Clinical trial NCT04097028
Conditions: Clinical Stage IIA Esophageal Adenocarcinoma AJCC v8 Clinical Stage IIA Gastroesophageal Junction Adenocarcinoma AJCC v8 Clinical Stage III Esophageal Adenocarcinoma AJCC v8 Clinical Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8 Clinical Stage IVA Esophageal Adenocarcinoma AJCC v8 Clinical Stage IVA Gastroesophageal Junction Adenocarcinoma AJCC v8 Pathologic Stage IIB Esophageal Adenocarcinoma AJCC v8 Pathologic Stage IIB Gastroesophageal Junction Adenocarcinoma AJCC v8 Pathologic Stage III Esophageal Adenocarcinoma AJCC v8 Pathologic Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8 Pathologic Stage IIIA Esophageal Adenocarcinoma AJCC v8 Pathologic Stage IIIA Gastroesophageal Junction Adenocarcinoma AJCC v8 Pathologic Stage IIIB Esophageal Adenocarcinoma AJCC v8 Pathologic Stage IIIB Gastroesophageal Junction Adenocarcinoma AJCC v8 Pathologic Stage IVA Esophageal Adenocarcinoma AJCC v8 Pathologic Stage IVA Gastroesophageal Junction Adenocarcinoma AJCC v8
Sponsor: Roswell Park Cancer Institute
Start date: 2019-12-20; Completion date: 2025-02-05
Enrollment: 22 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well trifluridine/tipiracil and oxaliplatin work as the first line of treatment (induction) in treating patients with esophageal or gastroesophageal junction adenocarcinoma that can be removed by surgery (resectable). Drugs used in chemotherapy, such as trifluridine/tipiracil and oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

Detailed description:
PRIMARY OBJECTIVE:

-Evaluate the pathologic complete response (path CR) rate in participants with esophageal and gastroesophageal junction (GEJ) adenocarcinoma when trifluridine and tipiracil hydrochloride (trifluridine/tipiracil \[TAS-102\]) and oxaliplatin are used as induction chemotherapy prior to surgical resection.

SECONDARY OBJECTIVES:

* Evaluate the 2-year disease-free survival (DFS) and the 2-year overall survival (OS)
* To determinate the safety and tolerability of induction chemotherapy with trifluridine/tipiracil (TAS 102) and oxaliplatin followed by standard chemoradiation and surgery
* Evaluate the metabolic response to induction chemotherapy with TAS 102 and oxaliplatin in participants with esophageal and gastroesophageal junction (GEJ) adenocarcinoma prior to standard chemoradiation and surgical resection

EXPLORATORY OBJECTIVE:

-Correlate circulating tumor deoxyribonucleic acid (DNA) levels with disease recurrence and metabolic response on positron emission tomography (PET) computed tomography (CT).

OUTLINE:

Patients receive oxaliplatin intravenously (IV) over 2 hours on day 1 and trifluridine and tipiracil hydrochloride orally (PO) twice daily (BID) on days 1-5. Treatment repeats every 14 days for 3 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo standard of care chemoradiation therapy followed by surgery.

After completion of study treatment, patients are followed up every 3-6 months for years 1-2, every 6-12 months.

Arms: arm 1: Patients receive oxaliplatin IV over 2 hours on day 1 and trifluridine and tipiracil hydrochloride PO BID on days 1-5. Treatment repeats every 14 days for 3 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo standard of care chemoradiation therapy followed by surgery.
Interventions: intervention 1: Trifluridine and Tipiracil Hydrochloride intervention 2: Oxaliplatin
Intervention descriptions: intervention 1: Given PO intervention 2: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
Document Coversheet 
 
 Study Title:     Use of Trifluridine/ Tipiracil (TAS-102) and Oxaliplatin as Induction Chemotherapy in 
Resectable Esophageal and Gastroesophageal Junction (GEJ) Adenocarcinoma 
 
 
Institution/Site:  
Roswell Park Comprehensive Cancer Center 
Document (Approval/Update) Date: 
05/03/2023 
NCT Number: 
NCT04097028 
IRB Number 
I 443819 
 


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PROTOCOL TITLE:
Use of Trifluridine/ Tipiracil (TAS-102) and Oxaliplatin as Induction Chemotherapy in 
Resectable Esophageal and Gastroesophageal Junction (GEJ) Adenocarcinoma
PROTOCOL NUMBER:
I 443819
PRINCIPAL INVESTIGATOR:
Sarbajit Mukherjee, MD, MS
Roswell Park Comprehensive Cancer Center
Elm and Carlton Street
Buffalo, New York 14263
716-845-7405
Sarbajit.Mukherjee@RoswellPark.org
VERSION NUMBER: 1 -DATE: May 2, 2019
Amendment V11: 03MAY2023
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.
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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.......................................................................................................................7
8
Study Endpoints.......................................................................................................................8
9
Design......................................................................................................................................8
10
Treatment...............................................................................................................................10
11
Procedures Involved ..............................................................................................................14
12
Withdrawal of Subjects..........................................................................................................19
13
Risks to Subjects....................................................................................................................21
14
Potential Benefits to Subjects ................................................................................................22
15
Data and Specimen Banking..................................................................................................22
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............................................................................32
23
Sharing of Results with Subjects ...........................................................................................32
24
Setting....................................................................................................................................32
25
Provisions to Protect the Privacy Interests of Subjects .........................................................32
26
Resources Available ..............................................................................................................32
27
Prior Approvals......................................................................................................................32
28
Compensation for Research-Related Injury...........................................................................33
29
Economic Burden to Subjects................................................................................................33
30
Consent Process.....................................................................................................................33
31
Process to Document Consent in Writing..............................................................................33
32
Drugs or Devices ...................................................................................................................34
33
References..............................................................................................................................36
34
Appendices/ Supplements......................................................................................................39
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1
OBJECTIVES
1.1
Primary Objective

Evaluate the pathologic complete response (path CR) rate in participants with esophageal 
and gastroesophageal junction (GEJ) adenocarcinoma when trifluridine/tipiracil (TAS-
102) and oxaliplatin are used as induction chemotherapy prior to surgical resection.
1.2
Secondary Objectives

Evaluate the 2-year disease-free survival (DFS) and the 2-year overall survival (OS).

To determinate the safety and tolerability of induction chemotherapy with TAS-102 and 
oxaliplatin followed by standard chemoradiation and surgery.

Evaluate the metabolic response to induction chemotherapy with TAS-102 and oxaliplatin 
in participants with esophageal and gastroesophageal junction (GEJ) adenocarcinoma prior 
to standard chemoradiation and surgical resection.
1.3
Exploratory Objective

Correlate circulating tumor DNA (ctDNA) levels with disease recurrence and metabolic 
response on PET CT.
2
BACKGROUND
Esophageal cancer is a global health problem with an estimated annual incidence of 455,800 and 
400,200 annual deaths occurring in 2012 (1). In the US, the majority of the esophageal cancers are 
adenocarcinoma usually confined to the distal esophagus (2). On the other hand, the incidence of 
GEJ adenocarcinoma has also increased steadily in the US since the 1970s (2). Esophageal and 
GEJ adenocarcinoma present as a loco-regional disease in approximately 50% of the cases (3). 
Typically, a majority of these patients are treated with neoadjuvant chemoradiation followed by 
surgery. However, despite multimodality treatment, overall survival (OS) at five years is less than 
50% (4). It has been shown that achievement of path CR leads to an improved OS (5). However, 
concurrent chemoradiation produces a path CR in only about 20% patients (3, 6). Therefore, 
investigators have looked into strategies like induction chemotherapy (IC) before concurrent 
chemoradiation to improve path CR.
In a randomized Phase II trial to investigate whether induction chemotherapy (IC) using FOLFOX 
as an induction regimen before chemoradiation can improve path CR in esophageal cancer 
patients, Ajani et al. (3) concluded that IC neither improves path CR nor overall survival in a 
significant way. Traditionally, different chemotherapy regimens have been used in this setting: 
e.g., modified FOLFOX-6 and carboplatin + paclitaxel.
(TAS-102) has a distinct mechanism of action, differing from that of 5-FU. 5-FU leads to 
cytotoxicity by inhibiting thymidylate synthase (TS) without being directly incorporated into the 
DNA. Trifluridine, in addition to inhibiting TS, is incorporated into the DNA, causing single- and 
double-stranded DNA breaks and DNA instability (7). Tipiracil has additional anti-angiogenic 
properties. Therefore, the combination of TAS-102 has been shown to be active in both 5-FU 
sensitive and resistant tumors. A randomized Phase 3 study evaluated the efficacy of TAS-102 in 
refractory advanced gastric or gastroesophageal cancer patients. TAS-102 was found to improve 
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disease-free survival (PFS) and OS in this heavily pre-treated population (8). Based on the data 
presented above, we decided to examine the novel combination of TAS-102 and oxaliplatin.
We propose to use a novel combination of Trifluridine/tipiracil (TAS 102) and oxaliplatin as 
induction chemotherapy in localized esophageal and GEJ adenocarcinoma. This combination has 
been looked at in a Phase I trial with standard 3+3 design (9). The maximum tolerated dose (MTD) 
was TAS-102 35 mg/m2 BID and oxaliplatin 85 mg/m2.
If the proposed project is successful, it has the potential to introduce a novel treatment approach 
using a unique induction chemotherapy, which can be further tested concurrently with radiation as 
well as in the frontline metastatic setting in future clinical trials.
2.1
TAS-102
2.1.1
Preclinical Studies with TAS-102
TAS-102 consists of a thymidine-based nucleoside analog, trifluridine, and the thymidine 
phosphorylase inhibitor, tipiracil, at a molar ratio 1:0.5 (weight ratio, 1:0.471). The 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.
A detailed discussion of the preclinical pharmacology, pharmacokinetics, and toxicology of TAS-
102 can be found in the Investigator’s Brochure.
2.1.2
Clinical Studies with TAS-102
TAS-102 (LONSURF®) is indicated for the treatment of adult patients with metastatic gastric or 
gastroesophageal junction adenocarcinoma previously treated with at least two prior lines of 
chemotherapy that included a fluoropyrimidine, a platinum, either a taxane or irinotecan, and if 
appropriate, HER2/neu-targeted therapy.
The efficacy of TAS-102 was evaluated in TAGS (NCT02500043) , A Phase 3, international, 
randomized, double-blind, placebo-controlled study in patients with metastatic gastric or 
gastroesophageal junction (GEJ) adenocarcinoma previously treated with at least 2 prior regimens 
for advanced disease (10). In this study, patients (N=507) were randomized 2:1 to receive either 
TAS-102 (35 mg/m2 BID on Days 1–5 and 8–12 of each 28-day cycle) plus best supportive care 
or placebo plus best supportive care. TAS-102 was associated with significantly longer overall 
survival (compared with placebo) along with significant improvements in disease-free survival, 
the proportion of patients achieving disease control, and time to deterioration of ECOG 
performance status.
Please refer to TAS-102 (LONSURF®) Package Insert and Investigator’s Brochure for additional 
details.
2.2
Correlative Studies
The role of ctDNA in gastroesophageal cancer is evolving. Our previous work has used ctDNA to 
identify therapeutic targets otherwise not detectable from the primary tumor biopsy in 
gastroesophageal adenocarcinoma (11). Another study found that circulating tumor DNA (ctDNA) 
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level is prognostic in patients with resectable esophageal cancer (12). Metabolic response on PET 
has also been found to be predictive of long-term outcome in patients with resectable esophageal 
cancer, and PET CT is routinely being used in this patient population for re-staging purpose (13). 
In this study, we propose to collect the ctDNA level at five different time points: at diagnosis, after 
completion of induction chemotherapy, after completion of chemoradiation, after surgery and at 
the time of disease recurrence if this occurs. We plan to correlate the ctDNA level with disease 
recurrence and metabolic response on PET CT. The information obtained from ctDNA in this 
study may be used in designing future clinical trials as well as identifying new therapeutic targets.
2.3
Study Hypothesis
We hypothesize that induction chemotherapy with a novel combination of Trifluridine/tipiracil 
(TAS-102) and oxaliplatin before chemoradiation will increase the pathologic complete response 
(path CR) rate in localized esophageal and GEJ adenocarcinoma. This improved path CR may lead 
to a survival benefit.
3
INCLUSION AND EXCLUSION CRITERIA
NOTE: For blood Chemistry labs, Roswell Park clinical blood chemistries are performed on 
plasma unless otherwise indicated.
3.1
Inclusion Criteria
To be included in this study, participants must meet the following criteria:
1.
Age ≥ 18 years of age.
2.
Must have histologically proven loco-regional esophageal or gastroesophageal junction 
adenocarcinoma.
3.
Endoscopic ultrasound (EUS), or clinically determined node-positive disease with any T-
stage or T3-T4a with any N stage: Patients with EUS T4b and any M1 cancer will not be included.
4.
Must have potentially resectable disease.
5.
Have an ECOG Performance Status of 0-1. Refer to Appendix A.
6.
Have the following clinical laboratory values:
o
Hemoglobin ≥ 9 g/dL
o
Absolute neutrophil count ≥ 1500/mm3
o
Platelet count ≥ 100,000/mm3
o
Creatinine < 1.5 ULN
o
Bilirubin < 1.5 x ULN
o
AST/ALT ≤ 3 x ULN
7.
Capacity to take oral tablet(s) without difficulty.
8.
Participants of child-bearing potential must agree to use highly effective contraceptive 
methods (e.g., hormonal plus 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.
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9.
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 chemotherapy, thoracic radiotherapy or prior surgical resection for an esophageal 
tumor.
2.
Participants with known metastatic disease.
3.
Any concurrent active malignancy that requires active systemic intervention
4.
Grade 2 or higher peripheral neuropathy.
5.
Participants who have had major surgery or field radiation within 4 weeks prior to entering 
the study or those who have not recovered from adverse events due to agents administered more 
than 4 weeks earlier.
6.
Received an investigational agent within 4 weeks prior to enrollment.
7.
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric 
illness/social situations that would limit compliance with study requirements.
8.
Grade 3 or higher hypersensitivity reaction to oxaliplatin or grade 1-2 hypersensitivity 
reaction to oxaliplatin not controlled with premedication.
9.
Patient previously treated by TAS-102 or history of allergic reactions attributed to 
compounds of similar composition to TAS-102 or any of its excipients.
10.
Hereditary problems of galactose intolerance; e.g., Lapp lactase deficiency or glucose-
galactose malabsorption.
11.
Pregnant or nursing female participants.
12.
Unwilling or unable to follow protocol requirements.
13.
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 in order to prevent any risk to 
vulnerable populations:

Cognitively impaired adults/adults with impaired decision-making capacity

Individuals who are not yet adults (infants, children, teenagers)

Prisoners
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
Pregnant women
4
LOCAL AND STUDY-WIDE NUMBER OF SUBJECTS
A maximum of 41 evaluable participants are required for the primary analysis. To account for 
patients that may be non-evaluable, up to n=45 study subjects may be accrued. Approximately 
25 participants are expected to be accrued at Roswell Park, along with approximately 
10 participants accrued at each participating external site. Accrual is expected to take 4 years.
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 principal 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.

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 48 months with an additional 12 months of follow-up on study. After 
completion of 1 year on-study follow-up, the patient will be followed (monitored for survival 
status) as per standard of care: Year 1-Year 2, every 3-6 months; every 6–12 months for 3–5 years, 
then annually until disease progression or death, whichever occurs first.
The estimated time frame that the analysis of the primary endpoint would be evaluable is 
approximately 5 years after study commencement.
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8
STUDY ENDPOINTS
8.1
Primary Endpoint

Pathologic complete response rate: The path CR rate will be determined by pathologic 
examination of resected specimen: complete and partial response to induction 
chemotherapy followed by standard chemoradiation and surgery
8.2
Secondary Endpoints

Progression free survival rate (PFS): Evaluate the 2-year disease-free survival rate.

Overall survival (OS): Evaluate 2-year overall survival rate.

Toxicities as Assessed by CTCAE v5.0.

Post-operative complications, 30-day and 90-day post-op mortality.

Metabolic response as measured by the change in maximum standardized uptake value 
(SUV max) on PET-CT scans from pre-induction chemotherapy to post-induction 
chemotherapy. Patients will have a baseline PET CT and a repeat PET will be performed 
after induction chemotherapy and a blinded reviewer will assess change in SUV max 
from baseline. Patients with a >35% decrease in SUV max will be categorized as 
metabolic responders and those with a ≤35% decrease in SUV max will be categorized as 
metabolic non-responders.
8.3
Exploratory Endpoints

Circulating tumor DNA (ctDNA) levels will be determined at five time points: at diagnosis, 
after completion of induction chemotherapy, after completion of chemoradiation, after 
surgery and at disease recurrence or progression on study. Levels will be compared to 
disease recurrence and metabolic response on PET CT.
9
DESIGN
This is an open-label, multi-center, Phase 2 study of TAS-102 (trifluridine/tipiracil) administered 
with oxaliplatin before chemoradiation in participants with adenocarcinoma of the esophagus or 
GE junction. The study schema is depicted in Figure 1.
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Figure 1
Study Schema
Patients meeting the inclusion criteria will receive three cycles of TAS-102  (35 mg/m2 BID) and 
oxaliplatin (85 mg/m2) before undergoing concurrent chemoradiation (standard of care radiation 
dose of 5040 cGY will be utilized at all participating study sites) with weekly carboplatin (AUC 
2) and paclitaxel (50 mg/m2) for 6 weeks, followed by surgery.
Patients who receive at least one dose of the investigational treatment and eventually go to surgery 
will be evaluated for path CR (primary analysis), regardless if they discontinue treatment at any 
point prior to surgery. Patients who discontinue treatment before surgery due to toxicity or disease 
progression and end up not having surgery will be considered as non-responders. Patients, who 
discontinue treatment prior to surgery due to any other reason, will be considered non-evaluable 
for the primary analysis and will be replaced. These patients will be followed for the protocol 
defined safety/ toxicity period (unless they received no study drug/ procedure that would otherwise 
require this). They will not have any additional scheduled follow up visits and will not be followed 
for survival. Once a non-evaluable patient is beyond the safety follow-up window, they will be 
taken off study in an expedited way.
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10
TREATMENT
Treatment is intended for an outpatient setting.
10.1
TAS-102 and Oxaliplatin
Patients meeting the inclusion criteria will receive 3 cycles of TAS-102 and oxaliplatin induction 
chemotherapy prior to standard of care chemoradiation therapy (standard of care radiation dose of 
5040 cGY will be utilized at all participating study sites) with carboplatin and paclitaxel.
For the purpose of this study, 1 cycle= 14 days.
TAS-102 will be administered at the recommended dose of 35 mg/m², BID, orally, on Days 1–5 
of every 14-day cycle.
Oxaliplatin will be administered at a fixed dose of 85 mg/m², IV (over 2 hours) on Day 1 only of 
each cycle. On Day 1, the patient will get oxaliplatin first and then be instructed to take the TAS-
102.
Patients will be instructed to swallow TAS-102 tablets whole, with food. Patients are not to retake 
doses of TAS-102 that are vomited or missed and will be instructed to continue with the next 
scheduled dose.
10.2
TAS-102 Dose Modifications for Adverse Reactions
Obtain complete blood cell counts prior to treatment on Day 1 of each cycle.
Do not initiate the cycle of TAS-102 until:

Absolute neutrophil count (ANC) ≥ 1,500/mm3 or febrile neutropenia is resolved

Platelets ≥ 75,000/mm3

Grade 3 or 4 non-hematological adverse reactions are resolved to Grade 0 or 1
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
After recovery, resume TAS-102 after reducing the dose by 5 mg/m2/dose from the previous dose, 
if the following occur:

Febrile neutropenia

Uncomplicated Grade 4 neutropenia (which has recovered to ≥ 1,500/mm3) or 
thrombocytopenia (which has recovered to ≥ 75,000/mm3) that results in more than 1-week 
delay in start of next cycle

Non-hematologic Grade 3 or Grade 4 adverse reaction except for Grade 3 nausea and/or 
vomiting controlled by antiemetic therapy or Grade 3 diarrhea responsive to antidiarrheal 
medication
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A maximum of 3 dose reductions are permitted. 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.
10.3
TAS-102: Management of Adverse Effects
Severe Myelosuppression:
Severe and life-threatening (grade 3 or 4) bone marrow suppression (anemia, neutropenia, 
thrombocytopenia) has occurred, including fatalities (rare) related to neutropenic infection, sepsis, 
or septic shock. In clinical trials, slightly over 10% of patients received growth factor support. 

Monitor blood counts prior to treatment on Day 1 of each cycle, or more frequently if 
clinically necessary. May require therapy interruption and/or dose reduction.
Gastrointestinal Toxicity:
Trifluridine/tipiracil is associated with a moderate emetic potential; antiemetics are recommended 
to prevent nausea and vomiting (14). Nausea, vomiting, diarrhea, and abdominal pain have been 
commonly reported. Stomatitis may also occur.

Advise patients to report severe gastrointestinal toxicity to their health care provider.
10.4
Oxaliplatin: Management of Adverse Effects:
Acute toxicities: Longer infusion time (6 hours) may mitigate acute toxicities (e.g., 
pharyngolaryngeal dysesthesia).
Neurosensory events:

Persistent (> 7 days) grade 2 neurosensory events:
o
Reduce dose to 75 mg/m2

Consider withholding oxaliplatin for grade 2 neuropathy lasting > 7 days despite dose 
reduction.

Persistent (> 7 days) grade 3 neurosensory events: Consider discontinuing oxaliplatin.
Gastrointestinal toxicity (grade 3/4) occurring despite prophylactic treatment:

Delay next dose until recovery from toxicity, then reduce dose to 75 mg/m2
Hematologic toxicity (grade 4 neutropenia, febrile neutropenia, or grade 3/4 
thrombocytopenia):

Delay next dose until neutrophils recover to ≥ 1500/mm3 and platelets recover to 
≥ 75,000/mm3, then reduce dose to 75 mg/m2.
Pulmonary toxicity (unexplained respiratory symptoms including nonproductive cough, 
dyspnea, crackles, pulmonary infiltrates): Discontinue until interstitial lung disease or 
pulmonary fibrosis have been excluded.
Rhabdomyolysis: Discontinue for signs/symptoms of rhabdomyolysis.
Sepsis or septic shock: Withhold treatment.
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Cold sensitivity: Patients should be counseled to avoid ice-chips, cold drinks, and exposure to 
cold water or air as the neurotoxicity seen with oxaliplatin is often exacerbated by cold exposure. 
The duration of this cold-related neuropathy is not well defined and patients should exercise 
caution regarding cold exposure during the treatment cycle.
10.5
Management of adverse effects during concurrent chemoradiation with weekly 
Carbo+Taxol:
Chemotherapeutic toxicity

Hematologic Related Toxicity
o
If Day 8, 15, 22, 29, and 36 the ANC < 1,000/mm³ or Platelets < 50,000/mm³ or 
Hemoglobin < 9 g/dL as per the original CROSS regimen: delay chemotherapy by 
1 week until recovery above these values.
o
In case of febrile neutropenia (ANC < 0.5/L and fever > 38.5 0C) or in case of 
severe bleeding or requiring ³ 2 platelet transfusions further chemotherapy will be 
withheld.
o
Platelets will be transfused if <10,000 or <20,000 and febrile.  The cardiac 
monitoring will be continued until the end of chemoradiation. Baseline EKG and 
then as needed. Patients will be evaluated as per SOC by radiation oncology. If it 
is determined that radiation needs to be stopped, patients will come off the study

Non-hematologic Toxicity
These effects will be graded according to CTC recommendations for grading of acute and sub-
acute toxicity.
Reaction
Management of reaction
Renal
Creatinine < 1.5 x the upper limit of normal 
at
the day of retreatment.
Continue therapy.
Creatinine is > 1.5 x the upper limit of 
normal.

Establish intravenous infusion the 
evening preceding treatment at a rate 
to correct any volume deficits and 
produce a urine flow ³ 50 mL/h.

Repeat blood creatinine value in the 
morning:

< 1.5 x the upper limit of normal 
→
Proceed treatment.

> 1.5 x the upper normal limit →
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Stop chemotherapy.
Gastrointestinal
Mucositis with oral ulcers or protracted
vomiting despite antiemetic premedication.
Delay chemotherapy one week.
Neurologic
<CTC grade 2.
Continue therapy.
CTC > GRADE 2.
STOP CHEMOTHERAPY.
Cardiac
Asymptomatic bradycardia or isolated and 
asymptomatic ventricular extrasystoles.
Continue therapy under continuous cardiac
monitoring.
First degree AV block
Continue therapy under continuous cardiac
monitoring.
Symptomatic arrhythmia or AV block 
(except 1st degree) or other heart blocks.
Stop paclitaxel, manage arrhythmia 
according to standard practice, patient goes 
off protocol.
Other Major Organ Toxicity
CTC grade > 2 
(with the exception of esophagitis)
Stop therapy, patient goes off protocol 
treatment.
NOTE: For blood Chemistry labs, Roswell Park clinical blood chemistries are performed on plasma unless otherwise 
indicated.
Radiation toxicity
Radiotherapy, especially concurrent with chemotherapy can lead to acute esophagitis. In some 
cases, medical support and/or a feeding tube will be necessary.
In the event of grade 4 radiation induced esophagitis both chemotherapy and radiotherapy will be 
withheld until the esophagitis recovered to grade 3.
Other acute complications of the radiation therapy are erythema, cough, nausea, fatigue and weight 
loss.
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In the first weeks to six months after the irradiation radiation pneumonitis or fistula formation can 
occur.
10.6
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, intercurrent illness that prevents 
further administration of treatment, participant demonstrates an inability/refusal to comply with 
oral medication regime or, participant withdraws from study.
10.7
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 
clinic visit (see Appendix E)
11
PROCEDURES INVOLVED
The study-specific assessments are detailed in this section and outlined in Appendix G (Schedule 
of Procedures and Observations). Baseline and/or Screening assessments must be performed 
within 4 weeks 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.
11.1
Participant 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 4 weeks prior to first dose of study drug:

Medical history with pre-existing conditions

Physical examination, including vital signs (temperature, heart rate, respiratory rate, and 
blood pressure), body weight, and height: Height collected at baseline only.

ECOG Performance Status (Appendix A)

CBC

CMP

Pregnancy test for women of childbearing potential (within 7 days of starting induction 
chemotherapy)

Blood draw for ctDNA analysis

12-lead EKG/ ECG

Upper endoscopy/ endoscopic ultrasound (EGD with EUS)

FDG PET/ CT
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
Concomitant medications

Archival or fresh biopsy tissue obtained from EGD (archival will be requested if EGD 
performed prior to study enrollment; fresh if EGD performed while on study)
11.3
Evaluations Performed on Day 1 of each Induction Cycle

Physical examination, including vital signs

CBC

CMP

Concomitant medications

Adverse events
11.4
Evaluations Performed at End of Induction Chemotherapy Treatment
The following evaluations will be performed at the end of Induction Chemotherapy (within 2 
weeks) treatment or at time of treatment discontinuation:

Physical examination, including vital signs

ECOG Performance Status (Appendix A)

CBC

CMP

Blood draw for ctDNA analysis

FDG PET/ CT

Concomitant medications

Adverse events
11.5
Evaluations performed during chemoradiation (Weeks 2, 4, and 6 ± 1 week after 
starting chemoradiation)

Physical examination, including vital signs

ECOG Performance Status (Appendix A)

CBC

CMP

Concomitant medications

Adverse events
11.6
Evaluations Performed at End of Chemoradiation (within 4 weeks)

Physical examination, including vital signs

CBC

CMP
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
Blood draw for ctDNA analysis

CT chest, abdomen and pelvis with contrast

Concomitant medications

Adverse events
11.7
Evaluations Performed at Time of Surgical Resection

Physical examination, including vital signs

CBC

CMP

Blood draw for ctDNA analysis

Pathological assessment of the resected specimen to evaluate complete response

Concomitant medications

Adverse events
11.8
Post-Treatment Follow-Up Evaluations
Follow-up safety evaluations will occur 30 days (± 7 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
11.9
Long Term Follow-Up Evaluations
If asymptomatic:

History and Physical (with vital signs) every 3–6 months for 1 year following surgery. 

A one-time research-related blood draw for ctDNA analysis during the follow-up period 
(to be determined by the study physician)

After 1 year following surgery the patient will be followed as per standard of care: Year 
1-Year 2, every 3-6 months; every 6–12 months for 3–5 years, then annually until disease 
progression or death, whichever occurs first.

Chemistry profile and CBC, imaging studies and upper GI endoscopy and biopsy as 
clinically indicated will be performed as standard of care follow-up.

Survival status: At all follow-up timepoints until disease progression or death (telephone 
contact is acceptable).

If patient develops disease progression or is a non-responder while still on study and, a 
biopsy is performed as part of standard of care, FFPE (per section 11.11.2) will be 
requested for correlative analysis. 
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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 and cause of death will be recorded for those participants who die within 
30 days after last dose of study drug (telephone verification is acceptable).
11.10 Correlative Studies
11.10.1 Blood draw for ctDNA analysis
Blood samples will be collected (on Monday through Thursday only) via venipuncture for  ctDNA 
analysis. Samples will be collected using two, 10 mL Streck Cell-free DNA BCT® tubes.
Samples will be obtained on:

Baseline

After completion of induction chemotherapy (within 2 weeks)

After completion of chemoradiation (within 4 weeks)

After surgical resection (within 3 days of procedure)

Disease recurrence or progression on study
Samples will be kept at room temperature prior to processing.
Collect whole blood in Streck Cell-Free DNA BCT® tubes. The Streck collection tubes will be 
labeled with the participant’s initials, participant’s study number, clinical study number, protocol 
time point, and protocol day. Tubes should be filled completely. Immediately after collection, 
GENTLY INVERT TUBE(s) 10 times to ensure adequate mixing. Inadequate or delayed mixing 
may result in inaccurate test results.
Samples collected at Roswell Park will be sent at room temperature to the attention of Laboratory 
Medicine – Protocol Clinical Research Support (pneumatic Station 19) where they will get 
accessioned for tracking in the source document (external sites will follow their local SOPs for 
sample tracking). Once sample receipt has been documented, the whole blood samples will be 
transported on the same day (at ambient temperature) to the Roswell Park Hematologic 
Procurement Laboratory for processing for plasma and buffy coat (Appendix H) and storage until 
time of analysis.
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.
MULTI-SITE (EXTERNAL) SITES: Follow directions above for whole blood sample 
collection and processing. The Streck collection tubes will be labeled with the Subject ID # 
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(unique to External patients), initials, the participant’s study number, clinical study number, 
protocol time point, dose, and protocol day. The whole blood samples will be shipped out on the 
same day (at ambient temperature) to Roswell Park Comprehensive Cancer Center Hematologic 
Procurement Laboratory via Fed Express Overnight.
NO SATURDAY DELIVERY. Do not ship on a Friday or the day before a holiday.
Prior to sample shipment, please email the following individuals: linda.lutgen@roswellpark.org 
and brandon.martens@roswellpark.org.
Roswell Park Comprehensive Cancer Center
Hematologic Procurement Laboratory
Basic Science Bldg., S524
Attn: Linda Lutgen / Brandon Martens
Refer to Study Number– I 443819
Elm & Carlton Streets Buffalo, New York 14263
Tel: 716-845-8098
Address shipments and any questions regarding specimen processing to Linda Lutgen or 
Brandon Martens (see above for contact information).
11.11 Pathology
11.11.1 Formalin-Fixed Paraffin-Embedded (FFPE) Biopsy Samples
Baseline tumor specimens will be collected for all patients. This can be fresh EGD biopsy tissue 
(collect and process to FFPE block as per site usual procedure) or archival tumor tissue from 
available EGD tumor biopsies existing in the Paraffin Archive in the Department of Pathology (or 
sent to the Department from an outside institution):

One formalin-fixed paraffin embedded (FFPE) tissue block with >25 mm2 minimum 
surface area and ≥ 60 microns in total thickness PLUS 1 H&E slide, OR

10-20 unstained sections at 5-microns each on positively charged slides PLUS one H&E 
slide is required. Tumor content must be at least 30%.
These de-identified specimens will be labeled with clinical study # (I 443819), study-specific 
subject ID number, tissue accession number/block ID, Time Point, and serial section # (for slides) 
and will be sent to the Roswell Park Clinical Research Laboratory Services Office for storage. 
These samples will be batch shipped, upon PI request, for analysis at the conclusion of the study.
In patients that progress while on study and have a standard of care biopsy performed, fresh or 
archival tissue will be collected as above, if available.
11.11.2 Fresh Tumor Biopsy at time of Surgical Resection
The following FFPE sections from the surgical resection biopsy performed (following completion 
of chemoradiation) are required:

FFPE tumor block and 1 H&E, OR 10-20 unstained serially sectioned (on plus glass) FFPE 
slides and one adjacent H&E FFPE slide, all at 4µm-5µm thickness.
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Tissue samples are to be labeled with clinical study # (I 443819),  study-specific ID number, tissue 
accession number/block ID, protocol time point, and serial section # (for slides) and will be stored 
in CRLS (S-636, GBSB) and batch shipped, upon PI request, for analysis at the conclusion of the 
study.
Pathologic complete response rate (pathCR) will be determined by SOC pathologic examination 
of the tumor specimen obtained following resection.
In patients that have a pathologic complete response (pathCR) with no primary tumor being 
identified in tissue obtained at time of surgical resection, the following sections of tissue from the 
most recent neoplastic pre-treatment biopsy that exists in the Paraffin Archive in the Department 
of Pathology (or outside institution) will be requested:

10-20 unstained serially sectioned (on plus glass) FFPE slides and one adjacent H&E FFPE 
slide all at 4µm-5µm thickness.
Tissue samples are to be labeled with clinical study # (I 443819), study-specific subject ID number, 
tissue accession number/block ID, protocol time point, and serial section # (for slides). The FFPE 
sections will be stored in CRLS (S-636, GBSB) and batch shipped, upon PI request, for analysis 
at the conclusion of the study. For Multi-Site (External Sites): De-identified tissue samples using 
study-specific subject ID number and tissue accession# (GCP requires at least 2 identifiers) are to 
be sent at ambient temperature to Roswell Park Clinical Research Laboratory Services Office 
(Attn: Protocol Lab Team). The shipping label should read as follows:
Roswell Park Comprehensive Cancer Center
Elm & Carlton Streets
Clinical Research Laboratory Services Office
Gratwick Basic Science Building, S-636
Attn: Protocol Lab Team, I 443819 Samples
Buffalo, NY 14263
(716) 845-8917
Email: CRSLabPathTeam@RoswellPark.org
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. 
12
WITHDRAWAL OF SUBJECTS
All patients that receive any of the treatment combination will be included in the AE summaries.
Patients without a response assessment who discontinue treatment due to non-treatment (i.e. 
toxicity) and non-disease (i.e. disease progression) related reasons will be considered non-
evaluable for the primary analysis and will be replaced. These patients will be followed for the 
protocol defined safety/ toxicity period (unless they received no study drug/ procedure that would 
otherwise require this). They will not have any additional scheduled follow up visits and will not 
be followed for survival. Once a non-evaluable patient is beyond the safety follow-up window, 
they will be taken off study in an expedited way.
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Patients without a response assessment who discontinue treatment due to a treatment or disease 
related reason will be considered evaluable for the primary analysis and treated as non-responders.
Stopping Criteria for Toxicity
If study treatment is delayed by at least 3 weeks due to any Grade 3 or Grade 4 toxicity from 
induction chemotherapy, the patient will be taken off the study and will proceed to chemoradiation 
as clinically indicated. Once off study, the patient will be followed for the protocol defined safety 
period [follow-up safety evaluations will occur 30 days (± 3 days) after last dose of study drug or 
until resolution of any drug related toxicity, as per Appendix G). Once beyond the safety follow-
up window the patients will be taken off protocol and will be considered as non-responders. If 5 
or more patients are taken off the study to toxicity during stage 1 of the study, which aims to recruit 
22 patients, accrual will stop until further protocol amendments are made.
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

Noncompliance

Participant voluntary withdrawal
o
Patient-initiated discontinuation of study therapy: Even after a patient agrees to 
take part in this study, he or she may stop study therapy or withdraw from the 
study at any time. If study therapy is discontinued for reasons other than disease 
progression but the patient still allows the investigator to submit information, 
continue imaging as per NCCN guidelines until progression or until, at the 
investigator’s discretion, further treatment is begun. Patients will continue to be 
followed for survival. 
o
Patient-initiated withdrawal from the study: If a patient chooses to have no further 
interaction regarding the study (i.e., allow no future follow-up data to be 
submitted to NCCN), the investigator must provide NCCN with written 
documentation of the patient’s decision to fully withdraw from the study.

Sponsor decision
In addition to the conditions outlined above, the investigator may require a patient to discontinue 
study therapy if one of the following occurs:

The patient develops a serious side effect that he or she cannot tolerate or that cannot be 
controlled with other medications
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
The patient’s health gets worse

The patient is unable to meet the study requirements, or 

New information about the study therapy or other treatments for gastroesophageal cancer 
becomes available
If study therapy is discontinued for reasons other than progression, continue disease imaging as 
per NCCN guidelines until disease progression or until, at the investigator’s discretion, further 
treatment is begun. Patients will continue to be followed for survival. 
13
RISKS TO SUBJECTS
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
Oxaliplatin
The most common adverse reactions reported (incidence ≥ 40%) are peripheral sensory 
neuropathy, neutropenia, thrombocytopenia, anemia, nausea, increase in transaminases and 
alkaline phosphatase, diarrhea, emesis, fatigue, and stomatitis.
Anaphylactic reactions to oxaliplatin have been reported and may occur within minutes of 
administration. Epinephrine, corticosteroids, and antihistamines have been employed to alleviate 
symptoms of anaphylaxis.
13.3
Carboplatin 
The most common adverse reactions reporter (incidence (≥ 10%) are:
Pain, hyponatremia, hypomagnesemia, hypocalcemia, hypokalemia, vomiting, abdominal pain, 
nausea, bone marrow depression, anemia, leukopenia, neutropenia, thrombocytopenia, increased 
blood alkaline phosphatase, increased blood AST, weakness, decreased creatinine clearance, and 
increased blood urea nitrogen. 
Anaphylactic reactions to carboplatin have been reported and may occur within minutes of 
administration. Epinephrine, corticosteroids, and antihistamines have been employed to alleviate 
symptoms of anaphylaxis.
13.4
Paclitaxel
The most common adverse reactions reporter (incidence (≥ 10%) are:
Flushing, ECG abnormality, edema, hypotension, peripheral neuropathy, alopecia, skin rash, 
nausea, vomiting, diarrhea, mucositis, stomatitis, neutropenia, leukopenia, anemia, 
thrombocytopenia, hemorrhage, increased blood alkaline phosphatase, increased blood AST 
hypersensitivity reaction, infection injection site reaction, arthralgia, myalgia, weakness, and 
increased blood creatinine.
Anaphylaxis and severe hypersensitivity reactions characterized by dyspnea and hypotension 
requiring treatment, angioedema, and generalized urticaria have occurred in 2% to 4% of patients 
in clinical trials. Fatal reactions have occurred in patients despite premedication. We will pretreat 
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all patients with corticosteroids, diphenhydramine, and histamine H2 antagonists. We will not 
rechallenge patients who experience severe hypersensitivity reactions to paclitaxel.
14
POTENTIAL BENEFITS TO SUBJECTS
Based on the published data, TAS-102, in addition to its anti-metabolite properties, can induce 
single- and double-stranded DNA breaks and DNA instability (8). Tipiracil has additional anti-
angiogenic properties. It is currently approved by the FDA for treatment of advanced metastatic 
gastric or gastroesophageal junction (GEJ) adenocarcinoma. As such, it has the potential to 
increase the efficacy of standard of care therapy and improve pathologic response rates in localized 
or locally advanced esophageal or GEJ adenocarcinoma.
Pathologic response to neoadjuvant therapy is a prognostic biomarker for overall survival (15). 
With current standard treatment, complete pathologic response (path CR) is observed only in 20-
25% patients. Our expectation is to improve path CR by 15% with our proposed treatment. Besides, 
micrometastatic disease is treated earlier using induction chemotherapy and spares those patients 
from a major surgical approach who are destined to relapse early.
15
DATA AND SPECIMEN BANKING
All blood samples for correlative analysis will be sent to the Roswell Park Hematologic 
Procurement Laboratory for processing and storage until requested for planned assays at 
conclusion of the study. 
All tumor tissue samples will be sent to Roswell Park Clinical Research Laboratory Services for 
storage until requested by PI for analysis at the end of the study. Samples will be used for future 
analysis for other yet to be identified biomarkers that may be related to the clinical outcome of the 
study population.
Any clinical data that is associated with the samples, will be stored on a secure 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. 
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.
All research samples will be utilized for the planned study assays only. 
16
MEASUREMENT OF EFFECT
16.1
Solid Tumors
For the purposes of this study, every patient should have a baseline FDG PET-CT scan. Patients 
should be re-evaluated by a repeat PET-CT within 1 week after completion of induction 
chemotherapy. In addition, patients should have a chest/abdominal CT scan with contrast and 
pelvic CT with contrast after completion of the concurrent chemoradiation therapy. After surgery, 
patients will be followed as per NCCN guidelines.
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16.2
Pathologic Complete Response Rate
Pathologic complete response rate (path CR) will be determined by pathologic examination of 
resected specimen (i.e., complete and partial response to induction chemotherapy followed by 
standard chemoradiation and surgery). Refer to Appendix F.
16.3 PFS and OS
The survival outcomes (PFS and OS) are treated as bivariate time-to-event data. PFS is defined 
as the time from treatment until disease progression, death from disease, or last follow-up. OS is 
defined as the time from treatment until death due to any cause or last follow-up. The time to 
event outcomes will be summarized using standard Kaplan-Meier methods, where estimates of 
median survival will be obtained with 95% confidence intervals.
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 
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.
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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.
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.
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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 dates 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.
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.
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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 17.10.1 for details on reporting Unanticipated 
Problems.
17.8
Investigator Reporting: Notifying Taiho Oncology
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:

Unexpected Fatal or Life Threatening Suspected Adverse Reactions: Report to 
Taiho Oncology, Inc. within 24 hours

Serious & Unexpected Suspected Adverse Reactions: Report to Taiho Oncology, 
Inc. within 24 hours

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 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.
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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.
17.9.1 Other Reportable Events
For the purposes of this study, other experiences with TAS-102 shown below should also be 
reported to TAIHO:
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
17.9.2 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 (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. The Institution must provide final outcome of 
pregnancy to TAIHO. If any SAE(s) is observed in a study subject or fetus/child, then SAE(s) 
must also be reported to TAIHO 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 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')
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Requesting Follow-up Information:
The institution will provide TAIHO with details of whom TAIHO 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. Sarbajit Mukherjee.
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.

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 also 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. Unanticipated problems will be reported to 
NCCN at same time as Taiho.  SAEs may be emailed to ORPreports@nccn.org or faxed to 215-
358-7699.
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.
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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.

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 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 shall provide the Institution with the final version of this DSUR 
report within 15 calendar days after submission to health agencies and ethics committees.
The Food and Drug Administration has issued guidance to assist in assuring the safety of trial 
participants, maintaining compliance with good clinical practice (GCP), and minimizing risks to 
trial integrity during the COVID-19 pandemic. Those recommendations may be found at the link 
below: 
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https://www.fda.gov/regulatory-information/search-fda-guidance-documents/fda-guidance-
conduct-clinical-trials-medical-products-during-covid-19-pandemic. 
Changes in protocol conduct necessary to immediately assure patient safety, such as conducting 
telephone or video contact visits for safety monitoring rather than on-site visits, can be 
immediately implemented with subsequent review by the IRB and notification to the sponsor. 
Since this reflects a protocol deviation to the current protocol practice, documentation of 
deviations is required. Telephone or video communications with subjects should be utilized at the 
discretion of the site investigator taking into consideration the guidelines provided above. Besides 
treatment delay is allowed as per the investigators’ discretion as patients are worked-up, treated or 
hospitalized for COVID-19 or any related illness.
18
DATA MANAGEMENT AND CONFIDENTIALITY
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.
Clinical Data Management activities are performed using CTMS and EDC systems that enable the 
collection, cleaning and viewing of clinical trial data. CRS Clinical Data Manages designs and 
develops the study-specific database. 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. 
18.1
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.
18.2
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.
18.3
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
19.1
Sample Size Determination
The sample size calculations are based on the primary analysis, which evaluates the one-sided 
hypotheses about the actual path CR rate using the Simon two-stage minimax design. The 
historical path CR rate for the standard of care is at most 0.2 (
). If the actual path CR rate is 
𝜋0
, then the study design (n=n1+n2=22+19=41 evaluable patients) achieves 80.4% power at 
𝜋= 0.35
a significance level of α=0.1. To account for patients that may be non-evaluable, up to n=45 study 
subjects may be needed.
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19.2
Demographics and Baseline Characteristics
Patient characteristics will be summarized using the appropriate descriptive statistics.
19.3
Primary Analysis
The primary outcome is the pathologic CR; which is treated as a dichotomous variable and will be 
summarized using frequencies and relative frequencies. Historically, the path CR rate in this 
patient population is approximately 20%. We expect the path CR rate after induction 
chemotherapy to increase by 15% based on the study by Goodman et al. (13). As such, the 
following hypotheses will be evaluated using a two-stage minimax design:
HO: π ≤ 0.2 Versus HA: π > 0.2, where π is the actual path CR rate for metabolic responders.
In stage 1, n1=22 evaluable patients will be enrolled. If there are 4 or fewer path CRs, then the 
proposed treatment regimen will not be considering promising and the study will be suspended for 
futility. If there is 5 or more path CRs, an additional n2=19 evaluable patients will be enrolled in 
stage 2. If 12 or more response is observed in the total n=41 evaluable patients, then the proposed 
treatment regimen will be considered promising for further study. Otherwise, the proposed 
treatment regimen will not be considered promising.
Additionally, the path CR rate will be estimated using an 80% confidence interval obtained using 
Jeffrey’s prior method. Patients without a response assessment who discontinue treatment due to 
non-treatment (i.e. toxicity) and non-disease (i.e. disease progression) related reasons will be 
considered non-evaluable for the primary analysis and will be replaced.
19.4
Secondary Analysis
The overall and disease-specific survival will be summarized using standard Kaplan-Meier 
methods; where estimates of median survival and two-year survival rates will be obtained with 
90% confidence intervals.
19.5
Exploratory Analysis
Analysis of the ctDNA samples collected under this protocol will be batched and shipped to Natera, 
Inc. after processing in-house to be analyzed for ctDNA levels to fulfill the exploratory objective. 
Samples will be provided to Natera per an executed Research Collaboration Agreement in a de-
identified manner.
Shipping instructions for plasma/cfDNA: 
Place sample tubes in cryoboxes and then in an insulated shipping box. 
● Do not put more than four, 2 inch cryoboxes or two 4-6 inch cryoboxes in one insulated 
shipping box. 
● Fill with a sufficient amount of dry ice (5-10 lbs of dry ice per 24 hour period). 
● Use appropriate UN3373 and UN1845 approved shipping containers. Affix appropriate 
shipping labels to the outside of the box: UN3373 Biological Substance Category B and Dry 
Ice UN1845.
Ship packages to: 
Natera, Inc.
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Attn: RUO Operations
201 Industrial Rd., Suite 410
San Carlos, CA 94070
● Fill-out the shipping manifest with all relevant information. 
● Please send package tracking information and shipping manifest to: 
o RnD Samples team (ruoops@natera.com) 
       o cc: Your Alliance Manager Receiving Schedule 
● Hours of Operation: Natera accepts delivery of samples Monday through Friday 7:30 a.m.–
4:30 p.m. Pacific Time.
● Observed Holidays: The laboratory will be closed during observed holidays. Please contact 
the courier and laboratory to confirm that deliveries can be made prior to observed holidays.
19.6
Safety Analysis
Toxicities and adverse events (as per CTCAE v5.0) will be summarized by attribution and grade 
using frequencies and relative frequencies.
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 will be reviewed quarterly; Phase II, 
III and pilot investigator-initiated studies will be 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) termination of the study.
21
VULNERABLE POPULATIONS
Not applicable.
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 
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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
Previous experience: Sarbajit Mukherjee, MD: Principal Investigator: Dr. Mukherjee has 
experience in drafting clinical trial proposals, and he is currently a co-principal investigator of an 
investigator-initiated multicenter Phase 2 clinical trial. Besides, Dr. Mukherjee has previous 
experience in outside collaborations that led to peer-reviewed publications in high-impact factor 
journals like Nature Medicine.
Study site: Roswell Park Comprehensive Cancer Center is a nationally and internationally known 
cancer center with a history of timely completion of clinical trials. The study site does not have 
competing clinical trials.
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) 845-7405.
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 (or legal guardian) 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 
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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 
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
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.
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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, by and in accordance with the 
applicable regulatory requirements.
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 drugs provided, exercising accepted medical and pharmaceutical practices. Study 
drugs must be handled as cytotoxic agents and appropriate precautions taken per 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
Oxaliplatin
Oxaliplatin will not be supplied by the study and will be paid for by the patient’s insurance carrier 
as part of the standard-of-care treatment.
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33
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oncology : H&O. 2016;14(8):630-8. Epub 2016/08/04. PubMed PMID: 27487107.
8.
Shitara K, Doi T, Dvorkin M, Mansoor W, Arkenau HT, Prokharau A, Alsina M, Ghidini 
M, Faustino C, Gorbunova V, Zhavrid E, Nishikawa K, Hosokawa A, Yalcin S, Fujitani K, 
Beretta GD, Cutsem EV, Winkler RE, Makris L, Ilson DH, Tabernero J. Trifluridine/tipiracil 
versus placebo in patients with heavily pretreated metastatic gastric cancer (TAGS): a 
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randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2018;19(11):1437-48. 
Epub 2018/10/26. doi: 10.1016/s1470-2045(18)30739-3. PubMed PMID: 30355453.
9.
Hollebecque A, Calvo A, Andre T, Argiles G, Cervantes A, Leger C, Valette A, Amellal 
N, Fougeray R, Tabernero J. Phase I multicenter, open-label study to establish the maximum 
tolerated dose (MTD) of trifluridine/tipiracil (TAS-102) and oxaliplatin combination in patients 
(pts) with metastatic colorectal cancer (mCRC). Journal of Clinical Oncology. 
2018;36(4_suppl):816-. doi: 10.1200/JCO.2018.36.4_suppl.816.
10.
Shitara K, Doi T, Dvorkin M, Mansoor W, Arkenau H-T, Prokharau A, Alsina M, 
Ghidini M, Faustino C, Gorbunova V, Zhavrid E, Nishikawa K, Hosokawa A, Yalçın Ş, Fujitani 
K, Beretta GD, Cutsem EV, Winkler RE, Makris L, Ilson DH, Tabernero J. Trifluridine/tipiracil 
versus placebo in patients with heavily pretreated metastatic gastric cancer (TAGS): a 
randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet Oncology. 
2018;19(11):1437-48. doi: https://doi.org/10.1016/S1470-2045(18)30739-3.
11.
Pectasides E, Stachler MD, Derks S, Liu Y, Maron S, Islam M, Alpert L, Kwak H, 
Kindler H, Polite B, Sharma MR, Allen K, O'Day E, Lomnicki S, Maranto M, Kanteti R, 
Fitzpatrick C, Weber C, Setia N, Xiao SY, Hart J, Nagy RJ, Kim KM, Choi MG, Min BH, Nason 
KS, O'Keefe L, Watanabe M, Baba H, Lanman R, Agoston AT, Oh DJ, Dunford A, Thorner AR, 
Ducar MD, Wollison BM, Coleman HA, Ji Y, Posner MC, Roggin K, Turaga K, Chang P, 
Hogarth K, Siddiqui U, Gelrud A, Ha G, Freeman SS, Rhoades J, Reed S, Gydush G, Rotem D, 
Davison J, Imamura Y, Adalsteinsson V, Lee J, Bass AJ, Catenacci DV. Genomic Heterogeneity 
as a Barrier to Precision Medicine in Gastroesophageal Adenocarcinoma. Cancer discovery. 
2018;8(1):37-48. Epub 2017/10/06. doi: 10.1158/2159-8290.Cd-17-0395. PubMed PMID: 
28978556; PMCID: PMC5894850.
12.
Azad TD, Chaudhuri A, Newman AM, Stehr H, Schroers-Martin J, Chabon JJ, Fang P, 
Qiao Y, Liao ZX, Komaki R, Alizadeh AA, Lin SH, Diehn M. Circulating tumor DNA analysis 
for outcome prediction in localized esophageal cancer. Journal of Clinical Oncology. 
2017;35(15_suppl):4055-. doi: 10.1200/JCO.2017.35.15_suppl.4055.
13.
Goodman KA, Hall N, Bekaii-Saab TS, Ou F-S, Twohy E, Meyers MO, Boffa DJ, 
Mitchell K, Perry K, Frankel WL, Venook AP, O'Reilly EM, Ilson DH. Survival outcomes from 
CALGB 80803 (Alliance): A randomized phase II trial of PET scan-directed combined modality 
therapy for esophageal cancer. Journal of Clinical Oncology. 2018;36(15_suppl):4012-. doi: 
10.1200/JCO.2018.36.15_suppl.4012.
14.
Hesketh PJ, Kris MG, Basch E, Bohlke K, Barbour SY, Clark-Snow RA, Danso MA, 
Dennis K, Dupuis LL, Dusetzina SB, Eng C, Feyer PC, Jordan K, Noonan K, Sparacio D, 
Somerfield MR, Lyman GH. Antiemetics: American Society of Clinical Oncology Clinical 
Practice Guideline Update. Journal of Clinical Oncology. 2017;35(28):3240-61. doi: 
10.1200/jco.2017.74.4789. PubMed PMID: 28759346.
15.
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 
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(version 1.1). European Journal of Cancer. 2009;45(2):228-47. doi: 
http://dx.doi.org/10.1016/j.ejca.2008.10.026.
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34
APPENDICES/ SUPPLEMENTS
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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
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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: Use of Trifluridine/ Tipiracil and Oxaliplatin as Induction Chemotherapy in Resectable 
Esophageal and Gastroesophageal Junction (GEJ) Adenocarcinoma
INCLUSION CRITERIA
Yes
No
N/A
All answers must be “Yes” or “N/A” for participant enrollment.
Date
1.
Age ≥ 18 years of age.
2.
Must have histologically proven loco-regional esophageal or 
gastroesophageal junction adenocarcinoma.
3.
Endoscopic ultrasound (EUS), or clinically determined node-positive 
disease with any T-stage or T3-T4a with any N stage: Patients with 
EUS T4b and any M1 cancer will not be included.
4.
Must have potentially resectable disease.
5.
Have an ECOG Performance Status of 0-1. Refer to Appendix A.
6.
Have the following clinical laboratory values

Hemoglobin ≥ 9 g/dL

Absolute neutrophil count ≥ 1500/mm3

Platelet count ≥ 100,000/mm3

Creatinine < 1.5 ULN

Bilirubin < 1.5 x ULN

AST/ALT ≤ 3 x ULN
7.
Capacity to take oral tablet(s) without difficulty.
8.
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.
9.
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: __________________________________________________
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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: Use of Trifluridine/ Tipiracil and Oxaliplatin as Induction Chemotherapy in Resectable 
Esophageal and Gastroesophageal Junction (GEJ) Adenocarcinoma
EXCLUSION CRITERIA
Yes
No
N/A
All answers must be “No” or “N/A” for participant enrollment.
Date
1.
Prior chemotherapy, thoracic radiotherapy or prior surgical resection for 
an esophageal tumor.
2.
Participants with known metastatic disease.
3.
Any concurrent active malignancy that requires active systemic 
intervention.
4.
Grade 2 or higher peripheral neuropathy.
5.
Participants who have had major surgery or field radiation within 
4 weeks prior to entering the study or those who have not recovered 
from adverse events due to agents administered more than 4 weeks 
earlier.
6.
Received an investigational agent within 4 weeks prior to enrollment.
7.
Uncontrolled intercurrent illness including, but not limited to, ongoing 
or active infection, symptomatic congestive heart failure, unstable 
angina pectoris, cardiac arrhythmia, or psychiatric illness/social 
situations that would limit compliance with study requirements.
8.
Grade 3 or higher hypersensitivity reaction to oxaliplatin or grade 1-2 
hypersensitivity reaction to oxaliplatin not controlled with 
premedication
9.
Patient previously treated by (TAS-102) or history of allergic reactions 
attributed to compounds of similar composition to TAS-102 or any of 
its excipients.
10. Hereditary problems of galactose intolerance; e.g., Lapp lactase 
deficiency or glucose-galactose malabsorption.
11. Pregnant or nursing female participants.
12. Unwilling or unable to follow protocol requirements.
13. 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: __________
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Printed Name of Investigator: _________________________________________________
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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 Comprehensive Cancer Center
CRS Quality Assurance (QA) Office
CRS-QA@RoswellPark.org
Elm and Carlton Streets
Buffalo, New York 14263
Telephone:
Monday - Friday; 7:00 AM to 4:00 PM EST
716-845-3870
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 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 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 (CRS-QA@RoswellPark.org) to the 
Roswell Park CRS QA 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 CRS QA Coordinator at (CRS-QA@RoswellPark.org).
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.
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
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 CRS 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.
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 CRS QA Coordinator within 1 business day of 
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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 OnCore SAE form

MedWatch 3500A
All serious adverse events via a MedWatch Form need to be sent to the Taiho Oncology, Inc., via 
fax: 609-750-7371 or e-mail: TAS-102_Safety@taihooncology.com (please note the underscore 
between ‘102’ and ‘Safety’).
MedWatch reports must clearly specify SAE term(s) and corresponding investigator causality 
assessment.
The principal investigator or designee will inform Roswell (via email using both the OnCore 
SAE form and MEDWATCH 3500A form) within twenty-four (24) hours of first awareness of 
any event that meets the above criteria. Both forms should include all available information, 
including a brief narrative describing the SAE, attributions, and any other relevant information. 
Upload all related (redacted) source information into OnCore along with the completed forms 
signed by the PI. Forms will be submitted to the CRS QA Office via email to 
SafetyEventReporting@RoswellPark.org.
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 CRS 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 CRS QA Coordinator at: CRS-
QA@RoswellPark.org.
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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 1-Day 5 0 of every 14-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. 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 
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
Please remember to bring this calendar and your pill bottle (including any unused pills) with you to your next study 
appointment.
_________________________________________________________________________
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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) : ___________________________________
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Appendix F
NCCN Principles of Pathologic Review
Reproduced from: NCCN Guidelines Version 1.2019
Esophageal and Esophagogastric Junction Cancers


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Appendix G Schedule of Procedures and Observations
Induction 
Chemotherapy 
(IC)
Cycle 1-Cycle 3
Time point 
Screening1
Day 1
of each cycle
End of IC
(within 
2 weeks)
During 
chemoradiation 
(Weeks 2, 4 and 
6 ± 1 week after 
starting 
chemoradiation)
End of 
CRT
(within 
4 weeks)
At time of 
Surgical 
Resection
Follow-Up 
Safety 
evaluation2
Long 
Term 
Follow-
Up3
Clinical Procedures
Medical History
X
X
Pre-Existing Conditions
X
Physical Examination4 , 
including vital signs5
X
X
X
x
X
X
X
ECOG Performance Status
X
X
X
Concomitant Medications
X6
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
Survival Status
X
Laboratory Procedures
Hematology7
X
X
X
X
X
X
Chemistry8
X
X
X
X
X
X
Pregnancy Test (Urine or 
Blood)
X
Blood Draw for Correlative 
Analysis13
X
X
X
X
X9
Tissue12
X12a
X12b
X12c
Imaging Procedures
ECG/EKG (12-Lead)
X
EGD with EUS
X
Imaging for Tumor/ Disease 
Assessment (FDG PET CT/ 
CT CAP)
X
X
X


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Induction 
Chemotherapy 
(IC)
Cycle 1-Cycle 3
Time point 
Screening1
Day 1
of each cycle
End of IC
(within 
2 weeks)
During 
chemoradiation 
(Weeks 2, 4 and 
6 ± 1 week after 
starting 
chemoradiation)
End of 
CRT
(within 
4 weeks)
At time of 
Surgical 
Resection
Follow-Up 
Safety 
evaluation2
Long 
Term 
Follow-
Up3
Treatment Regimen/Drug 
Administration
TAS-102
X10
Oxaliplatin
X11
Carboplatin
X 
Paclitaxel
X
Radiation
X
1
Performed within 4 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
If asymptomatic: 
→ History and Physical (with vital signs) every 3–6 months for 1 year following surgery.
→After 1 year following surgery the  patient will be followed as per standard of care: Year 1-Year 2, every 3-6 months; every 6–12 months for 3–5 y, then annually until 
disease progression or death, whichever occurs first
→ Chemistry profile and CBC, imaging studies and upper GI endoscopy and biopsy as clinically indicated will be performed as standard of care follow-up 
4
Research/study-specific assessments should be performed within 4 weeks (± 2 weeks) prior to the start of treatment. 
5
Vital signs (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
Once during the follow-up period (to be determined by study physician): at time of disease recurrence./progression on study. See Section 11.10.1.
10
TAS-102 will be administered at the recommended dose of 35 mg/m², BID, orally, on Days 1–5 of every 14-day cycle.
11
Oxaliplatin will be administered at a fixed dose of 85 mg/m², IV (over 2 hours) on Day 1 only of each cycle. On Day 1, the patient will get oxaliplatin first and then be 
instructed to take the TAS-102.
12
Refer to Section 11.1
12a. Tissue collection at baseline, either fresh tissue from the esophagogastroduodenoscopy (EGD) if done post-consent, or archival if the EGD was already done prior to 
study enrollment 


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12b. Pathological assessment of the resected specimen to evaluate complete response. FFPE sections from the surgical resection biopsy performed following completion 
of chemoradiation biopsy will be requested.  In patients that have a pathologic complete response (pathCR) with no primary tumor being identified in tissue obtained at 
time of surgical resection, archival pre-treatment neoplastic tissue will be requested. 
12c. In addition to on-trial tissue biopsies, if patient develops disease progression or is a non-responder while still on study and a biopsy is performed as part of standard 
of care, FFPE (per section 11.11.2) will be requested for correlative analysis.
13
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Appendix H
Whole Blood Sample Processing
Procedure for the Isolation of Buffy Coat and Plasma from Whole Blood
1.
Requirements
a.
Use two (2) Streck Cell-Free DNA BCT tubes (black and tan top) to collect whole 
blood.
b.
Use aseptic techniques and draw blood from the patient into the Streck BCT tube(s). 
Make sure to collect full volume to ensure correct blood to anticoagulant ratio.
c.
Immediately after the blood is drawn, thoroughly mix the blood with the anticoagulant 
by gently inverting the Streck BCT tube(s) ten (x10) times.
d.
Use aseptic techniques to process whole blood.
e.
Store Streck BCT tubes at room temperature (between 18 - 30°C) for a minimum of 
1 hour and maximum of 12 hours until processing. Process Streck tubes no more than 
7 days after collection. Do not freeze Streck BCT tubes prior to processing.
f.
Note on the case report form date/time of blood collection.
2.
Procedure
a.
Centrifuge Streck BCT tube(s) at 3220 x g for 30 minutes at 22°C. Do not use brake 
to stop centrifuge.
b.
Make sure all blood tube processing is performed under a laminar hood to avoid 
contamination.
c.
Using a sterile transfer pipette, remove the plasma (yellow-clear liquid) stopping 
5mm above the buffy coat (the thin gray-white layer) to ensure no aspiration of buffy 
coat and/or red blood cells/erythrocytes and transfer to a sterile 15 ml centrifuge tube.  
No cells or debris should be present in the plasma.
d.
Re-centrifuge the 15-ml centrifuge tube using the same or new cap at 3220 x g for 15 
minutes at 22°C and using a new sterile transfer pipet, remove the plasma stopping 
5mm above any debris pellet.
APPROVED RPCI IRB
10/6/2023


Roswell Park Protocol No.: I 443819
03MAY2023
Page 56 of 56
e.
Aliquot the plasma from each tube into a 2 mL sterile cryovial (approximately 2). The 
screw cap polypropylene cryogenic tubes will be labeled with the participant’s initials, 
participant’s study number, clinical study number, protocol time point, dose, and 
protocol day..
f.
Immediately freeze the cryovials in a -70°C to -80°C freezer.
g.
Store frozen plasma cryovials in a -70°C to -80°C freezer until ready to ship.
h.
Using a new sterile transfer pipette, slowly remove the buffy coat (the thin gray-white 
layer located above the red blood cells/erythrocytes). Avoid aspirating excessive 
amounts of the red blood cells while collecting the buffy coat.
i.
Aliquot the buffy coat from one of the tubes into a 2-mL sterile cryovial. Note: Only 
one cryovial of buffy coat per case is required.
j.
Immediately freeze buffy coat vials in a -70°C to -80°C freezer.
k.
Store frozen buffy coat vials in a -70°C to -80°C freezer until ready to ship.
Whole blood samples will be processed and stored at Roswell Park’s Hematological Procurement 
Facility until requested by the Principal Investigator for batch shipping at time of analysis.
APPROVED RPCI IRB
10/6/2023