Clinical trial NCT01571284
Conditions: Colorectal Cancer Metastatic
Sponsor: Sanofi
Start date: 2012-05-30; Completion date: 2017-01-31
Enrollment: 781 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Primary Objective:

To provide metastatic colorectal cancer participants with access to aflibercept and to document the overall safety in these participants

Secondary Objective:

To document the Health-Related Quality of Life of aflibercept in this participants population

Detailed description:
Each participants will be treated until disease progression, unacceptable toxicity, death, Investigator's decision or participant's refusal for further treatment (whichever comes first). Participants were followed-up during study treatment and for at least 30 days after last administration.

Arms: arm 1: Aflibercept 4 mg/kg IV infusion over 60 minutes followed by Irinotecan 180 mg/m\^2 IV infusion over 90 minutes and Leucovorin 400 mg/m\^2 IV infusion over 120 minutes at the same time followed by 5-Fluorouracil (5-FU) 400 mg/m\^2 IV bolus over 2-4 minutes followed by 5-FU 2400 mg/m\^2 continuous IV infusion over 46 hours on Day 1 of each cycle (1 Cycle = 2 weeks), until disease progression (DP), unacceptable toxicity, death, Investigator's decision or participant's refusal of further treatment.
Interventions: intervention 1: AFLIBERCEPT AVE0005 intervention 2: FOLFIRI
Intervention descriptions: intervention 1: Pharmaceutical form:Concentrate for solution for infusion Route of administration: Intravenous intervention 2: irinotecan, 5-FU and leucovorin

Protocol documents:
Prot_000.pdf: 
.
Property of Sanofi - strictly confidential 
Page No: 1 of 70 
CLINICAL TRIAL PROTOCOL
COMPOUND: AFLIBERCEPT
A Multicenter, Single arm, Open Label Clinical Trial to Evaluate the Safety 
and Health-Related Quality of Life of Aflibercept in Patients with Metastatic 
Colorectal Cancer (mCRC) Previously Treated with an Oxaliplatin-
Containing Regimen  
STUDY NUMBER: AFLIBC06097 
VERSION NUMBER: 1.0  
DATE: 10 Feb 2012
WHO Universal Trial Number (UTN): U1111-1125-8949 
EudraCT number: 2011-005724-17 
IND Number: 009948 
« Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of
Sanofi (or any of its affiliated companies). The use of such confidential information must be restricted to the recipient for the
agreed purpose and must not be disclosed, published or otherwise communicated to any unauthorized persons, for any 
reasons, in any form whatsoever without the prior written consent of Sanofi (or the concerned affiliated company); ‘affiliated 
company’ means any corporation, partnership or other entity which at the date of communication or afterwards (i) controls 
directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning direct or indirect ownership or 
more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity.» 
 
NCT number:NCT01571284




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LOCAL REPRESENTATIVE OF 
THE SPONSOR 
Company:  
Address
Tel:
Fax
EMERGENCY TELEPHONE 
NUMBERS 
According to the sponsor identification:  
sanofi-aventis groupe to be completed by 
global team. 
For European Community countries keep 
sanofi-aventis groupe and add affiliate address 
as the “Local representative of the sponsor”. 
For other countries, “Local sponsor” should
Optional 
To be completed locally with a 24h / out of 
hours local phone number.


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TABLE OF CONTENTS 
1.
SYNOPSIS................................................................................................................................... 7
2.
FLOW CHART ........................................................................................................................... 13
2.1
Study Flow chart......................................................................................................................... 13
3.
CLINICAL TRIAL PROTOCOL AGREEMENT FORM .............................................................. 15
4.
LIST OF ABBREVIATIONS....................................................................................................... 16
5.
INTRODUCTION AND RATIONALE ......................................................................................... 18
5.1
Colorectal cancer ....................................................................................................................... 18
5.2
Metastatic colorectal cancer treatment....................................................................................... 18
5.3
Aflibercept background............................................................................................................... 20
5.4
Study rationale ........................................................................................................................... 21
6.
STUDY OBJECTIVES ............................................................................................................... 22
6.1
Primary....................................................................................................................................... 22
6.2
Secondary .................................................................................................................................. 22
7.
STUDY DESIGN ........................................................................................................................ 22
7.1
Description of the protocol.......................................................................................................... 22
7.2
Duration of study ........................................................................................................................ 23
8.
SELECTION OF PATIENTS ...................................................................................................... 23
8.1
Number of patients planned ....................................................................................................... 23
8.2
Inclusion criteria ......................................................................................................................... 23
8.3
Exclusion criteria ........................................................................................................................ 24
9.
TREATMENTS........................................................................................................................... 26
9.1
Investigational Medicinal Product............................................................................................... 26
9.2
Non Investigational Medicinal Products (Background treatments)............................................. 27
9.3
Dosage and schedule of administration ..................................................................................... 28
9.4
Packaging and labeling .............................................................................................................. 36
9.5
Storage conditions...................................................................................................................... 36
9.6
Responsibilities .......................................................................................................................... 36
9.7
Retrieval and/or destruction of treatments ................................................................................. 36
9.8
Concomitant treatment............................................................................................................... 37
9.9
Post-Study treatment.................................................................................................................. 38
9.10
Treatment accountability and compliance .................................................................................. 38
10.
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT ........................................... 38
10.1
Efficacy....................................................................................................................................... 38
10.2
Safety ......................................................................................................................................... 38
10.3
Health-related quality of life outcomes ....................................................................................... 39
11.
PATIENT SAFETY..................................................................................................................... 40
11.1
Safety instructions...................................................................................................................... 40
11.2
Adverse Events monitoring ........................................................................................................ 40
11.3
Definitions of Adverse Event (AE) and Serious Adverse Event (SAE)....................................... 41
11.4
Obligation of the investigator regarding safety reporting............................................................ 42
11.5
Obligations of the sponsor.......................................................................................................... 43
 


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12.
HANDLING OF PATIENT TEMPORARY OR DEFINITIVE TREATMENT DISCONTINUATION 
AND OF PATIENT STUDY DISCONTINUATION...................................................................... 44
12.1
Temporary treatment discontinuation with Investigational Medicinal Product............................ 44
12.2
Permanent treatment discontinuation......................................................................................... 44
12.3
Procedure for withdrawal of patients from study ........................................................................ 45
12.4
Consequence ............................................................................................................................. 45
13.
STUDY PROCEDURES............................................................................................................. 45
13.1
Visit schedule ............................................................................................................................. 45
13.2
Definition of source data............................................................................................................. 47
14.
STATISTICAL CONSIDERATIONS .......................................................................................... 48
14.1
Statistical and analytical plans ................................................................................................... 48
14.2
Determination of sample size..................................................................................................... 48
14.3
Analysis variables....................................................................................................................... 48
14.4
Analysis populations................................................................................................................... 49
14.5
Statistical methods ..................................................................................................................... 50
14.6
Interim analysis .......................................................................................................................... 51
15.
ETHICAL AND REGULATORY STANDARDS ......................................................................... 52
15.1
Ethical principles ........................................................................................................................ 52
15.2
Laws and regulations ................................................................................................................. 52
15.3
Informed consent........................................................................................................................ 52
15.4
Institutional Review Board/Independent Ethics Committee (IRB/IEC) ....................................... 52
16.
STUDY MONITORING............................................................................................................... 53
16.1
Responsibilities of the investigator(s)......................................................................................... 53
16.2
Responsibilities of the sponsor................................................................................................... 53
16.3
Source document requirements ................................................................................................. 54
16.4
Use and completion of Case Report Forms (CRFs) and additional request .............................. 54
16.5
Use of computerized systems .................................................................................................... 54
17.
ADMINISTRATIVE RULES........................................................................................................ 54
17.1
Curriculum Vitae......................................................................................................................... 54
17.2
Record retention in study site(s)................................................................................................. 54
18.
CONFIDENTIALITY ................................................................................................................... 55
19.
PROPERTY RIGHTS ................................................................................................................. 55
20.
DATA PROTECTION................................................................................................................. 55
21.
INSURANCE COMPENSATION................................................................................................ 56
22.
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES............................. 56
23.
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF A 
SITE ........................................................................................................................................... 56
23.1
Decided by the sponsor in the following cases: ......................................................................... 56
23.2
Decided by the investigator........................................................................................................ 57
24.
CLINICAL TRIAL RESULTS ..................................................................................................... 57
25.
PUBLICATIONS AND COMMUNICATIONS............................................................................. 57
 


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26.
CLINICAL TRIAL PROTOCOL AMENDMENTS....................................................................... 57
27.
BIBLIOGRAPHIC REFERENCES ............................................................................................. 59
28.
APPENDICES............................................................................................................................ 62
Appendix A
HRQL questionnaires (EORTC-QLQ C30 – EORTC CR29 – EQ-5DTM)...................... 63
Appendix B
ECOG performance status scale.................................................................................... 69
Appendix C
National Cancer Institute Common Terminology Criteria for Adverse Events................ 70
 


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1.
SYNOPSIS 
COMPOUND: AFLIBERCEPT
STUDY No.: AFLIBC06097 
TITLE
A multicenter, single arm, open label clinical trial to evaluate 
the safety and Health-Related Quality of life of aflibercept in 
patients with metastatic colorectal cancer (mCRC) previously 
treated with an oxaliplatin-containing regimen  
TRIAL LOCATION 
International
Europe, North America, Asia and Latin America
STUDY OBJECTIVE(S) 
Primary objective: 
 
To provide mCRC patients (similar to the patients 
evaluated in the VELOUR phase III trial) and Investigators 
with access to aflibercept, prior to its marketing 
authorisation and/or commercial availability and to 
document the aflibercept overall safety in this patient 
population.
Secondary objective:
 
To document the Health-Related Quality of Life (HRQL) of 
aflibercept in this patient population. 
STUDY DESIGN 
This is a prospective, phase IIIb/IV, International, Multicenter, 
Single Arm, Open-label Study.
Each patient will be treated until disease progression, 
unacceptable toxicity, death, Investigator’s decision or 
patient’s refusal for further treatment (whichever come first). 
Patients will be followed-up during treatment and for at least 
30 days after last treatment (either aflibercept or FOLFIRI) 
administration (for safety assessment).  
STUDY POPULATION 
Main selection criteria: 
Inclusion criteria:
- 
Histologically or cytologically proven adenocarcinoma of 
the colon or rectum 
- 
Metastatic disease 
- 
Age 18 years 
- 
ECOG PS 0-1 
- 
One and only one prior chemotherapeutic regimen for 
metastatic disease. This prior chemotherapy must be an 
oxaliplatin containing regimen. Patients must have 
progressed during or following the last administration of 
the oxaliplatin based chemotherapy. Patients relapsing 
within 6 months of completion of oxaliplatin adjuvant 
chemotherapy are also eligible.
- 
Signed written informed consent obtained prior to 
inclusion.
 


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Exclusion criteria:
- 
Prior therapy with irinotecan 
- 
Inadequate bone marrow function: 
x 
Absolute neutrophil counts (ANC) < 1.5 x 109/L
x 
Platelet count < 100 x 109/L
x 
Hemoglobin < 9.0 g/dL 
- 
Inadequate liver function tests: 
x 
Total bilirubin >1.5 x ULN 
x 
Transaminases >3 x ULN (unless liver metastasis are 
present, 5 x ULN in that case) 
x 
Alkaline phosphatase >3 x ULN (unless liver 
metastasis are present, 5 x ULN in that case) 
- 
Less than 4 weeks elapsed from prior radiotherapy or 
prior chemotherapy to the time of inclusion. Less than 4 
weeks following major surgery to the time of inclusion or 
until the surgical wound is fully healed whichever came 
later (48 hours in case of minor surgical procedure or 
until wound full healing observed). 
- 
Treatment with any investigational drug within 30 days 
prior to inclusion. 
- 
Adverse events (with exception of alopecia, peripheral 
sensory neuropathy and those listed in specific exclusion 
criteria) from any prior anti cancer therapy of grade >1 
(National Cancer Institute Common terminology Criteria 
[NCI CTCAE] v.4.0) at the time of inclusion. 
- 
History of brain metastases, uncontrolled spinal cord 
compression, or carcinomatous meningitis or new 
evidence of brain or leptomeningeal disease. 
- 
Other prior malignancy. Adequately treated basal cell or 
squamous cell skin cancer, carcinoma in situ of the cervix 
or any other cancer from which the patient has been 
disease free for > 5 years are allowed. 
- 
Any of the following within 6 months prior to inclusion: 
myocardial infarction, severe/unstable angina pectoris, 
coronary/peripheral artery bypass graft, NYHA class III or 
IV congestive heart failure, stroke or transient ischemic 
attack.
- 
Any of the following within 3 months prior to inclusion: 
Grade 
3-4 
gastrointestinal 
bleeding/hemorrhage, 
treatment 
resistant 
peptic 
ulcer 
disease, 
erosive 
oesophagitis or gastritis, infectious or inflammatory bowel 
disease, diverticulitis, pulmonary embolism or other 
uncontrolled thromboembolic event. 
- 
Occurrence of deep vein thrombosis within 4 weeks, prior 
to inclusion. 
 


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- 
Known acquired immunodeficiency syndrome (AIDS-
related illnesses) or known HIV disease requiring 
antiretroviral treatment. 
- 
Any severe acute or chronic medical condition, which 
could impair the ability of the patient to participate to the 
study or to interfere with interpretation of study results. 
- 
Known dihydropyrimidine dehydrogenase deficiency 
- 
Predisposing colonic or small bowel disorders in which 
the symptoms were uncontrolled as indicated by baseline 
of > 3 loose stools daily. 
- 
Prior history of chronic enteropathy, inflammatory 
enteropathy, 
chronic 
diarrhea, 
unresolved 
bowel 
obstruction/sub-obstruction, more than hemicolectomy, 
extensive small intestine resection with chronic diarrhea. 
- 
History of anaphylaxis or known intolerance to atropine 
sulphate or loperamide or appropriate antiemetics to be 
administered in conjunction with FOLFIRI. 
- 
Treatment with concomitant anticonvulsivant agents that 
are 
CYP3A4 
inducers 
(phenytoin, 
phenobarbital, 
carbamazepine), unless discontinued >7 days. 
- 
Patients with known Gilbert’s syndrome. 
- 
Pregnant or breast-feeding women. Positive pregnancy 
test (serum or urine ȕ-HCG) for women of reproductive 
potential.
- 
Patients with reproductive potential (female and male) 
who do not agree to use an accepted effective method of 
contraception during the study treatment period and for at 
least 6 months following completion of study treatment. 
The definition of effective method will be left to the 
investigator’s judgment. 
- 
For female patients enrolled in United Kingdom, the 
following methods of contraception are acceptable: oral 
contraceptives accompanied by the use of a second 
method of contraception, as it is not known how oral 
contraceptives interact with study medications or Intra 
Uterine Device (IUD) or women who are surgically sterile, 
or women who are post –menopausal or other reasons 
have no chance of becoming pregnant. 
Exclusion criteria related to Aflibercept:
- 
Urine protein-creatinine ratio (UPCR) >1 on morning spot 
urinalysis or proteinuria > 500 mg/24-h. 
- 
Serum creatinine > 1.5 x upper limit of normal (ULN). If 
creatinine 1.0-1.5 x ULN, creatinine clearance, calculated 
according to Cockroft-Gault formula, < 60 ml/min will 
exclude the patient. 
- 
Uncontrolled hypertension (defined as blood pressure > 
140/90 mmHg or systolic blood pressure >160 mmHg 
 


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Total expected number of patients: 
Expected number of sites:
when diastolic blood pressure < 90 mmHg, on at least 2 
repeated determinations on separate days, or upon 
clinical judgement) within 3 months prior to study 
inclusion.
- 
Patients on anticoagulant therapy with unstable dose of 
warfarin and/or having an out-of-therapeutic range INR 
(>3) within the 4 weeks prior to inclusion. 
- 
Evidence of clinically significant bleeding diathesis or 
underlying coagulopathy (e.g. INR>1.5 without vitamine K 
antagonist therapy), non-healing wound. 
Approximately 900
Approximately 150.  
All sites located in the US will be considered under IND 
obligations while all the other sites outside US will not be 
under IND. 
INVESTIGATIONAL MEDICINAL 
PRODUCT/ NON 
INVESTIGATIONAL MEDICINAL 
PRODUCTS (BACKGROUND 
TREATMENTS) 
Formulation(s):
Route(s) of administration: 
Dose regimen: 
Aflibercept for IV administration supplied as a sterile, non-
pyrogenic, colorless to pale-yellow colored, 25 mg/mL 
solution, packaged in a type 1, clear borosilicate glass vial 
closed with a flanged cap with tear-off lid and inserted sealing 
disc, Flurotec® (PTFE) coated. 
Two aflibercept drug product vial sizes available: 
- 
100 mg/4 mL in a 5 mL vial 
- 
200 mg/8 mL in a 10 mL vial 
The content of the vials must be diluted prior to infusion.  
Background treatments products (marketed formulation):  
- 
Irinotecan, Fluorouracil (5-FU) and Leucovorin (LV):  see 
manufacturer’s 
product 
information 
for 
handling, 
administration and storage. 
Commercially available products will be used. 
Intravenous (I.V.) infusion 
Aflibercept: 4 mg/kg over 1 hour on Day 1 followed by 
FOLFIRI, administered as follows:   
- 
dl-leucovorin: 400 mg/m² over 2 hours infusion on day 1  
- 
Irinotecan: 180 mg/m² over 90-minute infusion, on day 1, 
followed by bolus 5-FU 400 mg/m² and 5-FU continuous 
infusion 2400 mg/m² over 46 hours infusion. 
Or as individualized by physician’s clinical judgment. 
 


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Treatment cycle to be administered every 2 weeks. 
Study treatment (aflibercept and FOLFIRI) has to be 
discontinued upon documentation of disease progression.  
If FOLFIRI (or either of its components) is permanently 
discontinued, then aflibercept should be continued until 
disease progression or unacceptable toxicity or patient’s 
refusal of further treatment.  
If aflibercept is permanently discontinued, then FOLFIRI can 
be continued until disease progression or unacceptable 
toxicity or patient’s refusal of further treatment.  
The end of treatment will be the date of the last treatment 
administration, either aflibercept or FOLFIRI whichever comes 
last.
Patient treatment after aflibercept and FOLFIRI permanent 
discontinuation is at investigator discretion.  
Dose reduction and/or treatment delay and/or treatment 
discontinuation are planned in case of severe toxicity. 
Therapeutic use of Granulocyte Colony-Stimulating Factor (G-
CSF) may be considered (if consistent with the local 
institutional treatment practice), upon occurrence of a first 
episode of grade >3 neutropenia and as secondary 
prophylaxis for subsequent cycles, in patients who may be at 
increased risk for neutropenia complications. 
The starting dose of irinotecan and/or 5-FU components of 
FOLFIRI regimen should take into consideration toxicities 
from prior regimens received by the patient and the patient 
characteristics (like UGT1A1*28 allele status, when known). 
In 
case 
drugs 
(5FU) 
administered 
during 
previous 
chemotherapy regimen were reduced due to toxicity, the 
decision to administer or not the full starting dose of FOLFIRI 
(irinotecan, 5FU continuous and/or bolus infusion) will be left 
to the investigator decision based on his/her clinical 
judgement of patient benefit at time of inclusion (provided all 
patient eligibility criteria are fulfilled). To start with a reduced 
dose of FOLFIRI may be considered. 
PRIMARY STUDY ENDPOINT 
SECONDARY ENDPOINT 
Primary endpoint:
- 
Safety: 
o treatment-emergent adverse events (TEAEs) 
will be assessed: terminology (according to 
MedDRA - Medical Dictionary for Regulatory 
Activities), frequency and severity (according to 
NCI 
CTCAE 
V4.0), 
seriousness 
and 
relatedness; 
o Laboratory abnormalities according to NCI-
CTC V4.0. 
Secondary endpoint:
- 
Health-Related Quality of Life (HRQL) assessed by 
 


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using changes from baseline in scores derived from 
the following questionnaires: 
o EORTC QLQ-C30 (version 3);  
o EQ-5DTM (version 4) 
Exploratory endpoint (optional):
- 
Health-Related Quality of Life (HRQL) assessed by 
using changes from baseline in scores derived from 
the following questionnaires: 
o EORTC 
QLQ 
CR29 
(disease 
specific 
supplement to QLQ-C30). 
SAFETY CRITERIA  
Data collected for the assessment of safety: 
- 
Number of cycles administered, duration of dosing in 
weeks, cumulative dose received and reason for End of 
Treatment (EOT). Dose delays, omission and reductions 
will also be analyzed. 
- 
Adverse Events (AEs)/Serious Adverse Events (SAEs) 
STATISTICAL CONSIDERATIONS 
No formal sample size calculation is performed. 
The safety population (all included patients who received at 
least part of one dose of treatment) will be used to document 
safety.
Only descriptive summaries will be provided. 
Interim analyses are planned during the course of the study, 
in 
order 
to 
obtain 
preliminary 
results 
on 
baseline 
characteristics, HRQL and safety data. 
DURATION OF STUDY PERIOD 
The study is planned to be initiated in the second quarter of 
2012 in Europe and in the United States, simultaneously or 
sequentially in the other involved countries.  
In each country, patient recruitment will end when aflibercept 
(ZALTRAP) becomes commercially available (i.e. accessible 
to the patient as per each country regulation). Patients 
already included will continue to be treated until disease 
progression, death, unacceptable toxicity, Investigator’s 
decision or patient’s refusal of further treatment. 
 


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2.
FLOW CHART 
2.1 Study Flow chart 
Baseline
Treatment
Evaluation
Every cycle 
End of Treatment 
(EOT)
(30 days after last 
treatment)
Post-treatment 
FUP
Informed consent
X
Inclusion/exclusion criteria 
X
Demography 
X
Prior Medical/Surgical History & 
Cancer History, Prior Medication 
History
X
Clinical examination 
X
X
X
Hematology (a)
X
X
Biochemistry (b)
X
X
Urinalysis (c)
X
X
Concomitant medication (d)
X
X
Aflibercept + FOLFIRI (e)
Every 2 weeks (within 3 days from inclusion) 
AE / SAE (f)
X
X
X
X
Health-Related Quality of Life (g)
EORTC- QLQ C30/ QLQ-CR29*/  
EQ-5DTM
X
I
N
C
L
U
S
I
O
N
X (every odd cycle 
starting from C3) 
X
a)
Hematology (hemoglobin, WBC, ANC, platelet count); prothrombin time (expressed as INR) only for patients under VKA therapy 
b)
Biochemistry (sodium, chloride, potassium, calcium, blood urea nitrogen (BUN)/urea, creatinine, glucose, SGOT (AST), SGPT (ALT), 
alkaline phosphatase, LDH, total bilirubin, total protein, albumin. 
c)
Urinalysis: prior to inclusion perform UPCR/proteinuria to determine patient elegibility as per section 8.3. Following inclusion dipstick (WBC, 
RBC, urinary protein) will be assessed on morning urine spot before treatment administration. If urine protein on dipstick is >2+, perform 
UPCR before treatment administration. During study treatment, 24-hour urine collection should be performed to quantify proteinuria when 


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UPCR>1; in case UPCR >2 or in case a proteinuria from renal origin is associated with hematuria then a work-up for considering thrombotic 
microangiopathy should be considered. 
d)
Concomitant medications: G-CSF, pre-medications, antidiarrheal, Vitamin K antagonist, heparins, antihypertensive medications, SAEs 
corrective therapies, and any further anticancer treatment started within 30 days of last treatment administration (aflibercept/Folfiri), should 
be documented into e-CRF.  
e)
Treatment with aflibercept will start on Cycle 1 Day 1 just before FOLFIRI administration and then repeated every 2 weeks. 
f)
Adverse Events (AEs), regardless of seriousness or relationship to study treatment (aflibercept/Folfiri), will be collected from the time the 
patient signs the informed consent form up to 30 days after the last treatment administration (aflibercept or Folfiri). Following the 30 day 
EOT visit all ongoing SAEs (regardless of relationship with study treatment) as well as ongoing related AEs and new related SAEs will have 
to be collected and followed till resolution/stabilisation (stabilisation being defined as an event ongoing without any change for at least 3 
months). Vital signs or ECG abnormalities are to be recorded as Adverse Events only if they are medically relevant: symptomatic, requiring 
corrective treatment, leading to discontinuation/dose modification (reduction and/or delay) and/or fulfilling a seriousness criterion. 
Laboratories abnormalities are to be recorded as AE only if they are serious or leading to discontinuation/dose modification. 
g)
Health-Related Quality of Life (QoL questionnaires): to be self-administered by the patient at the center, prior to informing the patient about 
disease evolution, before the next study treatment and before any other assessment is performed. A key person (e.g., research nurse) at 
each center should be responsible for questionnaire data collection, in order to optimize compliance of the patient and to ensure 
completeness of the data. The collection will be done at baseline (before first treatment administration), before the treatment administration 
at the beginning (D1) of every odd cycle (cycle 3, 5, etc) and at the end of treatment visit.  
* QLQ-CR29 as optional: if it is completed at baseline it should be collected at all further time-points as per EORTC-C30 questionnaire. 


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3.
CLINICAL TRIAL PROTOCOL AGREEMENT FORM 
I, ………………………………………………………………………, the investigator, have examined 
the above-referenced Sanofi clinical trial protocol and have fully discussed the objectives of this 
clinical trial and the content of this clinical trial protocol with the sponsor’s team. 
I agree to conduct the clinical trial according to this clinical trial protocol and to comply with its 
requirements, subject to ethical and safety considerations.  
In understand that, should the decision be made by the sponsor to terminate prematurely or 
suspend the clinical trial at any time for whatever reason, such decision will be communicated to 
me in writing. Conversely, should I decide to withdraw from execution of the clinical trial, I will 
communicate such decision in writing to the sponsor.  
INVESTIGATOR
NAME:
DATE: _____________________________  
(e.g., 05 February 2010) 
Signature: ______________________________  
 
FOR THE SPONSOR 
NAME:
ADDRESS:
SIGNATORY 
NAME:
DATE: _____________________________  
(e.g., 05 February 2010) 
Signature: ______________________________  
 


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4.
LIST OF ABBREVIATIONS 
5-FU
5-Fluorouracil
AE
Adverse Event
AIDS
Acquired Immunodeficiency Syndrome 
ALT
(SGPT)
Alanine 
Aminotransferase 
(or 
Serum 
Glutamate-Pyruvate 
Transferase) 
ANC
Absolute neutrophil count  
AST
(SGOT)
Aspartate Aminotransferase (or Serum Glutamate-Oxaloacetate 
Transferase) 
BSA
Body Surface Area 
BP
Blood Pressure 
BUN
Blood Urea Nitrogen 
CNS
Central nervous system 
CRF
Case Report Form 
CTCAE
Common Terminology Criteria for Adverse Events 
DRF
Discrepancy Resolution Form 
DVT
Deep Venous Thrombosis 
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group 
FUP
Follow-up
FOLFIRI
Irinotecan/bolus-infusion-5-Fluorouracil/Leucovorin 
FOLFOX
Oxaliplatin/bolus-infusion-5-Fluorouracil/Leucovorin 
GCP
Good Clinical Practices 
HCG
Human Chorionic Gonadotrophin 
HIV
Human Immunodeficiency Virus 
HR
Hazard Ratio 
HRQL
Health-Related Quality of Life 
HSR
Hypersensitivity Reaction 
ICF
Informed Consent Form 
ICH
International Conference on Harmonization 
IEC
Independent Ethical Committee 
IFL
Irinotecan/5-Fluorouracil (weekly 4/6)/Leucovorin 
Ig
Immunoglobulin 
INR
International Normalized Ratio 
IMP
Investigational Medicinal Product 
IND
Investigational New Drug   
 


STUDY N° AFLIBC06097                                                                                                                                         VERSION 1.0/ 10 Feb 2012 
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IRB/IEC
Institutional Review Board/Independent Ethics Committee 
IV
Intravenous
LDH
Lactate Dehydrogenase 
LV
Leucovorin
mCRC
Metastatic Colorectal Cancer 
MedDRA
Medical Dictionary for Regulatory Activities 
MRI
Magnetic Resonance Imaging 
NCI
National Cancer Institute 
NYHA
New York Heart Association 
OS
Overall Survival 
PD
Progressive Disease 
PFS
Progression-Free Survival 
PI
Package Insert
PIGF
Placental Growth Factor 
PS
Performance Status 
RBC
Red Blood Cell 
RPLS
Reversible posterior Leuko-encephalopathy  
ORR
Overall Response Rate 
SAE
Serious Adverse Event
SAP
Statistical Analyses Plan 
SD
Standard Deviation 
TMA
Thrombotic micro-angiopathy 
ULN
Upper Limit of Normal 
UPCR
Urinary Protein-Creatinine Ratio 
VEGF
Vascular Endothelial Growth Factor 
WBC
White Blood Cell 
 


STUDY N° AFLIBC06097                                                                                                                                         VERSION 1.0/ 10 Feb 2012 
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5.
INTRODUCTION AND RATIONALE 
5.1 Colorectal cancer 
Colorectal cancer is among the most frequent tumor types in the western countries, being the third 
most commonly diagnosed cancer in males (after lung and prostate) and the second most common 
in females (after breast cancer) with an increasing incidence in the low-risk area countries (Ref. 1).
In 2008, the incidence of colorectal cancer was over 1.2 million cases, with mortality over 600,000 
worldwide (Ref. 2). The end prognosis is dependent upon the extent of the disease. The five year 
survival rate in early localized stage of about 90% decreases to approximately 60-65% after spread 
to adjacent organ(s) or lymph nodes and is about 5-8% after spread to distant sites (Ref.3).
When diagnosed before nodal involvement, treatment is usually limited to surgical resection (and 
radiotherapy for patients with rectal cancer). Patients with nodal involvement are candidates for 
adjuvant chemotherapy following initial surgery in the attempt to prevent metastatic recurrence of 
the disease. Once spread to distant sites, treatment essentially consists of palliative 
chemotherapy.
Despite the fact that 75% to 80% of all the patients with colorectal carcinoma will present at a 
stage when all gross carcinoma can be surgically removed, almost half of these patients will 
develop metastatic disease. Furthermore, typically 20% to 25% of the patients present with 
metastatic disease at diagnosis. Although mortality rates have been decreasing due to improved 
treatment options and early detection, once metastases are present median overall survival with 
available combination therapy is around 24 months (Ref. 4, Ref. 5, Ref. 6).
5.2 Metastatic colorectal cancer treatment 
For many years, chemotherapy for colorectal cancer has been based on the use of the 
antimetabolite 5-fluorouracil (5-FU), administered with leucovorin (LV). Modifications in the 
administration schedules of this combination have yielded improvements in its use, with the 
fortnightly administration of bolus 5-FU and LV followed by 5-FU infusion, demonstrating improved 
activity (in terms of response rate and PFS) and safety over the so-called Mayo regimen (monthly 
5-day bolus regimen) (Ref. 7). This combination, however, did not result in any improvement on 
survival (Ref. 8).
Improved survival in patients with colorectal cancer was not observed until the development of 
oxaliplatin and the topoisomerase I inhibitor irinotecan when phase 3 studies combining any of 
those agents with 5-FU and LV in a first-line metastatic setting showed median overall survival of 
15 to 19 months (Ref. 9, Ref. 10, Ref. 11).
Currently, initial therapy in patients with mCRC is based on oxaliplatin-based chemotherapy
(FOLFOX, 
capecitabine/oxaliplatin) 
or 
FOLFIRI 
(fortnightly 
leucovorin/bolus-infusional 
5-
FU/irinotecan). IFL, a previously used irinotecan-based regimen, is no longer used routinely due to 
safety concerns and has largely been replaced by FOLFIRI.  
Therapy after first progression of the disease is based on a crossover from oxaliplatin treatment to 
irinotecan or vice-versa. The results from sequential therapy, reported by Tournigand et al, in a 
study in which patients with newly diagnosed mCRC were randomized to FOLFOX followed by 
FOLFIRI or the reverse sequence as first and second-line treatments support this approach (Ref.
5).
Todays standard treatments for mCRC have evolved to include the addition of targeted biologic 
therapies to the combination of 5-FU/LV with either oxaliplatin (FOLFOX) or irinotecan (FOLFIRI). 
 


STUDY N° AFLIBC06097                                                                                                                                         VERSION 1.0/ 10 Feb 2012 
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Targets for biologic therapies include vascular endothelial growth factor (VEGF) and epidermal 
growth factor receptor (EGFR). 
Anti-VEGF therapy
Several malignant tumors are dependent on angiogenesis (the growth of new blood vessels from 
existing vasculature) to maintain a source of nutrition and oxygen from the body to support their 
growth and metastasis. VEGF has become a major target for anti-angiogenic therapy because its 
overexpression in several tumor types (including tumors of the gastro-intestinal tract) has been 
associated with increased tumor vascularity, proliferation, progression, invasion, metastasis, and 
poor prognosis.
Furthermore, it has been shown that the level of VEGF is particularly elevated in patients with 
metastatic colorectal cancer, suggesting that the VEGF-induced increase in vascular permeability 
may contribute to the formation of malignant ascites.  
mCRC is one of the first malignancy in which a clear benefit was demonstrated with an anti-VEGF 
treatment in randomized clinical trials.  
Bevacizumab is a humanized monoclonal antibody that targets VEGF-A, a member of the VEGF-
receptor activating ligands. It has demonstrated a survival benefit in the first-line [in combination 
with IFL, FOLFIRI and FOLFOX (Ref. 6, Ref. 12) and second-line (in combination with FOLFOX) 
treatment of mCRC (Ref. 13).
In a recent press release a statement was made that bevacizumab tested in combination with 
standard chemotherapy (either irinotecan or oxaliplatin based) as second line treatment following a 
first-line treatment with standard chemotherapy in combination with bevacizumab, met its primary 
endpoint of overall survival. More results are awaited (ML18147 study) and expected to be 
presented at an upcoming medical oncology conference. 
Anti-EGFR therapies
Both cetuximab and panitumumab (respectively a chimeric and a fully human monoclonal antibody 
binding to EGFR) demonstrated activity in patients with refractory mCRC (Ref. 14, Ref. 15). After 
early indications that cetuximab could improve efficacy when combined with irinotecan in mCRC 
(Ref. 16), the phase 3 CRYSTAL study of FOLFIRI with or without cetuximab in first-line patients 
was able to demonstrate a significant improvement in PFS (the primary objective) and response 
rate in patients treated with cetuximab and FOLFIRI (Ref. 17), but showed no statistically 
significant improvement in overall survival. Post-hoc analysis, performed to evaluate the impact of 
KRAS status on the effect of adding cetuximab to FOLFIRI, demonstrated that patients with KRAS 
mutations received no benefit from cetuximab (Ref. 18). Similar results in the same patient setting 
were reported with the combination of cetuximab with the FOLFOX regimen (Ref. 19). Recently, a 
phase 3 trial with panitumumab combined to FOLFOX in the first-line setting and to FOLFIRI in the 
pre-treated setting, failed to demonstrate a significant survival advantage over FOLFOX and over 
FOLFIRI, respectively, even in wild type KRAS mCRC patients (Ref. 20, Ref. 21).
Initial therapy in patients with mCRC is actually based on oxaliplatin/5-FU/LV or on irinotecan/5-
FU/LV chemotherapy combined with bevacizumab followed by the alternate sequence in second 
line setting, either with or without biologics.
Cetuximab and panitumumab are palliative options for patients whose tumors harbor wild-type 
KRAS, but their addition to chemotherapy has not yet shown a significant improvement in overall 
survival. 
 


STUDY N° AFLIBC06097                                                                                                                                         VERSION 1.0/ 10 Feb 2012 
5.3 Aflibercept background 
Aflibercept (referred also as VEGF-Trap or AVE0005) is a novel antiangiogenic agent. It is a 
recombinantly-produced fusion protein consisting of human VEGF receptor extracellular domains 
(from both VEGFR1 and VEGFR2) fused to the Fc portion of human IgG1 (Immunoglobulin G1).  
Figure 1 – Aflibercept schematic representation (VEGF Trap)  
Aflibercept interferes with the biological actions of VEGF by complexing VEGF in the blood stream 
and extravascular space and preventing it from interacting with its receptors on endothelial cells. 
The molecule functions as a soluble decoy receptor for VEGF with high affinity to all VEGF-A 
isoforms (i.e. binds more tightly to aflibercept than to native receptors), VEGF-B and placental 
growth factor (PlGF1 and PIGF2) and with a long circulating half life. 
Aflibercept was designed to prevent the growth of primary and metastatic tumors by blocking tumor 
angiogenesis and vascular permeability. 
In preclinical studies aflibercept inhibited tumor growth, either as single agent or in combination 
with chemotherapy, in a variety of mouse tumor models and acted synergistically when combined 
with standard chemotherapeutic agents,  5-fluorouracil and irinotecan included. 
Phase I and early phase II clinical trials demonstrated activity in a range of tumor types with 
increased responses when used in combination with chemotherapy, including also 5-fluorouracil 
and irinotecan (phase I trial TCD6118). 
The pharmacokinetics of free aflibercept appeared to be linear between the 2 and 7 mg/kg dose 
levels while bound aflibercept increased with dose between 0.3 and 2 mg/kg, reaching a plateau 
thereafter between 2 and 7 mg/kg, suggesting that free aflibercept is present in sufficient amount to 
bind all endogenous VEGF at these higher dose levels.  
The 4 mg/kg dose, administered once every 2 weeks, was selected for development, as it 
appeared to provide an adequate aflibercept free/bound ratio at the end of a q2 week dosing 
interval, at the steady state. 
The preliminary activity observed in the dose escalation Phase I (TCD6118) with standard doses of 
irinotecan/5FU/LV together with the above mentioned preclinical activity were the basis for the 
conduction of the pivotal phase III study EFC10262/VELOUR in mCRC patients. 
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STUDY N° AFLIBC06097                                                                                                                                         VERSION 1.0/ 10 Feb 2012 
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The VELOUR phase III double-blind clinical trial has been conducted in 1.226 patients with 
metastatic colorectal cancer (mCRC) who progressed during or after the completion of treatment 
with an oxaliplatin-based regimen. Patients were randomised either to receive aflibercept 4 mg/kg 
in combination with FOLFIRI (n=612) every 2 weeks or FOLFIRI every 2 weeks (n=614) alone. 
Primary endpoint was overall survival (target hazard ratio (HR) was 0.8 with 90% power and a 2-
sided type I error of 0.05); secondary endpoints included Progression-free survival (PFS), overall 
response rate (ORR), safety and pharmacokinetic. Stratification factors were prior bevacizumab 
therapy (that was permitted) and ECOG PS. Approximately 28% of patients in each arm received 
prior bevacizumab as part of their initial treatment. 
The median number of cycles delivered was 9 in the aflibercept arm compared to 8 in the placebo 
one. OS was based on 863 death events out of 1216 treated patients.  
The median OS was significantly longer in the aflibercept arm (13.5 months) compared to placebo 
(12.06 months) with an HR= 0.817 [95% CI, 0.71-0.94], p = 0.0032. The survival curves separated 
early and continued to separate throughout the follow-up period. The clinical benefit of aflibercept 
treatment is further observed by the increase in the 2-year survival rate. Median PFS was 
significantly higher in the aflibercept arm, with an absolute increase of 2.23 months over the 
placebo arm (6.9 months versus 4.67 mo; HR=0.76 [95%CI, 0.58-0.99], p=0.00007), representing 
approximately a 25% reduction in the risk of disease progression. The ORR (evaluable population) 
in the aflibercept arm was significantly higher than in placebo (19.8% versus 11.1%, p=0.0001).  
Pre-specified subgroup analyses (accounting for stratification factors and patient characteristics)
supported consistency and robustness of the efficacy results (OS and PFS) across all domains, 
including prior treatment with bevacizumab, with no evidence of interaction between treatment and 
prior bevacizumab exposure. A significant interaction was observed between treatment arm and 
the presence of liver metastases only, indicating a greater treatment effect in this group of patients, 
as compared with patients with disease not confined to the liver or no liver disease. 
Adverse events (AEs) were similar to the safety profile of FOLFIRI chemotherapy. Grade 3-4 
adverse events (AEs) with > 2% higher incidence in aflibercept arm vs placebo were diarrhea, 
asthenia/fatigue, 
stomatitis/ulceration, 
infections, 
hypertension, 
GI/abdominal 
pain, 
neutropenia/neutropenic complications and proteinuria. AEs leading to treatment discontinuation 
occurred in 26.6% and 12.1% of patients in aflibercept and placebo arm respectively. For 
aflibercept the most common causes were asthenia/fatigue, infections, diarrhea, hypertension and 
venous thromboembolic events. The incidence of grade 3-4 adverse events were as expected with 
the anti-VEGF class of agents, and were similar among patients with and without prior 
bevacizumab exposure. Grade 3-4 hypertension occurred in 16.6% and 20.5% of these groups, 
respectively. Prior treatment with bevacizumab did not appear to significantly impact the safety 
profile of aflibercept (Ref. 22, Ref. 23).
Further details on preclinical, clinical safety and preliminary efficacy are provided in the 
Investigator’s Brochure, which contains comprehensive information on aflibercept (Ref. 24).
5.4 Study rationale 
Treatment options for patient with previously treated metastatic colorectal cancer are limited and, 
prior to the public presentation of the VELOUR study results, no biological therapies have been 
shown to provide a survival benefit in the second-line setting in patients who are being treated with 
FOLFIRI. This still remains to be the case and at need to add another treatment option to the 
current battery of therapies. 
 


STUDY N° AFLIBC06097                                                                                                                                         VERSION 1.0/ 10 Feb 2012 
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Aflibercept is the first therapeutic agent in combination with FOLFIRI to demonstrate survival 
benefit in non-selected patients with mCRC who had progressed following an oxaliplatin-based 
regimen.
Aflibercept in the oncology setting is an investigational agent and has not been approved for 
marketing by any Regulatory Authority to date. VELOUR results will serve as basis of worldwide 
marketing authorization dossier filings. 
The use of a non-registered product within a pre-approval access program (i.e. before marketing 
authorisation is released) may be a treatment option for patients with an unmet medical need for 
which no suitable or clinically satisfactory similar alternative is currently available or when similar 
alternative treatments failed. 
The results of the VELOUR trial are expected to generate significant interest and increase demand 
for accessing aflibercept because of the medical need, among the 2L mCRC patients. 
This study is therefore required to allow patients and physicians access to aflibercept for the 
management of mCRC patients having progressed after an oxaliplatin-based regimen.  
This study will permit collection of data from the VELOUR target patient population in the real-life 
setting and across different geographical areas with the aim to capture utility values derived from 
Quality of Life (QoL) instruments and everyday practice safety data in order to raise awareness of 
the anticipated toxicities typical of the anti-angiogenic class and to further extend understanding of 
recently reported benefit patient showed from VELOUR.
Investigators who had previous experience with aflibercept (i.e., who have had at least one patient 
treated in the VELOUR trial) or have extensive experience in administering anti-angiogenic agents 
will be invited to participate in this study.  
Investigators who have not previously participated in the VELOUR trial will be specifically trained 
on the use of aflibercept and the management of its adverse events. 
6.
STUDY OBJECTIVES 
6.1 Primary
To provide mCRC patients (similar to the patients evaluated in the VELOUR phase III trial) and 
Investigators with access to aflibercept, prior to its marketing authorisation and/or commercial 
availability and to document the aflibercept overall safety in this patient population. 
6.2 Secondary
To document the Health-Related Quality of Life (HRQL) of aflibercept in this patient population. 
7.
STUDY DESIGN 
7.1 Description of the protocol 
This is a phase IIIb/IV, international, multicenter, single arm, open-label study.
 


STUDY N° AFLIBC06097                                                                                                                                         VERSION 1.0/ 10 Feb 2012 
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7.2 Duration of study  
The study will be initiated in the second quarter of 2012 in Europe and in the United States, 
simultaneously or sequentially in the other involved countries.  
In each country patient recruitment will end when aflibercept (ZALTRAP) becomes commercially 
available (i.e. accessible to the patient as per each country regulation).  
Patients already on study will continue to be treated until disease progression, death, unacceptable 
toxicity, Investigator’s decision or patient’s refusal of further treatment, whichever comes first. 
8.
SELECTION OF PATIENTS 
8.1 Number of patients planned 
It is planned to include a total of approximately 900 patients in this study, from around 150 
investigational sites, over about 20 months of accrual. 
Global study accrual will be terminated when the anticipated number of patients has been achieved 
across all study sites. 
Actively treated patients from VELOUR (EFC10262) study who will be still under treatment with 
aflibercept at the time of initiation of this study will be allowed to rollover on to this study if 
according to their treating Investigator’s opinion they are continuing to derive benefit from 
treatment with aflibercept.  
No confirmation of entry criteria will be required for these patients provided they meet the criteria to 
initiate a subsequent cycle of therapy.  
A new patient number will be assigned to these patients, however the patient number from the 
VELOUR study and the new study number will be annotated on a specific form to be able to track 
individual patients from the parental protocol to this study. 
8.2 Inclusion criteria 
I01
Histologically or cytologically proven adenocarcinoma of the colon or rectum
I02
Metastatic disease 
I03
Age 18 years
I04
ECOG PS 0-1 
I05
One and only one prior chemotherapeutic regimen for metastatic disease This prior 
chemotherapy must be an oxaliplatin containing regimen. Patients must have 
progressed during or following the last administration of the oxaliplatin based 
chemotherapy. Patients relapsing within 6 months of completion of oxaliplatin 
adjuvant chemotherapy are also eligible. 
I06
Signed written informed consent
 


STUDY N° AFLIBC06097                                                                                                                                         VERSION 1.0/ 10 Feb 2012 
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8.3 Exclusion criteria 
E01
Prior therapy with irinotecan 
E02
Inadequate bone marrow function as follow:
x
Absolute neutrophil count (ANC) < 1.5 x 109/L
x 
Platelet count < 100 x 109/L
x 
Hemoglobin < 9.0 g/dL 
E03
Inadequate liver function tests: 
x
Total bilirubin >1.5 x ULN 
x 
Transaminases >3 x ULN (unless liver metastasis are present, 5 x ULN in that case) 
x
Alkaline phosphatase >3 x ULN (unless liver metastasis are present, 5 x ULN in that 
case)
E04 
Less than 4 weeks elapsed from prior radiotherapy or prior chemotherapy to the time 
of inclusion. Less than 4 weeks following major surgery to the time of inclusion or 
until the surgical wound is fully healed, whichever came later (48 hours in case of 
minor surgical procedure or until wound full healing observed) (ref to section 9.1.3
for examples of minor surgeries). 
E05
Treatment with any investigational drug within 30 days prior to inclusion. 
E06
Adverse events (with exception of alopecia, peripheral sensory neuropathy and 
those listed in specific exclusion criteria) from any prior anti cancer therapy of grade 
>1 (National Cancer Institute Common terminology Criteria [NCI CTCAE] v.4.0) at 
the time of inclusion. 
E07
History of brain metastases, uncontrolled spinal cord compression, or carcinomatous 
meningitis or new evidence of brain or leptomeningeal disease. 
E08
Other prior malignancy. Adequately treated basal cell or squamous cell skin cancer, 
carcinoma in situ of the cervix or any other cancer from which the patient has been 
disease free for > 5 years are allowed. 
E09
Any of the following within 6 months prior to inclusion: myocardial infarction, 
severe/unstable angina pectoris, coronary/peripheral artery bypass graft, NYHA 
class III or IV congestive heart failure, stroke or transient ischemic attack. 
E10
Any of the following within 3 months prior to inclusion: Grade 3-4 gastrointestinal 
bleeding/hemorrhage, treatment resistant peptic ulcer disease, erosive oesophagitis 
or gastritis, infectious or inflammatory bowel disease, diverticulitis, pulmonary 
embolism or other uncontrolled thromboembolic event. 
E11
Occurrence of deep vein thrombosis within 4 weeks, prior to inclusion. 
E12
Known acquired immunodeficiency syndrome (AIDS-related illnesses) or known HIV 
disease requiring antiretroviral treatment. 
E13
Any severe acute or chronic medical condition, which could impair the ability of the 
patient to participate to the study or to interfere with interpretation of study results. 
 


STUDY N° AFLIBC06097                                                                                                                                         VERSION 1.0/ 10 Feb 2012 
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E14
Known dihydropyrimidine dehydrogenase deficiency 
E15
Predisposing colonic or small bowel disorders in which the symptoms were 
uncontrolled as indicated by baseline of > 3 loose stools daily. 
E16
Prior history of chronic enteropathy, inflammatory enteropathy, chronic diarrhea, 
unresolved bowel obstruction/sub-obstruction, more than hemicolectomy, extensive 
small intestine resection with chronic diarrhea. 
E17
History of anaphylaxis or known intolerance to atropine sulphate or loperamide or 
appropriate antiemetics to be administered in conjunction with FOLFIRI. 
E18
Treatment with concomitant anticonvulsivant agents that are CYP3A4 inducers 
(phenytoin, phenobarbital, carbamazepine), unless discontinued >7 days. 
E19
Patients with known Gilbert’s syndrome. 
E20
Pregnant or breast-feeding women. Positive pregnancy test (serum or urine ȕ-HCG) 
for women of reproductive potential.  
E21
Patients with reproductive potential (female and male) who do not agree to use an 
accepted effective method of contraception during the study treatment period and for 
at least 6 months following completion of study treatment. The definition of effective 
method will be left to the investigator’s judgment. 
E22
For female patients enrolled in United Kingdom, the following methods of 
contraception are acceptable: oral contraceptives accompanied by the use of a 
second method of contraception, as it is not known how oral contraceptives interact 
with study medications or Intra Uterine Device (IUD) or women who are surgically 
sterile, or women who are post –menopausal or other reasons have no chance of 
becoming pregnant. 
Exclusion criteria related to aflibercept:
E23
Urine protein-creatinine ratio (UPCR) >1 on morning spot urinalysis or proteinuria > 
500 mg/24-h. 
E24
Serum creatinine > 1.5 x upper limit of normal (ULN). If creatinine 1.0-1.5 x ULN, 
creatinine clearance, calculated according to Cockroft-Gault formula, < 60 ml/min will 
exclude the patient. 
E25
Uncontrolled hypertension (defined as blood pressure > 140/90 mmHg or systolic 
blood pressure >160 mmHg when diastolic blood pressure < 90 mmHg, on at least 2 
repeated determinations on separate days, or upon clinical judgement) within 3 
months prior to study inclusion. 
E26
Patients on anticoagulant therapy with unstable dose of warfarin and/or having an 
out-of-therapeutic range INR (>3) within the 4 weeks prior to inclusion. 
E27
Evidence of clinically significant bleeding diathesis or underlying coagulopathy (e.g. 
INR>1.5 without vitamine K antagonist therapy), non-healing wound. 
No waiver, prospective or retrospective, to deviate in any way from the inclusion/exclusion criteria 
can be granted to investigators. 
 




STUDY N° AFLIBC06097                                                                                                                                         VERSION 1.0/ 10 Feb 2012 
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The volume of aflibercept to be administered to each patient, and hence the rate of infusion, will be 
based on each patient’s weight. The pharmacist or designee will prepare the dosing solution as 
follows:
 
Calculate the number of aflibercept vials needed according to the patient’s body weight, 
and the aflibercept intended dose. 
Then:
 
Withdraw the exact volume of aflibercept needed, according to body weight and intended 
dose, from vials, 
 
And dilute directly into the infusion bag (0.9% NaCl or 5% dextrose) to obtain a final 
concentration for the diluted solution ranging from 0.6 mg/ml to 8.0 mg/ml. 
Infusion can be conducted by gravity or, with an IV infusion pump, or with a syringe pump using 
administration sets made of above listed materials. 
Aflibercept IV dose should be infused over 1 hour. The infusion should not exceed 2 hours at 
ambient temperature (approximately 25°C). 
9.1.3
Precautions
All IMP packages are to be inspected upon receipt at the study site and the individual vials 
inspected prior to being drawn up. If a vial is chipped or any particulate matter or cloudiness is 
detected, the vial is not to be used. Cloudy or damaged vials are to be reported to the sponsor and 
returned to the refrigerator until instructions have been given. As aflibercept is a protein, the vials 
are not to be shaken. 
Given the investigational nature of the product and to provide the patients with the maximum level 
of safety in case of an unexpected event, the following requirements must be fulfilled before any 
administration of the Investigational Medicinal Product can start and for a minimum of 1 hour 
following the completion of the infusion:  
Immediate access to appropriate resuscitative equipment. 
Appropriately qualified and trained personnel must be on site.  
Aflibercept should not be administered less than 48 hours following minor surgical procedures 
(e.g., fine needle biopsy/aspiration, placement of a central venous access device, or 
removal/biopsy of a skin lesion), or until evidence of wound healing (e.g., scab formation) is 
observed, whichever is longer. Aflibercept may be administered peripherally via peripheral venous 
catheter inserted prior to and removed immediately following peripherally administered doses. 
Infusion and hypersensitivity reactions may occur during or shortly after intravenous administration 
of protein therapeutics. If infusion or hypersensitivity reactions occur in a given patient, institutional 
treatment guidelines for similar therapeutic agents or protocol guidelines should be followed (see 
Table 3). In case of severe reaction (grade t 3) aflibercept should be permanently discontinued.  
9.2 Non Investigational Medicinal Products (Background treatments) 
Marketed formulation of irinotecan, 5-FU and leucovorin will be used. For all these products refer to 
package insert or summary of product characteristics for details on description, preparation, 
administration, warnings and precautions for use. 
The Sponsor will not provide these products. 
 


STUDY N° AFLIBC06097                                                                                                                                         VERSION 1.0/ 10 Feb 2012 
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9.3 Dosage and schedule of administration 
On day 1 of each cycle patients will receive aflibercept followed by irinotecan, 5-FU and leucovorin 
(FOLFIRI regimen). This treatment will be repeated every 2 weeks. 
Aflibercept: 4 mg/kg will be administered IV over 1 hour on Day 1, every 2 weeks, prepared and 
administered as described in Section 9.1.2.
FOLFIRI administration will immediately follow the aflibercept one. The dosage and schedule used 
in the VELOUR trial are described hereafter, for reference.  
 
Irinotecan 180 mg/m2 IV infusion in 500 mL D5W over 90 minutes and dl leucovorin* 400 
mg/m² IV infusion over 2 hours, at the same time, in bags using a Y-line, followed by: 
 
5-FU 400 mg/m² IV bolus given over 2-4 minutes, followed by: 
 
5-FU 2400 mg/m² continuous IV infusion in 500 mL D5W (recommended) over 46-hours. 
The starting dose of irinotecan and/or 5-FU components of FOLFIRI regimen should take into 
consideration toxicities from prior regimens received by the patient and the patient characteristics 
(e.g. UGT1A1*28 allele status, when known). In case drugs (5FU) administered during previous 
chemotherapy regimen were reduced due to toxicity, the decision to administer or not the full 
starting dose of FOLFIRI (irinotecan, 5FU continuous and/or bolus infusion) is left to the 
investigator’s decision based on his/her clinical judgement of patient benefit at time of inclusion in 
this trial. Reduced doses of 5-FU to those that were tolerable when used with the previous regimen 
would be acceptable.  Similar consideration and clinical judgement should be used when 
determining the initial starting dose of irinotecan. 
*400 mg /m² of leucovorin expressed in dl racemic. When the l-isomer form is used the dose should be 
divided by 2, i.e. 200 mg/m² 
Doses should be based upon actual body weight measured before each administration.  
In case BSA > 2.0 m², the actual doses of irinotecan and 5-FU should be adjusted to a maximum 
BSA of 2.0 m², for safety reasons. 
9.3.1
Premedication
Cholinergic adverse effects (including early diarrhea): unless contra-indicated, 0.25 -1mg 
intravenous or subcutaneous atropine may be given. 
Antiemetic: appropriate prophylactic anti-emetic therapy is left to current hospital practices.  
Granulocyte-colony stimulating factor (G-CSF): therapeutic use of Granulocyte Colony-Stimulating 
Factor (G-CSF) may be considered (if consistent with the local institutional treatment practice), 
upon occurrence of a first episode of grade >3 neutropenia and as secondary prophylaxis for 
subsequent cycles, in patients who may be at increased risk for neutropenia complications. 
9.3.2
Schedule modification 
Cycle length is 2 weeks (± 2 days). Delays of up to 2 weeks in case of unresolved toxicity at the 
time of planned re-administration are permitted (note that in some circumstances, administration of 
aflibercept could be omitted for one cycle as indicated in Table 2 and Table 3 and ). Doses may be 
modified or infusion delayed for toxicity as described in Section 9.3.3. New cycles of therapy may 
not begin until any drug-related toxicity has been adequately resolved. The treatment will continue 
until a definitive treatment discontinuation criterion is met (see Section 12.2.1).
 


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9.3.3
Dosage modification 
Dose adjustment and/or cycle delay are planned in case of toxicity. Dose adjustments will be made 
according the worst grade toxicity. Toxicities will be graded according the NCI-CTC AE V. 4.0 scale 
(Ref. 30) (Appendix C). Patient will receive the next cycle after recovery of the toxicity. 
If a patient experiences several toxicities and there are conflicting recommendations, the most 
conservative dose adjustment recommended (dose reduction appropriate to the most severe 
toxicity) should be followed. Once a dose has been decreased, intra-patient re-escalation back to 
the previous dose level is not permitted. 
In case of toxicity from treatment, administration should be delayed until: 
 
neutrophil count is t 1.5 X 109/L and platelet count is t 75 X 109/L 
 
recovery to grade d 1 for other toxicities (except alopecia and if otherwise specified). 
The maximum delay allowed is of 2 weeks. 
If FOLFIRI (the whole regimen or any of its components) is permanently discontinued, then 
aflibercept should be continued until disease progression or unacceptable toxicity or patient’s 
refusal of further treatment.  
If aflibercept is permanently discontinued, then FOLFIRI can be continued until disease 
progression or unacceptable toxicity or patient’s refusal of further treatment.  
The end of treatment will be the date of the last treatment administration, either aflibercept or 
FOLFIRI whichever comes last.
9.3.3.1
Aflibercept
Aflibercept dose reduction is described in the Table 1. Only one dose reduction is allowed.  
Sponsor should be contacted by Investigator for discussion on a case by case basis if deemed 
appropriate, upon clinical judgment.
Table 1 – Aflibercept dose reduction level 
Initial dose
(mg/kg) 
Dose reduction, 
level – 1 
(mg/kg) 
Aflibercept
4
o
2
Actions considered for aflibercept according to the type of toxicity, are described in Table 2 and 
Table 3.
 


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Table 2 – Dose modifications for aflibercept 
Toxicity 
Grade
Action
Hypertension  
Grade d 2
Grade 3 
(requiring 
more than one 
drug or more 
intensive
therapy than 
previously)  
Grade 4 
Initiate antihypertensive drug therapy (see recommendation below) 
and close monitoring of blood pressure for further adjustment, as 
needed.  
No dose modification and no delay. 
Modify antihypertensive drug therapy (see recommendation below).  
Delay the administration of both FOLFIRI and aflibercept for a 
maximum of 2 weeks, until recovery to blood pressure (BP) d 140/90 
or to systolic BP < 160 if diastolic BP < 90 for patients with known 
history of isolated systolic hypertension: 
x 
If BP is controlled within 2 weeks delay: 
- First episode: re-administer FOLFIRI and aflibercept at the 
same dose. 
- Second episode: re-administer FOLFIRI and aflibercept, 
with aflibercept reduced to dose level -1. 
-Third episode, discontinue aflibercept. 
x 
If 
BP 
is 
still 
uncontrolled 
despite 
appropriate 
anti 
hypertensive treatment and after 2 weeks delay: 
Administer FOLFIRI and discontinue aflibercept for 1 cycle; 
the reintroduction of aflibercept at a dose reduced to dose 
level – 1 will be reconsidered at the time of the administration 
of the subsequent cycle (in combination with FOLFIRI), only 
if BP is controlled at the time of re-administration.  
x 
In case of re-occurrence of grade 3 BP, in presence of 
maximal/optimal antihypertensive therapy despite dose 
reduction of aflibercept, or if BP is still uncontrolled despite 1 
omission of administration of aflibercept, the patients will be 
permanently discontinued from aflibercept. FOLFIRI will be 
continued if the investigator thinks the patient is benefiting 
from it.
Seek cardiologist opinion, and permanently discontinue aflibercept. 
Toxicity 
Grade
Action to be taken 
Arterial 
thromboembolic 
events (e.g.:
myocardial infarction, 
or stroke, etc) 
documented by 
appropriate tests  
Any Grade 
Permanently discontinue aflibercept 
Hemorrhage 
Grade 3-4 
Permanently discontinue aflibercept 
GI perforation/ 
fistula formation 
Any Grade 
Permanently discontinue treatment. 
 


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Grade
Action to be taken 
Toxicity 
Reversible posterior 
Leuko-
encephalopathy 
syndrome 
documented with 
appropriate tests 
Any grade 
Permanently discontinue treatment. 
Venous
Thromboembolic 
Event documented 
by appropriate tests 
Grade 3 
(DVT) 
Grade 4 (PE) 
First episode: Treat DVT with heparins and continue treatment a
Second episode despite appropriate anticoagulation: Permanently 
discontinue aflibercept 
Permanently discontinue aflibercept b
a Based on investigator’s judgement in assessing potential risk of extension and/or embolization. 
b Continuation of aflibercept may be considered, depending on individual patient benefit/risk assessment in 
case of incidental discovery of asymptomatic pulmonary embolism.
Hypertension therapy recommendations:

For patients without prior antihypertensive therapy, at the time of the hypertensive episode 
a close monitoring of the BP (every 2 weeks is recommended) should be initiated for 
adjustment in treatment, as needed. Ultimately, antihypertensive treatment must be 
individualized based on the presence of comorbidity factors such as diabetes, 
cardiovascular or renal disease, additionally taking into account the safety and the efficacy 
of any prior antihypertensive therapy received. Oral and/or intravenous sodium intake 
should be carefully monitored in these patients. 

For patients already under anti-hypertensive therapy, efforts should be done to optimize the 
existing therapy before adding other agents as required to control the BP.  
When hypertension is accompanied by signs or symptoms of end organ damage such as 
hypertensive retinopathy, kidney function abnormalities (like progressive proteinuria), or any signs 
or symptoms of cardiovascular morbidity or central nervous system (CNS) morbidity, aflibercept 
should be interrupted. 
Proteinuria:
Determination and management of proteinuria: 
Prior to each administration of aflibercept perform a urine dipstick for WBC, RBC and protein 
(morning spot urine).
If proteinuria is < 2+ on the dipstick in absence of hematuria, aflibercept should be administered as 
planned.
If the proteinuria is > 2+ on the dipstick, UPCR (Urinary Protein/urinary Creatinine Ratio) should be 
performed prior to administration of aflibercept. 
Urinary protein creatinine ratio (UPCR) corresponds to the ratio of urinary protein and urinary 
creatinine concentrations (expressed in mg/dL). There is a high correlation between morning 
UPCR and 24-hour proteinuria in patients with normal or reduced renal function. This ratio provides 
an accurate quantification of 24-hour urinary protein excretion (Ref. 25).
UPCR to detect proteinuria, should be done on morning urine spot. If UPCR > 1, 24-hour urine 
collection to grade proteinuria will be performed. In addition, in case UPCR is greater than 2 or in 
 


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case of proteinuria of renal origin (according to urinary protein electrophoresis and/or nephrologist 
judgement) is associated with hematuria (microscopic or macroscopic), then a work up for 
considering thrombotic microangiopathy should be initiated and a nephrologist consultation be 
considered. 
Delay in availabilty of the results should not delay consultation wth a nephrologist.  
Actions with regard to aflibercept dosing will depend on the presence of hematuria and the level of 
24-hour proteinuria results. Only one dose level reduction for aflibercept is foreseen. 
Aflibercept administration should be suspended for 2 grams of proteinuria/24 hours and restarted 
when proteinuria is <2 grams/24 hours. If there is recurrence, the administration should be 
suspended until <2 grams/24 hours and then the dose reduced to 2 mg/kg.  
Aflibercept treatment should be discontinued in patients who develop nephrotic syndrome or TMA. 
Proteinuria should always be assessed taking into account the presence or absence of 
hematuria and the blood pressure status of the patient. 
Reversible posterior leuko-encephalopathy (RPLS) or clinical symptoms related to vasogenic 
edema of the white matter. 
Clinical presentations are variable and may include headache, altered mental status, seizure and 
cortical visual deficit. Hypertension is a risk factor. MRI scans are key to diagnosis and typically 
demonstrate vasogenic edema (hyperintensity in T2 and FLAIR images and hypodensity in T1 
images) predominently in the white matter of the posterior parietal and occipital lobes; less 
frequently, the anterior distributions and the gray matter may also be involved. RPLS should be in 
the differential diagnosis in patients presenting with unexplained mental status change, visual 
disturbance, seizure, or other CNS findings. RPLS is potentially reversible with early recognition of 
symptoms and timely correction of the underlying causes, including control of BP and interruption 
of the offending drug, which are important in order to prevent progression to irreversible tissue 
damage.
Gastro-intestinal perforation:
Patients should be monitored for signs and symptoms of GI perforation as this has been reported 
with anti-VEGF agents as a class. 
Hypersensitivity reaction:
In case of hypersensitivity reaction, institutional treatment guidelines for this type of AEs, or the 
following proposed guideline in Table 3 can be applied. Pre-treatment with corticosteroids and/or 
antihistamines may be considered in subsequent cycles. 
 


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Table 3 – Acute infusion reaction management 
Symptom Severity 
Intervention Recommendation 
Mild-Moderate
e.g., NCI CTCAE grade  2 cutaneous reaction, pruritus, 
flushing, rash, dyspnea, tachycardia, hypotension, anxiety, 
headache, myalgias, edema, nausea 
Stop aflibercept infusion; 
Give diphenhydramine 50 mg IV and/or IV 
dexamethasone 10 mg; 
Resume aflibercept infusion after subject 
recovery. 
Severe
e.g., symptomatic bronchospasm, generalized urticaria, 
systolic BP  80 mm Hg, angioedema, anaphylaxis 
Stop aflibercept infusion; 
Give IV diphenhydramine 50 mg and/or IV 
dexamethasone 10 mg and/or epinephrine 
as needed; 
Permanently discontinue aflibercept. 
Wound healing complications/surgery 
The half-life of bound aflibercept is approximately 20 days. Suspend aflibercept for at least 4 
weeks prior to elective surgery.  
Aflibercept therapy should not be administered for at least 4 weeks following major surgery and not 
until the surgical wound is fully healed.  
For minor surgery such as central venous access port placement, biopsy and tooth extraction, 
aflibercept may be initiated/restarted once the surgical wound is fully healed.  Aflibercept should be 
permanently discontinued in patients who develop wound dehiscence or compromised wound 
healing requiring medical intervention.
 


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9.3.3.2
FOLFIRI
In addition to optimizing supportive care, irinotecan and 5-FU dose adjustments based on the worst 
toxicity encountered during the previous cycle, may be recommended. These are at investigator’s 
discretion considering the current local prescribing information and the standard clinical practice. 
The following tables describe recommended chemotherapy dose modifications on Day 1 of a new 
cycle. These are minimum standards but more stringent/significant dose modifications can be 
instituted upon clinical judgment. 
Table 4 – FOLFIRI dose reduction level 
Initial dose (%)  
Dose Reduction, level – 1 
(% of initial dose) 
Dose Reduction, level – 2 
(% of initial dose) 
Irinotecan
100
o
85-80 
o
70-60 
Bolus 5-FU 
100
o
80
o
60
Infusional 5-FU 
100
o
80
o
60
Note: in general a dose reduction of irinotecan by 15-20% and of 5-FU, bolus and infusion, of 20% may be 
considered.
Table 5 - Chemotherapy dose modifications for hematologic toxicity 
Hematologic Toxicity 
Grade 2 
Grade 3-4 
Associated measure 
Isolated neutropenia 
NA
No dose reduction, except if 
grade 
4 
neutropenia 
>7 
days.
Febrile neutropenia 
and neutropenic 
sepsis
NA
 First episode: reduce 
irinotecan by 1 dose level*. 
 Second episode: reduce 5-
FU bolus by 1 dose level. 
 Third episode: discontinue 
chemotherapy. 
 Administer G-CSF upon 
occurrence of first event of 
grade 3 neutropenia 
 Administer prophylactic G-
CSF in subsequent cycles 
Thrombocytopenia
Full dose 
 First episode: reduce 5-FU 
(bolus and infusion) by 1 
dose level. 
 Second episode: reduce 
irinotecan by 1 dose level. 
 Third episode: discontinue 
chemotherapy. 
Notes:  
x 
Depending on institution guidelines decision to reduce the dose could be postponed to after initiation 
of G-CSF 
 


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Table 6 – Chemotherapy dose modifications for non-hematologic toxicity 
Non-Hematologic 
Toxicity 
Grade 2 
Grade 3 
Grade 4 
Diarrhea
Full dose 
 First episode: reduce irinotecan by 1 dose level 
 Second episode: reduce 5-FU (bolus and infusion) 
by 1 dose level. 
 Third episode: discontinue chemotherapy. 
Stomatitis
Full dose 
Reduce 5-FU (bolus and 
infusion) by 1 dose level. 
Reduce 5-FU (bolus 
and infusion) by 2 
dose levels. 
Palmar-Plantar
Erythrodysesthesia 
Full dose 
Reduce 5-FU (bolus and 
infusion) by 1 dose level. 
NA
Bilirubin increase 
Delay next infusion until 
recovery to grade d 1 
(bilirubin d 1.5 x ULN): 
 First episode, no dose 
reduction 
 Second episode, reduce 
irinotecan by 1 dose level 
 Third episode, reduce 
irinotecan by a second 
dose level 
 Fourth episode, 
permanently discontinue 
irinotecan. 
Persisting grade 2 (bilirubin 
>1.5 x ULN and d 3 x ULN) 
after 2 weeks delay: 
 First episode, reduce 
irinotecan by 2 dose levels 
 Second episode, 
permanently discontinue 
irinotecan. 
Delay next infusion until 
recovery to grade d 2 
(bilirubin d 3 x ULN). 
Persisting grade 3 (bilirubin 
>3.0 x ULN and d 10 x ULN) 
after 2 weeks delay, 
permanently discontinue 
irinotecan. 
Permanently 
discontinue FOLFIRI. 
Transaminases 
increase 
No dose reduction 
Delay next infusion until 
recovery to grade d 2. 
Persisting grade 3 after 2 
weeks delay, permanently 
discontinue irinotecan. 
Permanently 
discontinue FOLFIRI. 
Alkaline
Phosphatase (ALP) 
increase 
No dose reduction 
Delay next infusion until 
recovery to grade d 2. 
Persisting grade 3 after 2 
weeks delay, permanently 
discontinue irinotecan. 
Permanently 
discontinue FOLFIRI. 
Hypersensitivity 
reaction 
Discontinue irinotecan if related to irinotecan 
 


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9.3.3.3
Other toxic effects 
Any other dose modification in study treatment that are not described above may be performed at 
the discretion of the investigator, provided that criteria for patient withdrawal from study treatment 
described in Section 12.2.1, have not been met. Chemotherapy should be held for a maximum of 
two weeks from the planned date of reinfusion until resolution to  grade 1, and then reinstituted, if 
medically appropriate. A dose reduction of subsequent doses will be considered. These patients 
will be withdrawn from study treatment if >2 dose reductions for FOLFIRI or greater than 1 dose 
reduction for aflibercept are needed. 
9.4 Packaging and labeling 
This is an open-label Study and the treatments will not be blinded. 
Packaging number and quantity of vials dispensed to each patient will be recorded in the electronic 
Case Report Form (e-CRF)/Drug accountability form.
The content of the labeling is in accordance with the local regulatory specifications and 
requirements.
9.5 Storage conditions 
Aflibercept must be refrigerated at 2–8°C (36-46°F) in a locked area with restricted access and 
handled in accordance with the manufacturer’s instructions. Vials should be stored according to 
their labeling and kept in their box until use. 
For irinotecan, 5-FU and leucovorin refer to the respective package insert or summary of product 
characteristics. 
9.6 Responsibilities
The investigator, the hospital pharmacist, or other personnel allowed to store and dispense 
Investigational Medicinal Product is responsible for ensuring that the Investigational Medicinal 
Product used in the clinical trial is securely maintained as specified by the sponsor and in 
accordance with the applicable regulatory requirements. 
All Investigational Medicinal Product shall be dispensed in accordance with the investigator's 
prescription and it is the investigator's responsibility to ensure that an accurate record of 
Investigational Medicinal Product issued and returned is maintained. 
Any quality issue noticed with the receipt or use of an Investigational Medicinal Product (deficient 
IMP in condition, appearance, pertaining documentation, labeling, expiry date, etc.) should be 
promptly notified to the sponsor, who will initiate a complaint procedure. 
Under no circumstances shall the investigator supply Investigational Medicinal Product to a third 
party, allow the Investigational Medicinal Product to be used other than as directed by this clinical 
trial protocol, or dispose of Investigational Medicinal Product in any other manner. 
9.7 Retrieval and/or destruction of treatments 
9.7.1
Partially used or unused treatment 
All used treatment vials (IMP) will be destroyed by the study site after an accurate accountability 
has been performed and countersigned by the investigator (or pharmacist).  
 


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All unused vials of aflibercept will be destroyed on site or retrieved by the Sponsor, depending on 
local requirements.  
The Investigator will not destroy the unused Investigational Medicinal Product unless the Sponsor 
provides written authorization.
A detailed treatment log of the destroyed and/or returned Investigational Medicinal Product will be 
established with the Investigator (or the pharmacist) and countersigned by the Investigator and the 
Monitoring Team.
9.7.2
Potential recall 
A potential defect in the quality of Investigational Medicinal Product may be subject to initiation by 
the sponsor of a recall procedure. In this case, the investigator will be responsible for promptly 
addressing any request made by the sponsor, in order to recall Investigational Medicinal Product 
and eliminate potential hazards. 
9.8 Concomitant treatment 
During the Study, the Investigator may prescribe concomitant medications as deemed necessary.  
Supportive treatment as medically indicated for the patient’s well-being, consistent with optimal 
patient care (including hyper-alimentation, blood transfusion, heparins and anti-coagulation 
medications, erythropoietin, treatment for pain relief) and unlikely to interfere with the 
Investigational Medicinal Product may be prescribed at the Investigator’s discretion (except for 
those  contraindicated for any component of FOLFIRI regimen as per local prescribing 
information).
Antihypertensive medications: some recommendations are described in section 9.3.3.1.
Antidiarrheal medications: in case of occurrence of late diarrhea loperamide 4 mg at onset of 
diarrhea, then 2 mg q2h until the patient is diarrhea free for 12 hours (and octreotide in case of 
loperamide failure) can be considered.  
Granulocyte-colony stimulating factor (G-CSF): therapeutic use of Granulocyte Colony-Stimulating 
Factor (G-CSF) may be considered (in agreement with the local institutional treatment practice), 
upon occurrence of a first episode of grade >3 neutropenia and as secondary prophylaxis for 
subsequent cycles, in patients who may be at increased risk for neutropenia complications. 
During treatment with aflibercept the Vitamin K antagonists should be used with caution. 
The following concomitant treatments are not allowed during the study:  
x 
Other anticancer therapies, investigational therapies or devices 
x 
Concomitant radiotherapy 
x 
Anticonvulsivant 
agent 
that 
are 
CYP 
3A4 
inducers: 
phenytoin, 
phenobarbital, 
carbamazepine as well CYP 3A4 inhibitors: e.g. ketoconazole  
Patient with reproductive potential should be advised to adhere to an accepted and effective 
method(s) of birth control while on treatment and for at least 6 months after its last administration.
 


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9.9 Post-Study treatment 
Patients will continue to be treated as long as they are benefiting from the study treatment and they 
have nor met study withdrawal criteria as defined in section 12.2.1. After withdrawal from study 
treatment the patient will be switched to any appropriate therapy as per Investigator clinical 
decision.
9.10 Treatment accountability and compliance 
The Hospital Pharmacist or authorized person will inventory and acknowledge of receipt of all 
shipments of the IMP (aflibercept). Any discrepancies or quality issue upon receipt should be 
notified to the Sponsor. Administration of the study drug in accordance with the protocol will be 
supervised by the Investigator or delegate.  
The Investigator (or delegate) or pharmacist will keep accurate records of the quantities of the IMP 
dispensed (with the corresponding batch numbers) to each patient and will fill in the Treatment Log 
Forms. All these data will be also reported in the e-CRF. 
The monitor in charge of the study will ensure that the Treatment Log Form is filled in on an 
ongoing basis and will check the e-CRF by comparing the recorded data with the treatment Log 
Form.
The person responsible for drug administration to the patient will record precisely the date and time 
when drug is administered to the patient.  
10. ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT 
10.1 Efficacy 
Efficacy will not be assessed. 
10.2 Safety 
Safety profile will be determined by the incidence of adverse events (AEs) including serious 
adverse events (SAEs). AEs will be collected from the time the patient signs the informed consent 
form through 30 days after the last administration of the treatment (either aflibercept or FOLFIRI). 
Toxicity will be graded according to the National Cancer Institute Common Terminology Criteria for 
Adverse Events, Version 4.0 (NCI CTCAE v 4.0) and summarized using MedDRA terminology. 
Information on the following parameters will be collected by the investigator and reported in the e-
CRF:
x 
Clinical examination, including body weight, ECOG PS (Appendix B) and BP. 
x 
Laboratory data:

Complete blood count and clinical chemistry 

Urinalysis
x 
AEs and SAEs. 
Laboratory safety work-up will be carried out by local laboratory according to standard operating 
procedures.
 


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Note: Any abnormal laboratory value or medical investigation result must be immediately 
rechecked for confirmation before making a decision of permanent discontinuation of 
Investigational Medicinal Product for the concerned patient  
The study-specific and general safety criteria are developed in Section 11 - Patient Safety. 
10.3 Health-related quality of life outcomes 
Health related quality of life evaluation will be performed using the following questionnaires 
(Appendix A):
o
EORTC QLQ-C30 (version 3);  
o EORTC QLQ CR29 (disease specific supplement to QLQ-C30) - optional;  
o EQ-5DTM
Data will be collected in a patient booklet separated from the e-CRF. 
Instruments description
x 
EORTC QLQ-C30 (version 3). 
The EORTC-QLQ-C30 is a cancer-specific instrument that contains 30 questions and provides a 
multi-dimensional assessment of Patient Reported Outcomes (PRO).  The validity and reliability of 
the EORTC-QLQ-C30 has been established in various types of cancers (Ref. 26).
The EORTC-QLQ-C30 is one of the standard instruments used in oncology for the evaluation of 
new chemotherapies and provides a comprehensive assessment of the principal PRO dimensions 
identified as relevant by cancer subjects (physical functioning, emotional functioning, cognitive 
functioning, role functioning, social functioning, global QOL, impact of symptoms and of toxicities).  
The first 28 questions of the QLQ-C30 V3.0 questionnaire use a 4-category response system (not 
at all/a little/quite a bit/very much) that correspond to numeric values 1, 2, 3, 4, respectively. Then 
for each item a high score represents a high level of symptomatology/problem. The last 2 
questions represent patient assessment of overall health and quality of life. These items are coded 
on a 7-point response category scale, 1 being very poor and 7 excellent, with no label between. 
The recall period is the past week. 
x 
EORTC QLQ CR29 (disease specific supplement to QLQ-C30) – optional. 
The EORTC QLQ-C30 can be supplemented by a module specific to colorectal cancer, the 
EORTC QLQ-CR29 colorectal cancer module (Ref. 27) which includes four scales (urinary 
frequency, faecal seepage, stool consistency and body image) and 19 single items assessing other 
common problems following treatment for colorectal cancer. 
x 
EQ-5DTM questionnaire 
The EQ-5DTM is a standardized health-related quality of life questionnaire developed by the 
EuroQOL Group in order to provide a simple, generic measure of health for clinical and economic 
appraisal (Ref. 28.  EQ-5DTM essentially consists of 2 pages: the EQ-5DTM descriptive system 
and the Visual Analogue Scale (VAS).  The EQ-5DTM is a well-validated and researched 
assessment tool which has been widely used and supported in QOL assessment across a range of 
disease areas, including oncology. 
The EQ-5DTM descriptive system comprises 5 dimensions: mobility, self care, usual activities, 
pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problem, some problems, 
 


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and severe problems. The 5 dimensional 3-level system can be converted into a single index utility 
score. Values for the 243 theoretically possible health states defined by the EuroQOL classification 
were calculated using a regression model and weighted according to the social preferences of the 
UK population (Ref. 29). The minimum value for the single index utility score is -0.594, which 
corresponds to a level 3 (severe problems) for the 5 dimensions.  The maximum value for this 
index is 1.0, which corresponds to a full health (level 1, no problem) for the 5 dimensions. 
The VAS records the respondent’s self-rated health on a vertical visual analogue scale. The VAS 
‘thermometer’ has endpoints of 100 (Best imaginable health state) at the top and 0 (Worst 
imaginable health state) at the bottom. This information can be used as a quantitative measure of 
health outcome as judged by the individual respondents. 
Timing of Assessment
The above described questionnaires have been designed for self-completion. 
Baseline assessment should be obtained from all patients. All the questionnaires will be 
administered within 3 days prior to the first treatment administration, but in any case before the 
patient is given the first dose. While on treatment assessments should occur before the treatment 
administration at the beginning of every odd cycle (day 1 of cycle 3, 5, etc) and at the end of 
treatment visit. 
Questionnaires should be self-administered by the patient at the center, prior to informing the 
patient about disease evolution, before the next study treatment and before any other assessment 
is performed.
For the quality of life questionnaires it is mandatory that a key person (e.g., research nurse) at 
each center should be responsible for questionnaire data collection, in order to optimize 
compliance of the patient and to ensure completeness of the data.  
A HRQL analysis will be detailed in the SAP. 
11. PATIENT SAFETY 
11.1 Safety instructions 
Adverse Events (AEs), regardless of seriousness or relationship to study treatment, will be 
collected from the time the patient signs the informed consent form up to 30 days after the last 
administration of treatment (either aflibercept or FOLFIRI). 
Details and schedule of requested evaluations are given in Sections 2 and 13.
If a finding meets the criteria for a SAE, then the appropriate procedures for reporting such events 
should be followed as described in Section 11.4.2.
After the 30 day FUP period all ongoing SAEs (regardless of relationship with study treatment) as 
well as ongoing related AEs and new SAEs, that are considered to be related to study treatment, 
will have to be collected and followed till resolution/stabilization (stabilization being defined as an 
event ongoing without any change for at least 3 months). 
11.2 Adverse Events monitoring 
All events must be managed and reported in compliance with all applicable regulations, and 
included in the final clinical study report. 
 


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11.3 Definitions of Adverse Event (AE) and Serious Adverse Event (SAE) 
An Adverse Event is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment.  
A Serious Adverse Event is any untoward medical occurrence that at any dose: 
o Results in death or;  
o Is life-threatening or;  
Note: The term "life-threatening" in the definition of "serious" refers to an event in which the patient was at risk 
of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it 
were more severe.  
o Requires inpatient hospitalization or prolongation of existing hospitalization or;  
o Results in persistent or significant disability/incapacity or;  
o Is a congenital anomaly/birth defect;  
o Is a medically important event:  
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the other outcomes listed in the definition above.  
Elective hospitalizations for the administration of the treatment or due to social circumstances or 
hospitalizations for surgeries that were planned before the enrollment into the study (e.g. planned 
surgery for metastases resection after treatment discontinuation) will not be considered SAEs 
(unless there is complication from surgery [e.g. hemorrhage or wound infection or wound healing 
difficulties etc.]) in which case the complication should be reported as AE(s)/SAE(s). 
Note: The following medical important events intend to serve as a guideline for determining which 
condition has to be considered as a medically important event. It is not intended to be exhaustive: 
x 
Intensive treatment in an emergency room or at home for: 
o allergic bronchospasm,  
o blood dyscrasias (i.e., agranulocytosis, aplastic anemia, bone marrow aplasia, 
myelodysplasia, pancytopenia, etc),  
o convulsions (seizures, epilepsy, epileptic fit, absence, etc.) 
x 
Development of drug dependency or drug abuse, 
x 
ALT > 3 ULN + total bilirubin > 2 ULN or asymptomatic ALT increase  > 10 ULN , 
x 
Suicide attempt or any event suggestive of suicidality, 
x 
Syncope, loss of consciousness (except if documented as a consequence of blood sampling), 
x 
Bullous cutaneous eruptions, 
x 
Cancers diagnosed during the study or aggravated during the study (only if judged as 
unusual/significant by the investigator), 
x 
Chronic neurodegenerative diseases (newly diagnosed) or aggravated during the study.  
 


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11.4 Obligation of the investigator regarding safety reporting 
11.4.1 Adverse Events 
All Adverse Events regardless of seriousness or relationship to the treatment (either aflibercept or 
FOLFIRI), spanning from the signature of the informed consent form until the 30 days after the last 
administration of the treatment,(aflibercept/FOLFIRI) are to be recorded on the corresponding 
page(s) included in the Case Report Form. 
Whenever possible, diagnosis or single syndrome should be reported instead of symptoms. The 
investigator should specify the date of onset, intensity, action taken with respect to Investigational 
Medicinal Product and Non Investigational Medicinal Product, corrective treatment/therapy given, 
additional investigations performed, outcome and his/her opinion as to whether there is a 
reasonable possibility that the Adverse Event was caused by the Investigational Medicinal Product 
and/or Non Investigational Medicinal Product. 
Signs/symptoms that are present or occurred from the time the patient signed the informed 
consent to first study treatment administration (i.e. even in the absence of any administration of 
Investigational Medicinal Product), will be recorded as Adverse Event only if they are still present 
at the time of first study treatment administration or if they are serious. 
Vital signs or ECG abnormalities are to be recorded as Adverse Events only if they are considered 
medically relevant: symptomatic, requiring corrective treatment, leading to discontinuation/dose 
modification (reduction and/or delay) and/or fulfilling a seriousness criterion.  
Laboratory abnormalities are to be recorded as Adverse Events only if they lead to treatment 
discontinuation/dose modification and/or fulfill a seriousness criterion. 
11.4.2 Serious Adverse Events 
In the case of a Serious Adverse Event the investigator must immediately:
y 
ENTER (within 1 working day) the information related to the SAE in the appropriate screens 
of the e-CRF; the system will automatically send a notification to the monitoring team after 
approval of the Investigator within the e-CRF or after a standard delay. 
y 
SEND (preferably by fax or by e-mail) the photocopy of all examinations carried out and the 
dates on which these examinations were performed, to the representative of Sanofi 
monitoring team whose name, address and fax number appear on this Protocol. Care should 
be taken to ensure that the patient's identity is protected and the patient's identifiers in the 
clinical trial are properly mentioned on any copy of source document provided to the sponsor. 
For laboratory results, include the laboratory normal ranges 
y 
All further data updates should be recorded in the e-CRF as appropriate, and further 
documentation as well as additional information (for Lab data, concomitant Medication, 
patient status ..) should be sent (by fax or e-mail) to the monitoring team within 1 working day 
of knowledge. In addition, any effort should be made to further document each Serious AE 
that is fatal or life threatening as soon as information is available and anyway within the week 
(7 days) following initial notification. 
y 
A back-up plan is used (using paper flow) when the e-CRF system does not work. 
 


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11.4.3 Safety Observations 
The investigator should take all appropriate measures to ensure the safety of the patients, notably 
he/she should follow up the outcome of any Adverse Events (clinical signs, laboratory values or 
other, etc.) until the return to normal or consolidation of the patient's condition;  
y 
In case of any Serious Adverse Event, the patient must be followed up until clinical recovery 
is complete and laboratory results have returned to normal, or until progression has been 
stabilized. This may imply that follow-up will continue beyond the 30 days follow-up period 
and that additional investigations may be requested by the monitoring team;  
y 
In case of any Serious Adverse Event brought to the attention of the investigator at any time 
after cessation of the treatment and considered by him/her to be caused by the treatment 
with a reasonable possibility, this should be reported to the monitoring team.  
11.4.4 Pregnancy 
Pregnancy should be recorded as an AE in all cases. It should be qualified as an SAE only if it 
fulfills SAE criteria.
In the event of pregnancy, the treatment should be discontinued and the sponsor informed 
immediately (i.e. within 1 working day), even not fulfilling a seriousness criterion, using the AE form 
together with the SAE complementary form to be sent to the representative of the monitoring team 
whose name, address and fax number appear on the clinical trial protocol.  
Follow-up of the pregnancy is mandatory until the outcome has been determined.  
11.4.5 Overdose
A symptomatic overdose (accidental or intentional) even not fulfilling a seriousness criterion, is to 
be reported to the sponsor immediately (within 1 working day) using the SAE complementary form 
to be sent to the representative of the monitoring team whose name, address and fax number 
appear on the clinical trial protocol. 
An overdose of study treatment is defined as: 
FOLFIRI:
For the purpose of safety reporting (as described above) dosing of 30% above the 
intended/planned dose of either irinotecan or 5-FU should be considered as an overdosage. 
Aflibercept:
The highest doses of aflibercept that have been administered so far are 7 mg/kg IV every 2 weeks 
and 9 mg/kg IV every 3 weeks. No overdoses have been reported so far.  
In this protocol an aflibercept overdose is defined as 30% above the intended/planned dose.
The circumstances (i.e., accidental or intentional) should be clearly specified in the verbatim and 
symptoms, if any, entered on separate AE forms. Based on investigator’s best clinical judgment, 
patients experiencing overdose should be monitored for the onset of known anti-VEGF toxicities 
(e.g. hypertension, proteinuria, etc.). 
11.5 Obligations of the sponsor
During the course of the study, the sponsor will report in an expedited manner all SAEs that are
both unexpected and at least reasonably related to the IMP (SUSAR), to the competent/ health 
 


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authorities, ethics committee(s) as appropriate and to the investigators in accordance with local 
regulatory timelines.
In addition, the sponsor should report in an expedited manner all SAEs that are expected and at 
least reasonably related to the IMP to the competent/ health authorities, according to local 
regulations.
Any AE not consistent with events listed as expected in the most current Investigator’s Brochure of 
aflibercept and/or contained within the reference safety information for irinotecan, 5-FU and 
leucovorin on file in the Pharmacovigilance Department will be considered as unexpected. 
The sponsor should report all safety observations made during the conduct of the trial in the CSR.  
12. HANDLING OF PATIENT TEMPORARY OR DEFINITIVE TREATMENT DISCONTINUATION 
AND OF PATIENT STUDY DISCONTINUATION 
12.1 Temporary treatment discontinuation with Investigational Medicinal Product 
Re-initiation of treatment with the IMP should be done under close and appropriate clinical and/or 
laboratory monitoring once the Investigator has considered according to his/her best medical 
judgment that the responsibility of the IMP in the occurrence of the concerned event was unlikely 
and if the selection criteria for the study are still met (ref to Sections 8.2 and 8.3).
All temporary treatment discontinuation and date of treatment re-initiation should be recorded by 
the Investigator in the e-CRF when considered to be confirmed.
12.2 Permanent treatment discontinuation
Permanent treatment discontinuation is any treatment discontinuation associated with the definitive 
decision from the investigator or the patient not to re-expose the patient to the treatment at any 
time.
12.2.1 List of criteria for permanent treatment discontinuation  
The patients may withdraw from the treatment if they decide to do so, at any time and irrespective 
of the reason, or this may be due to the investigator’s decision if, in his/her opinion, continuation of 
the study treatment would be detrimental to the patient’s well being, such as: 
x 
Disease progression (as per investigator assessment) 
x 
Unacceptable AE(s) not manageable by symptomatic therapy, dose delay or dose 
modification (see Section 9.3.2 and Section 9.3.3)
x
Intercurrent illness that prevents further administration of study treatment 
All efforts should be made to document the reasons for treatment discontinuation and this should 
be documented in the e-CRF. 
12.2.2 Handling of patients after permanent treatment discontinuation 
Patients should be followed up to 30 days after the last administration of the treatment (either 
aflibercept or FOLFIRI). 
 


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Following the 30-day follow-up visit, ongoing SAEs (regardless of causality), ongoing related AEs 
and new related SAEs should recorded/followed as described in Section 11.
All permanent treatment discontinuation should be recorded by the investigator in the appropriate 
pages when considered to be confirmed. 
12.3 Procedure for withdrawal of patients from study 
The patients may withdraw from the study, before study completion if they decide to do so, at any 
time and irrespective of the reason, or this may be the investigator’s decision: 
All study withdrawals should be recorded by the investigator in the appropriate pages when 
considered as confirmed. 
If possible, the patients are assessed using the procedure normally planned for the 30 day follow-
up visit.
For patients who fail to return to the site the investigator should make every effort to re-contact the 
patient, to identify the reason why he/she failed to attend the visit, and to determine his/her health 
status, including at least his/her vital status.  
Patients who did not complete the study and for whom no endpoint data are available should be 
considered as lost to follow-up. The statistical analysis plan will specify how these patients lost to 
follow-up for their primary endpoints will be considered. 
12.4 Consequence
Patients who have been withdrawn from the study cannot be re-included in the study. Their 
inclusion and treatment number must not be reused.  
13. STUDY PROCEDURES 
13.1 Visit schedule 
Data will be collected at baseline, at each cycle and at the end of treatment. Each cycle consists of 
14 days (± 2 days). Cycle length may be extended if additional time is required for resolution of 
study treatment-related toxicities or other adverse events.  
Each patient will be treated until disease progression, death, unacceptable toxicity, Investigator’s 
decision or patient refusal of further treatment. 
Each potential patient will be examined before the start of the study to determine his/her eligibility 
for participation.  
The written informed consent will have to be signed by the patient before any protocol specific 
procedure is performed. 
13.1.1 Pre-treatment assessment (Baseline) 
The following data will be collected as baseline:  
o Informed Consent 
o Demography: age, gender and race 
 


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o Vital signs (height, weight, ECOG performance status, BP and other signs and 
symptoms, if medically relevant), within one week of first treatment infusion)
o Colon Cancer History (diagnosis including  primary site and histopathology) 
o Prior anticancer therapies (surgery, radiotherapy and chemotherapy) 
o Prior Medical/Surgical History (including cardiovascular risk factors and prior vascular 
events if any) 
o Prior medications will be recorded, if medically relevant (i.e. VKA, antihypertensive 
medications, etc), from 1 week prior to the start of the study treatment 
o Most recent laboratory evaluations (within one week of first treatment infusion):
 
Hematology: hemoglobin, white blood cells (WBC), ANC, platelet counts. 
 
Blood Chemistry: sodium, chloride, potassium, calcium, blood urea nitrogen 
(BUN)/urea, creatinine (if creatinine 1.0-1.5 x ULN then creatinine clearance, 
calculated according to Cockroft-Gault formula), total protein, albumin, SGOT 
(AST), SGPT (ALT), alkaline phosphatase, total bilirubin, LDH, glucose. 
 
Coagulation tests: prothrombin time expressed as INR only in patients under 
treatment with Vitamine K antagonist. 
 
Urinalysis: dipstick [WBCs, red blood cells (RBCs)] and UPCR on morning urine 
spot or proteinuria assessed on 24-hour urine collection. 
 
Pregnancy test in women of reproductive potential: serum or urine ȕ-hCG.
o Health-Related Quality of Life (before first treatment infusion):
 
EORTC QLQ-C30;  
 
EORTC QLQ CR29 (optional); 
 
EQ-5DTM.
Patient inclusion will take place once the consented patient has completed all the necessary 
baseline assessment and is deemed eligible for study entry by the investigator or designee. The 
results of the baseline examinations will be recorded in each included patient’s CRF. Source 
documentation to support the baseline results must be maintained in the patient’s medical record.  
Treatment should begin as soon as possible after inclusion (possibly within 3 days). 
13.1.2 During study treatment period 
Data collection:
o Vital signs: ECOG PS, body weight, BP (before each study treatment dosing) 
o Concomitant medications if medically relevant (see also the flow chart, Section 2.1).
o
Laboratory evaluations  (performed before each study treatment dosing) 
 
Hematology: hemoglobin, WBC, ANC, platelet counts. 
 
Blood Chemistry: sodium, chloride, potassium, calcium, BUN/urea, creatinine, 
total protein, albumin, SGOT (AST), SGPT (ALT), alkaline phosphatase, total 
bilirubin, LDH, glucose. 
 
Coagulation tests: prothrombin time expressed as INR for patients under 
treatment with VKA 
 
Urinalysis: dipstick (WBCs, RBCs, urinary protein) and UPCR on morning urine 
spot and/or the 24-hour urine collection (see Section 9.3.3.1).
 


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o  Study treatment (aflibercept/FOLFIRI) administration (including dose delays and dose 
reductions)
o AEs/SAEs (from signature of informed consent up to 30 days after last administration of 
treatment)
o Health-Related Quality of Life: before treatment administration at the beginning of every 
odd cycle (on D1 of cycle 3, 5, etc.) 
 
EORTC QLQ-C30;  
 
EORTC QLQ CR29 (optional); 
 
EQ-5DTM.
13.1.3 End of treatment (30-day Follow-up visit) 
All patients have to continue to be observed for at least 30 days after the final dose of the 
treatment (either aflibercept or FOLFIRI). 
Data collection:  
o Date and reason for aflibercept discontinuation
o Date of last FOLFIRI administration and reason for discontinuation
o Vital signs: ECOG PS, BP
o Concomitant medications if medically relevant (including further anticancer treatment 
started within 30 days of last treatment administration, if any. See also the flow chart, 
Section 2.1)
o AEs/SAEs 
o Patient’s status 
o Health-Related Quality of Life: EORTC QLQ-C30, EORTC QLQ-CR29 (optional) and 
EQ-5DTM.
13.1.4 Post treatment Follow-up period  
The following data will be collected: 
o Related AEs and all SAEs, ongoing at the end of the study treatment, or new related 
SAEs will be recorded until recovery, or until progression has been stabilized.
13.2 Definition of source data 
Source data includes all information in original records and certified copies of original records of 
clinical findings, observations, or other activities necessary for the reconstruction and evaluation of 
the study.  Source data are contained in source documents. 
Source documents are original documents, data and records (e.g. hospital records, clinical and 
office charts, laboratory notes, memoranda, patient diaries or evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies or transcripts certified after 
verification as being accurate and complete, microfiches, photographic negatives, microfilm or 
magnetic media, X-rays, patient files, and records kept at the pharmacy, at the laboratories, and at 
medical-technical departments) involved in the clinical study. Source documentation must be 
maintained to support information provided within a CRF. 
 


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14. STATISTICAL CONSIDERATIONS 
14.1 Statistical and analytical plans 
The material of this Section is the basis for the Statistical Analysis Plan for the study. This plan 
may be revised during the study to accommodate clinical trial protocol amendments and to make 
changes to adapt to unexpected issues in study execution and data that affect planned analysis. 
Thus a final plan should be issued before database lock. 
14.2 Determination of sample size 
No formal sample size calculation has been done. The Safety analyses of this study will be 
descriptive in nature, and the table below provides the precision (95% CI) associated to a variety of 
AE event rates for a targeted sample size of 900 patients: 
Table 7 : Expected 95% CI for various event rates 
Overall
sample size 
p=10% 
p=20% 
p=30% 
p=40% 
p=50% 
900
[8.0%; 12.0%]
[17.4%; 22.6%]
[27.0%; 33.0%]
[36.8%; 43.2%]
[46.7%; 53.3%]
14.3 Analysis variables 
14.3.1 Demographic and baseline characteristics 
Standard demographic and baseline characteristics (including age, gender, race, height and 
weight), medical and surgical history, cancer diagnosis and prior anticancer therapy will be 
summarised at baseline. 
Baseline safety variables will also be assessed. These variables include vital signs and main 
laboratory parameters.
Baseline value is defined as the last value or measurement taken before the first dose of 
treatment.
14.3.2 Efficacy variables 
Not applicable.
14.3.3 Safety variables 
Analysis of safety will be performed by summarizing AEs and laboratory data. 
The safety variables include: 
x 
AEs 
o On-treatment period: On-treatment period is the period from the first dose of 
treatment to 30 days after the last dose of treatment (either aflibercept or Folfiri).  
 


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o Treatment-emergent AEs (TEAEs): A TEAE is defined as an AE that is reported 
during the on-treatment period defined above. 
o Post-treatment AEs: A “post-treatment AE” is defined as an AE that developed or 
worsened or became serious more than 30 days after the last dose of treatment 
(aflibercept or Folfiri). 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
x 
Discontinuation (including reason for discontinuation and discontinuation due to AEs) 
x 
Blood pressure and ECOG performance status 
x 
Major laboratory safety parameters 
o Hematology: WBC, neutrophil, platelets, and hemoglobin. 
o Blood chemistry: sodium, chloride, potassium, calcium, BUN/urea, creatinine, total 
protein, albumin, SGOT (AST), SGPT (ALT), alkaline phosphatase, total bilirubin, 
LDH, glucose. 
o Urinalysis: Dipstick (WBCs, RBCs and protein), Urinary Protein-to-creatinine Ratio 
(UPCR).
14.3.4 Health economic/ Health-Related Quality of life variables  
Health Related Quality of Life:
x
EORTC QLQ-C30 questionnaire: change from baseline for the Global health status (scoring 
of items 29 & 30), the five functional scales (Physical, Role, Emotional, Cognitive and 
Social), the three symptom scales (Fatigue, Nausea/vomiting and Pain) and the other 
single items  
x 
EQ-5DTM: change on health-related QoL and utility. 
Exploratory endpoint: 
x 
EORTC QLQ-CR29 questionnaire (specific colorectal module - optional): change from 
baseline for the four scales (urinary frequency, faecal seepage, stool consistency and body 
image) and the other single items.  
HRQL analysis will be detailed in the SAP. 
14.4 Analysis populations 
Patients previously treated with aflibercept (i.e. the patients participating to VELOUR/EFC10262 
trial that were allowed to rollover into this study) will not be included in any analysis population and 
their data will be listed separately. 
14.4.1 Efficacy populations 
Not applicable.
 


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14.4.2 Safety population 
The safety population will consist of the patients who have signed the informed consent form and 
who have received at least part of one dose of study treatment. 
14.4.3 HRQL analysis population  
Health related quality of life analysis will be performed in the patients who completed the 
questionnaires at baseline and at least one assessment post baseline and who have received at 
least part of one dose of study treatment. 
14.4.4 Disposition of patients
The number of patients in the safety population will be provided. 
In addition, reasons for treatment discontinuation as well as reasons for withdrawal from the study 
will be summarized.
14.5 Statistical methods 
All statistical analyses will be descriptive (no formal statistical tests will be performed). 
The following information will be provided for continuous variables: number of patients (N), mean, 
standard deviation, median, 25th and 75th percentiles, as well as minimum and maximum.  
Number and percentage of patients will be provided for categorical variables. 
All statistical analyses will be based on the Safety population. Health-related quality of life variables 
will be summarized on the HRQL analysis population. 
Sub group analyses per country or region will also be provided as appropriate. 
Final analysis will be performed after the global Data Base Lock. 
14.5.1 Demographics and baseline characteristics 
All patient demographic characteristics, medical and surgical history, cancer diagnosis and prior 
anticancer therapy will be tabulated. 
14.5.2 Extent of study treatment exposure and compliance 
Extent of exposure will be assessed as follows: 
Number of patients treated, number of cycles administered, duration of dosing (weeks), cumulative 
dose (mg/kg for aflibercept and mg/m² for FOLFIRI regimen compounds) and dose intensity 
(mg/kg/week for aflibercept and mg/m²/week for FOLFIRI regimen compounds) will be 
summarized. Dose delays, omissions and dose reductions will also be analyzed. 
14.5.3 Analysis of efficacy variables 
Not applicable.
14.5.4 Analysis of safety data 
Summary of safety data will also be performed by cycle (when applicable). For each of the safety 
parameters, a baseline value will be defined as the last value or measurement taken up to the first 
dose of treatment. 
 


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14.5.4.1
Analysis of adverse events 
The following frequency distributions of adverse events (incidence tables presented by SOC and 
PT and worst intensity as graded by the NCI CTCAE, version 4.0) will be provided for the Safety 
population: TEAE, possibly related TEAE, Serious TEAE, TEAE leading to death, TEAE leading to 
permanent treatment discontinuation. 
The number and percentage of patients who die will be presented. 
14.5.4.2
Laboratory variables analysis 
Hematological toxicities will be assessed from laboratory parameters.  
Qualitative and quantitative results will be summarized for hematological toxicities. Qualitative data 
(worst NCI CTCAE grade) will be summarized by patient.  
Biochemistry and urinalysis will be analyzed using the worst NCI CTCAE grade, whenever 
applicable (laboratory normal ranges, otherwise) calculated from laboratory values. Specific 
attention will be given to incidence of proteinuria and impairment of renal function. 
14.5.4.3
Analysis of vital sign variables 
By visit descriptive analyses of vital signs (ECOG PS, BP) will be provided for observed values and 
change from baseline. 
14.5.5 Analysis of health economics / Health-Related Quality of life variables 
The compliance profile over time will be summarized (number and percentage of forms received 
versus expected, and number and percentage of forms evaluable versus expected).  
x 
EORTC QLQ-C30 questionnaire 
A descriptive summary by assessment and change from baseline to each assessment for 
the Global health status (scoring of items 29 & 30), the five functional scales (Physical, 
Role, 
Emotional, 
Cognitive 
and 
Social), 
the 
three 
symptom 
scales 
(Fatigue, 
Nausea/vomiting and Pain) and the other single items will be described. 
x 
EQ-5DTM questionnaire  
The responses to each EQ-5DTM item will be presented at each assessment. This will 
contain information on the frequency and proportion with its 95% CI of the population 
reporting level 1 (no problems), level 2 (some problems) and level 3 (extreme problems) per 
item. Descriptive summary statistics (size, mean, standard deviation, median, range) will be 
provided for the single index utility score and the VAS at each assessment. Change from 
baseline will be also described.
Exploratory endpoint: 
x 
EORTC QLQ-CR29 questionnaire (specific colorectal module - optional) 
A descriptive summary by assessment and change from baseline to each assessment for 
the four scales (urinary frequency, faecal seepage, stool consistency and body image) and 
the other single items will be described. 
14.6 Interim analysis 
It is planned to perform interim analyses during the course of the study, in order to obtain 
preliminary results on baseline characteristics, HRQL and safety data. 
 


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Details will be provided in the SAP.
15. ETHICAL AND REGULATORY STANDARDS 
15.1 Ethical principles 
This clinical trial will be conducted in accordance with the principles laid down by the 18th World 
Medical Assembly (Helsinki, 1964) and all applicable amendments laid down by the World Medical 
Assemblies, and the ICH guidelines for Good Clinical Practice. 
In compliance with Sanofi public disclosure commitments, this clinical trial will be recorded in a 
public registry website before the enrollment of the first patient. The registry will contain basic 
information about the trial sufficient to inform interested patients (and their healthcare practitioners) 
how to enroll in the trial. 
15.2 Laws and regulations 
This clinical trial will be conducted in compliance with all international laws and regulations, and 
national laws and regulations of the country(ies) in which the clinical trial is performed, as well as 
any applicable guidelines. 
15.3 Informed consent 
The investigator (according to applicable regulatory requirements), or a person designated by the 
investigator, and under the investigator's responsibility, should fully inform the Patient of all 
pertinent aspects of the clinical trial including the written information giving approval/favorable 
opinion by the Ethics Committee. All participants should be informed to the fullest extent possible 
about the study, in language and terms they are able to understand. 
Prior to a patient’s participation in the clinical trial, the written Informed Consent Form and any 
other local applicable documents in accordance with local laws and regulations, should be signed, 
name filled in and personally dated by the patient or by the patient’s legally acceptable 
representative, and by the person who conducted the informed consent discussion. A copy of the 
signed and dated written Informed Consent Form must be provided to the patient. 
The Informed Consent Form used by the investigator for obtaining the patient's informed consent 
must be reviewed and approved by the sponsor prior to submission to the appropriate Ethics 
Committee for approval/favorable opinion. 
15.4 Institutional Review Board/Independent Ethics Committee (IRB/IEC) 
The investigator or the sponsor must submit this clinical trial protocol to the appropriate Ethics 
Committee, and is required to forward to the sponsor a copy of the written and dated approval/ 
favorable opinion signed by the chairman with ethics committee(s) composition. 
The clinical trial (study number, clinical trial protocol title and version number), the documents 
reviewed (clinical trial protocol, Informed Consent Form, Investigator’s Brochure, investigator’s CV, 
etc.), the list of voting members and their qualifications and the date of the review should be clearly 
stated on the written ethics committee approval/favorable opinion. 
Investigational Medicinal Product will not be released at the study site and the clinical trial will not 
start until a copy of this written and dated approval/ favorable opinion has been received by the 
sponsor.
 


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During the clinical trial, any amendment or modification to the clinical trial protocol should be 
submitted to the Ethics Committee. It should also be informed of any event likely to affect the 
safety of patients or the continued conduct of the clinical trial, in particular any change in safety. All 
updates to the Investigator’s Brochure should be sent to the ethics committee(s). 
If requested, a progress report is sent to the ethics committee(s) annually and a summary of the 
clinical trial’s outcome at the end of the clinical trial. 
16. STUDY MONITORING 
16.1 Responsibilities of the investigator(s) 
The investigator(s) undertake(s) to perform the clinical trial in accordance with this clinical trial 
protocol, ICH guidelines for Good Clinical Practice and the applicable regulatory requirements. 
The investigator is required to ensure compliance with all procedures required by the clinical trial 
protocol and with all study procedures provided by the sponsor (including security rules). The 
investigator agrees to provide reliable data and all information requested by the clinical trial 
protocol (with the help of the e-Case Report Form [CRF], Discrepancy Resolution Form [DRF] or 
other appropriate instrument) in an accurate and legible manner according to the instructions 
provided and to ensure direct access to source documents by sponsor representatives. 
If any circuit includes transfer of data, particular attention should be paid to the confidentiality of the 
patient's data to be transferred.   
The investigator may appoint such other individuals as he/she may deem appropriate as sub-
investigators to assist in the conduct of the clinical trial in accordance with the clinical trial protocol. 
All sub-investigators shall be appointed and listed in a timely manner. The sub-investigators should 
be supervised by and under the responsibility of the investigator. The investigator should provide 
them with a copy of the clinical trial protocol and all necessary information. 
16.2 Responsibilities of the sponsor 
The sponsor of this clinical trial is responsible to competent/ health authorities for taking all 
reasonable steps to ensure the proper conduct of the clinical trial as regards ethics, clinical trial 
protocol compliance, and integrity and validity of the data recorded on the Case Report Forms. 
Thus, the main duty of the monitoring team is to help the investigator and the sponsor maintain a 
high level of ethical, scientific, technical and regulatory quality in all aspects of the clinical trial. 
At regular intervals during the clinical trial, the site will be contacted, through monitoring visits, 
letters or telephone calls, by a representative of the monitoring team to review study progress, 
investigator and patient compliance with clinical trial protocol requirements and any emergent 
problems. During these monitoring visits, the following but not exhaustive list of points should be 
scrutinized with the investigator: patient informed consent, patient eligibility, patient recruitment and 
follow-up, Serious Adverse Event documentation and reporting, Investigational Medicinal Product 
allocation, patient compliance with the clinical trial protocol and the Investigational Medicinal 
Product regimen, Investigational Medicinal Product accountability, concomitant therapy use and 
quality of data. 
 


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16.3 Source document requirements 
According to the ICH guidelines for Good Clinical Practice, the monitoring team must check the 
Case Report Form entries against the source documents, except for the pre-identified source data 
directly recorded in the Case Report Form. The Informed Consent Form will include a statement by 
which the patient allows the sponsor’s duly authorized personnel, the ethics committee(s), and the 
competent/ health authorities to have direct access to source data which support the data on the 
Case Report Forms (e.g., patient's medical file, appointment books, original laboratory records, 
etc.). Such personnel, bound by professional secrecy, must keep confidential all personal identity 
or personal medical information (according to confidentiality rules). 
16.4 Use and completion of Case Report Forms (CRFs) and additional request 
Data will be collected using an electronic Case Report Form (e-CRF). All CRFs should be 
completed in their entirety to ensure accurate interpretation of data. 
It is the responsibility of the Investigator to maintain adequate and accurate - CRFs (according to 
the technology used) designed by the Sponsor to record (according to Sponsor instructions) all 
observations and other data pertinent to the clinical investigation. 
For each patient, baseline data will be reviewed by Sanofi in order to ensure the patient is eligible 
for this study.  
The computerized handling of the data by the Sponsor after completion of the e-CRFs may 
generate additional requests (DRF) to which the Investigator is obliged to respond by confirming or 
modifying the data questioned. 
16.5 Use of computerized systems 
Computerized systems will be used to create, modify, maintain, archive, retrieve or transmit data 
(monitoring tool, data entry and statistical analysis). 
17. ADMINISTRATIVE RULES 
17.1 Curriculum Vitae 
An updated copy of the curriculum vitae limited to the experience, qualification and training for 
each investigator and sub-investigator should be provided to the sponsor prior to the beginning of 
the clinical trial. 
17.2 Record retention in study site(s) 
The investigator must maintain confidential all study documentation, and take measures to prevent 
accidental or premature destruction of these documents. 
It is recommended that the investigator retain the study documents at least fifteen (15) years after 
the completion or discontinuation of the clinical trial, unless otherwise specified in the investigator 
Agreement in line with national standards and/or local laws. 
However, applicable regulatory requirements should be taken into account in the event that a 
longer period is required. 
 


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The investigator must notify the sponsor prior to destroying any study essential documents 
following the clinical trial completion or discontinuation. 
If the investigator's personal situation is such that archiving can no longer be ensured by him/her, 
the investigator shall inform the sponsor and the relevant records shall be transferred to a mutually 
agreed upon designee. 
18. CONFIDENTIALITY 
All information disclosed or provided by the sponsor (or any company/ institution acting on their 
behalf), or produced during the clinical trial, including, but not limited to, the clinical trial protocol, 
the CRFs, the Investigator's Brochure and the results obtained during the course of the clinical 
trial, is confidential. The investigator and any person under his/her authority agree to undertake to 
keep confidential and not to disclose the information to any third party without the prior written 
approval of the sponsor. 
However, the submission of this clinical trial protocol and other necessary documentation to the 
ethics committee(s) is expressly permitted, the ethics committee(s) members having the same 
obligation of confidentiality. 
The sub-investigators shall be bound by the same obligation as the investigator. The investigator 
shall inform the sub-investigators of the confidential nature of the clinical trial. 
The investigator and the sub-investigators shall use the information solely for the purposes of the 
clinical trial, to the exclusion of any use for their own or for a third party's account. 
19. PROPERTY RIGHTS 
All information, documents and Investigational Medicinal Product provided by the sponsor or its 
designee are and remain the sole property of the sponsor. 
The investigator shall not mention any information or the Investigational Medicinal Product in any 
application for a patent or for any other intellectual property rights. 
All the results, documents and inventions, which arise directly or indirectly from the clinical trial in 
any form, shall be the exclusive property of the sponsor. 
The sponsor may use or exploit all the results at its own discretion, without any limitation to its 
property right (territory, field, continuance). The sponsor shall be under no obligation to patent, 
develop, market or otherwise use the results of the clinical trial. 
20. DATA PROTECTION 
The patient's personal data and investigator's personal data which may be included in the sponsor 
database shall be treated in compliance with all applicable laws and regulations. 
When archiving or processing personal data pertaining to the investigator and/or to the patients, 
the sponsor shall take all appropriate measures to safeguard and prevent access to this data by 
any unauthorized third party. 
 


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21. INSURANCE COMPENSATION 
The sponsor certifies that it has taken out a liability insurance policy covering all clinical trials under 
its sponsorship.  This insurance policy is in accordance with local laws and requirements. The 
insurance obtained by the sponsor does not relieve the investigator and his/ her collaborators from 
maintaining their own liability insurance policy. A copy of the insurance certificate will be provided 
to the ethic committees and/ or competent/ health authorities in countries requiring this 
documentation.
22. SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES 
For the purpose of ensuring compliance with the clinical trial protocol, Good Clinical Practice and 
applicable regulatory requirements, the investigator should permit auditing by or on the behalf of 
the sponsor and inspection by applicable regulatory authorities. 
The investigator agrees to allow the auditors/ inspectors to have direct access to his/ her study 
records for review, being understood that this personnel is bound by professional secrecy, and as 
such should not disclose any personal identity or personal medical information. 
The investigator should make every effort to help with the performance of the audits and 
inspections, giving access to all necessary facilities, data, and documents. 
As soon as the investigator is notified of a future inspection by the authorities, he will inform the 
sponsor and authorize the sponsor to participate in this inspection. 
The confidentiality of the data verified and the protection of the patients should be respected during 
these inspections. 
Any result and information arising from the inspections by the regulatory authorities should be 
immediately communicated by the investigator to the sponsor. 
The investigator shall take appropriate measures required by the sponsor to take corrective actions 
for all problems found during the audit or inspections. 
23. PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF A 
SITE
23.1 Decided by the sponsor in the following cases: 
x
If the information on the product leads to doubt as to the benefit/ risk ratio; 
x 
If the investigator has received from the sponsor all Investigational Medicinal Product, 
means and information necessary to perform the clinical trial and has not included any 
patient after a reasonable period of time mutually agreed upon; 
x 
If the aim of the clinical trial has become outdated or is no longer of interest; 
x 
In the event of breach by the investigator of a fundamental obligation under this 
agreement, including but not limited to breach of the clinical trial protocol, breach of the 
applicable laws and regulations or breach of the ICH guidelines for Good Clinical 
Practice;
In any case the sponsor will notify the investigator of its decision by written notice. 
 


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23.2 Decided by the investigator 
The investigator must notify (at least 30 days prior to discontinuation) the sponsor of his/ her 
decision and give the reason in writing. 
In all cases (decided by the sponsor or by the investigator), the appropriate ethics committee(s) 
and competent/ health authorities should be informed.  
24. CLINICAL TRIAL RESULTS 
The sponsor will be responsible for preparing a Clinical Study Report. 
When the data from all investigational sites have been fully analyzed by the sponsor, the latter will 
communicate the results of the clinical trial to the investigator(s). 
Regardless of the study outcome the sponsor is committed to publishing the results. 
25. PUBLICATIONS AND COMMUNICATIONS 
The sponsor recognizes the investigator's right to utilize data derived from the clinical trial for 
teaching purposes, communication at congresses and scientific publications. Nevertheless, in 
order to ensure the accuracy and scientific value of the information, while preserving the 
independence and accountability of the investigator, and the confidentiality of the information, only 
checked and validated data will be used. To that effect, it is essential that the parties exchange and 
discuss, prior to any publication or communication, any draft publication or communication made 
by the investigator. 
The investigator shall send to the sponsor a copy of the manuscript for review and possible 
comments at least forty-five (45) calendar days in advance of the date of submission to the journal 
and at least twenty (20) days in advance for abstracts. The publication shall be delayed until a 
written response is received by the sponsor, not to exceed ninety (90) days. The sponsor can 
delay publication or communication for a limited time in order to protect the confidentiality or 
proprietary nature of any information contained therein, it being understood that the sponsor 
cannot refuse its consent without reasonable cause. The investigator agrees to include the 
modifications requested by the sponsor, provided they do not jeopardize the accuracy and/or the 
scientific value of the publication.  
The investigator shall not use the name(s) of the sponsor and/or its employees in advertising or 
promotional material or publication without the prior written consent of the sponsor. The sponsor 
shall not use the name(s) of the investigator and/or the collaborators in advertising or promotional 
material or publication without having received his/her and/ or their prior written consent(s). 
The sponsor has the right at any time to publish the results of the clinical trial. 
26. CLINICAL TRIAL PROTOCOL AMENDMENTS 
All appendices attached hereto and referred to herein are made part of this clinical trial protocol. 
The investigator should not implement any deviation from, or changes of the clinical trial protocol 
without agreement by the sponsor and prior review and written approval/ favorable opinion from 
the ethics committee(s) of an amendment, except where necessary to eliminate an immediate 
hazard(s) to clinical trial patients, or when the change(s) involves only logistical or administrative 
aspects of the trial. Any change agreed upon shall be recorded in writing, the written amendment 
must be signed by the investigator and by the sponsor and the signed amendment be filed with this 
clinical trial protocol. 
 


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Any amendment to the clinical trial protocol requires written approval/ favorable opinion by the 
ethics committee(s) prior to its implementation, unless there are overriding safety reasons. 
In some instances, an amendment may require a change to the Informed Consent Form. The 
investigator must receive an ethics committee approval/ favorable opinion concerning the revised 
Informed Consent Form prior to implementation of the change. 
 


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27. BIBLIOGRAPHIC REFERENCES 
Ref. 1 Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA: 
Cancer J Clin. 2011; 61(2):69-90. 
Ref. 2 Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. GLOBOCAN 2008, Cancer 
Incidence and Mortality Worldwide: IARC CancerBase No. 10 [Internet]. Lyon, France: 
International Agency for Research on Cancer; 2010.  
Ref.3 Chu E. Clin Colorectal Canc. 2011; Epub. 6. GLOBOCAN2008. Available at: 
http://globocan.iarc.fr/factsheets/cancers/colorectal.asp. 
Ref. 4 Van Cutsem E, Nordlinger B, Cervantes A and on behalf of the ESMO Guidelines Working 
Group. Advanced colorectal cancer: ESMO Clinical Practice Guidelines for treatment. Ann Oncol. 
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Ref. 5 Tournigand C, André T, Achille E, Lledo G, Flesh M, Mery-Mignard D, Quinaux E, Couteau 
C, Buyse M, Ganem G, Landi B, Colin P, Louvet C, de Gramont A. FOLFIRI Followed by 
FOLFOX6 or the Reverse Sequence in Advanced Colorectal Cancer: A Randomized GERCOR 
Study. Journal of Clinical Oncology 2004;22(2):229-237. 
Ref. 6 Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, 
Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F. 
Bevacizumab plus Irinotecan, Fluorouracil, and Leucovorin for Metastatic Colorectal Cancer. The 
New England Journal of Medicine 2004;350(23):2335-2342. 
Ref. 7 de Gramont A, Bosset JF, Milan C, Rougier P, Bouché O, Etienne PL, et al. Randomized 
trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose 
leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: a French 
intergroup study. J Clin Oncol. 1997; 15(2):808-15. 
Ref. 8 Advanced Colorectal Cancer Meta-Analysis Project. Modulation of fluorouracil by leucovorin 
in patients with advanced colorectal cancer: evidence in terms of response rate. J Clin Oncol. 
1992; 10(6):896-903 
Ref. 9 Goldberg RM Morton RF, Sargent DJ, Fuchs CS, Ramanathan RK, Williamson SK, et al. 
BP. N9741: oxaliplatin (OXAL) or CPT-11 + 5-fluorouracil (5FU)/leucovorin (LV) or OXAL + CPT-11 
in advanced colorectal cancer (CRC). Initial toxicity and response data from a GI Inter Group 
Study. Proceedings of the American Association for Cancer Research. 2002; 25(Suppl 3):13. 
Ref. 10 Douillard JY, Sobrero A, Carnaghi C, Comella P, Diaz-Rubio E, Santoro A, et al. Metastatic 
colorectal cancer: integrating irinotecan into combination and sequential chemotherapy. Annals of 
Oncology. 2003; 14(Suppl 2):ii7-ii12. 
Ref. 11 Saltz L, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ, et al. Irinotecan plus 
Fluorouracil and Leucovorin for Metastatic Colorectal Cancer. N Engl J Med. 2000; 343(13):905-
14.
Ref. 12 Saltz LB, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, 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. 2008; 26(12):2013-9. 
 


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Ref. 13 Giantonio BJ, Catalano PJ, Meropol NJ, O'Dwyer PJ, Mitchell EP, Alberts SR, Schwartz 
MA, Benson AB. 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:N16S. 
Ref. 14 Jonker DJ, O'Callaghan CJ, Karapetis CS, Zalcberg JR, Tu D, Au HJ, et al. Cetuximab for 
the treatment of colorectal cancer. N Engl J Med. 2007; 357(20):2040-8. 
Ref. 15 Van Cutsem E, Peeters M, Siena S, Humblet Y, Hendlisz A, Neyns B, et al. Open-label 
phase III trial of panitumumab plus best supportive care compared with best supportive care alone 
in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007; 
25(13):1658-64.
Ref. 16 Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, et al. Cetuximab 
monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N 
Engl J Med. 2004; 351(4):337-45. 
Ref. 17 Van Cutsem E, Nowacki M, Lang I, Cascinu S, Shchepotin I, Maurel J, et al. Randomized 
phase III study of irinotecan and 5-FU/FA with or without cetuximab in the first-line treatment of 
patients with metastatic colorectal cancer (mCRC): The CRYSTAL trial. J Clin Oncol. 2007 ASCO 
Annual Meeting Proceedings (Post-Meeting Edition). Vol 25, No 18S (June 20 Supplement), 2007: 
4000.
Ref. 18 Van Cutsem E, Lang I, D'haens G, Moiseyenko V, Zaluski J, Folprecht G et al. KRAS 
status and efficacy in the first-line treatment of patients with metastatic colorectal cancer (mCRC) 
treated with FOLFIRI with or without cetuximab: The CRYSTAL experience. 2008 ASCO Annual 
Meeting.J Clin Oncol 26: 2008 (May 20 suppl; abstr 2). 
Ref. 19 Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, et al. 
Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of 
metastatic colorectal cancer. J Clin Oncol. 2009; 27(5):663-71. Epub 2008 Dec 29. 
Ref. 20 Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, et al. Randomized, 
phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) 
versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic 
colorectal cancer: the PRIME study. J Clin Oncol. 2010; 28(31):4697-705. Epub 2010 Oct 4. 
Ref. 21 Peeters M, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y, et al. Randomized 
phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared 
with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin 
Oncol. 2010; 28(31):4706-13. Epub 2010 Oct 4. 
Ref. 22 Eric van Cutsem, Josep Tabernero, et al. Intravenous (iv) aflibercept versus placebo in 
Combination with irinotecan/5-fu (Folfiri) for second line treatment of metastatic colorectal cancer 
(mCRC): Results of a multinational phase III trial (EFC10262- Velour).  Annals of Oncology, 2011: 
22 (Suppl 5), Abstract O-0024. 
Ref. 23 Tabernero J, Van Cutsem E, Lakomy R, Prausova J, Ruff P, Van Hazel G, Moiseyenko V, 
Ferry D, Mckendrick J. et al on the behalf of the VELOUR investigators. Results from VELOUR, a 
phase III study of aflibercept versus placebo in combination with FOLFIRI for the treatment of 
patients with previously treated metastatic colorectal cancer. Eur J Cancer. 2011; 47(2): Abstract 
6LBA.
Ref. 24 Aflibercept Investigator’s Brochure Edition 11, dated on November 25, 2011. 
 


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Ref. 25 Morales JV, Weber R, Wagner MB, et al. Is morning urinary protein/creatinine ratio a 
reliable estimator of 24-hour proteinuria in patients with glomerulonephritis and different levels of 
renal function? J Nephrol 2004, 17:666-672.  
Ref. 26 Aaronson NK, Ahmedzai S, Bergman B et al. The European Organization for Research 
and Treatment of Cancer QLQ-C30: A quality of life instrument for use in international clinical trials 
in oncology. J Nat Cancer Inst 1993; 85: 364-76. 
Ref. 27 Whistance RN et al. Clinical and psychometric validation of the EORTC QLQ-CR29 
questionnaire module to assess health-related quality of life in patients with colorectal cancer. 
European journal of Cancer 2009; 45: 3017-26. 
Ref. 28 EuroQol - A new facility for the measurement of health-related quality of life. The EuroQol 
Group. Health Policy. 1990 Dec; 16(3):199-208. 
Ref. 29 Dolan P. Modeling valuations for EuroQol health states. Medical Care Vol 35, No. 11, pp. 
1095-1108. 1997. 
Ref. 30 Common Terminology Criteria for Adverse Events (CTCAE) v4.03 June 14, 2010.  
 

SAP_001.pdf: 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to template: QSD-002643 VERSION 3.0 (05-DEC-2011)
Page 1 
STATISTICAL ANALYSIS PLAN (FINAL AMENDED #3)
AFLIB_C_06097 A Multicenter, Single arm, Open Label Clinical Trial to Evaluate the 
Safety and Health-Related Quality of Life of Aflibercept in Patients with Metastatic 
Colorectal Cancer (mCRC) Previously Treated with an Oxaliplatin-Containing Regimen
 
 
 
 
 
 
 
STUDY BIOSTATISTICIAN:
Sanofi Biostatistician: 
CRO Biostatistician:
                
France
Spain
              
BIOSTATISTICS GMA PROJECT LEADER: 
France
DATE OF ISSUE: 01-June-2016
Total number of pages:
83
NCT number:NCT01571284


Statistical Analysis Plan (Final amended #3) 
 
01-Jun 2016 
AVE0005-AFLIBC06097 / AVE0005-AFLIBL06266 
  
Version number: 4.0  
Property of Sanofi - strictly confidential 
Page 2 
TABLE OF CONTENTS 
 
STATISTICAL ANALYSIS PLAN (FINAL AMENDED #3) ............................................................................. 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................................................................... 5 
1 
OVERVIEW AND INVESTIGATIONAL PLAN ................................................................................ 7 
1.1 
STUDY DESIGN AND RANDOMIZATION ...................................................................................... 7 
1.2 
OBJECTIVES ................................................................................................................................... 7 
1.2.1 
Primary objectives ............................................................................................................................ 7 
1.2.2 
Secondary objectives ....................................................................................................................... 8 
1.3 
DETERMINATION OF SAMPLE SIZE ............................................................................................. 8 
1.4 
STUDY PLAN ................................................................................................................................... 8 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL .................................. 9 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN ..................... 11 
1.6.1 
Modifications to version 1 made in version 2 ................................................................................. 11 
1.6.2 
Modifications to version 2 made in final amended version 3 ......................................................... 12 
1.6.3 
Modifications to version 3 made in final amended version 4 ......................................................... 15 
2 
STATISTICAL AND ANALYTICAL PROCEDURES .................................................................... 17 
2.1 
ANALYSIS ENDPOINTS ............................................................................................................... 17 
2.1.1 
Demographic and baseline characteristics .................................................................................... 17 
2.1.2 
Prior or concomitant medications (other than anticancer therapies) ............................................. 19 
2.1.3 
Efficacy endpoints .......................................................................................................................... 20 
2.1.3.1 
Primary efficacy endpoint(s) .......................................................................................................... 20 
2.1.3.2 
Secondary efficacy endpoint(s) ...................................................................................................... 20 
2.1.4 
Safety endpoints ............................................................................................................................ 20 
2.1.4.1 
Adverse events variables ............................................................................................................... 20 
2.1.4.2 
Deaths ............................................................................................................................................ 21 
2.1.4.3 
Laboratory safety variables ............................................................................................................ 21 
2.1.4.4 
Vital signs variables ....................................................................................................................... 22 
2.1.4.5 
Electrocardiogram variables .......................................................................................................... 22 
2.1.5 
Pharmacokinetic variables ............................................................................................................. 23 
2.1.6 
Pharmacodynamic/genomics endpoints ........................................................................................ 23 
2.1.7 
Quality-of-life endpoints ................................................................................................................. 23 


Statistical Analysis Plan (Final amended #3) 
 
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Page 3 
2.1.8 
Health economic endpoints ............................................................................................................ 23 
2.1.9 
Further therapy after discontinuation of study treatment administration during the study ............. 23 
2.2 
DISPOSITION OF PATIENTS ....................................................................................................... 24 
2.2.1 
Randomization and drug dispensing irregularities ......................................................................... 24 
2.3 
ANALYSIS POPULATIONS ........................................................................................................... 24 
2.3.1 
Efficacy populations ....................................................................................................................... 24 
2.3.2 
Safety population ........................................................................................................................... 25 
2.3.2.1 
Important protocol deviations ......................................................................................................... 25 
2.3.3 
HRQL analysis populations ............................................................................................................ 25 
2.4 
STATISTICAL METHODS ............................................................................................................. 26 
2.4.1 
Demographics and baseline characteristics .................................................................................. 26 
2.4.2 
Prior or concomitant medications (other than anticancer therapies) ............................................. 26 
2.4.3 
Extent of study treatment exposure and compliance ..................................................................... 27 
2.4.3.1 
Extent of study treatment exposure ............................................................................................... 27 
2.4.3.2 
Study treatment dosing modifications ............................................................................................ 29 
2.4.3.3 
Compliance .................................................................................................................................... 31 
2.4.4 
Analyses of efficacy endpoints ....................................................................................................... 31 
2.4.5 
Analyses of safety data .................................................................................................................. 31 
2.4.5.1 
Analyses of adverse events ........................................................................................................... 31 
2.4.5.2 
Deaths ............................................................................................................................................ 37 
2.4.5.3 
Analyses of laboratory variables .................................................................................................... 38 
2.4.5.4 
Analyses of vital sign variables ...................................................................................................... 39 
2.4.5.5 
Analyses of electrocardiogram variables ....................................................................................... 40 
2.4.5.6 
Analyses of other safety endpoints ................................................................................................ 40 
2.4.6 
Analyses of pharmacokinetic and pharmacodynamic variables .................................................... 40 
2.4.7 
Analyses of quality of life/health economics variables ................................................................... 40 
2.4.8 
Further therapy after discontinuation of study treatment administration during the study ............. 42 
2.5 
DATA HANDLING CONVENTIONS .............................................................................................. 43 
2.5.1 
General conventions ...................................................................................................................... 43 
2.5.2 
Missing data ................................................................................................................................... 43 
2.5.3 
Windows for time points ................................................................................................................. 45 
2.5.4 
Unscheduled visits ......................................................................................................................... 45 
2.5.5 
Pooling of centers for statistical analyses ...................................................................................... 45 
2.5.6 
Statistical technical issues ............................................................................................................. 46 
3 
INTERIM ANALYSES .................................................................................................................... 47 
3.1 
FIRST INTERIM ANALYSIS .......................................................................................................... 47 
3.2 
SECOND INTERIM ANALYSIS ..................................................................................................... 48 


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3.3 
THIRD INTERIM ANALYSIS .......................................................................................................... 48 
3.4 
FOURTH INTERIM ANALYSIS ...................................................................................................... 52 
3.5 
FIFTH INTERIM ANALYSIS .......................................................................................................... 58 
4 
DATABASE LOCK ........................................................................................................................ 59 
5 
SOFTWARE DOCUMENTATION ................................................................................................. 60 
6 
REFERENCES ............................................................................................................................... 61 
7 
LIST OF APPENDICES ................................................................................................................. 62 
APPENDIX A 
POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES CRITERIA ...................... 63 
APPENDIX B 
SUMMARY OF STATISTICAL ANALYSES ........................................................................ 64 
APPENDIX C 
THROMBOVASCULAR EVENTS AND/OR CARDIOVASCULAR RISK FACTORS .......... 65 
APPENDIX D 
AE GROUPING ................................................................................................................... 70 
APPENDIX E 
SOC SORTING ORDER ...................................................................................................... 73 
APPENDIX F 
ANTI-COAGULANT THERAPIES ........................................................................................ 74 
APPENDIX G 
ANTI-HYPERTENSIVE THERAPIES .................................................................................. 75 
APPENDIX H 
SCORING OF HEALTH RELATED QUALITY OF LIFE EQ-5D QUESTIONNAIRE ........... 76 
APPENDIX I 
SCORING OF HEALTH RELATED QUALITY OF LIFE EORTC QLQ C30 AND CR 
29 QUESTIONNAIRES .................................................................................................................. 78 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
5-FU 
5-Fluorouracil 
AE 
Adverse Event  
ALT 
(SGPT) 
Alanine 
Aminotransferase 
(or 
Serum 
Glutamate-Pyruvate 
Transferase) 
AST 
(SGOT) 
Aspartate Aminotransferase (or Serum Glutamate-Oxaloacetate 
Transferase) 
BSA 
Body Surface Area 
BUN 
Blood Urea Nitrogen 
CI 
Confidence Interval 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECOG 
Eastern Cooperative Oncology Group 
FUP 
Follow-up 
FOLFIRI 
Irinotecan/bolus-infusion-5-Fluorouracil/Leucovorin 
HBP 
High Blood Pressure 
HLGT 
High-level group term 
HLT 
High-level term 
HRQL 
Health-Related Quality of Life 
HUS 
INR 
Hemolytic Uremic Syndrome 
International Normalized Ratio 
IMP 
Investigational Medicinal Product 
IV 
Intravenous 
LDH 
Lactate Dehydrogenase 
LLT 
Lower-level term 
LV 
Leucovorin 
mCRC 
Metastatic Colorectal Cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
MID 
Minimal Important Difference 
NCI 
National Cancer Institute 
PS 
Performance Status 
PT 
Preferred term 


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QoL 
Quality of Life 
RPLS 
Reversible posterior leukoencephalopathy syndrome 
SOC 
System organ class 
SAP 
Statistical Analyses Plan 
SD 
Standard Deviation 
TMA 
Thrombotic micro-angiopathy 
ULN 
Upper Limit of Normal 
UPCR 
Urinary Protein-Creatinine Ratio 
WHO-DD 
World Health Organization-Drug Dictionary  
WBC 
White Blood Cell 
 
 


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1 
OVERVIEW AND INVESTIGATIONAL PLAN   
This statistical analysis plan (SAP) provides a comprehensive and detailed description of strategy 
and statistical technique to be used to realize the analysis of data for aflibercept (AVE0005) study 
protocols AFLIB_C_06097 (ASQoP) and AFLIB_L_06266 (AFEQT).  
1.1 
STUDY DESIGN AND RANDOMIZATION 
The study AFLIB_C_06097 is a prospective, phase IIIb/IV, international, multicenter, single arm 
and open-label study to evaluate the safety and Health-Related Quality of life of aflibercept in 
patients with metastatic colorectal cancer (mCRC) previously treated with an oxaliplatin-
containing regimen. 
It is planned to include a total of about 900 patients, from around 150 investigational sites, over 
about 20 months of accrual. 
. 
These two studies has the same design (patients, visit schedules and treatment) , the same way of 
collecting data (eCRF) and the same statistical analyses. 
1.2 
OBJECTIVES 
1.2.1 Primary objectives 
The objective of study AFLIB_C_06097 is to document the aflibercept overall safety in the 
mCRC patients (similar to the ones evaluated in the VELOUR phase III trial) while providing the 
patients and investigators with access to aflibercept, prior to its marketing authorisation and/or 
commercial availability. 
.


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1.2.2 Secondary objectives 
To document the Health-Related Quality of Life (HRQL) of aflibercept in the same patient 
population. 
1.3 
DETERMINATION OF SAMPLE SIZE 
No formal sample size calculation has been done. The Safety analyses of this study will be 
descriptive in nature, and the table below provides the precision (95% CI) associated to a variety 
of AE event rates for a targeted sample size of 900 [AFLIB_C_06097] /
] 
patients: 
Overall 
sample size
p=10%
p=20%
p=30%
p=40%
p=50%
900
[8.0%; 12.0%]
[17.4%; 22.6%]
[27.0%; 33.0%]
[36.8%; 43.2%]
[46.7%; 53.3%]
1.4 
STUDY PLAN 
The study AFLIB_C_06097 is started in the second quarter of 2012 in Europe and in the United 
States, simultaneously or sequentially in the other involved countries.  
In each country (except UK and Germany) patient recruitment will end when aflibercept 
(ZALTRAP) becomes commercially available (i.e. accessible to the patient as per each country 
regulation). In the UK, study accrual will be terminated when the anticipated number of patients 
has been achieved across all study sites. In Germany, the recruitment will stop at the end of global 
study in others countries. 
Patients will be considered screened upon signing the Informed Consent Form (ICF). Baseline 
period will correspond to the timeframe between the signature of ICF and the first study treatment 
administration (either Aflibercept or FOLFIRI). The treatment period will consist of 2-week 
treatment cycles, and will start at first product infusion.
Each patient will be treated until disease progression, unacceptable toxicity, death, Investigator’s 
decision or patient’s refusal for further treatment (whichever comes first). The patients will be 
followed-up during treatment and for at least 30 days after last study treatment administration 
(either aflibercept or FOLFIRI) administration (for safety assessment). Beyond this date all 
ongoing SAEs (regardless of relationship with study treatment) as well as ongoing related AEs 
and new SAEs, that are considered to be related to study treatment, will have to be collected and 


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followed till resolution/stabilization (stabilization being defined as an event ongoing without any 
change for at least 3 months). 
Health related quality of life evaluation will be performed using the following questionnaires  
o EORTC QLQ-C30 (version 3);  
o EORTC QLQ CR29 (disease specific supplement to QLQ-C30) - optional;  
o EQ-5DTM 
Baseline assessment should be obtained from all patients. All the questionnaires will be 
administered within 3 days prior to the first treatment administration, but in any case before the 
patient is given the first dose. While on treatment assessments should occur before the treatment 
administration at the beginning of every odd cycle starting from cycle 3 (day 1 of cycle 3, 5, etc) 
and at the end of treatment visit. Data will be collected in a patient booklet separated from the e-
CRF 
Laboratory data (hematology, biochemistry, urinalysis) and vital signs will be collected at 
baseline and at each cycle. 
For more information, see study flowchart of the Protocols. 
A summary is presented here below. 
 
 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL  
Changes between the statistical section of the protocol and the present SAP are listed below. 
 
Baseline 
Treatment  
Evaluation 
 
Every cycle 
End of Treatment 
(EOT) 
(30 days after last 
aflibercept treatment) 
Post-treatment 
FUP 
Informed consent  
X 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
Demography 
X 
 
 
 
Prior Medical/Surgical History & 
Cancer History, Prior Medication 
History 
X 
 
 
 
Clinical examination 
X 
X 
X 
 
Hematology (a) 
X 
X 
 
 
Biochemistry (b) 
X 
X 
 
 
Urinalysis (c) 
X 
X 
 
 
Concomitant medication (d) 
 
X 
X 
 
Aflibercept + FOLFIRI (e) 
 
Every 2 weeks (within 3 days from inclusion) 
AE / SAE (f) 
X 
X 
X 
X 
Health-Related Quality of Life (g) 
EORTC- QLQ C30/ QLQ-CR29*/  
EQ-5DTM  
X 
 
I 
N 
C 
L 
U 
S 
I 
O 
N 
 
 
 
X (every odd cycle 
starting from C3) 
X 
 
 


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Table 1 – Changes in the statistical section of the protocol 
SAP 
version  
number 
Date 
approved 
Rationale 
Description of statistical changes 
1 
26-Sep-2012 
Clarification 
Health related quality of life analysis will be 
performed in the patients, who have signed 
the informed consent form and who 
completed the questionnaires at baseline and 
at least one assessment post baseline and 
have received at least part of one dose of study 
treatment. 
 
 
Upgrade of version 
NCI CT version 4.0 to 4.03 
2 
11-Dec-2012 
Definition of the safety population in 
the context of interim analyses 
See section 1.6.1, modification 1 
 
 
Definition of the emergence period in 
the context of interim analyses 
See section 1.6.1, modification 1 
3 
 
Clarification of variables for extent 
study treatment exposure 
See Section 1.6.2,  
 
 
Clarification of the QoL population 
Clarification of classification according  
to prior anticancer therapies received 
Handling of relapse date and adverse 
event end dates incomplete 
Files used to build tables concerning 
AE grouping 
Clarification on laboratory analysis   
G-CSF presentation 
Adverse events clarifications 
Updates on appendices F and G   
Reasons of permanent and premature 
discontinuation 
 
 
 
See Section 1.6.2 
 
 


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1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN 
1.6.1 Modifications to version 1 made in version 2 
1. Given the short time between the cutoff date and the planned date of database lock, the data 
cleaning process will be only possible for data collected before the cutoff date. Thus, Adverse 
Events will be analyzed only in cycles that are completed before cutoff date (completed means 
that administration of next cycle or end of study visit or death, occurred before or at time of cutoff 
date). In this purpose, the definition of safety population and the emergence period for AE will be 
modified in the context of interim analyses (sections 3.1 and 3.2): 
x for interim analyses, safety population will be defined as the patients who have signed the 
informed consent form, who received at least part of one dose of study treatment (either 
aflibercept or FOLFIRI), and who completed cycle 1. 
x for patients still on treatment, emergence period for the AE is defined as the period from the 
first study treatment intake to the end of last cycle completed before the cutoff date  
2. Local needs for interim results will occur at very different periods and the frequency of 
interim analyses initially planned will not cover those needs in term of timing. Moreover, the first 
interim analysis will concern less patients than expected, and complementary results will be 
needed later. Finally, it is possible that new countries participate to the study, which will lead to 
postpone the end of study. Consequently, additional interim analyses will occur during the course 
of the study. The section 3 of the SAP will be introduced by the following sentence: 
x Two interim analyses are planned so far during the course of the study, in order to obtain 
preliminary results on baseline characteristics, HRQL and safety data. However, depending 
on regulatory requests in participating countries, additional interim analyses are likely to be 
planned. Future changes in the calendar of interim analyses will be stated in further 
amendments of the SAP, if any. 
3. For interim analyses, the tables of exposure section are planned to be analyzed on the 
subpopulation of patients who discontinued the treatment before cutoff date. Only 5 patients 
discontinued the treatment before 5 November 2012 (i.e. cut-off date for the first IA). 
Consequently, it has been decided not to produce those tables for this analysis. Consequently, in 
section 3.1, the following tables have been removed from the list of planned tables: 15.1.4-1, 
15.1.4-2, 15.1.4-3, 15.1.4-4 and 15.1.4-5. However, exposure tables are still planned for interim 
analysis #2. 
4. A new table specific for interim analyses has been added (15.1.1-3b), to assess the number of 
patients (ongoing at time of IAs cut-off) who completed cycle 1, cycle 2… and thereafter. This 
table will be provided for the safety population. The purpose of this table is to give a picture of 
patient’s disposal at cutoff date, since table 15.1.4-1 is provided only for the subpopulation 
patients who discontinued the treatment. 
5. This version of SAP also includes five additional minor changes: 


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x In the summary of prior chemotherapy (section 2.1.1), the maintenance therapies based on 
bevacizumab only have been added.
x In the summary of deaths (section 2.4.5.2), the analysis of all deaths and all fatal AEs will be 
performed on all included patients. Safety population remains the population of analysis for 
summary tables of treatment emergent fatal AEs.
x For interim analyses (section 3.1 and 3.2), the table 15.5.2 – 4 that summarizes the visual 
scale of EQ-5D questionnaire, has been added.
x In section 2.5.4, the handling of unscheduled visits during the same cycle is described more 
precisely.
x In the Appendix I, the initial formula for fatigue score was incorrect. The right formula is FA 
Score  ^RS  1  3`.
1.6.2 Modifications to version 2 made in final amended version 3 
1. Clarifications have been added for derivations of variables used for extent of study treatment 
exposure. 
2. For the second analysis interim the part of the definition of Health related quality of life EQ-
5D, EORTC-C30 and EORTC –CR29 analysis population ‘..who completed the questionnaire 
at baseline’ has been considered as to have an evaluable baseline assessment, independently of 
the answer reported to the question ‘Was the questionnaire completed?’ in the module QoL 
Questionnaires of the eCRF. To have an evaluable assessment means: 
x
To have a evaluable single index utility score for health related quality of life EQ-
5D:
x
To have at least one evaluable score for any of the scales (Global health status, 
functional scales or symptom scales/items) for EORTC-C30 . 
x
To have at least one evaluable score for any of the scales (Functional scales or 
symptom scales/items) for EORTC-CR29 
The corresponding clarifications have been added to section 2.3.3 HRQL Population.  
3. For the second analysis interim in case of having two questionnaires for the same visit, the 
analysis procedure has been the following:  
x
If baseline and cycle 1 questionnaires, the closest to the first administration study drug has 
been analyzed. 
x
For the other cycles, the closest before or the day 1 of cycle has been analyzed.
x
From now on and for future analysis, the following time windows will be used for the QoL 
analysis (section 2.5.3): only the questionnaires filled in: 


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 - “from 21 days before cycle 1 to the day of cycle 1” for the baseline 
assessment will be kept. 
 -“from 7 days before the cycle to the day of the cycle” for the cycles 3, 5, 7 
… assessments will be kept. 
 “for EOT within [15,45] days of last administration 
 if several QoL done for the same patient in a given time window, then the 
closest to cycle 1 for baseline, and the closest to the cycle for cycles 3, 5, 7 
… will be kept 
 
4. Table 15.1.2 -5 (Prior anticancer therapies): The cases:‘ First Line followed by  Not 
Applicable in the intent field’  will be identified and sent to Sanofi  in order to be classified 
in the proper group.”. 
5. Table 15.1.2 -5 (Prior anticancer therapies): For the second IA, Relapse dates incomplete 
have been imputed to 15 when the day is missing and to 01JUL when day and month 
missing since a list of these cases was sent to Sanofi and no doubts regarding the timeframe 
between end of prior regimen and relapse. However for each interim and final analysis a 
list will be sent to Sanofi for its approval. See section 2.5 
6. For the second interim analysis tables 15.3.1 -20. 15.3.1 -21, 15.3.1 -22 and 15.3.1 -23 
concerning AE group terms, have been programmed using the following documents 
provided by Sanofi: 
x list_for_grouping_Meddra_v151_ASQOP.xls : it gives the list of PT to be used for 
all AE grouping (except 'Diarrhea' and 'Stomatitis and ulcerations'), column (with 
Yes) to have the list of PTs to be used.  
x Stomatis_ulceration.xls: it gives the list of PT to be used for AE group 'Stomatitis 
and ulceration'. 
x These documents will be updated at each upgrade of the MedDRA dictionary 
7. To extend the adverse events to the cycles, for incomplete AE end date, the last day of the 
month will be imputed, as it is the worst case. See section 2.5 
8. For demographic characteristics, height (cm) and body surface area (m²), have been added 
to table 15.1.2- 1a and 15.1.2- 1b. See section 2.1.1 Demographic characteristics. 
9. Section 2.1.1 Medical or surgical history, the information will be summarized to system 
organ class and high level term instead of system organ class and preferred term as 
indicated the previous version. 


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10. Section 2.1.1 Prior anticancer therapies, the information ‘Bevacizumab among patients 
with biologic agent’ has been added to tables 15.1.2 -5a and 15.1.2 -5b for each intentional 
group (neoadjuvant/adjuvant, advance only and neoadjuvant/adjuvant +advanced). 
11. The laboratory parameters classification has been updated. See section 2.1.4.3  
12. Important deviations on inclusion/exclusion criteria have been updated. See section 2.3.2.1 
13. G-CSF presentation has been updated. See section 2.4.2 Prior or concomitant medications 
(other than anticancer therapies) and table 15.1.3 -5 for more details. 
14. Analysis of adverse events: the following classifications have been added to section of 
‘Overview of treatment-emergent adverse events, summarizing number (%) of patients 
with any’  and ‘grouping by primary SOC and PT, by worst NCI grade:’  
x Treatment-emergent adverse possibly related  
x Treatment-emergent adverse event leading to permanent treatment discontinuation 
x Treatment-emergent adverse event leading to premature treatment discontinuation 
(either early discontinuation of FOLFIRI (last component of FOLFIRI) with 
aflibercept continued, or early discontinuation of aflibercept /with FOLFIRI 
continued) 
See section 2.4.5.1 for more details. 
15. For each of grouping adverse events the summary of : Among patients with any of the 
above grouped term events, the number of patients with a first occurrence during treatment 
will be summarized with the cycle of first occurrence, worst grade, cycle of occurrence of 
the worst grade and action taken regarding the study treatment, has been added to this new 
version. See section 2.4.5.1 for more details 
16.  The summary statistics (including number, mean, median, standard deviation, minimum 
and maximum) of laboratory parameters (and changes from baseline) per visit or study 
assessment has been deleted for this version.. 
17. Appendix F and G have been updated, see corresponding section. 
18. Reason of premature discontinuation (for aflibercept and FOLFIRI separately) will be also 
described. See section 2.2 Disposition of patients. 
19. EQ-5D questionnaires:  
EQ-5D questionnaires will be also described using a frequency table for each of the 5 
dimensions. Shift tables between baseline and other cycles will be provided overall for each 
of the 5 dimensions (mobility, self-care, usual activities, pain/discomfort and 
anxiety/depression). Change from Baseline in the EQ-5D scores to each of the cycle will 
also be summarised by overall and each of the 5 dimensions. See section 2.4.7. 


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x Value for Stable disease on treatment will be computed using treatment period    
assessments starting from baseline instead of cycle 3. See section 2.4.7. 
x The 95%CI will be also added for all 'mean' of the  tables on QoL 15.5.2- 2 and   
15.5.2-4 
20. EORTC QLQ-C30 questionnaires:  
x The percentage of patients with ‘Symptom evolution from baseline’ in term of    
deterioration, (i.e. for GHS and functioning scale a change from baseline equal or 
smaller than minus 10 and for symptoms scales a change from baseline equal or 
greater than 10) for each assessment will be also presented by subgroups and overall.  
x The 95%CI will be also added for all 'mean' of the  tables on QoL 15.5.3- 2,    
15.5.3-3 and 15.5.3 -4 
21. EORTC QLQ-CR29 questionnaires:  
x The percentage of patients with ‘Symptom evolution from baseline’ in term of    
deterioration, (i.e. for GHS and functioning scale a change from baseline equal or 
smaller than minus 10 and for symptoms scales a change from baseline equal or 
greater than 10) for each assessment will be also presented by subgroups and overall. 
x The 95%CI will be also added for all 'mean' of the  tables on QoL 15.5.4- 2 and    
15.5.4-3 
22. Section 3.3 Third Interim Analysis has been added for this version 
23. Section 2.1.1 For the fourth Interim Analysis on Prior anticancer therapy, ‘With 
Bevacizumab (Y/N)’ will be present for the group neoadjuvant/adjuvant +advanced , when 
given as advanced. 
24. Deaths presentations have been modified . For more details see section 2.4.5.2 
25. Section 4.4 Fourth Interim Analysis has been added for this version 
26. Parodontopathy has been added to the AE grouping, after the fourth interim analysis, for 
more details see section 2.4.5.1 
27. Summary of reason for permanent treatment discontinuation  will also be described. See 
Section 2.2 
28. Any grade 3-4 related TEAE and  any Serious related TEAE  have been added to  
Overview of adverse events. 
 
1.6.3 Modifications to version 3 made in final amended version 4 
This version of SAP is only applicable for the AFLIB_C_06097 program. 


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In order to satisfy local and global needs for interim results, an additional interim analysis 
was planned in Q3 2016. The section 3 of the SAP will be introduced by the following 
sentence: 
The amended #2 SAP takes into account the two first additional interim analyses, and this 
current amended #3 SAP takes into account this last additional interim analyses.  
And the section 3.5 of the SAP will be introduced by the following sentence: 
A fifth interim analysis was performed during the second quarter 2016. This interim 
analysis was concerned patients in AFLIB_C_06097 program only. 
The statistical report contained the same tables as the ones planned for the fourth interim 
analysis. 
 


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2 
STATISTICAL AND ANALYTICAL PROCEDURES 
2.1 
ANALYSIS ENDPOINTS 
2.1.1 Demographic and baseline characteristics 
The baseline is defined as the last value or measurement taken before the first dose of treatment.  
All baseline safety parameters (apart from those listed below) are presented along with the on-
treatment summary statistics in the safety section (2.4.5). 
Demographic characteristics 
Demographic variables are: 
 gender (Male, Female),  
 race (White, Black or African american, Asian, other),  
 age in years (quantitative and qualitative variable : <65, [65 - 75[ and ≥75 years),  
 weight (kg.),  
 height (cm.),  
 body surface area (m²), computed as 0.007184 × weight (kg) 0.425 × height (cm) 
0.725(variation of DuBois and DuBois formula).  
Medical or surgical history 
Medical (or surgical) history including detailed cardiovascular risk factors and prior vascular 
events if any (see Appendix C for further detail).  
This information will be coded using the version of Medical Dictionary for Regulatory Activities 
(MedDRA) currently in effect at Sanofi at the time of database lock, and the information will be 
summarized according to system organ class and high level term. 
Disease characteristics at baseline   
Specific disease history includes primary tumor location (colon, recto sigmoid, rectum and other) 
histology type (adenocarcinoma and other), metastases site at study entry (liver, lung, distant 
lymph nodes, ovaries, peritoneum, bone and other), number of metastases sites (qualitative 
variable : 1, >1), time from initial histological diagnosis to date of inclusion (in months) and 
ECOG performance status (0-1). 
 
 


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Prior anticancer therapies 
Anticancer therapies include chemotherapy, surgery and radiotherapy: 
 Prior anticancer therapies (excluding surgeries and radiotherapy) 
o Intent (neoadjuvant/adjuvant, advanced only, neoadjuvant/Adjuvant + advanced) 
o For patient entering directly from neoadjuvant/adjuvant anti-cancer therapy : 
 Relapse more than six months after completion of adjuvant chemotherapy 
(Y/N) 
 Oxaliplatin(Y/N), 
 Oxaliplatin-based chemotherapy (oxaliplatin only, oxaliplatin + 
fluoropyrimidine, oxaliplatin + fluoropyrimidine + biologic agent), 
 Bevacizumab (Y/N). 
 Bevacizumab among patients with biologic agent  
o For patient with advanced chemotherapy only : 
 Oxaliplatin (Y/N), 
 Oxaliplatin-based chemotherapy (oxaliplatin only, oxaliplatin + 
fluoropyrimidine, oxaliplatin + fluoropyrimidine + biologic agent), 
 Bevacizumab (Y/N), 
o Maintenance therapy with bevacizumab only (Y/N). 
 Bevacizumab among patients with biologic agent  
 
o For patient with neoadjuvant/adjuvant followed by advanced chemotherapy: 
 Relapse less than six months after completion of adjuvant chemotherapy (Y/N), 
 Oxaliplatin(Y/N) in neoadjuvant/adjuvant chemotherapy. 
 Oxaliplatin(Y/N) in advanced chemotherapy. 
 Oxaliplatin-based chemotherapy (oxaliplatin only, oxaliplatin + 
fluoropyrimidine, oxaliplatin + fluoropyrimidine + biologic agent)  in advanced 
chemotherapy.   
 Bevacizumab (Y/N) in advanced chemotherapy 
 Bevacizumab (Y/N) 
o Maintenance therapy with bevacizumab only (Y/N). 
 Bevacizumab among patients with biologic agent  
 
o Cumulative duration of oxaliplatin-based regimens (months), time from end of last 
advanced chemotherapy to inclusion (months), time from end of 
neoadjuvant/adjuvant treatment to inclusion (months) 
o Reason for discontinuation of prior advanced chemotherapy  


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o Time from the end of prior adjuvant therapy to inclusion (months) (only for 
patients included directly after adjuvant)  
o Reason for discontinuation of prior adjuvant therapy (only for patients included 
directly after adjuvant)  
 
 Prior surgery  for colorectal cancer (Y/N) and type of surgery (colon primary tumor 
resection, rectum primary tumor resection, metastasis resection, palliative surgery) & time 
from last primary tumor or metastasis resection to inclusion (months) 
 Prior anti-cancer radiation therapy (Y/N), site (bone, colon, rectum, liver, pelvis and other) 
and intent (curative and palliative), time from last radiation therapy to inclusion (months)  
Vital signs  
 Systolic blood pressure (mmHg), 
 Diastolic blood pressure (mmHg), 
 
Any technical details related to computation, dates, and handling of missing dates are described in 
Section 2.5.  
2.1.2 Prior or concomitant medications (other than anticancer therapies) 
All medications taken within 1 week before the first infusion of the study treatment and until the 
end of the study are to be reported in the case report form pages. 
All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD) 
version currently in effect at Sanofi at the time of database lock and the information will be 
summarized by therapeutic class and anatomic class. 
x 
Prior medications are those the patient used prior (within 1 week before the first infusion 
of the study treatment) to the first dose of study treatment. Prior medications can be 
discontinued before first administration or can be ongoing during treatment phase.   
x 
Concomitant medications are any treatments received by the patient concomitantly to any 
study treatment (either aflibercept or FOLFIRI), from the first dose of study treatment to 
30 days after the last dose of study treatment. Concomitant medications do not include 
medications started during the post-treatment period (as defined in the observation period 
in Section 2.1.4).  
x 
Post-treatment medications are those the patient took in the period starting 31 days after 
the last study treatment dose (either aflibercept or FOLFIRI). 
A given medication can be classified as a prior medication and/or a concomitant medication 
and/or a post-treatment medication. Any technical details related to computation, dates, 
imputation for missing dates are described in Section 2.5. 


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2.1.3 Efficacy endpoints 
Not applicable. 
2.1.3.1 Primary efficacy endpoint(s) 
Not applicable. 
2.1.3.2 Secondary efficacy endpoint(s) 
Not applicable. 
2.1.4 Safety endpoints 
The safety analysis will be based on the reported adverse events and other safety information, 
such as clinical laboratory data, vital signs and ECOG performance status. 
Observation period  
The observation period will be divided into 3 periods: 
x 
The pre-treatment period is defined as the time from the informed consent date up to the 
time of the first dose of study treatment (aflibercept or FOLFIRI, whichever is first). 
x 
The on-treatment period is defined as the time from first dose of study treatment 
(aflibercept or FOLFIRI, whichever is first) up to 30 days after the last dose of study 
treatment (aflibercept or FOLFIRI, whichever is last). 
x 
The post-treatment period is defined as the period of time starting 31 day after the dose of 
study treatment (aflibercept or FOLFIRI, whichever is last) up to end of post-treatment 
follow-up period (see below). 
2.1.4.1 Adverse events variables 
Adverse events are collected from the time patient gives the informed consent up to 30 days after 
the last dose of study treatment. After the 30 day FUP period all ongoing SAEs (regardless of 
relationship with study treatment) as well as ongoing related AEs and new related SAEs will have 
to be collected and followed till resolution/stabilization (stabilization being defined as an event 
ongoing without any change for at least 3 months). Adverse events are defined as any newly 
occurring sign or symptom as well as any pre-existing sign or symptom that worsens in severity. 
Adverse event observation period: 
 
x 
Pre-treatment AEs defined as any adverse event starting (i.e. newly occurring) or 
worsening in severity (if pre-existing) from the signed informed consent date up to first 
administration of the study treatment (either aflibercept or FOLFIRI) 
x 
Treatment-emergent AEs (TEAEs): defined as adverse events starting or worsening in 
severity (if pre-existing) during the on-treatment period defined above. 


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x 
Post-treatment AEs are adverse events starting or worsening in severity (if pre-existing) 
during the post-treatment period 
All adverse events will be coded to a lower-level term (LLT), preferred term (PT), high-level term 
(HLT), high-level group term (HLGT), and associated primary system organ class (SOC) using 
the version of Medical Dictionary for Regulatory Activities (MedDRA) currently in effect at 
Sanofi at the time of database lock. 
2.1.4.2 Deaths 
The deaths observation period are per the observation periods defined above.  
x 
Death on-study: deaths occurring during the on-study observation period 
x 
Death on-treatment: deaths occurring during the treatment-emergent adverse event period 
or if assessed as related to study treatment any time thereafter. 
2.1.4.3 Laboratory safety variables 
Clinical laboratory data consists of blood analysis, including hematology, clinical chemistry, and 
urinalysis. Clinical laboratory values after conversion will be analyzed into standard international 
units and international units will be used in all listings and tables. 
Blood samples for clinical laboratories and urine samples will be taken before each study 
treatment dosing unless otherwise specified. In case of several labs assessments in the same cycle, 
the worst result will be chosen. The laboratory parameters will be classified as follows. 
x 
Hematology  
- 
Hemoglobin 
- 
platelet count 
- 
WBC 
- 
Neutrophils 
x 
INR (only for patients under VKA therapy) 
x 
Electrolytes 
- 
sodium, 
- 
Corrected calcium (mg/dL) will be computed as: measured total calcium (mg/dL)-
[0.8*serum albumin(g/dL)-4.0]  
- 
potassium 
x 
Renal and liver function parameters: 
- 
Creatinine 
- 
calculated creatinine clearance (3060 mL/mn, ≥30mL/mn and <60mL/mn ≥60mL/mn 
and <80mL/mn, ≥80mL/mn), as reported by the investigator,  calculated either by 
Cockroft-Gault, or MDRD 


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- 
AST, 
- 
ALT, 
- 
Alkaline phosphatase, 
- 
total bilirubin, 
x 
Other biochemistry parameters : 
- 
glucose, 
- 
albumin 
x 
Non gradable parameters:  
- 
LDH, 
- 
total proteins, 
- 
BUN 
- 
urea 
- 
total protein 
x 
Urine samples will be collected as follows. 
- 
Dipstick urinalysis - white blood cells, red blood cells , protein 
- 
Morning spot urinalysis -  protein, creatinine, UPCR [if proteinuria is t2 on dipstick 
then UPCR should be performed] 
- 
24-hour urinalysis - urinary volume, protein (urine), creatinine (urine), hemoglobin, 
red blood cells [if UPCR >1, then 24-hour urinalysis should be performed] 
 
The NCI grades for each lab variable will be derived according to NCI-CTCAE 4.03, whenever 
applicable. For non-gradable parameters, laboratory values “out of normal ranges” will be 
summarized. For ALT, AST, Alkaline phosphatase, total bilirubin and creatininemia, missing local 
normal ranges will be replaced by generic normal ranges 
Laboratory “out of normal ranges” abnormalities will be derived using laboratory normal ranges. 
The formulas used for converting laboratory parameters in standard international units will be 
provided in the conversion factor panel (FACTOR_20101119.xls file). 
2.1.4.4 Vital signs variables 
Systolic and diastolic blood pressure, weight and ECOG performance status as measured on 
Day 1 of each cycle.   
2.1.4.5 Electrocardiogram variables 
Not applicable.  


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2.1.5 Pharmacokinetic variables  
Not applicable.  
2.1.6 Pharmacodynamic/genomics endpoints  
Not applicable.  
2.1.7 Quality-of-life endpoints  
Health Related Quality of Life:  
 EQ-5DTM: observed values and changes from baseline health-related QoL visual scale and 
utility score. 
 EORTC QLQ-C30 questionnaire: observed values and changes from baseline for the 
Global health status (scoring of items 29 & 30), the five functional scales (Physical, Role, 
Emotional, Cognitive and Social), the three symptom scales (Fatigue, Nausea/vomiting 
and Pain) and the other single items  
Exploratory endpoint: 
 EORTC QLQ-CR29 questionnaire (specific colorectal module - optional): observed values 
and changes from baseline for the four scales (body image, anxiety, weight, sexual 
interest) and the other single items.  
EORTC QLQ-CR29 questionnaire is optional in the countries where it is available : Brazil, 
Canada, Denmark, Germany, Italy, Netherlands, Norway, Spain, Sweden, UK, USA. 
2.1.8 Health economic endpoints  
Not applicable.  
2.1.9 Further therapy after discontinuation of study treatment administration during the 
study 
Further therapies after discontinuation of study treatment (aflibercept and FOLFIRI) include 
radiation and anti-cancer therapies: 
 Further anticancer therapies (excluding surgeries and radiotherapy) 
o Chemotherapies (fluoropyrimidine, irinotecan, oxaliplatin, folonic acid / 
leuvocorin, other) 
o Biologic agents (bevacizumab, cetuximab, panitumumab, regorafenib, other) 


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o Time from last study treatment administration to the start of the new anticancer 
therapies  (months) 
 Anti-cancer radiation therapy (Y/N), site (bone, colon, rectum, liver, pelvis and other), 
intent (curative and palliative) and time from last study treatment administration to 
radiation (months). 
2.2 
DISPOSITION OF PATIENTS 
The number and percentage of patients screened, included and treated will be presented by 
country and overall. Study completion status (for aflibercept and FOLFIRI separately) and 
reasons for withdrawals will be described as per EOT eCRF forms , using frequency tables. 
Reasons of permanent and premature discontinuation (for aflibercept and FOLFIRI separately) 
will be also described. 
 Screened patients: all patients with signed ICF and at least part of baseline assessment 
performed 
 Included patients: all patients with signed ICF and answer to “will the patient continue into 
the study” is Yes 
 Screen failure patients: all screened patients who do not continue after the baseline visit  
 Treated patients: all patients who took at least one dose of study treatment. 
Additionally, the analysis populations will be summarized in a table by number (%) of patients 
x 
Safety population 
x 
Health related quality of life population(s)  
Percentages will be calculated using the number of included patients as the denominator. The 
disposition of patients will be also presented overall and by country. 
2.2.1 Randomization and drug dispensing irregularities 
Not applicable. 
2.3 
ANALYSIS POPULATIONS 
2.3.1 Efficacy populations 
Not applicable. 


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2.3.2 Safety population 
The safety population will consist of the patients who have signed the informed consent form and 
who have received at least part of one dose of study treatment (either aflibercept or FOLFIRI). 
2.3.2.1 Important protocol deviations 
The summary of important protocol deviations will be based on the safety population. Other 
deviations will not be summarized in the Clinical Study Report. 
Important protocol deviations are defined as follows: 
x Important deviations on inclusion/exclusion criteria 
 No histologically or cytologically proven adenocarcinoma of the colon or rectum 
 Non-metastatic disease 
 More than one prior chemotherapeutic regimen for advanced disease 
 No prior oxaliplatin containing regimen for advanced disease 
 Relapse more than 6 months (≥ 7 months) after completion of adjuvant oxaliplatin-based 
chemotherapy, for patients entered in the trial directly after adjuvant chemotherapy. 
 Absence of signed and dated informed consent prior to enrollment in the study 
 Prior therapy with IRINOTECAN 
 No relapse after the 1st line of Oxaliplatin or adjuvant oxaliplatin-based chemotherapy for 
patients entered in the trial directly after adjuvant chemotherapy 
x Other important deviations 
 Other anticancer therapies than Aflibercept and Folfiri during the treatment 
2.3.3 HRQL analysis populations  
Those populations are subsets of the safety population. 
Health related quality of life EQ-5D analysis will be performed in the patients who have signed 
the informed consent form, who have an evaluable EQ-5D questionnaire at baseline and at least 
one evaluable assessment post baseline and have received at least part of one dose of study 
treatment. (either aflibercept or FOLFIRI).   
Health related quality of life EORTC-C30 analysis will be performed in the patients who have 
signed the informed consent form, who have an evaluable EORTC QLQ C30 questionnaire at 
baseline and at least one evaluable assessment post baseline and have received at least part of one 
dose of study treatment. (either aflibercept or FOLFIRI). 
Health related quality of life EORTC-CR29 analysis will be performed in the patients who have 
signed the informed consent form, who have an evaluable the EORTC QLQ CR29 questionnaire 
at baseline and at least one evaluable assessment post baseline and have received at least part of 
one dose of study treatment. (either aflibercept or FOLFIRI). 


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  To have an evaluable assessment means:  
x To have a single index utility score for health related quality of life EQ-5D  
x To have at least one score for any of the scales (Global health status, functional 
scales or symptom scales/items) for EORTC-C30. 
x  To have at least one score for any of the scales (Functional scales or symptom 
scales/items) for EORTC-CR29 
2.4 
STATISTICAL METHODS 
All statistical analyses will be descriptive in nature and no formal statistical test will be 
performed. Analysis of baseline characteristics and safety analyses of safety will be performed on 
the Safety population.  
In general, the descriptive summary for continuous data will include the number of non-missing 
observations (n), mean, standard deviation, median, 25%-percentile and 75%-percentile, 
minimum and maximum. The number of patients with missing data will be displayed when 
relevant. 
In general, categorical data will be summarized for each treatment group using counts (n) and 
percentages (%). The number of patients with missing data will be displayed when relevant, but it 
will not be included in the denominator for the calculation of percentages unless otherwise 
specified. 
2.4.1 Demographics and baseline characteristics 
All Patients will be described at baseline (characteristics of patients, medical history, cancer 
history - all parameters from section 2.1.1) using descriptive statistics presented at previous 
section. As part of Quality of Life analysis, the following tables will also be presented for the 
HQRL analysis population: 15.1.2 – 1, 15.1.2 – 2 and 15.1.2 – 5. 
2.4.2 Prior or concomitant medications (other than anticancer therapies) 
The prior and concomitant medications will be presented for the safety population.  
Medications will be summarized according to the WHO-DD dictionary, considering the first digit 
of the anatomic category (ATC) class (anatomic category) and the first 3 digits of the ATC class 
(therapeutic category). All ATC codes corresponding to a medication will be summarized, and 
patients will be counted once in each ATC category (anatomic or therapeutic) linked to the 
medication. Therefore patients may be counted several times for the same medication.  
The table for prior medications will be sorted by decreasing frequency of ATC followed by all 
other therapeutic classes based on the overall incidence. In case of equal frequency regarding 
ATCs (anatomic or therapeutic categories), alphabetical order will be used. 


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Prior anti-hypertensive therapy will be presented by therapeutic class (calcium channel blocker, 
beta blocker, ACE inhibitor, diuretic, etc) with a distinction between patients having prior 
hypertension at baseline (information obtained from Medical History form and based on group 
term), and those who have not. 
Prior anti-coagulant therapy will be presented by therapeutic class (vitamin K antagonist, 
heparins, …) with a distinction between patients having prior thrombovascular event at baseline 
(based on grouped term), and those  without prior thrombovascular event at study entry . 
The tables for concomitant medications will be sorted by decreasing frequency of ATC followed 
by all other therapeutic classes. In case of equal frequency regarding ATCs (anatomic or 
therapeutic categories), alphabetical order will be used.  
G-CSF will be summarized in number (%) at cycle 1 and at any cycle (except cycle 1)  and by 
intent. 
G-CSF at cycle 1 will be identified by: start date of G-CSF between two days before first 
administration (day 1 cycle 1) and the day before day 1 cycle 2. 
G-CSF at any cycle (except cycle 1) will be identified by: start date of G-CSF between day 1 
cycle 2 and 30 last days after end of treatment. 
A listing of post-treatment medications will be provided for the safety population. 
2.4.3 Extent of study treatment exposure and compliance  
The extent of study treatment exposure will be summarized by actual treatment within the safety 
population (Section 2.3.2). 
2.4.3.1 Extent of study treatment exposure 
Extent of exposure will be assessed as follows: 
Number of patients treated, number of cycles administered, duration of dosing (weeks) will be 
summarized for Aflibercept/FOLFIRI together, and for each drug separately. Total actual dose or 
Cumulative actual dose (mg/kg for aflibercept and mg/m² for FOLFIRI regimen compounds) and 
dose intensity (mg/kg/week for aflibercept and mg/m²/week for FOLFIRI regimen compounds) 
and relative dose intensity (%) will be summarized for each drug separately. Dose delays, 
omissions and dose reductions will also be analyzed. 
 
The overall extent of exposure will be assessed for each patient as: 
 
x 
Actual number of weeks on treatment is defined as:  
Duration of dosing (weeks) = (date of last cycle day 1 – date of first cycle day 1 + 14)/7.  
regardless of unplanned intermittent discontinuations (see Section 2.5.2 for calculation in case 
of missing or incomplete data).   


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x First treatment administration: if aflibercept and FOLFIRI are taken on different 
dates, the first of both dates will be used. 
x Last treatment administration: if aflibercept and FOLFIRI are discontinued on 
different dates, the last of both dates will be used.   
x 
Total number of cycles (k), determined by the longest duration of each individual drug 
In this section, the “dose” refers to a measurement with the unit of mg/kg for aflibercept and 
mg/m2 for irinotecan and 5-FU. The exposure will be assessed for the safety population based on 
following measurements for each patient. The following calculations will be performed for each 
drug separately (aflibercept, irinotecan and 5FU (bolus+infusion)). 
 
x Total number of cycles of study therapy (K) for each drug and overall (i.e. number of cycles 
with at least one dose intake of aflibercept and/or FOLFIRI). 
 
 
The total actual dose by drug (or cumulative dose by drug, mg/kg or mg/m2) will be calculated for 
each drug as the sum of the actual doses (in mg/kg or mg/m2) at each cycle:  
¦
 
K
1
k
[k]
 
Cycle
in 
 
Dose
 
Actual
 =
 
Dose
 
Actual
 
Total
 
where K = total number of treatment cycles received by the patient. 
x The actual dose intensity (mg/m2/week or mg/kg/week) is defined as the cumulative dose 
divided by the actual number of weeks on treatment: 
ent
on  treatm
  
  weeks
of
  
no.
  
Actual
Received
  
Dose
  
Actual
  
Total
 =
Intensity 
  
Dose
 
Actual
 
For each drug, the « actual dose intensity” will be calculated based on the overall actual number of 
weeks on treatment (or duration of dosing, in weeks, as defined above). Example: for a patient 
who received 12 cycles of aflibercept within 24 weeks, and 10 cycles of FOLFIRI, the actual dose 
intensity for 5-FU is calculated as: total dose of 5-FU received over 10 cycles, divided by 24 
(actual number of weeks on treatment). 
x Planned dose intensity (mg/m2/week or mg/kg/week): 
nt
on treatme
 
 weeks
of
 # 
Planned
 
Dose
  
Planned
  
Total
 =
Intensity 
  
Dose
 
Planned
 
The total planned dose will be calculated by the sum of the planned dose at each cycle: 
¦
 
K
1
k
[k]
 
Cycle
in 
 
Dose
 
Planned
 =
 
Dose
 
Planned
 
Total
 
where K = total number of treatment cycles received by the patient.  


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The number of weeks on study treatment can be defined as: 
Planned # of weeks on treatment = K*2 
x The relative dose intensity (in %)  is defined as the ratio of the actual dose intensity to the 
planned dose intensity: 
100
Intensity
  
Dose
  
Planned
Intensity
  
Dose
  
Actual
 =
Intensity 
  
Dose
 
Relative
u
. 
2.4.3.2 Study treatment dosing modifications 
Summary statistics will be provided for dose reduction, cycle delay and dose omission as defined 
below. A dose modification is defined as a dose reduction and/or a dose delay and/or a dose 
omission. For the first cycle, dose (at Day 1) different from the protocol dose will be considered 
as dose modified. 
x Dose reduction:  dose reduction will be derived using the definition provided in Table 2 to 
Table 4 compared to the previous dose.  For the second and subsequent cycles, a dose is 
deemed to have been reduced if the dose level a patient receives differs from the previous 
actual dose level The first cycle will not be counted for a reduction  
x Dose delays:  a cycle is deemed to have been delayed if start date of the current cycle (day 1 
cycle n) – start date of previous cycle (day 1 cycle n-1) >16 days (i.e. > 2 days compared to 
the theoretical length of a cycle) 
x Dose omission:  for each drug at a given cycle, if the drug is missing but the other drug(s) in 
the combination is/are not missing, then the missing drug is considered “omitted” for that 
cycle. After a dose omission, the treatment can re-start at a lower dose level than prior to dose 
omission. In this case, dose reduction will also be considered at the time the treatment restarts. 
If treatment is not restarted, it will be considered as premature treatment discontinuation, not 
dose omission. 
Dose information variables will be summarized descriptively (number, mean, SD, median, Q1:Q3, 
minimum, and maximum).  
The following summaries will be provided:  
x For each study drug (aflibercept, irinotecan and 5-FU), number of patients with at least 
one dose modification (dose reduction only, dose omission only, dose reduction followed 
by dose omission, dose omission followed by dose reduction, dose not given as per 
protocol at cycle 1 [only for aflibercept] and lower dose at cycle 1 [for irinotecan and 5-
FU])  
x number of patients with at least one cycle delayed (with delay classification in days: 
between 3 and 7 days, more than 7 days)  
x number of cycles of aflibercept and number of cycles of chemotherapy omitted  
x number of cycles of aflibercept and number of cycles of chemotherapy given at a reduced 
dose, by dose level, excluding dose omission  
  
 


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Table 2 – Aflibercept actual dose level definition 
Actual dose level 
(mg/kg) 
Actual dose administered 
(mg/kg) 
Upper dose 
5  d Dose 
4 
3  d Dose < 5 
2 
1  d Dose < 3 
Under dose 
0 < Dose < 1 
No dose  
administered 
0 
 
Table 3 – Irinotecan actual dose level definition 
Actual dose level 
(mg/m²)  
Actual dose administered 
(mg/m²) 
Upper dose 
195  d Dose 
180 
165  d Dose < 195 
150 
135  d Dose < 165 
120 
105  d Dose < 135 
Under dose 
0 < Dose < 105 
No dose  
administered 
0 
 
Table 4 – 5-FU actual dose level definition (bolus + infusional) 
Actual dose level 
(mg/m²)  
Actual dose administered 
(mg/m²) 
Upper dose 
3080  d Dose 
2800 
2520  d Dose < 3080 
2240 
1960  d Dose < 2520 
1680 
1400  d Dose < 1960 
Under dose 
0 < Dose < 1400 
No dose  
administered 
0 
Cases of overdoses: 
An overdose of study treatment is defined as: 
x FOLFIRI: dosing of 30% above the intended/planned dose of either irinotecan or 5-FU 
should be considered as an overdosage. 


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x Aflibercept: an aflibercept overdose is defined as 30% above the intended/planned dose. 
The circumstances (i.e., accidental or intentional) should be clearly specified in the verbatim and 
symptoms, if any, entered on separate AE forms. Based on investigator’s best clinical judgment, 
patients experiencing overdose should be monitored for the onset of known anti-VEGF toxicities 
(e.g. hypertension, proteinuria, etc.). 
A listing summarizing overdoses will be provided. 
2.4.3.3 Compliance  
Not applicable. 
2.4.4 Analyses of efficacy endpoints 
Not applicable. 
2.4.5 Analyses of safety data 
The summary of safety results will be presented overall. Summary of safety data will also be 
performed by cycle (where applicable) 
All safety analyses will be performed on the safety population as defined in Section 2.3.2, unless 
otherwise specified, using the following common rules: 
x 
Safety data in patients who do not belong to the safety population will be listed separately 
x 
 The baseline value is defined as the last available value before the first dose of treatment 
x 
Some summary tables of adverse events will be summarized overall but also by age, and 
prior bevacizumab status (yes or no). If not specified, the summary will be provided 
overall only. 
 
2.4.5.1 Analyses of adverse events 
The primary focus of adverse event reporting will be on treatment-emergent adverse events 
(TEAE). Pretreatment and posttreatment adverse events will be described separately.  
TEAEs will be summarized with respect to frequency, incidence, intensity/severity (as graded by 
the NCI CTCAE, version 4.03), relationship, and when appropriate, chronicity and cumulative 
nature. The following grades are defined: 1, 2, 3 and 4. 
Summaries will be provided for all grades combined, for grades (3, 4) combined and for grades (3, 4) 
separately, unless otherwise specified. The summary tables will provide the number (%) of patients 
with at least one adverse event. When specified, the number (%) of cycles will be also provided. 


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Laboratory results are reported as adverse events only if leading to permanent study treatment, 
discontinuation, to study treatment dose modification (cycle delay or dose reduction), and/or fulfill a 
seriousness criterion. 
If an adverse event date/time of onset (occurrence, worsening, or becoming serious) is incomplete, 
the adverse event will be considered, according a conservative principle, as treatment emergent 
unless there is definitive information to determine it is pretreatment or posttreatment.  Details on 
classification of adverse events with missing or partial onset dates are provided in Section 2.5.2. 
The following treatment-emergent adverse event summaries will be generated for the safety 
population. 
x 
Overview of treatment-emergent adverse events, summarizing number (%) of patients 
with any 
- 
Treatment-emergent adverse event 
- 
Treatment-emergent adverse possibly related  
- 
Grade 3-4 treatment-emergent adverse event (combined) 
- 
Grade 3-4 related  treatment-emergent adverse event 
- 
Serious treatment-emergent adverse event 
- 
Serious related treatment-emergent adverse event 
- 
Treatment-emergent adverse event leading to death 
- 
Treatment-emergent adverse event leading to permanent treatment discontinuation 
- 
Treatment-emergent adverse event leading to premature treatment discontinuation 
(either early discontinuation of FOLFIRI (last component of FOLFIRI) with 
aflibercept continued, or early discontinuation of aflibercept/with FOLFIRI continued) 
 
The same overview will be provided by patient/cycle (except fatal outcome and permanent and 
premature discontinuation). 
The following frequency distributions of adverse events (incidence tables) will be provided for the 
safety population and all grades, grades 3-4, grade 3 and grade 4. 
x 
All treatment-emergent adverse event by primary SOC, HLGT, HLT, PT and worst NCI 
grade, showing number (%) of patients with at least 1 treatment-emergent adverse event 
sorted by the SOC internationally agreed order.  The other levels (HLGT, HLT, PT) will 
be presented in alphabetical order. This sorting order will be applied to all other similar 
tables, unless otherwise specified. 
x 
All treatment-emergent adverse events by primary SOC and PT and worst NCI grade, 
showing the number (%) of patients with at least 1 treatment-emergent adverse event, 
sorted by the internationally agreed SOC order and by decreasing incidence of PTs within 
each SOC. This sorting order will be applied to all other similar tables, unless otherwise 
specified. 


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x 
All treatment-emergent adverse events by primary SOC and PT and worst NCI grade, 
showing the number (%) of patient-cycles with at least 1 treatment-emergent adverse 
event. 
x 
All treatment-emergent adverse events by primary SOC and PT, worst NCI grade and age, 
showing the number (%) of patients with at least 1 treatment-emergent adverse event. 
x 
All treatment-emergent adverse events by primary SOC and PT, worst NCI grade and 
prior bevacizumab, showing the number (%) of patients with at least 1 treatment-emergent 
adverse event. 
x 
All treatment-emergent adverse events possibly related to study treatment by primary SOC 
and PT and worst NCI grade, showing the number (%) of patients with at least 1 
treatment-emergent adverse event. 
Analysis of all treatment emergent serious adverse event(s) 
x 
All treatment-emergent serious adverse events by primary SOC, HLGT, HLT, and PT and 
worst NCI grade, showing the number (%) of patients with at least 1 serious treatment-
emergent adverse event. 
x 
All treatment-emergent serious adverse events by primary SOC and PT and worst NCI 
grade, showing the number (%) of patients with at least 1 treatment-emergent adverse 
event. 
x 
All treatment-emergent serious adverse events possibly related to study treatment, by 
primary SOC and PT and worst NCI grade, showing the number (%) of patients with at 
least 1 treatment-emergent serious adverse event.   
Analysis of all treatment emergent non serious adverse event(s) 
x 
All treatment-emergent non serious adverse events by primary SOC and PT and worst NCI 
grade, showing the number (%) of patients with at least 1 treatment-emergent adverse 
event with a % > 5 % 
Analysis of all treatment-emergent adverse event(s) leading to treatment discontinuation 
x 
All treatment-emergent adverse events leading to permanent treatment discontinuation, by 
primary SOC, HLGT, HLT, and PT and worst NCI grade, showing the number (%) of 
patients. 
x 
All treatment-emergent adverse events leading to permanent treatment discontinuation, by 
primary SOC and PT, by worst NCI grade 
x 
All treatment-emergent adverse events leading to premature treatment discontinuation, by 
primary SOC and PT, by worst NCI grade 
x 
All treatment-emergent adverse events leading to Aflibercept discontinuation (premature 
or permanent), by primary SOC and PT, by worst NCI grade 
x 
All treatment-emergent adverse events leading to premature discontinuation of Aflibercept 
, by primary SOC and PT, by worst NCI grade 


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x 
All treatment-emergent adverse events leading to FOLFIRI discontinuation (premature or 
permanent), by primary SOC and PT, by worst NCI grade. 
x 
All treatment-emergent adverse events leading to premature discontinuation of FOLFIRI , 
by primary SOC and PT, by worst NCI grade 
Analysis of all treatment-emergent adverse event(s) leading to dose modification  
x 
All treatment-emergent adverse events leading to dose modification (reduction and/or 
interruption and/or delay), by primary SOC and PT and worst NCI grade, showing the 
number (%) of patients, sorted by the sorting order defined above. 
x 
All treatment-emergent adverse events leading to dose reduction by primary SOC and PT 
and worst NCI grade, showing the number (%) of patients, sorted by the sorting order 
defined above. 
x 
All treatment-emergent adverse events leading to dose interruption by primary SOC and 
PT and worst NCI grade, showing the number (%) of patients, sorted by the sorting order 
defined above. 
x 
All treatment-emergent adverse events leading to dose delay by primary SOC and PT and 
worst NCI grade, showing the number (%) of patients, sorted by the sorting order defined 
above. 
Grouping of adverse events and/or laboratory abnormalities  
Grouping of adverse events and/or laboratory abnormalities based on MedDRA preferred terms 
and/or laboratory tests will be performed as clinically relevant. The grouping of adverse events 
terms will be done for at least the following items (all categories except renal events and 
proteinuria are fully defined from selected AE preferred terms):  
x 
Proteinuria (derived from AE form when PT is proteinuria or nephrotic syndrome and 
from selected preferred term, see 0, or derived from laboratory data, see section 2.4.5.3)  
x 
Renal failure events (based on the terms defined below):  
- Calculated creatinine clearance < 30 mL/mn (from laboratory data) , as reported by the 
investigator (in case of creatinine >ULN), calculated either by Cockroft –Gault, or 
MDRD 
- Grade 3 or 4 serum creatinine increase (from laboratory data)  
- Grade 3 or 4 renal failures adverse events (reported in the AE page, defined from 
selected preferred term, see 0).  
The following categories will be defined from the CRF AE page, and selected preferred terms (see 0 
for further information):  
x 
Cardiac dysfunction  
x 
Neutropenic complications  
x 
Arterial thromboembolic event  
x 
Venous thromboembolic event  


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x 
All thrombovascular events, i.e. arterial or venous thromboembolic events 
x 
Haemorrhage  
x 
Hypertension  
x 
Gastrointestinal perforation  
x 
Fistula from gastrointestinal origin  
x 
Fistula from other origin  
x 
Osteonecrosis  
x 
Compromised wound healing  
x 
Drug reaction among which Acute drug reaction will be identified 
x 
RPLS  
x 
Proteinuria 
x 
Renal events including Thrombotic microangiopathy (TMA), and Hemolytic and uremic 
syndrome (HUS)) 
x 
Diarrhea 
x 
Stomatitis and ulcerations 
x 
Parodontopathy 
The following summary tables will be provided for those pre-specified grouped term adverse 
events: 
x 
Treatment-emergent adverse events by grouped term, SOC and PT, and worst NCI grade, 
showing the number (%) of patients with at least 1 pre-specified adverse event, sorted by 
alphabetical order of grouped terms and by decreasing incidence of PTs within each 
grouped term. This sorting order will be applied to all other similar tables, unless 
otherwise specified. 
x 
Treatment-emergent adverse events by grouped term, SOC and PT, and worst NCI grade, 
showing the number (%) of patients/cycles with at least 1 adverse event. 
x 
Treatment-emergent adverse events by grouped term, SOC and PT, worst NCI grade, and 
class of age (<65, ≥65 years), showing the number (%) of patients with at least 1 adverse 
event. 
x 
Treatment-emergent adverse events by grouped term SOC and PT, worst NCI grade, and 
prior bevacizumab (Y/N), showing the number (%) of patients with at least 1 adverse 
event. 
 
For each of these grouped terms AEs, the following summaries will be provided:  
x 
Among patients with any of the above grouped term events, the number of patients with a 
first occurrence during treatment will be summarized with the cycle of first occurrence, the 
worst grade, cycle of occurrence of the worst grade and action taken regarding the study 
treatment. 


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Hypertension will be described overall and by subgroup: patients with HBP at baseline and patients 
without HBP at baseline. 
x 
For patients with prior HBP (i.e. registered in Medical History and based on grouped term), 
anti-hypertensive therapy will be presented as described in section 2.4.2 (see also Appendix 
G). During the treatment, number of patients with no change in blood pressure control or with 
a worsening HBP will be summarized, using the cycle of worsening, the worst grade and the 
cycle of the worst grade. Action taken regarding study treatment will also be summarized and 
corrective treatment associated will be described.  
x 
Among patients without prior HBP, the number of patients with a first occurrence during 
treatment will be summarized with the cycle of first occurrence, the worst grade, and cycle of 
occurrence of the worst grade. The action taken regarding study treatment will also be 
summarized and the corrective treatment associated will be described  
 
Arterial events will be described overall by age (≥65 vs <65), by prior arterial event at baseline (yes vs 
no) and by prior bevacizumab (yes vs no);  
 
Incidence of haemorrhage may be displayed among patients with thrombocytopenia (any grades)  
 
Thrombovascular events will be described overall and by subgroup:  
patients with thrombovascular event at baseline,  
patients without thrombovascular events at baseline and without anti-coagulant therapy as   
prophylaxis and  patients without thrombovascular event at baseline but receiving anti-coagulant 
therapy as prophylaxis. 
 
x 
For patients with new thrombovascular event and with thrombovascular event at baseline (i.e. 
registered in Medical History and based on grouped terms), concomitant anti-coagulant 
therapy will be presented by therapeutic class (vitamin K antagonist, heparins, …). Number 
of anti-coagulant treatments by patient will also be summarized. List of corresponding 
ATC codes is provided in Appendix F. 
x 
For patients with new thrombovascular event and without thrombovascular event at 
baseline  ), concomitant anti-coagulant therapy will be presented by therapeutic class (vitamin 
K antagonist, heparins, …). Number of anti-coagulant treatments by patient will also be 
summarized. List of corresponding ATC codes is provided in Appendix F. 
 
A listing of all adverse events from this list will be provided in Appendix of the CSR with verbatim, 
preferred term, start date, duration (in days), grade, cycle at onset, corrective therapy, relation with 
study treatment, action taken with study treatment, seriousness criteria and outcome. 
Analysis of pretreatment and post-treatment adverse events  
x 
Listing of all pretreatment adverse events 
x 
Listing of all pretreatment adverse events leading to study discontinuation  
x 
Listing of all post-treatment new related to treatment serious adverse events  
 


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Sorting within tables ensures the same presentation for the set of all adverse events within the 
observation period (pretreatment, treatment-emergent, and posttreatment).  For that purpose, the 
table of all treatment-emergent adverse events presented by SOC and PT sorted by the 
internationally agreed SOC order and decreasing frequency of PTs within SOCs will define the 
presentation order for all other tables unless otherwise specified.     
Pre and post-treatment AEs will be summarized in separate tables. Among patients with post-
treatment AEs, number of patients who received further anti-cancer therapy will be displayed (if 
started within the on-treatment period). 
An overview of pretreatment and/or post-treatment adverse events will be presented as a listing if 
only a few. 
2.4.5.2 Deaths 
The following summaries of deaths will be generated for the safety population:  
x 
Number (%) of patients who died during the on-treatment and post-treatment phase death  
and main cause for death (AE, disease progression, other reasons) 
x 
All TEAEs leading to death by primary SOC , HLGT, HLT, and PT showing number (%) 
of patients sorted by internationally agreed SOC order, with HLGT, HLT, and PT 
presented in alphabetical order within each SOC and in order of worst NCI grade 
x 
All TEAEs leading to death, by primary SOC and PT showing number (%) of patients 
sorted by internationally agreed SOC order, with PT presented in alphabetical order within 
each SOC and in order of worst NCI grade 
x 
Fatal AEs in the context of disease progression (deaths within 30 days with cause of death 
equal to disease progression) by primary SOC and PT, and by worst NCI grade, showing 
number (%) of patients sorted by internationally agreed SOC order, and with PT presented 
in alphabetical order within each SOC. 
x 
Fatal AEs in other context than disease progression (deaths within 30 days with cause of 
death different from disease progression, or death more than 30 days with cause of death 
equal to AE) by primary SOC and PT, and by worst NCI grade, showing number (%) of 
patients sorted by internationally agreed SOC order, and with PT presented in alphabetical 
order within each SOC. 
x 
Related AEs leading to death in other context than disease progression (deaths within 30 
days with cause of death different from disease progression, or death more than 30 days 
with cause of death equal to AE) by primary SOC and PT, and by worst NCI grade, 
showing number (%) of patients sorted by internationally agreed SOC order, and with PT 
presented in alphabetical order within each SOC.  
A summary of deaths for included but not treated patients will be also provided 
A listing of all deaths will be provided  
 


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2.4.5.3 Analyses of laboratory variables  
Hematological and clinical biochemistry toxicities will be assessed from laboratory test 
parameters.  Each test result will be graded by NCI common terminology criteria (version 4.03).   
For haematology and biochemistry, each assessment performed from the 2nd day of cycle N to the 1st 
day of cycle N+1 will be assigned to cycle N. The 1st day of any cycle will be the date of the 1st 
treatment infusion (aflibercept, irinotecan or 5FU) for this cycle, whichever is first.  
Parameters measured on the day of the first infusion (cycle 1, day 1) will be considered as baseline 
measurements. On-treatment period will start at first infusion + 1 day for all laboratory parameters.  
For the last cycle, any assessment performed from the 2nd day of the cycle and within 30 days from 
the last infusion of the cycle, whichever the last, will be assigned to this last cycle. 
For a given parameter, a patient (respectively, a cycle) will be considered as evaluable if at least one 
measure of this parameter is available on-treatment. 
The frequency tables of each laboratory parameter by worst NCI grade during the treatment 
period based on the number of patients will be provided. The summary tables will present the 
frequency of patients with any grade (All grades) of abnormal laboratory tests and with Grade 3 
and grade  4 pooled and separately abnormal laboratory tests. 
For the non-NCI gradable parameter (chloride, urea, total protein, BUN. LDH), frequency of 
patients outside normal ranges during the treatment period will be provided. 
INR will be summarized by the upper value by patient using frequencies by class: <1.5, 1.5 ≤ and 
< 3, 3 ≤and < 5, ≥5. 
Creatinine clearance will be summarized by the lowest value recorded by patient and by patient-
cycles, using summary statistics. Frequencies by class ((≥ 80 mL/mn , ≥ 60 mL/mn and <80 
mL/mn, ≥ 30 mL/mn and < 60 mL/mn, < 30 mL/mn) will also be provided. 
For proteinuria, the grade will be derived based on the following table: 
Table 5 – Derivation of Proteinuria grade 
 
Grade 
Spot urine protein 
(mg/dL) 
24-hour proteinuria 
(g/24h) 
Dipstick result 
Grade 1 
30-100 
<1.0  
1+ 
Grade 2 
>100-300 
1.0-3.4  
2+  3+ 
Grade 3 
>300 
>=3.5 
NA 
Grade 4 
                                                                           NA as per CTC v 4.0.3                               - 
 
 
 
 


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A frequency table (n and %) of proteinuria by worst grade, assessed either by spot sample 
(dipstick/urine protein) or 24h urine collection, during the treatment period based on number of 
evaluable patients and number of evaluable cycles will be provided. In case both spot urine sample 
and 24h urine collection are available, only worst grade will be kept, whichever type of measurement 
A frequency table of hematuria (positive dipstick for RBC: +; ++ or +++) will be presented. 
The time (weeks) to onset of grade ≥2 proteinuria will be calculated as well as the duration of this 
event from the grade ≥2 occurrence to recovery to a grade <2. In addition, the occurrence of grade 
≥2 proteinuria concomitant or not to hematuria (positive dipstick for RBC  or reported in AE page) 
will be summarized. 
The urine protein-to-creatinine ratio (UPCR) will be derived based on protein and creatinine 
values assessed on morning spot urinalysis. UPCR will be described according to the following 
classes: [0-1], ]1-2], ]2-3], >3. Time to UPCR>1 and duration of UPCR >1 will be summarized. In 
addition, the occurrence of UPCR >1 concomitant or not to hematuria (positive dipstick for RBC or 
reported in AE page) will be summarized. 
The occurrence of grade ≥2 proteinuria concomitant or not to hematuria (positive dipstick for RBC or 
reported in AE page) and concomitant or not to HBP (from AE page, i.e. new hypertension or 
worsening hypertension, as previously defined in section 2.4.5.1) will be summarized. Concomitance 
of events will be defined as follows:  
x 
if proteinuria was diagnosed from 24h or spot urine sample or dipstick and hematuria from 
dipstick, events will be considered as concomitant if diagnosed on the same day ± 3 days.  
x 
if proteinuria was diagnosed from 24h or spot urine sample  or dipstick and hematuria was 
reported in AE page, events will be considered as concomitant if proteinuria was diagnosed in 
the interval [hematuria start date; hematuria stop date] ± 3 days.  
x 
proteinuria will be considered as concomitant with hypertension if grade≥3 proteinuria was 
diagnosed (from spot urine sample or from 24h urine sample ) at the same cycle as cycle of 
first occurrence of grade 3 hypertension.  
The occurrence of UPCR >1 concomitant or not to hematuria will be summarized. Concomitance will 
be defined applying the same rule as defined above.  
A listing will be provided for all patients with concomitant proteinuria and hematuria, the listing 
should include thrombotic microangiopathy/HUS if present (at any time). 
2.4.5.4 Analyses of vital sign variables 
For vital signs, each assessment performed from the 2nd day of cycle N to the 1st day of cycle 
N+1 will be assigned to cycle N. Parameters measured during baseline visit or on the day of the 
first infusion (Cycle 1, Day 1) will be considered as baseline measurements. On-treatment period 
will start at first infusion + 1 day for all parameters.  
For the last cycle, any assessment performed from the 2nd day of the cycle and within 30 days 
from the last infusion of the cycle, whichever the last, will be assigned to this last cycle.  


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For a given parameter, a patient (respectively a cycle) will be considered as evaluable if at least 
one measure of this parameter is available on-treatment.  
The summary statistics (including number, mean, median, Q1, Q3, standard deviation, minimum 
and maximum) of all vital signs variables (and changes from baseline) will be calculated for each 
visit or study assessment (baseline, on-treatment within 30 days of last treatment intake).   
 
 
x For Blood pressure (SBP, DBP), the summary statistics will be provided for measurements 
and change-from-baseline at each cycle. The BPs are also summarized based on the 
number of patients with at least one potentially clinically significant abnormality criteria 
(PCSA) occurring during the on treatment period according to baseline status. The PCSA 
criteria are provided in Appendix A. 
x For ECOG performance status, a shift table will be provided for the last and worst 
evaluations respectively relative to baseline. 
2.4.5.5 Analyses of electrocardiogram variables 
Not applicable.  
2.4.5.6 Analyses of other safety endpoints 
Not applicable. 
2.4.6 Analyses of pharmacokinetic and pharmacodynamic variables 
Not applicable.  
2.4.7 Analyses of quality of life/health economics variables 
The analysis of HRQL will be performed in patients of the HQRL analysis populations. For a 
given questionnaire, a patient will be considered as evaluable if at least one baseline and one post-
baseline assessment of this questionnaire is available. The scoring algorithms of the 
questionnaires are presented in Appendix H and Appendix I. 
The HQRL populations will be divided in subgroups according to the reason of treatment 
discontinuation (Disease progression vs. Adverse Events or Other). For the interim analyses, a 
third subgroup will consist of patients still on-treatment. If there are not enough patients (at least 
20 per subgroup), patients who discontinued for other reasons than disease progression, will be 
pooled with on-treatment patients. 
The compliance profile over time will be summarized (number and percentage of forms received 
versus expected, and number and percentage of forms evaluable versus expected). 
 
x EQ-5DTM questionnaire  


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Single index utility score and VAS will be described at baseline and at cycle 3, cycle 5, 
cycle 7… and within 30 days of last treatment using descriptive statistics (n, mean, 
standard deviation, median, minimum and maximum), by subgroup and overall. Changes 
of health-related quality of life (single index utility score and VAS) from baseline to other 
cycles will be summarized using standard descriptive statistics. Change from baseline will 
also be presented by subgroup and overall.  
EQ-5D questionnaires will be also described using a frequency table for each of the 5 dimensions. 
Shift tables between baseline and other cycles will be provided overall for each of the 5 
dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression). Change 
from Baseline in the EQ-5D scores to each of the cycle will also be summarised by overall and 
each of the 5 dimensions. 
Mean and SD values of single index utility score will be computed for each of the 
following status: Stable disease on treatment, Discontinued Stable disease, Progressive 
disease. 
- Value for Stable disease on treatment will be computed using treatment-period 
assessments, starting from baseline to last cycle. Since there are several measures per 
patient, the mean will be estimated using the mean of patients means. 
- Value for Discontinued Stable disease will be computed using the QoL within 30 days of 
last treatment for those patients discontinuing not due to disease progression 
- Value for Progressive disease will be computed using the QoL within 30 days of last 
treatment for those patients discontinuing due to disease progression 
 
x EORTC QLQ-C30 questionnaire 
A descriptive summary by assessment and change from baseline to each assessment for the 
Global health status (scoring of items 29 & 30), the five functional scales (Physical, Role, 
Emotional, Cognitive and Social), the three symptom scales (Fatigue, Nausea/vomiting 
and Pain) and the other single items will be described, by subgroup and overall. 
The percentage of patients  with ‘Symptom evolution from baseline’  in term of 
deterioration , (i.e. for GHS and functioning scale a change from baseline equal or smaller 
than minus 10 and for symptoms scales a change from baseline equal or greater than 10) 
and improvement (i.e. for GHS and functioning scale a change from baseline equal or 
greater than 10 and for symptoms scales a change from baseline equal or smaller than 
minus 10) for each assessment will be also presented by subgroups and overall. 
 
 
x EORTC QLQ-CR29 questionnaire (specific colorectal module - optional) 
A descriptive summary by assessment and change from baseline to each assessment for the 
four scales (body image, anxiety, weight, sexual interest) and the other single items will be 
described, by subgroup and overall. 
The percentage of patients  with ‘Symptom evolution from baseline’  in term of 
deterioration , (i.e. for functioning scale a change from baseline equal or smaller than 


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minus 10 and for symptoms scales a change from baseline equal or greater than 10) and 
improvement (i.e. for functioning scale a change from baseline equal or greater than 10 
and for symptoms scales a change from baseline equal or smaller than minus 10)  will be 
also presented by subgroups and overall. 
2.4.8 Further therapy after discontinuation of study treatment administration during the 
study 
A summary table will be provided for further anti-cancer therapies and further radiotherapy. The 
number of patients, the drugs received (chemotherapies and/or biologicals) and the time from last 
treatment received to first therapy start (in weeks) will be summarized. 
 
 


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2.5 
DATA HANDLING CONVENTIONS 
Some general rules of data handling conventions are listed below  
2.5.1 General conventions 
In general, the baseline value of an analysis variable is defined as the last observation before the first 
dose of the treatment. 
 
2.5.2 Missing data 
 
For categorical variables, patients with missing data are not included in calculations of 
percentages unless otherwise specified.  When relevant, the number of patients with missing data 
is presented. 
In general, no imputation is planned for missing data. The following approaches are default methods 
for missing data handling. Some exploratory analyses can be planned with different strategies for 
treating missing outcomes.  
Categorical data at baseline will be summarized using counts (n) and percentages (%). The number of 
patients with missing data may be mentioned, but will not be included in the denominator for the 
calculation of percentages unless otherwise specified.  
Continuous data: The analyses and summaries for variables with continuous scales will be based on 
observed data only. However, the number of patients with missing observations will be provided.  
 
Handling of missing data for adverse events 
AE: missing data will not be imputed. When any information (start date of AE, first study 
treatment administration date, cycle 1 date) is missing, the TEAE will be determined by the 
following conservative principle: an AE will be considered a TEAE if it cannot be confirmed that 
the event is not a TEAE due to missing data.  
To extend the adverse events to the cycles, for incomplete AE end date (day missing), the last day 
of the month will be imputed, as it is the worst case. 
Handling of missing assessment of relationship of adverse events to study treatment 
If the assessment of the relationship to study treatment is missing, then the relationship to study 
treatment has to be assumed and the adverse event considered as such in the frequency tables of 
possibly related adverse events, but no imputation should be done at the data level. 


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Handling of missing grades of adverse events 
If the grade is missing for 1 of the treatment-emergent occurrences of an adverse event, the 
maximal severity on the remaining occurrences will be considered.  If the severity is missing for 
all the occurrences, a “missing” category will be added in the summary table. 
 
For determination of concomitance of hematuria (reported as AE) with proteinuria or with UPCR, no 
imputation will be performed in case of incomplete date of AE. Events will be considered concomitant 
if they occurred in the same cycle.  
 
Handling of partial date of histological diagnosis 
Partial date of diagnosis of mCRC will be imputed to calculate the time from initial histological 
diagnosis till study entry. 
 If the month is present the 15 of the month will be used (day is not collected). 
 If year is present and month is missing then the 1st July will be used. 
No replacement will be done in listings 
Handling of medication missing/partial dates 
No imputation of medication start/end dates will be performed. If a medication date is missing or 
partially missing, so it can not be determined whether it was taken prior or concomitantly, it will 
be considered as a prior and concomitant medication.  
Incomplete date of first further therapy: if the day of first further therapy date is missing, the date will 
be imputed to the first day of the month or the day after last study treatment administration, whichever 
comes last. 
Handling of missing data in HQRL questionnaires 
EQ-5D 
There will be no imputation of missing data. If one of the five answers of the Quality of life 
questionnaire is missing, the single index score will not be calculated. 
EORTC QLQ-C30 and CR29 
Missing values for the subscales of the EORTC QLQ-C30 and the QLQ-CR29 will be calculated 
according to the EORTC Scoring Manual [1, 2]. Scales will utilize all completed items to derive 
the score of each scale. For a multi-item subscale, if at least 50% of the constituent items have 
been completed, the subscale will be calculated using all the items that have been completed (see 
example in Appendix I). However, if less than 50% of the constituent items have been answered, 
then the scale score will be considered missing. Using this scoring algorithm, none of the single-
item subscales will be computed and hence missing values will remain missing. 
In addition to the above, in the event that there are entirely missing assessments (i.e., the measure 
was not completed at a specific time point), no imputation will occur. 




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2.5.6 Statistical technical issues 
Not applicable 


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3 
INTERIM ANALYSES 
Two interim analyses during the course of the study were planned in the initial SAP, in order to 
obtain preliminary results on baseline characteristics, HRQL and safety data. 
 The amended #2 SAP takes into account the two first 
additional interim analyses, and this current amended #3 SAP takes into account this last 
additional interim analyses. 
3.1 
FIRST INTERIM ANALYSIS 
An interim analysis was performed in January 2013, this interim analysis concerned patients in 
both programs AFLIB_C_06097 and
. 
For interim analyses, safety population was defined as the patients who have signed the informed 
consent form, who received at least part of one dose of study treatment (either aflibercept or 
FOLFIRI), and who completed cycle 1. Data analyzed correspond to data obtained at Baseline and 
on-treatment and all adverse events declared from baseline to 30 days after last cycle. For patients 
withdrawn, all declared adverse events were taken into account. 
For patients still on treatment, emergence period for the AE was defined as the period from the 
first study treatment intake to the end of last cycle completed before the cutoff date. 
Laboratory data were not presented in this interim analysis. 
For quality of life, only patient with one baseline and one post baseline assessment were taken 
into account. 
The statistical report contained the following tables: 
- Demographic data :15.1.1-1, 15.1.1-2, 15.1.1-3 (subpopulation of patients who ended treatment), 
15.1.1-3b, 15.1.2-1 (safety population and HQRL EQ-5D population) , 15.1.2-2 (safety population 
and HQRL EQ-5D population), 15.1.2-3, 15.1.2-4, 15.1.2-5 (safety population and HQRL EQ-5D 
population),
- Adverse events and deaths:15.3.1-1, 15.3.1-2, 15.3.1-4, 15.3.1-5, 15.3.1-6, 15.3.1-7, 15.3.1-8, 
15.3.1-10, 15.3.1-11, 15.3.1-13 (subpopulation of patients who ended treatment), 15.3.1-16, 
15.3.1-20, 15.3.1-21, 15.3.1-22, 15.3.1-23, 15.3.2-1, 15.3.2-3, 15.3.2-4, 15.3.2-5, 15.3.2-6, 15.3.2-
7, 15.3.2-8
- QoL data:15.5.1-1, 15.5.2-1, 15.5.2-2, 15.5.2-3, 15.5.2-4, 15.5.3-1, 15.5.3-2, 15.5.3-3, 15.5.3-4, 
15.5.4-1, 15.5.4-2, 15.5.4-3.
- Listings 15.3.1-2 and 15.3.2-1 will also be presented. 
Subpopulation of patients who ended treatment stands for patients who ended both Aflibercept 
and FOLFIRI and with last cycle completed; patients still taking one product or patients with last 
cycle ongoing on cutoff date will not be part of this subgroup. Tables will be adapted to the visits 
selected for this interim analysis. Separate analyses with local patients only were also performed 


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with patients from UK. 
3.2 
SECOND INTERIM ANALYSIS 
A second interim analysis was performed during 2nd semester 2013. This interim analysis 
concerned patients in both programs AFLIB_C_06097 and 
For interim analyses, safety population wasdefined as the patients who have signed the informed 
consent form, who received at least part of one dose of study treatment (either aflibercept or 
FOLFIRI), and who completed cycle 1. Data analyzed wascorresponded to all data obtained from 
baseline up to the minimum between 30 days after the last cycle before the cutoff date and the day 
before the subsequent cycle (the number of cycles can vary from one patient to another). For 
patients still on treatment, emergence period for the AE was defined as the period from the first 
study treatment intake to the end of last cycle completed before the cutoff date. 
Laboratory data was not presented in this interim analysis. 
For quality of life, only patient with one baseline and one post baseline assessment was taken into 
account. 
The statistical report contained the following tables: 
- Demographic data :15.1.1-1, 15.1.1-2, 15.1.1-3 (subpopulation of patients who ended treatment), 
15.1.1-3b, 15.1.2-1 (safety population and HQRL EQ-5D population) , 15.1.2-2 (safety population 
and HQRL EQ-5D population), 15.1.2-3, 15.1.2-4, 15.1.2-5 (safety population and HQRL EQ-5D 
population), 15.1.2-6, 15.1.2-7
- Exposure: 15.1.4-1(subpopulation of patients who ended treatment), 15.1.4-2 (subpopulation of 
patients who ended treatment), 15.1.4-3 (subpopulation of patients who ended treatment), 15.1.4-4 
(subpopulation of patients who ended treatment), 15.1.4-5 (subpopulation of patients who ended 
treatment), 
- Adverse events and deaths:15.3.1-1, 15.3.1-2, 15.3.1-4, 15.3.1-5, 15.3.1-6, 15.3.1-7, 15.3.1-8, 
15.3.1-10, 15.3.1-11, 15.3.1-13 (subpopulation of patients who ended treatment), 15.3.1-16, 
15.3.1-20, 15.3.1-21, 15.3.1-22, 15.3.1-23, 15.3.2-1, 15.3.2-3, 15.3.2-4, 15.3.2-5, 15.3.2-6, 15.3.2-
7, 15.3.2-8
- QoL data:15.5.1-1, 15.5.2-1, 15.5.2-2, 15.5.2-3, 15.5.2-4, 15.5.3-1, 15.5.3-2, 15.5.3-3, 15.5.3-4, 
15.5.4-1, 15.5.4-2, 15.5.4-3.
- Listings 15.3.1-2 and 15.3.2-1 was also presented. 
This analysis was also performed by country (only for a selection of countries). 
3.3 
THIRD INTERIM ANALYSIS 
A third interim analysis was performed during last quarter 2013. This interim analysis was 
concerned patients in both programs AFLIB_C_06097 and 


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The statistical report contained the following tables: 
 
15.1 DEMOGRAPHIC DATA 
 
15.1.1 DISPOSITION OF PATIENTS 
 
Table 15.1.1 - 1 Summary of patients included in the study – All patients  
Table 15.1.1 - 2 Number of patients by country, site and treatment received – All patients  
Table 15.1.1 - 3 End of treatment – Patients who ended treatment [a] 
 
Listing 15.1.1 -3: Listing of patients who ended treatment [a] for ‘other reason’ 
Table 15.1.1 – 3 b Number of treated patients by cycle number – Safety Population (interim 
analyses only)  
Table 15.1.1 - 4 Important protocol deviations – Safety Population  
 
15.1.2 DEMOGRAPHIC, BASELINE DATA AND MEDICATIONS 
 
Table 15.1.2 - 1a Demographic and baseline characteristics– Safety Population 
 
Table 15.1.2 - 1b Demographic and baseline characteristics– QOL EQ-5D Population 
 
Table 15.1.2 - 2a Disease characteristics– Safety Population 
 
Table 15.1.2 - 2b Disease characteristics– QOL EQ-5D Population  
Table 15.1.2 - 3 Prior Surgeries – Safety Population  
Table 15.1.2 - 4 Prior Radiation – Safety Population  
Table 15.1.2 – 5 Prior Anti-Cancer Therapies – Safety Population  
Table 15.1.2 - 5b Prior Anti-Cancer Therapies – QOL EQ-5D Population  
Table 15.1.2 - 7  Summary of hematological parameters at baseline by NCI grade – Safety 
Population 
Table 15.1.2 - 8  Summary of INR at baseline by ranges – Safety Population 
Table 15.1.2 - 9 Summary of electrolytes at baseline by NCI grade – Safety Population 
Table 15.1.2 - 10 Summary of renal and liver function parameters at baseline by NCI grade – 
Safety Population 
Table 15.1.2 - 11 Summary of creatinine clearance at baseline – Safety Population 
Table 15.1.2 - 12 Summary of other biochemistry parameters at baseline by NCI grade – Safety 
Population 
Table 15.1.2 - 13 Summary of non gradable biochemistry parameters at baseline – Safety 
Population 
Table 15.1.2 - 14 Summary of urinary analyses at baseline –Safety Population  
 
15.1.4 STUDY EXPOSURE 
Table 15.1.4 - 1  Number of patients by cycle and Overall treatment exposure – Safety Population 
Only for Patients who ended treatmet (For Interim Analysis) 
Table 15.1.4 -1bNumber of patients by cycle and Overall treatment exposure- Safety Population 
Table 15.1.4 - 2  Aflibercept treatment exposure, cumulative dose and dose intensity – Safety 
Population Only for Patients who ended treatment (For Interim Analysis) 
Table 15.1.4 - 3  5-FU treatment exposure, cumulative dose and dose intensity – Safety 
Population Only for Patients who ended treatment (For Interim Analysis) 
Table 15.1.4 - 4  Irinotecan treatment exposure, cumulative dose and dose intensity – Safety 
Population Only for Patients who ended treatment (For Interim Analysis) 
Table 15.1.4 - 5  Summary of patients with cycle delay and/or dose modification (by study drug) – 


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Safety Population Only for Patients who ended treatment (For Interim Analysis) 
15.3 SAFETY DATA 
15.3.1 DISPLAY OF ADVERSE EVENTS 
Table 15.3.1 - 1 Overview of adverse events: Number (%) of patients – Safety Population 
Table 15.3.1 - 2 Overview of adverse events: Number (%) of patient-cycles – Safety Population  
Table 15.3.1 - 4 Summary of TEAEs by system organ class and preferred term and worst NCI 
grade – Number (%) of patients – Safety Population 
Table 15.3.1 - 5 Summary of TEAEs by system organ class and preferred term and worst NCI 
grade – Number (%) of patient-cycles – Safety Population 
Table 15.3.1 - 6 Summary of TEAEs by primary system organ class and preferred term, worst 
NCI grade and age – Number (%) of patient – Safety Population 
Table 15.3.1 - 7 Summary of TEAEs by primary system organ class and preferred term, worst 
NCI grade and prior bevacizumab – Number (%) of patient – Safety Population 
Table 15.3.1 - 8 All treatment-emergent adverse events possibly related to study treatment by 
primary SOC and PT and worst NCI grade.-Safety Population 
Table 15.3.1 - 10 All treatment-emergent serious adverse events by primary SOC and PT and 
worst NCI grade.-Safety Population  
Table 15.3.1 - 11 All treatment-emergent serious adverse events possibly related to study 
treatment, by primary SOC and PT and worst NCI grade. –Safety Population  
Table 15.3.1 - 14 All treatment-emergent adverse events leading to permanent treatment 
discontinuation, by primary SOC, PT and worst NCI grade. .- Patients Who Ended Treatment 
Table 15.3.1 - 15 All treatment-emergent adverse events leading to premature treatment 
discontinuation, by primary SOC, PT and worst NCI grade-Safety Population  
Table 15.3.1 - 16 All treatment-emergent adverse events leading to Aflibercept discontinuation 
(premature or permanent), by primary SOC and PT and worst NCI grade.-Safety Population 
Table 15.3.1 - 17 All treatment-emergent adverse events leading to premature discontinuation of 
Aflibercept, by primary SOC and PT and worst NCI grade.-Safety Population 
Table 15.3.1 - 18 All treatment-emergent adverse events leading to FOLFIRI discontinuation 
(premature or permanent), by primary SOC and PT and worst NCI grade.-Safety Population 
Table 15.3.1 - 19 All treatment-emergent adverse events leading to premature discontinuation of 
FOLFIRI, by primary SOC and PT and worst NCI grade.-Safety Population 
Table 15.3.1 - 20 All treatment-emergent adverse events leading to dose modification, by primary 
SOC and PT and worst NCI grade.-Safety Population 
Table 15.3.1 - 24 Summary of TEAEs of specific interest by grouped terms, primary system organ 
class and preferred term, and worst NCI grade – Number (%) of patient – Safety Population 
Table 15.3.1 - 25 Summary of TEAEs of specific interest by grouped terms, primary system organ 
class and preferred term, and worst NCI grade – Number (%) of patient-cycles – Safety 
Population 
Table 15.3.1 - 26 Summary of TEAEs of specific interest by grouped terms, primary system organ 
class and preferred term, worst NCI grade and age – Number (%) of patient – Safety Population 
Table 15.3.1 - 27 Summary of TEAEs of specific interest by grouped terms, primary system organ 
class and preferred term, worst NCI grade and prior bevacizumab – Number (%) of patient – 
Safety Population 
Table 15.3.1 -56 Summary of Pre-Treatment AEs by System Organ Class and Preferred Term and 
Worst NCI Grade- Number of patients – Safety Population 
  


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15.3.2 ANALYSIS OF DEATHS 
Table 15.3.2 - 1 Summary of deaths and cause of deaths – All Included patients 
Table 15.3.1- 1a Summary of deaths and cause of deaths – Safety Population 
Table 15.3.2 - 3 All fatal adverse events by primary SOC and PT and worst NCI grade– All 
included patients. 
Table 15.3.2 - 4 Treatment emergent adverse events leading to death by primary SOC and PT and 
worst NCI grade– Safety population. 
Table 15.3.2 - 5 Treatment emergent adverse events leading to death during the on treatment 
period in the context of disease progression by primary SOC and PT and worst NCI grade– Safety 
population. 
Table 15.3.2 - 6 Treatment emergent adverse events leading to death in other context than disease 
progression by primary SOC and PT and worst NCI grade– Safety population. 
Table 15.3.2 - 7 Treatment emergent adverse events possibly related to study treatment leading to 
death in other context than disease progression by primary SOC and PT and worst NCI grade– 
Safety population. 
15.3.3 ANALYSIS OF LABORATORY VARIABLES 
Table 15.3.3 - 1 Summary of abnormal hematological parameters during treatment (worst grade 
per patient) – Safety Population 
Table 15.3.3 - 2  Summary of INR during treatment (worst value per patient) – Safety Population 
Table 15.3.3 - 3 Summary of abnormal electrolytes during treatment (worst grade per patient)– 
Safety Population  
Table 15.3.3 - 4  Summary of renal and liver function parameters during treatment (worst grade 
per patient)– Safety Population 
Table 15.3.3 - 5  Summary of creatinine clearance during treatment (worst value per patient) – 
Safety Population 
Table 15.3.3 – 6 Summary of other biochemistry parameters during treatment (worst grade per 
patient)- Safety Population 
Table 15.3.3 - 7 Summary of non gradable biochemistry parameters during treatment (worst value 
per patient)– Safety Population 
Table 15.3.3 - 8 Summary of patients with proteinuria events – Safety Population 
Table 15.3.3 - 9  Summary of of proteinuria and UPCR during treatment - Number (%) of 
patients– Safety Population 
Table 15.3.3 - 14 Summary of patients with renal failure events – Safety Population  
15.5 QUALITY OF LIFE 
15.5.1 ENROLLMENT 
Table 15.5.1 - 1 Enrollement summary – All patients 
15.5.2 EQ-5D QUESTIONNAIRE 
 
Table 15.5.2 - 1 QOL EQ-5D Completion Rates by Cycle – Safety Population 
Table 15.5.2 - 2 Quality of life: Single index utility score – QOL EQ-5D population 
Table 15.5.2 - 3 Single index utility score by assessment status - QOL EQ-5D population  
Table 15.5.2 - 4 Quality of life: Visual Analogue Scale - QOL EQ-5D population 
Table 15.5.2 - 5 Quality of life: Description of the EQ-5D questionnaire - QOL EQ-5D population 
Table 15.5.2- 6a Quality of life: Description of the EQ-5D questionnaire- Mobility- Shift table 
between baseline and each cycle –QOL-EQ-5D population 
Table 15.5.2- 6b Quality of life: Description of the EQ-5D questionnaire- Self-care- Shift table 


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between baseline and each cycle –QOL-EQ-5D population 
Table 15.5.2- 6c Quality of life: Description of the EQ-5D questionnaire- Usual activities- Shift 
table between baseline and each cycle –QOL-EQ-5D population 
Table 15.5.2- 6d Quality of life: Description of the EQ-5D questionnaire- Pain/discomfort- Shift 
table between baseline and each cycle –QOL-EQ-5D population 
Table 15.5.2- 6e Quality of life: Description of the EQ-5D questionnaire- Anxiety/Depression- 
Shift table between baseline and each cycle –QOL-EQ-5D population 
Table 15.5.2- 7a Quality of life: Description of the EQ-5D questionnaire- Evolution of Mobility- 
at each cycle  –QOL-EQ-5D population 
Table 15.5.2- 7b Quality of life: Description of the EQ-5D questionnaire- Evolution of Self-care- 
at each cycle  –QOL-EQ-5D population 
Table 15.5.2- 7c Quality of life: Description of the EQ-5D questionnaire- Evolution of Usual 
activities- at each cycle  –QOL-EQ-5D population 
Table 15.5.2- 7d Quality of life: Description of the EQ-5D questionnaire- Evolution of 
Pain/discomfort- at each cycle  –QOL-EQ-5D population 
Table 15.5.2- 7e Quality of life: Description of the EQ-5D questionnaire- Evolution of 
Anxiety/Depression- at each cycle  –QOL-EQ-5D population 
 
 
15.5.3 EORTC-QLQ C30 QUESTIONNAIRE 
Table 15.5.3 - 1 EORTC-QLQ C30 Completion Rates by Cycle –Safety Population 
Table 15.5.3 - 2 EORTC-QLQ C30 : Global health status - QOL EORTC30 population 
Table 15.5.3 - 3 EORTC-QLQ C30 : Functional scales - QOL EORTC30 population 
Table 15.5.3 - 4 EORTC-QLQ C30 : Symptoms scales / items - QOL EORTC30 population 
15.5.4 EORTC-QLQ CR29 QUESTIONNAIRE 
Table 15.5.4 - 1 EORTC-QLQ CR29 Completion Rates by Cycle- Safety Population 
 
Table 15.5.4 - 2 EORTC-QLQ CR29 : Functional scales - QOL EORTC CR29 population 
Table 15.5.4 - 3 EORTC-QLQ CR29 : Symptoms scales / items - QOL EORTC30 population 
Listing 15.3.2 - 1 All adverse events leading to death. 
3.4 
FOURTH INTERIM ANALYSIS 
A fourth interim analysis was performed during the first quarter 2014. This interim analysis was 
concerned patients in both programs AFLIB_C_06097 and 
.
The statistical report contained the following tables: 
15.1 DEMOGRAPHIC DATA 
 
15.1.1 DISPOSITION OF PATIENTS 
 
Table 15.1.1 - 1 Summary of patients included in the study - All patients  
Table 15.1.1 - 2 Number of patients by country, site and treatment received - All patients  
Table 15.1.1 - 3 Summary of reason for permanent treatment discontinuation - Patients who ended 
treatment[a] 
 


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Table 15.1.1 - 3a Reason for premature discontinuation of one component of the treatment - 
Patients who ended treatment [a] 
 
Listing 15.1.1 - 3: Listing of reasons of treatment discontinuation for patients who ended 
treatment [a]  
Table 15.1.1 - 3b Number of patients with complete cycle - Safety population 
 
Table 15.1.1 - 4 Important protocol deviations - Safety Population  
 
15.1.2 DEMOGRAPHIC, BASELINE DATA 
 
Table 15.1.2 - 1a Demographic and baseline characteristics - Safety Population 
 
Table 15.1.2 - 1b Demographic and baseline characteristics - QOL EQ-5D Population 
 
Table 15.1.2 - 2a Disease Characteristics - Safety Population 
 
Table 15.1.2 - 2b Disease Characteristics - QOL EQ-5D Population 
 
Table 15.1.2 - 3 Prior Surgeries - Safety Population  
Table 15.1.2 - 4 Prior Radiation - Safety Population  
Table 15.1.2 - 5 Prior Anti-Cancer Therapies - Safety Population  
Table 15.1.2 - 5b Prior Anti-Cancer Therapies - QOL EQ-5D Population  
Table 15.1.2 - 6a Relevant medical/surgical history reported by Primary Soc and HLT- Safety 
Population 
 
Table 15.1.2 - 6b Summary of patients with history of thrombovascular event and/or presence of 
cardiovascular risk factors (grouped term) – Safety Population 
 
Table 15.1.2 - 7 Summary of hematological parameters at baseline by NCI grade- Safety 
Population 
 
Table 15.1.2 - 8 Summary of INR at baseline by ranges- Safety Population  
Table 15.1.2 - 9 Summary of electrolytes at baseline by NCI grade- Safety Population 
 
Table 15.1.2 - 10 Summary of renal and liver function parameters at baseline by NCI grade- 
Safety Population 
 
Table 15.1.2 - 11 Summary of creatinine clearance at baseline- Safety Population  
Table 15.1.2 - 12 Summary of other biochemistry parameters at baseline by NCI grade- Safety 
Population 
 
Table 15.1.2 - 13 Summary of non gradable biochemistry parameters at baseline- Safety 
Population 
 
Table 15.1.2 - 14 Summary of urinary analysis at baseline- Safety Population 
 
15.1.4 STUDY EXPOSURE  
Table 15.1.4 - 1 Number of patients by cycle and Overall treatment exposure - Patients who ended 
treatment 
 
Table 15.1.4 - 1b Number of patients by cycle and Overall treatment exposure - Safety population
 
 
Table 15.1.4 - 2 Aflibercept treatment exposure, cumulative dose and dose intensity - Patients 
who ended treatment  
Table 15.1.4 - 3 5-FU treatment exposure, cumulative dose and dose intensity - Patients who 
ended treatment 
 
Table 15.1.4 - 4 Irinotecan treatment exposure, cumulative dose and dose intensity - Patients who 
ended treatment 
 
Table 15.1.4 - 5 Summary of patients with cycle delay and/or dose modification (by study drug)- 
Patients who ended treatment  
 


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15.3 SAFETY DATA  
15.3.1 DISPLAY OF ADVERSE EVENTS  
Table 15.3.1 - 1 Overview of adverse events: Number (%) of patients - Safety population  
Table 15.3.1 - 2 Overview of adverse events: Number (%) of patient-cycles - Safety population  
Table 15.3.1 - 3 Number of patients with TEAEs by Primary SOC, HLGT, HLT and PT and 
Worst NCI Grade - Safety Population 
 
Table 15.3.1 - 4 Summary of TEAEs by Primary SOC and PT and Worst NCI Grade - Number of 
patients - Safety Population  
Table 15.3.1 - 5 Summary of TEAEs by Primary SOC and PT and Worst NCI Grade - Number of 
patients-cycles - Safety Population 
 
Table 15.3.1 - 6 Summary of TEAEs by Primary SOC and PT and Worst NCI Grade and Age - 
Number of patients - Safety Population 
 
Table 15.3.1 - 7 Summary of TEAEs by Primary SOC and Preferred Term and Worst NCI Grade 
and Prior Bevacizumab - Number of patients – Safety Population  
Table 15.3.1 - 8 All TEAEs Possibly Related to Study Treatment by Primary SOC and PT and 
Worst NCI grade - Number of patients - Safety Population  
Table 15.3.1 - 9 All Serious TEAEs by Primary SOC, HLGT, HLT and PT and Worst NCI Grade 
- Number of patients- Safety Population 
 
Table 15.3.1 - 10 All Serious TEAEs by Primary SOC and PT and Worst NCI grade - Number of 
patients - Safety Population  
Table 15.3.1 - 11 All Serious TEAEs Possibly Related to Study Treatment by Primary SOC and 
PT and Worst NCI grade - Number of patients – Safety Population  
Table 15.3.1 - 13 All TEAEs leading to permanent discontinuation by Primary SOC, HLGT, HLT 
and PT and Worst NCI Grade - Number of patients -  Patients who ended treatment 
 
Table 15.3.1 - 14 All TEAEs Leading to Permanent Treatment Discontinuation by Primary SOC 
and PT and Worst NCI grade - Number of patients - Patients Who Ended Treatment 
 
Table 15.3.1 - 15 All TEAEs Leading to Premature Treatment Discontinuation by Primary SOC 
and PT and Worst NCI grade - Number of patients – Safety Population 
 
Table 15.3.1 - 16 All TEAEs Leading to Aflibercept Discontinuation (premature or permanent) by 
Primary SOC and PT and Worst NCI grade - Number of patients - Safety Population 
 
Table 15.3.1 - 17 All TEAEs Leading to Premature Discontinuation of Aflibercept by Primary 
SOC and PT and Worst NCI grade - Number of patients - Safety Population 
 
Table 15.3.1 - 18 All TEAEs Leading to FOLFIRI Discontinuation (premature or permanent) by 
Primary SOC and PT and Worst NCI grade - Number of patients - Safety Population 
 
Table 15.3.1 - 19 All TEAEs Leading to Premature Discontinuation of FOLFIRI by Primary SOC 
and PT and Worst NCI grade - Number of patients - Safety Population 
 
Table 15.3.1 - 20 All TEAEs Leading to Dose Modification by Primary SOC and PT and Worst 
NCI grade - Number of patients - Safety Population  
Table 15.3.1 - 21 All TEAEs Leading to Dose Reduction by Primary SOC and PT and Worst NCI 
grade - Number of patients - Safety Population 
 
Table 15.3.1 - 22 All TEAEs Leading to Dose Interruption by Primary SOC and PT and Worst 
NCI grade - Number of patients - Safety Population  
Table 15.3.1 - 23 All TEAEs Leading to Dose Delay by Primary SOC and PT and Worst NCI 
grade - Number of patients - Safety Population 
 
Table 15.3.1 - 24 Summary of TEAEs of Specific Interest by Grouped Terms, Primary SOC and 


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PT and Worst NCI Grade - Number of patients – Safety Population 
Table 15.3.1 - 25 Summary of TEAEs of Specific Interest by Grouped Terms, Primary SOC and 
PT and Worst NCI Grade - Number of patient-cycles – Safety Population  
Table 15.3.1 - 26 Summary of TEAEs of Specific Interest by Grouped Terms, Primary SOC and 
PT and Worst NCI Grade and age - Number of patients - Safety Population 
 
Table 15.3.1 - 27 Summary of TEAEs of Specific Interest by Grouped Terms, Primary SOC and 
PT and Worst NCI Grade and prior use of bevazizumab - Number of patients - Safety Population  
Table 15.3.1 - 28 Treatment-emergent adverse events of specific interest:Summary of patients 
with cardiac dysfunction (based on grouped term) - Safety Population 
 
Table 15.3.1 - 29 Treatment-emergent adverse events of specific interest: Summary of patients 
with neutropenic complication (based on grouped term) - Safety Population 
 
Table 15.3.1 - 30 Treatment-emergent adverse events of specific interest: Summary of patients 
with haemorrhage (based on grouped term) - Safety Population 
 
Table 15.3.1 - 31 Treatment-emergent adverse events of specific interest: Summary of patients 
with haemorrage (based on grouped term) for patients with on treatment thrombocytopenia - 
Safety Population 
 
Table 15.3.1 - 32 Treatment-emergent adverse events of specific interest: Summary of patients 
with gastrointestinal perforation (based on grouped term) - Safety Population 
 
Table 15.3.1 - 33 Treatment-emergent adverse events of specific interest: Summary of patients 
with fistula from gastrointestinal origin (based on grouped term) - Safety Population 
 
Table 15.3.1 - 34 Treatment-emergent adverse events of specific interest: Summary of patients 
with fistula from other origin (based on grouped term) - Safety Population  
Table 15.3.1 - 35 Treatment-emergent adverse events of specific interest: Summary of patients 
with osteonecrosis (based on grouped term) - Safety Population 
 
Table 15.3.1 - 36 Treatment-emergent adverse events of specific interest: Summary of patients 
with compromised wound healing (based on grouped term) - Safety Population 
 
Table 15.3.1 - 37 Treatment-emergent adverse events of specific interest: Summary of patients 
with acute drug reaction (based on grouped term) - Safety Population 
 
Table 15.3.1 - 38 Treatment-emergent adverse events of specific interest: Summary of patients 
with RPLS (based on grouped term) - Safety Population 
 
Table 15.3.1 - 40 Treatment-emergent adverse events of specific interest: Summary of patients 
with renal events including thrombotic microangiopathy (TMA) and haemolytic and uremic 
syndrome (HUS) (based on grouped term) - Safety Population 
 
Table 15.3.1 - 41 Treatment-emergent adverse events of specific interest: Summary of patients 
with diarrhea (based on grouped term) - Safety Population  
Table 15.3.1 - 42 Treatment-emergent adverse events of specific interest: Summary of patients 
with stomatitis and ulcerations (based on grouped term) - Safety Population 
 
Table 15.3.1 - 43 Treatment-emergent adverse events of specific interest: Summary of patients 
with arterial thromboembolic event (based on grouped term) - Safety Population  
Table 15.3.1 - 43b Treatment-emergent adverse events of specific interest: Summary of patients 
with arterial thromboembolic event  (based on grouped term) for patients without or with prior 
arterial event (based on grouped term)- Safety Population  
Table 15.3.1 - 44 Treatment-emergent adverse events of specific interest: Summary of patients 
with venous thromboembolic event (based on grouped term) - Safety Population  
Table 15.3.1 - 45 Treatment-emergent adverse events of specific interest: Summary of patients 
with thrombovascular events, i.e arterial or venous thromboembolic events (based on grouped 


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term) - Safety Population 
 
Table 15.3.1 - 46 Treatment-emergent adverse events of specific interest: Summary of patients 
with thrombovascular events, i.e arterial or venous thromboembolic events (based on grouped 
term) among patients with prior thrombovascular events at baseline (based on grouped term) – 
Safety Population 
 
Table 15.3.1 - 52 Treatment-emergent adverse events of specific interest: Summary of patients 
with hypertension (based on grouped term) - Safety Population 
 
Table 15.3.1 - 53 Treatment-emergent adverse events of specific interest: Summary of patients 
with hypertension (based on grouped term) among patients with prior hypertension (based on 
grouped term) - Safety Population 
 
Table 15.3.1 - 55 Treatment-emergent adverse events of specific interest: Summary of patients 
with hypertension (based on grouped term) among patients without prior history of hypertension 
at baseline (based on grouped term) - Safety Population 
 
Table 15.3.1 - 57 Summary of Pre-Treatment AEs by Primary SOC and PT and Worst NCI Grade 
- Number of patients - Safety Population 
 
 
15.3.2 ANALYSIS OF DEATHS 
 
Table 15.3.2 - 1 Summary of Deaths and Cause of Deaths- Safety Population 
 
Table 15.3.2 - 2 Summary of Deaths and Cause of Deaths- Included but not treated patients 
 
Table 15.3.2 - 3 All TEAE leading to death by Primary SOC, HLGT,  HLT and PT and Worst 
NCI Grade - Number of patients - Safety Population 
Table 15.3.2 - 4 All TEAEs leading to death by Primary SOC and PT and Worst NCI Grade - 
Safety Population 
 
Table 15.3.2 - 6 Summary of Fatal AEs in the Context of Disease Progression by Primary SOC 
and PT and Worst NCI Grade -  Safety Population  
Table 15.3.2 - 7 Summary of Fatal AEs in Other Context Than Disease Progression by Primary 
SOC and PT and Worst NCI Grade -  Safety Population 
 
Table 15.3.2 - 8 Summary of Related AEs Leading to Death In Other Context Than Disease 
Progression  by Primary SOC and PT and Worst NCI Grade -  Safety Population 288 
Listing 15.3.2 - 1 Listing of all deaths 
 
Listing 15.3.2 - 2 All Adverse Events leading to death 
 
 
15.3.3 ANALYSIS OF LABORATORY VARIABLES 
 
Table 15.3.3 - 1 Summary of Abnormal Hematological Parameters During Treatment (Worst 
Grade Per Patient)- Safety Population 
 
Table 15.3.3 - 2 Summary of INR During Treatment (Worst Value Per Patient)- Safety Population 
Table 15.3.3 - 3 Summary of Abnormal Electrolytes Parameters During Treatment (Worst Grade 
Per Patient)- Safety Population 
 
Table 15.3.3 - 4 Summary of Renal and Liver Function Parameters During Treatment (Worst 
Grade Per Patient)- Safety Population 
 
Table 15.3.3 - 5 Summary of Creatinine Clearance During Treatment (Worst Value Per Patient)- 
Safety Population 
 
Table 15.3.3 - 6 Summary of Other Biochemistry Parameters During Treatment (Worst Grade Per 
Patient)- Safety Population 
 
Table 15.3.3 - 7 Non Gradable Biochemistry Parameters – Number of Patients With On-
Treatment Abnormalities– Safety Population 


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Table 15.3.3 - 8 Summary of Patients With Proteinuria Events During Treatment- Safety 
Population 
 
Table 15.3.3 - 9 Summary of Proteinuria and UPCR During Treatment– Number (%) of Patients - 
Safety Population 
 
Table 15.3.3 - 14 Summary of Patients With Renal Failure Events During treatment- Safety 
Population 
 
 
15.5 QUALITY OF LIFE 
 
15.5.1 ENROLLMENT 
 
Table 15.5.1 - 1 Enrollment Summary 
 
15.5.2 EQ-5D QUESTIONNAIRE 
 
Table 15.5.2 - 1 QOL EQ-5D Completion Rates by Cycle - Safety Population 
 
Table 15.5.2 - 2 Quality of Life: Single Index Utility Score - QOL EQ-5D Population 
 
Table 15.5.2 - 3 Single index utility score by assessment status - QOL EQ-5D population  
Table 15.5.2 - 4 Quality of life: Visual Analogue Scale - QOL EQ-5D population  
Table 15.5.2 - 5 Quality of life: Description of the EQ-5D questionnaire - QOL EQ-5D population 
Table 15.5.2 - 6a Quality of life: Description of the EQ-5D questionnaire - Mobility- Shift table 
between baseline and each cycle - QOL EQ-5D population.  
Table 15.5.2 - 6b Quality of life: Description of the EQ-5D questionnaire - Self-care - Shift table 
between baseline and each cycle - QOL EQ-5D population.  
Table 15.5.2 - 6c Quality of life: Description of the EQ-5D questionnaire - Usual activities - Shift 
table between baseline and each cycle - QOL EQ-5D population.  
Table 15.5.2 - 6d Quality of life: Description of the EQ-5D questionnaire - Pain/discomfort - Shift 
table between baseline and each cycle - QOL EQ-5D population.  
Table 15.5.2 - 6e Quality of life: Description of the EQ-5D questionnaire - Anxiety/Depression - 
Shift table between baseline and each cycle - QOL EQ-5D population. 
 
Table 15.5.2 - 7a Quality of life: Description of the EQ-5D questionnaire - Evolution of Mobility 
at each cycle - QOL EQ-5D population. 
 
Table 15.5.2 - 7b Quality of life: Description of the EQ-5D questionnaire - Evolution of Self-care 
at each cycle - QOL EQ-5D population. 
 
Table 15.5.2 - 7c Quality of life: Description of the EQ-5D questionnaire - Evolution of Usual 
activities at each cycle - QOL EQ-5D population. 
 
Table 15.5.2 - 7d Quality of life: Description of the EQ-5D questionnaire - Evolution of 
Pain/discomfort at each cycle - QOL EQ-5D population. 
 
Table 15.5.2 - 7e Quality of life: Description of the EQ-5D questionnaire - Evolution of 
Anxiety/Depression at each cycle - QOL EQ-5D population. 
 
15.5.3 EORTC-QLQ C30 QUESTIONNAIRE 
 
Table 15.5.3 - 1 EORTC-QLQ C30 Completion Rates by Cycle - Safety Population 
 
Table 15.5.3 - 2 EORTC-QLQ C30: Global Health Status - QOL EORTC30 Population  
Table 15.5.3 - 3 EORTC-QLQ C30: Functional Scales - QOL EORTC30 Population 
 
Table 15.5.3 - 4 EORTC-QLQ C30: Symptom Scales / Items - QOL EORTC30 Population 
 
15.5.4.EORTC-QLQ CR29 QUESTIONNAIRE 
 
Table 15.5.4 - 1 EORTC-QLQ C29 Completion Rates by Cycle - Safety Population 
 
Table 15.5.4 - 2 EORTC-QLQ C29: Functional Scales - QOL EORTC29 Population 
 
Table 15.5.4 - 3 EORTC-QLQ C29: Symptom Scales / Items - QOL EORTC29 Population 
 
 


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3.5 
FIFTH INTERIM ANALYSIS 
A fifth interim analysis was performed during the second quarter 2016. This interim analysis was 
concerned patients in AFLIB_C_06097 program only. 
 
The statistical report contained the same tables as the ones planned for the fourth interim analysis. 


Statistical Analysis Plan (Final amended #3) 
 
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4 
DATABASE LOCK 
The database is planned to be locked around 8 weeks after last patient last visit. We will have 2 
Database lock (1 AFEQT and 1ASQoP) at different time. 


Statistical Analysis Plan (Final amended #3) 
 
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5 
SOFTWARE DOCUMENTATION 
All summaries and statistical analyses will be generated using SAS version 9.2 or higher. 


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6 
REFERENCES 
 
1. Aaronson NK, Cull A, Kaasa S, Sprangers MAG.  The European Organization for Research 
and Treatment of Cancer (EORTC) modular approach to quality of life assessment in 
oncology: an update. In: Spilker B, editor. Quality of Life and Pharmacoeconomics in Clinical 
Trials. 2nd ed. New York: Raven Press, 1996:179-89. 
2. Fayers P, Aaronson N, Bjordal K, Groenvold M, Curran D, & Bottomley A. EORTC QLQ-
C30 Scoring Manual. 2001. EORTC, Brussels.  
3. Dolan P. Modeling valuations for EuroQol health states. Medical Care Vol 35, No. 11, pp. 
1095-1108. 1997