Clinical trial NCT02860546
Conditions: Refractory Metastatic Colorectal Cancer
Keywords: Refractory Metastatic Colorectal cancer TAS-102 Nivolumab Microsatellite Stable Programmed cell death protein1 (PD 1)
Sponsor: Taiho Oncology, Inc.
Start date: 2016-08-29; Completion date: 2017-09-07
Enrollment: 18 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
A Phase 2 Study with Safety Lead-in, Evaluating TAS-102 Plus Nivolumab in Participants with Microsatellite Stable Refractory Metastatic Colorectal Cancer

Detailed description:
This is a multicenter, single arm, safety lead-in, Phase 2 study, using Simon's 2 stage design evaluating the safety and efficacy of TAS-102 plus nivolumab in participants with Microsatellite-stable refractory metastatic colorectal cancer

Stage 1: Participants will be enrolled and after Cycle 1 treatment, they will be evaluated for the safety and tolerability of the combination therapy. Assuming a tolerated dose is confirmed additional participants evaluable for response will be enrolled and followed for a minimum of 6 months and there will be an interim analysis to assess the safety and efficacy to determine whether the second stage will open for enrollment.

Stage 2: Additional participant evaluable for response assessment will be enrolled and followed for a minimum of 6 months.

Arms: arm 1: Participants received a dose of 35 milligrams per meter square (mg/m\^2) of TAS-102 tablets orally twice per day (BID) within 1 hour after completion of morning and evening meals, in 4-week cycle. In each 4-week cycle, TAS-102 was administered for 2 weeks, as 5 days a week with 2 days rest, followed by a 14-day rest. Also participants received 3 milligrams per kilogram per dose (mg/kg/dose) Nivolumab intravenous (I.V) infusion over 60 minutes every 14 days (on Day 1 and Day 15 of each 4-week cycle).
Interventions: intervention 1: TAS-102 intervention 2: nivolumab
Intervention descriptions: intervention 1: One Arm Only (of TAS 102 plus nivolumab) intervention 2: One Arm Only (of TAS 102 plus nivolumab)

Protocol documents:
Prot_000.pdf: 
Clinical Study Report 
16.1 Study Information 
1.
PROTOCOL AND AMENDMENTS
The final global protocol for study TO-TAS-102-203 (Original version, dated 14 June 2016) is 
provided in this appendix.  This original protocol was not amended at any time during or after 
the study. 


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TAS-102 
Protocol No. TO-TAS-102-203 
Metastatic Colorectal Cancer 
TO-TAS-102-203 Version 1.0 14 June 2016 
Page 2 of 80 
1.
SYNOPSIS
Name of Sponsor/Company: 
Taiho Oncology, Inc. 
Name of Investigational Product: 
TAS-102 and nivolumab 
Name of Active Ingredients: 
TAS-102: trifluridine (FTD) and tipiracil hydrochloride (TPI); 
Nivolumab: nivolumab 
Title of Study: 
A Phase 2 Study with Safety Lead-in, Evaluating TAS-102 Plus Nivolumab in Patients with 
Microsatellite-Stable Refractory Metastatic Colorectal Cancer 
Protocol Number: 
TO-TAS-102-203 
Phase of Development: 
2 
Indication: 
Refractory metastatic colorectal cancer 
Background/Rationale: 
•
TAS-102 is an oral combination of 1M trifluridine (FTD) and 0.5M tipiracil
hydrochloride (TPI).
•
The primary mechanism of action of FTD, an antineoplastic thymidine-based
nucleoside analog, is incorporated into DNA via phosphorylation, resulting in a
different cytotoxic mechanism from 5-fluorouracil and 2’-deoxy-5-
fluorouridine (uracil-based thymidylate synthase inhibitors).
•
TAS-102 has been shown to significantly improve overall survival (OS) in
patients with metastatic colorectal cancer (mCRC) who have been previously
treated with, or are not candidates for fluoropyrimidine-, oxaliplatin-, and
irinotecan-based chemotherapy, an anti-vascular endothelial growth factor
(VEGF) biological therapy, and an anti-epidermal growth factor receptor
(EGFR) therapy.9
•
Treatment with pembrolizumab (an anti-programmed cell death-1 [PD-1]
antibody similar to nivolumab), shows activity in patients with mCRC.
However, in patients with microsatellite instability (MSI) tumors, anti-PD-1
activity was much higher than in patients with microsatellite-stable (MSS)
tumors. The median progression-free survival (PFS) and OS were not
reached in the MSI-high mCRC patient. In contrast, the median PFS and
OS were 2.2 months and 5.0 months, respectively, in the cohort with MSS
mCRC patients (hazards ratio for PFS was 0.10 [P < .001], and hazards ratio for
OS was 0.22 [P = .05]). Moreover, the overall response rate (ORR) for mCRC
patients with MSI-high and MSS was 40% and 0%, respectively.10
•
In a preclinical study, the tumor growth inhibitory activity of TAS-102 in
combination with an anti-mouse PD-1 antibody was significantly higher than
that of each monotherapy against mouse colorectal cancer cell (CMT-93/MSS
cell line). The results of this preclinical study showed that synergistic effects
occurred when using TAS-102 with anti-mouse PD-1 antibody in mouse
colorectal cancer cells.
•
The proposed mechanism for the observed additive or synergistic effect is an
increase in tumor immunogenicity after treatment with TAS-102, leading to a
better tumor response to anti-PD-1 antibody therapy. Increased tumor
immunogenicity may be triggered by TAS-102 DNA incorporation. This
Phase 2 study will examine this hypothesis.


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TAS-102 
Protocol No. TO-TAS-102-203 
Metastatic Colorectal Cancer 
TO-TAS-102-203 Version 1.0 14 June 2016 
 
Page 5 of 80 
9. Women of childbearing potential must have a negative pregnancy test (urine or 
serum) within 7 days before starting study drugs. Both males and females must 
agree to use effective birth control during the study (before the first dose and for 
6 months after the last dose of study drugs) 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 consecutive months without an alternative medical cause. For 
both males and females, see Section 7.7.3 for definitions of contraceptive 
methods considered effective for this protocol. 
10. Is able to take medications orally (ie, study drug must not be administered via a 
feeding tube). 
11. Willingness and ability to comply with scheduled visits, treatment plans, 
laboratory tests, and other study procedures. 
Exclusion Criteria 
1. Has a serious illness or medical condition including, but not limited to the 
following: 
a. 
Other concurrently active malignancies excluding malignancies that are 
disease-free for more than 3 years or carcinoma-in-situ deemed cured by 
adequate treatment. 
b. Known brain metastasis or leptomeningeal metastasis. 
c. 
Active infection (ie, body temperature ≥ 38°C because of infection) 
including active or unresolved pneumonia/pneumonitis. 
d. Intestinal obstruction, pulmonary fibrosis, renal failure, liver failure, or 
clinically significant cerebrovascular disorder and evidence of interstitial 
lung disease. 
e. 
Uncontrolled diabetes. 
f. 
Myocardial infarction within 12 months before enrollment severe/unstable 
angina, symptomatic congestive heart failure New York Heart Association 
class III or IV 
 
g. Gastrointestinal hemorrhage (grade ≥ 3) within 2 weeks before enrollment. 
h. Known human immunodeficiency virus or acquired immunodeficiency 
syndrome-related illness, or chronic or acute hepatitis B or hepatitis C. 
i. 
Psychiatric disease that may increase the risk associated with study 
participation or study drug administration, or may interfere with the 
interpretation of study results.  
j. 
History of any autoimmune disease: Patients with a history of 
inflammatory bowel disease, including ulcerative colitis and Crohn’s 
Disease, are excluded from this study, as are patients with a history of 
symptomatic disease (eg, rheumatoid arthritis, systemic progressive 
sclerosis [scleroderma], systemic lupus erythematosus, autoimmune 
vasculitis [eg, Wegener’s Granulomatosis]); central nervous system or 
motor neuropathy considered of autoimmune origin (eg, Guillain-Barre 
Syndrome and Myasthenia Gravis, multiple sclerosis). Patients with 
Graves’ disease will be allowed. 
k. Patients with a condition requiring systemic treatment with either 
corticosteroids (> 20 mg daily prednisone equivalent) or other 
immunosuppressive medications within 14 days of Cycle 1 Day 1. Inhaled 
or topical steroids, and adrenal replacement steroids doses ≤ 20 mg daily 
prednisone or equivalent, are permitted in the absence of active 
autoimmune disease.  
2. Treatment with any of the following within the specified time frame before 
enrollment: 
a. 
Major surgery within the past 4 weeks (the surgical incision should be fully 
healed before study drug administration). 
b. Any anticancer therapy within the past 3 weeks before enrollment. 
c. 
Extended field radiation within the past 4 weeks or limited field radiation 


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TAS-102 
Protocol No. TO-TAS-102-203 
Metastatic Colorectal Cancer 
TO-TAS-102-203 Version 1.0 14 June 2016 
 
Page 7 of 80 
Statistical Methods: 
Study Populations 
The study populations for all analyses are defined as follows: 
• 
Safety Population: Includes all patients who received at least 1 dose of study 
drug. It will be the primary population for safety analyses. 
• 
DLT Evaluable Population: Includes all patients in the safety population in 
Stage 1, prior to confirming the recommended dose, who completed at least 
1 cycle (28 days) of study treatment with at least 80% of the study treatment 
administered, unless the treatment was interrupted because of a DLT. 
• 
Efficacy Population: Includes all patients in the safety population who 
completed at least 6 months of tumor follow-up (evaluable irRC and/or 
RECIST assessments), unless the patient progressed or died before the 6-month 
follow-up. 
Efficacy Analyses 
Tumor response assessments and disease progression will be evaluated in this study 
using the irRC and RECIST criteria. The RECIST and irRC response assessments 
will be performed by the investigators for the study. Descriptive statistics, such as 
incidence of responses (ORR and DCR), Kaplan-Meier estimates for PFS and OS, 
and associated 95% confidence intervals will be provided.  
Safety Analyses 
Simple descriptive statistics will be provided for safety endpoints, 
demographic/baseline characteristics, and study drug exposure. Safety endpoints 
will primarily include incidence of AEs and changes from baseline (grade changes) 
in clinical laboratory tests. 
Sample Size 
Justification: 
Sample size considerations are based on a 2-stage minimax Simon design, testing a 
null hypothesis (poor response) of 10% or less immune-related overall response 
(irOR) versus an alternative hypothesis (promising response) of 30% or greater irOR 
at an approximate 5% 1-sided significance level and 80% power. In Stage 1 (futility 
assessment), enrollment will include 15 evaluable patients for irOR assessment and 
accrual will continue to Stage 2, if at least 2 of 15 (13%) patients respond (partial 
response or complete response). The probability of early stopping assuming poor 
response is about 55%. In Stage 2, if the Stage 1 futility boundary is exceeded, an 
additional 10 patients evaluable for irOR assessment will be enrolled, for a total of 
at least 25 evaluable patients. Further development will be considered promising if 
at least 6 of 25 (24%) patients respond. 
If the initial dose is not tolerated in the first 6 patients in Stage 1, an additional 
6 DLT-evaluable patients will be enrolled at the reduced dose. Assuming a 10 to 
15% nonevaluability for DLT and/or irRC assessment rate, a total of 30 to 
35 patients is expected to be enrolled in the study.  
Interim Analyses:  
The first 6 patients will be enrolled and will be evaluated for the safety and 
tolerability of the combination therapy after Cycle 1.  
In Stage 1, at the point that the ninth patient is enrolled (or a total of at least 
15 patients evaluable for response assessment at the target dose), enrollment will 
stop, and there will be an assessment of safety and efficacy to determine whether the 
second stage will open for enrollment. 
 


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CCI


TAS-102 
Protocol No. TO-TAS-102-203 
Metastatic Colorectal Cancer 
TO-TAS-102-203 Version 1.0 14 June 2016 
 
Page 13 of 80 
9.1.8. 
Performance Status .....................................................................................................47 
9.1.9. 
Clinical Laboratory Evaluations .................................................................................47 
9.1.9.1. 
Hematology .................................................................................................................48 
9.1.9.2. 
Serum Chemistry ........................................................................................................49 
9.1.9.3. 
Urinalysis ....................................................................................................................49 
9.1.10. 
Pregnancy Testing ......................................................................................................50 
9.1.11. 
Tumor Measurements .................................................................................................50 
9.1.12. 
Prior and Concomitant Medications ...........................................................................51 
9.1.13. 
Adverse Event Assessments .......................................................................................51 
9.2. 
Assessments by Visit ..................................................................................................51 
9.2.1. 
Baseline Procedures Before Enrollment .....................................................................51 
9.2.1.1. 
Day −28 through Day −1 ............................................................................................51 
9.2.1.2. 
Day −7 through Day −1 ..............................................................................................52 
9.2.2. 
On Treatment Period ...................................................................................................52 
9.2.2.1. 
Cycle 1 Day 1 .............................................................................................................52 
9.2.2.2. 
Cycle 1 Day 15 ...........................................................................................................52 
9.2.2.3. 
Subsequent Cycles - Cycle X Day 1 ...........................................................................53 
9.2.2.4. 
Subsequent Cycles – Cycle X Day 15 ........................................................................53 
9.2.2.5. 
Every 2 cycles from Start of Treatment ......................................................................53 
9.2.3. 
End of Treatment Visit ...............................................................................................54 
9.2.4. 
30-Day Safety Follow-up Visit ...................................................................................54 
9.2.5. 
Survival Follow-up after 30-Day Safety Visit ............................................................55 
10. 
EFFICACY ASSESSMENT CRITERIA ...................................................................56 
10.1. 
Method of Imaging .....................................................................................................56 
10.2. 
Immune-related Response Criteria .............................................................................56 
10.2.1. 
Immune-related Response Criteria Definitions ..........................................................56 
10.2.2. 
Immune-related Response Criteria .............................................................................57 
10.3. 
Response Evaluation Criteria in Solid Tumors ..........................................................58 
10.3.1. 
RECIST Tumor Definitions ........................................................................................58 
10.3.2. 
RECIST Response Criteria .........................................................................................60 
10.3.2.1. 
RECIST Target and Non-target Response Assessments ............................................60 
10.3.2.2. 
RECIST Overall Response Assessment .....................................................................62 
10.3.3. 
RECIST Best Overall Response Assessment .............................................................62 


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TAS-102 
Protocol No. TO-TAS-102-203 
Metastatic Colorectal Cancer 
TO-TAS-102-203 Version 1.0 14 June 2016 
Page 15 of 80 
13.3. 
Institutional Review Board/Independent Ethics Committee Approval ......................71 
14.
ADMINISTRATIVE CONSIDERATIONS ..............................................................72 
14.1. 
Protocol Amendments ................................................................................................72 
14.2. 
Curriculum Vitae ........................................................................................................72 
14.3. 
Administrative Structure .............................................................................................72 
14.4. 
Monitoring Procedures ...............................................................................................72 
14.4.1. 
Investigator’s Responsibilities ....................................................................................72 
14.4.2. 
Sponsor’s Responsibilities ..........................................................................................72 
14.4.3. 
Source Documents ......................................................................................................73 
14.4.4. 
Case Report Form .......................................................................................................73 
14.4.5. 
Sponsor’s Audits and Regulatory Inspections ............................................................73 
14.5. 
Archiving of Records ..................................................................................................74 
14.6. 
Final Report ................................................................................................................74 
14.7. 
Use and Publication of Study Results .........................................................................74 
14.8. 
Financial Disclosure ...................................................................................................74 
14.9. 
Termination of the Study ............................................................................................75 
15.
CONFIDENTIALITY AND DATA PROTECTION .................................................75 
16.
SIGNATURES OF SPONSOR AND INVESTIGATOR ..........................................76 
17.
LIST OF REFERENCES ............................................................................................77 
 
 
 


TAS-102 
Protocol No. TO-TAS-102-203 
Metastatic Colorectal Cancer 
TO-TAS-102-203 Version 1.0 14 June 2016 
 
Page 16 of 80 
LIST OF TABLES 
Table 1: 
Study Schedule .............................................................................................................8 
Table 2: 
Number of Tablets Per Dose .......................................................................................39 
Table 3: 
TAS-102 Dose Reduction Levels and Number of Tablets per Dose ..........................40 
Table 4: 
TAS-102 Dose Modification Criteria for Non-hematologic Toxicities .....................41 
Table 5: 
TAS-102 Dose Hold Criteria for Hematologic Toxicities Related to 
Myelosuppression .......................................................................................................42 
Table 6: 
TAS-102 Resumption Criteria for Hematologic Toxicities related to 
Myelosuppression .......................................................................................................42 
Table 7: 
Recommended Dose Modifications for Nivolumab ...................................................44 
Table 8: 
Hematology Laboratory Parameters ...........................................................................49 
Table 9: 
Serum Chemistry Laboratory Parameters ...................................................................49 
Table 10: Derivation of irRC Overall Responses13 .....................................................................58 
Table 11: Time Point Response for Patients with Target (± Non-target) Disease ......................62 
 


TAS-102 
Protocol No. TO-TAS-102-203 
Metastatic Colorectal Cancer 
TO-TAS-102-203 Version 1.0 14 June 2016 
 
Page 17 of 80 
LIST OF FIGURES 
Figure 1: 
Mechanism of Antitumor Activity of TAS-102 .........................................................22 
 


TAS-102 
Protocol No. TO-TAS-102-203 
Metastatic Colorectal Cancer 
TO-TAS-102-203 Version 1.0 14 June 2016 
Page 18 of 80 
4.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation 
Definition 
5-FU 
5-fluorouracil 
AE 
Adverse event 
ALT 
Alanine aminotransferase (SGPT) 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate aminotransferase (SGOT) 
BID 
Twice daily 
BSA 
Body surface area 
BSC 
Best supportive care 
CI 
Confidence interval 
CR 
Complete response 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCR 
Disease control rate 
DLT 
Dose-limiting toxicity 
DNA 
Deoxyribonucleic acid 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EGFR 
Epidermal growth factor receptor 
FDG-PET 
fluorodeoxyglucose positron emission tomography 
FTD 
Trifluridine 
G-CSF 
Granulocyte colony-stimulating factor 
GCP 
Good Clinical Practice 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human 
Use 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
irCR 
Immune-related complete response 
irOR 
Immune-related overall response 


TAS-102 
Protocol No. TO-TAS-102-203 
Metastatic Colorectal Cancer 
TO-TAS-102-203 Version 1.0 14 June 2016 
 
Page 19 of 80 
Abbreviation 
Definition 
irORR 
Immune-related overall response rate 
irPD 
Immune-related progressive disease 
irPR 
Immune-related partial response 
irRC 
Immune-related response criteria 
irSD 
Immune-related stable disease 
IU 
International units 
KRAS 
GTPase KRas; V-Ki-ras2 Kirsten rat sarcoma viral oncogene 
homolog 
mAb 
Monoclonal antibody 
mCRC 
Metastatic colorectal cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
MSI 
Microsatellite instability 
MSS 
Microsatellite stable 
NCI 
National Cancer Institute 
NYHA 
New York Heart Association 
ORR 
Overall response rate 
OS 
Overall survival 
PD 
Progressive disease 
PD-1 
Programmed cell death-1 
PD-L1 
Programmed cell death ligand-1 
PFS 
Progression free survival 
PR 
Partial response 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RECOURSE 
Refractory Colorectal Cancer Study 
(TPU-TAS-102-301 Phase 3 study; NCT01607957) 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAR 
Serious Adverse Reaction 
SD 
Stable disease 
SPD 
Sum of the products of the 2 largest perpendicular diameters 
TOI 
Taiho Oncology, Inc. 
TP 
Thymidine phosphorylase  


TAS-102 
Protocol No. TO-TAS-102-203 
Metastatic Colorectal Cancer 
TO-TAS-102-203 Version 1.0 14 June 2016 
 
Page 20 of 80 
Abbreviation 
Definition 
TPI 
Tipiracil hydrochloride  
ULN 
Upper limit of normal 
VEGF 
Vascular endothelial growth factor 


TAS-102 
Protocol No. TO-TAS-102-203 
Metastatic Colorectal Cancer 
TO-TAS-102-203 Version 1.0 14 June 2016 
 
Page 21 of 80 
5. 
INTRODUCTION 
5.1. 
TAS-102 
Detailed information on the nonclinical and clinical experience with TAS-102 is provided in the 
Investigator’s Brochure (IB). 
5.1.1. 
Mechanism of Action 
TAS-102 is an oral combination drug of an antineoplastic thymidine-based nucleoside analogue, 
trifluridine (FTD) and a thymidine phosphorylase (TP) inhibitor, tipiracil hydrochloride (TPI). 
After uptake into cancer cells, FTD is phosphorylated by thymidine kinase, further metabolized 
in cells to a deoxyribonucleic acid (DNA) substrate, and incorporated directly into DNA, thereby 
interfering with DNA function to prevent cell proliferation. When orally administered, FTD is 
rapidly degraded to an inactive form by TP. Co-administration of TPI, an inhibitor of TP, with 
FTD prevents the rapid degradation of FTD, resulting in a significant increase in systemic 
exposure to FTD. 
Trifluridine incorporation into DNA is markedly higher than that of other nucleoside analogues. 
The degree of incorporation of FTD into DNA ranges from approximately 10-fold up to 700-fold 
greater in comparison with that of 2’-deoxy-5-fluorouridine. Trifluridine also exhibits 
thymidylate synthase inhibition.1-6 Results of in vivo studies showed FTD incorporation into 
DNA to be the primary mechanism of antitumor activity with oral administration. Trifluridine 
alone, when orally administered, is rapidly degraded to an inactive form, 5-trifluoromethyluracil 
by TP. Co-administration of TPI with FTD increases the concentration of FTD in the body 
leading to augmentation of cytotoxicity by FTD.7 In preclinical studies, FTD incorporation into 
DNA in tumor was shown to increase with divided daily administration compared with once 
daily administration. Figure 1 shows the mechanism of antitumor activity of TAS-102. 


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TAS-102 
Protocol No. TO-TAS-102-203 
Metastatic Colorectal Cancer 
TO-TAS-102-203 Version 1.0 14 June 2016 
 
Page 26 of 80 
(irORR) because it is a modification of the ORR and is widely utilized in clinical trials 
evaluating treatments with immune-oncology products. 
Regarding safety profiles of each drug as reflected in their respective US product inserts, 
TAS-102 treatment mainly caused myelosuppressive toxicities in the RECOURSE Phase 3 
study, as well as other AEs at a frequency of ≥ 10% for anemia, neutropenia, asthenia/fatigue, 
nausea, thrombocytopenia, decreased appetite, diarrhea, vomiting, abdominal pain, and pyrexia. 
Nivolumab treatment mainly caused rash in patients with melanoma with a frequency of ≥ 20% 
as well as other immune-mediated adverse reactions. Since there is no overlap between the 
2 safety profiles, a dose-escalation design is not essential for this study but a safety lead-in 
period is necessary to determine the tolerability of TAS-102 in combination with nivolumab. 
5.2.3. 
Selection of TAS-102 Dose 
TAS-102 (35 mg/m2/dose) will be administered orally BID, within 1 hour after completion of 
morning and evening meals, for 5 days a week with 2 days rest for 2 weeks, followed by a 
14-day rest. This treatment cycle will be repeated every 4 weeks. 
The safety and tolerability of this TAS-102 regimen was demonstrated in a Phase 3, 
multinational, randomized, double-blind study (RECOURSE; TPU-TAS-102-301), in which 
TAS-102 was shown to significantly improve OS compared with placebo in patients with 
mCRC, who had been previously treated with, or were not candidates for fluoropyrimidine-, 
oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and an 
anti-EGFR therapy.8  
In the RECOURSE study, the most common AEs associated with TAS-102 treatment were 
myelosuppressive toxicities. Up to 20% of patients receiving TAS-102 experienced grade 3 or 
grade 4 hematologic events related to anemia and neutropenia/leukopenia; however, the 
incidence of febrile neutropenia was low (3.8%). These events were generally manageable with 
reductions in dose, delays in cycle initiation and occasional use of granulocyte colony-
stimulating factor (G-CSF). Only 3 patients discontinued treatment because of hematologic AEs, 
and there was only 1 treatment-related death because of neutropenia-related infection. Events of 
nausea, decreased appetite, diarrhea, and vomiting related to treatment were common in the 
TAS-102 group (20.1% to 39.4%); however, these AEs were rarely grade 3 or grade 4. The 
incidence of stomatitis among patients receiving TAS-102 was 7.9%; grade 3 or grade 4 events 
of stomatitis were rare (0.4%). In addition, hand-foot syndrome was reported in only 2.3% of 
patients receiving TAS-102 (all grade 1 or grade 2), which was the same percentage reported in 
the placebo arm.  
Trifluridine, the active principal of TAS-102, is primarily metabolized by TP in the 
gastrointestinal tract and liver. Nivolumab is a therapeutic monoclonal antibody (mAb), expected 
to be catabolized into amino acids by general degradation process. As nivolumab is not a 
cytokine modulator, it is unlikely to have an effect on drug metabolizing enzymes or transporters 
in terms of inhibition or induction. There are no potential mechanisms of pharmacokinetic drug 
interactions for the combination of TAS-102 and nivolumab. Furthermore, the mechanism of 
action and the safety profiles of TAS-102 and nivolumab are also quite different. Therefore, the 
recommended dosage of each agent, 35 mg/m2 for TAS-102 and 3 mg/kg for nivolumab is 
selected as the starting dose. 


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CCI


TAS-102 
Protocol No. TO-TAS-102-203 
Metastatic Colorectal Cancer 
TO-TAS-102-203 Version 1.0 14 June 2016 
 
Page 28 of 80 
(DLT), then the dose of TAS-102 will be reduced (after discussion between the investigator and 
Sponsor) and an additional 6 patients will be enrolled. If the DLT is considered related to 
TAS-102, the investigator should follow the recommended dose modifications in Section 8.2.4. 
If the DLT is considered related to nivolumab, the investigator should follow the 
discontinuation/withhold criteria listed in Section 8.2.6. If the DLT relationship is unclear to 
either TAS-102 or nivolumab, but is not disease related, then both TAS-102 and nivolumab 
should be interrupted and the TAS-102 dose should be reduced at the next dose cycle.  
Accrual will not be halted while the review is being conducted if no DLTs are identified. Any 
outcome of this safety review will be communicated in a timely manner to the participating 
investigators so that they may notify their Institutional Review Boards (IRBs).  
Assuming a tolerated dose is confirmed (up to 1 DLT in 6 patients), at least 9 additional patients 
evaluable for response will be enrolled and followed for a minimum of 6 months. At the point 
that the ninth patient is enrolled (or a total of at least 15 patients evaluable for response 
assessment at the target dose), enrollment will stop, and there will be an interim analysis to 
assess the safety and efficacy to determine whether the second stage will open for enrollment. To 
proceed to Stage 2, two or more patients out of the 15 patients in Stage 1 will need to 
demonstrate a PR or complete response (CR) within a 6-month tumor follow-up period. If there 
are fewer than 2 responders in Stage 1, then the study will be stopped.  
Stage 2: An additional 10 patients evaluable for response assessment will be enrolled and 
followed for a minimum of 6 months.  
The following TAS-102 related AEs will be considered DLTs (only AEs occurring in Cycle 1 
will be DLT evaluable): 
Hematological toxicities 
1. Grade 4 neutropenia lasting > 7 days 
2. Grade 4 febrile neutropenia and fever ≥ 38°C for over 1 hour 
3. Grade 4 thrombocytopenia or grade 3 thrombocytopenia associated with bleeding or 
requiring transfusions 
Non-hematological toxicities  
1. Grade 3 or grade 4 non-hematologic toxicity (excluding alopecia, nausea, vomiting, 
diarrhea) 
2. Grade 3 or grade 4 nausea/vomiting lasting > 48 hours and uncontrolled by aggressive 
anti-emetic therapy, including serotonin 5-HT3 receptor antagonists (eg, ondansetron) 
3. Grade 3 or grade 4 diarrhea lasting > 48 hours and unresponsive to antidiarrheal 
medication 
Drug-related toxicities 
1. Any drug-related toxicity resulting in > 2 weeks delay in initiation of Cycle 2 (ie, cannot 
start Cycle 2 until Day 43 or later) 
2. Any drug-related toxicity that prevents completion of 80% compliance for either drug in 
Cycle 1 


TAS-102 
Protocol No. TO-TAS-102-203 
Metastatic Colorectal Cancer 
TO-TAS-102-203 Version 1.0 14 June 2016 
 
Page 29 of 80 
The combination of TAS-102 and nivolumab is expected to trigger immune-mediated responses, 
which require activation of the immune system before the observation of clinical responses. Such 
immune activation may take weeks to months to become evident. Some patients may have an 
objective volume increase of tumor lesions or other disease parameters within weeks after the 
start of dosing. Such patients may not have had sufficient time to develop immune system 
activation or, in some patients, tumor volume or other disease parameter increases may represent 
infiltration of lymphocytes into the original tumor. Therefore, tumors will be evaluated with both 
RECIST and irRC to determine objective responses.  
TAS-102 (35 mg/m2/dose) will be administered orally BID, within 1 hour after completion of 
morning and evening meals, for 5 days a week with 2 days rest for 2 weeks, followed by a 
14-day rest, repeated every 4 weeks. Nivolumab (3 mg/kg/dose) will be administered 
intravenously over 60 minutes every 14 days on Day 1 and Day 15. 
A contrast-enhanced computed tomography (CT) scan of the chest and abdomen (pelvis if 
clinically indicated) within 28 days before Day 1 of Cycle 1 and every 2 cycles thereafter will be 
performed during study treatment. On-site tumor assessments will be performed by the 
investigator or local radiologist. Tumor assessments will be analyzed using RECIST and irRC. 
For patients who discontinue treatment for reasons other than radiologic disease progression, 
every effort should be made to perform an end-of-treatment tumor assessment before the start of 
new anticancer therapy. Patients that discontinue treatment for reasons other than disease 
progression should continue to be followed for tumor response every 2 cycles until the patient 
develops radiologic disease progression (or death) or initiation of new anticancer therapy 
(whichever occurs first). Tumor assessments should be performed according RECIST and irRC. 
If the CT scan was obtained before the patient signed the informed consent form (ICF), the CT 
scan may be used if the date of the scan is within 28 days before Day 1 of Cycle 1. 
Survival status (alive or dead) should be obtained at scheduled 8-week time intervals until study 
discontinuation criteria are met.  
Standard safety monitoring will be performed and AEs will be graded using the National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. 
7.2. 
Study Duration 
Patients will be treated until the patient meets the discontinuation criteria (see Section 7.5).  
For the purpose of final analyses, the study will be considered completed when all patients have 
discontinued from treatment or 12 months after the first day of treatment with TAS-102 plus 
nivolumab of the last patient enrolled, whichever occurs first. Upon data cutoff, patients ongoing 
with study treatment may continue with their treatment and be followed for safety. 
Measurements of efficacy and data collection may be reduced.  
7.3. 
Study Population 
Approximately 30 to 35 male and female patients with mCRC will be enrolled in a Simon’s 
2-stage design. 


TAS-102 
Protocol No. TO-TAS-102-203 
Metastatic Colorectal Cancer 
TO-TAS-102-203 Version 1.0 14 June 2016 
 
Page 30 of 80 
7.3.1. 
Inclusion Criteria 
A patient must meet all of the following inclusion criteria to be eligible for enrollment in this 
study: 
1. Has provided written informed consent. 
2. Patient with confirmed histologically proven metastatic or locally advanced colorectal 
adenocarcinoma who is MSS (ie, not MSI) based on either an analysis of tissue from a 
prior biopsy or based on tissue from a new biopsy. 
3. Patient with the presence of at least 1 lesion with measurable disease as defined by 
10 mm in the longest diameter for a soft tissue lesion or 15 mm in the short axis for a 
lymph node by RECIST and irRC criteria for a response assessment. 
4. Patient has received at least 2 prior lines of standard chemotherapies for mCRC and is 
refractory to or failing those chemotherapies. 
a. Standard chemotherapy must include ALL of the following agents: 
i. Fluoropyrimidines, irinotecan, and oxaliplatin 
ii. An anti-VEGF biological therapy (eg, bevacizumab or aflibercept or ramucirumab) 
iii. At least 1 of the anti-EGFR mAbs (cetuximab or panitumumab) for RAS wild-type 
patients. 
5. Age ≥ 18 years. 
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 at the time of 
enrollment. 
7. Life expectancy of ≥ 4 months. 
8. Has adequate organ function as defined by the following criteria: 
a. Absolute neutrophil count of ≥ 1500/mm3 (ie, ≥ 1.5 × 109/L by International Units 
[IU]). 
b. Platelet count of ≥ 100,000/mm3 (IU: ≥ 100 × 109/L) 
c. Hemoglobin value of ≥ 9.0 g/dL (If patient required previous blood transfusions, a 
hemoglobin value must be obtained > 2 weeks after the last blood transfusion.) 
d. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) value of ≤ 3.0 
× upper limit of normal (ULN).  
e. Total serum bilirubin value of ≤ 1.5 × ULN 
f. Serum creatinine value of ≤ 1.5 mg/dL. 
9. Women of childbearing potential must have a negative pregnancy test (urine or serum) 
within 7 days before starting study drugs. Both males and females must agree to use 
effective birth control during the study (before the first dose and for 6 months after the 
last dose of study drugs) 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 consecutive months without an 
alternative medical cause. For both males and females, see Section 7.7.3 for definitions of 
contraceptive methods considered effective for this protocol. 


TAS-102 
Protocol No. TO-TAS-102-203 
Metastatic Colorectal Cancer 
TO-TAS-102-203 Version 1.0 14 June 2016 
 
Page 31 of 80 
10. Is able to take medications orally (ie, study drug must not be administered via a feeding 
tube). 
11. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, 
and other study procedures. 
7.3.2. 
Exclusion Criteria 
1. Has a serious illness or medical condition including, but not limited to the following: 
a. Other concurrently active malignancies excluding malignancies that are disease-free 
for more than 3 years or carcinoma-in-situ deemed cured by adequate treatment.  
b. Known brain metastasis or leptomeningeal metastasis. 
c. Active infection (ie, body temperature ≥ 38°C because of infection) including active 
or unresolved pneumonia/pneumonitis. 
d. Intestinal obstruction, pulmonary fibrosis, renal failure, liver failure, or clinically 
significant cerebrovascular disorder and evidence of interstitial lung disease. 
e. Uncontrolled diabetes. 
f. Myocardial infarction within 12 months before enrollment, severe/unstable angina, 
symptomatic congestive heart failure New York Heart Association class III or IV 
. 
g. Gastrointestinal hemorrhage (grade ≥ 3) within 2 weeks before enrollment. 
h. Known human immunodeficiency virus or acquired immunodeficiency 
syndrome-related illness, or chronic or acute hepatitis B or hepatitis C. 
i. Psychiatric disease that may increase the risk associated with study participation or 
study drug administration, or may interfere with the interpretation of study results. 
j. History of any autoimmune disease: Patients with a history of inflammatory bowel 
disease, including ulcerative colitis and Crohn’s Disease, are excluded from this 
study, as are patients with a history of symptomatic disease (eg, rheumatoid arthritis, 
systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, 
autoimmune vasculitis [eg, Wegener’s Granulomatosis]); central nervous system or 
motor neuropathy considered of autoimmune origin (eg, Guillain-Barre Syndrome 
and Myasthenia Gravis, multiple sclerosis). Patients with Graves’ disease will be 
allowed. 
k. Patient with a condition requiring systemic treatment with either corticosteroids 
(> 20 mg daily prednisone equivalent) or other immunosuppressive medications 
within 14 days of Cycle 1 Day 1. Inhaled or topical steroids, and adrenal replacement 
steroids doses ≤ 20 mg daily prednisone or equivalent, are permitted in the absence of 
active autoimmune disease. 
2. Treatment with any of the following within the specified time frame before enrollment: 
a. Major surgery within the past 4 weeks (the surgical incision should be fully healed 
before study drug administration). 
b. Any anticancer therapy within the past 3 weeks before enrollment. 
c. Extended field radiation within the past 4 weeks or limited field radiation within the 
past 2 weeks before enrollment. 
d. Any investigational drug/device received within the past 4 weeks or 5 times the 
half-life (whichever is shorter) before enrollment. 


TAS-102 
Protocol No. TO-TAS-102-203 
Metastatic Colorectal Cancer 
TO-TAS-102-203 Version 1.0 14 June 2016 
 
Page 32 of 80 
3. Previous treatment with TAS-102. 
4. Prior treatment with anti-PD-1, anti-PD-L1, anti- programmed cell death ligand-2, 
anti-CD137, anti-OX-40, anti-CD40, anti-cytotoxic T lymphocyte-associated antigen-4 
antibodies, or any other immune checkpoint inhibitors. 
5. Unresolved toxicity of NCI CTCAE ≥ grade 2 attributed to any prior therapies (excluding 
anemia, alopecia, skin pigmentation, and platinum-induced neurotoxicity). 
6. Prior events of immune-mediated pneumonitis, immune-mediated colitis, immune-
mediated hepatitis, immune-mediated endocrinopathies, immune-mediated nephritis and 
renal dysfunction, immune-mediated rash, immune-mediated encephalitis, and history of 
infusion reactions to nivolumab. 
7. Known or assumed hypersensitivity to TAS-102 or nivolumab or any of its ingredients, 
including polysorbate 80-containing infusion. 
8. Previous severe hypersensitivity reaction to treatment with another mAb. 
9. Pregnant or lactating female. 
10. Inappropriate for entry into this study in the judgment of the investigator. 
7.4. 
Treatment Assignment 
7.4.1. 
Patient Numbering 
Study sites will enter patient demographic and baseline data into the electronic case report form 
(eCRF) in order to receive a patient number. 
The eCRF will assign each patient a unique patient number. All patient numbers will be 6 digits; 
the first 3 digits will be the site number and the last 3 digits will be the patient’s number. This 
patient number will be maintained throughout the study and will not be reassigned. Patients who 
withdraw consent or discontinue from the study after being assigned a patient number will retain 
their initial number.  
Study drug administration should begin within 3 calendar days after enrollment as described 
in Section 8. 
For patients who sign an ICF but are not enrolled and patients who are enrolled but never dosed, 
see the eCRF Completion Guidelines for instruction on which eCRF pages to complete. 
7.4.2. 
Randomization 
This is not a randomized study design. 
7.4.3. 
Blinding 
This is an open-label design study.  
7.4.4. 
Replacement of Patients 
Patients will not be replaced. An adequate number of patients will be enrolled until the 
pre-specified number of evaluable patients at each stage is met.  


TAS-102 
Protocol No. TO-TAS-102-203 
Metastatic Colorectal Cancer 
TO-TAS-102-203 Version 1.0 14 June 2016 
 
Page 33 of 80 
7.5. 
Discontinuation of Study Treatment 
Patients will receive study drug until a discontinuation criterion is met. 
A patient is considered discontinued from study treatment when the decision to permanently stop 
both study treatments is made, including those decisions made during study drug interruptions 
and recovery periods. 
Study drugs should be continued whenever possible. In case study drug is stopped, it should be 
determined if the stop can be made temporarily; permanent study drug discontinuation should be 
a last resort. Any study drug discontinuation should be fully documented. 
7.5.1. 
Treatment Discontinuation Criteria 
The reason for discontinuation of treatment should be documented in the patient source 
documents. 
Patients can be discontinued from treatment for the following reasons: 
• 
Patient request at any time irrespective of the reason 
• 
Patients with tumor progression by irRC 
• 
Clinical progression 
• 
Patient experiences an irreversible, treatment-related, grade 4, clinically relevant, 
non-hematologic event 
• 
Unacceptable AEs, or change in underlying condition such that the patient can no 
longer tolerate therapy, including: 
a. A maximum dose delay > 28 days from the scheduled start date of the next cycle 
b. Need for more than 3 dose reductions of TAS-102 (or minimum 20 mg/m2/dose 
BID) 
c. Discontinuation of both TAS-102 and nivolumab; patient may be considered for 
continuation of nivolumab or TAS-102 single therapy at the investigator’s 
discretion 
• 
Physician’s decision including need for other anticancer therapy not specified in the 
protocol or surgery or radiotherapy to the only site(s) of disease being evaluated in 
this protocol 
• 
Pregnancy 
7.5.2. 
End of Treatment Procedures 
Upon discontinuation of treatment the investigator must: 
• 
Notify the clinical research associate immediately 
• 
Complete the Study Treatment Discontinuation Form in the eCRF, specifying the 
reason for the patient’s withdrawal from treatment 
• 
If a patient is discontinued because of clinical progression, associated nonserious AEs 
should be reported on the treatment discontinuation page of the eCRF 


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TAS-102 
Protocol No. TO-TAS-102-203 
Metastatic Colorectal Cancer 
TO-TAS-102-203 Version 1.0 14 June 2016 
Page 35 of 80 
Hematologic Support 
Administer hematologic support as medically indicated (eg, blood transfusions, G-CSF, 
erythropoietin) according to the institutional site standards. If there are no standard procedures 
for the use of growth factors, follow American Society of Clinical Oncology (ASCO) 2015 
Guidelines for Use of Hematopoietic Colony-Stimulating Factors, available 
at http://www.instituteforquality.org/practice-guidelines. 
Management of Diarrhea 
Educate both patients and patients’ families regarding the potential seriousness of 
chemotherapy-induced diarrhea. Instruct patients to immediately contact the clinical site staff at 
the first sign of loose stools. 
Provide patients with loperamide or other standard antidiarrheal therapy and instruct the patient 
on how to use it at the first sign of diarrhea. 
Monitor the patient’s fluid and electrolyte balance, with appropriate intervention as clinically 
indicated with fluids and electrolyte replacement, antibiotics, and antiemetics. 
Infection prophylaxis with oral antibiotics must be considered for patients with persistent 
diarrhea beyond 24 hours, or coincident with grade ≥ 3 neutropenia. 
Administer prophylactic treatment for diarrhea as clinically indicated. 
If there are no institutional standards, refer to the guidelines published by Benson AB et al in 
Journal of Clinical Oncology.11  
Management of Nausea and Vomiting 
Administer antiemetics as clinically indicated. If there are no institutional standards refer to the 
ASCO Guidelines for Antiemetics in Oncology.12  
7.7.3. 
Effective Contraception During the Study 
Both males and females must agree to use effective birth control during the study (before the first 
dose and for 6 months after the last dose) if conception is possible during this interval. Female 
patients who are considered not to be of childbearing potential must have a history of being 
postmenopausal (no menses for 12 consecutive months without an alternative medical cause), or 
hysterectomy that is clearly documented in the patient’s source documents. 
For women of childbearing potential, including female study participants and partners of male 
participants, effective contraception is defined as follows: 
•
Combined (estrogen and progestogen containing) hormonal contraception associated
with inhibition of ovulation:
− Oral
− Intravaginal
− Transdermal
•
Progestogen -only hormonal contraception associated with inhibition of ovulation:
− Oral


TAS-102 
Protocol No. TO-TAS-102-203 
Metastatic Colorectal Cancer 
TO-TAS-102-203 Version 1.0 14 June 2016 
 
Page 36 of 80 
− 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 women of childbearing potential should use a combination 
of male condom with a cap, diaphragm, or sponge with spermicide during the trial and for 
6 months after the last dose of study drug. 
7.8. 
Dietary Restrictions 
TAS-102 should be taken with a glass of water within 1 hour after completion of the morning 
and evening meals. There are no dietary restrictions for nivolumab. 
8. 
STUDY TREATMENT 
At the beginning of each patient treatment cycle, study sites will weigh the patient and calculate 
the patient’s body surface area (BSA), and determine the recommended study drug dosage. No 
increase in dose because of an increase in BSA is permitted. 
The BSA will be calculated using the following DuBois formula (all BSA calculations are 
rounded to 2 decimal places) or institutional standards at the respective study site. 
BSA (m²) = ([Body Weight (kg)]0.425 × [Height (cm)]0.725) × 0.007184 
Please note the following: 
• 
Dose escalations (for TAS-102, on a mg/m2 basis) of study drugs are not permitted at 
any time 
• 
Only 3 dose reductions of TAS-102 are permitted. There will be no dose reductions 
for nivolumab. 
• 
Only a ≤ 28-day delay in the start of the next treatment cycle for TAS-102 is 
permitted (see Section 8.2.4.4). 
Study treatment should be started within 3 calendar days after enrollment and should be 
administered as outlined in the following sections of the protocol. The investigator always has 
the right to deviate from the established rules for dose modification at her/his discretion if he or 
she believes a more conservative approach is needed in the management of related or unrelated 
AEs. However, doses must be modified at least to the extent specified in Section 8.2.4. All 
deviations from protocol-specified dose modifications must be documented. 
Patients will receive study drugs until one of the discontinuation criteria listed in Section 7.5.1 is 
met. 


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TAS-102 
Protocol No. TO-TAS-102-203 
Metastatic Colorectal Cancer 
TO-TAS-102-203 Version 1.0 14 June 2016 
 
Page 38 of 80 
will be used for the TO-TAS-102-203 study. The drug description and storage information can 
be found in the Patient Package Insert of the commercial label.  
Nivolumab, which will be supplied in an approved commercial package (single vials in 
individual cartons), will be labeled with information including the following: 
• Protocol Number 
• Sponsor name 
• Investigational caution statement 
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. 
All study drug must be kept in a locked area with access restricted to specific study personnel. 
8.2. 
Study Drug Administration 
8.2.1. 
TAS-102 Treatment Regimen 
Each treatment cycle will be 28 days in duration. TAS-102 dosage is calculated according to 
BSA. 
One TAS-102 treatment cycle consists of the following: 
• 
Days 1 through 5: TAS-102 (35 mg/m2/dose) orally BID 
• 
Days 6 through 7: rest 
• 
Days 8 through 12: TAS-102 (35 mg/m2/dose) orally BID 
• 
Days 13 through 28: rest 
Study drug should be taken only on Days 1-5 and 8-12 of each cycle. If doses are missed or held 
on those days, the patient should not make up for missed doses. 
Patients should begin taking TAS-102 (Day 1) with the morning dose. Both the morning and 
evening doses should be taken at approximately the same time every day. TAS-102 should be 
taken with a glass of water within 1 hour after completion of the morning and evening meals. 
8.2.2. 
Number of Tablets per TAS-102 Dose 
TAS-102 tablet calculation is presented in Table 2, which shows the number of tablets that are 
needed per calculated BSA. 
• 
Study drug should only be given on Days 1 through 5 and Days 8 through 12 of each 
cycle even if doses are missed or held for any reason during Days 1 through 12. 
• 
Extension of study treatment into Days 6 and 7 or into the rest period (Days 13 
through 28) is not permitted. 


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Metastatic Colorectal Cancer 
TO-TAS-102-203 Version 1.0 14 June 2016 
 
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Table 2: 
Number of Tablets Per Dose 
TAS-102 Dose 
(2 × daily) 
BSA 
(m2) 
Dosage in mg 
(2 × daily) 
Total daily 
dose (mg) 
Tablets Per Dose 
15 mg 
20 mg 
35 mg/m2 
< 1.07 
35 
70 
1 
1 
1.07 - 1.22 
40 
80 
0 
2 
1.23 - 1.37 
45 
90 
3 
0 
1.38 - 1.52 
50 
100 
2 
1 
1.53 - 1.68 
55 
110 
1 
2 
1.69 - 1.83 
60 
120 
0 
3 
1.84 - 1.98 
65 
130 
3 
1 
1.99 - 2.14 
70 
140 
2 
2 
2.15 - 2.29 
75 
150 
1 
3 
≥ 2.30 
80 
160 
0 
4 
Abbreviation: BSA=body surface area (calculate to 2 decimal places). 
8.2.3. 
Instructions for Patients for Handling TAS-102 
The patient must be instructed in the handling of TAS-102 as follows: 
• 
To store the study drug at room temperature 
• 
To only remove from the study drug kit the amount of tablets needed at the time of 
dosing 
• 
To wash their hands after handling study drug 
• 
Not to remove doses in advance of the next scheduled dosing 
• 
To make every effort to take doses on schedule 
• 
To report any missed doses 
• 
To take study drug within 1 hour after completing a meal (morning and evening meal) 
with a glass of water 
• 
If the patient vomits after taking study drug, the patient should not take another dose 
• 
To keep study drug in a safe place and out of reach of children 
• 
To bring all used and unused study drug kits to the site at each visit 
8.2.4. 
TAS-102 Dose Modifications 
8.2.4.1. 
Dose Reduction Levels 
TAS-102 dose reductions to be applied in case of toxicity and the number of tablets for each 
calculated BSA are described in Table 3. Patients are permitted dose reduction(s) to a minimum 
dose of 20 mg/m2 (40 mg/m2/day) in 5 mg/m2 steps. 


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Metastatic Colorectal Cancer 
TO-TAS-102-203 Version 1.0 14 June 2016 
 
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Table 3: 
TAS-102 Dose Reduction Levels and Number of Tablets per Dose 
TAS-102 
Dose (2 × 
daily) 
BSA 
(m2) 
Dosage in mg 
(2 × daily) 
Total daily 
dose (mg) 
Tablets per Dose 
15 mg 
20 mg 
Level 1 Dose Reduction: From 35 mg/m2 to 30 mg/m2 
30 mg/m2 
< 1.09 
30 
60 
2 
0 
1.09 - 1.24 
35 
70 
1 
1 
1.25 - 1.39 
40 
80 
0 
2 
1.40 - 1.54 
45 
90 
3 
0 
1.55 - 1.69 
50 
100 
2 
1 
1.70 - 1.94 
55 
110 
1 
2 
1.95 - 2.09 
60 
120 
0 
3 
2.10 - 2.28 
65 
130 
3 
1 
≥ 2.29 
70 
140 
2 
2 
Level 2 Dose Reduction: From 30 mg/m2 to 25 mg/m2 
25 mg/m2 
< 1.10 
25a 
50a 
2 (PM)a 
1 (AM)a 
1.10 - 1.29 
30 
60 
2 
0 
1.30 - 1.49 
35 
70 
1 
1 
1.50 - 1.69 
40 
80 
0 
2 
1.70 - 1.89 
45 
90 
3 
0 
1.90 - 2.09 
50 
100 
2 
1 
2.10 - 2.29 
55 
110 
1 
2 
≥ 2.30 
60 
120 
0 
3 
Level 3 Dose Reduction: From 25 mg/m2 to 20 mg/m2 
20 mg/m2 
< 1.14 
20 
40 
0 
1 
1.14 – 1.34 
25a 
50a 
2 (PM)a 
1 (AM)a 
1.35 – 1.59 
30 
60 
2 
0 
1.60 – 1.94 
35 
70 
1 
1 
1.95 – 2.09 
40 
80 
0 
2 
2.10 – 2.34 
45 
90 
3 
0 
≥ 2.35 
50 
100 
2 
1 
Abbreviations: AM = morning; BSA=body surface area (calculate to 2 decimal places); PM = evening. 
a At a total daily dose of 50 mg, patients should take 1 x 20-mg tablet in the morning and 2 x 15-mg tablets in the 
evening. 
If dose modification fails to result in achieving minimal criteria to resume treatment, the 
investigator should discontinue study drug. 
Should the toxicities that require dose reduction recur after dose reduction to 20 mg/m2, study 
drug should be discontinued. 


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Protocol No. TO-TAS-102-203 
Metastatic Colorectal Cancer 
TO-TAS-102-203 Version 1.0 14 June 2016 
 
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8.2.4.2. 
Dose Modifications in Response to Non-hematologic Toxicities 
Rules for study drug dosing modifications for treatment-related non-hematologic AEs are 
provided in Table 4. At the discretion of the investigator, patients may continue on study drug at 
the same dose without reduction or interruption for drug-related AEs (irrespective of grade) 
considered unlikely to become serious or life threatening (including, but not limited to, fatigue, 
alopecia, changes in libido, and dry skin). 
Table 4: 
TAS-102 Dose Modification Criteria for Non-hematologic Toxicities 
Gradea 
Dose Hold/Resumption 
within a 28-day Treatment 
Cycle 
Dose Adjustment for  
Next Cycle 
Grade 1 or 2 
Any occurrence 
Maintain treatment at the same 
dose level 
None 
Grade 3a or Higher 
First, second, or third occurrence 
Suspend treatment until Grade 0 
or 1 
Reduce by 1 dose level from the 
previous level 
Fourth occurrence 
Discontinue treatment 
Discontinue treatment 
a Except for grade 3 nausea and/or vomiting controlled by aggressive antiemetic therapy or diarrhea responsive to 
antidiarrheal medication. 
If there is any uncertainty about continuing therapy or resuming therapy in a patient 
with ≥ grade 3 non-hematologic drug-related AEs, the case must be discussed with the Sponsor’s 
medical monitor before continuing therapy. 
8.2.4.3. 
Dose Modifications in Response to Hematologic Toxicities 
Criteria for dose hold and resumption in response to hematologic toxicities related to 
myelosuppression are described in Table 5 and Table 6, respectively. 
NOTE: For all patients with decreases in neutrophils and/or platelets, the next cycle of study 
treatment should not be started until the resumption criteria in Table 6 are met; these resumption 
criteria apply to the start of the next cycle for all patients regardless of whether or not the hold 
criteria were met. 


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Metastatic Colorectal Cancer 
TO-TAS-102-203 Version 1.0 14 June 2016 
 
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Table 5: 
TAS-102 Dose Hold Criteria for Hematologic Toxicities Related to 
Myelosuppression 
Parameter 
Hold Criteria 
Conventional Units 
SI Units 
Neutrophils 
< 500/mm3 
< 0.5 × 109/L 
Platelets 
< 50,000/mm3 
< 50 × 109/L 
Abbreviation: SI = Standard International. 
Table 6: 
TAS-102 Resumption Criteria for Hematologic Toxicities related to 
Myelosuppression 
Parameter 
Resumption Criteriaa 
Conventional Units 
SI Units 
Neutrophils 
≥ 1500/mm3  
≥ 1.5 × 109/L 
Platelets 
≥ 75,000/mm3 
≥ 75 × 109/L 
Abbreviation: SI = Standard International. 
a These resumption criteria apply to the start of the next cycle for all patients regardless of whether or not the hold 
criteria were met. 
Criteria for dose reduction in response to hematologic toxicities are as follows: 
• 
Uncomplicated neutropenia or thrombocytopenia ≤ grade 3, do not require a 
reduction in dose of study drug. 
• 
Patients who experience uncomplicated grade 4 neutropenia or thrombocytopenia that 
results in a ≤ 1 week delay of the start of the next cycle should start the next cycle at 
the same dose level. 
• 
Patients who experience uncomplicated grade 4 neutropenia or thrombocytopenia that 
results in a > 1 week delay of the start of the next cycle should start the next cycle at 
one reduced dose level as described in Table 3. 
Patients who experience complicated ≥ grade 3 neutropenia or thrombocytopenia should be 
considered for administration of hematopoietic growth factors, or for a dose reduction in the next 
cycle or both, dependent on the severity of the complication. 
In the event of febrile neutropenia: 
• 
Interrupt dosing until toxicity resolves to grade 1 or baseline 
• 
When resuming dosing, decrease the dose level by 5 mg/m2/dose from the previous 
dose level (as per Table 3). 
8.2.4.4. 
TAS-102 Dose Resumption 
If the patient recovers from toxicities requiring dose delay during the 2-week treatment period of 
a cycle (treatment Days 1 through 5 and Days 8 through 12), and no dose reduction is required, 
study drug may be resumed during that cycle. If a dose reduction is required, study drug should 


TAS-102 
Protocol No. TO-TAS-102-203 
Metastatic Colorectal Cancer 
TO-TAS-102-203 Version 1.0 14 June 2016 
 
Page 43 of 80 
be resumed at the start of the next cycle at the appropriate dose level as shown in Table 3. Do not 
increase the study drug dose after it has been reduced. 
If the patient recovers from toxicities requiring dose delay during the recovery period (Days 13 
through 28), start the next cycle on schedule at the appropriate dose level based 
on Section 8.2.4.2 and Section 8.2.4.3 above. If the toxicities that are defined above do not 
recover during the treatment or rest period, the start of the next cycle can be delayed for a 
maximum of 28 days from the scheduled start date of the next cycle. If resumption criteria are 
met by this maximum 28-day delay, start the next cycle at the appropriate dose level. 
Patients who require more than a 28-day delay in the scheduled start date of the next cycle will 
have study drug discontinued. Discontinuation of both TAS-102 and nivolumab will lead to 
discontinuation from the study. Future treatment will then be at the discretion of the investigator. 
8.2.5. 
Nivolumab Treatment Regimen 
The dose of nivolumab is calculated according to the patient’s weight. All doses of nivolumab 
will be administered to the patient by study site personnel on Days 1 and 15 of each cycle. The 
nivolumab should be administered on the same cycle as the TAS-102. Hence, if there is a delay 
in the TAS-102 dosing, the same delay should be applied to the nivolumab dosing. 
One nivolumab treatment cycle consists of the following: 
• 
Day 1: nivolumab (3 mg/kg/dose) intravenous over 60 minutes 
• 
Days 2 through 14: rest 
• 
Day 15: nivolumab (3 mg/kg/dose) intravenous over 60 minutes 
• 
Days 16 through 28: rest 
8.2.5.1. 
Nivolumab Preparation and Administration 
Prepare nivolumab for administration according to the instructions in the package insert.  
8.2.6. 
Nivolumab Dose Modifications 
Recommendations for nivolumab dose modifications are listed in Table 7 . For patients who 
experience mild or moderate infusion reactions, the infusion should either be interrupted or the 
rate should be slowed. If a patient has a severe or life-threatening infusion reaction, the 
nivolumab should be discontinued. Discontinuation of both TAS-102 and nivolumab will lead to 
discontinuation from the study. Future treatment will then be at the discretion of the investigator. 
 


TAS-102 
Protocol No. TO-TAS-102-203 
Metastatic Colorectal Cancer 
TO-TAS-102-203 Version 1.0 14 June 2016 
 
Page 44 of 80 
Table 7: 
Recommended Dose Modifications for Nivolumab 
Adverse Reaction  
Severitya 
Dose Modification 
Colitis 
Grade 2 or grade 3 diarrhea or 
colitis 
Withhold doseb 
Grade 4 diarrhea or colitis  
Permanently discontinue 
Pneumonitis 
Grade 2 pneumonitis 
Withhold doseb 
Grade 3 or grade 4 pneumonitis 
Permanently discontinue 
Hepatitis 
Aspartate aminotransferase 
(AST) or alanine 
aminotransferase (ALT) more 
than 3 and up to 5 × the upper 
limit of normal (ULN) or total 
bilirubin more than 1.5 and up to 
3 × the ULN 
Withhold doseb 
AST or ALT more than 5 × the 
ULN or total bilirubin more than 
3 × the ULN 
Permanently discontinue 
Hypophysitis 
Grade 2 or grade 3 hypophysitis  
Withhold doseb 
Grade 4 hypophysitis 
Permanently discontinue 
Adrenal Insufficiency 
Grade 2 adrenal insufficiency 
Withhold doseb 
Grade 3 or grade 4 renal 
insufficiency  
Permanently discontinue 
Type 1 Diabetes 
Grade 3 hyperglycemia 
Withhold doseb 
Grade 4 hyperglycemia 
Permanently discontinue 
Nephritis and Renal Dysfunction 
Serum creatinine more than 1.5 
and up to 6 × the ULN  
Withhold doseb 
Serum creatinine more than 6 × 
the ULN 
Permanently discontinue 
Rash 
Grade 3 rash 
Withhold doseb 
Grade 4 rash 
Permanently discontinue 
Encephalitis 
New-onset moderate or severe 
neurologic signs or symptoms 
Withhold doseb 
Immune-mediated encephalitis  
Permanently discontinue 
Other 
Other grade 3 adverse reaction, 
first occurrence  
Withhold doseb 
Recurrence of same grade 3 
adverse reaction  
Permanently discontinue 


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Protocol No. TO-TAS-102-203 
Metastatic Colorectal Cancer 
TO-TAS-102-203 Version 1.0 14 June 2016 
 
Page 45 of 80 
Adverse Reaction  
Severitya 
Dose Modification 
Life threatening or grade 4 
adverse reaction  
Permanently discontinue 
Requirement for 10 mg per day 
or greater prednisone or 
equivalent for more than 
12 weeks  
Permanently discontinue 
Persistent grade 2 or grade 3 
adverse reactions lasting 
12 weeks or longer  
Permanently discontinue 
a Toxicity was graded per the National Cancer Institute Common Terminology Criteria for Adverse 
Events version 4.0. 
b Resume treatment when the adverse reaction returns to grade 0 or 1. 
8.3. 
Treatment Compliance  
Compliance to all study drug administration should be documented in the patient’s source 
documents. 
8.4. 
Study Drug Accountability 
In accordance with International Council for Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (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.  
Dose reductions, interruptions, and reason for these actions must be recorded in the patient’s 
source documents. 
All used and unused study drug shipped to the investigator must be returned to the Sponsor or its 
representative. If on-site destruction is required by site policy, such requirements must be 
documented in the institution’s Standard Operating Procedure and provided to the Sponsor or its 
representative for review. 
No study drugs are to be used outside of this study. 
9. 
STUDY ASSESSMENTS 
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 (up to 28 days 
before enrollment). 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 7.3.1 and Section 7.3.2. 


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TAS-102 
Protocol No. TO-TAS-102-203 
Metastatic Colorectal Cancer 
TO-TAS-102-203 Version 1.0 14 June 2016 
 
Page 47 of 80 
9.1.6. 
Physical Examination 
A complete physical examination will be performed at the time points listed below: 
• 
Within 7 days before study drug administration on Day 1 of Cycle 1 
• 
Beginning with Cycle 2, obtain within 24 hours before the start of study treatment on 
Day 1 of every cycle 
• 
End of Treatment visit (if applicable) 
• 
30-day Safety Follow-up visit 
9.1.7. 
Baseline Signs and Symptoms 
Signs and symptoms present after signature of the ICF and within 7 days before study treatment 
on Day 1 of Cycle 1 should be recorded in the patient’s source documents. 
• 
Height, Vital Sign Measurements, and Weight 
• 
The patient’s height will be obtained only during baseline before study drug 
administration within 7 days before Day 1 of Cycle 1. The patient’s vital sign 
measurements (blood pressure, heart rate, body temperature, and respiration rate) will 
be collected at the time points listed below. All the vital sign measurements are to be 
obtained with the patient in a position that is consistent for all time points for each 
patient. 
• 
Beginning with Cycle 2, obtain within 24 hours before the start of study drug 
administration on Day 1 of every cycle 
• 
End of Treatment visit (if applicable) 
• 
30-day Safety Follow-up visit 
• 
Weight will be collected within 7 days of Day 1 Cycle 1, Cycle 1 Day 15, Day 1 and 
Day 15 of all subsequent cycles, End of Treatment visit, and at the 30-day Safety 
Follow-up visit.  
9.1.8. 
Performance Status 
An ECOG performance status score 
 will be 
obtained at the following time points: 
• 
Within 28 days before study drug administration on Day 1 of Cycle 1 
• 
Obtain within 24 hours before the start of study drug administration on Day 1 in 
every cycle and Day 15 
• 
End of Treatment visit (if applicable) 
• 
30-day Safety Follow-up visit 
9.1.9. 
Clinical Laboratory Evaluations 
Samples for hematology, serum chemistry and urinalysis assessments will be collected and 
measured as described in Section 9.1.9.1, Section 9.1.9.2, and Section 9.1.9.3. Laboratory 
assessments obtained before the signing of the ICF may be used as screening laboratory values if 


TAS-102 
Protocol No. TO-TAS-102-203 
Metastatic Colorectal Cancer 
TO-TAS-102-203 Version 1.0 14 June 2016 
 
Page 48 of 80 
they were obtained within 7 days before administration of study drug 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 11.1, 
Adverse Events/Serious Adverse Events and Section 11.2, Laboratory Evaluations). In addition, 
follow the criteria for repeat testing listed in Section 11.2.2 as needed. 
9.1.9.1. 
Hematology 
Blood samples for hematology assessments will be obtained at the following time points and 
when clinically indicated:  
• 
Within 7 days before Day 1 of Cycle 1 (Laboratory results obtained before signing 
the ICF may be used if the results were obtained within 7 days before Day 1 of 
Cycle 1.) 
• 
Day 15 of each cycle 
• 
Beginning with Cycle 2, obtain blood samples within 24 hours before the start of 
study drug administration on Day 1 of every cycle 
• 
End of Treatment visit (if applicable) 
• 
30-day Safety Follow-up visit 
In addition, the criteria for repeat testing listed in Section 11.2.2, will be followed as needed. 
Hematology parameters that will be measured are listed in Table 8. 


TAS-102 
Protocol No. TO-TAS-102-203 
Metastatic Colorectal Cancer 
TO-TAS-102-203 Version 1.0 14 June 2016 
 
Page 49 of 80 
Table 8: 
Hematology Laboratory Parameters 
Hemoglobin  
White blood cell (WBC) count with 
differential (automated): 
Hematocrit 
Neutrophils 
Platelets 
Lymphocytes 
Red blood cell count 
Monocytes 
 
Eosinophils 
 
Basophils 
9.1.9.2. 
Serum Chemistry 
Blood will be collected at the following time points for serum chemistry assessments: 
• 
Within 7 days prior to Day 1 of Cycle 1 (Laboratory results obtained before signing 
the ICF may be used if the results were obtained within 7 days before Day 1 of 
Cycle 1.) 
• 
Day 15 of each cycle 
• 
For all subsequent cycles, obtain within 24 hours before the start of study drug 
administration on Day 1 of every cycle 
• 
End of Treatment Visit (if applicable) 
• 
30-day Safety Follow-up Visit. 
In addition, follow the criteria for repeat testing listed in Section 11.2.2 as needed. 
Table 9 lists the serum chemistry parameters that will be measured. 
Table 9: 
Serum Chemistry Laboratory Parameters 
ALT  
Creatinine 
Chloride 
AST  
Blood urea nitrogen 
Calcium 
Alkaline phosphatase 
Sodium 
Albumin 
Bilirubina 
Potassium 
Glucose 
Thyroid stimulating hormone 
Thyroxine 4 (T4) 
 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase. 
a In case of elevation in total bilirubin, fractionation (direct/indirect) should be performed. 
9.1.9.3. 
Urinalysis 
Collect urine samples for qualitative (dipstick) analysis, to include tests for protein, glucose, 
urobilinogen, red blood cell count, and white blood cell count, at the time points listed below: 
• 
Within 7 days before Day 1 of Cycle 1 (Laboratory results obtained before signing 
the ICF may be used if the results were obtained within 7 days before Day 1 of 
Cycle 1.) 


TAS-102 
Protocol No. TO-TAS-102-203 
Metastatic Colorectal Cancer 
TO-TAS-102-203 Version 1.0 14 June 2016 
 
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• 
As clinically indicated thereafter 
If a new abnormality is identified, quantitative urinalysis should be performed. 
In addition, follow the criteria for repeat testing listed in Section 11.2.2 as needed. 
9.1.10. 
Pregnancy Testing 
If the patient is female and of childbearing potential, pregnancy testing by assessment of serum 
or urine beta-human chorionic gonadotrophin will be conducted at the following time points and 
the date, time, and test results should be recorded in the patient’s source documents (Note: More 
frequent pregnancy assessments should be performed if required by local law): 
• 
Within 7 days prior to Day 1 of Cycle 1 
• 
End of Treatment or 30-day Safety Follow-up Visit 
Female patients who are considered not to be of child bearing potential must have a history of 
being post-menopausal (no menses for 12 consecutive months without an alternative medical 
cause), or hysterectomy that is clearly documented in the patient’s source documents. 
9.1.11. 
Tumor Measurements 
Tumor assessments/contrast-enhanced CT scans of the chest and abdomen (and pelvis, if 
clinically indicated) must be obtained at each time point listed below for all patients:  
• 
Within 28 days before Day 1 of Cycle 1. Scans obtained before the patient signs the 
ICF may be used if the date of the scan is within 28 days of enrollment. 
• 
Every 2 cycles during study treatment 
• 
For patients who discontinue treatment because of radiologic disease progression by 
irRC, an additional tumor assessment is not required at the End of Treatment visit. 
• 
For patients who discontinued treatment for reasons other than radiologic disease 
progression by irRC, every effort should be made to perform an end of treatment 
tumor assessment before the start of new anticancer therapy and should be followed 
for tumor response every 2 cycles until the patient develops radiologic disease 
progression (or death) or initiation of new anticancer therapy (whichever occurs first).  
On-site tumor assessments will be performed by the investigator or local radiologist according to 
RECIST criteria and irRC. Results of these assessments including response for target and 
non-target lesions and appearance of new lesions will be the basis for the continuation or 
discontinuation of study drug. Response definitions are provided in Section 10.3.1.  
Patients with tumor progression determined by irRC or laboratory parameters before their 
6-month evaluation but without rapid clinical deterioration or change in performance status who 
do not require additional immediate therapy, may continue to be treated with and clinically 
observed after the assigned imaging schedule to allow detection of a subsequent tumor response. 
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. 


TAS-102 
Protocol No. TO-TAS-102-203 
Metastatic Colorectal Cancer 
TO-TAS-102-203 Version 1.0 14 June 2016 
 
Page 51 of 80 
The same method of assessment and the same technique must be used to characterize each 
identified and reported lesion at baseline, throughout the study, and during the follow-up period. 
All patients’ files and radiological assessments must be available for source verification and may 
be submitted for extramural review for initial assessment of antitumor activity.  
Results of any unscheduled evaluations should be recorded in the patient’s source documents. 
9.1.12. 
Prior and Concomitant Medications 
All therapies and medications, prescription and over-the-counter, will be collected from the time 
the ICF is signed through the 30-day Safety Follow-Up visit, including any medication used to 
treat AEs or SAEs during the Safety Follow-up Period. Use of concomitant medication should be 
documented in the patient’s source documents.  
The time of initiation of new anticancer therapy received during the 30-day Safety Follow-up 
Period will be collected. 
During the survival follow-up period, only anticancer therapies will be collected. 
9.1.13. 
Adverse Event Assessments  
Patients will be monitored for any untoward medical events (AEs or SAEs) from the time of 
signed informed consent through 30 days after last dose of study drug or until the start of new 
antitumor therapy, whichever is earlier. 
Serious AEs should be reported to Taiho Oncology, Incorporated (TOI) Pharmacovigilance or its 
designee. If serious medical occurrences or deaths outside the 30-day follow-up period are 
reported to or observed by the investigator that he/she believes are related to the administration 
of the study drug, it is the investigator’s responsibility to report this occurrence to TOI 
Pharmacovigilance or its designee. See Section 11.1.1 and Section 11.1.2, respectively, for 
definitions and detailed reporting of AEs and SAEs. 
9.2. 
Assessments by Visit 
See Section 9.1 for details about specific assessments. 
9.2.1. 
Baseline Procedures Before Enrollment 
9.2.1.1. 
Day −28 through Day −1 
• 
Signature of ICF 
• 
Review of inclusion and exclusion criteria 
• 
Medical history 
• 
Histological confirmation of mCRC from either the primary or metastatic site of 
disease 
• 
ECOG performance status 
• 
Tumor measurement (by CT scan) 
• 
Concomitant medication 


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TAS-102 
Protocol No. TO-TAS-102-203 
Metastatic Colorectal Cancer 
TO-TAS-102-203 Version 1.0 14 June 2016 
 
Page 55 of 80 
• 
Vital sign measurements (blood pressure, heart rate, body temperature, 
respiration rate) and body weight 
• 
ECOG performance status  
• 
Blood samples for chemistry and hematology 
• 
Pregnancy test  
• 
Concomitant medication, including any new anticancer therapy and time of 
initiation 
• 
AE/SAE assessment 
9.2.5. 
Survival Follow-up after 30-Day Safety Visit 
The following assessments should be obtained at scheduled 8-week time intervals during the 
survival follow-up period (these may be telephonic): 
• Tumor measurement (by CT scan, see Section 10) every 2 cycles until 
radiologic disease progression (for patients who discontinued treatment for 
reasons other than disease progression) or initiation of new anticancer therapy 
(whichever occurs first) 
• Concomitant medications – collect antitumor therapies only 
• Contact patient/caregiver to determine survival status (alive/dead) 
• SAE collection only if the SAE is related to study drug 
Patients will be followed for survival until the study discontinuation criteria are met. The 
investigators will be informed when these criteria are reached. 


TAS-102 
Protocol No. TO-TAS-102-203 
Metastatic Colorectal Cancer 
TO-TAS-102-203 Version 1.0 14 June 2016 
 
Page 56 of 80 
10. 
EFFICACY ASSESSMENT CRITERIA 
The determination of antitumor efficacy will be based on objective tumor assessments made by 
the investigator/local radiologist according to the irRC13 and revised RECIST criteria of 
unidimensional evaluation.14 Treatment decisions by the investigator will also be based on these 
criteria.  
Considering that the primary endpoint is response-related, a confirmation of response is required 
after a minimum of 4 weeks. 
10.1. 
Method of Imaging 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess the 
antitumor effect of treatment. All measurements should be recorded in metric notation using a 
ruler or calipers. 
Contrast-enhanced CT is the preferred method for tumor assessments. If contrast agent is 
contraindicated in a patient, obtain a non-contrast chest CT and enhanced magnetic resonance 
imaging (MRI) of the abdomen (and pelvis if clinically indicated). 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 and MRI may be used for tumor measurement. 
Clinical lesions will only be considered measurable when they are superficial (eg, skin nodules, 
palpable lymph nodes). In the case of skin lesions, documentation by color photography, 
including a ruler to estimate the size of the lesion, is recommended. 
Ultrasound should not be used to measure tumor lesions that are clinically not easily accessible 
for objective response evaluation (eg, visceral lesions). Ultrasound is a possible alternative to 
clinical measurements of superficial palpable nodes, subcutaneous lesions, and thyroid nodules. 
Ultrasound might also be useful to confirm the complete disappearance of superficial lesions 
usually assessed by clinical examination. 
An additional fluorodeoxyglucose positron emission tomography (FDG-PET) scan may help 
confirm the diagnosis of suspicious lymph nodes as needed. A “positive” FDG-PET scan lesion 
is one that is FDG avid “with an uptake greater than twice that of the surrounding tissue on the 
attenuation corrected image.” However, this scan is not mandatory. A FDG-PET scan alone 
cannot replace a MRI or contrast-enhanced CT. 
10.2. 
Immune-related Response Criteria 
10.2.1. 
Immune-related Response Criteria Definitions 
Measureable Disease: Neoplastic masses that can be precisely measured in 2 in-plane 
perpendicular diameters. Both its longest diameter and it longest perpendicular must be 
≥ 10 mm. Lymph nodes must be measureable in 2 perpendicular diameters. Both its longest 
diameter and its longest perpendicular must be ≥ 15 mm. Malignant lymph nodes must be 


TAS-102 
Protocol No. TO-TAS-102-203 
Metastatic Colorectal Cancer 
TO-TAS-102-203 Version 1.0 14 June 2016 
 
Page 57 of 80 
measurable in 2 perpendicular diameters. Both its longest diameter and its longest perpendicular 
must be ≥ 15 mm. The quantitative endpoint will be defined as the product of the longest 
diameter with its longest perpendicular.  
Non-measurable disease: Non-measurable diseases are those that are not suitable for quantitative 
assessment over time. These include: 
• 
Neoplastic masses that are too small to measure, because their longest uninterrupted 
diameter or longest perpendicular are < 10 mm. 
• 
Neoplastic masses whose boundaries cannot be distinguished. This includes masses 
that cannot be demarcated from surrounding tissue because of inadequate contrast, 
masses with overly complex morphology, or those with highly heterogeneous tissue 
composition. 
• 
Other types of lesions that are confidently felt to represent neoplastic tissue, but 
difficult to quantify in a reproducible manner. These include bone metastases, 
leptomeningeal metastases, malignant ascites, pleural/pericardial effusions, 
inflammatory breast disease, lymphangitis cutis/pulmonis cystic lesions, ill-defined 
abdominal masses, etc. 
For irRC, only index lesions selected at baseline and measurable new lesions are taken into 
account.  
10.2.2. 
Immune-related Response Criteria 
At the baseline tumor assessment, the sum of the products of the 2 largest perpendicular 
diameters (SPD) of all index lesions (5 lesions per organ, up to 10 visceral lesions and 
5 cutaneous index lesions) is calculated. 
At each subsequent tumor assessment, the SPD of the index lesions and of new, measurable 
lesions (≥ 5 × 5 mm; up to 5 new lesions per organ: 5 new cutaneous lesions and 10 visceral 
lesions) are added together to provide the total time-point tumor burden: 
Tumor burden = SPDindex lesions + SPDnew, measureable lesions 
Overall responses using irRC are defined as follows and presented in Table 10: 
• 
Complete Response (immune-related CR [irCR]): Complete disappearance of all 
tumor lesions (whether measurable or not, and no new lesions). Complete response 
must be confirmed by repeated, consecutive assessments made no less than 4 weeks 
from the date first documented. 
• 
Partial Response (immune-related PR [irPR]): Decrease in SPD of 50% or greater by 
a consecutive assessment at least 4 weeks after first documentation. 
• 
Stable Disease (immune-related SD [irSD]): Failure to meet criteria for irCR or irPR, 
in absence of progressive disease (irPD).  
• 
Progressive Disease (immune-related PD [irPD]): At least 25% increase in SPD 
relative to nadir (minimum recorded tumor burden). Confirmation by a repeat, 
consecutive assess no less than 4 weeks from the date first documented. 


TAS-102 
Protocol No. TO-TAS-102-203 
Metastatic Colorectal Cancer 
TO-TAS-102-203 Version 1.0 14 June 2016 
 
Page 58 of 80 
Table 10: 
Derivation of irRC Overall Responses13  
Measurable Response 
Non-measurable Response 
Overall Response 
Index and New, 
Measurable Lesions 
(Tumor Burden) %a 
Non-index Lesions 
New, Non-measurable 
Lesions 
Using irRC 
↓ 100 
Absent 
Absent 
irCRb 
↓ 100 
Stable 
Any 
irPRb 
↓ 100 
Unequivocal 
progression 
Any 
irPRb 
↓ ≥ 50 
Absent/stable 
Any 
irPRb 
↓ ≥ 50 
Unequivocal 
progression 
Any 
irPRb 
↓ < 50 to < 25 ↑ 
Absent/stable 
Any 
irSDb 
↓ < 50 to < 25 ↑ 
Unequivocal 
progression 
Any 
irSDb 
≥ 25 ↑ 
Any 
Any 
irPDb 
Abbreviations: irCR = immune-related complete response; irPD = immune-related progressive disease; irPR = 
immune-related partial response; irRC = immune-related response criteria; irSD = immune-related stable disease. 
Note: Complete response and partial response must be confirmed by repeated, consecutive assessments made no less 
than 4 weeks from the date first documented.  
a Assuming response (irCR and irPR) and progression (irPD) are confirmed by a second, consecutive assessment at 
least 4 weeks apart. 
b Decreases assessed relative to baseline, including measurable lesions only (> 5 × 5 mm). 
If a patient is classified as having irPD at a postbaseline tumor assessment, then confirmation of 
irPD by a second scan in the absence of rapid clinical deterioration is required. The definition of 
confirmation of progression represents an increase in tumor burden ≥ 25% compared with the 
nadir at 2 consecutive time points at least 4 weeks apart. It is recommended that this be done at 
the discretion of the investigator because follow-up with observation alone may not be 
appropriate for patients with a rapid decline in performance irRC (Table 10), as most of these 
late responding patients have a trend toward response within 4 weeks after initial irPD. A patient 
may continue receiving study drug treatment if the patient is classified as having irPD at a 
postbaseline tumor assessment and shows no signs of clinical progression. 
10.3. 
Response Evaluation Criteria in Solid Tumors 
10.3.1. 
RECIST 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. 


TAS-102 
Protocol No. TO-TAS-102-203 
Metastatic Colorectal Cancer 
TO-TAS-102-203 Version 1.0 14 June 2016 
 
Page 59 of 80 
• 
Measurable pathological lymph nodes: A malignant lymph node must be considered 
pathologically enlarged with high suspicion of metastasis and measure ≥ 15 mm in 
the short axis when assessed by CT scan. The short axis is defined as the longest 
linear dimension perpendicular to the node’s longest diameter as assessed within the 
same plane that the scan was acquired. 
Only measurable lesions can be selected as target lesions. 
Non-measurable Lesions: Non-measurable lesions include: 
• 
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 per organ and 5 lesions in total, 
representative of all involved organs/tissues should be identified as target lesions. 
• 
Target lesions should be selected on the basis of their size (visceral lesion with the 
longest diameter and lymph node with the measurement of short axis), be 
representative of all involved organs/tissues, but in addition should be those that lend 
themselves to reproducible repeated measurements. 
• 
When recording tumor measurements, the longest diameter will be measured for each 
non-nodal target lesion. For measurable pathological lymph nodes that may be 
identified as target lesions, the short axis measurement will be combined with the 
measurements of non-nodal (ie, visceral lesion) target lesions. Therefore, in cases of 
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 and measured at each 
subsequent time point. 
The sum of the diameters for all target lesions will be calculated and recorded. The baseline sum 
will be used as a reference to further characterize any objective tumor assessment in the 
measurable dimension of the disease. 
• 
Assign a measurement to all target lesions regardless of size. An option of “too small 
to measure” will be provided if a measurement cannot be assigned. A value of zero 
should only be assigned in the case of a CR. 
• 
An option of “Not Assessable” for a lesion will only apply to lesions that cannot be 
read due to technical reasons, for example: 
1. CT artifact. 
2. Patient positioning where the lesions are obstructed or cannot be seen. 
3. Lesions that may not be seen in their entirety because of CT slice thickness. 


TAS-102 
Protocol No. TO-TAS-102-203 
Metastatic Colorectal Cancer 
TO-TAS-102-203 Version 1.0 14 June 2016 
 
Page 60 of 80 
• 
In cases where a lesion divides into 2 lesions, the longest diameters of the fragmented 
portions should be added together to calculate the target lesion sum.  
• 
In cases where 2 lesions coalesce, a plane between them may be maintained that 
would aid in obtaining maximal diameter measurements of each individual lesion. If 
the lesions have truly coalesced such that they are no longer separable, the vector of 
the longest diameter in this instance should be the maximal longest diameter for the 
“coalesced lesion”. 
Non-target Lesions: 
• 
Non-target lesions include all non-measurable lesions and measurable lesions that 
have not been selected as target lesions 
• 
Lymph nodes that have a short axis < 10 mm are considered non-pathological and 
should not be recorded. 
• 
Any equivocal lesion without clear diagnosis (eg, uncharacteristic solitary lung 
nodule without biopsy, uncharacteristic thyroid mass lesion without fine needle 
aspiration) may be considered a non-target lesion if it cannot be differentiated from a 
benign lesion.  
• 
All other lesions (or sites of disease), including pathological lymph nodes, should be 
identified as non-target lesions and should also be recorded at Baseline. 
Measurements are not required, but their presence, absence, or unequivocal 
progression should be followed throughout the study. 
It is possible to record multiple non-target lesions involving the same organ as a single item on 
the eCRF (eg, multiple enlarged pelvic lymph nodes or multiple liver metastasis). 
10.3.2. 
RECIST 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 9.1.11.  
10.3.2.1. RECIST Target and Non-target Response Assessments  
10.3.2.1.1. RECIST Criteria for Assessment of Tumor Response 
Assessments will be made based on the following definitions14: 


TAS-102 
Protocol No. TO-TAS-102-203 
Metastatic Colorectal Cancer 
TO-TAS-102-203 Version 1.0 14 June 2016 
 
Page 61 of 80 
TARGET LESIONS 
Lesions Response: 
Definition: 
Complete Response (CR) 
The disappearance of all target lesions. Any pathological lymph nodes must 
have reduction in short axis to < 10 mm. 
Partial Response (PR) 
At least a 30% decrease in the sum of diameters of the target lesions, taking as a 
reference the baseline sum diameters. 
Progressive Disease (PD) 
At least a 20% increase in the sum of diameters of the target lesions, taking as a 
reference the smallest sum on study, including the baseline sum. In addition to 
the relative increase of 20%, the sum must also demonstrate an absolute increase 
of at least 5 mm. Definitive new lesion presence also indicates progression. 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD, taking as a reference the smallest sum diameters while on study. 
 
NON-TARGET LESIONS 
Lesions Response: 
Definition: 
Complete Response (CR) 
The disappearance of all non-target lesions. All lymph nodes must be non-
pathological morphologically (ie, < 10 mm in short axis in size). 
Non-CR/Non-PD 
A persistence of ≥ 1 non-target lesion(s)/ not reaching the extent of “unequivocal 
progression”. 
Progressive Disease (PD) 
Unequivocal progression of existing non-target lesions (see definition below). 
 
Progression in Non-target Disease:  
There must be an overall level of substantial worsening in non-target disease such that, even in 
the presence of 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 diameter in a measurable lesion). 
10.3.2.1.2. Additional Criteria to Consider When Assessing Tumor Response 
When effusions are known to be a potential adverse effect of treatment, cytological confirmation 
of the neoplastic origin of any effusion that appears or worsens during treatment when the 
measurable tumor has met criteria for response or SD is not mandatory, but might be performed 
to differentiate between response (or SD) and PD when substantial change of effusion and or 
ascites is noted. 
For equivocal findings of progression (eg, very small and uncertain new lesions; cystic changes 
or necrosis in existing lesions), treatment may continue until the next scheduled assessment. If at 


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the next scheduled assessment, progression is confirmed, the date of progression should be the 
earlier date when progression was suspected. 
10.3.2.2. RECIST Overall Response Assessment 
Assessments will be made based on definitions14 provided in Table 11.  
Table 11: 
Time Point Response for Patients with Target (± Non-target) Disease 
Target Lesions 
Non-target Lesions 
New Lesion 
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 
PD 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Abbreviations: CR = complete response; PD = progressive disease; PR = partial response; SD = stable disease. 
10.3.3. 
RECIST Best Overall Response Assessment 
The best overall response as per RECIST criteria is the best response recorded from the start of 
the study treatment until the end of treatment. 
11. 
REPORTING SAFETY INFORMATION 
11.1. 
Adverse Events and Serious Adverse Events 
11.1.1. 
Adverse Events 
An AE is any untoward medical condition that occurs in a patient while participating in a clinical 
study and does not necessarily have a causal relationship with the use of the study drugs. 
Treatment-emergent AEs are AEs that occur from the initiation of any study treatment 
administration, and do not necessarily have a causal relationship to the use of the study 
treatments.  
Provide a complete and specific clinical diagnosis as an AE verbatim term. If a diagnosis is not 
available, then report signs and symptoms. The CTCAE terms are to be used to assess 
severity/provide the grade for each AE that is reported. 
Refer to Section 11.1.5, Section 11.1.6, and Section 11.1.7 for definitions and reporting of 
pregnancy, medication errors, and overdose, respectively.  


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Any untoward medical event that occurs outside the period of patient follow-up (30 days after 
the last dose of study treatment or until the start of new antitumor therapy, whichever is earlier) 
is not considered an AE unless determined by the investigator to have a causal relationship with 
the study treatment. 
If any SAEs are observed after the patient follow-up period has ended, only those SAEs 
determined to have a causal relationship with the study drugs will be recorded in the case report 
form. 
Symptoms or laboratory or instrumental (eg, electrocardiographic) abnormalities of a pre-
existing disease, such as cancer or other disease, should not be considered an AE. However, 
occurrences of new symptoms as well as worsening of pre-existing medical conditions are 
considered AEs. In addition, a new laboratory or instrumental abnormality that has a clinical 
impact on a patient (eg, resulting in study drugs dose reduction, treatment delay, treatment 
discontinuation, requires treatment due to abnormal values, or is considered medically important 
by the investigator) is considered an AE, unless it is considered part of clinical manifestations to 
a clinical diagnosis that is already reported as an AE. 
Adverse events will be reported from the time of informed consent through the period of patient 
follow-up (30 days after the last dose of study drugs or until the start of new antitumor therapy, 
whichever is earlier). Document all AEs in the source documents. Documentation should include 
onset and resolution, severity/grade, relationship to study drugs, and outcome of the event. 
Causal relationship: 
When assessing AE causal relationship to study drugs, relationship to TAS-102 and nivolumab 
will be assessed independently. 
1. Reasonably possible: The AE is related if it follows a reasonable temporal sequence from 
administration of study drugs and, one of the following conditions is true: 
• 
A positive de-challenge. This means that the event resolves when the drug is 
stopped. 
• 
A positive re-challenge. This means that the event reappears when the drug is 
restarted. 
• 
Or, the event cannot be reasonably explained by the patient’s clinical state 
and/or other administered therapies. 
2. Not reasonably possible: The AE is not related when there is no reasonable possibility 
that the study drugs caused the event. For the purposes of safety reporting, “no reasonable 
possibility” means there is no evidence to suggest a causal relationship between the drug 
and the AE. 
Reasonable possibility is provided by the following examples of types of evidence that 
would suggest a causal relationship between drug and AE: 
• 
A single occurrence of an event that is uncommon and known to be strongly 
associated with drug exposure (eg, angioedema, hepatic injury, Stevens-Johnson 
syndrome) 


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• 
One or more occurrences of an event that is not commonly associated with drug 
exposure, but is otherwise uncommon in the population exposed to drug (eg, 
tendon rupture) 
Outcome:  
• 
Resolved without sequelae 
• 
Resolved with sequelae 
• 
Resolving (can only be used for SAEs and cannot be a final outcome) 
• 
Unresolved 
• 
Death 
Any unresolved AEs should be followed until the earliest occurrence of one of the following: 
• 
AE has resolved. 
• 
AE has stabilized. An AE cannot be considered stabilized while the patient is on 
study drug. Ongoing AEs must be assessed for stabilization 30 days post study 
drug discontinuation. 
• 
The start of new antitumor therapy. 
11.1.2. 
Serious Adverse Events  
An SAE (experience) is any untoward medical occurrence that at any time: 
a. Results in death (see Section 11.1.3). 
b. Is life threatening. 
NOTE: The term "life threatening" in the definition of "serious" refers to an event in 
which the patient was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it were more severe. 
c. Requires inpatient hospitalization or prolongation of existing hospitalization. The 
following are not considered hospitalizations for the purposes of assessing 
seriousness: 
− Emergency room visits less than 24 hours. 
− Hospitalizations for preplanned procedures. 
− Hospitalization for study-related treatment and procedures. 
d. Results in persistent or significant incapacity or disability, where disability is defined 
as a substantial disruption of a person’s ability to conduct normal life functions, either 
reported or defined as per clinical judgment. 
e. Is a congenital anomaly/birth defect (if exposure to product just before conception or 
during pregnancy resulted in an adverse outcome in the child). 
f. Is any other important medical event, eg, may not result in death, be life-threatening, 
or require hospitalization, but based upon appropriate medical judgment, it may 
jeopardize the patient and may require medical or surgical intervention to prevent one 
of the outcomes listed in the points above. Examples of such events are: intensive 


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treatment in an emergency room or at home for allergic bronchospasm; and blood 
dyscrasias or convulsions that do not result in hospitalization. 
Serious adverse events must be reported to Taiho Pharmacovigilance or designee within 
24 hours from the time the investigator first becomes aware of the SAE. Comprehensive 
information available at the time of initial reporting (including narrative description, medical 
history and concomitant medications) needs to be provided with careful consideration regarding 
causality and serious criteria. The SAE reporting process and contact information for reporting 
the SAE are provided in the eCRF/SAE Completion Guidelines. 
After the initial SAE notification to Taiho Pharmacovigilance or designee, follow-up SAE 
information will be submitted each time that important follow-up information (eg, diagnosis, 
outcome, causality assessment, results of specific investigations) becomes available. 
All SAEs within the follow-up window (eg, within 30 days after the last dose of study 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 investigational product, it is the investigator’s responsibility to report this 
occurrence to Taiho Pharmacovigilance or designee. 
A serious adverse reaction (SAR) is any event that meets the definition of an SAE and is 
considered related to the administration of study drugs. An unexpected SAR is defined as any 
SAR, the nature or severity of which is not consistent with the applicable product information 
(eg, IB for an unauthorized investigational product or summary of product characteristics for an 
authorized product). 
11.1.3. 
Reporting of Deaths 
All deaths occurring through the 30-day follow-up period must be reported in the eCRF within 
24 hours. 
1. Death due to disease progression: 
Disease progression (radiologic or clinical) with the outcome of death will not be 
reported as an SAE. However, relevant signs, symptoms and complications of disease 
progression (radiologic or clinical) must be reported as an AE or SAE if it meets the 
serious criteria. It should be indicated that the signs, symptoms and complications are 
related to disease progression. 
2. Death due to other causes: 
Deaths due to reasons other than disease progression must be reported as an SAE. 
Death is not an acceptable AE/SAE term. Death is an outcome of an SAE. 
When reporting a death in the eCRF, the investigator will be required to identify which of the 
following best describes the category of death:  
• 
Toxicity for study drugs 
• 
Radiologic disease progression 


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• 
Clinical disease progression 
• 
Other causes 
11.1.4. 
Disease Progression 
1. How to report events related to non-fatal disease progression: 
a. Disease progression is not an acceptable AE term. In cases of non-fatal disease 
progression, the relevant signs, symptoms and complications should be reported as an 
AE unless they meet the serious criteria. If any of the signs, symptoms and 
complications meets any of the serious criteria, they should be reported as an SAE. In 
both cases it should be indicated whether the signs, symptoms and complications are 
related to disease progression. 
b. Radiologic disease progression without relevant signs, symptoms and complications 
will not be reported as an AE or SAE. 
2. How to report events related to fatal disease progression: 
a. See Section 11.1.3, Reporting of Deaths. 
11.1.5. 
Pregnancy 
If a patient becomes pregnant while in the study, the study treatment must be immediately 
discontinued. Pregnancy information for a female patient should be reported within 24 hours 
from the time the investigator first becomes aware of a pregnancy or its outcome. This should be 
performed by completing a Pregnancy Form and faxing it to Taiho Pharmacovigilance or 
designee. 
New and/or corrected information regarding the pregnancy obtained after submitting the initial 
Pregnancy Form must be submitted by faxing an updated Pregnancy Form to Taiho 
Pharmacovigilance or designee. 
If outcome of the pregnancy is a stillbirth, congenital anomaly/birth defect, or a serious event in 
the mother, report as an SAE to Taiho Pharmacovigilance or designee. 
11.1.6. 
Medication Errors 
A medication error is defined as any accidental incorrect administration of a medicinal product. 
The error may be related to the administration of a wrong medication, nature of the medication, 
route of administration, dosage or frequency of the treatment as specified in this protocol 
(including omission of one or more administrations). 
• 
Medication errors with study drugs and concomitant medication treatment will 
not be recorded in the eCRF unless they result in an AE. 
• 
Medication errors with study drugs that result in an overdose will be captured as 
an AE in the eCRF.  
• 
Medication errors with study drugs that do not result in an AE should be 
handled as follows: 
− If it results in the omission of an administration, an incorrect dose (relative 
to that specified in this protocol), or the administration of more than the 


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prescribed dose (but does not meet the overdose criteria), it will be 
identified through the recording of study drug accountability data in the 
eCRF and does not need to be reported as an AE. 
− If it results in an overdose, incorrect route of administration, or 
administration of an incorrect study drug, it will be reported as an AE. 
Based on the above criteria, medication errors that are captured as an AE on the eCRF should be 
reported to Taiho Pharmacovigilance or designee within 24 hours from the time the investigator 
first becomes aware of its occurrence following the same process as described for the SAEs even 
if it does not meet any of the criteria of an SAE. 
11.1.7. 
Overdose 
An overdose with TAS-102 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 accidental or intentional overdose with TAS-102 regardless of whether it is associated with 
an AE (even if not fulfilling a seriousness criterion) is to be captured as an AE on the eCRF and 
reported to Taiho Pharmacovigilance or designee within 24 hours from the time the investigator 
first becomes aware of its occurrence following the same process as described for the SAEs. 
There is no known antidote available in case of TAS-102 overdose. Overdose should be 
managed aggressively with close monitoring and administration of prophylactic and 
symptomatic therapies to prevent or correct potential side effects. 
Overdose with nivolumab is defined as administering quantities above the 
recommended/schedule dosage per the nivolumab label, large enough to overwhelm the 
homeostasis, disrupting wellbeing, or causing severe illness and/or death. Any overdose with 
nivolumab associated with AEs should be reported to Taiho Pharmacovigilance or designee 
within 24 hours from the time the investigator becomes aware of the overdose. Included in this 
category are intentional overdose and accidental overdose by medication error.  
An accidental or intentional overdose for concomitant medication should only be reported if it is 
associated with an AE. 
11.2. 
Laboratory Evaluations 
11.2.1. 
Reporting and Evaluation of Laboratory Test Results 
Laboratory tests are to be performed as required per protocol. All laboratory values that are out 
of the normal range are to be evaluated for their clinical significance before exposing the patient 
to the next dose of study drug. 
The laboratory must provide normal reference ranges. 
Any laboratory abnormality that has a clinical impact on the patient, eg, results in delay of study 
drug dosing, study discontinuation, requires treatment because of abnormal values, or is 
considered by the investigator to be medically important, must be reported as an AE, unless it is 
considered a supporting laboratory result to a clinical diagnosis that is already reported as an AE. 


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If there is a question or concern, please call the Sponsor’s medical monitor. All laboratory data 
will be analyzed using NCI CTCAE grade criteria. 
11.2.2. 
Repeat Testing 
Repeat the evaluation of any clinically significant laboratory test, as clinically indicated, until the 
value returns to the baseline level or clinically stabilizes, or until another treatment is given. 
11.3. 
Physical Examination and Performance Status 
Perform physical examinations and performance status evaluations as described in the study 
procedures section of the protocol. If changes are observed, determine whether they meet the 
definition of an AE. All observations and evaluations should be documented. 
11.4. 
Vital Sign Measurements and Body Weight 
Verify and document vital sign measurements and body weight. If a clinically significant change 
is observed, repeat the measurement as clinically indicated and evaluate for its clinical relevance 
and whether it meets the definition of an AE. 
12. 
STATISTICS 
A Statistical Analysis Plan (SAP) that includes a more technical and detailed description 
(including templates for tables, listings, and figures) of the planned statistical summaries 
analyses will be prepared. 
12.1. 
Study Populations 
The study populations for all analyses are defined as: 
• Safety Population: Includes all patients who received at least 1 dose of study drug. It 
will be the primary population for safety analyses. 
• DLT Evaluable Population: Included all patients in the safety population in Stage 1, 
prior to confirming the recommended dose, who completed at least 1 cycle (28 days) 
of study treatment with at least 80% of the study treatment administered, unless the 
treatment was interrupted because of a DLT. 
• 
Efficacy Population: Includes all patients in the safety population who completed at 
least 6 months of tumor follow-up (evaluable irRC and/or RECIST assessments), 
unless the patient progressed or died before the 6-month follow-up. 
12.2. 
Study Endpoints 
12.2.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is irORR which is defined as the incidence of complete (irCR) 
and partial (irPR) responses in the efficacy population.  


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12.3.2. 
Efficacy Analysis 
Descriptive statistics such as incidence of responses (ORR and DCR) for each set of criteria, and 
associated 95% confidence intervals (CIs) will be provided.  
For the time to event endpoints, PFS (both sets of tumor response criteria), the Kaplan-Meier 
estimates will be derived and the associated 95% CIs will be provided. 
12.3.3. 
Safety Analyses 
The safety evaluations will focus on AEs and laboratory assessments. All patients included in the 
ITT Population will be evaluated in the safety analysis. 
Adverse events will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA) terminology and the severity of the toxicities will be graded according to the NCI 
CTCAE criteria, where applicable. Concomitant medications will be coded according to the 
World Health Organization Drug Dictionary. Hematological and chemistry laboratory 
parameters will be graded according to the NCI CTCAE criteria, where applicable.  
All AEs will be summarized (incidence) and listed by the system organ class, preferred term, 
toxicity/severity grade, and causal relationship to study drugs. In addition, separate summaries of 
the DLTs, at each dose level as applicable, SAEs, and grade 3 and 4 AEs will be presented. 
Absolute values, changes from baseline, and shifts for hematology and serum chemistry 
parameters will be summarized by cycle. In addition, worst severity grade, and time to event will 
also be summarized. 
12.4. 
Justification of Sample Size 
Sample size considerations are based on a 2-stage minimax Simon’s design, testing a null 
hypothesis (poor response) of 10% or less immune-related overall response (irOR) versus an 
alternative hypothesis (promising response) of 30% or greater irOR at an approximate 5% 1-
sided significance level and 80% power. In Stage 1 (futility assessment), enrollment will include 
15 evaluable patients for irOR assessment and accrual will continue to Stage 2, if at least 2 of 15 
(13%) patients respond (PR or CR). The probability of early stopping assuming poor response is 
about 55%. In Stage 2, if the Stage 1 futility boundary is exceeded, an additional 10 patients 
evaluable for irOR assessment will be enrolled, for a total of at least 25 evaluable patients. 
Further development will be considered promising if at least 6 of 25 (24%) patients respond. 
If the initial dose is not tolerated in the first 6 patients in Stage 1, an additional 6 DLT-evaluable 
patients will be enrolled at the reduced dose. Assuming a 10-15% non-evaluability for DLT 
and/or irRC assessment rate, a total of 30 to 35 patients is expected to be enrolled in the study. 
12.5. 
Interim Analyses 
An interim analysis for efficacy and futility is planned for the study after Stage 1 enrollment is 
completed. At the point that the ninth patient is enrolled (or a total of at least 15 patients 
evaluable for response assessment at the target dose), enrollment will stop, and there will be an 
assessment of safety and efficacy to determine whether the second stage of an additional 10 
patients evaluable for response will be enrolled. 


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13. 
ETHICS 
13.1. 
Ethical Considerations 
It is mandatory that all considerations regarding the protection of human subjects be carried out 
in accordance with the protocol, Good Clinical Practice (GCP), ICH Guidelines, the ethical 
principles that have their origin in the Declaration of Helsinki, and all applicable regulatory 
requirements. 
13.2. 
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 IRB/Independent Ethics Committee (IEC). 
13.3. 
Institutional Review Board/Independent Ethics Committee Approval 
The study must be approved by an appropriately constituted IRB/IEC, as required in Chapter 3 of 
the ICH E6 Guidelines. 
The IRB/IEC must provide written approval of the study. The written approval/favorable opinion 
should include protocol (title, number and version number), list of documents reviewed (eg, 
protocol, ICF, IB, curriculum vitae), 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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14. 
ADMINISTRATIVE CONSIDERATIONS 
14.1. 
Protocol Amendments 
No change to the protocol may be made without the agreement of Taiho Oncology, Inc. Any 
amendment to the original protocol will be made by Taiho Oncology, Inc. and will be submitted 
to the IRB/IEC and appropriate regulatory authorities for approval or notification. 
14.2. 
Curriculum Vitae 
All investigators and any sub-investigator(s) must provide Taiho Oncology, Inc. with current 
(within 2 years) signed and dated copies of their own curriculum vitae listing the experience, 
qualifications, and training before the beginning of the study. 
14.3. 
Administrative Structure 
The administrative structure of the study (eg, Contract Research Organizations) will be provided 
to all sites. 
14.4. 
Monitoring Procedures 
14.4.1. 
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. 
14.4.2. 
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 study site 
monitor (Clinical Research Associate) is to help the investigator and the Sponsor maintain a high 
level of ethical, scientific, technical, regulatory, and quality in all aspects of the trial. 
At regular intervals during the trial, the site will be contacted, through monitoring visits, letters 
or telephone calls by the Sponsor or its representatives to review study progress, investigator and 
patient’s compliance with requirements, and follow up on any issues to be addressed. During the 


TAS-102 
Protocol No. TO-TAS-102-203 
Metastatic Colorectal Cancer 
TO-TAS-102-203 Version 1.0 14 June 2016 
 
Page 73 of 80 
monitoring visits, source documents, informed consent, recruitment, SAE documentation and 
reporting, investigational product accountability, concomitant medications, AEs, eCRFs, and 
queries will be reviewed with the investigator. 
14.4.3. 
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, subject’s evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate and complete, microfiches, photographic negatives, 
microfilm or magnetic media, X-rays, subject files, and records kept at the pharmacy, at 
laboratories, and at medical-technical departments involved in the clinical trial). 
The informed consent will include a statement by which the patient allows the Sponsor’s duly 
authorized personnel, the IRB/IEC, and regulatory authorities to have direct access to original 
records supporting eCRF data. 
The use of pencil and correction fluids is not accepted for recording clinical research 
information. Corrections in source documents must be done by crossing out with a single line, 
then initialing and dating and recording the corrected information. 
14.4.4. 
Case Report Form 
Electronic case report forms will be provided by the Sponsor. 
Investigators will be provided with detailed eCRF Completion Guidelines that will identify the 
required data points to be collected, how to document them, and when the data should be 
documented. 
It is the responsibility of the investigator to maintain adequate and accurate eCRFs to record 
(according to the eCRF Completion Guidelines) all observations and other data pertinent to the 
clinical trial obtained during scheduled or unscheduled visits. All eCRFs should be fully 
completed to ensure accurate data interpretation.  
The computerized handling of the data by the Sponsor after entry of data via eCRFs may 
generate additional requests via electronic queries or other means to which the investigator is 
obliged to respond by confirming or modifying the data questioned. These requests with their 
responses will be included in the eCRFs held by the investigator and Sponsor. 
14.4.5. 
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 


TAS-102 
Protocol No. TO-TAS-102-203 
Metastatic Colorectal Cancer 
TO-TAS-102-203 Version 1.0 14 June 2016 
Page 74 of 80 
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. 
14.5. 
Archiving of Records 
The investigator is responsible for the retention of all study documents according to institutional 
policies, local laws, ICH guidelines E6 – GCP, Sections 4.9.4 and 4.9.5 and, for studies 
conducted under an Investigational New Drug application, the US Code of Federal Regulations 
Title 21 part 312.62. For more information on USA requirements and ICH Guidelines, please 
go to http://www.fda.gov and http://www.ema.europa.eu. 
The investigator agrees to inform the Sponsor in writing of the intention to remove or destroy 
any study-related records. Before contacting the Sponsor, the investigator must ensure that 
institutional and local requirements (for example, ICH Guidelines) have been satisfied. The 
Sponsor will evaluate the investigator’s request and provide authorization for destruction of such 
records to the investigator in writing. 
In the event that all retention of records requirements have been fulfilled, but the Sponsor 
requests that the investigator maintain the records for a longer period of time, additional 
arrangements will be made. 
14.6. 
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. 
14.7. 
Use and Publication of Study Results 
The investigator agrees that the Sponsor maintains the right to use the results of this study in 
their original form and/or in a global report for submission to governmental and regulatory 
authorities of any country. Data from this study must not be published without prior 
authorization from the Sponsor. 
The results of the study may be presented during scientific symposia or published in a scientific 
journal only after review by the Sponsor in accordance with the guidelines set forth in the 
applicable publication or financial agreement. 
14.8. 
Financial Disclosure 
Financial disclosure for clinical investigators will be obtained and record keeping of financial 
records will be in accordance with local regulatory requirements and US Code of Federal 
Regulations Title 21 part 54. 


TAS-102 
Protocol No. TO-TAS-102-203 
Metastatic Colorectal Cancer 
TO-TAS-102-203 Version 1.0 14 June 2016 
 
Page 75 of 80 
14.9. 
Termination of the Study 
If the Sponsor and/or the investigator should discover conditions arising during the study that 
indicate it should be terminated, an appropriate schedule for termination will be instituted. The 
Sponsor also reserves the right to discontinue this study for administrative reasons at any time. 
15. 
CONFIDENTIALITY AND DATA PROTECTION 
All information provided to the investigator by the Sponsor or Sponsor’s representatives, 
information produced during the clinical trial including, but not limited to the protocol, eCRF, 
IB, and the results obtained during the course of the trial is confidential. The members of the 
research team agree not to discuss such information in any way without prior written permission 
from the Sponsor. 
However, the submission of the protocol and necessary documentation to the IRB/IEC is 
permitted. The IRB/IEC members have the same obligation of confidentiality. 
The patient’s personal data and investigator’s personal data that may be included in the 
Sponsor’s database shall be treated in compliance with all applicable laws and regulations. 
When processing and archiving personal data pertaining to the investigator and or to the patients, 
the Sponsor or its representatives shall take all appropriate measures to safeguard and prevent 
access to this data by any unauthorized third party. 


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TAS-102 
Protocol No. TO-TAS-102-203 
Metastatic Colorectal Cancer 
TO-TAS-102-203 Version 1.0 14 June 2016 
Page 77 of 80 
17.
LIST OF REFERENCES
1. Heidelberger C, Parsons DG, Remy DC. Syntheses of 5-trifluoromethyluracil and 5-
trifluoromethyl-2’-deoxyuridine. J Med Chem. 1964;7:1-5.
2. Gottschling H, Heidelberger C. Fluorinated pyrimidines. XIX. Some biological effects of
5-trifluoromethyluracil and 5-trifluoromethyl-2’-deoxyuridine on escherichia coli and
bacteriophage T4B. J Mol Biol. 1963;7:541-60.
3. Reyes P, Heidelberger C. Fluorinated pyrimidines. XXVI. Mammalian thymidylate
synthetase: its mechanism of action and inhibition by fluorinated nucleotides. Mol
Pharmacol. 1965;1:14-30.
4. Heidelberger C, Anderson SW. Fluorinated pyrimidines. XXI. The tumor-inhibitory
activity of 5-trifluoromethyl-2’-deoxyuridine. Cancer Res. 1964;24:1979-85.
5. Heidelberger C, Boohar L, Kampschroer B. Fluorinated pyrimidines. XXIV. In vivo
metabolism of 5-trifluoromethyluracil-2-C14 and 5-trifluoromethyl-2’-deoxyuridine-2-
C14. Cancer Res. 1965;25:377-81.
6. Santi DV, Sakai TT. Thymidylate synthetase. Model studies of inhibition by
5-trifluoromethy-2’-deoxyuridylic acid. Biochemistry. 1971;10:3598-3607.
7. Fukushima M, Suzuki N, Emura T, Yano S, Kazuno H, Tada Y, et al. Structure and
activity of specific inhibitors of thymidine phosphorylase to potentiate the function of
antitumor 2’-deoxyribonucleosides. Biochem Pharmacol. 2000;59:1227-1236.
8. Mayer RJ, Van Cutsem, Falcone A, et al. Randomized trial of TAS-102 for refractory
metastatic colorectal cancer. N Engl J Med. 2015;372:1909-19.
9. American Cancer Society. Cancer Facts & Figures 2016. Atlanta: American Cancer
Society; 2016.
10. Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair
deficiency. N Engl J Med. 2015;372(26): 2509-20.
11. Benson AB 3rd, Ajani JA, Catalano RB, Engelking C, Kornblau SM, Martenson JA Jr, et
al. Recommended guidelines for the treatment of cancer treatment-induced diarrhea. J
Clin Oncol. 2004;22(14):2918-26.
12. American Society of Clinical Oncology, Kris MG, Hesketh PJ, Somerfield MR, Feyer P,
Clark-Snow R, et al. American Society of Clinical Oncology guidelines for antiemetics in
oncology: update 2006. J Clin Oncol. 2006;24:2932-47.
13. Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy
activity in solid tumors: immune-related response criteria. Clin Cancer Res.
2009;15(23):7412-20. Epub 2009 Nov 24.
14. Eishehaurer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New
response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1).
Eur J Cancer. 2009;45:228-47.







SAP_001.pdf: 
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Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan - Protocol #TO-TAS102-203 
October 31, 2017 
 
3 
 
TECHNICAL SUMMARY REPORT (TSR) 
 
 
Name of Sponsor/Company 
Taiho Oncology, Inc. 
Individual Study Table Referring 
to Part of the Dossier: 
Volume: 
(For National Authority Use 
Only): 
Name of Finished Product: 
LONGSURF 
Page: 
 
Name of Active Ingredient: 
trifluridine (FTD) and tipiracil 
hydrochloride (TPI)  
 
Protocol:  
TO-TAS-102-203  
 
Title Of Study:  
A Phase 2 Study with Safety Lead-in, Evaluating TAS-102 Plus Nivolumab in Patients with Microsatellite-
Stable Refractory Metastatic Colorectal Cancer 
 
Investigators: 
Study Center(s): about 10 
 


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Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan - Protocol #TO-TAS102-203 
October 31, 2017 
 
6 
 
Statistical methods: 
Study Populations 
The study populations for all analyses are defined as follows: 
• 
Safety Population: Includes all patients who received at least 1 dose of study drug. It will be the primary 
population for safety analyses. 
• 
DLT Evaluable Population: Includes all patients in the safety population in Stage 1, prior to confirming the 
recommended dose, who completed at least 1 cycle (28 days) of study treatment with at least 80% of the 
study treatment administered, unless the treatment was interrupted because of a DLT. 
• 
Efficacy Population: Includes all patients in the safety population who completed at least 6 months of tumor 
follow-up (evaluable irRC and/or RECIST assessments), unless the patient progressed or died before the 
6-month follow-up. 
Efficacy Analyses 
Tumor response assessments and disease progression will be evaluated in this study using the irRC and RECIST 
criteria. The RECIST and irRC response assessments will be performed by the investigators for the study. 
Descriptive statistics, such as incidence of responses (ORR and DCR), Kaplan-Meier estimates for PFS and OS, 
and associated 95% confidence intervals will be provided.  
Safety Analyses 
Simple descriptive statistics will be provided for safety endpoints, demographic/baseline characteristics, and 
study drug exposure. Safety endpoints will primarily include incidence of AEs and changes from baseline (grade 
changes) in clinical laboratory tests. 
 
 


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Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan - Protocol #TO-TAS102-203 
October 31, 2017 
 
9 
 
11.1.2. 
Definition of Treatment Emergent Adverse Event .....................................................38 
11.1.3. 
Definition of Serious Adverse Event ..........................................................................38 
11.1.4. 
Definition of Treatment Emergent Adverse Event of Special Interest .......................39 
11.2. 
Summaries of Adverse Event .....................................................................................39 
11.2.1. 
Overview of Adverse Events ......................................................................................39 
11.2.2. 
Summaries of Adverse Events ....................................................................................40 
11.2.3. 
DLT of the Combination Therapy ..............................................................................41 
11.3. 
Clinical Laboratory Data ............................................................................................41 
11.3.1. 
Hematology .................................................................................................................42 
11.3.2. 
Serum Chemistry ........................................................................................................43 
11.3.3. 
Urinalysis ....................................................................................................................43 
11.4. 
Vital Signs, Height, Weight ........................................................................................43 
11.5. 
Physical Examination .................................................................................................43 
11.6. 
ECG ............................................................................................................................43 
12. 
INTERIM ANALYSIS ...............................................................................................44 
 
 
 
 
 
 


Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan - Protocol #TO-TAS102-203 
October 31, 2017 
 
10 
 
LIST OF TABLES 
Table 1: 
List of Abbreviations ..................................................................................................11 
Table 2: 
Study Schedule ...........................................................................................................20 
Table 3: 
Hematology Laboratory Parameters ...........................................................................42 
Table 4: 
Serum Chemistry Laboratory Parameters ...................................................................43 
 


Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan - Protocol #TO-TAS102-203 
October 31, 2017 
 
11 
 
1. 
LIST OF ABBREVIATIONS 
Sample text is provided in the table below.  The list should be tailored to the specific 
requirements of the protocol and the terminology used in the analysis plan. 
Table 1: 
List of Abbreviations 
Abbreviation 
Term 
µmol or mkmol 
Micromole 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of Covariance 
ANOVA 
Analysis of Variance 
AST 
Aspartate Aminotransferase  
b.i.d. 
Twice Daily 
BP 
Blood Pressure 
BSA  
Body Surface Area  
bpm 
Beats per Minute 
BUN 
Blood Urea Nitrogen 
C 
Center 
°C 
Degrees Celsius 
Ca 
Calcium 
Cl 
Chloride 
CrCl  
Creatinine Clearance  
CMH 
Cochran Mantel-Haenszel 
COSTART 
Coding Symbols for Thesaurus of Adverse Reaction Terms 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
DCR  
Disease Control Rate  
DL 
Deciliter 
DLT 
Dose-Limiting Toxicity 
DOB 
Date of Birth 
dy 
Days 
EOS 
End of Study 
oF 
Degrees Fahrenheit 


Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan - Protocol #TO-TAS102-203 
October 31, 2017 
 
12 
 
g 
Grams 
GCP 
Good Clinical Practices 
GGT 
Gamma-Glutamyl Transferase 
HGB 
Hemoglobin 
ICD-9 
International Classification of Diseases – 9th Edition 
In 
Inches 
IR 
Immediate Release 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat Population 
irCR 
Immune-related complete response 
irOR 
Immune-related overall response 
irORR 
Immune-related overall response rate 
irPD 
Immune-related progressive disease 
irPR 
Immune-related partial response 
irRC 
Immune-related response criteria 
irSD 
Immune-related stable disease 
IU 
International units 
K 
Potassium 
Kg 
Kilogram 
L 
Liter 
Lb 
Pounds 
LDH 
Lactate Dehydrogenase 
LLN 
Lower Limit of Normal 
LOCF 
Last Observation Carried Forward 
mAb 
Monoclonal antibody 
mCRC 
Metastatic colorectal cancer 
MedDRA 
Medical Dictionary for Regulatory Activities Terminology 
meq 
Milliequivalent 
mg 
Milligrams 
mL 
Milliliter 
mmHg 
Millimeters of Mercury 
mo 
Months 
MRI 
Magnetic resonance imaging 


Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan - Protocol #TO-TAS102-203 
October 31, 2017 
 
13 
 
MSI 
Microsatellite instability 
MSS 
Microsatellite stable 
N 
Total Sample Size 
Na 
Sodium 
ng 
Nanograms 
NIMH 
National Institute of Mental Health 
OC 
Observed Cases 
OTC 
Over the Counter Medication 
PCS 
Potential Clinical Significance 
PP 
Per-Protocol Population 
PFS 
Progression free survival 
PR 
Partial response 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RECOURSE 
Refractory Colorectal Cancer Study 
(TPU-TAS-102-301 Phase 3 study; NCT01607957) 
RBC 
Red Blood Cell Count 
S 
Sex 
s.d. 
Standard Deviation 
SAE 
Serious Adverse Event 
SAS 
Statistical Analysis System  
SI 
System International 
SD 
Stable disease 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
SR 
Sustained Release 
TG 
Treatment Group 
ULN 
Upper Limit of Normal 
VAS 
Visual Analogue Scale 
VEGF 
Vascular endothelial growth factor 
WBC 
White Blood Cell Count 
WHO 
World Health Organization  
yr 
Years 
 


Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan - Protocol #TO-TAS102-203 
October 31, 2017 
 
14 
 
2. 
INTRODUCTION 
 
The purpose of this statistical analysis plan (SAP) is to describe the planned analyses and data 
displays to be included in the Clinical Study Report (CSR) for Protocol #TO-TAS102-203 
Protocol Revision Chronology: 
Protocol 
14 June 2016 
Original 
This SAP was developed per standard operating procedure S-CS-001 and guidance document G-
CS-001, G-CS-018, G-CS-020. 
All decisions regarding final analysis, as defined in this SAP document, will be made prior to 
Database Freeze (unblinding) of the study data.  
 


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CCI


Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan - Protocol #TO-TAS102-203 
October 31, 2017 
 
18 
 
Hematological toxicities 
1. Grade 4 neutropenia lasting > 7 days 
2. Grade 4 febrile neutropenia and fever ≥ 38°C for over 1 hour 
3. Grade 4 thrombocytopenia or grade 3 thrombocytopenia associated with bleeding or 
requiring transfusions 
Non-hematological toxicities  
1. Grade 3 or grade 4 non-hematologic toxicity (excluding alopecia, nausea, vomiting, 
diarrhea) 
2. Grade 3 or grade 4 nausea/vomiting lasting > 48 hours and uncontrolled by aggressive 
anti-emetic therapy, including serotonin 5-HT3 receptor antagonists (e.g., ondansetron) 
3. Grade 3 or grade 4 diarrhea lasting > 48 hours and unresponsive to antidiarrheal 
medication 
Drug-related toxicities 
1. Any drug-related toxicity resulting in > 2 weeks delay in initiation of Cycle 2 (ie, cannot 
start Cycle 2 until Day 43 or later) 
2. Any drug-related toxicity that prevents completion of 80% compliance for either drug in 
Cycle 1 
The combination of TAS-102 and nivolumab is expected to trigger immune mediated responses, 
which require activation of the immune system before the observation of clinical responses. Such 
immune activation may take weeks to months to become evident. Some patients may have an 
objective volume increase of tumor lesions or other disease parameters within weeks after the start 
of dosing. Such patients may not have had sufficient time to develop immune system activation 
or, in some patients, tumor volume or other disease parameter increases may represent infiltration 
of lymphocytes into the original tumor. Therefore, tumors will be evaluated with both RECIST 
and irRC to determine objective responses.  
TAS-102 (35 mg/m2/dose) will be administered orally BID, within 1 hour after completion of 
morning and evening meals, for 5 days a week with 2 days rest for 2 weeks, followed by a 14 day 
rest, repeated every 4 weeks. Nivolumab (3 mg/kg/dose) will be administered intravenously over 
60 minutes every 14 days on Day 1 and Day 15. 
A contrast-enhanced computed tomography (CT) scan of the chest and abdomen (pelvis if 
clinically indicated) within 28 days before Day 1 of Cycle 1 and every 2 cycles thereafter will be 
performed during study treatment. On-site tumor assessments will be performed by the investigator 
or local radiologist. Tumor assessments will be analyzed using RECIST and irRC. For patients 
who discontinue treatment for reasons other than radiologic disease progression, every effort 
should be made to perform an end-of-treatment tumor assessment before the start of new anticancer 
therapy. Patients that discontinue treatment for reasons other than disease progression should 
continue to be followed for tumor response every 2 cycles until the patient develops radiologic 
disease progression (or death) or initiation of new anticancer therapy (whichever occurs first). 
Tumor assessments should be performed according RECIST and irRC. If the CT scan was obtained 


Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan - Protocol #TO-TAS102-203 
October 31, 2017 
 
19 
 
before the patient signed the informed consent form (ICF), the CT scan may be used if the date of 
the scan is within 28 days before Day 1 of Cycle 1. 
Survival status (alive or dead) should be obtained at scheduled 8-week time intervals until study 
discontinuation criteria are met.  
Standard safety monitoring will be performed and AEs will be graded using the National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. 
 


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Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan - Protocol #TO-TAS102-203 
October 31, 2017 
 
23 
 
 
4.2. 
Sample Size Considerations 
4.2.1. 
Sample Size Justifications 
Sample size considerations are based on a 2-stage minimax Simon’s design, testing a null 
hypothesis (poor response) of 10% or less immune-related overall response (irOR) versus an 
alternative hypothesis (promising response) of 30% or greater irOR at an approximate 5% 1-sided 
significance level and 80% power. In Stage 1 (futility assessment), enrollment will include 15 
evaluable patients for irOR assessment and accrual will continue to Stage 2, if at least 2 of 15 
(13%) patients respond (PR or CR). The probability of early stopping assuming poor response is 
about 55%. In Stage 2, if the Stage 1 futility boundary is exceeded, an additional 10 patients 
evaluable for irOR assessment will be enrolled, for a total of at least 25 evaluable patients. Further 
development will be considered promising if at least 6 of 25 (24%) patients respond. 
If the initial dose is not tolerated in the first 6 patients in Stage 1, an additional 6 DLT-evaluable 
patients will be enrolled at the reduced dose. Assuming a 10-15% non-evaluability for DLT and/or 
irRC assessment rate, a total of 30 to 35 patients is expected to be enrolled in the study. 
 
 
4.3. 
Randomization 
No randomization will be performed because it is the single arm Study. 
 
 
4.4. 
Clinical Assessments 
 
4.4.1. 
Height, Weight and Vital Signs 
Patient’s vital signs (blood pressure, heart rate, body temperature, and respiration rate), height and 
body weight will be collected at the time points presented in the Study Schedule (Table 2 ). All 
the vital signs will be taken in a position that is consistent for all time points for each patient. 
 
4.4.2. 
ECOG Performance Status 
An ECOG performance status score will be collected at the following time points (refer to Table 2): 
• Within 28 days before study drug administration on Day 1 of Cycle 1 
• Obtain within 24 hours before the start of study drug administration on Day 1 in every 
cycle and Day 15 
• End of Treatment visit (if applicable) 


Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan - Protocol #TO-TAS102-203 
October 31, 2017 
 
24 
 
• 30-day Safety Follow-up visit 
 
4.4.3. 
Laboratory Evaluations 
Clinical laboratory assessments will include hematology, serum chemistry and urinalysis tests 
described below. 
 
4.4.3.1. 
Hematology 
Blood samples for hematology assessments will be obtained at the following time points and 
when clinically indicated:  
• Within 7 days before Day 1 of Cycle 1 (Laboratory results obtained before signing 
the ICF may be used if the results were obtained within 7 days before Day 1 of 
Cycle 1.) 
• Day 15 of each cycle 
• Beginning with Cycle 2, obtain blood samples within 24 hours before the start of 
study drug administration on Day 1 of every cycle 
• End of Treatment visit (if applicable) 
• 30-day Safety Follow-up visit 
In addition, the criteria for repeat testing will be followed as needed. Hematology parameters that 
will be measured are listed in Section 11.3.1. 
4.4.3.2. 
Serum Chemistry 
Blood will be collected at the following time points for serum chemistry assessments: 
• Within 7 days prior to Day 1 of Cycle 1 (Laboratory results obtained before signing 
the ICF may be used if the results were obtained within 7 days before Day 1 of 
Cycle 1.) 
• Day 15 of each cycle 
• For all subsequent cycles, obtain within 24 hours before the start of study drug 
administration on Day 1 of every cycle 
• End of Treatment Visit (if applicable) 
• 30-day Safety Follow-up Visit. 
Hematology parameters that will be measured are listed in Section 11.3.2. 
4.4.3.3. 
Urinalysis 
Urine samples for qualitative (dipstick) analysis will be collected to run tests for protein, glucose, 
urobilinogen, red blood cell count, and white blood cell count, at the time points listed below: 


Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan - Protocol #TO-TAS102-203 
October 31, 2017 
 
25 
 
• Within 7 days before Day 1 of Cycle 1 (Laboratory results obtained before signing 
the ICF may be used if the results were obtained within 7 days before Day 1 of 
Cycle 1.) 
• As clinically indicated thereafter 
If a new abnormality is identified, quantitative urinalysis should be performed. 
 
 


Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan - Protocol #TO-TAS102-203 
October 31, 2017 
 
26 
 
5. 
PLANNED ANALYSES 
5.1. 
Interim Analyses 
An interim analysis for efficacy and futility is planned for the study after Stage 1 enrollment is 
completed. At the point that at least 15 patients are enrolled evaluable for response assessment at 
the target dose, enrollment will stop, and there will be an assessment of safety and efficacy to 
determine whether the second stage of an additional 10 patients evaluable for response will be 
enrolled. 
 
 
5.2. 
Final Analyses 
Final analysis (once the decision is made to proceed with Stage 2) will be performed according 
to the instructions presented in the current version of SAP 
 
 
 


Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan - Protocol #TO-TAS102-203 
October 31, 2017 
 
27 
 
6. 
STUDY POPULATIONS 
6.1. 
Safety Population 
The “Safety (SAF) Population” is defined as all subjects who receive at least one dose of study 
medication. This population will be used in the assessment and reporting of safety data.  
 
 
6.2. 
DLT Evaluable (DLTE) Population 
DLT Evaluable (DLTE) Population is defined as all subjects in the safety population in Stage 1, 
prior to confirming the recommended dose, who completed at least 1 cycle (28 days) of study 
treatment with at least 80% of the study treatment administered, unless the treatment was 
interrupted because of a DLT.  
 
 
6.3. 
Efficacy Population 
Efficacy Population is defined as all subjects in the safety population who completed at least 6 
months of tumor follow-up (evaluable irRC and/or RECIST assessments), unless the patient 
progressed or died before the 6-month follow-up. This population will be used for efficacy 
analyses.  
 
 
 


Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan - Protocol #TO-TAS102-203 
October 31, 2017 
 
28 
 
7. 
DERIVED AND TRANSFORMED DATA 
 
7.1. 
Age (relatively to the first dose taken) 
Subject’s age in years (whole number, no decimals) will be calculated using date of the first dose 
taken as the reference point. An appropriate SAS expression recommended by SAS Institute for 
calculation of a correct age of a person will be applied to calculate the age. The expression is 
supposed to take into account leap years and other peculiarities of the Gregorian calendar. The 
formula reads as follows:  
  Age (year) = INT(INTCK(“MONTH”, date of informed consent – date of birth)/12)  
    IF MONTH(date of birth) = MONTH(date of informed consent)  
      THEN Age = Age - (DAY(date of birth) > DAY(date of informed consent));  
where INT( ) function (SAS) returns the integer part of the result, INTCK(“MONTH”, DATE2 – 
DATE1) function (SAS) returns a number of months between DATE1 and DATE2, MONTH( ) 
and DAY( ) – standard SAS functions returning month and day of the month of the argument, 
correspondingly. 
 
 
7.2. 
Study Day 
If the date of interest (e.g., start of the cycle #i, onset of SAE, lab test date, etc.) occurs on or after 
the first dose date then study day will be calculated as (date of interest – date of first dose) + 1. If 
the date of interest occurs prior to the first dose date then study day will be calculated as (date of 
interest – date of first dose). There will be no study day 0. 
 
 
7.3. 
Baseline 
Baseline assessment is defined as the last valid/non-missing measurement obtained prior to 
administration of the first dose of study medication. If the time of the medication and/or time of 
the assessment is not available, baseline is defined as last valid measurement obtained prior to or 
on the date of administration of the first dose of study medication  
If the multiple results are available that were obtained at the same date and there is no reasonable 
way to uncover their chronological order, the average value will be used as a baseline (for 
continuous variables).  
All recorded valid data will be considered for analysis of baseline values (including test performed 
at unscheduled visits). 
 


Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan - Protocol #TO-TAS102-203 
October 31, 2017 
 
29 
 
7.4. 
Change From Baseline 
Change from baseline is calculated as (post-baseline result – baseline result).  
Percent change from baseline is calculated as (change from baseline/baseline result * 100).  
If either the baseline or the post-baseline result is missing, the change from baseline and/or 
percentage change from baseline is set to missing as well. 
 
 
7.5. 
Day 1  
The date of first administration of study medication (first dosing) is defined as Day 1 of treatment 
(D1). The date of first administration of study medication (first dosing) within the Cycle N is 
defined as Day 1 of the Cycle N (CND1). 
 
 
7.6. 
End of Study Day 
If the date of End of Study (EOS) occurs on or after the first dose date then EOS day will be 
calculated as (EOS date – date of first dose) + 1. If the EOS date occurs prior to the first dose date 
then EOS day will be calculated as (EOS date – date of first dose).  
 
 
7.7. 
Visit Windows 
Windows mentioned in the protocol of the present study are used for operational purposes only 
and they will not be utilized for any analysis.  
For the purpose of analysis lab tests, vital examinations, ECOG performance status, tumor 
assessments, etc. will be assigned to an appropriate cycle according to the start date of this cycle 
and the start date of the next one. In general, Cycle N will be defined as all days starting with Day 
2 of the Cycle N until the Day 1 (including) of the Cycle (N+1). Detailed instructions how an 
assignment should be performed will be presented under the “Data Handling and Programming 
Specifications” document.  
For the purpose of presentation of AE and/or CM in the listings an assignment to the appropriate 
cycle will be performed. In general, Cycle N will be defined as all days starting with Day 1 of the 
Cycle N till the day (including) before Day 1 of the Cycle (N+1). For the last cycle a standard 30 
days window after the last dose will be applied. Detailed instructions how an assignment should 
be performed will be presented under the “Data Handling and Programming Specifications” 
document. 
 
 


Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan - Protocol #TO-TAS102-203 
October 31, 2017 
 
30 
 
7.8. 
Multiple Assessments 
When valid multiple assessments within the same cycle (refer to ) are available their presentation 
will depend on the specific output. Detailed instruction for analysis will be presented in the “Data 
Handling and” document. 
 


Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan - Protocol #TO-TAS102-203 
October 31, 2017 
 
31 
 
8. 
GENERAL ANALYSIS 
8.1. 
Subject Disposition 
A complete accounting of subject participation in the study will be presented according to 
requirements provided by ICH Guideline for Industry, 1996 (Structure and Content of Clinical 
Study Reports [CSR]). The purpose of this table is to track subjects from informed written consent 
through their exit from the study and to account for subject evaluation in major analyses of efficacy 
and safety, including reasons for early study termination or withdrawal. 
 
 
8.2. 
Dose-Limiting Toxicity 
The following TAS-102 related AEs will be considered DLTs (only AEs occurring in Cycle 1 will 
be DLT evaluable): 
Hematological toxicities 
1. Grade 4 neutropenia lasting > 7 days. 
2. Grade 4 febrile neutropenia and fever ≥ 38°C for over 1 hour. 
3. Grade 4 thrombocytopenia or grade 3 thrombocytopenia associated with bleeding or 
requiring transfusions. 
Non-hematological toxicities  
1. Grade 3 or grade 4 non-hematologic toxicity (excluding alopecia, nausea, vomiting, 
diarrhea). 
2. Grade 3 or grade 4 nausea/vomiting lasting > 48 hours and uncontrolled by aggressive anti-
emetic therapy, including serotonin 5-HT3 receptor antagonists (e.g., ondansetron). 
3. Grade 3 or grade 4 diarrhea lasting > 48 hours and unresponsive to antidiarrheal 
medication. 
Drug-related toxicities 
1. Any drug-related toxicity resulting in > 2 weeks delay in initiation of Cycle 2 (i.e., cannot 
start Cycle 2 until Day 43 or later). 
2. Any drug-related toxicity that prevents completion of 80% compliance for either drug in 
Cycle 1. 
 
 
8.3. 
Demographic and Baseline Characteristics 
The demographic and baseline characteristics will be summarized and tabulated. The list of 
characteristics that will be summarized include but are not limited to the following:  
• Gender  


Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan - Protocol #TO-TAS102-203 
October 31, 2017 
 
32 
 
• Age (years) (#)  
• Age group (<65 years, >=65 years)  
• Race (White, Black, Asian, American Indian or Alaska Native, Native Hawaiian or 
Other Pacific Islander, Not Collectable, Other)  
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not Collectable, Unknown)  
• ECOG status at baseline (0, 1)  
• Height (cm) (#)  
• Weight (kg) (#)  
• BSA (m2) (#)  
(#) indicates a continuous variable to be summarized. 
 
 
8.4. 
Subject Inclusion and Exclusion Criteria 
Information regarding subject’s inclusion and exclusion criteria will be listed on an individual 
subject basis.  
Patients who were dosed but have not met all inclusion and/or exclusion criteria will be identified 
and listed and inclusion/exclusion criteria that were not met. 
Listings only. 
 
 
8.5. 
Medical History 
 
8.5.1. 
Cancer Medical History  
 
• 
Primary Cancer Type (colon, rectum, colorectal) 
• 
Location of primary tumor (Cecum, Ascending colon, Transverse colon, Descending 
Colon, Sigmoid colon, Rectum, Unknown, Other) 
• 
Histology type (refer to appropriate CRF page) 
• 
Time from initial diagnosis to the first dose (#) 
• 
Time from confirmed first metastases to the first dose (#) 
• 
Number of metastatic sites (1-2, ≥3) 
• 
RAS status at baseline (Wild, Mutant) 
• 
KRAS status at baseline (Wild, Mutant) 
• 
NRAS status at baseline (Wild, Mutant) 
• 
BRAF status at baseline 


Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan - Protocol #TO-TAS102-203 
October 31, 2017 
 
33 
 
 
8.5.2. 
Non-Cancer Medical History  
All information regarding subjects non-cancer medical history will be presented in the listings 
only.  
 
 
8.6. 
Prior, Concomitant, and Survival Follow-up Medications and 
Therapies  
 
8.6.1. 
Prior Anti-Cancer Therapies  
Prior anti-cancer therapies will be summarized for the safety population and will include the 
following: 
• 
Number of prior regimens (<2, 2, 3, 4≤) 
• 
Prior surgery (Yes, No) 
• 
Prior Radiotherapy (Therapeutic, Palliative, None) 
 
8.6.2. 
Prior and Concomitant Medications 
Prior and concomitant medications will be listed for the safety population. All concomitant 
medications and therapies will be coded using WhoDDE (September 2015) and summaries will 
use the system organ class and preferred term codes, as appropriate.  
 
8.6.3. 
Post-study Anti-cancer Treatment  
Post-study anti-cancer treatments initiated during the follow-up period (ref Figure 2) will be listed. 
The time to start of the new anti-cancer treatment will be defined as the start date of the new anti-
cancer therapy minus the date of last dose of study medication + 1. If the start date of the new anti-
cancer treatment is missing, the time to start of anti-cancer therapy will be missing for that patient. 
 
 
8.7. 
Exposure to Study Medication  
Exposure will be summarized and tabulated for the safety population for each study drug. Study 
drug administration for number of cycles initiated will be summarized by cycle and overall for 
each study drug. Dose level by cycle will be summarized for each study drug. Patients with at least 
one dose reduction and first cycle with target dose reduction will be summarized for each study 
drug. The total dose administered (mg/m2), dose intensity (mg/m2/wk), relative dose intensity 
(ratio to planned) will be summarized. 


Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan - Protocol #TO-TAS102-203 
October 31, 2017 
 
34 
 
 


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Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan - Protocol #TO-TAS102-203 
October 31, 2017 
 
36 
 
9.4.2. 
Immune-related Progression-Free Survival (irPFS) 
Immune-related progression free survival is defined as the time (in months) from the date of first 
dose of TAS-102 until the date of the investigator-assessed radiological disease progression (based 
on irRC) or death due to any cause. Patients who are alive with no disease progression at the 
moment of the analysis cut-off date will be censored at the date of the last tumor assessment. 
Patients with clinical but not radiologic evidence of progression will be censored at the date of the 
last radiologic tumor assessment. An additional analysis using clinical progression as an event will 
be performed in addition to the main examination described above.  
PFS in the safety population will be summarized using Kaplan Meier estimates and further 
characterized in terms of the median and survival probability at 2, 4, 6, 8 months, along with the 
corresponding 2-sided 95% CI for the estimates. Confidence intervals for median survival are 
based upon the methods of Brookmeyer and Crowley. 
 
9.4.3. 
RECIST Progression-Free Survival (RECIST PFS) 
RECIST-based progression free survival is defined as the time (in months) from the date of first 
dose of TAS-102 until the date of the investigator-assessed radiological disease progression (based 
on RECIST 1.1) or death due to any cause. Results will be summarized in the same manner as it 
was described in Section 9.4.2 above for the irPFS.  
 
9.4.4. 
Disease Control Rate (DCR) 
Disease Control Rate will be presented for immune response evaluation and RECIST-based 
evaluation. DCR is defined as the proportion of patients with objective evidence of radiologic CR, 
PR or SD and is based on the Overall Best Response from each patient as determined from 
investigator response assessments. Disease control rate (DCR) will be analyzed using the same 
methodology as that for ORR. 
 
9.4.5. 
Overall Survival (OS) 
Overall Survival (OS) is defined as the time from the first dose of the study treatment to the death 
in the safety population. Patients alive at the time of the study discontinuation will be censored. 
Survival results will be listed only. 
 


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Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan - Protocol #TO-TAS102-203 
October 31, 2017 
 
38 
 
11. 
SAFETY AND TOLERABILITY 
11.1. 
Adverse Events  
11.1.1. 
Definition of Adverse Event  
An adverse event (AE) is defined as any untoward medical occurrence in a clinical investigation 
of a patient that may or may not have casual relationship with treatment (21 CFR 312.32(a)). An 
AE can therefore be any unfavorable and unintended sign (including a clinically significant 
abnormal laboratory finding), symptom, or disease temporally associated with the clinical study, 
independent of the relationship to the investigational product.  
Any AE that started after signing of informed consent and before treatment start date will be 
presented in the Medical History section of the summary tables.  
Any adverse event starting more than 30 days after the last dose of study medication will be 
excluded from the summary analyses, unless the event caused patient discontinuation from the 
study.  
 
11.1.2. 
Definition of Treatment Emergent Adverse Event  
Treatment-emergent adverse events (TEAEs) will be defined as those events, which meet one of 
the two criteria:  
• started on or after treatment start date (first dose of study medication  Cycle1, Day 1) 
through 30 days after treatment end date (last dose of study medication)  
• started before treatment start date and became worse (more severe) after treatment start 
date (first dose of study medication  Cycle1, Day 1) through 30 days after treatment end 
date (last dose of study medication)  
 
Only treatment-emergent adverse events will be summarized, non-treatment emergent AEs will 
be listed only.  
 
11.1.3. 
Definition of Serious Adverse Event  
SAE, as per FDA regulations defined in 21 CFR 312.32(a), is considered “serious” if, in the view 
of either the Investigator or Sponsor, it results in any of the following outcomes: death, a life-
threatening adverse event, in-patient hospitalization or prolongation of existing hospitalization, a 
persistent or significant /incapacity or substantial disruption of the ability to conduct normal life 
functions, or a congenital anomaly/birth defect. Important medical events that may or may not 
result in death, be life-threatening, or require hospitalization may be considered a serious adverse 
drug experience when, based upon appropriate medical judgment, they may jeopardize the subject 
and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition.  
If either the Sponsor or Investigator believes that the event is serious, the event must be considered 
serious and evaluated by the Sponsor for expedited reporting (21 CFR 312.32(a) and 312.32(c) 
(1)).  
 


Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan - Protocol #TO-TAS102-203 
October 31, 2017 
 
39 
 
11.1.4. 
Definition of Treatment Emergent Adverse Event of Special Interest  
The TEAEs of special interest (TEAESI) will be selected based on the list of appropriate MedDRA 
terms provided by the Sponsor. The TEAESI will include, but will not be limited by, following 
items: Hepatobiliary Abnormality-Related, Renal Impairment, Hematologic Impairment-Related 
or Infection-Related adverse events. The full list will be provided before the database of the study 
is locked. The lists of terms (PTs) will be located in Appendices. 
 
 
11.2. 
Summaries of Adverse Event  
All adverse event verbatim text will be coded and classified by system organ class (SOC) and 
preferred term (PT) using the MedDRA (Version 18.1). AE summary tables will use the following 
algorithms for counting subject events within the summary tables:  
• Preferred term rows: Each subject is counted once within each unique preferred term at the 
maximum grade. Subjects experiencing the same AE preferred term several times with 
different grades would only be counted once with the maximum grade.  
• System organ class rows: Each subject is counted only once in the maximum grade at each 
system organ class level, although they may have several different preferred term events 
within the same SOC.  
• Any event row: Each subject with an event is counted only once at the maximum grade 
although they may have several events. For drug related AE table, each subject with an 
event is counted only once at the most related although they may have several events.  
 
Unless specified otherwise, the summaries of adverse events will be based on the safety 
population.  
TEAEs will be presented in alphabetical order of System Organ Class and within each System 
Organ Class, in decreasing order of the total number of combined TAS-102 patients who 
experienced each TEAE at the preferred term level. 
 
 
11.2.1. 
Overview of Adverse Events  
AE incidence will be calculated by the worst CTCAE grade at every level of summarization (SOC 
or PT), i.e., if a patient has multiple occurrences of the same AE with different toxicity grades 
during a period, the patient will be accounted for in AE frequency tabulation in the worst grade. 
An overall summary table (overview) of all adverse events will be presented, summarizing:  
• Total number of TEAE  
• Total number of TESAE  
• Total number of DLT 
• Total number and percentage of subjects with at least one TEAE  


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Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan - Protocol #TO-TAS102-203 
October 31, 2017 
 
41 
 
• TEAEs (all and grades 3-5) leading to death summarized by SOC and PT (SAF 
population; listing only)  
• Serious TEAEs (all and grades 3-5) summarized by SOC and PT (SAF population)  
• Serious TEAEs (all and grades 3-5) related to study drug summarized by SOC and PT, 
(two separate table – for TAS-102 and Nivolumab; SAF population)  
 
11.2.3. 
DLT of the Combination Therapy 
Dose-Limiting Toxicity are defined according to the criteria described in the Study Protocol. All 
DLT results (if any) will be presented in the form of listings.  
 
 
11.3. 
Clinical Laboratory Data 
All laboratory values will be converted to SI units and classified as normal, low, or high based on 
normal ranges (converted to SI units if needed) supplied by the laboratory performed the test. 
Laboratory categories will be expressed in terms of the L (below LLN), N (between LLN and 
ULN) and H (above ULN) classifications for numerical measurements and normal, abnormal for 
characteristic measurements. Additionally, abnormal laboratory values will be presented 
according to the NCI CTCAE v4.3 laboratory toxicity grades. All laboratory data will be coded 
with CTCAE grade, where CTCAE grading is available. 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 
 
 will be utilized and flagged in the database.  
Changes in the NCI CTCAE grade from baseline to the worst grade recorded post-baseline (by 
visit and overall) will be tabulated in the form of shift tables. Applicable bi-directional laboratory 
tests will be represented by two one-directional separate tests (hypo- and hyper-). The definition 
of hypo- and hyper-toxicity grades follows the definition provided by the NCI CTCAE v4.3 
definition document. Laboratory tables with CTCAE grading will only be produced for laboratory 
parameters for which CTCAE grading is available. An overall shift summary will also be provided 
comparing baseline to worst post-dose toxicity observed across all visits.  
The number and percentage of patients with laboratory abnormalities of Grade 3 or Grade 4 that 
worsened from baseline by ≥ 1 grade or are missing at baseline will be summarized. For patients 
with more than 1 value recorded in a cycle/group of cycles, the abnormality with the highest grade 
will be selected for tabulation.  
If multiple results of an arbitrary test of clinical labs are reported for within analysis window then 
the reported value will be derived as follows (hypo- and hyper- directions for bi-directional tests 
will be presented separately):  
 
• For CTCAE Laboratory Toxicity Grade the result with the highest CTCAE grade will be 
reported. If there are two or more results of the same CTCAE grade then the 


Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan - Protocol #TO-TAS102-203 
October 31, 2017 
 
42 
 
largest/smallest result will be used for summary tables. If there are two or more results of 
the same CTCAE grade and the same values then the latest result will be used.  
• For the following clinical lab tests (Hematocrit - having no appropriate CTCAE grading) 
the result with the largest/smallest (i.e., most abnormal) value will be reported in 
hyper/hypo one-directional version of the test, correspondingly. If there are two or more 
results showing the same value then the latest result will be used.  
• For other bi-directional clinical lab tests the result with the abnormal value will be reported 
in final output. If there are two or more abnormal results then the latest result will be used  
• For one-directional clinical lab tests the result with the most abnormal value 
(largest/smallest – depending on test direction) will be reported in final output. If there are 
two or more abnormal results showing the same value then the latest result will be used.  
 
All observed (including unscheduled) laboratory parameters will be listed. The supportive listings 
for hematology, serum chemistry, and urinalysis will include the subject number, subject age and 
sex; laboratory test, lab test units, lab test result, and the lower and upper limits of normal (provided 
by the local laboratory where the test was performed); sample collection date, time of collection, 
and relative day; type of visit. The listing will be sorted by laboratory parameter, subject number, 
and by time points within laboratory parameter and subject number. Abnormal results will be 
flagged based on the categories mentioned above. 
 
11.3.1. 
Hematology 
The following tests (Table 4 ) will be summarized and tabulated, all other hematology tests will be 
listed only: 
Table 3: 
Hematology Laboratory Parameters 
Hemoglobin  
White blood cell (WBC) count with 
differential (automated): 
Hematocrit 
Neutrophils 
Platelets 
Lymphocytes 
Red blood cell count 
Monocytes 
 
Eosinophils 
 
Basophils 
 
 
 


Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan - Protocol #TO-TAS102-203 
October 31, 2017 
 
43 
 
11.3.2. 
Serum Chemistry 
The following tests (Table 4 ) will be summarized and tabulated, all other serum chemistry tests will 
be listed only: 
Table 4: 
Serum Chemistry Laboratory Parameters 
ALT  
Creatinine 
Chloride 
AST  
Blood urea nitrogen 
Calcium 
Alkaline phosphatase 
Sodium 
Albumin 
Bilirubin 
Potassium 
Glucose 
Thyroid stimulating hormone 
Thyroxine 4 (T4) 
 
 
In case of elevation in total bilirubin, fractionation (direct/indirect) should be performed. 
 
11.3.3. 
Urinalysis 
Urinalysis (qualitative [dipstick] analysis) will include tests for protein, glucose, urobilinogen, 
RBC, and WBC. If a new abnormality is identified during the Study, quantitative urinalysis should 
be performed. 
 
 
11.4. 
Vital Signs, Height, Weight 
Height, weight and vital signs will be listed only. Vital signs (VS) will include: systolic/diastolic 
blood pressure, body temperature, heart rate and respiratory rate.  
 
 
11.5. 
Physical Examination 
According to the recent updates in CDISC “Guide for implementation” the results of physical 
examination (abnormalities only) are collected as part of adverse events or medical history (based 
on the appropriate dates and time).  
 
 
11.6. 
ECG 
ECG data were not collected and will not be analyzed in any way. 
 
 


Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan - Protocol #TO-TAS102-203 
October 31, 2017 
 
44 
 
12. 
INTERIM ANALYSIS 
An interim analysis for efficacy and futility is planned for the study after Stage 1 enrollment is 
completed. At the point that the ninth patient is enrolled (or a total of at least 15 patients evaluable 
for response assessment at the target dose), enrollment will stop, and there will be an assessment 
of safety and efficacy to determine whether the second stage of an additional 10 patients evaluable 
for response will be enrolled. 
The planned interim analysis will be performed according to the algorithms presented in the 
current SAP. No separate document (e.g., SAP for Interim Analysis) for the interim analysis will 
be produced.  
 
 










Taiho Oncology, Inc. 
 
 
Statistical Analysis Plan - Protocol #TO-TAS102-203 
 
October 31, 2017 
 
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