Clinical trial NCT02384759
Conditions: Colorectal Neoplasms
Keywords: cancer, colorectal,
Sponsor: Federation Francophone de Cancerologie Digestive
Start date: 2015-05-01; Completion date: 2021-06-01
Enrollment: 117 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is what the FFCD 11-01 - PRODIGE 25 trial proposes to study, as a preliminary for strategic studies evaluating the usefulness of including targeted therapeutics from the first line with aflibercept +/- LV5FU2.

Detailed description:
The aflibercept-5-FU combination has never been evaluated as yet. Aflibercept, at a dose of 4 mg/kg, has already been used in combination with 5-FU at the doses used in the simplified LV5FU2 regimen (folinic acid 400 mg/m2 IV in 90 min, then 5-FU 400 mg/m2 IV bolus on D1, followed by continuous perfusion of 5-FU 2,400 mg/m2 in 46h) (23) as part of the above-mentioned VELOUR trial, evaluating its combination with FOLFIRI (= simplified LV5FU2 + irinotecan). This trial was preceded by a phase I trial validating the doses used (24). It is therefore not necessary to perform a phase I trial if you use the same doses of 5-FU without irinotecan, within the context of a strategy for reducing toxicity in patients to be treated over a long period, and not search for the maximum tolerated dose of the combination.

The aflibercept-LV5FU2 combination can be useful for patients who will never be resectable or operable, and for whom 5-FU monotherapy can be suggested to delay the toxicities of combined chemotherapies. Within this context, it is possible for aflibercept to provide a survival benefit. The previous VELOUR trial (18) did not indicate that toxicity would have a major effect on quality of life and increase the hope of prolonged progression-free survival in the arm with aflibercept.

This is what the FFCD 11-01 - PRODIGE 25 trial proposes to study, as a preliminary for strategic studies evaluating the usefulness of including targeted therapeutics from the first line.

This trial will evaluate the efficacy of the combination and its tolerance by studying toxicities and quality of life. Quality of life will be studied via the EORTC questionnaire QLQ-C30.

The thymidylate synthase polymorphism type 2R2R-2R3R versus 3R3R seems to predict greater efficacy of 5-FU monotherapy. Stratification in this criterion will confirm or negate the prognostic or predictive nature of 5-FU efficacy linked to these polymorphisms.

The draft version of this trial has been studied and evaluated by the scientific council of the Fédération Francophone de Cancérologie Digestive (FFCD) then the Digestive Group of the Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) within the framework of their Partnership for Research in Digestive Oncology (PRODIGE cooperation).

Arms: arm 1: Aflibercept + LV5FU2 arm 2: LV5FU2
Interventions: intervention 1: aflibercept intervention 2: LV5FU2
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
 
PRODIGE 25 -FOLFA 
Version 3.1 of 21.08.2014  
Page 1 on 38 
 
PRODIGE 25 (FFCD 11-01) - FOLFA 
RANDOMIZED PHASE II STUDY EVALUATING AFLIBERCEPT IN 
COMBINATION WITH THE LV5FU2 REGIMEN IN FIRST-LINE 
TREATMENT OF NON-RESECTABLE METASTATIC COLORECTAL 
CANCER 
EudraCT No. 2014-001837-10 
 
 
COORDINATOR :  
Dr Jean Louis LEGOUX 
Hepato-Gastroenterology Department 
La Source Hospital 
14, avenue de l'Hôpital - BP 86709 
45067 ORLEANS CEDEX2 
Tel: 02 38 51 47 04 - Fax: 02 38 51 46 94 
Email: jean-louis.legoux@chr-orleans.fr 
 
CO-COORDINATOR (UNICANCER group) 
Dr Valérie BOIGE 
Gustave Roussy Institute 
Department of Gastroenterology 
114 rue Edouard Vaillant 
94805 VILLEJUIF CEDEX 
Tel: 01 42 11 43 11- Fax: 01 42 11 52 88 
Email: vboige@igr.fr 
CO-COORDINATOR (ANGH group) 
Dr Roger FAROUX 
Les Oudairies Hospital 
HGE Department 
Boulevard Stéphane Moreau 
85925 LA ROCHE SUR YON CEDEX 9 
Tel: 02 51 44 61 68- Fax: 02 51 44 62 99 
Email: roger.faroux@chd-vendee.fr
 
 
TRIAL STEERING COMMITTEE 
Laurent BEDENNE, Valérie BOIGE, Michel DUCREUX, Roger FAROUX, Pierre LAURENT-PUIG, Jean-
Louis LEGOUX, Karine LE MALICOT, Marie MOREAU 
SPONSOR AND RANDOMIZATION-MANAGEMENT-ANALYSIS CENTER (RMAC) :  
Fédération Francophone de Cancérologie Digestive (FFCD), Faculty of Medicine, 7, Boulevard Jeanne d'Arc, 
BP 87900, 21079 Dijon Cedex 
 
Administrative Director : 
Cécile GIRAULT 
 
 
 
 
 
Tel : 03 80 66 80 13 - Fax : 03 80 38 18 41 
 
 
 
 
 
Email: cecile.girault@u-bourgogne.fr 
 
 
Statistician : 
 
 
Karine LE MALICOT 
 
 
 
 
Tel: 03 80 39 34 71 - Fax: 03 80 38 18 41 
 
 
 
 
Email: karine.le-malicot@u-bourgogne.fr 
 
 
Project manager : 
 
Marie MOREAU 
 
 
 
 
 
Tel: 03 80 39 34 04 - Fax: 03 80 38 18 41 
 
 
 
 
 
Email: marie.moreau@u-bourgogne.fr 
 
 
 
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This document is the property of the Fédération Francophone de Cancérologie Digestive and may not be transmitted, reproduced, published or used - in 
whole or in part - without the express permission of the Fédération Francophone de Cancérologie Digestive.


 
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TABLE OF CONTENTS 
1. 
OBJECTIVES OF THE STUDY ................................................................................................. 11 
1.1 
Main objective ..................................................................................................................................... 11 
1.2 
Secondary objectives ........................................................................................................................... 11 
2. 
PATIENT SELECTION .............................................................................................................. 11 
2.1 
Inclusion criteria .................................................................................................................................. 11 
2.2 
Criteria for non-inclusion ..................................................................................................................... 11 
3. 
INCLUSION ASSESSMENT ...................................................................................................... 12 
3.1 
Assessment of the disease .................................................................................................................... 12 
4. 
RANDOMIZATION ..................................................................................................................... 13 
4.1 
Randomization of patients ................................................................................................................... 13 
4.2 
Stratification ........................................................................................................................................ 13 
5. 
DIAGRAM OF THE STUDY ...................................................................................................... 14 
6. 
TREATMENT ............................................................................................................................... 15 
6.1 
Aflibercept administration (arm A) ..................................................................................................... 15 
6.2 
Administration of simplified LV5FU2 (arms A and B) ....................................................................... 16 
6.3 
Modifications to treatment modalities based on tolerance................................................................... 16 
6.3.1 
Aflibercept .................................................................................................................................. 16 
6.3.2 
Chemotherapy ............................................................................................................................. 18 
6.3.3 
Criteria for stopping chemotherapy during treatment ................................................................. 19 
6.3.4 
Premedications and concomitant treatments ............................................................................... 20 
6.4 
Contraindicated treatments .................................................................................................................. 20 
7. 
PATIENT MONITORING .......................................................................................................... 20 
7.1 
During treatment .................................................................................................................................. 20 
7.2 
After stopping treatment for progression ............................................................................................. 21 
7.3 
After discontinuation of treatment for reasons other than progression : .............................................. 21 
8. 
BIOLOGICAL LOGISTICS ....................................................................................................... 21 
8.1 
Determination of Thymidylate Synthase polymorphisms (required for randomization) ..................... 22 
8.2 
Study of Treg lymphocytes .................................................................................................................. 22 
8.3 
Tumor sample ...................................................................................................................................... 23 
8.4 
Storage of Blood Samples .................................................................................................................... 23 
9. 
MANAGEMENT OF SERIOUS ADVERSE EVENTS (SIA) .................................................. 23 
10. STATISTICAL ANALYSIS ........................................................................................................ 25 
10.1 
Provisional schedule of the study ........................................................................................................ 25 
10.2 
Judging criteria .................................................................................................................................... 26 
10.2.1 
Primary efficacy endpoint ........................................................................................................... 26 
10.2.2 
Secondary criteria........................................................................................................................ 26 
10.3 
Calculation of the number of subjects needed ..................................................................................... 27 
10.4 
Statistical Analysis Plan ....................................................................................................................... 28 
10.4.1 
Populations of analysis ................................................................................................................ 28 


 
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10.4.2 
Evaluation of the criteria ............................................................................................................. 28 
10.5 
Independent committee ........................................................................................................................ 29 
11. BACKGROUND INFORMATION AND RATIONALE FOR THE STUDY ........................ 29 
11.1 
Colorectal cancers ................................................................................................................................ 29 
11.1.1 
Incidence ..................................................................................................................................... 29 
11.1.2 
Surgical treatment of metastatic colorectal cancer ...................................................................... 29 
11.1.3 
Non-surgical treatment of unresectable or non-operable patients ............................................... 30 
11.1.3.1 
Chemotherapy ......................................................................................................................... 30 
11.1.3.2 
Targeted therapies (biotherapies) .......................................................................................... 30 
11.2 
Rationale for the Study ........................................................................................................................ 34 
12. REFERENCES .............................................................................................................................. 34 
13. ADMINISTRATIVE CONSIDERATIONS ............................................................................... 36 
14. PUBLICATION RULES .............................................................................................................. 37 
15. APPENDICES ......................................................................... ERREUR ! SIGNET NON DEFINI. 
APPENDIX 1: INFORMED CONSENT ..................................... ERREUR ! SIGNET NON DEFINI. 
ANNEX 2: BIOLOGICAL STUDY PROTOCOL ANNEX 1: TRANSLATIONAL 
BIOLOGICAL STUDIES .............................................................. ERREUR ! SIGNET NON DEFINI. 
APPENDIX 3: WHO PERFORMANCE INDEX - CLEARANCE CALCULATION .... ERREUR ! 
SIGNET NON DEFINI. 
APPENDIX 4: RECIST CRITERIA V1.1 ................................... ERREUR ! SIGNET NON DEFINI. 
APPENDIX 5: TOXICITY ASSESSMENT - NCI-CTC SCALE VERSION 4.0 ............ ERREUR ! 
SIGNET NON DEFINI. 
APPENDIX 6: QUALITY OF LIFE QUESTIONNAIRE QLQ-C30 ...... ERREUR ! SIGNET NON 
DEFINI. 
APPENDIX 7: SUMMARY OF STUDY PRODUCT CHARACTERISTICS (5 FU, FOLINIC 
ACID, AFLIBERCEPT) ................................................................ ERREUR ! SIGNET NON DEFINI. 
APPENDIX 8: SERIOUS ADVERSE EVENT REPORT FORM ............ ERREUR ! SIGNET NON 
DEFINI. 
APPENDIX 9: PUBLICATION RULES FOR PRODIGY TRIALS ....... ERREUR ! SIGNET NON 
DEFINI. 
APPENDIX 10: CERTIFICATE OF INSURANCE ................... ERREUR ! SIGNET NON DEFINI. 
APPENDIX 11: FAVOURABLE OPINION OF THE CPP ....... ERREUR ! SIGNET NON DEFINI. 
APPENDIX 12: ANSM AUTHORIZATION .............................. ERREUR ! SIGNET NON DEFINI. 
 
 
 


 
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LIST OF ABBREVIATIONS 
 
 
 
ALAT  
Alanine aminotransferase (or SGPT: serum glutamic pyruvic transaminase) 
ANSM 
ASAT 
National Agency for the Safety of Medicines and Health Products 
Aspartate-aminotransferase (or SGOT: serum glutamic oxaloacetic transaminase) 
ASCO 
American Society of Clinical Oncology 
BPC 
Good Clinical Practice 
GMP 
Good Manufacturing Practices 
PPC 
Committee for the Protection of Persons 
CI 
Investigator's binder 
CISD 
Independent Data Monitoring Committee 
CO 
CRB 
Observation booklet 
Biological Resource Center 
RTA 
Translational Research Committee 
CTC  
Common Toxicity Criteria 
DCI 
International non-proprietary name 
DPD 
dihydropyrimidine dehydrogenase 
ECG 
Electrocardiogram  
EGF  
Epidermal growth factor 
EGFR 
Epidermal growth factor receptor 
EI 
Adverse event 
ISG 
Serious adverse event 
5FU 
5-fluorouracil 
FFCD 
French-speaking Federation of Digestive Oncology 
FNCLCC 
National Federation of Cancer Centres  
HCG 
Human chorionic gonadotropin 
HR 
"Hazard ratio 
HTA 
Hypertension  
IC 
Confidence interval 
IHC 
Immunohistochemistry 
MRI 
Magnetic resonance imaging 
IV 
Intravenous 
j 
Day 
LDH 
Lactate dehydrogenase 
LSN 
Upper limit of normal 
LV 
Leucovorin (= folinic acid) 
N 
Normal  
NCI-CTCAE 
National Cancer Institute - Common Toxicity Criteria for Adverse Events 
NFS 
Blood count 
WHO 
World Health Organization 
PAL 
PA 
Alkaline phosphatases 
Blood pressure 
PAD 
Diastolic blood pressure 
NOT 
Systolic blood pressure 
PNN 
Neutrophils 
SG 
Overall survival 
SSP 
CT 
Progression-free survival 
CT scan 
TP 
Prothrombin level 
TS 
Thymidylate synthase 
UICC 
International Union Against Cancer 
Vs 
Versus 


 
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PROTOCOL ACCEPTANCE FORM 
 
PRODIGE 25 (FFCD 11-01) - FOLFA: Randomized phase II study evaluating aflibercept in combination 
with LV5FU2 as first-line treatment for unresectable metastatic colorectal cancer 
 
Eudract No. 2014-001837-10 
Version 3.0 of 30.06.2014 
This version of the protocol is approved by : 
The Promoter:  
Ms. Cécile GIRAULTDate : 30.06.2014Signature 
:  
The Coordinator:  
Dr Jean Louis LEGOUXDate 
: 30.06.2014Signature
 
:  
 
I, the undersigned, Doctor :   .......................................................................... 
 
 
 
 
 
After having read the requirements of this research, the protocol and its appendices, I hereby certify that I will 
conduct this trial in compliance with Good Clinical Practice and in accordance with the applicable provisions of 
the Public Health Code. 
In particular, I agree to: 
- 
to respect the protocol as well as all modifications notified to me by the Promoter 
- 
agree to supervise the research in the center and to train my collaborators in the conduct of the 
research and to provide a nominal list  
- 
have each patient sign a written consent after having read the information note intended for him/her, 
before any research is carried out 
- 
Report serious adverse events or developments within 24 hours of learning of them, and as specified 
in the protocol  
- 
respect the inclusion and non-inclusion criteria, as well as the start and end dates of the study 
- 
participate in the biological part of the study and send the samples according to the recommendations 
- 
complete all the items in the observation book, ensure the quality of the data collection and the proper 
management of the products  
- 
Retain research data and documents for 15 years after the study is completed  
- 
inform the Sponsor of any conflict of interest situation that may affect my scientific independence in 
the context of the research 
- 
inform the Sponsor without delay of any action, whether amicable or contentious, brought by a person 
involved in the research or his or her beneficiaries, which may call into question the responsibility of 
the Sponsor 
- 
accept periodic visits by the Sponsor's representatives, and make available to them all source 
documents and materials related to the research in order to ensure quality control of the data recorded 
in the case report book. I agree to an audit by the Sponsor or one of its representatives and/or an 
inspection by the health authorities.  
- 
respond by phone or mail to requests for corrections or clarifications regarding the observation book 
- 
Allow time for the ARC FFCD to sign the forms, answer any questions and take action 
Date:  
 
 
 
           Signature: 
 
 
 
 
 
 
STAMP of the CENTER : 
 
 
Send the original to the CRGA of the FFCD - 7 bd Jeanne d'Arc - BP 87900 - 21079 Dijon Cedex 
SYNOPSIS 


 
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Title of the study  
Randomized phase II study evaluating aflibercept in combination with LV5FU2 
as first-line treatment for unresectable metastatic colorectal cancer  
Judging criteria 
Principal: 
- 
Rate of patients alive and without radiological progression within 6 months 
(RECIST 1.1) by investigator 
 
Secondary:  
- 
Tolerance of LV5FU2- aflibercept combination (NCI-CTC v4.0) 
- 
Quality of life: EORTC QLQ-C30 and time to definitive deterioration in quality of 
life 
- 
Overall survival at 1 and 3 years 
- 
Best response to study treatment (RECIST V1.1) by investigator at 1 year 
- 
Rate of patients alive and without radiological progression within 6 months 
(RECIST 1.1) by centralized review  
- 
Rate of alive patients without radiological progression at 1 year (RECIST 1.1) by 
investigator 
- 
Rate of patients alive and without clinical and/or radiological progression at 6 
months and 1 year by investigator 
- 
Resectability for curative purposes at 1 year 
- 
Prognostic character of thymidylate synthase (TS) polymorphisms within 6 months 
Inclusion criteria 
- 
Age ≥ 65 years 
- 
General condition WHO < 2 
- 
Histologically proven metastatic adenocarcinoma of the rectum or colon on the 
primary tumor or a metastasis, unresectable and/or non-operable patient 
- 
Non or minimally symptomatic metastases 
- 
At least one measurable target according to RECIST v1.1 criteria not previously 
irradiated 
- 
No prior treatment of metastatic disease. Prior chemotherapy in the adjuvant setting 
completed 6 months or more prior to diagnosis of metastasis is allowed 
- 
Adequate laboratory workup: Hb > 9 g/dl, neutrophils > 1500 /mm3 , platelets > 
100,000/mm3 , total bilirubin < 1.5 LSN, creatinine clearance > 50 mL/min 
(Cockroft and Gault formula), creatinine level < 1.5 x LSN, PAL < 5 x LSN, AST 
and ALT < 5 x LSN, GGT < 5x LSN 
- 
Proteinuria (dipstick) < 2+; if > 2+, do 24-hour proteinuria which should be ≤1g,  
- 
Patients treated with anticoagulants (coumadin, wafarin) are eligible for inclusion if 
close monitoring of INR can be performed. A change of anticoagulant treatment to a 
low molecular weight heparin is preferable if the indications are respected 
- 
Centralized genotyping of thymidylate synthase (TS) on blood DNA 
- 
Patient who signed the informed consent 
 
Criteria for non-
inclusion 
- 
Patients whose primary tumor is symptomatic and in place (occlusion; hemorrhage)  
- 
Presence of brain metastases, uncontrolled spinal cord compression, carcinomatous 
meningitis, signs of brain or leptomeningeal involvement 
- 
Macro-nodular peritoneal carcinosis (risk of perforation) 
- 
Uncontrolled hypercalcemia 
- 
Uncontrolled hypertension (SBP >150 mm Hg and DBP >100 mm Hg) or history of 
hypertensive crisis or hypertensive encephalopathy  
- 
Progressive disease not balanced during the last 6 months: hepatic insufficiency, 
renal insufficiency, respiratory insufficiency 
- 
Myocardial infarction, severe/unstable angina, coronary artery bypass grafting, 
NYHA class III or IV congestive heart failure, stroke, or transient ischemic attack in 
the 6 months prior to inclusion 
- 
The following conditions within 3 months prior to inclusion: grade 3 or 4 
gastrointestinal bleeding/hemorrhage, treatment-resistant peptic ulcer, ulcerated 
esophagitis or gastritis, infectious or inflammatory bowel disease, diverticulitis, 
pulmonary embolism or other uncontrolled thromboembolic event, unhealed bone 
fractures 
- 
Major surgery within 28 days of starting treatment  
- 
Known acquired immunodeficiency syndrome (AIDS-related illnesses) or known 
HIV infection requiring antiretroviral therapy 


 
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- 
History of hematologic malignancy or cancer except those treated for more than 5 
years and considered cured, carcinoma in situ of the uterine cervix and treated skin 
cancers (excluding melanoma) 
- 
Any contraindication to the drugs used in the study  
- 
Known DPD deficiency 
- 
Patients treated with the new oral anticoagulants (such as rivaroxaban XARELTO®, 
apixaban ELIQUIS®, dabigatran PRADAXA®) unless they are being replaced by 
VKAs 
- 
Impossibility to undergo the medical follow-up of the trial for geographical, social 
or psychological reasons 
Study design and 
treatment plan 
Phase II, open-label, randomized, multicenter study.  
Patients will be treated every 14 days with: 
- 
LV5FU2 simplified every 2 weeks: folinic acid 400 mg/m2  IV over 90 min, then 
5FU 400 mg/m2  IV bolus at D1, followed by continuous infusion of 5FU 2400 
mg/m2 over 46 h. 
- 
Preceded or not by an IV infusion of aflibercept 4 mg/kg over 1 hour 
Duration of treatment  
Until progression or unacceptable toxicity 
Stratification  
A 1 : 1 randomization by minimization will be performed according to the following 
stratification factors: 
- 
Center 
- 
Age: < 75 years vs > 75 years  
- 
TS-5'UTR polymorphism of thymidylate synthase: 2R2R-2R3R versus 3R3R 
genotype  
- 
Metastatic site: 1 vs > 1 
Statistical methodology All analyses will be performed on a modified intention-to-treat basis. 
Quantitative variables will be described using the median, mean, standard deviation of the 
mean, inter-quartile range, minimum and maximum. Qualitative variables will be described by 
their frequency, the 95% confidence interval will be calculated using the exact method. 
Overall survival and progression-free survival curves will be estimated using the Kaplan-Meier 
method.  
Sample calculation and 
justification 
In the FFCD 2000-05 study using LV5FU2 in the same indication, the median progression-
free survival was 5.7 months.  
Hypothesis: 
H0 : A 6-month live progression-free rate of 40% or less is considered unattractive.  
H1 : a rate of patients alive and progression-free at 6 months of more than 40% is necessary to 
consider the treatment interesting; a progression-free survival rate at 6 months of 60% is 
expected. 
With a one-sided alpha risk of 5%, 56 evaluable patients in each arm (total 112 patients) would 
need to be included to achieve 90% power under the considered H1 hypothesis (calculations 
using the exact binomial distribution). 
If 29 or more patients are alive and not progressing at 6 months, the efficacy of the treatment 
arm studied can be considered interesting.  
Expected number of 
patients 
Taking into account a 5% rate of lost to follow-up, 118 patients (59 patients per group) should 
be included 
Ancillary study 
Study of Treg lymphocytes in blood samples and study of VEGF receptors in tumor samples 
Planned study period 
Theoretical start date of inclusions: January 2015  
Theoretical end date of inclusions: December 2017  
Final study analysis: July 2018 
 


 
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EXAMINATION AND FOLLOW-UP SCHEDULE 
 
*: Complete biological check-up: CBC/platelets, blood ionogram, Ca2+ , Mg2+ , creatinine, albumin, PT, AST, ALT, alkaline phosphatases, total, free and conjugated 
bilirubin, LDH, proteinuria (+ 24 hour proteinuria if > 2+), INR 
 
BEFORE 
TREATMENT 
DURING TREATMENT and if treatment is stopped without 
progression 
AFTER STOPPING FIRST-LINE 
TREATMENT (progression) 
Within 3 weeks 
prior to 
randomization 
Before each 
course of LV5FU2 
Every 8 weeks 
Even if spaced for 
toxicity  
 End of treatment 
consultation (30 
days after the date 
of the last 
administration) 
Every 3 months for 2 years then 
every 6 months for 1 year 
Clinical and biological informed consent 
X 
 
 
 
 
CLINICAL EXAMINATION 
 
 
 
 
 
Weight, height, body surface area, blood pressure 
X 
X 
X 
  X 
X 
General status WHO 
X 
X 
X 
 X  
X 
Quality of Life Questionnaire (QLQ-C30)  
X 
 
X 
X 
 
Toxicity Assessment NCI-CTC V4.0 
X**** 
X 
X 
X 
X 
ECG 
X 
 
 
 
 
MORPHOLOGICAL EXAMINATIONS 
Spiral thoracoabdomino-pelvic CT (TAP) without and 
with injection or MRI injected with gadolinium + non-
injected thoracic CT 
X*** 
 
X*** 
 
 
BIOLOGICAL ASSESSMENT 
Biological check-up 
X* 
X** 
X* 
X** 
 
ACE marker 
X 
 
X 
 
X 
BIOLOGICAL STUDY 
 
 
 
 
 
Determination of the 2R2R-2R3R versus 3R3R 
mutation of thymidylate synthase  
- 
2 EDTA tubes (5 mL of blood) (Georges 
Pompidou European Hospital - Biochemistry 
Laboratory Dr LORIOT)  
X 
  
 
 
 
Prognostic value of Treg lymphocytes 
- 
3 x 10 mL heparinized tubes (Georges 
Pompidou European Hospital - INSERM - Dr 
TERME)   
X (before the 
1ière treatment) 
Before the 3ième 
treatment (D28 
before 
administration) 
 
 
 
KRAS and BRAF status  
To be completed by the centers and entered in the CRF 
X 
 
 
 
 


 
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** Biological check-up before each course of chemotherapy: CBC, platelets, creatininemia, proteinuria (dipstick) + 24-hour proteinuria if > 2+, INR strongly 
recommended for patients on AVK 
*** : An anonymized copy of the imaging is to be sent to the FFCD for centralized review (inclusion CT scan + 3 evaluation CT scans) 
**** : Search for pre-existing symptoms at inclusion 


 
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1. 
Objectives of the study 
1.1 
Main objective  
The primary objective of the study is to evaluate the efficacy of aflibercept combined with 5FU monotherapy 
by considering the rate of patients alive and without radiological progression at 6 months according to the 
investigator. 
1.2 
Secondary objectives  
The secondary objectives of the study are to evaluate: 
- 
Safety of aflibercept in combination with 5FU and folinic acid (NCI CTC v4.0) 
- 
Quality of life according to the EORTC QLQ-C30 score and time to definitive deterioration in quality 
of life 
- 
Overall survival at 1 and 3 years 
- 
The rate of patients alive and without radiological progression within 6 months (RECIST 1.1) 
according to the centralized review  
- 
The rate of patients alive and without radiological progression at 1 year (RECIST 1.1) according to 
the investigator 
- 
The rate of patients alive and without clinical and/or radiological progression within 6 months and at 
1 year by investigator 
- 
The best response to study treatment (RECIST 1.1 criteria) at 1 year according to the investigator 
- 
Resectability for curative purposes at 1 year 
 
We will try to confirm the prognostic character of the TS-5'UTR genotype of thymidylate synthase on the main 
criterion of the study, on both treatment arms combined.  
 
2. 
Patient selection  
2.1 
Inclusion criteria 
- 
Age ≥ 65 years 
- 
General condition WHO less than 2 
- 
Histologically proven metastatic adenocarcinoma of the rectum or colon on the primary tumor or a 
metastasis, unresectable and/or non-operable patient 
- 
Non or minimally symptomatic metastases 
- 
At least one measurable target according to RECIST v1.1 criteria not previously irradiated 
- 
No prior treatment of metastatic disease. Prior chemotherapy in the adjuvant setting completed 6 
months or more prior to diagnosis of metastasis is allowed 
- 
Adequate laboratory workup: Hb > 9 g/dl, neutrophils > 1500 /mm3 , platelets > 100 000/mm3 , total 
bilirubin < 1.5 ULN, creatinine < 1.5 x ULN, creatinine clearance > 50 mL/min (Cockroft and Gault 
formula), PAL < 5 x ULN, AST and ALT < 5 x ULN, GGT < 5 x ULN 
- 
Proteinuria (dipstick) < 2+; if > 2+, do 24-hour proteinuria which should be ≤ 1 g,  
- 
Patients treated with anticoagulants (coumadin, wafarin) are eligible for inclusion if close monitoring 
of INR can be performed. A change of anticoagulant treatment to a low molecular weight heparin is 
preferable if the indications are respected 
- 
Genotyping of thymidylate synthase (TS) on blood DNA 
- 
Patient who signed the informed consent 
2.2 
Non-inclusion criteria  
- 
Patients whose primary tumor is symptomatic and in place (occlusion; hemorrhage)  
- 
Presence of brain metastases, uncontrolled spinal cord compression, carcinomatous meningitis, signs 
of brain or leptomeningeal involvement 


 
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- 
Macro-nodular peritoneal carcinosis (risk of perforation) 
- 
Uncontrolled hypercalcemia 
- 
Uncontrolled hypertension (SBP >150 mmH and DBP >100 mmHg) or history of hypertensive crisis 
or hypertensive encephalopathy  
- 
Any progressive disease not balanced during the last 6 months: hepatic insufficiency, renal 
insufficiency, respiratory insufficiency  
- 
Myocardial infarction, severe/unstable angina, coronary artery bypass grafting, NYHA class III or IV 
congestive heart failure, stroke, or transient ischemic attack in the 6 months prior to inclusion 
- 
The following conditions within 3 months prior to inclusion: grade 3 or 4 gastrointestinal 
bleeding/hemorrhage, treatment-resistant peptic ulcer, ulcerated esophagitis or gastritis, infectious or 
inflammatory bowel disease, diverticulitis, pulmonary embolism or other uncontrolled thromboembolic 
event, unhealed bone fractures 
- 
Major surgery within 28 days of starting treatment  
- 
Known acquired immunodeficiency syndrome (AIDS-related illnesses) or known HIV infection 
requiring antiretroviral therapy 
- 
Anti-tumor treatments other than those in the study (chemotherapy, targeted therapy, immunotherapy) 
- 
History of hematologic malignancy or cancer except those treated for more than 5 years and 
considered cured, carcinoma in situ of the uterine cervix and treated skin cancers (excluding 
melanoma) 
- 
Any contraindication to the drugs used in the study 
- 
Known DPD deficiency 
- 
Patients treated with the new oral anticoagulants (such as rivaroxaban XARELTO®, apixaban 
ELIQUIS®, dabigatran PRADAXA®) unless they are being replaced by VKAs 
- 
Impossibility to undergo the medical follow-up of the trial for geographical, social or psychological 
reasons 
3. 
INCLUSION ASSESSMENT  
3.1 
Assessment of the disease 
 
The inclusion assessment is to be performed within 3 weeks prior to randomization. It includes: 
 
Full clinical examination:  
- 
Description of clinical signs related to the tumor disease 
- 
Weight, height, body surface 
- 
Blood pressure (SAP and DBP) 
- 
General status WHO 
- 
Possible history of venous thrombosis, 5-FU toxicity, and treated hypertension 
 
Biological check-up:  
- 
Blood count (hemoglobin, PNN, platelets), creatinine level, blood ionogram, calcium level, PT, 
albumin level, total, free and conjugated bilirubin level, transaminases, alkaline phosphatases, LDH, 
proteinuria (urine dipstick) and 24h proteinuria if dipstick > 2+.  
- 
Sampling for biological research study (thymidylate synthase, Treg lymphocyte; see chapter 8) 
- 
Marker : ACE 
 
Morphological evaluation of the tumor:  
- 
Spiral thoracoabdomino-pelvic (TAP) scan, without and with contrast injection, performed no more 
than 3 weeks before randomization.  
In case of contraindication to iodinated contrast injection, a hepatic or abdominal MRI with gadolinium 
injection and a thoracic CT scan without injection can be performed.  
Morphological examinations should be the same throughout the patient's follow-up.  
Make an anonymized copy of the images to be sent to the CRGA of the FFCD for centralized 
review. 
Quality of Life Questionnaires:  
- 
QLQ-C30 questionnaire completed 


 
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Search for thymidilate synthase (TS) polymorphisms (blood) 
- 
It will be done in the biochemistry department of the Georges Pompidou European Hospital. The 
investigator will send 2 EDTA tubes of 5mL of the patient's blood according to the pre-established 
regulatory procedures (see chapter 8: biological logistics). The results will be faxed to the investigator 
within 10 working days. 
 
RAS and BRAF status 
- 
They will be performed routinely in each center and the results collected in the observation booklet.  
 
Biological study on the prognostic value of Treg lymphocytes: 
- 
ième3 x 10 mL heparinized blood tubes before the first treatment and 3 x 10 mL heparinized blood tubes 
before the third treatment (see chapter 8) 
- 
Establishment of a collection of tumor samples for pooled analysis with other studies (see Chapter 8) 
 
4. 
RANDOMIZATION 
4.1 
Randomization of patients 
o As soon as a patient is selected to enter the study, he/she is informed and asked to accept and sign the 
informed consent form. This consent mentions the determination of the thymidilate synthase 
polymorphism on his lymphocytes (blood sample), the study of regulatory T lymphocytes and vascular 
growth factors 
 
o A blood sample is taken and sent to the biochemistry department of the Georges Pompidou European 
Hospital. These samples will later be sent to the FFCD's EPIGENETEC BRC for archiving. 
 
o With the result of the thymidilate synthase polymorphism, the investigator can randomize the patient 
according to the stratification factors defined for the study 
 
o WHO general status will be checked with the patient, possibly by telephone consultation, within 48 
hours prior to randomization 
The randomization will be carried out by the CRGA of the FFCD after reception of the fax of randomization 
(form 1 of the observation booklet) at 03 80 38 18 41. The CRGA is open from Monday to Friday from 9 am 
to 6 pm.  
The randomization number and treatment arm will be communicated to the investigator and the pharmacist by 
return fax. 
After randomization of the patient, treatment should be started within a maximum of 2 weeks. 
An observation booklet will be sent at the opening of the center. An observation booklet will be sent after each 
randomization. 
The 1ière randomization in a center will trigger the dispatch of aflibercept treatment. Aflibercept stock 
management for subsequent inclusions will be done by the center's pharmacy.  
 
4.2 
Stratification  
A 1:1 randomization by minimization will be performed according to the following stratification factors: 
- 
Center 
- 
Age: < 75 years vs > 75 years  
- 
TS-5'UTR polymorphism of thymidylate synthase: 2R2R-2R3R versus 3R3R genotype  
- 
Metastatic site: 1 vs > 1 
 


 
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5. 
DIAGRAM OF THE STUDY 
 
 
 
 
 
 
 
R 
Experimental arm = Arm A 
 
Aflibercept (4 mg/kg) + LV5FU2s every 14 days until progression 
Reference arm = Arm B  
 
LV5FU2s every 14 days until progression 


 
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6. 
TREATMENT  
In this academic research, the drugs for the LV5FU2 treatments (drugs with MA used in their indication) will 
be taken from the hospital stock in accordance with article L1121-16-1 of the Public Health Code. 
 
Aflibercept will be provided as part of the study. 
The traceability of the products will be ensured by the pharmacies.  
 
 
 
 
 
 
 
 
ARM A: LV5FU2s + aflibercept administration scheme 
 
 
 
 
 
 
 
 
ARM B: LV5FU2s administration scheme 
 
6.1 
Administration of aflibercept (arm A) 
 
Aflibercept [25 mg/mL IV infusion solution - 8 mL vials (200 mg/vial)], should be administered at the 
beginning of each chemotherapy course. Vials should be stored in the refrigerator at 2-8°C in the original 
packaging and protected from light. 
Aflibercept will be administered at 4 mg/kg and should be diluted directly into the infusion bag (100ml) with 
sterile 0.9% sodium chloride or G5%. Diluted solutions should be administered using infusion sets with a 0.2 
micron polyethersulfone filter. Infusion sets should be made of one of the following materials: polyvinyl 
chloride (PVC) containing bis(2ethylhexyl-) phthalate -(DEHP), DEHP-free PVC containing trioctyl 
trimellitate (TOTM), polypropylene, polyethylene-lined PVC or polyurethane. Note: Polyvinylidene fluoride 
(PVDF) or nylon filters should not be used. 
The solution should be prepared in a sterile environment. 
Aflibercept should be administered over 1 hour. The preparation should not exceed 2 hours at room temperature 
(25°C). 
 
5 FU bolus  
400 mg/m². 
Folinic acid 
 400 mg/m² (or 200 
mg/m² if Elvorine) 
5 FU continuous 
2400 mg/m². 
2h 
46h 
< 10 minutes 
5 FU bolus  
400 mg/m². 
Folinic acid 
 400 mg/m² (or 200 
mg/m² if Elvorine) 
5 FU continuous 
2400 mg/m². 
2h 
46h  
< 10 minutes 
Aflibercept 
4mg/kg 
1 h 
1 h 


 
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Male patients should use contraception for the duration of treatment and for up to 6 months after discontinuation 
of treatment. 
6.2 
Administration of simplified LV5FU2 (arms A and B)  
Folinic acid is administered as an IV infusion at a dose of 400 mg/m² (or 200 mg/m² if Elvorine) over 2 hours. 
The 5 Fu bolus is administered within 10 minutes at 400 mg/m² in 100 cc of G5%. 
Continuous 5-Fu is administered IV at a dose of 2400 mg/m² over 46 hours.   
 
 
6.3 
Modifications to treatment modalities based on tolerance 
6.3.1 Aflibercept  
In the event of aflibercept-related toxicity, dose adjustments should be made based on the highest grade of 
toxicity observed according to the NCI-CTC version 4.0 scale. 
If the patient has multiple toxicities, the adjustment will be made according to the highest toxicity.  
Once the dose has been decreased, it is not permitted to increase it again. 
 
Aflibercept should be administered if PNN > 1400/mm3  and platelets > 90,000/mm3 and after recovery to a 
grade < 1 for all other toxicities (except alopecia). If there is a recurrence of febrile neutropenia or neutropenic 
sepsis after 5FU dose reduction, consideration may be given to reducing the aflibercept dose to 2 mg/kg (see 
Product Monograph). 
 
Toxicity 
Grade (NCICTC V4.0) 
Action 
Hypertension 
Grade < 2 
Initiate 
antihypertensive 
therapy 
or 
modify 
antihypertensive therapy if necessary. 
No change in dose, no postponement of treatment 
Grade 3 (requiring more 
than one antihypertensive 
treatment or requiring 
intensification of 
antihypertensive treatment) 
Postpone LV5FU2 and aflibercept (maximum 2 weeks), 
until recovery of BP (blood pressure) < 140/90 or to a SBP 
< 160 if DBP <90 for patients with known history of 
isolated systolic hypertension: 
• 
If BP is controlled within 2 weeks of deferral 
▪ 1ier 
event: 
re-administer 
LV5FU2 
and 
aflibercept at the same dose 
▪ 2ième episode: re-administer LV5FU2 at the 
same dose and re-administer aflibercept at 2 
mg/Kg 
▪ 3ième event: permanent discontinuation of 
aflibercept, resumption of LV5FU2 
• 
If after 2 weeks of deferral BP is still not controlled 
despite antihypertensive treatment: restart LV5FU2 
at the same dose and stop aflibercept for one cycle 
of LV5FU2 (14 days). Re-evaluate BP at the next 
cycle and restart aflibercept at 2 mg/kg if BP 
controlled.  
• 
In the event of recurrence of Grade 3 despite 
optimal antihypertensive therapy and aflibercept 
dose reduction, or if BP is still uncontrolled despite 
aflibercept deferral for 2 weeks (4 weeks after the 
last 
administration): 
DEFINITELY 
STOP 
aflibercept. LV5FU2 can be continued. 
Grade 4 
When hypertension is accompanied by symptoms of organ 
failure such as hypertensive retinopathy, impaired renal 


 
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function (such as increased proteinuria), symptoms of 
cardiovascular or central nervous system morbidity, 
aflibercept should be discontinued. 
DEFINITIVE WITHDRAWAL of aflibercept and 
cardiological advice  
 
 
Toxicity 
Grade (NCI-CTC v4.0) 
Action 
Arterial 
thromboembolic 
event 
Whatever the grade 
DEFINITELY DISCONTINUE 
aflibercept 
Venous 
thromboembolic 
event 
Grade 3 
1ier episode: treatment with heparin and 
continuation of ablibercept1 
2ième episode despite appropriate 
anticoagulant therapy: DEFINITELY 
STOP aflibercept 
Grade 4 
DEFINITELY DISCONTINUE 
aflibercept2 
Hemorrhage  
Grade 3-4 
DEFINITELY DISCONTINUE 
aflibercept 
Intestinal 
perforation/fistula 
formation at any 
anatomical site  
Whatever the grade 
DEFINITELY DISCONTINUE 
aflibercept 
Reversible posterior 
leukoencephalopathy 
syndrome3 
Whatever the grade 
DEFINITELY DISCONTINUE 
aflibercept 
1 After evaluation of the risk of extension and/or embolism according to the investigator's judgment 
2 Continuation of aflibercept may be considered, depending on the benefit/risk balance, in the event of secondary discovery 
of asymptomatic pulmonary embolism  
3Appearance of vasogenic edema of the white matter and predominant in the posterior parieto-occipital regions: 
symptoms: Acute and abrupt HTA (DBP > 120mmHg), psychomotor slowing, headache, confusion, restlessness, 
lethargy, nausea, vomiting, convulsions (initially focal), transient coma, memory disturbances, visual disturbances 
(blurred vision, scintillating scotoma, visual neglect, hemianopsia, cortical blindness) 
 
Proteinuria 
A urine dipstick test should be performed prior to each administration of aflibercept (protein, red blood cells, 
leukocytes): 
- 
If proteinuria is < 2+ and there is no hematuria, aflibercept can be administered 
- 
If proteinuria is > 2+, aflibercept should be withheld and reintroduced as soon as 24-hour proteinuria 
is < 2g. If proteinuria > 2g/24h recurs, aflibercept should be withheld until 24-hour proteinuria < 2g 
and reintroduced at 2 mg/kg 
 
Aflibercept should be permanently discontinued if the patient develops nephrotic syndrome or thrombotic 
microangiopathy, suspected on the basis of proteinuria-hematuria.  
 
The 24-hour proteinuria assay can be replaced by the ratio of urine urea to creatinine on morning voiding, 
expressed in mg/dl. If this ratio is > 1, 24-hour proteinuria should be measured. If it is greater than 2, a 
nephrological opinion should be sought. 
 
Hypersensitivity reaction to aflibercept 
 
Severity of the symptom 
Recommendation 
Light and moderate 
SUSPEND the aflibercept infusion 


 
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Example: Grade < 2: skin reaction, pruritus, flush, 
rash, dyspnea, tachycardia, hypotension, anxiety, 
headache, myalgia, edema, nausea 
- 
Administer diphenydramine 50 mg IV 
and/or dexamethasone 10 mg IV 
- 
Resume aflibercept infusion after recovery 
Severe 
Example: symptomatic bronchospasm, generalized 
urticaria, PAS < 80 mmHg, angioedema, 
anaphylaxis 
STOP aflibercept infusion 
- 
Administer diphenydramine 50 mg IV 
and/or dexamethasone 10 mg IV and/or 
epinephrine if necessary 
- 
DEFINITELY DISCONTINUE 
aflibercept 
 
 
Unhealed wound/surgery 
The ½ life of aflibercept is approximately 20 days. Suspend aflibercept at least 4 weeks before any surgery. 
Aflibercept should be administered at least 4 weeks after surgery and after complete healing.  
For minor procedures (implantable chamber placement, biopsies, tooth extraction), aflibercept can be 
reintroduced as soon as healing is complete. 
Aflibercept should be permanently discontinued if there is a wound opening or failure of a wound to heal 
requiring medical intervention. 
  
6.3.2 Chemotherapy  
Before each treatment, the following should be checked: blood count, creatinine level, proteinuria (urine 
dipstick) and 24-hour proteinuria if dipstick > 2+.  Proteinuria may be omitted if LV5FU2 is administered 
without aflibercept. Chemotherapy will be started if: 
- 
PNN 1400/mm3 
- 
Plates 90 000/mm3 
- 
Hemoglobin 9.5 g (if necessary after transfusion) 
The chemotherapy course will be delayed by one week: in case of moderate hematological toxicity (PNN < 
1400/mm3 and/or platelets < 90,000/mm3 ), persistent digestive toxicity (oral ulcerations, diarrhea, or grade 3-
4 esophagitis) or other grade 3-4 toxicity. The dose of 5FU will then be modified according to the instructions 
in Tables 1 and 2. 
In the event of elevated creatinine levels, additional investigations will be carried out by the investigator who 
will decide whether or not additional therapeutic measures should be taken or if progression on treatment should 
be diagnosed. 
 
Chemotherapy toxicities are assessed using the NCI CTCAE version 4.0 scale (Appendix 6). 
Table 1.  Dose adjustment of 5-FU for the following courses after a one-week postponement of the course 
due to toxicity 
 
TOXICITY the day before or the day before the treatment 
5-FU 
PNN 1400, platelets 90 000 
100 % 
1,000 PNN < 1,400 and/or 75,000 platelets < 90,000  
50% bolus 
and/or persistent grade 1 or 2 digestive toxicity 
75% 
continuous 
infusion 
PNN < 1000 and/or platelets < 75 000 
and/or persistent grade 3-4 digestive toxicity 
No 5FU and 8 
day delay 


 
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TOXICITY in the intercourse  
5-FU 
Grade 3-4 febrile neutropenia, Grade 4 neutropenia (PNN < 500), 
Grade  
3-4 thrombocytopenia (<50000) and/or Grade 3-4 digestive toxicity 
0% bolus  
and 75% 
continuous 
infusion**.  
 
* Digestive toxicity: mucitis, diarrhea, epigastralgia. 
 
** Provided that there is no residual toxicity on the day of the treatment that would require a further 8-day 
delay in treatment 
Reminder:  
Grade 3 febrile neutropenia (NCI CTC V4.0) = presence of decreased neutrophils (any decrease) associated with 
fever. 
Grade 4 febrile neutropenia (NCI CTC V4.0) = decrease in neutrophils (any decrease) associated with life-threatening 
fever and/or requiring emergency management. 
Table 2. Dose adjustment of 5-FU for subsequent courses after a 2ème episode of toxicity, after a 1ère dose 
reduction and a further one-week delay  
TOXICITY the day before or the day before the treatment after 
a 2ème episode of toxicity, after a first dose reduction and a new 
postponement of the treatment 
5-FU 
PNN 1400, platelets 90 000 
0 % bolus 
1000 PNN < 1400 and/or 75000 platelets < 90 000  
 
0% bolus and 
75% 
continuous 
infusion 
Isolated persistent grade 1 or 2 digestive toxicity  
50% 
continuous 
infusion 
PNN < 1000 and/or platelets < 75000 
and/or persistent grade 3-4 digestive toxicity 
No 5FU and 8 
day delay 
TOXICITY IN THE INTERCOURSE 
5-FU 
Grade 3-4 febrile neutropenia, Grade 4 neutropenia (PNN < 500), 
Grade  
3-4 thrombocytopenia (<50000) and/or Grade 3-4 digestive toxicity 
0% bolus and 
50% 
continuous 
infusion 
 
* Digestive toxicity: mucitis, diarrhea, esophagitis. 
 
** Provided there is no residual toxicity at D21 requiring a further 8-day delay in treatment 
 
No change in folinic acid dose. 
 
6.3.3 Criteria for stopping chemotherapy during treatment 
 
- 
Major toxicity requiring permanent discontinuation of treatment: 
▪ 
If aflibercept-related toxicity requires discontinuation for 4 or more consecutive weeks (i.e., with a 
margin of 2 days for each 7-day deferral for chemotherapy toxicity, a total of 28 + 8 days = 36 days), 
then aflibercept is permanently discontinued. 
- 
Serious or unexpected event requiring discontinuation of treatment: 
▪ 
In case of discontinuation of aflibercept due to an intercurrent event (radiotherapy, hospitalization for 
other reasons than toxicity, ...), the resumption of aflibercept will be left to the investigator's choice. 
The treatment will then be collected within the framework of the study (in the observation booklet). 
▪ 
Aflibercept may be discontinued immediately and permanently at the sole discretion of the 
investigator, if deemed necessary for the patient. 


 
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- 
Refusal to proceed, at the patient's request, or after withdrawal of consent by the patient (to be 
documented). 
- 
Life-threatening toxic reaction in the opinion of the physician caring for the patient. 
- 
Progressive disease. 
- 
If aflibercept is deferred or discontinued, concurrent chemotherapy (LV5FU2) may be continued as 
described in this protocol. 
- 
If LV5FU2 chemotherapy is discontinued, aflibercept may be continued as described in this protocol. 
- 
If chemotherapy is deferred for one to three weeks, aflibercept will also be deferred and restarted at the 
same time as the chemotherapy according to the protocol. Evaluation of chemotherapy toxicity for deferral 
should be done on a weekly basis to avoid unnecessary delay in restarting chemotherapy. 
Patients will be followed until death according to the protocol schedule and treatment types will be 
collected after progression on the first line of treatment. 
 
6.3.4 Premedications and concomitant treatments 
Treatments considered necessary for the well-being of the patient may be administered at the discretion of the 
investigator.  
If anemia occurs, it will be treated according to its mechanism: spoliation, inflammatory or bone marrow failure. 
Subcutaneous administration of growth factor is permitted: 
- for the treatment of Grade 3-4 febrile neutropenia 
- as secondary prophylaxis from day 5 to day 11 after the occurrence of neutropenic events during the previous 
chemotherapy cycle. These neutropenic events are: grade 3-4 febrile neutropenia, proven infections with 
concomitant grade 3-4 neutropenia, grade 4 neutropenia > 7 days. Growth factor will be used for all 
subsequent cycles. 
6.4 
Contraindicated treatments  
With 5FU: yellow fever vaccine, live attenuated vaccines, phenytoin for prophylaxis. 
7. 
PATIENT MONITORING  
7.1 
During treatment  
- Before each course of chemotherapy:  
o 
Complete clinical examination: weight, body surface area, general condition WHO, blood pressure 
o 
Biological check-up: CBC, platelets, creatinine, proteinuria (urine dipstick) and 24-hour 
proteinuria if dipstick > 2+. 
o 
Treg lymphocyte biological study: 3 x 10 mL heparinized blood tubes before the 3ième treatment 
(do not collect and send sample on Friday)  
o 
Toxicity assessment according to NCI-CTC Version 4.0 
 
- Every 8 weeks, even when spaced out for toxicity: 
o 
Clinical examination: Weight, body surface area, general condition, WHO, blood pressure 
 
o 
Biological check-up: Hemoglobin, PNN, platelets, creatinine, blood ionogram, calcemia, TP, total, 
free and conjugated bilirubin, transaminases, alkaline phosphatases, LDH, 24-hour proteinuria if 
urine dipstick > 2+, INR for patients on AVK, ACE 
 
o 
Morphological evaluation of the disease: (every 8 weeks even after stopping the treatment for 
toxicity, in order to show the date of progression) 


 
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- 
Spiral thoracoabdomino-pelvic CT scan, without and with contrast injection 
- 
In case of contraindication to iodinated contrast injection, hepatic or abdominal MRI with 
gadolinium injection and thoracic CT scan without injection. 
 
 
FOR CENTRALIZED PROOFREADING :  
During the first 6 months following the patient's inclusion, send to the FFCD (CD ROM or 
ARC FFCD) an anonymized copy of each morphological evaluation (i.e. 3 evaluations + 
inclusion imaging)  
o QLQ-C30 Quality of Life Questionnaire completed 
 
7.2 
After discontinuation of treatment for progression 
Patients will be reviewed in consultation 30 days +/- 2 days after discontinuation of study treatment: 
- 
Complete clinical examination (weight, general condition WHO, BP) 
- 
Evaluation of toxicities 
- 
Biological workup: CBC, platelets, creatinine, proteinuria (dipstick) + 24-hour proteinuria if 
> 2+. 
- 
Quality of Life Questionnaire QLQ-C30 
 
Patients will then be seen in consultation every 3 months for 2 years and every 6 months for 1 year: 
  
- 
Clinical examination with search for late toxicities of the first line treatment 
- 
Additional examinations required by their new treatments 
 
CAUTION: Male patients should continue to use effective contraception for at least 6 months after 
discontinuing treatment.  
7.3 
After discontinuation of treatment for reasons other than progression: 
Patients will be reviewed in consultation 30 days +/- 2 days after stopping the treatment: 
- 
Complete clinical examination (weight, general condition WHO, BP) 
- 
Evaluation of toxicities 
- 
Biological work-up: CBC, platelets, creatinine, proteinuria (dipstick) + 24-hour proteinuria if 
> 2+. 
- 
Quality of Life Questionnaire QLQ-C30 
 
Patients will then be seen in consultation every 2 months until progression, with : 
- 
Clinical examination with search for late toxicities of the first line treatment 
- 
Additional examinations required by their new treatments 
- 
Evaluation of the progression (biological and morphological protocol examinations every 8 
weeks). 
After progression, patients will be seen in consultation every 3 months for 2 years and then every 6 months for 
1 year (see chapter 7.2). 
 
CAUTION: Male patients should continue to use effective contraception for at least 6 months after 
discontinuing treatment.  
8. 
ORGANIC LOGISTICS 
 


 
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8.1 
Determination of Thymidylate Synthase polymorphisms (required for randomization) 
Required samples  
2 x 5 ml EDTA tubes of blood at the time of inclusion. 
 
Shipment of the tubes, via the DHL box provided at the opening of the center to :  
Dr Marie-Anne LORIOT 
Biochemistry Laboratory 
Georges Pompidou European Hospital (HEGP) 
20 Le Blanc Street 
75015 PARIS 
 
Use only the DHL box containing the DHL slip for the HEGP Biochemistry Laboratory. 
 
After sending this box, the box necessary for the inclusion of the next patient will be sent to the investigating 
center. 
 
8.2 
Study of Treg lymphocytes 
 
Required samples  
3 x 10 ml heparinized tubes of blood   
- 
before the administration of the first cycle of chemotherapy (except on Fridays) 
- 
before the third cycle of chemotherapy, on the patient's arrival, avoiding Friday 
 
Sampling kits will be sent to each center upon opening (2 DHL boxes each containing 3 x 10 mL heparinized 
tubes and the appropriate forms).  
 
The tubes must be delivered to the laboratory and packaged within 24 hours. This is why shipments should 
not be made on Friday. 
 
These samples will be sent at room temperature by specialized carrier (DHL) to :  
 
 
 
 
Ms. Magali TERME 
INSERM U970 unit, team 10,  
PARCC-HEGP 
 56 Leblanc Street 
75015 PARIS 
 
For these samples before C1 and before C3, use only the DHL boxes containing the delivery note to the 
INSERM HEGP unit. 
 
After each shipment of a DHL box, a new DHL box will be sent for subsequent patients.  
 
Summary of blood samples: 
 
Withdrawals 
Before randomization 
Before C1 
Before C3 
TS 
(required 
for 
randomization) 
2 x 5 mL EDTA tubes 
 
 
Treg lymphocytes 
and vascular growth 
factors 
 
3 x 10 mL heparinized 
tubes  
3 x 10 mL heparinized 
tubes 


 
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DHL box 
Address : Mme Loriot 
HEGP - Laboratoire de 
Biochimie 20 rue Le 
Blanc 75015 PARIS 
Address to be sent to: 
Mme Terme HEGP - 
Unité INSERM U970- 
équipe 10 56 rue Le 
Blanc 75015 PARIS 
Address to be sent to: 
Mme Terme HEGP - 
Unité INSERM U970- 
équipe 10 56 rue Le 
Blanc 75015 PARIS 
 
8.3 
Tumor sample 
 
One paraffin-embedded tumor block or 2-3 paraffin-embedded diagnostic biopsies  
Shipping kit 
Upon receipt of the form indicating the number of biopsies or tumor blocks to be sent, you will receive a pre-
stamped max letter that will allow the samples to be shipped. 
 These samples will be sent to : 
Pr Pierre LAURENT-PUIG 
CRB Epigenetec, INSERM Unit U775 
45 rue des Sts Pères 
75006 PARIS 
 
8.4 
Storage of blood samples  
 
The samples, once the TS determination has been carried out at the HEGP, will be transferred to the FFCD 
Biological Resource Center, named EPIGENETEC (45 rue des Saints Pères, 75006 PARIS), directed by Pr 
Pierre LAURENT PUIG. They will be stored there for the time necessary to set up the subsequent analyses. 
 
Constitution of a collection of tumor samples at the FFCD's biological resource center (EPIGENETEC) for 
grouped analysis with those of other studies (see Chapter 8). 
9. 
MANAGEMENT OF SERIOUS ADVERSE EVENTS (SIA)  
Security assessment parameters 
Safety will be assessed by evaluating the general and clinical condition of the patients and by collecting events 
occurring between visits during consultations, by regular blood tests. Toxicities will be assessed using the NCI-
CTC-AE version 4.0 toxicity scale (see Appendix 6). 
In case of an emergency, the patient, his family or his physician should call the investigator to inform him of 
an event. 
 
Definitions 
a. Adverse Event (AE) 
An adverse event is a harmful occurrence in a person who is a subject of biomedical research, whether or not 
the occurrence is related to the research or the product being investigated. 
 
All adverse events will be recorded in the case report form on the "toxicity" pages provided for this purpose, 
up to 30 days after the last administration and beyond if related to the study products. The most severe grade of 
the intercourse will be recorded in the case report form (NCI-CTC version 4 or severity grade according to the 
investigator's judgment when the toxicity is not objectively gradable). 
 
b. Serious Adverse Event (SAE) 
A serious adverse event is any event that   
• 
Resulting in death, 
• 
Life-threatening, 
• 
Leading to hospitalization or prolonged hospitalization, 


 
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• 
Causing permanent disability or severe temporary incapacity, 
• 
Causing a birth defect, fetal malformation or abortion, 
• 
Medically significant (examples: overdoses, second cancers, and new developments may be considered 
medically significant) 
 
The terms disability and incapacity correspond to any temporary or permanent physical or psychological 
handicap, clinically significant and affecting the physical activity and/or quality of life of the patient. 
 
Any clinical event or laboratory result considered serious by the investigator and not corresponding to the 
severity criteria defined above is considered medically significant. They may put the patient at risk and 
require medical intervention to prevent an outcome corresponding to one of the above mentioned severity 
criteria (e.g. overdose, second cancers, pregnancies and new events may be considered as medically 
significant). 
 
If a patient's partner declares a pregnancy, the sponsor must be informed without delay via the serious 
adverse event notification form (no severity criteria will then be checked).  
 
c. Undesirable Effect  
Any noxious and unintended response to an investigational drug at any dose or to any investigational 
component. An adverse reaction is serious if it meets a severity criterion. 
 
d. Unexpected Serious Adverse Effect 
An unexpected serious adverse reaction is an event that is not mentioned, or is different in nature, intensity, or 
evolution from the product reference document (or RCPs). 
 
e. New fact 
A new fact can be: an unexpected frequency of an expected SAE, an SAE related to the trial procedure, 
insufficient efficacy in life-threatening diseases, clinical data. 
 
f. Intensity (or severity) 
The intensity criterion should not be confused with the severity criterion, which is used as a guide to define 
reporting obligations. 
The intensity of the events will be estimated according to the extract of the CTC-AE version 4.0 classification 
(see 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 activity 
Moderate (grade 2): disrupts the patient's usual daily activity 
Severe (grade 3): prevents the patient's usual daily activity 
Very severe (grade 4): requires resuscitative measures / life threatening 
Death (grade 5). 
 
g. Causal relationship 
Related: an event is said to be related when a causal relationship between the event and the product under study 
can reasonably be suspected  
Unrelated: an event is said to be unrelated when a causal relationship between the event and the product under 
study cannot reasonably be suspected 
Doubtful: causality is said to be "doubtful" when there is a doubt about the causal relationship between the 
event and the product under study (the relationship can then neither be formally excluded nor formally affirmed) 
 
h. Responsibility of the promoter 
Upon receipt of the investigator's report of the serious adverse event, the sponsor should issue an opinion on 
the causal relationship between the serious adverse event and the study product(s).  
If the serious adverse event is related by the investigator and/or sponsor to one of the study products (i.e., it is 
a serious adverse event), the investigator and/or sponsor must establish the expected or unexpected nature of 
this event. 


 
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If it is a serious unexpected adverse reaction, or if it is a new fact, the sponsor writes an initial report which will 
be transmitted to the ANSM, the CPP and the EMA (via EudraVigilance) within 7 days in case of death or life-
threatening situation, otherwise within 15 days. 
If it is an expected serious adverse event, it will be collected for the semi-annual and annual safety reports. 
 
Events not to be considered serious  
The progression of the disease as seen on imaging should not be considered as an SAE. On the other hand, 
events potentially linked to the progression but which may be secondary to the treatment should be reported 
(e.g. thromboembolic events, haemorrhagic phenomena, perforations, etc.) 
Due to the severity of the disease in this study, certain conditions defined as SAEs will be excluded from the 
SAE reporting procedure, namely:  
- 
Hospitalization or surgery specifically related to the treatment of the disease 
- 
Hospitalization performed to simplify study treatments or procedures 
 
In this essay the reference documents will be: 
• 
For aflibercept, the investigator brochure   
• 
For 5-fluorouracil, the Summary of Product Characteristics for Fluorouracil Arrow® 50 mg (Appendix 
8) 
• 
For folinic acid, the Summary of Product Characteristics for Elvorine® (Appendix 8) 
 
The versions of the PCRs used for the definition of expected or unexpected will be the latest available on the 
anniversary date of the start of the trial. 
 
What to do  
 
The investigator informs the sponsor of all Serious Adverse Events (Expected and Unexpected), whether or not 
attributable to the research, that occur during the study or within 30 days of the last treatment administration.  
 
All Delayed Serious Adverse Events (occurring after this 30-day period) considered reasonably related to the 
protocol treatment(s) or research should be reported without time limitation. 
 
The report is made by faxing the "notification of a serious adverse event" form (cf. appendix 9), documented 
as precisely as possible, dated and signed, within 24 working hours following the observation of the SAE, to 
the FFCD's Randomization Management Analysis Center (CRGA) by fax ( 03 80 38 18 41). 
 
The investigator is responsible for appropriate medical follow-up of patients until resolution or stabilization of 
the effect or until the patient's death. This may sometimes involve extending this follow-up beyond the trial 
patient's protocol follow-up period. 
 
He/she transmits the additional information to the sponsor using an SAE reporting form (checking the Follow-
up No. X box to specify that it is a follow-up report and not an initial report) within 24 hours of obtaining it. It 
also forwards the last follow-up to the resolution or stabilization of the SAE.  
It responds to requests for additional information to document the initial observation. 
10. 
STATISTICAL ANALYSIS 
The study is open-label, randomized (LV5FU2 alone versus LV5FU2 + aflibercept), non-comparative, and 
multi-center.  
 
10.1 
Provisional schedule of the study 
The expected rate of inclusion is 5 patients per month. 


 
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First inclusion: January 2015 
End of inclusions: January 2017 
First analysis of the study: December 2017  
Final analysis of the study: July 2018 
 
10.2 
Criteria of judgment 
10.2.1 Primary efficacy endpoint 
The primary endpoint of this trial is the rate of patients alive and progression-free within 6 months (+/- 15 days) 
after randomization. Progression will be assessed by the investigator according to RECIST 1.1 criteria based 
on imaging studies performed every 8 weeks, even in case of deferred treatments. 
Clinical progressions, not confirmed on imaging, will not be counted in the primary endpoint.  
Patients with progression on imaging studies prior to 6 months will be considered to be in progression at 6 
months. Patients operated on their primary tumor before 6 months will be considered as non-progressive at 6 
months. 
 
A medical review will be carried out to decide on the case of each patient lost to follow-up or not evaluable at 
6 months without identified progression before 6 months; in view of the patient's complete file, the patient may 
be considered as a treatment failure (progression), or as truly non-evaluable and not participating for the primary 
endpoint (a rate of 5% of additional patients has been planned for these situations). 
 
10.2.2 Secondary criteria 
- The rates of patients alive and progression-free according to the investigator will be evaluated at different 
time points: 6 months (primary endpoint) and 1 year. 
o There are 2 definitions of progression depending on the investigator: either radiological 
progression alone (at 1 year) or clinical and/or radiological progression (at 6 months and 1 
year). 
- Progression-free survival: Progression-free survival (median) may be estimated by the investigator. It will 
be defined as the time between the date of randomization and the date of the first radiological progression 
(RECIST 1.1 criteria) according to the investigator or death; patients alive without progression will be 
censored at the date of point or at the date of last informative examination if it is earlier. 
- Live and progression-free rates according to centralized review (RECIST 1.1 criteria) will be estimated 
at 6 months and 1 year. 
o A centralized review of the imaging evaluations (CT or MRI with injection + chest CT) 
during the first 6 months will be performed. If centralized review is not possible for some 
CT scans, the response according to RECIST v1.1 criteria will be that estimated by the 
investigator. 
- Best response at 1 year: evaluated from all radiological examinations of the patients according to the 
RECIST 1.1 criteria according to the investigator; it will be described by the rates according to the different 
categories: complete response, partial response, stability, progression or not evaluable 
- 1-year and 3-year overall survival: defined by the time from the date of randomization to the date of death; 
living patients will be censored at the earlier of the point or last date. 
- Tolerance: evaluated by the toxicities observed and graded according to NCI-CTC v4.0; in particular, 
cutaneous toxicities of grade 2 or higher will be analyzed; the evolution of weight and WHO performance 
index will be described, as well as the SAEs. The time to onset of grade 3-4 toxicity will be studied. 
- Quality of life: measured by the EORTC QLQ C30 questionnaire, completed at baseline and at each 
assessment visit during treatment, and at follow-up visits after cessation of treatment (every 3 months for 2 
years and every 6 months for 1 year). Time to definitive deterioration of the QLQ-C30 global health score 
will be estimated; it is defined as the time from the date of randomization to the first date of a score decrease 


 
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of 5 points or more (from inclusion) without subsequent improvement of more than 5 points or death; living 
patients without deterioration of more than 5 points will be censored at the date of point or last quality of life 
assessment if earlier. 
- Resectability with curative intent at 1 year: patients who have had their tumors (primary and/or secondary) 
resected after treatment (mentioning the R0, R1 or R2 character), after re-evaluation of their file in a 
multidisciplinary consultation meeting.  
- Prognostic character of thymidylate synthase polymorphisms on the rate of patients alive and 
progression-free at 6 months across both arms. 
 
10.3 
Calculation of the number of subjects needed 
 
In the FFCD 2000-05 study using LV5FU2 in the same indication, the median progression-free survival was 
5.7 months.  
The primary endpoint of the PRODIGE 25 study is progression-free survival within 6 months of randomization. 
The assumptions for calculating the number of subjects required are: 
- H0 : A 6-month live progression-free rate of 40% or less is considered unattractive.  
- H1 : a rate of patients alive and progression-free at 6 months of more than 40% is necessary to consider the 
treatment interesting; a progression-free survival rate at 6 months of 60% is expected. 
 
With a one-sided alpha risk of 5%, 56 evaluable patients in each arm (total 112 patients) would need to be 
included to achieve 90% power under the considered H1 hypothesis (calculations according to the exact 
binomial distribution)). 
Taking into account a 5% rate of lost to follow-up, 118 patients should be included. 
 
The decision rule is as follows: 
- 
If 29 or more patients are alive and progression-free at 6 months, the efficacy of the treatment arm 
studied can be considered attractive. 
 
 
This decision rule will only apply to the combination arm (LV5FU2 + Aflibercept). In the event that the trial 
continues into Phase III, the chemotherapy-only arm will be the control arm. 
 
Depending on the number of patients actually lost to follow-up or deemed not evaluable, the decision rules for 
considering the treatment to be of value in terms of efficacy will be reviewed. 
 
As an exploratory measure, the rates of patients alive and progression-free within 6 months will be compared 
between the two arms using a one-tailed Fisher exact test. This comparison will only be relevant in case of 
positive results; a negative result could in no case be interpreted as no difference between the two arms, for 
several reasons: 
- 
the calculation of the number of patients was not done with a view to comparing the treatment arms; 
therefore, the power to show a difference is not sufficient; 
- 
This study is a phase II study, and the assumptions used for the enrollment calculation are not yet precise 
enough to design a comparative study at this time; 
- 
the H assumption0 chosen does not represent the expected progression-free survival rate in the monotherapy 
arm, but the cut-off deemed necessary to consider an evaluation of the chemotherapy plus aflibercept arm 
in a legitimate phase III trial; thus, the difference between the H assumption0 and the H assumption1 is 
currently overestimated for a comparative study. 
 
No interim analysis is planned. Nevertheless, the independent data review committee will be alerted in case of 
a significant number of AEs reported by the study pharmacovigilance.  
 


 
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10.4 
Statistical analysis plan 
 
10.4.1 Populations of analysis  
ITT population: All patients included in the study regardless of inclusion and non-inclusion criteria and 
analyzed according to the treatment assigned by randomization 
 
Modified ITT population (mITT): All patients in the ITT population with at least one assessment for the 
primary endpoint (imaging).  
 
Per-Protocol (PP) population: All patients in the mTBI population: 
- 
who have received at least 2 courses of chemotherapy at any dose (and 2 days of aflibercept in the 
corresponding arm),  
- 
and whose WHO status at inclusion was ≤ 2 
 
Tolerance Population: All patients included in the study who received at least one dose of treatment (regardless 
of dose and treatment). The analysis will be performed according to the actual treatment administered (presence 
or absence of at least 1 day of aflibercept administration). 
 
The analysis of the primary and secondary efficacy endpoints will be performed in ITTm.   
 
The primary endpoint and efficacy criteria will also be evaluated on the per-protocol population.  
 
The safety analysis will be performed on the tolerance population. 
 
10.4.2 Evaluation of the criteria 
General considerations  
All analyses will be performed using SAS software version 9.3 or higher or STATA V10 or higher. A statistical 
analysis plan will be written before the database is frozen. Any subsequent modification of this plan will have 
to be detailed, argued and commented in an updated version. These modifications may concern additional 
exploratory analyses not initially envisaged. 
 
Continuous variables will be described using mean, standard deviation, median, interquartile range, minimum 
and maximum. Categorical variables will be described using frequencies and percentages. The 95% confidence 
intervals will be provided for the primary endpoint. 
Evaluation of effectiveness criteria 
 
The rate of patients alive and progression-free at 6 months will be calculated based on the investigator's 
assessment at 6 months +/- 15 days. It will be described using a percentage and a 95% confidence interval. 
 
Survivals and times will be estimated by the Kaplan-Meier method. They will be described by medians and 
rates at different time points with their 95% confidence intervals. 
 
The median follow-up time will be calculated using the "reverse Kaplan-Meier" method. 
 
The best response to treatment will be reported using percentages and numbers with their 95% confidence 
intervals. 
 
Exploratory analysis of factors predictive of treatment response (progression vs. non-progression) will be 
performed by logistic regression; multivariate logistic regression will also consider treatment arm and 
stratification factors. 


 
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Evaluation of tolerance criteria 
 
The number of cycles, dose received, and dose intensities will be described, as well as the percentage of patients 
who had a dose change or delay in administration with the related reasons.  
 
The evolution of the WHO performance index and weight will be described. 
 
The number of toxicities, by type and grade, will be reported over all treatment cycles. The percentage of 
patients with at least one grade 3-4 toxicity, at least one grade 5 toxicity, and those with maximum grade 1-2 
toxicity will be calculated. 
 
The time to grade 3-4 toxicity will be calculated by the Kaplan-Meier method. 
The analysis of SAEs will be performed by the FFCD Pharmacovigilance Department. Quality of life will be 
assessed using the QLQ-C30 questionnaires. 
 
Each score will be described at each measurement time by treatment arm (until one quarter of the baseline 
population is still followed). Means of change from inclusion to last assessment will be calculated in each arm. 
For the overall health score, a longitudinal analysis will be performed. The rate of patients with an improved 
score (increase of more than 5 points compared to inclusion), deteriorated score (decrease of at least 5 points 
(included)) and the rate of patients with a stabilized score at the last assessment will be reported using 
percentages and frequencies. An estimate of the time to deterioration of the quality of life score will be made 
using the Kaplan-Meier method.  
 
10.5 
Independent committee  
 
An independent committee will be set up with an odd number of members including at least two physicians, a 
statistician and a pharmacovigilance expert. It will meet to rule on the safety data. It may also meet at any time 
during the trial when the Sponsor deems it useful. 
 
11. 
BACKGROUND INFORMATION AND RATIONALE FOR THE STUDY 
11.1 
Colorectal cancers 
11.1.1 Incidence 
Colorectal cancers are the leading cancer incidence in France when both sexes are combined, with nearly 40,000 
new cases in 2010 (1). Most of these cancers are diagnosed at the metastatic stage and it is estimated that about 
50% become metastatic during their evolution. These cancers preferentially affect elderly subjects (median age 
72 years for men, 75 years for women). Their incidence increases with age (2). Crude survival is 44%, relative 
survival 56% in France (3). In the 1990s, with the emergence of chemotherapy and improved postoperative 
survival, unadjusted survival increased from 54% to 57%.  
 
11.1.2 Surgical treatment of metastatic colorectal cancer 
Surgical removal is the only curative treatment. Thanks to advances in surgical techniques and 
anesthesia/resuscitation, an increasing number of patients can benefit from removal of the primary tumor and 
metastases. With the introduction of oxaliplatin and irinotecan in the therapeutic armamentarium, the 
resectability rate has increased but is known mainly from publications of series from specialized surgical centers 
(4) or on more or less selected patients from randomized studies. However, it seems certain that the use of 
certain chemotherapy combinations, in particular 5FU-oxaliplatin-irinotecan (FOLFOXIRI or FOLFIRINOX), 
is accompanied (5) by an increase in the resectability rate. Combinations of biochemotherapy (5FU and 
oxaliplatin or irinotecan) with an anti-VEGF antibody, bevacizumab (6), and with an anti-r EGF antibody, 


 
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cetuximab (7), also appear to increase the resectability rate of borderline metastases. Several ongoing 
randomized trials are exploring these avenues. 
However, it has been shown (8) that the resection of all sites where metastases are initially located, especially 
in the liver, is essential, as their disappearance on current morphological examinations is not predictive of their 
definitive sterilization. For some patients with numerous metastatic sites in the liver segments and/or lung fields, 
there is therefore no hope of R0 secondary resection after aggressive chemotherapy. 
Other patients cannot benefit from a resection of their primary tumor or their metastases because of their non-
operability: old age, co-morbidities in particular cardiovascular.  
11.1.3 Non-surgical treatment of unresectable or non-operable patients  
11.1.3.1 
Chemotherapy 
For these two categories of patients, three well-conducted randomized studies (9-11) have shown that starting 
chemotherapy with a 5FU-based monotherapy does not affect the overall survival of patients provided that they 
switch to a combination of oxaliplatin or irinotecan in the second line. The convergence of these studies supports 
this statement with an excellent level of evidence. It appears, but these are only hypotheses from subgroup 
studies of two of these studies (MRC, FFCD), that impaired general status (WHO 2 and above) and/or the 
presence of more than one metastatic site are predictive of a survival advantage of the dual-therapy arms versus 
5FU monotherapy. However, the differences are only statistically insignificant trends. 
The search for factors predictive of the efficacy of dual therapy with oxaliplatin versus monotherapy led to the 
isolation of a thymidylate synthase (TS) genotype that, when present in the tumor host, is predictive of a better 
efficacy of this dual therapy (12): the progression-free survival benefit of first-line FOLFOX versus LV5FU2 
was observed only in patients with a 5'UTR TS genotype of 2R/2R (HR=0.39; 95% CI, 0.23-0.68) or 2R/3R 
(HR=0.59; 95% CI, 0.42-0.82) respectively. Conversely, patients with TS-5'UTR 3R/3R genotype did not 
benefit from the addition of oxaliplatin (HR=0.96; 95% CI, 0.66-1.40). It is thus reasonable to think that the 
3R3R genotype seems to be associated with an efficacy of 5-FU monotherapy as good as that of the FOLFOX 
combination. It is therefore interesting to validate this hypothesis by a prospective study stratifying patients on 
this criterion. If this genotype is predictive of the efficacy of 5-FU, this would also allow the two arms of a 
randomized study to be unbalanced on this criterion. 
11.1.3.2 
Targeted therapies (biotherapies)  
Anti-angiogenic 
Among recent studies, only one phase III study (13) evaluated the first-line combination of a targeted therapy 
(anti-VEGF antibody), bevacizumab, with 5FU (capecitabine) monotherapy. It showed a benefit on first-line 
progression, but no overall survival advantage for patients who received this anti-angiogenic therapy: the 
absence of bevacizumab in the first line was compensated by the administration of oxaliplatin, irinotecan or 
both in the second line or more in 68% of cases initially treated with capecitabine alone. The older Hurwitz 
study (14) with an obsolete comparator arm, IFL combination since discontinued, had shown a benefit in 
progression-free survival and overall survival (20.3 versus 15.6 months) but the subsequent lines of treatment, 
received by only 50% of patients, were not consistent with those that can be offered currently and did not 
include bevacizumab. The Kabbinavar trial (15), a combination of two cohorts of patients treated in two trials 
involving elderly subjects deemed unsuitable for irinotecan, shows an overall survival advantage for the arm 
treated with bevacizumab plus 5FU alone, but the subsequent lines received by patients are not well reported 
and the trial is also difficult to interpret. Therefore, it is not possible to recommend routine use of bevacizumab 
in the first line following these trials. In addition, the effect of this drug on overall survival has been proven in 
only two clinical trials. For other cancer sites, a larger number of phase III trials using bevacizumab have led 
to conflicting results that alter the certainty that this targeted therapy is unavoidable (16). 
Two other multitargeted molecules with a predominantly anti-angiogenic focus, regorafenib (17) as a single 
agent and aflibercept in combination with 5FU and irinotecan in the VELOUR trial (FOLFIRI regimen) (18,19), 
have shown a significant effect on overall survival in second- or subsequent-line therapy 
Aflibercept 


 
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This molecule is a recombinant fusion protein consisting of a fusion of the extracellular domain of the human 
vascular endothelial growth factor (VEGF) receptor with the Fc portion of human immunoglobulin G1 or IgG1 
(Figure 1). Specifically, Aflibercept contains extracellular domain portions of two different vascular growth 
factors (VEGFRs): VEGFR1 (also described as Fit-1) and VEGFR2 (also described as KDR or Fik-1). 
Aflibercept is a drug presented as a sterile liquid for intravenous (IV) administration. It binds to VEGF in the 
picomolar range (pmol/L) and to placental growth factor (PIGF) with lower affinity. The affinity constants 
(KD) for binding to the two human VEGF isoforms, VEGF165 and VEGF121, are 0.50 pmol/L and 0.36 
pmol/L, respectively. The KD for human PlGF2 is 39 pmol/L. The purpose of binding aflibercept to these 
ligands in vivo is to block angiogenesis and cell permeability, as aflipecept-bound VEGF can no longer interact 
with the endothelial wall. Aflibercept cannot mediate ADCC or CDC activity in endothelial and tumor cell 
lines. 
Its activity has been studied in a broad pharmacological field against early and advanced solid tumors: sarcomas, 
ovarian, prostate, mammary, colon and gastric carcinomas, as a single agent or in combination with cytotoxic 
drugs. In a mouse model of ovarian and renal carcinomatous ascites, Aflibercept inhibited ascites formation 
and reduced tumor growth. 
  
 
Figure 1 - Schematic representation of Aflibercept (VEGF Trap)  
 
 
 
 
 
 
 
 
 
 
Two studies specifically examined serum Aflibercept levels in animal models by ELISA: free Aflibercept (not 
bound to VEGF) and bound Aflibercept (Aflibercept complexed to VEGF, 1:1 ratio). After IV administration 
in all animal species studied, free Aflibercept had a low clearance (0.5 to 3 mL/h/kg), a low volume of 
distribution (69 to 226 mL/kg), and a long apparent elimination half-life: T1/2 of 48 to 98 hours. Based on the 
correlation between exposure and activity in pre-clinical models, the proposed pharmacological target in 
humans for safe administration is such that excess free aflibercept is present.  
The toxicity profile of aflibercept was evaluated in monkeys. 
The main microscopic abnormalities were observed in the bone, nasal cavity, kidneys, ovaries and adrenals.  
- 
Bones: thickening of the cortices and osteo-cartilaginous exostoses of the axial skeleton and 
extremities, correlated with a "pulled-in shoulder" attitude on clinical examination. 
- 
Nasal cavity: degeneration/regeneration of respiratory and olfactory epithelium, atrophy/loss of nasal 
septum and/or turbinates, often associated with hemorrhages and superinfected exudates. 


 
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- 
Kidneys: increased glomerular mesangial matrix, associated in some individuals with hypoprotidemia, 
hypoalbuminemia, elevated BUN, proteinuria and/or microalbuminuria. 
- 
Ovaries: decrease in the number of mature follicles, granular and/or thecal cells associated with 
inhibition of reproductive function. 
- 
Adrenals: decreased vacuolization in the adrenergic fascicle zone and cytoplasmic eosinophilia. 
In addition, focal proliferation/degeneration abnormalities were observed in several organs, particularly the 
digestive tract, bladder, heart and brain of some monkeys. Elevated liver enzymes were noted in some 
individuals, associated with portal inflammation and necrosis. Administration of aflibercept resulted in 
decreased sperm motility and an increased rate of morphologically abnormal sperm. 
Most of these abnormalities associated with aflibercept administration occurred at the lowest doses tested (1.5 
to 3 mg/kg/dose).  
With the exception of bone and nasal abnormalities, aflibercept-induced changes resolved within 5 months of 
discontinuation. 
Aflibercept did not induce a frequent immune response in monkeys treated for 3 months by SC or IV, with an 
increased incidence of an antigenic response when treated for 6 months. 
In male mice, 3 months of subcutaneous administration induced a significant reduction in microvessel density 
mainly in the liver, pancreatic islets, thyroid follicles at all doses, and less markedly in the pituitary and adipose 
tissue. Single administration in rodents induced a moderate, prolonged and reversible elevation of systolic and 
diastolic blood pressure. The induced hypertension in rats was sensitive to several classes of antihypertensive 
drugs, such as angiotensin-converting enzyme inhibitors, calcium channel blockers, adrenergic receptor 
antagonists, and NO modulators.  
In rabbits, aflibercept moderately delayed parietal repair and wound healing as early as 
0.3mg/kg/administration. 
As of 01/31/2010, aflibercept has been administered to more than 3100 patients included in trials involving 
solid cancer tumors, 76 healthy subjects, 41 patients with ophthalmic disease, at doses up to 800 μg/kg SC twice 
weekly, 7 mg/kg IV every 2 weeks and 9 mg/kg IV every 3 weeks. The most frequently reported unexpected 
side effects when prescribed as monotherapy were fatigue, hypertension, headache, nausea, abdominal pain, 
dysphonia, diffuse musculoskeletal, extremity, and lumbar pain, anorexia, vomiting, hemorrhage (mainly 
epistaxis), constipation, diarrhea, respiratory abnormalities (mainly dyspnea), arthralgias, edema, proteinuria, 
cough, fever, myalgias, and weight loss. The toxicities described in the phase III VELOUR study in combination 
with FOLFIRI chemotherapy (5FU, folinic acid, irinotecan) are given in Tables 1 and 2. In this study, performed 
as a second-line treatment in a patient population similar to this new study, the toxicity profile of aflibercept 
was considered acceptable and predictable within the known complications of anti-angiogenic agents. Adding 
aflibercept to biochemotherapy with 5FU and irinotecan resulted in an increase in the specific toxicity of this 
chemotherapy, in particular the rate of neutropenia, diarrhea and stomatitis.  
Pharmacologic target was achieved at a dose ≥2 mg/kg IV every 2 weeks.  Free aflibercept remained in excess 
of bound aflibercept over interval dosing at this dose and above. Tumor responses and stabilizations (>1 year) 
were observed at dose levels ≥800 μg/kg SC and ≥1 mg/kg IV for aflibercept alone and in combination with 
cytotoxic drugs. 
Its activity on tumor growth was similar to that obtained with monotherapy when combinations with paclitaxel, 
docetaxel, or irradiation were used in animal models, and was synergistic with 5-fluorouracil (5-FU), and 
irinotecan.  
 
Table 1. Most frequent adverse events in the phase III VELOUR trial  
(excluding events in the anti-angiogenic class) 
 
Population evaluated for toxicity 
of patients 
Placebo, N = 605 
Aflibercept N = 611 


 
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All grades 
Grade 3-4 
All grades 
Grade 3-4 
Diarrhea 
56.5 
7.8 
69.2 
19.3 
Neutropenia 
56.3 
29.5 
67.8 
36.7 
Complicated neutropenia 
- 
2.8 
- 
5.7 
Asthenia 
50.2 
10.6 
60.4 
16.9 
Stomatitis & ulcerations 
34.9 
5.0 
54.8 
13.7 
Thrombocytopenia 
33.8 
1.7 
47.4 
3.3 
Infections 
32.7 
6.9 
46.2 
12.3 
Anorexia 
23.8 
1.8 
31.9 
3.4 
Weight loss 
14.4 
0.8 
31.9 
2.6 
Erythro-dysesthesia palmo-plantar  
4.3 
0.5 
11.0 
2.8 
Skin hyperpigmentation 
2.8 
0 
8.2 
0 
Dehydration 
3.0 
1.3 
9.0 
4.3 
Van Cutsem E et al, ESMO WCGI 2011 
Table 2. Adverse events considered to be associated with Anti-VEGF activity  
in the phase III VELOUR trial (total population) 
 
Population evaluated for toxicity 
of patients 
Placebo/FOLFIRI, N=605 
Aflibercept/FOLFIRI, N=611 
 
All grades 
Grade 3/4 
All grades 
Grade 3/4 
Proteinuria 
40.7 
1.2 
62.2 
7.9 
Hypertension  
10.7 
1.5 
41.4 
19.3 
Hemorrhage 
19.0 
1.7 
37.8 
2.9 
 
of intestinal origin  
5.1 
1.0 
10.0 
2.0 
Dysphonia 
3.3 
0 
25.4 
0.5 
Headaches 
8.8 
0.3 
22.3 
1.6 
Venous thromboembolic events 
7.3 
6.3 
9.3 
7.9 
Thromboembolic event  
Arterial 
1.5 
0.5 
2.6 
1.8 
Fistula 
0.5 
0.2 
1.5 
0.3 
Delayed healing 
0.8 
0 
0.5 
0.3 
Intestinal perforation 
0.5 
0.3 
0.5 
0.5 
Van Cutsem E et al, ESMO WCGI 2011 
Complete information regarding aflibercept will be provided to the trial investigators. 
Anti-EGFr (epidermal growth factor receptor)  


 
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A large international multicenter study, the Cristal trial, showed that the combination of weekly cetuximab with 
the FOLFIRI regimen in the first line of treatment gave patients receiving it a progression-free survival and 
overall survival advantage (20), provided that their tumor did not have a K-RAS mutation. A difference in 
progression-free survival had already been shown in second-line treatment after failure of 5FU- and irinotecan-
based chemotherapy in a phase II study (21). For some, it seems more interesting to place this treatment later 
in the management of patients. A strategy study evaluating these two types of therapeutic sequences would be 
useful. 
The cetuximab-oxaliplatin combination has also been evaluated in first-line therapy in combination with 5FU. 
In the OPUS trial (22), the cetuximab-FOLFOX combination provided a progression-free survival benefit. In 
combination with the Xelox (xeloda-oxaliplatin) regimen, cetuximab did not provide an overall survival benefit 
(23).  The addition of the skin toxicities of this oral 5FU and cetuximab is thought to have induced a decrease 
in the dose-intensity of cytotoxic treatment, explaining this negative result. 
The combination of cetuximab and 5FU has not been evaluated to date.  
 
11.2 
Rationale for the study 
The combination of aflibercept and 5FU alone has not been evaluated to date. 
Aflibercept at a dose of 4 mg/kg has already been used in combination with 5FU at the doses used in the 
simplified LV5FU2 regimen (folinic acid 400 mg/m2  IV over 90 min, followed by 5FU 400 mg/m2  as an IV 
bolus at D1, followed by a continuous infusion of 5FU 2400 mg/m2 over 46 h) (23) in the above-mentioned 
VELOUR trial, evaluating its combination with FOLFIRI (= simplified LV5FU2 + irinotecan). This study was 
preceded by a phase I trial validating the doses used (24). There is therefore no need for a phase I study if the 
same doses of 5FU are used, without irinotecan, as part of a strategy to de-escalate toxicity in patients to be 
managed over a long period of time, and not to find the maximum tolerable dose of the combination. 
The aflibercept-LV5FU2 combination may be of interest in patients who will never be resectable or operable 
and in whom 5-FU monotherapy may be proposed to delay the toxicities of chemotherapy combinations. In this 
setting, it is possible that aflibercept may provide a survival advantage. The preliminary VELOUR study (18) 
does not suggest that toxicity will have a significant impact on quality of life and suggests that progression-free 
survival will be prolonged in the aflibercept arm.  
This is what the FFCD 11-01 study, PRODIGE 25, proposes to study as a preliminary to strategic studies 
evaluating the usefulness of using targeted therapies from the first line. 
This study will evaluate both the efficacy of the combination and its tolerance, through the study of toxicities 
and quality of life. Quality of life will be studied through the EORTC QLQC30 questionnaire. 
The 2R2R-2R3R versus 3R3R polymorphism of thymidylate synthase seems to predict better efficacy of 5FU 
monotherapy. Stratification on this criterion will allow to confirm or not the prognostic or predictive character 
of the efficacy of 5FU associated with these polymorphisms.  
The project of this study was studied and validated by the scientific council of the French-speaking Federation 
of Digestive Oncology (FFCD) then by the Digestive Group of UNICANCER within the framework of their 
Partnership for Research in DIGEstive Oncology (PRODIGE). 
12. 
REFERENCES  
 
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digestive cancers in France between 1980 and 2005 and projections for the year 2010. EJC 2011, Eur J Cancer Prev. 
2011 Sep; 20(5):375-80. 
2- Remontet L, Estève J, Bouvier AM, et al. Cancer incidence and mortality in France over the period 1978-2000.  Rev 
Epidemiol Sante Publique 2003;51:3-30.  
3- Bouvier AM, Delafosse P, Faivre Jean. Colon-rectum. 137-144. In Survival of cancer patients in France. Study of 
the FRANCIM network registries. Spinger- Verlag France, 2007, 406 p. 


 
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4- Wicherts DA, de Haas RJ, Adam R. Bringing unresectable liver disease to resection with curative intent. Eur J Surg 
Oncol. 2007 Dec;33 Suppl 2:S42-51.  
5- Falcone A, Ricci S, Brunetti I, Pfanner E et al, Gruppo Oncologico Nord Ovest. Phase III trial of infusional 
fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, 
leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo 
Oncologico Nord Ovest. J Clin Oncol. 2007 May 1;25(13):1670-6. 
6- Wong R, Cunningham D, Barbachano Y, Saffery C, Valle J, Hickish T, Mudan S, Brown G, Khan A, Wotherspoon 
A, Strimpakos AS, Thomas J, Compton S, Chua YJ, Chau I. A multicentre study of capecitabine, oxaliplatin plus 
bevacizumab as perioperative treatment of patients with poor-risk colorectal liver-only metastases not selected for 
upfront resection. Ann Oncol. 2011 Feb 1.  
7- Folprecht G, Gruenberger T, Bechstein WO, Raab HR, Lordick F, Hartmann JT, Lang H, Frilling A, 
Stoehlmacher J, Weitz J, Konopke R, Stroszczynski C, Liersch T, Ockert D, Herrmann T, Goekkurt E, Parisi F, 
Köhne CH. Tumour response and secondary resectability of colorectal liver metastases following neoadjuvant 
chemotherapy with cetuximab: the CELIM randomised phase 2 trial. Lancet Oncol. 2010 Jan; 11(1):38-47.  
8- Benoist S, Brouquet A, Penna C, Julié C, El Hajjam M, Chagnon S, Mitry E, Rougier P, Nordlinger B. Complete 
response of colorectal liver metastases after chemotherapy: does it mean cure? J Clin Oncol. 2006 Aug 
20;24(24):3939-45. 
9- Seymour MT, Maughan TS, Ledermann JA, Topham C, James R, Gwyther SJ, et al. Different strategies of 
sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC 
FOCUS): a randomised controlled trial. Lancet 2007;370:143-52 
10- Bouché O, Castaing M, Etienne PL, Texereau P, Auby D, Bedenne L, et al. Randomized strategic trial of 
chemotherapy in metastatic colorectal cancer (FFCD 2000-05): Preliminary results. J Clin Oncol 2007;25 (Suppl 
18S):4069a. 
11- Koopman M, Antonini NF, Douma J, Wals J, Honkoop AH, Erdkamp FL, et al. Sequential versus combination 
chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III 
randomised controlled trial. Lancet 2007;370:135-42. 
12- Boige V, Mendiboure J, Pignon JP, Loriot MA, Castaing M, Barrois M, Malka D, Trégouët DA, Bouché O, Le 
Corre D, Miran I, Mulot C, Ducreux M, Beaune P, Laurent-Puig P. Pharmacogenetic assessment of toxicity and 
outcome in patients with metastatic colorectal cancer treated with LV5FU2, FOLFOX, and FOLFIRI: FFCD 
2000-05. J Clin Oncol. 2010 May 20;28(15):2556-64. 
13- Tebbutt NC, Wilson K, Gebski VJ, Cummins MM, Zannino D, van Hazel GA, Robinson B, Broad A, Ganju V, 
Ackland SP, Forgeson G, Cunningham D, Saunders MP, Stockler MR, Chua Y, Zalcberg JR, Simes RJ, Price TJ. 
Capecitabine, bevacizumab, and mitomycin in first-line treatment of metastatic colorectal cancer: results of the 
Australasian Gastrointestinal Trials Group Randomized Phase III MAX Study. J Clin Oncol. 2010 Jul 
1;28(19):3191-8. 
14-  Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, 
Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F. Bevacizumab plus irinotecan, fluorouracil, and 
leucovorin for metastatic colorectal cancer. N Engl J Med. 2004 Jun 3;350(23):2335-42. 
15- Kabbinavar FF, Hurwitz HI, Yi J, Sarkar S, Rosen O. Addition of bevacizumab to fluorouracil-based first-line 
treatment of metastatic colorectal cancer: pooled analysis of cohorts of older patients from tworandomized clinical 
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16- Ocana A, Amir E, Vera F, Eisenhauer EA, Tannock IF. Addition of bevacizumab to chemotherapy for treatment 
of solid tumors: similar results but different conclusions. J Clin Oncol 2011;29:254-256. 
17- Rogerafenib Grothey A, ASCO GI 2012 
18- Velour Van Cutsem E, ASCO 2012. Van Cutsem E, Tabernero J, Lakomy R, Prenen H, Prausova J, Macarulla T, 
Ruff P, van Hazel GA, Moiseyenko V, Ferry D, McKendrick J, Polikoff J, Tellier A, Castan R, Allegra C. 
Addition of aflibercept to fluorouracil, feucovorin, and irinotecan improves survival in a phase III randomized 
trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin 
Oncol 20012;30  
19- Velour Tabernero J, ESMO 2011 
20-  E. Van Cutsem, I. Lang, G. Folprecht, M. Nowacki, C. Barone, I. Shchepotin, J. Maurel, D. Cunningham, I. 
Celik, C. Kohne. Cetuximab plus FOLFIRI: Final data from the CRYSTAL study on the association of KRAS and 
BRAF biomarker status with treatment outcome. J Clin Oncol 28:15s, 2010 (suppl; abstr 3570) 
21- Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, et al. Cetuximab monotherapy and 
cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004;351:337-45.  
22- Bokemeyer C, Bondarenko I, Hartmann JT, de Braud F, Schuch G, Zubel A, Celik I, Schlichting M, Koralewski 
P. Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic 
colorectal cancer: the OPUS study. Ann Oncol. 2011 Jan 12 [Epub ahead of print]. 
23- Maughan TS, Adams R, Smith CG, Seymour MT, Wilson RH, Meade AM, Fisher D, Madi A, Cheadle J, Kaplan 
RS, MRC COIN Trial Investigators. Identification of potentially responsive subsets when cetuximab is added to 
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24- Van Cutsem E, Khayat D, Verslype C, Billemont B, Tejpar S, Meric JB, Karen Soussan-Lazard K, Assadourian S, 
Cartot-Cotton S, Rixe O.  Phase I dose-escalation study of intravenous aflibercept administered in combination 
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13. 
CONSIDERATIONS  
14. 
ADMINISTRATIVE  
 
STUDY SPONSOR 
 
The sponsor of the study is the Fédération Francophone de Cancérologie Digestive (FFCD). The study was 
registered under the number EudraCT 2014-001837-10. 
  
REMINDER OF THE TEXTS IN FORCE 
 
This test will be carried out according to the new European Directive 2001/20/EC.  
 
LIABILITY INSURANCE 
 
Insurance was taken out by the sponsor on 12/05/2014 under number 137681, in accordance with Article L 
1121-10 of the Public Health Code (Appendix 11).  
 
REQUEST FOR AUTHORIZATION TO THE CPP AND ANSM 
 
This protocol received the favorable opinion of the CPP (Committee for the Protection of Persons) OUEST I 
of Tours on xx/xx/2014 (Appendix 12). 
This protocol received authorization from the ANSM (Agence Nationale de Sécurité du médicament et des 
produits de santé) on xx/xx/2014 (Appendix 13). 
 
COLLECTION OF THE PATIENT'S CONSENT 
 
The investigator undertakes to obtain the patient's written clinical and biological consents (information sheets 
and consent forms in Appendix 1 and 2) before the patient is included in the study. A copy of these consents 
must be kept by the investigator for 15 years, to be presented to the regulatory authorities in case of inspection. 
The original must be given to the patient. 
 
HOSPITAL MANAGEMENT INFORMATION AND RESEARCH AGREEMENT 
 
Prior to the implementation of the study, the hospital management will be informed by the sponsor of the 
investigator's interest in participating in this trial. 
A research agreement will be established between the administrator of the investigating center and the sponsor.  
 
DATA ARCHIVING 
 
The files will remain confidential and can only be consulted under the responsibility of the doctors in charge of 
the patients. The sponsor and the health authorities in case of inspection will have direct access to these 
documents. 
At the end of the trial, the observation book will be kept for 15 years by the investigator. 
 
COMPUTER SUPPORT 
 


 
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In accordance with the text of the law n° 78-17 of January 6, 1978 modified by the law of August 9, 2004, 
relating to data processing, files and freedoms, the data of the trial will be recorded in a data bank of the Center 
of Randomization and Management Analysis of the FFCD, with the exception of the elements relating to the 
identity of the patients. 
 
DATA PROCESSING 
 
The FFCD's Center for Randomization, Management and Analysis (CRGA) will be responsible for data 
management and analysis.  
 
MONITORING, QUALITY ASSURANCE AND INSPECTIONS BY AUTHORITIES 
 
The investigator agrees in advance that the records of the patients included in the trial may be consulted by a 
person mandated by the FFCD and/or by the health authorities to conduct an audit. On-site visits to the files, 
scheduled after agreement by the investigator, may take place during or after the period of inclusion in the trial 
This protocol will be monitored by the FFCD's mobile ARCs.  
15. 
PUBLICATION RULES 
They will be in accordance with those established in the framework of the PRODIGE Partnership (Annex 10) 


 
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