A Phase II Study of TAS-102, Irinotecan and Bevacizumab in Pre-Treated Metastatic Colorectal Cancer (TABAsCO)
Phase: PHASE2
Conditions: Advanced Colorectal Carcinoma, Metastatic Colon Adenocarcinoma, Metastatic Rectal Adenocarcinoma, Recurrent Colon Adenocarcinoma, Recurrent Colorectal Adenocarcinoma, Recurrent Rectal Adenocarcinoma, Stage III Colon Cancer AJCC v8, Stage III Colorectal Cancer AJCC v8, Stage III Rectal Cancer AJCC v8, Stage IIIA Colon Cancer AJCC v8, Stage IIIA Colorectal Cancer AJCC v8, Stage IIIB Colorectal Cancer AJCC v8, Stage IIIB Rectal Cancer AJCC v8, Stage IIIC Colon Cancer AJCC v8, Stage IIIC Colorectal Cancer AJCC v8, Stage IV Colon Cancer AJCC v8, Stage IVA Colorectal Cancer AJCC v8, Stage IVA Rectal Cancer AJCC v8, Stage IVB Colon Cancer AJCC v8, Stage IVB Colorectal Cancer AJCC v8, Stage IVB Rectal Cancer AJCC v8, Stage IVC Colon Cancer AJCC v8, Stage IVC Colorectal Cancer AJCC v8, Stage IVC Rectal Cancer AJCC v8, Unresectable Colon Adenocarcinoma, Unresectable Colorectal Carcinoma, Unresectable Rectal Adenocarcinoma
Sponsor: Roswell Park Cancer Institute

Document Coversheet 
 
 Study Title: 
 A Phase II Study of TAS-102, Irinotecan, and Bevacizumab in Pre-treated Metastatic Colorectal Cancer 
(TABAsCO)   
 
 
Institution/Site:  
Roswell Park Comprehensive Cancer Center 
Document (Approval/Update) Date: 
08/02/2022 
NCT Number: 
NCT04109924 
IRB Number 
I 444019 
 

07/14/2022
Page 1 of 55
PROTOCOL TITLE:
A Phase II Study of TAS-102, Irinotecan, and Bevacizumab in Pre-treated Metastatic 
Colorectal Cancer (TABAsCO)
PROTOCOL NUMBER:
I 444019
PRINCIPAL INVESTIGATOR:
Christos Fountzilas, MD
Roswell Park Comprehensive Cancer Center
Elm and Carlton Street
Buffalo, New York 14263
716-845-8974
Christos.Fountzilas@roswellpark.org
VERSION NUMBER: Initial DATE: 05/02/2019
Amendment 1: 09/04/2019
Amendment 2: 01/10/2020 
Amendment 3: 02/03/2020
Amendment 4: 05/21/2020 
Amendment 5: 01/14/2021
Amendment 6: 04/01/2021 
Amendment 7: 05/05/2021
Amendment 8: 10/12/2021
Amendment 9: 10/27/2021
Amendment 10: 07/14/2022
Confidentiality Statement
Any and all information presented in this document shall be treated as confidential and shall 
remain the exclusive property of the party (ies) mentioned above (Roswell Park Cancer Institute 
Corporation d/b/a Roswell Park Comprehensive Cancer Center). The use of such confidential 
information must be restricted to the recipient for the agreed purpose and must not be disclosed, 
published, or otherwise communicated to any unauthorized persons, for any reason, in any form 
whatsoever without the prior written consent of the party(ies) above.
APPROVED RPCI IRB
8/2/2022

Roswell Park Protocol No.: I 444019
07/14/2022
Page 2 of 55
Table of Contents
1
Objectives ................................................................................................................................3
2
Background..............................................................................................................................3
3
Inclusion and Exclusion Criteria .............................................................................................5
4
Local and Study-Wide Number of Subjects ............................................................................7
5
Local and Study-Wide Recruitment Methods .........................................................................7
6
Multi-Site Research .................................................................................................................7
7
Study Timelines.......................................................................................................................8
8
Study Endpoints.......................................................................................................................8
9
Design......................................................................................................................................8
10
Treatment.................................................................................................................................9
11
Procedures Involved ..............................................................................................................19
12
Withdrawal of Subjects..........................................................................................................22
13
Risks to Subjects....................................................................................................................22
14
Potential Benefits to Subjects ................................................................................................23
15
Data and Specimen Banking..................................................................................................23
16
Measurement of Effect ..........................................................................................................23
17
Safety Evaluation...................................................................................................................23
18
Data Management and Confidentiality..................................................................................30
19
Statistical Plan .......................................................................................................................31
20
Provisions to Monitor the Data to Ensure the Safety of Subjects..........................................32
21
Vulnerable Populations..........................................................................................................32
22
Community-Based Participatory Research............................................................................33
23
Sharing of Results with Subjects ...........................................................................................33
24
Setting....................................................................................................................................33
25
Provisions to Protect the Privacy Interests of Subjects .........................................................33
26
Resources Available ..............................................................................................................33
27
Prior Approvals......................................................................................................................33
28
Compensation for Research-Related Injury...........................................................................33
29
Economic Burden to Subjects................................................................................................34
30
Consent Process.....................................................................................................................34
31
Process to Document Consent in Writing..............................................................................34
32
Drugs or Devices ...................................................................................................................35
33
References..............................................................................................................................37
34
Appendices/ Supplements......................................................................................................39
APPROVED RPCI IRB
8/2/2022

Roswell Park Protocol No.: I 444019
07/14/2022
Page 3 of 55
1
OBJECTIVES
1.1
Primary Objective

Determine the median progression free survival (PFS) benefit of FOLFIRI naïve patients 
treated with TAS-102 + irinotecan + bevacizumab as compared to historic control groups 
treated with FOLFIRI + bevacizumab
1.2
Secondary Objectives

Estimate the objective response rate (ORR), median overall survival (OS), and adverse 
event (AE) profile
2
BACKGROUND
Colorectal cancer remains the 2nd most common cause of cancer related death in the US. Despite 
improvements in systemic therapy and deeper understanding of patient selection for therapies, 
after first line therapy, median achieved progression free survival (PFS) stands near 6 months with 
median overall survival (OS) at 11-13 months (1-3). FOLFIRI with bevacizumab remains a 
standard second line treatment, with bevacizumab being the most common biologic and FOLFIRI 
the most common chemotherapy regimen utilized in the second-line setting in the US (4, 5). 
Second-line treatment with FOLFIRI + an anti-angiogenic agent has typically produced a median 
PGS in the range of 6-7 months (1-3).While such regimens are clearly active, further gains are 
desperately needed.
2.1
Study Drugs
2.1.1
TAS-102
Preclinical Studies with TAS-102
TAS-102 (Lonsurf®) consists of a thymidine-based nucleoside analog, trifluridine, and the 
thymidine phosphorylase inhibitor, tipiracil, with a molar ratio of 1:0.5. Inclusion of tipiracil 
increases trifluridine exposure by inhibiting its metabolism by thymidine phosphorylase.
Following uptake into cancer cells, trifluridine is incorporated into DNA, interferes with DNA 
synthesis and inhibits cell proliferation. Trifluridine/tipiracil demonstrated anti-tumor activity 
against KRAS wild-type and mutant human colorectal cancer xenografts in mice.
TAS-102 has a distinct mechanism of action from 5-FU and in preclinical models can overcome 
5-FU resistance (6). With a twice daily dosing schedule, DNA incorporation is thought to be the 
major mechanism of action; the base excision repair (BER) pathway and glycosylation responses 
also appear to differ from that seen with 5-fu-mediated DNA damage (7). Further, there is additive 
effect when TAS-102 is combined with irinotecan in 5-FU sensitive and resistant cell lines (8). 
Interestingly, induction of apoptosis is most efficient in vitro when the irinotecan metabolite, SN-
38, is administered 24 hours prior to TAS-102(9).
A detailed discussion of the preclinical pharmacology, pharmacokinetics, and toxicology of TAS-
102 can be found in the Investigator’s Brochure.
APPROVED RPCI IRB
8/2/2022

Roswell Park Protocol No.: I 444019
07/14/2022
Page 4 of 55
Clinical Studies with TAS-102
In September 2015, TAS-102 was FDA approved for use in refractory metastatic colorectal cancer 
on the basis of the RECOURSE trial. The Phase III RECOURSE trial randomized 800 patients 
(2:1) to TAS-102 vs placebo and demonstrated an improvement in median OS (7.1 vs 5.3 mo, HR 
0.68; p < 0.001) as well as PFS (HR 0.47; p < 0.001)(10). The most common side effects seen 
were marrow suppression (anemia, neutropenia, and thrombocytopenia), fatigue, nausea, 
vomiting, and anorexia. In light of this, TAS-102 has been introduced into the clinic as a standard 
of care agent in the refractory setting. Biomarkers predictive of efficacy remain elusive.
As TAS-102 carries potential to overcoming 5-FU resistance due to differing mechanisms of 
action, initial clinical efforts have been taken to combine TAS-102 with agents commonly used in 
1st and 2nd–line therapy. The Phase II TASCO1 study evaluated the potential of a TAS-102 based 
regimen to outperform classic fluoropyrimidines, capecitabine, when either was combined with 
bevacizumab. The primary endpoint was PFS. There was a non-significant trend toward superior 
outcome with TAS-102, as compared to capecitabine, with a median PFS of 9.23 vs 7.82 months 
(HR 0.71, 95% CI 0.48, 1.06). Interestingly, OS appeared to be improved with TAS-102 in this 
study, at 18 months vs 16.16 months (HR 0.56, 95% CI 0.32, 0.98), suggesting that TAS-102 may 
confer greater benefit than capecitabine (11).
This agent has also been combined with oxaliplatin and irinotecan successfully. When combined 
with irinotecan (180 mg/m2 every 14 days) and bevacizumab (5 mg/kg every 14 days), TAS-102 
is able to be safely dosed at 25 mg/m2 twice daily, days 1-5 of a 14 day regimen(12). Given in this 
fashion, neutropenia, and leucopenia are the most common ≥ grade 3 AEs. Grade 3 diarrhea was 
noted in 12% of patients, fatigue in 8% and other severe AEs occurring ~ 8% of patients or less. 
Notably in the expansion cohort of this Phase 1 study where 21/24 (88%) patients had received 
prior irinotecan, 3 (13%) PRs were observed (2 previously irinotecan exposed) and 17/24 (71%) 
patients achieved stable disease, with a median PFS of 7.9 months. 1/3 of patients were on study 
for > 40 weeks. This compares favorably to the second-line TML, VELOUR and RAISE studies, 
which produced median PFS results of 5.7, 6.9, and 5.7 months, respectively(1-3).
The above cited Phase I data was established within an irinotecan pre-treated population, all but 3 
patients having had prior irinotecan. As such, one might expect greater efficacy to be seen in an 
irinotecan naïve population. To test this hypothesis, we propose a single arm Phase II study of 
TAS-102, irinotecan and bevacizumab as second-line therapy in individuals with metastatic 
colorectal cancer who received first-line fluoropyrimidine and oxaliplatin-based therapy.
2.1.2
Irinotecan
Irinotecan is a derivative of camptothecin. Camptothecin interact specifically with the enzyme 
topoisomerase I, which relieves torsional strain in DNA by inducing reversible single-strand 
breaks. Irinotecan and its active metabolite SN-38 bind to the topoisomerase I-DNA complex and 
prevent relegation of these single-strand breaks. Current research suggests that the cytotoxicity of 
irinotecan is due to double-strand DNA damage produced during DNA synthesis when replication 
enzymes interact with the ternary complex formed by topoisomerase I, DNA, and either irinotecan 
or SN-38. Mammalian cells cannot efficiently repair these double-strand breaks. Irinotecan is a 
standard agent used in the treatment of advanced colorectal cancer, with multiple supporting 
studies in the second-line setting.
APPROVED RPCI IRB
8/2/2022

Roswell Park Protocol No.: I 444019
07/14/2022
Page 5 of 55
2.1.3
Bevacizumab
Bevacizumab binds VEGF and prevents the interaction of VEGF to its receptors (Flt-1 and KDR) 
on the surface of endothelial cells. The interaction of VEGF with its receptors leads to endothelial 
cell proliferation and new blood vessel formation in in vitro models of angiogenesis. 
Administration of bevacizumab to xenotransplant models of colon cancer in nude (athymic) mice 
caused reduction of microvascular growth and inhibition of metastatic disease progression. 
Bevacizumab has demonstrated efficacy in the second line setting and is a standard option which 
is considered in combination with chemotherapy (1, 13).
2.2
Rationale for Study Combination 
Following first line chemotherapy for metastatic colorectal cancer, as part of second-line 
chemotherapy, typically the fluoropyrimidine, 5-FU, is continued with a switch of the other agents. 
In the US, the majority of patients have traditionally received 1st line therapy with FOLFOX + a 
biologic, making FOLFIRI + bevacizumab a very common second-line treatment. This regimen is 
expected to confer a PFS of approximately 6 months, with median survival standing in the range 
of 11-13 months (1-3).
TAS-102 has a distinct mechanism of action from 5-FU and in preclinical models can overcome 
5-FU resistance. In limited direct comparisons to classic fluoropyrimidines (capecitabine), there 
are signs that TAS-102 may possess greater activity. Safety in combining TAS-102 with irinotecan 
and bevacizumab has already been demonstrated, with encouraging activity beyond what would 
be expected with FOLFIRI + bevacizumab.
Thus, we hypothesize that in the second-line metastatic setting:
1. TAS-102-based combination therapy (TAS-102 + irinotecan + bevacizumab) will 
demonstrate greater efficacy than the historic comparator, FOLFIRI (5-FU + Leucovorin 
+ irinotecan) + bevacizumab.
2. The combination will demonstrate a favorable toxicity profile with TAS-102 administered 
at the previously established regimen-specific MTD of 25 mg/m2 twice daily for 5 days of 
a 14-day treatment, with standard dose irinotecan and bevacizumab.
3
INCLUSION AND EXCLUSION CRITERIA
3.1
Inclusion Criteria
NOTE: For blood Chemistry labs, Roswell Park clinical blood chemistries are performed on 
plasma unless otherwise indicated.
To be included in this study, participants must meet the following criteria:
1. Age ≥ 18 years old.
2. Advanced colorectal cancer (metastatic or unresectable): Histologically or cytological 
proven adenocarcinoma of the colon or rectum which is metastatic or otherwise incurable.
3. Prior treatment with a fluoropyrimidine (5-FU or capecitabine) and oxaliplatin in the 
metastatic/unresectable setting OR, recurrence within 12 months of adjuvant therapy with 
a regimen that included oxaliplatin.
APPROVED RPCI IRB
8/2/2022

Roswell Park Protocol No.: I 444019
07/14/2022
Page 6 of 55
4. Have an ECOG Performance Status of 0-1. Refer to Appendix A.
5. Have the following clinical laboratory values: 

Hemoglobin ≥ 9 g/dL

Absolute neutrophil count ≥ 1500/mm3

Platelet count ≥ 100,000/mm3

Creatinine < 1.5 ULN or if ≥ 1.5 x ULN CRCL ≥ 30 mL/min (by Cockroft-Gault)

Bilirubin < 1.5 x ULN

AST/ALT ≤ 2.5 x ULN or ≤ 5 x ULN if with hepatic metastases
6. Have measurable disease per RECIST 1.1 criteria present.
7. Participants of child-bearing potential must agree to use adequate contraceptive methods 
(e.g., hormonal or barrier method of birth control; abstinence) prior to study entry. Should 
a woman become pregnant or suspect she is pregnant while she or her partner is 
participating in this study, she should inform her treating physician immediately.
8. Participant must understand the investigational nature of this study and sign an Independent 
Ethics Committee/Institutional Review Board approved written informed consent form 
prior to receiving any study related procedure.
Refer to Appendix B for the Investigator Study Eligibility Verification Form: Inclusion Criteria.
3.2
Exclusion Criteria
Participants will be excluded from this study for the following:
1. Prior treatment with TAS-102 or irinotecan.
2. Anti-cancer therapy within 2 weeks of the planned first dose of study medication.
3. Unresolved toxicities from prior therapy of > Grade 1, excluding alopecia or similar 
toxicities which are not deemed to be clinically significant or put the participant at greater 
risk. Grade 2 neuropathy is permitted.
4. Major surgery within 4 weeks of anticipated start of therapy.
5. Uncontrolled hypertension: systolic blood pressure ≥ 150, diastolic blood pressure ≥ 100.
6. Unstable angina, symptomatic congestive heart failure or cardiac arrhythmia requiring anti-
arrhythmic therapy (beta-blockers, calcium channel blockers and digoxin are allowed).
7. Arterial or venous thrombotic or embolic events within 3 months of study initiation, unless 
well controlled on stable anti-coagulation for ≥ 2 weeks. This excludes uncomplicated 
catheter associated venous thrombosis.
8. History of cerebrovascular or myocardial ischemia within 6 months of initiation.
9. NCI CTCAE v 5.0 Grade 3 or greater hemorrhage within the past 4 weeks.
10. Proteinuria ≥ 2+, unless 24-hour urine collection demonstrates ≤ 1 g of protein OR spot 
protein: creatinine demonstrates a ratio of ≤ 1.
11. Untreated brain metastases.
12. History of abnormal glucuronidation of bilirubin (Gilbert’s Syndrome).
APPROVED RPCI IRB
8/2/2022

Roswell Park Protocol No.: I 444019
07/14/2022
Page 7 of 55
13. History of second primary malignancy within 3 years prior to enrollment, excluding in-situ 
cervical carcinoma, non-melanoma skin cancer or malignancy of equivalent risk which is 
highly unlikely to require systemic treatment in the next 2 years.
14. Have known active infection which would heighten the risk of complications.
15. Pregnant or nursing female participants.
16. Unwilling or unable to follow protocol requirements.
17. Any condition which in the Investigator’s opinion deems the participant an unsuitable 
candidate to receive study drug.
Refer to Appendix C for the Investigator Study Eligibility Verification Form: Inclusion Criteria.
3.3
Inclusion of Women and Minorities
Both men and women and members of all races and ethnic groups are eligible for this study.
3.4
Special Populations
The following special populations are excluded from this study:

Cognitively impaired adults/adults with impaired decision-making capacity

Individuals who are not yet adults (infants, children, teenagers)

Prisoners

Pregnant women
4
LOCAL AND STUDY-WIDE NUMBER OF SUBJECTS
A maximum of 36 evaluable participants are required for the primary analysis. To account for 
potential dropouts, a total of 42 patients may be accrued. Approximately 20 participants are 
expected to be accrued at Roswell Park with approximately 20 participants accrued from the 
accompanying external sites (collectively). Accrual is expected to take 36 months.
5
LOCAL AND STUDY-WIDE RECRUITMENT METHODS
Participants will be identified/recruited/screened from patients at the GI clinic at Roswell Park and 
participating sites and from multi-disciplinary conference discussion.
6
MULTI-SITE RESEARCH
This is a multi-site study. It is the responsibility of the lead investigator to ensure that:

All sites have the most current version of the protocol, consent document, and HIPAA 
authorization.

All required approvals (initial, continuing review and modifications) have been obtained 
at each site (including approval by the site’s IRB of record).

All modifications have been communicated to sites and approved (including approval by 
the site’s IRB of record) before the modification is implemented.
APPROVED RPCI IRB
8/2/2022

Roswell Park Protocol No.: I 444019
07/14/2022
Page 8 of 55

All engaged participating sites will safeguard data, including secure transmission of data, 
as required by local information security policies.

All local site investigators will conduct the study in accordance with applicable federal 
regulations and local laws.

All non-compliance with the study protocol or applicable requirements will be reported in 
accordance with local policy.
Refer to Appendix D: Instructions for Multi-Site Studies for additional details.
7
STUDY TIMELINES
Accrual is expected to take 36 months with an additional 24 months of follow-up. The estimated 
time frame that the analysis of the primary endpoint would be evaluable is approximately 4 years 
(48 months) after study commencement.
8
STUDY ENDPOINTS
8.1
Primary Endpoint

The primary endpoint is the median progression free survival (PFS) of the study 
population. This will be assessed via the Response Evaluation Criteria in Solid Tumors 
(RECIST) version 1.1 guidelines after every 2 cycles (8 weeks) of therapy.
8.2
Secondary Endpoints

Objective response rate (ORR) will be tabulated based on RECIST v1.1 criteria.

Median overall survival (OS) from the date of enrollment to the time of death will be 
documented.

Aggregate rates of adverse events as measured by CTCAE v 5.0 will be recorded to 
objectively measure toxicities of the combination therapy.
9
DESIGN
This is an open-label, non-randomized, multi-center, Phase II study of TAS-102, irinotecan, and 
bevacizumab in participants with advanced (metastatic or unresectable) colorectal cancer who 
have received prior treatment with a fluoropyrimidine (5-FU or capecitabine) and oxaliplatin or, 
who have had a recurrence within 12 months of adjuvant therapy with a regimen that included 
oxaliplatin. For study purposes, a cycle will be defined as 28 days. Response assessment via CT 
imaging (or MRI) will be obtained every 8 weeks. Treatment will continue until disease 
progression, in the absence of unacceptable toxicity or patient/provider choice.
Treatment is intended for an outpatient setting. The study schema is depicted in Figure 1.
Figure 1
Study Schema
Multi-center single-arm Phase III study
Metastatic or unresectable colorectal cancer patients after the first line 5-FU and 
oxaliplatin-based therapy
Estimated enrollment= 42 patients
1 cycle= 28 days
Irinotecan IV (180 mg/m2) on Days 1 & 15
Bevacizumab IV ( 5mg/kg) on Days 1 & 15
TAS-102 PO (25 mg/m2) twice daily on Days 2-6 & 16-20
Primary endpoint: Progression free survival
Secondary endpoint: Objective response rate, Overall survival, Disease specific survival, 
and Rates of adverse events
Treatment continuation until disease progression, unacceptable toxicity, or 
patient’s/provider’s choice
As clinically necessary, response assessment via CT/MRI after every 8 weeks of therapy
APPROVED RPCI IRB
8/2/2022

Roswell Park Protocol No.: I 444019
07/14/2022
Page 9 of 55
10 TREATMENT
Based upon the presented safety data (NCT01916447) and the pre-clinical data regarding 
sequencing, the following would be administered every 28 days:

Irinotecan (180 mg/m2) IV Day 1 and Day 15 of each treatment cycle

Bevacizumab* (5 mg/kg) IV Day 1 and Day 15 of each treatment cycle

TAS-102 (25 mg/m2) twice daily, orally, on Day 2- Day 6 and Day 16- Day 20 of each 
cycle
* Use of bevacizumab biosimilars at the same dose is allowed.
Figure 2 provides a graphical representation of the treatment cycle.
Figure 2
Treatment Dosing and Duration
Patients will present for evaluation on Days 1 and 15 of every cycle. Subjects must meet the below 
criteria (Table 1) to be eligible to proceed with treatment on either of Days 1 or 15 of each cycle. 
Patients will continue treatment until the development of progressive disease or intolerable 
toxicity; barring a patient or investigator-related decision to discontinue therapy for other reasons.
Table 1
Criteria for Retreatment before Treatment Initiation

ANC ≥ 1,500/ mm3 or febrile neutropenia is resolved

Platelet count ≥ 75,000/mm3

AST and/or ALT CTCAE grade < or equal to five times ULN and Bilirubin < 1.5 X ULN

Any additional non-hematologic toxicity of Grade ≥ 3 which is potentially attributable to 
TAS-102 or irinotecan must have resolved to Grade ≤ 1 (or baseline)*
* Patients with bevacizumab related complications which require holding of bevacizumab may continue 
the other agents, if appropriate.
APPROVED RPCI IRB
8/2/2022

Roswell Park Protocol No.: I 444019
07/14/2022
Page 10 of 55
10.1 Dose Modifications and Treatment Delays
NOTE: Please refer to Table 1 for criteria for retreatment before treatment initiation on Day 
1 and Day 15 of each cycle. If patients discontinue one of the medications due to intolerance, they 
are permitted to and should be advised to continue on treatment with the other agents. For any dose 
reduction which would decrease irinotecan below 90 mg/m2 or TAS-102 below 20 mg/m2 BID, 
the respective agent should be discontinued altogether. If a toxicity (including those not 
specifically described below) is deemed to be clearly related to only one drug, dose modification 
of only that singular drug is permitted. Bevacizumab is administered at a singular dose basis. Thus, 
qualifying events will result in a hold or discontinuation of therapy rather than dose modification. 
If any of the 3 agents has to be discontinued for toxicity, patients can remain on treatment with the 
other 2 (i.e. TAS-102/bevacizumab or irinotecan/bevacizumab or irinotecan/TAS-102). Patients 
can remain on study if 2 agents have to be discontinued for toxicity (i.e. irinotecan or TAS-102) 
provided that they continue to derive clinical benefit from participation in the study. Patients who 
have to stop both irinotecan and TAS-102 will be taken off study.
10.1.1 TAS-102 Dose Modifications for Adverse Reactions
TAS-102 is to be initiated at the recommended dose of 25 mg/m2 up to a maximum of 80 mg per 
dose (based on the trifluridine component) orally twice daily with food or within one hour of 
completion of morning and evening meals, on Days 2 through 6 and Days 16 through 20 of each 
28-day cycle. Initial dosing calculation based on body surface area (BSA) with dose rounded to 
the nearest 5 mg increment. Please refer to Table 2 for calculation of the initial dosage and the 
number of tablets per dose. 
As applicable, this table can be utilized to determine the optimal pill combinations at the time of 
any dose reductions, as well. In the instance that TAS-102 is dose reduced, simply calculate the 
new dose based upon the BSA, utilizing the 20 mg/m2 dose level. Round the dose to the nearest 5 
mg. The table then provides guidance as to the number and strength of tablets that would be 
recommended. Permanently discontinue TAS-102 in patients who are unable to tolerate a 
dose of 20 mg/m2 orally twice daily. Do not escalate TAS-102 dosage after it has been reduced.
Within a treatment cycle, withhold TAS-102 for any of the following:

Absolute neutrophil count (ANC) < 500/mm3 or febrile neutropenia

Platelets < 50,000/mm3

Grade 3 or 4 non-hematologic adverse reaction
Table 2
TAS-102 Initial Dose Calculation
BSA (m2)
Total Daily 
dosing (mg: 
AM + PM)
Dose (mg) 
administered 
twice daily
Tablets per 
dose -15 mg
Tablets per 
dose-20 mg
<1.07
501
25
21
11
1.07-1.22
60
30
2
0
1.23-1.52
70
35
1
1
1.53-1.682
80
40
0
2
APPROVED RPCI IRB
8/2/2022

Roswell Park Protocol No.: I 444019
07/14/2022
Page 11 of 55
1.69-1.83
90
45
3
0
1.84-1.98
100
50
2
1
1.99-2.14
100
50
2
1
2.15-2.29
110
55
1
2
2.30-2.49
120
60
0
3
2.5-2.69
130
65
3
1
2.7-2.89
140
70
2
2
2.9-3.09
150
75
1
3
>3.09
160
80
0
4
1. Daily total doses lower than 50 mg should not be utilized. At this daily dosing, 20 mg would be administered in the AM and 30 mg 
in the PM, with the tablet combination described.
2. For participants with BSA > 1.69 m2, the maximum dose is not to exceed 80 mg (i.e., 80 mg AM and 80 mg PM).
TAS-102 tablets to be taken as whole and not to be crushed.
If a dose is vomited or missed, the dose should not be retaken, and the patient should continue with 
the next scheduled dose.
Once the dose is established, dosing recalculation is not necessary unless there is a more than 10% 
change in weight. At the investigator’s discretion, dosing may be adjusted for changes of < 10%.
10.1.2 Irinotecan Dose Modifications for Adverse Reactions
Dosage: To be administered at a dose of 180 mg/m2 as an IV infusion on Days 1 & 15 in 
conjunction with an antiemetic regimen. A 5HT-3 blocker as well as a corticosteroid is the 
recommended minimum prior to infusional treatments (e.g. palonosetron 0.25 mg IV or 
ondansetron 16 mg IV, with dexamethasone 12 mg po). The choice of regimen for nausea 
prophylaxis is to be per institutional standard of care.
10.1.3 Dose Modifications and Toxicity Management
Table 3 depicts dose levels, which correspond to toxicity-related dose modifications, described in 
the section(s) below. Permanently discontinue TAS-102 in patients unable to tolerate a dose of 
20 mg/m2 orally twice a day.
Table 3
Dose Levels
Agent
Initial 
Dose 
(Level 0)
Level -1
Level -2
Level -3
Level -4
Irinotecan
180 
mg/m2
150 mg/m2
150 mg/m2
120 mg/m2
90 mg/m2
TAS-102
25 mg/m2 
BID
25 mg/m2 
BID
20 mg/m2 BID
20 mg/m2 BID
20 mg/m2 
BID
Bevacizumab
5 mg/kg
No dose 
reduction 
No dose 
reduction 
No dose 
reduction 
No dose 
reduction 
APPROVED RPCI IRB
8/2/2022

Roswell Park Protocol No.: I 444019
07/14/2022
Page 12 of 55
I.
Management of Hematologic Toxicities
a. Thrombocytopenia
Table 4
Dose Modifications for Thrombocytopenia
Grade
(NCI CTCAE version 5.0)
Treatment Delay
Irinotecan
TAS-102
Grade 1 or LLN - 
75,000/mm3
Hold until platelet 
count ≥ 75000 /mm3
Continue at same 
dose level
Continue at 
same dose level
Grade 2 or LLN - 
<75000/mm3, 1st occurrence
Hold until platelet 
count ≥ 75000 /mm3
Continue at same 
dose level
Continue at 
same dose level
Grade 2 or LLN - 
<75000/mm3, each 
subsequent occurrence
Hold until platelet 
count ≥ 75000 /mm3
Dose reduce by one 
level (e.g. level -1)
Dose reduce by 
one level (e.g. 
level -1)
Grade 3 or <50000-
25,000/mm3
Grade 4 or <25,000/mm3, 
each occurrence
Hold until platelet 
count ≥ 75000/mm3
Dose reduce by one 
level (e.g. level -1)
Dose reduce by 
one level (e.g. 
level -1)
LLN= Lower limit of normal
b. Neutropenia
Table 5
Dose Modifications for Neutropenia *
Grade 
(NCI CTCAE version 5.0)
Treatment 
delay
Irinotecan
TAS-102
Grade 1 or Grade 2 (< 7 
days)
ANC < LLN - 1000/mm3 
Hold until ANC 
≥ 1500/mm3 
Continue at same 
dose level
Continue at same 
dose level
Grade 2 ≥ 7 days
ANC < LLN – 1000/mm3
Hold until ANC 
≥ 1500/mm3
Dose reduce by one 
level (e.g. level -1)
Dose reduce by one 
level (e.g. level -1) 
Grade 3 or ANC < 1000-
500/mm3
Grade 4 or ANC <500/mm3, 
each occurrence
Hold until ANC 
≥ 1500/mm3
Dose reduce by one 
level (e.g. level -1)
Dose reduce by one 
level (e.g. level -1) 
LLN= Lower limit of normal, ANC= absolute neutrophil count
* If neutropenia grade 2 or higher lasts ≥ 7 days, prophylactic non-pegylated granulocyte stimulating 
growth factor (G-CSF, i.e. filgrastim or biosimilar) should be considered, to be initiated 24 hours 
after the last TAS-102 dose (when study treatment dosing restarts).
APPROVED RPCI IRB
8/2/2022

Roswell Park Protocol No.: I 444019
07/14/2022
Page 13 of 55
c.
Febrile Neutropenia
Table 6
Dose Modifications for Febrile Neutropenia*
Febrile Neutropenia
Treatment delay
Irinotecan
TAS-102
1st occurrence
Hold dose until 
resolved
Dose reduce by one 
level (e.g. level -1)
Dose reduce by one 
level (e.g. level -1)
2nd occurrence
Hold dose until 
resolved
Dose reduce by one 
level (e.g. level -2) 
Dose reduce by one 
level (e.g. level -2)
3rd occurrence 
Hold
Permanently 
discontinue
Permanently 
discontinue
* ANC <1000/mm3 with a single temperature of 38.3 degrees C (101 degrees F) or a sustained temperature 
of >= 38 degrees C (100.4 degrees F) for more than one hour.
In case of febrile neutropenia (1st occurrence), prophylactic non-pegylated G-CSF, i.e. filgrastim or 
biosimilar) has to be initiated 24 hours after the last TAS-102 dose (when study treatment dosing 
restarts), unless the patient is already on for prior neutropenia.
II.
Management of Non- Hematologic Toxicities
Note: For early-onset diarrhea, diaphoresis or bradycardia resulting from irinotecan infusion, 
consider the following:

Atropine, 0.4 mg, subcutaneous, PRN or 0.2 mg, subcutaneous, PRN for a total of up to 
1 mg.
a. Diarrhea
Table 7
Dose Modifications for Diarrhea1
Grade
(NCI CTCAE version 5.0) 2
Irinotecan
TAS-102
Grade 1 or 2
Continue at same dose level
Continue at same dose level
Intolerable grade 2 
Grade 3 or 4: 1st occurrence
Dose reduce to next level 
(level -1)
Dose reduce to next level 
(level -1)
Grade 3 or 4: 2nd occurrence
Dose reduce to next level 
(level -2)
Dose reduce to next level 
(level -2)
Grade 3 or 4: each additional 
occurrence 3
Dose reduce to next level 
(level -3, etc.) 3
Dose reduce to next level 
(level -3, etc.) 3
1. This table refers to modifications for diarrhea optimally managed with supportive measures. If sub-
optimally managed with anti-motility agents, oral hydration, institution of these measures should precede 
any dose reductions.
2. Grade 1= Increase of <4 stools/day over baseline or mild increase in ostomy output; Grade 2= Increase 
of 4-6 stools/day over baseline or moderate increase in ostomy output limiting ADLS; Grade 3= Increase 
of >=7 stools/day needing hospitalization or severe increase in ostomy output limiting ADLS; Grade 4= 
Life-threatening consequences; urgent intervention indicated
3. Discontinue irinotecan and TAS-102 if dose level -4 is not tolerated (irinotecan at 90 mg/m2).
APPROVED RPCI IRB
8/2/2022

Roswell Park Protocol No.: I 444019
07/14/2022
Page 14 of 55
b. Other Non- Hematological Toxicities
Table 8
Dose Modifications for Other Non- Hematological Toxicities
Grade
(NCI CTCAE version 5.0)
Irinotecan
TAS-102
Grade 1 or 2
Continue at same dose level
Continue at same dose level
Grade 3 or 4: each 
occurrence*
Delay infusion by 1-2 weeks 
or until recovered to grade 1 or 
baseline condition
Dose reduce to next level (e.g. 
level 1)
Delay dose by 1-2 weeks or 
until recovered to grade 1 or 
baseline condition
Dose reduce to next level (e.g. 
level 1)
Infusion reaction
Reduce the infusion rate by 
50% for NCI CTC Grade 1 or 
2 and non-serious NCI CTC 
Grade 3 infusion reactions. 
Immediately and permanently 
discontinue drug for serious 
infusion reactions, requiring 
medical intervention and/or 
hospitalization.
n/a
* Note: If it is deemed by the investigator that only 1 of the drugs is responsible for the AE of interest then, 
only that particular drug need be subjected to the dose modification criteria described herein.
10.1.4 Bevacizumab Specific Dose Modifications for Adverse Reactions
Dosage: Bevacizumab or bevacizumab biosimilar is to be administered as an intravenous (IV) at 
the dose of 5 mg/kg on Days 1 & 15 over 10 minutes or per institutional policy.

Do not initiate bevacizumab until at least 28 days following major surgery. Hold 
bevacizumab until any surgical incision has fully healed.

Monitor blood pressure at every visit during treatment with bevacizumab. Treat with 
appropriate anti-hypertensive therapy as per standard of care. Continue to monitor blood 
pressure at regular intervals in patients with bevacizumab -induced or -exacerbated 
hypertension after discontinuation of bevacizumab.
APPROVED RPCI IRB
8/2/2022

Roswell Park Protocol No.: I 444019
07/14/2022
Page 15 of 55
Dosing guidance for bevacizumab related toxicities

Hypertension
Table 9
Bevacizumab Dose Modifications for Hypertension
Hypertension*
Occurrence
Bevacizumab management
Grade 2
Systolic BP 140 - 159 mm Hg 
or diastolic BP 90 - 99 mm Hg
Any
Maintain current dose
Grade 3
Systolic BP >=160 mm Hg or 
diastolic BP >=100 mm Hg
Any 
Hold until BP is <160/100 
Grade 4 including RPLS** or 
hypertensive encephalopathy 
or crisis
1st 
Discontinue
* Grading as Common Terminology Criteria for Adverse Events (CTCAE) v 5.0.
** Reversible posterior leukoencephalopathy (RPLS) or posterior reversible encephalopathy syndrome 
(PRES): A disorder characterized by headaches, mental status changes, visual disturbances, and/or seizures 
associated with imaging findings of posterior leukoencephalopathy. It is an acute or subacute reversible 
condition.

Proteinuria
Proteinuria will be monitored by urinalysis (UA) dipstick or 24-hour urine on Day 1 of every cycle. 
UA dipstick values >2+ protein should be confirmed by 24-hour collection and management based 
upon 24-hour protein values. In lieu of 24-hour urine collection, spot protein: creatinine 
measurement and calculation may be utilized. Patients may continue therapy while awaiting 24-
hour urine protein assessment.
UPC = protein concentration (mg/dL) / creatinine concentration (mg/dL). To obtain urine 
protein/creatinine (UPC) ratio from random urine sample (i.e., not 24-hour urine):
a.
Obtain at least 4 mL of a random urine sample.
b. Determine protein concentration (mg/dL)
c.
Determine creatinine concentration (mg/dL)
d. Divide b by c
UPC directly correlates with the amount of protein excreted in the urine per 24 hours (i.e., UPC of 
1 should be equivalent to Ig protein in a 24hr urine collection).
APPROVED RPCI IRB
8/2/2022

Roswell Park Protocol No.: I 444019
07/14/2022
Page 16 of 55
Table 10
Bevacizumab Dose Modifications for Proteinuria
Proteinuria
Occurrence
Bevacizumab management
1st to 3rd occurrence
Hold until recovery to 24 hr 
urine protein < 2g, then 
resume at current dose
2+ and 3+ proteinuria; 
urinary protein 
2.0- < 3.5 g/24 hrs
4th occurrence
Discontinue
Urinary protein ≥ 3.5 g/24 
hrs; 4+ proteinuria
1st occurrence
Discontinue

Hemorrhage
Table 11
Dose Modifications for Hemorrhage
Hemorrhage*
Occurrence
Bevacizumab management
Grade 2 non-pulmonary or 
non-CNS
Any
Maintain current dose
Grade 2 pulmonary
Any
Discontinue
Grade 3 or 4
Any
Discontinue
Any grade CNS hemorrhage 
Any
Discontinue
* The following terms from NCI CTCAE version 5.0 may be considered for reporting purposes: Vitreous 
hemorrhage, Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, Duodenal hemorrhage. 
Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, Hemorrhoidal hemorrhage, 
Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal hemorrhage, Lower gastrointestinal hemorrhage, 
Oral hemorrhage, Pancreatic hemorrhage, Rectal hemorrhage. Retroperitoneal hemorrhage, Upper 
Gastrointestinal hemorrhage, Hepatic hemorrhage, Intraoperative hemorrhage, Postoperative hemorrhage, 
Tracheal hemorrhage, Intracranial hemorrhage, Renal hemorrhage, Ovarian hemorrhage, Prostatic 
hemorrhage, Spermatic cord hemorrhage, Testicular hemorrhage, Uterine hemorrhage, Vaginal 
hemorrhage, Bronchopulmonary hemorrhage, Laryngeal hemorrhage, Mediastinal hemorrhage, Pharyngeal 
hemorrhage, and Pleural hemorrhage.

Venous Thromboembolism
Table 12
Dose Modifications for Venous Thromboembolism (VTE)
Grade*
Occurrence
Bevacizumab management
Grade 2
Any
Maintain current dose
Grade 3**
Any
Hold until stable full -dose 
anticoagulation is achieved (at 
least 48 hours), then resume at 
current dose
Grade 4**
Any
Discontinue
APPROVED RPCI IRB
8/2/2022

Roswell Park Protocol No.: I 444019
07/14/2022
Page 17 of 55
* The following terms from NCI CTCAE version 5.0 may be considered for reporting purposes: Superior 
vena cava syndrome, Portal vein thrombosis, and Vascular access complication.
**The following criteria must be met by patients who experience a Grade 3 or 4 VTE: (a) No evidence of 
tumor involving major blood vessels on current CT scan; (b) No use of warfarin; (c) No use of anti-platelet 
agents during full dose anticoagulation; (d) May use low molecular weight heparin or oral factor Xa 
inhibitors; (e) No Grade 3 or 4 hemorrhagic event while on anticoagulation; and (f) Clinically stable on a 
stable dose of low molecular weight heparin or other anticoagulant for at least 48 hours prior to resuming 
study drug treatment.

Arterial Thromboembolism
Table 13
Dose Modifications for Arterial thromboembolism (ATE)
ATE Toxicity Grade*
Occurrence
Bevacizumab management
Any grade
Any
Discontinue
* The following terms from NCI CTCAE version 5.0 may be considered for reporting purposes: Stroke, 
Acute coronary syndrome, Myocardial infarction, visceral arterial ischemia, Ischemia Cerebrovascular. 
This does not apply to pulmonary embolism.

Besides the above-mentioned points, discontinue bevacizumab for: 
o
Gastrointestinal perforations (gastrointestinal perforations, fistula formation in the 
gastrointestinal tract, intra-abdominal abscess), fistula formation involving an 
internal organ. 
o
Wound dehiscence and wound healing complications requiring medical 
intervention, unless minor and rapidly resolving, in which case only a hold of 
dosing is necessary.

Hold bevacizumab for: 
o
At least 4 weeks prior to elective surgery. Do not administer Bevacizumab until the 
wound is fully healed.
o
Severe infusion reactions.
10.2 General Concomitant Medication and Supportive Care
Antiemetic agents would be given on Day 1 and Day 15 of treatment, starting at least 30 minutes 
before administration of all therapy and for subsequent use as needed. A 5HT-3 blocker as well as 
a corticosteroid is the recommended minimum prior to infusional treatments (e.g. palonosetron 
0.25 mg IV or ondansetron 16 mg IV, with dexamethasone 12 mg po). Additional agents, 
including NK1 antagonists (e.g. aprepitant), olanzapine, or benzodiazepines may be utilized, as 
deemed necessary by the investigator. The choice of regimen for nausea prophylaxis is to be per 
institutional standard of care, considering that this is a moderately emetogenic regimen. 
Irinotecan clearance is diminished in patients with hepatic impairment while exposure to the active 
metabolite SN-38 is increased relative to that in patients with normal hepatic function. Do not 
administer to patients with serum bilirubin > 2.0 mg/dL, or transaminase > 3 times the upper limit 
of normal if no liver metastasis, or transaminase > 5 times the upper limit of normal with liver 
metastasis.
APPROVED RPCI IRB
8/2/2022

Roswell Park Protocol No.: I 444019
07/14/2022
Page 18 of 55
If necessary, growth factor support is permitted during the study protocol. For neutropenia or 
neutropenic fever, G-CSF should be utilized as stated above in Section 10.1.3 (Dose modifications 
and toxicity management: I. Management of Hematologic Toxicities). Given the protracted course 
of administration, non-pegylated agents (e.g. filgrastim) are preferred for use.
10.2.1 Supportive Medications
Management of diarrhea: Patients should have loperamide readily available to begin treatment 
for late diarrhea. Begin loperamide at the first episode of poorly formed or loose stools or the 
earliest onset of bowel movements more frequent than normal. One dosage regimen for loperamide 
is 4 mg at the first onset of late diarrhea and then 2 mg every 2 hours until the patient is diarrhea-
free for at least 12 hours. Loperamide is not recommended to be used for more than 48 consecutive 
hours at these doses, because of the risk of paralytic ileus. Monitor and replace fluid and 
electrolytes. Use antibiotic support for ileus, fever, or severe neutropenia. 
10.2.2 Permitted Concomitant Medications
Any medications needed to alleviate treatment related side effects or cancer related symptoms are 
permitted, except for those prohibited below in Section 10.2.3.
10.2.3 Prohibited Concomitant Medications
TAS-102: Caution is required when using drugs that are human thymidine kinase substrates, e.g., 
zidovudine. Such drugs, if used concomitantly with TAS-102, may theoretically compete with the 
effector of TAS-102, 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. 
Irinotecan: Do not administer irinotecan along with strong CYP3A4 inducers or strong CYP3A4 
Inhibitors.
Please refer to Appendix G for a list of potentially interacting drugs.
10.3 Duration of Treatment
Participants may remain on study and continue to receive treatment in the absence of disease 
progression, unacceptable toxicity and withdrawal from study, inter-current illness that prevents 
further administration of treatment, participant demonstrates an inability/refusal to comply with 
oral medication regime or, participant withdraws from study.
10.4 Compliance
TAS-102 will be self-administered (in tablet form) BID by the study participant and documented 
in the provided drug diary. The participant will be asked to bring the diary with him/her to each 
clinical visit (see Appendix E). 
11 PROCEDURES INVOLVED
The study-specific assessments are detailed in this section and outlined in Appendix F (Schedule 
of Procedures and Observations). Baseline and/or Screening assessments must be performed 
APPROVED RPCI IRB
8/2/2022

Roswell Park Protocol No.: I 444019
07/14/2022
Page 19 of 55
within 14 days prior to the first dose of investigational product. Any results falling outside of the 
reference ranges may be repeated at the discretion of the investigator. All on-study visit procedures 
are allowed a window of 7 days unless otherwise noted.
NOTE: For blood Chemistry labs, Roswell Park clinical blood chemistries are performed on 
plasma unless otherwise indicated.
11.1 Participant Randomization and/ or Registration:
Eligibility of each participant will be established prior to registration.
Informed consent MUST be completed prior to receiving any study related procedures.
11.2 Baseline Evaluations
The following will be performed within 2 weeks prior to first dose of study drug:

Medical history (including all prior anti-tumoral therapy related to their current 
colorectal cancer diagnosis.

Physical examination.

Vital signs (i.e., temperature, heart rate, respiratory rate, blood pressure, body weight, and 
height). Height measured at baseline only.

ECOG Performance Status (Appendix A).

Concomitant Medications: List any medications that are ongoing, or that will be 
discontinued, within 1 week prior to first dose of study drug.

Hematology: (CBC with automated differentials) WBC, RBC, HGB, HCT, platelet, MCV, 
MCH, MCHC, % neutrophils, absolute neutrophils, % monocytes, absolute monocytes, % 
eosinophils, absolute eosinophils, % basophils, absolute basophils, % lymphocyte, absolute 
lymphocyte, platelet confirmation (as clinically indicated), and differential confirmation 
(as clinically indicated).

Chemistry (CMP): chloride, CO2, potassium, sodium, BUN, glucose, calcium, creatinine, 
total protein, albumin, total bilirubin, alkaline phosphatase, AST, ALT, A/G ratio, 
BUN/creatinine ratio, osmol (Calc), anion gap).

Pregnancy test (urine, serum) in females of childbearing potential.

Dipstick urine or 24- hour urine collection for total protein assessment.

ECG/EKG: 12-lead.
A CT/MRI for disease assessment will be performed within 4 weeks prior to the first dose of the 
study drugs.
11.3 Evaluations Performed on Day 1 and Day 15 of Each Cycle

Physical examination

Vital signs

Concomitant medications

Adverse events
APPROVED RPCI IRB
8/2/2022

Roswell Park Protocol No.: I 444019
07/14/2022
Page 20 of 55

Hematology: CBC

Chemistry: CMP

Tumor marker: Carcinoembryonic antigen (CEA), to be measured on day 1 of each cycle 
only.

Irinotecan (IV) and bevacizumab (IV). Note: TAS-102 will be administered orally, BID on 
Days 2-6 and Days 16-20 of each 28-day cycle.
11.4 Tumor Response Assessment:

As clinically necessary, response assessment with either a contrast enhanced CT scan or 
MRI every 8 weeks (± 7 days).
11.5 Evaluations Performed at End of Treatment
The following evaluations will be performed at the end of treatment or at time of treatment 
discontinuation:

Physical examination, including vital signs 

ECOG Performance Status

Hematology: CBC

Chemistry: CMP

Concomitant medication: List any ongoing medications with dose changes, as applicable.

Adverse events
11.6 Post-Treatment Follow-Up Evaluations
Follow-up safety evaluations will occur 30 days (± 3 days) after last dose of study drug or until 
resolution of any drug-related toxicity (telephone contact is acceptable).

Concomitant medications: List any ongoing medications with dose changes, as applicable.

Adverse events
11.7 Long Term Follow-Up Evaluations
Medical record review will be performed approximately every 6 months for up to 2 years after 
completion of treatment to assess survival status.
Participants who are unavailable for follow-up evaluations should be classified as lost to follow-
up for 1 of the following reasons:

Lost to follow-up: For a participant to be considered lost to follow-up, the investigator must 
make two separate attempts to re-establish contact with the participant. The attempts to re-
establish participant contact must be documented (e.g., certified letter).

Death: Date of death will be recorded for those participants who die during f/u after 
completion of the study treatment.
APPROVED RPCI IRB
8/2/2022

Roswell Park Protocol No.: I 444019
07/14/2022
Page 21 of 55
12 WITHDRAWAL OF SUBJECTS

Patients who are unable to reasonably comply with study procedures or are putting 
themselves or the study team at excess risks may be forced to withdraw from the study.

At their own discretion, subjects may withdraw from the study for any reason.

Every effort should be made to obtain follow-up imaging studies until progressive disease 
is noted, in order to document the time to progressive disease.
12.1 Treatment Discontinuation
Upon treatment discontinuation all end of treatment evaluations and tests will be conducted. All 
participants who discontinue due to an AE must be followed until the event resolves or stabilizes. 
Appropriate medical care should be provided until signs and symptoms have abated, stabilized, or 
until abnormal laboratory findings have returned to acceptable or pre-study limits. The final status 
of the AE will be reported in the participant’s medical records and the appropriate eCRF.
Reasons for treatment discontinuation should be classified as follows:

Death

Progressive disease

Toxicity: treatment related or unrelated

Investigator judgment
o
The Investigator may discontinue a participant if, in his/her judgment, it is in the 
best interest of the participant to do so.

Noncompliance

Participant voluntary withdrawal
o
A participant may withdraw from the study at any time, for any reason. If a 
participant discontinues treatment, an attempt should be made to obtain information 
regarding the reason for withdrawal.

Sponsor decision
13 RISKS TO SUBJECTS
Please refer to the package inserts for a comprehensive description of the potential adverse effects 
of the three agents utilized in this study.
13.1 TAS-102
The most common adverse reactions or laboratory abnormalities (≥ 10%) are anemia, neutropenia, 
fatigue/asthenia, nausea, thrombocytopenia, decreased appetite, diarrhea, vomiting, and pyrexia
13.2 Irinotecan
Common adverse reactions (≥30%) observed in combination therapy clinical studies are: nausea, 
vomiting, abdominal pain, diarrhea, constipation, anorexia, mucositis, neutropenia, leukopenia 
(including lymphocytopenia), anemia, thrombocytopenia, asthenia, pain, fever, infection, 
abnormal bilirubin, alopecia.
APPROVED RPCI IRB
8/2/2022

Roswell Park Protocol No.: I 444019
07/14/2022
Page 22 of 55
13.3 Bevacizumab/Bevacizumab Biosimilar
Most common adverse reactions incidence (incidence > 10%) are epistaxis, headache, 
hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation 
disorder, back pain and exfoliative dermatitis.
14 POTENTIAL BENEFITS TO SUBJECTS
The patients will receive a treatment that may be more effective than the standard of care in this 
setting: FOLFIRI (5-FU + leucovorin + irinotecan) and bevacizumab or an anti-EGFR therapy (for 
RAS wt patients)
15 DATA AND SPECIMEN BANKING
Any clinical data that is associated with the study will be stored on a secured server in the 
Department of Medicine, will be accessible only by the PI, co-investigators and PI-designated data 
manager and, will be password protected. All computer entry and networking programs will be 
done using PIDs only. Any clinical data and/or specimens that are used for future studies will be 
de-identified before being released from the PI’s laboratory.
Note: All investigator or analyzing research laboratories housing research samples need to 
maintain current Temperature Logs and study-specific Sample Tracking and Shipping Logs. The 
Principal Investigator/Laboratory Manager must ensure that the stated lab(s) have a process in 
place to document the receipt/processing/storage/shipping of study-related samples/specimens. 
This is required for both observational and interventional clinical studies collecting clinical 
samples.
16 MEASUREMENT OF EFFECT
16.1 Solid Tumors
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) guideline 
(version 1.1) (14)[Eur J Ca 45:228-247, 2009]. Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes 
are used in the RECIST 1.1 criteria.
For the purposes of this study, patients should be re-evaluated for response every 8 weeks while 
on therapy. In addition to a baseline scan, confirmatory scans should also be obtained 8 weeks 
following initial documentation of objective response.
Refer to Appendix H for a summary of RECIST 1.1 criteria.
17 SAFETY EVALUATION
17.1 Adverse Events
An adverse event or adverse experience (AE) is any untoward medical occurrence associated with 
the use of a drug in humans, whether or not considered drug related. Therefore, an AE can be ANY 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or not 
APPROVED RPCI IRB
8/2/2022

Roswell Park Protocol No.: I 444019
07/14/2022
Page 23 of 55
considered related to the medicinal (investigational) product (attribution of ‘unrelated’, ‘unlikely’, 
‘possible’, ‘probable’, or ‘definite’).
An AE is considered “unexpected” if it is not listed in the investigator brochure or is not listed at 
the specificity or severity that has been observed; or if an investigator brochure is not required or 
available, is not consistent with the risk information described in the general investigational plan 
in other study-related documents.
17.2 Diagnosis Versus Signs and Symptoms
If known, a diagnosis should be recorded on the CRF rather than individual signs and symptoms 
(e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases). However, if a constellation of signs and/or symptoms cannot be clinically 
characterized as a single diagnosis or syndrome at the time of reporting, each individual event 
should be recorded as an AE or SAE on the CRF. If a diagnosis is subsequently established, it 
should be reported as follow-up information.
17.3 Adverse Events Occurring Secondary to Other Events
In general, AEs occurring secondary to other events (e.g., cascade events or clinical sequelae) 
should be identified by their primary cause. For example, if severe diarrhea is known to have 
resulted in dehydration, it is sufficient to record only diarrhea as an AE or SAE on the CRF.
However, clinically significant AEs occurring secondary to an initiating event that are separated 
in time should be recorded as independent events on the CRF. For example, if a severe 
gastrointestinal hemorrhage leads to renal failure, both events should be recorded separately on 
the CRF.
17.4 Abnormal Laboratory Values
Only clinically significant laboratory abnormalities that require active management will be 
recorded as AEs or SAEs on the CRF (e.g., abnormalities that require study drug dose 
modification, discontinuation of study treatment, more frequent follow-up assessments, further 
diagnostic investigation, etc.).
If the clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g., alkaline 
phosphatase and bilirubin 5 x the upper limit of normal associated with cholecystitis), only the 
diagnosis (e.g., cholecystitis) needs to be recorded on the Adverse Event CRF.
If the clinically significant laboratory abnormality is not a sign of a disease or syndrome, the 
abnormality itself should be recorded as an AE or SAE on the CRF. If the laboratory abnormality 
can be characterized by a precise clinical term, the clinical term should be recorded as the AE or 
SAE. For example, an elevated blood potassium level of 7 mEq/L should be recorded as 
“hyperkalemia”.
Observations of the same clinically significant laboratory abnormality from visit to visit should 
not be repeatedly recorded as AEs or SAEs on the CRF, unless their severity, seriousness, or 
etiology changes.
APPROVED RPCI IRB
8/2/2022

Roswell Park Protocol No.: I 444019
07/14/2022
Page 24 of 55
17.5 Preexisting Medical Conditions (Baseline Conditions)
A preexisting medical condition should be recorded as an AE or SAE only if the frequency, 
severity, or character of the condition worsens during the study. When recording such events on 
an Adverse Event CRF, it is important to convey the concept that the preexisting condition has 
changed by including applicable descriptors (e.g., “more frequent headaches”).
17.6  Grading and Reporting Adverse Events
17.6.1 Grading and Relationship to Drug
The descriptions and grading scales found in the CTEP Version 5.0 of the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) will be utilized for AE reporting. CTEP 
Version 5.0 of the CTCAE is identified and located at:
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
AEs not covered by specific terminology listed should be reported with common medical 
terminology, and documented according to the grading scales provided in the CTCAE Version 5.0.
The relationship of event to study drug will be documented by the Investigator as follows:
Unrelated: The event is clearly related to other factors such as the participant’s clinical state, other 
therapeutic interventions or concomitant drugs administered to the participant.
Unlikely: The event is doubtfully related to investigational agent(s). The event was most likely 
related to other factors such as the participant’s clinical state, other therapeutic interventions, or 
concomitant drugs.
Possible: The event follows a reasonable temporal sequence from the time of drug administration 
but could have been produced by other factors such as the participant’s clinical state, other 
therapeutic interventions or concomitant drugs.
Probable: The event follows a reasonable temporal sequence from the time of drug administration 
and follows a known response pattern to the study drug. The event cannot be reasonably explained 
by other factors such as the participant’s clinical state, therapeutic interventions or concomitant 
drugs.
Definite: The event follows a reasonable temporal sequence from the time of drug administration, 
follows a known response pattern to the study drug, cannot be reasonably explained by other 
factors such as the participant’s condition, therapeutic interventions or concomitant drugs; AND 
occurs immediately following study drug administration, improves upon stopping the drug, or 
reappears on re-exposure.
17.6.2 Reporting Adverse Events
Routine AEs occurring between the start date of intervention until 30 days after the last 
intervention, or until the event has resolved, the study participant is lost to follow-up, the start of 
a new treatment, or until the study investigator assesses the event(s) as stable or irreversible, will 
be reported. New information will be reported after it is received.
APPROVED RPCI IRB
8/2/2022

Roswell Park Protocol No.: I 444019
07/14/2022
Page 25 of 55
Guidelines for Routine Adverse Event Reporting for Phase 2 Studies 
(Regardless of Expectedness)
Attribution
Grade 1
Grade 2
Grade 3
Grade 4
Unrelated
X
X
Unlikely
X
X
Possible
X
X
X
X
Probable
X
X
X
X
Definite
X
X
X
X
17.7 Serious Adverse Events
A serious adverse event (SAE) is any adverse event (experience) that in the opinion of either the 
investigator or sponsor results in ANY of the following:

Death.

A life-threatening adverse event (experience). Any AE that places a participant or 
participants, in the view of the Investigator or sponsor, at immediate risk of death from the 
reaction as it occurred. It does NOT include an AE that, had it occurred in a more severe 
form, might have caused death.

Inpatient hospitalization or prolongation of existing hospitalization (for > 24 hours).

A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions.

A congenital anomaly or birth defect.

Important Medical Event (IME) that, based upon medical judgment, may jeopardize the 
participant and may require medical or surgical intervention to prevent one of the outcomes 
listed above.
17.7.1 Reporting Serious Adverse Events
All new SAEs occurring from the date the participant signs the study consent until 30 days after 
the last intervention or a new treatment is started, whichever comes first, will be reported. The 
Roswell Park SAE Source Form is to be completed with all available information, including a brief 
narrative describing the SAE and any other relevant information.
SAEs occurring after the 30 day follow-up period that the investigator determines to be possibly, 
probably or definitely related to the study intervention should be reported.
SAEs that are unexpected and possibly, probably or definitely related must be reported as an 
Unanticipated Problem. Please refer to Section 17.10 for details on reporting Unanticipated 
Problems.
17.8 Investigator Reporting: Notifying Taiho Oncology, Inc.
1
The Principal Investigator at each participating site will monitor the patient for adverse 
events and fulfil all the reporting requirements to FDA in accordance with Applicable 
Laws. The Principal Investigator will also inform Taiho Oncology of serious adverse 
events:
APPROVED RPCI IRB
8/2/2022

Roswell Park Protocol No.: I 444019
07/14/2022
Page 26 of 55
o
Unexpected Fatal or Life Threatening Suspected Adverse Reactions: Report to 
Taiho Oncology, Inc. within 24 hours
o
Serious & Unexpected Suspected Adverse Reactions: Report to Taiho Oncology, 
Inc. within 24 hours
o
All other Serious cases (Expected and Related; Expected and Not related; 
Unexpected and Not related): Report to Taiho Oncology within 2 weeks of 
awareness
2
All serious adverse events via a MedWatch Form need to be sent to:
Taiho Oncology, Inc.
fax: 609-750-7371 or e-mail: TAS-102_Safety@taihooncology.com 
(please note the underscore between ‘102’ and ‘Safety’)
AND
NCCN at:
ORPreports@nccn.org 
or
FAX: (215) -358-7699
3
MedWatch reports must clearly specify SAE term(s) and corresponding investigator 
causality assessment.
4
Taiho Oncology will send SUSARs to Regulatory Authorities via a MedWatch form within 
7 Calendar Days for all fatal/life threatening events and 15 Calendar Days for all other 
serious events.
17.8.1 Other Reportable Occurrences
For the purposes of this study, other experiences with the TAS-102 shown below should also be 
reported to Taiho Oncology:
1. Drug exposure during pregnancy and lactation, or paternal drug exposure (see following 
section)
2. Experience in patients below 18 years of age (depending on Inclusion criteria)
3. Lack of drug effect
4. Unintended beneficial effect
5. Any suspected transmission of an infectious agent by a medicinal product
6. Product quality complaints associated with possible safety issue(s) 
7. Drug or food interaction
8. Overdose
9. Medication error
10. Misuse
11. Occupational exposure
APPROVED RPCI IRB
8/2/2022

Roswell Park Protocol No.: I 444019
07/14/2022
Page 27 of 55
17.8.2 Reporting of Exposure during Pregnancy and Lactation, or Paternal Drug 
Exposure
The Institution will report Exposure During Pregnancy and Lactation, or Paternal Drug Exposure 
on any subject while participating in the study, and following exposure to TAS-102, to Taiho 
Oncology (as specified below) using copies of the original Pregnancy Report Form and within two 
weeks of first becoming aware of the pregnancy or exposure. If the partner of a study subject 
becomes pregnant, the Institution may collect information about the pregnancy and birth if the 
partner agrees.
The study subject will also be followed by the Institution to determine the outcome of the 
pregnancy (including any premature termination of the pregnancy). Information on the status of 
the mother and child will be forwarded to Taiho Oncology. The Institution must provide final 
outcome of pregnancy to Taiho Oncology. If any SAE(s) is observed in a study subject or 
fetus/child, then SAE(s) must also be reported to Taiho Oncology following SAE Reporting 
guidelines. 
Routing of Drug Exposure during Pregnancy and Lactation, or Paternal Drug Exposure Reports
Such reports and Information as outlined above, Including Investigator causality assessments 
against all concerned Taiho Oncology IMP(s) and English translations where reporting Is from a 
non-English speaking country, shall be sent:

By facsimile to PV CONTACT NUMBER :609-750-7371 OR

By e-mail to: TAS-102_Safety@taihooncology.com (please note the underscore between 
'102' and 'Safety') AND NCCN at: ORPreports@nccn.org or FAX: (215)-358-7699.
Requesting Follow-up Information:
The institution will provide Taiho Oncology with details of whom Taiho Oncology shall address 
requests for follow up Information on SAE and pregnancy cases reported from this study, and 
further agree to update such contact details as necessary. At the time of this Agreement, all such 
requests should be addressed to: Dr. Christos Fountzilas.
17.9 Follow-Up for Serious Adverse Events
All related SAEs should be followed to their resolution, until the study participant is lost to 
follow-up, the start of a new treatment, or until the study investigator assesses the event(s) as stable 
or irreversible. New information will be reported when it is received.
17.10 Unanticipated Problems
An Unanticipated Problem (UP) is any incident, experience, or outcome that meets all of the 
following criteria:

Unexpected (in terms of nature, severity, or frequency) given:
o
The research procedures that are described in the study-related documents, 
including study deviations, as well as issues related to compromise of participant 
privacy or confidentiality of data.
o
The characteristics of the participant population being studied.
APPROVED RPCI IRB
8/2/2022

Roswell Park Protocol No.: I 444019
07/14/2022
Page 28 of 55

Related or possibly related to participation in the research (possibly related means there is 
a reasonable possibility that the incident, experience, or outcome may have been caused by 
the procedures involved in the research).

Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized and if in relation to an AE is deemed Serious per Section 17.7.
17.10.1 Reporting Unanticipated Problems
The Reportable New Information (RNI) Form will be submitted to the CRS Quality Assurance 
(QA) Office within 1 business day of becoming aware of the Unanticipated Problem. After review, 
CRS QA Office will submit the RNI to the IRB.
When becoming aware of new information about an Unanticipated Problem, submit the updated 
information to CRS QA Office with an updated Reportable New Information Form. The site 
Investigator or designated research personnel will report all unanticipated problems to the IRB in 
accordance with their local institutional guidelines.
17.11 FDA Reporting
When Roswell Park is the IND holder the following describes the FDA reporting requirements by 
timeline for AEs and new safety findings that meet the criteria outlined below:
Within 7 Calendar Days
Any adverse event that meets ALL the following criteria:

Related or possibly related to the use of the study drug;

Unexpected; and

Fatal or life-threatening.
Within 15 Calendar Days
Any adverse event that meets ALL the following criteria:

Related or possibly related to the use of the study drug;

Unexpected; and

Serious but not fatal or life-threatening;
Or, meets ANY of the following criteria:

A previous adverse event that is not initially deemed reportable but is later found to fit the 
criteria for reporting (report within 15 days from when event was deemed reportable).

Any findings from other studies, including epidemiological studies, pooled analysis of 
multiple studies, or other clinical studies conducted with the study drug that suggest a 
significant risk in humans exposed to the drug.

Any findings from animal or in vitro testing that suggest a significant risk for human 
participants including reports of mutagenicity, teratogenicity, or carcinogenicity or reports 
of significant organ toxicity at or near the expected human exposure.
APPROVED RPCI IRB
8/2/2022

Roswell Park Protocol No.: I 444019
07/14/2022
Page 29 of 55

Any clinically important increase in the rate of occurrence of a serious, related or possibly 
related adverse event over that listed in the protocol or investigator brochure.
Sponsors are also required to identify in IND safety reports, all previous reports concerning similar 
adverse events and to analyze the significance of the current event in the light of the previous 
reports.
Reporting Process
The principal investigator or designee will complete and submit a FDA Form 3500A MedWatch 
for any event that meets the above criteria. Forms will be submitted to the CRS QA Office via 
email to CRSQA@RoswellPark.org.
SAE Reconciliation
Reconciliation shall be performed quarterly as an exchange of Line Listings or other means in 
English. On a quarterly basis, the institution shall provide to Taiho Oncology, Inc., a line listing 
or other means of cumulative SAE received to date. At the end of the Clinical Trial a global 
reconciliation shall be performed. Please reference contact information when sending this 
reconciliation. All serious adverse events via a MedWatch Form need to be sent to the FDA and 
to Taiho Oncology, Inc., via fax: 609-750-7371 or e-mail: TAS-102_Safety@taihooncology.com 
(please note the underscore between “102” and “Safety”).
DSUR
If requested by Institution, Taiho Oncology shall provide the Institution with the final version of 
this DSUR report within 15 calendar days after submission to health agencies and ethics 
committees.
18 DATA MANAGEMENT AND CONFIDENTIALITY
18.1 Data Collection
Full build studies are managed by Roswell Park CRS Data Management for analysis by Roswell 
Park Biostatisticians. All electronic case report form (eCRF) data are captured for these studies.
Data management activities are performed using a CTMS system that enables the collection, 
cleaning and viewing of clinical trial data. CRS data management designs the study-specific 
database and facilitates development by the Information Technology team. Once the database 
design is approved by the Investigator, Statistician, and Clinical Research Coordinator, the 
database is put into production and data entry can begin. Data can be entered and changed only by 
those with the rights to do so into the eCRFs.
18.2 Maintenance of Study Documents
Essential documents will be retained per Roswell Park’s policy for 6 years from the study 
termination date. These documents could be retained for a longer period, however, if required by 
the applicable local regulatory requirements or by an agreement with Roswell Park.
APPROVED RPCI IRB
8/2/2022

Roswell Park Protocol No.: I 444019
07/14/2022
Page 30 of 55
18.3 Revisions to the Protocol
Roswell Park may make such changes to the protocol as it deems necessary for safety reasons or 
as may be required by the U.S. FDA or other regulatory agencies. Revisions will be submitted to 
the IRB/ERC for written approval before implementation.
18.4 Termination of the Study
Roswell Park may terminate the study at any time upon immediate notice if it believes termination 
is necessary for the safety of participants enrolled in the study.
19 STATISTICAL PLAN
Design: This is a single-arm Phase II study of TAS-102, irinotecan, and bevacizumab in FOLFIRI 
naïve patients.
Analysis Cohorts: All patients that receive any treatment will be included in the safety summary. 
All patients that receive any treatment will be included in the primary and secondary analyses, 
regardless of the treatment received (intent-to-treat analysis). A sensitivity analysis will be 
conducted on the set of patients that received their treatment per-protocol.
19.1 Sample Size Determination
The sample size calculations are based on the primary analysis, which evaluates the progression-
free survival (PFS) using a one-sided, one-sample log-rank test. Based on published data, we 
expect the median PFS for the FOLFIRI + bevacizumab to be 6 months. If the proposed TAS-102 
+ irinotecan + bevacizumab can demonstrate a median PFS of 9 months (hazard ratio [HR] ≈ 0.67), 
then we’d consider it the superior treatment combination and consider it for further study.
Assuming the above median PFS and that the PFS times are exponentially distributed, PASS 
(version 15.0.3) indicates a sample size of n=36 subjects would achieve 80.5% power (at α = 0.1) 
to detect such an effect (HR ≈ 0.67).
To account for potential deviations from assumptions and potential dropouts, a total of n=42 
patients may be accrued. Accrual is expected to take 36 months with an additional 24 months of 
follow-up.
19.2 Demographics and Baseline Characteristics
Patient demographic and clinical characteristics will be summarized using the appropriate 
descriptive statistics.
19.3 Primary Analysis
The primary objective is to evaluate the PFS of FOLFIRI naïve patients treated with TAS-102 + 
irinotecan + bevacizumab as compared to historic controls group treated with FOLFIRI + 
bevacizumab. The primary endpoint is PFS, which is treated as bivariate time-to-event data and 
defined as the time from treatment until disease progression, death due to disease, or last follow-
up. Based on previously published studies, we expect the FOLFIRI + bevacizumab to have a 
median PFS of approximately 6 months. If the TAS-102 + irinotecan + bevacizumab combination 
APPROVED RPCI IRB
8/2/2022

Roswell Park Protocol No.: I 444019
07/14/2022
Page 31 of 55
has a median PFS of 9 months (HR≈0.67), then we’d consider it the superior treatment 
combination and consider it for further study. Therefore, we will test the following hypotheses 
using a one-sided, one-sample log-rank test:
 versus 
,
𝐻𝑜:𝑀50 = 6
𝐻𝐴:𝑀50 > 6
where 
is the true median PFS for patients treated with TAS-102 + irinotecan + bevacizumab. 
𝑀50
The PFS will be summarized using standard Kaplan-Meier methods, where estimates of the 
median PFS and 6/12-month PFS rates will be obtained with 90% confidence intervals. The final 
analysis will be conducted either: 1) 12-months after enrollment of the final subject; or 2) once all 
subjects have experienced a progression event, whichever occurs earlier.
19.4 Secondary Analysis
The secondary objects are to evaluate objective response, overall and disease-specific survival, 
and safety and tolerability.
Objective response is treated as a dichotomous variable and will be summarized using frequencies 
and relative frequencies. Using Jeffrey’s prior method, a 90% confidence interval about the true 
ORR will be obtained for each treatment group.
Overall survival (OS) is treated as bivariate time-to-event data and defined as the time from 
treatment until death due to any cause or last follow-up. Disease-specific survival (DSS) is treated 
as bivariate time-to-event data and defined as the time from treatment until death due to disease or 
last follow-up. OS and DSS will be summarized using standard Kaplan-Meier methods; where 
estimates of the median survival and 12-month rates are obtained with 90% confidence intervals.
19.5 Safety Analysis
Treatment related adverse events (as per CTCAE v5.0) will be summarized by grade using 
frequencies and relative frequencies. All patients that receive any treatment will be included in the 
safety summary
19.6 Interim Analysis
No formal interim analyses or criteria for early termination are planned.
20 PROVISIONS TO MONITOR THE DATA TO ENSURE THE SAFETY OF 
SUBJECTS
The Roswell Park Data Safety Monitoring Committee will assess the progress of the study, the 
safety data, and critical efficacy endpoints (Phase I studies are reviewed quarterly; Phase II, III 
and pilot investigator-initiated studies are reviewed semi-annually). The DSMC will review the 
study and will make recommendations that include but not limited to; (a) continuation of the study, 
(b) modifications to the design, (c) suspension of, or (d) or termination of the study.
21 VULNERABLE POPULATIONS
Not applicable.
APPROVED RPCI IRB
8/2/2022

Roswell Park Protocol No.: I 444019
07/14/2022
Page 32 of 55
22 COMMUNITY-BASED PARTICIPATORY RESEARCH
Not applicable.
23 SHARING OF RESULTS WITH SUBJECTS
Individual response data is shared with the participant as a part of their clinical care.
24 SETTING
All study treatment will be administered on an outpatient basis. Participants will be 
identified/recruited/screened from patients at the Gastrointestinal Clinic at Roswell Park and at the 
participating site clinics, and from multi-disciplinary conference discussion.
25 PROVISIONS TO PROTECT THE PRIVACY INTERESTS OF SUBJECTS
Any data, specimens, forms, reports, video recordings, and other records that leave the site will be 
identified only by a participant identification number (Participant ID, PID) to maintain 
confidentiality. All records will be kept in a limited access environment. All computer entry and 
networking programs will be done using PIDs only. Information will not be released without 
written authorization of the participant.
26 RESOURCES AVAILABLE
The gastrointestinal oncology service at Roswell Park sees a large volume of patients with 
colorectal cancer with approximately 250 new patients per year annually over the last decade. Over 
this time, at least 30-60 patients per year have presented with metastatic disease at diagnosis and 
a substantial portion of patients under active surveillance develop recurrent, incurable disease. Dr. 
Christos Fountzilas is an experienced clinical investigator, having joined Roswell Park Cancer 
Institute and the GI medical oncology team in 2017. He has previously conducted multiple 
pharmaceutical run, investigator initiated and NCI-sponsored studies, including one NCCN funded 
study in refractory mCRC. 
In the last 12 months, we had a randomized second-line study open in this setting (NCT02753127) 
where we enrolled 7 patients over this time. Unfortunately, there were multiple screen-fails due to 
the relatively stringent inclusion criteria (global rate 30-40%) and randomization is a documented 
barrier to accrual(15). Thus, we would expect that in a non-randomized study, with more 
permissive inclusion criteria, we would enroll ≥ 10 patients/year. To complete enrollment swiftly, 
we would propose enlisting three additional centers in the study, led by experienced investigators: 
Rutgers Cancer Institute of New Jersey, Moffitt Cancer Center, and Fox Chase Cancer 
Center/Temple University. In this manner, we would anticipate that analysis of the primary 
endpoint would be evaluable approximately 4 years (48 months) after study commencement.
27 PRIOR APPROVALS
Not applicable.
28 COMPENSATION FOR RESEARCH-RELATED INJURY
If the subject believes they have been injured as a direct result of their participation in this research 
study, they will be advised to notify the Roswell Park Patient Advocate at (716) 845-1365 or the 
Study Doctor at (716) 845-8974.
APPROVED RPCI IRB
8/2/2022

Roswell Park Protocol No.: I 444019
07/14/2022
Page 33 of 55
Medical diagnosis and treatment for the injury will be offered, and a determination will be made 
regarding appropriate billing for the diagnosis and treatment of the injury. A financial counselor 
(716-845-3161) will be able to provide an explanation of coverage and to answer questions the 
subject may have regarding study related billing.
The subject is not prevented from seeking to collect compensation for injury related to malpractice, 
fault, or blame on the part of those involved in the research.
29 ECONOMIC BURDEN TO SUBJECTS
The participants will not be subject to any economic burden.
30 CONSENT PROCESS
This study will not be initiated until the protocol and informed consent document(s) have been 
reviewed and approved by a properly constituted Institutional Review Board (IRB) or Independent 
Ethics Committee (IEC). Each participant shall read, understand, and sign an instrument of 
informed consent prior to performance of any study-specific procedure. It is the responsibility of 
the investigator to ensure that the participant is made aware of the investigational nature of the 
treatment and that informed consent is given.
The Investigator is responsible for the retention of the participant log and participant records; 
although personal information may be reviewed by authorized persons, that information will be 
treated as strictly confidential and will not be made publicly available. The investigator is also 
responsible for obtaining participant authorization to access medical records and other applicable 
study specific information according to Health Insurance Portability and Accountability Act 
regulations (where applicable).
This study will be conducted in compliance with all applicable laws and regulations of the state 
and/or country and institution where the participant is treated. The clinical trial should be 
conducted in accordance with the ethical principles embodied in the Belmont Report: Ethical 
Principles and Guidelines for the Protection of Human Subjects of Research, consistent with good 
clinical practice and the applicable regulatory requirements and according to the guidelines in this 
protocol, including attached appendices.
31 PROCESS TO DOCUMENT CONSENT IN WRITING
The Investigator (or IRB specified designee) is responsible for obtaining written consent from each 
participant in accordance with GCP guidelines using the approved informed consent form, before 
any study specific procedures (including screening procedures) are performed. The informed 
consent form acknowledges all information that must be given to the participant according to 
applicable GCP guidelines, including the purpose and nature of the study, the expected efficacy 
and possible side effects of the treatment(s), and specifying that refusal to participate will not 
influence further options for therapy. Any additional information that is applicable to the study 
must also be included. Additional national or institutionally mandated requirements for informed 
consent must also be adhered to. The participant should also be made aware that by signing the 
consent form, processing of sensitive clinical trial data and transfer to other countries for further 
processing is allowed.
The Investigator or designee shall provide a copy of the signed consent form to the participant and 
the signed original shall be maintained in the Investigator File. A copy of the signed consent form 
APPROVED RPCI IRB
8/2/2022

Roswell Park Protocol No.: I 444019
07/14/2022
Page 34 of 55
must be filed in the participant file. At any stage, the participant may withdraw from the study and 
such a decision will not affect any further treatment options.
32 DRUGS OR DEVICES
Roswell Park will cross-file on the IND for TAS-102.
32.1 TAS-102 (Lonsurf®)
32.1.1 Active Substance and Source
TAS-102 contains FTD and TPI as active ingredients with a molar ratio of 1:0.5. TAS-102 drug 
products are immediate-released film coated tablets, available in 2 strengths (15 mg and 20 mg 
tablet, expressed as FTD content). The inactive ingredients of the TAS-102 15 mg and 20 mg 
tablets are lactose monohydrate, pregelatinized starch, stearic acid, hypromellose, polyethylene 
glycol, titanium dioxide, red ferric oxide (only 20 mg tablet), and magnesium stearate.

TAS-102 tablet (15 mg) contains 15 mg FTD and 7.065 mg TPI (corresponding to 6.14 mg 
tipiracil) as active ingredients. The appearance is white, round, biconvex film-coated 
tablets.

TAS-102 tablet (20 mg) contains 20 mg FTD and 9.42 mg TPI (corresponding to 8.19 mg 
tipiracil) as active ingredients. The appearance is pale red, round, biconvex film-coated 
tablets.
32.1.2 Drug Shipment
TAS-102 (Lonsurf®) will be provided by Taiho Oncology, Inc. and shipped to the participating 
sites.
The date of receipt and the amount of drug received will be documented. Drug shipment records 
will be retained by the investigational pharmacist or designee.
32.1.3 Storage and Stability
The Investigator or designate will be responsible for ensuring that the investigational product is 
securely maintained in a locked, limited-access facility, as specified and in accordance with the 
applicable regulatory requirements.
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).
TAS-102 tablets (15 mg and 20 mg) are stable at 25°C 60% relative humidity (RH) for 36 months 
and 40°C 75% RH for 6 months in blister packaging with desiccant in aluminum pouch.
Drug storage temperature will be maintained and recorded, as applicable.
Refer to the Pharmacy Manual for additional details.
32.1.4 Handling and Disposal
The Investigator or designee will be responsible for dispensing and accounting for all 
investigational drug provided by the Sponsor exercising accepted medical and pharmaceutical 
practices. Study drugs must be handled as cytotoxic agents and appropriate precautions taken per 
APPROVED RPCI IRB
8/2/2022

Roswell Park Protocol No.: I 444019
07/14/2022
Page 35 of 55
the institution’s environmentally safe handling procedures. All investigational drugs will be 
dispensed in accordance with the Investigator’s prescription or written order.
All products dispensed will be recorded on a product accountability record. Records of product lot 
numbers and dates received will be entered on a product accountability form. This record will be 
reviewed by the Sponsor’s staff or representative during periodic monitoring visits. It is the 
Investigator’s responsibility to ensure that an accurate record of investigational drug issued and 
returned is maintained.
Excess drug will be destroyed according to standard practices after properly accounting for the 
dispensing. Partially used vials of study drug will not be re-used for other participants.
Under no circumstances will the Investigator supply investigational drug to a third party or allow 
the investigational drug to be used in a manner other than as directed by this protocol.
32.2 Irinotecan
Irinotecan is FDA approved as a second-line therapy for patients with metastatic carcinoma of the 
colon or rectum whose disease has recurred or progresses following initial fluorouracil-based 
therapy.
Irinotecan will be administered as an intravenous infusion over 90 minutes according to 
institutional guidelines. Please refer to package insert.
32.3 Bevacizumab/Bevacizumab biosimilar
Bevacizumab and bevacizumab biosimilars are FDA approved for the treatment of Metastatic 
colorectal cancer, in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-
oxaliplatin-based chemotherapy for second-line treatment in patients who have progressed on a 
first-line bevacizumab-containing regimen.
Bevacizumab or bevacizumab biosimilar will be administered as an IV infusion (5 mg/kg) over 10 
minutes or per institutional policy. 
Please refer to package insert for additional details.
APPROVED RPCI IRB
8/2/2022

Roswell Park Protocol No.: I 444019
07/14/2022
Page 36 of 55
33 REFERENCES
1.
Bennouna J, Sastre J, Arnold D, Osterlund P, Greil R, Van Cutsem E, von Moos R, 
Vieitez JM, Bouche O, Borg C, Steffens CC, Alonso-Orduna V, Schlichting C, Reyes-Rivera I, 
Bendahmane B, Andre T, Kubicka S, Investigators MLS. Continuation of bevacizumab after first 
progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet 
Oncol. 2013;14(1):29-37. Epub 2012/11/22. doi: 10.1016/S1470-2045(12)70477-1. PubMed 
PMID: 23168366.
2.
Van Cutsem E, Tabernero J, Lakomy R, Prenen H, Prausova J, Macarulla T, Ruff P, van 
Hazel GA, Moiseyenko V, Ferry D, McKendrick J, Polikoff J, Tellier A, Castan R, Allegra C. 
Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase 
III randomized trial in patients with metastatic colorectal cancer previously treated with an 
oxaliplatin-based regimen. Journal of clinical oncology : official journal of the American Society 
of Clinical Oncology. 2012;30(28):3499-506. Epub 2012/09/06. doi: 
10.1200/JCO.2012.42.8201. PubMed PMID: 22949147.
3.
Tabernero J, Yoshino T, Cohn AL, Obermannova R, Bodoky G, Garcia-Carbonero R, 
Ciuleanu TE, Portnoy DC, Van Cutsem E, Grothey A, Prausova J, Garcia-Alfonso P, Yamazaki 
K, Clingan PR, Lonardi S, Kim TW, Simms L, Chang SC, Nasroulah F, Investigators RS. 
Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with 
metastatic colorectal carcinoma that progressed during or after first-line therapy with 
bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, 
multicentre, phase 3 study. The Lancet Oncology. 2015;16(5):499-508. Epub 2015/04/17. doi: 
10.1016/S1470-2045(15)70127-0. PubMed PMID: 25877855.
4.
Bikov KA, Mullins CD, Hung A, Seal B, Onukwugha E, Hanna N. Patterns of Biologics 
Use Across Treatment Lines in Elderly (Age >65) Medicare Patients With Metastatic Colon 
Cancer. The oncologist. 2016;21(6):676-83. Epub 2016/04/30. doi: 10.1634/theoncologist.2015-
0199. PubMed PMID: 27125751; PMCID: PMC4912356.
5.
Abrams TA, Meyer G, Schrag D, Meyerhardt JA, Moloney J, Fuchs CS. Chemotherapy 
usage patterns in a US-wide cohort of patients with metastatic colorectal cancer. Journal of the 
National Cancer Institute. 2014;106(2):djt371. Epub 2014/02/11. doi: 10.1093/jnci/djt371. 
PubMed PMID: 24511107.
6.
Emura T, Murakami Y, Nakagawa F, Fukushima M, Kitazato K. A novel antimetabolite, 
TAS-102 retains its effect on FU-related resistant cancer cells. International journal of molecular 
medicine. 2004;13(4):545-9. Epub 2004/03/11. PubMed PMID: 15010854.
7.
Emura T, Suzuki N, Yamaguchi M, Ohshimo H, Fukushima M. A novel combination 
antimetabolite, TAS-102, exhibits antitumor activity in FU-resistant human cancer cells through 
a mechanism involving FTD incorporation in DNA. Int J Oncol. 2004;25(3):571-8. Epub 
2004/08/04. PubMed PMID: 15289858.
8.
Nukatsuka M, Nakagawa F, Saito H, Sakata M, Uchida J, Takechi T. Efficacy of 
combination chemotherapy using a novel oral chemotherapeutic agent, TAS-102, with irinotecan 
APPROVED RPCI IRB
8/2/2022

Roswell Park Protocol No.: I 444019
07/14/2022
Page 37 of 55
hydrochloride on human colorectal and gastric cancer xenografts. Anticancer Res. 
2015;35(3):1437-45. Epub 2015/03/10. PubMed PMID: 25750295.
9.
Matsuoka K, Takechi T. Combined efficacy and mechanism of trifluridine and SN-38 in 
a 5-FU-resistant human colorectal cancer cell lines. Am J Cancer Res. 2017;7(12):2577-86. Epub 
2018/01/10. PubMed PMID: 29312810; PMCID: PMC5752697.
10.
Mayer RJ, Van Cutsem E, Falcone A, Yoshino T, Garcia-Carbonero R, Mizunuma N, 
Yamazaki K, Shimada Y, Tabernero J, Komatsu Y, Sobrero A, Boucher E, Peeters M, Tran B, 
Lenz HJ, Zaniboni A, Hochster H, Cleary JM, Prenen H, Benedetti F, Mizuguchi H, Makris L, 
Ito M, Ohtsu A, Group RS. Randomized trial of TAS-102 for refractory metastatic colorectal 
cancer. N Engl J Med. 2015;372(20):1909-19. Epub 2015/05/15. doi: 10.1056/NEJMoa1414325. 
PubMed PMID: 25970050.
11.
Lesniewski-Kmak K MV, Saunders M,  Wasan H, Argiles G, Borg C, Creemers G, 
Fedyanin M, Glynne-Jones R, Pfeiffer P, Punt C, Stroyakovskiy D, Ten Tije A, Van de Wouw 
A, Kanehisa A, Fougeray R, Lopez Busto N,  Amellal N, Van Cutsem E. Phase II study 
evaluating trifluridine/tipiracil + bevacizumab and capecitabine + bevacizumab in first-line 
unresectable metastatic colorectal cancer (mCRC) patients who are non-eligible for intensive 
therapy (TASCO1): Results of the primary analysis Annals of Oncology, Volume 29, Issue 
suppl_5, June 2018.
12.
Varghese AM CD, Hersch J, et al. A phase 1 expansion study of trifluridine and tipiracil 
in combination with irinotecan and bevacizumab in patients with metastatic colorectal cancer. 
Poster presented at 2018 American Society of Clinical Oncology (ASCO) Annual Meeting, June 
1‒5, 2018, Chicago, IL, USA.
13.
Giantonio BJ, Catalano PJ, Meropol NJ, O'Dwyer PJ, Mitchell EP, Alberts SR, Schwartz 
MA, Benson AB, 3rd, Eastern Cooperative Oncology Group Study E. Bevacizumab in 
combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated 
metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. 
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 
2007;25(12):1539-44. Epub 2007/04/20. doi: 10.1200/JCO.2006.09.6305. PubMed PMID: 
17442997.
14.
Eisenhauer EA, Therasse P, Bogaerts 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 tumours: Revised RECIST guideline 
(version 1.1). European Journal of Cancer. 2009;45(2):228-47. doi: 
http://dx.doi.org/10.1016/j.ejca.2008.10.026.
15.
Dias AL, Chao JH, Lee D, Wu Y, Kloecker GH. Patient perceptions concerning clinical 
trials in oncology patients. Contemp Clin Trials Commun. 2016;4:179-85. Epub 2016/09/21. doi: 
10.1016/j.conctc.2016.09.005. PubMed PMID: 29736480; PMCID: PMC5935901.
APPROVED RPCI IRB
8/2/2022

Roswell Park Protocol No.: I 444019
07/14/2022
Page 38 of 55
34 APPENDICES/ SUPPLEMENTS
APPROVED RPCI IRB
8/2/2022

Roswell Park Protocol No.: I 444019
07/14/2022
Page 39 of 55
Appendix A
ECOG Performance Status Scores
Description
Status
Fully active, able to carry on all pre-disease performance without restriction.
0
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, e.g., light housework, office work.
1
Ambulatory and capable of all self-care but unable to carry out any work activities.
2
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours.
3
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.
4
Dead
5
APPROVED RPCI IRB
8/2/2022

Roswell Park Protocol No.: I 444019
07/14/2022
Page 40 of 55
Appendix B
INVESTIGATOR STUDY ELIGIBILITY VERIFICATION FORM
INCLUSION CRITERIA
Participant Name: (Multi-site: use participant initials): ___________________________
Medical Record No.: (Multi-site: use participant ID): _____________________________
Title: A Phase II Study of TAS-102, Irinotecan, and Bevacizumab in Pre-treated Metastatic 
Colorectal Cancer (TABAsCO)
INCLUSION CRITERIA
Yes
No
N/A
All answers must be “Yes” or “N/A” for participant enrollment.
Date
1.
Age ≥ 18 years old.
2.
Advanced colorectal cancer (metastatic or unresectable): Histologically 
or cytological proven adenocarcinoma of the colon or rectum which is 
metastatic or otherwise incurable.
3.
Prior treatment with a fluoropyrimidine (5-FU or capecitabine) and 
oxaliplatin in the metastatic/unresectable setting OR, recurrence within 
12 months of adjuvant therapy with a regimen that included oxaliplatin.
4.
Have an ECOG Performance Status of 01. Refer to Appendix A.
5.
Have the following clinical laboratory values:

Hemoglobin ≥ 9 g/dL

Absolute neutrophil count ≥ 1500/mm3

Platelet count ≥ 100,000/mm3)

Creatinine < 1.5 ULN or if ≥ 1.5 x ULN with CRCL ≥ 30 mL/min 
(by Cockroft-Gault)

Bilirubin < 1.5 x ULN

AST/ALT ≤ 2.5 x ULN or ≤ 5 x ULN if with hepatic metastases
6.
Have measurable disease per RECIST 1.1 criteria present.
7.
Participants of child-bearing potential must agree to use adequate 
contraceptive methods (e.g., hormonal or barrier method of birth 
control; abstinence) prior to study entry. Should a woman become 
pregnant or suspect she is pregnant while she or her partner is 
participating in this study, she should inform her treating physician 
immediately.
8.
Participant must understand the investigational nature of this study and 
sign an Independent Ethics Committee/Institutional Review Board 
approved written informed consent form prior to receiving any study 
related procedure.
Investigator Signature: ___________________________________
Date: ___________
Printed Name of Investigator: __________________________________________________
APPROVED RPCI IRB
8/2/2022

Roswell Park Protocol No.: I 444019
07/14/2022
Page 41 of 55
Appendix C
INVESTIGATOR STUDY ELIGIBILITY VERIFICATION FORM
EXCLUSION CRITERIA
Participant Name: (Multi-site: use participant initials): ___________________________
Medical Record No.: (Multi-site: use participant ID): _____________________________
Title: A Phase II Study of TAS-102, Irinotecan, and Bevacizumab in Pre-treated Metastatic 
Colorectal Cancer (TABAsCO)
EXCLUSION CRITERIA
Yes
No
N/A
All answers must be “No” or “N/A” for participant enrollment.
Date
1.
Prior treatment with TAS-102 or irinotecan.
2.
Anti-cancer therapy within 2 weeks of the planned first dose of study 
medication.
3.
Unresolved toxicities from prior therapy of > Grade 1, excluding 
alopecia or similar toxicities which are not deemed to be clinically 
significant or put the participant at greater risk. Grade 2 neuropathy is 
permitted.
4.
Major surgery within 4 weeks of anticipated start of therapy.
5.
Uncontrolled hypertension: systolic blood pressure ≥ 150, diastolic 
blood pressure ≥ 100.
6.
Unstable angina, symptomatic congestive heart failure or cardiac 
arrhythmia requiring anti-arrhythmic therapy (beta-blockers, calcium 
channel blockers and digoxin are allowed).
7.
Arterial or venous thrombotic or embolic events within 3 months of 
study initiation, unless well controlled on stable anti-coagulation for > 2 
weeks. This excludes uncomplicated catheter associated venous 
thrombosis.
8.
History of cerebrovascular or myocardial ischemia within 6 months of 
initiation.
9.
NCI CTCAE v 5.0 Grade 3 or greater hemorrhage within the past 
4 weeks.
10. Proteinuria ≥ 2+, unless 24-hour urine collection demonstrates ≤ 1 g of 
protein OR spot protein: creatinine demonstrates a ratio of ≤ 1.
11. Untreated brain metastases.
12. History of abnormal glucuronidation of bilirubin (Gilbert’s Syndrome).
13. History of second primary malignancy within 3 years prior to 
enrollment, excluding in-situ cervical carcinoma and non-melanoma 
skin cancer or malignancy of equivalent risk which is highly unlikely to 
require systemic treatment in the next 2 years.
14. Have known active infection which would heighten the risk of 
complications.
15. Pregnant or nursing female participants.
16. Unwilling or unable to follow protocol requirements.
APPROVED RPCI IRB
8/2/2022

Roswell Park Protocol No.: I 444019
07/14/2022
Page 42 of 55
EXCLUSION CRITERIA
Yes
No
N/A
All answers must be “No” or “N/A” for participant enrollment.
Date
17. Any condition which in the Investigator’s opinion deems the participant 
an unsuitable candidate to receive study drug.
Participant meets all entry criteria:
  Yes
  No
If “NO”, do not enroll participant in study.
Investigator Signature: ___________________________________
Date: __________
Printed Name of Investigator: _________________________________________________
APPROVED RPCI IRB
8/2/2022

Roswell Park Protocol No.: I 444019
07/14/2022
Page 43 of 55
Appendix D
Instructions for Multi-Site (External) Studies
1.
CONTACT INFORMATION
All questions related to the protocol or study implementation should be directed to:
Roswell Park Cancer Institute
CRS Quality Assurance (QA) Network Office
CRSNetworkCoordinators@RoswellPark.org
Elm and Carlton Streets 
Buffalo, New York 14263
Telephone:
Monday - Friday; 7: 00 AM to 3: 30 PM EST
716-845-8084
After hours, weekends, and holidays request the Roswell Park Investigator
716-845-2300
2.
INFORMED CONSENT

Informed consent must be obtained by the site Investigator/designee from any participants 
wishing to participate, prior to any procedures or treatment.

An informed consent template is provided by Roswell Park and can be amended to reflect 
institutional requirements.

All consent changes must be reviewed by Roswell Park CRS QA Network Office prior to 
submission to the site IRB.

The informed consent must be IRB approved.

Always check that the most up to date version of the IRB approved consent is being used.

Within 5 business days, notify the Roswell Park CRS QA Network Office of all participant 
withdrawals or consent to limited study participation and appropriately document the 
discontinuation and the reason(s) why.
3.
PARTICIPANT REGISTRATION
The participant completes the Gender, Race, and Ethnicity Form and this is placed in the study 
binder.
Roswell Park does not grant exceptions to eligibility criteria.
Phase 2 Protocol Registration Instructions
The Subject Screening and Enrollment Log must be emailed 
(CRSNetworkCoordinators@RoswellPark.org) to the Roswell Park CRS QA Network Office 
within 1 business day of the date the participant is consented. Once the Investigator has 
determined that eligibility has been met, complete the eligibility check list and email it to the 
Roswell Park Network QA Coordinator at CRSNetworkCoordinators@RoswellPark.org.
APPROVED RPCI IRB
8/2/2022

Roswell Park Protocol No.: I 444019
07/14/2022
Page 44 of 55
4.
STUDY DEVIATIONS

If a deviation has occurred to eliminate hazard, this must be reported to the Roswell Park 
Network, site IRB and any other regulatory authority involved in the study.

ALL study deviations will be recorded on the Study Deviation Log.

Participants inadvertently enrolled with significant deviation(s) from the study-specified 
criteria will be removed from the study, at the discretion of the Principle Investigator.
5.
STUDY DOCUMENTATION

Study documents must be filled out completely and correctly. Ditto marks are not allowed.

If an entry has been documented in error put a single line through the entry and initial and 
date the change. The Roswell Park Network QA Coordinator must be able to read what has 
been deleted.

Do NOT use white-out, magic marker, scratch-outs.

Do NOT erase entries.

Use only black ink for documentation on the accountability form and any other study 
forms.

It is the responsibility of Roswell Park to inform the Investigator/ institution as to when 
these documents no longer need to be retained. If, for any reason, the Investigator desires 
to no longer maintain the study records, they may be transferred to another institution, 
another investigator, or to Roswell Park upon written agreement between the Investigator 
and Roswell Park.
6.
DRUG ACCOUNTABILITY
Drug accountability must be strictly maintained.

Responsibility rests solely with the Investigator but can be delegated as appropriate (e.g., to 
pharmacy personnel).

A drug accountability record form (DARF) will record quantities of study drug received, 
dispensed to participants and wasted, lot number, date dispensed, participant ID number 
and initials, quantity returned, balance remaining, manufacturer, expiration date, and the 
initials of the person dispensing the medication.

Study drug supply will only be used in accordance with the IRB approved study.

Drug accountability forms are protocol and agent specific; they are study source documents 
and will be used to verify compliance with the study.

An inventory count must be performed with each transaction. Any discrepancies shall be 
documented and explained.

Drug accountability forms must be stored with study related documents.

Each medication provided for this study and each dosage form and strength must have its 
own DARF.

Dispensing the wrong study supply is considered a medication error.

NEVER replace investigational agents with commercial product.

Do NOT “transfer”, “borrow” or “replace” supplies between studies.
APPROVED RPCI IRB
8/2/2022

Roswell Park Protocol No.: I 444019
07/14/2022
Page 45 of 55
7.
SERIOUS ADVERSE EVENT REPORTING
The site Investigator or designated research personnel will report all SAEs, whether related or 
unrelated to the investigational agent(s) to the IRB in accordance with their local institutional 
guidelines. The site will notify the Roswell Park Network QA Coordinator within 1 business day 
of being made aware of the SAE to SafetyEventReporting@roswellpark.org. A preliminary written 
report must follow within 1 business day of the first notification using the following forms:

Roswell Park SAE Source form

MedWatch 3500A
A complete follow-up report must be sent to the Roswell Park Network QA Coordinator when 
new information becomes available.
8.
UNANTICIPATED PROBLEM REPORTING
An unanticipated problem (UP) is any incident, experience, or outcome that meets all of the criteria 
in Section 17.10.
For all adverse events occurring that are unanticipated and related or possibly related to the 
research drug, biologic or intervention, the participating physician or delegated research staff from 
each site will notify their local IRB in accordance with their local institutional guidelines. The 
site must also notify the Roswell Park Network QA Coordinator within 1 business day of being 
made aware of the Unanticipated Problem by completing the Roswell Park Unanticipated 
Problem Report Form and emailing it to the Roswell Park Network QA Coordinator.
APPROVED RPCI IRB
8/2/2022

Roswell Park Protocol No.: I 444019
07/14/2022
Page 46 of 55
Appendix E
Study Drug Diary
Study No.: ______________
Subject’s Name: ____________________________
Drug Name: _____________
Cycle #: ______
Medical Record No.: _________________________
TAS-102 Study Drug Calendar
Please complete this calendar on the days that you take the study drug. The study medication is to be taken whole, 
with food on Day 2-Day 6 and on Day 16-Day 20 of every 28-day treatment cycle. Fill in the date for each day in the 
1st row, write the drug dose that you take each day in the 2nd row, and write the total number of tablets (number of 
15 mg tablets and/or number of 20 mg tablets) you take each day in the 3rd and 4th row. 
On days you do not take any study drug; please write “0” in drug dose box. If your dose changes record the new dose 
level.
Start Date: ________________
Dose: _____________
Number of 15 mg tablets: _________
Number of 20 mg tablets: _________
Take the prescribed number of tablet(s) (15 mg, 20 mg, or combination) each time (AM and PM), about 12 hours 
apart. Swallow TAS-102 tablets whole, with food or within one hour of completion of morning and evening meals. 
Do not to retake doses of TAS-102 that are vomited or missed- if this happens; continue with the next scheduled dose
Cycle Day
Day 1
Day 2
Day 3 
Day 4
Day 5
Day 6 
Day 7
Date
Dose
Number of 
15 mg 
tablets 
taken
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
Number of 
20 mg 
tablets 
taken
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
Cycle Day
Day 8
Day 9
Day 10
Day 11
Day 12
Day 13
Day 14
Date
Dose
Number of 
pills taken
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
APPROVED RPCI IRB
8/2/2022

Roswell Park Protocol No.: I 444019
07/14/2022
Page 47 of 55
Cycle Day
Day 15
Day 16
Day 17
Day 18
Day 19
Day 20
Day 21
Date
Dose
Number of 
15 mg 
tablets 
taken
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
Number of 
20 mg 
tablets 
taken
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
Cycle Day
Day 22
Day 23
Day 24
Day 25
Day 26
Day 27
Day 28
Date
Dose
Number 
of pills 
taken
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
Please remember to bring this calendar and your pill bottle (including any unused pills) with you to your next study 
appointment.
_________________________________________________________________________
Coordinator’s Use Only
% 𝐶𝑜𝑚𝑝𝑙𝑖𝑎𝑛𝑐𝑒=(
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑃𝑖𝑙𝑙𝑠 𝑇𝑎𝑘𝑒𝑛
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑃𝑖𝑙𝑙𝑠 𝑆𝑐ℎ𝑒𝑑𝑢𝑙𝑒𝑑) × 100
_____% 𝐶𝑜𝑚𝑝𝑙𝑖𝑎𝑛𝑐𝑒=  (
             
        ) × 100
Subject’s Signature: _________________________________________
Date: ____________
CRC’s Signature: ____________________________________________
Date: _____________
Investigator’s Signature: _______________________________________
Date : _____________
Investigator (printed name): ___________________________________
APPROVED RPCI IRB
8/2/2022

Roswell Park Protocol No.: I 444019
07/14/2022
Page 48 of 55
Appendix F
Schedule of Procedures and Observations
Cycle 1
and
additional cycles
Post-Treatment Follow-Up
Time point 
Screening1
Day
1
Day
2-6
Day
15
Day
16-20
Every 8 
weeks (±7 
days) 
End of 
Treatment/
(± 3 days)
SafetyFollow-Up2
Long Term 
Follow-Up3
Clinical Procedures
Medical History
X
Pre-Existing Conditions
X
Physical Examination4, 
including vital signs5
X
X
X
X
ECOG Performance 
Status
X
X
Concomitant Medications
X6
X
X
X
X
Adverse Events
X
X
X
X
Survival Status 
Assessment
X
Laboratory Procedures
Hematology7
X
X
X
X
Chemistry8
X
X
X
X
Tumor Marker (CEA)
X
Dipstick urine or 24 hr 
urine protein
X
X
Pregnancy Test (Urine or 
Serum)
X
Imaging Procedures
ECG/EKG (12-lead)
X
Imaging for Tumor/ 
Disease Assessment (CT or 
MRI)9
X
X

Roswell Park Protocol No.: I 444019
07/14/2022
Page 49 of 55
Cycle 1
and
additional cycles
Post-Treatment Follow-Up
Time point 
Screening1
Day
1
Day
2-6
Day
15
Day
16-20
Every 8 
weeks (±7 
days) 
End of 
Treatment/
(± 3 days)
SafetyFollow-Up2
Long Term 
Follow-Up3
Treatment Regimen/Drug 
Administration
TAS-102
X
X
Irinotecan
X
X
Bevacizumab*
X
X
1
Performed within two weeks prior to treatment start (unless otherwise noted).
2
Follow-up safety evaluations will occur 30 days (± 3 days) after last dose of study drug or until resolution of any drug related toxicity (telephone contact 
is acceptable).
3
Medical record review will be performed approximately every 6 months, for up to 2 years, to ascertain survival status.
4
Research/study-specific assessments should be performed no earlier than two weeks prior to the start of treatment.
5
Vital signs should be performed no earlier than two weeks prior to the start of treatment (temperature, heart rate, respiratory rate, and blood pressure), 
body weight, and height: Height collected at baseline only.
6
Medications ongoing, or discontinued, within 1 week prior to first dose of study drug.
7
Hematology (CBC with automated differentials): WBC, RBC, HGB, HCT, platelet, MCV, MCH, MCHC, % neutrophils, absolute neutrophils, % 
monocytes, absolute monocytes, % eosinophils, absolute eosinophils, % basophils, absolute basophils, % absolute lymphocyte, platelet confirmation (as 
clinically indicated), and differential confirmation (as clinically indicated). Note: Participants experiencing Grade 4 neutropenia should be monitored 
according to institutional guidelines. As needed at each study visit as determined by the Investigator or study physician.
8
Chemistry (CMP): chloride, CO2, potassium, sodium, BUN, glucose, calcium, creatinine, total protein, albumin, total bilirubin, alkaline phosphatase, 
AST, ALT, A/G ratio, BUN/creatinine ratio, osmol (Calc), anion gap). NOTE: For blood Chemistry labs, Roswell Park clinical blood chemistries are 
performed on plasma unless otherwise indicated.
9
Baseline CT imaging (or MRI if necessary) is to be performed up to 4 weeks prior to the start of study treatment. CT imaging (or MRI if necessary) will 
be performed every 8 weeks ± 7 days while on study treatment, as clinically necessary. Disease evaluation according to RECIST v. 1.1 (See Section 16).
* Or bevacizumab biosimilar

Roswell Park Protocol No.: I 444019
07/14/2022
Page 50 of 55
Appendix G
Cytochrome p450 Drug Interactions
Table A. Cytochrome p450 inhibitors *
Strong Inhibitors
Moderate Inhibitors
Weak Inhibitors
Boceprevir
Cobicistat
Conivaptan
Danoprevir and ritonavir,
Elvitegravir and ritonavir
Lopinavir 
and 
ritonavir, 
Paritaprevir 
and 
ritonavir 
Ombitasvir and/or dasabuvir
Saquinavir and ritonavir
Telaprevir, tipranavir and ritonavir
Nelfinavir
Indinavir and ritonavir 
Grapefruit Juice
Itraconazole
Ketoconazole
Posaconazole
Troleandomycin
Voriconazole
Clarithromycin
Diltiazem
Idelalisib
Nefazodone
Aprepitant
Cimetidine
Ciprofloxacin
Clotrimazole
Crizotinib
Cyclosporine
Dronedarone
Erythromycin
Fluconazole
Fluvoxamine
Imatinib
Tofisopam
Verapamil
Chlorzoxazone
Cilostazol
Fosaprepitant
Istradefylline
Ivacaftor
Lomitapide
Ranitidine
Ranolazine
Tacrolimus
Ticagrelor
Table B. Cytochrome p450 inducers*
Strong Inducers
Phenytoin, Rifampin
*For more information, please see: 
https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionsl
abeling/ucm093664.htm#table3-2
APPROVED RPCI IRB
8/2/2022

Roswell Park Protocol No.: I 444019
07/14/2022
Page 51 of 55
Appendix H
RECIST 1.1 Criteria
Objective Tumor Response
All protocol-defined imaging studies must be performed at the investigative site or sponsor-
approved facility using protocol-defined parameters. The same method of assessment and the same 
technique should be used to characterize each identified and reported lesion at baseline and during 
follow-up. RECIST 1.1 will be used to assess objective tumor response.
Target Lesions
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative 
of all involved organs, will be identified as target lesions and recorded and measured at baseline. 
Target lesions will be selected on the basis of their size. Lesions with the longest diameter (short 
axis for lymph nodes) and are ≥ 10 mm (CT and MRI), ≥ 15 mm lymph nodes, > 20 mm CXR and 
are for accurate repetitive measurements (either by imaging techniques or clinically) will be 
chosen. A sum of the longest diameter (short axis for lymph nodes) of all target lesions will be 
calculated and reported as the baseline sum diameters. This will be used as reference to further 
characterize the objective tumor response of the measurable dimension of the disease.
Complete Response (CR): Disappearance of all target lesions. Any lymph nodes must have a 
reduction in short axis to < 10 mm. Changes in tumor measurements must be confirmed by 
repeat studies performed no less than 6 weeks after the criteria for response are first met.
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters. Changes in tumor measurements must be 
confirmed by repeat studies performed no less than 6 weeks after the criteria for response 
are first met.
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as references the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. The appearance of one or more new 
lesions is also considered progression.
Stable Disease (SD): Neither a sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum diameter while on study. 
Participants having a documented response with no confirmation of the response will be 
listed with stable disease.
Non-Target Lesions
All other small lesions (longest diameter < 10 mm or lymph nodes ≥ 10 mm to < 15 mm short 
axis) and non-measurable lesions (i.e., leptomeningeal disease, ascites, pleural or pericardial 
effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, blastic bone 
lesions, or abdominal masses / abdominal organomegaly identified by physical exam that is not 
measurable by imaging) should be identified as non-target lesions and indicated as present in the 
source documents at baseline. The general location will also be documented on the images drawing 
a regularly-shaped Region of Interest. Measurements of the non-target lesions will not be 
performed, but the presence or absence of each should be noted throughout follow-up and 
evaluation.
APPROVED RPCI IRB
8/2/2022

Roswell Park Protocol No.: I 444019
07/14/2022
Page 52 of 55
Complete Response: Disappearance of all non-target lesions and normalization of tumor 
marker level, if applicable. All lymph nodes must be non-pathological in size (< 10 mm 
short axis).
Non-Complete Response/Non-Progressive Disease: Persistence of 1 or more non-target 
lesion(s) and/or maintenance of tumor marker level above the upper limits of normal.
Progressive Disease: Appearance of 1 or more new lesions or the unequivocal progression of 
existing non-target lesions. Although a clear progression of non-target lesions is 
exceptional, in such circumstances, the opinion of the treating physician should prevail, 
and the progression status should be confirmed at a later time.
Evaluation of Response
Time point response assessments will be performed every 8 weeks. To determine time point 
response, refer to Table 14 and Table 15 below.
Table 14
Time Point Response Criteria: target (+/- non-target disease)
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/Non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
Table 15
Time Point Response Criteria: non-target disease only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD1
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
1
Non-CR/non-PD is preferred over SD for non-target disease since SD is used as endpoint for assessment of 
efficacy in trials so to assign this category when no lesions can be measured is not advised.
The best overall response is the best response recorded from the start of study treatment until the 
end of treatment, taking into account any requirement for confirmation. In general, the 
participant’s best response assignment will depend on the achievement of both measurement and 
confirmation criteria and will be determined by combining the participant’s status of target lesions, 
non-target lesions, and new lesions.
APPROVED RPCI IRB
8/2/2022

Roswell Park Protocol No.: I 444019
07/14/2022
Page 53 of 55
Symptomatic Deterioration: Participants with global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease progression at that time, and 
not related to study treatment or other medical conditions should be reported as progressive disease 
due to “symptomatic deterioration.” Every effort should be made to document objective 
progression even after discontinuation of treatment due to symptomatic deterioration. 
Symptomatic deterioration that may lead to discontinuation of treatment includes, but is not limited 
to, symptoms such as:

Weight loss > 10% of body weight.

Worsening of disease-related symptoms (e.g., worsening dyspnea, increasing 
pain/increasing requirement for narcotic analgesics).

Decline in performance status of > 1 level on ECOG scale.
Guidelines for Evaluation of Measurable Disease
All measurements should be taken and recorded in metric notation. All baseline evaluations should 
be performed as closely as possible to the beginning of treatment and never more than 4 weeks 
before the beginning of the treatment.
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam.
Clinical Lesions: Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥ 10 mm diameter as 
assessed using calipers (e.g., skin nodules). In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended.
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 is preferable.
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. MRI is also acceptable in certain situations (e.g., for body scans).
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal resolution; 
however, there are many image acquisition variables involved in MRI, which greatly impact image 
quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI is variable 
globally. 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. Furthermore, 
as with CT, the modality used at follow-up should be the same as was used at baseline and the 
lesions should be measured/assessed on the same pulse sequence. It is beyond the scope of the 
RECIST guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases. 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.
APPROVED RPCI IRB
8/2/2022

Roswell Park Protocol No.: I 444019
07/14/2022
Page 54 of 55
PET-CT: At present, the low dose or attenuation correction CT portion of a combined PET-
CT is not always of optimal diagnostic CT quality for use with RECIST measurements. 
However, 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. Note, however, that the 
PET portion of the CT introduces additional data which may bias an investigator if it is not 
routinely or serially performed. 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety 
for independent review at a later date and, because they are operator dependent, it cannot 
be guaranteed that the same technique and measurements will be taken from one 
assessment to the next. If new lesions are identified by ultrasound in the course of the study, 
confirmation by CT or MRI is advised. If there is concern about radiation exposure at CT, 
MRI may be used instead of CT in selected instances.
Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor evaluation 
is not advised. However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence 
following complete response (CR) or surgical resection is an endpoint.
Tumor Markers: Tumor markers alone cannot be used to assess response. If markers are 
initially above the upper normal limit, they must normalize for a participant to be 
considered in complete clinical response.
Cytology, Histology: These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such 
as germ cell tumors, where known residual benign tumors can remain).
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.
FDG-PET: While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease). New lesions on the basis of 
FDG PET imaging can be identified according to the following algorithm:
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion.
No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive 
FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-
up CT scans are needed to determine if there is truly progression occurring at that site (if 
so, the date of PD will be the date of the initial abnormal FDG-PET scan). If the positive 
FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that is not 
progressing on the basis of the anatomic images, this is not PD.
FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in cases 
where a residual radiographic abnormality is thought to represent fibrosis or scarring. The 
APPROVED RPCI IRB
8/2/2022

Roswell Park Protocol No.: I 444019
07/14/2022
Page 55 of 55
use of FDG-PET in this circumstance should be prospectively described in the protocol 
and supported by disease-specific medical literature for the indication. However, it must 
be acknowledged that both approaches may lead to false positive CR due to limitations of 
FDG-PET and biopsy resolution/sensitivity.
Note: A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image.
APPROVED RPCI IRB
8/2/2022