A Phase 1 Study of E7090 in Subjects With Solid Tumor
Phase: PHASE1
Conditions: Tumors
Sponsor: Eisai Co., Ltd.

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E7090-J081-101 
 
 
Date: 13 July 2018 (V9.0) 
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1 
TITLE PAGE 
 
Clinical Study Protocol 
Study Protocol 
Number: 
E7090-J081-101 
Study Protocol 
Title: 
A Phase 1 Study of E7090 in Subjects with Solid Tumor 
Sponsor: 
Eisai Co., Ltd. 
 
 
Sponsor’s 
Investigational 
Product Name: 
E7090 
Indication: 
Solid tumor 
Phase: 
Phase 1 
Approval Date: 
V1.0 
1 August 2014 
 
V2.0 
4 September 2014 
 
V3.0 
13 November 2014 
 
V4.0 
29 January 2016 
 
V5.0 
4 April 2016 
 
V6.0 
22 April 2016 
 
V7.0 
3 July 2017 
 
V8.0 
25 October 2017 
 
V9.0 
13 July 2018 
GCP Statement: 
This study is to be performed in full compliance with International 
Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) and all applicable local 
Good Clinical Practice (GCP) and regulations.  All required study 
documentation will be archived as required by regulatory 
authorities. 
Confidentiality 
Statement: 
This document is confidential.  It contains proprietary information 
of Eisai (the sponsor).  Any viewing or disclosure of such 
information that is not authorized in writing by the sponsor is 
strictly prohibited.  Such information may be used solely for the 
purpose of reviewing or performing this study. 

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Date: 13 July 2018 (V9.0) 
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2 
CLINICAL PROTOCOL SYNOPSIS 
Compound No.:  E7090 
Name of Active Ingredient:  
5-({2-[({4-[1-(2-Hydroxyethyl)piperidin-4-yl]phenyl}carbonyl)amino]pyridin-4-yl}oxy)-6- 
(2-methoxyethoxy)-N-methyl-1H-indole-1-carboxamide butanedioate (2:3) 
Study Protocol Title 
A phase 1 study of E7090 in subjects with solid tumor 
Site(s) 
Study region (Country):  Japan 
Study sites:  1 site in Part 1, about 14 to 17 sites in Part 2 (planned) 
Study Period and Phase of Development 
FPI:  November 2014 
LPI:  September 2018 (planned) 
Phase 1 
Objectives 
Primary objective 
• To investigate the tolerability and safety of E7090 in patients with solid tumors 
Secondary objectives 
• To estimate the maximum tolerated dose (MTD) of E7090 (only in Part 1) 
• To assess the pharmacokinetics (PK) of E7090 
• To estimate the recommended dose for subsequent phase studies 
• To preliminarily evaluate the antitumor activity of E7090 
Exploratory objectives 
• To investigate the pharmacodynamic (PD) markers and pharmacogenomics (PGx) of E7090 
• To investigate the PK, PD markers, and PGx relationship for E7090 
• To assess overall survival (OS) and progression-free survival (PFS) with E7090 treatment (only in 
Part 2) 
• To analyze plasma and urinary metabolites of E7090 
Study Design 
This is a phase 1 study of E7090 in patients with solid tumors, consisting of 2 parts (Part 1 and Part 
2).  In Part 1, patients with solid tumors receiving E7090 will be evaluated for dose-limiting toxicities 
(DLTs) to estimate its MTD.  Part 2 will include patients with gastric cancer carrying the FGFR2 
gene amplification or FGFR2 protein overexpression and patients with cholangiocarcinoma harboring 
FGFR2-fusion genes among patients with solid tumors.  E7090 will be administered at 1 or 2 doses 
selected from among the doses studied in Part 1 to evaluate its tolerability and safety in detail and its 
efficacy preliminarily.  On the basis of the results from Part 1 and Part 2, the recommended dose for 
subsequent phase studies will be estimated.  The dose for Part 2 will be determined through 
discussion among the investigator, the sponsor, the medical expert, and if necessary, the Data and 
Safety Monitoring Advisor. 
 

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Study Design Overview
(1)
Part 1: Part 1 will include patients with solid tumors and will consist of a pretreatment period, a 
treatment period, and a follow-up period. The pretreatment period involves informed consent, 
screening test, subject registration, and baseline assessment. The treatment period consists of 
Cycle 0, and Cycle 1 and subsequent cycles. Cycle 0 is 7 days long, and Cycle 1 and 
subsequent cycles are 28 days long. In Cycle 0, subjects will take a single dose of E7090 at the 
dose for each dose group on Day 1 for PK evaluation. In Cycle 1 and subsequent cycles, 
subjects will take E7090 at the dose for each dose group once daily continuously until any of the 
criteria in Section 9.3.3.1 “Discontinuation Criteria for Individual Subjects” is met. The follow-
up period involves the early discontinuation procedures and final observation.
Method of subject’s dose assignment
Dose assignment will be performed using a modified toxicity probability interval (mTPI) design.
According to an established target DLT rate of 25% for this study, 3 toxicity probability 
intervals are defined as 20% to 30% (proper dosing), 0% to 20% (underdosing), and 30% to 
100% (overdosing). In accordance with the rules of the mTPI design based on these intervals, 
each subject will be assigned a dose of E7090. The decision rules for all dose assignment will 
be calculated in advance on the basis of the mTPI design, presented as the “Decision Rules for 
Dose Assignment” below.
Decision Rules for Dose Assignment
Number of subjects treated at each dose
2
4
6
8
10
Number of subjects 
with DLT
0
E
E
E
E
E
1
D a
S
S
E
E
2
D, U
D
S
S b
S
3
D, U
D
S
S b
4
D, U
D, U
D, U
S
5
D, U
D, U
D, U
E = Escalate to the next higher dose, S = Stay at the current dose, D = De-escalate to the next lower dose, U =
The current dose is unacceptably toxic (ie, Do not re-register any subject in this dose)
Target DLT rate and its corresponding interval, 25%, 20% to 30%; Cohort size, 2 subjects
Rules for the number of subjects per dose being above 10 are omitted.
a: Extra subjects may be added for the initial dose.
b: Early termination of registration may be considered.
Two subjects will be registered at each dose level. In a new dose group, the safety of the first 
subject should be evaluated before enrollment of the second and subsequent subjects. On the 
basis of the number of subjects with DLT at each dose level, assignment of the next dose will be 
determined according to the Decision Rules for Dose Assignment. If DLT develops in 1 of the 
2 subjects at the initial dose level, however, extra subjects may be added through discussion
Part 1
Safety and preliminary efficacy evaluations
Patients with gastric cancer carrying FGFR2 gene amplification 
or protein overexpression
Patients with cholangiocarcinoma harboring FGFR2-fusion genes
MTD estimation
Solid tumor
(All patients)
Select 1 or 2 
doses
Part 2

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among the investigator, the sponsor, and the medical expert.  At this time, advice may be 
obtained from the Data and Safety Monitoring Advisor as necessary.  Any subject not evaluable 
for DLT (eg, a subject discontinuing the study during Cycle 1 for reasons other than the 
development of DLT) should be replaced at the dose level for the subject.  Under the mTPI 
design, subject registration will be closed when the DLT rate at the initial dose is much higher 
than the target DLT rate (25%) or when the prespecified maximum sample size (approximately 
20 subjects) is reached.  However, the maximum sample size will be adjusted as required.  For a 
particular dose, subject registration may be closed early if a subsequent subject is highly likely 
to be allocated to the dose.  The mTPI design is described in the “Statistical Methods.” 
Method of determining the dose for the next dose group 
The dose for the next dose group will be determined according to the degree of toxicities 
(adverse events possibly related to E7090) observed in subjects in the immediately preceding 
dose group during Cycle 0 and Cycle 1 (see the table below).  The dose for the next dose group 
will be escalated by 100% if all toxicities observed in the immediately preceding dose group 
during Cycle 0 and Cycle 1 are Grade 1 or lower.  If a Grade 2 toxicity is observed in 1 subject, 
the next dose will be escalated by 50%.  If Grade 2 toxicities are observed in 2 subjects or if 
Grade 3 or higher toxicities are observed in 1 or more subjects, the next dose will be escalated 
by 33%. 
When a dose is escalated or de-escalated by 1 dose level according to the mTPI design, if there 
is a higher or lower dose level evaluated previously, subjects will be added to the immediately 
preceding dose level evaluated previously, instead of following the “Method of Determining the 
Dose for the Next Dose Group” shown below.  In addition, an intermediate dose may be added, 
if necessary, on the basis of the safety or PK of the previously evaluated dose.  The addition of a 
new dose level will be determined through discussion among the investigator, the sponsor, the 
medical expert, and if necessary, the Data and Safety Monitoring Advisor. 
Method of Determining the Dose for the Next Dose Group 
Dose escalation for the next 
dose group (%) 
Toxicities observed during Cycle 0 and Cycle 1 (a) 
100 
Grade WR[LFLW\RQO\ 
50 
Grade 2 toxicity in 1 subject 
33 
*UDGHWR[LFLW\LQVXEMHFWVRU*UDGHWR[LFLW\LQVXEMHFW 
(a) Excluding clinically insignificant events such as laboratory abnormalities requiring no treatment 
Transition to the next dose group will be determined through discussion among the investigator, 
the sponsor, and the medical expert.  At this time, advice may be obtained from the Data and 
Safety Monitoring Advisor as necessary.  Safety data from subjects excluded from the DLT 
analysis population will also be considered when determining transition to the next dose group 
(including changes in the assignment of a dose and the percentage of dose escalation). 
 
(2) Part 2:  Part 2 will include patients with solid tumors, consisting of the following cohorts: 
Gastric cancer cohort:  Patients with gastric cancer carrying an amplified FGFR2 gene or 
overexpressed FGFR2 protein (including patients with gastroesophageal junction cancer 
diagnosed as adenocarcinoma) 
Cholangiocarcinoma cohort:  Patients with cholangiocarcinoma harboring FGFR2-fusion genes 

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Part 2 will consist of a pretreatment period, a treatment period, and a follow-up period. 
The pretreatment period consists of Screening 1, Screening 2, and baseline assessment.  In 
Screening 1, each subject will be examined for FGFR genetic abnormalities in the tumor, and in 
Screening 2, each subject will be examined for the other eligibility criteria.  Separate written 
informed consent will be obtained before the start of Screening 1 and Screening 2.  Screening 1 
will include gastric cancer patients with documented FGFR2 gene amplification and 
cholangiocarcinoma patients with documented FGFR2-fusion genes.  In addition, Screening 1 
will also include any gastric cancer patient with an unknown FGFR2 amplification status who 
has an archived tumor sample available for the confirmation of FGFR2 protein expression.  No 
biopsy should be performed at Screening 1. 
In Screening 1, the following will be confirmed: 
• For patients with the documented genetic abnormalities mentioned above, the documents 
necessary for genetic testing will be submitted to the sponsor to confirm the presence of 
genetic abnormalities. 
• For gastric cancer patients with unknown genetic abnormalities who have an archived tumor 
sample available for the confirmation of the FGFR2 protein expression mentioned above, the 
archived tumor sample will be sent to the central laboratory to confirm the presence of 
FGFR2 protein overexpression with immunohistochemical staining. 
Patients considered eligible according to either of the criteria above are eligible to enter into 
Screening 2. 
Because no biopsy is permitted in Screening 1, adverse advents will be collected only after 
informed consent for Screening 2 is obtained.  Patients meeting all of the inclusion criteria and 
not meeting any of the exclusion criteria in Screening 2 will be considered eligible for treatment, 
and study treatment will be started after baseline assessment.  In Screening 2, a biopsy will be 
performed in all patients, other than those who have only a tumor lesion not amenable to biopsy 
for safety reasons.  The treatment period will consist of 28-day treatment cycles, and patients 
will take the study drug once daily continuously until any of the criteria in Section 9.3.3.1 
“Discontinuation Criteria for Individual Subjects” is met.  The follow-up period will involve the 
early discontinuation procedures and the final observation. 
Number of Subjects 
Part 1 
20 subjects (planned) 
Part 2 
15 to 20 subjects (planned) (10 with gastric cancer and 5 to 10 with cholangiocarcinoma) 
Inclusion Criteria (for both Part 1 and Part 2) 
(1) Patients providing voluntary written consent for the participation in this study 
(2) Patients who have been given a sufficient explanation of the requirements in this study and are 
willing and able to follow them 
(3) Patients aged \HDUVDWWKHWLPHRILQIRUPHGFRQVHQW 
(4) Patients with a histological or cytological diagnosis of solid tumor 
(5) Patients who have not responded to standard treatment or for whom no other appropriate 
treatment is available 
(6) Patients with adequate major organ function 

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1) +HPRJORELQ g/dL ( g/dL in Part 2) 
2) 1HXWURSKLOFRXQWî3/ȝ/ 
3) 3ODWHOHWFRXQWî4/ȝ/ 
4) 7RWDOELOLUXELQWLPHVWKH institutional upper limit of normal (ULN) 
5) AST and ALT WLPHVWKH ULN (.0 times the ULN in the presence of intrahepatic bile 
duct cancer or liver metastases) 
6) 6HUXPFUHDWLQLQHWLPHVWKHULN 
(7) &RUUHFWHGVHUXPFDOFLXP8/1 
Corrected serum calcium = sHUXPFDOFLXPPJG/íserum albumin [g/d/@î 
(to be corrected only for subjects with a serum albumin <4 g/dL) 
(8) %ORRGSKRVSKDWHULN 
(9) Patients with an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 to 
1 
(10) Patients expected to survive for 3 months or longer after registration (Part 1) or the start of study 
treatment (Part 2) 
(11) Patients with the following time intervals between prior therapy and study treatment in this 
study: 
1) Anticancer therapy 
(a) Other investigational products, antibody therapy:  ZHHNVKDOI-lives are 
acceptable for other investigational products with a known half-life) 
(b) Anticancer agents (excluding small molecule targeted drugs), surgical therapy, 
radiation therapy:  ZHHNV 
(c) Endocrine therapy, immunotherapy, small molecule targeted drugs:  ZHHNV 
2) Supportive therapy 
(a) Blood transfusions, blood products, hematopoietic factor products including 
granulocyte colony-stimulating factor (G-CSF) products:  ZHHNV 
(12) Women of childbearing potential must have practiced contraception since 28 days before 
registration (Part 1) or 28 days before the start of study treatment (Part 2), and must agree to use 
medically effective contraception (eg, the subject is using intrauterine devices,* condoms with 
spermicide,* contraceptive implants,** or oral contraceptives;* or the subject’s male partner is 
confirmed to have no sperm after vasectomy)Note throughout the study period (for 30 days after 
the final study drug administration).  Any subject practicing contraception by abstinence must 
agree to practice contraception with condoms with spermicide during the study period and for 
30 days after the final study drug administration.  Women of childbearing potential using any 
oral contraceptive are to use the oral contraceptive at a fixed dose for at least 4 weeks before 
study drug administration and continue to use the same oral contraceptive during the study 
period and for 30 days after the final study drug administration. 
All women will be considered to have childbearing potential, except for postmenopausal women 
(being amenorrheic for at least 12 consecutive months without suspected causes including age) 
and women undergoing sterilization (bilateral tubal ligation at least 1 month before study 
treatment, hysterectomy, or bilateral oophorectomy at least 1 month before study treatment). 
Note: Whether the drug/medical device has been approved or authorized in Japan (*, yes; **, no) 
(13) Male participants or their female partners meeting the criteria above (when the partner is a 
woman with no childbearing potential or will use medically effective contraception throughout 
the study period and for 30 days after final study drug administration) 

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Inclusion Criteria (for Part 2 only) 
(14) Patients whose solid tumors have been confirmed to meet either of the following in Screening 1: 
1) Patients with gastric cancer carrying an amplified FGFR2 gene or an overexpressed FGFR2 
protein (including patients with gastroesophageal junction cancer diagnosed as 
adenocarcinoma) 
2) Patients with cholangiocarcinoma harboring FGFR2-fusion genes 
(15) Patients with a target lesion that can be evaluated according to RECIST 1.1 
(16) Patients meeting both of the following criteria 1) and 2) concerning tumor sample submission: 
1) Patients agreeing to submit any tumor sample collected in the past 
2) Patients agreeing to submit any biopsy sample in Screening 2 (excluding those who have 
only a tumor lesion not amenable to biopsy for safety reasons) 
Exclusion Criteria 
(1) Patients with a brain metastasis accompanied by clinical symptoms or requiring treatment 
(2) Patients with any of the following clinically significant cardiovascular disorders: 
1) New York Heart Association (NYHA) Grade III or higher cardiac disease (Appendix 1) 
2) Unstable angina pectoris or myocardial infarction within 6 months before enrollment in this 
study (Part 1) or within 6 months before the start of study treatment (Part 2) 
3) QTc >480 msec (Fridericia method) 
4) Arrhythmia requiring treatment 
(3) Patients with serious systemic infection requiring treatment including bacterial infection and 
fungal infection 
(4) Patients with a positive test result for human immunodeficiency virus (HIV) 
(5) Patients with celomic fluid retention requiring drainage 
(6) Patients with any of the following previous or concurrent corneal or retinal diseases: 
1) *UDGHFRUQHDOGLVRUGHU 
2) Active macular disease (eg, age-related macular degeneration, central serous 
chorioretinopathy) 
(7) Patients in whom the adverse effects of prior treatment have not recovered to Grade 1 or lower, 
except for alopecia and Grade 2 peripheral neuropathy 
(8) Patients with active malignancy within 36 months before the start of study treatment (excluding 
the primary disease, and carcinomas in situ such as completely treated melanoma in situ, basal 
or squamous cell carcinoma of the skin, carcinoma in situ of the cervix, and early-stage large 
bowel cancer) 
(9) Patients with prior therapy targeting FGFR2 
(10) Patients who are using any CYP3A inhibitor or inducer (Appendix 2) and will require it during 
VWXG\WUHDWPHQWWKHUHPXVWEHDWLPHLQWHUYDORIGD\VEHWZHHQWKHILQDOGRVHRIWKHVHGUXJV
and the start of study treatment) 
(11) Patients known to be intolerant to any of the ingredients of the study drug (or excipients) 
(12) Patients unable to take drugs orally or with malabsorption syndrome (patients undergoing 
gastrectomy may be enrolled) 
(13) Patients with mental or physical disorders, such as alcoholism and drug dependence, considered 
to preclude the participation in this study in the opinion of the investigator or subinvestigator 

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(14) Pregnant or breastfeeding patients (breastfeeding patients may not be enrolled even if they 
discontinue breastfeeding) 
(15) Any others considered ineligible for the participation in this study in the opinion of the 
investigator or subinvestigator 
Study Treatment 
E7090 will be administered orally once daily.  Study drug consists of 1, 1.5, 5, 20, and 60 mg 
capsules (Part 1) and 35 mg tablets (Part 2).  The initial dose in Part 1 will be 1 mg and the starting 
dose in Part 2 will be 140 mg. 
Administration schedule 
(1) Part 1 
1) Cycle 0 (for 7 days) 
A single dose of E7090 at the dose for each group will be administered on Day 1 to evaluate 
its PK following single administration.  Subjects will take a single dose of E7090 in the 
fasting state on waking after an at least 10-hour overnight fast.  Subjects will be prohibited 
from eating or drinking for 2 hours after administration, except for drinking water. 
2) Cycle 1 and subsequent cycles (for 28 days each) 
Subjects will start Cycle 1 between the 8th and 10th days after administration in Cycle 0 and 
take E7090 once daily continuously.  Subjects will take E7090 at least 2 hours after 
breakfast, and will not eat anything for 1 hour after administration.  On the 8th day of Cycle 
1, however, subjects will take E7090 in the fasting state on waking after an at least 10-hour 
overnight fast for PK evaluation.  Subjects will be prohibited from eating or drinking for 2 
hours after administration, except for drinking water.  Study treatment may be continued 
unless any of the criteria in Section 9.3.3.1 “Discontinuation Criteria for Individual 
Subjects” is met. 
(2) Part 2 
Subjects will take E7090 at least 2 hours after breakfast and will not eat anything for 1 hour 
after administration.  On Day 1 and Day 8 of Cycle 1, however, subjects will take E7090 in the 
fasting state on waking after an at least 10-hour overnight fast for PK evaluation.  Subjects will 
be prohibited from eating or drinking for 2 hours after administration, except for drinking water.  
Study treatment may be continued unless any of the criteria in Section 9.3.3.1 “Discontinuation 
Criteria for Individual Subjects” is met. 
Methods of dose interruption and reduction 
(1) Part 1 
1) Cycle 1 
(a) If a DLT is observed 
Study treatment will be interrupted immediately.  When the investigator or 
subinvestigator considers it possible to continue the study, study treatment may be 
restarted at a 1-level dose reduction once the toxicity resolves to Grade 0 to 1 or 
baseline. 
(b) If no DLT is observed 
Study treatment will not be interrupted until a DLT is observed.  However, when the 
investigator or subinvestigator considers interruption clinically necessary, study 
treatment may be interrupted and restarted at the same dose as appropriate.  No dose 
reduction will be permitted. 

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2) Cycle 2 and subsequent cycles 
If any E7090-related toxicity is observed, the following criteria for dose 
interruption/reduction should be followed. 
Criteria for Dose Interruption/Reduction 
E7090-related toxicity a 
Management 
Dose after restart 
Grade 1 or tolerable Grade 2 b 
Continue study treatment 
No change 
Intolerable Grade 2 b or Grade 3 
Interrupt treatment until the toxicity 
resolves to Grade 0 to 1 or baseline c 
Same dose or 1-level dose 
reduction 
Grade 4 d 
Discontinue study treatment 
NA 
a: Laboratory abnormalities not requiring treatment will be excluded. 
b: The tolerability of Grade 2 will be determined by the investigator or subinvestigator. 
c: When the investigator or subinvestigator considers interruption clinically acceptable, study treatment may be 
restarted also when the toxicity resolves to tolerable Grade 2. 
d: Any laboratory abnormality considered non-life-threatening will be excluded and managed as a Grade 3 event. 
 
(2) Part 2 
If any E7090-related toxicity or hyperphosphatemia is observed, the “Criteria for Dose 
Interruption/Reduction” and the “Criteria for Dose Interruption/Reduction Based on 
Hyperphosphatemia,” respectively, should be followed.  If study treatment is continued after the 
dose reduction, the dose will be reduced step-by-step to 105 mg, 70 mg, and then 35 mg. 
Criteria for Dose Interruption/Reduction 
Toxicity a 
Criteria 
Management 
Hematological 
Grade 3 toxicity is observed. 
Interrupt treatment until the toxicity resolves to Grade 2 
or lower and restart at the same dose as that before 
interruption 
Grade 4 toxicity is observed. 
Interrupt treatment until the toxicity resolves to Grade 2 
or lower and restart at a 1-level dose reduction 
Non-
hematological 
Intolerable Grade 2 b or Grade 3 toxicity is 
observed. 
Interrupt treatment until the toxicity resolves to Grade 1 
or baseline and restart at a 1-level dose reduction 
Grade 4 c toxicity is observed. 
Discontinue treatment d 
a: Laboratory abnormalities not requiring treatment will be excluded. 
b: The tolerability of Grade 2 will be determined by the investigator or subinvestigator. 
c: Any laboratory abnormality considered non-life-threatening by the investigator or subinvestigator will be managed as 
a Grade 3 event instead of a Grade 4 event. 
d: If study treatment is considered clinically beneficial to the subject by the investigator or subinvestigator, treatment 
may be interrupted until the toxicity resolves to Grade 1 or baseline and restarted at a 1-level dose reduction. 
 
Criteria for Dose Interruption/Reduction Based on Hyperphosphatemia 
Criteria 
Management 
Serum pKRVSKDWHOHYHOLV5.5 mg/dL DQG7.0 mg/dL. 
Start treatment of hyperphosphatemia. 
Despite appropriate treatment of hyperphosphatemia,a serum 
pKRVSKDWHOHYHOVDQG9.0 mgG/ODVWIRU2 weeks,b or 
serum pKRVSKDWHOHYHOVDUH9.1 mg/dL. 
Interrupt treatment until serum phosphate 
OHYHOVGHFUHDVHWR7.0 mg/dL and restart 
treatment at a 1-level dose reduction. 
a: This refers to treatments, such as diet therapy and hyperphosphatemia drugs, considered appropriate by the 
investigator or subinvestigator. 

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b: Any subject with a serum pKRVSKDWHOHYHORImg/dL should visit the study site 1 week later and undergo 
measurement of serum phosphate levels for the evaluation of hyperphosphatemia. 

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Duration of Treatment 
Treatment with E7090 will be continued until any of the following discontinuation criteria is met. 
Discontinuation Criteria for Individual Subjects 
(1) Subject’s refusal to continue study participation or withdrawal of consent 
(2) Major inclusion/exclusion criteria violation after registration (Part 1) or enrollment (Part 2) 
(3) Difficulty in continuing the study due to an adverse event in the opinion of the investigator or 
subinvestigator 
(4) Subject’s pregnancy 
(5) Disease progression (except when the investigator or subinvestigator considers study treatment 
clinically beneficial to the subject) 
(6) Dose reduction to <1 mg (Part 1) or 35 mg (Part 2) required due to an adverse drug reaction 
(7) Other cases where the investigator or subinvestigator considers study discontinuation 
appropriate 
Concomitant Drug/Therapy 
Prohibited concomitant drugs/therapies 
(1) Cycle 0 and Cycle 1 (Part 1 only) 
1) Treatments, changes in dosage, and changes in drugs to prevent DLT occurrence 
(2) From the time of registration (Part 1) or the start of study treatment (Part 2) to the time of the 
discontinuation of study treatment 
1) Treatments for malignant tumors other than E7090 (eg, surgical therapy, chemotherapy, 
endocrine therapy, palliative radiotherapy, or immunotherapy) except for drugs for bone 
lesions (eg, bisphosphonates, anti-RANKL monoclonal antibodies) that have been used 
since before the registration in this study (Part 1) or the start of study treatment (Part 2) 
2) Drugs that inhibit or induce CYP3A (see Appendix 2 for relevant drugs) 
3) Other investigational products 
Assessments 
(1) Efficacy assessments 
Tumor assessment (target lesion, non-target lesion, presence/absence of new lesions) will be 
performed using RECIST 1.1.  Tumor markers will also be determined.  Survival follow-up will 
be terminated 2 years after the last subject’s registration (Part 2). 
(2) Pharmacokinetic (PK) assessments 
Blood and urine samples will be collected to determine plasma and urine E7090 concentrations.  
In addition, plasma and urine E7090 metabolites will be analyzed in an exploratory manner. 
(3) PD and PGx assessments 
[Part 1] 
1) Blood 
Blood samples will be collected to determine the following biomarkers (but not limited to): 
(a) FGF23 
(b) 1,25-(OH)2-Vitamin D 
(c) 
 
(d) Angiogenesis markers (eg, VEGF, FGF) 
(e) Circulating tumor DNA 
CCI

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2) Archived tumor 
If available, an archived tumor sample (optional) will be obtained to determine the following 
biomarkers (but not limited to): 
(a) FGFR 
3) Biopsied tumor 
At screening and on the 15th day of Cycle 1 (optional), biopsy tumor samples will be 
collected to determine the following biomarkers: 
(a) FGFR 
(b) Phosphorylated FGFR 
(c) ERK 
(d) Phosphorylated ERK 
[Part 2] 
1) Blood 
Blood samples will be collected to determine the following biomarkers (but not limited to): 
(a) FGF23 
(b) 1,25-(OH)2-Vitamin D 
(c) 
 
(d) Angiogenesis markers (eg, VEGF, FGF) 
(e) Circulating tumor DNA 
2) Archived tumor 
If any sample collected in the past is available, an archived tumor sample should be 
submitted (mandatory). 
3) Biopsied tumor 
Except for subjects who have only a tumor lesion not amenable to biopsy for safety reasons, 
samples obtained from the biopsy performed in Screening 2 must be submitted (mandatory).  
In addition, samples obtained from the biopsy performed on the 15th day of Cycle 1 will be 
submitted (optional). 
For 2) and 3) above, immunohistochemical staining or comprehensive genomic analysis will 
be performed to evaluate their correlation with the efficacy of E7090.  In addition, samples 
will be archived for the development of diagnostic agents. 
(4) Safety assessments 
Safety will be assessed through monitoring and recording of all adverse events and serious 
adverse events.  Laboratory tests, vital signs, 12-lead ECGs, ECOG-PS, physical findings, and 
ophthalmologic examination will be evaluated at prespecified time points. 
In addition, DLTs will be assessed to determine the MTD.  The nature, frequency, and severity 
of adverse events will be evaluated, and the severity of adverse events will be graded using the 
CTCAE v4.03.  DLTs will be defined as the following events occurring during Cycle 0 and 
Cycle 1 considered to be possibly related to E7090.  DLTs will be determined through 
discussion among the investigator, the sponsor, and the medical expert.  At this time, advice 
may be obtained from the Data and Safety Monitoring Advisor as necessary. 
1) DLT criteria 
(a) FHEULOHQHXWURSHQLDRU*UDGHQHXWURSHQLDSHUVLVWLQJIRUGD\V 
(b) Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia requiring platelet 
transfusions 
CCI

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(c) *UDGH non-hematological toxicity, except for the following: 
a) Clinically insignificant laboratory abnormalities 
b) Toxicity WKDWFDQEHFRQWUROOHGWR*UDGHE\EHVWVXSSRUWLYHFDUH 
(d) Potentially clinically significant, new radiographic mineralization in the soft tissue, 
kidneys, intestines, heart, lungs, or other organs 
(e) Hyperphosphatemia meeting either of the following: 
a) Serum SKRVSKDWHOHYHO!PJG/SHUVLVWLQJIRUGD\VGHVSLWHEHVWWUHDWPHQW 
b) Serum phosphate level >9 mg/dL despite best treatment 
(f) 
TUHDWPHQWLQWHUUXSWLRQIRUGD\VGXULQJ&\FOHDQG&\FOH required by possibly 
E7090-related toxicity, except IRUWUHDWPHQWLQWHUUXSWLRQIRUGD\VIRUUHDVRQVRWKHU
than toxicity.  In this case, the subject will be removed from the DLT evaluation and 
replaced by a new subject. 
2) Determination of the MTD 
The MTD of E7090 will be determined using the mTPI design.  At the end of Part 1, the MTD will be 
selected as a dose with the smallest difference from the target DLT rate of 25% according to the 
posterior distribution of the DLT rate for each dose. 
Bioanalytical Methods 
E7090 concentrations in plasma and urine and PD markers in blood will be determined using a 
validated method of measurement. 
Statistical Methods 
Statistical design concerning the modified toxicity probability interval method in Part 1: 
The MTD of E7090 will be determined using the mTPI design.  The mTPI design uses a 
beta/binomial hierarchical model in a Bayesian statistical framework to calculate the posterior 
probabilities of 3 intervals that reflect the relative distance between the target DLT rate of 25% and 
the DLT rate for each dose level. 
The decision rules for finding doses are based on the calculation of the unit probability mass (UPM) 
of the 3 intervals corresponding to 0% to 20% (underdosing), 20% to 30% (proper dosing), and 30% 
to 100% (overdosing) in terms of toxicity.  The UPM of each interval is defined as the probability of 
the interval divided by the length of the interval, and the interval with the largest UPM indicates the 
decision on the next dose level to be assigned:  dose escalation (E), staying at the current dose (S), 
and dose de-escalation (D). 
These dose assignment rules minimize the posterior expected loss in the Bayes’ rule when equal prior 
expected losses are used for E, S, and D in a decision-theoretic framework.  The decision rules for all 
dose assignment will be calculated in advance, as presented in Table 1. 
The MTD will be determined when the posterior probability of the DLT rate at the initial dose 
exceeding 25% exceeds 95% (ie, an unacceptable DLT rate exceeding the target DLT rate) or when a 
prespecified maximum sample size of approximately 20 subjects is reached.  However, the maximum 
sample size will be adjusted as necessary according to the actual number of dose levels to be 
evaluated and the number of subjects evaluable for DLT.  In addition, if the Bayesian predictive 
probability of being S when another 10 subjects are added to a dose level is 80% or higher (ie, if it is 
highly likely that subsequent registered subjects will also be assigned to the dose level), subject 
registration may be closed early to determine the MTD. 
The MTD will be defined as the dose with the smallest difference between the target DLT rate of 
25% and an estimated DLT rate at each dose among all the evaluated doses for which the posterior 
probability of the DLT rate exceeding 25% is 95% or lower.  The isotonically transformed posterior 
mean under a beta posterior distribution with non-informative beta prior distribution Beta (0.005, 

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0.005) will be used to determine the estimated DLT rate at each dose.  The pooled-adjacent-violators 
algorithm (PAVA) will be used to maintain the monotonic increase of the DLT rate with increasing 
dose level. 
Efficacy endpoints 
The efficacy endpoints to be calculated will include the best overall response (BOR) according to 
RECIST 1.1, objective response rate (ORR), disease control rate (DCR), progression-free survival 
(PFS), overall survival (OS), and percent changes from baseline in the sum of the diameters of target 
lesions (when appropriate).  BOR includes complete response (CR), partial response (PR), stable 
disease (SD), progression of disease (PD), and not evaluable (NE), where SD must to be achieved 
beyond 7 weeks after the first dose.  In this study, CR and PR will require no confirmation based on 
the next response evaluation beyond 4 weeks.  ORR is defined as the proportion of subjects with a 
BOR of CR or PR.  DCR is defined as the proportion of subjects with a BOR of CR, PR, or SD.  PFS 
is defined as the time from the date of the first dose to the date of the first event (disease progression 
or death due to any cause, whichever comes first).  OS is defined as the time from the date of the first 
dose to the date of death due to any cause. 
Tolerability/Safety endpoints 
The tolerability endpoint will include DLTs.  The safety endpoints will include adverse events, 
laboratory tests, vital signs, weight, 12-lead ECG, ECOG-PS, and ophthalmologic examination. 
PK endpoints 
Blood and urine samples will be collected for PK analysis to determine E7090 concentrations in 
plasma and urine.  Metabolites of E7090 in plasma and urine will be analyzed in an exploratory 
manner. 
PD and PGx endpoints 
The PD and PGx endpoints will include measurements of biomarkers (in blood and tumor tissue) and 
their percent changes.  Of these, the PGx endpoints refer to measurements of circulating tumor DNA 
in blood and measurements of genetic mutations in biopsied tumor tissues. 
Analysis sets 
The DLT analysis set is the group of subjects completing treatment with E7090 in Cycle 0 and Cycle 
ZLWKDFRPSOLDQFHUDWHRIDQGHYDOXDWHGIRU'/7DQGVXEMHFWVH[SHULHQFLQJ'/7LQ&\FOH
or Cycle 1 in Part 1.  This analysis set will be used to estimate the MTD in Part 1. 
The safety analysis set is the group of subjects receiving at least 1 dose of E7090. 
The efficacy analysis set is the group of subjects receiving at least 1 dose of E7090 with at least 1 
tumor assessment at baseline and after administration.  This analysis set will be used for the interim 
assessment in Part 2. 
The PK analysis set is the group of subjects receiving at least 1 dose of E7090 with data from which 
at least 1 PK parameter can be calculated. 
The PD and PGx analysis set is the group of subjects receiving at least 1 dose of E7090 with at least 1 
PD or PGx data. 
Efficacy analyses 
Part 1:  Efficacy analyses will be performed using the efficacy analysis set.  On the basis of tumor 
assessments according to RECIST 1.1, the BOR will be summarized for each group and overall.  In 
subjects with non-target lesions only, a BOR of non-CR/non-PD will be categorized into SD. 

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Part 2:  Analysis results will be summarized for each cohort and overall.  In addition to the analyses 
similar to those for Part 1, ORR, DCR, and their exact two-sided 95% confidence intervals will be 
calculated.  PFS and OS will also be summarized and plotted over time using the Kaplan-Meier 
method.  When appropriate, a waterfall plot will be created for the percent change from baseline in 
the sum of the diameters of target lesions at the time of maximum tumor reduction after 
administration. 
Pharmacokinetic analyses 
The PK analysis set will be used to summarize E7090 plasma concentrations and PK parameters and 
perform other PK analyses.  A non-compartmental analysis of plasma and urine E7090 concentrations 
will be performed to calculate PK parameters including Cmax, tmax, AUC, and renal clearance.  
Detailed methods and results of the exploratory metabolite analysis will be provided in a separately 
prepared analysis plan and report, and its results will not be included in the clinical study report. 
PD and PGx analyses 
PD and PGx analyses will be performed using the PD and PGx analysis set.  Measurements of 
biomarkers (in blood and tumor tissue) and their percent changes will be evaluated visually with the 
use of figures and tables.  If necessary, correlations of measurements of biomarkers and their 
percentage changes with the efficacy and safety of E7090 will be analyzed, or various exploratory 
analyses will be performed.  Results of other comprehensive analyses will not be included in the 
clinical study report. 
Tolerability/Safety analyses 
DLT analyses will be performed using the DLT analysis set.  The number and percentage of subjects 
with DLTs will be summarized.  DLTs will also be summarized by type.  Other safety analyses will 
be performed using the safety analysis set.  The number and percentage of subjects with treatment-
emergent adverse events and serious adverse events will be summarized by system organ class (SOC) 
and preferred term (PT).  Summary statistics will be used to summarize the results of laboratory tests, 
vital signs, weight, 12-lead ECG, ECOG-PS, and ophthalmologic examination as well as their 
changes from baseline. 
Interim Analyses 
No interim analysis taking into consideration adjustment for type I and II errors will be performed in 
this study. 
In the gastric cancer cohort in Part 2, an interim efficacy evaluation will be performed, and if no 
responder is observed in 5 evaluable subjects, the cohort may discontinue further enrollment.  The 
duration of follow-up of subjects with continuous SD will be determined through discussion with the 
sponsor. 
This criterion is based on the posterior distribution of Bayesian statistics.  When a non-informative 
beta prior distribution Beta (1,1) is used, the discontinuation criterion corresponds to the case where 
the probability of ORR being 40% or higher is less than 10% in the posterior distribution of the 5 
subjects at the time of evaluation.  In cases other than the number of evaluable subjects established as 
the discontinuation criterion, if necessary, it will be acceptable to consider interim evaluations and 
discontinuation of enrollment based on the posterior distribution and criteria described above. 
The ORR threshold of 40% has been established as a beneficial effect size, taking the mechanism of 
action of E7090 into consideration. 

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Sample Size Rationale 
The primary objective of this study is to evaluate the tolerability and safety of E7090.  The sample 
size for Part 1 has been set to approximately 20 subjects, assuming the number of dose levels to be 
evaluated of 9 and a cohort size of 2 on the basis of the recommended sample size to reach the MTR 
in the mTPI design.  When deemed necessary, the sample size may be adjusted, depending on the 
actual number of dose levels to be evaluated and the number of evaluable subjects for DLT. 
The sample size for Part 2 has been set to approximately 10 subjects or 5 to 10 subjects per cohort, 
considering its feasibility, to allow further safety evaluation and the preliminary antitumor effect 
evaluation. 

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3 
TABLE OF CONTENTS 
1 
TITLE PAGE .....................................................................................................................1 
2 
CLINICAL PROTOCOL SYNOPSIS ...............................................................................2 
3 
TABLE OF CONTENTS .................................................................................................17 
4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................23 
5 
ETHICS............................................................................................................................25 
5.1 
Institutional Review Boards/Independent Ethics Committees ..............................25 
5.2 
Ethical Conduct of the Study .................................................................................25 
5.3 
Subject Information and Informed Consent ...........................................................25 
6 
INVESTIGATORS AND STUDY PERSONNEL ..........................................................26 
7 
INTRODUCTION ...........................................................................................................27 
7.1 
Fibroblast Growth Factor Receptor .......................................................................27 
7.2 
E7090 .....................................................................................................................27 
7.3 
Nonclinical Studies of E7090 ................................................................................27 
7.3.1 
Pharmacodynamics ......................................................................................27 
7.3.2 
Pharmacokinetics and Drug Metabolism .....................................................28 
7.3.3 
Toxicology ...................................................................................................29 
7.4 
Clinical Experience ................................................................................................29 
7.5 
Study Rationale ......................................................................................................30 
7.5.1 
Rationale for the Study Design ....................................................................30 
7.5.1.1 
Referenced Guidelines and Guidances ................................................30 
7.5.1.2 
Rationale for the Initial Dose for Part 1 ...............................................30 
7.5.1.3 
Rationale for the Starting Dose for Part 2 ............................................31 
7.5.1.4 
Rationale for Once-Daily Dosing ........................................................31 
7.5.1.5 
Rationale for Targeting Patients with Solid Tumors in Part 1 .............31 
7.5.1.6 
Rationale for the Use of the mTPI Design in Part 1 ............................32 
7.5.1.7 
Rationale for Determining the Dose for the Next Dose Group ...........32 
7.5.1.8 
Rationale for Including Patients with Gastric Cancer Carrying an 
Amplified FGFR2 Gene or an Overexpressed FGFR2 Protein and 
Patients with Cholangiocarcinoma Harboring FGFR2-Fusion 
Genes in Part 2 .....................................................................................33 
7.5.1.9 
Rationale for Selecting 1 or 2 Doses from among the Part 1 Doses 
in Part 2 ................................................................................................33 
7.5.2 
Methods of Evaluating Adverse Drug Reactions Expected from 
Nonclinical Toxicity Studies........................................................................33 
8 
STUDY OBJECTIVES ....................................................................................................34 
8.1 
Primary Objective ..................................................................................................34 
8.2 
Secondary Objectives.............................................................................................34 

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8.3 
Exploratory Objectives ..........................................................................................34 
9 
INVESTIGATIONAL PLAN ..........................................................................................35 
9.1 
Overall Study Design and Plan ..............................................................................35 
9.1.1 
Part 1 ............................................................................................................35 
9.1.1.1 
Pretreatment Period ..............................................................................36 
9.1.1.2 
Treatment Period ..................................................................................36 
9.1.1.3 
Follow-up Period .................................................................................37 
9.1.2 
Part 2 ............................................................................................................37 
9.1.2.1 
Pretreatment Period ..............................................................................38 
9.1.2.2 
Treatment Period ..................................................................................38 
9.1.2.3 
Follow-up Period .................................................................................39 
9.2 
Discussion of Study Design, Including Choice of Control Groups .......................39 
9.3 
Selection of Study Population ................................................................................39 
9.3.1 
Inclusion Criteria .........................................................................................39 
9.3.2 
Exclusion Criteria ........................................................................................41 
9.3.3 
Removal of Subjects from Therapy or Assessment .....................................43 
9.3.3.1 
Discontinuation Criteria for Individual Subjects .................................43 
9.4 
Treatment ...............................................................................................................43 
9.4.1 
Treatment Administered (Part 1) .................................................................44 
9.4.1.1 
Initial Dose ...........................................................................................44 
9.4.1.2 
Administration Schedule ......................................................................44 
9.4.1.3 
Method of Subject’s Dose Assignment................................................45 
9.4.1.4 
Method of Determining the Dose for the Next Dose Group ................46 
9.4.1.5 
Examples of Dose Assignment and Dose Escalation ..........................48 
9.4.1.6 
Determination of Transition to the Next Dose Group .........................49 
9.4.1.7 
Definition of Dose-Limiting Toxicity (DLT) ......................................49 
9.4.1.8 
Criteria for Dose Interruption/Reduction .............................................50 
9.4.2 
Treatment Administered (Part 2) .................................................................51 
9.4.2.1 
Starting Dose ........................................................................................51 
9.4.2.2 
Administration Schedule ......................................................................51 
9.4.2.3 
Criteria for Dose Interruption/Reduction .............................................52 
9.4.3 
Estimation of the Recommended Dose for Subsequent Phase Studies........53 
9.4.4 
Identity of Investigational Product...............................................................53 
9.4.4.1 
Chemical Name and Structural Formula of E7090 ..............................53 
9.4.4.2 
Comparator Drug .................................................................................54 
9.4.4.3 
Labeling for Study Drug ......................................................................54 
9.4.4.4 
Storage Conditions ...............................................................................54 
9.4.5 
Method of Assigning Subjects to Treatment Groups ...................................54 

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9.4.6 
Selection of Doses in the Study ...................................................................59 
9.4.7 
Selection and Timing of Dose for Each Subject ..........................................59 
9.4.8 
Blinding........................................................................................................59 
9.4.9 
Prior and Concomitant Therapy ...................................................................59 
9.4.9.1 
Drug-Drug Interactions ........................................................................59 
9.4.9.2 
Prohibited Concomitant Therapies and Drugs .....................................59 
9.4.10 
Treatment Compliance .................................................................................60 
9.4.11 
Drug Supplies and Accountability ...............................................................60 
9.5 
Study Assessments .................................................................................................60 
9.5.1 
Assessments .................................................................................................60 
9.5.1.1 
Demographic Assessments ..................................................................60 
9.5.1.2 
Pretreatment Assessments ....................................................................61 
9.5.1.2.1 
Medical History, Current Medical Conditions, Prior Treatment ...61 
9.5.1.2.2 
Other Pretreatment Assessments Specific to the Study or 
Target Disease ................................................................................62 
9.5.1.3 
Efficacy Assessments...........................................................................62 
9.5.1.3.1 
Assessment of Tumor Lesions .......................................................62 
9.5.1.3.2 
Tumor Markers ..............................................................................64 
9.5.1.3.3 
Survival Follow-up ........................................................................64 
9.5.1.4 
Pharmacokinetic, Pharmacodynamic, and Pharmacogenomic 
Assessments .........................................................................................65 
9.5.1.4.1 
Pharmacokinetic Assessments .......................................................65 
9.5.1.4.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Assessments ...................................................................................67 
9.5.1.5 
Safety Assessments ..............................................................................70 
9.5.1.5.1 
Adverse Events ..............................................................................71 
9.5.1.5.2 
Serious Adverse Events and Events Associated with Special 
Situations........................................................................................73 
9.5.1.5.3 
Laboratory Measurements .............................................................74 
9.5.1.5.4 
Vital Signs, Weight, and Height Measurements ............................75 
9.5.1.5.5 
Physical Examinations ...................................................................75 
9.5.1.5.6 
Electrocardiograms ........................................................................75 
9.5.1.5.7 
Ophthalmological Examinations ....................................................76 
9.5.1.5.8 
ECOG-PS .......................................................................................76 
9.5.1.5.9 
Pregnancy Test ...............................................................................76 
9.5.1.5.10 Transcutaneous Arterial Oxygen Saturation Measurement ...........76 
9.5.1.6 
Compliance with Study Treatment ......................................................76 
9.5.1.7 
Concomitant Drugs and Therapies .......................................................76 
9.5.2 
Schedule of Procedures/Assessments ..........................................................77 

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9.5.2.1 
Schedule of Procedures/Assessments in Part 1 ....................................77 
9.5.3 
Appropriateness of Measurements ...............................................................82 
9.5.4 
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations ..............................................................82 
9.5.4.1 
Reporting of Serious Adverse Events ..................................................82 
9.5.4.2 
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding .......................................................................................82 
9.5.4.3 
Reporting of Events Associated with Special Situations .....................83 
9.5.4.3.1 
Reporting of Adverse Events Associated with Study Drug 
Overdose, Misuse, Abuse, or Medication Error ............................83 
9.5.4.4 
Expedited Reporting ............................................................................84 
9.5.4.5 
Breaking the Blind ...............................................................................84 
9.5.4.6 
Regulatory Reporting of Adverse Events ............................................84 
9.5.5 
Completion/Discontinuation of Subjects .....................................................84 
9.5.6 
Abuse or Diversion of Study Drug ..............................................................84 
9.5.7 
Confirmation of Medical Care by Another Physician .................................84 
9.6 
Data Quality Assurance .........................................................................................85 
9.6.1 
Data Collection ............................................................................................85 
9.6.2 
Clinical Data Management ..........................................................................85 
9.7 
Statistical Methods .................................................................................................85 
9.7.1 
Statistical and Analytical Plans ....................................................................85 
9.7.1.1 
Study Endpoints ...................................................................................85 
9.7.1.1.1 
Primary Endpoints .........................................................................85 
9.7.1.1.2 
Secondary Endpoints .....................................................................86 
9.7.1.1.3 
Exploratory Endpoints ...................................................................86 
9.7.1.2 
Definitions of Analysis Sets.................................................................86 
9.7.1.3 
Subject Disposition ..............................................................................86 
9.7.1.4 
Demographic and Other Baseline Characteristics ...............................87 
9.7.1.5 
Prior and Concomitant Therapy ...........................................................87 
9.7.1.6 
Efficacy Analyses ................................................................................87 
9.7.1.6.1 
Primary Efficacy Analysis .............................................................87 
9.7.1.6.2 
Secondary Efficacy Analyses ........................................................88 
9.7.1.6.3 
Exploratory Efficacy Analyses ......................................................88 
9.7.1.7 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses ...................................................................88 
9.7.1.7.1 
Pharmacokinetic Analyses .............................................................88 
9.7.1.7.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses .........................................................................................88 
9.7.1.8 
Safety Analyses ....................................................................................89 

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9.7.1.8.1 
Extent of Exposure .........................................................................89 
9.7.1.8.2 
Adverse Events ..............................................................................89 
9.7.1.8.3 
Laboratory Values ..........................................................................90 
9.7.1.8.4 
Vital Signs ......................................................................................91 
9.7.1.8.5 
Electrocardiograms ........................................................................91 
9.7.1.8.6 
Other Safety Analyses....................................................................91 
9.7.2 
Determination of Sample Size .....................................................................91 
9.7.3 
Interim Analysis ...........................................................................................92 
9.7.4 
Other Statistical/Analytical Issues ...............................................................92 
9.7.5 
Procedures for Revising the Statistical Analysis Plan .................................93 
10 REFERENCE LIST .........................................................................................................94 
11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES) .......96 
11.1 
Changes to the Protocol .........................................................................................96 
11.2 
Adherence to the Protocol ......................................................................................96 
11.3 
Monitoring Procedures...........................................................................................96 
11.4 
Recording of Data ..................................................................................................97 
11.5 
Identification of Source Data .................................................................................97 
11.6 
Retention of Records..............................................................................................97 
11.7 
Auditing Procedures and Inspection ......................................................................98 
11.8 
Handling of Study Drug .........................................................................................98 
11.9 
Publication of Results ............................................................................................98 
11.10 Disclosure and Confidentiality ..............................................................................99 
11.11 Discontinuation of Study .......................................................................................99 
11.12 Subject Insurance and Indemnity ...........................................................................99 
12 APPENDICES ...............................................................................................................100 
 

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LIST OF IN-TEXT TABLES 
Table 1 
Decision Rules for Dose Assignment ........................................................45 
Table 2 
Method of Determining the Dose for the Next Dose Group ......................47 
Table 3 
Examples of Dose Corrections...................................................................47 
Table 4 
Criteria for Dose Interruption/Reduction (Part 1) ......................................51 
Table 5 
Criteria for Dose Interruption/Reduction (Part 2) ......................................52 
Table 6 
Criteria for Dose Interruption/Reduction Based on Hyperphosphatemia 
(Part 2) .......................................................................................................53 
Table 7 
Examples of Tumor Markers .....................................................................64 
Table 8 
Blood Sampling Schedule for PK Evaluation (Part 1) ...............................65 
Table 9 
Blood Sampling Schedule for PK Evaluation (Part 2) ...............................67 
Table 10 
Blood Sampling Schedule for PD and PGx Evaluations (Part 1) ..............68 
Table 11 
Blood Sampling Schedule for PD and PGx Evaluations (Part 2) ..............70 
Table 12 
Clinical Laboratory Tests ...........................................................................74 
Table 13 
Schedule of Procedures/Assessments in Part 1 ..........................................78 
Table 14 
Schedule of Procedures/Assessments in Part 2 ..........................................80 
 
LIST OF IN-TEXT FIGURES 
Figure 1 
Study Design Overview .............................................................................35 
Figure 2 
Outline of Study Design for Part 1 ............................................................36 
Figure 3 
Outline of Study Design for Part 2 ............................................................37 
Figure 4 
Process for Subject’s Dose Assignment ....................................................46 
Figure 5 
Example of Dose Assignment and Dose Escalation ..................................48 
Figure 6 
Subject Registration Procedure (Part 1) .....................................................56 
Figure 7 
Subject Enrollment Procedure (Part 2) ......................................................58 
 

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4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase (GPT) 
AST 
aspartate aminotransferase (GOT) 
AUC 
area under the plasma 
concentration-time curve 
BUN 
blood urea nitrogen 
CL 
total clearance 
Cmax 
maximum observed concentration 
CR 
complete response 
CRM 
Continual Reassessment Method 
CT 
computed tomography 
CTCAE 
Common Toxicity Criteria for Adverse Events 
CYP/CYP3A4 
cytochrome P450/cytochrome P450 3A4 
DCR 
disease control rate 
DLT 
dose limiting toxicity 
ECOG  
Eastern Cooperative Oncology Group 
FGF/FGFR 
fibroblast growth factor/fibroblast growth factor receptor 
FISH 
fluorescence in situ hybridization 
GCP 
Good Clinical Practice 
Ȗ-GTP 
gamma glutamyl transferase 
HBs 
hepatitis B virus surface antigen 
hCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
ICH 
International Conference on Harmonization 
JCOG  
Japan Clinical Oncology Group 
LC-MS/MS 
liquid chromatography with tandem mass spectrometry 
LDH 
lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
mTPI 
modified toxicity probability interval 

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Abbreviation 
Term 
NA 
not applicable 
NE 
not evaluable 
NGS 
next-generation sequencing 
NYHA 
New York Heart Association 
ORR 
objective response rate 
OS 
overall survival 
PAVA 
pooled-adjacent-violators algorithm 
PD 
progressive disease 
PET 
positron emission tomography 
PFS 
progression-free survival 
PGx 
pharmacogenomics 
PR 
partial response 
PS 
performance status 
PT 
preferred term 
QT 
QT interval 
RECIST 
Response Evaluation Criteria in Solid Tumor 
RT-PCR 
real-time polymerase chain reaction 
SD 
stable disease 
SOC 
system organ class 
SOP 
standard operating procedures 
t1/2 
terminal elimination phase half-life 
TEAE 
treatment-emergent adverse event 
TEMAV 
treatment emergent markedly abnormal laboratory values 
tmax 
time at which the highest drug concentration occurs 
TNM classification 
tumor, nodes, metastasis classification 
ULN 
upper limit of normal 
UPM 
unit probability mass 
VZ 
volume of distribution at terminal phase 
WHO 
United Nations World Health Organization 
 

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5 
ETHICS 
5.1 
Institutional Review Boards/Independent Ethics Committees 
The protocol, informed consent form (ICF), and appropriate related documents must be 
reviewed and approved by an Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC) constituted and functioning in accordance with ICH E6 (Good Clinical 
Practice), Section 3, and any local regulations.  Any protocol amendment or revision to the 
ICF will be resubmitted to the IRB/IEC for review and approval, except for changes 
involving only logistical or administrative aspects of the study (eg, change in CRA[s], 
change of telephone number[s]).  Documentation of IRB/IEC compliance with the ICH E6 
and any local regulations regarding constitution and review conduct will be provided to the 
sponsor. 
Documented study approval from the IRB/IEC chairman must be sent to the head of the 
medical institution with a copy to the sponsor before study start and the release of any study 
drug to the site by the sponsor or its designee (ICH E6, Section 4.4).  If the IRB/IEC decides 
to suspend or terminate the study, the head of the medical institution will immediately send 
the notice of study suspension or termination by the IRB/IEC to the sponsor. 
Study progress is to be reported to IRB/IECs annually (or as required) via the head of the 
medical institution in accordance with GCP.  The sponsor will submit, depending on local 
regulations, periodic reports and inform the investigator and the IRB/IEC via the head of the 
medical institution of any reportable adverse events (AEs) per GCP and local IRB/IEC 
standards of practice.  Upon completion of the study, the investigator will provide the 
IRB/IEC and the sponsor via the head of the medical institution with a brief report of the 
outcome of the study. 
5.2 
Ethical Conduct of the Study 
This study will be conducted in accordance with standard operating procedures of the 
sponsor (or designee), which are designed to ensure adherence to GCP guidelines as required 
by the following: 
x 
Principles of the World Medical Association Declaration of Helsinki - Ethical Principles 
for Medical Research Involving Human Subjects 
x 
GCP 
x 
Standards stipulated in Article 14, Paragraph 3, and Article 80-2 of the Pharmaceutical 
Affairs Law (Law No. 145, 1960) 
5.3 
Subject Information and Informed Consent 
As part of administering the informed consent document, the investigator must explain to 
each subject (or the subject’s guardian/legally authorized representative) the nature of the 
study, its purpose, the procedures involved, the expected duration, the potential risks and 
benefits involved, any potential discomfort, potential alternative procedure(s) or course(s) of 
treatment available to the subject, and the extent of maintaining confidentiality of the 

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subject’s records.  Each subject must be informed that participation in the study is voluntary, 
that he/she may withdraw from the study at any time, and that withdrawal of consent will not 
affect his/her subsequent medical treatment or relationship with the treating physician. 
This informed consent should be given by means of a standard written statement, written in 
nontechnical language.  The subject or the subject’s legally acceptable representative should 
understand the statement before signing and dating it and will be given a copy of the signed 
document.  If a subject is unable to read or if a legally acceptable representative is unable to 
read, an impartial witness should be present during the entire informed consent discussion.  
After the ICF and any other written information to be provided to subjects is read and 
explained to the subject or the subject’s legally acceptable representative, and after the 
subject or the subject’s legally acceptable representative has orally consented to the subject’s 
participation in the study and, if capable of doing so, has signed and personally dated the 
ICF, the witness should sign and personally date the consent form.  The subject will be asked 
to sign an ICF before any study-specific procedures are performed (at the Screening).  No 
subject can enter the study before his/her informed consent has been obtained. 
An unsigned copy of an IRB/IEC-approved ICF must be prepared in accordance with ICH 
E6, Section 4, and all applicable regulations.  Each subject must sign an approved ICF before 
study participation.  The form must be signed and dated by the investigator, subinvestigator 
(study coordinator, as necessary).  The original, signed ICF for each subject will be verified 
by the sponsor and kept on file according to local procedures at the site. 
The subject or the subject’s legally authorized representative should be informed in a timely 
manner if new information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study.  The communication of this information 
should be documented. 
The ICF for genetic testing will be prepared separately from that for study participation, and 
genetic testing will be conducted in subjects who have consented to the testing.  In Part 1, 
genetic testing involving the use of blood samples is required and subjects who do not 
consent to such testing cannot be included in this clinical study, whereas those who do not 
consent to genetic testing of tumor samples can still be eligible for this study.  In Part 2, 
genetic testing involving the use of blood and tumor samples are required (tumor samples 
will not be obtained from subjects who cannot submit an archived tumor sample collected in 
the past or who are not amenable to biopsy). 
6 
INVESTIGATORS AND STUDY PERSONNEL 
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor).  Part 1 will be conducted at 1 medical institution in Japan, and Part 2 will be 
conducted at approximately 14 to 17 medical institutions (planned) in Japan. 
The name and telephone and fax numbers of the medical monitor and other contact personnel 
at the sponsor are listed in Appendix 3. 

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7 
INTRODUCTION 
7.1 
Fibroblast Growth Factor Receptor 
Fibroblast growth factor receptors (FGFR) are transmembrane tyrosine kinase receptors 
consisting of 4 types:  FGFR-1, -2, -3, and -4.  There are 18 FGFs known as ligands involved 
in FGF/FGFR signaling.  It is known that binding of FGF to FGFR activates numerous 
pathways involved in cellular functions such as cellular proliferation and survival via the 
MAP kinase pathway (RAS/RAF/MEK/ERK pathways) and PI3K/AKT pathway (Haugsten 
EM, et al., 2010) (Turner N, Grose R, 2010) (Dieci MV, et al., 2013). 
In cancer cells, not only signal activation is induced by increased expression of FGF/FGFR 
or by supply of FGF by peritumoral tissues, but also constant downstream signaling 
activation is triggered by various FGFR gene abnormalities such as translocations, point 
mutations, and gene amplifications.  Accordingly, associated tumorigenicity, increased 
metastasis/invasiveness, and drug resistance have been reported (Haugsten EM, et al., 2010) 
(Turner N, Grose R, 2010) (Dieci MV, et al., 2013). 
Analyses of clinical samples have revealed FGFR gene abnormalities or FGF/FGFR 
overexpression in various types of cancers including lung cancer, breast cancer, endometrial 
cancer, gastric cancer, and bladder cancer (Haugsten EM, et al., 2010) (Turner N, Grose R, 
2010) (Dieci MV, et al., 2013), some of which have been associated with prognosis or drug 
resistance (Kim HR, et al., 2013) (Jung EJ, et al., 2012) (Byron SA-, et al., 2012).  Also in 
vascular endothelial cells, it has been reported that FGF/FGFR signaling is a major 
angiogenesis signaling pathway like VEGF/KDR and PDGF/PDGFR signaling pathways, 
and it has been suggested that FGF/FGFR signaling is involved in the investment in the 
resistance to VEGF/KDR inhibitors (Casanovas O, et al., 2005). 
These findings indicate that FGFR inhibitors are expected to have direct effects on tumors 
with activated FGFR signaling and antiangiogenic effects on tumor blood vessels. 
7.2 
E7090 
E7090, an oral FGFR kinase inhibitor developed at Eisai Tsukuba Research Laboratories, 
selectively inhibits FGFR-1, -2, and -3.  Its excellent antitumor effects on a variety of human 
cancer cell lines with FGFR abnormalities (eg, gene translocation, point mutation, 
amplification) observed in nonclinical pharmacology studies indicate a promising efficacy in 
cancer patients, especially those with FGFR abnormalities. 
7.3 
Nonclinical Studies of E7090 
7.3.1 
Pharmacodynamics 
[Primary Pharmacodynamic Studies] 
 
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
 
 
 
 
 
 
 
 
 
7.3.2 
Pharmacokinetics and Drug Metabolism 
 
 
 
 
 
 
 
 
 
 
 
 
 
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7.3.3 
Toxicology 
 
 
 
 
 
 
 
 

 

 

 
 
 
 
 
 
 
7.4 
Clinical Experience 
As of 28 March 2017, 24 patients (2 each in the 1, 2, 4, 8, 16, and 30 mg groups and 3 each 
in the 60, 100, 140, and 180 mg groups) have been enrolled in Part 1 of this study.  
Commonly reported adverse events (20% across the groups) included hyperphosphatemia 
(37.5%);  increased blood creatinine and nausea (33.3% each);  diarrhea (29.2%);  increased 
ALT and fatigue (25.0% each);  and constipation, increased lipase, pyrexia, and tumor pain 
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(20.8% each).  Reported Grade 3 adverse events included increased ALT (2 subjects in the 
180 mg group), increased AST (1 subject in the 180 mg group), decreased appetite (1 subject 
in the 180 mg group), decreased neutrophil count (1 subject in the 180 mg group), vomiting 
(1 subject in the 180 mg group), and decreased lymphocyte count (1 subject in the 60 mg 
group), all of which were Grade 3 in severity.  DLTs (Grade 3 increased AST and increased 
ALT) occurred in 1 subject in the 180 mg group.  Three serious adverse events were reported 
in 2 subjects in the 8 mg group (cancer pain and dyspnea each in 1 subject) and 1 subject in 
the 30 mg group (pyrexia), all of which were assessed as unrelated to study treatment.  No 
adverse events led to death or treatment discontinuation. 
7.5 
Study Rationale 
This study is a phase 1 study of E7090 designed to investigate the pharmacological profile of 
E7090 when administered to humans for the first time.  The study consists of Part 1 and Part 
2. 
7.5.1 
Rationale for the Study Design 
7.5.1.1 
Referenced Guidelines and Guidances 
This study was designed with reference to “Guidelines for Clinical Evaluation Methods of 
Anticancer Drugs” (PFSB/ELD Notification No. 1101001 dated 1 November 2005), ICH S9 
“Guidelines for Nonclinical Evaluation Methods of Anticancer Drugs” (PFSB/ELD 
Notification No. 0604-1 dated 4 June 2010), “Guidance for Establishing Safety in First-in-
Human Studies During Drug Development” (PFSB/ELD Notification No. 0402-1 dated 2 
April 2012), and “Technical Guidance on In Vitro Companion Diagnostics and 
Corresponding Therapeutic Products” (Administrative Notice dated 26 December 2013). 
7.5.1.2 
Rationale for the Initial Dose for Part 1 
The initial dose of E7090 for this study was established with reference to ICH S9 
“Guidelines for Nonclinical Evaluation Methods of Anticancer Drugs” (PFSB/ELD 
Notification No. 0604-1 dated 4 June 2010).  This guideline states that for many small-
molecule drugs, their initial dose should be usually set at 1/10 the severely toxic dose (STD 
10;  toxicity associated with lethality, life-threatening toxicities, or irreversible toxicities) in 
10% of rodent test animals, or at 1/6 the highest non-severely toxic dose (HNSTD) in the 
case where non-rodents are the most appropriate test species. 
 
 
 
 
 
 
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Taking subject safety into consideration, the dose of 1.46 mg calculated on the basis of the 
toxicity study in rats (more susceptible to toxicity) has been selected to set the initial dose at 
1 mg, which is below 1.46 mg. 
7.5.1.3 
Rationale for the Starting Dose for Part 2 
On the basis of the data from Part 1, the starting dose for Part 2 has been set at 140 mg.  In 
Part 1, patients were enrolled in the following order:  1 mg (n = 2), 2 mg (n = 2), 4 mg (n = 
2), 8 mg (n = 2), 16 mg (n = 2), 30 mg (n = 2), 60 mg (n = 3), 100 mg (n = 3), 180 mg (n = 
3), and 140 mg (n = 3).  Because a DLT was observed in 1 subject in the 180-mg cohort 
(Grade 3 increased AST/ALT) and no DLT was observed in the 140-mg cohort, 140 mg has 
been selected as the recommended dose for Part 2. 
7.5.1.4 
Rationale for Once-Daily Dosing 
Physiological PK models were used to estimate the PK profile of E7090 in humans.  
 
 
 
 
 
elimination half-life following oral dose was estimated to be 27 to 48 hours.  
Given that administration once daily was considered to be adequate to maintain the plasma 
concentration of E7090, a once-daily dosing schedule was selected. 
7.5.1.5 
Rationale for Targeting Patients with Solid Tumors in Part 1 
Part 1 will include patients with solid tumors.  As described in Section 7.3.1 “Primary 
Pharmacodynamic,” E7090 is expected to be effective particular in patients with FGF/FGFR 
gene abnormalities because it showed its effects on cell lines where FGF/FGFR signaling is 
constantly active.  It has been reported that FGF/FGFR signaling is a major angiogenesis 
signaling pathway like VEGF/KDR and PDGF/PDGFR signaling pathways, and it has been 
suggested that FGF/FGFR signaling is involved in the investment in the resistance to 
VEGF/KDR inhibitors (Casanovas O, et al., 2005).  It is therefore considered that E7090 is 
also expected to be effective in patients without FGF/FGFR abnormalities.  The “Technical 
Guidance on In Vitro Companion Diagnostics and Corresponding Therapeutic Products” 
(Administrative Notice dated 26 December 2013) states, “It is important to establish a drug 
development strategy that reflects the need to evaluate negative patients at an earlier stage.  
For instance, both biomarker-positive and negative patients should be evaluated earlier phase 
clinical studies such as exploratory dose-response studies.”  Therefore, although E7090 is 
expected to be effective particularly for patients with FGF/FGFR abnormalities, it has been 
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determined that Part 1 will include patients with solid tumors with or without FGF/FGFR 
abnormalities. 
7.5.1.6 
Rationale for the Use of the mTPI Design in Part 1 
In Part 1, the MTD will be determined by assigning doses to subjects according to a modified 
toxicity probability interval (mTPI) design.  Unlike the commonly used 3 + 3 design, the 
mTPI design, a Bayes-based adaptive assignment method, enables the true MTD 
corresponding to the target DLT rate to be selected more precisely on the basis of a statistical 
rationale (Ji Y, et al., 2013).  Similarly, many articles have reported that the continual 
reassessment method (CRM), a well-known Bayes-based adaptive assignment method, and 
its extended design enable more precise selection of the MTD than the 3 + 3 design and have 
superior operating characteristics (Thall PF, Lee SJ, 2003) (Iasonos A, et al., 2008) (Le 
Tourneau C, et al., 2009).  Before the start of a study, however, these designs based on 
complicated dose-response models require careful configuration of prior information to 
obtain desired operating characteristics or establishment of a structure to allow the treating 
physician to know the dose to be allocated to the next subject in a timely manner (Ji Y, et al., 
2010).  Although these designs have recently been used in an increasing number of cases 
because of improved environments to implement them through the availability of free 
software, the simpler 3 + 3 design is still preferred frequently and these designs are not used 
widely despite their superior operating characteristics (Ji Y, et al., 2013). 
On the other hand, the mTPI design can be used easily like the 3 + 3 design because it 
requires no complicated dose-response models, and has been reported to have operating 
characteristics that are non-inferior to those of the CRM through simulations (Ji Y, et al., 
2010).  In addition, the mTPI design is safer for subjects than the CRM because it can 
averagely minimize the proportion of subjects experiencing DLTs during a study and the 
number of subjects allocated to a toxic dose that may exceed the target DLT rate (Ji Y, et al., 
2010).  The mTPI design was also presented at the 2013 ASCO Pre-Annual Meeting 
Seminar, and cases using the design have been reported in recent years (Ji Y, et al., 2013). 
It has thus been determined that the mTPI design will be used for subject’s dose assignment 
in Part 1. 
7.5.1.7 
Rationale for Determining the Dose for the Next Dose Group 
In phase 1 studies of an anticancer drug, it is considered important to minimize the number of 
subjects treated in the group receiving the low dose in which biological activity cannot be 
expected, and to escalate the dose while safety is considered carefully in the group receiving 
the high dose for which toxicities are expected to develop (Simon R, et al., 1997).  In this 
study, taking these requirements into account, it has been determined that in low-dose 
groups, subjects will take DHVFDODWHGGRVHZKHQWKH\KDYH*UDGHWR[LFLties only, 
and in high-dose groups, subjects will take a 50% or 33% escalated dose after a toxicity is 
observed, depending on the severity of the toxicity, while sufficient attention is paid to the 
development of toxicities.  This escalation method ensures subject safety and meets ethical 
considerations because the percentage of dose escalation can be determined according to the 
severity of toxicities observed in each dose group. 

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7.5.1.8 
Rationale for Including Patients with Gastric Cancer Carrying an Amplified 
FGFR2 Gene or an Overexpressed FGFR2 Protein and Patients with 
Cholangiocarcinoma Harboring FGFR2-Fusion Genes in Part 2 
Given that responses were achieved in patients with gastric cancer carrying an amplified 
FGFR2 gene in Part 1 of this study, gastric cancer carrying an amplified FGFR2 gene or an 
overexpressed FGFR2 protein is expected to be a promising target for E7090. 
In addition, a Japanese research group recently identified an in-frame fusion transcript 
(FGFR2 fusion gene) involving FGFR2 and other genes (BICC1 gene or AHCYL1 gene) in 
cholangiocarcinoma (Arai Y1, et al., 2014), suggesting that it may be a promising target for 
FGFR inhibitors.  Therefore, cholangiocarcinoma harboring FGFR2-fusion genes is expected 
to be a promising target for E7090. 
7.5.1.9 
Rationale for Selecting 1 or 2 Doses from among the Part 1 Doses in Part 2 
The objective of this design is to select a dose that can maintain adequate efficacy with low 
toxicity as the recommended dose for subsequent phase studies.  For many small-molecule 
kinase inhibitors to date, although the MTD determined in phase 1 studies were selected as 
their recommended dose for subsequent phase studies (Hidalgo M, et al., 2001) (Strumberg 
D, et al., 2005), recent years have seen some subjects in whom the development of adverse 
drug reactions (ADRs) specific to small-molecule kinase inhibitors, such as hand-and-foot 
syndrome, precluded continuation of study treatment (Lacouture ME, et al., 2008) (Manchen 
E, et al., 2011).  It is therefore considered important to pursue regimens that allow long-term 
administration to patients in the future development of small-molecule kinase inhibitors.  In 
this design, when 2 doses are selected for Part 2, and if the efficacy of the drug is considered 
to be maintained with the lower dose of them, it will be possible to select the lower dose as 
the recommended dose. 
7.5.2 
Methods of Evaluating Adverse Drug Reactions Expected from Nonclinical 
Toxicity Studies 
Mineralization associated with hyperphosphatemia and thinning of the corneal epithelium 
were observed in the non-clinical toxicity studies.  These changes were considered 
attributable to FGFR kinase inhibition by E7090 as its pharmacological action.  Given that 
hyperphosphatemia and corneal abnormalities have also been seen in clinical studies of 
similar drugs, special attention needs to be paid to these toxicities in this study. 
[Evaluation of mineralization] 
Since mineralization is induced by the deposition of phosphate combined with calcium in the 
blood, it is important to evaluate and control serum phosphate levels.  In this study, it is 
stipulated that serum phosphate levels must be measured at study visits and that high 
phosphate levels will be managed in accordance with the criteria for dose 
interruption/reduction shown in Table 6.  In addition, it is stipulated that necessary tests (eg, 
X-ray) will be performed if any clinical symptoms suggestive of mineralization are observed. 

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[Evaluation of thinning of the corneal epithelium] 
Serious corneal thinning could greatly reduce the patient’s QOL, therefore requiring special 
attention.  In Part 1, the dose-escalation part of this study, to rigorously evaluate the effect of 
E7090 on the eyes, the ophthalmologist at each study site participated in the study as a 
subinvestigator and performed the following tests on prespecified evaluation days:  visual 
acuity, funduscopy (mydriatic test when necessary), slit-lamp examination (fluorescein 
staining when necessary), and anterior segment optical coherence tomography (OCT) to 
evaluate the corneal epithelium. 
In Part 1, prespecified tests have revealed no significant thinning of the corneal epithelium, 
but Grade 1 retinal adverse events were observed.  In Part 2, taking these findings into 
consideration, anterior segment OCT will be replaced by posterior segment OCT to evaluate 
the retina.  More specifically, visual acuity, funduscopy (mydriatic test when necessary), slit-
lamp examination (fluorescein staining when necessary), and posterior segment OCT to 
evaluate the retina will be performed on prespecified evaluation days in Part 2. 
8 
STUDY OBJECTIVES 
8.1 
Primary Objective 
To investigate the tolerability and safety of E7090 in subjects with solid tumors 
8.2 
Secondary Objectives 
(1) 
To estimate the maximum tolerated dose (MTD) of E7090 (only in Part 1) 
(2) 
To assess the pharmacokinetics (PK) of E7090 
(3) 
To estimate the recommended dose for subsequent phase studies 
(4) 
To preliminarily evaluate the antitumor activity of E7090 
8.3 
Exploratory Objectives 
(1) 
To investigate the pharmacodynamic (PD) markers and pharmacogenomics (PGx) of 
E7090 
(2) 
To investigate the PK, PD markers, and PGx relationship for E7090 
(3) 
To assess overall survival (OS) and progression-free survival (PFS) with E7090 
treatment (only in Part 2) 
(4) 
To analyze plasma and urinary metabolites of E7090 

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9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
This study is a dose-escalation, open-label study in patients with solid tumors who have not 
responded to standard treatment or for whom no other appropriate treatment is available, 
which consists of 2 parts (Part 1 and Part 2). The study design overview is shown in Figure 
1. In Part 1, patients with solid tumors receiving E7090 will be evaluated for dose-limiting 
toxicities (DLTs) to estimate its MTD. In Part 2, E7090 will be evaluated for its tolerability 
and safety in detail and its efficacy preliminarily in patients with gastric cancer carrying an 
amplified FGFR2 gene or an overexpressed FGFR2 protein and patients with 
cholangiocarcinoma harboring FGFR2-fusion genes. Part 2 will include patients with solid 
tumors, consisting of a gastric cancer cohort and a cholangiocarcinoma cohort. In Part 2, 
after evaluation of the safety, efficacy, and PK/PD data obtained in Part 1, 1 or 2 doses will 
be selected from among the doses studied in Part 1 to expand the study population. On the 
basis of the results from Part 1 and Part 2, the recommended dose for future studies will be 
estimated. The dose for Part 2 will be determined through discussion among the investigator, 
the sponsor, the medical expert, and if necessary, the Data and Safety Monitoring Advisor.
Figure 1
Study Design Overview
9.1.1
Part 1
The study design for Part 1 is outlined in Figure 2. Part 1 will consist of a pretreatment 
period, a treatment period, and a follow-up period.
Part 1
MTD estimation
Solid tumor
(All patients)
Safety and preliminary efficacy evaluations
Patients with gastric cancer carrying FGFR2 gene amplification or 
protein overexpression
Patients with cholangiocarcinoma harboring FGFR2-fusion genes
Select 1 or 2 
doses
Part 2

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Figure 2
Outline of Study Design for Part 1
9.1.1.1
Pretreatment Period
The pretreatment period will involve informed consent, screening, subject registration, and 
baseline assessment. Prior to any study-related investigation or assessment, written informed 
consent will be obtained from each subject after giving an adequate explanation about the 
details of this study. At screening, it will be confirmed that each subject meets all of the 
inclusion criteria and none of the exclusion criteria. Screening will occur within 14 days 
prior to the first dose of study treatment. Subjects confirmed to be eligible by screening will 
be registered and undergo baseline assessment within 4 days prior to the first dose of study 
treatment.
9.1.1.2
Treatment Period
The treatment period will consist of Cycle 0, Cycle 1, Cycle 2, and subsequent cycles.
In Cycle 0, subjects will take a single dose of E7090 at the dose for each dose group on Day 
1 for PK evaluation.
In Cycle 1 and subsequent cycles, each consisting of 28 days, subjects will take repeated 
doses. Subjects will be hospitalized from Day 1 of Cycle 0 to the morning of Day 15 of 
Cycle 0
Treatment period
Pretreatment period
Informed consent
Screening
Registration
Single dose
Final observation
Final dose
Prior to treatment
Follow-up period
Baseline assessment
Cycle 1
Cycle 2 and 
subsequent cycles
30 days after 
final dose
14 days
Hospitalization
GD\V
28 days/cycle
Discontinuation 
procedures
GD\V
7-9 days
Repeated dose
DLT observation

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Cycle 1. The investigator or subinvestigator will carefully evaluate the results of the physical 
examination performed on Day 15 of Cycle 1 and all test results to determine from a medical 
standpoint whether each subject can be managed on an outpatient basis. If continued 
hospitalization is considered necessary from the aspect of subject safety, hospitalization will 
be continued after Day 15 of Cycle 1. In Cycle 0 and Cycle 1, DLTs will be monitored and 
evaluated. Treatment may be continued unless any of the criteria in Section 9.3.3.1
“Discontinuation Criteria for Individual Subjects” is met.
9.1.1.3
Follow-up Period
The follow-up period will involve the early discontinuation procedures and final observation.
If any of the criteria in Section 9.3.3.1 “Discontinuation Criteria for Individual Subjects” is 
met, study treatment will be discontinued and the early discontinuation procedures will be 
performed within 7 days after study discontinuation. In addition, the final observation will 
be performed within 30 days (+7 days) after the final dose of study treatment.
9.1.2
Part 2
The study design for Part 2 is outlined in Figure 3. Part 2 will consist of a pretreatment 
period, a treatment period, and a follow-up period.
Figure 3
Outline of Study Design for Part 2
Part 2 will include patients with solid tumors, consisting of the following cohorts:
x
Gastric cancer cohort: Patients with gastric cancer carrying an amplified FGFR2 gene or 
an overexpressed FGFR2 protein (including patients with gastroesophageal junction 
cancer diagnosed as adenocarcinoma)
Treatment period
Pretreatment period
Prior to treatment
Follow-up period
Final dose
Cycle 1 and subsequent cycles
30 days after 
final dose
GD\V
Screening 1
Screening 2
Repeated dose
Final observation
28 days/cycle
GD\V
Baseline assessment
Discontinuation 
procedures
Survival follow-up

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x 
Cholangiocarcinoma cohort:  Patients with cholangiocarcinoma harboring FGFR2-fusion 
genes 
For any cohort for which no more patient enrollment is anticipated, enrollment may be 
discontinued before completion of enrollment of the planned sample size. 
9.1.2.1 
Pretreatment Period 
The pretreatment period will consist of Screening 1, Screening 2, and baseline assessment.  
In Screening 1, each subject will be examined for FGFR genetic abnormalities in the tumor, 
and in Screening 2, each subject will be examined for the other eligibility criteria.  Separate 
written informed consent will be obtained before the start of Screening 1 and Screening 2. 
Screening 1 will include gastric cancer patients with documented FGFR2 gene amplification 
and cholangiocarcinoma patients with documented FGFR2-fusion genes.  In addition, 
Screening 1 will also include any gastric cancer patient with unknown FGFR2 amplification 
status who has an archived tumor sample available for the confirmation of FGFR2 protein 
expression.  No biopsy should be performed at Screening 1. 
In Screening 1, the following will be confirmed: 
x 
For patients with the documented genetic abnormalities mentioned above, the documents 
necessary for genetic testing will be submitted to the sponsor to confirm the presence of 
genetic abnormalities. 
x 
For gastric cancer patients with unknown genetic abnormalities who have an archived 
tumor sample available for confirmation of the FGFR2 protein expression mentioned 
above, the archived tumor sample will be sent to the central laboratory to confirm the 
presence of FGFR2 protein overexpression with immunohistochemical staining. 
Patients considered eligible according to either of the criteria above are eligible to enter into 
Screening 2. 
Because no biopsy is permitted in Screening 1, adverse advents will be collected after 
informed consent for Screening 2 is obtained.  Patients meeting all of the inclusion criteria 
and none of the exclusion criteria in Screening 2 will be considered eligible for treatment, 
and study treatment will be started after baseline assessment.  In Screening 2, a biopsy will 
be performed in all patients, other than those who have only a tumor lesion not amenable to 
biopsy for safety reasons.  Screening 2 will occur within 14 days prior to the first dose of 
study treatment.  Subjects confirmed to be eligible by screening will be registered and 
undergo baseline assessment within 4 days prior to the first dose of study treatment. 
9.1.2.2 
Treatment Period 
The treatment period will consist of 28-day treatment cycles.  Study treatment may be 
continued unless any of the criteria in Section 9.3.3.1 “Discontinuation Criteria for Individual 
Subjects” is met. 

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9.1.2.3 
Follow-up Period 
The follow-up period will involve the early discontinuation procedures and final observation. 
If any of the criteria in Section 9.3.3.1 “Discontinuation Criteria for Individual Subjects” is 
met, study treatment will be discontinued and the early discontinuation procedures will be 
performed within 7 days after study discontinuation.  In addition, final observation will be 
performed within 30 days (+7 days) after the final dose of study treatment.  Subjects will be 
followed for survival every 12 weeks (±2 weeks) from the time of study treatment 
discontinuation.  When necessary, follow-up survival may be performed at unspecified time 
points. 
9.2 
Discussion of Study Design, Including Choice of Control Groups 
No control group will be established in this study.  The rationale for the design of this study 
is described in Section 7.5.1 “Rationale for the Study Design.” 
9.3 
Selection of Study Population 
Approximately 20 subjects will be enrolled in Part 1.  Approximately 10 subjects with gastric 
cancer confirmed to carry an amplified FGFR2 gene or an overexpressed FGFR2 protein and 
approximately 5 to 10 subjects with cholangiocarcinoma confirmed to harbor FGFR2-fusion 
genes will be enrolled in Part 2.  Subjects who meet all of the inclusion criteria and none of 
the exclusion criteria will be eligible to take the study drug. 
9.3.1 
Inclusion Criteria 
For both Part 1 and Part 2 
(1) 
Patients providing voluntary written consent for the participation in this study 
(2) 
Patients who have been given a sufficient explanation of the requirements in this study 
and are willing and able to follow them 
(3) 
Patients ageG\HDUVDWWKHWLPHRILQIRUPHGFRQVHQW 
(4) 
Patients with a histological or cytological diagnosis of solid tumor 
(5) 
Patients who have not responded to standard treatment or for whom no other 
appropriate treatment is available 
(6) 
Patients with adequate major organ function 
1) 
+HPRJORELQ g/dL ( g/dL in Part 2) 
2) 
1HXWURSKLOFRXQWî3/ȝ/ 
3) 
3ODWHOHWFRXQWî4/ȝ/ 
4) 
7RWDOELOLUXELQWLPHVWKH institutional upper limit of normal (ULN) 

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5) 
AST and ALT WLPHVWKH ULN (.0 times the ULN in the presence of 
intrahepatic bile duct cancer or liver metastases) 
6) 
6HUXPFUHDWLQLQHWLPHVWKHULN 
(7) 
&RUUHFWHGVHUXPFDOFLXP8/1 
Corrected serum calcium = sHUXPFDOFLXPPJG/ísHUXPDOEXPLQ>JG/@î 
(to be corrected only for subjects with a serum albumin <4 g/dL) 
(8) 
%ORRGSKRVSKDWHULN 
(9) 
Patients with an Eastern Cooperative Oncology Group (ECOG) Performance Status 
(PS) of 0 to 1 
(10) Patients expected to survive for 3 months or longer after registration (Part 1) or the start 
of study treatment (Part 2) 
(11) Patients with the following time intervals between prior therapy and study treatment in 
this study: 
1) 
Anticancer therapy 
(a) 
Other investigational products, antibody therapy:  ZHHNVKDOI-lives 
are acceptable for other investigational products with a known half-life) 
(b) 
Anticancer agents (excluding small molecule targeted drugs), surgical 
therapy, radiation therapy:  Zeeks 
(c) 
Endocrine therapy, immunotherapy, small molecule targeted drugs:  
weeks 
2) 
Supportive therapy 
(a) 
Blood transfusions, blood products, hematopoietic factor products 
including granulocyte colony-stimulating factor (G-CSF) products:  
weeks 
(12) Women of childbearing potential must have practiced contraception since 28 days 
before registration (Part 1) or 28 days before the start of study treatment (Part 2), and 
must agree to use medically effective contraception (eg, the subject is using intrauterine 
devices,* condoms with spermicide,* contraceptive implants,** or oral 
contraceptives;*  or the subject’s male partner is confirmed to have no sperm after 
vasectomy)Note throughout the study period (for 30 days after the final study drug 
administration).  Any subject practicing contraception by abstinence must agree to 
practice contraception with condoms with spermicide during the study period and for 
30 days after the final study drug administration.  Women of childbearing potential 
using any oral contraceptive are to use the oral contraceptive at a fixed dose for at least 

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4 weeks before study drug administration and continue to use the same oral 
contraceptive during the study period and for 30 days after the final study drug 
administration. 
All women will be considered to be of childbearing potential unless they are 
postmenopausal women (amenorrheic for at least 12 consecutive months, in the 
appropriate age group, and without other known or suspected cause) or have been 
sterilized surgically (ie, bilateral tubal ligation, total hysterectomy, or bilateral 
oophorectomy, all with surgery at least 1 month before dosing). 
Note:  Whether the drug/medical device has been approved or authorized in Japan (*, 
yes; **, no) 
(13) Male participants or their female partners meeting the criteria above (when the partner 
is a woman with no childbearing potential or will use medically effective contraception 
throughout the study period and for 30 days after final study drug administration) 
For Part 2 only 
(14) Patients whose solid tumors have been confirmed to meet either of the following in 
Screening 1: 
1) 
Patients with gastric cancer carrying an amplified FGFR2 gene or an 
overexpressed FGFR2 protein (including patients with gastroesophageal junction 
cancer diagnosed as adenocarcinoma) 
2) 
Patients with cholangiocarcinoma harboring FGFR2-fusion genes 
(15) Patients with a target lesion that can be evaluated according to RECIST 1.1 
(16) Patients meeting both of the following criteria 1) and 2) concerning tumor sample 
submission: 
1) 
Patients agreeing to submit any tumor sample collected in the past 
2) 
Patients agreeing to submit any biopsy sample in Screening 2 (excluding those 
who have only a tumor lesion not amenable to biopsy for safety reasons) 
9.3.2 
Exclusion Criteria 
(1) 
Patients with a brain metastasis accompanied by clinical symptoms or requiring 
treatment 
(2) 
Patients with any of the following clinically significant cardiovascular disorders: 
1) 
New York Heart Association (NYHA) Grade III or higher cardiac disease 
(Appendix 1) 

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2) 
Unstable angina pectoris or myocardial infarction within 6 months before 
enrollment in this study (Part 1) or within 6 months before the start of study 
treatment (Part 2) 
3) 
QTc >480 msec (Fridericia method) 
4) 
Arrhythmia requiring treatment 
(3) 
Patients with serious systemic infection requiring treatment including bacterial 
infection and fungal infection 
(4) 
Patients with a positive test result for human immunodeficiency virus (HIV) 
(5) 
Patients with celomic fluid retention requiring drainage 
(6) 
Patients with any of the following previous or concurrent corneal or retinal diseases: 
1) 
*UDGHFRUQHDOGLVRUGHU 
2) 
Active macular disease (eg, age-related macular degeneration, central serous 
chorioretinopathy) 
(7) 
Patients in whom the adverse effects of prior treatment have not recovered to Grade 1 
or lower, except for alopecia and Grade 2 peripheral neuropathy 
(8) 
Patients with active malignancy within 36 months before the start of study treatment 
(excluding the primary disease, and carcinomas in situ such as completely treated 
melanoma in situ, basal or squamous cell carcinoma of the skin, carcinoma in situ of 
the cervix, and early-stage large bowel cancer) 
(9) 
Patients with prior therapy targeting FGFR2 
(10) Patients who are using any CYP3A inhibitor or inducer (Appendix 2) and will require 
LWGXULQJVWXG\WUHDWPHQWWKHUHPXVWEHDWLPHLQWHUYDORIGD\VEHWZHHQWKHILQDO
dose of these drugs and the start of study treatment) 
(11) Patients known to be intolerant to any of the ingredients of the study drug (or 
excipients) 
(12) Patients unable to take drugs orally or with malabsorption syndrome (patients 
undergoing gastrectomy may be enrolled) 
(13) Patients with mental or physical disorders, such as alcoholism and drug dependence, 
considered to preclude the participation in this study in the opinion of the investigator 
or subinvestigator 
(14) Pregnant or breastfeeding patients (breastfeeding patients may not be enrolled even if 
they discontinue breastfeeding) 

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(15) Any others considered ineligible for the participation in this study in the opinion of the 
investigator or subinvestigator 
9.3.3 
Removal of Subjects from Therapy or Assessment 
The investigator or subinvestigator may discontinue treatment for a subject undergoing study 
treatment or withdraw the subject from the study at any time for safety or administrative 
reasons.  The subject may decide to discontinue study treatment or withdraw from the study 
at any time for any reason.  The reason for discontinuation will be documented.  If a subject 
discontinues study treatment but agrees to continue study-related procedures, specified 
assessments at the time of study treatment completion will be performed, protocol-specified 
information will be collected, and survival follow-up (Part 2 only) will be performed (unless 
the subject withdraws consent).  The investigator or subinvestigator should confirm whether 
the subject will withdraw from study treatment but agree to continue protocol-specified, off-
treatment study visits, procedures, and survival follow-up.  If a subject withdraws consent, 
the date will be documented in the source documents.  The primary reason for 
discontinuation and all other reason(s) contributing to the subject’s discontinuation from 
study treatment should be recorded in the case report form (CRF).  In addition, the date of the 
last dose of study treatment will be recorded in the CRF. 
9.3.3.1 
Discontinuation Criteria for Individual Subjects 
Treatment with E7090 will be continued until any of the following discontinuation criteria is 
met: 
(1) 
Subject’s refusal to continue study participation or withdrawal of consent 
(2) 
Major inclusion/exclusion criteria violation after registration (Part 1) or enrollment 
(Part 2) 
(3) 
Difficulty in continuing the study due to an adverse event in the opinion of the 
investigator or subinvestigator 
(4) 
Subject’s pregnancy 
(5) 
Disease progression (except when the investigator or subinvestigator considers study 
treatment clinically beneficial to the subject) 
(6) 
Dose reduction to <1 mg (Part 1) or 35 mg (Part 2) required due to an adverse drug 
reaction 
(7) 
Other cases where the investigator or subinvestigator considers study discontinuation 
appropriate 
9.4 
Treatment 
The study drug for this study is E7090 in the following formulations, 1, 1.5, 5, 20, and 60 mg 
capsules (Part 1) and 35 mg tablets (Part 2), which will be administered orally once daily.  

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However, the dosage regimen may be modified if a different dosage regimen (eg, twice 
daily) is shown to be more appropriate on the basis of efficacy, safety, or PK evaluations.  A 
change in the dosage regimen will be determined through discussion among the investigator, 
the sponsor, the medical expert, and the Data and Safety Monitoring Advisor. 
9.4.1 
Treatment Administered (Part 1) 
9.4.1.1 
Initial Dose 
The initial dose will be 1 mg once daily.  The rationale for selecting this initial dose is 
described in Section 7.5.1.2 “Rationale for the Initial Dose for Part 1.” 
9.4.1.2 
Administration Schedule 
(1) 
Cycle 0 
A single dose of E7090 at the dose for each group will be administered on Day 1 to 
evaluate its PK following single administration.  Subjects will take a single dose of 
E7090 in the fasting state on waking after an at least 10-hour overnight fast.  Subjects 
will be prohibited from eating or drinking for 2 hours after administration, except for 
drinking water. 
(2) 
Cycle 1 (28 days) 
Subjects will start Cycle 1 between the 8th and 10th days after administration in Cycle 
0 and take E7090 once daily continuously.  Subjects will take E7090 at least 2 hours 
after breakfast, without eating anything for 1 hour after administration.  For PK 
evaluation, subjects will be instructed not to take E7090 on the morning of each visit 
day.  On Day 8 of Cycle 1, however, subjects will take E7090 in the fasting state on 
waking after an at least 10-hour overnight fast for PK evaluation.  Subjects will be 
prohibited from eating or drinking for 2 hours after administration, except for drinking 
water. 
(3) 
Cycle 2 and subsequent cycles (28 days each) 
Subjects will take E7090 once daily continuously.  Subjects will take E7090 at least 2 
hours after breakfast, without eating anything for 1 hour after administration.  For PK 
evaluation, subjects will be instructed not to take E7090 on the morning of Day 1 of 
each cycle. 
Study treatment may be continued unless any of the criteria in Section 9.3.3.1 
“Discontinuation Criteria for Individual Subjects” is met. 
Precautions for administration 
(1) 
If vomiting occurs after dosing, the subject will be considered to have taken the study 
drug and will not be given the study drug again. 

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(2) 
It is clear that E7090 is metabolized by CYP3A4.  Since it is known that grapefruit and 
Saint John’s wort (Hypericum perforatum) inhibit or induce CYP3A, subjects will be 
instructed to avoid consuming grapefruit, its juice, or foods containing Saint John’s 
wort (Hypericum perforatum). 
(3) 
Subjects will be instructed to document whether they took the study drug and when 
they took it in the dosing diary. 
(4) 
Since it is currently unknown whether E7090 may cause phototoxicity, subjects will be 
instructed to avoid long-term sunlight exposure. 
9.4.1.3 
Method of Subject’s Dose Assignment 
Dose assignment will be performed using a modified toxicity probability interval (mTPI) 
design.  According to an established target DLT rate of 25% for this study, 3 toxicity 
probability intervals are defined as 20% to 30% (proper dosing), 0% to 20% (underdosing), 
and 30% to 100% (overdosing).  In accordance with the rules of the mTPI design based on 
these intervals, each subject will be assigned a dose of E7090.  The decision rules for all dose 
assignment will be calculated in advance on the basis of the mTPI design, presented as the 
“Decision Rules for Dose Assignment” below (Table 1) (see Appendix 4 for details). 
Table 1 
Decision Rules for Dose Assignment 
 
 
Number of subjects treated at each dose 
 
 
2 
4 
6 
8 
10 
Number of subjects 
with DLT 
0 
E 
E 
E 
E 
E 
1 
D a 
S 
S 
E 
E 
2 
D, U 
D 
S 
S b 
S 
3 
 
D, U 
D 
S 
S b 
4 
 
D, U 
D, U 
D, U 
S 
5 
 
 
D, U 
D, U 
D, U 
E = Escalate to the next higher dose, S = Stay at the current dose, D = De-escalate to the next 
lower dose, U = The current dose is unacceptably toxic (ie, Do not re-register any subject in this 
dose) 
Target DLT rate and its corresponding interval, 25%, 20% to 30%;  Cohort size, 2 subjects 
Rules for the number of subjects per dose being above 10 are omitted. 
a: Extra subjects may be added for the initial dose. 
b: Early termination of registration may be considered. 
 
Two subjects will be registered at each dose level.  In a new dose group, the safety of the first 
subject should be evaluated before enrollment of the second and subsequent subjects.  On the 
basis of the number of subjects with DLT at each dose level, assignment of the next dose will 
be determined according to Table 1.  If DLT develops in 1 of the 2 subjects at the initial dose 
level, however, extra subjects may be added through discussion among the investigator, the 
sponsor, and the medical expert.  At this time, advice may be obtained from the Data and 
Safety Monitoring Advisor as necessary.  Any subject not evaluable for DLT (eg, a subject 

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discontinuing the study during Cycle 1 for reasons other than the development of DLT) 
should be replaced at the dose level for the subject. Under the mTPI design, subject 
registration will be closed when the DLT rate at the initial dose is much higher than the target 
DLT rate (25%) or when the prespecified maximum sample size (approximately 20 subjects) 
is reached. However, the maximum sample size will be adjusted as required. For a 
particular dose, subject registration may be closed early if a subsequent subject is highly 
likely to be allocated to the dose. The mTPI design is described in Section 9.7.4 “Other 
Statistical/Analytical Issues.” Figure 4 shows the process for subject’s dose assignment 
based on Table 1.
Figure 4
Process for Subject’s Dose Assignment
9.4.1.4
Method of Determining the Dose for the Next Dose Group
The dose for the next dose group will be determined according to the degree of toxicities 
(adverse events possibly related to E7090) observed in subjects in the immediately preceding 
2 ౛ᢞ୚
2 ౛୰DLT Ⓨ⌧0 ౛
2 ౛୰DLT Ⓨ⌧1 ౛
E㸸୍ẁ㝵ቑ㔞
᪂つ⏝㔞ࣞ࣋ࣝ㸽
D㸸୍ẁ㝵ῶ㔞
2 ౛ᢞ୚㏣ຍ
Yes
ᙜヱ⏝㔞ࡢྜィ౛ᩘ࡜DLT Ⓨ⌧౛ᩘ࡟ᇶ࡙ࡁ㸪ḟ⏝㔞Ỵᐃ
E㸸୍ẁ㝵ቑ㔞㸪S㸸ྠ⏝㔞࡟㏣ຍ㸪D㸸୍ẁ㝵ῶ㔞㸦⾲1㸧
Part 1ྜィ⣙20౛ᢞ୚㸭ึᅇ⏝㔞
ࡢᚸᐜᛶ࡞ࡋ㸭᪩ᮇⓏ㘓⤊஢㸽
ྍ⬟
Yes
DLT ホ౯
Part 1 ⤊஢
MTD ᥎ᐃ
No
No
New dose level?
Treat 2 subjects
DLT occurs in 0 of 2
'/7RFFXUVLQ1 of 2
E:  Escalate 1 level
D:  De-escalate 1 level
Treat another 2 subjects
Evaluate DLT
Determine the next dose according to the total number of subjects at the current 
dose and the number of subjects with DLTs
E, Escalate 1 level; S, Stay at the current dose; D, De-escalate 1 level (Table 1)
Complete Part 1
Estimate the 
MTD
About 20 subjects treated in total in Part 
1/Initial dose is not tolerable/Early 
closure of registration?

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dose group during Cycle 0 and Cycle 1.  The dose for the next dose group will be escalated 
by 100% if all toxicities observed in the immediately preceding dose group during Cycle 0 
and Cycle 1 are Grade 1 or lower.  If a Grade 2 toxicity is observed in 1 subject, the next 
dose will be escalated by 50%.  If Grade 2 toxicities are observed in 2 subjects or if Grade 3 
or higher toxicities are observed in 1 or more subjects, the next dose will be escalated by 
33% (Table 2). 
When a dose is escalated or de-escalated by 1 dose level according to the mTPI design, if 
there is a higher or lower dose level evaluated previously, subjects will be added to the 
immediately preceding dose level evaluated previously, instead of following Table 2.  In 
addition, an intermediate dose may be added, if necessary, on the basis of the safety or PK of 
the previously evaluated dose.  The addition of a new dose level will be determined through 
discussion among the investigator, the sponsor, the medical expert, and if necessary, the Data 
and Safety Monitoring Advisor. 
Table 2 
Method of Determining the Dose for the Next Dose Group 
Dose escalation for the 
next dose group (%) 
Toxicities observed during Cycle 0 and Cycle 1 (a) 
100 
Grade toxicity only 
50 
Grade 2 toxicity in 1 subject 
33 
*UDGHWR[LFLW\LQVXEMHFWVRU*UDGHWR[LFLW\LQVXEMHFW 
(a) Excluding clinically insignificant events such as laboratory abnormalities requiring no treatment 
 
Since theoretical values calculated using the above method of determining the dose may 
become fractions that cannot be formulated with the capsule potencies (1, 1.5, 5, 20, and 
60 mg) used in this study, the actual dose will be determined by correcting theoretical values 
according to the rules (1) to (3) below.  Table 3 shows some examples of dose corrections. 
(1) 
Round off the 3rd digit of a calculated theoretical value (to obtain a rounded off value). 
(2) 
Examine whether the rounded off value can be formulated with the capsule potencies. 
When it is possible, use the rounded off value as the actual dose. 
(3) 
When it is not possible, use the dose closest to and not exceeding the rounded off value 
among the doses that can be formulated with the capsule potencies as the actual dose. 
Table 3 
Examples of Dose Corrections 
 
Theoretical value 
Round off value obtained by 
rounding off the 3rd digit 
Actual dose 
Case A 
3.99 mg 
4.0 mg 
4.0 mg 
Case B 
6.65 mg 
6.7 mg 
6.5 mg 
 

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Case A:
The value calculated by rounding off the 3rd digit of the theoretical value of 
3.99 mg is 4.0 mg.
The actual dose will be 4.0 mg because it can be formulated with a 1-mg capsule.
Case B:
The value calculated by rounding off the 3rd digit of the theoretical value of 
6.65 mg is 6.7 mg.
It is not possible to formulate 6.7 mg with the capsules used in this study. The 
actual dose will be 6.5 mg because 6.5 mg (1.5-mg and 5-mg capsules) is the dose 
closest to and not exceeding 6.7 mg among the doses that can be formulated with 
the capsules used in this study.
If treatment compliance is expected to be markedly decreased due to an increased number of 
capsules to be taken to meet the dose required by the rules above, it is acceptable to select a 
lower dose through discussion between the investigator and the sponsor.
9.4.1.5
Examples of Dose Assignment and Dose Escalation
On the basis of Section 9.4.1.3 “Method of Subject’s Dose Assignment” and Section 9.4.1.4
“Method of Determining the Dose for the Next Dose Group,” a hypothetical example of dose 
assignment and dose escalation is shown in Figure 5.
Figure 5
Example of Dose Assignment and Dose Escalation
Dose
DLT, 1 subject
DLT, 1 subject
2 
subjects
(Grade 2, 1 subject)
(Grade 2, 2 subjects)
(Grade 2, 1 subject)
(Grade 3, 1 subject)
DLT 1, subject
DLT 1, subject
*UDGHRQO\
Time
2 
subjects
2 
subjects
2 
subjects
2 
subjects
2 
subjects
2 
subjects
2 
subjects
2 
subjects
2 
subjects

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(1) 
,IRQO\*UDGH$'5VRFFXULQWKHVXEMHFWVLQWKHPJJURXSLQ&\FOHDQG&\FOH
1, the next dose will be 100% escalated to 2 mg according to the method of 
determining the dose for the next dose group (Table 2).  The doses after 2 mg will also 
be escalated according to the severity of ADRs occurring in Cycle 0 and Cycle 1, as 
shown in Figure 5. 
(2) 
Any DLT in 1 of the 2 subjects in the 8 mg group would correspond to “D (de-
escalation to the next lower dose)” according to the method of subject’s dose 
assignment (Table 1).  Therefore, the dose will be de-escalated to the already evaluated 
next lower dose of 6 mg. 
(3) 
The 8 mg group will have a total of 4 subjects.  Any DLT in 2 of the 4 subjects in the 
8 mg group would correspond to “D (de-escalation to the next lower dose)” according 
to the subject’s dose assignment (Table 1).  Therefore, the dose will be de-escalated to 
the already evaluated next lower dose of 6 mg. 
(4) 
Any DLT in 1 of the 6 subjects in the 6 mg group would correspond to “S (stay at 
current dose)” according to subject’s dose assignment (Table 1).  Therefore, new 
subjects will be added to the same dose level (6 mg group). 
9.4.1.6 
Determination of Transition to the Next Dose Group 
Transition to the next dose group will be determined through discussion among the 
investigator, the sponsor, and the medical expert according to Section 9.4.1.3 “Method of 
Subject’s Dose Assignment” and Section 9.4.1.4 “Method of Determining the Dose for the 
Next Dose Group.”  At this time, advice may be obtained from the Data and Safety 
Monitoring Advisor as necessary.  Safety data from subjects excluded from the DLT analysis 
population will also be considered when determining transition to the next dose group 
(including changes in the assignment of a dose and the percentage of dose escalation). 
9.4.1.7 
Definition of Dose-Limiting Toxicity (DLT) 
DLTs will be assessed to determine the MTD.  The nature, frequency, and severity of adverse 
events will be evaluated, and the severity of adverse events will be graded using the CTCAE 
v4.03.  DLTs will be defined as the following events occurring during Cycle 0 and Cycle 1 
considered to be possibly related to E7090.  DLTs will be determined through discussion 
among the investigator, the sponsor, and the medical expert.  At this time, advice may be 
obtained from the Data and Safety Monitoring Advisor as necessary. 
DLT criteria 
(1) 
Febrile QHXWURSHQLDRU*UDGHQHXWURSHQLDSHUVLVWLQJIRUGD\V 
(2) 
Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia requiring platelet 
transfusions 

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(3) 
*UDGHQRQ-hematological toxicity, except for the following: 
a) 
Clinically insignificant laboratory abnormalities 
b) 
Toxicity WKDWFDQEHFRQWUROOHGWR*UDGHE\EHVWVXSSRUWLYHFDUH 
(4) 
Potentially clinically significant, new radiographic mineralization in the soft tissue, 
kidneys, intestines, heart, lungs, or other organs 
(5) 
Hyperphosphatemia meeting either of the following: 
a) 
Serum SKRVSKDWHOHYHO!PJG/SHUVLVWLQJIRUGD\VGHVSLWHEHVWWUHDWPHQW 
b) 
Serum phosphate level >9 mg/dL despite best treatment 
(6) 
TUHDWPHQWLQWHUUXSWLRQIRUGD\VGXULQJ&\FOHDQG&\FOH required by possibly 
E7090-UHODWHGWR[LFLW\H[FHSWIRUWUHDWPHQWLQWHUUXSWLRQIRUGD\VIRUUHDVRQVRWKHU
than toxicity.  In this case, the subject will be removed from the DLT evaluation and 
replaced by a new subject. 
Considerations in determining the DLT 
(1) 
If Grade 4 neutropenia or a serum phosphate level exceeding 7 mg/dL is observed, 
additional hematology or blood biochemistry will be performed so as to confirm the 
duration of the toxicity. 
(2) 
If no additional test can be performed by Day 8 after the day when Grade 4 neutropenia 
or a serum phosphate level exceeding 7 mg/dL is first observed (ie, Day 1), handling of 
the adverse event and determination of the DLT will be determined through discussion 
among the investigator, sponsor, and medical advisors.  In this case, advice may be 
obtained from the Data and Safety Monitoring Advisor as necessary. 
9.4.1.8 
Criteria for Dose Interruption/Reduction 
(1) 
Cycle 1 
1) 
If a DLT is observed 
Study treatment will be interrupted immediately.  When the investigator or 
subinvestigator considers it possible to continue the study, study treatment may 
be restarted at a 1-level dose reduction once the toxicity resolves to Grade 0 to 1 
or baseline. 
2) 
If no DLT is observed 
Study treatment will not be interrupted until a DLT is observed.  However, when 
the investigator or subinvestigator considers interruption clinically necessary, 
study treatment may be interrupted and restarted at the same dose as appropriate.  
No dose reduction will be permitted. 

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(2) 
Cycle 2 and subsequent cycles 
If any E7090-related toxicity is observed, treatment will be interrupted or the dose will 
be reduced according to the criteria shown in Table 4. 
Table 4 
Criteria for Dose Interruption/Reduction (Part 1) 
E7090-related toxicity a 
Management 
Dose after restart 
Grade 1 or tolerable Grade 2 b 
Continue study treatment 
No change 
Intolerable Grade 2 b or Grade 3 Interrupt treatment until the toxicity 
resolves to Grade 0 to 1 or baseline c 
Same dose or 1-level dose 
reduction 
Grade 4 d 
Discontinue study treatment 
NA 
a: Laboratory abnormalities not requiring treatment will be excluded. 
b: The tolerability of Grade 2 will be determined by the investigator or subinvestigator. 
c: When the investigator or subinvestigator considers interruption clinically acceptable, study treatment may 
be restarted also when the toxicity resolves to tolerable Grade 2. 
d: Any laboratory abnormality considered non-life-threatening will be excluded and managed as a Grade 3 
event. 
 
Up to 2 dose reductions due to toxicity will be permitted.  At the first dose reduction, the 
dose will be de-escalated to the dose of the next lower dose group.  At the second dose 
reduction, the dose will be de-escalated to the dose of the second lower dose group.  The 
sponsor should be consulted for more than 2 dose reductions.  The study will be discontinued 
if the dose needs to be reduced below 1 mg.  No dose escalation should be performed in the 
same subject. 
9.4.2 
Treatment Administered (Part 2) 
9.4.2.1 
Starting Dose 
E7090 will be administered orally at 140 mg once daily.  If any E7090-related toxicity is 
observed, treatment will be interrupted or the dose will be reduced according to the criteria 
shown in 9.4.2.3 
9.4.2.2 
Administration Schedule 
Subjects will take E7090 at least 2 hours after breakfast, and will not eat anything for 1 hour 
after administration.  On Day 1 and Day 8 of Cycle 1, however, subjects will take E7090 in 
the fasting state on waking after an at least 10-hour overnight fast for PK evaluation.  
Subjects will be prohibited from eating or drinking for 2 hours after administration, except 
for drinking water.  For PK evaluation, subjects will be instructed not to take E7090 on the 
morning of Day 1 of Cycle 2 and subsequent cycles.  Study treatment may be continued 
unless any of the criteria in Section 9.3.3.1 “Discontinuation Criteria for Individual Subjects” 
is met. 

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Precautions for administration 
(1) 
If vomiting occurs after dosing, the subject will be considered to have taken the study 
drug and will not be given the study drug again. 
(2) 
It is clear that E7090 is metabolized by CYP3A4.  Since it is known that grapefruit and 
Saint John’s wort (Hypericum perforatum) inhibit or induce CYP3A, subjects will be 
instructed to avoid consuming grapefruit, its juice, or foods containing Saint John’s 
wort (Hypericum perforatum). 
(3) 
Since it is currently unknown whether E7090 may cause phototoxicity, subjects will be 
instructed to avoid long-term sunlight exposure. 
9.4.2.3 
Criteria for Dose Interruption/Reduction 
If any E7090-related toxicity or hyperphosphatemia is observed, the criteria in Table 5 and 
Table 6, respectively, should be followed.  If study treatment is continued after the dose 
reduction, the dose will be reduced step-by-step to 105 mg, 70 mg, and then 35 mg. 
To ensure subject safety, study treatment should be restarted as soon as possible if treatment 
is interrupted due to events not stipulated in Table 5 or Table 6. 
Table 5 
Criteria for Dose Interruption/Reduction (Part 2) 
Toxicity a 
Criteria 
Management 
Hematological 
Grade 3 toxicity is observed. 
Interrupt treatment until the toxicity resolves to 
Grade 2 or lower and restart at the same dose as 
that before interruption 
Grade 4 toxicity is observed. 
Interrupt treatment until the toxicity resolves to 
Grade 2 or lower and restart at a 1-level dose 
reduction 
Non-
hematological 
Intolerable Grade 2 b or 
Grade 3 toxicity is observed. 
Interrupt treatment until the toxicity resolves to 
Grade 1 or baseline and restart at a 1-level dose 
reduction 
Grade 4 c toxicity is 
observed. 
Discontinue treatment d 
a: Laboratory abnormalities not requiring treatment will be excluded. 
b: The tolerability of Grade 2 will be determined by the investigator or subinvestigator. 
c: Any laboratory abnormality considered non-life-threatening by the investigator or subinvestigator will be 
managed as a Grade 3 event instead of a Grade 4 event. 
d: If study treatment is considered clinically beneficial to the subject by the investigator or subinvestigator, 
treatment may be interrupted until the toxicity resolves to Grade 1 or baseline and restarted at a 1-level 
dose reduction. 
 

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Table 6 
Criteria for Dose Interruption/Reduction Based on 
Hyperphosphatemia (Part 2) 
Criteria 
Management 
Serum pKRVSKDWHOHYHOLV5.5 mg/dL and 7.0 
mg/dL. 
Start treatment of hyperphosphatemia. 
Despite appropriate treatment of 
hyperphosphatemia,a serum pKRVSKDWHOHYHOV
and 9.0 mgG/ODVWIRU2 weeks,b or serum 
pKRVSKDWHOHYHOVDUH9.1 mg/dL. 
Interrupt treatment until serum phosphate 
levels decrease to 7.0 mg/dL and restart 
treatment at a 1-level dose reduction. 
a: This refers to treatments, such as diet therapy and hyperphosphatemia drugs, considered appropriate by the 
investigator or subinvestigator. 
b: Any subject with a serum pKRVSKDWHOHYHORImg/dL should visit the study site 1 week later and undergo 
measurement of serum phosphate levels for the evaluation of hyperphosphatemia. 
 
9.4.3 
Estimation of the Recommended Dose for Subsequent Phase Studies 
The recommended dose for subsequent phase studies will be estimated considering an overall 
discussion of efficacy, safety, and PK data and changes in PD markers in Part 1 and Part 2.  
For example, if 2 doses are selected in Part 2 and the lower dose is effective in some subjects, 
this lower dose may be selected as the recommended subsequent phase dose, provided that 
the dose appears to be useful as an anticancer agent on the basis of the balance between its 
efficacy and safety.  In this case, safety data not only from Cycle 1 but also from Cycle 2 and 
subsequent cycles will be considered.  The recommended subsequent phase dose will be 
estimated through discussion among the investigator, the sponsor, the medical expert, and if 
necessary, the Data and Safety Monitoring Advisor. 
9.4.4 
Identity of Investigational Product 
The study drug will be supplied by the sponsor in labeled containers. 
9.4.4.1 
Chemical Name and Structural Formula of E7090 
Test drug code:  E7090 
Generic name:  To be determined 
Chemical name: 5-({2-[({4-[1-(2-Hydroxyethyl)piperidin-4-
yl]phenyl}carbonyl)amino]pyridin-4-yl}oxy)-6-(2-methoxyethoxy)-N-
methyl-1H-indole-1-carboxamide butanedioate (2:3) 
Molecular formula:  C32H37N5O6Â3/2C4H6O4 
Molecular weight:  764.81 

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Structural formula: 
 
9.4.4.2 
Comparator Drug 
Not applicable. 
9.4.4.3 
Labeling for Study Drug 
The following information has to be provided.  Detailed information on labeling and 
packaging is provided in Appendix 5. 
x 
For clinical study use only 
x 
Name and address of the sponsor 
x 
Chemical name/drug identifier 
x 
Lot number/batch number 
x 
Storage conditions, expiration date if necessary 
9.4.4.4 
Storage Conditions 
The study drug will be stored in accordance with the specified storage conditions.  The study 
drug manager (or designee) will monitor the temperature at the storage location to ensure that 
the study drug is maintained within an established temperature range.  The study drug 
manager (or designee) is responsible for ensuring that the temperature is monitored 
throughout the total duration of the study and that records are maintained; the temperature 
should be recorded by using a temperature data acquisition system, automatic recording 
device, or by manual means at each medical institution. 
9.4.5 
Method of Assigning Subjects to Treatment Groups 
This is an open-label study.  All subjects who provide signed informed consent to participate 
in this study and satisfy all eligibility requirements (see Section 9.3) will be assigned to take 
E7090.  There is no randomization in this study.  The subject registration procedure is shown 
in Figure 6 (Part 1) and Figure 7 (Part 2). 
[Part 1] 
(1) 
The investigator, subinvestigator, or clinical study collaborator will assign a sponsor-
specified subject ID number to each patient providing written informed consent for 
study participation and document this information in the Subject Screening Log. 
N
O
N
O
NH
CH3
O
O
H3C
N
H
O
N
HO
HO2C
CO2H
3/2

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(2) 
The investigator or subinvestigator will screen each patient and determine his/her 
eligibility based on the inclusion/exclusion criteria.  The investigator, subinvestigator, 
or clinical study collaborator will document the result of eligibility determination in the 
Subject Screening Log. 
(3) 
On the basis of the screening result and patient characteristics of each patient 
determined to be eligible, the investigator, subinvestigator, or clinical study 
collaborator will enter necessary information in the Subject Registration Form 
(Appendix 6) and send the form via fax to the Subject Registration Center. 
(4) 
The Subject Registration Center will check the eligibility of each patient on the basis of 
the Subject Registration Form sent by fax.  When determining a patient to be ineligible, 
the Subject Registration Center will enter the reason for ineligibility in the Notice of 
Ineligibility and send the notice by fax to the investigator, subinvestigator, or clinical 
study collaborator.  The investigator or subinvestigator will confirm the reason for 
ineligibility and will not administer the study drug to the patient. 
(5) 
If the Subject Registration Form has any defect (eg, omissions), the Subject 
Registration Center will inquire the defect of the investigator, subinvestigator, or 
clinical study collaborator. 
(6) 
When determining a patient to be eligible, the Subject Registration Center will enter 
his/her subject ID number, date of confirmation of registration, and dose to be 
administered in the Registration Confirmation Form and send the form by fax to the 
investigator, subinvestigator, or clinical study collaborator, and the sponsor (subject 
registration). 
(7) 
The investigator, subinvestigator, or clinical study collaborator will confirm the 
information entered in the Registration Confirmation Form. 

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Figure 6
Subject Registration Procedure (Part 1)
[Part 2]
(1)
The investigator, subinvestigator, or clinical study collaborator will assign a sponsor-
specified subject ID number to each patient providing written informed consent for 
Screening 1 and document this information in the Subject Screening Log.
(2)
For a patient known to have FGF/FGFR genetic abnormality, the investigator, 
subinvestigator, or clinical study collaborator will submit necessary documents about 
the genetic abnormality to the sponsor. The sponsor will check the documents about 
the genetic abnormality and notify the investigator, subinvestigator, or clinical study 
collaborator of the patient’s eligibility/ineligibility by e-mail or fax.
Study site
Subject Registration Center
Entry in the 
Subject 
Registration 
Log
Screening
(Eligibility 
determination)
Eligible
Ineligible
Do not 
register
Enter in the 
Subject 
Registration Form
Fax the form to the Subject Registration Center
Confirmation of 
eligibility
Confirmation of the reason 
for ineligibility
(No study drug administration)
Eligible
Ineligible
Enter the reason 
for ineligibility in 
the Notice of 
Ineligibility
Registration
Notice by fax
Notice by fax
Confirmation of information 
entered in the Registration 
Confirmation Form
Enter the following in the 
Registration Confirmation Form:
• Date of confirmation of 
registration
• Subject ID Number
• Dose to be administered
Inquiry about defects
Informed consent

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(3) 
If it is not known whether a gastric cancer patient has a FGF/FGFR genetic 
abnormality, the investigator, subinvestigator, or clinical study collaborator will submit 
an archived sample to the central laboratory.  The central laboratory will report the 
result of genetic abnormality test to the sponsor and the study site.  The patient will be 
determined to be eligible for Screening 1 if the test result is positive and ineligible for 
Screening 1 if the test result is negative. 
(4) 
The investigator, subinvestigator, or clinical study collaborator will enter the result of 
the patient’s eligibility for Screening 1 in the Subject Screening Log, and patients who 
are determined to be eligible will go to the procedure for Screening 2. 
(5) 
The investigator or subinvestigator will screen the patient providing written informed 
consent for Screening 2 and determine his/her eligibility according to the 
inclusion/exclusion criteria.  The investigator, subinvestigator, or clinical study 
collaborator will document the result of eligibility determination in the Subject 
Screening Log. 
(6) 
After the investigator and the subinvestigator determine the eligibility of the patient 
through the screening test, the investigator, subinvestigator, or clinical study 
collaborator will promptly document the eligibility/ineligibility determined by the 
screening test, the planned start date of study treatment (when the patient is eligible), 
and the planned date of baseline assessment (when the baseline assessment is 
performed separately) in the Subject Eligibility Confirmation Form (Appendix 6:  Part 
2) and notify the sponsor by e-mail or fax. 
(7) 
The investigator or subinvestigator will check the result of the baseline assessment 
against the inclusion/exclusion criteria to determine the eligibility of the patient again, 
and document the result of eligibility determination in the Subject Screening Log.  
After confirmation of his/her eligibility, the patient will start study treatment. 

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Figure 7
Subject Enrollment Procedure (Part 2)
Subject ID Number
Known to 
have genetic 
abnormality
Confirm the following:
• Eligibility/Ineligibility
• Planned start date of study 
treatment
• Planned date of baseline 
assessment
Ineligible
(1)
Enter in the 
Subject 
Registration 
Log
(2)
(3)
(4)
(7)
Confirmation of 
eligibility
(6)
Eligible
(5)
Genetic 
abnormality
unknown
Confirmation of 
eligibility
Enter eligibility for Screening 2 
in the Subject Registration Form
Notice of 
ineligibility
Necessary 
information
Reconfirmation of eligibility by baseline 
assessment
Start study treatment only when the patient
is eligible
Informed consent for Screening 1
Enter eligibility for Screening 1 
in the Subject Registration Form
Informed consent for Screening 2
Screening
(Eligibility 
determination)
Study site
Sponsor
Central laboratory
Test of 
tumor 
sample

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9.4.6 
Selection of Doses in the Study 
The appropriateness of selection of the doses for Part 1 and Part 2 of this study is justified in 
Section 7.5.1 “Rationale for the Study Design,” Section 7.5.1.2 “Rationale for the Initial 
Dose for Part 1,” and Section 7.5.1.3 “Rationale for the Starting Dose for Part 2.” 
9.4.7 
Selection and Timing of Dose for Each Subject 
The selection and timing of dose for each subject is described in Section 9.4 “Treatment.” 
9.4.8 
Blinding 
The study will not be blinded. 
9.4.9 
Prior and Concomitant Therapy 
All concomitant therapies used after the time of informed consent (after the time of informed 
consent for Screening 2 in Part 2) until the date of final observation will be recorded in the 
CRF.  Additionally, all diagnostic, therapeutic, or surgical procedures relating to malignancy 
should be recorded, except for medications used for non-treatment purposes (eg, contrast 
agents, test agents, antiseptic agents, fluids used for drug preparations or flushes). 
9.4.9.1 
Drug-Drug Interactions 
CYP3A4 has been identified as the major enzyme that metabolizes E7090 in non-clinical 
studies.  See Appendix 2 for CYP3A inhibitors or inducers. 
9.4.9.2 
Prohibited Concomitant Therapies and Drugs 
The following concomitant therapies and drugs will be prohibited. 
(1) 
Cycle 0 and Cycle 1 (Part 1 only) 
1) 
Treatments, changes in dosage, and changes in drugs to prevent DLT occurrence 
(2) 
From the time of registration (Part 1) or the start of study treatment (Part 2) to the time 
of the discontinuation of study treatment 
1) 
Treatments for malignant tumors other than E7090 (eg, surgical therapy, 
chemotherapy, endocrine therapy, palliative radiotherapy, or immunotherapy) 
except for drugs for bone lesions (eg, bisphosphonates, anti-RANKL monoclonal 
antibodies) that have been used since before the registration in this study (Part 1) 
or the start of study treatment (Part 2) 
2) 
Drugs that inhibit or induce CYP3A (see Appendix 2 for relevant drugs) 
3) 
Other investigational products 

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9.4.10 
Treatment Compliance 
The investigator, subinvestigator, or clinical study collaborator will check and keep records 
of treatment compliance for each subject during the study.  Clinical research associates 
(CRAs) will review treatment compliance during site visits and at the completion of the 
study. 
9.4.11 
Drug Supplies and Accountability 
The study drug manager or designee will be responsible for the accountability of all study 
drugs (dispensing, inventory, and record keeping) by following the sponsor’s instructions for 
handling of study drugs and adhering to GCP guidelines as well as other requirements. 
Under no circumstances will the investigator or subinvestigator allow the study drug to be 
used for purposes other than as directed by this protocol.  Study drugs will  not be dispensed 
to any individual who is not enrolled in the study. 
The study drug manager or designee must maintain an accurate and timely record of the 
following:  the number of study drugs received, the number of study drugs dispensed to 
subjects, the number of study drugs dispensed to subjects but not used (unused study drug-1), 
the number of study drugs shipped to the medical institution but not dispensed to subjects 
(unused study drug-2), and the number of study drugs returned to the sponsor (sum of unused 
study drug-1 and unused study drug-2);  where applicable, destruction of reconciled study 
drugs at the medical institution should also be recorded.  These records include, but may not 
be limited to:  (a) documentation of receipt of study drugs, (b) study drug dispensing/return 
reconciliation log for each subject, (c) study drug accountability log, (d) documentation of 
return of study drugs, and (e) logs of any destruction of study drugs that occurs at the medical 
institution. 
The study drugs and inventory records must be made available, upon request, for inspection 
by the study monitor or a representative of the health authority during site visits.  Upon 
completion of drug accountability and after the receipt/return documentation of the study 
drugs have been submitted to the sponsor, the study drug manager or designee will return all 
unused study drugs (including empty boxes) to the sponsor.  Such study drugs will be 
collected by the monitor directly and returned to the sponsor’s designated depot. 
Study drug accountability will be reviewed by the monitor over the duration of the study 
such as during site visits and at the completion of the study. 
9.5 
Study Assessments 
9.5.1 
Assessments 
9.5.1.1 
Demographic Assessments 
The investigator, subinvestigator, or clinical study collaborator will assess each patient 
providing written informed consent for necessary information to confirm the inclusion and 
exclusion criteria, and document this information in the Subject Registration Form (Part 1) 

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and the Subject Eligibility Confirmation Form (Part 2).  The investigator, subinvestigator, or 
clinical study collaborator will also assess each patient providing written informed consent 
for the following subject demography information, and document the information in the 
CRF.  For any information already assessed during the confirmation of the inclusion and 
exclusion criteria, the investigator, subinvestigator, or clinical study collaborator may enter 
the data entered in the Subject Registration Form (Part 1) and the Subject Eligibility 
Confirmation Form (Part 2) in the CRF, instead of assessing such information again. 
(1) 
Subject ID Number 
(2) 
Date of signed written informed consent 
(3) 
Sex 
(4) 
Ethnicity 
(5) 
Race 
(6) 
Date of birth 
9.5.1.2 
Pretreatment Assessments 
9.5.1.2.1 
Medical History, Current Medical Conditions, Prior Treatment 
Medical history (including surgical history) and current medical conditions will be assessed 
at the screening visit.  All medical history considered by the investigator or subinvestigator to 
affect the safety, efficacy, and PK evaluations and all current medical conditions confirmed 
at the screening visit will be recorded in the CRF.  For prior treatment, the following 
information will be assessed: 
(1) 
Initial diagnosis (site of the primary lesion, date of diagnosis, method of diagnosis 
[histology/cytology], histologic type, staging classification specific to each carcinoma, 
and corresponding stage [eg, TNM classification]) 
(2) 
Prior treatment for the primary disease 
1) 
Surgical therapy (date of surgery, site of surgery) 
2) 
Radiation therapy (site of radiation, date of last radiation) 
3) 
Anticancer therapy (drug name, best overall response [BOR] for each regimen, 
total dose when necessary, dates of the first and last doses) 
4) 
Other therapies (therapy name, dates of the first and last procedures) 

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9.5.1.2.2 
Other Pretreatment Assessments Specific to the Study or Target Disease 
(1) 
For subjects with tumors harboring FGF/FGFR genetic abnormality (Part 1) and all 
subjects entering Screening 2 (Part 2), the following information will be recorded in the 
CRF: 
1) 
Type of FGF/FGFR genetic abnormality (translocation, point mutation, 
amplification, other) 
2) 
Diagnostic method for FGF/FGFR genetic abnormality (FISH, immunostaining, 
RT-PCR, NGS, other) 
3) 
Site of the sample tested for FGF/FGFR genetic abnormality and date of the 
sample collected 
4) 
Date of FGF/FGFR genetic abnormality test 
5) 
Status of FGF/FGFR protein expression 
(2) 
Use of contact lenses at the screening visit will be assessed and documented in the 
CRF. 
9.5.1.3 
Efficacy Assessments 
Tumor evaluation in this study will be performed by the treating physician according to 
RECIST 1.1 (Appendix 7).  Antitumor effects will be assessed on the basis of images taken 
under the same conditions as those at the screening visit with the use of appropriate 
equipment such as CT or MRI.  Assessments at the screening visit will include overall tumor 
site assessment (presence or absence of target lesions [tumor lesions and lymph node 
lesions], presence or absence of non-target lesions), target lesion assessment (site, tumor 
diameter, assessment date, measurement method), and non-target lesion assessment (site, 
assessment, assessment date, diagnostic method).  Results of these assessments will be 
documented in the CRF.  After the screening visit, target lesions, non-target lesions, new 
lesions (presence or absence of lesions, site, date of development, diagnostic method), and 
overall response will be assessed, and results of these assessments will be documented in the 
CRF. 
Third-party assessments of antitumor effects or safety may be performed as necessary.  In 
such cases, the investigator, subinvestigator, or clinical study collaborator will provide image 
data via electronic media to the sponsor if requested. 
9.5.1.3.1 
Assessment of Tumor Lesions 
Chest X-rays will not be used to assess target lesions. 
Assessment methods for each site are as follows: 
x 
Head:  CT or MRI 

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x 
Chest:  CT 
x 
Abdomen:  CT or MRI 
x 
Pelvis:  CT or MRI 
x 
Other sites:  CT, MRI, or other method 
x 
Visible or palpable clinical lesions:  Clinical evaluation 
(1) 
CT or MRI 
CT or MRI will be performed with contrast, except in subjects not amenable to 
oral/intravenous contrast agents (due to allergy or renal dysfunction).  In subjects not 
amenable to contrast agents, a plain CT scan without contrast will be performed.  In 
subjects not amenable to intravenous contrast agents, CT with oral contrast may be 
considered, and for the abdominal or pelvic region, MRI with intravenous gadolinium 
may be considered. 
Low-dose CT images from positron emission tomography with CT (PET/CT), CT 
images for attenuation correction, or ultrasonography will not be used to assess tumors.  
When a skin lesion is recorded in a color digital photo, a millimeter scale ruler and a 
label describing the subject ID number and the date should be included in the photo.  
Measurements should be performed with calipers. 
1) 
At screening 
x 
The head, chest, abdomen, pelvis, and sites of known or suspected lesions 
will be assessed. 
x 
Any data obtained before informed consent, as long as obtained within 28 
days before the start of study treatment, may be used. 
2) 
In Cycle 2 and subsequent cycles 
x 
The chest, abdomen, pelvis, tumor sites present at the time of screening, and 
any other sites of newly suspected lesions will be assessed. 
(2) 
Clinical evaluation 
It is recommended that any lesion allowing visual inspection should be assessed using a 
color photo that contains a ruler to allow assessment of its size.  For any palpable 
lesion, its size will be assessed by clinical examination and the results will be recorded 
in source documents. 
Tumor lesion assessment will be performed at the time of screening, every 8 weeks starting 
from Day 1 of Cycle 1 (Day 1 of each odd-numbered cycle [±7 days]), and at the time of 
discontinuation (+7 days).  Assessments may be added as clinically required.  Any data 
obtained within 28 days before discontinuation may be used as data at the time of 
discontinuation. 

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9.5.1.3.2 
Tumor Markers 
The investigator or subinvestigator will identify any tumor markers considered to be 
appropriate for the primary disease from among CEA, CA19-9, CA72-4, STN, and other 
tumor markers.  Examples of tumor markers are listed in Table 7.  The investigator or 
subinvestigator will assess identified tumor markers according to the schedules in Table 13 
and Table 14 and document assessment results in the CRF.  Tumor marker assessment will 
be performed at the time of screening, every 8 weeks starting from Day 1 of Cycle 1 (Day 1 
of each odd-numbered cycle [±7 days]), and at the time of discontinuation (+7 days).  
Assessments may be added as clinically required.  Any data obtained within 28 days before 
discontinuation may be used as data at the time of discontinuation. 
Table 7 
Examples of Tumor Markers 
Tumor 
Serum tumor markers a 
Breast cancer 
CEA, CA15-3, ST-439 
Large bowel cancer, gastric cancer 
CEA 
Pancreas cancer 
CA19-9 
Prostate cancer 
PSA, PAP 
Hepatocellular carcinoma 
AFP, PIVKA-II 
Ovarian cancer 
CA125 
Testicular cancer 
AFP, hCG, LDH 
Trophoblastic tumor 
hCG 
Lung cancer (small cell) 
NSE, ProGRP 
Neuroblastoma 
Vanillylmandelic acid (VMA), catecholamine, 
neuron-specific enolase (NSE) 
Thyroid cancer 
Thyroglobulin, calcitonin 
Carcinoid tumor 
5-HIAA 
a: Recommended serum tumor markers.  Not all markers are listed.  If there is any other marker known to be 
useful in individual subjects, it is desirable to use the marker. 
 
9.5.1.3.3 
Survival Follow-up 
Subjects will be followed for survival every 12 weeks (±2 weeks) from the time of study 
treatment discontinuation.  Follow-up is to be continued until the confirmation of death.  For 
any antitumor therapy, which is known as of the assessment to be provided for the subject 
after completion of study treatment, its start date and end date will be recorded.  Survival 
follow-up will be terminated 2 years after the last subject’s registration (Part 2). 

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9.5.1.4 
Pharmacokinetic, Pharmacodynamic, and Pharmacogenomic Assessments 
9.5.1.4.1 
Pharmacokinetic Assessments 
(1) 
Plasma concentration measurement 
Blood samples will be collected at the time points shown in Table 8 (Part 1) and  
Table 9 (Part 2), and the plasma concentrations of E7090 and its active metabolite, E7090-
M2, will be determined using a validated LC-MS/MS method.  In Part 1, remaining samples 
from the unchanged E7090 measurement will be used for exploratory metabolite analyses.  
See Appendix 8 for a description of collection, handling, and shipping procedures of the 
samples.  Regarding sampling time points, the actual time of blood sampling will be 
documented in the CRF. 
Table 8 
Blood Sampling Schedule for PK Evaluation (Part 1) 
Cycle 
Sampling 
day 
Sampling time point 
Allowable sampling 
time interval 
Blood sampling 
volume 
Cycle 0 
Day 1 
 
Predose 
:LWKLQí60 minutes 
2 mL at each 
time point 
30 minutes postdose 
Within ±10 minutes 
1 hour postdose 
Within ±10 minutes 
2 hours postdose 
Within ±10 minutes 
3 hours postdose 
Within ±10 minutes 
5 hours postdose 
Within ±10 minutes 
10 hours postdose 
Within ±30 minutes 
Day 2 
24 hours postdose 
Within ±60 minutes 
Day 3 
48 hours postdose 
Within ±60 minutes 
Day 4 
72 hours postdose 
Within ±60 minutes 
Cycle 1 
Day 1 
Predose 
:LWKLQí60 minutes 
Day 3 
Predose 
:LWKLQí60 minutes 
Day 8 
Predose 
:LWKLQí60 minutes 
30 minutes postdose 
Within ±10 minutes 
1 hour postdose 
Within ±10 minutes 
2 hours postdose 
Within ±10 minutes 
3 hours postdose 
Within ±10 minutes 
5 hours postdose 
Within ±10 minutes 
10 hours postdose 
Within ±30 minutes 
Day 9 
Predose 
:LWKLQí60 minutes 
Day 15 
Predose 
:LWKLQí60 minutes 
Day 22 
Predose 
:LWKLQí60 minutes 

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Cycle 2 and 
subsequent 
cycles 
Day 1 
Predose 
:LWKLQí60 minutes 
 

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Table 9 
Blood Sampling Schedule for PK Evaluation (Part 2) 
Cycle 
Sampling 
day 
Sampling time point 
Allowable sampling 
time interval 
Blood sampling 
volume 
Cycle 1 
Day 1 
 
Predose 
:LWKLQí60 minutes 
2 mL at each 
time point 
30 minutes postdose 
Within ±10 minutes 
1 hour postdose 
Within ±10 minutes 
2 hours postdose 
Within ±10 minutes 
3 hours postdose 
Within ±10 minutes 
5 hours postdose 
Within ±10 minutes 
10 hours postdose 
Within ±30 minutes 
24 hours postdose 
(Predose on Day 2) 
:LWKLQí60 minutes 
Day 8 
 
Predose 
:LWKLQí60 minutes 
30 minutes postdose 
Within ±10 minutes 
1 hour postdose 
Within ±10 minutes 
2 hours postdose 
Within ±10 minutes 
3 hours postdose 
Within ±10 minutes 
5 hours postdose 
Within ±10 minutes 
10 hours postdose 
Within ±30 minutes 
24 hours postdose 
(Predose on Day 9) 
:LWKLQí60 minutes 
Day 15 
Predose 
:LWKLQí60 minutes 
Cycle 2 and 
subsequent 
cycles 
Day 1 
Predose 
:LWKLQí60 minutes 
 
(2) 
Urinary concentration measurement 
Urinary PK measurements will be performed in Part 1 only.  On Day 8 of Cycle 1 in Part 1, a 
24-hour urine collection will be performed to determine the urinary concentration of 
unchanged E7090.  In addition, remaining samples will be used for exploratory metabolite 
analyses.  The start time of urine collection (at study drug administration), end time of urine 
collection, urine volume, and amount of ethanol added will be recorded in the CRF.  See 
Appendix 8 for a description of collection, handling, and shipping procedures of the samples. 
9.5.1.4.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Assessments 
Blood, archived tumor, and biopsied tumor samples will be obtained for PD and PGx 
assessments.  The following measurements may be increased as necessary, depending on new 
findings or progress of science.  These measurements will be obtained to understand the 

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pharmacological response of E7090, identify biomarkers useful in predicting treatment 
effects, and develop diagnostic agents. 
[Part 1] 
(1) 
In blood samples 
Blood samples will be collected according to the procedures and methods shown in Table 10 
to determine blood biomarkers.  For sampling time points, the actual time of blood sampling 
will be recorded in the CRF.  See Appendix 9 for a description of collection, handling, and 
shipping procedures of the samples. 
The following measurements will be determined: 
1) 
FGF23 
2) 
1,25-(OH)2-Vitamin D 
3) 
 
4) 
Angiogenesis markers (eg, VEGF, FGF) 
5) 
Circulating tumor DNA 
Table 10 
Blood Sampling Schedule for PD and PGx Evaluations (Part 1) 
Cycle 
Sampling 
day 
Sampling time 
point 
Allowable sampling 
time interval 
Sampling 
volume 
Measurement 
At baseline 
Within 4 days after start of treatment 
15 mL 
5) 
Cycle 0 
Day 1 
Predose 
:LWKLQí60 minutes 
7 mL 
1) to 4) 
3 hours postdose 
Within ±10 minutes 
7 mL 
5 hours postdose 
Within ±10 minutes 
7 mL 
10 hours 
postdose 
Within ±30 minutes 
7 mL 
Day 2 
24 hours 
postdose 
Within ±60 minutes 
7 mL 
Day 3 
48 hours 
postdose 
Within ±60 minutes 
7 mL 
Day 4 
72 hours 
postdose 
Within ±60 minutes 
7 mL 
Cycle 1 
Day 1 
Predose 
:LWKLQí60 minutes 
7 mL 
Day 3 
Predose 
:LWKLQí60 minutes 
7 mL 
Day 8 
Predose 
:LWKLQí60 minutes 
7 mL 
Day 15 
Predose 
:LWKLQí60 minutes 
7 mL 
CCI

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Odd-numbered 
cycles (Cycle 3 
and subsequent 
cycles) 
Day 1 
Predose 
:LWKLQí60 minutes 
10 mL 
5) 
 
(2) 
In archived tumor samples 
If available, archived tumor samples will be evaluated for FGFR protein expression by 
immunohistochemical staining.  See Appendix 9 for a description of collection, handling, and 
shipping procedures of the samples.  If known, the date of sample collection and the organ 
from which the tumor has been collected will be recorded in the CRF. 
(3) 
In biopsied tumor samples 
Tumor biopsies will be collected at screening and on Day 15 of Cycle 1 to determine protein 
expression of the following factors by immunohistochemical staining.  Tumor biopsies 
should be taken from the same organ whenever possible.  The actual time of sample 
collection will be recorded in the CRF.  See Appendix 9 for a description of collection, 
handling, and shipping procedures of the samples.  The date of sample collection and the 
organ from which the tumor has been collected will be recorded in the CRF. 
(a) 
FGFR 
(b) 
Phosphorylated FGFR 
(c) 
ERK 
(d) 
Phosphorylated ERK 
[Part 2] 
(1) 
In blood samples 
Blood samples will be collected according to the procedures and methods shown in Table 11 
to determine blood biomarkers.  For sampling time points, the actual time of blood sampling 
will be recorded in the CRF.  See Appendix 9 for a description of collection, handling, and 
shipping procedures of the samples. 
The following measurements will be determined: 
1) 
FGF23 
2) 
1,25-(OH)2-Vitamin D 
3) 
 
4) 
Angiogenesis markers (eg, VEGF, FGF) 
CCI

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5) 
Circulating tumor DNA 
Table 11 
Blood Sampling Schedule for PD and PGx Evaluations (Part 2) 
Cycle 
Sampling 
day 
Sampling 
time point 
Allowable 
sampling time 
interval 
Sampling 
volume 
Measurement 
At baseline 
Within 4 days after start of treatment 
15 mL 
5) 
Cycle 1 
Day 1 
Predose 
:LWKLQí60 minutes 7 mL 
1) to 4) 
Day 8 
Predose 
:LWKLQí60 minutes 7 mL 
Day 15 
Predose 
:LWKLQí60 minutes 7 mL 
Odd-numbered 
cycles (Cycle 3 and 
subsequent cycles) 
Day 1 
Predose 
:LWKLQí60 minutes 10 mL 
5) 
 
(2) 
In archived tumor samples 
If any sample collected in the past is available, an archived tumor sample should be 
submitted (mandatory).  If known, the date of sample collection and the organ from which 
the tumor has been collected will be recorded in the CRF. 
(3) 
In biopsied tumor samples 
Except for subjects who have only a tumor lesion not amenable to biopsy for safety reasons, 
samples obtained from the biopsy performed in Screening 2 must be submitted (mandatory).  
Any reason for infeasible biopsy will be recorded in source documents.  The date of sample 
collection and the organ from which the tumor has been collected will be recorded in the 
CRF.  In addition, a biopsy tumor sample will be collected on Day 15 of Cycle 1 (optional).  
Tumor biopsies should be taken from the same organ whenever possible.  The actual time of 
sample collection will be recorded in the CRF.  See Appendix 9 for a description of 
collection, handling, and shipping procedures of the samples.  The date of sample collection 
and the organ from which the tumor has been collected will be recorded in the CRF. 
For (2) and (3) above, immunohistochemical staining or comprehensive genomic analysis 
will be performed to evaluate their correlation with the efficacy of E7090.  In addition, 
samples will be archived for the development of diagnostic agents (see Appendix 9 for 
details). 
9.5.1.5 
Safety Assessments 
Safety assessments will consist of the following: 
All adverse events including serious and nonserious events (changes in CTCAE v4.03 grades 
[for both increasing and decreasing severity]), DLTs (Part 1 only), laboratory tests 

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(hematology, blood chemistry, and urinalysis), vital signs, ECGs, ECOG-PS, 
ophthalmological examinations, and physical examinations. 
9.5.1.5.1 
Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical 
investigation subject administered an investigational product.  An AE does not necessarily 
have a causal relationship with the medicinal product.  For this study, the study drug is 
E7090. 
The criteria for identifying AEs in this study are: 
x 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
whether or not considered related to the investigational product (For Part 2, events 
observed after informed consent for Screening 2 will be assessed) 
x 
Any new disease or exacerbation of an existing disease.  However, worsening of the 
primary disease should be captured under efficacy assessments as disease progression 
rather than as an AE. 
x 
Any deterioration in nonprotocol-required measurements of a laboratory value or other 
clinical test (eg, ECG or x-ray) that results in symptoms 
x 
Any deterioration in nonprotocol-required measurements of a laboratory value or other 
clinical test (eg, ECG or x-ray) that results in a change in treatment or discontinuation of 
study drug 
x 
Recurrence of an intermittent medical condition (eg, headache) not present pretreatment 
(Baseline) 
x 
An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, withdrawal of study drug, or withholding 
of study drug, whether prescribed in the protocol or not 
It is the responsibility of the investigator and subinvestigator to review all laboratory findings 
in all subjects and determine if they constitute an AE. 
The investigator or subinvestigator should determine whether a laboratory result, abnormal or 
not, should be classified as an AE if it: 
x 
Leads to discontinuation of study treatment 
x 
Leads to withholding (interruption) of study treatment until some test result becomes 
clear 
x 
Requires a medical intervention (eg, potassium supplement for hypokalemia) 
x 
Leads to any out-of-range laboratory value (the investigator or subinvestigator will 
determine whether the laboratory result meets any of the definitions of AEs considering 
the subject’s current or previous medical condition) 
x 
Is considered by the investigator or subinvestigator to be an AE (excluding values related 
to lymphocyte, albumin, cholesterol, and glucose) because of its clinically significant 

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changes:  ZRUVHQLQJE\JUDGHVRI&7&$(YFRPSDUHGWREDVHOLQHDQGIXUWKHU
ZRUVHQLQJE\JUDGHV 
All AEs observed during the study (for Part 2, after informed consent for Screening 2) will 
be recorded in the CRF.  All AEs, regardless of relationship to study drug or procedure, 
should be collected beginning from the time the subject signs the informed consent form (for 
Part 2, after informed consent for Screening 2) through the last visit (30 days after the last 
dose of study treatment).  If it is necessary to start a new anticancer agent immediately due to 
deterioration of the subject’s condition, the final observation may be performed before 30 
days after the last dose of study treatment but must be performed before the start of the new 
anticancer agent. 
With regard to serious adverse events (SAEs), events occurring by the time of final 
observation should be collected.  For a screening failure due to the development of an AE, 
the name and seriousness of the AE will be recorded in the CRF. 
Any laboratory abnormality considered to constitute an AE should be recorded in the CRF. 
Abnormal laboratory values should not be listed as separate AEs if they are considered to be 
part of the clinical syndrome that is being reported as an AE.  Medical and scientific 
judgment should be exercised in deciding whether an isolated laboratory abnormality should 
be classified as an AE. 
Abnormal ECG (QTc) results, if not otherwise considered part of a clinical symptom that is 
being reported as an AE, should be considered an AE if the QTc interval is more than 450 ms 
and there is an increase of more than 60 ms from baseline.  Any ECG abnormality that the 
investigator or subinvestigator considers as an AE should be recorded in the CRF. 
Disease progression will not be treated as an AE.  If any unfavorable changes associated with 
disease progression (eg, worsening pain, pleural effusion) are observed, these changes will be 
recorded as AEs. 
All AEs must be followed until the last visit (30 days after the last dose of study treatment) or 
resolution, whichever comes first.  If it is necessary to start a new anticancer agent 
immediately due to deterioration of the subject’s condition, the final observation may be 
performed before 30 days after the last dose of study treatment but must be performed before 
the start of the new anticancer agent.  All SAEs must be followed until resolution or, if 
resolution is unlikely, until stabilization, although follow-up may be terminated on the basis 
of the medical judgment of the investigator or subinvestigator. 
Every effort must be made by the investigator or subinvestigator to categorize each AE 
according to its severity and its relationship to the study treatment. 
Assessing Severity of Adverse Events 
The severity of AEs will be graded on a 5-point scale according to CTCAE v4.03 and 
recorded in the CRF (changes in CTCAE v4.03 grades [for both increasing and decreasing 
severity]). 

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Assessing Relationship to Study Treatment 
Items to be considered when assessing the relationship of an AE to the study treatment are: 
x 
Temporal relationship of the onset of the event to the initiation of the study treatment 
x 
The course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable 
x 
Whether the event is known to be associated with the study treatment or with other 
similar treatments 
x 
The presence of risk factors in the study subject known to increase the occurrence of the 
event 
x 
The presence of nonstudy, treatment-related factors that are known to be associated with 
the occurrence of the event 
Classification of Causality 
Not related: 
A causal relationship between the study drug and the AE is not a 
reasonable possibility. 
Related: 
A causal relationship between the study drug and the AE is a reasonable 
possibility. 
9.5.1.5.2 
Serious Adverse Events and Events Associated with Special Situations 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
x 
Results in death 
x 
Is life-threatening (ie, the subject was at immediate risk of death from the adverse event 
as it occurred;  this does not include an event that, had it occurred in a more severe form 
or was allowed to continue, might have caused death) 
x 
Requires inpatient hospitalization or prolongation of existing hospitalization 
x 
Results in persistent or significant disability/incapacity 
x 
Is a congenital anomaly/birth defect (in the child of a subject who was exposed to the 
study drug) 
Other important medical events that may not be immediately life-threatening or result in 
death or hospitalization but, when based on appropriate medical judgment, may jeopardize 
the subject or may require intervention to prevent one of the outcomes in the definition of 
SAE listed above should also be considered SAEs.  Medical and scientific judgment should 
be exercised in deciding whether expedited reporting is appropriate in such situations. 
In addition to the above, other events of interest include pregnancy or exposure to study drug 
through breastfeeding;  AEs associated with study drug overdose, misuse, abuse, or 
medication error (see Section 9.5.4.2 and Section 9.5.4.3).  These events associated with 
special situations are to be captured using the SAE procedures but are to be considered as 

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SAEs only if they meet one of the above criteria.  All AEs associated with special situations 
(excluding normal births) are to be reported on the CRF whether or not they meet the criteria 
for SAEs. 
All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization. 
The following hospitalizations are not considered to be SAEs because there is no “adverse 
event” (ie, there is no untoward medical occurrence) associated with the hospitalization: 
x 
Hospitalizations for respite care 
x 
Planned hospitalizations required by the protocol 
x 
Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed after study drug administration) 
x 
Hospitalization for administration of study drug or insertion of access for administration 
of study drug 
x 
Hospitalization for routine maintenance of a device (eg, battery replacement) that was in 
place before study entry 
9.5.1.5.3 
Laboratory Measurements 
Clinical laboratory tests to be performed, including hematology, blood chemistry, and 
urinalysis, are summarized in Table 12.  The Schedule of Procedures/Assessments (Table 13 
and Table 14) shows the visits and time points at which blood for clinical laboratory tests and 
urine for urinalysis will be collected in the study. 
Table 12 
Clinical Laboratory Tests 
Category 
Parameters 
Hematology 
RBC count, hemoglobin, hematocrit, platelets, WBC count, and 
WBC count with differential (neutrophils, lymphocytes, 
monocytes, eosinophils, basophils) 
Blood chemistry 
 
Liver function tests 
ALP, AST, $/7Ȗ-GTP, total bilirubin, direct bilirubin 
Renal function tests 
BUN, creatinine 
Other 
Blood glucose, albumin, cholesterol, triglycerides, phosphorus, 
LDH, total protein, uric acid, lipase, amylase, Na, K, Cl, Ca, CRP 
Blood coagulation tests 
Activated partial thromboplastin time (aPTT) 
Urinalysis 
pH, protein, glucose, ketone bodies, occult blood 
Virus tests (screening only) 
HBs antigen, HCV antibodies, HIV antibodies 
 
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 9.5.1.5.1).  In these instances, the AE corresponding to the laboratory 
abnormality will be recorded in the CRF. 

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For laboratory abnormalities meeting the criteria of SAEs (see Section 9.5.1.5.2), the 
investigator must fax or email the SAE report to the sponsor using the SAE form (see Section 
9.5.4.1 “Reporting of Serious Adverse Events”).  In addition, test results for any AEs 
determined through laboratory tests performed during nonprotocol-required visits will also be 
recorded in the CRF. 
[Monitoring of serum phosphorus levels] 
Nonclinical toxicity studies have reported mineralization associated with hyperphosphatemia, 
which are considered attributable to the inhibition of FGFR kinase, the pharmacological 
action of E7090.  Given that similar events have also been observed in clinical studies of 
similar drugs, attention needs to be paid to such toxicities in this study.  If high serum 
phosphorus levels are observed, the criteria for dose interruption/reduction shown in Table 6 
should be followed.  In addition, any necessary test (eg, X-ray) should be performed if any 
clinical symptom suggestive of mineralization is observed. 
9.5.1.5.4 
Vital Signs, Weight, and Height Measurements 
Vital sign measurements (ie, systolic and diastolic blood pressure [mmHg], pulse [beats per 
minute], respiratory rate [per minute], body temperature [°C], weight [kg], height [cm] 
[screening only]) will be obtained at the visits designated in the Schedule of 
Procedures/Assessments (Table 13 and Table 14) by a validated method.  Blood pressure and 
pulse will be measured with the subject at rest and sitting. 
9.5.1.5.5 
Physical Examinations 
Physical examinations will be performed at the visits designated in the Schedule of 
Procedures/Assessments (Table 13 and Table 14).  Physical examinations will include the 
head, eyes, ears, nose, throat, neck, chest (include the heart and lungs), abdomen, four limbs, 
skin, and a neurological examination.  Results of physical examinations will be documented 
in the medical records at the site.  Only changes from screening physical examination 
findings that meet the definition of an AE will be recorded in the CRF. 
9.5.1.5.6 
Electrocardiograms 
Electrocardiograms will be obtained at the visits designated in the Schedule of 
Procedures/Assessments (Table 13 and Table 14).  Standardized 12-lead ECG recordings will 
be used.  Electrocardiogram parameters (heart rate, PR interval, QRS interval, QRS axis, QT 
interval, RR interval) will be recorded in the CRF.  In addition, ECG findings (normal, 
abnormal not clinically significant, abnormal clinically significant) will also be recorded. 
An ECG abnormality may meet the criteria of an AE as described in this protocol (Section 
9.5.1.5.1).  In these instances, the AE corresponding to the ECG abnormality will be recorded 
in the CRF. 
For ECG abnormalities meeting the criteria of an SAE (see Section 9.5.1.5.2), the 
investigator must fax or email the SAE report (including the ECG report) to the sponsor 
using SAE form (see Section 9.5.4.1 “Reporting of Serious Adverse Events”). 

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9.5.1.5.7 
Ophthalmological Examinations 
Ophthalmological examinations will be performed at the visits designated in the Schedule of 
Procedures/Assessments (Table 13 and Table 14).  Examinations in Part 1 will include visual 
acuity, funduscopy (mydriatic test when necessary), slit-lamp examination (fluorescein 
staining when necessary), and anterior segment optical coherence tomography (OCT) to 
evaluate the corneal epithelium.  Corneal epithelial thickness will be measured by anterior 
segment OCT and recorded in the CRF.  Examinations in Part 2 will include visual acuity, 
funduscopy (mydriatic test when necessary), slit-lamp examination (fluorescein staining 
when necessary), and posterior segment OCT to evaluate the retina. 
9.5.1.5.8 
ECOG-PS 
ECOG-PS will be assessed according to Appendix 10 at the visits designated in the Schedule 
of Procedures/Assessments (Table 13 and Table 14). 
9.5.1.5.9 
Pregnancy Test 
Serum or urine hCG tests will be performed in females of childbearing potential at the visits 
designated in the Schedule of Procedures/Assessments (Table 13 and Table 14). 
9.5.1.5.10 Transcutaneous Arterial Oxygen Saturation Measurement 
Arterial oxygen saturation will be measured with a pulse oximeter at the visits designated in 
the Schedule of Procedures/Assessments (Table 13 and Table 14). 
9.5.1.6 
Compliance with Study Treatment 
The investigator, subinvestigator, or clinical study collaborator will instruct subjects on the 
proper administration of the study drug.  Compliance with study treatment (date of 
administration, dose administered, time of administration [only on the previous day and the 
day of PK evaluation shown in Table 8], reason for any change) will be assessed and 
recorded in the CRF. 
9.5.1.7 
Concomitant Drugs and Therapies 
The investigator, subinvestigator, or clinical study collaborator will instruct subjects to 
comply with the stipulations on prohibited concomitant treatments in Section 9.4.9.2 
“Prohibited Concomitant Therapies and Drugs,” and investigate concomitant treatment 
according to the following. 
(1) 
Concomitant drugs 
At each visit, all drugs used from the time of written informed consent (for Part 2, informed 
consent for Screening 2) through the end of the last observation period will be investigated, 
and the information listed below will be recorded in the CRF.  If the subject is treated at 
another department or hospital, the treating physician will be interviewed if necessary.  If it is 
necessary to start a new anticancer agent immediately due to deterioration of the subject’s 

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condition, final observation may be performed before 30 days after the last dose of study 
treatment but must be performed before the start of the new anticancer agent. 
Drug name, route of administration, reason for use, start date of treatment, and end date of 
treatment (date when the treatment is completed or “continued treatment after the last visit”) 
For drugs used to treat hyperphosphatemia or Grade 3 ADRs, the dosage regimen as well as 
the information above will be recorded in the CRF. 
(2) 
Concomitant therapies 
At each visit, all therapies provided from the time of written informed consent (for Part 2, 
informed consent for Screening 2) through the end of the last observation period will be 
investigated, and the information listed below will be recorded in the CRF.  If the subject is 
treated at another department or hospital, the treating physician will be interviewed if 
necessary. 
Therapy name, reason for therapy, start date of therapy, and end date of therapy (date when 
the therapy is completed or “continued therapy after the last visit”) 
9.5.2 
Schedule of Procedures/Assessments 
9.5.2.1 
Schedule of Procedures/Assessments in Part 1 
Schedule of procedures/assessments in Part 1 and Part 2 is shown in Table 13 and Table 14, 
respectively. 
 

 
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Table 13 
Schedule of Procedures/Assessments in Part 1 
Phase 
Pretreatment 
Treatment 
Follow-up 
Period 
IC 
Screening Registration Baseline d 
Cycle 0 
Cycle 1 
Cycle 2 and subsequent cycles 
Discontinuation 
Final 
observation v 
Day  
 
Within 14 
days 
predose 
 
Within 4 
days 
predose 
1 
2 
1 i 
3 
8 
(±1) 
15 
(±1) 
22 
(±1) 
1 
(±3)n 
8 o 
(±3) 
15 
(±3) 
22 o 
(±3) 
(+7) 
30 days after 
last dose 
(+7) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Registration 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject demographics 
Prior treatment 
Previous/current condition 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height, viral test 
 
X b 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
X 
 
X 
 
 
X j 
 
X 
X 
X 
X 
 
X 
 
X t 
 
Vital signs 
Transcutaneous arterial 
oxygen saturation 
 
X 
 
X 
X e 
X f 
X j 
 
X 
X 
X 
X 
X 
X 
X 
X t 
X 
Physical examination 
 
X 
 
X 
 
 
X j 
 
X 
X 
X 
X 
X 
X 
X 
X t 
X 
ECOG-PS 
 
X 
 
X 
 
 
X j 
 
 
 
 
X 
 
 
 
X t 
 
12-lead ECG 
 
X 
 
 
X e 
 
X j 
 
X 
 
X 
X 
 
X o 
 
X t 
 
Urinalysis 
 
X 
 
X 
 
 
X j 
 
X 
X 
X 
X 
X 
X 
X 
X t 
X 
Hematology 
Blood chemistry 
Blood coagulation 
 
X 
 
X 
 
X f  
X j 
X w 
X 
X 
X 
X 
X 
X 
X 
X t 
X 
Ophthalmology 
 
X 
 
 
 
 
 
 
 
X 
 
X p 
 
 
 
X t 
X 
Pregnancy 
(if applicable) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Tumor evaluation 
Tumor markers 
 
X c 
 
 
 
 
X q 
X u 
 
PK (blood) 
 
 
 
 
X g 
X j 
X j 
X k 
X j 
X j 
X j 
 
 
 
 
 
PK (urine) 
 
 
 
 
 
 
 
 
X l 
 
 
 
 
 
 
 
 
PD markers and PGx (blood) 
 
 
 
X 
X h 
X j 
X j 
X j 
X j 
 
X r 
 
 
 
 
 
Archived tumor a 
X s 
Biopsied tumor a 
 
X 
 
 
 
 
 
 
 
X m 
 
 
 
 
 
 
 
E7090 administration 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant drugs/therapies 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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a) To be performed only when consent is obtained. 
b) Any available viral test data obtained within 6 months before the start of study treatment may be used as screening data. 
c) Any data obtained within 28 days before the start of study treatment may be used (any data obtained before informed consent may also be used). 
d) For assessments performed at both screening and baseline, if screening assessment is performed within 4 days after the start of study treatment, baseline assessment may be omitted. 
e) To be performed 2 to 4 hours postdose. 
f) 
To be performed  24 hours (±60 minutes) postdose. 
g) To be performed predose and 0.5, 1, 2, 3, 5, 10, 24, 48, and 72 hours postdose. 
h) To be performed predose and 3, 5, 10, 24, 48, and 72 hours postdose. 
i) 
Cycle 1 will be started between Day 8 and Day 10 after administration in Cycle 0. 
j) 
To be performed predose. 
k) To be performed predose and 0.5, 1, 2, 3, 5, 10, and 24 hours postdose. 
l) 
A 24-hour urine collection will be performed. 
m) To be performed within ±2 days. 
n) To be performed within +3 days only in Cycle 2. 
o) In Cycle 3 and subsequent cycles, the test/observation may be omitted only if the investigator or subinvestigator considers that the safety of the subject is ensured. 
p) To be performed on Day 1 of Cycle 2.  To be performed every 8 weeks (on Day 1 [±3 days] of even-numbered cycles) thereafter. 
q) Tumor evaluation and tumor marker assessment will be performed every 8 weeks (on Day 1 [±7 days] of odd-numbered cycles) after Day 1 of Cycle 1, and more frequently if clinically indicated. 
r) 
To be performed in odd-numbered cycles after Cycle 3. 
s) To be obtained during the study period whenever possible. 
t) 
Any available data obtained within 7 days before discontinuation may be used as data at discontinuation. 
u) Any available data obtained within 28 days before discontinuation may be used as data at discontinuation. 
v) If it is necessary to start a new anticancer agent immediately due to deterioration of the subject’s condition, the final observation may be performed before 30 days after the last dose of study 
treatment but must be performed before the start of the new anticancer agent. 
w) Only blood chemistry (blood phosphorus level) will be performed. 
 

 
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Table 14 
Schedule of Procedures/Assessments in Part 2 
Phase 
Pretreatment 
Treatment 
Follow-up 
Period 
Screening 
1 
Screening 2 
Baseline c 
Cycle 1 
Cycle 2 and subsequent cycles 
Discontinuation 
Final 
observation r 
Day  
 
 
Within 14 
days before 
dose 
Within 4 
days before 
dose 
1 
8 
(±2) 
15 
(±2) 
22 
(±2) 
1 
(±3) 
8 l 
(±3) 
15 
(±3) 
22 l 
(±3) 
(+7) 
30 days after 
last dose 
(+7) 
Consent for tumor test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Consent for study 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Subject demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior treatment 
Previous/current 
condition 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Height, viral test  
 
 
X b 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
 
X 
X 
 
X 
X 
X 
X 
 
X 
 
X p 
 
Vital signs 
Transcutaneous arterial 
oxygen saturation 
 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X p 
X 
Physical examination 
 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X p 
X 
ECOG-PS 
 
 
X 
X 
 
 
 
 
X 
 
 
 
X p 
 
12-lead ECG 
 
 
X 
 
 
X 
 
X 
X 
 
X l 
 
X p 
 
Urinalysis 
 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X p 
X 
Hematology 
Blood chemistry 
Blood coagulation 
 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X p 
X 
Ophthalmology 
 
 
X c 
 
 
 
X i 
 
X m 
 
 
 
X p 
X 
Pregnancy 
(if applicable) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
Tumor evaluation 
Tumor markers 
 
 
X c 
 
X j 
X q 
 
PK (blood) 
 
 
 
 
X f 
X h 
X g 
 
X g 
 
 
 
 
 
PD markers and PGx 
(blood) 
 
 
 
X 
X g 
X g 
X g 
 
X n 
 
 
 
 
 
Archived tumor  
X a 
 
X o 
Biopsied tumor 
 
 
X d 
 
 
 
X k  
 
 
 
 
 
 
 
E7090 administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
drugs/therapies 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Survival follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
X s 

 
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a) Only in gastric cancer patients with available samples to allow confirmation of FGFR2 protein expression at the time of informed consent for Screening 1.  Patients in whom the presence of FGFR2 
gene amplification is unknown but the presence of FGFR2 protein overexpression is confirmed by central laboratory may enter Screening 2. 
b) Any available viral test data obtained within 6 months before the start of study treatment may be used as screening data. 
c) Any data obtained within 28 days before the start of study treatment may be used (any data obtained before informed consent may also be used). 
d) Excluding patients with only a tumor lesion not amenable to biopsy for safety reasons. 
e) For assessments performed at both screening and baseline, if screening assessment is performed within 4 days after the start of study treatment, baseline assessment may be omitted. 
f) 
To be performed predose and 0.5, 1, 2, 3, 5, 10, and 24 hours (predose on Day 2) postdose. 
g) To be performed predose. 
h) To be performed predose and 0.5, 1, 2, 3, 5, 10, and 24 hours (predose on Day 9) postdose on Day 8.  PK evaluation may be performed within +1 or +2 GD\VQRWí2 RUí1 days). 
i) 
To be performed within ±3 days. 
j) 
Tumor evaluation and tumor marker assessment will be performed every 8 weeks (on Day 1 [±7 days] of odd-numbered cycles) after Day 1 of Cycle 1, and more frequently if clinically indicated. 
k) Only in patients providing consent (optional). 
l) 
In Cycle 3 and subsequent cycles, test/observation may be omitted only if the investigator or subinvestigator considers the subject safe.  +RZHYHULIWKHEORRGSKRVSKRUXVOHYHOLV7.1 mg/dL on 
Day 1 or Day 15, blood phosphorus levels should be measured to evaluate hyperphosphatemia. 
m) To be performed on Day 1 (±3 days) of Cycle 2.  To be performed every 8 weeks (on Day 1 [±3 days] of even-numbered cycles) thereafter. 
n) To be performed in odd-numbered cycles after Cycle 3. 
o) To be obtained during the study period whenever possible. 
p) Any available data obtained within 7 days before discontinuation may be used as data at discontinuation. 
q) Any available data obtained within 28 days before discontinuation may be used as data at discontinuation. 
r) 
If it is necessary to start a new anticancer agent immediately due to deterioration of the subject’s condition, the final observation may be performed before 30 days after the last dose of study 
treatment but must be performed before the start of the new anticancer agent. 
s) To be performed every 12 weeks (±2 weeks) after the time of discontinuation of study treatment. 
 

 
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9.5.3 
Appropriateness of Measurements 
All clinical assessments are standard measurements commonly used in studies of solid 
cancers. 
The tolerability and safety assessments to be performed in this study, including vital signs, 
ECGs, ECOG-PS, ophthalmology, physical examinations, laboratory tests (hematology, 
blood chemistry, urinalysis), and AEs, are standard evaluations to ensure subject safety. 
9.5.4 
Reporting of Serious Adverse Events, Pregnancy, and Events Associated 
with Special Situations 
9.5.4.1 
Reporting of Serious Adverse Events 
All SERIOUS ADVERSE EVENTS, regardless of their relationship to study treatment, must 
be reported on a completed SAE form by email or fax as soon as possible but no later than 24 
hours from the date the investigator becomes aware of the event.  However, any event 
resulting in death or life-threatening event should be reported immediately by telephone 
before completing an SAE form and reported to the sponsor within 1 business day using an 
SAE form (Appendix 11 or Uniform Format 12). 
All SAEs, regardless of causality assessment, occurring through the last visit must be 
collected.  All SAEs must be followed to resolution, or, if resolution is unlikely, to 
stabilization.  Although SAEs are followed to resolution, or, if resolution is unlikely, to 
stabilization, follow-up may be terminated on the basis of the medical judgment of the 
investigator or subinvestigator.  Any SAE judged by the investigator or subinvestigator to be 
possibly related to the study treatment (or any protocol-required procedure) should be 
reported to the sponsor regardless of the length of time that has passed since study 
completion. 
The detailed contact information for reporting of SAEs is provided in Appendix 3. 
It is very important that the SAE report form be filled out as completely as possible at the 
time of the initial report.  This includes the investigator’s assessment of causality. 
Any relevant follow-up information received on SAEs should be forwarded within 1 business 
day of its receipt.  If the relevant follow-up information changes the investigator’s 
assessment of causality, this should also be noted on the follow-up SAE form. 
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the sponsor. 
9.5.4.2 
Reporting of Pregnancy and Exposure to Study Drug Through Breastfeeding 
Any pregnancy in which the estimated date of conception is either before the last visit or 
within 30 days of last study treatment, or any exposure to study drug through breastfeeding 
during study treatment or within 30 days of last study treatment, must be reported. 

 
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If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported, regardless of the length of time that has passed since the exposure to 
study treatment. 
A congenital anomaly, death during perinatal period, an induced abortion, or a spontaneous 
abortion should be considered to be an SAE and reported in the same time frame and format 
as all other SAEs (see Section 9.5.4.1 “Reporting of Serious Adverse Events”). 
Pregnancies or exposure to study drug through breastfeeding must be reported by fax or 
email as soon as possible but no later than 1 business day from the date the investigator 
becomes aware of the information.  The contact information for the reporting of pregnancies 
and exposure to study drug through breastfeeding is provided in Appendix 3.  The Pregnancy 
Report Form (Appendix 12) must be used for reporting.  The investigator must follow all 
pregnancies to outcome, and it must be reported to the sponsor using the Pregnancy Outcome 
Form (Appendix 13) as soon as possible but no later than 1 business day from the date the 
investigator becomes aware of the outcome. 
A subject who becomes pregnant must be withdrawn from the study. 
9.5.4.3 
Reporting of Events Associated with Special Situations 
9.5.4.3.1 
Reporting of Adverse Events Associated with Study Drug Overdose, Misuse, 
Abuse, or Medication Error 
Adverse events associated with study drug overdose, misuse, abuse, and medication error 
refer to AEs associated with uses of the study drug (including the use by subjects themselves) 
outside of that specified by the protocol.  Overdose, misuse, abuse, and medication error are 
defined as follows: 
Overdose 
Accidental or intentional use of the study drug in an amount higher than the 
protocol-defined dose 
Misuse 
Intentional and inappropriate use of study drug not in accordance with the protocol 
Abuse 
Sporadic or persistent intentional excessive use of study drug accompanied by 
harmful physical or psychological effects 
Medication 
error 
Any unintentional event that causes or leads to inappropriate study drug use or 
subject harm while the study drug is in the control of site personnel or the subject 
 
All AEs associated with overdose, misuse, abuse, or medication errors should be captured on 
the Adverse Event CRF and also reported using the procedures detailed in Reporting of 
Serious Adverse Events (Section 9.5.4.1) even if the AEs do not meet serious criteria.  Abuse 
is always to be captured as an AE.  If the AE associated with an overdose, misuse, abuse, or 
medication error does not meet serious criteria, it must still be reported using the SAE form 
and in an expedited manner but should be noted as nonserious on the SAE form and the 
Adverse Event CRF. 

 
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9.5.4.4 
Expedited Reporting 
The sponsor must inform investigators, the head of the medical institution and regulatory 
authorities of reportable events, in compliance with applicable regulatory requirements, on an 
expedited basis (ie, within specific time frames).  For this reason, it is imperative that sites 
provide complete SAE information in the manner described in Reporting of Serious Adverse 
Events (Section 9.5.4.1). 
9.5.4.5 
Breaking the Blind 
Not applicable. 
9.5.4.6 
Regulatory Reporting of Adverse Events 
Adverse events will be reported by the sponsor or a third party acting on behalf of the 
sponsor to regulatory authorities in compliance with local and regional law and established 
guidance.  The format of these reports will be dictated by the local and regional 
requirements. 
9.5.5 Completion/Discontinuation of Subjects 
A subject may elect to discontinue the study at any time for any reason.  All subjects who 
discontinue the study are to complete the study’s early discontinuation procedures indicated 
in the Schedule of Procedures/Assessments (Table 13 and Table 14). 
The investigator or subinvestigator will promptly explain to the subject involved that the 
study will be discontinued for that subject and provide appropriate medical treatment and 
other necessary measures for the subject.  A subject who has ceased to return for visits will 
be followed up whenever possible by mail, phone, or other means. 
For a subject who discontinues early from the study, 1 of the primary reasons for study 
discontinuation will be recorded in the CRF.  In addition to the primary reason, the subject 
may indicate 1 or more secondary reasons for discontinuation. 
9.5.6 
Abuse or Diversion of Study Drug 
Not applicable. 
9.5.7 
Confirmation of Medical Care by Another Physician 
The investigator will instruct subjects to inform site personnel when they are planning to 
receive medical care by another physician.  At each visit, the investigator will ask the subject 
whether he/she has received medical care by another physician since the last visit or is 
planning to do so in the future.  When the subject is going to receive medical care by another 
physician, the investigator, with the consent of the subject, will inform the other physician 
that the subject is participating in the clinical study. 
 

 
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9.6 
Data Quality Assurance 
This study will be organized, performed, and reported in compliance with the protocol, 
SOPs, working practice documents, and applicable regulations and guidelines.  Site audits 
will be made periodically by the sponsor’s or the CRO’s qualified compliance auditing team, 
which is an independent function from the study team responsible for conduct of the study. 
9.6.1 
Data Collection 
Data required by the protocol will be collected on the CRFs.  As defined by GCP, the CRF is 
a printed, optical, or electronic document designed to record all of the protocol-required 
information to be reported to the sponsor on each study subject. 
Data collection on the CRF must follow the instructions described in the CRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the CRF.  The investigator must sign the completed CRF to attest to 
its accuracy, authenticity, and completeness. 
Completed, original CRFs are the sole property of the sponsor and should not be made 
available in any form to third parties without written permission from Eisai, except to those 
relevant parties designated by the sponsor or representatives of appropriate regulatory 
authorities. 
9.6.2 
Clinical Data Management 
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All 
data, both CRF and external data (eg, laboratory data), will be entered into a clinical system. 
9.7 
Statistical Methods 
All statistical analyses will be performed after the study is completed and the database is 
locked.  Statistical analyses will be performed using SAS software or other validated 
statistical software as required.  Details of the statistical analyses will be included in a 
separate statistical analysis plan (SAP). 
9.7.1 
Statistical and Analytical Plans 
The statistical analyses of this study data are described in this section.  Further details of the 
analytical plan will be provided in the SAP, which will be finalized before database lock. 
9.7.1.1 
Study Endpoints 
9.7.1.1.1 
Primary Endpoints 
x 
DLT (Part 1) 
x 
Safety endpoints (AEs, laboratory tests, vital signs, weight, 12-lead ECG, ECOG-PS, 
ophthalmology) 

 
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9.7.1.1.2 
Secondary Endpoints 
x 
PK parameters 
x 
Efficacy endpoints (best overall response [BOR], objective response rate [ORR], disease 
control rate [DCR], percent change from baseline in the sum of the diameters of tumor 
target lesions [if appropriate]) 
9.7.1.1.3 
Exploratory Endpoints 
x 
PD markers 
x 
PGx 
x 
Efficacy endpoints (progression-free survival [PFS], overall survival [OS]) 
9.7.1.2 
Definitions of Analysis Sets 
The DLT analysis set is the group of subjects completing treatment with E7090 in Cycle 0 
DQG&\FOHZLWKDFRPSOLDQFHUDWHRIDQGHYDOXDWHGIRU'/7DQGVXEMHFWV
experiencing DLT in Cycle 0 or Cycle 1 in Part 1.  This analysis set will be used to estimate 
the MTD in Part 1. 
The safety analysis set is the group of subjects receiving at least 1 dose of E7090. 
The efficacy analysis set is the group of subjects receiving at least 1 dose of E7090 with at 
least 1 tumor assessment at baseline and after administration.  This analysis set will be used 
for the interim assessment in Part 2. 
The PK analysis set is the group of subjects receiving at least 1 dose of E7090 with data from 
which at least 1 PK parameter can be calculated. 
The PD and PGx analysis set is the group of subjects receiving at least 1 dose of E7090 with 
at least 1 PD or PGx data. 
The inclusion/exclusion of each analysis set will be summarized for each group in Part 1, for 
each cohort in Part 2, for the combined groups in each part, and for all study groups 
combined. 
9.7.1.3 
Subject Disposition 
Subjects providing informed consent, registered subjects, screening failures, and reasons for 
screen failure will be presented.  Subjects treated, subjects not treated, subjects completing 
the study, subjects discontinuing the study, and reasons for study discontinuation will be 
presented.  Similarly, subjects completing study treatment, reasons for treatment completion, 
subjects discontinuing study treatment, and reasons for treatment discontinuation will be 
presented. 
In this study, subjects completing the study will be defined as those completing DLT 
assessment appropriately in Part 1 and those completing the early discontinuation procedures 
or final observation in Part 2.  Subjects completing study treatment will be defined as those 

 
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discontinuing study treatment due to disease progression or those continuing study treatment 
at the end of the study. 
9.7.1.4 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics for the safety analysis set will be summarized 
for each group in Part 1, for each cohort in Part 2, for the combined groups in each part, and 
for all study groups combined.  Continuous demographic and baseline variables include age 
and weight.  Categorical variables include sex, race, ethnicity, ECOG-PS, primary lesion site, 
presence or absence of prior treatment (surgical therapy, radiation therapy, anticancer 
therapy, other therapies), use or non-use of contact lenses, and presence or absence and type 
of FGF/FGFR genetic abnormalities (translocation, point mutation, amplification, other). 
9.7.1.5 
Prior and Concomitant Therapy 
All investigator terms for medications recorded in the CRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary (WHO DD).  The number 
(percentage) of subjects who took prior and concomitant medications will be summarized on 
the safety analysis set for each group in Part 1, for each cohort in Part 2, for the groups 
combined in each part, and for all study groups combined.  In addition, the number 
(percentage) of subjects who took prior and concomitant medications will be summarized by 
appropriate Anatomical Therapeutic Chemical (ATC) class showing treatment classes (when 
specifying relevant ATC classes, such as anatomical class, therapeutic class, pharmacologic 
class, and chemical class) and WHO DD preferred terms.  Prior medications will be defined 
as medications stopped before the first dose of the study drug.  Concomitant medications will 
be defined as medications that (1) started before the first dose of study drug and were 
continuing at the time of the first dose of study drug, or (2) started on or after the date of the 
first dose of study drug up to the last observation.  All prior medications and concomitant 
medications will be presented in subject data listings. 
9.7.1.6 
Efficacy Analyses 
Efficacy analyses will be performed using the efficacy analysis set. 
9.7.1.6.1 
Primary Efficacy Analysis 
No primary efficacy endpoint will be established because this study is a phase 1 study. 
Part 1 
On the basis of tumor assessments according to RECIST 1.1, the number and percentage of 
subjects with a BOR will be summarized for each group and overall.  The BOR includes 
complete response (CR), partial response (PR), stable disease (SD), progression of disease 
(PD), and not evaluable (NE).  In subjects with non-target lesions only, a BOR of non-
CR/non-PD will be categorized into SD, where SD must to be achieved beyond 7 weeks after 
the first dose.  In this study, CR and PR will require no confirmation based on the next 
response evaluation beyond 4 weeks. 

 
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Part 2 
Analysis results will be summarized for each cohort and for all cohorts combined. 
When there are 2 treatment groups, analysis results will be summarized for each treatment 
group and for all treatment groups combined. 
In addition to the analyses for Part 1, the number and proportion of subjects with ORR or 
DCR and their corresponding exact two-sided 95% confidence intervals will be calculated.  
ORR is defined as the proportion of subjects with a BOR of CR or PR.  DCR is defined as 
the proportion of subjects with a BOR of CR, PR, or SD. 
PFS and OS will also be summarized and plotted over time using the Kaplan-Meier method. 
PFS is defined as the time from the date of the first dose to the date of the first event (disease 
progression or death due to any cause, whichever comes first).  OS is defined as the time 
from the date of the first dose to the date of death due to any cause. 
When appropriate, a waterfall plot will be created for the percent change from baseline in the 
sum of the diameters of target lesions at the time of maximum tumor reduction after 
administration. 
When appropriate, changes over time in tumor markers will also be analyzed. 
9.7.1.6.2 
Secondary Efficacy Analyses 
Not applicable. 
9.7.1.6.3 
Exploratory Efficacy Analyses 
Not applicable. 
9.7.1.7 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses 
9.7.1.7.1 
Pharmacokinetic Analyses 
The PK analysis set will be used to summarize E7090 plasma concentrations and PK 
parameters and perform other PK analyses.  A non-compartmental analysis of plasma and 
urine E7090 concentrations will be performed to calculate PK parameters including Cmax, 
tmax, AUC, and renal clearance.  Detailed methods and results of the exploratory metabolite 
analysis will be provided in separately prepared analysis plan and report, and its results will 
not be included in the clinical study report. 
9.7.1.7.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses 
Pharmacodynamic and PGx analyses 
PD and PGx analyses will be performed using the PD and PGx analysis set.  Measurements 
of biomarkers (in blood and tumor tissue) and their percent changes will be evaluated 

 
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visually with the use of figures and tables.  If necessary, correlations of measurements of 
biomarkers and their percentage changes with the efficacy and safety of E7090 will be 
analyzed, or various exploratory analyses will be performed.  Results of other comprehensive 
analyses will not be included in the clinical study report. 
9.7.1.8 
Safety Analyses 
DLT analyses will be performed using the DLT analysis set.  Other safety analyses will be 
performed using the safety analysis set.  Descriptive statistics for safety data (number of 
subjects, mean, standard deviation, median, minimum, and maximum for continuous 
variables;  number and percentage of subjects for categorical variables) will be calculated on 
an “as treated” basis for each group in Part 1, for each cohort in Part 2, for all groups 
combined in each part, and for all study groups combined.  Safety variables include adverse 
events (AEs), clinical laboratory parameters, vital signs, transcutaneous arterial oxygen 
saturation, weight, 12-lead ECG, ECOG-PS, and ophthalmology.  For safety analyses, study 
Day 1 will be defined as the date of the first dose of study drug. 
9.7.1.8.1 
Extent of Exposure 
The number of treatment cycles, duration of treatment, total exposure person-time, number of 
doses given, total dosage given, strength of dose used, and dose ratio (actual dose/planned 
dose) will be summarized. 
9.7.1.8.2 
Adverse Events 
Analysis of DLTs 
The number (percentage) of subjects with DLTs in Part 1 will be calculated.  DLTs will also 
be tabulated by type.  In addition, estimated values based on the posterior distribution of 
Bayesian statistics will be presented. 
The MTD will be estimated on the basis of the DLTs and the method outlined in Section 
9.7.4. 
Analysis of Adverse Events 
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA).  AEs will be coded to the MedDRA lower level term (LLT) closest to the 
verbatim term.  The linked MedDRA preferred term (PT) and primary system organ class 
(SOC) are also captured in the database. 
A treatment-emergent adverse event (TEAE) is defined as an AE that emerges during 
treatment, having been absent at pretreatment (baseline) or: 
x 
Reemerges during treatment, having been present at pretreatment (baseline) but stopped 
before treatment, or 

 
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x 
Worsens in severity during treatment relative to the pretreatment state, when the AE is 
continuous. 
Only those AEs that are treatment-emergent will be included in summary tables.  All AEs, 
treatment-emergent or otherwise, will be presented in subject data listings. 
The incidence of TEAEs will be reported as the number (percentage) of subjects with TEAEs 
by SOC and PT.  A subject will be counted only once within an SOC and PT, even if the 
subject experienced more than 1 TEAE within a specific SOC and PT.  The number 
(percentage) of subjects with TEAEs will also be summarized by highest CTCAE v4.03 
grade. 
TEAEs possibly related to the study drug (ADRs) will be summarized by SOC and PT. 
ADRs include AEs judged to be causally related to the study drug.  In addition, the number 
(percentage) of subjects with ADRs will also be summarized by highest CTCAE v4.03 grade. 
The number (percentage) of subjects with TEAEs leading to death will be summarized by 
SOC and PT.  A subject data listing of all AEs leading to death will be provided. 
The number (percentage) of subjects with treatment-emergent serious adverse events (SAEs) 
will be summarized by SOC and PT.  A subject data listing of all SAEs will be provided. 
The numbers (percentages) of subjects with TEAEs leading to discontinuation from study 
drug, subjects with TEAEs leading to the dose reduction, and subjects with TEAEs leading to 
dose interruption will be summarized by SOC and PT.  Subject data listings of these AEs will 
be provided. 
9.7.1.8.3 
Laboratory Values 
Laboratory results will be summarized using Système International (SI) units.  For all 
continuous variables listed in Section 9.5.1.5.3, the measured value at and the change from 
baseline to each postbaseline time point will be calculated for each time point using 
descriptive statistics.  The number (percentage) of subjects for ordinal categorical variables 
will be summarized, and changes from baseline to each postbaseline time point will be 
reported using shift tables.  Percentages will be calculated on the basis of the number of 
subjects with both nonmissing baseline and relevant postbaseline results. 
The CTCAE grades at each evaluation time point and highest postdose grade will be 
summarized for those variables included in the classification according to CTCAE ver. 4.03.  
Changes in grade from baseline to each postbaseline time point will be reported using shift 
tables. 
Laboratory test results will be classified according to whether the value was below (L), 
within (N), or above (H) the laboratory parameter’s reference range and will be tabulated. 
Treatment-emergent markedly abnormal laboratory values (TEMAVs) seen postdose will be 
identified according to CTCAE ver. 4.03 as required. 

 
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9.7.1.8.4 
Vital Signs 
For vital signs parameters (systolic and diastolic BP, pulse, respiratory rate, and body 
temperature), transcutaneous arterial oxygen saturation, and weight, the measured value at 
and the change from baseline to each postbaseline time point will be calculated for each time 
point using descriptive statistics. 
9.7.1.8.5 
Electrocardiograms 
ECG assessments will be performed using the results obtained at each time point.  For ECG 
parameters, the measured value at and the change from baseline to each postbaseline time 
point will be calculated for each time point using descriptive statistics. 
Changes in ECG parameters from baseline to each time point will be classified as normal, 
abnormal not clinically significant, or abnormal clinically significant, and presented using 
shift tables. 
In addition, the number (percentage) of subjects with at least 1 postdose abnormal ECG 
result that falls under any of the following categories will be calculated: 
x 
Absolute QTcF interval prolongation >450 ms 
x 
Absolute QTcF interval prolongation >480 ms 
x 
Absolute QTcF interval prolongation >500 ms 
x 
QTC interval increases from baseline >30 ms 
x 
QTC interval increases from baseline >60 ms 
9.7.1.8.6 
Other Safety Analyses 
ECOG-PS 
The classification of ECOG-PS at each time point and the worst postdose classification of 
ECOG-PS will be summarized. 
Ophthalmology 
For the measured value of corneal epithelial thickness at each time point and its change from 
baseline, descriptive statistics for each time point will be calculated. 
9.7.2 
Determination of Sample Size 
The primary objective of this study is to evaluate the tolerability and safety of E7090. 
The sample size for Part 1 has been set to approximately 20 subjects, assuming the number of 
dose levels to be evaluated of 9 and a cohort size of 2 on the basis of the recommended 
sample size to reach the MTR in the mTPI design (Ji Y, et al., 2013).  When deemed 
necessary, the sample size may be adjusted, depending on the actual number of dose levels to 
be evaluated and the number of evaluable subjects for DLT. 

 
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The sample size for Part 2 has been set to approximately 10 subjects or 5 to 10 subjects per 
cohort, considering its feasibility, to allow further safety evaluation and preliminary 
antitumor effect evaluation. 
9.7.3 
Interim Analysis 
No interim analysis taking into consideration adjustment for type I and II errors will be 
performed in this study. 
In the gastric cancer cohort in Part 2, an interim efficacy evaluation will be performed, and if 
no responder is observed in 5 evaluable subjects, the cohort may discontinue further 
enrollment.  The duration of follow-up of subjects with continuous SD will be determined 
through discussion with the sponsor. 
This criterion is based on the posterior distribution of Bayesian statistics.  When a non-
informative beta prior distribution Beta (1,1) is used, the discontinuation criterion 
corresponds to the case where the probability of ORR being 40% or higher is less than 10% 
in the posterior distribution of the 5 subjects at the time of evaluation.  In cases other than the 
number of evaluable subjects established as the discontinuation criterion, if necessary, it will 
be acceptable to consider interim evaluations and discontinuation of enrollment based on the 
posterior distribution and criteria described above. 
The ORR threshold of 40% has been established as a beneficial effect size, taking the 
mechanism of action of E7090 into consideration. 
9.7.4 
Other Statistical/Analytical Issues 
Study Design 
The MTD of E7090 will be determined using the mTPI design (Ji Y, et al., 2010).  The mTPI 
design uses a beta/binomial hierarchical model in a Bayesian statistical framework to 
calculate the posterior probabilities of 3 intervals that reflect the relative distance between the 
target DLT rate of 25% and the DLT rate for each dose level. 
The decision rules for finding doses are based on the calculation of the unit probability mass 
(UPM) of the 3 intervals corresponding to 0% to 20% (underdosing), 20% to 30% (proper 
dosing), and 30% to 100% (overdosing) in terms of toxicity.  The UPM of each interval is 
defined as the probability of the interval divided by the length of the interval, and the interval 
with the largest UPM indicates the decision on the next dose level to be assigned:  dose 
escalation (E), staying at the current dose (S), and dose de-escalation (D). 
These dose assignment rules minimize the posterior expected loss in the Bayes’ rule when 
equal prior expected losses are used for E, S, and D in a decision-theoretic framework.  The 
decision rules for all dose assignment will be calculated in advance. 

 
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Determination of the MTD 
The MTD will be determined when the posterior probability of the DLT rate at the initial 
dose exceeding 25% exceeds 95% (ie, an unacceptable DLT rate exceeding the target DLT 
rate) or when a prespecified maximum sample size of approximately 20 subjects is reached.  
However, the maximum sample size will be adjusted as necessary according to the actual 
number of dose levels to be evaluated and the number of subjects evaluable for DLT.  In 
addition, if the Bayesian predictive probability of being S when another 10 subjects are 
added to a dose level is 80% or higher (ie, if it is highly likely that subsequent registered 
subjects will also be assigned to the dose level), subject registration may be closed early to 
determine the MTD. 
The MTD will be defined as the dose with the smallest difference between the target DLT 
rate of 25% and an estimated DLT rate at each dose among all the evaluated doses for which 
the posterior probability of the DLT rate exceeding 25% is 95% or lower.  The isotonically 
transformed posterior mean under a beta posterior distribution with non-informative beta 
prior distribution Beta (0.005, 0.005) will be used to determine the estimated DLT rate at 
each dose.  The pooled-adjacent-violators algorithm (PAVA) will be used to maintain the 
monotonic increase of the DLT rate with increasing dose level (Bartholomew, D, 1983). 
9.7.5 
Procedures for Revising the Statistical Analysis Plan 
If the SAP needs to be revised after the study starts, the sponsor will determine how the 
revision impacts the study and how the revision should be implemented.  The details of the 
revision will be documented and described in the clinical study report. 

 
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10 REFERENCE LIST 
Haugsten EM, Wiedlocha A, Olsnes S, Wesche J.  Roles of Fibroblast Growth Factor 
Receptors in Carcinogenesis.  Mol Cancer Res.  2010;8:1439-52. 
Turner N, Grose R.  Fibroblast growth factor signalling:  from development to cancer.  Nat 
Rev Cancer.  2010;10:116-29. 
Dieci MV, Arnedos M, Andre F, Soria JC.  Fibroblast growth factor receptor inhibitors as a 
cancer treatment:  from a biologic rationale to medical perspectives.  Cancer Discov.  
2013;3:264-79. 
Kim HR, Kim DJ, Kang DR, Lee JG, Lim SM, Lee CY, et al.  Fibroblast growth factor 
receptor 1 gene amplification is associated with poor survival and cigarette smoking dosage 
in patients with resected squamous cell lung cancer.  J Clin Oncol.  2013;31:731-7. 
Jung EJ, Jung EJ, Min SY, Kim MA, Kim WH.  Fibroblast growth factor receptor 2 gene 
amplification status and its clinicopathologic significance in gastric carcinoma.  Hum Pathol.  
2012;43:1559-66. 
Byron SA, Gartside M, Powell MA, Wellens CL, Gao F, Mutch DG, et al.  FGFR2 point 
mutations in 466 endometrioid endometrial tumors:  relationship with MSI, KRAS, PIK3CA, 
CTNNB1 mutations and clinicopathological features.  PLoS One.  2012;7:e30801. 
Casanovas O, Hicklin DJ, Bergers G, Hanahan D.  Drug resistance by evasion of 
antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors.  Cancer 
Cell.  2005;8:299-309. 
Ji Y, Wang, S.  Modified Toxicity Probability Interval Design:  A Safer and More Reliable 
Method Than the 3 + 3 Design for Practical Phase I Trials.  J Clin Oncol.  2013;31:1785-91. 
Thall PF, Lee SJ.  Practical model-based dose-finding in phase I clinical trials:  methods 
based on toxicity.  Int J Gynecol Cancer.  2003;13:251-61. 
Iasonos A, Wilton AS, Riedel ER, Seshan VE, Spriggs DR.  A comprehensive comparison of 
the continual reassessment method to the standard 3+3 dose escalation scheme in Phase I 
dose-finding studies.  Clin Trials.  2008;5:465-77. 
Le Tourneau C, Lee JJ, Siu LL.  Dose escalation methods in phase I cancer clinical trials.  J 
Natl Cancer Inst.  2009;101:708-20. 
Ji Y, Liu P, Li Y, Bekele BN.  A modified toxicity probability interval method for dose-
finding trials.  Clin Trials.  2010;7:653-63. 
Simon R, Freidlin B, Rubinstein L, Arbuck SG, Collins J, Christian MC.  Accelerated 
titration designs for phase I clinical trials in oncology.  J Natl Cancer Inst.  1997;89:1138-47. 

 
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Arai Y, Totoki Y, Hosoda F, Shirota T, Hama N, Nakamura H, et al.  Fibroblast growth 
factor receptor 2 tyrosine kinase fusions define a unique molecular subtype of 
cholangiocarcinoma.  Hepatology.  2014;59:1427-34. 
Hidalgo M, Siu LL, Nemunaitis J, Rizzo J, Hammond LA, Takimoto C, et al.  Phase I and 
pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase 
inhibitor, in patients with advanced solid malignancies.  J Clin Oncol.  2001;19:3267-79. 
Strumberg D, Richly H, Hilger RA, Schleucher N, Korfee S, Tewes M, et al.  Phase I clinical 
and pharmacokinetic study of the Novel Raf kinase and vascular endothelial growth factor 
receptor inhibitor BAY 43-9006 in patients with advanced refractory solid tumors.  J Clin 
Oncol.  2005;23:965-72. 
Lacouture ME, Reilly LM, Gerami P, Guitart J.  Hand foot skin reaction in cancer patients 
treated with the multikinase inhibitors sorafenib and sunitinib.  Ann Oncol.  2008;19:1955-
61. 
Manchen E, Robert C, Porta C.  Management of tyrosine kinase inhibitor-induced hand-foot 
skin reaction:  viewpoints from the medical oncologist, dermatologist, and oncology nurse.  J 
Support Oncol.  2011;9:13-23. 
Bartholomew, D. Isotonic inference. In:  Samuel K, Norman LJ, editors.  Encyclopedia of 
Statistical Science volume 4, New York:  Wiley-Interscience.  1983;260-5. 
 

 
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11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE 
PROCEDURES) 
11.1 Changes to the Protocol 
Any change to the protocol requires a written protocol amendment or administrative change 
that must be approved by the sponsor before implementation.  Amendments specifically 
affecting the safety of subjects, the scope of the investigation, or the scientific quality of the 
study require additional approval by the applicable IRBs/IECs.  These requirements should in 
no way prevent any immediate action from being taken by the investigator, or by the sponsor, 
in the interest of preserving the safety of all subjects included in the study.  If the investigator 
determines that an immediate change to or deviation from the protocol is necessary for safety 
reasons to eliminate an immediate hazard to the subjects, the sponsor’s medical monitor and 
the IRB/IEC for the site must be notified immediately.  The sponsor must notify the health or 
regulatory authority as required per local regulations. 
Protocol amendments that affect only administrative aspects of the study may not require 
submission to health or regulatory authority or the IRB/IEC, but the head of the medical 
institution should be kept informed of such changes as required by local regulations.  In these 
cases, the sponsor may be required to send a letter to the IRB/IEC and the head of the 
medical institution detailing such changes. 
11.2 Adherence to the Protocol 
The investigator or subinvestigator will conduct the study in strict accordance with the 
protocol. 
11.3 Monitoring Procedures 
The sponsor’s/CRO’s CRA will maintain contact with the investigator and designated staff 
by telephone, letter, or email between study visits.  Monitoring visits to each site will be 
conducted by the assigned CRA as described in the monitoring plan.  The head of the 
medical institution will allow the CRA to inspect the clinical, laboratory, and pharmacy 
facilities to assure compliance with GCP and local regulatory requirements.  The CRFs and 
subject’s corresponding original medical records (source documents) are to be fully available 
for review by the sponsor’s representatives at regular intervals.  These reviews verify 
adherence to the study protocol and data accuracy in accordance with local regulations.  All 
records at the site are subject to inspection by the local auditing agency and to IRB/IEC 
review. 
In accordance with GCP, source documents include, but are not limited to, the following: 
x 
Clinic, office, or hospital charts 
x 
Copies or transcribed health care provider notes that have been certified for accuracy 
after production 
x 
Recorded data from automated instruments (eg, x-rays, sonograms, CT scans, MRI 
images, radioactive images, ECGs, EEGs, polysomnograms, pulmonary function tests) 

 
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regardless of how these images are stored, including microfiche and photographic 
negatives 
x 
Pain, quality of life, or medical history questionnaires completed by subjects 
x 
Records of telephone contacts 
x 
Diaries or evaluation checklists 
x 
Drug distribution and accountability logs maintained in pharmacies or by research 
personnel 
x 
Laboratory results and other laboratory test outputs (eg, urine pregnancy test results) 
x 
Correspondence regarding a study subject’s treatment between physicians or memoranda 
sent to the IRBs/IECs 
x 
CRF components (eg, questionnaires) that are completed directly by subjects and serve as 
their own source 
11.4 Recording of Data 
A CRF is required and must be completed for each subject by qualified and authorized 
personnel.  All data on the CRF must reflect the corresponding source document, except 
when a section of the CRF itself is used as the source document.  Any correction to entries 
made on the CRF must be documented in a valid audit trail where the correction is dated, the 
individual making the correct is identified, the reason for the change is stated, and the 
original data are not obscured.  Only data required by the protocol for the purposes of the 
study should be collected. 
The investigator must sign each CRF.  The investigator will report the CRFs to the sponsor 
and retain a copy of the CRFs. 
11.5 Identification of Source Data 
All data to be recorded on the CRF must reflect the corresponding source documents.  For 
the following items, the data recorded directly on the CRF are to be considered source data: 
x 
DMC:  Ethnicity, Race 
x 
ANTI-CAN:  Given As, Best response for procedure 
x 
PREV RADTHRPY:  Has Tumor Lesion at the Site Progressed Since Radiotherapy? 
x 
SCRN DISP:  Primary Reason for Discontinuation 
x 
FINAL/ET-TRT:  Did the subject complete study treatment as defined per protocol?, Are 
there any other reasons for discontinuation? 
x 
FINAL/ET-STUDY:  Primary reason for discontinuation from the study, Are there any 
other reasons for discontinuation? 
x 
SMED ORAL:  Dose Reason 
11.6 Retention of Records 
The circumstances of completion or termination of the study notwithstanding, the head of the 
medical institution is responsible for retaining all study documents, including but not limited 

 
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to the protocol, copies of CRFs, the Investigator’s Brochure, and regulatory agency 
registration documents, ICFs, and IRB/IEC correspondence).  The site should plan to retain 
study documents, as directed by the sponsor, for at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 3 years have elapsed since the formal 
discontinuation of clinical development of the investigational product.  It is requested that at 
the completion of the required retention period, or should the investigator retire or relocate, 
the investigator contact the sponsor, allowing the sponsor the option of permanently retaining 
the study records. 
11.7 Auditing Procedures and Inspection 
In addition to routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the sponsor’s 
SOPs to evaluate compliance with the principles of ICH GCP and all applicable local 
regulations.  If a government regulatory authority requests an inspection during the study or 
after its completion, the investigator must inform the sponsor immediately. 
11.8 Handling of Study Drug 
All study drug will be supplied to a designated pharmacist by the sponsor.  Drug supplies 
must be kept in an appropriate secure area (eg, locked cabinet) and stored according to the 
conditions specified on the drug labels.  The study drug manager must maintain an accurate 
record of the shipment and dispensing of the study drug in a drug accountability ledger, a 
copy of which must be given to the sponsor at the end of the study.  An accurate record of the 
date and amount of study drug dispensed to each subject must be available for inspection at 
any time.  The CRA will visit the site and review these documents along with all other study 
conduct documents at appropriate intervals once study drug has been received by the site. 
All drug supplies are to be used only for this study and not for any other purpose.  The study 
drug manager must not destroy any drug labels or any partly used or unused drug supply 
before approval to do so by the sponsor.  At the conclusion of the study and as appropriate 
during the study, the study drug manager will return all used and unused drug containers, 
drug labels, and a copy of the completed drug disposition form to the sponsor’s CRA. 
11.9 Publication of Results 
All manuscripts, abstracts, or other modes of presentation arising from the results of the 
study must be reviewed and approved in writing by the sponsor in advance of submission 
pursuant to the terms and conditions set forth in the executed Clinical Trial Agreement 
between the sponsor/CRO and the institution/investigator.  The review is aimed at protecting 
the sponsor’s proprietary information existing either at the date of the commencement of the 
study or generated during the study. 
The detailed obligations regarding the publication of any data, material results, or other 
information generated or created in relation to the study shall be set out in the agreement 
between each investigator and the sponsor or CRO, as appropriate. 

 
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11.10 Disclosure and Confidentiality 
The contents of this protocol and any amendments and results obtained during the study 
should be kept confidential by the investigator, the investigator’s staff, and the IRB/IEC and 
will not be disclosed in whole or in part to others, or used for any purpose other than 
reviewing or performing the study, without the written consent of the sponsor.  No data 
collected as part of this study will be used in any written work, including publications, 
without the written consent of the sponsor.  These obligations of confidentiality and non-use 
shall in no way diminish such obligations as set forth in either the Confidentiality Agreement 
or Clinical Trial Agreement executed between the sponsor/CRO and the 
institution/investigator. 
All persons assisting in the performance of this study must be bound by the obligations of 
confidentiality and non-use set forth in either the Confidentiality Agreement or Clinical Trial 
Agreement executed between the institution/investigator and the sponsor/CRO. 
11.11 Discontinuation of Study 
The sponsor reserves the right to discontinue the study for medical reasons or any other 
reason at any time.  If a study is prematurely terminated or suspended, the sponsor will 
promptly inform the investigators/institutions and regulatory authorities of the termination or 
suspension and the reason(s) for the termination or suspension.  The IRB/IEC will also be 
informed promptly and provided the reason(s) for the termination or suspension by the 
sponsor or by the investigator/institution, as specified by the applicable regulatory 
requirement(s). 
The investigator reserves the right to discontinue the study should his/her judgment so 
dictate. If the investigator terminates or suspends a study without prior agreement of the 
sponsor, the investigator should inform the institution where applicable, and the 
investigator/institution should promptly inform the sponsor and the IRB/IEC and provide the 
sponsor and the IRB/IEC with a detailed written explanation of the termination or 
suspension.  Study records must be retained as noted above. 
11.12 Subject Insurance and Indemnity 
The sponsor will provide insurance for any subjects participating in the study in accordance 
with all applicable guidelines and regulations. 

 
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12 APPENDICES 
Appendix 1: 
NYHA Classification 
Appendix 2: 
Drugs Affecting the Activity of Drug-Metabolizing Enzyme CYP3A 
Appendix 3: 
Study Administrative Structure 
Appendix 4: 
Dose Allocation according to the Modified Toxicity Probability Interval 
(mTPI) Design 
Appendix 5: 
Type, Packaging, and Labeling of Study Drug 
Appendix 6: 
Subject Registration Form 
Appendix 7: 
RECIST Criteria for Evaluation of Tumor Shrinkage Effect 
Appendix 8: 
Procedures for Collecting, Handling, and Shipping Samples for Drug 
Concentration Measurement 
Appendix 9: 
Procedures for Collecting, Handling, and Shipping Samples for 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses 
Appendix 10: ECOG Performance Status 
Appendix 11: Serious Adverse Event Report Form 
Appendix 12: Pregnancy Report Form 
Appendix 13: Pregnancy Outcome Report Form 
 

 
1 
 
A Phase 1 Study of E7090 in Subjects with Solid Tumor 
㸦Protocol Number: E7090-J081-101㸧 
 
Revision History 
 
 
Section 
Before Revision 
(Version 8.0, Date: 25 Oct 2017) 
After Revision 
(Version 9.0, Date: 13 Jul 2018) 
Reason for 
Revision 
2 
Number of Subjects 
Part 1 
20 subjects (planned) 
Part 2 
15 subjects (planned) (10 with gastric cancer and 5 with 
cholangiocarcinoma) 
Number of Subjects 
Part 1 
20 subjects (planned) 
Part 2 
15 to 20 subjects (planned) (10 with gastric cancer and 5 to 10 with 
cholangiocarcinoma) 
To increase 
subjects with 
cholangiocarcin
oma 
2 
The sample size for Part 2 has been set to approximately 10 subjects or 
5 subjects per cohort, considering its feasibility, to allow further safety 
evaluation and the preliminary antitumor effect evaluation. 
The sample size for Part 2 has been set to approximately 10 subjects or 
5 to 10 subjects per cohort, considering its feasibility, to allow further 
safety evaluation and the preliminary antitumor effect evaluation. 
The same as 
above 
9.3 
Approximately 20 subjects will be enrolled in Part 1.  Approximately 
10 subjects with gastric cancer confirmed to carry an amplified FGFR2 
gene or an overexpressed FGFR2 protein and approximately 5 subjects 
with cholangiocarcinoma confirmed to harbor FGFR2-fusion genes 
will be enrolled in Part 2.  Subjects who meet all of the inclusion 
criteria and none of the exclusion criteria will be eligible to take the 
study drug. 
Approximately 20 subjects will be enrolled in Part 1.  Approximately 
10 subjects with gastric cancer confirmed to carry an amplified FGFR2 
gene or an overexpressed FGFR2 protein and approximately 5 to 10 
subjects with cholangiocarcinoma confirmed to harbor FGFR2-fusion 
genes will be enrolled in Part 2.  Subjects who meet all of the 
inclusion criteria and none of the exclusion criteria will be eligible to 
take the study drug. 
The same as 
above 
9.7.2 
The sample size for Part 2 has been set to approximately 10 subjects or 
5 subjects per cohort, considering its feasibility, to allow further safety 
evaluation and preliminary antitumor effect evaluation. 
The sample size for Part 2 has been set to approximately 10 subjects or 
5 to 10 subjects per cohort, considering its feasibility, to allow further 
safety evaluation and preliminary antitumor effect evaluation. 
The same as 
above 
 

 
1 
 
A Phase 1 Study of E7090 in Subjects with Solid Tumor 
㸦Protocol Number: E7090-J081-101㸧 
 
Revision History 
 
25 Oct 2017 
Section 
Before Revision 
(Version 7.0, Date:  03 Jul 2017) 
After Revision 
(Version 8.0, Date:  25 Oct 2017) 
Reason for 
Revision 
9.3.1 
9.3.1 
Inclusion Criteria 
Patients with the following time intervals between prior therapy and 
study treatment in this study: 
… 
Supportive therapy 
Blood transfusions, blood products, hematopoietic factor products 
including granulocyte colony-stimulating factor (G-CSF) products:  
3 weeks 
9.3.1 
Inclusion Criteria 
Patients with the following time intervals between prior therapy and 
study treatment in this study: 
… 
Supportive therapy 
Blood transfusions, blood products, hematopoietic factor products 
including granulocyte colony-stimulating factor (G-CSF) products:  
2 weeks 
To reset the 
therapy 
duration based 
on the common 
criterion, 
considering the 
data in Part 1 
9.3.2 
9.3.2 Exclusion Criteria 
No corresponding criterion 
9.3.2 
Exclusion Criteria 
(8) Patients with active malignancy within 36 months before the start 
of study treatment (excluding the primary disease, and carcinomas in 
situ such as completely treated melanoma in situ, basal or squamous 
cell carcinoma of the skin, carcinoma in situ of the cervix, and early-
stage large bowel cancer) 
To accurately 
evaluate the 
preliminary 
efficacy in 
Part 2 
9.4.5 
 
9.4.5 
Method of Assigning Subjects to Treatment Groups 
[Part 2] 
After the investigator and the subinvestigator determine the eligibility 
of the patient through the screening test, the investigator, 
subinvestigator, or clinical study collaborator will promptly notify the 
sponsor by e-mail or fax of the eligibility/ineligibility determined by 
the screening test, the planned start date of study treatment (when the 
patient is eligible), and the planned date of baseline assessment (when 
the baseline assessment is performed separately). 
9.4.5 
Method of Assigning Subjects to Treatment Groups 
[Part 2] 
After the investigator and the subinvestigator determine the eligibility 
of the patient through the screening test, the investigator, 
subinvestigator, or clinical study collaborator will promptly document 
the eligibility/ineligibility determined by the screening test, the planned 
start date of study treatment (when the patient is eligible), and the 
planned date of baseline assessment (when the baseline assessment is 
performed separately) in the Subject Eligibility Confirmation Form 
(Appendix 6:  Part 2) and notify the sponsor by e-mail or fax. 
 
To clarify the 
operation 
management 
 

 
1 
 
A Phase 1 Study of E7090 in Subjects with Solid Tumor 
㸦Protocol Number: E7090-J081-101㸧 
 
Revision History 
 
03 Jul 2017 
Section 
Before Revision 
(Version 6.0, Date:  22 Apr 2016) 
After Revision 
(Version 7.0, Date:  03 Jul 2017) 
Reason for 
Revision 
2 
Site(s) 
Study sites:  1 site in Part 1, multiple sites in Part 2 (the number of 
sites undetermined) 
 
Site(s) 
Study sites:  1 site in Part 1, about 14 to 17 sites in Part 2 (planned) 
For updated 
information 
2 
Study Period and Phase of Development 
FPI:  November 2014 
LPI:  November 2017 (planned) 
Study Period and Phase of Development 
FPI:  November 2014 
LPI:  September 2018 (planned) 
For updated 
information 
2 
Study Design 
Part 2 will include patients with solid tumors carrying the FGF/FGFR 
genetic abnormalities (such as translocation, point mutation and 
amplification) (including patients with cholangiocarcinoma harboring 
FGFR2-fusion genes [such as FGFR2-AHCYL1 translocation and 
FGFR2-BICC1 translocation]). 
 
Study Design 
Part 2 will include patients with gastric cancer carrying the FGFR2 
gene amplification or FGFR2 protein overexpression and patients with 
cholangiocarcinoma harboring FGFR2-fusion genes among patients 
with solid tumors. 
To clarify 
targeted patients 
2 
Study Design Overview 
Part 2 will include patients with solid tumors carrying the FGF/FGFR 
genetic abnormalities (cholangiocarcinoma and others). 
Study Design Overview 
Part 2 will include patients with gastric cancer carrying FGFR2 gene 
amplification or protein overexpression, or patients with 
cholangiocarcinoma harboring FGFR2-fusion genes. 
 
To clarify 
targeted patients 
2 
9.1.2 
(2) Part 2:  Part 2 will include patients with solid tumors harboring 
FGF/FGFR gene abnormalities. 
Part 2 will consist of a pretreatment period, a treatment period, and a 
follow-up period. 
The pretreatment period consists of informed consent obtainment, 
screening, enrollment, and baseline assessment.   
In Part 2, 1 or 2 doses will be selected from the doses considered in 
Part 1.  Dose-selection will be made in consideration of efficacy, 
safety, pharmacokinetics and changes in pharmacodynamic markers, 
through discussion among the investigator, the sponsor and the medical 
expert (plus Data and Safety Monitoring member if necessary).  The 
effect of food on E7090 pharmacokinetics will be considered in 6 
patients (aim). A pharmacokinetic comparison will be carried out 
between the fasting state and the high fat-fed state of the same patients. 
The date for blood sampling will be determined after the review of 
(2) Part 2:  Part 2 will include patients with solid tumors, consisting 
of the following cohorts: 
Gastric cancer cohort:  Patients with gastric cancer carrying an 
amplified FGFR2 gene or overexpressed FGFR2 protein (including 
patients with gastroesophageal junction cancer diagnosed as 
adenocarcinoma) 
Cholangiocarcinoma cohort:  Patients with cholangiocarcinoma 
harboring FGFR2-fusion genes 
Part 2 will consist of a pretreatment period, a treatment period, and a 
follow-up period. 
The pretreatment period consists of Screening 1, Screening 2, and 
baseline assessment.  In Screening 1, each subject will be examined 
for FGFR genetic abnormalities in the tumor, and in Screening 2, each 
subject will be examined for the other eligibility criteria.  Separate 
written informed consent will be obtained before the start of Screening 
To clarify the 
screening 
method 
 
To delete the 
consideration of 
the food effect 

 
2 
 
Section 
Before Revision 
(Version 6.0, Date:  22 Apr 2016) 
After Revision 
(Version 7.0, Date:  03 Jul 2017) 
Reason for 
Revision 
pharmacokinetics in Part 1. 
1 and Screening 2.  Screening 1 will include gastric cancer patients 
with documented FGFR2 gene amplification and cholangiocarcinoma 
patients with documented FGFR2-fusion genes.  In addition, 
Screening 1 will also include any gastric cancer patient with an 
unknown FGFR2 amplification status who has an archived tumor 
sample available for the confirmation of FGFR2 protein expression.  
No biopsy should be performed at Screening 1 
In Screening 1, the following will be confirmed: 
• 
For patients with the documented genetic abnormalities mentioned 
above, the documents necessary for genetic testing will be submitted to 
the sponsor to confirm the presence of genetic abnormalities. 
• 
For gastric cancer patients with unknown genetic abnormalities 
who have an archived tumor sample available for the confirmation of 
the FGFR2 protein expression mentioned above, the archived tumor 
sample will be sent to the central laboratory to confirm the presence of 
FGFR2 protein overexpression with immunohistochemical staining. 
Patients considered eligible according to either of the criteria above are 
eligible to enter into Screening 2. 
Because no biopsy is permitted in Screening 1, adverse advents will be 
collected only after informed consent for Screening 2 is obtained.  
Patients meeting all of the inclusion criteria and not meeting any of the 
exclusion criteria in Screening 2 will be considered eligible for 
treatment, and study treatment will be started after baseline assessment.  
In Screening 2, a biopsy will be performed in all patients, other than 
those who have only a tumor lesion not amenable to biopsy for safety 
reasons.  The treatment period will consist of 28-day treatment cycles, 
and patients will take the study drug once daily continuously until any 
of the criteria in Section 9.3.3.1 “Discontinuation Criteria for 
Individual Subjects” is met.  The follow-up period will involve the 
early discontinuation procedures and the final observation. 
2 
Number of Subjects 
Part 2 
10 subjects per cohort (planned) 
Number of Subjects 
Part 2 
15 subjects (planned) (10 with gastric cancer and 5 with 
cholangiocarcinoma) 
 
To change the 
study design 
2 
9.3.1 
Inclusion Criteria (for both Part 1 and Part 2) 
(6) 
Patients with adequate major organ function 
1) +HPRJORELQ g/dL 
5) AST and ALT WLPHVWKH ULN 
 
Inclusion Criteria (for both Part 1 and Part 2) 
(6) 
Patients with adequate major organ function 
1) +HPRJORELQ g/dL ( g/dL in Part 2) 
5) AST and ALT .0 times the ULN (.0 times the ULN in the 
presence of intrahepatic bile duct cancer or liver metastases) 
To change the 
criteria, 
considering the 
targeted 
population and 

 
3 
 
Section 
Before Revision 
(Version 6.0, Date:  22 Apr 2016) 
After Revision 
(Version 7.0, Date:  03 Jul 2017) 
Reason for 
Revision 
(10) Patients expected to survive for 3 months or longer after 
registration 
 
(12) Women 
of 
childbearing 
potential 
must 
have 
practiced 
contraception since 28 days before registration, and …. 
 
Inclusion Criteria (for Part 2 only) 
(14) Patients with solid tumors harboring FGF/FGFR genetic 
abnormalities (such as amplification, point mutation and translocation) 
 
(10) Patients expected to survive for 3 months or longer after 
registration (Part 1) or the start of study treatment (Part 2) 
 
(12) Women of childbearing potential must have practiced 
contraception since 28 days before registration (Part 1) or 28 days 
before the start of study treatment (Part 2), and …. 
 
Inclusion Criteria (for Part 2 only) 
(14) Patients whose solid tumors have been confirmed to meet either 
of the following in Screening 1: 
1) Patients with gastric cancer carrying an amplified FGFR2 gene or 
an overexpressed FGFR2 protein (including patients with 
gastroesophageal junction cancer diagnosed as adenocarcinoma) 
2) Patients with cholangiocarcinoma harboring FGFR2-fusion genes 
(15) Patients with a target lesion that can be evaluated according to 
RECIST 1.1 
(16) Patients meeting both of the following criteria 1) and 2) 
concerning tumor sample submission: 
1) Patients agreeing to submit any tumor sample collected in the 
past 
2) Patients agreeing to submit any biopsy sample in Screening 2 
(excluding those who have only a tumor lesion not amenable to 
biopsy for safety reasons) 
 
the data in 
Part 1 
 
To clarify the 
criteria 
2 
9.3.2 
Exclusion Criteria 
(2) 
Patients with any of the following clinically significant 
cardiovascular disorders: 
2) Unstable angina pectoris or myocardial infarction within 6 
months before enrollment in this study 
(6) 
Patients with previous or concurrent *UDGHFRUQHDOGLVRUGHU 
(7) 
Patients in whom the adverse effects (except for alopecia) of 
prior treatment have not recovered to Grade 1 or lower 
(11) Patients unable to take drugs orally or with malabsorption 
syndrome 
Exclusion Criteria 
(2) 
Patients with any of the following clinically significant 
cardiovascular disorders: 
2) Unstable angina pectoris or myocardial infarction within 6 
months before enrollment in this study (Part 1) or within 6 
months before the start of study treatment (Part 2) 
(6) 
Patients with any of the following previous or concurrent corneal 
or retinal diseases: 
1) *UDGHFRUQHDOGLVRUGHU 
2) Active macular disease (eg, age-related macular degeneration, 
central serous chorioretinopathy) 
(7) 
Patients in whom the adverse effects of prior treatment have not 
recovered to Grade 1 or lower, except for alopecia and Grade 2 
To change the 
criteria, 
considering the 
targeted 
population and 
the data in 
Part 1 

 
4 
 
Section 
Before Revision 
(Version 6.0, Date:  22 Apr 2016) 
After Revision 
(Version 7.0, Date:  03 Jul 2017) 
Reason for 
Revision 
peripheral neuropathy 
(9) 
Patients with prior therapy targeting FGFR2 
(12) Patients unable to take drugs orally or with malabsorption 
syndrome (patients undergoing gastrectomy may be enrolled) 
2 
9.4 
9.4.2.2 
Study Treatment 
E7090 will be administered orally once daily.  Study drug consists of 
1, 1.5, 5, 20, and 60 mg capsules.  The initial dose will be 1 mg. 
Administration schedule 
(2) 
Part 2 
Subjects will take E7090 at least 2 hours after breakfast and will not 
eat anything for 1 hour after administration.  Study treatment may be 
continued unless any of the criteria in Section 9.3.3.1 “Discontinuation 
Criteria for Individual Subjects” is met. 
A pharmacokinetic comparison will be carried out between the fasting 
state and the high fat-fed state of the same patients, to review the effect 
of food on E7090 pharmacokinetics in 6 patients (aim).  When E7090 
is administered to subjects in the fasting state, the subjects will take 
E7090 in the fasting state on waking after an at least 10-hour overnight 
fast for PK evaluation.  Subjects will be prohibited from eating or 
drinking for 2 hours after administration, except for drinking water.  
When E7090 is administered to subjects in the high fat-fed state, the 
subjects will take E7090 within 30 minutes after starting to eat a high 
fat diet as a breakfast.  The dates for PK evaluation in the fasting state 
and in the high-fat fed state will be determined after PK evaluation in 
Part 1. 
 
Study Treatment 
E7090 will be administered orally once daily.  Study drug consists of 
1, 1.5, 5, 20, and 60 mg capsules (Part 1) and 35 mg tablets (Part 2).  
The initial dose in Part 1 will be 1 mg and the starting dose in Part 2 
will be 140 mg. 
Administration schedule 
(2) 
Part 2 
Subjects will take E7090 at least 2 hours after breakfast and will not 
eat anything for 1 hour after administration.  On Day 1 and Day 8 of 
Cycle 1, however, subjects will take E7090 in the fasting state on 
waking after an at least 10-hour overnight fast for PK evaluation.  
Subjects will be prohibited from eating or drinking for 2 hours after 
administration, except for drinking water.  Study treatment may be 
continued unless any of the criteria in Section 9.3.3.1 “Discontinuation 
Criteria for Individual Subjects” is met. 
To add tablets 
 
For updated 
information 
 
To delete 
consideration of 
food effect 
2 
9.4.2.2 
Methods of dose interruption and reduction 
(2) 
Part 2 
The criteria for dose interruption and reduction (dose and the possible 
number of dose reduction) will be determined after evaluation of safety 
data in Part 1. 
Methods of dose interruption and reduction 
(2) 
Part 2 
If any E7090-related toxicity or hyperphosphatemia is observed, the 
“Criteria for Dose Interruption/Reduction” and the “Criteria for Dose 
Interruption/Reduction Based on Hyperphosphatemia,” respectively, 
should be followed.  If study treatment is continued after the dose 
reduction, the dose will be reduced step-by-step to 105 mg, 70 mg, and 
then 35 mg. 
 
Criteria for Dose Interruption/Reduction 
E7090-related 
Management 
Dose after restart 
To set the data 
based on the 
data in Part 1 

 
5 
 
Section 
Before Revision 
(Version 6.0, Date:  22 Apr 2016) 
After Revision 
(Version 7.0, Date:  03 Jul 2017) 
Reason for 
Revision 
toxicity a 
Grade 1 or 
tolerable Grade 2 b 
Continue study treatment 
No change 
Intolerable Grade 
2 b or Grade 3 
Interrupt treatment until the 
toxicity resolves to Grade 0 
to 1 or baseline c 
Same dose or 1-level 
dose reduction 
Grade 4 d 
Discontinue study 
treatment 
NA 
a: Laboratory abnormalities not requiring treatment will be excluded. 
b: The tolerability of Grade 2 will be determined by the investigator 
or subinvestigator. 
c: When the investigator or subinvestigator considers interruption 
clinically acceptable, study treatment may be restarted also when 
the toxicity resolves to tolerable Grade 2. 
d: Any laboratory abnormality considered non-life-threatening will 
be excluded and managed as a Grade 3 event. 
 
 
2 
9.4.2.2 
Methods of dose interruption and reduction 
No corresponding description 
Methods of dose interruption and reduction 
Criteria for Dose Interruption/Reduction Based on Hyperphosphatemia 
Criteria 
Management 
Serum phospKDWHOHYHOLV5.5 mg/dL 
DQG7.0 mg/dL. 
Start treatment of 
hyperphosphatemia. 
Despite appropriate treatment of 
hyperphosphatemia,a serum phosphate 
OHYHOVDQG9.0 mgG/ODVWIRU2 
weeks,b or serum phosphate levels are 
9.1 mg/dL. 
Interrupt treatment until 
serum phosphate levels 
GHFUHDVHWR7.0 mg/dL and 
restart treatment at a 1-level 
dose reduction. 
a: This refers to treatments, such as diet therapy and 
hyperphosphatemia drugs, considered appropriate by the 
investigator or subinvestigator. 
b: Any subject with a serum pKRVSKDWHOHYHORImg/dL should 
visit the study site 1 week later and undergo measurement of serum 
phosphate levels for the evaluation of hyperphosphatemia. 
 
To set the data 
based on the 
data in Part 1 
2 
9.3.3.1 
Duration of Treatment 
Treatment with E7090 will be continued until any of the following 
discontinuation criteria is met. 
Discontinuation Criteria for Individual Subjects 
Duration of Treatment 
Treatment with E7090 will be continued until any of the following 
discontinuation criteria is met. 
Discontinuation Criteria for Individual Subjects 
To clarify the 
terms 
 
For updated 

 
6 
 
Section 
Before Revision 
(Version 6.0, Date:  22 Apr 2016) 
After Revision 
(Version 7.0, Date:  03 Jul 2017) 
Reason for 
Revision 
(2) 
Major inclusion/exclusion criteria violation after registration 
(6) 
Dose reduction to <1 mg required due to an adverse drug reaction 
(2) 
Major inclusion/exclusion criteria violation after registration 
(Part 1) or enrollment (Part 2) 
(6) 
Dose reduction to <1 mg (Part 1) or 35 mg (Part 2) required due 
to an adverse drug reaction 
information 
2 
9.4.9.2 
Concomitant Drug/Therapy 
Prohibited concomitant drugs/therapies 
(1) 
Cycle 0 and Cycle 1 (Part 1 only) 
1) Treatments, changes in dosage, and changes in drugs to prevent 
DLT occurrence 
(2) 
From the time of registration to the time of the discontinuation of 
study treatment 
1) Treatments for malignant tumors other than E7090 (eg, surgical 
therapy, chemotherapy, endocrine therapy, palliative 
radiotherapy, or immunotherapy) except for drugs for bone 
lesions (eg, bisphosphonates, anti-RANKL monoclonal 
antibodies) that have been used since before the registration in 
this study 
 
Concomitant Drug/Therapy 
Prohibited concomitant drugs/therapies 
(1) 
Cycle 0 and Cycle 1 (Part 1 only) 
1) Treatments, changes in dosage, and changes in drugs to prevent 
DLT occurrence 
(2) 
From the time of registration (Part 1) or the start of study 
treatment (Part 2) to the time of the discontinuation of study 
treatment 
1) Treatments for malignant tumors other than E7090 (eg, surgical 
therapy, chemotherapy, endocrine therapy, palliative 
radiotherapy, or immunotherapy) except for drugs for bone 
lesions (eg, bisphosphonates, anti-RANKL monoclonal 
antibodies) that have been used since before the registration in 
this study (Part 1) or the start of study treatment (Part 2) 
 
To clarify the 
terms 
2 
 
Assessments 
(1) 
Efficacy assessments 
Tumor assessment (target lesion, non-target lesion, presence/absence of 
new lesions) will be performed using RECIST 1.1.  Tumor markers 
will also be determined. 
Assessments 
(1) 
Efficacy assessments 
Tumor assessment (target lesion, non-target lesion, presence/absence of 
new lesions) will be performed using RECIST 1.1.  Tumor markers 
will also be determined.  Survival follow-up will be terminated 2 
years after the last subject’s registration (Part 2). 
 
To clarify the 
follow-up 
period 
2 
(3) 
PD and PGx assessments 
For 2) and 3) above, comprehensive genomic analysis will be 
performed to evaluate their correlation with the efficacy of E7090.  In 
addition, samples will be archived for the development of diagnostic 
agents. 
 
(3) 
PD and PGx assessments 
[Part 2] 
1) Blood 
Blood samples will be collected to determine the following 
biomarkers (but not limited to): 
(a) 
FGF23 
(b) 
1,25-(OH)2-Vitamin D 
(c) 
 
(d) 
Angiogenesis markers (eg, VEGF, FGF) 
(e) 
Circulating tumor DNA 
2) Archived tumor 
If any sample collected in the past is available, an archived tumor 
sample should be submitted (mandatory). 
To clarify the 
measurement 
items in Part 2 
CCI

 
7 
 
Section 
Before Revision 
(Version 6.0, Date:  22 Apr 2016) 
After Revision 
(Version 7.0, Date:  03 Jul 2017) 
Reason for 
Revision 
3) Biopsied tumor 
Except for subjects who have only a tumor lesion not amenable to 
biopsy for safety reasons, samples obtained from the biopsy 
performed in Screening 2 must be submitted (mandatory).  In 
addition, samples obtained from the biopsy performed on the 
15th day of Cycle 1 will be submitted (optional). 
For 2) and 3) above, immunohistochemical staining or 
comprehensive genomic analysis will be performed to evaluate 
their correlation with the efficacy of E7090.  In addition, 
samples will be archived for the development of diagnostic 
agents. 
 
2 
Bioanalytical Methods 
E7090 concentrations in plasma and urine and PD markers in blood 
will be determined using a validated method of measurement. 
Bioanalytical Methods 
Concentrations of E7090 and its metabolites in plasma and urine and 
PD markers in blood will be determined using a validated method of 
measurement. 
To clarify that 
the metabolites 
of E7090 will 
be measured as 
well 
2 
Analysis sets 
The efficacy analysis set is the group of subjects receiving at least 1 
dose of E7090 with at least 1 tumor assessment at baseline and after 
administration. 
Efficacy analyses 
Part 2:  In addition to the analyses similar to those for Part 1, ORR, 
DCR, and their exact two-sided 95% confidence intervals will be 
calculated. 
Analysis sets 
The efficacy analysis set is the group of subjects receiving at least 1 
dose of E7090 with at least 1 tumor assessment at baseline and after 
administration.  This analysis set will be used for the interim 
assessment in Part 2. 
Efficacy analyses 
Part 2:  Analysis results will be summarized for each cohort and 
overall.  In addition to the analyses similar to those for Part 1, ORR, 
DCR, and their exact two-sided 95% confidence intervals will be 
calculated. 
Changes based 
on the updated 
study design 
2 
9.7.3 
 
Interim Analyses 
No interim analysis is planned in this study. 
Interim Analyses 
No interim analysis taking into consideration adjustment for type I and 
II errors will be performed in this study. 
In the gastric cancer cohort in Part 2, an interim efficacy evaluation 
will be performed, and if no responder is observed in 5 evaluable 
subjects, the cohort may discontinue further enrollment.  The duration 
of follow-up of subjects with continuous SD will be determined 
through discussion with the sponsor. 
This criterion is based on the posterior distribution of Bayesian 
statistics.  When a non-informative beta prior distribution Beta (1,1) is 
used, the discontinuation criterion corresponds to the case where the 
probability of ORR being 40% or higher is less than 10% in the 
posterior distribution of the 5 subjects at the time of evaluation.  In 
To change the 
study design 

 
8 
 
Section 
Before Revision 
(Version 6.0, Date:  22 Apr 2016) 
After Revision 
(Version 7.0, Date:  03 Jul 2017) 
Reason for 
Revision 
cases other than the number of evaluable subjects established as the 
discontinuation criterion, if necessary, it will be acceptable to consider 
interim evaluations and discontinuation of enrollment based on the 
posterior distribution and criteria described above. 
The ORR threshold of 40% has been established as a beneficial effect 
size, taking the mechanism of action of E7090 into consideration. 
 
2 
9.7.2 
Sample Size Rationale 
The sample size for Part 2 has been set to approximately 10 subjects 
per cohort, to allow further safety evaluation and the preliminary 
antitumor effect evaluation. 
Sample Size Rationale 
The sample size for Part 2 has been set to approximately 10 subjects or 
5 subjects per cohort, considering its feasibility, to allow further safety 
evaluation and the preliminary antitumor effect evaluation. 
To change the 
study design 
5.3 
5.3 Subject Information and Informed Consent 
The ICF for genetic testing will be prepared separately from that for 
study participation, and genetic testing will be conducted in subjects 
who have consented to the testing.  Genetic testing involving the use 
of blood samples is required and subjects who do not consent to such 
testing cannot be included in this clinical study, whereas those who do 
not consent to genetic testing of tumor samples can still be eligible for 
this study. 
5.3 Subject Information and Informed Consent 
The ICF for genetic testing will be prepared separately from that for 
study participation, and genetic testing will be conducted in subjects 
who have consented to the testing.  In Part 1, genetic testing involving 
the use of blood samples is required and subjects who do not consent to 
such testing cannot be included in this clinical study, whereas those 
who do not consent to genetic testing of tumor samples can still be 
eligible for this study.  In Part 2, genetic testing involving the use of 
blood and tumor samples are required (tumor samples will not be 
obtained from subjects who cannot submit an archived tumor sample 
collected in the past or who are not amenable to biopsy). 
 
To change the 
study design 
6 
6. INVESTIGATORS AND STUDY PERSONNEL 
This study will be conducted by qualified investigators under the 
sponsorship of Eisai (the sponsor).  Part 1 will be conducted at 1 
medical institution in Japan. 
6. INVESTIGATORS AND STUDY PERSONNEL 
This study will be conducted by qualified investigators under the 
sponsorship of Eisai (the sponsor).  Part 1 will be conducted at 1 
medical institution in Japan, and Part 2 will be conducted at 
approximately 14 to 17 medical institutions (planned) in Japan. 
For updated 
information 
7.3.1 
7.3.1 Pharmacodynamics 
[Primary Pharmacodynamic Studies] 
In nude mouse models transplanted subcutaneously with SNU-16 and 
NCI-H1581, E7090 (6.25 to 50 mg/kg as E7090 succinate) given orally 
once daily for 14 days exhibited significant, dose-dependent antitumor 
effects, without decreasing body weight.  At 50 mg/kg, tumor growth 
was inhibited almost completely.
7.3.1 Pharmacodynamics 
[Primary Pharmacodynamic Studies] 
In nude mouse models transplanted subcutaneously with SNU-16 and 
NCI-H1581, E7090 (6.25 to 50 mg/kg as E7090 succinate) given orally 
once daily for 14 days exhibited significant, dose-dependent antitumor 
effects, without decreasing body weight.  At 50 mg/kg, tumor growth 
was inhibited almost completely.
In nude mouse models transplanted subcutaneously with 
cholangiocarcinoma derived from patients with the FGFR2-BICC1 
fusion gene, E7090 (5 to 50 mg/kg as E7090 succinate) given orally 
once daily for 15 days exhibited significant antitumor effects at 15 
mg/kg or higher.  At 50 mg/kg, tumor reduction was observed. 
For updated 
information 

 
9 
 
Section 
Before Revision 
(Version 6.0, Date:  22 Apr 2016) 
After Revision 
(Version 7.0, Date:  03 Jul 2017) 
Reason for 
Revision 
 
7.4 
No corresponding description 
7.4 
Clinical Experience 
As of 28 March 2017, 24 patients (2 each in the 1, 2, 4, 8, 16, and 30 
mg groups and 3 each in the 60, 100, 140, and 180 mg groups) have 
been enrolled in Part 1 of this study.  Commonly reported adverse 
events (20% across the groups) included hyperphosphatemia (37.5%);  
increased blood creatinine and nausea (33.3% each);  diarrhea 
(29.2%);  increased ALT and fatigue (25.0% each);  and 
constipation, increased lipase, pyrexia, and tumor pain (20.8% each).  
Reported Grade 3 adverse events included increased ALT (2 subjects 
in the 180 mg group), increased AST (1 subject in the 180 mg group), 
decreased appetite (1 subject in the 180 mg group), decreased 
neutrophil count (1 subject in the 180 mg group), vomiting (1 subject 
in the 180 mg group), and decreased lymphocyte count (1 subject in 
the 60 mg group), all of which were Grade 3 in severity.  DLTs 
(Grade 3 increased AST and increased ALT) occurred in 1 subject in 
the 180 mg group.  Three serious adverse events were reported in 2 
subjects in the 8 mg group (cancer pain and dyspnea each in 1 subject) 
and 1 subject in the 30 mg group (pyrexia), all of which were assessed 
as unrelated to study treatment.  No adverse events led to death or 
treatment discontinuation. 
 
For updated 
information 
7.5.1.3 
No corresponding description 
7.5.1.3 Rationale for the Starting Dose for Part 2 
On the basis of the data from Part 1, the starting dose for Part 2 has 
been set at 140 mg.  In Part 1, patients were enrolled in the following 
order:  1 mg (n = 2), 2 mg (n = 2), 4 mg (n = 2), 8 mg (n = 2), 16 mg 
(n = 2), 30 mg (n = 2), 60 mg (n = 3), 100 mg (n = 3), 180 mg (n = 3), 
and 140 mg (n = 3).  Because a DLT was observed in 1 subject in the 
180-mg cohort (Grade 3 increased AST/ALT) and no DLT was 
observed in the 140-mg cohort, 140 mg has been selected as the 
recommended dose for Part 2. 
 
For updated 
information 
7.5.1.8 
7.5.1.8 Rationale for Including Patients with Solid Tumors 
Harboring FGF/FGFR Genetic Abnomalities 
Although E7090 is expected to be effective by targeting genetic 
abnormalities strongly contributing to FGF/FGFR signal activation, it 
is not easy to make an accurate prediction of its contribution level. 
There are many kinds of genetic abnormalities including translocation, 
point mutation, amplification.  It was reported that there were some 
cases in which the contribution level of the same genetic abnormality 
7.5.1.8 Rationale for Including Patients with Gastric Cancer 
Carrying 
an 
Amplified 
FGFR2 
Gene 
or 
an 
Overexpressed FGFR2 Protein and Patients with 
Cholangiocarcinoma 
Harboring 
FGFR2-Fusion 
Genes in Part 2 
Given that responses were achieved in patients with gastric cancer 
carrying an amplified FGFR2 gene in Part 1 of this study, gastric 
cancer carrying an amplified FGFR2 gene or an overexpressed FGFR2 
For updated 
information 

 
10 
 
Section 
Before Revision 
(Version 6.0, Date:  22 Apr 2016) 
After Revision 
(Version 7.0, Date:  03 Jul 2017) 
Reason for 
Revision 
differed dependent on the cancer type (Dienstmann R1, etc., 2014).  
Therefore, it is reasonable to include patients with solid tumors 
harboring FGF/FGFR genetic abnormalities, to search for cancer type 
or genetic abnormalities for which E7090 seems to be effective. 
A Japanese research group recently identified an in-frame fusion 
transcript (FGFR2 fusion gene) involving FGFR2 and other genes 
(BICC1 gene or AHCYL1 gene) in cholangiocarcinoma (Arai Y1, et 
al., 2014), suggesting that it may be a promising target for FGFR 
inhibitors.  Therefore, cholangiocarcinoma harboring FGFR2-fusion 
genes is expected to be a promising target for E7090.
protein is expected to be a promising target for E7090. 
In addition, a Japanese research group recently identified an in-frame 
fusion transcript (FGFR2 fusion gene) involving FGFR2 and other 
genes (BICC1 gene or AHCYL1 gene) in cholangiocarcinoma (Arai 
Y1, et al., 2014), suggesting that it may be a promising target for 
FGFR inhibitors.  Therefore, cholangiocarcinoma harboring FGFR2-
fusion genes is expected to be a promising target for E7090. 
7.5.2 
7.5.2 Methods of Evaluating Adverse Drug Reactions 
Expected from Nonclinical Toxicity Studies 
[Evaluation of mineralization] 
Since mineralization is induced by the deposition of phosphate 
combined with calcium in the blood, it is important to evaluate and 
control serum phosphate levels.  In this study, it is stipulated that 
serum phosphate levels must be measured at study visits and that high 
phosphate levels will be managed in a medically proper manner. 
 
[Evaluation of thinning of the corneal epithelium] 
Serious corneal thinning could greatly reduce the patient’s QOL, 
therefore requiring special attention.  In Part 1, the dose-escalation 
part of this study, to rigorously evaluate the effect of E7090 on the 
eyes, the ophthalmologist at each study site participated in the study as 
a subinvestigator and performed the following tests on prespecified 
evaluation days:  visual acuity, funduscopy (mydriatic test when 
necessary), slit-lamp examination (fluorescein staining when 
necessary), and anterior segment optical coherence tomography (OCT) 
to evaluate the corneal epithelium.  After the review of clinical 
findings for each test, the necessity for each test in Part 2 will be 
reconsidered. 
7.5.2 Methods of Evaluating Adverse Drug Reactions 
Expected from Nonclinical Toxicity Studies 
[Evaluation of mineralization] 
Since mineralization is induced by the deposition of phosphate 
combined with calcium in the blood, it is important to evaluate and 
control serum phosphate levels.  In this study, it is stipulated that 
serum phosphate levels must be measured at study visits and that high 
phosphate levels will be managed in accordance with the criteria for 
dose interruption/reduction shown in Table 6. 
 
[Evaluation of thinning of the corneal epithelium] 
Serious corneal thinning could greatly reduce the patient’s QOL, 
therefore requiring special attention.  In Part 1, the dose-escalation 
part of this study, to rigorously evaluate the effect of E7090 on the 
eyes, the ophthalmologist at each study site participated in the study as 
a subinvestigator and performed the following tests on prespecified 
evaluation days:  visual acuity, funduscopy (mydriatic test when 
necessary), slit-lamp examination (fluorescein staining when 
necessary), and anterior segment optical coherence tomography (OCT) 
to evaluate the corneal epithelium. 
In Part 1, prespecified tests have revealed no significant thinning of the 
corneal epithelium, but Grade 1 retinal adverse events were observed.  
In Part 2, taking these findings into consideration, anterior segment 
OCT will be replaced by posterior segment OCT to evaluate the retina.  
More specifically, visual acuity, funduscopy (mydriatic test when 
necessary), slit-lamp examination (fluorescein staining when 
necessary), and posterior segment OCT to evaluate the retina will be 
performed on prespecified evaluation days in Part 2. 
To update the 
method of 
evaluation 
based on the 
data in Part 1 
9.1 
 
9.1 Overall Study Design and Plan 
No corresponding description 
9.1 Overall Study Design and Plan 
Part 2 will include patients with solid tumors, consisting of a gastric 
To clarify the 
targeted patients 

 
11 
 
Section 
Before Revision 
(Version 6.0, Date:  22 Apr 2016) 
After Revision 
(Version 7.0, Date:  03 Jul 2017) 
Reason for 
Revision 
cancer cohort and a cholangiocarcinoma cohort. 
 
9.3 
9.3 Selection of Study Population 
Approximately 20 subjects will be enrolled in Part 1.  Approximately 
10 subjects will be enrolled per dose cohort in Part 2.  In other words, 
selection of 1 dose in Part 1 will lead to approximately 10 subjects, 
while selection of 2 doses will lead to approximately 20 subjects.  
Subjects who meet all of the inclusion criteria and none of the 
exclusion criteria will be eligible to take the study drug. 
9.3 Selection of Study Population 
Approximately 20 subjects will be enrolled in Part 1.  Approximately 
10 subjects with gastric cancer confirmed to carry an amplified FGFR2 
gene or an overexpressed FGFR2 protein and approximately 5 subjects 
with cholangiocarcinoma confirmed to harbor FGFR2-fusion genes 
will be enrolled in Part 2.  Subjects who meet all of the inclusion 
criteria and none of the exclusion criteria will be eligible to take the 
study drug. 
To change the 
study design 
9.4.5 
9.4.5 Method of Assigning Subjects to Treatment Groups 
This is an open-label study.  All subjects who provide signed 
informed consent to participate in this study and satisfy all eligibility 
requirements (see Section 9.3) will be assigned to take E7090.  There 
is no randomization in this study.  The subject registration procedure 
is shown in Figure 6. 
9.4.5 Method of Assigning Subjects to Treatment Groups 
This is an open-label study.  All subjects who provide signed 
informed consent to participate in this study and satisfy all eligibility 
requirements (see Section 9.3) will be assigned to take E7090.  There 
is no randomization in this study.  The subject registration procedure 
is shown in Figure 6 (Part 1) and Figure 7 (Part 2). 
For updated 
information 
9.4.5 
9.4.5 Method of Assigning Subjects to Treatment Groups 
No corresponding description 
9.4.5 Method of Assigning Subjects to Treatment Groups 
 
[Part 2] 
(1) 
The investigator, subinvestigator, or clinical study collaborator 
will assign a sponsor-specified subject ID number to each patient 
providing written informed consent for Screening 1 and 
document this information in the Subject Screening Log. 
(2) 
For a patient known to have FGF/FGFR genetic abnormality, the 
investigator, subinvestigator, or clinical study collaborator will 
submit necessary documents about the genetic abnormality to the 
sponsor.  The sponsor will check the documents about the 
genetic abnormality and notify the investigator, subinvestigator, 
or clinical study collaborator of the patient’s 
eligibility/ineligibility by e-mail or fax. 
(3) 
If it is not known whether a gastric cancer patient has a 
FGF/FGFR genetic abnormality, the investigator, subinvestigator, 
or clinical study collaborator will submit an archived sample to 
the central laboratory.  The central laboratory will report the 
result of genetic abnormality test to the sponsor and the study 
site.  The patient will be determined to be eligible for Screening 
1 if the test result is positive and ineligible for Screening 1 if the 
test result is negative. 
(4) 
The investigator, subinvestigator, or clinical study collaborator 
will enter the result of the patient’s eligibility for Screening 1 in 
For updated 
information 

 
12 
 
Section 
Before Revision 
(Version 6.0, Date:  22 Apr 2016) 
After Revision 
(Version 7.0, Date:  03 Jul 2017) 
Reason for 
Revision 
the Subject Screening Log, and patients who are determined to be 
eligible will go to the procedure for Screening 2. 
(5) 
The investigator or subinvestigator will screen the patient 
providing written informed consent for Screening 2 and 
determine his/her eligibility according to the inclusion/exclusion 
criteria.  The investigator, subinvestigator, or clinical study 
collaborator will document the result of eligibility determination 
in the Subject Screening Log. 
(6) 
After the investigator and the subinvestigator determine the 
eligibility of the patient through the screening test, the 
investigator, subinvestigator, or clinical study collaborator will 
promptly notify the sponsor by e-mail or fax of the 
eligibility/ineligibility determined by the screening test, the 
planned start date of study treatment (when the patient is 
eligible), and the planned date of baseline assessment (when the 
baseline assessment is performed separately). 
(7) 
The investigator or subinvestigator will check the result of the 
baseline assessment against the inclusion/exclusion criteria to 
determine the eligibility of the patient again, and document the 
result of eligibility determination in the Subject Screening Log.  
After confirmation of his/her eligibility, the patient will start 
study treatment. 
9.4.5 
No corresponding description 
Figure 7 Subject Enrollment Procedure (Part 2) was added. 
For updated 
information 
9.4.6 
9.4.6 Selection of Doses in the Study 
The appropriateness of selection of the doses is justified in Section 
7.5.1 “Rationale for the Study Design” and Section 7.5.1.2 “Rationale 
for the Initial Dose.” 
9.4.6 Selection of Doses in the Study 
The appropriateness of selection of the doses for Part 1 and Part 2 of 
this study is justified in Section 7.5.1 “Rationale for the Study Design,” 
Section 7.5.1.2 “Rationale for the Initial Dose for Part 1,” and Section 
7.5.1.3 “Rationale for the Starting Dose for Part 2.” 
For updated 
information 
9.4.9 
 
9.4.9 Prior and Concomitant Therapy 
All concomitant therapies used after the time of informed consent until 
the date of final observation will be recorded in the CRF. 
9.4.9 Prior and Concomitant Therapy 
All concomitant therapies used after the time of informed consent 
(after the time of informed consent for Screening 2 in Part 2) until the 
date of final observation will be recorded in the CRF. 
To clarify the 
statement 
9.5.1.1 
9.5.1.1 
Demographic Assessments 
The investigator, subinvestigator, or clinical study collaborator will 
assess each patient providing written informed consent for necessary 
information to confirm the inclusion and exclusion criteria, and 
document this information in the Subject Registration Form.  The 
investigator, subinvestigator, or clinical study collaborator will also 
assess each patient providing written informed consent for the 
9.5.1.1 
Demographic Assessments 
The investigator, subinvestigator, or clinical study collaborator will 
assess each patient providing written informed consent for necessary 
information to confirm the inclusion and exclusion criteria, and 
document this information in the Subject Registration Form (Part 1) 
and the Subject Eligibility Confirmation Form (Part 2).  The 
investigator, subinvestigator, or clinical study collaborator will also 
To clarify the 
statement 

 
13 
 
Section 
Before Revision 
(Version 6.0, Date:  22 Apr 2016) 
After Revision 
(Version 7.0, Date:  03 Jul 2017) 
Reason for 
Revision 
following subject demography information, and document the 
information in the CRF.  For any information already assessed during 
the confirmation of the inclusion and exclusion criteria, the 
investigator, subinvestigator, or clinical study collaborator may enter 
the data entered in the Subject Registration Form in the CRF, instead 
of assessing such information again. 
assess each patient providing written informed consent for the 
following subject demography information, and document the 
information in the CRF.  For any information already assessed during 
the confirmation of the inclusion and exclusion criteria, the 
investigator, subinvestigator, or clinical study collaborator may enter 
the data entered in the Subject Registration Form (Part 1) and the 
Subject Eligibility Confirmation Form (Part 2) in the CRF, instead of 
assessing such information again. 
9.5.1.2.2 
9.5.1.2.2 Other Pretreatment Assessments Specific to the 
Study or Target Disease 
(1) 
For subjects with tumors harboring FGF/FGFR genetic 
abnormality, the following information will be recorded in the 
CRF: 
1) 
Type of FGF/FGFR genetic abnormality (translocation, point 
mutation, amplification, other) 
2) 
Diagnostic method for FGF/FGFR genetic abnormality (FISH, 
immunostaining, RT-PCR, NGS, other) 
3) 
Date of the sample collected for FGF/FGFR genetic 
abnormality 
4) 
Date of FGF/FGFR genetic abnormality test 
9.5.1.2.2 Other Pretreatment Assessments Specific to the 
Study or Target Disease 
(1) 
For subjects with tumors harboring FGF/FGFR genetic 
abnormality (Part 1) and all subjects entering Screening 2 (Part 
2), the following information will be recorded in the CRF: 
1) Type of FGF/FGFR genetic abnormality (translocation, point 
mutation, amplification, other) 
2) Diagnostic method for FGF/FGFR genetic abnormality (FISH, 
immunostaining, RT-PCR, NGS, other) 
3) Site of the sample tested for FGF/FGFR genetic abnormality and 
date of the sample collected 
4) Date of FGF/FGFR genetic abnormality test 
5) Status of FGF/FGFR protein expression 
To clarify the 
statement 
 
For updated 
information 
9.5.1.3.1 
9.5.1.3.1 Assessment of Tumor Lesions 
Chest X-rays will not be used to assess target lesions. 
Assessment methods for each site are as follows: 
z Brain:  CT or MRI 
9.5.1.3.1 Assessment of Tumor Lesions 
Chest X-rays will not be used to assess target lesions. 
Assessment methods for each site are as follows: 
z Head:  CT or MRI 
Correction in 
view of 
consistency of 
the term 
9.5.1.3.3 
No corresponding description 
9.5.1.3.3 Survival Follow-up 
Subjects will be followed for survival every 12 weeks (±2 weeks) from 
the time of study treatment discontinuation.  Follow-up is to be 
continued until the confirmation of death.  For any antitumor therapy, 
which is known as of the assessment to be provided for the subject 
after completion of study treatment, its start date and end date will be 
recorded.  Survival follow-up will be terminated 2 years after the last 
subject’s registration (Part 2). 
To clarify the 
method of 
survival follow-
up 
9.5.1.4.1 
9.5.1.4.1 Pharmacokinetic Assessments 
(1) 
Plasma concentration measurement 
Blood samples will be collected at the time points shown in Table 8 
9.5.1.4.1 Pharmacokinetic Assessments 
(1) 
Plasma concentration measurement 
Blood samples will be collected at the time points shown in Table 8 
To clarify that 
the metabolite 
of E7090 will 

 
14 
 
Section 
Before Revision 
(Version 6.0, Date:  22 Apr 2016) 
After Revision 
(Version 7.0, Date:  03 Jul 2017) 
Reason for 
Revision 
(Part 1) and Table 9 (Part 2), and the plasma concentrations of E7090 
will be determined using a validated LC-MS/MS method. 
(Part 1) and Table 9 (Part 2), and the plasma concentrations of E7090 
and its active metabolite, E7090-M2, will be determined using a 
validated LC-MS/MS method.
be measured. 
9.5.1.4.1 
 
Table 9 Blood Sampling Schedule for PK Evaluation (Part 
2) 
Cycle 
Sampling day 
Sampling 
time 
point 
Allowable 
sampling 
time 
interval 
Blood 
samplin
g 
volume 
Cycle 1 
Day 1 
Predose 
:LWKLQí60 
minutes 
2 mL at 
each 
time 
point 
Day 8 
Predose 
:LWKLQí60 
minutes 
Day 15 
Predose 
:LWKLQí60 
minutes 
Date 
undetermineda) 
(in the fasting 
condition) 
Predose 
WithLQí60 
minutes 
30 
minutes 
postdose 
Within ±10 
minutes 
1 hour 
postdose 
Within ±10 
minutes 
2 hours 
postdose 
Within ±10 
minutes 
3 hours 
postdose 
Within ±10 
minutes 
5 hours 
postdose 
Within ±10 
minutes 
10 hours 
postdose 
Within ±30 
minutes 
24 hours 
postdose 
Within ±60 
minutes 
Date 
undetermined 
Predose 
:LWKLQí60 
minutes 
Table 9 
Blood Sampling Schedule for PK Evaluation (Part 
2) 
Cycle 
Sampling day 
Sampling 
time point 
Allowable 
sampling 
time 
interval 
Blood 
sampling 
volume 
Cycle 1 
Day 1 
Predose 
Within 
í60 
minutes 
2 mL at 
each 
time 
point 
30 
minutes 
postdose 
Within 
±10 
minutes 
1 hour 
postdose 
Within 
±10 
minutes 
2 hours 
postdose 
Within 
±10 
minutes 
3 hours 
postdose 
Within 
±10 
minutes 
5 hours 
postdose 
Within 
±10 
minutes 
10 hours 
postdose 
Within 
±30 
minutes 
24 hours 
postdose 
(Predose 
on Day 2) 
Within 
í60 
minutes 
Day 8 
Predose 
Within 
í60 
minutes 
To update the 
measurement 
time points 
 
To delete 
consideration of 
food effect 

 
15 
 
Section 
Before Revision 
(Version 6.0, Date:  22 Apr 2016) 
After Revision 
(Version 7.0, Date:  03 Jul 2017) 
Reason for 
Revision 
a) (in the high 
fat-fed 
condition) 
30 
minutes 
postdose 
Within ±10 
minutes 
1 hour 
postdose 
Within ±10 
minutes 
2 hours 
postdose 
Within ±10 
minutes 
3 hours 
postdose 
Within ±10 
minutes 
5 hours 
postdose 
Within ±10 
minutes 
10 hours 
postdose 
Within ±30 
minutes 
24 hours 
postdose 
Within ±60 
minutes 
Cycle 2 
and 
subsequent 
cycles 
Day 1 
Predose 
Within í60 
minutes 
 
 
30 
minutes 
postdose 
Within 
±10 
minutes 
1 hour 
postdose 
Within 
±10 
minutes 
2 hours 
postdose 
Within 
±10 
minutes 
3 hours 
postdose 
Within 
±10 
minutes 
5 hours 
postdose 
Within 
±10 
minutes 
10 hours 
postdose 
Within 
±30 
minutes 
24 hours 
postdose 
(Predose 
on Day 9) 
Within 
í60 
minutes 
Day 15 
Predose 
Within 
í60 
minutes 
Cycle 2 and 
subsequent 
cycles 
Day 1 
Predose 
Within 
í60 
minutes 
 
 
9.5.1.4.2 
9.5.1.4.2 
Pharmacodynamic, 
Pharmacogenomic, 
and 
Other Biomarker Assessments 
No corresponding description 
9.5.1.4.2 Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Assessments 
[Part 2] 
(1) 
In blood samples 
Blood samples will be collected according to the procedures and 
methods shown in Table 11 to determine blood biomarkers.  For 
sampling time points, the actual time of blood sampling will be 
recorded in the CRF.  See Appendix 9 for a description of collection, 
handling, and shipping procedures of the samples. 
For updated 
information 

 
16 
 
Section 
Before Revision 
(Version 6.0, Date:  22 Apr 2016) 
After Revision 
(Version 7.0, Date:  03 Jul 2017) 
Reason for 
Revision 
The following measurements will be determined: 
1) 
FGF23 
2) 
1,25-(OH)2-Vitamin D 
3) 
 
4) 
Angiogenesis markers (eg, VEGF, FGF) 
5) 
Circulating tumor DNA 
 
Table 11 
Blood Sampling Schedule for PD and PGx 
Evaluations (Part 2) 
Cycle 
Samplin
g day 
Samplin
g time 
point 
Allowable 
sampling 
time 
interval 
Samp
ling 
volu
me 
Measur
ement 
At baseline 
Within 4 days after start of 
treatment 
15 
mL 
5) 
Cycle 1 
Day 1 
Predose 
Within 
í60 
minutes 
7 mL 
1) to 4) 
Day 8 
Predose 
Within 
í60 
minutes 
7 mL 
Day 15 
Predose 
Within 
í60 
minutes 
7 mL 
Odd-
numbered 
cycles 
(Cycle 3 
and 
subsequent 
cycles) 
Day 1 
Predose 
Within 
í60 
minutes 
10 
mL 
5) 
 
 
9.5.1.4.2 
9.5.1.4.2 Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Assessments 
(2) 
In archived tumor samples 
If any sample collected in the past is available, an archived tumor 
sample should be submitted (mandatory).  If known, the date of 
sample collection and the organ from which the tumor has been 
collected will be recorded in the CRF. 
For updated 
information 
CCI

 
17 
 
Section 
Before Revision 
(Version 6.0, Date:  22 Apr 2016) 
After Revision 
(Version 7.0, Date:  03 Jul 2017) 
Reason for 
Revision 
(3) 
In biopsied tumor samples 
Except for subjects who have only a tumor lesion not amenable to 
biopsy for safety reasons, samples obtained from the biopsy 
performed in Screening 2 must be submitted (mandatory).  Any 
reason for infeasible biopsy will be recorded in source documents.  
The date of sample collection and the organ from which the tumor 
has been collected will be recorded in the CRF.  In addition, a 
biopsy tumor sample will be collected on Day 15 of Cycle 1 
(optional).  Tumor biopsies should be taken from the same organ 
whenever possible.  The actual time of sample collection will be 
recorded in the CRF.  See Appendix 9 for a description of 
collection, handling, and shipping procedures of the samples.  The 
date of sample collection and the organ from which the tumor has 
been collected will be recorded in the CRF. 
 
9.5.1.5.1 
9.5.1.5.1 Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a patient 
or clinical investigation subject administered an investigational 
product.  An AE does not necessarily have a causal relationship with 
the medicinal product.  For this study, the study drug is E7090. 
The criteria for identifying AEs in this study are: 
z 
Any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated 
with the use of an investigational product, whether or not 
considered related to the investigational product 
9.5.1.5.1 Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a patient 
or clinical investigation subject administered an investigational 
product.  An AE does not necessarily have a causal relationship with 
the medicinal product.  For this study, the study drug is E7090. 
The criteria for identifying AEs in this study are: 
z 
Any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated 
with the use of an investigational product, whether or not 
considered related to the investigational product (For Part 2, events 
observed after informed consent for Screening 2 will be assessed) 
 
To clarify the 
statement 
9.5.1.5.1 
9.5.1.5.1 Adverse Events 
All AEs observed during the study will be recorded in the CRF.  All 
AEs, regardless of relationship to study drug or procedure, should be 
collected beginning from the time the subject signs the informed 
consent form through the last visit (30 days after the last dose of study 
treatment). 
9.5.1.5.1 Adverse Events 
All AEs observed during the study (for Part 2, after informed consent 
for Screening 2) will be recorded in the CRF.  All AEs, regardless of 
relationship to study drug or procedure, should be collected beginning 
from the time the subject signs the informed consent form (for Part 2, 
after informed consent for Screening 2) through the last visit (30 days 
after the last dose of study treatment). 
 
To clarify the 
statement 
9.5.1.5.3 
 
9.5.1.5.3 Laboratory Measurements 
[Monitoring of serum phosphorus levels] 
Nonclinical toxicity studies have reported mineralization associated 
with hyperphosphatemia, which are considered attributable to the 
inhibition of FGFR kinase, the pharmacological action of E7090.  
9.5.1.5.3 Laboratory Measurements 
[Monitoring of serum phosphorus levels] 
Nonclinical toxicity studies have reported mineralization associated 
with hyperphosphatemia, which are considered attributable to the 
inhibition of FGFR kinase, the pharmacological action of E7090.  
For updated 
information 

 
18 
 
Section 
Before Revision 
(Version 6.0, Date:  22 Apr 2016) 
After Revision 
(Version 7.0, Date:  03 Jul 2017) 
Reason for 
Revision 
Given that similar events have also been observed in clinical studies of 
similar drugs, attention needs to be paid to such toxicities in this study.  
If high serum phosphorus levels are observed, they should be managed 
in a medically proper manner (such as diet therapy, dose interruption, 
dose reduction and hyperphosphatemia drugs).  In addition, any 
necessary test (eg, X-ray) should be performed if any clinical symptom 
suggestive of mineralization is observed. 
 
Given that similar events have also been observed in clinical studies of 
similar drugs, attention needs to be paid to such toxicities in this study.  
If high serum phosphorus levels are observed, the criteria for dose 
interruption/reduction shown in Table 6 should be followed.  In 
addition, any necessary test (eg, X-ray) should be performed if any 
clinical symptom suggestive of mineralization is observed. 
9.5.1.5.7 
9.5.1.5.7 Ophthalmological Examinations 
Ophthalmological examinations will be performed at the visits 
designated in the Schedule of Procedures/Assessments (Table 13 and 
Table 14).  Examinations in Part 1 will include visual acuity, 
funduscopy (mydriatic test when necessary), slit-lamp examination 
(fluorescein staining when necessary), and anterior segment optical 
coherence tomography (OCT) to evaluate the corneal epithelium.  
Corneal epithelial thickness will be measured by anterior segment OCT 
and recorded in the CRF.  The necessity for examinations in Part 2 
will be reconsidered, after the effect of E7090 on the eyes is reviewed. 
9.5.1.5.7 Ophthalmological Examinations 
Ophthalmological examinations will be performed at the visits 
designated in the Schedule of Procedures/Assessments (Table 13 and 
Table 14).  Examinations in Part 1 will include visual acuity, 
funduscopy (mydriatic test when necessary), slit-lamp examination 
(fluorescein staining when necessary), and anterior segment optical 
coherence tomography (OCT) to evaluate the corneal epithelium.  
Corneal epithelial thickness will be measured by anterior segment OCT 
and recorded in the CRF.  Examinations in Part 2 will include visual 
acuity, funduscopy (mydriatic test when necessary), slit-lamp 
examination (fluorescein staining when necessary), and posterior 
segment OCT to evaluate the retina. 
 
For updated 
information 
9.5.1.7 
9.5.1.7 Concomitant Drugs and Therapies 
The investigator, subinvestigator, or clinical study collaborator will 
instruct subjects to comply with the stipulations on prohibited 
concomitant treatments in Section 9.4.9.2 “Prohibited Concomitant 
Therapies and Drugs,” and investigate concomitant treatment 
according to the following. 
(1) 
Concomitant drugs 
At each visit, all drugs used from the time of written informed consent 
through the end of the last observation period will be investigated, and 
the information listed below will be recorded in the CRF.  If the 
subject is treated at another department or hospital, the treating 
physician will be interviewed if necessary.  If it is necessary to start a 
new anticancer agent immediately due to deterioration of the subject’s 
condition, final observation may be performed before 30 days after the 
last dose of study treatment but must be performed before the start of 
the new anticancer agent. 
Drug name, reason for use, start date of treatment, and end date of 
treatment (date when the treatment is completed or “continued 
treatment after the last visit”) 
9.5.1.7 Concomitant Drugs and Therapies 
The investigator, subinvestigator, or clinical study collaborator will 
instruct subjects to comply with the stipulations on prohibited 
concomitant treatments in Section 9.4.9.2 “Prohibited Concomitant 
Therapies and Drugs,” and investigate concomitant treatment 
according to the following. 
(1) 
Concomitant drugs 
At each visit, all drugs used from the time of written informed consent 
(for Part 2, informed consent for Screening 2) through the end of the 
last observation period will be investigated, and the information listed 
below will be recorded in the CRF.  If the subject is treated at another 
department or hospital, the treating physician will be interviewed if 
necessary.  If it is necessary to start a new anticancer agent 
immediately due to deterioration of the subject’s condition, final 
observation may be performed before 30 days after the last dose of 
study treatment but must be performed before the start of the new 
anticancer agent. 
Drug name, route of administration, reason for use, start date of 
treatment, and end date of treatment (date when the treatment is 
To clarify the 
statement 

 
19 
 
Section 
Before Revision 
(Version 6.0, Date:  22 Apr 2016) 
After Revision 
(Version 7.0, Date:  03 Jul 2017) 
Reason for 
Revision 
 
(2) 
Concomitant therapies 
At each visit, all therapies provided from the time of written informed 
consent through the end of the last observation period will be 
investigated, and the information listed below will be recorded in the 
CRF.  If the subject is treated at another department or hospital, the 
treating physician will be interviewed if necessary. 
 
completed or “continued treatment after the last visit”) 
 
(2) 
Concomitant therapies 
At each visit, all therapies provided from the time of written informed 
consent (for Part 2, informed consent for Screening 2) through the end 
of the last observation period will be investigated, and the information 
listed below will be recorded in the CRF.  If the subject is treated at 
another department or hospital, the treating physician will be 
interviewed if necessary. 
9.5.2 
Table 14 
Schedule of Procedures/Assessments in Part 2 
a) To be performed only when consent is obtained. 
b) Any available viral test data obtained within 6 months before the 
start of study treatment may be used as screening data. 
c) Any data obtained within 28 days before the start of study treatment 
may be used (any data obtained before informed consent may also 
be used). 
d) For assessments performed at both screening and baseline, if 
screening assessment is performed within 4 days after the start of 
study treatment, baseline assessment may be omitted. 
e) To be performed predose. 
f) The test/observation may be omitted only if the investigator or 
subinvestigator considers that the safety of the subject is ensured. 
g) To be performed on Day 1 of Cycle 2.  To be performed every 8 
weeks (on Day 1 [±3 days] of even-numbered cycles) thereafter. 
h) Tumor evaluation and tumor marker assessment will be performed 
every 8 weeks (on Day 1 [±7 days] of odd-numbered cycles) after 
Day 1 of Cycle 1, and more frequently if clinically indicated. 
i) To be performed predose on Day 8 and Day 15.  In addition, the 
effect of food on E7090 pharmacokinetics will be considered.  A 
pharmacokinetic comparison will be carried out between the fasting 
state and the high fat-fed state of the same patients during Cycle 1.  
The dates for PK evaluation in the fasting state and in the high-fat 
fed state will be determined after PK evaluation in Part 1. 
j) To be performed in odd-numbered cycles after Cycle 3. 
k) To be obtained during the study period whenever possible. 
l) Any available data obtained within 7 days before discontinuation 
may be used as data at discontinuation. 
m) Any available data obtained within 28 days before discontinuation 
may be used as data at discontinuation. 
n) If it is necessary to start a new anticancer agent immediately due to 
Table 14 
Schedule of Procedures/Assessments in Part 2 
a) Only in gastric cancer patients with available samples to allow 
confirmation of FGFR2 protein expression at the time of informed 
consent for Screening 1.  Patients in whom the presence of FGFR2 
gene amplification is unknown but the presence of FGFR2 protein 
overexpression is confirmed by central laboratory may enter 
Screening 2. 
b) Any available viral test data obtained within 6 months before the 
start of study treatment may be used as screening data. 
c) Any data obtained within 28 days before the start of study treatment 
may be used (any data obtained before informed consent may also 
be used). 
d) Excluding patients with only a tumor lesion not amenable to biopsy 
for safety reasons. 
e) For assessments performed at both screening and baseline, if 
screening assessment is performed within 4 days after the start of 
study treatment, baseline assessment may be omitted. 
f) To be performed predose and 0.5, 1, 2, 3, 5, 10, and 24 hours 
(predose on Day 2) postdose. 
g) To be performed predose. 
h) To be performed predose and 0.5, 1, 2, 3, 5, 10, and 24 hours 
(predose on Day 9) postdose on Day 8.  PK evaluation may be 
performed within +1 or +2 GD\VQRWí2 RUí1 days). 
i) To be performed within ±3 days. 
j) Tumor evaluation and tumor marker assessment will be performed 
every 8 weeks (on Day 1 [±7 days] of odd-numbered cycles) after 
Day 1 of Cycle 1, and more frequently if clinically indicated. 
k) Only in patients providing consent (optional). 
l) In Cycle 3 and subsequent cycles, test/observation may be omitted 
only if the investigator or subinvestigator considers the subject safe.  
To change the 
study design  
 
For updated 
information 

 
20 
 
Section 
Before Revision 
(Version 6.0, Date:  22 Apr 2016) 
After Revision 
(Version 7.0, Date:  03 Jul 2017) 
Reason for 
Revision 
deterioration of the subject’s condition, the final observation may 
be performed before 30 days after the last dose of study treatment 
but must be performed before the start of the new anticancer agent. 
o) To be performed every 12 weeks (±1 weeks) after the time of 
discontinuation of study treatment. 
However, LIWKHEORRGSKRVSKRUXVOHYHOLV7.1 mg/dL on Day 1 or 
Day 15, blood phosphorus levels should be measured to evaluate 
hyperphosphatemia. 
m) To be performed on Day 1 (±3 days) of Cycle 2.  To be performed 
every 8 weeks (on Day 1 [±3 days] of even-numbered cycles) 
thereafter. 
n) To be performed in odd-numbered cycles after Cycle 3. 
o) To be obtained during the study period whenever possible. 
p) Any available data obtained within 7 days before discontinuation 
may be used as data at discontinuation. 
q) Any available data obtained within 28 days before discontinuation 
may be used as data at discontinuation. 
r) If it is necessary to start a new anticancer agent immediately due to 
deterioration of the subject’s condition, the final observation may 
be performed before 30 days after the last dose of study treatment 
but must be performed before the start of the new anticancer agent. 
s) To be performed every 12 weeks (±2 weeks) after the time of 
discontinuation of study treatment. 
 
 

 
1 
 
A Phase 1 Study of E7090 in Subjects with Solid Tumor 
㸦Protocol Number: E7090-J081-101㸧 
 
Revision History 
 
22 Apr 2016 
Section 
Before Revision 
(Version 5.0, Date:  04 Apr 2016) 
After Revision 
(Version 6.0, Date:  22 Apr 2016) 
Reason for 
Revision 
2 
Transition to the next dose group will be determined through 
discussion among the investigator, the sponsor, and the medical expert.  
At this time, advice may be obtained from the Data and Safety 
Monitoring Advisor as necessary.  Safety data from subjects excluded 
from the DLT analysis population will also be considered when 
determining transition to the next dose group. 
Transition to the next dose group will be determined through 
discussion among the investigator, the sponsor, and the medical expert.  
At this time, advice may be obtained from the Data and Safety 
Monitoring Advisor as necessary.  Safety data from subjects excluded 
from the DLT analysis population will also be considered when 
determining transition to the next dose group (including changes in the 
assignment of a dose and the percentage of dose escalation). 
 
To clarify the 
statement 
9.4.1.6 
9.4.1.6 
Determination of Transition to the Next Dose Group 
Transition to the next dose group will be determined through 
discussion among the investigator, the sponsor, and the medical expert 
according to Section 9.4.1.3 “Method of Subject’s Dose Assignment” 
and Section 9.4.1.4 “Method of Determining the Dose for the Next 
Dose Group.”  At this time, advice may be obtained from the Data 
and Safety Monitoring Advisor as necessary.  Safety data from 
subjects excluded from the DLT analysis population will also be 
considered when determining transition to the next dose group. 
9.4.1.6 
Determination of Transition to the Next Dose Group 
Transition to the next dose group will be determined through 
discussion among the investigator, the sponsor, and the medical expert 
according to Section 9.4.1.3 “Method of Subject’s Dose Assignment” 
and Section 9.4.1.4 “Method of Determining the Dose for the Next 
Dose Group.”  At this time, advice may be obtained from the Data 
and Safety Monitoring Advisor as necessary.  Safety data from 
subjects excluded from the DLT analysis population will also be 
considered when determining transition to the next dose group 
(including changes in the assignment of a dose and the percentage of 
dose escalation). 
 
9.5.2 
Table 13 Schedule of Procedures/Assessments in Part 1 
 
Period 
Cycle 1 
Day  
1 i 
3 
8 
(±1) 
15 
(±1) 
22 
(±1) 
Hematology 
Blood chemistry 
Blood 
coagulation 
X j 
 
X 
X 
X 
 
Table 13 Schedule of Procedures/Assessments in Part 1 
 
Period 
Cycle 1 
Day  
1 i 
3 
8 
(±1) 
15 
(±1) 
22 
(±1) 
Hematology 
Blood chemistry 
Blood 
coagulation 
X j 
X w 
X 
X 
X 
w) Only blood chemistry (blood phosphorus level) will be performed. 
 
To monitor 
blood 
phosphorus 
levels 
 

 
1 
 
A Phase 1 Study of E7090 in Subjects with Solid Tumor 
㸦Protocol Number: E7090-J081-101㸧 
 
Revision History 
 
04 Apr 2016 
Section 
Before Revision 
(Version 4.0, Date: 29 Jan 2016) 
After Revision 
(Version 5.0, Date: 04 Apr 2016) 
Reason for 
Revision 
2 
Study Treatment 
E7090 will be administered orally once daily.  Study drug consists of 
1, 1.5, 5, and 20 mg capsules. 
Study Treatment 
E7090 will be administered orally once daily.  Study drug consists of 
1, 1.5, 5, 20, and 60 mg capsules. 
To use 60 mg 
capsules 
9.4 
9.4 Treatment 
The study drug for this study is E7090 in the following formulations, 1, 
1.5, 5, and 20 mg capsules …. 
9.4 Treatment 
The study drug for this study is E7090 in the following formulations, 1, 
1.5, 5, 20, and 60 mg capsules …. 
9.4.1.4 
9.4.1.4 
Method of Determining the Dose for the Next Dose 
Group 
…. 
Since theoretical values calculated using the above method of 
determining the dose may become fractions that cannot be formulated 
with the capsule potencies (1, 1.5, 5, and 20 mg) used in this study, …. 
9.4.1.4 
Method of Determining the Dose for the Next Dose 
Group 
…. 
Since theoretical values calculated using the above method of 
determining the dose may become fractions that cannot be formulated 
with the capsule potencies (1, 1.5, 5, 20, and 60 mg) used in this study, 
…. 
 

 
1 
 
A Phase 1 Study of E7090 in Subjects with Solid Tumor 
㸦Protocol Number: E7090-J081-101㸧 
 
Revision History 
 
29 Jan 2016 
Section 
Before Revision 
(Version 3.0, Date:  13 Nov 2014) 
After Revision 
(Version 4.0, Date:  29 Jan 2016) 
Reason for 
Revision 
2 
Administration schedule 
2) Cycle 1 and subsequent cycles (for 28 days each) 
Subjects will start Cycle 1 between the 8th and 10th days after 
administration in Cycle 0 and take E7090 once daily continuously.  
Subjects will take E7090 at least 2 hours after breakfast, and will not 
eat anything for 1 hour after administration.  Study treatment may be 
continued unless any of the criteria in Section 9.3.3.1 “Discontinuation 
Criteria for Individual Subjects” is met. 
Administration schedule 
2) Cycle 1 and subsequent cycles (for 28 days each) 
Subjects will start Cycle 1 between the 8th and 10th days after 
administration in Cycle 0 and take E7090 once daily continuously.  
Subjects will take E7090 at least 2 hours after breakfast, and will not 
eat anything for 1 hour after administration.  On the 8th day of Cycle 
1, however, subjects will take E7090 in the fasting state on waking 
after an at least 10-hour overnight fast for PK evaluation.  Subjects 
will be prohibited from eating or drinking for 2 hours after 
administration, except for drinking water.  Study treatment may be 
continued unless any of the criteria in Section 9.3.3.1 “Discontinuation 
Criteria for Individual Subjects” is met. 
 
Because it is 
thought that the 
steady-state PK 
can be 
evaluated on 
the 8th day of 
Cycle 1, based 
on the half 
life of E7090 
9.4.1.2 
(2) Cycle 1 (28 days) 
Subjects will start Cycle 1 between the 8th and 10th days after 
administration in Cycle 0 and take E7090 once daily continuously.  
Subjects will take E7090 at least 2 hours after breakfast, without eating 
anything for 1 hour after administration.  For PK evaluation, subjects 
will be instructed not to take E7090 on the morning of each visit day. 
(3) Cycle 2 and subsequent cycles (28 days each) 
Subjects will take E7090 once daily continuously.  Subjects will take 
E7090 at least 2 hours after breakfast, without eating anything for 1 
hour after administration.  For PK evaluation, subjects will be 
instructed not to take E7090 on the morning of Day 1 of each cycle.  
On Day 1 of Cycle 2, however, subjects will take E7090 in the fasting 
state on waking after an at least 10-hour overnight fast for PK 
evaluation.  Subjects will be prohibited from eating or drinking for 2 
hours after administration, except for drinking water. 
(2) Cycle 1 (28 days) 
Subjects will start Cycle 1 between the 8th and 10th days after 
administration in Cycle 0 and take E7090 once daily continuously.  
Subjects will take E7090 at least 2 hours after breakfast, without eating 
anything for 1 hour after administration.  For PK evaluation, subjects 
will be instructed not to take E7090 on the morning of each visit day.  
On Day 8 of Cycle 1, however, subjects will take E7090 in the fasting 
state on waking after an at least 10-hour overnight fast for PK 
evaluation.  Subjects will be prohibited from eating or drinking for 2 
hours after administration, except for drinking water. 
(3) Cycle 2 and subsequent cycles (28 days each) 
Subjects will take E7090 once daily continuously.  Subjects will take 
E7090 at least 2 hours after breakfast, without eating anything for 1 
hour after administration.  For PK evaluation, subjects will be 
instructed not to take E7090 on the morning of Day 1 of each cycle. 
 

 
2 
 
9.5.1.4.1 
Table 8 Blood Sampling Schedule for PK Evaluation (Part 
1) 
Cycle 
Sampling 
day 
Sampling time 
point 
Allowable sampling 
time interval 
Cycle 0 
… 
… 
… 
Cycle 1 
Day 1 
Predose 
:LWKLQí60 minutes 
Day 3 
Predose 
:LWKLQí60 minutes 
Day 8 
Predose 
:LWKLQí60 minutes 
Day 15 
Predose 
:LWKLQí60 minutes 
Day 22 
Predose 
:LWKLQí60 minutes 
Cycle 2 
Day 1 
Predose 
:LWKLQí60 minutes 
30 minutes 
postdose 
Within ±10 minutes 
1 hour postdose 
Within ±10 minutes 
2 hours postdose 
Within ±10 minutes 
3 hours postdose 
Within ±10 minutes 
5 hours postdose 
Within ±10 minutes 
10 hours postdose 
Within ±30 minutes 
Day 2 
Predose 
:LWKLQí60 minutes 
Cycle 3 
and 
subsequent 
cycles 
Day 1 
Predose 
:LWKLQí60 minutes 
 
 
Table 8 Blood Sampling Schedule for PK Evaluation (Part 
1) 
Cycle 
Samplin
g day 
Sampling time 
point 
Allowable sampling 
time interval 
Cycle 0 
… 
… 
… 
Cycle 1 
Day 1 
Predose 
:LWKLQí60 minutes 
Day 3 
Predose 
:LWKLQí60 minutes 
Day 8 
Predose 
:LWKLQí60 minutes 
30 minutes 
postdose 
Within ±10 minutes 
1 hour postdose 
Within ±10 minutes 
2 hours postdose 
Within ±10 minutes 
3 hours postdose 
Within ±10 minutes 
5 hours postdose 
Within ±10 minutes 
10 hours postdose 
Within ±30 minutes 
Day 9 
Predose 
:LWKLQí60 minutes 
Day 15 
Predose 
:LWKLQí60 minutes 
Day 22 
Predose 
:LWKLQí60 minutes 
Cycle 2 
and 
subsequent 
cycles 
Day 1 
Predose 
:LWKLQí60 minutes 
 
Because it is 
thought that the 
steady-state PK 
can be 
evaluated on 
the 8th day of 
Cycle 1, based 
on the half 
life of E7090 
9.5.1.4.1 
(2) Urinary concentration measurement 
Urinary PK measurements will be performed in Part 1 only.  On Day 
1 of Cycle 2 in Part 1, a 24-hour urine collection will be performed to 
determine the urinary concentration of unchanged E7090. 
(2) Urinary concentration measurement 
Urinary PK measurements will be performed in Part 1 only.  On Day 
8 of Cycle 1 in Part 1, a 24-hour urine collection will be performed to 
determine the urinary concentration of unchanged E7090. 
Because it is 
thought that the 
steady-state 
metabolite 
analysis can be 
performed on 
the 8th day of 
Cycle 1, based 
on the half 
life of E7090 

 
3 
 
9.5.2 
Table 13 Schedule of Procedures/Assessments in Part 1 
Phase 
Treatment 
 
Period 
Cycle 1 
Cycle 2 
Day  
1 i 
3 
8 
(±1) 
15 
(±1) 
22 
(±1) 
1 
(±3) 
PK (blood) 
X j 
X j 
X j 
X j 
X j 
X p 
PK (urine) 
 
 
 
 
 
X q 
j) To be performed predose. 
p) To be performed predose and 0.5, 1, 2, 3, 5, 10, and 24 hours 
postdose only in Cycle 2.  To be performed predose in Cycle 3 and 
subsequent cycles. 
q) A 24-hour urine collection will be performed only in Cycle 2. 
 
Table 13 Schedule of Procedures/Assessments in Part 1 
Phase 
Treatment 
 
Period 
Cycle 1 
Cycle 2 
Day  
1 i 
3 
8 
(±1) 
15 
(±1) 
22 
(±1) 
1 
(±3) 
PK (blood) 
X j 
X j 
X k 
X j 
X j 
X j 
PK (urine) 
 
 
X l 
 
 
 
j) To be performed predose. 
k) To be performed predose and 0.5, 1, 2, 3, 5, 10, and 24 hours 
postdose. 
l) A 24-hour urine collection will be performed. 
 
Because the 
above changes 
were reflected 
in Table 13 
Schedule of 
Procedures/Ass
essments in 
Part 1 
9.7.1.7.2 
Pharmacodynamic and PGx analyses 
PD and PGx analyses will be performed using the PD and PGx analysis 
set. 
Pharmacodynamic and PGx analyses 
PD and PGx analyses will be performed using the PD and PGx analysis 
set. 
Deletion of the 
underline 
(correction of 
error) 
 

 
1 
 
A Phase 1 Study of E7090 in Subjects with Solid Tumor 
㸦Protocol Number: E7090-J081-101㸧 
 
Revision History 
 
13 Nov 2014 
Section 
Before Revision 
(Version 2.0, Date:  04 Sep 2014) 
After Revision 
(Version 3.0, Date:  13 Nov 2014) 
Reason for 
Revision 
2 
9.4.1.4 
 
Dose escalation for the 
next dose group (%) 
Toxicities observed during Cycle 0 
and Cycle 1 (except for alopecia) 
100 
Grade WR[LFLW\RQO\ 
50 
Grade 2 toxicity in 1 subject 
33 
Grade 2 toxicity in 2 subjects or 
*UDGHWR[LFLW\LQVXEMHFW 
 
 
Dose escalation for the 
next dose group (%) 
Toxicities observed during Cycle 0 
and Cycle 1 (a) 
100 
Grade WR[LFLW\RQO\ 
50 
Grade 2 toxicity in 1 subject 
33 
Grade 2 toxicity in 2 subjects or 
*UDGHWR[LFLW\LQVXEMHFW 
(a) Excluding clinically insignificant events such as laboratory 
abnormalities requiring no treatment 
 
Correction of 
the description 
(based on the 
actual 
operation) 
9.5.1.3.1 
9.5.1.3.1 Assessment of Tumor Lesions 
…. 
(1) CT or MRI 
CT or MRI will be performed with contrast, except in subjects allergic 
to oral/intravenous contrast agents.  In subjects allergic to contrast 
agents, a plain CT scan without contrast will be performed.  In 
subjects allergic to intravenous contrast agents, CT with oral contrast 
may be considered, and for the abdominal or pelvic region, MRI with 
intravenous gadolinium may be considered. 
9.5.1.3.1 Assessment of Tumor Lesions 
…. 
(1) CT or MRI 
CT or MRI will be performed with contrast, except in subjects not 
amenable to oral/intravenous contrast agents (due to allergy or renal 
dysfunction).  In subjects not amenable to contrast agents, a plain CT 
scan without contrast will be performed.  In subjects not amenable to 
intravenous contrast agents, CT with oral contrast may be considered, 
and for the abdominal or pelvic region, MRI with intravenous 
gadolinium may be considered. 
Correction of 
the description 
(based on the 
actual 
operation) 
 

 
1 
 
A Phase 1 Study of E7090 in Subjects with Solid Tumor 
㸦Protocol Number: E7090-J081-101㸧 
 
Revision History 
 
04 Sep 2014 
Section 
Before Revision 
(Version 1.0, Date:  01 Aug 2014) 
After Revision 
(Version 2.0, Date:  04 Sep 2014) 
Reason for 
Revision 
2 
9.3.1 
Inclusion Criteria (for both Part 1 and Part 2) 
(12) Women of childbearing potential must have practiced 
contraception since 28 days before registration (Part 1) or 28 days 
before the start of study treatment (Part 2), and must agree to use 
medically effective contraception (eg, the subject is using intrauterine 
devices, condoms with spermicide, contraceptive implants, or oral 
contraceptives; or the subject’s male partner is confirmed to have no 
sperm after vasectomy) throughout the study period (for 30 days after 
the final study drug administration).  Any subject practicing 
contraception by abstinence must agree to practice contraception with 
condoms with spermicide during the study period and for 30 days after 
the final study drug administration.  Women of childbearing potential 
using any oral contraceptive are to use the oral contraceptive at a fixed 
dose for at least 4 weeks before study drug administration and continue 
to use the same oral contraceptive during the study period and for 30 
days after the final study drug administration. 
All women will be considered to be of childbearing potential unless 
they are postmenopausal women (amenorrheic for at least 12 
consecutive months, in the appropriate age group, and without other 
known or suspected cause) or have been sterilized surgically (ie, 
bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, 
all with surgery at least 1 month before dosing). 
 
Inclusion Criteria (for both Part 1 and Part 2) 
(12) Women of childbearing potential must have practiced 
contraception since 28 days before registration (Part 1) or 28 days 
before the start of study treatment (Part 2), and must agree to use 
medically effective contraception (eg, the subject is using intrauterine 
devices,* condoms with spermicide,* contraceptive implants,** or oral 
contraceptives;*  or the subject’s male partner is confirmed to have no 
sperm after vasectomy)Note throughout the study period (for 30 days 
after the final study drug administration).  Any subject practicing 
contraception by abstinence must agree to practice contraception with 
condoms with spermicide during the study period and for 30 days after 
the final study drug administration.  Women of childbearing potential 
using any oral contraceptive are to use the oral contraceptive at a fixed 
dose for at least 4 weeks before study drug administration and continue 
to use the same oral contraceptive during the study period and for 30 
days after the final study drug administration. 
All women will be considered to be of childbearing potential unless 
they are postmenopausal women (amenorrheic for at least 12 
consecutive months, in the appropriate age group, and without other 
known or suspected cause) or have been sterilized surgically (ie, 
bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, 
all with surgery at least 1 month before dosing). 
Note:  Whether the drug/medical device has been approved or 
authorized in Japan (*, yes; **, no) 
 
To clarify 
whether the 
drugs/medical  
devices have 
been 
approved or 
authorized in 
Japan 
2 
9.3.1 
Inclusion Criteria (for both Part 1 and Part 2) 
(13) Participants or their female partners meeting the criteria above 
(when the partner is a woman with no childbearing potential or will use 
medically effective contraception throughout the study period and for 
30 days after final study drug administration) 
Inclusion Criteria (for both Part 1 and Part 2) 
(13) Male participants or their female partners meeting the criteria 
above (when the partner is a woman with no childbearing potential or 
will use medically effective contraception throughout the study period 
and for 30 days after final study drug administration) 
To clarify  
the 
contraception 
rule in male 
participants 

 
2 
 
Section 
Before Revision 
(Version 1.0, Date:  01 Aug 2014) 
After Revision 
(Version 2.0, Date:  04 Sep 2014) 
Reason for 
Revision 
2 
9.3.2 
9.3.2 Exclusion Criteria 
(14) Pregnant or breastfeeding patients 
9.3.2 Exclusion Criteria 
(14) 
Pregnant or breastfeeding patients (breastfeeding patients may 
not be enrolled even if they discontinue breastfeeding) 
To clarify that 
breastfeeding 
patients may 
not be 
enrolled even 
if they 
discontinue 
breastfeeding 
2 
9.3.3.1 
9.3.3.1 
Discontinuation Criteria for Individual Subjects 
Treatment with E7090 will be continued until any of the following 
discontinuation criteria is met: 
(1) Subject’s refusal to continue study participation or withdrawal of 
consent 
(2) Major inclusion/exclusion criteria violation after registration (Part 
1) or enrollment (Part 2) 
(3) Difficulty in continuing the study due to an adverse event in the 
opinion of the investigator or subinvestigator 
(4) Subject’s pregnancy 
(5) Disease progression (except when the investigator or 
subinvestigator considers study treatment clinically beneficial to 
the subject) 
(6) Other cases where the investigator or subinvestigator considers 
study discontinuation appropriate 
9.3.3.1 
Discontinuation Criteria for Individual Subjects 
Treatment with E7090 will be continued until any of the following 
discontinuation criteria is met: 
(1) Subject’s refusal to continue study participation or withdrawal of 
consent 
(2) Major inclusion/exclusion criteria violation after registration (Part 
1) or enrollment (Part 2) 
(3) Difficulty in continuing the study due to an adverse event in the 
opinion of the investigator or subinvestigator 
(4) Subject’s pregnancy 
(5) Disease progression (except when the investigator or 
subinvestigator considers study treatment clinically beneficial to 
the subject) 
(6) Dose reduction to <1 mg required due to an adverse drug reaction 
(7) Other cases where the investigator or subinvestigator considers 
study discontinuation appropriate 
To clarify that 
study treatment 
will be 
discontinued 
when dose 
reduction to 
<1 mg is 
required 
9.4.1.8 
9.4.1.8 Criteria for Dose Interruption/Reduction 
Up to 2 dose reductions due to toxicity will be permitted.  At the first 
dose reduction, the dose will be de-escalated to the dose of the next 
lower dose group.  At the second dose reduction, the dose will be de-
escalated to the dose of the second lower dose group.  The sponsor 
should be consulted for more than 2 dose reductions.  No dose 
escalation should be performed in the same subject. 
9.4.1.8 Criteria for Dose Interruption/Reduction 
Up to 2 dose reductions due to toxicity will be permitted.  At the first 
dose reduction, the dose will be de-escalated to the dose of the next 
lower dose group.  At the second dose reduction, the dose will be de-
escalated to the dose of the second lower dose group.  The sponsor 
should be consulted for more than 2 dose reductions.  The study will 
be discontinued if the dose needs to be reduced below 1 mg.  No dose 
escalation should be performed in the same subject. 

 
3 
 
Section 
Before Revision 
(Version 1.0, Date:  01 Aug 2014) 
After Revision 
(Version 2.0, Date:  04 Sep 2014) 
Reason for 
Revision 
2 
9.4.1.7 
9.4.1.7 
Definition of Dose-Limiting Toxicity (DLT) 
(1) 
Febrile neutropenia RU*UDGHQHXWURSHQLDSHUVLVWLQJIRUGD\V 
9.4.1.7 
Definition of Dose-Limiting Toxicity (DLT) 
(1) Febrile neutropenia, RU*UDGHQHXWURSHQLDSHUVLVWLQJIRUGD\V 
To clarify that 
the onset of 
febrile 
neutropenia 
itself 
corresponds to 
DLT 
9.1.1.2 
9.1.1.2 
Treatment Period 
In Cycle 1 and subsequent cycles, each consisting of 28 days, subjects 
will take repeated doses.  Subjects will be hospitalized from Day 1 of 
Cycle 0 to the morning of Day 15 of Cycle 1.  In Cycle 0 and Cycle 1, 
DLTs will be monitored and evaluated.  Treatment may be continued 
unless any of the criteria in Section 9.3.3.1 “Discontinuation Criteria 
for Individual Subjects” is met. 
9.1.1.2 
Treatment Period 
In Cycle 1 and subsequent cycles, each consisting of 28 days, subjects 
will take repeated doses.  Subjects will be hospitalized from Day 1 of 
Cycle 0 to the morning of Day 15 of Cycle 1.  The investigator or 
subinvestigator will carefully evaluate the results of the physical 
examination performed on Day 15 of Cycle 1 and all test results to 
determine from a medical standpoint whether each subject can be 
managed on an outpatient basis.  If continued hospitalization is 
considered necessary from the aspect of subject safety, hospitalization 
will be continued after Day 15 of Cycle 1.  In Cycle 0 and Cycle 1, 
DLTs will be monitored and evaluated.  Treatment may be continued 
unless any of the criteria in Section 9.3.3.1 “Discontinuation Criteria 
for Individual Subjects” is met. 
To clarify that 
the investigator 
or 
subinvestigator 
will determine 
whether each 
subject can be 
discharged or 
not after 
medical 
evaluation 
9.4.1.2 
9.4.2.2 
9.4.1.2 
Administration Schedule 
Precautions for administration 
No corresponding description 
 
9.4.2.2 
Administration Schedule 
Precautions for administration 
No corresponding description 
9.4.1.2 
Administration Schedule 
Precautions for administration 
(4) Since it is currently unknown whether E7090 may cause 
phototoxicity, subjects will be instructed to avoid long-term sunlight 
exposure. 
 
9.4.2.2 
Administration Schedule 
Precautions for administration 
(3) Since it is currently unknown whether E7090 may cause 
phototoxicity, subjects will be instructed to avoid long-term sunlight 
exposure. 
 
To notify that 
long-term 
sunlight 
exposure should 
be avoided, 
given that 
phototoxicity 
due to E7090 
cannot be 
completely 
ruled out 

 
4 
 
Section 
Before Revision 
(Version 1.0, Date:  01 Aug 2014) 
After Revision 
(Version 2.0, Date:  04 Sep 2014) 
Reason for 
Revision 
2 
9.4.1.3 
9.4.1.3 Method of Subject’s Dose Assignment 
Two subjects will be registered at each dose level. 
9.4.1.3 Method of Subject’s Dose Assignment 
Two subjects will be registered at each dose level.  In a new dose 
group, the safety of the first subject should be evaluated before 
enrollment of the second and subsequent subjects. 
To clarify that 
the safety of the 
first subject will 
be evaluated 
before 
enrollment of 
the second and 
subsequent 
subjects, 
because of the 
First-In-Human 
study of E7090 
9.4.1.6 
9.4.1.6 Determination of Transition to the Next Dose Group 
Transition to the next dose group will be determined through 
discussion among the investigator, the sponsor, and the medical expert 
according to Section 9.4.1.3 “Method of Subject’s Dose Assignment” 
and Section 9.4.1.4 “Method of Determining the Dose for the Next 
Dose Group.”  At this time, advice may be obtained from the Data 
and Safety Monitoring Advisor as necessary. 
9.4.1.6 Determination of Transition to the Next Dose Group 
Transition to the next dose group will be determined through 
discussion among the investigator, the sponsor, and the medical expert 
according to Section 9.4.1.3 “Method of Subject’s Dose Assignment” 
and Section 9.4.1.4 “Method of Determining the Dose for the Next 
Dose Group.”  At this time, advice may be obtained from the Data 
and Safety Monitoring Advisor as necessary.  Safety data from 
subjects excluded from the DLT analysis population will also be 
considered when determining transition to the next dose group. 
 
To clarify that 
transition to the 
next dose group 
will be 
determined, 
after 
consideration of 
the safety data 
from subjects 
excluded from 
the DLT 
analysis 
population 
9.5.1.5.3 
9.5.1.5.3 Laboratory Measurements 
Table 12 Clinical Laboratory Tests 
Category 
Parameters 
No corresponding 
description 
No corresponding description 
 
9.5.1.5.3 Laboratory Measurements 
Table 12 Clinical Laboratory Tests 
Category 
Parameters 
Blood coagulation 
tests 
Activated partial thromboplastin time (aPTT) 
 
To add a 
laboratory item 

 
5 
 
Section 
Before Revision 
(Version 1.0, Date:  01 Aug 2014) 
After Revision 
(Version 2.0, Date:  04 Sep 2014) 
Reason for 
Revision 
9.5.1.5.10 
No corresponding description 
9.5.1.5.10 
Transcutaneous 
Arterial 
Oxygen 
Saturation 
Measurement 
Arterial oxygen saturation will be measured with a pulse oximeter at 
the visits designated in the Schedule of Procedures/Assessments (Table 
13 and Table 14). 
To add a 
laboratory item 
9.5.2 
Table 13 Schedule of Procedures/Assessments in Part 1 
Table 14 Schedule of Procedures/Assessments in Part 2 
No corresponding description 
Table 13 
Schedule of Procedures/Assessments in Part 1 
Table 14 
Schedule of Procedures/Assessments in Part 2 
Addition of “Transcutaneous arterial oxygen saturation” as a laboratory 
item with the same frequency as that of vital signs 
Addition of “Blood coagulation” as a laboratory item with the same 
frequency as that of hematology and blood chemistry 
To add a 
laboratory item 
9.7.1.8 
9.7.1.8 Safety Analyses 
Safety variables include adverse events (AEs), clinical laboratory 
parameters, vital signs, weight, 12-lead ECG, ECOG-PS, and 
ophthalmology. 
9.7.1.8 Safety Analyses 
Safety variables include adverse events (AEs), clinical laboratory 
parameters, vital signs, transcutaneous arterial oxygen saturation, 
weight, 12-lead ECG, ECOG-PS, and ophthalmology. 
To add a 
laboratory item 
9.7.1.8.4 
9.7.1.8.4 Vital Signs 
For vital signs parameters (systolic and diastolic BP, pulse, respiratory 
rate, and body temperature), and weight, the measured value at and the 
change from baseline to each postbaseline time point will be calculated 
for each time point using descriptive statistics. 
9.7.1.8.4 Vital Signs 
For vital signs parameters (systolic and diastolic BP, pulse, respiratory 
rate, and body temperature), transcutaneous arterial oxygen saturation, 
and weight, the measured value at and the change from baseline to each 
postbaseline time point will be calculated for each time point using 
descriptive statistics. 
To add a 
laboratory item