Conditions: Refractory Metastatic Colorectal Cancer
Keywords: trifluridine/tipiracil/lonsurf TAS102 bevacizumab avastin RAS status (wild type, mutant)
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 492
Healthy volunteers: no

Brief summary:
This study is designed as an international, open-label, controlled two-arm, randomized phase III comparison study evaluating the efficacy and safety of trifluridine/tipiracil in combination with bevacizumab versus trifluridine/tipiracil monotherapy in patients with refractory mCRC.

Detailed description:
This is an international, open-label, controlled two-arm, randomised phase III study evaluating the efficacy and safety of trifluridine/tipiracil in combination with bevacizumab versus trifluridine/tipiracil monotherapy in patients with refractory mCRC. The analysis will be done after 331 events are reported. In order to observe this number of events, 490 patients will be randomised (1:1) to receive trifluridine/tipiracil in combination with bevacizumab (experimental arm) or trifluridine/tipiracil monotherapy (control arm).

Arms:
arm 1: Participants were administered 35 milligrams per square meter per dose (mg/m²/dose) trifluridine/tipiracil (FTD/TPI) orally twice a day (BID), within 1 hour after completion of morning and evening meals, 5 days on (Day 1 to 5 and Day 8 to 12) with 2 days off (Day 6 to 7 an Day 13 to 14), over 2 weeks, followed by a 14-day rest; with bevacizumab (5 milligrams per kilogram \[mg/kg\], intravenous \[IV\] infusion administered every 2 weeks (Day 1 and Day 15). This treatment cycle was repeated every 4 weeks. arm 2: Participants were administered 35 mg/m²/dose of FTD/TPI orally BID, within 1 hour after completion of morning and evening meals, 5 days on (Day 1 to 5 and Day 8 to 12) with 2 days off (Day 6 to 7 and Day 13 to 14), over 2 weeks, followed by a 14-day rest. This treatment cycle was repeated every 4 weeks.

Interventions: intervention 1: Trifluridine/Tipiracil intervention 2: Bevacizumab
Intervention descriptions: intervention 1: Taken by mouth two times a day, 5 days on/2 days off, over 2 weeks, followed by a 14-day rest intervention 2: administered every 2 weeks (Day 1 and Day 15)

Protocol document:
Prot_000.pdf: 
 
 
 
 
Document title 
AMENDED CLINICAL STUDY PROTOCOL 
Study official title 
An 
open-label, 
randomised, 
phase III 
study 
comparing 
trifluridine/tipiracil in combination with bevacizumab to 
trifluridine/tipiracil monotherapy in patients with refractory 
metastatic colorectal cancer (SUNLIGHT study) 
Study brief title 
Phase III study of trifluridine/tipiracil in combination with 
bevacizumab vs trifluridine/tipiracil single agent in patients with 
refractory metastatic colorectal cancer 
Study public title 
A study of trifluridine/tipiracil and bevacizumab in patients with 
resistant colorectal cancer that has spread (metastatic)  
Test drug code 
Trifluridine/tipiracil (also known as S 95005 or TAS-102) 
Indication(s) 
Refractory metastatic colorectal cancer  
Development phase 
Phase III 
Protocol code 
CL3-95005-007 
EudraCT Number 
2020-001976-14 
Universal Trial Number Not applicable 
Investigational New Drug 
Application Number 
 
Sponsor 
Institut de Recherches Internationales Servier (I.R.I.S.) (outside 
the U.S.) 
Taiho Oncology, Inc. (TOI) (in the U.S.)  
International 
Coordinator 
 
 
  
 
  
Date of the document 
30 December 2020 
Version of the document Final version 
Version number 
2.0 
 
*.&::::::_ 
I.R.I.S. 
------:::- SERVIER 
Institut de Recherches Intemationales Servier 
.Siege oocial - 50, rue Camot - 92284 Suresnes cedex - France - Tel. 01.55. 72.60.00 - w,,-w.5'efVier.com 
S~.\R.L. au capital de 7.895 euros• 319 416 756 RCS Naoferre 
CCI
PPD


Trifluridine/tipiracil 
Clinical study protocol no. CL3-95005-007 – Final version 
© I.R.I.S / TOI – 30 Dec 2020 - Confidential 
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Substantial 
Amendment(s) 
integrated 
No 
Final version date 
Countries concerned 
1.0 
30 Dec 2020 
ALL 
CONFIDENTIAL 
I 
I 


Trifluridine/tipiracil 
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VERSION LIST 
Protocol 
No 
Substantial 
amendment 
No 
Final version 
date 
Countries 
concerned 
Nature of modifications 
1.0 
NA 
10 June 2020 
ALL 
Not Applicable 
1.1 
NA 
12 Oct 2020 
FRA 
See Appendix 9 
1.2 
NA 
05 Nov 2020  
ITA, DNK, 
DEU 
See Appendix 10 
2.0 
1 
30 Dec 2020 
ALL 
- This multinational study will be
conducted under the sponsorship of
Taiho Oncology, Inc. (TOI) for
sites in the U.S.
- New exclusion criteria for patients
with 
uncontrolled 
hypertension,
patients with history of any life-
threatening VEGF related adverse
event and patients with proteinuria
- Clarification on the inclusion criteria
4
- Clarification on the definition of the
end of study.
- Change of the time window to
perform the tumour assessment
- Baseline ECG obtained prior to
patient signed ICF may be used if the
date of ECG is within 28 days of
randomisation.
-
Clarification 
in 
the 
IMP
management section
- Clarification in the reasons for
discontinuation 
and 
restart 
of
treatment period, in case of COVID-
19 infection.
-
Clarification 
on 
follow-up
procedures in case of withdrawal of
consent.
- Clarification on the certification of
the scales to be used during the study.
- Correction of the definition of
overdose.
- Clarification in the section 8.7
Definition of Events requiring an
immediate notification (ERIN)
- Clarification on the reporting of fatal
events 
occurring 
between 
ICF
signature and IMP administration


Trifluridine/tipiracil 
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- Minor precisions in statistical and
safety parts of the protocol.
- Minor modifications in section 14.
Data handling included archiving of
patient’s data from 15 years to 25
years.
-
Clarifications on data sharing
section
- Addition of US Product Information
in appendix 7


Trifluridine/tipiracil 
Clinical study protocol no. CL3-95005-007 – Final version 
© I.R.I.S / TOI – 30 Dec 2020 - Confidential 
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SYNOPSIS 
Name of the sponsor: 
I.R.I.S. (outside U.S.)/TOI (in U.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, phase III study comparing trifluridine/tipiracil in combination with 
bevacizumab to trifluridine/tipiracil monotherapy in patients with refractory metastatic colorectal cancer 
Protocol No.: CL3-95005-007 
Study Brief Title: Phase III study of trifluridine/tipiracil in combination with bevacizumab vs 
trifluridine/tipiracil single agent in patients with refractory metastatic colorectal cancer 
Study Public Title: A study of trifluridine/tipiracil and bevacizumab in patients with resistant colorectal cancer 
that has spread (metastatic) 
Steering Committee Chairman:
 
Study centre(s): 
Total number of countries: approximately 10-12 
Total number of centres: approximately 100-110 
Study period: 
­ Study duration for the patient: approximately 4 months of treatment + follow-up
period for survival 
­ Study initiation date (planned date of first visit first patient): approximately Q4 2020 
­ Study completion date (19 months after the first IMP intake of the last patient
randomised): approximately Q2 2023 
Study development 
phase:  
Phase III 
Objectives / Endpoints: 
Primary 
­ To demonstrate the superiority of trifluridine/tipiracil in combination with bevacizumab over
trifluridine/tipiracil monotherapy in terms of Overall Survival (OS) in patients with refractory metastatic 
colorectal cancer (mCRC). 
Secondary 

Progression-free survival (PFS)

Overall response rate (ORR)

Disease control rate (DCR)

Safety and tolerability

Quality of life (QoL)
Methodology: 
This is an international, open-label, controlled two-arm, randomised phase III comparison study evaluating the 
efficacy and safety of trifluridine/tipiracil in combination with bevacizumab versus trifluridine/tipiracil 
monotherapy in patients with refractory mCRC. 
Patients will be randomly assigned in a (1:1) ratio to receive trifluridine/tipiracil plus bevacizumab (experimental 
arm) or trifluridine/tipiracil as monotherapy (control arm). Randomisation will take place once the consented 
patient has completed all the necessary baseline procedures and deemed eligible for study entry. Treatment 
assignment will be done centrally via an Interactive Web Response System (IWRS) stratified by:   

Geographic region (North America, European Union, Rest of the World)

Time since diagnosis of first metastasis (<18 months, ≥18 months)

RAS status (wild type, mutant)
Number of included patients: 
Planned: 490 patients (245 patients in the trifluridine/tipiracil + bevacizumab arm and 245 patients in the 
trifluridine/tipiracil monotherapy arm). 
PPD


Trifluridine/tipiracil 
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Name of the sponsor: 
I.R.I.S. (outside U.S.)/TOI (in U.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: 
Number of primary events: 
Expected: 331 events (deaths) are required for the main analysis. 
Diagnosis and main criteria for inclusion: 
Inclusion criteria: 
Demographic characteristics 
1.
Male or female patient aged ≥18 years old at the time of ICF signature (or legal age depending on local
country regulation)
Medical and therapeutic criteria 
2.
Has histologically confirmed unresectable adenocarcinoma of the colon or rectum (all other histological 
types are excluded)
3.
RAS status must have been previously determined (mutant or wild-type) based on local assessment of
tumour biopsy
Wild type is defined as KRAS (exon 2, 3 and 4) and NRAS (exon 2, 3 and 4) wild type.
Mutant is defined as at least KRAS or NRAS mutant (any exon, any mutation).
4.
Has received a maximum of 2 prior chemotherapy regimens for the treatment of advanced colorectal
cancer and had demonstrated progressive disease or intolerance to their last regimen
­ 
Prior treatment regimens for the treatment of advanced colorectal cancer must have included a
fluoropyrimidine, irinotecan, oxaliplatin, an anti-VEGF monoclonal antibody and/or an anti-EGFR
monoclonal antibody for RAS wild-type patients
­ 
Patients who have received adjuvant/neoadjuvant chemotherapy and had recurrence during or
within 6 months of completion of the adjuvant/neoadjuvant chemotherapy can count the 
adjuvant/neoadjuvant therapy as one regimen of chemotherapy for advanced disease 
5.
Has measurable or non-measurable disease as defined by RECIST version 1.1
6.
Is able to swallow oral tablets
7.
Estimated life expectancy ≥12 weeks
8.
Has an Eastern Cooperative Oncology Group (ECOG) performance status ≤1. ECOG should remain ≤1 
during all the screening period (from screening visit to randomisation) (Appendix 2).
9.
Has adequate organ function as defined by the following laboratory values obtained within 7 days prior
to randomisation:
- Absolute neutrophil count ≥1.5 x 109/L
- Haemoglobin ≥9 g/dL. In case of blood transfusion, the haemoglobin assessment must be performed
2 weeks or more after the transfusion.
- Platelet count ≥100 x 109/L
- Creatinine clearance ≥50 mL/min, assessed using the Cockcroft & Gault formula (Appendix 4)
- Total serum bilirubin <1.5 x upper limit of normal (ULN) (unless Gilbert disease confirmed)
- Aspartate aminotransferase (AST; SGOT) and alanine aminotransferase (ALT; SGPT) ≤ 2.5 x ULN
(unless if liver function abnormalities are due to underlying liver metastasis, AST (SGOT) and ALT
(SGPT) ≤ 5 x ULN)
- Adequate coagulation function for all patients. For patients receiving anti-coagulant therapy (except
platelet antiaggregates) the adequate therapeutic levels of INR should be confirmed
10. Female of childbearing potential (as defined in Section 5.3) must have been tested negative in a serum
pregnancy test within 7 days prior to randomisation
11. Female of childbearing potential (as defined in Section 5.3) and males with partners of childbearing
potential must agree to use a highly effective method of birth control (as described in Section 5.3), as
well as their partners lasting at least 6 months after the last dose of IMP
Informed consent 
12. Has provided written informed consent obtained prior to any study-specific procedure as described in
Section 13.3.


Trifluridine/tipiracil 
Clinical study protocol no. CL3-95005-007 – Final version 
© I.R.I.S / TOI – 30 Dec 2020 - Confidential 
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Name of the sponsor: 
I.R.I.S. (outside U.S.)/TOI (in U.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: 
Exclusion criteria 
General criteria 
13. More than 2 prior chemotherapy regimens for the treatment of advanced colorectal cancer
14. In the investigator’s opinion, the patient is unlikely to be compliant with the oral medication regimen
or the requirements of the study for scheduled evaluations
15. Pregnancy, lactating female or possibility of becoming pregnant during the study
16. Participation in another interventional study within 4 weeks prior to randomisation. Participation in
study follow-up part without IMP administration, non-interventional registry or epidemiological study
is allowed
17. Patients currently receiving or having received anticancer therapies within 4 weeks prior to
randomisation
18. Already randomised in this study
Medical and therapeutic criteria 
19. Has not recovered from clinically relevant non-hematologic CTCAE grade ≥ 3 toxicity of previous
anticancer therapy prior to randomisation (excluding alopecia, and skin pigmentation)
20. Has symptomatic central nervous system metastases that are neurologically unstable or requiring
increasing doses of steroids to control CNS disease
21. Had major surgery within 4 weeks prior to randomisation (the surgical incision should be fully healed
prior to study drug administration), or has not recovered from side effects of previous surgery, or patient
that may require major surgery during the study
22. In the investigator’s opinion, patient with chronic gastrointestinal disorders that might significantly
interfere with proper absorption of the study treatments
23. Has hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose
malabsorption
24. Has severe or uncontrolled active acute or chronic infection
25. Has active or history of interstitial lung disease and/or pneumonitis, or pulmonary hypertension.
26. Known Hepatitis B Virus infection determined as HBsAg positive and / or known Hepatitis C Virus
infection determined as detection of HCV RNA in serum or plasma by a sensitive quantitative
molecular method
27. Known carriers of HIV antibodies
28. In the investigator’s opinion, uncontrolled diabetes mellitus even under treatment
29a. Confirmed uncontrolled arterial hypertension (defined as systolic blood pressure ≥ 150 mm Hg and/or
diastolic blood pressure ≥ 100 mm Hg) or uncontrolled or symptomatic arrhythmia 
30. Deep arterial thromboembolic events including cerebrovascular accident or myocardial infarction
within the last 6 months prior to randomisation
31. Severe/unstable angina, symptomatic congestive heart failure New York Heart Association (NYHA)
class III or IV (Appendix 3)
32. Drainage for ascites, pleural effusion or pericardial fluid within 4 weeks prior to randomisation
33. Other malignancies including those which were radically treated and for which the remission period at
the time of screening is less than five years. Exemptions for this minimally required duration of
remission period may be applied for carcinoma in situ of the cervix and basal cell skin cancer that are
deemed to be cured by adequate treatment
34. Treatment with systemic immunosuppressive therapy (except steroids given in prophylactic setting or
at a chronic low dose [≤20 mg/day prednisone equivalent])
35. Prior radiotherapy if completed less than 4 weeks before randomisation, except if provided as a short
course for symptoms palliation only. Tumour lesions if previously irradiated may not be chosen as
target lesions for response evaluation


Trifluridine/tipiracil 
Clinical study protocol no. CL3-95005-007 – Final version 
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Name of the sponsor: 
I.R.I.S. (outside U.S.)/TOI (in U.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: 
36. In the investigator’s opinion, any clinically significant medical condition (e.g. organ dysfunction) or
laboratory abnormality likely to jeopardize the patient’s safety or to interfere with the conduct of the
study
Criteria related to trifluridine/tipiracil administration 
37. Has previously received trifluridine/tipiracil
38. History of allergic reactions attributed to compounds of similar composition to trifluridine/tipiracil or
any of its excipients
39. Any contraindication present in the EU Product Information of trifluridine/tipiracil (Appendix 7)
Criteria related to bevacizumab administration 
40. History of allergic reactions or hypersensitivity to bevacizumab or any of its excipients
41. History of hypersensitivity to Chinese Hamster Ovary cell products or other recombinant human or
humanised antibodies
42. Serious non-healing wound, non-healing ulcer or non-healing bone fracture
43. Deep venous thromboembolic event within 4 weeks prior to randomisation
44. Known coagulopathy that increases risk of bleeding, bleeding diatheses. Any other
haemorrhage/bleeding event CTCAE grade ≥ 3 within 4 weeks prior to randomisation
45. Any contraindication present in the EU Product Information of bevacizumab (Appendix 7)
46. History of any life-threatening VEGF-related adverse event
47. Proteinuria ≥ 1 g/24 hours or 2+ by dipstick.
For concomitant medication, refer to Section 6.3 
Test drug: trifluridine/tipiracil + bevacizumab 
Trifluridine/tipiracil (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. 
Comparator: trifluridine/tipiracil 
Trifluridine/tipiracil (35 mg/m²/dose) will be administered orally 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. 
This treatment cycle will be repeated every 4 weeks. 
Duration of treatment: 
Active treatment period: 
Patients will be treated until they meet a discontinuation criterion as described in the Section 5.6.1. Patients will 
be on treatment as long as they continue trifluridine/tipiracil. Bevacizumab monotherapy is not allowed. 
Follow-up period: 
After the withdrawal visit, all treated patients will be followed every 8 weeks: 

for tumour assessment (unless patient had discontinued study treatments for radiologic disease
progression or withdrawal of consent) until radiologic progression regardless of initiation of a new
anticancer therapy,

for survival status until death or until end of the study is reached (whichever occur first).
If a patient is still receiving study medication at the end of the study, please see Section 6.5 for procedures to be 
followed. 
Criteria for evaluation: 
Efficacy measurements: 
Tumour assessments will be performed as per RECIST version 1.1 (Eisenhauer, 2009) at baseline and then every 
2 cycles from C1D1 until radiologic progression or end of study. 
Safety measurements: 
Standard safety monitoring will be performed and adverse events (AEs) will be graded using the National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Event Requiring 


Trifluridine/tipiracil 
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Name of the sponsor: 
I.R.I.S. (outside U.S.)/TOI (in U.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: 
Immediate Notification (ERIN) will be reported up to 30 calendar days after the last IMPs 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. 
Other measurements: 
Quality of life assessments will be performed at baseline, at each cycle and at withdrawal visit using EORTC 
QLQ-C30 (Appendix 5) and EQ-5D-5L (Appendix 6) questionnaires. 
Data Safety Monitoring Board: 
An independent Data Safety Monitoring Board (DSMB) will periodically review and evaluate the safety data 
for patient safety, study conduct and progress and will recommend continuation, discontinuation, or study 
modification. The detailed composition, role, and organization of the DSMB are specified in a separate DSMB 
charter 
Specific COVID-19 situation 
In case of highly suspected COVID-19 infection (based on typical symptoms or typical chest CT scan images) 
or confirmed COVID-19 infection (based on positive COVID-19 biological testing), the study treatment(s) 
should be immediately interrupted. 
The study treatment(s) could be restarted if patient is asymptomatic and a period of at least 15 days after the 
diagnosis has been respected with or without new testing (in case of new testing, the result should be negative). 


Trifluridineltipiracil 
Clinical study protocol no. CLJ-95005-007 - Final version
Contractual signatories 
I, the undersigned, have read the foregoing protocol and the "Participant information and consent form" 
document attached to the protocol and agree to conduct the study in compliance with such documents, Good 
Clinical Practice and the applicable regulatory requirements. 
INVESTIGATOR: 
NAME 
CENTER NUMBER 
DATE 
SIGNATURE 
SPONSOR'S MEDICALLY RESPONSIBLE PERSON 
NAME 
DATE 
SIGNATURE 
 OR DESIGNEE: 
NAME 
 
DATE 
SIGNATURE 
© I.R.l.SITO/-30 Dec 2020 - Confidential 
101113 
PPD
PPD
PPD


Trifluridine/tipiracil 
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Table of contents 
Table of contents ...................................................................................................................... 11 
List of tables ............................................................................................................................. 16 
List of figures ........................................................................................................................... 17 
List of appendices ..................................................................................................................... 18 
List of abbreviations ................................................................................................................. 19 
1. ADMINISTRATIVE STRUCTURE OF THE STUDY ................................................. 21 
2. BACKGROUND INFORMATION ................................................................................. 22 
2.1. Overview of disease pathogenesis, epidemiology and current treatment ....................... 22 
2.2. Trifluridine/tipiracil ........................................................................................................ 22 
2.2.1. Mechanism of action of trifluridine/tipiracil ................................................................ 22 
2.2.2. Clinical data of trifluridine/tipiracil in refractory mCRC (RECOURSE study) .......... 23 
2.3. Trifluridine/tipiracil in combination with bevacizumab ................................................. 24 
2.3.1. Non-clinical data .......................................................................................................... 24 
2.3.2. Clinical data .................................................................................................................. 24 
2.3.2.1. 
Phase I/II C-TASK FORCE study ........................................................................... 24 
2.3.2.2. 
Phase II, the Danish trial .......................................................................................... 25 
2.4. Study design and selection of dose ................................................................................. 25 
2.4.1. Study design ................................................................................................................. 25 
2.4.2. Selection of dose regimens ........................................................................................... 26 
2.4.2.1. 
Experimental arm ..................................................................................................... 26 
2.4.2.2. 
Control arm .............................................................................................................. 26 
3. STUDY OBJECTIVES AND ENDPOINTS ................................................................... 27 
3.1. Primary objective ............................................................................................................ 27 
3.2. Secondary objectives ...................................................................................................... 27 
3.3. Endpoints ........................................................................................................................ 27 
3.3.1. Primary endpoint .......................................................................................................... 27 
3.3.2. Secondary endpoints ..................................................................................................... 27 
4. STUDY DESIGN ............................................................................................................... 28 
4.1. Investigational Plan ......................................................................................................... 28 
4.1.1. Study plan ..................................................................................................................... 28 
4.1.2. Investigation schedule .................................................................................................. 29 
4.2. Measures to minimise bias .............................................................................................. 34 
4.3. Study products and blinding systems.............................................................................. 34 
4.3.1. Products administered .................................................................................................. 34 
4.3.2. IMP management.......................................................................................................... 35 
4.3.2.1. 
Trifluridine/tipiracil ................................................................................................. 37 
4.3.2.2. 
Bevacizumab ............................................................................................................ 37 
4.3.3. Management of blinding systems ................................................................................. 37 
4.4. Discontinuation of the study ........................................................................................... 37 
4.4.1. Premature discontinuation of the study or temporary halt ........................................... 37 
4.4.2. Discontinuation of the study in the event of objective reached .................................... 38 


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4.5. Source data ...................................................................................................................... 38 
5. SELECTION AND WITHDRAWAL OF PARTICIPANTS ........................................ 39 
5.1. Inclusion criteria ............................................................................................................. 39 
5.1.1. Demographic characteristics ........................................................................................ 39 
5.1.2. Medical and therapeutic criteria ................................................................................... 39 
5.1.3. Informed consent .......................................................................................................... 40 
5.2. Exclusion criteria ............................................................................................................ 40 
5.2.1. General criteria ............................................................................................................. 40 
5.2.2. Medical and therapeutic criteria ................................................................................... 40 
5.3. Definition of women of childbearing potential and contraception methods .................. 41 
5.4. Retest management during screening period .................................................................. 42 
5.5. Additional information recorded at the inclusion visit ................................................... 42 
5.6. Participant withdrawal .................................................................................................... 42 
5.6.1. Withdrawal criteria ....................................................................................................... 42 
5.6.2. Procedure ...................................................................................................................... 43 
5.6.3. Lost to follow-up .......................................................................................................... 44 
6. TREATMENT OF PARTICIPANTS .............................................................................. 45 
6.1. IMPs administered .......................................................................................................... 45 
6.1.1. Trifluridine/tipiracil plus bevacizumab arm ................................................................. 45 
6.1.2. Trifluridine/tipiracil monotherapy arm ......................................................................... 45 
6.1.3. Trifluridine/tipiracil administration .............................................................................. 46 
6.1.4. Bevacizumab administration ........................................................................................ 47 
6.2. IMPs dispensing .............................................................................................................. 47 
6.3. Previous and concomitant treatments ............................................................................. 48 
6.3.1. Prohibited treatments .................................................................................................... 48 
6.3.1.1. 
Before the study ....................................................................................................... 48 
6.3.1.2. 
During the study treatment period ........................................................................... 48 
6.3.2. Authorised treatments ................................................................................................... 48 
6.4. IMP compliance .............................................................................................................. 49 
6.5. Discontinuation of the IMP............................................................................................. 49 
7. ASSESSMENT OF EFFICACY ...................................................................................... 50 
7.1. Efficacy measurements ................................................................................................... 50 
7.2. Methods and measurement times .................................................................................... 50 
7.2.1. Measurement times ....................................................................................................... 50 
7.2.2. Method of imaging ....................................................................................................... 50 
7.2.3. Tumour definitions ....................................................................................................... 51 
7.2.3.1. 
Measurable lesions ................................................................................................... 51 
7.2.3.2. 
Non-measurable lesions ........................................................................................... 51 
7.2.3.3. 
Special considerations regarding lesion measurability ............................................ 51 
7.2.4. Documentation of “target” and “non-target” lesions .................................................... 52 
7.2.4.1. 
Target lesions ........................................................................................................... 52 
7.2.4.2. 
Non-target lesions .................................................................................................... 53 
7.2.5. Response criteria .......................................................................................................... 53 
7.2.5.1. 
Target and Non-target Response Assessments ........................................................ 53 


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7.2.5.2. 
New lesions .............................................................................................................. 54 
7.2.5.3. 
Overall Response Assessment ................................................................................. 55 
7.2.6. Best Overall Response Assessment .............................................................................. 55 
8. ASSESSMENT OF SAFETY ........................................................................................... 56 
8.1. Specification of safety parameters .................................................................................. 56 
8.2. Methods and measurement times .................................................................................... 56 
8.2.1. Electrocardiogram (ECG) ............................................................................................. 56 
8.2.2. ECOG Performance Status ........................................................................................... 56 
8.2.3. Height, Vital Signs, Weight.......................................................................................... 56 
8.2.4. Physical Examination ................................................................................................... 57 
8.2.5. Clinical Laboratory Evaluations ................................................................................... 57 
8.2.5.1. 
Haematology ............................................................................................................ 58 
8.2.5.2. 
Biochemistry ............................................................................................................ 58 
8.2.5.3. 
Coagulation .............................................................................................................. 59 
8.2.5.4. 
Urinalysis ................................................................................................................. 59 
8.2.5.5. 
Pregnancy Testing ................................................................................................... 60 
8.3. Definition of Adverse events .......................................................................................... 60 
8.4. Definition of Serious adverse events .............................................................................. 61 
8.5. Definition of Overdose ................................................................................................... 61 
8.6. Definition of Adverse event of special interest .............................................................. 61 
8.7. Definition of Events requiring an immediate notification (ERIN) ................................. 62 
8.8. Classification of an adverse event (seriousness, severity, causality, expectedness) ....... 62 
8.9. Reporting procedures ...................................................................................................... 63 
8.9.1. Time frame for AE reporting ........................................................................................ 63 
8.9.2. Responsibilities of the investigator .............................................................................. 64 
8.9.2.1. 
Documentation of the event ..................................................................................... 64 
8.9.2.2. 
Follow-up of adverse events .................................................................................... 64 
8.9.2.3. 
Special situations (pregnancy, overdoses, intake of IMP by a person around 
the patient) ............................................................................................................... 65 
8.9.2.4. 
Recording methods in the e-CRF ............................................................................ 65 
8.9.2.5. 
Procedure for an event requiring an immediate notification ................................... 65 
8.9.3. Responsibilities of the sponsor ..................................................................................... 66 
8.10. Responsibilities of Data Safety Monitoring Committee ................................................. 67 
8.11. Management of treatment dose adaptations due to toxicities ......................................... 67 
8.11.1. Trifluridine/tipiracil ...................................................................................................... 67 
8.11.2. Bevacizumab ................................................................................................................ 68 
8.12. Recommendations regarding treatment of toxicities ...................................................... 69 
8.12.1. Management of nausea and vomiting ........................................................................... 69 
8.12.2. Management of diarrhoea ............................................................................................. 69 
8.12.3. Management of mucosal injury .................................................................................... 70 
8.12.4. Management of febrile neutropenia and anaemia ........................................................ 70 
9. OTHER ASSESSMENTS NOT SPECIFICALLY RELATED TO EFFICACY
OR SAFETY ...................................................................................................................... 71 
9.1. Assessments done at baseline ......................................................................................... 71 
9.1.1. Assessments related to inclusion criteria. ..................................................................... 71 
9.1.1.1. 
Informed consent ..................................................................................................... 71 


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9.1.1.2. 
Histological/Cytological Confirmation ................................................................... 71 
9.1.1.3. 
RAS status ............................................................................................................... 71 
9.1.2. Assessments not related to inclusion criteria................................................................ 71 
9.1.2.1. 
Patient Numbering ................................................................................................... 71 
9.1.2.2. 
Demography ............................................................................................................ 71 
9.1.2.3. 
Medical history ........................................................................................................ 71 
9.1.2.4. 
Previous surgery, radiotherapy and treatments related to the colorectal cancer ...... 71 
9.1.2.5. 
Baseline Signs and Symptoms ................................................................................. 71 
9.1.2.6. 
Primary tumour localisation .................................................................................... 72 
9.1.2.7. 
BRAF status and MMR/MSI status ......................................................................... 72 
9.2. Measurement of drug concentration ............................................................................... 72 
9.3. Pharmacodynamics measurements ................................................................................. 72 
9.4. Assessment of biomarkers .............................................................................................. 72 
9.5. Quality of Life ................................................................................................................ 72 
10.
STATISTICS ................................................................................................................. 73 
10.1. Statistical analysis ........................................................................................................... 73 
10.1.1. Analysis sets / Treatment groups .................................................................................. 73 
10.1.1.1. Analysis sets ............................................................................................................ 73 
10.1.1.2. Treatment groups ..................................................................................................... 73 
10.1.2. Statistical methods ........................................................................................................ 73 
10.1.2.1. General considerations ............................................................................................. 73 
10.1.2.2. Disposition and baseline characteristics .................................................................. 73 
10.1.2.3. Treatments of patients .............................................................................................. 74 
10.1.2.4. Efficacy analysis ...................................................................................................... 74 
10.1.2.4.1. Primary estimand based on the OS ........................................................................ 75 
10.1.2.4.1.1. Primary analysis .................................................................................................. 76 
10.1.2.4.1.2. Sensitivity analyses ............................................................................................. 76 
10.1.2.4.1.3. Supplementary analyses ...................................................................................... 76 
10.1.2.4.2. Additional estimand based on OS ......................................................................... 77 
10.1.2.4.3. Secondary estimands based on PFS, ORR, and DCR ........................................... 78 
10.1.2.5. Quality of Life analysis ........................................................................................... 79 
10.1.2.6. Safety analysis ......................................................................................................... 80 
10.1.2.6.1. Adverse events ...................................................................................................... 80 
10.1.2.6.2. Clinical laboratory evaluation ............................................................................... 81 
10.1.2.6.3. Vital signs, clinical examination and other observations related to safety ........... 81 
10.1.2.6.3.1. Vital signs and clinical examination ................................................................... 81 
10.1.2.6.3.2. Electrocardiogram ............................................................................................... 81 
10.1.2.7. Biomarkers analysis ................................................................................................. 81 
10.1.2.8. Interim analysis ........................................................................................................ 82 
10.2. Determination of sample size ......................................................................................... 82 
11.
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ........................................ 83 
12.
QUALITY CONTROL AND QUALITY ASSURANCE .......................................... 83 
12.1. Study monitoring ............................................................................................................ 83 
12.1.1. Before the study ............................................................................................................ 83 
12.1.2. During the study ........................................................................................................... 83 


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12.2. Computerised medical file .............................................................................................. 84 
12.3. Audit - Inspection ........................................................................................................... 85 
12.4. Supervisory committees .................................................................................................. 85 
13.
ETHICS ......................................................................................................................... 86 
13.1. Institutional Review Board(s)/Independent Ethics Committee(s) .................................. 86 
13.2. Study conduct ................................................................................................................. 86 
13.3. Participant information and informed consent ................................................................ 86 
13.4. Modification of the information and consent form ......................................................... 86 
14.
DATA HANDLING AND RECORD KEEPING ....................................................... 88 
14.1. Study data ....................................................................................................................... 88 
14.2. Data management ........................................................................................................... 89 
14.3. Archiving ........................................................................................................................ 89 
16.
OWNERSHIP OF THE RESULTS – DATA SHARING POLICY AND
PUBLICATION POLICY ................................................................................................ 90 
17.
ADMINISTRATIVE CLAUSES ................................................................................. 92 
17.1. Concerning the sponsor and the investigators ................................................................ 92 
17.1.1. Persons to inform .......................................................................................................... 92 
17.1.2. Substantial protocol amendment and amended protocol .............................................. 92 
17.1.3. Final study report .......................................................................................................... 92 
17.2. Concerning the sponsor .................................................................................................. 93 
17.3. Concerning the investigator ............................................................................................ 93 
17.3.1. Confidentiality - Use of information ............................................................................ 93 
17.3.2. Organisation of the centre ............................................................................................ 94 
17.3.3. Documentation supplied to the sponsor ....................................................................... 94 
18.
REFERENCES .............................................................................................................. 95 
19.
APPENDICES ............................................................................................................... 97 
CCI


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List of tables 
Table (4.1.2) 1 - Investigation schedule of trifluridine/tipiracil and bevacizumab arm ........... 30 
Table (4.1.2) 2 - Investigation schedule of trifluridine/tipiracil monotherapy arm ................. 32 
Table (4.3.1) 1 - Description of trifluridine/tipiracil ................................................................ 34 
Table (4.3.1) 2 - Description of bevacizumab .......................................................................... 34 
Table (4.3.1) 3 - Description of the packaging of trifluridine/tipiracil .................................... 35 
Table (4.3.1) 4 - Description of the packaging of bevacizumab .............................................. 35 
Table (6.1.3) 1 - Number of tablets of trifluridine/tipiracil per dose (standard dose) 
according to body surface area ................................................................................................. 46 
Table (6.1.3) 2 - Number of tablets of trifluridine/tipiracil per dose (reduced dose) 
according to body surface area ................................................................................................. 47 
Table (7.2.5.1) 1 – Target lesions response definitions ........................................................... 53 
Table (7.2.5.1) 2 – Non-target lesions response definitions ..................................................... 54 
Table (7.2.5.3) 1 - Time point response for patients with target (±non-target) disease ........... 55 
Table (8.2.5.2) 1 - Correspondence between urea and BUN values ........................................ 59 
Table (8.2.5.4) 1 - Correspondence between qualitative and quantitative proteinuria 
values ........................................................................................................................................ 59 
Table (8.11.1) 1 - Dose interruption and resumption criteria for haematological 
toxicities related to myelosuppression ..................................................................................... 67 
Table (8.11.1) 2 - Recommended dose modifications in case of haematological adverse 
event related to myelosuppression ........................................................................................... 68 
Table (8.11.1) 3 - Recommended dose modifications in case of non-haematological 
adverse event related to trifluridine/tipiracil ............................................................................ 68 
Table (9.1.2.6) 1 - Primary tumour localisation ....................................................................... 72 
Table (17.3.3) 1 - Investigation schedule of trifluridine/tipiracil and bevacizumab arm ....... 115 
Table (17.3.3) 2 - Investigation schedule of trifluridine/tipiracil monotherapy arm ............. 115 


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List of figures 
Figure (4.1.1) 1 - Study plan .................................................................................................... 28 
Figure (8.9.1) 1 - Rules for AE reporting ................................................................................. 63 


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List of appendices 
Appendix 1: World Medical Association Declaration of Helsinki .......................................... 98 
Appendix 2: Patient performance status ................................................................................. 104 
Appendix 3: New York Heart Association (NYHA) classification ....................................... 105 
Appendix 4: Cockroft formula (Cockroft et al., 1976) .......................................................... 106 
Appendix 5: EORCT QLQ-C30 ............................................................................................. 107 
Appendix 6: EQ-5D-5L .......................................................................................................... 109 
Appendix 7: Link to trifluridine/tipiracil and bevacizumab Product Information ................. 111 
Appendix 8: DATA PROTECTION / GDPR (General Data Protection Regulation of 27 
April 2016 n°2016/679) ......................................................................................................... 112 


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List of abbreviations 
AE 
: Adverse Event 
ALT 
: Alanine aminotransferase 
AST 
: Aspartate aminotransferase 
bid 
: bis in die (twice a day) 
BRAF 
: v-Raf murine sarcoma viral oncogene homolog B
BSA 
: Body Surface Area 
BSC 
: Best supportive care 
BUN 
: Blood urea nitrogen 
CA 
: Competent Authorities 
CEA 
: Carcinoembryonic antigen 
CI 
: Confidence Interval 
cm 
: Centimetre 
CMP 
: Clinical Monitoring Plan 
CR 
: Complete response 
CRC 
: Colorectal Cancer 
CT 
: Computerized tomography 
CTCAE 
: Common terminology criteria for adverse events 
CV 
: Curriculum Vitae 
DCR 
: Disease control rate 
DNA 
: Deoxyribonucleic acid 
DSMB 
: Data Safety Monitoring board 
EEA 
: European Economic Area 
ECG 
: ElectroCardioGram 
ECOG 
: Eastern Cooperative Oncology Group 
e-CRF
: Electronic Case Report Form 
EGFR
: Epidermal growth factor receptor 
EMA
: European medicine agency 
EORTC
: European organisation for research and treatment of cancer 
e-PRO
: Electronic Patient Reported Outcome 
ERIN 
: Event Requiring Immediate Notification 
FAS 
: Full Analysis Set 
FDA 
: Food and Drug Administration 
FTD 
: Trifluridine 
g 
: Gram 
G/L 
: Giga (109) per litre 
GCP 
: Good Clinical Practice 
G-CSF
: Granulocyte colony-stimulating factor 
GGT 
: Gamma-Glutamyl Transferase (Gamma-Glutamyl 
Transpeptidase) 
HIV 
: Human Immunodeficiency Virus 
HR 
: Hazard Ratio 
I.R.I.S.
: Institut de Recherches Internationales Servier 
ICF 
: Informed consent form 
ICH 
: International Council for Harmonisation 
IEC 
: Independent Ethics Committee 
IMP 
: Investigational Medicinal Product: a pharmaceutical form of an 
active ingredient or placebo being tested or used as a reference 
in a clinical trial (test drug / reference product) 


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INR 
: International normalized ratio 
IRB 
: Institutional Review Board 
IV 
: IntraVenous (route) 
IWRS 
: Interactive web response system 
kg 
: kilogram 
KRAS 
: V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog
L 
: Litre 
LDH 
: Lactate DeHydrogenase 
mCRC 
: Metastatic colorectal cancer 
MedDRA 
: Medical Dictionary for Regulatory Activities 
mg 
: Milligram 
min 
: Minute 
mL 
: Millilitre 
mm 
: Millimetre 
MMR 
: Mismatch repair 
MRI 
: Magnetic resonance imaging 
MSI 
: Microsatellite instability 
MSS 
: Microsatellite stable 
NCCN 
: National comprehensive cancer network 
NCI-CTCAE 
: National Cancer Institute - Common Terminology Criteria for 
Adverse Events 
ng 
: nanogram 
NS 
: Not statistically Significant 
NYHA 
: New York Heart Association 
ORR 
: Overall response rate 
OS 
: Overall Survival 
PET 
: Positron emission tomography 
PD 
: Progression disease 
PFS 
: Progression free survival 
PPS 
: Per Protocol Set 
PR 
: Partial response 
PS 
: Performance status 
QoL 
: Quality of life 
RAS 
: Rat sarcoma viral oncogene homolog 
RECIST 
: Response evaluation criteria in solid tumours 
SAE 
: Serious Adverse Event 
SAP 
: Statistical Analysis Plan 
SD 
: Stable disease 
SGOT 
: Serum glutamo-oxalaczetique transaminase 
SGPT 
: Serum glutamo-pyruvate transaminase 
SS 
: Safety Set 
TOI 
: Taiho Oncology, Inc. 
TP 
: thymidine phosphorylase 
TPI 
: Tipiracil hydrochloride 
ULN 
: Upper Limit of reference range 
VEGF 
: Vascular endothelial growth factor 
WBC 
: White Blood Cells 
WHO 
: World Health Organization 
βHCG 
: Beta human chorionic gonadotropin 


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1.
ADMINISTRATIVE STRUCTURE OF THE STUDY
Non sponsor parties, sponsor parties and Contract Research Organisation responsible for local 
management of the study are described in a separate document entitled Administrative part of 
clinical study protocol. 
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 8.10 and 
12.4. 


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2.
BACKGROUND INFORMATION
2.1. Overview of disease pathogenesis, epidemiology and current treatment 
Over 1.8 million new colorectal cancer (CRC) cases and 881,000 deaths was estimated to occur 
in 2018, accounting for about 1 in 10 cancer cases and deaths. Worldwide, CRC is the third 
most common cancer in terms of incidence but second in terms of mortality. There is a wide 
geographical variation in incidence across the world; incidence rates vary with 8-fold and 6-
fold by world region. The highest rates are found in Europe (e.g., in Hungary, Slovenia, 
Slovakia, the Netherlands, and Norway), in Australia/New Zealand, Northern America, and 
Eastern Asia (Japan and the Republic of Korea, Singapore [in females]) (Globocan, 2018). 
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 (Ayez, 2011) (Van Cutsem, 2010).  
The overall prognosis of patients with metastatic CRC (mCRC) has improved significantly in 
the past decades, and the average survival is 30 months nowadays (Formica, 2015). Although 
some patients with mCRC can be cured through surgical and ablative techniques, the disease 
remains incurable in most cases and there is clearly a need for new therapeutic approaches. 
In patients with unresectable disease, chemotherapy is the mainstay of treatment. Various 
combinations of the drugs may be used for the treatment of these patients at some point during 
the duration of their disease (Van Cutsem, 2014) (NCCN, 2019). The choice of chemotherapy 
is based upon the consideration of the goals of therapy, the type and timing of prior therapies, 
and the differing toxicity profiles of the constituent drugs. Historically, a combined regimen 
containing a fluoropyrimidine formed the backbone of chemotherapy for decades. However, 
the introduction of monoclonal antibodies targeting VEGF receptor and the use of EGFR 
inhibitors for a subset of mCRC patients with RAS wild-type tumours, have shown to 
improve clinical outcomes when combined with chemotherapy (Baldus, 2010). 
An increasing number of patients with mCRC can receive 3 or more lines of therapy (Bekaii-
Saab, 2018). Treatments in this setting include regorafenib (a multitargeted tyrosine kinase 
inhibitor), trifluridine/tipiracil, antibodies that target EGFR for patients with RAS wild-type 
tumours (if no prior exposure), and, where approved, anti-programmed cell death protein 1 
inhibitors for patients with microsatellite instability-high mCRC (Van Cutsem, 2014) (NCCN, 
2019). Clinical trials of emerging agents, new treatment combinations, and novel therapies are 
still needed to continue the efforts to improve outcomes for patients with 
mCRC.VanCutsem2014a 
2.2. Trifluridine/tipiracil 
Detailed information on the nonclinical and clinical experience with trifluridine/tipiracil is 
provided in the Investigator’s Brochure. 
2.2.1. 
Mechanism of action of trifluridine/tipiracil 
Trifludirine/tipiracil, also known as S 95005 or TAS-102 is a combination of an anti-neoplastic 
thymidine-based nucleoside analogue, trifluridine (FTD), and the thymidine phosphorylase 
inhibitor, tipiracil hydrochloride (TPI), at a molar ratio 1:0.5, formulated as two dosage 
strengths of 15 mg/6.14 mg and 20 mg/8.19 mg immediate release film coated tablets. 
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 


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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. 
The antitumour effect was highly correlated with the amount of FTD incorporation into tumour 
DNA, and FTD was preferentially incorporated into DNA of tumour tissues as compared to 
that of normal tissues. FTD was markedly incorporated into DNA compared with 
fluoropyrimidines and other nucleoside analogues. Divided daily dosing enhanced the amounts 
of FTD incorporation into DNA and its antitumour effect. 
This mechanism of action of trifluridine/tipiracil differentiates it from conventional 
fluoropyrimidines, which are uracil-based, and for which the primary mode of action is 
thymidylate synthase inhibition. In nonclinical studies, trifluridine/tipiracil demonstrated 
antitumour activity against both 5-FU sensitive and resistant colorectal cancer cell lines. 
2.2.2. 
Clinical data of trifluridine/tipiracil in refractory mCRC (RECOURSE study) 
Trifluridine/tipiracil was approved as monotherapy for the treatment of adult patients with 
advanced mCRC based on the results from RECOURSE study. 
In this phase III, multinational, randomised, double-blind study (Mayer, 2015), the efficacy and 
safety of trifluridine/tipiracil (35 mg/m² twice daily [BID] on days 1–5 and 8–12 every 28 days) 
plus best supportive care (BSC) was compared to placebo plus BSC in patients with 
histologically confirmed mCRC, who had received prior treatment fluoropyrimidine-, 
oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and an anti-
EGFR therapy when appropriate. The primary efficacy endpoint was overall survival (OS), and 
the supportive secondary endpoint was progression-free survival (PFS). 
A total of 800 patients were randomised (2:1) to receive trifluridine/tipiracil (n=534) or placebo 
(n=266). Patients were stratified by KRAS status (wild-type, mutant); time since diagnosis of 
first metastasis (<18 months, ≥18 months); and geographic region (Japan, Western [United 
States, European Union and Australia]). 
The median OS (mOS) was 7.1 months for the trifluridine/tipiracil group versus 5.3 months 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 trifluridine/tipiracil compared to placebo (HR=0.48, 95% CI: 0.41, 0.57, 
p<0.0001); median PFS (mPFS) was 2.0 months for the trifluridine/tipiracil group versus 1.7 
months for the placebo group. 
In general, results for OS consistently favoured trifluridine/tipiracil across the stratification 
groups and other pre-specified subgroups including age (<65 vs ≥65 years) and Eastern 
Cooperative Oncology Group (ECOG) performance status (0 vs 1). Among all randomised 
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. Among 
these refractory patients, risk reduction in OS with trifluridine/tipiracil remained favourable and 
statistically significant (HR=0.75). 
Among the population evaluable for tumour response (502, trifluridine/tipiracil; 258, placebo) 
there was no difference between the treatment groups with respect to overall response rate 
(ORR) (8 patients with partial response in the trifluridine/tipiracil group; 1 patient with 
complete response in the placebo group). However, there was a substantial difference in the 
percentage of patients with best overall response of stable disease (42.4%, trifluridine/tipiracil; 


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15.9%, placebo) leading to a significant difference in disease control rate (DCR) between the 
trifluridine/tipiracil and placebo groups (27.7%, 95% CI: [21.5, 34.0]; p<0.0001). 
In addition, a statistically significant 34% risk reduction in worsening ECOG performance 
status (time to ECOG performance status ≥2) was observed for trifluridine/tipiracil compared 
to placebo, suggesting that quality of life (QoL) was maintained while on trifluridine/tipiracil 
treatment. 
The most common adverse events (AE) associated with trifluridine/tipiracil treatment were 
bone marrow and gastrointestinal toxicities. Among the 533 patients who received 
trifluridine/tipiracil, 38% had neutropenia of grade ≥3, 4% had febrile neutropenia and 18% 
experienced anaemia of grade ≥3. These events were generally manageable with reductions in 
dose, delays in cycle initiation and occasional use of granulocyte colony-stimulating factor 
(G-CSF). 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 trifluridine/tipiracil 
group (20.1% to 39.4%); however, these AEs were rarely grade 3 or 4. The incidence of 
stomatitis among patients receiving trifluridine/tipiracil was 7.9%; grade 3 or 4 events of 
stomatitis were rare (0.4%). In addition, hand-foot syndrome was reported in only 2.3% of 
patients receiving trifluridine/tipiracil (all grade 1 or 2), which was the same percentage 
reported in the placebo arm. 
As of the cut-off date, the average number of weeks of exposure was 12.7 weeks in 
trifluridine/tipiracil group and 6.8 weeks in placebo group (median of 6.7 weeks and 5.7 weeks, 
respectively). In the trifluridine/tipiracil group, 53 (9.9%) patients had a single dose reduction, 
18 (3.4%) patients had 2 reductions, and 2 (0.4%) patients had 3 reductions (up to 3 dose 
reductions allowed per protocol). 
2.3. Trifluridine/tipiracil in combination with bevacizumab 
2.3.1. 
Non-clinical data 
The antitumour effects of trifluridine/tipiracil in combination with bevacizumab were assessed 
using mice bearing human SW48 (KRAS wild type cell lines) or HCT116 (KRAS mutant cell 
lines) colorectal carcinoma xenograft (Tsukihara, 2015). Trifluridine/tipiracil and bevacizumab 
alone inhibited tumour growth. Combined trifluridine/tipiracil and bevacizumab treatment had 
superior antitumour activity compared to either drug alone, and had no significant effect on the 
body weight compared to trifluridine/tipiracil monotherapy. Moreover, phosphorylated 
trifluridine levels were increased when trifluridine/tipiracil was combined with bevacizumab 
suggesting that bevacizumab increases trifluridine accumulation in tumour DNA. 
2.3.2. 
Clinical data 
Trifluridine/tipiracil in combination with bevacizumab for mCRC refractory to standard 
therapies has previously been evaluated in two separate clinical studies. 
2.3.2.1. 
Phase I/II C-TASK FORCE study 
The C-TASK FORCE is an Investigator Initiated phase I/II study of trifluridine/tipiracil in 
combination with bevacizumab for mCRC refractory to standard therapies conducted in 
Japanese patients (Kuboki, 2017). 
Twenty-five patients were enrolled from February to July 2014 (phase I-part, n=6; phase II-
part, n=19). The recommended phase II dose was determined to be trifluridine/tipiracil 


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35 mg/m²/dose BID on days 1-5 and days 8-12 in combination with bevacizumab 5 mg/kg on 
days 1 and 15, every 4 weeks.  
The centrally assessed PFS rate at 16 weeks in 21 patients in the primary analysis was 42.9% 
(80% CI: 27.8, 59.0%). The mPFS centrally assessed in the 21 patients was: 3.7 months (95% 
CI: 2.0, 5.4). For all 25 patients enrolled, the investigator-assessed PFS at 16 weeks was 60% 
(95% CI: 39, 79) and mPFS by investigator assessment was 5.6 months (95% CI: 3.4, 7.6). The 
mOS (at final cut-off date for analysis) was 11.4 months (95% CI: 7.6, 13.9). 
The most common grade ≥3 AEs above 10% were neutropenia 18 (72%), leukopenia 11 (44%), 
anemia 4 (16%), febrile neutropenia 4 (16%) and thrombocytopenia 3 (12%). Twenty-two 
patients (88%) required a treatment delay, 6 patients (24%) required at least one dose reduction 
(primarily due to neutropenia), and there were no treatment-related deaths. In addition, the 
incidence of hand-foot syndrome among patients treated with trifluridine/tipiracil (2.3%) is 
lower than that commonly observed with fluoropyrimidines including capecitabine. 
2.3.2.2. 
Phase II, the Danish trial 
The Danish trial is an Investigator Initiated, open-label, randomised, phase II study of 
trifluridine/tipiracil in combination with bevacizumab for mCRC refractory to standard 
therapies conducted in Denmark (Pfeiffer, 2020). Patients were enrolled and randomly assigned 
(1:1) to receive trifluridine/tipiracil (35 mg/m² BID on days 1–5 and 8–12 every 28 days) alone 
or combined with bevacizumab (5 mg/kg on days 1 and 15) until progression, unacceptable 
toxicity, or patient decision to withdraw. Randomisation was stratified by institution and RAS 
mutation status. The primary endpoint was investigator-evaluated PFS.  
From August 2017 to October 2018, 93 patients were enrolled and randomly assigned to 
trifluridine/tipiracil (n=47) or trifluridine/tipiracil plus bevacizumab (n=46). The mPFS was 2.6 
months (95% CI: 1.6, 3.5) in the trifluridine/tipiracil group versus 4.6 months (3.5, 6.5) in the 
trifluridine/tipiracil plus bevacizumab group (HR 0.45 [95% CI: 0.29, 0.72]; p=0.0015).  
The most frequent grade ≥3 AEs was neutropenia (18 [38%] of 47 in the trifluridine/tipiracil 
monotherapy group vs 31 [67%] of 46 in the trifluridine/tipiracil plus bevacizumab group). 
Serious AEs were observed in 21 (45%) patients in the trifluridine/tipiracil group and 19 (41%) 
in the trifluridine/tipiracil plus bevacizumab group. Treatment-related serious AEs in the 
trifluridine/tipiracil monotherapy group were (one patient for each) vomiting, obstipation, 
febrile neutropenia, and vomiting, and in the trifluridine/tipiracil plus bevacizumab group were 
febrile neutropenia (three patients) and diarrhoea (one patient). No deaths were deemed 
treatment related. 
2.4. Study design and selection of dose 
2.4.1. 
Study design 
This present study is designed as an international, open-label, controlled two-arm, randomised 
phase III comparison study evaluating the efficacy and safety of trifluridine/tipiracil in 
combination with bevacizumab versus trifluridine/tipiracil monotherapy in patients with 
refractory mCRC.  
Due to the difference between the two arms in term of bevacizumab injection (1 vs 0), this study 
must be performed in open-label. 


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This study aims to demonstrate superior efficacy of trifluridine/tipiracil in combination with 
bevacizumab through a reduction in the risk of death compared to trifluridine/tipiracil 
monotherapy.  
OS is the primary endpoint of the study as recommended by European medicines agency (EMA) 
guideline on the evaluation of anticancer medicinal products in man (EMA, 2017) and by Food 
and Drug Administration (FDA) guideline on the clinical trial endpoints for the approval of 
cancer drugs and biologics guidance for industry (FDA, 2018).  
The study will be conducted in compliance with the protocol, Good Clinical Practice, the ethical 
principles that have their origin in the Declaration of Helsinki (Appendix 1) and the applicable 
regulatory requirements. 
2.4.2. 
Selection of dose regimens 
The recommended starting dose of trifluridine/tipiracil is 35 mg/m²/dose BID as long as benefit 
is observed or until unacceptable toxicity occurs (Appendix 7).  
A bevacizumab regimen of 5 mg/kg is a recommended dose for use in combination with 
fluoropyrimidine-based regimens for treatment of mCRC (Appendix 7). 
2.4.2.1. 
Experimental arm 
Trifluridine/tipiracil 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 administered IV every 2 weeks (day 1 and day 15). This treatment cycle will 
be repeated every 4 weeks.  
2.4.2.2. 
Control arm 
Trifluridine/tipiracil 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. 
This treatment cycle will be repeated every 4 weeks.  


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3.
STUDY OBJECTIVES AND ENDPOINTS
3.1. Primary objective 
The primary objective is to demonstrate the superiority of trifluridine/tipiracil in combination 
with bevacizumab over trifluridine/tipiracil monotherapy in terms of OS in patients with 
refractory mCRC. 
3.2. Secondary objectives 
Secondary objectives are to estimate the effect of trifluridine/tipiracil in combination with 
bevacizumab versus trifluridine/tipiracil monotherapy in terms of PFS, ORR, and DCR in 
patients with refractory mCRC. Other secondary objectives are to compare the safety and 
tolerance, and the impact on QoL of trifluridine/tipiracil in combination with bevacizumab to 
trifluridine/tipiracil monotherapy in patients with refractory mCRC. 
3.3. Endpoints 
3.3.1. 
Primary endpoint 
OS is defined as the observed time elapsed between the date of randomisation and the date of 
death due to any cause. 
3.3.2. 
Secondary endpoints 
­ PFS is based on investigator judgement and defined as the time elapsed between the 
randomisation and the date of radiologic tumour progression (according to RECIST version 
1.1 (Eisenhauer, 2009) or death from any cause. 
­ ORR is defined as the proportion of patients with objective evidence of complete response 
(CR) or partial response (PR) according to RECIST version 1.1 criteria and using 
investigator’s tumour assessment. 
­ DCR is defined as the proportion of patients with objective evidence of CR or PR or stable 
disease (SD) according to RECIST version 1.1 criteria and using investigator’s tumour 
assessment. 
­ Safety and tolerability are assessed by the incidence of AEs, laboratory tests (haematology, 
biochemistry, coagulation and urinalysis), physical examination and ECOG PS (Appendix 
2), vital signs (blood pressure, heart rate, body temperature and body weight), ECG 
parameters and time to ECOG PS deterioration to ≥2 since randomisation.    
­ QoL is assessed by two questionnaires EORTC QLQ-C30 and EQ-5D-5L (Appendix 5 and 
Appendix 6). 


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4.
STUDY DESIGN
4.1. Investigational Plan 
4.1.1. 
Study plan 
This is an international, open-label, controlled two-arm, randomised phase III study evaluating 
the efficacy and safety of trifluridine/tipiracil in combination with bevacizumab versus 
trifluridine/tipiracil monotherapy in patients with refractory mCRC. 
The analysis will be done after 331 events are reported. In order to observe this number of 
events, 490 patients will be randomised (1:1) to receive trifluridine/tipiracil in combination with 
bevacizumab (experimental arm) or trifluridine/tipiracil monotherapy (control arm). 
Considering the anticipated rapid enrolment and event accumulation in this population, there is 
no planned interim analysis for efficacy or futility. 
Randomisation will take place once the consented patient has completed all the necessary 
baseline procedures and is deemed eligible for study entry. The stratification factors will be: 
­ geographic region (North America, European Union, Rest of the World), 
­ time since diagnosis of first metastasis (<18 months, ≥18 months),  
­ RAS status (wild-type, mutant). 
For more details about the statistical analyses and the sample size calculation please refer to the 
Section 10.  
The study plan is shown in Figure (4.1.1) 1. 
Figure (4.1.1) 1 - Study plan 
Il!!nQw: 
evaluation 
QoL 
Randomisation 
s3 
aays 
1st cycle (28 days) 
I 
I 
I 
I!!!nQw: evaluation 
every 2 cycles !fil1ll 
radiologic 
progression 
QoL 
QoL 
2°0 cycle (28 days) 
Subsequent cycles 
(28 days) 
I 
I 
I 
I 
I 
I 
w1 1 w2 1 w3 1 w4 
w1 1 w2 1 w3 1 w4 
w1 
1 w2 1 w3 1 w4 
D-2B 
D1 
DB 
D1 5 
D22 
D1 
DB 
D1 5 
D22 
D1 
DB 
D15 
D22 
Screening period 
Treatment period 
- I!!!nQw: evaluation 
- Survival 
! 
Withdrawal j Follow up 
visit 
every B 
(up lo 4 weeks after 
weeks 
last IMP intake) 
. - . - . - -
Follow-up 
period 


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The study start is defined as the date of the first visit of the first patient. 
The study will be divided into the following periods for each patient: 
­ Screening visit (up to 28 days prior to randomisation): to obtain informed consent. 
­ Screening period/Inclusion: to check the eligibility of the patient to be included and 
randomised in the study. 
­ Randomisation: patients will be randomly assigned to one of the two treatment arms: 
Trifluridine/tipiracil in combination with bevacizumab: trifluridine/tipiracil (starting dose
at 35 mg/m2/dose) will be administered orally BID 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.
Trifluridine/tipiracil: trifluridine/tipiracil (starting dose at 35 mg/m2/dose) will be
administered orally BID for 5 days on/2 days off, for 2 weeks, followed by a 14-day rest.
This treatment cycle will be repeated every 4 weeks.
­ Treatment period: randomised patients should receive the first dose of study treatments 
(day 1 of cycle 1) within 3 days after randomisation.  
Patients will be treated until they meet a discontinuation criterion as described in Section 
5.6.1. Patients will be considered on treatment as long as the patients continue with 
trifluridine/tipiracil. Bevacizumab monotherapy is not allowed. 
­ Withdrawal visit: within 4 weeks following the date of IMPs withdrawal and prior to the 
start of a new anticancer therapy. 
­ Follow-up period: after the withdrawal visit, a follow-up will be done every 8 weeks as 
described in Section 5.6.2 until death or end of study. 
The end of study will occur 19 months after the first IMP intake of the last patient randomised 
and is defined as the date of the last follow-up of the last patient (including a contact phone) or 
the date of the last contact attempt if the last patient is declared lost to follow-up.  
If some patients are still receiving study treatments when the end of study is met, please see 
Section 6.5 for procedures to be followed. 
Due to the exceptional circumstances in relation to the coronavirus disease pandemic, the 
sponsor, in accordance with competent regulatory authority’s guidelines, could decide to 
implement precautionary measures during the study to ensure patients safety, while maintaining 
compliance with GCP and study data integrity. These precautionary measures will remain in 
effect only for the duration of national public health emergency. 
4.1.2. 
Investigation schedule 
Table (4.1.2) 1 and Table (4.1.2) 2 describe the efficacy, safety and other assessments 
performed during the study. 
The study schedule must be followed, however, under special conditions, (e.g., bank holidays, 
weekends…), a window of +/- 3 days (from planned CXD1) is allowed for the start of a new 
treatment cycle and a window of +/- 7 days (from planned CXD1) is allowed for tumour 
assessment and follow-up visits, as long as the proper order is maintained.  
For further practical details, methods of measurement are provided in Sections 7, 8 and 9. 
The approximate total volume of blood collected per patient for the screening period and per 
cycle during the study will be 40 mL. 


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Table (4.1.2) 1 - Investigation schedule of trifluridine/tipiracil and bevacizumab arm 
Procedure 
Screening visit / Screening 
period / Inclusion 
Randomisation 
On-Treatment period 
Withdrawal visit 
Follow-up 
period 
CYCLE 1 (28 days) 
SUBSEQUENT CYCLES (28 days) 
Day of Cycle 
Day of Cycle 
Every 2 
cycles 
within 4 weeks after ttt 
withdrawal and before 
new anticancer ttt 
Every 8 weeks, 
until death or 
end of study 
≤ 28 days prior 
randomisation 
≤ 7 days prior 
randomisation 
≤ 3 days prior 
C1D1 
1 
15 
1 
15 
Sign informed consent form1 
X 
 
Inclusion / exclusion criteria 
X 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
IWRS2 
X 
X 
X 
X 
X 
X 
X 
Efficacy measurements 
 
 
Tumour measurements3 
X 
 
 
 
 
 
 
X 
X 
X 
Survival status4 
 
 
 
 
 
 
X 
Safety measurements 
Baseline signs & symptoms and 
height 
X 
ECG15 
X 
 
 
 
 
 
 
 
X 
 
Pregnancy testing 
X5 
X6 
ECOG Performance Status 
X7 
X9 
X11 
X 
Physical examination 
X 
X9 
X10 
X11 
X12
X 
Vital signs and weight 
X 
X9 
X10 
X11 
X12
 
X 
 
Haematology 
 
X8 
 
X9 
X10 
X11 
X12 
 
X 
 
Biochemistry 
 
X8 
 
X9 
X10 
X11 
 
 
X 
 
Coagulation 
X8 
X9 
X11 
X 
Urinalysis 
X 
X9 
X10 
X11 
X 
Concomitant treatments 
X 
 
 
 
 
 
 
 
X13
AE assessment 
X 
 
 
 
 
 
 
 
 
Other measurements 
 
 
 
 
 
 
 
 
 
 
Quality of Life assessment14 
X 
X (prior to any 
procedure) 
X 
IMPs 
 
 
 
 
 
 
 
 
 
 
Trifluridine/tipiracil intake 
 
D1 to D5 and  
D8 to D12 
D1 to D5 and 
D8 to D12 
 
 
Bevacizumab IV administration 
 
 
 
X 
X 
X 
X 
 
 
 
1--------------------,t---------+----------------------
1--------------------it---------+----------------------
1--------------------it---------+---------------------------------1--------+-----------it--------+---------+------+-----------+--- ----.... 
I----------------+---------------------------------------------
1--------------------ll---------+--------+-------------------------1--------+----------ll-------+---------+------t-----------¼---------1 
,_ ___ 
l--------------------it---------+---------------------------------1--------+-----------it--------+---------+------+-----------+-------.... 
.... 
1--------------------it---------+---------------------------------1--------+-----------it--------+---------+------+-----------+--- ----.... 
1--------------------it---------+---------------------------------1--------+-----------it--------+---------+------+-----------+--- ----.... 
.... 
,_ ______________ ____,,__ _______ , ______ ___,_ _________________________ ,_ ______ -+-----------i,__ ______ _, _______________ 
,____ __________ 
_,___ ______ .... 
---------------------------------+----------;~-------------- ----------------- --------------- ------------ ---------------1---------•------------- ---------------------- ---------------
---------------------------------+----------;~-------------- ----------------- --------------- ------------ ---------------!---------•------------- ---------------------- ---------------


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1.
Sign Informed Consent Form (ICF): written informed consent must be obtained during the screening visit, prior to the performance of any study procedure. 
2.
IWRS: to obtain patient's number at screening, randomisation of patient, allocation and re-allocation of therapeutic units (other visits) and to register the end of treatment for a patient at withdrawal visit. 
3.
Tumour measurements: tumour assessments should be performed according to RECIST version 1.1. The same method of assessment and the same technique must be used for all evaluations. At each time
point, obtain imaging-based evaluation of the chest, abdomen, and pelvis at a minimum (other localisations if clinically indicated) and clinical examination. 
a.
Baseline: tumour assessment will be done within 28 days prior to randomisation. Images obtained prior to patient signed ICF may be used if the date of the images is within 28 days of randomisation 
and if in line with methods and techniques that will be used during study. 
b.
Treatment period: tumour assessments will be done every 2 cycles from C1D1
c.
Withdrawal visit: tumour assessments will be performed only if not performed within previous 8 weeks. Every effort should be made to perform the end of treatment tumour assessments prior to the 
start of new anticancer therapy. 
d.
Follow-up period: unless patient had discontinued study treatments for radiologic disease progression or withdrawal of consent, obtain tumour assessments within 8 weeks after the last previous
tumour assessment and then every 8 weeks until documentation of radiologic disease progression, regardless of initiation of a new anticancer therapy. 
4.
Survival status: obtain survival status (alive/dead) at scheduled 8-week intervals until patient death or end of the study. The information can be obtained remotely by using various wired and wireless
telecommunication technologies including but not limited to telephone, internet and shared electronic medical records.. 
5.
Pregnancy testing at screening period: with serum βHCG test only. Note: more frequent pregnancy tests should be performed if required by local law.
6.
Pregnancy testing at withdrawal: only if not performed within the previous 4 weeks (with serum βHCG or highly sensitive urine test). 
7.
ECOG Performance Status during the screening period: the patient’s performance status must remain 0 or 1 during the screening period and at the time of randomisation for the patient to remain eligible.
8.
Laboratory tests (haematology, biochemistry, coagulation) during screening period: an assessment performed by the study site’s certified laboratory as per routine clinical practice, on samples collected before 
ICF signature is acceptable and may not be repeated, only if the assessment is fully satisfying study protocol criteria in terms of completeness and time schedule. 
9.
Study procedures prior to the first study treatments administration: to be done by the study site’s certified laboratory at C1D1 prior to study treatments administration only if baseline procedures have been done
more than 7 days prior to C1D1. 
10.
Study procedures at C1D15: obtain within 48 hours prior to bevacizumab administration. 
11.
Study procedures at day 1 of subsequent cycles ≥2: obtain within 48 hours prior to day 1 study treatments administration. Verify that patients with toxicities have met resumption criteria prior to administering 
study treatments. 
12.
Study procedures at day 15 of subsequent cycles ≥2: obtain within 48 hours prior to bevacizumab administration (not mandatory in case of permanent discontinuation of bevacizumab). 
13.
Concomitant medications during follow-up period: only anticancer therapies will be collected.
14.
Quality of life: EORTC QLQ-C30 and EQ-5D-5L will be performed at baseline, every cycle (prior to any study procedure) and at withdrawal visit. 
15.
ECG during screening period: ECG obtained prior to patient signed ICF may be used if the date of the ECG is within 28 days of randomisation.


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Table (4.1.2) 2 - Investigation schedule of trifluridine/tipiracil monotherapy arm 
Procedure 
Screening visit / Screening 
period / Inclusion 
Randomisation 
On-Treatment period 
Withdrawal visit 
Follow-up 
period 
CYCLE 1 (28 days) 
SUBSEQUENT CYCLES (28 days) 
Day of Cycle 
Day of Cycle 
Every 2 cycles 
within 4 weeks after ttt 
withdrawal and before 
new anticancer ttt 
Every 8 weeks, 
until death or 
end of study 
≤ 28 days prior 
randomisation 
≤ 7 days prior 
randomisation 
≤ 3 days prior 
C1D1 
1 
15 
1 
Sign informed consent form1 
X 
 
 
 
 
 
 
 
 
Inclusion / exclusion criteria 
X 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
IWRS2 
X 
X 
X 
X 
X 
Efficacy measurements 
 
 
 
 
 
 
 
 
 
Tumour measurements3 
X 
 
 
 
 
 
X 
X 
X 
Survival status4 
 
 
 
 
 
X 
Safety measurements 
 
 
 
 
 
 
 
 
 
Baseline signs & symptoms and 
height 
X 
ECG13 
X 
 
 
 
 
 
 
X 
 
Pregnancy testing 
 
X5 
 
 
 
 
 
X6 
 
ECOG Performance Status 
 
X7 
 
X9 
 
X10 
 
X 
 
Physical examination 
 
X 
 
X9 
X 
X10 
 
X 
 
Vital signs and weight 
 
X 
 
X9 
X 
X10 
 
X 
 
Haematology 
 
X8 
 
X9 
X 
X10 
 
X 
 
Biochemistry 
 
X8 
 
X9 
X 
X10 
 
X 
 
Coagulation 
 
X8 
 
X9 
 
X10 
 
X 
 
Urinalysis 
 
X 
 
X9 
X 
X10 
 
X 
 
Concomitant treatments 
X 
 
 
 
 
 
 
 
X11 
AE assessment 
X 
 
 
 
 
 
 
 
Other measurements 
 
 
 
 
 
 
 
 
 
Quality of Life assessment12 
X 
X (prior to any 
procedure) 
X 
IMPs 
Trifluridine/tipiracil intake 
 
D1 to D5 and  
D8 to D12 
D1 to D5 and D8 to D12 
1------------------1>---------+---------------------- ----------------------------------+----------+--------------------------------- -------------------------------+-----------+--------I 
1------------------11---------+---------------------- -------------------------1--------+-------+--------------------------------- -------------------------------+-----------+--------I 
1------------------11---------+·---------------------- -------------------------1--------+-------+·--------------------------------- -------------------------------+-----------+--------I 
1-----------------+----------------------- ---------------------- -------------------------1--------+----------+--------------------------------- -------------------------------+-----------+--------I 
1------------------10--------+-----------<--------------------------o----------+---------<f-------------<>----------t-----------¼--------< 
1-----------------+----------------------- ---------------------- ----------------------------------+---------+--------------------------------- -------------------------------+---------------------------1 
-------------------------------+-----------+----------1 
1------------------1>--------+--------------------------------------1--------+---------<f-------------1>----------t------------1--------< 
1------------------1>--------+--------------------------------------1--------+---------<f-------------1>----------t------------1--------< 
1------------------1>--------+--------------------------------------1--------+---------<f-------------1>----------t------------1--------< 
l------------------1>--------+--------+-------------------------1--------+---------<f-------------1>----------t------------t--------< 
l------------------1>--------+--------------------------------------l--------+---------<f-------------<>----------t------------t--------i 
1------------------11---------+--------------------------------1--------+---------lc-----------11----------t-----------f---------1 
1----------------11---------+--------------------------------1--------+---------lr-----------11----------t-----------f---------1 
1------------------1>--------+--------------------------------------1--------+---------<f-------------1>----------t------------1--------< 
1------------------1>--------+--------------------------------------1--------+---------<f-------------1>----------t------------1--------< 
l------------------1>--------+--------------------------------------l--------+---------<f-------------<>----------t------------t--------i 
1------------------+----------------------- ---------------------- -------------------------!'--------+---------+--------------------------------- -------------------------------+-----------+-----------1 
----------------------------------1----------1~-------------- ----------------- --------------- ---------------------------•--------------------- ---------------------- ---------------


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1.
Sign Informed Consent Form (ICF): written informed consent must be obtained during the screening visit, prior to the performance of any study procedure. 
2.
IWRS: to obtain patient's number at screening, randomisation of patient, allocation and re-allocation of therapeutic units (other visits) and to register the end of treatment for a patient at withdrawal visit. 
3.
Tumour measurements: tumour assessments should be performed according to RECIST version 1.1. The same method of assessment and the same technique must be used for all evaluations. At each time
point, obtain imaging-based evaluation of the chest, abdomen, and pelvis at a minimum (other localisations if clinically indicated) and clinical examination. 
a.
Baseline: tumour assessment will be done within 28 days prior to randomisation. Images obtained prior to patient signed ICF may be used if the date of the images is within 28 days of randomisation 
and if in line with methods and techniques that will be used during study. 
b.
Treatment period: tumour assessments will be done every 2 cycles from C1D1
c.
Withdrawal visit: tumour assessments will be performed only if not performed within previous 8 weeks. Every effort should be made to perform the end of treatment tumour assessments prior to the 
start of new anticancer therapy. 
d.
Follow-up period: unless patient had discontinued study treatments for radiologic disease progression or withdrawal of consent, obtain tumour assessments within 8 weeks after the last previous 
tumour assessment and then every 8 weeks until documentation of radiologic disease progression, regardless of initiation of a new anticancer therapy. 
4.
Survival status: obtain survival status (alive/dead) at scheduled 8-week intervals until patient death or end of the study. The information can be obtained remotely by using various telecommunication technologies 
including but not limited to telephone, internet and shared electronic medical records. 
5.
Pregnancy testing at screening period: with serum βHCG test only. Note: more frequent pregnancy tests should be performed if required by local law. 
6.
Pregnancy testing at withdrawal: only if not performed within the previous 4 weeks (with serum βHCG or highly sensitive urine test). 
7.
ECOG Performance Status during the screening period: the patient’s performance status must remain 0 or 1 during the screening period and at the time of randomisation for the patient to remain eligible.
8.
Laboratory tests (haematology, biochemistry, coagulation) during screening period: an assessment performed by the study site’s certified laboratory as per routine clinical practice, on samples collected before 
ICF signature is acceptable and may not be repeated, only if the assessment is fully satisfying study protocol criteria in terms of completeness and time schedule. 
9.
Study procedures prior to the first study treatments administration: to be done by the study site’s certified laboratory at C1D1 prior to study treatments administration only if baseline procedures have been done
more than 7 days prior to C1D1. 
10.
Study procedures at day 1 of subsequent cycles ≥2: obtain within 48 hours prior to day 1 study treatments administration. Verify that patients with toxicities have met resumption criteria prior to administering 
study treatments. 
11.
Concomitant medications during follow-up period: only anticancer therapies will be collected.
12.
Quality of life: EORTC QLQ-C30 and EQ-5D-5L will be performed at baseline, every cycle (prior to any study procedure) and at withdrawal visit. 
13 
ECG during screening period: ECG obtained prior to patient signed ICF may be used if the date of the ECG is within 28 days of randomisation. 


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4.2. Measures to minimise bias 
The following measures will be taken in order to minimise bias: 
­ Stratification by geographic region (North America, European Union, Rest of the World), 
the time since diagnosis of first metastasis (<18 months, ≥18 months) and RAS status (wild 
type, mutant). 
­ Randomisation, allocation, reallocation and dose adjustment will be centralised by IWRS. 
­ The QoL questionnaires (EORTC QLQ-C30 and EQ-5D-5L) will be completed by the 
patient, independently of the study personnel, at the beginning of each visit and prior to any 
study procedure. These questionnaires will be completed in the local language using an 
electronic device (e-PRO). In case the patient is not able to use the e-PRO, a caregiver (not 
a medical/investigator staff) will be allowed to read the questions to the patient and to collect 
the answer without any interpretation of the questions and the answers. The objective is to 
enhance the validity of QoL data by reducing missing data and improving the completion 
rate. Completion of paper versions of the QoL questionnaires is not allowed by the protocol. 
­ Strategic sponsor personnel will not have access to the arms of treatment. This will be 
detailed in a separate document. 
4.3. Study products and blinding systems 
4.3.1. 
Products administered 
Trifluridine/tipiracil and bevacizumab will be supplied by Les Laboratoires Servier Industrie 
(Gidy, France) or a subcontracted company. The bevacizumab to be used in the U.S. will be 
sourcing from Genentech, Inc. 
Table (4.3.1) 1 and Table (4.3.1) 2 provide a description of the study treatments. 
Table (4.3.1) 1 - Description of trifluridine/tipiracil 
Trifluridine/tipiracil 15 mg 
Trifluridine/tipiracil 20 mg 
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 (4.3.1) 2 - Description of bevacizumab 
Bevacizumab 4 ml 
Bevacizumab 16 ml 
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 (4.3.1) 3 and Table (4.3.1) 4 provide a description of the packaging of the study 
treatments.  
Table (4.3.1) 3 - Description of the packaging of trifluridine/tipiracil 
 Table (4.3.1) 3 (Cont'd) - Description 
 
Trifluridine/tipiracil 
15 mg 
Trifluridine/tipiracil 
20 mg 
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 
“S 95005 15” of 1 card with 
desiccant 
1 aluminium foil pouch 
“S 95005 20” 
of 1 card with desiccant 
Table (4.3.1) 4 - Description of the packaging of bevacizumab 
Bevacizumab 4 ml 
Bevacizumab 16 ml 
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. 
4.3.2. 
IMP management 
In this study, the IMPs are trifluridine/tipiracil and bevacizumab. 
The IMPs will be sent by Les Laboratoires Servier Industrie (Gidy, France) (except for 
bevacizumab to be used in the U.S.) either directly to the study sites or to sub-distribution 
centres or to local pharmacies depending on the geographic areas and the local regulatory 
requirements. Bevacizumab to be used in the U.S. will be sent from a subcontracted company 
located in the U.S. directly to the U.S. study sites. 
The investigator and/or the pharmacist of the study site should only use the IMPs provided for 
the patients involved in the study. 
The investigator and/or pharmacist of the study site is responsible for: 
­ IMPs receipt and storage according to the local procedures and requirements,
­ IMPs temperature monitoring,
­ IMPs dispensing according to treatment arm assigned by the IWRS,
­ maintaining records of IMPs inventory at study site,
­ IMPs collection for destruction.
Storage 
The IMPs should be stored in a secure area with restricted access. For specific storage 
conditions, please refer to the Product Information (Appendix 7). 
The investigator and/or pharmacist of the study site will record temperature storage daily using 
 “Therapeutic Unit temperature log sheet - centre” (recording Min-
Max temperature every working day) or an equivalent document. 
CCI


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In case of temperature deviation, the investigator and/or pharmacist should immediately: 
­ block the IWRS for the concerned IMPs and place them in quarantine, 
­ alert the sponsor monitor and forward all required information, 
­ put in place an adequate corrective/preventive action after the first temperature deviation 
occurs, in order to avoid recurrence. 
IMPs management will be verified on a regular basis by the study monitor. 
The investigator and/or the pharmacist of the study site and/or a designated person from their 
study team must complete in real time all the documents provided by the sponsor concerning 
IMPs management (therapeutic unit tracking form or an equivalent document…). Therapeutic 
unit tracking form, or an equivalent document, is the source document to fulfil. 
All defects or deterioration of IMPs or of their packaging, including complaints set out by a 
patient (change of taste, appearance…) are to be reported to the sponsor monitor, or to the 
IWRS.  
Destruction of the IMPs 
Destruction of the IMPs is the responsibility of the sponsor and/or of the investigator and/or the 
pharmacist of the study site. 
Remaining treatments (used and unused IMPs, except for used vials of bevacizumab) will 
subsequently be collected and stored according to the local procedures and requirements, by 
the person responsible for the IMPs management. 
A certificated of 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 IMPs will be defined by the sponsor and adapted to the study site. IMPs 
collection and destruction form will be completed before the shipment of IMPs to destruction. 
Destruction of IMPs 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 vials will be collected and destroyed according to local procedure by 
the study site at the time of preparation/administration along with other wastes. Thus, 
accountability and recovery by monitor are not applicable for used vials of bevacizumab. 


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In case of batch recall 
In the event of anticipated return of IMPs to the sponsor (i.e., batch recall), the sponsor will 
prepare a notification letter for the investigator and/or pharmacist of the study site. On letter 
receipt, the investigator and/or the pharmacist will have to identify the patients in possession of 
the IMPs 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. 
4.3.2.1. 
Trifluridine/tipiracil 
Trifluridine/tipiracil tablets should not be sucked, chewed, crushed or kept in mouth. Direct 
contact of the powder from tablets containing trifluridine/tipiracil 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. 
The patient must be instructed in the handling of study medication as follows:  
­ To store the study medication at room temperature, 
­ To keep study medication in a safe place and out of reach of children, 
­ To take study medication within 1 hour after completing a meal (morning and evening 
meals) with a glass of water, 
­ To make every effort to take doses on schedule, 
­ To remove from the study medication kit, only the number of tablets needed at the time of 
dosing and not to remove doses in advance of the next scheduled dosing, 
­ To wash their hands after handling study medication, 
­ To report any missed doses to the investigator. If doses are missed or held, the patient should 
not make up for missed doses, 
­ If the patient vomits after taking study medication, the patient should not take another dose, 
­ To bring all used and unused study medication kits to the study site at each visit. 
4.3.2.2. 
Bevacizumab 
Bevacizumab will be provided as commercially available product with clinical labelling. For 
handling conditions and cleaning procedures instructions, please refer to the Product 
Information (Appendix 7). 
4.3.3. 
Management of blinding systems  
Not applicable. 
4.4. Discontinuation of the study 
4.4.1. 
Premature discontinuation of the study or temporary halt 
This study may be temporarily halted or prematurely discontinued at any time for any sufficient 
reasonable cause. After having informed the International Coordinator, the sponsor or the Data 
Safety Monitoring Board (DSMB) or the Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) or the Competent Authorities (CA) may terminate the study before its 
scheduled term. The IRB/IECs and CA will be informed according to local regulations. 
If the study is prematurely discontinued, the ongoing patients should be seen as soon as 
possible, and the assessments described in Section 5.6 should be performed.  


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Under some circumstances, the investigator may be informed of additional procedures to be 
followed in order to ensure that adequate consideration is given to the protection of the patient’s 
interests. 
In case of temporary halt, the study may resume once concerns about safety, protocol 
compliance, data quality are addressed and satisfy the sponsor, International Coordinator, the 
DSMB, the IRB/IEC and CA. 
4.4.2. 
Discontinuation of the study in the event of objective reached 
Not applicable. 
4.5. Source data  
Source data and source documents of the study site 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) will be considered as source 
document, 
­ Therapeutic unit tracking form, or an equivalent document, 
­ e-PRO service provider’s database will be considered as source data.


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5.
SELECTION AND WITHDRAWAL OF PARTICIPANTS
5.1. Inclusion criteria 
5.1.1. 
Demographic characteristics 
1. Male or female patient aged ≥18 years old at the time of ICF signature (or legal age
depending on local country regulation)
5.1.2. 
Medical and therapeutic criteria 
2. Has histologically confirmed unresectable adenocarcinoma of the colon or rectum (all
other histological types are excluded).
3. RAS status must have been previously determined (mutant or wild-type) based on local
assessment of tumour biopsy
Wild type is defined as KRAS (exon 2, 3 and 4) and NRAS (exon 2, 3 and 4) wild type.
Mutant is defined as at least KRAS or NRAS mutant (any exon, any mutation).
4a. Has received a maximum of 2 prior chemotherapy regimens for the treatment of 
advanced colorectal cancer and had demonstrated progressive disease or intolerance to 
their last regimen 
­ Prior treatment regimens for the treatment of advanced colorectal cancer must
have included a fluoropyrimidine, irinotecan, oxaliplatin, an anti-VEGF 
monoclonal antibody and/or an anti-EGFR monoclonal antibody for RAS wild-
type patients 
­ Patients who have received adjuvant/neoadjuvant chemotherapy and had
recurrence during or within 6 months of completion of the adjuvant/neoadjuvant 
chemotherapy can count the adjuvant/neoadjuvant therapy as one regimen of 
chemotherapy for advanced disease 
5. Has measurable or non-measurable disease as defined by RECIST version 1.1
6. Is able to swallow oral tablets
7. Estimated life expectancy ≥12 weeks
8. Has an Eastern Cooperative Oncology Group (ECOG) performance status ≤1. ECOG
should remain ≤1 during all the screening period (from screening visit to randomisation)
(Appendix 2).
9. Has adequate organ function as defined by the following laboratory values obtained
within 7 days prior to randomisation:
- Absolute neutrophil count ≥1.5 x 109/L
- Haemoglobin ≥9 g/dL. In case of blood transfusion, the haemoglobin assessment must
be performed 2 weeks or more after the transfusion.
- Platelet count ≥100 x 109/L
- Creatinine clearance ≥50 mL/min, assessed using the Cockcroft & Gault formula
(Appendix 4)
- Total serum bilirubin <1.5 x upper limit of normal (ULN) (unless Gilbert disease
confirmed)
- Aspartate aminotransferase (AST; SGOT) and alanine aminotransferase (ALT; SGPT)
≤ 2.5 x ULN (unless if liver function abnormalities are due to underlying liver
metastasis, AST (SGOT) and ALT (SGPT) ≤ 5 x ULN)
- Adequate coagulation function for all patients. For patients receiving anti-coagulant
therapy (except platelet antiaggregates) the adequate therapeutic levels of INR should
be confirmed


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10. Female of childbearing potential (as defined in Section 5.3) must have been tested
negative in a serum pregnancy test within 7 days prior to randomisation
11. Female of childbearing potential (as defined in Section 5.3) and males with partners
of childbearing potential must agree to use a highly effective method of birth control
(as described in Section 5.3, as well as their partners lasting at least 6 months after
the last dose of IMP
5.1.3. 
Informed consent 
12. Has provided written informed consent obtained prior to any study-specific
procedure as described in Section 13.3.
5.2. Exclusion criteria 
5.2.1. 
General criteria 
13. More than 2 prior chemotherapy regimens for the treatment of advanced colorectal
cancer
14. In the investigator’s opinion, the patient is unlikely to be compliant with the oral
medication regimen or the requirements of the study for scheduled evaluations
15. Pregnancy, lactating female, or possibility of becoming pregnant during the study
16. Participation in another interventional study within 4 weeks prior to randomisation.
Participation in study follow-up part without IMP administration, non-
interventional registry or epidemiological study is allowed
17. Patients currently receiving or having received anticancer therapies within 4 weeks
prior to randomisation
18. Already randomised in this study
5.2.2. 
Medical and therapeutic criteria 
19. Has not recovered from clinically relevant non-hematologic CTCAE grade ≥ 3
toxicity of previous anticancer therapy prior to randomisation (excluding alopecia,
and skin pigmentation)
20. Has symptomatic central nervous system metastases that are neurologically unstable
or requiring increasing doses of steroids to control CNS disease
21. Had major surgery within 4 weeks prior to randomisation (the surgical incision
should be fully healed prior to study drug administration), or has not recovered from
side effects of previous surgery, or patient that may require major surgery during
the study
22. In the investigator’s opinion, patient with chronic gastrointestinal disorders that
might significantly interfere with proper absorption of the study treatments
23. Has hereditary problems of galactose intolerance, total lactase deficiency or
glucose-galactose malabsorption
24. Has severe or uncontrolled active acute or chronic infection
25. Has active or history of interstitial lung disease and/or pneumonitis, or pulmonary
hypertension.
26. Known Hepatitis B Virus infection determined as HBsAg positive and / or known
Hepatitis C Virus infection determined as detection of HCV RNA in serum or
plasma by a sensitive quantitative molecular method
27. Known carriers of HIV antibodies
28. In the investigator’s opinion, uncontrolled diabetes mellitus even under treatment


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29a. Confirmed uncontrolled arterial hypertension (defined as systolic blood pressure ≥ 150 
mm Hg and/or diastolic blood pressure ≥ 100 mm Hg) or uncontrolled or symptomatic 
arrhythmia 
30. Deep arterial thromboembolic events including cerebrovascular accident or myocardial
infarction within the last 6 months prior to randomisation
31. Severe/unstable angina, symptomatic congestive heart failure New York Heart
Association (NYHA) class III or IV (Appendix 3)
32. Drainage for ascites, pleural effusion or pericardial fluid within 4 weeks prior to
randomisation
33. Other malignancies including those which were radically treated and for which the
remission period at the time of screening is less than five years. Exemptions for this
minimally required duration of remission period may be applied for carcinoma in situ
of the cervix and basal cell skin cancer that are deemed to be cured by adequate
treatment
34. Treatment with systemic immunosuppressive therapy (except steroids given in
prophylactic setting or at a chronic low dose [≤20 mg/day prednisone equivalent])
35. Prior radiotherapy if completed less than 4 weeks before randomisation, except if
provided as a short course for symptoms palliation only. Tumour lesions if previously
irradiated may not be chosen as target lesions for response evaluation
36. In the investigator’s opinion, any clinically significant medical condition (e.g. organ
dysfunction) or laboratory abnormality likely to jeopardize the patient’s safety or to
interfere with the conduct of the study
Criteria related to trifluridine/tipiracil administration 
37. Has previously received trifluridine/tipiracil
38. History of allergic reactions attributed to compounds of similar composition to
trifluridine/tipiracil or any of its excipients
39. Any contraindication present in the EU Product Information of trifluridine/tipiracil
(Appendix 7)
Criteria related to bevacizumab administration 
40. History of allergic reactions or hypersensitivity to bevacizumab or any of its excipients
41. History of hypersensitivity to Chinese Hamster Ovary cell products or other
recombinant human or humanised antibodies
42. Serious non-healing wound, non-healing ulcer or non-healing bone fracture
43. Deep venous thromboembolic event within 4 weeks prior to randomisation
44. Known coagulopathy that increases risk of bleeding, bleeding diatheses. Any other
haemorrhage/bleeding event CTCAE grade ≥ 3 within 4 weeks prior to randomisation
45. Any contraindication present in the EU Product Information of bevacizumab (Appendix
7)
46. History of any life-threatening VEGF-related adverse event
47. Proteinuria ≥ 1 g/24 hours or 2+ by dipstick.
For concomitant medication, refer to Section 6.3. 
5.3. Definition of women of childbearing potential and contraception methods 
Women of childbearing Potential 
A woman is considered of childbearing potential, i.e. fertile, following menarche and until 
becoming post-menopausal unless permanently sterile. Permanent sterilization methods include 


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hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is 
defined as no menses for 12 months without an alternative medical cause. 
Highly effective contraception methods for the study 
Highly effective methods of birth control refer to those which result in a low failure rate (i.e. 
less than 1% per year), when used consistently and correctly, such as combined hormonal 
contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), 
progestogen-only hormonal contraception when associated with inhibition of ovulation (oral, 
injectable, implantable), some intra uterine devices, intrauterine hormone-releasing system, true 
sexual abstinence (when this is in line with the preferred and usual lifestyle of the patient), 
bilateral tubal occlusion, male sterilization (vasectomy).  
Women using hormonal contraceptive must also use a barrier method i.e. condom or occlusive 
cap (diaphragm or cervical/vault caps) 
5.4. Retest management during screening period 
A patient who has a laboratory result(s) that does not satisfy the entrance criteria may have the 
test(s) repeated providing that the investigator judges it relevant according to the patient 
previous results, or medical history and if s/he considers laboratory abnormalities are likely to 
be transient. Results of the test(s) repeated should be obtained within the allowed screening 
period. In this case the patient will not be required to sign another informed consent, and the 
original patient number assigned by the investigator will be used. 
In any case, the last result available for each parameter must be considered for the patient 
inclusion. 
5.5. Additional information recorded at the inclusion visit 
Not applicable 
5.6. Participant withdrawal 
5.6.1. 
Withdrawal criteria 
Information to be collected during the last visit is given in Section 5.6.2. These follow-up 
modalities are used to ensure the efficacy and safety evaluation of all patients who received the 
IMPs. 
Patient will be on treatment as long as the patient continues with trifluridine/tipiracil. 
Bevacizumab monotherapy is not allowed. 
Pregnancy (see Section 8.9.2.3) and End of study (as defined in Section 4.1.1). will lead to 
premature study discontinuation. 
The reasons for discontinuation of treatment period are: 
­ Adverse events incompatible with continuation of the study treatments according to the 
judgment of the investigator, including no recovery in safety parameters or according to the 
following predefined criteria: 
A maximum dose delay >28 days from the scheduled start date of the next cycle


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Need for more than 3 dose reductions of trifluridine/tipiracil (maximum of 3 dose
reductions allowed as described in Section 8.11.1)
­ Protocol deviation if it interferes with the study evaluations and/or if it jeopardises patient’s 
safety, e.g. any medical event requiring administration of an unauthorised concomitant 
treatment (see Section 6.3) 
­ Radiologic progressive disease documented by CT-scan or MRI 
­ Clinical progressive disease manifested by symptomatic deterioration 
­ Non-medical reason (to be carefully described) e.g. consent withdrawal, patient’s removal 
­ Other, physician decision (for medical reasons that cannot be included in any of the criteria 
listed above) 
5.6.2. 
Procedure 
Upon discontinuation of study treatments, the investigator must: 
­ Notify the sponsor monitor immediately,  
­ Register the end of treatment for the patient in the IWRS, 
­ Complete the e-CRF, specifying the reason for the study patient’s withdrawal. If there are 
several reasons, the investigator must indicate the main reason. The investigator should 
document the discontinuation in the corresponding medical file. 
A withdrawal visit should take place within 4 weeks after the date of IMP withdrawal and prior 
to the start of a new anticancer therapy. 
In the case of discontinuation due to an AE (event requiring immediate notification [ERIN] 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 8.9.2.2). 
This information is recorded in that part of the e-CRF form which concerns adverse events. If 
the investigator cannot collect the information from a visit, s/he must collect it from the doctor 
ensuring the follow-up of the patient. 
In the case of discontinuation due to an ERIN, please refer to Section 8.7. 
Follow-up period: 
After the withdrawal visit, a follow-up will be done every 8 weeks: 
for tumour assessment (unless patient had discontinued study treatments for radiologic
disease progression or withdrawal of consent) until radiologic progression regardless of
initiation of a new anticancer therapy,
for survival status until death or the end of the study (whichever occur first). This follow-
up can be done remotely by using various telecommunication technologies including but
not limited to phone, internet and shared electronic medical records.
Patients are at any time free to discontinue their participation in the study. If patients wish to 
withdraw their consent to treatment period (i.e. both study treatments and study assessments), 
they will be asked if they are willing to continue with Follow-up period for survival status 
(which can be done by phone). If patients wish to withdraw their consent to further participation 
in the study entirely (treatment period and follow-up period), this should be clearly documented 
in the patient notes and in the clinical study database. 
During the follow-up period, the patient can participate to another clinical study. 
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A patient is considered discontinued from follow-up period only if one of the following 
occurs: 
­ Patient dies, 
­ At the end of study or if study is terminated by the sponsor or CA. 
The dispositions to be taken after IMPs discontinuation are described in Section 6.5. 
5.6.3. 
Lost to follow-up 
When the investigator has no news of the patient, s/he must make every effort to contact him/her 
or a person around him/her (phone calls, letters including registered ones…), to establish the 
reason for the discontinuation of IMPs and to suggest the patient comes to a withdrawal visit. 
If all these attempts to contact the patient fail, the investigator can then declare the patient “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 study site will login to the IWRS at the beginning of each treatment cycle to record the 
given cycle number, the patient’s height (screening period only) and weight for calculation of 
the patient’s body surface area (BSA) to obtain the recommended trifluridine/tipiracil dosage. 
In addition, the IWRS will use the patient’s weight to calculate the correct dosage of 
bevacizumab. 
In the experimental arm (trifluridine/tipiracil in combination with bevacizumab), study site will 
have to connect also to login to the IWRS at D15 of each treatment cycle for bevacizumab 
administration.  
The BSA will be calculated by the IWRS using the following DuBois formula (all BSA 
calculations are rounded to 2 decimal places) (Du Bois, 1916): 
BSA (m²) = ([Body Weight (kg)]0.425 x [Height (cm)]0.725) x 0.007184. 
The study sites are required to use: 
­ scales for patient’s weight measurement having a valid calibration or a maintenance 
certificate, 
­ the BSA calculation provided by the IWRS when determining trifluridine/tipiracil (even if 
it differs from the BSA provided by the site software), 
­ the trifluridine/tipiracil and bevacizumab doses calculated by the IWRS (even if it differs 
from the doses provided by study site’s software). 
For treatment dose adaptations due to toxicities, please refer to Section 8.11. 
Specific COVID-19 situation: 
In case of highly suspected COVID-19 infection (based on typical symptoms or typical chest 
CT scan images) or confirmed COVID-19 infection (based on positive COVID-19 biological 
testing), the study treatment(s) should be immediately interrupted. 
The study treatment(s) could be restarted if patient is asymptomatic and a period of at least 15 
days after the diagnosis has been respected with or without new testing (in case of new testing, 
the result should be negative). 
6.1.1. 
Trifluridine/tipiracil plus bevacizumab arm 
Each treatment cycle will be 28 days in duration. One treatment cycle consists of the following: 
­ Days 1-5: oral intake of trifluridine/tipiracil and bevacizumab IV infusion on day 1 
­ Days 6 -7: rest 
­ Days 8-12: oral intake of trifluridine/tipiracil 
­ Days 13-14: rest 
­ Day 15: bevacizumab IV infusion 
­ Days 16-28: rest 
6.1.2. 
Trifluridine/tipiracil monotherapy arm 
Each treatment cycle will be 28 days in duration. One treatment cycle consists of the following: 


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­ Days 1-5: oral intake of trifluridine/tipiracil 
­ Days 6 -7: rest 
­ Days 8-12: oral intake of trifluridine/tipiracil 
­ Days 13-28: rest 
6.1.3. 
Trifluridine/tipiracil administration 
­ Trifluridine/tipiracil dosage is calculated according to BSA. Table (6.1.3) 1 shows the 
number of tablets that are needed per calculated BSA for a dose of 35 mg/m². Table (6.1.3) 2 
shows the number of tablets that are needed per calculated BSA for a reduced dose 
(30 mg/m², 25 mg/m² and 20 mg/m²). 
­ If at the beginning of the new treatment cycle, a patient’s body weight decreases by ≥10% 
from baseline, the IWRS will recalculate the patient’s BSA and provide the study site with 
the adjusted trifluridine/tipiracil dosage. 
­ In case of change of dose level, the IWRS will provide the study site with the adjusted 
trifluridine/tipiracil dosage. 
­ No increase in trifluridine/tipiracil dose due to increase in BSA is permitted. 
­ Trifluridine/tipiracil should be taken with a glass of water within 1 hour after completion of 
morning and evening meals. 
­ Trifluridine/tipiracil 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. Extension of study treatment into days 6 to 7 or into the rest period (days 13 through 
28) is not permitted.
­ Any missed doses reported by the patient should be recorded in the e-CRF. 
Table (6.1.3) 1 - Number of tablets of trifluridine/tipiracil per dose (standard dose) according to body 
surface area 
Trifluridine/tipiracil 
Dose 
(2x daily) 
BSA 
(m2) 
Dosage in mg 
(2x daily) 
Total daily 
dose (mg) 
Tablets per dose (2x daily) 
15 mg/6.14 mg 
20 mg/8.19 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) 
1----------t--------------------------------- ----------------------+-----------+-------------< 
1----------t--------------------------------- ----------------------+-----------+-------------< 
1---------t--------------------------------- ----------------------+----------+-------------1 
1----------t--------------------------------- ----------------------+-----------+-------------< 


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Table (6.1.3) 2 - Number of tablets of trifluridine/tipiracil per dose (reduced dose) according to body 
surface area 
Trifluridine/tipiracil
Dose (2x daily) 
BSA 
(m2) 
Dosage in mg 
(2x daily) 
Total daily 
dose (mg) 
Tablets per dose (2x daily) 
15 mg/6.14 mg 
20 mg/8.19 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/8.19 mg tablet in the morning and 2 x 15 mg/6.14 
mg tablets in the evening. BSA=body surface area (calculate to 2 decimal places) 
6.1.4. 
Bevacizumab administration 
At each visit, the IWRS will provide the study site with the adjusted bevacizumab dosage based 
on the patient’s actual weight. The study site can round this dose at the nearest 0.5 mL. Refer 
to the Product Information (Appendix 7) for instructions regarding administration of 
bevacizumab. If there is a medical condition developed that requires bevacizumab to be 
permanently withdrawn the patient may continue with trifluridine/tipiracil alone. 
Bevacizumab should not be administrated alone in case of dose delay due to trifluridine/tipiracil 
toxicities. The cycle will be delayed, and bevacizumab will be restarted at the same time of 
trifluridine/tipiracil. 
6.2. IMPs dispensing 
The treatment arm will be allocated via IWRS using a central randomisation (1:1) to 
trifluridine/tipiracil in combination with bevacizumab or trifluridine/tipiracil monotherapy with 
stratification by the geographic region (North America, European Union, Rest of the World), 
the time since diagnosis of first metastasis (<18 months, ≥18 months) and the RAS status (wild 
type, mutant). 


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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 study 
treatment label collection form or on the prescription form when the study treatments are 
dispensed by a pharmacist. 
6.3. Previous and concomitant treatments 
6.3.1. 
Prohibited treatments 
6.3.1.1. 
Before the study 
Patients are not permitted to receive: 
­ Previous investigational or anticancer therapy for mCRC within 4 weeks prior to 
randomisation, 
­ Treatment with systemic immunosuppressive therapy (except steroids given in prophylactic 
setting or at a chronic low dose [≤20 mg/day prednisone equivalent]), 
­ Radiotherapy in the last 4 weeks prior to randomisation (except if provided as a short course 
for symptoms palliation only). 
6.3.1.2. 
During the study treatment period 
Patients are not permitted to receive: 
­ Any other investigational or any other anticancer therapy, including chemotherapy, 
immunotherapy, biological response modifiers, or endocrine therapy, 
­ Treatment with systemic immunosuppressive therapy (except steroids given in prophylactic 
setting or at a chronic low dose [≤20 mg/day prednisone equivalent] or short-term 
administration of steroids at daily doses higher than authorized by the protocol in situations 
of acute care management). 
For other precautions of use and interactions of concomitant treatment with bevacizumab please 
refer to Product Information (Appendix 7). 
6.3.2. 
Authorised treatments 
­ Palliative radiotherapy is permitted. As far as possible, the irradiation of target lesions must 
be avoided. Pre-clinical data showed that trifluridine/tipiracil is a radiosensitizer, but no 
clinical data are available for the concomitant treatment with trifluridine/tipiracil and 
radiotherapy, so caution is required, and close monitoring of patients is needed. 
­ It is strongly recommended that patients treated with anti-vitamin K treatment will be switch 
to low molecular weight heparin. 
­ Warning for patients receiving trifluridine/tipiracil: 
Caution is required when using drugs that are human thymidine kinase substrates, e.g., 
zidovudine. Such drugs, if used concomitantly with trifluridine/tipiracil, 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, didanosine and abacavir. 


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6.4. IMP compliance 
The number of trifluridine/tipiracil tablets dispensed and returned by the patient is to be counted 
by the investigator or a designated person from his/her team and recorded in the e-CRF and 
therapeutic unit tracking form, or an equivalent document. 
If the patient did not bring back all blisters dispensed at the previous visit, the investigator must 
estimate the number of trifluridine/tipiracil tablets taken by the patient since the previous visit, 
by questioning him/her. 
In case of missed dose, the patient must indicate the reason to the investigator. 
The compliance will be assessed from the method described above and from the questioning of 
the patient at the beginning of each cycle. 
6.5. Discontinuation of the IMP 
After the discontinuation of the IMPs, patient’s treatment is left to the physician’s discretion. 
After completion of the study (see Section 4.1.1 for end of study definition), patients currently 
being treated will be offered the option to continue the treatments outside of the study. 
The sponsor will be responsible for the IMPs dispensing to the patients who are eligible to 
continue the treatments. The IMPs will be not assigned through IWRS, and IMPs will be 
manually assigned to patients by the investigator and/or pharmacist of the study site, based on 
the patient’s BSA at the time of study completion.  
Specific rules may be followed in some countries according to local regulation. 


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7.
ASSESSMENT OF EFFICACY
7.1. Efficacy measurements 
Efficacy measurements performed during the study are indicated in Table (4.1.2) 1 and 
Table (4.1.2) 2. 
7.2. Methods and measurement times 
7.2.1. 
Measurement times 
Tumour assessments/imaging of the chest, abdomen, and pelvis at a minimum (other 
localisations if clinically indicated) will be obtained at each time point listed below for all 
patients: 
­ Baseline within 28 days prior to randomisation. 
Note: Images obtained prior to patient signed ICF may be used if the date of the images is 
within 28 days of randomisation and if in line with methods and techniques that will be used 
during study 
­ Every 2 cycles from C1D1 until radiologic progression is documented (including at the 
withdrawal visit if not done in the previous 8 weeks). 
­ For patients who were withdrawn for reasons other than radiologic disease progression or 
consent withdrawal, every 8 weeks during the follow up period until the patient experienced 
radiologic progression, regardless of the initiation of a new anticancer therapy. 
Note: 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 study treatments. Symptoms of clinical progression must be documented in the 
patient’s source documents and in AE form. Tumour assessments will continue every 8 weeks 
until a radiologic progression is documented. 
7.2.2. 
Method of imaging 
­ The same method of assessment and the same technique should be used to characterise each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation 
should always be done rather than clinical examination unless the lesion(s) being followed 
cannot be imaged but are assessable by clinical exam. 
­ Images must be acquired of the chest, abdomen and pelvis at a minimum (other localisations 
if clinically indicated) at each time point. 
­ Only CT or MRI must be used for tumour measurement (see specific cases below). 
­ Contrast enhanced CT is the preferred method for tumour assessments. If contrast agent is 
contraindicated in a patient, obtain at least a non-contrast chest CT and enhanced magnetic 
resonance imaging (MRI) of the abdomen and pelvis. 
Specific cases: 
­ If new lesions are identified by ultrasound in the course of the study, a confirmation by CT 
or MRI is needed. 
­ Clinical lesions will only be considered measurable when they are superficial and ≥10mm 
diameter as assessed using calipers (e.g. skin nodules). For the case of skin lesions, 
documentation by colour photography including a ruler to estimate the size of the lesion is 
recommended. When lesions can be evaluated by both clinical exam and imaging, imaging 


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evaluation should be undertaken since it is more objective and may also be reviewed at the 
end of the study. 
­ In case of PET CT-scan, the CT portion of the PET–CT can be used for RECIST 
measurements. 
7.2.3. 
Tumour definitions 
At baseline, tumour lesions/lymph nodes will be categorised measurable or non-measurable as 
describe in Sections 7.2.3.1, 7.2.3.2, and 7.2.3.3. 
7.2.3.1. 
Measurable lesions 
­ 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 with a CT-scan slice thickness no greater than 5 mm (when CT scans
have slice thickness greater than 5 mm, the minimum size for a measurable lesion should
be twice the slice thickness),
10 mm caliper measurement by clinical exam (lesions which cannot be accurately
measured with calipers should be recorded as non-measurable),
­ 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 no greater than 5 mm). At 
baseline and in follow-up, only the short axis will be measured and followed. 
7.2.3.2. 
Non-measurable lesions 
­ 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. 
­ All non-measurable lesions can only be selected as non-target lesions. 
7.2.3.3. 
Special considerations regarding lesion measurability 
­ 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 definition, simple cysts,
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable
lesions, if they meet the definition of measurability described above. However, if


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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 not considered measurable unless 
there has been demonstrated progression in the lesion. 
7.2.4. 
Documentation of “target” and “non-target” lesions 
7.2.4.1. 
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. 
­ 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. 
­ 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, 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. 
Specific situations: 
­ Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), 
even if the nodes regress to below 10 mm 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. 
­ 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’. In this case a value 
must 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. 
­ 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’. 
­ An option of ‘Not Assessable’ for a lesion will only apply to lesions that that cannot be read 
due to technical reasons, for example: 
CT artefact.
Patient positioning where the lesions are obstructed or cannot be seen.


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Lesion that may not be seen in their entirety due to CT slice thickness.
7.2.4.2. 
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. 
­ 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. 
For additional guidance refer to RECIST 1.1. (Eisenhauer, 2009) and RECIST 1.1: Update and 
clarification (Schwartz, 2016). 
7.2.5. 
Response criteria 
On-site assessments will include the assessment of: 
­ Target and non-target tumour responses. 
­ New lesions if any 
­ Overall response. 
The above assessments will be made as per the time points identified in Section 4.1.2. 
7.2.5.1. 
Target and Non-target Response Assessments 
The definition of responses for Target and Non-target lesions is presented in Table (7.2.5.1) 1 
and Table (7.2.5.1) 2 respectively. 
Table (7.2.5.1) 1 – Target lesions response definitions 
TARGET LESIONS 
Lesions Response 
Definition 
Complete Response (CR) 
The disappearance of all target lesions. 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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Table (7.2.5.1) 2 – Non-target lesions response definitions 
NON-TARGET LESIONS 
Lesions Response 
Definition 
Complete Response (CR) 
The disappearance of all non-target 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 (not reaching the extent of ‘unequivocal 
progression). 
Progressive Disease (PD) 
Unequivocal progression of existing non-target lesions (see definition below). 
(Note: the appearance of one or more new lesions is also considered progression). 
When the patient has measurable disease and non-measurable disease, to achieve “unequivocal 
progression” on the basis of the non-target disease, there must be an overall level of 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.  
Tumour markers alone cannot be used to assess objective tumour response. If CEA level is 
initially above the upper normal limit, however, it must normalise for a patient to be considered 
in complete response. 
For additional guidance refer to RECIST 1.1. (Eisenhauer, 2009) and RECIST 1.1: Update and 
clarification (Schwartz, 2016). 
7.2.5.2. 
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. 
­ 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. 
­ For new lesions discovered by FDG-PET scan please refers to RECIST 1.1 (Eisenhauer, 
2009).  


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7.2.5.3. 
Overall Response Assessment 
Assessments will be based on the definitions provided in Table (7.2.5.3) 1. 
Table (7.2.5.3) 1 - Time point response for patients with target (±non-target) disease 
 Table (7.2.5.3) 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 
7.2.6. 
Best Overall Response Assessment 
The best overall response as per RECIST 1.1 is the best response recorded from the start of the 
study treatment until the end of treatment. 
In this study, the minimum time from baseline to assess a response of “stable disease” is 
6 weeks. 


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8.
ASSESSMENT OF SAFETY
All AEs and other situations relevant to the safety of the patients must be followed up, 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 study. 
8.1. Specification of safety parameters 
Safety measurements performed during the study are indicated in Table (4.1.2) 1 and 
Table (4.1.2) 2. 
8.2. Methods and measurement times 
8.2.1. 
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. ECG obtained prior to patient signed ICF may be 
used if the date is within 28 days of randomisation. 
­ Withdrawal visit. 
8.2.2. 
ECOG Performance Status 
Obtain an ECOG performance status score (Appendix 2) at the following time points:  
­ Within 7 days prior to randomisation. 
­ At C1D1 prior to study treatments administration only if there is more than 7 days since 
screening assessment. 
Note: ECOG must remain 0 or 1 during the baseline period and at the time of randomisation 
for the patient to remain eligible. 
­ Beginning with cycle 2, and for all subsequent cycles, obtain within 48 hours prior to study 
treatments administration. 
­ Withdrawal visit. 
8.2.3. 
Height, Vital Signs, Weight 
Obtain the patient’s height within 7 days prior to randomisation. 
Collect the patient’s vital signs (blood pressure, heart rate, body temperature) and body weight 
at the following time point: 
­ Within 7 days prior to randomisation. 
­ At C1D1 prior to study treatments administration only if there is more than 7 days since 
screening assessment. 
­ At C1D15. 
­ Beginning with cycle 2, and for all subsequent cycles,  
o
At D1, obtain within 48 hours prior to study treatments administration,
o
At D15 (only for patients in the trifluridine/tipiracil with bevacizumab arm), obtain
within 48 hours prior to bevacizumab administration.
(not mandatory in case of permanent discontinuation of bevacizumab).
­ Withdrawal visit. 


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Obtain all the vital signs in a position that is consistent for all time points for each patient. 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 and place the cuff at heart level. 
For weight measurement, only scales with a valid calibration or maintenance certificate must 
be used throughout the study. 
8.2.4. 
Physical Examination 
Perform a complete physical examination at the following time points: 
­ Within 7 days prior to randomisation. 
­ At C1D1 prior to study treatments administration only if there is more than 7 days since 
screening assessment. 
­ At C1D15. 
­ Beginning with cycle 2, and for all subsequent cycles,  
o
At D1, obtain within 48 hours prior to study treatments administration,
o
At D15 (only for patients in the trifluridine/tipiracil with bevacizumab arm), obtain
within 48 hours prior to bevacizumab administration.
(not mandatory in case of permanent discontinuation of bevacizumab).
­ Withdrawal visit. 
8.2.5. 
Clinical Laboratory Evaluations 
Laboratory tests will be collected and analysed by the study site’s certified laboratory during 
screening period and at C1D1 only if there is more than 7 days since screening assessment. 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. 
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. 
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. 
Any laboratory abnormality that has a clinical impact on the patient, e.g., results in delay of 
study medications 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 analysis to a clinical diagnosis that is already reported as an AE.  
All laboratory data will be analysed using NCI-CTCAE grade criteria (version 5.0). 
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. 


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8.2.5.1. 
Haematology 
Collect sample for haematological assessments at the following time points and when clinically 
indicated: 
­ Within 7 days prior to randomisation. 
­ At C1D1 prior to study treatments administration only if there is more than 7 days since 
screening assessment. 
Note: For screening and pre-dose C1D1, an assessment performed by the study site’s certified 
laboratory as per routine clinical practice, on samples collected before ICF signature, is 
acceptable and may not be repeated, only if the assessment is fully satisfying study protocol 
criteria in terms of completeness and time schedule. 
­ At C1D15 
Note: for patients in the trifluridine/tipiracil with bevacizumab arm, obtain within 48 hours 
prior to bevacizumab administration, 
­ Beginning with cycle 2, and for all subsequent cycles,  
o
At D1, obtain within 48 hours prior to study treatments administration,
o
At D15 (only for patients in the trifluridine/tipiracil with bevacizumab arm), obtain
within 48 hours prior to bevacizumab administration.
(not mandatory in case of permanent discontinuation of bevacizumab).
­ Withdrawal visit. 
Measure the following haematology parameters: haemoglobin, red blood cell count, white 
blood cell (WBC) count and differential count (neutrophils, lymphocytes), platelets. 
Note: for neutrophils and lymphocytes, parameters must be available in absolute value (not in 
percentage of WBC). 
8.2.5.2. 
Biochemistry 
Collect sample at the following time points for biochemistry assessments: 
­ Within 7 days prior to randomisation. 
­ At C1D1 prior to study treatments administration only if there is more than 7 days since 
screening assessment. 
Note: For screening and pre-dose C1D1, an assessment performed by the study site’s certified 
laboratory as per routine clinical practice, on samples collected before ICF signature, is 
acceptable and may not be repeated, only if the assessment is fully satisfying study protocol 
criteria in terms of completeness and time points. 
­ At C1D15 
Note: for patients in the trifluridine/tipiracil with bevacizumab arm, obtain within 48 hours 
prior to bevacizumab administration, 
­ Beginning with cycle 2, and for all subsequent cycles, 
o
At D1, obtain within 48 hours prior to study treatments administration
­ Withdrawal visit. 
Measure the following serum chemistry parameters: albumin, ionogram (sodium, potassium, 
chloride, total calcium, magnesium, phosphate), blood urea nitrogen (BUN), serum creatinine, 
glucose, AST (SGOT), ALT (SGPT), GGT, alkaline phosphatase, total bilirubin (in case of 
elevation in total bilirubin, fractionation (direct/indirect) should be performed), LDH. 


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Note: If BUN is not available, use the following conversion: 
Table (8.2.5.2) 1 - Correspondence between urea and BUN values 
BUN (mmol/L) = UREA (mmol/L) 
BUN (mg/dL) = UREA (mg/dL) x 0,467 
BUN (mg/dL) = UREA (mmol/L) / 0,3571 
8.2.5.3. 
Coagulation 
Collect sample at the following time points for International normalized ratio (INR): 
­ Within 7 days prior to randomisation. 
­ At C1D1 prior to study treatments administration only if there is more than 7 days since 
screening assessment. 
Note: For screening and pre-dose C1D1, an assessment performed by the study site’s certified 
laboratory as per routine clinical practice, on samples collected before ICF signature, is 
acceptable and may not be repeated, only if the assessment is fully satisfying study protocol 
criteria in terms of completeness and time points.  
­ Beginning with cycle 2, and for all subsequent cycles,  
o
At D1, obtain within 48 hours prior to study treatments administration
­ Withdrawal visit. 
8.2.5.4. 
Urinalysis 
Collect urine samples for qualitative analysis of proteinuria at the following time points: 
­ Within 7 days prior to randomisation. 
­ At C1D1 prior to study treatments administration only if there is more than 7 days since 
screening assessment. 
­ At C1D15 
Note: for patients in the trifluridine/tipiracil with bevacizumab arm, obtain within 48 hours 
prior to bevacizumab administration, 
­ Beginning with cycle 2, and for all subsequent cycles,  
o
At D1, obtain within 48 hours prior to study treatments administration
­ Withdrawal visit. 
If dipstick proteinuria ≥ 2+, a 24 hours-collection urine is required, and quantitative assessment 
of proteinuria will be performed. 
Note: If only quantitative proteinuria is done by the study site, the correspondence between 
quantitative and qualitative values must be clearly described. 
If no correspondence is available, please use the one in the table below: 
Table (8.2.5.4) 1 - Correspondence between qualitative and quantitative proteinuria values 
 Table (8.2.5.4) 1 (Cont'd) - Correspondence between qualitative and quantitative proteinuria values 
 
­ Negative < 10 mg/dL 
­ 2+ [100 – 300[ mg/dL 
­ Trace [10-30] mg/dL 
­ 3+ [300-1000] mg/dL 
­ 1+ [30 – 100] mg/dL 
­ 4+ > 1000 mg/dL 


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8.2.5.5. 
Pregnancy Testing 
If the patient is female 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 7 days prior to randomisation (only serum test).  
­ Withdrawal visit (if not performed within previous 4 weeks). 
Note: more frequent pregnancy tests should be performed if required by local law. 
8.3. Definition of Adverse events 
An AE 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 study treatments and/or 
experimental procedures, occurring or detected from the date the patient signs the information 
and consent form, irrespective of the period of the study (periods without administration of the 
study treatments are also concerned). 
An adverse event can therefore be: 
­ any unfavourable and unintended sign (including an abnormal finding from an additional 
examination such as 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 patient 
entered the study (increase in frequency and/or intensity), including the studied pathology, 
and detected during a study visit or at an additional examination or occurred since the previous 
study visit (including relevant event reported in patient’s diary or safety evaluation scale). 
Of note: 
­ Any hospitalisation for administration of anti-tumoural treatment and/or associated 
protocol (during or after the study) or other care measures for cancer (e.g. overnight 
hospital stay to receive a blood or platelets transfusion), for social reasons, educational 
purpose (e.g. learning of diabetes management by the patient) or routine check-up should 
not be considered as an adverse event and should not be reported in the e-CRF. 
­ The following procedures, whether planned before the study or not, whether leading to a 
hospitalisation or not, should not be reported in the e-CRF and kept in the source data 
(or patient file):   
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).


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8.4. Definition of 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 normal life, in other words leads to a persistent 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.
8.5. Definition of Overdose 
This refers to any intake of a quantity of IMP or a product other than the IMP taken as part of 
the protocol (NIMP) which is above the maximum dose recommended in the study protocol, 
independently of the occurrence of any adverse event. 
The quantity should be considered per administration or cumulatively regarding the maximum 
dose recommended in the study protocol. An overdose with trifluridine/tipiracil is defined as 
taking a dose beyond the recommended dose in one day or beyond the recommended total dose 
in each cycle (i.e., 35 mg/m²/dose or >160 mg/day for trifluridine/tipiracil). 
There is no known antidote available in case of trifluridine/tipiracil overdose. Overdose should 
be managed aggressively with close monitoring and administration of prophylactic and 
symptomatic therapies to prevent or correct potential side effects. 
For bevacizumab: please refer to Product Information (Appendix 7) for overdose management 
information. 
8.6. Definition of Adverse event of special interest 
Not applicable. 


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8.7. Definition of Events requiring an immediate notification (ERIN) 
An event must be notified immediately (i.e. without delay and within 24 hours following 
knowledge at the latest) to the sponsor if it is: 
­ a serious adverse event, 
­ an overdose of the study treatments even if asymptomatic,  
­ any intake of the study treatments by a person around the patient, 
­ a pregnancy, 
­ any events of COVID-19. 
8.8. Classification of an adverse event (seriousness, severity, causality, expectedness) 
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 study treatments. This evaluation must be assessed by the investigator and reported in the 
AE form. In addition, the sponsor will be responsible for the evaluation the expectedness of 
the event (See Section 8.9.3). 
The Seriousness should be evaluated according to international guidance (see definition 
Section 8.3, in accordance with ICH Topic E2A and DIRECTIVE 2001/20/EC OF THE 
EUROPEAN PARLIAMENT AND OF THE COUNCIL of 4 April). 
The severity of all AEs will be graded according to the NCI-CTCAE 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 study treatments, to the experimental procedures or to disease 
progression must be assessed when reporting the AE in the AE form. Cases ticked “related” by 
the investigator or judged by the sponsor as having a reasonable suspected causal relationship 
to the study treatments (AE linked to the mechanism of action of the study treatments…), will 
be considered as Suspected Adverse Drug Reaction. In general, if a relationship between AE 
and drug is at least reasonably possible (i.e. the relationship cannot be ruled out) it is to be 
considered as “related”. 
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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8.9. Reporting procedures 
8.9.1. 
Time frame for AE reporting 
Any event meeting the above mentioned definitions (see Sections 8.3 to 8.7) must be reported 
to the sponsor on an adverse event form if it occurred: 
-
before the first intake of the IMPs, for event 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 (NIMP),
-
at any time after the first intake of the IMPs up to the patient’s last IMPs intake for all
events,
-
up to 30 calendar days after the patient’s last IMPs intake for all ERIN, regardless of
the supposed role of the research (IMP, NIMP, 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, NIMP or experimental procedure).
Of note, events occurring between the signature of the ICF and the first study treatments 
administration for which the investigator does not consider an association with any 
procedure/condition required by the study protocol must be reported as medical history or 
as signs or symptoms related to the studied disease in the dedicated form of the e-CRF. 
Fatal event, related or not to the research, occurring between ICF signature and first IMP 
intake, should be reported on AE form.  
Figure (8.9.1) 1 - Rules for AE reporting 
All other AEs 
 to be reported as
Medical history
OR 
Signs & symptoms
related to the
studied disease
All fatal events and 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 IMPs 
Patient’s last IMPs 
intake 
30 calendar days 
after the patient’s 
last IMPs intake  


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8.9.2. 
Responsibilities of the investigator 
For any adverse event and special situation mentioned above the investigator must: 
­ Note in the patient’s medical file the date on which he/she learned of the event (at a follow-
up visit or a telephone contact with the patient or a third person, …) and any other relevant 
information which he/she has learned of the event,  
­ Assess the event in terms of seriousness, intensity and causality, 
­ Report the event to the sponsor using the AE form (in case of ERIN, the reporting should 
be done immediately), 
­ Document the event with additional useful information,  
­ Ensure the follow-up of the event,  
­ Fulfil his/her regulatory obligations to the CA and/or to the IRB/IEC, in accordance with 
local regulations. 
Moreover, the investigator must report to the sponsor and/or to the IRB/IEC and/or to the CA 
in accordance with the local regulation, any new information that might materially influence 
the benefit-risk assessment of the study treatments or that would be sufficient to consider 
changes in the study treatments administration or in the overall conduct of the clinical 
investigation. 
8.9.2.1. 
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. 
8.9.2.2. 
Follow-up of adverse events 
The investigator must ensure that follow-up of the patient 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 AE 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 AE has not resolved at the patient's final visit, the patient 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 patient is not done by the investigator him/herself (hospitalisation, 
followed by a specialist or the patient's general practitioner, …), the investigator will do 
everything to establish/maintain contact with the person/department in charge of follow-up of 
the patient. 


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8.9.2.3. 
Special situations (pregnancy, overdoses, intake of IMP by a person around the 
patient) 
Pregnancy 
If a female patient in the study becomes pregnant, the investigator must: 
­ stop immediately the study treatments, 
­ 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 patient 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 overdoses, details regarding
other medicinal products or substance,
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 patient 
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. 
8.9.2.4. 
Recording methods in the e-CRF 
AE must be documented on the “Adverse Event” page of the e-CRF. 
In case of chronic disease: 
­ if the disease is known when the patient 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 eventwhich will clearly describe the diagnosis. 
8.9.2.5. 
Procedure for an event requiring an immediate notification 
In case of an event requiring an immediate notification, the investigator must: 


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­ Immediately after being informed of this event, fill in the patient’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 a serious adverse event, 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 or by e-mail 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. 
8.9.3. 
Responsibilities of the sponsor 
In accordance with international guidance, 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. 
In addition, the sponsor is responsible for determining whether an AE is expected or 
unexpected. An AE will be considered unexpected if the nature, severity, or frequency of the 
event is not consistent with the risk information previously described for the IMP. 
Independently of the regulatory obligations of the investigator, the sponsor must report the 
pharmacovigilance data and any new safety finding likely to affect the benefit /risk balance of 
the product, required in ICH GCP guidelines and local regulations, to the appropriate 


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Authorities, to all the investigators involved and to the trial subjects involved - through the 
investigators - as mentioned in Section 13.4.  
The concerned authorities will be notified as soon as possible by the sponsor of the DSMB 
recommendations if any, where relevant for the safety of subjects (i.e. modification or 
termination of the study).  
8.10. Responsibilities of Data Safety Monitoring Committee 
As described in Section 12.4, the DSMB is an independent group of experts which provides 
expertise and recommendations to the International Coordinator and sponsor.  
In accordance with the charter and the rules for functioning, the DSMB is responsible for 
reviewing the safety data on a regular basis and providing written recommendations to the 
International Coordinator and the sponsor regarding the conduct of the study. 
8.11. Management of treatment dose adaptations due to toxicities 
For patients who have experienced a dosing modification, 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 e-CRF. 
General rules: 
­ Before starting a new treatment cycle, toxicity must have resolved as specified in the 
Sections 8.11.1 and 8.11.2. 
­ Treatment interruptions are regarded as lost treatment days and missed doses should not be 
replaced; the planned treatment schedule should be maintained. 
8.11.1. Trifluridine/tipiracil 
All toxicities related to trifluridine/tipiracil must have resolved to grade 1 or baseline before the 
start of a new treatment cycle. 
In the event of haematological and/or non-haematological toxicities, rules for 
trifluridine/tipiracil dose interruption and resumption are provided in Table (8.11.1) 1; rules for 
dose modifications are provided in Table (8.11.1) 2 and Table (8.11.1) 3. 
A new treatment cycle with trifluridine/tipiracil can be started only if neutrophils count is ≥1.5 
x 109/L and platelets count is ≥75 x 109/L. 
Table (8.11.1) 1 - Dose interruption and resumption criteria for haematological toxicities related to 
myelosuppression 
Parameter 
Interruption criteria* 
Resumption criteria** 
Neutrophils 
<0.5 × 109/L 
≥1.5 × 109/L 
Platelets 
<50 × 109/L 
≥75 × 109/L 
* Interruption criteria apply only during active treatment intake period (i.e., D1-5 and D8-12)
based on an unscheduled laboratory assessment.
**Resumption criteria apply to the start of the next cycle for all patients regardless of whether 
or not the interruption criteria were met. 


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Table (8.11.1) 2 - Recommended dose modifications in case of haematological adverse event related to 
myelosuppression 
Adverse event related to myelosuppression 
Recommended dose modifications 
Febrile neutropenia 
- Don’t start a new treatment cycle until the resumption
criteria are met (Table (8.11.1) 1).
- When resuming dosing, decrease the dose level by
5 mg/m² from the previous dose level (Table (6.1.3) 2).
- Dose reductions are permitted to a minimum dose of
20 mg/m²/dose twice daily.
- Do not increase dose after it has been reduced.
CTCAE Grade 4 neutropenia count <0.5 × 109/L 
that results in more than 1 week’s delay in start of 
next cycle. 
CTCAE Grade 4 thrombocytopenia <25 × 109/L 
that results in more than 1 week’s delay in start of 
next cycle. 
Table (8.11.1) 3 - Recommended dose modifications in case of non-haematological adverse event related to 
trifluridine/tipiracil 
Adverse event related to trifluridine/tipiracil 
Recommended dose modifications 
CTCAE non-hematologic grade 3 or 4 adverse 
reaction; except for grade 3 nausea and/or vomiting 
controlled by antiemetic therapy or diarrhoea 
responsive to antidiarrheal medicinal products. 
- Don’t start a new treatment cycle until toxicity resolves
to grade 1 or baseline.
- When resuming dosing, decrease the dose level by
5 mg/m² from the previous dose level (Table (6.1.3) 2).
- Dose reductions are permitted to a minimum dose of
20 mg/m²/dose twice daily.
- Do not increase dose after it has been reduced.
If the patient recovers from toxicities requiring treatment interruption: 
­ during the 2-week active treatment intake period of a cycle (treatment D1-D12) 
if no dose reduction is required, trifluridine/tipiracil may be resumed during that cycle.
Missed doses must not be caught up
if a dose reduction is required, trifluridine/tipiracil should be resumed at the start of the
next treatment cycle at the appropriate dose level.
­ during the rest period (D13-28): 
start the next cycle on schedule at the appropriate trifluridine/tipiracil dose level.
If the toxicities do not resolve during the given cycle to grade 1 or baseline, the start of the next 
cycle must be delayed for a maximum of 28 days from the scheduled start date of the next cycle. 
If more than 28 days are needed to recover, the patient will be withdrawn from treatment as 
described in the Section 5.6.1. 
8.11.2. Bevacizumab 
Dose reduction for adverse reactions is not recommended. If indicated, therapy should either 
be permanently discontinued or temporarily suspended as described in the Product Information 
(Appendix 7). If there is a medical condition developed that requires bevacizumab to be 
permanently withdrawn, the patient may continue with trifluridine/tipiracil alone. 
Bevacizumab should not be administrated alone in case of dose delay due to trifluridine/tipiracil 
toxicities. The cycle will be delayed, and bevacizumab will be restarted at the same time of 
trifluridine/tipiracil. 


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8.12. Recommendations regarding treatment of toxicities 
8.12.1. Management of nausea and vomiting 
Trifluridine/tipiracil has emetogenic potential. 
­ A single antiemetic agent, such as dexamethasone, a 5-HT3 receptor antagonist or a 
dopamine receptor antagonist, such as metoclopramide may be considered for prophylaxis. 
­ If a patient experiences acute or delayed nausea or vomiting due to trifluridine/tipiracil, it is 
advised that, at the next cycle, a higher antiemetic regimen may be given. 
­ In case a patient experiences of anticipatory nausea and vomiting, benzodiazepines are 
recommended. 
(Roila, 2016), (Hesketh, 2016) 
8.12.2. Management of diarrhoea 
Educate both patients and patients’ families regarding the potential seriousness of 
chemotherapy-induced diarrhoea. Instruct patients to immediately contact the study site staff at 
the first sign of loose stool. The patient should be instructed to record the number of stools and 
report symptoms indicating a complicated diarrhoea (see list below). 
Educate the patient regarding the dietary measures to be taken in case of diarrhoea. 
Provide patients with loperamide (or other standard antidiarrheal therapy) and instruct the 
patient on how to use it at the first sign of diarrhoea. 
Monitor the patient’s fluid and electrolyte balance, with appropriate intervention as clinically 
indicated with fluids and electrolyte replacement (Benson III, 2004). 
Mild to moderate diarrhoea (grade 1 or 2 according to NCT-CTCAE without complications): 
­ It is recommended to start dietary modifications and standard antidiarrheal therapy for 
example loperamide at an initial dose of 4 mg followed by 2 mg every 4 hours or after every 
unformed stool (not to exceed 16 mg/day).  
­ If diarrhoea resolves with antidiarrheal therapy, the dietary modifications should be 
continued (with a gradually addition of solid foods). Antidiarrheal therapy may be 
discontinued when the patient has been diarrhoea-free for at least 12 hours.  
­ If diarrhoea persists for more than 24 hours, the dose of antidiarrheal therapy should be 
increased (for loperamide increase to 2 mg every 2 hours), and oral antibiotics may be started 
as prophylaxis for infection.  
­  If diarrhoea has not resolved after 48 hours on initial treatment, the patient should be started 
on a second-line antidiarrheal agent. 
Complicated diarrhoea: 
­ Any grade 3 or 4 diarrhoea is classified as “complicated”. In addition, grade 1 or 2 diarrhoea 
and at least one of the following symptoms are also considered as complicated: 
fever, sepsis, moderate to severe cramping,
grade 2 nausea/vomiting,
decreased performance status,
neutropenia,
frank bleeding,
dehydration
­ Aggressive management of complicated cases should involve  
intravenous (IV) fluids;


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octreotide at a starting dose of 100 to 150 µg SC tid or IV (25 to 50 µg/h) if the patient is
severely dehydrated, with dose escalation up to 500 µg until diarrhoea is controlled,
administration of antibiotics (e.g., fluoroquinolone).
­ Stool work-up (evaluation for blood, faecal leukocytes, C difficile, Salmonella, E coli, 
Campylobacter, and infectious colitis), complete blood count, and electrolyte profile should 
be performed. 
­ Continue intervention as described until the patient has been diarrhoea-free for 24 hours. 
8.12.3. Management of mucosal injury 
Mucositis refers to mucosal damage secondary to cancer therapy occurring in the oral cavity; 
pharyngeal, laryngeal, and oesophageal regions; and other areas of the gastrointestinal tract. 
Oral mucositis presents as erythema and/or ulceration of the oral mucosa. Gastrointestinal 
mucositis presents with debilitating symptoms such as pain, nausea/vomiting, and diarrhoea. 
Prevention and education of the patient: 
­ The patient must be appropriately educated about oral complications before treatment and 
be advised to have regular dental examinations and inform the health care professional at 
first signs and symptoms of oral complications. Sources of trauma (e.g. sharp edges and ill-
fitting prostheses) should be eliminated and painful stimuli such as hot foods and drinks and 
hard, sharp, or spicy foods should be avoided. 
­ Sodium bicarbonate mouthwash can be used to rinse the mouth (4 to 6 times a day) as long 
as the patient is treated by bevacizumab. 
Treatment of mucositis: 
­ 0.5% doxepin mouthwash and transdermal fentanyl may be used to treat pain due to oral 
mucositis. 
­ For bevacizumab-related stomatitis: 
The frequency of use of sodium bicarbonate containing mouthwash can be increased, if
necessary, up to each hour to treat stomatitis.
Sugarless chewing gum or candy, salivary substitutes or sialagogues should be considered
to treat oral dryness.
Adequate pain management, e.g. anaesthetic mouthwashes (viscous lidocaine 2%),
coating agents, or systemic analgesics following the WHO pain management ladder may
be provided.
Coating agents, topical analgesic or anti-inflammatory agents, topical anaesthetics, and
alternative mouthwashes may be considered.
(Lalla, 2014), (Peterson, 2015) 
8.12.4. Management of febrile neutropenia and anaemia 
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 Recommendations for 
the Use of WBC Growth Factors: American Society of Clinical Oncology Clinical Practice 
Guideline Update, 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.  


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9.
OTHER ASSESSMENTS NOT SPECIFICALLY RELATED TO EFFICACY OR
SAFETY
9.1. Assessments done at baseline 
9.1.1. 
Assessments related to inclusion criteria. 
9.1.1.1. 
Informed consent 
Obtain signed and dated ICF from the patient during the screening visit prior to the 
implementation of study procedures required by the protocol. Please refers to Section 13.3. 
9.1.1.2. 
Histological/Cytological Confirmation 
Histological confirmation of adenocarcinoma of the colon or rectum should be documented in 
the patient’s source documents. The pathology report should be available in the patient’s source 
documents. 
9.1.1.3. 
RAS status 
RAS status will be collected in the e-CRF and must have been determined based on local 
assessment of tumour biopsy and documented in the patient’s source documents. 
9.1.2. 
Assessments not related to inclusion criteria. 
9.1.2.1. 
Patient Numbering 
Once the patient has signed ICF, the study site will connect to the IWRS for patient’s 
registration and to obtain a patient's number (see the IWRS manual for details). Each patient 
will be assigned a unique 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. 
9.1.2.2. 
Demography 
Collect demography data (age, sex, ethnic origin). 
9.1.2.3. 
Medical history 
Obtain a complete medical history. 
Of note, events occurring between the signature of the ICF and the first study treatments 
administration for which the investigator does not consider an association with any 
procedure/condition required by the study protocol must be reported as medical history in the 
dedicated form of the e-CRF. 
9.1.2.4. 
Previous surgery, radiotherapy and treatments related to the colorectal cancer 
Collect previous surgery, radiotherapy and treatments related to the colorectal cancer. 
9.1.2.5. 
Baseline Signs and Symptoms 
Signs and symptoms related to the colorectal cancer present following ICF signature and before 
the first study treatments administration should be recorded in the patient’s source documents. 


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9.1.2.6. 
Primary tumour localisation 
The localisation of the primary tumour will be collected in the e-CRF if available. 
Note: the localisation is defined in the table below: 
Table (9.1.2.6) 1 - Primary tumour localisation 
 Table (9.1.2.6) 1 (Cont'd) - Primary tumour localisation 
 
Right 
Left 
­ Cecum 
­ Appendix 
­ Ascending colon 
­ Hepatic flexure 
­ Transverse colon 
­ Splenic flexure 
­ Descending colon 
­ Sigmoid colon 
­ Rectosigmoid 
segment 
­ Rectum 
In the case the patient presents multiple tumours in both sides, the disease will be considered 
as “right-sided”. 
9.1.2.7. 
BRAF status and MMR/MSI status  
BRAF status and MMR/MSI status will be collected in the e-CRF if available. 
9.2. Measurement of drug concentration 
Not applicable. 
9.3. Pharmacodynamics measurements 
Not applicable. 
9.4. Assessment of biomarkers 
Not applicable. 
9.5. Quality of Life 
EORTC Quality of Life Questionnaire - Core Questionnaire (EORTC QLQ-C30) (Appendix 5) 
and 5Q-5D-5L (Appendix 6) will be completed by the patient on an e-PRO, independently of 
the study personnel at the following time points, at the beginning of each visit: 
­ Within 7 days prior to randomisation (baseline), 
­ Every cycle, prior to any study procedure, 
­ Withdrawal visit. 
Patients will be provided with specific instructions in order to be comfortable with the tablet 
and enhance the quality of the data. In case the patient is not able to use e-PRO, a caregiver (not 
a medical/investigator staff) will be allowed to read the questions to the patient and to collect 
the answer without any interpretation of the questions and the answers. Data entered by the 
patient will be sent to a central database via a secured transfer. 


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10. STATISTICS
10.1. Statistical analysis 
Statistical analysis will be produced by the Center of Excellence Methodology and Data 
Valorisation. 
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. Analysis sets / Treatment groups 
10.1.1.1. Analysis sets  
­ Full Analysis Set (FAS): 
In accordance with the intention-to-treat principle and the section 5.2.1 of ICH E9 guideline, 
all patients to whom a therapeutic unit was randomly assigned using IWRS. Patients in the FAS 
will be analysed in the arm they were assigned by randomization. 
­ Safety Set (SS): 
All patients having taken at least one dose of IMPs. Patients will be analyzed according to the 
treatment actually received. 
10.1.1.2. Treatment groups 
Treatment groups considered for the analysis will be the following: 
­ Trifluridine/tipiracil + bevacizumab 
­ Trifluridine/tipiracil 
10.1.2. Statistical methods 
10.1.2.1. General considerations 
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 or to censoring): total number of patients, total 
number and percentage of patients having an event overall and by level of adjustment 
qualitative variable, number of patients at risk, number of patients with censored data, 
number of patients with event of interest. 
10.1.2.2. Disposition and baseline characteristics 
The patients’ disposition and baseline characteristics will be described in the FAS by treatment 
arms 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 well as the disposition of 


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patients, including reasons for discontinuation and protocol deviations at baseline and during 
study. 
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. 
10.1.2.3. Treatments of patients 
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. 
The follow-up duration will be calculated overall and in each arm with the reverse Kaplan-
Meier method. 
The 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 as 
protocol deviation. 
10.1.2.4. Efficacy analysis 
Primary objective 
The primary objective is to demonstrate the superiority of trifluridine/tipiracil in combination 
with bevacizumab over trifluridine/tipiracil monotherapy in terms of OS in patients with 
refractory mCRC. 
Secondary objectives 
Secondary objectives are to estimate the effect of trifluridine/tipiracil in combination with 
bevacizumab versus trifluridine/tipiracil monotherapy in terms of PFS, ORR, and DCR in 
patients with refractory mCRC.  
Other secondary objectives are to compare the safety and tolerance, and the impact on quality 
of life (QoL) of trifluridine/tipiracil in combination with bevacizumab to trifluridine/tipiracil 
monotherapy in patients with refractory mCRC. 
Intercurrent events 
During the study the following intercurrent events could occur: 
Administration of further anti-cancer therapy
Treatment discontinuation
Treatment switch (from trifluridine/tipiracil in combination with bevacizumab to
trifluridine/tipiracil monotherapy and from trifluridine/tipiracil monotherapy to
trifluridine/tipiracil in combination with bevacizumab)
Estimands of interest 
The attributes treatment and population will be the same for all estimands of interest: 
­ Treatment: Trifluridine/tipiracil + bevacizumab vs trifluridine/tipiracil monotherapy. 
­ Population: Full Analysis Set (FAS).  


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The following estimands will be studied: 
Estimand 
Variable 
Population 
level 
summary 
Handling IEs 
Primary estimand: effect of the randomized 
treatments on the survival duration in all subjects 
regardless of whether or not intercurrent events 
occur 
OS 
HR 
Treatment policy 
strategy 
Effect of the randomized treatments on the survival 
duration in all subjects before patients receive 
further anti-cancer therapy 
OS 
HR 
While on 
treatment strategy 
Effect of the randomized treatments on 
progression-free survival in all subjects regardless 
of whether or not intercurrent events occur 
PFS 
HR 
Treatment policy 
strategy 
Effect of the randomized treatments on response in 
all subjects before modification of randomized 
treatment 
ORR 
DCR 
Risk 
difference 
While on 
treatment strategy 
With: 
­ OS: overall survival defined as the observed time elapsed between the date of randomization 
and the date of death due to any cause 
­ PFS: progression-free survival based on investigator judgement and defined as the time 
elapsed between the randomization and the date of radiologic tumour progression (according 
to RECIST version 1.1 (Eisenhauer, 2009) or death from any cause. 
­ ORR: overall response rate defined as the proportion of patients with objective evidence of 
complete response (CR) or partial response (PR) according to RECIST version 1.1 criteria 
and using investigator’s tumour assessment, 
­ DCR: disease control rate defined as the proportion of patients with objective evidence of 
CR or PR or stable disease (SD) according to RECIST version 1.1 criteria and using 
investigator’s tumour assessment. 
Estimands and the way for handling IEs will be detailed in the following paragraphs. 
10.1.2.4.1. Primary estimand based on the OS 
As explained before, the primary estimand of interest is the effect of the randomized treatments 
on the survival duration in all subjects regardless of whether or not intercurrent events occur 
(treatment policy strategy). The motivation for this choice is to assess the efficacy of the 
trifluridine/tipiracil in combination with bevacizumab compared to trifluridine/tipiracil 
monotherapy under the ITT principle (intercurrent events are considered to be part of the 
treatments being compared). 
All data collected during the trial regardless of occurrence of an IE will be used. This is aligned 
with the treatment policy strategy. 


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10.1.2.4.1.1. Primary analysis 
The distribution of OS will be compared between the two treatment groups using a stratified 
log-rank test at one-sided 2.5% level of significance (stratification factors based on IWRS data). 
OS for each arm will be summarized using Kaplan Meier curves and further characterized in 
terms of the median and survival probabilities at 6, 12 and 18 months along with the 
corresponding 2-sided 95% CI for the estimates. 
The hazard ratio of OS with its 95% confidence interval will be estimated with a stratified Cox 
proportional hazard model (stratification factors based on IWRS data). 
For missing data (not linked to intercurrent events), i.e. patients without documentation of death 
(lost to follow-up, withdrawal of consent, administrative end of study), the OS will be censored 
on the last contact date the patient was known to be alive or the cut-off date, whichever is 
earlier.  
10.1.2.4.1.2. Sensitivity analyses 
As sensitivity analyses, the following analyses will be done: 
­ The proportional hazards assumption will be checked. If relevant, other statistical method 
could be used. 
­ The distribution of OS will be compared between the treatment groups using an unstratified 
log-rank test and the hazard ratio (together with associated 95% CI) resulting from an 
unstratified Cox model will be presented. 
­ OS analysis excluding patients not fulfilling one of the following criteria: 
Has histologically confirmed unresectable adenocarcinoma of the colon or rectum
Has received a maximum of 2 prior chemotherapy regimens for the treatment of advanced
colorectal cancer and had demonstrated progressive disease or intolerance to their last
regimen
Has measurable or non-measurable metastatic lesion(s) as defined by Response
Evaluation Criteria in Solid Tumours (RECIST) version 1.1
Has an Eastern Cooperative Oncology Group (ECOG) performance status ≤1
More than 2 prior chemotherapy regimens for the treatment of advanced colorectal cancer
Has previously received trifluridine/tipiracil
Does not currently received or has not received anticancer therapies within 4 weeks prior
to randomisation
Other sensitivity analyses will be defined in the SAP if necessary. 
10.1.2.4.1.3. Supplementary analyses 
Subgroup analyses 
OS subgroup analyses are planned to further explore the homogeneity of the treatment effect 
across patient subsets. Depending on the sample size, the following subgroups will be 
examined: region (North America, European Union, Rest of the World), time since diagnosis 
of 1st metastasis (<18, ≥18 months), RAS (wild, mutant), location of primary disease (right, 
left), ECOG performance status (0, 1), gender (female, male), age (<70, ≥70 years), prior 


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surgical resection (yes, no), number of metastatic sites (1-2, ≥3), neutrophils to lymphocytes 
ratio (NLR<3, NLR≥3), number of prior regimens, BRAF (wild, mutant) and MSI status 
(MSI-H, MSS/MSI-L), prior bevacizumab (yes, no), subsequent regorafenib (yes, no). 
An unstratified Cox-regression model with treatment arm as predictor variable will be fitted 
separately for each subgroup category. The hazard ratio for treatment along with the associated 
95% confidence interval will be provided. 
10.1.2.4.2. Additional estimand based on OS 
The other estimand based on OS is defined in order to assess the effect of the randomized 
treatments on the survival time in all subjects before patients receive further anti-cancer therapy 
(while on treatment strategy). The aim of this estimand is to evaluate the effect of the study 
treatment without a potential effect of another therapy 
The use of data post intercurrent events will be different according to the IE: 
-
For IE “administration of further anti-cancer therapy” and “treatment switch”: data
obtained post IE will not be used for the analysis. OS will be censored at the time of
administration of further anti-cancer therapy.
-
For IE “treatment discontinuation”: time of death for any cause after treatment
discontinuation will be taken into account.
These strategies are aligned with this estimand. 
The distribution of OS will be compared between the two treatment groups using a stratified 
log-rank test at one-sided 2.5% level of significance (stratification factors based on IWRS data). 
For missing data (not linked to intercurrent events), i.e. patients without documentation of death 
(lost to follow-up, withdrawal of consent, administrative end of study), the OS will be censored 
on the last contact date the patient was known to be alive or the cut-off date, whichever is 
earlier. 
Other estimands will be defined in the SAP if necessary. 
CCI


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10.1.2.4.3. Secondary estimands based on PFS, ORR, and DCR 
Secondary estimand based on PFS 
Important secondary estimands of interest is the effect of the randomized treatments on 
progression-free survival in all subjects regardless of whether or not intercurrent events occur 
(treatment policy strategy).  
All data collected during the trial regardless of occurrence of an IE will be used. This is aligned 
with the estimand and the treatment policy strategy. 
The following analyses will be done as primary analyses: 
The distribution of PFS will be compared between the two treatment groups using a
stratified log-rank test at one-sided 2.5% level of significance (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 3, 6, 9 and 12 months
along with the corresponding 2-sided 95% CI for the estimates.
The hazard ratio of PFS with its 95% confidence interval will be estimated with a
stratified Cox proportional hazard model (stratification factors based on IWRS data).
PFS is identified as the key secondary variable. A hierarchical testing strategy, where PFS is to 
be statistically evaluated and interpreted only if the primary efficacy estimand OS is 
significantly different between the 2 treatment groups, will be used to control the overall type- 
I error rate. 
The following analyses will be done as sensitivity analyses: 
The distribution of PFS will be also compared between the treatment groups using an
unstratified log-rank test and the hazard ratio (together with associated 95% CI) resulting
from an unstratified Cox model will be presented.
An analysis that considers clinical progression and administration of further anti-cancer
therapy as PFS events in addition to the radiological progression or death.
For missing data (not linked to intercurrent events), i.e. patients who were lost to follow-up or 
who have withdrawn their consent without radiological progression or reached the time point 
of analysis without a known record of death or radiological progression, the PFS will be 
censored at the date of last evaluable tumour assessment or the cut-off date, whichever is earlier. 
The same subgroup analyses as used for the primary estimand will be done for PFS. 
Secondary estimands based on ORR and DCR 
Other secondary estimand of interest are the effect of the randomized treatments on response 
in all subjects before modification of randomized treatment. 
Responses recorded after intercurrent event will be excluded. This is aligned with the estimand 
and the treatment while on treatment strategy. 


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The following analyses will be done: 
­ ORR based on the investigator’s tumour assessment will be compared in the FAS between 
treatment arms using Fisher’s exact test and 2-sided 95% Clopper-Pearson CIs. A 2-sided 
95% CI for the difference in ORR between the two treatment arms will also be provided 
based on the normal approximation. If a stratified analysis is required a Cochran-Mantel-
Haenszel (CMH) test will be used. A 2-sided 95% CI for the difference in ORR between the 
two treatment arms will also be provided based on the normal approximation. 
­ DCR based on the investigator’s tumour assessment will be compared in the FAS between 
treatment arms using Fisher’s exact test and 2-sided 95% Clopper-Pearson CIs. A 2-sided 
95% CI for the difference in DCR between the two treatment arms will also be provided 
based on the normal approximation. If a stratified analysis is required a Cochran-Mantel-
Haenszel (CMH) test will be used. A 2-sided 95% CI for the difference in DCR between the 
two treatment arms will also be provided based on the normal approximation. 
As supplementary analysis, ORR and DCR will be evaluated on population evaluable for 
tumour response.   
For missing data (not linked to intercurrent events), an unfavourable outcome will be taken into 
account.  
10.1.2.5. Quality of Life analysis 
Endpoints: 
­ EORTC QLQ-C30 questionnaire  
­ EORTC EQ-5D-5L questionnaire 
Analysis:  
­ EORTC QLQ-C30: 
Patients from the FAS should have completed at least one questionnaire item at baseline and 
during the study period will be analysis in the arm they were assigned by randomization. 
The raw QoL data will be scored according to the EORTC scoring manual and the change in 
score from baseline in the global health status (GHS) scale is identified as the primary QoL 
variable of interest. 
The completion and compliance rates will be summarised by treatment group for each 
scheduled assessment timepoints. 
The completion rate is defined as the rate of patients who completed the QoL instrument among 
patients of FAS. 
The compliance rate is defined as the rate of patients who completed the QoL instrument among 
patients still on treatment at each visit. 
Baseline values and changes in scores from baseline (GHS and each sub-scale score) will be 
summarized at each scheduled assessment time point by descriptive. 
A repeated-measures mixed-effects model (SAS PROC MIXED) that includes terms for 
treatment arms, baseline stratification factors, baseline sub-scale score and time of visit will be 
used to compare the two treatment groups with respect to changes from baseline in the 3 sub-
scales scores longitudinally over time (GHS, functional scale and symptoms scale).  


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Time to definitive ≥10 points deterioration from baseline in the GHS and in each sub-scale, will 
be compared between the two treatment arms in the FAS using the stratified log-rank test at a 
2-sided 5% level of significance (strata based on IWRS data). Death will be considered to be a
deterioration event of QoL. Patients receiving any further anti-neoplastic therapy before
definitive worsening will be censored at the date of their last QoL assessment before starting
this therapy. Patients that have not worsened as of the cutoff date for the analysis will be
censored at the date of their last assessment (questionnaire) before the cutoff. Patients without
evaluable questionnaire at baseline will be censored at their randomization date + 1 day. The
distributions will be described using Kaplan-Meier curves including the median time to
definitive 10 points deterioration.
­ EORTC EQ-5D-5L: 
EQ-5D-5L assessment will be considered non-evaluable when responses are missing for one or 
more of the dimensions. Patients from the FAS with an evaluable EQ-5D-5L assessment at 
baseline and at least one evaluable assessment post baseline will be analysed in the arm they 
were assigned by randomization. 
The dimensional 5-level system will be converted into a single index utility score: the utility 
index will be derived according to Euroqol specific country algorithms. 
The completion and compliance rates will be summarised by treatment group for each 
scheduled assessment timepoints. 
The completion rate is defined as the rate of patients with evaluable EQ-5D-5L assessment 
among patients of FAS. 
The compliance rate is defined as the rate of patients with evaluable EQ-5D-5L assessment 
among patients still on treatment at each visit. 
A breakdown table to include the proportions of reported problems at baseline versus each 
scheduled assessment timepoint will be presented in each dimension of EQ-5D-5L by treatment 
arms. 
Baseline values and changes in score from baseline in EQ-5D-5L VAS and EQ-5D-5L health 
utility index will be presented by treatment arms at each scheduled assessment timepoint by 
descriptive statistics (N, mean/proportion median, SD, Q1, Q3).  
A repeated-measures mixed-effects model (SAS PROC MIXED) that includes terms for 
treatment, baseline stratification factors, baseline score and time of visit will be used to compare 
the two treatment groups with respect to changes from baseline in the EQ-5D-5L VAS and EQ-
5D-5L health utility index.  
10.1.2.6. Safety analysis 
All patients included in the Safety set (SS) will be evaluated by treatment arms unless otherwise 
specified. 
10.1.2.6.1. Adverse events 
Number of events, number and percentage of patients reporting at least one event, presented by 
primary system organ class and/or preferred term (depending on the analysis), will be provided 
for serious adverse events and emergent adverse events over the study and treatment periods, 
respectively. 


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Emergent adverse events will be described according to the seriousness, the intensity, the 
relationship, the action taken regarding the IMP, the requirement of added therapy, the outcome 
and the time to onset. 
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. 
10.1.2.6.2. Clinical laboratory evaluation 
For haematological, biochemistry, urinary and coagulation parameters, descriptive statistics on 
value at baseline, on value at each post-baseline visit under treatment, on last post-baseline 
value under treatment and, on change from baseline to last post-baseline value under treatment 
will be provided. 
For all clinical laboratory parameters (except urinary parameters), the following analysis will 
be performed: 
Laboratory parameters classified (number and percentage of patients in each class) according 
to these reference ranges and using shift tables from baseline to the worst (high and/or low) 
values under treatment. 
10.1.2.6.3. Vital signs, clinical examination and other observations related to safety 
10.1.2.6.3.1. 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. 
Time to ECOG performance status worsening will be analyzed in the FAS using Kaplan-Meier 
methodology and compared between treatment groups with a stratified logrank test (strata based 
on IWRS data). To be considered as a worsening, the ECOG PS must be increased by at least 
one category and to at least a minimal PS value of 2. Patients without ECOG PS worsening will 
be censored at the last recorded ECOG PS assessment. 
10.1.2.6.3.2. 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 
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).  
10.1.2.7. Biomarkers analysis 
Not applicable. 


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10.1.2.8. Interim analysis 
Not applicable.   
10.2. Determination of sample size 
Calculations are done with EAST 6.4 software. 
A maximum of 331 events (deaths for any cause) will be required for the primary analysis to 
detect a hazard ratio of 0.70 with 90% power using a log-rank test at one-sided cumulative 2.5% 
level of significance. Based on the data from the RECOURSE study (Mayer, 2015), the median 
duration of OS in the control group is expected to be around 7.1 months. A hazard ratio of 0.70 
translates into 3 months increase of the median OS in the experimental arm (10.1 months) 
compared to the control arm. Based on the assumption that enrolment will continue for 
approximately 12 months, and that about 5%/year of the subjects will drop out, a total of 490 
patients randomized in a 1:1 ratio will be needed to observe the 331th OS events approximately 
9 months after the last patient randomization. 


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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 CA to have direct access to source data / documents. 
12. QUALITY CONTROL AND QUALITY ASSURANCE
12.1. Study monitoring 
Study site monitoring is conducted to ensure that the rights and well-being of human subjects 
are protected, that the reported trial data are accurate, complete, and verifiable, and that the 
conduct of the trial is in compliance with the currently approved protocol/amendment(s), 
with Good Clinical Practice (GCP), and with applicable regulatory requirement(s).  
Monitoring for this study will be performed by the structure mentioned in Section 1. 
Details of study site monitoring are documented in a Clinical Monitoring Plan (CMP). The 
CMP describes in detail who will conduct the monitoring, at what frequency monitoring will 
be done, at what level of detail monitoring will be performed, and the distribution of monitoring 
reports.  
12.1.1. Before the study 
The investigator will allow the monitor to visit the study site and facilities where the study will 
take place in order to ensure compliance with the protocol requirements. 
12.1.2. During the study 
The investigator will allow the monitor to: 
­ review of the study site’s processes and procedures,  
­ verify appropriate clinical investigator supervision of study site staff and third-party vendors, 
­ inspect the study site, the facilities and the material used for the study, 
­ meet all members of his/her team involved in the study, 
­ consult the documents relevant to the study, 
­ have access to the e-CRF (i.e. access to an analogic phone line or his/her computer) and/or 
to the e-PRO service provider’s database to check that they been filled out correctly, 
­ check that the e-CRF and e-PRO have been filled out correctly, 
­ directly access source documents for comparison of data therein with the data in the e-CRF 
and the e-PRO service provider’s database, 
­ verify that the study is carried out in compliance with the protocol and local regulatory 
requirements. 
The 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. 


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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 not validated by the sponsor, the investigator 
undertakes: 
­ at the start of the study, to print the medical files of all patients 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 patients. The monitor will personally sign and date the first (or last) 
page then initial all pages in each paper print-out. 
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 
patients 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 patients. 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 patients. 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 him/her and by the 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 the 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...). 


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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 CA may also carry out an inspection in the 
facilities of the sponsor and/or the study site(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 CA 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 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 patients 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 CA and persons responsible for the audit to the 
computerised medical files of all patients, 
­ 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. 
12.4. Supervisory committees 
The DSMB will comprise of medical oncologist and statisticians, all independent from the 
sponsor and investigative sites and selected as to avoid conflict of interest and having 
experience in randomised clinical trials in oncology involving a DSMB. 
The primary objective of this DSMB is to provide independent safety monitoring comparing 
safety between the both study arms. 
A DSMB charter will be written to establish well-defined standard operating procedures 
including meeting proceedings and structure, data assessments, documentation and record 
keeping, process for DSMB recommendations, and regulatory reporting as applicable. The 
charter will be written with procedures ensuring the minimization of bias. 
DSMB recommendations will be forwarded to the IRB/IEC/CA only if relevant for the safety 
of patients. 


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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, the insurance certificate, the trifluridine/tipiracil Investigator’s Brochure, the 
Product Information of bevacizumab will be submitted to 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 1), with the GCP and with the 
applicable regulatory requirements. 
13.3. Participant information and informed consent 
In any case, the patient (and/or his/her legal representative, when required) 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 required to collect written consent from 
each patient before his/her participation in the study. Prior to this, the investigator or his/her 
delegate must inform each patient of the objectives, benefits, risks and requirements imposed 
by the study, as well as the nature of the IMPs. 
The patient 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. 
One, or two if required by local regulation, original information and consent form(s)must be 
completed, dated and signed personally by the participant and by the person responsible for 
collecting the informed consent. 
If the patient is unable to read, an impartial witness should be present during the entire informed 
consent discussion. The patient 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 patient will be given one signed copy (or original if required by local regulation) of the 
information and consent form. A signed 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 CA. 


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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, except for an amendment 
required to eliminate an immediate risk to the study patients. 
Each patient affected by the amendment or an independent witness must complete, date and 
sign one, or two if required by local regulation, originals of the new version of the information 
and consent form together with the person who conducted the informed consent. He/she will 
receive one signed copy (or original, if required by local regulation) of the amendment to the 
information and consent form. The signed original(s) will be kept by the investigator. 


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14. DATA HANDLING AND RECORD KEEPING
14.1. Study data 
A 21 CFR Part 11-compliant electronic data capture system is going to be used for this study. 
An 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. in compliance with its specifications. The investigator 
or a designated person from his/her team will be trained for the use of the e-CRF by the sponsor 
or Sponsor’s representatives. 
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 patient’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 patient visit, and all other documents provided by the sponsor (e.g. documents relating to 
the study treatments management…). 
Data recorded directly on e-CRF and considered as source data (see Section 4.5) must be 
collected immediately in the e-CRF. The other e-CRF forms must be completed as soon as 
possible following each visit. 
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 INFORM 
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. 
Data will be verified in accordance with the monitoring strategy defined for the study. 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 patient, 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 or an authorized member of his/her team will have to 
download from the e-CRF an electronic file containing patient data from his/her centre for 
archiving it in the study file (see Section 14.3). 


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14.2. Data management 
Data are collected via an e-CRF and stored in a secured database. 
For data collected on the e-CRF, the Clinical Data Management 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 
respond to the query and make any necessary changes to the data. 
For data transferred from e-PRO, the Clinical Data Management of I.R.I.S. is responsible for 
data transfer: e-PRO provider provides electronic transfer of computerised data to the Clinical 
Data Management of I.R.I.S. Data are transferred according to a transfer protocol issued by the 
I.R.I.S. data manager.
For data transferred from IWRS, the Data & Clinical Logistics of I.R.I.S. is responsible for data 
transfer: IWRS provider provides 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 and procedures using MedDRA, 
­ medications using World Health Organization, Drug Dictionary (WHO-Drug). 
The coding process is described in a specification manual. 
The investigator ascertains he/she will apply due diligence to avoid protocol deviations. Under 
no circumstances should the investigator contact the sponsor or its representatives monitoring 
the study, if any, to request approval of a protocol deviation, as no deviations are permitted. If 
the investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by the sponsor 
and approved by the IRB/IEC it cannot be implemented. All important protocol deviations will 
be recorded and reported in the clinical study report. 
When data validation is achieved, a reviewof 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 the study treatments codes will be unblinded and made available 
for data analysis. 
14.3. Archiving 
The investigator will keep all information relevant to the study for at least 25 years after the 
end of the study, or more if specified by the local regulation.  
At the end of the study, the investigator or an authorized member of his/her team will download 
an electronic copy of each participant’s data from the e-CRF and should keep it in a reliable, 
secure and durable location. The file includes all data and comments reported in the e-CRF, the 
history of all queries and signatures and the full audit trail reports.  
The file must include appropriate restrictions (password protection) and adequate protection 
from loss, physical damage or deterioration for the duration of the archiving period. 


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16. OWNERSHIP OF THE RESULTS – DATA SHARING POLICY AND
PUBLICATION POLICY
I.R.I.S. and TOI, acting as the study sponsor, assume full responsibilities relating to this
function and retains exclusive property rights over the results of the study, which it may use as
it deems fit.
I.R.I.S. and TOI will ensure that the key design elements of this protocol will be posted in a
publicly accessible database such as clinicaltrials.gov. In addition, upon study completion and
finalization of the study report, the results of this study will be either submitted for publication
and/or posted in a publicly accessible database of clinical study results.
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. in 
accordance with the guidelines set forth in the applicable publication policy or financial 
agreement. 
The investigator, who submitted the project, shall take the sponsor's comments into due 
consideration.  
As the study is a multicentre one, the first publication must be performed only with data 
collected from several study sites and analysed under the responsibility of I.R.I.S. and TOI. 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 other investigators and I.R.I.S. and TOI has been provided. 
The publication policy will be defined in a separate document 
Data Sharing Policy is available at https://clinicaltrials.servier.com/data-request-portal/. 
Researchers can ask for a study protocol, patient-level and/or study-level clinical trial data 
including clinical study report. 
They can ask for all interventional clinical studies: 
•
submitted for new medicines and new indications approved after 1 January 2014 in the
European Economic Area (EEA) or the United States.
CCI


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•
Where Servier or an affiliate are the Marketing Authorization Holders. The date of the
first Marketing Authorization of the new medicine (or the new indication) in one of
the EEA Member States will be considered within this scope.
In addition, Servier’s data sharing policy includes all interventional clinical studies in 
patients: 
•
sponsored by Servier,
•
with a first patient enrolled as of 1 January 2004 onwards,
•
for New Chemical Entity or New Biological Entity (new pharmaceutical form
excluded) for which development has been terminated before any Marketing
authorization (MA) approval.
The datasets generated and/or analysed during the current study will be available upon request 
from clinicaltrials.servier.com after the Marketing Authorisation has been granted. 
Summary results and a lay summary will be published on clinicaltrials.servier.com within 12 
months after the end of the study.  
The results will be submitted for publication in scientific literature within 18 months after the 
end of the study.  


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17. ADMINISTRATIVE CLAUSES
17.1. Concerning the sponsor and the investigators 
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. 
With the agreement of the patient, the investigator will inform the patient’s general practitioner 
about his/her patient’s participation in a clinical study. 
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 and approved by the International Coordinator 
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 the 
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, except for a measure required to eliminate an 
immediate risk to the study patients. 
When the submission is performed by the investigator or the International 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 CA 
in accordance with local regulations. 
17.1.3. Final study report 
The study report(s) will be drafted by Centre of Excellence Methodology and Data Valorisation 
of I.R.I.S. in compliance with I.R.I.S. standard operating procedure. 
The sponsor’s representative and International Coordinator must mutually agree on the final 
version. One copy of the final report must be dated and signed by the International Coordinator 
and by sponsor’s representatives. 
If the clinical trial is still on-going but ended in the European countries, the statistical analysis 
will not be relevant before the end of the study worldwide. Therefore, the clinical study report, 
the summary of the results of the clinical trial together with a summary that is understandable 
to a layperson will be submitted where applicable within 1 year after the end of the clinical trial 
worldwide. 


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17.2. Concerning the sponsor 
This multinational study will be conducted under the sponsorship of I.R.I.S (in all countries 
except the United States) and TOI in the United States.  
The sponsor undertakes to: 
­ supply the investigator with adequate and sufficient information concerning the study 
treatments administered during the study to enable him/her to carry out the study, 
­ supply the investigator with the trifluridine/tipiracil Investigator’s brochure,  
­ supply the investigator with the bevacizumab Product Information, 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.
Guidance for the investigator
for all reference products used in the study
­ obtain any authorisation to perform the study and/or import licence for the study treatments 
administered that may be required by the local authorities before the beginning of the study, 
­ provide the International Coordinatorannually, or with another frequency defined by the 
local regulations, with a document describing study progress which is to be sent to the 
IRB/IEC(s). 
­ take all the necessary precautions to maintain the safety of the processed data, in particular 
their confidentiality, their integrity and their availability, by assessing risks identified 
concerning personal data protection. The following measures will be implemented (non 
exhaustive):   
-
Management of authorisation to access to personal data (e-CRF)
-
Identification and authentication measures before accessing personal data (e-CRF)
-
Traceability measures for the access to and modification of personal data (e-CRF)
-
Secured data transfer
-
Time limit for storing personal data
­ handle any security breach by implementing an internal committee (including CISO, DPO, 
communication department…) in order to qualify the security incident (Information systems, 
nature and number of personal data impacted), to define an action plan for corrective actions 
and to notify to relevant person (authority and/or if needed individuals). 
17.3. Concerning the investigator 
17.3.1. Confidentiality - Use of information 
All documents and information given to the investigator by the sponsor with respect to 
trifluridine/tipiracil and study CL3-95005-007 are strictly confidential. 
The investigator expressly agrees that data on his/her professional and clinical experience is 
collected by the sponsor on paper 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 his/her own personal data by applying to the 
sponsor. 
In case patient wants to exercise his/her rights regarding personal data protection, he/she will 
contact the investigator. The investigator will forward the request to the sponsor (Appendix 8). 


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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 patients. 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. and/or TOI, except to the representatives of the CA, and only at their request. In the
latter case, the investigator commits himself/herself to informing I.R.I.S. and/or TOI. prior to
disclosure of information to these authorities.
A patient screening log and a full identification and enrolment list of each patient will be 
completed and kept in a safe place by the investigator who should agree to provide access on 
site to the auditor and/or the representatives of the CA. The information will be treated in 
compliance with professional secrecy. 
The patient screening log must be completed from the moment the investigator checks that a 
patient could potentially take part in the study (by assessment of patient 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 (co-investigator, nurse…) and any other person involved in the study for 
this centre (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 site. 
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 local regulation, 
­ 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 patients’ medical 
follow-up/study-related decision process and persons involved in the measurement of main 
assessment criteria). 


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18. REFERENCES
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Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries.  CA Cancer 
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Eisenhauer EA., et al. "New response evaluation criteria in solid tumours: Revised RECIST 
guideline (version 1.1)." European Journal of Cancer 45 (2009): 228-247.  
Formica V, Roselli M. Targeted therapy in first line treatment of RAS wild type colorectal 
cancer. World J Gastroenterol. 2015;21(10):2871-2874. 
Hesketh PJ., et al. "Antiemetics: American Society of Clinical Oncology focused guideline 
update." Journal of Clinical Oncology, 2016: 381-386.  
Kuboki Y., et al. "TAS-102 plus bevacizumab for patients with metastatic colorectal cancer 
refractory to standards therapies (C-TASK FORCE): an investigator-initiated, open-label, 
single-arm, multicentre, phase 1/2 study." Lancet Oncology, 2017.  
Lalla RV., et al. "MASCC/ISOO Clinical practice guidelines for the management of mucositis 
secondary to cancer therapy." Cancer, 2014: 1453-1461. 
Mayer R., et al. "Randomised trial of TAS-102 for refractory metastatic colorectal cancer." 
The New England Journal of Medicine, 2015: 1901-1919.  
National Comprehensive Cancer Network. "Clinical Practice Guidelines in Oncology: Rectal 
cancer version 2.2019." NCCN, 2019.  
National Comprehensive Cancer Network. "Clinical Practice Guidelines in Oncology: Colon 
cancer Version 2.2019." NCCN, 2019.  
Pfeiffer P, Yilmaz M, Möller S, et al. TAS-102 with or without bevacizumab in patients 
with chemorefractory metastatic colorectal cancer: an investigator-initiated, open-label, 
randomised, phase 2 trial. Lancet Oncol. 2020; 21: 412-420.  
Peterson DE., et al. "Management of oral and gastrointestinal mucosal injury: ESMO clinical 
practice guidelines for diagnosis, treatment, and follow-up." Annals of Oncology, 2015: 139-
151.


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Roila F., et al. "2016 MASCC and ESMO guideline update for the prevention of 
chemotherapy- and radiotherapy-induced nausea and vomiting and of nausea and vomiting in 
advanced cancer patients." Annals of Oncology, 2016: 119-133.  
Schwartz L., et al. "RECIST 1.1-Update and clarification: from the RECIST committee." 
European Journal of Cancer, 2016: 132-137. 
Tsukihara H., et al. "Efficacy of combination chemotherapy using a novel oral 
chemotherapeutic agent, TAS-102, together with bevacizumab, cetuximab, or panitumumab 
on human colorectal cancer xenografts." Oncology reports, 2015: 2135-2142.  
Van Cutsem E, Nordlinger B, Cervantes A. Advanced colorectal cancer: ESMO Clinical 
Practice Guidelines for treatment. Ann Oncol. 2010; 21(Suppl. 5):v93-v97.  
Van Cutsem E, Cervantes A, Nordlinger B, Arnold D. Metastatic colorectal cancer: ESMO 
Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014a; 25 
Suppl 3:iii1-iii9.  
Other regulatory references: 
European Medicines Agency. Guideline on the evaluation of anticancer medicinal products in 
man. EMA/CHMP/205/95/Rev.5. 22 September 2017. 
European Medicines Agency. "Appendix 1 to the guidelines on the evaluation of anticancer 
medicinal products in man. Methodological consideration for using progression-free survival 
(PFS) or disease-free survival (DFS) in confirmatory trials. EMA/CHMP/27994/2008/Rev.1." 
December 13, 2012. (b) 
Food and Drug Administration. Clinical Trial Endpoints for the Approval of Cancer Drugs 
and Biologics Guidance for Industry. December 2018. 
ICH E6 (R2), Integrated Addendum to Good Clinical Practice (GCP), Step 5, Adopted by 
CHMP, 15 December 2016, issued as EMA/CHMP/ICH/135/1995 
ICH Topic E9 – Statistical Principles for Clinical Trials: Adopted by CPMP, March 1998, 
issued as CPMP/ICH/363/96/step 5. 
ICH Topic E2A – Clinical Safety Data Management: Definitions and Standards for Expedited 
Reporting, issued as CPMP/ICH/377/95. 
Detailed guidance on the collection, verification and presentation of adverse event/reaction 
reports arising from clinical trials on medicinal products for human use (‘CT-3’), (2011/C 
172/01) 
DIRECTIVE 2001/20/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL 
of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of 
the Member States relating to the implementation of good clinical practice in the conduct of 
clinical trials on medicinal products for human use). 
Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 
on clinical trials on medicinal products for human use. 


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19. APPENDICES


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Appendix 1: World Medical Association Declaration of Helsinki 
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 well as applicable
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 result 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 in
comparison with foreseeable benefits to them and to other individuals or groups affected
by the condition under investigation.


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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
provisions.
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


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consideration the laws and regulations of the country or countries in which the research 
is to be performed as well as applicable 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 individual 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
general outcome and results of the study.
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.


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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 necessary 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 new intervention must be tested against
those of the best proven intervention(s), except in the following circumstances:
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable;
or
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 intervention will not be subject to additional risks of serious or irreversible
harm as a result of not receiving the best proven intervention.


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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 2: Patient 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 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. Comfortable 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 4: Cockroft formula (Cockroft et al., 1976) 
CreatClear [mL/min] = ((140 – Age [years]) / SerumCreat [µmol/L]) * Weight [kg]* Sex 
Male = 1.23 
Female = 1.04 
Ref : Cockcroft DW., et al. "Prediction of creatinine clearance from serum creatinine." Nephron, 
1976: 31-41.  


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Appendix 5: EORCT QLQ-C30 
'i. c are· iatcr,tsicd in smru:· lhians all!l!!.lrt y 1.1 and )'0.1.11" lulh. Pk.as.: IDL'i'l!IU alll of lh:: (jUC'S'IJJ0116 ~•ou:sclf lry' 
cireJfo,g lb..:= number lhat bcsa.ap;pli..:::s ro you. lbcrc arc M "ri_!;i)n"' or 
The- infurmatfon lhat you 
prm•idc· will remain stricllly 
IPh:ssc- liill 
!f'0.1.1r ini1i11Js: 
Your birth ' 
, IVfcmth, Y,C'fil : 
· ' nih, Year): 
I. 
I 
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31 
I 
!ilttnonm .acti.villic-s.,. 
~er Sl.liJ='l' 
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l!ilde 
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Durio: the pad wHk: 
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Were you I 1m1tcdl m (U"SUm,n Yl!lllf hllh'b1..:::s or !!II 
Q o.i~e 
a Bil· 
3 
3 
3 
3 
3 
a Bil· 
3 
11:isl.lre time 
llivitie!i? 
2 
3 
9_ 
Were •ou SOOTI o:l'M:'Sth?
-;_ 
I,,,......,,,......
_ -7 -
3 
H&\'ll: ymu bad pain'! 
( v 
3 
:~ ::roo:.:7.::.~,., 
'-' .~ 
11. H&\...: yoo fdt v...:el:? 
./, _/, 
14,.. Ha...-.:: oo fi:[t aalm:stecl? 
15. Ha...-.:: you ,,om~d? 
16. Ha~ you be-en clill1lili md? 
Pili::BSC go on ro the- m:·XJt eagi;: 
2 
2 
2 
3 
3 
3 
3 
4 
4 
4 
'\fery 
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4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 


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As published in Aaronson NK., 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." Journal of the national cancer institute, 1993: 365-376 
During the p:ui li' w~ek: 
Not at 
A 
Q uite 
ery 
AU 
Liilfle 
a S il 
~tuch 
17. HM...: )'00 had oie:rrhca. 
Ilk Wcri:- •oo it:ircd? 
19'. Uid pairi 
with y !I.Ir 011.11 
tiivrtics? 
20. Herve • 00 . 
~ifc I)' in 
Ofl thmns, 
li~c- rcadi 
a riyvsr;ia:pcr ,or 
_..,,. 
'.!..4,. Did yoo fttl dcprc!iScd? 
.,,,,,...... J 
25. Herve • 00 had oimc I)' l~~ng(! 
25. ~ &.'>}~Ur physic~l,C1lJ1Jd~
-1'-~dJeal~
-•rc31ln1!= 
_ ) 
1111:cnti=rm \:mih . our fam _ 
1. c-. 
27. Hes :cur ph)·sic21I 1C1lI11diti.oo or mcdJ _ 
iru:cm:rm ,:mih ·au, social 21cti\•iti s?I 
.,J 
18,. Hes}'Cur 
mcdJ~:mne:nt 
/ 
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2 
2 
2 
2 
2 
2 
2 
2 
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c-al!ISCd you financial dlflindlie'S? 
/ / .  
.For tbr· foUo~'ling qur,sfin:n · p1r·ase r:L~~
num, bemreeo I ,and 7 that 
1hr ·,t a;ppl'ies to ·110 
/
n/ 
,.. How• old :•""' ,..,-3~,rall ~
fl, dwu\": ""'• N .,, 
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1 /7 
30. How• old •oumc,..,-~<rall ,..llt ot•tr .. ria •~ 
-~• 
/ 
/ 
2 
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l:xoc'lk m 


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Appendix 6: EQ-5D-5L 
Under eadhl heading, please lick ~he ONE lbox ~hat best describes your heallh TODAY 
MOBILITY 
11 have no pro'blerns. in walkiing about 
I have slliglilt probtems in wa1king about 
11 have moderate problems in wall!clng about 
I have sever,e prob .ems in wa1kin:g abolilt 
I am unable to walk about 
SEJLF-CARE 
I have no problems. washing or dressing myselif 
I have slight probtems washing or d ress1ing myse1f 
I have moderate problems wastling or dressin.g myself 
I have sever,e probtems waslhii ng or dr,essing myseilf 
I am unable to wash or dr,ess myselif 
USUAL ACTIVlTIES (e.g. won'(, s-rudy, hOliSl!HfKJ.rl'(, family Of feisure activities) 
I have no problems. ,do1ing my us111al acti11i.tr.es 
I have slliglilt probtems ,doing my ooual a.cti,vilies 
I have moderate probfems doing my usua1 aoliivilies 
I have severe problems C!IOii\9 my ooual actii\i'iliies 
I am unable to do my usual acti11i.ti:es 
PAIN J Dl&CO'MFORT 
II have no pain or discomfort 
I lhave slight pain or discomfort 
I have moderate pain or d1soomfol1 
I lhave severe pain or discomfort 
I have ,e.xtreme IPain or discomfort 
ANXIETY .I DEPRESSION 
I ,am Mt anxious or- delPressed 
I ,am s!iglilUy anxr.ous or depressed 
I am moderately arroous or d~ressed 
I am sever,ely anxious or depressed! 
I am ex~remely anoo'iou;s or ,depr,essed 
[J 


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As published in Van Reenen M., et al. EQ-5D-5L User guide Version 2.1. 2015  
We wour.d like LO know how good or bad your he.allh is r,ooA Y. 
ihis scale is numbered from O LO HO. 
100 me.ans ~he best rhea.1th you call'I i.magine. 
O meaM the worst health you can iina.gine . 
Mark .an X on the scale t.o ill'ldicate how your health is TODAY. 
Now, please wrire the number you marked on the scale in the box bel'.ow. 
YOUR HEAL TH lODA'i - D 
Thi;i best health 
you can imagine 
100 
The worst health 
you can imagine 
95 
90 
85 
80 
75 
70 
65 
60 
55 
50 
45 
40 
35 
30 
25 
20 
15 
10 
5 
0 


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Appendix 7: Link to trifluridine/tipiracil and bevacizumab Product Information 
For contraindication of bevacizumab and trifluridine/tipiracil (exclusion criteria n°39 
and 45)  
All the sites, regardless of location, must refer to the EU Product Information of the 
corresponding drug available on the EMA website (see links below).  
For topics not linked to contraindication of bevacizumab and trifluridine/tipiracil 
EMA: applicable for all countries outside the U.S 
Trifluridine/tipiracil (Lonsurf®):  
https://ema.europa.eu/en/medicines/human/EPAR/lonsurf 
Bevacizumab (Avastin®):  
https://ema.europa.eu/en/medicines/human/EPAR/avastin 
US FDA: applicable for the U.S.  
Trifluridine/tipiracil (Lonsurf®): 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/207981s009lbl.pdf 
Bevacizumab (Avastin®): 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125085s336lbl.pdf 


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Appendix 8: DATA PROTECTION / GDPR (General Data Protection Regulation of 27 
April 2016 n°2016/679) 
INSTRUCTIONS 
TO 
INVESTIGATOR 
FOR 
HANDLING 
DATA 
RIGHTS 
REQUESTS 
In the framework of a research study/clinical trial, a participant to the study may exercise his/her 
rights, i.e. may ask I.R.I.S. (as data controller) for:  
•
access to his/her data
•
rectification of inaccurate/incomplete information
•
restriction of processing of data
•
objection to processing of data
•
data portability (receiving his/her data in a readable format)
In accordance with the Informed Consent Form and information notice provided to participant, 
we requested participant to contact you first for exercising their rights.  
Request for exercise of rights: 
•
has to be a written one (either originating from an (e)-mail from a participant or from
request expressed orally to you and put in written)
•
has to be sent by you by e-mail or by mail to I.R.I.S. ( as data controller) to central
address 
or local Servier address as mentioned in
ICF/information notice provided/available
DO 
Instructions to be followed by you 
DON’T 
What you should not do 
E-mail title: Data protection rights
Do not forward participant e-mail (if 
applicable) 
Study name/number 
Participant number 
No information regarding participant 
identity:  
No participant’s name, e-mail address, 
participant’s signature 
As soon as possible without exceeding a 
week 
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I.R.I.S. and INVESTIGATOR responsibilities
GDPR requirement:  
It is mandatory for I.R.I.S. as data controller to provide an answer to participant/volunteer 
within 1 month following the request (article 12 of GDPR) 
Clinical trials requirements:  
It is prohibited for I.R.I.S. as a sponsor to know the identity of the participants/volunteer 
participating to studies  
I.R.I.S. responsability
Investigator responsability 
Forward/inform I.R.I.S. of the 
request 
YES 
Timelines 
Answer within 1 month 
once expressed by the 
participant 
Request: transmitted to I.R.I.S. 
as soon as expressed by the 
participant 
Answer: transmitted by you to 
participant as soon as sent by 
I.R.I.S.
Answer the request 
YES 

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 (SAP) 
Study official title 
An open-label, randomised, phase III study comparing 
trifluridine/tipiracil in combination with bevacizumab to 
trifluridine/tipiracil monotherapy in patients with refractory 
metastatic colorectal cancer 
Study brief title 
Phase III study of trifluridine/tipiracil in combination with 
bevacizumab vs trifluridine/tipiracil single agent in patients with 
refractory metastatic colorectal cancer 
Test drug code 
Trifluridine/tipiracil (also known as S 95005 or TAS-102) 
Indication(s) 
Refractory metastatic colorectal cancer 
Development phase 
Phase III 
Protocol code 
CL3-95005-007 
EudraCT Number 
2020-001976-14 
Universal Trial Number Not applicable 
Sponsor 
Institut de Recherches Internationales Servier (I.R.I.S.) 
Date of the document 
02 August 2022 
Version of the document Version 2.0 
Author(s) of the 
document 
 
 
CONFIDENTIAL 
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PPD


S95005 
CL3-95005-007 - Statistical Analysis Plan - Version 2.0 
© I.R.I.S – 11 July 2022 – Confidential 
Follow up of versions 
Version Release date 
(dd/mm/yyyy) 
Key modifications(*) 
Impact 
V1.0 
06/11/2020 
Not applicable. 
V2.0 
02/08/2022 
-
Section 2.3: update of subgroup
categories
-
Section 3.1: addition of
methodology for data Handling
according to a survival cut-off date
-
Section 3.2.1: addition of the
description of changes and
accommodations du to COVID-19
-
Section 3.2.4.1: update of age
categories and removal of shift table
of geographic region eCRF*IWRS
as automatic region completion in
both sources
-
Sections 3.2.4.2 & 4.2.1.3.2:
addition of ‘Time from first
metastasis diagnosis to
randomization’ definition and
addition of precision on staging
classifications
-
Section 3.2.4.5: updates of previous
therapies descriptive analyses
-
Section 3.3.1.1: update of classes
for treatment duration and number
of cycles
-
Section 3.3.2: addition of G-CSF
treatment intakes analysis
-
Section 3.4.1.3.2: update of
covariate categories
-
Section 3.4.1.3.1: addition of a
sensitivity analysis (supportive 3)
for secondary estimand based on
PFS (FDA IND 
-
Section 3.5.2: addition of TEAE
related to disease progression and
leading to death analyses
-
Section 3.6: addition of figures
displaying mean changes in QoL
from baseline by scheduled
assessment time point
-
Section 3.6.1: update of categories
of changes from baseline
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Section 4.1.5: update of first and
last trifluridine/tipiracil intake dates
by first and last IMP intake dates
-
Section 4.2.1.3.4: modification of
the definition of a previous
metastatic drug treatment
-
Sections 6 & 6.1: update of the
treatment period and after treatment
period definitions considering both
IMPs and a time window of 30 days
-
Section 6.3: Total calcium
(biochemistry) moved to non-
gradable parameter (not defined as
per CTCAE)
-
Sections 7.1 & 7.2: update of
scheduled assessment time point
definitions to take into account
information from ePRO and eCRF;
addition of withdrawal
questionnaire definition
(*) Main changes as compared to the statistical analyses planned in the protocol for the first 
SAP signed version (1.0). Main changes from the previous signed version for the other SAP 
signed version(s). 
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Table of contents 
Table of contents ........................................................................................................................ 4 
List of tables ............................................................................................................................... 7 
List of figures ............................................................................................................................. 8 
List of abbreviations ................................................................................................................... 9 
1. INTRODUCTION ............................................................................................................. 12 
1.1. Study objectives .............................................................................................................. 12 
1.2. Study design .................................................................................................................... 12 
1.2.1. Study plan ..................................................................................................................... 12 
1.2.2. Randomisation .............................................................................................................. 13 
1.3. Determination of sample size ......................................................................................... 14 
2. ANALYSIS SETS AND SUBGROUPS / TREATMENT GROUPS ............................ 15 
2.1. Analysis sets ................................................................................................................... 15 
2.2. Treatment groups ............................................................................................................ 15 
2.3. Subgroups ....................................................................................................................... 15 
3. STATISTICAL METHODS ............................................................................................. 16 
3.1. General considerations .................................................................................................... 16 
3.2. Disposition and baseline characteristics ......................................................................... 19 
3.2.1. Disposition of patients .................................................................................................. 19 
3.2.2. Protocol deviations ....................................................................................................... 19 
3.2.3. Study population ........................................................................................................... 19 
3.2.4. Demographic data and other baseline characteristics ................................................... 19 
3.2.4.1. 
Demographic characteristics .................................................................................... 19 
3.2.4.2. 
History of cancer ...................................................................................................... 20 
3.2.4.3. 
Signs and symptoms related to colorectal cancer .................................................... 21 
3.2.4.4. 
Medical and surgical history not related to colorectal cancer ................................. 21 
3.2.4.5. 
Previous therapies related to colorectal cancer ........................................................ 22 
3.2.4.6. 
Vital signs at baseline .............................................................................................. 22 
3.2.4.7. 
ECG at baseline ....................................................................................................... 23 
3.2.4.8. 
Clinical laboratory at baseline ................................................................................. 23 
3.3. Treatments ...................................................................................................................... 23 
3.3.1. Extent of exposure and treatment compliance .............................................................. 23 
3.3.1.1. 
Trifluridine/tipiracil ................................................................................................. 23 
3.3.1.2. 
Associated agent: bevacizumab ............................................................................... 24 
3.3.2. Concomitant treatments and new anti-cancer therapies ............................................... 24 
3.4. Efficacy analysis ............................................................................................................. 25 
3.4.1. Primary estimand based on the OS ............................................................................... 26 
3.4.1.1. 
Primary analysis ....................................................................................................... 27 
3.4.1.2. 
Sensitivity analyses .................................................................................................. 27 
3.4.1.3. 
Supplementary analysis ........................................................................................... 28 
3.4.1.3.1. Subgroup analysis .................................................................................................. 28 
3.4.2. Additional estimand based on OS ................................................................................ 28 
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3.4.3. Secondary estimands based on PFS, ORR and DCR ................................................... 29 
3.4.3.1. 
Secondary estimand based on PFS .......................................................................... 29 
3.4.3.2. 
Secondary estimands based on ORR and DCR ....................................................... 34 
3.5. Safety analysis ................................................................................................................ 34 
3.5.1. Adverse events.............................................................................................................. 35 
3.5.2. Death............................................................................................................................. 35 
3.5.3. Clinical laboratory evaluation ...................................................................................... 35 
3.5.4. Vital signs, clinical examination and other observations related to safety ................... 36 
3.5.5. ECG .............................................................................................................................. 36 
3.6. QoL ................................................................................................................................. 37 
3.6.1. EORTC QLQ-C30 ........................................................................................................ 37 
3.6.2. EQ-5D-5L ..................................................................................................................... 38 
4. APPENDIX A: DATA HANDLING AND PROGRAMMING
SPECIFICATIONS ........................................................................................................... 40 
4.1. General analytic definitions ............................................................................................ 40 
4.1.1. Expressions ................................................................................................................... 40 
4.1.2. Value prior to treatment / under treatment ................................................................... 41 
4.1.3. General duration derivation and conversion ................................................................. 41 
4.1.4. Analysable value .......................................................................................................... 42 
4.1.5. First and last IMP intake dates ..................................................................................... 42 
4.1.6. Other dates .................................................................................................................... 43 
4.2. Specific analytic definitions and data handling conventions .......................................... 43 
4.2.1. Study patients: Disposition, baseline characteristics and follow-up ............................ 43 
4.2.1.1. 
Disposition of patients ............................................................................................. 43 
4.2.1.2. 
Protocol deviations .................................................................................................. 43 
4.2.1.3. 
Demographic data and other baseline characteristics .............................................. 44 
4.2.1.3.1. Demographic data .................................................................................................. 44 
4.2.1.3.2. History of Colorectal cancer .................................................................................. 44 
4.2.1.3.3. Medical history and surgical or medical procedures history other than 
colorectal cancer .................................................................................................... 46 
4.2.1.3.4. Previous therapies for colorectal cancer ................................................................ 46 
4.2.1.3.5. Initial tumour assessment ...................................................................................... 47 
4.2.1.4. 
Extent of exposure and treatment compliance ......................................................... 47 
4.2.1.5. 
Concomitant treatments ........................................................................................... 50 
5. APPENDIX B: EFFICACY .............................................................................................. 55 
5.1. Non-confirmed Best overall response ............................................................................. 55 
5.2. Lesions diameters ........................................................................................................... 55 
5.3. Events and censoring dates ............................................................................................. 56 
5.4. Proportional hazard assumption ...................................................................................... 57 
6. APPENDIX C: SAFETY .................................................................................................. 58 
6.1. Adverse events ................................................................................................................ 58 
6.2. Death ............................................................................................................................... 61 
6.3. Clinical laboratory evaluation ......................................................................................... 61 
6.4. Vital signs and clinical examination ............................................................................... 65 
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6.5. Electrocardiogram ........................................................................................................... 65 
7. APPENDIX D: QUALITY OF LIFE ............................................................................... 66 
7.1. QLQ C30 scores .............................................................................................................. 66 
7.2. EQ5D-5L ........................................................................................................................ 68 
8. APPENDIX E: SOFTWARE AND PROGRAMMING CODES .................................. 69 
9. REFERENCES .................................................................................................................. 71 
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List of tables 
Table (3.4) 1 - Summary of estimands of interest associated to primary objective ................. 25 
Table (3.4) 2 - Summary of estimands of interest associated to secondary objective ............. 26 
Table (3.4.1.1) 1 - Event and Censoring Rules for primary OS ............................................... 27 
Table (3.4.2) 1 - Event and Censoring Rules for OS considering intercurrent events ............. 29 
Table (3.4.3.1) 1 - Event and Censoring Rules for primary PFS ............................................. 30 
Table (3.4.3.1) 2 - Event and Censoring Rules for PFS in supportive analysis 2 .................... 32 
Table (3.5.4) 1 - Event and Censoring Rules for time to ECOG performance status 
worsening ECOG of ≥ 2 ........................................................................................................... 36 
Table (4.1.2) 1 - Time frame .................................................................................................... 41 
Table (4.1.2) 2 - Time frame of cycle n ................................................................................... 41 
Table (4.1.4) 1 - Definition of analysable value ...................................................................... 42 
Table (4.1.5) 1 - Substitution rules of IMP intake dates .......................................................... 42 
Table (4.1.6) 1 - Substitution rules of death date ..................................................................... 43 
Table (4.1.6) 2 - Substitution rules of dates if no specific management is defined ................. 43 
Table (4.2.1.3.2) 1 - Substitution rules of History of colorectal cancer ................................... 45 
Table (4.2.1.3.2) 2 - RAS status ............................................................................................... 45 
Table (4.2.1.3.2) 3 - Staging based on classification ............................................................... 46 
Table (4.2.1.5) 1 - Substitution rules of concomitant treatments intake dates ......................... 52 
Table (4.2.1.5) 2 - Substitution rules of further anti-tumour therapy intake dates ................... 53 
Table (5.1) 1 - BOR when confirmation of CR and PR not required ...................................... 55 
Table (6.1) 1 - Emergence of adverse events in case of missing severity/grade (if any) ......... 60 
Table (6.1) 2 - Substitution rules of AE dates .......................................................................... 60 
Table (6.1) 3 - Substitution rules of recovery date ................................................................... 60 
Table (6.3) 1 - Gradable and non-gradable laboratory parameters .......................................... 62 
Table (6.3) 2 - Definition of CTCAE grade - Version 5.0 - Gradable parameters .................. 63 
Table (6.4) 1 - Patient performance status ............................................................................... 65 
Table (7.1) 1 - QLQ-C30 Score Algorithm .............................................................................. 66 
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List of figures 
Figure (1.2.1) 1 - Study plan .................................................................................................... 13 
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List of abbreviations 
% 
: 
Percentage 
AE 
: 
Adverse Event 
ALT 
: 
ALanine (Amino)Transferase 
ALP 
: 
ALkaline Phosphatase 
AST 
: 
ASpartate (Amino)Transferase 
BID 
: 
bis in die (twice a day) 
BOR 
: 
Best Overall Response 
bpm 
: 
beats per minute (heart rate unit) 
BSA 
: 
Body Surface Area 
CHMP 
: 
Committee for Medicinal Products for Human Use 
CI 
: 
Confidence Interval 
CL 
: 
Total CLearance 
cm 
: 
Centimetre 
CMH 
: 
Cochran-Mantel-Haenszel 
CR 
: 
Complete Response 
e-CRF
: 
electronic-Case Report Form 
CTCAE 
: 
Common Terminology Criteria for Adverse Events 
DBP 
: 
Diastolic Blood Pressure 
DCR 
: 
Disease Control Rate 
DI 
: 
Dose Intensity 
EAE 
: 
Emergent Adverse Event 
ECG 
: 
ElectroCardioGram 
ECOG PS 
: 
Eastern Cooperative Oncology Group Performance Status 
EMA 
: 
European Medicines Agency 
EORTC 
: 
European Organisation for Research and Treatment of Cancer 
FAS 
: 
Full Analysis Set 
g 
: 
Gram 
G/L 
: 
Giga (109) per litre 
GGT 
: 
Gamma-Glutamyl Transferase (Gamma-Glutamyl Transpeptidase) 
h 
: 
Hour 
HR 
: 
Heart Rate 
HR 
: 
Hazard Ratio 
ICH 
: 
International Conference on Harmonization 
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i.e.
: 
id est 
IME 
: 
Important Medical Event 
IMP 
: 
Investigational Medicinal Product 
INR 
: 
International Normalized Ratio 
I.R.I.S.
: 
Institut de Recherches Internationales Servier 
IS 
: 
Included Set 
IU 
: 
International Unit 
IV 
: 
IntraVenous (route) 
IWRS 
: 
Interactive Web Response System 
kg 
: 
Kilogram 
KRAS 
: 
V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog
L 
: 
Litre 
LDH 
: 
Lactate DeHydrogenase 
LLN 
: 
Lower Limit of Normal laboratory reference range 
m 
: 
Metre 
mCRD 
: 
Metastatic colorectal cancer 
MedDRA 
: 
Medical Dictionary for Regulatory Activities 
MSI 
: 
Microsatellite Instability 
mg 
: 
Milligram 
min 
: 
Minute 
Min 
: 
Minimum 
mL 
: 
Millilitre 
mm 
: 
Millimetre 
mmol 
: 
Millimole 
MMRM 
: 
Mixed-effects Model for Repeated Measures 
msec 
: 
millisecond 
NA 
: 
Not Applicable 
NCI 
: 
National Cancer Institute 
ng 
: 
Nanogram 
NLR 
: 
Neutrophils lymphocytes ratio 
ORR 
: 
Overall Response Rate 
OS 
: 
Overall Survival 
PD 
: 
Progressive Disease 
PFS 
: 
Progression Free Survival 
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PR 
: 
Partial Response 
PT 
: 
Preferred Term 
PV 
: 
PharmacoVigilance 
QLQ 
: 
Quality of Life Questionary 
QoL 
: 
Quality of Life 
QTc 
: 
QT interval corrected for heart rate 
QTcB 
: 
Bazett’s corrected QT interval 
QTcF 
: 
Fridericia’s corrected QT interval 
RBC 
: 
Red Blood Cells 
RDI 
: 
Relative Dose Intensity 
s 
: 
Second 
SAE 
: 
Serious Adverse Event 
SAP 
: 
Statistical Analysis Plan 
SBP 
: 
Systolic Blood Pressure 
SD 
: 
Standard Deviation 
SDTM 
: 
Study Data Tabulation Model 
SD 
: 
Stable Disease 
SEAE 
: 
Serious Emergent Adverse Event 
SOC 
: 
System Organ Class 
SS 
: 
Safety Set 
TLG 
: 
Tables, Listings and Graphs 
TR 
: 
Tumour Response 
TUDD 
: 
Time until definitive deterioration 
ULN 
: 
Upper Limit of Normal laboratory reference range 
WBC 
: 
White Blood Cells 
WHO 
: 
World Health Organization 
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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 primary objective is to demonstrate the superiority of trifluridine/tipiracil in combination 
with bevacizumab over trifluridine/tipiracil monotherapy in terms of Overall Survival (OS) in 
patients with refractory metastatic colorectal cancer (mCRC). 
Secondary objectives are to estimate the effect of trifluridine/tipiracil in combination with 
bevacizumab versus trifluridine/tipiracil monotherapy in terms of Progression Free Survival 
(PFS), Overall Response Rate (ORR), and Disease Control Rate (DCR) in patients with 
refractory mCRC. Other secondary objectives are to compare the safety and tolerance, and the 
impact on Quality of Life (QoL) of trifluridine/tipiracil in combination with bevacizumab to 
trifluridine/tipiracil monotherapy in patients with refractory mCRC. 
1.2. Study design  
This present study is designed as an international, open-label, controlled two-arm, randomised 
phase III comparison study evaluating the efficacy and safety of trifluridine/tipiracil in 
combination with bevacizumab versus trifluridine/tipiracil monotherapy in patients with 
refractory mCRC. 
1.2.1. 
Study plan  
The analysis will be done after 331 events are reported. In order to observe this number of 
events, 490 patients will be randomised (1:1) to receive trifluridine/tipiracil in combination with 
bevacizumab (experimental arm) or trifluridine/tipiracil monotherapy (control arm). 
Considering the anticipated rapid enrolment and event accumulation in this population, there is 
no planned interim analysis for efficacy or futility. 
Randomisation will take place once the consented patient has completed all the necessary 
baseline procedures and is deemed eligible for study entry. The stratification factors will be: 
- Geographic region (North America, European Union, Rest of the World). 
- Time since diagnosis of first metastasis (< 18 months, ≥ 18 months). 
- RAS status (wild-type, mutant).  
The study will be divided into the following periods for each patient:  
- Screening visit (up to 28 days prior to randomisation): to obtain informed consent. 
- Screening period/Inclusion: to check the eligibility of the patient to be included and 
randomised in the study. 
- Randomisation: patients will be randomly assigned to one of the two treatment arms: 
Trifluridine/tipiracil in combination with bevacizumab: trifluridine/tipiracil (starting dose
at 35 mg/m2/dose) will be administered orally BID 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.
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Trifluridine/tipiracil: trifluridine/tipiracil (starting dose at 35 mg/m2/dose) will be
administered orally BID for 5 days on/2 days off, for 2 weeks, followed by a 14-day rest.
This treatment cycle will be repeated every 4 weeks.
- Treatment period: randomised patients should receive the first dose of study treatments 
(day 1 of cycle 1) within 3 days after randomisation. 
Patients will be treated until they meet a discontinuation criterion. Patients will be considered 
on treatment as long as the patients continue with trifluridine/tipiracil. Bevacizumab 
monotherapy is not allowed.  
- Withdrawal visit: within 4 weeks following the date of IMPs withdrawal and prior to the 
start of a new anticancer therapy. 
- Follow-up period: after the withdrawal visit, a follow-up will be done every 8 weeks until 
death or end of study. 
The end of study will occur 19 months after the first IMP intake of the last patient randomised 
and is defined as the date of the last follow-up of the last patient (including a contact phone) or 
the date of the last contact attempt if the last patient is declared lost to follow-up. 
The study plan is shown in Figure (1.2.1) 1. 
Figure (1.2.1) 1 - Study plan 
1.2.2. 
Randomisation  
Patients will be randomly assigned in a (1:1) ratio to receive trifluridine/tipiracil plus 
bevacizumab (experimental arm) or trifluridine/tipiracil as monotherapy (control arm). 
Randomisation will take place once the consented patient has completed all the necessary 
baseline procedures and deemed eligible for study entry. Treatment assignment will be done 
centrally via an Interactive Web Response System (IWRS) stratified by: 
- Geographic region (North America, European Union, Rest of the World). 
- Time since diagnosis of first metastasis (< 18 months, ≥ 18 months). 
- RAS status (wild type, mutant). 
Due to the difference between the two arms in term of bevacizumab injection (1 vs 0), this study 
must be performed in open-label. 
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1.3. Determination of sample size   
Calculations are done with EAST 6.4 software. 
A maximum of 331 events (deaths for any cause) will be required for the primary analysis to 
detect a hazard ratio of 0.70 with 90% power using a log-rank test at one-sided cumulative 2.5% 
level of significance. Based on the data from the RECOURSE study (Mayer, 2015) the median 
duration of OS in the control group is expected to be around 7.1 months. A hazard ratio of 
0.70 translates into 3 months increase of the median OS in the experimental arm (10.1 months) 
compared to the control arm. Based on the assumption that enrolment will continue for 
approximately 12 months, and that about 5%/year of the subjects will drop out, a total of 
490 patients randomised in a 1:1 ratio will be needed to observe the 331th OS events 
approximately 9 months after the last patient randomisation. 
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2.
ANALYSIS SETS AND SUBGROUPS / TREATMENT GROUPS
2.1. Analysis sets   
Screened set: All patients screened. 
Included set (IS): All included patients. 
Full analysis set (FAS): In accordance with the intention-to-treat principle and the 
Section 5.2.1 of ICH E9 guideline, all patients to whom a therapeutic unit was randomly 
assigned using IWRS. Patients in the FAS will be analysed in the arm they were assigned by 
randomisation. 
Safety set (SS): All patients having taken at least one dose of trifluridine/tipiracil. Patients will 
be analyzed according to the treatment actually received. 
2.2. Treatment groups  
- Trifluridine / tipiracil (starting dose at 35 mg/m²/dose) BID + bevacizumab (5 mg/kg IV). 
- Trifluridine / tipiracil (starting dose at 35 mg/m²/dose) BID. 
2.3. Subgroups  
Depending on the sample size, the following subgroups will be examined: region IWRS (North 
America, European Union, Rest of the World), time since diagnosis of 1st metastasis IWRS (< 18, 
≥ 18 months), RAS IWRS (wild, mutant), location of primary disease (right, left), ECOG 
performance status (0, ≥1), gender (female, male), age (< 65, ≥ 65 years), prior surgical resection 
(yes, no), number of metastatic sites (1-2, ≥ 3), neutrophils to lymphocytes ratio (NLR < 3, 
NLR ≥ 3), number of prior metastatic drug regimens (1, ≥2) , BRAF (wild, mutant) and MSI status 
(MSI-H, MSS/MSI-L), prior bevacizumab (yes, no), subsequent regorafenib (yes, no). 
Subgroup analyses are detailed in Section 3.4.1.3.1. 
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3.
STATISTICAL METHODS
3.1. General considerations  
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. 
Descriptive summary statistics (n, mean (SD), median, min and max) will be provided for 
variables measured on a continuous scale. 
The frequency distribution (n, %) will be provided for variables measured on a nominal scale. 
Handling of data according to a survival cut-off date 
A survival cut-off date will be established for the analyses of the primary estimand based on 
the OS, the additional estimand based on the OS, the secondary estimands based on the PFS, 
the time from randomisation to worsening ECOG performance status of ≥ 2 and the time until 
definitive deterioration of 10 points in EORTC QLQ-C30 questionnaire subscales. 
The survival cut-off date will be defined based on the actual date of the occurrence of the 331st 
OS event. 
Patients having an OS event after the survival cut-off date will be censored at the survival cut-
off date. 
Patients having a PFS event after the survival cut-off date will be censored at the last evaluable 
tumour assessment date prior to the survival cut-off date. 
Patients having a worsening ECOG performance status of ≥ 2 event after the survival cut-off 
date will be censored at the last ECOG PS assessment date prior to the survival cut-off date. 
Patients having a definitive deterioration of 10 points in EORTC QLQ-C30 questionnaire 
subscales event after the survival cut-off date will be censored at the last QoL assessment date 
prior to the survival cut-off date. 
Clopper-Pearson Confidence interval (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… n-1: 
( (1 +
𝑛−𝑛1+1
𝑛1 𝐹(1−𝛼2
⁄ ,2𝑛1,2(𝑛−𝑛1+1)))
−1
, (1 +
𝑛−𝑛1
(𝑛1+1)𝐹(𝛼2
⁄ ,2(𝑛1+1),2(𝑛−𝑛1)))
−1
) 
Where F(α,b,c) is the αth percentile of the F distribution with b and c degrees of freedom. 
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Where 
2
2
/
z
 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. 
Kaplan Meier survival analysis  
Kaplan Meier survival analysis (Kaplan and Meier, 1958) will be used for time dependent 
variables. The objective is to describe time-to-event variable, 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. 
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 P (T > t) = 0.5 
The Kaplan-Meier method is based on conditional probabilities calculations and enables to 
compute non-parametric estimates of the survival function. 
The survival function is estimated at each time-point as: 
The number of patients with no Event on 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
With: 
- 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. 
Cox regression models can then be used to study the impact of covariates. 
Cox proportional hazards model 
The cox model (Cox, 1972) explores the relationship and the effect of several risk factors on 
survival. 
It estimates and tests the hazard ratio between different groups. In the cox regression model, 
explanatory variables could be continuous or categorical. 
The cox regression model does not make any parametric assumption about the survival 
probability distribution of each group, however it does assume a proportional hazard between 
two groups. 
The proportional hazard model can be expressed as: 
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ℎ(𝑡) = h0(t) exp (βX) 
Where X is the explanatory variables matrix, β is the regression coefficients matrix and h0(t)is 
the baseline hazard function. 
By dividing both sides of the above equation by h0 (t) and taking logarithms, we obtain: 
ln ( ℎ(𝑡)
ℎ0(𝑡)) = 𝛽𝑋 
We call h(t) / h0(t) the hazard ratio.  
Because cox regression model assumes the proportional hazard between different groups, it’s 
necessary to check this assumption before concluding the estimations. If the proportional 
hazard assumption does not fit the data, other models should be considered. 
Kalbfleisch and Prentice confidence interval for S (t) 
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))
Restricted mean survival time (RMST) 
The RMST (Irwin, 1949) is defined as the area under the curve of the survival function S(t) up 
to a time τ (<∞): 
𝜇τ =∫𝑆(𝑡)𝑑𝑡 ,
τ
0
 
where S(t) is the survival function of a time-to-event variable of interest. 
A natural estimator for μτ is: 
µ̂τ =∫Ŝ(𝑡)𝑑𝑡 ,
τ
0
 
where Ŝ(𝑡) is the KM estimator for S(t). 
τ will be the minimum of the largest observed event time in each of the two groups. 
In addition, to take into account the stratification factor used at randomisation (region (North 
America, European Union, Rest of the World), time since diagnosis of 1st metastasis (< 18, 
≥ 18 months), RAS status (wild, mutant)), an ANCOVA type adjusted analysis proposed by 
Tian et al. will be performed: 
Let Y be the restricted mean survival time, and let Z be the treatment indicator. Also, let X 
denote a q-dimensional baseline covariate vector. Tian’s method consider the following 
regression model: 
𝐸(𝑌|𝑍, 𝑋) =  𝛼+ 𝛽 𝑍+ 𝛾𝑋 
where (α,β,γ) is a (q+2)-dimension unknown parameter vector. Tian’s method (Tian, 2014) 
utilizes an inverse probability censoring weighting technique to handle censored observations. 
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3.2. Disposition and baseline characteristics  
Description of disposition of patients and baseline characteristics will be performed by 
treatment arm and overall.  
Specific definitions on disposition of patients and baseline characteristics are provided in 
4 Appendix A. 
3.2.1. 
Disposition of patients  
Disposition of patients will be described in the Screened Set before and at inclusion and in the 
FAS after the inclusion. 
Changes and accommodations due to COVID-19 will also be described. 
3.2.2. 
Protocol deviations  
All important protocol deviations before or at inclusion, as well as after inclusion, will be 
described in the FAS, by category of deviations based on ICH E3 guideline and ICH E3 Q&A. 
The following subset of important protocol deviations will also be described: 
- Has histologically confirmed unresectable adenocarcinoma of the colon or rectum. 
- Has received a maximum of 2 prior chemotherapy regimens for the treatment of advanced 
colorectal cancer and had demonstrated progressive disease or intolerance to their last 
regimen. 
- Has measurable or non-measurable metastatic lesion(s) as defined by Response Evaluation 
Criteria in Solid Tumours (RECIST) version 1.1. 
- Has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1. 
- More than 2 prior chemotherapy regimens for the treatment of advanced colorectal cancer. 
- Has previously received trifluridine/tipiracil. 
- Does not currently received or has not received anticancer therapies with 4 weeks prior to 
randomisation. 
A first analysis will be made considering all important protocol deviations and a second analysis 
considering only the subset of important protocol deviations.  
3.2.3. 
Study population  
The number of patients in each study population and the reasons for exclusion will be 
summarized. 
Moreover, a listing of patients’ stratification factors and a listing of patients with discrepancies 
between IWRS and eCRF stratification factors will be provided in the IS. 
3.2.4. 
Demographic data and other baseline characteristics   
3.2.4.1. 
Demographic characteristics   
The following demographic and baseline variables will be summarized for patients in the FAS: 
- Age (years). 
- Age (< 65 years, ≥ 65 years). 
- Age (< 70 years, ≥ 70 years). 
- Age (< 75 years, ≥ 75 years). 
- Age (Adults (18-64 years, from 65 to 74 years, from 75 to 84 years, 85 years and over)). 
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- Gender (Female, Male). 
- Ethnic origin (White, American Indian or Alaska native, Asian, Black or African American, 
Native Hawaiian/ Other Pacific Islander, Other). 
- Geographic region (North America, European Union, Rest of the World). 
- Country. 
- Pregnancy test. 
3.2.4.2. 
History of cancer  
Nature and duration of cancer will be summarized in the FAS according to the following 
variables: 
- Primary diagnosis in classes (Colon, Rectal, Other) (4 Appendix A). 
- Primary tumour site (Right colon, Left colon, Rectum, Transverse colon, Other) 
(4 Appendix A). 
- Primary tumour localisation (Right, Left) (4 Appendix A). 
- Stage at diagnosis according to AJCC, Dukes or Astler-Coller modified Dukes’ 
classification. 
- Stage at diagnosis in classes (I-II, III, IV). 
- Current tumour status: in relapse (Yes, No). 
- Current tumour status: metastasis (Yes, No). 
- Site of metastasis (lymph node, lung, liver, bone, brain, skin, peritoneal, soft tissue, other). 
- Number of metastatic sites. 
- Number of metastatic sites in classes (1-2, ≥ 3). 
- Disease duration (years). 
- Disease duration in classes (≤ 1, ]1, 2], ]2, 4], > 4 years). 
- Time from first metastasis diagnosis to randomization (months) documented in the e-CRF. 
- Time from first metastasis diagnosis to randomization in classes (< 18, ≥ 18 months) 
documented in the e-CRF. 
- Time from first metastasis diagnosis to randomization in classes (< 18, ≥ 18 months) 
documented in the IWRS: 
Progression free interval (months).
Progression free interval in classes (≤ 1 (immediate), ]1;6] (early), ]6 to 12]
(intermediate), > 12 months (late)).
Treatment free interval (months).
Treatment free interval in classes (≤1 (immediate), ]1;6] (early), ]6 to 12] (intermediate),
> 12 months (late)).
RAS mutational status performed (Yes, No).
Site of the tumour biopsy (primary tissue, metastatic (lymph node, lung metastasis, liver
metastasis, other metastasis)).
RAS status documented in the e-CRF (wild type, mutant type, NE).
RAS status documented in the IWRS (wild type, mutant type).
KRAS status (wild type, mutant type).
KRAS mutant status:
▪Mutation type Codon 12 (Yes, No, Not done, Unknown):
-
If Mutation type Codon 12: Gly12Asp (G12D), Gly12Val (G12V), Gly12Cys
(G12C), Gly12Ser (G12S), Gly12Ala (G12A), Gly12Arg (G12R), Other.
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▪Mutation type Codon 13 (Yes, No, Not done, Unknown):
-
If Mutation type Codon 13: Gly13Asp (G13D), Other.
▪Mutation type Codon 59 (Yes, No, Not done, Unknown).
▪Mutation type Codon 61 (Yes, No, Not done, Unknown).
▪Mutation type Codon 117 (Yes, No, Not done, Unknown).
▪Mutation type Codon 146 (Yes, No, Not done, Unknown).
▪Mutation other type (Yes, No).
•
NRAS Status (wild type, mutant type).
•
NRAS mutant status:
▪Mutation type Codon 12 (Yes, No, Not done, Unknown):
-
If Mutation type Codon 12: Gly12Asp (G12D), Gly12Cys (G12C), Gly12Ser
(G12S), Other.
▪Mutation type Codon 13 (Yes, No, Not done, Unknown):
-
If Mutation type Codon 13 : Gly13Val (G13V), Gly13Arg (G13R), Other.
▪Mutation type Codon 59 (Yes, No, Not done, Unknown).
▪Mutation type Codon 61 (Yes, No, Not done, Unknown).
▪Mutation type Codon 117 (Yes, No, Not done, Unknown).
▪Mutation other type (Yes, No).
•
BRAF mutational status determined (Yes, No).
•
BRAF status (wild type, mutant type, unknown/not interpretable):
▪If BRAF mutant type (Val600Glu (V600E), Unknown, Other)).
•
MMR or MSI performed (Yes, No).
•
MMR/MSI status (MSI-H/Mismatch repair deficient, MSS/MSI-L/Mismatch repair
proficient, Unknown/Not interpretable).
A shift table crossing RAS status as documented in the e-CRF versus BRAF status will be 
provided. 
A shift table crossing RAS status as documented in the IWRS versus RAS status in the e-CRF 
will be provided. The same analysis will be provided for the time from diagnosis to first 
metastasis (< 18, ≥ 18 months) as documented in the IWRS versus in the e-CRF. 
A listing of the history of colorectal cancer will also be provided. It will include the following 
information: Disease duration, time from first metastasis diagnosis to randomization, primary 
diagnosis, primary tumour site and metastatic sites. 
3.2.4.3. 
Signs and symptoms related to colorectal cancer  
Number and percent of patients with existing signs and symptoms related to mCRC at baseline 
will be summarized by SOC and PT according to the MedDRA dictionary (latest available 
version at the analysis date) for patients in the FAS. The same analysis will be duplicated 
according the NCI-CTCAE grade. 
3.2.4.4. 
Medical and surgical history not related to colorectal cancer  
Medical and surgical history not related to colorectal cancer will be summarized by SOC and 
PT according to the MedDRA dictionary (latest available version at the analysis date) for 
patients in the FAS. 
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3.2.4.5. 
Previous therapies related to colorectal cancer  
Previous drug treatments will be described by pharmacological class, pharmacological 
sub-class, therapeutic class and preferred name (WHO-DD classification, latest available 
version at the analysis date). Previous surgery procedures related to colorectal cancer will be 
summarized by SOC and PT according to the MedDRA dictionary (latest available version at 
the analysis date). All previous therapies for the colorectal cancer will be summarized according 
to the following variables for patients in the FAS:  
- Previous surgery (Yes, No). 
- Previous palliative surgery (Yes, No). 
- Previous curative surgery (Yes, No). 
- Previous radiotherapy (Yes, No). 
- Previous curative radiotherapy (Yes, No).  
- Previous palliative radiotherapy (Yes, No). 
- Previous drug treatments (Yes, No). 
- Combination of previous therapies.  
- Previous neo-adjuvant drug treatment (Yes, No). 
- Previous adjuvant drug treatment (Yes, No). 
- Previous adjuvant and neo-adjuvant drug treatment (Yes, No). 
- Previous adjuvant or neo-adjuvant drug treatment (Yes, No). 
- Previous metastatic drug treatment (Yes, No). 
- Previous metastatic fluoropyrimidine (Yes, No). 
- Previous metastatic irinotecan (Yes, No). 
- Previous metastatic oxaliplatin (Yes, No). 
- Previous metastatic anti-VEGF monoclonal Anti Body (Yes, No). 
- Previous metastatic anti-EGFR monoclonal Anti Body (Yes, No). 
- Previous metastatic anti-EGFR monoclonal Anti Body (Yes, No) in RAS wild type patients 
only as documented in the e-CRF. 
- Number of prior drug regimens.  
- Number of prior drug regimens in classes (1, 2, 3, ≥4). 
- Number of prior adjuvant or neoadjuvant drug regimens.  
- Number of prior metastatic drug regimens.  
- Number of prior metastatic drug regimens in classes (1, 2, ≥3). 
- Reason for treatment discontinuation of the last drug regimen prior to randomisation 
(Toxicity, Progressive disease, Other). 
3.2.4.6. 
Vital signs at baseline  
Vital signs and clinical examination will be described in the FAS, in terms of quantitative values 
for Supine Systolic Blood Pressure - SBP (mmHg), Supine Diastolic Blood Pressure - DBP 
(mmHg), Heart Rate - HR (bpm), Weight (Kg), Temperature (°C), BSA (m2) and by classes: 
- SBP (< 90, [90, 140[, ≥140 mmHg). 
- DBP (< 60, [60, 90[, ≥ 90 mmHg). 
- HR (< 60, [60, 100[, ≥ 100 mmHg). 
- ECOG (0, 1, 2, 3, 4). 
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- BSA (< 1.07, [1.07,1.23[, [1.23, 1.38[, [1.38, 1.53[, [1.53, 1.69[, [1.69, 1.84[, [1.84, 1.99[, 
[1.99, 2.15[, [2.15, 2.30[, ≥ 2.30). 
3.2.4.7. 
ECG at baseline  
The frequency distribution (n, %) of patients with an ECG performed as well as heart rate 
(b.p.m) (< 60, [60, 100[ ,≥ 100), uncorrected QT, Fridericia’s corrected QT, Bazett’s corrected 
QT and RR intervals will be described in terms of quantitative values and in classes, considering 
thresholds defined in ICH E14 (i.e., ≤ 450,] 450; 480],] 480; 500] and > 500 ms) in the FAS. 
Both Fridericia’s correction (𝑄𝑇𝑐𝐹 = 𝑄𝑇/2√𝑅𝑅) and Bazett’s correction (𝑄𝑇𝑐𝐵 = 𝑄𝑇/3√𝑅𝑅) 
will be used for QTc interval. 
3.2.4.8. 
Clinical laboratory at baseline  
All laboratory data will be analysed using NCI-CTCAE grade criteria. 
Clinical laboratory parameters will be summarized according to the following classes: 
- For highest and/or lowest gradable parameters at baseline: (Grade 0, Grade 1, Grade 2, 
Grade 3, Grade 4). 
- For non-gradable parameters and gradable parameters without baseline, except for creatinine 
clearance: (< LLN, [LLN, ULN], > ULN). 
- For urinalysis parameter: proteinuria (Absence, Trace, Presence (+, More than one +)). 
- Neutrophils-lymphocyte ratio (NLR) (< 3, ≥ 3). 
- Neutrophils-lymphocyte ratio (NLR) (< 5, ≥ 5). 
Creatinine clearance will be categorised in 4 levels of impairment and analysed by classes 
(severe, moderate, mild, normal): 
- 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). 
3.3. Treatments  
3.3.1. 
Extent of exposure and treatment compliance  
3.3.1.1. 
Trifluridine/tipiracil  
Extent of exposure and treatment compliance of trifluridine/tipiracil will be described in the SS 
by patient for each treatment arm including: 
- Treatment duration (months). 
- Treatment duration in classes (≤ 2, ]2; 4], ]4-6], ]6-8], ]8; 10], > 10 months). 
- Follow-up duration (months) with median based on reverse Kaplan Meier method. 
- Number of cycles per patient. 
- Number of cycles per patient (1, 2, …, > 10 cycles). 
- Number of cycles per patient (< 2, [2-4],]4-6], ]6-8], ]8-10], > 10 cycles). 
- Cumulative dose (mg/m2). 
- Dose intensity (DI) (mg/m2/week). 
- Relative Dose Intensity (RDI) (%). 
- RDI in classes (≤ 60,] 60-80],] 80-100],] 100- 110], > 110%). 
- Patients with at least one dose reduction (Yes, No). 
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- Number of dose reduction per patient.  
- Number of dose reduction per patient (1, 2, 3, > 3 reductions). 
- Number of patients by actual dose level on day 1 of each cycle. 
- Patients with at least one dispensation postponed (Yes, No). 
- Number of dispensation postponed per patient.  
- Number of dispensation postponed per patient (1, 2, 3, > 3 dispensations postponed). 
- Patients with at least one unplanned treatment interruption (Yes, No). 
- Number of unplanned treatment interruption per patient. 
- Number of unplanned treatment interruption in classes (1, 2, 3, > 3 unplanned treatment 
interruptions). 
Individual listings by cycle will be provided including: cumulative dose, planned dose intensity, 
DI, RDI, total number of tablets given, estimated and returned (15 or 20 mg for 
trifluridine/tipiracil), cycle duration (days), duration of unplanned treatment interruption (days), 
reason for interruption, dispensation postponed (Yes, No), reason for dispensation postponed 
(medical reason, non-medical reason) and dose reduction (Yes, No). 
Individual listing per patient will be provided including: number of cycles, cumulative dose, 
planned dose intensity, DI, RDI, treatment duration, number of cycles with unplanned treatment 
interruption, number of cycles with dispensation postponed and number of dose reductions. 
3.3.1.2. 
Associated agent: bevacizumab  
Number of infusion per patients, patients without partial dose administered, patients with at 
least one missed intake, number of cycles with at least one missed intake, cumulative dose 
(mg/kg), DI (mg/kg/week), RDI (%) and RDI in classes (≤ 60,] 60-80],] 80-100],] 100- 110], 
> 110%) will be described by patient in the SS.
Individual listing by cycle will be provided including: number of intake, reason for miss-intake, 
cumulative dose, planned dose intensity, DI, RDI, cycle duration (days), cycle with full dose 
administered (Yes, No) and reason for incomplete volume infusion (medical reason, 
non-medical reason). 
Individual listing per patient will be provided including: number of cycles, number of intakes, 
cumulative dose, planned dose intensity, DI, RDI, treatment duration, number of cycles with at 
least one partial dose administered and number of cycles with at least one missed intake. 
3.3.2. 
Concomitant treatments and new anti-cancer therapies  
Drug treatments will be described by pharmacological class, pharmacological sub-class, 
therapeutic class and preferred name (WHO-DD classification, latest available version at the 
analysis date). Post-study surgeries and radiotherapy procedures related to colorectal cancer 
will be summarized by SOC and PT according to the MedDRA dictionary (latest available 
version at the analysis date). All concomitant treatments and new anti-cancer therapies will be 
summarized according to the following variables: 
- Concomitant treatment (Yes, No).  
- Received new anti-cancer therapies (Yes, No). 
- Received new surgery (Yes, No). 
- Received new radiotherapy (Yes, No). 
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Concomitant treatments taken at inclusion, those taken before, during and after the treatment 
period, as well as new anticancer therapies (as defined in efficacy part) will be described in the 
SS and in the FAS. 
For concomitant treatments, individual listing will be provided including pharmacological 
class, pharmacological sub-class, therapeutic class and preferred name, medications starting 
and ending date, administration schedule and dose unit administered. The listing will include 
medications starting on or after the start of study treatment or medications starting prior to the 
start of study treatment and continuing after the start of study treatment. 
The number and percentage of patients receiving: 
- At least one concomitant G-CSF treatment. 
- At least one concomitant G-CSF treatment for primary prophylaxis. 
- At least one concomitant G-CSF treatment for secondary prophylaxis. 
- At least one concomitant G-CSF treatment for therapeutic use. 
will be described in the SS for each treatment arm during the treatment period. 
3.4. Efficacy analysis  
Efficacy analyses will be carried out in the FAS by treatment arm. 
Tumour response is evaluated according to the “New Response Evaluation Criteria in Solid 
Tumours: Revised RECIST guideline” (version 1.1) (Eisenhauer et al, 2009) 
Strata will be based on IWRS data, unless otherwise specified. 
Brookmeyer and Crowley confidence interval methodology will be applied for median and 
Kalbfleisch and Prentice confidence interval methodology for survival probabilities. 
Primary objective and associated estimands of interest 
The primary objective is to demonstrate the superiority of trifluridine/tipiracil in combination 
with bevacizumab over trifluridine/tipiracil monotherapy in terms of OS in patients with 
refractory mCRC. 
Table (3.4) 1 - Summary of estimands of interest associated to primary objective 
Estimand 
Variable 
Population 
level 
summary 
Handling IEs 
Treatment 
condition 
Population 
Primary estimand: effect of the 
randomised treatments on the 
survival duration in all subjects 
regardless of whether or not 
intercurrent events occur 
OS 
HR 
Treatment 
policy 
strategy 
trifluridine/tipiracil 
+ bevacizumab
potentially 
followed by 
further anti-cancer 
therapy vs 
trifluridine/tipiracil 
monotherapy 
potentially 
followed by 
further anti-cancer 
therapy 
Full 
Analysis Set 
(FAS) 
Additional estimand: effect of 
the randomised treatments on 
the survival duration in all 
subjects before patients receive 
further anti-cancer therapy 
OS 
HR 
While on 
treatment 
strategy 
trifluridine/tipiracil 
+ bevacizumab vs
trifluridine/tipiracil
monotherapy 
Full 
Analysis Set 
(FAS) 
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Intercurrent event  
During the study the following intercurrent events could occur: 
- Administration of further anti-cancer therapy. 
- Treatment discontinuation. 
- Treatment switch (from trifluridine/tipiracil in combination with bevacizumab to 
trifluridine/tipiracil 
monotherapy 
and 
from 
trifluridine/tipiracil 
monotherapy 
to 
trifluridine/tipiracil in combination with bevacizumab (i.e. planned arm different from actual 
arm)). 
Secondary objectives and associated estimands of interest 
Secondary objectives are to estimate the effect of trifluridine/tipiracil in combination with 
bevacizumab versus trifluridine/tipiracil monotherapy in terms of PFS, ORR, and DCR in 
patients with refractory mCRC. 
Table (3.4) 2 - Summary of estimands of interest associated to secondary objective 
Estimand 
Variable 
Population 
level 
summary 
Handling IEs 
Treatment 
condition 
Population 
Secondary estimand: effect of 
the randomised treatments on 
progression-free survival in all 
subjects regardless of whether 
or not intercurrent events occur 
PFS 
HR 
Treatment 
policy 
strategy 
trifluridine/tipiracil 
+ bevacizumab
potentially 
followed by 
further anti-cancer 
therapy vs 
trifluridine/tipiracil 
monotherapy 
potentially 
followed by 
further anti-cancer 
therapy 
Full 
Analysis 
Set (FAS) 
Secondary estimand: effect of 
the randomised treatments on 
response in all subjects before 
modification of randomised 
treatment 
ORR 
DCR 
Risk 
difference 
While on 
treatment 
strategy 
trifluridine/tipiracil 
+ bevacizumab vs
trifluridine/tipiracil
monotherapy 
Full 
Analysis 
Set (FAS) 
Another secondary objective is to compare the impact on QoL of trifluridine/tipiracil in 
combination with bevacizumab to trifluridine/tipiracil monotherapy in patients with refractory 
mCRC. 
3.4.1. 
Primary estimand based on the OS  
The primary estimand of interest is the effect of the randomised treatments on the survival 
duration in all subjects regardless of whether or not intercurrent events occur (treatment policy 
strategy). The motivation for this choice is to assess the efficacy of the trifluridine/tipiracil in 
combination with bevacizumab compared to trifluridine/tipiracil monotherapy under the ITT 
principle assuming further anti-cancer therapies represent clinical practice (intercurrent events 
are considered to be part of the treatments being compared). 
All data collected during the trial regardless of occurrence of an IE will be used. This is aligned 
with the treatment policy strategy. 
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3.4.1.1. 
Primary analysis  
Overall survival is defined as the time elapsed between the date of randomisation and the date 
of death due to any cause. For patients without documentation of death, the OS will be censored 
at the last contact date the patient was known to be alive. 
Table (3.4.1.1) 1 - Event and Censoring Rules for primary OS 
Event/Censor 
Decision 
Date of event or censor to consider for analysis 
Death 
Event 
 date of death 
Patient alive without documented 
death 
Censor 
date of last contact* 
* Maximum date among completed dates relative to patient’s information
The distribution of OS will be compared between the two treatment groups using a stratified 
log-rank test at one-sided 2.5% level of significance (stratification factors based on IWRS data). 
OS for each arm will be summarized using Kaplan Meier curves and further characterized in 
terms of the median and survival probabilities at 6, 12 and 18 months along with the 
corresponding 2-sided 95% CI for the estimates.  
The hazard ratio of OS with its 95% confidence interval will be estimated with a stratified Cox 
proportional hazard model (stratification factors based on IWRS data).  
For missing data (not linked to intercurrent events), i.e. patients without documentation of death 
(lost to follow-up, withdrawal of consent, administrative end of study), the OS will be censored 
on the last contact date the patient was known to be alive or the survival cut-off date, whichever 
is earlier. 
Underlying assumptions of proportional hazards will be checked using Schoenfeld Residuals 
test and graphical methods (Log cumulative hazard curve, etc…). If proportionality is not 
observed, sensitivity analyses other than those already planned in the SAP could be carried out. 
3.4.1.2. 
Sensitivity analyses   
As sensitivity analyses, the following analyses will be done: 
- The distribution of OS will be compared between the treatment groups using an unstratified 
log-rank test and the hazard ratio (together with associated 95% CI) resulting from an 
unstratified Cox model will be presented. 
- The distribution of OS excluding patients not fulfilling one of the following criteria: 
Has histologically confirmed unresectable adenocarcinoma of the colon or rectum.
Has received a maximum of 2 prior chemotherapy regimens for the treatment of advanced
colorectal cancer and had demonstrated progressive disease or intolerance to their last
regimen.
Has measurable or non-measurable metastatic lesion(s) as defined by Response
Evaluation Criteria in Solid Tumours (RECIST) version 1.1.
Has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1.
More than 2 prior chemotherapy regimens for the treatment of advanced colorectal
cancer.
Has previously received trifluridine/tipiracil.
Does not currently received or has not received anticancer therapies within 4 weeks prior
to randomisation
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Will be compared between the treatment groups using a stratified log-rank test 
(stratification factors based on IWRS data) and the hazard ratio (together with associated 
95% CI) resulting from a stratified Cox proportional hazard model (stratification factors 
based on IWRS data) will be presented. 
- The Restricted Mean Survival Time (RMST) for OS will be reported with its 95% 
confidence interval in each treatment group. The difference in RMST between treatment 
groups will be tested. 
3.4.1.3. 
Supplementary analysis  
3.4.1.3.1. 
Subgroup analysis   
OS subgroup analyses are planned in the FAS to further explore the homogeneity of the 
treatment effect across patient subsets. Depending on the sample size, the subgroups, as defined 
in Section 2.3 will be examined. 
An unstratified Cox-regression model with treatment arm as predictor variable will be fitted 
separately for each subgroup category. The hazard ratio for treatment along with the associated 
95% confidence interval will be provided. 
Forest Plot of Hazard Ratios for treatment effect on primary estimand based on OS by selected 
subgroup will be provided. 
3.4.2. 
Additional estimand based on OS  
The other estimand based on OS is defined in order to assess the effect of the randomised 
treatments on the survival time in all subjects before patients receive further anti-cancer therapy 
(while on treatment strategy). The aim of this estimand is to evaluate the effect of the study 
treatment without taking into account any potential effects of another anti-cancer therapy.  
The use of data post intercurrent events will be different according to the IE: 
- For IE “administration of further anti-cancer therapy” (5 Appendix B) and “treatment 
switch”: data obtained post IE will not be used for the analysis. OS will be censored at the 
time of administration of further anti-cancer therapy. 
- For IE “treatment discontinuation”: time of death for any cause after treatment 
discontinuation will be taken into account. 
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Table (3.4.2) 1 - Event and Censoring Rules for OS considering intercurrent events 
Event/Censor 
Decision 
Date of event or censor to consider for analysis 
Death before or at administration 
of further anti-cancer therapy, 
treatment switch and treatment 
discontinuation 
Event 
Date of death 
Death after treatment 
discontinuation and before or at 
administration of further anti-
cancer therapy and treatment 
switch 
Event 
Date of death 
Death after administration of 
further anti-cancer therapy or 
treatment switch 
Censor 
Min (date of administration of further anti-cancer 
therapy;date of treatment switch) 
Patient alive without documented 
death and with administration of 
further anti-cancer therapy or 
treatment switch 
Censor 
Min (date of administration of further anti-cancer 
therapy;date of treatment switch) 
Patient alive without documented 
death and without administration 
of further anti-cancer therapy and 
treatment switch 
Censor 
Date of last contact* 
* Maximum date among completed dates relative to patient’s information
The distribution of OS will be compared between the two treatment groups using a stratified 
log-rank test at one-sided 2.5% level of significance (stratification factors based on IWRS data). 
OS for each arm will be summarized using Kaplan Meier curves and further characterized in 
terms of the median and survival probabilities at 6, 12 and 18 months along with the 
corresponding 2-sided 95% CI for the estimates.  
The hazard ratio of OS with its 95% confidence interval will be estimated with a stratified Cox 
proportional hazard model (stratification factors based on IWRS data). 
For missing data (not linked to intercurrent events), i.e. patients without documentation of death 
(lost to follow-up, withdrawal of consent, administrative end of study), the OS will be censored 
on the last contact date the patient was known to be alive or the survival cut-off date, whichever 
is earlier. 
3.4.3. 
Secondary estimands based on PFS, ORR and DCR  
3.4.3.1. 
Secondary estimand based on PFS  
Important secondary estimands of interest is the effect of the randomised treatments on 
progression-free survival in all subjects regardless of whether or not intercurrent events occur 
(treatment policy strategy). The PFS is based on investigator judgement and is defined as the 
time elapsed between the randomisation and the date of radiologic tumour progression 
(according to RECIST version 1.1 (Eisenhauer, 2009) or death from any cause. 
All data collected during the trial regardless of occurrence of an IE will be used. This is aligned 
with the estimand and the treatment policy strategy. 
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Table (3.4.3.1) 1 - Event and Censoring Rules for primary PFS 
Event/Censor 
Decision 
Date of event or censor to consider for analysis 
Documented first radiological 
progression 
Event 
Date of 1st radiological PD assessment 
Death without radiological 
progression  
Event 
Date of Death 
Patient alive without documented 
radiological progression  
Censor 
Date of last evaluable tumour assessment (non-NE) 
Patient lost to follow-up without 
documented radiological 
progression  
Censor 
Date of last evaluable tumour assessment (non-NE) 
No baseline or post-baseline 
tumour assessment 
Censor 
Date of randomisation 
For missing data (not linked to intercurrent events), i.e. patients who were lost to follow-up or 
who have withdrawn their consent without radiological progression or reached the time point 
of analysis without a known record of death or radiological progression, the PFS will be 
censored at the date of last evaluable tumour assessment or the survival cut-off date, whichever 
is earlier. 
The following analyses will be done as primary analyses: 
- The distribution of PFS will be compared between the two treatment groups using a stratified 
log-rank test at one-sided 2.5% level of significance (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 3, 6, 9 and 12 months along with the 
corresponding 2-sided 95% CI for the estimates. 
- The hazard ratio of PFS with its 95% confidence interval will be estimated with a stratified 
Cox proportional hazard model (stratification factors based on IWRS data). 
PFS is identified as the key secondary variable. A hierarchical testing strategy, where PFS is to 
be statistically evaluated and interpreted only if the primary efficacy estimand OS is 
significantly different between the 2 treatment groups, will be used to control the overall type-I 
error rate. 
Sensitivity analyses 
The following analyses will be done as sensitivity analyses: 
- PFS sensitivity analysis to address the impact of stratification (supportive 1): the distribution 
of PFS will be also compared between the treatment groups using an unstratified log-rank 
test and the hazard ratio (together with associated 95% CI) resulting from an unstratified 
Cox model will be presented. 
- PFS sensitivity analysis to address the impact of further therapies and clinical progression 
(supportive 2): an analysis that considers clinical progression and administration of further 
anti-cancer therapy as PFS events in addition to the radiological progression or death. 
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- PFS sensitivity analysis to address the impact of further therapies and missing tumour 
assessments (supportive 3): an analysis censoring the PFS duration at the date of last 
evaluable tumour assessment before or the day of administration of further anti-cancer 
therapy and censoring patients with radiological progression or who die after ≥ 2 consecutive 
missed radiological assessments at the latest evaluable assessment prior to the missing 
assessments. Based on the time interval (distance) between the last evaluable tumor 
assessment date and the event date, if the distance is greater than (2*8) + 2 = 18 weeks then 
the analysis will assume two missing assessments. The threshold is formed based on the 
protocol specified interval between the tumor assessments plus 2 weeks. 
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Table (3.4.3.1) 2 - Event and Censoring Rules for PFS in supportive analysis 2 
Event/Censor 
Decision 
Date of event or censor to consider for analysis 
Documented first radiological 
progression without previous 
clinical progression nor new anti-
cancer therapy or documented 
first radiological progression with 
new anti-cancer therapy at the 
same date without previous 
clinical progression or 
documented first radiological 
progression with clinical 
progression at the same date 
without new anti-cancer therapy 
or documented first radiological 
progression with clinical 
progression and with new anti-
cancer therapy at the same date 
Event 
Date of 1st radiological PD assessment 
Clinical progression without 
previous radiological progression 
nor new anti-cancer therapy or 
clinical progression with new anti-
cancer therapy at the same date 
without previous radiological 
progression 
Event 
Minimum of: 
•
Date of withdrawal if reason for withdrawal =
progressive disease
•
Date of progression in AE e-CRF page (PT
“Malignant neoplasm progression” with code
MedDRA 10051398)
•
Date of first progression at the follow-up visit
Death without radiological 
progression and without clinical 
progression and (without previous 
new anti-cancer therapy or with 
previous new anti-cancer therapy 
at the same date)  
Event 
Date of Death 
Patient receiving new anti-cancer 
therapy before any radiological 
progression, any death and any 
clinical progression  
Event 
Date of start of new therapy 
Patient alive without documented 
radiological progression, any 
clinical progression and any new 
anti-cancer therapy 
Censor 
Date of last evaluable tumour assessment (non-NE) 
Patient lost to follow-up without 
documented radiological 
progression, any clinical 
progression and any new anti-
cancer therapy 
Censor 
Date of last evaluable tumour assessment (non-NE) 
No baseline or post-baseline 
tumour assessment 
Censor 
Date of randomisation 
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Table (3.4.3.1) 3 - Event and Censoring Rules for PFS in supportive analysis 3 
Event/Censor 
Decision 
Date of event or censor to consider for analysis 
Documented first radiological 
progression not preceded by ≥2 
consecutive missed tumour 
assessments* and without new 
anti-cancer therapy previously 
reported 
Event 
Date of 1st radiological PD assessment 
Death not preceded by ≥2 
consecutive missed tumour 
assessments* without radiological 
progression and without new anti-
cancer therapy previously 
reported 
Event 
Date of Death 
Patient alive without documented 
radiological progression and 
without new anti-cancer therapy 
previously reported 
Censor 
Date of last evaluable tumour assessment (non-NE) 
Patient receiving new anti-cancer 
therapy before any radiological 
progression or death not preceded 
by ≥2 consecutive missed tumour 
assessments* 
Censor 
Date of last evaluable tumour assessment (non-NE) prior 
to or the day of new anti-cancer therapy 
Patient receiving new anti-cancer 
therapy before any radiological 
progression or death preceded by 
≥2 consecutive missed tumour 
assessments* 
Censor 
Min(Date of last evaluable tumour assessment (non-NE) 
prior to or the day of new anti-cancer therapy; Date of 
last evaluable tumour assessment (non-NE) prior to 
missing visits) 
Document first radiological 
progression or death preceded by 
≥2 consecutive missed tumour 
assessments* without new anti-
cancer therapy previously 
reported  
Censor 
Date of last evaluable tumour assessment (non-NE) prior 
to missing visits 
Patient lost to follow-up without 
documented radiological 
progression and without new anti-
cancer therapy previously 
reported 
Censor 
Date of last evaluable tumour assessment (non-NE) 
No baseline or post-baseline 
tumour assessment 
Censor 
Date of randomisation 
* Based on the time interval (distance) between the last evaluable tumor assessment date and the event date, if the distance is 
greater than (2*8) + 2 = 18 weeks then the analysis will assume two missing assessments.
For missing data (not linked to intercurrent events), i.e. patients who were lost to follow-up or 
who have withdrawn their consent without radiological progression or reached the time point 
of analysis without a known record of death or radiological progression, the PFS will be 
censored at the date of last evaluable tumour assessment or the survival cut-off date, whichever 
is earlier. 
The same subgroup analyses as used for the primary estimand will be done for PFS. 
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3.4.3.2. 
Secondary estimands based on ORR and DCR  
Other secondary estimand of interest are the effect of the randomised treatments on response in 
all subjects before modification of randomised treatment.  
Responses recorded after intercurrent event will be excluded. This is aligned with the estimand 
and the while on treatment strategy. 
The frequency distribution of Best Overall Response (BOR) will be provided on the FAS 
according to the following classes: CR, PR, SD, Non CR/ Non PD, PD, NE. 
The following analyses will be done: 
- Overall Response Rate (ORR) is based on the investigator’s tumour assessment and is 
defined as the proportion of patients with objective evidence of complete response (CR) or 
partial response (PR) according to RECIST version 1.1 criteria and using investigator’s 
tumour assessment. 
ORR will be described using 2-sided 95% Clopper-Pearson CIs in each treatment arm. A 
Fisher’s exact test and a 2-sided 95% CI for the difference in ORR between the two treatment 
arms will also be provided based on the normal approximation. If a stratified analysis is 
required a Cochran-Mantel-Haenszel (CMH) test will be used. 
- Disease Control Rate (DCR) is based on the investigator’s tumour assessment and is defined 
as the proportion of patients with objective evidence of CR or PR or stable disease (SD) 
according to RECIST version 1.1 criteria and using investigator’s tumour assessment.  
DCR will be described using 2-sided 95% Clopper-Pearson CIs in each treatment arm. A 
Fisher’s exact test and a 2-sided 95% CI for the difference in DCR between the two treatment 
arms will also be provided based on the normal approximation. If a stratified analysis is 
required a Cochran-Mantel-Haenszel (CMH) test will be used. 
As supplementary analysis, BOR, ORR and DCR will be evaluated on population evaluable for 
tumour response,i.e., all patients of the FAS with measurable disease at baseline (at least one 
target lesion) and with at least one tumour evaluation while on treatment (with the same method 
of measurement as baseline). 
For missing data (not linked to intercurrent events), an unfavourable outcome will be taken into 
account. 
3.5. Safety analysis   
All safety analyses will be performed in the SS. 
Calculation rules for safety endpoints and other specific definitions are provided in 
6 Appendix C. 
Adverse events (AEs) will be graded using the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE version 5.0) with the most recently available 
version. 
Subgroup analyses of adverse events and Grade 3 or 4 clinical laboratory abnormalities will be 
performed based on the following patient characteristics at baseline:  
- ECOG performance status (0, 1). 
- Age (< 65, ≥ 65 years). 
- Gender. 
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- Baseline creatinine clearance (< 60ml/min, ≥ 60ml/min). 
3.5.1. 
Adverse events  
Number of events, number and percentage of patients reporting at least one event, presented by 
SOC and/or PT (depending on the analysis) for each treatment arm, will be provided for serious 
adverse events (SAE) and emergent adverse events (EAE) over the study and treatment periods, 
respectively. 
EAE and SEAE will be described for each treatment arm according to: 
- Worst grade. 
- Severity. 
- Relationship (related to trifluridine/tipiracil, related to bevacizumab, related to the 
combination (trifluridine/tipiracil or bevacizumab) (7 Appendix D). 
- Outcome (recovered/resolved, recovered/resolved with sequelae, recovering/resolving, not 
recovered/not resolved, fatal, unkown). 
- Leading to drug withdrawal. 
EAE will be also described for each treatment arm according to: 
- Action taken regarding trifluridine/tipiracil (drug interrupted, dose reduced, dose delayed, 
dose reduced and delayed, dose not changed), action taken regarding bevacizumab (drug 
interrupted, dose delayed). 
- EAE related to disease progression. 
- EAE leading to death. 
- Requirement of added therapy. 
Non SEAE (EudraCT analyses) and Non SEAE related (related to trifluridine/tipiracil, related 
to bevacizumab, related to the combination (trifluridine/tipiracil or bevacizumab)) will be 
described by SOC and PT for each treatment arm. 
Of note, the seriousness and the relationship with trifluridine/tipiracil and/or bevacizumab are 
based on investigator opinion but also include sponsor decision to upgrade seriousness and/or 
relationship. 
3.5.2. 
Death  
Number of deaths will be described on each period (during the treatment and follow-up period 
/ during the treatment period / during the follow-up period) by treatment arm.  
Reason of death on each period will be provided. TEAE leading to death and TEAE related to 
disease progression and leading to death will be presented by SOC and PT during the treatment 
period / during the treatment or follow-up periods. During the follow-up period, reason of death 
(PD, other) will be summarized.  
Listing of patients who died during the treatment period or during the follow-up period will be 
provided. 
3.5.3. 
Clinical laboratory evaluation  
For haematological, biochemistry, coagulation and urinary parameters, descriptive statistics on 
value at baseline, on value at each cycle under treatment (worst value at each cycle), on worst 
value under treatment, on last post-baseline value under treatment and, on change from baseline 
to each cycle (worst value at each cycle) under treatment, to worst value under treatment and 
to last post-baseline value under treatment will be provided. 
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Number and percentage of patients for each laboratory parameter classified according to: 
reference ranges (< LLN/≥ LLN or ≤ ULN/> ULN) for non-gradable parameters except 
creatinine clearance, grade (Grade 0, Grade 1, Grade 2, Grade 3, Grade 4) for gradable 
parameters, following classes for proteinuria (Absence, Trace, Presence (+, More than one +)) 
and following classes for creatinine clearance (severe, mild, moderate, normal) and using shift 
tables from baseline to the worst (high and/or low) class or value under treatment will be 
described by treatment arm. 
Some parameters with grade dependent on baseline value (no grade cannot be computed at 
baseline). 
3.5.4. 
Vital signs, clinical examination and other observations related to safety 
Vital signs and clinical examination will be described, in terms of value at baseline, value at 
each cycle (worst value at each cycle) under treatment, worst value under treatment and last 
post-baseline value under treatment; as well as in terms of change from baseline to each cycle 
(worst value at each cycle) under treatment, to worst value under treatment, to last post-baseline 
value under treatment by treatment arm. Vital signs and clinical examination will be also 
described by classes. 
Time from randomisation to worsening ECOG performance status of ≥ 2 will be analysed in 
the FAS using Kaplan-Meier methodology and compared between treatment groups with a 
stratified log-rank test (strata based on IWRS data). To be considered as a worsening, the ECOG 
PS must be increased by at least one category and to at least a minimal PS value of 2. Death 
will be considered as worsening of ECOG PS ≥ 2. Patients without ECOG PS worsening as of 
the survival cut-off date will be censored at the last recorded ECOG PS assessment. 
Table (3.5.4) 1 - Event and Censoring Rules for time to ECOG performance status worsening 
ECOG of ≥ 2  
Event/Censor 
Decision 
Date of event or censor to consider for analysis 
ECOG from 0-1 at baseline to ≥ 2 
post baseline  
Event 
Date of first worsening ECOG assessment 
ECOG from 2 at baseline to ≥ 3 post 
baseline 
Event 
Date of first worsening ECOG assessment 
Death without previous ECOG ≥ 2 
deterioration 
Event 
Date of Death 
Patient without worsening ECOG 
with at least a minimum ECOG 
value of 2 (ECOG from 0 at baseline 
to 1 post baseline, same ECOG 
value at baseline and post baseline) 
Censor 
Date of last ECOG assessment 
No baseline or/and no post baseline 
ECOG evaluation 
Censor 
Date of randomisation 
3.5.5. 
ECG  
ECG parameters will be described, in terms of value at baseline and last post-baseline value 
under treatment; as well as, for quantitative endpoints, in terms of change from baseline to last 
post-baseline value under treatment Moreover values and changes from baseline of uncorrected 
and corrected (Fridericia’s correction and Bazett’s correction) QT interval and RR will also be 
described in classes, considering the thresholds defined in ICH E14: 
- ≤ 450,] 450; 480],] 480; 500] and > 500 ms for values. 
- ≤ 30,] 30; 60] and > 60 msec for changes.  
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3.6. QoL  
3.6.1. 
EORTC QLQ-C30  
The QLQ-C30 is a cancer specific instrument that contains 30 questions and provides a multi-
dimensional assessment of health related QoL. The QLQ-C30 is composed of five functional 
scales, three symptom scales, six single items and a global health status (GHS). 
The raw scores are linearly transformed to give standard scores in the range of 0-100. Higher 
scores in the global and functioning scales and lower scores in the symptom/single scales 
indicate better quality of life. 
The number of patients from the FAS who have completed at least one questionnaire item will 
be described by treatment group at each visit as well as the reasons of non-completion among 
patients still on treatment. 
For the QLQ-C30 analyses, patients from the FAS who have completed at least one 
questionnaire item at baseline and during the study period will be analysed in the arm they were 
assigned to at randomisation, unless otherwise specified. 
The raw QoL data will be scored according to the EORTC scoring manual and the change in 
score from baseline in the GHS scale is identified as the primary QoL variable of interest. 
For each QLQ-C30 scale, the completion and compliance rates will be summarised by treatment 
group for each scheduled assessment timepoints. 
The completion rate is defined as the rate of patients with a non-missing scale score among 
patients of the FAS.  
The compliance rate is defined as the rate of patients with a non-missing scale score among 
patients of the FAS still on treatment at each visit. 
Absolute difference less than 5 points in the scores represent ‘no change’ (Osoba D, 1998), 
absolute difference of 5-10 points in the scores represents a small change, 10-20 points a 
moderate change and greater than 20 points a large change from the patient’s perspective. Any 
difference greater than 10 points will be considered as clinically significant. 
Descriptive statistics will be used to summarize baseline values, post-baseline values and 
changes from baseline in the GHS and sub-scale scores at each scheduled assessment time point 
prior to any procedure (at each cycle and at withdrawal visit) and by classes (large benefit, 
moderate benefit, small benefit, no change, small deterioration, moderate deterioration, and 
large deterioration) for each treatment arm.  
Figures will be displayed in order to show the evolution of each sub-scale score from baseline 
values to post-baseline values at each scheduled assessment time point prior to any procedure 
(at each cycle and at withdrawal visit). 
A repeated-measures mixed-effects model (SAS PROC MIXED) that includes terms for 
treatment arms, baseline stratification factors, baseline sub-scale score and time to visit (at each 
scheduled assessment time point) will be used to compare the two treatment groups with respect 
to changes from baseline in the sub-scales scores longitudinally over time (Global health status, 
functional scales and symptoms scales). Treatment arms by time to visit interaction will be 
explored as well. The most suitable covariance structure will be chosen according to Akaike’s 
Information Criterion and Schwartz’ Bayesian Criterion, between unstructured, compound 
symmetric and autoregressive of order 1. 
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Time Until Definitive Deterioration (TUDD) of 10 points will be compared for each treatment 
arm. TUDD is defined as the interval between baseline date and the first worsening in QoL 
score ≥ 10 points compared to baseline QoL score with no later improvement above this 
threshold observed during the study. Death is considered as deterioration of QoL. Patients 
receiving any further anti-tumoral treatment before definitive worsening will be censored at the 
date of their last QoL assessment before starting this therapy. Patients that have not definitively 
worsened as of the cut-off date for the analysis will be censored at the date of their last 
assessment before the cut-off. Patients with a missing scale score at baseline will be censored 
at their randomisation date + 1 day.  
TUDD of 10 points in each sub-scale will be compared between the two treatment arms using 
the stratified log-rank test at a 2-sided 5% level of significance. The distributions will be 
described using Kaplan-Meier curves including the median time to definitive 10 points 
deterioration along with the 95% confidence intervals. 
3.6.2. 
EQ-5D-5L  
The EQ-5D 5L is a standardized health utility measure developed by the EuroQOL Group in 
order to provide a simple, generic measure of health for clinical and economic appraisal. It is 
composed of 5 questions focused on mobility, self-care, usual activities, pain/discomfort and 
anxiety/depression, and a Visual analogue scale (VAS). Each of the 5 questions has 5 levels: 
no problem, slight problems, moderate problems, severe problems and extreme problems.  
The VAS records the respondent’s self-rated health on a vertical visual analogue scale. The 
VAS ‘thermometer’ has endpoints of 100 (Best imaginable health state) at the top and 0 (Worst 
imaginable health state) at the bottom. This information can be used as a quantitative measure 
of health outcome as judged by the individual respondents. 
For the EQ-5D 5L analyses, patients from the FAS with an evaluable EQ-5D-5L assessment at 
baseline and at least one evaluable assessment post baseline will be analysed in the arm they 
were assigned to at randomisation, unless otherwise specified. 
The dimensional 5-level system will be converted into a single index utility score: values for 
the 3125 theoretically possible health states defined by the EuroQol classification are calculated 
using a regression model (Busschbach et al., 2003). 
The index utility score will be derived according to Euroqol specific country value set. For all 
countries, the French Value Set will be used to generate health utility scores. 
The number of patients from the FAS who have completed at least one questionnaire item will 
be described by treatment group at each visit as well as the reasons of non-completion among 
patients still on treatment. 
The completion and compliance rates will be summarized by treatment group for each 
scheduled assessments timepoints. 
The completion rate is defined as the rate of patients with evaluable EQ-5D-5L assessment 
among patients of FAS. 
The compliance rate is defined as the rate of patients with evaluable EQ-5D-5L assessment 
among patients still on treatment at each visit among patients of FAS. 
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A breakdown table to include the proportions of reported problems at baseline versus each 
scheduled assessment timepoint (at each cycle and at withdrawal visit) will be presented in each 
dimension of EQ-5D-5L by treatment arm. 
Descriptive statistics will be used to summarize baseline values and changes from baseline in 
EQ-5D-5L VAS and EQ-5D-5L health utility index by treatment arm at each scheduled 
assessment time point prior to any procedure (at each cycle and at withdrawal visit).  
Figures will be displayed in order to show the evolution of EQ-5D-5L VAS and EQ-5D-5L health 
utility index from baseline values to post-baseline values at each scheduled assessment time 
point prior to any procedure (at each cycle and at withdrawal visit). 
A repeated-measures mixed-effects model (SAS PROC MIXED) that includes terms for 
treatment, baseline stratification factors, baseline score and time to visit prior to any procedure 
(at each scheduled assessment time point) will be used to compare the two treatment groups 
with respect to changes from baseline in the EQ-5D-5L VAS and EQ-5D-5L health utility 
index. Treatment arms by time to visit interaction will be explored as well. The most suitable 
covariance structure will be chosen according to Akaike’s Information Criterion and Schwartz’ 
Bayesian Criterion, between unstructured, compound symmetric and autoregressive of order 1. 
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4.
APPENDIX A: DATA HANDLING AND PROGRAMMING SPECIFICATIONS
4.1. General analytic definitions  
4.1.1. 
Expressions  
Reliable value for biological and coagulation samplings is identified in datasets with flag 
BIOFG_parameter name (“Non analysable value”) different from 1 and non-missing result. 
For other panels, reliable value is a non-missing result. 
Value at baseline is defined as the last reliable value prior to treatment intake 
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 reliable value.  
Post-baseline value is defined as a reliable value after the first study treatments intake. 
Last value is defined as the last reliable post-baseline value of the criteria of interest during 
treatment period. 
Withdrawal value is defined as the reliable value of the criteria of interest during the 
withdrawal visit. 
Lowest value is defined as the lowest value during the treatment period. 
Highest value is defined as the highest value during the treatment period. 
Worst (lowest/highest) value at cycle i is defined as the worst (lowest/highest) value at cyclei. 
Change from baseline to worst (lowest/highest) value at cycle i is calculated as: 
Worst value at the Cyclei - Value at baseline. 
Change from baseline to last value is calculated as: 
Last value - Value at baseline. 
Change from baseline to worst (highest/lowest) value is calculated as: 
Worst value - Value at baseline. 
Change from baseline to withdrawal value is calculated as: 
Withdrawal value - Value at baseline. 
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4.1.2. 
Value prior to treatment / under treatment  
Table (4.1.2) 1 - Time frame 
Criteria 
Value prior to treatment if 
measured between (D1=) days 
before and (D2=) days after the 
first treatment intake (D1 and D2 
included) 
Post-baseline value on 
studied/interest period if measured 
between (D1=) days after the first 
treatment intake and until (D2=) 
days after the last treatment intake 
as defined in Section 4.1.5 (D1 and 
D2 included) 
Tumour assessment 
(all lesions) 
D1 = -∞ 
D2 = Xsup 
D1 = Xinf 
D2 = 30 
Biochemistry/haematology/ 
coagulation/urinanalysis 
D1 = -∞* 
D2 = Xsup* 
D1 = Xinf* 
D2 = 30 
Vital signs and physical 
examinations 
D1 = -∞* 
D2 = Xsup* 
D1 = Xinf* 
D2 = 30 
Pregnancy test 
D1 = -∞* 
D2 = Xsup 
D1 = NA 
D2 = NA 
ECG 
D1 = -∞ 
D2 = Xsup 
D1 = Xinf 
D2 = 30 
QoL (score, completion, 
compliance) 
D1 = -∞ 
D2 = Xsup** 
D1 = Xinf** 
D2 = +∞ 
QoL (reason of non-
completion) 
D1 = -∞ 
D2 = Xsup*** 
D1 = Xinf*** 
D2 = +∞ 
AE expected 
D1 = -∞ 
D2 = Xsup 
D1 = Xinf 
D2 = 30 
-∞ : the last evaluable assessment before the first treatment intake date where visit<”C001” 
-∞*: the last evaluable assessment before the first treatment intake date where visit≤”C001D001”  
Xsup: 0 and” Visit< “C001” 
Xsup*: 0 and” Visit≤ “C001D001” 
Xsup**: 0 
Xsup***: Visit ≤ “A000” 
Xinf: 0 and” Visit ≥ “C001”  
Xinf*: 1 and” Visit ≥ “C001”,(Note: C001UNS is considered as a post-dose assessment when reported the same date as the first treatment 
intake) 
Xinf**: 1 
Xinf***: Visit > “A000” 
Table (4.1.2) 2 - Time frame of cycle n 
Notations 
Definitions 
Cycle n 
Start date: First trifluridine/tipiracil intake date of cycle n 
End date: The day before the 1st trifluridine/tipiracil intake of cycle (n+1) 
➢
It means that assessments planned the same day but before the 1st
trifluridine/tipiracil drug intake in cycle (n+1) are part of cycle n.
For the last cycle, End date = min ((*), date of death). 
(*) first intake date of last cycle +27 days for trifluridine/tipiracil monotherapy and  
max (first intake date of trifluridine/tipiracil of last cycle +27 days, first intake date 
of bevacizumab of last cycle +27 days) for trifluridine/tipiracil + bevacizumab arm 
The Data Management variable VISIT in exposure dataset will be used to determine 
the start date of each cycle. 
4.1.3. 
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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4.1.4. 
Analysable value  
Table (4.1.4) 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. 
ECG parameters 
For the analysis of QT criteria per measurement time, only scheduled values will be 
analyzed.  
4.1.5. 
First and last IMP intake dates  
For patients having taken at least one dose of IMP, the dates of first and last IMP intake on the 
analysis period will be defined as follows: 
- The date of the first IMP intake = min (first trifluridine/tipiracil intake date, first 
bevacizumab infusion date) within the analysis period. 
- The date of the last IMP intake = max (last trifluridine/tipiracil intake date, last bevacizumab 
infusion date) within the analysis period. 
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 (4.1.5) 1 - Substitution rules of IMP intake dates 
Date to substitute 
Substituted date 
First IMP intake 
../mmm/yyyy 
Inclusion date* if complete with same month and year 
Otherwise: 
01/mmm/yyyy 
../…/yyyy 
Inclusion date* if complete with same year 
Otherwise: 
01/JAN/yyyy 
../.../…. 
Inclusion date*if totally incomplete 
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** 
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
- 
* inclusion date (or dispensation date if inclusion date is missing, or randomization date if dispensation date is missing) 
- 
** 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.
- 
Note:  
Cycles with both missing first and last IMP intake dates and with number of returned tablets equal to number of tablets delivered 
at the previous cycle (or with estimated number of tablets taken equal to 0) will not be taken into account. 
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4.1.6. 
Other dates   
The rules for substitution of missing or incomplete death date are as follows: 
Table (4.1.6) 1 - Substitution rules of death date 
Date to substitute 
Substituted date 
Death date 
../mmm/yyyy 
Last available date* if same month and year 
Otherwise: 
01/mmm/yyyy 
../…/yyyy 
Last available date* if same year 
Otherwise: 
01/JAN/yyyy 
../.../…. 
No substitution 
Notes: 
../mmm/yyyy = missing day 
../.../ yyyy = missing day and month 
../.../.... = totally missing date 
- * Last available date is defined as maximum date among completed dates relative to patient’s information otherwise.
If no specific management of dates is defined, missing information is substituted as defined 
below:  
Table (4.1.6) 2 - Substitution rules of dates if no specific management is defined 
Date to substitute 
Substituted date 
Date 
../mmm/yyyy 
01/mmm/yyyy 
../…/yyyy 
01/JAN/yyyy 
../.../…. 
No substitution 
Note: 
../mmm/yyyy = missing day 
../.../ yyyy = missing day and month 
../.../.... = missing date 
4.2. Specific analytic definitions and data handling conventions  
4.2.1. 
Study patients: Disposition, baseline characteristics and follow-up  
4.2.1.1. 
Disposition of patients  
All treatment withdrawal reasons occurred in the study will be taken into account (adverse 
event, protocol deviation, progressive disease (radiological progressive disease, clinical 
progressive disease, radiological and clinical progressive disease), non-medical reason (consent 
withdrawal from study treatment, consent withdrawal including survival follow-up), lost to 
follow-up, physician decision or other medical reason). 
4.2.1.2. 
Protocol deviations  
Deviation categories have been defined in order to gather all the deviations relative to the same 
topic. 
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. 
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4.2.1.3. 
Demographic data and other baseline characteristics   
4.2.1.3.1. 
Demographic data   
Age is calculated as difference between year of informed consent and year of date of birth. 
Geographic region is defined from Enrollment e-CRF page: 
- North America: USA. 
- European Union: Austria, Belgium, Denmark, France, Germany, Hungary, Italy, Poland and 
Spain. 
- Rest of the World: Brazil, Ukraine and Russia. 
4.2.1.3.2. 
History of Colorectal cancer  
Primary diagnosis in classes, colon (including colorectal) versus rectal versus other, will be 
defined according to the codelists 4012.0 (colon and colorectal cancer) and 4013.0 (rectal 
cancer). If a patient is not associated with any of these lists, he will be considered as other. 
Primary tumour localisation:  
- Right if primary tumour site = right colon(1) or transverse or other* 
- Left if primary tumour site = left colon(2) or rectum 
(1) As per protocol, right colon should include ascending colon, cecum, appendix and hepatic
flexure.
(2) As per protocol, left colon should include descending colon, sigmoid colon, splenic flexure
and rectosigmoid segment.
*Other: in the case the patient present multiple tumours in both sides, the disease will be
considered as “right-sided”.
Site of metastasis is defined from History of colorectal cancer e-CRF page. 
Number of metastatic site is defined as the number of distinct site of metastasis (whether the 
site is considered for target or non-target lesion) from History of colorectal cancer e-CRF page. 
Sites filled in ‘Other’ will be counted as 1 site.  
Disease duration 
Disease duration (years) is defined as (Randomisation date – date of the first diagnosis)/365.25 
Time from first metastasis diagnosis to randomization 
Time from first metastasis diagnosis to randomization (months) is defined as (Randomization 
date – date of the first metastasis diagnosis)/30.44 
Progression free interval 
Progression free interval (months) is defined as (Date of progression prior to the randomisation 
date – date of end of the last prior anti-cancer therapy*)/30.44. 
The progression free interval of patients progressing during the last regimen is estimated to last 
one day. 
*Including drug treatment, radiotherapy and surgery (whatever the intent).
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Treatment free interval 
Treatment free interval (months) is defined as (Date of first trifluridine/tipiracil intake – date of 
end of the last prior anti-cancer therapy*)/30.44. 
*Including drug treatment, radiotherapy and surgery.
Of note, in case of partial or incomplete date: 
Table (4.2.1.3.2) 1 - Substitution rules of History of colorectal cancer 
Missing diagnosis date 
Substituted diagnosis date 
../mm/yyyy 

Diagnosis date = 01/mm/yyyy 
../…/yyyy 

Diagnosis date = 01/01/yyyy 
Missing metastasis date 
Substituted metastasis date 
../mm/yyyy 

Metastasis date = 01/mm/yyyy 
../…/yyyy 

Metastasis date =01/01/yyyy 
Missing start date of the last prior 
therapy 
Substituted start date of the last prior therapy 
../mm/yyyy 

start date of the last prior therapy = 01/mm/yyyy 
../…/yyyy 

start date of the last prior therapy = 01/01/yyyy 
Missing end date 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   
Missing start date of a previous 
treatment 

Substituted start date of a previous treatment 
../mmm/yyyy 

01/mmm/yyyy 
../…/yyyy 

01/JAN/yyyy 
../.../…. 

Inclusion date 
Note: 
../mm/yyyy = missing day 
../.../ yyyy = missing day and month 
  ../.../....  = missing date 
RAS status 
Table (4.2.1.3.2) 2 - RAS status 
KRAS 
NRAS 
RAS 
MUTANT 
whatever (mutant, wild, missing) 
MUTANT 
whatever (mutant, wild, missing) 
MUTANT 
MUTANT 
WILD 
WILD 
WILD 
MISSING 
WILD 
NE 
WILD 
MISSING 
NE 
MISSING 
MISSING 
NE 
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Stage at diagnosis 
Table (4.2.1.3.2) 3 - Staging based on classification 
Stage in classes 
AJCC stage 
Dukes’ classification 
Astler-Coller modified Dukes’ classification 
Stage 0 
- 
- 
I-II
Stage I 
A 
A 
I-II
Stage I 
A 
B1 
I-II
Stage II-A 
B 
B2 
I-II
Stage II-B 
B 
B2 
I-II
Stage II-C 
B 
B3 
III 
Stage III-A 
C 
C1 
Stage III-B 
C 
C2 
C 
C1/C2 
C 
C1 
Stage III-C 
C 
C2 
C 
C2/C3 
C 
C3 
IV 
Stage IV-A 
D 
D 
Stage IV-B 
Stage IV-C 
4.2.1.3.3. 
Medical history and surgical or medical procedures history other than 
colorectal cancer   
The existence of a history (Yes/No) is defined from the presence, or not, of a Primary system 
organ class and/or Preferred term. 
4.2.1.3.4. 
Previous therapies for colorectal cancer  
The anatomical therapeutic chemical 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 “anatomical therapeutic chemical classification” and/or a “preferred name” for the previous 
drug treatment at inclusion visit.  
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The existence of a previous metastatic drug treatment (Yes, No) is defined from the 
presence, or not of an “anatomical therapeutic chemical classification” and/or a “preferred 
name” for the previous drug treatment: 
- Given in palliative indication. 
- Given in adjuvant or neoadjuvant indication and with a progression before or within 
6 months after the drug treatment completion 
The existence of a previous therapy (Yes, No) is defined from the presence or not of a surgery, 
radiotherapy and/or a drug treatment. 
The existence of a previous curative surgery (Yes, No) is defined from the presence or not 
of a surgery with a curative indication. 
The existence of a previous palliative surgery (Yes, No) is defined from the presence or not 
of a surgery with a palliative indication. 
The existence of a previous curative radiotherapy (Yes, No) is defined from the presence or 
not of a previous radiotherapy with a curative, adjuvant or neoadjuvant indication. 
The existence of a previous palliative radiotherapy (Yes, No) is defined from the presence 
or not of a previous radiotherapy with a palliative indication. 
The existence of a previous fluoropyrimidine drug treatment (Yes, No) is defined from the 
presence, or not of a previous drug treatment belonging to the list 3678.0. 
The existence of a previous irinotecan drug treatment (Yes, No) is defined from the 
presence, or not of a previous drug treatment belonging to the list 3674.0. 
The existence of a previous oxaliplatin drug treatment (Yes, No) is defined from the 
presence, or not of a previous drug treatment belonging to the list 3675.0. 
The existence of a previous anti-VEGF monoclonal antibody drug treatment (Yes, No) is 
defined from the presence, or not of a previous drug treatment belonging to the list 4281.0. 
The existence of a previous anti-EGFR monoclonal antibody drug treatment (Yes, No) is 
defined from the presence, or not of a previous drug treatment belonging to the list 4280.0. 
Number of prior drug regimens is calculated as the sum of previous drug treatments whatever 
the intent. 
Number of prior metastatic drug regimens is calculated as the sum of previous metastatic 
drug treatments. 
4.2.1.3.5. 
Initial tumour assessment  
Not applicable. 
4.2.1.4. 
Extent of exposure and treatment compliance  
Treatment duration for trifluridine/tipiracil  
Treatment duration (months) for trifluridine/tipiracil is defined as ([min (first intake date of the 
last cycle + 27days, death date) - first trifluridine/tipiracil intake date] +1)/30.44. 
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Treatment duration for bevacizumab in trifluridine/tipiracil + bevacizumab arm  
Treatment duration (months) for bevacizumab in trifluridine/tipiracil is defined as [(min (first 
intake date of the last cycle + 27days, death date) - first intake date) +1] / 30.44. 
In case of missing or incomplete first intake date of the last cycle, the last intake date of the last 
cycle will be considered. 
Cycle duration for trifluridine/tipiracil 
Duration of cycle i (weeks) for trifluridine/tipiracil is defined as [[first trifluridine/tipiracil 
intake of cycle (i+1)] – [first trifluridine/tipiracil intake of cycle i]] / 7. 
Of note, the duration of the last cycle for trifluridine/tipiracil will be estimated to be 28 days 
for the calculation of Dose Intensity and Relative Dose Intensity at the last cycle. 
Cycle duration for bevacizumab 
Duration of cycle i (weeks) for bevacizumab is defined as [[first trifluridine/tipiracil intake of 
cycle (i+1)] – [first trifluridine/tipiracil intake of cycle i]] / 7. 
Of note, the duration of the last cycle for bevacizumab will be estimated to be 28 days 
(trifluridine/tipiracil + bevacizumab arm) for the calculation of Dose Intensity and Relative 
Dose Intensity at the last cycle. 
Follow-up duration 
The follow-up duration (months) is calculated as the duration between the last available date 
and the randomisation date [last available date* – randomisation date +1]/30.44. The events of 
interest are being alive or lost to follow-up and death is censored. 
* Last available date is defined as date of death if patient died, and as maximum date among
completed dates relative to patient’s information otherwise.
Number of cycles for trifluridine/tipiracil (resp. bevacizumab) 
The number of cycles with trifluridine/tipiracil will be defined based on exposure data. A 
patient is considered to enter in a cycle if there is at least one intake date. 
Real administrated dose (mg) for trifluridine/tipiracil 
On a time period, real administered dose for trifluridine/tipiracil (mg) = Number of capsules 
15 mg taken*15 + Number of capsules 20 mg taken*20 
With: 
- Number of capsules taken = Number of capsules dispensed - Number of capsules returned 
Else, if Number of capsules returned is missing, Number of capsules taken = Estimated number 
of capsules taken. 
Real administrated dose (mg) for bevacizumab 
On a time period, real administered dose for bevacizumab (mg) = sum of total dose 
administrated (full + incomplete doses).  
Note: Avastin Summary of Product Characteristics (SmPC): Each ml of concentrate contains 
25 mg of bevacizumab so 5mg of bevacizumab corresponds to 0.2 mL and 7.5 mg corresponds 
to 0.3 mL. 
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Planned dose intensity (PDI) for trifluridine/tipiracil (mg/m²/week) 
10 days of intake 
per cycle 
35 mg/m2 (bid) 
(70 mg/m²/day) 
𝟕𝟎(mg/m²/day) ∗𝟏𝟎
4 (wk)
Planned dose intensity (PDI) for bevacizumab (mg/kg/week) 
2 days of intake 
per cycle 
5 mg/kg (qd) 
(5 mg/kg/day) 
𝟓(mg/kg/day) ∗𝟐
4 (wk)
Cumulative dose 
The cumulative dose (mg/m²) for trifluridine/tipiracil 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) = 
∑
(𝑅𝑒𝑎𝑙 𝐴𝑑𝑚𝑖𝑛𝑖𝑠𝑡𝑟𝑎𝑡𝑒𝑑 𝑑𝑜𝑠𝑒 (𝑚𝑔)
𝐵𝑆𝐴 (𝑚2)
)
𝑡𝑖𝑚𝑒𝑝𝑒𝑟𝑖𝑜𝑑
 
Where BSA is calculated in the ClinTrial database by the data management. 
The cumulative dose (mg/kg) for the 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) = 
∑
(𝑅𝑒𝑎𝑙 𝐴𝑑𝑚𝑖𝑛𝑖𝑠𝑡𝑟𝑎𝑡𝑒𝑑 𝑑𝑜𝑠𝑒 (𝑚𝑔)
𝑤𝑒𝑖𝑔ℎ𝑡 (𝑘𝑔)
)
𝑡𝑖𝑚𝑒𝑝𝑒𝑟𝑖𝑜𝑑
 
Dose intensity (DI) per patient 
The dose intensity (mg/m²/week) for trifluridine/tipiracil per patient is defined as the 
cumulative dose (mg/m²) received during the treatment period divided by the total treatment 
duration in weeks. 
𝐷𝐼 (𝑚𝑔/𝑚²/𝑤𝑘) 𝑝𝑒𝑟 𝑝𝑎𝑡𝑖𝑒𝑛𝑡 = 𝐶𝑢𝑚𝑢𝑙𝑎𝑡𝑖𝑣𝑒 𝑑𝑜𝑠𝑒 (𝑚𝑔/𝑚²)
𝑇𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝑑𝑢𝑟𝑎𝑡𝑖𝑜𝑛 (𝑤𝑒𝑒𝑘𝑠)
The dose intensity (mg/kg/week) for the bevacizumab per patient is defined as the cumulative 
dose (mg/kg) received during the treatment period divided by the total treatment duration in 
weeks. 
𝐷𝐼 (𝑚𝑔/𝑘𝑔/𝑤𝑘) 𝑝𝑒𝑟 𝑝𝑎𝑡𝑖𝑒𝑛𝑡 = 𝐶𝑢𝑚𝑢𝑙𝑎𝑡𝑖𝑣𝑒 𝑑𝑜𝑠𝑒 (𝑚𝑔/𝑘𝑔)
𝑇𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝑑𝑢𝑟𝑎𝑡𝑖𝑜𝑛 (𝑤𝑒𝑒𝑘𝑠)
Dose intensity (DI) per cycle 
The dose intensity (mg/m²/week) for trifluridine/tipiracil per cycle is defined as the cumulative 
dose (mg/m²) received during the cycle divided by the cycle duration in weeks. 
𝐷𝐼 (𝑚𝑔/𝑚²/𝑤𝑘) 𝑎𝑡 𝑐𝑦𝑐𝑙𝑒 𝑖 = 𝐶𝑢𝑚𝑢𝑙𝑎𝑡𝑖𝑣𝑒 𝑑𝑜𝑠𝑒 (𝑚𝑔/𝑚²) 𝑟𝑒𝑐𝑒𝑖𝑣𝑒𝑑 𝑎𝑡 𝑐𝑦𝑐𝑙𝑒 𝑖
𝐷𝑢𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑐𝑦𝑐𝑙𝑒 𝑖 (𝑤𝑒𝑒𝑘𝑠)
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The dose intensity (mg/kg/week) for the bevacizumab per cycle is defined as the cumulative 
dose (mg/kg) received during the cycle divided by the cycle duration in weeks. 
𝐷𝐼 (𝑚𝑔/𝑘𝑔/𝑤𝑘) 𝑎𝑡 𝑐𝑦𝑐𝑙𝑒 𝑖 = 𝐶𝑢𝑚𝑢𝑙𝑎𝑡𝑖𝑣𝑒 𝑑𝑜𝑠𝑒 (𝑚𝑔/𝑘𝑔) 𝑟𝑒𝑐𝑒𝑖𝑣𝑒𝑑 𝑎𝑡 𝑐𝑦𝑐𝑙𝑒 𝑖
𝐷𝑢𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑐𝑦𝑐𝑙𝑒 𝑖 (𝑤𝑒𝑒𝑘𝑠)
RDI per patient 
The RDI (%) per patient is defined as the ratio of the DI to the initial PDI. 
𝑅𝐷𝐼 (%) 𝑝𝑒𝑟 𝑝𝑎𝑡𝑖𝑒𝑛𝑡 = 
𝐷𝐼 
𝑃𝑙𝑎𝑛𝑛𝑒𝑑 𝑑𝑜𝑠𝑒 𝑖𝑛𝑡𝑒𝑛𝑠𝑖𝑡𝑦 ∗100 
RDI per cycle 
The relative dose intensity (%) per cycle is defined as the ratio of the dose intensity at cycle i 
to the planned dose intensity. 
𝑅𝐷𝐼 (%) 𝑎𝑡 𝑐𝑦𝑐𝑙𝑒 𝑖 = 
𝐷𝐼 𝑎𝑡 𝑐𝑦𝑐𝑙𝑒 𝑖 
𝑃𝑙𝑎𝑛𝑛𝑒𝑑 𝑑𝑜𝑠𝑒 𝑖𝑛𝑡𝑒𝑛𝑠𝑖𝑡𝑦∗100 
Dose reduction for trifluridine/tipiracil 
A cycle with a dose reduction is defined according to the trifluridine/tipiracil dispensing e-CRF 
page (dose level modified since the last cycle (Yes, No)). 
Partial dose administered for bevacizumab 
Partial dose administered for the bevacizumab is defined by an answer “No” at the eCRF 
interrogation “Was full dose administered?”. 
Missed intake for bevacizumab 
A missed intake for the bevacizumab is defined by an answer “No” at the e-CRF interrogation 
“Did the patient receive the associated agent infusion?”. 
Dispensation postponed for trifluridine/tipiracil 
A cycle with a dispensation postponed is defined according to the trifluridine/tipiracil 
dispensing e-CRF page (Dispensation postponed (Yes, No)). 
Unplanned treatment interruption for trifluridine/tipiracil 
A treatment interruption is defined according to the number of days between two consecutive 
end of treatment intake and start of treatment intake when this duration is one day or longer. 
Treatment interruption (days) = (date of treatment restarted - date of last dose intake before 
interruption) -1.  
Note: only intra-cycle interruptions will be considered 
If at least one of the end or restart intake date is missing then the number of interruption days 
will be defined according to the e-CRF page (Number of days of interruption). 
4.2.1.5. 
Concomitant treatments  
The anatomical therapeutic chemical 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. 
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- 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 the treatment period for which treatments: 
- With start date < first trifluridine / tipiracil intake date are taken into account. 
During the treatment period for which treatments: 
- With start date ≥ first trifluridine/tipiracil intake date and < (*), or 
- With start date ≤ first trifluridine/tipiracil intake date and stop date ≥ first trifluridine / 
tipiracil intake date or missing 
After the treatment period for which treatments:  
- With start date ≥ (*), or 
- With start date ≤ (*) and stop date > (*) or missing. 
(*) first intake date of last cycle +28 days for trifluridine/tipiracil monotherapy and max (first 
intake date of last cycle +28 days of trifluridine/tipiracil, first intake date of last cycle +28 days 
of bevacizumab) for trifluridine/tipiracil + bevacizumab arm 
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The following rules for substitution of missing or incomplete start and stop dates are so that 
the concomitance period is maximised: 
Table (4.2.1.5) 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 
../.../…. 
If stop date is non-missing and inferior to inclusion 
date then: 
Stop date 
Else: 
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 (4.2.1.5) 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 trifluridine/tipiracil intake date 
then  
Last trifluridine/tipiracil intake date  
otherwise 
01/mm/yyyy 
../…/yyyy 
If the year is the same as the year of the last 
trifluridine/tipiracil intake date then  
Last trifluridine/tipiracil intake date,  
otherwise 
01/01/yyyy 
../.../…. 
Last trifluridine/tipiracil 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 
The last trifluridine/tipiracil intake corresponds to the real last trifluridine/tipiracil intake within the analysis period. 
The existence of a concomitant G-CSF treatment (Yes, No) is defined from the presence, or 
not, of a CMCLAS= “COLONY STIMULATING FACTORS”. 
Primary prophylaxis is defined as: 
- A G-CSF intake start date at cycle 1 and no neutropenia at cycle 1, or 
- A G-CSF intake start date at cycle 1 and neutropenia at cycle 1 and neutropenia onset date 
> G-CSF intake start date.
Only the first G-CSF intake start date is considered. 
Secondary prophylaxis is defined as: 
- Neutropenia at any cycle (cycle i) and a G-CSF intake start date at further cycles (cycle i+1, 
i+2, …) and neutropenia onset date < G-CSF intake start date. 
Therapeutic use is defined as: 
- Neutropenia onset date = G-CSF intake start date. 
- Neutropenia onset date + 1 day = G-CSF intake start date. 
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Of note: 
- If a G-CSF intake is defined both as a secondary prophylaxis and as a therapeutic use, then 
it will be defined as a therapeutic use only. 
- A patient may have more than one indication related to G-CSF use. 
- The following MedDRA codes/preferred terms (PTs) reported are considered as 
neutropenia: 
MedDRA PTs codes 
MedDRA PTs 
10029354 
Neutropenia 
10049151 
Neutropenic sepsis 
10016288 
Febrile neutropenia 
10029366 
Neutrophil count decreased 
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5.
APPENDIX B: EFFICACY
5.1.  Non-confirmed Best overall response  
Best overall response is defined as the best overall response across all time points excluding 
“Follow-up” e-CRF information. If applicable, responses recorded after intercurrent events will 
be excluded. 
When SD 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 
(8 weeks) 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 (PD). 
*: Progression/Death due to progression before the end of cycle 2: 
- According to tumoral evaluation. 
- Withdrawal reason status.  
- Or before 8 weeks after the treatment start on AE e-CRF page (PT « Malignant neoplasm 
progression » with code MedDRA 10051398.) 
In case of best overall response missing under the studied period, this one will be considered as 
Non Evaluable (NE).  
Complete response (CR) and partial response (PR) will not be confirmed following initial 
documentation of overall response. 
Table (5.1) 1 - BOR when confirmation of CR and PR not required 
5.2. Lesions diameters  
Relative change of the sum of the lesions diameters (%) 
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 done prior to randomisation. 
Overall response 
Overall response 
BOR 
First time point (i) 
Next time point (i+1) 
CR 
Whatever the overall response 
CR 
PR 
Whatever the overall response 
other than CR 
PR 
SD 
PD 
SD (if the time length between the study randomisation 
and the SD is ≥ 6 weeks), otherwise, PD 
SD 
SD or NE or missing 
SD (if the time length between the study randomisation 
and one of the SD is ≥ 6 weeks), otherwise, NE  
PD 
Whatever the overall response 
PD 
NE or missing 
PD 
PD 
NE or missing 
NE or missing 
NE 
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Relative change from baseline of the sum of the lesions diameters (%) is defined at cycle i as 
follow: 
(sum of the lesions diameters at the cycle i − sum of the lesions diameters at baseline
sum of the lesions diameters at baseline
)
∗100 
Relative change from NADIR (SMALLEST) of the sum of the lesions diameters (%) is defined 
at cycle i as follow: 
(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
)
∗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 follow: 
 min
𝑖
𝑖>0
(sum of the lesions diameters at the cycle i − sum of the lesions diameters at baseline
sum of the lesions diameters at baseline
) ∗100 
5.3. Events and censoring dates  
Date of treatment switch 
Date of switch from trifluridine/tipiracil in combination with bevacizumab to 
trifluridine/tipiracil 
monotherapy 
or 
from 
trifluridine/tipiracil 
monotherapy 
to 
trifluridine/tipiracil in combination with bevacizumab. 
1st radiological PD assessment: 
Date of the first assessment of the series of the tests that determined PD. 
The date of first progression is defined as the first date of PD where the overall response is PD. 
The date of PD 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 latest 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”. 
- Date of PD for new lesion: If there is at least one new lesion at cycle i, the date of PD for 
new lesions is the earliest date of examination among the new lesions at cycle i. 
1st clinical PD assessment 
min ( 
Date of withdrawal if reason for withdrawal = “Clinical Progressive disease” or “Radiological 
and clinical progressive disease”. 
Date of progression in AE e-CRF page (Is this event related to disease progression). 
Date of PD according to the patient’status filled in the follow-up e-CRF page. 
) 
Death date 
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min(  
date of death from AE e-CRF page. 
date of death from follow-up/status of the patient e-CRF page. 
) 
New anti-cancer therapy considered for efficacy analyses will be defined by: 
- A concomitant medication with a pharmacological class, including antineoplastic agents, 
immunotherapy and endocrine therapy from codelist number = 3997.0. 
- A concomitant medication based on all investigational drugs from codelist number = 3594.2. 
- A further therapy reported in Post-study e-CRF pages. 
Lost to follow-up 
Patient lost to follow-up is defined by an answer “Lost to follow-up” and/or “Non-medical 
reason” related to consent withdrawal* at the eCRF interrogation “Reason for withdrawal from 
the study”. 
*related to consent withdrawal is defined as one of the two following subcategories:
- “Consent withdrawal from study treatment period and survival follow-up”.
5.4. Proportional hazard assumption  
The proportional hazard assumption across treatment arms will be checked. 
The plot of the « log of the negative log of the estimated survivor function » (LLS) against log 
time will be done to provide an empirical check of the appropriateness of the proportional 
hazards model assumption. Under this assumption, the LLS curves should be approximately 
parallel across treatment groups. In addition, a Schoenfeld Residuals test will be performed to 
test whether the slope of scaled Schoenfeld residuals on time is zero or not. If the slope is not 
zero then the proportional hazard assumption has been violated. As there are certain types on 
non-proportionality that will not be detected by the tests of non-zero slopes alone but that might 
become obvious when looking at the graphs of the residuals, the graph of the scaled Schoenfeld 
residuals will be drawn. If necessary, sensitivity analyses other than those planned in the SAP 
could be carried out, in the framework of the validation of the assumptions underlying the 
model. 
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6.
APPENDIX C: SAFETY
The periods considered for the analysis of adverse events, deaths and clinical laboratory 
evaluation are: 
- During the treatment period: 
With date ≥ first IMP intake date and <=last IMP intake date as defined in the
Section 4.1.5 + 30 days.
- After the treatment period: 
With date > last IMP intake date as defined in the Section 4.1.5 + 30 days.
6.1. Adverse events  
Each medical concept of adverse events coded according to the internal "multiple medical 
concept" process is taken into account as a single adverse event in the statistical analysis. 
The modalities of the adverse event (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. 
Emergent adverse events on treatment are defined as all adverse events: 
- Which occur between the first IMP intake date (included) and the last IMP intake date "+ 
30 days" (included), considering the definition of last IMP intake date defined in 
Section 4.1.5 
or 
- Which occur before the first IMP intake date and which worsen (in terms of severity) or 
become serious according to the investigator opinion between the first IMP intake date 
(included) and the last IMP intake date "+ 30 days" (included), considering the definition of 
last IMP intake date defined in Section 4.1.5. 
Note: Adverse events occurring or worsening or becoming serious on the day of the first IMP 
intake (if any) is considered as emergent. 
Serious adverse events are defined as all adverse events upgraded by the sponsor during the 
IME or PharmacoVigilance (PV) process (upgrade of seriousness) or considered as "serious" 
from investigator assessment. 
Serious adverse events from investigator assessment are defined as all adverse events 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. 
A fatal adverse event corresponds to an adverse event with “Fatal” as outcome. 
Adverse events related to trifluridine/tipiracil correspond to adverse events with relationship 
forced by the sponsor during the PV process (upgrade of relationship for adverse events 
assessed as serious according to investigator or sponsor opinion) or considered as "related" from 
investigator assessment. In other cases, the adverse events are considered as "not related to 
trifluridine/tipiracil". 
Adverse events related to study drug from investigator assessment correspond to adverse events 
associated with the answer "Related" to the "Is this event related to test drug 
(trifluridine/tipiracil)" question. 
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Adverse events related to Bevacizumab correspond to adverse events associated with the 
answer "Related" to the "Is this event related to the associated agent (Bevacizumab)" question. 
Adverse events related to the combination (trifluridine/tipiracil + bevacizumab or 
trifluridine/tipiracil monotherapy) correspond to adverse events associated with the answer 
"Related" to the "Is this event related to test drug (trifluridine/tipiracil)" question and/or with 
the aswer “Related” to the "Is this event related to the associated agent (Bevacizumab)" 
question. 
Adverse events related to disease progression correspond to adverse events associated with 
the answer "Related" to the "Is this event related to disease progression" question. 
The following information will be taken into account: 
- For the analyses where the severity of the adverse event is considered, the worst severity 
from the day of emergence and during the studied period (i.e. between the first IMPintake 
date (included) and the last IMP intake date (as defined in Section 4.1.5) “+ 30 days” 
(included) will be taken into account. 
- The number of patient by worst grade: for each patient, system organ class and preferred 
term, we analyze the worst grade of events. 
- The number of event by worst grade: for each patient, system organ class and preferred term, 
we analyse 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 study drug 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 emergent adverse event leading to studied treatment 
withdrawal reported after the last IMP intake date (as defined in Section 4.1.5) “+ 30 days”, 
the adverse event 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 adverse event with NCI CTCAE grade 3, 4 or 5. 
- Any grade corresponds to an adverse event with NCI CTCAE grade 1, 2, 3, 4 or 5. 
- All multicoded events will be taken into account in the analyses. 
- For the analysis of recovered emergent adverse event during / after treatment period, an EAE 
is considered as recovered "during treatment period" ("after end of treatment period", 
respectively) if the associated outcome is “recovered" or "recovered with sequelae" and 
occurs between the first IMP intake date and the last IMP intake date (as defined in 
Section 4.1.5) “+ 30 days” (included) (strictly after the last IMP intake date (as defined in 
Section 4.1.5) “+ 30 days”, respectively). 
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The following rules are applied in case of missing severity: 
Table (6.1) 1 - Emergence of adverse events in case of missing severity/grade (if any) 
Severity/Grade 
Adverse event considered as 
Nearest before the first 
study drug/associated 
agent intake date 
During the study 
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 (6.1) 2 - Substitution rules of AE dates 
Date to substitute 
Substituted date 
(Episode date) 
../mmm/yyyy 
If same month and year than first IMP intake date then: 
   First IMPintake date 
Else: 
   01/mmm/yyyy 

../…/yyyy
If same year than first IMP intake date then: 
   First IMPintake date 
Else: 
   01/JAN/yyyy 

../.../….
   First IMP intake 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: 
Table (6.1) 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 action taken and dates of the 
six seriousness criteria for this adverse event. 
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6.2. 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) e-CRF pages.  
In case of death reported on ‘Adverse Event’ page, the date of death is compared to the date of 
last intake (as defined in Section 4.1.5) “+ 30 days” to classify occurrence on-treatment or 
during follow-up. 
6.3. 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. 
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Table (6.3) 1 - Gradable and non-gradable laboratory parameters 
Laboratory 
parameters 
Parameter 
Highest 
Lowest 
Biochemistry 
Gradable 
Sodium 
Hypernatremia 
Hyponatremia 
Biochemistry 
Gradable 
Potassium 
Hyperkalemia 
Hypokalemia 
Biochemistry 
Gradable 
Magnesium 
Hypermagnesemia 
Hypomagnesemia 
Biochemistry 
Gradable 
Serum creatinine 
High creatinine 
NA 
Biochemistry 
Gradable 
Albumin 
NA 
Low albumin 
Biochemistry 
Gradable 
Glucose 
NA 
Hypoglycemia 
Biochemistry 
Gradable 
GGT 
High GGT* 
NA 
Biochemistry 
Gradable 
AST 
High AST* 
NA 
Biochemistry 
Gradable 
ALT 
High ALT* 
NA 
Biochemistry 
Gradable 
Alkaline 
phosphatase 
High alkaline 
phosphatase* 
NA 
Biochemistry 
Gradable 
Total bilirubin 
High total bilirubin* 
NA 
Haematology 
Gradable 
Haemoglobin 
High haemoglobin* 
anemia 
Haematology 
Gradable 
White blood cells 
NA 
Low WBC 
Haematology 
Gradable 
Neutrophils 
NA 
Low neutrophils 
Haematology 
Gradable 
Lymphocytes 
High lymphocytes 
Low lymphocytes 
Haematology 
Gradable 
Platelets 
NA 
Low platelets 
Coagulation 
Non-
gradable 
INR 
High INR 
NA 
Biochemistry 
Non-
gradable 
Creatinine 
clearance** 
NA 
Low creatinine clearance 
Biochemistry 
Non-
gradable 
Chloride 
High chloride 
Low chloride 
Biochemistry 
Non-
gradable 
Blood urea 
nitrogen 
High urea nitrogen 
NA 
Biochemistry 
Non-
gradable 
Total calcium 
High total calcium 
Low total calcium 
Biochemistry 
Non-
gradable 
LDH 
High LDH 
NA 
Biochemistry 
Non-
gradable 
Phosphate 
NA 
Hypophosphatemia 
Haematology 
Non-
gradable 
Red blood cells 
High RBC 
Low RBC 
*: Grade cannot be computed at baseline (grading depends on normality/abnormality of baseline value) 
**: Creatinine clearance is calculated in the ClinTrial database (by the data management department) if the data 
was not reported in the e-CRF. 
Laboratory reference limits and CTCAE grades are reported in the database. 
For the parameters which are gradable according to CTCAE v5.0, the grades will be derived 
using the local laboratory reference limits in analysis datasets. 
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Table (6.3) 2 - Definition of CTCAE grade - Version 5.0 - Gradable parameters 
Parameter 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Sodium (mmol/L) - 
Hypernatremia 
]ULN;150] 
]150;155] 
]155;160] 
>160
Sodium (mmol/L) - 
Hyponatremia 
[130;LLN[ 
[120;130[ 
< 120 
Potassium (mmol/L) - 
Hyperkalemia 
]ULN;5.5] 
]5.5;6] 
]6;7] 
>7
Potassium (mmol/L) - 
Hypokalemia 
[3.0;LLN[ 
[2.5;3.0[ 
<2.5 
Calcium (mmol/L) - 
Hypercalcemia 
Magnesium (mmol/L) - 
Hypermagnesemia 
]ULN;1.23] 
]1.23;3.30] 
> 3.30
Magnesium (mmol/L) - 
Hypomagnesemia 
[0.5;LLN[ 
[0.4;0.5[ 
[0.3;0.4[ 
<0.3 
Albumin (g/L) - Low 
[30; LLN[ 
[20; 30[ 
< 20 
Glucose (mmol/L) - 
Hypoglycemia 
[3.0;LLN[ 
[2.2;3.0[ 
[1.7;2.2[ 
< 1.7 
ALAT increased 
>ULN – 3.0 x ULN
if 
baseline 
is
normal [≤ULN];
1.5 x baseline – 3.0
x 
baseline 
if 
baseline 
is 
abnormal [ > ULN] 
>3.0 x ULN – 5.0 x
ULN if baseline is
normal[≤ULN];
>3.0 x baseline –
5.0 x baseline if
baseline 
is
abnormal [ > ULN]
>5.0 x ULN – 20.0
x ULN if baseline
is normal [≤ULN];
>5.0 x baseline –
20.0 x baseline if
baseline 
is
abnormal [ > ULN]
>20.0 x ULN x
ULN if baseline is
normal [≤ULN];
>20.0 x baseline if
baseline 
is
abnormal [ > ULN]
ALP increased 
>ULN – 2.5 x ULN
if 
baseline 
is 
normal 
[≤ULN]; 
2.0 x baseline – 2.5 
x 
baseline 
if 
baseline 
is 
abnormal [ > ULN] 
>2.5 x ULN – 5.0 x
ULN if baseline is
normal [≤ULN];
2.5 x baseline – 5.0
x 
baseline 
if 
baseline 
is 
abnormal [ > ULN] 
>5.0 x ULN – 20.0
x ULN if baseline
is normal [≤ULN];
>5.0 x baseline –
20.0 x baseline if
baseline 
is
abnormal [ > ULN]
>20.0 x ULN if
baseline is normal
[≤ULN];
>20.0 x baseline if
baseline 
is
abnormal [ > ULN]
ASAT increased 
>ULN – 3.0 x ULN
if 
baseline 
is
normal [≤ULN];
1.5 x baseline – 3.0
x 
baseline 
if 
baseline 
is 
abnormal [ > ULN] 
>3.0 x ULN – 5.0 x
ULN if baseline is
norma [≤ULN]l;
>3.0 x baseline –
5.0 x baseline if
baseline 
is
abnormal [ > ULN]
>5.0 x ULN – 20.0
x ULN if baseline
is normal [≤ULN];
>5.0 x baseline –
20.0 x baseline if
baseline 
is
abnormal [ > ULN]
>20.0 x ULN if
baseline is normal
[≤ULN];
>20.0 x baseline if
baseline 
is
abnormal [ > ULN]
GGT increased 
>ULN – 2.5 x ULN
if 
baseline 
is
normal[≤ULN];
2.0 x baseline – 2.5
x 
baseline 
if 
baseline 
is 
abnormal [ > ULN] 
>2.5 x ULN – 5.0 x
ULN if baseline is
normal [≤ULN];
>2.5 x baseline –
5.0 x baseline if
baseline 
is
abnormal [ > ULN]
>5.0 x ULN – 20.0
x ULN if baseline
is normal [≤ULN];
>5.0 x baseline –
20.0 x baseline if
baseline 
is
abnormal [ > ULN]
>20.0 x ULN if
baseline is normal
[≤ULN];
>20.0 x baseline if
baseline 
is
abnormal [ > ULN]
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Table (6.3) 2 (Cont’d) - Definition of CTCAE grade - Version 5.0 - Gradable parameters 
Parameter 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Serum creatinine increased >ULN – 1.5 x ULN >1.5 x baseline – 
3.0 x baseline (if 
baseline available) 
OR  
>1.5 x ULN – 3.0 x
ULN
>3.0 x baseline (if
baseline available)
OR
>3.0 x ULN – 6.0 x 
ULN
>6.0 x ULN
Total bilirubin increased 
>ULN – 1.5 x ULN
if 
baseline 
is
normal [≤ULN];
1.0 x baseline – 1.5
x 
baseline 
if 
baseline 
is 
abnormal [>ULN] 
>1.5 x ULN – 3.0 x
ULN if baseline is
normal [≤ULN];
>1.5 x baseline –
3.0 x baseline if
baseline 
is
abnormal [>ULN]
>3.0 x ULN – 10.0
x ULN if baseline
is normal [≤ULN];
>3.0 – 10.0 x 
baseline if baseline
is 
abnormal
[>ULN]
>10.0 x ULN if
baseline is normal
[≤ULN];
>10.0 x baseline if
baseline 
is
abnormal [>ULN]
Haemoglobin increased 
> ULN and
increase from 
baseline ]0 ;20]
(g/L)
> ULN and
increase from 
baseline ]20 ;40]
(g/L)
> ULN and
increase from 
baseline > 40 (g/L)
Haemoglobin (g/L) - 
Anemia 
[100;LLN[ 
[80;100[ 
< 80 
White Blood Cells (G/L) - 
Low 
[3.0;LLN[ 
[2.0;3.0[ 
[1.0;2.0[ 
< 1.0 
Neutrophils (G/L) - Low 
[1.5;LLN[ 
[1.0;1.5[ 
[0.5;1.0[ 
<0.5 
Lymphocytes (G/L) - Low [0.8;LLN[ 
[0.5;0.8[ 
[0.2;0.5[ 
<0.2 
Lymphocytes (G/L) - High 
]4.0;20.0] 
>20
Platelets (G/L) - Low 
[75;LLN[ 
[50;75[ 
[25;50[ 
<25 
Any grade corresponds to a laboratory value with NCI CTCAE grade 0, 1, 2, 3 or 4. 
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 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.  
Urinary results 
The category ‘Present’ corresponds to results ‘+’, ‘++’, ‘+++’ and ‘++++’. 
The category ‘More than one +’ corresponds to results ‘++’, ‘+++’ and ‘++++’. 
Worst value 
For the urinalysis parameters, the worst class will correspond to ‘Presence’ class, then ‘Trace’ 
and finally ‘Absence’ will be considered as normal class. 
For creatinine clearance, the worst class will correspond to “severe” category, then “moderate”, 
then “mild” and finally “normal”. 
Baseline and post baseline worst grade for High and Low:  
- Low: If the result is below lower normal range limit, Low = grade (for gradable parameter), 
Else Low = 0. 
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- High: If the result is above upper normal range limit, High = grade (for gradable parameter), 
Else High = 0. 
The neutrophils-lymphocyte ratio (NLR) is defined as the absolute neutrophil count/absolute 
lymphocyte count 
6.4. Vital signs and clinical examination  
Worst value by cycle and overall 
For ECOG, weight, BSA, SBP, DBP and HR, the worst (highest) value will be derived. 
For weight, BSA, SBP, DBP and HR, the worst (lowest) value will be derived.  
Last value under treatment 
For ECOG, weight, BSA, SBP, DBP and HR, the last value under treatment will be derived. 
Change from baseline 
For weight, BSA, SBP, DBP and HR, the change from baseline to worst value at each cycle 
under treatment, to last post-baseline value under treatment and to worst (high and/or low) value 
by treatment arm will be derived. 
Body Surface Area 
BSA is calculated in the ClinTrial database (by data management department) using the height 
at inclusion visit and the weight at a corresponding cycle. This derived BSA will be used for 
compliance/exposure calculations as well as for vital signs and clinical examination analyses. 
The BSA will be calculated using the following DuBois formula (all BSA calculations are 
rounded to 2 decimal places) (Du Bois, 1916). 
BSA (m²) = ([Body Weight (kg)] 0.425 x [Height (cm)] 0.725) x 0.007184 
ECOG performance status 
Table (6.4) 1 - Patient performance status 
GRADE 
STATUS 
ECOG 
0 
Normal unrestricted activity 
1 
Arduous physical activity restricted, but patient able to walk unaided and 
perform light work 
2 
Able to walk unaided and independent but unable to work more than half-time 
3 
Much less independent. Spends more than half his / her time in bed or seated. 
4 
Incapable of looking after him / herself. Completely confined to bed or to a chair 
6.5.  Electrocardiogram  
Change from baseline to each post baseline visit = Post baseline absolute prolongation - 
Absolute prolongation at baseline 
Change from baseline to last visit = Last absolute prolongation - Absolute prolongation at 
baseline. 
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7.
APPENDIX D: QUALITY OF LIFE
7.1. QLQ C30 scores  
The QLQ – C30 is a cancer specific instrument that contains 30 questions and provides a multi-
dimensional assessment of health-related quality of life. The QLQ – C30 is composed of five 
functional scales, three symptom scales, six single items and a global health status. 
The raw scores are linearly transformed to give standard scores in the range of 0-100. Score 
algorithm is provided below.  
Higher scores in the global and functional scales and lower scores in the symptom/single scales 
indicate better quality of life. 
Table (7.1) 1 - QLQ-C30 Score Algorithm 
* Item range is the difference between the possible maximum and the minimum response to individual items; most items 
take values from 1 to 4, giving range = 3.† (revised) scales are those that have been changed since version 1.0, and their 
short names are indicated in this manual by a suffix “2” – for example, PF2.
QLQ C30 scores will be computed using the response to individual items noted Ix. 
For the QLQ-C30, raw scores and scores will be calculated as follows using: 
- For all scales, the Raw Score (RS), is the mean of the component items: 
RS = (I1 + I 2 +...+ In) / n 
- For Functional scales: 
Score = {1 - (RS−1) / range} ×100 
- For Symptom scales, single items and global health status: 
Score = {(RS - 1) / range} ×100 
Global health status: 
Score1: Global health status/QOL: ((I29+I30)/2-1)/6 * 100 
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Functional scales: 
Score2: Physical functioning: 
(1 - ((I1+I2+I3+I4+I5)/5 -1)/3) * 100 
Score3: Role functioning: 
(1 - ((I6+I7)/2-1)/3) * 100 
Score4: Emotional functioning: 
(1 - ((I21+I22+I23+I24)/4-1)/3) * 100 
Score5: Cognitive functioning: 
(1 - ((I20+I25)/2-1)/3) * 100 
Score6: Social functioning:  
(1 - ((I26+I27)/2-1)/3) * 100 
Symptom scales: 
Score7: Fatigue: 
((I10+I12+I18)/3-1)/3 * 100 
Score8: Nausea and vomiting: 
((I14+I15)/2-1)/3 * 100 
Score9: Pain:  
((I9+I19)/2-1)/3 * 100 
Single item scales: 
Score10: Dyspnoea:  
(I8-1)/3 * 100 
Score11: Insomnia: 
 
(I11-1)/3 * 100 
Score12: Appetite loss: 
(I13-1)/3 * 100 
Score13: Constipation: 
(I16-1)/3 * 100 
Score14: Diarrhoea:  
(I17-1)/3 * 100 
Score15: Financial difficulties: 
(I28-1)/3 * 100 
For the QLQ-C30 analysis: 
- QoL baseline questionnaire will be defined as the last questionnaire with at least one 
completed item prior to C1D1 included. 
- QoL baseline score will be defined according to the QoL baseline questionnaire. 
Scale scores in case of missing items 
- Single item scales: in case of missing item, no scale score is computed. 
- Multi-item scales: if at least half of the items from the scale have been answered, assume 
that the missing items have values equal to the average of those items which are present for 
that respondent. Then, the scale score is computed as described above. 
Scheduled assessment time point  
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 or at the 1st administration of 
the following cycle according to the questionnaire completion date reported in the ePRO.  
In case of unscheduled assessment, the QoL assessment will not be considered. 
The description of reasons for non-completion at each scheduled time point will be based on 
the eCRF reported time point for the corresponding “Quality of life assessment” page. 
Withdrawal questionnaire 
The quality of life of a patient at withdrawal will be based on the answers provided by the 
patient in the first questionnaire completed at or after the withdrawal date. 
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7.2. EQ5D-5L  
The EQ-5D 5L is a standardized health utility measure developed by the EuroQOL Group in 
order to provide a simple, generic measure of health for clinical and economic appraisal. It is 
composed of 5 questions focused on mobility, self-care, usual activities, pain/discomfort and 
anxiety/depression, and a Visual analogue scale (VAS). Each of the 5 questions has 5 levels: 
no problem, slight problems, moderate problems, severe problems and extreme problems.  
The VAS records the respondent’s self-rated health on a vertical visual analogue scale. The 
VAS ‘thermometer’ has endpoints of 100 (Best imaginable health state) at the top and 0 (Worst 
imaginable health state) at the bottom. This information can be used as a quantitative measure 
of health outcome as judged by the individual respondents. 
The dimensional 5-level system will be converted into a single index utility score: values for 
the 3125 theoretically possible health states defined by the EuroQol classification are calculated 
using a regression model (Busschbach et al, 2003). 
The index utility score will be derived according to Euroqol specific country value set. For all 
countries, the French Value Set will be used to generate health utility scores. 
For the EQ-5D analysis: 
- EQ-5D 5L utility score will be considered non evaluable when responses are missing for one 
or more of the dimensions. 
- Baseline questionnaire will be defined as the last evaluable questionnaire prior to C1D1 
included. 
- Baseline score will be defined according to the baseline questionnaire. 
EQ-5D 5L will be considered evaluable when questionnaire responses are completed for all the 
dimensions. 
Scheduled assessment time point  
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 or at the 1st administration of 
the following cycle according to the questionnaire completion date reported in the ePRO.  
In case of unscheduled assessment, the QoL assessment will not be considered. 
The description of reasons for non-completion at each scheduled time point will be based on 
the eCRF reported time point for the corresponding “Quality of life assessment” page. 
Withdrawal questionnaire 
The quality of life of a patient at withdrawal will be based on the answers provided by the 
patient in the first questionnaire completed at or after the withdrawal date. 
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8.
APPENDIX E: SOFTWARE AND PROGRAMMING CODES
Cox proportional hazard model stratifying for the stratification factors 
PROC PHREG data = work.data; 
model TIME* CENSOR(censoredval) = ARM / RL TIES=efron; 
strata STRAT1 STRAT2 STRAT3 ; 
RUN; 
Stratified log-rank test 
PROC LIFETEST data= work.data alpha=0.05 method=KM; 
time TIME *CENSOR (censoredval);   
strata STRAT1 STRAT2 STRAT3 / group=ARM; 
RUN; 
Cox proportional hazard model: stepwise procedure 
PROC PHREG data = work.data; 
model TIME* CENSOR(censoredval)= STRAT1 STRAT2 STRAT3 
ALL_FACTORS /risklimits ties=efron selection=stepwise slstay=0.10 slentry=0.10 
include=3; 
RUN; 
PROC PHREG data = work.data; 
model TIME* CENSOR(censoredval)= ARM STRAT1 STRAT2 STRAT3 
SIG_FACTORS /risklimits ties=efron; 
RUN; 
Fisher’s exact test 
PROC FREQ data = work.data; 
tables ARM * VAR / fisher; 
RUN; 
Cochran-mantel-haenszel stratified analysis 
PROC FREQ DATA= work.data; 
tables STRAT1*STRAT2*STRAT3 *ARM * VAR / CMH; 
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 method=KM; 
time TIME *CENSOR (censoredval);  
strata ARM; 
id USUBJID; 
RUN; 
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Mixed model repeated measures 
PROC MIXED data= work.data;  
class ARM STRAT1 STRAT2 STRAT3 VISIT ; 
model CH_QoL_Score = BASE_QoL_Score ARM STRAT1 STRAT2 STRAT3 
VISIT VISIT*ARM; 
lsmeans ARM VISIT VISIT*ARM /cl pdiff adjust=tukey; 
repeated VISIT / subject=usubjid type=un or AR(1) or cs; 
RUN; 
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9.
REFERENCES
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) version 5.0 
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 
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and Spain”. In: Brooks R, Rabin R, de Charro F, editors. The measurement and valuation of health status using 
EQ-5D: a European perspective. Dordrecht: Kluwer Academic Publishers; 2003. 
C. J. Clopper and E. S. Pearson, The Use of Confidence or Fiducial Limits Illustrated in the Case of the Binomial
Biometrika Vol. 26, No. 4 (Dec., 1934), pp. 404-413.
D. R. Cox, Regression Models and Life-Tables Journal of the Royal Statistical Society. Series B (Methodological),
Vol. 34, No. 2. (1972), pp. 187-220.
Du Bois D, Du Bois EF. A formula to estimate the approximate surface area if height and weight be known. 1916. 
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Irwin, JO. The standard error of an estimate of expectation of life, with special reference to expectation of 
tumourless life in experiments with mice. Journal of Hygiene. 1949;47(2):188. 
Kalbfleisch, J. D. and Prentice, R. L. (2002). The Statistical Analysis of Failure Time Data, 2nd edition. New 
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Kaplan E L, Meier P. Nonparametric estimation from incomplete observations. Journal of the American Statistical 
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Mallinckrodt, C.H., Lin, Q. and Molenberghs M. A structured framework for assessing sensitivity to missing data 
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MMRM). 
Mayer R., et al. "Randomised trial of TAS-102 for refractory metastatic colorectal cancer." The New England 
Journal of Medicine, 2015: 1901-1919.  
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Link to Avastin SmPC: 
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000582/human_med_000663.
jsp&mid=WC0b01ac058001d124. 
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