Conditions: Advanced Bile Duct Carcinoma Advanced Gallbladder Carcinoma Refractory Bile Duct Carcinoma Refractory Gallbladder Carcinoma Stage III Distal Bile Duct Cancer AJCC v8 Stage III Gallbladder Cancer AJCC v8 Stage III Intrahepatic Bile Duct Cancer AJCC v8 Stage IIIA Distal Bile Duct Cancer AJCC v8 Stage IIIA Gallbladder Cancer AJCC v8 Stage IIIA Intrahepatic Bile Duct Cancer AJCC v8 Stage IIIB Distal Bile Duct Cancer AJCC v8 Stage IIIB Gallbladder Cancer AJCC v8 Stage IIIB Intrahepatic Bile Duct Cancer AJCC v8 Stage IV Distal Bile Duct Cancer AJCC v8 Stage IV Gallbladder Cancer AJCC v8 Stage IV Intrahepatic Bile Duct Cancer AJCC v8 Stage IVA Gallbladder Cancer AJCC v8 Stage IVB Gallbladder Cancer AJCC v8
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 28
Healthy volunteers: no

Brief summary:
This phase II trial studies how well trifluridine/tipiracil and irinotecan work in treating patients with biliary tract cancer that has spread to other places in the body (advanced) and has not responded to treatment (refractory). Trifluridine/tipiracil and irinotecan may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVE:

I. Determine the efficacy of trifluridine and tipiracil hydrochloride (trifluridine/tipiracil) in combination with irinotecan hydrochloride (irinotecan) in patients with refractory biliary tract cancers using progression-free survival (PFS) at 16 weeks.

SECONDARY OBJECTIVES:

I. Assess the safety and tolerability of trifluridine/tipiracil in combination with irinotecan in patients with refractory biliary tract cancers through adverse event monitoring.

II. Further explore the efficacy of trifluridine/tipiracil in combination with irinotecan in patients with refractory biliary tract cancers by overall response rates (ORR), disease control rates (DCR), and overall survival (OS).

CORRELATIVE RESEARCH:

I. To determine if the number of circulating tumor cells (CTCs) or the level of cell-free deoxyribonucleic acid (DNA) (cfDNA) at baseline is prognostic or predictive to the response to therapy.

II. To determine if changes in CTCs or cfDNA correlate with efficacy endpoints. III. To determine if drug response from a parallel ex vivo trial using patient-derived tumor organoid correlates with clinical response to trifluridine/tipiracil plus irinotecan.

IV. To evaluate the role of thymidine kinase 1 (TK1) in predicting the clinical benefit of trifluridine/tipiracil plus irinotecan and discover potential mechanisms of resistance using patient-derived tumor organoid and pre-treatment biopsy specimen.

EXPLORATORY RESEARCH:

I. To evaluate patients who received prior treatment with fluorouracil (5-FU) independently from the entire population in the following areas: PFS, safety and tolerability, ORR, DCR, and OS.

OUTLINE:

Patients receive trifluridine and tipiracil hydrochloride orally (PO) twice daily (BID) on days 1-5 and irinotecan hydrochloride (IV) over 90 minutes on day 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity.

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

Arms:
arm 1: Patients receive trifluridine and tipiracil hydrochloride PO BID on days 1-5 and irinotecan hydrochloride IV over 90 minutes on day 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Irinotecan intervention 2: Irinotecan Hydrochloride intervention 3: Trifluridine and Tipiracil Hydrochloride
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given PO

Protocol document:
Prot_SAP_000.pdf: 




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Table of Contents 
MC1941 - Phase II Trial of Trifluridine/Tipiracil in Combination with Irinotecan in Biliary Tract Cancers
 ...................................................................................................................................................................... 1 
Protocol Resources ........................................................................................................................................ 2 
Table of Contents .......................................................................................................................................... 3 
Schema .......................................................................................................................................................... 4 
1.0 
Background ................................................................................................................................... 5 
2.0 
Goals ............................................................................................................................................. 8 
3.0 
Registration Patient Eligibility ...................................................................................................... 9 
4.0  
Test Schedule .............................................................................................................................. 11 
5.0 
Stratification Factors OR Grouping Factor: None ...................................................................... 12 
6.0 
Registration Procedures .............................................................................................................. 12 
7.0 
Protocol Treatment ...................................................................................................................... 14 
8.0 
Dosage Modification Based on Adverse Events ......................................................................... 16 
9.0 
Ancillary Treatment/Supportive Care ......................................................................................... 19 
10.0 
Adverse Event (AE) Monitoring and Reporting ......................................................................... 20 
11.0 
Treatment Evaluation/Measurement of Effect ............................................................................ 34 
12.0 
Descriptive Factors ..................................................................................................................... 39 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient ............................................................ 39 
14.0 
Body Fluid Biospecimens ........................................................................................................... 41 
15.0 
Drug Information ........................................................................................................................ 45 
16.0 
Statistical Considerations and Methodology ............................................................................... 51 
17.0  
Pathology Considerations/Tissue Biospecimens......................................................................... 57 
18.0 
Records and Data Collection Procedures .................................................................................... 61 
19.0  
Budget ......................................................................................................................................... 62 
20.0 
References ................................................................................................................................... 63 
Appendix I 
ECOG Performance Status ............................................................................................... 66 
Appendix II 
Patient Medication Diary .................................................................................................. 67 
 
 


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Schema 
 
Registration 
 
 
↓ 
 
 
Treatment with 
trifluridine/tipiracil Days 1-5  
and irinotecan Day 1 
 
 
↓ 
 
 
Events at any time: 
Disease Progression 
Intolerable adverse effects 
Patient refusal 
 
 
↓ 
 
 
Event monitoring 
 
Cycle = 14 days 
 
Generic name: trifluridine/tipiracil (FTD/TPI; TAS-102) 
Brand name(s): Lonsurf® 
Mayo Abbreviation: FTD/TPI  
Availability: Supplied by Taiho Pharmaceuticals 
Generic name: irinotecan 
Brand name(s): Camptosar® 
Mayo Abbreviation:  
Availability: Commercial 


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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 12,190 
patients will be diagnosed with BTCs in 2018 in United States. (Siegel et al. 2018) 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 et al. 1996; Sharma 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 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 
Trifluridine/tipiracil 
Trifluridine/tipiracil is a novel oral nucleoside consisting of α, α, α-trifluorothymidine 
(trifluridine) and 5-chloro-6-(2-iminopyrrolidin-1-yl) methyl-2,4 (1H,3H)-
pyrimidinedione hydrochloride (tipiracil). The active antitumor component is trifluridine 
which inhibits thymidylate synthase and is incorporated into DNA in tumor cells. 
Tipiracil is a thymidine phosphorylase inhibitor which prevents trifluridine from 
degradation. Therefore, trifluridine/tipiracil is mechanistically different from 5-
fluorouracil (5-FU). 
The clinical safety and efficacy of trifluridine/tipiracil was evaluated in the RECOURSE 
study conducted in patients with previously treated metastatic colorectal cancer (mCRC). 
(Mayer et al. 2015) A total of 800 patients were randomized to receive 
trifluridine/tipiracil plus best supportive care (BSC) or placebo 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 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 
trifluridine/tipiracil compared to 5.3 months in the placebo group (hazard ratio: 0.68; 
95% CI: 0.56-0.78). Median PFS was 2 months in trifluridine/tipiracil group and 1.7 
months in placebo group (hazard ratio: 0.48; 95% CI: 0.41-0.57). Common adverse 
events included fatigue, nausea, vomiting, diarrhea, anorexia and cytopenias. In addition, 
trifluridine/tipiracil also showed improved median OS compared to placebo in the phase 
3 TAGS trial of 507 patients with refractory gastric and gastroesophageal junction cancer 
who had received at least two prior therapies. (Shitara et al. 2018) 
The clinical activity of trifluridine/tipiracil has also been explored in combination with 
cytotoxic agents such as oxaliplatin and irinotecan in patients with mCRC whose disease 
progressed after at least one line of therapy. A phase I trial of trifluridine/tipiracil plus 
oxaliplatin in 17 patients with mCRC did not observe dose limiting toxicities (DLTs) 
with 23.5% Grade 3/4 neutropenia, 5.9% Grade 3/4, and 5.9% peripheral sensory 
neuropathy. These results were comparable to historical control. The recommended dose 
for phase II study was trifluridine/tipiracil 35 mg/m2 BID (Days 1-5 every 2 weeks) with 
oxaliplatin 85 mg/m2 (Day 1). Eight (47%) patients had stable disease. One (2.1%) 


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patient had a partial response. (Hollebecque et al. 2018) The combination of 
trifluridine/tipiracil and irinotecan was evaluated in 26 patients with advanced 
gastrointestinal tumors. The majority of patients had CRC (81%) whose disease 
progressed after at least one previous line of therapy. The study declared the maximum 
tolerated dose (MTD) as trifluridine/tipiracil 25 mg/m2 on Days 1-5 and irinotecan 
180 mg/m2 on Day 1 every 14-day cycle based on two observed DLTs (Grade 3 fatigue 
and Grade 2 neutropenia) in the trifluridine/tipiracil 30 mg/m2 and irinotecan 180 mg/m2 
cohort. In the subsequent dose expansion cohort of 24 patients with refractory mCRC 
treated with trifluridine/tipiracil, irinotecan, and bevacizumab, 10 (42%) patients had 
Grade 3/4 neutropenia, 3 (12.5%) patients had Grade 3/4 diarrhea. Three (12.5%) patients 
had a partial response and the disease control rate was 83% with median PFS of 
7.9 months. (Varghese et al. 2018a; Varghese et al. 2018b) 
1.3 
Study Rationale 
Fluoropyrimidine and irinotecan-based regimens are frequently utilized for treatment of 
advanced BTCs despite the fact that they are not FDA approved. (Huggett et al. 2014; 
Rogers et al. 2014) In retrospective studies, fluoropyrimidine based treatments have been 
shown to be associated with improved survival. (Huggett et al. 2014) However, there are 
only limited small prospective studies reported utilizing fluoropyrimidines. Single agent 
5-FU in early trials has yielded response rates of 10% with median OS of approximately 
6 months as a first line treatment. (Choi et al. 2000) S-1, a combination of tegafur (that is 
converted to 5-FU in the liver), 5-chloro-2,4-dihydroxypyridine (inhibitor of 
dihydropyrimidine dehydrogenase) and potassium oxonate has also shown modest 
activity in advanced BTCs as a single agent. (Ueno et al. 2004) The same applies to 
single agent irinotecan as demonstrated in a small phase 2 trial where the response rate of 
advanced BTCs was 8%. (Sanz-Altamira et al. 2001) 
Combination therapies such as 5-FU or capecitabine plus irinotecan as 2nd-line therapy 
for advanced BCTs are associated with better response rates at the expense of increased 
toxicities. The combination of 5-FU and irinotecan in an early trial demonstrated a 
response rate of 10% in 17 patients. (Feisthammel et al. 2007) A more recent randomized 
phase 2 trial compared capecitabine plus irinotecan with irinotecan alone as 2nd-line 
therapy in 60 patients with advanced BTCs. The authors found that the capecitabine plus 
irinotecan arms showed a significantly higher response rate of 13.3% vs 6.7% and disease 
control rate of 63% vs 50% with a similar toxicity profile, other than hand-foot syndrome 
which is unique to capecitabine. (Zheng et al. 2018) Addition of other agents to this 
combination in the 2nd-line setting was proven to have non-superior activity but 
significantly increased toxicities. (Larsen et al. 2018; Guion-Dusserre et al. 2015) These 
studies suggest that there may be a role for fluoropyrimidines in combination with 
irinotecan in advanced BTCs. 
The mechanism of trifluridine/tipiracil is distinct from fluoropyrimidine, which provided 
several advantages over 5-FU. Clinically with a twice daily dosing schedule of 
trifluridine/tipiracil, incorporation into DNA is the primary mechanism of action for 
antitumor effects instead of thymidine synthase inhibition when it was given with 
continuous infusion as 5-FU. Tipiracil is a potent inhibitor of thymidine phosphorylase, 
which is the enzyme that degrades trifluridine and helps maintain adequate plasma 
concentration needed for its activity. Thereby, the antitumor activity of trifluridine is 
more sustained compared to 5-FU, whose inhibition of thymidylate synthase rapidly 
disappears after rapid drug elimination. (Lenz et al. 2015; Tanaka et al. 2014) 
Trifluridine/tipiracil has shown activity in both fluoropyrimidine sensitive and resistant 


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tumors. (Emura et al. 2004a; Emura et al. 2004b) The primary mechanism of resistance to 
5-FU seems to be the decrease in activity of orotate phosphoribosyl transferase resulting 
in decrease in cellular uptake of 5-FU in the RNA fraction. (Murakami et al. 2000) There 
is no change in thymidylate synthase level. Trifluridine has demonstrated activity in 5-FU 
resistant colorectal and gastric cancer cell lines, as activity of trifluridine/tipiracil is not 
dependent on orotate phosphoribosyltransferase. (Lenz et al. 2015) Autophagy has also 
shown to play a role in resistance to 5-FU but not to trifluridine. (Bijnsdorp et al. 2010) 
The potential superiority of trifluridine/tipiracil to 5-FU has also be implicated in a 
randomized phase 2 trial of trifluridine/tipiracil with bevacizumab versus capecitabine 
with bevacizumab as first-line therapy in patients with metastatic CRC who were not 
eligible for intensive therapy. The trifluridine/tipiracil plus bevacizumab arm had longer 
median OS of 18.0 months versus 16.1 months in the capecitabine plus bevacizumab arm 
with HR 0.56 (95% CI: 0.32-0.98). (Lesniewski-Kmak et al. 2018)  
Our group (PI: Amit Mahipal) has recently completed accrual of 28 patients from 
October 2017 to August 2018 to a phase 2 trial evaluating the single-agent activity of 
trifluridine/tipiracil in metastatic refractory BTCs (NCT03278106). Eligible patients had 
at least one gemcitabine-based chemotherapy and were treated with trifluridine/tipiracil at 
the dose of 35 mg/m2 bid, Days 1-5 and 8-12 of a 28–day cycle. All patients received at 
least one (1) cycle of trifluridine/tipiracil. Median number of cycles received was 3 
(range 1-8). The most common Grade 3 or worse adverse events were neutrophil count 
decreased (44.4%), anemia (22.2%), alkaline phosphatase increased (22.2%), blood 
bilirubin increased (18.5%), and white blood cell decreased (18.5%), without any 
unexpected safety signals. Among 27 evaluable patients for response, the best response 
was stable disease in 13 (48%) patients. PFS rate at 16 weeks was 9/27 [33.3%; 95% 
confidence interval (CI): 16.5-54.0%]. Median PFS and OS were 3.9 (2.0-6.7) and 6.8 
(5.8-12.3) months, respectively. 
The early toxicities and efficacy data from our study on single-agent trifluridine/tipiracil 
in advanced BTCs and previously discussed phase I studies of trifluridine/tipiracil plus 
irinotecan in mCRCs are encouraging and suggest that trifluridine/tipiracil in 
combination with irinotecan may have better clinical activity in advanced BTCs than 
trifluridine/tipiracil alone. 
1.4 
Study Design 
This is a single-arm, phase 2 trial to assess the efficacy of trifluridine/tipiracil plus 
irinotecan in advanced, refractory BTCs. The primary endpoint of this study is 16-week 
PFS rate. If 30% of patients remain progression-free at 16-weeks, this trial will be 
considered a success warranting bigger trials. A two-stage phase II design will be 
utilized. In the first stage, 15 patients will be enrolled. If 2 or more patients are 
progression-free and alive at 16 weeks, additional 10 patients will be enrolled. If 5 or 
fewer patients out of 25 evaluable patients remain progression-free at 16 weeks then the 
regimen will be considered ineffective. The total sample size of this study is 28 to 
account for 3 possible non-evaluable subjects. Patient will receive trifluridine/tipiracil at 
the dose of 25 mg/m2 on Days 1-5 and irinotecan 180 mg/m2 on Day 1of each 14-day 
cycle. Patient will receive treatment until disease progression or unacceptable toxicities. 
Patients will undergo restaging scans every 4 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 (cfDNA) and circulating 
tumor cells (CTCs) at baseline, after 4 cycles and at progression. We will collect tumor 
biopsy specimens before treatment initiation to develop patient-derived tumor organoid. 
 
 


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Enrollment Plan 
 
Refractory Biliary Tract 
Cancers  
 
 
↓ 
 
 
Stage 1: Enroll 15 patients 
 
 
↓ 
 
 
≥2/15 remain progression-free 
and alive at 16 weeks 
 
 
no ↓ 
yes ↓ 
 
 
 
Stop enrollment 
 
Enroll additional 
10 patients 
 
 
 
2.0 
Goals  
2.1 
Primary Goal 
Determine the efficacy of trifluridine/tipiracil in combination with irinotecan in patients 
with refractory biliary tract cancers using progression-free survival (PFS) at 16 weeks. 
2.2 
Secondary Goals 
2.21 
Assess the safety and tolerability of trifluridine/tipiracil in combination with 
irinotecan in patients with refractory biliary tract cancers through adverse event 
monitoring. 
2.22 
Further explore the efficacy of trifluridine/tipiracil in combination with 
irinotecan in patients with refractory biliary tract cancers by overall response 
rates (ORR), disease control rates (DCR), and overall survival (OS). 
2.3 
Correlative Research 
2.31 
To determine if the number of circulating tumor cells (CTCs) or the level of cell-
free DNA (cfDNA) at baseline is prognostic or predictive to the response to 
therapy. 
2.32 
To determine if changes in CTCs or cfDNA correlate with efficacy endpoints. 
2.33 
To determine if drug response from a parallel ex vivo trial using patient-derived 
tumor organoid correlates with clinical response to trifluridine/tipiracil plus 
irinotecan 
2.34 
To evaluate the role of thymidine kinase 1 (TK1) in predicting the clinical benefit 
of trifluridine/tipiracil plus irinotecan and discover potential mechanisms of 
resistance using patient-derived tumor organoid and pre-treatment biopsy 
specimen. 
2.4 
Exploratory Research 
2.41 
To evaluate patients who received prior treatment with 5-FU independently from 
the entire population in the following areas: PFS, safety and tolerability, ORR, 
DCR, and OS. 


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3.0 
Registration 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 the gallbladder who have received at least one line of systemic 
anticancer therapy.  
Note: Patients who have either progressed on or are intolerant to the prior therapy 
can be included in this study. 
3.13 
Measurable disease as defined by RECIST criteria (See Section 11.0)  
NOTE: Tumor lesions in a previously irradiated area are not considered 
measurable disease. Disease that is measurable by physical examination only is 
not eligible. 
3.14 
ECOG Performance Status (PS) of 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. 
3.17 
Provide written informed consent. 
3.18 
Willing to return to enrolling institution for follow-up (during the Active 
Monitoring Phase of the study). 
3.19 
Willingness to provide mandatory blood and tissue specimens for correlative 
research (see Sections 14.0 and 17.0). 
 
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. 


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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. 
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. 
3.29 
Previous treatment with irinotecan or irinotecan-based chemotherapy for biliary 
tract cancers. 
 


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4.0  
Test Schedule 
4.1 
Test schedule for BTCs 
 
Active Monitoring Phase 
Tests and procedures1 
≤21 days 
prior to 
registration 
Prior to 
C1D1 
Tx 
D1 of 
each 
cycle 
Every 4 
cycles 
End of 
treatment 
Safety follow-up: 
30 days post 
treatment 
Window 
 
 
±7 days 
±7 days 
±7 days 
±7 days 
History and exam, Wt, PS  
X 
 
X 
 
X 
X 
Height 
X 
 
 
 
 
 
Adverse event assessment 
X 
 
X 
 
X 
X 
Pregnancy test2 
X 
 
 
 
 
 
Hematology group:  
CBC with differential  
X 
 
X 
 
X 
X 
Chemistry group3 
X 
 
X 
 
X 
X 
CA19-9 
 
X4 
 
X5 
X 
 
Tumor measurement6 
X7 
 
 
X8 
X 
 
Tumor biopsy 
 
X9R 
 
 
 
 
Research blood specimens 
(see Section 14.0)10R 
 
X 
X10 
 
X 
 
Research tissue specimens 
(see Section 17.0) 11R 
 
X 
 
 
 
 
Patient medication diary 
(Appendix II)12 
 
 
X 
 
X 
 
Cycle = 14 days 
R Research funded (see Section 19.0) 
 
                                                     
1 All tests and procedures should be performed as needed for clinical care at treating physician’s discretion. 
2 For persons of childbearing potential only: Must be done ≤7 days prior to registration. 
3 Chemistry: albumin, alkaline phosphatase, AST, ALT, total and direct bilirubin, creatinine, potassium, sodium 
4 Baseline prior to Cycle 1, Day 1, then every 4 cycles or as clinically indicated 
5 To be performed ≤7 days prior to planned Day 1 of Cycles 5, 9, etc., or as clinically indicated 
6 To be performed per Mayo Clinic institutional guidelines – suggest CT (chest, abdomen, and pelvis)  
or CT (chest) and MRI (abdomen, pelvis) 
7 Can be performed ≤28 days prior to registration 
8 To be performed ≤7 days prior to planned Day 1 of Cycles 5, 9, etc., or as clinically indicated 
9 Research biopsy after registration and prior to treatment on C1D1. Research biopsy may be omitted after 
discussion with PI, if it is not medically feasible or exceeds lab capacity. 
10 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) 
11 Research tissue specimens to be collected during research biopsy any time between registration and prior to 
treatment on C1D1 (see Section 17.0). Biopsy can be omitted for patients for whom investigator deems it unsafe. 
12 The diary must begin the day the patient starts taking the medication, and must be completed per protocol and 
returned to the treating institution at each visit. 


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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 
Registration (Step 1):  
To register a patient, access the Mayo Clinic Cancer Center (MCCC) web page and enter 
the 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 website. If unable to access the website, call the MCCC 
Registration Office at (507) 284-2753 between the hours of 8 a.m. and 4:30 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 an MCCC subject ID number must be 
available as noted in the instructions. It is the responsibility of the individual 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 of materials 
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.  
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) at the Registration Office 
 
If the necessary documentation is not submitted in advance of attempting 


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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 Research 
6.41 
Mandatory 
A mandatory correlative research component is part of this study, the patient will 
be automatically registered onto this component (see Sections 3.19, 14.0 and 
17.0). 
6.42 
Banking 
At the time of registration, the following will be recorded: 
• 
Patient has/has not given permission to store and use his/her sample(s) for 
future research on cancer at Mayo Clinic. 
• 
Patient has/has not given permission to store and use his/her sample(s) for 
future research to learn, prevent, or treat other health problems. 
• 
Patient has/has not given permission for MCCC to give his/her sample(s) to 
researchers at other institutions. 
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 ≤14 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 
7.1 
Treatment Schedule 
All patients will receive study medication trifluridine/tipiracil (FTD/TPI) with irinotecan 
in a 14-day treatment cycle. Trifluridine/tipiracil is available in 15 and 20 mg tablets. 
Study medication should be administered as outlined in the protocol. 
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. 
Trifluridine/tipiracil is administered in 14-day cycles. The starting dose of 
trifluridine/tipiracil is 25 mg/m2. The study drug will be administered on Days 1-5 of 14-
day cycle. If a patient starts treatment in the afternoon on Day 1 and can't take the 
morning dose of trifluridine/tipiracil, patient will take trifluridine/tipiracil on the morning 
on Day 6. This will allow patients to receive full dose of the therapy. No additional doses 
of trifluridine/tipiracil will be made up through the treatment cycle.  
Irinotecan is administered in 14-day cycles. The starting dose of irinotecan is 180 mg/m2. 
It will be administered on Day 1 of 14-day cycle. 
7.11 
Treatment medication table 
Agent 
Route 
Day 
Starting Dose 
Trifluridine/tipiracil (FTD/TPI) 
PO 
1-5 
25 mg/m2/dose twice daily 
Irinotecan 
IV 
1 
180 mg/m2/dose once 
None 
 
6-14 
No treatment 
Cycle = 14 days 
NOTE: On days when irinotecan and FTD/TPI are both administered, prefer 
morning dose of FTD/TPI taken in the clinic, if possible 
7.12 
Trifluridine/tipiracil dose calculation based on BSA 
Trifluridine/tipiracil dose 
(twice daily) 
BSA (m2) 
Dosage in mg 
(twice daily) 
Tablets per dose 
15 mg 
20 mg 
25 mg/m2 
<1.10 
25a 
2 (PM)a 
1 (AM)a 
25 mg/m2 
1.10-1.29 
30 
2 
0 
25 mg/m2 
1.30-1.49 
35 
1 
1 
25 mg/m2 
1.50-1.69 
40 
0 
2 
25 mg/m2 
1.70-1.89 
45 
3 
0 
25 mg/m2 
1.90-2.09 
50 
2 
1 
25 mg/m2 
2.10-2.29 
55 
1 
2 
25 mg/m2 
≥2.30 
60 
0 
3 
a At a total daily dose of 50 mg, patients should take 1× 20-mg tablet in the morning and 
2 × 15-mg tablets in the evening. 
7.13 
Irinotecan 
Irinotecan dose calculation is based on BSA per institutional standards. 
Irinotecan should be given IV per institutional standards. Package insert 
recommended infusion time is 90 minutes. 
NOTE: On days when irinotecan and FTD/TPI are both administered, prefer 
morning dose of FTD/TPI is taken in the clinic, if possible. 


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7.2 
Self-administration statement for FTD/TPI 
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 
7.3 
Treatment by local medical doctor (LMD) 
Treatment by a local medical doctor (LMD) is not allowed on this study. 
7.4 
Discontinuation of study treatment 
Study treatment will be discontinued for any of the following: 
• 
Disease progression 
• 
Unacceptable adverse events 
• 
Non-compliance (need to be discussed with PI) 
• 
Withdrawal of consent by the patient 
• 
Provider’s discretion for patient’s best interest (need to be discussed with PI) 
In rare circumstances, patient can be continued beyond progression if the investigator 
determines that patient is benefitting from the treatment. This decision will need to be 
made in conjunction with PI and will be only allowed in exceptional circumstances. 
 
 
 


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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 trifluridine/tipiracil or 
irinotecan for toxicities will be considered if an adverse event is at least possibly related to 
trifluridine/tipiracil or irinotecan. Dose modification will be done only for study drug related 
adverse event only.  
If either drug is delayed for more than 28 days due to adverse event possibly, probably, or 
definitely related to study drug, then discontinue that drug  
If one drug is discontinued due to adverse events, the patient continues on trial on the other drug. 
If both drugs are discontinued, the patient goes to event monitoring. 
NCI Common Terminology Criteria for Adverse Events (CTCAE) current version 5.0* will be 
utilized for dose modification unless otherwise specified. Up to three dose level reductions are 
allowed. Once reduced for an adverse event, no increase in dose of trifluridine/tipiracil will be 
allowed. 
* 
Located at 
 
Definitions: 
 Omit = The current dose(s) for the specified drug(s) during a cycle is skipped. The 
patient does not make up the omitted dose(s) at a later time. 
 Hold/Delay = The current dose(s) of all drugs during a cycle is delayed. The patient does 
make up the delayed dose(s) when the patient meets the protocol criteria to restart drugs. 
 Discontinue = The specified drug(s) are totally stopped. 
8.1  
Dose Levels (Based on Adverse Events in Tables 8.2 and 8.3) 
Dose Level 
Trifluridine/tipiracil (FTD/TPI) 
Irinotecan 
0* 
25 mg/m2/dose BID 
180 mg/m2/dose 
-1 
25 mg/m2/dose BID 
150 mg/m2/dose 
-2 
20 mg/m2/dose BID 
150 mg/m2/dose 
-3 
20 mg/m2/dose BID 
120 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. 
NOTE: Permanently discontinue FTD/TPI in patients unable to tolerate a dose of 
20 mg/m2 PO BID. 
 


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8.11 
Trifluridine/tipiracil dose calculation after dose modifications based on BSA 
Trifluridine/tipiracil dose 
(twice daily) 
BSA (m2) 
Dosage in mg 
(twice daily) 
Tablets per dose 
15 mg 
20 mg 
20 mg/m2 
<1.14 
20 
0 
1 
20 mg/m2 
1.14-1.34 
25a 
2 (PM)a 
1 (AM)a 
20 mg/m2 
1.35-1.59 
30 
2 
0 
20 mg/m2 
1.60-1.94 
35 
1 
1 
20 mg/m2 
1.95-2.09 
40 
0 
2 
20 mg/m2 
2.10-2.29 
45 
3 
0 
20 mg/m2 
≥2.30 
50 
2 
1 
a For 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 (occurring within a cycle of 
treatment) 
8.21 
For non-specified adverse events following criteria for dose modification will be 
used for adverse events occurring during the cycle: 
CTCAE 
Adverse Events1 
ACTION 
Grade 1 or 2 
Treat as scheduled 
Grade 3 or 4 
Omit treatment until resolved to ≤Grade 2 
If any Reduce the dose of FTD/TPI by one 
dose level 
1 Except for anemia, alopecia, clinically insignificant laboratory abnormalities, 
and inadequately treated nausea, vomiting, and diarrhea. 
8.22 
For specified adverse events the following criteria for dose modification will be 
used for adverse events occurring during the cycle: 
CTCAE 
System/Organ Class 
CTCAE 
Adverse Events 
ACTION 
Investigations 
Neutrophil count decreased 
≥Grade 4 
<500/mm3 
Omit treatment for the 
duration of the cycle 
Investigations 
Platelet count decreased 
≥Grade 3 
<50,000/mm3 
Omit 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) 
 
 


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8.3 
Dose Modifications at the Time of Retreatment (Beginning of a new cycle) 
8.31 
The dose modification guidelines for non-specified adverse events on Day 1 of 
each cycle of the treatment are mentioned below: 
CTCAE 
Adverse Events1 
ACTION 
Grade 1 or 2 
Treat as scheduled 
Grade 3 or 4 
Delay treatment until resolved to ≤Grade 2  
Reduce the dose of both drugs by one dose level 
1 Except for anemia, alopecia, clinically insignificant laboratory abnormalities, 
and inadequately treated nausea, vomiting, and diarrhea. 
8.32 
The dose modification guidelines for specified adverse events on Day 1 of each 
cycle of the treatment are mentioned below: 
CTCAE 
System/Organ Class 
CTCAE 
Adverse Events 
ACTION 
Blood and lymphatic 
system disorders 
Febrile 
neutropenia 
(≥Grade 3) 
Delay treatment by 1 week (see Section 9.0 
for supportive care guidelines) 
If resolved within 1 week (7 days), retreat 
at same dose 
Reduce dose by one dose level of both 
drugs for next treatment only if there is 
more than one week delay in start of next 
cycle 
Investigations 
Neutrophil count 
decreased 
≥Grade 2 
<1500/mm3 
Delay treatment by 1 week (see Section 9.0 
for supportive care guidelines) 
If resolved to ≤Grade 1 within 1 week 
(7 days), retreat at same dose 
Reduce dose by one dose level of both 
drugs for next treatment only if there is 
more than one week delay in start of next 
cycle 
Investigations 
Platelet count 
decreased 
<75,000/mm3 
Delay treatment by 1 week(see Section 9.0 
for supportive care guidelines) 
If resolved to ≤Grade 1 within 1 week 
(7 days), retreat at same dose 
Reduce dose by one dose level of both 
drugs for next treatment only if there is 
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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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 
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 
5.0 will be utilized for AE reporting. All appropriate treatment areas should have access 
to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP web site: 
 
a. Identify the grade and severity of the event using the CTCAE version 5.0. 
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, (if 
an investigator brochure is not required, otherwise described in the general 
investigational plan).  
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 












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progression under the system organ class (SOC) of Gneral disorders and 
administration site conditions. 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. 
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 will be reported. Three options are available to describe the event: 
o Neoplasms benign, malignant and unspecified, (incl cysts and polyps) 
Leukemia secondary to oncology chemotherapy (e.g., Acute Myeloctyic 
Leukemia [AML]) 
o Neoplasms benign, malignant and unspecified, (incl cysts and polyps) 
Myelodysplastic syndrome (MDS) 
o Neoplasms benign, malignant and unspecified, (incl cysts and polyps) 
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 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. If the baby is born with a birth defect or anomaly, a second 
expedited report is required. 
Prior to obtaining private information about a pregnant woman and her infant, the 
investigator must obtain consent from the pregnant woman and the newborn 
infant’s parent or legal guardian before any data collection can occur. A consent 
form will need to be submitted to the IRB for these subjects if a pregnancy 
occurs. If informed consent is not obtained, no information may be collected. 
In cases of fetal death, miscarriage or abortion, the mother is the patient. In cases 
where the child/fetus experiences a serious adverse event other than fetal death, 
the child/fetus is the patient. 
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 








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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: 
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. 


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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 
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 trifluridine/tipiracil 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 trifluridine/tipiracil 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 trifluridine/tipiracil overdose. 
Overdose should be managed aggressively with close monitoring and 
administration of prophylactic and symptomatic therapies to prevent or correct 
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11.0 
Treatment Evaluation/Measurement of Effect  
NOTE: This study uses protocol RECIST v1.1 template dated 2/16/2011. See the footnote for the 
table regarding measurable 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)13. 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). 
NOTE: 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 
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. 
                                                     
13 Eisenhauer EA, Therasse P, Bogaert J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, 
Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria 
in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer 45(2): 228-247, 2009. 


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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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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. 
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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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 
Measurement 
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. 


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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 
MSD (Section 11.41). In addition, the PBSD must also 
demonstrate an absolute increase of at least 0.5 cm from the 
MSD. 
c. See Section 11.32 for details in regards to the requirements for 
PD via FDG-PET imaging. 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR, 
nor sufficient increase to qualify for PD taking as reference the 
MSD. 
11.433 
Evaluation of Non-Target Lesions & Non-target Lymph Nodes 
Complete Response (CR): All of the following must be true: 
a. Disappearance of all non-target lesions. 
b. Each non-target lymph node must have a reduction in short 
axis to <1.0 cm. 
Non-CR/Non-PD: Persistence of one or more non-target lesions or 
non-target lymph nodes. 
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. Unequivocal progression of existing non-target lesions and 
non-target lymph nodes. (NOTE: Unequivocal progression 
should not normally trump target lesion and target lymph node 
status. It must be representative of overall disease status 
change.) 
c. See Section 11.32 for details in regards to the requirements for 
PD via FDG-PET imaging. 
11.44  Overall Objective Status 
The overall objective status for an evaluation is determined by combining the 
patient’s status on target lesions, target lymph nodes, non-target lesions, non-
target lymph nodes, and new disease as defined in the following tables: 
11.441 
For Patients with Measurable Disease 
Target Lesions & 
Target Lymph Nodes 
Non-Target Lesions & 
Non-Target Lymph 
Nodes 
New 
Sites of Disease 
Overall Objective 
Status 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
CR 
Non-CR/Non-PD 
No 
PR 
CR/PR 
Not All Evaluated* 
No 
PR** 
SD 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
No 
SD 


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Target Lesions & 
Target Lymph Nodes 
Non-Target Lesions & 
Non-Target Lymph 
Nodes 
New 
Sites of Disease 
Overall Objective 
Status 
Not all evaluated 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
No 
Not Evaluated (NE) 
PD 
Unequivocal PD 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
Yes or No 
PD 
CR/PR/SD/PD/Not all 
Evaluated 
Unequivocal PD 
Yes or No 
PD 
CR/PR/SD/PD/Not all 
Evaluated 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
Yes 
PD 
*See Section 11.431 
** NOTE: This study uses the protocol RECIST v1.1 template dated 2/16/2011. 
For data collection and analysis purposes the objective status changed from SD to 
PR in the MCCC protocol RECIST v1.1 template as of 2/16/2011 and to match 
RECIST v1.1 requirement. 
11.45  Symptomatic Deterioration 
Patients with global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time, and not 
either related to study treatment or other medical conditions, should be reported 
as PD due to “symptomatic deterioration.” Every effort should be made to 
document the objective progression even after discontinuation of treatment due to 
symptomatic deterioration. A patient is classified as having PD due to 
“symptomatic deterioration” if any of the following occur that are not either 
related to study treatment or other medical conditions: 
• 
Weight loss >10% of body weight. 
• 
Worsening of tumor-related symptoms. 
• 
Decline in performance status of >1 level on ECOG scale. 
12.0 
Descriptive Factors  
12.1 
Prior treatment: 1 vs 2 vs 3+ 
12.2 
Primary site of tumor: Gallbladder vs intrahepatic vs extrahepatic biliary tract cancer 
12.3 
Degree of differentiation: Well vs moderately vs poorly differentiated vs 
undifferentiated/anaplastic vs cannot be assessed/unknown 
12.4 
ECOG performance status: 0 vs 1 
12.5 
Prior treatment with fluoropyrimidine based regimen: Yes vs no 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient  
13.1 
Continuation of treatment 
Patients who are CR, PR, or SD will continue treatment per protocol. 


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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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14.0 
Body Fluid Biospecimens 
14.1  
Summary Table of Research Blood and Body Fluid Specimens to be Collected for this Protocol 
Research (Section for 
more information) 
Specimen 
Purpose  
(check all that 
apply) 
Mandatory 
or Optional 
Blood or 
Body Fluid 
being 
Collected 
Type of 
Collection 
Tube (color 
of tube top) 
Volume to 
collect per 
tube (# of 
tubes to be 
collected) 
Baseline 
prior to 
Cycle 1, 
Day 1  
Cycle 3, 
Day 1 
End of 
treatment 
Process 
at site? 
(Yes or 
No) 
Temperature 
Conditions 
for Storage 
/Shipping 
Circulating biomarker 
work  
(Section 14.2 and 14.3) 
☒ Correlative 
☐ Eligibility 
Confirmation 
☐ Banking 
☐ Other 
(specify) 
Mandatory 
Whole blood 
for DNA, 
buffy coat, 
WBCs and 
plasma* 
EDTA tube 
(purple top) 
10 mL 
(1) 
X 
X 
X 
Yes 
Frozen on dry 
ice 
cfDNA based studies  
(Section 14.2 and 14.3) 
☒ Correlative 
☐ Eligibility 
Confirmation 
☐ Banking 
☐ Other 
(specify) 
Mandatory 
Whole blood 
for platelet 
poor plasma  
Streck 
cfDNA BCT 
10 mL 
(2) 
X 
X 
X 
None 
Ship same day 
at ambient 
temperature 
CTC based studies  
(Section 14.2 and 14.3) 
☒ Correlative 
☐ Eligibility 
Confirmation 
☐ Banking 
☐ Other 
(specify) 
Mandatory Whole blood 
for CTCs 
AccuCyte 
tube 
10 mL 
(1) 
X 
X 
X 
None 
Ship same day 
at ambient 
temperature 
* DNA extraction from whole blood to be done at each site 
 
 
 


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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. 
14.23  Blood/blood products must be collected and shipped according to specific 
instructions provided in the kit and the table above. 
14.3 
Shipping 
14.31 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). 
14.32 Specimens collected in the Streck cfDNA BCT and AccuCyte tubes should be 
shipped at ambient temperature on the same day they are drawn. 
14.33 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. 
14.34 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.) 
14.4 
Processing 
NOTE: BAP Shared Resource will process the specimens. 
14.41 Double spun, platelet poor plasma will be derived from the Streck cfDNA BCT 
tubes using established laboratory processes, and stored at ≤-65ºC by BAP. 
14.42 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 ≤-65ºC by BAP according to patient consent information. 
14.43 Whole blood collected in the AccuCyte tubes will be provided directly to 
 laboratory at Mayo Clinic Rochester to isolate and retain 
CTCs. 
14.44 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. 


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14.5 
Background and Methodology 
14.51 ctDNA 
Detection of cancer specific mutations from the peripheral blood is an area of 
active investigation in many different types 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 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 heterogeneous tumor). (Diehl et al. 2005; 
Diehl et al. 2008; Dawson 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. 
14.52 CTCs 
That CTCs have biologic relevance in epithelial malignancies is increasingly 
clear, as their relative abundance in the peripheral blood has strong correlations 
with disease related outcomes in early stage and advanced breast cancer. (Liu et 
al. 2009; Liu 2014) 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 


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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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15.0 
Drug Information 
15.1 
Trifluridine/tipiracil (FTD/TPI, TAS-102, Lonsurf®) 
15.11 Background 
Trifluridine/tipiracil (FTD/TPI) is an orally available combination drug of an 
antineoplastic thymidine-based nucleoside analogue, 1M trifluridine, and 0.5 M 
tipiracil hydrochloride. Trifluridine is incorporated into deoxyribonucleic acid of 
tumor cells following phosphorylation. Tipiracil inhibits degradation of 
trifluridine by thymidine phosphorylase. 
15.12  Formulation 
Trifluridine/tipiracil contains trifluridine (FTD) and tipiracil (TPI) as active 
ingredients with a molar ratio of 1:0.5. Trifluridine/tipiracil drug products are 
immediate-released film coated tablets, with two strengths of 15 mg and 20 mg 
(expressed as trifluridine). The inactive ingredients of the FTD/TPIl 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. 
Trifluridine/tipiracil (FTD/TPI) tablet (15 mg) contains 15 mg trifluridine and 
7.065 mg tipiracil as active ingredients. The appearance is white, round, 
biconvex, film-coated, tablets. 
Trifluridine/tipiracil (FTD/TPI) tablet (20 mg) contains 20 mg trifluridine and 
9.42 mg tipiracil as active ingredients. The appearance is pale red, round, 
biconvex, film-coated,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 
Please see Pharmacy Manual provided by Taiho Oncology for this study. 
Recommended to take within 1 hour after completion of the morning and evening 
meals. 
The recommended dosage of FTD/TPI is 35 mg/m2 up to a maximum of 80 mg 
per dose (based on the trifluridine component) orally twice daily with food on 
Days 1 through 5 and Days 8 through 12 of each 28-day cycle until disease 
progression or unacceptable toxicity. Round dose to the nearest 5 mg increment. 
Instruct patients to swallow FTD/TPI tablets whole. 
Instruct patients not to retake doses of FTD/TPI that are vomited or missed and to 
continue with the next scheduled dose. 
15.15 Pharmacokinetic information 
Protein Binding: Trifluridine: >96% (primarily to albumin); Tipiracil: <8% 


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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 (55% [as inactive metabolite FTY and trifluridine 
glucuronide isomers]; <3% [as unchanged drug]; feces (<3% [as unchanged 
drug]); expired air (<3%) 
Tipiracil: Urine (~27% [as tipiracil and 6-HMU]; feces (50% [as tipiracil and 6-
HMU]) 
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 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 adverse events, ≥10%: 
Blood and lymphatic: Anemia, leukopenia, neutropenia, thrombocytopenia 
Gastrointestinal: Diarrhea, nausea, vomiting 
General: Fatigue 
Metabolism and nutrition: Decreased appetite 
Common known potential adverse events, ≥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 adverse events, <1% (Limited to important or 
life-threatening): 
Blood and lymphatic: Pancytopenia 
Gastrointestinal: Ascites, colitis, ileus, acute pancreatitis, subileus 
General: General physical health deterioration 


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Infections: Bacterial infection, biliary tract infection, enteritis infection, urinary 
tract infection 
Investigations: Blood lactate dehydrogenase increased 
Metabolism and nutrition: Dehydration 
Respiratory: Pulmonary embolism 
15.18 Drug procurement 
FTD/TPI will be provided free of charge by Taiho Oncology. 
15.19 Nursing guidelines 
15.191  Instruct Patients to take FTD/TPI within 1 hour after completion of 
morning or evening meal with a glass of water.  
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. 
15.2 
Irinotecan (Camptosar®, CPT11) 
15.21 Background 
Irinotecan and its active metabolite SN-38 bind to the topoisomerase I-DNA 
complex and prevent religation of the cleaved DNA strand. This results in the 
accumulation of cleavable complexes and double-strand DNA breaks. As 
mammalian cells cannot efficiently repair these breaks, cell death consistent with 
S-phase cell cycle specificity occurs, leading to termination of cellular 
replication. 
15.22  Formulation 
Commercially available for injection 20 mg/mL (2 mL, 5 mL, 25 mL) [contains 
sorbitol 45 mg/mL; do not use in patients with hereditary fructose intolerance].. 
15.23 Preparation and storage 
Store intact vials at controlled room temperature 15-30°C (59-86°F) and protect 
from light. Doses should be diluted in 250-500 mL D5W or 0.9% NaCl to a final 
concentration of 0.12-2.8 mg/mL. Solutions diluted in D5W are stable for 24 
hours at room temperature or 48 hours under refrigeration at 2ºC to 8ºC. 
Solutions diluted in 0.9% NaCl may precipitate if refrigerated. Do not freeze. 


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15.24 Administration 
Administer as IV infusion, usually over 90 minutes. 
15.25 Pharmacokinetic information 
Distribution: Vd: 33-150 L/m2 
Protein binding, plasma: Predominantly albumin; Parent drug: 30% to 68%, SN-
38 (active metabolite): ~95% 
Metabolism: Primarily hepatic to SN-38 (active metabolite) by carboxylesterase 
enzymes; SN-38 undergoes conjugation by UDP- glucuronosyl transferase 1A1 
(UGT1A1) to form a glucuronide metabolite. Conversion of Irinotecan to SN-38 
is decreased and glucoronidation of SN-38 is increased in patients who smoke 
cigarettes, resulting in lower levels of the metabolite and overall decreased 
systemic exposure. SN-38 is increased by UGT1A1*28 polymorphism (10% of 
North Americans are homozygous for UGT1A1*28 allele). Patients homozygous 
for the UGT1A1*28 allele are at increased risk of neutropenia; initial one-level 
dose reduction should be considered for both single-agent and combination 
regimens. The lactones of both Irinotecan and SN-38 undergo hydrolysis to 
inactive hydroxyl acid forms. 
Half-life elimination: SN-38: mean terminal 10-20 hours 
Time to peak: SN-38: Following 90-minute infusion ~1 hour 
Excretion: Within 24 hours: urine: Irinotecan (11% to 20%), metabolites (SN-38 
<1%, SN-38 glucuronide, 3%) 
15.26 Potential drug interactions 
Cytochrome P450 Effect: Substrate (major) of CYP2B6, 3A4, P-
glycoprotein, SLCO1B1 and UGT1A1 
Increased Effect/Toxicity: CYP2B6 and CYP3A4 inhibitors may 
increase the levels/effects of irinotecan. Bevacizumab may increase the 
adverse effects of Irinotecan (e.g., diarrhea, neutropenia). Ketoconazole 
increases the levels/effects of irinotecan and active metabolite; discontinue 
ketoconazole 1 week prior to irinotecan therapy; concurrent use is 
contraindicated. 
Decreased Effect: CYP2B6 and CYP3A4 inducers may decrease the 
levels/effects of irinotecan.  
Ethanol/Nutrition/Herb Interactions Herb/Nutraceutical: St John’s wort 
decreases therapeutic effect of irinotecan; discontinue ≥2weeks prior to 
irinotecan therapy; concurrent use is contraindicated. 
15.27 Known potential adverse events 
Consult the package insert for the most current and complete information 
including U.S. Boxed Warnings pertaining to severe diarrhea and severe 
myelosuppression. 
Common known potential adverse events, >10%: 
Cardiovascular: Vasodilation 
Central nervous system: Cholinergic toxicity (includes rhinitis, increased 
salivation, miosis, lacrimation, diaphoresis, flushing and intestinal 
hyperperistalsis); fever, pain, dizziness, insomnia, headache, chills 
Dermatologic: Alopecia, rash 


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Endocrine & metabolic: Dehydration 
Gastrointestinal: Late onset diarrhea, early onset diarrhea, nausea, abdominal 
pain, vomiting, cramps, anorexia, constipation, mucositis, weight loss, flatulence, 
stomatitis 
Hematologic: Anemia, leukopenia, thrombocytopenia, neutropenia 
Hepatic: Bilirubin increased, alkaline phosphatase increased  
Neuromuscular & skeletal: Weakness, back pain 
Respiratory: Dyspnea, cough, rhinitis 
Miscellaneous: Diaphoresis, infection 
Less common known adverse events, 1% - 10%:  
Cardiovascular: Edema, hypotension, thromboembolic events 
Central nervous system: Somnolence, confusion 
Gastrointestinal: Abdominal fullness, dyspepsia 
Hematologic: Neutropenic fever, hemorrhage, neutropenic infection 
Hepatic: AST increased, ascites and/or jaundice 
Respiratory: Pneumonia 
Rare known potential adverse events, <1% (Limited to important or life-
threatening):  
ALT increased, amylase increased, anaphylactoid reaction, anaphylaxis, angina, 
arterial thrombosis, bleeding, bradycardia, cardiac arrest, cerebral infarct, 
cerebrovascular accident, circulatory failure, colitis, dysrhythmia, embolus, 
gastrointestinal bleeding, gastrointestinal obstruction, hepatomegaly, 
hyperglycemia, hypersensitivity, hyponatremia, ileus, interstitial pulmonary 
disease (IPD), intestinal perforation, ischemic colitis, lipase increased, 
lymphocytopenia, megacolon, MI, myocardial ischemia, neutropenic typhlitis, 
pancreatitis, paresthesia, peripheral vascular disorder, pulmonary embolus, 
pulmonary toxicity (dyspnea, fever, reticulonodular infiltrates on chest x-ray), 
renal failure (acute), renal impairment, syncope, thrombophlebitis, thrombosis, 
typhlitis, ulceration, ulcerative colitis 
15.28 Drug procurement 
Commercial supplies. Pharmacies or clinics shall obtain supplies from normal 
commercial supply chain or wholesaler. 
15.29 Nursing guidelines 
15.291  
If possible, check for any history of hypersensitivity reaction to any 
previous drug formulated with polysorbate 80. 
15.292  
Cholinergic symptoms of lacrimation, nasal congestion, diaphoresis, 
flushing, ABD cramping, and diarrhea can occur at the beginning, 
during, or immediately after the CPT-11 infusion. It is suggested that 
the patient remain in the treatment area for a minimum of one hour 
following the completion of the very first CPT-11 infusion. If diarrhea 
occurs within one hour of infusion, refer to Section 9.2 for 
management. 
15.293  
Patient education is extremely important. Impress on the patient the 
importance of compliance with treatment of diarrhea management (see 
Section 9.1). Stress the need for prompt recognition and early 
intervention. Motivate the patient to report any complications 


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immediately. The cholera-like syndrome can be unresponsive to 
conventional antidiarrheals and can result in severe dehydration. 
15.294  
Ondansetron and diphenhydramine should provide good relief from the 
nausea/vomiting/cramping. Avoid prochlorperazine on the day of 
treatment due to its association with akathisia (motor restlessness). 
Prochlorperazine may be taken between treatments. 
15.295  
Advise avoidance of excess caffeine, a GI stimulant. Avoid magnesium 
based antacids such as Mylanta, Maalox, Rolaids, MOM, Mag-Ox 400, 
and Tylenol with antacid. 
15.296  
The pulmonary toxicity seen is usually manifested by dyspnea 
beginning 42-175 days after treatment and occurs at a cumulative dose 
ranging from 400-1000 mg/m2 (median 750). Instruct patient to report 
any cough or SOB. 
15.297  
Patients are at risk for developing eosinophilia and will improve on 
steroid therapy. 
15.298  
Hepatic enzyme elevations have been transient and did not require 
intervention. 
15.299a Monitor CBC closely. Leukopenia occurs primarily as neutropenia but 
can be severe and dose-limiting. The simultaneous occurrence of 
Grade 4 diarrhea and Grade 4 neutropenia are rare but may render the 
patient more susceptible to polymicrobial sepsis and potentially death. 
15.299b Advise patients of probable hair loss. 
 


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16.0 
Statistical Considerations and Methodology 
16.1 
Overview 
This protocol will assess the efficacy of trifluridine/tipiracil plus irinotecan in patients 
with refractory cholangiocarcinoma using a two 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 trifluridine/tipiracil plus irinotecan 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), disease control rate (DCR), and adverse events. 
16.11  Primary Endpoint 
The primary endpoint for this study is 16-week progression-free survival 
associated with trifluridine/tipiracil plus irinotecan 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 two stage design (Simon) uses 15 
or 25 patients to test the null hypothesis that the true success proportion in a 
given patient population is at most 10%. 
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). 
16.211 
STAGE 1: Enter 15 patients into the study. If 1or fewer successes are 
observed in the first 15 evaluable patients, we will consider this 
regimen ineffective in this patient population and terminate this study. 
Otherwise, if the number of successes is at least 2, we will proceed to 
Stage 2. 
16.212 
STAGE 2: Enter an additional 10 patients into the study. If 5 or fewer 
successes are observed in the first 25 evaluable patients, we will 
consider this regimen ineffective in this patient population. If 6 or 
more successes are observed in the first 25 evaluable patients, we may 
recommend further testing of this regimen in subsequent studies in this 
population. 
16.213 
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 process. Analyses involving over accrued 
patients are discussed in Section 16.34. 
16.214 
NOTE: We will not suspend accrual between stages to allow the first 
15 patients to become evaluable, unless undue toxicity is observed. 


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16.22 Sample Size 
The two-stage study design to be utilized is fully described in Section 16.21. A 
minimum of 15 and 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 
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 . . . 
0.10 0.15 0.20 0.25 0.30 
then the probability of declaring that the 
regimen warrants further studies is . . 
0.03 0.16 0.38 0.61 0.80 
and the probability of stopping at stage 1 is . . . 
0.56 0.31 0.17 0.08 0.04 
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,  begun treatment, and undergone restaging scans 
(unless deemed to have clinical progression by investigator) will be 
considered evaluable for the primary endpoint. 


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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. 
16.313 
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. For efficacy outcomes, the 
same population defined in Section 16.311 will be used as the evaluable 
population. For adverse event outcomes, all consented patients eligible to begin 
treatment will be evaluated. 
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 as their best 
response. ORR will be reported descriptively and a 95% confidence 
interval will be reported. 
16.322 
Disease Control Rate (DCR):  
Disease control rate is defined as the proportion of patients who 
experience a partial response, complete response, or have stable 
disease as their best response. DCR will be reported descriptively and a 
95% confidence interval will be reported. 
16.322 
Progression-Free Survival (PFS): 
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 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 NCI CTCAE 
version 5.0. We will also closely monitor adverse events throughout 
the study. 


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16.33  Correlative Research 
16.331 
To determine if CTCs or 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 drug response from a parallel ex vivo trial using 
patient-derived tumor organoid correlates with clinical response to 
trifluridine/tipiracil plus irinotecan. 
16.334 
To evaluate the role of thymidine kinase 1 (TK1) in predicting the 
clinical benefit of trifluridine/tipiracil plus irinotecan and discover 
potential mechanisms of resistance using patient-derived tumor 
organoid and pre-treatment biopsy specimen. 
16.34 Exploratory Analysis 
To explore the population of patients that received prior treatment with 5-FU, 
patients within this cohort will be evaluated for endpoints that may include, but 
not be limited to: PFS, safety and tolerability, ORR, DCR, and OS. 
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 events 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 experience a Grade 4 
or 5 adverse event at least possibly related to study treatment with the 
exception of transient laboratory events or cytopenias that 
resolve/improve within 7 days. 
• 
if after the first 10 patients have been treated, 30% of all patients enrolled 
and treated experience a Grade 4 or 5 adverse event with the exception of 
transient laboratory events or cytopenias that resolve/improve within 
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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. 
16.5 
Subset Analyses for Minorities 
16.51 Study availability 
This study will be available to all eligible patients, regardless of gender, race or 
ethnic origin.  
16.52 Statistical analysis by subset 
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 analyses will 
look for differences in treatment effect based on racial groupings, the sample size 
is not increased in order to provide additional power for subset analyses.  
16.53 Regional population 
The geographical region served by MCCC has a population which includes 
approximately 3% minorities. Expected sizes of racial by gender subsets 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 
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 


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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. 


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17.0  
Pathology Considerations/Tissue Biospecimens 
17.1  
Summary Table of Research Tissue Specimens to be Collected for this Protocol 
Research Study  
(Section for more 
information) 
Specimen Purpose 
 (check all that apply) 
Mandatory 
or Optional 
Type of 
Tissue to 
Collect 
Block, Slides, 
Core, etc.  
(# of each to 
submit) 
Baseline, 
prior to 
Cycle 1 
Day 1* 
Process 
at site? 
(Yes or 
No) 
Temperature 
Conditions for 
Storage 
/Shipping 
Patient-derived tumor 
organoid culture and 
studies  
(Section 17.2 and 17.3) 
☒ Correlative 
☐ Eligibility Confirmation 
☐ Banking 
☐ Other (specify)  
Mandatory 
Fresh 
Tissue 
3 cores 
X 
No 
Cold ice pack 
Immunohistochemistry 
(section 17.2 and 17.3) 
☒ Correlative 
☐ Eligibility Confirmation 
☐ Banking 
☐ Other (specify) 
Mandatory 
Formalin 
Fixed 
Paraffin 
Embedded 
1 block from 
4th core 
collected at 
same time as 
fresh tissue 
cores 
X 
No 
Ambient 
*If baseline biopsy cannot be done (e.g., because not medically feasible or lack of lab capacity), and PI agrees, patient is still eligible. 
17.2 
Correlative Tissue Collection  
17.21 Tissue Kits will be provided for this protocol. 
Interventional radiologist performing image-guided core biopsy of targeted tumor for research will contact personnel at 
the assigned laboratory at each Mayo Clinic site to obtain tissue kits.  
17.23 Fresh Tissue 
17.231 
Three cores of fresh tumor tissue will be submitted after registration and prior to Cycle 1 Day 1 of treatment. 
17.232 
Fresh tissue must be labeled with the protocol number, study patient ID number, and the time and date of the 
biopsy. 
17.233 
Fresh tissue must be collected and shipped according to specific instructions provided in tissue kit and the table 
above. 
17.234 
Fresh tissue must be stored in tissue media in cold ice pack (~0ºC) 


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17.23 Paraffin Embedded Tissue 
17.231 
One block of BTC tumor tissue from research biopsy will be submitted 
after registration and prior to Cycle 1 Day 1 of treatment.  
17.232 
Paraffin embedded tissue must be labeled with the protocol number, 
study patient ID number, and the time and date of the biopsy.  
17.233 
Paraffin embedded tissue must be collected and shipped according to 
specific instructions provided in the table above. 
17.234 
 Paraffin embedded tissue can be stored at ambient temperature. 
17.24 Shipping 
17.241  Verify that ALL sections of the Tissue 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 Tissue Specimen Submission Form into the remote data entry 
system within 7 days after specimen collection (see Forms Packet). 
17.242  Fresh tissue specimens collected in tissue media should be shipped 
overnight in cold ice pack (~0ºC) to the laboratory of 
 
 
17.25 Processing 
17.251 
Paraffin embedded tissue block 
DLMP or BAP/PRC Shared Resource will process the paraffin 
embedded tissue specimens according to routine protocols.  
17.252 
Fresh tissue cores 
The laboratory of 
 will process the fresh 
tissue specimens. 
The fresh tissue specimens will be minced into ~0.5 mm fragments in 
1 mL resuspension media. They will be digested to single cells and 
plated with Matrigel and culture media.  
17.3 
Background and Methodology 
17.31 Patient-derived tumor organoid 
Preclinical tumor models are important tools to study cancer biology, develop 
novel therapeutics, and provide information for treatment decisions. However 
currently available tumor models such as cell lines, transgenic mice and patient-
derived xenograft (PDX) model have inherent limitations that can adversely 
affect the translation of preclinical findings to the clinic. Patient-derived tumor 
organoid is a 3-D cell culture which enables the establishment of ex vivo tumor 
model from scant core-needle biopsy specimen in a timely manner. These tumor 
organoids recapitulate both phenotypes and genotypes of the donor tumor. 
(Vlachogiannis et al. 2018) The laboratory of 
 at 
our institution has successfully established such tumor organoids from core-
biopsy tumor specimens donated by patients with metastatic cholangiocarcinoma. 
The established tumor organoids were ready for drug screening and related 
molecular studies within 4-6 weeks of the biopsy. Though the concordance 


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between treatment effect in tumor organoids and the clinical benefit observed in 
the donor patients have been reported, the role of tumor organoids has not been 
prospectively evaluated in clinical trials of patients with advanced BTCs. Here, 
we aim to 1) determine if drug response from a parallel ex vivo trial using 
patient-derived tumor organoid correlates with clinical response to 
trifluridine/tipiracil plus irinotecan and 2) to evaluate the role of thymidine 
kinase 1 in predicting the clinical response to trifluridine/tipiracil plus irinotecan 
(Edahiro et al. 2018; Yoshino et al. 2018) and discover potential mechanisms of 
resistance and sensitivity. 
 


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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 Section 4 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 (genetic sequencing report), 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 
Labeling 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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19.0  
Budget 
19.1 
Costs charged to patient: routine clinical care 
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 (such as irinotecan), 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: 
• 
Trifluridine/tipiracil will be provided by Taiho Oncology 
• 
Research biopsy performed after registration and prior to treatment on Cycle 1, Day 1 
• 
Correlative studies 
• 
Collection, processing and storage of blood for research. 
19.3 
Other budget concerns: 
Taiho Oncology will provide a grant through NCCN to Mayo Clinic to help with costs 
for the conduct of this study. 
Mayo Clinic Cancer Center will provide Development funding to cover additional costs 
associated with the conduct of this study. 
 
 


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20.0 
References 
 
Bijnsdorp, Irene V.; Peters, Godefridus J.; Temmink, Olaf H.; Fukushima, Masakazu; Kruyt, Frank A. 
(2010): Differential activation of cell death and autophagy results in an increased cytotoxic potential for 
trifluorothymidine compared to 5-fluorouracil in colon cancer cells. In International journal of cancer 
126 (10), pp. 2457–2468. DOI: 10.1002/ijc.24943. 
Choi, C. W.; Choi, I. K.; Seo, J. H.; Kim, B. S.; Kim, J. S.; Kim, C. D. et al. (2000): Effects of 5-
fluorouracil and leucovorin in the treatment of pancreatic-biliary tract adenocarcinomas. In American 
journal of clinical oncology 23 (4), pp. 425–428. 
Dawson, Sarah-Jane; Tsui, Dana W. Y.; Murtaza, Muhammed; Biggs, Heather; Rueda, Oscar M.; Chin, 
Suet-Feung et al. (2013): Analysis of circulating tumor DNA to monitor metastatic breast cancer. In The 
New England journal of medicine 368 (13), pp. 1199–1209. DOI: 10.1056/NEJMoa1213261. 
Diehl, Frank; Li, Meng; Dressman, Devin; He, Yiping; Shen, Dong; Szabo, Steve et al. (2005): Detection 
and quantification of mutations in the plasma of patients with colorectal tumors. In Proceedings of the 
National Academy of Sciences of the United States of America 102 (45), pp. 16368–16373. DOI: 
10.1073/pnas.0507904102. 
Diehl, Frank; Schmidt, Kerstin; Choti, Michael A.; Romans, Katharine; Goodman, Steven; Li, Meng et al. 
(2008): Circulating mutant DNA to assess tumor dynamics. In Nature medicine 14 (9), pp. 985–990. DOI: 
10.1038/nm.1789. 
Edahiro, Keitaro; Iimori, Makoto; Kobunai, Takashi; Morikawa-Ichinose, Tomomi; Miura, Daisuke; 
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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 
 
 
From