Clinical trial NCT02500043
Conditions: Refractory Metastatic Gastric Cancer
Keywords: Gastric Cancer Metastatic Gastric Cancer
Sponsor: Taiho Oncology, Inc.
Start date: 2016-02-24; Completion date: 2019-12-19
Enrollment: 507 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this trial is to compare the effects of TAS-102 and best supportive care (BSC) with Placebo (an inactive drug) and best supportive care on metastatic gastric cancer.

Detailed description:
This is a multinational, double-blind, two-arm, parallel, randomized, Phase 3 study evaluating the efficacy and safety of TAS-102 plus BSC versus placebo plus BSC in participants with metastatic gastric cancer who have previously received at least 2 prior regimens for advanced disease. Eligible participants will be centrally randomized (2:1) to TAS-102 + BSC (experimental arm) or placebo + BSC (control arm).

Arms: arm 1: Participants received 35 milligrams per meter square (mg/m\^2) of TAS-102 tablets orally twice daily (BID) for 5 days per week (i.e., from Days 1 to 5 and Days 8 to 12) for 2 weeks followed by 14 days rest in each 28-day cycle along with BSC until a discontinuation criterion (participant withdrawal, disease progression, irreversible treatment-related Grade 4 non-hematologic event, physician's decision, pregnancy or death) was met. arm 2: Participants received 35 mg/m\^2 of matching placebo for TAS-102 tablets orally BID for 5 days per week (i.e., from Days 1 to 5 and Days 8 to 12) for 2 weeks followed by 14 days rest in each 28-day cycle along with BSC until discontinuation criterion (participant withdrawal, disease progression, irreversible treatment-related Grade 4 non-hematologic event, physician's decision, pregnancy or death) was met.
Interventions: intervention 1: TAS-102 intervention 2: Placebo
Intervention descriptions: intervention 1: 35 mg/m2/dose of TAS-102 orally, twice daily on days 1-5 and days 8-12 of each 28-day cycle. intervention 2: 35 mg/m2/dose of placebo orally, twice daily on days 1-5 and days 8-12 of each 28-day cycle.

Protocol documents:
Prot_000.pdf: 
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TAS-102 
Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
TO-TAS-102-302_Protocol_Amendment 2.0_05May2016 
Page 2 of 94 
The information contained in this document is the property of Taiho Oncology, Inc. (TOI) and Taiho 
Pharmaceutical Co., Ltd. (TPC).  This document contains strictly confidential information and no part of 
this document may be published or disclosed, except as necessary to obtain consent from persons who are 
considering participation in the study, without the prior written approval of TOI or TPC. 


TAS-102 
Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
TO-TAS-102-302_Protocol_Amendment 2.0_05May2016 
Page 3 of 94 
2. 
SYNOPSIS 
Name of Sponsor/Company:  
Taiho Oncology, Inc.; Taiho Pharmaceutical Co., Ltd. 
Name of Investigational Product:  
TAS-102 
Name of Active Ingredients:  
trifluridine (FTD) and tipiracil hydrochloride (TPI) 
Title of Study:   
RANDOMIZED, DOUBLE-BLIND, PHASE 3 STUDY EVALUATING TAS-102 PLUS BEST 
SUPPORTIVE CARE (BSC) VERSUS PLACEBO PLUS BSC IN PATIENTS WITH METASTATIC 
GASTRIC CANCER REFRACTORY TO STANDARD TREATMENTS 
Protocol Number:  
TO-TAS-102-302 
Phase of Development: 
3 
Indication: 
Refractory metastatic gastric cancer 
Background/Rationale: 
 
TAS-102 is an oral combination of 1M trifluridine (FTD) and 0.5M tipiracil 
hydrochloride (TPI). 
 
The primary mechanism of action of FTD, an antineoplastic thymidine-based 
nucleoside analog, is incorporation into DNA via phosphorylation, resulting in a 
different cytotoxic mechanism from 5-fluorouracil (5-FU) and 2’-deoxy-5-
fluorouridine (FdUrd) (uracil-based thymidylate synthase inhibitors).   
 
FTD, when orally administered, is rapidly degraded to an inactive form by 
thymidine phosphorylase (TP).  Co-administration of an inhibitor of TP (TPI) 
with FTD prevents the rapid degradation of FTD, resulting in a significant 
increase in systemic exposure to FTD. 
 
In a previous Phase 3 global trial (RECOURSE; TPU-TAS-102-301), TAS-102 
was shown to significantly improve overall survival (OS) in patients with 
metastatic colorectal cancer (mCRC) who have been previously treated with, or 
are not candidates for fluoropyrimidine-, oxaliplatin- and irinotecan-based 
chemotherapy, an anti-vascular endothelial growth factor (VEGF) biological 
therapy, and an anti-epidermal growth factor receptor (EGFR) therapy (Mayer 
et al, 2015). 
 
In a Phase 2 study conducted in Japan (EPOC1201), the efficacy and safety of 
TAS-102 was evaluated in patients with metastatic gastric cancer who had 
failed standard chemotherapies including fluoropyrimidines, platinum and any 
of the taxanes or irinotecan.  The results demonstrated that TAS-102 was well 
tolerated; and TAS-102 treatment (35 mg/m2 twice daily [BID]) led to an OS of 
8.7 months with a disease control rate (DCR) of 65.5% (Muro et al, 2013).   
 
This Phase 3 study will compare the efficacy, including OS, and safety of TAS-
102 combined with best supportive care (BSC) to placebo plus BSC in patients 
with metastatic gastric cancer who have previously received at least 2 prior 
regimens for advanced disease and were refractory to or unable to tolerate their 
last prior therapy.   


TAS-102 
Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
TO-TAS-102-302_Protocol_Amendment 2.0_05May2016 
Page 4 of 94 
Study Objective/ 
Endpoints: 
To evaluate the following endpoints in patients with refractory metastatic gastric 
cancer receiving TAS-102 plus BSC (experimental arm) or placebo plus BSC 
(control arm): 
Primary 
 
Overall survival (OS) 
Key Secondary 
 
Progression-free survival (PFS) based on Investigator assessment of 
radiologic images 
 
Safety and tolerability 
Other Secondary 
 
Overall response rate (ORR) 
 
Disease control rate (DCR) 
 
Time to deterioration of Eastern Cooperative Oncology Group (ECOG) 
performance status to score of 2 or higher 
 
Quality of life (QoL) (EORTC QLQ-C30 and QLQ-STO22) 
Study Design: 
This is a multinational, double-blind, two-arm, parallel, randomized, Phase 3 study 
evaluating the efficacy and safety of TAS-102 plus BSC versus placebo plus BSC in 
patients with metastatic gastric cancer who have previously received at least 2 prior 
regimens for advanced disease.  Eligible patients will be centrally randomized (2:1) 
to TAS-102 + BSC (experimental arm) or placebo + BSC (control arm) and 
stratified by:   
 
Region (rest of world [ROW] vs. Japan) 
 
ECOG performance status (0 vs. 1) 
 
Prior treatment with ramucirumab (yes vs. no) 
No. of Patients Planned: 
Approximately 500 patients will be randomized using a treatment allocation of 2:1 
(TAS-102 plus BSC: placebo plus BSC).  A target of 384 events (deaths) will be 
required for the primary analysis. 
Diagnosis/Main Criteria 
for Inclusion: 
Male and female patients age 18 years or older (20 years or older for patients 
enrolled in Japan) with histologically confirmed, non-resectable, metastatic gastric 
adenocarcinoma including adenocarcinoma of the gastroesophageal (GE) junction, 
and an ECOG performance status of 0 or 1, who have received at least 2 prior 
regimens (at least 1 cycle per regimen) for advanced disease, and were refractory to 
or unable to tolerate their last prior therapy.   
 
Prior regimen(s) must have included a fluoropyrimidine, platinum, and 
either a taxane- and/or irinotecan-containing regimen; patients whose 
tumors are known to be HER2-neu-positive (HER2+) must have received 
prior anti-HER2+ therapy if available. 
 
Patients have progressed based on imaging during or within 3 months of the 
last administration of their last prior regimen.   
 
Patients who have withdrawn from their last prior regimen due to 
unacceptable toxicity warranting discontinuation of treatment and 
precluding retreatment with the same agent prior to progression of disease 
will also be eligible to enter the study. 
 
Patients who have received postoperative adjuvant chemotherapy or 
chemo-radiotherapy, and had recurrence during or within 6 months of 
completion of the adjuvant chemotherapy are allowed to count the adjuvant 
therapy as one prior regimen for advanced disease.  Patients who have 
received pre- and post-operative adjuvant chemotherapy, and had 
recurrence during or within 6 months of completion of the adjuvant 
chemotherapy are allowed to count the adjuvant therapy as one prior 


TAS-102 
Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
TO-TAS-102-302_Protocol_Amendment 2.0_05May2016 
Page 5 of 94 
regimen only if the same regimen was administered both pre- and post-
operatively.   
Treatment Regimens: 
TAS-102 (starting dose of 35 mg/m2/dose) or placebo will be administered orally 
BID, within 1 hour after completion of morning and evening meals, for 5 days a 
week with 2 days rest for 2 weeks, followed by a 14-day rest, repeated every 
4 weeks.   
Patients will receive blinded study medication until a discontinuation criterion is met 
or until completion of the primary endpoint analysis, whichever is sooner.   
Study Duration: 
After the end of treatment, all patients will be followed for survival every 4 weeks 
until death or until the target number of events (deaths) is met.   
If the primary endpoint of the study is met and efficacy as well as safety support a 
favorable benefit/risk ratio for TAS-102, patients currently or previously treated 
with placebo who continue to meet study eligibility criteria will be offered the 
option to crossover to open-label TAS-102.  Patients receiving TAS-102 will also be 
switched to open-label TAS-102 at that time.  Patients who receive open-label 
TAS-102 treatment after conclusion of survival follow-up will be followed for 
safety and tumor response according to the site standard of care. 
Efficacy Criteria for 
Evaluation: 
Computed tomography (CT) scans will be performed every 8 weeks.  On-site tumor 
assessments will be performed by the Investigator/local radiologist.   
Tumor assessments will be analyzed using Response Evaluation Criteria in Solid 
Tumors (RECIST) criteria (Version 1.1, 2009).  Progression-free survival will be 
determined for all patients.  
Quality of Life assessments will be performed prior to start of dose administration in 
each cycle. 
Safety Criteria for 
Evaluation: 
Standard safety monitoring will be performed and adverse events (AEs) will be 
graded using the National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) Version 4.03. 
Statistical Methods: 
Study Populations 
The study populations for all analyses are defined as follows. 
 
Intent-to-Treat (ITT) population:  This population includes all randomized 
patients and is the primary population for all efficacy parameters.  All 
analyses using this population will be based on the treatment assigned by 
Interactive Voice/Web Response System (IXRS). 
 
As-Treated (AT) population: This population includes all patients who took 
part of any dose of study treatment. This population is for safety analyses. 
All analyses using this population will be based on the treatment actually 
received. 
 
Tumor Response (TR) Population:  All patients in the ITT population with 
measurable disease (at least one target lesion) at baseline and with at least 
one tumor evaluation while on treatment.  (Patients who have disease 
progression or a cancer-related death prior to their first on treatment tumor 
evaluation will also be considered evaluable.)  All analyses using this 
population will be based on the treatment assigned by IXRS. 
Primary Efficacy Endpoint (OS) 
OS is defined as the time from the date of randomization to the date of death.  If 
death is not observed during the study, the time will be censored at the last date 
patient is known to be alive or the cut-off date, whichever is earlier.  For the primary 
analysis of OS, the two treatment arms will be compared using the stratified log-
rank test using the 3 stratification factors in the randomization as per IXRS 
assignment.  The hazard ratio (HR) will be estimated, along with the associated 2-


TAS-102 
Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
TO-TAS-102-302_Protocol_Amendment 2.0_05May2016 
Page 6 of 94 
sided 95% confidence intervals (CI), using a stratified Cox’s proportional hazard 
(CPH) model.  Survival for each arm will be summarized using Kaplan Meier 
curves and further characterized in terms of the median and survival probability at 3, 
6, 9 and 12 months, along with the corresponding 2-sided 95% CI for the estimates. 
Statistical Methods 
(continued): 
Key Secondary Efficacy Endpoint (PFS) 
PFS will be evaluated from date of randomization to the first occurrence of 
radiologic progression or death.  Treatment comparisons for PFS will use similar 
analytical methods as the OS endpoint.   
Other Secondary Efficacy Endpoints 
ORR and DCR will be compared between treatment arms using Fisher’s exact test 
and associated 95% CIs will also be derived.  Time to deterioration of ECOG 
performance status to a score of 2 or higher will be analyzed as described for PFS.  
Change in QoL scores prior to cycles 2, 3 and 4 will be determined for the summary, 
all domains and single items by subtracting each patient’s score from their 
corresponding baseline score. For each domain, the proportion of patients with 
deteriorating, stable or improving scores prior to cycles 2, 3 and 4 will be compared 
using Fisher’s exact test. Time to QoL deterioration will be evaluated for each arm 
using Kaplan-Meier estimates and compared using the log-rank test.  
Safety Analyses 
Simple descriptive statistics will be provided for safety endpoints and 
demographic/baseline characteristics. 
Sample Size 
Justification: 
The study is designed to detect with 90% power a HR for death of 0.70 (30% risk 
reduction) in the TAS-102 arm compared with the placebo arm with an overall 
1-sided type 1 error of 0.025.  A variable accrual period of 18 months and a 5%/year 
loss to survival follow-up rate has been assumed.  Using a treatment allocation of 
2:1 (TAS-102:placebo) of 500 patients, 384 deaths will be targeted for the final OS 
analysis. 
Interim Analyses:   
One interim analysis for efficacy and futility is planned to be performed after 
approximately one-half of the total target events are observed.  
Independent Data 
Monitoring Committee: 
An independent Data Monitoring Committee (DMC) will periodically assess the 
cumulative safety data and results of the interim analysis and recommend study 
continuation, discontinuation, or study modification.  A description of the roles and 
responsibilities of the DMC and details of the review processes and monitoring 
guidelines are provided in a separate DMC charter. 
 


TAS-102 
Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
TO-TAS-102-302_Protocol_Amendment 2.0_05May2016 
Page 7 of 94 
3. 
STUDY SCHEDULES 
Figure 1: 
Study Design Schema 
 
 


TAS-102 
Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
TO-TAS-102-302_Protocol_Amendment 2.0_05May2016 
Page 8 of 94 
Table 1: 
Study Schedule 
 
Baseline Period 
On-Treatment Period 
End of Treatment/ 
End of Study Period 
Visit ID / Procedure 
 
CYCLE 1 
SUBSEQUENT CYCLES
End of 
Treat-
ment16 
30-Day 
Safety 
Follow-
up Visit 
Survival 
Follow-
up 
Baseline Day 
Day of Cycle14
Day of Cycle14
-28 to -1 
-7 to -1 
1 
12 
15 
End of 
Recovery 
1 
12 
15 
End of 
Recovery 
Sign ICF 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
Enrollment 
X2 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X3 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Histological Confirmation 
X 
 
 
 
 
 
 
 
 
 
 
 
 
HER2 status (if available) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination4 
 
X 
 
 
 
 
X15 
 
 
 
X
X 
 
Baseline Signs & Symptoms 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs5 & Weight 
 
X 
 
 
 
 
X15 
 
 
 
X 
X 
 
ECOG Performance Status 
X 
 
X6 
 
 
 
X15 
 
 
 
X 
X 
 
Hematology7 
 
X 
 
X 
 
X15 
 
 
X 
X 
 
Serum Chemistry7 
 
X 
 
X 
 
X15 
 
 
X 
X 
 
Urinalysis7 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test8 
 
X
 
 
 
 
 
 
 
 
X 
X 
 
Tumor Measurements9 
X 
 
 
 
 
 
 
 
 
X9 
X9
 
X9 
Quality of Life Assessment18 
 
X18
 
 
 
 
X18 
 
 
 
X18
 
Concomitant Medications10 
X 
 
 
 
 
 
 
 
 
 
 
10
X11
AE/SAE Assessment12 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
TAS-102 or Placebo 
Treatment13 
 
 
X 
(D 1-5) 
X 
(D 8-12) 
 
 
X 
(D 1-5) 
X 
(D 8-12) 
 
 
 
 
 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
 
X17 
1 
Sign ICF: Written informed consent should be obtained prior to the performance of any study procedure. 
2 
Enrollment: Enroll patient by entering baseline data into the electronic case report form (eCRF) in order to receive a unique 6-digit patient number.   
3 
Randomization:  Central randomization via IXRS following confirmation of baseline eligibility criteria.  The maximum screening period is 28 days; eligible 
patients must be randomized by Day 29 of screening.  The patients should receive the first dose of study medication within 3 calendar days of randomization.   
4  Physical Exam:  Beginning with Cycle 2, and for all subsequent cycles, perform within 24 hours prior to Day 1 study drug administration.   
5 
Vital Signs: Heart rate, blood pressure, body temperature, respiratory rate; beginning with Cycle 2, and for all subsequent cycles; collect within 24 hours 
prior to Day 1 study drug administration.   
6 
ECOG Performance Status:  Collect at time of randomization (within 3 calendar days prior to start of study treatment on Day 1 of Cycle 1) and within 
24 hours prior to start of study treatment in every cycle thereafter. 
(Footnotes continue on next page) 


TAS-102 
Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
TO-TAS-102-302_Protocol_Amendment 2.0_05May2016 
Page 9 of 94 
7 
Hematology, Serum Chemistry, Urinalysis:  Hematology and serum chemistry assessments will be performed at Baseline (within 7 days prior to Day 1 of 
Cycle 1; on Day 15 of Cycle 1; and within 24 hours prior to Day 1 study drug administration of Cycles ≥2.  Urinalysis is required at Baseline and thereafter 
as clinically indicated.  Laboratory results obtained prior to signing ICF may be used if the results were obtained within 7 days prior to Day 1 of Cycle 1. 
8 
Pregnancy Test:  Pregnancy test is required at Baseline (within 7 days prior to Day 1 of Cycle 1) and at End of Treatment and 30-day Safety Follow-up visit.  
More frequent pregnancy assessments may be performed as required by local law.   
9 
Tumor Measurements:  Obtain a contrast-enhanced computed tomography (CT) scan of the chest and abdomen (and pelvis, if clinically indicated) within 
28 days prior to Day 1 of Cycle 1 and every 8 weeks thereafter during study treatment.  If a patient discontinues treatment due to radiologic disease 
progression, additional tumor assessment is not required at the End of Treatment visit.  For patients who discontinue treatment for reasons other than 
radiologic disease progression, every effort should be made to perform an end of treatment tumor assessment prior to the start of new anticancer therapy.  
Patients that discontinued treatment for reasons other than disease progression should continue to be followed for tumor response every 8 weeks until the 
patient develops radiologic disease progression (or death) or initiation of new anticancer therapy (whichever occurs first).  Tumor assessments should be 
performed according to RECIST criteria (v. 1.1, 2009).  CT scans obtained prior to signing ICF may be used if the date of the scan is within 28 days prior to 
Day 1 of Cycle 1. 
10 Concomitant Medications:  Collect from time of signed Informed Consent Form (ICF) through the end of therapy, including any medications used to treat 
AEs or SAEs; at the 30-day safety follow-up period, collect date of initiation of any new anticancer therapy. 
11 Concomitant Medications:  Collect anticancer therapies only during survival follow-up. 
12 AE/SAE Assessment:  Monitor patients for any untoward medical events from the first dose of study drug through the 30-day safety follow-up period or 
until initiation of new anticancer treatment, whichever comes first.  Adverse events reported from time of signed ICF to first dose of study drug should be 
recorded as Medical History. 
13 Study Drug Treatment:  TAS-102 or placebo will be administered twice daily (BID) on Days 1 through 5 and 8 through 12 of each cycle. 
14 Assessment Windows:  A window of +/-3 days is allowable for study procedures (+/-7 days allowable for CT scans), as long as the proper order is 
maintained. 
15 Subsequent Cycles ≥2:  Obtain within 24 hours prior to Day 1 study drug administration.  Prior to starting subsequent cycles, verify that patients with 
toxicities have met resumption criteria prior to administering study drug. 
16 End of Treatment:  Assessments will be performed at time of withdrawal of study medication (TAS-102 or Placebo).  If the decision to discontinue study 
medication is made within 2 weeks after the patient’s last treatment visit, an End of Treatment Visit is not required unless deemed clinically necessary by 
the Investigator.  If the decision to discontinue study medication (due to proven radiologic disease progression or other reasons) is made more than 2 weeks 
after the last treatment visit, an End of Treatment Visit is required.  If this visit occurs within 2 weeks of the 30-day Safety Follow-up Visit, the 2 visits can 
be combined. 
17 Survival Status:  Obtain survival status (alive/dead) at scheduled 4-week time intervals until death.  Survival status should be collected until the target 
number of events (deaths) is met.  
18 Quality of Life:  Patients should complete the EORTC – QLQ-C30 and QLQ-STO22 questionnaires within 7 days prior to randomization, prior to dose 
administration on Day 1 of Cycles ≥2, and at the 30-day safety follow-up if not performed within the prior 4 weeks.   
  


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TAS-102 
Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
TO-TAS-102-302_Protocol_Amendment 2.0_05May2016 
Page 11 of 94 
8.7. 
Patients Continuing Treatment after Completion of Final Analysis ..........................32 
8.8. 
Other Medications and Therapies ...............................................................................32 
8.8.1. 
Prohibited Medications and Therapies .......................................................................32 
8.8.2. 
Concomitant Medications and Therapies ...................................................................32 
8.8.3. 
Effective Contraception During Study .......................................................................33 
8.9. 
Dietary Restrictions ....................................................................................................34 
9. 
STUDY TREATMENT ..............................................................................................35 
9.1. 
Description and Labeling ............................................................................................35 
9.1.1. 
TAS-102 .....................................................................................................................35 
9.1.2. 
TAS-102 Placebo ........................................................................................................36 
9.1.3. 
Packaging and Storage ................................................................................................36 
9.2. 
Study Medication Administration ...............................................................................36 
9.2.1. 
Treatment Regimen ....................................................................................................36 
9.2.2. 
Number of Tablets per Dose .......................................................................................37 
9.2.3. 
Instruction to Patients for Handling Study Medication ..............................................37 
9.2.4. 
Dose Modifications .....................................................................................................38 
9.2.4.1. 
Dose Reduction Levels ...............................................................................................38 
9.2.4.2. 
Dose Modification in Response to Non-hematologic Toxicities ................................40 
9.2.4.3. 
Dose Modification in Response to Hematologic Toxicities .......................................40 
9.2.4.4. 
Dose Resumption ........................................................................................................41 
9.3. 
Open-label TAS-102 ...................................................................................................42 
9.4. 
Treatment Compliance ................................................................................................42 
9.5. 
Study Drug Accountability .........................................................................................42 
10. 
STUDY ASSESSMENTS ..........................................................................................43 
10.1. 
All Study Procedures ..................................................................................................43 
10.1.1. 
Informed Consent .......................................................................................................43 
10.1.2. 
Randomization/Start of Treatment .............................................................................43 
10.1.3. 
Medical History ..........................................................................................................43 
10.1.4. 
Histologic Confirmation .............................................................................................43 
10.1.5. 
Human Epidermal Growth Factor Receptor 2 (HER2) Status ....................................43 
10.1.6. 
Physical Examination .................................................................................................43 
10.1.7. 
Baseline Signs and Symptoms ....................................................................................44 
10.1.8. 
Height, Vital Signs, Weight ........................................................................................44 


TAS-102 
Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
TO-TAS-102-302_Protocol_Amendment 2.0_05May2016 
Page 12 of 94 
10.1.9. 
Performance Status (ECOG) .......................................................................................44 
10.1.10. 
Clinical Laboratory Evaluations .................................................................................44 
10.1.10.1.  Hematology .................................................................................................................44 
10.1.10.2.  Serum Chemistry ........................................................................................................45 
10.1.10.3.  Urinalysis ....................................................................................................................45 
10.1.11. 
Pregnancy Testing ......................................................................................................46 
10.1.12. 
Quality of Life ............................................................................................................46 
10.1.13. 
Tumor Measurements .................................................................................................46 
10.1.14. 
Concomitant Medications and Therapies ...................................................................47 
10.1.15. 
Adverse Event Assessment .........................................................................................47 
10.2. 
Assessments by Visit ..................................................................................................47 
10.2.1. 
Baseline Procedures Prior to Randomization .............................................................47 
10.2.1.1. 
Day -28 through Day -1 ..............................................................................................47 
10.2.1.2. 
Day -7 through Day -1 ................................................................................................48 
10.2.2. 
Cycle 1 Day 1 .............................................................................................................48 
10.2.3. 
Cycle 1 Day 15 ...........................................................................................................48 
10.2.4. 
Subsequent Cycles - Cycle X Day 1 ...........................................................................49 
10.2.5. 
Every 8 Weeks from Start of Treatment .....................................................................49 
10.2.6. 
End of Treatment Visit ...............................................................................................49 
10.2.7. 
30-Day Safety Follow-up Visit ...................................................................................50 
10.2.8. 
Survival Follow-up after 30-Day Safety Visit ............................................................50 
11. 
EFFICACY ASSESSMENT CRITERIA ...................................................................51 
11.1. 
Method of Imaging .....................................................................................................51 
11.2. 
Tumor Definitions ......................................................................................................51 
11.3. 
Response Criteria ........................................................................................................53 
11.3.1. 
Target and Non-target Response Assessments ...........................................................53 
11.3.1.1. 
Criteria for Assessment of Tumor Response ..............................................................53 
11.3.1.2. 
Additional Criteria to Consider When Assessing Tumor Response ...........................54 
11.3.2. 
Overall Response Assessment ....................................................................................55 
11.4. 
Best Overall Response Assessment ............................................................................55 
12. 
REPORTING SAFETY INFORMATION .................................................................56 
12.1. 
Adverse Events/Serious Adverse Events ....................................................................56 
12.1.1. 
Adverse Events ...........................................................................................................56 


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TAS-102 
Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
TO-TAS-102-302_Protocol_Amendment 2.0_05May2016 
Page 15 of 94 
LIST OF TABLES 
Table 1: 
Study Schedule .............................................................................................................8 
Table 2: 
Number of Tablets per Dose .......................................................................................37 
Table 3: 
TAS-102 Dose Reduction Levels and Number of Tables per Dose ...........................39 
Table 4: 
TAS-102 Dose Modification Criteria for Non-hematologic Toxicities .....................40 
Table 5: 
TAS-102 Dose Hold Criteria for Hematologic Toxicities Related to 
Myelosuppression .......................................................................................................40 
Table 6: 
TAS-102 Resumption Criteria for Hematologic Toxicities Related to 
Myelosuppression .......................................................................................................41 
Table 7: 
Time Point Response for Patients with Target (± Non-target) Disease ......................55 
Table 8: 
Time Point Response for Patients with Only Non-target Disease ..............................55 
 


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TAS-102 
Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
TO-TAS-102-302_Protocol_Amendment 2.0_05May2016 
Page 17 of 94 
5. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
5-FU 
5-fluorouracil 
AE 
Adverse event 
AIDS 
Acquired immunodeficiency syndrome 
AJCC 
American Joint Committee on Cancer 
ALT 
Alanine aminotransferase (SGPT) 
ANC 
Absolute neutrophil count 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate aminotransferase (SGOT) 
AT 
As treated (population) 
β-HCG 
Beta-human chorionic gonadotrophin 
BID 
Twice daily 
BSA 
Body surface area 
BSC 
Best supportive care 
BUN 
Blood urea nitrogen 
C 
Degrees Celsius 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
cm 
Centimeter 
CPH 
Cox proportional hazards 
CR 
Complete response 
CRA 
Clinical Research Associate 
CRC 
Colorectal cancer  
CRF 
Case report form 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCR 
Disease control rate 
dL 
Deciliter 
DMC 
Data Monitoring Committee 
DNA 
Deoxyribonucleic acid 


TAS-102 
Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
TO-TAS-102-302_Protocol_Amendment 2.0_05May2016 
Page 18 of 94 
Abbreviation 
Definition 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EGFR 
Epidermal growth factor receptor 
EORTC 
European Organization for Research and Treatment of Cancer
EORTC QLQ-C30 
EORTC Quality of Life Questionnaire - Core Questionnaire 
EORTC QLQ-STO22 
EORTC Quality of Life Questionnaire - Gastric-specific 
module 
EU 
European Union 
F 
Degrees Fahrenheit 
FDG-PET 
Fluorodeoxyglucose positron emission tomography 
FdUrd 
2’-deoxy-5-fluorouridine 
FTD 
Trifluridine.  ,,-trifluorothymidine 
g 
Gram 
G-CSF 
Granulocyte colony-stimulating factor 
GCP 
Good Clinical Practice 
GE 
Gastroesophageal 
HER2 
Human epidermal growth factor receptor 2 
HER2+ 
HER2-neu-positive 
HIV 
Human immunodeficiency virus 
HR 
Hazard ratio 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat (population) 
IU 
International Units 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone-releasing system  
IXRS 
Interactive Voice/Web Response System 
Kg 
Kilogram 


TAS-102 
Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
TO-TAS-102-302_Protocol_Amendment 2.0_05May2016 
Page 19 of 94 
Abbreviation 
Definition 
KRAS 
GTPase KRas; V-Ki-ras2 Kirsten rat sarcoma viral oncogene 
homolog 
L 
Liter 
m2 
Meters squared 
mCRC 
Metastatic colorectal cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mm 
Millimeter 
MRI 
Magnetic resonance imaging 
NCI 
National Cancer Institute 
NYHA 
New York Heart Association 
ORR 
Overall response rate 
OS 
Overall survival 
PD 
Progressive disease 
PFS 
Progression free survival 
PR 
Partial response 
PS 
Performance status 
PT 
Preferred term (MedDRA) 
QoL 
Quality of Life 
RBC 
Red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RECOURSE 
Refractory Colorectal Cancer Study 
(TPU-TAS-102-301 Phase 3 study; NCT01607957) 
ROW 
Rest of world 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAR 
Serious Adverse Reaction 
SD 
Stable disease 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
SI 
International System (of Units) 
SOC 
System Organ Class (MedDRA) 
SOP 
Standard Operating Procedure 


TAS-102 
Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
TO-TAS-102-302_Protocol_Amendment 2.0_05May2016 
Page 20 of 94 
Abbreviation 
Definition 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TOI 
Taiho Oncology, Inc. 
TP 
TPase; Thymidine phosphorylase 
TPC 
Taiho Pharmaceutical Co., Ltd. 
TPI 
Tipiracil hydrochloride.  5-chloro-6-[(2-iminopyrrolidin-1-
yl)methyl]pyrimidine-2,4-(1H,3H)-dione monohydrochloride 
TR 
Tumor response (evaluable population) 
TS 
Thymidylate synthase 
ULN 
Upper limit of normal 
USA 
United States of America 
VEGF 
Vascular endothelial growth factor 
VEGFR-2 
Vascular endothelial growth factor-2 
WBC 
White blood cell 
WHODD 
World Health Organization Drug Dictionary 


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TAS-102 
Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
TO-TAS-102-302_Protocol_Amendment 2.0_05May2016 
Page 23 of 94 
antibody, has been shown to increase OS when administered alone5 or in combination with 
paclitaxel6 in patients who have progressed following first-line therapy; and was recently 
approved in select countries for second-line therapy of gastric cancer.  However, after failure of 
first- and second-line therapies, there are no approved or standard 3rd line treatments.   
6.2.2. 
Rationale for Study Design 
This present study is designed as a randomized, double-blind, Phase 3 study comparing TAS-102 
plus best supportive care (BSC) to placebo plus BSC in patients with metastatic gastric cancer 
who have received at least 2 prior regimens for advanced disease and were refractory or unable 
to tolerate their last prior therapy.   
A placebo-controlled design was considered appropriate as there are currently no standard 
therapies for patients with metastatic gastric cancer who have failed first- and second-line 
therapies. 
Approximately 500 patients will be randomized 2:1 to TAS-102 plus BSC or placebo plus BSC.  
In order to ensure comparability of groups, patients will be stratified by geographic region (rest 
of world [ROW] vs Japan); Eastern Cooperative Oncology Group (ECOG) performance status 
(0 vs 1); and prior ramucirumab treatment (yes vs. no).  
Overall survival was chosen as the primary endpoint because it is the gold standard endpoint for 
cancer indications in which there are no other therapy options with demonstrated survival 
benefit.  Measurement of this endpoint is not questionable and patients with either measurable or 
non-measurable disease can be evaluated without the possibility of discrepancies in 
interpretations.  
Standard safety assessments, including assessment of the type, incidence, severity (graded by 
National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE], 
Version 4.03), timing, seriousness, and relatedness of AEs and laboratory assessments will be 
used. 
6.2.3. 
Selection of TAS-102 Dose  
TAS-102 (35 mg/m2/dose) will be administered orally BID, within 1 hour after completion of 
morning and evening meals, for 5 days a week with 2 days rest for 2 weeks, followed by a 
14-day rest.  This treatment cycle will be repeated every 4 weeks.   
The safety and tolerability of this TAS-102 regimen was demonstrated in a Phase 3, 
multinational, randomized, double-blind study (RECOURSE; TPU-TAS-102-301), in which 
TAS-102 was shown to significantly improve OS compared to placebo in patients with 
metastatic colorectal cancer (mCRC), who had been previously treated with, or were not 
candidates for fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-
vascular endothelial growth factor (VEGF) biological therapy, and an anti-epidermal growth 
factor receptor (EGFR) therapy.7   
In addition, a statistically significant 34% risk reduction in worsening ECOG performance status 
(time to ECOG performance status ≥2) was observed for TAS-102 compared to placebo, 
suggesting that quality of life was maintained while on TAS-102 treatment. 
 


TAS-102 
Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
TO-TAS-102-302_Protocol_Amendment 2.0_05May2016 
Page 24 of 94 
In the RECOURSE study, the most common AEs associated with TAS-102 treatment were 
myelosuppressive and gastrointestinal toxicities.  Up to 20% of patients receiving TAS-102 
experienced Grade 3 or 4 hematologic events related to anemia and neutropenia/leukopenia; 
however, the incidence of febrile neutropenia was low (3.8%).  These events were generally 
manageable with reductions in dose, delays in cycle initiation and occasional use of granulocyte 
colony-stimulating factor (G-CSF).  Only 3 patients discontinued treatment due to hematologic 
AEs, and there was only one treatment-related death due to neutropenia-related infection.  Events 
of nausea, decreased appetite, diarrhea and vomiting related to treatment were common in the 
TAS-102 group (20.1% to 39.4%); however, these AEs were rarely Grade 3 or 4.  The incidence 
of stomatitis among patients receiving TAS-102 was 7.9%; Grade 3/4 events of stomatitis were 
rare (0.4%).  In addition, hand-foot syndrome was reported in only 2.3% of patients receiving 
TAS-102 (all Grade 1 or 2), which was the same percentage reported in the placebo arm.   
In a Phase 2 study conducted in Japan,1 this TAS-102 regimen was also well-tolerated in patients 
(N=29) with metastatic gastric cancer who had failed prior therapies.  Common Grade 3 or 4 
AEs included neutropenia, leukopenia, anemia, and anorexia.  Only one case of febrile 
neutropenia was observed, and there were no treatment-related deaths as described in 
Section 6.1.2.2 above.   


TAS-102 
Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
TO-TAS-102-302_Protocol_Amendment 2.0_05May2016 
Page 25 of 94 
7. 
STUDY OBJECTIVES 
The objectives of this study are to evaluate the following endpoints in patients with refractory 
metastatic gastric cancer receiving TAS-102 plus BSC or placebo plus BSC: 
Primary 
 Overall survival (OS) 
Key Secondary 
 Progression-free survival (PFS) based on Investigator assessment of radiologic 
images 
 Safety and tolerability 
Other Secondary 
 Overall response rate (ORR) 
 Disease control rate (DCR) 
 Time to deterioration of Eastern Cooperative Oncology Group (ECOG) performance 
status to score of 2 or higher 
 Quality of Life (QoL) (EORTC QLQ-C30, QLQ-STO22)8 
 


TAS-102 
Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
TO-TAS-102-302_Protocol_Amendment 2.0_05May2016 
Page 26 of 94 
8. 
INVESTIGATIONAL PLAN 
8.1. 
Overall Study Design 
This is a multinational, double-blind, two-arm, parallel, randomized, Phase 3 study evaluating 
the efficacy and safety of TAS-102 plus BSC versus placebo plus BSC in patients with 
metastatic gastric cancer who have received at least 2 prior regimens for advanced disease.  The 
study will be conducted under the sponsorship of Taiho Pharmaceutical Co., Ltd. for sites in 
Japan and Taiho Oncology, Inc. for sites in the rest of the world (ROW). 
Eligible patients will be centrally randomized (2:1) to TAS-102 + BSC (experimental arm) or 
placebo + BSC (control arm) using a dynamic allocation method (biased coin) via an Interactive 
Voice/Web Response System (IXRS), stratified by: 
 Region (ROW vs. Japan) 
 ECOG performance status (0 vs. 1) 
 Prior treatment with ramucirumab (yes vs. no) 
Study medication should be started within 3 calendar days after the date of randomization and 
continue until a discontinuation criterion is met or until completion of the primary endpoint 
analysis, whichever is sooner.   
TAS-102 (35 mg/m2/dose) or placebo will be administered orally BID, within 1 hour after 
completion of morning and evening meals, for 5 days a week with 2 days rest for 2 weeks, 
followed by a 14-day rest, repeated every 4 weeks.   
Computed tomography (CT) scans will be performed at baseline and every 8 weeks thereafter 
until disease progression.  On-site tumor assessments will be performed by the Investigator/local 
radiologist.  Tumor assessments will be analyzed using Response Evaluation Criteria in Solid 
Tumors (RECIST) criteria (Version 1.1, 2009).  If patient discontinuation is for reasons other 
than radiologic disease progression (ie, with intolerable side effects), patients will be followed 
every 8 weeks for tumor response until radiologic disease progression or initiation of new 
anticancer therapy (whichever occurs first). 
Quality of life assessments (EORTC QLQ-C30 and QLQ-STO22) will be performed prior to 
start of dose administration in each cycle. 
Standard safety monitoring will be performed and AEs will be graded using the NCI CTCAE 
Version 4.03. 
8.2. 
Study Duration 
After discontinuation of study treatment, all patients will be followed for survival every 4 weeks 
until death or until the target number of events (deaths) is met, unless the patient has withdrawn 
consent from the trial. Patients may request discontinuation of study treatment but agree to 
survival follow-up (this is not considered withdrawal of consent from the trial).   
The final analysis will be performed once 384 events (deaths) are reached.  If the primary 
endpoint of the study is met and efficacy as well as safety support a favorable benefit/risk ratio 


TAS-102 
Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
TO-TAS-102-302_Protocol_Amendment 2.0_05May2016 
Page 27 of 94 
for TAS-102, patients currently or previously treated with placebo who continue to meet study 
eligibility criteria will be offered the option to crossover to open-label TAS-102.  Patients who 
are currently receiving TAS-102 will also be switched to open-label TAS-102 at that time.   
Patients who receive open-label TAS-102 treatment after conclusion of survival follow-up will 
be followed for safety and tumor response according to the site standard of care (see 
Section 9.3).  The end of study is defined as completion of safety follow-up for the last patient 
who discontinues study treatment, including patients who receive open-label TAS-102. 
8.3. 
Study Population 
Approximately 500 male and female patients with metastatic gastric cancer will be randomized.   
8.3.1. 
Inclusion Criteria 
A patient must meet all of the following inclusion criteria to be eligible for enrollment in this 
study:   
1. Has provided written informed consent. 
2. Has histologically confirmed non-resectable, metastatic gastric adenocarcinoma including 
adenocarcinoma of the gastroesophageal (GE) junction as defined by the American Joint 
Committee on Cancer (AJCC) staging classification (7th ed., 2010).  Documentation of 
histology of the tumor (primary or metastasis) will be required prior to enrollment.  
Gastroesophageal junction involvement must be documented by endoscopic, radiologic, 
surgical or pathology report.   
3. Has previously received at least 2 prior regimens (at least 1 cycle per regimen) for 
advanced disease and were refractory to or unable to tolerate their last prior therapy:   
a. Prior regimen(s) must have included a fluoropyrimidine, platinum, and either a 
taxane- and/or irinotecan-containing regimen; patients whose tumors are HER2-neu-
positive (HER2+) must have received prior anti-HER2+ therapy if available. 
b. Patients have progressed based on imaging during or within 3 months of the last 
administration of their last prior regimen.   
c. Patients who have withdrawn from their last prior regimen due to unacceptable 
toxicity warranting discontinuation of treatment and precluding retreatment with the 
same agent prior to progression of disease will also be eligible to enter the study. 
d. Patients who have received postoperative adjuvant chemotherapy or chemo-
radiotherapy, and had recurrence during or within 6 months of completion of the 
adjuvant chemotherapy are allowed to count the adjuvant therapy as one prior 
regimen for advanced disease.  Patients who have received pre- and post-operative 
adjuvant chemotherapy, and had recurrence during or within 6 months of completion 
of the adjuvant chemotherapy are allowed to count the adjuvant therapy as one prior 
regimen only if the same regimen was administered both pre- and post-operatively.   
4. Has measureable or nonmeasurable disease as defined by RECIST 1.1 criteria. 
5. Is able to take medications orally (ie, study drug must not be administered via a feeding 
tube). 
6. Is ≥18 years of age (≥20 years for patients in Japan). 


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TAS-102 
Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
TO-TAS-102-302_Protocol_Amendment 2.0_05May2016 
Page 29 of 94 
j. Psychiatric disease that may increase the risk associated with study participation or 
study drug administration, or may interfere with the interpretation of study results.  
2. Has had treatment with any of the following within the specified time frame prior to 
randomization: 
a. Major surgery within prior 4 weeks (the surgical incision should be fully healed prior 
to study drug administration). 
b. Any anticancer therapy within prior 3 weeks. 
c. Extended field radiation within prior 4 weeks or limited field radiation within prior 
2 weeks. 
d. Any investigational drug/device received within prior 4 weeks. 
3. Has previously received TAS-102. 
4. Has unresolved toxicity of greater than or equal to CTCAE Grade 2 attributed to any 
prior therapies (excluding anemia, alopecia, skin pigmentation, and platinum-induced 
neurotoxicity).  
5. Is a pregnant or lactating female. 
6. Is inappropriate for entry into this study in the judgment of the Investigator. 
7. Known or assumed hypersensitivity to TAS-102 or any of its ingredients. 
8.4. 
Treatment Assignment 
8.4.1. 
Patient Numbering 
Study sites will enter patient demographic and baseline data into the electronic Case Report 
Form (eCRF) in order to receive a patient number. 
The eCRF will assign each patient a unique patient number.  All patient numbers will be 6 digits; 
the first 3 digits will be the site number and the last 3 digits will be the patient’s number.  This 
patient number will be maintained throughout the study and will not be reassigned.  Patients who 
withdraw consent or discontinue from the study after being assigned a patient number will retain 
their initial number.   
8.4.2. 
Randomization 
Once patient confirmation of eligibility and the criteria for randomization have been met, 
patients will be centrally randomized in a 2:1 ratio to TAS-102 plus BSC or placebo plus BSC 
via an IXRS based on a dynamic allocation method (biased coin). 
The institutional designee will login to the IXRS and will enter the patient number, patient 
initials, stratification criteria, and other patient data as outlined in the IXRS manual.   
Patients will be stratified by the following factors: 
 Region (ROW vs. Japan) 
 ECOG performance status (0 vs. 1) 
 Prior treatment with ramucirumab (yes vs. no) 


TAS-102 
Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
TO-TAS-102-302_Protocol_Amendment 2.0_05May2016 
Page 30 of 94 
The IXRS will assign kit numbers for study medication (TAS-102 or placebo) corresponding to 
the patient’s treatment assignment, inform the study site user of the kit number that has been 
assigned to the patient, and provide instructions for the dispensing of study drug.  Please refer to 
the IXRS manual for detailed information.   
If a patient is mistakenly given a study treatment that is not the treatment assigned by the IXRS, 
the IXRS help desk must be notified immediately.  The reason for the misallocation of the study 
treatment must be documented by the study site. 
If the misallocation of the study treatment results in the patient being initiated in the alternate 
arm from which they were assigned at randomization, the patient will continue to receive this 
treatment for the rest of the study.   
Study medication administration should begin within 3 calendar days after randomization as 
described in Section 9.   
For patients who sign an informed consent form (ICF) but are not randomized and patients who 
are randomized but never dosed, see the eCRF Completion Guidelines for instruction on which 
eCRF pages to complete.   
After the final analysis is performed and the study has been unblinded, if the primary endpoint of 
the study is met and efficacy as well as safety support a favorable benefit/risk ratio for TAS-102, 
patients currently or previously treated with placebo who continue to meet study eligibility 
criteria will be offered the option to crossover to open-label TAS-102.  Patients who are 
currently receiving TAS-102 will also be switched to open-label TAS-102 at that time.  Patients 
who receive open-label TAS-102 will continue to have study medication kits (open-label) 
assigned through the IXRS system (see Section 9.3).   
8.4.3. 
Blinding 
This is a double-blind study.  TAS-102 tablets of each strength, 15-mg or 20-mg, and the 
corresponding placebo tablets, 15-mg placebo and 20-mg placebo, respectively, will be identical 
in appearance and will be packaged in identical containers (see Section 9.1).  During the conduct 
of the study, the treatment assignment will be unknown to all patients, investigators, and 
ancillary study personnel at each study site, and to employees of Taiho Oncology, Inc. and Taiho 
Pharmaceutical Co., Ltd.   
See Section 12.1.8 for procedures related to breaking of the study blind. 
8.4.4. 
Replacement of Patients 
No patients will be replaced at any time during this study. 
8.5. 
Discontinuation of Study Treatment 
Patients will receive study medication until a discontinuation criterion (see Section 8.5.1) is met 
or until completion of the primary endpoint analysis, whichever is sooner. 
A patient is considered discontinued from study treatment when the decision to permanently stop 
study medication is made, including those decisions made during study medication interruptions 
and recovery periods.   


TAS-102 
Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
TO-TAS-102-302_Protocol_Amendment 2.0_05May2016 
Page 31 of 94 
Study medication should be continued whenever possible.  In case study medication is stopped, it 
should be determined if the stop can be made temporarily; permanent study medication 
discontinuation should be a last resort.  Any study medication discontinuation should be fully 
documented.   
8.5.1. 
Treatment Discontinuation Criteria 
The reason for discontinuation of treatment should be documented in the patient source 
documents. 
Patients can be withdrawn from treatment for the following reasons:  
 Patient request at any time irrespective of the reason. 
 RECIST-defined disease progression. 
 Clinical progression. 
 Patient experiences an irreversible, treatment-related, Grade 4, clinically relevant, 
non-hematologic event.   
 Unacceptable AEs, or change in underlying condition such that the patient can no 
longer tolerate therapy, including:  
 A maximum dose delay >28 days from the scheduled start date of the next cycle 
of TAS-102. 
 Need for more than 3 dose reductions of TAS-102 (maximum of 3 dose 
reductions allowed as described in Section 9.2.4). 
 Physician’s decision including need for other anticancer therapy not specified in the 
protocol or surgery or radiotherapy to the only site(s) of disease being evaluated in 
this protocol. 
 Pregnancy. 
8.5.2. 
End of Treatment Procedures 
Upon discontinuation of treatment the Investigator must: 
 Notify the Clinical Research Associate (CRA) immediately;  
 Register End of Treatment for the patient in the IXRS; 
 Complete the Study Treatment Discontinuation Form in the eCRF, specifying the reason 
for the patient’s withdrawal from treatment. 
 If a patient is discontinued due to clinical progression, associated nonserious AEs should 
be reported on the treatment discontinuation page of the eCRF. 


TAS-102 
Protocol No. TO-TAS-102-302 
Metastatic Gastric Cancer 
TO-TAS-102-302_Protocol_Amendment 2.0_05May2016 
Page 32 of 94 
8.6. 
Discontinuation from Study Follow-up 
As described in Section 10.1.13, patients who discontinue study treatment for reasons other than 
radiologic disease progression (eg, intolerable side effects) should continue to be followed for 
tumor response every 8 weeks until the patient develops radiologic disease progression (or death) 
or initiation of new anticancer therapy (whichever occurs first).   
All treated patients will be followed for survival every 4 weeks until death, or until the target 
number of events is reached (whichever is sooner), unless the patient has withdrawn consent 
from the trial.  Patients may request discontinuation of study treatment but agree to survival 
follow-up (this is not considered withdrawal of consent from the trial).  The Investigator should 
make every effort to contact the patient or primary caregiver to determine his/her survival status.  
Times and dates of contact must be documented in the patient’s records. 
A patient will be considered “Discontinued from Study Follow-up” when one of the following 
occurs: 

Patient dies

Target number of events (384 events) is reached and final analysis performed

Study is stopped based on Data Monitoring Committee (DMC) recommendation

Study is terminated by the Sponsor or Regulatory Agencies
8.7. 
Patients Continuing Treatment after Completion of Final Analysis
Procedures to be followed if patients who are continuing to receive study medication at the 
conclusion of survival follow-up for the study (target number of events reached and final 
analysis performed) are described in Section 9.3.   
The end of study is defined as completion of safety follow-up for the last patient who 
discontinues study treatment, including patients who are switched to open-label TAS-102 after 
completion of final analysis. 
8.8. 
Other Medications and Therapies 
8.8.1. 
Prohibited Medications and Therapies 
Patients are not permitted to receive any other investigational or any other anticancer therapy, 
including chemotherapy, immunotherapy, biological response modifiers (BRMs), or endocrine 
therapy (except for megestrol acetate and steroids at doses less than or equal to 20 mg of 
prednisone equivalent per day for ≤2 weeks) during the study treatment period. 
Palliative radiotherapy is not permitted while the patient is receiving study treatment.   
8.8.2. 
Concomitant Medications and Therapies 
Caution is required when using drugs that are human thymidine kinase substrates, eg, 
zidovudine. Such drugs, if used concomitantly with TAS-102, may compete with the effector, 
trifluridine, for activation via thymidine kinases. Therefore, when using antiviral drugs that are 
human thymidine kinase substrates, monitor for possible decreased efficacy of the antiviral 


TAS-102 
Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
TO-TAS-102-302_Protocol_Amendment 2.0_05May2016 
Page 33 of 94 
agent, and consider switching to an alternative antiviral agent that is not a human thymidine 
kinase substrate, such as lamivudine, zalcitabine, didanosine and abacavir. 
The following medications may be given concomitantly under the following guidelines: 
Hematologic Support 
Administer hematologic support as medically indicated (eg, blood transfusions, G-CSF, 
erythropoietin, etc) according to the institutional site standards.  If there are no standard 
procedures for the use of growth factors, follow American Society of Clinical Oncology (ASCO) 
2006 Guidelines for Use of Hematopoietic Colony-Stimulating Factors, available at 
http://www.instituteforquality.org/practice-guidelines; or the European Organization for 
Research and Treatment of Cancer (EORTC) update to 2010 guidelines for the use of G-CSF,9 
available at http://www.eortc.org/investigators-area/eortc-guidelines.  
Management of Diarrhea 
Educate both patients and patients’ families regarding the potential seriousness of chemotherapy-
induced diarrhea.  Instruct patients to immediately contact the clinical site staff at the first sign of 
loose stool. 
Provide patients with loperamide or other standard antidiarrheal therapy and instruct the patient 
on how to use it at the first sign of diarrhea. 
Monitor the patient’s fluid and electrolyte balance, with appropriate intervention as clinically 
indicated with fluids and electrolyte replacement, antibiotics, and antiemetics. 
Infection prophylaxis with oral antibiotics must be considered for patients with persistent 
diarrhea beyond 24 hours, or coincident with Grade ≥3 neutropenia.   
Administer prophylactic treatment for diarrhea as clinically indicated. 
If there are no institutional standards, refer to the guidelines published by Benson AB et al in 
Journal of Clinical Oncology.10 
Management of Nausea/Vomiting 
Administer antiemetics as clinically indicated.  If there are no institutional standards refer to the 
ASCO Guidelines for Antiemetics in Oncology.11   
8.8.3. 
Effective Contraception During Study 
Both males and females must agree to use effective birth control during the study (prior to the 
first dose and for 6 months after the last dose) if conception is possible during this interval. 
Female patients who are considered not to be of childbearing potential must have a history of 
being postmenopausal (no menses for 12 months without an alternative medical cause), or 
hysterectomy that is clearly documented in the patient’s source documents. 
For women of childbearing potential, including female study participants and partners of male 
participants, effective contraception is defined as follows: 
 combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: 
o oral 


TAS-102 
Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
TO-TAS-102-302_Protocol_Amendment 2.0_05May2016 
Page 34 of 94 
o intravaginal 
o transdermal 
 progestogen-only hormonal contraception associated with inhibition of ovulation: 
o oral 
o injectable 
o implantable 
 intrauterine device (IUD) 
 intrauterine hormone-releasing system (IUS) 
 bilateral tubal occlusion 
 vasectomized partner with documentation of the success of the vasectomy 
 complete abstinence from heterosexual intercourse (periodic abstinence is not a safe 
method) 
Male patients with partners who are women of childbearing potential should use a combination 
of male condom with either cap, diaphragm or sponge with spermicide during the trial and for 
6 months after the last dose of study medication. 
8.9. 
Dietary Restrictions 
TAS-102 should be taken with a glass of water within 1 hour after completion of the morning 
and evening meals.   


TAS-102 
Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
TO-TAS-102-302_Protocol_Amendment 2.0_05May2016 
Page 35 of 94 
9. 
STUDY TREATMENT 
Study sites will call/login to the IXRS at the beginning of each patient treatment cycle to record 
the current cycle number, record the patient’s current weight and obtain the patient’s body 
surface area (BSA), and obtain the recommended study medication dosage.   
If at the beginning of the next treatment cycle, a patient’s body weight decreases by ≥10% from 
baseline, the IXRS will recalculate the patient’s BSA and provide the site with the adjusted study 
medication dosage.  No increase in dose due to increase in BSA is permitted. 
The BSA will be calculated by the IXRS using the following DuBois formula (all BSA 
calculations are rounded to 2 decimal places). 
BSA (m²) = ([Body Weight (kg)]0.425 x [Height (cm)]0.725) x 0.007184 
Study sites are required to use the BSA calculation provided by the IXRS when determining 
patient doses unless their institutional policies do not permit it. 
Please note the following: 
 Dose escalations (on a mg/m2 basis) of study medication are not permitted at any time. 
 Only 3 dose reductions of study medication are permitted. 
 Only a 28-day delay in the start of the next treatment cycle is permitted (see 
Section 9.2.4.4). 
Study treatment should be started within 3 calendar days after randomization and should be 
administered as outlined in the following sections of the protocol.  The Investigator always has 
the right to deviate from the established rules for dose modification at her/his discretion if he 
believes a more conservative approach is needed in the management of related or unrelated AEs.  
However, doses must be modified at least to the extent specified in Section 9.2.4.  All deviations 
from protocol-specified dose modifications must be documented.   
Patients will receive blinded study medication until one of the discontinuation criteria listed in 
Section 8.5.1 is met. 
9.1. 
Description and Labeling 
9.1.1. 
TAS-102 
TAS-102 contains trifluridine (FTD) and tipiracil hydrochloride (TPI) as active ingredients with 
a molar ratio of 1:0.5.   
TAS-102 is formulated as an immediate-release film-coated tablet, which is supplied in 
2 strengths (expressed as FTD content):   
 The 15 mg white, round tablet contains 15 mg FTD and 7.065 mg TPI as active 
ingredients. 
 The 20 mg pale-red, round tablet contains 20 mg FTD and 9.42 mg TPI as active 
ingredients. 


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TAS-102 
Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
TO-TAS-102-302_Protocol_Amendment 2.0_05May2016 
Page 37 of 94 
Study medication should be taken only on Days 1-5 and 8-12 of each cycle.  If doses are missed 
or held on those days, the patient should not make up for missed doses.   
TAS-102 should be taken with a glass of water within 1 hour after completion of morning and 
evening meals.   
9.2.2. 
Number of Tablets per Dose 
The study drug tablet calculation is presented in Table 2, which shows the number of tablets that 
are needed per calculated BSA.  
 Study medication should only be given on Days 1 through 5 and Days 8 through 12 of 
each cycle even if doses are missed or held for any reason during Days 1 through 12.   
 Extension of study treatment into Days 6 and 7 or into the rest period (Days 13 
through 28) is not permitted.   
Any missed doses reported by the patient should be recorded in the patient’s source documents. 
Table 2: 
Number of Tablets per Dose 
TAS-102 Dose 
(2x daily) 
BSA 
(m2) 
Dosage in mg
(2x daily) 
Total daily
dose (mg) 
Tablets per dose 
15 mg 
20 mg 
35 mg/m2 
< 1.07 
35 
70 
1 
1 
1.07 - 1.22 
40 
80 
0 
2 
1.23 - 1.37 
45 
90 
3 
0 
1.38 - 1.52 
50 
100 
2 
1 
1.53 - 1.68 
55 
110 
1 
2 
1.69 - 1.83 
60 
120 
0 
3 
1.84 - 1.98 
65 
130 
3 
1 
1.99 - 2.14 
70 
140 
2 
2 
2.15 - 2.29 
75 
150 
1 
3 
≥2.30 
80 
160 
0 
4 
BSA=body surface area (calculate to 2 decimal places) 
9.2.3. 
Instruction to Patients for Handling Study Medication 
The patient must be instructed in the handling of study medication as follows: 
 To store the study medication at room temperature 
 To only remove from the study medication kit the amount of tablets needed at the 
time of dosing 
 To wash their hands after handling study medication 
 Not to remove doses in advance of the next scheduled dosing 
 To make every effort to take doses on schedule 
 To report any missed doses 


TAS-102 
Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
TO-TAS-102-302_Protocol_Amendment 2.0_05May2016 
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 To take study medication within 1 hour after completing a meal (morning and 
evening meal) with a glass of water 
 If the patient vomits after taking study medication, the patient should not take another 
dose 
 To keep study medication in a safe place and out of reach of children 
 To bring all used and unused study medication kits to the site at each visit 
9.2.4. 
Dose Modifications 
9.2.4.1. 
Dose Reduction Levels 
Study medication dose reductions to be applied in case of toxicity and the number of tablets for 
each calculated BSA are described in Table 3.  Patients are permitted dose reduction(s) to a 
minimum dose of 20 mg/m2 (40 mg/m2/day) in 5 mg/m2 steps.   


TAS-102 
Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
TO-TAS-102-302_Protocol_Amendment 2.0_05May2016 
Page 39 of 94 
Table 3: 
TAS-102 Dose Reduction Levels and Number of Tables per Dose 
TAS-102 
Dose (2x daily) 
BSA 
(m2) 
Dosage in 
mg 
(2x daily) 
Total daily
dose (mg) 
Tablets per dose 
15 mg 
20 mg 
Level 1 Dose Reduction:  From 35 mg/m2 to 30 mg/m2 
30 mg/m2 
< 1.09 
30 
60 
2 
0 
1.09 - 1.24 
35 
70 
1 
1 
1.25 - 1.39 
40 
80 
0 
2 
1.40 - 1.54 
45 
90 
3 
0 
1.55 - 1.69 
50 
100 
2 
1 
1.70 - 1.94 
55 
110 
1 
2 
1.95 - 2.09 
60 
120 
0 
3 
2.10 - 2.28 
65 
130 
3 
1 
≥ 2.29 
70 
140 
2 
2 
Level 2 Dose Reduction:  From 30 mg/m2 to 25 mg/m2 
25 mg/m2 
< 1.10 
25a 
50a 
2 (PM)a 
1 (AM)a 
1.10 - 1.29 
30 
60 
2 
0 
1.30 - 1.49 
35 
70 
1 
1 
1.50 - 1.69 
40 
80 
0 
2 
1.70 - 1.89 
45 
90 
3 
0 
1.90 - 2.09 
50 
100 
2 
1 
2.10 - 2.29 
55 
110 
1 
2 
≥ 2.30 
60 
120 
0 
3 
Level 3 Dose Reduction:  From 25 mg/m2 to 20 mg/m2 
20 mg/m2 
< 1.14 
20 
40 
0 
1 
1.14 – 1.34 
25a 
50a 
2 (PM)a 
1 (AM)a 
1.35 – 1.59 
30 
60 
2 
0 
1.60 – 1.94 
35 
70 
1 
1 
1.95 – 2.09 
40 
80 
0 
2 
2.10 – 2.34 
45 
90 
3 
0 
≥ 2.35 
50 
100 
2 
1 
a At a total daily dose of 50 mg, patients should take 1 x 20-mg tablet in the morning and 2 x 15-mg tablets in the 
evening. 
BSA=body surface area (calculate to 2 decimal places) 
If dose modification fails to result in achieving minimal criteria to resume treatment, the 
Investigator should discontinue study medication.   
Should the toxicities that require dose reduction recur after dose reduction to 20 mg/m2, study 
medication should be discontinued.   


TAS-102 
Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
TO-TAS-102-302_Protocol_Amendment 2.0_05May2016 
Page 40 of 94 
9.2.4.2. 
Dose Modification in Response to Non-hematologic Toxicities 
Rules for study medication dosing modifications for treatment-related non-hematologic AEs are 
provided in Table 4.  At the discretion of the Investigator, patients may continue on study 
medication at the same dose without reduction or interruption for drug-related AEs (irrespective 
of grade) considered unlikely to become serious or life-threatening (including, but not limited to, 
fatigue, alopecia, changes in libido, and dry skin).   
Table 4: 
TAS-102 Dose Modification Criteria for Non-hematologic Toxicities 
Gradea 
Dose Hold/Resumption 
within a 28-day Treatment Cycle 
Dose Adjustment for  
Next Cycle 
Grade 1 or 2 
Any occurrence 
Maintain treatment at the same dose level 
None 
Grade 3a or Higher 
1st, 2nd, or 3rd 
occurrence 
Suspend treatment until Grade 0 or 1 
Reduce by 1 dose level from the 
previous level 
4th occurrence 
Discontinue treatment 
Discontinue treatment 
a Except for Grade 3 nausea and/or vomiting controlled by aggressive antiemetic therapy or diarrhea responsive to 
antidiarrheal medication. 
If there is any uncertainty about continuing therapy or resuming therapy in a patient with 
Grade ≥3 non-hematologic drug-related AEs, the case must be discussed with the Sponsor’s 
Medical Monitor prior to continuing therapy.   
9.2.4.3. 
Dose Modification in Response to Hematologic Toxicities 
Criteria for dose hold and resumption in response to hematologic toxicities related to 
myelosuppression are described in Table 5 and Table 6, respectively.   
NOTE: For all patients with decreases in neutrophils and/or platelets, the next cycle of study 
treatment should not be started until the resumption criteria in Table 6 are met; these resumption 
criteria apply to the start of the next cycle for all patients regardless of whether or not the hold 
criteria were met.  
Table 5: 
TAS-102 Dose Hold Criteria for Hematologic Toxicities Related to 
Myelosuppression 
Parameter 
Hold Criteria 
Conventional Units 
SI Units 
Neutrophils 
<500/mm3 
<0.5  109/L 
Platelets 
<50,000/mm3 
<50  109/L 
SI=International System 


TAS-102 
Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
TO-TAS-102-302_Protocol_Amendment 2.0_05May2016 
Page 41 of 94 
Table 6: 
TAS-102 Resumption Criteria for Hematologic Toxicities Related to 
Myelosuppression 
Parameter 
Resumption Criteriaa 
Conventional Units 
SI Units 
Neutrophils 
≥1500/mm3  
≥1.5  109/L 
Platelets 
≥75,000/mm3 
≥75  109/L 
a These resumption criteria apply to the start of the next cycle for all patients regardless of whether or not the hold 
criteria were met. 
SI=International System 
Criteria for dose reduction in response to hematologic toxicities are as follows: 
 Uncomplicated neutropenia or thrombocytopenia ≤Grade 3 do not require a reduction 
in dose of study medication.   
 Patients who experience uncomplicated Grade 4 neutropenia or thrombocytopenia 
that results in a ≤1 week delay of the start of the next cycle should start the next cycle 
at the same dose level. 
 Patients who experience uncomplicated Grade 4 neutropenia or thrombocytopenia 
that results in a >1 week delay of the start of the next cycle should start the next cycle 
at one reduced dose level as described in Table 3. 
Patients who experience complicated ≥Grade 3 neutropenia or thrombocytopenia should be 
considered for administration of hematopoietic growth factors, or for a dose reduction in the next 
cycle or both, dependent on the severity of the complication. 
In the event of febrile neutropenia: 
 Interrupt dosing until toxicity resolves to Grade 1 or baseline 
 When resuming dosing, decrease the dose level by 5 mg/m2/dose from the previous dose 
level (as per Table 3). 
9.2.4.4. 
Dose Resumption 
If the patient recovers from toxicities requiring dose delay during the 2-week treatment period of 
a cycle (treatment Days 1 through 5, 8 through 12), and no dose reduction is required, study 
medication may be resumed during that cycle.  If a dose reduction is required, study medication 
should be resumed at the start of the next cycle at the appropriate dose level as shown in Table 3.  
Do not increase study medication dose after it has been reduced. 
If the patient recovers from toxicities requiring dose delay during the recovery period (Days 13 
through 28), start the next cycle on schedule at the appropriate dose level based on 
Section 9.2.4.2 and Section 9.2.4.3 above.  If the toxicities that are defined above do not recover 
during the treatment or rest period, the start of the next cycle can be delayed for a maximum of 
28 days from the scheduled start date of the next cycle.  If resumption criteria are met by this 
maximum 28-day delay, start the next cycle at the appropriate dose level.   


TAS-102 
Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
TO-TAS-102-302_Protocol_Amendment 2.0_05May2016 
Page 42 of 94 
Patients who require more than a 28-day delay in the scheduled start date of the next cycle will 
have study medication discontinued.   
9.3. 
Open-label TAS-102 
After completion of the primary analysis, if the primary endpoint of the study was met and 
efficacy, as well as safety, support a favorable benefit/risk ratio for TAS-102, and after site 
notification and unblinding, patients currently being treated with placebo and those previously 
treated with placebo who continue to meet study eligibility criteria will be offered the option to 
receive open-label TAS-102.  The decision to crossover to open-label TAS-102 should be made 
within 3 months of notification that the patient was receiving placebo.  Patients who are currently 
receiving double-blind TAS-102 will also be switched to open-label TAS-102 at that time.   
For patients who receive open-label TAS-102, open-label study medication kits will be assigned 
by IXRS based on the patient’s BSA at the time of initiation of open-label TAS-102.   
Patients who receive open-label TAS-102 treatment after conclusion of survival follow-up 
should be followed for safety and tumor response according to the site standard of care.  Study 
medication and dose modification procedures described in Section 9.2 should continue to be 
followed.  
Adverse events leading to treatment discontinuation, serious AEs (SAEs) and deaths should 
continue to be documented in the eCRF and reported to the Sponsor as described in Section 12.1.  
Date and reason for treatment discontinuation should also be recorded in the eCRF.   
The end of study is defined as completion of safety follow-up (for any AEs leading to treatment 
discontinuation, SAEs or deaths) for the last patient who discontinues study treatment. 
9.4. 
Treatment Compliance 
Compliance to all study medication administration should be documented in the patient’s source 
documents. 
9.5. 
Study Drug Accountability 
In accordance with International Council for Harmonisation (ICH) and local regulatory 
requirements, the Investigator and/or the person responsible for dispensing investigational drug 
must be able at all times to account for all investigational product provided to the site.  Prior to 
drug dispensation, the person responsible for dispensing the drug must call/login to the IXRS, 
complete the information required on the labels of study medication, and update study logs with 
the required information (eg, kit number and expiration date). 
Dose reductions, interruptions, and reason for these actions must be recorded in the patient’s 
source documents. 
All used and unused study medication shipped to the Investigator must be destroyed by the site 
or returned to the Sponsor or its representative. Destruction by the site is the preferred method 
for disposing study medication. Sites must provide the institution’s Standard Operating 
Procedure (SOP) to the Sponsor or its representative for review. If on-site destruction is not 
allowed, the return of study medication will be arranged regionally. No study medication is to be 
used outside of this study. 


TAS-102 
Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
TO-TAS-102-302_Protocol_Amendment 2.0_05May2016 
Page 43 of 94 
10. 
STUDY ASSESSMENTS 
The study assessments are described by procedure in Section 10.1 and by visit in Section 10.2.  
All information required by the protocol must be recorded.   
The study schedule must be followed; however, under special conditions, eg, holidays, 
weekends, etc, a window of ±3 days is allowable for study procedures, as long as the proper 
order is maintained, and a window of ±7 days is allowable for CT scans, and follow-up visits.  
During the Baseline period (up to 28 days prior to randomization), these windows are not 
applicable.   
10.1. 
All Study Procedures 
10.1.1. 
Informed Consent 
Obtain signed and dated ICF from the patient prior to the implementation of study procedures 
required by the protocol.  A copy of the signed and dated ICF should be given to the patient. 
10.1.2. 
Randomization/Start of Treatment 
Following confirmation of eligibility, patients will be randomized via IXRS and should receive 
the first dose of study treatment (Day 1 of Cycle 1) within 3 calendar days after randomization.  
The maximum screening period is 28 days; eligible patients must be randomized by Day 29 of 
screening.   
10.1.3. 
Medical History 
Obtain a complete medical history within 28 days prior to study medication administration.  
Record the patient’s medical history on the Medical History section of the eCRF.   
Any AEs/SAEs reported from the time of signed ICF until the first dose of study medication 
should be recorded on the Medical History section of the eCRF.   
10.1.4. 
Histologic Confirmation 
Obtain confirmation of gastric adenocarcinoma via pathology report at Baseline (pathology may 
be from primary tumor or metastasis).  The pathology report should be available in the patient’s 
source documents. 
10.1.5. 
Human Epidermal Growth Factor Receptor 2 (HER2) Status 
Record the patient’s HER2 status at Baseline, if available. 
10.1.6. 
Physical Examination 
Perform a complete physical examination at the time points listed below: 
 Within 7 days prior to Day 1 of Cycle 1 
 Beginning with Cycle 2, obtain within 24 hours prior to start of study treatment in 
every cycle 


TAS-102 
Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
TO-TAS-102-302_Protocol_Amendment 2.0_05May2016 
Page 44 of 94 
 End of Treatment Visit (if applicable) 
 30-day Safety Follow-up Visit 
10.1.7. 
Baseline Signs and Symptoms 
Signs and symptoms present following signature of ICF and within 7 days prior to study 
treatment on Day 1 of Cycle 1 should be recorded in the patient’s source documents.   
10.1.8. 
Height, Vital Signs, Weight 
Obtain the patient’s height within 7 days prior to Day 1 of Cycle 1. 
Collect the patient’s vital signs (blood pressure, heart rate, body temperature, and respiration 
rate) and body weight at the time points listed below.  Obtain all the vital signs in a position that 
is consistent for all time points for each patient. 
 Within 7 days prior to Day 1 of Cycle 1 
 Beginning with Cycle 2, obtain within 24 hours prior to start of study treatment in 
every cycle 
 End of Treatment Visit (if applicable) 
 30-day Safety Follow-up Visit 
10.1.9. 
Performance Status (ECOG) 
Obtain an ECOG performance status score at the following time points: 
 Within 28 days prior to Day 1 of Cycle 1 
 At time of randomization (within 3 calendar days prior to start of study treatment on 
Day 1 of Cycle 1) 
 Beginning with Cycle 2, obtain within 24 hours prior to start of study treatment in 
every cycle 
 End of Treatment Visit (if applicable) 
 30-day Safety Follow-up Visit 
10.1.10. 
Clinical Laboratory Evaluations 
10.1.10.1. Hematology 
Collect blood for hematological assessments at the following time points and when clinically 
indicated: 
 Within 7 days prior to Day 1 of Cycle 1 (Laboratory results obtained prior to signing 
ICF may be used if the results were obtained within 7 days prior to Day 1 of Cycle 1.) 
 Day 15 of Cycle 1 
 Beginning with Cycle 2, obtain within 24 hours prior to start of study treatment in 
every cycle 


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 End of Treatment Visit (if applicable) 
 30-day Safety Follow-up Visit 
In addition, follow the criteria for repeat testing listed in Section 12.2.2 as needed. 
Measure the following hematology parameters: 
Red blood cell (RBC) count 
White blood cell (WBC) count with differential (automated): 
Hemoglobin  
     Neutrophils 
Hematocrit 
     Lymphocytes 
Platelets 
     Monocytes 
 
     Eosinophils 
     Basophils 
10.1.10.2. Serum Chemistry 
Collect blood at the following time points for serum chemistry assessments: 
 Within 7 days prior to Day 1 of Cycle 1 (Laboratory results obtained prior to signing 
ICF may be used if the results were obtained within 7 days prior to Day 1 of Cycle 1.) 
 Day 15 of Cycle 1 
 For all subsequent cycles, obtain within 24 hours prior to start of study treatment in 
every cycle 
 End of Treatment Visit (if applicable) 
 30-day Safety Follow-up Visit. 
In addition, follow the criteria for repeat testing listed in Section 12.2.2 as needed. 
Measure the following serum chemistry parameters: 
ALT (SGPT) 
Creatinine 
Chloride 
AST (SGOT)  
Blood urea nitrogen (BUN) 
Calcium 
Alkaline phosphatase 
Sodium 
Albumin 
Bilirubina 
Potassium 
Glucose 
a In case of elevation in total bilirubin, fractionation (direct/indirect) should be performed. 
10.1.10.3. Urinalysis 
Collect urine samples for qualitative (dipstick) analysis, to include tests for protein, glucose, 
urobilinogen, RBC, and WBC, at the time points listed below: 
 Within 7 days prior to Day 1 of Cycle 1 (Laboratory results obtained prior to signing 
ICF may be used if the results were obtained within 7 days prior to Day 1 of Cycle 1.) 
 As clinically indicated thereafter 
If a new abnormality is identified, quantitative urinalysis should be performed.   


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CCI


TAS-102 
Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
TO-TAS-102-302_Protocol_Amendment 2.0_05May2016 
Page 47 of 94 
If the Investigator determines that a patient develops clinical progression manifested by 
symptomatic deterioration but not supported by radiologic evidence of progression, the patient 
should stop treatment.  Symptoms of clinical progression must be documented in the patient’s 
source documents.  Every effort should be made to document objective progression even after 
discontinuation of treatment. 
If a patient is withdrawn due to radiologic disease progression, additional CT scans are not 
required at the end of treatment. 
The same method of assessment and the same technique must be used to characterize each 
identified and reported lesion at Baseline, throughout the study, and during the follow-up period.   
All patients’ files and radiological assessments must be available for source verification.  Results 
of any unscheduled evaluations should be recorded in the patient’s source documents. 
10.1.14. 
Concomitant Medications and Therapies 
Collect all therapies and medications, prescription and over-the-counter, from the time of signed 
ICF through the 30-day Safety Follow-Up Visit, including any medication used to treat AEs or 
SAEs during the safety follow-up period.  Use of concomitant medication should be documented 
in the patient’s source documents. 
At the 30-day Safety Follow-Up Visit, collect any new anticancer therapy and the date of 
initiation.   
During the survival follow-up period, collect only anticancer therapies. 
10.1.15. 
Adverse Event Assessment 
Any untoward medical events (AEs or SAEs) that occur from the first dose of study medication 
(Day 1, Cycle 1) through 30 days after last dose of study medication should be recorded in the 
AE section of the eCRF.  Any AEs/SAEs that occur from the time of signed informed consent 
until the first dose of study drug should be reported on the Medical History section of the eCRF.   
SAEs should be reported to Taiho Pharmacovigilance or designee.  If any medical occurrences 
outside the 30-day follow-up period are reported to or observed by the Investigator that he/she 
believes are related to the administration of the study medication, it is the Investigator’s 
responsibility to record those events on the eCRF and, if any of those events are serious, then the 
Investigator has to report this occurrence to Taiho Pharmacovigilance or designee.  See 
Section 12.1.1 and Section 12.1.2, respectively, for definitions and detailed reporting of AEs and 
SAEs.   
10.2. 
Assessments by Visit 
See Section 10.1 for details about specific assessments. 
10.2.1. 
Baseline Procedures Prior to Randomization 
10.2.1.1. Day -28 through Day -1 
 Signature of Informed Consent Form 
 Medical history 


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Metastatic Gastric Cancer 
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 Histological confirmation of gastric adenocarcinoma from either the primary or 
metastatic site of disease 
 HER2 status (if available) 
 ECOG performance status 
 Tumor measurement (by CT scan) 
 Concomitant medication 
10.2.1.2. Day -7 through Day -1 
 Physical examination 
 Baseline signs and symptoms 
 Height 
 Vital signs (blood pressure, heart rate, body temperature, respiration rate) and body 
weight 
 Blood samples for hematology and serum chemistry 
 Urine sample for urinalysis 
 Quality of life assessment (EORTC QLQ-C30, QLQ-STO22) 
 Pregnancy test 
10.2.2. 
Cycle 1 Day 1 
Contact the IXRS when the patient meets the minimum criteria for initiation of study treatment 
to randomize the patient.  Instructions for randomization are described in detail in the IXRS 
Instructions Manual.  Study treatment should be started within 3 calendar days after 
randomization. 
 ECOG performance status (confirmation of eligibility) 
 Dispense study medication 
 Concomitant medication 
 AE/SAE assessment 
10.2.3. 
Cycle 1 Day 15 
 Blood samples for hematology and serum chemistry 
 Concomitant medication 
 AE/SAE assessment 


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Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
TO-TAS-102-302_Protocol_Amendment 2.0_05May2016 
Page 49 of 94 
10.2.4. 
Subsequent Cycles - Cycle X Day 1 
Obtain within 24 hours prior to Day 1 study drug administration.  Prior to starting subsequent 
cycles, verify that patients with toxicities have met resumption criteria prior to administering 
study drug. 
 Physical examination 
 Vital signs (blood pressure, heart rate, body temperature, respiration rate) and body 
weight 
 ECOG performance status 
 Blood samples for hematology and serum chemistry 
 Dispense study medication 
 Concomitant medication 
 AE/SAE assessment  
 Quality of life assessment (EORTC QLQ-C30, QLQ-STO22) prior to administration 
of study medication 
 
10.2.5. 
Every 8 Weeks from Start of Treatment 
 Tumor measurement/assessment (CT scan) 
 
10.2.6. 
End of Treatment Visit 
If the decision to discontinue blinded study medication is made within 2 weeks after the patient’s 
last treatment visit, an End of Treatment Visit is not required unless deemed clinically 
necessary by the Investigator.  If the decision to discontinue study medication (due to proven 
radiologic disease progression or other reasons) is made more than 2 weeks after the last 
treatment visit, an End of Treatment Visit is required.  If this visit occurs within 2 weeks of the 
30-day Safety Follow-up Visit, the 2 visits can be combined. 
Perform the following assessments: 
 Physical examination 
 Vital signs (blood pressure, heart rate, body temperature, respiration rate) and body 
weight 
 ECOG performance status  
 Blood samples for chemistry and hematology 
 Pregnancy test 
 For patients who discontinue treatment for reasons other than radiologic disease 
progression, every effort should be made to perform an end of treatment tumor 
assessment prior to the start of new anticancer therapy.   


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Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
TO-TAS-102-302_Protocol_Amendment 2.0_05May2016 
Page 50 of 94 
 Concomitant medication, including any new anticancer therapy and time of initiation 
 AE/SAE assessment 
10.2.7. 
30-Day Safety Follow-up Visit 
A Safety Follow-up visit will be conducted 30 days after the patient’s last dose of study 
medication.  If the patient will be starting new anticancer therapy within the 30-day window after 
the last dose of study medication, the 30-day Safety Follow-up Visit should be performed prior 
to the start of new anticancer therapy.  If the patient is unable to return to the site prior to the 
initiation of new treatment, a follow-up phone call can be conducted by the site to collect any 
new safety information that occurred between the end of study treatment and the initiation of the 
new treatment.   
Perform the following assessments:   
 Physical examination 
 Vital signs (blood pressure, heart rate, body temperature, respiration rate) and body 
weight 
 ECOG performance status  
 Blood samples for chemistry and hematology 
 Pregnancy test  
 Quality of life assessment (EORTC QLQ-C30, QLQ-STO22) if not performed within 
the previous 4 weeks 
 Concomitant medication, including any new anticancer therapy and time of initiation 
 AE/SAE assessment 
10.2.8. 
Survival Follow-up after 30-Day Safety Visit 
The following assessments should be obtained at scheduled 4-week (±7 days) time intervals 
during the survival follow-up period: 
 Tumor measurement (by CT scan, see Section 11) every 8 weeks until radiologic disease 
progression (for patients who discontinued treatment for reasons other than disease 
progression) or initiation of new anticancer therapy (whichever occurs first) 
 Concomitant medications – collect antitumor therapies only 
 Contact patient/caregiver to determine survival status (alive/dead) 
 SAE collection only if the SAE is related to study medication 
Patients will be followed for survival until the target number of events is reached.  The 
Investigators will be informed when this target is reached.   


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Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
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11. 
EFFICACY ASSESSMENT CRITERIA 
The determination of antitumor efficacy will be based on objective tumor assessments made by 
the Investigator/local radiologist according to the revised RECIST criteria (version 1.1, 2009) of 
unidimensional evaluation.12  Treatment decisions by the Investigator will also be based on these 
criteria. 
11.1. 
Method of Imaging 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at Baseline and during follow-up.  Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess the 
antitumor effect of treatment.  All measurements should be recorded in metric notation using a 
ruler or calipers. 
Contrast enhanced CT is the preferred method for tumor assessments.  If contrast agent is 
contraindicated in a patient, obtain a non-contrast chest CT AND enhanced magnetic resonance 
imaging (MRI) of the abdomen (and pelvis if clinically indicated).  Spiral CT should be 
performed using a 5 mm or less contiguous reconstruction algorithm.  Images must be acquired 
of the chest and abdomen (and pelvis if clinically indicated or obtained at Baseline) at each time 
point.  Only CT and MRI may be used for tumor measurement.   
Clinical lesions will only be considered measurable when they are superficial (eg, skin nodules, 
palpable lymph nodes).  In the case of skin lesions, documentation by color photography, 
including a ruler to estimate the size of the lesion, is recommended. 
Ultrasound should not be used to measure tumor lesions that are clinically not easily accessible 
for objective response evaluation (eg, visceral lesions).  Ultrasound is a possible alternative to 
clinical measurements of superficial palpable nodes, subcutaneous lesions, and thyroid nodules.  
Ultrasound might also be useful to confirm the complete disappearance of superficial lesions 
usually assessed by clinical examination. 
An additional fluorodeoxyglucose positron emission tomography (FDG-PET) scan may help 
confirm the diagnosis of suspicious lymph nodes as needed.  A “positive” FDG-PET scan lesion 
is one that is FDG avid “with an uptake greater than twice that of the surrounding tissue on the 
attenuation corrected image.”  However, this scan is not mandatory.  FDG-PET scan alone 
cannot replace a MRI or contrast-enhanced CT. 
For additional guidance refer to revised RECIST criteria (version 1.1, 2009),12 specifications for 
standard anatomical radiological imaging. 
11.2. 
Tumor Definitions 
Measurable Lesions: 
 Measurable visceral lesions:  Lesions that can be accurately measured in at least 
1 dimension with the longest diameter (to be recorded) ≥10 mm by CT scan if using 
slice thickness of 5 mm or less, or at least double the slice thickness of the CT or MRI 
scan if the slice thickness is >5 mm.   


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Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
TO-TAS-102-302_Protocol_Amendment 2.0_05May2016 
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 Measurable pathological lymph nodes:  A malignant lymph node must be considered 
pathologically enlarged with high suspicion of metastasis and measure ≥15 mm in the 
short axis when assessed by CT scan.  The short axis is defined as the longest linear 
dimension perpendicular to the node’s longest diameter as assessed within the same 
plane that the scan was acquired.   
Only measurable lesions can be selected as target lesions. 
Non-measurable Lesions:  Non-measurable lesions include: 
1. Small visceral metastatic lesions that have a longest dimension less than 10 mm or if slice 
thickness is greater than 5 mm less than twice the slice thickness.  
2. Abnormal and suspected metastatic lymph nodes that are ≥10 mm to <15 mm in the short 
axis. 
3. Truly non-measurable lesions (eg, ascites and peritoneal carcinomatosis). 
All non-measurable lesions can only be selected as non-target lesions. 
Target Lesions: 
 All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs/tissues should be identified as target lesions. 
 Target lesions should be selected on the basis of their size (visceral lesion with the 
longest diameter and lymph node with the measurement of short axis), be 
representative of all involved organs/tissues, but in addition should be those that lend 
themselves to reproducible repeated measurements.   
 When recording tumor measurements, the longest diameter will be measured for each 
non-nodal target lesion.  For measurable pathological lymph nodes that may be 
identified as target lesions, the short axis measurement will be combined with the 
measurements of non-nodal (ie, visceral lesion) target lesions.  Therefore, in cases of 
complete response (CR) when abnormal nodes have been used as target lesions, the 
sum of diameters will not reduce to a null value. 
 Target lesions will be followed up and measured at each subsequent time point. 
 The sum of the diameters for all target lesions will be calculated and recorded.  
The baseline sum will be used as a reference to further characterize any objective 
tumor assessment in the measurable dimension of the disease. 
 Assign a measurement to all target lesions regardless of size.  An option of ‘too small 
to measure’ will be provided if a measurement cannot be assigned.  A value of zero 
should only be assigned in the case of a CR. 
 An option of ‘Not Assessable’ for a lesion will only apply to lesions that cannot be 
read due to technical reasons, for example: 
 CT artifact. 
 Patient positioning where the lesions are obstructed or cannot be seen. 
 Lesions that may not be seen in their entirety due to CT slice thickness. 


TAS-102 
Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
TO-TAS-102-302_Protocol_Amendment 2.0_05May2016 
Page 53 of 94 
 In cases where a lesion divides into 2 lesions, the longest diameters of the fragmented 
portions should be added together to calculate the target lesion sum.  
 In cases where 2 lesions coalesce, a plane between them may be maintained that 
would aid in obtaining maximal diameter measurements of each individual lesion.  If 
the lesions have truly coalesced such that they are no longer separable, the vector of 
the longest diameter in this instance should be the maximal longest diameter for the 
‘coalesced lesion’. 
Non-target Lesions: 
 Non-target lesions include all non-measurable lesions and measurable lesions that 
have not been selected as target lesions 
 Lymph nodes that have a short axis <10 mm are considered non-pathological and 
should not be recorded. 
 Any equivocal lesion without clear diagnosis (eg, uncharacteristic solitary lung 
nodule without biopsy, uncharacteristic thyroid mass lesion without fine needle 
aspiration) may be considered a non-target lesion if it cannot be differentiated from a 
benign lesion.  
 All other lesions (or sites of disease), including pathological lymph nodes, should be 
identified as non-target lesions and should also be recorded at Baseline.  
Measurements are not required, but their presence, absence, or unequivocal 
progression should be followed throughout the study. 
 It is possible to record multiple non-target lesions involving the same organ as a 
single item on the eCRF (eg, multiple enlarged pelvic lymph nodes or multiple liver 
metastases). 
11.3. 
Response Criteria 
On-site assessments will include the assessment of: 
1. Target and non-target tumor responses. 
2. Overall response. 
The above assessments will be made as per the time points identified in Section 10.1.13. 
11.3.1. 
Target and Non-target Response Assessments 
11.3.1.1. Criteria for Assessment of Tumor Response 
Assessments will be based on the definitions below. 


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Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
TO-TAS-102-302_Protocol_Amendment 2.0_05May2016 
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TARGET LESIONS 
Lesions Response: 
Definition: 
Complete Response (CR) 
The disappearance of all target lesions. Any pathological lymph nodes must 
have reduction in short axis to <10 mm. 
Partial Response (PR) 
At least a 30% decrease in the sum of diameters of the target lesions, taking as a 
reference the baseline sum diameters. 
Progressive Disease (PD) 
At least a 20% increase in the sum of diameters of the target lesions, taking as a 
reference the smallest sum on study, including the baseline sum.  In addition to 
the relative increase of 20%, the sum must also demonstrate an absolute increase 
of at least 5 mm.  Definitive new lesion presence also indicates progression. 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD, taking as a reference the smallest sum diameters while on study. 
 
NON-TARGET LESIONS 
Lesions Response: 
Definition: 
Complete Response (CR) 
The disappearance of all non-target lesions.  All lymph nodes must be non-
pathological morphologically (ie, <10 mm in short axis in size).   
Non-CR/Non-PD 
A persistence of 1 non-target lesion(s)/ not reaching the extent of ‘unequivocal 
progression.’   
Progressive Disease (PD) 
Unequivocal progression of existing non-target lesions (see definition below). 
 
Progression in Non-target Disease:  
There must be an overall level of substantial worsening in non-target disease such that, even in 
the presence of stable disease (SD) or partial response (PR) in target disease, the overall tumor 
burden has increased sufficiently to merit discontinuation of therapy.   
Because worsening in non-target disease cannot be easily quantified, a useful test that can be 
applied when assessing patients for unequivocal progression is to consider if the increase in 
overall disease burden based on the change in non-measurable disease is comparable in 
magnitude to the increase that would be required to declare progressive disease (PD) for 
measurable disease; ie, an increase in tumor burden representing an additional 73% increase in 
‘volume’ (which is equivalent to a 20% increase in diameter in a measurable lesion). 
11.3.1.2. Additional Criteria to Consider When Assessing Tumor Response 
When effusions are known to be a potential adverse effect of treatment, cytological confirmation 
of the neoplastic origin of any effusion that appears or worsens during treatment when the 
measurable tumor has met criteria for response or SD is not mandatory, but might be performed 
to differentiate between response (or SD) and PD when substantial change of effusion and or 
ascites is noted. 
For equivocal findings of progression (eg, very small and uncertain new lesions; cystic changes 
or necrosis in existing lesions), treatment may continue until the next scheduled assessment.  If at 


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Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
TO-TAS-102-302_Protocol_Amendment 2.0_05May2016 
Page 55 of 94 
the next scheduled assessment, progression is confirmed, the date of progression should be the 
earlier date when progression was suspected.   
11.3.2. 
Overall Response Assessment 
Assessments will be based on the definitions provided in Table 7 and Table 8 below.  
Table 7: 
Time Point Response for Patients with Target (± Non-target) Disease 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD or 
Not all evaluated 
No 
PR 
PR 
Non-PD or Not all 
evaluated 
No 
PR 
SD 
Non-PD or Not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
Not evaluable 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
Table 8: 
Time Point Response for Patients with Only Non-target Disease 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/Non-PD 
No 
Non-CR/Non-PD 
Not all evaluated 
No 
Not evaluable 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
11.4. 
Best Overall Response Assessment 
The best overall response as per RECIST criteria (version 1.1, 2009) is the best response 
recorded from the start of the study treatment until the end of treatment.   


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Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
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Page 56 of 94 
12. 
REPORTING SAFETY INFORMATION 
12.1. 
Adverse Events/Serious Adverse Events 
12.1.1. 
Adverse Events 
An adverse event (AE) is any untoward medical condition that occurs in a patient while 
participating in a clinical study and does not necessarily have a causal relationship with the use 
of the study medication. 
Treatment emergent AEs are AEs that occur from the initiation of any study treatment 
administration, and do not necessarily have a causal relationship to the use of the study 
treatment.  
Provide a complete and specific clinical diagnosis as an AE verbatim term.  If a diagnosis is not 
available, then report signs and symptoms.  The Common Terminology Criteria for Adverse 
Events (CTCAE Version 4.03) terms are to be used to assess severity/provide the grade for each 
AE that is reported. 
Refer to Section 12.1.5, Section 12.1.6, and Section 12.1.7 for definitions and reporting of 
pregnancy, medication errors, and overdose, respectively.  
Any untoward medical event that occurs outside the period of patient follow-up (30 days after 
the last dose of study treatment or until the start of new antitumor therapy, whichever is earlier) 
is not considered an AE unless determined by the Investigator to have a causal relationship with 
the study treatment. 
If any SAEs are observed after the patient follow-up period has ended, only those SAEs 
determined to have a causal relationship with the study medication will be recorded in the case 
report form. 
Symptoms or laboratory or instrumental (eg, electrocardiographic) abnormalities of a pre-
existing disease, such as cancer or other disease, should not be considered an AE.  However, 
occurrences of new symptoms as well as worsening of pre-existing medical conditions are 
considered AEs.  In addition, a new laboratory or instrumental abnormality that has a clinical 
impact on a patient (eg, resulting in study medication dose reduction, treatment delay, treatment 
discontinuation, requires treatment due to abnormal values, or is considered medically important 
by the Investigator) is considered an AE, unless it is considered part of clinical manifestations to 
a clinical diagnosis that is already reported as an AE. 
AEs will be reported from the first dose of study medication through the period of patient follow-
up (30 days after the last dose of study medication or until the start of new antitumor therapy, 
whichever is earlier).  Document all AEs in the source documents.  Documentation should 
include onset and resolution/stabilization dates, severity/grade, relationship to study medication, 
and outcome of the event.   


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Protocol No. TO-TAS-102-302 
 
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Causal relationship: 
1. Reasonably Possible:  The AE is related if it follows a reasonable temporal sequence 
from administration of study medication and, one of the following conditions is true: 
 A positive de-challenge.  This means that the event resolves when the drug is stopped. 
 A positive re-challenge.  This means that the event reappears when the drug is 
restarted. 
 Or, the event cannot be reasonably explained by the patient’s clinical state and/or 
other administered therapies. 
2. Not Reasonably Possible:  The AE is not related when there is no reasonable possibility 
that the study medication caused the event.  For the purposes of safety reporting, “no 
reasonable possibility” means there is no evidence to suggest a causal relationship 
between the drug and the AE.   
Reasonable possibility is provided by the following examples of types of evidence that 
would suggest a causal relationship between drug and AE: 
 A single occurrence of an event that is uncommon and known to be strongly 
associated with drug exposure (eg, angioedema, hepatic injury, Stevens-Johnson 
syndrome) 
 One or more occurrences of an event that is not commonly associated with drug 
exposure, but is otherwise uncommon in the population exposed to drug (eg, tendon 
rupture) 
Outcome:  
 Resolved without sequelae 
 Resolved with sequelae 
 Resolving (can only be used for SAEs and cannot be a final outcome) 
 Unresolved 
 Death 
Any unresolved AEs should be followed until the earliest occurrence of one of the following: 
 AE has resolved. 
 AE has stabilized.  An AE cannot be considered stabilized while the patient is on 
study medication.  Ongoing AEs must be assessed for stabilization 30 days post study 
medication discontinuation. 
 The start of new antitumor therapy. 


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Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
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12.1.2. 
Serious Adverse Events (SAE) 
A Serious Adverse Event (experience) or reaction is any untoward medical occurrence that at 
any time: 
a. Results in death (see Section 12.1.3). 
b. Is life-threatening. 
NOTE: The term "life-threatening" in the definition of "serious" refers to an event in 
which the patient was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it were more severe. 
c. Requires inpatient hospitalization or prolongation of existing hospitalization.  The 
following are not considered hospitalizations for the purposes of assessing 
seriousness: 
 Emergency room visits less than 24 hours. 
 Hospitalizations for preplanned procedures. 
 Hospitalization for study-related treatment and procedures. 
d. Results in persistent or significant incapacity or disability, where disability is defined 
as a substantial disruption of a person’s ability to conduct normal life functions, either 
reported or defined as per clinical judgment. 
e. Is a congenital anomaly/birth defect (if exposure to product just before conception or 
during pregnancy resulted in an adverse outcome in the child). 
f. Is any other important medical event, eg, may not result in death, be life-threatening, 
or require hospitalization, but based upon appropriate medical judgment, it may 
jeopardize the patient and may require medical or surgical intervention to prevent one 
of the outcomes listed in the points above.  Examples of such events are intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias or convulsions that do not result in hospitalization; or development of drug 
dependency or drug abuse. 
Serious adverse events must be reported to Taiho Pharmacovigilance or designee within 
24 hours from the time the Investigator first becomes aware of the SAE.  Comprehensive 
information available at the time of initial reporting (including narrative description, medical 
history and concomitant medications) needs to be provided with careful consideration regarding 
causality and serious criterion.  The SAE reporting process and contact information for reporting 
the SAE are provided in the eCRF/SAE Completion Guidelines. 
After the initial SAE notification to Taiho Pharmacovigilance or designee, follow-up SAE 
information will be submitted each time that important follow-up information (eg, diagnosis, 
outcome, causality assessment, results of specific investigations) becomes available.   
All SAEs within the follow-up window (eg, within 30 days after the last dose of study 
medication or until the start of new antitumor therapy, whichever is earlier) established in the 
protocol will be reported to Taiho Pharmacovigilance or designee.   
If serious medical occurrences including deaths outside the follow-up window established by the 
protocol are reported to or observed by the Investigator that he/she believes are related to the 


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Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
TO-TAS-102-302_Protocol_Amendment 2.0_05May2016 
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administration of the investigational product, it is the Investigator’s responsibility to report this 
occurrence to Taiho Pharmacovigilance or designee.   
A serious adverse reaction (SAR) is any event that meets the definition of an SAE and is 
considered related to the administration of study medication.  An unexpected SAR is defined as 
any SAR, the nature or severity of which is not consistent with the applicable product 
information (eg, Investigator’s Brochure for an unauthorized investigational product or summary 
of product characteristics for an authorized product).   
All SAEs, SARs and suspected unexpected serious adverse reactions (SUSARs) will be 
reported as per European Union (EU) reporting requirements and local laws and regulations.   
12.1.3. 
Reporting of Deaths 
All deaths occurring through the 30-day follow-up period must be reported in the eCRF within 
24 hours. 
1. Death due to disease progression: 
Disease progression (radiologic or clinical) with the outcome of death will not be 
reported as an SAE.  However, relevant signs, symptoms and complications of disease 
progression (radiologic or clinical) must be reported as an AE or SAE if it meets the 
serious criteria.  It should be indicated that the signs, symptoms and complications are 
related to disease progression. 
2. Death due to other causes: 
Deaths due to reasons other than disease progression must be reported as an SAE. 
Death is not an acceptable AE/SAE term.  Death is an outcome of an SAE. 
When reporting a death in the eCRF, you will be required to identify which of the following best 
describes the category of death:   
 Toxicity for study drug 
 Radiologic disease progression 
 Clinical disease progression 
 Other causes 
12.1.4. 
Disease Progression 
1. How to report events related to non-fatal disease progression: 
a. Disease progression is not an acceptable AE term.  In cases of non-fatal disease 
progression, the relevant signs, symptoms and complications should be reported as an 
AE unless they meet the serious criteria.  If any of the signs, symptoms and 
complications meets any of the serious criteria, they should be reported as an SAE.  
In both cases it should be indicated whether the signs, symptoms and complications 
are related to disease progression. 
b. Radiologic disease progression without relevant signs, symptoms and complications 
will not be reported as an AE or SAE. 


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Metastatic Gastric Cancer 
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2. How to report events related to fatal disease progression: 
a. See Section 12.1.3, Reporting of Deaths. 
12.1.5. 
Pregnancy 
If a patient becomes pregnant while in the study, the study treatment must be immediately 
discontinued.  Pregnancy information for a female patient should be reported within 24 hours 
from the time the Investigator first becomes aware of a pregnancy or its outcome.  This should be 
performed by completing a Pregnancy Form and faxing it to Taiho Pharmacovigilance or 
designee.   
New and/or corrected information regarding the pregnancy obtained after submitting the initial 
Pregnancy Form must be submitted by faxing an updated Pregnancy Form to Taiho 
Pharmacovigilance or designee. 
If outcome of the pregnancy is a stillbirth, congenital anomaly/birth defect, or a serious event in 
the mother, report as an SAE to Taiho Pharmacovigilance or designee. 
12.1.6. 
Medication Errors 
A medication error is defined as any accidental incorrect administration of a medicinal product.  
The error may be related to the administration of a wrong medication, nature of the medication, 
route of administration, dosage or frequency of the treatment as specified in this protocol 
(including omission of one or more administrations). 
 Medication errors with study medication and concomitant medication treatment will 
not be recorded in the eCRF unless they result in an AE. 
 Medication errors with study medication that result in an overdose will be captured as 
an AE in the eCRF.  
 Medication errors with study medication that do not result in an AE should be 
handled as follows: 
 If it results in the omission of an administration, an incorrect dose (relative to that 
specified in this protocol), or the administration of more than the prescribed dose 
(but does not meet the overdose criteria), it will be identified through the 
recording of study drug accountability data in the eCRF and does not need to be 
reported as an AE. 
 If it results in an overdose, incorrect route of administration, or administration of 
an incorrect study drug, it will be reported as an AE. 
Based on the above criteria, medication errors that are captured as an AE on the eCRF should be 
reported to Taiho Pharmacovigilance or designee within 24 hours from the time the Investigator 
first becomes aware of its occurrence following the same process as described for the SAEs even 
if it does not meet any of the criteria of an SAE. 


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Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
TO-TAS-102-302_Protocol_Amendment 2.0_05May2016 
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12.1.7. 
Overdose 
An overdose with TAS-102 for this clinical trial is defined as: 
 Taking a dose beyond the recommended dose in one day or beyond the recommended 
total dose in each cycle. 
An accidental or intentional overdose with TAS-102 regardless of whether it is associated with 
an AE (even if not fulfilling a seriousness criterion) is to be captured as an AE on the eCRF and 
reported to Taiho Pharmacovigilance or designee within 24 hours from the time the Investigator 
first becomes aware of its occurrence following the same process as described for the SAEs. 
There is no known antidote available in case of TAS-102 overdose.  Overdose should be 
managed aggressively with close monitoring and administration of prophylactic and 
symptomatic therapies to prevent or correct potential side effects. 
An accidental or intentional overdose for concomitant medication should only be reported if it is 
associated with an AE.   
12.1.8. 
Breaking the Study Blind 
Prior to completion of the final analysis, unblinding of the study treatment will not occur unless 
it is needed to manage a patient’s medical condition.   
 In an emergency, when specific knowledge of the patient’s treatment assignment is 
needed to manage a patient’s medical condition, the Investigator can unblind the 
patient by calling the IXRS to obtain the patient’s treatment assignment.  It is 
recommended that the Investigator then informs the Sponsor’s Medical Monitor of 
the case.   
 In a non-emergent situation, the Investigator should attempt to contact the Sponsor’s 
Medical Monitor to discuss the case prior to unblinding.  
Irrespective of emergent or non-emergent situations, if unblinding occurs, the Investigator must 
record the date and the reason for unblinding.  The Investigator must not disclose the unblinding 
information. 
When a patient has a SUSAR event (see Section 12.1.2), the blind will be broken for that patient 
by specific Taiho Pharmacovigilance personnel via the IXRS.  If the patient is found to be on 
TAS-102, the SUSAR will be submitted to Regulatory Authorities; if the patient is found to be 
on placebo, the SUSAR will not be submitted to Regulatory Authorities, unless requested.  To 
maintain the blind, all SUSARs are distributed to site Investigators via a blinded Council for 
International Organizations of Medical Sciences (CIOMS) report. 
12.2. 
Laboratory Evaluations 
12.2.1. 
Reporting and Evaluation of Laboratory Test Results 
Laboratory tests are to be performed as required per protocol.  All laboratory values that are out 
of the normal range are to be evaluated for their clinical significance before exposing the patient 
to the next dose of study medication.   
The laboratory must provide normal reference ranges.   


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Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
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Any laboratory abnormality that has a clinical impact on the patient, eg, results in delay of study 
medication dosing, study discontinuation, requires treatment due to abnormal values, or is 
considered by the Investigator to be medically important, must be reported as an AE, unless it is 
considered a supporting lab to a clinical diagnosis that is already reported as an AE.  If there is a 
question or concern, please call the Sponsor’s Medical Monitor.  All laboratory data will be 
analyzed using NCI CTCAE grade criteria (Version 4.03).   
12.2.2. 
Repeat Testing 
Repeat the evaluation of any clinically significant laboratory test, as clinically indicated, until the 
value returns to the baseline level or clinically stabilizes, or until another treatment is given. 
12.3. 
Physical Examination and Performance Status 
Perform physical examinations and performance status evaluations as described in the Study 
Procedures section of the protocol.  If changes are observed, determine whether they meet the 
definition of an AE.  Document all observations and evaluations. 
12.4. 
Vital Signs and Body Weight 
Verify and document vital signs and body weight.  If a clinically significant change is observed, 
repeat the measurement as clinically indicated and evaluate for its clinical relevance and whether 
it meets the definition of an AE.   


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Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
TO-TAS-102-302_Protocol_Amendment 2.0_05May2016 
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13. 
STATISTICS 
A Statistical Analysis Plan (SAP) that includes a more technical and detailed description 
(including templates for Tables, Listings, and Figures) of the planned statistical summaries 
analyses will be prepared. 
13.1. 
Study Populations 
The safety and efficacy study populations will be defined as follows: 
 Intent-to-Treat (ITT) population:  This population includes all randomized patients 
and is the primary population for all efficacy parameters.  All analyses using this 
population will be based on the treatment assigned by IXRS. 
 As-Treated (AT) population: This population includes all patients who took part of 
any dose of the study treatment.  This population will be used for safety analyses.  All 
analyses using this population will be based on the treatment actually received. 
 Tumor Response (TR) evaluable population:  This population includes all patients in 
the ITT population with measurable disease (at least one target lesion) at baseline and 
with at least one tumor evaluation while on treatment (except for early disease 
progression/cancer-related death).  All analyses using this population will be based on 
the treatment assigned by IXRS.   
13.2. 
Study Endpoints 
13.2.1. 
Primary Efficacy Endpoint – Overall Survival 
Survival is the primary endpoint of this study and is defined as the time from the date of 
randomization to the death date.  In the absence of death confirmation or for patients alive as of 
the OS cut-off date, survival time will be censored at the date of last study follow-up, or the cut-
off date, whichever is earlier. 
The OS cut-off date used for the primary analysis will be based on the date of the 384th death in 
the study.  With the OS cut-off date being event driven, for operational efficiency, the cut-off 
date for all other study endpoints will be fixed at close proximity of the OS cut-off date, when 
the milestone is nearing completion.   
13.2.2. 
Key Secondary Efficacy Endpoint - PFS 
Progression free survival is defined as the time from the date of randomization until the date of 
the investigator-assessed radiological disease progression or death due to any cause.  Patients 
who are alive with no disease progression as of the analysis cut-off date will be censored at the 
date of the last tumor assessment.  Patients who receive non-study cancer treatment before 
disease progression, or patients with clinical but not radiologic evidence of progression will be 
censored at the date of the last evaluable tumor assessment before the non-study cancer treatment 
is initiated.  Detailed censoring rules are outlined in the SAP. 


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Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
TO-TAS-102-302_Protocol_Amendment 2.0_05May2016 
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13.2.3. 
Other Secondary Efficacy Endpoints 
13.2.3.1. Overall Response Rate (ORR) 
The assessment of ORR will be based on Investigator review of the images.  ORR is defined as 
the proportion of patients with objective evidence of CR or PR.   
At the analysis stage, the best overall response will be assigned for each patient as the best 
response recorded from all responses recorded after study randomization.  If applicable, 
responses recorded after disease progression or initiation of non-study cancer treatment will be 
excluded.  A patient’s best response assignment of SD needs to be maintained for at least 
6 weeks after study randomization.  Per RECIST 1.1, responses of PR or CR in studies with 
survival as the primary endpoint do not have a minimum time requirement to maintain the 
response.12  
13.2.3.2. Disease Control Rate (DCR) 
The assessment of DCR will parallel that of ORR, with DCR defined as the proportion of 
patients with objective evidence of CR, PR, or SD.   
13.2.3.3. Time to Deterioration of ECOG Performance Status 
The time to deterioration of ECOG performance status is defined as the time from randomization 
to the first date on which an ECOG performance status score of 2 or higher is observed. 
13.2.3.4. Quality of Life 
The EORTC QoL questionnaire (QLQ) is an integrated system for assessing the health-related 
QoL of cancer patients participating in international clinical trials. The core questionnaire, the 
QLQ-C30, incorporates 5 functional scales (physical, role, cognitive, emotional, and social), 
3 symptom scales (fatigue, pain, and nausea and vomiting), a global health status scale, and a 
number of single items assessing additional symptoms commonly reported by cancer patients 
(dyspnea, loss of appetite, insomnia, constipation and diarrhea) and perceived financial impact of 
the disease.  
The gastric cancer module (QLQ-STO22) is meant for use among gastric cancer patients varying 
in disease stage and treatment modality.   
 
13.3. 
Analytical Methods 
13.3.1. 
Patient Disposition, Baseline and Treatment Characteristics 
13.3.1.1. Patient Disposition 
The number of patients in each study population and the reasons for exclusion, along with any 
randomization and/or stratification errors will be summarized.  In addition, patients that 
discontinue study treatment or study follow-up will also be summarized, along with reasons for 
study discontinuation. 


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TAS-102 
Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
TO-TAS-102-302_Protocol_Amendment 2.0_05May2016 
Page 68 of 94 
testing and preserve the overall 1-sided study significance level of 0.025.  A fixed HR boundary 
will be used to assess futility (non-binding).  Additional details will be provided in the DMC 
charter. 


TAS-102 
Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
TO-TAS-102-302_Protocol_Amendment 2.0_05May2016 
Page 69 of 94 
14. 
ETHICS 
14.1. 
Ethical Considerations 
It is mandatory that all considerations regarding the protection of human subjects be carried out 
in accordance with the protocol, Good Clinical Practice (GCP), ICH Guidelines, the ethical 
principles that have their origin in the Declaration of Helsinki, and all applicable regulatory 
requirements. 
14.2. 
Informed Consent and Patient Information 
Obtaining informed consent must be done according to the guidelines provided in the 
Declaration of Helsinki, ICH E6 Guideline for GCP, and local regulations. 
The Investigator (according to applicable regulatory requirements) or a person designated by the 
Investigator and under the Investigator’s responsibility should fully inform patients of all 
pertinent aspects of the clinical trial.  All participants should be informed to the fullest extent 
possible about the study in a language and in terms they are able to understand. 
Prior to participation in the trial, the written ICF is to be signed and personally dated by the 
patient or by the patient’s legal representative and by the person who conducted the ICF 
discussion.  A copy of the signed and dated ICF will be provided to the patient.  The ICF used 
must have had prior approval by the Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC). 
14.3. 
Institutional Review Board/Independent Ethics Committee Approval 
The study must be approved by an appropriately constituted IRB/IEC, as required in Chapter 3 of 
the ICH E6 Guidelines. 
The IRB/IEC must provide written approval of the study.  The written approval/favorable 
opinion should include protocol (title, number and version number), list of documents reviewed 
(eg, protocol, ICF, IB, curriculum vitae, etc), and the date of the review. 
The Investigator is required to submit a copy of the written and dated IRB/IEC 
approval/favorable opinion to the Sponsor or its representative prior to initiation of this study. 
Investigational product will not be released to the trial site and the Investigator will not start the 
trial until this written IRB/IEC approval/favorable opinion is received by the Sponsor or its 
representative. 
The Investigator is responsible for obtaining renewal of approval throughout the duration of the 
study.  Timeframes for renewal will be based on IRB/IEC requirements but renewal at least 
annually is required by regulations.   
At the end of the trial, the IRB/IEC will be notified of the conclusion of the trial and its outcome. 


TAS-102 
Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
TO-TAS-102-302_Protocol_Amendment 2.0_05May2016 
Page 70 of 94 
15. 
ADMINISTRATIVE CONSIDERATIONS 
15.1. 
Protocol Amendments 
No change to the protocol may be made without the agreement of Taiho Oncology, Inc.  Any 
amendment to the original protocol will be made by Taiho Oncology, Inc. and will be submitted 
to the IRB/IEC and appropriate regulatory authorities for approval or notification.   
15.2. 
Curriculum Vitae 
All Investigators and any sub-investigator(s) must provide Taiho Oncology, Inc. with current 
(within 2 years) signed and dated copies of their own curriculum vitae listing the experience, 
qualifications, and training prior to the beginning of the study. 
15.3. 
Administrative Structure 
The administrative structure of the study (eg, Contract Research Organizations) will be provided 
to all sites.   
15.4. 
Data Monitoring Committee (DMC) 
A DMC will be established for this study to provide additional, independent oversight that can 
enhance safety of study participants and the study conduct.  The DMC will comprise of 
clinicians and a statistician, all independent from the Sponsor and investigative sites and selected 
as to avoid conflict of interest.  
The primary objectives of this DMC are to provide independent safety monitoring comparing 
safety between the study groups and to provide a recommendation based on the planned interim 
analysis. 
A DMC charter will be written to establish well-defined standard operating procedures including 
meeting proceedings and structure, data assessments, documentation and record keeping, process 
for DMC recommendations, and regulatory reporting as applicable.  The charter will be written 
with procedures ensuring the minimization of bias, such as maintaining confidentiality of any 
interim data. 
15.5. 
Monitoring Procedures 
15.5.1. 
Investigator’s Responsibilities 
The Investigator agrees to conduct the study in accordance with the Clinical Trial Protocol, ICH 
guidelines E6 – GCP, Section 4 – Investigator’s obligations and the applicable regulatory 
requirements. 
The Investigator is required to ensure compliance with the protocol and other procedures 
provided by the Sponsor.  The Investigator agrees to provide reliable data and all information 
required by the protocol, eCRF, SAE forms, and Data Resolution Forms or any other appropriate 
instrument.  This information must be accurate, legible and according to instructions provided. 


TAS-102 
Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
TO-TAS-102-302_Protocol_Amendment 2.0_05May2016 
Page 71 of 94 
The Investigator must ensure that the Sponsor, Sponsor’s representatives and regulatory agencies 
will have access to such documentation. 
The Investigator may appoint sub-Investigators to assist in the conduct of the trial.  All sub-
Investigators shall be appointed and listed in a timely manner.  They will be supervised and work 
under the responsibility of the Investigator. 
15.5.2. 
Sponsor’s Responsibilities 
The Sponsor is responsible to health authorities for taking all reasonable steps to ensure the 
proper conduct of the clinical trial protocol with regard to ethics, protocol compliance, and 
integrity and validity of the data recorded in the eCRFs.  Thus, the main duty of the study site 
monitor (CRA) is to help the Investigator and the Sponsor maintain a high level of ethical, 
scientific, technical, regulatory, and quality in all aspects of the trial. 
At regular intervals during the trial, the site will be contacted, through monitoring visits, letters 
or telephone calls by the Sponsor or its representatives to review study progress, Investigator and 
patient’s compliance with requirements, and follow up on any issues to be addressed.  During the 
monitoring visits, source documents, informed consent, recruitment, SAE documentation and 
reporting, investigational product accountability, concomitant medications, AEs, eCRFs, and 
queries will be reviewed with the Investigator. 
15.5.3. 
Source Documents 
According to ICH guidelines the monitor will check the eCRF entries against the source 
documents.  Source documents are original documents, data, and records (eg, hospital records, 
clinical and office charts, laboratory notes, memoranda, subject’s evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate and complete, microfiches, photographic negatives, 
microfilm or magnetic media, X-rays, subject files, and records kept at the pharmacy, at 
laboratories, and at medical-technical departments involved in the clinical trial). 
The Informed Consent will include a statement by which the patient allows the Sponsor’s duly 
authorized personnel, the IRB/IEC, and regulatory authorities to have direct access to original 
records supporting eCRF data. 
The use of pencil and correction fluids is not accepted for recording clinical research 
information.  Corrections in source documents must be done by crossing out with a single line, 
then initialing and dating and recording the corrected information. 
15.5.4. 
Case Report Form 
Electronic CRFs will be provided by the Sponsor. 
Investigators will be provided with detailed eCRF Completion Guidelines that will identify the 
required data points to be collected, how to document them, and when the data should be 
documented. 
It is the responsibility of the Investigator to maintain adequate and accurate eCRFs to record 
(according to the eCRF Completion Guidelines) all observations and other data pertinent to the 


TAS-102 
Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
TO-TAS-102-302_Protocol_Amendment 2.0_05May2016 
Page 72 of 94 
clinical trial obtained during scheduled or unscheduled visits.  All eCRFs should be fully 
completed to ensure accurate data interpretation.  
The computerized handling of the data by the Sponsor after entry of data via eCRFs may 
generate additional requests via electronic queries or other means to which the Investigator is 
obliged to respond by confirming or modifying the data questioned.  These requests with their 
responses will be included in the eCRFs held by the Investigator and Sponsor. 
15.5.5. 
Sponsor’s Audits and Regulatory Inspections 
For the purpose of ensuring compliance with the protocol, GCP and applicable regulatory 
requirements, the Investigator will permit auditing by the Sponsor or its representative and 
inspections by regulatory authorities. 
The Investigator agrees to allow the auditors and inspectors to have direct access to the study 
records for review.  The people performing these activities will not disclose any personal identity 
or personal medical information assessed. 
The Investigator will make every effort to help with the performance of the audits and 
inspections, giving access to all necessary facilities, data and documents pertaining to the clinical 
trial.  As soon as the Investigator is notified of a planned inspection by the regulatory authorities 
or IRB/IEC, the Investigator will inform the Sponsor.  Any results arising from such inspections 
will be immediately communicated by the Investigator to the Sponsor.  The Investigator shall 
take appropriate measures required by the Sponsor to take corrective actions for all problems 
found during audits and or inspections. 
15.6. 
Archiving of Records 
The Investigator is responsible for the retention of all study documents according to institutional 
policies, local laws, ICH guidelines E6 – GCP, Sections 4.9.4 and 4.9.5 and, for studies 
conducted under an Investigational New Drug (IND) application, the USA Code of Federal 
Regulation (CFR) Title 21 part 312.62.  For more information on USA requirements and ICH 
Guidelines, please go to http://www.fda.gov and http://www.ema.europa.eu.   
The Investigator agrees to inform the Sponsor in writing of the intention to remove or destroy 
any study-related records.  Prior to contacting the Sponsor, the Investigator must ensure that 
institutional and local requirements (for example, ICH Guidelines) have been satisfied.  The 
Sponsor will evaluate the Investigator’s request and provide authorization for destruction of such 
records to the Investigator in writing.  
In the event that all retention of records requirements have been fulfilled, but the Sponsor 
requests that the Investigator maintain the records for a longer period of time, additional 
arrangements will be made. 
15.7. 
Final Report 
Whether the study is completed or prematurely terminated, a final report of the study will be 
written by the Sponsor or its designee and submitted to the regulatory agency(ies), as required by 
the applicable regulations. 


TAS-102 
Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
TO-TAS-102-302_Protocol_Amendment 2.0_05May2016 
Page 73 of 94 
The final study report will be retained by the Sponsor or by any other subsequent owner of this 
drug, for 5 years beyond the lifetime of the product. 
15.8. 
Use and Publication of Study Results 
The Investigator agrees that the Sponsor maintains the right to use the results of this study in 
their original form and/or in a global report for submission to governmental and regulatory 
authorities of any country.  Data from this study must not be published without prior 
authorization from the Sponsor. 
The results of the study may be presented during scientific symposia or published in a scientific 
journal only after review by the Sponsor in accordance with the guidelines set forth in the 
applicable publication or financial agreement. 
15.9. 
Financial Disclosure 
Financial disclosure for clinical Investigators will be obtained and record keeping of financial 
records will be in accordance with local regulatory requirements and CFR Title 21 part 54. 
15.10. 
Termination of the Study 
If the Sponsor and/or the Investigator should discover conditions arising during the study that 
indicate it should be terminated, an appropriate schedule for termination will be instituted.  The 
Sponsor also reserves the right to discontinue this study for administrative reasons at any time.   


TAS-102 
Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
TO-TAS-102-302_Protocol_Amendment 2.0_05May2016 
Page 74 of 94 
16. 
CONFIDENTIALITY AND DATA PROTECTION 
All information provided to the Investigator by the Sponsor or Sponsor’s representatives, 
information produced during the clinical trial including, but not limited to the protocol, eCRF, 
IB, and the results obtained during the course of the trial is confidential.  The members of the 
research team agree not to discuss such information in any way without prior written permission 
from the Sponsor. 
However, the submission of the protocol and necessary documentation to the IRB/IEC is 
permitted.  The IRB/IEC members have the same obligation of confidentiality. 
The patient’s personal data and Investigator’s personal data that may be included in the 
Sponsor’s database shall be treated in compliance with all applicable laws and regulations. 
When processing and archiving personal data pertaining to the Investigator and or to the patients, 
the Sponsor or its representatives shall take all appropriate measures to safeguard and prevent 
access to this data by any unauthorized third party. 


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TAS-102 
Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
TO-TAS-102-302_Protocol_Amendment 2.0_05May2016 
Page 76 of 94 
18. 
LIST OF REFERENCES 
                                                 
1  Muro K, Doi T, Bando H, Yasui H, Nishina T, Yamaguchi K et al. Multicenter phase 2 study 
of TAS-102 monotherapy in patients with pretreated advanced gastric cancer.  Manuscript in 
preparation. 
2  Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, 
Forman D, Bray, F.  GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: 
IARC CancerBase No. 11 [Internet].  Lyon, France: International Agency for Research on 
Cancer; 2013. Available from: http://globocan.iarc.fr  
3   National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in 
Oncology. Gastric cancer. V.3.2015.  http://www.nccn.org. 
4  Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, et al.  Trastuzumab 
in combination with chemotherapy versus chemotherapy alone for treatment of HER2-
positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-
label, randomised controlled trial.  The Lancet. 2010;376:687-97. 
5  Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, et al.  Ramucirumab 
monotherapy for previously treated advanced gastric or gastro-oesophageal junction 
adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, 
phase 3 trial.  Lancet.  2014;383:31-39. 
6  Wilke H, Muro K, Van Cutsem E, Oh S-C, Bodoky G, Shimada Y, et al. Ramucirumab plus 
paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric 
or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised 
phase 3 trial.  Lancet Oncol. 2014;15:1224–35. 
7  Mayer RJ, Van Cutsem E, Falcone A, Yoshino T, Garcia-Carbonero R, Mizunuma N et al. 
Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med 
2015;372:1909-19. 
8  Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al.  The European 
Organisation for Research and Treatment of Cancer QLQ-C30: A quality-of-life instrument 
for use in international clinical trials in oncology. Journal of the National Cancer Institute 
1993;85:365-76. 
9  Aapro MS, Bohlius J, Cameron DA, Dal Lago L, Donnelly JP, Kearney N, et al.  2010 
update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce 
the incidence of chemotherapy-induced febrile neutropenia in adult patients with 
lymphoproliferative disorders and solid tumours.  Eur J Cancer. 2011;47(1):8-32.   
10  Benson AB 3rd, Ajani JA, Catalano RB, Engelking C, Kornblau SM, Martenson JA Jr, et al.  
Recommended guidelines for the treatment of cancer treatment-induced diarrhea.  J Clin 
Oncol. 2004;22(14):2918-26. 


TAS-102 
Protocol No. TO-TAS-102-302 
 
Metastatic Gastric Cancer 
TO-TAS-102-302_Protocol_Amendment 2.0_05May2016 
Page 77 of 94 
                                                                                                                                                             
11  American Society of Clinical Oncology, Kris MG, Hesketh PJ, Somerfield MR, Feyer P, 
Clark-Snow R, et al. American Society of Clinical Oncology guidelines for antiemetics in 
oncology: update 2006. J Clin Oncol. 2006;24:2932-47. 
12  Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al.  New 
response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J 
Cancer. 2009;45:228-47.   
13  Ohtsu A, Ajani JA, Bai Y-X, Bang Y-J, Chung H-C, Pan H-M, et al.  Everolimus for 
previously treated advanced gastric cancer: results of the randomized, double-blind, phase III 
GRANITE-1 study.  J Clin Oncol. 2013;31:3935-43. 


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Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan – Protocol TO-TAS-102-302  
April 27, 2018 
 
3 
 
TECHNICAL SUMMARY REPORT (TSR) 
 
 
Name of Sponsor/Company 
 Taiho Oncology, Inc.; Taiho 
Pharmaceutical Co., Ltd. 
Individual Study Table Referring 
to Part of the Dossier: 
Volume: 
(For National Authority Use 
Only): 
Name of Finished Product: 
{LONSURF} 
Page: 
 
Name of Active Ingredient: 
trifluridine (FTD) and tipiracil 
hydrochloride (TPI) 
Protocol: 
TO-TAS-102-302 
 
Title Of Study: 
RANDOMIZED, DOUBLE-BLIND, PHASE 3 STUDY EVALUATING TAS-102 PLUS BEST SUPPORTIVE 
CARE (BSC) VERSUS PLACEBO PLUS BSC IN PATIENTS WITH METASTATIC GASTRIC CANCER 
REFRACTORY TO STANDARD TREATMENTS 
Investigators: 
Study Center(s):  
At least 120 
Studied period (years): 
18 months   
Phase of development: Phase 3 
Objectives: 
Primary: 
The primary objective of this study is to evaluate overall survival in patients with refractory 
metastatic gastric cancer receiving TAS-102 plus BSC or placebo plus BSC 
Key Secondary: 
The key secondary objective of this study is to evaluate progression-free survival in patients with refractory 
metastatic gastric cancer receiving TAS-102 plus BSC or placebo plus BSC. 
Other Secondary: 
Other secondary objectives of this study are to evaluate overall response rate, disease control rate, time to 
deterioration of ECOG performance and quality of life in patients with refractory metastatic gastric cancer receiving 
TAS-102 plus BSC or placebo plus BSC. 
 
Methodology: 
Double blind comparative study (investigational drug vs placebo) 
Number of Subjects (planned and analyzed): 
Approximately 500 patients will be randomized using a treatment allocation of 2:1 (TAS-102 plus BSC: placebo 
plus BSC). A target of 384 events (deaths) will be required for the primary analysis. 


Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan – Protocol TO-TAS-102-302  
April 27, 2018 
 
4 
 
Diagnosis and main criteria for inclusion (see protocol Section 2): 
Male and female patients age 18 years or older (20 years or older for patients enrolled in Japan) with histologically 
confirmed, non-resectable, metastatic gastric adenocarcinoma including adenocarcinoma of the gastroesophageal 
junction, and an ECOG performance status of 0 or 1, who have received at least 2 prior regimens (at least 1 cycle per 
regimen) for advanced disease, and were refractory to or unable to tolerate their last prior therapy. 
 
Prior regimens must have included a fluoropyrimidine, platinum, and either a taxane- and/or irinotecan-
containing regimen; patients whose tumors are known to be HER2-neu-positive (HER2+) must have received 
prior anti-HER2+ therapy if available. 
 
Patients have progressed based on imaging during or within 3 months of the last administration of their last 
prior regimen. 
 
Patients who have withdrawn from their last prior regimen due to unacceptable toxicity warranting 
discontinuation of treatment and precluding retreatment with the same agent prior to progression of disease 
will also be eligible to enter the study. 
 
Patients who have received postoperative adjuvant chemotherapy and radiotherapy, and had recurrence 
during or within 6 months of completion of the adjuvant chemotherapy are allowed to count the adjuvant 
therapy as one prior regimen for advanced disease. Patients who have received pre- and post-operative 
adjuvant chemotherapy, and had recurrence during or within 6 months of completion of the adjuvant 
chemotherapy are allowed to count the adjuvant therapy as one prior regimen only if the same regimen was 
administered both pre- and post-operatively. 
Test product, dose and mode of administration: 
TAS-102 (starting dose of 35 mg/m2/dose) will be administered orally twice daily (BID), within 1 hour after 
completion of morning and evening meals, for 5 days a week with 2 days rest for 2 weeks, followed by a 14-day rest, 
repeated every 4 weeks.  Patients will receive blinded study medication until a discontinuation criterion is met or until 
completion of the primary endpoint analysis, whichever is sooner. 
Duration of treatment: 
After the end of treatment, all patients will be followed for survival every 4 weeks   until death or until the target 
number of events (deaths) is met. If the primary endpoint of the study is met and efficacy as well as safety support a 
favorable benefit/risk ratio for TAS-102, patients currently or previously treated with placebo who continue to meet 
study eligibility criteria will be offered the option to crossover to open-label TAS-102. Patients receiving TAS-102 
will also be switched to open-label TAS-102 at that time. Patients who receive open-label TAS-102 treatment after 
conclusion of survival follow-up will be followed for safety and tumor response according to the site standard of care. 
Reference therapy, dose and mode of administration: 
Placebo (starting dose of 35 mg/m2/dose) will be administered orally twice daily (BID), within 1 hour after completion 
of morning and evening meals, for 5 days a week with 2 days rest for 2 weeks, followed by a 14-day rest, repeated 
every 4 weeks.   
Criteria for evaluation (see protocol section x.n): 
Efficacy: 
Computed tomography (CT) scans will be performed every 8 weeks. On-site tumor assessments will be performed 
by the Investigator/local radiologist. Tumor assessments will be analyzed using Response Evaluation Criteria in 
Solid Tumors (RECIST) criteria (Version 1.1, 2009). Progression-free survival will be determined for all patients. 
Quality of Life assessments will be performed prior to start of dose administration in each cycle 
 
Safety: 
 Standard safety monitoring will be performed and adverse events (AEs) will be graded using the National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. 


Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan – Protocol TO-TAS-102-302  
April 27, 2018 
 
5 
 
Statistical methods: 
Study Populations 
The study populations for all analyses are defined as follows. 
• Intent-to-Treat (ITT) population: This population includes all randomized patients and is the primary population for 
all efficacy parameters. All analyses using this population will be based on the treatment assigned by IXRS. 
• As-Treated (AT) population: This population includes all patients who took at least one dose of study treatment. This 
population is for safety analyses. All analyses using this population will be based on the treatment actually received.  
• Tumor Response (TR) Population: All patients in the ITT population with measurable disease (at least one target 
lesion) at baseline and with at least one tumor evaluation while on treatment. (Patients who have disease progression 
or a cancer-related death prior to their first on treatment tumor evaluation will also be considered evaluable.) All 
analyses using this population will be based on the treatment assigned by IXRS. 
 
Primary Efficacy Endpoint (OS) 
OS is defined as the time from the date of randomization to the date of death. If death is not observed during the study, 
the time will be censored at the last date the patient is known to be alive or the cut-off date, whichever is earlier. For 
the primary analysis of OS, the two treatment arms will be compared using the stratified log-rank test using the 3 
stratification factors in the randomization as per IXRS assignment. The hazard ratio will be estimated, along with the 
associated 2-sided 95% confidence intervals (CI), using a stratified Cox’s proportional hazard (CPH) model. Survival 
for each arm will be summarized using Kaplan Meier curves and further characterized in terms of the median and 
survival probability at 3, 6, 9 and 12 months, along with the corresponding 2-sided 95% CI for the estimates. 
 
Key Secondary Efficacy Endpoint (PFS) 
PFS will be evaluated from date of randomization to the first occurrence of radiologic progression or death. 
Treatment comparisons for PFS will use similar analytical methods as the OS endpoint. 
 
Other Secondary Efficacy Endpoints 
ORR and DCR will be compared between treatment arms using Fisher’s exact test and associated 95% CIs will also 
be derived. Time to deterioration of ECOG performance status to a score of 2 or higher will be analyzed as described 
for PFS. Change in QoL scores prior to cycles 2, 3 and 4 will be determined for the summary, all domains and single 
items by subtracting each patient’s score from their corresponding baseline score. For each domain, the proportion of 
patients with deteriorating (vs stable or improving) scores prior to cycles 2, 3 and 4 will be compared using Fisher’s 
exact test. Time to QoL deterioration will be evaluated for each arm using Kaplan-Meier estimates and compared 
using the log-rank test. 
 
Safety Analyses 
Simple descriptive statistics will be provided for safety endpoints and demographic/baseline characteristics. 
 
 
 
 
 


Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan – Protocol TO-TAS-102-302  
April 27, 2018 
 
6 
 
TABLE OF CONTENTS 
1. 
LIST OF ABBREVIATIONS.....................................................................................11 
2. 
INTRODUCTION ......................................................................................................15 
3. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................16 
3.1. 
Study Objectives .........................................................................................................16 
3.1.1. 
Primary Objective .......................................................................................................16 
3.1.2. 
Key Secondary Objectives ..........................................................................................16 
3.1.3. 
Other Secondary Objectives .......................................................................................16 
3.2. 
Study Endpoints ..........................................................................................................16 
3.2.1. 
Primary Efficacy Endpoint .........................................................................................16 
3.2.2. 
Key Secondary Efficacy Endpoints ............................................................................17 
3.2.3. 
Other Secondary Efficacy Endpoints ..........................................................................17 
4. 
STUDY DESIGN .......................................................................................................19 
4.1. 
Summary of Study Design ..........................................................................................19 
4.2. 
Definition of Study Drugs ..........................................................................................20 
4.3. 
Sample Size Considerations .......................................................................................21 
4.3.1. 
Sample Size Justifications ..........................................................................................21 
4.4. 
Randomization ............................................................................................................21 
4.5. 
Clinical Assessments ..................................................................................................21 
4.5.1. 
Vital Signs, Height and Weight ..................................................................................21 
4.5.2. 
Performance Status .....................................................................................................21 
4.5.3. 
Laboratory Evaluations ...............................................................................................22 
4.5.4. 
Pregnancy Testing ......................................................................................................22 
4.5.5. 
Quality of Life ............................................................................................................23 
4.5.6. 
Tumor Measurements .................................................................................................23 
4.5.7. 
Concomitant Medications ...........................................................................................24 
5. 
PLANNED ANALYSES ............................................................................................25 
5.1. 
Interim Analyses .........................................................................................................25 
5.2. 
Final Analyses ............................................................................................................25 
6. 
STUDY DURATION AND VISIT SCHEDULE ......................................................26 
7. 
ANALYSIS POPULATIONS ....................................................................................29 
7.1. 
Intent-To-Treat (ITT) Population ...............................................................................29 


Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan – Protocol TO-TAS-102-302  
April 27, 2018 
 
7 
 
7.2. 
As-Treated (AT) Population (Safety Population) .......................................................29 
7.3. 
Tumor Response(TR) Population ...............................................................................29 
8. 
DERIVED AND TRANSFORMED DATA ..............................................................30 
8.1. 
Age (relatively to Informed Consent Date) ................................................................30 
8.2. 
Study Day ...................................................................................................................30 
8.3. 
Baseline .......................................................................................................................30 
8.4. 
Change from Baseline .................................................................................................31 
8.5. 
Day 1 ...........................................................................................................................31 
8.6. 
End of Study ...............................................................................................................31 
8.7. 
Visit Windows ............................................................................................................31 
8.8. 
Multiple Assessments .................................................................................................32 
8.9. 
Time Adjusted Incident Rate (per 100 Subject Year) ................................................32 
8.10. 
Days to “Recovery” (Grade 3 or Grade 4 abnormalities) ...........................................32 
8.11. 
Creatinine Clearance/Level ........................................................................................32 
8.12. 
Renal Function ............................................................................................................33 
8.13. 
Handling of Missing Data ...........................................................................................33 
8.13.1. 
Missing Efficacy Endpoints ........................................................................................33 
8.13.2. 
Missing Start and Stop Dates for Prior and Concomitant Medication .......................33 
8.13.3. 
Missing Start and Stop Dates for Adverse Events ......................................................33 
8.13.4. 
Missing Birth Date ......................................................................................................34 
8.13.5. 
Missing Exposure End Date .......................................................................................34 
8.13.6. 
Partial or Missing Date of Start of Antitumor Therapy ..............................................34 
8.14. 
Countries in EU ..........................................................................................................34 
9. 
GENERAL ANALYSIS .............................................................................................35 
9.1. 
Subjects Disposition ...................................................................................................35 
9.2. 
Protocol Deviations ....................................................................................................35 
9.2.1. 
CSR Reportable Protocol Deviation ...........................................................................35 
9.2.2. 
Major CSR Reportable Protocol Deviation ................................................................36 
9.3. 
Demographic and Baseline Characteristics ................................................................37 
9.4. 
Subject Inclusion and Exclusion Criteria ...................................................................37 
9.5. 
Medical History ..........................................................................................................38 
9.5.1. 
Cancer Medical History ..............................................................................................38 
9.5.2. 
Non-Cancer Medical History ......................................................................................38 


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Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan – Protocol TO-TAS-102-302  
April 27, 2018 
 
10 
 
LIST OF TABLES 
Table 1: 
List of Abbreviations ..................................................................................................11 
Table 2: 
Schedule of the Study. ................................................................................................27 
 
 


Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan – Protocol TO-TAS-102-302  
April 27, 2018 
 
11 
 
1. 
LIST OF ABBREVIATIONS 
In order to facilitate the interpretation of abbreviations used in this SAP, a comprehensive list 
(sorted alphabetically) of abbreviations was created for reader’s convenience and references.   
Table 1: 
List of Abbreviations 
Abbreviation 
Term 
µmol or mkmol 
Micromole 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of Covariance 
ANOVA 
Analysis of Variance 
AT 
As-Treated Population ( Safety Population) 
AST 
Aspartate Aminotransferase  
b.i.d. 
Twice Daily 
BSA 
Body Surface Area 
BSC 
Best Supportive Care 
BP 
Blood Pressure 
bpm 
Beats per Minute 
BUN 
Blood Urea Nitrogen 
C 
Center 
°C 
Degrees Celsius 
Ca 
Calcium 
Cl 
Chloride 
CrCl 
Creatinine Clearance 
CMH 
Cochran Mantel-Haenszel 
COSTART 
Coding Symbols for Thesaurus of Adverse Reaction Terms 
CR 
Complete Response 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
CT 
Computer Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCR 
Disease Control Rate 
DL 
Deciliter 


Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan – Protocol TO-TAS-102-302  
April 27, 2018 
 
12 
 
DMC 
Data Monitoring Committee 
DOB 
Date of Birth 
dy 
Days 
ECOG 
Eastern Cooperative Oncology Group 
oF 
Degrees Fahrenheit 
FTD 
Trifluridine 
g 
Grams 
GCP 
Good Clinical Practices 
GGT 
Gamma-Glutamyl Transferase 
HGB 
Hemoglobin 
HR 
Hazard Ratio 
ICD-9 
International Classification of Diseases – 9th Edition 
ICF 
Informed Consent Form 
In 
Inches 
IR 
Immediate Release 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat Population 
IU 
International Units 
K 
Potassium 
Kg 
Kilogram 
L 
Liter 
Lb 
Pounds 
LDH 
Lactate Dehydrogenase 
LLN 
Lower Limit of Normal 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities Terminology 
meq 
Milliequivalent 
mg 
Milligrams 
mL 
Milliliter 
mmHg 
Millimeters of Mercury 
mo 
Months 
N 
Total Sample Size 
Na 
Sodium 


Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan – Protocol TO-TAS-102-302  
April 27, 2018 
 
13 
 
ng 
Nanogram 
NIMH 
National Institute of Mental Health 
OC 
Observed Cases 
ORR 
Overall Response Rate 
OS 
Overall Survival 
OTC 
Over the Counter Medication 
PCS 
Potential Clinical Significance 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetic 
PP 
Per-Protocol Population 
PR 
Partial Response 
QoL 
Quality of Life 
QTc 
QT duration corrected for heart rate 
QTcB 
QT duration corrected for heart rate by Bazett’s formula 
QTcF 
QT duration corrected for heart rate by Fridericia’s formula 
RAP 
Reporting and Analysis Plan 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RBC 
Red Blood Cell Count 
ROW1 
Rest of World 1 (Everything except Japan) 
ROW2 
Rest of World 2 (Everything except US, EU, Japan) 
ROW3 
Rest of World 3 (Everything except US) 
S 
Sex 
s.d./SD 
Standard Deviation 
SD 
Stable Disease 
SAE 
Serious Adverse Event 
SAS 
Statistical Analysis System  
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
SR 
Sustained Release 
TEAE 
Treatment Emergent Adverse Event 
TEAESI 
Treatment Emergent Adverse Event of Special Interest 
TG 
Treatment Group 
TS 
Transdermal Delivery System-Placebo 


Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan – Protocol TO-TAS-102-302  
April 27, 2018 
 
14 
 
ULN 
Upper Limit of Normal 
VAS 
Visual Analogue Scale 
WBC 
White Blood Cell Count 
WHO 
World Health Organization  
yr 
Years 
 


Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan – Protocol TO-TAS-102-302  
April 27, 2018 
 
15 
 
2. 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the planned analyses and data 
displays to be included in the Clinical Study Report (CSR) for Protocol TO-TAS-102-302. 
Protocol Revision Chronology: 
Protocol TO-TAS-102-302 
30-JUN-2015 
Original 
 
 
 
This SAP was developed per standard operating procedure S-CS-001 and guidance document G-
CS-001, G-CS-018, G-CS-020. 
All decisions regarding final analysis, as defined in this SAP document, will be made prior to 
Database Freeze (unblinding) of the study data. Further information can be found in the DMC 
Charter or protocol. 
 
 


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Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan – Protocol TO-TAS-102-302  
April 27, 2018 
 
18 
 
(dyspnea, loss of appetite, insomnia, constipation and diarrhea) and perceived financial impact of 
the disease. 
The gastric cancer module (QLQ-STO22) is meant for use among gastric cancer patients varying 
in disease stage and treatment modality. 
 
 


Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan – Protocol TO-TAS-102-302  
April 27, 2018 
 
19 
 
4. 
STUDY DESIGN 
4.1. 
Summary of Study Design 
This is a multinational, double-blind, two-arm, parallel, randomized, Phase 3 study evaluating the 
efficacy and safety of TAS-102 plus BSC versus placebo plus BSC in patients with metastatic 
gastric cancer who have received at least 2 prior regimens for advanced disease. The study will be 
conducted under the sponsorship of Taiho Pharmaceutical Co., Ltd. for sites in Japan and Taiho 
Oncology, Inc. for sites in the rest of the world (ROW). 
Eligible patients will be centrally randomized (2:1) to TAS-102 + BSC (experimental arm) or 
placebo + BSC (control arm) using a dynamic allocation method (biased coin) via an Interactive 
Voice/Web Response System (IXRS), stratified by: 
• 
Region (ROW1 vs. Japan) 
• 
ECOG PS (0 vs. 1) 
• 
Prior treatment with ramucirumab (yes vs. no) 
Study medication should be started within 3 calendar days after the date of randomization and 
continue until a discontinuation criterion is met or until completion of the primary endpoint 
analysis, whichever is sooner. 
TAS-102 (35 mg/m2/dose) or placebo will be administered orally BID, within 1 hour after 
completion of morning and evening meals, for 5 days a week with 2 days rest for 2 weeks, followed 
by a 14-day rest, repeated every 4 weeks [1, 2, 3, 4, 5, 6, 7]. 
Computed tomography (CT) scans will be performed at baseline and every 8 weeks thereafter until 
disease progression. On-site tumor assessments will be performed by the Investigator/local 
radiologist. Tumor assessments will be analyzed using Response Evaluation Criteria in Solid 
Tumors (RECIST) criteria (Version 1.1, 2009). If patient discontinuation is for reasons other than 
radiologic disease progression (i.e., with intolerable side effects), patients will be followed every 
8 weeks for tumor response until radiologic disease progression or initiation of new anticancer 
therapy (whichever occurs first). 
Quality of life assessments (EORTC QLQ-C30 and QLQ-STO22) will be performed prior to start 
of dose administration in each cycle. 
Flow chart of the Study is presented in the Figure 1. 
 


Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan – Protocol TO-TAS-102-302  
April 27, 2018 
 
20 
 
Figure 1. Flow chart of the Study. 
 
 
4.2. 
Definition of Study Drugs 
TAS-102 (Study Drug) is an oral combination of an antineoplastic thymidine-based nucleoside 
analogue (trifluridine [FTD]) and a thymidine phosphorylase inhibitor (tipiracil hydrochloride 
[TPI]). Following uptake into cancer cells, FTD is phosphorylated by thymidine kinase, further 
metabolized in cells to a deoxyribonucleic acid (DNA) substrate, and incorporated directly into 
DNA, thereby interfering with DNA function to prevent cell proliferation. When orally 
administered, FTD is rapidly degraded to an inactive form by thymidine phosphorylase (TP). Co-
administration of TPI, an inhibitor of TP, with FTD prevents the rapid degradation of FTD, 
resulting in a significant increase in systemic exposure to FTD. 
 
 


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Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan – Protocol TO-TAS-102-302  
April 27, 2018 
 
22 
 
• Beginning with Cycle 2, obtain within 24 hours prior to start of study treatment in  
every cycle 
• End of Treatment Visit (if applicable) 
• 30-day Safety Follow-up Visit 
 
4.5.3. 
Laboratory Evaluations 
Clinical laboratory assessments will include hematology, serum chemistry and urinalysis tests 
described below. 
4.5.3.1. 
Hematology 
Samples of the patient’s blood will be collected for hematological assessments at the following 
time points (Table 2) and when clinically indicated: 
• Within 7 days prior to Day 1 of Cycle 1 (Laboratory results obtained prior to signing ICF 
may be used if the results were obtained within 7 days prior to Day 1 of Cycle 1.) 
• Day 15 of Cycle 1 
• Beginning with Cycle 2, obtain within 24 hours prior to start of study treatment in every 
cycle 
• End of Treatment Visit (if applicable) 
• 30-day Safety Follow-up Visit 
4.5.3.2. 
Serum Chemistry 
Samples of the patient’s blood will be collected for chemistry assessments at the following time 
points (Table 2) and when clinically indicated: 
• Within 7 days prior to Day 1 of Cycle 1 (Laboratory results obtained prior to signing ICF 
may be used if the results were obtained within 7 days prior to Day 1 of Cycle 1.) 
• Day 15 of Cycle 1 
• For all subsequent cycles, obtain within 24 hours prior to start of study treatment in every 
cycle 
• End of Treatment Visit (if applicable) 
• 30-day Safety Follow-up Visit. 
4.5.3.3. 
Urinalysis 
Samples of the patient’s urine will be collected for qualitative (dipstick) analysis within 7 days 
prior to Day 1 of Cycle 1 (Laboratory results obtained prior to signing ICF may be used if the 
results were obtained within 7 days prior to Day 1 of Cycle 1.) and when clinically indicated.  
 
4.5.4. 
Pregnancy Testing 
For patients who are female and of childbearing potential, perform pregnancy testing with serum 
or urine beta-human chorionic gonadotrophin (β-HCG) at the following time points and record 
the date, time, and test results in the patient’s source document  (Note: More frequent pregnancy 
assessments should be performed if required by local law).  


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CCI


Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan – Protocol TO-TAS-102-302  
April 27, 2018 
 
24 
 
If a patient is withdrawn due to radiologic disease progression, additional CT scans are not 
required at the end of treatment. 
The same method of assessment and the same technique must be used to characterize each 
identified and reported lesion at Baseline, throughout the study, and during the follow-up period. 
All patients’ files and radiological assessments must be available for source verification. Results 
of any unscheduled evaluations should be recorded in the patient’s source documents. 
 
4.5.7. 
Concomitant Medications 
All therapies and medications, prescription and over-the-counter, from the time of signed ICF 
through the 30-day Safety Follow-Up Visit, will be collected and summarized in the tables. This 
will include any medication used to treat AEs or SAEs during the safety follow-up period.  
At the 30-day Safety Follow-Up Visit, any new anticancer therapy and the date of initiation will 
be collected. 
During the survival follow-up period, only anticancer therapies will be collected. 
 
 
 


Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan – Protocol TO-TAS-102-302  
April 27, 2018 
 
25 
 
5. 
PLANNED ANALYSES 
5.1. 
Interim Analyses 
One interim analysis for efficacy and futility is planned for the study after approximately 1/2 of 
the total target events are observed (192 deaths). The Lan-DeMets alpha-spending approach will 
be used with O'Brien-Fleming stopping boundaries to guide the efficacy evaluation at the interim 
and final OS analysis. This approach will account for multiple testing and preserve the overall 1-
sided study significance level of 0.025. A fixed HR boundary will be used to assess futility (non-
binding). Additional details will be taken from the final analysis plan described in the present SAP 
(please refer to the Section 10 and to the Section 12 for additional details). 
 
 
5.2. 
Final Analyses 
Final analysis is planned for the study when the total target events are observed (384 deaths). The 
final analysis will follow instructions presented in this SAP. 
 
 


Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan – Protocol TO-TAS-102-302  
April 27, 2018 
 
26 
 
6. 
STUDY DURATION AND VISIT SCHEDULE 
The study was designed presuming accrual period of 18 months and a 5%/year loss to survival 
follow-up rate. Using a treatment allocation of 2:1 (TAS-102 : placebo) of 500 patients, 384 deaths 
will be targeted for the final OS analysis. 
Based on these design operating characteristics and assuming a median survival time of 
approximately 5 months in the control arm, the primary analysis target events milestone will be 
reached approximately 8 months after the last patient is randomized in the study. The median OS 
in the control arm was estimated based on the observed median OS of 3.8 months in the placebo 
arm of the 2nd line Phase 3 ramucirumab (REGARD) study and the observed median OS of 4.3 
months in the placebo arm of the 2nd & 3rd line Phase 3 everolimus (GRANITE) study [13]. The 
estimate was further increased to 5 months to account for the higher control median projected in 
the Japanese population. 
After the end of treatment, all patients will be followed for survival every 4 weeks until death or 
until the target number of events (deaths) is met. If the primary endpoint of the study is met and 
efficacy as well as safety support a favorable benefit/risk ratio for TAS-102, patients currently or 
previously treated with placebo who continue to meet study eligibility criteria will be offered the 
option to crossover to open-label TAS-102. Patients receiving TAS-102 will also be switched to 
open-label TAS-102 at that time. Patients who receive open-label TAS-102 treatment after 
conclusion of survival follow-up will be followed for safety and tumor response according to the 
site standard of care. 
The study schedule of events and assessments can be found in Table 2 . 
 


Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan – Protocol TO-TAS-102-302  
 
April 27, 2018 
 
27 
 
 
Table 2: 
Schedule of the Study. 
 
1 Sign ICF: Written informed consent should be obtained prior to the performance of any study procedure. 
2 Enrollment: Enroll patient by entering baseline data into the electronic case report form (eCRF) in order to receive a unique 6-digit patient number. 
3 Randomization: Central randomization via IXRS following confirmation of baseline eligibility criteria. Patients should receive the first dose of study medication within 3 
calendar days of randomization. 
4 Physical Exam: Beginning with Cycle 2, and for all subsequent cycles, perform within 24 hours prior to Day 1 study drug administration. 
5 Vital Signs: Heart rate, blood pressure, body temperature, respiratory rate; beginning with Cycle 2, and for all subsequent cycles; collect within 24 hours prior to Day 1 study 
drug administration. 
6 ECOG Performance Status: Collect within 24 hours prior to Day 1 study drug administration for all cycles. 


Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan – Protocol TO-TAS-102-302  
 
April 27, 2018 
 
28 
 
7 Hematology, Serum Chemistry, Urinalysis: Hematology and serum chemistry assessments will be performed at Baseline (within 7 days prior to Day 1 of Cycle 1; on Day 15 of 
Cycle 1; and within 24 hours prior to Day 1 study drug administration of Cycles ≥2. Urinalysis is required at Baseline and thereafter as clinically indicated. Laboratory 
results obtained prior to signing ICF may be used if the results were obtained within 7 days prior to Day 1 of Cycle 1. 
8 Pregnancy Test: Pregnancy test is required at Baseline (within 7 days prior to Day 1 of Cycle 1) and at either the End of Treatment or 30-day Safety Followup visit. More 
frequent pregnancy assessments may be performed as required by local law. 
9 Tumor Measurements: Obtain a contrast-enhanced computed tomography (CT) scan of the chest and abdomen (and pelvis, if clinically indicated) within 28 days prior to Day 1 of 
Cycle 1 and every 8 weeks thereafter during study treatment. If a patient discontinues treatment due to radiologic disease progression, additional tumor assessment is not required 
at the End of Treatment visit. For patients who discontinue treatment for reasons other than radiologic disease progression, every effort should be made to perform an end of 
treatment tumor assessment prior to the start of new anticancer therapy. Patients that discontinued treatment for reasons other than disease progression should continue to be 
followed for tumor response every 8 weeks until the patient develops radiologic disease progression (or death) or initiation of new anticancer therapy (whichever occurs first). 
Tumor assessments should be performed according to RECIST criteria (v. 1.1, 2009). CT scans obtained prior to signing ICF may be used if the date of the scan is within 28 days 
prior to Day 1 of Cycle 1. 
10 Concomitant Medications: Collect from time of signed Informed Consent Form (ICF) through the end of therapy, including any medications used to treat AEs or SAEs; at the 
30-day safety follow-up period, collect date of initiation of any new anticancer therapy. 
11 Concomitant Medications: Collect anticancer therapies only during survival follow-up. 
12 AE/SAE Assessment: Monitor patients for any untoward medical events from the first dose of study drug through the 30-day safety follow-up period or until initiation of new 
anticancer treatment, whichever comes first. Adverse events reported from time of signed ICF to first dose of study drug should be recorded as Medical History. 
13 Study Drug Treatment: TAS-102 or placebo will be administered twice daily (BID) on Days 1 through 5 and 8 through 12 of each cycle. 
14 Assessment Windows: A window of +/-3 days is allowable for study procedures (+/-7 days allowable for CT scans), as long as the proper order is maintained. 
15 Subsequent Cycles ≥2: Obtain within 24 hours prior to Day 1 study drug administration. Prior to starting subsequent cycles, verify that patients with toxicities have met 
resumption criteria prior to administering study drug. 
16 End of Treatment: Assessments will be performed at time of withdrawal of study medication (TAS-102 or Placebo). If the decision to discontinue study medication is made 
within 2 weeks after the patient’s last treatment visit, an End of Treatment Visit is not required unless deemed clinically necessary by the Investigator. If the decision to 
discontinue study medication (due to proven radiologic disease progression or other reasons) is made more than 2 weeks after the last treatment visit, an End of Treatment Visit is 
required. If this visit occurs within 2 weeks of the 30-day Safety Follow-up Visit, the 2 visits can be combined. 
17 Survival Status: Obtain survival status (alive/dead) at scheduled 4-week time intervals until death. Survival status should be collected until the target number of events (deaths) is 
met. 
18 Quality of Life: Patients should complete the EORTC – QLQ-C30 and QLQ-STO22 questionnaires within 7 days prior to randomization, prior to dose administration on Day 1 
of Cycles ≥2, and at the 30-day safety follow-up if not performed within the prior 4 weeks.. 
 
 
 


Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan – Protocol TO-TAS-102-302 
April 27, 2018 
 
29 
 
7. 
ANALYSIS POPULATIONS  
7.1. 
Intent-To-Treat (ITT) Population 
The “Intent-to-Treat (ITT) Population” comprises all randomized patients, regardless of whether 
or not study drug was administered. This population will serve as the primary population for the 
analysis of the efficacy data. All analyses using this population will be based on the treatment 
assigned by IXRS. 
 
 
7.2. 
As-Treated (AT) Population (Safety Population) 
The “As-Treated (AT) Population” is defined as all subjects who receive at least one dose of study 
medication. This population will be used in the assessment and reporting of safety data. The “As-
Treated Population” is equivalent to “Safety Population”. This population will be used for safety 
analyses. All analyses using this population will be based on the treatment actually received. 
 
 
7.3. 
Tumor Response(TR) Population 
The “Tumor Response (TR) Population” will include all patients in the ITT population that meet 
both of the two following criteria: 
1. Subject has measurable disease (at least one target lesion) at baseline; 
2. Subject has at least one post-baseline evaluation or early disease progression/cancer-related 
death occurred before first evaluation on treatment (post-baseline) took place.  
All analyses using this population will be based on the treatment assigned by IXRS. 
 


Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan – Protocol TO-TAS-102-302 
April 27, 2018 
 
30 
 
8. 
DERIVED AND TRANSFORMED DATA 
8.1. 
Age (relatively to Informed Consent Date) 
Subject’s age in years (whole number, no decimals) will be calculated using date of informed 
consent (IC) as the reference point. An appropriate SAS expression recommended by SAS Institute 
for calculation of a correct age of a person will be applied to calculate the age. The expression is 
supposed to take into account leap years and other peculiarities of the Gregorian calendar. The 
formula reads as follows: 
Age (year) = INT(INTCK(“MONTH”, date of informed consent  – date of birth)/12) 
  IF MONTH(date of birth) = MONTH(date of informed consent )  
       THEN Age = Age - (DAY(date of birth) > DAY(date of informed consent )); 
where INT( ) function (SAS) returns the integer part of the result, INTCK(“MONTH”, DATE2 – 
DATE1) function (SAS) returns a number of months between DATE1 and DATE2, MONTH( ) 
and DAY( ) – standard SAS functions returning month and day of the month of the argument, 
correspondingly.  
 
 
8.2. 
Study Day 
If the date of interest occurs on or after the first dose/randomization date then study day will be 
calculated as (date of interest – date of first dose/randomization) + 1. If the date of interest occurs 
prior to the first dose/randomization date then study day will be calculated as (date of interest – 
date of first dose/randomization). If the date of the first dose is different from the date of 
randomization (protocol allows 3 day window between randomization and start of the treatment), 
the date of the first dose will be used in the aforementioned calculations. There will be no study 
day 0. 
 
 
8.3. 
Baseline 
Baseline assessment is defined as the last valid/non-missing measurement obtained prior to 
administration of the first dose of study medication.  If the time of the medication and/or time of 
the assessment is not available, baseline is defined as last valid measurement obtained prior to or 
on the date of administration of the first dose of study medication  
If the multiple results are available that were obtained at the same date and there is no reasonable 
way to uncover their chronological order, the average value will be used as a baseline (for 
continuous variables). 
All recorded valid data will be considered for analysis of baseline values (including test performed 
at unscheduled visits). 
  


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Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan – Protocol TO-TAS-102-302 
April 27, 2018 
 
32 
 
 
8.8. 
Multiple Assessments 
When valid multiple assessments within the same cycle (refer to ) are available their presentation 
will depend on the specific output. Detailed instruction for analysis will be presented in and in the 
“Data Handling Guidance”). 
 
 
8.9. 
Time Adjusted Incident Rate (per 100 Subject Year) 
The incidence rate (per 100 patient year) of a given event/TEAE is defined as the number of 
patients experiencing the event/TEAE during time at risk divided by the total time of patients at 
risk to contribute an event to the analysis multiplied by 100 (per 100 patient year). 
Here Time at risk [patient years] = (date of first onset of event/TEAE - study drug start date + 
1)/365.25. If the event/TEAE of interest did not occur for a patient, time at risk will be censored 
at the end of the event/TEAE period, which is defined in Section 11.1.2  
 
 
8.10. 
Days to “Recovery” (Grade 3 or Grade 4 abnormalities) 
The number of days to “recovery” for the Grade 3 or Grade 4 abnormalities (that worsen from 
baseline or had missing baseline) in clinical lab tests for a subject is defined as the number of days 
from the moment when this abnormality is recorded for the first time until the time (subsequent 
event) when CTCAE grade for this test is reduced to a value 2 or 1. If the test continues to 
demonstrate the same (or higher) CTCAE grade (i.e., Grade 3 or Grade 4) continuing to the end of 
the study or the subject’s death (whichever occurs earlier), the duration is censored at either the 
end of the study or the subject’s death as appropriate.  
 
 
8.11. 
Creatinine Clearance/Level 
The creatinine level/clearance will be calculated using well-accepted Cockcroft-Gault equation. 
The formula allows the creatinine clearance to be estimated from the serum creatinine in a patient 
with a stable serum creatinine. The expression read as follows: 
For males:  
𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶[𝑚𝑚𝑚𝑚/𝑚𝑚𝑚𝑚𝑚𝑚] =
(140−𝑎𝑎𝑎𝑎𝑎𝑎[𝑦𝑦𝑦𝑦𝑦𝑦𝑦𝑦𝑦𝑦])∗𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤ℎ𝑡𝑡[𝑘𝑘𝑘𝑘])
𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 [𝜇𝜇𝜇𝜇𝜇𝜇𝜇𝜇/𝐿𝐿]
× 1.228 
For females:  𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶[𝑚𝑚𝑚𝑚/𝑚𝑚𝑚𝑚𝑚𝑚] =
(140−𝑎𝑎𝑎𝑎𝑎𝑎[𝑦𝑦𝑦𝑦𝑦𝑦𝑦𝑦𝑦𝑦])∗𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤ℎ𝑡𝑡[𝑘𝑘𝑘𝑘])
𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 [𝜇𝜇𝜇𝜇𝜇𝜇𝜇𝜇/𝐿𝐿]
× 1.044 
 
 


Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan – Protocol TO-TAS-102-302 
April 27, 2018 
 
33 
 
8.12. 
Renal Function 
The creatinine level/clearance will be used to identify the renal function. For the purpose of the 
present SAP the following subdivision will be used (round the calculated result for the creatinine 
clearance to the nearest whole number before application of the table below):  
 
 
Renal Function 
Creatinine Clearance 
(CrCl) 
Normal 
≥90 mL/min 
Mild Impairment 
60-89 mL/min 
Moderate Impairment 
30-59 mL/min 
Severe Impairment 
≤29 mL/min 
 
 
 
8.13. 
Handling of Missing Data 
8.13.1. 
Missing Efficacy Endpoints 
No imputation of the missing data will be performed, unless otherwise specified, for example, 
censoring rules, as applicable.  
 
8.13.2. 
Missing Start and Stop Dates for Prior and Concomitant Medication 
Incomplete concomitant medication start and/or stop dates will be imputed as follows.  If either 
the start of medication date is completely missing or the month and/or year of the start date is 
missing, the start date will be set to the first dose date.  If only the day is missing, the day will be 
set to the first day of the month except if the start month is the same as the first dose month.  If the 
latter is true, the start day will be set to the first dose day.  No imputations will be applied to the 
stop date.  Imputed dates will be flagged in the individual supportive subject data listings. 
 
8.13.3. 
Missing Start and Stop Dates for Adverse Events 
No imputation for stop dates of TEAEs will be performed.  
Missing and/or partial start dates of TEAEs will be imputed using the algorithms presented in the 
. 


Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan – Protocol TO-TAS-102-302 
April 27, 2018 
 
34 
 
 
8.13.4. 
Missing Birth Date 
Incomplete birthday date will be imputed as follows. If only the day is missing (i.e., both year and 
month are known and valid), the day will be set to the first day of the month. Otherwise, if both 
the day and month are missing (i.e., year only is known and valid), the day will be set to the first 
day of the first month (January 1st). Imputed dates of birth will be flagged in the individual 
supportive subject data listings. 
 
8.13.5. 
Missing Exposure End Date 
Incomplete or missing exposure end date (last cycle) will be imputed assuming that subject took 
the full 12 days course of the study drug. If the subject discontinued treatment or died during this 
period (12 days since the start of the cycle) than the date used for imputation will be the date of 
treatment discontinuation or death. If the subject discontinued treatment and died during this 
period than the date used for imputation will be the earliest of these two dates (treatment 
discontinuation and death). 
 
8.13.6. 
Partial or Missing Date of Start of Antitumor Therapy 
The instructions presented in this subsection will be applied when it will be required to check if 
post-baseline antitumor therapy (specifically: systemic therapies, radiotherapy and cancer 
surgeries) was initiated prior to a response assessment. 
1. Incomplete/partial date start of antitumor therapy will be imputed only if day only is 
missing. In this the last day of the month will be used for imputation. 
2. Incomplete/partial date start of antitumor therapy will not be imputed only if month or year 
or both month and year are missing. In this case the patient will be considered as having 
received no post-baseline anti-tumor therapy.  
 
 
8.14. 
Countries in EU 
For the purpose of the present study the following countries will be defined as belonging to EU: 
1. Belgium, Czech Republic, France, Germany, Ireland, Italy, Poland, Portugal, Romania, Spain, 
United Kingdom. 
2. Belarus, Israel, Russian Federation, Turkey 


Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan – Protocol TO-TAS-102-302 
April 27, 2018 
 
35 
 
9. 
GENERAL ANALYSIS 
9.1. 
Subjects Disposition 
A complete accounting of subject participation in the study will be presented according to 
requirements provided by ICH Guideline for Industry, 1996 (Structure and Content of Clinical 
Study Reports [CSR]) [15 ].  The purpose of this table is to track subjects from informed written 
consent through their exit from the study and to account for subject evaluation in major analyses 
of efficacy and safety, including reasons for early study termination or withdrawal. 
 
 
9.2. 
Protocol Deviations 
A set of “protocol deviations”/“major protocol deviations” is defined as a means to measure 
adherence to key aspects of the protocol. Summary of all major Protocol Deviations (at study 
entrance and during the study period) by type of deviation will be provided. 
A summary of all protocol deviations (at study entrance and during the study period) by type of 
deviation will be provided. 
A patient will be considered as having a protocol CSR reportable deviation if she/he meets at least one of 
the criteria presented below. These subjects will be identified based on reviews of the data prior to final 
unblinding of the treatment codes.  
 
9.2.1. 
CSR Reportable Protocol Deviation 
A CSR reportable Protocol Deviation is related to inclusion/exclusion criteria, conduct of the trial, 
patient management or patient assessments that impact the safety of the subjects or jeopardize the 
quality of the study data. 
During the conduct of protocol TAS-102-302 the following categories will be used for CSR 
reportable Protocol Deviations: 
RD1 - A subject that did not meet entry criteria 
RD2 - A subject that developed withdrawal criteria but was not withdrawn 
RD3 - A subject that received the wrong treatment or incorrect dose 
RD4 - A subject that received an excluded medication 
RD5 - Critical ICF, GCP and other Protocol Deviations 
A CSR non-reportable Protocol Deviation may be important to address and document as part of 
site management and oversight, but is not considered reportable in the CSR. 
The following categories will be used to capture non-reportable PDs. 
NRD1 - SAE reporting 
NRD2 - Informed consent 


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Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan – Protocol TO-TAS-102-302 
April 27, 2018 
 
37 
 
Study period: 
MRD7 - Patient received incorrect treatment (i.e. randomized to one arm but received the other 
arm) 
MRD8 - Other concurrent chemotherapy or radiotherappy administered while receiving study 
medication 
 
The number of patients with CSR Reportable deviations of one or more criteria and the number of 
patients with major CSR reportable protocol deviations will be listed and tabulated for all patients 
(including screen failures) and ITT population. 
 
 
9.3. 
Demographic and Baseline Characteristics 
The demographic and baseline characteristics will be summarized. The list of characteristics that 
will be summarized include but are not limited to the following: 
• 
Gender 
• 
Age (years) (#) 
• 
Age group 1 (<65 years, ≥65 years) 
• 
Age group 2 (3 groups: (<65 years, 65≤ - <75, 75≤ years) 
• 
Race (White, Black, Asian, American Indian or Alaska Native, Native Hawaiian or Other 
Pacific Islander, Not Collectable, Other) 
• 
Race Group (White, Asian, Other) 
• 
Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not Collectable, Unknown) 
• 
Region 1 (Japan, Rest of the World 1) 
• 
Region 2 (US, EU, Japan) 
• 
Region 3 (US, Rest of the World 3) 
• 
ECOG status at baseline (0, 1) 
• 
Height (cm) (#) 
• 
Weight (kg) (#) 
• 
BSA (m2) (#) 
• 
BSA (m2) by Region 2 (#) 
• 
Renal function at baseline (Normal/Mild/Moderate based on Cockcroft-Gault formula) 
 (#) indicates a continuous variable to be summarized.  
 
 
9.4. 
Subject Inclusion and Exclusion Criteria 
Information regarding subject’s inclusion and exclusion criteria will be listed on an individual 
subject basis. 
Patients who were randomized but have not met all inclusion and/or exclusion criteria will be 
identified and summarized by treatment arm and inclusion/exclusion criteria that were not met. 


Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan – Protocol TO-TAS-102-302 
April 27, 2018 
 
38 
 
 
 
9.5. 
Medical History  
Significant medical history will be summarized for the AT population. The patients are 
summarized using counts and percentages. All medical histories will be coded using MedDRA 
version 16.1 (or greater) and summaries will use the system organ class and preferred term codes, 
as appropriate.  
 
9.5.1. 
Cancer Medical History 
 
• 
Primary Cancer Type (gastric, gastroesophageal (GE) junction, both)  
• 
Tumor Grade (WellDifferentiated, Moderately Differentiated, Poorly Differentiated, 
Unknown or Missing)  
• 
Histology subtype (intestinal, diffused, mixed, unknown or N/A)  
• 
Location of Primary Tumor 
• 
Previous gastrectomy (Yes, No)  
• 
Time from Initial Diagnosis to Randomization (months) 
• 
Time from Confirmed Metastasis to Randomization (months) 
• 
Number of prior regimens (<2, 2, 3, 4≤)  
• 
Prior Treatment with Fluoropyrimidine (Yes, No) 
• 
Prior Treatment with Platinum (Yes, No) 
• 
Prior Treatment with Irinotecan (Yes, No)  
• 
Prior Treatment with Taxane (Yes, No)  
• 
Prior Treatment with Ramucirumab (Yes, No)  
• 
Measurable disease (Yes, No)  
• 
Number of metastatic sites (1-2, ≥3)  
• 
Presence of liver metastases (Yes, No)  
• 
Presence of lung metastases (Yes, No)  
• 
Presence of peritoneal metastases (Yes, No)  
• 
HER2 status  
 
 
9.5.2. 
Non-Cancer Medical History  
Non-cancer-related medical history will be presented as it is described in the beginning of the 
Section 9.5. 
 
 


Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan – Protocol TO-TAS-102-302 
April 27, 2018 
 
39 
 
9.6. 
Prior, Concomitant, and Survival Follow-up Medications and 
Therapies  
 
9.6.1. 
Prior Anti-Cancer Therapies  
Prior anti-cancer therapies will be summarized for the AT population and will include the 
following: 
• 
Number of prior regimens (<2, 2, 3, 4≤) 
• 
Prior therapies (fluoropyrimidine, platinum, taxane, irinotecan, ramicurumab, 
immunotherapy (PD1/PDL1) containing regimens, HER2i). 
• 
Prior Treatment with Ramucirumab (Yes, No) 
• 
Prior Treatment with Irinotecan (Yes, No) 
• 
Prior Treatment with Taxane (Yes, No) 
• 
Prior Treatment with Fluoropyrimidine (Yes, No) 
• 
Prior Treatment with Platinum (Yes, No) 
• 
Prior Treatment with HER2i  
• 
Prior Treatment with Immunotherapy (PD1/PDL1) (Yes, No) 
• 
Prior surgery (Yes, No) 
• 
Previous gastrectomy (Yes, No) 
• 
Prior Radiotherapy (Yes, No) 
 
9.6.2. 
Prior and Concomitant Medications 
Prior and concomitant medications will be summarized for the AT population. The patients are 
summarized using counts and percentages. All concomitant medications and therapies will be 
coded using WhoDDE (September 2015) and summaries will use the system organ class and 
preferred term codes, as appropriate.  
All medications, prescription and over-the-counter, from the time of signed ICF through the 30-
day Safety Follow-Up Visit, will be collected and summarized in the tables. This will include any 
medication used to treat AEs or SAEs during the safety follow-up period. Summarization will be 
performed separately for prior and concomitant medications (two different tables). 
 
9.6.3. 
Non-study Systemic Anti-cancer Treatment during Survival Follow-up Period 
Patients receiving non-study systemic anti-cancer treatments initiated during the follow-up period 
will be summarized in a table by treatment arm.  The table will display the number and type of 
new non-study systemic anti-cancer treatments.  The time to start of the new anti-cancer treatment 
will be presented as a listing and is defined as the start date of the new anti-cancer therapy minus 
the date of last dose of study medication + 1.  If the start date of the new anti-cancer treatment is 
missing, the time to start of anti-cancer therapy will be missing for that patient. 
 
 


Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan – Protocol TO-TAS-102-302 
April 27, 2018 
 
40 
 
9.7. 
Exposure to Study Medication  
Exposure will be summarized and tabulated for the AT population. Study drug administration for 
number of cycles initiated will be summarized by cycle and overall for each treatment group.  Dose 
level by cycle will be summarized for each treatment group. Patients with at least one dose 
reduction and first cycle with target dose reduction will be summarized for each treatment group. 
The number of delays in cycle initiation ≥ 8 days and the 1st delay ≥ 8 days will be summarized by 
cycle and overall for each treatment group. The number of delays in cycle initiation of ≥ 4 days 
will also be presented. Duration of cycles (excluding last cycle) will be summarized by cycle and 
overall for each treatment group. The number of patients that received ≥ 90% of cycle 1 target 
dose, received ≥ 80% of cycle 1 target dose will be summarized for cycle 1, cycles > 1 and entire 
study for each treatment group. Patients receiving more than 100% of the cycle 1 target dose or 
the current cycle dose will be summarized in interval categories of 20% (e.g. >100% to 120%, 
>120% to 140%, etc.) The total dose administered (mg/m2), dose intensity (mg/m2/wk), relative 
dose intensity (ratio to planned) will be summarized. 
 
 
9.8. 
Duration of Survival Follow-up  
A summary table showing the duration of follow-up will be presented by treatment arm for the 
ITT and AT population. The follow-up period for the purpose of this analysis is defined as the 
time starting on the date randomized until the last day of contact, or the day of withdrawal from 
study or the day of death, whichever occurs last (note, this definition of the survival follow – up 
period is different from one used in the Study Protocol). It will be summarized using the reverse 
Kaplan-Meier method (deaths are censored, censored subjects constitute events at the censored 
time) [22]. 
 
 


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Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan – Protocol TO-TAS-102-302 
April 27, 2018 
 
47 
 
11. 
SAFETY ANALYSES 
This Section contains instructions how the analysis of the safety aspects of the collected data will 
be performed and presented. As a general rule (unless otherwise is stated) efficacy analysis will 
use values of stratification factors collected on CRF pages. 
 
 
11.1. 
Adverse Events  
11.1.1. 
Definition of Adverse Event 
An adverse event (AE) is defined as any untoward medical occurrence in a clinical investigation 
of a patient that may or may not have casual relationship with treatment (21 CFR 312.32(a)). An 
AE can therefore be any unfavorable and unintended sign (including a clinically significant 
abnormal laboratory finding), symptom, or disease temporally associated with the clinical study, 
independent of the relationship to the investigational product.  
Any AE that started after signing of informed consent and before treatment start date will be 
presented in the Medical History section of the summary tables. 
Any adverse event starting more than 30 days after the last dose of study medication will be 
excluded from the summary analyses, unless the event caused patient discontinuation from the 
study.  
 
11.1.2. 
Definition of Treatment Emergent Adverse Event 
Treatment-emergent adverse events (TEAE) will be defined as those events, which meet one of 
the two criteria: 
• started on or after treatment start date (first dose of study medication  Cycle1, Day 1) 
through 30 days after treatment end date (last dose of study medication) 
• started before treatment start date and became worse (more severe) after treatment start 
date (first dose of study medication  Cycle1, Day 1) through 30 days after treatment end 
date (last dose of study medication) 
Only treatment-emergent adverse events will be summarized, non-treatment emergent AE will be 
listed only.  
 
11.1.3. 
Definition of Serious Adverse Event 
SAE, as per FDA regulations defined in 21 CFR 312.32(a), is considered “serious” if, in the view 
of either the Investigator or Sponsor, it results in any of the following outcomes: death, a life-
threatening adverse event, in-patient hospitalization or prolongation of existing hospitalization, a 
persistent or significant /incapacity or substantial disruption of the ability to conduct normal life 
functions, or a congenital anomaly/birth defect. Important medical events that may or may not 
result in death, be life-threatening, or require hospitalization may be considered a serious adverse 
drug experience when, based upon appropriate medical judgment, they may jeopardize the subject 
and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. 


Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan – Protocol TO-TAS-102-302 
April 27, 2018 
 
48 
 
If either the Sponsor or Investigator believes that the event is serious, the event must be considered 
serious and evaluated by the Sponsor for expedited reporting (21 CFR 312.32(a) and 312.32(c) 
(1)). 
 
11.1.4. 
Definition of Treatment Emergent Adverse Event of Special Interest 
The TEAEs of special interest (TEAESI) will be selected based on the list of appropriate MedDRA 
terms provided by the Sponsor. The TEAESI will include the following items: Gastrointestinal 
(nausea, vomiting and diarrhea), Hematologic Impairment-Related adverse events. The full list 
will be provided before the study is unblinded. The lists of terms (PTs) will be located in 
Appendices (). 
 
 
11.2. 
Summaries of Adverse Event  
All adverse event verbatim text will be coded and classified by system organ class (SOC) and 
preferred term (PT) using the MedDRA (Version 20.1). AE summary tables will use the 
following algorithms for counting subject events within the summary tables: 
• Preferred term rows: Each subject is counted once within each unique preferred term 
at the maximum grade. Subjects experiencing the same AE preferred term several 
times with different grades would only be counted once with the maximum grade. 
• System organ class rows: Each subject is counted only once in the maximum grade at 
each system organ class level, although they may have several different preferred 
term events within the same SOC. 
• Any event row: Each subject with an event is counted only once at the maximum 
grade although they may have several events. For drug related AE table, each subject 
with an event is counted only once at the most related although they may have several 
events. 
Unless specified otherwise, the summaries of adverse events will be based on the safety 
population. 
TEAEs will be presented in alphabetical order of System Organ Class and within each System 
Organ Class, in decreasing order of the total number of combined TAS-102 patients who 
experienced each TEAE at the preferred term level. 
 
11.2.1. 
Overview and Summaries of Adverse Events 
AE incidence will be calculated by the worst CTCAE grade at every level of summarization (SOC 
or PT), i.e., if a patient has multiple occurrences of the same AE with different toxicity grades 
during a period, the patient will be accounted for in AE frequency tabulation in the worst grade. 
An overall summary table (overview) of all adverse events will be presented, summarizing: 


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Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan – Protocol TO-TAS-102-302 
April 27, 2018 
 
51 
 
Completely missing or partially missing AE onset dates will be queried and every reasonable effort 
will be made to resolve the issue and to obtain accurate AE information from site, investigator or 
any other trustful source. Once all attempts of this kind has failed, the missing or partially missing 
AE onset date will be imputed.   
The following algorithm should be used to impute adverse event start dates for which only partial 
information is available. 
1. If onset date is completely missing or the year of the end date is missing: 
a. Set onset date to the date of the first treatment if the end date of the AE (if available) 
remains sensible after imputation (i.e., imputed start date precedes end date). 
b. Set onset date to the 1st of January of the same year as the end date is if the end date 
of the AE (if available) presumes that the AE ended before the first treatment of the 
study. 
2. If (year is present and month and day are missing) or (year and day are present and month 
is missing): 
a. If year = year of the first dose, then set month and day to month and day of first 
dose. 
b. If year ≠ year of the first dose, then set month and day to January 1st. 
3. If month and year are present and day is missing: 
a. If year and month = year and month of first dose, then set month and day to month 
and day of first dose. 
b. If year and month ≠ year and month of first dose, then impute the first day of the 
available month. 
Imputed dates will be flagged in the individual supportive subject listings. 
 
 
11.3. 
Pregnancy  
On study pregnancy, if any, will be reported in a data listing. 
 
 
11.4. 
Overdose  
All occurrences of overdosing (accidental or intentional; regardless of whether it is associated with 
an AE) will be reported in a data listing. 
 
 


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Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan – Protocol TO-TAS-102-302 
April 27, 2018 
 
53 
 
the values lying within the normal range. The definition of hypo- and hyper-toxicity grades follows 
the definition provided by the NCI CTCAE v4.3 definition document. Laboratory tables with 
CTCAE grading will only be produced for laboratory parameters for which CTCAE grading is 
available. An overall shift summary will also be provided comparing baseline to worst post-dose 
toxicity observed across all visits. 
The number and percentage of patients with laboratory abnormalities of Grade 3 or Grade 4 that 
worsened from baseline by ≥ 1 grade or are missing at baseline will be summarized. For patients 
with more than 1 value recorded in a cycle/group of cycles, the abnormality with the highest grade 
will be selected for tabulation. 
Time to event/worst grading will be assessed for selected clinical tests (hemoglobin, neutrophils, 
platelets) were CTCAE grading is available. The time to event/worst grading is defined as time 
from the date of the first dose of study medication to the date of the first occurrence of worth post-
baseline CTCAE grade. If multiple events of the same worst grading occur, the earliest occurrence 
will be used. If no abnormal post-baseline values were recorded, the time to event/worst grading 
will be censored.  
Presentation of the time to event/worst grading will be based on the Kaplan-Meier product-limit 
method is applied to estimate the mean, standard deviation, median, 25% percentile, and 75% 
percentile of the time to event/worst grading. 
All observed (including unscheduled) laboratory parameters will be listed. The supportive listings 
for hematology, serum chemistry, and urinalysis will include the subject number, subject age and 
sex; laboratory test, lab test units, lab test result, and the lower and upper limits of normal (provided 
by the local laboratory where the test was performed); sample collection date, time of collection, 
and relative day; type of visit. The listing will be sorted by laboratory parameter, subject number, 
and by time points within laboratory parameter and subject number.  Abnormal results will be 
flagged based on the categories mentioned above. 
Specific rules how to handle clinical laboratory data can be found in the . 
 
11.6.1. 
Hematology 
The following test will be summarized and tabulated, all other hematology tests will be listed only: 
Red blood cells count (RBC) 
White Blood Cells (WBC) 
 
Hemoglobin 
Neutrophils (absolute value) 
Neutrophils (%) 
Hematocrit 
Lymphocytes (absolute value) 
Lymphocytes (%) 
Platelets 
Monocytes (absolute value) 
Monocytes (%) 
 
Eosinophils (absolute value) 
Eosinophils (%) 
 
Basophils (absolute value) 
Basophils (%) 
 


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Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan – Protocol TO-TAS-102-302 
April 27, 2018 
 
57 
 
13. 
DATA MONITORING COMMITTEE 
A DMC is established for this study to provide additional, independent oversight that can enhance 
safety of study participants and the study conduct. The DMC comprises of clinicians and a 
statistician, all independent from the Sponsor and investigative sites and selected as to avoid 
conflict of interest. 
The primary objectives of this DMC are to provide independent safety monitoring comparing 
safety between the study groups and to provide a recommendation based on the planned interim 
analysis. 
A DMC charter has been written to establish well-defined standard operating procedures including 
meeting proceedings and structure, data assessments, documentation and record keeping, process 
for DMC recommendations, and regulatory reporting as applicable. The charter is written as a 
separate stand alone document and contains procedures ensuring the minimization of bias, such as 
maintaining confidentiality of any interim data. 
 
 


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Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan – Protocol TO-TAS-102-302 
April 27, 2018 
 
59 
 
15. 
REFERENCES 
 
1. 
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60 
 
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Controlled Clinical Trials. 1996; 17: 343-346. 
 
  
 
 
 
 


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