Conditions: Pancreatic Cancer
Keywords: metastatic pancreatic adenocarcinoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 7
Healthy volunteers: no

Brief summary:
This is an open-label, non-randomized, sequentially enrolling single arm phase II trial to evaluate the activity of TAS-102 in previously treated metastatic and locally advanced unresectable pancreatic cancer after progression through or intolerance to first or second line chemotherapy. Trial therapy will consist of TAS-102 (Lonsurf®) 35 mg/m2 to be given orally twice daily on days 1-5 and 8-12 with cycles repeating every 28 days. The primary endpoint is to determine the progression free survival (PFS) in subjects with unresectable pancreatic adenocarcinoma.

Detailed description:

Arms:
arm 1: TAS-102

Interventions: intervention 1: TAS-102
Intervention descriptions: intervention 1: TAS-102 (35 mg/m2/dose) orally 2 times daily beginning the morning of Day 1 of each cycle and ending the evening of Day 5 of each cycle, as well as beginning the morning of Day 8 and ending the evening of Day 12 of each cycle. No TAS-102 will be given on Days 6-7 or Days 13-28 of each cycle.

Protocol document:
Prot_SAP_000.pdf: 
1 
 
A Phase II Trial of TAS-102 (Lonsurf®) in Patients with Metastatic or Locally Advanced Unresectable Pancreatic Adenocarcinoma after 
Progression through First Line Chemotherapy  
UF-STO-PANC-003; UF-GI-006 
PI: Jennifer Duff, MD 
 
Protocol 
Version 
Number 
Protocol Version 
Date 
Affected Section(s) 
Summary of Revisions Made 
2.0 
19November2019 
Cover Page 
Updated study staff, added keywords, minor edits 
 
Throughout 
Minor edits for spelling, grammar, and clarification 
Definitions 
PDO changed to PMO 
Signature pages 
Removed: 
Pre-filled information 
Added: 
Subsite signature page 
Synopsis 
Added: 
Funding Source 
Updated: 
Inclusion/exclusion criteria 
Study enrollment period and duration 
1.4 
Rationale for 
Regimen/Doses/Schedule 
Removed: 
Subjects who have received radiation therapy to any indicator lesion must have 
demonstrated progressive growth of the lesion to be assessable.  Subjects must be willing to 
use contraception; are neither pregnant nor lactating; have an anticipated life expectancy of 
at least 3 months; have normal end-organ function and limited comorbidities. 
2 Objectives and 
Endpoints 
Added: 
The primary endpoint, PFS is defined as the duration of time from study entry to time of 
progression or death or the date of last contact, whichever occurs first. 
 
Definition of treatment compliance (% of completion of the treatment) 
3.2 
Inclusion Criteria 
Removed: 
Histologic or cytologic confirmed adenocarcinoma of the pancreas. 
 
Documented radiologic progression on or intolerance to first or second line chemotherapy 
which was prescribed for metastatic pancreatic adenocarcinoma or locally advanced 
unresectable disease . Intolerance is defined as any sign or symptom from chemotherapy 


2 
 
that resulted in stopping the treatment prematurely before progression of disease or the 
subject’s desire to stop chemotherapy treatment without evidence of progression. 
 
Subjects of childbearing potential must be using an effective means of contraception 
including but not limited to barrier methods, birth control, intrauterine devices.  
Histologic diagnosis of pancreatic adenocarcinoma that has been treated previously with one 
or two lines of chemotherapy.  
Previous surgery and/or radiotherapy to a non-target lesion may have been performed up to 
4 weeks  prior to the date the subject signs the informed consent form , but there must be 
evidence of disease progression radiographically or intolerance to first or second line 
chemotherapy.   
Subjects must have provided written informed consent and be willing to comply with all 
study-related procedures. 
 
Added: 
Clinical diagnosis of confirmed of adenocarcinoma of the pancreas, with pathologic 
confirmation of adenocarcinoma. 
Subjects must have measurable disease per RECIST 1.1 criteria. 
 
Refractory or intolerant to 1 or 2 prior regimens of standard chemotherapy for metastatic or 
locally advanced pancreatic cancer. 
a. Patients who have progressed based on imaging during or within 3 months of the last 
administration of each standard chemotherapy, or 
b. Patients who have withdrawn from standard treatment due to unacceptable toxicity 
warranting discontinuation of treatment and precluding retreatment with the same agent 
prior to progression of disease will also be eligible to enter the study. 
 
Updated: 
Subjects on anticoagulation need to have no evidence of uncontrolled bleeding and be on a 
stable anticoagulation dose for at least 2 weeks prior to the date the subject signs the 
informed consent formstarts study drug. 
 
Metastatic or locally advanced unresectable disease.  Subjects without clear evidence of 
distant metastatic disease will be presented at multidisciplinary tumor board for discussion 
of disease resectability. 
 


3 
 
AST and ALT equal to or less than 3 times the upper limit of normal for patients without 
hepatic involvement, or  AST and ALT equal to or less than 5 times the upper limit of 
normal for patients with hepatic involvement 
 
Absolute neutrophil count >1500/ mm3 
 
Platelet count >75‚000/ mm3 
 
3.3 
Exclusion Criteria 
Removed: 
Decline using effective means of contraception if sexually active 
 
No history of an invasive malignancy within the five years prior to initiating therapy on this 
protocol. Subjects may have prior in situ carcinomas (such as of the breast or cervix), non-
melanoma skins cancers, Rai Stage 0 chronic lymphocytic leukemia or monoclonal 
gammopathy of uncertain significance and still otherwise qualify for enrollment on this 
protocol 
 
Radiotherapy to the target lesion within 2 weeks of the date the subject signs the informed 
consent form 
 
Major surgery within  4 weeks of the date the subject signs the informed consent form (the 
surgical incision should be fully healed prior to study medication administration). 
 
Antineoplastic, biologic or anti-cancer treatment within prior 3 weeks.  A 3 week washout 
period will be required prior to beginning study treatment if subjects have received anti-
cancer treatment within this time frame. 
 
Lingering NCI-CTCAE toxicity grade 2 or higher from prior cancer treatments (excluding 
anemia, alopecia, skin pigmentation, and platinum induced neurotoxicity) > 28 days after 
the date the subject signs the informed consent form 
 
Subjects with severe hepatic enzyme impairment manifesting as total bilirubin greater than 
1.5mg/dL or greater than 3 times the upper limit of normal of AST or ALT.) 
 
Other concurrently active malignancies excluding malignancies that are disease free for 
more than 5 years of carcinoma-in-situ deemed cured by adequate treatment 


4 
 
 
Women or men of childbearing potential who are unwilling or unable to use an acceptable 
method to avoid pregnancy for the entire study period and for at least 4 weeks after the last 
dose of study drug.  
 
Added: 
Intervention for ascites or pleural effusions within 4 weeks before first dose of study drug 
 
Previous surgery and/or radiotherapy may have been performed 2 or more weeks prior to the 
date the subject starts study treatment, provided that it was to a non-target lesion and there is 
still evidence of target lesion disease progression radiographically or intolerance to first or 
second line chemotherapy. 
 
Major surgery within 4 weeks before first dose of study drug (the surgical incision should be 
fully healed prior to drug administration). 
 
Any anticancer therapy within 3 weeks before first dose of study drug (with the exception of 
bevacizumab, which must not have been taken within 4 weeks before first dose of study 
drug). 
 
Extended field radiation within 4 weeks before first dose of study drug or limited field 
radiation within 2 weeks before first dose of study drug. 
 
Any investigational agent received within prior 4 weeks before first dose of study drug 
 
Subjects must not have more than one active malignancy at the time of enrollment (Patients 
with a prior or concurrent malignancy whose natural history or treatment does not have the 
potential to interfere with the safety or efficacy assessment of the investigational regimen 
[as determined by the treatment physician and approved by the PI] may be included).  
 
Has unresolved toxicity of greater than or equal to Common Terminology Criteria for 
Adverse Events (CTCAE) Grade 2 attributed to any prior therapies (excluding anemia, 
alopecia, skin pigmentation, and platinum-induced neurotoxicity). 
 
Updated: 


5 
 
Myocardial infarction or ischemia within the 6 months before Cycle 0 Day 0 first dose of 
study drug 
 
Known untreated or unstable brain metastases or leptomeningeal disease 
 
Active infection (ie, body temperature > or equal to 38-degree C due to infection) 
4. 
Registration Procedures 
 
Updated : 
All consented subjects must be entered intoregistered with  the University of Florida’s 
Clinical Trial Management System (OnCore)UF Health Cancer Center prior to assignment 
of a subject identification number. participation in this trial. The study team must submit the 
completed study specific eligibility checklist, supporting source documentation and a copy 
of the signed informed consent document(s) to the UFHCC Project Management Office 
(PMO: PMO@cancer.ufl.edu) or their assigned Project Manager.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 
eligibility checklists or eligibility packets with missing or incomplete information may be 
returned to the study team. Upon receipt of a completed eligibility packet, the designated 
Project Manager will review the source to verify eligibility and assign a subject number. If 
eligibility cannot be confirmed, the project manager will query the site for clarification or 
additional documents as needed. Subjects failing to meet all study eligibility requirements 
will not be able to participate in the trial. 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 subjects will be maintained by the study 
site.. 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. 
5.1 
Treatment 
Schedule/Administration 
Removed: 
All participants will have histologic or cytologic confirmed metastatic or locally advanced 
unresectable pancreatic adenocarcinoma with measurable disease that was previously treated 
with and progressed or were intolerant to first or second line chemotherapy which was 
prescribed for metastatic pancreatic adenocarcinoma or locally advanced unresectable 
disease. Intolerance is defined as any sign or symptom from chemotherapy that resulted in 


6 
 
stopping the chemotherapy treatment prematurely before progression of disease or the 
subject’s desire to stop treatment without evidence of progression 
 
TAS-102 must only be administered on Days 1 through 5 and Days 8 through 12 of 
each cycle even if doses are missed or held for any reason during Days 1 through 12.   
 
Extension of TAS-102 treatment into the recovery period (Days 6 and 7; Days 13 
through 28) is not permitted. 
 
Any missed doses reported by the subject should be recorded in the subject’s source 
documents. Subjects should not take additional doses to make up for missed or held doses.  
 
Added: 
The patient must be instructed in the handling of study medication as follows: 
• 
To store the study medication at room temperature 
• 
To only remove from the study medication kit the amount of tablets needed at the 
time of dosing 
• 
Not to remove doses in advance of the next scheduled dosing 
• 
To make every effort to take doses on schedule 
• 
To take study medication within 1 hour after completing a meal (morning and 
evening meals) with a glass of water per the dose schedule 
• 
If the patient vomits after taking study medication, the patient should not take 
another dose. 
• 
To keep study medication in a safe place and out of reach of children 
• 
To bring all used and unused study medication kits to the site at each visit 
 
Any missed doses reported by the subject should be recorded in the subject’s source 
documents. Subjects should not take additional doses to make up for missed or held doses. 
 
Updated: 
Treatment must begin within 28 days of the date the subject is entered into the CTMS 
(OnCore). 
 
Upon confirmation of eligibility and provision of subject study number, subjects will receive 
TAS-102 at the following dose and schedule. 
 


7 
 
Complete blood count (CBC) with differential will be checked on the first day of each cycle, 
every 28 days, or within 72 hours of each cycle upon completion of Cycle 1 to 
accommodate subjects with long travel distance and on Day 15 of each cycle to monitor for 
development of anemia and neutropenia.  In the absence of significant treatment-related 
abnormalities, and documentation of an ANC greater than or equal to 1500/ mm3 and 
platelet count of greater than or equal to 75,000/ mm3 treatment cycles will continue every 
28 days until subject intolerance, subject discontinuation, or disease progression. All 
subjects experiencing toxicities will require the documentation of return to baseline values 
prior to the initiation of subsequent courses of therapy. Use of granulocyte colony 
stimulating factor and packed red cell transfusions can be considered to maintain adequate 
bone marrow function according to institutional standards. If no standards are in place for 
the use of growth factors, then follow the 2015 ASCO Clinical Practice Guidelines for use 
of WBC growth factors.  A maximum of three dose reductions in decrements of 5 mg per 
square meter are allowed for toxicity to a minimum dose of 20mg/m2. Do not escalate dose 
once it has been reduced. Tumor status will be assessed every two cycles. Participants will 
continue on therapy until the development of unacceptable toxicity, disease progression, or 
participant desire to discontinue protocol therapy. 
 
5.2 
Dose Calculations 
Removed: 
TAS-102 is to be taken within 1 hour of completion of morning and evening meals. 
 
Days 1 through 5: TAS-102 (35 mg/m2/dose) orally 2 times daily with the first dose 
administered in the morning of Day 1 of each cycle and the last dose administered in the 
evening of Day 5. 
 
Days 8 through 12: TAS-102 (35 mg/m2/dose) orally 2 times daily with the first dose 
administered in the morning of Day 8 of each cycle and the last dose administered in the 
evening of Day 12 
5.3 
Concomitant Therapy 
Updated: 
Use of anti-neoplastic or anti-tumor agents therapies not part of the study therapytreatment, 
including surgery, chemotherapy, radiation therapy, immunotherapy, and hormonal 
anticancer therapy, is not permitted while participating in this study.  Use of erythropoietin 
stimulating agents are is also not permitted.  Study participants may receive additional 
investigational antineoplastic therapies upon completion of their participation in this 
protocol.  Use of concurrent investigational agents is not permitted. 
 


8 
 
Any therapy or medication (except study drugs), administered from screening first dose of 
study drug until 30 days after the last dose of either study drug, is considered a concomitant 
therapy or medication. 
 
5.3.1 
Allowed Concomitant 
Therapy 
Removed: 
Use of granulocyte colony stimulating factor and packed red cell transfusions can be 
considered to maintain adequate bone marrow function according to institutional standards. 
If no standards are in place for the use of growth factors, then follow the 2015 ASCO 
Clinical Practice Guidelines for use of WBC growth factors. 
 
Added: 
Use of granulocyte colony stimulating factor and packed red cell transfusions are permitted 
to maintain adequate bone marrow function according to institutional standards. If no 
standards are in place for the use of growth factors, then follow the 2015 ASCO Clinical 
Practice Guidelines for use of WBC growth factors 
Updated: 
Subjects may continue on their chronic medications. Subjects on anticoagulation need to 
have no evidence of bleeding and be on a stable anticoagulation dose for at least 2 weeks 
prior to first dose of study drug trial enrollment. 
5.3.2 
Prohibited Concomitant 
Therapy 
Added: 
Cancer-related surgery 
 
Updated: 
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 strictly 
palliative radiation therapy to a single symptomatic lesion will not be considered clinical 
progression for the purposes of determining PFS.  
 
5.4.1 
Dose Modification 
Explained 
Added: 
Table 2: TAS-102 Dose Modification Table 
 
Updated: 
Subjects are permitted dose reduction(s) to a minimum dose of 20 mg/m2 (40 mg/m2/day) in 
5 mg/m2 (10 mg/m2/day) steps.  A maximum of three dose reductions in decrements of 5 mg 


9 
 
per square meter are allowed for toxicity to a minimum dose of 20mg/m2.  Do not escalate 
dose once it has been reduced.  Refer to Table 2 located in this sub-section. 
 
5.4.2 
Non-Hemotologic 
Toxicity 
Updated: 
If there is any uncertainty about continuing study medication or resuming study medication 
in a subject with Grade ≥3 non-hematologic toxicities, the case must be discussed with the 
UFHCC Data and Safety Integrity Committee (DISC)Sponsor’s Medical Monitor prior to 
continuing treatment. 
6.2 
Study Treatment 
Discontinuation 
Removed: 
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 subjects, requiring 
dose reduction to the dose level -1. If this occurs, the protocol will be amended to allow for 
a more tolerable dosing of TAS102.  Intolerability will be defined as the occurrence of the 
following dose-limiting toxicities 
Updated: 
Study treatment will be withheld under the following circumstances: 
 
• 
Grade 4 neutropenia (ANC less than 500/mm3 or febrile neutropenia) lasting > 7 
days, until ANC is resolved to greater than 1500/mm3 or febrile neutropenia is 
resolved 
• 
Grade 4 thrombocytopenia or grade 3 thrombocytopenia with bleeding (platelets 
less than 50,000/mm3), until platelet count resolved to greater than or equal to 
75,000/mm3 
• 
Grade 3 or 4 nausea or vomiting lasting > 48 hours and is uncontrolled by 
aggressive antiemetic therapy 
• 
Grade 3 or 4 diarrhea lasting > 48 hours and is unresponsive to antidiarrheal 
medication 
• 
Other grade 3 or 4 non-hematologic toxicity until the adverse reaction has resolved 
to Grade 0 or 1resulting in a > 2 week delay in the initiation of the next cycle  
 
A subject will be discontinued from protocol therapy under the following circumstances: 
• 
Any therapy or medication (except study drugs), administered from screening until 
30 days Any adverse event which, in the Investigator’s opinion, requires termination 
of the study medication. 


10 
 
• 
Disease progression, unless at the discretion of the Principal Investigator (in 
collaboration with any co-sponsors or collaborators) determines continued treatment 
with study drug is appropriate. 
• 
Substantial non-compliance (>25% of missed doses with the exception of dose 
delays and dose modifications per protocol, or accounting for dose-related 
instructions from research team staff due to adverse events), with the requirements 
of the study. 
• 
The subject presents with a beta-HCG test consistent with pregnancy and is 
confirmed to be pregnant..  Pregnancy will be reported along the same timelines as a 
serious adverse event. 
• 
The subject 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 the study or its results. 
The Investigator will make every reasonable effort to keep each subject in the study unless it 
is in the subject’s best interests to discontinue participation.  If a subject is removed from the 
study or declines further participation, all End of Treatment evaluations should be 
performed if the subject 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 subjects are followed up for survival status and 
progression (as applicable) after the End of Treatment Visit. 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 subjects participating in the study who receive study drug, 
even for a brief period of time.  Subjects who discontinue following entry study consent will 
have relevant information completed and recorded on the CRF.  All subjects 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 subject should die during the trial or within 30 days of stopping receiving 
study treatment, the Investigator will inform the UF Health Data Integrity and Safety 
Committee (DISC). 
 
7.1 
Study Schedule of 
Events 
Removed:  
Pretreatment and On-treatment measurements: 
All screening procedures should be completed within 28 days of treatment except for serum 
pregnancy testing which should be completed within 7 days of treatment. 
 


11 
 
History & Physical, Vital Signs, ECOG PS, CMP, CBC w Diff and CA19-9 are not required 
to be repeated at treatment initiation if they were completed within 7 days prior to Cycle 1 
Day 1.  
 
7.3 
On-Study Evaluations 
Removed: 
For the Day 15 CBC w/Diff to be collected each cycle, notify the investigator if any of the 
following are observed in the lab results: 
- 
Absolute neutrophil count less than or equal to 500 µL (consider G-CSF; to be 
performed at the provider’s discretion); 
- 
Platelets less than 50 thousand/mm3 (transfuse if 10 thousand/mm3 or less); or 
- 
Hemoglobin less than 7 g/dL (consider PRBC transfusion; to be performed at the 
providers’ discretion). 
7.5 
Follow Up/Survival 
Updated:: 
Follow-up evaluations may consist of the interim medical history, physical examination, 
imaging, CBC, or comprehensive metabolic panel.  Any X-rays, CT or MRI scans, or other 
studies (such as PET scans, bone scans, biopsies, etc.) will be done as clinically indicated 
and up to the discretion of the treating physician.  
 
After this one-year follow-up period is over, subjects will continued to be followed for 
survival until death, withdrawal, or lost to follow up. If subjects are entered onto another 
study protocol, they will no longer be followed.  If subjects are lost to follow-up, every 
effort will be made at least quarterly to attempt to locate that subject and to determine their 
health status. Evaluations may consist of the interim medical history, physical examination, 
imaging, CBC, comprehensive metabolic panel Any X-rays, CT or MRI scans, or other 
studies (such as PET scans, bone scans, biopsies, etc.) will be done as clinically indicated 
and up to the discretion of the treating physician. For subjects that come off protocol for 
reasons other than progressive disease, then CT or MRI scans will be performed every 8 
weeks to document disease progression. until disease progression is shown or another anti-
cancer therapy is initiated.  Vital statistics may be assessed and recorded every 3 months 
after the completion of study treatment 
10.2 
Period of Observation 
Updated: 
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. 
10.3 
Removed: 
10.3 Procedures for Eliciting Adverse Events 
 


12 
 
Documenting and 
Reporting of Adverse 
Events by Investigator 
A consistent methodology of non-directive questioning for eliciting AEs at all patient 
evaluation time points should be adopted.  Examples of non-directive questions include:  
• 
“How have you felt since your last clinical visit?” 
• 
“Have you had any new or changed health problems since you were last here?” 
 
Each recorded AE or SAE will be described by its duration (i.e., start and end dates), 
severity, regulatory seriousness criteria if applicable, suspected relationship to the 
investigational product (see following guidance), and actions taken with the study drug in 
response to the event. 
 
10.4.1 
Serious Adverse Events 
Added: 
Institution SAE and Pregnancy Reporting Information 
 
 
 
SAEs  and pregnancies must be reported to the UFHCC CRO Project 
Management Office (PMO), or assigned designee at: 
  
Email: pmo@cancer.ufl.edu  
 
As well as entered in OnCore, the study CTMS. 
 
 
 
Updated: 
At the time of the annual DSUR (data-lock point), a list of all AEs which led to 
discontinuation, subjects with fatal events, and demographic information for all subjects 
exposed to TAS-102 must all be submitted to Taiho. 
 
UFHCC PMO and DISC Reporting Requirements 
 
Serious adverse events (SAE's) must be documented on an SAE report form and emailed 
reported to UFHCC Project Management Office (PMO; pmo@cancer.ufl.edu) and entered 
into OnCore within 24 hours of discovery of the event.  If only limited details are known, 
these should be reported within that time frame and follow up reports can be submitted for 
elaboration, clarifications, or corrections.  Any email correspondence must be kept in the 
trial file at the study site. The site investigator is responsible for informing the IRB and/or 


13 
 
the Regulatory Authority of the SAE as per local requirements.  SAEs must also be reported 
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 submitted to the UFHCC PMO (pmo@cancer.ufl.edu), 
stating that this is a follow-up to a 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, and whether the participant continued or withdrew from study participation.  PMO 
will confirm that the event and any necessary follow-ups are reported to the UFHCC Data 
and Safety Integrity Committee (DISC), Taiho Oncology, and any other regulatory 
authorities as required.  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. 
 
10.5 
IND Safety Reports 
Unrelated to the Trial 
Updated: 
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. 
11.3 
Methods and Timing for 
Assessment and 
Recording Safety 
Variables 
Removed: 
Death as a result of disease progression endpoints are only to be assessed as efficacy 
measures and not as AEs or SAEs unless the events that led to death met the serious criteria. 
 
Updated: 
The investigator is responsible for ensuring that all AEs and SAEs that are observed or 
reported during the study are recorded on the CRF and reported to Taiho in accordance with 
protocol instructions and clinical trial agreement.  


14 
 
 
12.1 
Sample Size 
Determination 
Removed: 
Assuming at least the last evaluable subject derives benefit from the anticipated maximal 
number of six cycles, the length of the entire study will be approximately 24 months. 
 
Updated: 
This is a pilot phase II single-arm study, with a primary endpoint of progression-free 
survival (PFS) to evaluate efficacy of TAS-102.  And Additional obhective of the study is to 
evaluate the feasibility and safety of a regimen of daily TAS-102 administered to subjects 
with metastatic or unresectable pancreatic adenocarcinoma after progression through or 
intolerance to first- or second-line chemotherapy. The primary efficacy analysis will be an 
intent-to-treat comparison of the PFS curve with a reference historical control.  From past 
studies3, the median PFS and/or time to progression (TTP) for subjects with metastatic or 
unresectable pancreatic adenocarcinoma in the second line of treatment is variable ranging 
from 6 weeks to 22 weeks.   Assuming exponential distributions on PFS on both current 
study population and the referent population, a sample size of 333 evaluable subjects who 
will receive the same level of dose will ensure to have at least 80% power to detect an 
improvement of 3 weeks of median PFS (i.e. from 6 weeks to 9 weeks).  The sample size 
and power derivations were based on one-sample log rank test by Wu (2015)14 at one-sided 
significance level of 0.10.  It is assumed that the survival time distributions of both groups 
(historical and this proposed experiment groups) are approximately the Weibull distribution 
with a shape parameter of ~1.0. Accounting for about ~10% ineligible/inevaluable subjects, 
the total number of subjects to be accrued to this cohort will be 37, which is expected to be 
completed within 24 months. Assuming at least the last evaluable subject derives benefit 
from the anticipated maximal number of 6 cycles, the length of the entire treatment study 
will be approximately 30 months.   
 
The remaining 27 subjects will also be closely monitored for TAS-102 related toxicities 
continuously. The study will be temporarily closed for detailed review if the number of 
observed adverse events listed in the definition of intolerability in section 6.2 is greater than 
or equal to the corresponding boundary (as shown in the following Table 79). The actual 
power (based on exact binomial test) of declaring the investigational treatment is too toxic 
are approximately 88.5%, 66.2%, 35.4% and 11.9% when the true toxicity rates are 44%, 
36%, 28% and 20%, respectively. 
  
Table 7. Pocock boundaries for toxicity monitoring for the remaining 27 subjects 


15 
 
# of evaluable subjects 
2 
3-4 
5-7 
8-10 
11-
13 
14-
17 
18-
20 
21-
24 
25-
27 
Pocock boundary 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
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 
received two cycles of therapy as planned. 
 
12.2  
Analysis of Baseline and 
Demographic 
Characteristics   
Updated: 
The analysis of demographic characteristics (age, gender, ethnicity) and baseline 
characteristics, including weight change, performance status, and histologic subtype, will be 
primarily descriptive due to the small subject numbers. 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 subject outcomes.  All data will be summarized using 
descriptive statistics (mean/variance, median/range, frequency/proportion) along with 
graphical illustration as needed. Continuous variables will be compared to historical controls 
using the Wilcoxon rank sum test, and discrete outcomes will be compared using the exact 
Chi-square test. 
12.3  
Primary and Secondary 
Endpoint Efficacy 
Analysis 
Updated: 
The primary endpoint to this study will be to determine progression-free survival following 
TAS-102 therapy.  Kaplan-Meier mean estimates and survival curves of progression-free 
survival rates will be calculated. 
A secondary endpoint of this study will be overall survival/TTP following treatment with 
TAS-102.  Kaplan-Meier estimates and survival curves of overall survival rates will be 
calculated. Other secondary endpoints include response rates, clinical benefit rate (CR + PR 
+ SD), toxicities, and reversibility of toxicities, and compliance with intended treatment) 
will also be estimated along with exact 95% binomial confidence intervals.  
No multiplicity will be adjusted for the secondary endpoints. All data analysis will be 
conducted in reproducible fashion and the results will be reported regardless of the statistical 
significance. 
13.1 
Data Integrity and 
Safety Committee 
Removed: 
The PI will summarize and provide DISC with all pertinent data related to the level of risk 
assigned by SRMC.  This protocol summary will include a minimum of the following: 


16 
 
• 
The UF IRB assigned protocol number, UFHCC assigned protocol number, protocol 
title, PI name, data coordinator name or primary study coordinator, regulatory 
coordinator name, and statistician. 
• 
Date of initial UF IRB approval, date of most recent consent UF IRB 
approval/revision, date of UF IRB expiration, study status, and phase of the study. 
• 
Study target accrual and study actual accrual. 
• 
Protocol objectives with supporting data and list of number of study participants 
who have met each objective. 
• 
Measures of efficacy. 
• 
Early stopping rules with supporting data and a list of the number of study 
participants who have met the early stopping rules. 
• 
Summary of toxicities and protocol deviations. 
• 
Summary of any recent literature which may affect the safety or ethics of the trial. 
 
13.2 
On-site Data Monitoring 
Updated: 
UFHCC (University of Florida Health Cancer Center) Quality Assurance team and/or 
project management officers will perform remote monitoring and may make 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 
completion and validated against with data submitted electronically via the Electronic Data 
Capture. . The site investigator/institution guarantee access to source documents by UFHCC 
or its designee and appropriate regulatory agencies.  As part of the responsibilities assumed 
by conducting the 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. 
 
13.3 
Principal Investigator 
(PI) Responsibilities 
Removed: 
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.  
Added: 
Per IRB requirements, the PI is personally responsible for conducting and supervising the 
conduct of human subjects research by “protecting the rights, safety, and welfare of subjects 
under the investigator’s care.” The PI also must ensure that all the research conducted is 
done so in an ethical manner and in accordance with all federal, state, and local laws and 
regulations, institutional policies, and the requirements of the IRB. 


17 
 
 
Oversight is defined as “management by overseeing the performance or operation of a 
person or group; watchful care, superintendence, general supervision”. Any person serving 
as a PI has voluntarily accepted these responsibilities and is expected to fully comply with 
these requirements, as outlined in the UFHCC Guidance: Principal Investigator 
Responsibilities and Oversight.  
15.1 
Good Clinical Practice 
Updated: 
All potential serious breaches must be reported to the UFHCC Project Management Office 
(PMO; PMO@cancer.ufl.edu, who will then report the breach to the UFHCC DISC) and the 
IRB of record UF Health Cancer Center Data Integrity and  Safety Committee (DISC) 
immediately. 
15.2 
Institutional Review 
Board 
Removed: 
The Principal Investigator is responsible for keeping the IRB apprised of the progress of the 
study and of any changes made to the protocol as deemed appropriate, but in any case the 
IRB must be updated at least once a year. 
15.6 
Protocol Amendments 
Added: 
Protocol amendments will not be implemented without prior written IRB approval. All 
amendments will be submitted to the IRB and SRMC (as applicable), and written 
verification that the amendment was submitted and subsequently approved is to be obtained, 
and notification will sent out to the applicable study teams, prior to implementing the 
amendment.   
 
On an emergency-basis, to eliminate an immediate safety hazard to a subject, a protocol 
deviation may be implemented immediately, provided the IRB and UFHCC CRO PMO 
(pmo@cancer.ufl.edu) are notified within 5 business days with a full justification and 
description of the event. 
15.7 
Case Report Forms 
Removed: 
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. 
 
Added: 
The Principal Investigator and/or his/her designee, will prepare and maintain adequate and 
accurate participant case histories with observations and data pertinent to the study.  Study 
specific Case Report Forms (CRFs) will document protocol-required outcomes for safety 


18 
 
monitoring and data analysis.  All study data will be entered electronically in an Electronic 
Data Capture system in accordance with the protocol schedule of events and guidelines 
developed in the Data Management Plan for the study, using a secure access account.   
All protocol data 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. 
16 
Compliance with Laws 
and Regulations 
Removed: 
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. 
 
Updated: 
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 Project 
Management Officer or assigned designee.  All studies must be registered prior to 
enrollment of the first participant.  The Protocol Management Officer or assigned designee 
will maintain the responsibility of updating trials registered with ClinicalTrials.gov. Per 
FDA requirement, 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.  The PMO will determine if registration and updates to the NCI 
CTRP are required. 
 
 


1 
 
A Phase II Trial of TAS-102 (Lonsurf®) in Patients with Metastatic or Locally Advanced Unresectable Pancreatic Adenocarcinoma after 
Progression through First Line Chemotherapy  
UF-STO-PANC-003; UF-GI-006 
PI: Jennifer Duff, MD 
 
Protocol 
Version 
Number 
Protocol Version 
Date 
Affected Section(s) 
Summary of Revisions Made 
2.0 
19November2019 
Cover Page 
Updated study staff, added keywords, minor edits 
 
Throughout 
Minor edits for spelling, grammar, and clarification 
Definitions 
PDO changed to PMO 
Signature pages 
Removed: 
Pre-filled information 
Added: 
Subsite signature page 
Synopsis 
Added: 
Funding Source 
Updated: 
Inclusion/exclusion criteria 
Study enrollment period and duration 
1.4 
Rationale for 
Regimen/Doses/Schedule 
Removed: 
Subjects who have received radiation therapy to any indicator lesion must have 
demonstrated progressive growth of the lesion to be assessable.  Subjects must be willing to 
use contraception; are neither pregnant nor lactating; have an anticipated life expectancy of 
at least 3 months; have normal end-organ function and limited comorbidities. 
2 Objectives and 
Endpoints 
Added: 
The primary endpoint, PFS is defined as the duration of time from study entry to time of 
progression or death or the date of last contact, whichever occurs first. 
 
Definition of treatment compliance (% of completion of the treatment) 
3.2 
Inclusion Criteria 
Removed: 
Histologic or cytologic confirmed adenocarcinoma of the pancreas. 
 
Documented radiologic progression on or intolerance to first or second line chemotherapy 
which was prescribed for metastatic pancreatic adenocarcinoma or locally advanced 
unresectable disease . Intolerance is defined as any sign or symptom from chemotherapy 


2 
 
that resulted in stopping the treatment prematurely before progression of disease or the 
subject’s desire to stop chemotherapy treatment without evidence of progression. 
 
Subjects of childbearing potential must be using an effective means of contraception 
including but not limited to barrier methods, birth control, intrauterine devices.  
Histologic diagnosis of pancreatic adenocarcinoma that has been treated previously with one 
or two lines of chemotherapy.  
Previous surgery and/or radiotherapy to a non-target lesion may have been performed up to 
4 weeks  prior to the date the subject signs the informed consent form , but there must be 
evidence of disease progression radiographically or intolerance to first or second line 
chemotherapy.   
Subjects must have provided written informed consent and be willing to comply with all 
study-related procedures. 
 
Added: 
Clinical diagnosis of confirmed of adenocarcinoma of the pancreas, with pathologic 
confirmation of adenocarcinoma. 
Subjects must have measurable disease per RECIST 1.1 criteria. 
 
Refractory or intolerant to 1 or 2 prior regimens of standard chemotherapy for metastatic or 
locally advanced pancreatic cancer. 
a. Patients who have progressed based on imaging during or within 3 months of the last 
administration of each standard chemotherapy, or 
b. Patients who have withdrawn from standard treatment due to unacceptable toxicity 
warranting discontinuation of treatment and precluding retreatment with the same agent 
prior to progression of disease will also be eligible to enter the study. 
 
Updated: 
Subjects on anticoagulation need to have no evidence of uncontrolled bleeding and be on a 
stable anticoagulation dose for at least 2 weeks prior to the date the subject signs the 
informed consent formstarts study drug. 
 
Metastatic or locally advanced unresectable disease.  Subjects without clear evidence of 
distant metastatic disease will be presented at multidisciplinary tumor board for discussion 
of disease resectability. 
 


3 
 
AST and ALT equal to or less than 3 times the upper limit of normal for patients without 
hepatic involvement, or  AST and ALT equal to or less than 5 times the upper limit of 
normal for patients with hepatic involvement 
 
Absolute neutrophil count >1500/ mm3 
 
Platelet count >75‚000/ mm3 
 
3.3 
Exclusion Criteria 
Removed: 
Decline using effective means of contraception if sexually active 
 
No history of an invasive malignancy within the five years prior to initiating therapy on this 
protocol. Subjects may have prior in situ carcinomas (such as of the breast or cervix), non-
melanoma skins cancers, Rai Stage 0 chronic lymphocytic leukemia or monoclonal 
gammopathy of uncertain significance and still otherwise qualify for enrollment on this 
protocol 
 
Radiotherapy to the target lesion within 2 weeks of the date the subject signs the informed 
consent form 
 
Major surgery within  4 weeks of the date the subject signs the informed consent form (the 
surgical incision should be fully healed prior to study medication administration). 
 
Antineoplastic, biologic or anti-cancer treatment within prior 3 weeks.  A 3 week washout 
period will be required prior to beginning study treatment if subjects have received anti-
cancer treatment within this time frame. 
 
Lingering NCI-CTCAE toxicity grade 2 or higher from prior cancer treatments (excluding 
anemia, alopecia, skin pigmentation, and platinum induced neurotoxicity) > 28 days after 
the date the subject signs the informed consent form 
 
Subjects with severe hepatic enzyme impairment manifesting as total bilirubin greater than 
1.5mg/dL or greater than 3 times the upper limit of normal of AST or ALT.) 
 
Other concurrently active malignancies excluding malignancies that are disease free for 
more than 5 years of carcinoma-in-situ deemed cured by adequate treatment 


4 
 
 
Women or men of childbearing potential who are unwilling or unable to use an acceptable 
method to avoid pregnancy for the entire study period and for at least 4 weeks after the last 
dose of study drug.  
 
Added: 
Intervention for ascites or pleural effusions within 4 weeks before first dose of study drug 
 
Previous surgery and/or radiotherapy may have been performed 2 or more weeks prior to the 
date the subject starts study treatment, provided that it was to a non-target lesion and there is 
still evidence of target lesion disease progression radiographically or intolerance to first or 
second line chemotherapy. 
 
Major surgery within 4 weeks before first dose of study drug (the surgical incision should be 
fully healed prior to drug administration). 
 
Any anticancer therapy within 3 weeks before first dose of study drug (with the exception of 
bevacizumab, which must not have been taken within 4 weeks before first dose of study 
drug). 
 
Extended field radiation within 4 weeks before first dose of study drug or limited field 
radiation within 2 weeks before first dose of study drug. 
 
Any investigational agent received within prior 4 weeks before first dose of study drug 
 
Subjects must not have more than one active malignancy at the time of enrollment (Patients 
with a prior or concurrent malignancy whose natural history or treatment does not have the 
potential to interfere with the safety or efficacy assessment of the investigational regimen 
[as determined by the treatment physician and approved by the PI] may be included).  
 
Has unresolved toxicity of greater than or equal to Common Terminology Criteria for 
Adverse Events (CTCAE) Grade 2 attributed to any prior therapies (excluding anemia, 
alopecia, skin pigmentation, and platinum-induced neurotoxicity). 
 
Updated: 


5 
 
Myocardial infarction or ischemia within the 6 months before Cycle 0 Day 0 first dose of 
study drug 
 
Known untreated or unstable brain metastases or leptomeningeal disease 
 
Active infection (ie, body temperature > or equal to 38-degree C due to infection) 
4. 
Registration Procedures 
 
Updated : 
All consented subjects must be entered intoregistered with  the University of Florida’s 
Clinical Trial Management System (OnCore)UF Health Cancer Center prior to assignment 
of a subject identification number. participation in this trial. The study team must submit the 
completed study specific eligibility checklist, supporting source documentation and a copy 
of the signed informed consent document(s) to the UFHCC Project Management Office 
(PMO: PMO@cancer.ufl.edu) or their assigned Project Manager.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 
eligibility checklists or eligibility packets with missing or incomplete information may be 
returned to the study team. Upon receipt of a completed eligibility packet, the designated 
Project Manager will review the source to verify eligibility and assign a subject number. If 
eligibility cannot be confirmed, the project manager will query the site for clarification or 
additional documents as needed. Subjects failing to meet all study eligibility requirements 
will not be able to participate in the trial. 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 subjects will be maintained by the study 
site.. 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. 
5.1 
Treatment 
Schedule/Administration 
Removed: 
All participants will have histologic or cytologic confirmed metastatic or locally advanced 
unresectable pancreatic adenocarcinoma with measurable disease that was previously treated 
with and progressed or were intolerant to first or second line chemotherapy which was 
prescribed for metastatic pancreatic adenocarcinoma or locally advanced unresectable 
disease. Intolerance is defined as any sign or symptom from chemotherapy that resulted in 


6 
 
stopping the chemotherapy treatment prematurely before progression of disease or the 
subject’s desire to stop treatment without evidence of progression 
 
TAS-102 must only be administered on Days 1 through 5 and Days 8 through 12 of 
each cycle even if doses are missed or held for any reason during Days 1 through 12.   
 
Extension of TAS-102 treatment into the recovery period (Days 6 and 7; Days 13 
through 28) is not permitted. 
 
Any missed doses reported by the subject should be recorded in the subject’s source 
documents. Subjects should not take additional doses to make up for missed or held doses.  
 
Added: 
The patient must be instructed in the handling of study medication as follows: 
• 
To store the study medication at room temperature 
• 
To only remove from the study medication kit the amount of tablets needed at the 
time of dosing 
• 
Not to remove doses in advance of the next scheduled dosing 
• 
To make every effort to take doses on schedule 
• 
To take study medication within 1 hour after completing a meal (morning and 
evening meals) with a glass of water per the dose schedule 
• 
If the patient vomits after taking study medication, the patient should not take 
another dose. 
• 
To keep study medication in a safe place and out of reach of children 
• 
To bring all used and unused study medication kits to the site at each visit 
 
Any missed doses reported by the subject should be recorded in the subject’s source 
documents. Subjects should not take additional doses to make up for missed or held doses. 
 
Updated: 
Treatment must begin within 28 days of the date the subject is entered into the CTMS 
(OnCore). 
 
Upon confirmation of eligibility and provision of subject study number, subjects will receive 
TAS-102 at the following dose and schedule. 
 


7 
 
Complete blood count (CBC) with differential will be checked on the first day of each cycle, 
every 28 days, or within 72 hours of each cycle upon completion of Cycle 1 to 
accommodate subjects with long travel distance and on Day 15 of each cycle to monitor for 
development of anemia and neutropenia.  In the absence of significant treatment-related 
abnormalities, and documentation of an ANC greater than or equal to 1500/ mm3 and 
platelet count of greater than or equal to 75,000/ mm3 treatment cycles will continue every 
28 days until subject intolerance, subject discontinuation, or disease progression. All 
subjects experiencing toxicities will require the documentation of return to baseline values 
prior to the initiation of subsequent courses of therapy. Use of granulocyte colony 
stimulating factor and packed red cell transfusions can be considered to maintain adequate 
bone marrow function according to institutional standards. If no standards are in place for 
the use of growth factors, then follow the 2015 ASCO Clinical Practice Guidelines for use 
of WBC growth factors.  A maximum of three dose reductions in decrements of 5 mg per 
square meter are allowed for toxicity to a minimum dose of 20mg/m2. Do not escalate dose 
once it has been reduced. Tumor status will be assessed every two cycles. Participants will 
continue on therapy until the development of unacceptable toxicity, disease progression, or 
participant desire to discontinue protocol therapy. 
 
5.2 
Dose Calculations 
Removed: 
TAS-102 is to be taken within 1 hour of completion of morning and evening meals. 
 
Days 1 through 5: TAS-102 (35 mg/m2/dose) orally 2 times daily with the first dose 
administered in the morning of Day 1 of each cycle and the last dose administered in the 
evening of Day 5. 
 
Days 8 through 12: TAS-102 (35 mg/m2/dose) orally 2 times daily with the first dose 
administered in the morning of Day 8 of each cycle and the last dose administered in the 
evening of Day 12 
5.3 
Concomitant Therapy 
Updated: 
Use of anti-neoplastic or anti-tumor agents therapies not part of the study therapytreatment, 
including surgery, chemotherapy, radiation therapy, immunotherapy, and hormonal 
anticancer therapy, is not permitted while participating in this study.  Use of erythropoietin 
stimulating agents are is also not permitted.  Study participants may receive additional 
investigational antineoplastic therapies upon completion of their participation in this 
protocol.  Use of concurrent investigational agents is not permitted. 
 


8 
 
Any therapy or medication (except study drugs), administered from screening first dose of 
study drug until 30 days after the last dose of either study drug, is considered a concomitant 
therapy or medication. 
 
5.3.1 
Allowed Concomitant 
Therapy 
Removed: 
Use of granulocyte colony stimulating factor and packed red cell transfusions can be 
considered to maintain adequate bone marrow function according to institutional standards. 
If no standards are in place for the use of growth factors, then follow the 2015 ASCO 
Clinical Practice Guidelines for use of WBC growth factors. 
 
Added: 
Use of granulocyte colony stimulating factor and packed red cell transfusions are permitted 
to maintain adequate bone marrow function according to institutional standards. If no 
standards are in place for the use of growth factors, then follow the 2015 ASCO Clinical 
Practice Guidelines for use of WBC growth factors 
Updated: 
Subjects may continue on their chronic medications. Subjects on anticoagulation need to 
have no evidence of bleeding and be on a stable anticoagulation dose for at least 2 weeks 
prior to first dose of study drug trial enrollment. 
5.3.2 
Prohibited Concomitant 
Therapy 
Added: 
Cancer-related surgery 
 
Updated: 
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 strictly 
palliative radiation therapy to a single symptomatic lesion will not be considered clinical 
progression for the purposes of determining PFS.  
 
5.4.1 
Dose Modification 
Explained 
Added: 
Table 2: TAS-102 Dose Modification Table 
 
Updated: 
Subjects are permitted dose reduction(s) to a minimum dose of 20 mg/m2 (40 mg/m2/day) in 
5 mg/m2 (10 mg/m2/day) steps.  A maximum of three dose reductions in decrements of 5 mg 


9 
 
per square meter are allowed for toxicity to a minimum dose of 20mg/m2.  Do not escalate 
dose once it has been reduced.  Refer to Table 2 located in this sub-section. 
 
5.4.2 
Non-Hemotologic 
Toxicity 
Updated: 
If there is any uncertainty about continuing study medication or resuming study medication 
in a subject with Grade ≥3 non-hematologic toxicities, the case must be discussed with the 
UFHCC Data and Safety Integrity Committee (DISC)Sponsor’s Medical Monitor prior to 
continuing treatment. 
6.2 
Study Treatment 
Discontinuation 
Removed: 
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 subjects, requiring 
dose reduction to the dose level -1. If this occurs, the protocol will be amended to allow for 
a more tolerable dosing of TAS102.  Intolerability will be defined as the occurrence of the 
following dose-limiting toxicities 
Updated: 
Study treatment will be withheld under the following circumstances: 
 
• 
Grade 4 neutropenia (ANC less than 500/mm3 or febrile neutropenia) lasting > 7 
days, until ANC is resolved to greater than 1500/mm3 or febrile neutropenia is 
resolved 
• 
Grade 4 thrombocytopenia or grade 3 thrombocytopenia with bleeding (platelets 
less than 50,000/mm3), until platelet count resolved to greater than or equal to 
75,000/mm3 
• 
Grade 3 or 4 nausea or vomiting lasting > 48 hours and is uncontrolled by 
aggressive antiemetic therapy 
• 
Grade 3 or 4 diarrhea lasting > 48 hours and is unresponsive to antidiarrheal 
medication 
• 
Other grade 3 or 4 non-hematologic toxicity until the adverse reaction has resolved 
to Grade 0 or 1resulting in a > 2 week delay in the initiation of the next cycle  
 
A subject will be discontinued from protocol therapy under the following circumstances: 
• 
Any therapy or medication (except study drugs), administered from screening until 
30 days Any adverse event which, in the Investigator’s opinion, requires termination 
of the study medication. 


10 
 
• 
Disease progression, unless at the discretion of the Principal Investigator (in 
collaboration with any co-sponsors or collaborators) determines continued treatment 
with study drug is appropriate. 
• 
Substantial non-compliance (>25% of missed doses with the exception of dose 
delays and dose modifications per protocol, or accounting for dose-related 
instructions from research team staff due to adverse events), with the requirements 
of the study. 
• 
The subject presents with a beta-HCG test consistent with pregnancy and is 
confirmed to be pregnant..  Pregnancy will be reported along the same timelines as a 
serious adverse event. 
• 
The subject 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 the study or its results. 
The Investigator will make every reasonable effort to keep each subject in the study unless it 
is in the subject’s best interests to discontinue participation.  If a subject is removed from the 
study or declines further participation, all End of Treatment evaluations should be 
performed if the subject 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 subjects are followed up for survival status and 
progression (as applicable) after the End of Treatment Visit. 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 subjects participating in the study who receive study drug, 
even for a brief period of time.  Subjects who discontinue following entry study consent will 
have relevant information completed and recorded on the CRF.  All subjects 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 subject should die during the trial or within 30 days of stopping receiving 
study treatment, the Investigator will inform the UF Health Data Integrity and Safety 
Committee (DISC). 
 
7.1 
Study Schedule of 
Events 
Removed:  
Pretreatment and On-treatment measurements: 
All screening procedures should be completed within 28 days of treatment except for serum 
pregnancy testing which should be completed within 7 days of treatment. 
 


11 
 
History & Physical, Vital Signs, ECOG PS, CMP, CBC w Diff and CA19-9 are not required 
to be repeated at treatment initiation if they were completed within 7 days prior to Cycle 1 
Day 1.  
 
7.3 
On-Study Evaluations 
Removed: 
For the Day 15 CBC w/Diff to be collected each cycle, notify the investigator if any of the 
following are observed in the lab results: 
- 
Absolute neutrophil count less than or equal to 500 µL (consider G-CSF; to be 
performed at the provider’s discretion); 
- 
Platelets less than 50 thousand/mm3 (transfuse if 10 thousand/mm3 or less); or 
- 
Hemoglobin less than 7 g/dL (consider PRBC transfusion; to be performed at the 
providers’ discretion). 
7.5 
Follow Up/Survival 
Updated:: 
Follow-up evaluations may consist of the interim medical history, physical examination, 
imaging, CBC, or comprehensive metabolic panel.  Any X-rays, CT or MRI scans, or other 
studies (such as PET scans, bone scans, biopsies, etc.) will be done as clinically indicated 
and up to the discretion of the treating physician.  
 
After this one-year follow-up period is over, subjects will continued to be followed for 
survival until death, withdrawal, or lost to follow up. If subjects are entered onto another 
study protocol, they will no longer be followed.  If subjects are lost to follow-up, every 
effort will be made at least quarterly to attempt to locate that subject and to determine their 
health status. Evaluations may consist of the interim medical history, physical examination, 
imaging, CBC, comprehensive metabolic panel Any X-rays, CT or MRI scans, or other 
studies (such as PET scans, bone scans, biopsies, etc.) will be done as clinically indicated 
and up to the discretion of the treating physician. For subjects that come off protocol for 
reasons other than progressive disease, then CT or MRI scans will be performed every 8 
weeks to document disease progression. until disease progression is shown or another anti-
cancer therapy is initiated.  Vital statistics may be assessed and recorded every 3 months 
after the completion of study treatment 
10.2 
Period of Observation 
Updated: 
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. 
10.3 
Removed: 
10.3 Procedures for Eliciting Adverse Events 
 


12 
 
Documenting and 
Reporting of Adverse 
Events by Investigator 
A consistent methodology of non-directive questioning for eliciting AEs at all patient 
evaluation time points should be adopted.  Examples of non-directive questions include:  
• 
“How have you felt since your last clinical visit?” 
• 
“Have you had any new or changed health problems since you were last here?” 
 
Each recorded AE or SAE will be described by its duration (i.e., start and end dates), 
severity, regulatory seriousness criteria if applicable, suspected relationship to the 
investigational product (see following guidance), and actions taken with the study drug in 
response to the event. 
 
10.4.1 
Serious Adverse Events 
Added: 
Institution SAE and Pregnancy Reporting Information 
 
 
 
SAEs  and pregnancies must be reported to the UFHCC CRO Project 
Management Office (PMO), or assigned designee at: 
  
Email: pmo@cancer.ufl.edu  
 
As well as entered in OnCore, the study CTMS. 
 
 
 
Updated: 
At the time of the annual DSUR (data-lock point), a list of all AEs which led to 
discontinuation, subjects with fatal events, and demographic information for all subjects 
exposed to TAS-102 must all be submitted to Taiho. 
 
UFHCC PMO and DISC Reporting Requirements 
 
Serious adverse events (SAE's) must be documented on an SAE report form and emailed 
reported to UFHCC Project Management Office (PMO; pmo@cancer.ufl.edu) and entered 
into OnCore within 24 hours of discovery of the event.  If only limited details are known, 
these should be reported within that time frame and follow up reports can be submitted for 
elaboration, clarifications, or corrections.  Any email correspondence must be kept in the 
trial file at the study site. The site investigator is responsible for informing the IRB and/or 


13 
 
the Regulatory Authority of the SAE as per local requirements.  SAEs must also be reported 
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 submitted to the UFHCC PMO (pmo@cancer.ufl.edu), 
stating that this is a follow-up to a 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, and whether the participant continued or withdrew from study participation.  PMO 
will confirm that the event and any necessary follow-ups are reported to the UFHCC Data 
and Safety Integrity Committee (DISC), Taiho Oncology, and any other regulatory 
authorities as required.  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. 
 
10.5 
IND Safety Reports 
Unrelated to the Trial 
Updated: 
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. 
11.3 
Methods and Timing for 
Assessment and 
Recording Safety 
Variables 
Removed: 
Death as a result of disease progression endpoints are only to be assessed as efficacy 
measures and not as AEs or SAEs unless the events that led to death met the serious criteria. 
 
Updated: 
The investigator is responsible for ensuring that all AEs and SAEs that are observed or 
reported during the study are recorded on the CRF and reported to Taiho in accordance with 
protocol instructions and clinical trial agreement.  


14 
 
 
12.1 
Sample Size 
Determination 
Removed: 
Assuming at least the last evaluable subject derives benefit from the anticipated maximal 
number of six cycles, the length of the entire study will be approximately 24 months. 
 
Updated: 
This is a pilot phase II single-arm study, with a primary endpoint of progression-free 
survival (PFS) to evaluate efficacy of TAS-102.  And Additional obhective of the study is to 
evaluate the feasibility and safety of a regimen of daily TAS-102 administered to subjects 
with metastatic or unresectable pancreatic adenocarcinoma after progression through or 
intolerance to first- or second-line chemotherapy. The primary efficacy analysis will be an 
intent-to-treat comparison of the PFS curve with a reference historical control.  From past 
studies3, the median PFS and/or time to progression (TTP) for subjects with metastatic or 
unresectable pancreatic adenocarcinoma in the second line of treatment is variable ranging 
from 6 weeks to 22 weeks.   Assuming exponential distributions on PFS on both current 
study population and the referent population, a sample size of 333 evaluable subjects who 
will receive the same level of dose will ensure to have at least 80% power to detect an 
improvement of 3 weeks of median PFS (i.e. from 6 weeks to 9 weeks).  The sample size 
and power derivations were based on one-sample log rank test by Wu (2015)14 at one-sided 
significance level of 0.10.  It is assumed that the survival time distributions of both groups 
(historical and this proposed experiment groups) are approximately the Weibull distribution 
with a shape parameter of ~1.0. Accounting for about ~10% ineligible/inevaluable subjects, 
the total number of subjects to be accrued to this cohort will be 37, which is expected to be 
completed within 24 months. Assuming at least the last evaluable subject derives benefit 
from the anticipated maximal number of 6 cycles, the length of the entire treatment study 
will be approximately 30 months.   
 
The remaining 27 subjects will also be closely monitored for TAS-102 related toxicities 
continuously. The study will be temporarily closed for detailed review if the number of 
observed adverse events listed in the definition of intolerability in section 6.2 is greater than 
or equal to the corresponding boundary (as shown in the following Table 79). The actual 
power (based on exact binomial test) of declaring the investigational treatment is too toxic 
are approximately 88.5%, 66.2%, 35.4% and 11.9% when the true toxicity rates are 44%, 
36%, 28% and 20%, respectively. 
  
Table 7. Pocock boundaries for toxicity monitoring for the remaining 27 subjects 


15 
 
# of evaluable subjects 
2 
3-4 
5-7 
8-10 
11-
13 
14-
17 
18-
20 
21-
24 
25-
27 
Pocock boundary 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
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 
received two cycles of therapy as planned. 
 
12.2  
Analysis of Baseline and 
Demographic 
Characteristics   
Updated: 
The analysis of demographic characteristics (age, gender, ethnicity) and baseline 
characteristics, including weight change, performance status, and histologic subtype, will be 
primarily descriptive due to the small subject numbers. 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 subject outcomes.  All data will be summarized using 
descriptive statistics (mean/variance, median/range, frequency/proportion) along with 
graphical illustration as needed. Continuous variables will be compared to historical controls 
using the Wilcoxon rank sum test, and discrete outcomes will be compared using the exact 
Chi-square test. 
12.3  
Primary and Secondary 
Endpoint Efficacy 
Analysis 
Updated: 
The primary endpoint to this study will be to determine progression-free survival following 
TAS-102 therapy.  Kaplan-Meier mean estimates and survival curves of progression-free 
survival rates will be calculated. 
A secondary endpoint of this study will be overall survival/TTP following treatment with 
TAS-102.  Kaplan-Meier estimates and survival curves of overall survival rates will be 
calculated. Other secondary endpoints include response rates, clinical benefit rate (CR + PR 
+ SD), toxicities, and reversibility of toxicities, and compliance with intended treatment) 
will also be estimated along with exact 95% binomial confidence intervals.  
No multiplicity will be adjusted for the secondary endpoints. All data analysis will be 
conducted in reproducible fashion and the results will be reported regardless of the statistical 
significance. 
13.1 
Data Integrity and 
Safety Committee 
Removed: 
The PI will summarize and provide DISC with all pertinent data related to the level of risk 
assigned by SRMC.  This protocol summary will include a minimum of the following: 


16 
 
• 
The UF IRB assigned protocol number, UFHCC assigned protocol number, protocol 
title, PI name, data coordinator name or primary study coordinator, regulatory 
coordinator name, and statistician. 
• 
Date of initial UF IRB approval, date of most recent consent UF IRB 
approval/revision, date of UF IRB expiration, study status, and phase of the study. 
• 
Study target accrual and study actual accrual. 
• 
Protocol objectives with supporting data and list of number of study participants 
who have met each objective. 
• 
Measures of efficacy. 
• 
Early stopping rules with supporting data and a list of the number of study 
participants who have met the early stopping rules. 
• 
Summary of toxicities and protocol deviations. 
• 
Summary of any recent literature which may affect the safety or ethics of the trial. 
 
13.2 
On-site Data Monitoring 
Updated: 
UFHCC (University of Florida Health Cancer Center) Quality Assurance team and/or 
project management officers will perform remote monitoring and may make 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 
completion and validated against with data submitted electronically via the Electronic Data 
Capture. . The site investigator/institution guarantee access to source documents by UFHCC 
or its designee and appropriate regulatory agencies.  As part of the responsibilities assumed 
by conducting the 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. 
 
13.3 
Principal Investigator 
(PI) Responsibilities 
Removed: 
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.  
Added: 
Per IRB requirements, the PI is personally responsible for conducting and supervising the 
conduct of human subjects research by “protecting the rights, safety, and welfare of subjects 
under the investigator’s care.” The PI also must ensure that all the research conducted is 
done so in an ethical manner and in accordance with all federal, state, and local laws and 
regulations, institutional policies, and the requirements of the IRB. 


17 
 
 
Oversight is defined as “management by overseeing the performance or operation of a 
person or group; watchful care, superintendence, general supervision”. Any person serving 
as a PI has voluntarily accepted these responsibilities and is expected to fully comply with 
these requirements, as outlined in the UFHCC Guidance: Principal Investigator 
Responsibilities and Oversight.  
15.1 
Good Clinical Practice 
Updated: 
All potential serious breaches must be reported to the UFHCC Project Management Office 
(PMO; PMO@cancer.ufl.edu, who will then report the breach to the UFHCC DISC) and the 
IRB of record UF Health Cancer Center Data Integrity and  Safety Committee (DISC) 
immediately. 
15.2 
Institutional Review 
Board 
Removed: 
The Principal Investigator is responsible for keeping the IRB apprised of the progress of the 
study and of any changes made to the protocol as deemed appropriate, but in any case the 
IRB must be updated at least once a year. 
15.6 
Protocol Amendments 
Added: 
Protocol amendments will not be implemented without prior written IRB approval. All 
amendments will be submitted to the IRB and SRMC (as applicable), and written 
verification that the amendment was submitted and subsequently approved is to be obtained, 
and notification will sent out to the applicable study teams, prior to implementing the 
amendment.   
 
On an emergency-basis, to eliminate an immediate safety hazard to a subject, a protocol 
deviation may be implemented immediately, provided the IRB and UFHCC CRO PMO 
(pmo@cancer.ufl.edu) are notified within 5 business days with a full justification and 
description of the event. 
15.7 
Case Report Forms 
Removed: 
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. 
 
Added: 
The Principal Investigator and/or his/her designee, will prepare and maintain adequate and 
accurate participant case histories with observations and data pertinent to the study.  Study 
specific Case Report Forms (CRFs) will document protocol-required outcomes for safety 


18 
 
monitoring and data analysis.  All study data will be entered electronically in an Electronic 
Data Capture system in accordance with the protocol schedule of events and guidelines 
developed in the Data Management Plan for the study, using a secure access account.   
All protocol data 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. 
16 
Compliance with Laws 
and Regulations 
Removed: 
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. 
 
Updated: 
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 Project 
Management Officer or assigned designee.  All studies must be registered prior to 
enrollment of the first participant.  The Protocol Management Officer or assigned designee 
will maintain the responsibility of updating trials registered with ClinicalTrials.gov. Per 
FDA requirement, 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.  The PMO will determine if registration and updates to the NCI 
CTRP are required. 
 
 


 
 
A Phase II Trial of TAS-102 (Lonsurf®) in Patients with Metastatic or Locally Advanced 
Unresectable Pancreatic Adenocarcinoma after Progression through First Line 
Chemotherapy  
 
Protocol Number: 
 
 
UF-STO-PANC-003; UF-GI-006 
 
IRB#:  
 
 
 
IRB201601319 
 
External Identifier:  
 
IIT-USA-0115 (Taiho) 
 
 
 
 
 
 
Coordinating Center: 
 
University of Florida 
 
Principal Investigator:  
 
Jennifer M. Duff, MD 
 
 
University of Florida 
 
 
1600 SW Archer Road 
 
 
Gainesville, FL  32608-1135 
 
 
Telephone: 352-548-6000 x4454 
 
 
Fax:  352-548-6463 
 
 
 
 
 
Email: jennifer.duff@medicine.ufl.edu 
 
Statistician:  
 
 
Ji-Hyun Lee, DrPH 
 
Protocol Manager:  
 
pmo@cancer.ufl.edu                                                      
 
Clinical Phase: 
 
 
Phase II 
 
IND Status:  
 
 
Exempt 
 
Investigational Agent: 
 
TAS-102 (Lonsurf®)  
 
 
 
Date of Original Protocol:  
23Jan2017 
 
Date of Current Protocol:  
19November 2019 
 
Version of Current Protocol: 
2.0 
 
Keywords: 
 
 
 
pancreatic adenocarcinoma, chemotherapy, metastatic  
pancreatic cancer 
 
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 
 
 
1. 
INTRODUCTION ..................................................................................................................................... 15 
1.1 
Background ......................................................................................................................................... 15 
1.2 
TAS-102 (Lonsurf®) Cancer Therapy ....................................................................................... 16 
1.3 
Clinical Experience ........................................................................................................................... 16 
1.4 
Rationale for Regimen/Doses/Schedule ................................................................................. 16 
2. 
OBJECTIVES AND ENDPOINTS ...................................................................................................... 16 
2.1 
Primary ................................................................................................................................................. 16 
2.2 
Secondary objectives and endpoints ........................................................................................ 16 
3. 
SELECTION OF SUBJECTS ................................................................................................................ 17 
3.1 
Number of Subjects .......................................................................................................................... 17 
3.2 
Inclusion Criteria .............................................................................................................................. 17 
3.3 
Exclusion Criteria ............................................................................................................................. 18 
3.4 
Inclusion of Women and Minorities .......................................................................................... 19 
4. 
REGISTRATION PROCEDURES ....................................................................................................... 20 
5. 
STUDY TREATMENT............................................................................................................................ 20 
5.1 
Treatment Schedule/Administration: ...................................................................................... 20 
5.2 
Dose Calculations .............................................................................................................................. 21 
5.3 
Concomitant Therapy ..................................................................................................................... 21 
5.3.1 
Allowed Concomitant Therapy ........................................................................................... 22 
5.3.2 
Prohibited Concomitant Therapy ...................................................................................... 22 
5.4 Dose Modifications ................................................................................................................................ 23 
5.4.1 
Dose Modification Explained ............................................................................................... 23 
5.4.2 
Non- Hematologic Toxicity ................................................................................................... 24 
5.4.3 
Hematologic Toxicity .............................................................................................................. 25 
6 
TREATMENT DISCONTINUATION ............................................................................................... 26 
6.1 
Removal of Subjects From Study ................................................................................................ 26 
6.2 
Study Treatment Discontinuation .............................................................................................. 26 
6.3 
Replacement of Subjects ................................................................................................................ 27 
7 
STUDY PROCEDURES ......................................................................................................................... 27 
7.1 
Study Schedule of Events ............................................................................................................... 27 
7.2 
Screening Evaluations .................................................................................................................... 29 
7.3 
On-Study Evaluations ...................................................................................................................... 29 


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7.4 
End of Treatment/Off Therapy Measurements (within 30 days post-last dose) .... 29 
7.5 Follow up/Survival ................................................................................................................................ 29 
8 
CRITERIA FOR DISEASE EVALUATION .................................................................................... 30 
9 
STUDY DRUG INFORMATION ........................................................................................................ 34 
9.1 
Study Drug Name   TAS-102 (Lonsurf®) .................................................................................. 34 
9.1.1 
Drug Supply   TAIHO Oncology, Inc. ................................................................................. 34 
9.1.2 
Contraindications:  none ....................................................................................................... 34 
9.1.3 
Special Warnings and Precautions for Use .................................................................... 34 
9.1.4 
Adverse Event Profile ............................................................................................................. 35 
10 ADVERSE EVENTS ................................................................................................................................ 36 
10.1     Definitions .......................................................................................................................................... 36 
10.1.1 
Adverse Event ....................................................................................................................... 36 
10.1.2 
Serious Adverse Event ....................................................................................................... 36 
10.1.3 
Non-Serious Adverse Event ............................................................................................. 37 
10.2 Period of Observation ..................................................................................................................... 37 
10.3 Documenting and Reporting of Adverse Events by Investigator ................................... 38 
10.3.1 
Assessment of Causal Relationship of Study Drug ................................................. 38 
10.3.2 
Intensity of Adverse Events ............................................................................................. 39 
10.3.3 
Action Taken with Study Drug ....................................................................................... 40 
10.3.4 
Definition of Outcome ........................................................................................................ 41 
10.4 Immediately Reportable Events ................................................................................................. 41 
10.4.1 
Serious Adverse Events ..................................................................................................... 41 
10.4.2 Other Events Requiring Immediate Reporting .................................................................. 42 
10.5 IND Safety Reports Unrelated to this Trial ................................................................................ 44 
11   ASSESSING SAFETY .............................................................................................................................. 44 
11.1  Specfications of Safety Analysis .................................................................................................... 44 
11.2  Safety Analysis ..................................................................................................................................... 44 
11.3  Methods and Timing for Assessment and Recording Safety Variables ......................... 45 
11.4  Type and Duration of Follow-up of Adverse Events ............................................................. 45 
12.   STATISTICAL METHODS ................................................................................................................... 45 
12.1 Sample Size Determination ................................................................................................................ 45 
12.2 Analysis of Baseline and Demographic Characteristics ....................................................... 46 
12.3 Primary and Secondary Endpoint Efficacy Analysis .............................................................. 46 
13 DATA AND SAFETY MONITORING .............................................................................................. 47 


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13.1 Data Integrity and Safety Committee ........................................................................................ 47 
13.2 Data Monitoring ................................................................................................................................ 47 
13.3 Principal Investigator (PI) Responsibilities ........................................................................... 48 
14 EMERGENCY PROCEDURES ............................................................................................................ 48 
14.1  Emergency Contact ............................................................................................................................ 48 
14.2 Emergency Treatment ....................................................................................................................... 48 
15 ADMINISTRATIVE CONSIDERATIONS ...................................................................................... 48 
15.1 Good Clinical Practice ........................................................................................................................ 48 
15.2  Institutional Review Board ............................................................................................................. 49 
15.3  Delegation of Investigator Responsibilities ............................................................................. 49 
15.4  Subject Information and Informed Consent ............................................................................ 50 
15.5 Confidentiality ...................................................................................................................................... 50 
15.6  Protocol Amendments ...................................................................................................................... 50 
15.7 Case Report Forms ........................................................................................................................... 51 
16 COMPLIANCE WITH LAWS AND REGULATIONS ................................................................ 51 
17 REFERENCES............................................................................................................................................ 53 
  
 
 


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ABBREVIATIONS   
 
AE 
adverse event 
ALT 
alanine transaminase (also SGPT) 
ANC 
absolute neutrophil count 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate transaminase (also SGOT) 
AUC 
area under curve 
BCG 
Bacillus Calmette-Guérin 
BID 
twice daily 
BSA 
body surface area 
BUN 
blood urea nitrogen 
CA 
cancer antigen 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CL 
Clearance 
CMP 
comprehensive metabolic panel 
CR 
complete remission 
CRF 
case report form 
CT 
computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DISC 
Data Integrity and Safety Committee 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
DOB 
date of birth 
DSUR 
Drug Safety Update Report 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EGFR 
epidermal growth factor receptor 
FDA 
Food and Drug Administration 
FDG-PET 
fluorodeoxyglucose-positron emission tomography 
FSH 
follicle stimulating hormone 
FU 
fluorouracil 
GCP 
Good Clinical Practice 
HRT 
hormone replacement therapy 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 


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IU 
International Unit 
IV 
intravenous 
m 
meter(s) 
mg 
milligram(s) 
mL 
milliliter(s) 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
NYHA 
New York Heart Association 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PMO 
Project Management Office 
PFS 
progression free survival 
PI 
principal investigator 
PO 
orally or by mouth 
PR 
partial remission 
PRBC 
packed red blood cells 
PS 
performance status 
PT 
prothrombin time  
PTT 
partial thromboplastin time 
RBC 
red blood cells 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SD 
stable disease 
SGOT 
serum glutamic oxaloacetic transaminase (also AST) 
SGPT 
serum glutamic pyruvate transaminase (also ALT) 
Tmax 
time to maximum plasma concentration 
TTP 
time to progression 
UF 
University of Florida 
UFHCC 
University of Florida Health Cancer Center 
ULN 
upper limit of normal 
US 
United States 
WBC 
white blood cell  
WHO 
World Health Organization 
WOCBP 
women of childbearing potential 
 
 
 
 


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Protocol Signature Page 
 
A Phase II Trial of TAS-102 (Lonsurf®) in Patients with Metastatic or Locally Advanced 
Unresectable Pancreatic Adenocarcinoma after Progression Through First Line 
Chemotherapy  
 
 
 
Principal Investigator: 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
Date 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
Name of Facility 
 
 
 
 
 
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 Signature Page 
A Phase II Trial of TAS-102 (Lonsurf®) in Patients with Metastatic or Locally Advanced 
Unresectable Pancreatic Adenocarcinoma after Progression Through First Line 
Chemotherapy 
 
 
Site Principal Investigator: 
 
 
 
 
 
 
Signature of Investigator 
 
Date 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
Name of Facility 
 
 
 
 
 
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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STUDY SCHEMA 
 
Chemotherapy 
 
TAS-102 (Lonsurf®) 35 mg/m2 PO BID on days 1-5 and 8-12 
 
Cycles repeated every 28 days 
 
 
 


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PROTOCOL SYNOPSIS 
 
Title: 
A Phase II Trial of TAS-102 (Lonsurf®) in Patients with Metastatic 
or Locally Advanced Unresectable Pancreatic Adenocarcinoma after 
Progression Through First Line Chemotherapy 
Funding Source: 
Taiho Oncology 
Objectives: 
To evaluate the efficacy, safety, and feasibility of TAS-102 in 
previously treated metastatic and locally advanced unresectable 
pancreatic adenocarcinoma after progression through or intolerance 
to first or second line chemotherapy 
Study Schema: 
Drugs / Doses / 
Length of 
Treatment 
Days 1 through 5: TAS-102 (35 mg/m2/dose) orally 2 times daily 
with the first dose administered in the morning of Day 1 of each 
cycle and the last dose administered in the evening of Day 5. TAS-
102 is to be taken within 1 hour of completion of morning and 
evening meals. 
 
Days 6 through 7: Rest 
 
Days 8 through 12: TAS-102 (35 mg/m2/dose) orally 2 times daily 
with the first dose administered in the morning of Day 8 of each 
cycle and the last dose administered in the evening of Day 12. TAS-
102 is to be taken within 1 hour of completion of morning and 
evening meals. 
 
Days 13 through 28: Rest 
 
Treat subjects on protocol until progression of disease on the study 
drug or intolerance after pre-specified dose reductions or subject 
desire to come off treatment 
Endpoints: 
Primary Endpoint: 
• The progression free survival (PFS) defined as the duration of 
time from study entry to time of progression or death or the date 
of last contact, whichever occurs first. 
 
Secondary Endpoints: 
• The objective response rate (ORR) by RECIST 1.1 criteria 
• The Clinical Benefit Rate (CR + PR + SD) 
• The time to progression (TTP) 
• Overall survival (OS) 
• The safety profile and tolerability in this population 
• Compliance with intended treatment 


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Study Design: 
Open-label, non-randomized, sequentially enrolling single arm phase 
II trial  
Accrual Goal: 
33 subjects 
Inclusion 
Criteria: 
o Clinical diagnosis of adenocarcinoma of the pancreas, 
with pathologic confirmation of adenocarcinoma. 
o Subjects must have measurable disease per RECIST 1.1 
criteria. 
o Metastatic or locally advanced unresectable disease.  
Subjects without clear evidence of distant metastatic 
disease will be presented at multidisciplinary tumor board 
for discussion of disease resectability. 
o Refractory or intolerant to 1 or 2 prior regimens of 
standard chemotherapy for metastatic or locally advanced 
pancreatic cancer. 
a. Patients who have progressed based on imaging during 
or within 3 months of the last administration of each 
standard chemotherapy, or 
b. Patients who have withdrawn from standard treatment 
due to unacceptable toxicity warranting discontinuation 
of treatment and precluding retreatment with the same 
agent prior to progression of disease will also be eligible 
to enter the study  
o TAS102 will be planned to start  after disease progression 
on first or second line chemotherapy, provided any prior 
chemotherapy-related toxicities have resolved to less than 
or equal to Grade 1 or baseline within 28 days of the date 
the subject signs the informed consent form.  Grade 2 or 
greater toxicities including alopecia, skin pigmentation, 
and platinum induced neurotoxicity/neuropathy  are 
acceptable for starting on trial, as these toxicities do not 
preclude treatment with TAS-102 
o ECOG Performance Status of 0-2 
o Capacity to understand and sign the informed consent 
document 
o Able to take medications orally 
o Life expectancy > 12 weeks  
o Age >18 years 
Subjects of childbearing potential must be using an  
o Subjects on anticoagulation need to have no evidence of 
uncontrolled bleeding and be on a stable anticoagulation 
dose for at least 2 weeks prior to the date the subject 
starts study drug.  
o Women of childbearing potential (WOCBP) must be 
using an adequate method of contraception to avoid 


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pregnancy throughout the study and for at least 3 months 
after the last dose of study drug to minimize the risk of 
pregnancy.   Prior to signing the informed consent form, 
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.   
o 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. 
o 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. 
o Baseline laboratory values (bone marrow, renal, hepatic) 
must include:   
 Adequate bone marrow function: 
-Absolute neutrophil count >1500/mm3 
-Platelet count >75‚000/ mm3 
-HGB equal to or greater than 7g/dL 
 Renal function: 
-Serum creatinine < 1.5 mg  
 Hepatic function: 
-Total bilirubin < 1.5 mg/dL 
-AST and ALT equal to or less than 3 times the 
upper limit of normal for patients without hepatic 
involvement, or  AST and ALT equal to or less 
than 5 times the upper limit of normal for patients 
with hepatic involvement 
-Serum calcium < 12 mg/dl 
Exclusion 
Criteria: 
• Pregnant or lactating females 
• Previously taken TAS-102 
• Myocardial infarction or ischemia within the 6 months before 
first dose of study drug 
• Uncontrolled‚ clinically significant dysrhythmia  


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• Intervention for ascites or pleural effusions within 4 weeks 
before first dose of study drug 
• Previous surgery and/or radiotherapy may have been 
performed 2 or more weeks prior to the date the subject starts 
study treatment, provided that it was to a non-target lesion 
and there is still evidence of target lesion disease progression 
radiographically or intolerance to first- or second-line 
chemotherapy. 
•  Major surgery within 4 weeks before first dose of study drug 
(the surgical incision should be fully healed prior to drug 
administration). 
• Any anticancer therapy within 3 weeks before first dose of 
study drug (with the exception of bevacizumab, which must 
not have been taken within 4 weeks before first dose of study 
drug). 
• Extended field radiation within 4 weeks before first dose of 
study drug or limited field radiation within 2 weeks before 
first dose of study drug. 
• Any investigational agent received within prior 4 weeks 
before first dose of study drug 
• Subjects must not have more than one active malignancy at 
the time of enrollment (Patients with a prior or concurrent 
malignancy whose natural history or treatment does not have 
the potential to interfere with the safety or efficacy 
assessment of the investigational regimen [as determined by 
the treatment physician and approved by the PI] may be 
included).  
• Has unresolved toxicity of greater than or equal to Common 
Terminology Criteria for Adverse Events (CTCAE) Grade 2 
attributed to any prior therapies (excluding anemia, alopecia, 
skin pigmentation, and platinum-induced neurotoxicity). 
• Any co-morbid condition that‚ in the view of the attending 
physician‚ renders the subject at high risk from treatment 
complications including but not limited to chronic infections, 
uncontrolled diabetes, congestive heart failure according to 
the NYHA criteria, untreated brain metastases, liver or renal 
failure, gastrointestinal hemorrhage.  
• Known untreated and unstable brain metastases or 
leptomeningeal disease 
• Active infection 
• Prisoners or subjects who are involuntarily incarcerated 
or subjects who are compulsorily detained for treatment 
of either a psychiatric or physical illness. 


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Efficacy 
Assessments: 
Mid cycle monitoring: 
CT or MRI of thorax, abdomen, and pelvis (may be obtained up to 
one calendar week prior to first day of each odd numbered cycle)  
Statistical 
Considerations: 
The analysis of demographic characteristics (age, gender, tobacco 
abuse history and ethnicity) and baseline characteristics, including 
weight change, performance status, and histologic subtype, will 
primarily be descriptive.  
 
Kaplan-Meier estimates and survival curves for PFS, TTP and overall 
survival will be calculated. Secondary endpoints include response 
rates, clinical benefit rate (CR + PR + SD), toxicities and reversibility 
of toxicities) will also be estimated along with exact 95% binomial 
confidence intervals 
Estimated 
Enrollment 
Period: 
30 months 
Estimated Last 
Subject 
Enrollment Date: 
June 15, 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1. INTRODUCTION 
1.1 Background 
 
Metastatic pancreatic adenocarcinoma carries a dismal prognosis with median survival rates of 3-
6 months in those untreated. Over the past decade, despite oncologic advancements, there has 
been little influence on the long-term survival of these patients. Single agent gemcitabine was 
primarily used to improve disease related symptoms associated with advanced pancreatic 
adenocarcinoma, but it had minimal impact on survival.  Over the last five years, more 
aggressive combination chemotherapy regimens such as gemcitabine and nab-paclitaxel and 
FOLFIRINOX (5-fluorouracil, leucovorin, oxaliplatin and irinotecan) have emerged proving 
more efficacious compared to gemcitabine alone and yielding a survival advantage. The MPACT 
study compared gemcitabine and nab-paclitaxel to gemcitabine alone in patients with untreated 
metastatic pancreatic adenocarcinoma and demonstrated a significant increase in survival with 
the combination regimen (8.5 months in the gemcitabine plus nab-paclitaxel arm versus 6.7 
months in the gemcitabine arm; HR 0.72 (95% CI: 0.62, 0.84); p < 0.0001)1. The PRODIGE 
study assessed first line treatment with FOLFIRINOX versus gemcitabine demonstrating 
improved survival with multi-agent chemotherapy. The median overall survival was 11.1 months 
compared to 6.8 months in the gemcitabine arm (HR for death, 0.57; p<0.001)2. In November 
2015, the FDA approved nanoliposomal irinotecan in combination with 5-fluorouracil (5-FU) 
and leucovorin as second line therapy for metastatic pancreatic adenocarcinoma in patients that 
had progressed following a gemcitabine based regimen. The addition of nanoliposomal 
irinotecan to 5-FU and leucovorin demonstrated a 2 month survival benefit compared to those 
treated with 5-FU and leucovorin alone3. Prior to this study, there was little objective evidence 
supporting second-line therapy offering patients a survival advantage. A few trials (mainly phase 
II) that studied treatment in the second line setting suggested limited benefit in select patients4-6. 
Indeed, consensus national guidelines now consistently support the role of second line therapy 
for otherwise fit patients (NCCN Guidelines as reference) and for patients whose performance 
status remains optimal, third line treatment can be considered. Despite the clinical use of these 
therapies, the median survival for patients with metastatic pancreatic adenocarcinoma continues 
to be less than 1 year substantiating the need for more effective treatments.  
 
TAS-102 (Lonsurf®) is a combination drug of an oral nucleoside, trifluridine, and thymidine  
phosphorylase inhibitor, tipiracil hydrochloride. The nucleoside incorporates into DNA eliciting 
an anti-tumor effect and the thymidine phosphorylase inhibitor prevents enzymatic breakdown of 
the drug resulting in increased trifluridine bioavailability. It was FDA approved for use in 
patients with refractory metastatic colorectal cancer after progression on two or more standard 
chemotherapy regimens8. TAS-102 demonstrated a survival benefit despite all patients having 
being treated previously with 5-FU, which supports an alternative mechanism of action 
overcoming chemoresistance. TAS-102’s efficacy is currently being investigated in other 
gastrointestinal cancers, specifically, metastatic gastric cancer refractory to standard therapies. 
Given the cross reactivity of many chemotherapy agents along the GI cancer spectrum (i.e., 
antimetabolites, platinums, topoisomerase inhibitors), the mechanism of action and chemical 
backbone of TAS-102 make it an attractive option to explore this agent in advanced pancreatic 
adenocarcinoma.  
 


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This protocol intends to study the activity and tolerability of TAS-102 in the treatment of 
metastatic or locally advanced unresectable pancreatic adenocarcinoma after progression on or 
intolerance to first or second line chemotherapy. 
1.2 TAS-102 (Lonsurf®) Cancer Therapy 
 
Each treatment cycle will be 28 days in duration. One treatment cycle consists of the following: 
 
Days 1 through 5: TAS-102 (35 mg/m2/dose) orally 2 times daily with the first dose 
administered in the morning of Day 1 of each cycle and the last dose administered in the evening 
of Day 5.  TAS-102 is to be taken within 1 hour of the morning and evening meal.  
 
Days 6 through 7: Rest 
 
Days 8 through 12: TAS-102 (35 mg/m2/dose) orally 2 times daily with the first dose 
administered in the morning of Day 8 of each cycle and the last dose administered in the evening 
of Day 12. TAS-102 is to be taken within 1 hour of the morning and evening meal. 
 
Days 13 through 28: Rest 
Subjects should take study medication (TAS-102) with a glass of water within 1 hour after 
completion of their morning and evening meals. 
1.3 Clinical Experience 
 
TAS-102 is FDA approved for the treatment of metastatic colon cancer after progression on 
multiple lines of therapy including EGFR inhibitors in KRAS/NRAS wild-type patients.  It has 
not yet been studied in pancreatic adenocarcinoma. 
1.4 Rationale for Regimen/Doses/Schedule 
 
The study will use the same dose of TAS-102 that is FDA approved for the use in metastatic 
colon cancer. It has previously been shown to be efficacious in patients that have been treated 
with 5-fluorouracil.  
 
2. OBJECTIVES AND ENDPOINTS 
2.1 Primary  
 
• To determine progression free survival (PFS). The primary endpoint, PFS, is defined as 
the duration of time from study entry to time of progression or death or the date of last 
contact, whichever occurs first. 
2.2 Secondary objectives and endpoints 
 
• To determine the objective response rate (ORR) by RECIST 1.1 criteria 


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• To determine the Clinical Benefit Rate (CR + PR + SD) 
• To determine the time to progression (TTP) 
• To determine overall survival (OS) 
• To determine the safety profile and tolerability in this population 
• To determine compliance with intended treatment (% of completion of the treatment) 
3. SELECTION OF SUBJECTS 
3.1 Number of Subjects 
 
A total of 33 patients with metastatic or locally advanced unresectable pancreatic 
adenocarcinoma after progression through first line chemotherapy. 
3.2 Inclusion Criteria  
Subjects must meet all of the following criteria to be eligible for study participation: 
• Clinical diagnosis of confirmed of adenocarcinoma of the pancreas, with pathologic 
confirmation of adenocarcinoma. 
• Subjects must have measurable disease per RECIST 1.1 criteria. 
• Metastatic or locally advanced unresectable disease.  Subjects without clear evidence of 
distant metastatic disease will be presented at multidisciplinary tumor board for discussion of 
disease resectability. 
• Refractory or intolerant to 1 or 2 prior regimens of standard chemotherapy for metastatic or 
locally advanced pancreatic cancer. 
a. Patients who have progressed based on imaging during or within 3 months of the last 
administration of each standard chemotherapy, or 
• b. Patients who have withdrawn from standard treatment due to unacceptable toxicity 
warranting discontinuation of treatment and precluding retreatment with the same agent prior 
to progression of disease will also be eligible to enter the study.TAS102 will be planned to 
start after disease progression on first- or second-line chemotherapy, provided any prior 
chemotherapy-related toxicities have resolved to less than or equal to Grade 1 or baseline 
within 28 days of the date the subject signs the informed consent form.  Grade 2 or 
greater toxicities including 
alopecia, 
skin 
pigmentation, 
and 
platinum 
induced 
neurotoxicity/neuropathy are acceptable for starting on trial, as these toxicities do not preclude 
treatment with TAS-102 
• ECOG Performance Status of 0-2 
• Capacity to understand and sign the informed consent document 
• Able to take medications orally 
• Life expectancy > 12 weeks as predicted by the treating oncologist’s clinician judgement 
• Age >18 years 
• Subjects on anticoagulation need to have no evidence of uncontrolled bleeding and be on a 
stable anticoagulation dose for at least 2 weeks prior to the date the subject starts study drug. 
• 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 signing the informed consent 


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form, 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: 
o Amenorrhea that has lasted for ≥ 12 consecutive months without another cause, or 
o 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. 
• 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. 
• Baseline laboratory values (bone marrow, renal, hepatic) must include:   
o Adequate bone marrow function: 
 Absolute neutrophil count >1500/ mm3 
 Platelet count >75‚000/ mm3 
 HGB equal to or greater than 7g/dL 
o Renal function: 
 Serum creatinine < 1.5 mg  
o Hepatic function: 
 Total bilirubin < 1.5 mg/dL 
 AST and ALT equal to or less than 3 times the upper limit of normal 
for patients without hepatic involvement, or  AST and ALT equal to or 
less than 5 times the upper limit of normal for patients with hepatic 
involvement 
 Serum calcium < 12 mg/dl 
3.3 Exclusion Criteria 
      Subjects with any of the following will not be eligible for study participation: 
• Pregnant or lactating females 
• Previously taken TAS-102 
• Myocardial infarction or ischemia within the 6 months before first dose of study drug 
• Uncontrolled‚ clinically significant dysrhythmia  
• Intervention for ascites or pleural effusions within 4 weeks before first dose of study drug 
• Previous surgery and/or radiotherapy may have been performed 2 or more weeks prior to 
the date the subject starts study treatment, provided that it was to a non-target lesion and 
there is still evidence of target lesion disease progression radiographically or intolerance 
to first- or second-line chemotherapy. 
• Major surgery within 4 weeks before first dose of study drug (the surgical incision should 
be fully healed prior to drug administration). 
• Any anticancer therapy within 3 weeks before first dose of study drug (with the exception 
of bevacizumab, which must not have been taken within 4 weeks before first dose of 
study drug). 


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• Extended field radiation within 4 weeks before first dose of study drug or limited field 
radiation within 2 weeks before first dose of study drug. 
• Any investigational agent received within prior 4 weeks before first dose of study drug 
Subjects must not have more than one active malignancy at the time of enrollment 
(Patients with a prior or concurrent malignancy whose natural history or treatment does 
not have the potential to interfere with the safety or efficacy assessment of the 
investigational regimen [as determined by the treatment physician and approved by the 
PI] may be included). 
• Has unresolved toxicity of greater than or equal to Common Terminology Criteria for 
Adverse Events (CTCAE) Grade 2 attributed to any prior therapies (excluding anemia, 
alopecia, skin pigmentation, and platinum-induced neurotoxicity). 
• Any co-morbid condition that‚ in the view of the attending physician‚ renders the subject 
at high risk from treatment complications including but not limited to chronic infections, 
uncontrolled diabetes, congestive heart failure according to the NYHA criteria, untreated 
brain metastases, liver or renal failure, gastrointestinal hemorrhage.  
• 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. 
• Known untreated or unstable brain metastases or leptomeningeal disease 
• Active infection  
• Prisoners or subjects who are involuntarily incarcerated orsubjects who are compulsorily 
detained for treatment of either a psychiatric or physical illness. 
• 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 of all races and ethnic groups will be eligible for this trial. 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. Only adults (age >18 years of age) capable of 
providing their own consent will be eligible. 
 


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4. REGISTRATION PROCEDURES 
All consented subjects must be entered into the University of Florida’s Clinical Trial 
Management System (OnCore) prior to assignment of a subject identification number.  The study 
team must submit the completed study specific eligibility checklist, supporting source 
documentation and a copy of the signed informed consent document(s) to the UFHCC Project 
Management Office (PMO: PMO@cancer.ufl.edu) or their assigned Project Manager. Unsigned 
eligibility checklists or eligibility packets with missing or incomplete information may be 
returned to the study team. Upon receipt of a completed eligibility packet, the designated Project 
Manager will review the source to verify eligibility and assign a subject number. If eligibility 
cannot be confirmed, the project manager will query the site for clarification or additional 
documents as needed. Subjects failing to meet all study eligibility requirements will not be able 
to participate in the trial. 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 subjects will be maintained by the study site. 
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:  
Treatment must begin within 28 days of the date the subject is entered into the CTMS (OnCore). 
Upon confirmation of eligibility and provision of subject study number, subjects will receive 
TAS-102 at the following dose and schedule. The number of tablets of each strength that are 
needed for the 35 mg/m2 dose per BSA level is shown in Table 1.  
 
Table 1.  Dose Calculations Based off BSA 
TAS-102 
Dose 
(2x daily) 
BSAa 
(m2) 
Dosage in 
mg 
(2x daily) 
Total daily 
dose (mg) 
 
Tablets per dose 
 
    15 mg                  20 mg 
35 mg/m2 
< 1.07 
35 
70 
1 
1 
1.07 - 1.22 
40 
80 
0 
2 
1.23 - 1.37 
45 
90 
3 
0 
1.38 - 1.52 
50 
100 
2 
1 
1.53 - 1.68 
55 
110 
1 
2 
1.69 - 1.83 
60 
120 
0 
3 
1.84 - 1.98 
65 
130 
3 
1 
1.99 - 2.14 
70 
140 
2 
2 
2.15 - 2.29 
75 
150 
1 
3 
≥2.30 
80 
160 
0 
4 
 
a Calculate body surface area (BSA) to 2 decimal places. 


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Each treatment cycle will be 28 days in duration. One treatment cycle consists of the following: 
 
Days 1 through 5: TAS-102 (35 mg/m2/dose) orally 2 times daily with the first dose administered 
in the morning of Day 1 of each cycle and the last dose administered in the evening of Day 5. 
 
Days 6 through 7: Rest 
 
Days 8 through 12: TAS-102 (35 mg/m2/dose) orally 2 times daily with the first dose 
administered in the morning of Day 8 of each cycle and the last dose administered in the evening 
of Day 12. 
 
Days 13 through 28: Rest 
 
The patient must be instructed in the handling of study medication as follows: 
• To store the study medication at room temperature 
• To only remove from the study medication kit the amount of tablets needed at the time of 
dosing 
• Not to remove doses in advance of the next scheduled dosing 
• To make every effort to take doses on schedule 
• To take study medication within 1 hour after completing a meal (morning and evening 
meals) with a glass of water per the dose schedule 
• If the patient vomits after taking study medication, the patient should not take another 
dose. 
• To keep study medication in a safe place and out of reach of children 
 
To bring all used and unused study medication kits to the site at each visit 
Any missed doses reported by the subject should be recorded in the subject’s source documents. 
Subjects should not take additional doses to make up for missed or held doses.  
 
Complete blood count (CBC) with differential will be checked on the first day of each cycle, every 
28 days, or within 72 hours of each cycle upon completion of Cycle 1 to accommodate subjects 
with long travel distance and on Day 15 of each cycle to monitor for development of anemia and 
neutropenia.  In the absence of significant treatment-related abnormalities, and documentation of 
an ANC greater than or equal to 1500/ mm3 and platelet count of greater than or equal to 75,000/ 
mm3 treatment cycles will continue every 28 days until subject intolerance, subject 
discontinuation, or disease progression. Tumor status will be assessed every two cycles.  
 
5.2 Dose Calculations 
 
Refer to ‘Table 1. Dose Calculation Table Based off BSA” in Section 5.1. 
 
5.3 Concomitant Therapy     
 


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Use of anti-neoplastic or anti-tumor therapies not part of the study treatment, including surgery, 
chemotherapy, radiation therapy, immunotherapy, and hormonal anticancer therapy, is not 
permitted while participating in this study.  Use of erythropoietin stimulating agents is also not 
permitted.  Use of concurrent investigational agents is not permitted. 
 
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 
 
Any therapy or medication (except study drugs), administered from first dose of study drug until 
30 days after the last dose of either study drug, is considered a concomitant therapy or 
medication. However, if another course of anticancer therapy is initiated prior to the 30-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. 
5.3.1 Allowed Concomitant Therapy 
 
Subjects may continue on their chronic medications. Subjects on anticoagulation need to have no 
evidence of bleeding and be on a stable anticoagulation dose for at least 2 weeks prior to first dose 
of study drug. 
Use of granulocyte colony stimulating factor and packed red cell transfusions are permitted to 
maintain adequate bone marrow function according to institutional standards. If no standards are 
in place for the use of growth factors, then follow the 2015 ASCO Clinical Practice Guidelines for 
use of WBC growth factors 
5.3.2 Prohibited Concomitant Therapy 
 
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  
• Hormonal anticancer therapy not specified in this protocol 
• Chemotherapy not specified in this protocol  
• Investigational agents other than the study drug in this trial  
• 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 


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• Erythropoietin stimulating agents  
• Radiation therapy 
• Cancer-related surgery 
 
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 strictly palliative radiation 
therapy to a single symptomatic lesion will not be considered clinical progression for the 
purposes of determining PFS.  
 
5.4 Dose Modifications 
Doses will be reduced or modified if AEs are observed according to the criteria described below. 
The National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events Version 
4.0.3 (CTCAE) will be used to grade adverse event toxicity 
(http://evs.nci.nih.gov/ftp1/CTCAE/About.html).    
5.4.1 Dose Modification Explained 
 
Subjects are permitted dose reduction(s) to a minimum dose of 20 mg/m2 (40 mg/m2/day) in 5 
mg/m2 (10 mg/m2/day) steps.  A maximum of three dose reductions in decrements of 5 mg per 
square meter are allowed for toxicity to a minimum dose of 20mg/m2.  Do not escalate dose once 
it has been reduced.  Refer to Table 2 located in this sub-section. 
 
Table 2: TAS-102 Dose Modification Table 
 


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5.4.2 Non- Hematologic Toxicity 
 
Refer to Table 3 located in this sub-section. 
 
These toxicities can be AEs or laboratory abnormalities such as hepatobiliary or renal laboratory 
findings. 
 
 
 


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Table 3: TAS-102 Dose Modification Schedule for Non-hematologic Toxicities 
 
Gradea 
Dose Hold/Resumption 
within a 
28-day Treatment Cycle 
 
Dose Adjustment for 
Next Cycle 
 
Grade 1 or 2 
Any occurrence 
Maintain treatment at the 
same dose level 
None 
Clinically concerning or treatment-related Grade 3b or higher 
1st, 2nd, or 3rd 
occurrence 
 
Suspend treatment until 
Grade 0 or 1 
Reduce by 1 dose level from 
the previous level 
 
4th occurrence 
Discontinue treatment 
Discontinue treatment 
 
a Note: For toxicities (AEs or laboratory abnormalities) considered unlikely to become serious or 
life-threatening (including, but not limited to, fatigue, alopecia, changes in libido, and dry skin),  
subjects may continue on study medication at the same dose without reduction or interruption at 
the discretion of the Investigator (irrespective of grade). 
b Except for Grade 3 nausea and/or vomiting controlled by aggressive antiemetic therapy or 
diarrhea responsive to antidiarrheal medication.  If there is any uncertainty about continuing 
study medication or resuming study medication in a subject with Grade ≥3 non-hematologic 
toxicities, the case must be discussed with the UFHCC Data and Safety Integrity Committee 
(DISC) prior to continuing treatment. 
5.4.3 Hematologic Toxicity 
 
Obtain complete blood cell counts prior to and on Day 15 of each cycle.  
 
Do not initiate the cycle of LONSURF® until:  
• Absolute neutrophil count (ANC) is greater than or equal to 1,500/mm3 or febrile 
neutropenia is resolved  
• 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, withhold LONSURF® 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 LONSURF® after reducing the dose by 5 mg/m2/dose 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 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  


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• 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  
 
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 
subjects will be maintained by the study site. 
6.2 Study Treatment Discontinuation 
 
Study treatment will be withheld under the following circumstances:: 
 
• Grade 4 neutropenia (ANC less than 500/mm3 or febrile neutropenia), until ANC is 
resolved to greater than 1500/mm3 or febrile neutropenia is resolved 
• Grade 4 thrombocytopenia or grade 3 thrombocytopenia with bleeding (platelets less than 
50,000/mm3), until platelet count resolved to greater than or equal to 75,000/mm3 
• Other grade 3 or 4 non-hematologic toxicity, until the adverse reaction has resolved to 
Grade 0 or 1 
 
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) determines continued treatment with study drug is 
appropriate. 
• Substantial non-compliance (>25% of missed doses with the exception of dose delays 
and dose modifications per protocol, or dose-related instructions from research team staff 
due to adverse events), with the requirements of the study. 
• The subject presents with a beta-HCG test consistent with pregnancy and is confirmed to 
be pregnant.  Pregnancy will be reported along the same timelines as a serious adverse 
event. 
• The subject 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 the study or its results. 


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• The development of a second malignancy that requires treatment, which would interfere 
with this study. 
• The subject is lost to follow-up. 
• 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 subject in the study unless it is 
in the subject’s best interests to discontinue participation.  If a subject is removed from the study 
or declines further participation, all End of Treatment evaluations should be performed if the 
subject 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 subjects are followed up for survival status and progression (as applicable) after the End of 
Treatment Visit. 
 
Relevant visit data should be entered on the CRF and any unused study medication will be 
accounted for and returned for all subjects participating in the study who receive study drug.  
Subjects who discontinue following study consent will have relevant information completed and 
recorded on the CRF.  All subjects 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 subject should die within 30 days of receiving 
study treatment, the Investigator will inform the UF Health Data Integrity and Safety Committee 
(DISC).   
 
6.3 Replacement of Subjects 
 
Subjects lost to follow up along with other clinical variables without values are considered as 
missing data. We are not planning to do missing data imputation. These subjects will not be 
replaced on the trial unless they were lost to follow-up prior to receiving a single dose of the 
study drug. 
7 STUDY PROCEDURES 
7.1 Study Schedule of Events 
 
See Table 4 located in this section. 
 
 
 
 
 
 
 


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Table 4: Study Schedule and Procedures 
 
 
 
Evaluation 
Screeninga 
Treatment Phasel (1 cycle = 28 days) 
End of 
treatment 
(within 30 
days post 
last dose) 
Follow 
Up 
Before each 
cycle 
(within 3 
days) 
D15 of each 
cycle 
(± 3 days) 
Odd # 
cycles 
(± 7 
days) 
History & Physical 
X 
X 
 
 
 
X 
Xi 
Performance Status 
X 
X 
 
 
X 
 
Vital Signsb 
X 
X 
 
 
X 
 
AE Assessment 
X 
X 
 
 
X 
Xj 
Concomitant Meds 
X 
X 
 
 
X 
Xk 
ECGc 
X 
 
 
 
 
 
Pregnancy testd 
X 
 
 
 
 
 
Urine analysis 
X 
 
 
 
 
 
CMPe,f 
X 
X 
 
 
X 
 
Magnesium 
X 
X 
 
 
X 
 
CBC w/Diffe 
X 
X 
Xm 
 
X 
 
PT/INRg 
X 
 
 
 
 
 
CA19-9 
X 
X 
 
 
 
 
CT or MRIh 
X 
 
 
X 
 
X 
Survival Status 
 
 
 
 
 
X 
a. 
All screening procedures should be completed within 28 days of treatment except for serum pregnancy testing which should be 
completed within 7 days of treatment.  History & Physical, Vital Signs, ECOG PS, CMP, CBC w Diff and CA19-9 are not 
required to be repeated at treatment initiation if they were completed within 7 days prior to Cycle 1 Day 1. 
b. 
Vital signs include height, weight, blood pressure, pulse, temperature and pain level (subjective 1-10 self-reported 
scale).  Height should be obtained at screening only. 
c. 
ECGs will be obtained at screening.  Subjects who are placed on QT prolonging medications while on study should have ECGs 
performed at regular intervals (interval timing is at the discretion of the treating investigator).    
d. 
Pregnancy testing will be done for all females of childbearing age at Screening prior to TAS-102 initiation.  Standard-of-care 
pregnancy testing will be conducted any time clinical signs present for potential pregnant state, e.g., amenorrhea, other 
physical signs, or symptoms of pregnancy. 
e. 
Laboratory testing may be performed up to 72 hours prior to day 1 of the next cycle of therapy. 
f. 
CMP: Na, K, Cl, CO2, Glucose, BUN, Creatinine, Ca, Albumin, Total Bilirubin, Alk Phos, Total Protein, AST, ALT. 
g. 
PT/INR should be followed closely for subjects on warfarin.   
h. 
CT of the chest, abdomen and pelvis or CT of the chest and MRI of the abdomen and pelvis are allowed.  Consistent imaging 
modality should be used throughout the study.  Imaging should be performed every 8 weeks (+/- 7 days) beginning with Cycle 
3 until disease progression. 
i. 
H&P is required at 30 days (+ 7 days) following the last dose of study drug.  Additional H&Ps are required as needed to follow 
ongoing AEs.   
j. 
Adverse events should be followed for 30 days after the last dose of protocol therapy or until the initiation of subsequent 
treatment.  AEs continuing > 30 days should be monitored until resolution. 
k. 
Subjects or providers should be contacted every 3 months to assess survival status and subsequent therapies. 
l. 
TAS-102 (Lonsurf®) is administered 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. 
m. For CBC w/diff to be obtained at Day 15 of each cycle, notify the investigator if any of the following parameters are observed 
in the lab results: 1) ANC ≤ 500 µL, 2) platelets < 50 thou/mm3, or 3) Hgb < 7 g/dL. 
 


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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. 
All screening procedures should be completed within 28 days of treatment except for serum 
pregnancy testing which should be completed within 7 days of treatment.  History & Physical, 
Vital Signs, ECOG PS, CMP, CBC w Diff and CA19-9 are not required to be repeated at 
treatment initiation if they were completed within 7 days prior to Cycle 1 Day 1. 
7.3 On-Study Evaluations  
 
Please refer to Table 3 located in section 7.1. 
7.4 End of Treatment/Off Therapy Measurements (within 30 days post-last dose) 
 
Subjects will be treated until progression of disease, study drug intolerance that is not resolved or 
amendable to dose reduction, or subject desires to go off study. 
 
Interim history and physical examination, including vital signs and performance status 
Review of concomitant medications 
Laboratory studies: 
 
• CBC with differential count 
• Comprehensive metabolic panel 
• Magnesium 
• CA 19-9 
 
7.5 Follow up/Survival 
 
Please refer to Table 4 located in Section 7.1. 
 
For the purpose of this study, subjects will be seen in follow-up at least every three months until 
one year after the completion of study treatment.  Follow-up evaluations may consist of the 
interim medical history, physical examination, imaging, CBC, or comprehensive metabolic 
panel.  Any X-rays, CT or MRI scans, or other studies (such as PET scans, bone scans, biopsies, 
etc.) will be done as clinically indicated and up to the discretion of the treating physician.  
 
After this one-year follow-up period is over, subjects will be continued to be followed for 
survival until death, withdrawal, or lost to follow up.  If subjects are lost to follow-up, every 
effort will be made at least quarterly to attempt to locate that subject and to determine their 
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For subjects that come off protocol for reasons other than progressive disease, then CT or MRI 
scans will be performed every 8 weeks to document disease progression. until disease 
progression is shown or another anti-cancer therapy is initiated.   
 
8 CRITERIA FOR DISEASE EVALUATION 
Tumor response will be assessed using RECIST 1.1i criteria. 
8.1 Tumor Measurement Using RECIST 1.1 Criteria 
Measurable disease: the presence of at least one measurable lesion. If the measurable disease is 
restricted to a solitary lesion, its neoplastic nature should be confirmed by cytology/histology. 
Measurable lesions: lesions that can be accurately measured in at least one dimension (the 
longest diameter), and with a minimum size of 10 mm by CT scan, or 10 mm by caliper 
measurement during clinical exam, or 20 mm by chest X-ray. 
− A malignant lymph node may be considered pathologically enlarged and measurable 
if it is ≥ 15 mm in short axis by CT scan.  
− A lytic or mixed blastic-lytic bone lesion, with identifiable soft tissue component 
which is evaluable by CT or MRI, may be considered as measurable lesion if the soft 
tissue component meets the criteria for measurable lesions.  
− Cystic metastases may be considered as measurable lesions if they meet the criteria 
for measurable lesions, however, non-cystic lesions, if present, are preferred as target 
lesions.  
− Tumor lesions in an area previously subjected to loco-regional treatment, may be 
considered measurable if there has been demonstrated progression.  
Non-measurable lesions: all other lesions, including simple cysts, small lesions (longest diameter 
< 10 mm or pathological lymph nodes with ≥ 10 to < 15 mm short axis) and other truly non-
measurable lesions. These include: leptomeningeal disease; ascites; pleural/pericardial effusion; 
inflammatory breast disease; lymphangitis cutis/pulmonis; abdominal masses that are not 
measurable by reproducible imaging techniques; blastic bone lesions.  
All measurements should be recorded in metric notation, using a ruler or calipers. All baseline 
evaluations should be performed as close as possible to the treatment start and never more than 
4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. 


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Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules, 
palpable lymph nodes), and ≥ 10 mm diameter using calipers. For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesions is 
recommended. Whenever possible, imaging evaluation should be preferred over clinical exam. 
Chest CT is preferred over chest X-ray, particularly when progression is an important endpoint. 
The measurability of lesion by CT scan is based on the assumption that CT slice thickness is 
≤ 5 mm.  
8.2 Baseline Documentation of Target and Non-target Lesions 
When more than one measurable lesion is present at baseline, all lesions up to a maximum of 
five lesions total (and a maximum of two lesions per organ) 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 longer diameter) and 
their suitability for accurate repetitive measurements (either by imaging techniques or clinically). 
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. The baseline sum 
diameters will be used as reference to further characterize any objective tumor regression in the 
measurable dimension of the disease. 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as ‘present’ ‘absent’, or in rare cases ‘unequivocal progression’. 
Multiple non-target lesions involving the same organ may be recorded as a single item. 
8.3 Response Criteria 
Evaluation of target lesions 
Complete Response (CR): disappearance of all target lesions. Any pathological lymph nodes 
must have reduction in short axis to < 10 mm. 
Partial Response (PR): at least a 30% decrease in the sum of diameters of the target lesions 
taking as reference the baseline sum diameters. 
Progression (PD): at least a 20% increase in the sum of diameters of the target lesions taking as 
reference the smallest sum on study, and an absolute increase of at least 5 mm. The appearance 
of one or more new lesions is also considered progression. 
Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD taking as references the smallest sum diameters while on the study. 


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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 (< 10 mm short axis). 
Non-complete response (non-CR)/non-progression (non-PD): persistence of one or more non-
target lesion(s) or/and maintenance of tumor marker level above the normal limits. 
Progressive disease (PD): unequivocal appearance of one or more new malignant lesions. 
Unequivocal progression of existing non-target lesions. Although a clear progression of non-
target lesions only is exceptional, in such circumstances, the opinion of the treating physician 
should prevail and the progression status should be confirmed later on by a review panel (or 
study chair/primary 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).  In general, the subject’s best response 
assignment will depend on the achievement of both measurement and confirmation criteria. 
Table 5 provides a summary of the overall response status calculation at each time point for 
patients who have measurable disease at baseline. When subjects have non-measurable (therefore 
non-target) disease only, Table 6 should be used. 
Table 5. Evaluation of Best Overall Response: Subjects with Target Disease, with or 
without Non-target Disease 
Target Lesion 
Non-target Lesions 
New Lesions 
Overall 
Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
PR 
Non-PD or not at all 
evaluate 
No 
PR 
SD 
Non-PD or not at all 
evaluated 
No 
SD 
Not at all evaluated 
Non-PD 
No 
Inevaluable 
PD 
Any 
Yes or No 
PD 


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Table 5. Evaluation of Best Overall Response: Subjects with Target Disease, with or 
without Non-target Disease 
Target Lesion 
Non-target Lesions 
New Lesions 
Overall 
Response 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
Table 6. Evaluation of Best Overall Response: Subjects with Non-target Disease 
Only 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/ non-PD 
No 
Non-CR/ non-PDa 
Not all evaluated 
No 
Inevaluable 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
a‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as endpoint for assessment of efficacy in some trials so to assign this category 
when no lesions can be measured is not advised. 
When nodal disease is included in the sum of target lesions and the nodes decrease to ‘normal’ 
size (<10 mm), they may still have a measurement reported on scans. This measurement should 
be recorded even though the nodes are normal in order not to overstate progression should it be 
based on increase in size of the nodes.  
Subjects 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. 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue.  
When the evaluation of complete response depends upon this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) before confirming the 
complete response status. FDG-PET may be used to upgrade a response to a CR in a manner 


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similar to a biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring. 
For equivocal findings of progression (e.g. very small and uncertain new lesions; cystic changes 
or necrosis in existing lesions), treatment may continue until the next scheduled assessment. If at 
the next scheduled assessment, progression is confirmed, the date of progression should be the 
earlier date when progression was suspected. 
8.4 Confirmation 
In non-randomized trials where response is the primary endpoint, confirmation of PR or CR must 
be confirmed by repeat measurements that should be performed no less than 4 weeks after the 
criteria for response are first met. In this trial, as overall response rate is a secondary endpoint, 
confirmation of response in the form of a PR or CR will occur 8 weeks after the criteria for 
response are first met, since restaging imaging per the protocol will be performed every other 
chemotherapy cycle (ie every 8 weeks).   
In randomized trials or studies where the primary endpoints are stable disease or progression, 
confirmation of response is not required. Elimination of the requirement for response 
confirmation may increase the importance of central review to protect against bias, particularly 
in studies which are not blinded.  
In the case of SD, follow-up measurements must have met the SD criteria at least once after 
study entry at a minimum interval of 6-8 weeks. 
9 STUDY DRUG INFORMATION 
9.1 Study Drug Name   TAS-102 (Lonsurf®) 
9.1.1 Drug Supply   TAIHO Oncology, Inc. 
9.1.2 Contraindications:  none 
9.1.3 Special Warnings and Precautions for Use 
 
Myelosuppression  
In Study 1, LONSURF® caused severe and life-threatening myelosuppression (Grade 3-4) 
consisting of anemia (18%), neutropenia (38%), thrombocytopenia (5%) and febrile neutropenia 
(3.8%). One patient (0.2%) died due to neutropenic infection. In Study 1, 9.4% of LONSURF®-
treated patients received granulocyte-colony stimulating factors.  
Obtain complete blood counts prior to and on Day 15 of each cycle of LONSURF® and more 
frequently as clinically indicated. Withhold LONSURF® for febrile neutropenia, Grade 4 
neutropenia, or platelets less than 50,000/mm3. Upon recovery, resume LONSURF® at a reduced 
dose.  
 
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Based on animal studies and its mechanism of action, LONSURF® 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.  
Advise pregnant women of the potential risk to the fetus. Advise females of reproductive 
potential to use effective contraception during treatment with LONSURF®.  
9.1.4 Adverse Event Profile 
 
Table 7.  Per Patient Incidence of Adverse Drug Reactions (≥5%) in Study 1** Occurring 
More Commonly (>2%) than in Patients Receiving Placebo 
Adverse Reactions  
LONSURF®  
(N=533)  
Placebo  
(N=265)  
All Grades  
Grades 3-4  
All Grades  
Grades 3-4 
Gastrointestinal disorders  
Nausea  
48%  
2%  
24%  
1%  
Diarrhea  
32%  
3%  
12%  
<1%  
Vomiting  
28%  
2%  
14%  
<1%  
Abdominal 
pain  
21%  
2%  
18%  
4%  
Stomatitis  
8%  
<1%  
6%  
0%  
General disorders and administration site conditions  
Asthenia/fatigu
e  
52%  
7%  
35%  
9%  
Pyrexia  
19%  
1%  
14%  
<1%  
Metabolism and nutrition disorders  
Decreased 
appetite  
39%  
4%  
29%  
5%  
Nervous system disorders  
Dysgeusia  
7%  
0%  
2%  
0%  
Skin and subcutaneous tissue disorders  
Alopecia  
7%  
0%  
1%  
0%  
**Study 1: a randomized (2:1), double-blind, placebo-controlled trial in which 533 patients 
(median age 63 years; 61% men; 57% White, 35% Asian, 1% Black) with previously treated 
metastatic colorectal cancer received LONSURF® as a single agent at a dose of 35 mg/m2/dose 
administered twice daily on Days 1 through 5 and Days 8 through 12 of each 28-day cycle. The 
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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 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 
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• 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. 
 
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 (e.g., 
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 
 
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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 adverse events that occur during the study until 30 days following the last dose 
of study treatment (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:   
 


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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.  
 
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 4.0.3. For all other adverse events not described in the CTCAE, the intensity 
will be assessed by the Investigator using the following categories (see Table 8): 
 
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 
 


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Table 8.  Adverse Event Grading (Severity) Scale 
Grade 
Severity 
Alternate Description a 
1 
Mild (apply event-specific 
NCI-CTCAE grading criteria) 
Transient or mild discomfort 
(< 48 hours); no interference 
with the subject’s daily 
activities; no medical 
intervention/therapy required 
2 
Moderate (apply event-specific  
NCI-CTCAE grading criteria) 
Mild to moderate interference 
with the subject’s daily 
activities; no or minimal 
medical intervention/therapy 
required 
3 
Severe (apply event-specific  
NCI-CTCAE grading criteria) 
Considerable interference with 
the subject’s daily activities; 
medical intervention/therapy 
required; hospitalization 
possible 
4 
Very severe, life threatening,  
or disabling (apply 
event-specific NCI-CTCAE 
grading criteria) 
Extreme limitation in activity; 
significant medical 
intervention/therapy required, 
hospitalization probable 
5 
Death related to AE 
 
Note:  Regardless of severity, some events may also meet regulatory serious 
criteria.  Refer to definitions of an SAE. 
Use these alternative definitions for Grade 1, 2, 3, and 4 events when the 
observed or reported AE is not in the NCI-CTCAE listing. 
 
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. 
 
Only one item should be chosen. If multiple actions apply, the following “worst case” scenario 
hierarchy should be used to determine the preferred entry: 
 
Discontinued > dose decreased > therapy interrupted. 


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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 
 
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 and not to report SAEs. 
 
At the time of the annual DSUR (data-lock point), a list of all AEs which led to discontinuation, 
subjects with fatal events, and demographic information for all subjects exposed to TAS-102 
must all be submitted to Taiho. 
 
UFHCC PMO and DISC Reporting Requirements 
 
Serious adverse events (SAE's) must be reported to UFHCC Project Management Office (PMO; 
pmo@cancer.ufl.edu) and entered into OnCore within 24 hours of discovery of the event.  If only 
limited details are known, these should be reported within that time frame and follow up reports 
can be submitted for elaboration, clarifications, or corrections.  Any email correspondence must 
be kept in the trial 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.  SAEs must also be 
reported 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 submitted to the UFHCC PMO (pmo@cancer.ufl.edu), stating 
that this is a follow-up to a previously reported SAE and giving the date of the original report. 


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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, and whether the 
participant continued or withdrew from study participation.  PMO will confirm that the event and 
any necessary follow-ups are reported to the UFHCC Data and Safety Integrity Committee 
(DISC), Taiho Oncology, and any other regulatory authorities as required.   
All AEs that do not meet any of the criteria for serious should be regarded as non-serious AEs. 
 
 
Institution SAE and Pregnancy Reporting Information 
 
 
SAEs  and pregnancies must be reported to the UFHCC CRO Project 
Management Office (PMO), or assigned designee at: 
  
Email: pmo@cancer.ufl.edu  
 
As well as entered in OnCore, the study CTMS. 
 
 
10.4.2 Other Events Requiring Immediate Reporting 
 
Pregnancies, overdoses, and medication errors should be documented and reported per the SAE 
reporting guidelines in section 10.4.1 above. 
 
10.4.2.1 
Pregnancy 
  
If a subject becomes pregnant while in the study, the study treatment must be immediately 
discontinued.  Pregnancy information for a female subject should be reported within 24 hours 
from the time the Investigator first becomes aware of a pregnancy or its outcome.  This should be 
performed by completing a Pregnancy Form and faxing it to Taiho Pharmacovigilance or 
designee.   
 
New and/or corrected information regarding the pregnancy obtained after submitting the initial 
Pregnancy Form must be submitted by faxing an updated Pregnancy Form to Taiho 
Pharmacovigilance or designee. 
 
If outcome of the pregnancy is a stillbirth, congenital anomaly/birth defect, or a serious event in 
the mother, report as an SAE to Taiho Pharmacovigilance or designee. 
 
All pregnancies, regardless of outcome, must be also reported to the UFHCC PMO 
(pmo@cancer.ufl.edu) and DISC, including pregnancies that occur in the female partner of a 
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10.4.2.2 
Overdose 
 
An overdose with TAS-102 is defined as: 
• Taking a dose beyond the recommended dose in one day or beyond the recommended 
total dose in each cycle. 
• An accidental or intentional overdose with TAS-102 regardless of whether it is 
associated with an AE (even if not fulfilling a seriousness criterion)  
 
These events are to be captured as an AE on the eCRF and reported to Taiho Pharmacovigilance 
or designee within 24 hours from the time the Investigator first becomes aware of its occurrence 
following the same process as described for the SAEs. 
 
There is no known antidote available in case of TAS-102 overdose.  Overdose should be 
managed aggressively with close monitoring and administration of prophylactic and 
symptomatic therapies to prevent or correct potential side effects. 
 
An accidental or intentional overdose for concomitant medication should only be reported if it is 
associated with an AE.   
 
Although overdose (dose variance of >10%) and cancer are not always serious by regulatory 
definition, these events should also be reported to the UFHCC PMO (pmo@cancer.ufl.edu) and 
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. 
 
10.4.2.3 
Medication Error 
 
A medication error is defined as any accidental incorrect administration of a medicinal product.  
The error may be related to the administration of a wrong medication, nature of the medication, 
route of administration, dosage or frequency of the treatment as specified in this protocol 
(including omission of one or more administrations). 
• Medication errors with study medication and concomitant medication treatment will not 
be recorded in the eCRF unless they result in an AE or overdose. 
• Medication errors with study medication that result in an overdose will be captured as an 
AE in the eCRF.  
• Medication errors with study medication that do not result in an AE should be handled as 
follows: 
o If it results in the omission of an administration, an incorrect dose (relative to that 
specified in this protocol), or the administration of more than the prescribed dose 
(but does not meet the overdose criteria), it will be identified through the 


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recording of study drug accountability data in the eCRF and does not need to be 
reported as an AE. 
o If it results in an overdose, incorrect route of administration, or administration of 
an incorrect study drug, it will be reported as an AE. 
Based on the above criteria, medication errors that are captured as an AE on the eCRF should be 
reported to UFHCC PMO (pmo@cancer.ufl.edu) and Taiho Pharmacovigilance or designee 
within 24 hours from the time the Investigator first becomes aware of its occurrence following 
the same process as described for the SAEs even if it does not meet any of the criteria of an SAE. 
 
10.5  IND Safety Reports Unrelated to this Trial 
 
IND safety reports not occurring on this trial but involving the study intervention  received 
from outside sources will be forwarded to participating sites for submission to their 
Institutional Review Boards per their guidelines. 
11   ASSESSING SAFETY 
 
11.1  Specfications of Safety Analysis   
 
Safety assessments will consist of monitoring and recording protocol-defined adverse events (AEs) 
and serious adverse events (SAEs); measurement of protocol-specified hematology, clinical 
chemistry, and urinalysis variables; measurement of protocol-specified vital signs; and other 
protocol-specified tests that are deemed critical to the safety evaluation of the study drug(s). 
 
Death as a result of disease progression is only to be assessed as efficacy measures and not as AEs 
or SAEs unless the events that led to death met the serious criteria.  
 
The terms “severe” and “serious” are not synonymous.  Severity (or intensity) refers to the grade 
of a specific AE, e.g., mild (Grade 1), moderate (Grade 2), or severe (Grade 3) myocardial 
infarction.  “Serious” is a regulatory definition (see previous definition) and is based on subject or 
event outcome or action criteria usually associated with events that pose a threat to a subject’s life 
or functioning.  Seriousness (not severity) serves as the guide for defining regulatory reporting 
obligations from the Sponsor to applicable regulatory authorities.  
 
Severity and seriousness should be independently assessed when recording AEs and SAEs on the 
CRF. 
 
11.2  Safety Analysis   
 
Subjects will be examined and graded each cycle for subjective/objective evidence of developing 
toxicity according to NCI-CTCAE version 4.03 toxicity criteria. Incidence tables will be generated 
to summarize incidence of subjects reporting at least one episode of each specific adverse event, 
incidence of adverse events causing withdrawal, and incidence of serious adverse events. Subjects 
will have laboratory values assessed prior to and on Day 15 of each cycle.  
 


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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 subjects 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 subjects 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 
subject group and by dose levels. Dose-toxicity curves will be fitted to the final data to estimate 
the toxicity rates of each dose levels. 
 
11.3  Methods and Timing for Assessment and Recording Safety Variables   
 
The investigator is responsible for ensuring that all AEs and SAEs that are observed or reported 
during the study are recorded on the CRF and reported to Taiho in accordance with protocol 
instructions and clinical trial agreement.  
 
11.4  Type and Duration of Follow-up of Adverse Events   
 
All AEs and SAEs that are encountered during the protocol-specified AE reporting period should 
be followed to their resolutions, or until the investigator assesses them as stable at the time of the 
30-day safety follow-up, or the subject is lost to follow-up.  Resolution of AEs and SAEs (with 
dates) should be documented on the appropriate AE or SAE CRF page and in the subject’s medical 
record to facilitate source data verification. 
 
For some SAEs, the Sponsor or its designee may follow-up by telephone, fax, electronic mail, 
and/or a monitoring visit to obtain additional case details deemed necessary to appropriately 
evaluate the SAE report (e.g., hospital discharge summary, consultant report, or autopsy report). 
12.   STATISTICAL METHODS 
The following sub-sections provide an overview of the statistical considerations and analyses. 
 
12.1 Sample Size Determination 
 


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This is a pilot phase II single-arm study, with a primary endpoint of progression-free survival 
(PFS), to evaluate efficacy of TAS-102.   Additional objective of the study is to evaluate the 
feasibility and safety of a regimen of daily TAS-102 administered to subjects with metastatic or 
unresectable pancreatic adenocarcinoma after progression through or intolerance to first- or 
second-line chemotherapy.  The primary efficacy analysis will be an intent-to-treat comparison 
of the PFS curve with a reference historical control.  From past studies3, the median PFS and/or 
time to progression (TTP) for subjects with metastatic or unresectable pancreatic 
adenocarcinoma in the second line of treatment is variable ranging from 6 weeks to 22 weeks.  
Assuming exponential distributions on PFS on both current study population and the referent 
population, a sample size of 33 evaluable subjects who will receive the same level of dose will 
ensure to have at least 80% power to detect an improvement of 3 weeks of median PFS (i.e. from 
6 weeks to 9 weeks). The sample size and power derivations were based on one-sample log rank 
test by Wu (2015)14 at one-sided significance level of 0.10. It is assumed that the survival time 
distributions of both groups (historical and this proposed experiment groups) are approximately 
the Weibull distribution with a shape parameter of ~1.0. Accounting for about ~10% 
ineligible/inevaluable subjects, the total number of subjects to be accrued to this cohort will be 
37, which is expected to be completed within 24 months. Assuming at least the last evaluable 
subject derives benefit from the anticipated maximal number of 6 cycles, the length of the entire 
treatment study will be approximately 30 months.  
 
A subject is considered eligible for toxicity evaluation if they have received at least one dose of 
TAS-102.  
 
12.2 Analysis of Baseline and Demographic Characteristics   
 
The analysis of demographic characteristics (age, gender, ethnicity) and baseline characteristics, 
including weight change, performance status, and histologic subtype, will be primarily 
descriptive due to the small subject numbers.  All data will be summarized using descriptive 
statistics (mean/variance, median/range, frequency/proportion) along with graphical illustration 
as needed.  
 
12.3 Primary and Secondary Endpoint Efficacy Analysis    
 
The primary endpoint to this study will be to determine progression-free survival following TAS-
102 therapy.  Kaplan-Meier mean estimates and survival curves of progression-free survival rates 
will be calculated. 
 
A secondary endpoint of this study will be overall survival/TTP following treatment with TAS-
102.  Kaplan-Meier estimates and survival curves will be calculated. Other secondary endpoints 
include response rates, clinical benefit rate (CR + PR + SD), toxicities, reversibility of toxicities, 
and compliance with intended treatment will also be estimated along with exact 95% binomial 
confidence intervals.  
 
No multiplicity will be adjusted for the secondary endpoints. All data analysis will be conducted 
in reproducible fashion and the results will be reported regardless of the statistical significance.  


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13 DATA AND SAFETY MONITORING 
 
13.1Data Integrity and Safety Committee 
 
This protocol will be reviewed and monitored by the University of Florida Health Cancer Center 
Data Integrity and Safety Committee (UFHCC 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 
 
In compliance with the UFHCC data and safety monitoring plan, the PI will provide a Data 
Integrity and Safety Committee Report to DISC at the predetermined timelines for the level of 
risk category assigned during the initial SRMC (Scientific Review and Monitoring Committee) 
review, which occurs prior to initial IRB approval. 
 
UFHCC investigator-initiated protocols will be classified into one of the following categories of 
risk: 
 
 
Level 1 – Low risk non-therapeutic interventional trials. 
 
Level 2 – Moderate risk therapeutic (i.e., drug, biologic, or device) trials using FDA  
    approved or commercially available compounds or interventions. 
 
Level 3 – High risk therapeutic trials (i.e., investigator-sponsored INDs, Phase I trials,  
    studies requiring biosafety approval, or other areas that may be designated by  
   NIH as high risk). 
 
Level 4 – Complex trials involving very high risk to subjects and a high-level complexity  
    (i.e., first in human or gene transfer studies). 
 
13.2 Data Monitoring 
 
UFHCC (University of Florida Health Cancer Center) Quality Assurance team and/or project 
management officers will perform remote monitoring and may 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 completion and validated against with data submitted 
electronically via the Electronic Data Capture. The site investigator/institution guarantee access 
to source documents by UFHCC or its designee and appropriate regulatory agencies.  As part of 
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maintain and have available for monitoring adequate case records (accurate source documents 
and CRFs) for the subjects treated under this protocol. 
 
The trial site may also be subject to quality assurance audit by any collaborating sponsors or their 
designee as well as inspection by appropriate regulatory agencies.  
 
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. 
13.3  Principal Investigator (PI) Responsibilities 
 
Per IRB requirements, the PI is personally responsible for conducting and supervising the 
conduct of human subjects research by “protecting the rights, safety, and welfare of subjects 
under the investigator’s care.” The PI also must ensure that all the research conducted is done so 
in an ethical manner and in accordance with all federal, state, and local laws and regulations, 
institutional policies, and the requirements of the IRB. 
 
Oversight is defined as “management by overseeing the performance or operation of a person or 
group; watchful care, superintendence, general supervision”. Any person serving as a PI has 
voluntarily accepted these responsibilities and is expected to fully comply with these 
requirements, as outlined in the UFHCC Guidance: Principal Investigator Responsibilities and 
Oversight. 
 
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.  
14 EMERGENCY PROCEDURES 
 
14.1  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. 
14.2 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. 
15 ADMINISTRATIVE CONSIDERATIONS 
 
15.1 Good Clinical Practice 
 


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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 
initiation of the study.  
 
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 UFHCC Project Management Office 
(PMO; PMO@cancer.ufl.edu, who will then report the breach to the UFHCC DISC) and the IRB 
of record. 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. 
15.2  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 study will be conducted in accordance with 
U.S. FDA, applicable national and local health authority, and IRB requirements 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, adverse events and other information (e.g., amendments, and administrative 
letters) according to regulatory requirements or institution procedures. 
15.3  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 
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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. 
 
15.4  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 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 in the site study binder or in each 
subject’s study file. The PI will not undertake any measures specifically required only for the 
clinical study until valid consent has been obtained. 
15.5 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 Data Integrity and Safety Committee, 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. 
15.6  Protocol Amendments 
 
Once the study has started, amendments should be made only in exceptional cases.  
Protocol amendments will not be implemented without prior written IRB approval. All 
amendments will be submitted to the IRB and SRMC (as applicable), and written verification 
that the amendment was submitted and subsequently approved is to be obtained, and notification 
will sent out to the applicable study teams, prior to implementing the amendment.   


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On an emergency-basis, to eliminate an immediate safety hazard to a subject, a protocol 
deviation may be implemented immediately, provided the IRB and UFHCC CRO PMO 
(pmo@cancer.ufl.edu) are notified within 5 business days with a full justification and description 
of the event. 
 
15.7 Case Report Forms 
 
The Principal Investigator and/or his/her designee, will prepare and maintain adequate and 
accurate participant case histories with observations and data pertinent to the study.  Study 
specific Case Report Forms (CRFs) will document protocol-required outcomes for safety 
monitoring and data analysis.  All study data will be entered electronically in an Electronic Data 
Capture system in accordance with the protocol schedule of events and guidelines developed in 
the Data Management Plan for the study, using a secure access account.   
 
All protocol data 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. Record Retention 
 
U.S. FDA regulations (21 CFR §312.62[c]) require that records and documents pertaining to the 
conduct of this study and the distribution of investigational drug, including CRFs, consent forms, 
laboratory test results, and medication inventory records, must be retained by the Principal 
Investigator for 2 years after marketing application approval.  If no application is filed, these 
records must be kept 2 years after the study is discontinued and the U.S. FDA and the applicable 
national and local health authorities are notified.  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 subject 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 
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. 
16 COMPLIANCE WITH LAWS AND REGULATIONS 
 


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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 Project  Management 
Officer or assigned designee.  All studies must be registered prior to enrollment of the first 
participant.  The Protocol Management Officer or assigned designee will maintain the 
responsibility of updating trials registered with ClinicalTrials.gov. Per FDA requirement, 
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.  The PMO will 
determine if registration and updates to the NCI CTRP are required. 
 
 


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