Clinical trial NCT03278106
Conditions: Cholangiocarcinoma Stage III Gallbladder Cancer AJCC v7 Stage IIIA Gallbladder Cancer AJCC v7 Stage IIIB Gallbladder Cancer AJCC v7 Stage IV Gallbladder Cancer AJCC v7 Stage IVA Gallbladder Cancer AJCC v7 Stage IVB Gallbladder Cancer AJCC v7
Sponsor: Mayo Clinic
Start date: 2017-10-20; Completion date: 2021-09-16
Enrollment: 28 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well trifluridine/tipiracil hydrochloride combination agent TAS-102 (TAS-102) works in treating participants with biliary tract cancers that have spread to other places in the body. Drugs used in the chemotherapy, such as trifluridine/tipiracil hydrochloride combination agent TAS-102, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

Detailed description:
PRIMARY OBJECTIVES:

I. Determine the efficacy of trifluridine/tipiracil hydrochloride combination agent TAS-102 (FTD/TPI \[TAS-102\]) in patients with refractory cholangiocarcinoma using progression-free survival at 16 weeks.

SECONDARY OBJECTIVES:

I. Assess the safety and tolerability of FTD/TPI (TAS-102) in patients with refractory cholangiocarcinoma through adverse event monitoring.

II. Further explore the efficacy of FTD/TPI (TAS-102) in patients with refractory cholangiocarcinoma by overall response rates, progression-free survival, and overall survival.

TERTIARY OBJECTIVES:

I. Determine if circulating tumor cells (CTCs) or cell-free deoxyribonucleic acid (DNA) (cfDNA) at baseline correlates with prognosis or response to therapy.

II. Determine if change in CTCs or cfDNA correlates with efficacy endpoints. III. Determine if different mutational status of the tumor will affect efficacy endpoints.

OUTLINE:

Patients receive trifluridine/tipiracil hydrochloride combination agent TAS-102 orally (PO) twice daily (BID) on days 1-5 and 8-12. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 3 months for up to 2 years.

Arms: arm 1: Patients receive trifluridine/tipiracil hydrochloride combination agent TAS-102 orally PO BID on days 1-5 and 8-12. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Laboratory Biomarker Analysis intervention 2: Trifluridine/Tipiracil Hydrochloride Combination Agent TAS-102
Intervention descriptions: intervention 1: Correlative studies intervention 2: Given PO

Protocol documents:
Prot_SAP_000.pdf: 




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Table of Contents 
Phase II Trial of FTD/TPI (TAS-102) in Biliary Tract Cancers ................................................................... 1 
Protocol Resources ........................................................................................................................................ 2 
Table of Contents .......................................................................................................................................... 3 
Schema .......................................................................................................................................................... 4 
1.0 
Background ................................................................................................................................... 5 
2.0 
Goals ............................................................................................................................................. 8 
3.0 
Patient Eligibility .......................................................................................................................... 9 
4.0  
Study Schedules .......................................................................................................................... 11 
5.0 
Stratification Factors OR Grouping Factor: ................................................................................ 12 
6.0 
Registration Procedures .............................................................................................................. 12 
7.0 
Protocol Treatment ...................................................................................................................... 14 
8.0 
Dosage Modification Based on Adverse Events ......................................................................... 15 
9.0 
Ancillary Treatment/Supportive Care ......................................................................................... 18 
10.0 
Adverse Event (AE) Monitoring and Reporting ......................................................................... 19 
11.0 
Treatment Evaluation .................................................................................................................. 31 
12.0 
Descriptive Factors ..................................................................................................................... 36 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient ............................................................ 36 
14.0 
Body Fluid Biospecimens ........................................................................................................... 38 
15.0 
Drug Information ........................................................................................................................ 42 
16.0  
Statistical Considerations and Methodology ............................................................................... 45 
18.0 
Records and Data Collection Procedures .................................................................................... 50 
19.0  
Budget ......................................................................................................................................... 51 
20.0 
References ................................................................................................................................... 52 
Appendix I 
ECOG Performance Status ............................................................................................... 55 
Appendix II 
Patient Medication Diary .................................................................................................. 56 
 
.


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Schema 
 
 
Registration 
 
 
↓ 
 
 
Treatment with FTD/TPI (TAS-102)  
Days 1-5 and 8-12 of 28-day cycle 
 
 
↓ 
 
 
At any time: 
Disease Progression 
Intolerable adverse effects 
Patient refusal 
 
 
↓ 
 
 
Event Monitoring 
 
Cycle = 28 days 
 
 
 
 
 
 
 
Generic name: trifluridine/tipiracil (FTD/TPI; TAS-102) 
Brand name(s): Lonsurf® 
Mayo Abbreviation: TBD 
Availability: Mayo Clinic Pharmacy 
 
 


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1.0 
Background  
1.1 
Biliary Tract Cancer 
Biliary tract cancers (BTCs) include malignant intrahepatic and extrahepatic 
cholangiocarcinomas, gallbladder and ampullary cancers. It is estimated that 11,420 
patients will be diagnosed with BTCs in 2016 in United States.(Siegel, Miller et al. 2016) 
Globally, both the incidence and mortality from BTCs is increasing with much higher 
incidences in a few regions. Most patients with BTCs present with unresectable or 
metastatic disease. Even in patients with resectable disease, the recurrences are frequent. 
The median survival of patients with advanced BTCs is less than 4.5 months.(Glimelius, 
Hoffman et al. 1996; Sharma, Dwary et al. 2010)  Combination gemcitabine and cisplatin 
has been established as first line standard of care treatment based on the Advanced 
Biliary Tract Cancer-02 (ABC-02) phase III trial.(Valle, Wasan et al. 2010) 
Unfortunately, the median overall survival (OS) was less than a year in this trial. There is 
no FDA approved second line option for patients with advanced BTCs. There is a huge 
unmet need to develop novel therapies to improve outcome for patients diagnosed with 
BTCs. 
 
1.2 
FTD/TPI (TAS-102; trifluridine/tipiracil) 
FTD/TPI (TAS-102; Lonsurf; trifluridine/tipiracil) is a novel oral nucleoside consisting 
of α,α,α-trifluorothymidine (FTD) and 5-chloro-6-(2-iminopyrrolidin-1-yl) methyl-2,4 
(1H,3H)-pyrimidinedione hydrochloride (TPI) at a molar ratio of 1:0·5. The active 
antitumor component of FTD/TPI is FTD which inhibits thymidylate synthase and is 
incorporated into DNA in tumor cells. 
 
Trifluridine, an antineoplastic thymidine-based nucleoside analogue, is described 
chemically as 2’-deoxy-5-(trifluoromethyl) uridine, and has the following structural 
formula: 
 
 
Trifluridine has a molecular formula C10H11F3N2O5 and a molecular weight of 296.20. 
Trifluridine is a white crystalline powder, soluble in water, ethanol, 0.01 mol/L 
hydrochloric acid, 0.01 mol/L sodium hydroxide solution; freely soluble in methanol, 
acetone; sparingly soluble in 2-propanol, acetonitrile; slightly soluble in diethyl ether; 
and very slightly soluble in isopropyl ether. 
 
Tipiracil hydrochloride, a thymidine phosphorylase inhibitor, is described chemically as 
5-chloro-6-[(2-iminopyrrolidin-1-yl)methyl]pyrimidine-2,4-(1H,3H)-dione 
monohydrochloride or 2,4(1H,3H)-Pyrimidinedione, 5-chloro-6-[(2-imino-1-
pyrrolidinyl)methyl]-, hydrochloride (1:1), and has the following structural formula: 


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The clinical efficacy and safety of FTD/TPI was evaluated in an international, 
randomized, double-blind, placebo-controlled study (RECOURSE study) conducted in 
patients with previously treated metastatic colorectal cancer (CRC). A total of 800 
patients were randomized 2:1 to receive trifluridine/tipiracil (n = 534) plus best 
supportive care (BSC) or matching placebo (n = 266) plus BSC. Patients received 35 
mg/m2 trifluridine/tipiracil or matching placebo orally twice daily after meals on Days 1–
5 and 8–12 of each 28-day cycle until disease progression or unacceptable toxicity. The 
primary efficacy outcome measure was overall survival (OS) and an additional efficacy 
outcome measure was progression-free survival (PFS). Patient demographics and 
baseline characteristics were similar between groups. The median age was 63 years, 61% 
were male, and 58% and 35% were White and Asian respectively. The RECOURSE 
study met the efficacy endpoints of significant improvement in OS and PFS compared to 
placebo in patients with refractory mCRC whose disease had progressed after standard 
therapies. The median OS was 7.1 months with FTD/TPI compared to 5.3 months in 
placebo group (Hazard ratio: 0.68; 95% CI: 0.56-0.78). Median PFS was 2 months in 
FTD/TPI group and 1.7 months in placebo group (Hazard ratio: 0.48; 95% CI: 0.41-0.57). 
The objective response rate was 1.6%. Common adverse events included fatigue, nausea, 
vomiting, diarrhea, anorexia and cytopenias. Table 1 lists the common adverse events 
associated with FTD/TPI. 
 
Table 1: Adverse events (>5%) in the RECOURSE study occurring more commonly than 
placebo. 
Adverse Events 
Trifluridine/tipiracil 
 
Placebo 
 
 
All Grades 
Grade 3-4 All Grades Grades 3-4 
Gastrointestinal Disorders 
Nausea 
48% 
2% 
24% 
1% 
Diarrhea 
32% 
3% 
12% 
<1% 
Vomiting 
28% 
2% 
14% 
<1% 
Abdominal Pain 
21% 
2% 
18% 
4% 
Stomatitis 
8% 
<1% 
6% 
0% 
General disorders 
Asthenia/fatigue 
52% 
7% 
35% 
9% 
Pyrexia 
19% 
1% 
14% 
<1% 
Metabolism and nutrition disorders 
Decrease appetite 
39% 
4% 
29% 
5% 
Nervous system disorders 
Dysgeusia 
7% 
0% 
2% 
0% 
Skin and subcutaneous tissue disorders 
Alopecia 
7% 
0% 
1% 
0% 


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Adverse Events 
Trifluridine/tipiracil 
 
Placebo 
 
 
All Grades 
Grade 3-4 All Grades Grades 3-4 
Blood and lymphatic disorders 
Anemia 
77% 
18% 
33% 
3% 
Neutropenia 
67% 
38% 
1% 
0% 
Thrombocytopenia 
42% 
6% 
8% 
<1% 
 
1.3 
Study Rationale 
Fluoropyrimidine-based regimens are frequently utilized for treatment of BTCs despite 
the fact that they are not FDA approved.(Huggett, Passant et al. 2014; Rogers, Law et al. 
2014) On retrospective analysis, fluoropyrimidine based treatments have shown to be 
associated with improved survival.(Huggett, Passant et al. 2014) However, there are only 
limited small prospective studies reported utilizing fluoropyrimidines. Single agent 5-
fluorouracil has yielded response rates of 10-32% with median OS of approximately 6 
months as a first line treatment.(Falkson, MacIntyre et al. 1984; Choi, Choi et al. 2000) 
Addition of other chemotherapy agents including platinum agents and irinotecan are 
associated with better response rates at the expense of increase toxicities. However, none 
of the combination regimens have consistently demonstrated superiority over single agent 
fluoropyrimidine alone.(Hezel and Zhu 2008) The combination of 5-flourouracil and 
irinotecan demonstrated a response rate of 10% in a study of 30 patients.(Feisthammel, 
Schoppmeyer et al. 2007) Another study evaluating the combination of 5-fluorouracil and 
cisplatin reported response rates of 24% with median survival of 10 months in the first 
line setting.(Ducreux, Rougier et al. 1998) Capecitabine and cisplatin combination 
demonstrated median progression free survival ranging from 2.5-3.7 months in untreated 
advanced BTCs.(Kim, Chang et al. 2003; Hong, Lee et al. 2007) S-1, a combination of 
tegafur (that is converted to 5-flouorouracil in the liver), 5-chloro-2,4-dihydroxypyridine 
(inhibitor of dihydropyrimidine dehydrogenase) and potassium oxonate has also shown 
activity in advanced BTCs as a single agent.(Ueno, Okusaka et al. 2004) These studies 
suggest there may be a role for fluoropyrimidines in advanced BTCs. 
 
The active antitumor component of FTD/TPI  is FTD is incorporated into DNA in tumor 
cells. FTD has also shown to inhibit thymidylate synthase in tumor xenograft models. 
The incorporation into DNA is known to have antitumor effects, because inhibition of 
thymidylate synthase caused by oral FTD rapidly disappears after the drug's elimination. 
The mechanism of action of FTD/TPI is somewhat dependent on its dosing 
schedule.(Lenz, Stintzing et al. 2015) Greater inhibition of thymidylate synthase was 
observed with continuos infusion of FTD than twice daily dosing.(Tanaka, Sakamoto et 
al. 2014) In contrast, the level of incorporation into DNA was higher with twice-daily 
oral dosing. Thus, clinically with twice daily dosing schedule of FTD/TPI, incorporation 
into DNA is the primary mechanism of action for antitumor effects. TPI is a potent 
inhibitor of thymidine phosphorylase, which is the enzyme that degrades FTD and helps 
maintain adequate plasma concentration needed for its activity. 
 
The mechanism of FTD/TPI is thus different from single agent fluoropyrimidine and has 
shown activity in both fluoropyrimidine sensitive and resistant tumors.(Emura, 
Nakagawa et al. 2004; Emura, Suzuki et al. 2004)The primary mechanism of resistance to 
5-fluorouracil seems to be decrease in activity of orotate phosphoribosyltransferase 
resulting in decrease in cellular uptake of 5-fluorouracil in the RNA fraction.(Murakami, 
Kazuno et al. 2000) There is no change in the levels of thymidylate synthase. FTD has 
demonstrated activity in 5-fluorouracil resistant colorectal and gastric cell lines as 


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Protocol Version Date: 21Jun2018 
activity of FTD/TPI is not dependent upon orotate phosphoribosyltransferase.(Lenz, 
Stintzing et al. 2015) Autophagy has also shown to play a role in resistance to 5-
fluorouracil but not to FTD.(Bijnsdorp, Peters et al. 2010). These studies suggest that 
FTD/TPI may have better clinical activity in advanced BTCs than fluoropyrimidine 
alone. 
1.4 
Study Design 
This is the single arm phase II trial to assess the efficacy of FTD/TPI in advanced, 
refractory BTCs. The primary end point of this study is 16-week progression-free 
survival. If 30% of patients remain progression-free at 16-weeks, this trial will be 
considered a success warranting bigger trials We will accrue 25 evaluable patients using 
a single stage design. The total sample size of this study is 28 to account for 3 possible 
non-evaluable subjects.  
 
Patient will receive FTD/TPI at the dose of 35 mg/m2 on Days 1-5 and 8-12 of 28-day 
cycle. Patient will receive treatment until disease progression or unacceptable toxicities. 
Patients will undergo restaging scans every 2 cycles. Subjects will be monitored for 
adverse events from the beginning of the study drug to 28 days after the last dose. We 
will collect blood samples for determination of cell free DNA and circulating tumor cells 
at baseline, after 2 cycles and at progression. 
2.0 
Goals  
2.1 
Primary Goal 
Determine the efficacy of FTD/TPI (TAS-102) in patients with refractory 
cholangiocarcinoma using progression-free survival at 16 weeks. 
2.2 
Secondary Goals 
2.21  
Assess the safety and tolerability of FTD/TPI (TAS-102) in patients with 
refractory cholangiocarcinoma through adverse event monitoring. 
2.22 
Further explore the efficacy of FTD/TPI (TAS-102) in patients with refractory 
cholangiocarcinoma by overall response rates, progression-free survival, and 
overall survival.   
2.3 
Correlative Research 
2.31 
Determine if circulating tumor cells (CTCs) or cell-free DNA (cfDNA) at 
baseline correlates with prognosis or response to therapy. 
2.32 
Determine if change in CTCs or cfDNA correlates with efficacy endpoints. 
2.33 
Determine if different mutational status of the tumor will affect efficacy 
endpoints. 
 


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3.0 
Patient Eligibility 
3.1 
Registration – Inclusion Criteria  
3.11 
Age ≥ 18 years. 
3.12 
Histological confirmation of advanced biliary tract cancers including cancers 
originating in gallbladder who have received at least one line of systemic 
anticancer therapy.  
Note: Patients who have either progressed or are intolerant to the prior therapy 
can be included in this study. 
3.13 
Measurable disease as defined in Section 11.0. 
3.14 
ECOG Performance Status (PS) 0 or 1 (Appendix I). 
3.15 
The following laboratory values obtained ≤21 days prior to registration.  
• 
Absolute neutrophil count (ANC) ≥1500/mm3 
• 
Platelet count ≥100,000/mm3 
• 
Total bilirubin ≤1.5 × upper limit of normal (ULN)  
• 
Aspartate transaminase (AST) or Alanine transaminase (ALT) ≤3 × ULN 
• 
Creatinine ≤1.5 × ULN 
3.16 
Negative pregnancy test done ≤7 days prior to registration, for persons of 
childbearing potential only. 
3.17a 
Provide written informed consent. 
3.17b Willing to return to enrolling institution for follow-up (during the Active 
Monitoring Phase of the study). 
3.17c 
Willing to provide blood samples for correlative research purposes. 
3.2 
Registration – Exclusion Criteria  
3.21 
Any of the following because this study involves an agent that has potential 
genotoxic, mutagenic and teratogenic effects: 
• 
Pregnant persons 
• 
Nursing persons 
• 
Persons of childbearing potential who are unwilling to employ adequate 
contraception for at least 3 months after the last dose of the study drug 
3.22 
Co-morbid systemic illnesses or other severe concurrent disease which, in the 
judgment of the investigator, would make the patient inappropriate for entry into 
this study or interfere significantly with the proper assessment of safety and 
toxicity of the prescribed regimens. 
3.23 
Immunocompromised patients and patients known to be HIV positive and 
currently receiving antiretroviral therapy. NOTE: Patients known to be HIV 
positive, but without clinical evidence of an immunocompromised state, are 
eligible for this trial. 
3.24 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance 
with study requirements. 
3.25 
Receiving any other investigational agent which would be considered as a 
treatment for the primary neoplasm ≤21 days prior to registration.. 


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3.26 
Receiving any anticancer therapy for biliary tract cancer ≤21 days prior to 
registration. 
3.27 
Other active malignancy requiring treatment in ≤6 months prior to registration.  
EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix.  
NOTE: If there is a history of prior malignancy, they must not be receiving other 
specific treatment for their cancer.  
3.28 
History of myocardial infarction ≤6 months prior to registration, or congestive 
heart failure requiring use of ongoing maintenance therapy for life-threatening 
ventricular arrhythmias. 
 


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4.0  
Study Schedules 
4.1 
Test schedule 
 
Screening 
Active Treatment 
End of Treatment 
Tests and Procedures 
≤21 days 
prior 
to registration 
D1 of each 
cycle 
D8 of Cycle 1 
only 
Every 2 
cycles 
End of 
Treatment 
Safety follow up: 
30 days post 
treatment 
window 
 
±7 days 
±3 days 
±7 days 
±7 days 
±7 days 
History and exam, Wt, PS 
X 
X 
X 
 
X 
X 
Height 
X 
 
 
 
 
 
Adverse event assessment 
X 
X 
X 
 
X 
X 
Pregnancy test1 
X 
 
 
 
 
 
Hematology: 
CBC with differential 
X 
X 
X 
 
X 
X 
Chemistry2 
X 
X 
X 
 
X 
X 
CA19-93 
 
X 
 
X4 
X 
 
Tumor imaging - CT (chest, abdomen, 
pelvis) or CT (chest) and MRI (abdomen, 
pelvis) 
X5 
 
 
X6 
X 
 
Research blood specimens7,R 
 
X 
 
 
X 
 
Patient Medication Diary (Appendix II) 8 
 
X 
 
 
 
 
Cycle = 28 days; R=Research funded 
 
                                                     
1 For persons of childbearing potential only. Must be done ≤7 days prior to registration. 
2 Chemistry: Na, K, albumin, AST, ALT, alkaline phosphatase, total and direct bilirubin, creatinine 
3 Baseline prior to Cycle 1, Day 1, then every two cycles or as clinically indicated 
4 To be performed ≤7 days prior to planned Day 1 of odd numbered cycles (Cycle 3, 5, 7 etc) or as clinically indicated 
5 Can be performed ≤28 days prior registration 
6 To be performed ≤7 days prior to planned Day 1 of odd numbered cycles (Cycle 3, 5, 7 etc) or as clinically indicated 
7 Research blood specimens to be collected on Cycle 1 Day 1 (or any time between registration and Cycle 1 Day 1), Cycle 3 Day 1 and end of treatment (see 
Section 14.0) 
8 The diary must begin the day the patient starts taking the medication and must be completed per protocol and returned to the treating institution 


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4.2 
Event Monitoring/Survival Follow-up 
 
Event Monitoring Phase1 
q. 3 months 
until PD 
At PD 
After PD  
q. 3 months 
Death 
New Primary 
Event Monitoring 
X 
X 
X 
X 
At each 
occurrence 
1. If a patient is still alive 2 years after registration, no further follow-up is required. 
 
 
5.0 
Stratification Factors OR Grouping Factor:  
None 
6.0 
Registration Procedures 
6.1 
To register a patient 
To register a patient, access the Mayo Clinic Cancer Center (MCCC) web page and enter 
the remote registration/randomization application. The registration/randomization 
application is available 24 hours a day, 7 days a week. Back up and/or system support 
contact information is available on the Web site. If unable to access the Web site, call the 
MCCC Registration Office at 
 between the hours of 8 a.m. and 5:00 p.m. 
Central Time (Monday through Friday). 
The instructions for the registration/randomization application are available on the 
MCCC web page
 and detail the process for 
completing and confirming patient registration. Prior to initiation of protocol treatment, 
this process must be completed in its entirety and a MCCC subject ID number must be 
available as noted in the instructions. It is the responsibility of the individual and 
institution registering the patient to confirm the process has been successfully completed 
prior to release of the study agent. Patient registration via the registration/randomization 
application can be confirmed in any of the following ways: 
• 
Contact the MCCC Registration Office 
 If the patient was fully 
registered, the MCCC Registration Office staff can access the information from the 
centralized database and confirm the registration. 
• 
Refer to “Instructions for Remote Registration” in section “Finding/Displaying 
Information about A Registered Subject.” 
6.2 
Verification 
Prior to accepting the registration, registration/randomization application will verify the 
following: 
• 
IRB approval at the registering institution 
• 
Patient eligibility 
• 
Existence of a signed consent form 
• 
Existence of a signed authorization for use and disclosure of protected health 
information  
6.3 
Documentation of IRB approval 
Documentation of IRB approval must be on file in the Registration Office before an 
investigator may register any patients.  


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In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) at the Registration Office (fax: 
507-284-0885). If the necessary documentation is not submitted in advance of attempting 
patient registration, the registration will not be accepted and the patient may not be 
enrolled in the protocol until the situation is resolved. 
When the study has been permanently closed to patient enrollment, submission of annual 
IRB approvals to the Registration Office is no longer necessary. 
6.4 
Correlative studies 
A mandatory translational research component is part of this study; the patient will be 
automatically registered onto this component (Sections 3.17c, 14.0). 
6.5 
Treatment on protocol 
Treatment on this protocol must commence at Mayo Clinic under the supervision of a 
medical oncologist. 
6.6 
Treatment start 
Treatment cannot begin prior to registration and must begin ≤28 days after registration. 
6.7 
Pretreatment 
Pretreatment tests/procedures (see Section 4.0) must be completed within the guidelines 
specified on the test schedule. 
6.8 
Baseline symptoms 
All required baseline symptoms (see Section 10.6) must be documented and graded. 
6.9 
Study Conduct 
The clinical trial will be conducted in compliance with regulations (21 CFR 312, 50, and 
56), guidelines for Good Clinical Practice (ICH Guidance E6), and in accordance with 
general ethical principles outlined in the Declaration of Helsinki; informed consent will 
be obtained from all participating patients; the protocol and any amendments will be 
subject to approval by the designated IRB prior to implementation, in accordance with 21 
CFR 56.103(a); and subject records will be stored in a secure location and subject 
confidentiality will be maintained. The investigator will be thoroughly familiar with the 
appropriate use of the study drug as described in the protocol and Investigator’s 
Brochure. Essential clinical documents will be maintained to demonstrate the validity of 
the study and the integrity of the data collected. Master files should be established at the 
beginning of the study, maintained for the duration of the study and retained according to 
the appropriate regulations.  
 
 


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7.0 
Protocol Treatment 
All patients will receive study medication FTD/TPI (TAS-102) in a 28-day treatment cycle. 
FTD/TPI (TAS-102) is available in 15 and 20 mg tablets. Study medication should be 
administered as outlined in the protocol. 
7.1 
Treatment Schedule 
Use actual weight or estimated dry weight if fluid retention. BSA needs to be rounded to 
2 decimal places. The study medication needs to be stored at the room temperature. 
FTD/TPI (TAS-102) is administered in 28-day cycle. The starting dose of FTD/TPI 
(TAS-102) is 35 mg/m2. The study drug will be administered on Days 1-5 and 8-12 of 
28-day cycle. The treatment regimen consists of following: 
Agent 
Route 
Day 
Starting Dose 
FTD/TPI 
(TAS-102) 
PO 
1-5 
35 mg/m2/dose twice 
daily 
None 
 
6-7 
No treatment 
FTD/TPI 
(TAS-102) 
PO 
8-12 
35 mg/m2/dose twice 
daily 
None 
 
13-28 
No treatment 
 
The study drug dose calculation based on BSA is as follows: 
FTD/TPI (TAS-102) dose 
(twice daily) BSA (m2) 
Dosage in mg 
(twice daily) 
Tablets per dose 
15 mg 
20 mg 
35 mg/m2 
<1.07 
35 
1 
1 
35 mg/m2 
1.07-1.22 
40 
0 
2 
35 mg/m2 
1.23-1.37 
45 
3 
0 
35 mg/m2 
1.38-1.52 
50 
2 
1 
35 mg/m2 
1.53-1.68 
55 
1 
2 
35 mg/m2 
1.69-1.83 
60 
0 
3 
35 mg/m2 
1.84-1.98 
65 
3 
1 
35 mg/m2 
1.99-2.14 
70 
2 
2 
35 mg/m2 
2.15-2.29 
75 
1 
3 
35 mg/m2 
≥2.30 
80 
0 
4 
 
7.2 
Self-administration statement  
Patients can be instructed in administration techniques and granted treatment 
independence. Any missed doses will be recorded. Patients will be instructed to: 
• 
Store the study medication at room temperature 
• 
Take the study medication on schedule 
• 
Report any missed doses 
• 
Take study medication within 1 hour after completing morning or evening meals 
with a glass of water 
• 
If the patient vomits after taking the study medication, the dose should not be 
replaced. 
• 
Return the unused medication at end of every cycle. 
• 
If a patient forgets to take a dose (morning or evening), the missed dose should 
not be made up 


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Protocol Version Date: 21Jun2018 
7.3 
Treatment by local medical doctor 
Treatment by a local medical doctor (LMD) is not allowed on this study. 
 
8.0 
Dosage Modification Based on Adverse Events  
For the first two cycles, strictly follow the modifications in this table. Thereafter, these 
modifications should be regarded as guidelines to produce mild-to-moderate, but not 
debilitating, side effects. Under exceptional circumstances, at the investigator discretion (in 
consultation with principal investigator) dose modifications or treatment interruption or 
continuation can be considered if it’s considered to be in the best interest of a patient. If 
multiple adverse events are seen, administer dose based on greatest reduction required for any 
single adverse event observed. Reductions apply to treatment given in the preceding cycle and 
are based on adverse events observed since the prior dose. The criteria for dose modifications 
of FTD/TPI (TAS-102) for toxicities will be considered if an adverse event is at least possibly 
related to FTD/TPI (TAS-102).  
NCI Common Terminology Criteria for Adverse Events (CTCAE) current version 4.0* will be 
utilized for dose modification unless otherwise specified. Upto three dose level reductions are 
allowed. Once reduced for an adverse event, no increase in dose of TAS-102 will be allowed. 
* 
Located at http:/ctep.cancer.gov/protocolDevelopment/electronic applications.ctc.htm 
8.1  
Dose Levels (Based on Adverse Events in Section 8.2 and 8.3) 
8.11 
FTD/TPI (TAS-102) dose levels 
Dose 
Level 
FTD/TPI (TAS-102) 
0* 
35 mg/m2/dose 
-1 
30 mg/m2/dose 
-2 
25 mg/m2/dose 
-3 
20 mg/m2/dose 
*Dose level 0 refers to the starting dose. 
NOTE: Adverse events requiring a dose-reduction step for any or all drugs beyond the 
three dose-reduction steps (levels –1, –2 and -3) will be at the discretion of the treating 
physician, if the decision is made for the patient to be kept on study. These dose 
reductions must be clearly recorded in reported clinical data.  
8.12 
The study drug dose calculation after dose modifications based on BSA is as 
follows: 
FTD/TPI (TAS-102) dose 
(twice daily) 
BSA 
(m2) 
Dosage in mg 
(twice daily) 
Tablets per dose 
15 mg 
20 mg 
Dose Level -1 (30 mg/m2) 
 
 
 
 
 
<1.09 
30 
2 
0 
1.09-1.24 
35 
1 
1 
1.25-1.39 
40 
0 
2 
1.40-1.54 
45 
3 
0 
1.55-1.69 
50 
2 
1 
1.70-1.94 
55 
1 
2 


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FTD/TPI (TAS-102) dose 
(twice daily) 
BSA 
(m2) 
Dosage in mg 
(twice daily) 
Tablets per dose 
15 mg 
20 mg 
1.95-2.09 
60 
0 
3 
2.10-2.28 
65 
3 
1 
≥2.29 
70 
2 
2 
Dose Level -2 (25 mg/m2) 
 
 
 
 
 
<1.10 
251 
2 (PM) 1 
1 (AM) 1 
 
1.10-1.29 
30 
2 
0 
 
1.30-1.49 
35 
1 
1 
 
1.50-1.69 
40 
0 
2 
 
1.70-1.89 
45 
3 
0 
 
1.90-2.09 
50 
2 
1 
 
2.10-2.29 
55 
1 
2 
 
≥2.30 
60 
0 
3 
Dose Level -3 (20 mg/m2) 
 
 
 
 
 
<1.14 
20 
0 
1 
 
1.14-1.34 
251 
2 (PM) 1 
1 (AM) 1 
 
1.35-1.59 
30 
2 
0 
 
1.60-1.94 
35 
1 
1 
 
1.95-2.09 
40 
0 
2 
 
2.10-2.29 
45 
3 
0 
 
≥2.30 
50 
2 
1 
1For the total daily dose of 50 mg, patients should take 1 × 20-mg tablet in the 
morning and 2 × 15-mg tablets in the evening. 
8.2 
Dose Modifications Based on Interval Adverse Events during the cycle 
8.21 
For non-specified adverse events the following criteria for dose modification 
will be used for adverse events occurring during the cycle: 
CTCAE  
Adverse Events1 
Action for FTD/TPI (TAS-102) 
Grade 1 or 2 
Treat as scheduled 
Grade 3 or 4 
Hold treatment until resolved to ≤Grade 2 
Reduce the dose by one dose level 
1  Except for alopecia, clinically insignificant laboratory abnormalities, and 
inadequately treated nausea, vomiting and diarrhea.  
 
 
 


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8.22 
For specified adverse events following criteria for dose modification will be 
used for adverse events occurring during the cycle: 
CTCAE Adverse Events 
Action for FTD/TPI (TAS-102) 
Neutrophil count decreased  
<500/mm3 
Hold treatment for the duration of the cycle 
Platelet count decreased 
<50,000/mm3 
Hold treatment for the duration of the cycle 
 
G-CSF can be used in this trial at the discretion of treating physician (see 
Section 9.2) 
 
8.3 
Dose Modifications at the Time of Retreatment (Beginning of new cycle) 
8.31 
The dose modification guidelines for FTD/TPI (TAS-102) for non-specified 
adverse events on Day 1 of each cycle of the treatment is mentioned below: 
CTCAE 
Adverse Events1 
Action for FTD/TPI (TAS-102) 
Grade 1 or 2 
Treat as scheduled 
Grade 3 or 4 
Delay Treatment until resolve to ≤Grade 2. Reduce the 
dose by one dose level. 
1  Except for alopecia, clinically insignificant laboratory abnormalities, and inadequately 
treated nausea, vomiting and diarrhea.  
 
8.32 
The dose modification guidelines for FTD/TPI (TAS-102) for specified adverse 
events on Day 1 of each cycle of the treatment is mentioned below: 
 
CTCAE {  
Adverse Events 
Action for FTD/TPI (TAS-102) 
Neutrophil count decreased 
<1,500/mm3 
Delay treatment by 1 week 
Reduce dose by one dose level for next 
treatment only if febrile neutropenia or 
uncomplicated Grade 4 neutropenia occurs 
that requires more than one week delay in start 
of next cycle 
Platelet count decreased 
<75,000/mm3 
Delay treatment by 1 week 
Reduce dose by one dose level for next 
treatment only if Grade 4 thrombocytopenia 
occurs that requires more than one week delay in 
start of next cycle 
 
 
 
 


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9.0 
Ancillary Treatment/Supportive Care 
9.1 
Full supportive care  
Patients should receive full supportive care while on this study. This includes blood 
product support, antibiotic treatment, and treatment of other newly diagnosed or 
concurrent medical conditions. All blood products and concomitant medications such as 
antidiarrheals, analgesics, and/or antiemetics received from the first day of study 
treatment administration until 30 days after the final dose will be recorded in the medical 
records. 
9.2 
Blood products and growth factors 
Blood products and growth factors should be utilized as clinically warranted and 
following institutional policies and recommendations. The use of growth factors should 
follow published guidelines of the Journal of Clinical Oncology, Volume 33, No 28 
(October 1), 2015: pp. 3199-3212 (WBC growth factors) AND Journal of Clinical 
Oncology, Volume 28, No 33 (November 20), 2010: pp. 4955-5010 
(darbepoetin/epoetin). 
9.3 
Antiemetics 
Antiemetics may be used at the discretion of the attending physician. 
9.4 
Diarrhea 
Diarrhea could be managed conservatively with loperamide. The recommended dose of 
loperamide is 4 mg at first onset, followed by 2 mg every 2-4 hours until diarrhea free 
(maximum 16 mg/day). 
In the event of Grade 3 or 4 diarrhea, the following supportive measures are allowed: 
hydration, octreotide, and antidiarrheals.  
If diarrhea is severe (requiring intravenous rehydration) and/or associated with fever or 
severe neutropenia (grade 3 or 4), broad-spectrum antibiotics must be prescribed. Patients 
with severe diarrhea or any diarrhea associated with severe nausea or vomiting should be 
hospitalized for intravenous hydration and correction of electrolyte imbalances. 
 
 


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10.0 
Adverse Event (AE) Monitoring and Reporting  
The site principal investigator is responsible for reporting any/all serious adverse events to the 
sponsor as described within the protocol, regardless of attribution to study agent or treatment 
procedure. 
The sponsor/sponsor-investigator is responsible for notifying FDA and all participating 
investigators in a written safety report of any of the following: 
• 
Any suspected adverse reaction that is both serious and unexpected. 
• 
Any findings from laboratory animal or in vitro testing that suggest a significant risk for 
human subjects, including reports of mutagenicity, teratogenicity, or carcinogenicity. 
• 
Any findings from epidemiological studies, pooled analysis of multiple studies, or 
clinical studies, whether or not conducted under an IND and whether or not conducted by 
the sponsor, that suggest a significant risk in humans exposed to the drug 
• 
Any clinically important increase in the rate of a serious suspected adverse reaction over 
the rate stated in the protocol or Investigator’s Brochure (IB). 
Summary of SAE Reporting for this study  
(please read entire section for specific instructions): 
WHO: 
WHAT form: 
WHERE to send: 
All sites 
Pregnancy Reporting 
http://ctep.cancer.gov/protocolDevelopment/electronic a
pplications/docs/PregnancyReportFormUpdated.pdf 
Mayo Sites – attach to MCCC 
Electronic SAE Reporting Form 
 and submit to 
 
Mayo Clinic 
Sites 
Mayo Clinic Cancer Center SAE Reporting Form 
http://livecycle2.mayo.edu/workspace/?startEndpoint=
MC4158-56/Processes/MC4158-56-Process.MC4158-
56  
AND attach 
MedWatch 3500A: 
http://www.fda.gov/downloads/AboutFDA/ReportsMa
nualsForms/Forms/UCM048334.pdf 
Submit to 
 
Will automatically be sent to 
 
Definitions 
Adverse Event 
Any untoward medical occurrence associated with the use of a drug in humans, whether or 
not considered drug related.  
Suspected Adverse Reaction 
Any adverse event for which there is a reasonable possibility that the drug caused the adverse 
event. 
Expedited Reporting 
Events reported to sponsor within 24 hours, 5 days or 10 days of study team becoming aware 
of the event. 
Routine Reporting 
Events reported to sponsor via case report forms 


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Events of Interest 
Events that would not typically be considered to meet the criteria for expedited reporting, but 
that for a specific protocol are being reported via expedited means in order to facilitate the 
review of safety data (may be requested by the FDA or the sponsor).  
Unanticipated Adverse Device Event (UADE) 
Any serious adverse effect on health or safety or any life-threatening problem or death caused 
by, or associated with, a device, if that effect, problem, or death was not previously identified 
in nature, severity, or degree of incidence in the investigational plan or application (including 
a supplementary plan or application), or any other unanticipated serious problem associated 
with a device that relates to the rights, safety, or welfare of subjects 
10.1 
Adverse Event Characteristics 
CTCAE term (AE description) and grade: The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting. All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site: 
(http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm) 
a. Identify the grade and severity of the event using the CTCAE version 4.0. 
b. Determine whether the event is expected or unexpected (see Section 10.2). 
c. Determine if the adverse event is related to the study intervention (agent, treatment or 
procedure) (see Section 10.3). 
d. Determine whether the event must be reported as an expedited report. If yes, 
determine the timeframe/mechanism (see Section 10.4).  
e. Determine if other reporting is required (see Section 10.5). 
f. Note: All AEs reported via expedited mechanisms must also be reported via the 
routine data reporting mechanisms defined by the protocol (see Sections 10.6 and 
18.0). 
NOTE: A severe AE is NOT the same as a serious AE, which is defined in Section 10.4. 
10.2 
Expected vs. Unexpected Events  
Expected events - are those described within the Section 15.0 of the protocol, the study 
specific consent form, package insert (if applicable), and/or the investigator brochure. 
Unexpected adverse events or suspected adverse reactions are those not listed in Section 
15.0 of the protocol, the study specific consent form, package insert (if applicable), or in 
the investigator brochure (or are not listed at the specificity or severity that has been 
observed); if an investigator brochure is not required or available, is not consistent with 
the risk information described in the general investigational plan. 
Unexpected also refers to adverse events or suspected adverse reactions that are 
mentioned in the investigator brochure as occurring with a class of drugs but have not 
been observed with the drug under investigation. 
An investigational agent/intervention might exacerbate the expected AEs associated with a 
commercial agent. Therefore, if an expected AE (for the commercial agent) occurs with a 
higher degree of severity or specificity, expedited reporting is required. 
NOTE: *The consent form may contain study specific information at the discretion of the 
Principal Investigator; it is possible that this information may NOT be included in the 
protocol or the investigator brochure. Refer to protocol or IB for reporting needs. 


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10.3 
Attribution to agent(s) or procedure 
When assessing whether an adverse event (AE) is related to a medical agent(s) medical or 
procedure, the following attribution categories are utilized: 
Definite - The AE is clearly related to the agent(s)/procedure. 
Probable - The AE is likely related to the agent(s)/procedure. 
Possible - The AE may be related to the agent(s)/procedure. 
Unlikely - The AE is doubtfully related to the agent(s)/procedure. 
Unrelated - The AE is clearly NOT related to the agent(s)/procedure. 
10.31 AEs Experienced Utilizing Investigational Agents / Commercial Agent(s) 
NOTE: When a commercial agent(s) is (are) used on the same treatment arm as 
the investigational agent/intervention (also, investigational drug, biologic, 
cellular product, or other investigational therapy under an IND), the entire 
combination (arm) is then considered an investigational intervention for 
reporting. 
• An AE that occurs on a combination study must be assessed in accordance with the 
guidelines for investigational agents/interventions.  
• An AE that occurs prior to administration of the investigational agent/intervention 
must be assessed as specified in the protocol. In general, only Grade 4 and 5 AEs 
that are unexpected with at least possible attribution to the commercial agent require 
an expedited report, unless hospitalization is required. Refer to Section 10.4 for 
specific AE reporting requirements or exceptions. 
An investigational agent/intervention might exacerbate the expected AEs associated 
with a commercial agent. Therefore, if an expected AE (for the commercial agent) 
occurs with a higher degree of severity or specificity, expedited reporting is 
required. 
• An increased incidence of an expected adverse event (AE) is based on the 
patients treated for this study at their site. A list of known/expected AEs is 
reported in the package insert or the literature, including AEs resulting from a 
drug overdose. 
• Commercial agent expedited reports must be submitted to the FDA via MedWatch 
3500A for Health Professionals (complete all three pages of the form). 
http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM0
48334.pdf 
or 
http://www.fda.gov/AboutFDA/ReportsManualsForms/Forms/ListFormsAlphabe
tically/default.htm 
Instructions for completing the MedWatch 3500A: 
http://www.fda.gov/downloads/Safety/MedWatch/HowToReport/DownloadFor
ms/UCM387002.pdf 
10.32 EXPECTED Serious Adverse Events: Protocol Specific Exceptions to 
Expedited Reporting 
For this protocol only, the following Adverse Events/Grades are expected to occur 
within this population and do not require Expedited Reporting. These events must still 
be reported via Routine Reporting (see Section 10.6).* 


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*Report any clinically important increase in the rate of a serious suspected 
adverse reaction (at your study site) over that which is listed in the protocol or 
investigator brochure as an expedited event.  
*Report an expected event that is greater in severity or specificity than expected 
as an expedited event. 
CTCAE 
System Organ Class 
(SOC) 
Adverse event/ Symptoms 
CTCAE Grade at which the event 
will not be reported in an expedited 
manner1 
General disorders and 
administrations site 
conditions 
Fatigue  
≤Grade 3 
Malaise 
≤Grade 3 
Gastrointestinal disorders 
Nausea 
≤Grade 3 
Vomiting 
≤Grade 3 
Diarrhea 
≤Grade 3 
Blood and lymphatic 
system disorders 
Anemia 
≤Grade 4 
Investigations 
Lymphocyte count decreased 
≤Grade 4 
 
Neutrophil count decreased 
≤Grade 4 
 
Platelet count decreased 
≤Grade 4 
 
White blood cell count 
decreased 
≤Grade 4 
1 These exceptions only apply if the adverse event does not result in hospitalization. If the adverse 
event results in hospitalization, then the standard expedited adverse events reporting 
requirements must be followed.  
Specific protocol exceptions to expedited reporting should be reported expeditiously by 
investigators ONLY if they exceed the expected grade of the event. 
The following hospitalizations are not considered to be SAEs because there is no “adverse event” 
(i.e., there is no untoward medical occurrence) associated with the hospitalization: 
● Hospitalizations for respite care 
● Planned hospitalizations required by the protocol 
● Hospitalization planned before informed consent (where the condition requiring the hospitalization 
has not changed post study drug administration) 
● Hospitalization for elective procedures unrelated to the current disease and/or treatment on this trial 
● Hospitalization for administration of study drug or insertion of access for administration of study 
drug 
● Hospitalization for routine maintenance of a device (e.g., battery replacement) that was in place 
before study entry 
● Hospitalization, or other serious outcomes for signs and symptoms of progression of the cancer.] 
 
 






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Note: If there is no language in the protocol indicating that pregnancy is not 
considered an adverse experience for this trial, and if the consent form does not 
indicate that subjects should not get pregnant/impregnate others, then any 
pregnancy in a subject/patient or a male patient’s partner (spontaneously 
reported) which occurs during the study or within 120 days of completing the 
study should be reported as a UPIRTSO. 
Mayo Clinic Cancer Center (MCCC) Institutions: 
If the event meets the criteria for IRB submission as a Reportable 
Event/UPIRTSO, provide the appropriate documentation and use the Mayo 
Clinic Cancer Center Expedited Event Report form 
http://livecycle2.mayo.edu/workspace/?startEndpoint=MC4158-
56/Processes/MC4158-56-Process.MC4158-56, to submit to 
CANCERCROSAFETYIN@mayo.edu. The Mayo Regulatory Affairs Office 
will review and process the submission to the Mayo Clinic IRB. 
10.52 Death 
Note: A death on study requires both routine and expedited reporting 
regardless of causality, unless as noted below. Attribution to treatment or 
other cause must be provided. 
Any death occurring within 30 days of the last dose, regardless of attribution to 
an agent/intervention under an IND/IDE requires expedited reporting within 
24-hours. 
Any death occurring greater than 30 days with an attribution of possible, 
probable, or definite to an agent/intervention under an IND/IDE requires 
expedited reporting within 24-hours. 
Reportable categories of Death  
• 
Death attributable to a CTCAE term. 
• 
Death Neonatal: A disorder characterized by cessation of life during the 
first 28 days of life.  
• 
Death NOS: A cessation of life that cannot be attributed to a CTCAE term 
associated with Grade 5. 
• 
Sudden death NOS: A sudden (defined as instant or within one hour of the 
onset of symptoms) or an unobserved cessation of life that cannot be 
attributed to a CTCAE term associated with Grade 5. 
• 
Death due to progressive disease should be reported as Grade 5 
“Neoplasms benign, malignant and unspecified (including cysts and 
polyps) – Other (Progressive Disease)” under the system organ class 
(SOC) of the same name. Evidence that the death was a manifestation of 
underlying disease (e.g., radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a disease process) 
should be submitted. 
Per NIH OBA Appendix M, should a patient die during the study or study 
follow-up, no matter what the cause, the study doctor will ask the patient’s 
family for permission to perform an autopsy. If permission is granted, a copy 
of the autopsy report will be sent to the sponsor after all identifying 
information has been removed. An autopsy will help the researchers learn 


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Protocol Version Date: 21Jun2018 
more about the safety and efficacy of the treatment. Patients should advise 
their families about their wishes regarding autopsy. 
10.53 Secondary Malignancy 
• 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, radiation 
or chemotherapy). A secondary malignancy is not considered a metastasis of 
the initial neoplasm. 
• 
All secondary malignancies that occur following treatment with an agent under 
an IND/IDE will be reported. Three options are available to describe the event: 
o Leukemia secondary to oncology chemotherapy (e.g., Acute Myeloctyic 
Leukemia [AML]) 
o Myelodysplastic syndrome (MDS) 
o Treatment-related secondary malignancy 
• 
Any malignancy possibly related to cancer treatment (including AML/MDS) 
should also be reported via the routine reporting mechanisms outlined in each 
protocol. 
10.54 Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is 
NOT a metastasis from the initial malignancy). Second malignancies require ONLY 
routine reporting unless otherwise specified. 
10.55 Pregnancy, Fetal Death, and Death Neonatal  
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. 
If a female subject (or female partner of a male subject) taking investigational 
product becomes pregnant, the subject taking should notify the Investigator, and 
the pregnant female should be advised to call her healthcare provider 
immediately. The patient should have appropriate follow-up as deemed necessary 
by her physician. 
NOTE: When submitting Mayo Expedited Adverse Event Report reports for 
“Pregnancy”, “Pregnancy loss”, or “Neonatal loss”, the potential risk of exposure 
of the fetus to the investigational agent(s) or chemotherapy agent(s) should be 
documented in the “Description of Event” section. Include any available medical 
documentation. Include this form: 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/docs/Pregna
ncyReportFormUpdated.pdf 
 


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Protocol Version Date: 21Jun2018 
10.551 
Pregnancy 
Pregnancy should be reported in an expedited manner as Grade 3 
“Pregnancy, puerperium and perinatal conditions - Other 
(pregnancy)” under the Pregnancy, puerperium and perinatal 
conditions SOC. Pregnancy should be followed until the outcome is 
known. 
10.552 
Fetal Death 
Fetal death is defined in CTCAE as “A disorder characterized by death 
in utero; failure of the product of conception to show evidence of 
respiration, heartbeat, or definite movement of a voluntary muscle after 
expulsion from the uterus, without possibility of resuscitation.” 
Any fetal death should be reported expeditiously, as Grade 4 
“Pregnancy, puerperium and perinatal conditions - Other 
(pregnancy loss)” under the Pregnancy, puerperium and perinatal 
conditions SOC. 
10.553 
Death Neonatal 
Neonatal death, defined in CTCAE as “A disorder characterized by 
cessation of life occurring during the first 28 days of life” that is felt by 
the investigator to be at least possibly due to the investigational 
agent/intervention, should be reported expeditiously.  
A neonatal death should be reported expeditiously as Grade 4 
“General disorders and administration - Other (neonatal loss)” 
under the General disorders and administration SOC.  
10.6 
Required Routine Reporting  
10.61 Baseline and Adverse Events Evaluations 
Pretreatment symptoms/conditions to be graded at baseline and adverse events to 
be graded at each evaluation.  
Grading is per CTCAE v4.0 unless alternate grading is indicated in the table 
below: 
CTCAE  
System/Organ/Class (SOC) 
Adverse event/Symptoms 
Baseline 
Each 
evaluation 
Blood and lymphatic system 
disorders 
Anemia 
X 
X 
Gastrointestinal Disorders 
Abdominal Pain 
X 
X 
Baseline # of stools 
X 
 
Diarrhea 
 
X 
Nausea 
X 
X 
Vomiting 
X 
X 
General disorders 
Fatigue 
X 
X 
Investigations 
Neutrophil count decreased 
X 
X 
 
Platelet count decreased 
X 
X 
Metabolism and nutrition 
disorders 
Anorexia 
X 
X 
 
 
 


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Protocol Version Date: 21Jun2018 
10.62 All other AEs 
Submit via appropriate MCCC Case Report Forms (i.e., paper or electronic, as 
applicable) the following AEs experienced by a patient and not specified in 
Section 10.6: 
10.621 Grade 2 AEs deemed possibly, probably, or definitely related to the study 
treatment or procedure. 
10.622 Grade 3 and 4 AEs regardless of attribution to the study treatment or 
procedure. 
10.623 Grade 5 AEs (Deaths) 
10.6231 
Any death within 30 days of the patient’s last study 
treatment or procedure regardless of attribution to the study 
treatment or procedure. 
10.6232 
Any death more than 30 days after the patient’s last study 
treatment or procedure that is felt to be at least possibly 
treatment related must also be submitted as a Grade 5 AE, 
with a CTCAE type and attribution assigned. 
10.7 
Late Occurring Adverse Events 
Refer to the instructions in the Forms Packet (or electronic data entry screens, as 
applicable) regarding the submission of late occurring AEs following completion of the 
Active Monitoring Phase (i.e., compliance with Test Schedule in Section 4.0). 
10.8 
Taiho Oncology Additional Event Reporting Instructions 
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.  
After the initial SAE notification to Taiho Pharmacovigilance or designee, follow-up 
SAE information will be submitted each time that important follow-up information (e.g., 
diagnosis, outcome, causality assessment, results of specific investigations) becomes 
available. 
All SAEs within the follow-up window (e.g., 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. 
10.81 Reporting of Deaths 
All deaths occurring through the 30-day follow-up period must be reported to 
Taiho Pharmacovigilance or designee within 24 hours. 
1. Death due to disease progression: 


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Protocol Version Date: 21Jun2018 
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, the investigator will be required to identify which of the 
following best describes the category of death:  
• 
Toxicity for study drugs 
• 
Radiologic disease progression 
• 
Clinical disease progression 
• 
Other causes 
10.82 Disease Progression 
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. 
10.83 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. 
10.84 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 


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Protocol Version Date: 21Jun2018 
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 reported unless they result in 
an AE. 
• 
Medication errors with study drugs that result in an overdose 
will be reported as an AE.  
• 
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 prescribed dose (but 
does not meet the overdose criteria), it will be identified 
through the recording of study drug accountability data in 
the CRF 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 
CRF 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. 
10.85 Overdose 
An overdose with FTD/TPI (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 FTD/TPI (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 CRF 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 FTD/TPI (TAS-102) overdose. 
Overdose should be managed aggressively with close monitoring and 
administration of prophylactic and symptomatic therapies to prevent or correct 
potential side effects. 
An accidental or intentional overdose for concomitant medication should only be 
reported if it is associated with an AE. 
To Report to Taiho Pharmacovigilance: 
  
 
 
 


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Protocol Version Date: 21Jun2018 
11.0 
Treatment Evaluation 
NOTE: This study uses protocol RECIST v1.1 template dated 2/16/2011. See the footnote for the 
table regarding measureable disease in Section 11.44, as it pertains to data collection and 
analysis. 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guidelines 
(version 1.1) (Eisenhauer et al). Changes in the largest diameter (unidimensional measurement) 
of the tumor lesions and the short axis measurements in the case of lymph nodes are used in the 
RECIST guideline. 
11.1 
Schedule of Evaluations 
For the purposes of this study, patients should be reevaluated every 8 weeks. In addition 
to a baseline scan, confirmatory scans should also be obtained 8 weeks following initial 
documentation of objective response. 
11.2 
Definitions of Measurable and Non-Measurable Disease 
11.21  Measurable Disease 
11.211 A non-nodal lesion is considered measurable if its longest diameter can 
be accurately measured as ≥2.0 cm with chest x-ray, or as ≥1.0 cm with 
CT scan, CT component of a PET/CT, or MRI.  
11.212 A superficial non-nodal lesion is measurable if its longest diameter is 
≥1.0 cm in diameter as assessed using calipers (e.g. skin nodules) or 
imaging. In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is 
recommended. 
11.213 A malignant lymph node is considered measurable if its short axis is 
>1.5 cm when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  
Tumor lesions in a previously irradiated area are considered measurable disease 
under the following conditions:  
a) New lesion that has developed after radiation is completed 
b) Definite increase in the size of the previously irradiated lesion. 
11.22 Non-Measurable Disease 
11.221 All other lesions (or sites of disease) are considered non-measurable 
disease, including pathological nodes (those with a short axis ≥1.0 to 
<1.5 cm). Bone lesions, leptomeningeal disease, ascites, pleural/ 
pericardial effusions, lymphangitis cutis/pulmonis, inflammatory breast 
disease, and abdominal masses (not followed by CT or MRI), are 
considered as non-measurable as well. 
Note: ‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions. In addition, lymph nodes that have a short axis 
<1.0 cm are considered non- pathological (i.e., normal) and should not be 
recorded or followed. 
 
 


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Protocol Version Date: 21Jun2018 
11.3 
Guidelines for Evaluation of Measurable Disease 
11.31 Measurement Methods: 
• 
All measurements should be recorded in metric notation (i.e., decimal 
fractions of centimeters) using a ruler or calipers. 
• 
The same method of assessment and the same technique must be used to 
characterize each identified and reported lesion at baseline and during 
follow-up. For patients having only lesions measuring at least 1 cm to less 
than 2 cm must use CT imaging for both pre- and post-treatment tumor 
assessments. 
• 
Imaging-based evaluation is preferred to evaluation by clinical examination 
when both methods have been used at the same evaluation to assess the 
antitumor effect of a treatment.  
11.32 Acceptable Modalities for Measurable Disease: 
Conventional CT and MRI: This guideline has defined measurability of lesions 
on CT scan based on the assumption that CT slice thickness is 5 mm or less. 
If CT scans have slice thickness greater than 5 mm, the minimum size for a 
measurable lesion should be twice the slice thickness.  
• 
As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type 
and site of disease. The lesions should be measured on the same pulse 
sequence. Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans. 
Body scans should be performed with breath-hold scanning techniques, if 
possible. 
• 
PET-CT: If the site can document that the CT performed as part of a PET-CT 
is of identical diagnostic quality to a diagnostic CT (with IV and oral 
contrast), then the CT portion of the PET-CT can be used for RECIST 
measurements and can be used interchangeably with conventional CT in 
accurately measuring cancer lesions over time.  
• 
Chest X-ray: Lesions on chest x-ray are acceptable as measurable lesions 
when they are clearly defined and surrounded by aerated lung. However, CT 
scans are preferable. 
• 
Physical Examination: For superficial non-nodal lesions, physical 
examination is acceptable, but imaging is preferable, if both can be done. In 
the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended. 
• 
FDG-PET: FDG-PET scanning is allowed to complement CT scanning in 
assessment of progressive disease [PD] and particularly possible 'new' 
disease. A ‘positive’ FDG-PET scanned lesion is defined as one which is 
FDG avid with an update greater than twice that of the surrounding tissue on 
the attenuation corrected image; otherwise, an FDG-PET scanned lesion is 
considered ‘negative.’ New lesions on the basis of FDG-PET imaging can be 
identified according to the following algorithm: 
a. Negative FDG-PET at baseline with a positive FDG-PET at follow-up is 
a sign of PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  


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Protocol Version Date: 21Jun2018 
i. 
If the positive FDG-PET at follow-up corresponds to a new site of 
disease confirmed by CT, this is PD.  
ii. If the positive FDG-PET at follow-up is not confirmed as a new site 
of disease on CT at the same evaluation, additional follow-up CT 
scans (i.e., additional follow-up scans at least 4 weeks later) are 
needed to determine if there is truly progression occurring at that 
site. In this situation, the date of PD will be the date of the initial 
abnormal PDG-PET scan.  
iii If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the 
anatomic images, it is not classified as PD. 
11.33 Measurement at Follow-up Evaluation:  
A subsequent scan must be obtained 8 weeks following initial documentation of 
an objective status of either complete response (CR) or partial response (PR).  
In the case of stable disease (SD), follow-up measurements must have met the 
SD criteria at least once after study entry at a minimum interval of 8 weeks 
(see Section 11.44). 
The 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 stable disease is mandatory to differentiate between response or 
stable disease (an effusion may be a side effect of the treatment) and 
progressive disease. 
• 
Cytologic and histologic techniques can be used to differentiate between PR 
and CR in rare cases (e.g., residual lesions in tumor types such as germ cell 
tumors, where known residual benign tumors can remain.) 
11.4 
Measurement of Effect 
11.41 Target Lesions & Target Lymph Nodes 
• 
Measurable lesions (as defined in Section 11.21) up to a maximum of 5 
lesions representative of all involved organs, should be identified as “Target 
Lesions” and recorded and measured at baseline. These lesions can be non-
nodal or nodal (as defined in 11.21), where no more than 2 lesions are from 
the same organ and no more than 2 malignant nodal lesions are selected.  
Note: If fewer than 5 target lesions and target lymph nodes are identified (as 
there often will be), there is no reason to perform additional studies beyond 
those specified in the protocol to discover new lesions.  
• 
Target lesions and target lymph nodes should be selected on the basis of their 
size, be representative of all involved sites of disease, but in addition should 
be those that lend themselves to reproducible repeated measurements. It may 
be the case that, on occasion, the largest lesion (or malignant lymph node) 
does not lend itself to reproducible measurements in which circumstance the 
next largest lesion (or malignant lymph node) which can be measured 
reproducibly should be selected.  
• 
Baseline Sum of Dimensions (BSD): A sum of the longest diameter for all 
target lesions plus the sum of the short axis of all the target lymph nodes will 
be calculated and reported as the baseline sum of dimensions (BSD). The 


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Protocol Version Date: 21Jun2018 
BSD will be used as reference to further characterize any objective tumor 
response in the measurable dimension of the disease.  
• 
Post-Baseline Sum of the Dimensions (PBSD): A sum of the longest 
diameter for all target lesions plus the sum of the short axis of all the target 
lymph nodes will be calculated and reported as the post-baseline sum of 
dimensions (PBSD). If the radiologist is able to provide an actual measure 
for the target lesion (or target lymph node), that should be recorded, even if it 
is below 0.5 cm. If the target lesion (or target lymph node) is believed to be 
present and is faintly seen but too small to measure, a default value of 0.5 cm 
should be assigned. If it is the opinion of the radiologist that the target lesion 
or target lymph node has likely disappeared, the measurement should be 
recorded as 0 cm. 
• 
The minimum sum of the dimensions (MSD) is the minimum of the BSD and 
the PBSD. 
11.42 Non-Target Lesions & Non-Target Lymph Nodes 
Non-measurable sites of disease (Section 11.22) are classified as non- target 
lesions or non-target lymph nodes and should also be recorded at baseline. These 
lesions and lymph nodes should be followed in accord with 11.433. 
11.43 Response Criteria 
11.431 
All target lesions and target lymph nodes followed by CT/MRI/PET-
CT/Chest X-ray/physical examination must be measured on re-
evaluation at evaluation times specified in Section 11.1. Specifically, a 
change in objective status to either a PR or CR cannot be done without 
re-measuring target lesions and target lymph nodes.  
Note: Non-target lesions and non-target lymph nodes should be 
evaluated at each assessment, especially in the case of first response or 
confirmation of response. In selected circumstances, certain non-target 
organs may be evaluated less frequently. For example, bone scans may 
need to be repeated only when complete response is identified in target 
disease or when progression in bone is suspected. 
11.432 
Evaluation of Target Lesions 
Complete Response (CR):All of the following must be true: 
a. Disappearance of all target lesions. 
b. Each target lymph node must have reduction in short axis to 
<1.0 cm. 
Partial Response (PR): At least a 30% decrease in PBSD (sum of the 
longest diameter for all target lesions plus the sum of the short axis 
of all the target lymph nodes at current evaluation) taking as 
reference the BSD (see Section 11.41). 
Progression (PD): At least one of the following must be true: 
a. At least one new malignant lesion, which also includes any 
lymph node that was normal at baseline (<1.0 cm short axis) and 
increased to ≥1.0 cm short axis during follow-up.  
b. At least a 20% increase in PBSD (sum of the longest diameter 
for all target lesions plus the sum of the short axis of all the 
target lymph nodes at current evaluation) taking as reference the 






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Protocol Version Date: 21Jun2018 
13.2 
Progressive disease (PD) 
Patients who develop PD while receiving therapy will go to the event-monitoring phase. 
13.3 
Off protocol treatment 
Patients who go off protocol treatment for reasons other than PD will go to the event-
monitoring phase per Section 4.0. Treatment decision during event-monitoring phase is at 
the discretion of the treating physician. 
13.4 
Duration of therapy for CR, PR or SD 
Patients who achieve a CR, PR or SD will continue to receive treatment per protocol until 
they develop PD or unacceptable toxicity.  
13.5 
Definition of Ineligible 
A patient is deemed ineligible if after registration, it is determined that at the time of 
registration, the patient did not satisfy each and every eligibility criteria for study entry. 
The patient may continue treatment off-protocol at the discretion of the physician as long 
as there are no safety concerns, and the patient was properly registered. The patient will 
go directly to the event-monitoring phase of the study (or off study, if applicable).  
• 
If the patient received treatment, all data up until the point of confirmation of 
ineligibility must be submitted. Event monitoring will be required per Section 18.0 of 
the protocol.  
• 
If the patient never received treatment, on-study material must be submitted. Event 
monitoring will be required per Section 4.0 of the protocol.  
13.6 
Definition of Major Violation 
A patient is deemed a major violation, if protocol requirements regarding treatment in 
cycle 1 of the initial therapy are severely violated that evaluability for primary end point 
is questionable. All data up until the point of confirmation of a major violation must be 
submitted. The patient will go directly to the event-monitoring phase of the study. The 
patient may continue treatment off-protocol at the discretion of the physician as long as 
there are no safety concerns, and the patient was properly registered. Event monitoring 
will be required per Section 4.0 of the protocol. 
13.7 
Definition of Cancel 
A patient is deemed a cancel if he/she is removed from the study for any reason before 
any study treatment is given. On-study material and the End of Active Treatment/Cancel 
Notification Form must be submitted. No further data submission is necessary. 
13.8 
Patient removal from study 
Patients may be removed from treatment on this study for any of the following reasons: 
• 
Progression of disease 
• 
Noncompliance with study procedures 
• 
Patient’s request to withdraw from the study or refusal of further therapy 
• 
Unacceptable adverse events: A patient may be removed from the study for any 
complication of treatment that the investigator feels is life threatening 
• 
Investigator discretion 
• 
Dose delay >28 days for treatment related AE NOTE: If a patient has clinical benefit 
from the study treatment, patient may continue on study at investigator discretion 
 


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Protocol Version Date: 21Jun2018 
14.0 
Body Fluid Biospecimens 
14.1  
Summary Table of Research Blood and Body Fluid Specimens to be Collected for this Protocol 
Biospecimen 
Mandatory or 
optional 
Timing 
Correlative science 
justification 
Information on 
submission 
EDTA tube 
(whole blood) 
Mandatory 
Serial draws 
circulating biomarker work 
Section 14.2 and 14.3 
Streck cfDNA BCT 
(whole blood) 
Mandatory 
Serial draws 
cfDNA based studies 
Section 14.2 and 14.3 
AccuCyte tube 
(whole blood) 
Mandatory 
Serial draws 
CTC based studies 
Section 14.2 and 14.3 
14.2 
Collection and Processing  
14.21 Sample collection should be restricted to Monday – Thursday. However, if the subject can only be seen on a Friday, 
please contact the Biospecimen Resource Manager for additional instructions (see protocol resource pages for contact 
information). 
14.22 Specimen tube(s) must be labeled with the protocol number, study patient ID number, and the time and date of the blood 
draw. 
 
 


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14.23 Blood/blood products must be collected and shipped according to specific instructions provided in the kit and the table 
below. 
Collection tube 
Volume to 
collect per 
tube (number 
of tubes to 
collect) 
Blood product 
being 
processed and 
submitted 
Timepoints 
Additional 
processing 
required at 
site 
Storage 
and shipping 
conditions 
Baseline 
Cycle 1 
Day 1** 
Cycle 3 
Day 1 
End of 
treatment 
EDTA tube 
(purple top) 
10 mL (1) 
Whole blood 
for DNA, buffy 
coat, WBCs and 
plasma* 
X 
X 
X 
Yes 
Frozen on dry 
ice 
Streck cfDNA 
BCT tube 
10 mL (2) 
Whole blood 
for platelet poor 
plasma 
X 
X 
X 
None 
Ship same day 
at ambient 
temperature 
AccuCyte tube 
10 mL (1) 
Whole blood 
for CTCs 
X 
X 
X 
None 
Ship same day 
at ambient 
temperature 
* DNA extraction from whole blood to be done at each site 
** Baseline samples may be procured any time after registration and prior to treatment on C1D1 
14.24 Shipping 
14.241 
Verify that ALL sections of the Blood Specimen Submission Form (see Forms Packet), BAP Requisition Form 
(provided in kit), and specimen collection labels are completed and filled in correctly. Enter information from 
the Blood Specimen Submission Form into the remote data entry system within 7 days after specimen collection 
(see Forms Packet). 
14.242 
Specimens collected in the Streck cfDNA BCT and AccuCyte tubes should be shipped at ambient temperature 
on the same day they are drawn.  
14.243 
Specimens collected in EDTA tubes should be processed for DNA from whole blood, a buffy coat back up and 
plasma aliquots then stored frozen. NOTE: DNA extraction must be done at site where it's collected. 
14.244 
Samples should be shipped to BAP Freezer Mondays – Thursdays according to kit instructions. Samples should 
not be sent on weekends or just prior to federal holidays. (If samples can only be shipped on Fridays, please 
contact the Biospecimen Resource Manager for additional instructions.) 


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Protocol Version Date: 21Jun2018 
14.25  Processing 
BAP Shared Resource will process the specimens. 
14.251 
Double spun, platelet poor plasma will be derived from the Streck 
cfDNA BCT tubes using established laboratory processes, and stored 
at -70ºC by BAP.  
14.252  
DNA will be extracted from whole blood, and white blood cells and 
plasma will be derived from remaining blood from the EDTA tubes, 
divided into aliquots, and stored at -70ºC by BAP according to patient 
consent information. 
14.253 
Whole blood collected in the AccuCyte tubes will be provided directly 
to Dr. Minetta Liu’s laboratory at Mayo Clinic Rochester to isolate and 
retain CTCs.  
14.254 
As part of ongoing research at the Mayo Clinic, we will retain residual 
whole blood, white blood cells, CTCs, DNA, and plasma for future 
research studies, according to patient consent information. Samples 
will be stored until specific analyses are identified and may be used for 
exploratory biomarker analyses, validation studies, or potential 
diagnostic development. As protocols are developed, they will be 
presented for IRB review and approval. 
14.3 
Background and Methodology 
14.31 ctDNA 
Detection of cancer specific mutations from the peripheral blood is an area of 
active investigation in many different type of cancers. An accumulating body of 
literature confirms an excellent correlation between mutations found in cancer 
tissues and mutations detected in cfDNA from the same patients.(Kim, Lee et al. 
2015) Changes in cfDNA also correlate well with tumor marker dynamics in 
serial sampling, suggesting that cfDNA mutant allele fraction changes reflect 
changes in disease burden over time and treatment. Plasma based DNA mutation 
detection should therefore provide longitudinal changes in the representative 
genomic landscape of the malignancy in a non-invasive manner, overcoming the 
two major limitations of tissue based DNA mutation analysis (invasiveness and 
limited sampling from a genetically heterogenous tumor).(Diehl, Li et al. 2005; 
Diehl, Schmidt et al. 2008; Dawson, Tsui et al. 2013) 
10 mL whole blood samples will be collected in Streck cfDNA BCT tubes. These 
specimens will be shipped immediately at ambient temperature to Mayo Clinic 
Rochester and then processed to aliquots of platelet poor plasma within 7 days of 
collection using standard protocols. Samples will be stored until we are ready for 
DNA extraction and mutational analysis.  
Mutation analysis will be performed on the baseline cfDNA samples including 
FGFR and Her-2. Selected mutations identified at baseline will be verified and 
quantified in all cfDNA samples using ultrasensitive digital droplet PCR based 
assays.  
14.32 CTCs 
That CTCs have biologic relevance in epithelial malignancies is 


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increasingly clear, as their relative abundance in the peripheral blood has 
strong correlations with disease related outcomes in early stage and 
advanced breast cancer.(Cristofanilli, Budd et al. 2004; Hayes, 
Cristofanilli et al. 2006; Liu, Shields et al. 2009; Bidard, Peeters et al. 
2014; Liu 2014; Campton, Ramirez et al. 2015)1-5 Beyond simple 
enumeration, molecular profiling of these cells may provide clinically 
relevant predictive information to guide the selection of therapy. Deriving 
detailed molecular signatures for isolated CTCs may also facilitate drug 
discovery by assessing the markers unique to progression, such that 
relapsing patients may be treated for their current molecular disease.  
The RareCyte CTC technology is a comprehensive, reproducible and 
highly sensitive dual-platform for collecting, identifying and analyzing 
CTCs that does not rely on EpCAM expression for enrichment.6 The front 
end AccuCyte system is based fundamentally on the density of CTCs, 
which is within the range of the buffy coat; a unique separation tube and 
collector device allow for virtually complete harvesting of the buffy coat 
into a small volume for application to a microscopic slide without cell 
lysis or wash steps, a potential source of CTC loss. The follow-up 
CyteFinder system is an automated scanning digital microscope and image 
analysis system that presents high-resolution images of candidate cells 
stained with well-characterized markers before definitive classification as 
a CTC. Importantly, CyteFinder includes an integrated device 
(CytePicker™) for CTC retrieval that is mechanically precise, enabling 
the isolation of DNA derived from single or pooled CTCs advanced 
genomic analyses including the detection of specific mutations and 
targeted NGS. The Mayo group has established experience detecting and 
isolated purified CTCs from breast cancer patients, as well as the 
capability to design 4- or 6-marker panels to capture specific phenotypic 
populations of CTCs.  
10 mL whole blood samples will be collected in AccuCyte Blood 
Collection Tubes, which contain the proprietary RareCyte cell 
preservative. These samples will be shipped immediately at ambient 
temperature to Mayo Clinic Rochester and then processed through the 
RareCyte system within 3 days of collection. CTCs will be captured onto 
glass slides (8 slides per blood sample) for subsequent immunofluorescent 
staining, selection, and single cell isolation. The markers used for CTC 
identification will include DAPI or SYTOX orange, cytokeratin, and 
EpCAM at a minimum. CD45 will be used to distinguish WBCs (CD45 
positive) from CTCs (CD45 negative). Pure populations of CTCs will then 
be isolated and stored for subsequent molecular analyses, as yet to be 
determined.  
 


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Protocol Version Date: 21Jun2018 
15.0 
Drug Information 
15.1 
FTD/TPI (TAS-102; Lonsurf®; Trifluridine (FTD) / Tipiracil hydrochloride (TPI)) 
15.11 Background 
FTD/TPI is an orally available combination drug of an antineoplastic 
thymidine-based nucleoside analogue, 1M trifluridine (FTD), and 0.5 M 
tipiracil hydrochloride (TPI). FTD is incorporated into deoxyribonucleic acid 
of tumor cells following phosphorylation. TPI inhibits degradation of FTD by 
thymidine phosphorylase. 
15.12 Formulation 
FTD/TPI contains trifluridine (FTD) and tipiracil (TPI as active ingredients with 
a molar ratio of 1:0.5. TAS-102 drug products are immediate-released film 
coated tablets, with two strengths of 15 mg and 20 mg (expressed as FTD). The 
inactive ingredients of the TAS-102 15 mg and 20 mg tablets are lactose 
monohydrate, pregelatinized starch, stearic acid, hypromellose, polyethylene 
glycol, titanium dioxide, red ferric oxide (only 20 mg tablet), and magnesium 
stearate. 
FTD/TPI (TAS-102) tablet (15 mg) contains 15 mg FTD and 7.065 mg 
TPI as active ingredients. The appearance is white round tablet. 
FTD/TPI (TAS-102) tablet (20 mg) contains 20 mg FTD and 9.42 mg TPI 
as active ingredients. The appearance is pale red round tablet. 
15.13 Preparation and storage 
Store at 20°C to 25°C (68°F to 77°F); excursions are permitted from 15°C to 
30°C (59°F to 86°F).  If stored outside of original bottle, discard after 30 days  
15.14 Administration 
Recommended to take within 1 hour after completion of the morning and evening 
meals. 
15.15 Pharmacokinetic information 
Protein Binding: Trifluridine:  >96% (primarily to albumin); Tipiracil:  <8% 
Metabolism: Trifluridine and tipiracil are not metabolized by cytochrome P450 
(CYP) enzymes. Trifluridine is mainly eliminated by metabolism via thymidine 
phosphorylase to form an inactive metabolite, 5-(trifluoromethyl) uracil (FTY)  
Half-life elimination: Trifluridine: 2.1 hours (at steady state); Tipiracil:  2.4 
hours (at steady state)  
Time to peak, plasma: ~2 hours 
Excretion: Trifluridine: Urine (<2% [as unchanged drug]; ~19% [as inactive 
metabolite FTY]); Tipiracil: Urine (~29% [as unchanged drug] . 
15.16 Potential Drug Interactions 
Caution is required when using drugs that are human thymidine kinase 
substrates, e.g., zidovudine. Such drugs, if used concomitantly with FTD/TPI, 
may theoretically compete with the effector of FTD/TPI, i.e., FTD, for 
activation via thymidine kinases. Therefore, when using antiviral drugs that 
are human thymidine kinase substrates, monitor for possible decreased 
efficacy of the antiviral agent, and consider switching to an alternative 


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antiviral agent that is not a human thymidine kinase substrate such as: 
lamivudine, zalcitabine, didanosine, abacavir, etc. 
15.17 Known potential adverse events:  
Very common known potential toxicities, ≥10%: 
Blood and lymphatic:  Anemia, leukopenia, neutropenia, thrombocytopenia 
Gastrointestinal:  Diarrhea, nausea, vomiting 
General:  Fatigue 
Metabolism and nutrition:  Decreased appetite 
 
Common known potential toxicities, ≥1% - <10% 
Blood and lymphatic:  Febrile neutropenia, lymphopenia, monocytosis 
Dermatologic:  Alopecia, dry skin, Palmar-plantar erythrodysesthesia syndrome, 
pruritis, rash 
Gastrointestinal:  Abdominal pain, constipation, oral disorder, stomatitis 
General:  Malaise, mucosal inflammation, edema, pyrexia 
Hepatobiliary:  Hyperbilirubinemia 
Infections:  Lower respiratory tract infection, upper respiratory tract infection 
Investigations:  Blood alkaline phosphatase increased, hepatic enzyme increased, 
weight decreased 
Metabolism and nutrition:  Hypoalbuminemia 
Nervous System:  Dizziness, dysgeusia, headache, peripheral neuropathy 
Psychiatric:  Insomnia 
Renal and urinary:  Proteinuria 
Respiratory:  Cough, dyspnea 
Vascular:  Flushing 
 
Uncommon known potential toxicities, <1% (Limited to important or life-
threatening):  
Blood and lymphatic:  Pancytopenia 
Gastrointestinal:  Ascites, colitis, ileus, acute pancreatitis, subileus 
General:  General physical health deterioration 
Infections:  Bacterial infection, biliary tract infection, enteritis infection, urinary 
tract infection  
Investigations:  Blood lactate dehydrogenase increased  
Metabolism and nutrition:  Dehydration 
Respiratory:  Pulmonary embolism 
 
 


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Protocol Version Date: 21Jun2018 
15.18 Drug procurement 
FTD/TPI (TAS-102) will be provided free of charge by Taiho Oncology. 
15.19 Nursing Guidelines 
15.191 
Instruct Patients to take FTD/TPI (TAS-102) within 1 hour after 
morning or evening meal with a glass of water. Patients will not make 
up for a missed dose. If a patient vomits after taking the study 
medication, the dose should not be replaced. 
15.192 
Patients may experience fatigue. Instruct patients in energy conserving 
lifestyle. 
15.193 
GI side effects are common, including nausea, decreased appetite, 
diarrhea, vomiting, and abdominal pain. 
15.194 
Cytopenias are common. Monitor CBC w/diff and instruct patients to 
report any signs or symptoms of infection and/or unusual bruising or 
bleeding to the study team. 
15.195 
Rarely Pulmonary embolism has been reported with this agent.  
Instruct patient to report any shortness of breath or chest pain to study 
team and/or seek out emergency medical attention. 
15.196 
Although uncommon, warn patients of the possibility of alopecia.  
 
 


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Protocol Version Date: 21Jun2018 
16.0  
Statistical Considerations and Methodology  
16.1 
Overview 
This protocol will assess the efficacy of FTD/TPI (TAS-102) in patients with refractory 
cholangiocarcinoma using a single stage phase II study design. This single arm Phase II 
trial will assess the 16-week progression-free survival rate (by RECIST v1.1) associated 
with FTD/TPI (TAS-102) in patients with refractory cholangiocarcinoma. We will adopt 
a PFS rate of 10% as the null hypothesis and PFS rate of 30% as the alternative 
hypothesis.  In addition to response, this study will also evaluate the overall response rate 
(ORR), progression-free survival (PFS), overall survival (OS), and adverse events. 
16.11 Primary Endpoint 
The primary endpoint for this study is 16-week progression-free survival 
associated with FTD/TPI (TAS-102) in patients with refractory 
cholangiocarcinoma.  
 
16.2 
Statistical Design:  
16.21 Decision Rule 
The largest success proportion where the proposed treatment regimen would be 
considered ineffective in this population is 10%, and the smallest success 
proportion that would warrant subsequent studies with the proposed regimen in 
this patient population is 30%. The following single stage design uses 25 
patients to test the null hypothesis that the true success proportion in a given 
patient population is at most 10%. If 5 or fewer successes are observed in the 25 
evaluable patients, we will consider this regimen ineffective in this patient 
population. If 6 or more successes are observed in the 25 evaluable patients, we 
may recommend further testing of this regimen in subsequent studies in this 
population. 
NOTE: We consider a success to be alive and progression-free by 16 weeks post-
registration (i.e. stable disease, partial response, or complete response). 
16.22 Sample Size:  
The single stage study design to be utilized is fully described in Section 16.21. A 
maximum of 25 evaluable patients will be accrued onto this phase II study unless 
undue toxicity is encountered. We anticipate accruing an additional 3 patients to 
account for ineligibility, cancellation, major treatment violation, or other reasons. 
Maximum projected accrual is therefore 28 patients.  
16.23 Accrual Time and Study Duration 
The anticipated accrual rate is approximately 2 patients per month. Therefore, the 
accrual period for this phase II study is expected to be between 7.5 and 14 
months, depending upon whether patients are accrued beyond the first stage. The 
final analysis can begin approximately 18 months after the trial begins, i.e. as 
soon as the last patient has been observed for 4 months.  
16.24 Power and Significance Level 
Assuming that the number of successes is binomially distributed, the significance 
level is 0.05 and the probability of declaring that this regimen warrants further 
studies (i.e. statistical power) under various success proportions and the 


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Protocol Version Date: 21Jun2018 
probability of stopping accrual after the first stage can be tabulated as a function 
of the true success proportion as shown in the following table. 
If the true success proportion is . . . 
0.1 
0.15 
0.2 
0.25 
0.30 
then the probability of declaring that the regimen 
warrants further studies is . . 
0.033 
0.160 
0.383 
0.622 
0.807 
16.25 Other Considerations 
Adverse events, quality/duration of response, and patterns of treatment failure 
observed in this study, as well as scientific discoveries or changes in standard 
care will be taken into account in any decision to terminate the study. 
16.3 
Analysis Plan 
The analysis for this trial will commence at planned time points (see 16.2) and at 
the time the patients have become evaluable for the primary endpoint. Such a 
decision will be made by the Statistician and Study Chair, in accord with CCS 
Standard Operating Procedures, availability of data for secondary endpoints (eg, 
laboratory correlates), and the level of data maturity. It is anticipated that the 
earliest date in which the results will be made available via manuscript, abstract, 
or presentation format is when patients have been on study for 16 weeks (i.e. 
received second scan). 
16.31 Primary Endpoint 
16.311 
Definition: The primary endpoint of this trial is the progression-free 
survival rate. This is defined as the proportion of evaluable patients 
who are progression-free (stable disease, partial response, complete 
response) at 16 weeks. All patients meeting the eligibility criteria who 
have signed a consent form and have begun treatment will be 
considered evaluable.  
16.312 
Estimation: The proportion of successes will be estimated by the 
number of successes divided by the total number of evaluable patients. 
Confidence intervals for the true success proportion will be calculated 
according to the approach of Clopper and Pearson. 
16.316 
Over Accrual: If more than the target number of patients are accrued, 
the additional patients will not be used to evaluate the stopping rule or 
used in any decision making processes; however, they will be included 
in final point estimates and confidence intervals as though they were 
accrued in the final stage. 
16.32 Secondary Endpoints  
The following endpoints will be evaluated: overall response rate, progression-free 
survival, overall survival, and adverse events.   
16.321 
Overall Response Rate (ORR): Overall response rate is defined as the 
proportion of patients who experience either a partial response or 
complete response by the given time point. ORR will be reported 
descriptively and a 95% confidence interval will be reported. 
16.322 
Progression-Free Survival:  Progression-free survival is defined as the 
time from study entry to the first of either disease progression or death 
from any cause, where disease progression will be determined based on 


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Protocol Version Date: 21Jun2018 
RECIST 1.1 criteria.  PFS will be estimated using the Kaplan-Meier 
method. The median PFS and 95% confidence interval will be 
reported. Patients will be censored at the last disease assessment date. 
16.323 
Overall Survival (OS): Overall survival is defined as the time from 
study entry to death from any cause. OS will be estimated using the 
Kaplan-Meier method. The median OS and 95% confidence interval 
will be reported. Patients will be censored at the date patient was last 
known to be alive. 
16.324 
Adverse events: The maximum grade for each type of adverse event by 
patient will be summarized by frequencies and percentages using 
CTCAE version 4.0. We will also closely monitor adverse events 
throughout the study.  
16.33 Correlative Research 
16.331 
To determine if CTCs of cfDNA at baseline will correlate with 
prognosis or response to therapy. 
16.332 
To determine if change in CTCs or cfDNA will correlate with efficacy 
endpoints. 
16.333 
To determine if different mutations status of the tumor will affect 
efficacy endpoints. 
16.4 
Data & Safety Monitoring: 
16.41 Review 
The study chair(s) and the study statistician will review the study at least twice a 
year to identify accrual, adverse event, and any endpoint problems that might be 
developing. The Mayo Clinic Cancer Center (MCCC) Data Safety Monitoring 
Board (DSMB) is responsible for reviewing accrual and safety data for this trial 
at least twice a year, based on reports provided by the MCCC Statistical Office. 
16.42 Adverse Event Stopping Rules 
The stopping rules specified below are based on the knowledge available at study 
development. We note that the Adverse Event Stopping Rule may be adjusted in 
the event of either (1) the study re-opening to accrual or (2) at any time during 
the conduct of the trial and in consideration of newly acquired information 
regarding the adverse event profile of the treatment(s) under investigation. The 
study team may choose to suspend accrual because of unexpected adverse event 
profiles that have not crossed the specified rule below. 
Accrual will  be temporarily suspended to this study if at any time we observe 
events considered at least possibly related to study treatment (i.e. an adverse 
event with attribute specified as “possible”, “probable”, or “definite”) that satisfy 
either of the following: 
 
If 3 or more patients in the first 10 treated patients (30% or higher after 
first 10 patients) experience at least one grade 4+ adverse event at least 
possibly related to the study treatment 
 
If one or more patients in the first 10 treated patients (20% or higher after 
first 10 patients) experience a grade 5 adverse event at least possibly 
related to the study treatment 


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Protocol Version Date: 21Jun2018 
We note that we will review Grade 4 and 5 adverse events deemed “unrelated” or 
“unlikely to be related”, to verify their attribution and to monitor the emergence 
of a previously unrecognized treatment-related adverse event. 
16.7 
Inclusion of Women and Minorities 
16.71 Availability 
This study will be available to all eligible patients, regardless of race, gender, or 
ethnic origin. 
16.72 Differential effects 
There is no information currently available regarding differential effects of this 
regimen in subsets defined by race, gender, or ethnicity, and there is no reason to 
expect such differences to exist. Therefore, although the planned analysis will, as 
always, look for differences in treatment effect based on racial and gender 
groupings, the sample size is not increased in order to provide additional power 
for subset analyses. 
16.73 Mayo Clinic Population 
Based on prior MC studies involving similar disease sites, we expect about 4 % 
of patients will be classified as minorities by race and about 50 % of patients will 
be women. Expected sizes of racial by gender subsets for patients registered to 
this study are shown in the following table: 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
1 
1 
2 
Not Hispanic or Latino 
13 
13 
26 
Ethnic Category: Total of all subjects 
14 
14 
28 
Racial Category 
American Indian or Alaskan Native 
0 
0 
0 
Asian 
0 
0 
0 
Black or African American 
1 
1 
2 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
13 
13 
26 
Racial Category: Total of all subjects 
14 
14 
28 
 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rican, South or Central 
American, or other Spanish culture or origin, regardless of race. The term “Spanish 
origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 


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Protocol Version Date: 21Jun2018 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the original 
peoples of North, Central, or South America, and who maintains tribal affiliations or 
community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, China, 
India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and 
Vietnam. (Note: Individuals from the Philippine Islands have been recorded as Pacific 
Islanders in previous data collection strategies.)  
Black or African American – a person having origins in any of the black racial 
groups of Africa. Terms such as “Haitian” or “Negro” can be used in addition to 
“Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of the 
original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle 
East, or North Africa. 
17.0  
Pathology Considerations/Tissue Biospecimens: None 
 


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Protocol Version Date: 21Jun2018 
18.0 
Records and Data Collection Procedures  
18.1 
Submission Timetable 
Data submission instructions for this study can be found in the Data Submission 
Schedule. 
18.2 
Event monitoring 
See 4.0 Test Schedule and Data Submission Schedule (DSS) for the event monitoring 
schedule. 
18.3 
CRF completion 
This study will use Medidata Rave for remote data capture (rdc) of all study data. 
18.4 
Site responsibilities 
Each site will be responsible for insuring that all materials contain the patient’s initials, 
MCCC registration number, and MCCC protocol number. Patient’s name must be 
removed. 
18.5 
Supporting documentation 
This study requires baseline supporting documentation of histologic diagnosis and 
staging of genetic mutations which includes the most recent tumor tissue biopsy 
pathology report. To submit these materials, they can be uploaded into the Supporting 
Documentation form in Medidata Rave®. These reports should be submitted within 
21 days of registration. 
This study requires supporting documentation for evidence of response to study therapy 
and progression after study therapy. Documentation of tumor genetic mutations is 
requested at any time, if available. 
18.6 
Labelling of materials 
Each site will be responsible for insuring that all materials contain the patient’s initials, 
MCCC registration number, and MCCC protocol number. Patient’s name must be 
removed. 
18.7 
Incomplete materials 
Any data entered into a form will result in that form being marked as “received.” 
However, missing data in each form will be flagged by edit checks in the database. 
18.8 
Overdue lists 
A list of overdue materials is automatically available to each site at any time. In addition, 
a list of overdue materials and forms for study patients will be generated monthly. The 
listings will be sorted by location and will include the patient study registration number. 
The appropriate co-sponsor/participant will be responsible to obtain the overdue material. 
18.9 
Corrections forms 
If a correction is necessary the QAS will query the site. The query will be sent to the 
appropriate site to make the correction in the database and respond back to the QAS.  
 
 


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Protocol Version Date: 21Jun2018 
19.0  
Budget 
19.1 
Costs charged to patient 
Routine clinical care costs will be the responsibility of the patient and/or the patient’s 
insurance company. This responsibility includes costs associated with surgery and with 
the administration of standard chemotherapy (carboplatin/paclitaxel or FOLFOX), and 
radiotherapy. These drugs are commercially available and will be the responsibility of the 
patient and/or the patient’s insurance company. 
19.2 
Tests to be research funded 
• 
FTD/TPI (TAS-102) will be provided by Taiho Oncology  
• 
Correlative studies  
• 
Collection, processing and storage of blood for research. 
19.3 
Other considerations 
Taiho Oncology will provide a grant to Mayo Clinic to help with costs for the conduct of 
this study. 
 
 
 


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Protocol Version Date: 21Jun2018 
20.0 
References 
Bidard, F. C., D. J. Peeters, et al. (2014). "Clinical validity of circulating tumour cells in patients with 
metastatic breast cancer: a pooled analysis of individual patient data." The Lancet. Oncology 15(4): 406-
414. 
 
Bijnsdorp, I. V., G. J. Peters, et al. (2010). "Differential activation of cell death and autophagy results in 
an increased cytotoxic potential for trifluorothymidine compared to 5-fluorouracil in colon cancer cells." 
International journal of cancer 126(10): 2457-2468. 
 
Campton, D. E., A. B. Ramirez, et al. (2015). "High-recovery visual identification and single-cell retrieval 
of circulating tumor cells for genomic analysis using a dual-technology platform integrated with 
automated immunofluorescence staining." BMC cancer 15: 360. 
 
Choi, C. W., I. K. Choi, et al. (2000). "Effects of 5-fluorouracil and leucovorin in the treatment of 
pancreatic-biliary tract adenocarcinomas." American journal of clinical oncology 23(4): 425-428. 
 
Cristofanilli, M., G. T. Budd, et al. (2004). "Circulating tumor cells, disease progression, and survival in 
metastatic breast cancer." The New England journal of medicine 351(8): 781-791. 
 
Dawson, S. J., D. W. Tsui, et al. (2013). "Analysis of circulating tumor DNA to monitor metastatic breast 
cancer." The New England journal of medicine 368(13): 1199-1209. 
 
Diehl, F., M. Li, et al. (2005). "Detection and quantification of mutations in the plasma of patients with 
colorectal tumors." Proceedings of the National Academy of Sciences of the United States of America 
102(45): 16368-16373. 
 
Diehl, F., K. Schmidt, et al. (2008). "Circulating mutant DNA to assess tumor dynamics." Nature 
medicine 14(9): 985-990. 
 
Ducreux, M., P. Rougier, et al. (1998). "Effective treatment of advanced biliary tract carcinoma using 5-
fluorouracil continuous infusion with cisplatin." Annals of oncology : official journal of the European 
Society for Medical Oncology 9(6): 653-656. 
 
Emura, T., F. Nakagawa, et al. (2004). "An optimal dosing schedule for a novel combination 
antimetabolite, TAS-102, based on its intracellular metabolism and its incorporation into DNA." 
International journal of molecular medicine 13(2): 249-255. 
 
Emura, T., N. Suzuki, et al. (2004). "A novel combination antimetabolite, TAS-102, exhibits antitumor 
activity in FU-resistant human cancer cells through a mechanism involving FTD incorporation in DNA." 
International journal of oncology 25(3): 571-578. 
 
Falkson, G., J. M. MacIntyre, et al. (1984). "Eastern Cooperative Oncology Group experience with 
chemotherapy for inoperable gallbladder and bile duct cancer." Cancer 54(6): 965-969. 
 
Feisthammel, J., K. Schoppmeyer, et al. (2007). "Irinotecan with 5-FU/FA in advanced biliary tract 
adenocarcinomas: a multicenter phase II trial." American journal of clinical oncology 30(3): 319-324. 
 
Glimelius, B., K. Hoffman, et al. (1996). "Chemotherapy improves survival and quality of life in 
advanced pancreatic and biliary cancer." Annals of oncology : official journal of the European Society for 
Medical Oncology / ESMO 7(6): 593-600. 


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Hayes, D. F., M. Cristofanilli, et al. (2006). "Circulating tumor cells at each follow-up time point during 
therapy of metastatic breast cancer patients predict progression-free and overall survival." Clinical cancer 
research : an official journal of the American Association for Cancer Research 12(14 Pt 1): 4218-4224. 
 
Hezel, A. F. and A. X. Zhu (2008). "Systemic therapy for biliary tract cancers." The oncologist 13(4): 
415-423. 
 
Hong, Y. S., J. Lee, et al. (2007). "Phase II study of capecitabine and cisplatin in previously untreated 
advanced biliary tract cancer." Cancer chemotherapy and pharmacology 60(3): 321-328. 
 
Huggett, M. T., H. Passant, et al. (2014). "Outcome and patterns of care in advanced biliary tract 
carcinoma (ABC): experience from two tertiary institutions in the United Kingdom." Tumori 100(2): 219-
224. 
 
Kim, S. T., W. S. Lee, et al. (2015). "Prospective blinded study of somatic mutation detection in cell-free 
DNA utilizing a targeted 54-gene next generation sequencing panel in metastatic solid tumor patients." 
Oncotarget 6(37): 40360-40369. 
 
Kim, T. W., H. M. Chang, et al. (2003). "Phase II study of capecitabine plus cisplatin as first-line 
chemotherapy in advanced biliary cancer." Annals of oncology : official journal of the European Society 
for Medical Oncology 14(7): 1115-1120. 
 
Lenz, H. J., S. Stintzing, et al. (2015). "TAS-102, a novel antitumor agent: a review of the mechanism of 
action." Cancer treatment reviews 41(9): 777-783. 
 
Liu, M. C. (2014). "By the numbers: does circulating tumor cell enumeration have a role in metastatic 
breast cancer?" Journal of clinical oncology : official journal of the American Society of Clinical 
Oncology 32(31): 3479-3482. 
 
Liu, M. C., P. G. Shields, et al. (2009). "Circulating tumor cells: a useful predictor of treatment efficacy in 
metastatic breast cancer." Journal of clinical oncology : official journal of the American Society of 
Clinical Oncology 27(31): 5153-5159. 
 
Murakami, Y., H. Kazuno, et al. (2000). "Different mechanisms of acquired resistance to fluorinated 
pyrimidines in human colorectal cancer cells." International journal of oncology 17(2): 277-283. 
 
Rogers, J. E., L. Law, et al. (2014). "Second-line systemic treatment for advanced cholangiocarcinoma." 
Journal of gastrointestinal oncology 5(6): 408-413. 
 
Sharma, A., A. D. Dwary, et al. (2010). "Best supportive care compared with chemotherapy for 
unresectable gall bladder cancer: a randomized controlled study." Journal of clinical oncology : official 
journal of the American Society of Clinical Oncology 28(30): 4581-4586. 
 
Siegel, R. L., K. D. Miller, et al. (2016). "Cancer statistics, 2016." CA: a cancer journal for clinicians 
66(1): 7-30. 
 
Tanaka, N., K. Sakamoto, et al. (2014). "Repeated oral dosing of TAS-102 confers high trifluridine 
incorporation into DNA and sustained antitumor activity in mouse models." Oncology reports 32(6): 
2319-2326. 
 


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Ueno, H., T. Okusaka, et al. (2004). "Phase II study of S-1 in patients with advanced biliary tract cancer." 
British journal of cancer 91(10): 1769-1774. 
 
Valle, J., H. Wasan, et al. (2010). "Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer." 
The New England journal of medicine 362(14): 1273-1281. 
 
 
 
 


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Appendix I 
ECOG Performance Status 
 
ECOG PERFORMANCE STATUS* 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair. 
5 
Dead 
*As published in Am. J. Clin. Oncol.: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: 
Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-
655, 1982. 
The ECOG Performance Status is in the public domain therefore available for public use. To duplicate the 
scale, please cite the reference above and credit the Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
From http://www.ecog.org/general/perf stat.html 
 
 


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Appendix II 
Patient Medication Diary 
Name  
 
Study ID Number  
 
 
Please complete this diary on a daily basis. Write in the number of pills that you took in the 
appropriate “Day” box. 
On the days that you do not take any study drug, please write in “0”. If you forget to take your 
dose, please write in “0”, but remember to take your prescribed dose at the next regularly 
scheduled time. 
Take your pills twice per day with water within one hour after a meal. 
If you experience any health/medical complaints or take any medication other than FTD/TPI 
(TAS-102), please record this information. 
 
Week of: _________________________ 
Study Drug  
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
FTD/TPI 
(TAS-102) 
AM 
PM 
AM 
PM 
AM 
PM 
AM 
PM 
AM 
PM 
15 mg tablets 
 
 
 
 
 
 
 
 
 
 
20 mg tablets 
 
 
 
 
 
 
 
 
 
 
 
Week of: ______________________ 
Do not take any TAS-102 this week 
 
Week of: _________________________ 
Study Drug  
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
FTD/TPI  
(TAS-102) 
AM 
PM 
AM 
PM 
AM 
PM 
AM 
PM 
AM 
PM 
15 mg tablets 
 
 
 
 
 
 
 
 
 
 
20 mg tablets 
 
 
 
 
 
 
 
 
 
 
 
Week of: ______________________ 
Do not take any FTD/TPI (TAS-102) this week 
Week of: ______________________ 
Do not take any FTD/TPI (TAS-102) this week 
Remember to bring this diary with you to your next appointment along with any FTD/TPI pill bottles 
(full, empty, or partially filled). 
Patient signature: ___________________________________________  
Date: ______________________ 
 
 




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Appendix III Taiho Tables for Frequency for Serious Adverse Drug Reactions for TAS-102 
The baseline frequency for serious adverse drug reactions by MedDRA System Organ Class (Version 
18.0) and preferred term in patients receiving FTD/TPI (TAS-102) monotherapya is as below (data taken 
from TAS-102 Global Investigator’s Brochure Ver 7.0 11Oct2016): 
MedDRA SOC 
Preferred Term 
Baselineb  
(N=769), n (%) 
Total Serious Related Advere Events 
60 (7.8) 
Blood and lymphatic system disorders 
Anaemia 
Disseminated intravascular coagulation 
Febrile neutropenia 
Leukopenia 
Neutropenia 
Pancytopenia 
Thrombocytopenia 
32 (4.2) 
10 (1.3) 
1 (0.1) 
18 (2.3) 
2 (0.3) 
5 (0.7) 
1 (0.1) 
1 (0.1) 
Gastrointestinal disorders 
Abdominal pain 
Anal fistula 
Ascite 
Colitis 
Constipation 
Diarrhoea 
Ileus 
Nausea 
Pancreatitis acute 
Subileus 
Vomiting 
16 (2.1) 
4 (0.5) 
1 (0.1) 
1 (0.1) 
2 (0.3) 
1 (0.1) 
3 (0.4) 
2 (0.3) 
2 (0.3) 
1 (0.1) 
1 (0.1) 
5 (0.7) 
General disorders and administration site conditions 
Fatigue 
General physical health deterioration 
Malaise 
5 (0.7) 
3 (0.4) 
1 (0.1) 
1 (0.1) 
Hepatobiliary disorders 
Cholangitis 
Liver disorder 
2 (0.3) 
1 (0.1) 
1 (0.1) 
Infections and infestations 
Bacteraemia 
11 (1.4) 
1 (0.1) 


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Protocol Version Date: 21Jun2018 
MedDRA SOC 
Preferred Term 
Baselineb  
(N=769), n (%) 
Infections and infestations (continued) 
Biliary tract infection 
Cellulitis 
Endophthalmitis 
Enteritis infections 
Lower respiratory tract infection 
Pelvic infection 
Pneumonia 
Pneumonia klebsiella 
Sepsis 
Septic shock 
Urinary tract infection 
11 (1.4) 
1 (0.1) 
1 (0.1) 
1 (0.1) 
1 (0.1) 
1 (0.1) 
1 (0.1) 
4 (0.5) 
1 (0.1) 
1 (0.1) 
1 (0.1) 
2 (0.3) 
Investigations 
Blood lactate dehydrogenase increased 
Haemoglobin decreased 
Neutrophil count decreased 
Platelet count decreased 
Weight decreased 
White blood cell count decreased 
4 (0.5) 
1 (0.1) 
1 (0.1) 
1 (0.1) 
1 (0.1) 
1 (0.1) 
2 (0.3) 
Metabolism and nutrition disorders 
Decreased appetite 
Dehydration 
Hypokalaemia 
Hyponatraemia 
6 (0.8) 
4 (0.5) 
3 (0.4) 
1 (0.1) 
1 (0.1) 
Renal and urinary disorders 
Acute kidney injury 
1 (0.1) 
1 (0.1) 
Respiratory, thoracic and mediastinal disorders 
Pulmonary embolism 
1 (0.1) 
1 (0.1) 
aTAS-102 studies investigating 35 mg/m2/dose monotherapy in patients with colorectal cancer. 
bOnly includes serious adverse events from protocols completed as of 24 July 2016: J001-10040010, 
J003-10040030, J004-10040040, TPU-TAS-102-101, TPU-TAS-102-102, TPU-TAS-102-103, TPU-
TAS-102-104, TPU-TAS-102-108, TPU-TAS-102-301.  
 
Further adverse events (>5%) in the RECOURSE study are mentioned in section 1.2. 
 
 


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The most frequently reported adverse vents (>10% in either pooled treatment group) reported for patients 
in the randomized studies (J003-10040030 and TPU-TAS-1-2-301 is as follows (data taken from TAS-
102 Global Investigator’s Brochure Ver 7.0 11Oct2016): 
MedDRA SOC 
Preferred Term 
Studies J003-10040030 and TPU-TAS-102-301 Combined 
TAS-102 (N=646), n (%) 
Placebo (N=322), n (%) 
All Grades 
Grade ≥3 
All Grades 
Grade ≥3 
Any adverse event 
635 (98.3) 
448 (69.3) 
299 (92.9) 
146 (45.3) 
Blood and lymphatic system disorder 
Anaemias 
Neutropenia 
311 (48.1) 
195 (30.2) 
29 (9.0) 
11 (3.4) 
216 (33.4) 
88 (13.6) 
22 (6.8) 
7 (2.2) 
156 (24.1) 
107 (16.6) 
0 
0 
Gastrointestinal disorders 
Abdominal pain 
Constipation 
Diarrhea 
Nausea 
Vomiting 
502 (77.7) 
83 (12.8) 
195 (60.6) 
37 (11.5) 
101 (15.6) 
12 (1.9) 
46 (14.3) 
10 (3.1) 
92 (14.2) 
1 (0.2) 
44 (13.7) 
3 (0.9) 
213 (33.0) 
23 (3.6) 
45 (14.0) 
1 (0.3) 
331 (51.2) 
15 (2.3) 
79 (24.5) 
3 (0.9) 
186 (28.8) 
15 (2.3) 
52 (16.1) 
1 (0.3) 
General disorders and administration site 
conditions 
Asthenia 
Fatigue 
Oedema peripheral 
Pyrexia 
457 (70.7) 
77 (11.9) 
168 (52.2) 
38 (11.8) 
97 (15.0) 
18 (2.8) 
30 (9.3) 
8 (2.5) 
246 (38.1) 
25 (3.9) 
82 (25.5) 
16 (5.0) 
67 (10.4) 
2 (0.3) 
31 (9.6) 
3 (0.9) 
114 (17.6) 
6 (0.9) 
44 (13.7) 
2 (0.6) 
Investigations 
Aspartate aminotransferase increased 
Blood alkaline phosphorase increased 
Blood bilirubin increased 
Haemoglobin decreased 
Neutrophil count decreased 
Platelet count decreased 
White blood cell count decreased 
399 (61.8) 
216 (33.4) 
132 (41.0) 
44 (13.7) 
53 (8.2) 
9 (1.4) 
34 (10.6) 
8 (2.5) 
64 (9.9) 
21 (3.3) 
41 (12.7) 
14 (4.3) 
78 (12.1) 
24 (3.7) 
27 (8.4) 
11 (3.4) 
85 (13.2) 
21 (3.3) 
9 (2.8) 
3 (0.9) 
229 (35.9) 
142 (22.0) 
2 (0.6) 
0 
125 (19.3) 
18 (2.8) 
7 (2.2) 
0 
232 (35.9) 
87 (13.5) 
3 (0.9) 
0 
Metabolism and nutrition disorders 
Decreased appetite 
319 (49.4) 
58 (9.1) 
123 (38.2) 
29 (9.0) 
278 (43.0) 
24 (3.7) 
97 (30.1) 
15 (4.7) 
Respiratory, thoracic and mediastinal 
disorders 
Cough 
Dyspnoea 
169 (26.2) 
33 (5.1) 
86 (26.7) 
18 (5.6) 
63 (9.8) 
2 (0.3) 
33 (10.2) 
2 (0.6) 
63 (9.8) 
16 (2.5) 
34 (10.6) 
10 (3.1)