A Phase II Trial of TAS-102 in Previously Treated Unresectable or Metastatic Squamous Cell Carcinoma of the Lung
Phase: PHASE2
Conditions: Squamous Cell Lung Carcinoma
Sponsor: University of Florida

 
A Phase II Trial of TAS-102 in Previously Treated Unresectable or Metastatic Squamous 
Cell Carcinoma of the Lung 
 
 
Protocol Number: 
 
 
UF-STO-LUNG-003  
 
Coordinating Center: 
 
University of Florida 
 
Principal Investigator:  
 
Dennie Jones, MD 
 
 
1601 SW Archer Road 
 
 
Gainesville, FL  32608-1135 
 
 
Telephone: 352-548-6000, ext. 4320 
 
 
Fax:  352-548-6463 
 
 
E-mail address:   Dennie.Jones@medicine.ufl.edu  
 
 
 
 
 
 
 
Dennie.Jones@VA.gov 
Statistician:  
 
 
Shu Wang, PhD 
 
Clinical Phase: 
 
 
Phase II 
 
IND Status:  
 
 
Exempt 
 
 
Investigational Agent: 
 
TAS-102 (Lonsurf®)  
 
 
Date of Original Protocol:  
June 26, 2016 
 
Date of Current Protocol:  
June 18, 2019 
 
Version of Current Protocol: 
Version 1.8 
 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the 
extent necessary to obtain informed consent, may not be disclosed to another party unless law 
or regulations require such disclosure.  Persons to whom the information is disclosed must be 
informed that the information is confidential and may not be further disclosed by them. 
 
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
Page 
 
 
Patients must fulfill all of the following criteria to be eligible for study entry: ...................... 8 
1. 
INTRODUCTION............................................................................................................ 13 
1.1 
Background .......................................................................................................................................... 13 
2. 
OBJECTIVES .................................................................................................................. 14 
2.1 
Primary ................................................................................................................................................... 14 
2.2 
Secondary .............................................................................................................................................. 14 
3. 
SELECTION OF SUBJECTS ........................................................................................ 14 
3.1 
Number of Subjects .......................................................................................................................... 14 
3.2 
Inclusion Criteria .............................................................................................................................. 14 
Patients must fulfill all of the following criteria to be eligible for study entry: .................... 14 
3.3 
Exclusion Criteria ............................................................................................................................. 16 
3.4 
Inclusion of Women and Minorities ....................................................................................... 17 
4. 
REGISTRATION PROCEDURES ................................................................................ 17 
5. 
STUDY TREATMENT ................................................................................................... 17 
5.1 
Treatment Schedule/Administration ................................................................................... 17 
5.2 
Concomitant Therapy ..................................................................................................................... 18 
5.3 
Dose Modifications ........................................................................................................................... 19 
5.3.1 
Dose Modification Table ...................................................................................................... 19 
5.3.2 
Non‐ Hematologic Toxicity ................................................................................................. 20 
5.3.3 
Hematologic Toxicity ............................................................................................................. 20 
5.4 
Supportive Care Guidelines ........................................................................................................ 21 
6. 
TREATMENT DISCONTINUATION .......................................................................... 21 
6.1 
Removal of Subjects From Study .............................................................................................. 21 
6.2 
Criteria For Study Treatment Discontinuation ............................................................... 21 
6.3 
Replacement of Subjects ............................................................................................................... 22 
6.4 
Study Discontinuation .................................................................................................................... 22 
7. STUDY PROCEDURES ........................................................................................................ 22 
7.1    Study Schedule of Events ................................................................................................................ 22 
7.2   Screening Evaluations ....................................................................................................................... 23 
7.3   On‐Study Evaluations ......................................................................................................................... 24 
7.4   End of Treatment .................................................................................................................................. 24 
7.5   Follow up/Survival .............................................................................................................................. 25 

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8.      CRITERIA FOR DISEASE EVALUATION .................................................................. 25 
8.1    Definitions ............................................................................................................................................... 25 
8.2    Response Criteria ................................................................................................................................ 28 
9.      STUDY DRUG INFORMATION .................................................................................... 31 
9.1    Study Drug Name ................................................................................................................................. 31 
9.1.1   Identification ................................................................................................................................. 31 
9.1.2    Packaging and Labeling ......................................................................................................... 31 
9.1.3    Drug Supply ................................................................................................................................... 32 
9.1.4   Storage, Handling and Dispensing .................................................................................... 32 
9.1.5    Drug Ordering and Accountability .................................................................................. 32 
9.1.6    Contraindications ...................................................................................................................... 32 
9.1.7    Special Warnings and Precautions for Use ................................................................. 32 
9.1.8   Interactions with Other Medications .............................................................................. 32 
9.1.9   Adverse Event Profile ............................................................................................................... 33 
10. 
ADVERSE EVENTS .............................................................................................................................. 51 
10.1 Definitions ............................................................................................................................................ 51 
10.1.1 
Adverse Event ........................................................................................................................ 51 
10.1.2 
Serious Adverse Event ...................................................................................................... 52 
10.1.3 
Non‐Serious Adverse Event ........................................................................................... 53 
10.2 Period of Observation .................................................................................................................... 53 
10.3 Documenting and Reporting of Adverse Events by Investigator .......................... 54 
10.3.1 
Assessment of Causal Relationship of Study Drug ........................................... 54 
10.3.2 
Intensity of Adverse Events ........................................................................................... 55 
10.3.3 
Action Taken with Study Drug ..................................................................................... 55 
10.3.4 
Definition of Outcome ....................................................................................................... 56 
10.4 Immediately Reportable Events ............................................................................................... 56 
10.4.1 
Serious Adverse Events .................................................................................................... 56 
10.4.2 
Other Events Requiring Immediate Reporting .................................................. 57 
10.5 IND Safety Reports Unrelated to this Trial......................................................................... 57 
11.    STATISTICAL METHODS ............................................................................................. 57 
11.1 Sample Size Determination ......................................................................................................... 57 
11.2 Analysis of Endpoints/Efficacy ................................................................................................. 58 
11.3 Analysis of Demographic and Baseline Characteristic................................................ 58 
11.4  Analysis of Safety Data .................................................................................................................... 58 

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12. 
DATA AND SAFETY MONITORING ......................................................................... 59 
12.1 Data Integrity and Safety Committee .................................................................................... 59 
12.2 On‐site Monitoring ........................................................................................................................... 59 
12.3 Principal Investigator Responsibilities ............................................................................... 60 
13. 
EMERGENCY PROCEDURES..................................................................................... 60 
13.1 Emergency Contact .......................................................................................................................... 60 
13.2 Emergency Identification of Investigational Products ............................................... 60 
13.3 Emergency Treatment ................................................................................................................... 60 
14. 
ADMINISTRATIVE CONSIDERATIONS .................................................................. 60 
14.1 Good Clinical Practice ..................................................................................................................... 60 
14.2 Institutional Review Board ......................................................................................................... 61 
14.3 Delegation of Investigator Responsibilities ...................................................................... 61 
14.4 Subject Information and Informed Consent ...................................................................... 61 
14.5 Confidentiality .................................................................................................................................... 62 
14.6 Protocol Amendments ................................................................................................................... 62 
14.7 Case Report Forms ........................................................................................................................... 62 
14.8 Record Retention .............................................................................................................................. 62 
15. COMPLIANCE WITH LAWS AND REGULATIONS ................................................... 63 
16. REFERENCES ...................................................................................................................... 63 
 
 
 

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ABBREVIATIONS   
AE 
adverse event 
ALT 
alanine transaminase (also SGPT) 
ANC 
absolute neutrophil count 
AST 
aspartate transaminase (also SGOT) 
AUC 
area under curve 
BSA 
body surface area 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CL 
clearance 
CR 
complete remission 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
GCP 
Good Clinical Practice 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IRB 
Institutional Review Board 
IV 
intravenous 
LDH 
lactic dehydrogenase 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MTD 
maximum tolerated dose 
PCR 
polymerase chain reaction 
PD 
pharmacodynamics 
PDO 
Protocol Development Office 
PK 
pharmacokinetics 
PR 
partial remission 
PT 
prothrombin time  
PTT 
partial thromboplastin time 
RBC 
red blood cells 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SC 
subcutaneous 
SD 
stable disease 
SGOT 
serum glutamic oxaloacetic transaminase (also AST) 
SGPT 
serum glutamic pyruvate transaminase (also ALT) 
Tmax 
time to maximum plasma concentration 
ULN 
upper limit of normal 
US 
United States 
WBC 
white blood cell  
WHO 
World Health Organization 

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Protocol Signature Page 
 
A Phase II Trial of TAS-102 in Previously Treated Unresectable or Metastatic Squamous 
Cell Carcinoma of the Lung 
 
 
 
Principal Investigator: 
 
 
 
 
 
 
Signature of Investigator 
 
Dennie V. Jones, Jr., MD 
 
Date 
 
 
 
Printed Name of Investigator 
 
University of Florida 
 
 
 
Name of Facility 
 
Gainesville, Florida 
 
 
 
Location of Facility (City/State) 
 
 
 
By my signature, I agree to personally supervise the 
conduct of this study and to ensure its conduct in 
compliance with the protocol, informed consent, IRB 
procedures, the Declaration of Helsinki, ICH Good 
Clinical Practices guidelines, and the applicable parts of 
the United States Code of Federal Regulations or local 
regulations governing the conduct of clinical studies. 
 
 
 

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PROTOCOL SYNOPSIS 
 
Title: 
A Phase II Trial of TAS-102 in Previously Treated Unresectable or 
Metastatic Squamous Cell Carcinoma of the Lung 
Rationale: 
One of the oldest antineoplastic agents available, 5-FU, has some 
activity against NSCLC. Capecitabine is an oral prodrug which is 
converted into 5-FU and its active metabolites, and has modest activity 
against NSCLC in combination with carboplatin. To date, there have 
only been three reports of the oral 5-FU prodrug UFT (uridine and 
ftorafur) administered to patients with NSCLC. In two small series a, 
low response rate was observed, although low doses of UFT were 
used. In the third trial, UFT was administered as post-surgical 
adjuvant therapy, and was associated with a statistically significant 
increase in 5-year survival. S-1 is a separate 5-FU prodrug which has 
activity in non-small cell lung cancer, and is approved in Japan for the 
treatment of NSCLC, either alone or in combination with a platinum 
based therapy. S-1 is composed of tegafur (the 5-FU prodrug); 5-
chloro-2, 4-dihydroxypyridine (CDHP), which reversibly inhibits 5-
FU degradation by dihydropyrimidine dehydrogenase (DPD); and 
potassium oxonate which blocks the phosphorylation of 5-FU within 
the gastrointestinal tract and reduces gastrointestinal toxicities. TAS-
102 is an oral drug which consists of a combination of trifluridine and 
tipiracil hydrochloride. Trifluridine is phosphorylated by thymidine 
kinase into its active form intracellularly, where is causes DNA strand 
termination and breaks, leading to its cytotoxic activity. Tipiracil 
hydrochloride inhibits thymidine phosphorylase, which then prevents 
the degradation of trifluridine. This drug was recently approved for 
the treatment of 5-FU-resistant colorectal cancers, and it has 
demonstrated activity in vitro against a broad spectrum of human 
tumor cell lines, including non-small cell lung cancer, especially the 
squamous cell variant. To date, there are no reports of a clinical 
evaluation of this agent in NSCLC, as is proposed here. This protocol 
will evaluate squamous cell NSCLC; nonsquamous cell NSCLC 
(adenocarcinomas, large cell carcinomas, and poorly differentiated 
p63-negative carcinomas) will not be evaluated in this protocol due to 
the potential for differential expression of thymidine kinase and 
thymidine phosphorylase by histology and the preclinical evidence for 
a lower level of cytotoxicity in those histologic variants. The dire 
outcome of patients with unresectable and/or metastatic non-small cell 
lung cancer with currently available therapies justifies the evaluation 
of new agents to determine their potential clinical benefit in this 
disease. 
Study 
Schema: 
Drugs / Doses / 
Length 
of 
Treatment 
Upon confirmation of eligibility and provision of written informed 
consent, subjects will receive TAS-102 (Lonsurf®) at its FDA-
approved dose and schedule, 35 mg/m2 up to a maximum of 80 mg per 
dose (based on the trifluridine component) orally twice daily within 

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one hour of completion of morning and evening meals on Days 1 
through 5 and Days 8 through 12 of each 28-day cycle until disease 
progression or unacceptable toxicity. Doses will be rounded to the 
nearest 5 mg increment. Additional doses will not be taken to make up 
for missed or held doses. Subjects will be monitored weekly during 
the first cycle for tolerance, and tumor status will be assessed every 
other cycle. Participants will continue on therapy until the 
development of unacceptable toxicity, disease progression, or 
participant desire to discontinue protocol therapy. 
Objectives: 
Primary Objective: 
 To determine the percentage of subjects who achieve an 
objective response by RECIST criteria 
 
Secondary Objectives: 
 To evaluate the qualitative and quantitative toxicities, and 
reversibility of toxicities, of this treatment by NCI CTC 
Version 4.0.3 criteria 
 To determine the progression-free survival, in months, of 
subjects receiving TAS-102 for the treatment of unresectable 
or metastatic recurrent squamous cell lung cancers 
 To determine the percentage of subjects who derive clinical 
benefit (objective response + stable disease) 
 To determine the median duration of responses in months 
 To determine the overall survival in months  
 To determine the percentage of expression of thymidine kinase 
and thymidine phosphorylase 
Study Design: 
Non-randomized, open label, sequentially enrolling phase II study 
with a Simon two-step enrollment design. 
Accrual Goal: 
Up to 30 subjects 
Inclusion 
Criteria: 
Patients must fulfill all of the following criteria to be eligible for study 
entry: 
 
Those who will be eligible will be all patients with unresectable and/or 
metastatic squamous cell non-small cell lung cancer who have disease 
which has been previously treated with an FDA- or NCCN-approved 
platinum doublet. Patients who have not received such therapy must 
have medical reasons for not receiving such therapy. Those who have 
a molecularly targetable genetic mutation in their tumor must have 
also received the appropriate specific therapy for that mutation. All 
will be appropriate candidates for chemotherapy treatment. All 
patients will have an ECOG performance status of <2 at the time of 
the initiation of therapy, adequate end-organ function, no severe 
comorbid disease, and ability to provide informed consent. 
 

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Subjects must meet all of the additional following criteria to be 
eligible for study participation: 
A. 
ECOG Performance Status ≤ 2  
B. 
Life expectancy > 12 weeks 
C. 
Male or female‚ age >18 years 
D. 
Patients of childbearing potential must be using an 
effective means of contraception. 
E. 
Histologic diagnosis of squamous cell lung cancer that is 
been treated adequately in the metastatic or unresectable 
setting with a platinum doublet chemotherapy regimen, 
and now has evidence of disease progression. Patients 
may have also received additional chemotherapy, such as 
an immune checkpoint inhibitor or no more than one 
additional cytotoxic agent (thus participants may have 
received between one to three prior lines of therapy for 
metastatic or unresectable disease) 
F. 
Those patients who have received platinum-based doublet 
therapy in the neoadjuvant or adjuvant setting will only be 
eligible if they have experienced disease progression after  
their last dose of cytotoxic chemotherapy 
G. 
For patients who have a neoplasm for which there 
currently exists a targeted therapy (such as to EGFR 
activating 
mutations, 
or 
ALK 
or 
ROS1 
gene 
rearrangements) must have received all such targeted 
therapies and either exhibited progressive disease through 
such treatments, or have been shown to be intolerant of 
such therapies, prior to enrollment on this study 
H. 
Baseline laboratory values (bone marrow, renal, hepatic):  
o Adequate bone marrow function: 
 Absolute neutrophil count >1000/µL  
 Potential subjects with benign ethnic 
neutropenia, often seen in African 
Americans and Afro-Caribbean men 
and women, may be enrolled after 
discussion with the PI, provided they 
have no other disqualifying features and 
no evidence of medical consequences 
of their neutropenia, such as repeated 
infections) 
 Platelet count >100‚000/µL 
o Renal function: 
 Serum creatinine < 2.0 mg  
o Hepatic function: 
 Bilirubin <1.5x normal  
o Serum calcium < 12 mg/dl 

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I. 
Women of childbearing potential (WOCBP) must be 
using an adequate method of contraception to avoid 
pregnancy throughout the study and for at least 6 months 
after the last dose of study drug to minimize the risk of 
pregnancy.   Prior to study enrollment, women of 
childbearing potential must be advised of the importance 
of avoiding pregnancy during trial participation and the 
potential risk factors for an unintentional pregnancy.  
WOCBP include any woman who has experienced 
menarche and who has not undergone successful surgical 
sterilization (hysterectomy, bilateral tubal ligation, or 
bilateral oophorectomy) or who is not post-menopausal. 
Post-menopause is defined as: 
 Amenorrhea that has lasted for ≥ 12 consecutive 
months without another cause, or 
 For women with irregular menstrual periods who are 
taking hormone replacement therapy (HRT), a 
documented serum follicle-stimulating hormone (FSH) 
level of greater than 35 mIU/mL. 
J. 
Males with female partners of child-bearing potential 
must agree to use physician-approved contraceptive 
methods 
(e.g., 
abstinence, 
condoms, 
vasectomy) 
throughout the study and should avoid conceiving 
children for 3 months following the last dose of study 
drug. 
K. 
Subjects must have provided written informed consent 
and be willing to comply with all study-related 
procedures.  
Exclusion 
Criteria: 
Subjects with any of the following will not be eligible for study 
participation: 
A. 
Pregnant or lactating females 
B. 
Patients with a mixed histology NSCLC, such as 
adenosquamous 
carcinoma, 
where 
the 
squamous 
component is <50% of the assessed lesion 
C. 
Patients with a mixed histology where there are ANY small 
cell elements 
D. 
Patients who have not received and progressed through, 
have not refused, or have not been intolerant of, a 
commonly utilized platinum-doublet therapy (cisplatin or 
carboplatin paired with docetaxel, paclitaxel, nab-
paclitaxel, 
gemcitabine, 
vinorelbine, 
etoposide 
or 
irinotecan) administered for the treatment of unresectable 
or metastatic lung cancer 
 
E. 
Patients who have not received the appropriate prior 
targeted therapy for their lung cancer 

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F. 
Any invasive malignancy treated within the prior 3 years 
prior to Cycle 1, Day 1 
G. 
Myocardial infarction or ischemia within the 6 months 
before Cycle 1‚ Day 1 
H. 
Uncontrolled‚ clinically significant dysrhythmia, or 
prolonged QT segment  
I. 
Uncontrolled malignant disease in the CNS (previously 
treated disease is eligible, provided it has been 
radiographically stable for at least four weeks)  
J. 
Radiotherapy within the 2 weeks before Cycle 1, Day 1. If 
any radiation has been administered to the target lesion 
there must be evidence of growth by radiographic 
assessments or physical examination 
K. 
Surgery within the 2 weeks before Cycle 1, Day 1 
L. 
Any co-morbid condition that‚ in the view of the attending 
physician‚ renders the patient at high risk from treatment 
complications 
M. 
Subjects unwilling to use an acceptable method to avoid 
pregnancy for the entire study period and for at least 24 
weeks after the last dose of study drug.  
N. 
History of any other disease, metabolic dysfunction, 
physical examination finding, or clinical laboratory 
finding giving reasonable suspicion of a disease or 
condition that contraindicates the use of protocol therapy 
or that might affect the interpretation of the results of the 
study or that puts the subject at high risk for treatment 
complications, in the opinion of the treating physician. 
O. 
Prisoners or subjects who are involuntarily incarcerated. 
P. 
Subjects who are compulsorily detained for treatment of 
either a psychiatric or physical illness. 
Q. 
Subjects demonstrating an inability to comply with the 
study and/or follow-up procedures. 
Efficacy 
Assessments: 
 
Each week of first cycle (days 1, 8, 15 and 22): 
 
Weight and performance status 
Physical exam 
Laboratory studies 
 
 CBC with differential count  
 Comprehensive metabolic panel, serum magnesium 
 
First and 15th day of each subsequent cycle: 
 
Weight and performance status 
Physical exam 
Laboratory studies 
 
 CBC with differential count  

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 Comprehensive metabolic panel, serum magnesium 
 
First day of every odd-numbered cycle (beginning at Cycle 3): 
 CT or MRI of thorax and abdomen, or PET/CT (may be 
obtained up to one calendar week prior to first day of each odd 
numbered cycle)  
Statistical 
Considerations: 
This is a pilot phase II study, so we are interested in evaluating the 
feasibility and safety of a regimen of daily TAS-102 administered to 
subjects with squamous cell lung cancer. To minimize the number of 
subjects exposed, the sample size will be determined by the 
anticipated response rate. A response rate of 20% or above to TAS-
102 will be of interest in subjects with previously-treated squamous 
cell lung cancer. Initially, 14 subjects will be evaluated for response, 
and if none of the 14 evaluable subjects experiences a partial or 
complete response, then the study will be terminated. If the true 
response rate is 20%, the chance of rejection error is less than 5%. 
However, in the event of one response among the first 14 subjects, 
further accrual will continue to a total of 30 evaluable subjects to 
estimate the response rate more precisely with a standard error of no 
more than 9%. A subject is considered eligible for toxicity evaluation 
if they have received at least one dose of TAS-102. A subject will be 
considered eligible for evaluation of activity if they have also received 
two cycles of therapy as planned.  
Estimated 
Enrollment 
Period: 
It is estimated that accrual to the first level (14 subjects) will be 
completed within nine months. If the study is fully accrued (30 
subjects) and at least the last such subject derives benefit from the 
anticipated maximal number of six cycles, then the length of the entire 
enrollment and treatment period will be approximately 24 months. 
Estimated Study 
Duration: 
Approximately 30 months 
 
 
 

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1. INTRODUCTION 
 
1.1 
Background 
 
Invasive cancer is the second most common cause of cancer death in both men and women in the 
United States. The data from the American Cancer Society projected 1,658,370 cases of cancer in 
2015, with approximately 589,430 deaths; nearly 1 in 4 deaths will be due to cancer.  While 
prostate and breast cancers are more common in men and women, respectively, lung cancer is still 
a far more lethal malignancy in either sex, with a five-year survival rate that is less than 15%.  
Surveillance, Epidemiology, and End-Results (SEER) database estimates for 2016 indicate that 
lung cancer will account for 224,390 new lung cancer cases, or 13.3% of all invasive cancer cases 
(not including non-melanoma skin cancer or in situ carcinomas), and there will be 158,080 lung 
cancer deaths, or 26.5% of all deaths. In men 33% of all deaths from cancer are going to be due to 
lung cancer, while in women, 5% of all cancer-related deaths are due to lung cancer.   
 
Approximately 70% of patients with unresectable non-small cell lung cancer (NSCLC) who 
receive and progress through frontline chemotherapy will be eligible for second line treatments. 
Any of the agents which are available for frontline therapy can be used in the salvage setting; 
crizotinib and ceritinib (for ALK gene translocations), AZD9291 (Tagrisso, for EGFR T790M 
mutation positive lesions), erlotinib, ramicirumab, docetaxel, and pemetrexed (in non-squamous 
cell carcinoma) are FDA-approved in the salvage setting based upon their demonstrated survival 
benefit in randomized phase III trials. All untargeted agents appear to be roughly equivalent in 
terms of clinical benefit, which is admittedly modest, with response rates <10%, clinical benefit 
rates of approximately 50%, and overall survivals of approximately 6 months. However, when 
agents are matched to their molecular targets, both response rates and progression-free and overall 
survivals tend to improve significantly. Still, a substantial number of patients may not benefit from 
the agents in the salvage treatment setting, thus it is critical to identify those patients who stand to 
benefit the most. 
 
One of the oldest antineoplastic agents available, 5-FU, has some activity against NSCLC. 
Capecitabine is an oral prodrug which is converted into 5-FU and its active metabolites, and has 
modest activity against NSCLC in combination with carboplatin. To date, there have only been 
three reports of the oral 5-FU prodrug UFT (uridine and ftorafur) administered to patients with 
NSCLC. In two small series a, low response rate was observed, although low doses of UFT were 
used. In the third trial, UFT was administered as post-surgical adjuvant therapy, and was associated 
with a statistically significant increase in 5-year survival. S-1 is a separate 5-FU prodrug which 
has activity in nonsmall cell lung cancer, and is approved in Japan for the treatment of NSCLC, 
either alone or in combination with a platinum. S-1 is composed of tegafur (the 5-FU prodrug); 5-
chloro-2, 4-dihydroxypyridine (CDHP), which reversibly inhibits 5-FU degradation by 
dihydropyrimidine dehydrogenase (DPD); and potassium oxonate which blocks the 
phosphorylation of 5-FU within the gastrointestinal tract and reduces gastrointestinal toxicities. 
TAS-102 is an oral drug which consists of a combination of trifluridine and tipiracil hydrochloride. 
Trifluridine is phosphorylated by thymidine kinase into its active form intracellularly, where is 
causes DNA strand termination and breaks, leading to its cytotoxic activity. Tipiracil 
hydrochloride inhibits thymidine phosphorylase, which then prevents the degradation of 
trifluridine. This drug was recently approved for the treatment of 5-FU-resistant colorectal cancers, 

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and it has demonstrated activity in vitro against a broad spectrum of human tumor cell lines, 
including nonsmall cell lung cancer, especially the squamous cell variant. To date, there are no 
reports of a clinical evaluation of this agent in NSCLC, as is proposed here. This protocol will 
evaluate squamous cell NSCLC; nonsquamous cell NSCLC (adenocarcinomas, large cell 
carcinomas, and poorly differentiated p63-negative carcinomas) will not be evaluated in this 
protocol due to the potential for differential expression of thymidine kinase and thymidine 
phosphorylase by histology and the preclinical evidence for a lower level of cytotoxicity in those 
histologic variants. The dire outcome of patients with unresectable and/or metastatic nonsmall cell 
lung cancer with currently available therapies justifies the evaluation of new agents to determine 
their potential clinical benefit in this disease. 
 
2. OBJECTIVES 
 
2.1 
Primary 
 
 To determine the percentage of subjects who achieve an objective response by RECIST criteria 
 
2.2 
Secondary 
 
 To evaluate the qualitative and quantitative toxicities, and reversibility of toxicities, of this 
treatment by NCI CTC Version 4.0.3 criteria 
 To determine the progression-free survival, in months, of subjects receiving TAS-102 for the 
treatment of unresectable or metastatic recurrent squamous cell lung cancers  
 To determine the percentage of subjects who derive clinical benefit (objective response + stable 
disease) 
 To determine the median duration of responses in months 
 To determine the overall survival in months  
 
3. SELECTION OF SUBJECTS 
 
3.1 
Number of Subjects 
 
This protocol will enroll up to a maximum of 30 subjects. 
 
3.2 
Inclusion Criteria  
 
Patients must fulfill all of the following criteria to be eligible for study entry: 
 
Those who will be eligible will be all patients with unresectable and/or metastatic squamous cell 
non-small cell lung cancer who have disease which has been previously treated with an FDA- or 
NCCN-approved platinum doublet. Patients who have not received such therapy must have 
medical reasons for not receiving such therapy. Those who have a molecularly targetable genetic 
mutation in their tumor must have also received the appropriate specific therapy for that mutation. 
All will be appropriate candidates for chemotherapy treatment. All patients will have an ECOG 
performance status of ≤2 at the time of the initiation of therapy, adequate end-organ function, no 
severe comorbid disease, and ability to provide informed consent. 

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Subjects must meet all of the additional following criteria to be eligible for study participation: 
A. 
ECOG Performance Status ≤ 2  
B. 
Life expectancy > 12 weeks 
C. 
Male or female‚ age >18 years 
D. 
Patients of childbearing potential must be using an effective means of contraception. 
E. 
Histologic diagnosis of squamous cell lung cancer that is been treated adequately in 
the metastatic or unresectable setting with a platinum doublet chemotherapy regimen  
and now has evidence of disease progression.Patients may have also received 
additional chemotherapy, such as an immune checkpoint inhibitor or no more than 
one additional cytotoxic agent (thus participants may have received between one to 
three prior lines of therapy for metastatic or unresectable disease).  
F. 
Those patients who have received platinum-based doublet therapy in the neoadjuvant 
or adjuvant setting will only be eligible if they have experienced disease progression 
after their last dose of cytotoxic chemotherapy 
G. 
For patients who have a neoplasm for which there currently exists a targeted therapy 
(such as to EGFR activating mutations, or ALK or ROS1 gene rearrangements) must 
have received all such targeted therapies and either exhibited progressive disease 
through such treatments, or have been shown to be intolerant of such therapies, prior 
to enrollment on this study 
H. 
Baseline laboratory values (bone marrow, renal, hepatic):   
a. Adequate bone marrow function: 
i. Absolute neutrophil count >1000/µL  
1. Potential subjects with benign ethnic neutropenia, often seen in 
African Americans and Afro-Caribbean men and women, may be 
enrolled after discussion with the PI, provided they have no other 
disqualifying features and no evidence of medical consequences of 
their neutropenia, such as repeated infections) 
ii. Platelet count >100‚000/µL 
b. Renal function: 
i. Serum creatinine < 2.0 mg  
c. Hepatic function: 
i. Bilirubin <1.5x normal  
d. Serum calcium < 12 mg/dl 
I. 
Women of childbearing potential (WOCBP) must be using an adequate method of 
contraception to avoid pregnancy throughout the study and for at least 6 months after 
the last dose of study drug to minimize the risk of pregnancy.   Prior to study 
enrollment, women of childbearing potential must be advised of the importance of 
avoiding pregnancy during trial participation and the potential risk factors for an 
unintentional pregnancy.  WOCBP include any woman who has experienced menarche 
and who has not undergone successful surgical sterilization (hysterectomy, bilateral 
tubal ligation, or bilateral oophorectomy) or who is not post-menopausal. Post-
menopause is defined as: 
J. 
Amenorrhea that has lasted for ≥ 12 consecutive months without another cause, or 

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K. 
For women with irregular menstrual periods who are taking hormone replacement 
therapy (HRT), a documented serum follicle-stimulating hormone (FSH) level of 
greater than 35 mIU/mL. 
L. 
Males with female partners of child-bearing potential must agree to use physician-
approved contraceptive methods (e.g., abstinence, condoms, vasectomy) throughout 
the study and should avoid conceiving children for 3 months following the last dose 
of study drug. 
M. 
Subjects must have provided written informed consent and be willing to comply with 
all study-related procedures.  
 
3.3 
Exclusion Criteria 
 
Subjects with any of the following will not be eligible for study participation: 
A. 
Pregnant or lactating females 
B. 
Patients with a mixed histology NSCLC, such as adenosquamous carcinoma, 
where the squamous component is <50% of the assessed lesion 
C. 
Patients with a mixed histology where there are ANY small cell elements 
D. 
Patients who have not received and progressed through, have not refused, or have 
not been intolerant of, a commonly utilized platinum-doublet therapy (cisplatin or 
carboplatin paired with docetaxel, paclitaxel, nab-paclitaxel, gemcitabine, 
vinorelbine, etoposide or irinotecan) administered for the treatment of unresectable 
or metastatic lung cancer 
 
E. 
Patients who have not received the appropriate prior targeted therapy for their lung 
cancer 
F. 
Any invasive malignancy treated within the prior 3 years prior to Cycle 1, Day 1 
G. 
Myocardial infarction or ischemia within the 6 months before Cycle 1‚ Day 1 
H. 
Uncontrolled‚ clinically significant dysrhythmia, or prolonged QT segment  
I. 
Uncontrolled malignant disease in the CNS (previously treated disease is eligible, 
provided it has been radiographically stable for at least four weeks)  
J. 
Radiotherapy within the 2 weeks before Cycle 1, Day 1. If any radiation has been 
administered to the target lesion there must be evidence of growth by radiographic 
assessments or physical examination 
K. 
Surgery within the 2 weeks before Cycle 1, Day 1 
L. 
Any co-morbid condition that‚ in the view of the attending physician‚ renders the 
patient at high risk from treatment complications 
M. 
Subjects unwilling to use an acceptable method to avoid pregnancy for the entire 
study period and for at least 24 weeks after the last dose of study drug.  
N. 
History of any other disease, metabolic dysfunction, physical examination finding, 
or clinical laboratory finding giving reasonable suspicion of a disease or condition 
that contraindicates the use of protocol therapy or that might affect the 
interpretation of the results of the study or that puts the subject at high risk for 
treatment complications, in the opinion of the treating physician. 
O. 
Prisoners or subjects who are involuntarily incarcerated. 
P. 
Subjects who are compulsorily detained for treatment of either a psychiatric or 
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Q. 
Subjects demonstrating an inability to comply with the study and/or follow-up 
procedures. 
 
3.4 
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this trial. 
 
4. REGISTRATION PROCEDURES 
 
All subjects must be registered with the UF Health Cancer Center prior to participation in this trial. 
The participating site must fax or email the completed study specific eligibility checklist and 
registration forms, supporting documents and signed informed consent to the Coordinating Center. 
Unsigned or incomplete forms will be returned to the site. Once documents are received, the 
designated Research Coordinator will review them to confirm eligibility and to complete the 
registration process. If eligibility cannot be confirmed, the research coordinator will query the site 
for clarification or additional documents as needed. Subjects failing to meet all study eligibility 
requirements will not be registered and will be unable to participate in the trial. 
 
5. STUDY TREATMENT 
 
All subjects entering the screening phase will receive a unique subject number. This number will 
be used to identify the subject throughout the study. Subjects withdrawn from the study will retain 
their subject number.  
 
5.1 
Treatment Schedule/Administration 
 
All participants will have unresectable, previously-treated squamous cell NSCLC who have 
previously been treated with a platinum doublet (or have refused such prior therapy); those who 
have a molecularly targetable genetic mutation in their tumor must have also received the 
appropriate specific therapy for that mutation. 
 
Both men and women of all races and ethnic groups will be eligible for this trial. This study was 
designed to include women and minorities, but will not be designed to measure differences of 
intervention effects. Men and women will be recruited with no preference to gender. No exclusion 
to this study will be based on race. Minorities will be actively recruited to participate. 
 
Eligible subjects will include those with radiographically-staged locally advanced or metastatic 
NSCLC who have received any prior therapy for the lesion(s). Patients who receive radiation 
therapy to any indicator lesion must have demonstrated progressive growth of the lesion to be 
assessable; be willing to use contraception; are neither pregnant nor lactating; are greater than 18 
years old and have an anticipated life expectancy of at least 12 weeks; have normal end-organ 
function and limited comorbidities, and are able to provide written informed consent. 
 
Upon confirmation of eligibility and provision of written informed consent, subjects will receive 
TAS-102 (Lonsurf®) at its FDA-approved dose and schedule, 35 mg/m2 up to a maximum of 80 
mg per dose (based on the trifluridine component) orally twice daily within one hour of completion 

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of morning and evening meals on Days 1 through 5 and Days 8 through 12 of each 28-day cycle 
until disease progression or unacceptable toxicity. Doses will be rounded to the nearest 5 mg 
increment. Additional doses will not be taken to make up for missed or held doses. Subjects will 
be monitored weekly during the first cycle for tolerance, and tumor status will be assessed every 
other cycle. Participants will continue on therapy until the development of unacceptable toxicity, 
disease progression, or participant desire to discontinue protocol therapy.  There is no set 
maximum of cycles, as patients who have responded and who are tolerating this regimen 
may continue it until withdrawal of consent, disease progression, development of undue 
toxicity, or death.  
 
Those whose disease is responding systemically but who develop CNS metastases as their only 
site of progression will have protocol therapy temporarily held for the delivery of brain 
radiotherapy (whole brain and/or gamma knife) and then resume protocol therapy.  
 
5.2 
Concomitant Therapy 
 
Relevant medical history should be obtained at screening and include prior medications and 
treatment history.  All medications taken within 3 weeks prior to screening, regardless of 
indication, should be recorded 
 
Use of any additional anti-neoplastic or anti-tumor agents not part of the study therapy, including 
chemotherapy, radiation therapy, immunotherapy, and hormonal anticancer therapy; these are not 
permitted while participating in this study. TAS-102 had minimal or no effect on the QTc interval; 
the drug was administered to 42 patients with advanced solid tumors with the recommended 
dosage regimen, but it had no large effect (i.e. > 20 ms) in the mean QTc interval when compared 
to placebo and no evident exposure-QT relationship was identified. Two of 42 patients (4.8%) had 
QTc greater than 500 msec and 1 of 42 patients (2.4%) had a QTc increase from baseline greater 
than 60 msec. The components of TAS-102 is not metabolized by the cytochrome P450 system, 
thus strong CYP inhibitors or inducers are not expected to have any effect on the metabolism of 
this drug. Study participants may receive additional investigational antineoplastic therapies upon 
completion of their participation in this protocol. Use of concurrent investigational agents is not 
permitted. 
 
 
Any therapy or medication (except study drugs), administered from screening until 28 days after 
the last dose of either study drug, is considered a concomitant therapy or medication. However, if 
another course of anti-cancer therapy is initiated prior to the 28-day follow-up period visit; a record 
of concomitant medications will no longer be performed. If the use of any concomitant treatments 
(medications or procedures) becomes necessary, the treatment must be recorded, including the 
name of the drug or treatment, dose, route, date, indication for use, expected duration, and 
frequency of treatment. Assessment and documentation of concomitant medications will be done 
at each visit. 
Subjects are prohibited from receiving the following therapies during the Screening and Treatment 
Phase of this trial:  
 Antineoplastic systemic chemotherapy or biological therapy  
 Immunotherapy not specified in this protocol  

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 Chemotherapy not specified in this protocol  
 Investigational agents other than the study drug in this trial  
 Radiation therapy  
 
NOTE: Radiation therapy to a symptomatic solitary lesion may be considered on an exceptional 
case by case basis after consultation with sponsor-investigator. The subject must have clear 
measurable disease outside the radiated field. Administration of palliative radiation therapy will 
be considered clinical progression for the purposes of determining PFS.  
 
Live vaccines within 30 days prior to the first dose of trial treatment and while participating in the 
trial. Examples of live vaccines include, but are not limited to, the following: measles, mumps, 
rubella, chicken pox, yellow fever, rabies, BCG, and typhoid (oral) vaccine. Seasonal influenza 
vaccines for injection are generally killed virus vaccines and are allowed. However, intranasal 
influenza vaccines (e.g. Flu - Mist®) are live attenuated vaccines, and are not allowed. 
 
5.3 
Dose Modifications 
 
The National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events Version 4 
(CTCAE) will be used to grade toxicity (http://evs.nci.nih.gov/ftp1/CTCAE/About.html).   
 
The starting dose of TAS-102 is 35 mg/m2 up to a maximum of 80 mg per dose (based on the 
trifluridine component) orally twice daily within one hour of completion of morning and evening 
meals on Days 1 through 5 and Days 8 through 12 of each 28-day cycle until disease progression 
or unacceptable toxicity. Doses will be rounded to the nearest 5 mg increment. Study medication 
will be administered on a 4 week schedule. Doses will be delayed or reduced for clinically 
significant (Grade 3-4) hematologic and non-hematologic toxicities that are related to protocol 
therapy according to the guidelines shown in the Dose Delays/Dose Modifications table that 
follows.  Dose modifications will follow predefined dose levels. Dose adjustments for hematologic 
toxicity are based on the blood counts obtained in preparation for the day of treatment. 
  
5.3.1 Dose Modification Table 
 
Dose level 0 (standard 
starting dose) 
35 mg/m2 po bid 
Dose level – 1 
30 mg/m2 po bid  
Dose level – 2 
25 mg/m2 po bid  
 
Intrapatient dose reduction and dose interruption will be permitted once a patient has experienced 
drug-related toxicity provided that the criteria for patient withdrawal from study treatment have 
not been met. All intrapatient dose reductions are relative to the lowest dose of the current cycle.  
 
For all toxicities, doses of TAS-102 will be modified based upon Day 1 and Day 15, complete 
blood cell counts. Day 1 TAS-102 dosing for each cycle will be held until: 
 Absolute neutrophil count (ANC) is greater than or equal to 1,500/mm3 or febrile 
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 Platelets are greater than or equal to 75,000/mm3 
 Grade 3 or 4 non-hematological adverse reactions are resolved to Grade 0 or 1 
 
Within a treatment cycle, TAS-102 will be withheld for any of the following: 
 Absolute neutrophil count (ANC) less than 500/mm3 or febrile neutropenia 
 Platelets less than 50,000/mm3  
 Grade 3 or 4 non-hematological adverse reactions 
 
After recovery, resume TAS-102 after reducing the dose by 5 mg/m2/dose (as above) from the 
previous dose level, if the following occur: 
 Febrile neutropenia 
 Uncomplicated Grade 4 neutropenia (which has recovered to greater than or equal to 
1,500/mm3, or baseline in subjects with benign ethnic neutropenia) or thrombocytopenia 
(which has recovered to greater than or equal to 75,000/mm3) that results in more than 1-
week delay in start of next cycle 
 Non-hematologic Grade 3 or Grade 4 adverse reaction except for Grade 3 nausea and/or 
vomiting controlled by antiemetic therapy or Grade 3 diarrhea responsive to antidiarrheal 
medication 
 
If a subject experiences more than one toxicity, dose reduction should be according to the toxicity 
with the highest grade. In the case of two or more toxicities of the same grade, the investigator 
may dose reduce according to that deemed most causally related to study treatment. If more than 
3 dose reductions are required, TAS-102 will be discontinued. Do not escalate dose after it has 
been reduced.  
 
5.3.2 Non- Hematologic Toxicity 
 
For Grade 3 and 4 toxicities, treatment should be withheld until the toxicity resolves to Grade 1 or 
less (or to baseline), then reinstituted (if medically appropriate) at a one level dose reduction. 
Nausea and vomiting or diarrhea must persist at Grade 3 or 4 despite maximal medical therapy. 
All agents should be dose reduced in cases where either agent may be the cause of a given toxicity. 
Patients must meet pre-treatment laboratory criteria (as specified in the inclusion criteria) at Day 
1 of each cycle to receive therapy administration. Patients will not be eligible for further treatment 
if resolution of toxicities requires a greater than 3-week delay in the start of the next cycle (five 
weeks from the start of the prior cycle).  
 
5.3.3 Hematologic Toxicity 
 

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Grade 1, 2 and 3 myelosuppression (neutropenia, thrombocytopenia), with recovery to pre-
treatment lab criteria as specified in the inclusion criteria, does not require dose modification. 
Grade 3 or 4 lymphopenia does not require dose reduction. Patients with a febrile Grade 4 
neutropenia >7 days or Grade 4 neutropenia associated with fever (one reading of oral temperature 
> 38.5° C, or three readings of oral temperature > 38.0° C in a 24-hour period) or Grade 4 
thrombocytopenia >7 days should be retreated after recovery at a one-dose level reduction during 
subsequent cycles. If any of these toxicities recurs, the patient should be dose reduced again in all 
subsequent cycles after recovery to pre-treatment lab criteria as specified in the inclusion criteria. 
Patients will not be eligible for further treatment if resolution of toxicities requires a greater than 
2-week delay in the start of the next cycle. Patients who need two dose level reductions of TAS-
102 will discontinue from the study. 
 
5.4 
Supportive Care Guidelines 
 
Patients should receive full supportive care, including transfusions of blood and blood products, 
antibiotics, antiemetics, antidiarrheals, analgesics, etc., when appropriate. Bisphosphonates or 
denosumab are allowed for patients with bone metastases. 
 
6. TREATMENT DISCONTINUATION 
 
6.1 
Removal of Subjects From Study 
 
Subjects who discontinue participation in the clinical study on their own or subjects who are 
withdrawn by the investigator, for reasons other than completion of treatment, disease progression 
or toxicity, will be defined as premature withdrawals.  
 
Subjects who are not initiated on study drug, but sign informed consent and undergo at least some 
of the screening procedures will be considered screening failures. A record of these patients will 
be maintained by the study site. 
 
6.2 
Criteria For Study Treatment Discontinuation 
 
A subject will be discontinued from protocol therapy under the following circumstances: 
 Any adverse event which, in the Investigator’s opinion, requires termination of the study 
medication. 
 Disease progression, unless at the discretion of the principal investigator (in collaboration with 
any co-sponsors or collaborators) continued treatment with study drug is appropriate. 
 Substantial non-compliance (>25% of missed doses accounting for delays and dose 
modifications per protocol or instructions from research team staff for AEs), with the 
requirements of the study. 
 The patient presents with a beta-HCG test consistent with pregnancy.  Pregnancy will be 
reported along the same timelines as a serious adverse event. 
 The patient uses illicit drugs or other substances that may, in the opinion of the Investigator, 
have a reasonable chance of contributing to toxicity or otherwise interfering with results. 
 The development of a second malignancy that requires treatment, which would interfere with 
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 The patient is lost to follow-up. 
 Interruption in study drugs administration for greater than 21 days (see Dose Modification 
section). 
 Development of an intercurrent illness or situation which would, in the judgment of the 
investigator, affect assessments of clinical status and study endpoints to a significant degree. 
 
The Investigator will make every reasonable effort to keep each patient in the study unless it is in 
the patient’s best interests to discontinue participation.  If a patient is removed from the study or 
declines further participation, all End of Treatment evaluations should be performed if the patient 
is willing and able to be assessed.  A description of the reason(s) for withdrawal from the study 
must be recorded on the case report form (CRF).  The Investigator should also ensure that all 
patients are followed up for survival status after the Final Visit. 
 
Relevant visit data should be entered on the CRF and any unused study medication will be 
accounted for and returned for all patients participating in the study, even for a brief period of 
time.  Patients who discontinue following entry will have relevant information completed and 
recorded on the CRF.  All patients who discontinue because of adverse events or clinically 
significant laboratory abnormalities should be followed up until they recover or stabilize, and the 
subsequent outcome will be recorded.  If any patient should die during the trial or within 30 days 
of stopping study treatment, the Investigator will inform the UF Health Data Integrity and Safety 
Committee.   
 
6.3 
Replacement of Subjects 
 
Subjects will be replaced if they have not received any doses of study drug prior to their continuing 
participation in the protocol for any reason, or if the patient wishes to discontinue participation in 
the protocol, but is not discontinued for disease progression, toxicity, or any of the reasons listed 
in section 6.2. 
 
 
6.4 
Study Discontinuation 
 
It is unlikely that the trial itself will require a premature termination.  However the trial will be 
stopped prematurely (prior to completion of accrual, protocol therapy, and follow-up) for safety 
reasons if the therapy at Dose level 0 is intolerable in the first six patients, requiring dose 
reduction to Dose level -1. 
 
 
7. STUDY PROCEDURES 
 
7.1    Study Schedule of Events 
 
 
 

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Day of Protocol 
Baseline2 
Day 1 
Each 
Cycle 
Day 15 
Each 
Cycle 
Day 1, odd 
cycles 
(beginning 
with Cycle 3) 
Off 
Treatment 
Follow 
Up 
Studies: 
 
 
 
 
 
 
H&P1 / PS / VS & TOX 
X 
X 
 
 
X 
X 
CBC w/ Diff. 
X 
X 
X 
 
X 
X 
CMP 
X 
X 
 
 
X 
X 
UA and Pregnancy Test 
X 
 
 
 
 
 
Diagnostic 
Imaging 
Scan / TA3 
X 
 
 
X 
 
X 
ECG 
X 
 
 
 
 
 
Concomitant 
Medications 
X 
X 
X 
 
X 
X 
Adverse Events 
X 
X 
X 
 
X 
X 
Treatment: 
 
 
 
 
 
 
TAS-102(Lonsurf®) 4 
 
X 
 
 
 
 
1) Abbreviations: H&P=History and Physical examination; PS=ECOG performance status; VS=vital signs 
(blood pressure, temperature, pulse and respiratory rates, weight and height); TOX=toxicity assessment; 
CBC/diff=complete blood count and white blood cell differential; CMP=12 item complete metabolic 
profile (sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, glucose, alkaline 
phosphatase, AST, ALT, total bilirubin, uric acid); UA=urinalysis; Pregnancy test only for women of 
childbearing potential. For the first cycle, the H&P, toxicity assessment, CBC and CMP are repeated 
weekly (Days 1, 8, 15 and 22). 
2) Baseline studies are repeated on day 1 if there are more than 14 days between baseline and day 1. The 
radiographic assessment must be repeated if there are more than 21 days between baseline and day 1. 
3) TA= Tumor assessment by RECIST Criteria by diagnostic CT scan, PET/CT scan and/or MRI scan.  
Scans are to be done within one calendar week prior to Day 1 of every odd-numbered cycle (beginning 
with Cycle 3). 
4) TAS-102 (Lonsurf®) is initially dosed as 35 mg/m2 up to a maximum of 80 mg per dose (based on the 
trifluridine component) orally twice daily within one hour of completion of morning and evening meals 
on Days 1 through 5 and Days 8 through 12 of each 28-day cycle. Doses will be rounded to the nearest 5 
mg increment. 
Follow up evaluations are also performed as appropriate clinically 
 
7.2   Screening Evaluations   
 
Written informed consent must be obtained prior to performing any study-specific evaluations or 
tests. Tests or evaluations performed as standard of care within the specified screening period, but 
prior to informed consent, may be accepted for this study and need not be repeated. 
 
Height, weight and performance status 
Physical exam 
Concomitant medication collection 
Laboratory studies: 
 
 CBC with differential count 

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 Comprehensive metabolic panel, serum magnesium 
 ECG 
 Urine pregnancy test (females of potential child-bearing status only) 
 CT or MRI of thorax and abdomen, or PET/CT  
 
7.3   On-Study Evaluations  
 
Each week of first cycle (days 1, 8, 15 and 22): 
 
Weight and performance status 
Physical exam 
Concomitant medication collection 
Adverse event collection 
Laboratory studies 
 
 CBC with differential count  
 Comprehensive metabolic panel, serum magnesium 
 
First day of each cycle (within 3 days): 
 
Weight and performance status 
Physical exam 
Concomitant medication collection 
Adverse event collection 
Laboratory studies 
 
 CBC with differential count  
 Comprehensive metabolic panel, serum magnesium 
 
Day 15 of each cycle: 
 
Concomitant medication collection 
Adverse event collection 
Laboratory studies 
 
 CBC with differential count  
 
First day of every odd-numbered cycle (beginning with Cycle 3): 
 CT or MRI of thorax and abdomen, or PET/CT (must be obtained within one calendar 
week prior to first day of each odd numbered cycle)  
 
7.4   End of Treatment 
 
Patients should be seen in the clinic or contacted by telephone to determine if any serious or non-
serious adverse events have occurred within 28 days (+ 3 days) of termination of TAS-102 dosing. 
 
Patients will be followed for 28 days after completion of the last course of any therapy for the 
documentation of adverse events and concomitant medications.  
 

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Off-therapy measurements: 
a. Toxicity assessment, interim medical history and physical examination 
b. Laboratory studies: 
 
 
CBC with differential count 
 
CMP 
 
7.5   Follow up/Survival 
 
 Patients will be seen in follow-up at least every three months for the first three years after the 
initiation of therapy, or the date of death, whichever occurs first.  Patients who are alive after 
three years will have follow up every six months for years four and five, then annual follow ups 
until date of death, or lost to follow up. Those patients who are lost to follow up will have every 
effort by telephone and mail to contact them for at least one month past their first missed clinic 
visit, with at least four documented attempts at contact to be made during that time. 
 
Evaluation will consist of an interim medical history and a physical examination. Additional 
studies, such as labs (CBC and CMP), and any X-rays, or CT, PET/CT, bone scans or MRI scans 
used in evaluation of response will be repeated as clinically indicated.  Other studies, such as, 
biopsies, will be performed as clinically indicated. 
 
8.      CRITERIA FOR DISEASE EVALUATION 
 
8.1    Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their dose of 
any of the three drugs in this study. 
 
Evaluable for objective response.  Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will 
be considered evaluable for response.  These patients will have their response classified according 
to the definitions stated below.  (Note:  Patients who exhibit objective disease progression prior to 
the end of cycle 1 will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline that are 
evaluable but do not meet the definitions of measurable disease, have received at least one cycle 
of therapy, and have had their disease re-evaluated will be considered evaluable for non-target 
disease.  The response assessment is based on the presence, absence, or unequivocal progression 
of the lesions.  
 
Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as ≥20 mm by chest x-ray or as ≥10 mm 
with CT scan, MRI, or calipers by clinical exam.  All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters). 
 

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Note:  Tumor lesions that are situated in a previously irradiated area are considered measurable 
only if they have demonstrated growth after completion of the radiation therapy.   
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a lymph node 
must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended 
to be no greater than 5 mm).  At baseline and in follow-up, only the short axis will be measured 
and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered 
non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pneumonitis, inflammatory breast disease, and abdominal masses 
(not followed by CT or MRI), are considered as non-measurable. 
 
Note:  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. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, if 
they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions. 
 
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.  It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement in which circumstance the next 
largest lesion which can be measured reproducibly should be selected.  A sum of the diameters 
(longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated 
and reported as the baseline sum diameters.  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. 
 
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.  
 
 
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. 
 

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The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
 
Clinical lesions.  Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed using calipers 
(e.g., skin nodules).  In the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray.  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI.  This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less.  If CT scans have slice thickness greater 
than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness.  MRI is 
also acceptable in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal resolution; 
however, there are many image acquisition variables involved in MRI, which greatly impact image 
quality, lesion conspicuity, and measurement.  Furthermore, the availability of MRI is variable 
globally.  As with CT, if an MRI is performed, the technical specifications of the scanning 
sequences used should be optimized for the evaluation of the type and site of disease.  Furthermore, 
as with CT, the modality used at follow-up should be the same as was used at baseline and the 
lesions should be measured/assessed on the same pulse sequence.  It is beyond the scope of the 
RECIST guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, the same type of scanner should be used and the image acquisition 
protocol should be followed as closely as possible to prior scans.  Body scans should be performed 
with breath-hold scanning techniques, if possible. 
 
PET-CT.  At present, the low dose or attenuation correction CT portion of a combined PET-CT is 
not always of optimal diagnostic CT quality for use with RECIST measurements.  However, if the 
site can document that the CT performed as part of a PET-CT is of identical diagnostic quality to 
a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be used for 
RECIST measurements and can be used interchangeably with conventional CT in accurately 
measuring cancer lesions over time.  Note, however, that the PET portion of the CT introduces 
additional data which may bias an investigator if it is not routinely or serially performed.   
 
Ultrasound.  Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement.  Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next.  If new lesions are identified by ultrasound in the course of the study, confirmation by CT or 
MRI is advised.  If there is concern about radiation exposure at CT, MRI may be used instead of 
CT in selected instances. 
 

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Endoscopy or Laparoscopy. The utilization of these techniques for objective tumor evaluation is 
not advised.  However, such techniques may be useful to confirm complete pathological response 
when biopsies are obtained or to determine relapse in trials where recurrence following complete 
response (CR) or surgical resection is an endpoint. 
 
Tumor Markers. Tumor markers alone cannot be used to assess response.  There are no validated 
tumor markers for NSCLC, and none are being evaluated here. 
 
Cytology or Histology. These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ 
cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease. 
 
FDG-PET. While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in assessment 
of progression (particularly possible 'new' disease).  New lesions on the basis of FDG-PET imaging 
can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If the positive 
FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up 
CT scans are needed to determine if there is truly progression occurring at that site (if so, the 
date of PD will be the date of the initial abnormal FDG-PET scan).  If the positive FDG-PET 
at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in cases 
where a residual radiographic abnormality is thought to represent fibrosis or scarring.  The use 
of FDG-PET in this circumstance should be prospectively described in the protocol and 
supported by disease-specific medical literature for the indication.  However, it must be 
acknowledged that both approaches may lead to false positive CR due to limitations of FDG-
PET and biopsy resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
 
8.2    Response Criteria 
 
Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological lymph nodes 
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Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target lesions, taking 
as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest 
on study).  In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm.  (Note:  the appearance of one or more new lesions is also considered 
progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum 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). 
 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a patient 
to be considered in complete clinical response. 
 
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):  Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not normally trump 
target lesion status.  It must be representative of overall disease status change, not a single lesion 
increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the treating 
physician should prevail in such circumstances, and the progression status should be confirmed at 
a later time by the review panel (or Principal Investigator). 
 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started).  The patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 

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CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks. from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**        Only for non-randomized trials with response as primary endpoint. 
***      In exceptional circumstances, unequivocal progression in non-target lesions may be 
            accepted as disease progression. 
 
Note:  Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
For Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
  
Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
 
 

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Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements.  
 
9.      STUDY DRUG INFORMATION 
 
9.1    Study Drug Name 
 
9.1.1   Identification 
 
TAS-102; Trifluridine (FTD) / Tipiracil hydrochloride (TPI); Lonsurf® (Taiho Oncology, 
Princeton, NJ) 
 
Active Drug Substance 
 
Trifluridine (FTD) 
Chemical Name: 2’-deoxy-5-(trifluoromethyl) uridine (IUPAC) 
Code Name: FTD, F3TdR, F3dThd 
Generic Name: Trifluridine 
Chemical Formula: C10H11F3N2O5 
Molecular Weight: 296.20 
Description: White crystals or crystalline powder 
Solubility: Soluble in water, sparingly soluble in 2-propanol 
 
Tipiracil Hydrochloride (TPI) 
Chemical Name: 5-chloro-6-[(2-iminopyrrolidin-1-yl) methyl] pyrimidine-2,4(1H,3H)-dione 
monohydrochloride (IUPAC) 
Code Name: TPI, TAS-1-462 
Generic Name: Tipiracil hydrochloride 
Chemical Formula: C9H11ClN4O2ꞏHCl 
Molecular Weight: 279.12 
Description: White crystals or crystalline powder 
Solubility: Soluble in water, very slightly soluble in ethanol and practically insoluble in diethyl 
ether 
 
9.1.2    Packaging and Labeling 
 
TAS-102 contains FTD and TPI as active ingredients with a molar ratio of 1:0.5. TAS-102 drug 
products are immediate-released film coated tablets, with two strengths of 15 mg and 20 mg 
(expressed as FTD). The inactive ingredients of the TAS-102 15 mg and 20 mg tablets are lactose 
monohydrate, pregelatinized starch, stearic acid, hypromellose, polyethylene glycol, titanium 
dioxide, red ferric oxide (only 20 mg tablet), and magnesium stearate.  
 
 TAS-102 tablet (15 mg) contains 15 mg FTD and 7.065 mg TPI as active ingredients. The 
appearance is white round tablet. 
 

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 TAS-102 tablet (20 mg) contains 20 mg FTD and 9.42 mg TPI as active ingredients. The 
appearance is pale red round tablet. 
 
Packaging type: blister package with desiccant in aluminum pouch 
 
Storage condition: room temperature (between 59°F to 86°F /15°C to 30°C) 
 
Stability: TAS-102 tablets (15 mg and 20 mg) are stable at 25°C 60% relative humidity (RH) for 
36 months and 40°C 75%RH for 6 months in blister packaging with desiccant in aluminum pouch. 
 
9.1.3    Drug Supply 
 
Drug for this protocol will be supplied by the manufacturer, Taiho Oncology. 
 
9.1.4   Storage, Handling and Dispensing 
 
Store at 20°C to 25°C (68°F to 77°F); excursions are permitted from 15°C to 30°C (59°F to 86°F). 
TAS-102 is a cytotoxic drug. Follow applicable special handling and disposal procedures. If stored 
outside of original bottle, discard after 30 days. 
 
9.1.5    Drug Ordering and Accountability 
 
9.1.6    Contraindications 
 
There are no known specific contraindications to receiving TAS-102, until or unless the subject 
displays intolerable toxicities upon initiation of therapy. 
 
9.1.7    Special Warnings and Precautions for Use 
 
Severe Myelosuppression TAS-102 has been associated with severe and life-threatening 
myelosuppression (Grade 3-4) consisting of anemia (18%), neutropenia (38%), thrombocytopenia 
(5%) and febrile neutropenia (3.8%), including a low fatality rate (0.2%) due to neutropenic 
infection. It has been recommended to obtain complete blood counts prior to and on Day 15 of 
each cycle of TAS-102 and more frequently as clinically indicated.  
 
 Embryo-Fetal Toxicity Based on animal studies and its mechanism of action, TAS-102 can cause 
fetal harm when administered to a pregnant woman. Trifluridine/tipiracil caused embryo-fetal 
lethality and embryo-fetal toxicity in pregnant rats when orally administered during gestation at 
dose levels resulting in exposures lower than those achieved at the recommended dose of 35 
mg/m2 twice daily. While the FDA-approved label advises that pregnant women be told of the 
potential risk to the fetus, such patients will be ineligible for participation in this protocol. 
 
9.1.8   Interactions with Other Medications 
 
No pharmacokinetic drug-drug interaction studies have been conducted with TAS-102. 
 

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9.1.9   Adverse Event Profile 
 
Derived from the TAS-102 Investigator’s Brochure, October 14, 2015 
 
 

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10. 
ADVERSE EVENTS 
 
10.1 
Definitions 
 
10.1.1 
Adverse Event 
 
The term “adverse event” includes any sign, symptom, syndrome, or illness that appears or 
worsens in a subject during the period of observation in the clinical study and that may impair the 
wellbeing of the subject. The term also covers laboratory findings or results of other diagnostic 
procedures that are considered to be clinically significant (e.g., that requires unscheduled 

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diagnostic procedures or treatment measures, or result in withdrawal from the study). 
 
The adverse event may be: 
 A new illness/condition; 
 Worsening of a sign or symptom of the condition under treatment, or of a concomitant 
illness/condition; 
 An effect of the study drug; or 
 A combination of 2 or more of these factors. 
 
No causal relationship with the study drug or with the clinical study itself is implied by the use of 
the term “adverse event.” 
 
Surgical procedures themselves are not adverse events; they are therapeutic measures for 
conditions that require surgery. The condition(s) for which the surgery is required may be an 
adverse event. Planned surgical measures permitted by the clinical study protocol and the 
condition(s) leading to these measures are not adverse events. 
 
When a clear diagnosis is available that explains the abnormal objective findings, this diagnosis 
will be recorded as an adverse event and not the abnormal objective findings (e.g., viral hepatitis 
will be recorded as the adverse event and not the transaminase elevation). If a definitive diagnosis 
is not available, then the sign(s) (e.g., clinically significant elevation of transaminase levels) or 
symptom(s) (e.g., abdominal pain) will be recorded as the adverse event. 
Adverse events fall into the categories “serious” and “non-serious.” 
 
10.1.2 
Serious Adverse Event 
 
A serious adverse event is one that at any dose of the study drug or at any time during the period 
of observation: 
 Results in death 
 Is life-threatening (defined as an event in which the subject was at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if 
it were more severe) 
 Requires inpatient hospitalization or causes prolongation of existing hospitalization (see 
note below for exceptions) 
 Results in persistent or significant disability/incapacity 
 Is a congenital anomaly/birth defect 
 Is an important medical event, defined as a medical event that may not be immediately life-
threatening or result in death or hospitalization but, based on appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention (e.g., medical, 
surgical) to prevent one of the other serious outcomes listed above. Examples of such 
events include but are not limited to intensive treatment in an emergency department or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization. “Medically important” should be marked only if no other serious criteria 
are met. 
 

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An “unexpected SAE” is any SAE for which the nature, specificity or severity is not consistent 
with the currently known adverse event profile of the investigational agent(s) and not listed in the 
current TAS-102 Global IB. 
 
NOTE: The following hospitalizations are not considered SAEs in UFHCC clinical studies: 
 a visit to the emergency room or other hospital department lasting less than 24 hours that 
does not result in admission (unless considered an “important medical event” or a 
life-threatening event) 
 elective surgery planned before signing consent 
 admissions as per protocol for a planned medical/surgical procedure 
 routine health assessment requiring admission for baseline/trending of health status (eg, 
routine colonoscopy) 
 medical/surgical admission for purpose other than remedying ill health state that was 
planned before study entry. Appropriate documentation is required in these cases. 
 admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (e.g., lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative). 
 
Clarification of the difference in meaning between “severe” and “serious” 
The term “severe” is often used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor 
medical significance (such as severe headache). Any grade ≥ 3 adverse event per CTCAE is 
generally considered severe AE. This is not the same as “serious,” which is based on the outcome 
or action criteria usually associated with events that pose a threat to life or functioning. Seriousness 
(not severity) serves as a guide for defining regulatory reporting obligations. 
 
10.1.3 
Non-Serious Adverse Event 
 
A non-serious adverse event is any adverse event not meeting any of the serious adverse event 
criteria. 
 
10.2 
Period of Observation 
 
Following the subject’s written consent to participate in the study, all SAEs must be collected, 
including those thought to be associated with protocol-specified procedures. Collection of all SAEs 
must continue for 30 days after the last administration of the investigational product or until the 
start of new anti-tumor therapy, whichever comes first. If applicable, SAEs must be collected that 
relate to any later protocol-specified procedure (e.g., a follow-up skin biopsy). The investigator 
should notify the DISC of any SAE occurring after this time period that is believed to be related 
to the investigational product or protocol-specified procedure. 
 
The investigator will begin collecting non-serious adverse event (NSAE) information at screening. 
This NSAE information should also be collected from the start of a placebo lead-in period or other 
observational period intended to establish a baseline status for the subjects.  Treated subjects, 
including those who were prematurely discontinued from the study, will be followed for any 
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(i.e., the Follow-up Visit).  However, if another course of anti-cancer therapy is initiated prior to 
the 30-day follow-up period visit, collection of adverse events will no longer be performed, with 
the exception of events that may be possibly, probably, or definitely related to the investigational 
agent or are clinically significant.  
 
10.3 
Documenting and Reporting of Adverse Events by Investigator 
 
All adverse events must be fully recorded in the subject’s case record form. 
 
Documentation must be supported by an entry in the subject’s file.  A laboratory test abnormality 
considered clinically relevant, e.g., causing the subject to withdraw from the study, requiring 
treatment or causing apparent clinical manifestations, or judged relevant by the investigator, 
should be reported as an adverse event.  Each event should be described in detail along with start 
and stop dates, severity, relationship to investigational product, action taken and outcome. 
 
Every attempt should be made to describe the adverse event in terms of a diagnosis that 
encompasses the component signs and symptoms. If only nonspecific signs or symptoms are 
present, then these should be recorded as separate diagnoses on the pages of the case report form. 
 
All subjects who have adverse events, whether considered associated with the use of study drug 
or not, must be monitored to determine the outcome. The clinical course of the adverse event will 
be followed according to accepted standards of medical practice, even after the end of the period 
of observation, until a satisfactory explanation is found or the Principal Investigator considers it 
medically justifiable to terminate follow-up. Should the adverse event result in death, a full 
pathologist’s report should be supplied, if possible. 
 
10.3.1 
Assessment of Causal Relationship of Study Drug 
 
The Investigator will provide an assessment of the potential causal relationship between adverse 
events and study medication by determining whether or not there is a reasonable possibility that 
the event was caused by the study medication. The relationship or association of the adverse event 
to the study medication will be characterized as not related, probably not related, possibly related, 
probably related, or related:   
 
Not Related: There is not a temporal relationship to the study drug administration or the adverse 
event is clearly due only to the progression of the underlying disease state, intercurrent illness, 
concomitant medication, concurrent therapy or other known cause. 
 
Probably Not Related:  There is little or no chance that the study drug administration caused the 
adverse event; the event is most likely due to another competing cause, including intercurrent 
illness, progression or expression of the disease state, or a reaction to a concomitant medication or 
concurrent therapy appearing to explain the reported adverse event.  
 
Possibly Related:  The association of the adverse event with the study drug administration is 
unknown; however, the adverse event is not reasonably attributed to any other condition.  
 

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Probably Related:  When a reasonable temporal relationship exists between the adverse event 
and the study drug administration; significant symptoms abate upon discontinuation of the study 
drug and there is a reasonable explanation based on known characteristics of the study drug and 
there is no clear association with preexisting disease or therapy, intercurrent illness, concurrent 
therapy or other factor(s). 
 
Related:  When the adverse event is a known side effect of the study drug or there is a temporal 
relationship to the administration of the study drug; or the adverse event reappears upon re-
administration of the study drug (rechallenge); or the significant symptoms of the adverse event 
abate upon discontinuation of the study drug (dechallenge). 
 
10.3.2 
Intensity of Adverse Events 
 
The intensity of adverse changes in physical signs or symptoms will be graded according to the 
CTCAE version 4.03.  For all other adverse events not described in the CTCAE, the intensity will 
be assessed by the Investigator using the following categories: 
 
Mild (Grade 1) – transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required. 
 
Moderate (Grade 2) – mild to moderate limitation in activity, some assistance may be needed; no 
or minimal medical intervention/therapy required. 
 
Severe (Grade 3) – marked limitation in activity, some assistance usually required; medical 
intervention/therapy required, hospitalization is possible. 
 
Life-threatening (Grade 4) – extreme limitation in activity, significant assistance required; 
significant medical intervention/therapy required, hospitalization or hospice care probable. 
 
Death (Grade 5) – the event resulted in death. 
 
10.3.3 
Action Taken with Study Drug 
 
The action the Investigator took with study drug as a result of the event should be recorded as one 
of the following: 
 
None – No action was taken with regard to the study drug as a result of the adverse event. 
 
Interrupted – Study drug was stopped due to the adverse event, but was later resumed at the same 
dose. 
 
Dose decreased – The dose of study drug was decreased as a result of the adverse event. 
 
Permanently discontinued – The subject was withdrawn from the study due to the adverse event. 
 
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hierarchy should be used to determine the preferred entry: 
 
Discontinued > dose decreased > therapy interrupted. 
 
10.3.4 
Definition of Outcome 
 
The outcome of the AE should be recorded as one of the following: 
 
Resolved without sequelae – The subject fully recovered from the adverse event with no 
observable residual effects. 
 
Resolved with sequelae – The subject recovered from the adverse event with observable residual 
effects. 
 
Not resolved – The adverse event was present at the time of last observation. 
 
Death – The subject died as a result of the adverse event. 
 
10.4 
Immediately Reportable Events 
 
10.4.1 
Serious Adverse Events 
 
Serious adverse events (SAE's) must be documented on a SAE Report Form must be emailed to 
the UFHCC DISC Safety Team within 5 days of discovery of the event. The original copy of the 
SAE Report and any email correspondence must be kept within the Trial Master File at the study 
site. The site investigator is responsible for informing the IRB and/or the Regulatory Authority 
of the SAE as per local requirements. 
 
Follow-up information will be emailed or faxed to the UFHCC using the SAE Report Form stating 
that this is a follow-up to the previously reported SAE and giving the date of the original report. 
Each re-occurrence, complication, or progression of the original event should be reported as a 
follow-up to that event regardless of when it occurs. The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated, whether the blind was 
broken or not (if applicable), and whether the participant continued or withdrew from study 
participation. 
 
The UFHCC Protocol Development Office (PDO) must also be notified of the SAE by email at 
PDO@cancer.ufl.edu within 24 hours of awareness of the event.  
 
Taiho Reporting Requirements 
 
All SAEs, as well as events of overdose, medication error, pregnancy (whether serious or non-
serious), to Taiho Oncology pharmacovigilance or designee within 24 hours of awareness.  SAEs 
will be reported to Taiho Oncology either by e-mail at TAS-102_Safety@taihopui.com or via fax 
at (609) 750-7371.  Any SAE inquiries to Taiho Oncology may be done by hotline phone at 
(609) 750-5303.  NOTE: The hotline phone number is for inquiries only; not to report SAEs. 
 

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At the time of the annual DSUR (data-lock point), all AEs which led to discontinuation; list of 
subjects with fatal events; and demographic information for all subjects exposed to TAS-102 
 
 
10.4.2 
Other Events Requiring Immediate Reporting 
 
All pregnancies, regardless of outcome, must be reported to the UFHCC DISC, including 
pregnancies that occur in the female partner of a male study subject. All pregnancies must be 
followed to outcome. 
 
Although overdose (dose variance of >25%) and cancer are not always serious by regulatory 
definition, these events should also be reported to the DISC in an expedited manner.  In case the 
overdose did not result in any adverse event, the Investigator should report this as “overdose, no 
adverse event” on the SAE form and provide the intended amount, as well as the actual amount, 
of drug administered.  In the event of overdose or exaggerated response, appropriate supportive 
measures should be employed.  Actual treatment should depend on the severity of the clinical 
situation and the judgment and experience of the treating physician. 
 
Pregnancies and overdoses should be documented and reported per the SAE reporting guidelines 
in section 10.4.1 above. 
 
10.5 
IND Safety Reports Unrelated to this Trial 
 
IND safety reports not occurring on this trial but involving the study intervention (outside SAEs) 
received from outside sources will be forwarded to participating sites for submission to their 
Institutional Review Boards per their guidelines.  
 
11.    STATISTICAL METHODS 
 
11.1 
Sample Size Determination 
 
This is a pilot phase II study, so we are interested in evaluating the feasibility and safety of a 
regimen of daily TAS-102 administered to subjects with squamous cell lung cancer. To minimize 
the number of subjects exposed, the sample size will be determined by the anticipated response 
rate. A response rate of 20% or above to TAS-102 will be of interest in subjects with previously-
treated squamous cell lung cancer. Initially, 14 subjects will be evaluated for response, and if none 
of the 14 evaluable subjects experiences a partial or complete response, then the study will be 
terminated. If the true response rate is 20%, the chance of rejection error is less than 5%. However, 
in the event of one response among the first 14 subjects, further accrual will continue to a total of 
30 evaluable subjects to estimate the response rate more precisely with a standard error of no more 
than 9%. A subject is considered eligible for toxicity evaluation if they have received at least one 
dose of TAS-102. A subject will be considered eligible for evaluation of activity if they have also 
received two cycles of therapy as planned.  
 

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Based upon the numbers of subjects seen at the University of Florida Cancer Center clinics and 
our accrual to other similar studies, it is estimated that accrual to the first level (14 subjects) will 
be completed within nine months. If the study is fully accrued (30 subjects) and at least the last 
such subject derives benefit from the anticipated maximal number of six cycles, then the length of 
the entire study will be approximately 24 months. 
 
11.2 
Analysis of Endpoints/Efficacy 
 
The primary endpoint to this study will be to document the objective rate of response by RECIST 
Criteria, version 1.1 of the participants in this trial which will be estimated along with exact 95% 
binomial confidence intervals. 
 
The secondary endpoints of this study will be to determine the rate of development of toxicities, 
and the reversibility of toxicities of this regimen; the Objective Response Rate (by RECIST 
Criteria); the Clinical Benefit Rate (objective response + disease stability rate); the median 
duration of response in months, and the median Overall Survival. 
 
A secondary endpoint of this study will be progression-free survival following TAS-102 therapy.  
Kaplan-Meier mean estimates and survival curves of progression-free survival rates will be 
calculated. Secondary endpoints include clinical benefit rate (CR + PR + SD), toxicities and 
reversibility of toxicities) will also be estimated along with exact 95% binomial confidence 
intervals. 
 
11.3 
Analysis of Demographic and Baseline Characteristic 
 
The analysis of demographic characteristics (age, gender, tobacco abuse history and ethnicity) and 
baseline characteristics, including weight change, performance status, and histologic subtype, will 
be primarily descriptive. However, they will be compared between the treatment arm and historical 
controls to determine if there is any imbalance, which might skew the results of the patient 
outcomes. These endpoints will be primarily descriptive in nature due to the small patient numbers; 
however, these results will be compared against historical US controls. Continuous variables will 
be compared to historical controls using either a two-sample t-test or Wilcoxon rank sum test 
depending on normality assumptions, and discrete outcomes will be compared using either Chi-
square or Fisher’s exact tests. 
 
11.4  Analysis of Safety Data 
 
Patients will be examined and graded each cycle for subjective/objective evidence of developing 
toxicity according to NCI-CTC version 4.03 toxicity criteria. Incidence tables will be generated to 
summarize incidence of patients reporting at least one episode of each specific adverse event, 
incidence of adverse events causing withdrawal, and incidence of serious adverse events. Patients 
will have laboratory values assessed weekly during the first cycle, and in the absence of grade 3 
or 4 toxicity, will subsequently have laboratory monitoring every cycle from cycle 2 onward. In 
the absence of significant treatment-related abnormalities, in subsequent courses patients will not 
require weekly laboratory evaluation, but will require the documentation of return to baseline 
values prior to the initiation of subsequent courses of therapy. All patients experiencing toxicities 

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will require the documentation of return to baseline values prior to the initiation of subsequent 
courses of therapy. 
 
All patients who received study drug will be included in the safety analysis of this combination 
regimen. Adverse event data and corresponding toxicity grades during treatment and during long-
term follow-up will be summarized in the form of tables. Incidence tables will be generated to 
summarize incidence of patients reporting at least one episode of each specific adverse event, 
incidence of adverse events causing withdrawal and incidence of serious adverse events. The total 
number of episodes for each event reported (Frequency Table), the severity and attribution to study 
therapy of each episode reported (Severity Table and Attribution Table) will also be displayed.  
Listings of adverse events by patients will include the time to onset, the duration of each event, 
the severity of each event, and the relationship of the event to study therapy, whether it was a 
serious event, and whether it caused withdrawal. Safety data will be summarized for the overall 
patient group and by dose levels. Dose-toxicity curves will be fitted to the final data to estimate 
the toxicity rates of each dose levels.    
 
12. 
DATA AND SAFETY MONITORING 
 
12.1 
Data Integrity and Safety Committee 
 
This protocol will be reviewed and monitored by the University of Florida Health Cancer Center 
(UFHCC) Data Integrity and Safety Committee (DISC) in accordance with their policies and 
procedures.  They will review and monitor study progress, toxicity, safety and other data from this 
trial. Questions about subject safety or protocol performance will be addressed with the sponsor-
investigator, statistician and study team members. Should any major concerns arise; the DISC will 
offer recommendations regarding whether or not to suspend the trial. 
 
UFHCC DISC data and safety monitoring activities include:  
 Review of clinical trial conducted for progress and safety  
 Review of all adverse events requiring expedited reporting as defined in the protocol  
 Review of reports generated by data quality control review process  
 Notification of the sponsor-investigator of recommended action  
 Notification of sites coordinated by the UFHCC of adverse events requiring expedited 
reporting and subsequent committee recommendations for study modifications 
 
12.2 
On-site Monitoring 
 
UFHCC monitors will make monitoring visits to the trial sites periodically during the trial to 
determine if sites are complying with the protocol. Source documents will be reviewed for 
verification of agreement with data as submitted via the data collection system. The site 
investigator/institution guarantee access to source documents by UFHCC or its designee and 
appropriate regulatory agencies.   
 
The trial site may also be subject to quality assurance audit by collaborating sponsors or their 
designee as well as inspection by appropriate regulatory agencies.  
 

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It is important for the site investigator and their relevant personnel to be available during the 
monitoring visits and possible audits and for sufficient time to be devoted to the process. 
 
12.3 
Principal Investigator Responsibilities 
 
As part of the responsibilities assumed by conducting this study, the Principal Investigator (PI) 
agrees to maintain and have available for monitoring adequate case records (accurate source 
documents and CRFs) for the subjects treated under this protocol.  
 
The PI will be primarily responsible for monitoring of adverse events, protocol violations, and 
other immediate protocol issues. The study coordinator will collect information on subjects 
enrolled through the use of electronic or paper adverse event (AE) forms, CRFs, and Informed 
Consent forms.  
 
13. 
EMERGENCY PROCEDURES 
 
13.1 
Emergency Contact 
 
In emergency situations, the treating physician should contact the Principal Investigator by 
telephone at the number listed on the title page of the protocol. 
 
13.2 
Emergency Identification of Investigational Products 
 
This is an unblinded, nonrandomized study. Thus, there will be no need for unmasking procedures, 
and the identification of the investigational product can be made by simple inquiry to the 
investigational pharmacy of UF Shands. 
 
13.3 
Emergency Treatment 
 
During and following a subject’s participation in the study, the treating physician and/or institution 
should ensure that adequate medical care is provided to a subject for any adverse events, including 
clinically significant laboratory values, related to the study. 
 
14. 
ADMINISTRATIVE CONSIDERATIONS 
 
14.1 
Good Clinical Practice 
 
The procedures set out in this study protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that the Principal Investigator and Co-
Investigators abide by Good Clinical Practice (GCP), as described in International Conference on 
Harmonization (ICH) Guideline E6 and in accordance with the general ethical principles outlined 
in the Declaration of Helsinki.  
 
The study will be conducted in compliance with the protocol. The protocol, any amendments, and 
the subject informed consent will receive Institutional Review Board (IRB) approval before 
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The Principal Investigator will conduct all aspects of this study in accordance with applicable 
national, state, and local laws of the pertinent regulatory authorities. 
 
All potential serious breaches must be reported to the UF Health Cancer Center Data Integrity and 
Safety Committee (DISC) immediately. A serious breach is a breach of the conditions and 
principles of GCP in connection with the study or the protocol, which is likely to affect, to a 
significant degree, the safety or physical or mental integrity of the subjects of the study or the 
scientific value of the study. 
 
14.2 
Institutional Review Board 
 
Before study initiation, the investigator must have written and dated approval from the IRB for the 
protocol, consent form, subject recruitment materials/process (e.g., advertisements), and any other 
written information to be provided to subjects. The investigator should also provide the IRB with 
a copy of the Investigator Brochure or product labeling, information to be provided to subjects, 
and any updates. The investigator should provide the IRB with reports, updates, and other 
information (e.g., amendments, and administrative letters) according to regulatory requirements or 
institution procedures. 
 
14.3 
Delegation of Investigator Responsibilities 
 
The Principal Investigator will ensure that all persons assisting with the study are adequately 
informed about the protocol, any amendments to the protocol, the study treatments, and their study-
related duties and functions. The Principal Investigator will maintain a list of Co-Investigators and 
other appropriately qualified persons to whom he has delegated significant study-related duties.  
 
Study personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks. This study will not use the services of study personnel 
where sanctions have been invoked or where there has been scientific misconduct or fraud (e.g., 
loss of medical licensure; debarment). Systems with procedures that ensure the quality of every 
aspect of the study will be implemented. 
 
14.4 
Subject Information and Informed Consent 
 
Before being enrolled in this clinical trial, the subject must consent to participate after the nature, 
scope, and possible consequences of the clinical study have been explained in a form 
understandable to him or her. An informed consent document that includes both information about 
the study and the consent form will be prepared and given to the subject. This document will 
contain all ICH, GCP, and locally required regulatory elements. The document must be in a 
language understandable to the subject and must specify the person who obtained informed 
consent. 
 
After reading the informed consent document, the subject must give consent in writing. The written 
informed consent will be obtained prior to conducting any study-related procedures or tests. The 
subject’s consent must be confirmed at the time of consent by the personally dated signature of the 

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person conducting the informed consent discussions. A copy of the signed consent document must 
be given to the subject. 
 
The PI will retain the original signed consent document. The PI will not undertake any measures 
specifically required only for the clinical study until valid consent has been obtained. 
 
14.5 
Confidentiality 
 
All records identifying the subject will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available. 
 
Should direct access to medical records require a waiver or authorization separate from the 
subject’s statement of informed consent, it is the responsibility of the Investigator to obtain such 
permission in writing from the appropriate individual.   
 
Subjects will be told that the IRB, UF Health DISC, or regulatory authorities may inspect their 
medical records to verify the information collected, and that all personal information made 
available for inspection will be handled in strictest confidence and in accordance with local data 
protection law. 
 
14.6 
Protocol Amendments 
 
Once the study has started, amendments should be made only in exceptional cases. The changes 
then become part of the study protocol. 
 
 
14.7 
Case Report Forms 
 
An electronic case report form (eCRF) is required and must be completed for each included 
subject. The completed dataset is the sole property of UFHCC and should not be made available 
in any form to third parties, except for authorized representatives of appropriate Health/Regulatory 
Authorities, without written permission from UFHCC. 
 
14.8 
Record Retention 
 
Study documentation includes all eCRFs, data correction forms or queries, source documents, 
Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., 
protocol and amendments, IRB correspondence and approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research study. 
 
Government agency regulations and directives require that all study documentation pertaining to 
the conduct of a clinical trial must be retained by the study investigator. In the case of a study with 
a drug seeking regulatory approval and marketing, these documents shall be retained for at least 
two years after the last approval of marketing application in an International Conference on 

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Harmonization (ICH) region.  In all other cases, study documents should be kept on file until three 
years after the completion and final study report of this investigational study. 
 
UF Health Cancer Center requires that all study documentation be maintained for at least 6 years 
from the date of final study publication.  No study records may be destroyed without prior 
authorization from UF. 
 
15. COMPLIANCE WITH LAWS AND REGULATIONS 
 
It is intended that the proposed study be conducted according to the International Conference on 
Harmonization E6 Guideline for Good Clinical Practice (GCP) and the Declaration of Helsinki.  
Please refer to the International Conference on Harmonization and GCP:  
http://www.fda.gov/oc/gcp/guidance.html; Declaration of Helsinki:   
http://www.fda.gov/oc/health/helsinki89.html; Code of Federal Regulations, Title 21: 
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch. cfm]  
 
All UF Health Cancer Center investigator-initiated trials, meeting the criteria of the FDAAA’s 
applicable clinical trials, will be registered with ClinicalTrials.gov by the Protocol Development 
Officer or assigned designee.  All studies must be registered no later than 21 days after enrollment 
of the first participant.  The Protocol Development Officer will maintain the responsibility of 
updating trials registered with ClinicalTrials.gov; per the FDA’s updating requirements of 
information must be updated at least every twelve months and the registry must be updated within 
thirty days of any changes in recruitment status or completion of the study. 
 
 
16. REFERENCES 
 
American Cancer Society. Cancer Facts & Figures 2015. Atlanta: American Cancer Society; 
2015.  
 
SEER Stat Fact Sheets: Lung and Bronchus Cancer. 
http://seer.cancer.gov/statfacts/html/lungb.html  Accessed 5-24-2016 
 
Weiden PL, Einstein AB, Rudolph RH. Cisplatin bolus and 5-FU infusion chemotherapy for 
non-small cell lung cancer. Cancer Treat Rep 1985 69:1253-1255. 
 
Weiden PL, Piantadosi S. Preoperative chemotherapy (cisplatin and fluorouracil) and radiation 
therapy in stage III non-small-cell lung cancer: a phase II study of the Lung Cancer Study Group. 
J Natl Cancer Inst. 1991 Feb 20;83(4):266-73. 
 
Sagar B, Estaphan F, Spell DW, Klementich F, Jones, Jr. DV. A Pilot Phase II Study Of 
Capecitabine With Carboplatin In Patients With Advanced Nonsmall Cell Lung Cancer. Internet 
J Oncol 2009; 6 (1).  
 

UF-STO-LUNG-003 
 
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Bertino EM, Bekaii-Saab T, Fernandez S, et al. A phase II study of modulated-capecitabine and 
docetaxel in chemonaive patients with advanced non-small cell lung cancer (NSCLC). Lung 
Cancer. 2013 Jan;79(1):27-32. doi: 10.1016/j.lungcan.2012.09.013. Epub 2012 Oct 16. 
 
Zhao HY, Chen GY, Huang Y, et al. Erlotinib plus capecitabine as first-line treatment for older 
Chinese patients with advanced adenocarcinoma of the lung (C-TONG0807): an open-label, 
single arm, multicenter phase II study.  Medicine (Baltimore). 2015 Jan;94(2):e249. doi: 
10.1097/MD.0000000000000249. 
 
Sandler A, Graham C, Baggstrom M, Herbst R, Zergebel C, Saito K, Jones D. An open-label, 
multicenter, three-stage, phase II study of s-1 in combination with cisplatin as first-line therapy 
for patients with advanced non-small cell lung cancer. J Thorac Oncol. 2011 Aug;6(8):1400-6. 
doi: 10.1097/JTO.0b013e31820d7805 
 
Aono N, Ito Y, Nishino K, et al.  A retrospective study of the novel combination of paclitaxel 
and S1 for pretreated advanced non-small cell lung cancer. Chemotherapy. 2012 58(6):454-60. 
doi: 10.1159/000345624. Epub 2013 Jan 31. 
 
Tomita Y, Oguri T, Takakuwa O, et al. S-1 monotherapy for previously treated non-small cell 
lung cancer: A retrospective analysis by age and histopathological type. Oncol Lett 2012 3: 405-
410. DOI: 10.3892/ol.2011.507 
 
Peters GJ. Therapeutic potential of TAS-102 in the treatment of gastrointestinal malignancies. 
Ther Adv Med Oncol 2015 Vol. 7(6) 340–356. DOI: 10.1177/1758834015603313 
 
Emura T, Nakagawa F, Fujioka A, Ohshimo H, Kitazato K. Thymidine kinase and thymidine 
phosphorylase level as the main predictive parameter for sensitivity to TAS-102 in a mouse 
model. Oncol Rep. 2004 Feb;11(2):381-7. 
 
Emura T, Murakami Y, Nakagawa F, Fukushima M, Kitazato K. A novel antimetabolite, TAS-
102 retains its effect on FU-related resistant cancer cells. Int J Mol Med. 2004 Apr;13(4):545-9. 
 
Emura T, Suzuki N, Yamaguchi M, Ohshimo H, Fukushima M. A novel combination 
antimetabolite, TAS-102, exhibits antitumor activity in FU-resistant human cancer cells through 
a mechanism involving FTD incorporation in DNA. Int J Oncol. 2004 Sep;25(3):571-8. 
 
Shintani M, Urano M, Takakuwa Y, Kuroda M, Kamoshida S. Immunohistochemical 
characterization of pyrimidine synthetic enzymes, thymidine kinase-1 and thymidylate synthase, 
in various types of cancer. Oncol Rep 2010 23: 1345-1350. DOI: 10.3892/or_00000770 
 
Lenz HJ, Stintzing S, Loupakis F. TAS-102, a novel antitumor agent: A review of the 
mechanism of action. Cancer Treat Rev. 2015 Nov;41(9):777-83. doi: 
10.1016/j.ctrv.2015.06.001. Epub 2015 Jun 6. 
 
Mayer RJ, Van Cutsem E, Alfredo Falcone A, et al. Randomized Trial of TAS-102 for 
Refractory Metastatic Colorectal Cancer. N Engl J Med 2015;372:1909-19. 

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DOI: 10.1056/NEJMoa1414325