Conditions: Gastric Adenocarcinoma GastroEsophageal Cancer
Keywords: Gastric Adenocarcinoma TAS-102 Irinotecan Gastroesophageal Adenocarcinoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 20
Healthy volunteers: no

Brief summary:
This is a phase Ib single-arm, open-label clinical trial determining the feasibility and efficacy of TAS-102 and irinotecan in subjects with advanced gastric and gastroesophageal adenocarcinoma. These are subjects who are not candidates for curative treatments and who have received at least one prior line of chemotherapy with a fluoropyrimidine and platinum agent.

Detailed description:
Treatment on study will be administered in 14 day cycles.

Arms:
arm 1: Patients receive TAS-102 25 mg/m2 PO twice daily on days 1-5 and and Irinotecan 180mg/m2 IV on day 1 every 14 days.

Interventions: intervention 1: TAS-102 intervention 2: Irinotecan
Intervention descriptions: intervention 1: Given PO intervention 2: Given IV

Protocol document:
Prot_SAP_000.pdf: 
Protocol #: UCI 18-125 
MP 11/04/20 
 
CONFIDENTIAL 
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PROTOCOL  
A Phase 1b multicenter study of TAS-102 in combination with irinotecan in patients with advanced 
recurrent or unresectable gastric and gastroesophageal adenocarcinoma after at least one line of 
treatment with a fluoropyrimidine and platinum containing regimen 
 
 
Principal Investigator:  
Farshid Dayyani, MD, PhD 
 
 
 
 
University of California Irvine  
 
 
 
 
Department of Medicine/Division of Hematology/Oncology 
 
 
 
 
101 The City Dr South, Orange, CA 92868 
 
 
 
 
(Phone) 714-456-8161  
 
 
 
 
(Fax) 714-456-2242 
 
 
 
 
Email: fdayyani@hs.uci.edu 
 
 
Sub-Investigator(s): 
 
Fa Chyi Lee, MD 
 
 
 
 
Jason Zell, DO 
 
 
 
 
Jennifer B. Valerin, MD 
 
 
 
 
Emad Elquza, MD 
 
 
 
 
Department of Medicine/Division of Hematology/Oncology 
 
Participating Site  
Principal Investigator(s):  
May Cho, MD 
 
 
 
 
Assistant Professor of Medicine 
 
 
 
 
Division of Hematology and Oncology 
 
 
 
 
UC Davis Comprehensive Cancer Center  
 
 
 
 
4501 X Street, Suite 3016, Sacramento, CA 95817  
 
 
 
 
Phone: (916) 703-5964 
 
 
 
 
maycho@ucdavis.edu  
 
Biostatistician: 
 
Thomas Taylor, PhD 
 
 
 
 
Principal Statistician 
 
 
 
 
University of California Irvine 
 
 
 
 
222 Irvine Hall, Irvine, CA 92697 
 
 
 
 
Phone: (949) 824-6903  
 
 
 
 
Email: thtaylor@uci.edu  
 
 
 
 
 
 
Coordinating Center:   
UC Irvine Chao Family Comprehensive Cancer Center 
 
 
 
 
101 The City Drive South, Orange CA 92868 
 
 
 
 
Contact: Jessica Spolarich, Clinical Research Manager 
 
 
 
 
Phone: 714-509-2450  
 
 
 
 
Email: uci18125@hs.uci.edu    
 
 
 
 
 
Study Drug: 
 
 
Trifluridine/tipiracil (TAS-102) [Lonsurf©] 
 
Funding Source:  
Taiho Pharmaceutical Co., Ltd., UCI CFCCC  
 
How is the Agent Supplied?:  Taiho Pharmaceutical Co., Ltd. 
 
Current Version: 
 
11/04/20 
 
Previous Versions: 
 08/11/20 
 
 
 04/06/20 
 
 
 09/25/19 


Protocol #: UCI 18-125 
MP 11/04/20 
 
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Page 2 of 75 
 
 
 09/03/19 
 
 
 08/09/19 
 
 
 
 
05/08/19 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol #: UCI 18-125 
MP 11/04/20 
 
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The signature below constitutes the approval of this protocol and the attachments, and provides the 
necessary assurances that this trial will be conducted according to all stipulations of the protocol, 
including all statements regarding confidentiality, and according to local legal and regulatory requirements 
and applicable U.S. federal regulations and ICH guidelines. 
 
 
 
Principal Investigator (PI) Name: ______________________________ 
 
 
 
PI Signature: _____________________________ 
 
 
 
Date: ____________________ 
 


Protocol #: UCI 18-125 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ....................................................................................................... 6 
STUDY SCHEMA ........................................................................................................................ 7 
STUDY SUMMARY ..................................................................................................................... 7 
1.0 
BACKGROUND AND RATIONALE .............................................................................. 8 
1.1 
Disease Background........................................................................................................ 8 
1.2 
Study Agent(s) Background and Associated Known Toxicities ..................................... 11 
1.3 
Other Agents .................................................................................................................. 28 
1.4 
Rationale ........................................................................................................................ 35 
2.0 
STUDY OBJECTIVES ................................................................................................... 35 
2.1 
Primary Objectives ......................................................................................................... 35 
2.2 
Secondary Objectives .................................................................................................... 35 
2.3 
Endpoints ....................................................................................................................... 36 
3.0 
PATIENT ELIGIBILITY .................................................................................................. 36 
3.1 
Inclusion Criteria ............................................................................................................ 36 
3.2 
Exclusion Criteria ........................................................................................................... 37 
4.0 
TREATMENT PLAN ....................................................................................................... 38 
4.1 
Treatment Dosage and Administration .......................................................................... 38 
4.2 
Toxicities and Dosing Delays/Dose Modifications ......................................................... 39 
4.3 
Concomitant Medications/Treatments ........................................................................... 40 
4.4 
Duration of Therapy ....................................................................................................... 41 
4.5 
Duration of Follow Up .................................................................................................... 41 
4.6 
Removal of Patients from Protocol Therapy .................................................................. 41 
4.7 
Patient Replacement ..................................................................................................... 42 
5.0 
STUDY PROCEDURES................................................................................................. 42 
5.1 
Screening/Baseline Procedures .................................................................................... 42 
5.2 
Registration Procedures for participating sites only ...................................................... 43 
5.3 
Procedures During Treatment ....................................................................................... 43 
5.4 
Follow-up Procedures .................................................................................................... 44 
5.5 
Time and Events Table .................................................................................................. 44 
5.6 
Removal of Subjects from Study ................................................................................... 45 


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6.0 
Measurement of Effect................................................................................................. 46 
6.1 
Antitumor Effect- Solid Tumors ...................................................................................... 46 
6.2 
Safety/tolerability ........................................................................................................... 50 
7.0 
ADVERSE EVENTS ....................................................................................................... 50 
7.1 
Experimental Therapy.................................................................................................... 50 
7.2 
Adverse Event Monitoring ............................................................................................. 52 
7.3 
Definitions ...................................................................................................................... 52 
7.4 
Reporting Requirements ................................................................................................ 55 
7.5 
Additional Reporting Requirements to CFCCC DSMB and Coordinating Center/Medical Monitor
 
59 
7.6 
Additional Clinical Reporting Requirements to Taiho .................................................... 61 
8.0 
DRUG INFORMATION .................................................................................................. 61 
8.1 
TAS-102 ......................................................................................................................... 61 
8.2 
Irinotecan ....................................................................................................................... 63 
9.0 
STATISTICAL CONSIDERATIONS ............................................................................ 64 
9.1 
Study Design/Study Endpoints ...................................................................................... 64 
9.2  
Sample Size and Accrual .............................................................................................. 64 
9.3 
Stopping for Futility: ....................................................................................................... 65 
9.4 
Continuous Monitoring for Excess Toxicity:................................................................... 65 
9.5 
Analyses of Secondary Endpoints and Ad-Hoc comparisons ....................................... 66 
10.0 
STUDY MANAGEMENT ............................................................................................ 66 
10.1 
Conflict of Interest .......................................................................................................... 66 
11.2 
Institutional Review Board (IRB) Approval and Consent ............................................... 66 
10.3 
Required Documentation (for multi-site studies) ........................................................... 67 
10.4 
Data Completion ............................................................................................................ 67 
10.5 
Data and Safety Monitoring/Auditing ............................................................................. 68 
10.6 
Protocol Deviations ........................................................................................................ 68 
10.7 
Amendments to the Protocol ......................................................................................... 68 
10.8 
Record Retention ........................................................................................................... 69 
10.9 
Obligations of Investigators ........................................................................................... 69 


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11.0 
REFERENCES ............................................................................................................ 69 
12.0 
APPENDICES .............................................................................................................. 72 


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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ALC 
Absolute Lymphocyte Count 
AST 
Aspartate Aminotransferase 
BSA 
Body Surface Area 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CMP 
Comprehensive Metabolic Panel 
CR 
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DSMB 
Data and Safety Monitoring Board 
ECOG 
Eastern Cooperative Oncology Group 
H&P 
History & Physical Exam 
HRPP 
Human Research Protections Program 
IV (or iv) 
Intravenously 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PBMCs 
Peripheral Blood Mononuclear Cells 
PD 
Progressive Disease 
PFS 
Progression Free Survival 
PFS-6 
Progression Free Survival at 6 months 
p.o. 
per os/by mouth/orally 
PR 
Partial Response 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SPGT 
Serum Glutamic Pyruvic Transaminase 
TAS-102 
Trifluridine/tipiracil 
WBC 
White Blood Cells 
 
 
 
 


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STUDY SCHEMA 
 
 
 
 
 
 
 
STUDY SUMMARY  
Title 
A Phase 1b multicenter study of TAS102 in combination with irinotecan 
in patients with advanced recurrent or unresectable gastric and 
gastroesophageal adenocarcinoma after at least one line of treatment 
with a fluoropyrimidine and platinum containing regimen 
Short Title 
TAS-102 and irinotecan in 2L+ gastric and gastroesophageal 
adenocarcinomas 
Protocol Number 
UCI 18-125 
Phase 
1b 
Methodology 
Open label, single arm 
Study Duration 
3 years 
Study Center(s) 
multi-center; 2-3 study sites 
Objectives 
Primary objective: To determine the feasibility and estimate the efficacy 
of trifluridine and tipiracil (TAS102) in combination with irinotecan in 
patients with advanced gastric and gastroesophageal adenocarcinoma 
(GC) Primary Endpoint: 6 months progression-free survival (PFS-6) 
Secondary Objective: efficacy, safety, Secondary Endpoint: overall 
survival, objective response rate, adverse events 
Number of Subjects 
20 
Diagnosis and Main 
Inclusion Criteria 
• Histologically proven unresectable or recurrent gastric or 
gastroesophageal adenocarcinoma  
• At least one prior chemotherapy regimen including a fluoropyrimidine 
and/or platinum agent  
• Age ≥ 18 years  
• Performance status (Eastern Cooperative Oncology Group) of 0 to 2  
• Adequate bone marrow function (ANC≥ 1,500/mcL); and platelet 
count≥ 80,000/mcl  
• Adequate liver function (total serum bilirubin level within normal 
institutional limits and serum transaminases<3 X ULN or ≤5 X ULN if 
liver metastasis is present);  
• Adequate renal function (serum creatinine level < 1.5 X upper limit of 
normal)  
• An expected survival period of >3 months 
Study Product(s), Dose, 
Route, Regimen 
Trifluridine/tipiracil (TAS-102) 25 mg/m2 p.o. days 1-5  
Irinotecan 180 mg/m2 i.v. day 1 Every 14 days 
 
 
TAS 102 25mg/m2 po twice daily day 1-5 
Irinotecan 180mg/m2 iv over 90 minutes day 1 
 
q 14 days  
CR, PR, or SD 
Continue protocol treatment 
PD 
Discontinue protocol treatment 


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Study Duration  
The study will consist of a screening period of up to 28 days, a treatment 
period (14 days cycles), and follow up every 3 months until death or up 
to 18 months after the last patient is enrolled, whichever occurs first. 
Subjects will be allowed to continue treatment on study until disease 
progression, unacceptable toxicity or withdrawal of consent.  
Statistical Methodology 
Main objective is to describe the feasibility of the combination regimen 
and estimate PFS-6. If the PFS-6 is less than 35%, futility will be 
declared. If the PFS-6 is 35% or greater, the study is positive. 
 
1.0 
BACKGROUND AND RATIONALE 
1.1 
Disease Background 
Gastric cancer is the 5th leading cancer and the 3rd leading cause of cancer-related 
deaths worldwide[1]. The incidence of GC varies with different geographic regions, with 
over 70% of GCs occurring in developing countries[2]. Gastric cancer often presents as 
advanced disease upon diagnosis, comprising approximately 40% of newly diagnosed 
cases in the United States (US) and Europe, and approximately 20% in Japan and 
Korea, where early detection is common[2]. 
 
Gastric cancer, including GEJ carcinoma, is a heterogeneous disease with several 
established risk factors, including environmental, genetic, and behavioral risks. There has 
been a steady decline in GC mortality attributable to dietary and lifestyle changes 
worldwide and to decreasing infection with Helicobacter pylori, which is considered the 
main cause of GC/GEJ in Asian countries[3]. However, the incidence of GEJ tumors has 
increased considerably due to increases in risk factors such as obesity and 
gastroesophageal reflux disease[1]. 
 
Gastroesophageal junction cancer anatomically straddles the distal esophagus and 
proximal stomach. Due to its anatomic location and given that, like GC, the majority of 
GEJ tumors are adenocarcinomas, GEJ tumors are frequently grouped together with GC. 
Adenocarcinoma is further classified into 2 distinct types: intestinal (well-differentiated) or 
diffuse (undifferentiated)[4]. 
 
Until optimal, tumor-specific treatment strategies are defined, advanced and metastatic 
GEJ cancer is treated and managed in a similar fashion to GC[5]. Platinum compounds 
(oxaliplatin and cisplatin) and fluoropyrimidines (5-fluorouracil, capecitabine, and 
tegafur/gimeracil/oteracil potassium [S1]) are generally considered as first-line (1L), 
standard-of-care treatment options in metastatic GC and GEJ cancer across geographic 
regions[6][7]. These platinum/fluoropyrimidine combinations are also generally accepted 
as active comparators in Phase 2 or Phase 3 randomized studies by health authorities 
worldwide[2]. The different biological characteristics and treatment approaches among 
regions result in different survival outcomes, with median overall survival (mOS) 
durations of 12 to 14 months in Asian countries and 8 to 11 months in the United States 
(US) and Europe[6][7]. 
 
While these cytotoxic agents are clinically active, with a 30% to 50% objective response 
rate (ORR) in the 1L GC treatment setting, this clinical activity is accompanied by 
significant toxicity. Grade 3/4 toxicities up to 77% have been reported for doublet 
regimens and > 80% for triplet regimens[8][9][10][11]. Hematological toxicity is the major 
problem; Grade 3/4 neutropenia has been reported in approximately 40% of participants 
treated with platinum doublets, and has increased to 82% when docetaxel was added on. 
Renal toxicity and neuropathy are the main reasons for discontinuation of platinum 
treatment. Gastrointestinal complaints are also common. Additionally, despite ORRs of 


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30% to 50%, chemotherapy has resulted in few participants achieving complete response 
(CR). 
 
Since it is increasingly unlikely to induce longterm remission in patients by a first-line 
treatment only, a potential way could be to expand the lines of treatment from the first- to 
the second-line and beyond[12]. Indeed, currently roughly 50% of patients progressing 
after firstline maintain acceptable general conditions and are still good candidates to 
receive further therapies[12]. Also, the benefit of second-line chemotherapy has been 
convincingly established in randomised trials[13][14][15], and more recently, the anti-
vascular endothelial growth factor receptor 2 (VEGFR-2) ramucirumab has shown to 
improve survival either as single agent over BSC[16] or combined with paclitaxel over 
paclitaxel alone in pretreated patients[17]. 
 
Monochemotherapy versus BSC 
 
Three are the landmark phase III randomised trials that successfully explored the role of 
second-line monochemotherapy in patients with GC. 
 
The German Arbeitsgemeinschaft Internistische Onkologie trial compared a 3-week 
schedule of irinotecan 250 mg/m² (escalated up to 350 mg/m² depending on toxicity) with 
BSC in patients with Eastern Cooperative Oncology Group performance status (ECOG 
PS) 0–2 who had received prior fluoropyrimidine/platinum combination and whose 
disease progressed during or within 6 months following first line[18]. Although the study 
was terminated prematurely due to poor accrual, among 40 enrolled patients the median 
OS was significantly longer in the irinotecan arm than in the BSC arm (4 vs 2.4 months, 
HR=0.48, p=0.023). The UK COUGAR-2 trial enrolled 168 patients to receive either 
docetaxel 75 mg/m² every 3 weeks plus BSC for a maximum of six cycles or BSC 
alone[19]. The median OS was improved with docetaxel compared with BSC (5.2 vs 3.6 
months, HR=0.67, p=0.01). Despite a higher incidence of grade 3–4 neutropenia, 
infection and febrile neutropenia, patients receiving docetaxel experienced less pain, 
nausea, vomiting and constiption and decreased dysphagia and abdominal pain. 
 
A Korean trial tried to answer the question about the optimal cytotoxics to be used in 
second line[20]. In this study, 202 patients with ECOG PS 0–1 and failing one or two prior 
chemotherapy lines were randomised in a 2:1 ratio to either salvage chemotherapy 
(docetaxel 60 mg/m² every 3 weeks or irinotecan 150 mg/m² every 2 weeks upon 
investigator’s choice) or BSC. The administration of second-line chemotherapy resulted 
in a significant improvement in OS compared with BSC (5.3 vs 3.8 months, HR=0.657, 
p=0.007), while no survival difference was recorded between docetaxel and irinotecan 
(5.2 vs 6.5 months, p=0.116). Even side effects were similar in both treatment arms. 
 
A meta-analysis of patient-level data from the abovementioned trials including a total of 
410 patients underscored the median OS gain of roughly 2 months for second-line 
monochemotherapy as compared with BSC, with a significant reduction in the risk of 
death by 37% (HR=0.63, p<0.0001). This benefit was conferred by both irinotecan and 
docetaxel and was of similar magnitude through patients of different ethnic origin[21]. Of 
note, when we consider these results we have to remind that the docetaxel benefit is 
limited to a 3-week schedule at a higher dose, while the weekly lower dose regimen did 
not seem to yield a similar advantage[15]. 
 
On the contrary, a weekly paclitaxel regimen provided an OS comparable to that 
achieved with irinotecan in 219 patients refractory to standard first-line treatment (9.5 vs 
8.4 months, HR=1.13, p=0.38)[14]. 
 


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Combination chemotherapy versus monochemotherapy 
 
Unlike the first-line setting, combination chemotherapy failed to demonstrate a survival 
benefit over single.-agent in pretreated AGC. In a small Korean phase II trial, irinotecan 
monotherapy was as effective as FOLFIRI in terms of ORR (17.2% vs 20%, p=0.525), 
PFS (2.2 vs 3.0 months, p=0.481) and OS (5.8 vs 6.7 months, p=0.514); grade 3–4 
toxicity was also superimposable between treatment arms[13]. In another Japanese 
phase III study comparing biweekly irinotecan (60 mg/m²) plus cisplatin (30 mg/m²) to 
biweekly irinotecan alone (150 mg/m²) in 130 patients refractory to S1-based first-line 
chemotherapy, PFS was significantly prolonged in the combination arm (3.8 vs 2.8 
months, HR 0.68, p=0.0398) but OS did not[22]. A meta-analysis of 10 randomised trials 
confirmed that doublet chemotherapy does not significantly improve OS compared with 
single agent, while resulting in more grade 3–4 myelosuppression, diarrhoea and fatigue, 
suggesting monochemotherapy as standard of care in this setting[23]. 
 
Ramucirumab: single agent and combinatorial approach 
 
In spite of negative results coming from first-line trials, the therapeutic exploitation of 
angiogenesis turned out to be effective in second line. Ramucirumab, a fully human 
immunoglobulin IgG1 monoclonal antibody targeting VEGFR-2, has been shown to 
significantly improve survival in two pivotal international phase III double-blind, placebo-
controlled trials. In the REGARD trial, 355 patients whose disease progressed within 
4 months of fluoropyrimidine or platinum-containing first-line chemotherapy or within 
6 months of completion of adjuvant therapy, and with an ECOG PS of 0–1, were 
randomised in a 2:1 ratio to either ramucirumab 8 mg/kg or placebo, intravenously every 
2 weeks.16 Patients receiving ramucirumab had an improvement in both OS (5.2 vs 3.8 
months, HR=0.776, p=0.047) and PFS (2.1 vs 1.3 months, HR=0.48, p<0.0001), with a 
reduction in the risk of death by 22% compared with placebo[16]. Also, the disease 
control rate was significantly higher in the experimental arm (49% vs 23%), although 
objective responses were infrequent with ramucirumab. The survival benefit remained 
significant after adjusting for main prognostic variables such as PS, tumour location and 
peritoneal disease. The efficacy of ramucirumab alone was comparable to that reported 
in phase III trials of second-line chemotherapy, with a more favourable toxicity profile. 
 
Similarly, in the RAINBOW trial, which is the largest second-line trial in GC, the addition 
of ramucirumab to weekly paclitaxel significantly prolonged either median OS (9.6 vs 7.4 
months, HR=0.807, p=0.017) or PFS (4.4 vs 2.9 months, HR=0.635, p<0.0001) when 
compared with paclitaxel monotherapy in 665 patients[17]. A decrease in the risk of death 
by 19% was seen and a significantly greater proportion of patients attained an objective 
response in the combination group than in the single-agent group (28% vs 16%, 
p=0.0001). These results are noteworthy especially in the light of poor risk feature of 
patients enrolled as demonstrated by the rate of peritoneal metastases higher than 40% 
in both the experimental and control arms. In a preplanned subgroup analysis, Asian 
patients derived less survival benefit than non-Asian. A dilution effect by poststudy 
discontinuation treatment as well as difference in pharmacokinetics has been advocated 
to explain this discrepant outcome. Interestingly, the survival benefit was achieved while 
maintaining patient quality of life, delaying symptom worsening and functional status 
deterioration[24]. The toxicity of ramucirumab was tolerable and, as expected, higher in 
the combination regimen. In the single-agent trial the most common AE was an increased 
risk of grade 3 or higher hypertension (8% vs 3%), while when combined with paclitaxel, 
ramucirumab resulted in significantly increased rates of grade 3–4 neutropenia (40.7% vs 
18.8%), though this did not translate into higher incidence of febrile neutropenia. 
Antiangiogenic class side effects such as proteinuria, bleeding and gastrointestinal 


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perforations were mainly infrequent, mild in grade and more commonly noted in the 
combination arm. 
 
Thirdline and later lines of therapy 
 
Until recently, no randomized trials with cytotoxics were available to show a survival 
benefit in 3L+ patients with mGAC. The TAGS trial was a global phase 3 study of adult 
patients with mGC who had received ≥ 2 prior regimens of chemotherapy. Patients were 
randomized 2:1 to receive FTD/TPI (35 mg/m2 BID on days 1–5 and 8–12 of each 28-
day cycle) or placebo, plus best supportive care. Median overall survival was 5·7 months 
(95% CI 4·8-6·2) in the trifluridine/tipiracil group and 3·6 months (3·1 -4·1) in the placebo 
group (hazard ratio 0·69 [95% CI 0·56-0·85]; one-sided p=0·00029, two-sided 
p=0·00058)[25]. 
ATTRACTION-2 was a randomized, double-blind, placebo-controlled, phase 3 trial done 
at 49 clinical sites in Japan, South Korea, and Taiwan in 493 patients with 2+ lines of 
prior treatment who were randomized to nivolumab or placebo[26]. The study met it’s 
primary endpoint of overall survival (HR 0.63, p<0.0001).  
KEYNOTE-059 was a global, open-label, single-arm, multicohort study in patients with 2+ 
lines of prior treatment[27]. Treatment consisted of pembrolizumab 200mg every 3 
weeks. ORR was the primary endpoint and ranged from 6.4% (PD-L1 negative 
population) to 15.5% (PD-L1 positive population). Median response duration was 
reported as 16.3 months in patients with PD-L1 positive tumors. 
  
 
Therefore, the medical unmet need in 2L+ mGAC patients are more efficacious options 
for patients who have significant peripheral neuropathy from 1L platinum based 
chemotherapy and thus are not candidates for a taxane based regimen in 2L. Similarly, 
patients who progress on 2L taxane based regimens have few standard options. 
1.2 
Study Agent(s) Background and Associated Known Toxicities 
TAS-102 is an orally available combination drug of an antineoplastic thymidine-based 
nucleoside analogue, 1M FTD, and 0.5 M TPI. TPI inhibits degradation of FTD by TPase. 
Following uptake into cells through nucleoside transporters, FTD is converted to its 
monophosphate F3dTMP by thymidine kinase. After further phosphorylation steps, its 
triphosphate F3dTTP is incorporated into DNA as substitute for thymidine triphosphate 
(Figure 1)[28]. 
 


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Figure 1 Mechanism of Antitumor Activity of TAS-102 
 
 
Optimal Regimen of TAS-102 
 
Comparison of antitumor effect between daily and intermittent administration (Study 
No. M96-029) 
 
TAS-102 was administered daily, intermittently, or weekly to mice implanted with 
human colorectal carcinoma cell line. TAS-102 was more effective, and without 
severe toxicity, with daily administration than with intermittent or once weekly 
administration. These data suggest that daily administration is the appropriate 
administration schedule of TAS-102. 
 
Comparison of antitumor effect between once daily and divided daily dose 
administration (Study No. 03-04-004) 
 
TAS-102 was administered once, twice, or three times a day for 2 weeks to mice 
implanted with human breast cancer cell line. TAS-102 exhibited an antitumor effect 
with administration at twice daily and three times daily, but not with once daily (single) 
administration. Moreover, the amount of FTD incorporation into tumor DNA was 
enhanced by divided dosing of TAS-102[29]. Based on these results, divided daily 
dosing is the appropriate schedule for TAS-102 administration orally. 
 
 
Antitumor Profiles of TAS-102 
 
Antitumor effect of TAS-102 against tumors insensitive to 5-FU-based anti-cancer 
agents (Study No. 03-04-005) 
 
An experiment with human gastric carcinoma xenograft mice was performed to 
confirm the efficacy of TAS-102 against tumors insensitive to 5-FU. TAS-102 150 
mg/kg/day (TID), S-1 8.3 mg/kg/day, or capecitabine 539 mg/kg/day were 


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administered for 14 days. Only the TAS-102 treatment group showed significant 
antitumor activity without any body weight loss. These results suggest that TAS-102 
is significantly effective against tumors insensitive to 5-FU. 
 
Antitumor effects of TAS-102 against 5-FU resistant human cancer xenografts 
compared with those of 5-FU or UFT (Experiment Nos. M95-058, 059, 061, 062, 065, 
and 066) 
 
The antitumor effects of TAS-102 against 5-FU resistant human cancer cell sublines 
were evaluated in nude mice xenografts and compared with those of intravenous 5-
FU, continuous infusion of 5-FU, and oral UFT (tegafur-uracil) therapies at 
toxicologically similar doses, at which each modality gave a similar body weight 
decrease to the mice. TAS-102 and UFT were administered orally once daily for 14 
days. 5-FU was administered using i.v. injections (15 mg/kg/day) or via a mini-
osmotic pump (20 mg/kg/day) in mice for 14 days. TAS-102 was significantly more 
effective against human cancer cell sublines with acquired-resistance to 5-FU than 
both 5-FU and UFT. 
 
Antitumor effect of TAS-102 against human colorectal carcinoma with low sensitivity 
to bevacizumab and cetuximab (Study No. M01-2007-0015) 
 
The antitumor effect of TAS-102 against human colorectal carcinoma xenograft was 
evaluated in nude mice and compared with those of bevacizumab and cetuximab. 
TAS-102 was administeredtwice daily for 14 days and bevacizumab and cetuximab 
were administered twice weekly for 2 weeks. TAS-102 was significantly effective 
against tumor that showed low sensitivity to bevacizumab and cetuximab. 
 
Antitumor effect of TAS-102 against small-cell lung carcinoma (Study Nos. 03-10-
005, M01-2008-0016, and 10-09-087) 
 
The antitumor effect of TAS-102 was evaluated in mice implanted with human small-
cell lung carcinoma xenograft, and compared with the antitumor efficacy of cisplatin 
(CDDP) and S-1. In the Lu-24 xenograft model, 75 mg/kg/day TAS-102 exhibited 
antitumor efficacy similar to that of CDDP. The antitumor efficacy of TAS-102 in 
doses greater than 150 mg/kg/day was superior to that of CDDP. In the Lu-134 
xenograft model, S-1 and CDDP showed antitumor efficacy but could not arrest 
tumor growth. TAS-102 exhibited high antitumor efficacy and suppressed tumor 
growth even after termination of drug administration. These results suggest that TAS-
102 might be effective against small-cell lung carcinoma. 
 
Consecutive suppression of tumor regrowth after the end of TAS-102 administration 
(Study No. M01-2006-0027) 
 
Since it was shown that FTD remains in DNA after FTD removal (Study No. 03-02-
017), the FTD in DNA may continue to have antitumor efficacy after the end of 
administration. The extent of tumor regrowth after TAS-102 administration was 
compared with that after other antitumor drugs. Mice implanted subcutaneously with 
human colorectal carcinoma were given TAS-102, 5-FU, Taxol, CDDP or CPT-11. 
TAS-102 exhibited continued suppression of tumor regrowth even after the end of its 
administration. 
 
Prolongation of life span in tumor-bearing mice by administration of TAS-102 (Study 
No. M01-2008-0013) 
 


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TAS-102, CPT-11, and cetuximab were administered to mice implanted 
intraperitoneally with human colorectal carcinoma to estimate the effect of 
suppression of tumor regrowth by FTD on prolongation of life span. The survival 
period in the TAS-102 administration group was longer than that in the other drug 
administration groups. The observed survival benefit of TAS-102 is considered to 
result from FTD's characteristic of suppressing tumor growth. 
 
 
Combination Therapy 
 
Antitumor efficacy of two-week administration with two-week discontinuation and one-
week administration with one-week discontinuation of TAS-102 combined with CPT-
11 (Study No. 12TB02) 
 
The antitumor efficacy of TAS-102 and CPT-11 combination therapy was evaluated 
using a nude mouse subcutaneous transplantation model of human colorectal cancer 
and the toxic effects of the combination therapy were investigated. The results of the 
analysis demonstrated significantly enhanced antitumor efficacy in all of the 
combined administration groups. A maximum decrease in body weight of 
approximately 25% was observed in both combination therapy groups. Diarrhea was 
observed in 6 of 6 animals in the two-week TAS-102 and CPT-11 combination group, 
while no animals in the two-cycle one-week TAS-102 and CPT-11 combination 
administration group developed diarrhea. These results suggest that two-week TAS-
102 and CPT-11 combination therapy and two-cycle one-week TAS-102 and CPT-11 
combination therapy enhances the antitumor efficacy of TAS-102. The body weight 
loss observed after 1 week of TAS-102 administration was less than that observed 
after 2 weeks of TAS-102 administration. 
 
Induction of immunogenic cell death (ICD) in combination treatment of TAS-
102/oxaliplatin and anti-tumor efficacy of TAS-102 with oxaliplatin/anti-PD-1 antibody 
using murine colorectal carcinoma (Study No. PHA-95005-001) 
 
The immunogenic properties of the TAS-102 combined with oxaliplatin were 
assessed in murine microsatellite stable CT26 colon carcinoma. In vitro, TAS-102 in 
combination with oxaliplatin is able to induce expression of ICD markers including 
calreticulin (CRT) exposure, high-mobility group box 1 (HMGB1) and ATP release 
compared to control. CRT exposure and HMGB1 release were significantly increased 
as compared to oxaliplatin alone. Notably, in vivo, the triple combination TAS-
102/oxaliplatin/anti-PD-1 led to significantly increased survival of the mice as 
compared to TAS-102/oxaliplatin (p<0.0001) and TAS-102/anti-PD-1 (p<0.001). 
These results suggest that TAS-102 combined with oxaliplatin is an inducer of ICD. 
 
Effect of TAS-102 in combination with an immunotherapy drug for treatment of 
mouse colorectal cancer (CMT-93 cell line) (Study No. 15PB10) 
 
In mice, subcutaneously implanted with the mouse colorectal cancer cell strain CMT-
93, the TAS-102 150 mg/kg/day monotherapy group, anti-mouse PD-1 antibody 0.1 
mg/body monotherapy group, and the TAS-102 150 mg/kg/day + anti-mouse PD-1 
antibody 0.1 mg/body combination therapy group all showed significant anti-tumor 
effect compared with the control group. Moreover, the combination therapy group 
showed a significant anti-tumor effect compared with either of the monotherapy 
groups (Figure 2). In addition, the toxicity was in the permissible range in all groups. 
The above results suggested that the combination treatment of TAS-102 + anti-
mouse PD-1 antibody produced a stronger anti-tumor effect than the TAS-102 or 


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anti-mouse PD-1 antibody monotherapies. Moreover, as toxicity was in the 
permissible range, similar effects can be expected clinically. 
 
 
Figure 2: Effect of TAS-102 in combination with an immunotherapy drug for treatment 
of mouse colorectal cancer (CMT-93 cell line) (Study No. 15PB10) 
 
 
Secondary Pharmacology 
 
The inhibitory effects of FTD, FTY and TPI against a typical receptor panel were 
screened in Study No. AB31436. 
 
A total of 87 receptors, enzymes and channels were evaluated including: ATPase, 
cholinesterase, cyclooxygenase, monoamine oxidase, peptidase, 
phosphodiesterase, protein kinase, adenosine, adrenergic, androgen, angiotensin, 
bradykinin, calcium channel, cannabinoid, chemokine, cholecystokinin, dopamine, 
endothelin, estrogen, gamma-aminobutyric acid, glucocorticoid, glutamate, glycine, 
histamine, leukotriene, melanocortin, muscarinic, neuropeptide, nicotinic, opiate, 
platelet activating factor, potassium channel, peroxisome proliferator-activated 
receptor, progesterone, serotonin, sodium channel, tachykinin, transporters, 
vasopressin. 
 
No significant interaction between FTD, TPI, FTY and the receptors, enzymes and 
channels tested has been reported up to the tested concentration of 10μM, which is 
in excess of the free maximum concentration of FTD, FTY and TPI in human plasma 
upon dosing with TAS-102 according to the clinical dosing regimen. It can thus be 
anticipated that no secondary pharmacological effects will occur. 
 
 
Safety Pharmacology 
 
In the core battery of safety pharmacology studies of TAS-102, no effects on the 
central nervous system, respiratory system, or in vivo cardiovascular system were 
observed. FTD and TPI had no effects on hERG current in vitro (Table 1). 
 
Table 1 Summary of Safety Pharmacology Studies 


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 
Pharmacokinetics and Metabolism in Animals 
 
The pharmacokinetic profile of TAS-102 has been investigated in rats and monkeys. 
The absorption, distribution, metabolism, and excretion of FTD and TPI were studied 
after oral dosing of TAS-102 with [14C]-FTD or TAS-102 with [14C]-TPI at a dose of 
50 mg FTD/kg and 23.6 mg TPI/kg in rats. The absorption, metabolism, and excretion 
were also studied after oral dosing at a dose of 10 mg FTD/kg and 4.71 mg TPI/kg in 
monkeys. Toxicokinetics of TAS-102 were investigated at dose levels of 15 to 450 
mg/kg in rat and 1.25 to 20 mg/kg in monkey in multiple studies. 
 
 
Absorption 
 
 
Single-dose Studies 
 
The plasma concentrations of FTD, FTY, and TPI were increased with increasing 
dose after oral administration of TAS-102 to rats at 15 to 450 mg/kg/day of TAS-102 
(Study No. B-3687). 
 
The extent of absorption of FTD and TPI that was calculated from the sum of 
excretion ratios of the radioactivity in the urine and expired air after oral 
administration of TAS-102 with [14C]-FTD or TAS-102 with [14C]-TPI to non-fasting 
male rats was more than 76% and 15% for FTD and TPI, respectively (Study Nos. 
AE-2350-2G and AE-2350-3G). 
The plasma concentrations of FTD, FTY, and TPI were increased with increasing 
dose after oral administration of TAS-102 to monkeys at 1.5 to 20 mg/kg/day of TAS-
102 (Study No. B-6227). 
 
The extent of absorption of FTD and TPI that was estimated from the excretion ratios 
of the radioactivity in the urine after oral administration of TAS-102 with [14C]-FTD or 
TAS-102 with [14C]-TPI to fasting male monkeys was at least 79.4% and 27.3% for 
FTD and TPI, respectively (Study No. AE-6930-G). 
 
 
Repeat-dose Studies 
 
The Cmax and AUC0-24 of FTD, FTY, and TPI were generally similar after the first 
dose and after repeated oral administration of TAS-102 to rats at doses of 15 to 450 
mg/kg/day daily for 2 weeks (Study No. B-3687). 
 


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No effect of repeated administration and no sex differences were observed on the 
Cmax of FTD, FTY, and TPI after oral administration of TAS-102 to rats at 50 to 450 
mg/kg/day daily for 4 weeks (Study No. B-3906). 
 
There was no marked difference in Cmax and AUC0-24 of FTD, FTY, and TPI in 
plasma after the first administration and after repeated oral administration of TAS-102 
to male and female monkeys at doses of 1.25 to 20 mg/kg/day daily for 13 weeks 
(Study No. B-6227). 
 
 
Other Absorption Studies 
 
The absorption site of FTD and TPI in the rat digestive tract was investigated by an in 
situ loop method using TAS-102 with [14C]-FTD or TAS-102 with [14C]-TPI. FTD was 
highly absorbed from the middle to distal portion of the small intestine, although its 
absorption was observed throughout the whole gastrointestinal tract. TPI was 
absorbed throughout the whole small intestine, but its absorption through stomach 
and colon was much lower than through other segments (Study No. 12DA13). 
 
 
Distribution 
 
 
In vitro Plasma Protein Binding 
 
The protein bindings of FTD at 0.5 to 50.0 μg/mL concentrations in rat, mouse, dog, 
monkey, and human plasma were in the range of 57.1% to 72.3%, 70.0% to 82.5%, 
37.8% to 45.4%, 87.8% to 91.5%, and 96.7% to 97.3%, respectively. Thus, species 
differences were observed on plasma protein binding of FTD. FTD bound mainly to 
human serum albumin. On the other hand, plasma protein bindings of TPI at 0.05 to 
5.0 μg/mL concentrations were below 8% in all species tested (Study Nos. AE-2350-
2G and AE-2350-3G). 
 
 
Tissue Distribution 
 
Whole body autoradiography was performed on 1 animal after oral administration of 
TAS-102 with [14C]-FTD to non-fasting male rats. At 30 min after dosing, the whole 
body autoradiogram showed that the levels of radioactivity in the kidney and stomach 
were higher than those in the other tissues. The levels of radioactivity in the heart, 
liver, lung, adrenal gland, pancreas, mandibular gland, bone marrow, pineal body, 
and spleen were low and comparable to that in the blood. The other tissues showed 
lower levels than blood. At 72 hr after administration, a trace level of radioactivity was 
found only in the thymus (Study No. AE-2350-3G). 
 
Whole body autoradiography was performed on 1 animal after oral administration of 
TAS-102 with [14C]-TPI to non-fasting male rats. At 1 hr after dosing, the whole body 
autoradiogram showed that the levels of radioactivity in the intestine and kidney were 
higher than those in the other tissues. The levels of radioactivity in the pancreas, 
liver, fat, stomach, and lung were low and comparable to that in the blood. The other 
tissues showed lower levels than blood. At 72 hr after administration, a trace level of 
radioactivity was found only in the intestinal contents (Study No. AE-2350-2G). 
 
Tissue distribution and elimination of radioactivity after oral administration of TAS-102 
with [14C]-FTD or TAS-102 with [14C]-TPI to pigmented rats were similar to those in 
albino rats. Radioactivity did not remain in the melanin-containing tissues. 
 


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 
Blood/Plasma Concentration Ratio 
 
Blood/plasma concentration ratios (Rb) of FTD in rat, monkey, and human were in 
the range of 0.701 to 0.788, 0.628 to 0.678, and 0.596 to 0.619, respectively. 
Meanwhile Rb of TPI in rat, monkey, and human was in the range of 0.776 to 0.865, 
0.634 to 0.680, and 0.581 to 0.661, respectively. FTD and TPI mainly distributed to 
plasma in rat, monkey, and human. There was no marked species difference on Rb 
(Study No. 11DA34). 
 
 
Placental and Embryo-fetal Transfer 
 
Radioactivity transfer to all fetus tissues was observed after administration of TAS-
102 with [14C]-FTD or TAS-102 with [14C]-TPI to pregnant rats. FTD, TPI and/or 
their metabolites transfer to the fetus across placenta (Study No. AE-6932-G). 
 
 
Excretion into Milk 
 
Radioactivity excretion into milk was observed after administration of TAS-102 with 
[14C]-FTD or TAS-102 with [14C]-TPI to nursing rats. Therefore, FTD, TPI and/or 
their metabolites are excreted into milk (Study No. AE-6933-G). 
 
 
Metabolism 
 
 
In vivo Metabolism 
 
FTY and an unknown metabolite, HFP1, were identified in rat plasma after oral 
administration of TAS-102 with [14C]-FTD. The structure of HFP1 was not identified. 
The major metabolite for FTD was FTY (Study No. AE-2350-3G). 
 
FTD and the metabolites, FTY, α-trifluoromethylureidopropionic acid (F3MUPA), and 
FTD glucuronides, were detected in monkey plasma collected at 1 hour after oral 
administration of TAS-102 with [14C]-FTD at a dose of 10 mg/kg to monkeys (Study 
No. AE-6930-G). Another metabolite, α-trifluoromethyl-β-alanine (F3MBA) was 
detected 6 hours and 12 hours after the administration. FTD, FTY, F3MUPA and FTD 
glucuronides were detected in monkey urine collected by 6 hours after administration. 
 
Only one metabolite of TPI, 6-hydroxymethyluracil (6-HMU), was identified in rat 
plasma after administration of TAS-102 with [14C]-TPI (Study Nos. AE-2350-2G and 
AE-4140). 
 
TPI and an unknown metabolite, T-Peak5, were detected in monkey plasma at 2 
hours after administration of TAS-102 with [14C]-TPI at 10 mg/kg (Study No. AE-
6930-G). Another metabolite, T-Peak3, was detected by 12 hours after the 
administration. TPI, T-Peak4, and imino-oxidated TPI were detected in monkey urine 
collected by 6 hours after the administration. Other metabolites included T-Peak2 and 
uracil. In addition, 6-HMU was also detected. The structures of T-Peak1, T-Peak2, T-
Peak3, T-Peak4, and T-Peak5 could not be identified. 
 
FTD was predominantly metabolized to FTY, and further transformed to ring-opening 
metabolites. FTD glucuronides were also detected in monkeys. TPI was largely non-
metabolized, with a number of minor biotransformation products observed. All 
metabolites of FTD or TPI observed in human clinical samples were also present in 
animal species. 


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 
In vitro Metabolism 
 
TPI is a specific inhibitor of TPase, which was shown to almost completely inhibit the 
metabolism of FTD in tissue crude extracts from human breast cancer and colon 
cancer.9 The mode of inhibition of human TPase by TPI is competitive inhibition, and 
the Ki is 0.017 μmol/L. 
 
Fukushima et al. reported the impact of TPI on the conversion from FTD to FTY using 
crude extracts from various animal tissues[30]. This report suggests a species-
specific inhibition of the conversion of FTD to FTY in the small intestines of human 
and monkey. The inhibitory effect of TPI on the metabolism of FTD in monkey was 
similar to that in human[30]. 
 
 
Elimination and Excretion 
 
 
Elimination 
 
In non-fasting male rat plasma, amount (%) of FTD, FTY, and HFP1 at 1 hr after 
administration of TAS-102 with [14C]-FTD was 9.9%, 81.9%, and 3.7%, respectively. 
In rat urine at 0-24 hr, the excretion of FTD, FTY, and HFP1 was 13.8%, 36.8%, and 
6.9% of the dose, respectively. Urinary excretion of FTD (13.8%) accounted for a 
minor portion of absorbed FTD (at least 76%, which was the sum of total radioactivity 
excreted into urine and expired air). Therefore, the main elimination route of FTD was 
metabolism (Study No. AE-2350-3G). 
 
In non-fasting male rat plasma, the amount (%) of TPI and 6-HMU at 2 hr after 
administration of TAS-102 with [14C]-TPI was 75.5% and 15.8%, respectively. In rat 
urine (0-24 hr), the excretion of TPI and 6-HMU was 9.9% and 3.3% of the dose, 
respectively. Urinary excretion of TPI (9.9%) accounted for a major portion of 
absorbed TPI (at least 15%, which was the sum of total radioactivity excreted into 
urine and expired air). Therefore, the main elimination route of TPI was excretion into 
urine (Study No. AE-2350-2G). 
 
In male monkey plasma, the amount (%) of FTD and its metabolites (FTY, F3MUPA, 
and FTD glucuronides [F-Peak 3a and F-Peak 3b]) at 1 hr after administration of 
TAS-102 with [14C]-FTD at 10 mg/kg were as follows: FTD, 56.2%; FTY, 26.1%; 
F3MUPA, 1.4%; and FTD glucuronides, 5.3%. These data show that FTY was the 
primary metabolite (Study No. AE-6930-G). Another metabolite, F3MBA, was 
detected 6 hrs and 12 hrs after the administration at 1.6% and 0.8%, respectively. In 
male monkey urine collected for 6 hr after the administration, the amount (%) of FTD, 
FTY, F3MUPA and FTD glucuronides were as follows: FTD, 41.4%; FTY, 43.0%; 
F3MUPA, 2.8%; and FTD glucuronides, 2.5%. These data indicate that FTY is the 
major metabolite found in urine. 
 
In male monkey plasma, the amounts (%) of TPI and an unknown metabolite, T-
Peak5, at 2 hrs after administration of TAS-102 with [14C]-TPI at 10 mg/kg were 
67.9% and 3.8%, respectively (Study No. AE-6930-G). In male monkey urine 
collected for 6 hrs after administration, the amounts (%) of TPI, T-Peak4, and imino-
oxidated TPI were 85.7%, 1.0%, and 1.1%, respectively. These results suggest that 
TPI is the primary component in plasma and urine. 
 
 
Excretion 
 


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After oral administration of TAS-102 with [14C]-FTD to non-fasting male rats, the 
excretion of radioactivity in the urine, feces, and expired air was 60.6%, 20.6%, and 
15.8% of the dose, respectively, up to 168 hr (total excretion 96.9%). After oral 
administration of TAS-102 with [14C]-FTD, the excretion of radioactivity in the bile 
was 0.4% of the dose up to 48 hr after dosing. Therefore, absorbed FTD and its 
metabolites were mainly excreted into urine (Study No. AE-2350-3G). 
 
After oral administration of TAS-102 with [14C]-TPI to non-fasting male rats, the 
excretion of radioactivity in the urine, feces, and expired air was 14.3%, 83.4%, and 
0.4% of the dose, respectively, up to 168 hr (total excretion 98.0%). After oral 
administration ofTAS-102 with [14C]-TPI, the excretion of radioactivity in the bile was 
0.2% of the dose up to 48 hr after dosing. Therefore, absorbed TPI and its 
metabolites were mainly excreted into urine (Study No. AE-2350-2G). 
 
After oral administration of TAS-102 with [14C]-FTD to fasting male monkeys, the 
excretion of radioactivity in the urine and feces was 79.4% and 3.8% of the dose, 
respectively, up to 168 hr (Study No. AE-6930-G). 
 
After oral administration of TAS-102 with [14C]-TPI to fasting male monkeys, the 
excretion of radioactivity in the urine and feces was 27.3% and 68.1% of the dose, 
respectively, up to 168 hr (Study No. AE-6930-G). 
 
 
Toxicology 
 
 
Single-dose Toxicity 
 
The single-dose (acute) oral toxicity of TAS-102 was investigated in the rat and dog. 
Dose levels (FTD equivalent) were 250, 500, 1000 and 2000 mg/kg. 
 
In the rat study, diarrhea was observed on the day of administration in the 250 mg/kg 
and above groups, but it recovered on the following day. Body weights in the 1000 
mg/kg group were lower than those in the control group on the day after 
administration, but thereafter, the values were similar to those in the control group. In 
the 2000 mg/kg group, 1/5 male and 4/5 females died on the day after administration 
or 2 days after administration. In this group, necrosis of glandular epithelial cells in 
the glandular stomach and intestines, erosion in the glandular stomach, deposition of 
basophilic material in the lamina propria mucosae in the glandular stomach, and 
necrosis of lymphocytes in the small intestine were observed (Study No. B-3685). 
 
In the dog study, animals at all dose levels demonstrated varying degrees of emesis 
for mainly up to 4 hr post dose. The severity of emesis was dose-related. Soft or 
liquid feces were observed in animals at all dose levels. Body weight loss and 
decreased food consumption were observed primarily during the first treatment week 
in the 500 mg/kg and above groups. In animals treated at 250 mg/kg, decreased food 
consumption was also noted during the first 2 to 3 days after treatment, but the effect 
was less pronounced than in other groups. One male dog treated at 2000 mg/kg was 
sacrificed moribund 7 days after treatment. In the moribund animal, vomitus, soft 
feces, reduced appetite, lung lesions, dark areas in the colon/ileum, and thickening of 
the wall in the duodenum/jejunum were observed (Study No. 87931). 
 
The lethal dose was 2000 mg/kg in both species. The main target organ of single 
dose toxicity seemed to be the digestive tract in rats and dogs. 
 
 
Repeat-dose Toxicity 


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 
Rat Studies 
 
TAS-102 was administered orally to rats at dose levels (FTD equivalent) of 15, 50, 
150 and 450 mg/kg/day in a 2-week study; 50, 150 and 450 mg/kg/day in a 4-week 
study; and 5, 15, 50 and 150 mg/kg/day in a 13-week study; and 10, 30, 100 and 280 
mg/kg/day in a 26-week study. 
 
In the 2-week study, no treatment-related changes were observed at the dose levels 
of 15 and 50 mg/kg/day and there were no mortalities in any dose group. In the 150 
mg/kg/day and above groups, necrosis of the glandular epithelial cells in the small 
intestine, and follicular atrophy of the mesenteric and submandibular lymph nodes 
were observed. Furthermore, in the 450 mg/kg/day group, decreased body weight 
gains and food consumption, decreased leukocyte counts and reticulocyte ratio, 
decreased spleen and thymus weights, and atrophy of the thymus were observed. 
The main target organs seemed to be the lymphatic-hematopoietic system and 
digestive tract (Study No. B-3687). 
 
In the 4-week study, no treatment-related changes were observed in the 50 
mg/kg/day group. In the 150 mg/kg/day and above groups, decreased body weight 
gains and food consumption, increased drug-induced crystal in the urine sediment, 
erosion of the glandular stomach, necrosis of glandular epithelial cells in the intestine, 
increased extramedullary hematopoiesis of the spleen, increased ovary weights, and 
increased small corpus luteum were observed. Furthermore, in the 450 mg/kg/day 
group, decreases in osmotic pressure and excretion of sodium, potassium, and 
chloride in the urine were observed; hematological changes included decreases in 
leukocyte and erythrocyte counts, reticulocyte ratio, hemoglobin, hematocrit and 
fibrinogen, and increases in mean corpuscular volume (MCV) and mean corpuscular 
hemoglobin (MCH); blood chemistry changes included decreases in total protein and 
γ-globulin, and increases in total cholesterol and total bilirubin; pathological changes 
included atrophy in the thymus, spleen and lymph nodes, and hypoplasia in the bone 
marrow. After a 4-week recovery period, various changes relating to the 
undernourished state were observed and considered to be caused by poor intake of 
food due to fractured incisors and malocclusion, and one male dosed at 450 
mg/kg/day eventually died. However, abnormalities of the incisors, such as 
degeneration or disarrangement in the ameloblasts/papillary cells/odontoblasts, 
would be expected to only occur in the rodents with continuously growing teeth but 
not in humans. The main target organs appeared to be the lymphatic-hematopoietic 
system and digestive tract (Study No. B-3906). 
 
In the 13-week study, no treatment-related changes were observed in the 5 and 15 
mg/kg/day groups and no mortalities were observed in any dose group. In the 50 
mg/kg/day and above groups, decreased leucocyte counts and increased MCH, 
increased apoptotic bodies in the glandular epithelial cells of the small intestine and 
fatty infiltration in the bone marrow were observed. Furthermore, in the 150 
mg/kg/day group, decreased erythrocyte counts, increased MCV and atrophy in the 
thymus were observed. Abnormalities of the incisors, such as disarrangement of the 
odontoblasts, were observed in the 50 mg/kg/day and above groups. After a 9-week 
recovery period, TAS-102 induced changes were considered reversible. The main 
target organs appeared to be the lymphatic-hematopoietic system and digestive tract 
(Study No. 07CA07). 
 
In the 26-week study, no toxic changes were observed in the 10 and 30 mg/kg/day 
groups and no mortalities were observed in the 100 mg/kg/day and less groups. In 


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the 280 mg/kg/day group (2-week cycle of 5 days of treatment followed by a 2-day 
rest period, and then a 14-day rest period), treatment-related deaths or moribundity 
occurred in 3 males and 3 females of 26 animals /sex/group including the satellite 
animals between Days 90 and 176. Dose-related changes were observed mainly in 
the hematopoietic-lymphatic system, small intestine and incisors in the 100 and 280 
mg/kg/day groups. Increased ovary weights were observed in all female dose groups; 
however, they were not accompanied by related histopathological findings. After a 9-
week recovery period, TAS-102 induced changes were considered reversible. The 
main target organs appeared to be the lymphatic-hematopoietic system and small 
intestine (Study No. B-8020). 
 
 
Monkey Studies 
 
TAS-102 was administered orally to monkeys at dose levels (FTD equivalent) of 1.9, 
7.5, 30 and 120 mg/kg/day in a 2-week study; 6.25, 25 and 100 mg/kg/day in a 4-
week study; and 1.25, 5 and 20 mg/kg/day in a 13-week study. 
 
In the 2-week study, no treatment-related changes were observed in males at dose 
levels of 1.9 mg/kg/day. Decreased leukocyte counts were observed in all TAS-102 
groups excluding the males administered 1.9 mg/kg/day. In the 30 mg/kg/day and 
above groups, soft/liquid feces, salivation, typhlitis, colitis, cryptal necrosis in the 
colon and cecum, and lymphoid atrophy in the spleen were observed. Furthermore, 
in the 120 mg/kg/day group, emesis, watery contents in the large intestine, villous 
atrophy in the small intestine, lymphoid atrophy in the lymph nodes, and bone 
marrow hypocellularity were observed. One male monkey dosed at 120 mg/kg/day 
was euthanized on Day 8 due to deteriorating condition. The main target organs 
appeared to be the lymphatic-hematopoietic system and digestive tract (Study No. 
87936). 
 
In the 4-week study, no treatment-related changes were observed in the 6.25 
mg/kg/day group and no mortalities were observed in any dose group. In the 25 
mg/kg/day and above groups, soft/liquid feces, dehydration, decreases in leukocyte 
counts, erythrocyte counts, hemoglobin and hematocrit, small thymus, 
raised/discoloration/dark areas in the cecum, lymphoid atrophy, and inflammation in 
the digestive tract were observed. Furthermore, in the 100 mg/kg/day group, emesis, 
decreased body weight and food consumption, increased platelet counts and mean 
corpuscular hemoglobin concentration (MCHC), decreased thymus weight, bone 
marrow hypocellularity, decreased myeloid/erythroid (M/E) ratio due to increased 
erythroid series, and abnormal nuclear maturation of bone marrow cells were 
observed. In addition, increases in blood urea nitrogen, creatinine and alanine 
aminotransferase (ALT) were observed as well as increases in excretion of 
creatinine, potassium and chloride in the urine. After a 4-week recovery period, TAS-
102 induced changes were considered reversible. The main target organs appeared 
to be the lymphatic-hematopoietic system and digestive tract (Study No. 87941). 
 
In the 13-week study, no treatment-related changes were observed in the 1.25 
mg/kg/day TAS-102 group. In the 5 mg/kg/day and above groups, decreases in body 
weight, food consumption, leukocyte counts and erythrocyte counts, and an increase 
in fibrinogen were observed. Furthermore, in the 20 mg/kg/day group, soft/liquid 
feces, decreased hemoglobin and hematocrit, inflammation in the rectum and atrophy 
in the spleen were observed. One female monkey dosed at 20 mg/kg/day was 
euthanized on Day 85 due to being moribund; this monkey showed remarkable 
changes in hematology, blood chemistry and histopathology which reflected the 
damage in the lymphatic-hematopoietic system and digestive tract as described 


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above. After a 9-week recovery period, TAS-102 induced changes were considered 
reversible. The main target organs appeared to be the lymphatic-hematopoietic 
system and digestive tract (Study No. B-6227). 
 
 
Dog Study 
 
TAS-102 was administered orally to dogs at dose levels (FTD equivalent) of 17, 50 
and 150 mg/kg/day in a 2-week study. 
All TAS-102 groups showed emesis, soft/liquid/reduced feces, decreased body 
weight and food consumption, decreased leukocyte counts, glandular/cryptal 
necrosis in the digestive tract, bone marrow hypocellularity, and lymphoid atrophy in 
the thymus, lymph nodes, spleen and intestine. These changes were more severe 
and occurred earlier in the higher-dose group. In the 50 mg/kg/day and above 
groups, decreased locomotor activity, weakness, tremors, hypothermia and blood 
chemical abnormalities were observed; all animals in these groups died or were 
euthanized on Day 5 to Day 8 due to being moribund. The main target organs 
appeared to be the lymphatic-hematopoietic system and digestive tract (Study No. 
87935). 
 
 
Genotoxicity 
 
A series of studies were performed to investigate the genotoxicity of TAS-102. 
TAS-102 was found to be mutagenic when tested in the in vitro reverse mutation 
assay using Salmonella typhimurium (TA100, TA1535, TA98 and TA1537) and 
Escherichia coli (WP2uvrA). In TA100, TA1535 and WP2uvrA, the number of 
revertant colonies induced by TAS-102 exceeded twice the number in solvent control 
(physiological saline), or there were dose-dependent increases in the number of 
revertant colonies with and without S9 mix. In TA98 and TA1537, however, the 
number of revertant colonies was not twice or more than in the vehicle control group 
with and without S9 mix, and there was no dose-dependent increase in the number 
of revertant colonies. These results indicate that TAS-102 induces base pair 
substitution type mutation (Study No. 00CA11). 
 
The in vitro potency for chromosomal aberration was investigated using Chinese 
hamster lung cells. Significant increases in the incidence of cells having structural 
chromosomal aberrations were observed in the TAS-102 treatment groups under 
conditions with and without S9 mix. No significant increases in the incidence of cells 
having numerical chromosomal aberrations were observed in any TAS-102 treatment 
groups under any treatment condition. These results indicate that TAS-102 is 
clastogenic (Study No. 00CA12). 
 
The micronucleus test was performed using bone marrow cells in mice. Significant 
increases in the frequency of micronucleated polychromatic erythrocyte (MNPCE) 
were observed in all TAS-102 groups. These results indicate that TAS-102 has in 
vivo inducing clastogenicity potency (Study No. 01CA15). 
 
 
Reproductive and Developmental Toxicity 
 
TAS-102 was tested in male and female fertility studies and in an embryo-fetal 
development study in rats. Dose levels (FTD equivalent) were 50, 150 and 450 
mg/kg/day in the male fertility study and 15, 50 and 150 mg/kg/day in the female 
fertility study and embryo-fetal development study. 
 


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In the male fertility study (Study No. R-908), male parental animals exhibited 
suppressed body weight gain and decreased food consumption in the 150 mg/kg/day 
and above groups and dark red spots in the glandular stomach in the 450 mg/kg/day 
group. No effects on fertility and early embryonic development were noted with 
respect to day until copulation, copulation index, conception rate, number of corpora 
lutea, number of implantation, implantation index, number of live embryos or viability 
index of embryos in any group. 
 
In the female fertility study (Study No. R-904), female parental animals exhibited 
suppressed body weight gain in the 50 mg/kg/day and above groups and decreased 
food consumption in the 150 mg/kg/day group. As for effects on fertility, increased 
numbers of corpora lutea and implantation were noted in the 150 mg/kg/day group. 
As for effects on embryonic development after implantation, decreased viability index 
of embryos was noted in the 150 mg/kg/day group. 
 
In the embryo-fetal development study (Study No. 04CA18), female parental animals 
exhibited suppressed body weight gain in the 50 mg/kg/day and above groups and 
decreased food consumption in the 150 mg/kg/day group. One female in the 150 
mg/kg/day group aborted at Day 21 of gestation. As for effects on embryo-fetal 
development, decreased fetal weights and delayed ossification in fetus were noted in 
the 50 mg/kg/day and above groups. The 150 mg/kg/day group exhibited increases 
in the rate of post implantation loss and the rate of fetuses with anomalies of external 
(mainly, kinked tail), viscera (mainly, malpositioned subclavian branch, 
retroesophageal subclavian and left umbilical artery), and skeleton (main sites with 
anomalies: vertebrae from cervix to tail, sternebrae and ribs). 
 
 
Other Toxicity Studies 
 
 
Phototoxicity Tests 
 
Two in vitro phototoxicity tests of FTD and TPI were conducted using Balb/3T3 clone 
A31 cells derived from mouse embryo. FTD and TPI did not induce phototoxic 
response in Balb/3T3 clone A31 cells in these tests (Study Nos. B110945 and 
B110946). 
 
 
Combination Toxicity Study of TAS-102 and CPT-11 in Rats 
 
A combination toxicity study of TAS-102 and CPT-11 in rats was conducted to 
compare the toxicity between 1- and 2-week interval regimens of TAS-102 in 
combination with CPT-11. TAS-102 was administered once a day using either a 1-
week on/1-week off regimen or a 2-week on/2-week off regimen for four weeks. CPT-
11 was administered twice at an interval of two weeks. Dose levels (FTD equivalent) 
were 0, 150, 300 and 450 mg/kg of TAS-102, and 0 and 60 mg/kg of CPT-11 (Study 
No. 12CB12). 
 
Prone position, panting and loose stool were observed in male rats receiving 60 
mg/kg CPT-11. 
 
Just before the second CPT-11 administration, significant decreases relative to 
control in body weight, food consumption, leukocyte counts, neutrophil counts, 
monocyte counts, hemoglobin, hematocrit and reticulocyte counts were noted in the 
2-week on/2-week off regimen groups compared with 1-week on/1-week off regimen 
groups. Neutrophil counts recovered just before the second CPT-11 in the 1-week 
on/1 week off regimen groups. Maximum percent differences in the body weight, 


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leukocyte counts and lymphocyte counts tended to be more decreased in the 2-week 
combination regimen group than those in the 1-week combination regimen group. 
The other percent differences from the control were comparable between 1-week and 
2-week regimens. No differences in the reversibility of the combination toxicity were 
noted between 1-week and 2-week regimens. Based on these results, the 1-week 
on/1-week off TAS-102 regimen was considered to be more tolerable in combination 
with CPT-11 administration, with milder toxicities compared to the 2-week on/2-week 
off TAS-102 regimen. 


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 
CLINICAL STUDIES 
 
 
Phase 1 Pharmacokinetic Study of TAS-102 in Combination with CPT-11 and 
Bevacizumab (Study TPU-TAS-102-109) 
 
Study TPU-TAS-102-109 is an ongoing Phase 1, open-label, non-randomized, dose-
escalation study of TAS-102 administered in combination with irinotecan in western (US) 
patients with advanced gastrointestinal tumors who are refractory to at least one line of 
chemotherapy for metastatic disease and for whom no curative therapy exists. The study 
consists of a dose-escalation phase (Part 1) to determine the MTD of TAS-102 in 
combination with irinotecan. Subjects are assigned to sequential dose-levels of TAS-102 
in combination with irinotecan. TAS-102 (starting dose of 20 mg/m2/dose) is administered 
orally BID from Day 1 through Day 5 followed by a recovery period from Day 6 through 
Day 14. CPT-11 is co-administered as an IV infusion with TAS-102 on Day 1 of the 14-
day treatment cycle. Once the MTD for TAS-102 and irinotecan combination is 
established, patients will be enrolled in an expansion phase (Part 2) to further evaluate 
the safety, PK, and preliminary efficacy of the MTD. The protocol was subsequently 
amended to investigate the safety of TAS-102 and irinotecan at the MTD when 
administered in combination with bevacizumab (expansion phase of study). 
 
As of 24 July 2017, a total of 50 patients received study treatment (26 patients have 
received TAS-102 + CPT-11 and 24 patients have received TAS-102 + CPT-11 + 
bevacizumab); 24 SAE cases and have been reported for 17 patients. 
 
The MTD of TAS-102 was determined as 25mg/m2/dose in combination with CPT-11 at 
180mg/m2. The study enrolled 24 patients in expansion and further enrollment was 
discontinued as the study reached its objective of the following: 
 
1. Defining the MTD for the triple combination and 
2. Demonstrating the preliminary ORR in 24 patients with mCRC. 
 
When evaluating the ORR of the enrolled patients as well the data maturity, the 
Supporter and Principal Investigator determined that the enrolled patients number should 
suffice to evaluate the overall safety as well as efficacy of the triplet combination. 
 
 
Phase 3 Study in Gastric Cancer (Study TO-TAS-102-302) 
 
This was a multinational, double-blind, two-arm, parallel, randomized, Phase 3 study 
evaluating the efficacy and safety of TAS-102 (35 mg/m2/dose BID) plus best 
supportive care (BSC) versus placebo plus BSC in patients with metastatic gastric 
cancer who have previously received at least 2 prior regimens for advanced disease. 
Eligible patients were randomized (2:1) to receive TAS-102 + BSC (experimental 
arm) or placebo + BSC (control arm) and stratified by region (rest of world vs. Japan), 
ECOG performance status (0 vs. 1), and prior treatment with ramucirumab (yes vs. 
no). 
 
Between Feb 24, 2016, and Jan 5, 2018, 507 patients were enrolled and randomly 
assigned, 337 to the trifluridine/tipiracil group and 170 to the placebo group. Median 
overall survival was 5·7 months (95% CI 4·8–6·2) in the trifluridine/tipiracil group and 
3·6 months (3·1–4·1) in the placebo group (hazard ratio 0·69 [95% CI 0·56–0·85]; 
one-sided p=0·00029, two-sided p=0·00058). Grade 3 or worse adverse events of 
any cause occurred in 267 (80%) patients in the trifluridine/tipiracil group and 97 


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(58%) in the placebo group. The most frequent grade 3 or worse adverse events of 
any cause were neutropenia (n=114 [34%]) and anaemia (n=64 [19%]) in the 
trifluridine/tipiracil group and abdominal pain (n=15 [9%]) and general deterioration of 
physical health (n=15 [9%]) in the placebo group. Serious adverse events of any 
cause were reported in 143 (43%) patients in the trifluridine/tipiracil group and 70 
(42%) in the placebo group. One treatment-related death was reported in each group 
(because of cardiopulmonary arrest in the trifluridine/tipiracil group and because of 
toxic hepatitis in the placebo group). 
 
This Phase 3 study was initiated based on the results of an Investigator-initiated 
Phase 2 study of TAS-102 conducted in Japanese patients with metastatic gastric 
cancer who had failed standard chemotherapies including fluoropyrimidines, platinum 
and any of the taxanes or irinotecan (EPOC1201)[31]. Common Grade 3 or 4 AEs 
included neutropenia (69.0%), leukopenia (41.4%), anemia (20.7%) and anorexia 
(10.3%). Only 2 (6.9%) patients discontinued treatment due to adverse events. No 
treatment-related deaths were observed. The disease control rate was 65.5% (95% 
CI: 45.7, 82.1). Median PFS was 2.9 months and median OS was 8.7 months. 
 
 
Phase 1 Dose-finding Study of TAS-102 in Combination with Oxaliplatin (Study 
CL1-95005-001) 
 
This is an ongoing Phase 1, open-label, non-randomized, dose-escalation study of TAS-
102 administered in combination with oxaliplatin (and with bevacizumab or nivolumab in 
expansion part) in patients with metastatic colorectal cancer who are refractory to at least 
one line of chemotherapy for metastatic disease. The study consists of a dose-escalation 
phase (Part 1) to determine the MTD of TAS-102 in combination with oxaliplatin. TAS-
102 (starting dose of 25 mg/m²/dose) is administered orally BID from Day 1 through Day 
5 followed by a recovery period from Day 6 through Day 14. Oxaliplatin is co-
administered as an IV infusion with TAS-102 on Day 1 of the 14-day treatment cycle. 
Once established, the MTD will be confirmed in 6 additional patients to define the 
recommended dose (RD). Then patients will be enrolled in an expansion phase (Part 2) 
to further evaluate the safety, PK, and preliminary efficacy of TAS-102 in combination 
with oxaliplatin and either bevacizumab or nivolumab. The expansion part will be divided 
into 2 cohorts: i) a cohort of up to 35 evaluable patients will receive bevacizumab in 
addition to the combination of TAS-102 and oxaliplatin administered at the RD, ii) a 
cohort of up to 35 evaluable patients will receive nivolumab in addition to the combination 
of TAS-102 and oxaliplatin administered at the RD. The inclusion in one or another cohort 
will be done at the discretion of the investigator and patients will be recruited 
simultaneously. It will not be possible to cross over onto the other cohort. 
 
As of 24 July 2017, 15 patients have received TAS-102 plus oxaliplatin. No patients have 
received bevacizumab or nivolumab; 15 SAE cases have been reported. The dose 
escalation is still ongoing, and the MTD is not defined yet. 
 
 
Phase 2 Study of TAS-102 in Combination with Bevacizumab (Study CL2-
95005-002) 
 
 
This study is an open-label, randomised, non-comparative Phase 2 study evaluating 
TAS-102 (35 mg/m²/dose BID) plus bevacizumab and capecitabine plus bevacizumab in 
the first-line treatment of patients with unresectable metastatic colorectal cancer who are 
non-eligible for intensive therapy (TASCO1 study). Patients are randomly assigned (1:1) 
to TAS-102 plus bevacizumab or capecitabine plus bevacizumab and stratified by RAS 
status (wild-type, mutant type), ECOG performance status (0 vs. 1 vs. 2) and country. 


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Evaluation of efficacy includes PFS based on investigator assessment on radiologic 
images, ORR, duration of response (DR), DCR and OS. 
 
As of 24 July 2017, the enrollment is completed and a total of 153 patients have been 
enrolled (77 patients have received TAS-102 + bevacizumab and 76 patients have 
received capecitabine + bevacizumab); 181 SAEs have been reported for 76 patients. 
 
This Phase 2 study was initiated based on the results of an Investigator Initiated Phase 
I/II dose-finding study of TAS-102 in combination with bevacizumab for mCRC refractory 
to standard therapies (C-TASK FORCE) conducted in Japanese patients.212223 Twenty-
five patients were enrolled from February to July 2014. The recommended Phase II dose 
was determined to be TAS-102 35 mg/m2 BID on Days 1-5 and Days 8-12 in 
combination with bevacizumab 5 mg/kg on Days 1 and 15, every 4 weeks. The most 
common Grade ≥3 AEs were neutropenia (72%), leukopenia (44%), febrile neutropenia 
(16%), anaemia (16%), thrombocytopenia (12%), and hypertension (8%). The study met 
its primary endpoint: the centrally assessed PFS rate at 16 weeks was 42.9% (80% CI: 
27.8-59.0%). Median OS (at final cutoff date for analysis) was 11.4 months (IQR 7.4 – 
15.6). 
1.3 
Other Agents 
 
Irinotecan (CPT-11) [Camptosar®] 
 
 
Mechanism of Action 
 
 
Irinotecan is a derivative of camptothecin. Camptothecins interact specifically with the 
enzyme topoisomerase I, which relieves torsional strain in DNA by inducing 
reversible single-strand breaks. Irinotecan and its active metabolite SN-38 bind to the 
topoisomerase I-DNA complex and prevent religation of these single-strand breaks. 
Current research suggests that the cytotoxicity of irinotecan is due to double-strand 
DNA damage produced during DNA synthesis when replication enzymes interact with 
the ternary complex formed by topoisomerase I, DNA, and either irinotecan 
hydrochloride or SN-38. Mammalian cells cannot efficiently repair these double-
strand breaks. 
 
 
Pharmacodynamics 
 
Irinotecan serves as a water-soluble precursor of the lipophilic metabolite SN-38. SN-38 
is formed from irinotecan by carboxylesterase-mediated cleavage of the carbamate bond 
between the camptothecin moiety and the dipiperidino side chain. SN-38 is approximately 
1000 times as potent as irinotecan as an inhibitor of topoisomerase I purified from human 
and rodent tumor cell lines. In vitro cytotoxicity assays show that the potency of SN-38 
relative to irinotecan varies from 2- to 2000-fold; however, the plasma area under the 
concentration versus time curve (AUC) values for SN-38 are 2% to 8% of irinotecan and 
SN-38 is 95% bound to plasma proteins compared to approximately 50% bound to 
plasma proteins for irinotecan. The precise contribution of SN-38 to the activity of 
CAMPTOSAR is thus unknown. Both irinotecan and SN-38 exist in an active lactone form 
and an inactive hydroxy acid anion form. A pH-dependent equilibrium exists between the 
two forms such that an acid pH promotes the formation of the lactone, while a more basic 
pH favors the hydroxy acid anion form. 
 
Administration of irinotecan has resulted in antitumor activity in mice bearing cancers of 
rodent origin and in human carcinoma xenografts of various histological types. 
 
 
Pharmacokinetics 


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After intravenous infusion of irinotecan in humans, irinotecan plasma concentrations 
decline in a multiexponential manner, with a mean terminal elimination half-life of about 6 
to 12 hours. The mean terminal elimination half-life of the active metabolite SN-38 is 
about 10 to 20 hours. The half-lives of the lactone (active) forms of irinotecan and SN-38 
are similar to those of total irinotecan and SN-38, as the lactone and hydroxy acid forms 
are in equilibrium. 
 
Over the recommended dose range of 50 to 350 mg/m2, the AUC of irinotecan increases 
linearly with dose; the AUC of SN-38 increases less than proportionally with dose. 
Maximum concentrations of the active metabolite SN-38 are generally seen within 1 hour 
following the end of a 90-minute infusion of irinotecan. Pharmacokinetic parameters for 
irinotecan and SN-38 following a 90-minute infusion of irinotecan at dose levels of 125 
and 340 mg/m2 determined in two clinical studies in patients with solid tumors are 
summarized in Table 2: 
 
Table 2. Summary of Mean (±Standard Deviation) Irinotecan and SN-38 
Pharmacokinetic Parameters in Patients with Solid Tumors 
 
 
Cmax - Maximum plasma concentration 
AUC0–24 - Area under the plasma concentration-time curve from time 
0 to 24 hours after the end of the 90-minute infusion 
t1/2 - Terminal elimination half-life 
Vz - Volume of distribution of terminal elimination phase 
CL - Total systemic clearance 
* 
Plasma specimens collected for 24 hours following the end of the 90-minute infusion. 
† 
Plasma specimens collected for 48 hours following the end of the 90-minute infusion. 
Because of the longer collection period, these values provide a more accurate reflection 
of the terminal elimination half-lives of irinotecan and SN-38. 
 
 
Distribution 
 
Irinotecan exhibits moderate plasma protein binding (30% to 68% bound). SN-38 is highly 
bound to human plasma proteins (approximately 95% bound). The plasma protein to 
which irinotecan and SN-38 predominantly binds is albumin. 
 
 
Metabolism 
 
Irinotecan is subject to extensive metabolic conversion by various enzyme systems, 
including esterases to form the active metabolite SN-38, and UGT1A1 mediating 
glucuronidation of SN-38 to form the inactive glucuronide metabolite SN-38G. Irinotecan 
can also undergo CYP3A4-mediated oxidative metabolism to several inactive oxidation 
products, one of which can be hydrolyzed by carboxylesterase to release SN-38. In vitro 


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studies indicate that irinotecan, SN-38 and another metabolite aminopentane carboxylic 
acid (APC), do not inhibit cytochrome P-450 isozymes. UGT1A1 activity is reduced in 
individuals with genetic polymorphisms that lead to reduced enzyme activity such as the 
UGT1A1*28 polymorphism. Approximately 10% of the North American population is 
homozygous for the UGT1A1*28 allele (also referred to as UGT1A1 7/7 genotype). In a 
prospective study, in which irinotecan was administered as a single-agent (350 mg/m2) 
on a once-every-3-week schedule, patients with the UGT1A1 7/7 genotype had a higher 
exposure to SN-38 than patients with the wild-type UGT1A1 allele (UGT1A1 6/6 
genotype). SN-38 glucuronide had 1/50 to 1/100 the activity of SN-38 in cytotoxicity 
assays using two cell lines in vitro. 
 
 
Excretion 
 
The disposition of irinotecan has not been fully elucidated in humans. The urinary 
excretion of irinotecan is 11% to 20%; SN-38, <1%; and SN-38 glucuronide, 3%. The 
cumulative biliary and urinary excretion of irinotecan and its metabolites (SN-38 and SN-
38 glucuronide) over a period of 48 hours following administration of irinotecan in two 
patients ranged from approximately 25% (100 mg/m2) to 50% (300 mg/m2). 
 
 
Effect of Age 
 
The pharmacokinetics of irinotecan administered using the weekly schedule was 
evaluated in a study of 183 patients that was prospectively designed to investigate the 
effect of age on irinotecan toxicity. Results from this trial indicate that there are no 
differences in the pharmacokinetics of irinotecan, SN-38, and SN-38 glucuronide in 
patients <65 years of age compared with patients ≥65 years of age. In a study of 162 
patients that was not prospectively designed to investigate the effect of age, small (less 
than 18%) but statistically significant differences in dose-normalized irinotecan 
pharmacokinetic parameters in patients <65 years of age compared to patients ≥65 years 
of age were observed. Although dose-normalized AUC0–24 for SN-38 in patients ≥65 
years of age was 11% higher than in patients <65 years of age, this difference was not 
statistically significant. No change in the starting dose is recommended for geriatric 
patients receiving the weekly dosage schedule of irinotecan. 
 
 
Effect of Gender 
 
The pharmacokinetics of irinotecan do not appear to be influenced by gender. 
 
 
Effect of Race 
 
The influence of race on the pharmacokinetics of irinotecan has not been evaluated. 
 
 
Effect of Hepatic Impairment 
 
Irinotecan clearance is diminished in patients with hepatic impairment while exposure to 
the active metabolite SN-38 is increased relative to that in patients with normal hepatic 
function. The magnitude of these effects is proportional to the degree of liver impairment 
as measured by elevations in total bilirubin and transaminase concentrations. However, 
the tolerability of irinotecan in patients with hepatic dysfunction (bilirubin greater than 2 
mg/dl) has not been assessed sufficiently, and no recommendations for dosing can be 
made. 
 
 
Effect of Renal Impairment 
 


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The influence of renal impairment on the pharmacokinetics of irinotecan has not been 
evaluated. Therefore, caution should be undertaken in patients with impaired renal 
function. CAMPTOSAR is not recommended for use in patients on dialysis. 
 
 
Drug Interactions 
 
Dexamethasone, a moderate CYP3A4 inducer, does not appear to alter the 
pharmacokinetics of irinotecan. 
 
 
NONCLINICAL TOXICOLOGY 
 
 
Carcinogenesis, Mutagenesis, Impairment of Fertility 
 
Long-term carcinogenicity studies with irinotecan were not conducted. Rats were, 
however, administered intravenous doses of 2 mg/kg or 25 mg/kg irinotecan once per 
week for 13 weeks (in separate studies, the 25 mg/kg dose produced an irinotecan Cmax 
and AUC that were about 7.0 times and 1.3 times the respective values in patients 
administered 125 mg/m2 weekly) and were then allowed to recover for 91 weeks. Under 
these conditions, there was a significant linear trend with dose for the incidence of 
combined uterine horn endometrial stromal polyps and endometrial stromal sarcomas. 
Irinotecan was clastogenic both in vitro (chromosome aberrations in Chinese hamster 
ovary cells) and in vivo (micronucleus test in mice). Neither irinotecan nor its active 
metabolite SN-38 was mutagenic in the in vitro Ames assay. 
 
No significant adverse effects on fertility and general reproductive performance were 
observed after intravenous administration of irinotecan in doses of up to 6 mg/kg/day to 
rats and rabbits; however, atrophy of male reproductive organs was observed after 
multiple daily irinotecan doses both in rodents at 20 mg/kg and in dogs at 0.4 mg/kg. In 
separate studies in rodents, this dose produced an irinotecan Cmax and AUC about 5 
and 1 times, respectively, of the corresponding values in patients administered 125 
mg/m2 weekly. In dogs this dose produced an irinotecan Cmax and AUC about one-half 
and 1/15th, respectively, of the corresponding values in patients administered 125 mg/m2 
weekly. 
 
 
CLINICAL STUDIES 
 
Irinotecan has been studied in clinical trials in combination with 5-fluorouracil (5-FU) and 
leucovorin (LV) and as a single agent. When given as a component of combination-agent 
treatment, irinotecan was either given with a weekly schedule of bolus 5-FU/LV or with an 
every-2-week schedule of infusional 5-FU/LV. Weekly and once-every-3-week dosage 
schedules were used for the single-agent irinotecan studies. Clinical studies of 
combination and single-agent use are described below. 
 
 
Metastatic Colorectal Cancer 
 
First Line Therapy in Combination with 5-FU/LV: Studies 1 and 2 
 
Two phase 3, randomized, controlled, multinational clinical trials support the use of 
CAMPTOSAR Injection as first-line treatment of patients with metastatic carcinoma of the 
colon or rectum. In each study, combinations of irinotecan with 5-FU and LV were 
compared with 5-FU and LV alone. Study 1 compared combination irinotecan/bolus 5-
FU/LV therapy given weekly with a standard bolus regimen of 5-FU/LV alone given daily 
for 5 days every 4 weeks; an irinotecan-alone treatment arm given on a weekly schedule 
was also included. Study 2 evaluated two different methods of administering infusional 5-


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FU/LV, with or without irinotecan. In both studies, concomitant medications such as 
antiemetics, atropine, and loperamide were given to patients for prophylaxis and/or 
management of symptoms from treatment. In Study 2, a 7-day course of fluoroquinolone 
antibiotic prophylaxis was given in patients whose diarrhea persisted for greater than 24 
hours despite loperamide or if they developed a fever in addition to diarrhea. Treatment 
with oral fluoroquinolone was also initiated in patients who developed an absolute 
neutrophil count (ANC) <500/mm3, even in the absence of fever or diarrhea. Patients in 
both studies also received treatment with intravenous antibiotics if they had persistent 
diarrhea or fever or if ileus developed. 
 
In both studies, the combination of irinotecan/5-FU/LV therapy resulted in significant 
improvements in objective tumor response rates, time to tumor progression, and survival 
when compared with 5-FU/LV alone. These differences in survival were observed in spite 
of second-line therapy in a majority of patients on both arms, including crossover to 
irinotecan-containing regimens in the control arm. Patient characteristics and major 
efficacy results are shown in Table 3. 
 
Table 3. Combination Dosage Schedule: Study Results 
 
 
 
* Study 1: N=225 (irinotecan/5-FU/LV),N=219 (5-FU/LV),N=223 (irinotecan) 
 Study 2: N=199 (irinotecan/5-FU/LV),N=186 (5-FU/LV) 
† Confirmed ≥ 4 to 6 weeks after first evidence of objective response 
‡ Chi-square test 
§ Log-rank test 


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Improvement was noted with irinotecan-based combination therapy relative to 5-FU/LV 
when response rates and time to tumor progression were examined across the following 
demographic and disease-related subgroups (age, gender, ethnic origin, performance 
status, extent of organ involvement with cancer, time from diagnosis of cancer, prior 
adjuvant therapy, and baseline laboratory abnormalities).  
 
Second-Line Therapy After 5-FU-Based Treatment 
 
4 Weekly Doses on a 6-Week Cycle: Studies 3, 4, and 5 
 
Data from three open-label, single-agent, clinical studies, involving a total of 304 patients 
in 59 centers, support the use of CAMPTOSAR in the treatment of patients with 
metastatic cancer of the colon or rectum that has recurred or progressed following 
treatment with 5-FU-based therapy. These studies were designed to evaluate tumor 
response rate and do not provide information on effects on survival and disease-related 
symptoms. In each study, CAMPTOSAR was administered in repeated 6-week cycles 
consisting of a 90-minute intravenous infusion once weekly for 4 weeks, followed by a 2-
week rest period. Starting doses of CAMPTOSAR in these trials were 100, 125, or 150 
mg/m2, but the 150-mg/m2 dose was poorly tolerated (due to high rates of grade 4 late 
diarrhea and febrile neutropenia). Study 3 enrolled 48 patients and was conducted by a 
single investigator at several regional hospitals. Study 4 was a multicenter study 
conducted by the North Central Cancer Treatment Group. All 90 patients enrolled in 
Study 4 received a starting dose of 125 mg/m2. Study 5 was a multicenter study that 
enrolled 166 patients from 30 institutions. The initial dose in Study 5 was 125 mg/m2 but 
was reduced to 100 mg/m2 because the toxicity seen at the 125-mg/m2 dose was 
perceived to be greater than that seen in previous studies. All patients in these studies 
had metastatic colorectal cancer, and the majority had disease that recurred or 
progressed following a 5-FU-based regimen administered for metastatic disease. In the 
intent-to-treat analysis of the pooled data across all three studies, 193 of the 304 patients 
began therapy at the recommended starting dose of 125 mg/m2. Among these 193 
patients, 2 complete and 27 partial responses were observed, for an overall response 
rate of 15.0% (95% Confidence Interval [CI], 10.0% to 20.1%) at this starting dose. A 
considerably lower response rate was seen with a starting dose of 100 mg/m2. The 
majority of responses were observed within the first two cycles of therapy, but responses 
did occur in later cycles of treatment (one response was observed after the eighth cycle). 
The median response duration for patients beginning therapy at 125 mg/m2 was 5.8 
months (range, 2.6 to 15.1 months). Of the 304 patients treated in the three studies, 
response rates to CAMPTOSAR were similar in males and females and among patients 
older and younger than 65 years. Rates were also similar in patients with cancer of the 
colon or cancer of the rectum and in patients with single and multiple metastatic sites. 
The response rate was 18.5% in patients with a performance status of 0 and 8.2% in 
patients with a performance status of 1 or 2. Patients with a performance status of 3 or 4 
have not been studied. Over half of the patients responding to CAMPTOSAR had not 
responded to prior 5-FU. Patients who had received previous irradiation to the pelvis 
responded to CAMPTOSAR at approximately the same rate as those who had not 
previously received irradiation. 
 
Once-Every-3-Week Dosage Schedule 
 
Single Arm Study: Study 6 
 
Data from an open-label, single-agent, single-arm, multicenter, clinical study involving a 
total of 132 patients support a once every-3-week dosage schedule of irinotecan in the 


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treatment of patients with metastatic cancer of the colon or rectum that recurred or 
progressed following treatment with 5-FU. Patients received a starting dose of 350 
mg/m2 given by 30-minute intravenous infusion once every 3 weeks. Among the 132 
previously treated patients in this trial, the intent-to-treat response rate was 12.1% (95% 
CI, 7.0% to 18.1%). 
 
Randomized Studies: Studies 7 and 8 
 
Two multicenter, randomized, clinical studies further support the use of irinotecan given 
by the once-every-3-week dosage schedule in patients with metastatic colorectal cancer 
whose disease has recurred or progressed following prior 5-FU therapy. In Study 7, 
second-line irinotecan therapy plus best supportive care was compared with best 
supportive care alone. In Study 8, second-line irinotecan therapy was compared with 
infusional 5-FU-based therapy. In both studies, irinotecan was administered intravenously 
at a starting dose of 350 mg/m2 over 90 minutes once every 3 weeks. The starting dose 
was 300 mg/m2 for patients who were 70 years and older or who had a performance 
status of 2. The highest total dose permitted was 700 mg. Dose reductions and/or 
administration delays were permitted in the event of severe hematologic and/or 
nonhematologic toxicities while on treatment. Best supportive care was provided to 
patients in both arms of Study 7 and included antibiotics, analgesics, corticosteroids, 
transfusions, psychotherapy, or any other symptomatic therapy as clinically indicated. In 
both studies, concomitant medications such as antiemetics, atropine, and loperamide 
were given to patients for prophylaxis and/or management of symptoms from treatment. If 
late diarrhea persisted for greater than 24 hours despite loperamide, a 7-day course of 
fluoroquinolone antibiotic prophylaxis was given. Patients in the control arm of the Study 
8 received one of the following 5-FU regimens: (1) LV, 200 mg/m2 IV over 2 hours; 
followed by 5-FU, 400 mg/m2 IV bolus; followed by 5-FU, 600 mg/m2 continuous IV 
infusion over 22 hours on days 1 and 2 every 2 weeks; (2) 5-FU, 250 to 300 mg/m2/day 
protracted continuous IV infusion until toxicity; (3) 5-FU, 2.6 to 3 g/m2 IV over 24 hours 
every week for 6 weeks with or without LV, 20 to 500 mg/m2/day every week IV for 6 
weeks with 2-week rest between cycles. Patients were to be followed every 3 to 6 weeks 
for 1 year. 
 
A total of 535 patients were randomized in the two studies at 94 centers. The primary 
endpoint in both studies was survival. The studies demonstrated a significant overall 
survival advantage for irinotecan compared with best supportive care (p=0.0001) and 
infusional 5-FU-based therapy (p=0.035). In Study 7, median survival for patients treated 
with irinotecan was 9.2 months compared with 6.5 months for patients receiving best 
supportive care. In Study 8, median survival for patients treated with irinotecan was 10.8 
months compared with 8.5 months for patients receiving infusional 5-FU-based therapy. 
Multiple regression analyses determined that patients' baseline characteristics also had a 
significant effect on survival. When adjusted for performance status and other baseline 
prognostic factors, survival among patients treated with irinotecan remained significantly 
longer than in the control populations (p=0.001 for Study 7 and p=0.017 for Study 8). 
Measurements of pain, performance status, and weight loss were collected prospectively 
in the two studies; however, the plan for the analysis of these data was defined 
retrospectively. When comparing irinotecan with best supportive care in Study 7, this 
analysis showed a statistically significant advantage for irinotecan, with longer time to 
development of pain (6.9 months versus 2.0 months), time to performance status 
deterioration (5.7 months versus 3.3 months), and time to > 5% weight loss (6.4 months 
versus 4.2 months). Additionally, 33.3% (33/99) of patients with a baseline performance 
status of 1 or 2 showed an improvement in performance status when treated with 
irinotecan versus 11.3% (7/62) of patients receiving best supportive care (p=0.002). 


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Because of the inclusion of patients with non-measurable disease, intent-to-treat 
response rates could not be assessed. 
1.4 
Rationale 
In 2L+ mGC/GEJ, taxanes with or without ramucirumab, irinotecan, and pembrolizumab 
in select patients (PD-L1 positive in 3L+ or MSI-high in 2L+) are recommended treatment 
options[17][16]. Irinotecan has been tested in multiple single arm and randomized trials in 
2L+ mGC, with reported ORR in the 15-29% range and median PFS of 2-3 
months[32][13]. The largest current randomized phase 3 trial in 2L mGC was the 
RAINBOW trial, demonstrating an improvement in mOS, mPFS and ORR with the 
combination of paclitaxel plus ramucirumab vs paclitaxel alone[17]. Despite these 
advances, outcomes for advanced GC remain poor with a mOS of 9.6 months and PFS-6 
of only 36%[17]. Until recently, no randomized phase 3 trial demonstrated a survival 
benefit in 3L+ mGC. The TAGS trial randomized 507 patients with 3L+ mGC in 2:1 ratio 
to either TAS102 or placebo and showed a significant improvement in mOS from 3.6 
months to 5.7 months (HR 0.69, P= 0.0003)[25]. One of the clinical challenges of 2L 
treatment with taxanes after 1L platinum containing regimens (in the U.S. mainly 
oxaliplatin) is the development and worsening of peripheral neuropathy, which often 
leads to dose reductions, treatment delays, and reduced QoL for patients. In the 
RAINBOW trial, 46% of patients in the combination arm developed neuropathy, 8% of 
which were grade 3. The WJOG 4007 trial compared irinotecan with paclitaxel in 2L mGC 
and found no difference in survival[14]. Thus, irinotecan can be regarded as one possible 
current standard option for 2L mGC. Early phase trials have evaluated the feasibility of 
TAS102 in combination with irinotecan +/- bevacizumab in patients with advanced 
colorectal adenocarcinoma. Doi et al completed a 3+3 dose escalation study and 
established a recommended dose of 50mg/m2/day (corresponding to 25mg/m2 bid) on 
days 1-5 and 8-12 with irinotecan 150mg/m2 on days 1 and 15 of a 28 day cycle[33]. 
More recently, TAS102 was combined with irinotecan and bevacizumab in mCRC in a 
modified dosing schedule (TAS102 at 25mg/m2 bid day 1-5, irinotecan 180mg/m2 day 1, 
bevacizumab 5mg/kg day 1, given every 14 days). The authors did not report any new 
safety signals, and encouraging activity in a cohort of heavily pretreated patients 
[Varghese AM et al. J Clin Oncol 36, 2018 (suppl; abstr 3546)]. 
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
2.1.1 
To estimate the efficacy of trifluridine and tipiracil (TAS102) in combination with 
irinotecan in patients with advanced gastric and gastroesophageal 
adenocarcinoma 
2.2 
Secondary Objectives  
 
2.2.1 
To describe the adverse events associated with trifluridine and tipiracil (TAS102) 
in combination with irinotecan in patients with advanced gastric and 
gastroesophageal adenocarcinoma 
 
2.2.2 
In patients with measurable disease, to describe any preliminary evidence of 
anti-tumor activity by assessment of objective response as determined by 
RECIST v1.1 in patients with advanced gastric and gastroesophageal 
adenocarcinoma 
 


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2.3 
Endpoints 
The primary endpoint is 6 months progression-free survival (PFS-6). 
The secondary endpoints are rates of drug-related grade 3-5 adverse events experienced 
within the first 8 weeks (2 cycles) of study treatment. These will be assessed via NCI’s 
CTCAE v5.0 toxicity criteria. Other secondary endpoints are best objective response rate 
by RECIST v1.1 in patients with measurable disease and overall survival. 
3.0 
PATIENT ELIGIBILITY 
3.1 
Inclusion Criteria 
 
 
3.1.1   Patients must have histologically or cytologically confirmed gastric or 
gastroesophageal adenocarcinoma 
 
 
3.1.2     Must have locally advanced, recurrent, or metastatic disease not amenable to 
curative intent surgery. 
 
 
3.1.3 
Must have progressed, or not tolerated, at least one line of treatment with a 
platinum and/or fluoropyrimidine containing regimen. At least one cycle of 
combination chemotherapy including a platinum (oxaliplatin, cisplatin, 
carboplatin) and/or fluoropyrimidine (capecitabine or 5-Fluorouracil) based 
regimen for advanced disease. Combination regimens with 
platinum/fluoropyrimidine containing a taxane and or a checkpoint inhibitor are 
allowed. Patients progressing within six months of perioperative chemotherapy or 
definitive chemoradiation for localized disease are eligible. Patients who have 
exhausted all other standard of care options are also eligible. 
 
 
 
3.1.4 
Age ≥ 18 years  
Because no dosing or adverse event data are currently available on the use of 
TAS-102 in patients <18 years of age, children are excluded from this study but 
will be eligible for future pediatric single-agent trials, if applicable. 
 
  
3.1.5   Performance status: ECOG performance status ≤2 (Appendix A). 
 
 
 
3.1.6  
Life expectancy of greater than 3 months 
       
 
 
3.1.7     Adequate organ and marrow function as defined below: 
- leukocytes 
 
≥ 3,000/mcL 
- absolute neutrophil count ≥ 1,500/mcL 
- platelets  
 
≥ 80,000/mcl 
- total bilirubin 
 
within normal institutional limits 
- AST(SGOT)/ALT(SPGT) ≤ 3 X institutional upper limit of normal or ≤ 5 X if 
liver metastases are present 
      - creatinine 
 
< 1.5 X upper limit of normal  
3.1.8  
The effects of TAS-102 on the developing human fetus at the recommended 
therapeutic dose are unknown.  For this reason and because topoisomerase 
inhibitors  are known to be teratogenic, women of child-bearing potential and 
men must agree to use adequate contraception (hormonal or barrier method of 
birth control; abstinence) prior to study entry, for the duration of study 
participation, and for 90 days following completion of therapy. Should a woman 
become pregnant or suspect she is pregnant while participating in this study, she 
should inform her treating physician immediately. 
 
3.1.8.1 A female of child-bearing potential is any woman (regardless of 


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sexual orientation, having undergone a tubal ligation, or 
remaining celibate by choice) who meets the following criteria: 
 
 
Has not undergone a hysterectomy or bilateral 
oophorectomy; or 
 
Has not been naturally postmenopausal for at least 12 
consecutive months (i.e., has had menses at any time in the 
preceding 12 consecutive months). 
 
3.1.9. 
Ability to swallow tablets 
 
3.1.10  Ability to understand and the willingness to sign a written informed consent. 
 
3.2 
Exclusion Criteria 
 
3.2.1 
Patients who have had major surgery within 4 weeks, or chemotherapy or 
radiotherapy within 2 weeks prior to Cycle 1 Day 1.   
 
3.2.2 
All toxicities attributed to prior anti-cancer therapy other than alopecia must have 
resolved to grade 1 or baseline  
 
3.2.3 
Patients may not be receiving any other investigational agents. 
 
3.2.4 
Patients with known brain metastases due to poor prognosis and because they 
often develop progressive neurologic dysfunction that would confound the 
evaluation of neurologic and other adverse events. 
 
3.2.5 
History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to TAS-102, irinotecan or other agents used in study. 
 
3.2.6 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with 
study requirements. 
 
3.2.7 
Prior treatment with irinotecan or TAS-102  
 
3.2.8 
History of another primary cancer within the last 3 years with the exception of 
non-melanoma skin cancer, early-stage prostate cancer, or curatively treated 
cervical carcinoma in-situ. 
 
3.2.9 
Inability to comply with study and follow-up procedures as judged by the 
Investigator 
 
3.2.10 Patients who are pregnant or nursing due to the potential for congenital   
 
 
  
abnormalities and the potential of this regimen to harm nursing infants.  
 
 
 
 
3.3  
Inclusion of Women, Minorities, Vulnerable Populations Both men and women and 
members of all races and ethnic groups are eligible for this trial. Non-English speaking, 
deaf, hard of hearing and illiterate individuals are eligible for this trial.  
 


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4.0 
TREATMENT PLAN 
4.1 
Treatment Dosage and Administration 
 
4.1.1 
Patients will be treated with TAS-102 25mg/m2 p.o. twice daily on days 1-5 and 
irinotecan 180mg/m2 i.v. on day 1 every 14 days. If ANC <1500/uL on day 1 of a 
cycle, then G-CSF will be added on day 6 for three days. Institutional standards 
should be followed in determining whether the subject’s body weight at baseline 
or beginning of each cycle should be used to determine the TAS-102 dosage. 
Doses must be re-calculated for patients who experience a ≥ 10% change in 
weight from baseline. Other dose re-calculations for changes in body weight < 
10% are permitted per institutional standards.   
 
REGIMEN DESCRIPTION 
 
Agent 
Premedications; 
Precautions 
 
Dose 
 
Route 
 
Schedule 
Cycle 
Length  
TAS-102 
None 
25 mg/m2 twice 
daily 
 
PO taken within 
1 hour after 
completion of 
morning and 
evening meals 
Days 1-5 
2 weeks 
(14 
days) 
 
Irinotecan 
Dexamethasone 
in NS 0.9% IVPB 
20MG over 
20min , give 
30min prior to 
irinotecan 
 
Palonosetron 
injection 0.25mg 
IV push over 30 
sec , give 30min 
prior to irinotecan 
 
Atropine 0.25mg 
s.c. every 4 
hours prn 
cholinergic 
reactions 
 
Supportive care 
for infusion 
reactions per 
institutional 
guidelines 
180 mg/m2 in  
250 
cc 
D5W 
over 90 min 
IV  
Day 1 
 
 
4.1.2 
Concomitant Medications   
 
If needed for neutropenia, patients will be taught to self-inject G-CSF at home.  
 
Odansetron 8mg tablets and diphenoxylate hydrochloride and atropine sulfate (Lomotil®) 
2.5mg/0.025mg tablets will be prescribed to manage associated nausea/vomiting and 
diarrhea/cramping at home. 


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4.2 
Toxicities and Dosing Delays/Dose Modifications 
Any patient who receives treatment on this protocol will be evaluable for toxicity. Each 
patient will be assessed for the development of toxicity according to the Time and Events 
table (Section 5.5). Toxicity will be assessed according to the NCI Common Toxicity 
Criteria for Adverse Events (CTCAE), version 5.0. Dose adjustments should be made 
according to the system showing the greatest degree of toxicity.  
 
 
 
Dose Modification Table  
 
Dose Level  
Agent  
Dose 
1 (starting dose) 
TAS-102 
25 mg/m2 
1 (starting dose) 
Irinotecan  
180 mg/m2 
 
 
 
-1 (20 % reduction) 
TAS-102 
20 mg/m2 
-1 (20% reduction) 
Irinotecan  
144 mg/m2 
 
 
 
-2 (40% reduction) 
Irinotecan 
108 mg/m2 
 
 
 
Hematological Toxicities 
 
Hematological Toxicity Dose Reductions for Agent A 
ANC 
Platelets 
Action 
≥ 1,500/L 
80,000/L 
None. 
 
1000-1499/L 
 
50,000-79,000/L 
-1st Occurrence: Hold current dose until ANC ≥ 
1,500/L and platelets ≥ 75,000/L. Do not 
replace missed doses. If reason for dose delay 
was neutropenia, give G-CSF s.c. for 3 days 
(300mcg for weight <75kg or 480mcg for weight 
≥75kg). Resume at same dose. 
-2nd Occurrence: Hold current dose until ANC ≥ 
1,500/L and platelets ≥ 75,000/L. Do not 
replace missed doses. If reason for dose delay 
was neutropenia, give G-CSF s.c. for 5 days 
(300mcg for weight <75kg or 480mcg for weight 
≥75kg).  Restart next treatment at 20% reduced 
dose (TAS-102 20mg/m2 and irinotecan 
144mg/m2).  
-3rd Occurrence: Hold current dose until ANC ≥ 
1,500/L and platelets ≥ 75,000/L. Do not 
replace missed doses. If reason for dose delay 
was neutropenia, give G-CSF s.c. for 7 days 
(300mcg for weight <75kg or 480mcg for weight 
≥75kg).  Restart next treatment at 40% reduced 
dose (irinotecan 108mg/m2) and discontinue 
TAS-102. 


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-4th Occurrence: Discontinue protocol therapy. 
 
500-999/L 
 
25,000-49,000/L 
-1st Occurrence: Hold current dose until ANC ≥ 
1,500/L and platelets ≥ 75,000/L. Do not 
replace missed doses. If reason for dose delay 
was neutropenia, give G-CSF s.c. for 5 days 
(300mcg for weight <75kg or 480mcg for weight 
≥75kg).  Restart next treatment at 20% reduced 
dose (TAS-102 20mg/m2 and irinotecan 
144mg/m2). 
 -2nd Occurrence: Hold current dose until ANC ≥ 
1,500/L and platelets ≥ 75,000/L. Do not 
replace missed doses. If reason for dose delay 
was neutropenia, give G-CSF s.c. for 7 days 
(300mcg for weight <75kg or 480mcg for weight 
≥75kg).  Restart next treatment at 40% reduced 
dose (irinotecan 108mg/m2) and discontinue 
TAS-102. 
-3rd Occurrence: Discontinue protocol therapy. 
 
<500/L 
 
<25,000/L 
-1st Occurrence: Hold current dose until ANC ≥ 
1,500/L and platelets ≥ 75,000/L. Do not 
replace missed doses. If reason for dose delay 
was neutropenia, give G-CSF s.c. for 7 days 
(300mcg for weight <75kg or 480mcg for weight 
≥75kg).  Restart next treatment at 20% reduced 
dose (TAS-102 20mg/m2 and irinotecan 
144mg/m2). 
-2nd Occurrence: Discontinue protocol therapy.  
 
Non-hematological Toxicities:  
Treatment may be delayed up to 4 weeks due to intolerable toxicities grade >1 based on investigator 
discretion. Imaging studies will need to be performed based on protocol schedule (i.e. not delayed due to 
dose delay). 
 
Non-hematological Toxicity Dose Reductions 
NCI CTC Grade 
TAS-102 
Irinotecan 
0-2 
No change from original starting 
dose  
No change from original starting dose 
3  
Hold until resolved to < Grade 2, 
then reduce to dose level -1, 
20mg/m2 
Hold until resolved to < Grade 2, then 
reduce to dose level -1, 144mg/m2 
Second episode of 
grade 3 or 4 toxicity 
Discontinue TAS-102 
Hold until resolved to < Grade 2, then 
reduce to dose level -2, 108mg/m2 
Third episode of 
grade 3 or 4 toxicity 
Remove subject from trial 
Remove subject from trial 
4.3 
Concomitant Medications/Treatments 
TAS-102 
 
Trifluridine is a substrate of thymidine phosphorylase, and is not metabolized by 
cytochrome P450 (CYP) enzyme. Tipiracil is not metabolized in either human liver or 
hepatocytes. In vitro studies indicated that trifluridine, tipiracil, and FTY did not inhibit the 


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CYP enzymes and had no inductive effect on CYP1A2, CYP2B6, or CYP3A4/5. In vitro 
studies indicated that trifluridine was not an inhibitor of or substrate for human uptake and 
efflux transporters. 
 
 
Irinotecan 
 
Strong CYP3A4 Inducers  
Exposure to irinotecan or its active metabolite SN-38 is substantially reduced in adult and 
pediatric patients concomitantly receiving the CYP3A4 enzyme-inducing anticonvulsants 
phenytoin, phenobarbital, carbamazepine, or St. John’s wort. The appropriate starting 
dose for patients taking these or other strong inducers such as rifampin and rifabutin has 
not been defined. Consider substituting non-enzyme inducing therapies at least 2 weeks 
prior to initiation of irinotecan therapy. Do not administer strong CYP3A4 inducers with 
irinotecan unless there are no therapeutic alternatives.  
 
Strong CYP3A4 or UGT1A1 Inhibitors 
Irinotecan and its active metabolite, SN-38, are metabolized via the human cytochrome 
P450 3A4 isoenzyme (CYP3A4) and uridine diphosphate-glucuronosyl transferase 1A1 
(UGT1A1), respectively. Patients receiving concomitant ketoconazole, a CYP3A4 and 
UGT1A1 inhibitor, have increased exposure to irinotecan and its active metabolite SN-38. 
Coadministration of Cirinotecan with other inhibitors of CYP3A4 (e.g., clarithromycin, 
indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telaprevir, 
voriconazole) or UGT1A1 (e.g., atazanavir, gemfibrozil, indinavir) may increase systemic 
exposure to irinotecan or SN-38. Discontinue strong CYP3A4 inhibitors at least 1 week 
prior to starting irinotecan therapy. Do not administer strong CYP3A4 or UGT1A1 
inhibitors with irinotecan unless there are no therapeutic alternatives. 
4.4 
Duration of Therapy 
In the absence of treatment delays due to adverse events, treatment may continue until: 
 
Disease progression as defined radiographic progression by RECIST v1.1 
criteria OR death OR symptomatic progression as clinically determined by 
the treating physician  
 
Inter-current illness that prevents further administration of treatment 
 
Unacceptable adverse event(s) 
 
Treatment held for more than 28 days 
 
Patient decides to withdraw from the study, OR 
 
General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
4.5 
Duration of Follow Up 
Patients will be followed every 3 months until death or 18 months after the last patient is 
enrolled, whichever occurs first. Follow-up after removal from treatment is every 3 
months (either clinic visit or phone call).   
4.6 
Removal of Patients from Protocol Therapy 
Patients will be removed from therapy when any of the criteria listed in Section 5.6 apply. 
Notify UCI CFCCC  via secure email (fdayyani@hs.uci.edu and uci18125@hs.uci.edu), 
and document the reason for study removal and the date the patient was removed in the 
Case Report Form. The patient should be followed-up per protocol.  


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4.7 
Patient Replacement 
Patients will not be replaced 
5.0 
STUDY PROCEDURES 
Telemedicine Visits 
In-person visits are the preferred study visit method for collection of the assessments and 
procedures. Study visits conducted by phone or videoconferencing technology (i.e., “virtual” or 
“telemedicine” visits), including adverse event assessments for patients, may be substituted for 
protocol-required in-person visits, if the site investigator determines that the phone/virtual visit is 
adequate to achieve the central purpose of the visit.  
 
5.1 
Screening/Baseline Procedures 
Assessments performed exclusively to determine eligibility for this study will be done only 
after obtaining informed consent. Assessments performed for clinical indications (not 
exclusively to determine study eligibility) may be used for baseline values even if the 
studies were done before informed consent was obtained as long as these assessments 
are completed within 28 days prior to registration. 
 
All screening procedures must be performed within 28 days prior to registration unless 
otherwise stated per protocol. The screening procedures include: 
5.1.1 Informed Consent 
5.1.2 Screening Confirmation 
   Patient information should be entered into Oncore within 1 business day of 
consent. Sites are responsible for assigning subject ID. Sites will be assigned a 
unique site code. Subject IDs should follow a format with the unique site code 
followed by the sequential patient ID. For example, Site Code-Sequential Number 
(i.e. for UCI’s first patient the subject ID will be 01-01, UCD’s first patient will be 
02-01). (Refer to Oncore SOP for Oncore data entry instructions) 
5.1.3 Medical history 
Complete medical, oncology and surgical history, history of infections 
5.1.4 Demographics 
Age, gender, race, ethnicity 
5.1.5 Review subject eligibility criteria 
5.1.6 Review previous and concomitant medications 
5.1.7 Physical exam  
5.1.8 Vital signs  
 
 
Temperature, pulse respirations, blood pressure, weight and height (height only 
at screening) 
5.1.9 ECOG Performance status 
Refer to Appendix A 


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5.1.10 
Hematology 
   Complete blood count with differential (CBC) 
5.1.11 
Serum chemistries 
Comprehensive metabolic panel (CMP) to include: albumin, alkaline 
phosphatase, ALT/SGPT, AST/SGOT, BUN, creatinine, electrolytes (sodium, 
potassium, calcium, chloride, bicarbonate), glucose, and total bilirubin. 
 
 
5.1.12 Tumor Markers (Optional)  
 
 
Carcinoembryonic antigen (CEA) and cancer-related antigen 19-9 (CA 19-9). 
5.1.13 
Pregnancy test (for females of child bearing potential) 
See section 3.1.8.1 for definition.  
5.1.14 
Tumor assessment 
To be performed with computed tomography of the chest (preferred with iv 
contrast) and abdomen/pelvis (preferred with iv contrast and oral contrast). CT 
abdomen/pelvis may be replaced with MRI Abdomen/pelvis (preferred with iv 
contrast) per clinical judgement of the treating physician. Additional imaging is 
indicated at baseline if there is clinical suspicion for other organ involvement 
(i.e. MRI or CT brain and bone scan). 
Imaging is to be performed at baseline within 28 days of starting treatment 
5.2 
Registration Procedures for participating sites only 
Prior to confirmation of registration the below items must be emailed via secure email to 
the initiating site for review and approval. 
 
1. Redacted source documentation required to confirm eligibility (including but 
not limited to): 
a. Pathology report 
b. Physical exam including ECOG, medical and oncology history 
c. All screening labs 
2. Signed eligibility criteria  
 
All items must be emailed via secure email to (fdayyani@hs.uci.edu and 
uci18125@hs.uci.edu) UCI CFCCC at least 3 business days before planned treatment 
start date. 
 
Upon receipt of all required documents, UCI CFCCC will provide confirmation of 
registration. Subjects may not begin study treatment without confirmation of registration.  
 
5.3 
Procedures During Treatment 
5.3.1 
Prior to Each Treatment Cycle 
 Physical exam, vital signs 
 ECOG Performance status  
 Hematology 
 Serum chemistries 


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 CEA and CA 19-9 (optional) – every 4 weeks  
 Adverse events 
 Study drug accountability 
 Review previous and concomitant medications 
 
Site must maintain an accurate and timely record of dispensing of study drug to 
subject, and receipt of all study drug and pill diaries. 
 
5.3.2 
Within 30 days after treatment termination 
 Physical exam, vital signs 
 ECOG Performance status  
 Hematology 
 Serum chemistries 
 Adverse events 
 Review previous and concomitant medications 
5.3.3 
Tumor Assessments 
 To be completed every 8 weeks (+/- one week) during first year of treatment 
and every 3 months (+/- one week) after the first year until patient comes off 
treatment  
5.4 
Follow-up Procedures 
Patients will be followed every three months after completion of (or early withdrawal from) 
study treatment until death or up to 18 months after the last patient is enrolled, whichever 
comes first.  
 
Review of systems and determination of live status if the visit is done  in clinic 
during the patient’s standard visit. If conducted by phone, only a determination of 
live status is needed. A review of systems is not needed if conducted by phone.  
5.5 
Time and Events Table 
 
If baseline evaluations are conducted within 1 week prior to C1D1 administration of protocol therapy, 
those assessments do not need to be repeated.  Scans must be done ≤4 weeks prior to the start of 
therapy.  In the event that the patient’s condition is deteriorating, laboratory evaluations should be 
repeated within 48 hours prior to initiation of the next cycle of therapy. 
 
 
 
Baseline 
-28 to -1 
days 
C1D1 +/- 
2 days 
At every 
cycle (14 
days) +/- 1 
days 
 
Administra
tion of 
irinotecan 
-1/+4 days  
q 8 
Weeks 
for first 
year, q 
3 
months 
after the 
first year 
+/- 1 
week 
Off 
Treatment 
Follow-
up (q 3 
months 
until 
death or 
up to 18 
months 
after last 
patient is 
enrolled, 
whicheve
r occurs 
first) +/- 
14 days  
Assessment 
 
 
 
 
 
 


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Informed Consent 
X 
 
 
 
 
 
History and PE***  
X 
X 
X 
 
X 
 
Baseline medical 
and oncology 
history 
X 
 
 
 
 
 
Concomitant 
Medications 
X 
X 
X 
 
X 
 
Performance 
Status 
X 
X 
X 
 
X 
 
Adverse Events  
 
X 
X 
 
X 
 
Tumor 
Measurements 
X 
 
 
X 
 
 
CT CAP or CT 
chest/MRI 
Abd/Pelvis 
X 
 
 
X 
 
 
CBC / CMP 
X 
X 
X 
 
X 
 
CEA and CA 19-9 
(optional)** 
X 
 
X (every 4 
weeks) 
 
 
 
Pregnancy Test* 
X 
 
 
 
 
 
Review of 
systems 
 
 
 
 
 
X**** 
Study Drug 
Accountability 
 
 
X 
 
X 
 
*Urine or serum pregnancy test is done according to local institutional standard and should 
be obtained ONLY in women of child-bearing potential.  
**This is an optional component and should only be collected if done according to local 
institutional standards.  
*** includes vital signs 
****This is only done when patients come in for their standard visit. If the visit is conducted by 
phone, only determination of live status is needed. A review of systems is not needed when 
the visit is done by phone. 
5.6 
Removal of Subjects from Study 
Patients can be taken off the study treatment and/or study at any time at their own 
request, or they may be withdrawn at the discretion of the investigator for safety, 
behavioral or administrative reasons. The reason(s) for discontinuation will be 
documented and may include: 
5.6.1 
Patient voluntarily withdraws from treatment (follow-up permitted);  
5.6.2 
Patient withdraws consent (termination of treatment and follow-up); 
5.6.3 
Patient is unable to comply with protocol requirements; 
5.6.4 
Patient demonstrates disease progression (unless continued treatment with 
study drug is deemed appropriate at the discretion of the investigator); 
5.6.5 
Patient experiences toxicity that makes continuation in the protocol unsafe; 
5.6.6 
Treating physician judges continuation on the study would not be in the patient’s 
best interest; 
5.6.7 
Patient becomes pregnant (pregnancy to be reported along same timelines as a 
serious adverse event); 


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5.6.8 
Development of second malignancy (except for basal cell carcinoma or 
squamous cell carcinoma of the skin) that requires treatment, which would 
interfere with this study; 
5.6.9 
Lost to follow-up. If a research subject cannot be located to document survival 
after 3 attempts including 1 mailed certified letter, the subject may be considered 
“lost to follow-up.”  
6.0 
Measurement of Effect 
6.1 
Antitumor Effect- Solid Tumors 
 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) 
Committee [JNCI 92(3):205-216, 2000]. Changes in only the largest diameter 
(unidimensional measurement) of the tumor lesions are used in the RECIST v1.1 criteria. 
6.1.1 
Definitions 
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of 
their first treatment with study drug. 
 
Evaluable for objective response. Only those patients who have measurable 
disease present at baseline, have received at least one cycle of therapy, and 
have had their disease re-evaluated will be considered evaluable for response. 
These patients will have their response classified according to the definitions 
stated below. (Note: Patients who exhibit objective disease progression prior to 
the end of cycle 1 will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at 
baseline that are evaluable but do not meet the definitions of measurable 
disease, have received at least one cycle of therapy, and have had their disease 
re-evaluated will be considered evaluable for non-target disease.  The response 
assessment is based on the presence, absence, or unequivocal progression of 
the lesions.  
 
6.1.2 
Disease Parameters 
Measurable disease. Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be recorded) 
as >20 mm with conventional techniques (CT, MRI, x-ray) or as >10 mm with 
spiral CT scan. All tumor measurements must be recorded in millimeters (or 
decimal fractions of centimeters). 
 
Note: Previously irradiated lesions are non-measurable except in cases of 
documented progression of the lesion since the completion of radiation therapy. 
 
 
Non-measurable disease. All other lesions (or sites of disease), including small 
lesions (longest diameter <20 mm with conventional techniques or <10 mm using 
spiral CT scan), are considered non-measurable disease. Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonis, inflammatory breast disease, abdominal masses (not followed by 
CT or MRI), and cystic lesions are all non-measurable. 
 


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Note:  Cystic lesions that meet the criteria for radiographically defined simple 
cysts should not be considered as malignant lesions (neither measurable nor 
non-measurable) since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are 
preferred for selection as target lesions 
 
Target lesions. All measurable lesions up to a maximum of 3 lesions per organ 
and 6 lesions in total, representative of all involved organs, should be identified 
as target lesions and recorded and measured at baseline. Target lesions should 
be selected on the basis of their size (lesions with the longest diameter) and their 
suitability for accurate repeated measurements (either by imaging techniques or 
clinically). A sum of the longest diameter (LD) for all target lesions will be 
calculated and reported as the baseline sum LD. The baseline sum LD will be 
used as reference by which to characterize the objective tumor response. 
 
Non-target lesions. All other lesions (or sites of disease) including any 
measurable lesions over and above the 6 target lesions should be identified as 
non-target lesions and should also be recorded at baseline. Measurements of 
these lesions are not required, but the presence or absence of each should be 
noted throughout follow-up.  
6.1.3 
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler 
or calipers. All baseline evaluations should be performed as closely as possible 
to the beginning of treatment and never more than 28 days before the beginning 
of the treatment. 
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination when 
both methods have been used to assess the antitumor effect of a treatment. 
 
Conventional CT and MRI. These techniques should be performed with cuts of 
10 mm or less in slice thickness contiguously. Spiral CT should be performed 
using a 5 mm contiguous reconstruction algorithm. This applies to tumors of the 
chest, abdomen, and pelvis. MRI is also acceptable in certain situations (e.g. for 
body scans).  Scans will be done within 28 days prior to cycle 1 and after that 
every 8 weeks (+/- 7 days) for the first year, then every 3 months after the first 
year until end of treatment. 
 
Cytology, Histology. These techniques can be used to differentiate between 
partial responses (PR) and complete responses (CR) in rare cases (e.g., residual 
lesions in tumor types, such as germ cell tumors, where known residual benign 
tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears 
or worsens during treatment when the measurable tumor has met criteria for 
response or stable disease is mandatory to differentiate between response or 
stable disease (an effusion may be a side effect of the treatment) and 
progressive disease. 
 


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6.1.4 
Response Criteria 
6.1.4.1 Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions, 
determined by two separate observations conducted not less than 4 
weeks apart. There can be no appearance of new lesions. 
 
Partial Response (PR): At least a 30% decrease in the sum of the 
longest diameter (LD) of target lesions, taking as reference the baseline 
sum LD. There can be no appearance of new lesions. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the LD 
of target lesions, taking as reference the smallest sum LD recorded since 
the treatment started, or the appearance of one or more new lesions. 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference the smallest sum 
LD since the treatment started. 
6.1.4.2 Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and 
normalization of tumor marker level. 
 
Incomplete Response/Stable Disease (SD): Persistence of one or more 
non-target lesion(s) and/or maintenance of tumor marker level above the 
normal limits. 
 
Progressive Disease (PD): Appearance of one or more new lesions 
and/or unequivocal progression of existing non-target lesions 
6.1.4.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of 
the treatment until disease progression/recurrence (taking as reference 
for progressive disease the smallest measurements recorded since the 
treatment started). The patient's best response assignment will depend 
on the achievement of both measurement and confirmation criteria. 
 
 
Target 
Lesions 
Non-
Target 
Lesions 
New Lesions 
Overall 
Response 
Best 
Response for 
this Category 
Also 
Requires: 
CR 
CR 
No 
CR 
>4 wks. 
confirmation 
CR 
Non-
CR/Non-
PD 
No 
PR 
 
>4 wks. 
confirmation 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
documented at 
least once >4 
wks. from 
baseline 
PD 
Any 
Yes or No 
PD 
 


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Any 
PD* 
Yes or No 
PD 
no prior SD, 
PR or CR 
Any 
Any 
Yes 
PD 
* 
In exceptional circumstances, unequivocal progression in non-target 
lesions may be accepted as disease progression. 
 
Note: 
Patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of 
disease progression at that time should be reported as 
“symptomatic deterioration”. Every effort should be made to 
document the objective progression even after discontinuation of 
treatment. 
 
 
 
 
For Patients with Non-Measurable Disease (i.e., Non-Target 
Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target 
disease since SD is increasingly used as an endpoint for assessment 
of efficacy in some trials so to assign this category when no lesions 
can be measured is not advised 
 
 
Note: If subjects respond to treatment and are able to have their disease 
resected, the patient’s response will be assessed prior to the surgery. 
 
 
6.1.5 
Duration of Response 
Duration of overall response: The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are 
first met for CR until the first date that recurrent disease is objectively 
documented. 
 
 
Duration of stable disease: Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the 
smallest measurements recorded since the treatment started.  
6.1.6 
Progression-Free Survival 
Progression-free survival (PFS) is defined as the duration of time from start of 
treatment to time of progression or death, whichever occurs first. 
 


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Progression is defined as death, radiographic progression as defined in 6.1.4.3, 
or clinical deterioration attributed to disease progression as judged by the 
investigator. 
 
 
6.2 
Safety/tolerability 
 
 Analyses will be performed for all patients having received at least one dose of study 
drug. The study will use the CTCAE version 5.0 for reporting of non-hematologic adverse 
events (http://ctep.cancer.gov/reporting/ctc.html) and modified criteria for hematologic 
adverse events. 
7.0 
ADVERSE EVENTS 
 
7.1 
Experimental Therapy 
For the most recent safety update, please refer to the current Investigator’s Brochure or 
Study Agent Prescribing Information. 
7.1.1 Contraindications 
Known hypersensitivity to irinotecan or its excipients. TAS-102 has no known 
contraindications. 
 
7.1.2 Special Warnings and Precautions for Use 
In Study 1, LONSURF (TAS-102) 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.  
 
Based on animal studies and its mechanism of action, LONSURF (TAS-102) can 
cause fetal harm when administered to a pregnant woman. Trifluridine/tipiracil 
caused embryo-fetal lethality and embryo-fetal toxicity in pregnant rats when 
orally administered during gestation at dose levels resulting in exposures lower 
than those achieved at the recommended dose of 35 mg/m2 twice daily. 
 
Diarrhea and Cholinergic Reactions: Early diarrhea (occurring during or shortly 
after infusion of CAMPTOSAR) is usually transient and may be accompanied by 
cholinergic symptoms. Consider prophylactic or therapeutic administration of 
0.25 mg to 1 mg of intravenous or subcutaneous atropine (unless clinically 
contraindicated). Late diarrhea (generally occurring more than 24 hours after 
administration of CAMPTOSAR) can occur. Monitor and replace fluid and 
electrolytes. Treat with loperamide. Use antibiotic support for ileus and fever. 
Interrupt CAMPTOSAR and reduce subsequent doses if severe diarrhea occurs. 
 
Myelosuppression: Manage promptly with antibiotic support. Interrupt 
CAMPTOSAR and reduce subsequent doses if necessary. 
 


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Patients with Reduced UGT1A1 Activity: Individuals who are homozygous for 
the UGT1A1*28 allele are at increased risk for neutropenia following initiation of 
CAMPTOSAR treatment. 
 
Hypersensitivity: Hypersensitivity reactions including severe anaphylactic or 
anaphylactoid reactions have been observed. Discontinue CAMPTOSAR if this 
occurs. 
 
Renal Impairment/Renal Failure: Rare cases of renal impairment and acute 
renal failure have been identified, usually in patients who became volume 
depleted from severe vomiting and/or diarrhea. 
 
Pulmonary Toxicity: Interstitial Pulmonary Disease (IPD)-like events, including 
fatalities, have occurred. Interrupt for new or progressive dysnpnea, cough, and 
fever pending evaluation. If IPD diagnosed, discontinue and institute appropriate 
treatment as needed.  
 
Embryofetal Toxicity: CAMPTOSAR can cause fetal harm when administered 
to a pregnant woman. 
 
Patients with Hepatic Impairment: In clinical trials, CAMPTOSAR has not been 
administered to patients with serum bilirubin > 2.0 mg/dL, or transaminases > 3 
times ULN if no liver metastases, or transaminases > 5 times ULN if liver 
metastases. With the weekly dosage schedule, patients with total bilirubin levels 
1.0–2.0 mg/dL had greater likelihood of grade 3–4 neutropenia. 
 
7.1.3 Interaction with other medications 
 
Exposure to irinotecan or its active metabolite SN-38 is substantially reduced in 
adult and pediatric patients concomitantly receiving the CYP3A4 enzyme-
inducing anticonvulsants phenytoin, phenobarbital, carbamazepine, or St. John's 
wort. The appropriate starting dose for patients taking these or other strong 
inducers such as rifampin and rifabutin has not been defined. Consider 
substituting non-enzyme inducing therapies at least 2 weeks prior to initiation of 
CAMPTOSAR therapy. Do not administer strong CYP3A4 inducers with 
CAMPTOSAR unless there are no therapeutic alternatives. 
Irinotecan and its active metabolite, SN-38, are metabolized via the human 
cytochrome P450 3A4 isoenzyme (CYP3A4) and uridine diphosphate-
glucuronosyl transferase 1A1 (UGT1A1), respectively. Patients receiving 
concomitant ketoconazole, a CYP3A4 and UGT1A1 inhibitor, have increased 
exposure to irinotecan hydrochloride and its active metabolite SN-38. 
Coadministration of CAMPTOSAR with other inhibitors of CYP3A4 (e.g., 
clarithromycin, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, ritonavir, 
saquinavir, telaprevir, voriconazole) or UGT1A1 (e.g., atazanavir, gemfibrozil, 
indinavir) may increase systemic exposure to irinotecan or SN-38. Discontinue 
strong CYP3A4 inhibitors at least 1 week prior to starting CAMPTOSAR therapy. 
Do not administer strong CYP3A4 or UGT1A1 inhibitors with CAMPTOSAR 
unless there are no therapeutic alternatives. 
 


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7.1.4 Adverse Reactions 
 
TAS-102: Severe Myelosuppression. 
 
Irinotecan: Common adverse reactions (≥30%) observed in combination therapy 
clinical studies are: nausea, vomiting, abdominal pain, diarrhea, constipation, 
anorexia, mucositis, neutropenia, leukopenia (including lymphocytopenia), 
anemia, thrombocytopenia, asthenia, pain, fever, infection, abnormal bilirubin, 
and alopecia. 
 
Common adverse reactions (≥30%) observed in single agent therapy clinical 
studies are: nausea, vomiting, abdominal pain, diarrhea, constipation, anorexia, 
neutropenia, leukopenia (including lymphocytopenia), anemia, asthenia, fever, 
body weight decreasing, and alopecia. 
 
Serious opportunistic infections have not been observed, and no complications 
have specifically been attributed to lymphocytopenia. 
 
7.2 
Adverse Event Monitoring 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of subjects enrolled in the studies as well as those 
who will enroll in future studies using similar agents. Adverse events are reported in a 
routine manner at scheduled times during a trial. Additionally, certain adverse events 
must be reported in an expedited manner to allow for optimal monitoring of patient safety 
and care.  
 
All patients experiencing an adverse event, regardless of its relationship to study drug, 
will be monitored until:  
 the adverse event resolves or the symptoms or signs that constitute the adverse 
event return to baseline;  
 any clinically significant laboratory values have returned to baseline;  
 there is a satisfactory explanation other than the study drug for the changes 
observed; or 
 death. 
 
Abnormal laboratory values are considered to be AEs only if they are assessed as 
clinically significant by the investigator.  
 
All AEs and clinically significant laboratory abnormalities should be assessed by the 
investigator for relationship to the combination of the drugs and entered into OnCore.  
7.3 
Definitions 
  
7.3.1 Event Definitions 
Adverse event (AE) - An adverse event is any untoward medical experience or 
change of an existing condition that occurs during or after treatment, whether or 
not it is considered to be related to the protocol intervention.  
 


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Unexpected Adverse Event [Modified from the definition of unexpected adverse 
drug experience in FDA regulations at 21 CFR 312.32 (a)] – An adverse event is 
unexpected if it is not listed in the investigator’s brochure and/or package insert; 
is not listed at the specificity or severity that has been observed; is not consistent 
with the risk information described in the protocol and/or consent; is not an 
expected natural progression of any underlying disease, disorder, condition, or 
predisposed risk factor of the research participant experiencing the adverse 
event. 
 
Expected Adverse Event - Any event that does not meet the criteria for an 
unexpected event OR is an expected natural progression of any underlying 
disease, disorder, condition, or predisposed risk factor of the research participant 
experiencing the adverse event. 
 
Serious Adverse Event (SAE) [21 CFR 312.32] - defined as any expected or 
unexpected adverse event that result in any of the following outcomes: 
 
Death 
 
Is life-threatening experiences (places the subject at immediate risk of 
death from the event as it occurred) 
 
Unplanned hospitalization equal or greater than 24 hours)) or 
prolongation of existing hospitalization 
 
A persistent or significant disability/incapacity 
 
A congenital anomaly/birth defect 
 
Any other adverse event that, based upon appropriate medical judgment, 
may jeopardize the subject’s health and may require medical or surgical 
intervention to prevent one of the outcomes listed above (examples of 
such events include allergic bronchospasm requiring intensive treatment 
in the emergency room or at home, blood dyscrasias of convulsions that 
do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse). 
 
Unanticipated problem (UP) - Any incident, experience or outcome that meets 
all three of the following criteria: 
1. Unexpected (in term nature, severity, or frequency) given the following: 
a) the research procedures described in the protocol-related documents 
such as the IRB approved research protocol, informed consent 
document or Investigator Brochure (IB); and b) the characteristics of the 
subject population being studied; AND 
2. Related or possibly related to participation in the research (possibly 
related means there is a reasonable possibility that the incident, 
experience, or outcomes may have been caused by the drugs, devices 
or procedures involved in the research); AND 
3. Suggests that the research places subjects or others at greater risk of 
harm (including physical, psychological, economic, or social harm) than 
previously known or recognized. 
 
Protocol Violation- A protocol violation is an accidental or unintentional change 
to or noncompliance with the IRB-approved protocol that increases risk or 
decreases benefit and/or affects the subject's rights, safety, welfare, and/or the 
integrity of the data. Examples of incidents that may be considered violations 
include: enrolling a participant who does not meet the inclusion criteria; obtaining 
verbal consent before the initiation of study procedures when the IRB requires 
signed, written informed consent; and failure to collect screening labs before 


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initiation of study procedures [Reference: Policy #57 UCI HRPP Policy and 
Procedure Glossary].  
 
Protocol Deviation- a protocol deviation is an accidental or unintentional change 
to the research protocol that does not increase risk or decrease benefit or have a 
significant effect on the participant’s rights, safety or welfare, or on the integrity of 
the data. Deviations may result from the action of the participant, researcher, or 
staff. Examples: a rescheduled study visit, an omitted routine safety lab for a 
participant with previously normal values; or failure to collect an ancillary self-
report questionnaire data (e.g., quality of life) [Reference: Policy #57 UCI HRPP 
Policy and Procedure Glossary].  
7.3.2 Characteristics and Severity of Adverse Events 
 
All non-hematologic adverse events will be graded according to the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The 
CTCAE v5 is available at: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm#ctc_
50  
 
If no CTCAE grading is available, the severity of an AE is graded as follows: 
Mild (grade 1): the event causes discomfort without disruption of normal daily 
activities. 
Moderate (grade 2): the event causes discomfort that affects normal daily 
activities. 
Severe (grade 3): the event makes the patient unable to perform normal daily 
activities or significantly affects his/her clinical status. 
Life-threatening (grade 4): the patient was at risk of death at the time of the 
event. 
Fatal (grade 5): the event caused death. 
o 
Expectedness:  AEs can be ‘Unexpected’ or ‘Expected’   
Expected: will be described in the following: Investigational Brochure, package 
insert, protocol and informed consent, safety profile of other drugs in the same 
class.  
Unexpected: Not listed in Investigational Brochure or not listed at the specificity 
or severity that has been observed. Not consistent with the risk information 
described in the general investigational plan. 
-Unexpected: (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the IRB-approved documents, such as the 
protocol and informed consent document; and (b) the characteristics of the 
subject population being studied; 
o 
Attribution of the AE:  
 
Definite – The AE is clearly related to the combination of TAS-102 and 
Irinotecan. 
 
Probable – The AE is likely related to the combination of TAS-102 and 
Irinotecan. 
 
Possible – The AE may be related to the combination of TAS-102 and 
Irinotecan. 
 
Unlikely – The AE is doubtfully related to the combination of TAS-102 
and Irinotecan. 


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 
Unrelated – The AE is clearly NOT related to the combination of TAS-
102 and Irinotecan. 
o 
Start Date 
 
Start date of the AE is the date that the first signs/symptoms were noted 
by the subject and/or investigator 
o 
Stop Date  
 
Stop date of the AE is the date at which the subjects recovered, the 
event resolved but with sequelae or the subject died.  
7.3.3 Serious Adverse Events 
A “serious” adverse event is defined in regulatory terminology as any untoward 
medical occurrence that: 
7.3.3.1 
Results in death. 
If death results from (progression of) the disease, the disease should 
be reported as event (SAE) itself. 
7.3.3.2 
Is life-threatening. 
(the patient was at risk of death at the time of the event; it does not 
refer to an event that hypothetically might have caused death if it were 
more severe). 
7.3.3.3 
Requires in-patient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours. 
 
 
 
 
Following events do not satisfy criteria for SAE: 
 
 
 
 
Hospitalizations for preplanned procedures 
 
 
 
 
Hospitalization for study-related treatment and procedures 
7.3.3.4 
Results in persistent or significant disability or incapacity. 
7.3.3.5 
Is a congenital anomaly/birth defect 
7.3.3.6 
Is an important medical event 
Any event that does not meet the above criteria, but that in the 
judgment of the investigator jeopardizes the patient, may be 
considered for reporting as a serious adverse event. The event may 
require medical or surgical intervention to prevent one of the 
outcomes listed in the definition of “Serious Adverse Event“.  
For example: allergic bronchospasm requiring intensive treatment in 
an emergency room or at home; convulsions that may not result in 
hospitalization; development of drug abuse or drug dependency. 
7.4 
Reporting Requirements  
 
All unanticipated problems, SAEs, non-compliance, serious or continuing non-
compliance, deviations, violations and prospective/planned deviations must be reported 
to the following entities and entered into OnCore according to the timelines mentioned 
below. Serious adverse events and adverse events will be collected from the time the 
research patient begins treatment until 30 days after the end of treatment. All adverse 


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events/serious adverse events should be followed until resolution or stabilization, or the 
subject dies or withdraws consent from participation in the study. 
 
 


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Event Type  
Coordinating Center/Medical 
Monitor 
UCI IRB  
Local IRB 
Taiho Oncology* 
CFCCC DSMB 
Unanticipated 
Problem  
Within 24 hours from date the site 
is aware of the event, the site 
should enter this information into 
OnCore. An email notification 
should also be sent via email to 
fdayyani@hs.uci.edu and 
uci18125@hs.uci.edu.  
Within 5 
business days 
submit an 
Unanticipated 
Problem 
Report (UP). 
Current policy 
can be found 
here. 
According to 
local 
institutional 
policies and 
guidelines 
 
Within 24 hours of learning of the event. 
Submit a MedWatch Form to Taiho via fax 
(609-750-7371) or email (TAS-
102_Safety@taihooncology.com)  
Within 5 days from 
date PI is aware of 
the event. This 
information must be 
reported into 
OnCore.  
AEs and SAEs (non-
Unanticipated 
Problem)  
Please refer to section 7.5 for 
reporting timeframes on AEs and 
SAEs.     
N/A  
All other SAEs should be reported within 2 
weeks of awareness. Please see section 
7.6 below for additional reporting for 
SAEs.   
Please refer to 
section 7.5  for 
clarification on 
reporting timeframes 
for AEs and SAEs.  
Non-compliance  
N/A 
N/A 
N/A 
Please refer to 
section 7.5 for 
reportable 
deviations/violations.   
Serious or 
continuing non-
compliance  
Within 24 hours via email to 
fdayyani@hs.uci.edu and 
uci18125@hs.uci.edu    
Within 5 
business days 
submit a New 
Information 
Report 
N/A 
Within 5 days from 
date PI is aware of 
the event.  
Prospective/Planned 
Deviations  
At least 5 business days prior to 
the event via email to 
fdayyani@hs.uci.edu and 
uci18125@hs.uci.edu for 
approval.    
At least 48 
hours prior to 
date the 
request is 
needed by. 
Submit a  
Prospective 
Deviation 
N/A  
At the time of 
progress review as 
aggregate reports.  


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Request form 
*Patients who become pregnant must be reported along same timelines as SAE.  Please reference section 7.6 below in regards additional safety information 
required to be reported to TAIHO for subjects who become pregnant. 
 
 
 


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7.5 
Additional Reporting Requirements to CFCCC DSMB and Coordinating Center/Medical Monitor  
All adverse events, serious adverse events, violations, deviations and unanticipated problems must be entered into OnCore. All participating institutions 
must enter the events into OnCore and notifying the coordinator center via email, according to the reporting requirements below.  
 
Adverse Event/ Serious Adverse Events  
Event Type  
Reporting Timeframe to 
CFCCC DMSB  
(Notification is done by 
entering this information into 
OnCore within the timelines 
below)  
Reporting Timeframe to 
Coordinating Center 
(Notification is done via email 
to fdayyani@hs.uci.edu and 
uci18125@hs.uci.edu within 
the timelines below)  
 
Unexpected SAE all attributions (unrelated, unlikely, possibly, 
probably, definite) 
 Grades 3-5  
 
Unexpected, Related (possible, probable, definite) AE occurring 
within 30 days of the last dose of treatment 
 
Grades 3,4 
5 business days from date the 
PI is aware of the event.  
Only report if the SAE 
occurred within 30 days of last 
dose of treatment. 
Notification must be 24 hours 
from date the site is aware of 
the event.  
 
Expected AE/SAE, all attributions (unrelated, unlikely, possibly, 
probably, definite) 
 
Grades 1-5 
Progress review as aggregate 
report. This information must 
be reported into OnCore.     
5 business days from the date 
the site is aware of the event 
 
Deviations/Violations 
Event Type  
Reporting Timeframe to CFCCC 
DSMB 
Reporting Timeframe to 
Coordinating Center (Or other 
entity monitoring/coordinating the 
trial) 
Violations as defined above (e.g. wrong dosage of drug 
administered, safety procedures not being conducted at specific 
time points). 
5 business days from the date the PI 
is aware of the event 
24 hours from the date the site is 
aware of the event 
Planned deviations (e.g. rescheduling a visit that will be out of 
window due to holiday) 
At the time of progress review as 
aggregate reports 
5 business days from the date the 
site is aware of the event  


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Deviation as defined above (e.g. rescheduled visit, a missed 
routine safety laboratory test for a participant with previously 
normal values) 
At the time of progress review as 
aggregate reports 
5 business days from the date the 
site is aware of the event 
All incidents (violations, deviations) that occurred during the 
study 
At the time of progress review, as 
aggregate reports. Includes 
violations that were promptly 
reported (within 5 days) will be 
included in the aggregate report for 
review 
 


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7.6 
Additional Clinical Reporting Requirements to Taiho 
SAE Reconciliation 
 
Reconciliation shall be performed quarterly as an exchange of Line Listings or other means in 
English. On a quarterly basis, the institution shall provide to TAIHO a line listing or other 
means of cumulative SAE received to date.  At the end of the Clinical Trial a global 
reconciliation shall be performed. Please reference contact information when sending this 
reconciliation.  All serious adverse events via a MedWatch Form need to be sent to  Taiho 
Oncology, Inc., via fax: 609-750-7371 or e-mail: TAS-102_Safety@taihooncology.com 
(please note the underscore between ‘102’ and ‘Safety’).   
 
DSUR 
 
If requested by Institution, TAIHO shall provide the Institution with the final version of 
this DSUR report within 15 calendar days after submission to health agencies and 
ethics committees.  
 
Pregnancy 
 
Drug Exposure During Pregnancy and Lactation, or Paternal Drug Exposure Reports 
 
The Institution will report Exposure During Pregnancy and Lactation, or Paternal 
Drug Exposure on any Clinical Trial Subject while participating in the Clinical 
Trial, and following exposure to a TAIHO IMP, to TAIHO (as specified below) 
using copies of the original Pregnancy Report Form and within two weeks of first 
becoming aware of the pregnancy or exposure. If the partner of a Clinical Trial 
Subject becomes pregnant, the Institution may collect information about the 
pregnancy and birth if the partner agrees. 
 
 
The Clinical Trial Subject will also be followed by the Institution to determine the 
outcome of the pregnancy (including any premature termination of the 
pregnancy). Information on the status of the mother and child will be forwarded to 
TAIHO. The Institution must provide final outcome of pregnancy to TAIHO. If any 
SAE(s) is observed in Clinical Trail Subject or fetus/child, then SAE(s) must also 
be reported to TAIHO following SAE Reporting guidelines.  
 
Routing of Drug Exposure During Pregnancy and Lactation, or Paternal Drug 
Exposure Reports 
o 
Such reports and Information as outlined above, Including Investigator 
causality assessments against all concerned TAIHO IMP(s) and English 
translations where reporting Is from a non-English speaking country, shall be 
sent: 
o 
by facsimile to PV CONTACT NUMBER :609-750-7371 OR 
o 
by e-mail to: TAS-102_Safety@taihooncology.com (please note the 
underscore between '102' and 'Safety') 
 
8.0 
DRUG INFORMATION 
8.1 
TAS-102 
 


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A list of the adverse events and potential risks associated with TAS-102 can be found in Section 7.1.   
 
 
Other names for the drug(s):  
trifluridine and tipiracil 
LONSURF 
 
 
Classification - type of agent: 
Antimetabolite 
 
 
Mode of action: 
TAS-102 is a combination of trifluridine, a nucleoside metabolic inhibitor, and tipiracil, 
a thymidine phosphorylase inhibitor. 
 
 
Storage and stability: 
 
Store at 20°C to 25°C (68°F to 77°F); excursions are permitted from 15°C to 
30°C (59°F to 86°F) [See USP Controlled Room Temperature]. 
 
LONSURF is a cytotoxic drug. Follow applicable special handling and disposal 
procedures. “OSHA Hazardous Drugs”. OSHA. 
(http://www.osha.gov/SLTC/hazardousdrugs/index.html) 
 
If stored outside of original bottle, discard after 30 days. 
 
 
Protocol dose:  
25mg/m2 twice daily for 5 days every 14 days 
 
 
Preparation: 
N/A 
 
 
Route of administration for this study: 
Oral  
 
 
Incompatibilities: 
None  
 
 
Availability: 
Provided by supporter 
 
 
Agent Ordering 
Taiho Pharmaceuticals Co., Ltd. 
Sub-site(s) will also order agent from Taiho Pharmaceuticals Co., Ltd. and the agent 
will ship directly to each site.  
 
 
Side effects:  
The most common adverse reactions (≥10%) are anemia, neutropenia, 
asthenia/fatigue, nausea, thrombocytopenia, decreased appetite, diarrhea, vomiting, 
abdominal pain, and pyrexia. 
 
 
Agent Accountability 
 
Accountability for the study drug at the study center is the responsibility of the 
Investigator. The Investigator will ensure that the study drug is used only in 
accordance with this protocol. Where allowed, the Investigator may choose to assign 
drug accountability responsibilities to a pharmacist or other appropriate individual. 


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The Investigator or delegate will maintain accurate drug accountability records 
indicating the drug’s delivery date to the site, inventory at the study center, use by 
each patient, and destruction.  
 
These records will adequately document that the patients were provided the doses as 
specified in the protocol and should reconcile all study drug received from Taiho. 
 
Study drug must not be used for any purpose other than the present study. Study 
drug that has been dispensed to a patient and returned unused must not be re-
dispensed to a different patient. 
 
Patients will receive instructions for home administration of TAS-102 according to the 
regimen description above. TAS-102 is to be taken within 1 hour after completion of 
morning and evening meals. If doses of TAS-102 are missed or held, the patient 
should not make up for the missed doses.  
 
Patients will be given a study medication diary to complete at home for TAS-102. 
Compliance with the dosing regimen will be assessed based on completion of the 
drug diary and return of unused drug (or empty bottles).  
 
IMP Destruction 
IMP will be destroyed by the sites  according to their institutional policies. 
Destruction logs should be made available to Taiho at the end of the study. 
IMP Returns 
Taiho will not accept returned IMP. 
8.2 
Irinotecan 
 
A list of the adverse events and potential risks associated with Irinotecan can be found in Section 7.1.   
 
 
Other names for the drug(s):  
CPT-11 
CAMPTOSAR 
 
 
Classification - type of agent: 
Topoisomerase I inhibitor 
 
 
Mode of action: 
Irinotecan is a derivative of camptothecin that inhibits the action of topoisomerase I. 
Irinotecan prevents religation of the DNA strand by binding to topoisomerase I-DNA 
complex, and causes double-strand DNA breakage and cell death. 
 
 
Storage and stability: 
 
Store at controlled room temperature 15° to 30°C (59° to 86°F). Protect from 
light. Keep the vial in the carton until the time of use. 
 
 
The solution is physically and chemically stable for up to 24 hours at room 
temperature (approximately 25°C) and in ambient fluorescent lighting. Solutions 
diluted in 5% Dextrose Injection, USP, and stored at refrigerated temperatures 
(approximately 2° to 8°C), and protected from light are physically and chemically 
stable for 48 hours. Refrigeration of admixtures using 0.9% Sodium Chloride 
Injection, USP, is not recommended due to a low and sporadic incidence of 


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visible particulates. Freezing CAMPTOSAR and admixtures of CAMPTOSAR 
may result in precipitation of the drug and should be avoided. 
 
 
Protocol dose:  
180 mg/m2 on day 1 every 14 days 
 
 
Preparation: 
Dilute in 5% Dextrose Injection, USP, (preferred) or 0.9% Sodium Chloride Injection, 
USP, to a final concentration range of 0.12 to 2.8 mg/mL according to institutional 
standards. 
 
 
Route of administration for this study: 
Intravenous infusion  
 
 
Incompatibilities: 
None  
 
 
Availability: 
Commercially available 
 
 
Agent Ordering 
Provided locally by the trial site 
 
 
Side effects:  
Common adverse reactions (≥30%) observed in combination therapy clinical studies 
are: nausea, vomiting, abdominal pain, diarrhea, constipation, anorexia, mucositis, 
neutropenia, leukopenia (including lymphocytopenia), anemia, thrombocytopenia, 
asthenia, pain, fever, infection, abnormal bilirubin, alopecia. 
 
Common adverse reactions (≥30%) observed in single agent therapy clinical studies 
are: nausea, vomiting, abdominal pain, diarrhea, constipation, anorexia, neutropenia, 
leukopenia (including lymphocytopenia), anemia, asthenia, fever, body weight 
decreasing, alopecia. 
 
9.0 
STATISTICAL CONSIDERATIONS 
9.1 
Study Design/Study Endpoints 
This is a prospective single arm open label multi-institutional study. The primary endpoint 
is rate of progression free survival at 6 months (PFS-6) after starting treatment. 
Progression is defined in section 6.1.6. 
Secondary endpoints include: 
 
Overall survival, defined as time from starting treatment to death from any cause. 
 
Objective response rate in patients with measurable disease as defined in 
section 6.0 
 
Safety as described in the adverse events in section 7.0 
 
9.2  
Sample Size and Accrual 
Based on recently published phase 3 data for advanced GAC, PFS-6 in 2L with optimal 
treatment is estimated at about 35%[17]. In 3L setting, the largest most contemporary 
randomized phase 3 trial of TAS-102 vs best supportive care (BSC) defined a PFS-6 of 
15% with single agent TAS-102 vs 6% with BSC.  The hypothesis is that the combination 


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of TAS-102 and irinotecan will improve PFS-6 compared to these recent historical 
controls. To estimate the efficacy, n= 20 patients will be enrolled. If at least n=7 patients 
have not progressed by 6 months (i.e. observed PFS-6 = 35%), then the observed PFS-6 
of 35% will have a one sided lower 95% CI of 17.5%[34]. This means the lower boundary 
for estimated efficacy is as good as or better than currently available options in 3L 
setting. 
 
The formula to calculate the lower boundary for the 95% CI is calculated as: 
 
95% confidence interval = effect size ± 1.645 × standard error of the effect size[34] 
 
The assumptions for this study are as follows: 
 
Number of responses to treatment = 7  
Number of subjects (N) = 20  
Observed proportion (P) = 7/20 = 0.35 (or 35%)  
Standard error of the true proportion (SE) = √ [P × (1 − P)]/N = (0.35 × 0.65)/20 = 0.107 
Lower boundary 95%CI = P - 1.645 × SE = 0.35 - 1.645 × 0.107 = 0.175 
 
Based on the total number of metastatic GAC seen at UC Irvine (n= 40 in 2017) and UC 
Davis, it is estimated that up to 5 patients are screened monthly and enrollment is 2 
patients per month. Based on these assumptions, accrual goal will be met within 12 
months of opening enrollment. Considering a minimum of 6 months of follow-up after the 
last patient in (to estimate PFS-6), final analysis will be performed up to 18 months after 
the last patient has started treatment. 
 
9.3 
Stopping for Futility: 
Efficacy is signaled by at least seven out of 20 being progression-free at six months.  
Therefore, if none of the first 14 evaluable enrollees is progression-free at six months, 
futility will be declared. 
9.4 
Continuous Monitoring for Excess Toxicity:  
 
All participants in trial are monitored for serious toxicity for the duration of their 
participation in the study.  Serious toxicities are given in Section 7.    A sequential 
Pocock-type boundary will inform decisions to continue or stop accrual for excess toxicity, 
as accrual proceeds (Ivanova, 2005).  The table below gives the cumulative number of 
participants enrolled and the corresponding cumulative number of participants showing 
serious toxicities that will signal the underlying risk of serious toxicity exceeds 33 percent 
(5% risk of type-1 error).   
 
Threshold Number of Cumulative Toxicities that Signal Excess Toxicity as a Function of 
Cumulative Number Enrolled* 
 
Cumulative 
Number 
Enrolled 
Threshold Number 
Showing Serious 
Toxicity to Stop 
Accrual 
1 
- 
2 
- 
3 
- 
4 
4 
5 
5 


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6 
5 
7 
6 
8 
7 
9 
7 
10 
7 
11 
8 
12 
8 
13 
9 
14 
9 
15 
10 
16 
10 
17 
11 
18 
11 
19 
12 
20 
12 
 
Pocock –type boundary with maximum acceptable probability of toxicity set 
to 33 percent and type-1 risk of five percent (Ivanova, 2005). 
 
9.5 
Analyses of Secondary Endpoints and Ad-Hoc comparisons 
Participants will be characterized on host and demographic factors, with continuous 
measures given as means or medians and categorical measires given as percents.  
Consistent with the phase-II nature of the research, we will examine the data in many 
ways to illuminate future research priorities.  We will estimate survival curves for 
progression-free and overall survival, and attempt to identify systematic differences 
between those who respond to treatment and those who do not.  Survival will be 
estimated by Kaplan-Meier methods.  If assumptions are met, we will model survival 
using Cox proportional- hazards, eliminating ties by subtracting a small, randomly 
generated amount from the observed times .  As may be indicated, we will transform data 
to correspond better to analytic requirements, using logit transforms for percent data and 
log or some other approach for continuous measures.  As the goals of these secondary 
analyses are to inform decisions about future research, no formal statistical hypothesis-
testing will be done, probabilities from statistical tests will augment clinical judgment in 
interpretation, and we will not regard overall, study-wise, error rates for these secondary 
analyses. 
10.0 
STUDY MANAGEMENT 
10.1 
Conflict of Interest 
 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, 
or financial gain greater than the minimum allowable by their institution, etc.) must have 
the conflict reviewed by their own institution’s COI committee. All investigators will follow 
the University conflict of interest policy. 
 
10.2 
Institutional Review Board (IRB) Approval and Consent  
It is expected that the IRB will have the proper representation and function in accordance 
with federally mandated regulations. The IRB should approve the consent form and 
protocol. 
 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) 
and to ethical principles that have their origin in the Declaration of Helsinki. 


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Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent form. 
Each consent form must include all the relevant elements currently required by the FDA 
Regulations and local or state regulations. Once this essential information has been 
provided to the patient and the investigator is assured that the patient understands the 
implications of participating in the study, the patient will be asked to give consent to 
participate in the study by signing an IRB-approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be 
signed and personally dated by the patient and by the person who conducted the 
informed consent discussion.  
 
10.3 
If a blind or illiterate person who cannot read and write is enrolled into the trial, 
they must be able to understand the implications of the participating in the study 
and be able to indicate approval or disapproval to the study entry. An impartial 
third party is required to witness the entire consent process and will also need to 
sign the consent form along with the subject and consenting investigator. 
Required Documentation (for multi-site studies) 
Before the study can be initiated at any site, the following documentation must be 
provided to UCI CFCCC. 
 
 
A copy of the official IRB approval letter for the protocol and informed consent 
 
IRB membership list 
 
CVs and medical licensure for the principal investigator and any associate 
investigators who will be involved in the study 
 
Form FDA 1572 appropriately filled out and signed with appropriate documentation  
 
Financial Disclosure statements for the PI and participating investigators, as 
necessary 
 
A copy of the IRB-approved consent form and HIPAA form  
 
IRB member list with their occupations and institutional affiliations or a general 
assurance number will be acceptable.  
 
CAP and CLIA Laboratory certification numbers and institution lab normal values 
 
Signed protocol signature page  
10.4 
Data Completion  
10.4.1 OnCore Date Entry  
Data, as indicated by Sponsor, will be entered into OnCore – UC Irvine’s Clinical Trial 
Management system. The Investigator is responsible for ensuring all entries are accurate 
and correct. The Investigator must maintain accurate source data that support OnCore 
data entry. All data will be entered as per Sponsor’s specification and timeframe.  
10.4.2 Recording of Events 
All investigator initiated treatment trials require that adverse events, serious adverse 
events, deviations, and unanticipated problems be entered into the clinical trial 
management system (CTMS), OnCore.  All entries must be entered in OnCore within the 
timelines specified in section 7.4-7.6 of being aware of the adverse event, serious 
adverse event, violation, deviation, or unanticipated problem.  Adverse events and 
violations/deviations and adverse events that are unanticipated problems that require 


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prompt reporting to the DSMB must be entered into OnCore according to the timelines as 
specified in section 7.4-7.6 
10.5 
Data and Safety Monitoring/Auditing 
10.5.1 Quality Assurance  
Quality assurance activities will be conducted as per UC Irvine Chao Family 
Comprehensive Cancer Center’s Quality Assurance Monitoring and Auditing Plan and at 
the discretion of the CFCCC Data and Safety Monitoring Board in order to ensure patient 
safety and data integrity oversight. By conducting internal monitoring and auditing, the 
CFCCC will ensure compliance with high quality standards and all applicable regulations, 
guidelines, and institutional policies. Trial monitoring and auditing may be completed 
remotely or on-site by the Quality Assurance Officer. Participating sites may follow their 
own internal quality assurance policies in order to maintain patient safety and data 
integrity oversight. The investigator must permit study-related monitoring/auditing and 
provide access to study-related materials.  
 
10.5.2 Data and Safety Monitoring Plan  
This is a risk level 2 study, as defined in the Chao Family Comprehensive Cancer 
Center (CFCCC) Data and Safety Monitoring Plan (DSMP) because it is a study in which 
the IND is exempt by the FDA.   
 
The Principal Investigator (PI), co-investigator, clinical research coordinator, and 
statistician are responsible for monitoring of data and safety for this study.  For studies 
that have stopping rules for safety and efficacy, the PI will be responsible for the 
implementation and make changes as applicable. The CFCCC Data and Safety 
Monitoring Board (DSMB) is an independent body responsible for the safety of study 
subjects as well as the data integrity of the protocol.  Data and safety will be reported to 
the DSMB with submission of progress reports that include aggregated reports of 
adverse events, serious adverse events, deviations, and violations.  In addition, all 
adverse events, deviations, and violations will be reported promptly to the DSMB for 
review according to section 7.4.   
10.6 
Protocol Deviations 
All protocol deviations will be reported in accordance with UCI IRB, UCI CFCCC Stern 
Center policies and the participating site’s IRB policies.  
10.7 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Principal Investigator. It should also be noted that when an 
amendment to the protocol substantially alters the study design or the potential risk to the 
patient, a revised consent form might be required.  
 
The written amendment, and if required the amended consent form, must be sent to the 
IRB for approval prior to implementation.  
 
Except for an emergency situation in which proper care for the protection, safety, and 
well-being of the study patient requires alternative treatment, the study shall be 
conducted exactly as described in the approved protocol. 
 
Due to restrictions instituted during the COVID-19 pandemic, planned clinic visits may be 
performed according to local institutional policy for natural disasters or a pandemic.  


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Whenever possible, on-site clinic visits will be replaced by telemedicine visits between 
the clinic staff and on-study patients. 
 
Emergency Modifications may be enacted if needed to ensure the safety, and well-being 
of the study patients.  Investigators may implement a deviation from, or a change of, the 
protocol to eliminate an immediate hazard(s) to trial subjects without prior IRB approval.  
For any such emergency modification implemented, an IRB modification form must be 
completed within five (5) business days of making the change. 
 
All other planned deviations from the protocol must have prior approval by the Principal 
Investigator and the IRB. Please refer to Section 7.3 for more information on how 
protocol deviations and violations are defined. It will also provide instructions on when 
and who to contact and obtain approval from for prospective deviations. Protocol 
deviations should also be reported to UCI IRB and DSMB. 
10.8 
Record Retention 
Study documentation includes all Case Report Forms, data correction forms or queries, 
source documents, Sponsor-Investigator correspondence, monitoring logs/letters, and 
regulatory documents (e.g., protocol and amendments, IRB correspondence and 
approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities 
and all reports and records necessary for the evaluation and reconstruction of the clinical 
research study. 
 
Government agency regulations and directives require that the study investigator must 
retain all study documentation pertaining to the conduct of a clinical trial. 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. 
10.9 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki. The Principal Investigator is responsible for personally overseeing the treatment 
of all study patients. The Principal Investigator must assure that all study site personnel, 
including sub-investigators and other study staff members, adhere to the study protocol 
and all FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and 
after study completion. 
 
The Principal Investigator at each institution or site will be responsible for assuring that all 
the required data will be collected and entered onto the Case Report Forms. Periodically, 
monitoring visits will be conducted and the Principal Investigator will provide access to 
his/her original records to permit verification of proper entry of data. At the completion of 
the study, all case report forms will be reviewed by the Principal Investigator and will 
require his/her final signature to verify the accuracy of the data. 
11.0 
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Protocol #: UCI 18-125 
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This material is the property of the UC Irvine Chao Family Comprehensive Cancer Center. Do not disclose or use except as authorized in writing 
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[18] 
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second-line chemotherapy in gastric cancer – A randomised phase III study of the 
Arbeitsgemeinschaft Internistische Onkologie (AIO),” Eur. J. Cancer, vol. 47, no. 15, pp. 2306–
2314, Oct. 2011. 
[19] 
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adenocarcinoma (COUGAR-02): an open-label, phase 3 randomised controlled trial,” Lancet 
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trial comparing chemotherapy plus best supportive care with best supportive care alone.,” J. Clin. 
Oncol., vol. 30, no. 13, pp. 1513–8, May 2012. 


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by the study sponsor. 
 
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[21] 
T. Janowitz et al., “Chemotherapy vs supportive care alone for relapsed gastric, gastroesophageal 
junction and oesophageal adenocarcinoma: a meta-analysis of patient-level data,” Br. J. Cancer, 
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K. Higuchi et al., “Biweekly irinotecan plus cisplatin versus irinotecan alone as second-line 
treatment for advanced gastric cancer: A randomised phase III trial (TCOG GI-0801/BIRIP trial),” 
Eur. J. Cancer, vol. 50, no. 8, pp. 1437–1445, May 2014. 
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B. M. X. H. Y. L. Y. W. Z. L. Yong Zhang, “Doublet Versus Single Agent as Second-line Treatment 
for Advanced Gastric Cancer: A Meta-analysis of 10 Randomized Controlled Trials,” Medicine 
(Baltimore)., vol. 95, no. 8, p. e2792, Feb. 2016. 
[24] 
S.-E. Al-Batran et al., “Quality-of-life and performance status results from the phase III RAINBOW 
study of ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously 
treated gastric or gastroesophageal junction adenocarcinoma,” Ann. Oncol., vol. 27, no. 4, pp. 
673–679, Apr. 2016. 
[25] 
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gastric cancer (TAGS): a randomised, double-blind, placebo-controlled, phase 3 trial,” Lancet 
Oncol., vol. 19, no. 11, pp. 1437–1448, Nov. 2018. 
[26] 
Y.-K. Kang et al., “Nivolumab in patients with advanced gastric or gastro-oesophageal junction 
cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, 
ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial.,” Lancet (London, 
England), vol. 390, no. 10111, pp. 2461–2471, Dec. 2017. 
[27] 
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Previously Treated Advanced Gastric and Gastroesophageal Junction Cancer,” JAMA Oncol., vol. 
4, no. 5, p. e180013, May 2018. 
[28] 
K. Sakamoto et al., “Crucial roles of thymidine kinase 1 and deoxyUTPase in incorporating the 
antineoplastic nucleosides trifluridine and 2’-deoxy-5-fluorouridine into DNA.,” Int. J. Oncol., vol. 
46, no. 6, pp. 2327–34, Jun. 2015. 
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T. Emura et al., “An optimal dosing schedule for a novel combination antimetabolite, TAS-102, 
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12.0 
APPENDICES 
APPENDIX A 
 
Performance Status Criteria 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs. 
50 
Requires considerable assistance 
and frequent medical care. 
3 
In bed >50% of the time.  
Capable of only limited self-care, 
confined to bed or chair more 
than 50% of waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX B 
 
Pill Diary 


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