
Arm B: FOLFIRINOX with maintenance via LV5FU2 
4 months (8 courses) of FOLFIRINOX then, if the disease has not progressed, 
LV5FU2 as maintenance until progression (resumption of FOLFIRINOX if 
progression) 
 
Arm C: FIRGEM  
Alternating 2 months of FOLFIRI3 (4 cures) with 2 months of gemcitabine (1000 
mg/m²/week). 3/4 weeks (2 courses) until progression or unacceptable toxicity 
Study endpoints 
Primary endpoint: 
The primary endpoint of this Phase II study is to evaluate the rate of patients alive 
and without radiological (RECIST V1.1) and/or clinical progression after 6 months 
in each arm, and to select the best therapeutic strategy for a future Phase III study.  
Secondary outcomes: 
- 
Duration of disease control 
- 
Progression-free survival  
- 
Time to progression during the maintenance treatment  
- 
Median time of maintenance treatment (arm B) 
- 
Objective response rate 
- 
Overall survival 
- 
Toxicity (NCI-CTC V4.0) 
- 
Overall survival 
- 
Rate of patients receiving a 2nd line therapy  
- 
Quality of life (EORTC QLQ-C30 questionnaire)  
- 
Geriatric fragility factors predictive of treatment failure in patients over the 
age of 65 years  
Methodology  
Multi-centre, open-label, randomised Phase II study  
Inclusion criteria 
 
• 
Pancreatic adenocarcinoma, confirmed by histology or cytology. 
• 
Metastatic disease 
• 
At least one measurable lesion according to RECIST V1.1 criteria 


 
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• 
No prior chemotherapy (adjuvant chemotherapy with gemcitabine or LV5FU2 
permitted if administered more than 6 months prior to inclusion) 
• 
No prior chemotherapy (except if there is at least one measurable lesion 
outside of the irradiation area) 
• 
Age > 18 years and ≤ 75 years 
• 
General condition: WHO 0-1 
• 
PNN ≥ 1500/mm3, platelets ≥ 100 000/mm3 
• 
Bilirubin ≤ 1.5 times ULN, creatinine < 120 μmol/L 
• 
Patient information leaflet and signed consent form  
Non-inclusion 
criteria 
 
• 
Another type of pancreatic tumours, especially endocrine tumour or involving 
acinar cells 
• 
Ampulloma 
• 
Cerebral or meningeal metastasis 
• 
Gilbert's Disease 
• 
Neuropathy > grade 1 
• 
Specific contraindications to the study treatments 
• 
History of chronic diarrhoea or inflammatory disease of colon or rectum, or 
bowel obstruction or bowel sub-obstruction not resolved with symptomatic 
treatment 
• 
Active progressive infection or another serious underlying condition likely to 
prevent the patient from receiving the treatment 
• 
Another concomitant cancer or a history of cancer within the last 5 years, 
except for in situ cancer of the neck of the uterus, or basal cell carcinoma, 
squamous cell carcinoma, considered as resolved 
• 
Significant previous cardiac and respiratory disease 
• 
Patient already enrolled in another therapeutic study with experimental 
treatment 
• 
Men and women of child-bearing potential not using an effective method of 
contraception 
• 
Pregnant women or women likely to become pregnant, or breast-feeding 


 
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• 
Patient under guardianship, safeguarding or legal protection measures, and 
persons deprived of liberty 
• 
Impossibility due to geographical, social or psychological reasons of 
complying with the follow-up schedule of the trial. 
Biological study 
A biological study will evaluate: 
- Constitutional genetic polymorphisms with an influence on the efficacy and 
tolerance of chemotherapy molecules (UGT1A1, ERCC1, GSTT1, MTHFR, DPD, 
TS, etc.). 
- A paraffin section study to identify immunohistochemical biomarkers predictive of 
response to treatment 
Statistical 
methodology 
 
The statistical analysis will involve all randomised intention-to-treat patients. 
Qualitative variables will be described in the form of numbers and percentage of the 
population concerned, with a 95% confidence interval. Quantitative variables are 
described using averages, standard deviations, medians and interquartile ranges, based 
on the type of distribution. 
For Phase II, the rate of patients alive and progression-free at 6 months will be 
described and a 95% confidence interval calculated using an exact test method. 
(Newcombe, SIM 1998). 
The Kaplan Meier method will be used to estimate overall survival in each arm. A 
description will be given of survival percentages at different times, with a 95% 
confidence interval. Median follow-up will be calculated using an inverse Kaplan 
Meier method (Shemper, 1996). 
Tolerance will be described using NCI-CTC 4.0.  
Calculation of 
sample size 
Clinical assumptions for the calculation of the sample size are as follows:  
- 
H0: rate of patients alive and progression-free at 6 months = 30%, no benefit  
- 
H1: rate of patients alive and progression-free at 6 months >30%, benefit 
 A 45% rate is expected. 
 
Based on a Fleming’s one-step plan (α=5%, power = 90%), 87 are to be randomised 
in each arm. Taking into account a 5% rate of patients lost to follow-up and non-
evaluable, 92 patients/arm will be randomised. Total = 276 patients 
 
Decision-making rules will only be applied to arms B and C. Arm A 
(FOLFIRINOX) is the reference arm.  
Out of the 87 evaluable patients:  
- If 33 patients or fewer are alive and progression-free at 6 months, the treatment will 
be considered as not effective  
- If 34 patients or more are alive and progression-free at 6 months, the treatment will 
be considered as effective .  
Length of inclusion 
and participation of 
each patient 
Number of patients required: 276  
Number of centres: 60 
Start of inclusions: December 2014 
End of inclusions: December 2016 
Analysis: June 2017  


 
 
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SCHEDULE OF EXAMINATIONS AND FOLLOW-UP 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BEFORE 
TREATMENT 
DURING TREATMENT 
and in the event of discontinuation of treatment without progression (e.g. toxicity or patient 
refusal) 
AFTER 
DISCONTINUA
TION OF 
TREATMENT 
due to 
progression 
(failure of 
strategies) 
In the 8 days prior to 
inclusion (except for 
CT)  
Arms A and B 
Arm C 
Every 8 weeks and 30 
days after the last 
administration of CT, 
regardless of the arm 
 
Every 6 
months until 
death 
Before each 
course  
On D8 of 
each 
course 
 
FOLFIRI3 
GEMCITABINE  
 
Before each 
administration 
 
Before each 
course 
 
On D8 of 
each 
course 
Clinical and biological informed consent 
X 
 
 
 
 
 
 
 
CLINICAL EXAMINATION 
 
Weight, body surface area 
X 
X 
 
X 
 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
WHO general condition 
X 
X 
 
X 
 
X 
X 
X 
Toxicity Assessment NCI-CTCAE version 4.0 
 
X 
X 
X 
X 
X 
X 
X 
QLQ-C30 
X 
 
 
 
 
 
X 
X 
Geriatric assessment for in patients over 65 years1 
X 
 
 
 
 
 
X 
 
LAB TEST ASSESSMENT 
 
Lab test assessment 
X2 
X4 
X4 
X5 
X5 
X5 
X2 
 
Pregnancy test  
X 
 
 
 
 
 
 
 
CA19 -9 and CEA markers 
X 
 
 
 
 
 
X 
 
PARA-CLINICAL EXAMINATIONS 
 
Thoracic-Abdominal-Pelvic CT scan  
X3 
 
 
 
 
 
X 
X 
ECG 
X3 
 
 
 
 
 
 
 
ANCILLARY BIOLOGY STUDY 
 
2 EDTA tubes of 5 or 7 mL of blood 
X  
 
 
 
 
 
 
 
Biopsies, or tumour block, fixed in paraffin 
X 
 
 
 
 
 
 
 
 
1: 
Oncodage score (G8), Charlson Index, MMSE, GDS (short version) 
2: 
Full lab test assessment: CBC, platelets, PT, serum sodium, serum potassium, calcium, bilirubinaemia (total and conjugated), blood creatinine, blood glucose, AST, ALT, alkaline phosphatase, LDH, protein in 
serum, blood albumin 
3:  
In the 3 weeks prior to inclusion. 
4:  
ARMS A and B: 
Before each chemotherapy course: CBC, platelets, bilirubinaemia (total, unconjugated and conjugated),  Every month (uneven courses), add blood albumin, serum sodium, potassium serum, blood creatinine, blood 
glucose 
On D8 of each course of FOLFIRINOX: CBC, platelets. If required, administer growth factors for subsequent courses.  
On D8 of the 1st course: blood creatinine, potassium serum and serum sodium. In Arm B, no systematic blood count on D8 of LV5FU2. 
5: 
ARM C: 
Before each FOLFIRI3 course: CBC, platelets, bilirubinaemia (total, unconjugated and conjugated), Every month (uneven courses), add blood albumin, serum sodium, potassium serum, blood creatinine, blood 
glucose 
On D8 of each course of FOLFIRI3: CBC, platelets 
Before each course of gemcitabine: CBC, platelets, bilirubinaemia (total, unconjugated and conjugated), AST, ALT  


 
 
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Study endpoints 
Primary endpoint 
The primary endpoint is to evaluate the rate of patients alive and without radiological (RECIST V1.1) 
and/or clinical progression after 6 months in each arm, and to select the best therapeutic strategy for a 
future Phase III study. 
Secondary endpoints 
The secondary endpoints of the study are: 
 
- 
Duration of disease control (see definition below) 
- 
Progression-free survival  
- 
Time to progression during maintenance  
- 
Median time of maintenance treatment (arm B)  
- 
Objective response rate according to RECIST 1.1 criteria at 2, 4 and 6 months 
- 
Best response to treatment  
- 
Overall survival 
- 
Tolerance of treatment (toxicity according to NCI-CTC V4.0), with particular attention to 
neurotoxicity grades and frequency of use of haematopoietic growth factors for haematological 
toxicity  
- 
Percentage of patients receiving a 2nd line therapy  
- 
Quality of life (QLQ-C30 EORTC v3.0 questionnaire)  
- 
Geriatric fragility factors predictive of treatment failure in elderly subjects ≥ 65 years 
 
In arm A (Folfirinox), duration of disease control is defined as the period of time between the 
randomisation date and the date of progression under treatment (clinical and/or radiological) or death 
(for any reason and at any time) or the date of switching lines. 
 
In arm B with maintenance (arm B), duration of disease control is defined as follows: 
• 
After progression during maintenance with LV5FU2 (PFS1), if the disease is not controlled 
after reintroduction of FOLFIRINOX (PFS2) then the duration of disease control is equal to 
the period of time between randomisation and progression before the reintroduction of 
FOLFIRINOX (PFS1). 


 
 
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• 
After progression during maintenance with LV5FU2 (PFS1), if the disease is not controlled 
after reintroduction of FOLFIRINOX then the duration of disease control is equal to the period 
of time between randomisation and progression (PFS2) with FOLFIRINOX (PFS1 + PFS2).  
 
In the FIRGEM arm (arm C), duration of disease control is defined as follows: 
If discontinuation of alternate treatments (FOLFIRI.3/Gemcitabine) is due to progression (PFS1) then: 
• 
If the disease is not controlled after changing the treatment then the duration of disease control 
is equal to the period of time between randomisation and progression before changing the 
treatment (PFS1). 
• 
If the disease is again controlled after changing the treatment, then the duration of disease 
control (stability, OR) is equal to the period of time between randomisation and progression 
(PFS2) with the treatment (PFS1 + PFS2) 
 
If the alternation of treatments is discontinued for a reason other than progression (e.g. toxicity, decision 
of the investigator, etc.), then the duration of disease control will be the period of time up to the first 
progression (PFS1). 
 
 
Ancillary biology studies: 
 
- 
Blood sample study of constitutional genetic polymorphisms with an influence on the efficacy 
and tolerance of chemotherapy molecules (UGT1A1, ERCC1, GSTT1, MTHFR, DPD, TS, 
etc.). 
- 
A paraffin section study to identify immunohistochemical biomarkers predictive of response to 
treatment. 
Patient selection at enrolment 
Inclusion criteria 
- 
Pancreatic adenocarcinoma, confirmed by histology or cytology. 
- 
Metastatic disease 
- 
At least one measurable lesion according to RECIST V1.1 criteria 
- 
No neuropathy  
- 
No prior chemotherapy (adjuvant chemotherapy with gemcitabine or LV5FU2 permitted if 
administered more than 6 months prior to inclusion) 
- 
No prior chemotherapy (except if there is at least one measurable lesion outside of the 
irradiation area) 
- 
Age > 18 years and ≤ 75 years  


 
 
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- 
General condition: WHO 0-1 
- 
Satisfactory haematological function: PNN ≥ 1500/mm3, platelets ≥ 100 000/mm3 
- 
Satisfactory liver function: bilirubin ≤ 1.5 times ULN  
- 
Satisfactory kidney function: creatinine < 120 μmol/L 
- 
Absence of heart failure or non-medically controlled angina pectoris or myocardial infarction 
within 6 months prior to inclusion 
- 
Patient information leaflet and signed consent form  
Non-inclusion criteria 
- 
Another type of pancreatic tumours, especially endocrine tumour or involving acinar cells 
- 
Ampulloma 
- 
Gilbert's Disease 
- 
Neuropathy > grade 1 (NCI-CTC version 4.0) 
- 
Cerebral or meningeal metastasis 
- 
Specific contraindications to the study treatments 
- 
History of chronic diarrhoea or inflammatory disease of colon or rectum, or bowel obstruction 
or bowel sub-obstruction not resolved with symptomatic treatment 
- 
Active progressive infection or another serious underlying condition likely to prevent the 
patient from receiving the treatment 
- 
Another concomitant cancer or a history of cancer within the last 5 years, except for in situ 
cancer of the neck of the uterus, or basal cell carcinoma, squamous cell carcinoma, considered 
as resolved 
- 
Significant previous cardiac and respiratory disease 
- 
Patient already enrolled in another therapeutic study with experimental treatment 
- 
Pregnant women or women likely to become pregnant, or breast-feeding 
- 
Patient under guardianship, safeguarding or legal protection measures, and persons deprived of 
liberty Impossibility due to geographical, social or psychological reasons of complying with 
the follow-up schedule of the trial. 
BASELINE ASSESSMENT 
 
A baseline assessment is required in the 8 days prior to initiation of treatment, except for para-clinical 
assessments which may be performed within 3 weeks prior to randomisation. 


 
 
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Full clinical examination including:  
 
- 
Measurement of weight, height, body surface area and vital signs (temperature, pulse, blood 
pressure) 
- 
WHO index   
 
Lab tests performed less than 7 days previously: 
 
- 
CBC, platelets, PT, sodium, potassium, calcium 
- 
Total bilirubin (unconjugated and conjugated), ALT, AST, alkaline phosphatase, LDH 
- 
Blood creatinine, blood glucose 
- 
Protein in serum, blood albumin 
- 
Marker: CA 19-9, CEA 
- 
Pregnancy test if women of childbearing potential  
 
Quality of Life questionnaire: 
 
- 
QLQ-C30 to be completed by the patient before randomisation (on the same day or within 
15 days prior to randomisation but before the first course) 
 
Geriatric assessment for patients aged over 65 years:  
 
• 
ONCODAGE score (G8) 
• 
Charlson Index  
• 
Mini-Mental State Examination (MMSE)  
• 
Short version of the Geriatric Depression Scale (GDS 15 to be completed by the patient) 
 
 
Morphological and para-clinical examination in the 3 weeks prior to inclusion: 
 
- 
Thoracic-Abdominal-Pelvic (CT PET) scan carried out less than 3 weeks earlier 
- 
ECG  
 
Biological study: 
- 
Collection of 2 EDTA tubes of 5 (or 7) ml of blood (for genotyping UGT1A1, ERCC1, 
GSTT1, MTHFR, DPD, TS and CDA1) 
 


 
 
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RANDOMISATION 
After signing the consent form and validating the results of the initial baseline assessment, eligible 
patients will be randomised at the Centre de Randomisation – Gestion – Analyse (CRGA) of the 
FFCD. 
  
The investigator is required to fax the completed and signed randomisation form to the CRGA at the 
FFCD:  
from Monday to Friday from 9 a.m. to 6 p.m. 
Fax: + 33 (0)3 80 38 18 41 / Tel: + 33 (0)3 80 66 80 13 
 
Confirmation of randomisation will be faxed back to the investigator with the patient registration 
number and arm allocated by randomisation.  
After randomisation of study patients, treatment should begin within 10 days. 
A case report form will be forwarded at the opening of the centre. A new case report form will then be 
sent after each randomised patient. 
 
Stratification 
 
Patients will be randomized (1:1:1) according to the minimisation technique based on the following 
stratification factors:  
- 
Centre 
- 
Biliary stent: Yes versus No 
- 
Age: ≤ 65 years versus > 65 years  
 
STUDY DESIGN  
 
 
 
 
 
 
 
*unless progression or unacceptable toxicity 
**** in case of progression, limiting toxicity with one of the 2 treatments, continuation of the other treatment until 
progression or unacceptable toxicity 
 
R 
Arm A: FOLFIRINOX (12 courses)* 
Arm B: FOLFIRINOX (8 courses)* then LV5FU2 (maintenance) then 
resumption of FOLFIRINOX until progression 
Arm C: FIRGEM: Alternation between 2 months of FOLFIRI.3 and 2 
months of GEMCITABINE** 


 
 
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        1        2          3        4         5           6         7         8          9         10 
 
 
MONTHS 
Evaluation CT scan after 6 months 
(regardless of number of courses received) 
If OR or S 
P 
FOLFIRINOX 
 
 
LV5FU2 
 
FOLFIRI3 
 
GEMCITABINE 
ARM A: FOLFIRINOX 12 
courses 
ARM B: FOLFIRINOX (8 
courses) then LV5FU2 as 
maintenance then 
resumption FOLFIRINOX 
until progression 
ARM C: FIRGEM 
alternation every 2 
months FOLFIRI 3 / 
Gemcitabine 
CT PET every 8 weeks 


 
 
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TREATMENTS  
Treatments are not supplied under the scope of the study. 
 
FOLFIRINOX (Arm A) 
 
 
FOLFIRINOX, courses administered every 2 weeks and a maximum of 12 courses. Subsequent 
treatments will left to the discretion of the investigator. 
 
▪ 
Oxaliplatin 85 mg/m2 D1 over 2 hours then 
▪ 
Irinotecan 180 mg/m2 D1 over 90 minutes 
▪ 
Folinic acid 400 mg/m2, D1 over 2 hours (during the irinotecan perfusion) 
▪ 
5-FU bolus 400 mg/m² D1 followed by 5-FU continuously 2400 mg/m2 in total over 46 hours, 
i.e. 1200 mg/m2 on D1 and 1200 mg/m² on D2. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment starts with the IV administration (2-hour infusion) of oxaliplatin at a dose of 85 mg/m², 
followed by the simultaneous IV administration (2-hour infusion) of folinic acid at a dose of 400 mg/m² 
and irinotecan at a dose of 180 mg/m² (IV infusion for 1 hour 30 min), to start immediately after the 
end of the oxaliplatin infusion. 5-FU is administered immediately after the infusion of folinic acid at a 
dose of 400 mg/m2 as a 5-minute IV bolus, followed by continuous 5FU infusion over 46 hours at 2400 
mg/m2.  
Warning: if the patient presents with cholinergic syndrome, secondary to irinotecan, atropine sulphate 
should be administered unless its use is contraindicated (see SmPC, Appendix 7). Atropine sulphate 
should then be used as prophylaxis for the next courses. 
 
 
Treatment will continue for a maximum of 12 courses, until: 
- 
disease progression 
Oxaliplatin 
85 mg/m² 
Folinic acid 
400 mg/m² (or 200 mg/m² 
if Elvorine) 
5 FU continuously 
2400 mg/m² 
Irinotecan  
180 mg/m² 
90 minutes 
2h 
46h (D1 and D2) 
2h 
5 FU bolus  
400 mg/m² 
< 10 minutes 


 
 
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- 
onset of unacceptable toxicity or 
- 
patient refusal.   
 
Further treatment is left to discretion of the investigator. 
 
 
FOLFIRINOX with maintenance via simplified LV5FU2 (Arm B) 
 
FOLFIRINOX for 4 months (8 courses, 1 course every 2 weeks), then if the disease is controlled 
(stability or objective response (CR or PR)), simplified LV5FU2 (1 course every 2 weeks) as 
maintenance until progression.  
 
FOLFIRINOX at the same doses as described above for arm A. 
 
Simplified LV5FU2 as maintenance until progression: 
• 
Folinic acid 400 mg/m² (200 mg/m² if Elvorine), as a 2-hour infusion followed by 
• 
5FU 400 mg/m² as a 10-minute bolus, followed by 5FU 2400 mg/m² as a 46-hour infusion.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If progression during the maintenance treatment, patients should start taking (unless contraindicated or 
refusal) a FOLFIRINOX regimen, until:  
- 
disease progression 
- 
onset of unacceptable toxicity or 
- 
patient refusal 
 
Further treatment is left to discretion of the investigator. 
Warning: if the patient presents with cholinergic syndrome, secondary to irinotecan, atropine sulphate 
should be administered unless its use is contraindicated (see SmPC, Appendix 7). Atropine sulphate 
should then be used as prophylaxis for the next courses. 
 
FIRGEM (Arm C)  
 
Folinic acid 
400 mg/m² (or 200 mg/m² 
if Elvorine) 
5 FU continuously 
2400 mg/m² 
2h 
46h (D1 and D2) 
5 FU bolus  
400 mg/m² 
< 10 minutes 


 
 
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Alternation every 2 months of FOLFIRI.3 (4 courses, 1 course every 2 weeks) and gemcitabine 1000 
mg / m2 (2 cycles of 3 courses, one course per week, 3 weeks out of 4).  
 
 
FOLFIRI.3:  
 
• 
Irinotecan 90 mg/m² on D1 as a 60-minute infusion with folinic acid  
• 
Folinic acid 400 mg/m² (or 200 mg/m² Elvorine) on D1 as a 2-hour infusion 
• 
5FU continuously 2000 mg/m² for 46 hour 
• 
Then irinotecan again at a dose of 90 mg/m² (1h) on D3, at the end of the 5-FU infusion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Warning: if the patient presents with cholinergic syndrome, secondary to irinotecan, atropine sulphate 
should be administered unless its use is contraindicated (see SmPC, Appendix 7). Atropine sulphate 
should then be used as prophylaxis for the next courses. 
 
GEMCITABINE:  
 
• 
1000 mg/m2 as a 30-minute infusion on D1, D8, D15, D29, D36 and D43 for 2 months (1 
injection per week for 3 weeks followed by 7 days of rest (1 week) and then resumption of 1 
injection per week for 3 weeks).  
 
 
In case of progression, limiting toxicity with one of the two treatments, it is recommended (unless 
contraindicated or refused) to continue the other treatment until progression, unacceptable toxicity or 
patient refusal. 
 
Further treatment is left to discretion of the investigator. 
 
 
Folinic acid 
400 mg/m² (or 200 mg/m² 
if Elvorine) 
5 FU continuously 
2000 mg/m² 
Irinotecan 
90 mg/m² 
1h 
2h 
46h (D1 and D2) 
Irinotecan  
90 mg/m² 
1h 


 
 
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DOSE ADJUSTMENT ACCORDING TO TOXICITY 
General principles: 
- All chemotherapy drugs should be administered on the day of the course, as long as the following 
criteria are respected: 
- 
PNN > 1500/mm3 
- 
Platelets > 100,000/mm3 
- 
Gastrointestinal toxicity < grade 1 
 
- If these criteria are not met, the course must be postponed for one week. 
- Treatment will resume with a dose adjustment according to the tables below and according to the 
maximum grade of toxicity observed in the period between courses. 
 
Treatment with 5FU should be discontinued in case of angina pectoris or myocardial infarction related 
to the 5FU treatment. 
- Treatment with 5FU should be reduced by 50% in case of serious liver function disorders. 
- Treatment with 5FU should be reduced by 50% in case of granulocytopenia between 2,000 and 
3,000/mm3 or thrombocytopenia below 100,000/mm3. Treatment discontinuation should be considered 
if granulocytopenia is less than 2000/mm3 or thrombocytopenia less than 80,000/mm3. 
- Irinotecan treatment should be discontinued if bilirubinaemia  is above 3x ULN (upper limit of 
normal). It should be reduced by 40% if the bilirubinaemia  elevation is between 1.5 and 3x ULN. 
 
Arm A and B FOLFIRINOX +/- LV5FU2: 
 
Toxicity observed on the day of the course   
 
Haematological toxicity on 
the day of the course 
POSTPONED 
COURSE 
DOSE REDUCTION 
Irinotecan  
Oxaliplatin  
LV5FU2 
PNN  1,500/ mm3 and 
platelets  100,000/mm3 
No postponement of 
course 
 
 
No dose reduction 
PNN < 1500/mm3 
Postpone treatment 
until PNN > 
1,500/mm3 (until D22 
or 
D29 if necessary) and 
resume the course 
with G-CSF. 
 
If not 
recovered on D29, 
discuss 
discontinuation 
of treatment, growth 
Factor, or 
maintenance alone of 
LV5FU2 
1st episode: reduce 
dose to 150 mg/m2 
 
2nd episode: maintain 
dose at 150 mg/m2 
 
3rd episode: 
Discontinue 
treatment or 
maintenance 
LV5FU2  
 
1st episode: no dose 
reduction  
 
2nd episode: reduce 
dose to 60 mg/m2 
 
3rd episode: 
Discontinue treatment 
or maintenance 
LV5FU2 
1st 
episode: 
No dose 
reduction 
Platelets < 100,000/mm3 
Until recovery 
(platelets > 
100,000/mm3). If not 
recovered on D29, 
1st episode: no dose 
reduction 
 
1st episode: reduce 
dose to 60 mg/m²  
 
1st 
episode: 
no 


 
 
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discuss 
discontinuation 
of treatment  
2nd episode: reduce 
dose to 150 mg/m2 
 
3rd episode: 
discontinue 
treatment 
 
2nd episode: maintain 
reduced dose 
 
3rd episode: 
discontinue treatment 
reduction 
of 
dose 
2nd 
episode: 
reduce the 
continuous 
infusion 
dose by 
25% 
 
Maximum toxicity observed during courses 
 
EVENTS 
REDUCE DOSE AT NEXT COURSE 
- Isolated febrile neutropenia* 
-Grade 4 neutropenia > 7 days 
- Infection with concomitant grade 3-4 
neutropenia 
 
1st episode: reduce the dose of irinotecan to 
150 mg/m² and add G-CSF 
2nd episode: also reduce the dose of 
oxaliplatin to 60 mg/m² 
3rd episode: discuss growth factors or 
reducing the treatment 
up to a level of maintenance alone with 
LV5FU2 
Grade 3-4 thrombocytopenia 
1st episode: reduce the dose of oxaliplatin to 
60 mg/m² 
2nd episode: also reduce the dose of 
irinotecan to 150 mg/m² and the dose of 
continuous 5-FU by 25% 
3rd episode: discontinue oxaliplatin and 
irinotecan, continue LV5FU2 
*Definition: fever during a period of bone marrow hypoplasia (PNN <500/mm3) with temperature > 38.5°C. 
Treatment will continue at the same doses, but with the addition for all remaining courses of G-CSF from D5 to 
D10. The first dose should not be administered within 24 hours following the end of the cytotoxic chemotherapy. 
Gastrointestinal toxicity 
 
EVENTS 
REDUCE DOSE AT NEXT COURSE 
-Isolated grade 3-4 diarrhoea or 
-Diarrhoea 
+ 
fever 
and/or 
grade 
3-4 
neutropenia 
1st episode: reduce the dose of irinotecan to 
150 mg/m² 
 
2nd episode: also reduce the dose of 
oxaliplatin to 60 mg/m² and the dose of 
continuous 5-FU by 25% 
 
3rd episode: discontinue irinotecan 
 
Resistant diarrhoea (> 48 h) despite anti-
diarrhoea treatment 
No reduction in the dose of irinotecan or 
oxaliplatin nor 5-FU after recovery unless 
grade 3-4 diarrhoea or diarrhoea + fever 
and/or grade 3-4 neutropenia 
In the event of haemorrhagic gastrointestinal ulceration or not, the 5 fluorouracil treatment should be 
discontinued until symptoms have disappeared. 
 
Other toxicity 
 


 
 
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Mucositis, “head-foot” syndrome: grade 3-4, reduce the continuous 5-FU by 25% for the 
next courses 
 
Toxicity specific to oxaliplatin: peripheral neuropathy 
 
Toxicity 
Toxicity duration 
< 7 days 
> 7 days et 
< 14 days 
Persistent between 
courses 
Paraesthesia/dysesthesia with 
no functional 
alteration (grade 1 NCI) 
No change 
No change 
No change 
Paraesthesia/dysesthesia with 
functional 
alteration but no affecting 
activities 
of daily living (grade 2 NCI) 
No change 
No change 
65 mg/m2 
Paraesthesia/dysesthesia with 
pain or 
functional alteration affecting 
activities 
of daily living (grade 3 NCI) 
65 mg/m2 
65 mg/m2 
Discontinue 
Persistent 
paraesthesia/dysesthesia, 
invalidating 
N/A 
N/A 
Discontinue 
Acute dysesthesia 
laryngopharyngeal 
Extend the next infusion time to 6 hours. 
Add (if not already done) 1 g of calcium gluconate and 1 g 
of magnesium sulphate 15 minutes before the oxaliplatin 
infusion, 
infusions to be repeated until the end of the oxaliplatin infusion 
 
If oxaliplatin is discontinued due to neurotoxicity, irinotecan and 5-FU should continue. 
 
 
 
Arm C FIRGEM (FOLFIRI 3 and GEMCITABINE)  
 
Adjustment table for FOLFIRI 3 - Toxicity between courses 
 
Toxicity/NCI 
Grade 
1 
2 
3-4 
Anaemia  
 
No dose reduction 
No dose reduction 
No dose reduction 
Neutropenia 
 
Thrombocytopenia 
No dose reduction 
No dose 
reduction*,** 
 - 5-FU 1600 mg/m² (48h) 
 - Irinotecan 80 mg/m² on 
D1 and D3 
  - Gemcitabine 800 mg/m² 
Diarrhoea 
 
No dose reduction 
No dose reduction*,** 
 - 5-FU No dose reduction 
 - Irinotecan 80 mg/m² on 
D1 and D3 
Other *** 
- 
- 
 - 5-FU 1600 mg/m² (48h) 
 - Irinotecan 80 mg/m² on 
D1 and D3 
 - Gemcitabine 800 mg/m² 


 
 
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* after recovery (grade 0 or 1 toxicity) 
** if no recovery after 2 weeks: (persistent diarrhoea or neutropenia > Grade 2 or thrombocytopenia > Grade 1), 
same dose reduction as for Grade 3-4. 
*** except alopecia, cholinergic syndrome, nausea / vomiting without adequate treatment  
The introduction of growth factors (EPO and G-CSF) is recommended in case of 
haematological toxicity, as per the marketing authorisation for these products. 
 
Adjustment table for GEMCITABINE - Toxicity between courses 
 
Haematological toxicity (weekly 
evaluation) 
DELAYED COURSE 
DOSE REDUCTION 
 
 
 
PNN > 1,000/mm3  
and platelets > 100,000/mm3 
No delayed course 
Administer 100% of the total dose 
500 < PNN  1,000/ mm3 
or  
50,000< platelets  100,000 mm3 
No delayed course 
Administer 75% of the total dose (25% 
dose reduction) 
PNN  500/ mm3 
or  
platelets  50,000/ mm3 
Delay the course until 
PNN > 500/mm3 and 
platelets > 50,000/mm3 
No dose reduction 
PNN: Polynuclear neutrophils 
 
 
Hepatic toxicity for Gemcitabine 
 
Increased hepatic transaminases are frequently observed. 
 
• 
If transaminases (ALT or AST or both) increase by at least 5 x ULN 
gemcitabine is continued with any reduction in dose. 
 
• 
If transaminases (ALT or AST or both) increase between 5 and 20 x ULN 
reduce the gemcitabine dose by 25% 
 
• 
If transaminases (ALT or AST or both) increase by more than 20 x ULN 
gemcitabine should be discontinued permanently. 
 
ULN: upper limit of normal 
 
Adjustment of Irinotecan doses for elevation of bilirubinaemia  
Irinotecan treatment should be discontinued if bilirubinaemia is above 3x ULN (upper limit of normal). 
It should be reduced by 40% if the bilirubinaemia elevation is between 1.5 and 3 x ULN. In all cases, 
obstruction of bile ducts should be investigated and treated, if possible. 
 
Pre-medication, concomitant treatments and contraindicated treatments 
Treatments considered necessary for the patient's well-being may be administered at the investigator's 
discretion.  


 
 
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If the patient presents with cholinergic syndrome, secondary to irinotecan, atropine sulphate should be 
administered unless its use is contraindicated (see SmPC, Appendix 7). Atropine sulphate should then 
be administered as prophylaxis for the next courses. 
The subcutaneous administration of a growth factor is permitted. 
According to EORTC 2010 recommendations [38], the risk of febrile neutropenia should be assessed 
before each chemotherapy course. Validated risk factors are age > 65 years, history of febrile 
neutropenia and advanced disease (which is the case for all patients included in this trial). 
 
In case of severe neutropenia, i.e. grade 3-4, patients are at high risk of febrile neutropenia and infection 
especially in the presence of concomitant diarrhoea. If these symptoms appear, the dose can be adjusted 
during the next course, and the prescription of haematopoietic growth factors considered. 
Administration of haematopoietic growth factors is not routinely recommended for the 1st course of 
FOLFIRINOX or FOLFIRI3 but may be indicated on a case-by-case basis depending on the clinical 
condition of the patient. Treatment with lenograstim (GRANOCYTE®), filgrastim (Neupogen®, 
ZARZIO®) or pegfilgrastim (NEULASTA®) is then recommended. 
Contraindicated treatments: 
With 5 FU: yellow fever vaccine, live attenuated vaccines, phenytoin for prophylactic use. 
With irinotecan: combination with St John’s Wort, yellow-fever vaccine. 
 
MONITORING OF PATIENTS  
Before each course:  
 
Arms A and B: FOLFIRINOX and FOLFIRINOX with LV5FU2 as maintenance 
Patients treated with FOLFIRINOX will be reviewed for a clinical assessment before each course to 
assess any toxicity and determine the resumption of treatment.  
 
Before each course, every 14 days: 
o Clinical examination: weight, WHO and vital signs (temperature, pulse, blood pressure. 
This examination should be adapted to each patient, at the discretion of the investigator. 
o Evaluation of tolerance (toxicity according to NCI-CT V4.0) 
o Laboratory test assessment:  
▪ 
Before each course: CBC, platelets; total, unconjugated and conjugated 
bilirubinaemia  
▪ 
On D8 of each course of FOLFIRINOX: CBC, platelets. If required, anticipate 
the administration of growth factors for subsequent courses. On D8 of the 1st 
course and subsequently, if the investigator deems useful: blood creatinine, 
potassium serum and serum sodium. A blood count is not systematically 
required on D8 of LV5FU2 in arm B. 
▪ 
Every month (uneven courses): in addition to CBC, platelets and 
bilirubinaemia , measure blood albumin, serum sodium, potassium serum, 
blood creatinine, blood glucose 


 
 
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However, depending on tolerance, additional consultations may be required. 
 
Arm C: FIRGEM 
Patients treated with gemcitabine will be reviewed for a clinical assessment before each administration 
to assess any toxicity and determine the continuation of treatment 
 
Before each administration of FOLFIRI.3, every 15 days:  
o Clinical examination: weight, WHO and vital signs (temperature, pulse, blood pressure. 
This examination should be adapted to each patient, at the discretion of the investigator. 
o Evaluation of tolerance (toxicity according to NCI-CT V4.0) 
o Laboratory test assessment:  
▪ 
Before each course: CBC, platelets, total, unconjugated and conjugated 
bilirubinaemia, blood creatinine, serum sodium, potassium serum, total 
protein. 
▪ 
On D8 of each course: CBC, platelets 
▪ 
Every month (uneven courses): in addition to CBC, platelets and 
bilirubinaemia , measure blood albumin, serum sodium, potassium serum, 
blood creatinine, blood glucose 
 
Before each administration of gemcitabine: every 7 days: 
o Clinical examination: weight, WHO and vital signs (temperature, pulse, blood pressure. 
This examination should be adapted to each patient, at the discretion of the investigator. 
o Evaluation of tolerance (toxicity according to NCI-CT V4.0) 
Laboratory test assessment: CBC, platelets, total, unconjugated and conjugated 
bilirubinaemia, AST, ALT. 
 
Evaluation every 8 weeks (for the three treatment arms) and/or within 30 following the 
final CT course 
 
Patients will be evaluated every 8 weeks, i.e.:  
 
o Clinical examination: weight, WHO and vital signs (temperature, pulse, blood pressure. 
This examination should be adapted to each patient, at the discretion of the investigator. 
o Lab testing: CBC, platelets, bilirubin (total, unconjugated and conjugated), PT, ALP, 
AST, ALT, sodium, potassium, calcium, blood glucose, creatinine, protein in serum, 
blood albumin, LDH 
o Markers: CA 19-9, CEA 
o Evaluation of toxicity from the previous cycle 


 
 
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o Morphological evaluation: CT - PET  
A CT- PET 6 months after initiation of treatment is MANDATORY, regardless 
of the number of courses received, to evaluate the primary endpoint criterion, 
unless progression before this point 
o Quality of Life Questionnaire QLQ-C30 version 3.0 
o Geriatric assessment for patients over 65 years: 
- 
ONCODAGE score (G8) 
- 
Charlson Index  
- 
Mini-Mental State Examination (MMSE)  
- 
Short version of the Geriatric Depression Scale - GDS 15 to be completed by the 
patient 
 
Follow-up after discontinuation of treatment (for the three treatment arms) 
 
After progression, patients will be followed up every 6 months until death: 
o Clinical examination: weight, WHO and vital signs (temperature, pulse, blood pressure. 
This examination should be adapted to each patient, at the discretion of the investigator. 
o Evaluation of persistent toxicity 
o CT - PET 
o QLQ-C30 
 
EARLY 
DISCONTINUATION 
OF 
THE 
TREATMENT 
AND 
SUBSEQUENT TREATMENTS 
 
• 
Early discontinuation of treatment 
 
Patients may discontinue the treatment early for the following reasons: 
- 
toxicity, 
- 
disease progression, 
- 
withdrawal of consent, 
- 
lost to follow-up, 
- 
patient refusal 
 
Wherever possible, patients who discontinue the treatment early will be followed up on the same basis 
as other patients during treatment (every 8 weeks until progression). 


 
 
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• 
 2nd line  
 
A second line of treatment is possible for each treatment arm: in Arms A and B; patients can receive 
gemcitabine and in Arm C or can receive FOLFOX IV. The decision is left to the discretion of the 
investigator. 
 
ANCILLARY STUDY LOGISTICS 
For patients who have signed the biological informed consent form, a description of the ancillary 
biological study is given in Appendix 3 of this protocol. 
 
Samples required  
- A blood sample consisting of 2 EDTA tubes of 5 (or 7) ml will be collected before initiation of 
treatment (at the baseline assessment or before the 1st course). 
 
Tubes are to be shipped, via the DHL box supplied at the opening of the centre, to:  
Centre de Ressource Biologique EPIGENETEC 
Unité INSERM UMR-S 1147 (ex 775) 
45 rue des Sts Pères, 75006 PARIS 
Headed by Professor Pierre Laurent-Puig 
 
Only use the DHL box containing the DHL slip for the INSERM UMR-S 1147 unit (ex 775). 
 
After sending the box, the box required for the next patient will be dispatched. 
 
- Tumour block fixed in paraffin.   
 
Blocks or slides are to be shipped, using the padded envelopes supplied at the opening of the centre, 
to:  
Centre de Ressource Biologique EPIGENETEC 
Unité INSERM UMR-S 1147 (ex 775) 
45 rue des Sts Pères, 75006 PARIS 
Headed by Professor Pierre Laurent-Puig 
 
Only use the DHL box containing the DHL slip for the INSERM UMR-S 1147 unit (ex 775). 
 
After sending the box, the box required for the next patient will be dispatched. 
 
 
MANAGEMENT OF SERIOUS ADVERSE EVENTS (SAE) 
Safety evaluation parameters 
Safety will be evaluated by assessing the general and clinical condition of patients and by collecting 
data on events occurring between visits during consultations, and by carrying out regular blood tests. 
Toxicity will be evaluated using the NCI-CTCAE scale, version 4.0 (Appendix 6). 
If any emergencies occur, the patient, his/her friends and family or family doctor should call the 
investigator to inform him/her of the event. 
Definitions 


 
 
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a. 
Adverse event (AE) 
An adverse event is a harmful medical occurrence in a biomedical research subject, whether or not 
it is related to the research or the investigational product. 
All adverse events are to be reported in the case report form on the pages intended for that purpose. 
b. 
Serious Adverse Event (SAE) 
Is considered as a serious adverse event, any event that 
• Causes death, 
• Is life-threatening, 
• Results in admission to hospital or extension of a hospital stay, 
• Causes permanent disability or severe temporary disability, 
• Causes a congenital anomaly/birth defect/abortion, 
• Is medically significant (e.g. overdose, second cancer, and new developments considered as 
medically significant). 
The terms ‘disability’ and ‘incapacity’ refer to any temporary or permanent physical or 
psychological disability that is clinically significant and has an impact on the physical activities 
and/or quality of life of the patient. 
Any clinical event or laboratory result considered serious by the investigator and not meeting the 
severity criteria defined above is considered as medically significant. Such events may endanger 
the patient and require medical intervention to prevent an outcome that fulfils one of the severity 
criteria mentioned above (e.g.: overdoses, second cancer, pregnancies and new developments may 
be considered medically significant). 
 
Pregnancy is an exclusion criteria in this study. However, if a pregnancy is discovered after 
inclusion, the female patient may be excluded from the study. The sponsor should be informed 
immediately using the form for reporting serious adverse events (no severity criteria will be ticked). 
The patient should then be monitored until the end of the pregnancy and the outcome of the 
pregnancy reported to the sponsor.  
c. 
Adverse effect 
Any untoward and unintended reaction to an investigational medicinal product, regardless of the 
dose administered or to any investigational item. The adverse effect is undesirable if it is subject 
to a severity criterion. 
d. 
Unexpected Serious Adverse Effect 
An unexpected serious adverse effect is an event that is not mentioned, or is different in nature, 
intensity, progression from that indicated in the Summary of Product Characteristics (or SmPCs) 
e. 
New development 
A new development may be: an unexpected frequency of an expected SAE, a SAE related to the 
trial procedure, insufficient efficacy in life-threatening diseases, clinical data. 
f. 
Intensity (or severity) 
An intensity criterion should not be confused with a severity criterion, which is used as a guideline 
to determine reporting obligations. 


 
 
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The intensity of the events will be estimated based on an extract of the CTC-AE classification 
version 4.0 (Appendix 6). The intensity of adverse events not listed in this classification will be 
assessed according to the following qualifiers: 
- 
Mild (Grade 1): does not affect the patient's usual daily activities 
- 
Moderate (Grade 2): disrupts the patient's usual daily activities  
- 
Severe (Grade 3): prevents the patient from doing their usual daily activities 
- 
Very Severe (Grade 4): requires resuscitation measures/ is life-threatening 
- 
Death (Grade 5) 
g. 
Causal relationship 
- 
Related: an event is said to be related when a causal relationship can reasonably be suspected 
between the event and the investigational product 
- 
Unrelated: an event is said to be unrelated when a causal relationship cannot reasonably be 
suspected between the event and the investigational product 
- 
Doubtful: causality is described as “doubtful” when there are questions about the causal 
relationship between the event and the investigational product (the relationship cannot then 
be formally excluded or formally confirmed) 
h. 
Sponsor liability 
As soon as a serious adverse event report is received from the investigator, the sponsor should 
issue an opinion on the causal relationship between the serious adverse event and the 
investigational product(s). 
If the serious adverse event is considered by the investigator and/or sponsor to be related to one of 
the investigational products (thus it is a serious adverse event), the expected or unexpected nature 
must be established. 
If it is an unexpected serious adverse event, or if it is a new development, the sponsor must prepare 
an initial report to be sent to the ANSM, the Ethics Committee and the EMA (via EudraVigilance) 
within 7 days in the event of death or a life-threatening prognosis; in all other cases, it must be sent 
within 15 days. 
If it is an expected adverse event, the event will be collated for inclusion in an annual safety report. 
 
Non-serious events 
Disease progression should not be considered as a SAE. 
Events potentially related to progression but which could also be secondary to the treatment should 
continue to be reported (e.g. thromboembolic events, bleeding events, perforations, etc.) 
Due to the severity of the disease in this study, some conditions determined as being SAEs are excluded 
from the SAE reporting procedure, namely: 
Hospitalisation or surgery related specifically to treatment of the disease 
Hospitalisation required to simplify study treatments or procedures 
In this trial the reference documents are: 
• 
For oxaliplatin, the Summary of Product Characteristics of Eloxatine® (Appendix 7) 


 
 
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• 
For 5-fluorouracil, the Summary of Product Characteristics of Fluorouracil Ebewe® 50 mg 
(Appendix 7) 
• 
For folinic acid, the Summary of Product Characteristics of ELVORINE® (Appendix 7)  
• 
For irinotecan, the Summary of Product Characteristics of Campto® (Appendix 7) 
• 
For gemcitabine, the Summary of Product Characteristics of Gemzar® (Appendix 7) 
The versions of the SmPCs used to determine the expected or unexpected nature of the event are those 
valid at the time of the analysis. 
 
Action to take 
The investigator shall notify the Sponsor of all Serious Adverse Events (expected and unexpected), 
whether or not they are attributable to the research, which have occurred during the study or within 30 
days after the final administration of treatment. 
All delayed Serious Adverse Events (i.e. occurring after this 30-day period) and reasonably considered 
to be related to the protocol treatment or research should be reported with no time limitations. 
Reports are to faxed to Centre de Randomisation Gestion Analyse (CRGA) at the FFCD within 24 
working hours using the "Serious Adverse Event Report" form (Appendix 10). The form must contain 
as much information as possible and be dated and signed. Fax number: +33 (0)3 80 38 18 41. 
The investigator is responsible for the appropriate medical follow-up of patients until resolution or 
stabilisation of the effect or until the death of the patient. At times this can require lengthy follow-up 
that continues even after the patient had left the study. 
The investigator forwards additional information to the sponsor using a SAE reporting form (ticking 
the Follow-up” box, to specify that it was a follow-up report and not an initial report) within 24 hours 
of receiving any such information. The investigator also forwards the last follow-up prior to the 
resolution or stabilisation of the SAE. 
Investigators are required to respond to requests for additional information in order to document the 
initial observation. 
STATISTICAL ANALYSIS 
Planned study schedule 
Number of centres: 60 
Start of inclusions: December 2014 
End of inclusions: December 2016 
Analysis: June 2017 
Calculation of the number of patients, statistical assumptions 
In this trial, two new strategies are evaluated for the treatment of metastatic pancreatic adenocarcinoma. 
 
The clinical assumptions retained are: 
H0: Rate of patients alive and progression-free at 6 month ≤ 30 % is unacceptable  
H1: Rate of patients alive and progression-free at 6 months >30 %, is beneficial. A 45% rate is expected. 
 


 
 
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Based on a Fleming’s one-step plan (α=5 %, power = 90 %), 87 patients are to be randomised in each 
arm. Taking into account a 5% rate of lost to follow-up and non-evaluable, 92 patients will have to be 
randomised per arm, a total of 276 patients. 
  
The decision rules are as follows: out of 87 evaluable patients: 
 
• 
If 33 patients or fewer are alive and progression-free at 6 months, the treatment will be 
considered as not effective.   
• 
If 34 patients or more are alive and progression-free at 6 months, then the treatment will be 
considered as effective.   
 
The decision rules will only apply to the FOLFIRINOX arm (arm B) with maintenance and to the 
FIRGEM arm (arm C); the FOLFIRINOX arm (arm A) is the control arm.   
 
Statistical analysis: 
 
All analyses will be performed as intention-to-treat (for all randomised patients regardless of 
inclusion/exclusion criteria). 
The primary endpoint and safety analyses will be performed on the evaluable patient population defined 
as ‘randomised patients who have received at least one treatment dose’.  
 
General considerations: 
 
For the description of the baseline population, analyses will be performed on the various treatment arms 
and on the entire population.  
For efficacy and safety analyses, the analyses will be presented by treatment. 
 
General statistics will be used to describe the variables, namely: for qualitative variables: frequencies 
and percentages and, for quantitative variables: mean, standard deviation, median, inter-quartile interval 
and range. 
 
For the rate of patients alive and progression-free at 6 months, a 95% confidence interval will be 
calculated using the exact method (Newcombe, SIM 1998).  
The Kaplan Meier (KM) method will be used to estimation survival rates and times. They will be 
described using medians and rates at different time points with a 95% confidence interval. 
Median survival time will be calculated using a reverse “KM” method. 
 
Safety will be evaluated by:  
- 
Treatment duration, dose-intensity, and ratio between dose received/theoretic dose.  
- 
Toxicity be described using NCI-CTC 4.0.  
- 
Serious adverse events will be described. 


 
 
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Endpoint criteria 
Primary efficacy outcome measure  
Progression is defined as radiological progression according to RECIST v1.1. criteria and/or the clinical 
opinion of the investigator. Progression or death (of any cause) is taken into account if the event occurs 
during the first 6 months of treatment.  
Secondary outcome measures 
- 
Duration of disease control (see definition below)  
- 
Progression-free survival is calculated as the time between the date of randomisation and the 
date of the first progression (local or metastatic) or clinical progression, date of death (of any 
cause). Patients who are progression-free and still living were censored on the date of last 
receiving news. 
- 
Overall survival is calculated as the time between the date of randomisation and the date of 
death (of any cause). Patients who are alive will be censored on the date of last receiving news. 
- 
Time to progression during maintenance is defined as the time between the end of induction 
treatment (FOLFIRINOX or FOLFIRI3) and the date of radiological progression during the 
maintenance period. 
- 
The duration of maintenance treatment (arm B) will be calculated as the time between the last 
FOLFIRINOX course and the date of progression resulting in the resumption of FOLFIRINOX. 
- 
Efficacy will be evaluated using the objective response rate according to RECIST 1.1 criteria 
at 2, 4 and 6 months.  
- 
Best response to treatment during the first 6 months will be derived.  
- 
The frequency of using haematopoietic growth factors for haematological toxicity will be 
described. 
- 
Percentage of patients receiving a 2nd line therapy will be described 
- 
Quality of life (QLQ-C30 EORTC v3.0 questionnaire) will be studied descriptively. Time to 
deterioration of quality of life will be analysed. 
- 
Tolerance will be described using NCI-CTC grades, Version 4.0.  Close attention will be paid 
to neurotoxicity 
 
 
In arm A (Folfirinox), duration of disease control is defined as the period of time between the 
randomisation date and the date of progression under treatment (clinical and/or radiological) or death 
(for any reason and at any time) or the date of switching lines. 
 
In arm B with maintenance (arm B), duration of disease control is defined as follows: 


 
 
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• 
After progression during maintenance with LV5FU2 (PFS1), if the disease is not controlled 
after reintroduction of FOLFIRINOX (PFS2) then the duration of disease control is equal to 
the period of time between randomisation and progression before the reintroduction of 
FOLFIRINOX (PFS1). 
• 
After progression during maintenance with LV5FU2 (PFS1), if the disease is not controlled 
after reintroduction of FOLFIRINOX then the duration of disease control is equal to the period 
of time between randomisation and progression (PFS2) with FOLFIRINOX (PFS1 + PFS2).  
 
In the FIRGEM arm (arm C), duration of disease control is defined as follows: 
If discontinuation of alternate treatments (FOLFIRI.3/Gemcitabine) is due to progression (PFS1) then: 
• 
If the disease is not controlled after changing the treatment then the duration of disease control 
is equal to the period of time between randomisation and progression before changing the 
treatment (PFS1). 
• 
If the disease is again controlled after changing the treatment, then the duration of disease 
control (stability, OR) is equal to the period of time between randomisation and progression 
(PFS2) with the treatment (PFS1 + PFS2) 
 
If the alternation of treatments is discontinued for a reason other than progression (e.g. toxicity, decision 
of the investigator, etc.), then the duration of disease control will be the period of time up to the first 
progression (PFS1). 
 
Event-free patients will be censored on the date of last radiological evaluation or on the cut-off date. 
 
STUDY COMMITTEES 
Independent committee 
An independent committee will be set up and will include at least three gastro-oncologists, a 
statistician/methodologist, and a pharmacovigilance officer. The independent committee will be 
contacted at any time during the protocol, whenever deemed necessary by the Sponsor. 
Steering committee 
A steering committee will be set up. The chairman of the steering committee will act as the study 
coordinator. This committee will also include the co-coordinators, the FFCD project manager for the 
study, the FFCD statistician, and the chairman of the Biological Research Committee. Its tasks will 
include taking research management decisions (amendment, early closure if necessary, etc.). This 
committee will meet as many time as necessary throughout the study. The steering committee will take 
all the necessary decisions about substantial amendments to the protocol, and the closure or extension 
of the study.  


 
 
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Medical review  
A medical review will be set up to check the quality of the clinical data collected. In the event of 
discrepancy between the data entered by the investigator and the medical review data, the data manager 
will send a request for clarification to the investigator. 
Biological research committee 
A Biological Research Committee will be established and its remit is to manage any problems 
encountered with the collection and banking of samples, as well as the organisation of the testing of 
samples. The committee will meet regularly and report on its proposals to the Steering Committee. This 
committee includes the study coordinator and a biologist; Professor Pierre Laurent Puig acts as the 
chairman of the committee. 
 
 
 
 
BASIS AND RATIONALE OF THE STUDY 
The incidence of pancreatic ductal adenocarcinoma is steadily increasing in most Western 
countries: in 2012 in France, 11662 new cases were reported (compared to 4887 in 2000), meaning that 
the incidence has more than doubled in 12 years. Mortality is closely related to incidence and it is the 
fourth highest cause of death [1]. For all stages of the disease, 5-year survival rates do not exceed 5% 
[2]. 
At the time of diagnosis, 50-60% of cases of pancreatic cancer have already reached the stage of visceral 
metastases. In addition, out of the 10-20% of patients able to benefit from curative resection, most will 
relapse, despite the advances in post-operative adjuvant chemotherapy (based on FU-folinic acid or 
gemcitabine) which has increased the survival rate after 5 years from 10 to 20% [3, 4, 5, 6].  
 
At a metastatic stage, pancreatic adenocarcinoma remains an incurable disease, associated with 
a median survival of 2 to 4 months without chemotherapy. Gemcitabine monotherapy offered the first 
glimmer of hope [7 ]; however, it was not until 2011, after 13 years of negative phase III studies, that 
major progress was achieved in the management of such pancreatic patients. A combination with 
FOLFIRINOX [8] allowed, in patients in good health at a metastatic stage with normal bilirubinaemia 
and under the age of 76 years, to increase their overall survival (from 6.8 to 11.1 months - p<0.0001) 
and progression-free survival (from 3.3 to 6.4 months – p<0.0001) compared to gemcitabine. The main 
toxicity of the treatment are haematological and gastrointestinal, related to the onset of reversible 
sensory neuropathy, in relation to oxaliplatin. 
According to INVS (French Institute for Public Health Surveillance) data, pancreatic-cancer patients in 
France under the age of 76 years (thus potentially eligible for a FOLFIRINOX regimen) account for 
58% of cases. Of this number, half are aged under the age of 65 years and the other half are aged 
between 65 and 75 years [9]. 
Due to increased life expectancy at birth (85 years for women, 78 years for men), the proportion of 
people over the age of 65 with pancreatic cancer is gradually increasing. In the study from T. Conroy 
et al, the median age of patients at baseline was 61 years and FOLFIRINOX chemotherapy remained 
beneficial in patients over 65 years of age [8]. A geriatric evaluation is used to identify the frailty of 
patients by assessing autonomy and social environment as well as screening for walking disorders, 
cognitive disorders, mood disorders and malnutrition. [10. Geriatric evaluation parameters are 
correlated with treatment tolerance and overall survival of elderly patients treated for cancer of the 
colon, oesophagus or ovaries [11, 12. No specific data exists for pancreatic cancer in elderly subjects. 


 
 
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It would be worthwhile investigating in older patients eligible for FOLFIRINOX whether geriatric 
frailty factors are predictive of treatment failure in order to better target the indications. 
 
FIRGEM is an original sequential treatment strategy [13]. This novel therapeutic approach 
allows patients to be administered 3 cytotoxic drugs (5FU, irinotecan and gemcitabine), with no known 
cross-resistance to each other, sequentially, which limits cumulative or non-cumulative toxicity and can 
preserve the patient's quality of life. In a randomised phase II study, patients received either FOLFIRI.3 
alternately every 2 months with gemcitabine (FIRGEM strategy) or gemcitabine alone, continuously. 
The FOLFIRI 3 regimen consisted of administering 50% of the dose of irinotecan before the continuous 
5FU and 50% at the end of the infusion of the continuous 5FU, to optimise the reciprocal modulations 
exerted by 5FU and irinotecan [14].  Overall survival was 11 months in the FIRGEM arm and 8.2 
months in the control arm.  The rate of progression-free survival after 6 months was 45% in the 
FIRGEM arm, extremely close to the numbers reported with FOLFIRINOX. Haematological and 
gastrointestinal toxicity were similar to those reported with FOLFIRINOX; however, this strategy does 
not induce limiting neurotoxicity and allows oxaliplatin to be used in second line. [13]  
 
To improve tolerance and efficacy of first-line chemotherapy in metastatic pancreatic 
adenocarcinoma, two attitudes can be evaluated: 
 
- A stop-and-go strategy, as in OPTIMOX-1 for metastatic colorectal cancer [15]: treatment with 
FOLFIRINOX and LV5FU2 as maintenance. FOLFIRINOX with LV5FU2 as maintenance has never 
been evaluated in pancreatic adenocarcinoma. This strategy, which is used in colorectal cancer, could 
improve the tolerance of FOLFIRINOX without reducing its efficacy. 
 
- A sequential strategy (the “FIRGEM” regimen) alternating FOLFIRI.3 with gemcitabine.  
 
Only one previous strategic phase III trial evaluating a second line of treatment exists [16]. 
 
The objective of this three-arm randomised study is to evaluate standard treatment with 
FOLFIRINOX (until disease progression or unacceptable toxicity), FOLFIRINOX with LV5FU2 
maintenance (in patients whose disease is controlled after 4 months, 8 courses) and treatment 
with FIRGEM. 
This 3-arm Phase II study could be used to design an extensive Phase II strategic study on 
maintenance or sequential strategies. 
 
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33. Vellas BJ, Wayne SJ, Romero L, Baumgartner RN, Rubenstein LZ, Garry PJ. «One-leg balance 
is an important predictor of injurious falls in older persons.» J Am Geriatr Soc. 45.6 (1997): 
735-8. 
  
34. Studenski S., Perera ., Patel K., Rosano C., Faulkner K., Inzitari M., Brach J., Chandler J., 
Cawthon P., Barrett Connor E., Nevitt M., Visser M., Kritchevsky S., Badinelli S., Harris T., 
Newman A.B., Cauley J., Ferrucci L., Guralnik J. "Gait Speed and Survival in Older Adults." JAMA 
(2011): Vol 305(1):50-58. 
 
35. Lee SJ, Lindquist K, Segal MR, Covinsky KE. «Development and validation of a prognostic index 
for 4-year mortality in older adults.» JAMA. 295.7 (2006): 801-8. 
 
36. Soubeyran P. et al. Validation of the G8 screening tool in geriatric oncology: The ONCODAGE 
project - ASCO Annual Meeting 2011 J Clin Oncol 29:550s; 2011 (suppl) abstr 9001.  
 
37. Yesavage, JA. «Geriatric Depression Scale.» Psychopharmacol Bull. 24.4 (1988): 709-11. 
 
38. Aapro MS et al. 2010 update on EORTC guidelines for the use of G-CSF… EJC 2011 ; 47 : 8-
32. 
 
 
ADMINISTRATIVE CONSIDERATIONS 
STUDY SPONSOR 
 
The study sponsor is Fédération Francophone de Cancérologie Digestive (FFCD). The study was 
registered under EudraCT number 2014-002574-36. 
 
REMINDER OF TEXTS IN FORCE 
 
This study will be conducted according to the French law in force, in accordance with the ethical 
principles of the Helsinki Declaration of 1964 revised in Edinburgh in 2000, the Good Clinical Practices 
of the International Harmonization Conference (ICH–E6, 17/07/96), the European Directive 
(2001/20/EC) on the conduct of clinical trials, the amended Huriet law (20/12/98) relating to the 
Protection of Persons Involved in Biomedical Research as well as the provisions stipulated by the 
French data protection agency (CNIL) (Law No. 94-548 of 1/07/94 supplementing Law No. 78-17 of 
6/01/78). 
 
CIVIL LIABILITY INSURANCE 
 
The sponsor has taken out insurance to cover its civil liability (number 137681 dated 09/05/2014), in 
compliance with Article L 1121-10 of the French public health code (Appendix 12). 
 


 
 
PRODIGE 35 - PANOPTIMOX 
Version 2.2 – 18/08/2014 authorised 
 
Page 39 of 40 
REQUEST FOR AUTHORISATION FROM THE EC AND ANSM 
 
This protocol has been approved by the EC (Ethics Committee) of SUD MEDITERRANEE II on 
11/07/2014 (Appendix 13). 
This protocol was authorised by the ANSM (French National Agency for Medicines and Health 
Products Safety) on 20/08/2014 (Appendix 14). 
 
COLLECTING THE CONSENT OF PATIENTS 
 
The investigator undertakes to collect, after providing information, the clinical and biological consents 
of the patient in writing (patient information leaflets and consent forms in Appendices 1 and 2) before 
the patient is enrolled in the study. The investigator must retain a duplicate copy of the consent 
documents for 15 years, to be shown to the supervisory authorities during any inspections. An original 
copy should be given to the patient. 
 
In accordance with the recommendations of the Cancer Plan (Measure 4.3.), this document has been 
submitted for review, advice and guidance to the Patient Committee for Clinical Research (CPRC) of 
the French League Against Cancer. 
 
INFORMATION FOR HOSPITAL MANAGEMENT AND RESEARCH AGREEMENT 
 
Before setting up the study, the hospital management will be informed by the sponsor of the 
investigator's interest in participating in this study. 
 
 
A research agreement will be drawn up at no additional cost between the administrator of the 
investigating centre and the sponsor. 
 
DATA ARCHIVING 
 
Records shall remain confidential and may only be consulted under the responsibility of the doctors 
taking care of the patients. During any inspections, the sponsor and the health authorities will have 
direct access to the documents. 
At the end of the study, the investigator will retain the case report form for 15 years. 
 
 IT MEDIA 
 
In accordance with the text of Law No. 78-17 of 6 January 1978, as amended by the Law of 9 August 
2004, relating to data processing, files and civil liberties, data from the study will be recorded in a 
computer database at the Centre de Randomisation et de Gestion Analyse of the FFCD. No elements 
revealing the identity of patients will be included. 
 
DATA PROCESSING 
 
Centre de Randomisation, de Gestion et d'Analyse (CRGA) of the FFCD is responsible for the 
management and analysis of data. 
 
MONITORING, QUALITY ASSURANCE AND INSPECTIONS BY THE AUTHORITIES 
 
The investigator agrees in advance that the records of patients enrolled will be consulted by a person 
mandated by the Sponsor and/or the health authorities to conduct an audit. On-site visits to view the 
files, scheduled after agreement of the investigator, may take place during or after the trial enrolment 
period. 
This protocol will be monitored by the mobile CRAs of the FFCD. 


 
 
PRODIGE 35 - PANOPTIMOX 
Version 2.2 – 18/08/2014 authorised 
 
Page 40 of 40 
PUBLICATION RULES 
Publication rules shall comply with those established by the PRODIGE group (Appendix 11). 
APPENDICES 
 

SAP_001.pdf: 
 
Statistical analysis plan - Final analysis - PRODIGE 35 - v2.0 : March  
2016Page 1 on 21 
 
 
 
 
 
 
 
 
 
 
             
 
 
 
 
 
 
 
 
 
 
 
RANDOMIZED PHASE II TRIAL IN METASTATIC PANCREATIC CANCER EVALUATING 
FOLFIRINOX +/- LV5FU2 IN MAINTENANCE  
AND FIRGEM IN 1ière LINE 
Phase II randomized - multicenter 
PRODIGE 35 
 
 
Statistical Analysis Plan 
Final analysis 
 
 
 
 
 
 
 
 
Version: 2.0 
Date: March 25, 2016 
 
Editor: Karine Le Malicot 
Review committee: Laetitia Dahan, Jérémie Bez , Emilie Maillard, Paolo Carni, Fadil Masskouri. 
 
 


 
Statistical analysis plan - Final analysis - PRODIGE 35 - v2.0 : March  
2016Page 2 on 21 
 
Developer 
Fédération Francophone de Cancérologie Digestive (FFCD),  
Faculty of Medicine,  
7, Boulevard Jeanne d'Arc, BP 87900,  
21079 Dijon Cedex 
 
Coordinator 
  
Pr Laetitia DAHAN  
Digestive Oncology Department 
Hôpital de la Timone, 264 rue Saint Pierre 
13005 MARSEILLE 
Tel. 04 91 38 60 23 
Email : Laetitia.DAHAN@ap-hm.fr 
 
 
Project Manager  
 
Mr Jérémie Bez 
FFCD 
Faculty of Medicine 
7 boulevard Jeanne d'Arc 
BP 87900, 21079, Dijon Cedex 
Tel.: 03 80 39 34 83  
Email : jérémie.bez@u-bourgogne.fr 
  
 
 


 
Statistical analysis plan - Final analysis - PRODIGE 35 - v2.0 : March  
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1 Table of contents 
1 
Table of contents .........................................................................................................................................................................................................3 
2 
Abbreviations and definitions ...............................................................................................................................................................................5 
3 
Introduction ..................................................................................................................................................................................................................6 
3.1 
Study objectives ...............................................................................................................................................................................................6 
3.1.1 
Main objective .............................................................................................................................................................................................6 
3.1.2 
Secondary objectives ................................................................................................................................................................................6 
3.1.3 
Exploratory studies...................................................................................................................................................................................7 
4 
Experimental design ..................................................................................................................................................................................................7 
4.1 
Study diagram ...................................................................................................................................................................................................7 
4.2 
Treatment arms ...............................................................................................................................................................................................7 
4.3 
Randomization and blinding ......................................................................................................................................................................8 
4.4 
Chronological sequence ...............................................................................................................................................................................8 
4.5 
Justification of the number of subjects required...............................................................................................................................9 
4.6 
Planning test analyses ...................................................................................................................................................................................9 
4.7 
Adjustments.......................................................................................................................................................................................................9 
5 
Study populations for analysis ........................................................................................................................................................................... 10 
5.1 
Definition of analysis populations ........................................................................................................................................................ 10 
5.1.1 
Intention-to-treat (ITT) population ............................................................................................................................................... 10 
5.1.2 
Modified intention-to-treat population (mITT) ........................................................................................................................ 10 
6 
General information on statistical methods ................................................................................................................................................ 10 
6.1 
Software ........................................................................................................................................................................................................... 10 
6.2 
Agreements concerning dates and durations .................................................................................................................................. 10 
6.3 
Conventions concerning missing data ................................................................................................................................................ 10 
6.4 
Baseline definition ....................................................................................................................................................................................... 10 
6.5 
Statistics ........................................................................................................................................................................................................... 11 
7 
Statistical analysis ................................................................................................................................................................................................... 12 
7.1 
Patient characteristics at randomization .......................................................................................................................................... 12 
7.1.1 
Characteristics at randomization - Eligibility ............................................................................................................................ 12 
7.1.2 
Demographics .......................................................................................................................................................................................... 13 
7.1.3 
Clinical features ....................................................................................................................................................................................... 13 
7.1.4 
Biological characteristics .................................................................................................................................................................... 13 
7.1.5 
Disease-related characteristics ........................................................................................................................................................ 14 
7.2 
Follow-up features ...................................................................................................................................................................................... 14 
7.2.1 
Definition of median follow-up time .............................................................................................................................................. 14 
7.2.2 
Evaluation of median follow-up time ............................................................................................................................................ 14 
7.3 
Evaluation of primary efficacy endpoint ........................................................................................................................................... 14 
7.3.1 
Definition of primary endpoint ........................................................................................................................................................ 14 
7.3.2 
Evaluation of primary endpoint ....................................................................................................................................................... 14 
7.4 
Evaluation of secondary efficacy criteria .......................................................................................................................................... 15 
7.4.1 
Duration of disease control ................................................................................................................................................................ 15 
7.4.2 
Progression-free survival .................................................................................................................................................................... 15 


 
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2016Page 4 on 21 
7.4.3 
Overall survival ........................................................................................................................................................................................ 16 
7.4.4 
Time to progress during interview ................................................................................................................................................. 16 
7.4.5 
Duration of maintenance treatment (Arm B only) .................................................................................................................. 16 
7.4.6 
Objective response rate and best tumor response during the first 6 months of treatment .................................. 16 
7.5 
Tolerance assessment ................................................................................................................................................................................ 17 
7.5.1 
Treatment administration .................................................................................................................................................................. 17 
7.5.2 
Toxicities .................................................................................................................................................................................................... 18 
7.5.3 
E.I.G ............................................................................................................................................................................................................... 18 
7.6 
Quality of life and geriatric assessment ............................................................................................................................................. 19 
7.6.1 
Quality of Life - QLQ-C30 ..................................................................................................................................................................... 19 
7.6.2 
Geriatric assessments ........................................................................................................................................................................... 19 
7.7 
Exploratory analysis ................................................................................................................................................................................... 20 
8 
Quality assurance ..................................................................................................................................................................................................... 20 
8.1 
Input ................................................................................................................................................................................................................... 20 
8.2 
Base monitoring............................................................................................................................................................................................ 20 
8.2.1 
Test analysis .............................................................................................................................................................................................. 20 
8.2.2 
Dual programming ................................................................................................................................................................................. 21 
 


 
Statistical analysis plan - Final analysis - PRODIGE 35 - v2.0 : March  
2016Page 5 on 21 
2 Abbreviations and definitions 
 
  
 
 
 
ACE 
embryonic carcino antigen 
ALAT  
Alanine aminotransferase (or SGPT: serum glutamic pyruvic transaminase) 
ANSM 
National Agency for the Safety of Medicines and Health Products 
ASAT 
Aspartate aminotransferase (or SGOT: serum glutamic oxaloacetic transaminase) 
PPC 
Comité de Protection des Personnes 
EI 
Undesirable event 
EIG 
Serious adverse event 
5FU 
5-fluorouracil 
FFCD 
French-speaking Federation of Digestive Oncology 
FOLFIRI 
Folinic acid - Fluorouracil - IRInotecan 
GDS 
Geriatric depression scale 
GGT 
Gamma glutamyl transpeptidase 
Hb 
Hemoglobin 
HR 
Hazard ratio  
ITT 
Intention to treat 
KM 
Kaplan Meier 
LDH 
Lactate dehydrogenase 
LSN 
Upper limit of normal 
MMSE 
Mini mental state examination 
N 
Normal  
NCI-CTCAE 
National Cancer Institute - Common Terminology Criteria for Adverse Events 
NFS 
Blood count 
WHO 
World Health Organization 
PAL 
Alkaline phosphatases 
PNN 
Neutrophil Polynuclear 
Q1-Q3 
Quartiles 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RC 
Complete Answer 
RP 
Partial response 
RO 
Objective answer 
PNN 
Neutrophils 
SG 
Overall survival 
SSP 
Progression-free survival 
SD 
Stable disease 
TAP 
Thoraco-Abdomino-Pelvic 
CT SCAN 
Computed tomography 
TP 
Prothrombin levels 


 
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3 Introduction 
3.1 Study objectives 
3.1.1 
Main objective 
The main aim of this Phase II study is to assess the rate of patients alive and free of radiological (RECIST V1.1) and/or 
clinical progression at 6 months in each arm, and to select the best therapeutic strategy for a future Phase III trial.  
 
3.1.2 
Secondary objectives 
 
The secondary objectives of the study are to evaluate: 
• 
Duration of disease control 
• 
progression-free survival  
• 
Progression time during maintenance treatment, 
• 
Median time on maintenance treatment (arm B) 
• 
Objective response rate 
• 
Overall survival 
• 
Toxicity according to NCI CTC v4.0 
• 
Overall survival 
• 
The rate of patients receiving 2nd-line therapy  
• 
Quality of life (EORTC QLQ-C30 questionnaire)  
• 
Geriatric frailty factors predictive of treatment failure in patients over 65. 
 
In arm A (Folfirinox), duration of disease control is defined as the time between the date of randomization and the date 
of treatment progression (clinical and/or radiological) or death (from any cause and at any time) or the date of line 
change. 
 
In arm B with maintenance (arm B), the duration of disease control is defined as follows: 
• 
After progression during LV5FU2 maintenance (SSP1), if the disease is not controlled after reintroduction of 
FOLFIRINOX (SSP2), then the duration of disease control will be equal to the time between randomization and 
progression before reintroduction of FOLFIRINOX (SSP1). 
• 
After progression during maintenance on LV5FU2 (PFS1), if the disease is again controlled after reintroduction 
of FOLFIRINOX, then the duration of disease control (stability, OR) will be equal to the time between 
randomization and progression (PFS2) on FOLFIRINOX (PFS1 + PFS2).  
 
In the FIRGEM arm (arm C), the duration of disease control is defined as follows: 
• 
If the discontinuation of alternating treatments (FOLFIRI.3/Gemcitabine) is due to progression (SSP1), then: 
• 
If the disease is not controlled after treatment change, then the duration of disease control will be equal to the 
time between randomization and progression before treatment change (PFS1). 
• 
If the disease is again controlled after a change of treatment, then the duration of control (stability, RO) of the 
disease will be equal to the time between randomization and progression (SSP2) under treatment (SSP1+ 
SSP2). 
 


 
Statistical analysis plan - Final analysis - PRODIGE 35 - v2.0 : March  
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If the discontinuation of alternating treatments is due to a cause other than progression (toxicity, investigator's 
decision, etc.), then the duration of disease control will be the time to first progression (PFS1). 
 
 
3.1.3 
Exploratory studies 
 
• 
Blood sampling study of constitutional genetic polymorphisms that can influence the efficacy and tolerance of 
chemotherapy molecules (UGT1A1, ERCC1, GSTT1, MTHFR, DPD, TS ...). 
• 
Study of kerosene sections for immunohistochemical biomarkers predictive of response to treatment. 
 
 
4 Experimental design 
 
4.1 Study diagram 
 
This is an open-label, Phase II, parallel-group (3-arm), multicenter trial.  
 
4.2 Treatment arms 
 
▪ 
Arm A: FOLFIRINOX (12 courses)   
▪ 
Arm B: FOLFIRINOX (8 courses) followed by LV5FU2 (maintenance), then resumption of FOLFIRINOX as the 
treatment progresses.   
▪ 
Arm C: FIRGEM: Alternating 2 months of FOLFIRI.3 and 2 months of GEMCITABINE   
 
 
 
 
 
 
 
 
 
 
 
R 
Arm A: FOLFIRINOX (12 courses of 
treatment)
Arm B: FOLFIRINOX (8 courses)* then LV5FU2 (maintenance), then 
return to FOLFIRINOX as the treatment progresses. 
Arm C: FIRGEM: Alternating 2 months of FOLFIRI.3 and 2 months of 
GEMCITABINE**. 


 
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4.3 Randomization and blinding 
 Patients will be randomized (1:1:1) using a minimization technique based on the following stratification factors:  
▪ 
Center 
▪ 
Biliary prosthesis: Yes vs. 
▪ 
Age: ≤ 65 years vs > 65 years  
 
4.4 Chronological sequence 
 
 
 
        1  2 3 4 5 6  
7 8 9 10 
 
 
MONTHS 
6-month assessment CT scan (regardless of 
the number of treatments performed) 
If RO or S 
P 
FOLFIRINOX 
 
 
LV5FU2 
 
FOLFIRI3 
 
GEMCITABINE 
ARM A: FOLFIRINOX 12 
courses of treatment 
BRAS B: FOLFIRINOX (8 
courses) then LV5FU2 for 
maintenance, then return to 
FOLFIRINOX as the 
treatment progresses. 
C-arm: FIRGEM alternating 
every 2 months FOLFIRI 3 / 
Gemcitabine 
CAT scan every 8 weeks 


 
Statistical analysis plan - Final analysis - PRODIGE 35 - v2.0 : March  
2016Page 9 on 21 
 
4.5 Justification of the number of subjects required 
 
In this trial, two new strategies are being evaluated in the treatment of metastatic pancreatic adenocarcinoma. 
 
The clinical assumptions used are as follows: 
H0 : A rate of patients alive and progression-free at 6 months ≤ 30% is unacceptable  
H1 : A rate of patients alive and progression-free at 6 months > 30% would be interesting. A rate of 45% is expected. 
 
According to Fleming's one-stage design (α = 5%, power = 90%) 87 patients per arm will be randomized. Taking into 
account a 5% rate of lost to follow-up and non-evaluables, 92 patients will be randomized per arm, for a total of 276 
patients. 
  
 
The decision rules are as follows: Of the 87 evaluable patients : 
 
• 
If 33 or fewer patients are alive and progression-free at 6 months, treatment is considered ineffective.   
• 
If 34 or more patients are alive and progression-free at 6 months, the treatment is considered effective.   
 
The decision rules will only be applied to the FOLFIRINOX arm (arm B) with maintenance and to the FIRGEM arm (arm 
C), with the FOLFIRINOX arm (arm A) being the reference arm.   
 
 
4.6 Planning test analyses 
 
A final analysis is planned after randomization of the 87 patients required for the arm-by-arm analysis. 
 
4.7 Adjustments 
 
Adjustments may be made to this analysis plan in the event of amendments to the protocol, or if phenomena not 
initially foreseen require statistical adaptations. In all cases, these modifications must be made before the database is 
frozen. 
 
 
 


 
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5 Study populations for analysis 
 
5.1 Definition of analysis populations  
 
5.1.1 
Intention-to-treat (ITT) population 
 
The intention-to-treat population is defined as all patients included in the study, regardless of eligibility criteria. 
 
5.1.2 
Modified intention-to-treat population (mITT) 
 
The modified intention-to-treat population is defined as all patients included in the study, irrespective of eligibility 
criteria and having received at least one dose of treatment (whatever the molecule). 
A list of patients excluded from the ITTm population will be provided with the reasons for their exclusion. 
 
6 General information on statistical methods 
 
Statistical analyses will be carried out by CRGA. 
 
6.1 Software 
Statistical analyses will be carried out using SAS software version 9.4. Some graphs may be produced using R software 
version 2.11 or later. 
 
6.2 Agreements concerning dates and durations 
Time since randomization will be defined as the time elapsed since the day of randomization, with the day of 
randomization taken as day 1. 
As a result, durations are calculated using the following rule, for example for the time elapsed between death and 
inclusion: day of death - day of inclusion + 1. 
The day preceding the day of inclusion (resp. the day preceding the day of treatment) will be considered as day -1 (day 
0 does not exist). 
 
The date of last news will be the date of the last examination or treatment. 
The following conversion rules will be used to convert numbers of days into numbers of months or years: 1 month = 
30.4375 days; 1 year = 365.25 days. 
 
6.3 Missing data conventions 
 
Except in the cases specified, missing data will not be replaced. 
 
6.4 Baseline definition 
 


 
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Baseline measurements are the last measurements taken before randomization. In the event of missing data, the last 
measurement taken before the first treatment is used. 
 
6.5 Statistics 
 
The confidence intervals provided will be two-sided 95% confidence intervals, except for the main criterion where the 
confidence interval calculated will be a one-sided 5% confidence interval. 
 
Quantitative data will be described using the following descriptive statistics: headcount, mean, standard deviation, 
median, first and third quartile, minimum and maximum. These statistics will be considered as the usual statistics for 
the analysis of quantitative variables. Quantitative variables can be categorized using their median or a cut-off known 
from the medical literature. 
 
Categorical variables will be summarized, using the following descriptive statistics: number, frequencies and 
percentages for each level of the variable. These statistics will be considered as the usual statistics for the analysis of 
qualitative variables. 
Where necessary, confidence intervals for the proportions will be calculated from the exact binomial distribution.  
 
For survival data : 
After describing the number of events according to treatment arm, time to progression, progression-free survival and 
overall survival will be estimated using the Kaplan Meier method, then described by curves and rates at different time 
points with their 95% confidence intervals.   
The median follow-up time is estimated using the inverse Kaplan-Meier method (Shemper, 1996). 
  
Descriptive baseline analyses will be presented by treatment arm and on the total population. Efficacy and safety 
results will be presented by treatment arm. 
 
No statistical comparison between arms is planned. 
 
 
 


 
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7 Statistical analysis 
 
Population ITT 
Population ITTm 
 
Description of Baseline 
 
 
Inclusion eligibility criteria 
X 
 
Demographic characteristics 
X 
 
Clinical features at inclusion 
X 
 
Biological characteristics at inclusion 
X 
 
Disease-related characteristics 
X 
 
Median follow-up time 
X 
 
Efficiency 
 
 
Main criterion 
X 
X 
Duration of disease control 
X 
X 
Overall 
survival, 
progression-free 
survival 
X 
X 
Time to progress during interview 
X 
 
Duration of maintenance treatment 
X 
 
Tumor response rate 
X 
 
Tolerance 
 
 
Treatment administration 
 
X 
Toxicities and frequency of use of 
hematopoietic growth factors 
 
X 
Quality of life 
 
X 
 
7.1 Patient characteristics at randomization 
 
7.1.1 
Characteristics at randomization - Eligibility 
 
Population: ITT 
Patient eligibility for randomization will be described by :  
▪ 
Number and percentage of patients who met all inclusion criteria 
▪ 
Number and percentage of patients who met all non-inclusion criteria 
▪ 
Number and percentage of patients who met all inclusion and non-inclusion criteria 
▪ 
Stratification criteria 
o 
Biliary prosthesis: Yes vs. 
o 
Age: ≤ 65 years vs > 65 years  
 
 
 


 
Statistical analysis plan - Final analysis - PRODIGE 35 - v2.0 : March  
2016Page 13 on 21 
 
7.1.2 
Demographic characteristics 
 
Population: ITT 
The following randomization characteristics will be described: 
▪ Age (years) ; 
▪ Inclusion center (number of patients included per center) ; 
▪ Gender (Male vs Female). 
 
 
7.1.3 
Clinical features 
 
Population: ITT 
The following randomization characteristics will be described: 
▪ Weight (kg) ; 
▪  WHO general condition (0 vs 1 vs 2). 
▪ G8 score 
▪ Charlson Index 
▪ MMSE score 
▪ GDS 15 score 
 
7.1.4 
Biological characteristics 
 
Population: ITT 
The following characteristics will be described at randomization: 
▪ Hemoglobin (g/dL) ; 
▪ Platelets (109 /L); 
▪ Leukocytes (/mm3 ) ; 
▪ PNN (/mm3 ) ; 
▪ Lymphocytes (/mm )3 
▪ TP (%) ; 
▪ Natremia (mmol/L) ; 
▪ Kalemia (mmol/L) ; 
▪ Potassium (mmol/L) 
▪ Albumin levels (g/L) ; 
▪ Glucose (g/L) 
▪ Protein level (mmol/L) 
▪ Total and conjugated bilirubin (μmol/L) ; 
▪ LDH (mmol/L) 
▪ ASAT, ALAT, PAL, GGT (by class: <Normal; 1xN < ≤3xN; > 3N or even 3xN/5xN). 
 


 
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7.1.5 
Disease-related characteristics 
 
Population: ITT 
The following randomization characteristics will be described: 
▪  Time since diagnosis of metastatic disease (months) 
▪ Primary surgery 
▪ Previous treatment and description of type of treatment 
▪ Metastatic localization 
 
7.2 Follow-up features 
7.2.1 
Definition of median follow-up time 
Population: ITT 
Median follow-up time is defined as the time interval between the date of randomization and the date of last news 
(patients alive or lost to follow-up) or, for deceased patients, the date of death (whatever the cause). 
  
7.2.2 
Evaluation of median follow-up time 
The median follow-up time (for living patients) and its 95% confidence interval will be calculated in months per 
treatment. It will be estimated using the inverse Kaplan Meier method. 
 
7.3 Evaluation of primary efficacy endpoint 
 
Population: ITTm and ITT 
 
7.3.1 
Definition of primary endpoint 
The primary endpoint is the rate of patients alive and progression-free at 6 months. Progression is defined as 
radiological progression according to RECIST v1.1 criteria and/or clinical progression according to the investigator. 
Progression or death (for any reason) will be considered if the event occurs within the first 6 months since 
randomization. 
6-month scans will be 6-month scans with a +/- 1-month window 
Patients with no evaluation at 6 months but later (8 months, for example) will be reviewed. 
  
7.3.2 
Evaluation of primary endpoint 
 
The primary endpoint will be assessed by treatment arm in the ITTm and ITT populations. A one-sided 5% confidence 
interval will be calculated using the exact method for each treatment arm. 
The decision rules will be applied to arms B and C, with arm A being the reference arm.  
As a reminder, for arms B and C, on the first 87 evaluable patients (from the ITTm population): 
• 
If 33 or fewer patients are alive and progression-free at 6 months, treatment is considered ineffective.   
• 
If 34 or more patients are alive and progression-free at 6 months, the treatment is considered effective.   
(Rules will be recalculated for the ITT population) 
  


 
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7.4 Evaluation of secondary efficacy endpoints 
 
7.4.1 
Duration of disease control 
Population: ITTm and ITT 
 
7.4.1.1 
Definition   
In arm A (FOLFIRINOX), the duration of disease control is defined as the time between the date of randomization and 
the date of treatment progression (clinical and/or radiological) or death (from any cause and at any time) or the date of 
line change. 
 
In the maintenance arm (arm B), the duration of disease control is defined as follows: 
• 
After progression during LV5FU2 maintenance (SSP1), if the disease is not controlled after reintroduction of 
FOLFIRINOX (SSP2), then the duration of disease control will be equal to the time between randomization and 
progression before reintroduction of FOLFIRINOX (SSP1). 
• 
After progression during maintenance on LV5FU2 (PFS1), if the disease is again controlled after reintroduction 
of FOLFIRINOX, then the duration of disease control (stability, OR) will be equal to the time between 
randomization and progression (PFS2) on FOLFIRINOX (PFS1 + PFS2).  
 
In the FIRGEM arm (arm C), the duration of disease control is defined as follows: 
• 
If the discontinuation of alternating treatments (FOLFIRI.3/Gemcitabine) is due to progression (SSP1), then: 
• 
If the disease is not controlled after treatment change, then the duration of disease control will be equal to the 
time between randomization and progression before treatment change (PFS1). 
• 
If the disease is again controlled after a change of treatment, then the duration of control (stability, RO) of the 
disease will be equal to the time between randomization and progression (SSP2) under treatment (SSP1+ 
SSP2). 
 
If the discontinuation of alternating treatments is due to a cause other than progression (toxicity, investigator's 
decision, etc.), then the duration of disease control will be the time to first progression (PFS1). 
Event-free patients will be censored at the date of last radiological evaluation or the point date. 
 
7.4.1.2 
Evaluation   
Duration of disease control will be described using standard descriptive statistics for each treatment arm. 
The time scale considered is the month. 
 
7.4.2 
Progression-free survival  
Population: ITT 
 
7.4.2.1 
Defining progression-free survival 
 
It is defined as the time interval between the date of randomization and the date of 1ère radiological progression or the 
date of first clinical progression or the date of death (all causes combined). Patients alive and progression-free will be 
censored at the date of last news. 


 
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7.4.2.2 
Assessment of progression-free survival 
 
The time scale considered is the month. 
Progression-free survival will be plotted using the Kaplan Meier estimator per treatment arm, and survival rates at 
different time points (6, 9, 12 and 18 months) will be calculated along with their 95% confidence intervals. 
 
7.4.3 
Overall survival  
Population: ITT 
 
7.4.3.1 
Defining overall survival 
 
It is defined as the time interval between the date of randomization and the date of death (whatever the cause). 
Patients lost to follow-up or alive at the time of analysis will be censored at the last news date. 
7.4.3.2 
Assessment of overall survival 
 
The time scale considered is the month. 
Overall survival will be plotted using the Kaplan Meier estimator per treatment arm, and survival rates at different time 
points (6, 9, 12 and 18 months) will be calculated along with their 95% confidence intervals. 
 
7.4.4 
Time to progress during maintenance (Arm B only) 
Population: ITTm   
 
7.4.4.1 
Definition   
 
Time to progression during maintenance is defined as the time between the end of induction therapy (FOLFIRINOX or 
FOLFIRI3) and the date of radiological progression during the maintenance period. 
 
7.4.4.2 
Evaluation   
Time to progression will be described using standard descriptive statistics for each treatment arm. 
 
7.4.5 
Duration of maintenance treatment (Arm B only) 
 
7.4.5.1 
Definition   
The duration of maintenance treatment (arm B) will be calculated as the time between Day 1 of the last course of 
FOLFIRINOX and the date of progression leading to resumption of FOLFIRINOX. 
 
7.4.5.2 
Evaluation   
 
The duration of maintenance treatment will be described using standard descriptive statistics for arm B only. 
 
7.4.6 
Objective response rate and best tumor response during the first 6 months of treatment 
Population: ITT 


 
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7.4.6.1 
Definition   
 
The objective response rate (complete response or partial response) according to RECIST 1.1 criteria at 2, 4 and 6 
months will be derived from the tumor response measured according to RECIST criteria (modified version 1.1) every 2 
months. 
Patients who die without an objective response (partial response or complete response = OR) or who are lost to follow-
up will not be considered as responders.   
The best response to treatment during the first 6 months will also be derived from radiological assessments at 2, 4 and 
6 months. 
 
7.4.6.2 
Evaluation   
Objective response at 2, 4 and 6 months will be described according to the categories Responder vs. Nonresponder by 
treatment arm. Patients with a NE response will be considered Nonresponders. 
 
Tumor responses at 2, 4 and 6 months, as well as the best response at the first 6 months of treatment, will be described 
according to the following 4 categories: Complete response / Partial response / Stability / Progression/ NE by 
treatment arm. 
 
 
7.5 Tolerance assessment 
Population: ITTm 
Tolerance will be assessed by treatment arm. 
Tolerance to treatment will be assessed by : 
▪ Duration of treatment, doses received, dose reductions and postponements; 
▪ Toxicities described according to NCI-CTC criteria version 4.0 ; 
▪ The frequency of use of hematopoietic growth factors for hematological toxicity 
▪ Percentage of patients receiving 2ème  line therapy 
 
7.5.1 
Treatment administration 
 
7.5.1.1 
Definition of treatment duration 
 
The duration of treatment will be described by: 
▪ 
Number of treatments per patient; 
▪ 
The duration of treatment (converted into months) will be calculated using the formula : 
Start date of last treatment - start date of first treatment + 1 day 
Therapeutic breaks and any postponed cure days during this period will not be subtracted from this duration. 
 
7.5.1.2 
Defining administered doses 
 
▪ 
Compliance is calculated using the formula : 
(Cumulative dose received (in mg) / theoretical protocol dose (in mg)) x 100 


 
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Protocol treatment doses depend on the treatment arm: 
• 
FOLFIRINOX (Arms A and B) 
Oxaliplatin = 85 mg/m² (in mg/m²) 
Irinotecan = 180 mg/m² (in French) 
5FU bolus = 400 mg/m² (1.5 mg/m²) 
Continuous 5FU = 2400 mg/m².  
• 
Simplified 5FU (Arm B) 
5FU bolus = 400 mg/m² (1.5 mg/m²) 
Continuous 5FU = 2400 mg/m².  
• 
FOLFIRI.3 
Irinotecan = 280 mg/m² (in mg/m²) 
 Continuous 5FU = 2000 mg/m²  
• 
GEMCITABINE 
 
1000 mg/m² (3 out of 4 weeks at D1, D8, D15, D29, D36 and D43 )  
 
7.5.1.3 
Postponement of courses of treatment, change of administration and reason for change, discontinuation of 
treatment and next line  
  
▪ 
The number and percentage of patients with at least one postponed treatment/cycle and the reasons for these 
postponements      
▪ 
The causes of dose modification will be presented. A list of others will be provided 
▪ 
Definitive discontinuation of protocol treatment and reasons for discontinuation will be described (number, %).   
A list of other causes of stoppage will be provided. 
▪ 
The number of patients receiving a subsequent line and subsequent treatments will be described. 
  
7.5.1.4 
Assessment of treatment administration parameters 
 
All parameters are described using standard descriptive statistics for each treatment arm. 
 
7.5.2 
Toxicities 
 
Toxicities will be described according to NCI-CTC version 4.0 criteria per treatment arm by : 
▪ Number of patients and toxicities by grade and type; 
▪ The number and percentage of patients with at least one toxicity over all courses of treatment according to grade; 
▪ The number and percentage of patients who experienced at least one maximum grade 3-4-5 toxicity over all courses 
of treatment or at least one maximum grade 1-2 toxicity; 
 
7.5.3 
E.I.G  
 
The pharmacovigilance department will provide a summary of all SAEs. 
 


 
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7.6 Quality of life assessment and Geriatric Assessment 
Population: ITT  
 
7.6.1 
Quality of Life - QLQ-C30 
 
Quality of life will be assessed using the QLQ-C30 questionnaire. 
 
7.6.1.1 
Definition  
It will be assessed using the QLQ-C30 (version 3) cancer questionnaire. The QLQ-C30 will be completed before 
inclusion and during the study. 
Internal validation of the 30-item QLQ-C30 questionnaire identified 15 dimensions and calculated 15 scores: 5 
functional ability scores (physical ability, ability to work or perform any household task, cognitive ability, emotional 
state, social state), a global quality of life score, a financial problems score and 8 symptom scores (fatigue, 
nausea/vomiting, pain, dyspnea, sleep disturbance, loss of appetite, constipation, diarrhea). 
  
For the QLQ-C30 scores of overall health, physical ability, cognitive ability and fatigue, longitudinal evolution will be 
studied, along with the percentage of symptomatic progression, defined as the percentage of patients with a score 
reduction of at least 5 points compared with inclusion, with no subsequent improvement. 
 
For the global health score, time to definitive deterioration will also be studied, defined as the time interval between the 
date of randomization and the date of a score decrease of more than 5 points (compared with the score at inclusion) 
without subsequent improvement of more than 5 points, or death, or the date of last news. Living patients without a 
score decrease of more than 5 points will be censored at last news. 
 
7.6.1.2 
Evaluation 
 
An estimate of the time to definitive deterioration of the global health score will be made using the Kaplan-Meier 
method, and compared, in an exploratory way, according to the treatment arm, by a Log Rank test. 
An exploratory analysis will be carried out to account for the possible non-random nature of non-completed 
questionnaires, using simple imputation or pattern mixture methods. Similarly, a comparison between arms will be 
carried out using mixed models of analysis of variance. The methods used may change as the literature in this field 
develops. 
 
7.6.2 
Geriatric assessments  
 
7.6.2.1 
Definition  
Geriatric parameters will be assessed every 2 months until progression, then 30 days after the last treatment. 
▪ 
Charlson Score (/28)  
▪ 
the Mini-Geriatric Depression Scale (GDS), a screening tool for depression,  
 
Score = sum of items coded yes=1  
no=0 (score between 0 and 4)   
score ≥ 1: very high probability of depression 
score = 0: very high probability of no depression 


 
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▪ 
the Mini-Mental State Examination (MMSE) scale, which explores cognitive functions (orientation, learning, 
attention and calculation, free recall, language, constructive praxis), 
The MMSE score is calculated by summing the answers to the 30 questions, and dividing by the number of 
items completed. If more than 15 MMSE items have not been completed, the MMSE score is coded as missing. 
Category ≤ 27/30, > 27/30 
 
▪ 
The G8 score: composed of 8 items: 
 
 
7 "Mini-Nutrional Assessment" items and chronological age 
   
 
Scores range from 0 to 17, and a score ≤ 14/17 indicates vulnerability or fragility.  
 
 
geriatric  
 
7.6.2.2 
Evaluation 
 
On an exploratory basis, in order to study the temporal evolution of geriatric scores and 
quality of life (Spitzer QoL Index, IADL, ...), mixed analysis of variance models 
for repeated measurements of each score in each arm. 
 
7.7 Exploratory analysis 
 
Not applicable 
 
8 Quality assurance 
 
8.1 Input 
 
Data entry and consistency checks are described in the data management plan. 
 
8.2 Base monitoring 
 
8.2.1 
Test analysis 
 
During the study, one or more test analyses may be carried out. All statistical analyses may be performed on the 
database extracted at that time. The purpose of these analyses is to : 
▪ anticipate the drafting of statistical analysis programs; 
▪ highlight inconsistencies in patient records not identified by data management rules; 
▪ identify problems not considered when drafting the protocol and statistical analysis plan. 
Problems encountered on patient files may be the subject of a request for additional information. Problems identified 
requiring modification or clarification of the protocol or analysis plan will be discussed with the coordinator.  
 


 
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8.2.2 
Dual programming 
 
Double programming of the main criterion will be carried out by two different statisticians. The results will be 
compared, and errors discussed and corrected.