A Randomized, Double-Blind, Phase III Study Comparing FTD/TPI Therapy Versus Placebo in Patients Who Are Positive for Blood Circulating Tumor DNA After Curative Resection of Colorectal Cancer
Phase: PHASE3
Conditions: Colorectal Neoplasms, Trifluridine and Tipiracil, Circulating Tumor DNA
Sponsor: National Cancer Center Hospital East

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A Randomized, Double-Blind, Phase III Study Comparing FTD/TPI 
Therapy Versus Placebo in Patients Who Are Positive for Blood Circulating 
Tumor DNA After Curative Resection of Colorectal Cancer 
Investigator-Initiated Protocol 
Protocol Number：EPOC 1905 
ALTAIR study 
Initial attack on latent metastasis using TAS-102 for circulating tumor 
DNA identified colorectal cancer patients after curative resection   
Representative of the coordinating 
investigators: Takayuki Yoshino 
Department of Gastroenterology and Gastrointestinal 
Oncology,  
National Cancer Center Hospital East 
6-5-1 Kashiwanoha, Kashiwa-shi, Chiba 277-8577 
TEL：04-7133-1111 
E-mail：tyoshino@east.ncc.go.jp 
 
Coordinating investigators: Hiroya Taniguchi 
Department of Gastrointestinal Medicine,  
Aichi Cancer Center 
1-1, Kakoden, Chikusa-ku, Nagoya 464-8681 
TEL: 05-2762-6111 
E-mail: hiroya.taniguchi@aichi-cc.jp 
Coordinating investigator: Takeshi Kato 
Department of Surgery, Osaka Medical Center 
2-1-14 Houenzaka, Chuo-ku, Osaka 540-0006 
TEL：06-6942-1331 
E-mail：ken-kato@momo.so-net.ne.jp 
Coordinating investigators: Jun Watanabe 
Department of Colorectal Surgery 
Kansai Medical University 
2-5-1 Shin-machi, Hirakata City, Osaka 573-1010 
TEL: 072-804-0101 
E-mail：watanabj@hirakata.kmu.ac.jp 
Coordinating Investigator: Akihiro Sato 
Clinical Research Support Office, National Cancer 
Center Hospital East 
6-5-1 Kashiwanoha, Kashiwa-shi, Chiba 277-8577 
TEL： 04-7133-1111 
E-mail：asato@east.ncc.go.jp 
Coordinating Investigator: Hideaki Bando 
Department of Gastroenterology and Gastrointestinal 
Oncology, National Cancer Center Hospital East 
6-5-1 Kashiwanoha, Kashiwa-shi, Chiba 277-8577 
TEL：04-7133-1111 
E-mail：hbando@east.ncc.go.jp 
 
 
Protocol number: EPOC1905 
Version number: Version 10.1 
Date of preparation: Jul 10, 2024 
Approved by 
Representative of the coordinating investigator 
Takayuki Yoshino 
 
 
(Signature)：                    (Date)：                               
 
 
Precautions for Confidential Information 
This protocol is confidential information and is provided to the coordinating investigators, principal 
investigators, subinvestigators, and trial collaborators who conduct the clinical trial (including external 
contractors such as SMO), the medical institutions participating in the trial, the Institutional Review Board, 
and the Data and Safety Monitoring Committee. 
Except for the explanation of the present trial to patients, this protocol may not be disclosed to any third 
party or used for any purpose other than the trial, without written approval of a coordinating investigator or the 
provider of the investigational drug. 

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Revision History: 
Version 
Number 
Date of 
Preparation 
Details of Revision 
Ver.1.0 
March 10, 2020 
Created 
Ver 2.0 
May 15, 2020 
Revised allocation factors, revised central review of 
images, and description adjustment 
Ver 3.0 
Sep 15, 2020 
Revised treatment modification criteria, discontinuation 
Criteria, clarification of description, and description 
adjustment 
Ver.3.1 
Feb 1, 2021 
Added the clarification to Inclusion Criteria, Exclusion 
Criteria. 
Ver.3.2 
Apr 6, 2021 
Added the clarification to Inclusion Criteria No.3 
Ver.4.1 
May 20, 2021 
Changes in affiliation of representatives of the 
coordinating investigators, changes in acceptable ranges 
for the start date of each course, clarification of 
procedures, and description adjustment 
 
Ver.4.2 
Jun 9, 2021 
Correction for Table 8.2 Study Calendar 
Ver.5.1 
Oct 13, 2021 
Added the clarification to Inclusion Criteria, Allocation 
method, Discontinuation of Study Treatment, Criteria for 
the Modification of Study Treatment. 
Correction for Table 8.2 Study Calendar 
 
Ver.6.1 
Feb 07, 2022 
Change Representative of the coordinating investigators, 
add the coordinating investigator, change allocation 
factors 
Ver.7.1 
Jul 07, 2022 
Delete the study coordinating investigator, Added the 
clarification to Inclusion Criteria No.3, Clarification of 
test/observation timing, Description adjustment 
Ver.8.1 
Feb 09, 2023 
Clarification of Inclusion Criteria (Not affect to Taiwan 
site due to Taiwan enrollment period was completed), 
Extended study enrollment period (only Japan),  
Change to the latest clinical trial data base  
Ver.9.1 
Jan 16, 2024 
Clarification of Disease-Free Survival 1 and Disease-Free 
Survival 2 
Ver.10.1 
Jul 10, 2024 
Change in affiliation of coordinating investigator, 
clarification of factors used in stratified analysis 
 
 
 

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List of Abbreviations 
ALT (GPT) 
Alanine aminotransferase (glutamate pyruvate transaminase) 
AST (GOT) 
Aspartate 
aminotransferase 
(glutamate 
oxaloacetate 
transaminase) 
BV 
Bevacizumab 
COI 
Conflict of interest 
CRF 
Case report form 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
Circulating tumor DNA 
DFS 
Disease-free survival 
DNA 
Deoxyribonucleic acid 
ECOG 
Eastern Cooperative Oncology Group 
EORTC 
QLQ-C30 
European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire Module C30 
EQ-5D-5L 
EuroQOL 5 dimensions 5-level 
FAS 
Full analysis set 
FTD/TPI 
Trifluridine/tipiracil 
GCP 
Good clinical practice 
G-CSF 
Granulocyte colony stimulating factor 
Hb 
Hemoglobin 
HBc 
Hepatitis B core 
HBV 
Hepatitis B virus 
HBs 
Hepatitis B surface 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HR 
Hazard ratio 
IRB 
Institutional Review Board 
ITT 
Intention to treat 
MRD 
Minimal residual disease 
MRI 
Magnetic resonance imaging 
OS 
Overall survival 
PFS 
Progression-free survival 
PMDA 
Pharmaceuticals and Medical Devices Agency 
PS 
Performance status 
RTSM 
Randomization and Trial Supply Management System 
SP 
Safety population 
T-Bil 
Total bilirubin 

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UICC 
Unio Internationalis Contra Cancrum 
 

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Synopsis 
Phase 
Phase III 
Objectives 
This trial will be conducted in patients who underwent curative 
resection of colorectal cancer and then tested positive in monitoring 
using SignateraTM, a system by Natera, Inc. for detecting blood 
circulating tumor DNA (ctDNA) for the detection of residual tumor, 
with no apparent relapse on imaging. The objective of the trial is to 
verify the efficacy and safety of preemptive treatment with 
trifluridine/tipiracil hydrochloride (FTD/TPI) compared with follow-
up, which is the standard of care. 
 
Primary endpoint: 
 
Disease-free survival 1*1*3 (DFS1) 
*1 In this trial, a DFS1 event is defined as a relapse, development of a 
secondary large intestine carcinoma lesion other than a relapse (an 
intramucosal cancer lesion will not be treated as an event), and death. 
 
Secondary endpoints： 
 
Rate of conversion to negative ctDNA 
 
Disease-free survival 2*2*3 (DFS2) 
 
Overall survival*3 (OS) 
 
Incidence of adverse events 
 
Treatment completion rate 
 
QOL 
*2 In this trial, a DFS2 event is defined as a relapse, development of a 
cancer lesion other than a relapse (secondary cancer), and death. 
*3 After the end of the trial period, subjects will be followed up for 5 years 
in a separate observational study. 
Study schema 
Study design 
This trial is a randomized, double-blind, multinational Phase III 
study to evaluate the efficacy and safety of preemptive treatment 
with FTD/TPI compared with administration of placebo as follow-
up, which is the standard of care, in patients who underwent 

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curative resection of colorectal cancer and then tested positive for 
ctDNA. 
Study 
population 
Patients who meet all of the inclusion criteria and do not meet any 
of the exclusion criteria will be enrolled as patients who will receive 
study treatment. 
Inclusion criteria: 
1. 
Patients who have been histopathologically diagnosed with 
colorectal adenocarcinoma (Stage II or lower/Stage III/M1) 
2. 
Patients who have undergone radical resection*1 of the primary 
and metastatic tumors 
*1 It is considered to be a radical resection if the tumor is 
exposed at the edge or on the surface of surgical detachment 
but is encapsulated. 
3.   Patients who are subject to postoperative chemotherapy  
according to the country guideline and/or medical practice,  
that is Stage III (T any N1*2/2 M0) and Stage IV (T any N  
any M1) (UICC TNM Classification, 8th Edition) for Taiwan 
must 
have 
a 
history*4 
of 
standard 
postoperative 
chemotherapy*3. 
*2 N1c (UICC TNM Classification, 8th Edition) is also included 
in this stage (tumor deposits, or satellite nodules, are seen in 
the adjacent soft tissues of the colon or rectum without 
subserosal layer or peritoneal coat, with no regional lymph 
node metastasis). 
*3 Treatments described in the current Japanese and overseas 
guidelines or study treatments conducted in clinical studies. 
*4 In case of patients who do not have a standard 
postoperative chemotherapy for rational reason, these  
patients can be enrolled. 
Note that if sites enroll such patients, record the reason  
for the decision to medical chart. 
4. 
Patients who tested positive for ctDNA using SignateraTM by 
an analysis*5 of the latest blood samples collected within 3 
months prior to enrollment 
*5 Analyses of blood samples using SignateraTM will be 
performed in a separate clinical study (see Section 2.10.1.2.). 
5. 
Patients with no obvious relapse confirmed by chest, 
abdominal, and pelvic CT scans, etc. 
6. 
Patients who are capable of oral ingestion 
7. 
Patients aged 20 years or older at the time of informed consent 

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8. 
Patients with an Eastern Cooperative Oncology Group (ECOG) 
performance status (PS) of 0 or 1 
9. 
Patients who have no severe disorder in major organs (such as 
the bone marrow, heart, lungs, liver, and kidneys) and meet the 
following criteria (Data obtained most recently and within 14 
days of the date of enrollment will be used for enrollment. Data 
obtained 2 weeks before the date of enrollment, on the same 
day of the week as the enrollment date, may be used for 
enrollment.) 
‐ 
Neutrophil count ≥ 1,500/mm3 
‐ 
Platelet count ≥ 100,000/mm3 
‐ 
Hemoglobin ≥ 8.0 g/dL 
‐ 
Serum creatinine ≤ 1.5 mg/dL 
‐ 
Total bilirubin ≤  1.5 mg/dL 
‐ 
ALT and AST ≤ 100 U/L 
10. Patients with no diarrhea or stomatitis of Grade 2 or severer 
according to Common Terminology Criteria for Adverse Events 
(CTCAE) v5.0 
11. Patients who voluntarily gave written consent to participate in 
the trial after receiving a thorough explanation of the trial 
before enrolling in the trial 
Exclusion criteria 
1. 
Patients with a history of treatment with FTD/TPI 
2. 
Patients with a history of treatment with 2 or more regimens 
of postoperative adjuvant chemotherapy*6 (Preoperative 
chemotherapy will not be counted as a regimen.) 
*6 The timing of initiation of the postoperative adjuvant 
chemotherapy will not be specified. 
3. 
Patients with a past history of a malignant tumor*7 other than 
colorectal adenocarcinoma. 
*7 Patients with a relapse-free survival period of 5 years or 
longer, or patients with basal cell or squamous cell carcinoma 
of the skin that is considered cured by local treatment, 
superficial bladder cancer, cervical cancer, carcinoma in situ 
(intraepithelial cancer) or lesions equivalent to intramucosal 
cancer, or non-metastatic prostate cancer not requiring 
systemic treatment may be enrolled. 
4. 
Patients with a local or systemic active infection requiring 
intervention 

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5. 
Patients who are positive for HBs antigen*8 or positive for HCV 
antibody*9 
*8 HBV-DNA testing is mandatory to be below the limit of detection for 
patients with a negative HBs antigen test, but with a positive test 
result for either HBs antibody or HBc antibody  
*9 Patients who are positive for HCV antibody but negative for  
HCV-RNA may be enrolled. 
6.   Patients who are positive for HIV antibody*11 (Patients who  
have not been tested for HIV antibody may be enrolled.) 
*11 Patients who are positive HIV antibody but negative for  
HIV-RNA may be enrolled. 
7.   Patients with poorly controlled infections or diabetes 
8.   Patients with a past history of interstitial lung diseases (such  
as interstitial pneumonia and pulmonary fibrosis) requiring 
treatment or extensive findings of these diseases on CT 
9.   Patients with a serious complication*10 
*10 Gastrointestinal hemorrhage, heart disease, glaucoma, etc. 
10.  Patients who have been receiving continuous systemic  
administration (oral or intravenous) of steroids (for 2 weeks or 
more at a dose of the equivalent of ≥ 10 mg/day of prednisolone) 
11.  Patients for whom enrollment in the trial is difficult because of  
clinically problematic psychiatric disorders 
12.  Pregnant or lactating women 
13.  Patients with reproductive potential who do not wish to use  
adequate contraceptive measures during the period of  
participation in the trial and during the contraception period 
(see “4.3 Pregnancy and Contraception”) 
14.  Patients who are judged by the attending physician to be 
ineligible for enrollment in the trial for other reasons 
Target number 
of 
subjects, 
statistical 
analyses 
Assuming that the median disease-free survival in the placebo 
group is 8 months, the hazard ratio in the study treatment group 
is 0.667, α = 0.05 (one-sided 0.025), 1 - β = 0.80, the enrollment 
period is 2 years, and the follow-up period is 1 year, the number of 
subjects required (number of events required) is calculated to be 
approximately 240 subjects (190 events). Depending on the subject 
accumulation status, increasing the target number of subjects will 
be considered to increase the power. 
Administration 
method 
One course consists of 28 days, and FTD/TPI or placebo will be 
orally administered twice daily on Days 1 to 5 and Days 8 to 12. The 

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administration will be repeated until completion of 6 courses or 
until any discontinuation criterion is met. 
Safety 
evaluation 
CTCAE v5.0 will be used for the evaluation. 
Efficacy 
evaluation 
Efficacy will be evaluated 2, 4, 6, 8, 10, 12, 15, 18, 24, 30, and 36 
months after the enrollment in this trial. 
In principle, the presence or absence of relapse will be assessed by 
chest, abdominal, and pelvic CT (for the definition of a relapse, see 
“8.3 Imaging Tests”). After the completion of the follow-up period, 
the investigation will be continued in a separate observational 
study. 
QOL 
QOL assessments using EORTC QLQ C-30 and EQ-5D-5L 
Screening 
and 
follow-up study 
The identification of ctDNA-positive patients prior to the 
enrollment in the trial and the observation after the completion of 
the follow-up period in the trial will be performed in separate 
“Genetic alteration and clinical record in radically resected 
colorectal cancer revealed by liquid biopsy and whole exome 
analysis (Abbreviated as GALAXY study)” (see Section 2.10.1.2). 
Planned study 
period 
Japan, planned enrollment period: From June 2020 to Jun 2023  
(3 years) 
(Taiwan, enrollment period: until March 2022) 
Planned observation period: A total of 1 year from the date of 
enrollment of the last subject 
Planned total study period: A total of 1.5 years from the date of 
enrollment of the last subject 
Representative 
of the 
coordinating 
investigators 
Takayuki Yoshino 
Department of Gastroenterology and Gastrointestinal Oncology,  
National Cancer Center Hospital East 
 
Planned study 
sites 
See Appendix 
 
 

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Table of Contents 
Synopsis ........................................................................................................ 5 
1 
Objectives ............................................................................................. 13 
2 
Background and Rationales for the Protocol ...................................... 14 
2.1 
Epidemiology of Colorectal Cancer ......................................................... 14 
2.2 
Standard of Care by Stage ...................................................................... 14 
2.3 
Postoperative Adjuvant Chemotherapy for Colorectal Cancer ................ 14 
2.4 
Follow-up After Colorectal Cancer Surgery ............................................ 16 
2.5 
SignateraTM, a Minimal Residual Disease Detection System .................. 16 
2.6 
Significance of ctDNA Testing for MRD Detection .................................. 17 
2.7 
FTD/TPI in Colorectal Cancer ................................................................ 17 
2.8 
Preemptive Treatment of ctDNA-positive Colorectal Cancer .................. 19 
2.9 
Rationale for Setting Treatment Plan ..................................................... 20 
2.10 
Study Design .......................................................................................... 21 
2.11 
Summary of Expected Benefits and Disadvantages Associated with Study 
Participation ...................................................................................................... 24 
3 
Criteria and Definitions Used in This Trial ........................................... 25 
3.1 
Stage Classification ................................................................................ 25 
3.2 
Classification Criteria for Histological Findings ..................................... 28 
3.3 
Performance status(ECOG Classification) .............................................. 29 
3.4 
Criteria for the Assessment of Adverse Events ....................................... 29 
3.5 
Criteria for Positive ctDNA..................................................................... 29 
4 
Eligibility Criteria .................................................................................. 30 
4.1 
Inclusion Criteria ................................................................................... 30 
4.2 
Exclusion Criteria ................................................................................... 31 
4.3 
Pregnancy and Contraception ................................................................. 32 
5 
Enrollment and Allocation .................................................................... 34 
5.1 
Enrollment Procedures ........................................................................... 34 
5.2 
Reminders for Enrollment ...................................................................... 34 
5.3 
Allocation Method ................................................................................... 35 
5.4 
Control of Allocation Information ........................................................... 36 
6 
Treatment Plan and Treatment Modification Criteria ........................... 37 

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6.1 
Study Treatment ..................................................................................... 37 
6.2 
Discontinuation of Study Treatment ....................................................... 39 
6.3 
Criteria for the Modification of Study Treatment ................................... 40 
6.4 
Specific Instructions for Subjects ............................................................ 43 
6.5 
Permitted Concomitant Therapy/Prohibited Concomitant Therapy ........ 44 
6.6 
Post-treatment ........................................................................................ 45 
7 
Information on Investigational Drug .................................................... 46 
7.1 
Drug Information .................................................................................... 46 
7.2 
Investigational Drug Accountability ....................................................... 48 
7.3 
Disclosure of Allocation Results .............................................................. 48 
7.4 
Expected Adverse Events ........................................................................ 48 
8 
Endpoints, Laboratory Tests and Assessment Schedule ................... 49 
8.1 
Observations and Tests ........................................................................... 49 
8.2 
Study Calendar ....................................................................................... 50 
8.3 
Imaging Tests ......................................................................................... 56 
8.4 
QOL Survey ............................................................................................ 56 
8.5 
Outcome Survey ..................................................................................... 60 
9 
Data Collection ..................................................................................... 61 
9.1 
Handling and Storage of CRF Data ........................................................ 61 
9.2 
Identification of Source Documents ........................................................ 61 
10 Reporting of Adverse Events ............................................................... 62 
10.1 
Assessment of Adverse Events ................................................................ 62 
10.2 
Reporting of Serious Adverse Events ...................................................... 64 
10.3 
Collection of Safety Information ............................................................. 66 
10.4 
Overdose ................................................................................................. 67 
10.5 
Medication Errors ................................................................................... 67 
10.6 
Information on Pregnancy and Lactation ............................................... 67 
11 Definition of Endpoints ........................................................................ 69 
11.1 
Definition of Primary Endpoint .............................................................. 69 
11.2 
Definition of Secondary Endpoints ......................................................... 70 
12 Statistical Matters ................................................................................. 72 
12.1 
Subject Handling .................................................................................... 72 
12.2 
Definition of Analysis Populations .......................................................... 72 
12.3 
Efficacy Analysis ..................................................................................... 72 

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12.4 
Data Handling ........................................................................................ 74 
12.5 
Target Number of Subjects ..................................................................... 74 
12.6 
Interim Analyses .................................................................................... 74 
13 Ethical Matters ...................................................................................... 75 
13.1 
Policies, Laws and Regulations, and Norms to Be Complied With in the 
Trial 75 
13.2 
Informed Consent ................................................................................... 75 
13.3 
Protection of Personal Information and Subject Identification ............... 77 
13.4 
Approval of the Institutional Review Board (IRB) .................................. 78 
13.5 
Management of Conflicts of Interest (COI) ............................................. 79 
13.6 
Compensation ......................................................................................... 79 
14 Monitoring and Auditing ...................................................................... 81 
14.1 
Monitoring .............................................................................................. 81 
14.2 
Protocol Deviations/Violations ................................................................ 81 
14.3 
Auditing .................................................................................................. 81 
14.4 
Direct Access ........................................................................................... 82 
15 Special Notes ........................................................................................ 83 
15.1 
Central Review of Images ....................................................................... 83 
15.2 
Record Retention .................................................................................... 83 
15.3 
Completion of Trial ................................................................................. 83 
15.4 
Termination at Medical Institutions ....................................................... 83 
15.5 
Suspension of the Trial and Premature Termination of the Entire Trial . 84 
16 Study Organization ............................................................................... 85 
16.1 
Organization for Conducting the Trial .................................................... 85 
16.2 
Source of Funds for the Clinical Trial ..................................................... 85 
17 Ownership of Study Results and Publication of Study Results ......... 86 
18 References ............................................................................................ 87 
 
Appendix 1: EORTC QLQ-C30 
Appendix 2: EQ-5D-5L 

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1 
Objectives 
This trial will be conducted in patients who underwent curative resection of colorectal 
cancer and then tested positive in monitoring using SignateraTM, a system by Natera, 
Inc. for detecting blood circulating tumor DNA (ctDNA) for the detection of residual 
tumor, with no apparent relapse on imaging. The objective of the trial is to verify the 
efficacy and safety of preemptive treatment with trifluridine/tipiracil hydrochloride 
(FTD/TPI) compared with follow-up, which is the standard of care. 

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2 
Background and Rationales for the Protocol 
2.1 Epidemiology of Colorectal Cancer 
Currently, colorectal cancer remains a life-threatening serious disease. The 
GLOBOCAN data show that every year in the whole world, 1.36 million people are newly 
diagnosed with colorectal cancer (746,000 men and 614,000 women; prevalence, 17.2 
per 100,000 people), and 693,000 people die of the disease (373,000 men and 320,000 
women), resulting in an annual mortality of 8.4 per 100,000 people.1) The American 
Cancer Society estimates that in the U.S., the number of new cases of colorectal cancer 
in 2017 was 95,520.2) In the World Health Organization (WHO) European Region, 
colorectal cancer is a tumor that ranks first in prevalence, with 471,000 new diagnosis 
each year and a mean mortality of 28.2 per 100,000 people.1) The American Cancer 
Society has reported that the 5-year survival rate for colon cancer by stage is 90% for the 
localized type (Stage I, IIA, and IIB), 71% for the regional type (Stage IIC and III), 
and 14% for the distant type (Stage IV), and that for rectal cancer by stage is 89% for the 
localized type (Stage I, IIA, and IIB), 70% for the regional type (Stage IIC and III), 
and 15% for the distant type (Stage IV).2) 
2.2 Standard of Care by Stage 
Radical surgical resection is performed for Stage I to III colorectal cancer. In general, 
the postoperative standard of care is observation for a progress for Stage I/II without 
pathological metastases to lymph nodes, and postoperative adjuvant chemotherapy is 
recommended for Stage III with pathological metastases to lymph nodes. However, 
postoperative adjuvant chemotherapy is considered in some Stage II patients with high 
risk factors for relapse. In Stage IV and relapsed cases with distant metastasis, surgical 
resection of metastatic lesions is considered if radical surgical treatment is possible, and 
perioperative chemotherapy is used in combination with the surgical resection according 
to the risk. If radical surgical treatment is difficult, systemic chemotherapy will be 
performed. 
2.3 Postoperative Adjuvant Chemotherapy for Colorectal Cancer 
As postoperative adjuvant chemotherapy for colorectal cancer, fluoropyrimidine 
monotherapy (capecitabine, 5-fluorouracil [5-FU]/leucovorin [LV], UFT+LV, S-1) or 
oxaliplatin combination therapy (CAPOX, FOLFOX) is performed for 6 months. As a 
postoperative adjuvant chemotherapy option for Stage III colon cancer, oxaliplatin 
combination therapy has reproducibly been shown to reduce the relative risk of 
relapse/death by approximately 20% compared to 5-FU/LV in multiple randomized 
studies,3-5) and is recommended as the most effective treatment option in both Japan and 

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Western countries. In addition, an integrated analysis of the optimal duration of 
treatment with oxaliplatin combination therapy for Stage III colon cancer (IDEA 
collaboration) has shown that the 3-month regimen was not non-inferior to the 6-month 
regimen in all subjects but was as effective as the 6-month regimen in inhibiting relapses 
in patients treated with CAPOX, especially in patients at low risk of relapse.6) For this 
reason, 3-month CAPOX therapy can be an option, especially for Stage III colon cancer 
with a low risk of relapse. In Stage IV colorectal cancer and recurrent colorectal cancer 
with distant metastases that can be curatively resected, chemotherapy such as 
oxaliplatin combination therapy is performed in the perioperative period in the same 
manner as in Stage III colorectal cancer. Postoperative adjuvant chemotherapy has not 
shown clear efficacy for inhibiting relapses of Stage II colon cancer, and performing 
postoperative adjuvant chemotherapy indiscriminately for Stage II colon cancer is not 
recommended. On the other hand, Western guidelines specify a group of patients at high 
risk of relapse within patients with Stage II colon cancer and recommend postoperative 
adjuvant chemotherapy for this group. The same treatment regimen as used for Stage 
III colon cancer has been recommended for this group. With respect to treatment period, 
an integrated analysis of the optimal duration of treatment with oxaliplatin combination 
therapy for patients with Stage II colon cancer with high-risk factors for relapse (IDEA 
collaboration) was conducted and showed that the 3-month regimen was not non-inferior 
to the 6-month regimen in all subjects.7) There is less evidence for postoperative adjuvant 
chemotherapy for rectal cancer than for the same therapy for colon cancer, and the 
former is performed in the same manner as the latter. In patients with curative resection 
of rectal cancer after preoperative chemoradiotherapy, postoperative adjuvant 
combination chemotherapy with oxaliplatin has been reported to be significantly 
superior to 5-FU/LV in inhibiting relapses,8) and oxaliplatin combination therapy is 
expected to be effective. With respect to adjuvant chemotherapy after resection of distant 
metastases, postoperative adjuvant chemotherapy after hepatectomy has been shown to 
be effective for inhibiting relapses;9-11) however, no randomized study that investigated 
the usefulness of postoperative adjuvant chemotherapy after resection of metastases of 
colorectal cancer other than liver metastases has been reported . Although the optimal 
treatment regimen for adjuvant chemotherapy after resection of distant metastases has 
not yet been established, it has been accepted in clinical practice to use oxaliplatin 
combination therapy, which is a recommended regimen of postoperative adjuvant 
chemotherapy for Stage III patients, for patients with resection of distant metastases 
who are clearly at a higher risk of relapse than Stage III patients. In addition, multiple 
studies have been conducted to verify whether regimens that have been shown to be 

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effective for unresectable large intestine carcinoma are effective as postoperative 
adjuvant chemotherapy, and Phase III studies have shown that none of irinotecan,12-14) 
bevacizumab (BV),15-17) or cetuximab18,19) provides additional benefit on the standard of 
care. 
2.4 Follow-up After Colorectal Cancer Surgery 
As the standard follow-up for colorectal cancer after curative resection, regular 
performance of history taking and medical examination, chest to pelvic computed 
tomography (CT) scan, tumor markers testing, and colonoscopy has been recommended 
by the guidelines. Although tumor markers have been reported to show abnormal values 
several months in advance of diagnostic imaging, the clinical benefits thereof for 
predicting relapses after radical surgical treatment of colorectal cancer have not been 
established. 
2.5 SignateraTM, a Minimal Residual Disease Detection System 
ctDNA (mutant allele) is known to has an extremely short plasma half-life (shorter 
than 2 hours) compared with tumor markers (such as CEA and CA19-9).20) After curative 
resection, therefore, ctDNA rapidly disappears from the blood if no residual cancer exists. 
Utilizing these characteristics of ctDNA, a diagnostic system for detecting minimal 
residual disease (MRD) using a next generation sequencing technology is being 
developed.21-24) SignateraTM is a novel ctDNA detection system for MRD detection 
developed by Natera Inc., U.S.A. First, whole exon analysis of tumor tissue samples is 
performed, followed by extraction of 16 somatic mutations from the detected tumor-
specific single nucleotide variants using an original program, and the primer set that 
detects these variants is established for each patient and tumor. SignateraTM is a test 
system that extracts ctDNA from the blood obtained postoperatively, using this primer 
set, and detects the presence or absence of somatic mutations derived from tumors using 
a next generation sequencer. In SignateraTM, the sensitivity limit for ctDNA allele 
frequency is 0.005%, the 90% sensitivity limit is 0.010%, and the specificity is at 
least 99.5%.25) In a multicenter prospective cohort study in patients with Stage I-III large 
intestine carcinoma, 130 patients with Stage I-III large intestine carcinoma were 
enrolled. The ctDNA positive rate at 30 days after the curative resection was 10.6%, and 
the relapse rate was 7 times or more higher in the ctDNA positive group than in the 
ctDNA negative group (hazard ratio [HR] = 7.2; 95% CI, 2.7-19.0). In addition, of the 58 
patients who were evaluable for ctDNA after completing postoperative adjuvant 
chemotherapy, 7 patients (12.0%) were positive for ctDNA, and 51 patients (88.0%) were 
negative for ctDNA, with relapse observed in all ctDNA-positive patients, which was 

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significantly higher than the relapse rate in ctDNA-negative patients (7/51 
patients, 13.7%) (HR = 17.5; 95% CI, 5.4-56.5). Moreover, of the 75 patients who were 
tested for ctDNA chronologically, 14 out of 15 ctDNA-positive patients (93.3%) had a 
relapse, and of the 60 patients who were negative for ctDNA, only 2 patients had a 
relapse. With respect to time to relapse, the median time to confirmation of a relapse by 
ordinary CT scan was 14.2 months, while the median time to detection of positive ctDNA 
was 5.5 months.22) 
2.6 Significance of ctDNA Testing for MRD Detection 
The ctDNA gene panel system for detecting MRD in colorectal cancer with curative 
resection is considered to be useful for identifying patients at an extremely high risk of 
relapse. The JSCCR Guidelines 2019 for the Treatment of Colorectal Cancer 
recommends selecting treatment regimens for postoperative adjuvant therapy according 
to the risk of relapse. If patients at high risk of relapse can be excluded, a population 
with good prognosis can be extracted and, by considering other clinical prognostic factors, 
postoperative adjuvant chemotherapy may be omitted in ctDNA-negative patients who 
have not undergone postoperative adjuvant chemotherapy. On the other hand, the 
clinical significance of ctDNA-positive patients is not only identification of patients at 
high risk of relapse or the surveillance of postoperative relapse through monitoring but 
also early detection of relapse and the improvement of treatment outcomes through 
intervention with systemic chemotherapy at the time when the relapse is still a minimal 
residual tumor. The Clinical Guidance for Genetic Testing in Colorectal Cancer 
Treatment Edition 4 in Japan recommends ctDNA gene panel testing for the detection 
of MRD in patients with advanced and recurrent resectable large intestine carcinoma as 
a repeatable test to identify groups at high risk of relapse. In the US, the Centers for 
Medicare & Medicaid Services (hereinafter referred to as “CMS”) decided to pay for 
SignateraTM as an MRD monitoring test after surgery of large intestine carcinoma (high 
risk Stage II colon cancer, Stage II rectal cancer, and Stage III colorectal cancer). 
2.7 FTD/TPI in Colorectal Cancer 
FTD/TPI (TAS-102) is a novel oral nucleoside antineoplastic agent containing, in 
a 1:0.5 ratio, trifluorothymidine (FTD) and a thymidine phosphorylase (TP) inhibitor 
that inhibits the degradation of FTD.26) FTD/TPI exhibits an antitumor effect by 
mechanisms that are different from thymidylate synthetase (TS) inhibition by 5-FU, i.e., 
not only by inhibiting TS but also by being incorporated into DNA through 
phosphorylation by thymidine kinase (TK) 1. In a nonclinical study, the antitumor effect 
of FTD/TPI on strains with a low sensitivity to 5-FU anticancer agents was tested using 

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nude mice with implanted human colon adenocarcinoma cells (DLD-1). In the study, 
FTD/TPI was shown to have a significant tumor suppression effect compared to 5-FU in 
a 5-FU resistant DLD-1 implanted mouse model.27) As a clinical study, a multicenter, 
multinational, double-blind, randomized, controlled Phase III study for the purpose of 
verifying the superiority of FTD/TPI to placebo administration (RECOURSE study) was 
conducted in patients with advanced/recurrent colorectal cancer who were refractory or 
intolerant after receiving at least 2 regimens of prior treatment, including a 
fluoropyrimidine antineoplastic agent, irinotecan, oxaliplatin, and an anti-VEGF 
monoclonal antibody and at least 1 type of anti-EGFR monoclonal antibody in cases 
where the KRAS gene was a wild type. Comparison with the placebo group in this study 
showed that the median overall survival (OS), which was the primary endpoint, was 
significantly longer in the FTD/TPI group (7.1 months) than in the placebo group (5.3 
months) (HR = 0.68; 95% CI, 0.58-0.81; p < 0.0001). The median progression-free survival 
(PFS) was also significantly longer in the FTD/TPI group (2.0 months) than in the 
placebo group (1.7 months) (HR = 0.48; 95% CI, 0.41-0.57; p < 0.0001). The response rate 
was 1.6% in the FTD/TPI group and 0.4% in the placebo group (p = 0.29), and the disease 
control rate was 44% in the FTD/TPI group and 16% in the placebo group (p < 0.001).28) 
On the basis of these results, FTD/TPI has been established as a standard late-line 
treatment and is listed in the guidelines in Japan and overseas. In this trial, the 
relatively frequent adverse events of FTD/TPI were gastrointestinal toxicity (such as 
nausea, anorexia, diarrhea, and vomiting) and hematotoxicity, and febrile neutropenia 
accounted for 3.8%. In addition, a multicenter, multinational, double-blind, randomized, 
Phase III comparative study for the purpose of verifying the superiority of FTD/TPI to 
placebo administration (TERRA study) was conducted in Asia (China, South Korea, 
Thailand) in patients with advanced/recurrent colorectal cancer who were refractory or 
intolerant after receiving at least 2 regimens of prior treatment. This study similarly 
showed that the median OS, which was the primary endpoint, was significantly longer 
in the FTD/TPI group (7.8 months) than in the placebo group (7.1 months) (HR 
= 0.79; 95% CI, 0.62-0.99; p = 0.035), and the median PFS was also significantly longer 
in the FTD/TPI group (2.0 months) than in the placebo group (1.8 months) (HR 
= 0.43, 95% CI, 0.34-0.54; p < 0.0001). The response rate was 1.1% in the FTD/TPI group 
and 0% in the placebo group (p = 0.554), and the disease control rate was 44.1% in the 
FTD/TPI group and 14.6% in the placebo group (p < 0.001).29) 
The efficacy of FTD/TPI as the initial treatment for advanced/recurrent colorectal 
cancer has also been reported. A randomized Phase II comparative study to verify the 
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BV in patients with untreated advanced/recurrent colorectal cancer for which intensive 
chemotherapy is not suited showed that the median PFS, which was the primary 
endpoint, tended to be longer in the FTD/TPI plus BV group (9.23 months in the FTD/TPI 
plus BV group and 7.82 months in the Cape plus BV group) (HR=0.71; 95% CI, 0.48-1.06), 
and the median OS was significantly longer in the FTD/TPI plus BV group (18.0 months) 
than in the Cape plus BV group (16.2 months) (HR=0.56; 95% CI, 0.32-0.98). 30) The 
results of this trial suggest that FTD/TPI also exhibits an antitumor effect in patients 
who have not used any fluoropyrimidine antineoplastic agent. 
On the other hand, no report is available on clinical studies to investigate the efficacy 
of FTD/TPI as postoperative adjuvant chemotherapy; however, the effect of FTD on 
cancer stem cells has been reported as the result of a preclinical study suggesting that 
FTD may inhibit relapses. Cancer stem cells are cells with replication competence and 
multipotency and are considered to be involved in cancer cells’ proliferation and 
differentiation, distant metastasis, and chemoresistance.31) Using a method called 
sphere-forming assay to quantify the number of cancer stem cells, 5FU and FTD were 
evaluated for their inhibitory effect on cancer stem cells. FTD showed a significant 
inhibition, suggesting that FTD may inhibit tumor relapse.32) 
2.8 Preemptive Treatment of ctDNA-positive Colorectal Cancer 
A meta-analysis that investigated the significance of multidisciplinary follow-up for 
colorectal cancer with curative resection using imaging tests such as CT, colonoscopy, 
and biomarkers such as tumor markers has been reported. In this investigation, 
multidisciplinary follow-up has been reported to have led to a significant extension of 
OS, an increase in the rate of identification of asymptomatic relapses, and an increase 
in the rate of curative resection upon confirmation of relapse.33) The incorporation of 
ctDNA testing for the purpose of detecting MRD in such multidisciplinary follow-up is 
expected to provide further extension of survival. ctDNA-positive patients are a group at 
an extremely high risk of relapse, and early treatment interventions in this group can 
be expected to lead to extended survival. FTD/TPI has been shown to extend prognosis 
in patients with unresectable large intestine carcinoma who are refractory or intolerant 
to treatment including fluoropyrimidine and oxaliplatin. Although the efficacy of this 
drug as a postoperative adjuvant chemotherapy has not been established, we thought 
that preemptive treatment with FTD/TPI in ctDNA-positive patients in whom the 
presence of minimal residual disease is strongly suspected is expected to inhibit relapses 
and extend survival. We planned this trial for this reason. 

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2.9 
Rationale for Setting Treatment Plan 
2.9.1 
Treatment Regimen for This Trial 
FTD/TPI or placebo: In 1 course consisting of 28 days, FTD/TPI 35 mg/m2/dose or 
placebo will be orally administered twice daily (after breakfast and dinner) for 5 
consecutive days, followed by withdrawal for 2 days. After repeating this cycle twice, the 
subject is withdrawn from study treatment for 14 days. This treatment will be continued 
until completion of 6 courses or until the subject meets any discontinuation criterion. 
Study treatment will be given to the subject either as an inpatient or an outpatient. 
2.9.2 
Rationale for Setting the Administration and Dosage of FTF/TPI★ 
In the study treatment used in this trial, we decided to use the administration and 
dosage that have been shown to be safe and effective in a multicenter, multinational, 
double-blind, randomized, controlled Phase III study for the purpose of verifying the 
superiority of FTD/TPI to placebo administration (RECOURSE study). 
2.9.3 
Efficacy of FTD/TPI 
See “2.7 FTD/TPI in Colorectal Cancer.” 
2.9.4 
Safety of FTD/TPI 
The representative adverse events observed in patients treated with FTD/TPI in the 
RECOURSE study and the TERRA study are shown in Table 2-1 below. 
Table 2-1 Adverse Events in the FTD/TPI Group 
 
Phase III Study 
(RECOURSE Study28) 
N=533 n (%) 
Phase III Study 
(TERRA Study29) 
N=271 n (%) 
 
All Grades 
Grade3/4 
All Grades 
Grade3/4 
Non-hematologic toxicity 
 
 
 
 
Nausea 
258 (48) 
10 (2) 
98 (36.2) 
2 (0.7) 
Vomiting 
148 (28) 
11 (2) 
50 (18.5) 
2 (0.7) 
Anorexia 
208 (39) 
19 (4) 
67 (24.7) 
2 (0.7) 
Fatigue 
188 (35) 
21 (4) 
55 (20.3) 
4 (1.5) 
Diarrhea 
170 (32) 
16 (3) 
40 (14.8) 
2 (0.7) 
Febrile neutropenia 
20 (4) 
20 (4) 
0 (0) 
0 (0) 
Hematotoxicity 
 
 
 
 
Neutropenia 
353 (67) 
200 (38) 
182 (67.2) 
90 (33.2) 
White blood cell decreased 
407 (77) 
113 (21) 
190 (70.1) 
56 (20.7) 
Anemia 
404 (77) 
96 (18) 
209 (77.1) 
48 (17.7) 

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Platelets decreased 
223 (42) 
27 (5) 
96 (35.4) 
8 (3.0) 
ALT increased 
126 (24) 
10 (2) 
48 (17.7) 
3 (1.1) 
AST increased 
155 (30) 
23 (4) 
63 (23.2) 
10 (3.7) 
Total bilirubin increased 
189 (36) 
45 (9) 
99 (36.5) 
19 (7.0) 
Creatinine increased 
71 (13) 
5 (<1) 
13 (4.8) 
3 (1.1) 
 
With respect to the long-term safety of FTD/TPI, adverse events have been 
investigated in patients who received study treatment for a long term (at least 180 days 
after the first dose) in the above-described RECOURSE study. Long-term administration 
in these patients was not reported to have caused new adverse events, an increase in the 
frequency of adverse events, or secondary cancers. 
2.10 
Study Design 
This trial is a randomized, double-blind, multinational Phase III study to evaluate the 
efficacy and safety of preemptive treatment with FTD/TPI compared with follow-up, 
which is the standard of care, in patients who underwent curative resection of colorectal 
cancer and then tested positive for ctDNA. If the results of this trial are promising, we 
intend to consult with the provider of the investigational drug about the application for 
approval of FTD/TPI for the indications of colorectal cancer that tested positive for 
ctDNA after curative resection. 
2.10.1 Patients 
2.10.1.1 Lines of Treatment 
This trial will be conducted in patients with resectable colorectal cancer who 
underwent curative resection and then tested positive in monitoring using SignateraTM, 
a system by Natera, Inc. for detecting blood circulating tumor DNA (ctDNA) for the 
detection of residual tumor. 
2.10.1.2 Patients Who Become Positive for ctDNA After Curative Resection 
The identification of ctDNA-positive patients for this trial will be performed in 
separate “Genetic alteration and clinical record in radically resected colorectal cancer 
revealed by liquid biopsy and whole exome analysis (Abbreviated as GALAXY study*).” 
This study will be conducted in patients who tested positive for ctDNA in the GALAXY 
study after undergoing curative resection. 
* GALAXY study: A study to perform SignateraTM in patients with colorectal cancer who are 
scheduled for radical surgery and construct a registry about the relationship between genetic 
alterations detected in tumor tissues and blood samples and clinical course. The timing of 

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SignateraTM testing is before surgery, 4 weeks after surgery, every 12 weeks after surgery until 48 
weeks after surgery, and then 72 weeks after surgery and 96 weeks after surgery. 
2.10.2 Endpoints 
The endpoints in this trial are as follows: 
Primary endpoint: 
 
Disease-free survival 1*1*3 (DFS1) 
*1 In this trial, a DFS1 event is defined as a relapse, development of a secondary colorectal cancer 
lesion other than a relapse (an intramucosal cancer lesion will not be treated as an event), and 
death. 
 
Secondary endpoints: 
 
Rate of conversion to negative ctDNA 
 
Disease-free survival 2*2*3 (DFS2) 
 
Overall survival*3 (OS) 
 
Incidence of adverse events 
 
Treatment completion rate 
 
QOL 
*2 In this trial, a DFS2 event is defined as a relapse, development of a cancer lesion other than a 
relapse (secondary cancer), and death. 
*3 After the end of the trial period, subjects will be followed up for 5 years in a separate observational 
study. 
2.10.3 Multinational Study 
This trial will be conducted as a multinational study enrolling subjects in Japan and 
Taiwan. The treatments for colorectal cancer such as surgery and chemotherapy in 
Japan and Taiwan are extremely similar, and this fact is considered to provide good 
background for a multinational study. This trial is regarded as one prospective 
multinational study in which the analysis will be performed jointly and will be conducted 
using a common protocol in Japan and Taiwan. 
2.10.4 Clinical Hypothesis and Rationale for Setting the Number of Subjects 
2.10.4.1 Clinical Hypothesis 
The clinical hypothesis is as follows: “In patients with colorectal cancer who tested 
positive for ctDNA after undergoing curative resection, administration of FTD/TPI is 
superior to follow-up , which is the standard of care, in DFS.” Clinical studies of adjuvant 

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chemotherapy after curative resection of colon cancer have shown a correlation between 
OS and DFS, and DFS is used as a surrogate endpoint for OS. Thus, reduction in the 
risk of relapse leads to a cure and, therefore, to an extended OS. On the other hand, 
clinical studies of drug therapies for unresectable large intestine carcinoma have shown 
that the correlation between PFS and OS has been becoming weak because of the 
emergence of new therapeutic drugs. On the other hand, several studies on initial 
treatment, including a Phase III study comparing FOLFOXIRI plus bevacizumab 
therapy versus FOLFIRI plus bevacizumab therapy (TRIBE study) and a Phase III study 
comparing FOLFIRI plus bevacizumab therapy versus FOLFIRI plus cetuximab therapy 
(FIRE-3 study), have shown an extension of OS.34,35) Thus, preemptive treatment 
performed when the tumor volume is low may extend not only DFS but also OS even in 
a ctDNA-positive population in which relapses may subsequently occur. 
2.10.4.2 Rationale for Setting the Target Number of Subjects 
The above-described RECOURSE study has shown that FTD/TPI is significantly 
superior to placebo in overall survival (5.3 months vs 7.1 months; HR = 0.68) and 
progression-free survival (2.0 months vs 1.7 months; HR = 0.48). It is assumed that 
similar efficacy is expected in ctDNA-positive patients. In addition, the median time from 
the date of the ctDNA-positive blood test to the CT diagnosis of a relapse in the ctDNA-
positive group is reported to be 8.7 months. Assuming that the median disease-free 
survival in the placebo group is 8 months, the hazard ratio in the study treatment group 
is 0.667, α = 0.05 (one-sided 0.025), 1 - β = 0.80, the enrollment period is 2 years, and the 
follow-up period is 1 year, after consideration of the period from the date of the ctDNA-
positive test to the date of enrollment in the study, the number of subjects required 
(number of events required) is calculated to be approximately 240 subjects (190 events). 
Depending on the subject accumulation status, increasing the target number of subjects 
will be considered to increase the power. 
2.10.4.3 Expected 
Subject 
Accumulation, 
Enrollment 
Period, 
and 
Planned 
Observation Period 
A total of 240 subjects will be enrolled in this trial during the enrollment period of 3 
years from June 2020. Depending on the subject accumulation status, increasing the 
number of subjects to the maximum 300 will be considered. 
The planned observation period will be 1 year from the date of enrollment of the last 
subject. Furthermore, after the end of the trial period, subjects will be followed up for 
approximately 5 years in a separate observational study. 

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2.11 
Summary of Expected Benefits and Disadvantages Associated with 
Study Participation 
2.11.1 Expected Benefits 
Patients with colorectal cancer who tested positive for ctDNA after undergoing 
curative resection is a population at an extremely high risk of relapse, and interventions 
with systemic chemotherapy in these patients as an MRD-positive population are 
expected to improve treatment outcomes. FTD/TPI is expected to extend survival and 
inhibit relapses in the above patients. Establishment of the efficacy and safety of 
FTD/TPI in the above-described patients is expected not only to extend the indications 
of FTD/TPI but also to establish a new disease classification (ctDNA-positive population) 
and provide new evidence. In addition, even patients who are assigned to the placebo 
group in this trial are expected to be followed up more closely than in normal follow-up, 
and this will contribute to early detection. 
2.11.2 Expected Risks and Disadvantages 
Various adverse events, such as hematotoxicity including neutropenia, which is the 
main adverse event caused by FTD/TPI, and gastrointestinal toxicity, may possibly occur. 
In order to minimize the risks and disadvantages of these adverse events, the 
coordinating investigator will determine whether the actual adverse event is an expected 
event. In addition, a system will be established in which necessary measures such as 
reporting to the Data and Safety Monitoring Committee and notification to medical 
institutions will be taken in cases where a serious adverse event or unexpected adverse 
event occurs. 

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3 
Criteria and Definitions Used in This Trial 
3.1 
Stage Classification 
In this trial, the “Japanese Classification of Colorectal, Appendiceal, and Anal 
Carcinoma, Ninth Edition” and “UICC TNM Classification, 8th Edition” will be followed. 
3.1.1 
Primary Tumor 
The location of large intestine carcinoma will be in accordance with the large intestine 
segmentation in the Japanese Classification of Colorectal, Appendiceal, and Anal 
Carcinoma, Ninth Edition.  
1) Colon 
a) Cecum (C) 
b) Ascending colon (A) 
c) Transverse colon (T) 
d) Descending colon (D)  
e) Sigmoid colon (S)  
2) Rectum  
a) Rectosigmoid (RS) 
b) Upper rectum (Ra) 
c) Lower rectum (Rb) 
3) Other 
a) Vermiform appendix (V)  
b) Anal canal (P) 
c) Perianal skin (E) 
3.1.2 
Macroscopic 
Classification 
(Japanese 
Classification 
of 
Colorectal, 
Appendiceal, and Anal Carcinoma, Ninth Edition) 
1) Basic classification 
Type 0: Superficial type  
Type 1: Polypoid type  
Type 2: Ulcerated type with clear margin 
Type 3: Ulcerated type with infiltration 
Type 4: Diffusely infiltrating type 
Type 5: Unclassified type 
2) Type 0: Subtypes of macroscopic type 0  
0-I: Protruded type 
0-Ip: Pedunculated type 
0-Isp: Subpedunculated type 

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0-Is: Sessile type 
0-II: Superficial type 
0-IIa: Elevated type 
0-IIb: Flat type 
0-IIc: Depressed type 
3.1.3 
Depth of Invasion [T] (Japanese Classification of Colorectal, Appendiceal, and 
Anal Carcinoma, Ninth Edition) 
TX: Primary tumor cannot be assessed 
T0: No evidence of primary tumor 
Tis: Tumor is confined to the mucosa (M) and does not invade the submucosa (SM) 
T1: Tumor is confined to the SM and does not invade the muscularis propria (MP) 
T1a: Tumor is confined to the SM, and invasion is within 1000 μm 
T1b: Tumor is confined to the SM, and invasion is 1000 μm or more, but it does 
not extend to the MP 
T2: Tumor invasion to, but not beyond, the MP 
T3: Tumor invades beyond the MP. 
In sites with serosa, the tumor grows into the subserosa (SS). 
In sites with no serosa, the tumor grows into the adventitia (A) 
T4: Tumor invades or perforates the serosa (SE) or directly invades other organs or 
structures (SI/AI) 
T4a: Tumor invades the serosa or perforates abdominal cavity via the burst through 
the serosa (SE) 
T4b: Tumor directly invades adjacent organs or structures (SI/AI) 
 
3.1.4 
Lymph Node Metastasis [N] (Japanese Classification of Colorectal, 
Appendiceal, and Anal Carcinoma, Ninth Edition) 
NX: Lymph node metastasis cannot be assessed 
N0: No evidence of lymph node metastasis* 
N1: Metastasis in 1-3 pericolic/perirectal or intermediate lymph nodes 
N1a: Metastasis in 1 lymph node 
N1b: Metastasis in 2-3 lymph nodes 
N2: Metastasis in 4 or more pericolic/perirectal or intermediate lymph nodes 
N2a: Metastasis in 4-6 lymph nodes 
N2b: Metastasis in 7 or more lymph nodes 

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N3: Metastasis in the main lymph node (s). In the lower rectal cancer, metastasis in 
the main and/or lateral lymph node (s) ** 
* N0 in the Japanese Classification of Colorectal, Appendiceal, and Anal Carcinoma, Ninth 
Edition includes N1c in the UICC TNM Classification, 8th Edition (tumor deposits, or satellite 
nodules, are seen in the adjacent soft tissues of the colon or rectum without subserosal layer or 
peritoneal coat, with no regional lymph node metastasis), which is eligible for this trial. 
** N3 in the Japanese Classification of Colorectal, Appendiceal, and Anal Carcinoma, Ninth 
Edition is treated as one of the regional lymph nodes or non-regional lymph nodes (M1) depending 
on the location of the metastasis in the UICC TNM Classification, 8th Edition. 
3.1.5 
Distant Metastasis [M] (Japanese Classification of Colorectal, Appendiceal, 
and Anal Carcinoma, Ninth Edition) 
M0: No distant metastasis 
M1: Distant metastasis 
M1a: Distant metastasis confined to one organ. Peritoneal metastasis not present 
M1b: Distant metastasis in more than one organ. Peritoneal metastasis not present 
M1c: Presence of peritoneal metastasis 
M1c1: Metastasis to the peritoneum only 
M1c2: Metastasis to the peritoneum and other distant metastasis 
 
3.1.6 
Degree of Progression (Stage) 
The degree of progression in the UICC TNM Classification, 8th Edition is shown. 
The T classification, N classification, and M classification in the Japanese 
Classification of Colorectal, Appendiceal, and Anal Carcinoma, Ninth Edition shown 
in Section 3.1.3 to 3.1.5 are converted into T classification, N classification, and M 
classification in the UICC TNM Classification, 8th Edition to determine the stage. 
 
M0 
M1 
M1a 
M1b 
M1c 
N0 
N1 
(N1a/N1b/N1c) 
N2a 
N2b,N3 
Regardless of N 
Tis 
0 
N/A 
T1 
I 
IIIA 
 
 
IVA 
IVB 
IVC 
T2 
 
 

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T3 
IIA 
 
IIIB 
 
T4a 
IIB 
 
IIIC 
T4b 
IIC 
 
3.2 
Classification Criteria for Histological Findings 
Histological findings will be classified according to the WHO Classification of Tumors 
of the Digestive System, 4th Edition.

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3.3 
Performance status (ECOG Classification) 
3.4 
Criteria for the Assessment of Adverse Events 
“Common Terminology Criteria for Adverse Events (CTCAE) v5.0” will be used to 
determine the terms and grades of adverse events. 
3.5 
Criteria for Positive ctDNA 
The liquid biopsy of blood samples required for the assessment of patients according 
to the eligibility criteria for this trial will be performed in the GALAXY study, in which 
SignateraTM will be used (see Section 2.10.1.2). 
 
 
PS 
Description 
0 
Fully active. 
Able to carry on all pre-disease performance without restriction. 
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. 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. 
Up and about more than 50% of waking hours. 
3 
Capable of only limited selfcare. 
Confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled. Cannot carry on any selfcare. 
Totally confined to bed or chair. 

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4 
Eligibility Criteria 
Patients who meet all of the inclusion criteria and do not meet any of the exclusion 
criteria will be enrolled as patients who will receive study treatment. 
4.1 
Inclusion Criteria 
1. 
Patients 
who 
have 
been 
histopathologically 
diagnosed 
with 
colorectal 
adenocarcinoma (Stage II or lower/Stage III/M1) 
2. 
Patients who have undergone radical resection*1 of the primary and metastatic 
tumors 
*1 It is considered to be a radical resection if the tumor is exposed at the edge or on 
the surface of surgical detachment but is encapsulated. 
3.  Patients who are subject to postoperative chemotherapy according to the country  
guideline and/or medical practice, that is Stage III (T any N1*2/2 M0) and Stage  
IV (T any N any M1) (UICC TNM Classification, 8th Edition) for Taiwan must  
have a history*4 of standard postoperative chemotherapy*3. 
*2 N1c (UICC TNM Classification, 8th Edition) is also included in this stage (tumor 
deposits, or satellite nodules, are seen in the adjacent soft tissues of the colon or 
rectum without subserosal layer or peritoneal coat, with no regional lymph node 
metastasis). 
*3 Treatments described in the current Japanese and overseas guidelines or study 
treatments conducted in clinical studies. 
*4   In case of patients who do not have a standard postoperative chemotherapy for 
rational reason, these patients can be enrolled.  
Note that if sites enroll such patients, record the reason for the decision  
to medical chart. 
4. 
Patients who tested positive for ctDNA using SignateraTM by an analysis*5 of the 
latest blood samples collected within 3 months prior to enrollment 
*5 Analyses of blood samples using SignateraTM will be performed in a separate 
clinical study (see Section 2.10.1.2.). 
5. 
Patients with no obvious relapse confirmed by chest, abdominal, and pelvic CT scans, 
etc. 
6. 
Patients who are capable of oral ingestion 
7. 
Patients aged 20 years or older at the time of informed consent 
8. 
Patients with an Eastern Cooperative Oncology Group (ECOG) performance status 
(PS) of 0 or 1 

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9. 
Patients who have no severe disorder in major organs (such as the bone marrow, 
heart, lungs, liver, and kidneys) and meet the following criteria (Data obtained most 
recently and within 14 days of the date of enrollment will be used for enrollment. 
Data obtained 2 weeks before the date of enrollment, on the same day of the week 
as the enrollment date, may be used for enrollment.) 
- 
Neutrophil count ≥ 1,500/mm3 
- 
Platelet count ≥ 100,000/mm3 
- 
Hemoglobin ≥ 8.0 g/dL 
- 
Serum creatinine ≤ 1.5 mg/dL 
- 
Total bilirubin ≤  1.5 mg/dL 
- 
ALT and AST ≤ 100 U/L 
10. Patients with no diarrhea or stomatitis of Grade 2 or severer according to CTCAE 
v5.0 
11. Patients who voluntarily gave written consent to participate in the trial after 
receiving a thorough explanation of the trial before enrolling in the trial 
4.2 
Exclusion Criteria 
1. 
Patients with a history of treatment with FTD/TPI 
2. 
Patients with a history of treatment with 2 or more regimens of postoperative 
adjuvant chemotherapy*6 (Preoperative chemotherapy will not be counted as a 
regimen.) 
*6 The timing of initiation of the postoperative adjuvant chemotherapy will not be 
specified. 
3. 
Patients with a past history of a malignant tumor*7 other than colorectal 
adenocarcinoma. 
*7 Patients with a relapse-free survival period of 5 years or longer, or patients with 
basal cell or squamous cell carcinoma of the skin that is considered cured by local 
treatment, superficial bladder cancer, cervical cancer, carcinoma in situ 
(intraepithelial cancer) or lesions equivalent to intramucosal cancer, or non-
metastatic prostate cancer not requiring systemic treatment may be enrolled. 
4. 
Patients with a local or systemic active infection requiring intervention 
5. 
Patients who are positive for HBs antigen*8 or positive for HCV antibody*9 
*8 HBV-DNA testing is mandatory to be below the limit of detection for patients with a negative 
HBs antigen test, but with a positive test result for either HBs antibody or HBc antibody  
*9 Patients who are positive for HCV antibody but negative for HCV-RNA may be 
enrolled. 

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6. 
Patients who are positive for HIV antibody*11 (Patients who have not been tested for 
HIV antibody may be enrolled.) 
*x11 Patients who are positive HIV antibody but negative for HIV-RNA may be  
enrolled. 
7. 
Patients with poorly controlled infections or diabetes 
8. 
Patients with a past history of interstitial lung diseases (such as interstitial 
pneumonia and pulmonary fibrosis) requiring treatment or extensive findings of 
these diseases on CT 
9. 
Patients with a serious complication*10 
*10 Gastrointestinal hemorrhage, heart disease, glaucoma, etc. 
10. Patients who have been continuously receiving systemic administration (oral or 
intravenous) of steroids (for 2 weeks or more at a dose of the equivalent of 
≥ 10 mg/day of prednisolone) 
11. Patients for whom enrollment in the trial is difficult because of clinically problematic 
psychiatric disorders 
12. Pregnant or lactating women 
13. Patients with reproductive potential who do not wish to use adequate contraceptive 
measures during the period of participation in the trial and during the contraception 
period (see “4.3 Pregnancy and Contraception”) 
14. Patients who are judged by the attending physician to be ineligible for enrollment 
in the trial for other reasons 
4.3 
Pregnancy and Contraception 
Women of childbearing potential (including those without menstruation for medical 
reasons such as chemical menopause) include all women who have experienced 
menarche, have not undergone sterilization (hysterectomy, bilateral tubal ligation, 
bilateral oophorectomy, or the like), and are not postmenopausal. “Postmenopausal” is 
defined as being amenorrheic continuously for 1 year or longer in the absence of a special 
reason. Women using oral contraceptives or mechanical contraceptive measures such as 
intrauterine devices or barrier methods are considered to have childbearing potential. If 
a female subject is judged to have no childbearing potential, the fact will be documented 
in the subject’s source documents. 
For both men and women of childbearing potential, the contraception period will be 
between the time point of informed consent and at least 6 months after the last dose of 
the investigational drug. 
With respect to contraception, subjects will need to agree to use an effective 
contraceptive method, avoid sexual intercourse, or take a reliable contraceptive measure 

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(double-barrier method that includes any 2 measures selected from diaphragm, condom, 
contraceptive sponge, spermicide, bilateral tubal ligation, and vasectomy). Effective 
methods of contraception include: 
• Combination hormonal contraceptives (containing estrogen and progestogen) that 
inhibit ovulation: 
- Oral contraceptive 
- Intravaginal contraceptive 
- Percutaneous contraceptive 
• Hormonal contraceptives containing progestogen only that inhibit ovulation: 
- Oral contraceptive 
- Injectable contraceptive 
- Implantable contraceptive 
•  Intrauterine device (IUD) 
•  Intrauterine hormone-releasing system (IUS) 
•  Bilateral tubal occlusion 
•  Vasectomy or vasectomy of the subject’s partner 
• Complete sexual abstinence (avoiding heterosexual intercourse from the time point 
of informed consent until at least 6 months after the last dose of the investigational 
drug). Periodic abstinence (calendar method, sympto-thermal method, and ovulation 
methods) is not acceptable as a method of contraception. 
 
Men must not perform sperm cryopreservation or donate sperm from the time point of 
informed consent, through the trial period, and until at least 6 months after the last dose 
of the investigational drug. If sperm preservation is needed, performing it before 
enrollment in this trial shall be considered. 
Women must not donate eggs or harvest eggs for their own use from the time point of 
informed consent, through the period of study treatment, and until at least 6 months after the 
last dose of the investigational drug. 

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5 
Enrollment and Allocation 
5.1 
Enrollment Procedures 
After ascertaining that the subject meets all inclusion criteria and none of the 
exclusion criteria and obtaining written informed consent from the subject as an eligible 
patient, the subject will be enrolled through a Web enrollment system. If eligibility is 
confirmed, the enrollment center will notify the medical institution of the registration 
number and the drug number obtained by allocation through the Web enrollment system. 
■ Contact information and hours for subject enrollment 
The URL of the Web enrollment system will be separately notified by “RTMS System 
Operation Manual.” 
(Enrollment is possible 24 hours a day, 365 days a year. However, in cases where the 
system becomes inaccessible due to maintenance, etc., such fact will be notified in 
advance on the information screen of the Web enrollment system.) 
■ Information about enrollment 
The contact information for the help desk, etc. will be separately notified by “RTMS 
System Operation Manual.” 
(Mon-Fri, 9:00 a.m. to 6:00 p.m., excluding Saturdays, Sundays, holidays, and 
December 29 to January 4) 
■ Information about subject inclusion criteria 
Coordinating investigators or the trial coordinating office 
E-mail: prj-altair_core@eps.co.jp 
5.2 
Reminders for Enrollment 
1) 
Enrollment after starting study treatment will not be permitted without an 
exception. 
2) 
Enrollment with incomplete confirmation of eligibility will not be permitted until 
all eligibility criteria have been met. 
3) 
Enrollment numbers will be issued after eligibility has been confirmed. 
Enrollment is completed by issuing an enrollment number. 
4) 
Enrolled subjects will not be withdrawn from enrollment (deleted from the 
database) except in cases of withdrawal of consent, including refusal to use the 
data for the research. In the case of a duplicate enrollment, the initial enrollment 
information (enrollment number) will be adopted under any circumstances. 
5) 
When an error or duplicate in enrollment is found, promptly notify a person in 
charge. 

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6) 
If the subject is seeing another hospital or department at the time of enrollment, 
the attending physician shall be informed of the fact that the subject will 
participate in this trial. 
5.3 
Allocation Method 
In enrollment, subjects will be randomized, in a 1:1 ratio, to the active drug (FTD/TPI) 
group or the placebo group by the Registration Center. In randomization, a minimization 
method using the following 4 factors as the allocation factors will be used in order to 
prevent bias. The detailed procedure of the allocation method will not be disclosed to 
participating investigators. 
 
[Allocation factors] 
(i) 
Age (less than 70 years/70 years or more) 
(ii) 
Site 
(iii) 
Disease stage (Stage II or lower/Stage III/M1) 
(iv) 
Primary location of lesion* (right colon/left colon/rectum) 
(v) 
ctDNA status at 1 month postoperatively  
(positive / negative or unmeasurable/Unmeasured) 
* right colon: cecum to transverse colon, left colon: descending colon to Rs,  
rectum: Ra/Rb 
 
[Rationale for setting allocation factors] 
(i) 
Age (less than 70 years/70 years or more): This factor is used as an allocation 
factor because the prognosis may differ with age. 
(ii) 
Site: This factor is used as an allocation factor because it has been reported that 
there was inter-site gap in the results of colon cancer surgery. 
(iii) 
Disease stage (Stage II or lower/Stage III/M1): This factor is used as an allocation 
factor because this trial includes colon and rectal cancer at different stages with 
different prognosis, and patients with resection of distant metastases (M1) have poor 
prognoses. In addition, it is specified that the proportion of M1 patients should be 
approximately 50% of the total. 

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(iv) 
Primary location of lesion (right colon/left colon/rectum): The survival after 
recurrence is reported to be poorer in patients with lesions in the right colon than 
in patients with lesions in the left colon. In addition, many of the previous reports 
of postoperative adjuvant chemotherapy are about colon cancer. Thus, right colon 
(cecum to transverse colon), left colon (descending colon to Rs), and rectum 
(Ra/Rb) are used as the stratification factors. 
(v) 
ctDNA 
status 
at 
1 
month 
postoperatively 
(positive 
/ 
negative 
or 
unmeasurable/Unmeasured): The prognosis may differ depending on the 
difference in the time tested positive for ctDNA 
5.4 
Control of Allocation Information 
This trial will be conducted in a double-blind manner. As the results of allocation will 
not appear on the enrollment confirmation email or the screens of the Web enrollment 
system, the allocation group data cannot be viewed by medical institutions, coordinating 
investigators, the trial coordinating office, monitors, etc. 
The results of allocation (allocation group data) will be stored electronically within the 
enrollment center, and only the enrollment center of this trial will have access to the 
allocation group table. 

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6 
Treatment Plan and Treatment Modification Criteria 
Treatment and treatment modifications will be made following the descriptions in this 
section, unless subject safety is threatened. In cases where following this protocol is 
considered to be medically hazardous, treatment modifications will be made according 
to the medical judgment of the principal investigator or sub-investigator (hereinafter, 
referred to as “investigator”). 
 
6.1 
Study Treatment 
The study treatment in this trial is treatment with FTD/TPI (TAS-102) or placebo. 
Study treatment will be initiated within 8 days after enrollment (including the date of 
enrollment). If administration of the investigational drug cannot be started within 8 days 
after enrollment, such fact shall be communicated to a coordinating investigator to 
consider the handling of the subject. Study treatment will be given to the subject either 
as an inpatient or an outpatient. 
The following terms will be used in this protocol: 
- 
Discontinuation: Not resuming the administration of the investigational drug 
- 
Delay: Delaying the administration of the investigational drug from the 
scheduled administration date 
- 
Skip: Not taking the investigational drug on the date of administration of the 
investigational drug within a course after the course has started 
- 
Withdrawal period: Period during which the investigational drug is not 
administered 
6.1.1 
Dose 
1) The initial dose of FTD/TPI will be 35 mg/m2/dose BID (70 mg/m2/day). For 
determining the actual dose, body surface area will be calculated for each patient, and 
the dose specified in “Table 6.1 Dose of FTD/TPI” will be administered twice daily after 
breakfast and after dinner. Body surface area will be calculated by the Web enrollment 
system. The medical institution will enter actual dose calculated by the institution into 
the web enrollment system and prescribe the investigational drug corresponding to the 
obtained drug number. 
2) Recalculation of dose due to body weight changes after the start of administration will 
be performed only when the subject lost body weight after the start of administration 
by 10% or more compared to the time of enrollment, by correcting the dose of FTD/TPI 
course by course. The drug number of investigational drugs prescribed in each course 

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will be obtained by entering actual dose calculated in the institution into the web 
enrollment system. 
The following formula will be used to calculate body surface area. If the dose is reduced 
once, the dose will not be increased. 
Dubois formula: Body surface area (m2) = weight (kg)0.425 x height (cm)0.725 x 71.84 
÷ 10000 
3) In the event of an overdose as defined below, the principal investigator will report the 
event to a coordinating investigator within 24 hours of learning of the event, and the 
coordinating investigator will report the event to the provider of the investigational drug 
within 1 business day. 
[Definition of overdose] An overdose is defined as having occurred when a patient takes 
the drug beyond the “recommended daily dose (mg/day)” or the “administration schedule.” 
Table 6.1 Dose of FTD/TPI 
Body Surface Area (m2)  
Daily Dose 
(mg/day) 
Single Dose (mg); Number of Tablets Prescribed 
Morning 
Evening 
Less than 1.07 
70 
35mg 
15-mg tablet × 1, 20-mg tablet × 1 
35mg 
15-mg tablet × 1, 20-mg tablet × 1 
Not less than 1.07 and 
less than 1.23 
80 
40mg 
20-mg tablet × 2 
40mg 
20-mg tablet × 2 
Not less than 1.23 and 
less than 1.38 
90 
45mg 
15-mg tablet × 3 
45mg 
15-mg tablet × 3 
Not less than 1.38 and 
less than 1.53 
100 
50mg 
15-mg tablet × 2, 20-mg tablet × 1 
50mg 
15-mg tablet × 2, 20-mg tablet × 1 
Not less than 1.53 and 
less than 1.69 
110 
55mg 
15-mg tablet × 1, 20-mg tablet × 2 
55mg 
15-mg tablet × 1, 20-mg tablet × 2 
Not less than 1.69 and 
less than 1.84 
120 
60mg 
20-mg tablet × 3 
60mg 
20-mg tablet × 3 
Not less than 1.84 and 
less than 1.99 
130 
65mg 
15-mg tablet × 3, 20-mg tablet × 1 
65mg 
15-mg tablet × 3, 20-mg tablet × 1 
Not less than 1.99 and 
less than 2.15 
140 
70mg 
15-mg tablet × 2, 20-mg tablet × 2 
70mg 
15-mg tablet × 2, 20-mg tablet × 2 
Not less than 2.15 
150 
75mg 
15-mg tablet × 1, 20-mg tablet × 3 
75mg 
15-mg tablet × 1, 20-mg tablet × 3 
 

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6.1.2 
Dosage Regimen 
1) 
In 1 course consisting of 28 days, FTD/TPI or placebo will be orally administered 
twice daily after breakfast and after dinner for 5 consecutive days (Days 1 to 5 and Days 8 
to 12), followed by withdrawal for 2 days. After repeating this cycle twice, the subject is 
withdrawn from study treatment for 14 days (see the figure). 
2) 
The start of administration on Day 1 may either be after breakfast or after dinner. 
The start of administration on Day 8 will be after breakfast if the start of administration 
on Day 1 was after breakfast and will be after dinner if the start of administration on 
Day 1 was after dinner. The time of start of administration on Day 1 may be changed in 
each course. 
3) 
Administration will be continued until 6 courses are completed or until any of the 
criteria described in “6.2.1. Discontinuation Criteria” is met. 
 
Figure. Dosage Regimen for FTD/TPI 
6.2 
Discontinuation of Study Treatment 
6.2.1 
Discontinuation Criteria 
Study treatment will be discontinued if any of the following criteria is met: 
1) 
Relapse of the primary disease 
2) 
Study treatment cannot be continued due to an adverse event 
(i) The planed start date of the next course is set as the first day, and the start of 
the next course is delayed more than the same day of the week 4 weeks later in 
accordance with “6.3. Criteria for the Modification of Study Treatment” 
(ii) After a dose reduction to 30 mg/day in accordance with “6.3. Criteria for the 
Modification of Study Treatment,” a further dose reduction is judged to be 
necessary 
3) 
The patient requested to discontinue study treatment 
4) 
Death during study treatment 
5) 
The subject is shown to be out of the scope of this trial 
6) 
The investigator judges that the trial needs to be discontinued 
7) 
Discontinuation due to reasons other than those described above 1) to 6) 

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6.2.2 
Data Collection and Subject Follow-Up After Discontinuation of Study 
Treatment 
If the subject meets any of the discontinuation criteria, study treatment will be 
discontinued, and then the time point of discontinuation and the reasons therefor will be 
recorded in the case report forms (CRFs), and the tests specified for the follow-up period 
will be performed. If the study treatment is discontinued due to relapse of the primary 
disease, 
only 
the 
outcome 
survey 
should 
be 
conducted 
after 
the 
discontinuation/completion tests and after 30 days test specified in Table 8.2 Study 
Calendar are conducted. However, these tests may not be performed if the investigator 
judges that such various types of tests cannot or need not be performed because of ethical 
considerations or in view of the safety and benefits of the subject. If various types of tests 
have not been performed, the investigator will state the reason for the judgment in the 
original document. 
6.3 
Criteria for the Modification of Study Treatment 
The investigator will assess which toxicity is attributed to FTD/TPI and adjust the 
dose of FTD/TPI according to the following recommendations. Dose modifications will 
always be based on the most severe preceding toxicity (CTCAE v5.0). Increasing the dose 
after a dose reduction will not be allowed. 
1) At the start of Course 2 and the subsequent courses 
(i) The course will be started after confirming that the subject meets all of the 
initiation and resumption criteria shown in Table 6.2. on the day of start of the 
course (acceptable range: ±3 days). 
(ii) If the subject does not meet all of the initiation and resumption criteria shown in 
Table 6.2., the start of the course will be delayed until the subject meets all of the 
criteria. 
(iii) The planed start date of the next course is set as the first day, and after delaying 
the start, if the subject does not meet all of the initiation and resumption criteria 
shown in Table 6.2. by the same day of the week 4 weeks later, study treatment 
will be discontinued. 
2) During administration in each course 
(i) If the subject meets any of the skip criteria shown in Table 6.2. during the 
administration period in each course, administration will be skipped until the 
subject meets all of the initiation and resumption criteria shown in the Table 6.2. 
(ii) Even in cases where the subject resumes administration in the same course, the 
subject will not take the planned but unadministered doses and will take the 
investigational drug according to the prescribed administration schedule (Days 1 

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to 5 and Days 8 to 12 of each course). In addition, any unused drug for missed doses 
shall not be taken later. 
(iii) In cases where the subject does not meet all of the initiation and resumption 
criteria shown in Table 6.2. by Day 12 after the skip, the next course will be started 
after confirming that the subject meets all of the initiation and resumption criteria 
shown in Table 6.2 after 14 days after the date of the last dose. 
(iv) The planed start date of the next course is set as the first day, and if the start of 
the next course is delayed more than the same day of the week 4 weeks later, study 
treatment will be discontinued. 
3) All time points (regardless of during administration, skipping, etc.) 
(i) If the subject meets any of the dose reduction criteria shown in Table 6.2., the dose 
will be reduced by 10 mg/day as the daily dose course by course (the dose will be 
reduced in the next course and will not be reduced during the current course). 
(ii) If a further dose reduction from 30 mg/day is required, study treatment will be 
discontinued. 
(iii) After a dose reduction, the dose will not be increased. 
 
Table 6.2. Initiation and Resumption Criteria, Skip Criteria, and Dose Reduction 
Criteria 
 
Initiation and Resumption 
Criteria 
Skip Criteria (Within a 
Course) 
Reduction 
Criteria*1 
Neutrophil 
count 
≧1,500/mm3 
＜1,000/mm3 
＜500/mm3 
Hemoglobin 
≧8.0 g/dL 
＜7.0 g/dL 
 
Platelet count 
≧75,000/mm3 
＜50,000/mm3 
＜50,000/mm3 
Total bilirubin 
≦1.5mg/dL 
＞2.0mg/dL 
 
AST(GOT) 
≦100U/L 
＞100U/L 
 
ALT(GPT) 
≦100U/L 
＞100U/L 
 
Creatinine 
≦1.5mg/dL 
＞1.5mg/dL 
 
Adverse events 
other than the 
above 
All adverse events*2 
≤ Grade 1 
All adverse events*2 
≥ Grade 3 
 
Other  
(judged by the 
investigator) 
The subject meets the above 
criteria and the investigator 
judges that study treatment 
can be initiated . 
The 
investigator 
judges 
that 
continuation 
of 
administration is difficult 
due to an adverse event 
that is not listed above.*3 
The investigator 
judges that a dose 
reduction 
is 
necessary 
to 
ensure the safety 
of the patient.*3 
Remarks 
If the investigator judges that it is difficult to initiate or 
resume a course from the viewpoint of ensuring patient 
 

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Initiation and Resumption 
Criteria 
Skip Criteria (Within a 
Course) 
Reduction 
Criteria*1 
safety, the course may be delayed or skipped even when 
the subject meets the above criteria.*3 
*1 
If the subject meets the dose reduction criteria, administration within the current course will be 
skipped, and the dose will be reduced in the next course. 
*2 
Alopecia, skin hyperpigmentation, and dysgeusia are excluded. In addition, any adverse event that 
is obviously judged not to be caused by the investigational drug may be excluded at the discretion 
of the investigator. In this case, the reasons for the judgment shall be recorded in the medical 
records, etc. 
*3 
The bases for the judgment shall be recorded in the medical records etc. 
 

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Table 6.3. Dose of FTD/TPI After Dose Reduction 
 
Daily 
Dose 
(mg/day) 
Single Dose (mg); Number of Tablets Prescribed 
Morning 
Evening 
30 
15mg 15-mg tablet × 1 
15mg 
15-mg tablet × 1 
40 
20mg 
  20-mg tablet × 1 
20mg 
    20-mg tablet × 1 
50 
20mg 
  20-mg tablet × 1 
30mg 
15-mg tablet × 2 
60 
30mg 15-mg tablet × 2 
30mg 
15-mg tablet × 2 
70 
35mg 15-mg tablet × 1, 20-mg 
tablet × 1 
35mg 
15-mg tablet × 1, 20-mg tablet 
× 1 
80 
40mg 
  20-mg tablet × 2 
40mg 
    20-mg tablet × 2 
90 
45mg 15-mg tablet × 3 
45mg 
15-mg tablet × 3 
100 
50mg 15-mg tablet × 2, 20-mg 
tablet × 1 
50mg 
15-mg tablet × 2, 20-mg tablet 
× 1 
110 
55mg 15-mg tablet × 1, 20-mg 
tablet × 2 
55mg 
15-mg tablet × 1, 20-mg tablet 
× 2 
120 
60mg 
  20-mg tablet × 3 
60mg 
    20-mg tablet × 3 
130 
65mg 15-mg tablet × 3, 20-mg 
tablet × 1 
65mg 
15-mg tablet × 3, 20-mg tablet 
× 1 
140 
70mg 15-mg tablet × 2, 20-mg 
tablet × 2 
70mg 
15-mg tablet × 2, 20-mg tablet 
× 2 
 
6.4 
Specific Instructions for Subjects 
The investigator or a trial collaborator will instruct the subject to comply with the 
method of administration of FTD/TPI and placebo and the following items. Medication 
compliance of FTD/TPI and placebo at an outpatient visit will be thoroughly interviewed 
and investigated (e.g., by collecting the investigational drug that has not been taken), 
and the results will be recorded in the medical records and the CRFs. 
[Instructions] 
1) 
Subjects will be instructed to take the FTD/TPI or placebo roughly within 1 hour 
after breakfast and dinner. 
2) 
Any subject who vomited after taking FTD/TPI or placebo will be instructed not 
to take any additional doses to compensate for the vomited drug. 
3) 
The investigator or a trial collaborator will instruct subjects to comply with the 
method of administration of FTD/TPI or placebo and to return the unused drug 
for any missed doses, etc. 

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4) 
Any subject who consults another hospital or department for another disease, etc. 
will be instructed to report to the hospital or department that the subject is 
participating in the trial, and any subject who needs to take a drug because of 
this consultation will be instructed to contact the investigator. 
5) 
Male subjects and female subjects of childbearing potential will be instructed to 
take reliable measures to avoid pregnancy from the date of consent until 6 
months after the last dose. 
6)  Subjects will be instructed to keep the investigational drug in a safe place out of 
reach of children under appropriate storage conditions and not to take the next 
dose of tablets out of the package in advance. 
6.5 
Permitted Concomitant Therapy/Prohibited Concomitant Therapy 
Concomitant therapy will include all medications taken by the subject from the start 
of study treatment until 30 days after the last administration of study treatment or until 
the day before the start of the post-treatment, whichever is earlier. All concomitant 
therapies shall be reported to the investigator and recorded in the medical records and 
the CRFs. 
Any treatment or surgical procedure that is not specified in the protocol and is 
performed during the trial period will be treated as concomitant therapy and must be 
recorded. Information to be recorded about concomitant medications and therapies will 
include the date of the use of the medication, treatment, or procedure and the reasons 
for using it. 
Any drugs used for various tests and diagnoses may not be reported in the CRFs, 
unless necessary to determine the causal relationship of adverse events and the like. 
6.5.1 
Permitted Concomitant Therapy 
In principle, concomitant medications/therapies deemed necessary for the subject are 
permitted. If the investigator is unsure whether a particular medication or procedure 
can be prescribed or used to a subject of this trial, the investigator shall contact a 
coordinating investigator. 
In the event of nausea, vomiting, or diarrhea, an effective symptomatic therapy shall 
be started. Loperamide is recommended as an initial treatment for diarrhea. 
G-CSF may be used for febrile neutropenia in accordance with the guideline of the 
medical institution or other guidelines (e.g., American Society of Clinical Oncology 
[ASCO] guidelines), but G-CSF shall not be used for the primary prevention of 
neutropenia. G-CSF shall be discontinued by 48 hours prior to the next cycle of study 
treatment. 

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6.5.2 
Prohibited Concomitant Therapy 
During the study treatment period, subjects will not be permitted to receive any cancer 
treatment (including surgery, chemotherapy, molecular target drugs, therapeutic 
antibodies, hormone therapy, immunotherapy, and radiation therapy) and any other 
investigational drugs. Except standard of care for the management of specific adverse 
events, concomitant use of long-term systemic steroid therapy (equivalent to treatment 
with 10 mg/day or more of prednisolone for 2 weeks or more) or other 
immunosuppressants will not be permitted. Inhaled corticosteroids or intraarticular 
corticosteroids will not be included in the prohibited therapy in this trial. 
Concomitant use of nutritional supplements, medications not prescribed by the 
investigator, and alternative/complementary therapy is not prohibited but not 
recommended. 
6.6 
Post-treatment 
In principle, after completion or discontinuation of the study treatment, no 
postoperative adjuvant therapy other than the study treatment will be performed for the 
primary disease until a relapse occurs or until follow-up of this trial is completed (1 year 
from the enrollment of the last patient). This limitation will not apply after a relapse 
occurs, or follow-up of the trial is completed. 

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7 
Information on Investigational Drug 
7.1 
Drug Information 
FTD/TPI is a novel nucleoside antineoplastic agent containing, in a molar ratio of 1:0.5, 
α,α,α-trifluorothymidine 
(FTD) 
and 
5-chloro-6-(2-iminopyrrolidin-1-yl) 
methyl-
2,4(1H,3H)-pyrimidinedione hydrochloride (TPI). The physicochemical findings on the 
active ingredient and an outline of the investigational drug are presented in the table. 
 
Table 7.1 Physicochemical Findings on Active Ingredient 
 
FTD 
TPI 
Generic name 
Trifluridine 
Tipiracil hydrochloride 
Chemical name α,α,α-trifluorothymidine 
5-chloro-6-(2-iminopyrrolidin-1-
yl)methyl-2,4(1H,3H)-pyrimidinedione 
hydrochloride 
Structural 
formula 
 
 
Molecular 
formula 
C10H11F3N2O5 
C9H11ClN4O2·HCl 
Molecular 
weight 
296.20 
279.12 
 
 
Table 7.2 Outline of Investigational Drug (FTD/TPI) 
Investigational drug 
code name 
TAS-102 
Dosage form 
Tablets 
TAS-102 tablets (15 mg): round 
TAS-102 tablets (20 mg): round 
Description 
TAS-102 tablets (15 mg): white tablets 
TAS-102 tablets (20 mg): light-red tablets 
Ingredients/quantity TAS-102 tablets (15 mg): One tablet contains 15 mg of FTD and 
7.065 mg of TPI. 
TAS-102 tablets (20 mg): One tablet contains 20 mg of FTD and 
9.42 mg of TPI. 
 

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TAS-102 tablets (15mg) and TAS-102 tablets (20mg) contain as 
additives lactose hydrate, partly pregelatinized starch, stearic 
acid, hypromellose, macrogol 6000, titanium oxide, iron 
sesquioxide (20 mg tablets only) and magnesium stearate. 
Expiration date 
See the Accountability Procedure for the Investigational Drug. 
Packaging form 
<TAS-102 tablets (15 mg)>  1 PTP sheet: TAS-102 15 mg × 10 
tablets 
<TAS-102 tablets (20 mg)>  1 PTP sheet: TAS-102 20 mg × 10 
tablets 
Labeling 
Labeling will include the investigational drug code name 
“TAS-102 or placebo,” content, manufacturing number, quantity, 
and storage and will display the fact that the investigational 
drug is for clinical trials. In addition to the above information, 
information 
required 
to 
comply 
with 
local 
regulatory 
requirements will be printed on the label. 
Storage of the drug 
product 
Store at room temperature (1-30°C). 
 
Table 7.3 Outline of the Investigational Drug (Placebo) 
Dosage form 
Tablets 
TAS-102 tablets (15 mg) placebo: round 
TAS-102 tablets (20 mg) placebo: round 
Description 
TAS-102 tablets (15 mg) placebo: white tablets 
TAS-102 tablets (20 mg) placebo: light-red tablets 
Ingredients/q
uantity 
Tablets that do not contain the active ingredient of the investigational 
drug (TAS-102) and are indistinguishable in appearance from the 
investigational drug (TAS-102) 
Expiration 
date 
See the Accountability Procedure for the Investigational Drug. 
Packaging 
form 
<TAS-102 tablets (15 mg) placebo>  1 PTP sheet: 10 tablets 
<TAS-102 tablets (20 mg) placebo>  1 PTP sheet: 10 tablets 
Labeling 
Labeling will include the investigational drug code name “TAS-102 or 
placebo,” content, manufacturing number, quantity, and storage and 
will display the fact that the investigational drug is for clinical trials. 
In addition to the above information, information required to comply 
with local regulatory requirements will be printed on the label. 
Storage of the 
drug product 
Store at room temperature (1-30°C). 
 

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7.2 
Investigational Drug Accountability 
The investigational drug TAS-102 tablets (15 mg), TAS-102 tablets (20 mg), and 
placebo tablets will be provided by the provider of the investigational drug, Taiho 
Pharmaceutical Co., Ltd. The investigational drug provider will also provide records of 
manufacturing of the investigational drug and records of the quality testing. The 
investigational drug will be sent from Taiho Pharmaceutical Co., Ltd. to the warehouse 
company through a packaging company, and will be distributed from warehouse 
company to each medical institution participating in the trial via a conveyancer, etc. 
7.3 
Disclosure of Allocation Results 
Disclosure of the allocation results for the entire trial is performed at the main analysis. 
Disclosure of the allocation results prior to main analysis will only be performed if it is 
necessary to ensure patient safety. Unless necessary, the allocation results shall not be 
disclosed. 
In cases where the investigator or an authorized designee needs to know the allocation 
results in an emergency, the investigator or designee report the necessary information 
(including subject enrollment number, and reasons for disclosure), and request 
disclosure of allocation to a coordinating investigator. Coordinating investigator perform 
emergency blind-breaking by entering necessary information in the Web enrollment 
system, and report the allocation results to the investigator or designee.  
Unblinded subjects need to discontinue the administration of the investigational drug. 
7.4 
Expected Adverse Events 
Of the adverse events of FTD/TPI, those whose occurrence itself or trend of occurrence 
such as the number, frequency, and condition of occurrence cannot be predicted from the 
current investigator’s brochure for the investigational drug will be treated as “unknown,” 
and those occurrence or trend of occurrence can be predicted will be treated as “known.” 

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8 
Endpoints, Laboratory Tests and Assessment Schedule 
8.1 
Observations and Tests 
The assessment items of this trial are as follows. All information required by the 
protocol will be recorded. 
Table 8.1 Observations and Tests 
Treatment status 
Dose of FTD/TPI (placebo), date of administration, presence or 
absence of dose modification and the reasons therefor, presence or 
absence of delay of administration and the reasons therefor 
Subject 
demographics 
Sex, age (at the time of informed consent)、Date of informed consent, 
medical history (including major diseases requiring outpatient 
treatment or inpatient hospitalization and medical history of 
malignancy), 
complications, 
prior 
treatment 
history 
(chemoradiotherapy or chemotherapy prior to curative resection, 
information on initial surgery in case of relapse) 
Patient ID for GALAXY study (at the time of determination of 
eligibility) 
ctDNA status at 1 month postoperatively, etc. 
Details of lesions 
Histopathological findings on the primary tumor: primary location 
(right colon/left colon/rectum), tissue-type, gross classification, depth 
of invasion, number of lymph node metastases 
Surgical findings: Extent of lymph node dissection, number of 
dissected lymph nodes, tumor diameter (maximum diameter), 
presence or absence of liver metastasis, presence or absence of 
peritoneal metastasis, presence or absence of other distant 
metastasis, stage classification, presence or absence of lymphatic 
invasion, presence or absence of venous invasion, presence or absence 
of neuroinvasion, presence or absence of extramural cancer deposits 
without lymph node structure 
Surgical information: Date of surgery, surgical procedure, approach 
(laparotomy, laparoscopy), presence or absence of combined resection 
of an organ and postoperative complications 
Physical 
measurements 
Height, weight 
Vital signs 
Systolic/diastolic blood pressure, pulse rate, body temperature 
* At all time points, measurements will be performed in the same posture 
by subject. 
Performance status 
ECOG PS 
Adverse events 
Presence or absence of adverse events and the severity thereof 
according to CTCAE v5.0, causal relationship with investigational 
drug, date of occurrence, date of reaction outcome, reaction outcome, 
presence or absence of treatment for investigational drug 
Concomitant 
medications/therapi
es 
Name of drug (or concomitant therapy), route of administration, 
period of concomitant use, reasons for concomitant use 
Electrocardiogram 
Resting 12-lead electrocardiogram 
Hematological tests 
Red blood cell count, Hb, white blood cell count, neutrophil count, 
lymphocyte count, platelet count 

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8.2 
Study Calendar 
Consent must be obtained prior to starting any trial-related assessments and 
procedures. The tests listed in “Table 8.1 Observations and Tests“ will be performed at 
the time points shown in “Table 8.2 Study Calendar” and when they are considered to be 
clinically required. If necessary, clinically significant laboratory assessments will be 
repeated until the test values return to baseline values or clinically stabilize or until 
another treatment is started. 
Biochemistry tests 
AST (GOT), ALT (GPT), ALP, LDH, albumin, total bilirubin, BUN, 
creatinine, electrolytes (Na, K, Cl, Ca), blood glucose 
Urinalysis 
Urine protein (qualitative) 
Pregnancy test 
Serologic test if pregnancy is suspected by urinalysis 
* To be performed in women who are premenopausal or who had the last 
menstruation less than 1 year ago. 
Infectious 
disease 
test*1 
HBs antigen, HBs antibody, and HBc antibody (HBV-DNA if 
needed*2), HCV antibody (HCV-RNA if needed*3), HIV antibody*4 
*1 Any test results performed within 12 months prior to enrollment may 
be used as substitutions. 
*2 HBV-DNA testing is mandatory to be below the limit of detection for 
patients with a negative HBs antigen test, but with a positive test result 
for either HBs antibody or HBc antibody  
*3 HCV-RNA testing is mandatory for patients with a positive test result 
for HCV antibody 
*4 HIV antibody testing is not mandatory. 
Tumor markers 
CEA/CA19-9 
Imaging tests 
Thoracic-abdominal-pelvic CT*1 or MRI*1 and, if needed, brain CT, 
brain MRI, and bone scintigraphy 
*1 This test may be performed without using a contrast agent in patients 
with allergies/hypersensitivity to contrast agents used for CT and MRI. 
However, the results will be assessed chronologically using the same 
modality. 
Total colonoscopy 
If the entire large intestine cannot be observed before or after 
surgery, perform it within one year after enrollment. Thereafter, 
every year if neoplastic lesion is observed, but every three to five 
years if there is no neoplastic lesion. If a total colonoscopy 
performed before or after surgery does not reveal any neoplastic 
lesion other than the target lesion, the test should be performed 
every three to five years after enrollment.    
 *1 For total colonoscopy, the results of the test performed at other hospitals 
may be used as substitutions. 
ctDNA test 
A ctDNA analysis will be performed using SignateraTM. 
QOL 
QOL assessments using EORTC QLQ C-30 and EQ-5D-5L 
Outcome survey 
Presence or absence of relapse; in the event of a relapse, the date of 
relapse (the date of imaging or biopsy), presence or absence of 
treatment, details thereof, and start date thereof 
Date of death or the date of final survival confirmation; in the event 
of death, cause of death 

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As long as the proper sequence of procedures, such as confirmation of initiation criteria 
and dose, and implementation of observations and tests, is maintained, a delay in 
starting study treatment of up to ±3 days will be allowed at the Course 2 and the 
subsequent courses. A delay in schedule due to a long period of public holidays, such as 
year-end to new-year holidays, will not be treated as a deviation. See also “Table 8.2 
Study Calendar” for the time window for study treatment and various tests. 

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Table 8.2 Study Calendar 
Administration Course 
Before 
Enrollment* 
During Study Treatment 
Period* 
At Discontinuation 
/Completion10) 
Follow-up 
Period 
At 
Recurrence 
 
 
 
Course 1 
Course 2 - 6 
 
 
 
Test/observation date 
Within  
28 
days17) 
Within 
14 
days17) 
D1 
D15 
D1** 
D15 
7) 
At 
discontinuati
on 
/completion9) 
After  
30 
days 
Up to  
1 
year 
Up to  
3  
years 
Up to 3 years 
Time window (days)  
 
 
-3 
±3 
±3 
±3 
-3～+7 
-3 ～
+7 
 
 
±1 month 
Treatment 
 
 
 
 
 
 
 
 
 
 
 
Administration of 
investigational drug 
 
 
●5,6) 
 
●6) 
 
 
 
 
 
 
Concomitant 
medications/therapies 
 
 
→ 
→ 
→ 
→ 
→ 
→ 
 
 
 
Examination findings1) 
 
 
 
 
 
 
 
 
 
 
Patient demographics 
● (until the day 
before enrollment) 
 
 
 
 
 
 
 
 
 
Details of lesions 
● (until the day 
before enrollment) 
 
 
 
 
 
 
 
 
 
Height 
 
● 
 
 
 
 
 
 
 
 
 
Weight 
 
● 
 
 
● 
 
● 
● 
 
 
 
Vital signs 
 
●4) 
●4) 
● 
●8) 
〇 
● 
● 
 
 
 
PS 
 
●4) 
●4) 
● 
●8) 
〇 
● 
● 
 
 
 
Subjective and 
objective symptoms 
 
●4) 
●4) 
● 
●8) 
〇 
● 
● 
 
 
 
Clinical findings1) 
 
 
 
 
 
 
 
 
 
 
 
Hematological tests 
 
●4) 
●4) 
● 
●8) 
〇 
● 
● 
 
 
 
Biochemistry tests 
 
●4) 
●4) 
● 
●8) 
〇 
● 
● 
 
 
 
Urinalysis 
 
●4) 
●4) 
● 
●8) 
〇 
● 
● 
 
 
 
Pregnancy test2) 
 
● 
 
 
 
 
 
 
 
 
 
Electrocardiogram 
● 
 
 
 
 
 
 
 
 
 
 
HBV/HCV/HIV 
●3) 
 
 
 
 
 
 
 
 
 
 
CEA/CA19-9 
● 
 
Every 8 weeks (± 1 week) until 1 year from enrollment12) 
●13) 
 
SignateraTM 
●11) 
 
Every 8 weeks (± 1 week) until 1 year from enrollment12) 
●14) 
●18) 
QOL 
● 
 
Every 8 weeks (± 1 week) from enrollment12) 
 
 
Imaging assessments 
 
 
 
 
 
 
 
 
 
 
Thoracic-abdominal-
pelvic CT or MRI 
● 
 
Every 8 weeks (± 1 week) until 1 year from enrollment12) 
●13) 
 
Total colonoscopy 
 
 
●15) 
 
Follow-up 
 
 
 
 
 
 
 
 
 
 
 
Outcome survey 
 
 
 
 
 
 
 
 
Every year16) 
 

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● Required 〇Performed as necessary 
*The test result performed within the acceptable range before obtaining informed 
consent may be used as substitutions for the pre-enrollment tests or the test result (pre-
dose) on Day 1 (QOL surveys will be conducted after obtaining informed consent). 
**If a test/observation for this day is postponed, it will be performed as one on Day 29. 
 
1) 
See “Table 8.1 Observations and Tests” for the details of examination findings 
and clinical findings. 
2) 
Performed in women who are premenopausal or who had the last 
menstruation less than 1 year ago. 
3) 
Any test results performed within 12 months prior to enrollment may be used 
as substitutions. 
4) 
In principle, the test (pre-dose) on Day 1 is performed after enrollment. 
However, the pre-enrollment tests performed within 3 days before 
administration may be used as the tests (pre-dose) on Day 1. The test will be 
performed before administration. If there are test results both within 3 days 
before administration and (pre-dose) on Day 1, the start of administration is 
judge by the test result (pre-dose) on Day 1. 
5) 
Administration of the investigational drug will be started within 8 days after 
enrollment including the date of enrollment. See Section 6.1 for dose and 
administration schedule. 
6) 
The investigational drug will be taken after all of the tests specified for each 
day of visit have been performed. 
7) 
The tests and observation on Day 15 after the start of Course 2 is not 
mandatory.  These tests and observation will be performed if the investigator 
judges that such various types of tests and observation need to be performed. 
8) 
The pre-course tests performed within 3 days before administration may be 
substituted for the tests on Day 1 (pre-dose). 
9) 
The 
time 
window 
will 
be 
from 
3 
days 
before 
the 
date 
of 
discontinuation/completion (28 days after the start of 6th course) to 7 days 
after the date of discontinuation/completion (28 days after the start of 6th 
course). However, if it is impossible to perform the tests and observations 
within the time window because of the subject’s condition, they will be 
performed as soon as possible. These tests and observations will not be 
required if they overlap with other specified tests and observations. 
10) The time window of the tests on Day 30 after discontinuation/completion tests 

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will be from 3 days before Day 30 after discontinuation/completion test to 7 
days after Day 30 after discontinuation/completion test. In cases where the 
post-treatment is performed, discontinuation/completion tests or tests on 
Day 30 after discontinuation/completion tests will be performed before the 
administration of post-treatment (If the post-treatment is started within 7 
days after the end of discontinuation, only the discontinuation tests is 
performed). The discontinuation tests or observation during follow-up period 
will not be required if study treatment is discontinued before administration 
of investigational drug. 
11) Subjects will have tested positive for ctDNA in the GALAXY study by an 
analysis of the latest blood samples collected within 3 months prior to 
enrollment. 
12) With the enrollment date as the first day, these tests will be performed as 
described even when treatment is delayed.  
Time window of test/observation is 1 week before and after including the 
same day of the week as reference date. 
13) With the enrollment date as the first day, these tests will be 
performed 15, 18, 24, 30, and 36 months (one month is defined as the same 
day of the following month) after enrollment.   
Time window of test/observation is 2 weeks before and after including the 
same day of the week as reference date. 
After the completion of the follow-up period, the investigation will be 
continued in a separate observational study. 
14) With the enrollment date as the first day, these tests will be performed 15, 18, 
and 24 months (one month is defined as the same day of the following month) 
after enrollment. 
Time window of test/observation is 2 weeks before and after including the 
same day of the week as reference date. 
15) If the entire large intestine cannot be observed preoperatively or  
postoperatively, this test will be performed within 1 year after enrollment.  
Thereafter, with the observation date as the first day, this test will be  
performed every year  if tumorous lesions are observed. If the entire large  
intestine can be observed preoperatively or postoperatively, and tumorous  
lesions are observed, with the observation date as the first day, this test will  
be performed every year if a total colonoscopy performed before or after surgery  
does not reveal any neoplastic lesion other than the target lesion, the test  

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should be performed every three to five years after enrollment. 
Time window of test/observation is 4 weeks before and after including the 
same day of the week as reference date. 
     16)  This survey will be performed from the end of treatment until death or the  
last follow-up of the trial (every year after enrollment). Time window of  
test/observation is 4 weeks before and after including the same day of the  
week as reference date. 
Even when direct follow-up is not possible because of patient transfer, etc., the 
outcome will be ascertained as far as possible by, for example, making 
inquiries at the hospital to which the subject is transferred, and the results of 
inquiries will be recorded in the medical records. 
17) The date includes the same day of the week as the registration day. 
18) If the test result which blood sampling date is within 1 month before and  
after (1 month defined as the same day of the following month) of recurrence  
date, additional blood test is not required. 
 
     

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8.3 
Imaging Tests 
In principle, the presence or absence of relapse will be ascertained by imaging tests 
and tumor markers every 8 weeks (± 1 week) from the date of enrollment until 1 year 
after enrollment in this trial and 15, 18, 24, 30, and 36 months (with a time window of 2 
weeks before and after these time points) after enrollment from Year 1 to 3. For CT 
assessments, contrast-enhanced CT of the chest, abdominal, and pelvic regions will be 
performed in principle. Imaging requirements are as follows: slice thickness: 5mm or less, 
anatomic coverage: from lung apex to inferior border of ischium.  
The definitive diagnosis of relapse will be made as follows: 
1) 
Liver metastasis: CT or MRI 
2) 
Lung metastasis: CT 
3) 
Lymph node metastasis: CT or MRI 
4) 
Peritoneal metastasis: CT or MRI 
5) 
Bone metastasis: CT or MRI, bone scintigraphy 
6) 
Local relapse: CT, MRI, total colonoscopy 
7) 
Other metastasis: Ultrasonography or CT, MRI 
If there is any cancer lesion other than a relapse, the location and date of confirmation 
(the date of imaging tests) will be reported in the CRFs.* 
*: Intramucosal cancer will not be treated as a relapse. 
[Definition of a relapse] 
Confirmation of a relapse finding that meets any of the following criteria is defined as 
a “relapse.” The date of relapse shall be the earliest date of diagnosis either by imaging 
or pathology. In addition, if a clinical diagnosis of a relapse is difficult, it is preferable to 
confirm the relapse by a biopsy. An increased tumor marker level alone will not be 
treated as a relapse. 
1) 
Diagnostic imaging: The date of imaging with a definitive diagnosis of a relapse on 
an image is defined as the date of relapse. 
2) 
Pathological diagnosis: If a relapse could not be diagnosed clinically and was 
diagnosed by a biopsy, the date of biopsy is defined as the date of relapse. 
In addition, the date and method of confirmation of a relapse will be reported in the 
CRFs. 
8.4 
QOL Survey 
The survey will be performed within 28 days prior to enrollment, and every 8 weeks 
(± 1 week) from the date of enrollment until 1 year after enrollment in this trial. As QOL 
questionnaires, EORTC QLQ-C30 and EQ-5D-5L will be used. The assessments for the 

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survey items will be performed after visiting the hospital and before receiving the 
investigator’s examination (including dosing). 
 
 

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[EQ-5D-5L Score] 
Mobility 
 
I have no problems walking. 
□ 
I have slight problems walking. 
□ 
I have moderate problems walking. 
□ 
I have severe problems walking. 
□ 
I am unable to walk. 
□ 
Self-care 
 
I have no problems washing or dressing myself. 
□ 
I have slight problems washing or dressing myself. 
□ 
I have moderate problems washing or dressing myself. 
□ 
I have severe problems washing or dressing myself. 
□ 
I am unable to wash or dress myself. 
□ 
Usual activities (e.g., work, study, housework, family or leisure 
activities) 
 
I have no problems doing my usual activities. 
□ 
I have slight problems doing my usual activities. 
□ 
I have moderate problems doing my usual activities. 
□ 
I have severe problems doing my usual activities. 
□ 
I am unable to do my usual activities. 
□ 
Pain/discomfort 
 
I have no pain or discomfort. 
□ 
I have slight pain or discomfort. 
□ 
I have moderate pain or discomfort. 
□ 
I have severe pain or discomfort. 
□ 
I have extreme pain or discomfort. 
□ 
Anxiety/depression 
 
I am not anxious or depressed. 
□ 
I am slightly anxious or depressed. 
□ 
I am moderately anxious or depressed. 
□ 
I am severely anxious or depressed. 
□ 
I am extremely anxious or depressed. 
□ 

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[EORTC QLQ C-30 Score] 
About physical symptoms 
Not at 
All 
A 
Little 
Quite 
a Bit 
Very 
Much 
Do you have any trouble doing strenuous 
activities, like carrying a heavy shopping bag or 
suitcase? 
1 
2 
3 
4 
Do you have any trouble taking a long walk? 
1 
2 
3 
4 
Do you have any trouble taking a short walk 
outside of the house? 
1 
2 
3 
4 
Do you need to stay in bed or a chair during the 
day? 
1 
2 
3 
4 
Do you need help with eating, dressing, washing 
yourself or using the toilet? 
1 
2 
3 
4 
 
During the past week: 
Not at 
All 
A 
Little 
Quite 
a Bit 
Very 
Much 
Were you limited in doing either your work or 
other daily activities? 
1 
2 
3 
4 
Were you limited in pursuing your hobbies or 
other leisure time activities? 
1 
2 
3 
4 
Were you short of breath? 
1 
2 
3 
4 
Have you had pain? 
1 
2 
3 
4 
Did you need to rest? 
1 
2 
3 
4 
Have you had trouble sleeping? 
1 
2 
3 
4 
Have you felt weak? 
1 
2 
3 
4 
Have you lacked appetite? 
1 
2 
3 
4 
Have you felt nauseated? 
1 
2 
3 
4 
Have you vomited? 
1 
2 
3 
4 
Have you been constipated? 
1 
2 
3 
4 
Have you had diarrhea? 
1 
2 
3 
4 
Were you tired? 
1 
2 
3 
4 
Did pain interfere with your daily activities? 
1 
2 
3 
4 

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Have you had difficulty in concentrating on 
things, like reading a newspaper or watching 
television?   
1 
2 
3 
4 
Did you feel tense? 
1 
2 
3 
4 
Did you worry? 
1 
2 
3 
4 
Did you feel irritable? 
1 
2 
3 
4 
Did you feel depressed? 
1 
2 
3 
4 
Have you had difficulty remembering things? 
1 
2 
3 
4 
Has 
your 
physical 
condition 
or 
medical 
treatment interfered with your family life? 
1 
2 
3 
4 
Has 
your 
physical 
condition 
or 
medical 
treatment interfered with your social activities? 
1 
2 
3 
4 
Has 
your 
physical 
condition 
or 
medical 
treatment caused you financial difficulties? 
1 
2 
3 
4 
 
How would you rate your overall health during the past week? 
1 
(Very poor) 
2 
3 
4 
5 
6 
7 
(Excellent) 
 
How would you rate your overall quality of life during the past week? 
1 
(Very poor) 
2 
3 
4 
5 
6 
7 
(Excellent) 
 
8.5 
Outcome Survey 
Survival status (in the event of death, cause of death) and the presence or absence of 
relapse will be surveyed every year (with a time window of 4 weeks before and after these 
time points) after enrollment in the enrolled subjects. Even when direct follow-up is not 
possible because of patient transfer, participation in another trial, etc., the outcome will 
be ascertained as far as possible by, for example, making inquiries at the hospital to 
which the subject is transferred, and the results of inquiries will be recorded in the 
medical records. For all subjects, the follow-up period will continue until death, loss to 
follow-up, withdrawal of consent, or completion of the trial, whichever occurs first. 

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9 
Data Collection 
9.1 
Handling and Storage of CRF Data 
EPS corporation will be in charge of data management, including management and 
storage of CRF data. A data management plan will be prepared, and restrictions on 
entries and access to the database will be set up in the plan to appropriately manage and 
store records. 
 
9.2 
Identification of Source Documents 
The source documents for this trial shall be as follows: 
• 
Medical records 
• 
Informed consent forms 
• 
QOL questionnaires 
• 
Drug accountability forms 
• 
Laboratory data 
• 
Diagnostic imaging films, etc. 

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10 
Reporting of Adverse Events 
10.1 
Assessment of Adverse Events 
10.1.1 Definition of an Adverse Event 
An adverse event can be any unfavorable and unintended sign (including an abnormal 
laboratory variation), symptom, or disease in a subject administered the investigational 
drug, whether or not considered related to the investigational drug. 
A subjective or objective symptom of Grade 1 or higher that has been observed since 
before the start of administration (at baseline evaluation) will be treated as an adverse 
event only when the grade of the adverse event worsens from the grade before the start 
of administration. 
10.1.2 How To Describe Adverse Events 
Each adverse event will be graded with the closest definition of Grades 1-5. 
If the diagnosis includes a sign (including an abnormal laboratory finding) or symptom, 
a diagnosis based on CTCAE v5.0, rather than individual signs or symptoms, will be 
recorded in the CRFs, whenever possible. 
A laboratory abnormality alone will be recorded as an adverse event only if it is judged 
by the investigator to meet any of the following criteria: 
(i) 
The abnormality has induced clinical signs or symptoms. 
(ii) 
The abnormality is judged to be clinically significant. 
(iii) 
The abnormality requires treatment. 
(iv) 
The abnormality requires an additional test (excluding cases where a retest alone 
is required). 
(v) 
The abnormality requires discontinuation, a delay, etc. of the investigational drug. 
10.1.3 Information to Be Included in the Description of Adverse Events 
The following information will be recorded in the CRFs for each adverse event that 
has occurred: 
(i) 
Term of adverse event 
(ii) 
Severity (CTCAE Grade 1-5 and “serious/non-serious”) 
(iii) 
Causal relationship to the investigational drug 
(iv) 
Date of onset, date of outcome, and outcome 
(v) 
Presence or absence of an action taken for the investigational drug 

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10.1.4 Causality Assessment 
The causal relationship with the investigational drug will be assessed into 2 classes as 
follows: If a reasonable causal relationship with the investigational drug cannot be ruled 
out, the assessment will be “related”; and if a reasonable causal relationship with the 
investigational product can be ruled out, the assessment will be “not related.” 
10.1.5 Actions to Be Taken at the Onset of an Adverse Event 
In the event of an adverse event, the investigator will immediately take appropriate 
measures. 
Follow-up will be performed until the symptom (or test value) is shown to have 
resolved or improved, even after the end of the period for the assessment of adverse 
events (see “10.1.6 Period for the Assessment of Adverse Events“). However, follow-up of 
adverse events may be terminated if any of the following apply. 
* Follow-up of adverse events will be terminated in the following cases: 
• The adverse event is not serious, and it is judged that a causal relationship can be 
ruled out. In addition, the adverse event occurred not less than 30 days after the 
date of the last dose. 
• The investigator judges that the symptom is stable and causes no medically 
significant problem. 
• A post-treatment has been performed, and the causal relationship with the 
investigational drug cannot be assessed. 
• Follow-up is difficult because of patient transfer, etc. 
• The subject refuses follow-up. 
• The subject dies. 
 
10.1.6 Period for the Assessment of Adverse Events 
In this trial, the period for the assessment of adverse events will be from “the start 
date of the administration of the investigational drug” to “30 days after the last dose of 
the investigational drug or the day before the start of post-treatment, whichever occurs 
first,” and adverse events occurring during this period will be collected. 
An adverse event that is judged to be causally related to the investigational drug will 
be collected even if the event occurred 31 days or more after the last dose of the 
investigational drug. 
An adverse event that is detected after confirmation of a relapse of the primary disease 
and is due to a progression of the primary disease that newly developed will not be 
collected. 

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10.2 
Reporting of Serious Adverse Events 
10.2.1 Definition of a Serious Adverse Event 
An adverse event that is specified in “10.1 Assessment of Adverse Events“ and that 
meets any of the following criteria is defined as a “serious adverse event”: 
(i) 
An adverse event that results in death 
(ii) 
An adverse event that is life-threatening 
(iii) 
An adverse event that results in persistent or significant disability/incapacity 
(iv) 
An adverse event that causes a congenital anomaly/birth defect 
(v) 
An adverse event that requires inpatient hospitalization or prolongation of 
existing hospitalization, excluding  
- Hospitalization or death due to progression of the primary disease (PD) 
- Hospitalization or prolongation of existing hospitalization for the purpose of 
reducing the burden of subjects who have to visit the hospital from remote areas 
-  Pre-planned 
hospitalization 
or 
prolongation 
of 
existing 
pre-planned 
hospitalization 
-  Hospitalization or prolongation of existing hospitalization not related to an 
adverse event 
-  Hospitalization or prolongation of existing hospitalization for less than 24 hours 
for observation purpose only 
(vi) 
An adverse event that is medically important, i.e., is defined as any event that 
may jeopardize the subject or may require medical or surgical intervention to 
prevent one of the outcomes listed above 
10.2.2 Procedure for Reporting from the Investigator to the Head of the Medical 
Institution and a Coordinating Investigator 
(i) Initial report 
If a serious adverse event (see “10.2.1 Definition of a Serious Adverse Event“) occurs, 
the investigator will immediately take appropriate measures. The subinvestigator will 
promptly report the event to the principal investigator. 
The principal investigator will report the event to the head of the medical institution 
within 24 hours of learning of the occurrence of the serious adverse event and also report 
it to a coordinating investigator and the trial coordinating office. 
The format and procedure for reporting serious adverse events will be based on 
“Procedure for Handling Safety Information.” 

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(ii) 
Follow-up reports 
The principal investigator will follow up on serious adverse events (see “10.1.45 
Causality Assessment 
The causal relationship with the investigational drug will be assessed into 2 classes 
as follows: If a reasonable causal relationship with the investigational drug cannot be 
ruled out, the assessment will be “related”; and if a reasonable causal relationship with 
the investigational product can be ruled out, the assessment will be “not related.” 
Actions to Be Taken at the Onset of an Adverse Event. Additional information shall 
be promptly reported to the head of the medical institution and a coordinating 
investigator in accordance with “Procedure for Handling Safety Information.” 
 
Contact information for coordinating investigators and the trial coordinating office: 
E-mail：prj-altair_core@eps.co.jp  
TEL：03-6759-9904  FAX：03-5842-6432 
 
The investigator will respond to any requests for further information from 
coordinating investigators, the head of the medical institution, the Institutional Review 
Board, and the provider of the investigational drug. 
10.2.3 Coordinating Investigators’ Reporting Obligations and Procedures 
With respect to the serious adverse events reported in the initial report and follow-up 
reports, a coordinating investigator will determine the seriousness, causal relationship, 
expectedness, and the need for reporting to regulatory authorities (Pharmaceuticals and 
Medical Devices Agency [PMDA]) (on the basis of “Article 80-2, Paragraph 6 of the Act 
on Securing Quality, Efficacy and Safety of Products Including Pharmaceuticals and 
Medical Devices” and “Article 273 of the Regulation for Enforcement of the Act on 
Securing Quality, Efficacy and Safety of Products Including Pharmaceuticals and 
Medical Devices”). 
The details of the reporting procedure will be in accordance with “Procedure for 
Handling Safety Information.” 
1) 
Reporting to each principal investigator 
A coordinating investigator will promptly report to each principal investigator the 
reported serious adverse event along with the results of the above-mentioned 
determination. Each principal investigator will report the event to the head of the 
medical institution, as soon as possible if necessary, in accordance with the rules of 
each medical institution. 
2) 
Reporting to the PMDA 

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If a coordinating investigator determines that it is necessary to report an event to 
the PMDA, the coordinating investigator takes actions on the basis of Article 273 of 
the Regulation for Enforcement of the Act on Securing Quality, Efficacy and Safety of 
Products Including Pharmaceuticals and Medical Devices and related notifications. 
3) 
Reporting to the Data and Safety Monitoring Committee 
If a coordinating investigator determines that a serious adverse event needs to be 
reviewed by the Data and Safety Monitoring Committee, the coordinating 
investigator will report the event to the committee in writing and seek the 
committee’s opinion about the principal investigator’s and the coordinating 
investigator’s views on the adverse event and the appropriateness of the response to 
the adverse event. 
4) 
Reporting to the provider of the investigational drug 
A coordinating investigator will promptly report the serious adverse event reported 
by the investigator to Taiho Pharmaceutical Co., Ltd., which is the provider of the 
investigational drug. In addition, if a coordinating investigator is requested to provide 
information other than “Serious Adverse Event Report,” the investigator will respond 
as needed. 
10.2.4 Responsibilities of the Data and Safety Monitoring Committee 
The Data and Safety Monitoring Committee will review the reports on adverse events 
and make recommendations in writing to the coordinating investigator regarding what 
actions to take, such as whether the trial should be continued and whether the protocol 
needs to be revised. The procedure will be based on the “Procedure of the Data and Safety 
Monitoring Committee,” which is established separately. 
10.3 
Collection of Safety Information 
When a coordinating investigator obtains information on the safety of the 
investigational drug from the provider of the investigational drug, the coordinating 
investigator will take actions on the basis of Article 273 of the Regulation for 
Enforcement of the Act on Securing Quality, Efficacy and Safety of Products Including 
Pharmaceuticals and Medical Devices and related notifications. The coordinating 
investigator will report the safety information to each principal investigator, and each 
investigator will report the information to the head of the medical institution as soon as 
possible in accordance with the rules of each medical institution. 
The details of the reporting procedure will be in accordance with “Procedure for 
Handling Safety Information.” 

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In addition, the coordinating investigator will determine whether the protocol and the 
informed consent form and written information need to be revised and whether the 
information needs to be explained to subjects and will take actions if necessary. 
10.4 
Overdose 
Any overdose will be recorded in the CRFs regardless of whether or not the overdose 
is associated with an adverse event. If applicable, any serious and non-serious adverse 
events associated with the overdose will be recorded in the adverse event section of the 
CRFs.  
If the overdose is associated with a serious adverse event, the principal investigator 
will report the event to the head of the medical institution and a coordinating 
investigator within 24 hours. The details of the reporting procedure will be in accordance 
with “Procedure for Handling Safety Information.” 
10.5 
Medication Errors 
A medication error in this trial is defined as any unintended error in the prescription, 
dispensation, and administration of the investigational drug that occurred while the 
investigational drug is being managed by a healthcare professional or subject. 
Any of the following medication errors, whether or not related to an adverse event or 
a serious adverse event, will be reported by the investigator to the provider of the 
investigational drug via the trial coordinating office using the reporting form specified 
by the provider of the investigational drug promptly after the investigator first learned 
of the occurrence of the error. 
・ An error in the administration of the investigational drug that resulted in an 
adverse event 
・ An error in the administration of the investigational drug that resulted in an 
overdose 
・ Inappropriate route of administration of the investigational drug 
・ Other incorrect administration of the investigational drug 
* A missed dose, an incorrect dose of the investigational drug, or a medication error 
that resulted in a dose that exceeds the prescribed dose (but does not meet the definition 
of an overdose) may not be reported using the reporting form and will be identified by 
the record of the use of the investigational drug in the CRFs. 
10.6 
Information on Pregnancy and Lactation 
Any information reported by a subject about pregnancy of a female subject or the 
partner of a male subject and lactation of a female subject during the period of 
participation in the trial or the contraception period for individual subjects will be 

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reported using the prescribed form in accordance with the procedure described in 
Section 10.2. In the case of a female subject, the study treatment will be discontinued. 
Reporting of the information by the investigator to the head of the medical institution 
will not be essential. The investigator will follow up on the delivery and report it in 
writing. 
 

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11 
Definition of Endpoints 
11.1 
Definition of Primary Endpoint 
11.1.1 Disease-Free Survival 1 (DFS1) 
A DFS1 event in this trial is defined as a relapse, development of a secondary large 
intestine carcinoma lesion other than a relapse (an intramucosal cancer lesion will not 
be treated as an event), and death, and DFS1 generally refers to relapse-free survival 
(RFS).  
For survives with no evidence of recurrence, DFS1 data will be censored at the last 
imaging date of confirmed no recurrence. Subjects for which no imaging have been 
performed, DFS1 data will be censored at the date of enrollment.  
In principle, events will be assessed by the investigator. 
1) 
Definition of DFS1 
The time from the date of enrollment to any of the following events, whichever occurs 
first: a relapse, the first development of a secondary large intestine carcinoma lesion 
other than a relapse (an intramucosal cancer lesion will not be treated as an event) that 
is confirmed after the date of enrollment, and death from any cause. 
2) 
Definition of an event 
(i) 
Relapse 
Confirmation of a relapse finding that meets any of the following criteria is defined 
as a “relapse.” The date of relapse shall be the earliest date of diagnosis either by 
imaging or pathology. In addition, if a clinical diagnosis of a relapse is difficult, it is 
preferable to confirm the relapse by a biopsy. An increased tumor marker level alone 
will not be treated as a relapse. 
A) Diagnostic imaging: The date of imaging with a definitive diagnosis of a relapse 
on an image is defined as the date of relapse. 
B) Pathological diagnosis: If a relapse could not be diagnosed clinically and was 
diagnosed by a biopsy, the date of biopsy is defined as the date of relapse. 
(ii) 
Secondary large intestine carcinoma lesion other than a relapse that is confirmed 
after the date of enrollment 
The date of the first confirmation of a secondary large intestine carcinoma lesion 
other than a relapse after the date of enrollment. An intramucosal cancer lesion will 
not be treated as an event. 
(iii) 
Death from any cause 

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11.2 
Definition of Secondary Endpoints 
11.2.1 Rate of Conversion to Negative ctDNA 
This rate is defined as the proportion of subjects who became negative for ctDNA at 
the test immediately after completion of study treatment. Rate of conversion to negative 
ctDNA has been investigated as a substitute indicator for DFS that can be assessed in a 
short period of time, although the clinical significance of the rate is not clear. It has been 
determined that in the future, investigators of the European Society for Medical 
Oncology (ESMO), Japan, and the U.S. will conduct a meta-analysis on data of individual 
subjects collected from clinical studies on ctDNA for the purpose of detecting MRD. Thus, 
it is possible that this endpoint may be recommended as an indicator of efficacy in the 
target patients of this trial by the time the results of this trial are available. In addition, 
this trial is a study designed to extend the indications of FTD/TPI to this target 
population of this trial depending on the results obtained, and the appropriateness of 
this endpoint will also be discussed with the PMDA, etc. in the future. This endpoint is 
treated as the key secondary endpoint at present and may be reclassified to a primary 
endpoint (co-primary endpoint) when the rationale is established for inclusion in the 
primary analysis. 
11.2.2 Disease-free survival 2 (DFS2) 
1) 
Definition of DFS2 
The time from the date of enrollment to any of the following events, whichever occurs 
first: a relapse, development of a cancer lesion other than a relapse (secondary cancer), 
and death from any cause. For survives with no evidence of recurrence, DFS2 data will 
be censored at the last imaging date of confirmed no recurrence. Subjects for which no 
imaging have been performed, DFS2 data will be censored at the date of enrollment.  
In principle, events will be assessed by the investigator. 
2) 
Definition of an event 
(i) 
Relapse 
The same definition as in DFS1 will be used. 
(ii) 
Cancer lesion other than a relapse (secondary cancer) 
Date of confirmation of a cancer lesion other than a relapse (secondary cancer). 
Gastric cancer localized to mucosa, large intestine carcinoma and esophageal 
carcinoma, and cervix carcinoma with curative resection, and basal cell carcinoma 
or squamous cell carcinoma of the skin are not treated as events. 
(iii) 
Death from any cause 

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11.2.3 Overall Survival (OS) 
1) 
Definition of OS 
The time from the date of enrollment to the date of death from any cause. In surviving 
subjects, the last date of confirmation of survival (the confirmation may be performed by 
telephone, and the fact of confirmation shall be recorded in the medical records.) will be 
treated as the end of this period. In subjects lost to follow-up, the last date of 
confirmation of survival before loss to follow-up will be treated as the end of this period.   
11.2.4 Incidence of Adverse Events 
For each of the adverse events due to the following study treatment, the frequency of 
cases with the worst grade in all courses according to CTCAE v5.0 will be calculated 
using all treated patients as the denominator. 
11.2.5 Treatment Completion Rate 
This rate will be calculated for each eligible subject in accordance with the following 
equation: 
Treatment completion rate (%) = number of treatment courses completed/6 × 100 
11.2.6 QOL 
QOL will be assessed using EORTC QLQ C-30 and EQ-5D-5L. 

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12 
Statistical Matters 
An outline of the statistical analysis plan is described below. The details will be 
described in the separately prepared statistical analysis plan. 
12.1 
Subject Handling 
Subject handling will be determined in accordance with the subject handling criteria. 
The subject handling criteria will be prepared based on clinical conferences. 
12.2 
Definition of Analysis Populations 
Each analysis population is defined in “Table 12-1 Analysis Populations.” 
 
Table 12-1 Analysis Populations 
Abbreviation Analysis Population 
Definition 
All enrolled 
subjects 
(ITT) 
Intention to treat 
Analysis population based on the intention 
to treat principle. 
This population is defined as the population 
obtained 
by 
excluding 
duplicate 
and 
erroneous enrollments from the subjects 
enrolled in this trial. 
FAS 
Full Analysis Set 
  
Analysis population that is close to the 
intention to treat principle as completely as 
possible. This population is defined as the 
population obtained by excluding subjects 
who meet any of the following criteria: 
• 
No 
study 
treatment 
has 
been 
administered at all. 
• Subjects who have been shown to be 
ineligible after enrollment and are judged to 
have a significant impact on the evaluation 
of the primary endpoint. 
SP 
Safety Analysis 
Population 
  
Population consisting of enrolled subjects 
who have received study treatment at least 
once. 
 
12.3 
Efficacy Analysis 
12.3.1 Primary Endpoint 
This endpoint will be assessed in the FAS. DFS curves will be estimated using the 
Kaplan-Meier method for DFS1, and the annual DFS ratio and the confidence interval 
will be calculated. A stratified log-rank test will be performed for the null hypothesis 
that the DFS curves of the two groups are equal. 

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The stratification factors, the allocation factors and categories shown in the table 
below, used for the stratified analyses were selected based on the results of the blinded 
review. Details of the analysis method are specified in the Statistical Analysis Plan.  
 
The strata (allocation factors) 
Categories 
Disease stage classification 
(3 categories) 
Stage II or lower 
Stage III 
M1 
ctDNA status one month after curative 
resection 
(2 categories) 
positive  
negative / unmeasurable / unmeasured 
 
 
12.3.2 Secondary Endpoints 
The analysis of the secondary efficacy endpoints is defined as follows: 
(i) 
See “11.2.1 Rate of Conversion to Negative ctDNA” for the rate of conversion to 
negative ctDNA. 
(ii) 
The same analyses as performed for the primary endpoint will also be performed on 
DFS2 Regarding overall survival, an unstratified analysis will be performed 
without setting stratification factors *. 
(iii) 
For each adverse event, the frequency of cases with the worst grade in all courses 
according to CTCAE v5.0 will be calculated. 
(iv) 
Treatment completion rate will be calculated on the basis of the definition described 
in “11.2.5. Treatment Completion Rate.” 
(v) 
With respect to QOL, the mean of each group and each time point and the standard 
error will be described chronologically for the analysis variables. In addition, 
intergroup comparisons will be made using approaches based on analysis of variance, 
model analysis, etc. 
*  The two stratification factors for DFS2 were disease stage (3 categories: Stage II or 
less, Stage III, M1) and ctDNA one month after curative resection (2 categories: 
Positive, Negative/Unmeasurable/Not measured). The analysis was performed using 
only single factor of disease stage for the stratified analyses for the overall survival. 
These stratification factors were determined based on the results of a blinded review.  
 Additionally, details of the analysis method are specified in the Statistical Analysis 
Plan. 
 

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12.4 
Data Handling 
How to handle data (e.g., requirements for inclusion in or exclusion from an analysis 
population) will be determined by the coordinating investigators after discussion. 
12.4.1 Handling of Missing Values and Outliers 
Imputation of missing values and analysis of outliers will not be performed in principle. 
However, if the existence of missing values and outliers that may significantly affect the 
results of analyses was found before data finalization, measures therefor will be 
described in the statistical analysis plan. 
12.4.2 Handling of Additional Analyses 
Analyses performed after the statistical analysis plan has been finalized will be 
treated as additional analyses. The results of additional analyses will either be reported 
in such a manner that it is clear that the analyses have not been planned in advance or 
be reported in the report of the results of additional analyses, which is separately 
prepared. 
12.5 
Target Number of Subjects 
Enrollment will be continued until it is confirmed that 240 subjects have been enrolled 
as the FAS of “subjects tested positive for ctDNA.” 
12.5.1 Rationale 
See “2.10.4 Clinical Hypothesis and Rationale for Setting the Number of Subjects.” 
12.6 
Interim Analyses 
No interim analysis on efficacy will be performed in principle because if an interim 
analysis was to be conducted 1 year after the start of the trial, only 20% of the planned 
events (190 events) would have occurred, and it is expected to be difficult to perform an 
interim analysis using statistical methods such as consumption function and predicted 
probability while subjects are being enrolled. However, periodical central monitoring will 
be performed on the status of occurrence of adverse events related to safety, treatment 
compliance, and study implementation status, and the result will be reported to the Data 
and Safety Monitoring Committee of this trial. 

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13 
Ethical Matters 
13.1 
Policies, Laws and Regulations, and Norms to Be Complied With in 
the Trial 
This trial will be conducted in compliance with the protocol, the Declaration of 
Helsinki, ICH-GCP guidelines, Article 80-2 of the Act on Securing Quality, Efficacy and 
Safety of Products Including Pharmaceuticals and Medical Devices, “Ordinance on the 
Standards for the Conduct of Clinical Trials on Drugs” (the Ministry of Health and 
Welfare Ordinance No. 28, dated March 27, 1997), the ordinances for the revisions 
thereof, and related notifications. 
13.2 
Informed Consent 
13.2.1 Information for Subjects 
The investigator will deliver the written information approved by the Institutional 
Review Board to the subject himself/herself and explain the following orally and 
thoroughly to the subject. 
(i) 
The fact that the trial involves research 
(ii) 
The purpose of the trial 
(iii) 
Name and contact information of the principal investigator or sub investigator 
(iv) 
Study methodology (including experimental aspects of the study and the 
inclusion criteria for subjects) 
(v) 
Anticipated clinical benefits and risks or inconveniences 
(vi) 
Presence or absence of alternative treatment methods and their expected 
important benefits and risks 
(vii) Expected duration of the subject’s participation in the trial 
(viii) The fact that the subject’s participation in the trial is voluntary and that the 
subject may refuse to participate or withdraw from the trial, at any time, 
without penalty or loss of benefits to which the subject is otherwise entitled 
(ix) 
The fact that monitors, auditors, the Institutional Review Board, etc., and 
regulatory authorities have access to the source documents related to medical 
care, without violating the confidentiality of the subject. The fact that by 
affixing name and seal or signature to a written informed consent form, the 
subject is authorizing such access 
(x) 
The fact that if the results of the trial are published, the subject’s 
confidentiality will be protected  

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(xi) 
The consultation office of the medical institution to make inquiries to or 
contact for further information regarding the trial and the rights of trial 
subjects and in the event of trial-related health damage 
(xii) The compensation and treatment available to the subject in the event of trial-
related health damage 
(xiii) The planned number of subjects involved in the trial 
(xiv) The fact that the subject will be informed in a timely manner if information 
becomes available that may be relevant to the subject’s willingness to continue 
participation in the trial 
(xv) Conditions or reasons under which the subject’s participation in the trial may 
be terminated 
(xvi) The expenses, if any, to the subject 
(xvii) The payment, if any, to the subject 
(xviii) The subject’s responsibilities 
(xix) Types of the Institutional Review Board that investigates and reviews the 
appropriateness, etc. of the clinical trial, matters to be investigated and 
reviewed by each Institutional Review Board, and other matters related to the 
Institutional Review Board involved in the clinical trial 
(xx) The fact that the subject may read the procedures, etc. for the Institutional 
Review Board under the preceding paragraph and that if the subject wishes 
to read the procedures, etc. of the Institutional Review Board, the subject is 
encouraged to make a request. In addition, if the procedures, etc. of the 
Institutional Review Board are on the website, the address of the website; if 
they are not, the fact that they are available for general public perusal 
(xxi) The possibility of secondary use of data 
13.2.2 Consent 
The investigator will explain this trial to the patient, give the patient enough time to 
think about the trial, confirm that the patient understands the trial well, and then 
request the subject to participate. If the patient consented to participate, the investigator 
who gave the explanation, the trial collaborator who gave a supplementary explanation, 
and the subject who was given the explanation and consented will each enter the date of 
explanation and the date of consent into the written informed consent from approved by 
the Institutional Review Board and sign it. The investigator will store the signed 
informed consent form in the medical records and hand a copy of the signed informed 
consent form to the subject. 

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If information becomes available that may affect the subject’s willingness to continue 
participation in the trial, the investigator will promptly communicate the information to 
the subject participating in the trial, will ascertain the subject’s willingness to continue 
participation in the trial, and record the result in writing. In addition, if the principal 
investigator judges that the informed consent form and written information need to be 
revised, on the basis of the information or for other reasons, the principal investigator 
will promptly revise these documents and obtain approval of the revision from the 
Institutional Review Board. After approval of the Institutional Review Board, an 
explanation will be given again using the revised informed consent form and written 
information, and re-consent will be obtained in writing. 
13.3 
Protection of Personal Information and Subject Identification 
With an understanding that information concerning privacy such as personal 
information should be protected intensively and handled cautiously under the spirit of 
respect for individual personalities, every effort will be made to protect privacy by taking 
thoroughgoing control measures, and the Act on the Protection of Personal Information 
(Act No. 57 of May 30, 2003) and the revisions thereof will be followed. 
13.3.1 Purpose of Use of Personal Information and Items Used 
1) 
Information that can identify an individual 
Subject identification number, enrollment number 
2) 
Management of anonymization and correspondence table 
Any personal information that is provided outside the medical institution will be 
anonymized in advance. As the minimum information required to identify a subject, 
subject identification number and enrollment number will be used as the 
“information that can identify an individual.” The correspondence table showing the 
correspondence between information such as patient name and enrollment number 
(subject identification number) will be controlled appropriately under the 
responsibility of the principal investigator at each medical institution in accordance 
with the policy of the medical institution. In other words, information that can 
identify an individual by itself without a correspondence table, such as the name of 
a subject, will not be disclosed to the outside from the medical institution. 
3) 
Method for Collecting Personal Information 
The subject’s personal information will be collected by entry of the information into 
the CRFs by the investigator or a trial collaborator and by reporting it to the Data 
Center. 

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13.3.2 Secondary Use of Data 
Data obtained in this trial may be used for secondary uses (such as translational 
researches, dossiers supporting overseas registration application for drugs or in vitro 
diagnostic products, and meta-analyses) in a form containing no link to personal 
identifiers, only if such use has been approved by the coordinating investigators and the 
provider of the investigational drug. 
13.3.3 Safety Control Administration System 
When using personal information, various safety control measures will be taken in 
accordance with the rules of each medical institution in order to minimize the risk of 
information leaks. The Data Center will be managed appropriately in accordance with 
the guidelines for personal information handled by the National Cancer Center Japan. 
13.3.4 Handling of Requests to Disclose Subject Information, etc. 
If a subject requests disclosure of privacy-related information belonging to this trial, 
the investigator of the medical institution in charge of the subject will handle the matter 
in principle. 
13.4 
Approval of the Institutional Review Board (IRB) 
13.4.1 Approval at the Start of Trial 
Before conducting this trial, the principal investigator must submit the documents 
specified in the GCP ordinance, such as the protocol and the informed consent form and 
written information, to the head of the medical institution and must obtain approval by 
the IRB. After approval of the IRB, the principal investigator will promptly send a copy 
of the IRB approval document and the informed consent form and written information 
used specifically by the medical institution to the trial coordinating office and retain the 
original IRB approval document. 
Individual medical institutions will not be allowed to make changes to the protocol. A 
common protocol will be used in all medical institutions. If the IRB requests modification 
of the protocol text, the principal investigator will consult with coordinating 
investigators and consider how to handle the matter. 
13.4.2 IRB Approval of Appropriateness of Continuation of Trial 
The appropriateness of continuing the trial must be reviewed annually by the IRB. If 
the IRB approves the continuation of the trial, the original IRB approval document will 
be retained. 

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13.4.3 Changes to the Protocol 
Any revision of the protocol, the informed consent form and written information, etc. 
will be made in accordance with the written procedures for the creation of each document. 
13.4.4 Categories of Changes to the Protocol 
In this trial, changes to the protocol will be handled as follows: 
1) 
Revision 
Revision refers to changes to the protocol. It requires approval of the IRB. 
2) 
Notification letter 
A notification letter will be issued if it is judged that before a protocol revision, 
the details of the revision need to be promptly communicated to the study 
personnel. The coordinating investigators will determine whether the revision 
requires review by the IRB of each medical institution and inform the institutions 
of the result. 
3) 
Q&A 
The interpretation of wordings of the protocol will be communicated to the study 
personnel by issuing Q&A. 
13.4.5 Approval of the IRB at the Time of Protocol Revision 
If the protocol is revised during the trial, the revised documents must be approved by 
the IRB. 
13.5 
Management of Conflicts of Interest (COI) 
The COI of the persons involved in this trial, such as investigators and coordinating 
investigators, will be managed appropriately according to the regulations of the medical 
institution. In addition, conflicts of interest in the company are being managed by the 
work rules and compliance programs of the company. 
The provider of the investigational drug (Taiho Pharmaceutical Co., Ltd.) will have no 
involvement in the matters related to the fundamentals of the trial, such as the operation 
of the trial and the interpretation of the results. Any additional studies (such as 
biomarker study and observational study) will be conducted after a collaborative study 
agreement has been concluded. 
13.6 
Compensation 
In the event of health damage to subjects attributable to this trial, the medical 
institution will compensate for the damage in accordance with “Procedure for 
Compensation for Health Damage,” even if the medical institution is not legally liable. 

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In this trial, such compensation will consist of provision of medical care and payment 
of health care costs, medical allowance, and compensation. The principles of 
compensation will not interfere with the subject’s right to claim for damages. 
 

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14 
Monitoring and Auditing 
14.1 
Monitoring 
Monitoring will be performed in accordance with “Monitoring Procedure.” 
On-site monitoring will verify that the trial is being conducted appropriately and that 
the reliability of data is maintained adequately, by means such as direct access to the 
source documents. After an on-site monitoring visit, a monitoring report will be prepared 
and submitted to the coordinating investigators, the persons conducting the clinical trial 
independently, and the head of the medical institution. 
Central monitoring will be performed periodically on the status of occurrence of 
adverse events related to safety, treatment compliance, and study implementation 
status, and the results will be reported to the Data and Safety Monitoring Committee. 
14.2 
Protocol Deviations/Violations 
The investigator will record any deviation from the protocol regardless of the reasons. 
Any deviation from the protocol that was caused to eliminate immediate hazards to the 
subjects and for other medically necessary reasons will be reported by the principal 
investigator in writing to the head of the medical institution in accordance with the 
procedure of the medical institution. In addition, the principal investigator will submit 
a copy of the document reported to the head of the medical institution to a coordinating 
investigator. 
Deviations will be classified into one of the following categories after consideration by 
coordinating investigators: 
1) 
Major deviation 
A deviation from the stipulations of the protocol that is clinically inappropriate and 
that meets multiple items of the following criteria will be classified as a “major deviation.” 
(i) 
A deviation that affects the evaluation of the endpoints of the trial 
(ii) 
An intentional or systematic deviation 
(iii) 
A dangerous or considerable deviation 
2) 
Deviation 
Deviations excluding those listed in (i) above 
14.3 
Auditing 
Auditors will perform audits in accordance with “Auditing Procedure” and “Auditing 
Plan” and verify that the trial is being conducted appropriately and that the reliability 
of data is maintained adequately, by means such as direct access to the source documents. 

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14.4 
Direct Access 
The medical institution will assist in monitoring, audits, and investigations by the IRB 
and regulatory authorities and provide direct access to all trial-related records such as 
source documents as necessary. A request from the provider of the investigational drug 
for direct access will be handled in the same manner. 

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15 
Special Notes 
15.1 
Central Review of Images 
In this trial, central review of images before enrollment will be performed at an 
independent institution. The principal investigator will submit subject images for 
central review. “Procedure of the Diagnostic Imaging Committee” will be prepared and 
implemented to specify the details of central review and the central review laboratory. 
15.2 
Record Retention 
15.2.1 Persons Conducting the Clinical Trial Independently 
Records will be retained until the day 5 years after the date of marketing approval (if 
it has been learned that the records are not attached to the application for approval, the 
day 3 years after the date of notification of such fact or the day 3 years after the 
discontinuation or completion of the trial, whichever comes later). The details will be in 
accordance with “Procedure for Record Retention.” 
15.2.2 Medical Institutions 
The head of the medical institution and the founder of the IRB will retain the essential 
documents and records to be retained in accordance with the GCP ordinance until one of 
the following dates, whichever comes later. If longer retention period is required, the 
head of the medical institution and the founder of the IRB will discuss the retention 
period and the retention method with coordinating investigators. The head of the 
medical institution will appoint a record retention manager for the retention of records. 
(i) The date of marketing approval of the test drug (if it has been notified that the 
development was terminated or that the results of the trial are not attached to 
the application for approval, the day 3 years after the date of decision of 
termination of development or the date of notification of the fact that the results 
are not attached to the application) 
(ii) The day 3 years after the date of termination or completion of the trial 
15.3 
Completion of Trial 
When the trial is completed, the principal investigator will notify the head of the 
medical institution of the fact in writing and report a summary of the trial results in 
writing to the head of the medical institution. 
15.4 
Termination at Medical Institutions 
If the persons conducting the clinical trial independently consider that a medical 
institution hinders the proper conduct of the trial because of major or continued 

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noncompliance with the GCP ordinance or the protocol, the persons conducting the 
clinical trial independently may terminate the trial at the medical institution. In this 
case, the persons conducting the clinical trial independently will report to the head of 
the medical institution in writing that the trial at the medical institution will be canceled. 
In addition, the persons conducting the clinical trial independently will report to the 
regulatory authorities in writing that the trial has been terminated. The investigator 
will promptly inform the subjects of the fact and provide appropriate medical care and 
take other necessary measures. 
 
15.5 
Suspension of the Trial and Premature Termination of the Entire Trial 
15.5.1 Suspension of the Trial 
If the principal investigator or a coordinating investigator judges that subject safety 
is considered to be significantly compromised because the occurrence of adverse events 
exceeded the acceptable range during the progress of the trial or because of serious 
adverse drug reactions or new information about the investigational drug and that thus 
the trial must be suspended, the principal investigator will promptly notify the head of 
the medical institution of the fact and the detailed reasons for the suspension in writing. 
In addition, the coordinating investigator will notify the regulatory authorities in writing 
that the clinical trial has been suspended. 
15.5.2 Termination of the Entire Trial 
If the principal investigator or a coordinating investigator judges that subject safety 
is considered to be significantly compromised because of serious adverse drug reactions 
or new information about the investigational drug and that thus the trial must be 
prematurely terminated, the principal investigator will promptly notify the head of the 
medical institution of the fact and the reasons for the termination in writing. In addition, 
the principal investigator will notify the regulatory authorities in writing that the 
clinical trial has been prematurely terminated. The investigator will promptly inform 
the subjects of the fact and provide appropriate medical care and take other necessary 
measures. 
 

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16 
Study Organization 
This trial is a multicenter, investigator-initiated clinical trial, with coordinating 
investigators. 
16.1 
Organization for Conducting the Trial 
See Appendix 1. 
16.2 
Source of Funds for the Clinical Trial 
This trial will be conducted with the investigational drug (including placebo) pro
vided to joint research institute Alpha A Co., Ltd. at no charge by Taiho Pharmac
eutical Co., Ltd. and funds provided by the company on the basis of a contract. H
ealth care cost for a subject other than the cost of the investigational drug will be
 borne by the subject, and compensation for subject burden will not be paid. 

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17 
Ownership of Study Results and Publication of Study 
Results 
Information about this trial will be disclosed on jRCT (Japan Registry of Clinical Trials) 
(https://jrct.niph.go.jp/) and, ClinicalTrials.gov (database of clinical trials) provided by the 
U.S National Library of Medicine. 
The study results will belong to the National Cancer Center Japan. Publication of the 
study results in an academic meeting or as a paper will be determined by the 
coordinating investigators after discussion with the principal investigators, etc. at the 
time of publication.  

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18 
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Appendix 1: EORTC QLQ-C30 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix 2: EQ-5D-5L