Clinical trial NCT03686488
Conditions: Gastric Adenocarcinoma Gastroesophageal Junction Adenocarcinoma Gastric Cancer
Sponsor: H. Lee Moffitt Cancer Center and Research Institute
Start date: 2018-12-20; Completion date: 2024-05-31
Enrollment: 23 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to find out if the combination of TAS 102 and Ramucirumab is safe and effective in patients with advanced, refractory gastric or gastroesophageal junction (GEJ) adenocarcinoma.

Detailed description:

Arms: arm 1: TAS 102 (Lonsurf) and Ramucirumab 10 MG/ML Intravenous Solution (CYRAMZA) administered concurrently.
Interventions: intervention 1: TAS 102 intervention 2: Ramucirumab 10 MG/ML Intravenous Solution [CYRAMZA]
Intervention descriptions: intervention 1: TAS 102 35 mg will be administered orally twice daily every 2 weeks. intervention 2: Ramucirumab 8 milligrams/kilogram will be administered as a 60 minute intravenous (IV) infusion every 2 weeks.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
A Phase II study of TAS 102 in Combination with Ramucirumab in 
Advanced, Refractory Gastric or Gastroesophageal Junction (GEJ) 
adenocarcinoma 
 
NCT03686488 
 
 
Version 1.7 
 
December 3, 2019 


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A Phase II study of TAS 102 in Combination with Ramucirumab in 
Advanced, Refractory Gastric or Gastroesophageal Junction (GEJ) 
adenocarcinoma 
 
MCC # 19477 
 
Principal Investigator: 
Dae Won Kim M.D. 
 
H. Lee Moffitt Cancer Center 
 
12902 Magnolia Drive, Tampa, Florida, 33612 
Telephone: 813-745-6898 
Fax: 813-745-7229 
E-mail: Daewon.Kim@moffitt.org 
 
 
 
Co-Investigators: 
 
 
 
 
 
Rutika Mehta 
                                                 Rutika.mehta@moffitt.org 
 
                                                 Iman Imanirad 
                                                 Iman.imanirad@moffitt.org 
 
                                                  
 
 
 
Statistician: 
Youngchul Kim, PhD 
 
Youngchul.kim@moffitt.org 
 
 
Protocol Version Date: 12/03/19 
 
Protocol Version Number: V1.7 
 
 
 
 
 
 
 
 
 
  
 
 
 


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Protocol Synopsis 
 
Title 
A Phase II study of TAS 102 in Combination with Ramucirumab in 
Advanced, Refractory Gastric or Gastroesophageal Junction (GEJ) 
Adenocarcinoma 
Clinical study phase Phase II 
Study Agents 
TAS 102 PO 
Ramucirumab IV 


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Background 
Gastric cancer is the second most lethal form of cancer worldwide. 
Patients with advanced gastric cancer experience a 5 year survival rate 
<10% even with multimodality therapy representing a clear unmet need 
for improved treatment. 
 
Tumor angiogenesis plays an essential role in cancer growth and 
metastasis, and therapies targeting tumor angiogenesis are used in a 
variety of malignancies. In advanced gastric and GEJ adenocarcinoma, 
ramucirumab 
(a 
monoclonal 
antibody 
against 
VEGFR2) 
has 
demonstrated clinical activity and has been approved as second line 
therapy. However, the clinical benefit and impact on tumor control is 
modest and transient with 8% of objective response rate and 2 months of 
progression free survival. The acquired tumor resistance to anti-
angiogenic therapy has been well established and is hypothesized to 
occur through several mechanisms including the upregulation of 
proangiogenic factors. Dual anti-angiogenic therapy has thus been 
proposed as tumors can not only develop resistance to one anti-
angiogenic pathway but can exhibit multiple angiogenic pathways at the 
outset. The efficacy of dual antiangiogenic blockade such as 
bevacizumab plus sorafenib, a vascular disrupting agent (OXi4503) plus 
bevacizumab and a PDGFR inhibitor (SU6668) plus a VEGFR2 inhibitor 
(semaxinib) has been confirmed in preclinical and clinical studies.  
 
TAS 102 is an oral cytotoxic agent with two active components; 
trifluridine which inhibits tumor cell growth by being incorporated into 
DNA during DNA synthesis and tipiracil which inhibits the metabolism 
of trifluridine, thereby prolonging its ability to exert effect. Tipiracil also 
inhibits platelet derived endothelial cell growth factor (PDEGF) which 
plays a key role with VEGF in tumor angiogenesis. The combination of a 
cytotoxic agent with an antiangiogenic agent has demonstrated a 
significant anticancer activity in multiple cancers by increasing drug 
accessibility secondary to normalization of the tumor vasculature and by 
enhanced direct cytotoxicity of cancer cells and endothelial cells. 
 
As there are known synergy of dual antiangiogenic therapy, and the 
combination of a cytotoxic agent with an antiangiogenic agent, the 
combination of TAS 102 with ramucirumab may potentially produce a 
synergistic tumor response by complete inhibition of tumor angiogenesis 
through the blockade of two major tumor angiogenic factors (VEGF and 
PDEGF) and by enhanced delivery of cytotoxic trifluridine to tumor 
through normalization of poorly organized, tortuous and hyperpermeable 
tumor vasculature.    
 
We hypothesize that a combination of TAS 102 and ramucirumab might 
increase efficacy without causing unmanageable toxicity.  


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Rationale  
We hypothesize that the combination of ramucirumab and TAS102 will 
be a safe and effective in metastatic gastric and GEJ adenocarcinoma by 
dual angiogenic inhibition of PDEGF and VEGF and by classic cytotoxic 
activity of trifluridine. 
Study objectives 
Primary Objective 
To determine the 6 month overall survival in patients with advanced, 
refractory gastric or gastroesophageal junction (GEJ) adenocarcinoma 
receiving TAS 102 in combination with ramucirumab. 
 
Secondary Objectives  
1. To determine the frequency and severity of adverse events and 
tolerability of TAS 102 plus ramucirumab in patients with advanced, 
refractory gastric or GEJ adenocarcinoma  
2. To determine the objective response rate of TAS 102 in combination 
with ramucirumab based on Response Evaluation Criteria in Solid 
Tumors (RECIST) v1.1    
3. To determine the progression free survival in patients with advanced, 
refractory gastric or GEJ adenocarcinoma receiving TAS 102 in 
combination with ramucirumab. 
 
Exploratory Objectives 
1. To evaluate potential correlations between blood biomarkers and 
clinical outcome using a multiplex assay evaluating circulating 
angiogenic biomarkers 


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Indication 
Patients with advanced, refractory gastric or GEJ adenocarcinoma 
Diagnosis and main 
criteria for 
inclusion 
• Age ≥18 years of age. 
• Histologically confirmed diagnosis of gastric or GEJ 
adenocarcinoma 
• Measurable or evaluable disease by Response Evaluation Criteria 
in Solid Tumors (RECIST) 1.1.  Stage IV or recurrent disease is 
required. 
• Patients must have received at least 1 line of prior treatment for 
advanced/metastatic gastric or GEJ adenocarcinoma.  
• ECOG Performance Score 0 or 1 
• Adequate bone marrow, liver and renal function as assessed by 
the following: 
o Hemoglobin > 8.0 g/dl 
o Absolute neutrophil count (ANC) > 1,000/mm3 independent of 
growth factor support 
o Platelet count > 100,000/mm3  
o Total bilirubin < 1.5 times ULN unless bilirubin rise is due to 
Gilbert’s syndrome or of non-hepatic origin 
o AST, ALT and Alkaline Phosphatase ≤2.5 times the ULN ( ≤5 x 
ULN for patients with liver involvement) 
o Creatinine clearance ≥ 30 ml/min 
Study design 
This is a single institutional phase II single arm two-stage design trial 
using the combination of TAS 102 and ramucirumab in advanced, 
refractory gastric or GEJ adenocarcinoma. Patients will enter daily use of 
study medication (TAS 102) in a medication diary for a measure of 
compliance (Appendix B) 
Number of subjects 25 
Plan for statistical 
analysis 
Overall survival (OS) will be defined as the time from starting on trial 
to date of death due to any cause. The final analysis will be conducted 
after the follow-time of the last patient exceeds 6 months. OS at 6 
months is the primary endpoint of the trial and will be estimated using 
the Kaplan-Meier method. The two-sided 95% confidence interval (CI) 
for median OS will be computed using log-log transformation. The 
sample size was determined based on the Simon’s two-stage minimax 
design. With one-sided 10% of type I error rate and 90% power, a 
sample of evaluable 25 patients will be evaluated (P0: 0.45, P1: 0.7); 15 
in first stage and additional 10 patients in second stage. If 7 or more out 
of 15 survive 6 months or more, the study goes on the second stage. The 
experimental treatment will be deemed to have good activity if ≥15 out 
of 25 patients survive 6 months or more. We will continue to recruit 
patients during interim analysis 
 
 


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Table of Contents 
 1. 
Introduction ............................................................................................................... 9 
 
Background ............................................................................................................... 9 
 
Angiogenesis ............................................................................................................. 9 
 
Ramucirumab .......................................................................................................... 10 
 
TAS 102 .................................................................................................................. 11 
 
Rationale ................................................................................................................. 12 
2. 
Study Objectives ..................................................................................................... 13 
3. 
Study Design ........................................................................................................... 13 
4. 
Eligibility ................................................................................................................ 14 
 
Inclusion Criteria .................................................................................................... 14 
 
Exclusion Criteria ................................................................................................... 15 
 
Withdrawal of Subjects from Study ....................................................................... 16 
4.3.1 
Screen Failures/Dropouts/Replacements ................................................................ 17 
4.3.2 
Patient Replacement ............................................................................................... 17 
5. 
Treatment Plan ........................................................................................................ 17 
 
Drug Administration ............................................................................................... 18 
5.1.1 
Management (dose Modifications and dose delays) for Treatment-Related Toxicity
 ................................................................................................................................ 19 
 
Concomitant therapy ............................................................................................... 28 
5.2.1 
Prohibited Concomitant Medications ..................................................................... 28 
 
Blinding .................................................................................................................. 29 
 
Drug Logistics and Accountability ......................................................................... 29 
6. 
Visit schedule and Assessments ............................................................................. 29 
 
Screening First Visit ............................................................................................... 29 
 
Cycle 1 Day 1 ......................................................................................................... 30 
 
Cycle 1 Day 15 ....................................................................................................... 30 
 
Subsequent cycles (Cycle X Day 1) ....................................................................... 30 
 
Subsequent cycles (Cycle X Day 15) ..................................................................... 30 
 
After every 3rd cycle (Cycle 3 Day 1, Cycle 6 Day 1, etc.) .................................... 31 
 
End of Treatment Visit and Follow up ................................................................... 31 
 
Calendar .................................................................................................................. 32 
7. 
Assessment types .................................................................................................... 34 
 
Pre-Treatment Assessments .................................................................................... 34 
 
Efficacy ................................................................................................................... 34 


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Safety ...................................................................................................................... 34 
8. 
Safety monitoring and reporting ............................................................................. 34 
 
Adverse Events ....................................................................................................... 34 
8.1.1 
Definitions .............................................................................................................. 34 
 
Safety Monitoring ................................................................................................... 35 
8.2.1 
Internal Monitoring Plan ......................................................................................... 36 
 
Reporting of Serious Adverse Events ..................................................................... 36 
 
Pregnancies ............................................................................................................. 37 
9. 
Statistical Methods and Data Analysis .................................................................... 38 
 
Definition of Study Endpoints ................................................................................ 38 
 
Determination of sample size ................................................................................. 38 
 
Statistical analysis ................................................................................................... 39 
10. 
Data Recording ....................................................................................................... 39 
 
Institutional Review Board (IRB) Approval and Consent ...................................... 39 
 
Data Management and Monitoring/Auditing .......................................................... 39 
 
Adherence to the Protocol ...................................................................................... 40 
 
Emergency Modifications ....................................................................................... 40 
 
Record Retention .................................................................................................... 40 
 
Obligations of Investigators .................................................................................... 40 
11. 
Ethical and Legal Aspects ...................................................................................... 41 
 
Ethical and Legal Conduct of the Study ................................................................. 41 
 
Subject Information and Consent ........................................................................... 41 
 
Confidentiality ........................................................................................................ 42 
12. 
Appendix ................................................................................................................. 42 
APPENDIX A: RECIST Criteria for Measuring Tumor Response Antitumor Effect ............. 42 
APPENDIX B: Medication Diary ............................................................................................. 47 
13. 
References ............................................................................................................... 49 
 


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1. Introduction 
 
Background 
Gastric cancer is the third leading cause of global cancer related death worldwide with 
approximately one million new cases diagnosed each year1. In 2017, 28,000 new cases of gastric 
cancer and 10,960 deaths are predicted in the United States2. In spite of the significant advances 
in treatment modalities including radiation therapy, surgery and chemotherapy, the overall 
clinical outcome for patients with advanced gastric cancer is poor with median overall survival 
of 4-6 months3. The treatment of patients with advanced gastric or gastroesophageal junction 
(GEJ) adenocarcinoma is quite challenging. Although chemotherapy regimens including 
docetaxel, capecitabine, irinotecan, cisplatin and oxaliplatin have showed significant survival 
benefit in advanced gastric cancer4,  a majority of patients experience disease progression within 
6 months and die within 1 year of systemic treatment5. Recent clinical studies demonstrated that 
chemotherapy combined with trastuzumab significantly improved clinical outcome in patients 
with human epidermal receptor 2 (HER-2) overexpressing gastric or GEJ adenocarcinoma6. 
Unfortunately, HER-2 overexpressing tumors represent approximately 20% of the total number 
of gastric and GEJ adenocarcinoma6,7. Therefore, there is a significant unmet need for new 
therapeutic approach to improve clinical outcome of patients with the advanced gastric and GEJ 
adenocarcinoma. 
 
 
Angiogenesis  
Angiogenesis is essential for tumor growth and metastasis. The increase in the tumor size and the 
functional abnormality of tumor vasculature result in tumor necrosis and tissue hypoxia which 
stimulates angiogenesis by induction of VEGF expression8. The binding of VEGF to VEGF 
receptors (VEGFR) regulates the angiogenesis signaling. Among 3 major receptors including 
VEGFR1, VEGFR2 and VEGFR3, VEGFR2 plays a key role in angiogenesis because it is 
widely considered to be the primary receptor mediating angiogenesis, whereas VEGFR1 and 
VEGFR3 are classically involved in other pathways such as monocyte chemotaxis, 
hematopoietic stem cell survival and lymphangiogenesis9. Several studies demonstrated that 
VEGFR2 inhibition reduced tumor growth and vascularity10, and the expression of VEGFR2 
correlated with the vessel count and the stage of disease in gastric cancer11. In addition, 
circulating VEGF levels are associated with increased tumor aggressiveness and reduced 
survival in patients with gastric cancer12,13.  
In contrast to normal vessels, tumor capillaries are tortuous, blunt-end and chaotic in their 
organization14, and blood flow does not reach each region of the tumor equally. Notably, the 
blood flow abnormalities induced by tumor angiogenesis decrease anticancer activity of 
radiation, chemotherapy and immunotherapy by limiting delivery of oxygen and cytotoxic drugs 
to cancer cells and by limiting access of immune effector cells in tumors15,16. 
Therefore, tumor angiogenesis is essential not only for tumor progression and metastasis but also 
for resistance to anticancer therapy. 
 


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Ramucirumab 
 
Ramucirumab, a human IgG1 monoclonal antibody against VEGFR2, prevents ligand binding 
and receptor mediated pathway activation in endothelial cells. Several studies have shown that 
VEGFR2 is the main mediator of several physiological and pathological effects including 
proliferation, migration, survival and permeability of endothelial cells in tumor angiogenesis17. 
Based on the importance of VEGFR2 in tumor angiogenesis, antibodies targeting VEGFR2 
(ramucirumab) was developed, and ramucirumab and its murine version, DC-101 showed to 
inhibit angiogenesis and the growth of several mouse and human tumors in preclinical studies18, 
providing evidence that the blockade of VEGFR2 is an effective strategy for the treatment of 
human cancer.  
 
Clinical Experience 
 
Clinical Pharmacokinetics 
Ramucirumab Fab fragments has high binding affinity (0.1nmol/L) to VEGFR2 effectively 
blocking VEGF binding (50% inhibitory concentration=1-2nmol/L) and causing inhibition of 
VEGF induced intracellular calcium mobilization and endothelial cell migration, mitogenesis 
and proliferation in vitro19. Ramucirumab has been evaluated in human subjects in multiple 
studies at doses ranging from 2mg/kg to 16mg/kg. A mean half-life of ramucirumab is 14-15 
days and at doses of ≥8mg/kg, the clearance profile of ramucirumab remains relatively stable20, 
indicating saturation of the VEGFR2 mediated clearance pathway. Maximum tolerated dose is 
13mg/kg once weekly21. Given the pharmacokinetics, 8mg/kg every 2 weeks is used for 
metastatic gastric or GEJ adenocarcinoma. 
 
Clinical Efficacy 
In a phase III study, ramucirumab demonstrated significant prolongation of median overall 
survival (OS) compared with placebo (5.2 vs 3.8 months) and improved 6 month overall survival 
rates from 31.6% to 41.8% in the second-line setting of advanced gastric and GEJ 
adenocarcinoma22. Another phase III study showed that ramucirumab plus paclitaxel was 
associated with high objective response (28% vs 16%), improved median PFS (4.4 vs 2.9 
months) and median OS (9.6 vs 7.4 months) compared with paclitaxel in refractory advanced 
gastric and GEJ adenocarcinoma23. Based on the two phase III studies, ramucirumab alone or 
combined with paclitaxel has been approved for the treatment of advanced gastric and GEJ 
adenocarcinoma following first-line therapy. 
 
Clinical Safety 
Ramucirumab is generally well tolerated. The most common adverse events are fatigue, 
abdominal pain, decreased appetite, hypertension, vomiting and anemia. 
The warnings and precautions for ramucirumab include: hemorrhage, arterial thrombotic events, 
gastrointestinal perforation, hypertension, reversible posterior leukoencephalopathy syndrome, 
wound healing impairment and bone marrow suppression. 
 


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TAS 102 
 
TAS 102 is a novel oral cytotoxic agent which consists of trifluridine which inhibits tumor cell 
growth by being incorporated into DNA during DNA synthesis and tipiracil which inhibits the 
metabolism of trifluridine. Trifluridine is a thymidine based nucleoside analogue that is 
metabolized to the triphosphate metabolite, which is then incorporated into DNA, resulting in 
cell cycle arrest and cell death by inhibition of DNA synthesis and function. Trifluridine retains 
antitumor activity in 5-FU resistant tumor cells24. However, trifluridine is rapidly degraded to its 
inactive form in the intestines and the liver (first-pass effect), and tipiracil (another component of 
TAS 102) helps to maintain adequate trifluridine plasma concentration by inhibition of 
thymidine phosphorylase (known as platelet derived endothelial cell growth factor). In addition 
to enhancement of trifluridine’s bioavailability by reducing its degradation, tipiracil possesses 
antiangiogenesis by inhibition of platelet derived endothelial cell growth factor (PDEGF) which 
plays a key role with VEGF in tumor angiogenesis25. PDEGF protects cancer cells from hypoxia- 
or chemotherapy- induced apoptosis by inhibition of mitochondrial release of cytochrome C, 
upregulation of BCL-2 and BCL-XL, suppression of the phosphorylation of p38 MAPK and 
inactivation of caspase 3 and 926. PDEGF also plays an essential role in tumor invasiveness and 
metastasis by enhancing the expression of genes involved in the epithelial to mesenchymal 
transition program such as MMP-1, MMP-7, MMP-9, urokinase-type plasminogen activator and 
VEGF27,28. Thus, by inhibiting PDEGF, tipiracil may have multiple anticancer properties 
independent of its synergism with trifluridine.  
 
Pre-Clinical Experience 
 
Preclinical studies demonstrated that TAS 102, the combination of trifluridine and tipiracil had 
increased plasmatic trifluridine levels and enhanced tumor growth inhibitory activity compared 
with trifluridine alone29. Interestingly, trifluridine and TAS 102 showed antitumor activity in 
cancer cells and xenograft models in both 5-FU naïve and 5-FU resistant tumor cells30. Inhibition 
of neovascular formation by tipiracil was also confirmed in a gelatin-sponge mouse model29. 
 
Clinical Experience 
 
Clinical Pharmacokinetics 
TAS 102 has been tested in multiple clinical trials with doses ranging from 30mg/m2/day to 160 
mg/m2/day (trifluridine dose). MTD was 70mg/m2/day when given twice a day on days 1-5 and 
8-12 of a 28 day cycle31. Postprandial administration is recommended for TAS 102 because 
trifluridine’s area under the curve is not changed by food but the maximum concentration of 
trifluridine decreases in neutrophils with postprandial administration32. Half-life of trifluridine 
and tipiracil is 2.1 hours and 2.4 hours, respectively. Given the pharmacokinetics, 35mg/m2 twice 
daily within 1 hour of completion of morning and evening meals on days 1 to 5 and days 8 to 12 
of a 28 day cycle is used for metastatic colorectal cancer. TAS 102 is not metabolized by 
cytochrome P450 (CYP) enzymes. 
 
 
Clinical Efficacy 
TAS 102 has been FDA approved for the treatment of metastatic colorectal cancer based on 


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prolongation of median OS (7.1 vs 5.3 months) compared with placebo in a phase III study33.  In 
a recent phase II study, TAS 102 was evaluated in patients with refractory advanced gastric 
cancer34. The median PFS and OS were 2.9 months and 8.7 months, respectively with disease 
control rate of 65.5% in the study.   
 
Clinical Safety 
The most common adverse events are anemia, neutropenia, thrombocytopenia, fatigue, nausea, 
decreased appetite, diarrhea, vomiting and abdominal pain. Grade 3 or higher neutropenia has 
been observed in 34% with 2% of febrile neutropenia, and there was no grade 5 toxicity related 
neutropenia in a randomized phase III study of TAS 10235. Interestingly, neutropenia caused by 
TAS 102 was associated with improved disease control rate and improved progression free 
survival in several studies36,37. 
The warnings and precautions for TAS 102 include: bone marrow suppression, gastrointestinal 
toxicity, hepatic impairment and renal impairment. 
 
Rationale  
The combination of TAS 102 and ramucirumab may potentially produce a synergistic tumor 
response by complete inhibition of tumor angiogenesis through the blockade of two major tumor 
angiogenic factors (VEGF and PDEGF) and enhanced delivery of cytotoxic trifluridine to tumor 
through normalization of poorly organized, tortuous and hyperpermeable tumor vasculature.    
 
Dual antiangiogenic therapy has been proposed as tumors can not only develop resistance to one 
anti-angiogenic pathway but also exhibit multiple angiogenic pathways at the outset. The 
efficacy of dual antiangiogenic blockade such as bevacizumab plus sorafenib, a vascular 
disrupting agent (OXi4503) plus bevacizumab and a PDGFR inhibitor (SU6668) plus a VEGFR2 
inhibitor (semaxinib) has been confirmed in preclinical and clinical studies38, although toxicity 
remains a concern. 
  
The combination of a cytotoxic agent with an antiangiogenic agent has demonstrated a 
significant anticancer activity in multiple cancers including gastric cancer, colorectal cancer, 
non-small cell lung cancer and ovarian cancer. The proposed mechanisms of benefit from the 
chemotherapy plus antiangiogenesis include 1) normalization of the tumor vasculature by 
altering vascular permeability and increasing drug accessibility39, 2) synergistic effects leading to 
enhanced direct cytotoxicity of cancer cells and/or endothelial cells40 and 3) decreased 
chemoresistance by alteration of cell proliferation pathway such as MAPK41 and Wnt/β-catenin 
signaling42. The combination of TAS 102 with VEGF inhibition (bevacizumab) was evaluated in 
preclinical and clinical studies, and the combination showed superior antitumor efficacy to TAS 
102 alone by increasing trifluridine accumulation43,44.  In addition, TAS 102 (35 mg/m2 twice a 
day) was safely combined with bevacizumab (5mg/kg every 2 weeks) without dose limiting 
toxicities in a phase1/2 study44.  
 
As there are known synergy of dual antiangiogenic therapy and the combination of a cytotoxic 
agent with an antiangiogenic agent in preclinical and clinical studies, we hypothesize that TAS 
102 added to ramucirumab will lead to a disease response and improve survival in refractory 
metastatic gastric and GEJ adenocarcinoma.  


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2. Study Objectives 
 
 
Primary Objective  
 
To determine the 6 month overall survival in patients with advanced, refractory gastric and GEJ 
adenocarcinoma receiving TAS 102 in combination with ramucirumab. 
 
Secondary Objectives 
1. To determine the frequency and severity of adverse events and tolerability of TAS 102 plus 
ramucirumab in patients with advanced, refractory gastric and GEJ adenocarcinoma  
2. To determine the efficacy of TAS 102 in combination with ramucirumab based on Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1    
3. To determine the progression free survival in patients with advanced, refractory gastric and 
GEJ adenocarcinoma receiving TAS 102 in combination with ramucirumab. 
 
Exploratory Objective 
 
1. To explore potential correlation between blood biomarkers and clinical outcome using a 
multiplex assay evaluating circulating angiogenic biomarkers (see 12.1 Correlative study) 
 
3. Study Design 
This is a single institutional phase II single arm, two-stage trial using ramucirumab and TAS 
102 in subjects with advanced, refractory gastric or GEJ adenocarcinoma. In the first stage, 15 
patients will be accrued. If 7 or more out of 15 survive 6 months or more, an additional 10 
patients will be accrued for a total of 25 patients. TAS 102 and ramucirumab will be 
concurrently administered with ramucirumab 8mg/kg every 2 weeks (Q2W) and TAS 102 at 
doses of 35 mg/m2 twice a day (Details on 5.1). After 2 cycles (1 cycle=28 days), response and 
progression will be evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) 
guidelines (version 1.1). Primary endpoint is 6 month overall survival. We will continue to 
recruit patients during interim analysis. Although no dose limiting toxicities of TAS 102 plus 
bevacizumab which has almost same mechanisms of action and safety profiles as ramucirumab 
were observed in a previous phase 1/2 study 44, unexpected toxicities can occur with this 
combination. Therefore, we will closely monitor first 6 patients for first 28 days. If none or one 
of these patients has a dose limiting toxicity, we will continue without dose adjustment. If  ≥ 2 
patients has a dose limiting toxicity, the dose will be decreased to level -1 (TAS 102: 30mg/m2 
twice a day and ramucirumab: 8mg/kg Q2W, details in table 1), and 6 additional patients will 
be enrolled at dose level -1. If none or one of these patients has a dose limiting toxicity at dose 
level -1 for first 28 days, we will use dose level -1. If  ≥ 2 patients has a dose limiting toxicity 
at dose level -1, the study will be terminated. First 6 or 12 patients depending on dose limiting 
toxicities will be used for primary and secondary objectives. Dose limiting toxicity is defined as 
a grade 3 or higher non-hematological toxicity excluding controllable nausea, vomiting, 
hypertension, diarrhea, transient electrolyte abnormalities and alopecia; grade 4 neutropenia 


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lasting 7 days or more; grade 3 or higher febrile neutropenia; grade 4 thrombocytopenia. 
 
 
 
4. Eligibility 
 
Inclusion Criteria 
 
1. Histologically confirmed diagnosis of gastric and GEJ adenocarcinoma  
2. Measurable or non-measurable disease by Response Evaluation Criteria in Solid Tumors 
(RECIST) 1.1.  Stage IV or recurrent disease is required. An irradiated lesion is considered 
evaluable only if it has shown enlargement since the completion of last radiation. 
3. Patients must have received and progressed with prior therapy. Prior therapy with 
ramucirumab is not allowed. Patients must have recovered from the toxic effects of the 
previous anti-cancer chemotherapy (with the exception of alopecia). 
4. ECOG Performance Score 0 or 1 
5. Estimated life expectancy > 3 months 
6. Adequate bone marrow, liver and renal function as assessed by the following: 
o Hemoglobin > 8.0 g/dl 
o Absolute neutrophil count (ANC) > 1,000/mm3 independent of growth factor support 
o Platelet count > 100,000/mm3  
o Total bilirubin < 1.5 times ULN unless bilirubin rise is due to Gilbert’s syndrome or of 
non-hepatic origin 
o AST, ALT and Alkaline Phosphatase ≤2.5 times the ULN ( ≤5 x ULN for patients with 
liver involvement) 
o Creatinine clearance ≥ 30 ml/min 
 
7. Patients must not have had chemotherapy, major surgery, monoclonal antibody therapy or 
experimental therapy within the 28 days prior to the start of TAS 102 administration.  
8. Women of childbearing potential must have a negative serum pregnancy test performed 
within 7 days prior to the start of study drug. Post-menopausal women (defined as no menses 
for at least 1 year) and surgically sterilized women are not required to undergo a pregnancy 
test. 
9. Subjects (men and women) of childbearing potential must agree to use adequate 
contraception beginning at the signing of the ICF until at least 4 months for both females and 
males after the last dose of study drug. The definition of adequate contraception will be based 
on the judgment of the principal investigator or a designated associate. 
10. Subjects must be able to understand and be willing to sign the written informed consent 
form. A signed informed consent form must be appropriately obtained prior to the conduct of 
any trial-specific procedure. Subjects must be willing and able to comply with scheduled 
visits, treatment schedule, laboratory testing, and other study requirements. 
 


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Exclusion Criteria 
1. Subjects with active CNS metastases are excluded. If CNS metastases are treated and 
subjects are at neurologic baseline for at least 2 weeks prior to enrollment, they will be 
eligible but will need a Brain MRI prior to enrollment.  
2. Women who are pregnant or breast-feeding 
3. Prior therapy with ramucirumab, bevacizumab, regorafenib or TAS 102. 
4. Previous or concurrent cancer within 3 years prior to treatment start EXCEPT for 
curatively treated cervical cancer in situ, non-melanoma skin cancer, superficial bladder 
tumors [Ta (non-invasive tumor), Tis (carcinoma in situ) and T1 (tumor invades lamina 
propria)]. 
5. Uncontrolled hypertension (systolic BP>140 mm Hg or diastolic BP>90 mmHg on 
repeated measurement  despite  optimal medical management). 
6. Any hemorrhage or bleeding event ≥ NCI CTCAE Grade 3 within 4 weeks prior to start of 
study medication.  
7. Persistent proteinuria ≥ Grade 3 on repeated measurement 
8. Substance abuse, medical, psychological or social conditions that may interfere with the 
patient’s participation in the study or evaluation of the study results. 
9. Subjects with an arterial thrombotic or thromboembolic event within 12 months of 
informed consent. 
 
10. Ascites, pleural effusion, or pericardial fluid requiring drainage in the last 4 weeks 
11. Known history of human immunodeficiency virus (HIV) infection or current chronic or 
active hepatitis B or C infection requiring treatment with antiviral therapy. 
12. Clinically significant cardiovascular disease such as unstable angina, uncontrolled or 
symptomatic arrhythmia, congestive heart failure, any Class 3 or 4 cardiac disease as defined 
by the New York Heart Association Functional Classification, or history of myocardial 
infarction within 6 months prior to first dose with study drug 
13. Unable to swallow capsules or disease significantly affecting gastrointestinal function 
and/or inhibiting small intestine absorption such as; malabsorption syndrome, resection of the 
small bowel, or poorly controlled inflammatory bowel disease affecting the small intestine. 
14. Child-Pugh B cirrhosis (or worse) or a history of hepatic encephalopathy 
15. History of stroke or intracranial hemorrhage within 6 months prior to enrollment. 


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16. Any illness or medical conditions that are unstable or could jeopardize the safety of the 
patient and his/her compliance in the study. 
17. Major surgery or a wound that has not fully healed within 4 weeks of enrollment. 
 
18. Patients who need anticancer chemotherapy other than the study drugs during the study 
or within 4 weeks of study enrollment.  Anti-cancer therapy is defined as any agent or 
combination of agents with clinically proven anti-tumor activity administered by any route 
with the purpose of affecting the malignancy, either directly or indirectly, including 
palliative and therapeutic endpoints.  
 
19. Patients who need hormonal therapy during the study or within 2 weeks of first study 
enrollment. 
 
20. Patients who need radiotherapy to target lesions during study or within 2 weeks of 
enrollment. 
 
21. Patients who had bone marrow transplant or stem cell rescue. 
 
22. Patients who need investigational drug therapy outside of this trial during or within 4 
weeks of first study treatment. 
 
 
Withdrawal of Subjects from Study 
 
Subjects must be withdrawn from the trial (treatment and procedures) for the following 
reasons:  
• Subject withdraws consent from study treatment and study procedures. A subject must be 
removed from the trial at his/her own request or at the request of his/her legally 
acceptable representative. At any time during the trial and without giving reasons, a 
subject may decline to participate further. The subject will not suffer any disadvantage as 
a result. 
• Pregnancy. Pregnancies will be reported to Taiho within 24 hours of having knowledge 
of the event. Pregnancy will not be reported as an SAE but the subject must be withdrawn 
from the trial immediately. (Note: subjects who have been withdrawn from treatment 
with study drug because of pregnancy should not undergo CT scans [with contrast]/MRI 
or bone scans while pregnant.) 
• If, in the investigator's opinion, continuation of the trial would be harmful to the subject's 
well-being. 
• Subject is lost to follow-up. 
• Death. 
 
All subjects who discontinue should comply with protocol specified follow-up and survival 
procedures. The ONLY exception to this requirement is when a subject withdraws consent for all 


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study procedures or loses the ability to consent freely (i.e., is imprisoned or involuntarily 
incarcerated for the treatment of either a psychiatric or physical illness). If a subject was 
withdrawn before completing the study, the reason for withdrawal must be entered on the 
appropriate case report form page. 
 
Subjects may be withdrawn from study treatment for the following reasons: 
• The subject is non-compliant with TAS 102 administration, ramucirumab 
administration, or trial procedures; including the use of anti-cancer therapy not 
prescribed by the study protocol. 
• Severe allergic reaction to TAS 102 or ramucirumab. 
• The development of a second cancer. 
• Development of an illness or situation which would, in the judgment of the 
investigator, significantly affect assessments of clinical status and trial endpoints. 
• Deterioration of ECOG performance status to 3 or 4. 
• Use of illicit drugs or other substances that may, in the opinion of the investigator, 
have a reasonable chance of contributing to toxicity or otherwise skewing trial result. 
Any subject removed from the trial will remain under medical supervision until discharge or 
transfer is medically acceptable. 
Any subject with progression of disease will come off of treatment except for patients deriving 
clinical benefit as deemed by the principal investigator with a maximum of 24 months on 
therapy. In all cases, the reason for withdrawal must be recorded in the CRF and in the subject's 
medical records. 
4.3.1 Screen Failures/Dropouts/Replacements 
A subject who discontinues study participation prematurely for any reasons except death, disease 
progression and severe toxicity is defined as a dropout. 
A subject who, for any reason (e.g., failure to satisfy the selection criteria), terminates the study 
before the time point used for the definition of “dropout” (see above) is regarded a “screening 
failure”. 
Subjects who withdraw from treatment (for any reason) may be replaced. 
4.3.2 Patient Replacement 
Dropout (see 4.3.1 for definition of “dropout”) patients will need to be replaced. 
Patients will be replaced if they come off treatment without any response evaluation for reasons 
other than drug related AE or disease progression. 
 
5. Treatment Plan 
 


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Drug Administration 
 
Ramucirumab 
Ramucirumab is provided as a liquid solution at a concentration of 10mg/ml in either 100mg 
(10ml) or 500mg (50ml) single dose vials. The drug product is stored as a liquid solution in a 
refrigerator at 2°C to 8°C until time of use. Ramucirumab is a sterile, preservative-free, clear to 
slightly opalescent and colorless to slightly yellow solution for intravenous infusion following 
dilution and preparation. After withdrawal of the required volume of ramucirumab from the 
vials, it can be further diluted with only 0.9% sodium chloride in an intravenous infusion 
container to a final volume of 250ml. The diluted ramucirumab can be administerd via infusion 
pump over 60 minutes (±15minutes) through a separate infusion line. When patients develop 
infusion reaction, we will follow 5.1.1.2.1 infusion related reaction management. The diluted 
ramucirumab solutions may be stored at room temperature for up to 4 hours or at 2 to 8°C for up 
to 24 hours.    
 
TAS 102 
TAS 102 should be administered orally twice a day within 1 hour of completion of morning and 
evening meals on Days 1 through 5 and Days 8 through 12 of each 28-day cycle. The tablets 
should be swallowed whole with water and should not be broken, or chewed.  
 
TAS-102 15 mg/7.065 mg (trifluridine/tipiracil hydrochloride) and 20 mg/9.42 mg 
(trifluridine/tipiracil hydrochloride) film coated tablets.  The film coated tablets can be printed 
or unprinted. 
TAS 102 tablets  are supplied in a blister card containing 20, 40 or 60 tablets. 
Keep TAS 102 out of the sight and reach of children. 
 
TAS 102 should be stored according to the storage conditions indicated on the label. The 
recommended storage condition for TAS 102 is 15°C to 23°C (59°F to 86°F).  
Each patient will enter daily use of TAS 102 in a medication diary (Appendix B) for a measure 
of compliance. A dairy card will be issued and returned at each cycle.  
 
Treatment 
Treatment will be administered on an outpatient basis. Reported AEs and potential risks are 
described in Section 8. Dose delays for TAS 102 and ramucirumab are described in Section 
5.1.6. No investigational or commercial agents or therapies other than those described below 
may be administered with the intent to treat the patient's malignancy. The dose of TAS is 
35mg/m2 (trifluridine dose) twice a day, taken orally. The dose of ramucirumab is 8mg/kg IV 
every 2 weeks. Each cycle will last for 4 weeks. 
 
 
Arm 
Ramucirumab Dose 
TAS 102* 
1 
8 mg/kg q2wk 
35mg/m2 BID 
 *To be given PO on days 1-5 and 8-12 of every 28 day cycle 
TAS102 (35mg/m2) twice a day was safely administered with anti-VEGF therapy (bevacizumab) 


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in a recent a phase 1/2 study44. Based on the data, each subject will receive TAS 102 35mg/m2 
twice a day and ramucirumab 8mg/kg Q2W continuously. Since unexpected toxicities can occur 
with this combination, we will closely monitor first 6 patients for first 28 days. If none or one of 
these patients has a dose limiting toxicity, we will continue without dose adjustment. If  ≥ 2 
patients has a dose limiting toxicity, the dose will be decreased to level -1 (TAS 102: 30mg/m2 
twice a day and ramucirumab: 8mg/kg Q2W, details in table 1), and 6 additional patients will be 
enrolled at dose level -1. If none or one of these patients has a dose limiting toxicity at dose level 
-1 for first 28 days, we will use dose level -1. If  ≥ 2 patients has a dose limiting toxicity at dose 
level -1, the study will be terminated. First 6 or 12 patients depending on dose limiting toxicities 
will be used for primary and secondary objectives. Dose limiting toxicity is defined as a grade 3 
or higher non-hematological toxicity excluding controllable nausea, vomiting, hypertension, 
diarrhea, transient electrolyte abnormalities and alopecia; grade 4 neutropenia lasting 7 days or 
more; grade 3 or higher febrile neutropenia; grade 4 thrombocytopenia. 
5.1.1 Management (dose Modifications and dose delays) for Treatment-
Related Toxicity 
All toxicities will be graded according to National Cancer Institute’s (NCI’s) Common 
Terminology Criteria for Adverse Events (CTCAE) (NCI CTCAE v 5). The study investigator 
will determine if either or both medications should be held. 
 
 
Dose reductions for AEs related to TAS 102 are permitted dose reductions to a minimum dose of 
20mg/m2 twice a day in 5mg/m2 steps. After dose reduction, escalation of dose is not allowed. 
 
Table 1. TAS 102 dose modifications 
 
TAS 102 dose 
(BID) 
BSA (m2)* 
Dosage in mg 
(BID) 
Total daily 
dose (mg) 
Tablets per dose 
15mg 
20mg 
Starting dose 
35mg/m2 
<1.07 
35 
70 
1 
1 
1.07-1.22 
40 
80 
0 
2 
1.23-1.37 
45 
90 
3 
0 
1.38-1.52 
50 
100 
2 
1 
1.53-1.68 
55 
110 
1 
2 
1.69-1.83 
60 
120 
0 
3 
1.84-1.98 
65 
130 
3 
1 
1.99-2.14 
70 
140 
2 
2 
2.15-2.29 
75 
150 
1 
3 
≥2.30 
80 
160 
0 
4 
Level 1 dose reduction: from 35mg/m2 to 30mg/m2 
30mg/m2 
<1.09 
30 
60 
2 
0 
1.09-1.24 
35 
70 
1 
1 
1.25-1.39 
40 
80 
0 
2 
1.4-1.54 
45 
90 
3 
0 
1.55-1.69 
50 
100 
2 
1 


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1.70-1.94 
55 
110 
1 
2 
1.95-2.09 
60 
120 
0 
3 
2.10-2.28 
65 
130 
3 
1 
≥2.29 
70 
140 
2 
2 
Level 2 dose reduction: from 30mg/m2 to 25mg/m2 
25mg/m2 
<1.10 
25 
50 
2 (PM)¶ 
1 (AM)¶ 
1.10-1.29 
30 
60 
2 
0 
1.30-1.49 
35 
70 
1 
1 
1.50-1.69 
40 
80 
0 
2 
1.70-1.89 
45 
90 
3 
0 
1.90-2.09 
50 
100 
2 
1 
2.09-2.29 
55 
110 
1 
2 
≥2.30 
60 
120 
0 
3 
Level 3 dose reduction: from 25mg/m2 to 20mg/m2 
20mg/m2 
<1.14 
20 
40 
0 
1 
1.14-1.34 
25 
50 
2 (PM)¶ 
1 (AM)¶ 
1.35-1.59 
30 
60 
2 
0 
1.60-1.94 
35 
70 
1 
1 
1.95-2.09 
40 
80 
0 
2 
2.10-2.29 
45 
90 
3 
0 
≥2.29 
50 
100 
2 
1 
* Calculate BSA to 2 decimal places. 
¶ At a total daily dose of 50mg, patients should take 1 x 20mg tablet in the morning and 2 x 
15mg tablets in the evening. 
 
Dose reductions of ramucirumab will be allowed only for proteinuria with 6 mg/kg for first 
episode of proteinuria (> 2 g/24 hours) and with 5 mg/kg for second episode of proteinuria (> 2 
g/24 hours). Only dose delay will be allowed for the other AEs related to ramucirumab. 
 
Table 2. Ramucirumab dose modifications 
Starting dose 
8mg/kg 
Level 1 dose reduction 
6mg/kg 
Level 2 dose reduction 
5mg/kg 
 
 
Dose modifications will not be required for AEs that are clearly not attributed to TAS 102 or 
ramucirumab (such as an accident) or for laboratory abnormalities that are not deemed to be 
clinically significant.  
 
If a subject experiences a clinically significant and/or unacceptable toxicity, dosing will be 
interrupted and supportive therapy administered as required.   
 


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5.1.1.1 Management for Treatment-Related Toxicity of TAS 102 
5.1.1.1.1 Non-hematologic toxicities of TAS 102 
Table 3. Non-hematologic toxicity management 
Grade¶ 
Dose hold/resumption within a 28-day 
treatment cycle 
Dose adjustment for next cycle 
Grade 1 or 2  
Any occurrence 
Maintain treatment at the same dose 
level 
None 
Grade 3* or higher 
1st, 2nd or 3rd 
occurrence 
Suspend treatment until Grade 0 or 
1 
Reduce by 1 dose level 
from the previous level 
4th occurrence 
Discontinue treatment 
Discontinue treatment 
¶ At the discretion of the investigator, patients may continue on study medication at the same 
dose without reduction or interruption for AEs (irrespective of grade) considered unlikely to 
become serious or life-thereating (including, but not limited to, fatigue, alopecia, changes in 
libido, and dry skin). 
* Except for grade 3 nausea and/or vomiting controlled by antiemetic therapy or diarrhea 
responsive to antidiarrheal medication. Moreover, if grade 4 non-hematotoxicity that is related to 
the protocol therapy is observed, protocol therapy is to be discontinued. However, in case of 
adverse events, which can clearly be judged to have derived from the primary disease, depending 
on the judgement of the investigator (subinvestigator) protocol therapy can be continued. In this 
case, the reason for this judgement must be recorded in the medical records, etc. (For example: 
Grade 3 cancer pain that is associated with the primary disease, Grade 3 weight loss that is 
associated with the primary disease, etc.) 
 
5.1.1.1.2 Hematologic toxicities of TAS 102 
Criteria for dose hold and resumption in response to hematologic toxicities related to 
myelosuppression are described in Table 2.  
Uncomplicated neutropenia or thrombocytopenia ≤ grade 3 does not require a reduction in dose 
of study medication. Patients who experience uncomplicated Grade 4 neutropenia or 
thrombocytopenia that results in a >1 week delay of the start of the next cycle should start the 
next cycle with dose reduction in 5mg/m2 step. If toxicity remains despite 4 dose reductions or at 
a minimum dose (15mg/m2 twice a day), discontinue TAS 102. 
 
Table 4. Hematologic toxicity management 
 


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Parameter 
Hold Criteria 
Resumption Criteria* 
Dose adjustment for 
next cycle 
Conventional 
Units 
SI units 
Neutrophils 
<500/mm3 
<0.5x109/L 
≥1500/mm3 
(IU: ≥1.5x109/L) 
  Details below¶  
Platelets 
<50,000/mm3 
<50x109/L 
≥75,000/mm3 
(IU: ≥75x109/L) 
Details below¶ 
* These resumption criteria apply to the start of the next cycle for all patients regardless of 
whether or not the hold criteria were met. Both conventional and SI (International System) units 
are presented in CTCAE v. 5. 
 
¶ 1) ≤ Grade 3 neutropenia or thrombocytopenia 
• If there are no complications (such as fever, infection or hemorrhage), there is no need 
to reduce the dose of TAS 102 
• If there are complications, the necessity of reducing dose should be considered also 
with regard to safety. 
• For neutropenia, pegfilgrastim or filgrastim can be administered at investigator’s 
discretion. 
  2) Grade 4 neutropenia or thrombocytopenia 
• When there are no complications, but initiation of the next cycle is delayed by more 
than one week, dose should be reduced by 1 level (Table 1) when starting next cycle 
(dose is not reduced when administered on the same weekday). If initiation is not 
delayed by more than one week, the next cycle can be initiated at the same dose level.  
• If there are complications, in consideration of the safety of the patient, dose should be 
reduced by 1 level (Table 1) when starting the next cycle. 
• For neutropenia, pegfilgrastim or filgrastim can be administered at investigator’s 
discretion. 
 
5.1.1.1.3 Dose resumption timing of TAS 102  
If the patient recovers from the toxicities to the resumption criteria defined above during the 2-
week treatment period (treatment Days 1 through 5, 8 through 12), and no dose reduction is 
required, study drug therapy may be resumed during that cycle.  
If a dose reduction is required, study drug therapy should be resumed at the start of the next 
cycle at the appropriate dose level according to instructions provided in Table 1 and 2. If the 
study drug dose is reduced, it must not be increased for subsequent cycles.  
If the toxicities that are defined above recover during the recovery period (Days 13 through 28), 
start the next cycle on schedule at the appropriate dose level according to instructions provided 
in Table 1, 3 and 4.  
If the toxicities that are defined above do not recover during the treatment or rest period, the start 
of the next cycle can be delayed for a maximum of 28 days from the scheduled start date of the 
next cycle. If resumption criteria are met by this maximum 28-day delay, start the next cycle at 
the appropriate dose level according to instructions provided in Table 1, 3 and 4. Patients who 


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require more than a 28-day delay in the scheduled start date of the next cycle will have study 
medication discontinued. 
 
 
5.1.1.2 Management for Treatment-Related Toxicity of ramucirumab 
Adverse events of concern which may be related with ramucirumab include are infusion-related 
reactions, hypertension, arterial or venous thromboembolic events, bleeding (hemorrhagic) 
events, proteinuria, cardiac events, gastrointestinal perforation, anemia, surgery and wound 
healing liver injury/liver failure, and reversible posterior leukoencephalopathy syndrome 
(RPLS). Listed below are guidelines on how to manage these toxicities. Dose reductions of 
ramucirumab will be allowed only for proteinuria with 6 mg/kg for first episode of proteinuria 
(2-3 g/24 hours) and with 5 mg/kg for second episode of proteinuria (2-3 g/24 hours) (details on 
table 2 and 5.1.1.2.4). Only dose delay will be allowed for the other AEs related to ramucirumab. 
 
 
5.1.1.2.1 Infusion related reactions 
For the treatment of infusion related reaction, institutional protocol can be used. If there is no 
institutional protocol, the following can be used for treatment of ramucirumab infusion-related 
reactions.  
 
Grade 
Management 
Grade 1 
• Slow the infusion rate by 50% 
• Monitor the patient for worsening of condition 
• For subsequent infusions, premedicate with 
diphenhydramine hydrochloride 50 mg I.V.; additional 
premedication may be administered at the 
investigator’s discretion 
Grade 2 
• Stop the infusion 
• Administer diphenhydramine hydrochloride 50 mg 
I.V., acetaminophen 650 mg orally for fever and 
oxygen 
• Resume the infusion at 50% of the prior rate once the 
infusion-related reaction has resolved or decreased to 
Grade 1; the infusion duration should not exceed 2 
hours 
• Monitor the patient for worsening of condition 
• For subsequent infusions, premedicate with 
diphenhydramine hydrochloride 50 mg I.V.; additional 
premedication may be administered at the 
investigator’s discretion 


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Grade 3 
• Stop the infusion and disconnect the infusion tubing 
from the patient 
• Administer diphenhydramine hydrochloride 50 mg 
I.V., dexamethasone 8-10 mg I.V. (or equivalent), 
bronchodilators for bronchospasm, and other 
medications/treatment as medically indicated 
• Patients who have a Grade 3 infusion-related reaction 
will be discontinued from study 
Grade 4 
• Stop the infusion and disconnect the infusion tubing 
from the patient 
• Administer diphenhydramine hydrochloride 50 mg 
I.V., dexamethasone 8-10 mg I.V. (or equivalent), and 
other medications/treatment as medically indicated. 
• Give epinephrine or bronchodilators as indicated 
• Hospital admission for observation may be indicated 
• Patients who have a Grade 4 infusion-related reaction 
will be discontinued from study 
 
For a second Grade 1 or 2 infusion-related reaction, administer dexamethasone 8-10 mg 
I.V.; then, for subsequent infusions, premedicate with diphenhydramine hydrochloride 50 
mg I.V., acetaminophen 650 mg orally, and dexamethasone 8-10 mg I.V. (or equivalent) 
 
 
5.1.1.2.2 Hypertension 
• If patients develop hypertension during the study, they should be treated with 
antihypertensive medications according to standard medical practice. 
• The following are treatment guidelines for ramucirumab related hypertension 
Grade 
Management 
Grade 1 or 2 
o If the hypertension is not associated with symptoms, 
continue ramucirumab and initiate antihypertensive therapy 
o If the hypertension is associated with symptoms, hold 
ramucirumab until symptoms resolve and initiate 
antihypertensive therapy 
Grade 3 
o For Grade 3 hypertension not associated with symptoms, 
continue ramucirumab with more intensive 
antihypertensive therapy. If systolic BP remains ≥ 160 mm 
Hg or diastolic BP ≥ 100 mm Hg > 2 weeks after initiation 
of additional antihypertensive therapy, hold ramucirumab 
while continuing appropriate antihypertensive therapy 
o If the hypertension is associated with symptoms, hold 
ramucirumab until symptoms resolve and initiate 


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antihypertensive therapy 
Grade 4 
o Patients with Grade 4 hypertension (life-threatening 
consequences, eg, malignant hypertension, transient or 
permanent neurologic deficit, hypertensive crisis; or urgent 
intervention indicated) or patients whose hypertension is 
poorly controlled (> 160 mm Hg systolic or > 100 mm Hg 
diastolic for > 4 weeks) despite (> 2 oral agents at MTD) 
will be discontinued from study therapy. 
 
 
5.1.1.2.3 Thromboembolic events 
• Investigators should perform all testing required to fully characterize arterial or venous 
thrombotic/vascular events.  
• Ramucirumab should be discontinued in the event of any Grade 3-4 arterial 
thromboembolic event or any Grade 3-4 venous thromboembolic event that is considered 
by the investigator to be life-threatening, or symptomatic and not adequately treated by 
anticoagulation therapy.  
• At the investigator’s discretion, ramucirumab may be continued in this setting of an 
incidentally diagnosed asymptomatic deep vein thrombosis or pulmonary embolism, or 
following a symptomatic deep vein thrombosis or pulmonary embolism when symptoms 
have resolved with the institution of anticoagulation therapy.  
• In the event that a patient experiences a Grade 4 pulmonary embolism or a Grade 3-4 
venous thromboembolic event that is considered by the investigator to be life-threatening, 
or symptomatic and not adequately treated by anticoagulation therapy, the patient will not 
receive further ramucirumab and be discontinued from study therapy.  
• Ramucirumab should also be discontinued, and a patient will be discontinued from study 
therapy in the setting of a deep vein thrombosis or pulmonary embolism that occurs or 
intensifies while the patient is receiving therapeutic anticoagulation therapy.  
 
 
5.1.1.2.4 Proteinuria 
If, while on ramucirumab, a patient has proteinuria ≥ 2+ per a dipstick or routine urinalysis test, 
ramucirumab will continue as scheduled, and a 24-hour urine collection will be conducted prior 
to the subsequent scheduled treatment in 2weeks.  
 
• The following are treatment guidelines for ramucirumab related proteinuria 


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Proteinuria 
Management 
< 2g/24hours urine 
• Continue on ramucirumab at the same dose without interruption 
2-3g/24hours urine 
(first episode) 
• Hold ramucirumab for 2 weeks  
• Repeat a 24-hour urine collection prior to next infusion.  
• Resume ramucirumab at a reduced dose level (6 mg/kg every 2 
weeks) once the protein level returns to < 2 g/24 hours. 
2-3g/24hours urine 
(second episode) 
• Hold ramucirumab for 2 weeks  
• Repeat a 24-hour urine collection prior to next infusion.  
• Resume ramucirumab at a reduced dose level (5 mg/kg every 2 
weeks) once the protein level returns to < 2 g/24 hours. 
2-3g/24hours urine 
(third episode) 
or >3g/24hours urine   
• Discontinue ramucirumab 
 
5.1.1.2.5 Hemorrhagic events 
Serious hemorrhagic adverse events have been reported from clinical studies investigating 
ramucirumab.  
• The following are treatment guidelines for ramucirumab related hemorrhage 
Grade 
Management 
Grade 1 or 2 
• Continue ramucirumab 
Grade 3 or 4 
• Discontinue ramucirumab 
 
 
 
5.1.1.2.6 Gastrointestinal perforation events 
An infrequent incidence of gastrointestinal perforations has been associated with some 
antiangiogenic therapeutic agents. These events may be associated with extensive 
abdominal/peritoneal disease burden. Gastrointestinal perforation has been reported from 
clinical studies investigating ramucirumab. Ramucirumab should be discontinued in the 
setting of any gastrointestinal perforation.  


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5.1.1.2.7 Reversible posterior leukoencephalopathy syndrome (RPLS) 
• Reversible posterior leukoencephalopathy syndrome (RPLS) is a clinical and radiologic 
syndrome typically consisting of reversible cortical neurological dysfunction and brain-
imaging findings of subcortical edema involving the posterior circulation, particularly the 
occipital lobes. The symptoms of RPLS most often include generalized seizures, 
headache, delirium, and cortical blindness, although these may vary significantly and 
occasionally include focal neurological deficits. Magnetic resonance imaging (MRI) 
represents the most reliable method for the diagnosis. Clinical symptoms and MRI 
abnormalities usually recover within days to weeks with proper management, although 
permanent neurologic dysfunction has been reported.  
• Because hypertension is an identified risk for ramucirumab, investigators should control 
BP. In addition, investigators should consider a diagnosis of RPLS in the setting of 
seizures, headache, nausea, delirium, visual changes, and/or other unexplained 
neurological symptoms, especially in combination with hypertension and MRI findings 
of hyperintensity on T2-weighted and fluid-attenuated inversion recovery images  
• If the diagnosis of RPLS is confirmed, ramucirumab DP should be permanently 
discontinued.  
 
5.1.1.2.8 Cardiac events 
• Patients with symptomatic CHF, unstable angina pectoris, or symptomatic or poorly 
controlled cardiac arrhythmia should not be enrolled in this study.  
• Ramucirumab should be discontinued in the event of any Grade 3-4 events consistent 
with CHF. 
5.1.1.2.9 Surgery and impaired wound healing 
• Surgery and impaired wound healing have been observed with some antiangiogenic 
agents.  
• Ramucirumab will not be administered to patients who have undergone major surgery 
within 28 days or have undergone central venous access device placement within 7 days 
prior to ramucirumab adminstration.  
• Patients with postoperative and other nonhealing wound complications are excluded, as 
are patients for whom major surgical procedures are planned. 
5.1.1.2.10 Liver injury/liver failure 
 
• Patients with Child-Pugh B cirrhosis (or worse), any degree cirrhosis, a history of hepatic 
encephalopathy, clinically meaningful ascites from cirrhosis, new occurrence of hepatic 
encephalopathy and/or hepatorenal syndrome from liver cirrhosis. Ramucirumab should 
be discontinued following a new occurrence of hepatic encephalopathy and/or 
hepatorenal syndrome resulting from liver cirrhosis. 
 


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Concomitant therapy  
• All patients should be maintained on the same medications throughout the study period, as 
medically feasible;  
• The investigator should instruct the patient to notify the study staff about any new medications 
he/she takes after the start of the study drug. All medications (other than study drug) and 
significant non-drug therapies (including physical therapy and blood transfusions) administered 
after the patient starts treatment with study drug must be recorded;  
• Administration of pegfilgrastim or filgrastim following initiation of protocol therapy is at 
investigator’s discretion for all patients; 
• Administration of erythropoietin or darbopoietin is allowed;  
• Administration of bisphosphonates is permitted at the investigator’s discretion 
• Transfusions of red blood cells, platelets, or other blood products are permitted at the 
investigator’s discretion 
• Patients must be instructed not to take any additional medications (including herbal 
supplements and over-the-counter products) during the trial without prior consultation with the 
investigator. All medications taken within 30 days of screening should be recorded. If 
concomitant therapy must be added or changed, the reason and name of the drug/therapy should 
be recorded;  
• In general, the use of any concomitant medication/therapies deemed necessary for the care of 
the patient are allowed, including drugs given prophylactically (e.g. antiemetics or steroids).  
• Premedication is recommended before ramucirumab administration (including first dose). 
Recommended premedication agents include histamine H1 antagonists such as diphenhydramine 
hydrochloride 50 mg I.V. (or equivalent). Additional premedication may be provided at the 
investigator’s discretion. 
 
5.2.1 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this trial: 
• Antineoplastic systemic chemotherapy, immunotherapy or biological therapy not 
specified in this protocol 
• Investigational agents other than TAS 102 or ramucirumab 
• Radiation therapy  
Subjects who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the trial.  Subjects may receive 
other medications that the investigator deems to be medically necessary. 
 
 


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Blinding 
This is an open-label trial.  There will be no randomization or blinding. 
 
 
Drug Logistics and Accountability 
 
All study drugs will be stored at the investigational site in accordance with good clinical 
practice (GCP) and GMP requirements and will be inaccessible to unauthorized personnel.  
Special storage conditions and a complete record of batch numbers and expiration dates can be 
found in Dr. Kim’s study file; the site-relevant elements, of this information will be available in 
the ISF.  The responsible site personnel will confirm receipt of study drugs and will use the 
study drugs only within the framework of this clinical study and in accordance with this 
protocol.  Receipt, distribution, return and destruction (if any) of the study drugs must be 
properly documented according to Moffitt Cancer Center protocol.  
 
6. Visit schedule and Assessments 
 
Screening First Visit 
Screening examinations will only be performed after having received the subject’s written 
informed consent.   
 
The following examinations will be performed within 28 days prior to the first treatment: 
 
• Written subject informed consent to be obtained prior to any screening assessments. 
• Complete medical history and physical examination, including demographics, surgery, 
therapies, medications, smoking, alcohol history, co-existing diseases, allergies, 
NYHA classification, vital signs (heart rate, respiration rate, temperature, and BP), 
weight and review of systems. 
• Baseline toxicities / AEs 
• ECOG Performance Status Assessment 
• 12-lead ECG 
• Radiologic assessment: CT scan or MRI with tumor measurement and disease 
assessment of non-measurable disease 
• Coagulation (PT-INR and aPTT) 
• Hematology (hemoglobin, HCT, RBC, WBC count with differential 
(neutrophils, bands, lymphocytes, monocytes, eosinophils and basophils) and 
platelet count 
• Chemistry (ALT, AST, alkaline phosphatase, total bilirubin, direct bilirubin, lactate 
dehydrogenase (LDH), creatine kinase, lipase, amylase, glucose, calcium 
phosphate, magnesium, bicarbonate, sodium, potassium, chloride, creatinine, blood 
urea nitrogen (BUN), total protein and albumin 
• Urinalysis   
• Hepatitis and HIV test 
• Serum pregnancy test (if applicable) 
• Radiologic assessment tests (CT scan or MRI) performed up to 4weeks prior to 


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obtaining informed consent can be used for screening purposes.    
 
 
Cycle 1 Day 1 
• History and assessment to include physical examination, vital signs (heart rate, 
respiration rate, temperature and BP) and review of systems 
• Toxicity/AE assessment 
• ECOG Performance Status Assessment 
• Hematology (hemoglobin, HCT, RBC, WBC with differential (neutrophils, 
bands, lymphocytes, monocytes, eosinophils and basophils) and platelet count 
• Chemistry (ALT, AST, AP, total bilirubin, direct bilirubin, glucose, calcium, 
phosphate, magnesium, bicarbonate, sodium, potassium, chloride, creatinine, 
BUN, total protein and albumin 
• Screening hematology, platelet count and chemistry can be used for cycle 1 day 
1 if screening tests are done within 5 days of cycle 1 day 1.  
• Issue a new diary card (Appendix B) 
• Urinalysis 
 
Cycle 1 Day 15 
• Hematology (hemoglobin, HCT, RBC, WBC with differential (neutrophils, 
bands, lymphocytes, monocytes, eosinophils and basophils) and platelet count 
• Chemistry (ALT, AST, AP, total bilirubin, direct bilirubin, calcium, phosphate, 
magnesium, bicarbonate, sodium, potassium, chloride, creatinine, BUN, total 
protein and albumin 
 
 
Subsequent cycles (Cycle X Day 1) 
• History and assessment to include brief examination, vital signs (heart rate, 
respiration rate, temperature and BP) and review of systems 
• Toxicity/AE assessment 
• ECOG Performance Status Assessment 
• Hematology (hemoglobin, HCT, RBC, WBC with differential (neutrophils, 
bands, lymphocytes, monocytes, eosinophils and basophils) and platelet count 
• Chemistry (ALT, AST, AP, total bilirubin, direct bilirubin, glucose, calcium, 
phosphate, magnesium, bicarbonate, sodium, potassium, chloride, creatinine, 
BUN, total protein and albumin 
• UA (if dipstick or routine urinalysis indicates proteinuria ≥ 2+, a 24-hour urine 
collection must be obtained in 2 weeks before next dose of ramucirumab) 
• Return an old diary card and issue a new diary card  
 
 
 
Subsequent cycles (Cycle X Day 15) 
• Hematology (hemoglobin, HCT, RBC, WBC with differential (neutrophils, 


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bands, lymphocytes, monocytes, eosinophils and basophils) and platelet count 
• Chemistry (ALT, AST, AP, total bilirubin, direct bilirubin, calcium, phosphate, 
magnesium, bicarbonate, sodium, potassium, chloride, creatinine, BUN, total 
protein and albumin 
 
 
After every 3rd cycle (Cycle 3 Day 1, Cycle 6 Day 1, etc.) 
 
• Tumor measurement/disease assessment according to RECIST 1.1 (please see 
Appendix B) 
• History and assessment to include brief examination, vital signs (heart rate, 
respiration rate, temperature and BP) and review of systems 
• Toxicity/AE assessment 
• ECOG Performance Status Assessment 
• Hematology (hemoglobin, HCT, RBC, WBC with differential (neutrophils, 
bands, lymphocytes, monocytes, eosinophils and basophils) and platelet count 
• Chemistry (ALT, AST, AP, total bilirubin, direct bilirubin, glucose, calcium, 
phosphate, magnesium, bicarbonate, sodium, potassium, chloride, creatinine, 
BUN, total protein and albumin 
• UA (if dipstick or routine urinalysis indicates proteinuria ≥ 2+, a 24-hour urine 
collection must be obtained in 2 weeks before next dose of ramucirumab) 
• Return an old diary card and issue a new diary card  
 
End of Treatment Visit and Follow up 
End of Treatment Visit 
 
• History and assessment to include brief examination, vital signs (heart rate, 
respiration rate, temperature and BP) and review of systems 
• Toxicity/AE assessment 
• ECOG Performance Status Assessment 
• Hematology (hemoglobin, HCT, RBC, WBC with differential (neutrophils, 
bands, lymphocytes, monocytes, eosinophils and basophils) and platelet count 
• Chemistry (ALT, AST, AP, total bilirubin, direct bilirubin, LDH, glucose, 
calcium, phosphate, magnesium, bicarbonate, sodium) 
• UA 
• Tumor measurement/disease assessment according to RECIST 1.1 (please see 
Appendix B) may be conducted if it has not been performed within the last 4 
weeks. 
 
Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the last 
dose of trial treatment.  All AEs that occur prior to the Safety Follow-Up Visit should be 
recorded.  Subjects with an AE of Grade > 1 will be followed until the resolution of the AE to 
Grade 0-1 or until the beginning of a new anti-neoplastic therapy, whichever occurs first.  SAEs 
that occur within 90 days of the end of treatment or before initiation of a new anti-cancer 


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treatment should also be followed and recorded. 
 
 
Survival Follow-up 
Once a subject experiences confirmed disease progression or starts a new anti-cancer therapy, the 
subject moves into the survival follow-up phase for 6 months and should be contacted by 
telephone every 12 weeks to assess for survival status until death, withdrawal of consent, or the 
end of the study, whichever occurs first. 
 
 
 
Calendar 
 
Screening 
within 28 
days of 
C1D1m 
Cycle 1 
Day 1    
± 3 
days 
and 
subseq
uent 
cycles 
Cycle 1 
day 15  ± 
3 days  
Cycle X 
day 1 ± 
5 day  
Cycle X 
day 15 ± 
5 day 
End of 
treatme
nt visitn 
Safet
y 
follo
w-up 
Surviv
al 
follow
-up 
Complete 
History/Phy
sicala 
X 
 
 
 
 
 
 
 
History & 
Assessment b 
 
X 
X 
X 
 
X 
X 
 
Toxicity 
Notation 
 
X 
X 
X 
 
X 
X 
 
ECOG 
X 
X 
X 
X 
 
X 
 
 
ECG 
X 
 
 
 
 
 
 
 
Tumor 
Measureme
nt/ 
Disease 
Assessmentc 
X 
 
 
X 
 
X 
 
 
Hematologyd 
X 
X 
X 
X 
X 
X 
 
 
Chemistrye 
X 
X 
X 
X 
X 
X 
 
 
Coagulationf 
X 
 
 
 
 
 
 
 
Urinalysisg 
X 
X 
 
X 
 
X 
 
 
24hr urine 
proteinh 
 
 
X 
X 
X 
X 
 
 
Hepatitis 
and HIV 
Screeningi 
X 
 
 
 
 
 
 
 
Serum 
X 
 
 
 
 
 
 
 


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a. Complete medical history and physical examination including demographics, surgery, 
therapies, medications, smoking, alcohol history, co-existing diseases, allergy, NYHA 
classification, vital signs (heart rate, respiration rate, temperature and BP), height, weight 
and review of systems.  
b. History and assessment including brief examination, vital signs and review of systems. 
Note all toxicities and adverse events, using CTCAE version 5. 
c. Tumor assessment using CT or MRI (at investigator’s discretion) will be collected at 
screening, after every 3 cycles, and as clinically indicated. Tumor response will be 
assessed using RECIST 1.1 criteria. Tumor measurement/disease assessment should be 
performed within 7 days at the beginning of every 3rd cycle. 
d. Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential 
(neutrophils, bands, lymphocytes, monocytes, eosinophils and basophils) and platelet 
count. 
e. ALT, AST, alkaline phosphatase, total bilirubin, direct bilirubin, LDH, creatine kinase, 
lipase, amylase glucose, calcium, phosphate, magnesium, bicarbonate, sodium, potassium, 
chloride, creatinine, blood urea nitrogen (BUN), total protein and albumin. 
f. PT-INR and aPTT. 
g. Urinalysis including blood, glucose, protein, specific gravity. If dipstick or routine 
urinalysis indicates proteinuria ≥ 2+, a 24-hour urine collection must be obtained in 2 
weeks. 
h. If necessary  
i. Hepatitis B surface antigen, surface antibody, core antigen and Hepatitis C antibody 
j. Pregnancy test will be performed at baseline for WOCBP and then only as clinically 
indicated 
k. Can be performed over the phone. After off treatment following disease progression, 
physical assessments (with lab tests performed at the discretion of the treating 
investigator) should take place every 3 months for up to two years or death. 
l. A diary card will be issued on day 1 of each cycle and the issued diary card will be 
returned on subsequent cycle   
m. Radiologic tests (CT scan or MRI) performed up to 4 weeks prior to obtaining informed 
consent can be used for screening purposes.    
Pregnancy, 
if applicable 
j 
Survival f/u 
k 
 
 
 
 
 
 
 
X 
Diary – 
Issued/Retur
ned l 
 
X 
 
X 
 
 
 
 


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n. Restaging imaging only to be performed if not done within the last 4 weeks 
 
7. Assessment types 
 
 
Pre-Treatment Assessments 
The nature of the study and the associated potential risks will be explained to all study candidates 
and a signed informed consent must be obtained before any study-specific Pre-Treatment 
procedures are performed. Pre-Treatment assessments must be completed and reviewed within 
21 days prior to the start of study drug treatment to ensure eligibility for study entry 
 
Pre-Treatment evaluations will include inclusion/exclusion criteria evaluation, demographic data 
collection, ECOG performance status, NYHA classification, medical and surgical history 
collection, vital signs, complete physical examination (including height and weight), 12-lead 
ECG, biochemistry, hematology and urinalysis, pregnancy test (urine or serum β- hCG in women 
of childbearing potential only), and tumor assessments 
 
Efficacy 
Response and progression will be evaluated using the international criteria proposed by 
the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) (see Appendix A). Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant 
lymph nodes are used in the RECIST criteria. 
 
Safety 
Safety assessments will consist of monitoring and recording all adverse events, including serious 
adverse events, the monitoring of hematology, blood chemistry, ECG and the regular monitoring 
of vital signs, and physical condition as shown in corresponding tables.  
 
 
8. Safety monitoring and reporting 
 
Adverse Events 
8.1.1 Definitions 
 
A serious adverse event is an undesirable sign, symptom or medical condition which: 
1. Is fatal or life-threatening. 
2. Requires or prolongs hospitalization. 
3. Results in persistent or significant disability/incapacity. 
4. Constitutes a congenital anomaly or a birth defect. 
5. Is medically significant, may jeopardize the subject and may require medical or surgical 


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intervention to prevent one of the outcomes listed above. 
 
Information about all adverse events, whether volunteered by the subject, discovered by 
investigator questioning, or detected through physical examination, laboratory test or other 
means, will be collected and recorded and followed as appropriate. An adverse event is any 
undesirable sign, symptom or medical condition occurring after starting study treatment. 
Medical conditions/diseases present before starting study treatment are only considered 
adverse events if they worsen after starting study treatment. Abnormal laboratory values or 
test results constitute adverse events only if they induce clinical signs or symptoms or require 
therapy. 
Full information from serious adverse events as well as adverse events concerning medication 
errors and overdose will be reported to Taiho Drug Safety or Designee. This can be performed 
by faxing it to Taiho or designee at (609) 750-7371 or via e-mail at TAS-
102_Safety@taihopui.com (please note the underscore between ‘102’ and ‘Safety’). 
In addition to the above, fatal events will also be documented by a separate death form, 
instead of reporting them as AE CTCAE grade. 
Events not considered to be serious adverse events are hospitalizations for the: 
• Routine  treatment  or  monitoring  of  the  studied  indication,  not  associated  with  any 
deterioration in condition. 
• Treatment, which was elective or pre-planned, for a pre-existing condition that did not 
worsen. 
• Treatment  on  an  emergency,  outpatient  basis  for  an  event  not  fulfilling  any  of  the 
definitions of serious given above and not resulting in hospital admission. 
Pregnancy, although not itself a serious adverse event, should also be reported on a serious 
adverse event form or pregnancy form and be followed up to determine outcome, including 
spontaneous or voluntary termination, details of birth, and the presence or absence of any 
birth defects or congenital abnormalities. 
Only the serious adverse event occurring after the patient has started taking the study 
medication, and until 4 weeks after the patient has stopped study participation must be 
reported. The period after discontinuing study drug may be extended if there is a strong 
suspicion that the drug has not yet been eliminated. 
Progression of the cancer under study is not considered an adverse event. 
 
 
 
Safety Monitoring  
Safety assessments will consist of monitoring and recording all adverse events and serious 
adverse events, the regular monitoring of hematology and blood chemistry parameters and 
regular physical examinations. Adverse events will be evaluated continuously throughout the 
study. Safety and tolerability will be assessed according to the NIH/NCI Common Terminology 


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Criteria for Adverse Events version 5.0 (CTCAE v5) that is available at: 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html 
Protocol Monitoring Committee (PMC); 
The PMC monitors its assigned ongoing research protocols for: adverse event reporting, data and 
safety monitoring, and internal audit findings. The PMC, upon review of any agenda item, may 
approve the study for continuation, require revisions, suspend or close a protocol. 
 
The PMC meets monthly and reviews accrual, patterns and frequencies of all adverse events, 
protocol violations and when applicable, internal audit results.  
 
 
Investigators of studies which are designated to be reviewed by the PMC for data and safety 
monitoring, shall provide a statistical report of the study’s progress and summary of adverse 
events and deviations based on the phase of the study and the associated risk of the study or more 
often if applicable.  
 
8.2.1 Internal Monitoring Plan 
 
Data will be captured in OnCore, Moffitt’s Clinical Trials Database.  
Regulatory documents and case report forms will be monitored internally according to Moffitt 
Cancer Center Monitoring Policies. Monitoring will be performed regularly by the MCC Clinical 
Monitoring Core for accuracy, completeness, and source verification of data entry, validation of 
appropriate informed consent process, reporting of SAEs, and adherence to the protocol, Good 
Clinical Practice (GCP) guidelines, and applicable regulatory requirements. 
 
 
Reporting of Serious Adverse Events 
All AEs will be recorded on the appropriate CRF. The Investigator will also identify the date 
of onset, date of resolution, seriousness, outcome, and the relationship to study drug. Every 
effort should be made to determine the cause of each AE and whether or not it is related to the 
study drugs. The relationship of the AE to the study drug must be rated and recorded following 
the guidelines outlined in the CTCAE v5. All the AEs will be reviewed by the Principal 
Investigator of the study. The 2 categories for AE grading are: 
 
1. Definite 
2. Probable 
3. Possible 
4. Unlike 
5. Unrelated 
The definition of serious adverse events (SAEs) is given in Section 8.1.1. 
Each serious adverse event must be followed up until resolution or stabilization, by submission 


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of updated reports to the designated person. An isolated laboratory abnormality that is assigned 
grade 4, according to CTC definition, is not reportable as an SAE; unless the investigator 
assesses that the event meets standard ICH criteria for an SAE.  CTC grade 4 baseline laboratory 
abnormalities that are part of the disease profile should not be reported as an SAE, specifically 
when they are allowed or not excluded by the protocol inclusion/exclusion criteria.   
 
To ensure patient safety, each serious adverse event must be reported to Dr. Kim expeditiously. 
Moffitt Cancer Center will report SAEs by completing an SAE report in OnCore, the electronic 
data capture system. If applicable, the site should also follow protocol guidelines for additional 
reporting to government agencies. 
 
When required, and according to local law and regulations, serious adverse events must be 
reported to the Ethics Committee and Regulatory Authorities.  
 
All serious adverse events should be reported to Taiho Drug Safety or Designee within 24 hours 
from the time that the investigator first becomes aware of the SAE. Comprehensive information 
available at the time of initial reporting (including narrative description, medical history and 
concomitant medications) needs to be provided with careful considerations regarding causality 
and serious criterion.  In the event of such an event, the investigator should refer to the 
Pharmacovigilance section of the contract for reporting procedures. 
 
Taiho Drug Safety: (email or by fax). This can be performed by faxing it to Taiho or designee 
at (609) 750-7371 or via e-mail at TAS-102_Safety@taihopui.com (please note the underscore 
between ‘102’ and ‘Safety’). 
 
The Investigator may report serious adverse events (SAEs) as described below. 
 
A MedWatch form available at http://www.fda.gov/medwatch/  
 
All reports shall be faxed to:  
 
PPD/PVG 
United States and Canada: Toll-Free Fax: 1-888-529-3580 
Rest of World: Toll-Free Fax: 93581-888-529-3580 (will automatically connect to 
PVGs toll-free safety fax number (1-888-529-3580) 
 
Pregnancies 
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject (spontaneously 
reported to them) that occurs during the trial. 
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, placebo treatment or a procedure.   


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Pregnancies and lactations that occur from the time of treatment allocation/randomization 
through 120 days following cessation of treatment, or 30 days following cessation of treatment 
if the subject initiates new anticancer therapy, whichever is earlier, must be reported by the 
investigator.  All reported pregnancies must be followed to the completion/termination of the 
pregnancy. Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform 
mole, blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth must be reported 
as serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported. 
Such events must be reported within 24 hours to the Principal Investigator. Within 24 hours of 
the Investigator becoming aware, the pregnancy must be reported to Taiho Drug Safety or 
Designee using the Pregnancy Form New and/or corrected information regarding the pregnancy 
obtained after submitting the initial Pregnancy Form must be submitted by faxing an updated 
Pregnancy Form to Taiho Pharmacovigilance or designee. This can be performed by faxing it 
to Taiho or designee at (609) 750-7371. 
 
9.   Statistical Methods and Data Analysis 
 
 
Definition of Study Endpoints 
To meet the objectives for this study, data for the following endpoints will be collected: 
• Safety and Tolerability  
• Tumor response by RECIST 1.1 (Secondary) 
• Exploratory biomarkers and cytokine multiples assay (Exploratory) 
 
Determination of sample size 
The primary objective of this study is overall survival at 6 months. Overall survival (OS) will be 
defined as the time from starting on trial to date of death due to any cause. Dropouts/screen 
failures defined in section 4.3.1. Patients will be considered inevaluable for the primary endpoint 
of 6 months of overall survival if they are not able to complete first cycle or if they are lost 
follow-up prior to 6 months from starting on trial except death. Inevaluable patients will be 
replaced. The study will test the null hypothesis of ≤45% of OS at 6 month against the alternative 
of ≥70% of OS at 6 month.   The sample size was determined based on the Simon’s two-stage 
minimax design. With one-sided 10% of type I error rate and 90% power, a sample of evaluable 
25 patients will be evaluated; 15 in first stage and additional 10 patients in second stage. If 7 or 
more out of 15 survive 6 months or more, the study goes on the second stage. The experimental 
treatment will be deemed to have good activity if ≥15 out of 25 patients survive 6 months or 
more. We will continue to recruit patients during interim analysis 
 


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Statistical analysis 
Overall survival (OS) is defined as the time from starting on trial to date of death due to any 
cause and progression-free survival (PFS) is defined as the duration of time from start of 
treatment to time of progression or death, whichever comes first. The final analysis will be 
conducted after the follow-time of the last patient exceeds 6 months. The primary endpoint of the 
study is OS at 6 month. The experimental treatment will be deemed to have good activity if ≥15 
out of 25 evaluable patients survive 6 months or more. OS will be estimated using the Kaplan-
Meier method and the two-sided 95% confidence interval (CI) for median OS will be computed 
using log-log transformation. 
The secondary endpoints in this study include toxicity, PFS and the objective response rate 
(ORR) defined as (complete response (CR) + partial response (PR)) using RECIST 1.1 criteria 
(Appendix A). ORR will be reported with 95% CI computed by the Clopper-Pearson method. 
The frequency and severity of adverse events and tolerability of the regimen will be summarized 
using descriptive statistics. PFS with 95% CI will be estimated. As exploratory objective, the 
association between biomarkers and clinical outcomes (ORR, OS and PFS) will be examined 
using multiple logistic regression and the multivariable Cox regression model. A p-value of 
<0.05 will be considered statistically significant. Frequency and severity of adverse events will 
be summarized using descriptive statistics. 
 
10. Data Recording 
 
 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. 
 
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. 
 Data Management and Monitoring/Auditing 
Data will be captured in OnCore, Moffitt’s Clinical Trials Database. Regulatory documents and 
case report forms will be monitored internally according to Moffitt Cancer Center Monitoring 
Policies.  Monitoring will be performed regularly to verify data is accurate, complete, and 


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verifiable from source documents; and the conduct of the trial is in compliance with the currently 
approved protocol/ amendments, Good Clinical Practice (GCP), and applicable regulatory 
requirements. 
 
 Adherence to the Protocol 
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. 
 Emergency Modifications 
Moffitt Cancer Center and Affiliate investigators may implement a deviation from, or a change 
of, the protocol to eliminate an immediate hazard(s) to trial subjects without prior H. Lee 
Moffitt Cancer Center or their respective institution’s approval/favorable opinion.  
For Institutions Relying on Moffitt’s IRB: 
For any such emergency modification implemented, a Moffitt IRB modification form must be 
completed by Moffitt Research Personnel within five (5) business days of making the change. 
 Record Retention 
Study documentation includes all eCRFs, data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory 
documents (e.g., protocol and amendments, IRB correspondence and approval, signed 
patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities and 
all reports and records necessary for the evaluation and reconstruction of the clinical research 
study. 
 
Government agency regulations and directives require that all study documentation pertaining 
to the conduct of a clinical trial must be retained by the study investigator. In all other cases, 
study documents should be kept on file until three years after the completion and final study 
report of this investigational study. 
 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. 
 


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11.   Ethical and Legal Aspects 
 Ethical and Legal Conduct of the Study 
The procedures set out in this protocol, pertaining to the conduct, evaluation, and documentation 
of this study, are designed to ensure that the investigator abide by Good Clinical Practice (GCP) 
guidelines and under the guiding principles detailed in the Declaration of Helsinki. The study 
will also be carried out in keeping with applicable local law(s) and regulation(s). 
Strict adherence to all specifications laid down in this protocol is required for all aspects of study 
conduct; the investigator may not modify or alter the procedures described in this protocol.   
Modifications to the study protocol will not be implemented by the investigator without 
discussion and agreement by Taiho. However, the investigator may implement a deviation from, 
or a change of, the protocol to eliminate an immediate hazard(s) to the trial subjects without prior 
IEC/IRB/Taiho approval/favorable opinion. As soon as possible, the implemented deviation or 
change, the reasons for it and, if appropriate, the proposed protocol amendment should be 
submitted to the IEC/IRB/head of medical institution. Any deviations from the protocol must be 
explained and documented by the investigator. 
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 will be responsible for assuring that all the required data will be 
collected and properly documented. 
 Subject Information and Consent 
Each subject/legal representative or proxy consenter will have ample time and opportunity to ask 
questions and will be informed about the right to withdraw from the study at any time without 
any disadvantage and without having to provide reasons for this decision. 
Only if the subject/legal representative or proxy consenter voluntarily agrees to sign the 
informed consent form and has done so, may he/she enter the study. Additionally, the 
investigator and other information provider (if any) will personally sign and date the form. The 
subject/legal representative or proxy consenter will receive a copy of the signed and dated form. 
The signed informed consent statement is to remain in the investigator site file or, if locally 
required, in the patient’s note/file of the medical institution. 
In the event that informed consent is obtained on the date that baseline study procedures are 
performed, the study record or subject’s clinical record must clearly show that informed consent 
was obtained prior to these procedures. 
1. If the patient is not capable of providing a signature, a verbal statement of consent can also be 
given in the presence of an impartial witness (independent of Taiho, and the investigator).  
This is to be documented by a signature from the informing physician as well as by a 
signature from the witness. 


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2. For adults under legal protection, consent shall be given by the legal guardian(s). The consent 
of an adult under legal protection shall also be requested where such a person is able to 
express his/her own will. His/her refusal or the withdrawal of his/her consent may not be 
disregarded. 
3. In emergency situations, when prior consent of the patient is not possible, the consent of the 
patient’s legal representative(s) or proxy consenter, if present, should be requested.  The 
patient should be informed about the study as soon as possible and his/her consent to 
continue the study should be requested. 
The informed consent form and any other written information provided to subjects/legal 
representatives or proxy consenters will be revised whenever important new information 
becomes available that may be relevant to the subject’s consent, or there is an amendment to the 
protocol that necessitates a change to the content of the subject information and/or the written 
informed consent form. The investigator will inform the subject/legal representative or proxy 
consenter of changes in a timely manner and will ask the subject to confirm his/her participation 
in the study by signing the revised informed consent form. Any revised written informed consent 
form and written information must receive the IEC/IRB`s approval/favorable opinion in advance 
of use. 
 Confidentiality 
All records identifying the subject will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available. 
Should direct access to medical records require a waiver or authorization separate from the 
subject’s statement of informed consent, it is the responsibility of the Investigator to obtain such 
permission in writing from the appropriate individual. 
 
 
12. Appendix 
APPENDIX A: RECIST Criteria for Measuring Tumor Response Antitumor Effect 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) (Eisenhauer et al., 2009). Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria. 
 
Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their first 
treatment with ramucirumab or TAS 102. 
 
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 


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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.) 
 
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 ≥10 mm with CT scan, MRI or 
calipers by clinical exam. All tumor measurements must be recorded in millimeters (or 
decimal fractions of centimeters). 
 
Note: Tumor lesions that are situated in a previously irradiated area might be considered 
measurable if the lesion has increased in size since the radiation. 
 
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a lymph 
node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis 
will be measured and followed. 
 
Non-measurable disease. All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are 
considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, and abdominal masses (not 
followed by CT or MRI), are considered as non-measurable. 
 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions 
in total, representative of all involved organs, should be identified as target lesions and 
recorded and measured at baseline. Target lesions should be selected on the basis of their size 
(lesions with the longest diameter), be representative of all involved organs, but in addition 
should be those that lend themselves to reproducible repeated measurements. It may be the 
case that, on occasion, the largest lesion does not lend itself to reproducible measurement in 
which circumstance the next largest lesion which can be measured reproducibly should be 
selected. A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) 
for all target lesions will be calculated and reported as the baseline sum diameters. If lymph 
nodes are to be included in the sum, then only the short axis is added into the sum. The 
baseline sum diameters will be used as reference to further characterize any objective tumor 
regression in the measurable dimension of the disease. 
 
Non-target lesions. All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target lesions and should also 
be recorded at baseline. Measurements of these lesions are not required, but the presence, 
absence, or in rare cases unequivocal progression of each should be noted throughout follow- 
up. 
 
Methods for Evaluation of Measurable Disease 
 


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All measurements should be taken and recorded in metric notation using a ruler or calipers. 
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
 
Clinical lesions. Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed 
using calipers (e.g., skin nodules). In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended. 
 
Conventional CT and MRI. This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the 
slice thickness. MRI is also acceptable in certain situations (e.g., for body scans). 
 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the evaluation of the 
type and site of disease. Furthermore, as with CT, the modality used at follow-up should be 
the same as was used at baseline and the lesions should be measured/assessed on the same 
pulse sequence. Ideally, the same type of scanner should be used and the image acquisition 
protocol should be followed as closely as possible to prior scans. Body scans should be 
performed with breath-hold scanning techniques, if possible. 
 
 
Response Criteria Evaluation of Target Lesions 
 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progression.) 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 


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qualify for PD, taking as reference the smallest sum diameters while on study. 
 
Evaluation of Non-Target Lesions 
 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). 
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s). 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. Unequivocal progression should not normally trump 
target lesion status. It must be representative of overall disease status change, not a single lesion 
increase. 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the Principal Investigator. 
 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The patient's best response assignment 
will depend on the achievement of both measurement and confirmation criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-PD/not 
evaluated 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
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 


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recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
 
Duration of stable disease: Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements. 
 
Progression-Free Survival (PFS) 
 
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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APPENDIX B: Medication Diary 
 
 
 
Day & 
date 
Time of 
morning 
dose 
What 
dose and 
how 
many 
tables 
and 
dose?  
 
Time of 
evening 
dose? 
What 
dose 
and how 
many 
tables 
and 
dose?  
 
List adverse effects 
/ changes in health 
and level of 
intensity 
List any other 
medication 
taken 
e.g.  01 
Mar 04 
e.g. 
07:30 
e.g. 
x 15mg-1 
x 20mg-1 
e.g. 19:00 
or 7 pm 
e.g.  
x 15mg-1, 
x 20mg-1 
e.g. As explained by  
study doctor and see  
***  below 
e.g.  2 “Name” 
tablets; time 
and reason. 
1 
 
 
□ 15mg-_ 
□ 20mg-_ 
 
□ 15mg-_ 
□ 20mg-_ 
 
 
2 
 
 
□ 15mg-_ 
□ 20mg-_ 
 
□ 15mg-_ 
□ 20mg-_ 
 
 
3 
 
 
□ 15mg-_ 
□ 20mg-_ 
 
□ 15mg-_ 
□ 20mg-_ 
 
 
4 
 
 
□ 15mg-_ 
□ 20mg-_ 
 
□ 15mg-_ 
□ 20mg-_ 
 
 
5 
 
 
□ 15mg-_ 
□ 20mg-_ 
 
□ 15mg-_ 
□ 20mg-_ 
 
 
6 
 
X 
X 
X 
X 
 
 
7 
 
X 
X 
X 
X 
 
 
8 
 
 
□ 15mg-_ 
□ 20mg-_ 
 
□ 15mg-_ 
□ 20mg-_ 
 
 
9 
 
 
□ 15mg-_ 
□ 20mg-_ 
 
□ 15mg-_ 
□ 20mg-_ 
 
 
10 
 
 
□ 15mg-_ 
□ 20mg-_ 
 
□ 15mg-_ 
□ 20mg-_ 
 
 
11 
 
 
□ 15mg-_ 
□ 20mg-_ 
 
□ 15mg-_ 
□ 20mg-_ 
 
 
12 
 
 
□ 15mg-_ 
□ 20mg-_ 
 
□ 15mg-_ 
□ 20mg-_ 
 
 
13 
 
X 
X 
X 
X 
 
 
14 
 
X 
X 
X 
X 
 
 
15 
 
X 
X 
X 
X 
 
 
16 
 
X 
X 
X 
X 
 
 
17 
 
X 
X 
X 
X 
 
 


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18 
 
X 
X 
X 
X 
 
 
19 
 
X 
X 
X 
X 
 
 
20 
 
X 
X 
X 
X 
 
 
21 
 
X 
X 
X 
X 
 
 
22 
 
X 
X 
X 
X 
 
 
23 
 
X 
X 
X 
X 
 
 
24 
 
X 
X 
X 
X 
 
 
25 
 
X 
X 
X 
X 
 
 
26 
 
X 
X 
X 
X 
 
 
27 
 
X 
X 
X 
X 
 
 
28 
 
X 
X 
X 
X 
 
 
 
 
**** Please assess the intensity of the problem or adverse event as follows: 
Mild   
= aware of sign or symptom, but it is easily tolerated 
Moderate    
= discomfort sufficient to cause interference with normal activities 
Severe     
= it is incapacitating, with inability to perform normal activities. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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