Conditions: Advanced or Metastatic Non-small Cell Lung Cancer
Keywords: NSCLC phase 2 study TAS-114 S-1
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 128
Healthy volunteers: no

Brief summary:
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 into TAS-114/S-1 arm versus S-1 control arm in a 1:1 ratio.

Detailed description:
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)

Arms:
arm 1: Participants received 400 milligrams (mg) of TAS-114 tablets orally twice daily (BID) along with 30 milligrams per meter square (mg/m\^2) of S-1 capsule BID for 2 weeks (Day 1 to 14), followed by 1 week recovery period (Day 15 to 21) in each 21 days cycle, until progressive disease (PD), occurrence of intolerable side effects, removal by the Investigator, or withdrawal of consent (maximum treatment duration: 51 weeks). arm 2: Participants received 30 mg/m\^2 of S-1 capsules BID for 2 weeks (Day 1 to 14) followed by 1 week recovery period (Day 15 to 21) in each 21 days cycle, until progressive disease (PD), occurrence of intolerable side effects, removal by the Investigator, or withdrawal of consent (maximum treatment duration: 38 weeks).

Interventions: intervention 1: TAS-114 intervention 2: S-1
Intervention descriptions: intervention 1: TAS-114 was a modulator of 5-fluorouracil (5-FU). intervention 2: S-1 was designed to provide oral delivery of 5-FU and to reduce the rate of degradation of 5-FU in vivo.

Protocol document:
Prot_000.pdf: 
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 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 
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Serum Chemistry5 
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Page 9 of 98


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Page 10 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. 
 
Page 11 of 98


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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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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) 
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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.  
Page 52 of 98


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). 
Page 54 of 98


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. 
Page 56 of 98


TAS-114 
Protocol TO-TAS-114-201 
Non-Small Cell Lung Cancer 
Amendment 1 27 September 2016 
Page 56 of 97 
 
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.  
 
 
Page 57 of 98


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. 
Page 58 of 98


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Protocol TO-TAS-114-201 
Non-Small Cell Lung Cancer 
Amendment 1 27 September 2016 
Page 58 of 97 
 
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 
Page 60 of 97 
 
• 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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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. 
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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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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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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]). 
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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).  
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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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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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TAS-114 
Protocol TO-TAS-114-201 
Non-Small Cell Lung Cancer 
Amendment 1 27 September 2016 
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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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TAS-114 
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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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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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. 
TAIHO Pharmaceutical Co., Ltd., Study No. 09DB23, In-house document, 2010. 
11. Yoshisue K. Mass balance and pharmacokinetics of 14C-TAS-114 after oral administration to 
rat. TAIHO Pharmaceutical Co., Ltd., Study No. 10DB21, In-house document, 2010. 
12. Besshi K. A 4-Week Oral Repeated Dose Toxicity Study of TAS-114 in Rats with a 2-Week 
Recovery Period. TAIHO Pharmaceutical Co., Ltd., Study No. 10CA04, In-house document, 
2010.  
13. Yada H. A 4-Week Oral Repeated Dose Toxicity Study of TAS-114 in Dogs with a 2-Week 
Recovery Period. TAIHO Pharmaceutical Co., Ltd., Study No. 10CA07, In-house document, 
2011.  
14. Kanie S. A 4-Week Oral Repeated Dose Toxicity Follow-up Study of Low-dose TAS-114 in 
Dogs. TAIHO Pharmaceutical Co., Ltd., Study No. 10CA28, In-house document, 2011.  
15. Saito K, Nagashima H, Noguchi K, et al. First-in-human, phase I dose-escalation study of 
single and multiple doses of a first-in-class enhancer of fluoropyrimidines, a dUTPase 
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TAS-114 
Protocol TO-TAS-114-201 
Non-Small Cell Lung Cancer 
Amendment 1 27 September 2016 
Page 88 of 97 
 
inhibitor (TAS-114) in healthy male volunteers. Cancer Chemother Pharmacol. 2014. 
73(3):577-83. 
16. Govindan R, Morgenzstern D, Kommor MD, Herbst RS, Schaefer P, Gandhi J, Saito K, 
Zergebel C, Schiller J. Phase II trial of S-1 as second-line therapy in patients with advanced 
non-small cell lung cancer. J Thorac Oncol. 2011 Apr;6(4):790-5. 
17. Zhu AX, Clark JW, Ryan DP, Meyerhardt JA, Enzinger PC, Earle CC, et al. Phase I and 
pharmacokinetic study of S-1 administered for 14 days in a 21-day cycle in patients with 
advanced upper gastrointestinal cancer. Cancer Chemother Pharmacol. 2007 Feb;59(3):285-
93. 
18. van Groeningen CJ, Peters GJ, Schornagel JH, Gall H, Noordhuis P, de Vries MJ, et al. 
Phase I clinical and pharmacokinetic study of oral S-1 in patients with advanced solid 
tumors. J Clin Oncol. 2000 Jul;18(14):2772-9. 
19. Scheulen ME, Saito K, Hilger RA, Mende B, Zergebel C, Strumberg D. Effect of food and a 
proton pump inhibitor on the pharmacokinetics of S-1 following oral administration of S-1 in 
patients with advanced solid tumors. Cancer Chemother Pharmacol. 2012 Mar;69(3):753-61. 
20. Staging Manual in Thoracic Oncology; TNM Classification of Malignant Tumours. 
International Association for the Study of Lung Cancer. 2009. 
21. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: Revised RECIST guideline (Version 1.1). Eur J 
Cancer. 2009 Jan;45(2):228-47. 
22. Benson AB, Ajani JA, Catalano RB, et al. Recommended guidelines for the treatment of 
cancer treatment-induced diarrhea. J Clin Oncol. 2004;22(14):2918-26.  
23. Hesketh PJ, Bohlke K, Lyman GH, Basch E, Chesney M, Clark-Snow RA, et al. 
Antiemetics: American Society of Clinical Oncology Focused Guideline Update. J Clin 
Oncol. 2016 Feb 1;34(4):381-6. 
24. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-55.  
 
 
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SAP_001.pdf: 
 
Statistical Analysis Plan 
Protocol No. TO-TAS-114-201 
Last Revision Date: 29NOV2017 
 
 
 
Page 1 of 44 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
Trial Sponsor: 
 
Taiho Oncology, Inc. (TOI) and Taiho 
Pharmaceutical Co. Ltd. (TPC) 
Protocol Number: 
TO-TAS-114-201 
IND Number: 
 
EUDRACT Number: 
2016-001806-40 
Investigational Drug: 
Indication: 
TAS-114/S-1 
Advanced or metastatic non-small cell  
lung cancer 
Drug Number: 
N/A 
Dosage Form/Strength: Tablets (TAS-114) / Capsules (S-1) 
 
 
Protocol Title: 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 
 
 
 
Last Revision Date: 
29NOV2017 
Final Sign-off Date: 
29NOV2017 
Archive Date: 
 
 
 
 
 
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Protocol No. TO-TAS-114-201 
Last Revision Date: 29NOV2017 
 
 
 
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CHANGE LOG FOR CHANGES MADE AFTER THE INITIAL APPROVAL 
 
 
 
Revision 
Date** 
 
Section(s) 
Modified 
 
Brief Description of Revision(s) or 
Reason(s) for Revision 
Modifications Reviewed and 
Approved by* 
Sponsor, Everest 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*   Provide person’s initial and last name. 
** Update the Last Revision Dates on the cover page and the document header. 
 
 
 


 
Statistical Analysis Plan 
Protocol No. TO-TAS-114-201 
Last Revision Date: 29NOV2017 
 
 
 
 Page 4 of 44 
 
 
TABLE OF CONTENTS 
 
1. 
INTRODUCTION ............................................................................................................................................8 
2. 
STUDY OBJECTIVES.....................................................................................................................................8 
2.1 
PRIMARY OBJECTIVE ...................................................................................................................................8 
2.2 
SECONDARY OBJECTIVES ............................................................................................................................9 
 
 
3. 
STUDY DESIGN ..............................................................................................................................................9 
3.1 
STUDY DESIGN ............................................................................................................................................9 
3.2 
RANDOMIZATION ........................................................................................................................................9 
3.3 
HYPOTHESIS TESTING ............................................................................................................................... 10 
3.4 
INTERIM ANALYSIS ................................................................................................................................... 10 
3.5 
SAMPLE SIZE ............................................................................................................................................. 10 
3.6 
STUDY PROCEDURES ................................................................................................................................. 10 
3.7 
SCHEDULE OF ASSESSMENTS..................................................................................................................... 12 
4. 
DATA AND ANALYTICAL QUALITY ASSURANCE ............................................................................. 16 
5. 
ANALYSIS POPULATIONS ........................................................................................................................ 16 
5.1 
INTENT-TO-TREAT (ITT) POPULATION ...................................................................................................... 16 
5.2 
TUMOR RESPONSE (TR) EVALUABLE POPULATION ................................................................................... 16 
5.3 
AS-TREATED (AT) POPULATION ............................................................................................................... 16 
 
 
6. 
SPECIFICATION OF ENDPOINTS AND VARIABLES .......................................................................... 17 
6.1 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ................................................................................... 17 
6.2 
EFFICACY .................................................................................................................................................. 17 
6.2.1 
Primary Efficacy Variables ....................................................................................................... 17 
6.2.2 
Secondary Efficacy Variables ................................................................................................... 19 
 
 
6.3 
SAFETY ..................................................................................................................................................... 22 
6.3.1 
Study Day and Visit Window Definitions ................................................................................ 22 
6.3.2 
Extent of Exposure to Study Medication .................................................................................. 23 
6.3.3 
Adverse Events ......................................................................................................................... 23 
6.3.4 
Deaths ....................................................................................................................................... 25 
6.3.5 
Laboratory Data ........................................................................................................................ 25 
6.3.6 
Vital Signs ................................................................................................................................ 26 
6.3.7 
Electrocardiogram (ECG) ......................................................................................................... 26 
6.3.8 
Physical Examination ............................................................................................................... 26 
6.3.9 
Pregnancy Test ......................................................................................................................... 26 
6.3.10 
Concomitant Medications and Therapies .................................................................................. 26 
6.3.11 
Other Diagnostics and Procedures ............................................................................................ 27 
6.3.12 
New Anti-Cancer Treatments ................................................................................................... 27 
7. 
STATISTICAL ANALYSIS .......................................................................................................................... 27 
7.1 
GENERAL DATA HANDLING RULES AND DEFINITIONS .............................................................................. 27 
7.2 
PATIENT DISPOSITION ............................................................................................................................... 28 
7.3 
PROTOCOL DEVIATIONS ............................................................................................................................ 28 
7.4 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ................................................................................... 29 
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Protocol No. TO-TAS-114-201 
Last Revision Date: 29NOV2017 
 
 
 
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7.5 
EFFICACY ANALYSES ................................................................................................................................ 29 
7.5.1 
Primary Efficacy ....................................................................................................................... 29 
7.5.2 
Secondary Efficacy ................................................................................................................... 31 
 
 
7.1 
SAFETY ANALYSES ................................................................................................................................... 32 
7.1.1 
Exposure of Study Treatment ................................................................................................... 32 
7.1.2 
Duration of Follow-Up ............................................................................................................. 32 
7.1.3 
Adverse Events ......................................................................................................................... 33 
7.1.4 
Deaths ....................................................................................................................................... 33 
7.1.5 
Laboratory Data ........................................................................................................................ 33 
7.1.6 
Vital Signs ................................................................................................................................ 34 
7.1.7 
Concomitant Medications and Therapies .................................................................................. 34 
7.1.8 
Other Diagnostics and Procedures ............................................................................................ 34 
7.1.9 
New Anti-Cancer Treatments ................................................................................................... 34 
7.1.10 
Other Safety Assessments ......................................................................................................... 34 
 
 
 
 
 
 
8. 
CHANGES FROM METHODS PLANNED IN THE PROTOCOL ......................................................... 36 
9. 
STATISTICAL SOFTWARE ........................................................................................................................ 36 
10. 
REFERENCES ............................................................................................................................................... 37 
 
 
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Protocol No. TO-TAS-114-201 
Last Revision Date: 29NOV2017 
 
 
 
 Page 6 of 44 
 
 
GLOSSARY OF ABBREVIATIONS 
Abbreviation 
Term 
5-FU 
5-fluorouracil 
AE 
Adverse event 
ALK 
Anaplastic lymphoma kinase 
AT 
As-treated 
BID 
Twice daily 
BSA 
Body surface area 
CI 
Confidence interval 
CPH 
Cox proportional hazards 
CR 
Complete Response 
CRF 
Case report form 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCR 
Disease control rate 
DPD 
Dihydropyrimidine dehydrogenase 
DR 
Duration of response 
dUTPase 
Deoxyuridine triphosphatase 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EGFR 
Epidermal growth factor receptor 
HR 
Hazard ratio 
ICF 
Informed consent form 
ITT 
Intent-to-treat 
IU 
International Units 
IXRS 
Interactive voice/web response system 
MedDRA 
Medical Dictionary For Regulatory Activities 
NCI 
National Cancer Institute 
NSCLC 
Non-small cell lung cancer 
OPRT 
Orotate phosphoribosyltransferase 


 
Statistical Analysis Plan 
Protocol No. TO-TAS-114-201 
Last Revision Date: 29NOV2017 
 
 
 
 Page 7 of 44 
 
 
GLOSSARY OF ABBREVIATIONS 
ORR 
Overall response rate 
OS 
Overall survival 
PD 
Progressive disease 
PFS 
Progression-free survival 
 
 
PR 
Partial response 
QA 
Quality assurance  
QC 
Quality control 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE  
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Stable disease 
SI 
International System (of Units) 
TR 
Tumor response 
WHO 
World Health Organization 
WHO-DDE 
World Health Organization - Drug Dictionary Enhanced 
WHO-HD 
World Health Organization - Herbal Dictionary 
 
 
 
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Statistical Analysis Plan 
Protocol No. TO-TAS-114-201 
Last Revision Date: 29NOV2017 
 
 
 
 Page 8 of 44 
 
 
1. INTRODUCTION 
Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality worldwide 
(Siegel et al, 2016). Despite treatment with immunotherapy, platinum- and taxane-based chemotherapy, 
patients with refractory metastatic NSCLC have a median survival of approximately 8 to 10 months. 
Moreover, there has been little overall survival improvement from several new agents, including 
pemetrexed, erlotinib and bevacizumab beyond very small subpopulations. Therefore, the majority of 
NSCLC cases remain a disease with high burden and unmet medical need. 
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 have been investigated and have demonstrated efficacy against a variety of 
carcinomas to date (Longley et al, 2003). 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 
mucosa have been developed (Shirasaka et al, 2009). However, chemotherapies using 5-FU or S-1 can 
cause intrinsic and acquired resistance to the 5-FU drugs. Studies indicate that deoxyuridine triphosphatase 
(dUTPase) may be one of the causal factors for resistance to 5-FU-based chemotherapies (Wilson et al, 
2012). Therefore, the development of new drugs that can be expected to achieve higher efficacy than the 
existing 5-FU drugs is urgently required. 
TAS-114 is a modulator of 5-fluorouracil (5-FU), and can enhance antitumor activity of 5-FU. S-1 is an oral 
fluoropyrimidine that combines tegafur (5-fluoro-1-(tetrahydro-2-furyl) uracil, FT), a prodrug of 5-FU. 
Based on non-clinical pharmacology and toxicology models, the combination of TAS-114 with S-1 has 
demonstrated a potential to enhance the antitumor activity of S-1 with acceptable changes in its toxicity 
profile. 
 
 
 
 
 
 
See Protocol Section 6 for details. 
2. STUDY OBJECTIVES 
2.1 
Primary Objective 
x 
To compare progression-free survival (PFS) of patients with advanced or metastatic 
NSCLC, when treated with TAS-114/S-1 combination versus S-1.  
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Protocol No. TO-TAS-114-201 
Last Revision Date: 29NOV2017 
Page 9 of 44 
2.2
Secondary Objectives
x
To investigate the overall survival (OS), overall response rate (ORR), disease control rate 
(DCR), and duration of response (DR). 
x
To investigate the safety and tolerability.
3. STUDY DESIGN
3.1
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. The overall study 
design is described in Figure 1. 
Figure 1 Study Schema
3.2
Randomization 
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:
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
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Statistical Analysis Plan 
Protocol No. TO-TAS-114-201 
Last Revision Date: 29NOV2017 
 
 
 
 Page 10 of 44 
 
 
• 
Geographical region (Region 1: Asian [Japan]; Region 2: Western [Europe and US]) 
• 
Histological subtypes (nonsquamous cell carcinoma [including mixed] and squamous cell 
carcinoma) 
3.3 
Hypothesis Testing 
The null and alternative hypotheses regarding PFS can be phrased in terms of the hazard ratio function, 
λGroup A / λGroup B, where λGroup A represents the hazard function of progression/death for patients in the Group 
A (TAS-114/S-1 arm) and λGroup B represents the hazard function of progression/death for patients in Group 
B (S-1 arm). A hazard ratio < 1 indicates that PFS is prolonged for patients in Group A compared with 
those patients in Group B. The null (H0) and alternative (Ha) hypotheses, respectively, can be written as 
follows: 
H0: λGroup A / λGroup B =1  
Ha: λGroup A / λGroup B <1. 
The hazard ratio (HR) and the corresponding 95% confidence interval (CI) and p-value (based on a one-
sided stratified log-rank test at the 0.05 significance level) will be estimated using a Cox proportional 
hazards model stratified by geographic region and histological subtypes. 
If the results from the log-rank test lead to the rejection of H0 in favor of Ha, it will be concluded that the 
TAS-114/S-1 arm is associated with longer PFS than patients in the S-1 control arm.  
3.4 
Interim Analysis 
No formal interim analysis is planned with respect to stopping the trial early or for lack of efficacy 
purposes. 
3.5 
Sample Size 
The planned sample size is approximately 124 advanced or metastatic NSCLC patients. The study is 
designed to differentiate 4.2 months median PFS of treatment with TAS-114/S-1 from 2.2 months median 
PFS of treatment with S-1 (hazard ratio of 0.524) with 80% statistical power and a 1-sided type 1 error of 
0.05. Using a treatment allocation of 1:1 (TAS-114/S-1: S-1), a target of 60 events (PD or deaths) will be 
required for the primary analysis, which corresponds to 71 events based on investigator review under the 
assumption that the discrepancy in PD events between the independent central review and investigator 
review is 15%. A total sample size of 124 patients is planned from the assumption that accrual period is 10 
months, the percentage of PFS events is 65%, and the percentage of patients lost to tumor follow-up caused 
by study discontinuation is 10%. 
3.6 
Study Procedures 
The following study procedures will be performed during the study: 
- 
Informed consent 
- 
Medical history 


 
Statistical Analysis Plan 
Protocol No. TO-TAS-114-201 
Last Revision Date: 29NOV2017 
 
 
 
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- 
Physical examination 
- 
Height, vital signs, and weight 
- 
Performance status 
- 
Electrocardiogram 
- 
Clinical laboratory evaluations 
- 
Pregnancy test 
- 
 
- 
Prior and concomitant medications (therapies) 
- 
Adverse event assessment 
- 
Tumor assessments/scans 
- 
30-day safety follow-up
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Protocol No. TO-TAS-114-201 
Last Revision Date: 29NOV2017 
 
 
 Page 12 of 44 
 
 
3.7 
Schedule of Assessments 
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 
Treatmenti) 
30-Day Safety 
Follow-up Visitii) 
Survival 
Follow-up 
-28 to -
1 
-7 to 
0iii) 
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 
Xiv) 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Baseline Signs and Symptoms 
X 
X 
X 
 
 
 
 
 
 
 
 
Physical Examv) 
X 
X 
Xv) 
X 
X 
Xv) 
 
 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Vital Signs/Weightv) 
X 
X 
 
 
 
Xv) 
 
 
X 
X 
 
Performance Statusv) 
X 
X 
X 
 
 
Xv) 
 
 
X 
X 
 
ECG 
X 
 
 
 
 
 
 
 
X 
X 
 
Hematologyv) 
X 
X 
 
X 
X 
Xv) 
Xv) 
 
X 
X 
 
Serum Chemistryv) 
X 
X 
 
X 
X 
Xv) 
Xv) 
 
X 
X 
 
Coagulationv) 
X 
X 
 
X 
X 
Xv) 
Xv) 
 
X 
X 
 
Urinalysis 
X 
X 
 
 
 
 
 
 
X 
X 
 
Pregnancy test vi) 
 
X 
 
 
 
 
 
 
 
 
 
Concomitant Medicationsvii) 
 
 
AE/Toxicity Assessmentvii) 
 
 
Tumor Assessmentviii) 
X 
 
 
 
 
 
 
Xviii) 
Xviii) 
 
 
TAS-114ix) 
 
 
 
 
 
 
 
 
S-1.x) 
 
 
 
 
 
 
 
 
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Protocol No. TO-TAS-114-201 
Last Revision Date: 29NOV2017 
 
 
 Page 13 of 44 
 
 
Visit ID/Procedure 
Baseline 
On-Treatment 
End of Treatment/Study 
Baseline Day 
Cycle 1 (Day of Cycle) 
Subsequent Cycles (Day of Cycle) 
End of 
Treatmenti) 
30-Day Safety 
Follow-up Visitii) 
Survival 
Follow-up 
-28 to -
1 
-7 to 
0iii) 
1 
8 
15 
1 
15 
End of 
Recovery 
 
 
 
Survival Statusxii) 
 
 
Abbreviations: AE = adverse event; BID = twice daily; ECG = electrocardiogram; ICF = informed consent; 
. 
i) 
End of Treatment: If the decision to discontinue TAS-114/S-1 is made within 2 weeks after the patient’s last treatment visit, an End of Treatment visit is not required unless 
deemed clinically necessary by the investigator. If the decision to discontinue TAS-114 (because of disease progression or other reasons) is made more than 2 weeks after the 
last treatment visit, an End of Treatment visit is required. See Section 10.4.1 of the protocol. 
ii) 30-Day Safety Follow-up Visit: If the patient starts new anticancer therapy within 30 days of the end of treatment, the 30-day Safety Follow-up visit should be performed 
before the start of new anticancer therapy within the 30-day window. See Section 11.13 of the protocol. 
iii) Baseline Assessment (Day -7 to -1) will be obtained within 7 days before treatment on Day 1 of Cycle 1. 
iv) Patient Number Assignment: A patient number will be assigned once a patient has entered study screening (ie, has signed the ICF). 
v) The physical exam, vital signs determination, weight, performance status, laboratory evaluations (hematology, serum chemistry, and coagulation) will be obtained within 1 day 
before study drug administration on Day 1 of each cycle. 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. 
vi) Pregnancy Test:  Pregnancy test is required at Baseline (within 7 days prior to Day 1 of Cycle 1) and at End of Treatment and 30-day Safety Follow-up visit.  More frequent 
pregnancy assessments may be performed as required by local law. 
vii) Concomitant medications and AE/toxicity assessments will be collected from the time of signing of the ICF through 30 days after administration of the last dose of study drug. 
viii) Tumor assessments/scans will be performed at baseline, at the end of every 6 weeks (± 7 days) beginning at Cycle 2 throughout all the treatment cycles, and at the time of 
discontinuation. See Section 11.12 of the protocol, Tumor Assessments/Scans for details. Computerized tomography (CT) scans obtained before signing the ICF may be used 
as the baseline tumor scan if it is within 28 days of the first study drug administration. If the patient has discontinued treatment for reasons other than radiologic disease 
progression, a CT scan should be performed every 6 weeks (± 1 week) until the patient starts new anticancer therapy visit. Following Cycle 6, CT assessments may be adjusted 
to every 9 weeks. 
ix) TAS-114 administration: orally BID together with S-1 on Days 1 through 14 of each cycle. See Section 9.1.2.1 of the protocol for TAS-114 Dose Levels. 
x) S-1 administration: orally BID together with TAS-114 on Days 1 through 14 of each cycle. 
xii)  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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Protocol No. TO-TAS-114-201 
Last Revision Date: 29NOV2017 
 
 
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Table 2 Study Schedule of S-1 Arm 
Visit ID/Procedure 
Baseline  
On-Treatment 
End of Treatment/Study  
Baseline Days 
Cycle 1 (Day of Cycle) 
Subsequent Cycles (Day of Cycle) 
End of 
Treatmenti) 
for S-1 
30-Day 
Safety 
Follow-up 
Visitii) 
Survival 
Follow-up 
-28 to -1 
-7 to 0iii) 
1 
8 
15 
1 
15 
End of 
Recovery 
 
 
 
Visit Window 
0 
0 
-1 to 0 
± 3 
± 3 
-1 to 0 
± 3 
± 3 
± 3 
-7 
 
Sign ICF 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion  
X 
 
X 
 
 
 
 
 
 
 
 
Assign Patient Number 
Xiv) 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Baseline Signs and 
Symptoms 
X 
X 
X 
 
 
 
 
 
 
 
 
Physical Examv) 
X 
X 
Xv) 
X 
X 
Xv) 
 
 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Vital Signs/Weightv) 
X 
X 
 
 
 
Xv) 
 
 
X 
X 
 
Performance Statusv) 
X 
X 
X 
 
 
Xv) 
 
 
X 
X 
 
ECG 
X 
 
 
 
 
 
 
 
X 
X 
 
Hematologyv) 
X 
X 
 
X 
X 
Xv) 
Xv) 
 
X 
X 
 
Serum Chemistryv) 
X 
X 
 
X 
X 
Xv) 
Xv) 
 
X 
X 
 
Coagulationv) 
X 
X 
 
X 
X 
Xv) 
Xv) 
 
X 
X 
 
Urinalysis 
X 
X 
 
 
 
 
 
 
X 
X 
 
Pregnancy testvi) 
 
X 
 
 
 
 
 
 
 
 
 
Concomitant 
Medicationsvii) 
 
 
AE/Toxicity 
Assessmentvii) 
 
 
Tumor Assessmentviii) 
X 
 
 
 
 
 
 
Xviii) 
Xviii) 
 
 
S-1 Treatmentix)  
 
 
 
 
 
 
 
 
Survival Statusxi) 
 
Abbreviations: AE = adverse event; BID = twice daily; ECG = electrocardiogram; ICF = informed consent; 
. 
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i) 
End of Treatment: If the decision to discontinue S-1 is made within 2 weeks after the patient’s last treatment visit, an End of Treatment visit is not required unless deemed 
clinically necessary by the investigator. If the decision to discontinue S-1 (because of disease progression or other reasons) is made more than 2 weeks after the last treatment 
visit, an End of Treatment visit is required. See Section 10.4.1 of the protocol. 
ii) 30-Day Safety Follow-up Visit: If the patient starts new anticancer therapy within 30 days of the end of treatment, the 30-day Safety Follow-up visit should be performed 
before the start of new anticancer therapy within the 30-day window. See Section 11.13 of the protocol. 
iii) Baseline Assessment (Day -7 to -1) will be obtained within 7 days before treatment on Day 1 of Cycle 1. 
iv) Patient Number Assignment: A patient number will be assigned once a patient has entered study screening (ie, has signed the ICF). 
v) The physical exam, vital signs determination, weight, performance status, laboratory evaluations (hematology, serum chemistry, and coagulation) will be obtained within 1 day 
before study drug administration on Day 1 of each cycle starting at Cycle 2. 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. 
vi) Pregnancy Test:  Pregnancy test is required at Baseline (within 7 days prior to Day 1 of Cycle 1) and at End of Treatment and 30-day Safety Follow-up visit.  More frequent 
pregnancy assessments may be performed as required by local law. 
vii) Concomitant medications and AE/toxicity assessments will be collected from the time of signing of the ICF through 30 days after administration of the last dose of study 
medication. 
viii) Tumor assessments/scans will be performed at baseline, at the end of every 6 weeks (± 7 days) beginning at Cycle 1 Day 1 throughout all the treatment cycles, and at the time 
of discontinuation. See Section 11.12 of the protocol, Tumor Assessments/Scans for details. Computerized tomography (CT) scans obtained before signing the ICF may be 
used as the baseline tumor scan if it is within 28 days of the first study drug administration.  If the patient has discontinued treatment for reasons other than radiologic disease 
progression, a CT scan should be performed within 2 weeks of the End of Treatment visit. Following Cycle 6, CT assessments may be adjusted to every 9 weeks. 
ix) S-1 administration: orally BID on Days 1 through 14 of each cycle.   
) 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 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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4. DATA AND ANALYTICAL QUALITY ASSURANCE 
The overall quality assurance procedures for the study data, statistical programming and analyses are 
described in the Everest’s Standard Operating Procedures. Detailed data management procedures are 
documented in the Data Management Plan, Data Validation Check Specifications, and Data Review Plan. 
Detailed statistical and programming quality control and quality assurance procedures are documented in 
the Statistical Analysis and Programming QC/QA Plan.  
The study endpoints and analytic approaches are both prospectively defined and documented in the protocol 
and in this SAP. The SAP will be finalized prior to the database lock. 
5. ANALYSIS POPULATIONS 
The analysis populations defined in this SAP differ slightly from the populations defined in the protocol in 
order to adhere to the FDA guidance (ICH E9). 
5.1 
Intent-to-Treat (ITT) Population 
The ITT population is defined as all patients randomized in the study, regardless of whether they actually 
received any study treatment (TAS-114 or S-1) or not. All analyses using this population will be based on 
the treatment assigned by IXRS. 
5.2 
Tumor Response (TR) Evaluable Population 
The TR evaluable population includes all patients in the ITT population with measurable disease (at least 
one target lesion) at baseline and with at least one tumor evaluation (Patients who have disease progression 
or have a cancer related death prior to their 1st tumor evaluation will also be considered evaluable.) All 
analyses using this population will be based on the treatment assigned by IXRS. 
5.3 
As-Treated (AT) Population 
The AT population is defined as all patients who received at least 1 dose of TAS-114 or S-1. All analyses 
using this population will be based on the treatment actually received. This population will be used for 
safety analyses. 
 
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6. SPECIFICATION OF ENDPOINTS AND VARIABLES 
6.1 
Demographic and Baseline Characteristics 
Demographics, baseline characteristics, cancer history, medical history/active symptoms and prior cancer 
treatments will be collected at the baseline Day -28 visit; medical history/active symptoms will be 
confirmed (and updated as needed) at the baseline Day -7 visit and Cycle 1 day 1 visit: 
• 
Demographic variables include age, sex, female reproductive status, race, ethnicity and geographic 
region. The age will be calculated as the integer part of (date of consent-date of birth)/365.25 for sites 
that collect date of birth. The age entered on the CRF will be used for sites that do not collect the date 
of birth. 
 
• 
Baseline characteristics include height, weight, and ECOG performance status. 
 
• 
Cancer history includes time from the initial diagnosis to first study drug dose, location of primary 
tumor, tumor grade, histology subtype, presence of metastases (yes vs. no), EGFR mutation (yes, no vs. 
unknown), ALK translocation (yes, no vs. unknown), ROS1 rearrangements (yes, no vs. unknown), and 
other gene abnormality (yes, no vs. unknown). Time from the initial diagnosis to first study drug dose 
(months) will be calculated as (first treatment dose date -date of original diagnosis) / 30.4375. Time 
from the metastatic diagnosis to first study drug dose (months) will be calculated will be calculated as 
(first treatment dose date- date of metastatic diagnosis) / 30.4375. If the day of the initial or metastatic 
diagnosis is missing, then the missing day will be imputed by the first day of the month for calculation 
purposes. If the day and month of the initial or metastatic diagnosis are both missing, then the missing 
day and month will be imputed by January 1st. 
 
• 
Medical history and active symptoms include diagnosis or symptoms entered on the Medical History 
and Active Symptoms form. Verbatim descriptions of diagnosis or symptoms will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA version 19.0).  
 
• 
Prior cancer treatments include medication/surgery entered on the Prior Radiotherapy form, the Prior 
Surgery form, the Prior Systemic Drug Therapies for Cancer form). 
 
• 
Prior medication on Concomitant Medications and Therapies form. Prior medication is defined as any 
medication with start date on or before the first day of study drug (TAS-114 or S-1), or checked to be 
prior to first study drug administration date, or medication with start date missing. 
 
Verbatim descriptions of prior medications will be mapped to the World Health Organization (WHO) 
Drug Dictionary Enhanced (WHO-DDE) and Herbal Dictionary (WHO-HD) (version Q1 2016).  
6.2 
Efficacy 
6.2.1 
Primary Efficacy Variables 
Progression-free survival (PFS) is defined as the time (in months) from the day of randomization to the start 
of radiologic disease progression or death (any cause), whichever occurs first: (earlier of: date of first 
radiologic PD or date of death [all cause] – date of randomization +1)/30.4375.  


 
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Progressive disease (PD) events assessed by the central independent review (blinded radiological review) 
will be used for primary efficacy analysis. Central tumor imaging assessments will be performed using 
RECIST guidelines (Version 1.1, 2009). 
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 (e.g. date of last evaluable tumor assessment) before receiving any new 
anti-cancer treatment. Patients without disease assessment post-baseline will be censored at the time of the 
randomization. 
Refer to Table 3 for censoring rules for progression-free survival. 
Table 3 – Censoring Rules for Progression-Free Survival  
Situation 
End Date 
Censored 
Documented radiological PD 
Date of the first tumor assessment that determined PD 
No 
Death during the study before PD Date of death 
No 
Treatment discontinuation for 
other than radiologic PD or death 
with no post-baseline tumor 
assessments 
Date of randomization 
Yes 
Treatment discontinuation for 
other than radiologic PD or death 
with post-baseline tumor 
assessments 
Date of last adequate tumor assessment prior to initiation 
of non-study anti-cancer treatment 
Yes 
Patients still followed without 
radiologic PD as of cut-off date 
Date of last adequate tumor assessment prior to cut-off 
date 
Yes 
Non-study anti-cancer treatment 
initiated before radiologic PD 
Date of last adequate tumor assessment prior to initiation 
of non-study anti-cancer treatment 
Yes 
Death or radiologic PD after a 
missed (or not available/not 
evaluable) tumor assessment  
 
Date of last adequate tumor assessment prior to missed 
tumor assessment 
A response assessment is considered “missed” if more than 
13 weeks (91 days) has elapsed since the last image-based 
response assessment. If a patient develops progressive 
disease or dies after this interval, the tumor response 
assessment will be excluded from the analysis and censored 
at the last evaluable assessment. However, if a response 
assigned as CR, PR, or SD is obtained after more than 13 
weeks, then the tumor response assessment will not be 
excluded from the analysis as long as no other censoring 
events have occurred.  
 
Note: If patient dies within the 13 weeks from the last non-
PD tumor assessment, death will be counted as a PFS event 
Yes 


 
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unless the non-study anti-cancer treatment is initiated. 
 
Only non-evaluable (NE) tumor 
assessments after CR, PR, or SD 
Date of last adequate tumor assessment prior to NE 
tumor assessments 
Yes 
No baseline tumor assessment 
Date of randomization 
Yes 
General Considerations: 
Tumor response assessment dates will be assigned based on the date the image was performed, not the date the 
image was assessed. 
 
Note: Tumor response assessments will be considered “adequate” for analysis if they are assigned as CR, 
PR, SD, or PD and are not censored (e.g., obtained within 13 weeks since the last assessment and prior to 
initiation of non-study anti-cancer treatment: systemic anti-cancer therapy, radiotherapy or cancer surgery). 
 
Tumor response assessments obtained after initiation of non-study anti-cancer treatment will not be 
included in the efficacy analyses, but will be flagged in the data listings. Tumor response assessments 
obtained the same day as initiation of non-study anti-cancer treatment will not be excluded. 
6.2.2 
Secondary Efficacy Variables 
6.2.2.1 
Overall Survival 
 
Overall survival (OS) in months is defined as the time from the day of randomization to death from any 
cause: (date of death – date of randomization +1)/30.4375. Patients who were alive at the end of study will 
be censored at the last date the patient is known to be alive. Patients without post-baseline information will 
be censored at the time of randomization. 
6.2.2.2 
Overall Response Rate and Disease Control Rate 
 
Overall response rate (ORR) is defined as the proportion of patients with objective evidence of complete 
response (CR) or partial response (PR). The evaluation of ORR will be based on 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 anti-cancer treatment will be excluded. 
The assessment of disease control rate (DCR) will parallel that of ORR, with DCR defined as the proportion 
of patients with objective evidence of complete response (CR), partial response (PR), or stable disease 
(SD). 
6.2.2.3 
Duration of Response 
 
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Duration of response is derived for those patients with objective evidence of PR or CR. DR (in months) 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: (date of first progression or death – date of first CR 
or PR +1)/30.4375.  
Patients who are alive and progression free as of the analysis cut-off date will be censored at their last 
evaluable tumor response assessment before initiation of any new anti-cancer cancer treatment. Refer to 
Table 4 for censoring rules for duration of response. 
Table 4 – Censoring Rules for Duration of Response 
Situation 
End Date 
Censored 
Documented radiological PD 
Date of the first tumor assessment that determined 
PD 
No 
Death during the study before PD Date of death 
No 
Patients still followed without 
radiologic PD as of cut-off date 
Date of last adequate tumor assessment prior to 
cut-off date 
Yes 
Non-study anti-cancer treatment 
initiated before radiologic PD 
Date of last adequate tumor assessment prior to 
initiation of non-study anti-cancer treatment 
Yes 
Death or radiologic PD after a 
missed (or not available/not 
evaluable) tumor assessment  
 
Date of last adequate tumor assessment prior to 
missed tumor assessment 
A response assessment is considered missed if more 
than 13 weeks (91 days) has elapsed since the last 
image-based response assessment.  If a patient 
develops progressive disease or dies after this 
interval, the tumor response assessment will be 
excluded from the analysis and censored at the last 
evaluable assessment.  However, if an adequate 
image-based response assigned as CR, PR, or SD is 
obtained after more than 13 weeks, then the tumor 
response assessment will not be excluded from the 
analysis as long as no other censoring events have 
occurred. 
 
Yes 
Only non-evaluable (NE) tumor 
assessments after CR or PR  
Date of last adequate tumor assessment prior to 
NE tumor assessments 
Yes 
General Considerations: 
Tumor response assessment dates will be assigned based on the date the image was performed, not the date the 
image was assessed. 
 


 
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Note: Tumor response assessments will be considered “adequate” for analysis if they are assigned as CR, 
PR, SD, or PD and are not censored (e.g., obtained prior to initiation of non-study anti-cancer treatment). 
 
Tumor response assessments obtained after initiation of non-study anti-cancer treatment (systemic anti-
cancer therapy, radiotherapy or cancer surgery) will not be included in the efficacy analyses, but will be 
flagged in the data listings. Tumor response assessments obtained the same day as initiation of non-study 
anti-cancer treatment will not be excluded. 


 
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6.3 
Safety 
Safety parameters that will be measured in the study are:  
1. Adverse events 
2. Laboratory measurements 
3. Vital signs 
4. ECG 
5. Physical examination 
6. ECOG performance status 
7. Pregnancy test 
8. Concomitant medications and therapies 
9. Other diagnostics and procedures  
 
6.3.1 
Study Day and Visit Window Definitions 
The study windows listed in Table 3 (based on visit dates) will be used to analyze physical examination, 
vital signs, height, weight, laboratory, ECOG and ECG measurements. 
Table 3 Safety Study Windows 
Visit 
Safety Parameters 
Target Day 
Window 
Baseline 
Physical Examination, 
Vital Signs, Height, 
Weight, ECOG, 
Laboratory 
Measurements, ECG 
Day -28 to Day 1  
 
Day -28 to 1 
Day 1 of Cycle 2 to 6 
All 
Day 1 of Cycle 
Day -1 to 1 of Cycle 
Day 1 of Cycle 7 and up 
Laboratory 
Measurements 
Day 1 of Cycle 
Day -2 to 1 of Cycle 
Physical Examination, 
Vital Sign, Height, 
Weight, ECOG, ECG 
Day 1 of Cycle 
Day -1 to 1 of Cycle 
Day 8 of all Cycles  
All 
Day 8 of Cycle 
Day 2  to 11 of Cycle 
Day 15 of Cycle 2 to 6 
All 
Day 15 of Cycle 
Day 12 of Cycle to Day -2 of 
next Cycle 
Day 15 of Cycle 7 and up 
Laboratory 
Measurements 
Day 15 of Cycle 
Day 12 of Cycle to Day -3 of 
next Cycle 
Physical Examination, 
Vital Sign, Height, 
Weight, ECOG, ECG 
Day 15 of Cycle 
Day 12 of Cycle to Day -2 of 
next Cycle 
End of Treatment 
All 
NA 
No window will be used 
30-Day Safety Follow-up  
All 
30 Days after Last Dose of 
Study Medication 
Last Dose of Study Medication 
+ 21 to Last Dose of Study 
Medication + 39 (i.e. +/- 9 
days) 


 
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For post-baseline scheduled visits, the CRF visit will be used as analysis visit (i.e. no window will be used). 
Both scheduled and unscheduled assessments are included in the safety analyses. If more than one 
assessment is measured within the same visit window, the value closest to the target study day will be used 
for the analysis. If multiple values are the same number of days away from the target study day, then the 
latter value will be used. For Visit where time window is not applicable, the latest value would be used. 
6.3.2 
Extent of Exposure to Study Medication 
The total dose received, number of treatment cycles received, and dose intensity will be derived using data 
from the TAS-114 and S-1 Administration form, and Study Drug Accountability form.  
 
The total dose received for each study drug is the sum of dose received at each cycle, and the number of 
cycle received is the number of cycles with at least one dose taken during a cycle.  
The treatment duration for each study drug (in weeks) is calculated from the date of first dose to the date 
of last dose + 7 or the start of new anti-cancer treatment, whichever is earlier, and then divided by 7. 
Dose intensity is defined as the total dose actually received divided by the planned dose (i.e., total dose that 
would be given if no doses were missed and/or no dose reductions were made for the duration of time the 
patient received any component of study treatment) multiplied by 100%. 
The planned dose for each drug at each cycle is as follows: 
• 
TAS-114: 400 mg x 2 (BID) x 14 Days  
• 
S-1: 30 mg/m2 x BSA x 2 (BID) x 14 Days  
where BSA (m²) = ([Body Weight (kg)] 0.425 x [Height (cm)] 0.725) x 0.007184. 
 
The total planned dose is the sum of planned doses over all cycles. 
The number of dose reductions, dose modifications, dose interruptions, and cycle delays will also be 
calculated.  
6.3.3 
Adverse Events 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA 
version 19.0) and the severity of the toxicities will be graded according to the NCI CTCAE 
(Version 4.03).  
Only treatment emergent adverse events will be included in summary tabulations. Treatment-
emergent adverse events will be defined as adverse events with onset dates on or after the first 
dose of study medication and within 30 days after the last dose of study medication. Adverse 
events will be summarized by system organ class (SOC) and preferred term (PT), and worst 
severity grade.  
Adverse Events Counting Rules 
1. A patient with more than one different adverse event in a particular system organ class (SOC) will 
be counted only once in the total of patients experiencing adverse events in that particular SOC.  


 
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2. A patient having experienced the same event (AE preferred term) more than once during the study 
will be counted only once in the number of patients with that event.  
3. If an event changes in intensity or in seriousness during the study, it will be counted only once with 
the worst grade and seriousness respectively. 
4. If the causal relationship to the study drug is assessed differently, it will be counted only once by 
considering the “Worst” documented degree of relationship. 
Missing Grade 
An AE with missing severity grade will not be imputed but will be considered as ‘>=3’ in the table 
presenting Grade 3 and above. 
Missing Relationship to Study Drug 
An AE with a missing relationship to study drug will be deemed as reasonably possible. Imputed values 
will not be listed in data listings. 
Adverse Events with Incomplete Dates 
The following algorithm should be used to estimate adverse event start dates for which only partial 
information is known:  
• 
Missing day and month  
- If the year is same as the year of first day on drug, then the day and month of the start date of 
drug will be assigned to the missing fields.  
- If the year is prior to the year of first day on drug, then December 31 will be assigned to the 
missing fields.  
- If the year is after the year of first day on drug, then January 1 will be assigned to the missing 
fields.  
 
• 
Missing month only  
- Treat day as missing and replace both month and day according to the above procedure.  
 
• 
Missing day only  
- If the month and year are same as the year and month of first day on drug, then the start date of 
drug will be assigned to the missing day. 
- If the month and year are before the year and month of first day on drug, then the last day of the 
month will be assigned to the missing day.  
- If the month and year are after the year and month of first day on drug, then the first day of the 
month will be assigned to the missing day.  
 
If the AE stop date is complete and the imputed start date as above is after the stop date, the start date will 
be imputed using the stop date.  
 
Adverse events with partially missing stop dates will be imputed a stop date as follows:  
- year is missing - date left missing.  


 
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- month is missing - impute 'December'.  
- day is missing - impute 'last day of that month'. 
 
6.3.4 
Deaths 
All deaths will be captured on the Death/Autopsy Form. 
6.3.5 
Laboratory Data 
Laboratory assessments include: 
• 
Hematology: red blood cell (RBC) count, hemoglobin, hematocrit, platelets, white blood cell 
(WBC) count with differential, neutrophils (both segmented and band neutrophils), lymphocytes, 
monocytes, eosinophils, basophils. 
• 
Serum chemistry: aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline 
phosphatase (ALK), albumin, total bilirubin (direct bilirubin, indirect bilirubin), creatinine, sodium, 
potassium, calcium, chloride, blood urea nitrogen (BUN) or urea, phosphorus, bicarbonate, glucose, 
creatine kinase (CK)/creatine phosphokinase [CPK] (creatine kinase MB, creatine kinase MM) .  
• 
Coagulation: international normalized ratio (INR), activated partial thromboplastin time (aPTT) 
• 
Urinalysis: urinary protein (qualitative), urinary glucose (qualitative), and urine specific gravity 
density. 
All laboratory data will be stored in the database with the units in which they are originally reported.  
Laboratory data in summary tables and subject data listings will be presented in the International System of 
Units (SI units; Système International d’Unités).  Laboratory data not reported in SI units will be converted 
to SI units before further processing or data analysis. 
Baseline value is the subject’s last observation prior to the initiation of study drug (including Cycle 1 Day 
1). 
Laboratory tests will be graded using NCI-CTCAE v4.03 toxicity grading (see Appendix 1).  
Time to maximum/worst grade 3 or 4 value (in days) is defined as the time from the date of first study 
treatment to the earliest date of maximum or minimum (nadir) laboratory parameter value with Grade 3 or 
above: (date of maximum/worst grade 3 or above – date of first study treatment + 1). If toxicity grade is 
defined for abnormal high/increase in NCI-CTCAE grading criteria, maximum is used. Otherwise, 
minimum (nadir) is used.  
If there is no grade 3 or 4 laboratory value, the time to worst grade 3 or 4 value analysis will be censored at 
their last available laboratory assessment before the initiation of any new anti-cancer treatment, if 
applicable.  
Time to resolution (in days) is defined as the time from the date of the worst grade 3 or 4 value to the 
earliest date of the laboratory parameter value return to baseline grade or below with an improvement of at 


 
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least one grade for the same type of abnormality (high/low): (date of return to baseline grade or below – 
date of worst grade 3 or above +1). 
In case the laboratory value does not return to baseline grade or below, the time to resolution analysis will 
be censored at their last available laboratory assessment before the initiation of any new anti-cancer 
treatment, if applicable. 
6.3.6 
Vital Signs 
Vitals signs include systolic/diastolic blood pressure, heart rate, respiratory rate, temperature, and weight. 
Baseline value is the subject’s last observation prior to the initiation of study drug (including Cycle 1 Day 
1). 
6.3.7 
Electrocardiogram (ECG) 
The electrocardiogram assessment includes the QT Interval (msec), QTc Interval (msec), RR Interval 
(msec) and the general result (interpretation). 
6.3.8 
Physical Examination 
A physical examination will be performed at baseline and at each cycle, but no result from the physical 
examination will be entered in the database. The significant findings from the physical examination will be 
reported in the Medical History (prior to study drug administration) or the Adverse Event (after study drug 
administration) forms.  
6.3.9 
Pregnancy Test 
A pregnancy test will be performed at baseline and at the End of Treatment and 30-day Safety Follow-up 
visit for females with childbearing potential.  
6.3.10 
Concomitant Medications and Therapies 
Concomitant medications will be collected for all visits. 
Verbatim descriptions of concomitant medications and therapies will be mapped to the World Health 
Organization (WHO) Drug Dictionary Enhanced (WHO-DDE) and Herbal Dictionary (WHO-HD) (version 
Q1 2016). 
Concomitant medication/treatment is any medication/treatment with start date on or after the initial 
dosing of TAS-114 or S-1, whichever occurs first. Medication/treatment that started before the first dose 
and continued during the study treatment will also be counted as concomitant medication/treatment. 
Concomitant Medications Counting Rules: 
A patient with more than one different medications in a particular medication class will be counted only 
once in the total of patients taking that particular medication class.  
 


 
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A patient having the same medication more than once during the study will be counted only once in the 
number of patients with that medication.  
Medications with Incomplete Dates:  
For concomitant medications with missing or partially missing start dates, they will be imputed, if 
necessary, using the same algorithm described for adverse event onset dates (see Section 6.3.3). If the stop 
date is missing or partially missing, the imputation rule is applied in the following order:  
1) year is missing - the medication will be considered to have been received at all periods after that period 
determined by the start date. Date left missing.  
2) month is missing - impute 'December'.  
3) day is missing - impute 'last day of that month'.  
6.3.11 
Other Diagnostics and Procedures 
Other diagnostics and procedures are collected though the entire study.  
6.3.12 
New Anti-Cancer Treatments 
New anti-cancer treatments are collected after the patients discontinue the study treatment on the Post-
Treatment form.  
Medications with Incomplete Dates:  
When checking to see if anti-cancer treatments is initiated prior to a response assessment in cases where the 
start date of the anti-cancer therapy is only partially provided, use the last day of the month if the day is 
missing. If the month or year is missing do not impute a date and do not count the patient as having 
received anti-tumor therapy. 
7. STATISTICAL ANALYSIS 
7.1 
General Data Handling Rules and Definitions 
All data collected on case report forms will be provided in listings, except data collected only for 
confirmation of study entry criteria and for study administrative purposes. If any randomized patient is 
found to not have valid documented informed consent, that patient’s data will be excluded from the report, 
except as necessary to document the error.  
All analyses will be conducted using SAS version 9.4. 
Except where specified, all continuous variables will be summarized with descriptive statistics (number of 
non-missing values, mean, standard deviation, median, Q1 and Q3, minimum and maximum) and all 
categorical variables will be summarized with frequency counts and percentages, by treatment group. 
Missing data will be maintained as missing unless specified otherwise.  For variables where missing data is 
imputed, the analysis dataset (ie. ADaM) will contain one variable with the imputed value and the original 
variable with missing maintained as missing. 


 
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7.2 
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 treatment discontinuation. The number of patients in each study population and reason 
for study treatment discontinuation will also be summarized by geographical region. 
7.3 
Protocol Deviations 
A CSR reportable Protocol Deviation is related to inclusion/exclusion criteria, conduct of the trial, patient 
management or patient assessments that impact the safety of the subjects or jeopardize the quality of the 
study data. 
During the conduct of protocol TAS-114-201 the following categories will be used for CSR reportable 
Protocol Deviations: 
• 
A subject that did not meet entry criteria 
• 
A subject that developed withdrawal criteria but was not withdrawn 
• 
A subject that received the wrong treatment or incorrect dose 
• 
A subject that received an excluded medication 
• 
Critical ICF, GCP and other Protocol Deviations 
A CSR non-reportable Protocol Deviation may be important to address and document as part of site 
management and oversight, but is not considered reportable in the CSR. 
The following categories will be used to capture non-reportable PDs. 
• 
SAE reporting 
• 
Informed consent 
• 
Study procedures 
• 
Investigational product (other than incorrect dose or wrong treatment) 
Refer to Protocol Deviation Plan, Section 2 for details. 
The key protocol violations include, but are not limited to: 
• 
No measurable disease (assessed by investigator or central independent review) 
• 
Did not receive at least 2 prior therapies for advanced or metastatic disease condition, including 
platinum doublet and pemetrexed, docetaxel, or immunotherapy 
• 
No documentation of 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 
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The number of patients with deviations of one or more criteria and the number of patients with key protocol 
violations will be listed and tabulated for all patients (including screen failures) and ITT population.  
7.4 
Demographic and Baseline Characteristics 
Demographics variables, baseline characteristics, cancer history, medical history/active symptoms and prior 
cancer treatment will be summarized by treatment group for the ITT population. Cancer history, prior 
systemic drug therapies, and standard prior systemic therapies (platinum doublet and pemetrexed, 
docetaxel, immunotherapy) will also be summaried by geographical region. 
 
All the data fields will also be presented in patient data listings. 
7.5 
Efficacy Analyses 
The following sections outline the planned analyses of the primary and secondary objectives of the study 
TO-TAS-114-201.  
Comparison of time-to-event endpoints (PFS, OR and DR) will be based on the Cox proportional hazard 
model, stratified or unstratified, as specified, where the hazard ratio (HR), corresponding 90% and 95% 
confidence interval, and p-values will be estimated. Details of the hypothesis testing for the PFS analysis 
are described in Section 3.3. Survival curves and the estimated median time-to-event will be provided by 
the Kaplan-Meier method (Kaplan and Meier, 1958). 
Overall response rate (ORR) and disease control rate (DCR) will also be compared between treatment 
groups using Fisher’s exact test. 
 
Refer to Appendix 2 for the SAS code used for the efficacy analyses.  
7.5.1 
Primary Efficacy 
The progression-free survival analysis will be based on the ITT population. 
PFS in the efficacy population will be compared between the TAS-114/S-1 and S-1 control treatment 
groups using the stratified log-rank test with a one-sided significance level of 5%.
 
 
 
  
 
Median time to PFS for each group being compared will be estimated using the Kaplan-Meier method, 
along with the corresponding 95% CI. Confidence intervals for median progression-free survival will be 
based upon the methods of Brookmeyer and Crowley. The 25th and 75th percentiles will also be calculated.                          
Kaplan Meier estimates of progression-free at 2, 4, 6 and 8 months and their confidence intervals 
(calculated with the log-log transformation methodology of Kalbfleisch and Prentice) will be tabulated. The 
Kaplan-Meier plots will be displayed. 
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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. 
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7.5.2 
Secondary Efficacy 
7.5.2.1 
Overall Survival 
The overall survival (OS) analysis will be based on the ITT population. 
The estimate of the hazard ratio and corresponding 95% CI will be provided using a univariate CPH model 
(only treatment effect in the model). Median time to OS for each group being compared will be estimated 
using the Kaplan-Meier method, along with the corresponding 95% CI. Confidence intervals for the median 
will be based upon the methods of Brookmeyer and Crowley. The 25th and 75th percentiles will also be 
calculated.  Kaplan Meier estimates at 3, 6, 9 and 12 months and their confidence intervals (calculated with 
the log-log transformation methodology of Kalbfleisch and Prentice) will be tabulated. 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.  
The stratified log-rank test will also be performed for the comparison of treatment effect using the same 
stratification factors used for PFS. 
The same multivariable analysis as for PFS will be performed for OS. 
OS will also be presented by geographical region. 
7.5.2.2 
Overall Response Rate and Disease Control Rate 
The overall response rate and disease control rate analyses will be based on the Tumor Response (TR) 
evaluable population. 
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 exact 95% CIs for each 
treatment group.  
Best response will be summarized into four RECIST categories: complete response (CR), partial response 
(PR), stable disease (SD), and progressive disease (PD). The summary will also include a category for 
unevaluable patients if applicable. 
 
ORR and DCR will also be presented by geographical region. 
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7.5.2.3 
Duration of Response 
The duration of response analysis will be based on the TR evaluable population, only for patients that have 
a CR or PR response. Duration of response will be analyzed in the same manner as OS. 
 
7.5.2.4 
Tumor Response Assessments - Investigator versus Central Independent Review 
The tumor response assessments based on the investigator’s review will be compared to the tumor response 
assessments based on the central independent review (blinded radiological review): 
- 
Discordance in best response will be tabulated 
- 
Summary statistics for the number of days between investigator date of progression and 
central independent review date of progression will be displayed 
 
7.1 
Safety Analyses 
All safety data will be summarized by treatment groups in tables and presented in patient data listings. The 
analysis population for all safety analyses will be the as-treated population. Patients are assigned to 
treatment groups for safety analyses based on the study treatment they actually received.  
7.1.1 
Exposure of Study Treatment 
The TAS-114/S-1 or S-1 control administration profile will be summarized with mean, standard deviation, 
median, minimum, and maximum for the total dose received, number of treatment cycles received, and dose 
intensity. Dose reduction, dose modifications, dose interruptions, subsequent cycle delays, dose 
discontinuation of TAS-114/S-1 or S-1 control, and their corresponding reasons will also be tabulated by 
treatment group. 
7.1.2 
Duration of Follow-Up  
A summary table showing the duration of follow-up will be presented by treatment arm for the ITT 
population. The follow-up period is defined as the time starting on the date randomized until the last day of 
contact, or the day of withdrawal from study or the day of death, whichever occurs last. The duration of 
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follow-up will be analyzed using the reversed Kaplan-Meier method, where deaths will be censored on the 
date of death. 
7.1.3 
Adverse Events 
All AEs 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 anti-cancer therapy, whichever is earlier) will 
be summarized (incidence) by the system organ class, preferred term, toxicity/severity grade, and causal 
relationship to TAS-114/S-1 or S-1 control.  
The following adverse events summaries will be reported: 
• 
Overall summary of safety including AEs, fatal AEs, treatment-related AEs, serious AEs, 
treatment-related serious AEs, AEs of grade 3 and above, AE leading to study drug interruption, 
AEs leading to study drug dose reduction, AEs leading to study drug administration 
• 
Incidence rates of AEs 
• 
Incidence rates of AEs related to study drug 
• 
Incidence rates of serious AEs 
• 
Incidence rates of serious treatment-related AEs 
• 
Incidence rates of AEs by NCI-CTCAE v4.03 grade 
• 
Incidence rates of AEs leading to study drug interruption by NCI-CTCAE v4.03 grade 
• 
Incidence rates of AEs leading to study drug dose reduction by NCI-CTCAE v4.03 grade 
• 
Incidence rates of AEs leading to study drug discontinuation by NCI-CTCAE v4.03 grade 
• 
Incidence rates of non-serious AEs  
• 
Incidence rates of AEs of special interest (based on the grouped AE terms in Appendix 4) 
 
Adverse events will also be summarized by geographical region. 
 
7.1.4 
Deaths 
Summaries of number of deaths and cause of death will be produced by treatment group.  
7.1.5 
Laboratory Data 
Hematology, serum chemistry, and coagulation results will be summarized by toxicity grade (using NCI-
CTCAE v4.03 toxicity grading – see Appendix 1 at baseline and post-baseline measurements that worsened 
by at least one grade. Local laboratory ranges will be used for grading. In the event a range is not available 
a standard set of lab ranges as detailed in Appendix 3 will be utilized and flagged in the database. 
The worst change from baseline in toxicity grade for selected laboratory parameters will also be presented 
in shift tables: in each treatment arm, the patient’s baseline grade will be cross-tabulated by the patient’s 
maximum post-baseline grade during the treatment. 
Time to maximum/worst grade 3 or 4 value and time to resolution will be summarized for all quantitative 
laboratory parameters if toxicity grade is defined in NCI-CTCAE v4.03. The Hematology parameters will 
include Hemoglobin, Hematocrit, RBC, WBC, ANC, Thrombocytopenia, and Platelets, and the Chemistry 


 
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parameters will include AST, ALT, Total Bilirubin, and Alkaline Phosphatase. Count of the events and the 
censored, minimum and maximum of the event time will be presented by treatment group. Meanwhile, 
median time to worst grade 3 or 4 value and time to resolution for each group being compared will be 
estimated using the Kaplan-Meier method, along with the corresponding 95% CI. 
The qualitative urinalysis results will be summarized by visit and treatment groups. A shift table for 
qualitative urinalysis results from baseline to worst past-baseline will also be presented. 
7.1.6 
Vital Signs 
Vitals signs (systolic/diastolic blood pressure, heart rate, respiratory rate, temperature, and weight) and their 
changes from baseline will be summarized by visit.  
7.1.7 
Concomitant Medications and Therapies 
Concomitant medications will be summarized by treatment groups and sorted alphabetically by 
Anatomical-Therapeutic-Chemical classification (ATC) class and preferred drug name. 
7.1.8 
Other Diagnostics and Procedures 
Other diagnostics and procedures will be summarized by treatment groups.  
7.1.9 
New Anti-Cancer Treatments 
New anti-cancer treatments will be summarized by treatment groups. The number and percentage of 
patients receiving any chemotherapy, radiotherapy, surgery, immunotherapy, and other treatments will be 
summarized descriptively for the ITT population. The number of regimens received by each patient will 
also be summarized. 
7.1.10 
Other Safety Assessments 
Results from the electrocardiogram and the ECOG performance status will be summarized by visit. 
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8. CHANGES FROM METHODS PLANNED IN THE PROTOCOL  
Time to treatment failure is added as a post hoc analysis.  
Any changes to methods planned in this statistical analysis plan will be documented in a revision to this 
statistical plan prior to database lock, or identified in the clinical study report. 
9. STATISTICAL SOFTWARE 
SAS Version 9.4 in the UNIX environment will be used for all statistical analyses. 
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10. REFERENCES 
1. Brookmeyer and Crowley, A Confidence Interval for the Median Survival Time, Biometrics 38, 29-41, 
March 1982. 
 
2. Kaplan, E. L. Meier, P. (1958). Nonparametric estimation from incomplete observations. J. Amer. 
Statist. Assn. 53 (282): 457–481. JSTOR 2281868. 
 
3. Longley DB, Harkin DP, Johnston PG. 5-fluorouracil: mechanisms of action and clinical strategies. Nat 
Rev Cancer. 2003; 3(5):330-338.  
 
4. 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. 
 
5. Siegel RL, Miller KD, Jemal A. Global Cancer Statistics CA Cancer J Clin 2016; 66:7–30. 
 
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. Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics, FDA guidance, May 2007.