Clinical trial NCT02848079
Conditions: Colorectal Neoplasms
Sponsor: Yale University
Start date: 2016-10-31; Completion date: 2020-06-02
Enrollment: 41 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study will examine the safety and effectiveness of oxaliplatin in combination with TAS-102 (TAS-OX) for treatment of patients with metastatic colorectal cancer whose cancer has progressed or recurred after FOLFOX chemotherapy.

Detailed description:
TAS-102 is an oral agent, which consists of a combination of a novel antimetabolite 5-trifluorothymidine (FTD) and a thymidine phosphorylase inhibitor (TPI) that prevents degradation of FTD. It has demonstrated activity in chemorefractory metastatic colorectal cancer (mCRC) patients. In the Japanese randomized phase II trial, TAS-102 improved medial overall survival when compared to placebo (9.0 vs.6.6 months, Hazard Ratio (HR) 0.56) in patients with mCRC refractory to 5-fluorouracil (5-FU), irinotecan and oxaliplatin. Subsequently, a randomized phase III study conducted in 13 countries (RECOURSE trial) confirmed this benefit on overall survival when compared to placebo (7.1 months vs. 5.3 months, HR 0.68) in patients with refractory metastatic colorectal cancer (CRC) 5.

Oxaliplatin is a third generation platinum compound, which is active when used together with 5-FU in the treatment of mCRC (FOLFOX). FOLFOX chemotherapy, which is frequently combined with anti-angiogenic agent Bevacizumab, is widely accepted as the preferred first-line regimen in the treatment of this disease in the US. Oxaliplatin is also frequently reintroduced in more advanced settings. Reintroduction is seen after progression on maintenance therapy, after resolution of previous treatment limiting neuropathy, after disease recurrence post adjuvant treatment or post metastasectomy. In the control arm of a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-go fashion in advanced colorectal cancer (OPTIMOX1 study), oxaliplatin was reintroduced in 27% of patients. Although patients derive clinical benefit when oxaliplatin is reintroduced, the response rates are not as robust as during initial exposures. Decreased efficacy may be at least in part due to prolonged exposure and resultant resistance to 5-FU, which is a backbone in maintenance and in oxaliplatin containing regimens. Hence, the investigators propose exploring the safety and efficacy of oxaliplatin in combination with an alternative anti-metabolite TAS-102 (TAS-OX).

TAS-102 has demonstrated activity in 5-FU refractory mCRC, so the investigators hypothesize that TAS-OX may serve as an alternative drug combination for patients who have progressed or recurred after FOLFOX, and who are candidates for additional oxaliplatin therapy.

This is a 2-part clinical trial with TAS-102 in combination with oxaliplatin. The first part will be a dose-finding run-in phase and will enroll 3-18 patients. The second part, the focus of this study, will be a single arm cohort , which will further evaluate the safety, as well as efficacy, of TAS-OX in the treatment of mCRC. The subjects in part 2 will be treated with the drug doses determined in Part 1 of the trial. Up to 50 patients will be enrolled in part 2. Anticipated enrollment may be as high as 68 patients. Maximum potential enrollment is listed under anticipated enrollment, below.

Arms: arm 1: Combination treatment with TAS-102 and oxaliplatin. Combination treatment with TAS-102 and oxaliplatin. TAS-102 is an oral medication; oxaliplatin (TAS-OX) is given by infusion. In Part 1 treatments were started at level 1 doses, which were based on prior clinical experience with the medications studied. Dose escalation followed a traditional "3+3" design. The subjects in Part 2 were treated with dose level 3.

Oxaliplatin infusion was given on day 1 of each cycle. TAS-102 was taken twice daily on days 1-5 of each cycle.
Interventions: intervention 1: combined TAS-102 and TAS-OX
Intervention descriptions: intervention 1: Combination treatment with TAS-102 and oxaliplatin. TAS-102 is an oral medication; oxaliplatin (TAS-OX) is given by infusion.

Protocol documents:
Prot_SAP_000.pdf: 
1(42) 
Drug Substance 
TAS-102 and oxaliplatin 
Study Number 
HIC# 1605017852 
Version Number  
6.0 
Date 
20-May-2020 
TAS-102 IN COMBINATION WITH OXALIPLATIN (TAS-OX) FOR 
REFRACTORY METASTATIC COLORECTAL CANCER 
Sponsor:  Yale Cancer Center 
Principal Investigator:  Jeremy Kortmansky, MD 
Study Team:   
Clinical Research Coordinator:  Christina Wiess 
Data Management/Clinical Research Assistant:  Danyell Williams 
Study Statistician: Marilyn Stolar, PhD 
Amendment History: 
 
Protocol Version Number 
Protocol Version Date 
Original 
19-May-2016 
2.0 
01-Aug-2017 
3.0 
4.0 
5.0 
6.0 
13-Dec-2017 
06-Apr-2018 
07-Jun-2018 
20-May-2020 


Clinical Study Protocol Synopsis 
Drug Substance TAS-102 and oxaliplatin  
Study Code HIC# 1605017852 
Version Number: 6.0 
Date: 20-May-2020 
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PROTOCOL SYNOPSIS 
Title of study:  TAS-102 in Combination with Oxaliplatin (TAS-OX) for Refractory 
Metastatic Colorectal Cancer. 
Study Phase: 1B/II 
Study Rationale:   
TAS-102 is an oral agent, which consists of a combination of a novel antimetabolite 5-
trifluorothymidine (FTD) and a thymidine phosphorylase inhibitor (TPI) that prevents 
degradation of FTD.  It has demonstrated activity in chemorefractory metastatic colorectal 
cancer (mCRC) patients.  In the Japanese randomized phase II trial, TAS-102 improved 
medial overall survival when compared to placebo (9.0 vs.6.6 months, HR 0.56) in subjects 
with mCRC refractory to 5-fluorouracil (5-FU), irinotecan and oxaliplatin.  Subsequently, a 
randomized phase III study conducted in 13 countries (RECOURSE trial) confirmed this 
benefit on overall survival when compared to placebo (7.1 months vs. 5.3 months, HR 0.68) 
in subjects with refractory metastatic colorectal cancer (CRC) 5.   
 
Oxaliplatin is a third-generation platinum compound, which is active when used together 
with 5-FU in the treatment of mCRC.  FOLFOX chemotherapy, which is frequently 
combined with anti-angiogenic agent Bevacizumab, is widely accepted as the preferred first-
line regimen in the treatment of this disease in the US.  Oxaliplatin is also frequently 
reintroduced in more advanced settings.  Reintroduction is seen after progression on 
maintenance therapy, after resolution of previous treatment limiting neuropathy, after disease 
recurrence post adjuvant treatment or post metastatectomy.  In the control arm of 
OPTIMOX1 study, oxaliplatin was reintroduced in 27% of subjects.  Although patients 
derive clinical benefit when oxaliplatin is reintroduced, the response rates are not as robust as 
during initial exposures.  Decreased efficacy may be at least in part due to prolonged 
exposure and resultant resistance to 5-FU, which is a backbone in maintenance and in 
oxaliplatin containing regimens.  Hence, we propose exploring the safety and efficacy of 
oxaliplatin in combination with an alternative anti-metabolite TAS-102 (TAS-OX).   
 
TAS-102 has demonstrated activity in 5-FU refractory mCRC, so we hypothesize that TAS-
OX may serve as an alternative drug combination for patients who have progressed or 
recurred after FOLFOX, and who are candidates for additional oxaliplatin therapy.  
 
Methodology:   
This is a 2-part clinical trial with TAS-102 in combination with oxaliplatin. The first part will 
be a dose-finding run-in phase. The second part will be a single arm expansion cohort study, 
which will further evaluate the safety, as well as efficacy, of TAS-OX in the treatment of 
mCRC.  Subjects will be treated with the study drugs until radiological evidence of disease 
progression or until treatment discontinuation secondary to adverse events.   
 
 


Clinical Study Protocol Synopsis 
Drug Substance TAS-102 and oxaliplatin  
Study Code HIC# 1605017852 
Version Number: 6.0 
Date: 20-May-2020 
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Objectives and Endpoints:   
Part 1:  Determination of an optimally tolerated dose (MTD) 
 
Part 2: 
Primary: 
• Overall Response Rate (ORR) 
Secondary: 
 
• Progression Free Survival (PFS) 
• Overall Survival (OS) 
• Disease Control Rate (DCR) 
• Duration of Response  
• Safety and Tolerability. 
 
Number of centers & participants:    
One center – Yale Cancer Center. 
Part 1: 3-18 subjects 
Part 2: 30 to 50 subjects will be enrolled in the phase 2 portion of the study according to the 
Bayesian analysis detailed in the protocol. 
 
Population:   
This study will enroll patients with histologically confirmed stage IV colon cancer (AJCC 7th 
edition) who have progressed after at least 2 lines of standard therapy that included 5-FU, 
irinotecan and oxaliplatin. 
 
Investigational drugs:   
TAS-102 (commercially available) 
Oxaliplatin (commercially available) 
 


Clinical Study Protocol Synopsis 
Drug Substance TAS-102 and oxaliplatin  
Study Code HIC# 1605017852 
Version Number: 6.0 
Date: 20-May-2020 
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TABLE OF CONTENTS 
PAGE 
TITLE PAGE ............................................................................................................................ 1 
TABLE OF CONTENTS ......................................................................................................... 4 
LIST OF APPENDICES .......................................................................................................... 6 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ......................................... 7 
EVALUATION SCHEDULE .................................................................................................. 9 
1. 
INTRODUCTION .......................................................................................................... 10 
1.1 
Colon Cancer ...................................................................................................... 10 
1.2 
TAS-102 ............................................................................................................... 10 
 
Mechanism of Action ....................................................................................... 10 
 
Clinical Experience with TAS-102................................................................... 10 
 
Rationale for Combining TAS-102 and Oxaliplatin. ....................................... 12 
1.3 
Benefit/risk and ethical assessment ................................................................... 12 
2. 
STUDY OBJECTIVES/ENDPOINTS ......................................................................... 13 
2.1 
Part 1 .................................................................................................................... 13 
2.2 
Part 2 .................................................................................................................... 13 
3. 
STUDY PLAN AND PROCEDURES .......................................................................... 13 
3.1 
Overall study design ........................................................................................... 13 
3.2 
Part 1 study design ............................................................................................. 13 
 
Treatment Regimen .......................................................................................... 14 
 
Dose-Limiting Toxicity Determination and Maximum Tolerated Dose 
Definition ....................................................................................................................... 14 
3.3 
Part 2 study design ............................................................................................. 15 
3.4 
Rationale for study design and doses ................................................................ 15 
3.5 
Study population ................................................................................................. 15 
4. 
PATIENT SELECTION CRITERIA ........................................................................... 16 
4.1 
Inclusion criteria. ................................................................................................ 16 
4.2 
Exclusion criteria. ............................................................................................... 16 
5. 
STUDY CONDUCT ....................................................................................................... 17 
5.1 
Treatments .......................................................................................................... 17 
 
TAS-102 ........................................................................................................... 17 
 
Oxaliplatin ........................................................................................................ 19 
5.2 
Concomitant and post-study treatment(s) ........................................................ 19 
5.3 
Restrictions during the study............................................................................. 20 
 
Administration of other anti-cancer agents ...................................................... 20 
 
Other concomitant treatment ............................................................................ 20 
 
Pregnancy and Contraception ........................................................................... 20 
5.4 
Subject enrollment and initiation of investigational product. ........................ 21 
5.5 
Visits and Assessments ....................................................................................... 21 
 
Visit Schedule and Assessments ...................................................................... 21 
 
Radiological Evaluations .................................................................................. 22 
5.6 
Treatment compliance ........................................................................................ 23 
 
Accountability .................................................................................................. 23 


Clinical Study Protocol Synopsis 
Drug Substance TAS-102 and oxaliplatin  
Study Code HIC# 1605017852 
Version Number: 6.0 
Date: 20-May-2020 
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5.7 
Procedures for handling subjects incorrectly enrolled or initiated on 
investigational product .................................................................................................. 23 
6. 
TOXICITY MANAGEMENT ...................................................................................... 23 
6.1 
General Toxicity Management Guidelines ....................................................... 23 
 
Dosing Modification in Response to Hematologic Toxicities.......................... 24 
 
Dosing Modification for Oxaliplatin Induced Neurotoxicity. .......................... 26 
 
Management of Oxaliplatin Hypersensitivity Reactions. ................................. 26 
 
Dosing Modifications in Response to Other Non-Hematologic Toxicities ...... 27 
7. 
DISCONTINUATION OF INVESTIGATIONAL PRODUCT................................. 27 
7.1 
Indications for Treatment Discontinuation ...................................................... 27 
7.2 
Procedures for discontinuation of a subject from investigational product ... 28 
7.3 
Withdrawal from study ...................................................................................... 28 
8. 
STUDY EFFICACY ASSESSMENTS ......................................................................... 28 
8.1 
Definition of measurable disease and target lesions ........................................ 28 
 
Measurable disease ........................................................................................... 28 
 
Non-measurable disease ................................................................................... 29 
 
Notes on measurability ..................................................................................... 29 
 
Target lesions .................................................................................................... 29 
 
Non-target lesions ............................................................................................. 30 
8.2 
Methods for Evaluation of Measurable Disease .............................................. 30 
8.3 
Response Criteria ............................................................................................... 30 
 
Evaluation of target lesions .............................................................................. 30 
 
Evaluation of non-target lesions ....................................................................... 31 
 
Evaluation of overall response ......................................................................... 31 
 
Progression free survival .................................................................................. 32 
 
Response rate .................................................................................................... 32 
9. 
STUDY SAFETY ASSESSMENTS .............................................................................. 32 
9.1 
Definitions ........................................................................................................... 32 
 
Adverse events .................................................................................................. 32 
 
Serious adverse event ....................................................................................... 33 
9.2 
Recording of adverse events .............................................................................. 33 
 
Adverse Events based on signs and symptoms ................................................ 33 
 
Adverse Events based on examinations and tests ............................................. 34 
 
Disease progression .......................................................................................... 34 
 
New cancers ...................................................................................................... 34 
 
Lack of efficacy ................................................................................................ 34 
 
Deaths ............................................................................................................... 34 
9.3 
Reporting of serious adverse events .................................................................. 35 
9.4 
Clinical safety assessment .................................................................................. 36 
 
Laboratory safety assessment ........................................................................... 36 
 
Physical examination ........................................................................................ 36 
 
Vital signs ......................................................................................................... 36 
 
ECG .................................................................................................................. 36 
 
Serum or urine pregnancy test .......................................................................... 37 
10. 
ETHICAL AND REGULATORY REQUIREMENTS ............................................ 37 
10.1 
Ethical conduct of the study .............................................................................. 37 


Clinical Study Protocol Synopsis 
Drug Substance TAS-102 and oxaliplatin  
Study Code HIC# 1605017852 
Version Number: 6.0 
Date: 20-May-2020 
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10.2 
Subject data protection ...................................................................................... 37 
10.3 
Ethics and regulatory review ............................................................................. 37 
10.4 
Informed consent ................................................................................................ 37 
10.5 
Changes to the protocol and informed consent form ...................................... 37 
10.6 
Audits and inspections ....................................................................................... 38 
11. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION ............. 39 
11.1 
Description of analysis sets ................................................................................ 39 
11.2 
Methods of statistical analyses .......................................................................... 39 
 
Demographics and Baseline Characteristics................................................. 39 
 
Efficacy Analyses ......................................................................................... 39 
 
Safety Analyses ............................................................................................ 39 
11.3 
Determination of sample size ............................................................................. 40 
11.4 
Data safety and monitoring plan ....................................................................... 40 
11.5 
Important medical procedures to be followed by the investigator ................ 40 
 
Pregnancy ..................................................................................................... 40 
 
Maternal exposure ........................................................................................ 40 
12. 
LIST OF REFERENCES ............................................................................................ 41 
13. 
APPENDIX ................................................................................................................... 42 
 
LIST OF APPENDICES 
Appendix A: ECOG Performance Status 


Clinical Study Protocol Synopsis 
Drug Substance TAS-102 and oxaliplatin  
Study Code HIC# 1605017852 
Version Number: 6.0 
Date: 20-May-2020 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation or 
special term 
Explanation 
AE 
ALT 
ANC 
AST 
DLT 
C 
CBC 
CMP 
CNS 
CR 
CRC 
CT 
CTCAE 
ECG 
ECOG 
ED 
EGFR 
EOT 
F 
FDA 
FTD 
GGT 
HR 
IC 
ICF 
ILD 
INR 
IV 
Kg 
LFT 
M 
MCV 
mCRC 
Mg 
MTD 
NCI 
Adverse event 
Alanine aminotransferase 
Absolute neutrophil count 
Aspartate aminotransferase 
Dose limiting toxicity 
Celsius 
Complete blood count 
Complete metabolic panel 
Central nervous system 
Complete response 
Colorectal cancer 
Computed tomography 
Common Terminology Criteria for Adverse Events 
Electrocardiogram 
Eastern Cooperative Oncology Group 
Effective dose 
Epidermal Growth Factor Receptor 
End of treatment 
Fahrenheit 
Food and Drug Administration 
Trifluorothymidine 
Gamma glutamyltransferase 
Hazard ratio 
Inhibitory concentration 
Informed consent form 
Interstitial lung disease 
International normalized ratio 
Intravenous 
Kilogram 
Liver function tests 
Molar 
Mean corpuscular volume 
Metastatic colorectal cancer 
Milligram 
Maximum tolerated dose 
National Cancer Institute 


Clinical Study Protocol Synopsis 
Drug Substance TAS-102 and oxaliplatin  
Study Code HIC# 1605017852 
Version Number: 6.0 
Date: 20-May-2020 
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NGS 
OAE 
PD 
PFS 
PLT 
PR 
PT 
PTT 
QD 
RECIST 
RR 
RTK 
SAD 
SAE 
SD 
TKI 
TP 
TPI 
TS 
ULN 
VEGF 
Next generation sequencing 
Other significant adverse events 
Progressive disease 
Progression free survival 
Platelets 
Partial response 
Prothrombin time 
Partial prothrombin time 
Daily 
Response Evaluation Criteria In Solid Tumor 
Response rate 
Receptor tyrosine kinase 
Short axis diameter 
Serious adverse event 
Stable disease 
Tyrosine kinase inhibitor 
Thymidine phosphorylase 
Tipiracil hydrochloride 
Thymidylate synthase 
Upper limit of normal 
Vascular Endothelial Growth Factor 
 
 
 


Clinical Study Protocol Synopsis 
Drug Substance TAS-102 and oxaliplatin  
Study Code HIC# 1605017852 
Version Number: 6.0 
Date: 20-May-2020 
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EVALUATION SCHEDULE 
Week 
0c 
1 
2 
3 
5 
7 
9 
11 
13 
15 
17+ 
End d 
Cycle 
 
1 
 
2 
3 
4 
5 
6 
7 
8 
9+ 
 
Oxaliplatin, IV 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
TAS-102, PO h 
 
Days 1-5 during each 14-day cycle. 
Informed Consent 
x 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
 
 
 
 
Medical History f 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant Medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Physical exam 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ECOG Performance Status 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Vital signs e 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ECG 
x 
 
 
 
 
 
 
 
 
 
 
 
Blood work a 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Serum CEA g 
 
x 
 
 
x 
 
x 
 
x 
 
x 
 
AE Evaluation 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Radiologic Evaluation b 
x 
 
 
 
 
 
x 
 
 
 
x 
 
ALL VISITS AND EVENTS WILL BE ALLOWED WITHIN + 48 HOUR WINDOW 
 
a. Complete blood count with differential, albumin, alkaline phosphatase, total bilirubin, bicarbonate, urea or 
BUN, calcium, chloride, creatinine, glucose, potassium, total protein, AST, ALT, sodium, magnesium.  
Coagulation tests including PTT and INR at screening; may be repeated if clinically indicated at subsequent 
visits.  Serum or urine pregnancy test (women of childbearing potential) will be obtained at the time of screening.   
b. CT chest/abdomen/pelvis or PET/CT will be done. Radiological evaluations will be performed every 8 weeks 
or more frequently if clinically indicated. Restaging scans may be spaced out to every 12 weeks after the first 2 
scans on treatment at the discretion of the treating physician.   
c. Within 14 days of treatment initiation. CT c/a/p scans will be done within 28 days of treatment. Informed 
consent can be obtained within 28 days of treatment initiation. 
d. Treatment will be continued until disease progression or intolerable toxicities. End of treatment visit will occur 
within 28 days after last dose of TAS-102 or prior to their next anti-cancer therapy, whichever happens first.  
e Vital signs will include measurement of weight, blood pressure, heart rate, temperature, and oxygen saturation.  
Height will be measured at the time of study enrollment only. 
f Includes medical, surgical and prior cancer treatment history. 
g CEA will be checked every 4 weeks (with every other cycle), including on day 1 of cycle 1. 
h TAS-102 pills are distributed by local pharmacy per Standard of Care (SOC) on Day 1 of each cycle. Subject 
pill diaries should be completed each cycle. 


Clinical Study Protocol Synopsis 
Drug Substance TAS-102 and oxaliplatin  
Study Code HIC# 1605017852 
Version Number: 6.0 
Date: 20-May-2020 
10(42) 
1. 
INTRODUCTION 
1.1 
Colon Cancer 
Colon cancer is the third most common cancer in the United States, and it accounts for 
approximately 9 % of all cancer deaths 1.  More than 100,000 new colon cancer cases were 
expected to be diagnosed in 2014, with about 20% of these cases having metastatic disease at 
presentation 1,2.  Unfortunately, only a small number of patients with stage IV disease can be 
cured with multimodality therapy.  Hence, systemic medical therapy is essential in 
management of these patients.  Over the last two decades a number of available systemic 
treatments for colon cancer have increased significantly.  They have improved both quality of 
life and overall survival, which now exceeds 2 years for stage IV disease 3.  These treatments 
include conventional chemotherapy agents (fluoropyrimidines, oxaliplatin, and irinotecan), 
angiogenesis inhibitors (bevacizumab and aflibercept), multitarget oral tyrosine kinase 
inhibitor (regorafenib), and anti-EGFR antibodies (cetuximab and panitumumab).  The 
optimal sequence for the use of the available drugs is not clear.  It is the exposure to all of the 
active agents that seems to be more important than the order of administration.  Hence, the 
more lines of therapy we can offer to patients, the more benefit patients can derive in terms of 
their survival and quality of life.  Development of alternative/novel treatment options are 
essential for our ability to treat this disease more effectively. 
1.2 
TAS-102  
 
Mechanism of Action 
TAS-102 is a novel functional antitumor nucleoside.  It is a combined form of 1 M trifluridine 
(FTD; α,α,α-trifluorothymidine) and 0.5 M tipiracil hydrochloride (TPI).  FTD is an 
antineoplastic antimetabolite 4.  It has at two different mechanism of actions.  It inhibits 
thymidylate synthase (TS), and is also incorporated into DNA 4,5.  The latter mechanism is 
different from the primary cytotoxic mechanism of 5-fluorouracil (5-FU).  When FTD is taken 
orally it is largely degraded to an inactive form by thymidine phosphorylase (TP).  This 
enzyme is present in gastrointestinal tract, liver, and tumor tissue.  TPI effectively inhibits TP, 
and co-administration of TPI with FTD prevents the rapid degradation of FTD in the body.  
TP has also been shown to play a role in promoting angiogenesis 6.  Hence, TAS-102 may 
exhibit some of its effects via the potential anti-angiogenic properties of TPI.   
 
Clinical Experience with TAS-102  
The safety and efficacy of TAS-102 have been studied in phase 1, 2 and 3 studies, with have 
been conducted in Japanese and Western populations.  These studies established proof of 
concept, appropriate dosing, and preliminary safety data for TAS-102.  As of 24 July 2014, 
1449 subjects participated in Taiho sponsored TAS-102 trials globally.  Details regarding the 
early phase studies are included in the Investigator’s Brochure for TAS-102. 
The efficacy and safety of TAS-102 in the treatment of mCRC subjects have been studied in 
a Phase 2 trial conducted in Japan and in a global Phase 3 trial (RECOURSE) conducted in 
the US, Europe, Australia and Japan.  In a randomized double-blind Japanese phase 2 trial 
169 subjects with metastatic chemorefractory CRC were randomized in a 2:1 fashion to 


Clinical Study Protocol Synopsis 
Drug Substance TAS-102 and oxaliplatin  
Study Code HIC# 1605017852 
Version Number: 6.0 
Date: 20-May-2020 
11(42) 
either TAS-102 or placebo 7.  In this trial, subjects in the TAS-102 group had significantly 
longer overall survival (OS) when compared to the placebo group (median OS 9.0 vs. 6.6 
months; HR 0.56; p=0.0011).  Subsequent international randomized phase III study 
(RECOURSE trial) was conducted in 13 countries.  Eight hundred patients with advanced 
refractory mCRC were randomized 2:1 to TAS-102 or placebo.  The results of this trial 
confirmed TAS-102 associated benefit on overall survival observed in the phase 2 Japanese 
trial.  Median OS in the TAS-102 group was 7.1 months versus 5.3 months in the placebo 
group (HR 0.68; p<0.0001) 7. In both of these studies, TAS-102 was well tolerated.  
Gastrointestinal and hematological toxicities were the most frequently observed toxicities.  
 
The adverse events presented below include adverse events reported from previous trial 
participants.  For subjects in the ongoing trials, no new serious adverse events in addition to 
those listed below have been reported.  However, the side effects shown below are not a 
complete.  Rare events of a non-severe nature are not listed, buy rare events of a severe 
nature are included below.  In addition, the list includes events that may or may not have 
been related to TAS-102 use.   
 
c. Likely, occurring in > 20% of participants (all grades): 
• GI: Nausea, vomiting, diarrhea 
• Blood: Leucopenia, neutropenia, anemia 
• General: Fatigue, asthenia, malaise 
• Metabolism: Decreased/loss of appetite, anorexia 
• Infection: Infections e.g. blood, lung, pelvis, eye, urinary tract, intestinal tract, skin, 
liver/biliary tract 
b. Common, occurring in 3 -20% of participants (all grades): 
• GI: Stomatitis, constipation, abdominal pain, indigestion 
• Blood: Thrombocytopenia 
• Skin: Alopecia, rash (changes in the color or texture of the skin, possible blistering 
and peeling) 
• Renal: Proteinuria 
• Nervous: Dysgeusia, headache 
• Musculoskeletal: Back pain, arthralgia 
• General: Pyrexia, asthenia 
• Metabolism: Hypoalbuminemia,  
• Psych: Anxiety 
• Hepatobiliary: Elevated liver enzymes, e.g. AST, ALT, bilirubin 
 
c. Rare but severe, occurring in < 3% of participants (grade 3 and above): 
• Cardiac: Myocardial infarction, myocardial ischemia, chest pain, bradycardia, 
tachycardia 
• Hepatobiliary: Hepatic failure, jaundice 
• Renal: Acute renal failure, hematuria 
• Nervous: Effects on cognitive or nerve function, seizure, decreased level of 
consciousness, thromboembolism 


Clinical Study Protocol Synopsis 
Drug Substance TAS-102 and oxaliplatin  
Study Code HIC# 1605017852 
Version Number: 6.0 
Date: 20-May-2020 
12(42) 
• GI: Colitis, intestinal fistula, small or large bowel obstruction, ascites, hemorrhage, 
intestinal ulcer 
• Respiratory: Pulmonary emboli, dyspnea, respiratory arrest, pneumonitis, epistaxis 
• Metabolism: Gout, dehydration 
• Vascular: Fainting, DVT, hypotension, blood clotting disorder, hot flushes, septic 
shock 
• Nervous: Dizziness, paresthesia 
• Musculoskeletal: Myalgia 
• General: Flu like symptoms 
 
Rationale for Combining TAS-102 and Oxaliplatin. 
Oxaliplatin is a third-generation platinum compound, which is active when used in 
combination with fluoropyrimidines in the treatment of mCRC.  FOLFOX chemotherapy, 
which includes bolus and infusion 5-FU, leucovorin and oxaliplatin, is widely accepted as the 
preferred first-line chemotherapy backbone in the treatment of mCRC in the US.  Oxaliplatin 
is also frequently reintroduced in more advanced settings.  Reintroduction is seen after 
progression on maintenance therapy, after resolution of previous treatment limiting 
neuropathy, after disease recurrence post adjuvant treatment or post metastatectomy.  
Although patients derive clinical benefit when oxaliplatin is reintroduced, the response rates 
are not as robust as during initial exposures.  Decreased efficacy may be at least in part due to 
prolonged exposure and resultant resistance to 5-FU, which is part of the maintenance and 
oxaliplatin and irinotecan containing treatment regimens.  
 
In this trial, we propose exploring the safety and efficacy of oxaliplatin in combination with 
an alternative anti-metabolite, TAS-102 (TAS-OX) in chemorefractory mCRC patients.  
FTD, an active antimetabolite in TAS-102, has mechanisms of cytotoxicity, which differs 
from 5-FU, as described above. Hence, the mechanisms underlying 5-FU resistance may not 
apply to TAS-102.  This is probably why TAS-102 was clinically effective for the 5-FU 
refractory patients in the previous studies 7,8.  In preclinical studies, synergism has been 
observed when oxaliplatin was combined with FTD 9.  We hypothesize that the combination 
of TAS-102 with oxaliplatin will serve as a novel clinically relevant treatment strategy for a 
patient population with limited effective treatment options. If successful, this drug 
combination can be studied further in earlier settings and in combination with biologics.  
 
1.3 
Benefit/risk and ethical assessment 
Based on current clinical experience with TAS-102, this drug is well tolerated when used as a 
single agent.  We suggest combining TAS-102 with oxaliplatin as a treatment for patients with 
chemotherapy refractory mCRC.  Patients who have previously been treated with at least 2 
lines of therapy that included 5-FU, oxaliplatin and irinotecan will be invited for participation 
in this trial.  Although increased toxicities may be seen when the two drugs are combined, we 
anticipate that this drug combination will be tolerable and will provide additional efficacy in a 
patient population with limited treatment options.  If this study has promising results, future 
trials may also explore the use of this drug combination in earlier lines of therapy and in 
combination with biologics. 


Clinical Study Protocol Synopsis 
Drug Substance TAS-102 and oxaliplatin  
Study Code HIC# 1605017852 
Version Number: 6.0 
Date: 20-May-2020 
13(42) 
2. 
STUDY OBJECTIVES/ENDPOINTS 
2.1 
Part 1 
The main objective of part 1 of the trial is determination of MTD and Recommended Phase 2 
Dose (RP2D) to be used in the expansion cohort in part 2.  
2.2 
Part 2 
Part 2 will evaluate the efficacy of the proposed drug combination in refractory mCRC and 
further evaluate its safety and tolerability.  
Primary Endpoint: 
• Overall Response Rate 
 
Secondary Endpoints: 
• Progression Free Survival 
• Overall Survival 
• Disease Control Rate 
• Duration of Response 
• Safety and Tolerability 
3. 
STUDY PLAN AND PROCEDURES 
3.1 
Overall study design 
The study is 2-part phase 1B trial conducted in one center.  The study will consist of three 
study periods: a screening period of 14 days or less, a treatment period, and a safety follow-up 
period of 28 days after treatment discontinuation. 
Part 1 is a dose finding phase with the objective to assess the safety and tolerability of the 
proposed drug combination and to identify the tolerated dose and a recommended Part 2 dose.  
Part 1 will enroll an estimated 3-18 subjects depending on the tolerability of the regimen.  The 
second part of the trial will be an open-label expansion study, which will include patients with 
metastatic chemorefractory CRC who have progressed on at least 2 lines of therapy that 
included 5-FU, oxaliplatin and irinotecan.  Part 2 will obtain further safety data of the 
proposed drug combination and will evaluate the anti-tumor efficacy and tolerability of TAS-
102 and oxaliplatin in this patient population.  Part 2 of the trial will enroll up to 50 subjects.  
In both parts, treatment will continue until radiological evidence of disease progression or 
development of unacceptable toxicities.    
3.2 
Part 1 study design 
Treatments will be started at level 1 doses (Table 1), which are based on prior clinical 
experience with the medications studied.  Dose escalation will follow a traditional “3+3” 


Clinical Study Protocol Synopsis 
Drug Substance TAS-102 and oxaliplatin  
Study Code HIC# 1605017852 
Version Number: 6.0 
Date: 20-May-2020 
14(42) 
design.  Treatments will continue until disease progression according to RECIST 1.1 criteria 
or development of unacceptable toxicities. 
 
3 + 3 Design: 
• A minimum of 3 subjects will be enrolled per dose level. 
• If none of the first 3 DLT-evaluable subjects experience a DLT, dose escalation may 
proceed to the next dose level. 
• If 1 of the first 3 DLT-evaluable subjects in a cohort experiences a DLT, additional 
subjects (up to a total of 6) will be enrolled in that cohort. 
• If fewer than one-third of DLT-evaluable subjects in a cohort experience DLTs (e.g., 
DLTs in fewer than 1 of 3 or 2 of 6 subjects), dose escalation may proceed. 
• If one-third or more of DLT-evaluable subjects (e.g., 2 or more of up to 6 DLT-
evaluable subjects) in a cohort experience DLTs, the MTD will have been exceeded 
and dose escalation will cease. Up to 6 DLT-evaluable subjects will be evaluated for 
DLT at the preceding dose level. 
• The highest dose level at which fewer than 2 of 6 DLT-evaluable subjects experience 
DLTs will be declared the MTD. 
• All dose reductions will be permanent. 
 
Treatment Regimen 
 
Each treatment cycle will be 14 days long.  Oxaliplatin infusion will be given on day 1 of each 
cycle.  TAS-102 will be taken twice daily on days 1-5 of each cycle.  All subjects will be 
started at dose level 1.  Doses will be escalated or de-escalated as outlined in Table 1. 
 
Table 1.  
DOSE LEVEL 
TAS-102 (mg/m2) BID,  
Days 1-5  
OXALIPLATIN (mg/m2) IV,  
Day 1 
1 
25 
85 
2 
30 
85 
3 
35 
85 
-1 
25 
65 
-2 
20 
65 
  
 
Dose-Limiting Toxicity Determination and Maximum Tolerated Dose 
Definition  
Dose-limiting toxicity (DLT) is defined as an adverse event (AE) during Cycle 1 that is 
possibly related to the study drug(s), is clinically significant and/or unacceptable and is judged 
to be a DLT by the investigator and fulfills any one of the following criterion using the 
National Cancer Institute’s (NCI) Common Terminology Criteria for Adverse Events 


Clinical Study Protocol Synopsis 
Drug Substance TAS-102 and oxaliplatin  
Study Code HIC# 1605017852 
Version Number: 6.0 
Date: 20-May-2020 
15(42) 
(CTCAE) v 4.0.  Each subject can be dose reduced a total of 2 times. All dose reductions are 
permanent. 
Definition of DLTs: 
• Grade 4 neutropenia with ANC < 500/mm3 lasting longer than 3 days. 
• Grade ≥ 3 febrile neutropenia with ANC < 1000/mm3 and temperature > 100.8° F. 
• Platelets <25,000/mm3.  
• Grade 4 treatment related non-hematologic toxicities excluding alopecia and 
neuropathy.   
• Delay of treatment for > 2 weeks due to toxicity. 
3.3 
Part 2 study design 
The subjects in part 2 will be treated with the drug doses determined in Part 1 of the trial.  The 
dose below the MTD that allows treatment every 14 days most consistently, without further 
dose delays, will be the Recommended Phase 2 dose.  Treatments will continue until disease 
progression according to RECIST 1.1 criteria or development of unacceptable toxicities. 
3.4 
Rationale for study design and doses 
The study will consist of two parts.  First part is a dose finding part since there is no prior 
experience with the concomitant use of TAS-102 and oxaliplatin.  Initial doses of the 
medications are selected based on past clinical experience.  Oxaliplatin is typically given as 
part of FOLFOX regimen at a dose of 85 mg/m2.  Since this is an approved dose for this 
combination, dose level 1 will start at this level for oxaliplatin.  Oxaliplatin dose may be 
deescalated as outlined in Table 1 depending on the development of DLTs.  In the 
RECOURSE trial, TAS-102 was used at the dose of 35 mg/m2 BID on days 1-5 and 8-12 every 4 
weeks. Because of concern for overlapping bone marrow toxicities between the two medications, 
TAS-102 will be started at 25 mg/m2 and escalated to goal dose level of 35 mg/m2 if no excess 
DLTs are observed during the dose escalation “3+3” phase of the study.  Each cycle will be 14 
days long. Oxaliplatin will be administered on day 1 of each cycle and TAS-102 will be taken on 
days 1-5 of each cycle, resulting in the same number of days on treatment per 4-week period as 
was done in the RECOURSE trial.  In the Part 2 of the study expansion cohort of subjects with 
refractory mCRC will be treated with the doses established in part 1.  
3.5 
Study population 
This study will specifically focus on patients with mCRC who have progressed on standard 
therapy including at least 5-FU, irinotecan and oxaliplatin, bevacizumab (unless 
contraindicated) and an anti-EGFR antibody, if RAS wild type.  


Clinical Study Protocol Synopsis 
Drug Substance TAS-102 and oxaliplatin  
Study Code HIC# 1605017852 
Version Number: 6.0 
Date: 20-May-2020 
16(42) 
4. 
PATIENT SELECTION CRITERIA 
4.1 
Inclusion criteria. 
1. Histologically confirmed stage IV colon cancer (AJCC 7th edition) that has progressed 
after standard therapy that included 5-FU, irinotecan and oxaliplatin. Patients who 
could not tolerate standard agents because of unacceptable, but reversible, toxicity 
necessitating their discontinuation will be allowed to participate.   
2. Patients who had received adjuvant chemotherapy and had recurrence during or 
within 6 months of completion of the adjuvant chemotherapy will be allowed to count 
the adjuvant therapy as one chemotherapy regimen.  
3. Progression of disease must be documented on the most recent scan. 
4. Presence of measurable disease (not required for Phase 1 portion of the trial). 
5. RAS mutation and MMR status must be determined (or tissue availability for testing 
if not already determined) 
6. Age 18 years or older. 
7. ECOG performance status 0-1. 
8. Life expectancy of at least 3 months. 
9. Patient with adequate organ function: 
a. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L 
b. Hemoglobin ≥ 9 g/dL  
c. Platelets (PLT) ≥ 75 x 109/L 
d. AST/ALT ≤ 5 x ULN  
e. Total serum bilirubin of ≤1.5 mg/dL (except for Grade 1 hyperbilirubinemia 
due solely to a medical diagnosis of Gilbert’s syndrome). 
f. Albumin ≥ 2.5 g/dL 
g. Serum creatinine ≤ 1.5 x institutional ULN (Cockcroft and Gault formula) 
10. Adequate contraception if applicable. 
11. Women who are nursing must discontinue nursing prior to enrollment in the program. 
12. Ability to take oral medication (i.e. no feeding tube). 
13. Patient able and willing to comply with study procedures as per protocol. 
14. Patient able to understand and willing to sign and date the written voluntary informed 
consent form (ICF) at screening visit prior to any protocol-specific procedures. 
4.2 
Exclusion criteria. 
1. Patients who have previously received TAS-102. 
2. Grade 2 or higher peripheral neuropathy.  


Clinical Study Protocol Synopsis 
Drug Substance TAS-102 and oxaliplatin  
Study Code HIC# 1605017852 
Version Number: 6.0 
Date: 20-May-2020 
17(42) 
3. Symptomatic CNS metastases requiring treatment. 
4. Other active malignancy within the last 3 years (except for non-melanoma skin cancer 
or a non-invasive/in situ cancer). 
5. Pregnancy or breast feeding.  
6. Current therapy with other investigational agents. 
7. Active infection with body temperature ≥38°C due to infection. 
8. Major surgery within prior 4 weeks (the surgical incision should be fully healed prior 
to drug administration). 
9. Any anticancer therapy within prior 3 weeks of first dose of study drug. 
10. History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to TAS-102. 
11. Current therapy with other investigational agents or participation in another clinical 
study or any investigational agent received within prior 4 weeks. 
12. Grade 3 or higher hypersensitivity reaction to oxaliplatin, or grade 1-2 hypersensitivity 
reaction to oxaliplatin not controlled with pre-medication. 
13. Has unresolved toxicity of greater than or equal to Common Terminology Criteria for 
Adverse Events (CTCAE) Grade 2 attributed to any prior therapies (excluding anemia, 
alopecia, skin pigmentation, and platinum-induced neurotoxicity). 
14. Extended field radiation within prior 4 weeks of first dose of study drug or limited 
field radiation within prior 2 weeks of first dose of study drug. 
15. Psychological, familial, or sociological condition potentially hampering compliance 
with the study protocol and follow-up schedule. 
16. Involvement in the planning and/or conduct of the study. 
17. Previous enrollment in the present study. 
5. 
STUDY CONDUCT 
5.1 
Treatments 
 
TAS-102 
5.1.1.1 
Dosing of TAS-102  
On Day 1-5 of each cycle TAS-102 (35 mg/m2/dose or MTD) will be taken orally 2 times 
daily (between 8 and 12 hours) with the first dose administered in the morning of Day 1 of 
each cycle and the last dose administered in the evening of Day 5 of each cycle.  TAS-102 
should only be given on Days 1 through 5 of each cycle even if doses are missed or held for 
any reason, extension of TAS-102 treatment into Days 6 -14 is not permitted.   
 


Clinical Study Protocol Synopsis 
Drug Substance TAS-102 and oxaliplatin  
Study Code HIC# 1605017852 
Version Number: 6.0 
Date: 20-May-2020 
18(42) 
The study medication tablet calculation is presented in Table 2, which shows the number of 
tablets that are needed according to a dose prescribed per calculated BSA.  If at the beginning 
of a treatment cycle, a subject’s body weight has decreased by ≥10% from baseline, the 
subject’s body surface area (BSA) must be recalculated and the study medication dosage 
adjusted. 
 
Table 2.  
NUMBER OF TAS-102 TABLETS PER DOSE* 
TAS-102 Dose 
(2x daily) 
BSAa (m2) a 
Dosage in mg 
(2x daily) 
Total daily 
dose (mg) 
Tablets per dose 
15 mg 
20 mg 
35 mg/m2 
< 1.07 
35 
70 
1 
1 
1.07 - 1.22 
40 
80 
0 
2 
1.23 - 1.37 
45 
90 
3 
0 
1.38 - 1.52 
50 
100 
2 
1 
1.53 - 1.68 
55 
110 
1 
2 
1.69 - 1.83 
60 
120 
0 
3 
1.84 - 1.98 
65 
130 
3 
1 
1.99 - 2.14 
70 
140 
2 
2 
2.15 - 2.29 
75 
150 
1 
3 
≥2.30 
80 
160 
0 
4 
30 mg/m2 
< 1.09 
30 
60 
2 
0 
1.09 - 1.24 
35 
70 
1 
1 
1.25 - 1.39 
40 
80 
0 
2 
1.40 - 1.54 
45 
90 
3 
0 
1.55 - 1.69 
50 
100 
2 
1 
1.70 - 1.94 
55 
110 
1 
2 
1.95 - 2.09 
60 
120 
0 
3 
2.10 - 2.28 
65 
130 
3 
1 
≥ 2.29 
70 
140 
2 
2 
25 mg/m2 
< 1.10 
25
b 
50
b 
2 (PM)
b 
1 (AM)
b 
1.10 - 1.29 
30 
60 
2 
0 
1.30 - 1.49 
35 
70 
1 
1 
1.50 - 1.69 
40 
80 
0 
2 
1.70 - 1.89 
45 
90 
3 
0 
1.90 - 2.09 
50 
100 
2 
1 
2.10 - 2.29 
55 
110 
1 
2 
≥ 2.30 
60 
120 
0 
3 
20 mg/m2 
< 1.14 
20 
40 
0 
1 
1.14 – 1.34 
25
b 
50
c 
2 (PM)
b 
1 (AM)
b 
1.35 – 1.59 
30 
60 
2 
0 
1.60 – 1.94 
35 
70 
1 
1 
1.95 – 2.09 
40 
80 
0 
2 
2.10 – 2.34 
45 
90 
3 
0 
≥ 2.35 
50 
100 
2 
1 
a Calculate BSA to 2 decimal places. 
b At a total daily dose of 50 mg, subjects should take 1 x 20 mg tablet in the morning and 2 x 15 mg tablets in the 
evening.  
* Tablets per dose may be provided in different combinations based on availability to attain the same dosage in mg and total 
daily dose 
 


Clinical Study Protocol Synopsis 
Drug Substance TAS-102 and oxaliplatin  
Study Code HIC# 1605017852 
Version Number: 6.0 
Date: 20-May-2020 
19(42) 
5.1.1.2 
Formulation of TAS-102 
TAS-102 is formulated as an immediate-release film-coated tablet, which is supplied in 2 
strengths (expressed as FTD content):  
• The 15-mg white, round tablet contains 15 mg FTD and 7.065 mg TPI as active 
ingredients.  
• The 20-mg pale-red, round tablet contains 20 mg FTD and 9.42 mg TPI as active 
ingredients.  
Both tablet strengths contain lactose monohydrate, pregelatinized starch, stearic acid, 
hypromellose, titanium dioxide, polyethylene glycol, and magnesium stearate. The 20-mg 
tablet also contains red ferric oxide.  
5.1.1.3 
Packaging and Storage  
TAS-102 15 and 20 mg tablets are commercially available and will be provided by the 
subject’s pharmacy.  
 
5.1.1.4 
Food Intake 
Subjects should take TAS-102 with a glass of water within 1 hour after completion of their 
morning and evening meals. 
 
Oxaliplatin 
Oxaliplatin will be given as a chemo infusion in 250 ml of 5% dextrose solution over 2 hours 
on day 1 of each cycle.  The starting dose of oxaliplatin will be determined in part 1 of the 
protocol and will be adjusted as needed based on toxicities observed in expansion cohort.  
Oxaliplatin dosing will be based on the subject’s baseline weight measurement. Weight will 
be measured on Day 1 of each 2-week treatment cycle. If there is a more than 10% change 
from the subject’s baseline weight measurement, the chemotherapy dose should be 
recalculated using the new weight.   
Supportive medications (e.g., anti-emetics, hydration, antihistamines, corticosteroids) will be 
administered according to institutional standards and the product package insert. 
5.2 
Concomitant and post-study treatment(s) 
Concomitant therapy includes any prescription medications or over-the-counter preparations 
used by a subject from ≤ 7 days prior to the first dose of study drug to the end of treatment 
visit.  All concomitant therapy, including anesthetic agents, vitamins, homeopathic/herbal 
remedies, nutritional supplements, must be recorded during the screening and treatment 
period, starting from the date of signature of informed consent, and ending at the End of 
Treatment (EOT) visit. After the EOT visit, only concomitant therapy indicated for treatment 
of an AE has to be reported. 


Clinical Study Protocol Synopsis 
Drug Substance TAS-102 and oxaliplatin  
Study Code HIC# 1605017852 
Version Number: 6.0 
Date: 20-May-2020 
20(42) 
5.3 
Restrictions during the study 
 
Administration of other anti-cancer agents 
Subjects must not receive any other concurrent anti-cancer therapy, including investigational 
agents, while on study treatment, with the exception of bevacizumab with the permission of 
the PI, if the treating physician feels this is important for the subject’s welfare.  All standard 
dosing, management and precautions should be observed. Subjects may continue the use of 
bisphosphonates for bone disease and corticosteroids for the symptomatic control of brain 
metastases provided the dose is stable before and during the study and they were started at 
least 4 weeks prior to beginning study treatment.  Full details of all of these treatments are 
recorded in the subject’s notes and appropriate section of the eCRF. 
 
Other concomitant treatment 
• The subject can receive a stable dose of corticosteroids during the study as long as 
these were started at least 4 weeks prior to treatment.   
• Live virus and bacterial vaccines should not be administered whilst the subject is 
receiving study medication and during the 28-day follow up period.   
• Caution is required when using drugs that are human thymidine kinase substrates, e.g., 
stavudine, zidovudine, telbivudine. Such drugs, if used concomitantly with TAS-102, 
may theoretically compete with the effector of TAS-102, i.e., FTD, for activation via 
thymidine kinases. Therefore, when using antiviral drugs that are human thymidine 
kinase substrates, monitor for possible decreased efficacy of the antiviral agent, and 
consider switching to an alternative antiviral agent that is not a human thymidine 
kinase substrate such as lamivudine, zalcitabine, didanosine, abacavir, etc. 
• Administration of hematologic support (e.g., blood transfusions, granulocyte colony-
stimulating factor [G-CSF], erythropoietin) is allowed as medically indicated 
according to the institutional site standards.    
 
Pregnancy and Contraception 
All subjects must be made fully aware of the information relating to the potential for 
reproductive toxicity as detailed in the Informed Consent Form.  Subjects of child bearing 
potential and their partners, who are sexually active, must agree to the use of two highly 
effective forms of contraception throughout their participation in the study and for 4 weeks 
after last dose of study drug(s). 
Women of childbearing potential 
Females of childbearing potential should use reliable methods of contraception from the time 
of screening until 4 weeks after discontinuing study treatment. Acceptable methods of 
contraception include abstinence, tubal ligation, combined oral, transdermal or intra-vaginal 
hormonal contraceptives, medroxyprogesterone injections (e.g., Depo-provera), copper-
banded intra-uterine devices, hormone impregnated intra-uterine systems and vasectomised 


Clinical Study Protocol Synopsis 
Drug Substance TAS-102 and oxaliplatin  
Study Code HIC# 1605017852 
Version Number: 6.0 
Date: 20-May-2020 
21(42) 
partners. All methods of contraception (with the exception of total abstinence) should be used 
in combination with the use of a condom by their male sexual partner for intercourse. 
 
Males 
Male subjects must use a condom during sexual intercourse with all sexual partners including 
a pregnant female partner during the study and for 4 weeks after discontinuing study 
treatment. However, where a sexual partner of a male participant is a woman of childbearing 
potential who is not using effective contraception, men must use a condom during sexual 
intercourse during the study and for 6 months after discontinuing study treatment. Male 
subjects should avoid procreation during the trial and for 6 months after discontinuing study 
treatment. 
5.4 
Subject enrollment and initiation of investigational product. 
Patients who are eligible for the study will be enrolled in the clinical trial after they provide 
informed consent for study participation.  There will be no randomization in this trial.  There 
will be identical enrollment criteria for Part 1 and Part 2 of the study.  This is an open label 
trial.  Subjects will continue to receive study treatment until disease progression or 
development of intolerable toxicities.  
5.5 
Visits and Assessments 
 
Visit Schedule and Assessments  
Week 0 – Screening Visit (within 14 days of treatment initiation) 
The following assessments and investigations will be conducted during the visit on Week 0: 
• 
Review eligibility criteria 
• 
Demographic data  
• 
Review cancer history 
• 
Review past medical history and surgical history  
• 
Vital Signs (weight, height, blood pressure, heart rate, temperature, oxygen 
saturation) 
• 
ECOG performance status determination (Appendix 1) 
• 
Complete physical examination 
• 
Medication reconciliation 
• 
Blood work (complete blood count (CBC), liver function tests (LFT), complete 
metabolic panel (CMP), magnesium). INR and PTT.  See Evaluation Schedule for 
additional information.  
• 
Pregnancy test for female subjects of childbearing potential 
• 
Obtain informed consent for trial enrollment  
 
Weeks 1, 3, 5, 7, 9, etc. – Cycles 1, 2, 3, 4, 5, etc. 
• 
Vital Signs (weight, blood pressure, heart rate, temperature, oxygen saturation) 


Clinical Study Protocol Synopsis 
Drug Substance TAS-102 and oxaliplatin  
Study Code HIC# 1605017852 
Version Number: 6.0 
Date: 20-May-2020 
22(42) 
• 
Medication reconciliation 
• 
ECOG performance status determination 
• 
Complete physical examination 
• 
Review occurrence or change of existing conditions 
• 
Review adverse events that have occurred since the previous visit (starting with 
week 2) 
• 
Document details of any new AEs and obtain any new information about AEs 
ongoing at the last visit 
• 
Lab work (CBC, CMP, LFT. Magnesium) 
• 
CEA will be checked every 4 weeks (with every other cycle), including on day 1 of 
cycle 1. 
• 
TAS-102 pills provided by local pharmacy per standard of care (SOC) 
• 
Oxaliplatin administration  
 
Week 2: Toxicity assessment during cycle 1 
• 
Vital Signs (weight, blood pressure, heart rate, temperature, oxygen saturation) 
• 
Medication reconciliation 
• 
ECOG performance status determination 
• 
Complete physical examination 
• 
Review occurrence or change of existing conditions 
• 
Review adverse events that have occurred since the previous visit  
• 
Document details of any new AEs and obtain any new information about AEs 
ongoing at the last visit 
• 
Lab work (CBC, CMP, LFT, Magnesium) 
 
End of Treatment: Within 28 days of last dose of TAS-102 or prior to their next anti-
cancer therapy, whichever happens first 
• 
Vital Signs (weight, blood pressure, heart rate, temperature, oxygen saturation) 
• 
Medication reconciliation 
• 
ECOG performance status determination 
• 
Complete physical examination 
• 
Review occurrence or change of existing conditions 
• 
Review adverse events that have occurred since the previous visit  
 
 
Radiological Evaluations 
Subjects will be required to have a restaging scan (CT chest/abdomen/pelvis or PET/CT) 
within 28 days of treatment initiation.  Restaging scans will be obtained every 8 weeks during 
the study duration.  Restaging scans may be spaced out to every 12 weeks after the first 2 
scans on treatment at the discretion of the treating physician.  Additional scans may be 
obtained in the event of clinical deterioration or development of new symptoms.  


Clinical Study Protocol Synopsis 
Drug Substance TAS-102 and oxaliplatin  
Study Code HIC# 1605017852 
Version Number: 6.0 
Date: 20-May-2020 
23(42) 
5.6 
Treatment compliance 
The study medication will be given in accordance with the protocol and the instructions of a 
site investigator.  The appropriate number of TAS-102 tablets for 5 days of treatment will be 
provided to subjects to be self-administered at home.  Subjects will be asked to bring the 
remaining trial medication to each visit for a compliance check.  The remaining tablets will be 
counted by the investigator/site staff and recorded at the investigator site.  Discrepancies 
between the number of tablets remaining and the calculated number of tablets the subjects 
should have taken must be documented and explained.  A pill diary will be provided and must 
be completed by the subject for each cycle. 
The investigator can withdraw a subject from the study in the event of serious and persistent 
non-compliance which jeopardizes the subject’s safety or render study results for this subject 
unacceptable.  Subjects who do not attend a minimum of 75% of scheduled study visits, unless 
due to exceptional circumstances, should be evaluated for compliance.  
 
Accountability 
The study drugs are both commercially available.  
 
The study personnel will account for all study medications dispensed and returned. Any drug 
accountability information will be recorded on the CRF.  Any discrepancies must be 
accounted for on the appropriate forms.  
 
5.7 
Procedures for handling subjects incorrectly enrolled or initiated 
on investigational product 
Subjects who are incorrectly enrolled in the study will be withdrawn from study participation. 
If study treatments have been initiated, subjects will discontinue study drug and be monitored 
for development of any toxicity for 28 days following their last dose of study drug. 
 
6. 
TOXICITY MANAGEMENT 
6.1 
General Toxicity Management Guidelines 
Any toxicity observed during the course of the study should be managed by interruption and/ 
or dose reduction of the drug if deemed appropriate by the Investigator.  Repeat dose 
interruptions are allowed as required, for a maximum of 28 days on each occasion.  If 
treatment is held > 28 days due to any reason, subject must be removed from protocol 
treatment. 
A new cycle of treatment may begin when the ANC is ≥ 1,500/mcl, the platelet count is ≥ 
75,000/mcl, and any treatment-related non-hematological toxicity has resolved to ≤ Grade 2.    
If toxicity reoccurs following re-challenge with TAS-102 and oxaliplatin, and if further dose 
interruptions are considered inadequate for management of toxicity, then the subject should be 
considered for dose reduction or must permanently discontinue treatment.  Treatment must be 


Clinical Study Protocol Synopsis 
Drug Substance TAS-102 and oxaliplatin  
Study Code HIC# 1605017852 
Version Number: 6.0 
Date: 20-May-2020 
24(42) 
interrupted after any NCI-CTCAE grade 4 adverse events that are considered to be related to 
treatment administration except myelosuppression which will be managed with dose 
modification. 
 
Dosing Modification in Response to Hematologic Toxicities. 
For all subjects with decreases in neutrophils and/or platelets, the next cycle of study 
treatment should not be started until the resumption criteria are met: ANC ≥ 1,500/mm3, the 
platelet count is ≥ 75,000/mm3.   
For subjects who experience neutropenia or thrombocytopenia, TAS-102 should be dose 
reduced as described in Tables 3 and 3a respectively.  If TAS-102 is already at 20 mg/m2, then 
oxaliplatin should be reduced by 1 dose level (to 65 mg/m2), however the doses should not be 
reduced beyond this.  All dose reductions are permanent.  
Subjects who experience Grade ≥ 3 neutropenia complicated by fever or Grade ≥ 3 
thrombocytopenia complicated by bleeding should be considered for administration of 
hematopoietic growth factors as per standard practices, and should undergo a dose reduction 
as described in Tables 3 and 3a respectively in the next cycle.     
For subjects who experience grade 2 neutropenia uncomplicated by fever and are delayed 
greater than 14 days should be given a growth factor and dose reduced as described in Table 3 
when ANC has recovered to 1,500/mm3. Growth factors should be considered only if a 
subject’s ANC count has not recovered within 14 days of treatment being held.  
If hematological abnormalities do not recover to the appropriate level before the start of the 
next cycle, treatment re-initiation can be delayed until ANC recovery for a maximum of 28 
days.  If treatment is held > 28 days beyond the intended start of the next cycle (6 weeks from 
prior dose) due to any reason, the subject must be removed from protocol treatment. 
 
TABLE 3:  DOSING GUIDELINES FOR NEUTROPENIA 
Neutropenia 
Recovery 
Re-initiation dose 
ANC < 1500/mm3 to > 
500/mm3 without fevers 
Hold until recovered to > 
1,500/mm3 
If delay < 7 days, no dose 
modification required. 
If delay is > 7 days and < 14 days, re-
initiate at -1 dose level of TAS-102. 
If delay is > 14 days, re-initiate at -2 
dose levels of TAS-102.  


Clinical Study Protocol Synopsis 
Drug Substance TAS-102 and oxaliplatin  
Study Code HIC# 1605017852 
Version Number: 6.0 
Date: 20-May-2020 
25(42) 
Neutropenia 
Recovery 
Re-initiation dose 
ANC < 1000/mm3 with 
single temperature of 
101.0 °F or sustained 
temperature of 100.4 °F 
for > 1 hour 
Hold until recovered to > 
1,500/mm3 and fever has 
resolved. 
If delay is < 14 days, re-initiate at -1 
dose level of TAS-102. 
If delay is > 14 days, re-initiate at -2 
dose levels of TAS-102. 
ANC < 500/mm3 
 
 
Hold until recovered to > 
1,500/mm3 
If delay is < 7 days, re-initiate at -1 dose 
level of TAS-102. 
If delay is > 7 days, re-initiate at -2 dose 
levels of TAS-102.  
 
TABLE 3a: DOSING GUIDELINES FOR THROMBOCYTOPENIA 
Thrombocytopenia  
Recovery  
Re-initiation dose  
Platelets <75,000/mm3 to > 
25,000/mm3 without 
bleeding 
Hold until recovered to > 
75,000/mm3 
If delay < 7 days, no dose 
modification required. 
If delay is > 7 days and < 14 
days, re-initiate at -1 dose 
level of TAS-102. 
If delay is > 14 days, re-
initiate at -2 dose levels of 
TAS-102. 
Platelets < 50,000/mm3 to > 
25,000/mm3 with bleeding 
Hold until recovered to > 
75,000/mm3 
If delay is < 14 days, re-
initiate at -1 dose level of 
TAS-102. 
If delay is > 14 days, re-
initiate at -2 dose levels of 
TAS-102. 
Platelets < 25,000/mm3 
Hold until recovered to > 
75,000/mm3 
Re-initiate at -2 dose levels 
of TAS-102.  
 


Clinical Study Protocol Synopsis 
Drug Substance TAS-102 and oxaliplatin  
Study Code HIC# 1605017852 
Version Number: 6.0 
Date: 20-May-2020 
26(42) 
 
Dosing Modification for Oxaliplatin Induced Neurotoxicity. 
For subjects who have persistent grade 2 neurosensory events that do not resolve, oxaliplatin 
should be reduced to 65 mg/m2 or next dose level.  Oxaliplatin should be discontinued if there 
are persistent Grade 3 neurosensory events. 
 
 Management of Oxaliplatin Hypersensitivity Reactions.  
In each case of hypersensitivity reaction, the treating investigator should institute treatment 
measures according to the best available medical practice.  Based on previous experience with 
oxaliplatin hypersensitivity reactions, the following treatment guidelines may be applicable. 
 
 
Toxicity Grade 
Oxaliplatin Modification 
1 
Decrease oxaliplatin infusion rate by 50% and monitor closely for any 
worsening symptoms. 
2 
Stop oxaliplatin infusion. Administer bronchodilators, oxygen, anti-
histamines and H1 blocker, etc. as medically indicated.  Resume 
infusion at 50% of previous rate after allergic/hypersensitivity reaction 
has resolved or decreased to Grade 1 in severity. Monitor closely for 
any worsening symptoms.  Institute premedication regimen prior to the 
next cycle.a 
3 or 4 
Stop oxaliplatin infusion immediately and disconnect infusion tubing 
from subject. Administer epinephrine, bronchodilators, antihistamines, 
glucocorticoids, intravenous fluids, vasopressor agents, oxygen, etc. as 
medically necessary. Discontinue all further oxaliplatin treatment.b 
a Prior to the next oxaliplatin infusion, subjects will be started on long-acting H1 antihistamines and 
oral dexamethasone (8 mg), which will be taken on the day before oxaliplatin infusion and on the 
morning of treatment.  On the morning of infusion, subjects will also receive 20 mg of oral 
dexamethasone at the infusion center as part of their premedication regimen.  Oxaliplatin infusion rate 
will be reduced by 50% from baseline.   If recurrent grade ≥2 reaction occurs, subjects will be 
withdrawn from the study.  
b  Subjects with CTCAE Grade ≥3 allergic reaction/hypersensitivity, which can be clearly attributed to 
oxaliplatin, will be permanently discontinued from the study. 
 
 
 


Clinical Study Protocol Synopsis 
Drug Substance TAS-102 and oxaliplatin  
Study Code HIC# 1605017852 
Version Number: 6.0 
Date: 20-May-2020 
27(42) 
 
Dosing Modifications in Response to Other Non-Hematologic Toxicities 
Grade/Occurrence 
Dose Hold/Resumption  
Dose Adjustment for Next Cycle 
1-2 
Any occurrence 
Continue without treatment delays. 
Supportive measures as needed. 
None 
≥ 3 
1st occurrence 
Suspend treatment until Grade 0 or 1. 
Decrease oxaliplatin by 1 dose level 
≥ 3 
2nd occurrence 
Suspend treatment until Grade 0 or 1. 
Decrease TAS-102 by 1 dose level. 
If TAS-102 already at 20 mg/m2, 
decrease oxaliplatin by 1 dose level. 
≥ 3 
3rd occurrence 
Discontinue treatment. 
Discontinue treatment. 
 
 
 
7. 
DISCONTINUATION OF INVESTIGATIONAL PRODUCT 
7.1 
Indications for Treatment Discontinuation 
In the absence of significant treatment delays due to adverse events determined to be possibly, 
probably, or definitely attributed to a study agent (as defined in Section 9.1), treatment may 
continue indefinitely or until one of the following criteria applies: 
• Objective disease progression according to RECIST criteria. Under some 
circumstances subjects may continue to receive study treatment after radiographic 
progression per RECIST 1.1 as long as they continue to experience clinical benefit in 
the opinion of the treating physician.   
• Intercurrent illness that prevents further administration of treatment. 
• Unacceptable adverse event(s). 
• Severe non-compliance to study protocol as judged by the investigator. 
• Subject becomes pregnant. 
• Subject is determined to be incorrectly enrolled (i.e., the subject does not meet the 
required inclusion/exclusion criteria for the study). 
• Subject decides to withdraw from the study (the subject is at any time free to 
discontinue treatment, without prejudice to further treatment). 
• General or specific changes in the subject's condition. 
• Treatment delay for any reason > 28 days from planned date of treatment. 


Clinical Study Protocol Synopsis 
Drug Substance TAS-102 and oxaliplatin  
Study Code HIC# 1605017852 
Version Number: 6.0 
Date: 20-May-2020 
28(42) 
7.2 
Procedures for discontinuation of a subject from investigational 
product  
All reasons for discontinuation of treatment must be documented in the EMR.  Any subject 
discontinuing investigational therapy should be seen at 30 days post treatment discontinuation 
visit for the evaluations, as outlined in the study schedule, or contacted at least 30 days after 
discontinuing study medication to collect and /or complete AE information. The subject’s 
tumor status should be assessed clinically and, if appropriate, disease progression should be 
confirmed by radiological assessment.  After discontinuation of the study medications, all 
ongoing or new AEs or SAEs must be followed until resolution unless, in the investigator’s 
opinion, the condition is unlikely to resolve due to the subject’s underlying disease, or the 
subject is lost to follow up.  
7.3 
Withdrawal from study 
Subjects who withdraw from the study before treatment initiation will be replaced by other 
eligible patients.  No subject replacement will take place if withdrawal occurs after treatment 
has been started.  
8. 
STUDY EFFICACY ASSESSMENTS 
Subjects who have received at least 1 cycle of chemotherapy will be included in efficacy 
assessments.  All efficacy assessments will be performed using RECIST criteria.  Imaging will 
be repeated every 8 weeks to evaluate disease response.  Restaging scans may be spaced out to 
every 12 weeks after the first 2 scans on treatment at the discretion of the treating physician.  
Imaging studies will be repeated prior to eight weeks if a subject develops new symptoms that 
warrant evaluation or if there is clinical concern for disease progression per discretion of the 
treating physician. 
8.1 
Definition of measurable disease and target lesions 
 
Measurable disease 
Measurable disease is defined differently for lymph nodes compared with other disease and 
will be addressed in a separate section below. 
1. Lesions that can be accurately measured in at least one dimension (longest 
diameter to be recorded) as ≥ 2.0 cm by chest x-ray, by ≥ 1.0 cm with CT or MRI 
scans, or ≥ 1.0 cm with callipers by clinical exam.  All tumor measurements must 
be recorded in decimal fractions of centimetres (or millimetres).  The defined 
measurability of lesions on CT scan is based on the assumption that CT slice 
thickness is 0.5 cm or less.  If CT scans have slice thickness greater than 0.5 cm, 
the minimum size for a measurable lesion should be twice the slice thickness.   
2. A malignant lymph node is to be considered pathologically enlarged and 
measurable if it measures ≥ 1.5 cm in SHORT AXIS (greatest diameter 


Clinical Study Protocol Synopsis 
Drug Substance TAS-102 and oxaliplatin  
Study Code HIC# 1605017852 
Version Number: 6.0 
Date: 20-May-2020 
29(42) 
perpendicular to the long axis of the lymph node) when assessed by scan (CT scan 
slice recommended being no greater than 0.5 cm). 
 
Non-measurable disease   
All other lesions (or sites of disease), including small lesions (longest diameter < 1.0 cm or 
pathologic lymph nodes with ≥ 1.0 cm to < 1.5 cm short axis), are considered non-measurable 
disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered non-measurable, as are previously radiated lesions 
that have not progressed. 
 
Notes on measurability 
1. For CT and MRIs, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  Body 
scans should by performed with breath-hold scanning techniques, if possible.  
2. PET-CT:  At present, the low dose or attenuation correction CT portion of a PET-
CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of 
a PET-CT is of identical diagnostic quality to a diagnostic CT, then the CT portion 
of the PET-CT can be used for RECIST measurements and can be used 
interchangeably with conventional CT. 
3. Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be 
used as a method of measurement. 
4. Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-
measurable) since they are, by definition, simple cysts. 
5. If a target lesion becomes very small some radiologists indicate that it is too small 
to measure.  If the lesion is actually still present, a default measurement of 0.5 cm 
should be applied.  If the radiologist believes the lesion has gone, a default 
measurement of 0.0 cm should be recorded. 
 
Target lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline.  Target lesions should be selected on the basis of their size (lesions with 
the longest diameter), be representative of all involved organs, but in addition should be those 
that lend themselves to reproducible repeated measurements.  A sum of the diameters (longest 
for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated.  If 
lymph nodes are to be included in the sum, then only the short axis is added into the sum. The 
baseline sum diameters will be used as reference to further characterize any objective tumor 
regression in the measurable dimension of the disease. 


Clinical Study Protocol Synopsis 
Drug Substance TAS-102 and oxaliplatin  
Study Code HIC# 1605017852 
Version Number: 6.0 
Date: 20-May-2020 
30(42) 
 
Non-target lesions 
All other lesions (or sites of disease) including any measurable lesions over and above the 5 
target lesions should be identified as non-target lesions and should also be recorded at 
baseline.  Measurements of these lesions are not required, but the presence, absence, or in rare 
cases unequivocal progression of each should be noted throughout follow-up. 
8.2 
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers. 
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. The same 
method of assessment and the same technique should be used to characterize each identified 
and reported lesion at baseline and during follow-up. 
 
1. Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as 
assessed using calipers (e.g., skin nodules). In the case of skin lesions, documentation 
by color photography, including a ruler to estimate the size of the lesion, is 
recommended. 
 
2. Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable. 
 
3. Conventional CT and MRI: This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less. If CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.  MRI is also acceptable in certain situations (e.g. for body 
scans). 
 
8.3 
Response Criteria 
 
Evaluation of target lesions 
Complete Response 
(CR): 
Disappearance of all targets extra nodal lesions and the regression 
of all nodal lesions to < 10 mm SAD. 
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters 


Clinical Study Protocol Synopsis 
Drug Substance TAS-102 and oxaliplatin  
Study Code HIC# 1605017852 
Version Number: 6.0 
Date: 20-May-2020 
31(42) 
Progressive Disease 
(PD): 
At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the 
baseline if that is the smallest on study). In addition to the relative 
increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. The appearance of one or more new 
lesions is considered progression. 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum of 
diameters while on study. 
 
 
Evaluation of non-target lesions 
Complete Response 
(CR): 
Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (< 
10 mm short axis) 
Non-CR/Non-PD: 
Persistence of one or more non-target lesion(s) and/or maintenance 
of tumor marker level above the normal limits 
Progressive Disease 
(PD): 
Unequivocal progression of existing non-target lesions and/or 
appearance of one or more new lesions * 
*Although a clear progression of “nontarget” lesions only is exceptional, in such circumstances, the 
opinion of the treating physician should prevail. 
 
 
Evaluation of overall response 
Target 
lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Incomplete response/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 


Clinical Study Protocol Synopsis 
Drug Substance TAS-102 and oxaliplatin  
Study Code HIC# 1605017852 
Version Number: 6.0 
Date: 20-May-2020 
32(42) 
 
 
 
Progression free survival 
Progression Free Survival (PFS) is defined as the time from the date of start of treatment to 
the date of first documented progression or any cause of death during the study.  Progression 
will be assessed by a CT scan according to RECIST criteria version 1.1.  This criterion will be 
estimated by the Kaplan-Meier method.  Subjects who have not progressed or died at the time 
of analysis will be censored at the time of their latest follow-up with clinically stable disease.  
This includes subjects who withdraw consent. 
 
 
Response rate  
Response rate is defined as the percentage of subjects with a confirmed complete response 
(CR) or partial response (PR) by investigator assessment as per RECIST criteria, version 1.1.  
A maximum of 5 measurable lesions in total (and up to 2 per organ) representative of all 
involved organs should be identified as target lesions at baseline and measured through the 
course of study treatment.  Target lesions should be selected based on their size and their 
suitability for accurate repeated measurements.  At baseline, the sum of the diameters (longest 
diameters (LD) for extra nodal target lesions and short axis diameters (SAD) for nodal 
lesions) will be calculated and reported as the baseline sum LD.  This baseline sum LD will be 
used as the reference by which to characterize the objective tumor response.  All other lesions 
should be identified as non-target lesions and should also be recorded at baseline. 
Measurements of these lesions are not required, but the presence or absence of each should be 
noted throughout the study. 
9. 
STUDY SAFETY ASSESSMENTS 
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section. 
9.1 
Definitions  
 
Adverse events 
An adverse event is the development of an undesirable medical condition or the deterioration 
of a pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product.  An undesirable medical condition 
can be symptoms (e.g. nausea, chest pain), signs (e.g. tachycardia, enlarged liver) or the 
abnormal results of an investigation (e.g. laboratory findings, electrocardiogram).  In clinical 
studies, an AE can include an undesirable medical condition occurring at any time, including 
run-in or washout periods, even if no study treatment has been administered. The term AE is 
used to include both serious and non-serious AEs. 


Clinical Study Protocol Synopsis 
Drug Substance TAS-102 and oxaliplatin  
Study Code HIC# 1605017852 
Version Number: 6.0 
Date: 20-May-2020 
33(42) 
 
Serious adverse event 
A serious adverse event is an AE occurring during any study phase (i.e., screening, run-in, 
treatment, wash-out, follow-up), at any dose of the study drugs that fulfills one or more of the 
following criteria: 
• Results in death 
• Is immediately life-threatening 
• Requires in-patient hospitalization or prolongation of existing hospitalization  
• Results in persistent or significant disability or incapacity  
• Is a congenital abnormality or birth defect 
• Is an important medical event that may jeopardize the subject or may require 
medical intervention to prevent one of the outcomes listed above. 
• The causality of SAEs (their relationship to all study treatment/procedures) will be 
assessed by the investigator(s) and communicated to Taiho Pharmacovigilance 
Operations or designee. 
9.2 
Recording of adverse events 
Non-serious adverse events and SAEs will be determined from the time the study drug is 
given, throughout the treatment period and up to and including the 28-day follow-up period.  
All grade 2 or higher AEs will be recorded.  Grade 1 AEs do not need to be recorded.  After 
withdrawal from treatment, subjects must be followed-up for all existing and new AEs for 28 
calendar days after the last dose of trial drug and/or until event resolution. All new AEs 
occurring during that period must be recorded (if SAEs, they must be reported to the Yale 
Data Safety Monitoring Committee (DSMC) and Yale University Human Investigation 
Committee (HIC) as per SOPs.).   AEs will be recorded per Yale Cancer Center (YCC) SOPs. 
 
All study-related toxicities/ SAEs must be followed until resolution, unless in the Treating 
Investigator’s opinion, the condition is unlikely to resolve due to the subject’s underlying 
disease. 
 
 
Adverse Events based on signs and symptoms 
When collecting AEs, the recording of diagnoses is preferred (when possible) to recording a 
list of signs and symptoms.  However, if a diagnosis is known and there are other signs or 
symptoms that are not generally part of the diagnosis, the diagnosis and each sign or symptom 
will be recorded separately. 


Clinical Study Protocol Synopsis 
Drug Substance TAS-102 and oxaliplatin  
Study Code HIC# 1605017852 
Version Number: 6.0 
Date: 20-May-2020 
34(42) 
 
Adverse Events based on examinations and tests 
Deterioration as compared to baseline in protocol-mandated laboratory values and vital signs 
should only be reported as AEs if they fulfill any of the SAE criteria or are the reason for 
discontinuation of treatment with the investigational product. 
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information.  Wherever possible, the reporting investigator 
will use the clinical, rather than the laboratory term (e.g. anemia versus low hemoglobin 
value).  In the absence of clinical signs or symptoms, clinically relevant deteriorations in non-
mandated parameters should be reported as AE(s). 
Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE/SAE.  Any new or aggravated clinically relevant abnormal medical 
finding at a physical examination as compared with the baseline assessment will be reported 
as an AE. 
 
Disease progression 
Disease progression can be considered as a worsening of a subject’s condition attributable to 
the disease for which the investigational product is being studied.  It may be an increase in the 
severity of the disease under study and/or increases in the symptoms of the disease.  The 
development of new or progression of existing metastasis during the study should be 
considered as disease progression and not an AE.  Events, which are unequivocally due to 
disease progression, should not be reported as an AE during the study. 
 
New cancers 
The development of a new primary cancer should be regarded as an AE and will generally 
meet at least one of the serious criteria (see Section 9.1.2).  New primary cancers are those 
that are not the primary reason for the administration of the study treatment and have 
developed after the inclusion of the patient into the study.  They do not include metastases of 
the original cancer.  Symptoms of metastasis or the metastasis itself should not be reported as 
an AE/SAE, as they are considered to be disease progression. 
 
Lack of efficacy 
When there is deterioration in the condition for which the study treatment(s) is being used, 
there may be uncertainty as to whether this is lack of efficacy or an AE.  In such cases, unless 
the PI or the reporting physician considers that the study treatment contributed to the 
deterioration of the condition, or local regulations state to the contrary, the deterioration 
should be considered to be a lack of efficacy and not an AE. 
 
Deaths 
All deaths that occur during the study, or within the protocol-defined 28-day post-study 
follow-up period after the administration of the last dose of study treatment, must be reported 


Clinical Study Protocol Synopsis 
Drug Substance TAS-102 and oxaliplatin  
Study Code HIC# 1605017852 
Version Number: 6.0 
Date: 20-May-2020 
35(42) 
as a serious adverse event as outlined in Section 9.3 within 24 hours from the time site 
personnel become aware of the death. 
When reporting a death in the CRF, it will be required to identify which of the following best 
describes the category of death: 
• Toxicity for study medication. 
• Radiological disease progression. 
• Clinical disease progression. 
• Other causes. 
Death should be reported according to YCC SOPs. 
9.3 
Reporting of serious adverse events 
Investigators and other site personnel must inform the Yale DSMC and Yale University HIC 
per the YCC SOPs on the required forms.   
All SAEs meeting the criteria for expedited reporting will be reported to the Yale University 
Human Investigation Committee (HIC) using HIC Form 710 FR 4: Unanticipated Problem 
Involving Risks to Subjects or Others (UPIRSOs), including Adverse Events (AEs) Reporting 
Form as per Human Research Protection Program (HRPP) Policy 710. 
The HIC does not require reporting of any other Adverse Event type. A copy of the HRPP 
Policy 710 Reporting Unanticipated Problems Involving Risks to Subjects or Others, 
including Adverse Events is available at: 
https://your.yale.edu/sites/default/files/irb_policy_710_reportingupirsosincludingadverseevent
s.pdf 
All SAEs within the safety follow-up window (e.g., within 28 days after the last dose of study 
medications or until the start of new antitumor therapy, whichever is earlier) established in the 
protocol will be reported. 
Non-serious adverse events and SAEs will be collected from the time consent is given, 
throughout the treatment period and up to and including the 28-day follow-up period.  After 
withdrawal from treatment, subjects must be followed-up for all existing and new AEs for 28 
calendar days after the last dose of trial drug and/or until event resolution.  All new AEs 
occurring during that period must be recorded (if SAEs, then they must be reported to the 
FDA as per their reporting criteria).  All study-related toxicities/ SAEs must be followed until 
resolution, unless in the Treating Investigator’s opinion, the condition is unlikely to resolve 
due to the subject’s underlying disease. 


Clinical Study Protocol Synopsis 
Drug Substance TAS-102 and oxaliplatin  
Study Code HIC# 1605017852 
Version Number: 6.0 
Date: 20-May-2020 
36(42) 
9.4 
Clinical safety assessment 
 
Laboratory safety assessment 
Full hematology assessments for safety should be performed during every visit and when 
clinically indicated.  This should include hemoglobin, platelets, mean cell volume (MCV), 
white blood cells (WBC), absolute differential white cell count (neutrophils, lymphocytes, 
monocytes, eosinophils and basophils).  If absolute differentials are not available, % 
differentials will be provided.  
Coagulation profile (activated partial thromboplastin time (aPTT) and international 
normalized ratio (INR) will be performed at baseline and if clinically indicated.  
Biochemistry assessments for safety (sodium, potassium, calcium, magnesium, glucose, 
creatinine, total bilirubin, alkaline phosphatase (Alk Phos), aspartate transaminase (AST), 
alanine transaminase (ALT), urea or blood urea nitrogen (BUN), total protein, and albumin 
should be performed at every visit or more frequently as clinically indicated.   
These tests will be performed by the hospital’s local laboratory.  Additional analyses may be 
performed if clinically indicated.  Any clinically significant abnormal laboratory values 
should be repeated as clinically indicated and recorded on the eCRF. 
 
Physical examination 
Complete physical exam will be performed before trial enrollment and during each treatment 
visit.  
 
Vital signs 
Vital signs will be obtained at every clinic visit.  Vital signs will include temperature, heart 
rate, respiration rate, oxygenation, and weight.  Height will be measured at the time of study 
enrollment.  Significant abnormalities will be recorded as an AE.  Blood pressure and pulse 
rate will be measured using automated BP measuring devise.  Body temperature will be 
measured in degrees Fahrenheit using an automated thermometer.   
 
ECG 
Baseline resting 12-lead ECG will be performed at the time of study enrollment.  Repeat ECG 
will be performed when clinically indicated during the course of the treatment. 
ECGs will be recorded at 25 mm/sec.  All ECGs should be assessed by the treating 
investigator as to whether they are clinically significantly abnormal / not clinically 
significantly abnormal.  If there is a clinically significant abnormal finding, the Investigator 
will record it as an AE on the eCRF.  The original ECG traces must be stored in the patient 
medical record as source data. 


Clinical Study Protocol Synopsis 
Drug Substance TAS-102 and oxaliplatin  
Study Code HIC# 1605017852 
Version Number: 6.0 
Date: 20-May-2020 
37(42) 
 
Serum or urine pregnancy test 
Pregnancy test on blood or urine samples will be performed for pre-menopausal women of 
childbearing potential within 14 days prior to the start of study treatment.  Tests will be 
performed by the hospital’s local laboratory.  If results are positive the subject is 
ineligible/must be discontinued from the study.  In the event of a suspected pregnancy during 
the study, the test should be repeated. 
10. 
ETHICAL AND REGULATORY REQUIREMENTS 
10.1 
Ethical conduct of the study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice and applicable 
regulatory requirements. 
10.2 
Subject data protection 
The Informed Consent Form will incorporate wording that complies with relevant data 
protection and privacy legislation.  In accordance with the Health Information Portability and 
Accountability Act (HIPAA), the written Informed Consent Form must include a subject 
authorization to release medical information to a regulatory authority, or Institutional Review 
Board (IRB), to grant access to subject’s medical information that includes all hospital records 
relevant to the study, including subjects’ medical history. 
10.3 
Ethics and regulatory review 
10.4 
Informed consent 
Provision of written Informed Consent will be obtained prior to any study-related procedures. 
The principal investigator will ensure that the subject is given full and adequate oral and 
written information about the nature, purpose, possible risk and benefit of the study. Subjects 
will also be notified that they are free to discontinue from the study at any time.  The subject 
will be given the opportunity to ask questions and allowed time to consider the information 
provided.  The original, signed written Informed Consent Form will be stored for the duration 
of the study. A copy of the signed written Informed Consent Form will be given to the subject. 
10.5 
Changes to the protocol and informed consent form 
In the event that there are any changes to the protocol, these changes will have to be first 
reviewed and approved by the Yale University IRB (Human Investigation Committee) via an 
amendment before any change is implemented.  Once approved, subjects will be notified of 
the protocol changes and will be provided with the updated ICF for their signature, if 
necessary. Subjects will also be provided with a copy of the updated ICF for their records 
whenever re-consent is required.  


Clinical Study Protocol Synopsis 
Drug Substance TAS-102 and oxaliplatin  
Study Code HIC# 1605017852 
Version Number: 6.0 
Date: 20-May-2020 
38(42) 
10.6 
Audits and inspections 
The PI will monitor the clinical trial for safety. The PI will assess all expedited adverse events 
and will periodically review all adverse events observed on the trial. Yale Cancer Center 
standard operating procedures (SOPs) for assessment and reporting of adverse events will be 
followed, which are in compliance with 21 CFR 312.32 and 312.22. The clinical trial data 
consisting of all required observations, AEs, and laboratory data will be entered into a 
computerized database in a timely manner. The accuracy and completeness of the database, 
timely submission of SAEs and compliance with the protocol, is assured by periodic auditing 
conducted by the Yale Center for Clinical Investigation’s Yale Data and Safety Monitoring 
Committee (DSMC) Committee.  
The Yale Cancer Center (YCC) Data and Safety Monitoring Committee (DSMC) will provide 
the primary oversight of data and safety monitoring. The Yale DSMC will review and monitor 
compliance, toxicity and deviations from this study. The committee is composed of clinical 
specialists with experience in oncology and who have no direct relationship with the study. 
Information that raises any questions about participant safety will be addressed with the 
Principal Investigator. 
The DSMC will review this protocol bi-annually, at a minimum. Information to be provided to 
the committee includes: a study narrative by the PI, a summary DSMC report produced by 
OnCore (which includes participant accrual, response, trial status history, SAEs, adverse 
events, deviations and survival); audit results, and monitoring reports, as applicable. Other 
information (e.g., scans, laboratory values, etc.) will be provided upon request. Upon 
completing the review, the DSMC will approve whether the study should continue as planned, 
require modification/ amendment, or be placed on administrative hold with accrual 
temporarily suspended. 
Trials being monitored by the YCC DSMC will remain under the YCC DSMC purview until a 
DSMC review has occurred that includes the research activity of the last subject who 
completed the intervention, or until the DSMC feels there are no patient safety concerns that 
require further monitoring. The DSMC will determine the length of continued DSMC review. 
The DSMC has authority to intervene in the conduct of these studies as necessary to ensure 
the safety of the participants and to maintain the highest quality in the clinical research 
performed at YCC. The DSMC has the authority to require additional monitoring and/ or more 
frequent reporting on study progress and serious adverse events.  
On a regular interval basis, status reports of all laboratory parameters, AEs and SAEs are 
reviewed by the PI to view composite data across subjects. Regular Weekly Disease Aligned 
Research Team meetings will be held to discuss ongoing subject treatment and adverse events. 
The Principal Investigator will distribute manufacturer provided safety reports and updated 
Toxicity Lists to Yale University HIC and all relevant personnel involved in the conduct of 
the study as per their policy (Yale University HRPP Policy 710). The Toxicity List, in 
addition to the Package Insert, will be used as a reference for reporting any new SAE. Possible 


Clinical Study Protocol Synopsis 
Drug Substance TAS-102 and oxaliplatin  
Study Code HIC# 1605017852 
Version Number: 6.0 
Date: 20-May-2020 
39(42) 
actions taken by the PIs or the Yale DSMC if a new unexpected toxicity is identified from the 
above safety review, or if the periodic review of all adverse events and laboratory data 
indicates a pattern of incidence or severity of toxicity that raises a safety concern, can be to: 
1. Revise consent form 
2. Amend the protocol 
3. Suspend the protocol 
11. 
STATISTICAL METHODS AND SAMPLE SIZE 
DETERMINATION 
11.1 
Description of analysis sets 
The following subject populations will be used in the study: 
• All enrolled subjects: All subjects who signed an informed consent form and were 
registered into the study. 
• All treated subjects: All subjects who received at least on dose of study medication. 
Analysis of safety and efficacy will be based on subjects who have received at least 1 
cycle of treatment. 
11.2 
Methods of statistical analyses 
 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized by dose levels using 
descriptive statistics. 
 
Efficacy Analyses 
Listing of tumor measurements will be provided by subject and study day at each dose level.  
Response rate will be calculated by dose level.  Descriptive statistics will be used to analyze 
efficacy data using historical data as reference.  In a published retrospective analysis, re-
challenge with 5-FU and oxaliplatin containing regimen resulted in an 18% response rate10.  
An observed response rate of at least 35% will warrant further trials with the proposed drug 
combination.   
 
Safety Analyses 
All recorded adverse events will be listed and tabulated by system organ class and dose level. 
Vital signs and clinical laboratory test results will be listed and summarized by dose level. 
Any significance physical examination findings and results of clinical laboratory test will be 
listed. 


Clinical Study Protocol Synopsis 
Drug Substance TAS-102 and oxaliplatin  
Study Code HIC# 1605017852 
Version Number: 6.0 
Date: 20-May-2020 
40(42) 
11.3 
Determination of sample size 
We anticipate that 3-18 subjects will be enrolled in the run-in portion of the study.  At most 
fifty subjects will be enrolled in the phase 2 portion of the study according to the Bayesian 
analysis plan shown in the table below.   
 
 
 
 
 
 
 
 
 
11.4 
Data safety and monitoring plan  
The principal investigator will be responsible for monitoring the data and assuring protocol 
compliance.  This study is reviewed once per week in the Disease Aligned Research Team 
meeting.  During these meetings, the principal investigator reviews data queries, SAE’s, 
deviations and regulatory issues related to this study.  Meeting minutes and attendance logs 
will only be provided upon request.  The principal investigator will also be responsible for 
conducting the safety reviews at the specified frequency, which must be conducted at a 
minimum of every 6 months (including when re-approval of the protocol is sought).  The Yale 
DSMC will be the monitoring committee of record.  Either the principal investigator, the IRB 
or Yale Data and Safety Monitoring Committee (DSMC) have the authority to stop or suspend 
the study or require modifications. 
11.5 
Important medical procedures to be followed by the investigator 
 
Pregnancy 
All outcomes of pregnancy should be reported to the DSMC and IRB per SOPs. 
 
Maternal exposure 
If a subject becomes pregnant during the course of the study, TAS-102 and oxaliplatin should 
be discontinued immediately. The outcome of any conception occurring from the date of the 
first dose until 3 months after the last dose should be followed up and documented. 
H0: p < 0.18 versus Ha: p > 0.35 
n 
Max 
number 
responders 
to stop for 
futility 
Min number 
responders 
to stop for 
success 
Pr (stop for 
futility 
when 
p=0.18) 
Pr (stop for 
futility 
when 
p=0.35) 
Pr (stop for 
success 
when 
p=0.18) 
Pr (stop for 
success 
when 
p=0.35) 
30 
5 
10 
0.5395 
0.0233 
0.0323 
0.6425 
35 
6 
11 
0.0951 
0.0097 
0.0139 
0.1034 
40 
8 
12 
0.1331 
0.0182 
0.0125 
0.0710 
45 
9 
13 
0.0388 
0.0057 
0.0109 
0.0479 
50 
11 
13 
0.0937 
0.0264 
0.0299 
0.0521 
Sum: 
1- α 
0.9003 
β 
0.0833 
α 
 0.0997 
1- β  
0.9167 


Clinical Study Protocol Synopsis 
Drug Substance TAS-102 and oxaliplatin  
Study Code HIC# 1605017852 
Version Number: 6.0 
Date: 20-May-2020 
41(42) 
12. 
LIST OF REFERENCES 
 
1. 
Siegel R, Ma J, Zou Z, et al: Cancer statistics, 2014. CA Cancer J Clin 64:9-29, 
2014 
 
2. 
Muratore A, Zorzi D, Bouzari H, et al: Asymptomatic colorectal cancer with 
un-resectable liver metastases: immediate colorectal resection or up-front systemic 
chemotherapy? Ann Surg Oncol 14:766-70, 2007 
 
3. 
Cremolini C, Loupakis F, Falcone A: FOLFOXIRI and bevacizumab for 
metastatic colorectal cancer. N Engl J Med 372:291-2, 2015 
 
4. 
Temmink OH, Emura T, de Bruin M, et al: Therapeutic potential of the dual-
targeted TAS-102 formulation in the treatment of gastrointestinal malignancies. Cancer Sci 
98:779-89, 2007 
 
5. 
Emura T, Suzuki N, Yamaguchi M, et al: A novel combination antimetabolite, 
TAS-102, exhibits antitumor activity in FU-resistant human cancer cells through a mechanism 
involving FTD incorporation in DNA. Int J Oncol 25:571-8, 2004 
 
6. 
Zhang X, Zheng Z, Shin YK, et al: Angiogenic factor thymidine phosphorylase 
associates with angiogenesis and lymphangiogenesis in the intestinal-type gastric cancer. 
Pathology 46:316-24, 2014 
 
7. 
Yoshino T, Mayer R, Falcone A, et al: Results Of a Multiceneter, Randomized, 
Double-Blind, Phase III Study of TAS-102 vs. Placebo, with Best Supportive Care, In Patients 
with Metastatic Colorectal Cacner Refractory To Standard Therapies (RECOURSE). Ann 
Oncol 25:Abstract O-0022, 2014 
 
8. 
Yoshino T, Mizunuma N, Yamazaki K, et al: TAS-102 monotherapy for 
pretreated metastatic colorectal cancer: a double-blind, randomised, placebo-controlled phase 
2 trial. Lancet Oncol 13:993-1001, 2012 
 
9. 
Temmink OH, Hoebe EK, van der Born K, et al: Mechanism of 
trifluorothymidine potentiation of oxaliplatin-induced cytotoxicity to colorectal cancer cells. 
Br J Cancer 96:231-40, 2007 
 
10. 
Townsend AR, Bishnoi S, Broadbridge V, et al: Rechallenge with oxaliplatin 
and fluoropyrimidine for metastatic colorectal carcinoma after prior therapy. Am J Clin Oncol 
36:49-52, 2013 
 
 


Clinical Study Protocol Synopsis 
Drug Substance TAS-102 and oxaliplatin  
Study Code HIC# 1605017852 
Version Number: 6.0 
Date: 20-May-2020 
42(42) 
13. 
APPENDIX 
Appendix 1. ECOG Performance Status. 
ECOG 
Performance Status 
Activity 
0 
Fully active, able to carry on all pre-disease performance without 
restrictions. 
1 
Restricted in physically strenuous activity, but ambulatory and able 
to carry out work of a light or sedentary nature, e.g. light house 
work, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any 
work activities.  Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours. 
4 
Completely disabled.  Cannot carry on any self-care.  100% 
confined to bed or chair. 
 
 
 
 
 
 
 
 
 
 
 

ICF_001.pdf: 
APPROVED BY THE YALE UNIVERSITY IRB 6/21/2019
Principal Investigator:
Jeremy Kortmansky, MD
HIC #: 
1605017852
Funding Source:
Yale Cancer Center
Protocol Version and Date:
5.0 dated 07-Jun-2018
Page 1 of 14
YCC v5.0 (26-Jun-2018) 
COMPOUND AUTHORIZATION AND CONSENT FOR PARTICIPATION IN A 
RESEARCH PROJECT
YALE UNIVERSITY SCHOOL OF MEDICINE – YALE-NEW HAVEN HOSPITAL: 
SMILOW CANCER HOSPITAL
Study Title: TAS-102 in Combination with Oxaliplatin (TAS-OX) for Refractory Metastatic 
Colorectal Cancer
Principal Investigator: Jeremy Kortmansky, MD
Principal Investigator’s Phone Number: 203-407-8002
24-Hour Phone Number: 203-407-8002
Principal Investigator’s Mailing Address: PO Box 208028, New Haven, CT 06520-8028
Funding Source: Yale Cancer Center
Invitation to Participate and Description of Project
You are invited to take part in a research study. The research study is designed to look at the 
safety and effects of TAS-102 in combination with oxaliplatin in subjects with metastatic 
colorectal cancer. You have been invited to take part because you have metastatic colorectal 
cancer that has returned after receiving standard chemotherapy, which included 5-FU, 
oxaliplatin, irinotecan, bevacizumab, and anti-EGFR monoclonal antibody (if you are RAS wild-
type).  
In order to decide whether or not you wish to be a part of this research study you should know 
enough about its risks and benefits to make an informed decision.  This consent form gives you 
detailed information about the study, which a member of the research team will discuss with you.  
This discussion should go over all aspects of this research: the purpose and nature of the research 
study, the procedures that will be performed, the risks of the study drug(s) and procedures, 
possible benefits, possible alternative treatments, your rights as a participant and other 
information about the research study. You should take whatever time you need to discuss the 
research study with your physician and family. The decision to participate or not is yours. Once 
you understand the study, you will be asked if you wish to participate; if so, you will be asked to 
sign and date where indicated on this form.
If you choose to participate, you will be told of any significant new findings that develop during 
the course of your participation in this study that may affect your willingness to continue to 
participate.
The research study is being funded by the Yale Cancer Center. Yale Cancer Center is providing 
research support.  Dr. Jeremy Kortmansky is the principal investigator of this study at Yale 
Cancer Center.
APPROVED BY THE YALE UNIVERSITY IRB 6/21/2019


APPROVED BY THE YALE UNIVERSITY IRB 6/21/2019
Principal Investigator:
Jeremy Kortmansky, MD
HIC #: 
1605017852
Funding Source:
Yale Cancer Center
Protocol Version and Date:
5.0 dated 07-Jun-2018
Page 2 of 14
YCC v5.0 (26-Jun-2018) 
Purpose
This is a two-part study. The purpose of this study is to study the safety of the combination of 
TAS-102 and oxaliplatin. This study will also evaluate the effect the study drugs have on your 
kind of cancer. 
The combination of study drugs that will be used in this research study, TAS-102 and 
oxaliplatin, is considered investigational. This means that the combination of study drugs has not 
been approved for commercial use by the United States Food and Drug Administration (FDA) in 
your type of cancer. On September 22, 2015, the United States Food and Drug Administration 
(FDA) approved TAS-102 (also known as Lonsurf) for the treatment of patients with metastatic 
colorectal cancer who have been previously treated with all standard approved drugs (i.e., 
fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biologic 
product, and an anti-EGFR monoclonal antibody, if RAS wild-type). Oxaliplatin and TAS-102 
are individually approved by the FDA for the treatment of patients with colorectal cancer that is 
advanced or has come back.  Since both drugs are approved for this setting of colorectal cancer, 
you or your insurance provider will be responsible for the costs of the commercially available 
drugs.
It is expected that up to 68 subjects will be enrolled at the Yale Cancer Center. Up to 18 will be 
enrolled to Part 1 and up to 50 will be enrolled in Part 2. 
Study Procedures
This study will be conducted in two parts. The first part will be done to find the dose of study 
drugs, TAS-102 in combination with oxaliplatin, that can safely be given to subjects with your 
kind of cancer. This is called a run-in phase. The second part will be done to further investigate 
the safety of the study drugs and to determine if the study drugs work in your kind of cancer. 
This is called an expansion phase. In both parts, you will continue to receive the study drugs 
until your disease progresses or you experience unacceptable toxicity. The study procedures are 
the same in each part and are explained below. The dose of study drug you will receive will vary 
based upon the part in which you are enrolled. Your study doctor will inform you of the dose of 
study drugs you are to receive. 
Tests and procedures that would be performed for your regular cancer care whether you are on 
this study or not, are called “standard of care.” All of the tests and procedures listed below that 
will be performed at your study visits, should you choose to participate in this study, are standard 
of care unless noted with an asterisk (*).
Screening Period
If you agree to participate and sign and date this form*, you will need to undergo a series of tests 
and procedures within 14 days of your first dose of study drugs, unless otherwise specified 
below, to determine if you are eligible to participate in the research study. You will come to the 
study site for screening tests and it is possible that more than one screening visit may be needed.  
The following tests or procedures will be performed during the visit(s):

Recording your demographic information including age, sex and race/ ethnicity
APPROVED BY THE YALE UNIVERSITY IRB 6/21/2019


APPROVED BY THE YALE UNIVERSITY IRB 6/21/2019
Principal Investigator:
Jeremy Kortmansky, MD
HIC #: 
1605017852
Funding Source:
Yale Cancer Center
Protocol Version and Date:
5.0 dated 07-Jun-2018
Page 3 of 14
YCC v5.0 (26-Jun-2018) 

Review of your medical and surgical history including a review of treatments and/ or 
surgeries previously received for your cancer

Review of any medications you have previously taken or are currently taking including 
prescriptions drugs, over-the-counter medications, herbal drugs and dietary supplements

Complete Physical examination 

Your physician will determine your activity level and your current ability to perform 
daily tasks called an Eastern Cooperative Oncology Group (ECOG) performance status

Vital signs including measurement of your weight, height, blood pressure, heart rate, 
body temperature and oxygen saturation (the level of oxygen in your blood)

12-lead Electrocardiogram (ECG) to measure the electrical activity of your heart
o
An ECG requires temporary placement of electrical sensors on your chest near 
your heard, on your wrists, and on your ankles

Routine laboratory tests of your blood to evaluate your blood cell counts, blood 
chemistry, kidney function, blood clotting ability, and any other safety evaluations.

Serum or urine pregnancy test (for women of childbearing potential only). You will not 
be able to participate if your pregnancy test is positive. 

Computerized Tomography (CT) or PET/CT scan of your chest, abdomen and pelvis 
within 28 days of your first dose of study drugs. The scan measures size and location of 
your tumors. You may be asked to drink a large cup of liquid contrast agent.
If the exams, tests and procedures completed during the screening period show that you meet all 
of the trial eligibility criteria, and if you choose to continue, you will proceed to the main part of 
the trial.
Treatment Period
You will be asked to return to the clinic to see your study doctor to take the first dose of the 
study drugs. At this time, your doctor will tell you how many pills of TAS-102 you will need to 
take at home. 
Please handle the TAS-102 as follows:

Store the TAS-102 at room temperature.

Keep the study drug in a safe place and out of reach of children.

Take the study drug with water within 1 hour after your morning and evening meal.

If you vomit after taking the study drug, do not take a replacement dose.

Take your doses on schedule.

Report any missed doses at your next study visit.
TAS-102 is taken in pill form with water within 1 hour of completing a meal and you will take 
the study drug orally (by mouth) twice a day from Day 1 through Day 5 of every cycle with the 
first dose in the morning of Day 1 and the last given in the evening of Day 5 (drug is taken every 
8 to 12 hours). This is followed by a recovery period (i.e., no study drug given) beginning Day 6 
through Day 14 of each cycle. The dose of TAS-102 to be given will be between 25 and 35mg/ 
m2. The dose you receive will be determined by when you join the study. Your study doctor will 
tell you what dose you will receive. 
APPROVED BY THE YALE UNIVERSITY IRB 6/21/2019


APPROVED BY THE YALE UNIVERSITY IRB 6/21/2019
Principal Investigator:
Jeremy Kortmansky, MD
HIC #: 
1605017852
Funding Source:
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Protocol Version and Date:
5.0 dated 07-Jun-2018
Page 4 of 14
YCC v5.0 (26-Jun-2018) 
Oxaliplatin is given as an intravenous (in a vein in your arm) infusion on Day 1 of each cycle 
when you are in the clinic for your study visits. The dose of oxaliplatin to be given is 85 mg/m2. 
All subjects will get the same dose of oxaliplatin. 
The following is a list of evaluations that you will undergo during the treatment period of the 
study:
Cycle 1 Day 1:

Review of your medical history

Review changes in your medications including prescriptions drugs, over-the-counter 
medications, herbal drugs and dietary supplements

Physical examination

Evaluate your ECOG performance status

Vital signs

Routine laboratory tests of your blood

Blood sample to test your Serum carcinoembryonic antigen (CEA) levels. CEA levels are 
checked to monitor colorectal cancer and if the study drugs are working in your cancer. 

Receive a prescription for TAS-102 to be filled at your local pharmacy

Receive a pill diary to record your doses of TAS-102 taken at home
Cycle 1 Day 8:

Review changes in your health and/ or medications including prescriptions drugs, over-
the-counter medications, herbal drugs and dietary supplements

Physical examination

Evaluate your ECOG performance status

Vital signs

Routine laboratory tests of your blood
Day 1 of each cycle thereafter (unless otherwise specified):

Review of your medical history

Review changes in your health and/ or medications including prescriptions drugs, over-
the-counter medications, herbal drugs and dietary supplements

Physical examination

Evaluate your ECOG performance status

Vital signs

Routine laboratory tests of your blood

Blood sample to test your Serum CEA levels starting with Cycle 3 and every odd cycle 
thereafter (i.e., Cycle 5, 7, 9, etc.)

CT or PET/CT scan of your chest, abdomen and pelvis starting on Day 1 of cycle 5 and 
every 8 weeks thereafter or more frequently if clinically indicated. The frequency may be 
changed to every 12 weeks at the discretion of your study doctor after your first 2 scans 
are completed during the treatment period. 
APPROVED BY THE YALE UNIVERSITY IRB 6/21/2019


APPROVED BY THE YALE UNIVERSITY IRB 6/21/2019
Principal Investigator:
Jeremy Kortmansky, MD
HIC #: 
1605017852
Funding Source:
Yale Cancer Center
Protocol Version and Date:
5.0 dated 07-Jun-2018
Page 5 of 14
YCC v5.0 (26-Jun-2018) 

Receive a prescription for TAS-102 to be filled at your local pharmacy

Receive a pill diary

Return your pill diary from the previous cycle
End of Treatment
The following procedures will be performed within 28 days of your last dose of study drugs, or 
prior to your next anti-cancer treatment, whichever occurs first:

Review of your medical history

Review changes in your health and/ or medications including prescriptions drugs, over-
the-counter medications, herbal drugs and dietary supplements

Physical examination

Evaluate your ECOG performance status

Vital signs

Routine laboratory tests of your blood

Return your pill diary from the previous cycle
Potential Risks, Side Effects, Discomforts and Inconveniences
Risks associated with TAS-102
As of 24 July 2016, a total of 2,480 subjects have been treated in clinical trials (Taiho sponsored 
or Investigator initiated). The side effects presented below include side effects reported by those 
subjects.  However, the side effects shown below are not a complete list, because rare events of a 
non-severe nature were not listed; however, rare events of a severe nature are listed. The list 
includes effects that both may or may have not been related to TAS-102 and you may experience 
some other side effects that are not listed. Though many of the side effects reported were mild to 
moderate in nature, some side effects may become severe and life-threatening, and could 
potentially worsen, leading to death.
You should talk with your study doctor about any side effects that you have while participating 
in this trial.
Likely, occurring in >20% (all levels of severity) of participants:

Digestive system: Nausea, vomiting, diarrhea

Blood: Lowered white blood cell counts/neutrophils (white blood cells are important in 
helping people fight off or prevent infections); Lowered red blood cell count (anemia). 
Red blood cells are important for carrying oxygen in the blood and decreased amounts 
can lead to symptoms such as tiredness or shortness of breath. These side effects are 
typically mild in nature when subjects are taking TAS-102 alone and blood counts are 
often slow to return to normal. The effect on your blood counts may be more severe in 
nature due to combination of TAS-102 and oxaliplatin being used in this study. 

General: Tiredness

Metabolism: Loss of appetite

Infection: Infections, e.g. blood (can be fatal), lung, pelvis, eye, urinary tract, intestinal 
tract, skin, liver/biliary tract, medical device (such as an indwelling catheter)
APPROVED BY THE YALE UNIVERSITY IRB 6/21/2019


APPROVED BY THE YALE UNIVERSITY IRB 6/21/2019
Principal Investigator:
Jeremy Kortmansky, MD
HIC #: 
1605017852
Funding Source:
Yale Cancer Center
Protocol Version and Date:
5.0 dated 07-Jun-2018
Page 6 of 14
YCC v5.0 (26-Jun-2018) 
Common, occurring in 3 -20% (all levels of severity) of participants:

Digestive system: Sores in mouth (stomatitis), constipation, abdominal pain, indigestion

Blood: Lowered platelet count (platelets are important in helping a person’s blood to clot 
when they are bleeding)

Skin: Hair loss, rash (changes in the color or texture of the skin, possible blistering and 
peeling

Kidney: Leakage of protein in urine

Nerve: Changes in sense of taste, headache

Musculoskeletal: back pain, joint pain

General: Fever, Weakness

Metabolism: Decreased blood protein

Psych: Anxiety

Liver: Abnormally high levels of enzymes produced by the liver (meaning that your liver 
is not working properly)
Rare but severe, occurring in ˂3% (severity level 3 and above) of participants:

Heart: Heart attack, heart muscle damage, chest pain, the heart beats too fast or too slow

Liver: Liver damage, yellow color of skin or eyes (jaundice)

Kidney: Kidney damage, blood in urine

Brain: Effects on brain or nerve function, seizure, decreased level of consciousness, 
blood clot

Digestive system: Inflammation of large bowel (symptoms with abdominal pain, 
diarrhea, and bloody stool), abnormal connection between digestive system and other 
areas (fistula), blockage of small or large bowel, accumulation of fluid in abdomen, 
bleeding, intestinal ulcer, inflammation of the pancreas

Lung: Blood clots in lung, difficulties in or cessation of breathing, inflammation of lung, 
nosebleed

Metabolism: Gout (high levels of uric acid with symptoms with red, tender, hot and 
swollen joints), dehydration

Vascular: Fainting, blood clot in leg, decreased blood pressure, blood clotting disorder, 
hot flushes

Nervous: Dizziness, Numbness and Tingling

Musculoskeletal: Muscle pain

General: Flu like symptoms, general physical health deterioration, swelling in legs
Post-marketing data
TAS-102 has been marketed in Japan as Lonsurf® since 26-May-2014. Approximately 7,000 
subjects have been exposed to Lonsurf in clinical studies and clinical practice settings in Asia. 
The following events have been reported from these subjects.

Blood: fever with low neutrophil count (can be fatal); blood clotting disorder (can be 
fatal); failure of bone marrow to produce sufficient numbers of red cells, white cells or 
APPROVED BY THE YALE UNIVERSITY IRB 6/21/2019


APPROVED BY THE YALE UNIVERSITY IRB 6/21/2019
Principal Investigator:
Jeremy Kortmansky, MD
HIC #: 
1605017852
Funding Source:
Yale Cancer Center
Protocol Version and Date:
5.0 dated 07-Jun-2018
Page 7 of 14
YCC v5.0 (26-Jun-2018) 
platelets (can be fatal); lowered platelet count (can be fatal); lowered counts of red cells, 
white cells and platelets together; lowered counts of red cells and white cells/neutrophils

Digestive system: infected fistula; diarrhea; bleeding GI ulcer; block in small or large 
bowel; nausea; tear in small bowel; vomiting

Eye: corneal disorder

General: fever; feeling tired; death

Heart: heart failure, heart beats too fast

Infection: infection; infection in blood; shock; urinary tract infection

Kidney: decreased kidney function

Liver: yellow color of skin or eyes (jaundice); infection in gall bladder; abnormal liver 
function

Metabolism: disturbance in electrolytes

Nervous: blood clot in brain (can be fatal)

Respiratory: pneumonia (can be fatal); interstitial pneumonia (can be fatal); respiratory 
distress syndrome (can be fatal); blood clot in lung
Risks associated with Oxaliplatin
The most common side effects include:

sensory and/or motor neuropathy (damage to nerves resulting in pain, loss of sensation, 
or inability to control muscles)

allergic reactions

pharyngolaryngeal dysesthesia (tightness or discomfort in the throat making it seem 
difficult to breathe or swallow)

interstitial lung disease or pulmonary fibrosis (damage to lung tissue)

liver toxicity

decrease in blood cells
Other Risks
Blood Collection and Intravenous (IV) catheter placement:
The risks of taking blood may include pain, redness, swelling and/or bruising where the needle 
enters your body, light-headedness and fainting. On rare occasions, local blood clot formation or 
infection with redness and irritation of the vein has occurred. The blood pressure cuff may cause 
discomfort or bruising to the upper arm.
Reproductive Risks:
Risks for Women
If you are pregnant or become pregnant, or if you are currently breastfeeding, you cannot take 
part in this study because you or your child may be exposed to an unknown risk. If you are a 
woman who can become pregnant, you must have a blood test that shows you are not pregnant 
before you can be enrolled in this study.  If the blood test is positive, you will not be enrolled in 
this study.
If you can become pregnant, you must agree to remain abstinent or use two birth control methods 
that are judged to be highly effective by your study doctor from the time you sign this consent 
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HIC #: 
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Funding Source:
Yale Cancer Center
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document until 4 weeks after your last dose of study drugs. Acceptable methods of contraception 
include abstinence, tubal ligation, combined oral, transdermal or intra-vaginal hormonal 
contraceptives, medroxyprogesterone injections (e.g., Depo-provera), copper-banded intra-
uterine devices, hormone impregnated intra-uterine systems and vasectomised partners. All 
methods of contraception (with the exception of total abstinence) should be used in combination 
with the use of a condom by a male partner.
Risks for Men
If your partner is able to become pregnant, you must agree to remain abstinent or use a condom 
plus from the time you sign this consent document until 4 weeks after your last dose of study 
drugs. If your partner is able to become pregnant and is not using effective contraception (see 
acceptable methods outlined above), you must agree to remain abstinent or use a condom during 
the study and for 6 months after your last dose of study drugs. Male subjects should avoid 
procreation during the trial and for 6 months after the last dose of study drugs.
Tell your study doctor right away if you suspect that you have become pregnant during the study.  
The study doctor or research staff will advise you of the possible risks to your unborn child and 
the options available to you.  The study team will ask if you, or your pregnant partner, are 
willing to provide information about the pregnancy and the outcome. You, or your pregnant 
partner, will be asked to review and sign a separate research authorization form at that time.
There may also be side effects, other than listed above that we cannot predict. Other drugs will 
be given to make side effects that occur less serious and less uncomfortable. Many side effects 
go away shortly after the drug or procedure is stopped, but in some cases side effects can be 
serious, long lasting or permanent.
For more information about risks and side effects, ask the researcher or contact their office at 
203-407-8002.
Benefits
If you agree to take part in this research study, we cannot guarantee that you will receive any 
benefits. We hope the information learned from this research study may benefit other patients 
with colorectal cancer in the future.
Economic Considerations
You will not be paid for taking part in this study. Tests and procedures that would be performed 
for your regular cancer care whether you are on this study or not are called “standard of care.” 
All of the tests and procedures listed in this consent form that will be performed at your study 
visits are standard of care unless noted with an asterisk (*). The administration of the study drug, 
oxaliplatin, will be charged to you or your insurance provider. You or your insurance provider 
will be responsible for the cost of TAS-102 and oxaliplatin. There will be no charge to you or 
your insurance provider for tests or procedures noted with an asterisk as these are performed for 
study purposes only. All other tests and procedures will be charged to you or your insurance 
provider in the usual way as these are standard of care. This may include other tests and 
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Jeremy Kortmansky, MD
HIC #: 
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Funding Source:
Yale Cancer Center
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procedures not listed in this consent if your doctor feels it is necessary for your care, such as 
additional laboratory tests.
Taking part in this research study may lead to added costs for you or your insurance provider.  
You are encouraged to speak with your insurance provider prior to entering the research study to 
find out your individual coverage. If you have difficulty determining your individual insurance 
coverage, you may call Dr. Jeremy Kortmansky’s office for assistance at 203-407-8002.  
You or your insurance provider will be charged for continuing medical care and/or 
hospitalization that are not a part of the research study.   
Treatment Alternatives
You do not have to participate in this study. Your other choices may include:

Getting treatment or care for your cancer without being in a study including taking TAS-
102, regorafenib alone or another oxaliplatin-based regimen if you have not taken these 
drugs before. 

Taking part in another study.

Receiving no treatment at this time.

Getting comfort care, also called palliative care; this type of care helps reduce pain, 
tiredness, appetite problems, and other problems caused by the cancer.  
Comfort care does not treat the cancer directly but instead is meant to improve how you 
feel.  Comfort care tries to keep you as active and comfortable as possible.  
Talk to your doctor about your choices before you decide if you will take part in this study.
Confidentiality and Authorization to collect, use and disclose Protected Health Information
For purposes of this study, Yale University, Yale-New Haven Hospital, and Dr. Jeremy 
Kortmansky will use medical information collected or created as part of the study, such as 
medical records and test results, which identifies you by name or in another way. Your consent 
to participate in the study means you agree that Yale University, Yale-New Haven Hospital, and 
Dr. Jeremy Kortmansky may obtain your medical information that they request for study 
purposes from your physicians and your other health care providers from the past or during your 
participation in the study. 
The protected health information that will be collected in this study includes demographics, 
medical history, physical examinations, routine lab tests, review of adverse events and 
medications you take (past and present), vital signs, CT or PET/CT scans, pregnancy tests, and 
records about any study drug(s) that you received.
Any identifiable information that is obtained in connection with this study will remain 
confidential and will be disclosed only with your permission or as permitted by U.S. or State 
law.  Examples of information that we are legally required to disclose include abuse of a child or 
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Yale Cancer Center
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elderly person, or certain reportable diseases such as HIV or hepatitis. When the results of the 
research are published or discussed in conferences, no information will be included that would 
reveal your identity unless your specific consent for this activity is obtained.  
We understand that information about you obtained in connection with your health is personal, 
and we are committed to protecting the privacy of that information.  If you decide to be in this 
study, the study staff will get information that identifies you and your protected health 
information.  This may include information that might directly identify you, such as your name, 
date of birth, and medical record number. We will replace your identifying information with a 
code that does not directly identify you. The study doctor will keep a link that identifies you to 
your coded information, and this link will be kept secure and available only to the Principal 
Investigator or selected members of the study team. Any information that can identify you will 
remain confidential. 
The records for this trial will be stored in locked cabinets and/or offices and password protected 
computers. The study team will only give this coded information to others to carry out this 
research study or to comply with federal laws and regulations. It is anticipated that records 
containing the information that links you to your coded information will be maintained 
indefinitely, as there are no plans at this time to destroy these records at the end of the study.  
Information about your study participation will be entered into your Electronic Medical Record 
(EMR). Once placed in your EMR, these results are accessible to all of your providers who 
participate in the EMR system. Information within your EMR may also be shared with others 
who are appropriate to have access to your EMR (e.g., health insurance company, disability 
provider.)
Information about you and your health which might identify you may be used by or given to: 

The U.S. Department of Health and Human Services (DHHS) agencies

Representatives from Yale University and the Human Investigation Committee (the 
committee or Institutional Review Board that reviews, approves, and monitors research 
on human subjects), who are responsible for ensuring research compliance.  These 
individuals are required to keep all information confidential

Your providers who are participants in the Electronic Medical Record (EMR) system

Those individuals at Yale who are responsible for the financial oversight of research 
including billings and payments

The study doctor, Dr. Jeremy Kortmansky, and the Yale study team

The U.S. Food and Drug Administration (FDA).  This is done so that the FDA can review 
information about the new drug product involved in this research.  The information may 
also be used to meet the reporting requirements of drug regulatory agencies.  

Drug regulatory agencies in other countries

Governmental agencies to whom certain diseases (reportable diseases) must be reported
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HIC #: 
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Funding Source:
Yale Cancer Center
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
Health care providers who provide services to you in connection with this study.

Laboratories and other individuals and organizations that analyze your health information 
in connection with this study, according to the study plan.

Data and Safety Monitoring Boards and others authorized to monitor the conduct of the 
Study
By signing this form, you authorize the use and/or disclosure of the information described 
above for this research study.  The purpose for the uses and disclosures you are authorizing is 
to ensure that the information relating to this research is available to all parties who may need 
it for research purposes.
All health care providers subject to HIPAA (Health Insurance Portability and Accountability 
Act) are required to protect the privacy of your information.  The research staff at Yale School 
of Medicine and Yale-New Haven Hospital is required to comply with HIPAA and to ensure 
the confidentiality of your information.  Some of the individuals or agencies listed above may 
not be subject to HIPAA and therefore may not be required to provide the same type of 
confidentiality protection. They could use or disclose your information in ways not mentioned 
in this form.  However, to better protect your health information, agreements are in place with 
these individuals and/or companies that require that they keep your information confidential. 
Authorized representatives of the Food and Drug Administration (FDA) may need to review 
records of individual subjects.  As a result, they may see your name, but they are bound by 
rules of confidentiality not to reveal your identity to others.
You have the right to review and copy your health information in your medical record in 
accordance with institutional medical records policies.  However, you will not be allowed to look 
at or copy your study related information until after the research is completed.  
This authorization to use and disclose your health information collected during your participation 
in this study will never expire.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you.  At most, the Web 
site will include a summary of the results. You can search this Web site at any time.
In Case of Injury
If you are injured while on study, seek treatment and contact the study doctor as soon as you are 
able.
Yale School of Medicine and Yale-New Haven Hospital do not provide funds for the treatment 
of research-related injury. If you are injured as a result of your participation in this study, 
treatment will be provided. You or your insurance carrier will be expected to pay the costs of this 
treatment.  No additional financial compensation for injury or lost wages is available.
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HIC #: 
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Funding Source:
Yale Cancer Center
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You do not give up any of your legal rights by signing this form.
Voluntary Participation and Withdrawal
Participation in this study is voluntary. You are free to choose not to take part in this research 
study.  Refusing to take part in this research study will not lead to penalty or loss of benefits to 
which you are otherwise entitled (such as your health care outside the study, the payment for 
your health care, and your health care benefits). However, you will not be able to enroll in this 
research study and will not receive study procedures as a study participant if you do not allow 
use of your information as part of this study.
Withdrawing From the Study:
If you decide to participate in this research study, you are free to stop and withdraw from this 
study at any time during its course. To withdraw from the study, you can call a member of the 
research team at any time and tell them that you no longer want to take part.  They will make 
sure that proper procedures are followed and a final visit is made for your safety. This will cancel 
any future research study appointments. 
The researchers may withdraw you from participating in the research if necessary. Your study 
doctor may end your participation in the study if you experience unacceptable toxicity, if you do 
not take the study drugs as directed and/ or if you do not follow the trial procedures as directed. 
Withdrawing from the study will involve no penalty or loss of benefits to which you are 
otherwise entitled. It will not harm your relationship with your own doctors or with Yale-New 
Haven Hospital.
If you choose not to give your consent by not signing this document, or if you cancel your 
consent later, then you will not be eligible to participate in this study and will not receive any 
study drugs provided as part of the study. Unless and until you do cancel the consent, it will 
remain valid and effective.
Withdrawing Your Authorization to Use and Disclose Your Health Information:
You may withdraw or take away your permission to use and disclose your health information at 
any time. You do this by telling the study staff or by sending written notice to the study doctor, 
Dr. Jeremy Kortmansky, at the address listed on page one of this form.  If you withdraw your 
permission, you will not be able to stay in this study.
When you withdraw your permission, no new health information identifying you will be 
gathered after that date.  Information that has already been gathered may still be used and given 
to others until the end of the research study, as necessary to insure the integrity of the study 
and/or study oversight.  
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Principal Investigator:
Jeremy Kortmansky, MD
HIC #: 
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Funding Source:
Yale Cancer Center
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Questions
We have used some technical terms in this form.  Please feel free to ask about anything you don't 
understand and to consider this research and the consent form carefully – as long as you feel is 
necessary – before you make a decision.
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HIC #: 
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Funding Source:
Yale Cancer Center
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Authorization and Permission
I have read (or someone has read to me) this form and have decided to participate in the project as 
described above.  Its general purposes, the particulars of my involvement and possible hazards and 
inconveniences have been explained to my satisfaction.  My signature also indicates that I have received a 
copy of this consent form.
By signing this form, I give permission to the researchers to use and give out information about me for 
the purposes described in this form.  By refusing to give permission, I understand that I will not be able to 
participate in this research. 
Study Participant (print name)
Signature
Date
Person obtaining consent (print 
name)
Signature
Date
Person obtaining consent (print 
name) – only if applicable, 
otherwise blank
Signature
Date
Interpreter/ Witness (print name) 
– only if applicable, otherwise blank
Signature
Date
 
If after you have signed this form you have any questions about your privacy rights, please contact the 
Yale Privacy Officer at (203) 432-5919.
If you have further questions about this project or if you have a research-related problem, you may 
contact the Principal Investigator, Dr. Jeremy Kortmansky, at 203-407-8002.  If you would like to talk 
with someone other than the researchers to discuss problems, concerns, and questions you may have 
concerning this research, or to discuss your rights as a research subject, you may contact the Yale Human 
Investigation Committee at (203) 785-4688. 
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