Conditions: Metastatic Colorectal Cancer
Keywords: colorectal cancer Metastatic
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 41
Healthy volunteers: no

Brief summary:
One of the treatments generally used to treat this disease is a chemotherapy called FOLFIRI. The purpose of this study is to improve the efficacy of the chemotherapy by adding a protein, similar to immunoglobulins, aflibercept, and to assess their tolerance.

Aflibercept is a protein that has already been studied in the treatment of metastatic colorectal cancers, in combination with a chemotherapy involving irinotecan in addition to 5FU (fluoropyrimidine) ( (FOLFIRI) as 2nd line treatment. It is marketed in Europe and it is authorized in the United States. Its addition to this chemotherapy combination has in fact brought about a benefit in terms of progression-free survival and overall survival.

The purpose of the study is to evaluate the efficacy and tolerance of this combination rather in the initial approach to the treatment of metastatic colorectal cancers and hence to evaluate it as 1st line treatment

Detailed description:

Arms:
arm 1: FOLFIRI and aflibercept (4 mg/m²) each 14 days until progression of disease

Interventions: intervention 1: FOLFIRI Protocol intervention 2: Aflibercept Injection
Intervention descriptions: intervention 1: injection of FOLFIRI and Aflibercept every 14 days until progression of disease intervention 2: injection of FOLFIRI and Aflibercept every 14 days until progression of disease

Protocol document:
Prot_000.pdf: 
 
FFCD 1302 
Version 1.1 – 24.01.2014 
Page 1 sur 27 
 
FFCD 1302  
EFFICACY AND SAFETY OF AFLIBERCEPT IN COMBINATION WITH 
FOLFIRI CHEMOTHERAPY AS FIRST-LINE TREATMENT IN PATIENTS 
WITH METASTATIC COLORECTAL   
Phase II single-arm multicenter 
EudraCT n° 2013-004081-33 
 
 
COORDONNATOR : 
 
Pr Julien TAIEB 
HÔPITAL EUROPEEN G. POMPIDOU 
Service d'Hépato-gastro-entérologie 
20 Rue Leblanc 
75015 PARIS 
. : 01 56 09 50 42 - Fax : 01 56 09 35 29 
email : julien.taieb@egp.aphp.fr 
 
 
CO-COORDONNATOR : 
 
Dr Orianne COLUSSI 
HÔPITAL EUROPEEN G. POMPIDOU 
Service d'Hépato-gastro-entérologie 
20 Rue Leblanc 
75015 PARIS 
.. : 01 56 09 35 53 - Fax : 01 56 09 35 29 
email : orianne.colussi@egp.aphp.fr 
 
 
 
 
Study Steering commitee 
Thomas APARICIO, Orianne COLUSSI, Karine LE MALICOT, Marie MOREAU, Jean Louis LEGOUX, Julien 
TAIEB, Magali TERME, Aziz ZAANAN 
 
PROMOTOR AND CENTER OF RANDOMIZATION AND ANALYSIS (CRGA) : 
Fédération Francophone de Cancérologie Digestive (FFCD), Faculté de Médecine, 7, Boulevard Jeanne d’Arc, BP 
87900, 21079 Dijon Cedex 
 
Administrative Director : 
Cécile GIRAULT 
 
.. : 03 80 66 80 13 – Fax : 03 80 38 18 41 
 
email : cecile.girault@u-bourgogne.fr 
 
 
Statistician : 
Karine LE MALICOT 
 
.. : 03 80 39 34 71 - Fax: 03 80 38 18 41 
 
email : karine.le-malicot@u-bourgogne.fr 
 
Project Manager : 
Marie MOREAU 
 
.. : 03 80 39 34 04 – Fax : 03 80 38 18 41 
 
email : marie.moreau@u-bourgogne.fr 
 
 
 
 
Confidential 
This document is the property of the Fédération Francophone de Cancérologie Digestive and cannot - in whole or in part - be transmitted, reproduced, 
published or used without the express permission of the Fédération Francophone de Cancérologie Digestive.  


 
FFCD 1302 
Version 1.1 – 24.01.2014 
Page 2 sur 27 
TABLE OF CONTENTS 
1. 
STUDY OBJECTIVE ....................................................................................................................... 4 
1.1 
Objectif principal ..................................................................................................................................... 4 
1.2 
Objectifs secondaires ............................................................................................................................... 4 
1.3 
Exploratory study ..................................................................................................................................... 4 
2. 
PATIENTS SELECTION ................................................................................................................. 4 
2.1 
Inclusion criteria ....................................................................................................................................... 4 
2.2 
Non inclusion criteria ............................................................................................................................... 5 
3. 
INCLUSION ASSESSMENT ........................................................................................................... 5 
4. 
INCLUSION ...................................................................................................................................... 6 
5. 
STUDY SCHEMA ............................................................................................................................. 7 
6. 
TREATMENT ................................................................................................................................... 7 
6.1 
Aflibercept administration........................................................................................................................ 8 
6.2 
FOLFIRI Administration.......................................................................................................................... 8 
6.3 
Tretament modifications in case of toxicity ............................................................................................. 8 
6.3.1 
Aflibercept ....................................................................................................................................... 8 
6.3.2 
FOLFIRI ........................................................................................................................................ 10 
6.3.3 
Criteria for Stopping Chemotherapy and/or Aflibercept ............................................................... 12 
6.3.4 
Concomitant treatments ................................................................................................................. 13 
6.4 
Contraindicated treatments ..................................................................................................................... 13 
7. 
PATIENTS MONITORING .......................................................................................................... 14 
7.1 
During the treatment .............................................................................................................................. 14 
7.2 
After discontinuation of the treatment for other reason than progression .............................................. 15 
7.3 
After the treatment discontinuation for progression ............................................................................... 15 
8. 
LOGISTIC FOR ANCILLARY STUDY ...................................................................................... 15 
9. 
SERIOUS ADVERSE EVENTS (SAE) ......................................................................................... 16 
10. STATISTICAL ANALYSIS ........................................................................................................... 18 
10.1 
Judgement endpoint ............................................................................................................................... 19 
10.1.1 
Main efficacy criteria .................................................................................................................... 19 
10.1.2 
Secondary criteria .......................................................................................................................... 19 
10.2 
Sample size calculation .......................................................................................................................... 20 
10.3 
Statistical analysis plan .......................................................................................................................... 20 
10.4 
Independant commitee ........................................................................................................................... 21 
10.5 
Imaging Review Committee/Radiology Panel ....................................................................................... 21 
10.6 
Steering committee ................................................................................................................................. 21 
10.7 
Biological committee ............................................................................................................................. 21 
11. BACKGROUND INFORMATION AND RATIONALE FOR THE STUDY........................... 21 
12. BIBLIOGRAPHY ........................................................................................................................... 24 
13. ADMINISTRATIVE CONSIDERATIONS.................................................................................. 26 


 
FFCD 1302 
Version 1.1 – 24.01.2014 
Page 3 sur 27 
REVIEW AND FOLLOW-UP SCHEDULE  
 
 
 
 
 
Before Treatment 
During  Treatment  
and in case of treatment stop without porgression  
After Treatment stop after 
progression  
Within 3 weeks 
before inclusion 
Before each cycle 
Every 8 weeks  
 
End of treatment 
examination (30 days 
after last 
administration)   
Every 3 months during 2 years 
and every 6 months until death 
Clinical and bioogical consent 
X 
 
 
 
 
Clinical Examination 
 
 
 
 
 
Weight, Height, Blood pressure   
X 
X 
X 
X 
X 
OMS General Status 
X 
X 
X 
X 
X 
Toxicities NCI-CTCAE version 4.0 
X**** 
X 
X 
X 
X 
MORPHOLOGICAL EXAMINATION*** 
Spiral thoraco-abdomino-pelvic CT scan (TDM-TAP), 
with and without injection of contrast agent, performed 
at most 3 weeks before inclusion. 
In case of contraindication to iodinated contrast 
injection, a hepatic or abdominal MRI with gadolinium 
injection and a thoracic scanner without injection may 
be performed 
X 
 
X 
 
X 
BIOLOGICAL EXAMININATION 
Biology 
X* 
X** 
X* 
X** 
X** 
Pregnancy test for women in period of genital activity 
(within 7 days prior to inclusion) 
X 
 
 
 
 
CEA 
X 
 
X 
 
 
ANCILLARY STUDY 
3 heparinized blood tubes of 10 mL  
 
X (Before 1st 
cycle) 
Before the 3rd  
cycle (D28 before 
administration) 
 
 
 
Biopsies, ou bloc de tumeur, fixées en paraffine 
X 
 
 
 
 


 
FFCD 1302 
Version 1.1 – 24.01.2014 
Page 4 sur 27 
1. 
Study Objective 
The objective of the study was to evaluate the efficacy and safety of a first-line combination of FOLFIRI 
chemotherapy and aflibercept in patients with metastatic colorectal cancer (mCRC). 
1.1 
Objectif principal 
The main objective is to evaluate the rate of 6-months progression-free patients (RECIST version 1.1) according to 
the investigator. 
1.2 
Objectifs secondaires 
The secondary objectives of the study are : 
 
Overall survival: median and rates at 2, 4, 6, and 12 months; 
 
Progression-free survival: median and rates at 2, 4, 6, and 12 months; 
 
Rate of progression-free patients at 6 months according to the centralized review. 
 
Time to progression 
 
Objective response rate at 2, 4, 6 and 12 months 
 
Disease control rates at 2, 4, 6 and 12 months 
 
Best tumor response 
 
Duration of disease control (RC, RP, SD) 
 
Duration to objective response (RC, RP) 
 
Toxicity evaluated using the NCI-CTCAE scale version 4.0 
 
1.3 
Exploratory study 
Variation of cytokines and immunoregulatory cells during treatment (ancillary study). 
 
2. 
Patients selection 
2.1 
Inclusion criteria 
- Age ≥ 18 years old 
- General Status WHO ≤ 2 
- Adenocarcinoma of the rectum or metastatic colon histologically proven or on primary tumor or metastasis 
- Non-resectable metastasis(s) and/or non-operable patient 
- At least one measurable target according to RECIST version 1.1 criteria, not previously irradiated 


 
FFCD 1302 
Version 1.1 – 24.01.2014 
Page 5 sur 27 
- Lack of prior treatment for metastatic disease. Previous adjuvant chemotherapy completed 6 months or more prior 
to the diagnosis of metastasis is permitted. 
- Adequate bioassay: Hb ≥ 9 g/dl, neutrophils ≥ 1500 /mm3 , platelets ≥ 100 000/mm3 , total bilirubin ≤ 1.5 x ULN, 
creatinine clearance > 50 mL/min (Cockroft and Gault formula), PAL < 5 x ULN, ASAT and ALAT ≤ 5 x ULN, 
GGT < 5 x ULN, 
- Proteinuria on urine strip < 2+. If ≥ 2+ do 24 hrs proteinuria which must be ≤ 1 g 
- Patient who signed the informed consent 
 
2.2 
Non inclusion criteria 
- Patients with clinical symptoms (occlusion, hemorrhage) 
- Presence of brain metastases, uncontrolled spinal cord compression, carcinomatous meningitis, signs of brain or 
leptomeningeal damage. 
- Gilbert's disease 
- Uncontrolled hypercalcemia 
- Uncontrolled hypertension (PAS > 150 mmHg and PAD > 100 mmHg) or history of hypertensive crisis or 
hypertensive encephalopathy 
- Any progressive disease that has not been balanced in the last 6 months: hepatic insufficiency, renal insufficiency, 
respiratory insufficiency. 
- Myocardial infarction, severe/unstable angina pectoris, coronary artery bypass grafting, NYHA class III or IV 
congestive heart failure, stroke or transient ischemic attack within 6 months prior to inclusion. 
- Gastrointestinal bleeding/hemorrhage grade 3 or 4, treatment-resistant peptic ulcer, erosive esophagitis or gastritis, 
infectious or inflammatory bowel disease, diverticulitis, pulmonary embolism or other uncontrolled thromboembolic 
event, unhealed bone fractures in the 3 months prior to inclusion 
- Major surgery within 28 days prior to the start of treatment 
- Known acquired immunodeficiency syndrome (AIDS-related illnesses) or known HIV infection requiring 
antiretroviral treatment 
- Treatment with CYP3A4 inducers, unless stopped for more than 7 days 
- History of haemopathic malignancy or cancer (except those treated for more than 5 years and considered cured), 
carcinoma in situ of the uterine cervix and skin cancer treated (melanoma excluded) 
- Lack of effective contraception in patients (male and/or female) of childbearing age, pregnant or breastfeeding 
women, women of childbearing age who have not had a pregnancy test. 
- Any contraindications to the drugs used in the study 
- Impossibility to undergo the medical follow-up of the trial for geographical, social or psychological reasons. 
- Patients on newer oral anticoagulants (such as rivaroxaban XARELTO® , apixaban ELIQUIS® , dabigatran 
PRADAXA® ) unless relayed by VKA 
 
3. 
INCLUSION ASSESSMENT  
The inclusion assessment must be completed within 3 weeks prior to inclusion and includes: 
 
 
Full clinical examination : 


 
FFCD 1302 
Version 1.1 – 24.01.2014 
Page 6 sur 27 
o 
- Weight, height, body surface area 
o 
- Blood pressure (SBP and DBP) 
o 
- General status WHO 
o 
- Search for pre-existing symptoms at inclusion 
 
Biological assessment : 
o 
- Hemoglobin (hemoglobin, PNN, platelets), creatinine, blood ionogram, magnesemia, serum calcium, PT, 
albuminemia, total, free and conjugated bilirubinemia, transaminases, alkaline phosphatases, LDH, proteinuria 
(urine test strip) and 24-hour proteinuria if test strip > 2+, INR for patients on VKA. 
o 
- Marker: ACE 
o 
- Pregnancy test for women in period of genital activity (within 7 days prior to inclusion) 
o 
- Specimen for the biological ancillary study if the patient has signed the biological consent form. 
 
Morphological evaluation of the tumor : 
o 
- Spiral thoraco-abdomino-pelvic CT scan (TDM-TAP), with and without injection of contrast agent, performed 
at most 3 weeks before inclusion. 
o 
In case of contraindication to iodinated contrast injection, a hepatic or abdominal MRI with gadolinium injection 
and a thoracic scanner without injection may be performed. 
o 
Morphological examinations should be the same throughout the follow-up of the patient. 
o 
Make a copy of the images which will be sent to the CRGA of the FFCD for centralized proofreading. 
 
Ancillary biological study on the prognostic value of Treg lymphocytes, monocytes, dendritic cells, pro-angiogenic 
factors (cf chapter 8), PlGF : 
o 
- 3 heparinized blood tubes of 10 mL (supplied by the Promoter) 
- 
before the first treatment (inclusion assessment or day of the first treatment before administration 
of the treatment) 
- 
before the 3rd cure (D28 before administration of the treatment) 
- Kerosene biopsies or tumor blocks for immunohistochemistry (PlGF) (prior to treatment administration). 
 
 
4. 
INCLUSION 
The inclusion will be made by the CRGA of the FFCD after receipt of the fax of inclusion (form 1 of the observation 
book) at 03 80 38 18 41. The CRGA is open from Monday to Friday from 9am to 6pm. 
A confirmation of inclusion will be faxed back to the investigator. 
After inclusion of the patient in the study, treatment should begin within 10 days. 
An observation notebook will be sent at the opening of the center. A new observation notebook will then be sent after 
each inclusion. 
The first inclusion in a center will trigger the sending of the aflibercept treatment. The management of the aflibercept 
stock for the subsequent inclusions will be done by the pharmacy of the center. The treatment will be sent by LC2, 
the company responsible for the distribution. 
 
 


 
FFCD 1302 
Version 1.1 – 24.01.2014 
Page 7 sur 27 
5. 
STUDY SCHEMA  
 
 
 
6. 
TREATMENT 
In this academic research, drugs from FOLFIRI administrations (drugs with MA used in their indication), and support 
drugs will be taken from hospital stock in accordance with article L1121-16-1 of the Public Health Code. 
Aflibercept will be provided free of charge by Sanofi as part of the study, and will be distributed by LC2. 
Product traceability will be ensured by pharmacies. 
 
 
 
 
 
 
 
 
 
 
5 FU bolus 
400 mg/m² 
Acide folinique 
400 mg/m² (or 200 mg/m² 
if Elvorine) 
5 FU continu 
2400 mg/m² 
2 h 
46 h 
< 10 minutes 
Aflibercept 
4 mg/kg 
1 h 
1 h 
Irinotécan 
180 mg/m² (IV 90 
min in Y AF) 


 
FFCD 1302 
Version 1.1 – 24.01.2014 
Page 8 sur 27 
6.1 
Aflibercept administration 
Aflibercept [25 mg/mL IV infusion solution - 8 mL vials (200 mg/vial)] should be administered at the start of each 
chemotherapy course. The vials should be stored in the original package in a refrigerator at 2-8°C and protected from 
light. 
Aflibercept should be administered at 4 mg/kg and should be diluted directly in the infusion bag with 0.9% sterile 
sodium chloride or G5%. Diluted solutions should be administered using infusion sets with a 0.2 micron polyether 
sulfone filter. Infusion sets should be made of one of the following materials: polyvinyl chloride (PVC) containing 
bis(2-ethylhexyl) phthalate (DEHP), non-DEHP PVC containing trioctyl trimellitate (TOTM), polypropylene, PVC 
coated internally with polyethylene or polyurethane. Please note: Polyvinylidene fluoride (PVDF) or nylon filters 
should not be used. 
The solution must be prepared in a sterile environment. 
Aflibercept will be administered within 1 hour. The preparation should not exceed 2 hours at room temperature 
(25°C). 
 
6.2 
FOLFIRI Administration 
Irotecan will be administered IV at a dose of 180 mg/m² as a 90-minute infusion and folinic acid Y infusion. 
Folinic acid will be administered IV at a dose of 400 mg/m² (or 200 mg/m² if Elvorine) as a 2-hour infusion in 250 
mL of G5%. 
The 5 FU bolus will be administered in less than 10 minutes at 400 mg/m² in 100 mL of G5%. 
The continuous 5 FU will be administered IV at a dose of 2400 mg/m² over 46 hours in G5% (qsp 230 mL, 5 mL/h). 
 
6.3 
Tretament modifications in case of toxicity 
6.3.1 Aflibercept 
In the case of aflibercept toxicity, dose adjustments should be made based on the highest observed toxicity grade on 
the NCI-CTCAE version 4.0 scale (Appendix 6). 
 
If the patient has multiple toxicities, dose titration should be based on the highest toxicity. 
Once the dose is decreased, no dose increase is permitted. 
Aflibercept will be administered if PNN > 1500/mm3 and platelets > 100,000/mm3 and after recovery to a grade < 
1 for any other toxicity (except alopecia). In febrile neutropenia or neutropenic sepsis: In the event of recurrence after 
decreasing the dose of irinotecan and 5FU, consideration may be given to reducing the dose of aflibercept to 2 mg/kg 
(see Product recommendations). 
 
Toxicity 
Grade 
(NCI-CTCAE 
version 4.0) 
Action 
Hypertension 
Grade < 2 
Start or modify antihypertensive treatment if necessary. 
No dose modification, no postponement of treatment. 
Grade 3 
(nécessitant plus 
d’un traitement 
antihypertenseur ou 
nécessitant 
d’intensifier le 
traitement 
antihypertenseur) 
 
Postpone administration of FOLFIRI and aflibercept 
(maximum 2 weeks) until recovery of BP (blood pressure) 
< 140/90 or to a MAP < 160 if MAP < 90 for patients with 
a known history of isolated systolic hypertension : 
o - If BP is controlled within 2 weeks of 
postponement 
 
1st event: Re-administer FOLFIRI and aflibercept at the 
same dose. 
 
2nd Episode: Re-administer FOLFIRI at the same dose 
and re-administer aflibercept at 2 mg/kg 


 
FFCD 1302 
Version 1.1 – 24.01.2014 
Page 9 sur 27 
 
3rd event: definitive stop of aflibercept, resumption of 
FOLFIRI 
 
- If after 2 weeks of delay, BP is still not controlled despite 
antihypertensive treatment: resume FOLFIRI at the same 
dose and stop aflibercept for one cycle of FOLFIRI (14 
days). Re-evaluate BP at the next cycle and restart 
aflibercept at 2 mg/kg if BP is controlled. 
 
If Grade 3 recurs despite optimal antihypertensive therapy 
and dose reduction of aflibercept, or if BP is still not 
controlled despite a 2-week delay of aflibercept (4 weeks 
after last administration): DEFINITIVE STOP of 
aflibercept. FOLFIRI can be continued. 
 
Grade 4 
When hypertension is accompanied by symptoms of organ 
failure such as hypertensive retinopathy, impaired renal 
function (such as increased proteinuria), symptoms of 
cardiovascular or central nervous system morbidity, 
aflibercept should be discontinued. 
DEFINITIVE discontinuation of aflibercept and Cardiac 
Advice  
Arterial 
thromboembolic 
event 
Whatever the grade 
is 
DEFINITIVE discontinuation of aflibercept 
Venous 
thromboembolic 
event 
Grade 3 
Episode 1: Heparin therapy and continuation of ablibercept1 
2nd episode despite appropriate anticoagulant treatment: 
DEFINITIVE STOPPING of aflibercept 
Grade 4 
DEFINITIVE STOPPING of aflibercept 
Haemorraghe  
Grade 3-4 
DEFINITIVE STOPPING of aflibercept 
Intestinal 
Perforation i/ 
intestinal fistul  
Whatever the grade 
is 
DEFINITIVE STOPPING of aflibercept 
Posterior 
Leucoencephalopat
hy postérieure   
Whatever the grade 
is 
DEFINITIVE STOPPING of aflibercept 
 
 
Proteinuria 
A urine test strip should be performed before each administration of aflibercept (proteins, red blood cells, 
leukocytes): 
- If proteinuria is < 2+ and there is no hematuria, aflibercept may be administered 
- If proteinuria is > 2+, do not administer aflibercept and reinstate it as soon as 24-hour proteinuria is < 2 g. If 
proteinuria > 2 g/24 reappears, aflibercept should be suspended until 24-hour proteinuria < 2 g and reintroduced at 
2 mg/kg 
Aflibercept should be permanently discontinued if the patient develops nephrotic syndrome or thrombotic 
microangiopathy, suspected on proteinuria-hematuria combination. 
 
 


 
FFCD 1302 
Version 1.1 – 24.01.2014 
Page 10 sur 27 
Hypersensibility reaction to aflibercept 
 
Symptom severity 
Recommandation 
Light and moderate 
Example: Grade < 2: skin reaction, pruritus, 
flush, rash, dyspnea, tachycardia, hypotension, 
anxiety, headache, myalgia, edema, nausea 
SUSPEND the aflibercept infusion 
- 
Administer diphenydramine 50 mg IV and/or 
dexamethasone 10 mg IV 
- 
Resume aflibercept infusion after recovery 
Severe 
Example: symptomatic bronchospasm, 
generalized urticaria, SBP < 80 mmHg, 
angioedema, anaphylaxis 
STOP the aflibercept infusion. 
- 
Administer diphenydramine 50 mg IV and/or 
dexamethasone 10 mg IV and/or epinephrine if 
necessary 
- 
DEFINITIVE STOP of aflibercept 
Non-healed 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 (e.g., chamber placement, biopsies, tooth extraction), aflibercept can be reintroduced as soon 
as healing is complete. 
Aflibercept should be permanently discontinued if there is an open wound or a non-healing wound requiring medical 
intervention. 
. 
6.3.2 FOLFIRI 
Before each treatment we will check: blood count, creatinine, proteinuria (urine test strip) and 24-hour proteinuria if 
test strip > 2+. Chemotherapy will be started if : 
- PNN 1,500/mm3 
- 100,000/mm3 wafers 
- Hemoglobin 9 g 
The chemotherapy cure will be delayed by one week: in case of moderate hematological toxicity (PNN < 1,500/mm3 
and/or platelets < 100,000/mm3), persistent digestive toxicity (oral ulcerations, diarrhea, or grade 3-4 esophagitis). 
The dose of 5FU will then be modified according to the instructions in Tables 1 and 2. 
If creatinine levels are elevated, further investigations will be carried out by the investigator who will judge whether 
additional therapeutic measures should be taken or whether progression under treatment should be diagnosed. 
Chemotherapy toxicities are assessed using the NCI-CTCAE version 4.0 scale. 
 
. 


 
FFCD 1302 
Version 1.1 – 24.01.2014 
Page 11 sur 27 
Table 1 : 
Adaptation of the dose of FOLFIRI according to the maximum toxicity on the day of the 
treatment or in between treatments.   
 
Grade 
(NCI-CTCAE version 4.0) 
5Fluorouracile 
Irinotécan 
Neutropenia, thrombopenia 
Grade 2 
 
Grade 3 
 
 
Grade 4 
 
 
 
- 
50% reduction of the bolus 
- 
Elimination of the bolus, 25% 
reduction of the continuous 5FU 
- 
Elimination of the bolus, 25% 
reduction of the continuous 5FU 
 
- No change 
 
- No change 
 
 
- 25% discount 
 
Febrile neutropenia 
 
Grade 3 
 
 
Grade 4 
 
 
Elimination of the bolus + G-CSF and if reccurence then definitive stop 
 
 
Adaptation according neutropenia grade 
Diarrhea despite a treatment 
Grade 2 
Grade 3 
 
Grade 4 
 
- 50% reduction of the bolus 
- 
50% 
bolus 
reduction, 
25% 
continuous 5FU reduction 
- Stop Chemotherapy 
 
 
- 
25% discount 
- 
25% discount % 
 
- 
Stop Chemotherapy 
Mucitis 
Grade 2 
Grade 3 
 
Grade 4 
 
- 
50% reduction of the bolus 
- 
Stop bolus, reduction de 25% of 
5FU continu 
- 
Stop Chemotherapy 
 
- 
No modification 
- 
No modification 
 
- 
Stop Chemotherapy 
Vomiting 
Grade 3 
Grade 4 
 
- 
No modification 
- 
Stop Chemotherapy 
 
- 
Réduction de 25 % 
- 
Stop Chemotherapy 
Hand-foot syndrome 
Grade 2 
Grade 3 
 
- 
25 % reduction of 5FU continu 
- 
50% reduction of the bolus, 50% 
reduction of the 5FU continu 
 
- 
No modification 
 
- 
No modification 
Toxicité non hématologique en 
dehors de l’alopécie 
Grade 3 
 
Grade 4 
 
 
- 
25 % reduction of 5FU continu and 
of the bolus 
- 
Stop Chemotherapy 
 
 
- 
25% discount  
- 
Stop Chemotherapy 
  
 
 


 
FFCD 1302 
Version 1.1 – 24.01.2014 
Page 12 sur 27 
 
Table 2 : 
Adaptation of the doses of 5-FU and irinotecan after a 2nd episode of toxicity, after a 1st dose 
reduction and a further postponement of one week.    
TOXICITY 
5-FU 
Irinotécan 
PNN  1400, platelets  90 000 
No bolus 
No modification 
1000  PNN < 1400 and/or 75 000  platelets < 90 000 
 
No bolus and 
75 % of 
continous IV 
Reduction of 
25 % 
Persisting digestive tox* of grade 1 or 2 isolated  
50 % of 
continous IV 
Reduction of 
25 % 
PNN < 1000 and/or platelets < 75000 
and/or persisting digestive toxicity* grade 3-4 
No 5FU and 
postponed of 8 
days 
No irinotecan 
Grade 4 febile neutropenia, grade 4 neutropenia (PNN < 500),  
thrombopenia 3-4 (<50000) and/or digestive toxicity* grade 3-4 
No bolus and 
50 % of 
continous IV 
Reduction of 
40 % 
  
No modification of folinic acid. 
 
6.3.3 Criteria for Stopping Chemotherapy and/or Aflibercept  
- 
Major toxicity requiring the definitive cessation of treatment: 
If aflibercept toxicity requires discontinuation for 4 or more consecutive weeks (i.e., a margin of 2 days for each 7-
day delay 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 the event of discontinuation of aflibercept due to an intercurrent event (radiotherapy, hospitalization for 
reasons other than toxicity, etc.), the investigator will decide whether or not to restart aflibercept. The 
treatment will then be collected as part of the study (in the CRF). 
 
Aflibercept can be stopped immediately and permanently at the investigator's sole discretion, if the 
investigator considers it necessary for the patient. 
- 
If aflibercept is delayed or discontinued, concomitant chemotherapy (FOLFIRI) may be continued as described in 
this protocol. 
- 
If FOLFIRI is discontinued, aflibercept will be stopped (no monotherapy administration). 
- 
If chemotherapy is postponed for one to three weeks, aflibercept will also be postponed and will be resumed at the 
same time as the chemotherapy according to the protocol. Chemotherapy toxicity assessment for deferral should 
be done weekly to avoid unnecessary delays in resumption. 
- 
Chemotherapy may be stopped if the patient refuses to continue at his or her request or withdraws consent (to be 
documented). 


 
FFCD 1302 
Version 1.1 – 24.01.2014 
Page 13 sur 27 
- 
A patient will stop chemotherapy following a life-threatening toxic reaction in the opinion of the patient's 
physician. 
- 
Progressive illness. 
Patients will be monitored until death and types of treatment will be collected after progression under the first 
line of treatment. 
 
6.3.4 Concomitant treatments 
 
Treatments considered necessary for the patient's well-being may be administered at the discretion of the investigator. 
Primary prevention of chemo-induced nausea and vomiting (AFSOS recommendations) : 
On D1 of chemotherapy 
- anti-5HT3: Odansetron (Zophren) IV 8 to 16 mg; 30 minutes before, 
- Aprepitant (Emend): per os, 125 mg, 1 hour before, 
- Dexamethasone: IV 8 to 16 mg or methylprednisolone hemisuccinate 80 mg IV. 
After chemotherapy 
- Aprepitant per os: 80 mg in the morning of D2 and D3. 
Primary prevention of mucites (AFSOS recommendations) : 
Prescriptions of mouthwashes : 
- Sodium bicarbonate 1.4% pure, without addition of any other product. As often as possible, minimum 8 to 10 times 
a day, in gargle and at a distance from meals. Oral hygiene advice (soft toothbrush). 
Primary prevention of diarrhea : 
- Hygieno-dietary rules: diet low in residues and good oral hydration. 
- In case of acute non-febrile diarrhea: loperamide 4 mg then 2 mg/2 h during at least 12 h after the last liquid stool, 
without exceeding 48 h. 
Atropine, 0.25 mg SC is authorized before the infusion of irinotecan, for the prevention of acute cholinergic 
syndrome. 
In case of anemia, it will be treated according to its mechanism: spoliation, inflammatory or by spinal cord 
insufficiency. 
The subcutaneous administration of growth factor is authorized: 
- as a curative treatment for 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 Grade 3-4 
concurrent neutropenia, Grade 4 neutropenia > 7 days. A growth factor will be used for all subsequent cycles. 
 
6.4 
Contraindicated treatments 
With 5 FU: yellow fever vaccine, live attenuated vaccines, prophylactic phenytoin.  


 
FFCD 1302 
Version 1.1 – 24.01.2014 
Page 14 sur 27 
7. 
PATIENTS MONITORING 
7.1 
During the treatment 
- 
Before each chemotherapy treatment : 
 
Clinical examination: weight, body surface area, WHO general condition, blood pressure 
 
Biological assessment: CBC, platelets, creatinine, proteinuria (urine test strip) and 24-hour 
proteinuria if test strip > 2+, INR strongly recommended for patients on VKA. 
 
Toxicity evaluation according to NCI-CTCAE version 4.0 
 
For patients participating in the ancillary biological study : 
 
Sampling of 3 heparinized tubes of blood of 10 mL before the 3rd treatment (J28 before 
administration) 
- 
Every 8 weeks, even if the cures for toxicity are spaced out: 
 
Clinical examination: weight, body surface area, WHO general condition, blood pressure 
 
Laboratory workup: Hemoglobin (hemoglobin, PNN, platelets), creatinine, blood ionogram, 
magnesemia, serum calcium, PT, albuminemia, total, free and conjugated bilirubinemia, 
transaminases, alkaline phosphatases, LDH, proteinuria (urine test strip) and 24-hour proteinuria 
if test strip > 2+, INR for patients on VKA. 
 
Toxicity evaluation according to NCI-CTCAE version 4.0 
 
Morphological evaluation of the disease (every 8 weeks even after cessation of treatment for 
toxicity, in order to highlight the date of progression): 
- 
Spiral thoraco-abdomino-pelvic spiral CT scan (TDM-TAP), with and without contrast agent 
injection 
- 
In case of contraindication to the injection of iodinated contrast, hepatic or abdominal MRI 
with gadolinium injection and thoracic scanner without injection. 
 
FOR CENTRALIZED REVIEW: 
During the first 12 months, do not forget to keep on CD a copy of each morphological evaluation and the 
corresponding report (i.e. 6 evaluations + inclusion imaging). 
The ARC FFCD will take care of making an anonymized copy of these imaging reports to centralize them at the 
CRGA on the "FFCD Images" platform using a secure transmission via the company ETIAM. 
. 


 
FFCD 1302 
Version 1.1 – 24.01.2014 
Page 15 sur 27 
7.2 
After discontinuation of the treatment for other reason than progression  
Patients will be seen again in consultation 30 days +/- 2 days after stopping the treatment: 
- 
Clinical examination (weight, general condition WHO, BP) 
- 
Evaluation of toxicities 
- 
Bioassay: CBC, platelets, creatinine, proteinuria (strip) + 24-hour proteinuria if ≥ 2+, INR highly 
recommended for patients on VKA 
 
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 
- 
Complementary examinations required by their new treatments 
- 
Evaluation of 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 until 
death. 
 
WARNING: Patients of childbearing age must continue to use effective contraception for at least 6 months after 
discontinuation of treatment. 
7.3 
After the treatment discontinuation for progression  
Patients will be seen for consultation 30 days after discontinuation of study treatment: 
- 
Clinical examination (weight, general condition WHO, BP) 
- 
Evaluation of toxicities 
- 
Bioassay: CBC, platelets, creatinine, proteinuria (strip) + 24-hour proteinuria if ≥ 2+, INR highly 
recommended for patients on VKA 
After progression, patients will be seen in consultation every 3 months for 2 years and then every 6 months until 
death with : 
- 
Clinical examination with search for late toxicities of the first line treatment 
- 
Complementary examinations required by their new treatments 
 
CAUTION: Patients of childbearing potential should continue to use effective contraception for at least 6 months 
after discontinuation of therapy. 
 
8. 
LOGISTIC FOR ANCILLARY STUDY 
Study of Treg lymphocytes, monocytes, dendritic cells, PlGF and proangiogenic factors on blood and biopsies 
BLOOD 
3 heparinized tubes of 10 mL blood 
- 
Before the first treatment course (on the day of the inclusion test or on the day of the first treatment course 
before administration of the treatment) 
- 
Before the 3rd chemotherapy treatment (D28 before treatment administration) 
Sending Kit 
Sampling kits will be sent at the opening of each center (2 DHL boxes each containing 3 heparinized 10 mL tubes 
and the ad hoc forms). Please use the DHL boxes containing the delivery slip to the INSERM unit for study FFCD 
1302.  After each shipment of DHL boxes, a new DHL box will be sent. 
 
 


 
FFCD 1302 
Version 1.1 – 24.01.2014 
Page 16 sur 27 
These samples will be sent at room temperature by specialized carrier (DHL) to  
: 
Dr Magali TERME 
Unité INSERM U970, équipe 10 
PARCC-HEGP 
56, rue Leblanc 
75015 PARIS 
The delivery time should be 24 hours, with pick-ups in the morning and DHL pick-up in the afternoon to allow 
delivery the next morning. 
NO PICK-UP OR SHIPMENT ON FRIDAYS. 
These samples will be analyzed upon receipt and no banking will be done.. 
 
BIOPSY/TUMOR SAMPLE 
2 to 3 paraffin-embedded diagnostic biopsies or 1 paraffin-embedded tumor block 
Sending Kit 
After receipt of the form indicating the number of biopsies or tumor blocks to be sent, you will receive a prepaid 
max letter that will allow the shipment of the samples. 
These samples will be sent to: 
Dr Magali TERME 
Unité INSERM U970, équipe 10 
PARCC-HEGP 
56, rue Leblanc 
75015 PARIS 
9. 
SERIOUS ADVERSE EVENTS (SAE) 
Security Assessment Parameters 
 
Safety evaluation will be done by assessing the general and clinical condition of patients and by collecting events 
occurring between visits during consultations, through regular blood tests. Toxicities will be assessed using the NCI-
CTCAE Toxicity Scale version 4.0 (Appendix 6). 
In the event of an emergency, the patient, his/her relatives or attending physician should call the investigator to inform 
him/her of an event. 
 
Definitions 
 
a. 
Adverse Event (AE) 
An adverse event is a harmful occurrence in a person who is involved in biomedical research, whether or not that 
occurrence is related to the research or the product that is the subject of the research. 
All adverse events will be recorded in the case report book on the pages provided. 
b. 
Serious Adverse Event (SAE) 
A serious adverse event is considered to be any event that 
- 
Leading to death, 
- 
Involving the vital prognosis, 


 
FFCD 1302 
Version 1.1 – 24.01.2014 
Page 17 sur 27 
- 
Resulting in hospitalization or an extension of hospitalization, 
- 
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 mental handicap that is 
clinically significant and affects the patient's physical activity and/or quality of life. 
Any clinical event or laboratory result that is considered serious by the investigator and that does not meet the criteria 
for seriousness 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 severity criteria mentioned above (examples: 
overdoses, second cancers, pregnancies and new developments may be considered medically significant). 
c. 
Undesirable Effect 
Any noxious and unintended response to an experimental drug at any dose or to any experimental component. An 
adverse reaction is serious if it meets a severity criterion. 
d. 
Undesirable Effect Serious Unexpected Serious 
An unexpected serious adverse reaction is an event not mentioned, or different in nature, intensity, or evolution from 
the product's reference document (or RCPs). 
e. 
New development 
A new fact may be: an unexpected frequency of an expected SAE, a SAE related to the trial procedure, insufficient 
efficacy in life-threatening diseases, clinical data. 
f. 
Intensity (or severity) 
The intensity criterion should not be confused with the severity criterion, which serves as a guide for defining 
reporting obligations. 
The intensity of events will be estimated according to the extract of the CTC-AE classification version 4.0 (Appendix 
6). The intensity of adverse events not listed in this classification will be assessed according to the following 
qualifiers: 
- 
Mild (grade 1): does not affect the patient's usual daily 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): imposes resuscitation measures / threatens the life prognosis 
- 
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 study product 
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. 
Sponsor's responsibility 
Upon receipt of the serious adverse event report established by the investigator, the sponsor should provide 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 the sponsor to one of the study products (i.e., it is a 


 
FFCD 1302 
Version 1.1 – 24.01.2014 
Page 18 sur 27 
serious adverse event), the investigator and/or the sponsor should establish the expected or unexpected nature of the 
serious adverse event. 
If it is an unexpected serious adverse event, or if it is a new development, the sponsor prepares an initial report that 
will be sent to the ANSM, the CPP and the EMA (via EudraVigilance) within 7 days in the case of death or life-
threatening events, otherwise within 15 days. 
If it is an expected serious adverse reaction, it will be collated for the drafting of semi-annual and annual safety 
reports. 
 
Events not to be considered as serious  
 
The progression of the disease should not be considered as a SAE. 
Events potentially related to the progression but which may also be secondary to the treatment will continue to be 
reported (e.g. thromboembolic events, haemorrhagic phenomena, perforations, etc.). 
Because of the seriousness of the disease in this study, certain conditions defined as SAEs will be excluded from the 
procedure for declaring a SAE, namely : 
- 
Hospitalization or surgery specifically related to the treatment of the disease 
- 
Hospitalization performed to simplify treatments or study procedures 
In this essay the reference documents will be : 
- 
For aflibercept, the Investigator's Brochure (provided in the Investigator's Binder) 
- 
For 5-fluorouracil, the Summary of Product Characteristics of Fluorouracil Ebewe® 50 mg (Appendix 7) 
- 
For Folinic Acid, the ELVORINE® Summary of Product Characteristics (Appendix 7) 
- 
For irinotecan, the Summary of Product Characteristics of Campto® (Appendix 7) 
The versions of the PCRs used to define the expected or unexpected character will be the latest available on the 
anniversary date of the trial start. 
Course of action 
The investigator informs the sponsor of all Serious Adverse Events (Expected and Unexpected), whether or not they 
are attributable to the research, that occur during the study or within 30 days after the last administration of treatment. 
All delayed Serious Adverse Events (occurring after this 30-day period) considered reasonably related to the protocol 
treatment(s) or research must be reported without time limitation. 
The report shall be made by faxing the "notification of a serious adverse event" form (Appendix 8), documented as 
precisely as possible, dated and signed, within 24 working hours following their observation to the Centre de 
Randomisation Gestion Analyse (CRGA) of the FFCD: by fax to 03 80 38 18 41. 
The investigator is responsible for the appropriate medical follow-up of patients until the resolution or stabilization 
of the effect or until the death of the patient. This may sometimes imply that this follow-up continues after the patient 
is discharged from the trial. 
Additional information is sent to the sponsor using an SAE reporting form (by checking the "Follow-up" box and 
incrementing the number to indicate that it is a follow-up report and not an initial report) within 24 hours of receiving 
it. It also transmits 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 


 
FFCD 1302 
Version 1.1 – 24.01.2014 
Page 19 sur 27 
10.1 
Judgement endpoint 
10.1.1 Main efficacy criteria 
 
The primary endpoint is the investigator's rate of alive and progression-free patients at 6 months. 
Progression is defined by : 
- 
Progression assessed by CT scan, according to the RECIST version 1.1 criteria. 
- 
Death from any cause 
 
10.1.2 Secondary criteria 
Secondary criteria are : 
- 
Overall survival is defined as the time from the date of inclusion of the patient to the patient's death, or the 
date of last news if the patient is alive. 
- 
Alive and progression-free rate at 6 months (RECIST version 1.1) based on centralized review. 
- 
Progression-free survival is defined as the time from the inclusion date to the date of first radiological 
progression as assessed by the investigator using the RECIST version 1.1 criteria or death (from any cause) 
or the latest news date if the patient is alive and progression-free. 
Overall survival and progression-free survival will be estimated at 2, 4, 6 and 12 months after inclusion and medians 
will also be estimated. 
- 
Time to progression is defined as the time from the inclusion date to the date of progression as assessed by 
the investigator using the RECIST criteria version 1.1. 
- 
Objective response rate (OR and OR) is defined as the number of patients with OR or OR, as assessed by the 
investigator using RECIST criteria version 1.1 at 2, 4, 6 and 12 months. 
- 
Time to objective response (CR and PR) is defined as the time from the date of inclusion to the date of 
complete or partial response, as assessed by the investigator using RECIST criteria version 1.1. 
- 
The rate of disease control (CR, PR and SD) is defined as the number of patients with CR, PR or stable 
disease, as assessed by the investigator using RECIST criteria version 1.1 at 2, 4, 6 and 12 months. 
- 
Duration of disease control is defined as the time from the inclusion date to the date of first progression in 
patients with a complete response, partial response or stable disease, as assessed by the investigator using 
RECIST criteria version 1.1. 
- 
The rate of live, progression-free patients at 6 months, as assessed by central review. 
- 
Rate of best response (CR, RP, SD or P), as assessed by the investigator using RECIST version 1.1 criteria. 
- 
Toxicities will be described according to the NCI-CTCAE classification version 4.0 and according 
to grades. 


 
FFCD 1302 
Version 1.1 – 24.01.2014 
Page 20 sur 27 
 
10.2 
Sample size calculation 
The endpoint was the rate of 6-months progression-free patients and the assumptions were as follows : 
H0: rate of 6-months progression-free patients of 55% or less is insufficient; 
H1: rate of 6-months progression-free patients greater than 55% would justify the efficacy of the treatment; a rate of 
75% is hoped for. 
With a risk of  one-sided alpha error of 5% and a power of 90%, using Simon's 2-step method (Minimax), it was 
required to include 49 patients. With a 10% rate of patients lost to follow-up, 54 patients were to be included. 
Step 1 : Over 33 first patients 
- 
If 20 or less than 20 patients are alive without any progression at 6 months, the study will be stopped ; 
- 
If 21 or more than 21 patients vivants are alive without any progression at 6 months, study will continue 
Inclusion will be stopped between step 1 and 2. 
At the end of step 2, over 49 patients 
- 
If 32 or less than 32 patients are alive without any progression at 6 months, the treatemnt will be considered as 
inefficient  
- 
 If 33 or more than 33 patients are alive without any progression at 6 months, the treatemnt will be considered 
as efficient  
 
The analysis of the primary endpoint will be performed in terms of intention to treat for all evaluable patients 
included in the study regardless of eligibility criteria and treatment received. 
 
The decision rules may be adapted according to the actual number of patients included in the trial. 
 
Patients not evaluated at 6 months will be reviewed according to the following rules: 
- If the patient has a later evaluation (7 months or more) and is not progressing at that time then he will be 
considered progression-free at 6 months. 
- If the patient has a documented progression within 2 months after 6 months then this patient will be considered to 
be progressing at 6 months. If the progression is documented beyond 8 months then the patient will not be 
considered progressive at 6 months. 
If a progression is documented prior to the 6-month assessment, the patient is considered to be progressing at 6 
months. 
A patient who has not had an assessment for more than 12 months is considered lost to follow-up. 
 
10.3 
Statistical analysis plan 
Populations   
The patients included in the study will be described. 
Analyses will be performed with intent to treat (ITT): all patients included in the study regardless of eligibility criteria 
and treatment received. 


 
FFCD 1302 
Version 1.1 – 24.01.2014 
Page 21 sur 27 
A per-protocol analysis (PP) of the primary endpoint will also be performed. The IP population is defined as ITT 
patients without major protocol violations, having received at least one dose of treatment and having at least one 
tumor evaluation within 6 months of treatment. 
Safety evaluable population: the ITT population having received at least one dose of treatment.Analyses principales 
 
A statistical analysis plan will be written before the database is frozen. 
Clinical variables will be described using percentages (95% confidence interval), mean (standard deviation) and 
median (Q1, Q3, Interquartile Interval, minimum and maximum). 
Survival and time estimation will be done using the Kaplan Meier (KM) method. They will be described by medians 
and rates at different temporalities with their 95% confidence intervals. 
The median follow-up time will be calculated using the reverse KM method. 
10.4 
Independant commitee 
An independent committee will be formed and will include at least two physicians, a statistician and a 
pharmacovigilance expert. The independent committee will meet every 6 months during the treatment period to 
decide on the tolerance data. It may be consulted at any time during the protocol when the sponsor deems it necessary. 
10.5 
Imaging Review Committee/Radiology Panel 
Anonymized copies of the evaluation reports will be centralized at the CRGA on the "FFCD Images" platform using 
a secure transmission via ETIAM. 
They will be reviewed at a later date by a panel of independent radiologists, who will confirm answers and progress 
dates once all of the study's exams have been retrieved. 
10.6 
Steering committee 
A Steering Committee will be set up. It will be chaired by the coordinator of the study, Pr. Julien TAIEB. This 
committee will also include the president of the SDFC, the SDFC statistician and the president of the Biological 
Research Committee (if applicable). Its mission will be, among others, to take decisions related to the management 
of the research (amendment, premature closure if necessary, ...). 
  
10.7 
Biological committee 
 
A Biological Research Committee will be established and its mission will be to manage problems related to sampling 
and banking as well as the organization of their analysis. The committee will meet regularly and will report on its 
proposals to the Board of Directors. This committee will include among others the study coordinator and a biologist; 
the president of this committee will be Dr. Magali TERME. 
11. 
BACKGROUND INFORMATION AND RATIONALE FOR THE STUDY  
 
Colorectal cancer is the 3rd most common cancer. In 2008, 1.24 million new cases were diagnosed worldwide and 
mortality due to this cancer was over 600,000 1(Ferlay 2010). The prognosis depends mainly on the extension of the 
disease to diagnosis. The 5-year survival rates are approximately 90% for localized stages at diagnosis, 60-65% in 
case of lymph node or neighbor organ invasion and only 5-8% in case of distant metastasis2 (Chu 2011). Despite the 


 
FFCD 1302 
Version 1.1 – 24.01.2014 
Page 22 sur 27 
fact that 75-80% of tumors are resectable at the time of diagnosis, nearly half of the patients will develop metastatic 
disease. Although mortality rates have been reduced due to new treatment options, once the metastatic stage is 
reached, median overall survival is a maximum of 24 months. The median survival was 21.5 months in patients 
treated with FOLFIIRI in the first line and then FOLFOX6 in the second line (n=109) and 20.6 months in patients 
treated with FOLFOX6 and then FOLFIRI (n=111), 3(Tournigand, 2004). 
 
 At the metastatic stage, one of the current therapeutic options is dual cytotoxic chemotherapy (FOLFIRI or 
FOLFOX) combined with targeted therapy (bevacizumab or anti-EGFR in the case of wild type KRAS status). 
Bevacizumab is a humanized monoclonal antibody that targets VEGF-A. It has shown a benefit in terms of 
progression-free survival (PFS), and less consistently in overall survival (OS), in first-line combination with 
FOLFOX or FOLFIRI 4-6 (Saltz 2008, Hurwitz 2004) and in second-line combination with FOLFOX 7 (Giantonio, 
2005). Cetuximab is a chimeric anti-EGFR. The Phase III CRYSTAL study comparing FOLFIRI with and without 
cetuximab in the first line showed an improvement in response rate and PFS in patients who received cetuximab8 
(Van Cutsem 2007). However, in this study there was no statistically significant difference between the 2 arms in 
overall survival. Patients with KRAS mutations do not benefit from treatment with cetuximab in combination with 
either FOLFOX or FOLFIRI9, 10 (Van Cutsem 2008, Bokemeyer 2009). In a study comparing these targeted therapies 
combined with FOLFIRI as a first-line treatment for mRCC, objective response rates (evaluated according to RECIST 
criteria) of 44% to 48% and progression-free survival of 7.5 to 8.9 months11 (Stintzing 2012) were found. This study 
therefore shows the efficacy of these triple therapies but does not allow to determine the superiority of one of the 2 
treatments over the other. The tolerance of these treatments was acceptable compared to dual chemotherapy alone. 
These trials show the value of adding a targeted therapy to cytotoxic chemotherapy as a first-line treatment for 
patients with metastatic colorectal cancer. 
 
Recently, aflibercept, a novel anti-angiogenic molecule targeting VEGF-A, VEGF-B, and PlGF (Placental Growth 
Factor), showed efficacy as a second-line treatment in patients with metastatic colorectal cancer in the VELOUR12 
phase III trial (Van Cutsem, 2012). The 1,226 patients who progressed after a first line of chemotherapy including 
oxaliplatin were included and randomized to either a FOLFIRI arm alone or a FOLFIRI arm + aflibercept. Survival 
(overall and progression-free) was statistically significantly increased in the FOLFIRI + aflibercept arm compared to 
the FOLFIRI + placebo arm (OS: 13.5 vs. 12.1 months, PFS: 6.9 vs. 4.7 months). In this trial, patients had received 
FOLFOX +/- bevacizumab as a first-line treatment for their mRCC and interestingly, even patients initially treated 
with bevacizumab (28%) benefited from the addition of aflibercept to chemotherapy. This suggests that this molecule 
could overcome resistance mechanisms to other anti-angiogenic treatments. 
 
 
There are currently no data on the combination of FOLFIRI + aflibercept as a first-line treatment for patients with 
mRCC. 
In addition, the immune system has been shown to play an important role in the control of tumor development and 
growth. Tumors develop mechanisms of escape from the immune system, such as the induction of immunoregulatory 
cells such as regulatory T lymphocytes (Treg). These regulatory cells are capable of reducing the host's anti-tumor 
immune response, thereby promoting tumor growth and metastatic spread. Modulating these regulatory cells could 
therefore make it possible to restore an effective immune response against the tumor and allow better control of its 
development. Certain pro-angiogenic factors are probably involved in the modulation of the immune system by 
tumors. Indeed, their receptors are present on certain immune cells. We have shown that VEGF can have a direct 
effect of induction of Treg proliferation via an action on VEGF-receptor 2 expressed by Treg 13 (Term et al Cancer 
Res 2013). VEGF could also have an indirect action mediated by the induction of immature dendritic cells. Several 
trials have shown that anti-angiogenic therapies have a positive action on the modulation of Treg in different mouse 
tumor models. In humans, the proportion of Treg is increased in the peripheral blood of patients with metastatic CRC 
compared to healthy volunteers. We have shown a decrease in the proportion of Treg in the peripheral blood of 
patients with metastatic CRC treated with bevacizumab in a first-line setting compared to patients treated with 
chemotherapy alone13 (Term 2013). Both VEGF and PlGF are capable of inhibiting dendritic cell (DC) maturation14 


 
FFCD 1302 
Version 1.1 – 24.01.2014 
Page 23 sur 27 
(Dikov 2005). To our knowledge, there are no data in the literature regarding the immunomodulatory effects of 
aflibercept on Treg and DC in humans. 
 
Therefore, aflibercept targets not only VEGF-A and B but also the Placental Growth Factor (PlGF). The Placental 
Growth Factor (PlGF) is a member of the VEGF family and is attached to the VEGFR-1 receiver. It acts in particular 
on the growth and maturation of blood vessels by promoting the proliferation, migration and survival of endothelial 
cells. Tumor cells but also stromal cells can produce PlGF. PlGF levels are correlated with tumor stage, metastatic 
invasion and inversely with survival in different solid tumors15 (Dewerchin 2012). PlGF can therefore promote tumor 
growth by stimulating blood vessel growth, but it also has immunomodulatory properties (recruitment of 
inflammatory cells, polarization of tumor infiltrating macrophages towards a pro-angiogenic macrophage phenotype, 
inhibition of dendritic cell maturation)14 (Dikov 2005). 
 
 Targeted therapies for VEGF increase serum PIGF levels in patients with mRCC16 (Kopetz JCO 2010). PlGF may 
attract VEGFR1-expressing cells to the tumor and thus contribute to resistance to anti-angiogenic therapies. 
Administration of aflibercept in patients with relapsed glioblastoma results in a decrease in a portion of VEGFR1-
expressing monocytes (CD14+ VEGFR1+), associated with radiological response to treatment17 (de Groot 2011). 
Therefore, we propose to analyze different monocyte subpopulations in patients with metastatic CRC treated with 
aflibercept. 
Finally, while VEGF-A has been studied in patients with CRC, there is very limited data on VEGF-B and PlGF 
(aflibercept target molecules). We therefore propose to analyze these different pro-angiogenic factors in patient 
plasma before and after 2 treatment cycles. On the other hand, PlGF expression could be analyzed by 
immunohistochemistry in tumors collected before treatment. 
This Phase II trial will evaluate the efficacy and safety of the combination aflibercept + FOLFIRI as first-line 
treatment in mRCC patients with an ancillary project that aims to test cytokines and monocytes, DC and Treg before 
and after treatment. The prognostic value of the response to aflibercept of these immune parameters will be analyzed. 
 
 


 
FFCD 1302 
Version 1.1 – 24.01.2014 
Page 24 sur 27 
 
12. 
BIBLIOGRAPHY 
1. 
Ferlay J, Shin H, Bray F, et al. Cancer Incidence and Mortality Worldwilde: IARC CancerBase No.10. 
International Agency for Research on Cancer 2010. 
2. 
Chu E. A decade of clinical colorectal cancer. Clin Colorectal Cancer. 2011 Dec;10(4):217. doi: 
10.1016/j.clcc.2011.10.002. Epub 2011 Nov 6. 
3. 
Tournigand C, Andre T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in 
advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. Volume 22. United States, 
2004:229-37. 
4. 
Saltz LB, Clarke S, Diaz-Rubio E, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy 
as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. Volume 26. 
United States, 2008:2013-9. 
5. 
Hurwitz H. Integrating the anti-VEGF-A humanized monoclonal antibody bevacizumab with chemotherapy 
in advanced colorectal cancer. Clin Colorectal Cancer 2004;4 Suppl 2:S62-8. 
6. 
Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin 
for metastatic colorectal cancer. N Engl J Med. Volume 350. United States: 2004 Massachusetts Medical 
Society, 2004:2335-42. 
7. 
Giantonio B, Catalano P, Meropol N, et al. High-dose bevacizumab improves survival when combined with 
FOLFOX4 in previously treated advanced colorectal cancer: Results from the Eastern Cooperative Oncology 
Group (ECOG) study E3200. . Journal of Clinical Oncology 2005;23. 
8. 
Van Cutsem E, Nowacki M, Lang I, et al. Randomized Phase II study of Irinotecan and 5-FU/FA with or 
without cetuximab in the first line treatment of patients with metastatic colorectal cancer: the CRYSTAL 
trial. Journal of Clinical Oncology 2007;25. 
9. 
Van Cutsem E, Lang I, D’Haens G, et al. KRAS sattus and efficacy in the first-line treatment of patients with 
metastatic colorectal cancer treated with FOLFIRI with or without cetuximab: the CRYSTAL experience. 
Journal of Clinical Oncology 2008;28. 
10. 
Bokemeyer C, Bondarenko I, Makhson A, et al. Fluorouracil, leucovorin, and oxaliplatin with and without 
cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. Volume 27. United States, 
2009:663-71. 
11. 
Stintzing S, Fischer von Weikersthal L, Decker T, et al. FOLFIRI plus cetuximab versus FOLFIRI plus 
bevacizumab as first-line treatment for patients with metastatic colorectal cancer-subgroup analysis of 
patients with KRAS: mutated tumours in the randomised German AIO study KRK-0306. Ann Oncol. Volume 
23. England, 2012:1693-9. 
12. 
Van Cutsem E, Tabernero J, Lakomy R, et al. Addition of aflibercept to fluorouracil, leucovorin, 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. Volume 30. United States, 2012:3499-
506. 
13. 
Terme M, Pernot S, Marcheteau E, et al. VEGFA-VEGFR pathway blockade inhibits tumor-induced 
regulatory T-cell proliferation in colorectal cancer. Cancer Res. Volume 73. United States, 2013:539-49. 
14. 
Dikov MM, Ohm JE, Ray N, et al. Differential roles of vascular endothelial growth factor receptors 1 and 2 
in dendritic cell differentiation. J Immunol. Volume 174. United States, 2005:215-22. 
15. 
Dewerchin M, Carmeliet P. PlGF: a multitasking cytokine with disease-restricted activity. Cold Spring Harb 
Perspect Med 2012;2. 
16. 
Kopetz S, Hoff PM, Morris JS, et al. Phase II trial of infusional fluorouracil, irinotecan, and bevacizumab 
for metastatic colorectal cancer: efficacy and circulating angiogenic biomarkers associated with therapeutic 
resistance. J Clin Oncol. Volume 28. United States, 2010:453-9. 


 
FFCD 1302 
Version 1.1 – 24.01.2014 
Page 25 sur 27 
17. 
de Groot JF. High-dose antiangiogenic therapy for glioblastoma: less may be more? Clin Cancer Res. 
Volume 17. United States: 2011 Aacr, 2011:6109-11. 
 
 
 


 
FFCD 1302 
Version 1.1 – 24.01.2014 
Page 26 sur 27 
13. 
ADMINISTRATIVE CONSIDERATIONS  
STUDY PROMOTOR 
 
The promoter of the study is the Fédération Francophone de Cancérologie Digestive (FFCD). The study has been 
registered under the number EudraCT 2013-004081-33. 
 
REMINDER OF THE TEXTS IN FORCE 
 
This test will be carried out according to the European Directive 2001/20/EC. 
 
CIVIL LIABILITY INSURANCE 
 
An insurance was subscribed by the promoter on 02/10/2013 under number 137.681, in accordance with article L 
1121-10 of the Public Health Code (Annex 11). 
 
REQUEST FOR AUTHORIZATION FROM THE CPP AND THE ANSM 
 
This protocol was authorized by the CPP (Committee for the Protection of Persons) ILE DE France VIII of Boulogne 
Billancourt on 19/12/2013 (Annex 11). 
This protocol received a favorable opinion from the ANSM (Agence Nationale de Sécurité du Médicament et des 
Produits de Santé) on January 30, 2014 (Annex 12). 
 
PATIENT'S CONSENT 
 
The investigator undertakes to collect the patient's written clinical and biological consents (information sheets and 
consent forms in Appendices 1 and 2) prior to the patient's inclusion 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. 
 
INFORMATION TO HOSPITAL MANAGEMENT AND RESEARCH AGREEMENT 
 
Prior to the implementation of the study, hospital management will be informed by the sponsor of the investigator's 
interest in participating in this trial. 
A research agreement will be established at no extra cost between the administrator of the investigator center and the 
sponsor. 
 
DATA ARCHIVING 
 
The records will remain confidential and can only be consulted under the responsibility of the physicians 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 case report will be kept for 15 years by the investigator. 
 
COMPUTER SUPPORT 
 
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 liberties, the trial data will be recorded in a computer database of the FFCD's 
Randomization and Management Analysis Center, excluding elements relating to the identity of patients. 
 
DATA PROCESSING 
 
The SSEF's Centre for Randomization, Management and Analysis (CRGA) will be responsible for data management 
and analysis. 
 
MONITORING, QUALITY ASSURANCE AND INSPECTIONS BY THE AUTHORITIES 


 
FFCD 1302 
Version 1.1 – 24.01.2014 
Page 27 sur 27 
 
The investigator agrees in advance that the included patient records may be consulted by a person mandated by the 
FFCD and/or by the health authorities to conduct an audit. On-site file visits, scheduled after agreement of the 
investigator, may take place during or after the inclusion period in the trial. 
This protocol will be monitored by the SFFCD's mobile CRAs. 
 

SAP_001.pdf: 
 
 
Statistical Analysis – Final analyses – FFCD 1302 – V3.0  14/09/2018 
Page 1 over 16 
 
 
 
 
 
 
 
 
 
Efficacy and safety of Aflibercept in combination with FOLFIRI chemotherapy 
as first-line treatment in patients with metastatic colorectal cancer 
Phase II single-arm - multicentric 
FFCD 1302 
 
Statistical Analyses Plan 
Final Analysis 
 
 
 
 
 
 
 
 
Version : 3.0 
Date : 14 September 2018 
 
Writter : Karine Le Malicot 
Review commitee : Julien Taieb, Alexandra Lapeyre, Lila Gaba, Fadil Masskouri. 
 
 


 
 
Statistical Analysis – Final analyses – FFCD 1302 – V3.0  14/09/2018 
Page 2 over 16 
 
Promotor 
FFCD 
Faculté de Médecine 
7 boulevard Jeanne d’Arc 
BP 87900, 21079, Dijon Cedex 
Tél. : 03 80 39 34 83  
Email : jérémie.bez@u-bourgogne.fr 
 
Coordonnator 
Pr Julien Taieb 
Hôpital Européen G. Pompidou 
Service d'Hépato-gastro-entérologie 
20 Rue Leblanc 
75015 PARIS 
 
Project Manager  
Mme Lila Gaba 
FFCD 
Faculté de Médecine 
7 boulevard Jeanne d’Arc 
BP 87900, 21079, Dijon Cedex 
Tél. : 03 80 39 34 83  
Email : lila.gaba@u-bourgogne.fr 
 
Head of biostatistics Mme Karine Le Malicot 
FFCD 
Faculté de Médecine 
7 boulevard Jeanne d’Arc 
BP 87900, 21079, Dijon Cedex 
Tél. : 03 80 39 34 71 - Fax : 03 80 38 18 41 
Email : karine.le-malicot@u-bourgogne.fr 
 
 


 
 
Statistical Analysis – Final analyses – FFCD 1302 – V3.0  14/09/2018 
Page 3 over 16 
Table of contents 
1 
Introduction ..................................................................................................................................................................................................................5 
1.1 
Study objectives ...............................................................................................................................................................................................5 
1.1.1 
Main objective .............................................................................................................................................................................................5 
1.1.2 
Secondary Objectives ...............................................................................................................................................................................5 
1.1.3 
Exploratory study ......................................................................................................................................................................................5 
1.2 
Study Schema ....................................................................................................................................................................................................5 
1.3 
Chronological sequence ...............................................................................................................................................................................6 
1.4 
Sample Size justification ..............................................................................................................................................................................6 
1.5 
Study steps .........................................................................................................................................................................................................6 
1.5.1 
First step : Interim analysis ...................................................................................................................................................................6 
1.5.2 
Second Step : Final Analysis ..................................................................................................................................................................6 
1.5.3 
Transition between the 2 stages .........................................................................................................................................................6 
1.6 
Analyses study planning. .............................................................................................................................................................................7 
1.7 
Ajustments .........................................................................................................................................................................................................7 
2 
Study Populations .......................................................................................................................................................................................................7 
2.1 
Definition ............................................................................................................................................................................................................7 
2.1.1 
Intent-to-treat population (ITT) .........................................................................................................................................................7 
2.1.2 
Modified Intent-to-treat population (mITT) .................................................................................................................................7 
3 
Statistical methods generalities ...........................................................................................................................................................................7 
1.1 
Softwares ............................................................................................................................................................................................................7 
3.1 
Conventions for dates and durations .....................................................................................................................................................7 
3.2 
Conventions for missing data ....................................................................................................................................................................8 
3.3 
Baseline definition ..........................................................................................................................................................................................8 
3.4 
Statistiques.........................................................................................................................................................................................................8 
4 
Statistical Analyses .....................................................................................................................................................................................................9 
1.1 
Final Analysis ....................................................................................................................................................................................................9 
4.1 
Baseline patients’s characteristics ..........................................................................................................................................................9 
4.1.1 
Eligibility........................................................................................................................................................................................................9 
4.1.2 
Demographic data .................................................................................................................................................................................. 10 
4.1.3 
Clinical characteristics.......................................................................................................................................................................... 10 
4.1.4 
Biological characteristics .................................................................................................................................................................... 10 
4.1.5 
Disease characteristics ......................................................................................................................................................................... 10 
4.2 
Follow-up ......................................................................................................................................................................................................... 11 
4.2.1 
Median time follow-up definition .................................................................................................................................................... 11 
4.2.2 
Evaluation .................................................................................................................................................................................................. 11 
4.3 
Main criterion ................................................................................................................................................................................................ 11 
4.3.1 
Evaluation .................................................................................................................................................................................................. 12 
4.4 
Secondary efficacy criteria ....................................................................................................................................................................... 12 


 
 
Statistical Analysis – Final analyses – FFCD 1302 – V3.0  14/09/2018 
Page 4 over 16 
4.4.1 
Rate of patients alive without progression ................................................................................................................................. 12 
4.4.2 
Overall survival ........................................................................................................................................................................................ 12 
4.4.3 
Progression-free survival .................................................................................................................................................................... 13 
4.4.4 
Time until progression ......................................................................................................................................................................... 13 
4.4.5 
Objective response rate at 2, 4, 6 and 12 months .................................................................................................................... 13 
4.4.6 
Time until objective response ........................................................................................................................................................... 14 
4.4.7 
Rate of disease control ......................................................................................................................................................................... 14 
4.4.8 
Disease control duration ..................................................................................................................................................................... 14 
4.4.9 
Best response ........................................................................................................................................................................................... 15 
4.5 
Safety Evaluation .......................................................................................................................................................................................... 15 
4.5.1 
Treatment administration .................................................................................................................................................................. 15 
4.5.2 
Toxicities .................................................................................................................................................................................................... 16 
4.5.3 
SAE and deaths ........................................................................................................................................................................................ 16 
4.6 
Exploratory analyses .................................................................................................................................................................................. 16 
 
 
 


 
 
Statistical Analysis – Final analyses – FFCD 1302 – V3.0  14/09/2018 
Page 5 over 16 
 
1 Introduction 
1.1 Study objectives 
The objective of the study was to evaluate the efficacy and safety of a first-line combination of FOLFIRI chemotherapy 
and aflibercept in patients with metastatic colorectal cancer (mCRC). 
 
1.1.1 
Main objective 
The main objective is to evaluate the rate of 6-months progression-free patients (RECIST version 1.1) according to the 
investigator. 
 
1.1.2 
Secondary Objectives 
The secondary objectives of the study are : 
 
Overall survival: median and rates at 2, 4, 6, and 12 months; 
 
Progression-free survival: median and rates at 2, 4, 6, and 12 months; 
 
Rate of progression-free patients at 6 months according to the centralized review. 
 
Time to progression 
 
Objective response rate at 2, 4, 6 and 12 months 
 
Disease control rates at 2, 4, 6 and 12 months 
 
Best tumor response 
 
Duration of disease control (RC, RP, SD) 
 
Duration to objective response (RC, RP) 
 
Toxicity evaluated using the NCI-CTCAE scale version 4.0 
 
 
1.1.3 
Exploratory study 
Variation of cytokines and immunoregulatory cells during treatment (ancillary study).Plan expérimental 
 
1.2 Study Schema 
 
This is an open-label, Phase II, single-arm, multi-center trial. 
 
 


 
 
Statistical Analysis – Final analyses – FFCD 1302 – V3.0  14/09/2018 
Page 6 over 16 
1.3 Chronological sequence 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.4 Sample Size justification 
The endpoint was the rate of 6-months progression-free patients and the assumptions were as follows : 
H0: rate of 6-months progression-free patients of 55% or less is insufficient; 
H1: rate of 6-months progression-free patients greater than 55% would justify the efficacy of the treatment; a rate of 
75% is hoped for. 
With a risk of  one-sided alpha error of 5% and a power of 90%, using Simon's 2-step method (Minimax), it was required 
to include 49 patients. With a 10% rate of patients lost to follow-up, 54 patients were to be included. 
 
1.5 Study steps 
1.5.1 
First step : Interim analysis 
 The interim analysis was performed in April 2017 and resulted in the termination of the study inclusions for non-
effective treatment. 
 
1.5.2 
Second Step : Final Analysis  
Non applicable 
 
1.5.3 
Transition between the 2 stages 
Non applicable 
 
Baseline examination 3 weeks 
before inclusion 
INCLUSION 
Treatment FOLFIRI + aflibercept 
Every 14 days until progression or toxicity leading to definitve stop of 
the treatment 
10 days max 
TDM-TAP or IRM + TDM T every 8 weeks 
 
2 months 
4 months 
6 months 
12 months … 
Aflibercept (D1) 
 
FOLFIRI (D1, 1 h after aflibercept administration -D3) 
 


 
 
Statistical Analysis – Final analyses – FFCD 1302 – V3.0  14/09/2018 
Page 7 over 16 
1.6 Analyses study planning. 
 
- The stage I analysis was performed after the inclusion of the 33rd patient and a minimum follow-up of 6 
months, i.e. in April 2018. It was recommended to stop the inclusions. 
 
- The final analysis is based on the 40 patients included in the study.  
 
1.7 Ajustments 
Adjustments may be made to this analysis plan in the event of amendments to the protocol, or if phenomena not initially 
anticipated require statistical adaptations. In all cases, these modifications must be made before the database is frozen. 
 
2 Study Populations  
  
2.1 Definition    
2.1.1 
Intent-to-treat population (ITT) 
The intent-to-treat population is defined as all patients included in the study, regardless of eligibility criteria and 
treatment received. 
 
2.1.2 
Modified Intent-to-treat population (mITT) 
The modified intent-to-treat population is defined as all patients included in the study, regardless of eligibility criteria 
and treatment received, with at least a radiological evaluation during the 6 months of treatment.  
 
3 Statistical methods generalities  
 
Statistical analyses will be carried out by the CRGA. 
1.1 Softwares 
 
Statistical analyses will be performed with SAS version 9.4 software. Some graphs may be produced using R software 
version 2.11 or later. 
 
3.1 Conventions for dates and durations 
The time since inclusion will be defined as the time elapsed since the day of inclusion, the day of inclusion being 
considered as day 1. 
Therefore, the durations will be calculated using the following rule, for example for the time from death to inclusion: day 
of death - day of inclusion + 1. 
The day before the day of inclusion (resp. the day before the day of treatment) will be considered as day -1 (day 0 does 
not exist). 
 
The last news date will be the date of the last examination performed or the last treatment or consultation. 


 
 
Statistical Analysis – Final analyses – FFCD 1302 – V3.0  14/09/2018 
Page 8 over 16 
The following conversion rules will be used to convert the number of days to the number of months or years: 1 month = 
30.4375 days; 1 year = 365.25 days. 
 
3.2 Conventions for missing data 
Except in specified cases, missing data will not be replaced. 
 
3.3 Baseline definition 
Baseline measurements will be the last measurements taken before inclusion. In the event of missing data, the last 
measurement taken before the first administration of treatment will be retained. 
 
3.4 Statistiques 
The confidence intervals provided will be one-sided 95% confidence intervals. 
Quantitative data will be described for the entire population, using the following descriptive statistics: population size, 
mean, standard deviation, median, first and third quartile, and minimum and maximum. These statistics will be 
considered standard statistics for the analysis of quantitative variables. Quantitative variables may be categorized using 
their median or a known cut-off from the medical literature. 
Qualitative variables will be summarized for the entire population, using the following descriptive statistics: number, 
frequencies and percentages for each level of the variable. These statistics will be considered as the usual statistics for 
the analysis of qualitative variables. 
Where necessary, confidence intervals for proportions will be calculated using the exact binomial law.  
For survival data : 
After description of the number of events, overall survival, survival in progression, time to progression, and time to 
objective response will be estimated using the Kaplan Meier method, then described by curves, by medians of survival, 
and rates at different temporalities, with their 95% confidence intervals. The confidence intervals for the rates will be 
constructed from the Greenwood variance calculated using the log-log transformation. 
The median follow-up time will be estimated by the inversed Kaplan-Meier method (Shemper, 1996). 
 
 


 
 
Statistical Analysis – Final analyses – FFCD 1302 – V3.0  14/09/2018 
Page 9 over 16 
4 Statistical Analyses 
1.1 Final Analysis 
 
ITT 
Population 
mITT 
Population 
Inclusion eligibility 
 
 
Demographics data 
 
 
Clinical data 
 
 
Biological data 
 
 
Disease characteristics 
 
 
Follow-up time 
 
 
Main criterion : Rate of patients alive and without 
progression at 6 months 
 
 
Rate of patients alive and without progression at 6 
months (centralized review) 
 
 
Overall survival 
 
 
Progression-Free survival 
 
 
Time until progression 
 
 
Objective response rate 
 
 
Disease control rate 
 
 
Disease control duration 
 
 
Best response 
 
 
Treatment administration  
 
 
Toxicities  
 
 
 
4.1 Baseline patients’s characteristics 
 
Number of patients making up each population (ITT, mITT) will be presented. 
 
4.1.1 
Eligibility 
Population : ITT 
Patient eligibility for inclusion will be described by :  
 
The number and percentage of patients meeting each inclusion criterion 
 
Number and percentage of patients who met all inclusion criteria 
 
Number and percentage of patients meeting each non-inclusion criterion 
 
Number and percentage of patients who met all non-inclusion criteria 
 
Number and percentage of patients who met all inclusion and non-inclusion criteria 
 
 


 
 
Statistical Analysis – Final analyses – FFCD 1302 – V3.0  14/09/2018 
Page 10 over 16 
 
4.1.2 
Demographic data 
Population : ITT 
Baseline characteristics will be decribed : : 
 Age (years) ; 
 Center (Number of patients by center) ; 
 Gender (Male vs Female). 
 
4.1.3 
Clinical characteristics 
Population : ITT 
Clinical characteristics will be decribed : : 
 Height (cm) ; 
 Weight (kg) ; 
  General statel OMS (0 vs 1 vs 2) ; 
 Arterial pressure 
 
4.1.4 
Biological characteristics 
Population : ITT 
Biological characteristics will be decribed : : 
 Hb (g/dL) ; 
 PNN neutrophiles (/mm3) ; 
 Platelets (103/ mm3) ; 
 Total Bilirubin (μmol/L) ; 
 Creatinie Clearance (mL/min) ; 
 PAL (‘≤Normal’ vs ‘>Normal - <3*Normal’ vs ‘≥ 3*Normal - <5*Normal’ vs ‘≥5*Normal’) 
 ASAT (‘≤Normal’ vs ‘>Normal - <3*Normal’ vs ‘≥ 3*Normal - <5*Normal’ vs ‘≥5*Normal’) 
 ALAT (‘≤Normal’ vs ‘>Normal - <3*Normal’ vs ‘≥ 3*Normal - <5*Normal’ vs ‘≥5*Normal’) 
 GGT (‘≤Normal’ vs ‘>Normal - <3*Normal’ vs ‘≥ 3*Normal - <5*Normal’ vs ‘≥5*Normal’) 
 Proteinuriare (<2+ vs ≥2+)  
 Leucocytes (/mm3) ; 
 TP (%) ; 
 Calcemia (mmol/L) ; 
 LDH (UI/L) ; 
 CEA (µg/L). 
 
4.1.5 
Disease characteristics 
Population : ITT 
Disease characteristics will be decribed : : 
 Statut K-RAS, N-RAS and B-RAF (Wild-Type vs Mutated vs Not done) ; 


 
 
Statistical Analysis – Final analyses – FFCD 1302 – V3.0  14/09/2018 
Page 11 over 16 
 Patient under AVK (No vs Yes) ; 
 Disease diagnostic (Primitive tumour vs Metastasis) ; 
If Primitive tumour  : 
o 
Localization (Colon vs  Rectum) ; 
o 
Resection (No vs Yes) ; If Yes, type of resection (R0 vs  R1 vs  R2) ; 
If Metastasis : 
o 
Number of localization ; 
o 
Total number of metastases ; 
o 
Localization (Liver vs  Lung vs  Bone vs  Other) ; 
o 
For each localization : Resection (No vs Yes) ; If Yes, type of resection (R0 vs  R1 vs  R2) ; 
 Adjuvant treatment (No vs Yes) ; 
If Yes : 
o 
Schema (‘Chemotherapy vs  ‘Chemotherapy + biotherapy’ vs  ‘Chemotherapy + Radiotherapy vs  ‘Other 
treatment’) ; 
o 
Number of cycles ; 
 
4.2 Follow-up 
A patient without an assessment for more than 12 months will be considered lost to follow-up. 
 
4.2.1 
Median time follow-up definition 
Population : ITT 
Median follow-up time is defined as the time interval between the inclusion date and the date of last news or date of 
death (regardless of cause). 
Patients lost to follow-up or alive at the time of analysis will be censored as of the last reported date. 
4.2.2 
Evaluation   
The median follow-up time, as well as its 95% confidence interval, will be calculated. It will be estimated by the reverse 
Kaplan Meier method. 
 
4.3 Main criterion  
Population : ITT 
Definition of the main judgment criterion : 
The primary endpoint is the rate of alive patients without progression (as assessed by the investigator) 6 months after 
inclusion. 
Progression is defined by : 
 
Progression assessed by CT scan, according to the RECIST version 1.1 criteria; 
 
Death from any cause. 
Patients without an assessment at 6 months will be reviewed according to the following rules: 


 
 
Statistical Analysis – Final analyses – FFCD 1302 – V3.0  14/09/2018 
Page 12 over 16 
 
If the patient has a later evaluation (7 months or more) and is not progressing at that time, then the patient will 
be considered progression-free at 6 months; 
 
If the patient presents a documented progression within 2 months of the 6 month assessment then the patient 
will be considered to be progressing at 6 months. If the progression is documented beyond 8 months then the 
patient will not be considered progressive at 6 months; 
 
If a progression is documented prior to the 6-month assessment, the patient is considered progressive at 6 
months. 
 
4.3.1 
Evaluation   
The primary endpoint will be described with usual statistics. 
 
Exploratory Analysis of the Primary Endpoint: The primary endpoint will be assessed on the total number of patients 
included in the study (ITTm). A one-sided 95% confidence interval will be calculated. 
 
4.4 Secondary efficacy criteria 
4.4.1 
Rate of patients alive without progression 
Population : mITT 
4.4.1.1 
Definition  
It is defined as the number of patients alive without progression at 6 months in centralized review. 
Progression is defined by : 
 
The progression evaluated by CT scan in centralized review, according to the RECIST version 1.1 criteria; 
 
Death, whatever the cause. 
 
Patients without imagery at 6 months will be reviewed according to the following rules: 
 
If the patient has an imagery later (7 months or more) and is not progressing at this date, then the patient will 
be considered progression-free at 6 months; 
 
If the patient presents a documented progression within 2 months of the 6 months then the patient will be 
considered to be progressing at 6 months. If the progression is documented beyond 8 months then the patient 
will not be considered progressive at 6 months; 
 
If a progression is documented prior to the 6-month assessment, the patient is considered progressive at 6 
months.  
 
4.4.1.2 
Evaluation   
The endpoint will be described with usual statistics. 
 
4.4.2 
Overall survival 
Population : ITT 
 


 
 
Statistical Analysis – Final analyses – FFCD 1302 – V3.0  14/09/2018 
Page 13 over 16 
4.4.2.1 
Definition   
It is defined as the time interval between the inclusion date and the date of death (regardless of cause). Patients lost to 
follow-up or alive at the time of analysis will be censored as of the date of last news. 
 
4.4.2.2 
Evaluation   
Time scale considered will be the month.  
Overall survival will be plotted using the Kaplan Meier estimator; median survival and rates at 2, 4, 6 and 12 months will 
be calculated with their 95% confidence intervals. 
 
4.4.3 
Progression-free survival 
Population : ITT 
4.4.3.1 
Definition   
It is defined as the delay between the inclusion date and the date of first radiological progression as assessed by the 
investigator according to RECIST version 1.1 criteria or the date of death (whatever the cause). Alive patients without 
radiological progression will be censored at the date of last news. 
 
4.4.3.2 
Evaluation  
Time scale considered will be the month.  
Progression-free survival will be plotted using the Kaplan Meier estimator; median survival and rates at 2, 4, 6 and 12 
months will be calculated with their 95% confidence intervals. 
 
4.4.4 
Time until progression 
Population : ITT 
4.4.4.1 
Definition   
It is defined as the time between the inclusion date and the date of progression as assessed by the investigator according 
to the RECIST criteria version 1.1. 
 
4.4.4.2 
Evaluation  
Time scale considered will be the month.  
The endpoint will be described with usual statistics. 
 
4.4.5 
Objective response rate at 2, 4, 6 and 12 months  
Population : ITT 
4.4.5.1 
Definition   
Objective Response (OR) is defined as the number of Partial Response (PR) or Complete Response (CR) patients evaluated 
by the investigator according to the RECIST version 1.1 criteria. 
The OR rate will be calculated at 2, 4, 6 and 12 months and described as follows:  
 
Objective response ; 
 
Stability 


 
 
Statistical Analysis – Final analyses – FFCD 1302 – V3.0  14/09/2018 
Page 14 over 16 
 
Progression 
 
Not evaluable 
 
4.4.5.2 
Evaluation  
The endpoint will be described at each time with usual statistics. 
 
4.4.6 
Time until objective response 
Population : ITT 
4.4.6.1 
Deinition   
Objective Response (OR) is defined as the number of Partial Response (PR) or Complete Response (CR) patients evaluated 
by the investigator using RECIST version 1.1 criteria. 
The time to objective response is defined as the time between the inclusion date and the date of first OR. 
 
4.4.6.2 
Evaluation   
Time scale considered will be the month.  
The endpoint will be described with usual statistics. 
 
4.4.7 
Rate of disease control 
Population : ITT 
4.4.7.1 
Definition   
Disease control is defined as the number of patients in Partial Response (PR) or Complete Response (CR) or Stability (S) 
as assessed by the investigator using the RECIST version 1.1 criteria. 
The disease control rate will be calculated at 2, 4, 6 and 12 months and described as follows:  
 
Disease Control ; 
 
Progression 
 
Not Evaluable 
 
4.4.7.2 
Evaluation  
The endpoint will be described at each time with usual statistics. 
 
4.4.8 
Disease control duration 
Population : ITT 
4.4.8.1 
Definition  
Disease control is defined as the number of patients in Partial Response (PR) or Complete Response (CR) or Stability (S) 
as assessed by the investigator using the RECIST version 1.1 criteria. 
Duration of disease control is defined as the time from the inclusion date to the date of first progression in patients with 
Complete Response, Partial Response, or Stability (S) as assessed by the investigator using RECIST criteria version 1.1. If 
no progression, then the date of death is taken, or if the patient is alive, the last reported date. 
 


 
 
Statistical Analysis – Final analyses – FFCD 1302 – V3.0  14/09/2018 
Page 15 over 16 
4.4.8.2 
Evaluation   
Time scale considered will be the month.  
The endpoint will be described with usual statistics. 
 
4.4.9 
Best response 
Population : ITT 
4.4.9.1 
Definition   
Best response is derived from the imagery evaluation 
 
4.4.9.2 
Evaluation  
The endpoint will be described with usual statistics. 
 
4.5 Safety Evaluation 
Population : mITT 
 
Safety will be evaluated : 
 
Duration of treatment, doses administered, modification of treatment doses ; 
 
Toxicities, collected after each treatment and described according to NCI-CTC version 4.0 criteria; 
 
4.5.1 
Treatment administration 
4.5.1.1 
Treatment duration 
The duration of treatment will be calculated by the formula : 
Date of D1 last cycle - date of D1 first cycle + 1 
The time scale considered will be the month and will be described according to the usual descriptive statistics. 
 
4.5.1.2 
Doses administered 
The number of cures will be described according to the usual descriptive statistics. 
 
The ratio "administered dose / theoretical dose x 100" will be calculated for each treatment and described according to 
the usual descriptive statistics. 
 
The theoretical dose of Aflibercept is 4 mg/kg; 
 
The theoretical dose of Irinotecan is 180 mg/m²; 
 
The theoretical dose of 5FU Bolus is 400 mg/m²; 
 
The theoretical dose of 5FU Continuous is 2400 mg/m². 
 
4.5.1.3 
Doses modification 
The change in dose will be described by : 
 
The number of patients with at least one reduced dose for at least one treatment; 
 
Reason for dose reduction 


 
 
Statistical Analysis – Final analyses – FFCD 1302 – V3.0  14/09/2018 
Page 16 over 16 
 
 
Dose changes will be described by treatment and according to the usual descriptive statistics. 
 
4.5.1.4 
 G-CSF administration 
The G-CSF administration will be described by : 
 
Patients with at least one administration of G-CSF ; 
 
Type of administration (primary vs. secondary) ; 
 
The product administered 
 
4.5.1.5 
Treatment stop and further lines  
Stop of the protocol treatment and the causes of treatment stop will be described (number, %).   
A list of other causes of discontinuation will be provided. 
The number of patients who have benefited from a subsequent line and subsequent treatments will be described. 
 
4.5.2 
Toxicities 
Toxicities will be described according to NCI-CTC Version 4.0 criteria by : 
 
The number and percentage of patients with at least one toxicity out of all cycles by grade; 
 
The number of patients by grade and by SOC and preferred term; 
 
4.5.3 
SAE and deaths 
A synthesis of the SAEs will be provided by pharmacovigilance. 
4.6 Exploratory analyses 
Not Applicable