A Randomized, Open-Label, Multi-Center, International Phase 2 Study of TAS-114 in Combination With S-1 in Patients With Advanced or Metastatic Non-Small Cell Lung Cancer
Phase: PHASE2
Conditions: Advanced or Metastatic Non-small Cell Lung Cancer
Sponsor: Taiho Oncology, Inc.

Abbreviated Clinical Study Report 
TAS-114-201 
16.1 Study Information 
1.
PROTOCOL AND AMENDMENTS
The final global protocol for study TAS-114-201 (Amendment 1.0, dated 27 September 2016) is 
provided in this appendix.  Other versions of the study protocol (including the original protocol 
dated 03 May 2016 and 2 amendments specific to sites in Japan) are available upon request. 
Page 1 of 98

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Page 3 of 98
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Page 4 of 98
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TAS-114 
Protocol TO-TAS-114-201 
Non-Small Cell Lung Cancer  
Amendment 1 27 September 2016 
Page 4 of 97 
 
Study Duration: 
Patients will receive the study drug according to the proposed treatment schedule until progressive 
disease (PD), occurrence of intolerable side effects, removal by the Investigator, or withdrawal of 
consent. A patient is considered discontinued from study treatment when either TAS-114/S-1 or S-1 
alone is discontinued.  
For the purpose of the final analyses, the study will be considered completed when all patients have 
discontinued from treatment or a minimum of 12 months from the date of the first day of treatment 
with TAS-114/S-1 or S-1 of the last patient enrolled or until the target number of events (deaths, 
n=80) is reached, whichever occurs first. 
Inclusion Criteria: 
A patient must meet all of the following inclusion criteria to be eligible for enrollment in this study. 
1. Provision of written informed consent consistent with International Council for Harmonisation  
(ICH)-Good Clinical Practice (GCP) guidelines and respective local law; 
2. Age ≥ 18 years old (≥ 20 years old in Japan); 
3. Histologically diagnosed or cytologically proven advanced or metastatic NSCLC patients, either 
Stage IIIB/Stage IV disease (according to Version 7 of the International Association for the Study 
of Lung Cancer Staging Manual in Thoracic Oncology), or recurrent disease following radiation 
therapy or surgical resection; 
4. Patients who had received at least 2 prior therapies for advanced or metastatic disease condition, 
including platinum doublet and pemetrexed, docetaxel, or immunotherapy, and were refractory to 
or unable to tolerate their last prior therapy. For patients with known epidermal growth factor 
receptor (EGFR) activating mutations or anaplastic lymphoma kinase translocations, and/or ROS1 
rearrangements, appropriate targeted treatment should have been used. The following histological 
tumor types are also eligible to be included: 
• 
Adenocarcinoma with bronchiolo-alveolar differentiation 
• 
Large cell carcinoma  
5. Tumor is locally advanced or metastatic and not suitable for surgery and radiotherapy is not 
indicated; 
6. Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 
criteria (Version 1.1, 2009); 
7. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1; 
8. Predicted life expectancy of at least 3 months; 
9. Able to take medications orally; 
10. Adequate organ function as defined by: 
• 
Adequate bone marrow function: absolute neutrophil count (ANC) ≥ 1500/mm3, hemoglobin 
≥ 10.0 g/dL, platelets ≥ 100,000/mm3 
• 
Adequate liver function: Total bilirubin ≤ 1.5 × upper limit of normal (ULN), aspartate 
aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 3 × ULN (existent liver metastases 
≤ 5 × ULN) 
• 
Adequate renal function: Calculated creatinine clearance ≥ 50 mL/min (Cockcroft-Gault 
Page 5 of 98

TAS-114 
Protocol TO-TAS-114-201 
Non-Small Cell Lung Cancer  
Amendment 1 27 September 2016 
Page 5 of 97 
 
Equation) 
11. Women of childbearing potential (WOCBP) must have a negative pregnancy test (urine or serum) 
within 7 days prior to starting the study drug. 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 are considered to not be of 
childbearing potential if they have a history of hysterectomy, or are post-menopausal defined as 
no menses for 12 months without an alternative medical cause. For both males and females, see 
Section 8.7.2 for definitions of contraceptive methods considered effective for this protocol; 
12. Willing and able to comply with required scheduled visits and study procedures. 
Exclusion Criteria: 
A patient will be excluded from this study if any of the following criteria are met: 
1. Treatment with any of the following within the specified time frame prior to the study drug 
administration: 
• 
Major surgery within prior 4 weeks and minor surgery within 7 days; 
• 
Radiotherapy for extended field within prior 4 weeks or limited field within prior 2 weeks; 
• 
Any anticancer therapy or investigational agent within prior 3 weeks. 
2. A serious illness or medical condition including but not limited to the following: 
• 
Patients with brain or subdural metastases are not eligible unless they have completed local 
therapy and have discontinued the use of therapeutic corticosteroids and are stable for at least 
1 month before study drug administration; 
• 
Known leptomeningeal metastatic disease; 
• 
Known acute or chronic active systemic infection; 
• 
Any cardiac disease, such as myocardial infarction, unstable angina, symptomatic congestive 
heart failure (CHF) New York Heart Association (NYHA) class III or IV within the last 
6 months. If > 6 months, cardiac function must be within normal limits and the patient must 
be free of cardiac-related symptoms; 
• 
Chronic nausea, vomiting, or diarrhea considered to be clinically significant by investigator’s 
discretion; 
• 
Current or past severe lung disease (eg, interstitial pneumonia, pulmonary fibrosis, or severe 
emphysema); 
• 
Pleural, peritoneal, or pericardial effusion which will require surgical intervention in the near 
term; 
• 
Any history or presence of poorly controlled gastrointestinal (GI) disorders that could affect 
the absorption of the trial drug (eg, Crohn’s disease, ulcerative colitis); 
• 
Known human immunodeficiency virus (HIV) or acquired immune deficiency syndrome 
(AIDS)-related illness, or chronic or acute hepatitis B or C; 
• 
Any other clinically significant acute or chronic medical or psychiatric condition or any 
laboratory abnormality that may increase the risk associated with study drug administration, 
or may interfere with the interpretation of study results; 
• 
Poorly controlled (despite medication) or severe diabetes mellitus; 
• 
Continuous systemic steroid administration (oral or intravenous); 
• 
Other concurrent active cancer (synchronous double cancer or heterochronous double cancer 
with a disease-free interval of 3 years or shorter, excluding lesions consistent with 
intraepithelial cancer, ie, carcinoma in situ, or intramucosal cancer) that is assessed as cured 
Page 6 of 98

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Page 7 of 98
CCI

TAS-114 
Protocol TO-TAS-114-201 
Non-Small Cell Lung Cancer  
Amendment 1 27 September 2016 
Page 7 of 97 
 
descriptively. Efficacy data for PFS, OS, ORR, DR, and DCR will be summarized descriptively. 
Page 8 of 98

TAS-114 
Protocol TO-TAS-114-201 
Non-Small Cell Lung Cancer 
Amendment 1 27 September 2016 
Page 8 of 97 
 
3. 
STUDY SCHEDULES 
Table 1: 
Study Schedule of TAS-114 and S-1 Arm 
Visit ID/Procedure 
Baseline 
On-Treatment 
End of Treatment/Study 
Baseline Day 
Cycle 1 (Day of Cycle) 
Subsequent Cycles (Day of Cycle) 
End of 
Treatment1 
30-Day Safety 
Follow-up Visit
2 
Survival 
Follow-up 
-28 to 
-1 
-7 to 
03 
1 
8 
15 
1 
15 
End of 
Recovery 
 
 
 
Visit Window 
0 
0 
-1 to 0 
± 3 
± 3 
-1 to 0 
± 3 
± 7 
± 3 
-7 
 
Sign ICF 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion  
X 
 
X 
 
 
 
 
 
 
 
 
Assign Patient Number 
X4 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Baseline Signs and 
Symptoms 
X 
X 
X 
 
 
 
 
 
 
 
 
Physical Exam5 
X 
X 
X5 
X 
X 
X5 
 
 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Vital Signs/Weight5 
X 
X 
 
X 
 
X5 
 
 
X 
X 
 
Performance Status5 
X 
X 
X 
 
 
X5 
 
 
X 
X 
 
ECG 
X 
 
 
 
 
 
 
 
X 
X 
 
Hematology5 
X 
X 
 
X 
X 
X5 
X5 
 
X 
X 
 
Serum Chemistry5 
X 
X 
 
X 
X 
X5 
X5 
 
X 
X 
 
Coagulation5 
X 
X 
 
X 
X 
X5 
X5 
 
X 
X 
 
Urinalysis 
X 
X 
 
 
 
 
 
 
X 
X 
 
Pregnancy test 6 
 
X 
 
 
 
 
 
 
 
 
 
Concomitant Medications7 
 
 
AE/Toxicity Assessment7 
 
 
 
 
Tumor Assessment8 
X 
 
 
 
 
 
 
X8 
X8 
 
 
TAS-1149 
 
 
 
 
 
 
 
 
S-1.10 
 
 
 
 
 
 
 
 
Page 9 of 98

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TAS-114 
Protocol TO-TAS-114-201 
Non-Small Cell Lung Cancer 
Amendment 1 27 September 2016 
Page 10 of 97 
 
12 Survival Follow-up: Obtain survival status (alive/dead) at scheduled 8-week intervals until death. Survival status should be collected for up to approximately 
12 months after the first dose of treatment with TAS-114/S-1 of the last patient enrolled or until the target number of events is reached, whichever occurs first, 
even if consent for study participation has been withdrawn. 
 
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Page 14 of 98
CCI
CCI

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Page 15 of 98
CCI

TAS-114 
Protocol TO-TAS-114-201 
Non-Small Cell Lung Cancer 
Amendment 1 27 September 2016 
Page 15 of 97 
 
9.2.3. 
Patient Instructions for Handling All Study Drug ......................................................50 
9.3. 
Accountability .............................................................................................................51 
9.4. 
Blinding ......................................................................................................................51 
10. 
STUDY VISITS AND BY-VISIT ASSESSMENTS .................................................52 
10.1. 
Screening/Baseline Visit and Assessments ................................................................52 
10.1.1. 
Screening (Days -28 to -1) ..........................................................................................52 
10.1.2. 
Baseline (Days -7 to 0) ...............................................................................................52 
10.2. 
Treatment Period Visits and Assessments ..................................................................53 
10.2.1. 
By-Visit Assessments for Cycle 1 ..............................................................................53 
10.2.1.1. 
Cycle 1, Day 1 Predose ...............................................................................................53 
10.2.1.2. 
Cycle 1, Day 1 Postdose .............................................................................................53 
10.2.1.3. 
Cycle 1, Day 8 (Week 2) Predose ...............................................................................53 
10.2.1.4. 
Cycle 1, Day 8 (Week 2) Postdose .............................................................................54 
10.2.1.5. 
Cycle 1, Day 15 (Week 3) Predose .............................................................................54 
10.2.2. 
By-Visit Assessments for Subsequent Cycles ............................................................54 
10.2.2.1. 
Subsequent Cycles, Day 1 (Week 1) Predose .............................................................54 
10.2.2.2. 
Subsequent Cycles, Day 1 (Week 1) Postdose ...........................................................54 
10.2.2.3. 
Subsequent Cycles, Day 15 (Week 3) Predose ...........................................................55 
10.3. 
End of Recovery .........................................................................................................55 
10.4. 
End of Treatment/Follow-Up .....................................................................................55 
10.4.1. 
End of Treatment Visit ...............................................................................................55 
10.4.2. 
30-Day Follow-Up Visit .............................................................................................56 
10.4.3. 
Survival Follow-up .....................................................................................................56 
11. 
STUDY PROCEDURES ............................................................................................57 
11.1. 
Informed Consent .......................................................................................................57 
11.2. 
Medical History ..........................................................................................................57 
11.3. 
Physical Examination .................................................................................................57 
11.4. 
Height, Vital Signs, and Weight .................................................................................57 
11.5. 
Performance Status .....................................................................................................58 
11.6. 
Electrocardiogram .......................................................................................................58 
11.7. 
Clinical Laboratory Evaluations .................................................................................58 
11.7.1. 
Hematology and Coagulation .....................................................................................59 
11.7.2. 
Serum Chemistry ........................................................................................................59 
Page 16 of 98

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Page 18 of 98
CCI

TAS-114 
Protocol TO-TAS-114-201 
Non-Small Cell Lung Cancer 
Amendment 1 27 September 2016 
Page 18 of 97 
 
18.2. 
Declaration of the Investigator ...................................................................................86 
19. 
REFERENCES ...........................................................................................................87 
 
Page 19 of 98

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Page 20 of 98
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Page 22 of 98
CCI

TAS-114 
Protocol TO-TAS-114-201 
Non-Small Cell Lung Cancer 
Amendment 1 27 September 2016 
Page 22 of 97 
 
5. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Table 3: 
Abbreviations and Specialist Terms 
Abbreviation or Specialist Term 
Explanation 
5-FU 
5-fluorouracil 
AE 
Adverse event 
AIDS 
acquired immune deficiency syndrome 
ALK 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration time curve 
BID 
Twice daily  
BRCA1 
breast cancer 1, early onset 
BRCA2 
breast cancer 2, early onset 
BSA 
body surface area 
CHF 
Congestive heart failure 
CI  
Confidence interval  
CK 
Creatine kinase 
CK-MB 
Creatine kinase (isoform heart muscle) 
CK-MM 
Creatine kinase (isoform skeletal muscle) 
CL/F 
Oral clearance 
Cmax 
Maximum observed plasma concentration 
CPK 
Creatine phosphokinase 
CR 
Complete response 
CRO 
Contract Research Organization 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
DCR 
Disease control rate 
DLT 
Dose-limiting toxicity 
DPD 
dihydropyrimidine dehydrogenase 
DR 
Duration of response 
dUMP 
2’-deoxyuridine-5’-monophosphate  
dUTP 
Deoxyuridine triphosphate 
dUTPase 
Deoxyuridine triphosphatase  
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
Page 23 of 98

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Page 24 of 98
CCI

TAS-114 
Protocol TO-TAS-114-201 
Non-Small Cell Lung Cancer 
Amendment 1 27 September 2016 
Page 24 of 97 
 
Abbreviation or Specialist Term 
Explanation 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Stable disease 
SI 
International System (of Units) 
t1/2 
Elimination half-life  
TKI 
tyrosine kinase inhibitor 
Tmax 
Time to maximum plasma concentration 
TOI 
Taiho Oncology, Incorporated 
TS 
Thymidylate synthase 
ULN 
Upper limit of normal 
UNG 
Uracil-DNA glycosylase 
US 
United States  
WBC 
White blood cell 
WHO 
World Health Organization 
WOCBP 
Women of childbearing potential 
 
Page 25 of 98

TAS-114 
Protocol TO-TAS-114-201 
Non-Small Cell Lung Cancer 
Amendment 1 27 September 2016 
Page 25 of 97 
 
6. 
INTRODUCTION AND STUDY RATIONALE 
6.1. 
Unmet Medical Need 
5-fluorouracil (5-FU), an anti-malignant tumor antimetabolite, was discovered by Heidelberger 
et al. in 19571. Chemotherapy regimens containing 5-FU drugs as the backbone are mainstays for 
the treatment of many cancers including breast, colorectal, and gastric cancer. Many combination 
chemotherapies employing 5-FU with chemical modulators such as leucovorin and other anti-
malignant tumor agents have been investigated and have demonstrated efficacy against a variety 
of carcinomas to date2. Oral fluoropyrimidines such as S-1, a fixed dose combination of tegafur, 
a prodrug of 5-FU, gimeracil, a dihydropyrimidine dehydrogenase (DPD) inhibitor that prevents 
degradation of 5-FU by the body and maintains 5-FU exposure, and oteracil potassium, an 
orotate phosphoribosyltransferase (OPRT) inhibitor that decreases the activity of 5-FU in normal 
gastrointestinal (GI) mucosa have been developed 3. However, chemotherapies using 5-FU or S-1 
can cause intrinsic and acquired resistance to the 5-FU drugs. In non-clinical models, 
overexpression of deoxyuridine triphosphatase (dUTPase) reduced the sensitivity of cancer cells 
to 2′-deoxy-5-fluorouridine (FdUrd) by fourfold–fivefold4 and transient suppression of dUTPase 
sensitized cancer cells to FdUrd with the intracellular accumulation of deoxyuridine triphosphate 
(dUTP).5 In clinical studies in patients with colorectal cancer (CRC), dUTPase expression in the 
tumor tissue appeared to correlate with poor prognosis and overall survival (OS) outcomes as 
well as resistance to 5-FU-based chemotherapy6. These observations indicate that dUTPase may 
be one of the causal factors for resistance to 5-FU-based chemotherapies. Therefore, the 
development of new drugs that can be expected to achieve higher efficacy than the existing 5-FU 
drugs is urgently required. 
Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality 
worldwide7. Despite treatment with immunotherapy, platinum- and taxane-based chemotherapy, 
patients with refractory metastatic NSCLC have a median survival of approximately 8 to 10 
months. Despite the increased number of treatment options available for patients with NSCLC, 
there has been little OS improvement from several new agents, including pemetrexed, erlotinib 
and bevacizumab beyond very small subpopulations. Overall, this group of patients only has an 
OS of about 8 months after progression from platinum agents. Once resistance to tyrosine kinase 
inhibitors (TKIs) occurs, the patients who have epidermal growth factor receptor (EGFR) 
mutations or anaplastic lymphoma kinase or ROS translocations will have a rapid disease 
progression.8 Therefore, the majority of NSCLC cases remain a disease with high burden and 
unmet medical need. 
6.2. 
TAS-114 
TAS-114 is a modulator of 5-FU. TAS-114 potently inhibits the conversion of 2’-deoxyuridine-
5’-triphosphate (dUTP; FdUTP) into 2’-deoxyuridine-5’-monophosphate (dUMP; FdUMP) by 
the reversible inhibition of dUTPase which acts as a gatekeeper protein for uracil and 5-FU 
misincorporation into DNA. 
TAS-114 itself does not have an antitumor effect. TAS-114 can enhance antitumor activity of 
5-FU. Section 6.4.1 describes the mechanism of action when TAS-114 is used in combination 
with 5-FU. 
Page 26 of 98

TAS-114 
Protocol TO-TAS-114-201 
Non-Small Cell Lung Cancer 
Amendment 1 27 September 2016 
Page 26 of 97 
 
6.2.1. 
ADME and Toxicological Profiles of TAS-114 
The pharmacokinetics (PK) of TAS-114 were evaluated in the Japanese healthy volunteers, and 
the plasma protein binding and metabolism of TAS-114 have been studied in non-clinical 
studies. 
6.2.1.1. 
Absorption 
The absorption of TAS-114 was increased dose-proportionality in healthy human volunteers 
under the fasting condition at dose ranges from 6 mg to 300 mg. The average of time to 
maximum plasma concentration (tmax) and elimination half-life (t1/2) were 1.00 hour to 2.00 hours 
and 1.49 hour to 3.38 hours, respectively, and multiple administration of TAS-114 at 60 mg and 
150 mg did not give any effects on the PK of TAS-114. Although the mean plasma 
concentrations of TAS-114 were increased by food at a dose of 60 mg, there was no significant 
food effect on TAS-114 absorption. 
6.2.1.2. 
Distribution 
The plasma protein binding ratios of TAS-114 were 78.1 to 81.5% in humans.9 
Metabolism 
Cytochrome P-450 (CYP) isozymes involved in the metabolism of TAS-114 were investigated 
using human hepatic microsomes in which various CYP isozymes were expressed.10 The results 
have shown that M-1, a primary metabolite of TAS-114, is produced specifically by CYP3A4. 
6.2.1.3. 
Excretion 
In humans, the urinary excretion of TAS-114 was only 1.28% to 5.56% of dose, suggesting that 
the urinary excretion of TAS-114 was a minor pathway of TAS-114 elimination. Based on the 
mass balance study of animals,11 the major elimination pathway of TAS-114 was considered to 
be metabolism and subsequent biliary excretion of TAS-114 metabolites. 
6.2.1.4. 
Drug Interactions  
In 2 drug interaction studies, the inhibitory effect of TAS-114 on various CYP isozymes was 
examined using human hepatic microsomes. The results showed that TAS-114 exhibited the 
most potent inhibitory effect on CYP2C9 (50% inhibitory concentration [IC50 value] = 
57.7 μmol/L), and the IC50 values for TAS-114 on the CYP isozymes other than CYP2C9 were 
100 μmol/L or higher. 
Enzyme induction for CYP isozymes by TAS-114 (including CYP3A4) was investigated using 
cryopreserved human hepatocytes during which enzyme induction (auto induction) for CYP3A4 
by TAS-114 was observed. However, in a Phase 1 clinical study in healthy volunteers, the 
plasma concentration of TAS-114 and the urinary excretion of cortisol and 6β-hydroxycortisol 
suggested that although enzyme induction of CYP3A4 occurred after multiple administration of 
TAS-114 at 150 mg/body/dose twice daily (BID), the extent of auto induction was minimal. 
TAS-114 did not induce other CYP isozymes, such as CYP1A2. An in vitro study using human 
liver S9 fraction showed that TAS-114 has the potential to inhibit DPD, an enzyme responsible 
for 5-FU degradation. 
Page 27 of 98

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Page 34 of 98
CCI

TAS-114 
Protocol TO-TAS-114-201 
Non-Small Cell Lung Cancer 
Amendment 1 27 September 2016 
Page 34 of 97 
 
8. 
INVESTIGATIONAL PLAN 
8.1. 
Study Design 
This is a randomized, open-label, Phase 2 study of TAS-114 administered in combination with 
S-1, to investigate the efficacy, safety, and tolerability of the TAS-114/S-1 regimen in patients 
with advanced or metastatic NSCLC. 
The study will be conducted internationally in 2 regions: Asian (Japan) and Western (Europe and 
US). Patients will be randomized to TAS-114/S-1 arm versus S-1 control arm in a 1:1 ratio. 
Randomization will take place once the consented patient has completed all the necessary 
baseline procedures and is deemed eligible for study entry. Treatment assignment will be done 
centrally using a dynamic allocation method (biased coin) via an interactive voice/web response 
system (IXRS) stratified by: 
• Geographical region (Region 1: Asian [Japan]; Region 2: Western [Europe and US]) 
• Histological subtypes (nonsquamous cell carcinoma [including mixed] and squamous 
cell carcinoma) 
The overall study design is described in Figure 3. 
Figure 3: 
Study Schema 
 
8.1.1. 
Study Duration 
Patients will receive the study drug according to the proposed treatment schedule until 
progressive disease (PD), occurrence of intolerable side effects, removal by the Investigator, or 
withdrawal of consent. A patient is considered discontinued from study treatment when either 
TAS-114/S-1 or S-1 alone is discontinued.  
For the purpose of the final analyses, the study will be considered completed when all patients 
have discontinued from treatment or a minimum of 12 months from the date of the first day of 
treatment with TAS-114/S-1 or S-1 of the last patient enrolled or until the target number of 
NSCLC
S-1 (30 mg/m2) 
Fasting for 2 weeks on, 1 week off BID
TAS-114 (400 mg/body) + S-1 (30 mg/m2)
Fasting for 2 weeks on, 1 week off BID
R
Stratification factors: 
1. Geographical: Region 1: Asian (Japan); Region 2: Western (Europe and US)
2. Histological subtypes: non-squamous (including mixed); squamous
R = Randomization
Page 35 of 98

TAS-114 
Protocol TO-TAS-114-201 
Non-Small Cell Lung Cancer 
Amendment 1 27 September 2016 
Page 35 of 97 
 
events (deaths, n=80) is reached, whichever occurs last. This analysis may still be done even if 
there are patients still on treatment. 
8.2. 
Study Population 
The study population will include male and female patients age 18 years or older (20 and older in 
Japan) with histologically or cytologically confirmed advanced or metastatic NSCLC for whom 
standard therapy no longer exists, based on local guidelines and practices, and according to the 
following inclusion and exclusion criteria. 
8.2.1. 
Inclusion Criteria 
A patient must meet all of the following inclusion criteria to be eligible for enrollment in this 
study: 
1. Provision of written informed consent consistent with International Council for 
Harmonisation (ICH)-Good Clinical Practice (GCP) guidelines, and respective local law; 
2. Age ≥ 18 years old (≥ 20 years old in Japan); 
3. Histologically diagnosed or cytologically proven advanced or metastatic NSCLC patients, 
either Stage IIIB/Stage IV disease (according to Version 7 of the International Association 
for the Study of Lung Cancer Staging Manual in Thoracic Oncology20), or recurrent disease 
following radiation therapy or surgical resection; 
4. Patients who had received at least 2 prior therapies for advanced or metastatic disease 
condition, including platinum doublet and pemetrexed, docetaxel, or immunotherapy and 
were refractory to or unable to tolerate their last prior therapy.  For patients with known 
EGFR activating mutations or anaplastic lymphoma kinase translocations and/or ROS1 
rearrangements, appropriate targeted treatment should have been used. The following 
histological tumor types are also eligible to be included: 
• Adenocarcinoma with bronchiolo-alveolar differentiation 
• Large cell carcinoma  
5. Tumor is locally advanced or metastatic and not suitable for surgery and radiotherapy is not 
indicated; 
6. Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 
criteria (Version 1.1, 2009)20; 
7. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (see Appendix A); 
8. Predicted life expectancy of at least 3 months; 
9. Able to take medications orally; 
10. Adequate organ function as defined by: 
a. Adequate bone marrow function: absolute neutrophil count (ANC) ≥ 1500/mm3, 
hemoglobin ≥ 10.0 g/dL, platelets ≥ 100,000/mm3 
b. Adequate liver function: Total bilirubin ≤ 1.5 × upper limit of normal (ULN), ALT/AST 
≤ 3 × ULN (existent liver metastases ≤ 5 × ULN) 
Page 36 of 98

TAS-114 
Protocol TO-TAS-114-201 
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c. Adequate renal function: Calculated creatinine clearance ≥ 50 mL/min (Cockcroft-Gault 
Equation) 
11. Women of childbearing potential (WOCBP) must have a negative pregnancy test (urine or 
serum) within 7 days prior to starting the study drug.  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 are considered to not 
be of childbearing potential if they have a history of hysterectomy, or are postmenopausal 
defined as no menses for 12 months without an alternative medical cause.  For both males 
and females, see Section 8.7.2 for definitions of contraceptive methods considered effective 
for this protocol;  
12. Willing and able to comply with required scheduled visits and study procedures. 
8.2.2. 
Exclusion Criteria 
A patient will be excluded from this study if any of the following criteria are met: 
1. Treatment with any of the following within the specified time frame prior to study drug 
administration: 
• Major surgery within prior 4 weeks and minor surgery within 7 days;  
• Radiotherapy for extended field within prior 4 weeks or limited field within prior 
2 weeks; 
• Any anticancer therapy or investigational agent within prior 3 weeks. 
2. A serious illness or medical condition including but not limited to the following: 
• Patients with brain or subdural metastases are not eligible unless they have 
completed local therapy and have discontinued the use of therapeutic corticosteroids 
and are stable for at least 1 month before study drug administration; 
• Known leptomeningeal metastatic disease; 
• Known acute or chronic active systemic infection; 
• Any cardiac disease, such as myocardial infarction, unstable angina, symptomatic 
congestive heart failure (CHF) New York Heart Association (NYHA) class III or IV 
(see Appendix B) within the last 6 months. If > 6 months, cardiac function must be 
within normal limits and the patient must be free of cardiac-related symptoms; 
• Chronic nausea, vomiting, or diarrhea considered to be clinically significant by 
investigator’s discretion; 
• 
Current or past severe lung disease (eg, interstitial pneumonia, pulmonary fibrosis, or 
severe emphysema); 
• Pleural, peritoneal, or pericardial effusion which will require surgical intervention in 
the near term; 
• Any history or presence of poorly controlled GI disorders that could affect the 
absorption of the trial drug (eg, Crohn’s disease, ulcerative colitis); 
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• Known human immunodeficiency virus (HIV) or acquired immune deficiency 
syndrome-related illness (AIDS), or chronic or acute hepatitis B or C; 
• Any other clinically significant acute or chronic medical or psychiatric condition or 
any laboratory abnormality that may increase the risk associated with study drug 
administration, or may interfere with the interpretation of study results; 
• Poorly controlled (despite medication) or severe diabetes mellitus; 
• Continuous systemic steroid administration (oral or intravenous); 
• Other concurrent active cancer (synchronous double cancer or heterochronous 
double cancer with a disease-free interval of 3 years or shorter, excluding lesions 
consistent with intraepithelial cancer, ie, carcinoma in situ, or intramucosal cancer) 
that is assessed as cured by local treatment. 
3. Concomitant treatment with the following drugs that may interact with S-1: 
• Sorivudine, brivudine, uracil, eniluracil, folinate/folinic acid, (enhance S-1 activity); 
• Cimetidine, dipyridamole, and nitroimidazoles, including metronidazole and 
misonidazole (may enhance S-1 activity); 
• Methotrexate (may enhance S-1 activity); 
• Clozapine (may increase risk and severity of hematologic toxicity with S-1); 
• Allopurinol (may diminish S-1 activity); 
• Phenytoin (S-1 may enhance phenytoin activity); 
• Flucytosine, a fluorinated pyrimidine antifungal agent (may enhance S-1 activity); 
• Coumarin-derivative anticoagulant (S-1 may enhance activity of coumarin-derivative 
anticoagulant). 
4. Known hypersensitivity to S-1 or its metabolites (eg, 5-FU); 
5. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or 
glucose/galactose malabasorption since S-1 contains lactose. 
6. Previous use of TAS-114, S-1, and 5-FU drugs; 
7. A pregnant or lactating female or possibly pregnant women, or men or women wishing to 
have children during the study period. 
8. A judgment of the investigator that the patient is inappropriate for study participation. 
8.3. 
Discontinuation Criteria 
A patient is considered discontinued from study treatment when the decision to permanently stop 
TAS-114 or S-1 for the TAS-114/S-1 arm and S-1 for the S-1 control arm is made, including 
those decisions made during TAS-114 or S-1 interruptions and recovery periods.  
Study drug should be continued whenever possible. In the event study drug is stopped, it should 
be determined if the stop can be made temporarily; permanent study drug discontinuation should 
be a last resort. If the decision to discontinue TAS-114 or S-1 is made within 2 weeks after the 
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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 TAS-114 or S-1 (because of disease 
progression or other reasons) is made more than 2 weeks after the last treatment visit, the End of 
Treatment visit is required. 
Any TAS-114 or S-1 discontinuation should be fully documented. 
8.3.1. 
End of Treatment Discontinuation Criteria 
The reason for discontinuation should be documented in the source documents. 
Patients can be withdrawn from treatment for the following reasons:  
• At their own request at any time irrespective of the reason. 
• RECIST-defined disease progression of solid tumors. 
• Clinical progression. 
• Unacceptable adverse events (AEs), or change in underlying condition such that the 
patient can no longer tolerate therapy, as evidenced by:   
− A maximum dose delay >14 days from the scheduled start date of the next cycle. 
− Need for more than 2 dose reductions of study drug (maximum of 2 dose 
reductions allowed as described in Section 9.1.2.1.) 
• Investigator’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. 
If there is strong evidence of clinical benefit and reasons to justify continuation of TAS-114 or 
S-1 dosing even though treatment discontinuation criteria have been met, this decision must be 
reviewed with the sponsor on a case-by-case basis, and continuation of therapy may be allowed 
assuming all other treatment resumption criteria have been met. 
Upon discontinuation of treatment the investigator is to ensure the following: 
• The clinical research associate must be notified immediately; and 
• The Study Treatment Discontinuation form in the electronic case report form (eCRF) 
must be completed, specifying the primary reason for the patient’s withdrawal from 
treatment. 
8.4. 
Patient Numbering and Treatment Allocation 
All patients will sign an informed consent form (ICF) and be assigned a unique patient number. 
The patient numbering process is defined in the Case Report Form Completion Manual. 
Investigative sites must complete all relevant eCRFs for all enrolled patients, even if the patient 
is not treated with study drug. 
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Randomization will take place once the consented patient has completed all the necessary 
baseline procedures and is deemed eligible for study entry. Treatment assignment will be done 
centrally using a dynamic allocation method (biased coin) via an IXRS stratified by: 
• 
Geographical region (Region 1: Asian [Japan]; Region 2: Western [Europe and US]) 
• 
Histological subtype (nonsquamous cell carcinoma [including mix] and squamous cell 
carcinoma). 
8.5. 
Replacement Criteria 
No patients will be replaced at any time during this study. 
8.6. 
Prohibited Medications and Therapies 
Patients are not permitted to receive any other investigational or any other anticancer therapy, 
including chemotherapy, immunotherapy, biological response modifiers, or antineoplastic 
endocrine therapy during the study treatment period. 
Palliative radiotherapy is not permitted while the patient is receiving study treatment. 
Other fluoropyrimidine-group antineoplastic agents such as 5-FU, tegafur, or flucytosine are not 
permitted within 7 days after withdrawal of TAS-114/S-1 or S-1.  
The following drugs are prohibited: 
Medication  
Reason for Exclusion  
Sorivudine  
Enhances S-1/5-FU activity  
Brivudine  
Enhances S-1/5-FU activity  
Uracil  
Enhances S-1/5-FU activity  
Eniluracil  
Enhances S-1/5-FU activity  
Folinate/Folinic acid  
Enhances S-1/5-FU activity  
Cimetidine  
May enhance S-1/5-FU activity  
Dipyridamole  
May enhance S-1/5-FU activity  
Nitroimidazoles including metronidazole & 
misonidazole  
May enhance S-1/5FU activity  
Methotrexate  
May enhance S-1/5FU activity  
Clozapine  
May increase risk and severity of hematologic 
toxicity with S-1  
Allopurinol  
May diminish S-1/5-FU activity  
Phenytoin  
S-1 may enhance phenytoin activity  
Flucytosine (a fluorinated pyrimidine antifungal 
agent)  
May enhance S-1/5-FU activity  
Coumarin-derivative anticoagulant including 
warfarin  
S-1 may enhance activity of coumarin-derivative 
anticoagulant  
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8.7. 
Concomitant Medications and Therapies 
8.7.1. 
Concomitant Medications and Therapies 
The following medications/therapies may be given concomitantly under the following 
guidelines:  
Hematologic Support  
Administer hematologic support as medically indicated (eg, blood transfusions, granulocyte 
colony-stimulating factor [G-CSF]) according to the institutional site standards. If there are no 
standard procedures for the use of growth factors, follow the American Society of Clinical 
Oncology (ASCO) Guidelines for Use of Hematopoietic Colony-Stimulating Factors available at 
www.asco.org.  
Management of Diarrhea  
Educate both patients and patients’ families and/or caregivers regarding the potential seriousness 
of chemotherapy-induced diarrhea. Instruct patients to immediately contact the clinical site staff 
at the first sign of a loose stool.  
If there are no institutional standards, refer to the guidelines published by Benson AB et al in 
Journal of Clinical Oncology.22  
In addition, patients should be instructed to report to the investigator or his or her designee the 
relevant information concerning their use of antidiarrheal medication and any episodes of 
diarrhea they experience.  
Management of Nausea/Vomiting  
Administer antiemetics as clinically indicated. If there are no institutional standards refer to the 
ASCO Guidelines for Antiemetics in Oncology.23 
Drug interactions with TAS-114  
Drug interaction studies have not been conducted. The following information is based on results 
from in vitro studies and clinical phase 1 study. Caution is advised if these drugs are given 
concomitantly (see Appendix E, Classification of Substrates, Inhibitors, and Inducers of 
Cytochrome P450 Isoenzymes and Transporters). 
CYP3A4/5 inhibitors  
CYP3A4/5 inhibitors may increase the concentration and activity of TAS-114. Care should be 
exercised when TAS-114 is co-administered with CYP3A4/5 inhibitors.  
CYP3A4 inducers  
CYP3A4 inducers may decrease the concentration and activity of TAS-114. Care should be 
exercised when TAS-114 is co-administered with CYP3A4 inducers.  
CYP3A4/5 substrates  
TAS-114 may decrease the concentration and activity of CYP3A4/5 substrates. Care should be 
exercised when TAS-114 is co-administered with CYP3A4/5 substrates.  
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Drug interactions with S-1  
Other fluoropyrimidines  
Co-administration of other fluoropyrimidines such as capecitabine, 5-FU, tegafur, or flucytosine 
can lead to additive toxicities, and is contraindicated. A minimum washout period of 7 days is 
recommended between administration of S-1 and other fluoropyrimidines. 
Sorivudine and brivudine  
Sorivudine or its chemically-related analogues such as brivudine irreversibly inhibit DPD, 
resulting in a significant increase in 5-FU exposure. This may lead to increased clinically 
significant fluoropyrimidine-related toxicities with potentially fatal outcomes. S-1 must not be 
used with sorivudine or brivudine or within 4 weeks of the last dose of sorivudine or brivudine. 
CYP2A6 inhibitors  
As CYP2A6 is the major enzyme responsible for the conversion of tegafur to 5-FU, 
co-administration of a known CYP2A6 inhibitor and S-1 should be avoided as effectiveness of 
S-1 could be decreased.  
Folinate/folinic acid  
Metabolites of folinate/folinic acid will form a ternary structure with thymidylate synthase (TS) 
and FdUMP, potentially increasing the cytotoxicity of 5-FU. Caution is advised as folinic acid is 
known to enhance the activity of 5-FU.  
Nitroimidazoles, including metronidazole and misonidazole  
No data are available on the concomitant use of nitromidazoles with S-1. However, 
nitromidazoles may reduce clearance of 5-FU and thus increase plasma levels of 5-FU. Caution 
is advised as co-administration may increase the toxicity of S-1.  
Methotrexate  
No data are available on the concomitant use of methotrexate with S-1. However, 
polyglutamated methotrexate inhibits thymidylate synthase and dihydrofolate reductase, 
potentially increasing cytotoxicity of 5-FU. Caution is advised as co-administration may increase 
the toxicity of S-1.  
Clozapine  
No data are available on the concomitant use of clozapine with S-1. However, due to possible 
additive pharmacodynamic effects (myelotoxicity), caution is advised as co-administration may 
increase the risk and severity of haematologic toxicity of S-1.  
Cimetidine  
No data are available on the concomitant use of cimetidine with S-1. However, co-administration 
may decrease clearance and, thus increase plasma levels of 5-FU. Caution is advised as co-
administration may increase the toxicity of S-1.  
Coumarin-derivative anticoagulant  
The activity of a coumarin-derivative anticoagulant was enhanced by S-1. Caution is advised as 
co-administration of S-1 and coumarin anticoagulation therapy may increase the risk of bleeding.  
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Phenytoin  
Fluoropyrimidines may increase phenytoin plasma concentration when administered 
concomitantly with phenytoin causing phenytoin toxicity. Frequent monitoring of phenytoin 
blood/plasma levels is advised when S-1 and phenytoin are administered concomitantly. If 
indicated, the dose of phenytoin should be adjusted according to the phenytoin Summary of 
Product Characteristics (SmPC). If phenytoin toxicity develops, appropriate measures should be 
taken.  
Other  
Based on non-clinical data, allopurinol may decrease antitumor activity due to suppression of 
phosphorylation of 5-FU. Therefore, concurrent administration with S-1 should be avoided. 
8.7.2. 
Effective Contraception During Study 
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 (see Section 8.2.1). 
For WOCBP, 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: 
− oral 
− intravaginal 
− transdermal 
• progestogen-only hormonal contraception associated with inhibition of ovulation: 
− oral 
− injectable 
− implantable 
• intrauterine device 
• intrauterine hormone-releasing system 
• 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 WOCBP 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 drug. 
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8.8. 
Dietary Restrictions 
TAS-114 and S-1 should be taken orally BID with a glass of water at least 1 hour before or after 
a meal. 
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9. 
STUDY DRUG 
Compliance to all study drug regimens should be documented in the patient’s source documents. 
9.1. 
Study Drug Administration and Dose Modification Procedures 
9.1.1. 
Treatment Regimen 
Each TAS-114/S-1 and S-1 treatment cycle will be 21 days: 14 days of treatment and 7 days of 
recovery. TAS-114 and S-1 will be administered orally BID with a glass of water at least 1 hour 
before or after a meal. 
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 BSA, and 
obtain the recommended study medication dosage of S-1. 
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 
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. 
9.1.1.1. 
TAS-114/S-1 Arm Drug administration 
Days 1 through 14: TAS-114 and S-1 orally BID (with a glass of water at least 1 hour before or 
1 hour after completion of morning and evening meals) with the first dose administered in the 
morning of Day 1 of each cycle and the last dose administered in the evening of Day 14.  
Days 15 through 21: Recovery. See required number of study drugs for TAS-114 (Table 6) and 
S-1 (Table 7). 
Table 6: 
Number of TAS-114 Tablets per Dose 
Tablets per dose 
(2x daily every 12 h) 
TAS-114 Dose 
(2x daily) 
100 mg tablets/dose 
(pale-yellow) 
400 mg 
4 
300 mg 
3 
200 mg 
2 
Extension of TAS-114/S-1 treatment into the recovery period is not permitted. 
Any missed doses reported by the patient should be recorded in the patient’s source documents. 
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Table 7: 
Number of S-1 Capsules per Dose 
S-1 Dose 
(2x daily) 
BSA 
(m2) 
Dosage in 
mg 
(2x daily) 
Total daily 
dose (mg) 
Capsules per dose 
(2x daily every 12 h) 
15 mg 
(brown/white) 
20 mg 
(white) 
30 mg/m2/dose 
≥2.25m2 
70 
140 
2 
2 
2.09-2.24m2 
65 
130 
3 
1 
1.92-2.08m2 
60 
120 
0 
3 
1.75-1.91m2 
55 
110 
1 
2 
1.59-1.74m2 
50 
100 
2 
1 
1.42-1.58m2 
45 
90 
3 
0 
1.25-1.41m2 
40 
80 
0 
2 
≤1.24m2 
35 
70 
1 
1 
25 mg/m2/dose 
≥2.25m2 
60 
120 
0 
3 
2.09-2.24m2 
55 
110 
1 
2 
1.92-2.08m2 
50 
100 
2 
1 
1.75-1.91m2 
45 
90 
3 
0 
1.59-1.74m2 
40 
80 
0 
2 
1.42-1.58m2 
40 
80 
0 
2 
1.25-1.41m2 
35 
70 
1 
1 
≤1.24m2 
30 
60 
2 
0 
20 mg/m2/dose 
≥2.25m2 
50 
100 
2 
1 
2.09-2.24m2 
45 
90 
3 
0 
1.92-2.08m2 
40 
80 
0 
2 
1.75-1.91m2 
35 
70 
1 
1 
1.59-1.74m2 
35 
70 
1 
1 
1.42-1.58m2 
30 
60 
2 
0 
1.25-1.41m2 
30 
60 
2 
0 
≤1.24m2 
20 
40 
0 
1 
9.1.1.2. 
S-1 Arm Drug Administration 
S-1 should only be given on Days 1 through 14 of each cycle even if doses are missed or held for 
any reason during Days 1 through 14. See required number of study drugs in Table 7 (S-1). 
Extension of S-1 treatment into the recovery period is not permitted. 
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Any missed doses reported by the patient should be recorded in the patient’s source documents. 
9.1.2. 
Dose Reduction/Modification Procedures 
Section 9.1.2.1 provides the amount that each treatment should be reduced. Section 9.1.2.2 
describes dose reductions for treatment-related toxicities. Section 9.1.2.3 provides the timing of 
dose resumption for both nonhematologic and hematologic toxicities and Section 9.1.2.4 
provides the guidance for starting subsequent cycles. Dose escalations are not permitted at any 
time for either study drug. At the discretion of the investigator, patients may continue on study 
drug at the same dose without reduction or interruption for AEs (irrespective of grade) 
considered unlikely to become serious or life threatening (including but not limited to fatigue and 
dry skin). In addition, at the discretion of the investigator, patients’ doses may be interrupted or 
reduced as medically needed.  
Dosages will be reduced/modified if AEs are observed according to the criteria described below. 
In the following sections, AE severity grades are based on the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) grade criteria (Version 4.03).  
9.1.2.1. 
Dose Reduction for TAS-114 and S-1 
If dose reductions are required because of AEs, both TAS-114 and S-1 should be reduced 
concurrently in the TAS-114/S-1 arm. As shown in Table 8, the dose of TAS-114 will be 
reduced from 400 mg BID to 300 mg BID, and the dose of S-1 will be reduced from 30 mg/m2 
BID to 25 mg/m2 BID. If a second dose reduction of TAS-114 is necessary, the dose of TAS-114 
will be reduced from 300 mg to 200 mg BID, and the dose of S-1 will be reduced from 25 mg/m2 
BID to 20 mg/m2 BID. No additional dose reductions for TAS-114 and S-1 will be allowed.  
Table 8: 
Dose Reduction for TAS-114 and S-1 
Dose Level 
TAS-114 (mg) 
S-1 (mg/m2) 
Starting dose 
400 
30 
First dose reduction 
300 
25 
Second dose reduction 
200 
20 
9.1.2.2. 
TAS-114 and S-1 Dose Reductions for Treatment-related Toxicities 
TAS-114 dose reductions are to be applied in case of a toxicity according to the criteria 
described below. The TAS-114 dose will be reduced by a dose level, for a maximum of 2 dose 
levels (see Section 9.1.2.1). Should the toxicities that require further dose reduction recur after 
the second dose reduction, the affected patient should be discontinued from treatment.  
If dose modification fails to result in achieving minimal criteria to resume treatment, the 
investigator should remove the patient from study treatment.  
S-1 dose reductions are to be applied concurrently for all TAS-114 dose reductions (see 
Section 9.1.2.1). 
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9.1.2.2.1. Dose Modification in Response to Nonhematologic Drug-related Toxicities 
Rules for dosing modifications for treatment-related non-hematologic toxicities are provided in 
Table 9. Hold both TAS-114 and S-1 when the dose hold criteria are met.  
Table 9: 
Dosing Modification Criteria for Non-Hematologic Drug-Related Toxicities 
Grade
1 
Dose Hold/Resumption within a 
21-day Treatment Cycle  
Dose Adjustment for Next Cycle  
Grade 1 or 2  
Maintain treatment at the same dose 
level  
None  
Grade 32 or higher  
Suspend treatment until Grade 0 or 1  
Reduce both TAS-114 and S-1 by 1 
dose level3 from the previous level not 
to exceed 2 dose levels 
1 At the discretion of the investigator, patients may continue on study drug at the same dose without reduction or 
interruption for AEs (irrespective of grade) considered unlikely to become serious or life threatening (including 
but not limited to fatigue and dry skin). 
2 Except for Grade 3 nausea and/or vomiting controlled by aggressive antiemetic therapy or diarrhea responsive to 
antidiarrheal medication. 
3 See Section 9.1.2.2 for the recommended dose level modifications.  
There will be no dose reductions after the second dose reduction. If there is any uncertainty 
about continuing therapy or resuming therapy in a patient with Grade ≥ 3 non-hematologic AEs, 
the case must be discussed with the designated Medical Monitor before continuing therapy.  
9.1.2.2.2. Dose Reduction in Response to Hematologic Toxicities 
Criteria for dose hold and resumption in response to hematologic toxicities related to 
myelosuppression are described in Table 10. Note that 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 11 are met even if the decreases did not meet the hold criteria.  
Uncomplicated neutropenia or thrombocytopenia ≤ Grade 3 does not require a reduction in dose 
of study drug. Patients who experience 1 or more of the following should start their next cycle at 
1 reduced dose level as described in Section 9.1.2.1.  
• Grade 3 or 4 neutropenia associated with fever and/or infection  
• Grade 3 or 4 thrombocytopenia associated with significant bleeding  
• Uncomplicated Grade 4 neutropenia or thrombocytopenia that results in a > 1 week delay 
of the start of the next cycle (if the delay is ≤ 1 week, the patient should start the next 
cycle at the same dose level).  
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Table 10: 
Dose Hold and Resumption Criteria for Hematologic Toxicities Related to 
Myelosuppression 
Parameter 
Hold Criteria 
Resumption Criteria1 
Conventional Units 
SI Units 
Neutrophils  
< 500/mm3 
< 0.5 × 10
9
/L 
≥ 1500/mm
3 (IU: ≥ 1.5 × 10
9
/L) 
Platelets  
25,000/mm
3  
< 25 × 10
9
/L 
≥ 100,000/mm
3 (IU: ≥100 × 10
9
/L) 
1 These resumption criteria apply to the start of the next cycle for all patients regardless of whether or not the hold 
criteria were met. 
Note: Both conventional and standard international (International System) units (IU) are presented in the Common 
Terminology Criteria for Adverse Events Version 4.03.  
9.1.2.3. 
Dose Resumption Timing for Nonhematologic and Hematologic Toxicities 
If the patient recovers from the toxicities to the resumption criteria defined in Section 9.1.2.2.2 
during the 2-week treatment period (treatment Days 1 through 14), and no dose reduction is 
required, study drug therapy may be resumed during the treatment period. If a dose reduction is 
required, study drug therapy should be resumed at the start of the next cycle at the appropriate 
dose level according to instructions provided in Section 9.1.2.2. If the TAS-114 and S-1 dose is 
reduced, the dose must not be increased for subsequent cycles. 
If the toxicities that are defined above recover during the recovery period (Days 15 through 21), 
start the next cycle on schedule at the appropriate dose level according to instructions provided 
in Section 9.1.2.2. 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 14 days. If resumption 
criteria are met by this maximum 14-day delay, start the next cycle at the appropriate dose level 
according to instructions provided in Section 9.1.2.2. 
Patients who require more than a 14-day delay in the scheduled start date of the next cycle will 
be discontinued from the study. 
9.1.2.4. 
Criteria for Starting Subsequent Cycle 
The minimal criteria to start a subsequent cycle are described in Table 11. If any of the criteria 
specified in this table are not met on the planned Day 1 of a subsequent treatment cycle, study 
treatment should be held. The subsequent cycle should be started when the patient meets the 
criteria. Please note calculated creatinine clearance criteria should be followed regardless of 
whether study drug-related or not. 
Page 49 of 98

TAS-114 
Protocol TO-TAS-114-201 
Non-Small Cell Lung Cancer 
Amendment 1 27 September 2016 
Page 49 of 97 
 
Table 11: 
Minimum Criteria to Start Subsequent Cycle 
Non-Hematologic  
Hematologic  
Baseline or ≤ Grade 1 (exceptions noted 
Section 9.1.2.2.1)   
Neutrophils ≥ 1500/mm3 (IU: ≥ 1.5 × 109/L)  
Platelet ≥ 100,000/mm3 (IU: ≥ 100 × 109/L)   
Calculated Creatinine Clearance1 
≥ 50 mL/min  
Start the cycle with no dose reduction  
30 to 49 mL/min   
Start the cycle at one reduced dose level for 
TAS-114 and S-1 
< 30 mL/min   
Suspend the cycle until ≥ 30 mL/min is met and 
then start treatment at one reduced dose level for 
TAS-114 and S-1 
Abbreviations: IU = international unit; min = minute. 
1 Calculated creatinine clearance must be calculated on Day 1 of every cycle before the start of study drug 
treatment.  
9.2. 
Description and Labeling 
9.2.1. 
TAS-114 
A description of the study drug and the recommended storage conditions are provided in 
Section 9.2.1.1 and Section 9.2.1.2 , respectively.  
TAS-114 100 mg tablets will be packaged in kits containing 20 tablets for Europe and US and 
120 tablets for Japan. TAS-114 is formulated as an immediate-release pale yellow oval tablet.   
Patients will be dispensed study drug at the beginning of each cycle. Each kit will be labeled 
with information including the following: 
a. Protocol number 
b. Sponsor name 
c. Storage conditions 
d. Directions for use 
e. Investigational caution statement 
f. Unique kit number 
Additional statements will be printed on the label(s) as required by local regulation. Study drug 
will be shipped from a regional Distribution Center directly to clinical sites. 
9.2.1.1. 
Description 
TAS-114 100-mg tablet is an oval pale-yellow uncoated tablet. 
9.2.1.2. 
Storage 
TAS-114 must be stored as labeled at room temperature (according to the country’s regulatory 
definition* for room temperature). 
All study drugs must be kept in a locked area with access restricted to specific study personnel. 
Page 50 of 98

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Page 51 of 98
CCI
CCI

TAS-114 
Protocol TO-TAS-114-201 
Non-Small Cell Lung Cancer 
Amendment 1 27 September 2016 
Page 51 of 97 
 
• 
Study drug should be kept in a safe place and out of sight and reach of children;   
• 
TAS-114/S-1 should be taken at least 1 hour before or after completing a meal (morning 
and evening meal) with a glass of water;   
• 
Doses are not to be replaced if the patient misses a dose or vomits a dose;   
• 
Make every effort to take doses on schedule;  
• 
Report any missed doses.  
9.3. 
Accountability 
In accordance with 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. The institutional designee is required to call the 
IXRS each time TAS-114 and S-1 study drug is received at the site.  
Dose reductions, interruptions, and reason for these actions must be recorded in the patient’s 
source documents and IXRS.  Prior to each treatment cycle, the person responsible for 
dispensing the drug must call/log in to the IXRS to provide the information required and to 
request additional study product. Accountability logs with the required information (eg, lot 
number and expiration date, patient ID number, unique id number of each treatment kit [IXRS], 
and dispensing date) will be maintained for the study. 
At the conclusion of the study, all used and unused TAS-114 and S-1 study drug shipped to the 
investigator must be returned to the sponsor or designated contract research organization (CRO). 
If on-site destruction is required by site policy, such requirements must be documented in the 
institution’s Standard Operating Procedures and provided to the sponsor or its representative for 
review. 
No TAS-114 or S-1 is to be used outside of this study. 
9.4. 
Blinding 
This is an open-label, randomized study.  
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TAS-114 
Protocol TO-TAS-114-201 
Non-Small Cell Lung Cancer 
Amendment 1 27 September 2016 
Page 52 of 97 
 
10. 
STUDY VISITS AND BY-VISIT ASSESSMENTS 
This section provides the by-visit list of assessments and procedures to be performed on each 
study day. 
Please note that the Screening/Baseline assessments (Section 10.1), End of Therapy/Early 
Termination assessments (Section 10.4.1), and Follow-Up assessments (Section 10.4.2) apply to 
all patients in the study. 
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 of procedures and assessments is 
maintained. A window of ± 7 days is allowable for computed tomography (CT) scans. These 
windows are not applicable during the screening period. 
10.1. 
Screening/Baseline Visit and Assessments 
Screening Visit assessments may be completed up to 28 days prior to the planned Day 1 date 
(Section 10.1.1); Baseline assessments and procedures should be completed within 3 days of 
Day 1 (Section 10.1.2). 
10.1.1. 
Screening (Days -28 to -1) 
The following assessments and procedures should be completed within 28 days of Day 1:  
• Obtain signed, written, informed consent prior to performing any study procedures. 
• Record inclusion and exclusion criteria. 
• Obtain patient study number from the electronic data capture (EDC) system. 
• Obtain medical history. 
• Record Baseline signs and symptoms. 
• Record current and concomitant medications. 
• Record ECOG performance status (see Section 11.5). 
• Obtain blood and urine samples for clinical laboratory assessments (hematology, 
serum chemistry, and urinalysis).   
• Obtain a 12-lead electrocardiogram (ECG). 
• CT scan and bone scan as described in Section 11.12. Tumor images obtained prior to 
the signed informed consent may be used as the Screening scan if they were obtained 
within 28 days of the 1st dose of study drug. 
10.1.2. 
Baseline (Days -7 to 0) 
The following assessments and procedures should be completed: 
• Record Baseline signs and symptoms. 
Page 53 of 98

TAS-114 
Protocol TO-TAS-114-201 
Non-Small Cell Lung Cancer 
Amendment 1 27 September 2016 
Page 53 of 97 
 
• Record current and concomitant medications. 
• Perform a full physical examination. 
• Record vital sign, height, and weight measurements. 
• Record ECOG performance status (see Section 11.5). 
• Obtain blood and urine samples for clinical laboratory assessments (hematology, 
serum chemistry, and urinalysis).   
• Obtain blood samples for coagulation parameters. 
• Pregnancy test  
10.2. 
Treatment Period Visits and Assessments 
By-visit assessments are shown in this section. 
10.2.1. 
By-Visit Assessments for Cycle 1 
Assessments for Cycle 1 are indicated in Table 1 for the TAS-114/S-1 treatment group and 
Table 2 for the S-1 treatment group and are listed below.  
10.2.1.1. Cycle 1, Day 1 Predose 
The following assessments and procedures should be completed: 
• Review Inclusion and Exclusion Criteria to ensure continued eligibility for the trial. 
• Record Baseline signs and symptoms. 
• Physical exam 
• Record ECOG Performance status (see Section 11.5) 
• Record current and concomitant medications. 
• Dispense TAS-114/S-1 or S-1 alone for Cycle 1. 
10.2.1.2. Cycle 1, Day 1 Postdose 
The following assessments and procedures should be performed: 
• Record AE/Toxicity assessments as needed. 
10.2.1.3. Cycle 1, Day 8 (Week 2) Predose 
The following assessments and procedures should be completed: 
• Update current and concomitant medications. 
• Perform a full physical examination. 
• Record vital sign measurements. 
• Obtain blood samples for clinical laboratory assessments (hematology and serum 
chemistry). 
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TAS-114 
Protocol TO-TAS-114-201 
Non-Small Cell Lung Cancer 
Amendment 1 27 September 2016 
Page 54 of 97 
 
• Obtain blood samples for coagulation parameters. 
10.2.1.4. Cycle 1, Day 8 (Week 2) Postdose 
The following assessments and procedures should be performed: 
• Record AE/Toxicity assessments as needed. 
10.2.1.5. Cycle 1, Day 15 (Week 3) Predose 
The following assessments and procedures should be completed: 
• Record current and concomitant medications. 
• Perform a full physical examination. 
• Obtain blood samples for clinical laboratory assessments (hematology, serum 
chemistry). 
• Obtain blood samples for coagulation parameters. 
• Record drug accountability. The return of all unused study drug should be confirmed, 
and all TAS-114/S-1 that was dispensed should be accounted for. 
• Record AE/Toxicity assessments as needed. 
10.2.2. 
By-Visit Assessments for Subsequent Cycles 
Assessments for subsequent cycles are listed below. 
10.2.2.1. Subsequent Cycles, Day 1 (Week 1) Predose 
The following assessments and procedures should be completed: 
• Record health changes since last visit. 
• Record current and concomitant medications. 
• Perform a full physical examination. 
• Record vital sign and weight measurements. 
• Record ECOG performance status (Section 11.5). 
• Obtain blood and urine samples for clinical laboratory assessments (hematology, 
serum chemistry). 
• Obtain blood samples for coagulation parameters. 
• Dispense TAS-114/S-1 for cycle. 
10.2.2.2. Subsequent Cycles, Day 1 (Week 1) Postdose 
The following assessments and procedures should be performed: 
• Record AE/Toxicity assessments as needed. 
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TAS-114 
Protocol TO-TAS-114-201 
Non-Small Cell Lung Cancer 
Amendment 1 27 September 2016 
Page 55 of 97 
 
10.2.2.3. Subsequent Cycles, Day 15 (Week 3) Predose 
The following assessments and procedures should be completed: 
• Update current and concomitant medications. 
• Obtain blood samples for clinical laboratory assessments (hematology and serum 
chemistry). 
• Obtain blood samples for coagulation parameters. 
• Record drug accountability. The return of all unused study drug should be confirmed, 
and all TAS-114/S-1 that was dispensed should be accounted for. 
• Record AE/Toxicity assessments as needed. 
10.3. 
End of Recovery 
Tumor assessment is done at the End of Recovery Visit. 
10.4. 
End of Treatment/Follow-Up 
The End of Therapy and the Follow-Up Visit assessments and procedures are described below. 
10.4.1. 
End of Treatment Visit 
These assessments and procedures should be performed as much as possible for any patient 
discontinuing from the study prior to completing a cycle of treatment, or if completing a cycle of 
treatment and deciding not to continue to the next cycle. 
• Record vital sign measurements. 
• Perform a full physical examination. 
• Record ECOG performance status. 
• Record concomitant medications. 
• Obtain a 12-lead ECG. 
• Obtain blood and urine samples for clinical laboratory assessments (hematology, 
serum chemistry, and urinalysis).  
• Obtain blood samples for coagulation parameters. 
• Record AE/Toxicity assessments.  
• Record the reason for discontinuation on the Discontinuation Record CRF page. 
• Record drug accountability. The return of all unused study drug should be confirmed, 
and all TAS-114/S-1 that was dispensed should be accounted for. 
• Schedule a clinic Follow-Up Visit in 30 days (± 14 days of the End of Therapy Visit). 
• Tumor assessment/CT and bone scans described in Section 11.12. 
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Protocol TO-TAS-114-201 
Non-Small Cell Lung Cancer 
Amendment 1 27 September 2016 
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10.4.2. 
30-Day Follow-Up Visit 
For any patient discontinuing from the study for any reason, the following assessments and 
procedures should be performed at the 30-Day Follow-Up Visit and should be performed prior to 
start of a new therapy; this visit should be omitted if it is within 14 days of the End of Therapy 
Visit: 
• Record vital sign and weight measurements. 
• Perform a full physical examination. 
• Record ECOG performance status. 
• Record concomitant medications. 
• Obtain a 12-lead ECG. 
• Obtain blood and urine samples for clinical laboratory assessments (hematology, 
serum chemistry, and urinalysis). 
• Obtain blood samples for coagulation parameters. 
• Record AE/Toxicity assessments. 
10.4.3. 
Survival Follow-up 
All patients will be followed for survival status (alive/dead) from the time of randomization and 
investigator will record time of disease progression. Obtain survival status (alive/dead) at 
scheduled 8-week intervals until death. Survival status should be collected for up to 
approximately 12 months after the first dose of treatment with TAS 114/S 1 of the last patient 
enrolled or until the target number of events is reached, whichever occurs first, even if consent 
for study participation has been withdrawn. 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.   
All patients will be followed for survival status (alive/dead) even if consent for other study 
procedures is withdrawn.  
 
 
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TAS-114 
Protocol TO-TAS-114-201 
Non-Small Cell Lung Cancer 
Amendment 1 27 September 2016 
Page 57 of 97 
 
11. 
STUDY PROCEDURES 
The study assessments are described by procedure in the following sections. All information 
required by the protocol must be recorded. 
The study schedule must be followed; however, in unavoidable circumstances (eg, holidays, 
weekends) a window of ± 3 days is allowable for study procedures as long as the proper order of 
procedures and assessments is maintained. A window of ± 7 days is allowable for CT scans and 
follow-up visits. These windows are not applicable during the Baseline Period. If any baseline 
assessments are repeated on Day 1 of Cycle 1, the site must ensure the patient meets the 
eligibility criteria listed in Section 8.2.1 and Section 8.2.2 before administration of the first dose 
of TAS-114. 
11.1. 
Informed Consent 
A signed and dated ICF will be obtained from the patient as required by the protocol before any 
baseline procedures are conducted. A signed copy of the ICF will be given to the patient. 
Patient number will be assigned once the patient has entered the Baseline Period, ie, has signed 
the ICF, during baseline within 28 days before first TAS-114/S-1 or S-1 control administration 
on Day 1 of Cycle 1. 
11.2. 
Medical History 
A complete medical history will be obtained during baseline within 28 days before first 
TAS-114/S-1 or S-1 control administration on Day 1 of Cycle 1. 
Existing signs and symptoms will be obtained within 7 days before TAS-114/S-1 or S-1 control 
administration on Day 1 of Cycle 1. Those pre-existing signs and symptoms and conditions are 
appropriately recorded in a respective medical history page. 
11.3. 
Physical Examination 
A complete physical examination will be performed at the time points listed below. 
• Baseline within 7 days before TAS-114/S-1 or S-1 control administration on Day 1 
and before administration of study drug on Days 1, 8, and 14 of Cycle 1. 
• Beginning with Cycle 2, obtain within 1 day before TAS-114/S-1 or S-1 control 
administration on Day 1. 
• End of treatment visit. 
• 30-day safety follow-up visit. 
11.4. 
Height, Vital Signs, and Weight 
The patient’s height will be obtained only during Baseline within 7 days before TAS-114/S-1 or 
S-1 control administration on Day 1 of Cycle 1. 
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Protocol TO-TAS-114-201 
Non-Small Cell Lung Cancer 
Amendment 1 27 September 2016 
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The patient’s vital signs (blood pressure, heart rate, body temperature, and respiration rate) and 
body weight will be collected at the time points listed below. All vital signs are to be obtained 
with the patient in a position that is consistent for all time points for each patient. 
• Baseline within 7 days before TAS-114/S-1 or S-1 control administration on Day 1 of 
Cycle 1. 
• Within 1 day before TAS-114/S-1 or S-1 control administration on Day 1 of Cycle 2 
and thereafter throughout all the treatment cycles. 
• End of treatment visit. 
• 30-day safety follow-up visit. 
11.5. 
Performance Status 
An ECOG Performance Status score (see Appendix A, ECOG Performance Status) will be 
obtained at the following time points: 
• Baseline within 28 days before the first TAS-114/S-1 or S-1 control administration on 
Day 1 of Cycle 1. 
• On Day 1 of Cycle 1 before the first dose. 
• Beginning with Cycle 2, obtain within 1 day before TAS-114/S-1 or S-1 control 
administration on Day 1. 
• End of treatment visit. 
• 30-day safety follow-up visit. 
11.6. 
Electrocardiogram  
A 12-lead resting ECG will be performed at the following time points: 
• Baseline within 28 days before TAS-114/S-1 or S-1 control administration on Day 1 
of Cycle 1.  
• End of treatment visit. 
• 30-day safety follow-up visit. 
11.7. 
Clinical Laboratory Evaluations 
Blood samples for hematology, coagulation, and serum chemistry assessments will be collected 
and measured as described in Section 11.7.1, Hematology and Coagulation, and Section 11.7.2, 
Serum Chemistry, respectively.  
Laboratory assessments obtained before the signing of the ICF may be used as screening 
laboratory values if they were obtained within 28 days before TAS-114/S-1 (Table 1) or 
S-1 control (Table 2) administration on Day 1 of Cycle 1. 
All laboratory results must be reviewed for clinically significant events. Any clinically 
significant event must be followed and reported as required by the protocol (see Section 13.1, 
Adverse Events/Serious Adverse Events and Section 13.2, Laboratory Evaluations).  
Page 59 of 98

TAS-114 
Protocol TO-TAS-114-201 
Non-Small Cell Lung Cancer 
Amendment 1 27 September 2016 
Page 59 of 97 
 
11.7.1. 
Hematology and Coagulation 
Blood for hematology and coagulation assessments will be collected at the following time points 
and when clinically indicated: 
• Baseline within 7 days before the first TAS-114/S-1 or S-1 control administration on 
Day 1 of Cycle 1. 
• On Days 8 and 15 of Cycle 1. 
• Beginning with Cycle 2, obtain within 1 day before TAS-114/S-1 or S-1 control 
administration on Day 1 and Day 15.  
• After Cycle 4, the Day 15 laboratory evaluations are not required unless clinically 
indicated by the Investigator.  
• After Cycle 6, the laboratory evaluations can be accepted within 2 days before study 
drug administration on Day 1 of each cycle, if there are no drug-related AEs greater 
than Grade 2 observed in the latest cycle. 
• End of treatment visit. 
• 30-day safety follow-up visit. 
In addition, the criteria for repeat testing listed in Section 13.2.2, will be followed as needed. 
The following hematology and coagulation parameters will be measured:  
Red blood cell (RBC) count 
White blood cell (WBC) count with differential 
Hemoglobin  
Neutrophilsa 
Hematocrit 
Lymphocytes 
Platelets 
Monocytes 
International normalized ratio 
(INR) 
Eosinophils 
Activated partial thromboplastin 
time (APTT) 
Basophils 
a Includes both segmented and band neutrophils. 
11.7.2. 
Serum Chemistry 
Blood will be collected at the following time points for serum chemistry assessments: 
• Baseline within 7 days before the first TAS-114/S-1 or S-1 control administration on 
Day 1 of Cycle 1 (must include creatine kinase [CK], which has to be repeated on 
Day 1 of Cycle 2 [± 3 days]). 
• On Days 8 and 15 of Cycle 1. 
• Beginning with Cycle 2, obtain within 1 day before TAS-114/S-1 or S-1 control 
administration on Day 1 and Day 15.  
• After Cycle 4, the Day 15 laboratory evaluations are not required unless clinically 
indicated by the Investigator.  
Page 60 of 98

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Protocol TO-TAS-114-201 
Non-Small Cell Lung Cancer 
Amendment 1 27 September 2016 
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• After Cycle 6, the laboratory evaluations can be accepted within 2 days before study 
drug administration on Day 1 of each cycle, if there are no drug-related AEs greater 
than Grade 2 observed in the latest cycle. 
• End of treatment visit. 
• 30-day safety follow-up visit. 
In addition, the criteria for repeat testing listed in Section 13.2.2, Repeat Testing, will be 
followed as needed. 
Table 12 lists the serum chemistry parameters that will be measured: 
Table 12: 
Laboratory Assessments for TAS-114/S-1 or S-1 control 
Alanine 
aminotransferase (ALT) 
Creatinine  
Sodium 
Aspartate 
aminotransferase (AST) 
Blood urea nitrogen (BUN) or 
urea 
Potassium  
Alkaline phosphatase 
(ALK) 
Phosphorus 
Bicarbonate  
Total bilirubina 
Calcium 
Glucose 
Albumin 
Chloride  
Creatine kinase (CK) creatine 
phosphokinase (CPK) b 
a Fractionation of bilirubin (= direct/indirect bilirubin or conjugated/unconjugated) must be performed in case of an 
elevation of total bilirubin. 
b Fractionation of CK into its isoforms must be performed in case of an elevation of CK (unless the isoform CK 
[isoform skeletal and heart muscle] [CK-MM and CK-MB] was tested, in which case a fractionation is no longer 
needed). If CK is abnormally elevated at Baseline (Day -7 to -1), the results of the fractionation must be available 
prior to starting TAS-114 treatment for that patient but do not have to be within normal reference range. 
11.7.3. 
Urinalysis 
Urine samples for qualitative analysis (“urine dipstick”) will be collected at the time points listed 
below: 
• Baseline within 7 days before the first TAS-114/S-1 or S-1 control administration on 
Day 1 of Cycle 1. 
• End of treatment visit 
• 30-day safety follow-up visit. 
In addition, the criteria for repeat testing listed in Section 13.2.2 will be followed as needed. 
The following parameters will be measured: 
Protein 
Glucose 
Urine density 
11.8. 
Pregnancy Test 
If the patient is female and of childbearing potential, pregnancy testing by assessment of serum 
or urine beta-human chorionic gonadotropin will be conducted 7 days before the first 
Page 61 of 98

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Page 62 of 98
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Page 63 of 98
CCI

TAS-114 
Protocol TO-TAS-114-201 
Non-Small Cell Lung Cancer 
Amendment 1 27 September 2016 
Page 63 of 97 
 
TAS-114/S-1 or S-1 control. Response definitions are provided in Section 12, Efficacy 
Assessment Criteria. 
If the investigator determines that a patient has developed 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 and must be reported as AEs. Every effort should be made to document 
objective progression even after discontinuation of treatment. 
The same method of assessment and the same technique must be used to characterize each 
identified and reported lesion at Screening, throughout the study, and during the follow-up 
period. 
All patients’ files and radiological assessments must be available for source verification and may 
be submitted for extramural review for final assessment of antitumor activity. Results of any 
unscheduled evaluations should be recorded in the patient’s source documents. 
11.13. 
30-Day Safety Follow-up 
A safety follow-up visit will be conducted 30 days after the last dose of TAS-114/S-1 or 
S-1 control. If the patient starts new anticancer therapy within 30 days of the last dose of 
TAS-114/S-1 or S-1 control, the 30-day safety follow-up visit should be performed before the 
start of new anticancer therapy within the 30-day window. If the patient is unable to return to the 
site before 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 discontinuation of study treatment and 
the initiation of the new anticancer treatment. 
Page 64 of 98

TAS-114 
Protocol TO-TAS-114-201 
Non-Small Cell Lung Cancer 
Amendment 1 27 September 2016 
Page 64 of 97 
 
12. 
EFFICACY ASSESSMENT CRITERIA 
12.1. 
Efficacy Assessment for Solid Tumors 
The determination of antitumor efficacy will be based on objective tumor assessments made by 
the investigator according to the revised RECIST guidelines (Version 1.1, 2009) of 
unidimensional evaluation. Calculated creatinine clearance treatment decisions by the 
investigator will also be based on these criteria. 
The RECIST guidelines (Version 1.1, 2009) instructs those conducting oncology trials designed 
with a primary endpoint that is response-related to require confirmation of response after a 
minimum of 4 weeks. 
12.1.1. 
Method of Imaging 
All patients with and without measurable disease are eligible for assessment. 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 a 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). A 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 scans 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. 
For additional guidance refer to the revised RECIST guidelines (Version 1.1, 2009)20 
specifications for standard anatomical radiological imaging, which are included in the Imaging 
Manual. 
12.1.2. 
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 TO-TAS-114-201 
Non-Small Cell Lung Cancer 
Amendment 1 27 September 2016 
Page 65 of 97 
 
• 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 include:   
• Small visceral metastatic lesions that have a longest dimension less than 10 mm, or if 
slice thickness is greater than 5 mm, less than twice the slice thickness.  
• Abnormal and suspected metastatic lymph nodes that are ≥ 10 mm to < 15 mm in the 
short axis. 
• Truly non-measurable lesions (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/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 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. 
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TAS-114 
Protocol TO-TAS-114-201 
Non-Small Cell Lung Cancer 
Amendment 1 27 September 2016 
Page 66 of 97 
 
• 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. 
The primary lesion should always be classified as a non-target lesion irrespective of its size and 
whether or not it can be accurately measured. 
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). 
12.1.3. 
Response Criteria 
On-site assessments will include the assessment of: 
• Target and non-target tumor responses 
• Overall response 
The above assessments will be made as per the time points identified in Section 11.12, Tumor 
Assessments/Scans. 
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TAS-114 
Protocol TO-TAS-114-201 
Non-Small Cell Lung Cancer 
Amendment 1 27 September 2016 
Page 67 of 97 
 
12.1.3.1. Target and Non-Target Response Assessments 
Assessments will be based on the definitions below. 
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) 
Disappearance of all non-target lesions and normalization 
of tumor marker level. All lymph nodes must be non-
pathological in size (< 10-mm short axis) 
Non-CR/Non-PD 
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal 
limits. 
Progressive Disease (PD) 
Unequivocal progression of existing non-target lesions (see 
definition below).  
 
Progression in Non-target Disease: 
There must be an overall level of substantial worsening in non-target disease such that, even in 
the presence of stable disease (SD) or 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 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 the diameter of a measurable lesion]). 
Page 68 of 98

TAS-114 
Protocol TO-TAS-114-201 
Non-Small Cell Lung Cancer 
Amendment 1 27 September 2016 
Page 68 of 97 
 
12.1.3.2. Additional Criteria to Consider When Making Tumor Response Assessments 
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. 
If a patient is discontinued from the study before PD occurs and receives palliative radiotherapy 
during the follow-up period, the irradiation site must be omitted from the response assessment of 
the patient; however, if the site is observed to demonstrate disease progression, this case should 
be judged as PD. 
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 
the next scheduled assessment, progression is confirmed, the date of progression should be the 
earlier date when progression was suspected.  
12.1.3.3. Overall Response Assessment 
Assessments will be based on the definitions provided in Table 13 and Table 14. 
Table 13: 
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 
Abbreviations: CR = complete response; PD = progressive disease; PR = partial response; SD = stable 
disease 
 
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TAS-114 
Protocol TO-TAS-114-201 
Non-Small Cell Lung Cancer 
Amendment 1 27 September 2016 
Page 69 of 97 
 
Table 14: 
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 
SD 
Not all evaluated 
No 
Not evaluable 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
Abbreviations: CR = complete response; PD = progressive disease; SD = stable disease 
12.1.4. 
Best Overall Response Assessment for Solid Tumors 
The best overall response for solid tumors will be assessed as defined in the Statistical Analysis 
Plan (SAP) per RECIST guidelines (Version 1.1, 2009).  
Page 70 of 98

TAS-114 
Protocol TO-TAS-114-201 
Non-Small Cell Lung Cancer 
Amendment 1 27 September 2016 
Page 70 of 97 
 
13. 
REPORTING SAFETY INFORMATION 
13.1. 
Adverse Events/Serious Adverse Events 
13.1.1. 
Adverse Events 
An AE is any untoward medical condition that occurs in a patient after treatment initiation and 
does not necessarily have a causal relationship with the use of the product. 
A complete and specific clinical diagnosis should be provided for the AE verbatim term. If a 
diagnosis is not available, then signs and symptoms should be reported. The NCI CTCAE 
(Version 4.03) terms are to be used to assess severity and provide the grade for each AE that is 
reported. 
For definitions and reporting of pregnancy, overdoses, and medication errors, refer to 
Section 13.1.5, Pregnancy, Section 13.1.6, Overdose, and Section 13.1.7, Medication Errors, 
respectively.  
Any untoward medical event that occurs outside the period of patient follow-up (30 days after 
the last dose of study drug or until the start of new antitumor therapy, whichever is earlier) is not 
required to be reported as an AE/SAE, unless it is assessed to be related to study drug by the 
investigator. 
Symptoms or laboratory or instrumental (eg, electrocardiographic) abnormalities of a 
pre-existing disease, such as cancer or other diseases, 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 drug dose reduction, treatment delay, 
treatment discontinuation) is considered an AE, unless it is considered part of clinical 
manifestations to a clinical diagnosis that is already reported as an AE. 
All AEs will be reported from the time a patient starts receiving study treatment through the 
period of patient follow-up (30 days after the last dose of study drug or until the start of new 
antitumor therapy, whichever is earlier). All AEs will be documented in the eCRF. 
Documentation should include onset and resolution/stabilization dates, severity/grade, 
relationship to study drug, and outcome of the event. All AEs should be entered in the eCRF 
within 10 business days from the time the investigator first becomes aware of the AE.  
Causal relationship is assessed based on the following: 
1. Select “Related” if the event follows a reasonable temporal sequence from administration of 
study drug and at least one of the following conditions is true: 
• A positive dechallenge: This means that the event improves or resolves after the drug 
is stopped (temporarily or permanently). 
• A positive rechallenge: This means that the event reappears after the drug is restarted. 
• The event cannot be reasonably explained by the patient’s clinical state and/or other 
therapies administered. 
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Protocol TO-TAS-114-201 
Non-Small Cell Lung Cancer 
Amendment 1 27 September 2016 
Page 71 of 97 
 
The circumstance that a causal relationship can sometimes not be ruled out is not sufficient to 
determine that the event is “related”. Instead, “related” should mean that there is evidence to 
suggest a causal relationship between the drug and the AE. A reasonable possibility is provided 
by the following example that would suggest a causal relationship between drug and the event: A 
single occurrence of an event that is uncommon and known to be strongly associated with drug 
exposure (eg, angioedema, Stevens-Johnson syndrome). 
2. Select “Not related” if there is no reasonable possibility that the study drug caused the event, 
or if the event does not follow a reasonable temporal sequence from administration of study 
drug and could have been produced by a documented pre-existing condition, concomitant 
medication, or patient’s clinical state. 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. 
Any ongoing AEs should be followed until the earliest occurrence of one of the following: 
• AE has resolved. 
• 30-Day Follow-up Visit. 
• The start of new antitumor therapy. 
• The patient withdrew consent. 
• The patient dies. 
13.1.2. 
Serious Adverse Events 
An SAE is an AE that falls into one or more of the following categories: 
a. Results in death. 
b. Is life threatening (eg, an event that, in the view of the investigator, places the patient at 
immediate risk of death from the event as it occurred [it does not include 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 < 24 hours. 
• Hospitalizations for preplanned procedures. 
• Hospitalization for study-related treatment and procedures. 
d. Results in persistent or significant disability or incapacity, 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 include allergic 
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Protocol TO-TAS-114-201 
Non-Small Cell Lung Cancer 
Amendment 1 27 September 2016 
Page 72 of 97 
 
bronchospasm requiring intensive treatment in an emergency room or at home, and blood 
dyscrasias or convulsions that do not result in inpatient hospitalization. 
Serious AEs 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 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 drug 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 
administration of the study drug, it is the investigator’s responsibility to report this occurrence to 
Taiho Pharmacovigilance or designee. 
Any ongoing SAEs should be followed until the earliest occurrence of one of the following: 
• SAE has resolved. 
• SAE has stabilized. An SAE can only be considered “stabilized” if the physical or 
laboratory AE being followed/assessed has remained constant (is not worsening) 
based on the investigator’s assessment for a minimum of 30 days post study drug 
discontinuation. 
• The start of new antitumor therapy. 
• The patient dies. 
13.1.3. 
Reporting of Deaths 
All deaths including death due to disease progression occurring through the 30-day follow-up 
period must be reported as an SAE within 24 hours: 
• Death is not an acceptable SAE term. Death is an outcome of an SAE. The primary 
cause of death should be reported as the SAE term.  
When reporting a death in the eCRF, site personnel will be required to identify which of the 
following best describes the category of death: 
• Toxicity caused by study drug. 
• Radiologic disease progression. 
• Clinical disease progression. 
• Other causes. 
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TAS-114 
Protocol TO-TAS-114-201 
Non-Small Cell Lung Cancer 
Amendment 1 27 September 2016 
Page 73 of 97 
 
13.1.4. 
Disease Progression  
How to report events related to nonfatal disease progression: 
• Disease progression is not an acceptable AE term. In cases of nonfatal disease 
progression, the relevant major symptoms, signs, and/or complications that led to the 
diagnosis of clinical disease progression should be reported as an AE. If the relevant 
symptoms, signs, and complications meet any of the serious criteria, they should be 
reported as SAEs. In both cases it should be indicated whether the symptoms, signs, 
and complications are related to clinical disease progression. 
How to report events related to fatal disease progression: 
• In cases of death due to clinical disease progression, the relevant major symptoms, 
signs, and/or complications that led to the diagnosis of clinical disease progression 
should be reported as SAE terms. Clinical disease progression may only be reported 
as an SAE term if none of the relevant symptoms or signs support a fatal outcome. 
13.1.5. 
Pregnancy 
If a patient becomes pregnant while in the study, the study treatment must be immediately 
discontinued. Pregnancy information in 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 
Pregnancy Form must be submitted by faxing an updated Pregnancy Form to Taiho 
Pharmacovigilance or designee. 
If the 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. 
13.1.6. 
Overdose 
An overdose with TAS-114 and S-1 for this clinical trial is defined as: 
Taking a dose beyond the recommended dose in 1 day or beyond the recommended total dose in 
each cycle.  
An overdose of TAS-114 and/or S-1 must be recorded on the AE and SAE Forms and reported to 
Taiho Pharmacovigilance, or designee, within 24 hours from the time the investigator first 
becomes aware of the overdose whether or not it was accidental or intentional, and whether or 
not the patient developed an AE (even if not fulfilling a seriousness criteria).  
There is no known antidote available in case of TAS-114 and/or S-1 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 medications should only be reported if it is 
associated with an AE. 
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Protocol TO-TAS-114-201 
Non-Small Cell Lung Cancer 
Amendment 1 27 September 2016 
Page 74 of 97 
 
13.1.7. 
Medication Errors 
A medication error for this clinical trial is defined as an 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 (including 
omission of one or more administrations). 
Please refer to the current eCRF Completion Guidelines for the details regarding reporting of 
medication errors to Taiho Pharmacovigilance or designee. 
The following types of medication errors, whether or not they meet the serious criteria, should be 
reported to Taiho Pharmacovigilance within 24 hours of first awareness, utilizing the AE and 
SAE forms in the eCRF: 
• Medication errors with study drug or concomitant medication resulting in an AE 
• Medication errors with study drug resulting in an overdose 
• Incorrect route of study drug administration 
• Administration of the incorrect study drug 
**Medication errors with the study drug that result in the omission of an administration, an 
incorrect dose, or the administration of more than the prescribed dose (but does not meet the 
overdose criteria), will not be reported as an AE, but will be identified through the recording of 
study drug accountability data in the eCRF.** 
13.1.8. 
Breaking the Study Blind 
This is an open-label study. 
13.2. 
Laboratory Evaluations 
13.2.1. 
Reporting and Evaluation of Laboratory Test Results 
Laboratory tests are to be performed as required per the 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 TAS-114/S-1 or S-1 control.   
The laboratory must provide normal reference ranges.   
Any laboratory abnormality that has a clinical impact on the patient (eg, results in delay of 
TAS-114/S-1 or S-1 control dosing, study discontinuation) must be reported as an AE, unless it 
is considered a supporting laboratory to a clinical diagnosis that is already reported as an AE. 
Febrile neutropenia must be reported as an AE and is defined as an ANC < 1000/mm3 with a 
single body temperature of > 38.3°C (101°F) or a sustained temperature of ≥ 38°C (100.4°F) for 
more than 1 hour. All laboratory data will be analyzed using NCI CTCAE grade criteria 
(Version 4.03). 
13.2.2. 
Repeat Testing 
Evaluation of any clinically significant laboratory test will be repeated, as clinically indicated, 
until the value returns to the baseline level or clinically stabilizes, or until new anticancer 
treatment, surgery, or radiotherapy is given. 
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Protocol TO-TAS-114-201 
Non-Small Cell Lung Cancer 
Amendment 1 27 September 2016 
Page 75 of 97 
 
13.3. 
Physical Examination and ECOG Performance Status 
Physical examinations and performance status evaluations will be performed as described in the 
Study Procedures section of the protocol. If changes are observed, the investigator will determine 
whether they meet the definition of an AE. All observations and evaluations will be documented. 
13.4. 
Vital Signs and Body Weight 
Vital sign measurements and body weight will be verified and documented. If a clinically 
significant change is observed, the measurement will be repeated as clinically indicated and 
evaluated for its clinical relevance and whether it meets the definition of an AE. 
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Protocol TO-TAS-114-201 
Non-Small Cell Lung Cancer 
Amendment 1 27 September 2016 
Page 76 of 97 
 
14. 
STATISTICS 
This section outlines the statistical methodology to be used to summarize the study results. An 
SAP will be prepared as a separate document. The SAP will include a more technical and 
detailed description of the planned statistical summaries and will be finalized prior to closing of 
the database.  
Study Populations 
The study populations include safety and efficacy populations. 
Safety and Efficacy Populations 
All safety and efficacy analyses will be based on patients who received at least 1 dose of 
TAS-114/S-1 or S-1 control.  
14.1. 
Statistical Analysis 
14.1.1. 
Patient Disposition, Baseline and Treatment Characteristics 
14.1.1.1. Patient Disposition 
The number of patients in each study population and the reasons for exclusion will be 
summarized. In addition, patients’ status with regard to study treatment and follow-up will also 
be summarized, along with the reasons for study discontinuation. 
14.1.1.2. Patient Baseline Characteristics 
Patient disease and baseline characteristics will be summarized using frequency distribution or 
descriptive statistics as appropriate. 
14.1.1.3. Study Treatment 
The TAS-114/S-1 or S-1 control administration profile will be summarized with respect to 
number of cycles taken, the dose intensity, dose modifications, reasons for deviations from the 
planned regimen, and the reason for discontinuing the study treatment. 
14.1.2. 
Efficacy Analysis 
Tumor assessments will be performed as described in Section 11.12, Tumor Assessments/Scans, 
for patients with solid tumors. The primary endpoint of PFS and secondary endpoints of ORR, 
DCR, and DR will be investigated based on the independent review of the images by the Core 
Imaging Laboratory. The investigators or local radiologists will evaluate the imaging studies for 
tumor response and/or progression. Response assessments will be made based on RECIST 
guidelines (Version 1.1, 2009) for solid tumors (see Section 12.1, Efficacy Assessment for Solid 
Tumors).  
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Protocol TO-TAS-114-201 
Non-Small Cell Lung Cancer 
Amendment 1 27 September 2016 
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14.1.2.1. Primary Efficacy Analysis 
14.1.2.1.1. Progression Free Survival 
PFS is defined as the time from the day of randomization to the start of disease progression or 
death (any cause), whichever occurs first, based on the blinded radiological review assessment of 
response. Patients who do not have disease progression or have not died will be censored at the 
last known time that the patient was progression free. 
PFS in the efficacy population will be compared between the 2 treatment groups using the 
stratified log-rank test with significance level of one-sided 5%. PD events assessed by the central 
independent review will be used for primary efficacy analysis. The estimate of the hazard ratio 
and corresponding 90% and 95% confidence interval (CI) will be provided using a Cox 
proportional hazards (CPH) model including treatment and the 2 stratifications factors in the 
model. The survival curves will be estimated using the Kaplan-Meier method. The primary 
analysis for PFS will be conducted after 60 events have been observed based on independent 
assessment or after all patients have been followed for at least 3 months, whichever is later. 
14.1.2.2. Secondary Efficacy Analysis 
14.1.2.2.1. Overall Survival 
OS is defined as the time from the day of randomization to any cause of death. The estimate of 
the hazard ratio and corresponding 95% CI will be provided using a univariate CPH model (only 
treatment effect in the model). The survival curves will be estimated using the Kaplan-Meier 
method. The unstratified log-rank test will be done for the comparison of treatment effect. 
14.1.2.2.2. Overall Response Rate and Disease Control Rate 
ORR is defined as the proportion of patients with objective evidence of CR or PR. The 
evaluation of ORR will be based on investigator assessment and/or central independent review of 
the images 
• Local CT image assessment and collect CT scans for central independent review  
At the analysis stage, the best overall response will be assigned for each patient as the best 
response recorded after initiation of study treatment. If applicable, responses recorded after 
disease progression or initiation of new anticancer treatment will be excluded.  
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.  
ORR and DCR in the efficacy population will be compared between the 2 treatment groups using 
Fisher’s exact test. The estimates and differences will be presented along with the associated 
95% CIs. 
14.1.2.2.3. Duration of Response 
DR is derived for those patients with objective evidence of PR or CR. DR is defined as the time 
from the first documentation of response (CR or PR) to the first documentation of objective 
tumor progression or death due to any cause. Patients who are alive and progression free as of 
Page 78 of 98

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Page 79 of 98
CCI

TAS-114 
Protocol TO-TAS-114-201 
Non-Small Cell Lung Cancer 
Amendment 1 27 September 2016 
Page 79 of 97 
 
15. 
ETHICS 
15.1. 
Ethical Considerations 
It is mandatory that all considerations regarding the protection of human subjects be carried out 
in accordance with the protocol, GCP, ICH Guidelines, the ethical principles that have their 
origin in the Declaration of Helsinki, and all applicable regulatory requirements. 
15.2. 
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. 
Before 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). 
15.3. 
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, applicable local regulations, and, for studies conducted under an 
Investigational New Drug (IND) application, the United States (US) Code of Federal 
Regulations Title 21 part 56. 
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, Investigator’s Brochure [IB], curriculum vitae), 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. 
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Protocol TO-TAS-114-201 
Non-Small Cell Lung Cancer 
Amendment 1 27 September 2016 
Page 80 of 97 
 
16. 
ADMINISTRATIVE CONSIDERATIONS 
16.1. 
Protocol Amendments 
No change to the protocol may be made without the joint agreement of both the investigator and 
sponsor. Any amendment to the original protocol will be made by sponsor and will be signed by 
both parties and submitted to the IRB/IEC and appropriate regulatory authorities for approval or 
notification. 
16.2. 
Curriculum Vitae 
All investigators and any sub-investigator(s) must provide sponsor 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. 
16.3. 
Administrative Structure 
The administrative structure of the study (eg, CROs) will be provided to all sites.   
In addition to ongoing safety monitoring during the study, a more comprehensive evaluation of 
the ongoing study safety profile will take place when key study milestones are met.  
16.4. 
Monitoring Procedures 
16.4.1. 
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. 
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. 
16.4.2. 
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 monitor 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. 
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Protocol TO-TAS-114-201 
Non-Small Cell Lung Cancer 
Amendment 1 27 September 2016 
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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, concomitant medications, AEs, eCRFs, and queries and 
respective responses will be reviewed with the investigator. 
16.4.3. 
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, patient’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, patient 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 following data will be recorded directly into the eCRFs and will be considered source data: 
• Reasons for concomitance, concomitant medication/therapy prescribed at other 
hospitals 
• Presence or absence of AEs, name of AEs, serious/non-serious, treatment on study 
therapy, causal relationship with study drug, and reasons for terminating follow-up. 
• Reasons for admission and discharge from the hospital, reasons for discontinuation or 
termination from the study, and reasons for death. 
16.4.4. 
Case Report Form 
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 
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 receipt of the eCRFs may generate 
additional requests via paper 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 appended to the eCRFs held by the investigator and sponsor. 
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Protocol TO-TAS-114-201 
Non-Small Cell Lung Cancer 
Amendment 1 27 September 2016 
Page 82 of 97 
 
16.4.5. 
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. 
16.5. 
Archiving of Records 
The investigator is responsible for the retention of all study documents according to institutional 
policies, local laws, ICH Parts 4.9.4 and 4.9.5 and, for studies conducted under an IND 
application, the US Code of Federal Regulations Title 21 part 312.62. For more information on 
US requirements and ICH Guidelines, please go to www.fda.gov and www.ema.europa.eu. 
The investigator agrees to inform sponsor in writing of the intention to remove or destroy any 
study-related records. Prior to contacting sponsor, the investigator must ensure that institutional 
and local requirements (for example, ICH Guidelines and Japanese Good Clinical Practice 
[J-GCP]) have been satisfied. The sponsor will evaluate the investigator’s request and will 
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 sponsor requests 
that the investigator maintain the records for a longer period of time, additional arrangements 
will be made. 
16.6. 
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. 
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. 
16.7. 
Use and Publication of Study Results 
All unpublished documentation (including the protocol, eCRF, and IB) given to the investigator 
is strictly confidential. All recipients must agree not to disclose the information contained herein 
to any person without the prior written authorization of the sponsor. The submission of these 
documents to the IRB/IEC is permitted. The investigator agrees that the sponsor maintains the 
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TAS-114 
Protocol TO-TAS-114-201 
Non-Small Cell Lung Cancer 
Amendment 1 27 September 2016 
Page 83 of 97 
 
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. 
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. 
16.8. 
Financial Disclosure 
Financial disclosure for clinical investigators and record keeping of financial records will be in 
accordance with local regulatory requirements. 
16.9. 
Termination of the Study 
In the event that the investigator is unable to continue the study and another suitable person is 
designated as the investigator, the sponsor must be notified in advance (30 days prior to notice). 
The new investigator must accept the responsibility in writing and be approved by the sponsor 
and the IRB/IEC. 
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. 
The investigator will be reimbursed for reasonable expenses incurred, if it is necessary to 
terminate the study or an individual patient's participation. The sponsor will not reimburse the 
investigator for the evaluation of patients if the evaluations are not conducted in compliance with 
the final protocol. 
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TAS-114 
Protocol TO-TAS-114-201 
Non-Small Cell Lung Cancer 
Amendment 1 27 September 2016 
Page 84 of 97 
 
17. 
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 are 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 which 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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Page 86 of 98
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PPD
PPD
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TAS-114 
Protocol TO-TAS-114-201 
Non-Small Cell Lung Cancer 
Amendment 1 27 September 2016 
Page 86 of 97 
 
18.2. 
Declaration of the Investigator 
A RANDOMIZED, OPEN-LABEL, MULTI-CENTER, INTERNATIONAL PHASE 2 STUDY 
OF TAS-114 IN COMBINATION WITH S-1 IN PATIENTS WITH ADVANCED OR 
METASTATIC NON-SMALL CELL LUNG CANCER 
 
Declaration of Investigator: 
I have read the above protocol, appendices, and referenced documents. I understand the contents 
and intend to fully comply with all requirements. No changes will be made without formal 
authorization by Taiho Oncology, Inc. in the form of a protocol amendment. I will work 
according to the moral, ethical, and scientific principles governing clinical research as set out in 
the protocol, GCP, ICH Guidelines, the ethical principles that have their origin in the Declaration 
of Helsinki, and all applicable regulatory requirements. 
I confirm that I am not banned from conducting clinical research and I will immediately contact 
Taiho Oncology, Inc. if I cannot fulfill my obligations to complete this protocol. 
Investigator 
Date: _______________ Signature: _______________________  
 
Name (block letters): __________________________________________ 
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Protocol TO-TAS-114-201 
Non-Small Cell Lung Cancer 
Amendment 1 27 September 2016 
Page 87 of 97 
 
19. 
REFERENCES 
1. Heidelberger C, Chaudhuri NK, Danneberg P, et al. Fluorinated pyrimidines, a new class of 
tumor inhibitory compounds. Nature. 1957;179:663-666. 
2. Longley DB, Harkin DP, Johnston PG. 5-fluorouracil: mechanisms of action and clinical 
strategies. Nat Rev Cancer. 2003;3(5):330-338. 
3. Shirasaka T. Development history and concept of an oral anticancer agent S-1 (TS-1): its 
clinical usefulness and future vistas. Jpn J Clin Oncol. 2009;39(1):2-15. 
4. Canman CE, Radany EH, Parsels LA, Davis MA, Lawrence TS, Maybaum J (1994) 
Induction of resistance to fluorodeoxyuridine cytotoxicity and DNA damage in human tumor 
cells by expression of Escherichia coli deoxyuridinetriphosphatase. Cancer Res 
54:2296-2298. 
5. Koehler SE, Ladner RD (2004) Small interfering RNA-mediated suppression of dUTPase 
sensitizes cancer cell lines to thymidylate synthase inhibition. Mol Pharmacol 66:620–626. 
6. Wilson, PM, LaBonte MJ, Lenz HJ, Mack PC, Ladner RD. Inhibition of dUTPase induces 
synthetic lethality with thymidylate synthase-targeted therapies in non-small cell lung cancer. 
Mol Cancer Ther. 2012. 11(3):616-28. 
7. Siegel RL, Miller KD, Jemal A. Global Cancer Statistics CA Cancer J Clin 2016;66:7–30. 
8. Kim MH, Shim HS, Kang DR, Jung JY, Lee CY, Kim DJ, et al. Clinical and prognostic 
implications of ALK and ROS1 rearrangements in never-smokers with surgically resected 
lung adenocarcinoma. Lung Cancer. 2014 Mar;83(3):389-95. 
9. Furushiro K. Investigation on Plasma Protein Binding of TAS-114-Species Difference and 
Human Plasma Binding Protein Fraction. TAIHO Pharmaceutical Co., Ltd., Study No. 
10DB04. 2010. Data on File. 
10. Furushiro K. Investigation of in vitro metabolism of TAS-114 in human liver samples. 
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