Conditions: Metastatic Colorectal Cancer
Keywords: metastatic colorectal cancer untreated first-line S95005 (Trifluridine/tipiracil) bevacizumab capecitabine
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 154
Healthy volunteers: no

Brief summary:
The main purpose of this study is to evaluate the progression-free survival (PFS) in patients receiving S 95005 + bevacizumab (experimental arm) or capecitabine + bevacizumab (control arm) as first-line treatment for unresectable metastatic colorectal cancer in patients non-eligible for intensive therapy.

Detailed description:

Arms:
arm 1: Trifluridine/tipiracil (S95005): film-coated tablets containing 15mg of trifluridine and 7.065mg of tipiracil hydrochloride, or 20mg of trifluridine and 9.42mg of tipiracil hydrochloride.

Bevacizumab: concentrate for solution for IV infusion containing 25mg/ml of bevacizumab.

Trifluridine/tipiracil was administered at 35 mg/m2/dose orally within 1 hour after completion of morning and evening meals, for 5 days on/2 days off, over 2 weeks, followed by a 14-day rest period, with bevacizumab administered intravenously at the dose of 5 mg/kg every 2 weeks at Day 1 and Day 15.This treatment cycle was repeated every 4 weeks. arm 2: Capecitabine was administered at 1250 mg/m² orally BID (bis in die)on Days 1-14 of each cycle, with bevacizumab (7.5 mg/kg, IV) administered on Day 1 of each cycle. This treatment cycle was repeated every 3 weeks

Interventions: intervention 1: Trifluridine/tipiracil + bevacizumab intervention 2: Capecitabine + bevacizumab
Intervention descriptions: intervention 1: Patients were treated withTrifluridine/tipiracil + bevacizumab regimen until they met a discontinuation criterion. intervention 2: Patients were treated with capecitabine+ bevacizumab regimen until they met a discontinuation criterion.

Protocol document:
Prot_000.pdf: 
  
   
 
 
Document title 
AMENDED CLINICAL STUDY PROTOCOL 
Study title 
 
An open-label, randomised, non-comparative phase 2 study 
evaluating 
S 95005 
(TAS-102) 
plus 
bevacizumab 
and 
capecitabine plus bevacizumab in patients with previously 
untreated metastatic COlorectal cancer who are non-eligible 
for intensive therapy (TASCO1 study) 
Test drug code 
S 95005 (trifluridine/tipiracil) 
Indication 
First-line treatment of metastatic colorectal cancer in patients 
non-eligible for intensive therapy 
Development phase 
Phase II 
Protocol code  
CL2-95005-002 
EudraCT Number 
2015-004544-18 
Universal Trial Number Not applicable 
Sponsor 
Institut de Recherches Internationales Servier (I.R.I.S.) 
International 
Coordinator 
Prof. Eric Van Cutsem, MD, PhD 
Gastroenterology/Digestive Oncology 
Leuven Cancer Institute 
University Hospitals Leuven 
3000 Leuven- Belgium 
Date of the document 
25th January 2017 
Version of the document  Final Version 
Substantial Amendment 
integrated 
No 
Final version date 
Countries concerned 
1 
17th March 2016 
ITA 
2 
17th May 2016 
All 
3 
30th August 2016 
DEU 
4 
25th January 2017 
All 
 
 
CONFIDENTIAL 
Merci d'adresser toute correspondance au : 
Siège social : 50, rue Carnot • 92284 Suresnes cedex • Tél.: 01.55.72.60.00
S.A.R.L. au capital de 7.800 euros • 319 416 756 RCS Nanterre
INSTITUT DE RECHERCHES INTERNATIONALES SERVIER
I.R.I.S.


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FOLLOW-UP OF VERSIONS 
 
Substantial 
amendment 
No 
Final version 
date 
Countries 
concerned 
Nature of amendments 
1 
17th March 
2016 
ITA 
See Appendix 6 
2 
17th May 2016 
All 
- Title update and addition of an acronym 
- Update of inclusion / non-inclusion criteria and 
forbidden treatment to be in line with capecitabine 
and bevacizumab SmPC, 
- Addition of a DSMB, 
- Addition of haematological assessment at CXD15 
in the experimental arm, 
- Clarification and update of the study duration for 
the patient (under treatment and after treatment 
withdrawal), 
- Clarification about laboratory tests (time point, 
CEA dosage…) 
- Corrections/clarifications of inconsistencies and 
typo  
3 
30th August 
2016 
DEU 
See Appendix 8 
4 
25th January 
2017 
All 
- The main objective of this substantial amendment 
is to implement the urgent safety measure which 
aims to revise the instructions given in the study 
protocol for the dose modifications for S 95005 in 
case of febrile neutropenia to be in line with the 
European Summary of Product Characteristics of 
Lonsurf®, 
- Update of the end of recruitment period, 
- Clarification on the definition of the end of the 
study, 
- Clarification on t he population targeted in the 
study that’s to say the first-line treatment of 
patients with unresectable metastatic colorectal 
cancer who are non-eligible for intensive therapy, 
- Update of inclusion, non-inclusion and withdrawal 
criteria, 
- Precision that all samplings for biochemistry in 
fasting condition is preferable but not mandatory, 
- Bicarbonate assessment becomes optional, 
- The section “8.4.1.1 Adverse events” has been 
updated to be in line with the upcoming “EMA 
guidelines 
on 
evaluation 
of 
an 
anticancer 
treatment”; 
- Corrections/clarifications of inconsistencies and 
typo. 


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STUDY SUMMARY SHEET 
Name of the sponsor: 
I.R.I.S.  
Individual 
Study 
Table 
Referring to Part of the 
Dossier 
(For National Authority Use only) 
Name of Finished Product: 
S 95005 (TAS-102)  
Volume: 
 
 
Name of Active Ingredient: 
trifluridine (FTD) and tipiracil 
hydrochloride (TPI) 
Page: 
 
Title of study:  
An open-label, randomised, non-comparative phase 2 study evaluating S 95005 (TAS-102) plus bevacizumab 
and capecitabine plus bevacizumab in patients with previously untreated metastatic COlorectal cancer who are 
non-eligible for intensive therapy. (TASCO1 study). 
Protocol No.: CL2-95005-002 
Coordinator(s)  
National coordinators and investigators: listed in a separate document 
Study centre(s): 
Total number of centres: Approximately 60 
Total number of countries: Approximately 12 
Study period (event driven trial): 
­ Study duration for the patient: approximately 1 year of treatment 
+ follow-up 
­ Planned study initiation date (planned date of first visit first 
patient): Q2 2016 
­ Planned end of recruitment period (planned date of first visit last 
patient): Q1 2017 March 2018 (approximately 24 months) 
­ Planned study completion date: (12 months after the follow-up 
start date of the last patient withdrawn planned date of last visit 
last patient): Q2 2019  
Study development phase:  
Phase II 
Objectives:  
Primary 
Progression-free survival (PFS) based on Investigator assessment of radiologic images 
 
Secondary 
­ Overall response rate (ORR) 
­ Duration of response (DR) 
­ Disease control rate (DCR) 
­ Overall survival (OS) 
­ Safety and tolerability 
­ Quality of life (QoL) (EORTC QLQ-C30 and QLQ-CR29) (Aaronson NK et al., 1993) 
 
Exploratory 
Evaluate the biomarkers potentially predictive of response and resistance to S 95005 given in combination 
using blood samples and archived tumour biopsy (if available). 
Methodology:  
This is a multinational, open-label, two-arm, randomised phase 2 study evaluating S 95005 + bevacizumab and 
capecitabine + bevacizumab in the first-line treatment of patients with previously untreated unresectable 
metastatic colorectal cancer (mCRC) who are non-eligible for intensive therapy. 
Patients will be randomised in a (1:1) ratio with the minimisation procedure proposed by Pocock and Simon 
(Pocock SJ et al., 1975). The stratification factors will be RAS status (wild-type, mutant type), ECOG 
performance status (0 vs. 1 vs. 2) and country. 
Number of participants: 
Total: approximately 150 


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Name of the sponsor: 
I.R.I.S.  
Individual 
Study 
Table 
Referring to Part of the 
Dossier 
(For National Authority Use only) 
Name of Finished Product: 
S 95005 (TAS-102)  
Volume: 
 
 
Name of Active Ingredient: 
trifluridine (FTD) and tipiracil 
hydrochloride (TPI) 
Page: 
 
In each group: approximately 75  
Number of primary events: 100 Progression Free Survival (PFS) events 
Diagnosis  
First-line treatment of patients with unresectable mCRC previously untreated who are non-eligible for 
intensive therapy. 
 
Inclusion criteria 
Informed consent  
1. 
Written informed consent will be obtained prior to any study-specific procedure. 
Demographic characteristics 
2. 
Male or Female participant aged ≥18 years old. 
Disease characteristics 
3. 
Has ECOG performance status of 0, 1 or 2 at the time of the randomisation. 
4. 
Has definitive histologically or cytologically confirmed adenocarcinoma of the colon or rectum. 
5. 
RAS status must have been determined (mutant or wild) based on local biological assessment on tumour 
biopsy. At least the following mutation must be determined: KRAS and NRAS Exon 2: codon 12 and 13. 
6. 
Has at least one measurable metastatic lesion (as defined by Response Evaluation Criteria in Solid 
Tumours [RECIST] version 1.1). Note: Unresectable metastatic disease must have been diagnosed within 
6 months prior to first day of study drug administration.  
7. 
No previous systemic anticancer therapy for unresectable metastatic colorectal cancer.  
8. 
Previous adjuvant (or neoadjuvant for patients with rectal cancer) chemotherapy is allowed only if it has 
been completed more than 6 months before start of study treatment.  
9. 
Patient is not a candidate for combination chemotherapy with irinotecan or oxaliplatin according to 
investigator’s judgment based on decision taken during a multidisciplinary meeting (if organised in the 
centre). 
10. Patient is not a candidate for curative resection of metastatic lesions according to investigator’s judgment 
based on decision taken during a multidisciplinary meeting (if organised in the centre). 
Medical and therapeutic criteria 
11. Is able to take medication orally (i.e., no feeding tube). 
12. Has adequate organ function as defined by the following laboratory values obtained within 5 days prior to 
randomisation: 
12.1. Haemoglobin value of ≥9.0 g/dL based on measurements obtained 2 weeks or more after last prior 
transfusion. 
12.2. Absolute neutrophil count (ANC) of ≥1.5 x 109/L. 
12.3. Platelet count ≥100 x 109/L. 
12.4. Total serum bilirubin of ≤1.5 x upper limit of normal (ULN) (except for Grade 1 hyperbilirubinemia 
due solely to a medical diagnosis of Gilbert’s syndrome). 
12.5. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 ULN; if liver function 
abnormalities are due to underlying liver metastasis, AST and ALT ≤5 x ULN. 
12.6. Creatinine clearance > 50 mL/min (using Cockcroft Gault formula). 
12.7. Urine dipstick test for proteinuria < 1+ or 24-hour urine collection <1000 mg for patients found with 
≥ 1+ on dipstick. 
13. Coagulation parameters in normal limit (or in therapeutic limit for patients treated with anticoagulant 
drugs): activated partial thromboplastin time (aPTT) and international normalized ratio (INR). 
14. Women of childbearing potential must have been tested negative in a serum pregnancy test within 5 days 
prior to randomisation. 
Within the frame of this study, female participants of childbearing potential and male participants with 
partners of childbearing potential must agree to use a highly effective method of birth control (i.e., 
pregnancy rate of less than 1% per year) during the study and for 6 months after the discontinuation of 


S 95005 
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Name of the sponsor: 
I.R.I.S.  
Individual 
Study 
Table 
Referring to Part of the 
Dossier 
(For National Authority Use only) 
Name of Finished Product: 
S 95005 (TAS-102)  
Volume: 
 
 
Name of Active Ingredient: 
trifluridine (FTD) and tipiracil 
hydrochloride (TPI) 
Page: 
 
study medication.  
Contraceptive methods that result in a low failure rate when used consistently and correctly include 
methods such as combined hormonal contraception associated with inhibition of ovulation (oral, 
intravaginal, transdermal), progestogen-only hormonal contraception associated with inhibition of 
ovulation (oral, injectable, implantable), some intrauterine devices (IUDs), intrauterine hormone-releasing 
system (IUS), true sexual abstinence (when this is in line with the preferred and usual lifestyle of the 
participant), bilateral tubal occlusion, or a female partner who is not of childbearing potential or a male 
partner who has had a vasectomy. Women and female partners using hormonal contraceptive must also 
use a barrier method i.e. condom or occlusive cap (diaphragm or cervical/vault caps). 
15. Is willing and able to comply with scheduled visits and study procedures. 
Non-inclusion criteria 
General criteria 
16. Foreseeable poor compliance to the study procedures. 
17. Is a pregnant or lactating female. 
18. Is inappropriate for entry into this study in the judgment of the Investigator. 
Medical and therapeutic criteria 
19. Has a serious illness or serious medical condition(s) including, but not limited to the following: 
19.1. Other concurrently active malignancies excluding malignancies that are in remission for more than 5 
years, or carcinoma-in-situ deemed cured by adequate treatment or basal cell carcinoma. 
19.2. Known brain metastasis or leptomeningeal metastasis.  
19.3. Active systemic infection (i.e., body temperature ≥38°C due to infection). 
19.4. At the time of screening, intestinal obstruction, pulmonary fibrosis, interstitial pneumonitis, renal 
failure, liver failure, or cerebrovascular disorder.  
19.5. Uncontrolled diabetes.  
19.6. Deep venous/arterial thromboembolic complication or bleeding diatheses or any other 
haemorrhage/bleeding event CTCAE grade > 3 within 4 weeks prior to randomisation. 
19.7. Cerebrovascular accident or myocardial infarction within the last 12 months, severe/unstable angina, 
uncontrolled or symptomatic arrhythmia, symptomatic congestive heart failure New York Heart 
Association (NYHA) class III or IV, uncontrolled hypertension.  
19.8. Known coagulopathy that increases risk of bleeding or a history of clinically significant 
haemorrhages in the past (including Grade ≥3 gastrointestinal haemorrhage) within 4 weeks prior to 
randomisation. 
19.9. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-
related illness, or hepatitis B or C as determined by serologic tests. 
19.10. Patients with autoimmune disorders or history of organ transplantation who require 
immunosuppressive therapy. 
19.11. Psychiatric disease that may increase the risk associated with study participation or study drug 
administration, or may interfere with the interpretation of study results. 
19.12. In the investigator’s opinion, significant malabsorption syndrome, significant chronic digestive or 
gastrointestinal inflammatory syndrome. 
20. Major surgery within 4 weeks prior to randomisation (the surgical incision should be fully healed prior to 
study drug administration). Note: indwelling catheter and portacath implantation are allowed.  
21.  Extended field radiation within 4 weeks or limited field radiation within 2 weeks prior to randomisation.  
22. Any investigational agent received within 4 weeks prior to randomisation. 
33. Participant already enrolled in the study (informed consent signed). 
 
Non-inclusion criteria related to administration of S 95005: 
23. Has previously received S 95005 or history of allergic reactions attributed to compounds of similar 
composition to S 95005 or any of its excipients. 


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Name of the sponsor: 
I.R.I.S.  
Individual 
Study 
Table 
Referring to Part of the 
Dossier 
(For National Authority Use only) 
Name of Finished Product: 
S 95005 (TAS-102)  
Volume: 
 
 
Name of Active Ingredient: 
trifluridine (FTD) and tipiracil 
hydrochloride (TPI) 
Page: 
 
31. Hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose 
malabsorption. 
 
Non-inclusion criteria related to administration of bevacizumab: 
24. History of allergic reactions or hypersensitivity to bevacizumab or any of its excipients. 
25. History of hypersensitivity to Chinese Hamster Ovary (CHO) cell products or other recombinant human or 
humanised antibodies. 
32. Any contraindication present in the SmPC of bevacizumab. 
 
Non-inclusion criteria related to administration of capecitabine: 
26. History of allergic reactions or hypersensitivity to capecitabine or any of its excipients or fluorouracil. 
27. History of severe and unexpected reaction to fluoropyrimidine therapy. 
28. Known complete absence of dihydropyrimidine dehydrogenase (DPD) activity. 
29. Treatment with sorivudine or its chemical related analogues, such as brivudine, within 4 weeks prior to 
randomisation 
30. Any contraindication present in the SmPC of capecitabine.  
Test drug/experimental arm: S 95005 + bevacizumab arm 
S 95005 (35 mg/m²/dose) will be administered orally twice a day (BID), within 1 hour after completion of 
morning and evening meals, 5 days on/2 days off, over 2 weeks, followed by a 14-day rest; with bevacizumab 
(5 mg/kg, IV) administered every 2 weeks (Day 1 and Day 15). This treatment cycle will be repeated every 4 
weeks. 
Control arm: Capecitabine + bevacizumab 
Capecitabine (1250 mg/m²) will be administered orally BID on Days 1–14 of each cycle, with bevacizumab 
(7.5 mg/kg, IV) administered on Day 1 of each cycle. This treatment cycle will be repeated every 3 weeks.  
 
Note: According to local clinical practice the starting dose of capecitabine could be reduced to 1000 mg/m² but 
could not be lower. 
Duration of treatment: 
Patients will be treated by the assigned combined regimen until they meet a discontinuation criterion as 
described in section 5.4.1. Patients will be considered to be on treatment as long as either component of the 
combination regimen continues to be administered unless the investigator judges that it is in the interest of the 
patient to withdraw from the study and to be treated outside of this protocol with a combine modality. If a 
patient discontinues study treatment for reasons other than radiologic disease progression (e.g., intolerable side 
effects), patients will be followed for tumour response until radiologic disease progression or initiation of new 
anticancer therapy (whichever occurs first). After progression, patients will be followed for survival until the 
end of the study (defined as the last visit of the last patient). 
 
The selection will be stopped once 100 PFS events (progression of disease [PD] or death) are reached or 150 
patients are randomised (whichever occurs first) and the on-going patients will continue the study without 
change until the end of the study. 
Once 100 PFS events (progression of disease [PD] or death) are reached the main study analysis will be 
performed.  
Criteria for evaluation: 
 
Efficacy measurements: 
Tumour assessments will be analysed using RECIST 1.1 (Eisenhauer EA et al., 2009). Every 8 weeks until 
progression, death or initiation of a new anticancer treatment (whichever occurs first).   
Quality of life assessments will be performed every 12 weeks. 
 
Safety measurements: 
Standard safety monitoring will be performed and adverse events (AEs) will be graded using the National 


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Name of the sponsor: 
I.R.I.S.  
Individual 
Study 
Table 
Referring to Part of the 
Dossier 
(For National Authority Use only) 
Name of Finished Product: 
S 95005 (TAS-102)  
Volume: 
 
 
Name of Active Ingredient: 
trifluridine (FTD) and tipiracil 
hydrochloride (TPI) 
Page: 
 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. The Event 
Requiring Immediate Notification (ERIN) not related will be reported during 100 days after the last study drug 
intake and the serious AEs related to the research will be reported without any time delay. 
Records of any change or addition of a new concomitant treatment at each visit. 
 
Pharmacokinetic measurements: 
Not applicable 
 
Biomarkers measurements: 
­ At C1D1 blood samples for proteomic and genomic analysis will be collected and at withdrawal visit only 
proteomic blood samples. 
­ Intratumoural biomarkers analysis (proteomic and genomic) will be performed from archival tumour 
biopsy (if available). 
Statistical methods:  
Study population 
­ Full Analysis Set (FAS): All randomised patients who have taken at least one dose of IMP will be included 
in the FAS. Based on the intention-to-treat principle, patients in the FAS will be analysed in the arm they 
were assigned by randomisation. 
­ Per Protocol Set (PPS): All patients of the FAS without relevant deviation(s), which could affect the 
evaluation of the IMP effect on the primary efficacy endpoint. 
­ Tumour Response (TR) Population: All patients in the PPS with measurable disease (at least one target 
lesion) at baseline and with at least one tumour evaluation while on treatment (with the same method of 
measurement as baseline).  Patients who have a cancer-related death prior to their first tumour evaluation 
will also be considered evaluable with PD as best overall response. 
­ Safety Set (SS): This set will correspond to patients who received at least one dose of IMP. Patients will be 
analysed according to the treatment actually received. Each patient will be classified into and analysed 
consistently within one (and only one) treatment group. 
­ Quality of Life Set (QLS): To be included in the QLS for the QLQ-C30 questionnaire, patients should have 
completed at least two third (i.e. at least 20 questions) of the questions of the baseline QLQ-C30 
questionnaire, and at least two third of the questions of a QLQ-C30 questionnaire during the study period. 
Same conditions for the QLQ-CR29 questionnaires. 
Efficacy analysis:  
All efficacy analyses will be performed in the FAS, unless otherwise specified.  
Primary endpoint:  
For the primary efficacy endpoint, PFS, the hazard ratio (HR) and the corresponding 2-sided 80% and 95% 
confidence intervals (CI) for S 95005+ bevacizumab versus capecitabine + bevacizumab will be estimated 
using a Cox proportional hazard model adjusting for the stratification factors based on IWRS data.   
PFS for each arm will be summarized using Kaplan Meier curves and further characterized in terms of the 
median and survival probabilities at 6, 12, 18, and 24 months along with the corresponding 2-sided 80% and 2-
sided 95% CI for the estimates. 
The primary analysis will be conducted in the FAS.  
Secondary endpoints: 
As a secondary analysis, the primary analysis of PFS will be repeated in the PPS. 
In order to assess the consistency of the primary analysis of PFS, another sensitivity analysis taking into 
account the further anti-cancer therapy as an event will be carried out both in the FAS and the PPS. 


PPD
PPD
PPD


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Table of contents 
Table of contents ........................................................................................................................ 9 
1. ADMINISTRATIVE STRUCTURE OF THE STUDY ................................................. 21 
2. BACKGROUND INFORMATION ................................................................................. 22 
2.1. Overview of disease pathogenesis, epidemiology and current treatment ....................... 22 
2.2. Mechanism of action of S 95005 .................................................................................... 22 
2.3. S 95005 in Refractory Metastatic Colorectal Cancer (mCRC): Summary of 
clinical data ..................................................................................................................... 23 
2.3.1. Clinical efficacy ............................................................................................................ 23 
2.3.2. Clinical safety and tolerability ...................................................................................... 24 
2.4. Rationale for Study and selection of dose ...................................................................... 24 
2.4.1. S 95005 in combination with bevacizumab-Non-clinical data ..................................... 25 
2.4.2. S 95005 in combination with bevacizumab-Clinical data ............................................ 25 
2.4.3. Study design ................................................................................................................. 26 
2.4.4. Selection of Dose Regimens ......................................................................................... 26 
3. STUDY OBJECTIVES AND PURPOSE ........................................................................ 27 
3.1. Primary objectives .......................................................................................................... 27 
3.2. Secondary objectives ...................................................................................................... 27 
3.3. Exploratory objectives .................................................................................................... 27 
4. STUDY DESIGN ............................................................................................................... 28 
4.1. Endpoints ........................................................................................................................ 28 
4.1.1. Primary endpoint .......................................................................................................... 28 
4.1.2. Secondary endpoints ..................................................................................................... 28 
4.1.3. Exploratory endpoints .................................................................................................. 28 
4.2. Experimental design ....................................................................................................... 29 
4.2.1. Study plan ..................................................................................................................... 29 
4.2.2. Study duration .............................................................................................................. 31 
4.2.3. Replacement of patients ............................................................................................... 31 
4.2.4. Discontinuation of study treatments ............................................................................. 31 
4.2.5. Investigation schedule .................................................................................................. 32 
4.2.6. Study Assessments ....................................................................................................... 37 
4.2.6.1. 
All Study Procedures ............................................................................................... 37 
4.2.6.1.1. Informed consent ................................................................................................... 37 
4.2.6.1.2. Patient Numbering ................................................................................................. 37 
4.2.6.1.3. Histological/Cytological Confirmation ................................................................. 38 
4.2.6.1.4. RAS/BRAF status .................................................................................................. 38 
4.2.6.1.5. Demography .......................................................................................................... 38 
4.2.6.1.6. Medical history ...................................................................................................... 38 
4.2.6.1.7. Previous surgery, radiotherapy and treatments related to the studied disease ...... 38 
4.2.6.1.8. Baseline Signs and Symptoms .............................................................................. 38 


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4.2.6.1.9. Physical Examination ............................................................................................ 38 
4.2.6.1.10. Electrocardiogram (ECG) ...................................................................................... 38 
4.2.6.1.11. Height, Vital Signs, Weight .................................................................................. 39 
4.2.6.1.12. ECOG Performance Status .................................................................................... 39 
4.2.6.1.13. Clinical Laboratory Evaluations ............................................................................ 39 
4.2.6.1.13.1. Haematology ....................................................................................................... 40 
4.2.6.1.13.2. Biochemistry ....................................................................................................... 40 
4.2.6.1.13.3. Coagulation ......................................................................................................... 40 
4.2.6.1.13.4. Urinalysis ............................................................................................................ 41 
4.2.6.1.13.5. Pregnancy Testing ............................................................................................... 41 
4.2.6.1.14. Dosage of Carcinoembryonic Antigen (CEA) ...................................................... 41 
4.2.6.1.15. Tumour Measurements .......................................................................................... 41 
4.2.6.1.16. Concomitant treatments ......................................................................................... 42 
4.2.6.1.17. Adverse Event Assessment ................................................................................... 42 
4.2.6.1.18. Quality of Life ....................................................................................................... 42 
4.2.6.1.19. Biomarkers assessment .......................................................................................... 43 
4.2.6.1.20. Inclusion/Non-inclusion criteria ............................................................................ 43 
4.2.6.1.21. Randomisation/Start of treatment .......................................................................... 43 
4.2.6.2. 
Assessments by Visit ............................................................................................... 43 
4.2.6.2.1. Baseline procedures prior to randomisation: screening period/Inclusion visit ..... 43 
4.2.6.2.1.1. Day -28 through Day 0 ........................................................................................ 43 
4.2.6.2.1.2. Day -5 through Day 0 .......................................................................................... 43 
4.2.6.2.2. Randomisation ....................................................................................................... 44 
4.2.6.2.3. Procedures prior to first study drug administration: .............................................. 44 
4.2.6.2.4. C1D1 ..................................................................................................................... 44 
4.2.6.2.5. Cycle 1 Day 15 ...................................................................................................... 44 
4.2.6.2.6. Subsequent Cycles (Cycle X Day 1) ..................................................................... 45 
4.2.6.2.7. Subsequent Cycles (Cycle X Day 15) (experimental arm only) ........................... 45 
4.2.6.2.8. Every 8 Weeks from Start of Treatment ............................................................... 45 
4.2.6.2.9. Every 12 Weeks from Start of Treatment ............................................................. 45 
4.2.6.2.10. Withdrawal visit (up to 4 weeks after the last test drug administration) ............... 45 
4.2.6.2.11. Follow-up .............................................................................................................. 46 
4.3. Measures to minimise bias .............................................................................................. 46 
4.4. Study products and blinding systems .............................................................................. 47 
4.4.1. Products administered .................................................................................................. 47 
4.4.2. IMPs management ........................................................................................................ 49 
4.4.2.1. 
Handling conditions and cleaning procedures. ........................................................ 50 
4.4.2.2. 
S 95005 .................................................................................................................... 50 
4.4.2.3. 
Bevacizumab ............................................................................................................ 50 
4.4.2.4. 
Capecitabine ............................................................................................................ 51 
4.4.3. Management of blinding systems ................................................................................. 51 
4.5. Discontinuation of the study ........................................................................................... 51 
4.5.1. Premature discontinuation of the study ........................................................................ 51 
4.5.2. Discontinuation of the study in the event of objective reached (event driven trial) ..... 51 
4.6. Source data ...................................................................................................................... 51 
5. SELECTION AND WITHDRAWAL OF PARTICIPANTS ........................................ 52 
5.1. Inclusion criteria ............................................................................................................. 52 
5.1.1. Informed consent .......................................................................................................... 52 


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5.1.2. Demographic characteristics ........................................................................................ 52 
5.1.3. Disease characteristics .................................................................................................. 52 
5.1.4. Medical and therapeutic criteria ................................................................................... 52 
5.2. Non-inclusion criteria ..................................................................................................... 53 
5.2.1. General criteria ............................................................................................................. 53 
5.2.2. Medical and therapeutic criteria ................................................................................... 53 
5.3. Additional information recorded at the inclusion visit ................................................... 55 
5.4. Participant withdrawal .................................................................................................... 55 
5.4.1. Withdrawal criteria ....................................................................................................... 55 
5.4.2. Procedure ...................................................................................................................... 56 
5.4.3. Lost to follow-up .......................................................................................................... 56 
6. TREATMENT OF PARTICIPANTS .............................................................................. 57 
6.1. IMPs administered .......................................................................................................... 57 
6.1.1. S 95005 plus bevacizumab arm .................................................................................... 57 
6.1.1.1. 
Treatment Regimen ................................................................................................. 57 
6.1.1.2. 
S 95005 administration ............................................................................................ 57 
6.1.1.3. 
Bevacizumab administration ................................................................................... 58 
6.1.2. Capecitabine plus bevacizumab arm ............................................................................ 58 
6.1.2.1. 
Treatment Regimen ................................................................................................. 58 
6.1.2.2. 
Capecitabine ............................................................................................................ 58 
6.1.2.3. 
Bevacizumab ............................................................................................................ 58 
6.2. IMPs dispensing .............................................................................................................. 59 
6.3. Previous and concomitant treatments ............................................................................. 59 
6.3.1. Prohibited Medications and Therapies ......................................................................... 59 
6.3.2. Concomitant Medications and Therapies ..................................................................... 59 
6.3.3. Effective contraception during study............................................................................ 60 
6.4. IMP compliance .............................................................................................................. 61 
6.5. Arrangements after the discontinuation of the IMP ........................................................ 61 
7. ASSESSMENT OF EFFICACY ...................................................................................... 62 
7.1. Efficacy measurements ................................................................................................... 62 
7.2. Methods and measurement times .................................................................................... 62 
7.2.1. Tumour assessment ...................................................................................................... 62 
7.2.1.1. 
Method of Imaging .................................................................................................. 62 
7.2.1.2. 
Tumour Definitions ................................................................................................. 63 
7.2.1.3. 
Response Criteria ..................................................................................................... 64 
7.2.1.3.1. Target and Non-target Response Assessments ...................................................... 64 
7.2.1.3.1.1. Criteria for Assessment of Tumour Response .................................................... 64 
7.2.1.3.1.2. Additional Criteria to Consider When Assessing Tumour Response ................. 65 
7.2.1.3.2. Overall Response Assessment ............................................................................... 66 
7.2.1.4. 
Best Overall Response Assessment ......................................................................... 66 
7.2.2. Quality of Life .............................................................................................................. 66 
8. ASSESSMENT OF SAFETY ........................................................................................... 67 
8.1. Safety measurements ...................................................................................................... 67 
8.2. Methods and measurement times .................................................................................... 67 


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8.2.1. Laboratory Evaluations ................................................................................................ 67 
8.2.1.1. 
Reporting and Evaluation of Laboratory Test Results ............................................ 67 
8.2.1.2. 
Repeat Testing ......................................................................................................... 67 
8.2.2. Physical Examination and Performance Status ............................................................ 67 
8.2.3. Vital Signs and Body Weight ....................................................................................... 67 
8.3. Management of toxicities and dose modifications ......................................................... 67 
8.3.1. S 95005 ......................................................................................................................... 68 
8.3.1.1. 
S 95005 dose reduction levels ................................................................................. 68 
8.3.1.2. 
S 95005 dose modification in response to non-hematologic toxicities ................... 69 
8.3.1.3. 
S 95005 dose modification in response to hematologic toxicities ........................... 69 
8.3.1.4. 
S 95005 dose resumption ......................................................................................... 70 
8.3.2. Capecitabine ................................................................................................................. 70 
8.3.3. Bevacizumab ................................................................................................................ 70 
8.4. Adverse events ................................................................................................................ 71 
8.4.1. Definitions .................................................................................................................... 71 
8.4.1.1. 
Adverse events ......................................................................................................... 71 
8.4.1.2. 
Serious adverse events ............................................................................................. 72 
8.4.1.3. 
Adverse event of special interest ............................................................................. 72 
8.4.1.4. 
Overdose .................................................................................................................. 73 
8.4.1.5. 
Events requiring an immediate notification (ERIN) ................................................ 73 
8.4.2. Responsibilities of the investigator .............................................................................. 73 
8.4.2.1. 
Time frame for AE reporting ................................................................................... 73 
8.4.2.2. 
Evaluation of seriousness, intensity and causality ................................................... 74 
8.4.2.3. 
Documentation of the event ..................................................................................... 75 
8.4.2.4. 
Follow-up of adverse events .................................................................................... 75 
8.4.2.5. 
Special situations (pregnancy, overdoses, intake of IMP by a person around 
the participant) ......................................................................................................... 75 
8.4.2.6. 
Recording Methods in the e-CRF ............................................................................ 76 
8.4.2.7. 
Procedure for an event requiring an immediate notification ................................... 76 
8.4.3. Responsibilities of the sponsor ..................................................................................... 77 
8.4.4. Responsibilities of Data Safety Monitoring Board ...................................................... 77 
9. OTHER ASSESSMENTS NOT SPECIFICALLY RELATED TO EFFICACY 
OR SAFETY ...................................................................................................................... 78 
9.1. Assessments related to selection/inclusion criteria. ........................................................ 78 
9.2. Measurement of drug concentration ............................................................................... 78 
9.3. Biomarkers ...................................................................................................................... 78 
9.3.1. Circulating biomarkers for genomic (circulating tumour DNA) .................................. 78 
9.3.2. Circulating biomarkers for proteomic .......................................................................... 78 
9.3.3. Archived biopsy (if available) ...................................................................................... 78 
9.3.4. Transfer of results ......................................................................................................... 78 
10. 
STATISTICS ................................................................................................................. 79 
10.1. Statistical analysis ........................................................................................................... 79 
10.1.1. Endpoints ...................................................................................................................... 79 
10.1.1.1. Efficacy endpoints ................................................................................................... 79 
10.1.1.1.1. Primary efficacy endpoint ..................................................................................... 79 
10.1.1.1.2. Secondary efficacy endpoints ................................................................................ 79 


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10.1.1.2. Safety endpoints ....................................................................................................... 80 
10.1.1.3. Other endpoints ........................................................................................................ 80 
10.1.2. Analysis sets ................................................................................................................. 80 
10.1.2.1. Analysis sets ............................................................................................................ 80 
10.1.3. Statistical methods ........................................................................................................ 81 
10.1.3.1. General considerations ............................................................................................. 81 
10.1.3.1.1. Statistical elements ................................................................................................ 81 
10.1.3.1.1.1. Descriptive statistics ........................................................................................... 81 
10.1.3.2. Study patients: Disposition, baseline characteristics and follow-up........................ 81 
10.1.3.3. Efficacy analysis ...................................................................................................... 82 
10.1.3.3.1. Primary efficacy endpoint ..................................................................................... 82 
10.1.3.3.1.1. Primary analysis .................................................................................................. 82 
10.1.3.3.1.2. Secondary analyses ............................................................................................. 82 
10.1.3.3.2. Secondary efficacy endpoints ................................................................................ 82 
10.1.3.4. Safety analysis ......................................................................................................... 83 
10.1.3.4.1. Adverse events ...................................................................................................... 83 
10.1.3.4.2. Clinical laboratory evaluation ............................................................................... 83 
10.1.3.4.3. Vital signs, clinical examination and other observations related to safety ........... 83 
10.1.3.4.3.1. Vital signs and clinical examination ................................................................... 83 
10.1.3.4.3.2. Electrocardiogram ............................................................................................... 83 
10.1.3.4.3.3. Quality of life analysis ........................................................................................ 84 
10.1.3.5. Biomarker analysis .................................................................................................. 84 
10.2. Determination of sample size ......................................................................................... 84 
11. 
DIRECT ACCESS TO SOURCE DATA / DOCUMENTS ...................................... 86 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................... 87 
12.1. Study monitoring ............................................................................................................ 87 
12.1.1. Before the study ............................................................................................................ 87 
12.1.2. During the study ........................................................................................................... 87 
12.2. Computerised medical file .............................................................................................. 87 
12.3. Audit - Inspection ........................................................................................................... 88 
12.4. Supervisory committees .................................................................................................. 89 
13. 
ETHICS ......................................................................................................................... 90 
13.1. Institutional Review Board(s)/Independent Ethics Committee(s) .................................. 90 
13.2. Study conduct ................................................................................................................. 90 
13.3. Participant information and informed consent ................................................................ 90 
13.4. Modification of the information and consent form ......................................................... 90 
14. 
DATA HANDLING AND RECORD KEEPING ....................................................... 92 
14.1. Study data ....................................................................................................................... 92 
14.2. Data management ........................................................................................................... 92 
14.3. Archiving ........................................................................................................................ 93 
15. 
INSURANCE ................................................................................................................. 94 
16. 
OWNERSHIP OF THE RESULTS - PUBLICATION POLICY ............................ 95 


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17. 
ADMINISTRATIVE CLAUSES ................................................................................. 96 
17.1. Concerning the sponsor and the investigator .................................................................. 96 
17.1.1. Persons to inform .......................................................................................................... 96 
17.1.2. Substantial protocol amendment and amended protocol .............................................. 96 
17.1.3. Final study report .......................................................................................................... 96 
17.2. Concerning the sponsor .................................................................................................. 96 
17.3. Concerning the investigator ............................................................................................ 97 
17.3.1. Confidentiality - Use of information ............................................................................ 97 
17.3.2. Organisation of the centre ............................................................................................ 97 
17.3.3. Documentation supplied to the sponsor ....................................................................... 98 
18. 
REFERENCES .............................................................................................................. 99 
19. 
APPENDICES ............................................................................................................. 101 


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List of tables 
Table (4.2.5) 1 - Investigation schedule of S 95005 + bevacizumab arm ................................ 33 
Table (4.2.5) 2 - Investigation schedule of capecitabine + bevacizumab arm ......................... 35 
Table (4.4.1) 1 - Description of S 95005 .................................................................................. 47 
Table (4.4.1) 2 - Description of capecitabine ........................................................................... 47 
Table (4.4.1) 3 - Description of bevacizumab .......................................................................... 47 
Table (4.4.1) 4 - Description of the packaging of S 95005 ...................................................... 48 
Table (4.4.1) 5 - Description of the packaging of capecitabine ............................................... 48 
Table (4.4.1) 6 - Description of the packaging of bevacizumab .............................................. 48 
Table (6.1.1.2) 1 - Number of tablets of S 95005 per dose ...................................................... 58 
Table (7.2.1.3) 1 - Time point response for patients with target (±non-target) disease ........... 66 
Table (8.3.1.1) 1 - S 95005 dose reduction levels and number of tablets per dose .................. 68 
Table (8.3.1.2) 1 - S 95005 dose modification criteria for non-hematologic toxicities ........... 69 
Table (8.3.1.3) 1 - S 95005 dose hold criteria for hematologic toxicities related to 
myelosuppression ..................................................................................................................... 69 
Table (8.3.1.3) 2 - S 95005 resumption criteria for hematologic toxicities related to 
myelosuppression ..................................................................................................................... 70 
 
 


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List of figures 
Figure (4.2.1) 1 - Study plan of S 95005 + bevacizumab arm ................................................. 30 
Figure (4.2.1) 2 - Study plan of capecitabine + bevacizumab arm .......................................... 30 
 
 


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List of appendices 
Appendix 1: Quality of life questionnaires ............................................................................ 102 
Appendix 2: Performance status ............................................................................................ 106 
Appendix 3: New Response Evaluation Criteria in Solid Tumours: Revised RECIST 1.1 ... 107 
Appendix 4: New York Heart Association (NYHA) classification ....................................... 118 
Appendix 5: World Medical Association declaration of Helsinki ......................................... 119 
Appendix 6: Substantial amendment No. 1 to the clinical study protocol ............................. 125 
Appendix 7: Capecitabine and bevacizumab SmPC .............................................................. 128 
Appendix 8: Substantial amendment No. 3 to the clinical study protocol ............................. 129 
 
 


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List of abbreviations 
ADL 
: 
Activities of Daily Living 
AE 
: 
Adverse Event 
AIDS 
: 
Acquired ImmunoDeficiency Syndrome 
ALAT 
: 
ALanine aminoTransferase 
am  
: 
ante meridiem 
ANC 
: 
Absolute Neutrophil Count 
aPTT 
: 
Activated Partial Thromboplastin Time 
ASAT 
: 
ASpartate aminoTransferase 
ß-HCG 
: 
Beta-Human Chorionic Gonadotrophin 
BID 
: 
bis in die (twice a day) 
BP 
: 
Blood Pressure 
BRAF 
 
v-Raf murine sarcoma viral oncogene homolog B 
BRM 
: 
Biological Response Modifiers 
BSA 
: 
Body Surface Area 
BSC 
: 
Best Supportive Care 
BUN 
: 
Blood Urea Nitrogen 
CD-ROM 
: 
Compact Disc – Read Only Memory 
CEA 
: 
CarcinoEmbryonic Antigen 
CI 
: 
Confidence Interval 
CR 
: 
Complete Response 
CRA 
: 
Clinical Research Associsate 
CRC 
: 
ColoRectal Cancer 
e-CRF  
: 
Electronic Case Report Form 
CRF 
: 
Case Report Form 
CRO 
: 
Contract Research Organisation 
CT 
: 
Computed Tomography 
CTCAE 
: 
Common Toxicity Criteria for Adverse Event 
CV 
: 
Curriculum Vitae 
DCR 
: 
Disease Control Rate 
dL 
: 
Decilitre 
DNA 
: 
DeoxyriboNucleic Acid 
DR 
: 
Duration of Response 
DSMB 
: 
Data Safety Monitoring Board 
ECG 
: 
ElectroCardioGram 
ECOG 
: 
Eastern Cooperative Oncology Group 
e.g. 
: 
Exempli gratia (for example) 
ERIN 
: 
Event Requiring Immediate Notification 
ESMO 
: 
European Society for Medical Oncology 
FAS 
: 
Full Analysis Set 
FDG-PET 
: 
FluoroDeoxyGlucose Positron Emission Tomography 
FTD 
: 
Trifluridine 
g 
: 
gram 
G-CSF 
: 
Granulocyte Colony-Stimulating Factor 
GCP 
: 
Good Clinical Practice 
GGT 
: 
Gamma-Glutamyl Transferase (Gamma-Glutamyl Transpeptidase) 
HIV 
: 
Human Immunodeficiency Virus 
HR 
: 
Heart Rate  
HR 
: 
Hazard Ratio 
I.R.I.S. 
: 
Institut de Recherches Internationales Servier 
IB 
: 
Investigator's Brochure 
ICH 
: 
International Conference on Harmonisation 
ICF 
: 
Informed Consent Form 
i.e. 
: 
id est (that is) 
IEC 
: 
Independent Ethics Committee 


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IMP 
: 
Investigational Medicinal Product: a p harmaceutical form of an active 
ingredient or placebo being tested or used as a reference in a clinical trial (test 
drug / reference product)  
INR 
: 
International Normalized Ration 
IRB 
: 
Institutional Review Board 
IWRS 
: 
Interactive Web Response System 
IUD 
: 
IntraUterine (contraceptive) Device 
IV 
: 
IntraVenous (route) 
IWRS 
: 
Interactive Web Response System 
KRAS 
 
V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog 
kg 
: 
kilogram 
L 
: 
Litre 
LDH 
: 
Lactate DeHydrogenase 
mCRC 
: 
Metastatic Colorectal Cancer 
MedDRA 
: 
Medical Dictionary for Regulatory Activities 
mg 
: 
milligram 
min 
: 
minute 
mL 
: 
Millilitre 
mm 
: 
Millimetre 
MRI 
: 
Magnetic Resonance Imaging 
NA 
: 
Not Applicable 
NCI 
: 
National Cancer Institute 
NCI-CTCAE 
: 
National Cancer Institute Common Toxicity Criteria for Adverse Event 
NCCN 
: 
National Comprehensive Cancer Network 
NE 
: 
Not Evaluated 
ng 
: 
nanogram 
NIS 
: 
Non Included Set 
NYHA 
: 
New York Heart Association 
ORR 
: 
Overall Response Rate 
OS 
: 
Overall Survival 
pm  
: 
post meridiem 
PD 
: 
Progressive Disease 
PET 
: 
Positron Emission Tomography 
PFS 
: 
Progression-Free Survival 
PPS 
: 
Per Protocol Set 
PR 
: 
Prothrombine Ratio 
QoL 
: 
Quality of Life 
QLQ 
: 
Quality of Life Questionnaire 
QLS 
: 
Quality of Life Set 
QTc 
: 
QT interval corrected for heart rate 
RBC 
: 
Red Blood Cells 
RECIST 
: 
Response Evaluation Criteria in Solid Tumours 
RS 
: 
Randomised Set 
RTV 
: 
Relative Tumour Volume 
SAE 
: 
Serious Adverse Event 
SAP 
: 
Statistical Analysis Plan 
SD 
: 
Standard Deviation   
SD 
: 
Stable Disease 
SE 
: 
Standard Error 
SI 
: 
International System 
SmPC 
: 
Summary of Product Characteristics 
SS 
: 
Safety Set 
test drug 
: 
Drug substance in a given dosage form, tested in a clinical trial. It usually 
corresponds to the Servier S 95005  
TP 
: 
Thymidine Phosphorylase 
TPI 
: 
Tipiracil Hydrochloride 
TR 
: 
Tumour Response 
TS 
: 
Thymidilate Synthase 
TU 
: 
Therapeutic Units 
ULN 
: 
Upper Limit of reference range 


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VEGF 
: 
Vascular Endothelial Growth Factor 
vs 
: 
versus 
WBC 
: 
White Blood Cells 
WHO 
: 
World Health Organization 
WHO-DD  
: 
World Health Organization, Drug Dictionary 


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1. ADMINISTRATIVE STRUCTURE OF THE STUDY 
This section is described in a separate document entitled “Administrative part of clinical study 
protocol”. 
This document, attached to the protocol, describes the following: 
­ Non sponsor parties; 
­ Sponsor parties;  
­ CRO responsible for local management of the study. 
The list of investigators for each country is given in separate documents attached to the 
protocol and entitled “Investigators list for [name of the country]”.  
The composition and role of the supervisory committees are described in sections 8.4.4 and 
12.4. 
 


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2. BACKGROUND INFORMATION 
2.1. Overview of disease pathogenesis, epidemiology and current treatment 
In 2012, there were 447 000 new cases of colorectal cancer (CRC) in Europe. CRC is the 
second most frequent cancer and represents 13.2% and 12.7% of all cancer cases in men and 
women, respectively. CRC was responsible for 215 000 deaths in Europe in 2012 (Ferlay J et 
al., 2013). This represents 11.6% and 13.0% of all cancer deaths in men and women, 
respectively (National Comprehensive Cancer Network (NCCN), Colon Cancer-Version 3.  
2015; National Comprehensive Cancer Network (NCCN), Rectal Cancer-Version 3. 2015). 
Approximately 25% of patients present with metastases at initial diagnosis and almost 50% of 
patients with CRC will develop metastases, contributing to the high mortality rates reported 
for CRC. The CRC-related 5-year survival rate approaches 60%. 
The treatment of mCRC is dependent upon many factors including the disease stage at 
presentation and the extent of metastatic spread.  For most patients with mCRC, the treatment 
intent is palliative rather than curative.  F or a small proportion of patients with resectable 
metastasis, surgery is the treatment option of choice.  In patients with unresectable disease, 
chemotherapy is the mainstay of treatment.  
First-line treatment options in patients with unresectable mCRC depend on w hether the 
patient is appropriate for intensive therapy. Current European Society for Medical Oncology 
(ESMO) (Van Cutsem E et al., 2014) guidelines define a subpopulation of patients who are 
without major symptoms or risk of rapid deterioration, and with low tolerance for aggressive 
therapies.  For these patients, the primary aim of therapy is prevention of tumour progression 
with prolongation of survival and maintenance of quality of life.   
Among patients with mCRC who are non-eligible for intensive therapy, recent ESMO and 
National Comprehensive Cancer Network (NCCN) (Van Cutsem E et al., 2014; National 
Comprehensive Cancer Network (NCCN), Colon Cancer-Version 3. 2015; National 
Comprehensive Cancer Network (NCCN), Rectal Cancer-Version 3. 2015) guidelines 
recommend fluorouracil or capecitabine with or without bevacizumab as first-line treatment.  
2.2. Mechanism of action of S 95005 
S 95005, also known as TAS-102, is a combination of an antineoplastic thymidine-based 
nucleoside analogue (trifluridine [FTD]) and a thymidine phosphorylase inhibitor (tipiracil 
hydrochloride [TPI]). It is marketed in Japan and USA since May 2014 and September 2015 
respectively. It has a marketing authorisation in the European Union since 25 April 2016 for 
the treatment of patients with metastatic colorectal cancer who have been previously treated 
with or are not considered candidates for, available therapies including fluoropyrimidine-, 
oxaliplatin- and irinotecan-based chemotherapies, anti-VEGF agents, and anti EGFR agents 
and currently being developed by Taiho and Institut de Recherches Internationales Servier. 
Following uptake into cancer cells, FTD is phosphorylated by thymidine kinase, further 
metabolized in cells to a deoxyribonucleic acid (DNA) substrate, and incorporated directly 
into DNA, thereby interfering with DNA function to prevent cell proliferation. When orally 
administered, FTD is rapidly degraded to an inactive form by thymidine phosphorylase (TP). 
Co-administration of TPI, an inhibitor of TP, with FTD prevents the rapid degradation of 
FTD, resulting in a significant increase in systemic exposure to FTD. 
FTD incorporation into DNA is markedly higher than that of other nucleoside analogues. The 
degree of incorporation of FTD into DNA ranges from approximately 10-fold up to 700-fold 
greater in comparison with that of 2’-deoxy-5-fluorouridine (FdUrd). FTD also exhibits 


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thymidylate synthase (TS) inhibition. However, results of in vivo studies show FTD 
incorporation into DNA to be the primary mechanism of antitumor activity with oral 
administration. 
This mechanism of action of S 95005 differentiates it from conventional fluoropyrimidines, 
which are uracil-based, and for which the primary mode of action is TS inhibition.  In 
nonclinical studies, S 95005 demonstrated antitumor activity against both 5-fluorouracil 
(5-FU) sensitive and resistant colorectal cancer cell lines. 
Detailed information on the nonclinical and clinical experience with S 95005 is provided in 
the Investigator’s Brochure (IB). 
2.3. S 95005 in Refractory Metastatic Colorectal Cancer (mCRC): Summary of clinical 
data 
2.3.1. Clinical efficacy 
In a Phase 3, multinational, randomized, double-blind study (RECOURSE; TPUI-TAS-102-
301) (Mayer JR et al., 2015) , the efficacy and safety of TAS-102 (35 mg/m2 twice daily 
[BID] for 5 days a week followed by 2 days of rest; for 2 weeks, followed by a 14-day rest, 
repeated every 4 weeks) plus best supportive care (BSC) was compared to placebo plus BSC 
in patients with histologically or cytologically confirmed metastatic colorectal cancer, who 
had received prior treatment with, or were not candidates for fluoropyrimidine-, oxaliplatin- 
and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and an anti-EGFR 
therapy. The primary efficacy endpoint was overall survival (OS), and the supportive 
secondary endpoint was progression-free survival (PFS). 
A total of 800 patients were randomized (2:1) to receive TAS-102 (n=534) or placebo 
(n=266) at a total of 101 study sites in 13 countries.  Patients were stratified by KRAS status 
(wild type, mutant); time since diagnosis of first metastasis (<18 months, ≥18 months); and 
region (Region 1: Asia [Japan]; Region 2: Western [United States, European Union and 
Australia]). 
The median OS was 7.1 months for the S 95005 group versus 5.3 m onths for the placebo 
group with a hazard ratio (HR) of 0.68 (95% confidence interval [CI]: 0.58, 0.81; p<0.0001).  
Results for PFS supported the OS results with a statistically significant improvement for 
TAS-102 compared to placebo (HR=0.48, 95% CI: 0.41, 0.57, p< 0.0001); median PFS was 
2.0 months for the TAS-102 group versus 1.7 months for the placebo group.   
In general, results for OS consistently favoured TAS-102 across the stratification groups 
(KRAS status, time since diagnosis of 1st metastasis, and geographic region) and other pre-
specified subgroups including age (<65 vs ≥65 years) and Eastern Cooperative Oncology 
Group (ECOG) performance status (0 vs 1).  A mong all randomized patients, 60.6% had 
received a fluoropyrimidine-containing regimen as their last regimen prior to randomisation, 
and 93.8% of those patients were refractory to fluoropyrimidine.  A mong these refractory 
patients, risk reduction in OS with TAS-102 remained favourable and statistically significant 
(HR=0.75).   
Among the population evaluable for tumour response (502, TAS-102; 258, placebo) there was 
no difference between the treatment groups with respect to overall response rate (ORR) (8 
patients with partial response in the TAS-102 group; 1 patient with complete response in the 
placebo group).  H owever, there was a substantial difference in the percentage of patients 
with best overall response of stable disease (42.4%, S 95005; 15.9%, placebo) leading to a 
significant difference in disease control rate (DCR) between the TAS-102 and placebo groups 
(27.7%, 95% CI: [21.5, 34.0]; p<0.0001).   


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In addition, a statistically significant 34% risk reduction in worsening ECOG performance 
status (time to ECOG performance status ≥2) was observed for TAS-102 compared to 
placebo, suggesting that quality of life was maintained while on TAS-102 treatment. 
This phase 3 study was the basis for the recent registration of the product in USA in 
September 2015 and in EU in April 2016 for the treatment of patients with metastatic 
colorectal cancer who have been previously treated with or are not considered candidates for, 
available 
therapies 
including 
fluoropyrimidine-, 
oxaliplatin- 
and 
irinotecan-based 
chemotherapies, anti-VEGF agents, and anti EGFR agents (ref: FDA label information of 
Lonsurf, 22 sept 2015 and EU product information of Lonsurf, 25 April 2016). 
 
2.3.2. Clinical safety and tolerability 
In the RECOURSE study, the most common adverse events (AEs) associated with TAS-102 
treatment were myelosuppressive and gastrointestinal toxicities. Among the 533 patients who 
received TAS-102, 38% had neutropenia of grade 3 or higher, 4% had febrile neutropenia and 
18% experienced anaemia of grade 3 or higher. These events were generally manageable with 
reductions in dose, delays in cycle initiation and occasional use of granulocyte colony-
stimulating factor (G-CSF) (Aapro MS et al., 2011). Only 3 patients discontinued treatment 
due to hematologic AEs, and there was one treatment-related death due to neutropenia-related 
infection. Events of nausea, decreased appetite, diarrhoea and vomiting related to treatment 
were common in the TAS-102 group (20.1% to 39.4%); however, these AEs were rarely 
Grade 3 or 4. The incidence of stomatitis among patients receiving TAS-102 was 7.9%; Grade 
3/4 events of stomatitis were rare (0.4%). In addition, hand-foot syndrome was reported in 
only 2.3% of patients receiving TAS-102 (all Grade 1 or 2), which was the same percentage 
reported in the placebo arm. 
2.4. Rationale for Study and selection of dose 
As mentioned in section 2.1, among patients with mCRC who are non-eligible for intensive 
therapy, recent ESMO and NCCN (Van Cutsem E et al., 2014; National Comprehensive 
Cancer Network (NCCN), Colon Cancer-Version 3. 2015; National Comprehensive Cancer 
Network (NCCN), Rectal Cancer-Version 3. 2015)  guidelines recommend fluorouracil or 
capecitabine with or without bevacizumab as f irst-line treatment. In a Phase 3 s tudy of 
patients with unresectable mCRC considered suitable for first-line treatment with capecitabine 
monotherapy, the combination of capecitabine and bevacizumab resulted in a significant 
prolongation of PFS (primary endpoint) compared to capecitabine alone (median PFS of 8.5 
months versus 5.7 months; HR=0.63 [95%CI: 0.50, 0.79], p<0.001) (Tebbutt NC et al., 2010). 
The addition of mitomycin to the combination regimen did not result in any further increase in 
PFS. There was no significant difference in median OS between groups. The most common 
Grade 3 or  4 t oxicities were hand-foot syndrome (16% in capecitabine arm; 26% in 
capecitabine+bevacizumab arm; 28% in capecitabine+bevacizumab+mitomycin arm) and 
diarrhoea (11% in capecitabine arm; 17% in capecitabine+bevacizumab arm; 16% in 
capecitabine+bevacizumab+mitomycin arm).  
Moreover, a subgroup analysis of this trial has been made to investigate whether age affected 
the improved outcome found in mCRC when bevacizumab is added to capecitabine 
chemotherapy (Price TJ et al., 2012). The addition of bevacizumab significantly improved 
PFS in geriatric patients (5.8 months in capecitabine arm versus 8.8 months in capecitabine + 
bevacizumab arm). Treatment was well tolerated with no signal of increased toxicity 
(including thromboembolism) when compared with those aged <75 years. 


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In a Phase 3 study of elderly patients (≥70 years) with previously untreated mCRC, the 
combination of bevacizumab and capecitabine was well tolerated and resulted in a significant 
increase in PFS (primary endpoint) compared to capecitabine alone (median PFS of 9.1 
months vs 5.1 months; HR=0.53 [95% CI: 0.41, 0.69], p<0.0001) (Cunningham D et al., 
2013). There was no significant difference in OS.  I n this study, the frequency of 
chemotherapy-related Grade ≥3 events was similar for the two treatment groups except for 
hand-foot syndrome, which was more frequent in the combination therapy group.   
This exploratory study will be performed to evaluate S 95005 + bevacizumab (experimental 
arm) and capecitabine + bevacizumab (control arm) as first-line treatment for unresectable 
metastatic colorectal cancer in patients non-eligible for intensive therapy. Metastatic 
colorectal cancer is mainly a disease of elderly patients and the diagnosis of colorectal cancer 
is about 69 years (median), however there is also a population younger which present decline 
organ function and comorbidities at diagnosis. Such patients are often excluded from 
randomised trials or are difficult to treat. 
2.4.1. S 95005 in combination with bevacizumab-Non-clinical data  
The antitumor effects of TAS-102 in combination with bevacizumab were assessed using a 
nude mouse xenograft model of colorectal cancer (Tsukihara H et al., 2015) TAS-102 and 
bevacizumab either alone or in combination, were administered to mice bearing SW48 
(KRAS wild type cell lines) or HCT116 (KRAS mutant cell lines) colorectaltumors. TAS-102 
and bevacizumab alone inhibited tumor growth. Moreover, combined TAS-102 and 
bevacizumab treatment had superior antitumor activity compared to either drug alone, and had 
no significant effect on the body weight compared to TAS-102 monotherapy. 
Growth inhibitory activity, based on the relative tumour volume (RTV) after 2 weeks of drug 
administration and time taken for the relative tumour volume to increase five-fold (RTV5), 
was significantly better with TAS-102 and bevacizumab combination treatment than with 
either TAS-102 or bevacizumab alone in SW48 and HCT116 tumour models.  
2.4.2. S 95005 in combination with bevacizumab-Clinical data 
Based on the demonstrated efficacy and tolerability of TAS-102 in patients with previously 
treated mCRC, including patients refractory to prior fluoropyrimidine treatment, a Phase 2 
study to evaluate the benefit of TAS-102 plus bevacizumab as first-line treatment of 
unresectable mCRC is warranted.  T he results of a P hase 1/2 study conducted in Japan 
suggest that the combination of TAS-102 and bevacizumab is well tolerated in patients with 
mCRC (Kuboki Y et al., 2015).In this study, the most common Grade ≥3 events were 
neutropenia (68%), leukopenia (40%), febrile neutropenia (16%), and hypertension (8%). 
Sixty-eight per cent (68%) of patients required a treatment delay, 24% required at least one 
dose reduction (primarily due to neutropenia), and there were no treatment-related deaths. In 
addition, as noted in section 2.3.2. above, the incidence of hand-foot syndrome among 
patients treated with TAS-102 is lower than that commonly observed with fluoropyrimidines 
including capecitabine. Thus, TAS-102 in combination with bevacizumab may offer a more 
tolerable treatment option for patients with unresectable mCRC requiring non-intensive 
therapy. 


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2.4.3. Study design 
This present study is designed as a randomised, open-label Phase 2 study evaluating S 95005 
plus bevacizumab and capecitabine plus bevacizumab as first-line treatment of unresectable 
mCRC in patients who are non-eligible for intensive therapy.  
In this phase 2 t rial, 100 Progression Free Survival (PFS) events are required to show a 
significant difference between the two arms with a 2-sided 80% confidence interval.  
 
In this Phase 2 trial, PFS was chosen as t he primary endpoint because delaying disease 
progression (with or without tumour shrinkage) is a key treatment aim in this population of 
patients non-eligible for intensive therapy.  
 
The primary aim of the translational part of the study is to assess potential predictive 
biomarkers for S 95005 in order to identify subgroup of patients having a greater degree of 
benefit with S 95005. This biomarker program also proposes to assess potential biomarkers of 
resistance to enable a better understanding of reasons for possible progression under treatment 
(Kalia M, 2015; Coghlin C et al., 2015; Gonzales-Pons M et al., 2015). 
2.4.4. Selection of Dose Regimens 
Experimental Arm 
S 95005 (35 mg/m2/dose) will be administered orally BID, within 1 hour after completion of 
morning and evening meals, for 5 days a week with 2 days rest for 2 weeks, followed by a 14 
day rest, with bevacizumab (5 mg/kg) administered IV every 2 weeks (Day 1 and Day 15). 
This treatment cycle will be repeated every 4 weeks.  
The safety and tolerability of a TAS-102 regimen of 35 mg/m²/dose BID for 5 days with 2 
days rest for 2 weeks, repeated every 28 days has been demonstrated in patients with mCRC. 
A bevacizumab regimen of 5 mg/kg every 2 weeks is a r ecommended dose for use in 
combination with fluoropyrimidine-based regimens for treatment of metastatic mCRC. In a 
Japanese Phase 1/2 study, this combination regimen of TAS-102 plus bevacizumab was well 
tolerated in patients with unresectable mCRC (Kuboki Y et al., 2015).  
 
Control Arm 
Capecitabine (1250 mg/m2) will be administered orally BID on Days 1–14 of each cycle, with 
IV bevacizumab (7.5 mg/kg) administered on Day 1 of each cycle. This treatment cycle will 
be repeated every 3 weeks.  
 
According to local clinical practice the starting dose of capecitabine could be reduced to 1000 
mg/m². This regimen capecitabine at a dose of 1000 mg/m² plus bevacizumab at 7.5 mg/kg 
was shown to be effective and well-tolerated as demonstrated in the Avex study (Cunningham 
D et al., 2013) (survival and progression free survival are similar to general population) and 
the subgroup analysis of the AGITG MAX trial (Price TJ et al., 2012). 
 
The study will be conducted in compliance with the protocol, Good Clinical Practice (GCP) 
and the applicable regulatory requirements.  
 


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3. STUDY OBJECTIVES AND PURPOSE 
The objectives of this study are to evaluate the following endpoints in patients receiving 
S 95005 + bevacizumab (experimental arm) or capecitabine + bevacizumab (control arm) as 
first-line treatment for unresectable metastatic colorectal cancer in patients non-eligible for 
intensive therapy. 
3.1. Primary objectives 
­ Progression-free survival (PFS) based on Investigator assessment of radiologic images 
3.2. Secondary objectives 
­ Overall response rate (ORR) 
­ Duration of response (DR) 
­ Disease control rate (DCR) 
­ Overall survival (OS)  
­ Safety and tolerability 
­ Quality of Life (QoL) (EORTC QLQ-C30, QLQ-CR29) (Aaronson NK et al., 1993; 
Appendix 1). 
3.3. Exploratory objectives 
­ Evaluate the biomarkers potentially predictive of response and resistance to S 95005 given 
in combination using blood samples and archived tumour biopsy (if available). 


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4. STUDY DESIGN 
This present study is designed as a randomised, open-label phase 2 study evaluating S 95005 
plus bevacizumab and capecitabine plus bevacizumab as first-line treatment of unresectable 
mCRC in patients who are non-eligible for intensive therapy.  
In this phase 2 t rial, 100 Progression Free Survival (PFS) events are required to show a 
significant difference between the two arms. In order to observe this number of events, 
approximately 150 pa tients will be randomised 1:1 to S 95005 plus bevacizumab 
(experimental arm) or capecitabine plus bevacizumab (control arm).  
Patients will be randomised with the minimisation procedure proposed by Pocock and Simon 
(Pocock SJ et al., 1975). The stratification factors will be RAS status (wild-type, mutant 
type), ECOG performance status (0 vs. 1 vs. 2) (Appendix 2) and country. 
 
PFS was chosen as the primary endpoint because delaying disease progression (with or 
without tumour shrinkage) is a key treatment aim in this population of patients eligible for 
non-intensive therapy. 
4.1. Endpoints  
4.1.1. Primary endpoint  
­ Progression free survival (PFS) is defined as the time from the date of randomisation until 
the date of the investigator-assessed radiological disease progression or death due to any 
cause according to RECIST 1.1 (Eisenhauer EA et al., 2009; Appendix 3). 
4.1.2. Secondary endpoints 
­ Overall Response Rate (ORR). The assessment of ORR will be based on Investigator 
review of the images according to RECIST 1.1 (Eisenhauer EA et al., 2009; Appendix 3). 
­ Duration of Response (DR) is derived for those patients with objective evidence of PR or 
CR. 
­ Disease control rate (DCR) 
­ Overall Survival 
­ Safety and tolerability assessed by: 
 Incidence of Adverse Events (AE). 
 Laboratory tests: haematology, blood biochemistry, coagulation, urinalysis. 
 Physical examination and performance status (ECOG). 
 Vital signs: blood pressure (BP), heart rate (HR), body t emperature, respiration rate, 
body weight. 
 12-leads ECG parameters. 
­ Quality Of Life assessed by a quality of life questionnaire (QLQ) (Aaronson NK et al., 
1993; Appendix 1). 
4.1.3. Exploratory endpoints 
­ Biomarkers using blood samples and archived tumour biopsy (if available). 


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4.2. Experimental design 
4.2.1. Study plan 
This is a multinational, open-label, two-arm, randomised phase 2 study evaluating S 95005 + 
bevacizumab and capecitabine + bevacizumab in the first-line treatment of patients with 
previously untreated unresectable mCRC who are non-eligible for intensive therapy. 
 
The study will be divided into the following periods for each patient: 
• Screening period and Inclusion (up to 28 days prior to randomisation): to obtain 
informed consent and to check the eligibility of the patient to be included and 
randomised in the study.  
Note: for the first patient in a centre, a period of at least 7 days is required between 
first connection to Interactive Web Response System (IWRS) during screening period 
(after ICF signature) and first day of study drug administration (Day 1 of Cycle 1) for 
logistical reasons (bevacizumab supply).  
• Randomisation: Included patients will be randomly assigned to one of the two 
treatment groups: 
 S 95005 + bevacizumab: S 95005 (35 mg/m2/dose) will be administered orally 
BID, within 1 hour after completion of morning and evening meals, for 5 days 
on/2 days off, for 2 weeks, followed by a  14-day rest, with bevacizumab 
(5 mg/kg) administered IV every 2 weeks (Day 1 and Day 15). This treatment 
cycle will be repeated every 4 weeks.  
 Capecitabine + bevacizumab: Capecitabine (1250 mg/m2) will be administered 
orally BID on Days 1–14 of each cycle, with IV bevacizumab (7.5 mg/kg) 
administered on Day 1 of each cycle. This treatment cycle will be repeated 
every 3 weeks. 
Note: According to local clinical practice the starting dose of capecitabine could be 
reduced to 1000 mg/m² but could not be lower. 
• Treatment period: Randomised patients should receive the first dose of study 
treatment (Day 1 of Cycle 1) no later than 3 days after randomisation. Each patient 
should receive at least 28 days of combination of S 95005+ bevacizumab or at least 21 
days of combination of capecitabine + bevacizumab except in case of safety concerns. 
Patients will be treated by the assigned combined regimen until they meet a 
discontinuation criterion as described in section 5.4.1. Patients will be considered to be 
on treatment as long as either component of the combination regimen continues to be 
administered unless the investigator judges that it is in the interest of the patient to 
withdraw from the study and to be treated outside of this protocol with a combine 
modality. The estimated PFS is 11.7 months in the S 95005 + bevacizumab group and 
9 months in the capecitabine + bevacizumab group (please refer to section 10 for more 
details). 
• Withdrawal visit: up to 4 weeks after the last dose of study drug administration. 
• Follow-up period: to obtain tumour assessment (every 8 weeks until disease 
progression or initiation of new anticancer therapy), patient survival data (date of 
death), and new anticancer treatments. During this period, the patient will be allowed 
to participate in a new clinical study or receive a new  
 
The study plan of both arms is shown in Figure (4.2.1) 1 and Figure (4.2.1) 2. 


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Figure (4.2.1) 1 - Study plan of S 95005 + bevacizumab arm 
 
 
Figure (4.2.1) 2 - Study plan of capecitabine + bevacizumab arm 
 


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4.2.2. Study duration 
Patients will be treated by the assigned combined regimen until they meet a discontinuation 
criterion as described in section 5.4.1. Patients will be considered to be on treatment as long 
as either component of the combination regimen continues to be administered unless the 
investigator judges that it is in the interest of the patient to withdraw from the study and to be 
treated outside of this protocol with a combine modality. 
After study drugs discontinuation: 
­ If a p atient discontinues study treatment for reasons other than radiologic disease 
progression (e.g., intolerable side effects), patients will be followed for tumour response 
until radiologic disease progression or initiation of new anticancer therapy (whichever 
occurs first).  
­ After progression, patient will be followed for survival status until the end of the study.  
The end of the study is defined as the last visit of the last patient. 
The selection will be stopped once 100 PFS events (progression of disease [PD] or death) are 
reached or 150 patients are randomised (whichever occurs first) and the on-going patients will 
continue the study without change until the end of the study.  
End of clinical study: 
­ The planned main study analysis will be performed after 100 PFS events are observed, 
leading to the release of the primary clinical study report. 
­ The end of clinical study is planned 12 months after the follow-up start date of the last 
patient withdrawn, leading to the release of the final statistical analysis and the final 
clinical study report. 
4.2.3. Replacement of patients 
No patients will be replaced at any time during this study. 
4.2.4. Discontinuation of study treatments 
For both treatment arms (experimental and control arm), treatment with either component of 
the combination regimen may continue after discontinuation of the other component unless 
the investigator judges that it is in the interest of the patient to withdraw from the study and to 
be treated outside of this protocol with a combine modality. Patients will be considered on 
treatment as long as either component of the combination regimen continues to be 
administered. 
A patient is considered discontinued from study treatment when the decision to permanently 
stop both components of the treatment regimen is made, including those decisions made 
during study medication interruptions and recovery periods.   
Study medication should be continued whenever possible. In case study medication is 
stopped, it should be determined if the stop can be made temporarily; permanent study 
medication discontinuation should be a last resort.  A ny study medication discontinuation 
should be fully documented. In any case, the patient should remain in the study as long as 
possible. 


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4.2.5. Investigation schedule 
Table (4.2.5) 1 and Table (4.2.5) 2 describe the measurement of safety and activity, assessed 
during the study. More details regarding methods and time-points are provided in section 
4.2.6. 
The results of all investigations / tests performed before inclusion visit must be available for 
patient’s visit and prior to the first study drug administration.  
During the course of the study, the results of all investigations / tests should be available at 
the time of the visit. 
Note: a window of +/- 3 days is allowed for study procedures and +/- 7 days for tumour 
assessment, as long as the proper order is maintained. 


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Table (4.2.5) 1 - Investigation schedule of S 95005 + bevacizumab arm 
Procedure 
Screening period/Inclusion 
On-Treatment period 
Withdrawal 
visit 
Follow-up period 
CYCLE 1 (28 days) 
SUBSEQUENT CYCLES (28 days) 
Day of Cycle17 
Day of Cycle17 
Every 
8 Weeks 
Every 
12 Weeks 
≤ 28 days prior 
randomisation 
≤ 5 days prior 
randomisation 
1/Randomisation 
15 
1 
15 
Sign ICF 
X1 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
Histological Confirmation 
X 
 
 
 
 
 
 
 
 
 
Previous surgery, radiotherapy and treatments  
X 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
X 
 
Inclusion/Non-inclusion criteria 
X 
 
 
 
 
 
 
 
 
 
Pregnancy Testing 
 
X2 
 
 
X3 
 
 
 
X3 
 
IWRS4 
 
 
 
 
 
 
 
 
 
 
Patient number 
X 
 
 
 
 
 
 
 
 
 
Randomisation5 
 
 
X 
 
 
 
 
 
 
 
Dispense S 950056 
 
 
X 
 
X 
 
 
 
 
 
Administer IV Bevacizumab6 
 
 
X 
X 
X 
X 
 
 
 
 
Efficacy measurements 
 
 
 
 
 
 
 
 
 
 
Tumour Measurements7 
X7 
 
 
 
 
 
X7 
 
X7 
X7 
CEA dosage 
 
X 
 
 
 
 
X8 
 
X8 
 
Survival Status 
 
 
 
 
 
 
 
 
 
X9 
Safety measurements 
 
 
 
 
 
 
 
 
 
 
Baseline Signs & Symptoms 
 
X 
 
 
 
 
 
 
 
 
Physical Examination 
 
X 
X10 
 
X11 
 
 
 
X 
 
ECOG Performance Status12 
 
X 
X 
 
X 
 
 
 
X 
 
Height 
 
X 
 
 
 
 
 
 
 
 
Vital Signs & Weight 
 
X 
X10 
X 
X11 
X 
 
 
X 
 
Haematology 
 
X 
X10 
X 
X11 
X 
 
 
X 
 
Coagulation 
 
X 
X10 
 
X11 
 
 
 
X 
 
Biochemistry 
 
X 
X10 
X 
X11 
 
 
 
X 
 
Urinalysis 
 
X 
X10 
X 
X11 
 
 
 
X 
 
Concomitant treatments 
X 
 
 
 
 
 
 
 
X 
X13 
AE Assessment14 
X 
 
 
 
 
 
 
 
X 
X 
Biomarkers assessment 
 
 
 
 
 
 
 
 
 
 
RAS/BRAF status15 
X 
 
 
 
 
 
 
 
 
 
Archived tumour biopsy (if available)  
 
 
X18 
 
 
 
 
 
 
 
Blood samples  
 
 
X19 
 
 
 
 
 
X 
 
Quality of Life Assessment 
 
X 
 
 
 
 
 
X16 
X16 
 
 Table (4.2.5) 1 (Cont'd) - Investigation schedule of S 95005 + bevacizumab arm 
 


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1. Sign Informed Consent Form (ICF): Written informed consent must be obtained prior to the performance of any study procedure. 
2. Pregnancy Testing at screening period: performed within 5 days prior to randomisation only with serum βHCG test.  
3. Pregnancy Testing from randomisation: performed from C2, within 48 h prior to Day 1, to withdrawal visit (only if not performed within the previous 4 weeks) with serum βHCG or highly sensitive urine test. 
4. IWRS: Once patient has signed ICF, connection to the IWRS for patient’s registration and e-CRF patient number (see the IWRS manual for details). 
5. Randomisation: Central randomisation via IWRS following confirmation of baseline eligibility criteria. Study medication should begin within 3 days after randomisation. 
6. Study Medication: Patients should receive the first dose of S 95005 (Day 1 of Cycle 1) within 3 days of randomisation. A connection to the IWRS should be performed to know the allocated kit number(s) to be 
dispensed to the patient. Bevacizumab will be provided by the Sponsor. Bevacizumab 5 mg/kg should be administered via IV infusion on Day 1 and Day 15 of each cycle following bevacizumab SmPC.  
NOTE: treatment with either component of the combination regimen may continue after discontinuation of the other component according to investigator judgment. 
7. Tumour Measurements: Obtain imaging based evaluation of the chest, abdomen, and pelvis (as clinically indicated) and clinical examination within 28 days prior to Day 1 of Cycle 1 and every 8 weeks 
thereafter. Images obtained prior to patient signed ICF may be used if the date of the images is within 28 days of randomisation.  
For patients who discontinue treatment for reasons other than radiologic disease progression, obtain tumour measurements within 8 weeks after the last previous tumour assessment. Every effort should be made 
to perform the end of treatment tumour assessment prior to the start of new anticancer therapy. Tumour Measurement at withdrawal visit will be performed only if not performed within previous 8 weeks. 
During the follow-up period, perform tumour measurements every 8 weeks until documentation of radiologic disease progression or initiation of new anticancer therapy (whichever occurs first).  
Tumour assessments should be performed according to RECIST 1.1 (Eisenhauer EA et al., 2009; Appendix 3). 
8. CEA dosage: This tumour marker will be followed with a dosage every 8 weeks (aligned on tumour assessments) and at withdrawal visit. Note: RECIST 1.1 request normalisation of tumour markers to have a 
complete response. 
9. Survival Status: Obtain survival status (alive/dead) at scheduled 8-week intervals until patient death or end of the study.  
10. Assessments to be performed within 24 hours (for clinical examination and vital signs/weight) or 48 hours (for laboratory assessments) before the first study drug administration on C1D1. If the screening 
assessments are done within 24/48 hours before C1D1, they do not need to be repeated. 
11. Subsequent Cycles ≥2: Obtain within 24 hours (for clinical examination and vital signs/weight) or 48 hours (for laboratory assessments) prior to Day 1 study drug administration.  Prior to starting subsequent 
cycles, verify that patients with toxicities have met resumption criteria prior to administering study drug. 
12. ECOG Performance Status: The patient’s performance status must remain 0, 1 or 2 during the baseline period and at the time of randomisation for the patient to remain eligible. Collect within 24 hours prior to 
Day 1 study drug administration for all cycles (Appendix 2).  
13. Concomitant Medications: Collect only anticancer therapies during survival follow-up. 
14. AE Assessment: AE will be recorded from the first dose of study medication until the withdrawal visit. Any AE that occur prior to the first dose of study medication should be recorded as Medical History 
except events associated with any procedure/condition required by the study protocol: procedure (exercise test, MRI, etc.), change or withdrawal of previous/concomitant treatment relating to the conditions of 
the protocol, or a product other than the test drug, taken as part of the protocol. Up to 100 days after last study drug intake report all ERIN, regardless of the supposed role of the research and all serious adverse 
event related to the research irrespective of the time of onset after the end of the study. For AE reporting instructions please refer to section 8.4.2.4.   
15. RAS/BRAF status: RAS mutation status should be documented prior to randomisation based on local biological assessment of tumour biopsy. At least the following mutation must be determined: KRAS and 
NRAS Exon 2: codon 12 and 13. BRAF mutation status will be documented if available.  
16. Quality of Life: Patients should complete the EORTC – QLQ-C30 and QLQ-CR29 questionnaires every 12 weeks during study treatment; and at the end of treatment if not performed within the prior 8 weeks. 
17. Assessment Windows: A window of +/-3 days is allowable for study procedures (+/-7 days allowable for images), as long as the proper order is maintained.  
18. Archived biopsy: the archived biopsy can be provided within 21 days after C1D1. 
19. Blood sample for genomic and proteomic analysis: To be obtained pre-dose. 


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Table (4.2.5) 2 - Investigation schedule of capecitabine + bevacizumab arm 
Procedure 
Screening period/Inclusion 
On-Treatment period 
Withdrawal 
visit 
Follow-up 
period 
CYCLE 1 (21 days) 
SUBSEQUENT CYCLES (21 days) 
Day of Cycle17 
Day of Cycle17 
Every 
8 Weeks 
Every 
12 Weeks 
≤ 28 days  
prior randomisation 
≤ 5 days  
prior randomisation 
1/Randomisation 
15 
1 
Sign ICF 
X1 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
Histological Confirmation 
X 
 
 
 
 
 
 
 
 
Previous surgery, radiotherapy and treatments  
X 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
X 
 
Inclusion/Non-inclusion criteria 
X 
 
 
 
 
 
 
 
 
Pregnancy Testing 
 
X2 
 
 
X3 
 
 
X3 
 
IWRS4 
 
 
 
 
 
 
 
 
 
Patient number 
X 
 
 
 
 
 
 
 
 
Randomisation5 
 
 
X 
 
 
 
 
 
 
Dispense capecitabine6 
 
 
X 
 
X 
 
 
 
 
Administer IV Bevacizumab6 
 
 
X 
 
X 
 
 
 
 
Efficacy measurements 
 
 
 
 
 
 
 
 
 
Tumour Measurements7 
X7 
 
 
 
 
X7 
 
X7 
X7 
CEA dosage 
 
X 
 
 
 
X8 
 
X8 
 
Survival Status 
 
 
 
 
 
 
 
 
X9 
Safety measurements 
 
 
 
 
 
 
 
 
 
Baseline Signs & Symptoms 
 
X 
 
 
 
 
 
 
 
Physical Examination 
 
X 
X10 
 
X11 
 
 
X 
 
ECOG Performance Status12 
 
X 
X 
 
X 
 
 
X 
 
Height 
 
X 
 
 
 
 
 
 
 
Vital Signs & Weight 
 
X 
X10 
 
X11 
 
 
X 
 
Haematology 
 
X 
X10 
X 
X11 
 
 
X 
 
Coagulation 
 
X 
X10 
 
X11 
 
 
X 
 
Biochemistry 
 
X 
X10 
X 
X11 
 
 
X 
 
Urinalysis 
 
X 
X10 
X 
X11 
 
 
X 
 
Concomitant treatments 
X 
 
 
 
 
 
 
X 
X13 
AE Assessment14 
X 
 
 
 
 
 
 
X 
X 
Biomarkers assessment 
 
 
 
 
 
 
 
 
 
RAS/BRAF status15 
X 
 
 
 
 
 
 
 
 
Archived tumour biopsy (if available)  
 
 
X18 
 
 
 
 
 
 
Blood samples 
 
 
X19 
 
 
 
 
X 
 
Quality of Life Assessment 
 
X 
 
 
 
 
X16 
X16 
 
 Table (4.2.5) 2 (Cont'd) - Investigation 
 


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1. Sign Informed Consent Form (ICF): Written informed consent must be obtained prior to the performance of any study procedure. 
2. Pregnancy Testing at screening period: performed within 5 days prior to randomisation only with serum βHCG test.  
3. Pregnancy Testing from randomisation: performed from C2, within 48 h prior to Day 1, to withdrawal visit (only if not performed within the previous 4 weeks) with serum βHCG or highly sensitive urine test. 
4. IWRS: Once patient has signed ICF, connection to the IWRS for patient’s registration and e-CRF patient number (see the IWRS manual for details). 
5. Randomisation: Central randomisation via IWRS following confirmation of baseline eligibility criteria. Study medication should begin within 3 days after randomisation. 
6. Study Medication: Patients should receive the first dose of capecitabine (Day 1 of Cycle 1) within 3 days of randomisation. A connection to the IWRS should be performed to know the allocated kit number(s) 
to be dispensed to the patient. Bevacizumab will be provided by the Sponsor. Bevacizumab 7.5 mg/kg should be administered via IV infusion on Day 1 of each cycle following bevacizumab SmPC. NOTE: 
treatment with either component of the combination regimen may continue after discontinuation of the other component according to investigator judgment. 
7. Tumour Measurements: Obtain imaging based evaluation of the chest, abdomen, and pelvis (as clinically indicated) and clinical examination within 28 days prior to Day 1 of Cycle 1 and every 8 weeks 
thereafter. Images obtained prior to patient signed ICF may be used if the date of the images is within 28 days of randomisation.  
For patients who discontinue treatment for reasons other than radiologic disease progression, obtain tumour measurements within 8 weeks after the last previous tumour assessment. Every effort should be made 
to perform the end of treatment tumour assessment prior to the start of new anticancer therapy. Tumour Measurement at withdrawal visit will be performed only if not performed within previous 8 weeks. 
During the follow-up period, perform tumour measurements every 8 weeks until documentation of radiologic disease progression or initiation of new anticancer therapy (whichever occurs first).  
Tumour assessments should be performed according to RECIST 1.1 (Eisenhauer EA et al., 2009; Appendix 3). 
8. CEA dosage: This tumour marker will be followed with a dosage every 8 weeks (aligned on tumour assessments) and at withdrawal visit. Note: RECIST 1.1 request normalisation of tumour markers to have a 
complete response. 
9. Survival Status: Obtain survival status (alive/dead) at scheduled 8-week intervals until patient death or end of the study  
10. Assessments to be performed within 24 hours (for clinical examination and vital signs/weight) or 48 hours (for laboratory assessments) before the first study drug administration on C1D1. If the screening 
assessments are done within 24/48 hours before C1D1, they do not need to be repeated. 
11. Subsequent Cycles ≥2: Obtain within 24 hours (for clinical examination and vital signs/weight) or 48 hours (for laboratory assessments) prior to Day 1 study drug administration.  Prior to starting subsequent 
cycles, verify that patients with toxicities have met resumption criteria prior to administering study drug. 
12. ECOG Performance Status: The patient’s performance status must remain 0, 1 or 2 during the baseline period and at the time of randomisation for the patient to remain eligible. Collect within 24 hours prior to 
Day 1 study drug administration for all cycles (Appendix 2).  
13. Concomitant Medications: Collect only anticancer therapies during survival follow-up. 
14. AE Assessment: AE will be recorded from the first dose of study medication until the withdrawal visit. Any AE that occur prior to the first dose of study medication should be recorded as Medical History 
except events associated with any procedure/condition required by the study protocol: procedure (exercise test, MRI, etc.), change or withdrawal of previous/concomitant treatment relating to the conditions of 
the protocol, or a product other than the test drug, taken as part of the protocol. Up to 100 days after last study drug intake report all ERIN, regardless of the supposed role of the research and all serious adverse 
event related to the research irrespective of the time of onset after the end of the study. For AE reporting instructions please refer to section 8.4.2.4.   
15. RAS/BRAF status: RAS mutation status should be documented prior to randomisation based on local biological assessment of tumour biopsy. At least the following mutation must be determined: KRAS and 
NRAS Exon 2: codon 12 and 13. BRAF mutation status will be documented if available.  
16. Quality of Life: Patients should complete the EORTC – QLQ-C30 and QLQ-CR29 questionnaires every 12 weeks during study treatment; and at the end of treatment if not performed within the prior 8 weeks. 
17. Assessment Windows: A window of +/-3 days is allowable for study procedures (+/-7 days allowable for images), as long as the proper order is maintained.  
18. Archived biopsy: the archived biopsy can be provided within 21 days after C1D1 
19. Blood sample for genomic and proteomic analysis: To be obtained pre-dose.


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4.2.6. Study Assessments 
The study assessments are described by procedure in section 4.2.6.1 and by visit in section 
4.2.6.2 and also indicated in the investigation schedules (Table (4.2.5) 1 and Table (4.2.5) 2). 
All information required by the protocol must be recorded. 
 
The study schedule must be followed. However, under special conditions (e.g., holidays, 
weekends, etc.) a window of +/ 3 days is allowed for study procedures and +/- 7 days for 
tumour assessment, as long as the proper order is maintained.   
During the screening period (up to 28 days prior to randomisation), these windows are not 
applicable except for tumour assessment.   
 
Any significant abnormality detected during safety assessments will need to be reported 
as an adverse event. 
The safety assessments will include: 
­ Record of adverse events and toxicity according to the National Cancer Institute Common 
Toxicity Criteria for Adverse Event (NCI-CTCAE) version v4.03 Jun 14, 2010.  
­ Physical examination, ECOG performance status (Appendix 2). 
­ ECG measurement. 
­ Vital signs measurements. 
­ Biological tests: haematology, blood biochemistry, coagulation, urinalysis. 
 
Abnormal laboratory values or test results will constitute an Adverse Event if they are : 
­ associated with signs and symptoms, or  
­ clinically significant in the investigators’opinion, or  
­ if they requires curative therapies. 
The intensity of all AEs will be graded according to NCI-CTCAE, V4.03 on a five-point scale 
(Grade 1 to 5). 
4.2.6.1. 
All Study Procedures 
4.2.6.1.1. 
Informed consent 
Obtain signed and dated Informed Consent Form (ICF) from the patient prior to the 
implementation of study procedures required by the protocol. An original copy of the signed 
and dated ICF should be given to the patient. 
4.2.6.1.2. 
Patient Numbering 
Once the patient has signed ICF, the centre will connect to the Interactive Web Response 
System (IWRS) for patient’s registration and e-CRF patient number during the screening 
period (see the IWRS manual for details). Each patient will be assigned a u nique patient 
number. This patient number will be maintained throughout the study and will not be 
reassigned. Patients who withdraw consent or discontinue from the study after being assigned 
a patient number will retain their initial number. 


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4.2.6.1.3. 
Histological/Cytological Confirmation 
Histological or cytological confirmation of adenocarcinoma of the colon or rectum should be 
documented in the patient’s source documents within 28 days prior to randomisation. The 
pathology report should be available in the patient’s source documents. 
4.2.6.1.4. 
RAS/BRAF status 
RAS mutation status based on local tumour biopsy assessment should be documented in the 
patient’s source documents within 28 days prior to randomisation. At least the following 
mutation must be determined: KRAS and NRAS Exon 2: codon 12 and 13. 
BRAF status will be documented in the eCRF if available.  
4.2.6.1.5. 
Demography 
Collect demography data within 28 days prior to randomisation. 
4.2.6.1.6. 
Medical history 
Obtain full relevant medical history within 28 days prior to randomisation.  
Any AE/SAEs that occur prior to the start of study drug administration should be reported as 
medical history, except for any event associated with any procedure/condition required by the 
study protocol which must be reported in the AE form (see section 8.4.2.1).  
4.2.6.1.7. 
Previous surgery, radiotherapy and treatments related to the studied 
disease 
Collect previous surgery, radiotherapy and treatments related to the studied disease within 28 
days prior to randomisation. 
4.2.6.1.8. 
Baseline Signs and Symptoms 
Signs and symptoms present following ICF signature and within 5 da ys prior to 
randomisation should be recorded in the patient’s source documents. 
4.2.6.1.9. 
Physical Examination 
Perform a complete physical examination at the time points listed below: 
• Within 5 days prior to randomisation. 
• At pre-dose of C1D1 only if there is more than 24 hours since screening period. 
• Beginning with Cycle 2, obtain within 24 hours prior to start of study treatment in 
every cycle. 
• Withdrawal visit. 
4.2.6.1.10. 
Electrocardiogram (ECG) 
Perform a 12-lead resting ECG at the time points listed below. Patients should be in a supine 
position for at least 10 min before recording.   
• Within 28 days prior to randomisation. 
• Withdrawal visit. 


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4.2.6.1.11. 
Height, Vital Signs, Weight 
Obtain the patient’s height within 5 days prior to randomisation. 
Collect the patient’s vital signs (BP, HR, body temperature and respiration rate) and body 
weight at the time points listed below. Obtain all the vital signs in a position that is consistent 
for all time points for each patient. 
• Within 5 days prior to randomisation. 
• At pre-dose of C1D1 only if there is more than 24 hours since screening period and 
C1D15. 
• Beginning with Cycle 2, obtain within 24 hours prior to start of study treatment in 
every cycle. 
• At CxD15 (experimental arm only). 
• Withdrawal visit. 
 
Blood pressure should be measured with the patient in supine position. When measuring 
blood pressure, particular care should be taken to: 
­ take measurements after at least 5 minutes rest;  
­ use a cuff appropriate to arm width; 
­ place the cuff at heart level. 
4.2.6.1.12. 
ECOG Performance Status 
Obtain an ECOG performance status score (Appendix 2) at the following time points:  
• Within 5 days prior to randomisation. 
• At pre-dose of C1D1 only if there is more than 24 hours since screening period. 
• Beginning with Cycle 2, obtain within 24 hours prior to start of study treatment in 
every cycle. 
• Withdrawal visit. 
4.2.6.1.13. 
Clinical Laboratory Evaluations 
All laboratory tests performed during patient’s visit (D1) will be assayed in identified 
laboratory at hospital. Inter visits laboratory tests (D15 or unscheduled tests) could be assayed 
by local laboratories.  
In all cases, the full validated set of normal ranges values will be collected, as well as any 
update in these values during the study and must be documented on the corresponding page of 
the e-CRF. 
All samplings for biochemistry should be taken in fasting conditions. 
It's preferable for all biochemistry blood samplings to be taken in fasting conditions except if 
the patient’s general health status does not permit it. 
 


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4.2.6.1.13.1. Haematology 
Collect sample for haematological assessments at the following time points and when 
clinically indicated: 
• Within 5 days prior to randomisation. 
• At pre-dose of C1D1 only if there is more than 48 hours since screening period. 
• On Day 15 of Cycle 1 in the control arm and at Day 15 of each cycle in the 
experimental arm. 
• For all subsequent cycles, obtain within 48 hours prior to Day 1 study treatment of 
each cycle. 
• Withdrawal visit. 
In addition, follow the criteria for repeat testing listed in section 8.2.1.2 as needed. 
 
Measure the following haematology parameters: haemoglobin, haematocrit, Red Blood Cell 
(RBC) count, White Blood Cell (WBC) count and differential count (neutrophils, 
lymphocytes, monocytes, eosinophils, basophils), platelets. 
4.2.6.1.13.2. Biochemistry 
Collect sample at the following time points for biochemistry assessments: 
• Within 5 days prior to randomisation. 
• At pre-dose of C1D1 only if there is more than 48 hours since screening period. 
• On Day 15 of Cycle 1. 
• For all subsequent cycles, obtain within 48 hours prior to Day 1 study treatment of 
each cycle. 
• Withdrawal visit. 
In addition, follow the criteria for repeat testing listed in section 8.2.1.2 as needed. 
 
Measure the following serum chemistry parameters: albumin, ionogram (Na, K, Cl, Ca, Mg, 
bicarbonate [optional], phosphate), Blood urea nitrogen (BUN), creatinine clearance, total 
proteins, glucose, ASAT, ALAT, GGT, Alkaline phosphatase, total bilirubin (in case of 
elevation in total bilirubin, fractionation (direct/indirect) should be performed), LDH. 
4.2.6.1.13.3. Coagulation  
Collect sample at the following time points for coagulation: 
• Within 5 days prior to randomisation. 
• At pre-dose of C1D1 only if there is more than 48 hours since screening period. 
• For all subsequent cycles, obtain within 48 hours prior to Day 1 study treatment of 
each cycle. 
• Withdrawal visit. 
In addition, follow the criteria for repeat testing listed in section 8.2.1.2 as needed. 
 
Measure the following coagulation parameters: activated partial thromboplastin time (aPTT) 
and International normalized ration (INR). 


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4.2.6.1.13.4. Urinalysis 
Collect urine samples for qualitative (dipstick) analysis, to include tests for protein, glucose, 
urobilinogen, RBC, and WBC, at the time points listed below: 
• Within 5 days prior to randomisation. 
• At pre-dose of C1D1 only if there is more than 48 hours since screening period. 
• On Day 15 of Cycle 1. 
• For all subsequent cycles, obtain within 48 hours prior to Day 1 study treatment of 
each cycle. 
• Withdrawal visit. 
If a new abnormality is identified, quantitative urinalysis should be performed.   
In addition, follow the criteria for repeat testing listed in section 8.2.1.2 as needed. 
If dipstick proteinuria ≥ 2+, a 24 hours-collection urine is required and quantitative 
assessment of proteinuria will be performed. 
4.2.6.1.13.5. Pregnancy Testing 
If the patient is female and of childbearing potential, perform pregnancy testing with serum 
beta-human chorionic gonadotropin (β-HCG) or highly sensitive urine test (except during 
screening period), at the following time points and record the date, time, and test results in the 
patient’s source documents: 
• Within 5 days prior to randomisation (only serum test).  
• Beginning with Cycle 2, obt ain within 48 hours prior to Day 1 s tudy drug 
administration of each cycle. 
• Withdrawal visit (if not performed within previous 4 weeks). 
Female patients who are considered not to be of childbearing potential must have a history of 
being post-menopausal (with a minimum of 1 year without menses without an alternative 
medical cause), bilateral salpingectomy, bilateral oophorectomy, or hysterectomy that is 
clearly documented in the patient’s source documents. 
4.2.6.1.14. 
Dosage of Carcinoembryonic Antigen (CEA) 
Collect blood at the following time points for serum chemistry assessments: 
• Within 5 days prior to randomisation. 
• Withdrawal visit (if not performed within previous 8 weeks). 
• Every 8 weeks (aligned on tumour assessments). 
 
Note: RECIST 1.1 request normalisation of tumour markers to have a complete response. 
4.2.6.1.15. 
Tumour Measurements 
Imaging studies of the chest, abdomen and pelvis (as clinically indicated) must be obtained at 
each time point listed below for all patients: 
• Within 28 days prior to randomisation. Tumour assessment obtained prior to patient 
ICF may be used if the date of the images is within 28 days of randomisation. 
• Every 8 weeks during study treatment.  
• Withdrawal visit if not performed within previous 8 weeks. 
• For patients who discontinue treatment for reasons other than radiologic disease 
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should be made to perform the end of treatment tumour assessment prior to the start of 
new anticancer therapy.   
• For patients who discontinued treatment for reasons other than radiologic disease 
progression, every 8 w eeks until the patient develops radiologic progression or the 
start of new anticancer treatment (whichever occurs first). 
On-site tumour assessments will be performed by the Investigator/local radiologist according 
to RECIST 1.1 (Eisenhauer EA et al., 2009; Appendix 3). Results of these assessments 
including response for target and non-target lesions and appearance of new lesions will be the 
basis for the continuation or discontinuation of study medication. Response definitions are 
provided in section 7.  
If the Investigator determines that a patient develops clinical progression manifested by 
symptomatic deterioration but not supported by radiologic evidence of progression, the 
patient should stop treatment. Symptoms of clinical progression must be documented in the 
patient’s source documents. Every effort should be made to document objective progression 
even after discontinuation of treatment. 
If a patient is withdrawn due to radiologic disease progression, additional tumour assessments 
are not required at the end of treatment. 
The same method of assessment and the same technique must be used to characterise each 
identified and reported lesion at screening period, throughout the study, and during the 
follow-up period.  
All patients’ files and radiological assessments must be available for source verification. 
Results of any unscheduled evaluations should be recorded in the patient’s source documents. 
4.2.6.1.16. 
Concomitant treatments 
Concomitant treatments are collected from the screening period through the end of therapy. 
Use of concomitant treatment should be documented in the patient’s source documents. 
At the Follow-Up Visit, collect any new anticancer therapy and the date of initiation.   
4.2.6.1.17. 
Adverse Event Assessment 
See section 8.4 for definitions and detailed reporting of AEs and SAEs.  
4.2.6.1.18. 
Quality of Life 
EORTC Quality of Life Questionnaire - Core Questionnaire (EORTC QLQ-C30) and CRC-
specific module (QLQ-CR29) (Appendix 1) will be completed by the patient, independently 
of the study personnel at the following time points, at the beginning of each concerned visit 
prior to other study measures: 
• Within 5 days prior to randomisation 
• Every 12 w eeks during study treatment (i.e., every 3 cycles for the S 95005 plus 
bevacizumab arm and every 4 cycles for the capecitabine plus bevacizumab arm). 
Note: QoL questionnaires should be completed prior to the administration of study 
medication at these time points. 
• Withdrawal visit (if not performed within the previous 8 weeks). 


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4.2.6.1.19. 
Biomarkers assessment 
Blood samples will be collected at: 
• C1D1 for proteomic and genomic analysis (after randomisation) pre-dose. 
• Withdrawal visit for proteomic analysis. 
 
If available archived tumour biopsy will be collected at: 
• Within 21 days after C1D1 for proteomic and genomic analysis (after randomisation). 
4.2.6.1.20. 
Inclusion/Non-inclusion criteria 
Confirm eligibility of patient within 28 days prior to randomisation. 
4.2.6.1.21. 
Randomisation/Start of treatment 
Following confirmation of eligibility, patients will be randomised via IWRS and should 
receive the first dose of study treatment (Day 1 of Cycle 1) within 3 days after randomisation.   
4.2.6.2. 
Assessments by Visit 
See section 4.2.6.1 for details about specific assessments. 
4.2.6.2.1. 
Baseline procedures prior to randomisation: screening period/Inclusion 
visit 
4.2.6.2.1.1. 
Day -28 through Day 0 
 Signature of Informed Consent Form 
 Connection to IWRS for patient’s registration and e-CRF patient number 
 Histological confirmation of adenocarcinoma of colon or rectum 
 RAS status 
 BRAF status (if available) 
 Demography 
 Inclusion/Non-inclusion criteria 
 Medical history 
 Previous surgery, radiotherapy and treatments related to the studied disease 
 12-lead ECG 
 Tumour measurement  
 Concomitant treatments 
 AE assessment: only events associated with any procedure/condition required by the 
study protocol: procedure (MRI, etc.), change or withdrawal of previous/concomitant 
treatment relating to the conditions of the protocol, or a product other than the test 
drug, taken as part of the protocol have to be reported in AE form (See section 8.4. for 
definitions and detailed reporting of AEs and SAEs)  
4.2.6.2.1.2. 
Day -5 through Day 0 
 Physical examination 
 Baseline signs and symptoms 
 Height 
 Vital signs (BP, HR body temperature, respiration rate) and body weight 
 ECOG performance status 
 Blood samples for haematology, serum chemistry, coagulation 


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 CEA dosage 
 Urine sample for urinalysis 
 Pregnancy test (only serum test) 
 Quality of life assessment (EORTC QLQ-C30, QLQ-CR29) 
 Concomitant treatments 
 AE assessment 
4.2.6.2.2. 
Randomisation 
Contact the IWRS when the patient complies with all inclusion criteria for initiation of study 
treatment to randomise the patient. Instructions for randomisation are described in detail in 
the IWRS Instructions Manual.  
Randomisation will be based on last ECOG, vital signs and clinical laboratory evaluations. 
Randomised patients should receive the first dose of study treatment (Day 1 of Cycle 1) no 
later than 3 days after randomisation. 
First dose of study treatment can be given on the same day as randomisation. 
4.2.6.2.3. 
Procedures prior to first study drug administration: 
Assessments to be performed only if there is more than 24 hours since screening period: 
 Physical examination and ECOG performance status  
 Vital signs (BP, HR, body temperature and respiration rate) and body weight 
 
Assessments to be performed only if there is more than 48 hours since screening period: 
 Clinical laboratory evaluations (haematology, biochemistry, coagulation and 
urinalysis) 
4.2.6.2.4. 
C1D1 
 Blood samples for proteomic and genomic analysis (pre-dose) 
 Dispense S 95005 (experimental arm) or capecitabine (control arm) 
 Administer IV bevacizumab (experimental and control arm) 
 Records of any change or addition of a new concomitant treatment 
 AE assessment 
 Archived tumour biopsy (if available) for proteomic and genomic analysis (within 21 
days after C1D1) 
4.2.6.2.5. 
Cycle 1 Day 15  
 Blood samples for haematology and biochemistry (obtain within 48h before the visit). 
 Urine sample for urinalysis (obtain within 48h before the visit). 
 Vital signs and weight (experimental arm only) (obtain within 24h before 
bevacizumab administration). 
 Administer IV bevacizumab (experimental arm only) 
 Records of any change or addition of a new concomitant treatment 
 AE assessment 


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4.2.6.2.6. 
Subsequent Cycles (Cycle X Day 1) 
Prior to starting subsequent cycles, verify that patients with toxicities have met resumption 
criteria prior to administering study drug. 
 
Obtain within 48 hours prior to Day 1 study drug administration: 
 Blood samples for haematology, biochemistry and coagulation  
 Urine sample for urinalysis 
 Pregnancy test (serum or highly sensitive urine test) 
 
Obtain within 24 hours prior to Day 1 study drug administration: 
 Physical examination 
 Vital signs (blood pressure, heart rate, body temperature, respiration rate) and body 
weight 
 ECOG performance status 
 
On Day 1: 
 Dispense S 95005 (experimental arm) or capecitabine (control arm) 
 Administer IV bevacizumab (experimental and control arm) 
 Records of any change or addition of a new concomitant treatment 
 AE assessment 
4.2.6.2.7. 
Subsequent Cycles (Cycle X Day 15) (experimental arm only) 
 Blood samples for haematology (obtain within 48h be fore bevacizumab 
administration). 
 Vital signs and weight (obtain within 24h before bevacizumab administration). 
 Administer IV bevacizumab  
 Records of any change or addition of a new concomitant treatment 
 AE assessment 
4.2.6.2.8. 
Every 8 Weeks from Start of Treatment 
 Tumour assessment 
 CEA dosage aligned on tumour assessments. 
4.2.6.2.9. 
Every 12 Weeks from Start of Treatment 
 Quality of life assessment (EORTC QLC-C30, QLQ-CR29) prior to other study 
measures and to administration of study medication. 
4.2.6.2.10. 
Withdrawal visit (up to 4 weeks after the last test drug administration) 
 Physical examination 
 12-lead ECG 
 Vital signs (blood pressure, heart rate, body temperature, respiration rate) and body 
weight 
 ECOG performance status  
 Blood samples for haematology, biochemistry and coagulation  
 Urine sample for urinalysis 
 Pregnancy test if not performed within the previous 4 weeks (serum or highly sensitive 
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 Quality of life assessment (EORTC QLQ-C30, QLQ-CR29) if not performed within 
the previous 8 weeks 
 Tumour assessment (if not performed within previous 8 weeks). 
 CEA dosage if not performed within previous 8 weeks. 
 Records of any change or addition of a new concomitant treatment 
 AE assessment 
 Blood samples for proteomic analysis 
The withdrawal visit will be conducted up to 4 weeks after the patient’s last dose of study 
medication. If the patient will be starting new anticancer therapy within the 4 weeks window 
after the last dose of study medication, the withdrawal visit should be performed prior to the 
start of new anticancer therapy.   
During treatment period, unscheduled exams could be performed on investigator’s judgment. 
4.2.6.2.11. 
Follow-up  
After the end of the participation in the study, the following assessments should be obtained 
during the follow-up period: 
­ For patients who discontinued treatment for reasons other than disease progression: tumour 
assessment every 8 w eeks until radiologic disease progression (or initiation of new 
anticancer therapy (whichever occurs first), 
­ Concomitant treatments – collect antitumor therapies only, 
­ Contact patient/caregiver every 8 weeks to determine survival status (alive/dead), 
­ AE assessment (please refer to section 8.4.2.1 for reporting instructions):  
 up to 100 calendar days after the participant's last study drug intake report all Events 
Requiring Immediate Notification (ERIN), regardless of the supposed role of the 
research. 
 irrespective of the time of onset after the end of the study in case of Serious Adverse 
Events (SAE) related to the research. 
 
Patients will be followed for survival until the end of the study. The Investigators will be 
informed when this time point is reached. 
4.3. Measures to minimise bias 
The following measures will be taken in order to minimise bias: 
­ Balanced central randomisation with a minimisation procedure stratified by RAS status 
(wild-type, mutant type), ECOG performance status (0 vs. 1 vs. 2) and country. 
­ Treatment allocation through an IWRS. 
­ The EORTC Quality of Life Questionnaires – Core questionnaire (EORTC QLQ-C30) and 
CRC-specific module (QLQ-CR29) will be completed by the patient, independently of the 
study personnel, at the beginning of each concerned visit prior to other study measures. 


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4.4. Study products and blinding systems 
This is an open-label study. No study medication blinding is required. 
4.4.1. Products administered  
Les Laboratoires Servier Industrie (Gidy, France) will manufacture the therapeutic units (TU) 
of S 95005.  
S 95005 contains trifluridine (FTD) and tipiracil hydrochloride (TPI) as active ingredients 
with a molar ratio of 1:0.5. 
Capecitabine and bevacizumab will be supplied by Les Laboratoires Servier Industrie (Gidy, 
France).  
, Table (4.4.1) 2 and Table (4.4.1) 3 provide a description of the study products  
Table (4.4.1) 1 - Description of S 95005  
  
 
S 95005  
S 95005 
Pharmaceutical form 
Immediate-release film-coated tablet 
Immediate-release film-coated tablet 
Unit dosage 
15 mg 
20 mg 
Appearance, colour 
White round tablet 
Pale-red round tablet 
Composition 
15 mg trifluridine and 7,065 mg 
tipiracil hydrochloride 
Lactose monohydrate 
20 mg trifluridine and 9,42 mg tipiracil 
hydrochloride 
Lactose monohydrate 
 
 
Table (4.4.1) 2 - Description of capecitabine 
   
 
Capecitabine  
150 mg 
Capecitabine 
500mg 
Pharmaceutical form 
 film-coated tablet 
 film-coated tablet 
Unit dosage 
150 mg 
500 mg 
Appearance, colour 
light peach tablets of biconvex, oblong 
shape with the marking 
‘150’ on the one side and ‘Xeloda’ on 
the other side 
peach tablets of biconvex, oblong shape 
with the marking 
‘500’ on the one side and ‘Xeloda’ on 
the other side 
Composition 
150 mg of capecitabine 
anhydrous lactose 
500 mg of capecitabine  
anhydrous lactose 
  
 
Table (4.4.1) 3 - Description of bevacizumab 
 Table (4.4.1) 3 (Cont'd) - Description 
  
 
Bevacizumab  
4ml 
Bevacizumab  
16ml 
Pharmaceutical form 
Concentrate for solution for infusion 
Concentrate for solution for infusion 
Unit dosage 
100 mg of bevacizumab 
400 mg of bevacizumab 
Appearance, colour 
Clear to slightly opalescent, colourless 
to pale brown liquid. 
Clear to slightly opalescent, colourless to 
pale brown liquid. 
Composition 
 Each ml of concentrate contains 25 mg 
of bevacizumab 
 Each ml of concentrate contains 25 mg 
of bevacizumab 
  


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Table (4.4.1) 4, Table (4.4.1) 5 and Table (4.4.1) 6 provide a description of the packaging of 
the study products 
Table (4.4.1) 4 - Description of the packaging of S 95005 
 Table (4.4.1) 4 (Cont'd) - Description 
  
 
S 95005 
15mg 
S 95005 
20mg 
Number of units of the 
pharmaceutical form per 
primary packaging 
1 card of 2 blisters of 10 tablets  
1 card of 2 blisters of 10 tablets 
Number 
of 
primary 
packaging per secondary 
packaging 
1 Aluminium foil pouch “S95005 
15” of 1 cards with desiccant 
1 Aluminium foil pouch “S95005 20” 
of 1 cards with desiccant 
  
 
Table (4.4.1) 5 - Description of the packaging of capecitabine 
 Table (4.4.1) 5 (Cont'd) - Description 
  
 
Capecitabine  
150 mg 
Capecitabine 
500mg 
Number of units of the 
pharmaceutical form per 
primary packaging 
10 tablets 
10 tablets 
Number 
of 
primary 
packaging per secondary 
packaging 
6 blisters 
 
“Capecitabine 150” 
12 blisters 
 
“Capecitabine 500” 
  
 
Table (4.4.1) 6 - Description of the packaging of bevacizumab 
 Table (4.4.1) 6 (Cont'd) - Description 
  
 
Bevacizumab  
4ml 
Bevacizumab  
16ml 
Number of units of the 
pharmaceutical form per 
primary packaging 
1 vial containing 100 mg of 
bevacizumab 
1 vial containing 400 mg of 
bevacizumab 
Number 
of 
primary 
packaging per secondary 
packaging 
1 vial per small box 
“Bevacizumab 4” 
1 vial per small box 
“Bevacizumab 16” 
  
The labelling of packages complies with the regulatory requirements of each country involved 
in the study, as well as the recommendations in appendix 13 of the European Guide to Good 
Manufacturing Practice.  


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4.4.2. IMPs management 
In this study the Investigational Medicinal Products (IMP) are S 95005, capecitabine and 
bevacizumab. 
 
The IMP will be sent by Les Laboratoires Servier Industrie (Gidy, France) either directly to 
the investigational centres or to sub-distribution centres or to local pharmacies depending on 
the geographic areas and the local regulatory requirements. 
 
IMP receipt, dispensing according to the experimental design of the study (for the description 
of dispensing methods, refer to section 6.2), accountability and collection are the 
responsibility of the investigator and/or pharmacist of the medical institution. 
 
IMP management will be verified on a regular basis by the study monitor. 
 
The investigator and/or the pharmacist of the medical institution and/or a designated person 
from their study team must complete in real time all the documents provided by the sponsor 
concerning IMP management (therapeutic unit tracking form or an equivalent document…). 
Therapeutic unit tracking form, or an equivalent document, is the source document to fulfil. 
The investigator and/or the pharmacist of the medical institution should only use the IMP 
provided for the participants involved in the study. 
 
All defects or deterioration of IMPs or their packaging are to be reported to the study monitor, 
and to the IWRS. The investigator will notify the monitor of all complaints set out by a 
participant (change of taste, appearance…). 
In the event of anticipated return of IMPs to the sponsor (batch recall), the sponsor will 
prepare an information letter intended for the investigator and/or pharmacist of the medical 
institution. This letter will be sent by the person locally responsible for the study to each study 
centre. On receipt of the letter, the investigator and/or the pharmacist will identify the 
participants in possession of the IMP at the moment the incident becomes known, by using, 
among other tools, the therapeutic unit tracking form or an equivalent document, and will 
contact them immediately. 
Destruction 
Destruction of the IMPs is the responsibility of the sponsor or the pharmacist of the medical 
institution. 
Remaining treatments (used and unused IMPs) will subsequently be collected and stored 
according to the local procedures and requirements, by the person responsible for the IMP 
management.  
A certificated destruction will be performed according to standard modalities for that class of 
product and the attestation must be sent to the sponsor. The practical procedures for 
destruction of unused IMP will be defined by the sponsor and adapted to the centre. An IMP 
collection and destruction form will be completed before the shipment of IMP to destruction. 
Destruction of IMP may be possible (after drug accountability and sponsor authorization) 
when the product has been used, has expired or after at least the last visit of the last treated 
patient. 
  
For bevacizumab, used Therapeutic Units (TUs) will be collected by the centre at the time of 
preparation/administration along with other wastes to be destroyed according to local 


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procedure. Thus, accountability and recovery by monitor are not applicable for used TUs of 
bevacizumab. 
Stability and storage 
Any country-specific requirements regarding packaging and storage of investigational drugs 
should be followed. 
The pharmacist is responsible for the IMP temperature monitoring on a daily basis using 
FONT-CIRT-FORM-311 “Therapeutic Unit temperature log sheet - centre” (recording Min-
Max temperature every working day) or an equivalent document.  
In case of temperature deviation, the pharmacist should immediately: 
1. block the IWRS for the concerned IMPs and place them in quarantine,  
2. alert the monitor or the local project manager if the monitor is absent, forward him all 
needed information and implement the instructions received. 
Furthermore, the pharmacist must put in place an adequate corrective/preventive action once 
the first temperature deviation occurs in order to avoid recurrence.  
 
IMPs should be stored in a secure area with restricted access. Specific storage conditions, if 
any, are mentioned on IMP labelling. 
4.4.2.1. 
Handling conditions and cleaning procedures.  
Study staff will carefully instruct patients on how to take S 95005 or capecitabine and the 
correct dose to take. 
4.4.2.2. 
S 95005 
S 95005 tablets should not be sucked, chewed, crushed or kept in mouth. Direct contact of the 
powder from tablets containing S 95005 with the skin or mucous membranes should be 
avoided. If such contact occurs, immediately begin wash with soap and running water for 
minimum 15 minutes. Personnel and patient should avoid exposure to crushed tablets.  
The patient must be instructed in the handling of study medication as follows:  
­ To store the study medication at room temperature 
­ To only remove from the study medication kit the amount of tablets needed at the time of 
dosing 
­ To wash their hands after handling study medication 
­ Not to remove doses in advance of the next scheduled dosing 
­ To make every effort to take doses on schedule 
­ To report any missed doses in the patient’s diary. If doses are missed or held on those days, 
the patient should not make up for missed doses.  
­ To take study medication within 1 hour after completing a meal (morning and evening 
meal) with a glass of water 
­ If the patient vomits after taking study medication, the patient should not take another dose 
­ To keep study medication in a safe place and out of reach of children 
­ To bring all used and unused study medication kits to the site at each visit 
4.4.2.3. 
Bevacizumab 
Bevacizumab will be provided as commercially available product with clinical labelling. For 
handling conditions and cleaning procedures instructions, please refer to the package insert 
and SmPC (Appendix 7). 


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4.4.2.4. 
Capecitabine 
Capecitabine will be provided as commercially available product with clinical labelling. For 
handling conditions and cleaning procedures instructions, please refer to the package insert 
and SmPC (Appendix 7). 
4.4.3. Management of blinding systems 
Not applicable 
4.5. Discontinuation of the study 
4.5.1. Premature discontinuation of the study 
After having informed the coordinators/investigators, the sponsor or the Coordinator or the 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) or the Competent 
Authorities may terminate the study before its scheduled term. Two copies of the written 
confirmation will be dated and signed by the coordinators. The IECs and Competent 
Authorities will be informed according to local regulations. 
4.5.2. Discontinuation of the study in the event of objective reached (event driven trial) 
The selection inclusion will be stopped once 100 PFS events (progression of disease [PD] or 
death) are reached or 150 patients are randomised (whichever occurs first) and the on-going 
patients will continue the study without change until the end of the study. 
Once 100 PFS events (progression of disease [PD] or death) are reached the main study 
analysis will be performed. 
 
After having informed the coordinators/investigators, the sponsor may terminate the study 
before its scheduled term. The IEC(s) and Competent Authorities will be informed according 
to local regulations. 
4.6. Source data  
Source data and source documents of the centre should be clearly identified in a specific, 
detailed and signed document before the beginning of the study.  
Patient’s medical file (e.g., ECG report, clinical laboratory examinations reports, tumour 
assessment reports and all other patient’s examinations results), patient diary, quality of life 
questionnaires (paper copies) will be considered as source document. 


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5. SELECTION AND WITHDRAWAL OF PARTICIPANTS 
5.1. Inclusion criteria 
5.1.1. Informed consent  
1. Written informed consent will be obtained prior to any study-specific procedure. 
5.1.2. Demographic characteristics 
2. Male or Female participant aged ≥18 years old. 
5.1.3. Disease characteristics 
3. Has ECOG performance status of 0, 1 or 2 (Appendix 2) at the time of the randomisation. 
4. Has definitive histologically or cytologically confirmed adenocarcinoma of the colon or 
rectum. 
5. RAS status must have been determined (mutant or wild) based on local biological 
assessment on tumour biopsy. At least the following mutation must be determined: KRAS 
and NRAS Exon 2: codon 12 and 13. 
6. Has at least one measurable metastatic lesion (as defined by Response Evaluation Criteria 
in Solid Tumours [RECIST] version 1.1; Eisenhauer EA et al., 2009; Appendix 3). Note: 
Unresectable metastatic disease must have been diagnosed within 6 months prior to first 
day of study drug administration.  
7. No previous systemic anticancer therapy for unresectable metastatic colorectal cancer.  
8. Previous adjuvant (or neoadjuvant for patients with rectal cancer) chemotherapy is 
allowed only if it has been completed more than 6 months before start of study treatment.  
9. Patient is not a candidate for combination chemotherapy with irinotecan or oxaliplatin 
according to investigator’s judgment based on decision taken during a multidisciplinary 
meeting (if organised in the centre). 
10. Patient is not a can didate for curative resection of metastatic lesions according to 
investigator’s judgment based on de cision taken during a multidisciplinary meeting (if 
organised in the centre).  
5.1.4. Medical and therapeutic criteria 
11. Is able to take medication orally (i.e., no feeding tube). 
12. Has adequate organ function as defined by the following laboratory values obtained 
within 5 days prior to randomisation: 
12.1.  Haemoglobin value of ≥9.0 g/dL based on measurements obtained 2 weeks or 
more after last prior transfusion. 
12.2.  Absolute neutrophil count (ANC) of ≥1.5 x 109/L. 
12.3.  Platelet count ≥100 x 109/L.  
12.4.  Total serum bilirubin of ≤1.5 x upper limit of normal (ULN) (except for Grade 1 
hyperbilirubinemia due solely to a medical diagnosis of Gilbert’s syndrome). 


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12.5.  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 x 
ULN; if liver function abnormalities are due to underlying liver metastasis, AST 
and ALT ≤5 x ULN. 
12.6.  Creatinine clearance > 50 mL/min (using Cockcroft Gault formula)  
12.7.  Urine dipstick test for proteinuria < 1+ or 24-hour urine collection <1000 mg for 
patients found with ≥ 1+ on dipstick. 
13. Coagulation parameters in normal limit (or in therapeutic limit for patients treated with 
anticoagulant drugs): activated partial thromboplastin time (aPTT) and international 
normalized ratio (INR) 
14. Women of childbearing potential must have been tested negative in a serum pregnancy 
test within 5 days prior to randomisation.  
Within the frame of this study, female participants of childbearing potential and male 
participants with partners of childbearing potential must agree to use a highly effective 
method of birth control (i.e., pregnancy rate of less than 1% per year) during the study and 
for 6 months after the discontinuation of study medication.  
Contraceptive methods that result in a low failure rate when used consistently and 
correctly include methods such as combined hormonal contraception associated with 
inhibition of ovulation (oral, intravaginal, transdermal), progestogen-only hormonal 
contraception associated with inhibition of ovulation (oral, injectable, implantable), some 
intrauterine devices (IUDs), intrauterine hormone-releasing system (IUS), true sexual 
abstinence (when this is in line with the preferred and usual lifestyle of the participant), 
bilateral tubal occlusion, or a female partner who is not of childbearing potential or a male 
partner who has had a vasectomy. Women and female partners using hormonal 
contraceptive must also use a barrier method (i.e. condom or occlusive cap (diaphragm or 
cervical/vault caps)). 
15. Is willing and able to comply with scheduled visits and study procedures. 
5.2. Non-inclusion criteria 
5.2.1. General criteria 
16. Foreseeable poor compliance to the study procedures. 
17. Is a pregnant or lactating female. 
18. Is inappropriate for entry into this study in the judgment of the Investigator. 
5.2.2. Medical and therapeutic criteria 
19. Has a serious illness or serious medical condition(s) including, but not limited to the 
following: 
19.1. Other concurrently active malignancies excluding malignancies that are in 
remission for more than 5 years, or carcinoma-in-situ deemed cured by adequate 
treatment or basal cell carcinoma. 
19.2. Known brain metastasis or leptomeningeal metastasis.  
19.3. Active systemic infection (i.e., body temperature ≥38°C due to infection). 


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19.4. At the time of screening, intestinal obstruction, pulmonary fibrosis, interstitial 
pneumonitis, renal failure, liver failure, or cerebrovascular disorder.  
19.5. Uncontrolled diabetes.  
19.6. Deep venous/arterial thromboembolic complication or bleeding diatheses or any 
other haemorrhage/bleeding event CTCAE grade > 3 w ithin 4 w eeks prior to 
randomisation. 
19.7. Cerebrovascular accident or myocardial infarction within the last 12 months, 
severe/unstable angina, uncontrolled or symptomatic arrhythmia, symptomatic 
congestive heart failure New York Heart Association (NYHA) class III or IV, 
uncontrolled hypertension.  
19.8. Known coagulopathy that increases risk of bleeding or a history of clinically 
significant haemorrhages in the past (including Grade ≥3 gastrointestinal 
haemorrhage) within 4 weeks prior to randomisation. 
19.9. Known human immunodeficiency virus (HIV) or acquired immunodeficiency 
syndrome (AIDS)-related illness, or hepatitis B or C as determined by serologic 
tests. 
19.10. Patients with autoimmune disorders or history of organ transplantation who 
require immunosuppressive therapy.   
19.11. Psychiatric disease that may increase the risk associated with study participation 
or study drug administration, or may interfere with the interpretation of study 
results.  
19.12. In the investigator’s opinion, significant malabsorption syndrome, significant 
chronic digestive or gastrointestinal inflammatory syndrome 
20. Major surgery within 4 weeks prior to randomisation (the surgical incision should be fully 
healed prior to study drug administration). Note: indwelling catheter and portacath 
implantation are allowed.  
21.  Extended field radiation within 4 weeks or limited field radiation within 2 weeks prior to 
randomisation.  
22. Any investigational agent received within 4 weeks prior to randomisation. 
33. Participant already enrolled in the study (informed consent signed). 
 
Non-inclusion criteria related to administration of S 95005: 
23. Has previously received S 95005 or history of allergic reactions attributed to compounds 
of similar composition to S 95005 or any of its excipients. 
31. Hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-
galactose malabsorption. 
 
Non-inclusion criteria related to administration of bevacizumab: 
24. History of allergic reactions or hypersensitivity to bevacizumab or any of its excipients. 
25. History of hypersensitivity to Chinese Hamster Ovary (CHO) cell products or other 
recombinant human or humanised antibodies. 
32. Any contraindication present in the SmPC of bevacizumab (Appendix 7). 
 


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Non-inclusion criteria related to administration of capecitabine: 
26. History of allergic reactions or hypersensitivity to capecitabine or any of its excipients or 
fluorouracil. 
27. History of severe and unexpected reaction to fluoropyrimidine therapy. 
28. Known complete absence of dihydropyrimidine dehydrogenase (DPD) activity. 
29. Treatment with sorivudine or its chemical related analogues, such as brivudine, within 4 
weeks prior to randomisation 
30. Any contraindication present in the SmPC of capecitabine (Appendix 7). 
5.3. Additional information recorded at the inclusion visit 
Not applicable 
5.4. Participant withdrawal 
5.4.1. Withdrawal criteria 
Information to be collected during the last visit of these patients is given in section 4.2.6.2.10. 
These follow-up modalities are used to ensure the efficacy and safety evaluation of all 
participants who received the IMP. 
 
Reason for premature discontinuation of the IMP(s) and premature discontinuation from the 
study are described below. Patients that discontinued from the study are also discontinued 
from IMP(s). 
 
The reasons for premature discontinuation of IMP(s) are: 
­ Patient experiences an irreversible, treatment-related, Grade 4, clinically relevant, 
non-hematologic event.   
­ Unacceptable AEs, or change in underlying condition such that the patient can no longer 
tolerate therapy, including:  
 A maximum dose delay >28 days from the scheduled start date of the next cycle for 
patients receiving S 95005 + bevacizumab 
 A maximum dose delay >21 days from the scheduled start date of the next cycle for 
patients receiving capecitabine + bevacizumab 
 Need for more than 3 dose reductions of S 95005 (maximum of 3 dose reductions 
allowed as described in section 8.3) for patients receiving S 95005 + bevacizumab. 
­ Refer to the bevacizumab and to the capecitabine SmPC (Appendix 7) for events requiring 
discontinuation of treatment.  
­ Physician’s decision including need for other anticancer therapy not specified in the 
protocol or surgery or radiotherapy to the only site(s) of disease being evaluated in this 
protocol. 
­ RECIST 1.1-defined disease progression. 
­ Clinical progression. 
 
Patients who withdrawn from treatment for another reason than progression will be followed: 
 for tumour assessment until progression, death or initiation of a new anticancer therapy 
(whichever occurs first)  
 for survival until the end of the study defined as the last visit of the last patient.  


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Patients who withdrawn from treatment for progression will be followed for survival until the 
end of the study defined as the last visit of the last patient. 
 
The reasons for premature discontinuation of study are: 
­ Patient request at any time irrespective of the reason. 
­ Pregnancy.  
­ Protocol deviation if it in terferes with the study evaluations and/or if it je opardises 
patient’s safety, e.g. any medical event requiring administration of an unauthorised 
concomitant treatment (section 6.3.1).  
 
If there is strong evidence of clinical benefit and reasons to justify continuation of dosing with 
study medication on protocol even though treatment discontinuation criteria have been met, 
this decision must be reviewed with the sponsor on a case by case basis. Pregnancy will lead 
to definitive treatment discontinuation in all cases. 
Note: patients will be considered to be on t reatment as long as either component of the 
combination regimen continues to be administered. 
5.4.2. Procedure 
Upon discontinuation of treatment the Investigator must: 
­ Notify your Clinical Research Associate (CRA) immediately;  
­ Register End of Treatment for the patient in the IWRS; 
­ Specify the data to be reported in the medical file and in the eCRF, with their chronology, 
with respect to the reason for the premature discontinuation of IMP for the withdrawal 
from the study, the main assessment criteria, and the medical follow-up data. If there are 
several reasons, the investigator must indicate the main reason. 
A withdrawal visit should always be suggested to the patient in case of discontinuation of 
both treatments in each arm and when it should be arranged (at the same time as the date of 
discontinuation of IMP, at the theoretical end-of-study date…).  
In the case of premature withdrawal from the study due to an adverse event (event requiring 
immediate notification or not), the investigator must make every effort to collect the 
information relating to the outcome of the event. If necessary, the information will be 
collected afterwards (see section 8.4.2.4). This information is recorded in that part of the 
electronic case report form which concerns adverse events. If the investigator cannot collect 
the information from a visit, he must collect it from the doctor ensuring the follow-up of the 
participant. 
If the study is stopped for other reason than the objective is reached (event driven trial), IMP 
is discontinued as a result of an event requiring immediate notification, the procedure 
described in section 8.4.1.5 is to be implemented. 
The dispositions to be taken after the IMP discontinuation are described in section 6.5. 
5.4.3. Lost to follow-up 
When the investigator has no n ews of the participant, he/she must make every effort to 
contact him/her or a person around him/her (phone calls, letters including registered ones, 
etc.), to establish the reason for the discontinuation of IMP and to suggest the participant 
comes to a withdrawal visit. If all these attempts to contact the participant fail, the investigator 
can then declare the participant “lost to follow-up”. The investigator should document all 
these attempts in the corresponding medical file. 


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6. TREATMENT OF PARTICIPANTS 
6.1. IMPs administered  
The centres will login to the IWRS at the beginning of each treatment cycle to record the 
current cycle number, record the patient’s height (baseline visit only) and current weight for 
calculation of the patient’s body surface area (BSA) to obtain the recommended S 95005 or 
capecitabine dosage. In addition, the IWRS will use the patient’s weight to calculate the 
correct dosage of bevacizumab.  
 
The BSA will be calculated by t he IWRS using the following DuBois formula (all BSA 
calculations are rounded to 2 decimal places) (DuBois, 1916). 
BSA (m²) = ([Body Weight (kg)]0.425 0.425 x [Height (cm)]0.725 0.725) x 0.007184 
 
Study sites are required to use the BSA calculation provided by the IWRS when determining 
S 95005 or capecitabine doses.  
 
Dose modifications and management of toxicities are described in section 8.3. 
6.1.1. S 95005 plus bevacizumab arm 
6.1.1.1. 
Treatment Regimen 
Each treatment cycle will be 28 da ys in duration. One treatment cycle consists of the 
following: 
­ Days 1-5: S 95005 (35 mg/m2/dose) orally twice daily; bevacizumab 5 mg/kg IV infusion 
on Day 1 
­ Days 6 -7: Rest 
­ Days 8-12:  S 95005 (35mg/m²/dose) orally twice daily 
­ Days 13-14: Rest 
­ Day 15: Bevacizumab 5 mg/kg/IV infusion on Day 15 
­ Days 16-28: Rest 
6.1.1.2. 
S 95005 administration 
S 95005 dosage is calculated according to body surface area (BSA). Table (6.1.1.2) 1 shows 
the number of tablets that are needed per calculated BSA.  
­ If at the beginning of the next treatment cycle, a patient’s body weight decreases by ≥10% 
from baseline, the IWRS will recalculate the patient’s BSA and provide the site with the 
adjusted S 95005 dosage.  
­ No increase in S 95005 dose due to increase in BSA is permitted. 
­ Study medication should only be given on Days 1 through 5 and Days 8 through 12 of each 
cycle. If doses are missed or held on those days, the patient should not make up for missed 
doses.  
­ Any missed doses reported by the patient should be recorded in the patient’s diary. 
­ Extension of study treatment into Days 6 to7 or into the rest period (Days 13 through 28) is 
not permitted.   


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­ S 95005 should be taken with a glass of water within 1 hour after completion of morning 
and evening meals. 
Table (6.1.1.2) 1 - Number of tablets of S 95005 per dose 
 Table (6.1.1.2) 1 (Cont'd) - Number 
 
S 95005 Dose 
(2x daily) 
BSA 
(m2) 
Dosage in mg 
(2x daily) 
Total daily 
dose (mg) 
Tablets per dose 
15 mg 
20 mg 
35 mg/m2 
< 1.07 
35 
70 
1 
1 
1.07 - 1.22 
40 
80 
0 
2 
1.23 - 1.37 
45 
90 
3 
0 
1.38 - 1.52 
50 
100 
2 
1 
1.53 - 1.68 
55 
110 
1 
2 
1.69 - 1.83 
60 
120 
0 
3 
1.84 - 1.98 
65 
130 
3 
1 
1.99 - 2.14 
70 
140 
2 
2 
2.15 - 2.29 
75 
150 
1 
3 
≥2.30 
80 
160 
0 
4 
  
BSA=body surface area (calculate to 2 decimal places) 
6.1.1.3. 
Bevacizumab administration 
Refer to the package insert for instructions regarding administration of bevacizumab. 
6.1.2.  Capecitabine plus bevacizumab arm 
6.1.2.1. 
Treatment Regimen 
Each treatment cycle will be 21 da ys in duration. One treatment cycle consists of the 
following: 
­ Days 1-14: Capecitabine (1250 mg/m2/dose) orally twice daily; bevacizumab 7.5 mg/kg IV 
infusion on Day 1 
­ Days 15-21: Rest 
 
Note: According to local clinical practice the starting dose of capecitabine could be reduced to 
1000 mg/m² but could not be lower. 
6.1.2.2. 
Capecitabine 
Refer to the package insert for instructions regarding administration of capecitabine. 
­ If at the beginning of the next treatment cycle, a patient’s body weight decreases by ≥10% 
from baseline, the IWRS will recalculate the patient’s BSA and provide the site with the 
adjusted capecitabine dosage.  
­ No increase in capecitabine dose due to increase in BSA is permitted. 
­ Any missed doses reported by the patient should be recorded in the patient’s diary. 
6.1.2.3. 
Bevacizumab 
Refer to the package insert for instructions regarding administration of bevacizumab. 
At each visit, the IWRS will provide the site with the adjusted bevacizumab dosage based on 
the patient’s actual weight. 
 


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6.2. IMPs dispensing  
The treatment group will be allocated via IWRS using a balanced central randomization (1:1) 
to S 95005 + bevacizumab or capecitabine + bevacizumab with stratification by RAS status 
(wild-type, mutant type), ECOG performance status (0 vs. 1 vs. 2) and country. 
 
A connection to the IWRS should be performed at each concerned visit to know the allocated 
kit number(s) to be dispensed to the patient (please see details in IWRS manual). 
 
The detachable portion of the label on the IMP box must be stuck by the investigator on an 
IMP label collection form or on the prescription form where the IMPs are dispensed by a 
pharmacist. 
6.3. Previous and concomitant treatments  
Collect all therapies and medications, prescription and over-the-counter, from the time of 
signed ICF through the withdrawal visit. Use of concomitant treatments should be 
documented in the patient’s source documents. 
At the Follow-Up Visit(s), collect any new anticancer therapy and the date of initiation.  
6.3.1. Prohibited Medications and Therapies 
Patients are not permitted to receive: 
­ Any other investigational or any other anticancer therapy, including chemotherapy, 
immunotherapy, biological response modifiers (BRMs), or endocrine therapy during the 
study treatment period, 
­ Adjuvant treatment for CRC within the 6 months before the first study drug administration, 
­ Previous systemic anticancer therapy for unresectable metastatic CRC at any time before 
the randomisation, 
­ Treatment with sorivudine or its chemical related analogues are forbidden within 4 weeks 
prior to randomisation and during the study. 
 
6.3.2. Concomitant Medications and Therapies 
Caution is required when using drugs that are human thymidine kinase substrates, e.g., 
zidovudine. Such drugs, if used concomitantly with S 95005, may compete with the effector, 
trifluridine, for activation via thymidine kinases. Therefore, when using antiviral drugs that 
are human thymidine kinase substrates, monitor for possible decreased efficacy of the 
antiviral agent, and consider switching to an alternative antiviral agent that is not a human 
thymidine kinase substrate, such as lamivudine, zalcitabine, didanosine and abacavir. 
Patient treated with oral anticoagulant treatment or heparins should be closely monitored 
especially in case of thrombopenia. 
 
For precautions of use and interactions of concomitant treatment with capecitabine or 
bevacizumab please refer to the corresponding updated SmPC of the drugs (Appendix 7). 
 
Palliative radiotherapy is permitted. As far as possible, the irradiation of target lesions must 
be avoided.  
 


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The following medications may be given concomitantly under the following guidelines: 
 
Hematologic Support 
Administer hematologic support as medically indicated (e.g., blood transfusions, granulocyte 
colony-stimulating factor [G-CSF], erythropoietin, etc.) according to the institutional site 
standards.  If there are no standard procedures for the use of growth factors, follow American 
Society of Clinical Oncology (ASCO) 2006 Guidelines for Use of Hematopoietic Colony-
Stimulating Factors, available at http://www.instituteforquality.org/practice-guidelines; or the 
European Organization for Research and Treatment of Cancer (EORTC) update to 2010 
guidelines for the use of G-CSF, available at http://www.eortc.org/investigators-area/eortc-
guidelines.  
 
Management of Diarrhoea 
Educate both patients and patients’ families regarding the potential seriousness of 
chemotherapy-induced diarrhoea. Instruct patients to immediately contact the clinical site 
staff at the first sign of loose stool. 
Provide patients with loperamide or other standard antidiarrheal therapy and instruct the 
patient on how to use it at the first sign of diarrhoea (Benson AB 3rd et al., 2004).  
Monitor the patient’s fluid and electrolyte balance, with appropriate intervention as clinically 
indicated with fluids and electrolyte replacement, antibiotics, and antiemetics. 
Infection prophylaxis with oral antibiotics must be considered for patients with persistent 
diarrhoea beyond 24 hours, or coincident with Grade ≥3 neutropenia.  
Administer prophylactic treatment for diarrhoea as clinically indicated. 
If there are no institutional standards, refer to the guidelines published by Benson AB 3rd et 
al., 2004. 
 
Management of Nausea/Vomiting 
Administer antiemetics as clinically indicated. If there are no institutional standards refer to 
the ASCO Guidelines for Antiemetics in Oncology (Kris MG et al., 2006).  
6.3.3. Effective contraception during study 
Female patients who are considered not to be of childbearing potential must have a history of 
being postmenopausal (with a minimum of 1 year without menses without an alternative 
medical cause), bilateral salpingectomy, bilateral oophorectomy), or hysterectomy that is 
clearly documented in the patient’s source documents. 
Within the frame of this study, female participants of childbearing potential and male 
participants with partners of childbearing potential must agree to use a h ighly effective 
method of birth control (i.e., pregnancy rate of less than 1% per year) during the study and for 
6 months after the discontinuation of study medication. Contraceptive methods that result in a 
low failure rate when used consistently and correctly include methods such as combined 
hormonal contraception associated with inhibition of ovulation (oral, intravaginal, 
transdermal), progestogen-only hormonal contraception associated with inhibition of 
ovulation (oral, injectable, implantable), intrauterine hormone-releasing system (IUS), some 
intrauterine devices (IUDs), bilateral tubal occlusion, true sexual abstinence (when this is in 
line with the preferred and usual lifestyle of the participant), or a female partner who is not of 
childbearing potential or a male partner who has had a vasectomy. 
Women and female partners using hormonal contraceptive must also use a barrier method (i.e. 
condom or occlusive cap (diaphragm or cervical/vault caps)). 


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6.4. IMP compliance 
The number of tablets (S 95005 and capecitabine) dispensed and the number of tablets 
(S 95005 and capecitabine) returned by the participant are to be counted by the pharmacist of 
the hospital or a d esignated person from his/her team and recorded in the eCRF and 
therapeutic tracking form. 
If the participant did not bring back all blisters (S 95005 and capecitabine) dispensed at the 
previous visit, the investigator must estimate the number of IMP units taken by the participant 
since the previous visit, by questioning him/her. 
Each participant must record all medications (S 95005 and capecitabine) taken together with 
corresponding times in a diary provided by the investigator. 
The compliance will be assessed from the method described above and from the questioning 
of the participant. 
6.5. Arrangements after the discontinuation of the IMP 
After the discontinuation of the IMP, the participant will access to an appropriate medical care 
by his doctor; who will provide the best support care 
Specific rules may be followed in some countries according to local regulation. 


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7. ASSESSMENT OF EFFICACY 
The determination of antitumor efficacy will be based on objective tumour assessments made 
by the Investigator according to the revised RECIST 1.1 (Eisenhauer EA et al., 2009; 
Appendix 3) of unidimensional evaluation. Treatment decisions by the Investigator will also 
be based on these criteria. 
7.1. Efficacy measurements 
Efficacy measurements performed during the study are indicated in Table (4.2.5) 1 and 
Table (4.2.5) 2. 
7.2. Methods and measurement times 
7.2.1. Tumour assessment 
7.2.1.1. 
Method of Imaging 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at Baseline and during follow-up.  Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess 
the antitumor effect of treatment. All measurements should be recorded in metric notation 
using a ruler or calipers. 
Contrast enhanced CT is the preferred method for tumour assessments. If contrast agent is 
contraindicated in a patient, obtain a non-contrast chest CT and enhanced magnetic resonance 
imaging (MRI) of the abdomen (and pelvis if clinically indicated). Spiral CT should be 
performed using a 5 mm or less contiguous reconstruction algorithm. Images must be 
acquired of the chest and abdomen (and pelvis if clinically indicated or obtained at Baseline) 
at each time point. Preferably, CT and MRI will be used for tumour measurement.  
Clinical lesions will only be considered measurable when they are superficial (e.g., skin 
nodules, palpable lymph nodes).  I n the case of skin lesions, documentation by colour 
photography, including a ruler to estimate the size of the lesion, is recommended. 
Ultrasound should not be used to measure tumour lesions that are clinically not easily 
accessible for objective response evaluation (e.g., visceral lesions). Ultrasound is a possible 
alternative to clinical measurements of superficial palpable nodes, subcutaneous lesions, and 
thyroid nodules.  Ultrasound might also be useful to confirm the complete disappearance of 
superficial lesions usually assessed by clinical examination. 
An additional fluorodeoxyglucose positron emission tomography (FDG-PET) scan may help 
confirm the diagnosis of suspicious lymph nodes as needed. A “positive” FDG-PET scan 
lesion is one that is FDG avid “with an uptake greater than twice that of the surrounding tissue 
on the attenuation corrected image.” However, this scan is not mandatory.  FDG-PET scan 
alone cannot replace a MRI or contrast-enhanced CT. 
For additional guidance refer to revised RECIST 1.1 (Eisenhauer EA et al., 2009; Appendix 
3). 


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7.2.1.2. 
Tumour Definitions 
Measurable Lesions: 
­ Measurable visceral lesions: Lesions that can be accurately measured in at least 
1 dimension with the longest diameter (to be recorded) ≥10 mm by CT scan if using slice 
thickness of 5 mm or less, or at least double the slice thickness of the CT or MRI scan if 
the slice thickness is >5 mm.   
­ Measurable pathological lymph nodes: A malignant lymph node must be considered 
pathologically enlarged with high suspicion of metastasis and measure ≥15 mm in the short 
axis when assessed by CT scan.  The short axis is defined as the longest linear dimension 
perpendicular to the node’s longest diameter as assessed within the same plane that the 
scan was acquired.  
Only measurable lesions can be selected as target lesions. 
 
Non-measurable Lesions: Non-measurable lesions include: 
­ Small visceral metastatic lesions that have a longest dimension less than 10 mm or if slice 
thickness is greater than 5 mm less than twice the slice thickness.  
­ Abnormal and suspected metastatic lymph nodes that are ≥10 mm to <15 mm in the short 
axis. 
­ Truly non-measurable lesions (e.g., ascites and peritoneal carcinomatosis). 
All non-measurable lesions can only be selected as non-target lesions. 
 
Target Lesions: 
­ All measurable lesions up to a m aximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs/tissues should be identified as target lesions. 
­ Target lesions should be selected on the basis of their size (visceral lesion with the longest 
diameter and lymph node with the measurement of short axis), be representative of all 
involved organs/tissues, but in addition should be those that lend themselves to 
reproducible repeated measurements.  
­ When recording tumour measurements, the longest diameter will be measured for each 
non-nodal target lesion.  For measurable pathological lymph nodes that may be identified 
as target lesions, the short axis measurement will be combined with the measurements of 
non-nodal (i.e., visceral lesion) target lesions.  Therefore, in cases of complete response 
(CR) when abnormal nodes have been used as target lesions, the sum of diameters will not 
reduce to a null value. 
 Target lesions will be followed up and measured at each subsequent time point. 
 The sum of the diameters for all target lesions will be calculated and recorded.  The 
baseline sum will be used as a reference to further characterize any objective tumour 
assessment in the measurable dimension of the disease. 
­ Assign a measurement to all target lesions regardless of size. An option of ‘too small to 
measure’ will be provided if a measurement cannot be assigned. A value of zero should 
only be assigned in the case of a CR. 
­ An option of ‘Not Assessable’ for a lesion will apply only to lesions that cannot be read 
due to technical reasons, for example: 
 CT artefact. 
 Patient positioning where the lesions are obstructed or cannot be seen. 
 Lesions that may not be seen in their entirety due to CT slice thickness. 


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 In cases where a lesion divides into 2 l esions, the longest diameters of the 
fragmented portions should be added together to calculate the target lesion sum.  
 In cases w here 2 lesions coalesce, a plane between them may be maintained that 
would aid in obtaining maximal diameter measurements of each individual lesion.  If 
the lesions have truly coalesced such that they are no longer separable, the vector of 
the longest diameter in this instance should be the maximal longest diameter for the 
‘coalesced lesion’. 
 
Non-target Lesions: 
­ Non-target lesions include all non-measurable lesions and measurable lesions that have not 
been selected as target lesions 
­ Lymph nodes that have a short axis <10 mm are considered non-pathological and should 
not be recorded. 
­ Any equivocal lesion without clear diagnosis (e.g., uncharacteristic solitary lung nodule 
without biopsy, uncharacteristic thyroid mass lesion without fine needle aspiration) may be 
considered a non-target lesion if it cannot be differentiated from a benign lesion.  
­ All other lesions (or sites of disease), including pathological lymph nodes, should be 
identified as non-target lesions and should also be recorded at Baseline.  Measurements are 
not required, but their presence, absence, or unequivocal progression should be followed 
throughout the study. 
­ It is possible to record multiple non-target lesions involving the same organ as a single 
item on the eCRF (e.g., multiple enlarged pelvic lymph nodes or multiple liver metastases). 
7.2.1.3. 
Response Criteria 
On-site assessments will include the assessment of: 
­ Target and non-target tumour responses. 
­ Overall response. 
The above assessments will be made as per the time points identified in section 4.2.6.1.15. 
7.2.1.3.1. 
Target and Non-target Response Assessments 
7.2.1.3.1.1. 
Criteria for Assessment of Tumour Response 
Assessments will be based on the definitions below. 
TARGET LESIONS 
Lesions Response 
Definition 
Complete Response (CR) 
The disappearance of all target Any pathological lymph nodes must have 
reduction in short axis to <10 mm. 
Partial Response (PR) 
At least a 30% decrease in the sum of diameters of the target lesions, taking as a 
reference the baseline sum diameters. 
Progressive Disease (PD) 
At least a 20% increase in the sum of diameters of the target lesions, taking as a 
reference the smallest sum on study, including the baseline sum.  In addition to 
the relative increase of 20%, the sum must also demonstrate an absolute increase 
of at least 5 mm.  Definitive new lesion presence also indicates progression. 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD, taking as a reference the smallest sum diameters while on study. 
 


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NON-TARGET LESIONS 
Lesions Response 
Definition 
Complete Response (CR) 
The disappearance of all non-target lesions lesions and normalisation of tumour 
marker level.  All lymph nodes must be non-pathological morphologically (i.e., 
<10 mm in short axis in size).   
Non-CR/Non-PD 
A persistence of ≥1 non-target lesion(s) and/or maintenance of tumour marker 
level above the normal limits. 
Progressive Disease (PD) 
Unequivocal progression of existing non-target lesions (see definition below). 
Progression in Non-target Disease:  
There must be an overall level of substantial worsening in non-target disease such that, even 
in the presence of SD or PR in target disease, the overall tumour burden has increased 
sufficiently to merit discontinuation of therapy.   
Because worsening in non-target disease cannot be easily quantified, a useful test that can be 
applied when assessing patients for unequivocal progression is to consider if the increase in 
overall disease burden based on t he change in non-measurable disease is comparable in 
magnitude to the increase that would be required to declare progressive disease (PD) for 
measurable disease; i.e., an increase in tumour burden representing an additional 73% 
increase in ‘volume’ (which is equivalent to a 20% increase diameter in a measurable lesion). 
7.2.1.3.1.2. 
Additional Criteria to Consider When Assessing Tumour Response 
When effusions are known to be a p otential adverse effect of treatment, cytological 
confirmation of the neoplastic origin of any effusion that appears or worsens during treatment 
when the measurable tumour has met criteria for response or SD is not mandatory, but might 
be performed to differentiate between response (or SD) and PD when substantial change of 
effusion and or ascites is noted. 
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  I f at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected.   
 
CEA will be followed with a dosage every 8 weeks (aligned on tumour assessments). The 
CEA assessments will be made as per the time points identified in section 4.2.6.1.14. 
CEA alone cannot be used to assess objective tumour response. If markers are initially above 
the upper normal limit (<2.5ng/ml for an adult non-smoker and <5ng/ml for a smoker), 
however, they must normalise for a patient to be considered in complete response. 


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7.2.1.3.2. 
Overall Response Assessment 
Assessments will be based on the definitions provided in Table (7.2.1.3) 1 below.  
 
Table (7.2.1.3) 1 - Time point response for patients with target (±non-target) disease 
 Table (7.2.1.3) 1 (Cont'd) - Time point 
    
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
or 
Not 
all 
evaluated 
No 
PR 
PR 
Non-PD or Not all evaluated 
No 
PR 
SD 
Non-PD or Not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
Not evaluable 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
  
 
  
7.2.1.4. 
Best Overall Response Assessment 
The confirmation of the response is required in this study. 
The best overall response as per RECIST 1.1 (Eisenhauer EA et al., 2009; Appendix 3) is the 
best confirmed response recorded from the start of the study treatment until the end of 
treatment. Complete or partial responses may be claimed only if the criteria for each are met 
at least 4 weeks later. In this circumstance, the best overall response can be interpreted as in 
Table 3 of the RECIST 1.1.  
7.2.2. Quality of Life 
The EORTC Quality of Life Questionnaires – Core questionnaire (EORTC QLQ-C30) and 
CRC-specific module (QLQ-CR29) (Appendix 1) will be used in this study. 
These 2 questionnaires should be filled in at the beginning of the visit prior to other study 
procedures. The investigator should explain to the patient how to complete the questionnaires 
but neither he/she nor the research staff can assist the patient with their completion. The 
patient should complete the questionnaires by him/herself in a quiet place. If the patient is 
unable to read, an impartial witness (independent of the research staff) can help the patient to 
fill in the questionnaires. The questionnaires are printed in duplicate on c opy paper. The 
original of each questionnaire will be collected by the study monitor and the copy will stay on 
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8. ASSESSMENT OF SAFETY 
8.1. Safety measurements 
Safety measurements performed during the study are indicated in Table (4.2.5) 1 and 
Table (4.2.5) 2. 
8.2. Methods and measurement times 
8.2.1. Laboratory Evaluations 
8.2.1.1. 
Reporting and Evaluation of Laboratory Test Results 
Laboratory tests are to be performed as required per protocol. All laboratory values that are 
out of the normal range are to be evaluated for their clinical significance before exposing the 
patient to the next dose of study medication.   
 
The laboratory must provide normal reference ranges.  
 
Any laboratory abnormality that has a clinical impact on the patient, e.g., results in delay of 
study medication dosing, study discontinuation, requires treatment due to abnormal values, or 
is considered by the Investigator to be medically important, must be reported as an AE, unless 
it is considered a supporting lab to a clinical diagnosis that is already reported as an AE.  If 
there is a question or concern, please call the sponsor.  All laboratory data will be analysed 
using NCI-CTCAE grade criteria (Version 4.03).  
8.2.1.2. 
Repeat Testing 
Repeat the evaluation of any clinically significant laboratory test, as clinically indicated, until 
the value returns to the baseline level or clinically stabilises, or until another treatment is 
given. 
8.2.2. Physical Examination and Performance Status 
Perform physical examinations and performance status evaluations as described in the Study 
Procedures section of the protocol.  If changes are observed, determine whether they meet the 
definition of an AE. Document all observations and evaluations. 
8.2.3. Vital Signs and Body Weight 
Verify and document vital signs and body weight. If a clinically significant change is 
observed, repeat the measurement as clinically indicated and evaluate for its clinical relevance 
and whether it meets the definition of an AE. 
8.3. Management of toxicities and dose modifications  
General notes regarding dose modifications. 
For patients who have experienced a dosing delay for starting treatment cycle, reasons for 
dose modifications or delays, the supportive measures taken, and the outcome will be 
documented in the patient's source documents and recorded in the eCRF. 


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Before starting a n ew treatment cycle, toxicity must have resolved as specified in the 
following sections. 
Treatment interruptions are regarded as lost treatment days and missed doses should not be 
replaced; the planned treatment schedule should be maintained. 
8.3.1. S 95005 
8.3.1.1. 
S 95005 dose reduction levels 
S 95005 dose reductions to be applied in case of toxicity and the number of tablets for each 
calculated BSA are described in Table (8.3.1.1) 1. 
Patients are permitted dose reduction(s) to a minimum dose of 20 mg/m2 BID (40 mg/m2/day) 
in 5 mg/m2 steps. 
Table (8.3.1.1) 1 - S 95005 dose reduction levels and number of tablets per dose 
 Table (8.3.1.1) 1 (Cont'd) -  
 
S 95005 
Dose (2x daily) 
BSA 
(m2) 
Dosage in mg 
(2x daily) 
Total 
daily 
dose (mg) 
Tablets per dose 
15 mg 
20 mg 
Level 1 Dose reduction: From 35 mg/m2 to 30 mg/m2 
30 mg/m2 
< 1.09 
30 
60 
2 
0 
1.09 - 1.24 
35 
70 
1 
1 
1.25 - 1.39 
40 
80 
0 
2 
1.40 - 1.54 
45 
90 
3 
0 
1.55 - 1.69 
50 
100 
2 
1 
1.70 - 1.94 
55 
110 
1 
2 
1.95 - 2.09 
60 
120 
0 
3 
2.10 - 2.28 
65 
130 
3 
1 
≥ 2.29 
70 
140 
2 
2 
Level 2 Dose Reduction: From 30 mg/m2 to 25 mg/m2 
25 mg/m2 
< 1.10 
25a 
50a 
2 (PM) a 
1 (AM) a 
1.10 - 1.29 
30 
60 
2 
0 
1.30 - 1.49 
35 
70 
1 
1 
1.50 - 1.69 
40 
80 
0 
2 
1.70 - 1.89 
45 
90 
3 
0 
1.90 - 2.09 
50 
100 
2 
1 
2.10 - 2.29 
55 
110 
1 
2 
≥ 2.30 
60 
120 
0 
3 
Level 3 Dose Reduction: From 25 mg/m2 to 20 mg/m2 
20 mg/m2 
< 1.14 
20 
40 
0 
1 
1.14 – 1.34 
25a  
50a 
2 (PM)a 
1 (AM)a  
1.35 – 1.59 
30 
60 
2 
0 
1.60 – 1.94 
35 
70 
1 
1 
1.95 – 2.09 
40 
80 
0 
2 
2.10 – 2.34 
45 
90 
3 
0 
≥ 2.35 
50 
100 
2 
1 
a At a total daily dose of 50 mg, patients should take 1 x 20-mg tablet in the morning and 2 x 15-mg tablets in the 
evening. 
BSA=body surface area (calculate to 2 decimal places) 


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If dose modification fails to result in achieving minimal criteria to resume treatment, the 
Investigator should discontinue S 95005. 
 
Should the toxicities that require S 95005 dose reduction recur after dose reduction to 
20 mg/m2, S 95005 should be discontinued. 
 
Do not increase study medication dose after it has been reduced. 
8.3.1.2. 
S 95005 dose modification in response to non-hematologic toxicities 
Rules for S 95005 dosing modifications for treatment-related non-hematologic AEs are 
provided in Table (8.3.1.2) 1. At the discretion of the Investigator, patients may continue on 
S 95005 at the same dose without reduction or interruption for drug-related AEs (irrespective 
of grade) considered unlikely to become serious or life-threatening (including, but not limited 
to, fatigue, alopecia, changes in libido, and dry skin).   
Table (8.3.1.2) 1 - S 95005 dose modification criteria for non-hematologic toxicities 
 Table (8.3.1.2) 1 (Cont'd) -  
    
Gradea 
Dose hold/Resumption 
within a 28-day treatment cycle 
Dose adjustment for  
next cycle 
Grade 1 or 2 
Any occurrence 
Maintain treatment at the same dose level 
None 
Grade 3a or Higher 
1st, 
2nd, 
or 
3rd 
occurrence 
Suspend treatment until Grade 0 or 1 or 
baseline 
Reduce by 1 dose level from the previous 
level 
4th occurrence 
Discontinue treatment 
Discontinue treatment 
a Except for Grade 3 nausea and/or vomiting controlled by aggressive antiemetic therapy or diarrhoea responsive 
to antidiarrheal medication. 
 
If there is any uncertainty about continuing therapy or resuming therapy in a patient with 
Grade ≥3 non-hematologic drug-related AEs, the case must be discussed with the Sponsor’s 
CRA prior to continuing therapy.  
8.3.1.3. 
 S 95005 dose modification in response to hematologic toxicities 
Criteria for dose hold and resumption in response to hematologic toxicities related to 
myelosuppression are described in Table (8.3.1.3) 1 and Table (8.3.1.3) 2 respectively. 
 
NOTE: For all patients with decreases in neutrophils and/or platelets, the next cycle of study 
treatment should not be started until the resumption criteria in Table (8.3.1.3) 2 are met even 
if the decreases did not meet the hold criteria. 
Table (8.3.1.3) 1 - S 95005 dose hold criteria for hematologic toxicities related to myelosuppression 
 
Parameter 
Hold criteria 
Conventional Units 
SI Units 
Neutrophils 
<500/mm3 
<0.5 × 109/L 
Platelets 
<50,000/mm3 
<50 × 109/L 
SI=International System 
 
 


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Table (8.3.1.3) 2 - S 95005 resumption criteria for hematologic toxicities related to myelosuppression 
 Table (8.3.1.3) 2 (Cont'd) -  
 Erreur ! Source du renvoi introuvable. (Cont'd) Erreur ! Source du renvoi introuvable. 
Parameter 
Resumption criteriaa 
Conventional Units 
SI Units 
Neutrophils 
≥1500/mm3  
≥1.5 × 109/L 
Platelets 
≥75,000/mm3 
≥75 × 109/L 
aThese resumption criteria apply to the start of the next cycle for all patients regardless of whether or not the hold 
criteria were met. 
SI=International System 
 
Criteria for S 95005 dose reduction in response to hematologic toxicities are as follows: 
In case of febrile neutropenia, Grade 4 neutropenia that results in more than 1 week delay in 
start of next cycle or Grade 4 thrombocytopenia that results in more than 1 week delay in start 
of next cycle:  
­ Interrupt dosing until toxicity resolves to Grade 1 or baseline, 
­ When resuming dosing, decrease the dose level by 5 mg/m²/dose from the previous dose 
level (Table (8.3.1.1) 1). 
 
For recommendation regarding use of G-CSF please refer to section 6.3.2. 
 
Patients who experience complicated ≥Grade 3 neutropenia or thrombocytopenia should be 
considered for administration of hematopoietic growth factors, or for a dose reduction in the 
next cycle or both, dependent on the severity of the complication. 
8.3.1.4. 
S 95005 dose resumption 
If the patient recovers from toxicities requiring dose delay: 
­ during the 2-week treatment period of a cycle (treatment D1-5 and D8-12) 
 If no dose reduction is required, S 95005 may be resumed during that cycle.  
 If a dose reduction is required, S 95005 should be resumed at the start of the 
next cycle at the appropriate dose level as shown in Table (8.3.1.3) 2. Do not 
increase study medication dose after it has been reduced. 
­ during the recovery period (D13-28): 
 start the next cycle on schedule at the appropriate S 95005 dose level based on 
sections 8.3.1.2 and 8.3.1.3 above.  
 
If the toxicities that are defined above do not recover during the treatment or rest period, the 
start of the next cycle can be delayed for a maximum of 28 days from the scheduled start date 
of the next cycle. If resumption criteria are met by this maximum 28-day delay, start the next 
cycle, according to the planned treatment schedule, at the appropriate dose level.   
 
Patients who require more than a 28-day delay in the scheduled start date of the next cycle 
will have S 95005 discontinued. 
8.3.2. Capecitabine 
Refer to the package insert for dose modification guidelines. 
8.3.3. Bevacizumab 
There are no recommended dose reductions for bevacizumab. Refer to the package insert for 
events requiring discontinuation or suspension of administration. 


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8.4. Adverse events 
All adverse events and other situations relevant to the safety of the participants must be 
followed up and fully and precisely documented in order to ensure that the sponsor has the 
necessary information to continuously assess the benefit-risk balance of the clinical trial. 
8.4.1. Definitions 
8.4.1.1. 
Adverse events 
An adverse event is defined as any untoward medical occurrence in a subject participating in a 
clinical study, whether or not there is a causal relationship with the IMP and/or experimental 
procedures, occurring or detected from the date the participant signs the information and 
consent form, irrespective of the period of the study (periods without administration of the 
IMP (e.g. run-in period) are also concerned). 
An adverse event can therefore be: 
­ any unfavourable and unintended sign, including an abnormal finding from an additional 
examination (e.g. lab tests, X-rays, ECG), and which is deemed clinically relevant by the 
investigator, 
­ any symptom or disease, 
­ any worsening during the study of a symptom or a disease already present when the 
participant entered the study (increase in frequency and/or intensity), including the studied 
pathology, and which is deemed clinically relevant by the investigator,  
detected during a study visit or at an additional examination or occurred since the previous 
study visit (including relevant event reported in participant’s diary or safety evaluation scale). 
 
Of note: 
­ Any hospitalisation for social reasons, educational purpose (e.g. learning of diabetes 
management by the participant) or routine check-up should not be considered as an adverse 
event and should not be reported in the CRF. 
­ The following procedures, whether planned before the study or not, whether leading to a 
hospitalisation or not, should be reported in the specific page “Procedures not 
subsequent to an adverse event” of the CRF:  
 therapeutic procedures related to a non-aggravated medical history (e.g. cataract 
extraction not due to an aggravation of the cataract during the study, haemodialysis 
sessions related to a renal insufficiency not aggravated during the study),  
 prophylactic procedures (e.g. sterilisation, wisdom teeth removal),  
 comfort procedures (e.g. cosmetic surgery),  
 control procedures of a pre-existing condition without aggravation (e.g. colonoscopy to 
control the remission of colon cancer). 
 Progression of underlying malignancy is not reported as an adverse event if it is clearly 
consistent with the suspected progression of the underlying cancer as defined by 
RECIST criteria, or other criteria as determined by protocol. Hospitalization due solely 
to the progression of underlying malignancy should NOT be reported as a serious 
adverse event. 
­ Clinical symptoms of progression may be reported as a dverse events if the symptom 
cannot be determined as exclusively due to the progression of the underlying malignancy, 
or does not fit the expected pattern of progression for the disease under study.  


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Symptomatic deterioration may occur in some patients. In this situation, progression is 
evident in the patient’s clinical symptoms, but is not supported by t he tumour 
measurements. Or, the disease progression is so evident that the investigator may elect not 
to perform further disease assessments. In such cases, the determination of clinical 
progression is based on symptomatic deterioration. These determinations should be a rare 
exception as every effort should be made to document the objective progression of 
underlying malignancy. 
If there is any uncertainty about an adverse event being due only to the disease under 
study, it should be reported as an AE or SAE. 
 
On the other hand, in the framework of this protocol, the following serious adverse events 
must not be notified immediately: 
­ any hospitalisation and/or surgical procedure planned before the entry of the participant in 
the study (without any worsening after entry in the study). 
­ hospitalisation for the administration of chemotherapy treatment or other care measures for 
cancer during the study and 100 days following last study drug intake. 
8.4.1.2. 
Serious adverse events 
Any adverse event that at, any dose: 
­ results in death, 
­ is life-threatening(1), 
­ requires inpatient hospitalization or prolongation of existing hospitalization, 
­ is medically significant(2), 
­ results in persistent or significant disability/incapacity(3), 
­ is a congenital anomaly/birth defect(4). 
 
(1) Life-threatening in this context refers to an event in which the participant 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.  
 
(2) Any event that might not be immediately life-threatening or result in death or 
hospitalisation, but might jeopardise the participant or might require intervention to prevent 
one of these outcomes (for example: oedema or allergic bronchospasm that required intensive 
treatment at home, blood dyscrasia, convulsions that do not result in hospitalisation, or 
development of drug dependence or drug abuse). The investigator should exercise his/her 
scientific and medical judgement to decide whether or not such an event requires expedited 
reporting to sponsor. 
 
(3) Disability/incapacity in this context refers to any event that seriously disrupts the ability of 
the participant to lead a n ormal life, in other words leads to a p ersistent or permanent 
significant change, deterioration, injury or perturbation of the participant's body functions or 
structure, physical activity and/or quality of life. 
(4) Congenital anomaly or birth defect refers to the exposure to the IMP before conception (in 
men or women) or during pregnancy that resulted in an adverse outcome in the child. 
8.4.1.3. 
Adverse event of special interest 
NA 


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8.4.1.4. 
Overdose 
This refers to any intake of a quantity of IMP which is above the maximum dose 
recommended, (i.e., 35 mg/m²/dose or > 160 mg/day for S 95005) in the study protocol, 
independently of the occurrence of any adverse event.  
The quantity should be considered per administration or cumulatively regarding the 
recommended total dose in each cycle. 
For capecitabine and bevacizumab: please refer to SmPC for overdose management 
information. 
8.4.1.5. 
Events requiring an immediate notification (ERIN) 
An event must be notified immediately (i.e. within 24 hours) to the sponsor if it is: 
­ a serious adverse event, 
­ an adverse event of special interest, 
­ an overdose of the IMP even if asymptomatic,  
­ any intake of the IMP by a person around the participant, 
­ a pregnancy. 
8.4.2. Responsibilities of the investigator 
For any adverse event and special situation mentioned above the investigator must: 
­ Note in the participant's medical file the date on which he/she learned of the event (at a 
follow-up visit or a telephone contact with the participant or a third person, …) and any 
other relevant information which he/she has learned of the event,  
­ Report the event to the sponsor using the AE form (in case of ERIN, the reporting should 
be done immediately),  
­ Evaluate the seriousness, intensity and causality, 
­ Document the event with additional useful information,  
­ Ensure the follow-up of the event,  
­ Fulfil his/her regulatory obligations to the Competent Authorities and/or to the IRB/IEC, 
in accordance with local regulations. 
8.4.2.1. 
Time frame for AE reporting 
Any event meeting the above mentioned definitions (see section 8.4.1) must be reported to the 
sponsor on an adverse event form if it occurred: 
­ before the first intake of the test drug, for event associated with any procedure/condition 
required by the study protocol: procedure (MRI, etc.), change or withdrawal of 
previous/concomitant treatment relating to the conditions of the protocol. 
­ at any time after the first intake of the test drug up to the participant’s last study drug 
intake for all events,  
­ after the participant’s last study drug intake: 
 up to 100 calendar days after the participant's last test drug intake for all ERIN, 
regardless of the supposed role of the research (IMP, or experimental procedure). 
 irrespective of the time of onset after the end of the study in case of serious adverse 
event related to the research (IMP, or experimental procedure). 
Of note, events occurring between the signature of the informed consent and the first 
administration of the test drug for which the investigator does not consider an association with 


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any procedure/condition required by the study protocol must be reported as medical history 
in the dedicated form of the e-CRF. 
 
All other adverse events 
 to be reported as Medical history 
 
 
 
 
 
 
 
 
Adverse Events associated 
with: 
- A procedure scheduled in the study 
protocol, 
- A change or withdrawal of previous 
/ concomitant treatment related to the 
conditions of the protocol, 
- A product other than the test drug, 
taken as part of the protocol. 
 
All adverse 
events 
 
All 
ERIN 
 
All SAE related to 
the research (IMP, non 
IMP, experimental 
procedure) 
 to be 
reported as 
Adverse 
Event 
 
 
  
  
  
 
Signing of the  
consent form  
1st administration 
of the test drug 
Participant's last 
test drug intake 
100 calendar days 
after the participant's 
last test drug intake 
 
 
 
 
 
 
8.4.2.2. 
Evaluation of seriousness, intensity and causality 
It is important that the investigator gives his/her own opinion regarding the seriousness, the 
intensity of the event as well as the cause-effect relationship between an adverse event and 
the test drug. This evaluation must be assessed by the investigator and reported in the AE 
form. 
The Seriousness should be evaluated according to international guidances (see definition in 
section 8.4.1.2 in accordance with ICH Topic E2A [ICH E2A, 1994] and DIRECTIVE 
2001/20/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 4 April 
[Directive 2001/20/EC, 2001]) . 
The intensity of all AEs will be graded according to the National Cancer Institute Common 
Toxicity Criteria for Adverse Event (NCI-CTCAE 4.03) on a five point scale (Grade 1 to 5): 
­ Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
­ Grade 2: Moderate; minimal, local or non-invasive intervention indicated; limiting age-
appropriate instrumental ADL1. 
­ Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL2. 
­ Grade 4: Life-threatening consequences; urgent intervention indicated. 
­ Grade 5: Death related to AE. 
The causal relationship to the test drug must be assessed when reporting the AE in the AE 
form. Only cases ticked “related” by the investigator or judged by the sponsor as having a 
                                                 
1 Instrumental Activities of Daily Living (ADL) refer to preparing meals, shopping for groceries or clothes, 
using the telephone, managing money, etc. 
2 Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and 
not bedridden”. 


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reasonable suspected causal relationship to the test drug will be considered as suspected 
Adverse Drug Reaction. In general, the expression reasonable causal relationship means to 
convey that there is evidence or arguments to suggest a causal relationship. 
8.4.2.3. 
Documentation of the event 
The investigator must ensure that all events are well documented. In particular for ERIN, 
he/she should provide the sponsor, as they become available, with anonymized copies of the 
documents which provide additional useful information, such as hospital admission reports, 
reports of further consultations, laboratory test reports, reports of other examinations aiding 
diagnosis or the autopsy report, if autopsy is performed. 
8.4.2.4. 
Follow-up of adverse events 
The investigator must ensure that follow-up of the participant is appropriate to the nature of 
the event, and that it continues until resolution if deemed necessary. 
Any change in terms of diagnosis, intensity, seriousness, measures taken, causality or 
outcome regarding an adverse event already reported must be written up in a new complete 
evaluation of the event documented on the “Adverse event” page previously created for the 
event. 
If the adverse event has not resolved at the participant's final visit in the study, the participant 
must be followed up suitably and any information on the outcome of the event will be noted 
on the “Adverse Event” page previously created for the event. 
If the follow-up of the participant is not done by the investigator him/herself (hospitalisation, 
followed by a specialist or the participant's general practitioner …), the investigator will do 
everything to establish/maintain contact with the person/department in charge of follow-up of 
the participant. 
8.4.2.5. 
Special situations (pregnancy, overdoses, intake of IMP by a person around 
the participant) 
Pregnancy  
If a female participant in the study becomes pregnant, the investigator must: 
­ stop immediately the test drug (if the pregnancy is a non-selection/non-inclusion criterion), 
­ report it on an “Adverse Event” page as well as on the specific paper pregnancy form (1st 
page) to be notified immediately (ERIN), 
­ contribute to the follow-up of this pregnancy and provide the sponsor with information 
concerning this follow-up (notably using the 2nd page of the specific paper pregnancy 
form). 
­ If the partner of a participant becomes pregnant during the course of the study, the 
pregnancy should not be reported in the e-CRF. The investigator should immediately 
contact the sponsor (contact details provided in the investigator’s study file) who will 
inform him/her about the procedure to be followed. 
Overdose of IMP  
­ In case of overdose, the investigator should report it on an “Adverse Event” page to be 
notified immediately (ERIN).  
­ Overdose should be followed-up to ensure that the information is as complete as possible 
with regards to:  
 dose details (number of units, duration,…) and, if multiple overdose, details regarding 
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 context of occurrence, i.e. intentional (suicide attempt, other reason) or accidental (error 
in prescription, administration, dispensing, dosage),  
 related signs and symptoms (“No related adverse events” to be reported otherwise),  
 outcome. 
 
Intake of IMP by a person around the participant 
This event should not be reported in the e-CRF. The investigator should immediately contact 
the sponsor (contact details provided in the investigator’s study file) who will inform him/her 
about the procedure to be followed. 
8.4.2.6. 
Recording Methods in the e-CRF 
Adverse events must be documented on the “Adverse Event” page of the e-CRF. 
In case of chronic disease: 
­ if the disease is known when the participant enters in the study, only worsening (increased 
frequency and/or intensity of the episodes/attacks) will be documented as an adverse event,  
­ if the disease is detected during the study and if repeated episodes enable diagnosis of a 
chronic disease, the episodes will be grouped on the “Adverse Event” page previously 
created for the event which will clearly describe the diagnosis. 
8.4.2.7. 
Procedure for an event requiring an immediate notification  
In case of an event requiring an immediate notification, the investigator must: 
­ Immediately after being informed of this event, fill in the participant's medical file as 
well as the “Adverse Event” page of the e-CRF according to the general instructions 
available in the e-CRF, without waiting for the results of the clinical outcome or of 
additional investigations. When data will be submitted into Inform, an e-mail will be 
immediately and automatically sent to the sponsor. 
­ Provide the sponsor (person designated in the contact details provided in the investigator’s 
study file), as they become available, with anonymized copies of the documents which 
provide additional useful information, 
­ Fulfil his/her regulatory obligations to the Competent Authorities and/or to the IRB/IEC, in 
accordance with local regulations. 
If an adverse event initially non-serious worsens and becomes serious (ERIN), this must be 
reported immediately on an “Adverse event” page of the e-CRF. 
In case the e-CRF is unavailable when the investigator was informed of the ERIN, he/she 
should: 
­ Immediately fill in a paper “Adverse event” page: 
 For serious event on a paper “Adverse event – Initial information” page,  
 For event initially non-serious on a paper “Adverse event – Initial information” page, 
and the worsening leading to seriousness on a paper “Adverse event – Additional 
information” page,  
­ Immediately send them by fax to the person(s) designated in the contact details provided in 
the investigator’s study file or outside working hours, the 24-hour phone line,  
­ As soon as the e-CRF becomes available, the investigator should enter these data in the 
“Adverse Event” page of the e-CRF. 


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8.4.3. Responsibilities of the sponsor 
In accordance with international guidances, the assessment of the seriousness and the 
causality of adverse events are usually made by the investigator but falls also under sponsor’s 
duties, who is responsible for ensuring that all suspected unexpected serious adverse reactions 
are reported to Competent Authorities and Ethics Committees.  
The sponsor will review the seriousness of the adverse events and the causality of (at least) 
the serious adverse events, whether reported by the investigator or upgraded by the sponsor. 
The causality and the seriousness may be upgraded (but never downgraded). Anonymized 
copies of documents providing useful information such as reports of further consultations, 
laboratory tests reports, reports of other examination aiding diagnosis may be asked for the 
event assessment. If the assessments of the investigator and the sponsor are different, both 
will be reported in the clinical study report. 
Independently of the regulatory obligations of the investigator, the sponsor must report the 
pharmacovigilance data to the appropriate Authorities and to all the investigators involved, 
according to the requirements stated in ICH Good Clinical Practice guidelines (ICH E6, 1996) 
and local regulations.  
8.4.4. Responsibilities of Data Safety Monitoring Board 
In accordance with the DSMB charter and the rules for DSMB functioning, the DSMB is 
responsible for reviewing the efficacy (including disease-related events and safety data on a 
regular basis (including disease-related events), and providing written recommendations to the 
International Coordinator and the Sponsor regarding the conduct of the study (modification or 
termination). 
 


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9. OTHER ASSESSMENTS NOT SPECIFICALLY RELATED TO EFFICACY OR 
SAFETY 
9.1. Assessments related to selection/inclusion criteria. 
Pregnancy test 
9.2. Measurement of drug concentration 
Not applicable 
9.3. Biomarkers  
9.3.1. Circulating biomarkers for genomic (circulating tumour DNA) 
Blood samples for tumour genomic analysis on circulating DNA will be collected into EDTA 
tubes at C1D1 predose before test drugs administration. The plasma will be separated by 
centrifugation and stored at <-70°C in an appropriate labelled storage cryotube and sent on 
dry ice. DNA will be extracted from plasma sample and subjected to genomic analysis 
including KRAS, NRAS and BRAF mutation to identify genetic events that may be 
associated with response or resistance to S 95005 and/or bevacizumab, according to a separate 
protocol.  
Their collections are mandatory for all patients in both arms. In addition, patients will be 
proposed to participate to an optional retrospective analysis. If the patient aggree by signing 
an separate ICF, backup DNA extracts may be retained up to 25 years after study closure in a 
storage repository for retrospective analysis according to local regulation.  
9.3.2. Circulating biomarkers for proteomic 
Blood samples for circulating proteins biomarkers analysis including thymidine kinase (TK1) 
and thymidine phosphorylase (TP) levels will be collected at C1D1 predose before test drugs 
administration and at withdrawal visit. After centrifugation, samples will be aliquoted and 
stored at < -70°C and sent on dr y ice. These samples will be processed for analysis of 
predictive and resistance biomarkers for S 95005 and/or bevacizumab response or biological 
activity, according to a separate protocol.  
Their collection is mandatory for all patients in both arms. Biological samples will be 
destroyed after analysis. 
9.3.3. Archived biopsy (if available) 
Archived tumour samples, collected at metastatic stage diagnosis, will be analysed to identify 
biomarkers that may predict response to S 95005 and capecitabine in combination with 
bevacizumab. Samples will be analysed to assess g enomic and proteomic expression 
including microsatellite instability. The analysis will be described in a separate analysis 
protocol. 
9.3.4. Transfer of results 
Results will be transferred to Data Management according to section 14.2. 


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10. STATISTICS 
10.1. Statistical analysis 
Statistical analysis will be performed using SAS software by a Contract Research 
Organisation under the responsibility of the Pole of Expertise Methodology and Data 
Valorisation of I.R.I.S. 
A Statistical Analysis Plan (SAP), and associated templates for Tables, Listings and Graphs, 
will be written and completed before database lock. These specifications will detail the 
implementation of all the planned statistical analyses in accordance with the main 
characteristics stated in the protocol. 
10.1.1. Endpoints 
10.1.1.1. Efficacy endpoints 
The efficacy endpoints are defined according to guidelines (ICH E9, 1998; EMEA 
Guidelines, 2005). 
10.1.1.1.1. 
Primary efficacy endpoint 
Progression free survival (PFS) is defined as the time from the date of randomization until 
the date of the investigator-assessed radiological disease progression or death due to any 
cause.  Patients who are alive with no disease progression as of the analysis cut-off date will 
be censored at the date of the last evaluable tumour assessment. Patients who receive non-
study cancer treatment before disease progression will be censored at the date of the last 
evaluable tumour assessment before the non-study cancer treatment is initiated.  D etailed 
censoring rules are outlined in the SAP. The PFS cut-off date used for the primary analysis 
will be based on the observation of the 100th event (PD or death) in the study.   
10.1.1.1.2. 
Secondary efficacy endpoints 
­ Disease Control Rate (DCR): The assessment of DCR will be based on Investigator 
review of the images. DCR is defined as the proportion of patients with objective evidence 
of confirmed CR or PR, or SD.   
­ Objective Response Rate (ORR): The assessment of ORR will be based on Investigator 
review of the images. ORR is defined as the proportion of patients with objective evidence 
of confirmed CR or PR.   
At the analysis stage, the best overall response will be assigned for each patient as the best 
confirmed response recorded from the start of the study treatment until the end of 
treatment.  If applicable, responses recorded after disease progression or initiation of non-
study cancer treatment will be excluded. A patient’s best response assignment of SD needs 
to be maintained for at least 6 weeks after study randomization. The minimum time 
requirement for response confirmation is 4 weeks. 
­ Duration of response (DR) is derived for those patients with objective evidence of PR or 
CR. DR is defined as the time from the first documentation of response (CR or PR) to the 
first documentation of objective tumour progression or death due to any cause. Patients 
alive and progression free as of the analysis cut-off date are censored at their last evaluable 
tumour response assessment prior to initiation of any non-study cancer treatment. 


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­ Overall Survival (OS) is defined as the time from the date of randomization to the date of 
death.  In the absence of death confirmation or for patients alive as of the OS cut-off date, 
survival time will be censored at the date of last study follow-up, or the cut-off date, 
whichever is earlier. Patients will be followed for OS until the end of the study (last visit of 
the last patient). 
10.1.1.2. Safety endpoints 
The safety endpoints are:  
­ Adverse events (AE) 
 Serious adverse events (SAE) during the study, according to the investigator or 
sponsor opinion 
 Emergent adverse event (EAE) under treatment 
­ Clinical laboratory evaluation 
 Biochemistry, haematology, coagulation parameters 
 Urinalysis parameters 
­ Physical examination and performance status (ECOG), 
­ Vital signs, 
­ ECG parameters 
10.1.1.3. Other endpoints 
The EORTC quality of life questionnaire (QLQ) is an integrated system for assessing the 
health-related quality of life (QoL) of cancer patients participating in international clinical 
trials. The core questionnaire, the QLQ-C30, incorporates 5 functional scales (physical, role, 
cognitive, emotional, and social), 3 symptom scales (fatigue, pain, and nausea and vomiting), 
a global health status scale, and a number of single items assessing additional symptoms 
commonly reported by cancer patients (dyspnoea, loss of appetite, insomnia, constipation and 
diarrhoea) and perceived financial impact of the disease.  
The colorectal cancer module (QLQ-CR29) is meant for use among colorectal cancer patients 
varying in disease stage and treatment modality.   
10.1.2. Analysis sets  
10.1.2.1. Analysis sets  
­ Non Included Set (NIS): All enrolled patients not selected or not included. 
­ Randomised Set (RS): All patients to whom a therapeutic unit was randomly assigned 
using IWRS. 
­ Full Analysis Set (FAS): All randomized patients who have taken at least one dose of 
IMP will be included in the FAS. Based on the intention-to-treat principle, patients in the 
FAS will be analysed in the arm they were assigned by randomization. 
­ Per Protocol Set (PPS): All patients of the FAS without relevant deviation(s), which 
could affect the evaluation of the IMP effect on the primary efficacy endpoint. 
­ Tumour Response (TR) Population: All patients in the PPS with measurable disease (at 
least one target lesion) at baseline and with at least one tumour evaluation while on 
treatment (with the same method of measurement as baseline). Patients who have a cancer- 


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related death prior to their first tumour evaluation will also be considered evaluable with 
PD as best overall response. 
­ Safety Set (SS): This set will correspond to patients who received at least one dose of 
IMP. Patients will be analysed according to the treatment actually received. Each patient 
will be classified into and analysed consistently within one (and only one) treatment group. 
­ Quality of Life Set (QLS): To be included in the QLS for the QLQ-C30 questionnaire, 
patients should have completed at least two third (i.e. at least 20 questions) of the questions 
of the baseline QLQ-C30 questionnaire, and at least two third of the questions of a QLQ-
C30 questionnaire during the study period. Same conditions for the QLQ-CR29 
questionnaires. 
The determination of the analysis sets will be finalised before the database lock. 
10.1.3. Statistical methods 
10.1.3.1. General considerations 
10.1.3.1.1. 
Statistical elements 
10.1.3.1.1.1. Descriptive statistics 
The following descriptive statistics will be provided depending on the nature of considered 
data: 
­ Qualitative data: number of observed values, number and percentage of patients per class. 
­ Quantitative data: number of observed values, mean and standard deviation, median, first 
and third quartiles, minimum and maximum. 
­ Survival data (time to event occurrence): total number of patients, total number and 
percentage of patients having an event overall, number of patients at risk, number of 
patients with censored data, number of patients with event of interest. 
10.1.3.2. Study patients: Disposition, baseline characteristics and follow-up 
The patients’disposition and baseline characteristics will be described in the RS by group and 
overall. 
The number of patients in each study population and the reasons for exclusion, along with any 
randomization and/or stratification errors will be summarized as w ell as t he disposition of 
patients at baseline, including reasons for discontinuation and protocol deviations. 
Characteristics of patients including demography, characteristics of the disease at diagnosis 
and study entry, medical history, prior therapy and concomitant medication at baseline will be 
summarised. 
Extent of exposure and treatment compliance, as well as concomitant medication during 
treatment period will be described in the SS. Extent of exposure includes number of cycles, 
cumulative dose, dose intensity, relative dose intensity, dose modifications (delay, reduction, 
interruption). 
The follow-up duration will be calculated overall and in each arm with the reverse Kaplan-
Meier method. 


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The number, type, and extent of use of non-study cancer treatment after study treatment 
discontinuation will be summarized.  Any use of non-study cancer treatment during the study 
treatment period will also be presented. 
10.1.3.3. Efficacy analysis 
All efficacy analyses will be performed in the FAS, unless otherwise specified.  
10.1.3.3.1. 
Primary efficacy endpoint 
10.1.3.3.1.1. Primary analysis 
For the primary efficacy endpoint, PFS, the hazard ratio and the corresponding 2-sided 80% 
and 2-sided 95% CIs for TAS-102 + bevacizumab versus capecitabine + bevacizumab will be 
estimated using a Cox proportional hazard model adjusting for the stratification factor based 
on IWRS data.   
PFS for each arm will be summarized using Kaplan Meier curves and further characterized in 
terms of the median and survival probabilities at 6, 12, 18, a nd 24 months along with the 
corresponding 2-sided 80% and 2-sided 95% CI for the estimates. 
The primary analysis will be conducted in the FAS.  
10.1.3.3.1.2. Secondary analyses 
Sensitivity PFS Analyses 
As a secondary analysis, the primary analysis of PFS will be repeated in the PPS. 
In order to assess the consistency of the primary analysis of PFS, another sensitivity analysis 
taking into account the further anti-cancer therapy as an event will be carried out both in the 
FAS and the PPS. 
Exploratory PFS Analyses 
Additional exploratory analyses for PFS will investigate the effect of specific factors either in 
a multivariate analysis setting (Cox regression model) or as the marginal effect in specific 
subgroups. These factors will include, but are not limited to, region, ECOG performance 
status, gender, age (<75, ≥75 years), prior adjuvant treatment, location of primary disease, 
surgical resection, number of metastatic sites (1, ≥2), presence of liver metastasis, RAS and 
BRAF status. Additional exploratory analyses will be defined in the SAP.  
10.1.3.3.2. 
Secondary efficacy endpoints 
Analysis of OS will use the same population and analytical methods as described for PFS in 
the section 10.1.3.3.1. 
Analysis of DR will also use similar analytical methods but based on the TR Population.   
DCR and ORR based on the TR Population will be evaluated in each arms with their 2-sided 
95% Clopper-Pearson CIs. 


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10.1.3.4. Safety analysis 
All patients included in the Safety set (SS) will be evaluated by treatment arm in the safety 
analysis, unless otherwise specified. 
10.1.3.4.1. 
Adverse events 
Adverse events will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA) terminology and the severity of the toxicities will be graded according to the NCI 
CTCAE criteria, v4.03, where applicable.  Concomitant medications will be coded according 
to the World Health Organization Drug Dictionary (WHODD). 
Number of events, number and percentage of patients reporting at least one event, presented 
by primary system organ class, and preferred term, will be provided for serious adverse events 
and emergent adverse events over the treatment periods. 
Emergent adverse events will be described according to the seriousness, the intensity, the 
relationship, the action taken regarding the IMP, and the time to onset. 
In addition, separate summaries of SAEs and Grade 3 and 4 AEs will be presented. 
Of note, the seriousness and the relationship to the IMP of the adverse event correspond to the 
investigator opinion or, in case of events upgraded by the sponsor for seriousness or for 
causality in case of SAE, to the sponsor opinion. 
10.1.3.4.2. 
Clinical laboratory evaluation 
Haematological and chemistry laboratory parameters will be graded according to the NCI 
CTCAE v.4.03 criteria, where applicable. Absolute values and changes from baseline will be 
summarized by cycle. In addition, worst severity grade, time to event, and time to resolution 
will also be summarized. 
In order to examine the evolution of toxicities the worst grade will be analysed in relation to 
the grade presented by the patient at baseline.  
Urinalysis abnormalities will be described. 
10.1.3.4.3. 
Vital signs, clinical examination and other observations related to safety 
10.1.3.4.3.1. Vital signs and clinical examination 
Vital signs and clinical examination will be described, in terms of value at baseline, value at 
each post-baseline visit under treatment and last post-baseline value under treatment; as well 
as in terms of change from baseline to each post baseline visit under treatment and to last 
post-baseline value under treatment. 
10.1.3.4.3.2. Electrocardiogram 
ECG parameters will be described, in terms of value at baseline, value at each post-baseline 
visit under treatment and last post-baseline value under treatment; as well as, for quantitative 
endpoints, in terms of change from baseline to each post baseline visit under treatment and to 
last post-baseline value under treatment. Moreover values and changes form baseline of 


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corrected QT interval will be described in classes, considering thresholds defined in ICH E14 
(i.e., ≤ 450, ] 450; 480], ]480; 500] and > 500 ms for values, and ≤ 30, ]30; 60] and > 60 ms 
for changes). 
10.1.3.4.3.3. Quality of life analysis 
EORTC QLQ-C30 and QLQ-CR29 questionnaire responses will be described separately in 
each arm using descriptive statistics. 
The Global Scale as well as the Functional Scales in Physical, Role, Emotional, Cognitive and 
Social dimensions as w ell as the 9 symptom scales: Fatigue, Nausea and vomiting, Pain, 
Dyspnoea, Insomnia, Appetite loss, Constipation, Diarrhoea, Financial difficulties of the 
QLQ-C30 will be assessed at each time point in the QLS. 
The EORTC QLQ-CR29 and its symptom and functional scales will be assessed in a similar 
manner as that described for the QLQ-C30.  
10.1.3.5. Biomarker analysis 
Exploratory analyses for PFS will investigate the effect of potential predictive biomarkers 
(RAS, BRAF and others) in a multivariate analysis setting (Cox regression model). The 
interaction between each biomarker and the treatment will be investigated. 
For other biomarkers, descriptive statistics will be provided. 
10.2. Determination of sample size 
A screening design approach has been utilized, where sample size considerations are based on 
estimating the PFS hazard ratio with certain precision in order to optimize a future Phase 3 
confirmatory design. The primary analysis will be conducted after 100 P FS events 
(progression of disease or death) are observed in approximately 150 patients randomized in 
the study, based on 1:1 randomization. The corresponding upper limit of the 2-sided 80% CI 
for an observed PFS HR of 0.77 would just exclude 1. The corresponding HR critical value 
for a 2-sided 95% CI would be 0.67. Additional confidence interval approximations for 
varying observed hazard ratios are shown in the table below: 
Observed HR 
Approximate confidence limits 
95% CI 
80% CI 
0.55 
0.37 - 0.81 
0.43 - 0.71 
0.60 
0.41 - 0.89 
0.46 - 0.78 
0.65 
0.44 - 0.96 
0.50 - 0.84 
0.67 
0.45 - 0.99 
0.52 - 0.86 
0.70 
0.47 - 1.04 
0.54 - 0.90 
0.75 
0.51 - 1.11 
0.58 - 0.97 
0.77 
0.52 - 1.14 
0.60 - 1.00 
0.80 
0.54 - 1.18 
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An accrual period of approximately 24 months and a 20%/year loss to PFS follow-up rate has 
been assumed to account for patients that discontinue treatment for reasons other than disease 
progression and a follow-up scan that confirms progression has not been obtained (e.g., 
patient discontinues study treatment due to toxicity and new therapy is initiated prior to 
documentation of disease progression). Assuming a median PFS time in the capecitabine + 
bevacizumab arm of approximately 9 months, if the observed PFS HR is 0.77, the primary 
PFS analysis target events milestone is projected at approximately 12 months after the last 
patient is randomized in the study (projected total study duration of 36 months until the PFS 
primary analysis milestone). 


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11. DIRECT ACCESS TO SOURCE DATA / DOCUMENTS 
The investigator will allow the monitors, the persons responsible for the audit, the 
representatives of the IRB/IEC, and of the Competent Authorities to have direct access to 
source data / documents. 


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12. QUALITY CONTROL AND QUALITY ASSURANCE 
12.1. Study monitoring 
12.1.1. Before the study 
The investigator will allow the monitor to visit the site and facilities where the study will take 
place in order to ensure compliance with the protocol requirements. 
Instruction manuals will be given to the investigators 
12.1.2. During the study 
The investigator will allow the monitor to: 
­ inspect the site, the facilities and the material used for the study, 
­ meet all members of his/her team involved in the study, 
­ consult all of the documents relevant to the study, 
­ have access to the electronic case report forms (i.e. access to an analogic phone line or 
his/her computer) 
­ check that the electronic case report forms have been filled out correctly, 
­ directly access source documents for comparison of data therein with the data in the 
electronic case report forms 
­ verify that the study is carried out in compliance with the protocol and local regulatory 
requirements. 
 
The study monitoring will be carried out at regular intervals, depending on the recruitment 
rate and / or the investigation schedule, and arranged between the investigator and monitor. 
 
All information dealt with during these visits will be treated as strictly confidential. 
12.2. Computerised medical file 
If computerised medical files are used, and if the computer system allows, no change made in 
the medical files by the investigator should obscure the original information. The record must 
clearly indicate that a change was made and clearly provide a means to locate and read the 
prior information (i.e. audit trail). The investigator will save data at regular intervals. 
The investigator must guarantee the integrity of the study data in the medical files by 
implementing security measures to prevent unauthorised access to the data and to the 
computer system. 
If the computerised medical files are considered as n ot validated by the sponsor, the 
investigator undertakes: 
­ at the start of the study, to print the medical files of all participants allowing a reliable 
verification of the study criteria (e.g. medical history/previous treatments/ characteristics of 
the studied disease documented within the period of time defined by the study protocol), 
­ during the study, to print in real time each data entry and each data change. 
 
The investigator will personally sign, date and give the number of pages on the first or last 
page of each print-out. At each visit by the monitor, the investigator will provide all the print-
outs of the medical files of the participants. The monitor will personally sign and date the first 
(or last) page then initial all pages in each paper print-out. 


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If the computer system allows the tracking of the changes made to the medical files, the 
investigator will supply the monitor, at each visit, with a print-out of the medical files of the 
participants and the records of the changes made. Each print-out will be personally dated and 
signed, by the investigator and the monitor on the first page. The number of pages will also be 
indicated by the investigator and the monitor on the first page. 
If the computerised medical files are considered as validated by the sponsor, the investigator 
undertakes to give access to the monitor to the computerised medical files of all participants. 
If the monitor cannot access to the tracking of the changes made to the medical files, the 
investigator will supply the monitor, at each visit, with a print-out of the records of the 
changes made to the medical files of the participants. Each print-out will be personally dated 
and signed, by the investigator and the monitor on the first page. The number of pages will 
also be indicated by the investigator and the monitor on the first page. 
 
The investigator undertakes to keep: 
­ all medical file print-outs signed and dated by hi m/her and by t he monitor when the 
computer system is considered as not validated by the sponsor,  
­ if the computer system used allows changes to be made, the print-outs of the audit trail 
when the computer system is considered as not validated by t he sponsor or when the 
monitor cannot access to the audit trail in the computer system, 
­ all original source-documents (originals of specific examinations, informed consent forms, 
therapeutic unit tracking form or an equivalent document...). 
12.3. Audit - Inspection 
The investigator should be informed that an audit may be carried out during or after the end of 
the study. 
The investigator should be informed that the Competent Authorities may also carry out an 
inspection in the facilities of the sponsor and/or the study centre(s). The sponsor will inform 
the investigators concerned immediately upon notification of a pending study centres 
inspection. Likewise, the investigator will inform the sponsor of any pending inspection. 
The investigator must allow the representatives of the Competent Authorities and persons 
responsible for the audit:  
­ to inspect the site, facilities and material used for the study, 
­ to meet all members of his/her team involved in the study, 
­ to have direct access to study data and source documents, 
­ to consult all of the documents relevant to the study. 
 
If the computerised medical file is considered as not validated, the investigator undertakes to 
provide all the source-documents and the print-outs of the medical files of the participants 
and, if the computer system used allows, the record of the changes made during the study. 
 
If the computerised medical file is considered as validated, the investigator undertakes to: 
­ give access to the representatives of the Competent Authorities and persons responsible for 
the audit to the computerised medical files of all participants, 
­ provide the print-outs of the changes made during the study, if the tracking of the changes 
made to the medical files cannot be accessed in the computer. 


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12.4. Supervisory committees 
An independent Data Safety Monitoring Board (DSMB) will be set-up in order to monitor 
safety data during the study. 
The DSMB is independent from the sponsor and is responsible for reviewing on a regular 
basis strictly confidential data related to the safety of the patients during the study. At any 
time if necessary the Committee may ask for any supplementary information. The DSMB will 
make appropriate recommendations to the Sponsor concerning the conduct of the study: 
continuation, amendment or suspension. 
 
The detailed composition, role, and organization of the DSMB will be specified in a separate 
and specific charter. 


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13. ETHICS 
13.1. Institutional Review Board(s)/Independent Ethics Committee(s) 
The study protocol, the "Participant information and consent form" document, the list of 
investigators document, the insurance documents, the SmPC of administered IMP will be 
submitted to (an) IRB(s)/IEC(s) by the investigator(s) or the national coordinator(s) or the 
sponsor in accordance with local regulations. 
The study will not start in a centre before written approval by corresponding IRB/IEC(s) has 
been obtained, the local regulatory requirements have been complied with, and the signature 
of the clinical study protocol of each contractual party involved has been obtained. 
13.2. Study conduct 
The study will be performed in accordance with the ethical principles stated in the Declaration 
of Helsinki 1964, as revised in Fortaleza, 2013 (Appendix 5). 
13.3. Participant information and informed consent 
In any case, the participant must be informed that he/she is entitled to be informed about the 
outcome of the study by the investigator. 
The investigator or a person designated by him/her is to collect written consent from each 
participant before his/her participation in the study. Prior to this, the investigator or his/her 
delegate must inform each participant of the objectives, benefits, risks and requirements 
imposed by the study, as well as the nature of the IMPs. 
The participant will be provided with an information and consent form in clear, simple 
language. He/she must be allowed ample time to inquire about details of the study and to 
decide whether or not to participate in the study. 
Two original information and consent forms must be completed, dated and signed personally 
by the participant and by the person responsible for collecting the informed consent. 
If the participant is unable to read, an impartial witness should be present during the entire 
informed consent discussion. The participant must give consent orally and, if capable of doing 
so, complete, sign and personally date the information and consent form. The witness must 
then complete, sign and date the form together with the person responsible for collecting the 
informed consent. 
The participant will be given one signed original information and consent form, the second 
original will be kept by the investigator. 
A copy of the information and consent form in the language(s) of the country is given in the 
“Participant information and consent form” document attached to the protocol. 
13.4. Modification of the information and consent form 
Any change to the information and consent form constitutes an amendment to this document 
and must be submitted for approval to the IRB/IEC(s), and if applicable to the Competent 
Authorities. 
A copy of the new version of the information and consent form in the language(s) of the 
country will be given in the amendment to the “Participant Information and consent form”. 
Such amendments may only be implemented after written approval of the IRB/IEC has been 
obtained and compliance with the local regulatory requirements, with the exception of an 
amendment required to eliminate an immediate risk to the study participants. 


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Each participant affected by the amendment or an independent witness must complete, date 
and sign two originals of the new version of the information and consent form together with 
the person who conducted the informed consent discussion. He/she will receive one signed 
original amendment to the information and consent form. 


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14. DATA HANDLING AND RECORD KEEPING 
14.1. Study data 
An electronic data capture system is going to be used for this study. An electronic case report 
form (e-CRF) is designed to record the data required by the protocol and collected by the 
investigator. 
The e-CRF will be produced by I.R.I.S. The investigator or a designated person from his/her 
team will be trained for the use of the e-CRF by the sponsor or the CRO. 
Data entry at the investigator’s site will be performed by the investigator or by the designated 
person from his/her team after completion of the participant’s Medical File. 
Upon entry, data will be transmitted via the Internet from the study centre to the study 
database. 
The investigator or the designated person from his/her team agrees to complete the e-CRF, at 
each participant visit, and all other documents provided by t he sponsor (e.g. documents 
relating to the IMP management). 
The e-CRF should be completed within a reasonable time after the visit of participant and 
before the next scheduled visit. Data recorded directly on e-CRF and considered as source 
data (see section 4.6) must be collected immediately in the e-CRF. 
All corrections of data on the e-CRF must be made by the investigator or by the designated 
person from his/her team using electronic data clarifications according to the provided 
instructions. All data modification will be recorded using the audit trail feature of software, 
including date, reason for modification and identification of the person who has made the 
change. 
In order to ensure confidentiality and security of the data, usernames and passwords will be 
used to restrict system access to authorised personnel only, whether resident within the 
investigator’s sites, the sponsor or third parties. 
The monitor must make certain that data are completed on the e-CRF.  
Key data subject to monitor’s verification are defined in the monitoring guide. After 
comparing these data to the source documents, the monitor will request correction / 
clarification from the investigator using electronic data clarifications that should be answered 
and closed as quickly as possible. 
Data can be frozen during the study after their validation. However the investigator has the 
possibility to modify a data if deemed via a request to the sponsor. 
After the last visit of the participant, the investigator or co-investigator must attest the 
authenticity of the data collected in the e-CRF by entering his/her user name and password. 
After the data base lock, the investigator will receive a CD-ROM containing participant data 
of his/her centre for the study file. 
14.2. Data management 
Data are collected via a CRF and stored in a secured database. 
For data collected on the e-CRF, the Data & Clinical Logistics of I.R.I.S. is responsible for 
data processing including data validation performed according to a specification manual 
describing the checks to be carried out. As a result of data validation, data may require some 
changes. An electronic data clarification form is sent to the investigator who is required to 
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For data transferred from centralisators, the Data & Clinical Logistics of I.R.I.S. is 
responsible for data transfer: IWRS, centralised laboratory, provide(s) electronic transfer of 
computerised data to the Data & Clinical Logistics of I.R.I.S. Data are transferred according 
to a transfer protocol issued by the I.R.I.S. data manager. 
The Medical Data Department of I.R.I.S. is responsible for data coding including: 
- medical / surgical history, adverse events, procedures and other specific panels 
using MedDRA, 
- medications using WHO-DD.  
The coding process is described in a specification manual. 
When data validation is achieved, a review of the data is performed according to the sponsor 
standard operating procedure. When the database has been declared to be complete and 
accurate, it will be locked and made available for data analysis. 
14.3. Archiving 
The investigator will keep all information relevant to the study for at least 15 years after the 
end of the study, or more if specified by the local regulation. 
At the end of the study, the investigator will be provided with a copy of each participant’s 
data on a C D-ROM support. These data include the completed e-CRF, all electronic CRF 
comments, history of all queries, all signature history and the full audit trail reports. 


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15. INSURANCE 
I.R.I.S., or any parent company of SERVIER GROUP in charge of the management of 
clinical trials, is insured under the liability insurance program subscribed by LES 
LABORATOIRES SERVIER to cover its liability as sponsor of clinical trials on a worldwide 
basis. 
Where an indemnification system and/or a mandatory policy are in place, I.R.I.S. or any 
parent company of SERVIER GROUP will be insured under a local and specific policy in 
strict accordance with any applicable law.  
All relevant insurance documentation are included in the file submitted to any authorities’ 
approval of which is required. 


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16. OWNERSHIP OF THE RESULTS - PUBLICATION POLICY 
I.R.I.S., acting as the study sponsor, assumes full responsibility relating to this function and 
retains exclusive property rights over the results of the study, which it may use as it deems fit. 
In order to allow this information to be used effectively, it is essential that the study results be 
communicated to the sponsor as soon as possible. 
 
As the study is a multicentre one, the first publication must be performed only with data 
collected from several centres and analysed under the responsibility of the Pole of Expertise 
Methodology and Data Valorisation of I.R.I.S. The investigator commits himself not to 
publishing or communicating data collected in only one centre or part of the centres before the 
publication of the complete results of the study, unless prior written agreement from the 
sponsor has been provided 
 
Any project of publication and/or communication relative to the study and/or relative to the 
obtained results during the study or after the study end shall be submitted to the sponsor at 
least 30 da ys for a publication and 15 da ys for an abstract before the forecasted date of 
communication and/or submission for a publication. The sponsor shall make comments on the 
project within 15 days for a publication and 7 days for an abstract, of receipt of the project. 
The investigator, who submitted the project, shall take the sponsor's comments into due 
consideration. In any case, should the investigator who submitted the project decide not to 
modify the project according to the sponsor's comments, it shall provide the sponsor with the 
grounds of its decision in writing. 
 
However, in the case where the sponsor is in the process of filing a patent application on the 
results of the study, the sponsor will be able to delay its authorisation for publication or 
communication of the results of the study until the date of international registration of the 
patent. 
 
Authorship rules for trial 
­ Authorship will follow the guidelines for the target journal. This especially considering the 
maximum number of authors permitted for the target journal. 
­ The maximum number of authors will usually be included. 
­ The Coordinator will be the last author. The first author on the main publication will be the 
highest recruiter. All other authors will be listed between the first and last author according 
to recruitment. 
­ Company Representative authors should not outnumber non-Company Representative 
authors and usually should not exceed 4. 
­ Company Representative authors should not be first author. 
­ Per centre, a total of 4 authors (depending on the maximum number permitted by the target 
journal) may be included in the authors list. 


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17. ADMINISTRATIVE CLAUSES 
17.1. Concerning the sponsor and the investigator 
17.1.1. Persons to inform 
In accordance with local regulations, the investigator and/or the sponsor will inform the 
Director of the medical institution, the pharmacist involved in the study and the Director of 
the analysis laboratory.  
17.1.2. Substantial protocol amendment and amended protocol 
If the protocol must be altered after it has been signed, the modification or substantial 
amendment must be discussed and approved by the coordinators and the sponsor. 
 
The substantial protocol amendment must be drafted in accordance with the sponsor standard 
operating procedure and an amended protocol must be signed by both parties. Both 
documents must be kept with the initial protocol. 
 
All substantial amendments and corresponding amended protocols must be sent by t he 
investigator(s) or the coordinator(s) or the sponsor, in accordance with local regulations, to 
the IRB/IEC that examined the initial protocol. They can only be implemented after a 
favourable opinion of the IRB/IEC has been obtained, local regulatory requirements have 
been complied with, and the amended protocol has been signed, with the exception of a 
measure required to eliminate an immediate risk to the study participants. 
 
When the submission is performed by t he investigator or the coordinator, the latter must 
transmit a copy of IRB/IEC’s new written opinion to the sponsor, immediately upon receipt. 
 
Furthermore, the substantial amendment and amended protocol are to be submitted to the 
Competent Authorities in accordance with local regulations. 
17.1.3. Final study report 
The study report will be drafted by the Biometry Department in compliance with I.R.I.S. 
standard operating procedure. 
 
The sponsor’s representative and the coordinators must mutually agree on the final version. 
One copy of the final report must be dated and signed by the coordinators and the Director of 
the Innovation Therapeutic Pole. 
17.2. Concerning the sponsor 
The sponsor undertakes to: 
­ supply the investigator with adequate and sufficient information concerning the IMP(s) 
administered during the study to enable him/her to carry out the study, 
­ supply the investigator with investigator’s brochure if the test drug is not marketed,  
­ supply the investigator with SmPC, the one best suited to ensure patient safety, and any 
potential updated version during the study: 
­ for the test drug if marketed, to be appended to Investigator’s brochure (Section 4. 
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­ for all reference products used in the study  
­ obtain any authorisation to perform the study and/or import licence for the IMP(s) 
administered that may be required by t he local authorities before the beginning of the 
study, 
­ provide the coordinators annually, or with another frequency defined by t he local 
regulations, with a document describing study progress which is to be sent to the 
IRB/IEC(s). 
17.3. Concerning the investigator 
17.3.1. Confidentiality - Use of information 
All documents and information given to the investigator by t he sponsor with respect to 
S 95005 (TAS-102) and study CL2-95005-002 are strictly confidential. 
The investigator expressly agrees that data on his/her professional and clinical experience is 
collected by the sponsor on pa per and computer, and stored for its sole use relating to its 
activities as the sponsor of clinical trials, in accordance with GCP.  
He/she has a right to access, modify, and delete any personal data by applying to the study 
monitor. 
The investigator agrees that he/she and the members of his/her team will use the information 
only in the framework of this study, for carrying out the protocol. This agreement is binding 
as long as the confidential information has not been disclosed to the public by the sponsor. 
The clinical study protocol given to the investigator may be used by him/her or his/her 
colleagues to obtain the informed consent of study participants. The clinical study protocol as 
well as any information extracted from it must not be disclosed to other parties without the 
written authorisation of the sponsor. 
The investigator must not disclose any information without the prior written consent from 
I.R.I.S., except to the representatives of the Competent Authorities, and only at their request. 
In the latter case, the investigator commits himself to informing I.R.I.S. prior to disclosure of 
information to these authorities. 
A participant screening log and a full identification and enrolment list of each participant will 
be completed and kept by the investigator who should agree to provide access on site to the 
auditor and/or the representatives of the Competent Authorities. The information will be 
treated in compliance with professional secrecy. 
The participant screening log must be completed from the moment the investigator checks 
that a participant could potentially take part in the study (by assessment of participant medical 
history during a visit or by examination of the medical file). 
17.3.2. Organisation of the centre 
Every person to whom the investigator delegates under his/her responsibility a part of the 
follow-up of the study (e.g. co-investigator, nurse) and any other person involved in the study 
for this centre (e.g. cardiologist, pharmacist) must figure in the "Organisation of centre" 
document. 
This document should be filled in at the beginning of the study and updated at any change of a 
person involved in the study in the centre. 


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17.3.3. Documentation supplied to the sponsor 
The investigator undertakes before the study begins: 
­ to provide his/her dated and signed English Curriculum Vitae (CV) (maximum 2 pages) or 
to complete in English the CV form provided by the sponsor and to send it to the sponsor, 
together with that of his/her co-investigator(s), 
­ to provide a detailed description of the methods, techniques, and investigational 
equipment, and the reference values for the parameters measured, 
­ to provide any other document required by l ocal regulation (e.g. Food & Drug 
Administration 1572 form), 
­ to send, a copy of the IRB/IEC’s opinion with details of its composition and the 
qualifications of its constituent members. 
The CVs of other members of the team involved in the study (if possible in English) will be 
collected during the course of the study (at least, members involved in the participants’ 
medical follow-up/study-related decision process and persons involved in the measurement of 
main assessment criteria). 
The investigator must send an e-mail to the Sponsor within 24 working hours to inform about 
the last follow-up of last participant (or the last contact attempt if the last participant is 
declared lost to follow-up) in the centre. 


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18. REFERENCES 
 
Aapro MS, Bohlius J, Cameron DA, Dal Lago L, Donnelly JP, Kearney N, Lyman GH, Pettengell R, Tjan-
Heijnen VC, Walewski J, Weber DC, Zielinski C; European Organisation for Research and Treatment of 
Cancer. 2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the 
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Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, Filiberti A, Flechtner H, Fleishman 
SB, de Haes JC, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-
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Benson AB 3rd, Ajani JA, Catalano RB, Engelking C, Kornblau SM, Martenson JA Jr, McCallum R, Mitchell 
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Coghlin C, Murray G. Biomarkers of colorectal cancer: recent advances and future challenges. Proteomics 
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Cunningham D, Lang I, Marcuello E, Lorusso V, Ocvirk J, Shin DB, Jonker D, Osborne S, Andre N, 
Waterkamp D, Saunders MP; AVEX study investigators. Bevacizumab plus capecitabine versus capecitabine 
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Detailed guidance on the collection, verification and presentation of adverse event/reaction reports arising 
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Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation 
criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47 
EMEA “Guideline on evaluation of anticancer medicinal products in man”. CPMP/EWP/205/95 rev.3- 
December 2005. 
Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S, Coebergh JW, Comber H, Forman D, Bray F. 
Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer. 2013 
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Gonzales-Pons M, Cruz-Correa M. Colorectal Cancer Biomarkers: Where Are We Now? BioMed Research 
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ICH Topic E6 – Guideline for Good Clinical Practice: Consolidated guideline finalised (step 4) in June 1996. 
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ICH Topic E2A – Clinical Safety Data Management: Definitions and Standards for Expedited Reporting, 
issued as CPMP/ICH/377/95.1994 
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Kris MG, Hesketh PJ, Somerfield MR, Feyer P, Clark-Snow R, Koeller JM, Morrow GR, Chinnery LW, 
Chesney MJ, Gralla RJ, Grunberg SM. American Society of Clinical Oncology guideline for antiemetics in 
oncology: update. J Clin Oncol. 2006 Jun 20;24(18):2932-47. 
Kuboki Y, Nishina T, Shinozaki E, Yamazaki K, Shitara K, OkamotoW, Kajiwara T, Matsumoto T, Tsushima 
T, Mochizuki N, Fukutani M, Nakamoto M, Hasegawa H, Sugama A, Nomura S, Sato A, Ohtsu A, Yoshino T. 
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Y, Tabernero J, Komatsu Y, Sobrero A, Boucher E, Peeters M, Tran B, Lenz HJ, Zaniboni A, Hochster H, 
Cleary JM, Prenen H, Benedetti F, Mizuguchi H, Makris L, Ito M, Ohtsu A; RECOURSE Study Group. 
Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 2015 May 
14;372(20):1909-19. 
National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN 
Guidelines). Colon Cancer-Version 3. 2015 
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Guidelines). Rectal Cancer-Version 3. 2015 
Pocock SJ, Simon R. Sequential treatment assignment with balancing for prognostic factors in the controlled 
clinical trial. Biometrics 1975; Vol. 31: 103-115 
Price TJ, Zannino D, Wilson K, Simes RJ, Cassidy J, Van Hazel GA, Robinson BA, Broad A, Ganju V, 
Ackland SP, Tebbutt NC. Bevacizumab is equally effective and no more toxic in elderly patients with 
advanced colorectal cancer: a subgroup analysis from the AGITG MAX trial: an international randomised 
controlled trial of Capecitabine, Bevacizumab and Mitomycin C. Ann Oncol. 2012 Jun;23(6):1531-6 
Tebbutt NC, Wilson K, Gebski VJ, Cummins MM, Zannino D, van Hazel GA, Robinson B, Broad A, Ganju 
V, Ackland SP, Forgeson G, Cunningham D, Saunders MP, Stockler MR, Chua Y, Zalcberg JR, Simes RJ, 
Price TJ. Capecitabine, bevacizumab, and mitomycin in first-line treatment of metastatic colorectal cancer: 
results of the Australasian Gastrointestinal Trials Group Randomized Phase III MAX Study. J Clin Oncol. 
2010 Jul 1;28(19):3191-8 
Tsukihara H, Nakagawa F, Sakamoto K, Ishida K, Tanaka N, Okabe H, Uchida J, Matsuo K, Takechi T. 
Efficacy of combination chemotherapy using a novel oral chemotherapeutic agent, TAS-102, together with 
bevacizumab, cetuximab, or panitumumab on human colorectal cancer xenografts. Oncol Rep. 2015 
May;33(5):2135-42 
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Metastatic colorectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. 
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2016. 
 


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19. APPENDICES 


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Appendix 1: Quality of life questionnaires 
 


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Appendix 2: Performance status 
Status 
Karnofsky 
Grade 
Status 
ECOG* - ZUBROD / WHO 
Normal, no complaints; no evidence of disease. 
100 
 
0 
Fully active, able to carry on all pre-
disease performance without restriction. 
Able to carry on normal activity; minor signs or 
symptoms of disease. 
90 
 
Normal activity with efforts; some signs or 
symptoms of disease. 
80 
 
 
1 
Restricted in physically strenuous activity 
but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light 
house work, office work. 
Cares for self; unable to carry on normal activity or 
to do active work. 
70 
 
Requires occasional assistance, but is able to care for 
most of his personal needs. 
60 
 
 
2 
Ambulatory and capable of all selfcare but 
unable to carry out any work activities. Up 
and about more than 50% of waking hours. 
Requires considerable assistance and frequent 
medical care. 
50 
 
Disabled; requires special care and assistance. 
40 
 
3 
Capable 
of 
only 
limited 
self-care,  
confined to bed or chair more than 50% of 
waking hours. 
Severely disabled; hospital admission is indicated 
although death not imminent. 
30 
 
Very sick; hospital admission necessary; Active 
supportive treatment necessary. 
20 
 
 
4 
Completely 
disabled.  
Cannot 
carry 
on 
any 
self-care.  
Totally confined to bed or chair. 
Moribund; fatal processes progressing rapidly. 
10 
Dead 
0              5 Dead 
* As published in Oken M.M., Creech R.H., Tormey D.C., Horton J., Davis T.E., McFadden E.T., Carbone P.P. 
Toxicity and Response Criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982 
 


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Appendix 3: New Response Evaluation Criteria in Solid Tumours: Revised RECIST 1.1 
(Eisenhauer EA et al., 2009) 
Measurability of tumour at baseline 
At baseline, tumour lesions/lymph nodes will be categorised measurable or non-measurable as 
follows: 
Measurable 
Tumour lesions: Must be accurately measured in at least one dimension (longest diameter in 
the plane of measurement is to be recorded) with a minimum size of: 
10 mm by CT-scan (CT-scan slice thickness no greater than 5 mm), 
10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured 
with calipers should be recorded as non-measurable), 
20 mm by chest X-ray. 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT-scan (CT-scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis 
will be measured and followed.  
 
Non-measurable 
All other lesions, including small lesions (longest diameter < 10 mm or pathological lymph 
nodes with ≥ 10 to < 15 mm short axis) as well as truly non-measurable lesions. Lesions 
considered truly non-measurable include: leptomeningeal disease, ascites, pleural or 
pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, 
abdominal masses/abdominal organomegaly identified by physical exam that is not 
measurable by reproducible imaging techniques. 
 
Special considerations regarding lesion measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment: 
Bone lesions: 
Bone scan, PET-scan or plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions, 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by cross sectional imaging techniques such as CT or MRI can be considered 
as measurable lesions if the soft tissue component meets the definition of measurability 
described above, 
Blastic bone lesions are non-measurable. 
Cystic lesions: 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
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‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if noncystic 
lesions are present in the same patient, these are preferred for selection as target lesions. 
Lesions with prior local treatment: 
Tumour lesions situated in a previously irradiated area, or in an area subjected to other loco-
regional therapy, are usually not considered measurable unless there has been demonstrated 
progression in the lesion. Study protocols should detail the conditions under which such 
lesions would be considered measurable. 
 
Tumour response evaluation 
 
Assessment of overall tumour burden and measurable disease 
To assess o bjective response or future progression, it is necessary to estimate the overall 
tumour burden at baseline and use this as a comparator for subsequent measurements. 
Only patients with measurable disease at baseline should be included in protocols where 
objective tumour response is the primary endpoint. Measurable disease is defined by t he 
presence of at least one measurable lesion. In studies where the primary endpoint is tumour 
progression (either time to progression or proportion with progression at a fixed date), the 
protocol must specify if entry is restricted to those with measurable disease or whether 
patients having non-measurable disease only are also eligible. 
 
Baseline documentation of ‘target’ and ‘non-target’ lesions 
When more than one measurable lesion is present at baseline all lesions up to a maximum of 
five lesions total (and a maximum of two lesions per organ) representative of all involved 
organs should be identified as target lesions and will be recorded and measured at baseline 
(this means in instances where patients have only one or two organ sites involved a maximum 
of two and four lesions respectively will be recorded). 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), 
be representative of all involved organs, but in addition should be those that lend themselves 
to reproducible repeated measurements. It may be the case that, on occasion, the largest lesion 
does not lend itself to reproducible measurement in which circumstance the next largest lesion 
which can be measured reproducibly should be selected. 
 
Lymph nodes merit special mention since they are normal anatomical structures which may 
be visible by imaging even if not involved by tumour. Pathological nodes which are defined 
as measurable and may be identified as target lesions must meet the criterion of a short axis of 
≥ 15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. 
The short axis of the node is the diameter normally used by radiologists to judge if a node is 
involved by solid tumour. Nodal size is normally reported as two dimensions in the plane in 
which the image is obtained (for CT scan this is almost always the axial plane; for MRI the 
plane of acquisition may be axial, saggital or coronal). The smaller of these measures is the 
short axis. For example, an abdominal node which is reported as being 20 mm x 30 mm has a 
short axis of 20 mm and qualifies as a malignant, measurable node. In this example, 20 mm 


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should be recorded as the node measurement. All other pathological nodes (those with short 
axis ≥ 10 mm but <15 mm) should be considered non-target lesions. Nodes that have a short 
axis < 10 mm are considered non-pathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters. If lymph nodes 
are to be included in the sum, then as noted above, only the short axis is added into the sum. 
The baseline sum diameters will be used as reference to further characterise any objective 
tumour regression in the measurable dimension of the disease. 
 
All other lesions (or sites of disease) including pathological lymph nodes should be identified 
as non-target lesions and should also be recorded at baseline. Measurements are not required 
and these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal 
progression’ (more details to follow). In addition, it is possible to record multiple non-target 
lesions involving the same organ as a single item on the case record form (e.g. ‘multiple 
enlarged pelvic lymph nodes’ or ‘multiple liver metastases’). 
 
Response criteria 
This section provides the definitions of the criteria used to determine objective tumour 
response for target lesions. 
 
Evaluation of target lesions: 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is 
also considered progression). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
 
Special notes on the assessment of target lesions 
Lymph nodes. Lymph nodes identified as target lesions should always have the actual short 
axis measurement recorded (measured in the same anatomical plane as t he baseline 
examination), even if the nodes regress to below 10 m m on study. This means that when 
lymph nodes are included as target lesions, the ‘sum’ of lesions may not be zero even if 
complete response criteria are met, since a normal lymph node is defined as having a short 
axis of < 10 mm. Case report forms or other data collection methods may therefore be 
designed to have target nodal lesions recorded in a separate section where, in order to qualify 
for CR, each node must achieve a short axis < 10 mm. For PR, SD and PD, the actual short 
axis measurement of the nodes is to be included in the sum of target lesions. 
 


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Target lesions that become ‘too small to measure’. While on study, all lesions (nodal and non-
nodal) recorded at baseline should have their actual measurements recorded at each 
subsequent evaluation, even when very small (e.g. 2 mm). However, sometimes lesions or 
lymph nodes which are recorded as target lesions at baseline become so faint on CT-scan that 
the radiologist may not feel comfortable assigning an exact measure and may report them as 
being ‘too small to measure’. When this occurs it is important that a value be recorded on the 
case report form. If it is the opinion of the radiologist that the lesion has likely disappeared, 
the measurement should be recorded as 0 mm. If the lesion is believed to be present and is 
faintly seen but too small to measure, a default value of 5 mm should be assigned (Note: It is 
less likely that this rule will be used for lymph nodes since they usually have a definable size 
when normal and are frequently surrounded by fat such as in the retroperitoneum; however, if 
a lymph node is believed to be present and is faintly seen but too small to measure, a default 
value of 5 mm should be assigned in this circumstance as well). This default value is derived 
from the 5 mm CT slice thickness (but should not be changed with varying CT slice 
thickness). The measurement of these lesions is potentially non-reproducible, therefore 
providing this default value will prevent false responses or progressions based upon 
measurement error. To reiterate, however, if the radiologist is able to provide an actual 
measure, that should be recorded, even if it is below 5 mm. 
 
Lesions that split or coalesce on treatment. When non-nodal lesions ‘fragment’, the longest 
diameters of the fragmented portions should be added together to calculate the target lesion 
sum. Similarly, as lesions coalesce, a plane between them may be maintained that would aid 
in obtaining maximal diameter measurements of each individual lesion. If the lesions have 
truly coalesced such that they are no longer separable, the vector of the longest diameter in 
this instance should be the maximal longest diameter for the ‘coalesced lesion’. 
 
Evaluation of non-target lesions 
This section provides the definitions of the criteria used to determine the tumour response for 
the group of non-target lesions. While some non-target lesions may actually be measurable, 
they need not be measured and instead should be assessed only qualitatively at the time points 
specified in the protocol. 
Complete Response (CR): Disappearance of all non-target lesions and normalisation of 
tumour marker level. All lymph nodes must be non-pathological in size (<10mm short axis). 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of 
tumour marker level above the normal limits. 
Progressive Disease (PD): Unequivocal progression (see comments below) of existing non-
target lesions. (Note: the appearance of one or more new lesions is also considered 
progression). 
 
Special notes on assessment of progression of non-target disease 
The concept of progression of non-target disease requires additional explanation as follows: 
When the patient also has measurable disease. In this setting, to achieve ‘unequivocal 
progression’ on t he basis of the non-target disease, there must be an overall level of 


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substantial worsening in non-target disease such that, even in presence of SD or PR in target 
disease, the overall tumour burden has increased sufficiently to merit discontinuation of 
therapy. A modest ‘increase’ in the size of one or more non-target lesions is usually not 
sufficient to quality for unequivocal progression status. The designation of overall progression 
solely on the basis of change in non-target disease in the face of SD or PR of target disease 
will therefore be extremely rare. 
When the patient has only non-measurable disease. This circumstance arises in some phase III 
trials when it is not a criterion of study entry to have measurable disease. The same general 
concepts apply here as noted above, however, in this instance there is no measurable disease 
assessment to factor into the interpretation of an increase in non-measurable disease burden. 
Because worsening in non-target disease cannot be easily quantified (by definition: if all 
lesions are truly non-measurable) a useful test that can be applied when assessing patients for 
unequivocal progression is to consider if the increase in overall disease burden based on the 
change in non-measurable disease is comparable in magnitude to the increase that would be 
required to declare PD for measurable disease: i.e. an increase in tumour burden representing 
an additional 73% increase in ‘volume’ (which is equivalent to a 20% increase diameter in a 
measurable lesion). Examples include an increase in a pleural effusion from ‘trace’ to ‘large’, 
an increase in lymphangitic disease from localised to widespread, or may be described in 
protocols as ‘sufficient to require a change in therapy’. If ‘unequivocal progression’ is seen, 
the patient should be considered to have had overall PD at that point. While it would be ideal 
to have objective criteria to apply to non-measurable disease, the very nature of that disease 
makes it impossible to do so, therefore the increase must be substantial. 
 
New lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal: i.e. not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumour (for example, some 
‘new’ bone lesions may be simply healing or flare of pre-existing lesions). This is particularly 
important when the patient’s baseline lesions show partial or complete response. For example, 
necrosis of a liver lesion may be reported on a CT scan report as a ‘new’ cystic lesion, which 
it is not. 
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. An example of this 
is the patient who has visceral disease at baseline and while on study has a CT or MRI brain 
ordered which reveals metastases. The patient’s brain metastases are considered to be 
evidence of PD even if he/she did not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of the 
initial scan. 
While FDG-PET response assessments need additional study, it is sometimes reasonable to 
incorporate the use of FDG-PET scanning to complement CT scanning in assessment of 


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progression (particularly possible ‘new’ disease). New lesions on t he basis of FDG-PET 
imaging can be identified according to the following algorithm: 
Negative FDG-PET at baseline, with a positive FDG-PET (a ‘positive’ FDG-PET scan lesion 
means one which is FDG avid with an uptake greater than twice that of the surrounding tissue 
on the attenuation corrected image) at follow-up is a sign of PD based on a new lesion. 
No FDG-PET at baseline and a positive FDG-PET at follow-up: 
If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by 
CT, this is PD. 
If the positive FDG-PET at follow-up is not confirmed as a n ew site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-
PET scan). 
If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT 
that is not progressing on the basis of the anatomic images, this is not PD. 
 
Evaluation of best overall response 
The best overall response is the best response recorded from the start of the study treatment 
until the end of treatment taking into account any requirement for confirmation. On occasion a 
response may not be documented until after the end of therapy so protocols should be clear if 
post-treatment assessments are to be considered in determination of best overall response. 
Protocols must specify how any new therapy introduced before progression will affect best 
response designation. The patient’s best overall response assignment will depend on t he 
findings of both target and non-target disease and will also take into consideration the 
appearance of new lesions. Furthermore, depending on t he nature of the study and the 
protocol requirements, it may also require confirmatory measurement. Specifically, in non-
randomised trials where response is the primary endpoint, confirmation of PR or CR is needed 
to deem either one the ‘best overall response’. 
 
Time point response 
It is assumed that at each protocol specified time point, a response assessment occurs. Table 1 
provides a summary of the overall response status calculation at each time point for patients 
who have measurable disease at baseline. 
 


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Table 1: Time point response: patients with target (+/- non-target) disease 
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD 
or 
not 
all 
evaluated 
No 
PR 
SD 
Non-PD 
or 
not 
all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = Not evaluable 
 
When patients have non-measurable disease only (therefore non-target), Table 2 is to be used. 
Table 2: Time point response: patients with non-target disease only 
Non-target lesions 
New lesions 
Overall response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD1 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
CR = complete response, PD = progressive disease, and NE = Not evaluable. 
1 = ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as endpoint for assessment of 
efficacy in some trials so to assign this category when no lesions can be measured is not advised. 
 
Missing assessments and inevaluable designation 
When no i maging/measurement is done at all at a particular time point, the patient is not 
evaluable (NE) at that time point. If only a subset of lesion measurements are made at an 
assessment, usually the case i s also considered NE at that time point, unless a convincing 
argument can be made that  the contribution of the individual missing lesion(s) would not 
change the assigned time point response. This would be most likely to happen in the case of 
PD. For example, if a patient had a baseline sum of 50 mm with three measured lesions and at 
follow-up only two lesions were assessed, but those gave a sum of 80 mm, the patient will 
have achieved PD status, regardless of the contribution of the missing lesion. 
 
Best overall response: all time points 
The best overall response is determined once all the data for the patient is known. 
Best response determination in trials where confirmation of complete or partial response is 
not required: Best response in these trials is defined as the best response across all time points 
(for example, a patient who has SD at first assessment, PR at second assessment, and PD on 


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last assessment has a best overall response of PR). When SD is believed to be best response, it 
must also meet the protocol specified minimum time from baseline. If the minimum time is 
not met when SD is otherwise the best time point response, the patient’s best response 
depends on the subsequent assessments. For example, a patient who has SD at first 
assessment, PD at second and does not meet minimum duration for SD, will have a best 
response of PD. The same patient lost to follow-up after the first SD assessment would be 
considered inevaluable. 
Best response determination in trials where confirmation of complete or partial response is 
required: Complete or partial responses may be claimed only if the criteria for each are met at 
a subsequent time point as specified in the protocol (generally 4 weeks later). In this 
circumstance, the best overall response can be interpreted as in Table 3. 
Table 3: Best overall response when confirmation of CR and PR required 
Overall response 
First time point 
Overall response 
Subsequent time point BEST overall response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PR1 
CR 
SD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
CR 
PD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
CR 
NE 
SD provided minimum criteria for SD duration met, 
otherwise NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
PR 
NE 
SD provided minimum criteria for SD duration met, 
otherwise NE 
NE 
NE 
NE 
 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = Not evaluable. 
1 = If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR criteria 
relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best response would 
depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be claimed when subsequent scans 
suggest small lesions were likely still present and in fact the patient had PR, not CR at the first time point. Under these 
circumstances, the original CR should be changed to PR and the best response is PR. 
 
Special notes on response assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to 
‘normal’ size (< 10 mm), they may still have a m easurement reported on scans. This 
measurement should be recorded even though the nodes are normal in order not to overstate 
progression should it be based on increase in size of the nodes. As noted earlier, this means 
that patients with CR may not have a total sum of ‘zero’ on the case report form (CRF). 


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In trials where confirmation of response is required, repeated ‘NE’ time point assessments 
may complicate best response determination. The analysis plan for the trial must address how 
missing data/assessments will be addressed in determination of response and progression. For 
example, in most trials it is reasonable to consider a patient with time point responses of PR-
NE-PR as a confirmed response. 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
‘symptomatic deterioration’. Every effort should be made to document objective progression 
even after discontinuation of treatment. Symptomatic deterioration is not a descriptor of an 
objective response: it is a reason for stopping study therapy. The objective response status of 
such patients is to be determined by evaluation of target and non-target disease as shown in 
Tables 1–3. 
Conditions that define ‘early progression, early death and inevaluability’ are study specific 
and should be clearly described in each protocol (depending on treatment duration, treatment 
periodicity). 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends upon this determination, it is 
recommended that the residual lesion be investigated (fineuneedle aspirate/biopsy) before 
assigning a status of complete response. FDG-PET may be used to upgrade a response to a 
CR in a manner similar to a b iopsy in cases where a residual radiographic abnormality is 
thought to represent fibrosis or scarring. The use of FDG-PET in this circumstance should be 
prospectively described in the protocol and supported by disease specific medical literature 
for the indication. However, it must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity. 
For equivocal findings of progression (e.g. very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment. If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected. 
 
Frequency of tumour re-evaluation 
Frequency of tumour re-evaluation while on treatment should be protocol specific and 
adapted to the type and schedule of treatment. However, in the context of phase II studies 
where the beneficial effect of therapy is not known, follow-up every 6–8 weeks (timed to 
coincide with the end of a cycle) is reasonable. Smaller or greater time intervals than these 
could be justified in specific regimens or circumstances. The protocol should specify which 
organ sites are to be evaluated at baseline (usually those most likely to be involved with 
metastatic disease for the tumour type under study) and how often evaluations are repeated. 
Normally, all target and non-target sites are evaluated at each assessment. In selected 
circumstances certain non-target organs may be evaluated less frequently. For example, bone 
scans may need to be repeated only when complete response is identified in target disease or 
when progression in bone is suspected. 
After the end of the treatment, the need for repetitive tumour evaluations depends on whether 
the trial has as a goal the response rate or the time to an event (progression/death). If ‘time to 


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an event’ (e.g. time to progression, disease-free survival, progression-free survival) is the 
main endpoint of the study, then routine scheduled re-evaluation of protocol specified sites of 
disease is warranted. In randomised comparative trials in particular, the scheduled 
assessments should be performed as identified on a calendar schedule (for example: every 6–8 
weeks on treatment or every 3–4 months after treatment) and should not be affected by delays 
in therapy, drug holidays or any other events that might lead to imbalance in a treatment arm 
in the timing of disease assessment. 
 
Confirmatory measurement/duration of response 
 
Confirmation 
In non-randomised trials where response is the primary endpoint, confirmation of PR and CR 
is required to ensure responses identified are not the result of measurement error. This will 
also permit appropriate interpretation of results in the context of historical data where 
response has traditionally required confirmation in such trials. However, in all other 
circumstances, i.e. in randomised trials (phase II or III) or studies where stable disease or 
progression are the primary endpoints, confirmation of response is not required since it will 
not add value to the interpretation of trial results. However, elimination of the requirement for 
response confirmation may increase the importance of central review to protect against bias, 
in particular in studies which are not blinded. 
In the case of SD, measurements must have met the SD criteria at least once after study entry 
at a minimum interval (in general not less than 6–8 weeks) that is defined in the study 
protocol. 
 
Duration of overall response 
The duration of overall response is measured from the time measurement criteria are first met 
for CR/PR (whichever is first recorded) until the first date that recurrent or progressive 
disease is objectively documented (taking as r eference for progressive disease the smallest 
measurements recorded on study). 
The duration of overall complete response is measured from the time measurement criteria are 
first met for CR until the first date that recurrent disease is objectively documented. 
 
Duration of stable disease 
Stable disease is measured from the start of the treatment (in randomised trials, from date of 
randomisation) until the criteria for progression are met, taking as reference the smallest sum 
on study (if the baseline sum is the smallest, this is the reference for calculation of PD). 
The clinical relevance of the duration of stable disease varies in different studies and diseases. 
If the proportion of patients achieving stable disease for a minimum period of time is an 
endpoint of importance in a particular trial, the protocol should specify the minimal time 
interval required between two measurements for determination of stable disease. 
Note: The duration of response and stable disease as well as the progression-free 
survival are influenced by the frequency of follow-up after baseline evaluation. It is not 
in the scope of this guideline to define a standard follow-up frequency. The frequency 


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should take into account many parameters including disease types and stages, treatment 
periodicity and standard practice. However, these limitations of the precision of the 
measured endpoint should be taken into account if comparisons between trials are to be 
made. 
 


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Appendix 4: New York Heart Association (NYHA) classification 
The Stages of Heart Failure NYHA Classification 
 
In order to determine the best course of therapy, physicians often assess the stage of heart 
failure according to the NYHA functional classification system.  This system relates 
symptoms to everyday activities and the patient's quality of life. 
 
Class 
Patient Symptoms 
Class I (Mild) 
No limitation of physical activity.  Ordinary physical activity does not cause undue 
fatigue, palpitation, or dyspnea (shortness of breath). 
Class II (Mild) 
Slight limitation of physical activity.  Co mfortable at rest, but ordinary physical 
activity results in fatigue, palpitation, or dyspnea. 
Class III (Moderate) 
Marked limitation of physical activity.  Comfortable at rest, but less than ordinary 
activity causes fatigue, palpitation, or dyspnea. 
Class IV (Severe) 
Unable to carry out any physical activity without discomfort.  Symptoms of cardiac 
insufficiency at rest.  If any physical activity is undertaken, discomfort is increased. 
 


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Appendix 5: World Medical Association declaration of Helsinki 
Ethical Principles for Medical Research Involving Human Subjects 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53th WMA General Assembly, Washington DC, USA, 2002 (Note of Clarification added) 
55th WMA General Assembly, Tokyo, Japan, 2004 (Note of Clarification added) 
59th WMA General Assembly, Seoul, Republic of Korea, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
Preamble 
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as 
a statement of ethical principles for medical research involving human subjects, 
including research on identifiable human material and data. 
 
The Declaration is intended to be read as a whole and each of its constituent paragraphs 
should be applied with consideration of all other relevant paragraphs. 
2. 
Consistent with the mandate of the WMA, the Declaration is addressed primarily to 
physicians. The WMA encourages others who are involved in medical research 
involving human subjects to adopt these principles 
General Principles 
3. 
The Declaration of Geneva of the WMA binds the physician with the words, “The 
health of my patient will be my first consideration,” and the International Code of 
Medical Ethics declares that, “A physician shall act in the patient's best interest when 
providing medical care.” 
4. 
It is the duty of the physician to promote and safeguard the health, well-being and rights 
of patients, including those who are involved in medical research. The physician's 
knowledge and conscience are dedicated to the fulfilment of this duty. 
5. 
Medical progress is based on research that ultimately must include studies involving 
human subjects. 
6. 
The primary purpose of medical research involving human subjects is to understand the 
causes, development and effects of diseases and improve preventive, diagnostic and 
therapeutic interventions (methods, procedures and treatments). Even the best proven 
interventions must be evaluated continually through research for their safety, 
effectiveness, efficiency, accessibility and quality. 
7. 
Medical research is subject to ethical standards that promote and ensure respect for all 
human subjects and protect their health and rights. 


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8. 
While the primary purpose of medical research is to generate new knowledge, this goal 
can never take precedence over the rights and interests of individual research subjects. 
9. 
It is the duty of physicians who are involved in medical research to protect the life, 
health, dignity, integrity, right to self-determination, privacy, and confidentiality of 
personal information of research subjects. The responsibility for the protection of 
research subjects must always rest with the physician or other health care professionals 
and never with the research subjects, even though they have given consent. 
10. 
Physicians must consider the ethical, legal and regulatory norms and standards for 
research involving human subjects in their own countries as w ell as ap plicable 
international norms and standards. No national or international ethical, legal or 
regulatory requirement should reduce or eliminate any of the protections for research 
subjects set forth in this Declaration. 
11. 
Medical research should be conducted in a manner that minimises possible harm to the 
environment. 
12. 
Medical research involving human subjects must be conducted only by individuals with 
the appropriate ethics and scientific education, training and qualifications. Research on 
patients or healthy volunteers requires the supervision of a competent and appropriately 
qualified physician or other health care professional. 
13. 
Groups that are underrepresented in medical research should be provided appropriate 
access to participation in research. 
14. 
Physicians who combine medical research with medical care should involve their 
patients in research only to the extent that this is justified by its potential preventive, 
diagnostic or therapeutic value and if the physician has good reason to believe that 
participation in the research study will not adversely affect the health of the patients 
who serve as research subjects. 
15. 
Appropriate compensation and treatment for subjects who are harmed as a r esult of 
participating in research must be ensured. 
Risk, Burdens and Benefits 
16. 
In medical practice and in medical research, most interventions involve risks and 
burdens. 
Medical research involving human subjects may only be conducted if the importance of 
the objective outweighs the risks and burdens to the research subjects. 
17. 
All medical research involving human subjects must be preceded by careful assessment 
of predictable risks and burdens to the individuals and groups involved in the research 


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in comparison with foreseeable benefits to them and to other individuals or groups 
affected by the condition under investigation. 
Measures to minimise the risks must be implemented. The risks must be continuously 
monitored, assessed and documented by the researcher. 
18. 
Physicians may not be involved in a research study involving human subjects unless 
they are confident that the risks have been adequately assessed and can be satisfactorily 
managed. 
When the risks are found to outweigh the potential benefits or when there is conclusive 
proof of definitive outcomes, physicians must assess whether to continue, modify or 
immediately stop the study. 
Vulnerable Groups and Individuals 
19. 
Some groups and individuals are particularly vulnerable and may have an increased 
likelihood of being wronged or of incurring additional harm. 
All vulnerable groups and individuals should receive specifically considered protection. 
20. 
Medical research with a vulnerable group is only justified if the research is responsive 
to the health needs or priorities of this group and the research cannot be carried out in a 
non-vulnerable group. In addition, this group should stand to benefit from the 
knowledge, practices or interventions that result from the research. 
Scientific Requirements and Research Protocols 
21. 
Medical research involving human subjects must conform to generally accepted 
scientific principles, be based on a thorough knowledge of the scientific literature, other 
relevant sources of information, and adequate laboratory and, as appropriate, animal 
experimentation. The welfare of animals used for research must be respected. 
22. 
The design and performance of each research study involving human subjects must be 
clearly described and justified in a research protocol. 
The protocol should contain a statement of the ethical considerations involved and 
should indicate how the principles in this Declaration have been addressed. The 
protocol should include information regarding funding, sponsors, institutional 
affiliations, potential conflicts of interest, incentives for subjects and information 
regarding provisions for treating and/or compensating subjects who are harmed as a 
consequence of participation in the research study. 
In clinical trials, the protocol must also describe appropriate arrangements for post-trial 
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Research Ethics Committees 
23. 
The research protocol must be submitted for consideration, comment, guidance and 
approval to the concerned research ethics committee before the study begins. This 
committee must be transparent in its functioning, must be independent of the researcher, 
the sponsor and any other undue influence and must be duly qualified. It must take into 
consideration the laws and regulations of the country or countries in which the research 
is to be performed as well as ap plicable international norms and standards but these 
must not be allowed to reduce or eliminate any of the protections for research subjects 
set forth in this Declaration. 
The committee must have the right to monitor on-going studies. The researcher must 
provide monitoring information to the committee, especially information about any 
serious adverse events. No amendment to the protocol may be made without 
consideration and approval by the committee. After the end of the study, the researchers 
must submit a final report to the committee containing a summary of the study’s 
findings and conclusions. 
Privacy and Confidentiality 
24. 
Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information. 
Informed Consent 
25. 
Participation by individuals capable of giving informed consent as subjects in medical 
research must be voluntary. Although it may be appropriate to consult family members 
or community leaders, no i ndividual capable of giving informed consent may be 
enrolled in a research study unless he or she freely agrees. 
26. 
In medical research involving human subjects capable of giving informed consent, each 
potential subject must be adequately informed of the aims, methods, sources of funding, 
any possible conflicts of interest, institutional affiliations of the researcher, the 
anticipated benefits and potential risks of the study and the discomfort it may entail, 
post-study provisions and any other relevant aspects of the study. The potential subject 
must be informed of the right to refuse to participate in the study or to withdraw consent 
to participate at any time without reprisal. Special attention should be given to the 
specific information needs of individual potential subjects as well as to the methods 
used to deliver the information. 
After ensuring that the potential subject has understood the information, the physician 
or another appropriately qualified individual must then seek the potential subject’s 
freely-given informed consent, preferably in writing. If the consent cannot be expressed 
in writing, the non-written consent must be formally documented and witnessed. 
All medical research subjects should be given the option of being informed about the 
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27. 
When seeking informed consent for participation in a research study the physician must 
be particularly cautious if the potential subject is in a dependent relationship with the 
physician or may consent under duress. In such situations the informed consent must be 
sought by an appropriately qualified individual who is completely independent of this 
relationship. 
28. 
For a potential research subject who is incapable of giving informed consent, the 
physician must seek informed consent from the legally authorised representative. These 
individuals must not be included in a research study that has no likelihood of benefit for 
them unless it is intended to promote the health of the group represented by the potential 
subject, the research cannot instead be performed with persons capable of providing 
informed consent, and the research entails only minimal risk and minimal burden. 
29. 
When a potential research subject who is deemed incapable of giving informed consent 
is able to give assent to decisions about participation in research, the physician must 
seek that assent in addition to the consent of the legally authorised representative. The 
potential subject’s dissent should be respected. 
30. 
Research involving subjects who are physically or mentally incapable of giving consent, 
for example, unconscious patients, may be done only if the physical or mental condition 
that prevents giving informed consent is a n ecessary characteristic of the research 
group. In such circumstances the physician must seek informed consent from the legally 
authorised representative. If no such representative is available and if the research 
cannot be delayed, the study may proceed without informed consent provided that the 
specific reasons for involving subjects with a condition that renders them unable to give 
informed consent have been stated in the research protocol and the study has been 
approved by a research ethics committee. Consent to remain in the research must be 
obtained as soon as possible from the subject or a legally authorised representative. 
31. 
The physician must fully inform the patient which aspects of their care are related to the 
research. The refusal of a patient to participate in a study or the patient’s decision to 
withdraw from the study must never adversely affect the patient-physician relationship. 
32. 
For medical research using identifiable human material or data, such as research on 
material or data contained in biobanks or similar repositories, physicians must seek 
informed consent for its collection, storage and/or reuse. There may be exceptional 
situations where consent would be impossible or impracticable to obtain for such 
research. In such situations the research may be done only after consideration and 
approval of a research ethics committee. 
Use of Placebo 
33. 
The benefits, risks, burdens and effectiveness of a n ew intervention must be tested 
against those of the best proven intervention(s), except in the following circumstances: 
Where no pr oven intervention exists, the use of placebo, or no i ntervention, is 
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Where for compelling and scientifically sound methodological reasons the use of any 
intervention less effective than the best proven one, the use of placebo, or no 
intervention is necessary to determine the efficacy or safety of an intervention 
and the patients who receive any intervention less effective than the best proven one, 
placebo, or no i ntervention will not be subject to additional risks of serious or 
irreversible harm as a result of not receiving the best proven intervention. 
Extreme care must be taken to avoid abuse of this option. 
Post-Trial Provisions 
34. 
In advance of a clinical trial, sponsors, researchers and host country governments should 
make provisions for post-trial access for all participants who still need an intervention 
identified as beneficial in the trial. This information must also be disclosed to 
participants during the informed consent process. 
Research Registration and Publication and Dissemination of Results 
35. 
Every research study involving human subjects must be registered in a publicly 
accessible database before recruitment of the first subject. 
36. 
Researchers, authors, sponsors, editors and publishers all have ethical obligations with 
regard to the publication and dissemination of the results of research. Researchers have 
a duty to make publicly available the results of their research on human subjects and are 
accountable for the completeness and accuracy of their reports. All parties should 
adhere to accepted guidelines for ethical reporting. Negative and inconclusive as well as 
positive results must be published or otherwise made publicly available. Sources of 
funding, institutional affiliations and conflicts of interest must be declared in the 
publication. Reports of research not in accordance with the principles of this 
Declaration should not be accepted for publication. 
Unproven Intervention in Clinical Practice 
In the treatment of an individual patient, where proven interventions do not exist or 
other known interventions have been ineffective, the physician, after seeking expert 
advice, with informed consent from the patient or a legally authorised representative, 
may use an unproven intervention if in the physician's judgment it offers hope of saving 
life, re-establishing health or alleviating suffering. This intervention should subsequently 
be made the object of research, designed to evaluate its safety and efficacy. In all cases, 
new information must be recorded and, where appropriate, made publicly available. 
 


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Appendix 6: Substantial amendment No. 1 to the clinical study protocol 
FINAL VERSION DATE: 
17/March/2016 
COUNTRIES CONCERNED: 
Italy 
CENTRES CONCERNED 
All 
 
NATURE OF AMENDMENT 
 
STUDY SUMMARY SHEET 
12. Has adequate organ function as defined by the following laboratory values obtained within 
5 days prior to first day of study drug administration: 
12.5. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5xULN; if 
liver function abnormalities are due to underlying liver metastasis, AST and ALT ≤5xULN. 
12.6. Serum creatinine of ≤1.5 mg/dL clearance ≥ 50 ml/min (using Cockcroft formula). 
Non-inclusion criteria related to administration of S 95005 
23. Has previously received S 95005 or history of allergic reactions attributed to compounds 
of similar or biologic composition to S 95005 or any of its excipients. 
 
Non-inclusion criteria related to administration of bevacizumab 
24. History of allergic reactions or hypersensitivity to bevacizumab or any of its excipients. 
25. History of hypersensitivity to Chinese Hamster Ovary (CHO) cell products or other 
recombinant human or humanised antibodies. 
 
Non-inclusion criteria related to administration of capecitabine 
26. History of allergic reactions or hypersensitivity to capecitabine or any of its excipients 
fluorouracil 
27. History of severe and unexpected reaction to fluoropyrimidine therapy. 
28. Known complete absence of dihydropyrimidine dehydrogenase (DPD) activity. 
29. Treatment with sorivudine or its chemical related analogues, such as brivudine, within 4 
weeks before the first study drug intake 
 “4. STUDY DESIGN” 
Section “4.2.1. Study plan” 
• Treatment period: Randomised patients should receive the first dose of study treatment 
(Day 1 of Cycle 1) no later than 3 days after randomisation. Each patient should receive at 
least 28 days of combination of S 95005+ bevacizumab or at least 21 days of combination 
of capecitabine + bevacizumab except in case of safety concerns. The maximum number of 
cycles is at the discretion of the investigator. Patients will be treated by the assigned 
combined regimen until they meet a discontinuation criterion as described in section 5.4.1. 
Patients will be considered to be on t reatment as long as either component of the 
combination regimen continues to be administered. The estimated median PFS is 11.7 
months in the S 95005 + bevacizumab group and 9 months in the capecitabine + 
bevacizumab group (please refer to section 10 for more details). 


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Section “5. SELECTION AND WITHDRAWAL OF PARTICIPANTS” 
Section “5.1. Inclusion Criteria” 
Section “5.1.4. Medical and therapeutic criteria” 
12. Has adequate organ function as defined by the following laboratory values obtained within 
5 days prior to first day of study drug administration: 
12.5. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5xULN; if 
liver function abnormalities are due to underlying liver metastasis, AST and ALT ≤5xULN. 
12.6. Serum creatinine of ≤1.5 mg/dL clearance ≥ 50 ml/min (using Cockcroft formula). 
Section “5.2. Non-inclusion criteria” 
Section “5.2.2. Medical and therapeutic criteria” 
Non-inclusion criteria related to administration of S 95005 
23. Has previously received S 95005 or history of allergic reactions attributed to compounds 
of similar or biologic composition to S 95005 or any of its excipients. 
 
Non-inclusion criteria related to administration of bevacizumab  
24. History of allergic reactions or hypersensitivity to bevacizumab or any of its excipients. 
25. History of hypersensitivity to Chinese Hamster Ovary (CHO) cell products or other 
recombinant human or humanised antibodies. 
 
Non-inclusion criteria related to administration of capecitabine 
26. History of allergic reactions or hypersensitivity to capecitabine or any of its excipients or 
fluorouracil.  
27. History of severe and unexpected reaction to fluoropyrimidine therapy. 
28. Known complete absence of dihydropyrimidine dehydrogenase (DPD) activity. 
29. Treatment with sorivudine or its chemical related analogues, such as brivudine, within 4 
weeks before the first study drug intake 
Section “5.4.1. Withdrawal criteria” 
Information to be collected during the last visit of these patients is given in Section 4.2.6.2.10. 
These follow-up modalities are used to ensure the efficacy and safety evaluation of all 
participants who received the IMP. 
The reasons for premature discontinuation of IMP are: 
[…] 
- Refer to the bevacizumab and to the capecitabine package insert SmPC (Appendix 
6) for events requiring discontinuation of treatment. 


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Section “6. TREATMENT OF PARTICIPANTS” 
Section “6.3.1. Prohibited Medication and Therapies”  
Patients are not permitted to receive any other investigational or any other anticancer therapy, 
including chemotherapy, immunotherapy, biological response modifiers (BRMs), or endocrine 
therapy during the study treatment period. 
Palliative radiotherapy is not permitted while the patient is receiving study treatment. 
Treatment with sorivudine or its chemical related analogues, such as brivudine, are forbidden 
during the study and within 4 weeks before the first study drug intake. 
Section “6.3.2. Concomitant Medication and Therapies”  
Caution is required when using drugs that are human thymidine kinase substrates, e.g., 
zidovudine. […]. 
Patient treated with oral anticoagulant treatment or heparins should be closely monitored 
especially in case of thrombopenia. 
For precautions for use and interactions of concomitant treatments with capecitabine or 
bevacizumab please refer to the corresponding SmPC of the drugs (Appendix 6). 
Addition of Appendix 6 “Capecitabine and bevacizumab SmPC” 
Capecitabine SmPC is available here: 
Link to European Medicines Agency (EMA) website 
Bevacizumab SmPC is available here: 
Link to European Medicines Agency (EMA) website 
 


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Appendix 7: Capecitabine and bevacizumab SmPC 
 
Capecitabine SmPC is available here:  
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000316/hu
man_med_001157.jsp&mid=WC0b01ac058001d124 
 
Bevacizumab SmPC is available here: 
http://www.ema.europa.eu/ema/index.jsp%3Fcurl=pages/medicines/human/medicines/000582
/human_med_000663.jsp 
 


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Appendix 8: Substantial amendment No. 3 to the clinical study protocol  
 
FINAL VERSION DATE:  
30th August 2016 
COUNTRIES CONCERNED: 
Germany 
CENTRES CONCERNED 
All 
 
NATURE OF AMENDMENT: 
 
Initial text 
Amended text 
Section “8.4.1.1 Adverse events” 
“An adverse event is defined as any untoward 
medical occurrence in a subject participating 
in a clinical study, whether or not there is a 
causal relationship with the IMP and/or 
experimental 
procedures, 
occurring 
or 
detected from the date the participant signs 
the information and consent form, irrespective 
of the period of the study (periods without 
administration of the IMP (e.g. run-in period) 
are also concerned). 
An adverse event can therefore be: 
­ 
any unfavourable and unintended sign, 
including an abnormal finding from an 
additional examination (lab tests, X-rays, 
ECG, …),  
­ 
any symptom or disease, 
­ 
any worsening during the study of a 
symptom or a disease already present when 
the participant entered the study (increase 
in frequency and/or intensity), including 
the studied pathology, 
and which is deemed clinically relevant by the 
investigator, detected during a study visit or at 
an additional examination or occurred since 
the previous study visit (including relevant 
event reported in participant’s diary or safety 
evaluation scale).” 
 
“An adverse event is defined as any untoward 
medical occurrence in a subject participating 
in a clinical study, whether or not there is a 
causal relationship with the IMP and/or 
experimental 
procedures, 
occurring 
or 
detected from the date the participant signs 
the information and consent form, irrespective 
of the period of the study (periods without 
administration of the IMP (e.g. run-in period) 
are also concerned). 
An adverse event can therefore be: 
­ 
any unfavourable and unintended sign, 
including an abnormal finding from an 
additional examination (lab tests, X-rays, 
ECG, …) which is deemed clinically 
relevant by the investigator, 
­ 
any symptom or disease, 
­ 
any worsening during the study of a 
symptom or a disease already present when 
the participant entered the study (increase 
in frequency and/or intensity), including 
the studied pathology, 
and which is deemed clinically relevant by the 
investigator, detected during a study visit or at 
an additional examination or occurred since 
the previous study visit (including relevant 
event reported in participant’s diary or safety 
evaluation scale).” 
 
 
 

SAP_001.pdf: 
 
 
I . R . I . S . 
 
I N S T I T U T D E R E C H E R C H E S I N T E R N A T I O N A L E S S E R V I E R 
 
 
 
 
Document title 
STATISTICAL ANALYSIS PLAN 
Study title 
An open-label, randomised, non-comparative phase 2 study 
evaluating S 95005 (TAS-102) plus bevacizumab and 
capecitabine plus bevacizumab in patients with previously 
untreated metastatic COlorectal cancer who are non-eligible 
for intensive therapy (TASCO1 study) 
 
Test drug code 
S 95005 
 
 
Indication 
First-line treatment of metastatic colorectal cancer in patients 
non-eligible for intensive therapy 
 
 
Development phase 
Phase II 
 
 
Protocol code 
CL2-95005-002 
 
 
EudraCT Number 
2015-004544-18 
 
 
Universal Trial Number Not applicable 
 
 
Sponsor 
Institut de Recherches Internationales Servier (I.R.I.S.) 
 
 
Date of the document 
21st March 2018 
 
 
Version of the document Final version 3.0 
 


PPD
PPD
PPD
PPD
PPD
PPD


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Table of contents 
Signatories .................................................................................................................................. 2 
Table of contents ........................................................................................................................ 3 
List of tables ............................................................................................................................... 6 
List of figures ............................................................................................................................. 7 
List of abbreviations ................................................................................................................... 8 
1. INTRODUCTION ............................................................................................................. 12 
1.1. Study objectives .............................................................................................................. 12 
1.2. Study design .................................................................................................................... 12 
1.2.1. Study plan ..................................................................................................................... 12 
1.2.2. Type of randomisation .................................................................................................. 14 
1.2.3. Investigation schedule .................................................................................................. 15 
1.3. Determination of sample size ......................................................................................... 20 
2. STATISTICAL ANALYSIS STRATEGY ...................................................................... 21 
3. ENDPOINTS ...................................................................................................................... 23 
3.1. Efficacy endpoints .......................................................................................................... 23 
3.2. Safety endpoints .............................................................................................................. 24 
3.3. QoL endpoints ................................................................................................................. 26 
3.4. Biomarkers endpoints ..................................................................................................... 27 
4. ANALYSIS SETS AND SUBGROUPS / TREATMENT GROUPS ............................ 28 
4.1. Analysis sets and subgroups ........................................................................................... 28 
4.2. Treatment groups ............................................................................................................ 29 
5. STATISTICAL METHODS ............................................................................................. 29 
5.1. General considerations .................................................................................................... 29 
5.1.1. Multiplicity issues ........................................................................................................ 29 
5.1.2. Handling of missing data .............................................................................................. 29 
5.1.3. Statistical elements ....................................................................................................... 29 
5.1.3.1. 
Descriptive statistics ................................................................................................ 29 
5.1.3.2. 
Estimation and statistical test ................................................................................... 30 
5.2. Study patients: Disposition, baseline characteristics and follow-up ............................... 30 
5.2.1. Disposition of patients .................................................................................................. 30 
5.2.2. Protocol deviations ....................................................................................................... 30 
5.2.3. Analysis sets and subgroups ......................................................................................... 30 
5.2.4. Demographic data and other baseline characteristics ................................................... 30 
5.2.5. Extent of exposure and treatment compliance .............................................................. 31 
5.2.6. Concomitant treatments ................................................................................................ 32 
5.2.7. Other observations related to patient follow-up ........................................................... 32 
5.3. Efficacy analysis ............................................................................................................. 32 
5.4. Biomarkers ...................................................................................................................... 34 


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5.4.1. Archived tumor biopsies analysis ................................................................................. 35 
5.4.1.1. 
Analysis of protein-expression by IHC ................................................................... 35 
5.4.1.2. 
Predictive objective: Analysis of protein-expression by IHC according to 
response ................................................................................................................... 35 
5.4.1.2.1. Qualitative analysis of protein-expression by IHC ............................................... 35 
5.4.1.2.1.1. Analysis of protein-expression by IHC according to DCR/ORR ....................... 35 
5.4.1.2.1.2. Analysis of protein-expression by IHC according to PFS .................................. 36 
5.4.1.3. 
Analysis of microsatellites ....................................................................................... 37 
5.4.1.3.1. Predictive objective: analysis of microsatellites according to DCR/ORR ............ 37 
5.4.2. Blood analysis .............................................................................................................. 37 
5.4.2.1. 
Analysis of Protein-expression by ELISA based on serum ..................................... 37 
5.4.2.2. 
Consistency of mutation results obtained centrally from blood samples and 
locally (from either blood or biopsy sample) .......................................................... 38 
5.5. Safety analysis ................................................................................................................ 38 
5.5.1. Dose limitant toxicity ................................................................................................... 38 
5.5.2. Adverse events.............................................................................................................. 38 
5.5.3. Death............................................................................................................................. 38 
5.5.4. Clinical laboratory evaluation ...................................................................................... 39 
5.5.5. Vital signs, clinical exam and other observations related to safety .............................. 39 
5.5.5.1. 
Vital signs and clinical examination ........................................................................ 39 
5.5.5.2. 
Electrocardiogram .................................................................................................... 39 
5.5.5.3. 
LVEF ....................................................................................................................... 40 
5.6. QoL analysis ................................................................................................................... 40 
6. INTERIM ANALYSIS ...................................................................................................... 40 
7. APPENDICES .................................................................................................................... 41 
7.1. General analytic definitions ............................................................................................ 41 
7.1.1. Expressions ................................................................................................................... 41 
7.1.2. Value prior to treatment / under treatment ................................................................... 42 
7.1.3. Analysable value .......................................................................................................... 43 
7.1.4. First and last study IMP intake dates ............................................................................ 43 
7.2. Specific analytic definitions and data handling conventions .......................................... 44 
7.2.1. Study patients: Disposition, baseline characteristics and follow-up ............................ 44 
7.2.1.1. 
Disposition of patients ............................................................................................. 44 
7.2.1.2. 
Protocol deviations .................................................................................................. 44 
7.2.1.3. 
Demographic data and other baseline characteristics .............................................. 44 
7.2.1.3.1. Demographic data .................................................................................................. 44 
7.2.1.3.2. History of CRC ...................................................................................................... 44 
7.2.1.3.3. Medical history and surgical or medical procedures history other than CRC ....... 45 
7.2.1.3.4. Previous therapies for CRC ................................................................................... 45 
7.2.1.3.5. Initial tumour assessment ...................................................................................... 46 
7.2.1.4. 
Extent of exposure and treatment compliance ......................................................... 46 
7.2.1.5. 
Concomitant treatments ........................................................................................... 49 
7.2.2. Efficacy......................................................................................................................... 51 
7.2.2.1. 
Antitumoral activity ................................................................................................. 51 
7.2.3. Biomarkers ................................................................................................................... 56 
7.2.3.1. 
Protein-expression by IHC ...................................................................................... 56 
7.2.3.1.1. Protein-expression by IHC occupancy .................................................................. 56 


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7.2.3.1.2. Protein-expression by IHC H-score ...................................................................... 56 
7.2.3.1.3. Biomarker classes based on protein-expression by IHC ....................................... 56 
7.2.3.2. 
Values out of limits of detection .............................................................................. 56 
7.2.4. Safety ............................................................................................................................ 57 
7.2.4.1. 
Dose Limitant Toxicity (DLT) ................................................................................ 57 
7.2.4.2. 
AEs .......................................................................................................................... 57 
7.2.4.3. 
Death ........................................................................................................................ 60 
7.2.4.4. 
Clinical laboratory evaluation .................................................................................. 60 
7.2.4.5. 
Vital signs, clinical examination and other observations related to safety .............. 63 
7.2.4.5.1. Vital signs and clinical examination ..................................................................... 63 
7.2.4.5.2. Electrocardiogram ................................................................................................. 64 
7.2.4.5.3. LVEF ..................................................................................................................... 64 
7.2.5. QoL ............................................................................................................................... 65 
7.3. Statistical methods details ............................................................................................... 65 
7.4. Software and programming codes .................................................................................. 65 
8. REFERENCES .................................................................................................................. 66 
 
 


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List of tables 
 
Table (1.2.3) 1 - Investigation schedule of S 95005 + bevacizumab arm ................................ 16 
Table (1.2.3) 2 - Investigation schedule of capecitabine + bevacizumab arm ......................... 18 
Table (7.1.2) 1 - Time frame .................................................................................................... 42 
Table (7.1.2) 2 - Time frame of cycle n ................................................................................... 42 
Table (7.1.3) 1 - Definition of analysable value ...................................................................... 43 
Table (7.1.4) 1 - Substitution rules of IMP intake dates .......................................................... 43 
Table (7.2.3.2) 1 - Substitution rules for protein-expression by ELISA biomarkers ............... 56 
Table (7.2.4.2) 1 - Emergence of adverse events in case of missing severity/grade (if 
any) ........................................................................................................................................... 59 
Table (7.2.4.2) 2 - Substitution rules of AE dates .................................................................... 59 
Table (7.2.4.2) 3 - Substitution rules of recovery date ............................................................. 60 
 
 
 
 


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List of figures 
Figure (1.2.1) 1 - Study plan of S 95005 + bevacizumab arm ................................................. 14 
Figure (1.2.1) 2 - Study plan of capecitabine + bevacizumab arm .......................................... 14 
 
 
 


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List of abbreviations 
AE 
: 
Adverse Event 
ALT 
: 
ALanine (Amino)Transferase 
ALP 
: 
ALkaline Phosphatase 
AST 
: 
ASpartate (Amino)Transferase 
ATC 
: 
Anatomical Therapeutic Chemical 
b.i.d. 
: 
bis in die (twice a day) 
BUN 
: 
Blood Urea Nitrogen 
BOR 
: 
Best Overall Response 
BP 
: 
Blood Pressure 
bpm 
: 
beats per minute (heart rate unit) 
BSA 
: 
Body Surface Area 
CHMP 
: 
Committee for Medicinal Products for Human Use 
CI 
: 
Confidence Interval 
cm 
: 
centimetre 
CPMP 
: 
Committee for Proprietary Medicinal Products 
CR 
: 
Complete Response  
CRC 
: 
ColoRectal Cancer 
mCRC 
: 
metastatic ColoRectal Cancer 
CRF 
: 
Case Report Form 
e-CRF 
: 
electronic-Case Report Form 
CRO 
: 
Contract Research Organization 
DBP 
: 
Diastolic Blood Pressure 
DLT 
: 
Dose Limiting Toxicity 
DR 
: 
Duration of response  
DCR 
: 
Disease control rate 
EAE 
: 
Emergent Adverse Event 
ECG 
: 
ElectroCardioGram 
ECOG 
: 
Eastern Cooperative Oncology Group 
e.g. 
: 
exempla gratia (for example) 
EMA 
: 
European Medicines Agency 
FAS 
: 
Full Analysis Set 
g 
: 
gram 
G/L 
: 
Giga (109) per litre 


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GGT 
: 
Gamma-Glutamyl Transferase (Gamma-Glutamyl Transpeptidase) 
h 
: 
hour 
HR 
: 
Hazard Ratio 
ICH  
: 
International Conference on Harmonization 
i.e. 
 
: 
id est 
IHC  
: 
ImmunoHistoChemistry 
IME 
: 
Important Medical Event 
IMP 
: 
Investigational Medicinal Product 
INR 
: 
International Normalized Ratio 
I.R.I.S. 
: 
Institut de Recherches Internationales Servier 
IRS 
: 
Interactive Response System 
IS 
: 
Included Set 
IU 
: 
International Unit 
IV 
: 
IntraVenous (route) 
IWRS 
: 
Interactive Web Response System 
kg 
: 
kilogram 
L 
: 
Litre 
LDH 
: 
Lactate DeHydrogenase 
LL 
: 
Lower Limit of normal laboratory reference range 
m 
: 
metre 
Max 
: 
Maximum 
MedDRA 
: 
Medical Dictionary for Regulatory Activities 
NCI CTCAE 
: 
National Cancer Institute Common Toxicity Criteria for Adverse 
Event 
NEAE 
: 
Non Emergent Adverse Event 
NSEAE 
: 
Non Serious Adverse Event 
µmol 
: 
micromole 
mg 
: 
milligram 
min 
: 
minute 
Min 
: 
Minimum 
mL 
: 
millilitre 
mm 
: 
millimetre 
mmHg 
: 
millimetre of mercury 
mmol 
: 
millimole 
NA 
: 
Not Applicable 


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NE 
: 
Not Evaluable 
NAE 
: 
Number of Adverse Events 
NEAE 
: 
Number of Emergent Adverse Events 
NLR 
: 
Neutrophil-Lymphocyte ratio 
ng 
: 
nanogram 
NIS 
: 
Non Included Set 
NPD 
: 
Number of Protocol Deviations 
ORR 
: 
Overall Response Rate 
% 
: 
percentage 
PCSA 
: 
Potentially Clinically Significant Abnormal value 
PD 
: 
Progressive disease 
PR 
: 
Partial Response 
PPS 
: 
Per Protocol Set 
PT 
: 
Preferred Term 
PV 
: 
PharmacoVigilance 
QLQ 
: 
Quality of Life Questionnaire 
QLQ-C30 
: 
Quality of Life Questionnaire - core questionnaire 
QLQ-CR29 
: 
Quality of Life Questionnaire - colorectal cancer specific module 
QLS 
: 
Quality of Life Set 
QoL 
: 
Quality of Life 
QTc 
: 
QT interval corrected for heart rate 
RBC 
: 
Red Blood Cells 
RD 
: 
Recommended Dose 
RES 
: 
Response Evaluable Set 
RS 
: 
Randomised Set 
s 
: 
second 
SAE 
: 
Serious Adverse Event 
SAP 
: 
Statistical Analysis Plan 
SBP 
: 
Systolic Blood Pressure 
SD 
: 
Stable Disease 
SEAE 
: 
Serious Emergent Adverse Event 
SERFAS 
: 
Serum Full Analysis Set 
SERTRS 
: 
Serum Tumour Response Set 
SOC 
: 
System Organ Class 


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SS 
: 
Safety Set 
TK1 
: 
Thymidine Kinase  
T/L 
: 
Tera (1012) per litre 
TLG 
: 
Tables, Listings and Graphs 
TP 
: 
Thymidine Phosphorylase 
TR 
: 
Tumour Response 
TSH 
: 
Thyroïd Stimulating Hormone 
TU 
: 
Therapeutic Unit 
TUMFAS 
: 
Archived Tumour Biopsies Full Analysis Set 
TUMTR 
: 
Archived Tumour Biopsies Tumour Response Set 
UL 
: 
Upper Limit of normal laboratory reference range 
WBC 
: 
White Blood Cells 
WHO 
: 
World Health Organisation 
 


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1. INTRODUCTION 
This Statistical Analysis Plan (SAP) details the planned analyses to be performed, 
in accordance with the main characteristics of the study protocol. 
The templates for Tables, Listings and Graphs (TLG) are described in a separate document. 
1.1. Study objectives 
The objectives of this study are to evaluate the following endpoints in patients receiving 
S 95005 + bevacizumab (experimental arm = arm 1) or capecitabine + bevacizumab (control 
arm = arm 2) as first-line treatment for unresectable metastatic colorectal cancer (mCRC) in 
patients non-eligible for intensive therapy. 
 
­ The primary objective is progression-free survival (PFS) based on investigator 
assessment of radiologic images. 
­ The secondary objectives are: 
 Overall response rate (ORR). 
 Duration of response (DR). 
 Disease control rate (DCR). 
 Overall survival (OS). 
 Safety and tolerability. 
 Quality of Life (QoL) (European Organization for Research and Treatment of Cancer 
(EORTC) quality of life questionnaire (QLQ) core questionnaire (QLQ-C30), colorectal 
cancer (CRC) specific module (QLQ-CR29)). 
 
­ The exploratory objective is to evaluate the biomarkers potentially predictive of response 
and resistance to S 95005 given in combination using blood samples and archived tumour 
biopsy (if available). 
1.2. Study design 
The study CL2-95002-002 is a randomised, open-label, phase 2 study evaluating S 95005 plus 
bevacizumab and capecitabine plus bevacizumab in the first-line treatment of patients with 
unresectable mCRC who are non-eligible for intensive therapy.  
 
In this phase 2 trial, 100 PFS events are required to describe the difference between the two 
arms. In order to observe this number of events, approximately 150 patients will be 
randomised 1:1 to S 95005 plus bevacizumab (experimental arm) or capecitabine plus 
bevacizumab (control arm).  
Patients will be randomised with the minimisation procedure proposed by Pocock and Simon 
(Pocock SJ et al, 1975) The stratification factors will be RAS status (wild-type, mutant type), 
Eastern Cooperative Oncology Group (ECOG) performance status (0 vs. 1 vs. 2) and country. 
1.2.1. Study plan 
The study is divided into the following periods: 


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­ Screening period and inclusion (up to 28 days prior to randomisation): to obtain informed 
consent and to check the eligibility of the patient to be included and randomised in the 
study. 
­ Randomisation: Included patients will be randomly assigned to one of the two treatment 
groups.  
­ Treatment period: with cycles of 28 days of combination of S 95005 + bevacizumab or 
cycles of 21 days of combination of capecitabine + bevacizumab except in case of safety 
concerns. The maximum number of cycles is at the discretion of the investigator. 
­ Withdrawal visit: up to 4 weeks after the last dose of study drug administration. 
­ Follow-up period:  
 Tumour assessment follow-up every 8 weeks after the end of the treatment period 
(for reasons other than radiologic disease progression),  
 Survival follow-up every 8 weeks until patient death or the end of the study 
(the last visit of the last patient). 
 
Investigational Medicinal Products (IMP) will be administered as follows: 
 
S 95005 + bevacizumab: 
­ Days 1-5: S 95005 (35 mg/m2/dose) orally twice daily; bevacizumab 5 mg/kg IntraVenous 
(IV) infusion on Day 1 
­ Days 6 -7: Rest 
­ Days 8-12:  S 95005 (35mg/m²/dose) orally twice daily 
­ Days 13-14: Rest 
­ Day 15: Bevacizumab 5 mg/kg/IV infusion on Day 15 
­ Days 16-28: Rest 
 
Capecitabine + bevacizumab: 
­ Days 1-14: Capecitabine (1000 or 1250 mg/m2/dose according to local clinical practice) 
orally twice daily; bevacizumab 7.5 mg/kg IV infusion on Day 1. 
­ Days 15-21: Rest. 
 
For both treatment arms, treatment with either component of the combination regimen may 
continue after discontinuation of the other component unless the investigator judges that it is 
in the interest of the patient to withdraw from the study and to be treated outside of this 
protocol with a combine modality. 
 
The study plans of both arms are shown in Figure (1.2.1) 1 and Figure (1.2.1) 2. 


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Figure (1.2.1) 1 - Study plan of S 95005 + bevacizumab arm 
 
 
Figure (1.2.1) 2 - Study plan of capecitabine + bevacizumab arm 
 
 
 
 
1.2.2. Type of randomisation 
The treatment group will be allocated via IWRS using a balanced central randomization (1:1) 
ratio with the minimisation procedure proposed by Pocock and Simon (Pocock SJ et al, 
1975). to S 95005 + bevacizumab or capecitabine + bevacizumab with stratification by RAS 
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1.2.3. Investigation schedule 
The investigation schedules of the 2 arms are described in Table (1.2.3) 1 and Table (1.2.3) 2. 
 


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Table (1.2.3) 1 - Investigation schedule of S 95005 + bevacizumab arm 
Procedure 
Screening period/Inclusion 
On-Treatment period 
Withdrawal 
visit 
Follow-up 
period 
CYCLE 1 (28 days) 
SUBSEQUENT CYCLES (28 days) 
Day of Cycle17 
Day of Cycle17 
Every 
8 Weeks 
Every 
12 Weeks 
≤ 28 days prior 
randomisation 
≤ 5 days prior 
randomisation 
1/Randomisation 
15 
1 
15 
Sign ICF 
X1 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
Histological Confirmation 
X 
 
 
 
 
 
 
 
 
 
Previous surgery, radiotherapy and treatments  
X 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
X 
 
Inclusion/Non-inclusion criteria 
X 
 
 
 
 
 
 
 
 
 
Pregnancy Testing 
 
X2 
 
 
X3 
 
 
 
X3 
 
IWRS4 
 
 
 
 
 
 
 
 
 
 
Patient number 
X 
 
 
 
 
 
 
 
 
 
Randomisation5 
 
 
X 
 
 
 
 
 
 
 
Dispense S 950056 
 
 
X 
 
X 
 
 
 
 
 
Administer IV Bevacizumab6 
 
 
X 
X 
X 
X 
 
 
 
 
Efficacy measurements 
 
 
 
 
 
 
 
 
 
 
Tumour Measurements7 
X7 
 
 
 
 
 
X7 
 
X7 
X7 
CEA dosage 
 
X 
 
 
 
 
X8 
 
X8 
 
Survival Status 
 
 
 
 
 
 
 
 
 
X9 
Safety measurements 
 
 
 
 
 
 
 
 
 
 
Baseline Signs & Symptoms 
 
X 
 
 
 
 
 
 
 
 
Physical Examination 
 
X 
X10 
 
X11 
 
 
 
X 
 
ECOG Performance Status12 
 
X 
X 
 
X 
 
 
 
X 
 
Height 
 
X 
 
 
 
 
 
 
 
 
Vital Signs & Weight 
 
X 
X10 
X 
X11 
X 
 
 
X 
 
Haematology 
 
X 
X10 
X 
X11 
X 
 
 
X 
 
Coagulation 
 
X 
X10 
 
X11 
 
 
 
X 
 
Biochemistry 
 
X 
X10 
X 
X11 
 
 
 
X 
 
Urinalysis 
 
X 
X10 
X 
X11 
 
 
 
X 
 
Concomitant treatments 
X 
 
 
 
 
 
 
 
X 
X13 
AE Assessment14 
X 
 
 
 
 
 
 
 
X 
X 
Biomarkers assessment 
 
 
 
 
 
 
 
 
 
 
RAS/BRAF status15 
X 
 
 
 
 
 
 
 
 
 
Archived tumour biopsy (if available)  
 
 
X18 
 
 
 
 
 
 
 
Blood samples  
 
 
X19 
 
 
 
 
 
X 
 
Quality of Life Assessment 
 
X 
 
 
 
 
 
X16 
X16 
 
 


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1. Sign Informed Consent Form (ICF): Written informed consent must be obtained prior to the performance of any study procedure. 
2. Pregnancy Testing at screening period: performed within 5 days prior to randomisation only with serum βHCG test.  
3. Pregnancy Testing from randomisation: performed from C2, within 48 h prior to Day 1, to withdrawal visit (only if not performed within the previous 4 weeks) with serum βHCG or highly sensitive urine test. 
4. IWRS: Once patient has signed ICF, connection to the IWRS for patient’s registration and e-CRF patient number (see the IWRS manual for details). 
5. Randomisation: Central randomisation via IWRS following confirmation of baseline eligibility criteria. Study medication should begin within 3 days after randomisation. 
6. Study Medication: Patients should receive the first dose of S 95005 (Day 1 of Cycle 1) within 3 days of randomisation. A connection to the IWRS should be performed to know the allocated kit number(s) to be 
dispensed to the patient. Bevacizumab will be provided by the Sponsor. Bevacizumab 5 mg/kg should be administered via IV infusion on Day 1 and Day 15 of each cycle following bevacizumab SmPC.  
NOTE: treatment with either component of the combination regimen may continue after discontinuation of the other component according to investigator judgment. 
7. Tumour Measurements: Obtain imaging based evaluation of the chest, abdomen, and pelvis (as clinically indicated) and clinical examination within 28 days prior to Day 1 of Cycle 1 and every 8 weeks 
thereafter. Images obtained prior to patient signed ICF may be used if the date of the images is within 28 days of randomisation.  
For patients who discontinue treatment for reasons other than radiologic disease progression, obtain tumour measurements within 8 weeks after the last previous tumour assessment. Every effort should be made 
to perform the end of treatment tumour assessment prior to the start of new anticancer therapy. Tumour Measurement at withdrawal visit will be performed only if not performed within previous 8 weeks. 
During the follow-up period, perform tumour measurements every 8 weeks until documentation of radiologic disease progression or initiation of new anticancer therapy (whichever occurs first).  
Tumour assessments should be performed according to RECIST 1.1  
8. 
CEA dosage: This tumour marker will be followed with a dosage every 8 weeks (aligned on tumour assessments) and at withdrawal visit. Note: RECIST 1.1 request normalisation of tumour markers to have a 
complete response 
9. Survival Status: Obtain survival status (alive/dead) at scheduled 8-week intervals until patient death or end of the study  
10. Assessments to be performed within 24 hours (for clinical examination and vital signs/weight) or 48 hours (for laboratory assessments) before the first study drug administration on C1D1. If the screening 
assessments are done within 24/48 hours before C1D1, they do not need to be repeated. 
11. Subsequent Cycles ≥2: Obtain within 24 hours (for clinical examination and vital signs/weight) or 48 hours (for laboratory assessments) prior to Day 1 study drug administration.  Prior to starting subsequent 
cycles, verify that patients with toxicities have met resumption criteria prior to administering study drug. 
12. ECOG Performance Status: The patient’s performance status must remain 0, 1 or 2 during the baseline period and at the time of randomisation for the patient to remain eligible. Collect within 24 hours prior to 
Day 1 study drug administration for all cycles  
13. Concomitant Medications: Collect only anticancer therapies during survival follow-up. 
14. AE Assessment: AE will be recorded from the first dose of study medication until the withdrawal visit. Any AE that occur prior to the first dose of study medication should be recorded as Medical History 
except events associated with any procedure/condition required by the study protocol: procedure (exercise test, MRI, etc.), change or withdrawal of previous/concomitant treatment relating to the conditions of 
the protocol, or a product other than the test drug, taken as part of the protocol. Up to 100 days after last study drug intake report all ERIN, regardless of the supposed role of the research and all serious adverse 
event related to the research irrespective of the time of onset after the end of the study.  
15. RAS/BRAF status: RAS mutation status should be documented prior to randomisation based on local biological assessment of tumour biopsy. At least the following mutation must be determined: KRAS and 
NRAS Exon 2: codon 12 and 13. BRAF mutation status will be documented if available.  
16. Quality of Life: Patients should complete the EORTC – QLQ-C30 and QLQ-CR29 questionnaires every 12 weeks during study treatment; and at the end of treatment if not performed within the prior 8 weeks. 
17. Assessment Windows: A window of +/-3 days is allowable for study procedures (+/-7 days allowable for images), as long as the proper order is maintained.  
18. Archived biopsy: the archived biopsy can be provided within 21 days after C1D1 
19. Blood sample for genomic and proteomic analysis: To be obtained pre-dose 


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Table (1.2.3) 2 - Investigation schedule of capecitabine + bevacizumab arm 
Procedure 
Screening period/Inclusion 
On-Treatment period 
Withdrawal 
visit 
Follow-up 
period 
CYCLE 1 (21 days) 
SUBSEQUENT CYCLES (21 days) 
Day of Cycle17 
Day of Cycle17 
Every 
8 Weeks 
Every 
12 Weeks 
≤ 28 days  
prior randomisation 
≤ 5 days  
prior randomisation 
1/Randomisation 
15 
1 
Sign ICF 
X1 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
Histological Confirmation 
X 
 
 
 
 
 
 
 
 
Previous surgery, radiotherapy and treatments  
X 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
X 
 
Inclusion/Non-inclusion criteria 
X 
 
 
 
 
 
 
 
 
Pregnancy Testing 
 
X2 
 
 
X3 
 
 
X3 
 
IWRS4 
 
 
 
 
 
 
 
 
 
Patient number 
X 
 
 
 
 
 
 
 
 
Randomisation5 
 
 
X 
 
 
 
 
 
 
Dispense capecitabine6 
 
 
X 
 
X 
 
 
 
 
Administer IV Bevacizumab6 
 
 
X 
 
X 
 
 
 
 
Efficacy measurements 
 
 
 
 
 
 
 
 
 
Tumour Measurements7 
X7 
 
 
 
 
X7 
 
X7 
X7 
CEA dosage 
 
X 
 
 
 
X8 
 
X8 
 
Survival Status 
 
 
 
 
 
 
 
 
X9 
Safety measurements 
 
 
 
 
 
 
 
 
 
Baseline Signs & Symptoms 
 
X 
 
 
 
 
 
 
 
Physical Examination 
 
X 
X10 
 
X11 
 
 
X 
 
ECOG Performance Status12 
 
X 
X 
 
X 
 
 
X 
 
Height 
 
X 
 
 
 
 
 
 
 
Vital Signs & Weight 
 
X 
X10 
 
X11 
 
 
X 
 
Haematology 
 
X 
X10 
X 
X11 
 
 
X 
 
Coagulation 
 
X 
X10 
 
X11 
 
 
X 
 
Biochemistry 
 
X 
X10 
X 
X11 
 
 
X 
 
Urinalysis 
 
X 
X10 
X 
X11 
 
 
X 
 
Concomitant treatments 
X 
 
 
 
 
 
 
X 
X13 
AE Assessment14 
X 
 
 
 
 
 
 
X 
X 
Biomarkers assessment 
 
 
 
 
 
 
 
 
 
RAS/BRAF status15 
X 
 
 
 
 
 
 
 
 
Archived tumour biopsy (if available)  
 
 
X18 
 
 
 
 
 
 
Blood samples 
 
 
X19 
 
 
 
 
X 
 
Quality of Life Assessment 
 
X 
 
 
 
 
X16 
X16 
 
 


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1. Sign Informed Consent Form (ICF): Written informed consent must be obtained prior to the performance of any study procedure. 
2. Pregnancy Testing at screening period: performed within 5 days prior to randomisation only with serum βHCG test.  
3. Pregnancy Testing from randomisation: performed from C2, within 48 h prior to Day 1, to withdrawal visit (only if not performed within the previous 4 weeks) with serum βHCG or highly sensitive urine test. 
4. IWRS: Once patient has signed ICF, connection to the IWRS for patient’s registration and e-CRF patient number (see the IWRS manual for details). 
5. Randomisation: Central randomisation via IWRS following confirmation of baseline eligibility criteria. Study medication should begin within 3 days after randomisation. 
6. Study Medication: Patients should receive the first dose of capecitabine (Day 1 of Cycle 1) within 3 days of randomisation. A connection to the IWRS should be performed to know the allocated kit number(s) 
to be dispensed to the patient. Bevacizumab will be provided by the Sponsor. Bevacizumab 7.5 mg/kg should be administered via IV infusion on Day 1 of each cycle following bevacizumab SmPC. NOTE: 
treatment with either component of the combination regimen may continue after discontinuation of the other component according to investigator judgment. 
7. Tumour Measurements: Obtain imaging based evaluation of the chest, abdomen, and pelvis (as clinically indicated) and clinical examination within 28 days prior to Day 1 of Cycle 1 and every 8 weeks 
thereafter. Images obtained prior to patient signed ICF may be used if the date of the images is within 28 days of randomisation.  
For patients who discontinue treatment for reasons other than radiologic disease progression, obtain tumour measurements within 8 weeks after the last previous tumour assessment. Every effort should be made 
to perform the end of treatment tumour assessment prior to the start of new anticancer therapy. Tumour Measurement at withdrawal visit will be performed only if not performed within previous 8 weeks. 
During the follow-up period, perform tumour measurements every 8 weeks until documentation of radiologic disease progression or initiation of new anticancer therapy (whichever occurs first).  
Tumour assessments should be performed according to RECIST 1.1. 
8. CEA dosage: This tumour marker will be followed with a dosage every 8 weeks (aligned on tumour assessments) and at withdrawal visit. Note: RECIST 1.1 request normalisation of tumour markers to have a 
complete response. 
9. Survival Status: Obtain survival status (alive/dead) at scheduled 8-week intervals until patient death or end of the study  
10. Assessments to be performed within 24 hours (for clinical examination and vital signs/weight) or 48 hours (for laboratory assessments) before the first study drug administration on C1D1. If the screening 
assessments are done within 24/48 hours before C1D1, they do not need to be repeated. 
11. Subsequent Cycles ≥2: Obtain within 24 hours (for clinical examination and vital signs/weight) or 48 hours (for laboratory assessments) prior to Day 1 study drug administration.  Prior to starting subsequent 
cycles, verify that patients with toxicities have met resumption criteria prior to administering study drug. 
12. ECOG Performance Status: The patient’s performance status must remain 0, 1 or 2 during the baseline period and at the time of randomisation for the patient to remain eligible. Collect within 24 hours prior to 
Day 1 study drug administration for all cycles.  
13. Concomitant Medications: Collect only anticancer therapies during survival follow-up. 
14. AE Assessment: AE will be recorded from the first dose of study medication until the withdrawal visit. Any AE that occur prior to the first dose of study medication should be recorded as Medical History 
except events associated with any procedure/condition required by the study protocol: procedure (exercise test, MRI, etc.), change or withdrawal of previous/concomitant treatment relating to the conditions of 
the protocol, or a product other than the test drug, taken as part of the protocol. Up to 100 days after last study drug intake report all ERIN, regardless of the supposed role of the research and all serious adverse 
event related to the research irrespective of the time of onset after the end of the study.  
15. RAS/BRAF status: RAS mutation status should be documented prior to randomisation based on local biological assessment of tumour biopsy. At least the following mutation must be determined: KRAS and 
NRAS Exon 2: codon 12 and 13. BRAF mutation status will be documented if available.  
16. Quality of Life: Patients should complete the EORTC – QLQ-C30 and QLQ-CR29 questionnaires every 12 weeks during study treatment; and at the end of treatment if not performed within the prior 8 weeks. 
17. Assessment Windows: A window of +/-3 days is allowable for study procedures (+/-7 days allowable for images), as long as the proper order is maintained.  
18. Archived biopsy: the archived biopsy can be provided within 21 days after C1D1 
19. Blood sample for genomic and proteomic analysis: To be obtained pre-dose


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1.3. Determination of sample size 
A screening design approach has been utilized, where sample size considerations are based on 
estimating the PFS hazard ratio (HR) with certain precision in order to optimize a future 
Phase 3 confirmatory design. The primary analysis will be conducted after 100 PFS events 
(progression of disease or death) are observed in approximately 150 patients randomized in 
the study, based on 1:1 randomisation. The corresponding upper limit of the 2-sided 80% 
confidence interval (CI) for an observed PFS HR of 0.77 would just exclude 1. 
The corresponding HR critical value for a 2-sided 95% CI would be 0.67. Additional CI 
approximations for varying observed HRs are shown in the table below: 
 
Observed HR 
Approximate confidence limits 
95% CI 
80% CI 
0.55 
0.37 - 0.81 
0.43 - 0.71 
0.60 
0.41 - 0.89 
0.46 - 0.78 
0.65 
0.44 - 0.96 
0.50 - 0.84 
0.67 
0.45 - 0.99 
0.52 - 0.86 
0.70 
0.47 - 1.04 
0.54 - 0.90 
0.75 
0.51 - 1.11 
0.58 - 0.97 
0.77 
0.52 - 1.14 
0.60 - 1.00 
0.80 
0.54 - 1.18 
0.62 - 1.03 
 
 
An accrual period of approximately 24 months and a 20%/year loss to PFS follow-up rate has 
been assumed to account for patients that discontinue treatment for reasons other than disease 
progression and a follow-up scan that confirms progression has not been obtained (e.g. patient 
discontinues study treatment due to toxicity and new therapy is initiated prior to 
documentation of disease progression). Assuming a median PFS time in the capecitabine 
+ bevacizumab arm of approximately 9 months, if the observed PFS HR is 0.77, the primary 
PFS analysis target events milestone is projected at approximately 12 months after the last 
patient is randomized in the study (projected total study duration of 36 months until the PFS 
primary analysis milestone). 
 
 
 
 


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2. STATISTICAL ANALYSIS STRATEGY 
The statistical analysis will be descriptive and analytic as this is a phase 2 study.  
 
The main characteristics at baseline (cf Section 5.2.4), the status of patients and protocol 
deviations will be described in the randomized set (RS) by arm and overall. Populations are 
defined on Section 4.1. 
Additionally, the following characteristics at baseline will be described in patients of the 
Tumor Sets (TUMFAS and TUMTR): (demography, disease history, medical history). 
 
The extent of exposure and treatment compliance, as well as concomitant medication during 
the treatment period will be described in the safety set (SS). 
 
Biomarkers will be studied by arm on the Tumor Sets (TUMFAS and TUMTR) for 
biomarkers measured on biopsies and on the Serum Set (SERFAS) for biomarkers measured 
on serum samples. 
 
The safety will be analysed in the Safety set (SS) unless otherwise specified. 
 
Efficacy analyses will be carried out on the Full Analysis Set (FAS), unless otherwise 
specified. 
 
Primary analysis of the PFS:  
 
HR and the corresponding 2-sided 80% and 2-sided 95% CIs for S 95005 + bevacizumab 
versus capecitabine + bevacizumab will be estimated using a Cox proportional hazard model 
adjusting for the stratification factors based on IWRS data (except country due to the large 
number of countries in the study). PFS will be summarized using Kaplan Meier curves and 
further characterized in terms of the median and survival probabilities at 6, 12, 18, and 
24 months 
along 
with 
the 
corresponding 
2-sided 
80% 
and 
2-sided 
95% 
CI 
(Brookmeyer and Crowley CI for median and Kalbfleisch and Prentice CI for survival 
probabilities). 
 
Secondary analyses of the PFS:  
 
The primary analysis will be repeated in the per protocol set (PPS) and another sensitivity 
analysis taking into account the further anti-cancer therapy as an event will be carried out both 
in the FAS and the PPS, the analysed parameter will be noted PFSs1. In addition, a sensitivity 
analysis of PFS taking into account clinical progression (i.e. not only based on radiological 
assessment) will be performed in the FAS and will be noted PFSs2. 
 
Additional exploratory analyses for PFS will investigate the effect of specific factors either in 
a stepwise multivariate analysis setting (Cox regression model) or as the marginal effect in 
specific subgroups including a Forest plot. These factors will include, but are not limited to, 
region, ECOG performance status, gender, age (≤ 65 years, ]65-75], > 75 years), 
prior adjuvant treatment, location of primary disease (including left/right colon…), surgical 
resection, number of metastatic sites (1, ≥ 2), presence of liver metastasis, RAS/BRAF status, 
Neutrophil-Lymphocyte ratio 3 (NLR) (< 3, ≥ 3) and NLR5 (< 5, ≥ 5), (cf NLR definitions in 
Section 7.2.2.1). 


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Analyses of secondary endpoints:  
Analysis of OS will use the same population and analytical methods as described for PFS in 
the primary analysis. 
Analysis of DR will also use similar analytical methods but based on the tumor response (TR) 
population. 
DCR and ORR based on the TR population will be evaluated in each arm with their 2-sided 
95% Clopper-Pearson CIs. 
 
Potential predictive biomarkers will be investigated by performing the PFS analysis described 
above (as well as DCR and ORR) according to the biomarker measured at baseline (TK1, TP, 
TS and MSI) analyzed at different cut-offs.  
 
The safety will be assessed with a description of adverse events (AEs) (serious and emergent), 
death, clinical laboratory evaluation (biochemistry, haematology, coagulation and urinalysis) 
using the National Cancer Institute Common Toxicity Criteria for Adverse Event 
(NCI CTCAE) classification, vital signs and clinical examination (including blood pressure, 
heart rate, temperature, body weight, respiratory rate and ECOG performance status) and 
ECG parameters on the SS; results will be presented by arm and overall.  
 
EORTC QLQ-C30 and QLQ-CR29 questionnaire responses will be described separately in 
each arm using descriptive statistics in the QLS30 and QLS29. 
The global Heath status as well as the Functional Scales in Physical, Role, Emotional, 
Cognitive and Social dimensions as well as the 9 symptom scales: Fatigue, Nausea and 
vomiting, Pain, Dyspnoea, Insomnia, Appetite loss, Constipation, Diarrhoea, Financial 
difficulties scores of the QLQ-C30 will be described at each timepoint. 
Functional scales (Body image, Anxiety, Sexual function men, Sexual function women) and 
symptom scales (Urinary frequency, Blood and mucus in stool, Stool frequency, Urinary 
incontinence, Dysuria, Abdominal pain, Buttock pain, Bloated feeling, Dry mouth, Hair loss, 
Trouble with taste, Weight, Flatulence, Faecal incontinence, Sore skin, Embarrassed by bowel 
movement, Stoma care problems, Impotence, Dyspareunia) scores will be described at each 
timepoint for EORTC QLQ-CR29.  
Only evaluable questionnaires will be used (more than 2/3 of the questions answered). 
The quality of life of a patient at the time of a scheduled assessment will be based on the 
answers provided by the patient in the last questionnaire completed before the 1st 
administration of the following cycle. The determination of the timing of a QoL assessment 
(week 12, week24…) will be based on the corresponding cycle number:  
Arm A: End of cycle 3 = week 12 / end of cycle 6 = week 24 
Arm B: End of cycle 4 = week12 / end of cycle 8 = week 24… 


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At baseline, only the questionnaires completed within the 14 days prior to the first drug 
administration will be considered (including questionnaires filled the day of first 
administration). If more than one questionnaire are available within this period, the last non-
missing questionnaire will be used. 
Any questionnaire that would be completed after the date of last administration plus 35 days 
will not be analysed. 
3. ENDPOINTS 
 
Calculation rules for endpoints and for their expressions are provided in Appendix 7.1 and 
Appendix 7.2, respectively 
3.1. Efficacy endpoints 
 
The detailed calculation rules for efficacy endpoints are provided in Appendix Section 7.2.2 
The efficacy endpoints are: 
­ BOR (CR / PR / SD / PD / NE): Best response is defined as the best response across all 
time points.  
­ PFS (months): defined as the time from the date of randomisation until the date of the 
investigator-assessed radiological disease progression or death due to any cause. 
Patients who are alive with no disease progression as of the analysis cut-off date will be 
censored at the date of the last evaluable tumor assessment, or at the cut-off date, 
whichever is earlier. Patients who receive non-study cancer treatment before disease 
progression will be censored at the date of the last evaluable tumor assessment before the 
non-study cancer treatment is initiated. The PFS cut-off date used for the primary analysis 
will be based on the observation of the 100th event (radiological PD or death) in the study.  
­ DCR (Yes / No): Proportion of patients with objective evidence of confirmed CR or PR, or 
SD as BOR. The assessment of DCR will be based on Investigator review of the images. 
­ ORR (Yes / No): Proportion of patients with objective evidence of confirmed CR or PR as 
BOR according to RECIST criteria in the population of interest. 
­ The assessment of ORR will be based on Investigator review of the images. 
­ DR (months): calculated among the responders (i.e. with BOR equal to CR or PR) as the 
time from the first documentation of response (CR or PR) to the first documentation of 
objective tumor progression or death due to any cause, whichever occurs first. 
Patients alive and progression free as of the analysis cut-off date are censored at their last 
evaluable tumor response assessment, or at the cut-off date, whichever is earlier, prior to 
initiation of any non-study cancer treatment. 
­ OS (months): Time from the date of randomisation to the date of death.  In the absence of 
death confirmation or for patients alive as of the OS cut-off date, survival time will be 
censored at the date of last study follow-up, or the cut-off date, whichever is earlier. 
Patients will be followed for OS until end of the study (last visit of the last patient). 
­ Relative change of the sum of the lesions diameters (%). 
­ Best relative change of the sum of the lesions diameters (%). 


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3.2. Safety endpoints 
The safety endpoints are: 
AEs: 
­ Serious adverse events (SAEs) during the study, according to the investigator or sponsor 
opinion. 
­ Emergent adverse event (EAE) under treatment: 
 All EAE 
 Serious EAE (SEAE), according to the investigator or sponsor opinion 
 Severe EAE 
 Non serious EAE (NSEAE), according to the investigator and sponsor opinion 
­ EAE of interest 
 Haematological toxicities: Febrile neutropenia, neutropenia, thrombocytopenia and 
anaemia 
 
Deaths: 
­ Death (Yes / No) 
­ Reason of death (Progressive disease, toxicity caused by this protocol, other) 
 
Clinical laboratory evaluation: 
­ Biochemistry, haematology and coagulation parameters expressed in terms of: 
 For gradable parameters: Albumin (g/L), Alkaline Phosphatase (IU/L), Total Bilirubin 
(µmol/L), Calcium (mmol/L), GGT (IU/L), Glucose (mmol/L), Potassium (mmol/L), 
Magnesium (mmol/L), Phosphate (mmol/L), Sodium (mmol/L), AST (IU/L), 
ALT(IU/L), Hemoglobin (g/L), White Blood Cells (WBC) (109/L), Platelets (109/L), 
Lymphocytes (109/L), Low Neutrophils (109/L), Serum creatinine (mmol/L), Activated 
Partial Thromboplastin Time (APTT) (seconds) and International normalized ration 
(INR). 
 Value and grade at baseline (and at each planned post-baseline visit under treatment). 
 Worst grade on treatment according to the grade at baseline. 
 
 For non-gradable parameters: Chloride (mmol/L), LDH (IU/L), Total Protein (g/L) 
Basophils (10 9/L), Eosinophils (10 9/L), Hematocrit (%), Monocytes (10 9/L), 
Red Blood Cells (RBC) (1012/L), Bicarbonate (mmol/L), Blood urea nitrogen (BUN) 
(mmol/L) and Creatinine clearance (mL/min) (Cockcroft formula). 
 Value and reference ranges at baseline. 
 Worst value on treatment according to baseline, by classes (< LL / [LL-UL] / > UL) 
or (normal, mild, moderate, severe) for creatinine clearance. 
 
 For parameters of special interest (Haemoglobin, neutrophils, platelets, low WBC, 
bilirubin ASAT, ALAT, creatinine clearance, serum creatinine and proteinuria): 
For hemoglobin, neutrophils, platelets, low WBC, ASAT, ALAT, bilirubin and serum 
creatinine: 
 Days to Most Extreme Value and Magnitude of Nadir for Laboratory Parameters of 
Interest With Grade 3 or 4 Abnormalities that Worsened from Baseline by at Least 
One Grade. 
 Recovery from the Most Extreme Value for Laboratory Parameters of Interest With 
Grade 3 or 4 Abnormalities that Worsened from Baseline by at Least One Grade. 
 


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For creatinine clearance: 
 Days to Most Extreme Value and Magnitude of Nadir for Laboratory Parameters of 
Interest with moderate or severe renal impairment that Worsened from Baseline by at 
Least One level of impairment(cf Section 7.2.4.4 for definition of levels of 
impairment). 
 Recovery from the Most Extreme Value for Laboratory Parameters of Interest With 
moderate or severe renal impairment that Worsened from Baseline by at Least One 
level of impairment  
  
­ For 
urinalysis 
parameters: 
Proteinuria, 
Glucosuria, 
Urobilinogen, 
Haematuria, 
Leucocyturia: 
 Value at baseline, by classes (negative, trace, positive (+, ++, +++)). 
 Worst value on treatment according to baseline, by classes (negative, trace, positive 
(+, ++, +++)). 
 
­ For tumour marker level given by CarcinoEmbryonic Antigen (CEA): 
 Quantitative value and value by classes (normal, abnormal) at baseline. 
 Worst value on treatment according to baseline and worst value by classes 
(normal, abnormal). 
 
Vital signs and clinical examination: 
­ ECOG PS (0, 1, 2, 3, 4) 
­ Weight (kg) 
­ Temperature (°C) 
­ Respiratory rate (breaths/min) 
­ Body Surface Area (BSA) (m²) 
­ Supine systolic blood pressure (SBP) (mmHg) 
­ Supine diastolic blood pressure (DBP) (mmHg) 
­ Supine heart rate (bpm).  
 
They will be expressed as: 
­ Value at baseline and worst post-baseline value under treatment. 
­ Change from baseline to worst post-baseline value under treatment, for weight, 
temperature, BSA, respiratory frequency, SBP, DBP and heart rate. 
 
ECG: 
­ Presence of clinically significant ECG abnormalities (yes/no) 
­ QT interval (msec) 
­ RR interval (msec) 
 
QT and RR interval will be expressed as: 
­ Value at baseline and at withdrawal visit. 
QT interval (msec) will be expressed as: 
­ Absolute prolongation at withdrawal visit. 
­ Change from baseline at withdrawal visit. 
 


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3.3. QoL endpoints 
For QLQ-C30: 
­ Functional scales: 
 Physical functioning:  
(1 - (((Q1+Q2+Q3+Q4+Q5)/5) -1)/3) * 100 
 Role functioning: 
 
(1 - (((Q6+Q7)/2)-1)/3) * 100 
 Emotional functioning:  
(1 - (((Q21+Q22+Q23+Q24)/4)-1)/3) * 100 
 Cognitive functioning:  
(1 - (((Q20+Q25)/2)-1)/3) * 100 
 Social functioning: 
 
(1 - (((Q26+Q27)/2)-1)/3) * 100 
­ Global health status: 
 Global health status/QOL: 
(((Q29+Q30)/2)-1)/6 * 100 
­ Symptom scales/Items: 
 Fatigue:  
 
 
(((Q10+Q12+Q18)/3)-1)/3 * 100 
 Nausea and vomiting:  
(((Q14+Q15)/2)-1)/3 * 100 
 Pain: 
 
 
 
(((Q9+Q19)/2)-1)/3 * 100 
 Dyspnoea: 
 
 
(Q8-1)/3 * 100 
 Insomnia: 
 
 
(Q11-1)/3 * 100 
 Appetite loss:  
 
(Q13-1)/3 * 100 
 Constipation: 
 
 
(Q16-1)/3 * 100 
 Diarrhoea: 
 
 
(Q17-1)/3 * 100 
 Financial difficulties:  
(Q28-1)/3 * 100 
 
For QLQ-CR29: 
­ Functional scales 
 Body image:  
 
 
(1 - (((Q45+Q46+Q47)/3)-1)/3) * 100  
 Anxiety:  
 
 
(1 - (Q43-1)/3) * 100 
 Sexual function men:   
((Q56-1) /3) * 100 
 Sexual function women:  
((Q58-1) /3) * 100  
 Weight:  
 
 
(1-(Q44-1) /3) * 100 
­ Symptom scales  
 Urinary frequency  
 
(((Q31+Q32)/2) -1) /3 * 100  
 Blood and mucus in stool  
(((Q38+Q39)/2) -1) /3 * 100  
 Stool frequency  
 
(((Q52+Q53)/2) -1) /3 * 100  
 Urinary incontinence   
(Q33-1) /3 * 100  
 Dysuria   
 
 
(Q34-1) /3 * 100  
 Abdominal pain  
 
(Q35-1) /3 * 100 
 Buttock pain  
 
 
(Q36-1) /3 * 100  
 Bloated feeling   
 
(Q37-1) /3 * 100  
 Dry mouth  
 
 
(Q40-1) /3 * 100  
 Hair loss  
 
 
(Q41-1) /3 * 100  
 Trouble with taste  
 
(Q42-1) /3 * 100  
 Flatulence  
 
 
(Q49-1) /3 * 100  
 Faecal incontinence  
 
(Q50-1) /3 * 100  
 Sore skin  
 
 
(Q51-1) /3 * 100  
 Embarrassed by bowel movement  
(Q54-1) /3 * 100  
 Stoma care problems   
 
(Q55-1) /3 * 100  
 Impotence  
 
 
 
(Q57-1) /3 * 100 
 Dyspareunia  
 
 
 
(Q59-1) /3 * 100 


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3.4. Biomarkers endpoints 
The 
following 
markers 
have 
been 
measured 
on 
both 
the 
experimental 
arm 
(S 95005+bevacizumab, arm 1) and the control arm (capecitabine+bevacizumab, arm 2): 
 
Archived tumor biopsies analysis 
The markers described in this subsection will be based on archived tumor biopsies, which can 
be provided within 21 days after C1D1 and will be considered as baseline value. 
 
a)  
The following criteria are available for each protein marker measured by IHC (TP, TK1, 
TS): 
i. H-score 
ii. Occupancy (defined in Section 7.2.3.1.1). 
In case of several subcellular staining localizations for one marker, analyses will be 
performed separately for each localization. 
For markers of interest, localizations of interest are the following: 
­ TP: tumor cytoplasm 
­ TK1: tumor cytoplasm and tumor nucleus 
­ TS: tumor cytoplasm and tumor nucleus. 
 
Based on 5 genes, the number of repetitions of DNA sequences is studied and the 
following summary information is provided: 
i. 
MSI status group: MSS/MSI-L and MSI-H. 
 
Blood analysis 
b) Protein-expression by ELISA 
The following criterion is available at baseline (C1D1 pre-dose) for each marker measured 
(TP): 
i. 
Concentration 
 
c) Mutations by Polymerase Chain Reaction (PCR) 
The following criterion is available at baseline (C1D1 pre-dose) for each marker measured 
(KRAS, NRAS, BRAF): 
i. Mutation status. 
 
 
 


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4. ANALYSIS SETS AND SUBGROUPS / TREATMENT GROUPS 
4.1. Analysis sets and subgroups 
­ Screened Set: All screened patients. 
 
­ Included Set: All included patients. 
 
­ Non-Included Set (NIS): All enrolled patients not included. 
 
­ Randomized Set (RS): All patients to whom a therapeutic unit (TU) was randomly 
assigned using IWRS. 
 
­ Full Analysis Set (FAS): All randomized patients who have taken at least one dose of 
IMP will be included in the FAS. Based on the intention-to-treat principle, patients in the 
FAS will be analysed in the arm they were assigned by randomisation. 
 
­ Per Protocol Set (PPS): All patients of the FAS without relevant deviation(s), 
which could affect the evaluation of the IMP effect on the primary efficacy endpoint. 
 
­ Tumor Response Population (TR Population): All patients in the PPS with measurable 
disease (at least one target lesion) at baseline and with at least one tumor evaluation while 
on treatment (with the same method of measurement on the same target lesion as baseline). 
Patients who have a cancer-related death prior to their first tumor evaluation will also be 
considered evaluable with PD as best overall response (BOR). 
 
­ Safety Set (SS): This set will correspond to patients who received at least one dose of 
IMP. Patients will be analyzed according to the treatment actually received. Each patient 
will be classified into and analyzed consistently within one (and only one) treatment group. 
 
­ Quality of Life Set 30 (QLS30): All patients of the FAS who have completed at least two 
third (i.e. at least 20 questions) of the questions of the baseline QLQ-C30 questionnaire, 
and at least two third of the questions of at least one QLQ-C30 questionnaire during the 
study period.  
 
­ Quality of Life Set 29 (QLS29): All patients of the FAS who have completed at least two 
third (i.e. 26/27 questions=at least 18 questions) of the questions of the baseline QLQ-C29 
questionnaire, and at least two third of the questions of at least one QLQ-C29 
questionnaire during the study period.  
 
­ Subgroups such as region, ECOG performance status, gender, age (≤ 65 years, ]65-75],  
> 75 years), prior adjuvant treatment, location of primary disease (colon (right/left..) / 
rectal), surgical resection, number of metastatic sites (1, ≥ 2), presence of liver metastasis, 
RAS and BRAF status, NLR3 (< 3, ≥ 3), NLR5 (< 5, ≥ 5) could be used in the analysis. 
 
­ Archived tumor biopsies Full Analysis Set (TUMFAS): All FAS patients with an 
analyzable value based on archived tumor biopsy. 
 


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 Archived tumor biopsies Tumor Response Set (TUMTR): All TR patients with an 
analyzable value based on archived tumor biopsy. 
 
 Serum Full Analysis Set (SERFAS): All FAS patients with an analyzable value at 
baseline based on serum sample. 
4.2. Treatment groups 
Two treatment groups: 
 
Arm 1: S 95005 + Bevacizumab  
Arm 2: Capecitabine + Bevacizumab  
 
will be administrated. 
 
Two subgroups in the Arm 2 Capecitabine + Bevacizumab by theoretical starting dose: 
 
Subgroup 1: Capecitabine 1000 mg/m2 
Subgroup 2: Capecitabine 1250 mg/m2 
5. STATISTICAL METHODS 
5.1. General considerations 
5.1.1. Multiplicity issues 
Not applicable. 
5.1.2. Handling of missing data 
Not applicable. 
5.1.3. Statistical elements 
5.1.3.1. Descriptive statistics 
Descriptive statistics depending on the nature of the criteria and the number of patients by 
arm: 
For qualitative data, number of observed values, number and percentage of patients per class 
will be presented. Unless otherwise specified in the TLG, no class "Missing" is considered. 
For quantitative data, number of observed values, mean, standard deviation, minimum and 
maximum, median, first and third quartiles.  
For Event: 
­ Number of patients (or cycles) having experienced the event (n). 
­ Number of events that occurred (for AE analyses only) (NAE). 
­ Number of patients (or cycles) at risk for the event (N). 
­ Global incidence rate (%). 
 (Calculated as the ratio between the number of patients (or cycles) having experienced the 
event (n) and the number of patients (or cycles) at risk at the beginning of the study (N)). 


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5.1.3.2. Estimation and statistical test 
Difference within an arm will be calculated as “visit of cycle” minus “baseline”. 
­ Fisher’s exact test will be used to assess the difference between the 2 arms in terms of 
DCR and ORR. 
­ The 95% Clopper-Pearson CI for rates will be computed by inverting the equal-tailed test 
based on the binomial distribution. 
­ Median duration and survival probability at 3, 6, 9, 12 and 24 months and 80% and 95% CI 
for time-dependent parameters will be estimated using Kaplan-Meier method Confidence 
intervals for median are based upon the methods of Brookmeyer and Crowley. Confidence 
intervals are calculated using the log-log transformation. A Cox proportional hazard model 
will be used to estimate HR and the corresponding 2-sided 80% and 2-sided 95% CIs 
­ Cox regression model to study impact of some factors. 
5.2. Study patients: Disposition, baseline characteristics and follow-up 
Description of disposition of patients (status, protocol deviations and analysis set), 
initial tumour assessment as well as treatment duration and extent of exposure and all other 
baseline characteristics will be performed by arm and overall. 
Specific definitions on disposition of patients, baseline characteristics and patient follow-up 
are provided in Appendix 7.2. 
5.2.1. Disposition of patients 
Disposition of patients will be described on RS by arm and overall. 
5.2.2. Protocol deviations 
Protocol deviations before or at inclusion, as well as after inclusion, will be described in the 
RS, by category of deviations by arm and overall. 
5.2.3. Analysis sets and subgroups 
The size of each analysis set and reasons for exclusion will be described. 
Listings of patients with their membership, or not, of each analysis set and subgroup and of 
excluded patients with reasons for exclusion will be provided. 
5.2.4. Demographic data and other baseline characteristics 
Demographic data and other baseline characteristics such as pregnancy test, disease history 
including smoking status, previous therapies, signs and symptoms, clinical laboratory 
evaluation, medical history and surgical or medical procedures history, mutation, vital signs 
and physical examination, ECG parameters and initial tumour assessment will be described on 
the RS. 
Previous chemotherapy will be detailed with regards to intent (neo-adjuvant/adjuvant). 
 
It is of note that previous therapies for CRC will also be described as combination 
(No previous 
therapy, 
Surgery 
only, 
Radiotherapy 
only, 
drug 
treatment 
only, 
Surgery + radiotherapy, Surgery + drug treatment, Radiotherapy + drug treatment, 
Surgery + radiotherapy + drug treatment, any previous therapy). 
 


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The following continuous data will be described in classes: 
­ Age (≤ 65 years, ]65-75],  > 75 years)  
­ Disease duration (≤ 1 year, ]1; 2 years] , ]2; 4 years] , > 4 years)  
­ Time from diagnosis of first metastases to randomization (in months) 
­ Progression free interval (≤ 1 Months,  ]1;6 Months], > 6 Months)  
­ Disease stage 
­ Details and number of organs involved 
­ Biomarkers (KRAS, NRAF, BRAF, RAS IWRS and RAS_CRF defined as follows: 
 RAS_CRF = mutant type IF KRAS = mutant OR NRAS = mutant 
 RAS_CRF = wild type IF KRAS = wild AND NRAS = wild 
 RAS_CRF = NE IF (KRAS = wild AND NRAS = missing) OR (KRAS = missing 
AND NRAS=wild) OR (KRAS=missing AND NRAS=missing)) 
­ PS (CRF value/IVRS value) 
­ NLR3 (< 3 vs. ≥ 3) 
­ NLR5 (< 5 vs. ≥ 5) 
­ N of patients with measurable disease 
­ N of patients with non-measurable disease only 
­ Supine SBP (< 90, [90, 140[, ≥ 140)  
­ Supine DBP (< 60, [60, 90[, ≥ 90) 
­ Supine heart rate (< 60, [60, 100[, ≥ 100) 
 
Moreover all previous treatments for CRC will be described by anatomical therapeutic 
chemical (ATC) code; as well as signs and symptoms related to CRC, medical history and 
surgical or medical procedure other than for CRC, by primary system organ class (SOC) and 
preferred term (PT). Previous surgery for CRC will be described by PT. 
 
5.2.5. Extent of exposure and treatment compliance 
Extent of exposure (number of cycles, number of patients per cycle, treatment duration 
(weeks)) will be described in the Safety Set for S 95005 and Capecitabine. Treatment 
compliance (Cumulative dose (mg/m2), Dose intensity (mg/m2/week) and Relative Dose 
Intensity (%)) will be described by arm, by patient and by cycle. 
 
Cumulative dose (mg/kg), Dose intensity (mg/kg/week) and Relative Dose Intensity (%) for 
the associated agent will be presented by arm, by patient and by cycle. 
 
Cumulative dose (mg/kg), Dose intensity (mg/kg/week) and Relative Dose Intensity (%) will 
be presented by patient and by cycle in subgroups 1000 mg/m2 and 1250 mg/m2 of the 
Capecitabine + Bevacizumab arm. 
 


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For  S 95005,  
Number of patients with full dose administered (Yes/No), number of patients with at least one 
cycle delayed (Yes/No), number of cycles delayed, reason for cycle delayed (Medical reason, 
non-medical reason), number of patients with at least one cycle reduced (Yes/No), number of 
cycles reduced, number of patients with at least one miss intake, number of miss intake, 
number of 15 mg tablets given to patient, number of 15 mg tablets returned, number of 20 mg 
tablets given to patient and number of 20 mg tablets returned will be described in the Safety 
Set.  
 
For Capecitabine, 
Number of patients with full dose administered (Yes/No), number of patients with at least one 
cycle delayed (Yes/No), number of cycles delayed, reason for cycle delayed (Medical reason, 
non-medical reason), number of patients with at least one cycle reduced (Yes/No), number of 
cycles reduced, number of patients with at least one miss intake, number of miss intake, 
number of 150 mg tablets given to patient, number of 150 mg tablets returned, number of 
500 mg tablets given to patient and number of 500 mg tablets returned will be described in the 
Safety Set.  
 
For Bevacizumab,  
Number of patients with full dose administered (Yes/No), number of patients with at least one 
cycle delayed (Yes/No), number of cycles delayed, reason for cycle delayed (Medical reason, 
non-medical reason), number of patients with at least one cycle reduced (Yes/No), number of 
cycles reduced, number of patients with at least one miss intake, number of miss intake, 
will be described in the Safety Set. 
 
It is of note that number of cycles (1 cycle / 2 cycles /…/>6 cycles), treatment duration 
(≤ 8 weeks / ]8; 24] weeks / ]24-36] weeks / ]36-48] / > 48 weeks), Relative Dose Intensity 
(RDI) (≤ 60, ]60-80], ]80-100], ]100- 110], and > 110%), number of cycles delayed 
(1 cycle / 2 cycles /…/> 3 cycles), number of cycles reduced (1 cycle / 2 cycles /…/> 
3 cycles) will also be described in classes. 
5.2.6. Concomitant treatments 
All concomitant treatments taken at inclusion and during the treatment period will be 
described in the Safety Set by ATC code. 
5.2.7. Other observations related to patient follow-up 
Not applicable. 
5.3. Efficacy analysis 
Calculation rules for expressions of efficacy endpoints, as well as general definitions (such as 
value prior to treatment / under treatment, analysable value, first and last IMP intake dates…), 
are provided in Section 7.1.  
Calculation rules for efficacy endpoints and other specific definitions are provided in 
Appendix 7.2. 


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Fisher’s exact test 
To assess the difference between the 2 arms in terms of DCR and ORR. 
 
Cox proportional hazard model adjusting on the stratification factors 
HR and the corresponding 2-sided 80% and 2-sided 95% CIs for S 95005 + Bevacizumab 
versus capecitabine + bevacizumab will be estimated using a Cox proportional hazard model 
adjusting for the stratification factors based on IWRS data (except country due to the large 
number of countries in the study). 
 
Clopper-Pearson CI 
To provide CI for estimates of ORR and DCR, Clopper-Pearson CI will be used. The exact or 
Clopper-Pearson confidence limits for the binomial proportion are constructed by inverting 
the equal-tailed test based on the binomial distribution. This method is attributed to Clopper 
and Pearson (1934).  
The Clopper-Pearson interval can be written as follows for n1 = 1, 2, 3, …, n-1 : 
 
൭ ቆ1 +
𝑛−𝑛1+1
𝑛1 𝐹ቀ1−𝛼2
ൗ,2𝑛1,2(𝑛−𝑛1+1)ቁቇ
−1
, ቆ1 +
𝑛−𝑛1
(𝑛1+1)𝐹ቀ𝛼2
ൗ,2(𝑛1+1),2(𝑛−𝑛1)ቁቇ
−1
൱  
 
Where F(α,b,c) is the αth percentile of the F distribution with b and c degrees of freedom. 
Where 
2
2
/
αz
 is the 100(1-α/2)th percentile of the standard normal distribution, α is the 
confidence level,
n
n
p
1
ˆ =
 is the proportion of observations and n  is the size of sample. 
 
Kalbfleisch and Prentice 
Kalbfleisch and Prentice (2002) got around the problem of having confidence intervals of >1 
or <0. The transformation is done by adopting: 
 
The estimated variance of log(-log(𝑆̂(𝑡)) is: 
𝜏2(𝑡) = 𝜎2[𝑆̂(𝑡)] / [𝑆̂(𝑡)𝑙𝑜𝑔(𝑆̂(𝑡))]2 
The 100(1-α)% confidence interval for S(t) is given by : 
[𝑆̂(𝑡)]exp (𝑧∝/2𝜎(𝑡)) ≤𝑆(𝑡) ≤[𝑆̂(𝑡)]exp (−𝑧∝/2𝜎(𝑡)) 
 
 
Kaplan Meier survival analysis 
Kaplan Meier survival analysis will be used for PFS, DR and OS. The objective is to describe 
time-to-event variables, without covariates, taking into account censored observations 
(for which the event was not experienced during the observation period) 
Event probabilities depend only on time. All subjects are assumed to behave similarly and 
computed survival functions are assumed to describe all subjects. Censored and uncensored 
observations behave the same. 
 
The survival function S(t) is the probability that a patient survives (has no event) at least up to 
and including time t.  


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­ S(t) = Pr (T > t) where S(t) denotes the survival distribution function and T is the time to 
the event of a selected patient. 
­ The median time to event is the time t so that Pr (T > t ) = 0.5 
 
The Kaplan-Meier method is based on conditional probabilities calculations and enables to 
compute nonparametric estimates of the survival function. 
 
 
The survival function is estimated at each time-point as 
 
The number of patients with no event at that time 
The total amount of patients who can have the event 
 
taking into account censored observations. 
 
The Kaplan-Meier estimate of S(t) is  
∏
≤
−
−−
=
t
t
i
i
i
i
n
d
n
t
S
)
(
)
(
)
(
)
(
)
(ˆ
 
♦ 
t(i) is the ith ordered event time 
♦ 
d(i) is the number of events at t(i) 
♦ 
n(i-) is the number of observations without event an instant before t(i) 
 
It is a non-parametric analysis; there is no hypothesis to check on distribution. 
In case of the censored and uncensored observations are different, results may be biased. 
In the same way, if covariates other than time are thought to be important in determining 
duration to outcome, results reported may not show important differences in groups formed 
by the covariates (ex., men vs. women). 
Cox regression models can then be used to study the impact of covariates. 
 
Multivariate analysis (stepwise procedure) 
 
Multivariate analysis will be performed using the Cox Proportional Hazard (CPH) model, 
including the two stratification factors (RAS status and ECOG) and the following set of 
potential prognostic/predictive factors (cf Section 2). A stepwise selection process will be 
applied to identify a final subset of prognostic/predictive factors in the model.  
 
Once the subset has been established (retaining factors significant at the 10% level), treatment 
will be added to the final model to assess its effect.  
5.4. Biomarkers 
Calculation rules for expressions of efficacy endpoints, as well as general definitions (such as 
value prior to treatment / under-treatment, analyzable value, first and last study drug intake 
dates…), are provided in Section 7.1. Calculation rules for efficacy endpoints and other 
specific definitions are provided in Appendix 7.2. 
All biomarkers analyses will be done separately for each arm unless specified otherwise. 


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5.4.1. Archived tumor biopsies analysis 
As mentioned in Section 2, the archived tumor biopsies sets (TUMFAS and TUMTR) will be 
described and the same analyses as in the clinical part of the SAP will be realized on the 
TUMFAS (PFS/OS, median survival and the corresponding 80%CI and 95%CI). 
5.4.1.1. Analysis of protein-expression by IHC 
Qualitative description: 
The percentage of patients presenting an occupancy (resp. H-score) >0 will be described, 
using all TUMFAS patients.  
 
Quantitative description: 
This will be done only on IHC biomarkers where at least 3 patients present an occupancy 
greater than 0. 
 
For all biomarkers of interest measured (TP, TK1, TS), the following elements will be 
provided in a summary table, for each arm (and for each localization in case of multiple 
localizations for a marker):  
­ Descriptive statistics at baseline, using all TUMFAS patients 
­ Boxplot 
­ Histogram 
 
All of the above will be done for H-score and occupancy separately. 
5.4.1.2. Predictive objective: Analysis of protein-expression by IHC according to 
response 
5.4.1.2.1. Qualitative analysis of protein-expression by IHC 
­ The cutoffs used to define bmk+/bmk- classes are indicated in Section 7.2.3.1. 
Additional cutoffs of interest could also be studied. 
5.4.1.2.1.1. Analysis of protein-expression by IHC according to DCR/ORR 
­ Biomarker classes (bmk+/ bmk -) will be described according to response groups 
(defined by ORR but also DCR) using value available at baseline (from archived biopsies) 
in the TUMTR and TUMFAS.  
­ Clopper-Pearson CIs will be used for response rates CIs. 
­ P-value comparing experimental arm vs. control arm will be based on a Fisher’s exact test. 
 
In each arm, for each biomarker, cutoff points will be defined as eligible if there are at least 
5 pts both in the bmk + and bmk - groups. 
 
­ For each biomarker and each cutoff point, the following elements will be provided in each 
arm: 
 Number of patients in bmk+/ bmk- groups 
 Within bmk+ pts 
 Contingency table comparing response (DCR/ORR) to treatment arm 
 Within bmk- pts 
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Additionally, to compare the experimental arm to the control arm, the following elements will 
be provided for each biomarker (only on eligible cutoff points): 
­ Within bmk+ pts: 
 Response rate (and its 95% CI) in each arm as well as p-value of experimental arm vs. 
control arm. 
­ Within bmk- pts: 
 Response rate (and its 95% CI) in each arm as well as p-value of experimental arm vs. 
control arm 
 
These analyses will be done on all biomarkers of interest: TP, TK1 and TS. 
All of the above will be done for each localization in case of multiple localizations for a 
marker. 
All of the above will be done for H-score and occupancy separately. 
5.4.1.2.1.2. Analysis of protein-expression by IHC according to PFS 
Biomarkers classes will be described according to PFS using value available at baseline in the 
TUMFAS.  
 
Cutoff points will be defined as eligible if in each arm there are at least 10 pts both in the 
bmk+ and bmk- groups. 
 
In each arm, for each biomarker, for all cutoff points, the following elements will be 
provided: 
­ Number of patients in each biomarker class. 
­ Median duration and 80% CI and 95% CI, estimated using Kaplan-Meier method. 
 
Additionally, for each biomarker, for eligible cutoff points, to compare the experimental arm 
to the control arm, the following elements will be provided: 
­ Hazard ratio, of experimental arm versus control arm, for bmk+ patients (as well as bmk- 
patients) and the corresponding 2-sided 80% and 2-sided 95% CIs and Wald Chi-square 
test p-value; HR will be estimated via a Cox model comparing duration with biomarker 
class, with no adjustment on randomization factors. 
­ Forest plot of Hazard Ratios and their corresponding 95% CI for PFS for bmk+ pts (as well 
as bmk- pts) by each eligible cutoff point. 
 
For each biomarker, based on the analyses described above, the best cutoff point will be 
defined. The following elements will then be provided using the best cutoff point as well as 
using the median as a cutoff point: 
­ Within control arm, Kaplan-Meier curve using bmk+ pts versus bmk- pts. 
­ Within experimental arm, Kaplan-Meier curve using bmk+ pts versus bmk- pts. 
­ Hazard ratio, of bmk+ versus bmk-, for control arm (as well as experimental patients) and 
the corresponding 2-sided 80% and 2-sided 95% CIs and Wald chi-square test p-value. 
­ Cox Model comparing duration with treatment, biomarker class and treatment*biomarker 
class interaction, with no adjustment on randomization factors ; following HRs will be 
provided: HR treatment arm vs experimental arm, independently of BMK class as well as 
HR BMK+ vs. BMK-, independently of treatment arm. 
­ Two-sided non-adjusted interaction test p-value. 
 


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These analyses will be done for PFS on all biomarkers of interest: TP, TK1 and TS. 
All of the above will be done for each localization in case of multiple localizations for a 
marker. 
 
All of the above will be done for H-score and occupancy separately. 
5.4.1.3. Analysis of microsatellites 
­ Microsatellites will be described using MSI status group (MSS/MSI-L versus MSI-H) 
value available at baseline in the TUMFAS. 
­ Clopper-Pearson CIs will be used for Odds-Ratios CIs. 
­ Based on MSI status group, the following element will be provided. 
­ Number of patients per MSI status group at baseline. 
5.4.1.3.1. Predictive objective: analysis of microsatellites according to DCR/ORR 
MSI status groups (MSS/MSI-L versus MSI-H) will be described according to response 
groups (defined by ORR but also DCR) using value available at baseline in the TUMTR and 
TUMFAS.  
 
For both arms, the following elements will be provided: 
­ Contingency table comparing response (DCR/ORR) to treatment arm, within each MSI 
status group (MSS/MSI-L versus MSI-H). 
­ Barplot by ORR (respectively DCR), within each MSI status group. 
 
The analyses described below will only be carried out if there are at least 10 MSI-H patients 
and at least 5 responding patients in the experimental arm. 
 
Additionally, to compare the experimental arm to the control arm, the following elements will 
be provided: 
­ Response rate (and its 95% CI) in each arm as well as p-value of experimental arm vs. 
control arm for MSS/MSI-L patients (resp. MSI-H pts). 
5.4.2. Blood analysis 
5.4.2.1. Analysis of Protein-expression by ELISA based on serum 
Biomarkers will be described using value available at baseline in the SERFAS.  
 
Qualitative description: 
The percentage of patients in each class (Below Lower Limit, In Range, Above Upper Limit) 
will be described. 
 
Quantitative description: 
This will be done only on ELISA biomarkers where the proportion of values in range is 
> 30%. 
 
The following elements will be provided in a summary table, for each arm:  
­ Descriptive statistics at baseline. 
­ Boxplot. 
 


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This will be done on biomarker of interest: TP. 
5.4.2.2. Consistency of mutation results obtained centrally from blood samples and 
locally (from either blood or biopsy sample) 
Biomarkers will be described using value available at baseline in the SERFAS, restricted to 
patients with local (based on PCR) and central (based on eCRF) value available. 
 
­ For each biomarker the following elements will be provided in each arm: 
 Contingency table comparing mutation status obtained with PCR and mutation status 
obtained based on the eCRF: 
 At the gene level 
 At the exon level 
 
This will be done for each biomarker of interest: KRAS, NRAS and BRAF. 
5.5. Safety analysis 
All safety analyses will be performed in the SS by arm. 
Calculation rules for expressions of safety endpoints, as well as general definitions (such as 
value prior to treatment / under treatment, analysable value, first and last IMP intake dates…), 
are provided in Section 7.1. 
Calculation rules for safety endpoints and other specific definitions are provided in 
Appendix 7.2. 
5.5.1. Dose limitant toxicity 
Not applicable. 
5.5.2. Adverse events 
Number of events, number and percentage of patients reporting at least one event, presented 
by primary SOC, high level group term (HLGT), high level term (HLT) and/or PT 
(depending on the analysis), will be provided for SAE and EAE over the study and treatment 
periods, respectively. 
EAE will be described according to the seriousness, the worst grade, the severity, 
the relationship, the action taken regarding the IMP, the requirement of added therapy and the 
outcome. 
Of note, the seriousness and the relationship to the IMP of the AE correspond to the 
investigator opinion or, in case of events upgraded by the sponsor for seriousness or for 
causality in case of SAE, to the sponsor opinion.  
5.5.3. Death 
Number of death will be described on each period (during the treatment and follow-up period 
/ during the treatment period / during the follow-up period). Reason of death on each period 
will be provided. During treatment period, reason will be presented by SOC and PT. 


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5.5.4. Clinical laboratory evaluation 
For all gradable parameters: 
Descriptive statistics on quantitative value and value by grade at baseline, worst grade on 
treatment according to the grade at baseline, change from baseline to the worst value. 
 
For all non-gradable parameters: 
Descriptive statistics on quantitative value and value by reference ranges at baseline, worst 
value on treatment according to baseline, by classes (<LL / [LL-UL] / >UL) or (normal, mild, 
moderate, severe) for creatinine clearance and change from baseline to worst value under 
treatment. 
 
For parameters of special interest: 
Days to most extreme value. 
Time to recovery from most extreme value. 
Scatter plot of highest/lowest (worst) post-baseline values on treatment according to baseline. 
 
For urinalysis parameters: 
Descriptive statistics on value at baseline, worst value during the treatment period according 
to baseline, by classes (negative, trace, positive (+, ++, +++)) and change from baseline to 
worst value under treatment. 
 
For CEA: 
Descriptive statistics on quantitative value and value by classes at baseline, quantitative worst 
value during the treatment period according to baseline and by classes and relative change 
from baseline to the worst value under treatment. 
 
5.5.5. Vital signs, clinical exam and other observations related to safety 
5.5.5.1. Vital signs and clinical examination 
­ Vital signs and clinical examination will be described, in terms of quantitative value and 
value by classes (SBP (< 90, [90, 140[, ≥ 140), DBP (< 60, [60, 90[, ≥ 90) and heart rate 
(< 60, [60, 100[, ≥ 100 )) at baseline; as well as in terms of worst value under treatment, 
change from baseline to worst value under treatment for weight, temperature, BSA, 
respiratory frequency, SBP, DBP and heart rate and worst value according to baseline by 
classes for weight, SBP, DBP, heart rate and ECOG. 
 
5.5.5.2. Electrocardiogram  
Moreover values and changes from baseline of corrected QT interval will be described in 
classes, considering thresholds defined in ICH E14 (i.e. ≤ 450, ]450; 480], ]480; 500] and 
> 500 ms for values, and ≤ 30, ]30; 60] and > 60 ms for changes).  
Values for RR interval will also be described in the same classes as QT interval. 
 
Clinically significant ECG abnormalities at withdrawal visit will be described, with number of 
patient and overall. 


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5.5.5.3. LVEF 
Not applicable. 
5.6. QoL analysis 
Patients of the QLS29 and QLS30 will be analysed for QoL in the arm they were assigned by 
randomisation. 
EORTC QLQ-C30 and QLQ-CR29 questionnaire responses will be described separately in 
each arm using descriptive statistics. 
Compliance for each questionnaire will be displayed per evaluation (baseline, week 12, week 
24…). Compliance is defined as the number of forms actually received as a proportion of 
those expected. The number of QoL questionnaires completed and evaluable per evaluation 
will also be given, for each questionnaire. 
As per protocol, the quality of life will be assessed every 12 weeks and at the withdrawal visit 
(if not performed within the prior 8 weeks.). The variation of the timing of questionnaire will 
be provided.  
Each parameter will be described at baseline. Changes of the scores from baseline (mean) will 
be provided at each timepoint (week 12, 24…). Figures will be displayed in order to show the 
evolution of each scale/item. 
6. INTERIM ANALYSIS 
 
One interim analysis for efficacy is planned on October 2017 or after 80 PFS events are 
observed (disease progression or death), whichever occurs first, to guide the preparation of the 
phase III study in the same indication. 
 
The interim analysis will be carried out on the Full Analysis Set (FAS). The main 
characteristics at baseline and the status of patients will be described. For the tumour response 
evaluation, patients Best Overall Response (BOR) will be described. DCR (Disease Control 
Rate) and ORR (Overall Response Rate) will be also evaluated in each arm with their 2-sided 
95% Clopper-Pearson CIs. 
 
PFS for each arm will be summarized using Kaplan Meier curves and further characterized in 
terms of the median and survival probabilities at 2, 4, 6, 8 and 10 months along with the 
corresponding 2-sided 80% and 2-sided 95% CI for the estimates. The analysis of OS 
(Overall Survival) will use the same approach. 
 
Additional exploratory analyses for PFS will investigate the marginal effect of specific 
subgroups including a Forest plot. These factors will include, but are not limited to, region, 
ECOG performance status, gender, age (≤ 65 years, ]65-75],  > 75 years), prior adjuvant 
treatment, location of primary disease (including left/right colon…), surgical resection, 
number of metastatic sites (1-2, ≥ 3), time since 1st metastasis diagnosis (≤ 4, > 4), presence of 
liver metastasis, RAS/BRAF status and Neutrophil-Lymphocyte ratio (< 3, ≥ 3). 


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7. APPENDICES 
7.1. General analytic definitions 
Definitions below correspond to calculation rules for expressions defined in Section 3, as well 
as definition of value prior to treatment / under treatment, analysable value, first and last IMP 
intake dates and other general definitions. 
7.1.1. Expressions 
Calculation rules for expressions defined in Section 3 are as follows. 
Reliable value  
For biological samplings: 
Identified in SUPPLB with flag biofg_name of the parameter. 
 
For other panels: Non-missing result 
For biomarkers: last analysable value  
 
Value at baseline is defined as the last reliable value prior to treatment. 
 
Note: In case of patient included and/or randomised but not treated (i.e. patients with 
treatment duration equal to 0): value at baseline is defined as the last analysable value prior to 
first cycle (i.e "Visit<C001"). 
Baseline value of cycle n is defined as the last reliable (i.e. last non-missing) value prior to 
first study treatment intake of cycle n. 
Value at the Cycle n Day n is defined as the first reliable (i.e. first non-missing) value at the 
visit. 
Post-baseline value is defined as available value after the first study drug intake or in case of 
missing first intake date visit superior (>) to C000. 
END value is defined as the last reliable post-baseline value of the criteria of interest during 
the period of interest.  
WORST value is defined as the worst reliable post-baseline value of the criteria of interest 
during the period of interest. 
LOWEST value is defined as the lowest value during the treatment period. 
HIGHEST value is defined as the highest value during the treatment period. 
Change from baseline to each Cycle n Day n is calculated as: 
Value at the Cyclen Dayn - Value at baseline. 
Change from baseline to end value is calculated as: 
End value - Value at baseline. 
Change from baseline to WORST value is calculated as: 
Worst value - Value at baseline. 
 
 


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7.1.2. Value prior to treatment / under treatment 
Table (7.1.2) 1 - Time frame 
Criteria 
Value prior to treatment if 
measured between (D1 =) days 
before  
and (D2 =) days after 
the first study drug intake 
(D1 and D2 included) 
 
Post-baseline value  
during treatment if measured 
between (D1 =) days after the first 
study drug intake and until (D2 =) 
days after the last study drug intake  
(D1 and D2 included) 
Tumour assessment 
D1 = 60  
D2 = Xsup 
D1 = Xinf 
D2 = Xsupf 
Biochemistry / haematology 
/ Coagulation/Urinalysis 
D1 = 14 
D2 = Xsup 
D1 = Xinf 
D2 = Xsupf 
Vital signs 
D1 = 14 
D2 = Xsup 
D1 = Xinf 
D2 = Xsupf 
BSA 
D1 = 14 
D2 = Xsup 
D1 = Xinf 
D2 = Xsupf 
ECG 
D1 = 60 
D2 = Xsup 
 
 
Mutation status 
D1 = 60 
D2 = Xsup 
D1 = Xinf 
D2 = Xsupf 
ECOG performance status 
D1 = 14 
D2 = Xsup 
D1 = Xinf 
D2 = Xsupf 
Quality of life 
D1 = 14 
D2 = Xsup 
D1 = Xinf 
D2 = Xsupf 
BMK 
D1 =  
D2 = Xsup 
D1 = Xinf 
D2 = Xsupf 
­ 
Xsup: 0  
­ 
Xinf: 1 
­ 
Xsupf = 35 for S 95005 + Bevacizumab arm and Capecitabine + Bevacizumab arm 
 
Table (7.1.2) 2 - Time frame of cycle n 
Notations 
Definitions 
Cycle n 
Start date: First study drug intake date of cycle n 
 
End date: The minute before the 1st study drug intake of cycle (n+1) 
 It means that assessments planned the same day but before the 1st study 
drug intake in cycle (n+1) are part of cycle n. 
• 
For the last cycle, End date = min ((*), date of death)  
(*) max(first intake date of last cycle + 21 days of capecitabine,  first intake date of 
last cycle + 21 days of bevacizumab)  
(*) max(first intake date of last cycle + 28 days of S 95005,  first intake date of last 
cycle + 28 days of bevacizumab)   
The Data Management variable VISIT in patient EXdataset will be used to 
determine the start date of each cycle. 
 
 
­ General duration derivation and conversion : 
 In instances where duration or times-to-event are calculated, the convention to be used 
unless otherwise specified is [later date] – [earlier date] + 1 day. 
 When converting a number of days to other units, the following conversion factors will 
be used: 1 year = 365.25 days; 1 month = 30.44 days. 


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7.1.3. Analysable value 
Table (7.1.3) 1 - Definition of analysable value 
General definition 
Non missing value 
Specific definitions 
Laboratory parameters Only reliable values are considered for analyses. Unreliable values are flagged into the 
database. 
Biomarkers 
- Archived tumor biopsies 
ddPCR 
Only values with PFSTAT ≠ Not Done and PFSPCCND=OK. 
ELISA 
Only values with LBSPCCND=OK. 
- Blood samples 
IHC 
Only values with LBSPCCND=ACCEPTABLE, GOOD or EXCELLENT and % cells 
tumor content (LBSCAT) >=10%. 
MSI 
Only values with % cells tumor content of IHC data (TP marker) >= 10% & 
LBSTRESC not equal to 'Unknown/ Not interpretable’. 
7.1.4. First and last study IMP intake dates 
The dates of first and last IMP intake on the analysis period will be defined as follows: 
­ The date substituted by the Data Management Department, if not missing. 
­ The date mentioned in the CRF, otherwise. 
 
After selection of the dates of first and last IMP intake as defined above, if these dates are 
missing or incomplete, the following substitution rules will be applied: 
Table (7.1.4) 1 - Substitution rules of IMP intake dates 
Date to substitute 
Substituted date 
First IMP intake 
../mmm/yyyy 
Randomisation date if complete with same month and year 
Otherwise: 
01/mmm/yyyy 
../…/yyyy 
if complete with same year 
Otherwise: 
01/JAN/yyyy 
../.../…. 
Randomisation date  if complete 
Last IMP intake 
../mmm/yyyy 
Last available date* if same month and year 
Otherwise: 
last day of the month/mmm/yyyy 
../…/yyyy 
Last available date* if same year 
Otherwise: 
31/DEC/yyyy 
../.../…. 
Last available date* 


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Notes: 
- Missing dates will be substituted only for patients having taken at least one dose of study treatment  
 ../mmm/yyyy = missing day 
 ../.../ yyyy = missing day and month 
 ../.../....  = totally missing date 
- * Last available date (only for patients included) is defined as date of death if patient died, and as 
maximum date among completed dates relative to patient’s information otherwise. 
7.2. Specific analytic definitions and data handling conventions 
7.2.1. Study patients: Disposition, baseline characteristics and follow-up 
7.2.1.1. Disposition of patients 
All withdrawal reasons occurring in the study will be taken into account. 
7.2.1.2. Protocol deviations 
For the description of protocol deviations, the 6 following categories are considered in 
accordance with ICH E3 guideline and ICH E3 Q&A: 
­ Selection/inclusion criteria not fulfilled. 
­ Patient having withdrawal criteria but not withdrawn. 
­ Incorrect treatment or dose received. 
­ Forbidden concomitant treatment. 
­ Endpoint assessment possibly affected. 
­ Safety possibly affected. 
7.2.1.3.  Demographic data and other baseline characteristics 
7.2.1.3.1. Demographic data 
Age is calculated as difference between year of informed consent and year of date of birth. 
7.2.1.3.2. History of CRC  
­ Disease duration 
Disease duration (years) is defined as (Randomisation date – date of the first diagnosis 
)/365.25 
 
­ The progression free interval 
Progression free interval (months) is defined as (Date of relapse – date of end of last prior 
therapy)/30.44 
Of note, this progression free interval of patients relapsing or progressing during the last line 
of treatment is estimated to last one day 
 


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Missing diagnosis date 
 
Substituted diagnosis date 
../mm/yyyy 
 
Diagnosis date=01/mm/yyyy 
../…/yyyy 
 
Diagnosis date=01/01/yyyy 
Missing start of the last prior 
therapy 
 
Substituted startdate of the last prior therapy 
../mm/yyyy 
 
start date of the last prior therapy =01/mm/yyyy 
../…/yyyy 
 
startdate of the last prior therapy =01/01/yyyy  
Missing end of the last prior 
therapy 
 
Substituted end date of the last prior therapy 
../mm/yyyy 
 
end date of the last prior therapy = start date of the last 
prior therapy + 1day if same month and year 
Otherwise: 
end date of the last prior therapy=01/mm/yyyy 
../…/yyyy 
 
end date of the last prior therapy=start date of the last prior 
therapy + 1day if same year 
Otherwise: 
end date of the last prior therapy=01/01/yyyy 
../…/… 
 
end date of the last prior therapy=start date of the last prior 
therapy + 1day  
Note: 
../mm/yyyy = missing day 
 
../.../ yyyy = missing day and month 
 
7.2.1.3.3. Medical history and surgical or medical procedures history other than CRC 
The existence of a history (Yes/No) is defined from the presence, or not, of a Primary SOC 
and/or PT. 
7.2.1.3.4. Previous therapies for CRC 
The ATC classification (ATC code = 5 digits) is composed of 4 levels: 
­ The first (1 digit) represents the anatomo-physiological class. 
­ The second (2 digits) represents the pharmacological class. 
­ The third (1 digit) represents the pharmacological sub-class. 
­ The last (1 digit) represents the therapeutic class. 
 
The existence of a previous surgery (Yes/No) is defined from the presence, or not of a SOC 
and/or a “preferred name” for previous surgery at inclusion visit. 
 
The existence of a previous radiotherapy (Yes/No) is defined from the presence or not of a 
verbatim for the previous radiotherapy involved site at inclusion visit. 
 
The existence of a previous drug treatment (Yes/No) is defined from the presence, or not of 
an “ATC classification” and/or a “preferred name” for the previous drug treatment at 
inclusion visit.  
 
The existence of a previous treatment (Yes/No) is defined from the presence of a surgery, 
radiotherapy and/or a drug treatment. 
 


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7.2.1.3.5. Initial tumour assessment 
Patients with measurable disease are defined as patients with at least one target lesion. 
Patients with non-measurable disease are defined as patients without target lesion and with 
at least one non-target lesion. 
7.2.1.4. Extent of exposure and treatment compliance 
Treatment duration for S 95005 
Treatment duration (weeks) for S 95005 is defined as [(min (first intake date of the last cycle 
+ 27 days, death date) - first IMP intake)+1] / 7 
 
In case of missing or incomplete first intake date of the last cycle, the last intake date of the 
last cycle will be considered.    
 
Treatment duration for Capecitabine 
Treatment duration (weeks) for capecitabine is defined as [(min (first intake date of the last 
cycle + 20 days, death date) - first IMP intake)+1] / 7 
 
Treatment duration for Bevacizumab in S 95005 + Bevacizumab arm 
Treatment duration (weeks) for bevacizumab in S 95005 + Bevacizumab arm is defined as 
[(min (first intake date of the last cycle + 27days, death date) - first intake)+1] / 7 
 
Treatment duration for Bevacizumab in Capecitabine + Bevacizumab arm 
Treatment duration (weeks) for bevacizumab in Capecitabine + Bevacizumab arm is defined 
as [(min (first intake date of the last cycle + 20 days, death date) - first intake)+1] / 7 
 
Cycle duration  
Duration of cycle i (weeks) is defined as [[first IMP intake of cycle (i+1)] – [first IMP intake 
of cycle i]] / 7 
 
Of note, the duration of the last cycle for S 95005 (respectively Capecitabine) will be 
estimated to be 4 weeks (respectively 3 weeks) for the calculation of DI and RDI for S 95005 
(respectively Capecitabine). By the way the total treatment duration for S 95005 (respectively 
Capecitabine) will correspond to the sum of all cycle durations. 
 
Numbers of cycles  
The number of cycles with study drug intake will be defined based on patient EX data. 
A patient is considered to enter in a cycle if there is at least one intake date. 
 
 
 
 


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Planned dose intensity (PDI) (mg/m²/week for S 95005 and Capecitabine, mg/kg/week for 
Bevacizumab) 
 
 
S 95005 
10 days of intake per cycle 
Dose : 35 mg/m2 (bid)  
(70 mg/m²/day)   
𝟕𝟎(mg/m²/day) ∗𝟏𝟎
4(𝑤𝑘)
 
 
 
 
Capecitabine 
14 days of intake per cycle 
Dose : 1000 mg/m2 (bid)  
(2000 mg/m²/day)   
𝟐𝟎𝟎𝟎(mg/m²/day) ∗𝟏𝟒
3(𝑤𝑘)
 
Dose : 1250 mg/m2 (bid)  
(2500 mg/m²/day)   
𝟐𝟓𝟎𝟎(mg/m²/day) ∗𝟏𝟒
3(𝑤𝑘)
 
 
 
Bevacizumab in S 95005 + 
Bevacizumab arm 
2 days of intake per cycle 
Dose : 5 mg/kg/day 
𝟓(mg/kg/day) ∗𝟐
4(𝑤𝑘)
 
 
 
 
Bevacizumab in Capecitabine + 
Bevacizumab arm 
1 day of intake per cycle 
Dose : 7,5 mg/kg/day 
𝟕. 𝟓(mg/kg/day)
3(𝑤𝑘)
 
 
Cumulative dose 
The cumulative dose (mg/m²) for S 95005 and Capecitabine per patient in a time period 
(during the treatment period or per cycle) is the sum of the total dose that the patient received 
within that period according to the compliance. 
 
𝐶𝑢𝑚𝑢𝑙𝑎𝑡𝑖𝑣𝑒 𝑑𝑜𝑠𝑒 (𝑚𝑔/𝑚²) = 
෍
ቆ𝑅𝑒𝑎𝑙 𝐴𝑑𝑚𝑖𝑛𝑖𝑠𝑡𝑟𝑎𝑡𝑒𝑑 𝑑𝑜𝑠𝑒 (𝑚𝑔)
𝐵𝑆𝐴 (𝑚2)
ቇ
𝑡𝑖𝑚𝑒𝑝𝑒𝑟𝑖𝑜𝑑
 
 
The cumulative dose (mg/kg) for Bevacizumab per patient in a time period (during the 
treatment period or per cycle) is the sum of the total dose that the patient received within that 
period according to the compliance. 
 
𝐶𝑢𝑚𝑢𝑙𝑎𝑡𝑖𝑣𝑒 𝑑𝑜𝑠𝑒 (𝑚𝑔/𝑘𝑔) = 
෍
ቆ𝑅𝑒𝑎𝑙 𝐴𝑑𝑚𝑖𝑛𝑖𝑠𝑡𝑟𝑎𝑡𝑒𝑑 𝑑𝑜𝑠𝑒 (𝑚𝑔)
𝑤𝑒𝑖𝑔ℎ𝑡 (𝑘𝑔)
ቇ
𝑡𝑖𝑚𝑒𝑝𝑒𝑟𝑖𝑜𝑑
 
 
For S 95005 real administrated dose = number of tablets of 15 mg taken * 15 + number of 
tablets of 20 mg taken * 20  
For Capecitabine real administrated dose = number of tablets of 150 mg taken *150 + number 
of tablets of 500 mg taken * 500 
 
Number of tablets taken = number of tablets dispensed – number of tablets returned 


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If number of tablets returned is missing, number of tablets taken = estimated number of 
tablets 
These information are collected in the compliance CRF pages. 
 
For Bevacizumab: 
If the question “Was full dose administred” is answered by “Yes”, real dose administred  = 
total planned dose administred. 
If the answer is “No” , real administred dose = actual volume administred. 
 
DI 
The DI (mg/m²/week) for S 95005 and Capecitabine per patient is defined as the cumulative 
dose (mg/m²) received during the whole treatment period divided by the total treatment 
duration in weeks. 
𝐷𝐼 (𝑚𝑔/𝑚²/𝑤𝑘) 𝑝𝑒𝑟 𝑝𝑎𝑡𝑖𝑒𝑛𝑡 = 𝐶𝑢𝑚𝑢𝑙𝑎𝑡𝑖𝑣𝑒 𝑑𝑜𝑠𝑒 (𝑚𝑔/𝑚²)
𝑇𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝑑𝑢𝑟𝑎𝑡𝑖𝑜𝑛 (𝑤𝑒𝑒𝑘𝑠) 
 
The DI (mg/kg/week) for Bevacizumab per patient is defined as the cumulative dose (mg/kg) 
received during the whole treatment period divided by the total treatment duration in weeks. 
𝐷𝐼 (𝑚𝑔/𝑘𝑔/𝑤𝑘) 𝑝𝑒𝑟 𝑝𝑎𝑡𝑖𝑒𝑛𝑡 = 𝐶𝑢𝑚𝑢𝑙𝑎𝑡𝑖𝑣𝑒 𝑑𝑜𝑠𝑒 (𝑚𝑔/𝑘𝑔)
𝑇𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝑑𝑢𝑟𝑎𝑡𝑖𝑜𝑛 (𝑤𝑒𝑒𝑘𝑠) 
 
The duration of the last cycle will be estimated to be 4 weeks for S 95005 and Bevacizumab 
in S 95005 + Bevacizumab arm and 3 weeks for Capecitabine and Bevacizumab in 
Capecitabine + Bevacizumab arm. 
 
RDI 
The RDI (%) per patient is defined as the ratio of the DI to the initial PDI (mg/m²/week). 
𝑅𝐷𝐼 (%) 𝑝𝑒𝑟 𝑝𝑎𝑡𝑖𝑒𝑛𝑡 = 
𝐷𝐼 
𝑃𝑙𝑎𝑛𝑛𝑒𝑑 𝑑𝑜𝑠𝑒 𝑖𝑛𝑡𝑒𝑛𝑠𝑖𝑡𝑦 ∗100 
 
Cycle delay 
A cycle delay is defined according to the Study medication dispensed CRF page (dispensation 
postponed (Yes/No)). Moreover a cycle delay of cycle i will be also considered if the duration 
of the cycle i is higher than 28 days for S 95005 and 21 days for capecitabine. No reason will 
be fulfilled if not retrieved. 
 
The delay in days will be derived, based on the dates of administration. 
 
For S 95005: 
Delay (days) of cycle i = (administration date of cycle i) – (administration of cycle i-1 +28 
days) 


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For Capecitabine: 
Delay (days) of cycle i = (administration date of cycle i) – (administration of cycle i-1 
+21 days) 
 
Cycle reduction 
A cycle reduction is defined according to the Study medication dispensed CRF page 
(dose modified compared to previous cycle (Yes/No)). 
7.2.1.5. Concomitant treatments 
The ATC classification (ATC code = 5 digits) is composed of 4 levels: 
­ The first (1 digit) represents the anatomo-physiological class. 
­ The second (2 digits) represents the pharmacological class. 
­ The third (1 digit) represents the pharmacological sub-class. 
­ The last (1 digit) represents the therapeutic class. 
The existence of a concomitant treatment (Yes/No) is defined from the presence, or not, 
of an Anatomical therapeutic chemical classification and/or Preferred name. 
The periods considered for the analysis are:  
­ At inclusion for which treatments: 
 With start date ≤ inclusion date and stop date ≥ inclusion date or missing are taken into 
account. Inclusion date is equal to the date of inclusion visit, i.e. A000/D000 visit date. 
­ Before treatment period for which treatments: 
 With start date < first IMP or associated agent intake date are taken into account.  
­ During the treatment period for which treatments: 
 With start date ≥ first IMP or associated agent intake date and < first IMP or associated 
agent intake date in the last cycle + 28 days for S 95005 (+ 21 days for Capecitabine), or  
 With start date ≤ first IMP or associated agent intake date and stop date ≥ first IMP or 
associated agent intake date or missing are taken into account. 
Concomitant treatments could be considered in one or several of the possible analysis periods. 
In case of missing or incomplete first IMP or associated agent intake date in the last cycle, 
the last completed IMP or associated agent intake date will be considered.    
The following rules for substitution of missing or incomplete start and stop dates are so that 
the concomitance period is maximised: 
 
 
 
 
 
 
 
 
 
 
 


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Table (7.2.1.5) 1 - Substitution rules of concomitant treatments intake dates 
Date to substitute 
Substituted date 
Start date 
../mmm/yyyy 
If the year and the month are the same as the year 
and the month of inclusion then  
Start date= Inclusion date,  
 
otherwise  
Start date=01/mm/yyyy 
../…/yyyy 
If the year is the same as the year of inclusion then  
Start date= Inclusion date,  
 
otherwise  
Start date=01/01/yyyy 
../.../…. 
Inclusion date 
Stop date 
../mmm/yyyy 
If patient died same month and year then 
Date of death 
Else 
Last day of the month/mmm/yyyy  
../…/yyyy 
If patient died same year then 
Date of death 
Else 
31/DEC/yyyy  
../.../…. 
If patient died then 
Date of death 
Else 
No substitution 
(i.e. treatment considered as still ongoing)  
Note: 
../mm/yyyy = missing day 
 
../.../ yyyy = missing day and month 
 
../.../....  = missing date 
 
 
 


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The following rules for substitution of totally or partially missing start and stop dates are used 
for concomitant treatments (only further anti-tumour therapy): 
Table (7.2.1.5) 2- Substitution rules of further anti-tumour therapy intake dates 
Date to substitute 
Substituted date 
Start date 
../mmm/yyyy 
If the year and the month are the same as the year 
and the month of  the last study drug/IMP intake date 
then  
Last study drug/IMP intake date  
 
otherwise  
01/mm/yyyy 
../…/yyyy 
If the year is the same as the year of the last study 
drug/IMP intake date then  
Last study drug/IMP intake date,  
 
otherwise  
01/01/yyyy 
../.../…. 
Last study drug/IMP intake date 
Stop date 
../mmm/yyyy 
If patient died same month and year then 
Date of death 
Else 
Last day of the month/mmm/yyyy ,  
 
 
../…/yyyy 
If patient died same year then 
Date of death 
Else 
31/DEC/yyyy 
../.../…. 
If patient died then 
Date of death 
Else 
No substitution 
(i.e. treatment considered as still ongoing)  
Note: 
../mm/yyyy = missing day 
 
../.../ yyyy = missing day and month 
 
../.../....  = completely missing date 
7.2.2. Efficacy 
7.2.2.1. Antitumoral activity 
Tumour response is evaluated according to the “New Response Evaluation Criteria in Solid 
Tumours: Revised RECIST guideline (version 1.1), Eisenhauer et al, 2009”. 
 
Overall response is evaluated by the investigator and is not recalculated by the statistical team 
(see the protocol paragraph 7.2.1.3.2 for more details about the overall response evaluation). 
 
Overall response date  
For each tumor evaluation, if the overall response is PD, the first examination date among 
target lesion, non-target lesion and new lesion showing a PD will be considered. For all other 
responses (CR, PR or SD), the last examination date will be taken into account. 
 


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Best overall response  
Best overall response is defined as the best overall response across all time points.  
When SD or Non CR/Non PD is believed to be best overall response, it needs to be assessed a 
minimum of 6 weeks after study randomisation. Otherwise, the best overall response will be 
NE, unless any PD was further documented, in which case BOR will be PD. 
A patient dead because of progression before the first assessment planned per protocol 
(cycle 2) will be considered as ‘early death’. If a patient progressed before this first 
assessment, he will be considered as ‘early progressive’. If any of these two events occur, 
the overall response of the patient will be resumed as progression. 
In case of best overall response missing under the studied period, this one will be considered 
as Non Evaluable (NE).  
Confirmation of CR and PR (assessed a minimum of 4 weeks after the first assessment of CR 
or PR) is needed to deem either one the BOR. 
 
The first response assessed during the follow-up period could be used to confirm a previous 
response observed during the treatment period.  However, if a patient received a new 
anti-tumoral treatment, only the tumor evaluations performed until the date of a new therapy 
(included) will be used for the calculation of the best overall response. 


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Table (7.2.2.1) 1 - BOR when confirmation of CR and PR required 
Overall response  
Overall response 
BOR 
First time point (i) 
 next 
time 
point (i+1) 
 
 
 
CR 
CR 
 CR (if the time length between the two assessment is  ≥ 4weeks) 
otherwise PR  
CR 
PR 
 -if the CR is truly met (disease reappearance after complete 
response) then we put PD 
 - if the CR is not truly met (subsequent scans show small lesions 
were likely still present) then we consider the first CR time point 
as a PR  so we have 2 cases: 
   * PR (if the time length between the two assessment is ≥ 4 
weeks) 
   * otherwise SD (the time length between the study 
randomisation and the first CR (“considered as PR”)  is not 
required) 
CR 
SD or  
Non CR/Non PD 
 SD (if the duration between CR and the study randomisation 
≥ 6 weeks) otherwise PD 
CR 
PD 
 SD (if the time length between the study randomisation and the 
CR is ≥ 6 weeks), otherwise, PD 
CR 
NE or missing 
 SD (if the time length between the study randomisation and the 
CR is ≥ 6 weeks), otherwise  NE 
PR 
CR 
 PR even if the time length between the two assessment is less 
than 4 weeks 
PR 
PR 
 PR (if the time length between the two assessment is  ≥ 4weeks) 
otherwise SD (the time length between the study randomisation 
and the first PR is not required) 
 If successive PR (PR- PR-PR) then the duration could be 
calculated with respect to the first PR assessment date (if the 
interval between  two consecutive assessment is less than 4 
weeks) 
PR 
SD or Non 
CR/Non PD 
 SD 
PR 
PD 
 SD (if the time length between the study randomisation and the 
PR is ≥ 6 weeks), otherwise, PD 
PR 
NE or missing (*) 
 SD (if the time length between the study randomisation and the 
PR is ≥ 6 weeks), otherwise  NE 
SD or Non 
CR/Non PD 
PD 
 SD or non CR/non PD (if the time length between the study 
randomisation and the SD is ≥ 6 weeks), otherwise, PD 
SD or Non 
CR/Non PD 
SD or Non 
CR/Non PD 
 SD or non CR/non PD (if the time length between the study 
randomisation and one of the SD is ≥ 6 weeks), otherwise, NE 
unless any PD was further documented 
SD or Non 
CR/Non PD 
NE or missing 
 SD or non CR/non PD (if the time length between the study 
randomisation and the SD is ≥ 6 weeks), otherwise, NE unless 
any PD was further documented 
PD 
Whatever the 
overall response 
 PD 
NE 
PD 
 PD 
NE 
NE 
 NE 
(*) In addition, we will consider a patient with time point responses of PR-NE-PR as a confirmed partial 
response. 


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The Relative change and the best relative change of the sum of lesions diameters will be only 
calculated if the overall response for the target lesions is not equal to ‘Non Evaluable’. 
 
Baseline value will be the sum of all target lesions measurements assessed before the first 
IMP intake 
 
Relative change of the sum of the lesions diameters (%) 
 
Relative change from baseline of the sum of the lesions diameters (%) is defined at cycle i 
(Ci) as follows: 
 
 ቀ
sum of the lesions diameters at the cycle i − sum of the lesions diameters (baseline)
sum of the lesions diameters (baseline)
ቁ∗100  
 
Relative change from SMALLEST of the sum of the lesions diameters (%) is defined at cycle 
i (Ci) as follows: 
 
 ቀ
sum of the lesions diameters at the cycle i − sum of the lesions diameters (SMALLEST) at baseline or cycle< i
sum of the lesions diameters (SMALLEST) at baseline or cycle< i
ቁ∗
100  
 
Best relative change of the sum of the lesions diameters (%) 
 
The best relative change from baseline of the sum of the lesions diameters (%) is defined as 
the greatest decrease of the sum of the lesions diameters recorded. It can be calculated as 
follows: 
 
  min 𝑖
𝑖>0
ቀ
sum of the lesions diameters at the cycle i (Ci)− sum of the lesions diameters (baseline)
sum of the lesions diameters (baseline)
ቁ∗100  
 
For: 
­ DR: Among responders (BOR= CR or PR); from date of first response  
­ PFS, PFSs1 (PFS with further anti-cancer treatment as an event): Overall; from 
randomisation date  
 
Until: 
 
Situation 
End date 
Censor 
Documented radiological PD  
 
- Date of the first assessment of the 
series of the tests that determined PD* 
in tumour assessments form 
No 
Death during the study before radiological 
PD  
 
- Date of death  
No 
Subjects still followed without radiologic PD 
as of cut-off date 
 
- Date of last adequate (non-NE) tumor 
assessment  or cut-off date whichever 
is earlier 
Yes 
Non-study anti-tumor treatment initiated 
before radiologic PD 
 
- Date of last adequate (non-NE) tumor 
assessment prior to initiation of non-
study antitumor treatment for PFS 
- Date of initiation of non-study 
antitumor treatment for PFSs1 
Yes for PFS and 
DR 
 
No for PFSs1  
 
 
No baseline or no post baseline tumor 
assessment 
- Date of randomisation 
Yes 


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For: 
­ PFSs2 (PFS including clinical progression): Overall; from randomisation date 
Until: 
 
Situation 
End date 
Censor 
Documented radiological or clinical PD  
 
- Date of the first assessment of the 
series of the tests that determined 
PD* (including AE form & 
discontinuation form) 
No 
Death during the study before PD  
 
- Date of death 
No 
Subjects still followed without radiologic or clinical 
PD as of cut-off date 
 
- Date of last adequate tumor (non-NE) 
assessment or cut-off date whichever 
is earlier 
Yes 
Non-study anti-tumor treatment initiated 
before radiologic / clinical PD 
 
- Date of last adequate (non-NE) tumor 
assessment prior to initiation of non-
study antitumor treatment  
Yes 
No baseline or no post baseline tumor assessment 
 
- Date of randomisation 
Yes 
 
For: 
- 
OS: Overall; from date of randomisation 
Until: 
 
Event/Censor 
Decision 
Date of event or censor to consider for analysis 
Death  
Not 
censored 
- Date of death from AE CRF page 
- Date of death from  follow-up/status of the patient CRF 
page 
Patient alive without documented 
death 
Censored 
- Date of last contact  
 
A codelist based on all investigational drugs (number=1533, corresponding to ATC 
Code=V03AX in CONCMED database) and the pharmacological class coded as ‘L02’ 
(Endocrine therapy) will be reviewed by ITP to identify all new anti-tumoral treatment 
(as hormonotherapy, immunotherapy, targeted agent…). The list 1533 reviewed by the 
medical coding is the list 3594.0 in WHODD 2016.1. 
 
* The date of first progression during the treatment period is defined as the date of PD at the 
first cycle where the overall response is PD. The date of PD at cycle i is defined as the earliest 
date among the following dates: 
 
­ Date of PD for target lesions: If the response for target lesions is PD at the cycle i, the date 
of PD for target lesions corresponds to the earliest date of examination among the target 
lesions at cycle i.  
­ Date of PD for non-target lesions: If the response for non-target lesions is PD at the cycle i, 
the date of PD for non-target lesions corresponds to the earliest date of examination among 
the non-target lesions showing a PD at the cycle i. A non-target lesion showing a PD is 
defined as a lesion where the status is “Unequivocal progression (UPD)” or the appearance 
of at least one new lesion. The appearance of a new lesion is defined as a lesion where the 
status at cycle i is new (TRSPID = NEW and TRORRES = Y) 


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Neutrophil-Lymphocyte ratio (NLR) = Absolute neutrophil count (109/L) / absolute 
lymphocyte count(109/L)/ 
7.2.3. Biomarkers 
7.2.3.1. Protein-expression by IHC 
7.2.3.1.1. Protein-expression by IHC occupancy 
Occupancy will be defined as: 
Occupancy = % cells marked 2+ + % cells marked 3+ 
7.2.3.1.2. Protein-expression by IHC H-score 
H-score will be defined as: 
H-score = 1*% cells marked 1 + 2*% cells marked 2 + 3*% cells marked 3+ 
7.2.3.1.3. Biomarker classes based on protein-expression by IHC 
For occupancy, for each biomarker, the following biomarker classes will be defined: 
­ bmk+: Occupancy ≥ x%; 
­ bmk-: Occupancy < x%. 
 
x belonging to (5;10;15;20;25;30;35; median(Occupancy). 
 
For H-score, for each biomarker, the following biomarker classes will be defined: 
­ bmk+: H-score ≥ median(H-score); 
­ bmk-: H-score < median(H-score). 
7.2.3.2. Values out of limits of detection 
For quantitative description of protein-expression by ELISA, missing values with a result flag 
not equal to “In ranges” will be substituted as follows:  
Table (7.2.3.2) 1 - Substitution rules for protein-expression by ELISA biomarkers 
Value 
Substituted by 
Below 
detection 
limit or Below fit 
curve limit (based 
on the result flag) 
LLOD / √2 
Above 
detection 
limit or Above fit 
curve limit (based 
on the result flag) 
ULOD 
 
If the lower (respectively upper) limit of detection is missing then it is replaced by the lower 
(respectively upper) limit of quantification in the substitution rules. 


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7.2.4. Safety 
7.2.4.1. Dose Limitant Toxicity (DLT) 
Not applicable. 
7.2.4.2. AEs 
Of note: + x days = + 35 days for S 95005 
              + x days = + 35 days for Capecitabine 
 
Only AEs with a "primary SOC", a "HLGT", a "HLT" and a "PT" are considered. 
 
Each medical concept of AEs coded according to the internal "multiple medical concept" 
process is taken into account as a single AE in the statistical analysis. 
The modalities of the AE (onset and end dates, severity, seriousness, action taken, additional 
therapy, relationship, outcome...) replicated by default to each medical concept are also taken 
into account in the statistical analyses of AEs by category. 
EAEs on treatment are defined as all AEs: 
 
­ which occur between the first IMP or associated agent intake date (included) and the last 
IMP intake date "+ 35 days" (included), 
or 
­ which occur before the first IMP or associated agent intake date and which worsen 
(in terms of severity) or become serious according to the investigator opinion between the 
first IMP or associated agent intake date (included) and the last IMP or associated agent 
intake date "+ 35 days" (included), 
or 
­ with an emergence forced by the sponsor during the Important Medical Event (IME) 
process (upgrade of seriousness) and at least one episode occurring between the first IMP 
or associated agent intake date (included) and the last IMP or associated agent intake date 
"+ 35 days" (included). 
­  
In case of multiple episodes of the same event before the first IMP or associated agent 
intake date, the episode nearest to the first IMP or associated agent intake date is taken into 
account. 
Note: AEs occurring or worsening or becoming serious on the day of the first IMP intake 
(if any) is considered as emergent. 
 
SAEs are defined as all AEs upgraded by the sponsor during the IME or PharmacoVigilance 
(PV) process (upgrade of seriousness) or considered as "serious" from investigator 
assessment. 
SAEs from investigator assessment are defined as all AEs fulfilling at least one of the 
following seriousness criteria for immediate notification: death, hospitalisation or 
prolongation of hospitalisation, medically important, life-threatening, disability/incapacity or 
congenital anomaly. 


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A fatal AE corresponds to an adverse event with “Death” as PT or “Fatal” as outcome or 
Severity = Grade 5. 
AEs related to IMP correspond to AEs with relationship forced by the sponsor during the PV 
process (upgrade of relationship for SAEs according to investigator or sponsor opinion) or 
considered as "related" from investigator assessment. In other cases, the AEs are considered 
as "not related to IMP". 
AEs related to IMP or associated agent from investigator assessment correspond to AEs 
associated with the answer "Related" to the "Is this event related to test drug?" or “Is this 
event related to the associated agent questions. 
 
Severity, action taken regarding the IMP, additional therapy requirement and seriousness are 
recorded for each episode of an AE, whereas only the last relationship with the IMP and the 
last outcome reported by the investigator are retained in the ClinTrial database. The following 
information will be taken into account: 
 
­ For the analyses where the relationship with MP and the outcome are considered, 
the information retained in the ClinTrial database will be taken into account. 
­ For the analyses where the severity of the AE is considered, the worst severity from the 
day of emergence and during the studied period will be taken into account. 
­ The number of patient by worst grade: for each patient, SOC and PT, we analyze the worst 
grade of events. 
­ The number of event by worst grade: for each patient, SOC and PT, we analyze the worst 
grade of each event. The percentage will be calculated as the number of events of the PT 
concerned at grade X divided by the total number of events of the PT concerned. 
­ For the analyses where the action taken regarding the IMP and the additional therapy 
requirement are considered, all the actions taken and additional therapy requirements 
recorded from the day of emergence and on the studied period will be taken into account. 
­ However, in case of an episode of an EAE leading to studied treatment withdrawal 
reported after the last IMP intake date "+ 35 days", the AE will be considered as leading to 
studied treatment withdrawal during the studied period. 
­ Seriousness is judged by event: if one episode is serious (whatever the time it occurs), 
the whole event will be considered as serious. 
­ A severe adverse event corresponds to an AE with NCI CTCAE grade 3, 4 or 5. 
­ Any grade corresponds to an AE with NCI CTCAE grade 1, 2, 3, 4 or 5. 
­ All multicoded events will be taken into account in the analyses. 
­ The existence of an AE (Yes / No) will be defined from the presence, or not, of a 
“primary SOC” and/or a “PT”. 
 
For the description of EAE recovered on treatment / after treatment: 
­ All EAE with "recovered", "recovered with sequelae" or "recovering/improving" as 
outcome will be taken into account. 
­ An EAE is considered as recovered "on treatment" ("after treatment", respectively) if the 
outcome occurs between the first IMP or associated agent intake date and the last IMP or 
associated agent intake date "+ 35 days" (included) (strictly after the last IMP or associated 
agent intake date "+ 35 days", respectively). 


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­ The date used to determine if the outcome occurs on treatment or after treatment is the 
recovery date for EAE with "recovered" or "recovered with sequelae" as outcome, and the 
date of AE last information(*) for EAE with "recovering/improving" as outcome. 
 
 (*) Date of AE last information is defined as the maximum between onset date, dates of 
modification of severity and dates of the six seriousness criteria for this AE. 
 
Time to onset: time between the first study drug intake date and the onset date of the first 
emergent episode of AE. 
The following rules are applied in case of missing severity: 
Table (7.2.4.2) 1 - Emergence of adverse events in case of missing severity/grade (if any) 
Severity/Grade 
 
 
AE considered as 
Nearest before the first 
IMP intake date 
During the 
treatment period 
Missing 
Missing 
→ 
Emergent 
Missing 
Grade 1 
→ 
Non emergent 
Missing 
Grade 2, 3, 4 or 5 
→ 
Emergent 
Grade 1, 2, 3 
Missing 
→ 
Emergent 
Grade 4 
Missing 
→ 
Non emergent 
 
 
The rules for substitution of missing or incomplete episode date (onset date, dates of the six 
seriousness criteria and dates of change of severity and action taken) are as follows: 
Table (7.2.4.2) 2 - Substitution rules of AE dates 
Date to substitute 
Substituted date                                       
(Episode date) 
../mmm/yyyy 
 If same month and year than first study drug/IMP 
intake date then: 
 First study drug/IMP intake date  
Else: 
01/mmm/yyyy 
 ../…/yyyy 
 If same year than first study drug/IMP intake date then: 
First study drug/IMP intake date 
Else: 
01/JAN/yyyy 
 ../.../…. 
 First study drug/IMPintake date 
Note: 
../mm/yyyy = missing day 
 ../.../ yyyy = missing day and month 
 ../.../....  = missing date 
 
 
The rules for substitution of missing or incomplete recovery dates, in case of AE outcome 
"recovered" or "recovered with sequelae" are as follows: 


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Table (7.2.4.2) 3 - Substitution rules of recovery date 
Date to substitute 
Substituted date 
../mmm/yyyy 
If same month and year than date of AE last 
information(*) then: 
Date of AE last information 
Else: 
Last day of the month /mmm/yyyy 
../…/yyyy 
If same year than date of AE last information(*) then: 
Date of AE last information 
Else: 
31/DEC/yyyy 
../.../…. 
Date of AE last information(*) 
Notes: 
- ../mmm/yyyy = missing day, 
../.../ yyyy = missing day and month, 
../.../....  = missing date. 
- (*) Date of AE last information is defined as the maximum between onset date, dates of change of severity 
and dates of the six seriousness criteria for this adverse event. 
 
Duration of AE (days) = recovery date (last episode) – onset date of AE + 1 
7.2.4.3. Death 
Death information are taken on ‘Adverse Event’ (serious criteria for immediate reporting = 
Death) and ‘Status of the patient at follow-up n° X’ (reason for not continuing/completed the 
follow-up period = Death) CRF pages.  
In case of death reported on ‘Adverse Event’ page, the date of death is compared to the date 
of last intake + 35 days to classify occurrence on-study or during follow-up. 
7.2.4.4. Clinical laboratory evaluation 
Values 
Only reliable values are considered for analyses. Unreliable values are flagged into the 
database. 
 
In case of multiple samples: 
­ For the description of the values at each planned post-baseline visit, only the first 
analysable one measured under treatment at the visit is taken into account. 
­ Otherwise, each post-baseline value (test, re-test, planned, unplanned) measured under 
treatment is taken into account for analyses. 
 
Units 
All parameters will be analysed in international units (IU). 
 
Abnormal values 
Abnormal values are described according to: 
- Reference laboratory ranges for the non-gradable parameters. 
- CTCAE grade for gradable parameters. 
Laboratory reference limits and CTCAE grades are reported in the database. 
 
Any grade corresponds to a laboratory value with NCI CTCAE grade 0, 1, 2, 3 or 4. 


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A grade 0 corresponds to a laboratory value within limit or reference range. 
 
The LOWEST value for a patient is defined as the lowest absolute laboratory value during 
the treatment period. 
A Lowest value for a cycle is defined as the lowest laboratory value in that cycle.  
The time to LOWEST value is defined from the date of the first drug intake to the sampling 
date of the LOWEST value. 
The time to LOWEST value in a cycle is defined from the first date of drug intake in that 
cycle to the sampling date of the LOWEST value. 
 
The HIGHEST value for a patient is defined as the highest laboratory value during the 
treatment period. 
A highest value for a cycle is defined as the highest laboratory value in that cycle.  
The time to HIGHEST value is defined from the date of the first drug intake to the sampling 
date of the HIGHEST value. 
The time to HIGHEST value in a cycle is defined from the first date of drug intake in that 
cycle to the sampling date of the HIGHEST value. 
 
The NADIR for a patient is defined as the worst (lowest or highest according to parameter) 
absolute laboratory value during the treatment period. 
A NADIR for a cycle is defined as the worst (lowest or highest according to parameter) 
laboratory value in that cycle.  
 
Urinary results 
The category positive includes results ‘+’, ‘++’ and ‘+++’. 
 
Creatinine clearance 
Creatinine clearance will be categorised in 4 levels of impairment: 
­ Normal renal function (CLcr ≥ 90 mL/min). 
­ Mild renal impairment (CLcr 60-89 mL/min). 
­ Moderate renal impairment (CLcr 30-59 mL/min). 
­ Severe (< 30mL/mn). 
 
CEA results 
CEA is abnormal if its value is out of lower and upper reference range. 
 
Relative change form baseline to worst value under treatment is given by: 
 
ቀ
Worst value under treatment− value at baseline
value at baseline
ቁ∗100  
 


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Worst value 
 
Worst value will be analysed as follow: 
  
Parameter 
Worst Highest 
Worst lowest 
Gradable sodium 
hypernatremia 
hyponatremia 
Gradable Potassium 
hyperkalemia 
hypokalemia 
Gradable calcium 
hypercalcemia 
hypocalcemia 
Gradable magnesium 
hypermagnesemia 
hypomagnesemia 
Gradable phosphates 
NA  
hypophosphatemia 
Gradable serum creatinine 
high creatinine 
NA  
Gradable albumin 
NA 
Low albumin 
Gradable glucose 
hyperglycemia 
hypoglycemia 
Gradable GGT 
high GGT 
NA   
Gradable AST 
high AST 
NA   
Gradable ALT 
high ALT 
NA   
Gradable alkaline phosphatase 
high alkaline 
phosphatase 
NA   
Gradable total bilirubin 
high total bilirubin  
NA   
Gradable haemoglobin 
high haemoglobin 
Anemia 
Gradable white blood cells 
leucocytosis 
low WBC 
Gradable neutrophils 
NA   
low Neutrophils 
Gradable lymphocytes 
high lymphocyte 
low lymphocyte 
Gradable platelets 
NA 
Low platelets 
Gradable INR 
high INR 
NA   
Gradable Activated 
Partial 
thromboplastin time 
high aPTT 
NA   
  
Haematocrit 
High haematocrit 
Low haematocrit  
  
Red Blood Cell Count 
High RBC 
Low RBC 
  
Monocytes 
High monocytes 
NA   
  
Eosinophils 
High eosinophil 
NA   
  
Basophils 
NA   
Low Basophil 
  
Chloride 
High chloride 
Low chloride 
  
Bicarbonate 
High bicarbonate 
Low bicarbonate 
  
Blood urea nitrogen 
NA   
High BUN  
  
Total protein 
High Proteins 
Low total Proteins 
  
LDH 
High LDH 
NA   
 
For the urinalysis parameters, the worst class will correspond to ‘Positive’ class, then ‘Trace’ 
and finally ‘Negative’ will be considered as normal class. 
For creatinine clearance, the worst class will correspond to “severe” category, 
then “moderate”, then “mild” and finally “normal”. 
 


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Worst grade for Hypo and Hyper:  
­ Hypo: If the lowest result is below lower normal range limit, Hypo =grade (for gradable 
parameter), Else Hypo=0. 
­ Hyper: If the highest result is above upper normal range limit, Hyper =grade (for gradable 
parameter), Else Hyper =0. 
 
Days to most extreme value: 
The “most extreme value” recorded, and the corresponding number of days to the most 
extreme value recorded, are summarized descriptively for Grade 3 or 4 abnormalities (or with 
moderate or severe renal impairment for creatinine clearance). This is expected to be limited 
to the selected “parameters of interest”. The “most extreme” is defined as the worst value 
(Nadir) that worsened from baseline by at least one grade (or one level of impairment for 
creatinine clearance) (or had a missing baseline). 
Note: In the event a patient had the same nadir at multiple times for a cycle, the first 
occurrence was selected. 
 
Days to recovery: 
The median number of days to ‘recovery’ in patients with Grade 3 or 4 abnormalities 
(or with moderate or severe renal impairment for creatinine clearance) that worsened from 
baseline is obtained from Kaplan-Meier estimates. 
 
‘Recovery’ in patients with Grade 3 or 4 laboratory abnormalities (or with moderate or severe 
renal impairment for creatinine clearance) that worsened from baseline is defined as the 
presence of a subsequent measurement (after the first occurrence of the most extreme value 
observed that has a value of Grade 3 or 4 (or has moderate or severe renal impairment for 
creatinine clearance)) of the parameter that is ≤ Grade 1 or ≤ baseline grade (or that had mild 
or normal renal impairment for creatinine clearance).  
 
Days to recovery is calculated as: 
For patients who recovered: (Date of recovery – date of most extreme value) +1 
 
For patients who did not recover: (Date of last subsequent value for that parameter – date of 
most extreme value) +1 
7.2.4.5. Vital signs, clinical examination and other observations related to safety 
7.2.4.5.1. Vital signs and clinical examination 
Worst value 
 
For ECOG, weight, BSA, SBP, DBP, HR and respiratory rate, the worst (highest) value will 
be derived. 
 
For weight, BSA, SBP, DBP and HR, the worst (lowest) value will be derived.  
Body Surface Area 
 
BSA (m²) = 0.007184x Weight (kg)0.425 x height (cm)0.725 
 


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ECOG performance status 
 
STATUS 
GRADE 
STATUS 
KARNOFSKY 
ECOG - ZUBROD / WHO 
Normal, no disorders 
100 
0 
Normal unrestricted activity 
Normal activity. Minor signs or symptoms of 
the disorder. 
90 
 
 
 
 
1 
Arduous physical activity restricted, but 
patient able to walk unaided and perform light 
work 
Activity normal with effort 
80 
 
 
Independent but incapable of normal 
activity or work 
70 
 
 
 
 
2 
Able to walk unaided and independent but 
unable to work more than half-time 
Requires occasional help, but able to cope 
with most personal needs. 
60 
 
 
Requires frequent help and medical care 
50 
 
 
 
 
3 
Much less independent. Spends more than half 
his / her time in bed or seated. 
Requires considerable help and medical care 
40 
 
 
Bedridden. Hospitalization indicated, even 
though death not imminent 
30 
 
 
 
 
4 
Incapable of looking after him / herself. 
Completely confined to bed or to a chair 
Gravely ill. Hospitalization necessary. 
Symptomatic treatment necessary 
20 
 
 
 
7.2.4.5.2. Electrocardiogram 
Unscheduled ECGs are not taken into account in the analysis. 
 
For all other analyses, all analyzable values are taken into account, whether at planned visit or 
not, initial sample or additional sample. 
 
Absolute prolongation at withdrawal visit = max (Absolute prolongation at withdrawal visit). 
Change from baseline = absolute prolongation - Absolute prolongation at baseline. 
7.2.4.5.3. LVEF 
Not applicable. 


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7.2.5. QoL 
For the QLQ-C30 and QLQ-CR29, raw scores and scores will be calculated as follows : 
 
­ For all scales, the Raw Score, RS, is the mean of the component items: 
 
Raw Score = RS = (I1 + I 2 +...+ In ) / n 
 
­ For Functional scales: 
 
Score = {1 - (RS−1) / range} ×100 
 
­ For Symptom scales / items and QoL:  
 
Score = {(RS - 1) / range}×100 
7.3. Statistical methods details 
Not applicable 
7.4. Software and programming codes 
Cox proportional hazard model adjusting for the stratification factors  
PROC PHREG data = work.data; 
model TIME* CENSOR(censoredval)= ARM RAS ECOG / RL TIES=efron; 
Run; 
 
Fisher’s exact test 
PROC FREQ DATA= work.data; 
   TABLES ARM * VAR / FISHER; 
RUN; 
 
Clopper Pearson CI 
PROC FREQ data=work.data; 
tables RESPONSERATE / binomial (exact); 
by ARM; 
run; 
Kaplan Meier survival analysis 
PROC LIFETEST data= work.data alpha=0.05/0.2 alphaqt=0.05/0.2  method=KM;  
 
TIME TIME *CENSOR(censoredval);   
strata ARM; 
id SUBJID, 
survival out=surv conftype=loglog ; /*Kalbfleisch and Prentice CI*/ 
run; 
 
 


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8. REFERENCES 
 
Sprangers MA, te Velde A, Aaronson NK: The construction and testing of the EORTC colorectal cancer-specific 
quality of life questionnaire module (QLQ-CR38). European Organization for Research and Treatment of Cancer 
Study Group on Quality of Life. Eur J Cancer 1999, 35(2):238-47. 
 
Gujral S, Conroy T, Fleissner C, et al: Assessing quality of life in patients with colorectal cancer: an update of 
the EORTC quality of life questionnaire. Eur J Cancer 2007, 43(10):1564-73. 
 
Whistance RN, Conroy T, Chie W, 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. Eur J Cancer 
2009, 45(17):3017-26. 
 
Fayers PMAN, Bjordal K, Groenvold M, Curran D, Bottomley A: The EORTC QLQ-C30 Scoring Manual. 
European Organisation for Research and Treatment of Cancer, Brussels;, 3 2001. 
 
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 Natl Cancer 
Inst 1993, 85(5):365-76. 
 
Guidelines 
 
Guideline on Missing Data in Confirmatory Clinical Trials – Adopted by CHMP, June 2010, issued as 
EMA/CPMP/EWP/1776/99 Rev. 1. 
 
ICH E3 - Structure and Content of Clinical Study Reports – Adopted by CPMP, December 1995, issued as 
CPMP/ICH/137/95/step 5. 
 
ICH E3 Q&A - Structure and Content of Clinical Study Reports - Questions & Answers (R1) - July 2012, issued 
as EMA/CHMP/ICH/435606/2012. 
 
ICH E9 - Statistical Principles for Clinical Trials - Adopted by CPMP, March 1998, issued as 
CPMP/ICH/363/96/step 5. 
 
ICH E14 – The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-
Antiarrhythmic drugs – Adopted by CHMP, May 2005, issued as CHMP/ICH/2/04. 
 
CTCAE (Common Terminology Criteria for Adverse Events) v4.0 
 
Points to consider 
 
Points to Consider on Adjustment for Baseline Covariates – Adopted by CPMP, May 2003, issued as 
CPMP/EWP/2863/99. 
 
Points to Consider on Multiplicity Issues in Clinical Trials – Adopted by CPMP, September 2002, issued as 
CPMP/EWP/908/99. 
 
Bibliography 
Benjamini, Y. and Hochberg, Y., On the Adaptive Control of the False Discovery Rate in Multiple Testing with 
Independent Statistics, Journal of Educational and Behavioral Statistics, 2000.  
 
Kaiser L., Adjusting for baseline: change or percentage change?. Statistics in Medicine, 1989 Oct; 8(10): 1183-
90 
 
Mallinckrodt, C.H., Lin, Q. and Molenberghs M. A structured framework for assessing sensitivity to missing 
data assumptions in longitudinal clinical trials. Pharmaceutical Statistics, 2013, 12, 1-6.  
New Response Evaluation Criteria in Solid Tumours: Revised RECIST guideline (version 1.1), Eisenhauer et al, 
2009 


 
I . R . I . S . 
 
I N S T I T U T D E R E C H E R C H E S I N T E R N A T I O N A L E S S E R V I E R 
 
 
Document title 
TEMPLATES FOR TABLES, LISTINGS AND GRAPHS 
(TLG) 
 
Study title 
An open-label, randomised, non-comparative phase 2 study 
evaluating S 95005 (TAS-102) plus bevacizumab and 
capecitabine plus bevacizumab in patients with previously 
untreated metastatic COlorectal cancer who are non-eligible 
for intensive therapy (TASCO1 study) 
 
Test drug code 
S 95005 
 
 
Indication 
First-line treatment of metastatic colorectal cancer in patients 
non-eligible for intensive therapy 
 
 
Development phase 
Phase II 
 
 
Protocol code 
CL2-95005-002 
 
 
EudraCT Number 
2015-004544-18 
 
 
Universal Trial Number Not applicable 
 
 
Sponsor 
Institut de Recherches Internationales Servier (I.R.I.S.) 
 
 
Date of the document 
21st March 2018  
 
 
Version of the document Final version 3.0 
 
 
 
CONFIDENTIAL 


PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Table of contents 
1. STUDY PATIENTS: DISPOSITION, BASELINE CHARACTERISTICS AND 
FOLLOW-UP....................................................................................................................... 8 
1.1. Disposition of patients ...................................................................................................... 8 
1.2. Protocol deviations ........................................................................................................... 9 
1.3. Analysis sets and subgroups ........................................................................................... 10 
1.4. Demographic data and other baseline characteristics ..................................................... 12 
1.4.1. Demographic data ......................................................................................................... 12 
1.4.2. Pregnancy test and contraception ................................................................................. 13 
1.4.3. History of studied disease ............................................................................................. 14 
1.4.4. Signs and Symptoms .................................................................................................... 16 
1.4.5. Medical history and surgical or medical procedures other than colorectal cancer ....... 17 
1.4.6. Clinical laboratory evaluation ...................................................................................... 18 
1.4.7. Previous therapies for colorectal cancer ....................................................................... 21 
1.4.8. Initial tumor assessment (Metastatic colorectal cancer) ............................................... 22 
1.4.9. Vital signs and clinical examination ............................................................................. 23 
1.4.10. Electrocardiogram ........................................................................................................ 24 
1.4.11. Mutation ....................................................................................................................... 25 
1.5. Extent of exposure and treatment compliance ................................................................ 26 
1.6. Concomitant treatments .................................................................................................. 34 
2. EFFICACY ANALYSIS ................................................................................................... 36 
3. BIOMARKERS ANALYSIS ............................................................................................ 48 
3.1. Protein-expression by IHC .............................................................................................. 48 
3.2. Protein-expression by IHC according to response .......................................................... 49 
3.2.1. Protein-expression by IHC according to DCR/ORR .................................................... 50 
3.2.2. Protein-expression by IHC according to PFS ............................................................... 51 
3.2.2.1. 
Protein-expression by IHC according to PFS – study of all eligible cutoffs ........... 51 
3.2.2.2. 
Protein-expression by IHC according to PFS – study of best cutoff point .............. 53 
3.3. Microsatellites ................................................................................................................. 55 
3.4. Protein-expression by ELISA ......................................................................................... 56 
3.5. Consistency of mutation results ...................................................................................... 57 
4. SAFETY ANALYSIS ........................................................................................................ 57 
4.1. DLTs ............................................................................................................................... 57 
4.2. Adverse events ................................................................................................................ 58 
4.3. Death ............................................................................................................................... 67 
4.4. Clinical laboratory evaluation ......................................................................................... 68 
4.5. Vital signs and clinical examination ............................................................................... 78 
4.6. Electrocardiogram ........................................................................................................... 80 
4.7. LVEF .............................................................................................................................. 80 
5. QOL .................................................................................................................................... 81 
 


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This document presents the templates for Tables, Listings and Graphs (TLG) associated with 
the analyses planned in the Statistical Analysis Plan (SAP). 
 
The correspondence between the SAP and TLG should be done using sections names 
(instead of sections numbers). 
 
Templates provided hereafter are produced with all the treatment groups. 
 
For analyses by cycles, refer to the Investigation Scheduled in Section 1.2.3 of the SAP to 
find details on cycles concerned and, if applicable, to the note providing specific information, 
associated to the shell considered.  
 
As concerns the decimal places, the following rules will be applied: 
­ Quantitative analyses: 
 Data precision + 1 decimal place for means, standard deviations, medians, first and third 
quartiles. 
 Same as data precision for minimums and maximums.  
­ Qualitative analyses: 
 1 decimal place for percentages in tables relative to coded data (adverse events, medical 
history/surgical or medical procedures history, previous/concomitant treatments), 
analysis sets and protocol deviations. 
 2 decimal places for percentages otherwise. 
­ Inferential analyses: 3 decimal places for p-value, displayed as < 0.001 if less than 0.001. 
In instances where the percentage calculation is not specified in footnote, the convention to be 
used is % = (n/Nobs)*100. 
 
 


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SUMMARY OF STATISTICAL ANALYSES 
 
Criterion / Analysis 
NIS IS 
RS FAS PPS TR SS QLS
29 
QLS
30 
TUM
FAS 
TUM
TR 
SER
FAS 
Study Patients: Disposition, baseline characteristics and Follow-Up 
Disposition of patients 
(Section 1.1) 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol deviations 
(Section 1.2) 
 
 
 
 
 
 
 
 
 
 
 
 
Analysis sets and 
subgroups 
(Section 1.3) 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
(Section 1.4.1) 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
(Section 1.4.2) 
 
 
 
 
 
 
 
 
 
 
History of studied 
disease (Section 1.4.3) 
 
 
 
 
 
 
 
 
 
 
 
 
Signs and symptoms 
(Section 1.4.4) 
 
 
 
 
 
 
 
 
 
 
 
 
Meical history and 
surgical or medical 
procedures other than 
studied disease 
(Section 1.4.5) 
 
 
 
 
 
 
 
 
 
 
 
 
Clinicalllaboratory 
evaluation 
(Section 1.4.6) 
 
 
 
 
 
 
 
 
 
 
 
 
Previous therapies for 
studied disease 
(Section 1.4.7) 
 
 
 
 
 
 
 
 
 
 
 
 
Initial tumor 
assessment 
(Section 1.4.8) 
 
 
 
 
 
 
 
 
 
 
 
 


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Criterion / Analysis 
NIS IS 
RS FAS PPS TR SS QLS
29 
QLS
30 
TUM
FAS 
TUM
TR 
SER
FAS 
Vital signs and clinical 
examination 
(Section 1.4.9) 
 
 
 
 
 
 
 
 
 
 
 
 
Electrocardiogram 
(Section 1.4.10) 
 
 
 
 
 
 
 
 
 
 
 
 
Mutation (1.4.11) 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment duration 
and extent of exposure 
(Section 1.5) 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
treatments 
(Section 1.6) 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy analysis 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy analysis 
(Section 2) 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarker analysis 
 
 
 
 
 
 
 
 
 
 
 
 
Protein-expression by 
IHC (Section 3.1) 
 
 
 
 
 
 
 
 
 
 
 
 
Protein-expression by 
IHC according to 
response (Section 3.2) 
 
 
 
 
 
 
 
 
 
 
 
 
Microsatellites 
(Section 3.3) 
 
 
 
 
 
 
 
 
 
 
 
 
Protein-expression by 
ELISA (Section 3.4) 
 
 
 
 
 
 
 
 
 
 
 
 
Consistency of 
mutation results 
(Section 3.5) 
 
 
 
 
 
 
 
 
 
 
 
 


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Criterion / Analysis 
NIS IS 
RS FAS PPS TR SS QLS
29 
QLS
30 
TUM
FAS 
TUM
TR 
SER
FAS 
Safety analysis 
 
 
 
 
 
 
 
 
 
 
 
 
DLTs (Section 4.1) 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
(Section 4.2) 
 
 
 
 
 
 
 
 
 
 
 
 
Death (Section 4.3) 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory 
evaluation 
(Section 4.4) 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs and clinical 
examination 
(Section 4.5) 
 
 
 
 
 
 
 
 
 
 
 
 
Electrocardiogram 
(Section 4.6) 
 
 
 
 
 
 
 
 
 
 
 
 
QOL analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLES, LISTINGS AND GRAPHS 
1. STUDY PATIENTS: DISPOSITION, BASELINE CHARACTERISTICS AND 
FOLLOW-UP 
1.1. Disposition of patients 
 
Status of patients – Screened Set (N = xx) - Disposition of patients before inclusion 
STATUS 
ALL 
SCREENED 
n (%) 
 
 
Included 
n (%) 
 
 
Excluded* 
n (%) 
 
                Withdrawal by subject 
n (%) 
 
                Screen failure  
n (%) 
 
                Adverse event 
n (%) 
 
n: number of patients related to the status 
    % = (n/N)*100  (N: number of screened patients)  
   *NIS 
 
 
 
 
 
Status of patients – Included Set (N = xx) - All analytical approaches 
Descriptive statistics at and after inclusion 
STATUS 
 
Arm 1  
(N = xx) 
Arm 2  
(N = xx) 
ALL      
(N = xx) 
INCLUDED 
Nobs 
 
 
 
 
 
 
In Conformity with the Protocol 
n (%) 
 
 
 
 
 
 
With Protocol Deviation(s) Before or at Inclusion 
n (%) 
 
 
 
 
 
WITHDRAWN DUE TO 
n (%) 
 
 
 
 
 
 
Adverse event 
n (%) 
 
 
 
 
 
 
Protocol deviation 
n (%) 
 
 
 
 
 
 
Progressive disease 
n (%) 
 
 
 
 
 
 
Non-medical reason 
n (%) 
 
 
 
 
 
 
Lost to follow-up 
n (%) 
 
 
 
 
 
 
Other, physician decision 
n (%) 
 
 
 
 
 
 
Patient’s refusal 
n (%) 
 
 
 
 
 
 
Death 
n (%) 
 
 
 
 
 
N: number of patients by arm 
n: number of patients related to the status 
% = (n/Nobs)*100 (Nobs: number of included patients by arm) 
 
 
 
 
 
STD table created 
using macro 
%_STATUS_ 
STD table created using 
macro %_STATUS_ 


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1.2. Protocol deviations 
For the following tables:  
­ (*) Before or at inclusion / After inclusion 
 
Protocol deviations – Randomised Set (N = xx) – (*): Number of protocol deviations and number of 
patients with at least one protocol deviation  
Follow-up of patients 
Protocol deviations 
Arm 1 
(N = xx) 
Arm2 
(N = xx) 
All 
(N = xx) 
 
NPD (1) n (2) % (3) NPD (1) n (2) % (3) NPD (1) n (2) % (3) 
ALL 
 
 
 
 
 
 
 
 
 
   Selection/inclusion criteria not fulfilled 
 
 
 
 
 
 
 
 
 
     xxxxxxxx 
 
 
 
 
 
 
 
 
 
     … 
 
 
 
 
 
 
 
 
 
   Patient 
having 
withdrawal 
criteria 
but 
not 
withdrawn 
 
 
 
 
 
 
 
 
 
     xxxxxxxx 
 
 
 
 
 
 
 
 
 
     … 
 
 
 
 
 
 
 
 
 
   Incorrect treatment or dose received 
 
 
 
 
 
 
 
 
 
     xxxxxxxx 
 
 
 
 
 
 
 
 
 
     … 
 
 
 
 
 
 
 
 
 
   Forbidden concomitant treatment 
 
 
 
 
 
 
 
 
 
     xxxxxxxx 
 
 
 
 
 
 
 
 
 
     … 
 
 
 
 
 
 
 
 
 
   Endpoint assessment possibly affected 
 
 
 
 
 
 
 
 
 
     xxxxxxxx 
 
 
 
 
 
 
 
 
 
     … 
 
 
 
 
 
 
 
 
 
   Safety possibly affected 
 
 
 
 
 
 
 
 
 
     xxxxxxxx 
 
 
 
 
 
 
 
 
 
     … 
 
 
 
 
 
 
 
 
 
(1) Number of protocol deviations (*) 
(2) Number of patients with at least one protocol deviation (*) 
(3) (n/N)*100 (N : number of patients by arm) 
 
 
 
 
STD table created using 
macro %_DEVIATION_ 


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1.3. Analysis sets and subgroups 
 
Analysis sets – All analysis sets – Value over time 
Distribution of patients by analysis set 
 
Arm 1 
Arm 2 
All 
Randomised Set (N=xx) 
n (%)  (1)  
 
 
Full Analysis Set (N=xx) 
n (%)  (1)  
 
 
Per Protocol Set (N=xx) 
n (%)  (1)  
 
 
Tumor Response pop (N=xx) 
n (%)  (1)  
 
 
Safety Set (N=xx) 
n (%)  (1)  
 
 
Quality of Life Set 29 
n (%)  (1)  
 
 
Quality of Life Set 30 
n (%)  (1)  
 
 
Archived Tumor Biopsies Full 
Analysis Set 
n (%)  (1)  
 
 
Archived Tumor Biopsies 
Tumor Response Set 
n (%)  (1)  
 
 
(1) n: Number of patients by arm in a given analysis set 
% : (n/N)*100 (N: Number of patients in a given analysis set) 
 
 
 
The reference and studied analysis sets are as follows: 
 
Reference set 
Studied set 
IS 
RS 
IS 
SS 
IS 
QLS29 
QLS30 
RS 
FAS 
FAS 
PPS 
PPS 
TR 
FAS 
TUMFAS 
RS 
TUMTR 
 
Analysis sets – All analysis sets – Value over time 
Comparison between analysis sets 
Arm 1 or Arm 2 or ALL 
 
         RS 
FAS 
PPS  
TR 
SS 
QLS 
IS 
% (1) 
 
 
 
 
 
 
RS 
 
 
 
 
 
 
 
FAS 
 
 
 
 
 
 
 
PPS 
 
 
 
 
 
 
 
(1) [Number of patients in the analysis set (notified in column)/Number of patients in the analysis set 
(notified in row)] x 100 
 
 
 
 
STD table created using macro 
%_TAB_ENS_PAT_ 
STD table created using 
macro %_TAB_ENS_PAT_ 


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Reasons for exclusion from the “Studied analysis set” – “Reference analysis set” – Value over time 
 
Arm 1 
(N = xx) 
Arm 2 
(N = xx) 
All 
(N = xx) 
Reasons for exclusion 
n 
(1) 
% 
(2) 
n 
(1) 
n 
(1) 
n 
(1) 
% 
(2) 
ALL 
 
 
 
 
 
 
DEVIATIONS 
 
 
 
 
 
 
    Exclusion class 1 
 
 
 
 
 
 
       Reason 1 
 
 
 
 
 
 
       … 
 
 
 
 
 
 
       Reason n 
 
 
 
 
 
 
    … 
 
 
 
 
 
 
OTHER 
 
 
 
 
 
 
    Exclusion class 1 
 
 
 
 
 
 
       Reason 1 
 
 
 
 
 
 
       … 
 
 
 
 
 
 
       Reason n 
 
 
 
 
 
 
    … 
 
 
 
 
 
 
(1) Number of patients with at least one reason for exclusion 
(2) (n/N)*100 (N: number of patients by arm) 
 
 
 
Analysis sets – Set 1 (N = xx) – Listing of patients by analysis set 
Arm 
Patient 
Set 1 
Set 2 
… 
Set n 
Arm 1   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Arm 2   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reasons for exclusion from the “Studied analysis set” – “Reference analysis set” – Listing of patients 
excluded 
Arm 
Patient 
Cycle 
Reasons for 
exclusion class 
Reasons for 
exclusion 
Comment 
Arm 1 
 
 
 
 
 
 
 
 
 
 
 
Arm 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
STD listing created using macro 
%_EDIT_ENS_PAT_ 
STD listing created using macro 
% EDIT REAS EXCL  
STD table created using macro 
% TAB REAS EXCL  


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1.4. Demographic data and other baseline characteristics 
1.4.1. Demographic data 
­ <Analysed> Set (RS, TUMFAS, TUMTR) 
 
Demographic data -  <Analysed> Set (N = xx)  
Descriptive statistics at baseline 
  
  
  
Arm 1 
(N = xx)   
Arm 2 
(N = xx)   
All 
(N = xx)    
Age (years)  
  
Nobs   
 
 
 
 
 
Mean ± SD   
 
 
 
 
 
Median   
 
 
 
 
 
Q1 ; Q3   
 
 
 
 
 
Min ; Max   
 
 
 
  
  
    
 
 
 
Age (years) in classes  Nobs 
 
 
 
 
 
≤ 65 years 
n (%) 
 
 
 
 
]65;75] 
n (%) 
 
 
 
 
> 75 years 
n (%) 
 
 
 
 
  
    
 
 
 
Gender  
Nobs  
 
 
 
 
 
Female  
n (%) 
 
 
 
 
Male 
n (%) 
 
 
 
 
  
    
 
 
 
Race  
Nobs  
 
 
 
 
 
Caucasian/White  
n (%) 
 
 
 
 
Black/African American 
n (%) 
 
 
 
 
Asian 
n (%) 
 
 
 
 
Other 
n (%) 
 
 
 
 
 
­ <Analysed> Set (IS, TUMFAS, TUMTR) 
 
Demographic data –<Analysed> Set (N = xx) – Value at the visit (EudraCT) 
Age (years) in EudraCT classes – Description – baseline  
  
  
Arm 1 
(N = xx)   
Arm 2 
(N = xx)    
All 
(N = xx)    
Nobs  
 
 
 
 
In utero 
n (%) 
 
 
 
Preterm newborn - gestational age < 37 wk 
n (%) 
 
 
 
Newborns (0-27 days) 
n (%) 
 
 
 
Infants and toddlers (28 days-23 months) 
n (%) 
 
 
 
Children (2-11 years) 
n (%) 
 
 
 
Adolescents (12-17 years) 
n (%) 
 
 
 
Adults (18-64 years)  
n (%) 
 
 
 
From 65 to 84 years 
n (%) 
 
 
 
85 years and over 
n (%) 
 
 
 
 
 
 


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1.4.2. Pregnancy test and contraception 
 
Pregnancy test and Contraception - Randomised Set (N = xx)  
Descriptive statistics at baseline 
  
  
  
Arm 1 
(N = xx)   
Arm 2  
N = xx)   
All 
(N = xx)   
PREGNANCY TEST 
Nobs 
 
 
 
 
 
YES 
n (%) 
 
 
 
 
NO 
n (%) 
 
 
 
 
NOT APPLICABLE 
n (%) 
 
 
 
 
 
 
 
 
 
IF YES:POSITIVE PREGNANCY 
TEST 
Nobs  
 
 
 
 
 
YES 
n (%) 
 
 
 
 
NO 
n (%) 
 
 
 
Nobs : Number of patients with available information by parameter  
 
 
 


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1.4.3. History of studied disease  
­ <Analysed> Set (RS, TUMFAS, TUMTR) 
 
History of the colorectal cancer - <Analysed> Set (N = xx)  
Descriptive statistics at baseline 
  
  
  
Arm 1 
(N = xx) 
Arm 2 
(N = xx) 
All 
(N = xx) 
PRIMARY DIAGNOSIS 
Nobs 
 
 
 
 
 
Level 1 
n (%) 
 
 
 
 
Level 2 
n (%) 
 
 
 
 
… 
n (%) 
 
 
 
 
Level k 
n (%) 
 
 
 
 
 
 
 
 
 
DISEASE DURATION (years) 
 
Nobs   
 
 
 
 
 
Mean ± SD   
 
 
 
 
 
Median   
 
 
 
 
 
Q1 ; Q3   
 
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
 
DISEASE DURATION (years)  
Nobs 
 
 
 
 
 
≤1 year 
n (%) 
 
 
 
 
]1; 2 years] 
n (%) 
 
 
 
 
]2; 4 years] 
n (%) 
 
 
 
 
>4 years 
n (%) 
 
 
 
 
 
 
 
 
 
PROGRESSION FREE INTERVAL 
(MONTHS) 
 
Nobs   
 
 
 
 
 
Mean ± SD   
 
 
 
 
 
Median   
 
 
 
 
 
Q1 ; Q3   
 
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
 
 
Nobs 
 
 
 
 
 
Level 1 
n (%) 
 
 
 
 
Level 2 
n (%) 
 
 
 
 
… 
n (%) 
 
 
 
 
Level k 
n (%) 
 
 
 
 
 
 
 
 
 
PRIMARY TUMOUR SITE 
Nobs 
 
 
 
 
 
Level 1 
n (%) 
 
 
 
 
Level 2 
n (%) 
 
 
 
 
… 
n (%) 
 
 
 
 
Level k 
n (%) 
 
 
 
 
 
 
 
 
 
HYSTOLOGY / CYTOLOGY 
Nobs 
 
 
 
 
 
Level 1 
n (%) 
 
 
 
 
Level 2 
n (%) 
 
 
 
 
… 
n (%) 
 
 
 
 
Level k 
n (%) 
 
 
 
Nobs : Number of patients with available information by parameter  
 
 


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History of the colorectal cancer - <Analysed> Set (N = xx)  
Descriptive statistics at baseline (Cont’d) 
STAGE AT DIAGNOSIS 
Nobs 
 
 
 
 
 
Level 1 
n (%)   
 
 
 
 
Level 2 
n (%)   
 
 
 
 
… 
n (%)   
 
 
 
 
Level k 
n (%)   
 
 
 
 
 
 
 
 
 
TUMOUR STATUS : IN RELPASE Nobs 
 
 
 
 
 
NO 
n (%)   
 
 
 
 
YES 
n (%)   
 
 
 
 
 
 
 
 
 
TUMOUR STATUS : 
METASTASIS 
Nobs 
 
 
 
 
 
NO 
n (%)   
 
 
 
 
YES 
n (%)   
 
 
 
 
 
 
 
 
 
CURRENT SMOKING 
Nobs 
 
 
 
 
 
NO 
n (%)   
 
 
 
 
YES 
n (%)   
 
 
 
Nobs : Number of patients with available information by parameter  
 
 
 
­ <Analysed> Set (RS, TUMFAS, TUMTR) 
 
History of of studied disease - <Analysed> Set (N = xx)  
Descriptive statistics of TNM at baseline 
 
 
 
 
Arm 1 
(N = xx) 
Arm 2 
(N = xx) 
All 
(N = xx) 
TNM: 
PRIMARY 
TUMOUR 
TNM: LYMPH 
NODES 
TNM: 
MESTASTASES 
Nobs  
 
 
 
LEVEL 1 
 
LEVEL 1 
 
LEVEL 1 
n (%)  
 
 
 
LEVEL 2 
 
LEVEL 2 
 
LEVEL 2 
n (%)  
 
 
 
….. 
 
….. 
 
….. 
n (%)  
 
 
 
LEVEL k 
 
LEVEL k 
 
LEVEL k 
n (%)  
 
 
 
 
 


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1.4.4. Signs and Symptoms 
Signs and symptoms related to colorectal cancer - Randomised Set (N = xx) 
Descriptive statistics by primary system organ class and preferred term at baseline 
PRIMARY SYSTEM ORGAN CLASS / 
PREFERRED TERM 
Arm 1  
(N = xx) 
Arm 2 
(N = xx) 
All 
(N = xx) 
 
n 
% 
n 
% 
n 
% 
ALL 
 
 
 
 
 
 
SOC-a 
 
 
 
 
 
 
    PT-aa 
 
 
 
 
 
 
    PT-ab 
 
 
 
 
 
 
... 
 
 
 
 
 
 
SOC-b 
 
 
 
 
 
 
    PT-ba 
 
 
 
 
 
 
    PT-bb 
 
 
 
 
 
 
... 
 
 
 
 
 
 
n: Number of patients with at least one signs or symptoms in a given  
preferred term or in a given primary system organ class 
%: (n/N)*100 (N: Number of patients by arm) 
 
Note: Within the table, a descending sorting will be carried out taking into account the number of patients with at least one signs 
or symptoms of the considered primary system organ class, preferred term 
 
 


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1.4.5. Medical history and surgical or medical procedures other than colorectal cancer 
(*)- Randomised Set (N = xx)  
Descriptive statistics by primary system organ class and preferred term at baseline 
PRIMARY SYSTEM ORGAN CLASS / 
PREFERRED TERM 
Arm 1 
(N = xx) 
Arm 2 
(N = xx) 
All 
(N = xx) 
 
n 
% 
n 
% 
n 
% 
ALL 
 
 
 
 
 
 
SOC-a 
 
 
 
 
 
 
    PT-aa 
 
 
 
 
 
 
    PT-ab 
 
 
 
 
 
 
... 
 
 
 
 
 
 
SOC-b 
 
 
 
 
 
 
    PT-ba 
 
 
 
 
 
 
    PT-bb 
 
 
 
 
 
 
... 
 
 
 
 
 
 
n: Number of patients with at least one (*) in a given preferred  
term or in a given primary system organ class 
%: (n/N)*100 (N: Number of patients by arm) 
 
Note: (*) Medical history other than colorectal cancer / Surgical or medical procedures history other than for colorectal cancer. 
Within the table, a descending sorting will be carried out taking into account the number of patients with at least one (*) of the 
considered primary system organ class, preferred term 
 
 
Macro %_HISTORY_04 


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1.4.6. Clinical laboratory evaluation 
For the following table: 
 
­ Gradable parameters 
Albumin (G/L), Sodium (mmol/L), Potassium (mmol/L), Calcium (mmol/L), Magnesium 
(mmol/L), phosphate (mmol/L), serum creatinine (μmol/L), glucose (mmol/L), ASAT 
(IU/L), ALAT (IU/L), GGT (IU/L), Alkaline phosphatase (IU/L), total bilirubin (μmol/L), 
haemoglobin (G/L), White Blood Cell (WBC) count (G/L), neutrophils (G/L), 
lymphocytes (G/L) and platelets (G/L), APTT and INR. 
 
 (*) Biochemical parameters / Haematological parameters / Coagulation. 
 (**) Low Albumin, high Alkaline Phosphatase, high Total Bilirubin, hypercalcemia, 
hypocalcemia, high GGT, hyperglycemia, hypoglycaemia, hyperkalemia, hypokalemia. 
 hypermagnesemia, hypomagnesemia, hypophosphatemia, hyponatremia, hypernatremia, 
high AST, high ALT, high haemoglobin, anemia, leucocytosis, low WBC, low platelets, 
high lymphocyte, low lymphocyte, low Neutrophils, high creatinine, aPTT 
prolonged/high aPTT and high INR. 
 
(*): (**) – Randomised Set (N = xx) – Value at baseline 
 
Arm 1  
(N = xx) 
Arm 2  
(N = xx) 
All 
(N = xx) 
BASELINE 
 
Nobs 
 
 
 
 
 
Mean ± SD 
 
 
 
 
 
Median 
 
 
 
 
 
Q1 ; Q3 
 
 
 
 
 
Min ; Max 
 
 
 
 
Grade 0 
n (%) 
 
 
 
 
Grade 1 
n (%) 
 
 
 
 
Grade 2 
n (%) 
 
 
 
 
Grade 3 
n (%) 
 
 
 
 
Grade 4 
n (%) 
 
 
 
 
For the following table: 
 
­ Non-gradable parameters: 
 (*) Biochemical parameters / Haematological parameters. 
 (**) Chloride (mmol/L), bicarbonate (mmol/L), blood urea nitrogen (BUN) (mmol/L), 
proteins (G/L), lactate dehydrogenase (IU/L), haematocrit (no unit), Erythrocytes (T/L), 
monocytes (G/L), eosinophils (G/L) and basophils (G/L). 
 
STD table created using macro  
%_LB_TAB1 


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(*): (**) – Randomised Set (N = xx) – Value at baseline 
 
Arm 1  
(N = xx) 
Arm 2  
(N = xx) 
All 
(N = xx) 
BASELINE 
 
Nobs 
 
 
 
 
 
Mean ± SD 
 
 
 
 
 
Median 
 
 
 
 
 
Q1 ; Q3 
 
 
 
 
 
Min ; Max 
 
 
 
 
<LL 
n (%) 
 
 
 
 
[LL-UL[ 
n (%) 
 
 
 
 
>UL 
n (%) 
 
 
 
 
 
Biochemical parameter: Creatinine clearance – Randomised Set (N = xx) – Value at baseline 
 
Arm 1  
(N = xx) 
Arm 2  
(N = xx) 
All 
(N = xx) 
BASELINE 
 
Nobs 
 
 
 
 
 
Mean ± SD 
 
 
 
 
 
Median 
 
 
 
 
 
Q1 ; Q3 
 
 
 
 
 
Min ; Max 
 
 
 
 
normal 
n (%) 
 
 
 
 
mild 
n (%) 
 
 
 
 
moderate 
n (%) 
 
 
 
 
severe 
n (%) 
 
 
 
 
 
 
For the following table: 
­ Urinalysis parameters 
 
 (**) Proteinuria, Glucosuria, Urobilinogen, Haematuria, Leucocyturia 
 
Urinalysis: (**) – Randomised Set (N = xx) – Value at baseline 
 
Arm 1  
(N = xx) 
Arm 2  
(N = xx) 
All 
(N = xx) 
BASELINE 
Nobs 
 
 
 
 
 
Negative 
n (%)   
 
 
 
 
Trace 
n (%)   
 
 
 
 
Positive 
n (%)   
 
 
 
 
                + 
n (%)   
 
 
 
 
                ++ 
n (%)   
 
 
 
 
                +++ n (%)   
 
 
 
 
 
 
 
 
STD table created using macro  
%_LB_TAB1 
STD table created using macro  
%_LB_TAB1 
STD table created using macro  
%_LB_TAB1 


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­ Neutrophil-Lymphocyte ratio 
 
Neutrophil-Lymphocyte ratio – Randomised Set (N = xx) – Value at baseline 
 
Arm 1  
(N = xx) 
Arm 2  
(N = xx) 
All 
(N = xx) 
BASELINE 
 
Nobs 
 
 
 
 
 
Mean ± SD 
 
 
 
 
 
Median 
 
 
 
 
 
Q1 ; Q3 
 
 
 
 
 
Min ; Max 
 
 
 
 
NLR < 3 
n (%) 
 
 
 
 
NLR ≥ 3 
n (%) 
 
 
 
 
NLR < 5 
n (%) 
 
 
 
 
NLR ≥ 5 
 
 
 
 
 
 
For the following table: 
­ Tumor markers 
 
 (**) CEA 
 
Tumor markers: (**) – Randomised Set (N = xx) – Value at baseline 
 
Arm 1  
(N = xx) 
Arm 2  
(N = xx) 
All 
(N = xx) 
BASELINE 
Nobs 
 
 
 
 
 
 
Mean ± SD 
 
 
 
 
 
Median 
 
 
 
 
 
Q1 ; Q3 
 
 
 
 
 
Min ; Max 
 
 
 
 
 
 
 
 
 
 
Abnormal 
n (%) 
 
 
 
 
Normal 
n (%) 
 
 
 
 
STD table created using macro  
%_LB_TAB1 


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1.4.7. Previous therapies for colorectal cancer  
­ <Analysed> Set (RS, TUMFAS, TUMTR) 
 
Previous therapies for colorectal cancer - <Analysed> Set (N = xx) 
Descriptive statistics at baseline 
 
Arm 1 
(N = xx) 
Arm 2 
(N = xx) 
All 
(N = xx) 
PREVIOUS SURGERY 
Nobs  
 
 
YES 
n (%)  
 
 
NO 
n (%)  
 
 
 
  
 
 
PREVIOUS RADIOTHERAPY 
Nobs  
 
 
YES 
n (%)  
 
 
NO 
n (%)  
 
 
 
  
 
 
PREVIOUS DRUG TREATMENT 
Nobs  
 
 
YES 
n (%)  
 
 
NO 
n (%)  
 
 
   IF YES 
  
 
 
   PREVIOUS NEO-ADJUVANT 
Nobs  
 
 
     YES 
n (%)  
 
 
     NO 
n (%)  
 
 
   PREVIOUS ADJUVANT 
Nobs  
 
 
     YES 
n (%)  
 
 
     NO 
n (%)  
 
 
   PREVIOUS NEO-ADJUVANT/ADJUVANT 
Nobs  
 
 
     YES 
n (%)  
 
 
     NO 
n (%)  
 
 
n: Number of patients with at least one previous therapy 
 
 
 
Combination of previous therapies for colorectal cancer - Randomised Set (N = xx) 
Descriptive statistics at baseline 
PREVIOUS THERAPIES 
Arm 1 
(N = xx) 
Arm 2 
(N = xx) 
ALL 
(N = xx) 
 
n 
% 
n 
% 
n 
% 
No previous therapy  
 
 
 
 
 
 
Surgery only 
 
 
 
 
 
 
Radiotherapy only 
 
 
 
 
 
 
Drug treatment only 
 
 
 
 
 
 
Surgery + radiotherapy 
 
 
 
 
 
 
Surgery +  drug treatment 
 
 
 
 
 
 
Radiotherapy + drug treatment 
 
 
 
 
 
 
Surgery + radiotherapy + drug treatment 
 
 
 
 
 
 
Any previous therapy  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Previous surgery for colorectal cancer - Randomised Set (N = xx)  
Descriptive statistics by surgical procedure preferred term at baseline 
PREFERRED TERM 
Arm 1  
(N = xx) 
Arm 2  
(N = xx) 
ALL 
(N = xx) 
 
n 
% 
n 
% 
n 
% 
ALL 
 
 
 
 
 
 
PT-aa 
 
 
 
 
 
 
PT-ab 
 
 
 
 
 
 
... 
 
 
 
 
 
 
n: Number of patients with at least one previous surgery in a given  
preferred term  
%: (n/N)*100 (N: Number of patients by arm)    
 
 
Note: Within the table, a descending sorting will be carried out taking into account the number  of patients with at least one 
previous surgery of the considered preferred term 
 
 
 
Previous drug treatment) for colorectal cancer 
 - Randomised Set (N = xx)  
Descriptive statistics by pharmacological class at baseline 
PHARMACOLOGICAL CLASS 
Arm 1  
(N = xx) 
Arm 2  
(N = xx) 
ALL 
(N = xx) 
 
n 
% 
n 
% 
n 
% 
ALL 
 
 
 
 
 
 
ATC-a level2 
 
 
 
 
 
 
ATC-b level2 
 
 
 
 
 
 
... 
 
 
 
 
 
 
n: Number of patients with at least one previous drug treatment in a given pharmacological class  
%: (n/N)*100 (N: Number of patients by arm) 
 
 
Note: Within the table, a descending sorting will be carried out taking into account the number of patients with at least one previous 
drug treatment of the considered pharmacological class 
 
 
1.4.8. Initial tumor assessment (Metastatic colorectal cancer) 
 
Initial tumour assessment - Randomised Set (N = xx)  
Descriptive statistics at baseline 
 
Arm 1  
(N = xx) 
Arm 2  
(N = xx) 
All 
(N = xx) 
Measurable disease 
Nobs  
 
 
YES 
n (%)  
 
 
NO 
n (%)  
 
 
 
  
 
 
Non measurable disease 
Nobs  
 
 
YES 
n (%)  
 
 
NO 
n (%)  
 
 
 
 
 
Macro %_TRT_04 
Macro %_TRT_04 


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1.4.9. Vital signs and clinical examination 
Vital signs – Randomised Set (N = xx)  
Descriptive statistics at baseline 
 
Arm 1  
(N = xx) 
Arm 2  
(N = xx) 
All 
(N = xx) 
ECOG PERFORMANCE 
STATUS 
Nobs  
 
 
 
0  
n (%)  
 
 
 
1  
n (%)  
 
 
 
2  
n (%)  
 
 
 
3  
n (%)  
 
 
 
4  
n (%)  
 
 
 
  
 
 
WEIGHT (kg) 
Nobs  
 
 
 
Mean ± SD   
 
 
 
Median  
 
 
 
Q1 ; Q3   
 
 
 
Min ; Max   
 
 
 
  
 
 
TEMPERATURE (°C) 
Nobs  
 
 
 
Mean ± SD   
 
 
 
Median  
 
 
 
Q1 ; Q3   
 
 
 
Min ; Max   
 
 
 
  
 
 
Respiratory rate (breaths/min) 
Nobs  
 
 
 
Mean ± SD   
 
 
 
Median  
 
 
 
Q1 ; Q3   
 
 
 
Min ; Max   
 
 
 
  
 
 
BSA (m²) 
Nobs  
 
 
 
Mean ± SD   
 
 
 
Median  
 
 
 
Q1 ; Q3   
 
 
 
Min ; Max   
 
 
 
  
 
 
Supine Heart rate (bpm) 
Nobs  
 
 
 
Mean ± SD   
 
 
 
Median  
 
 
 
Q1 ; Q3   
 
 
 
Min ; Max   
 
 
 
  
 
 
 
< 60  
n (%)  
 
 
 
[60, 100[ 
n (%)  
 
 
 
>= 100 
  
 
 
 
  
 
 
Supine SBP (mmHg)  
Nobs  
 
 
 
Mean ± SD   
 
 
 
Median  
 
 
 
Q1 ; Q3   
 
 
 
Min ; Max   
 
 
 
  
 
 
 
< 90 
n (%)  
 
 
 
[90, 140[ 
n (%)  
 
 
 
>= 140 
  
 
 
 
  
 
 
 
 


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Vital signs – Randomised Set (N = xx)  
Descriptive statistics at baseline (Cont’d) 
Supine DBP (mmHg)  
Nobs  
 
 
 
Mean ± SD   
 
 
 
Median  
 
 
 
Q1 ; Q3   
 
 
 
Min ; Max   
 
 
 
  
 
 
 
< 60 
n (%)  
 
 
 
[60, 90[ 
n (%)  
 
 
 
>= 90 
  
 
 
 
1.4.10. Electrocardiogram 
ECG – Randomised Set (N = xx)  
Descriptive statistics at baseline 
 
Arm 1 
(N = xx) 
Arm 2 
(N = xx) 
All 
(N = xx) 
PRESENCE OF CLINICALLY 
SIGNIFICANT ECG ABNORMALITIES 
n (%)  
 
 
 
  
 
 
RR interval (msec) 
Nobs     
 
 
 
Mean ± 
SD    
 
 
 
Median    
 
 
 
Q1 ; Q3    
 
 
 
Min ; Max    
 
 
  
     
 
 
 
≤ 450 ms  
n (%)     
 
 
 
]450;480 ms] 
n (%)     
 
 
 
] 480;500 ms] 
n (%)     
 
 
 
> 500 ms 
n (%)     
 
 
 
  
 
 
QT INTERVAL UNCORRECTED (ms) 
Nobs  
 
 
 
Mean ± SD   
 
 
 
Median  
 
 
 
Q1 ; Q3   
 
 
 
Min ; Max   
 
 
 
  
 
 
 
≤ 450 ms  
n (%)  
 
 
 
]450;480 ms] 
n (%)  
 
 
 
] 480;500 ms] 
n (%)  
 
 
 
> 500 ms 
n (%)  
 
 
 
 
 
ECG - Randomised Set (N = xx)  
List of clinically significant ECG abnormalities at baseline 
Arm 
Patient 
Cycle 
Analysis date 
Analysis value 
Clinically significant 
ECG abnormalies? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.4.11. Mutation 
Mutation - Randomised Set (N = xx)  
Descriptive statistics at baseline 
 
Arm 1  
(N = xx) 
Arm 2  
(N = xx) 
All 
(N = xx) 
Biopsy performed 
Nobs  
 
 
YES 
n (%)  
 
 
NO 
n (%)  
 
 
 
  
 
 
Site of biopsy 
Nobs  
 
 
 Primary tumour 
  
 
 
 Metastasis 
  
 
 
   Lung metastasis 
n (%)  
 
 
   Liver metastasis 
n (%)  
 
 
   Bone metastasis 
n (%)  
 
 
   Brain metastasis 
n (%)  
 
 
   Skin metastasis 
n (%)  
 
 
   Othser soft tissue 
n (%)  
 
 
   Other metastasis 
n (%)  
 
 
 
  
 
 
Method of biopsy 
  
 
 
 Sequencing/NGS 
  
 
 
 PCR 
  
 
 
 Unknown 
  
 
 
 Other 
  
 
 
 
  
 
 
BRAF STATUS 
Nobs  
 
 
WILD TYPE 
n (%)  
 
 
MUTANT TYPE 
n (%)  
 
 
NOT DONE 
n (%)  
 
 
 
  
 
 
BRAF MUTATION TYPE 
Nobs  
 
 
VAL600GLU 
n (%)  
 
 
UNKNOWN 
n (%)  
 
 
OTHER 
n (%)  
 
 
 
  
 
 
NRAS STATUS 
Nobs  
 
 
WILD TYPE 
n (%)  
 
 
MUTANT TYPE 
n (%)  
 
 
 
  
 
 
NRAS MUTATION TYPE 
Nobs  
 
 
MUTATION TYPE CODON 12 
Nobs  
 
 
YES 
n (%)  
 
 
NO 
n (%)  
 
 
MUTATION TYPE CODON 13X 
Nobs  
 
 
YES 
n (%)  
 
 
NO 
n (%)  
 
 
MUTATION TYPE CODON 61 
Nobs  
 
 
YES 
n (%)  
 
 
NO 
n (%)  
 
 
MUTATION TYPE CODON 146 
Nobs  
 
 
YES 
n (%)  
 
 
NO 
n (%)  
 
 
OTHER 
Nobs  
 
 
YES 
n (%)  
 
 
NO 
n (%)  
 
 
 
 


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Mutation - Randomised Set (N = xx)  
Descriptive statistics at baseline (Cont’d) 
 
  
 
 
KRAS STATUS 
Nobs  
 
 
WILD TYPE 
n (%)  
 
 
MUTANT TYPE 
n (%)  
 
 
 
  
 
 
KRAS MUTATION TYPE 
  
 
 
MUTATION TYPE CODON 12 
Nobs  
 
 
YES 
n (%)  
 
 
NO 
n (%)  
 
 
MUTATION TYPE CODON 13 
Nobs  
 
 
YES 
n (%)  
 
 
NO 
n (%)  
 
 
MUTATION TYPE CODON 61 
Nobs  
 
 
YES 
n (%)  
 
 
NO 
n (%)  
 
 
MUTATION TYPE CODON 117 
Nobs  
 
 
YES 
n (%)  
 
 
NO 
n (%)  
 
 
MUTATION TYPE CODON 146 
Nobs  
 
 
YES 
n (%)  
 
 
NO 
n (%)  
 
 
OTHER 
Nobs  
 
 
YES 
n (%)  
 
 
NO 
n (%)  
 
 
 
1.5. Extent of exposure and treatment compliance 
Extent of exposure and treatment compliance – Safety Set (N = xx) – During the treatment period 
Description – Value by patient 
  
  
  
Arm 1  
(N = xx) 
Arm 2 
(N = xx) 
Number of cycles  
  
Nobs   
 
 
 
 
Mean ± SD    
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max    
 
Number of cycles in classes  
Nobs 
 
 
 
 
1 cycle 
n (%)   
 
 
 
2 cycles 
n (%)   
 
 
 
…. 
n (%)   
 
 
 
> 6 cycles 
n (%)   
 
 
Treatment duration (weeks)  
  
Nobs   
 
 
 
 
Mean ± SD    
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max    
 
Treatment duration (weeks) 
 in classes   
Nobs 
 
 
 
 
≤ 8 weeks 
n (%)   
 
 
 
]8; 24] 
n (%)   
 
 
 
]24; 36] 
n (%)   
 
 
 
]36; 48] 
n (%)   
 
 
 
> 48 
n (%)   
 
 
N: Number of patients by arm 


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For the following table: 
(*) IMP / Associated Agent 
(**) Patient / Cycle 
 
Extent of exposure and treatment compliance (*) – Safety Set (N = xx) – During the treatment period 
Description by (**) 
 
 
 
Arm 1  
(N = xx) 
Arm 2 
(N = xx) 
Cumulative dose (1) 
 
Nobs   
 
 
 
 
Mean ± SD    
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max    
 
Dose Intensity  (2) 
 
Nobs   
 
 
 
 
Mean ± SD    
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max    
 
Relative Dose Intensity 
(%) 
 
Nobs   
 
 
 
 
Mean ± SD    
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max    
 
Relative Dose Intensity 
(%) in classes 
Nobs 
 
 
 
 
≤ 60 
n (%)   
 
 
 
]60;80] 
n (%)   
 
 
 
]80;100] 
n (%)   
 
 
 
]100; 110] n (%)   
 
 
 
>110   
n (%)   
 
 
 
(1) 
(mg/m2) for IMP, (mg/kg) for Associated Agent 
(2) 
(mg/m2/wk) for IMP, (mg/kg/wk) for Associated Agent 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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For the following table: 
(*) Patient / Cycle 
 
Extent of exposure and treatment compliance in Capecitabine + Bevacizumab arm by theoretical starting 
dose – Safety Set (N=xx) – During the treatment period 
Description by Cycle – Value by (*) 
 
 
 
Capecitabine 
1000 mg  
(N = xx) 
Capecitabine 
1250 mg 
(N = xx) 
Cumulative dose 
(mg/m2) 
 
Nobs   
 
 
 
 
Mean ± SD    
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max    
 
Dose Intensity 
(mg/m2/wk) 
 
Nobs   
 
 
 
 
Mean ± SD    
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max    
 
Relative Dose Intensity 
(%) 
 
Nobs   
 
 
 
 
Mean ± SD    
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max    
 
Relative Dose Intensity 
(%)  
in classes 
Nobs 
 
 
 
 
≤ 60 
n (%)   
 
 
 
]60;80] 
n (%)   
 
 
 
]80;100] 
n (%)   
 
 
 
]100; 110] n (%)   
 
 
 
>110   
n (%)   
 
 
 
 
 
Extent of exposure and treatment compliance – Safety Set (N = xx) – During the treatment period 
Description – Value by patient 
 
  
  
  
Arm 1 
(N = xx) 
Arm 2  
(N = xx) 
Cycles  
Nobs 
 
 
 
 
Cycle 1 
n (%)   
 
 
 
Cycle 1 
n (%)   
 
 
 
…. 
n (%)   
 
 
 
Cycle k 
n (%)   
 
 
n: Number of patients per cycle  
%: (n/N)*100 (N: Number of patients by arm)  
 
 
 
 
 
 
 


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Extent of exposure and treatment compliance – Safety Set (N = xx) – During the treatment period 
Description – Dose administration, Cycle delayed, cycle reduced and missed intake of IMP  
  
  
  
Arm 1 
(N = xx) 
Arm 2  
(N = xx) 
Number of patients with at least one 
cycle delayed 
Nobs 
 
 
 
 
Yes 
n (%)   
 
 
 
No 
n (%)   
 
 
  
  
    
 
 
Number of cycles delayed 
  
Nobs   
 
 
 
 
Mean ± SD    
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max    
 
Dispensiation postponed reason 
 
Nobs   
 
 
     Medical reason 
 
n (%)   
 
 
     Non-medical reason 
 
n (%)   
 
 
Number of patients with at least one 
cycle reduced 
Nobs 
 
 
 
 
Yes 
n (%)   
 
 
 
No 
n (%)   
 
 
Number of cycles reduced 
  
Nobs   
 
 
 
 
Mean ± SD    
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max    
 
Number of patients with at least one 
missed intake 
  
Nobs   
 
 
 
 
Mean ± SD    
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max    
 
Number of cycles with at least one 
missed intake 
  
Nobs   
 
 
 
 
Mean ± SD    
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max    
 
Number of missed intake 
  
Nobs   
 
 
 
 
Mean ± SD    
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max    
 
 
 
 
 
 
 
 
 


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Extent of exposure and treatment compliance – Safety Set (N = xx) – During the treatment period 
Description – Dose administration, Cycle delayed, cycle reduced and missed intake of associated agent  
  
  
  
Arm 1 
(N = xx) 
Arm 2  
(N = xx) 
Number of patients with full dose 
administered 
Nobs 
 
 
 
 
Yes 
n (%)   
 
 
 
No 
n (%)   
 
 
 
 
 
 
 
Number of cycles reduced 
  
Nobs   
 
 
 
 
Mean ± SD    
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max    
 
Number of patients with at least one 
missed infusion 
  
Nobs   
 
 
 
 
Mean ± SD    
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max    
 
Number of cycles with at least one 
missed intake 
  
Nobs   
 
 
 
 
Mean ± SD    
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max    
 
Number of missed intake 
  
Nobs   
 
 
 
 
Mean ± SD    
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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For the following listings: 
 (*) IMP, Associated agent 
 
 
Extent of exposure and treatment compliance – Safety Set (N = xx) – During the treatment period 
Listing of extent of exposure of (*) by patient 
 
 
 
(1) 
(mg/m2) for IMP, (mg/kg) for Associated Agent 
(2) 
(mg/m2/wk) for IMP, (mg/kg/wk) for Associated Agent 
 
 
 
 
 
Arm 
Theoretical 
starting dose 
of IMP 
(mg/m2) 
Patie
nt 
Number 
of cycle  
Treatment 
duration 
(weeks) 
Treatment 
duration 
in classes 
BSA at 
Baseline 
(m2) 
Cumu
lative 
dose 
(1) 
Planned 
Dose 
Intensity 
(2) 
Dose 
intensity 
(2) 
Relative 
Dose 
Intensity 
(%) 
Number 
of cycle 
delay 
Number 
of cycle 
reduced 
Arm 1 
 
 
 
 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
Arm 2 
 
 
 
 
 
 
 
 
 
 
 
 


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Extent of exposure and treatment compliance – Safety Set (N = xx) – During the treatment period 
Listing of extent of exposure of (*) by patient by cycle 
 
Arm 
Theoretical 
starting 
dose of 
IMP 
(mg/m2) 
Patient 
Number 
of cycle  
Cycle 
BSA 
(m2) 
Theoretic
al intake 
number 
(mg/day) 
Real 
intake 
number 
(mg/day) 
Cumulat
ive dose 
(1) 
Planned 
Dose 
Intensity 
(2) 
Dose 
intensity 
(2) 
Relative 
Dose 
Intensity 
(%) 
Cycle 
delay 
Cycle 
reduced 
Arm 1  
 
 
Cycle 1  
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle X  
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
Arm 2  
 
 
 
 
 
 
 
 
 
 
 
 
(1) 
(mg/m2) for IMP, (mg/kg) for Associated Agent 
(2) 
(mg/m2/wk) for IMP, (mg/kg/wk) for Associated Agent 
 
 


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Extent of exposure and treatment compliance – Safety Set (N = xx) – During the treatment period 
Listing of tablet distribution by patient – S95005 + Bevacizumab arm 
Arm 
Patient 
Number 
of cycle  
Number 
of 15 mg 
tablet 
given 
Number 
of 15 mg 
tablet 
return 
Number of 
15 mg 
tablet 
return 
(estimated) 
Number 
of 20 mg 
tablet 
given 
Number 
of 20 mg 
tablet 
return 
Number of 
20 mg 
tablet 
return 
(estimated) 
Arm 1 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
Arm 2 
 
 
 
 
 
 
 
 
 
 
Extent of exposure and treatment compliance – Safety Set (N = xx) – During the treatment period 
Listing of tablet distribution by patient by cycle – S95005 + Bevacizumab arm 
Arm 
Patient 
Number 
of cycle  
Cycle 
Number 
of 15 mg 
tablet 
given 
Number 
of 15 mg 
tablet 
return 
Number of 
15 mg 
tablet 
return 
(estimated) 
Number 
of 20 mg 
tablet 
given 
Number 
of 20 mg 
tablet 
return 
Number of 
20 mg 
tablet 
return 
(estimated) 
Arm 1 
 
 
Cycle 1 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
Cycle X 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
Arm 2 
 
 
 
 
 
 
 
 
 
 
Extent of exposure and treatment compliance – Safety Set (N = xx) – During the treatment period 
Listing of tablet distribution by patient – Capecitabine + Bevacizumab arm 
Arm 
Patient 
Number 
of cycle  
Number 
of 150 mg 
tablet 
given 
Number 
of 150 mg 
tablet 
return 
Number of 
150 mg 
tablet 
return 
(estimated) 
Number of 
500 mg 
tablet 
given 
Number of 
500 mg 
tablet 
return 
Number of 
500 mg 
tablet 
return 
(estimated) 
Arm 1 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
Arm 2 
 
 
 
 
 
 
 
 
 


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Extent of exposure and treatment compliance – Safety Set (N = xx) – During the treatment period 
Listing of tablet distribution by patient by cycle – Capecitabine + Bevacizumab arm 
Arm 
Patient 
Number 
of cycle  
Cycle 
Number 
of 150mg 
tablet 
given 
Number 
of 150mg 
tablet 
return 
Number of 
150mg 
tablet 
return 
(estimated) 
Number 
of 500mg 
tablet 
given 
Number 
of 500mg 
tablet 
return 
Number of 
500mg 
tablet 
return 
(estimated) 
Arm 1 
 
 
Cycle 1 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
Cycle X 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
Arm 2 
 
 
 
 
 
 
 
 
 
 
1.6. Concomitant treatments 
 
For the following 2 tables: 
­ (*) Concomitant treatments 
­ (**) at inclusion / before treatment period / during treatment period (***) concomitant 
treatment 
 
(*) - Safety Set (N = xx) – Description (**) 
Number of patients having taken at least one (***) by pharmacological class - Description of concomitant 
treatments 
PHARMACOLOGICAL CLASS 
Arm 1 
(N = xx) 
Arm 2          
(N = xx) 
ALL           
(N = xx) 
 
n (1) 
% (2) 
n (1) 
% (2) 
n (1) 
% (2) 
ALL 
 
 
 
 
 
 
ATC-a level 2 
 
 
 
 
 
 
ATC-b level 2 
 
 
 
 
 
 
… 
 
 
 
 
 
 
(1) Number of patients with at least one () (**) in a given pharmacological class  
(2) (n/N)*100 (N: number of patients by arm 
 
 
Note: Within the table, a descending sorting will be carried out taking into account the number of patients with at least one 
concomitant treatment of the considered pharmacological class 
 
 
 
STD table created using 
macro %_TRT_ 


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(*) - Safety Set (N = xx) – Description (**) 
Number of patients having taken at least one (***) by pharmacological class, pharmacological sub-class, 
therapeutic class and preferred name - Description of concomitant treatments 
PHARMACOLOGICAL CLASS/ 
PHARMACOLOGICAL SUB-CLASS/ 
THERAPEUTIC CLASS/ PREFERRED NAME 
 
Arm 1          
(N = xx) 
 
Arm 2          
(N = xx) 
ALL           
(N = xx) 
 
n (1) 
% (2) 
n (1) 
% (2) 
n (1) 
% (2) 
ALL 
 
 
 
 
 
 
ATC-a level 2 
 
 
 
 
 
 
 
+ ATC-a level 3 
 
 
 
 
 
 
 
 
-ATC-a level 4 
 
 
 
 
 
 
 
 
 
PN-aaaa 
 
 
 
 
 
 
 
 
 
PN-aaab 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
- ATC-b level 4 
 
 
 
 
 
 
 
 
 
PN-aaba 
 
 
 
 
 
 
 
 
 
PN-aabb 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
+ ATC-b level 3 
 
 
 
 
 
 
 
 … 
 
 
 
 
 
 
ATC-b level 2 
 
 
 
 
 
 
… 
 
 
 
 
 
 
(1) Number of patients with at least one (***) (**) in a given level  
(2) (n/N)*100 (N: number of patients by arm) 
 
Note: Within the table, a descending sorting will be carried out taking into account the number of patients with at least one concomitant 
treatment of the considered pharmacological class, pharmacological sub-class, therapeutic class and preferred name 
 
 
 
STD table created using 
macro %_TRT_ 


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2. EFFICACY ANALYSIS  
 
For the following table: 
­ <Analysed> Set (FAS, PPS, TR, TUMFAS, TUMTR) 
 
 
Arm 1 
(N = xx) 
Arm 2 
(N = xx) 
Descriptive Statistics 
Best overall response 
Nobs 
xx 
xx 
 
Complete response (CR)  
n (%) 
 
 
 
Partial response (PR) 
n (%) 
 
 
 
Stable disease (SD)  
n (%) 
 
 
 
Non complete response / non 
progressive disease (NON CR/NON PD) (1) 
n (%) 
 
 
 
Progressive disease (PD) 
n (%) 
 
 
 
Non evaluable (NE)  
n (%) 
 
 
Statistical analysis 
Objective response rate (2) 
n (%)   
 
 
95% (4)   
 
 
P-value (5) 
 
Disease control rate (3) 
n (%)   
 
 
95% (4) 
 
 
 
P-value (5) 
 
 (1) For patients with non-measurable disease 
 (2) Objective Response Rate (Best overall response = CR or PR) 
 
 (3) Disease control rate (Best overall response = CR or PR or SD) 
 (4) 95% Confidence interval of the estimate using Clopper Pearson method 
 (5) P-value given by Fisher's exact test 
 
 
 
For the following table and graph, parameter and the corresponding population are as follows: 
 
< Parameter>   PFS 
PFS 
PFS 
OS 
OS 
DR among 
responders 
PFSs1 
PFSs1 
PFSs2 
<Analysed> 
Set 
FAS 
PPS 
TUMFAS 
FAS 
TUMFAS 
TR 
FAS 
PPS 
FAS 
 
 
Antitumoral activity - <Analysed> Set (N = xx)  
Hazard ratio estimate for < Parameter> 
 
Arm 1 
(N = xx) 
Arm 2 
(N= xx) 
Hazard ratio* (relative to Arm 2) 
 
95% confidence interval 
 
80% confidence interval 
 
P-value 
 
* Cox proportional hazard model adjusting for the stratification factors 
 
 
 
 
 
 
 


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Antitumoral activity - <Analysed> Set (N = xx)  
Kaplan-Meier curves of < Parameter>   
 
 
For the following table, parameter and the corresponding population are as follows: 
 
< Parameter>   
PFS 
PFS 
PFS 
DR among 
responders 
<Analysed> Set 
FAS 
PPS 
TUMFAS 
TR 
 
 


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Antitumoral activity - <Analysed> Set (N = xx)  
Product-limit of Kaplan-Meier estimates for < Parameter>   
 
Arm 1 
(N = xx) 
Arm 2 
(N= xx) 
< Parameter>   
    Number of censors 
Nobs 
 
 
       Lost to follow-up without new treatment nor PD 
n (%) 
 
 
       Start of new anti-cancer therapy 
n (%) 
 
 
       Alive without new treatment nor PD 
n (%) 
 
 
    Number of events  
Nobs 
 
 
       Progression Disease (PD) 
n (%) 
 
 
       Death 
n (%) 
 
 
Median (months) 
 
 
95% confidence intervala 
 
 
80% confidence intervala 
 
 
 Min ; Max 
 
 
 
 
 
Survival probability at 6 months 
 
 
95% confidence intervalb 
 
 
80% confidence intervalb 
 
 
 
 
 
Survival probability at 12 months 
 
 
95% confidence intervalb 
 
 
80% confidence intervalb 
 
 
 
 
 
Survival probability at 18 months 
 
 
95% confidence intervalb 
 
 
80% confidence intervalb 
 
 
 
 
 
Survival probability at 24 months 
 
 
95% confidence intervalb 
 
 
80% confidence intervalb 
 
 
 
     a Methodology of Brookmeyer and Crowley 
 
     b Using log-log transformation methodology of Kalbfleisch and Prentice 
 
 


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­ For the following table: 
­ <Analysed> Set (FAS, PPS) 
 
Antitumoral activity - <Analysed> Set (N = xx)  
Product-limit of Kaplan-Meier estimates for PFSs1   
 
Arm 1 
(N = xx) 
Arm 2 
(N= xx) 
PFSs1   
    Number of censors 
Nobs 
 
 
       Lost to follow-up without new treatment nor PD 
n (%) 
 
 
       Alive without new treatment nor PD 
n (%) 
 
 
    Number of events  
Nobs 
 
 
       Start of new anti-cancer therapy 
n (%) 
 
 
       Progression Disease (PD) 
n (%) 
 
 
       Death 
n (%) 
 
 
Median (months) 
 
 
95% confidence intervala 
 
 
80% confidence intervala 
 
 
 Min ; Max 
 
 
 
 
 
Survival probability at 6 months 
 
 
95% confidence intervalb 
 
 
80% confidence intervalb 
 
 
 
 
 
Survival probability at 12 months 
 
 
95% confidence intervalb 
 
 
80% confidence intervalb 
 
 
 
 
 
Survival probability at 18 months 
 
 
95% confidence intervalb 
 
 
80% confidence intervalb 
 
 
 
 
 
Survival probability at 24 months 
 
 
95% confidence intervalb 
 
 
80% confidence intervalb 
 
 
 
     a Methodology of Brookmeyer and Crowley 
 
     b Using log-log transformation methodology of Kalbfleisch and Prentice 
 
 


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Antitumoral activity - Full analysis Set (N = xx)  
Product-limit of Kaplan-Meier estimates for PFSs2   
 
Arm 1 
(N = xx) 
Arm 2 
(N= xx) 
PFSs2   
    Number of censors 
Nobs 
 
 
       Lost to follow-up without new treatment nor PD 
n (%) 
 
 
       Alive without new treatment nor PD 
n (%) 
 
 
       Start of new anti-cancer therapy 
 
 
 
    Number of events  
Nobs 
 
 
       Progression Disease (PD) 
n (%) 
 
 
       Death 
n (%) 
 
 
Median (months) 
 
 
95% confidence intervala 
 
 
80% confidence intervala 
 
 
 Min ; Max 
 
 
 
 
 
Survival probability at 6 months 
 
 
95% confidence intervalb 
 
 
80% confidence intervalb 
 
 
 
 
 
Survival probability at 12 months 
 
 
95% confidence intervalb 
 
 
80% confidence intervalb 
 
 
 
 
 
Survival probability at 18 months 
 
 
95% confidence intervalb 
 
 
80% confidence intervalb 
 
 
 
 
 
Survival probability at 24 months 
 
 
95% confidence intervalb114 
 
 
80% confidence intervalb 
 
 
 
     a Methodology of Brookmeyer and Crowley 
 
     b Using log-log transformation methodology of Kalbfleisch and Prentice 
 
 
 


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­ <Analysed> Set (FAS, TUMFAS) 
 
Antitumoral activity – <Analysed> Set (N = xx)  
Product-limit of Kaplan-Meier estimates for overall survival   
 
Arm 1 
(N = xx) 
Arm 2 
(N= xx) 
Overall survival 
    Number of censors 
Nobs 
 
 
       Patient alive without documented death 
n (%) 
 
 
    Number of events  
Nobs 
 
 
       Death 
n (%) 
 
 
Median (months) 
 
 
95% confidence intervala 
 
 
80% confidence intervala 
 
 
 Min ; Max 
 
 
 
 
 
Survival probability at 6 months 
 
 
95% confidence intervalb 
 
 
80% confidence intervalb 
 
 
 
 
 
Survival probability at 12 months 
 
 
95% confidence intervalb 
 
 
80% confidence intervalb 
 
 
 
 
 
Survival probability at 18 months 
 
 
95% confidence intervalb 
 
 
80% confidence intervalb 
 
 
 
 
 
Survival probability at 24 months 
 
 
95% confidence intervalb 
 
 
80% confidence intervalb 
 
 
 
     a Methodology of Brookmeyer and Crowley 
 
     b Using log-log transformation methodology of Kalbfleisch and Prentice 
 
 


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PFS (Stepwise Model Multivariate Analysis) – FAS population 
Factor 
Levelsa 
P-Valueb 
Hazard 
Ratioc 
95% CIc 
[Low, High] 
 
Stratification Factors (In Base Model): 
 
RAS Status 
Wild Type (vs. Mutant Type) 
 
 
 
 
ECOG 
0 (vs. 1) 
 
 
 
 
0 (vs. 2) 
 
 
 
 
Additional Factors (for Selection): 
Factor 1 
Level 1 
 
 
 
 
… 
 
 
 
 
Level X 
 
 
 
 
… 
 
 
 
 
 
Factor X 
Level 1 
 
 
 
 
… 
 
 
 
 
Level X 
 
 
 
a The level in the numerator for the hazard ratio.  Factors with just two levels have just one level for hazard ratio. 
b Wald Chi-Square Test for Factor. 
c From Cox Regression with forward stepwise selection process ("entry" and "stay" alpha =0.1). Factors with more than two levels display each level of the factor and the hazard ratio is relative to all those 
not in that level. 
N.S. Not selected by stepwise procedure (not significant at alpha=0.1). 
 
 
 


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PFS (Final Stepwise Model Multivariate Analysis with Factor for Treatment) – FAS population 
Factor 
Levels 
P-Valuea 
Hazard 
Ratiob 
95% CIb 
[Low, High] 
Interaction 
P-Valuec 
 
Treatment 
Arm 1, Arm 2 
 
 
 
n/a 
 
RAS Status 
Wild Type, Mutant Type 
 
 
 
 
 
ECOG 
0, 1 
 
 
 
 
 
0, 2 
 
 
 
 
 
Factor 1 
Level1, …, Level X 
 
 
 
 
 
… 
 
 
 
 
 
 
Factor X 
Level1, …, Level X 
 
 
 
 
a Wald Chi-Square Test 
b Hazard of arm 1 (relative to arm 2) from Cox Regression including terms for all factors shown. 
c P-value for interaction with treatment from full model plus the 2-way interaction with just the factor shown (i.e. separate models including only 1 factor crossed with treatment). 
 
 


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Subgroup PFS analysis – FAS population 
 
Arm 1 
(N = xx) 
Arm 2 
(N = xx) 
Subgroup 
Variable 1 
 
 
 
 
Modality 1  
n (%) 
 
 
 
Mediana 
 
 
 
95%b 
 
 
 
HR 
 
 
95% 
 
… 
 
 
 
 
Modality X  
n (%) 
 
 
 
mediana 
 
 
 
95% b 
 
 
 
HR 
 
 
95% 
 
… 
 
 
 
Variable X 
 
 
 
 
Modality 1  
n (%) 
 
 
 
mediana 
 
 
 
95% b 
 
 
 
HR 
 
 
95% 
 
… 
 
 
 
 
Modality X  
n (%) 
 
 
 
mediana 
 
 
 
95% b 
 
 
 
HR 
 
 
95% 
 
a Kaplan-Meier estimates 
b Methodology of Brookmeyer and Crowley 
 
 
 
 
 


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Forest Plot of Hazard Ratios for Treatment Effect on Radiologic Progression-Free Survival by Selected Subgroups – FAS population 
 


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Antitumoral activity - Full Analysis Set (N = xx)  
Listing of the tumour response evaluation  
Arm 
Pati
ent 
BOR* 
Cycle 
OR# 
last 
trt 
intak
e 
with
- 
dra
wal 
visit 
with
- 
draw
al 
reas
on 
Type
¤ 
Resp
onse 
lesio
ns 
Date 
Presence 
of non-
target 
lesion 
Organ 
site 
Meth
od of 
meas
ure 
Sum of 
diamet
ers 
(mm) 
Relati
ve 
Chang
e from 
baseli
ne (%) 
Relati
ve 
Chang
e from 
nadir 
(small
est)  
(%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, Non CR/Non PD = Non Complete response/ Non progressive 
disease and NE = non-evaluable 
*Best Overall Response - Only during the treatment period     
 #Overall Response  
¤ Type: T = Target lesion, NT = Non target lesion, NL = New lesion 
 
 
Antitumoral activity - Full Analysis Set (N = xx) 
Listing of the best relative change of the sum of the lesions diameters from baseline  
Arm 
Patient 
Histological type 
Diagnosis 
LLT label 
Primary 
tumor 
Lymph 
nodes 
Metastases 
BOR* 
Best 
relative 
change 
from 
baseline 
(%) 
At least one 
new lesion 
under 
treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 * Best Overall Response - Only during the treatment period 
 This listing will be sorted by the best relative change value 
 


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Antitumoral activity - Full Analysis Set (N = xx) 
Bar chart of the best relative change of the sum of the lesions diameters from baseline (%) during the 
treatment period   
 
 
 
 


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3. BIOMARKERS ANALYSIS 
3.1. Protein-expression by IHC 
In case of several subcellular staining locations for one parameter, analyses will be performed 
separately for each location. 
 
For the following tables and graphs: 
­ <Analysed> Set (TUMFAS) 
­ Parameter : “name of biomarker” in “subcellular staining location” 
­ Group :Arm1/Arm2  
­ Measurement: H-score/Occupancy 
 
Protein expression by IHC - <Analysed> Set (N = xx) 
 Measurement – Description by class – Value at baseline 
 
Arm 1  
(N = xx) 
Arm 2  
(N = xx) 
Parameter 1 
 
Nobs  
 
 
>0 
n (%)  
 
 
=0 
n (%)  
 
 
 
  
 
Parameter x 
 
Nobs  
 
 
>0 
n (%)  
 
 
=0 
n (%)  
 
 
 
Following table and graphic will be provided if, for a given marker, at least 3 patients present 
an H-score/Occupancy greater than 0.  
 
Protein expression by IHC - <Analysed> Set (N = xx) 
 Measurement – Description – Value at baseline 
 
Arm 1  
(N = xx) 
Arm 2  
(N = xx) 
Parameter 1 
n    
 
 
Mean ± SD    
 
 
Median    
 
 
Q1 ; Q3    
 
 
Min ; Max    
 
 
  
 
Parameter x 
n    
 
 
Mean ± SD    
 
 
Median    
 
 
Q1 ; Q3    
 
 
Min ; Max    
 
 
 
 


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Protein expression by IHC - <Analysed> Set (N = xx) 
Measurement for parameter – Boxplot – Value at baseline 
 
 
 
Protein expression by IHC - <Analysed> Set (N = xx) 
Measurement for parameter – Group Patients – Histogram – Value at baseline 
 
 
3.2. Protein-expression by IHC according to response 
In case of several subcellular staining locations for one parameter, analyses will be 
performed separately for each location. 


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3.2.1. Protein-expression by IHC according to DCR/ORR 
For the following tables and graphs: 
­ <Analysed> Set (TUMFAS, TUMTR) 
­ (*) : defined by DCR / defined by ORR 
­ Parameter : “name of biomarker” in “subcellular staining location” 
­ Class: bmk+/bmk- 
­ Measurement: H-score/Occupancy 
­ Cutoff: Cutoff considered as eligible, i.e. if there are at least 5 patients in the bmk+ group 
as well as 5 patients in the bmk- group 
 
Following table and graph will be provided for each cutoff point considered as eligible, i.e. if 
there are at least 5 patients in the bmk+ group as well as 5 patients in the bmk- group.  
 
Analysis of IHC - <Analysed> Set (N = xx) 
Parameter – Patients groups based on Measurement – Comparison between treatment groups according to 
response (*)  
 
 
 
Arm 1  
(N = xx) 
Arm2 
(N = xx) 
 
 
Descriptive statistics 
Cutoff 1 
bmk+ 
 
  
 
 
 
Response (*)  
Nobs  
 
 
 
Responder 
n (%)  
 
 
 
Non responder 
n (%)  
 
Cutoff 1 
bmk- 
 
  
 
 
 
Response (*)  
Nobs  
 
 
 
Responder 
n (%)  
 
 
 
Non responder 
n (%)  
 
 
 
 
  
 
Cutoff x 
bmk+ 
 
  
 
 
 
Response (*)  
Nobs  
 
 
 
Responder 
n (%)  
 
 
 
Non responder 
n (%)  
 
Cutoff x 
bmk- 
 
  
 
 
 
Response (*)  
Nobs  
 
 
 
Responder 
n (%)  
 
 
 
Non responder 
n (%)  
 
 
 
 
  
 
Statistical analysis 
Response rate (*) 
Cutoff 1 
bmk+ 
 
  
n (%)  
 
  
95% CI (1)  
 
  
p-value(2)  
  
  
Cutoff 1 
bmk- 
 
  
n (%)  
 
  
95% CI (1)  
 
(1): 95%CI of the estimate using Clopper-Pearson method 
(2): Fisher’s exact test p-value 
 


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Analysis of IHC - <Analysed> Set (N = xx) 
Parameter – Patients groups based on Measurement – Comparison between treatment groups according to 
response (*) (Cont’d) 
  
p-value(2)  
  
  
Cutoff x 
bmk+ 
  
  
n (%)  
 
  
95% CI (1)  
 
  
p-value(2)  
Cutoff x 
bmk- 
 
  
n (%)  
 
  
95% CI (1)  
 
  
p-value(2)  
(1): 95%CI of the estimate using Clopper-Pearson method 
(2): Fisher’s exact test p-value 
 
3.2.2. Protein-expression by IHC according to PFS 
3.2.2.1. Protein-expression by IHC according to PFS – study of all eligible cutoffs 
For the following tables and graphs: 
­ <Analysed> Set (TUMFAS) 
­ Parameter: “name of biomarker” 
­ Measurement: H-score/Occupancy 
­ Class: bmk+/bmk- 
­ Cutoff: Cutoff considered as eligible, i.e. if there are at least 10 patients in the bmk+ group 
as well as 10 patients in the bmk- group 
 
Following table and graph will be provided for each cutoff point considered as eligible, 
i.e. if there are at least 10 patients in the bmk+ group as well as 10 patients in the bmk-group, 
in each arm.  
 
 


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Analysis of IHC - Antitumoral activity - <Analysed> Set (N = xx)  
Product-limit of Kaplan-Meier estimates for < Parameter> based on Measurement  
 
Class 1 
(N = xx) 
Class 2 
(N = xx) 
 
Arm 1 
(N = xx) 
Arm 2 
(N = xx) 
Arm 1 
(N = xx) 
Arm 2 
(N = xx) 
Cutoff 1   
    Number of censors 
Nobs 
 
 
 
 
       Lost to follow-up without new treatment nor PD 
n (%) 
 
 
 
 
       Start of new anti-cancer therapy 
n (%) 
 
 
 
 
       Alive without new treatment nor PD 
n (%) 
 
 
 
 
    Number of events  
Nobs 
 
 
 
 
       Progression Disease (PD) 
n (%) 
 
 
 
 
       Death 
n (%) 
 
 
 
 
Median (months) 
 
 
 
 
95% confidence intervala 
 
 
 
 
80% confidence intervala 
 
 
 
 
 Min ; Max 
 
 
 
 
 
 
 
 
 
Cutoff x 
    Number of censors 
Nobs 
 
 
 
 
       Lost to follow-up without new treatment nor PD 
n (%) 
 
 
 
 
       Start of new anti-cancer therapy 
n (%) 
 
 
 
 
       Alive without new treatment nor PD 
n (%) 
 
 
 
 
    Number of events  
Nobs 
 
 
 
 
       Progression Disease (PD) 
n (%) 
 
 
 
 
       Death 
n (%) 
 
 
 
 
Median (months) 
 
 
 
 
     95% confidence intervala 
 
 
 
 
     80% confidence intervala 
 
 
 
 
 Min ; Max 
 
 
 
 
      a Methodology of Brookmeyer and Crowley 
Analysis of IHC - Antitumoral activity - <Analysed> Set (N = xx)  
Hazard ratio estimate for < Parameter> - Patients groups based on Measurement 
 
 
Class 1 
(N = xx) 
Class 2 
(N = xx) 
 
 
Arm 1 
(N = xx) 
Arm 2 
(N = xx) 
Arm 1 
(N = xx) 
Arm 2 
(N = xx) 
Cutoff 1 
 
 
 
 
Hazard ratio* (relative to Arm 2) 
 
 
 
95% confidence interval 
 
 
 
80% confidence interval 
 
 
 
P-value (LOG-RANK) 
 
 
 
 
 
 
Cutoff x 
 
 
 
 
Hazard ratio* (relative to Arm 2) 
 
 
 
95% confidence interval 
 
 
 
80% confidence interval 
 
 
 
P-value (LOG-RANK) 
 
 
* Cox proportional hazard model without adjusting for the stratification factors 
 
 


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Analysis of IHC - <Analysed> Set (N = xx) 
Forest Plot of Hazard Ratios for Treatment Effect on PFS according to Parameter – Patients groups based 
on Measurement 
 
 
3.2.2.2. Protein-expression by IHC according to PFS – study of best cutoff point 
For the following tables and graphs: 
­ <Analysed> Set (TUMFAS) 
­ Parameter : “name of biomarker” 
­ Arm: arm1/arm2 
­ Class: bmk+/bmk- 
­ Cutoff: best cutoff/median cutoff 
 
Following table and graph will be provided only for best cutoff point, for each parameter.  
 
Analysis of IHC – Antitumoral activity - <Analysed> Set (N = xx) 
Kaplan-Meier curves of < Parameter>  (cutoff) - Arm 
 
 
 
 


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Analysis of IHC - Antitumoral activity - <Analysed> Set (N = xx)  
Hazard ratio estimate for < Parameter> (cutoff) – Patients groups based on Measurement 
 
Arm 1 
(N = xx) 
Arm 2 
(N= xx) 
 
Class 1 
(N = xx) 
Class 2 
(N = xx) 
Class 1 
(N = xx) 
Class 2 
(N = xx) 
Hazard ratio* (relative to bmk-) 
 
 
95% confidence interval 
 
 
80% confidence interval 
 
 
P-value (LOG-RANK) 
 
 
* Cox proportional hazard model without adjusting for the stratification factors 
 
Analysis of IHC - PFS - <Analysed> Set (N = xx)  
Evaluation of BMK effect and BMK*treatment interaction for < Parameter> (cutoff) – Patients groups 
based on Measurement 
Factor 
Levels 
P-Valuea 
Hazard 
Ratiob 
95% CIb 
[Low, High] 
Interaction 
P-Valuec 
 
Treatment 
Arm 1, Arm 2 
 
 
 
n/a 
 
BMK 
bmk+,bmk- 
 
 
 
 
 
a Wald Chi-Square Test 
b Hazard of arm 1 (relative to arm 2) from Cox Regression including terms for all factors shown. 
c P-value for interaction with treatment. 
 
 


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3.3. Microsatellites 
For the following tables and graphs: 
­ <Analysed> Set (TUMFAS, TUMTR) 
­  (*): defined by DCR / defined by ORR 
­ (**): MSS/MSI-L patients / MSI-H patients 
­ Group: Arm1/Arm2 
­ Class: Response level 
 
Analysis of microsatellites - <Analysed> Set (N = xx) 
 MSI status – Description by class– Value at baseline 
 
Arm 1  
(N = xx) 
Arm 2  
(N = xx) 
MSI status group 
Nobs  
 
MSS/MSI-L 
n (%)  
 
MSI-H 
n (%)  
 
 
 
Analysis of microsatellites - <Analysed> Set (N = xx) 
For (**) – Comparison between treatment groups according to response (*)  
 
Arm1  
(N = xx) 
Arm2 
(N = xx) 
Descriptive statistics 
Response (*)  
Nobs  
 
Responder 
n (%)  
 
Non responder 
n (%)  
 
Statistical analysis (***) 
Response rate (*) 
n (%)  
 
95% CI (1)  
 
p-value (2)  
(1): 95%CI of the estimate using Clopper-Pearson method 
(2): Fisher’s exact test p-value 
 
***: CI and p-value will be provided only if there are at least 10 MSI-H patients and 5 
responding patients in the experimental arm. 
 
Analysis of microsatellites - <Analysed> Set (N = xx) 
 For (**) – Barplot of response (*) 
 


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3.4. Protein-expression by ELISA 
For the following tables and graphs: 
­ Parameter  : “name of biomarker” “unit” 
­ Group : Arm1/Arm2 
Protein expression by ELISA – Serum Full Analysis Set (N = xx) 
 Description by class – Value at baseline 
 
Arm 1  
(N = xx) 
Arm 2  
(N = xx) 
Parameter 1 
 
Nobs  
 
 
Below <lower limit> 
n (%)  
 
 
In range 
n (%)  
 
 
Above <Upper limit> 
n (%)  
 
 
 
  
 
Parameter x 
 
Nobs  
 
 
Below <lower limit> 
n (%)  
 
 
In range 
n (%)  
 
 
Above <Upper limit> 
n (%)  
 
 
Following table and graphic will be provided if proportion of values In range is >30%.  
 
Protein expression by ELISA – Serum Full Analysis Set (N = xx) 
 Description – Value at baseline 
 
Arm 1  
(N = xx) 
Arm 2  
(N = xx) 
Parameter 1 
n    
 
 
Mean ± SD    
 
 
Median    
 
 
Q1 ; Q3    
 
 
Min ; Max    
 
 
  
 
Parameter x 
n    
 
 
Mean ± SD    
 
 
Median    
 
 
Q1 ; Q3    
 
 
Min ; Max    
 
 
Protein expression by ELISA – Serum Full Analysis Set (N = xx) 
Parameter - Boxplot – Value at baseline 
 
 


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3.5. Consistency of mutation results  
For the following tables and graphs: 
­ Parameter: “name of gene” at exon level 
­ Mutation: “name of mutation” 
­ Group: Arm1 / Arm2 
 
Mutation results – Serum Full Analysis Set (N = xx)  
 Parameter - In group (N = xx) - Restricted to patient having local and central values available - 
Comparison between local and central results  
 
 
Local result 
All 
 
Exon 1 
Exon x 
Exon Not 
available 
No mutation 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Central result 
 
 
 
 
 
Exon  1  
 
 
 
 
Exon  x  
 
 
 
 
Exon Not 
available 
 
 
 
 
 
No mutation  
 
 
 
 
All 
 
 
 
 
 
 
­ Parameter  : “name of gene” at gene level 
 
Mutation results – Serum Full Analysis Set (N = xx)  
 Parameter - Restricted to patient having local and central values available - Comparison between local 
and central results  
 
 
Arm 1 
(n = xx) 
Arm 2 
(n = xx) 
All 
 
 
Mutation 
Mutation 
not 
available 
No 
mutation 
Mutation 
Mutation 
not 
available 
No 
mutation 
 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
Central result 
 
 
 
 
 
 
 
Arm 1 
(n = xx) 
Mutation 
 
 
 
 
 
 
 
Mutation not 
available 
 
 
 
 
 
 
 
No mutation 
 
 
 
 
 
 
 
Arm 2 
(n =  xx) 
Mutation 
 
 
 
 
 
 
 
No mutation 
 
 
 
 
 
 
 
Mutation not 
available 
 
 
 
 
 
 
 
 
All 
 
 
 
 
 
 
 
 
4. SAFETY ANALYSIS 
4.1. DLTs 
Not applicable. 
 


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4.2. Adverse events 
­ (*) EAE / Serious EAE (with sponsor upgrade) 
 
 (*) – Safety Set (N = xx) – Crude incidence by PT 
On treatment  
PT 
Arm 1 
 (N = xx) 
Arm 2 
 (N = xx) 
ALL  
(N = xx) 
 
NEAE 
n 
% 
NEAE 
n 
% 
NEAE 
n 
% 
ALL 
 
 
 
 
 
PT - aaaa 
 
 
 
 
 
PT – bbab 
 
 
 
 
 
PT - abaa 
 
 
 
 
 
… 
 
 
 
 
 
N: Number of patients by arm 
NEAE: Number of (*) 
n: Number of patients with at least one (*) / %: (n/N)*100 
 
EAE – Safety Set (N=xx) – Crude incidence by SOC 
On treatment 
 
Primary SOC 
Arm 1 
 (N = xx) 
Arm 2 
 (N = xx) 
ALL  
(N = xx) 
 
NEAE 
n 
% 
NEAE 
n 
% 
NEAE 
n 
% 
ALL 
 
 
 
 
 
 
 
SOC – a 
 
 
 
 
 
 
 
SOC – b 
 
 
 
 
 
 
 
SOC – c 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
N: Number of patients by arm 
NEAE: Number of EAE 
n: Number of patients with at least one EAE / %: (n/N)*100 
 
STD table created using 
macro % AE TAB2 
STD table created using 
macro %_AE_TAB1 


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For the following table: 
­ (*) Serious AE (with sponsor upgrade) 
(**) During the study 
­ (*) EAE / EAE leading to IMP withdrawal / EAE related to IMP or associated agent (with 
sponsor upgrade) / Serious EAE (with sponsor upgrade) / Severe EAE / EAE of interest 
(hematological toxicities) / Non Serious EAE 
(**) On treatment 
 
(*)- Safety Set (N = xx) - Crude incidence by SOC and PT  
 
(**) 
 
Arm 1 
 (N=xx) 
Arm 2 
 (N=xx) 
ALL  
(N=xx) 
PRIMARY SOC / PT 
(#) 
n 
% 
(#) 
n 
% 
(#) 
% 
(#) 
ALL 
 
 
 
 
 
 
 
SOC - a 
 
 
 
 
 
 
 
 
PT – aaaa 
 
 
 
 
 
 
 
 
PT – aaab  
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
SOC - b 
 
 
 
 
 
 
 
 
PT – baaa 
 
 
 
 
 
 
 
 
PT – baab 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
N: Number of patients by arm 
(#) Number of (*) 
n: Number of patients with at least one (*) / %: (n/N)*100 
  
 


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EAE - Safety Set (N = xx) – Distribution by outcome and SOC and PT 
On treatment 
ALL or Arm 1 or Arm 2 (N = xx) 
 
RECOVERED/RESOLVED 
RECOVERED/RESOLVED WITH SEQUELAE 
 
 
ALL 
ALL 
RECOVERED/ 
RESOLVED 
RECOVERED/ 
RESOLVED 
WITH 
SEQUELAE 
RECOVERING/ 
RESOLVING 
NOT 
RECOVERED/ 
NOT 
RESOLVED 
FATAL 
UNKNOWN 
MISSING 
PRIMARY SOC / PT 
NEAE 
% 
NEAE 
% 
NEAE 
% 
NEAE 
% 
NEAE 
% 
NEAE 
% 
NEAE 
% 
NEAE 
% 
NEAE 
% 
ALL 
 100.0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SOC - a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PT – aaaa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PT – aaab 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SOC - b 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PT – baaa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PT – baab 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Latest outcome is considered  
N: Number of patients by arm 
NEAE: Number of EAE / %: (NEAE by outcome / Total NEAE)*100 
 
 


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EAE requiring additional therapy– Safety Set (N = xx) – Crude incidence  
On treatment 
REQUIRED ADDITIONAL THERAPY 
All 
 (N = xx) 
NEAE 
 n 
 % 
ALL 
 
 
 
New treatment or increase of on-going trt 
 
 
 
Surgical/medical procedure 
 
 
 
A patient can report more than one EAE and can be counted in several class levels 
N: Number of patients by arm 
NEAE: Number of EAE 
n: Number of patients with at least one EAE / %: (n/N)*100  
 
 
EAE by action taken – Safety Set (N = xx) – Crude incidence 
 On treatment 
ACTION TAKEN 
All (N = xx) 
  
 
NEAE 
% 
ALL 
 100.00 
 DRUG WITHDRAWN 
 
 
 DOSE REDUCED 
 
 
 DOSE NOT CHANGED 
 
 
 UNKNOWN 
 
 
 NOT APPLICABLE 
 
 
 TEMPORARILY  INTERRUPTED 
 
 
 TREATMENT DELAYED 
 
 
 TREATMENT DELAYED AND REDUCED 
 
 
 MISSING 
 
 
A patient can report more than one EAE and can be counted in several class levels 
N: Number of patients by arm 
NEAE: Number of EAE 
n: Number of patients with at least one EAE / %: (n/N)*100  
Missing: Action taken is considered as missing if for an EAE, action taken is 
missing for all episodes 
 
 
 
 
STD table created using 
macro %_AE_TAB9 


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For the following table: 
             -   (*) Summary table of EAE (with sponsor upgrade) 
 
 (*) – Safety Set (N = xx) – Crude incidence by SOC and PT 
On treatment 
 ALL or Arm 1 or Arm 2 (N = xx) 
 
EAE 
Severe EAE 
Serious EAE 
EAE leading to 
IMP 
withdrawal 
EAE related 
to IMP 
EAE leading to 
IMP 
withdrawal and 
related to study 
drug 
EAE related to 
bevacizumab 
PRIMARY SOC/PT 
NEAE n % NEAE n % NEAE n % NEAE n 
% NEAE n % NEAE n 
% NEAE n 
% 
ALL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SOC - a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       PT - aaaa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       PT - aaab 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       … 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SOC - b 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       PT - baaa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       PT - baab 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       … 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N: Number of patients by arm 
NEAE: Number of EAE 
n: Number of patients with at least one EAE / %: (n/N)*100 
STD table created using 
macro %_AE_TAB10A 


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For the following table: 
 
­ (*) Serious EAE (with sponsor upgrade) / Severe EAE (with sponsor upgrade) 
 
Summary table of (*) – Safety Set (N = xx) - Crude incidence by SOC and PT  
On treatment 
ALL or Arm 1 or Arm 2 (N = xx) 
 
(*) 
(*) leading to IMP 
withdrawal 
(*) related to IMP 
(*) leading to IMP 
withdrawal and related to 
IMP 
(*) related to bevacizumab 
PRIMARY SOC/PT 
NEAE 
n 
% 
NEAE 
n 
% 
NEAE 
n 
% 
NEAE 
n 
% 
NEAE 
n 
% 
ALL 
 
 
 
 
 
 
 
 
 
 
 
 
 
SOC - a 
 
 
 
 
 
 
 
 
 
 
 
 
 
       PT – aaaa 
 
 
 
 
 
 
 
 
 
 
 
 
 
       PT - aaab 
 
 
 
 
 
 
 
 
 
 
 
 
 
       … 
 
 
 
 
 
 
 
 
 
 
 
 
 
SOC - b 
 
 
 
 
 
 
 
 
 
 
 
 
 
       PT – baaa 
 
 
 
 
 
 
 
 
 
 
 
 
 
       PT – baab 
 
 
 
 
 
 
 
 
 
 
 
 
 
       … 
 
 
 
 
 
 
 
 
 
 
 
 
 
N: Number of patients by arml 
NEAE: Number of EAE 
n: Number of patients with at least one EAE / %: (n/N)*100 
STD table created using 
macro %_AE_TAB11A 


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For the following table: 
 
­  (*) EAE / EAE leading to IMP withdrawal / EAE related to IMP or associated agent (with sponsor upgrade) / Serious EAE (with sponsor 
upgrade) / Serious EAE related to IMP or associated agent / EAE of interest (hematological toxicities) on treatment  
 
 
(*) - Safety Set (N=xx) - Distribution of the number of (**) by worst grade 
Descriptive statistics by primary system organ class and preferred term on treatment 
ALL or Arm 1 or Arm 2 (N = xx) 
PRIMARY SOC/PT 
WORST GRADE 
Not graded or missing 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Any grade 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
ALL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SOC - a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       PT – aaaa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       PT - aaab 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       … 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SOC - b 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       PT – baaa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       PT – baab 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(**) event/patient 
If (**) = patient 
N: Number of patients by arm 
n: Number of patients with at least one (*) by worst grade / %: (n/N)*100 
If (**) = event 
N: Number of (*) by arm 
n Number of (*) by worst grade / %: (n/N)*100
STD table created using 
macro %_AE_TAB3A/B/C 


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Summary table of Serious EAE (EudraCT) – Safety Set (N = xx) - Crude incidence by SOC and PT  
On treatment  
ALL or Arm 1 or Arm 2 (N = xx)  
 
Serious EAE 
Serious EAE related 
IMP 
Serious EAE leading 
to death 
Serious EAE  leading 
to death and related 
to IMP 
PRIMARY SOC/PT NEAE 
n 
% 
NEAE 
n 
% 
NEAE 
n 
% 
NEAE 
n 
% 
ALL 
 
 
 
 
 
 
 
 
 
 
 
 
SOC - a 
 
 
 
 
 
 
 
 
 
 
 
 
       PT – aaaa 
 
 
 
 
 
 
 
 
 
 
 
 
       PT - aaab 
 
 
 
 
 
 
 
 
 
 
 
 
       … 
 
 
 
 
 
 
 
 
 
 
 
 
SOC - b 
 
 
 
 
 
 
 
 
 
 
 
 
       PT – baaa 
 
 
 
 
 
 
 
 
 
 
 
 
       PT – baab 
 
 
 
 
 
 
 
 
 
 
 
 
       … 
 
 
 
 
 
 
 
 
 
 
 
 
N: Number of patients by arm 
NEAE: Number of EAE 
n: Number of patients with at least one EAE / %: (n/N)*100 
Seriousness according to the investigator or sponsor opinion/ Relation according to investigator opinion 
 
 
EAE related to (*) - Safety Set (N = xx) 
Horizontal bar chart of the ten most frequent events according to the percentage of patients by worst 
grade and preferred term on treatment  
ALL (N = xx) 
 
The x-axis corresponds to the number of adverse events. 
For each preferred term grouped by primary system organ class, the number of adverse events by grade will be given. 
Preferred terms with at least two events will be defined as the adverse events of interest.   
 
(*)S 95005 or bevacizumab (arm1) / capecitabine or bevacizumab (arm2) 
 
 
 
 
STD table created using 
macro %_AE_TAB11A 


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For the following table: 
­  (*) EAE / Serious EAE (with sponsor upgrade) 
 
 (*) – Safety Set (N = xx) – Time to onset by SOC and PT – (°) 
On treatment 
ALL or Arm1 or Arm 2 (N = xx) 
 
TIME TO ONSET 
 
1st week of 
cycle 1 
Xth week of 
cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
> Cycle 4 
PRIMARY SOC/PT 
n nt 
% 
nt 
% 
nt 
% 
nt 
% 
nt 
% 
nt 
% 
ALL 
 
 
 
 
 
 
 
 
 
 
SOC - a 
 
 
 
 
 
 
 
 
 
 
       PT - aaaa 
 
 
 
 
 
 
 
 
 
 
       PT - aaab 
 
 
 
 
 
 
 
 
 
 
       … 
 
 
 
 
 
 
 
 
 
 
SOC - b 
 
 
 
 
 
 
 
 
 
 
       PT - baaa 
 
 
 
 
 
 
 
 
 
 
       PT - baab 
 
 
 
 
 
 
 
 
 
 
       … 
 
 
 
 
 
 
 
 
 
 
N: number of patients by arm 
Time to onset: time between the first study drug intake date and the onset date of the first emergent episode of AE 
n: Number of patients with at least one EAE 
nt: Number of patients with their first EAE in the class of time to onset / %: (nt / n)*100 
 
(°) Arm1/Arm2 
 
 
STD table created using 
macro %_AE_TAB4 


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4.3. Death 
Death - Safety Set (N = xx) 
Descriptive statistics during the treatment and follow-up period by treatment arm 
 
Arm 1 
(N = xx) 
Arm 2 
(N = xx) 
ALL 
(N = xx) 
DEATH 
Nobs  
 
 
  YES 
n (%) (%)  
 
 
  NO 
n (%)  
 
 
 
  
 
 
DEATH DURING THE TREATMENT PERIOD 
Nobs  
 
 
    YES 
n (%)   (%)  
 
 
    NO 
n (%)  
 
 
 
  
 
 
DEATH DURING THE FOLLOW-UP PERIOD 
Nobs    
 
 
    YES 
n (%)    
 
 
    NO 
n (%)    
 
 
 
Death - Safety Set (N = xx) 
Descriptive statistics during the treatment and follow-up period by treatment arm 
 
Arm 1 
(N = xx) 
Arm 2 
(N = xx) 
ALL 
(N = xx) 
CATEGORY OF DEATH 
Nobs  
 
 
  RADIOLOGIC DISEASE PROGRESSION 
n (%) 
 
 
 
  CLINICAL DISEASE PROGRESSION 
n (%) 
 
 
 
  TOXICITY 
n (%) 
 
 
 
  OTHER 
n (%) 
 
 
 
  NOT COLLECTED 
n (%) 
 
 
 
 
 
Death - Safety Set (N = xx) 
Descriptive statistics by primary system organ class and preferred term during the treatment period 
PRIMARY SYSTEM ORGAN 
CLASS / PREFERRED TERM 
Arm 1 
(N = xx) 
Arm 2 
(N = xx) 
ALL 
(N = xx) 
 
n 
% 
n 
% 
n 
% 
ALL 
 
 
 
 
 
 
SOC-a 
 
 
 
 
 
 
           PT-aaaa 
 
 
 
 
 
 
           PT-aaab 
 
 
 
 
 
 
           ... 
 
 
 
 
 
 
SOC-b 
 
 
 
 
 
 
           PT-bbab 
 
 
 
 
 
 
           ... 
 
 
 
 
 
 
N: Number of patients by arm 
n: Number of patients with at least one fatal AE  / %: (n/N)*100 
 
 
 
 
 
 
 
 
 
 


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Death - Safety Set (N = xx) 
Listing of patients who died during the treatment period or during the follow-up period 
Arm 
Patient 
number 
Disoncintuation reason 
Reason of 
death 
Period of 
death 
Serious Adverse Event 
(Preferred Term) 
Non-serious Adverse 
Event with action taken of 
discontinuation 
(Preferred Term) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.4. Clinical laboratory evaluation 
For the following table: 
­ Gradable parameters 
Albumin, Alkaline Phosphatase, Total Bilirubin, Calcium, GGT, Glucose, Potassium, 
Magnesium, Phosphate, Sodium, AST, ALT, Hemoglobin, WBC, Platelets: 
 Lymphocytes, Neutrophils, Serum creatinine, APTT and INR. 
 ­ (*) Biochemical parameters / Haematological parameters / Coagulation. 
 ­ (**) Low Albumin, high Alkaline Phosphatase, high Total Bilirubin, hypercalcemia, 
hypocalcemia, high GGT, hyperglycemia, hypoglycaemia, hyperkalemia, hypokalemia. 
 hypermagnesemia, hypomagnesemia, hypophosphatemia, hyponatremia, hypernatremia, 
high AST, high ALT, high haemoglobin, anemia, leucocytosis, low WBC, low platelets, 
high lymphocyte, low lymphocyte, low Neutrophils, high creatinine, aPTT 
prolonged/high aPTT  and high INR. 
 (***) Change from baseline to the worst value. 
 
(*): (**) - Safety set (N = xx) - Shift table of worst values on treatment according to baseline using grades 
ALL or Arm 1 or Arm 2 (N = xx) 
Arm 
(N = xx) 
 
On treatment 
Grade 0 
(1) 
Grade 1 
(2) 
Grade 2 
(3) 
Grade 3 
(4) 
Grade 4 
(5) 
All  
(6) 
n 
(%) 
n 
(%) 
n 
(%) 
n 
(%) 
n 
(%) 
n 
(%) 
Baseline Grade 0 
 
 
 
 
 
 
 
 
 
 
 
 
Grade 1 
 
 
 
 
 
 
 
 
 
 
 
 
Grade 2 
 
 
 
 
 
 
 
 
 
 
 
 
Grade 3 
 
 
 
 
 
 
 
 
 
 
 
 
Grade 4 
 
 
 
 
 
 
 
 
 
 
 
 
Any grade 
 
 
 
 
 
 
 
 
 
 
 
 
Missing 
 
 
 
 
 
 
 
 
 
 
 
 
All 
 
 
 
 
 
 
 
 
 
 
 (100.0) 
(1) Nb and % of patients with a worst grade = 0 on treatment 
(2) Nb and % of patients with a worst grade = 1 on treatment 
(3) Nb and % of patients with a worst grade = 2 on treatment 
(1) Nb and % of patients with a worst grade = 3 on treatment 
(5) Nb and % of patients with a worst grade = 4 on treatment 
(6) Nb and % of patients with at least one value on treatment post-inclusion 
% = n/N*100 
 
 
 


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(*): (**) - Safety set (N = xx) – (***) under treatment 
 
 
Arm 1 
(N = xx) 
Arm 2 
(N = xx) 
All 
(N = xx) 
Overall  
Nobs 
 
 
 
 
Mean ± SD 
 
 
 
 
Median 
 
 
 
 
Q1 ; Q3 
 
 
 
 
Min ; Max 
 
 
 
 
 
(*): (**) - Safety set (N = xx) – Descriptive statistics 
 
Arm 1 
(N = xx) 
Arm 2 
(N = xx) 
All 
(N = xx) 
Value at baseline  
Nobs 
 
 
 
 
Mean ± SD 
 
 
 
 
Median 
 
 
 
 
Q1 ; Q3 
 
 
 
 
Min ; Max 
 
 
 
 
 
 
 
 
Grade 0 
n (%) 
 
 
 
Grade 1 
n (%) 
 
 
 
Grade 2 
n (%) 
 
 
 
Grade 3 
n (%) 
 
 
 
Grade 4 
n (%) 
 
 
 
 
 
 
 
 
Value at planned post-baseline 
visit 1 
Nobs 
 
 
 
 
Mean ± SD 
 
 
 
 
Median 
 
 
 
 
Q1 ; Q3 
 
 
 
 
Min ; Max 
 
 
 
 
 
 
 
 
Grade 0 
n (%) 
 
 
 
Grade 1 
n (%) 
 
 
 
Grade 2 
n (%) 
 
 
 
Grade 3 
n (%) 
 
 
 
Grade 4 
n (%) 
 
 
 
 
 
 
 
 
Value at planned post-baseline 
visit X 
Nobs 
 
 
 
 
Mean ± SD 
 
 
 
 
Median 
 
 
 
 
Q1 ; Q3 
 
 
 
 
Min ; Max 
 
 
 
 
 
 
 
 
Grade 0 
n (%) 
 
 
 
Grade 1 
n (%) 
 
 
 
Grade 2 
n (%) 
 
 
 
Grade 3 
n (%) 
 
 
 
Grade 4 
n (%) 
 
 
 
 
 
 


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For the following table: 
­ Non-gradable parameters: 
Chloride, LDH, Total Protein, Basophils, Eosinophils, Hematocrit, Monocytes, RBC, 
Bicarbonate, BUN and creatinine clearance: 
 ­ (*) Biochemical parameters / Haematological parameters / Coagulation. 
 ­ (**) high chloride, low chloride, high LDH, high Proteins, low total proteins, 
low Basophils, high Eosinophils, low Haematocrit, high Haematocrit, high Monocytes, 
high RBC, low RBC, low Bicarbonate, high Bicarbonate, high BUN and creatinine 
clearance. 
  (***) Change from baseline to worst value. 
 
 
 (*): (**) - Safety set (N = xx) - Shift table of worst values on treatment according to baseline using 
reference ranges 
Arm 
(N=xx) 
On treatment 
< LL 
(1) 
[LL-UL] 
(2) 
> UL 
(3) 
All  
(4) 
n 
(%) 
n 
(%) 
n 
(%) 
n 
(%) 
Baseline < LL 
 
 
 
 
 
 
 
 
[LL-UL] 
 
 
 
 
 
 
 
 
> UL 
 
 
 
 
 
 
 
 
Missing 
 
 
 
 
 
 
 
 
All 
 
 
 
 
 
 
 (100.0) 
(1) Nb and % of patients with a worst value < LL on treatment 
(2) Nb and % of patients with a worst value in [LL-UL] on treatment 
(3) Nb and % of patients with a worst value > UL on treatment 
(4) Nb and % of patients with at least one value on treatment post-inclusion 
% = n/N*100 
 
Note: For some parameters, one single type of abnormality will be presented depending on the interest (High abnormality or Low 
abnormality) (ex: AST, ALT, Cholesterol...). When both types of abnormality are of interest, two tables need to be produce, one for 
each abnormality (e.g. Hypokalemia, Hyperkalemia) 
 
Biochemical parameter: Creatinine clearance - Safety set (N = xx) - Shift table of worst values on 
treatment according to baseline using reference ranges 
ALL (N = xx) 
 
Worst value on treatment 
normal 
(1) 
mild 
(2) 
moderate 
(3) 
severe 
(4) 
All  
(5) 
n 
(%) 
n 
(%) 
n 
(%) 
n 
(%) 
n 
(%) 
Baseline normal 
 
 
 
 
 
 
 
 
 
 
mild 
 
 
 
 
 
 
 
 
 
 
moderate 
 
 
 
 
 
 
 
 
 
 
severe 
 
 
 
 
 
 
 
 
 
 
missing 
 
 
 
 
 
 
 
 
 
 
All 
 
 
 
 
 
 
 
 
 (100.0) 
(1) Nb and % of patients with a worst value normal on treatment 
(2) Nb and % of patients with a worst value mild on treatment 
(3) Nb and % of patients with a worst value moderate on treatment 
(4) Nb and % of patients with a worst value severe on treatment 
(5) Nb and % of patients with at least one value on treatment post-baseline 
% = n/Nb of patients with at least one available post-baseline value on treatment*100 
 
 
 
 
 
 
STD table created using 
macro %_LB_TAB5 
STD table created using 
macro %_LB_TAB5 


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(*): (**) - Safety set (N = xx) – (***) under treatment 
 
Arm 1 
(N = xx) 
Arm 2 
(N = xx) 
All 
(N = xx) 
Overall  
Nobs 
 
 
 
 
Mean ± SD 
 
 
 
 
Median 
 
 
 
 
Q1 ; Q3 
 
 
 
 
Min ; Max 
 
 
 
 
 
(*): (**) - Safety set (N = xx) – Descriptive statistics 
 
Arm 1 
(N = xx) 
Arm 2 
(N = xx) 
All 
(N = xx) 
Value at Baseline 
Nobs 
 
 
 
 
Mean ± SD 
 
 
 
 
Median 
 
 
 
 
Q1 ; Q3 
 
 
 
 
Min ; Max 
 
 
 
 
 
 
 
 
< LL 
n (%) 
 
 
 
LL-UL] 
n (%) 
 
 
 
> UL 
n (%) 
 
 
 
 
 
 
For the following table: 
­ Urinalysis parameters: 
 (**)Proteinuria, Glucosuria, Urobilinogen, Haematuria, Leucocyturia. 
 (***) Change from baseline to worst value. 
 
 
Urinalysis: (**) - Safety set (N = xx) - Shift table of worst values on treatment according to baseline using 
reference ranges 
ALL or Arm 1 or Arm 2 (N = xx) 
Arm 
(N = xx) 
On treatment 
Negative 
(1) 
Trace 
(2) 
Positive 
(3) 
All  
(4) 
n 
(%) 
n 
(%) 
n 
(%) 
n 
(%) 
Baseline Negative 
 
 
 
 
 
 
 
 
Trace 
 
 
 
 
 
 
 
 
Positive 
 
 
 
 
 
 
 
 
Missing 
 
 
 
 
 
 
 
 
All 
 
 
 
 
 
 
 (100.0) 
(1) Nb and % of patients with a worst value negative on treatment 
(2) Nb and % of patients with a worst value trace on treatment 
(3) Nb and % of patients with a worst value positive on treatment 
(4) Nb and % of patients with at least one value on treatment post-inclusion 
% = n/N*100 
 
 
 
 
 
 
 
 
 
STD table created using 
macro %_LB_TAB5 


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Urinalysis - Safety set (N = xx) - Shift table of worst values positive on treatment according to baseline 
(**) 
ALL  (N = xx) 
Worst value positive on treatment 
+ 
(1) 
++ 
(1) 
++ 
(1) 
All  
(2) 
n 
(%) 
n 
(%) 
n 
(%) 
n 
(%) 
Baseline + 
 
 
 
 
 
 
 
 
++ 
 
 
 
 
 
 
 
 
+++ 
 
 
 
 
 
 
 
 
Missing 
 
 
 
 
 
 
 
 
All 
 
 
 
 
 
 
 (100.0) 
(1) Nb and % of patients with a worst value positive on treatment 
(2) Nb and % of patients with at least one value on treatment post-baseline 
% = n/Nb of patients with at least one available post-baseline value on treatment*100 
 
 
(*): (**) - Safety set (N = xx) – (***) under treatment 
 
Arm 1 
(N = xx) 
Arm 2 
(N = xx) 
All 
(N = xx) 
Overall  
Nobs 
 
 
 
 
Mean ± SD 
 
 
 
 
Median 
 
 
 
 
Q1 ; Q3 
 
 
 
 
Min ; Max 
 
 
 
 
 
 
Urinalysis: (**) - Safety set (N = xx) – Descriptive statistics  
 
Arm 1 
(N = xx) 
Arm 2 
(N = xx) 
All 
(N = xx) 
Value at Baseline 
Nobs 
 
 
 
 
Mean ± SD 
 
 
 
 
Median 
 
 
 
 
Q1 ; Q3 
 
 
 
 
Min ; Max 
 
 
 
 
 
 
 
 
Negative 
n (%) 
 
 
 
Trace 
n (%) 
 
 
 
Positive 
n (%) 
 
 
 
 
 
 
 
 


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­ Tumor markers (CEA) 
 (***) Relative change from baseline to worst value 
 
Tumor markers: (CEA) - Safety set (N = xx) - Shift table of worst values on treatment according to 
baseline 
ALL or Arm 1 or Arm 2 (N = xx) 
Arm 
(N = xx) 
On treatment 
Normal 
(1) 
Abnormal 
(2) 
All  
(3) 
n 
(%) 
n 
(%) 
n 
(%) 
Baseline Normal 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
Missing 
 
 
 
 
 
 
All 
 
 
 
 
 
 
(1) Nb and % of patients with a worst value normal on treatment 
(2) Nb and % of patients with a worst value abnormal on treatment 
(3) Nb and % of patients with at least one value on treatment post-inclusion 
% = n/N*100 
 
 
Tumor markers: (CEA) - Safety set (N = xx) – (***) under treatment 
 
Arm 1 
(N = xx) 
Arm 2 
(N = xx) 
All 
(N = xx) 
Overall  
Nobs 
 
 
 
 
Mean ± SD 
 
 
 
 
Median 
 
 
 
 
Q1 ; Q3 
 
 
 
 
Min ; Max 
 
 
 
 
 
 
Tumor markers: (CEA) - Safety set (N = xx) – Descriptive statistics 
 
Arm 1 
(N = xx) 
Arm 2 
(N = xx) 
All 
(N = xx) 
Baseline  
Nobs 
 
 
 
 
Mean ± SD 
 
 
 
 
Median 
 
 
 
 
Q1 ; Q3 
 
 
 
 
Min ; Max 
 
 
 
 
 
 
 
 
Normal 
n (%) 
 
 
 
Abnormal 
n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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For the following tables: 
­ Parameters of special interest: 
 (*) Haemoglobin, neutrophils, platelets, low WBC, bilirubin, ASAT, ALAT, creatinine 
clearance, serum creatinine and proteinuria. 
 
 (*) - Safety set (N = xx) - Scatter plot, value on treatment according to baseline 
 
 
 
 
 
(**) worst value on treatment 
Baseline (Unit) 
(*) (Unit) 
O Arm 1 (N= XX)       O Arm 2 (N = XX) 


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Safety set (N = xx) 
Days to Most Extreme Value and Magnitude of Nadir for Laboratory Parameters of Interest With Grade 
3 or 4 Abnormalities, or with moderate or severe renal impairment (for creatinine clearance) that 
Worsened from baseline by at Least One Grade or level of impairment (for creatinine clearance)  
Parameter 
Cycle 
Group 
Days to Nadira 
 
Value for Nadir 
Nb 
Mean 
(SD) 
Median 
(Min, 
Max) 
 
Nb 
Mean 
(SD) 
Median 
(Min, 
Max) 
Haemoglobin 
high (g/L) 
1 
Arm1 
 
 
 
 
 
Arm2 
 
 
 
 
… 
 
 
 
 
 
All 
Arm1 
 
 
 
 
 
Arm2 
 
 
 
Haemoglobin 
low (g/L) 
1 
Arm1 
 
 
 
 
 
Arm2 
 
 
 
 
… 
 
 
 
 
 
All 
Arm1 
 
 
 
 
 
Arm2 
 
 
 
Neutrophils 
(10E9/L) 
1 
Arm1 
 
 
 
 
 
Arm2 
 
 
 
 
… 
 
 
 
 
 
All 
Arm1 
 
 
 
 
 
Arm2 
 
 
 
a Days reflect cycle days (from start of cycle indicated) for cycles 1 - 4 and study days (from start of cycle 1) for All cycles. 
b Patients with a Grade 3 or 4 value, or with moderate or several renal impairment (for creatinine clearance),  recorded any time 
after first dose that worsened from baseline by at least one grade, or level of impairment (for creatinine clearance)  (or had a 
missing baseline). In the event a patient had the same nadir at multiple times for a cycle, the first occurrence was selected. 
 


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Safety set (N = xx) 
Days to Most Extreme Value and Magnitude of Nadir for Laboratory Parameters of Interest With Grade 
3 or 4 Abnormalities, or with moderate or severe renal impairment (for creatinine clearance) that 
Worsened from baseline by at Least One Grade or level of impairment (for creatinine clearance)  
Parameter 
Cycle 
Group 
Days to Nadira 
 
Value for Nadir 
Nb 
Mean 
(SD) 
Median 
(Min, 
Max) 
 
Nb 
Mean 
(SD) 
Median 
(Min, 
Max) 
Platelets 
(10E9/L) 
1 
Arm1 
 
 
 
 
 
Arm2 
 
 
 
 
… 
 
 
 
 
 
All 
Arm1 
 
 
 
 
 
Arm2 
 
 
 
Leukocytis 
 (10E9/L) 
1 
Arm1 
 
 
 
 
 
Arm2 
 
 
 
 
… 
 
 
 
 
 
All 
Arm1 
 
 
 
 
 
Arm2 
 
 
 
Bilirubin 
(µmol/L) 
1 
Arm1 
 
 
 
 
 
Arm2 
 
 
 
 
 
 
… 
 
 
 
 
 
All 
Arm1 
 
 
 
 
 
Arm2 
 
 
 
ASAT 
(IU/L) 
1 
Arm1 
 
 
 
 
 
Arm2 
 
 
 
 
… 
 
 
 
 
 
All 
Arm1 
 
 
 
 
 
Arm2 
 
 
 
ALAT 
(IU/L) 
1 
Arm1 
 
 
 
 
 
Arm2 
 
 
 
 
… 
 
 
 
 
 
All 
Arm1 
 
 
 
 
 
Arm2 
 
 
 
Creatinine 
clearance 
(mL/min) 
1 
Arm1 
 
 
 
 
 
Arm2 
 
 
 
 
… 
 
 
 
 
 
All 
Arm1 
 
 
 
 
 
Arm2 
 
 
 
Serum 
creatinine 
(mmol/L) 
1 
Arm1 
 
 
 
 
 
Arm2 
 
 
 
 
… 
 
 
 
 
 
All 
Arm1 
 
 
 
 
 
Arm2 
 
 
 
a Days reflect cycle days (from start of cycle indicated) for cycles 1 - 4 and study days (from start of cycle 1) for All cycles. 
b Patients with a Grade 3 or 4 value, or with moderate or several renal impairment (for creatinine clearance),  recorded any time 
after first dose that worsened from baseline by at least one grade, or level of impairment (for creatinine clearance)  (or had a 
missing baseline). In the event a patient had the same nadir at multiple times for a cycle, the first occurrence was selected. 
 
 
 


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Safety set (N = xx) 
Recovery from the most extreme value for laboratory parameters of interest with grade 3 or 4 
abnormalities, or moderate or severalimpairment (for creatinine clearance) that worsened from baseline 
by at least one grade or level of impairment (for creatinine clearance)  
Parameter 
Group 
Grade 3 or 4 
Na 
Patients with non-
censored data 
n (%)b 
Days to recovery: 
Median(min,max)c 
Haemoglobin high (g/L) 
Arm 1 
 
 
 
Arm 2 
 
 
 
 
 
Haemoglobin low (g/L) 
Arm 1 
 
 
 
Arm 2 
 
 
 
Neutrophils (10E9/L) 
Arm 1 
 
 
 
Arm 2 
 
 
 
Platelets 
(10E9/L) 
Arm 1 
 
 
 
Arm 2 
 
 
 
Low WBC 
 (10E9/L) 
Arm 1 
 
 
 
Arm 2 
 
 
 
Bilirubin 
(µmol/L) 
Arm 1 
 
 
 
Arm 2 
 
 
 
ASAT 
(IU/L) 
Arm 1 
 
 
 
Arm 2 
 
 
 
ALAT 
(IU/L) 
Arm 1 
 
 
 
Arm 2 
 
 
 
Creatinine clearance 
(mL/min) 
Arm 1 
 
 
 
Arm 2 
 
 
 
Serum creatinine 
(mmol/L) 
Arm 1 
 
 
 
Arm 2 
 
 
 
 
a Patients with a Grade 3 or 4 value, or with moderate or several renal impairment(for creatinine clearance), recorded any time after 
first dose that worsened from baseline by at least one grade, or level of impairment(for creatinine clearance) (or had a missing 
baseline). 
 
b Non-censored = patients who recovered (had a least one measurement recorded after the nadir that had grade <2 or <= the 
 
baseline grade, or that had mild or normal renal impairment (for creatinine clearance)). 
 
c Median days are obtained from Kaplan-Meier estimates that allows for inclusion of patients that did not recover (censored at last 
 
subsequent values recorded). Minimum and Maximum values may come from actual observed recovery times or from 
censoredobservations. 
 
 


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4.5. Vital signs and clinical examination 
Vital signs - Safety Set (N = xx)  
ECOG - Descriptive statistics at baseline 
 
 
Arm 1 
(N = xx) 
Arm 2 
(N = xx) 
ALL 
(N = xx) 
BASELINE 
Nobs  
 
 
 
0 
n (%)  
 
 
 
1 
n (%)  
 
 
 
2 
n (%)  
 
 
 
3 
n (%)  
 
 
 
4 
n (%)  
 
 
 
 
For the following 2 tables: 
­ (*): SBP (mmHg), DBP (mmHg), Heart rate (bpm) / Weight (kg) / BSA (m²),  
Temperature (°C), Respiratory rate (breaths/min). 
 
Vital signs - Safety Set (N = xx)  
(*) - Descriptive statistics under treatment 
 
 
Arm 1 
(N = xx) 
Arm 2 
(N = xx) 
ALL 
(N = xx) 
BASELINE 
Nobs  
 
 
 
Mean ± SD  
 
 
 
Median  
 
 
 
Q1 ; Q3  
 
 
 
Min ; Max  
 
 
(*) 
  
 
 
 
Level 1 
  
 
 
 
Level 2 
  
 
 
 
..... 
  
 
 
 
Level k 
  
 
 
 
  
 
 
WORST (lowest 
value) 
Nobs  
 
 
 
Mean ± SD  
 
 
 
Median  
 
 
 
Q1 ; Q3  
 
 
 
Min ; Max  
 
 
(*) 
  
 
 
 
LEVEL 1 
n (%)  
 
 
 
LEVEL 2 
n (%)  
 
 
 
..... 
  
 
 
 
LEVEL K 
n (%)  
 
 
 
  
 
 
WORST (highest 
value) 
Nobs  
 
 
 
Mean ± SD  
 
 
 
Median  
 
 
 
Q1 ; Q3  
 
 
 
Min ; Max  
 
 
(*) 
  
 
 
 
Level 1 
n (%)  
 
 
 
Level 2 
n (%)  
 
 
 
..... 
  
 
 
 
Level k 
n (%)  
 
 
(**): for SBP, DBP and Heart rate only 
 


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Vital signs - Safety Set (N = xx) 
(*) - Descriptive statistics on change from baseline to worst value under treatment 
 
Arm 1 
(N = xx) 
Arm 2 
(N = xx) 
ALL 
(N = xx) 
WORST 
(lowest) 
- 
BASELINE 
Nobs  
 
 
 
Mean ± SD   
 
 
 
Median  
 
 
 
Q1 ; Q3   
 
 
 
Min ; Max   
 
 
 
  
 
 
WORST 
(highest) 
- 
BASELINE 
Nobs  
 
 
 
Mean ± SD   
 
 
 
Median  
 
 
 
Q1 ; Q3   
 
 
 
Min ; Max   
 
 
 
 
For the following table: 
­ (*): SBP (mmHg) / DBP (mmHg) / Heart rate (bpm) / ECOG 
 
Vital signs - Safety set (N = xx) 
(*) - Descriptive statistics on worst value according to baseline by classes 
ALL or Arm 1 or Arm 2 (N = xx) 
 
Worst 
LEVEL 1 
LEVEL 2 
.... 
LEVEL K 
All 
BASELINE 
LEVEL 1 
n (%) 
 
 
 
 
LEVEL 2 
 
 
 
 
 
... 
 
 
 
 
 
LEVEL K 
 
 
 
 
 
Missing 
 
 
 
 
 
All 
 
 
 
 
Nobs (100%) 
Worst: Worst post-baseline value under treatment  
Worst lowest and worst highest for SBP, DBP and Heart rate 
Nobs = Total number of patients with at least one post-baseline value under treatment 
 
 
 
 
 
 
 
 
 
 
 


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4.6. Electrocardiogram 
 
ECG - Safety Set (N = xx)  
Descriptive statistics at withdrawal visit 
 
Arm 1 
(N = xx) 
Arm 2 
(N = xx) 
ALL 
(N = xx) 
PRESENCE OF CLINICALLY SIGNIFICANT 
ECG ABNORMALITY 
n (%)  
 
 
 
  
 
 
RR interval (msec) 
Nobs    
 
 
   ≤ 450 ms  
n (%)    
 
 
   ]450;480 ms] 
n (%)    
 
 
   ]480;500 ms] 
n (%)    
 
 
   > 500 ms 
n (%)    
 
 
 
  
 
 
ABSOLUTE PROLONGATION OF 
UNCORRECTED QT 
  
 
 
 
≤ 450 ms  
n (%)  
 
 
 
]450;480 ms] 
n (%)  
 
 
 
]480;500 ms] 
n (%)  
 
 
  > 500 ms 
n (%)  
 
 
 
  
 
 
CHANGE OF UNCORRECTED QT 
  
 
 
 
≤ 30  ms 
n (%)  
 
 
 
]30;60] ms 
n (%)  
 
 
 
> 60 ms 
n (%)  
 
 
 
 
 
ECG - Safety Set (N = xx)  
List of clinically significant ECG abnormalities at withdrawal visit 
Arm 
Patient 
Cycle 
Analysis date 
Analysis value 
Clinically significant 
ECG abnormalies? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.7. LVEF 
Not applicable. 
 
 
 
 
 
 
 
 
 
 
 
 
 


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5. QOL 
Quality of life – Quality of life Set 30 (N = xx) – QLQ-C30 
Response time from 1st intake to each timepoint 
Timepoint 
  
Arm 1 
(N = xx) 
Arm 2 
(N = xx) 
All 
(N = xx) 
Baseline 
Nobs   
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
12 weeks 
Nmissing 
 
 
 
 
Nnon evaluable 
 
 
 
 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
24 weeks  
Nmissing 
 
 
 
 
Nnon evaluable 
 
 
 
 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
 
 
 
 
….. 
Nmissing 
 
 
 
 
Nnon evaluable 
 
 
 
 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
* Analyses are done on evaluable questionnaires (more than 2/3 of the questions answered at the 
timepoint) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Quality of life – Quality of life Set 29 (N = xx) – QLQ-C29 
Response time from 1st intake to each timepoint 
Timepoint 
  
Arm 1 
(N=xx) 
Arm 2 
(N=xx) 
All 
(N=xx) 
Baseline 
Nobs   
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
12 weeks 
Nmissing 
 
 
 
 
Nnon evaluable 
 
 
 
 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
24 weeks  
Nmissing 
 
 
 
 
Nnon evaluable 
 
 
 
 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
 
 
 
 
….. 
Nmissing 
 
 
 
 
Nnon evaluable 
 
 
 
 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
* Analyses are done on evaluable questionnaires (more than 2/3 of the questions answered at the 
timepoint) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Quality of life – Quality of life Set 30 (N = xx) – QLQ-C30 
Descriptive statistics of the score at baseline 
  
  
Arm 1 
(N = xx) 
Arm 2 
(N = xx) 
All 
(N = xx) 
Global health status (QL2)  
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
  
    
 
 
 
Physical functioning (PF2) 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
  
    
 
 
 
Role functioning (RF2) 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
  
    
 
 
 
Emotional functioning (EF) 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
  
    
 
 
 
Cognitive functioning (CF)  
 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
Social functioning (SF)  
  Nevaluable*  
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
Fatigue 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
Nausea and vomiting 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
*Analyses are done on evaluable questionnaires (more than 2/3 of the questions answered 
at the timepoint) 


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Quality of life – Quality of life Set 30 (N = xx) – QLQ-C30 
Descriptive statistics of the score at baseline (Cont’d) 
  
  
Arm 1 
(N = xx) 
Arm 2 
(N = xx) 
All 
(N = xx) 
Pain 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
Dyspnoea 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
Insomnia 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
Appetite loss 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
Constipation 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
Diarrhoea 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
Financial difficulties 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
* Analyses are done on evaluable questionnaires (more than 2/3 of the questions 
answered at the timepoint) 
 
 
 
 
 
 
 
 


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Quality of life – Quality of life Set 29 (N = xx) – QLQ-CR29 
Descriptive statistics of the score at baseline 
  
  
Arm 1 
(N = xx) 
Arm 2 
(N = xx) 
All 
(N = xx) 
Body image 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
Anxiety 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
Sexual function men 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
Sexual function women 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
Urinary frequency 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
Blood and mucus in stool 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
Stool frequency 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
Urinary incontinence 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
*Analyses are done on evaluable questionnaires (more than 2/3 of the questions answered at the 
timepoint) 


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Quality of life – Quality of life Set 29 (N = xx) – QLQ-CR29 
Descriptive statistics of the score at baseline (Cont’d) 
  
  
Arm 1 
(N = xx) 
Arm 2 
(N = xx) 
All 
(N = xx) 
Dysuria 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
Abdominal pain 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
Buttock pain  
 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
Bloated feeling 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
Dry mouth 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
Hair loss 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
Trouble with taste 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
Weight 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
*Analyses are done on evaluable questionnaires (more than 2/3 of the questions answered at the 
timepoint) 


S 95005  
CL2-95005-002 - TLG attached to the SAP Final Version 3.0 
 
® I.R.I.S. 21 March 2018 - Confidential 
  87/94 
 
Quality of life – Quality of life Set 29 (N = xx) – QLQ-CR29 
Descriptive statistics of the score at baseline (Cont’d) 
  
  
Arm 1 
(N = xx) 
Arm 2 
(N = xx) 
All 
(N = xx) 
Flatulence 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
Faecal incontinence 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
Sore skin 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
Embarrassed by bowel movement Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
Stoma care problems 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
Impotence 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
Dyspareunia 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
*Analyses are done on evaluable questionnaires (more than 2/3 of the questions answered at the 
timepoint) 
 
 
 
 
 
 
 


S 95005  
CL2-95005-002 - TLG attached to the SAP Final Version 3.0 
 
® I.R.I.S. 21 March 2018 - Confidential 
  88/94 
 
Quality of life – Quality of life Set 30 (N = xx) – QLQ-C30 
Change of the score from baseline to (*) 
  
  
Arm 1 
(N = xx)   
Arm 2 
(N = xx)   
All 
(N = xx)    
Global health status (QL2)  
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
  
    
 
 
 
Physical functioning (PF2) 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
  
    
 
 
 
Role functioning (RF2 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
  
    
 
 
 
Emotional functioning (EF) 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
  
    
 
 
 
Cognitive functioning (CF)  
 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
Social functioning (SF)  
   Nevaluable*  
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
Fatigue 
   Nevaluable*  
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
Nausea and vomiting 
   Nevaluable*  
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 


S 95005  
CL2-95005-002 - TLG attached to the SAP Final Version 3.0 
 
® I.R.I.S. 21 March 2018 - Confidential 
  89/94 
 
Quality of life – Quality of life Set 30 (N = xx) – QLQ-C30 
Change of the score from baseline to (*) (Cont’d) 
  
  
Arm 1 
(N = xx)   
Arm 2 
(N = xx)   
All 
(N = xx)    
 
 
 
 
 
Pain 
   Nevaluable*  
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
Dyspnoea 
   Nevaluable*  
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
Insomnia 
   Nevaluable*  
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
Appetite loss 
   Nevaluable*  
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
Constipation 
   Nevaluable*  
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
Diarrhoea 
   Nevaluable*  
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
Financial difficulties 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
(*) timepoint = xxxx / yyyy / … 
*Analysis are done on evaluable questionnaires (more than 2/3 of the questions answered 
at the timepoint) 
 
 
 
 


S 95005  
CL2-95005-002 - TLG attached to the SAP Final Version 3.0 
 
® I.R.I.S. 21 March 2018 - Confidential 
  90/94 
 
Quality of life – Quality of life Set 29 (N = xx) – QLQ-CR29 
Change of the score from baseline to (*) 
  
  
Arm 1 
(N = xx) 
Arm 2 
(N = xx) 
All 
(N = xx) 
Body image 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
Anxiety 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
Sexual function men 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
Sexual function women 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
Urinary frequency 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
Blood and mucus in stool 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
Stool frequency 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
(*) timepoint =  / xxxx / yyyy / … 
*Analysis are done on evaluable questionnaires (more than 2/3 of the questions answered 
at the timepoint) 
 
 
 


S 95005  
CL2-95005-002 - TLG attached to the SAP Final Version 3.0 
 
® I.R.I.S. 21 March 2018 - Confidential 
  91/94 
 
Quality of life – Quality of life Set 29 (N = xx) – QLQ-CR29 
Change of the score from baseline to (*) (Cont’d) 
  
  
Arm 1 
(N = xx) 
Arm 2 
(N = xx) 
All 
(N = xx) 
Urinary incontinence 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
Dysuria 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
Abdominal pain 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
Buttock pain  
 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
Bloated feeling 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
Dry mouth 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
Hair loss 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
(*) timepoint =  / xxxx / yyyy / … 
*Analysis are done on evaluable questionnaires (more than 2/3 of the questions answered 
at the timepoint) 
 
 
 


S 95005  
CL2-95005-002 - TLG attached to the SAP Final Version 3.0 
 
® I.R.I.S. 21 March 2018 - Confidential 
  92/94 
 
Quality of life – Quality of life Set 29 (N = xx) – QLQ-CR29 
Change of the score from baseline to (*) (Cont’d) 
  
  
Arm 1 
(N = xx) 
Arm 2 
(N = xx) 
All 
(N = xx) 
Trouble with taste 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
Weight 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
Flatulence 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
Faecal incontinence 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
Sore skin 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
Embarrassed by bowel movement Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
Stoma care problems 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
(*) timepoint =  / xxxx / yyyy / … 
*Analysis are done on evaluable questionnaires (more than 2/3 of the questions answered 
at the timepoint) 
 
 
 


S 95005  
CL2-95005-002 - TLG attached to the SAP Final Version 3.0 
 
® I.R.I.S. 21 March 2018 - Confidential 
  93/94 
 
Quality of life – Quality of life Set 29 (N = xx) – QLQ-CR29 
Change of the score from baseline to (*) (Cont’d) 
  
  
Arm 1 
(N = xx) 
Arm 2 
(N = xx) 
All 
(N = xx) 
Impotence 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
Dyspareunia 
Nevaluable* 
 
 
 
 
Mean ± SD   
 
 
 
 
Median   
 
 
 
 
Q1 ; Q3   
 
 
 
 
Min ; Max   
 
 
 
 
 
 
 
 
(*) timepoint =  / xxxx / yyyy / … 
*Analysis are done on evaluable questionnaires (more than 2/3 of the questions answered 
at the timepoint) 
 
 
­ Scales of QLQ-30: 
 (*) Global health status (QL2), Physical functioning (PF2), Role functioning (RF2), 
Emotional functioning(EF), Cognitive functioning (CF), Social functioning (SF) , 
Fatigue, Nausea and vomiting, Pain, Dyspnoea, Insomnia, Appetite loss, Constipation, 
Diarrhoea, Financial difficulties scores. 
 
Quality of life – Quality of life Set 30 (N = xx) – QLQ-C30 
Mean change of the score from baseline to each timepoint 
(*) 
 
Analysis are done on evaluable questionnaires (more than 2/3 of the questions answered at the timepoint) 
 
 
-100
-80
-60
-40
-20
0
20
40
60
80
100
Baseline
12 weeks
24 weeks
36 weeks
Xx weeks
Change of the score from baseline 


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CL2-95005-002 - TLG attached to the SAP Final Version 3.0 
 
® I.R.I.S. 21 March 2018 - Confidential 
  94/94 
 
­ Scales of QLQ-29 
 (*) Body image, Anxiety, Sexual function men, Sexual function women, 
Urinary frequency, Blood  and mucus in stool, Stool frequency, Urinary incontinence, 
Dysuria, Abdominal pain, Buttock pain, Bloated feeling, Dry mouth, Hair loss, 
Trouble with taste, Weight, Flatulence, Faecal incontinence, Sore skin, Embarrassed by 
bowel movement, Stoma care problems, Impotence, Dyspareunia. 
 
Quality of life – Quality of life Set 29 (N = xx) – QLQ-C29 
Mean change of the score from baseline to each timepoint 
(*) 
 
Analysis are done on evaluable questionnaires (more than 2/3 of the questions answered at the timepoint) 
 
 
 
 
-100
-80
-60
-40
-20
0
20
40
60
80
100
Baseline
12 weeks
24 weeks
36 weeks
Xx weeks
Change of the score from baseline