Clinical trial NCT02540291
Conditions: Tumors
Keywords: E7046 Advanced malignancies malignancies
Sponsor: Eisai Inc.
Start date: 2015-07-30; Completion date: 2018-02-27
Enrollment: 31 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an open label, multicenter, Phase 1 study of E7046 to assess the safety and tolerability of E7046 and to determine the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D) of E7046.

Detailed description:
The study will be conducted in 2 parts: a dose escalation part to determine the MTD and/or RP2D of E7046, and a cohort expansion part with 6 to 16 participants to better characterize safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) at the RP2D. In the dose escalation part, increasing doses of E7046 will be administered to cohorts of 6 participants, at dose levels ranging from 125 mg to 750 mg.

Arms: arm 1: Participants with tumor types that harbor high levels of myeloid infiltrate based on the Cancer Genome Atlas (TCGA).
Interventions: intervention 1: E7046
Intervention descriptions: intervention 1: E7046 will be administered as a single agent orally once daily (QD) continuously in 21-day cycles. In the dose escalation part, increasing doses of E7046 ranging from 125 mg to 750 mg will be administered to cohorts of 6 participants. In the cohort expansion part, participants will be treated at the RP2D.

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol
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1
TITLE PAGE
CLINICAL STUDY PROTOCOL
Study Protocol 
Number:
E7046-G000-101
Study Protocol Title:
An Open-Label Multicenter Phase 1 Study of E7046 in Subjects With 
Selected Advanced Malignancies
Sponsor:
Eisai Inc.
155 Tice Boulevard
Woodcliff Lake, 
New Jersey 07677, USA
Eisai Ltd.
European Knowledge Centre
Mosquito Way
Hatfield, Hertfordshire 
AL10 9SN UK
Investigational Product 
Name:
E7046
Indication:
Multiple tumor types with high myeloid infiltrate
Phase:
Phase 1
Approval Date(s):
Original Protocol:
07 May 2015
Amendment 01:
Amendment 02: 
30 Dec 2015
03 August 2016
IND Number:
125272
EudraCT Number:
2014-004823-37
GCP Statement:
This study is to be performed in full compliance with 
International Conference on Harmonisation of Technical 
Requirements for Registration of 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.


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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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CLINICAL PROTOCOL SYNOPSIS
Study Protocol Title
An Open-Label Multicenter Phase 1 Study of E7046 in Subjects With Selected Advanced 
Malignancies
Objectives
Primary objectives are to:

assess the safety and tolerability of E7046

determine the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D) 
of E7046.
Secondary objectives are to evaluate:

pharmacokinetic (PK) profile of E7046.

objective response rate according to the immune-related RECIST (irRECIST)

time to response (TTR), duration of response (DOR), progression-free survival (PFS), disease 
control rate (DCR), and clinical benefit rate (CBR).
Exploratory objectives include:

explore efficacy according to modified RECIST 1.1

assess overall survival (OS)

explore the pharmacodynamic effect of E7046 on selected immune cell populations and 
selected biomarkers in tumor infiltrate and in peripheral blood.

explore 18FDG-PET as a biomarker of response 

explore the pharmacokinetic/pharmacodynamic (PK/PD) relationship. 
Study Design
This is an open label, multicenter, Phase 1 study of E7046, a small molecule inhibitor of  the 
prostaglandin E2 (PGE2) receptor type 4 (EP4). The study will be conducted in 2 parts: a dose 
escalation part to determine the MTD and/or RP2D of E7046, and a cohort expansion part with 6 to 
16 subjects to better characterize safety, efficacy, pharmacokinetics (PK), and pharmacodynamics 
(PD) at the RP2D.
In the dose escalation part, increasing doses of E7046 will be administered to cohorts of 6 subjects, at 
dose levels ranging from 125 mg to 750 mg, (see Table below). In the first dose cohort, staggered 
dosing starts will be employed to ensure exposure of a limited number of subjects in initial dosing.
Dose level
No. of Subjects
E7046 Dose
-1
6
75 mg QD
1
6
125 mg QD
2
6
250 mg QD
3
6
500 mg QD
4
6
750 mg QD


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Dose-limiting toxicities (DLTs) will be drug-related toxicities (considered related, probably related, 
or possibly related to E7046) and graded using NCI CTCAE 4.03 occurring during Cycle 1 and 
include:
•
Nonhematologic toxicity ≥ Grade 3 (except diarrhea, nausea and vomiting unless lasting >3 
days despite optimal supportive care)
•
Confirmed (with a second measurement after 24 hours) nonhematologic appropriately-graded 
laboratory findings of Grade ≥3 that were ≤ Grade 1 at baseline
•
Hematologic toxicity: Grade 4 neutropenia ≥5 days, or Grade 3 neutropenia with fever, Grade 4 
thrombocytopenia, or Grade 3 thrombocytopenia with bleeding or lasting >7 days
• Any other toxicity assessed as related to E7046 treatment, and which, in the opinion of the 
study investigator(s) and the sponsor physician constitutes a dose-limiting toxicity
• Missed ≥7 days of dosing in Cycle 1 due to drug-related toxicity (but not qualifying for a DLT).  
The following toxicities will not be considered DLTs:

Grade ≤3 adverse event of tumor flare (defined as local pain, irritation, or rash localized at 
sites of known or suspected tumor)

Grade ≤3 immune-related adverse event (irAE) that resolves to Grade ≤1 within 7 days (see 
protocol body for definition of irAE)
Subjects who for reasons other than drug related toxicity or a  DLT, fail to complete 75% of the 
planned total dose in Cycle 1, (equivalent to 16 out of  21 days) will be replaced.
The MTD is defined as one dose level below the dose level where ≥2 of 6 subjects experience a DLT.  
If ≤1/6 subjects in all dose cohorts experience a DLT, then an MTD will not have been reached.  In 
this case, the RP2D will be selected based on integrated evaluation of safety, tolerability, clinical 
benefit, PK, and PD data, for all dose levels tested. 
An expansion cohort of 6 to16 subjects will be enrolled to confirm the RP2D after completion of 
dose escalation part.  
Study Population
This study will be conducted in subjects with tumor types that harbor high levels of myeloid infiltrate 
based on the Cancer Genome Atlas (TCGA), in keeping with the expected action of E7046 on 
intratumoral immunosuppressive cells of myeloid lineage.
Approximately 30 to 40 subjects will be enrolled, 24 in the dose escalation part, and 6 to 16 subjects 
in the cohort expansion.
Study Treatment
E7046 will be administered as a single agent orally once daily (QD) continuously in 21-day cycles.  
Subjects will be required to fast 2 hours before and 2 hours after the E7046 dose. 
Subjects will discontinue study drug at the time of disease progression, development of unacceptable 
toxicity, withdrawal of consent or termination of the study program.


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Study Assessments
Efficacy Assessments
Tumor assessments will be performed by investigators based on both irRECIST and modified 
RECIST 1.1; however, the treatment decisions will be based on irRECIST. Tumor assessments will 
be carried out during the Pretreatment Phase and then every 6 weeks.
Pharmacokinetic Assessments
Blood samples for PK analyses will be collected during Cycle 1 on Day 1 and Day 8 at predose (0 h), 
0.5, 1, 2, 4, 6, 8, and 10 and 24h postdose. Urine samples for PK analyses will be collected during 
the Dose Escalation part only during Cycle 1.
The major metabolite identified in nonclinical species (M1) will also be analyzed.
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs, including all CTCAE grades 
(for both increasing and decreasing severity), and serious adverse events (SAEs); regular laboratory 
evaluation for hematology, blood chemistry, and urine values; and periodic measurement of vital 
signs, echocardiograms/MUGA scans, electrocardiograms (ECGs), and physical examinations.  The 
effects of E7046 on cardiovascular repolarization will be evaluated via continuous Holter/ECG 
monitoring. Subjects with decreasing hemoglobin levels or gastrointestinal symptoms indicative of 
gastrointestinal bleed should be evaluated for a potential gastrointestinal bleeding source as 
appropriate.
Statistical Methods
The sample size of 30 to 40 subjects is considered adequate for the purposes of selecting RP2D. The 
expected sample size for the dose escalation part of this trial will be up to 24 subjects  Per the dose 
escalation design adopted and modified from the traditional 3+3 design (see protocol body), there 
will be a maximum of 4 planned cohorts and there will be 6 subjects in each cohort to allow for 
adequate assessment of tolerability, clinical benefit, PK, PD data and integrated evaluation of safety 
so as to select RP2D.
Safety parameters will be summarized using descriptive statistics (mean, standard deviation, median, 
Q1, Q3, and range for continuous variables; numbers and percentages for categorical measures).
Efficacy parameters including ORR, response duration, time to response, PFS, DCR, and CBR will 
be listed and descriptively summarized as appropriate. For response duration and time to response, 
summary statistics (median Q1, Q3, and range) will be summarized for subjects achieving a best 
overall response of confirmed partial or complete response.  


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TABLE OF CONTENTS
1
TITLE PAGE.....................................................................................................................1
2
CLINICAL PROTOCOL SYNOPSIS...............................................................................3
3
TABLE OF CONTENTS...................................................................................................6
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..................................11
5
ETHICS............................................................................................................................14
5.1
Institutional Review Boards/Independent Ethics Committees ..............................14
5.2
Ethical Conduct of the Study.................................................................................15
5.3
Subject Information and Informed Consent...........................................................15
6
INVESTIGATORS AND STUDY PERSONNEL..........................................................16
7
INTRODUCTION ...........................................................................................................17
7.1
E7046 Background.................................................................................................17
7.1.1
E7046 Mechanism of Action .......................................................................17
7.1.2
Therapeutic Indication .................................................................................18
7.1.3
Preclinical Summary....................................................................................19
7.1.3.1
Pharmacology ......................................................................................19
7.1.3.2
Pharmacokinetics and Metabolism ......................................................19
7.1.3.3
Toxicology and Safety Pharmacology.................................................20
7.2
Study Rationale......................................................................................................21
8
STUDY OBJECTIVES....................................................................................................22
8.1
Primary Objectives.................................................................................................22
8.2
Secondary Objectives.............................................................................................22
8.3
Exploratory Objectives ..........................................................................................22
9
INVESTIGATIONAL PLAN..........................................................................................23
9.1
Overall Study Design and Plan..............................................................................23
9.1.1
Dose Escalation............................................................................................24
9.1.1.1
Dose Escalation Design .......................................................................24
9.1.1.2
Dose-Limiting Toxicities.....................................................................27
9.1.1.3
Maximum Tolerated Dose ...................................................................28
9.1.1.4
Selection of the Recommended Phase 2 Dose.....................................28
9.1.2
Cohort Expansion.........................................................................................29
9.1.3
Study Phases ................................................................................................29
9.1.3.1
Pretreatment Phase...............................................................................29
9.1.3.2
Treatment Phase...................................................................................29
9.1.3.3
Extension Phase ...................................................................................30
9.2
Discussion of Study Design...................................................................................31


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9.3
Selection of Study Population................................................................................32
9.3.1
Inclusion Criteria .........................................................................................32
9.3.2
Exclusion Criteria ........................................................................................34
9.4
Treatments..............................................................................................................36
9.4.1
Treatments Administered.............................................................................36
9.4.1.1
Dose modifications ..............................................................................36
9.4.2
Identity of Investigational Product...............................................................38
9.4.2.1
Chemical Name, Structural Formula of E7046....................................38
9.4.2.2
Comparator Drug .................................................................................38
9.4.2.3
Labeling for Study Drug......................................................................38
9.4.2.4
Storage Conditions...............................................................................38
9.4.3
Method of Assigning Subjects to Treatment Groups...................................39
9.4.4
Selection of Doses in the Study...................................................................39
9.4.5
Selection and Timing of Dose for Each Subject..........................................39
9.4.6
Blinding........................................................................................................39
9.4.7
Prior and Concomitant Therapy...................................................................39
9.4.8
Prohibitions and Restrictions During the Study Period...............................39
9.4.8.1
Food .....................................................................................................39
9.4.8.2
Physical Activity Restrictions..............................................................40
9.4.9
Treatment Compliance.................................................................................40
9.4.10
Drug Supplies and Accountability...............................................................40
9.5
Study Assessments.................................................................................................42
9.5.1
Demography, Disease History, and Other Baseline Assessments ...............42
9.5.2
Efficacy Assessments...................................................................................42
9.5.3
Pharmacokinetic Assessments .....................................................................44
9.5.4
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Assessments.................................................................................................45
9.5.4.1
Overview of Biomarker Approach.......................................................45
9.5.4.2
Protein and mRNA markers in serum..................................................46
9.5.4.3
Intratumoral immune cell populations.................................................46
9.5.4.4
Archival Tumor....................................................................................46
9.5.4.5
Circulating immune cell population.....................................................46
9.5.4.6
Blood plasma cell-free nucleic acid analysis.......................................47
9.5.4.7
Pharmacogenomic analysis..................................................................47
9.5.4.8
Urine biomarker analysis .....................................................................47
9.5.4.9
General.................................................................................................47
9.5.4.10
Exploratory Imaging Biomarkers ........................................................48


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9.5.5
Safety Assessments......................................................................................49
9.5.5.1
Adverse Events and Events Associated with Special Situations .........49
9.5.5.2
Serious Adverse Events and Events Associated with Special 
Situations..............................................................................................51
9.5.5.3
Laboratory Measurements ...................................................................52
9.5.5.4
Vital Signs and Weight Measurements................................................53
9.5.5.5
Physical Examinations.........................................................................54
9.5.5.6
Electrocardiograms ..............................................................................54
9.5.5.7
Echocardiograms or Multiple Gated Acquisition Scans......................54
9.5.5.8
Pregnancy Test.....................................................................................55
9.5.6
Schedule of Procedures/Assessments ..........................................................55
9.5.6.1
Schedule of Procedures/Assessments ..................................................55
9.5.6.2
Description of Procedures/Assessments Schedule...............................59
9.5.7
Appropriateness of Measurements...............................................................59
9.5.8
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations..............................................................59
9.5.8.1
Reporting of Serious Adverse Events..................................................59
9.5.8.2
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding .......................................................................................60
9.5.8.3
Reporting of Events Association with Special Situations....................60
9.5.8.3.1
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error ............................60
9.5.8.4
Expedited Reporting ............................................................................61
9.5.8.5
Breaking the Blind...............................................................................61
9.5.8.6
Regulatory Reporting of Adverse Events ............................................61
9.5.9
Completion/Discontinuation of Subjects.....................................................61
9.5.10
Confirmation of Medical Care by Another Physician .................................62
9.6
Data Quality Assurance .........................................................................................62
9.6.1
Data Collection ............................................................................................62
9.6.2
Clinical Data Management ..........................................................................62
9.7
Statistical Methods.................................................................................................63
9.7.1
Statistical and Analytical Plans....................................................................63
9.7.1.1
Study Endpoints...................................................................................63
9.7.1.2
Definitions of Analysis Sets.................................................................64
9.7.1.3
Subject Disposition..............................................................................65
9.7.1.4
Demographic and Other Baseline Characteristics ...............................65
9.7.1.5
Prior and Concomitant Therapy...........................................................65
9.7.1.6
Dose Escalation Primary Endpoints Analyses.....................................65


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9.7.1.7
Efficacy Analyses ................................................................................66
9.7.1.8
Pharmacokinetic Analyses...................................................................66
9.7.1.9
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses...............................................................................................66
9.7.1.10
Safety Analyses....................................................................................66
9.7.1.10.1
Extent of Exposure.........................................................................67
9.7.1.10.2
Adverse Events ..............................................................................67
9.7.1.10.3
Laboratory Values..........................................................................68
9.7.1.10.4
Vital Signs......................................................................................68
9.7.2
Determination of Sample Size .....................................................................68
9.7.3
Interim Analysis...........................................................................................68
9.7.4
Other Statistical/Analytical Issues ...............................................................68
9.7.5
Procedure for Revising the Statistical Analysis Plan...................................68
10
REFERENCE LIST .........................................................................................................69
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).......71
11.1
Changes to the Protocol .........................................................................................71
11.2
Adherence to the Protocol......................................................................................71
11.3
Monitoring Procedures...........................................................................................71
11.4
Recording of Data..................................................................................................72
11.5
Identification of Source Data.................................................................................72
11.6
Retention of Records..............................................................................................72
11.7
Auditing Procedures and Inspection......................................................................73
11.8
Handling of Study Drug.........................................................................................73
11.9
Publication of Results ............................................................................................73
11.10 Disclosure and Confidentiality ..............................................................................74
11.11 Discontinuation of Study .......................................................................................74
11.12 Subject Insurance and Indemnity...........................................................................74
12
APPENDICES .................................................................................................................75
LIST OF IN-TEXT TABLES
Table 1
Dose Cohorts in E7046 Dose-Escalation...................................................24
Table 2
E7046 Dose Reduction and Interruption Instructions................................37
Table 3
Imaging and Treatment After 1st Radiologic Evidence of PD..................44
Table 4
Biomarker assessments ..............................................................................45
Table 5
Clinical Laboratory Tests...........................................................................53
Table 6
Schedule of Procedures / Assessments in Study E7046-G000-101...........56


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LIST OF IN-TEXT FIGURES
Figure 1
Molecular Target for E7046 and Arachidonic Acid Cascade....................17
Figure 2
E7046 modulates immunosuppressive myeloid cells for cancer 
immune therapy .........................................................................................18
Figure 3
Schema for Dose Escalation ......................................................................26
Figure 4
Study Design..............................................................................................29
LIST OF APPENDICES
Appendix 1: Adaptation of RECIST for evaluation of immune therapy activity in 
solid tumors: Immune-Related Response Evaluation Criteria in Solid 
Tumors (irRECIST) ...................................................................................75
Appendix 2: Pre-Existing Autoimmune Diseases..............................................................80
Appendix 3: Cockcroft–Gault Calculation of Creatinine Clearance .................................81
Appendix 4: Common Terminology Criteria for Adverse Events (v4.03)........................82


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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AE
adverse event
BP
blood pressure
C1D1
Cycle 1 Day 1
CBR
clinical benefit rate
CRA
clinical research associate
CRC
colorectal cancer
CRF
case report form
CSF 1R
colony-stimulating factor-1 receptor
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P450
DCR
disease control rate
DOR
duration of response
DLT
dose-limiting toxicity
ECG
electrocardiograms
ECOG
Eastern Cooperative Oncology Group 
EP4
prostaglandin E2 (PGE2) receptor type 4
FDA
Food and Drug Administration
18FDG-PET
18fluorodeoxyglucose positron emission 
tomography
FFPE
formalin-fixed paraffin-embedded 
HCC
hepatocellular carcinoma 
HIV
human immunodeficiency virus 
ICF
informed consent form
ICH
International Conference on Harmonisation of 
Technical Requirements for Registration of 
Pharmaceuticals for Human Use
IEC
Independent Ethics Committee


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irAE
immune-related adverse event
irCR
immune-related complete response
irPD
immune-related progressive disease
irPR
immune-related partial response
irRECIST
immune-related Response Evalution Criteria
Criteria in Solid Tumors
irSD
immune-related stable disease
IRB
Institutional Review Board
LVEF
left ventricular ejection fraction
MDSC
myeloid-derived suppressor cells
MedDRA
Medical Dictionary for Regulatory Activities
MTD
maximum tolerated dose 
MUGA
multiple gated acquisition 
NSCLC
non-small cell lung cancer 
ORR
objective response rate 
OS
overall survival
PD
progressive disease, or pharmacodynamic(s)
PFS
progression-free survival
PGE2
prostaglandin E2
PK
pharmacokinetic(s)
POP
Proof of Principle
PR
Time from the beginning of the P wave (onset of 
atrial depolarization) to the beginning of the QRS 
complex
PT
preferred term
QD
once daily
QRS
Time taken for depolarization of the ventricles
QT
Time from the beginning of the QRS complex to 
the end of the T wave
QTc
QT interval corrected for heart rate
QTcF
QTc corrected for heart rate by the Friderichia 
method
RECIST
Response Evaluation Criteria In Solid Tumors


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RP2D
recommended Phase 2 dose 
SAP
statistical analysis plan
SAE
serious adverse event
SCCHN
squamous cell carcinoma of head and neck
SOC
system organ class
ssIR
suspected severe immune reaction
SUV
standardized uptake value
TAM
tumor-associated macrophages 
TEAE
treatment-emergent adverse event
ULN
upper limit of normal


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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 clinical 
research associate (CRA), change of telephone number).  Documentation of IRB/IEC 
compliance with the ICH E6 and any local regulations regarding constitution and review 
conduct will be provided to the sponsor.
A signed letter of study approval from the IRB/IEC chairman must be sent to the principal 
investigator (or if regionally required, 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 investigator (or if regionally required, 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) by the investigator or 
sponsor, depending on local regulatory obligations.  If the investigator is required to report to 
the IRB/IEC, he/she will forward a copy to the sponsor at the time of each periodic report.  
The investigator(s) or the sponsor will submit, depending on local regulations, periodic 
reports and inform the IRB/IEC (or if regionally required, the investigator and the relevant 
IRB via the head of the medical institution) of any reportable AEs per ICH guidelines and 
local IRB/IEC standards of practice.  Upon completion of the study, the investigator will 
provide the IRB/IEC with a brief report of the outcome of the study, if required.
At the end of the study, the sponsor should notify the IRB/IEC and Competent Authority 
(CA) within 90 days.  The end of the study will be the date of the last study visit for the last 
subject in the study.  The sponsor should also provide the IRB/IEC with a summary of the 
study’s outcome.  It is expected that the study duration will be 18 months.
In the case of early termination/temporary halt of the study, the investigator should notify the 
IRB/IEC and CA within 15 calendar days, and a detailed written explanation of the reasons 
for the termination/halt should be given.


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5.2
Ethical Conduct of the Study
This study will be conducted in accordance with standard operating procedures (SOPs) of the 
sponsor (or designee), which are designed to ensure adherence to GCP guidelines as required 
by the following:
•
Principles of the World Medical Association Declaration of Helsinki 2008
•
ICH E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, 
International Conference on Harmonisation of Pharmaceuticals for Human Use
•
Title 21 of the United States Code of Federal Regulations (US 21 CFR) regarding clinical 
studies, including Part 50 and Part 56 concerning informed subject consent and IRB 
regulations and applicable sections of US 21 CFR Part 312
•
A waiver from the IRB(s)/IEC(s) will be obtained before study initiation for non-US 
studies conducted under an Investigational New Drug (IND) application.
•
European Good Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 
2001/20/EC for studies conducted within any EU country.  All SUSARs will be reported, 
as required, to the Competent Authorities of all involved EU member states.
•
Article 14, Paragraph 3, and Article 80-2 of the Pharmaceutical Affairs Law (Law No. 
145, 1960) for studies conducted in Japan, in addition to Japan’s GCP
•
Other applicable regulatory authorities’ requirements or directives
5.3
Subject Information and Informed Consent
As part of administering the informed consent document, the investigator must explain to 
each subject (or 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 
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 


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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.  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 local regulations and provided to the sponsor.  Each subject 
must sign an approved ICF before study participation.  The form must be signed and dated by 
the appropriate parties.  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 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.
6
INVESTIGATORS AND STUDY PERSONNEL
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at approximately 3 investigational site(s) in the USA and potentially other locations 
globally.
The name and telephone and fax numbers of the medical monitor and other contact personnel 
at the sponsor are listed in the Investigator Study File provided to each site.


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7
INTRODUCTION
7.1
E7046 Background
7.1.1
E7046 Mechanism of Action
E7046 is a small molecule compound that is a specific inhibitor of the prostaglandin receptor 
EP4 (Figure 1 ). Prostaglandins play a key role in mediating inflammatory responses, and 
their effects on differentiation of monocytic cells have been subverted by tumors to maintain 
an immunosuppressive tumor microenvironment (Qian and Pollard, 2010; Heusinkveld and
van der Burg, 2011; Highfill, et al., 2014).
Figure 1
Molecular Target for E7046 and Arachidonic Acid Cascade
E7046 is a selective EP4 antagnoist. The molecular targets for the COX inhibitors are also shown for 
comparison.  COX = cyclooxygenase, DP = prostaglandin D2 receptor, EP4 = prostaglandin E2 receptor 4, FP = 
prostaglandin F2α receptor, IP = prostacyclin receptor, PG = prostaglandin, PGES = prostaglandin E synthase, 
PGI2 = prostacycline, TP = thromboxane receptor, TxA2 = thromboxane A2.
Through selective antagonism of EP4, which is one of the four known receptors for the 
prostaglandin PGE2, E7046 inhibits the differentiation and function of intratumoral 
monocytic myeloid lineage cells.  These target cells, which include tumor-associated 
macrophages (TAM) and myeloid-derived suppressor cells (MDSCs), contribute to the 
formation and maintenance of an immunosuppressive tumor microenvironment. E7046 thus 
acts to relieve tumor suppression of T-effector cells (Figure 2) (Baum, et al., 2013). This 
concept has been supported by preclinical experiments using a variety of genetic, cellular and 
molecular approaches, and animal models, in conjunction with the Cancer Genome Atlas
(TCGA) cancer bioinformatics to identify tumor types with high level of myeloid infiltrate.  
This mechanism of action is distinct from the T cell-targeting action of the immune 
checkpoint inhibitors (eg, ipilimumab CTLA4 antibody, and PD1/PDL1 antibodies) that have 
shown recent success in the clinic (Hodi, et al., 2010; Topalian, et al., 2012; Robert, et al.,
2014) (Figure 2).  


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Figure 2
E7046 modulates immunosuppressive myeloid cells for cancer 
immune therapy
E7046 inhibits the formation and function of immune suppressive M2Mand MDSC by antagonizing EP4
signaling in myeloid cells. Consequently, formation of antigen-presenting cells (DC and M1M) were increased 
to promote T effector cell (Teff)-mediated antitumor adapative immune response.  Drugs (approved of in 
development) that affect the different pathways are indicated. 
DC = dendritic cells, MDSC = myeloid-derived suppressor cell, M1M= M1 macrophage, Teff  = T effector 
cells, Treg = regulatory T cells.
7.1.2
Therapeutic Indication
E7046 is intended to be developed as a new type of cancer immune therapy targeting host 
immunosuppressive cells in the tumor microenvironment that are of myeloid lineage.
Tumor types that will be explored include pancreatic adenocarcinoma, renal clear cell 
carcinoma, squamous cell carcinoma of head and neck (SCCHN), non-small cell lung cancer 
(NSCLC), colorectal cancer (CRC), hepatocellular carcinoma (HCC), serous epithelial 
ovarian cancer, cervix cancer, transitional cell bladder cancer, and triple-negative breast 
cancer (TNBC).


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7.1.3
Preclinical Summary
7.1.3.1
Pharmacology
E7046 selectively inhibits binding of PGE2 to human EP4 and thus inhibits PGE2-EP4
mediated cellular signaling. Activity of E7046 is dependent on the presence of intact 
immune system. E7046 did not show any antiproliferative activity towards cancer cells in 
vitro; however, daily oral administration of E7046 in immunocompetent mice showed 
significant in vivo antitumor activity against multiple models of syngeneic murine tumors 
rich in myeloid cells. No such antitumor activity was observed in tumors that were growing 
in immunodeficient nude mice or in immunocompetent mice bearing syngeneic tumors with 
few infiltrating myeloid cells.
Treatment of tumor-bearing animals with E7046 significantly altered the populations and 
functions of immune cells, both in the tumors and in the periphery. Furthermore, in mouse 
syngeneic tumor models, the combination of E7046 with radiation, with radiation plus 
gemcitabine, or with immune checkpoint blockade agents such as anti-CTLA4 antibodies all 
showed significantly better antitumor activity compared with radiation, radiation plus 
gemcitabine, or immune checkpoint blockade agent alone. E7046 is thus considered a novel 
cancer immune therapy that has potential therapeutic effects in multiple human tumor types. 
7.1.3.2
Pharmacokinetics and Metabolism  
Pharmacokinetic (PK) profiles of E7046 after oral administration in mouse, rat and dog were 
characterized by fast absorption (median tmax range: 0.25-0.75 h), extensive distribution 
(mean Vss range: 3.85-7.18 L/kg), slow clearance (mean CL range: 0.27-1.35 L/h/kg), and 
slow elimination (t1/2 range: 3.60-19.17 h).
Bioavailability was moderate to high in all three species (%F range: 31.2 %-82.3 %) and was 
the highest in dogs. An enterohepatic circulation of E7046 was observed in both rat and 
dogs. Plasma protein binding of E7046 was 50% to 70% and constant within the range of 
concentrations tested (200 to 20000 ng/mL) in mouse, rat, dog, monkey, and human. The 
Cb/Cp ratio across species was approximately unity (1) suggesting an equal distribution 
between plasma and blood cells.
The major metabolite of E7046 was identified as an acyl-glucuronide of E7046 (ER-
000888188-000) from cryopreserved hepatocytes of human, mouse, rat, beagle dog and 
monkey. No human- unique metabolite was found. The main elimination path of E7046 in 
rats was via biliary excretion, while the renal clearance was a minor pathway in both rats and 
dogs.
The potential of CYP-mediated drug-drug interaction is predicted to be insignificant as 
E7046 showed neither CYP induction activity nor inhibition of any of the major CYP 
enzymes. E7046 did show weak time-dependent inhibition (TDI) of CYP3A.


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Human E7046 doses of 20 mg/man/day and 200 mg/man/day is predicted to sustain unbound 
drug concentration above human EP4 IC50 and IC90, respectively. In all mouse pharmacology 
models tested, 50 mg/kg was an effective antitumor dose. This corresponds to an equivalent 
human dose of 120 mg/man/day, which is a dose sustaining drug concentration of between 
IC50 and IC90  for human EP4.
7.1.3.3
Toxicology and Safety Pharmacology
Toxicity of E7046 was evaluated in single- and repeated-dose oral toxicity studies in male 
and female rats and dogs (up to 4 weeks). E7046 induced similar toxicities across preclinical 
species. Major findings in dogs and rats were limited to dose-dependent intestinal effects 
and testicular toxicity. Intestinal changes were characterized by abnormal stools which 
resulted in progressive weight loss at highest dose tested. In addition, E7046 induced minor 
changes in heart rate and blood pressure (BP) in the dog at exposures more than 2 fold higher 
than the predicted efficacious human exposure.
The proposed starting dose in humans of 125 mg is less than 1/9 of the human dose 
equivalent in dogs that caused only occasional mucous stool and slight testicular changes. If 
translated into the clinic, both would be considered acceptable changes in the intended 
subject population.  Based on the observed toxicities in preclinical species, E7046 may cause 
the side effects in humans including, but not limited to, the following:
Gastrointestinal system: Colitis, characterized by new onset of diarrhea, which may be
accompanied by abdominal pain and or gastrointestinal bleeding.
Testicular system:  Decreased testicular weight, hypo cellularity.
Cardiovascular system:  Reversible increase in heart rate and decrease in mean blood 
pressure.
Safety pharmacology of E7046 was evaluated in vitro for hERG channel inhibition and 
platelet aggregation, in vivo for cardiovascular function in dogs, and for respiratory and 
central nervous system functions and prostanoid metabolism in rats. No significant adverse 
effects of E7046 were observed in these studies except for an increase in heart rate, and a 
decrease of BP at 100 mg/kg of E7046 in dogs. Low risk of side effects in cardiovascular, 
respiratory and central nervous system is anticipated for E7046 in humans. 
Preclinical safety studies thus suggest that E7046 has an acceptable safety profile in the 
intended population at proposed clinical doses.


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7.2
Study Rationale
The interaction between cancer cells and the tumor microenvironment is complex, but recent 
research has begun to reveal the mechanisms by which a successful tumor embeds itself 
within a network of supporting normal cells, such that targeting the tumor microenvironment 
is at the forefront of developments in novel cancer therapy (Hanahan and Weinberg 2011). 
The human immune system is empowered to fight foreign antigens by a continuous 
surveillance around the whole body. Though immune cells are able to impair early tumor 
development in most people, in cancers that reach clinical attention, the immune system has 
become immune tolerant of the tumor tissue at both local and systemic levels (Schreiber, et 
al., 2011).
An approach to effectively break immune tolerance in cancer subjects holds the key to 
successful cancer immune therapy. Recent Food and Drug Administration (FDA) approval 
of two cancer immune therapies that specifically target cancer-hijacked immune support 
systems, anti-CTLA4 (Yervoy®; ipilimumab) and dendritic cells modified ex vivo
(Provenge®; sipuleucel T), exemplified this trend. Several additional therapies targeting the 
immune components of the tumor microenvironment (eg, nivolumab) are currently in clinical 
trials with very promising clinical effects (Brahmer, et al., 2012; Topalian, et al., 2012).
Immunosuppressive signals come from cancer cells as well as immune cells (Figure 2). 
CTLA4 blockade inhibits the suppressive signals from effector T cells (cytotoxic T cells and 
Th1/2 cells) themselves and from Treg cells, while PD1/PDL1 blockade mainly inhibits the 
signals from cancer cells (Brahmer, et al., 2012; Topalian, et al., 2012). Another 
immunosuppressive mechanism in the tumor microenvironment is supplied by myeloid cells.
Myeloid cells respond to signals in their local environment by acquiring a phenotype that is 
appropriate for the condition. These phenotypes are considered either type 1 (M1M), which 
are pro-inflammatory, antimicrobial and antitumor antigen-presenting macrophages, or type 
2 (M2M), which are pro-angiogenic, anti-inflammatory, immunosuppressive wound-healing 
MDSC and TAM.
The presence or accumulation of TAM and MDSC cells in tumors is well documented in the 
literature to be associated with a poorer prognosis in many types of human carcinomas and 
adenocarcinomas, including colon, pancreatic, lung, breast, head and neck squamous cell 
(HNSSC), prostate, hepatocellular carcinoma (HCC) and colorectal (CRC), thyroid, 
melanoma and others (Joyce and Pollard, 2009; Ganjoo, et al., 2011; Medrek, et al., 2012;
Zhang, et al., 2012).
Due to its exquisite receptor selectivity, oral bioavailability, strong preclinical safety profile, 
and unique antitumor mechanism, E7046 is an excellent candidate to be developed as a novel 
anticancer immune therapy by targeting immunosuppressive TAM/MDSC. Treatment with 
E7046 is intended to modify the immunosuppressive tumor microenvironment by inhibiting 
the accumulation of MDSC and TAM, and thus permitting enhanced host immune responses 
against the tumor.


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8
STUDY OBJECTIVES
8.1
Primary Objectives
The primary objective of the study is to:
Assess the safety/tolerability profile of E7046 as a single agent administered orally once 
daily, continuously in 21-day cycles, in subjects with selected advanced and/or recurrent 
malignancies.
Determine the MTD and/or RP2D of E7046.
8.2
Secondary Objectives
The secondary objectives of the study are to:
Evaluate the pharmacokinetic (PK) profile of E7046.
Evaluate the ORR according to immune-related RECIST (irRECIST) in subjects treated 
with E7046 with selected tumor types with high level of myeloid infiltrate
Evaluate the following additional efficacy endpoints according to irRECIST: time to 
response (TTR), duration of response (DOR), progression-free survival (PFS), disease 
control rate (DCR), and clinical benefit rate (CBR). 
8.3
Exploratory Objectives
The exploratory objectives of the study are to:
Explore efficacy according to modified RECIST 1.1, using the following endpoints: 
ORR, TTR, DOR, PFS, DCR, and CBR
Assess overall survival (OS)
Explore the pharmacodynamic effect of E7046 on selected immune cell populations and 
selected biomarkers in tumor infiltrate and in peripheral blood.
Explore 18FDG-PET as a biomarker of response 
Explore the pharmacokinetic/pharmacodynamic (PK/PD) relationship


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9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
This is an open label, multicenter, Phase 1 study that will be conducted in 2 parts: a dose 
escalation part and a cohort expansion part. The objective of the dose escalation part is to 
assess the safety and tolerability and determine the MTD and/or RP2D of E7046. In the 
cohort expansion part an additional 6 to 16 subjects will be treated at the RP2D to further
characterize safety, efficacy, PK, and PD. E7046 is a novel cancer immune therapy and as 
this is the first study in humans  therefore a cautious approach in the first cohort of subjects is 
prudent.  Staggered start of dosing in the first cohort will thus be implemented to ensure 
exposure of a limited number of subjects in the initial dosing cohort.
The applicability of conventional MTD finding Phase 1 designs for compounds with 
minimum expected toxicity has been discussed in various publications, and several 
alternative strategies have been advised (Rubinstein and Simon, 2003). Pharmacokinetics
based and minimal biologically active dose finding designs rely not only on having robust 
estimates from preclinical data but also the use of biological correlative response endpoints 
that might get complicated by issues of assay adequacy and access to biological tissues. 
Another strategy for Phase 1 studies of targeted compounds is to compare dose levels with 
regard to biological response in normal tissue using an optimized highly reproducible assay. 
If use of normal tissue for assessing biological response is not possible or if a highly 
reproducible assay is not available, characterisation f of an optimal biologic dose may not be 
feasible or might require a large sample size. 
The study design was selected taking these concerns into account. A major consideration 
was that the toxicities of E7046 are likely to be moderate in the dose range planned and an 
MTD may not be reached (according to preclinical results). It is anticipated that the RP2D 
will be selected based on integrated evaluation of safety, tolerability, clinical benefit, PK, and 
PD data, collected from all dose levels tested. Accordingly, a modification of the standard 
3+3 design was selected, where dose cohorts of 6 subjects will be enrolled at each of the 4 
dose levels to be tested so as to provide sufficient data for selecting RP2D in the absence of 
an MTD.


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9.1.1
Dose Escalation
9.1.1.1
Dose Escalation Design
E7046 will be tested in sequential escalating dose cohorts of 6 subjects per cohort, at the dose 
levels shown in Table 1. Subjects will be assigned to a dose level in the order of study entry.
Intermediate dose levels may be explored.
Table 1
Dose Cohorts in E7046 Dose-Escalation
Dose level
No. of Subjects
E7046 Dose
-1
6
75 mg QD
1
6
125 mg QD
2
6
250 mg QD
3
6
500 mg QD
4
6
750 mg QD
QD = once daily.
The schema for dose escalation is adopted and modified from the traditional 3+3 design and 
is shown in Figure 3. Dose limiting toxicities are defined in Section 9.1.1.2.


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Enrollment for first dose cohort (125 mg QD): (see Figure 3 Panel B)
In the first cohort, staggered dosing will be employed as described below.
Suspected severe immune reactions (ssIR) are defined as listed in the CTCAE v4,03 
"Immune System Disorders", including Allergic Reaction, Anaphylaxis, and Cytokine 
Release Syndrome.
First 3 subjects (Subjects 1, 2, and 3)

Initially one subject (Subject #1) will be enrolled and dosed.
o
If after 14 days of dosing no suspected severe immune reactions are observed, 
another 2 subjects (Subjects # 2 and 3) will be enrolled and dosed.
o
If within the first 14 days, Subject #1 experiences a suspected severe immune 
reaction, another subject (Subject #2) will be enrolled and dosed.

If after 14 days of dosing no suspected severe immune reactions are 
observed for Subject #2, another subject (Subject #3) will be enrolled and 
dosed.

If within the first 14 days, Subject #2 also experiences a suspected severe 
immune reaction, enrollment in this dose cohort will stop. A lower dose 
level of 75 mg QD (Dose Level -1) may be tested. Enrollment of the 6 
subjects at Dose Level -1 will follow the same staggered schema as 
described for Dose Level 1.
Next 3 subjects (Subjects 4, 5, and 6)

After evaluation of the first 3 subjects for DLTs after 21 days (Cycle 1), enrollment 
will continue as follows:
o
If ≤1 of 3 first subjects experiences DLTs in Cycle 1, the remaining 3 subjects 
(Subjects # 4, 5, and 6) in the first cohort will be enrolled and treated.
o
If >1 of 3 first subjects experiences DLTs in Cycle 1, a lower dose level of 75 mg 
(dose level -1) will be tested, following the same enrollment schema as described 
for Dose Level 1.
Enrollment of subsequent dose cohorts:

There will be no staggered dosing after the first dose cohort, however the subject 
enrolment will be controlled so that no more than one subject will be dosed on the 
same day.

If ≥2 of 6 subjects in any dose cohort experiences a DLT, then dose escalation will be 
stopped.

If ≤1 of 6 subjects in a dose cohort experiences a DLT, then 6 subjects will be 
enrolled at the next higher dose level. Dose escalation will continue until a dose level 
is reached where ≥2 subjects experience a DLT, or when 750 mg is reached based on


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an integrated evaluation of safety, tolerability, clinical benefit, PK, and
pharmacodynamic data, for all dose levels tested.
Additional enrollment (if necessary)
If needed for selection of RP2D, an additional 3 subjects may be enrolled at 1 or 2 selected 
dose levels.
Panel A: Overall Dose Escalation Schema
Panel B: First Dose Cohort (Staggered dosing)
ssIR = suspected severe immune reaction
Figure 3
Schema for Dose Escalation
6 subj
250mg QD
Level 2
500mg QD
Level 3
750mg QD
Level 4
Starting Dose 
Level 1 
125 mg QD
≤ 1 DLT
6 subj
6 subj
≥ 2 DLTs
75mg QD
Level -1
6 subj
6 subjects
Staggered dosing
(see Panel B)


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9.1.1.2
Dose-Limiting Toxicities 
Dose-limiting toxicities (DLTs) are any of the following drug related toxicities (any toxicities 
considered related, probably related, or possibly related to E7046) occurring during Cycle 1
as judged by the investigator. 

Nonhematologic toxicity ≥ Grade 3 (except diarrhea, nausea and vomiting unless 
lasting >3 days despite optimal supportive care)

Confirmed (with a second measurement after 24 hours) nonhematologic appropriately-
graded laboratory findings of Grade ≥3 that were ≤ Grade 1 at baseline 

Hematologic toxicity:
o
Grade 4 neutropenia for 5 days, or Grade 3 neutropenia with fever (fever is 
38.4 ºC),
o
Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia with bleeding or lasting 
>7 days

Any other toxicity assessed as related to E7046 treatment, and which in the opinion of
the study investigator(s) and the sponsor physician constitutes a dose-limiting toxicity

Subjects who have missed ≥7 days of dosing in Cycle 1 due to drug-related toxicity 
(but not qualifying for a DLT) will be assessed as experiencing a DLT.  
Grading of toxicities is based on National Cancer Institute - Common Terminology Criteria 
for Adverse Events (NCI CTCAE) v4.03 (Appendix 4).
Adverse events occurring after Cycle 1 may be considered DLTs upon discussion between 
the investigator(s) and the sponsor physician. 
The following toxicities will not be considered DLTs:

Grade ≤3 adverse event of tumor flare (defined as local pain, irritation, or rash 
localized at sites of known or suspected tumor)

Grade ≤3  immune-related adverse event (irAE) that resolves to Grade 1 or less within 
7 days, while not constituting a DLT for dose escalation purposes, may preclude further 
administration of study drug or study drug may be continued at a reduced dose after 
discussion and agreement with Eisai medical monitor.
o
An irAE, a subset ofAEs, is defined as a clinically significant adverse event of 
any organ that is associated with study drug exposure, of unknown etiology, and 
is consistent with an immune-mediated mechanism. Serologic, immunologic, and 
histologic (biopsy) data should be used to support an irAE diagnosis. Appropriate 
efforts should be made to rule out neoplastic, infectious, metabolic, toxin, or other 
etiologic causes of the irAE.
Subjects who for reasons other than drug related toxicity or a DLT, fail to complete 75% of the 
planned total dose in Cycle 1, (equivalent to 16 out of  21 days) will be replaced.


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Assessment of DLTs will be discussed and agreed to by investigator(s) and sponsor 
physician prior to proceeding to the next dose level, and the decision will be documented.
9.1.1.3
Maximum Tolerated Dose
The MTD is defined as one dose level below the dose level where ≥2 of 6 subjects 
experience a DLT. If ≤1 of 6 subjects in all dose cohorts experience a DLT, then an MTD has 
not been reached.
9.1.1.4
Selection of the Recommended Phase 2 Dose 
The RP2D will be selected based on integrated evaluation of safety, tolerability, clinical 
benefit, PK, and PD data, for all dose levels tested. The investigator and sponsor will jointly 
evaluate the data and select the RP2D.
Selection of the RP2D will take place after the last subject in the Dose Escalation part 
completes the Treatment Phase (Section 9.1.3.2).  
The RP2D will be the selected according to the following guidelines:
1. The RP2D will not exceed the MTD.
2. Toxicities other than DLTs will be considered, including: AEs assessed as related to 
study drug treatment but not considered dose-limiting, the nature and frequency of 
toxicities, and the emergence of any specific category of toxicities.
3. Evidence of clinical activity, as available.
4. Available pharmacodynamic data.
5. Consideration will be given to select RP2D dose that will sustain E7046 exposure above 
IC50 or IC90 values for EP4 inhibition for the duration of dosing period.
If two or more potential RP2D dose levels cannot be distinguished using the criteria above, 
cohort expansion (see below) may take place at up to 2 dose levels to obtain data for up to 6 
additional subjects per dose level. Selection of RP2D will be based on this larger dataset.
If serious related toxicities are observed in later cycles beyond Cycle 1 a reduction of the 
MTD and/or RP2D may be considered. This determination will be made by the investigators
and the sponsor physician, taking into account all available data.


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9.1.2
Cohort Expansion
An expansion cohort of 6 to 16 subjects will be enrolled and treated at the RP2D after 
completion of the dose escalation part.  The objective is to further evaluate safety and 
efficacy of E7046 at the RP2D and further characterize PK and PD.  Subjects will  be
selected from the same tumor types as in the dose escalation part.
9.1.3
Study Phases
The study will consist of three phases for each subject: Pretreatment Phase, Treatment 
Phase, and Extension Phase.
A schematic of the 3 Phases is shown in Figure 4.
PHASE
Pretreatment
Treatment
Extension
PERIOD
Screening
Baseline
Treatment
Cycle 1
Treatment Continuation
(Cycle 2 and beyond)
EOT
Follow
-Up
Day
–28 to –1
-3 to -1
D1
D8
D15
D1
D8
(C2-6 only)
VISIT
1
2
3
4
5
6, 8 etc
7, 9 etc
98
99
EOT = End of Treatment
Figure 4
Study Design
9.1.3.1
Pretreatment Phase
The Pretreatment Phase is 28 days before the first day of dosing, and consists of:

A Screening Period spanning Day -28 to Day -1, to obtain informed consent, assess 
disease characteristics at study entry, and to establish protocol eligibility

A Baseline Period, which consists of the last 3 days of the Screening period (Day -3 
to Day -1), to establish baseline characteristics and confirm eligibility to start
treatment.
9.1.3.2
Treatment Phase
Treatment Phase is Cycle 1 (Day 1 - 21) where evaluable subjects will be assessed for DLT. 
At the end of the Treatment Phase subjects continue to the Extension Phase.


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9.1.3.3
Extension Phase
The Extension Phase consists of 2 periods: 

Treatment Continuation Period, during which subjects will continue in Cycle 2 and 
beyond to receive the same treatment they received during the Treatment Phase.
The Treatment Continuation period will start at the end of the Treatment Phase and 
will end with the completion of the Off-Treatment Visit (which will occur within 30 
days after the last administration of the study drug). It consists of study drug treatment 
on a 21-day cycle, regardless of dose interruptions. Subjects will undergo safety and 
efficacy assessments as defined in Schedule of Procedures (Section 9.5.6.1) . Subjects 
will discontinue the study drug and become Off-Treatment at the time of disease 
progression, development of unacceptable toxicity, withdrawal of consent or 
termination of the study program.

A Follow-Up Period, for study assessments after discontinuation from study treatment.
The Follow-up Period will begin the day after the Off-Treatment Visit and will 
continue as long as the study subject is alive until the completion of the primary 
analysis, unless the subject withdraws consent or until the sponsor terminates the study.
Subjects, who discontinue study treatment without disease progression will continue to 
be followed and undergo tumor assessments every 6 weeks until disease progression or 
until the start of another anticancer treatment. In the follow-up period, subjects will be 
treated by the investigator according to the prevailing local standard of care. Subjects 
will be followed every 12 weeks (±1week) for survival, performance status and 
subsequent anticancer treatments. The sponsor may decide to terminate survival 
follow-up anytime during the Extension Phase or when all subjects have discontinued 
study treatment.


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9.2
Discussion of Study Design
This is an open label, multicenter, Phase 1 study that will be conducted in 2 parts: a dose 
escalation part and a cohort expansion part.
E7046 will be administered as a single agent orally once daily (QD) continuously in 21-day 
cycles. Animal PK studies have shown that a once daily schedule administered continuously 
is likely to be adequate to maintain systemic concentrations of E7046 in an efficacious range, 
at the doses planned (Section 7.1.3.2). 
E7046 will be tested in sequential escalating dose cohorts of 6 subjects per cohort, to identify 
a MTD and/or a RP2D (Section 9.1 for detailed discussion of the rationale for this design).
Preclinical studies suggest that toxicities are anticipated to be moderate in the dose range 
planned to be studied, and that an MTD may not be reached. In this case, the RP2D will be 
selected based on integrated evaluation of safety, tolerability, clinical benefit, PK, and PD 
data, for all dose levels tested. Dose cohorts of 6 subjects each will be enrolled at each of the 
4 dose levels to be tested, rather than employing a traditional 3+3 design. This number of 
subjects per cohort is expected to provide sufficient data for selecting a RP2D in the absence 
of an MTD.
The starting dose of 125 mg (first-in-human dose) is the human equivalent dose of 1/9 the 
minimally toxic dose in preclinical species.  Based on preclinical PK/PD data, this dose was 
also projected to be in the efficacious range based on sustaining exposure at IC50 – IC90 of 
EP4 inhibition in vitro and on effectiveness in animal tumor models. The maximum dose of 
750 mg is >5 fold the starting dose of 125 mg, the latter being an anticipated efficacious 
dose. The maximum dose is also limited by the number of capsules to be ingested 
(6 capsules, with current capsule strength) being close to the maximum feasible number of 
capsules that could be taken at a time.
This study will enroll subjects with tumor types that are characterized by high levels of 
myeloid infiltrate.  The expected action of E7046 is to inhibit immunosuppressive cells of 
myeloid lineage. Preclinical work showed that E7046 had antitumor activity in six syngeneic 
tumor models with significant intratumoral monocytic cell infiltration, but not in other two 
tumor models with minimal monocytic cell infiltration. Thus, this selected population is 
considered appropriate for the expected mechanism of action of E7046. 


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9.3
Selection of Study Population
Approximately 30 to 40 subjects in total will be enrolled: 24 in the Dose Escalation part and 
6 to 16 in the expansion cohort. Subjects who do not meet all of the inclusion criteria or who 
meet any of the exclusion criteria will not be eligible to receive study drug.
9.3.1
Inclusion Criteria
Subjects must meet all of the following criteria to be included in this study:
1.
Age ≥18 years. 
2.
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
3.
Life expectancy ≥12 weeks.  
4.
Subjects must have any of the following tumor types, confirmed by available pathology 
records or current biopsy, that is advanced, nonresectable, or recurrent and progressing 
since last antitumor therapy, and for which no alternative standard therapy exists:
pancreatic adenocarcinoma, renal clear cell carcinoma, SCCHN, NSCLC, colorectal 
cancer (CRC), hepatocellular carcinoma (HCC), ovarian serous epithelial cancer, 
bladder transitional cancer, cervical cancer and triple-negative breast cancer
5.
Prior chemotherapy or immunotherapy (tumor vaccine, cytokine, or growth factor given 
to control the cancer) must have been completed at least 4 weeks before study drug 
administration, and all AEs have either returned to baseline or stabilized.
6.
Prior definitive radiation therapy must have been completed at least 6 weeks before 
study drug administration and the irradiated lesions should show evidence of 
progression if they are intended to be considered target lesions. Prior palliative 
radiotherapy must be completed at least 2 weeks before study drug administration. The 
radiotherapy related side effects must have resolved before the study entry.  No 
radiopharmaceuticals (strontium, samarium) will be allowed within 8 weeks before 
study drug administration.
7.
Subjects must have accessible tumors and consent to repeated biopsy for performance of 
correlative tissue studies.
8.
Must have at least one measurable lesion per irRECIST (Appendix 1):
a.
At least 1 lesion of ≥10 mm in the longest diameter for a non-lymph node or ≥15 
mm in the short-axis diameter for a lymph node that is serially measurable 
according to irRECIST using computerized tomography/magnetic resonance 
imaging (CT/MRI).
b. Lesions that have had definitive external beam radiotherapy or locoregional 
therapies such as radiofrequency (RF) ablation or brachytherapy must show 
evidence of progressive disease to be deemed a target lesion.
9.
Prior treated brain or meningeal metastases must be without evidence of progression
(confirmed by MRI) for at least 8 weeks and off immunosuppressive doses of systemic 


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steroids (>10 mg/day prednisone or equivalent) for at least 4 weeks before study drug 
administration.
10. Immunosuppressive doses of systemic medications, such as steroids or absorbed topical 
steroids (doses >7.5 to 10 mg/day prednisone or equivalent) must be discontinued at 
least 2 weeks before study drug administration.
11. Subjects with prior Hepatitis B or C are eligible on the condition that subjects have 
adequate liver function as defined by Inclusion Criterion #16 and Exclusion Criterion #5.
12. Left ventricular ejection fraction (LVEF) >50% on echocardiography or multiple gated
acquisition (MUGA) scan.
13. Adequate renal function defined as serum creatinine <1.5 × ULN (or use SI units or 
calculated creatinine clearance ≥50 mL/min per the Cockcroft and Gault formula 
[Appendix 3]).
14. Adequate bone marrow function:
a.
Absolute neutrophil count (ANC) ≥1500/mm3 (≥1.5 × 103/μl)
b. Platelets ≥100,000/mm3 (≥ 100 × 109/L)
c.
Hemoglobin ≥9.0 g/dL
15. Adequate liver function: 
a.
Total bilirubin ≤1.5 × upper limit of normal (ULN) except for unconjugated 
hyperbilirubinemia of Gilbert’s syndrome.
b. Alkaline phosphatase, alanine aminotransferase (ALT), and aspartate 
aminotransferase (AST) ≤3 × ULN (≤5 × ULN if subject has liver metastases).  If 
alkaline phosphatase is >3 × ULN (in absence of liver metastases) or >5 × ULN 
(in presence of liver metastases) AND the subject also is known to have bone 
metastases, the liver-specific alkaline phosphatase must be separated from the 
total and used to assess the liver function instead of total alkaline phosphatase
16. Adequate blood coagulation function as evidenced by an International Normalized Ratio 
(INR) ≤1.5.
17. Willing and able to comply with all aspects of the protocol.
18. Provide written informed consent prior to any study-specific screening procedures.
19. Females must not be lactating or pregnant at screening or baseline (as documented by a 
negative beta-human chorionic gonadotropin [ß-hCG] test with a minimum sensitivity of 
25 IU/L or equivalent units of ß-hCG).  A separate baseline assessment is required if a 
negative screening pregnancy test was obtained more than 72 hours before the first dose 
of study drug.  All females will be considered to be of childbearing potential unless they 
are postmenopausal (at least 12 months consecutive amenorrheic, 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).  Females of childbearing potential must not 
have had unprotected sexual intercourse within 30 days prior to study entry and must 
agree to use a highly effective method of contraception, from the last menstrual period 


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prior to initiation of treatment, during Treatment Cycles, and for 30 days after the final 
dose of study treatment, and have a male partner who uses a condom.  Highly effective 
contraception includes:
a.
Double barrier methods of contraception such as condom plus diaphragm or 
cervical/vault cap with spermicide.
b. Placement of an intrauterine device.
c.
Established hormonal contraceptive methods:  oral, injectable, or implant.  
Females who are using hormonal contraceptives must have been on a stable dose 
of the same hormonal contraceptive product for at least 4 weeks prior to dosing 
and must continue to use the same contraceptive during the study and for 30 days 
after study drug discontinuation.
Female subjects exempt from this requirement are subjects who practice total 
abstinence or have a male partner who is vasectomized with confirmed azoospermia.  
If currently abstinent, the subject must agree to use a double barrier method as 
described above if they become sexually active during the Treatment Cycles, and for 
30 days after study drug discontinuation
20. Male subjects must have had a successful vasectomy (confirmed azoospermia) or they 
and their female partners must meet the criteria above (ie, not of childbearing potential 
or practicing highly effective contraception and use a condom throughout the study 
period and for 90 days after study drug discontinuation).
9.3.2
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from this study:
1.
Other malignancy active within the previous 2 years except for basal or squamous cell 
skin cancer, superficial bladder cancer or carcinoma in situ of the cervix or breast that 
has completed curative therapy.
2.
Subjects with any active autoimmune disease (Appendix 2) or a documented history of 
autoimmune disease, poorly controlled asthma or history of syndrome that required 
systemic steroids or immunosuppressive medications, except for subjects with vitiligo or 
resolved childhood asthma/atopy. Subjects with asthma who require intermittent use of 
bronchodilators (such as albuterol) will not be excluded from this study.
3.
Subjects with inflammatory bowel disease. 
4.
Known human immunodeficiency virus (HIV) infection.
5.
Active infection requiring therapy, including known positive tests for Hepatitis B 
surface antigen and hepatitis C virus (HCV) RNA.
6.
Major surgery within 4 weeks before the first dose of study drug. 
7.
Concurrent medical condition requiring the use of immunosuppressive medications, or 
immunosuppressive doses of systemic or absorbable topical corticosteroids except 
inhaled or intranasal corticosteroids (with minimal systemic absorption). 


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8.
Inability to take oral medication, or malabsorption syndrome or any other uncontrolled 
gastrointestinal condition (eg, nausea, diarrhea, or vomiting) that might impair the 
bioavailability of E7046.
9.
Any other major illness that, in the investigator’s judgment, will substantially increase 
the risk associated with the subject’s participation in this study.
10. Use of other investigational drugs within 28 days or at least 5 half-lives (whichever is 
shorter) before study drug administration.
11. Prior exposure to drugs that are antagonists of colony stimulating factor-1 receptor 
(CSF1R) like but not limited to emactuzumab (RG7155) (Roche), PLX3397 (Plexicon), 
JNJ40346627 (J & J).
12. Use of any live vaccines (eg, intranasal influenza, measles, mumps, rubella, oral polio, 
BCG, yellow fever, varicella, and TY21a typhoid vaccines) within 28 days.
13. Prolongation of corrected QT (QTcF) interval to >480 msec when electrolytes balance is 
normal.
14. Significant cardiovascular impairment: history of congestive heart failure greater than 
New York Heart Association (NYHA) Class II, uncontrolled arterial hypertension, 
unstable angina, myocardial infarction, or stroke within 6 months of the first dose of 
study drug; or cardiac arrhythmia requiring medical treatment (including oral 
anticoagulation).
15. Females who are pregnant (positive urine test) or breastfeeding.
16. Any history of a medical condition or a concomitant medical condition that, in the 
opinion of the investigator, would compromise the subject’s ability to safely complete 
the study.


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9.4
Treatments
9.4.1
Treatments Administered
E7046 will be administered as a single agent orally once daily (QD) continuously in 21-day 
cycles. Subjects will be required to fast 2 h before and 2 h after the E7046 dose. The daily 
dose should be taken at about the same time. Refer to Table 1 for doses to be administered.
E7046 is supplied as capsules in strengths of 75 mg and 125 mg.
Additional capsule 
strengths may be made available during the study. Drug will be supplied by the sponsor in 
labeled containers.
9.4.1.1
Dose modifications
Toxicity will be managed by concomitant medication (as appropriate), treatment interruption, 
dose reduction and treatment discontinuation, or a combination of these.
Dose reduction is allowed for all subjects during all cycles of treatment.
Subjects who experience a DLT in Cycle 1 may be allowed to continue study drug at a 
reduced dose after discussion with sponsor Medical monitor if this is judged to be in their 
best interest (see dose modification guidelines below).
Guidelines for dose adjustments
During E7046 treatment, dose interruptions and reductions due to toxicity will be 
implemented according to the instructions presented in Table 2. Any dosage interruptions of 
more than 3 days should be discussed with sponsor’s medical monitor to establish if longer 
dose interruption is needed. 


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Table 2
E7046 Dose Reduction and Interruption Instructions
E7046-related Toxicitya
During Therapy
Approximate dose adjustmentb
Grade 1
All occurrences
Continue E7046 treatment
Maintain dose level
Grade 2
1st occurrence
Interrupt E7046 until resolved 
to Grade ≤1 or baselinec
Maintain dose level
2nd occurrence 
(same toxicity)
Reduce by one dose level of starting dose
3rd occurrence 
(same toxicity)
Reduce by two dose levels of starting dose
4th occurrence 
(same toxicity)
Discuss with Sponsor 
Grade 3
1st occurrence
Interrupt E7046 until resolved 
to Grade ≤1 or baselinec
Reduce by one dose level of starting dose
2nd occurrence 
(same toxicity)
Reduce by two dose levels of starting dose
3rd occurrence 
(same toxicity)
Discontinue E7046 treatment
Not applicable
Grade 4:  Discontinue E7046d
a. Excluding alopecia and nausea, vomiting or diarrhea not receiving adequate treatment.
b. Subjects assigned to dose level -1 (75 mg) will not be dose-reduced and will not continue treatment under 
the conditions in which dose reduction is mandated. Subjects assigned to dose level 1 (125 mg) can only
be dose-reduced by one dose level and will not continue treatment under the conditions in which
reduction of two dose levels is mandated.
c. A delay of E7046 for more than 7 days due to any treatment-related toxicity must be discussed with the 
sponsor before treatment can be resumed.
d. Exclude Grade 4 hematologic toxicity of less than 72 hours duration.


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9.4.2
Identity of Investigational Product
9.4.2.1
Chemical Name, Structural Formula of E7046
•
Test drug code:  E7046
•
Generic name:  N/A
•
Chemical name: 4-{(1S)-1-[({3-(Difluoromethyl)-1-methyl-5-[3-
(trifluoromethyl)phenoxy]-1H-pyrazol-4-yl}carbonyl)amino]ethyl}benzoic acid
•
Molecular formula:  C22H18F5N3O4
•
Molecular weight:  483.40
•
Structural formula:
       
9.4.2.2
Comparator Drug
Not applicable.
9.4.2.3
Labeling for Study Drug
E7046 will be labeled in accordance with text that is in full regulatory compliance with each 
participating country and is translated into the required language(s) for each of those 
countries.
9.4.2.4
Storage Conditions
Study drug will be stored in accordance with the labeled storage conditions.  Temperature 
monitoring is required at the storage location to ensure that the study drug is maintained 
within an established temperature range.  The investigator or designee (or if regionally 
required, the head of the medical institution) 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 monitored continuously by using either an in-house validated data 
acquisition system, a mechanical recording device, such as a calibrated chart recorder, or by 
manual means, such that minimum and maximum thermometric values over a specific time 
period can be recorded and retrieved as required.


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9.4.3
Method of Assigning Subjects to Treatment Groups
See Sections 9.1.1 and 9.1.2.
9.4.4
Selection of Doses in the Study
See Section 9.3.
9.4.5
Selection and Timing of Dose for Each Subject
See Section 9.3.
9.4.6
Blinding
This is an open label study; the treatment will not be blinded.
9.4.7
Prior and Concomitant Therapy
The following are prohibited:

Drugs interfering with platelet aggregation, including NSAIDs  and anticoagulant s 
including LMWH, warfarin, anti-Xa agents
o
Physiological replacement of corticosteroid dosing representing physiological 
doses up to 7.5 mg/day will be allowed

Angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers 
(ARBs):  Subjects on these hypertensives at study entry should be switched to other 
hypertensives prior to study drug dosing

Other antitumor therapies such as chemotherapy, palliative radiotherapy, antitumor 
interventions (surgical resection, thoracocentesis, etc.), or antitumor immunotherapy.

Other investigational drugs
9.4.8
Prohibitions and Restrictions During the Study Period
9.4.8.1
Food 
Subjects are to fast 2 hours before and 2 hours after taking study medication.
On days when subjects will have 18FDG-PET/CT scans performed, they will refrain from 
eating (water intake is encouraged to maintain adequate hydration) for approximately 6 hours 
(specific instructions will be provided by the imaging core laboratory, including 
recommendations for morning and afternoon appointments, and for diabetic subjects) before 
injection of the radiotracer prior to scanning (ACR, 2006).


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9.4.8.2
Physical Activity Restrictions
To minimize uptake of radiotracer into muscle, the subject should avoid strenuous exercise or 
exposure to cold before undergoing a 18FDG-PET/CT examination for a minimum period of 
at least 6 hours but a target of 24 hours prior to the examination. Specific instructions will be 
provided by the imaging core laboratory.
9.4.9
Treatment Compliance
Records of treatment compliance for each subject will be kept during the study.  Clinical 
research associates (CRAs) will review treatment compliance during site visits and at the 
completion of the study.
9.4.10
Drug Supplies and Accountability
In compliance with local regulatory requirements, drug supplies will not be sent to the 
investigator (or if regionally required, the head of the medical institution or the designated 
pharmacist) until the following documentation has been received by the sponsor:
•
A signed and dated confidentiality agreement
•
A copy of the final protocol signature page, signed and dated by both the sponsor and 
investigator
•
Written proof of approval of the protocol, the ICFs, and any other information provided 
to the subjects by the IRB/IEC for the institution where the study is to be conducted
•
A copy of the IRB/IEC-approved ICF and any other documentation provided to the 
subjects to be used in this study
•
The IRB/IEC membership list and statutes or Health and Human Services Assurance 
number
•
A copy of the certification and a table of the normal laboratory ranges for the reference 
laboratory conducting the clinical laboratory tests required by this protocol
•
An investigator-signed and dated FDA Form (FDA 1572), where applicable
•
Financial Disclosure form(s) for the principal investigator (PI) and all subinvestigators 
listed on Form FDA 1572, where applicable
•
A signed and dated curriculum vitae (CV) of the PI including a copy of the PI’s current 
medical license (required in the US) or medical registration number on the CV
•
A signed and dated clinical studies agreement
•
A copy of the regulatory authority approval for the country in which the study is being 
conducted (if required), and the Import License (if required)


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The investigator and the study staff (or if regionally required, the head of the medical 
institution or the designated pharmacist) will be responsible for the accountability of all study 
drug (dispensing, inventory, and record keeping) following the sponsor’s instructions (if 
necessary, “Instructions for Handling of Investigational Products and Trial-Related 
Materials”) and adherence to Good Clinical Practice (GCP) guidelines as well as local or 
regional requirements.
Under no circumstances will the investigator allow the study drug to be used other than as 
directed by this protocol.  Study drug will not be dispensed to any individual who is not 
enrolled in the study.  
The site must maintain an accurate and timely record of the following:  receipt of all study 
drug, dispensing of study drug to the subject, collection and reconciliation of unused study 
drug that are either returned by the subjects or shipped to site but not dispensed to subjects, 
and return of reconciled study drug to the sponsor or (where applicable) destruction of 
reconciled study drug at the site.  This includes, but may not be limited to:  (a) 
documentation of receipt of study drug, (b) study drug dispensing/return reconciliation log, 
(c) study drug accountability log, (d) all shipping service receipts, (e) documentation of 
returns to the sponsor, and (f) certificates of destruction for any destruction of study 
drugs/study supplies that occurs at the site.  All forms will be provided by the sponsor.  Any 
comparable forms that the site wishes to use must be approved by the sponsor.
The study drug and inventory records must be made available, upon request, for inspection 
by a designated representative of the sponsor or a representative of a health authority (eg, 
FDA, MHRA).  As applicable, all unused study drug and empty and partially empty 
containers from used study drug are to be returned to the investigator (or if regionally 
required, the head of the medical institution or the designated pharmacist) by the subject and 
together with unused study drugs/study supplies that were shipped to the site but not 
dispensed to subjects are to be returned to the sponsor’s designated central or local depot(s) 
during the study or at the conclusion of the study, unless provision is made by the sponsor for 
destruction of study drug and containers at the site.  Destruction at the site will only occur 
under circumstances where regulation or supply type prohibits the return of study drug to the 
central or local depot(s).  Approval for destruction to occur at the site must be provided by 
the sponsor in advance.  Upon completion of drug accountability and reconciliation 
procedures by the site’s personnel and documentation procedures by the sponsor’s personnel, 
study drug that are to be returned to the sponsor’s designated central or local depot(s) must 
be boxed and sealed and shipped back to the central or local depot(s) following all local 
regulatory requirements.  In some regions, study drug may be removed from the site and 
hand delivered to the central or local depot by sponsor representatives.  Where study drugs 
are approved for destruction at the site, destruction will occur following the site’s standard 
procedures and certificates of destruction will be provided to the sponsor.
Drug accountability will be reviewed during site visits and at the completion of the study.


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9.5
Study Assessments
9.5.1
Demography, Disease History, and Other Baseline Assessments
Subject demography information will be collected at the Screening Visit.  Demography 
information includes date of birth (or age), sex, race/ethnicity.
Medical history, concomitant medications, physical examination, echocardiogram/MUGA, 
12-lead ECG, pregnancy test, vital signs, hematology, blood chemistry, urinalysis, surgical 
history and current medical conditions will be recorded at the Screening Visit.  All medical 
and surgical history must be noted in the medical history and current medical conditions Case 
Report Form (CRF). ECOG will be assessed.
Information on history of current malignancy will be collected, including tumor type and 
prior therapy, with response and duration of response for each therapy.
For tumor biopsy assessment,please refer to Section 9.5.4.3.
9.5.2
Efficacy Assessments
Tumor assessments will be performed by investigators based on both irRECIST and modified 
RECIST 1.1 at each assessment time point.  However, the treatment decisions by the 
Investigator will be based on irRECIST. The Sponsor may request that images acquired 
for tumor assessments be sent to an imaging core laboratory for archival and potential 
independent analysis. Tumor assessments will be carried out during the Pretreatment Phase 
and then every 6 weeks (during the 6th week; counting from C1D1) during treatment cycles 
in both the Treatment Phase and the Extension Phase. Screening Week 6 and Week 12 scans 
(unless the imaging core laboratory determines that the Screening 18FDG-PET scans do not 
have a FDG-PET-evaluable lesion) must be performed on a PET/CT scanner that is capable 
of acquiring diagnostic quality CT scans. CT scans (with oral and/or intravenous contrast) of 
chest, abdomen, and pelvis and of other known sites of disease will be obtained at Screening 
(within 28 days prior to Cycle 1 Day 1), using the above tumor assessment schedule, and as 
indicated clinically. Skin lesions may only be considered as non-index lesions (no 
photographs required) or as new lesions if they meet the minimum size criteria for a 
measurable lesion. Subjects with SCCHN must also have head and neck scans performed.  
Chest disease may not be followed using chest x-ray.  The same method of assessment must 
be used at all time points as used at Screening.
For subjects with TNBC or NSCLC, bone scans will be performed at the Screening Visit, 
every 24 weeks, or sooner if clinically indicated, and at confirmation of complete response
(irCR). Lesions identified on bone scans must be verified with correlative cross-sectional 
imaging.
A brain scan (CT with contrast or MRI with and without gadolinium chelate) must be 
performed at Screening to assess potential CNS disease and/or metastases.  For subjects with 


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previously treated eligible brain metastases, a brain scan must be performed at all tumor 
assessment time points.  For all subjects, a follow-up brain scan must be performed within 
one week to confirm a irCR in conjunction with the CT scans for response confirmation, or 
if clinically indicated. 
The first radiological assessment of tumor response status will be performed at Week 6, 
unless there is clinical indication warranting earlier radiologic imaging. If imaging at 6 
weeks shows immune-related stable disease (irSD), treatment will be continued and the next 
imaging studies will be conducted at Week 12. Responses (immune-related partial response 
[irPR] or irCR) should be confirmed no less than 4 weeks following the initial response
(generally at the next q6 weeks [every-6-weeks] scheduled tumor assessment visit). 
If the tumor assessment is immune-related progressive disease (irPD), treatment should 
continue and tumor assessments repeated at least 4 weeks later, but generally at the next 
scheduled tumor assessment time point in order to confirm irPD. If repeat imaging shows a 
reduction in the tumor burden compared to the initial scan demonstrating irPD, treatment 
may be continued.  If repeat imaging confirms irPD, subjects will be discontinued from study 
therapy.  In determining the tumor timepoint response, investigators should consider all 
target lesions as well as non-target lesions and new lesions.
The decision to continue study treatment after the first evidence of irPD is at the 
investigator’s discretion based on the clinical status of the subject as described in Table 3
below.  
Subjects may receive study treatment while waiting for confirmation of irPD if they are 
clinically stable as defined by the following criteria:

Absence of signs and symptoms (including worsening of laboratory values) indicating 
disease progression

No decline in ECOG performance status

Absence of rapid progression of disease 

Absence of progressive tumor at critical anatomical sites (eg, cord compression) 
requiring urgent alternative medical intervention
If PD is confirmed and the subject is experiencing extraordinary clinical benefit, site must 
contact Sponsor to discuss continuing treatment.


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Table 3
Imaging and Treatment After 1st Radiologic Evidence of PD
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
1st radiologic 
evidence of PD
Repeat imaging at 
>4 weeks at site to 
confirm PD
May continue study 
treatment at the 
investigator’s discretion 
while awaiting 
confirmatory scan by site
Repeat imaging at >4 
weeks to confirm PD 
per physician 
discretion only
Discontinue treatment
Subsequent
scan confirms 
PD
No additional 
imaging required
Discontinue treatment
No additional imaging 
required
N/A
Subsequent
scan shows SD, 
PR, or CR
Continue regularly 
scheduled imaging 
assessments 
Continue study treatment 
at the investigator’s 
discretion
Continue regularly 
scheduled imaging 
assessments 
May restart study 
treatment if condition 
has improved and/or is 
clinically stable per 
investigator’s discretion
CR = complete response, N/A = not applicable, PD = progressive disease, PR = partial response.
Subjects going off study without disease progression will also undergo tumor assessments 
every 6 weeks until disease progression is documented or another anticancer therapy is 
initiated.
irRECIST guidelines are described in Appendix 1.
Tumor assessments per modified RECIST 1.1 will follow Eisenhauer et al. (2009), however, 
up to 10 target lesions, up to 5 per organ, may be selected (as opposed to a maximum of 5 
target lesions, up to 2 per organ).
9.5.3
Pharmacokinetic Assessments
Blood samples for PK analyses will be collected during Cycle 1 on Day 1 and Day 8 at 
predose (0 h), 0.5, 1, 2, 4, 6, 8, and 10 and 24h postdose.
Urine samples for PK analyses will be collected during the Dose Escalation part only during 
Cycle 1.
Plasma and urine concentrations of E7046 will be measured by a validated liquid 
chromatography with tandem mass spectrometry (LC/MS/MS) method. The  major 
metabolite identified in nonclinical species (M1) will also be analysed.
Instructions on PK sample collection, handling, storage, and shipment of samples will be 
detailed in the study-specified Laboratory Manual to be provided to the site.


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9.5.4
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Assessments
9.5.4.1
Overview of Biomarker Approach
Pharmacodynamics (PD) biomarkers including Proof of Mechanism (POM) biomarkers to 
show target engagement and Proof of Principle (POP) biomarkers to show impact of E7046 
treatment on disease will be evaluated from collected samples.
Proof of Mechanism may be demonstrated by an alteration in expression of EP4 response 
genes and/or proteins, as EP4 is the molecular target of E7046.
POP for E7046 could be a change in intratumoral immune cell populations consistent with 
inhibition of EP4 signaling such as a decrease in the ratio of M2/Total TAM or an increase in 
the number of CD8+ T cells. POP could also be a decrease in the number or ratio of MDSC 
in circulation.
Retrospective testing for potential subject stratification (PS) markers will also be explored. 
Results from biomarker studies will be used to aid the selection of dose and for correlation 
with drug efficacy. The biomarker assessments planned for this study are summarized in 
Table 4. Details, including methodology and analyses, are described below.
Instructions for the processing, storage, and shipping of samples will be provided in the 
Laboratory Manual.
Table 4
Biomarker assessments
Biomarker sample
Time points
Analyses
Potential Utility
Plasma protein 
Predose C1D1, 24hr after first dose, 
C1D8, C1D15
TAM/MDSC-related cytokines, 
eg, PGE2,)
POM
Blood  mRNA
Predose C1D1, 24hr after first dose, 
C1D8, C1D15
Immune Gene expression
POM
Paired tumor biopsy
Predose and during Cycle 2
T cell and macrophage 
infiltration
POP
Archived tumor
Screening
To be decided
Whole blood
Baseline, predose C1D1, C1D8, 
C1D15, C2D1, C3D1, C5D1
Circulating MDSC
POP, POM, PS
Blood plasma
Baseline, time points for at each CT 
tumor assessment, and End of 
Treatment
Cell-free nucleic acid
Blood genomic DNA
Baseline
Pharmacogenomic analysis
PG
Urine
Cycle 1 Day 1 pre-dose (0-hr) and 
Cycle 1 Day 1 and Day 8 post-dose to 
6hr, 6 to-12hr, 12 to 24hr.
PGE2 metabolite
POM
C1D1 = Cycle 1 Day 1, MDSC = myeloid-derived suppressor cell, PG = prostaglandin, PGE =  prostaglandin e2, POM = 
Proof of Mechanism, POP = Proof of Principle, PS = subject stratification, TAM = tumor-associated macrophages).


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9.5.4.2
Protein and mRNA markers in serum
Blood samples will be collected for plasma protein biomarker analysis at the time points 
indicated in Table 6. Samples will be analyzed for PGE2 and other immune cell related 
markers (eg, cytokines) using global proteomic methods, enzyme-linked immunosorbent 
assay (ELISA), multiplex bead-based immunoassay, or other assays/methods and new 
technology.
Blood samples will also be collected for RNA analysis. Gene expression testing including 
but not limited to EP4 will be performed and correlated with PK, safety, or PD data.
9.5.4.3
Intratumoral immune cell populations
The following intratumoral changes reflect the immunological effects of E7046 that would 
constitute POP, and will be analyzed in paired tumor biopsy samples collected before and 
after E7046 treatment:

Decrease in the ratio of M2/total TAM

Increase in number of cytotoxic T cells (CD8+)
Quantitation of these cell populations will be by image analysis after IHC detection using 
immune cell infiltration markers (including but not limited to CD163, CD68, CD8) as well as
markers for general tumor/stromal architecture.
Paired tumor core needle biopsies will be obtained according to institutional standard 
operating procedures, with appropriate subject consent. Subjects should have the biopsy 
before administration of the first dose of E7046 and at any time during Cycle 2 or later, as 
long as the subject has had uninterrupted treatment at least 5 days prior to biopsy.
In the event that a subject is clinically required to have further tumor biopsy while on study,
FFPE tissue from the procedure should be obtained for shipment to Eisai or a designated 
central laboratory for exploratory biomarker analysis.
These biomarker assessments will provide information on intratumoral tissue target 
inhibition, relevant PD biomarkers and potential markers of response.
9.5.4.4
Archival Tumor
Archived, fixed tumor tissue will be collected (if available).  These tissues may be used for 
assessment of mutations and other genetic alterations or immune cell infiltration status and 
its associated molecules that may be important in the development and progression of cancer.
9.5.4.5
Circulating immune cell population 
Myeloid-derived suppressor cell  levels are anticipated to be affected by E7046 treatment as 
the generation of this cell population is EP4-dependent. Changes in MDSC in blood in 
response to E7046 treatment will be evaluated as a potential Proof of Principle biomarker. 


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MDSC levels at baseline will also be evaluated for any correlation with efficacy or safety 
outcomes.
Blood samples will be collected for measuring circulating MDSC. The time points are 
selected to explore both early (within days) and more delayed (weeks) effects of E7046 
treatment. MDSC will be quantitated by flow cytometry.
These assessments evaluating response-related and safety-related outcomes as well as being 
for potential use in diagnostic development are exploratory. When new research results 
emerge, the parameters and methods for the PD biomarker analysis may change.
9.5.4.6
Blood plasma cell-free nucleic acid analysis
A blood plasma sample will be collected for potential cell-free nucleic acid analysis. Nucleic 
acid isolated from blood plasma samples may be used to explore tumor genetic alterations, 
including mutations observed in archival tumor samples and mutations that may emerge with 
drug treatment.
9.5.4.7
Pharmacogenomic analysis
A blood sample will be collected for pharmacogenomics (PG) analysis. The role of DNA 
sequence variability on the absorption, distribution, metabolism, and elimination (ADME) of 
(insert study drug) may be evaluated in this study. Variation in E7046 exposure or the 
occurrence of AEs observed in the study population may be evaluated by correlation of 
single–nucleotide polymorphisms with PK, safety, or pharmacodynamic (PD) data. Genomic 
DNA extracted from blood samples may be used to confirm whether the DNA sequence 
variants observed in DNA extracted from tumor material are limited to the tumor.
9.5.4.8
Urine biomarker analysis
Urine for biomarker analyses will be collected from the unspun urine collected for urinalysis.
These samples will be used to explore urine protein, genetic changes, and drug metabolite. 
PGE-M is a stable major metabolite for PGE-2. Urinary PGE-M can be used to quantify 
systemic PGE-2 production and serve as biomarker for disease progression and drug 
response.
9.5.4.9
General
Data obtained will be used for research, to assist in developing safer and more effective 
treatments and will not be used to change the diagnosis of the subject or alter the therapy of 
the subject. The DNA will not be used to determine or predict risks for diseases that an 
individual subject does not currently have. Any sample or derivatives (DNA, RNA, and 
protein) may be stored for up to 15 years to assist in any research scientific questions related 
to E7046 or cancer and for potential diagnostic development.


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Archived tumor tissue samples and blood samples for PD, PG, and other biomarker 
assessments will be collected from all consented study subjects, except where prohibited by 
regional or local laws.
Samples may be used for biomarker discovery or validation to identify blood or tumor 
biomarkers that may be useful to predict treatment response (efficacy, PD), PK, and safety-
related outcomes. Samples may also be used for potential diagnostic development. In 
addition, biomarkers identified in other clinical studies may also be assessed in samples 
collected from subjects enrolled in this study. The decision to perform exploratory 
biomarker analysis will be based on the clinical outcome of the study, the signals observed in 
other clinical studies, and/or the scientific rationale of the study. 
9.5.4.10
Exploratory Imaging Biomarkers
Before each 18fluorodeoxyglucose-positron emission tomography (18FDG-PET)/CT (FDG-
PET/CT) examination, subjects will have a fasting serum glucose sample drawn and 
analyzed before injection of the 18FDG radiotracer. Serum glucose must be ≤120 mg/dL for 
nondiabetic or ≤200 mg/dL for diabetic subjects or the scan must be postponed or 
rescheduled. The FDG-PET/CT scans will be performed using the guidelines provided by 
the Imaging Core Laboratory designated by the sponsor. It is particularly critical that 
subjects are imaged within 1 hour ±10 minutes after injection of the radiotracer.
An FDG-PET/CT scan will be performed within 7 days before Cycle 1 Day 1. FDG-PET/CT 
scans will be sent to the Imaging Core Lab for assessment of evaluability. Subjects whose 
pretreatment scans show evidence of FDG avid tumor lesion(s) and are considered PET 
evaluable will have a second FDG-PET/CT scan performed coincident with the Week 6
tumor assessments and a third scan coincident with the Week 12 tumor assessments.  FDG-
PET/CT time points may be changed based on emergent data. All FDG-PET/CT scans will 
be quantitatively evaluated by the imaging core lab for imaging biomarkers of metabolic 
activity in select lymphoid tissue and malignant lesions, and tumor volume as specified in the 
Image Review Charter.
NOTE: Changes in standardized uptake value (SUV) should NOT be used to assess tumor 
response or progressive disease.  18FDG-PET assessment is for exploratory purposes only.


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9.5.5
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs, including all 
CTCAE grades (for both increasing and decreasing severity), and serious adverse events 
(SAEs); regular laboratory evaluation for hematology, blood chemistry, and urine values; and 
periodic measurement of vital signs, echocardiograms/MUGA scans, electrocardiograms 
(ECGs), and physical examinations as detailed in Table 6. The effects of E7046 on 
cardiovascular repolarization will be evaluated via continuous Holter/ECG monitoring.
Subjects with decreasing hemoglobin levels or gastrointestinal symptoms indicative of 
gastrointestinal bleed should be evaluated for a potential gastrointestinal bleeding source as 
appropriate. 
9.5.5.1
Adverse Events and Events Associated with Special Situations
An AE is any untoward medical occurrence in a subject 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 E7046.
The criteria for identifying AEs in this study are:
•
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 (Note:  Every sign or 
symptom should not be listed as a separate AE if the applicable disease [diagnosis] is 
being reported as an AE.)
•
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.
•
Any deterioration in nonprotocol-required measurements of a laboratory value or other 
clinical test (eg, ECG or x-ray) that results in symptoms, a change in treatment, or 
discontinuation of study drug
•
Recurrence of an intermittent medical condition (eg, headache) not present pretreatment 
(Baseline)
•
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.
All AEs observed during the study will be reported on the CRF.  All AEs, regardless of 
relationship to study drug or procedure, should be collected beginning from the time the 
subject signs the study ICF through the last visit and for 30 days after the subject’s last dose.  
Subjects who fail screening primarily due to AE(s) must have the AE(s) leading to screen 
failure reported on the Screening Disposition CRF.  Serious AEs will be collected for 28 days 
after the last dose.


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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.  It is the responsibility of the 
investigator to review all laboratory findings in all subjects and determine if they constitute 
an AE.  Medical and scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality should be classified as an AE.  Any laboratory abnormality 
considered to constitute an AE should be reported on the Adverse Event CRF. 
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 considers as an AE should be reported as such.
All AEs must be followed for 30 days after the subject’s last dose, or until resolution, 
whichever comes first.  All SAEs must be followed to resolution or, if resolution is unlikely, 
to stabilization.
Subjects with onset of an AE or deterioration of a preexisting AE will be followed until 
resolution to baseline status, start of a new anticancer treatment, or death.
Every effort must be made by the investigator to categorize each AE according to its 
severity and its relationship to the study treatment.
Assessing Severity of Adverse Events
Adverse events will be graded on a 5-point scale according to CTCAE v4.03 (Appendix 4).  
Investigators will report all CTCAE grades for AEs.
The criteria for assessing severity are different than those used for seriousness 
(Section 9.5.5.2 for the definition of an SAE).
Assessing Relationship to Study Treatment
Items to be considered when assessing the relationship of an AE to the study treatment are:
•
Temporal relationship of the onset of the event to the initiation of the study treatment
•
The course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable
•
Whether the event is known to be associated with the study treatment or with other 
similar treatments
•
The presence of risk factors in the study subject known to increase the occurrence of the 
event
•
The presence of nonstudy, treatment-related factors that are known to be associated with 
the occurrence of the event


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Classification of Causality
The relationship of each AE to the study drug will be recorded on the CRF in response to the 
following question:
Is there a reasonable possibility that the study drug caused the AE?
Yes (related)
A causal relationship between the study drug and the AE is a reasonable 
possibility.
No (not related) A causal relationship between the study drug and the AE is not a 
reasonable possibility.
9.5.5.2
Serious Adverse Events and Events Associated with Special Situations
A serious adverse event (SAE) is any untoward medical occurrence that at any dose:
•
Results in death
•
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)
•
Requires in subject hospitalization or prolongation of existing hospitalization
•
Results in persistent or significant disability/incapacity
•
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. 
For this study, the following events should always be considered serious and reported as an 
important medical event if it does not meet other serious criteria: gastrointestinal bleeding, 
colitis, irAE, Grade >2 diarrhea.
In addition to the above, events associated with special situations include pregnancy or 
exposure to study drug through breastfeeding; AEs associated with study drug overdose, 
misuse, abuse, or medication error.  These events associated with special situations are to be 
captured using the SAE procedures but are to be considered as SAEs only if they meet one of 
the above criteria.  All AEs associated with special situations 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.


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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:
•
Hospitalizations due to disease progression
•
Planned hospitalizations required by the protocol
•
Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed post study drug administration)
•
Hospitalization for administration of study drug or insertion of access for administration 
of study drug
•
Hospitalization for routine maintenance of a device (eg, battery replacement) that was in 
place before study entry
If possible, a blood sample for PK analysis should be drawn at the first report of an SAE or a 
severe unexpected AE and at its resolution.
9.5.5.3
Laboratory Measurements
Clinical laboratory tests to be performed, including hematology, chemistry, and urinalysis, 
are summarized in Table 5.  Subjects should be in a seated or supine position during blood 
collection.  The Schedule of Procedures/Assessments (Table 6) shows the visits and time 
points at which blood for clinical laboratory tests and urine for urinalysis will be collected in 
the study.


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Table 5
Clinical Laboratory Tests
Category
Parameters
Hematology
Hematocrit, hemoglobin, platelets, RBC count, and WBC count with differential 
(bands, basophils, eosinophils, lymphocytes, monocytes, neutrophils)
Coagulation panel* : Activated partial thromboplastin time (aPTT), thrombin 
time, PT, INR, fibrinogen 
Chemistry
Electrolytes
Chloride, potassium, sodium, calcium, phosphorus 
Liver function tests
Alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, total 
bilirubin
Renal function tests
Blood urea/blood urea nitrogen (UREA/BUN), creatinine
Other
Albumin, cholesterol, HDL, LDL triglycerides, lactate dehydrogenase, , total 
protein, uric acid. fasting glucose will be done at baseline and after that in 
conjuction with FDG-PET as per Table 6, or if urine dipstick examination finds 
glucose or ketones
Urinalysis (dipstick) 
Glucose, ketones, protein, and blood.  Microscopic examination (if blood or 
protein is abnormal in dipstick analysis)
RBC = red blood cell, WBC = white blood cell.
*Coagulation panel: baseline, weekly in cycle 1 and then once every cycle thereafter
Clinical laboratory tests will be performed by site local laboratories.  Laboratory certification 
as available will be included in the final clinical study report for this study.
All hematology, blood chemistry (including pregnancy test, as applicable), and urinalysis 
samples are to be obtained prior to study drug administration and results reviewed prior to 
administration/dispensing of study drug at the beginning of each treatment cycle. 
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (Section 9.5.5.1) and the CRF Completion Guidelines.  In these instances, the AE 
corresponding to the laboratory abnormality will be recorded on the Adverse Event CRF.
9.5.5.4
Vital Signs and Weight Measurements
Vital sign measurements (ie, systolic and diastolic BP [mmHg], pulse [beats per minute], 
respiratory rate [per minute], body temperature [in centigrade]), height, and weight (kg) will 
be obtained as designated in the Schedule of Procedures/Assessments (Table 6) by a 
validated method.  Blood pressure and pulse will be measured after the subject has been 
supine for 5 minutes.  All BP measurements should be performed on the same arm using the 
same cuff size and the same equipment.
When vital signs are to be obtained concurrently with PK or other blood samples, the vital 
sign measurements will be performed prior to drawing blood samples in order to maximize 


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the accuracy of blood sampling times while minimizing the potential effects of blood 
drawing on recordings obtained during safety assessments.
9.5.5.5
Physical Examinations
Comprehensive and abbreviated physical examinations will be performed as designated in
the Schedule of Procedures/Assessments (Table 6).  Documentation of the physical 
examination will be included in the source documentation at the site.  Significant findings at 
the Screening Visit will be recorded on the Medical History and Current Medical Conditions 
CRF.  Changes from screening physical examination findings that meet the definition of an 
AE will be recorded on the Adverse Events CRF.
Comprehensive Physical Examination
A comprehensive physical examination will include evaluations of the head, eyes, ears, nose, 
throat, neck, chest (including heart and lungs), abdomen, limbs, skin, and a complete 
neurological examination.  The subject will be queried regarding physical status and 
subjective symptoms as well. A urogenital examination will only be required in the presence 
of clinical symptoms related to this region.
Abbreviated Physical Examination
Health status will be assessed by brief evaluation of the chest (including heart and lungs), 
abdomen and limbs, and other physical conditions of note.  The subject must be queried 
regarding changes in physical status since the last examination.
9.5.5.6
Electrocardiograms
Twelve-lead electrocardiograms will be obtained as designated in the Schedule of 
Procedures/Assessments (Table 6).
An ECG abnormality may meet the criteria of an AE as described in this protocol 
(Section 9.5.5.1) and the CRF Completion Guidelines.  In these instances, the AE 
corresponding to the ECG abnormality will be recorded on the Adverse Events CRF.
Twelve-lead ECGs will be extracted from the same timepoints as for PK blood draws during 
the first 12 hous after dose on Day 1 and Day 8. Potential effects of E7046 on ECG 
parameters (heart rate, PR, QRS and QTcF) will be analyzed as change from predose 
baseline, by timepoint and for the QTcF interval, using exposure response analysis.
9.5.5.7
Echocardiograms or Multiple Gated Acquisition Scans
Echocardiograms or MUGA scans will be obtained as designated on the Schedule of 
Procedures/Assessments (Section 9.5.6.1, Table 6). A MUGA scan (using technetium-99m-
pertechnetate) or an echocardiogram to assess LVEF will be performed during the 
Pretreatment Phase (within 21 days before Cycle 1 Day 1), if clinically indicated, and during 
the Off-Treatment Visit (window of ±1 week).  MUGA scans and echocardiograms will be 
performed locally in accordance with the institution’s standard practice. Whichever modality 


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is used for an individual subject at screening should be repeated for all subsequent LVEF 
assessments for that subject.
9.5.5.8
Pregnancy Test
A serum β-hCG test will be performed for premenopausal women and postmenopausal 
women who have been amenorrheic for less than 12 months.  A 6-mL sample of blood will 
be taken at designated time points as specified in the Schedule of Procedures/Assessments 
(Table 6).
9.5.6
Schedule of Procedures/Assessments
9.5.6.1
Schedule of Procedures/Assessments
Table 6 presents the schedule of procedures/assessments for the study.


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Table 6
Schedule of Procedures / Assessments in Study E7046-G000-101
Phase
Pretreatmenta
Treatment
Extension
Period
Screening
Baseline
Cycle 1
Treatment Continuationb
(Cycle 2 and beyond)
Off-
Treatmentc
Follow-
upc
Visit
1
2
3
4
5
6, 8, etc.
7, 9, etc.
98
99
Day
-28 to -1
-3 to -1
1
8
15
1
8 (C2-6 only)
CRF
Procedures/Assessments
S
Informed consent
X
S
Inclusion/exclusion criteria
X
S
Medical history
X
S
Physical examinationd and Vital signse
X
X
X
X
X
X
X
N
Echocardiogram / MUGAf
X
X
S
Pregnancy testg
X
X
X
X
S
ECOG performance status
X
X
X
X
X
S
12-lead ECGsh
X
X
X
X
X
S
ECG Holter monitoringi
X
X
S
Hematology / Blood chemistryj
X
X
X
X
X
X
X
X
S
Urinalysisk
X
X
X
X
X
X
X
N
Genomic DNAl
X
S
PK and PD urine collectionm
X
X
S
PK blood samplesn
X
X
N
PD blood sampleso
X o
X
Xo
Xo
Xo
Xo
N
Paired tumor biopsy and archived tumorp
X
Xp
N
18FDG PET/CTq
X
Xq
S
Tumor assessments: CT or MRIr
X
Every 6 weeks or sooner if clinically indicated
S
CT or MRI of the brains
X
X
N
Bone Scant
X
Every 24 wks, or sooner if clinically indicated, and at confirmation of irCR
S
E7046 administrationu
Continuous daily dosing
S
Adverse Eventsv
X
X
X
X
S
Prior and concomitant medicationsv
X
X
X
X
S
Survival status w
X


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For CRF:  S = standard assessment, N = nonstandard assessment (study-specific), N/A = not applicable.
AE = adverse event, β-hCG = beta-human chorionic gonadotropin, BP = blood pressure, C1D1 = Cycle 1 Day 1, CR = complete response, CRF = case report form, CT = 
computed tomography, CTCs = circulating tumor cells, DNA = deoxyribonucleic acid, ECG = electrocardiograms, ECOG = Eastern Cooperative Oncology Group, 18FDG-PET = 
18fluorodeoxyglucose-positron emission tomography, h = hour, HR = heart rate, irPR = immune-related partial response, irRECIST = immune-related RECIST, IV = intravenous,
MDSC = myeloid-derived suppressor cell(s), MRI = magnetic resonance imaging, myeloid-derived suppressor cell, MUGA = multiple gated acquisition, PD = 
pharmacodynamic, PGE2 = prostaglandin e2, PK = pharmacokinetic, PR = partial response, RECIST = Response Evaluation Criteria In Solid Tumors, RR = respiratory rate, 
SCCHN = squamous cell carcinoma of head and neck, SAE = serious adverse event, TNBC = triple-negative breast cancer.
a.
The Screening Period extends from Day -28 to Day -1, except for signing of the informed consent form, which may be up to 8 weeks before the first dose of study drug.  The 
baseline assessments may be performed from Day -3 to Day -1 (before the first dose of E7046).  Screening assessments may be used as baseline assessments if performed 
within 72 hours of the first dose of study medication.
b. The off-treatment assessment should occur within 30 days after the final dose of study treatment. Subjects who discontinue study for reasons other than disease progression 
will be followed until disease progression or death.  All anticancer therapies will be collected (the sponsor may choose to stop the collection of therapies after the first 
anticancer treatment.
c.
Visit windows are allowed from Cycle 3 onwards as follows: Day 1 (±3 days), and Day 8 (±3 days). There must be at least 5 days between the Day 1 and Day 8 visit for any
given treatment cycle.
d. A comprehensive physical examination will be performed at the Screening Visit and at the Off-Treatment Visit.  A symptom-directed physical examination will be 
performed on Day 1 of all treatment cycles and at any time during the study, as clinically indicated.
e.
Vital signs include BP, HR, RR, and body temperature, as well as weight and height.  BP, HR, and RR will be collected after the subject has been sitting for 5 minutes.
Height will be measured at the Screening Visit only.
f.
MUGA scans or echocardiograms will be performed at Screening, during the Off-Treatment Visit (window of ±1 week), and if clinically indicated. MUGA scans and 
echocardiograms will be performed locally in accordance with the institution’s standard practice.
g. A serum pregnancy test (β-hCG) will be performed at screening for all premenopausal women and postmenopausal women who have been amenorrheic for less than
12 months.  A urine pregnancy test will be performed at baseline before the first E7046 dose, Cycle 1 Day 1and at the Off Treatment visit.
h. 12-Lead ECGs will be collected at the following time points: Screening (single) and Baseline (single unless abnormalities are observed or if clinically indicated, then in 
triplicate at 2-minute intervals); Day 1 of all cycles (before and after study drug administration); and at the Off-Treatment Visit.  In case of any alteration, or if clinically 
necessary, an echocardiogram and/or cardiac enzymes should be performed.
i.
Continuous Holter/ECGs (12-h/12-lead) to be collected during Cycle 1 on Day 1 and Day 8 at predose (3 timepoints within 45 minutes), and 0.5, 1, 2, 4, 6, 8, and 10 h 
postdose.  At each of these timepoints, subjects should be supinely resting for at least 10 minutes prior to and 5 minutes after the nominal time and the time points when the 
subject is supinely resting should be recorded. When coinciding, blood draws, vital signs and 12-lead safety ECGs should be performed immediately after the timewindow 
for ECG extraction.
j.
Hematology and blood chemistry samples will be obtained before drug administration.  Screening assessments may be used as baseline assessments if performed within 
72 hours of the first dose of study medication. Before drug administration on Cycle 1, Days 1 and 8, a complete blood count should be drawn. Coagulation panel: baseline, 
weekly in cycle 1 and then once every cycle thereafter. See Table 5 for list of tests.
k. Urine samples will be obtained before drug administration (either formal urinalysis or urine dipstick for protein and glucose are acceptable).
l.
Genomic DNA samples will be collected at baseline.  If it cannot be collected at the designated time point, it may be collected at a time point after baseline.
m. All urine excreted will be collected as follows: Cycle 1 Day 1 pre-dose (0-hr) and Cycle 1 Day 1 and Day 8 post-dose to 6hr, 6 to-12hr, 12 to 24hr. Total urine volume 
collected in each time interval will be recorded.  Urine will be analyzed for PK (E7046, M1 metabolite) and PD (PGE-M, metabolite of PGE2).
n. Blood samples for PK analyses will be collected during Cycle 1 on Day 1 and Day 8 at predose (0 h), 0.5, 1, 2, 4, 6, 8, and 10 and 24h postdose.
o. Blood samples for PD mRNA and protein biomarker analysis (one PAX gene tube and one lavender top EDTA tube) will be collected at the following time points:  predose 


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(0 h) on Cycle 1 Day 1, 24 h after first dose, Day 8, and Day 15.  Blood for cell free nucleic acid will be collected at C1D1 predose, at each tumor assessment, and at the end 
of treatment. Blood for MDSC in circulation will be collected at baseline, C1D1 predose, C1D8, C1D15, C2D1, C3D1, and C5D1.
p. Paired tumor biopsies will be obtained, with appropriate subject consent.  Subjects will have the biopsy before the first dose of E7046 and during Cycle 2, as long as the 
subject has had uninterrupted treatment at least 5 days prior to biopsy. In addition, archived fixed tumor tissue will be collected if available (instructions to be provided in a 
separate manual).
q.
18FDG PET/CT scans should be performed according to instructions provided by the imaging core lab and sent to the core lab for quantitative assessments.  Scans should be 
performed at baseline (within 7 days before C1D1) for all subejcts, repeat scans in conjunction with the Week 6 and Week 12 tumor assessments timepoints only for subjects 
with evidence of evaluable FDG avid tumor lesion(s) at screening.  18FDG-PET/CT scan timepoints may be changed based on emergent data.
Subjects must have a fasting serum glucose assessment performed before injection of the PET tracer for each scan.  FDG-PET/CT will not be performed if serum glucose is 
>120 mg/dl for nondiabetics or >200 mg/dl for diabetic subjects.
r.
Tumor assessments will be performed based on irRECIST and modified RECIST1.1. Treatment decisions will be based on irRECIST. Tumor assessments will be carried 
out during the Pretreatment Phase and then every 6 weeks (during the 6th week; counting from C1D1) during treatment cycles in both the Treatment Phase and the 
Extension Phase. CT scans (with oral and intravenous contrast) of chest, abdomen, and pelvis and of other known sites of disease will be obtained at Screening (within 28 
days prior to Cycle 1/ Day 1), using the above tumor assessment schedule, and as indicated clinically.  Skin lesions may only be considered as non-index lesions (no 
photographs required) or as new lesions to add to the tumor burden sum. Subjects with SCCHN must also have head and neck scans performed at all tumor assessment 
timepoints.  
MRI scans may be used instead of CT scans for (head, neck) abdomen and pelvis; however, chest must be assessed using CT.  Chest disease may not be followed using 
chest x-ray.  CT scans should be performed with oral and iodinated IV contrast and MRI scans with IV gadolinium chelate unless there is a medical contraindication to 
contrast.  If iodinated IV contrast is contraindicated, chest CT should be performed without IV contrast. The same method of assessment must be used at all time points as 
used at Screening.
s.
Screening brain scans will be performed by MRI pre- and post- gadolinium or CT with contrast within 4 weeks prior to C1D1.  During the Treatment Phase, CT/MRI of the 
brain will be performed if clinically indicated, and within a target of 1 week after a subject achieves a irCR.  For subjects with history of treated brain metastases, brain scans 
will be performed at every tumor assessment time point. The same methodology and scan acquisition techniques used at screening should be used throughout the study to
ensure comparability
t.
A bone scan (99m-technetium polyphosphonate scintigraphy, whole body bone MRI, or 18F-NaF) to assess bone metastases will be performed within 6 weeks prior to 
C1D1 and then every 24 weeks (within that 24th week) from C1D1 for tumor types known to metastasize to bone (eg TNBC, NSCLC, RCC.), or sooner if clinically 
indicated.  In subjects whose body CT/MRI scans indicate irCR has been achieved, a bone scan will be required at confirmation of irCR to exclude new bone metastases.  
The same methodology and acquisition techniques used at screening should be used throughout the study to ensure comparability.  If a non-target lesion is being followed by 
bone scan (not present on CT/MRI), and is not imaged at a follow-up time point because a bone scan is not required at that time point, the time point non-target lesion 
response will be based upon the other non-target lesions and will not be considered not evaluable (NE).  
u. E7046 should be taken daily at the dose assigned, with fasting 2 hours before and 2 hours after ingestion of E7046 capsules. On visit days, subjects should not take study 
medication before evaluations are performed.
v. Adverse events and prior and concomitant medications information to be collected at every study visit.
w. Subjects who discontinue study will be followed for survival.  Survival follow-up will be conducted approximately every 12 weeks on all subjects, unless they withdraw 
consent. Follow up on subsequent treatment and clinical response will be collected.  


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9.5.6.2
Description of Procedures/Assessments Schedule
Please refer to the footnotes in the table of the Schedule of Assessments.
9.5.7
Appropriateness of Measurements
All clinical assessments are standard measurements commonly used in oncology studies.
The safety assessments to be performed in this study, including hematology analyses, blood 
chemistry tests, urinalysis, radiologic studies, and assessment of AEs, are standard evaluations to 
ensure subject safety.
9.5.8
Reporting of Serious Adverse Events, Pregnancy, and Events Associated with 
Special Situations
9.5.8.1
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 when the investigator becomes aware of the event.
Serious adverse events, regardless of causality assessment, must be collected through the last 
visit and for 30 days after the subject’s last dose.  All SAEs must be followed to resolution or, if 
resolution is unlikely, to stabilization.  Any SAE judged by the investigator to be 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 the Investigator 
Study File.
For urgent safety issues, please ensure all appropriate medical care is administered to the 
subject and contact the appropriate study team member listed in the Investigator Study File.
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 follow-up information received on SAEs should be forwarded within 1 business day of its 
receipt.  If the 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.
The investigator must notify his/her IRB/IEC of the occurrence of the SAE, in writing, if 
required by their institution.  A copy of this communication must be forwarded to the sponsor to 
be filed in the sponsor’s Trial Master File.


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9.5.8.2
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 
28 days of last study treatment or any exposure to study drug through breastfeeding during study 
treatment or within 28 days of last study treatment must be reported.
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 are considered to be an SAE and should be reported in the same time frame and in the 
same format as all other SAEs (Section 9.5.8.1).
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 pregnancy.  The contact information for the reporting of pregnancies and exposure to study 
drug through breastfeeding is provided in the Investigator Study File.  The Pregnancy Report 
Form must be used for reporting.  All pregnancies must be followed to outcome.  The outcome 
of the pregnancy must be reported 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. A subject who becomes 
pregnant may remain in the study if the investigator judges that the potential benefit to the 
subject outweighs any potential risk to the subject or the fetus and the subject gives informed 
consent for the further participation.
9.5.8.3
Reporting of Events Association with Special Situations
9.5.8.3.1
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 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


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All AEs associated with overdose, misuse, abuse, or medication error should be captured on the 
Adverse Event CRF and also reported using the procedures detailed in Section 9.5.8.1 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.
9.5.8.4
Expedited Reporting
The sponsor must inform investigators (or, as regionally required, 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 above.
9.5.8.5
Breaking the Blind
Not applicable.
9.5.8.6
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.
All studies that are conducted within any European country will comply with European Good 
Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC.  All suspected 
unexpected serious adverse reactions (SUSARs) will be reported, as required, to the competent 
authorities of all involved European member states.
9.5.9
Completion/Discontinuation of Subjects
The investigator may withdraw the subject from the study at any time for safety or administrative 
reasons.  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 6).
The investigator 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 by mail, phone, or 
other means to gather information such as the reason for failure to return, the status of treatment 
compliance, the presence or absence of AEs, and clinical courses of signs and symptoms.
Subjects who discontinue early from the study will be discontinued for 1 of these primary 
reasons: AE(s), lost to follow-up, subject choice, withdrawal of consent, pregnancy, study 
terminated by sponsor, or other.  In addition to the primary reason, the subject may indicate 1 or 
more of secondary reasons for discontinuation.  Study disposition information will be collected 
on the Subject Disposition CRF.


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9.5.10
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.
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 and entered into a validated data 
management system that is compliant with all regulatory requirements.  As defined by ICH 
guidelines, 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 or designee as identified on Form FDA 1572 
must sign the completed CRF to attest to its accuracy, authenticity, and completeness.
Completed, original CRFs are the sole property of Eisai and should not be made available in any 
form to third parties without written permission from Eisai, except for authorized representatives 
of Eisai or 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.


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9.7
Statistical Methods
All statistical analyses will be performed by the sponsor or designee after the study is completed 
and the database is locked and released. Statistical analyses will be performed using WinNonlin 
and SAS software or other validated statistical software as required.  Details of the statistical 
analyses will be included in a separate statistical analysis plan (SAP).
Descriptive statistics will be used for continuous variables using n, mean, standard deviation 
(SD), median, Q1 (25th percentile), Q3 (75th percentile), minimum, and maximum, unless 
otherwise specified. Categorical variables will be summarized as number (percent) of subjects.
9.7.1
Statistical and Analytical Plans
For purposes of the final analysis, data cutoff will occur when the last enrolled subject  
completes 6 cycles of treatment (ie all subjects have been followed by a minimum of 6 cycles) or 
subjects discontinue early, whichever occurs first.  The statistical analyses of 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
Primary Endpoints (Dose Escalation part):

Safety/tolerability profile of E7046.  

MTD and/or the RP2D.
Secondary Efficacy endpoints:
Objective response rate 
The ORR is the proportion of subjects achieving a best overall response of confirmed partial 
or complete response (irPR + irCR), according to irRECIST (Appendix 1) from first dose date 
until disease progression/recurrence. Subjects who do not have a tumor response assessment 
for any reason will be considered nonresponders and will be included in the denominator 
when calculating the response rate.
Duration of response
Duration of response is defined as the time from the date of first documented confirmed 
irCR/irPR until the first documentation of confirmed disease progression or death, whichever 
comes first.
Progression-free survival 
Progressive-free survival is defined as the time from first dose date to the date of the first 
documentation of confirmed disease progression or death (whichever occurs first) using 
irRECIST.  The censoring rule for events will be defined in the SAP.


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Disease control rate 
The DCR is the proportion of subjects achieving irPR + irCR + irSD from first dose date 
until disease progression/recurrence.
Clinical benefit rate 
The CBR is the proportion of subjects achieving irPR + irCR + irSD [lasting at least 24 
weeks] from first dose date until disease progression/recurrence.
Exploratory endpoints:

ORR, DCR, CBR, PFS according to modified RECIST 1.1

Effect of E7046 on tumor 18FDG uptake and volume will be explored as potential early 
response biomarkers. Variables will include total tumor volume of target lesions, metabolic 
tumor volume (SUV >2.5), maximum SUV of a single pixel, metabolic peak of a 1 cm spot, 
and summed SUVs of target lesions. Summary statistics and change from baseline will be 
presented.

Effect of E7046 on 18FDG uptake by spleen and/or draining lymph nodes will be explored as 
a potential biomarker of immune activation. Variables will include total volume and 
metabolic volume of spleen and, where possible, draining lymph nodes, Summary statistics 
and change from baseline will be presented.
9.7.1.2
Definitions of Analysis Sets
Full Analysis Set will include all subjects who received at least one dose of study drug.  This 
will be the primary analysis set for efficacy evaluations, as well as for demographic and baseline 
characteristics.  This analysis set will also constitute the Safety Analysis Set.
DLT Evaluable Set will consist of those subjects who are evaluable for the DLTs (Section 
9.1.1.2). This will be the analysis set for DLT analysis.
Pharmacokinetic (PK) Analysis Set will include all subjects who have received at least one 
dose of study drug and have at least one evaluable plasma concentration.


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9.7.1.3
Subject Disposition
The number (percentage) of randomized and treated subjects will be summarized as well as 
subjects who completed the study/discontinued from the study and reasons for discontinuation by 
treatment group. The number (percentage) of subjects who completed the study 
treatment/discontinued from the study treatment and reasons for discontinuation will also be 
summarized by treatment cohort.
9.7.1.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics for the Full Analysis Set will be summarized and 
listed for each treatment cohort.  For continuous demographic/baseline variables including age, 
weight, and vital signs, results will be summarized and presented as N, mean, standard deviation, 
median, Q1, Q3, minimum and maximum values.  For categorical variables such as 
race/ethnicity, the number and percentage of subjects will be used.
9.7.1.5
Prior and Concomitant Therapy
All investigator terms (verbatim terms) for medications recorded in the CRF will be coded to an 
11-digit code using the World Health Organization Drug Dictionary (WHO DD) drug codes. 
Prior medications will be defined as medications that stopped before the first dose of 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 30 days after the subject’s last dose.  A listing
of prior and concomitant medications will be included in the clinical study report for this 
protocol.
9.7.1.6
Dose Escalation Primary Endpoints Analyses
Safety/tolerability profile of E7046 will be assessed. The incidence of treatment-emergent 
adverse events (TEAEs) and SAEs together with all other safety parameters will be summarized, 
by dose levels.  
Maximum tolerated dose. The incidence of DLTs by dose level will be tabulated. The MTD 
will be determined per protocol definition.
RP2D. The RP2D will be selected as described in Section 9.1.1.4.


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9.7.1.7
Efficacy Analyses
The ORR , response duration, time to response, PFS, DCR, and CBR will be listed and 
descriptively summarized as appropriate. 
Response duration and time to response:  Summary statistics (median Q1, Q3, and range) for 
will be summarized on subjects achieving a best overall response of confirmed partial or 
complete response (irPR + irCR). The time to response will be censored at the last tumor 
assessment for subjects who leave the study before a response, death or progression is 
observed. 
PFS: Subjects who discontinue from the study for reasons other than progression of disease 
will be treated as right-censored observations at the time of the last response evaluation 
(subjects who withdraw from the study due to progressive disease will be considered to have 
a disease progression between the last visit and the time of withdrawal). PFS (by irRECIST)
will be reported in both summary tables and Kaplan–Meier curve.
9.7.1.8
Pharmacokinetic Analyses
Plasma and urine concentrations of E7046 and its major metabolite M1 will be tabulated and 
summarized by dose level, day, and time.  PK parameters will be derived from plasma 
concentrations by noncompartmental analysis using actual times.  Minimally, the following PK 
parameters will be calculated: maximum drug concentration (Cmax), time to reach maximum 
concentration following drug administration (tmax), area under the concentration × time curve 
(AUC); and if data permit, elimination half-life (t½), total body clearance (CL), volume of 
distribution (Vd), renal clearance (CLr), accumulation ratio (R), and fraction excreted (fe).
9.7.1.9
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses
Pharmacodynamic, PG and other biomarker analyses may be performed and reported separately. 
Details of these analyses will be described in a separate analysis plan.
9.7.1.10
Safety Analyses
Evaluation of safety will be performed on the Safety Analysis Set.  Safety data to be evaluated 
include AEs, clinical laboratory results, vital signs, ECGs, and the results of physical 
examinations.
Safety assessments will consist of monitoring and recording all AEs and SAEs, using CTCAE 
version 4.03; regular laboratory evaluation for hematology, blood chemistry, and urine values;
and regular performance of physical examinations, periodic measurement of vital signs, ECGs,
and MUGA scans at baseline and as clinically indicated. 
Safety parameters will be summarized using descriptive statistics (mean, standard deviation, 
median, Q1, Q3, and range for continuous variables; numbers and percentages for categorical 
measures).


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The effects of E7046 on cardiovascular repolarization will be evaluated via 12-hour, 12-lead 
continuous Holter/ECG monitoring during Cycle 1 Day 1 and Day 8 in the Dose Escalation part 
of the study only.  Individual ECGs will be extracted in replicate from the Holter recordings at 
specified time points and will be evaluated by a central laboratory.  QT intervals will be 
measured from Lead II and will be corrected for QTc using Fridericia's (QTcF) correction 
factors.  The primary QTc parameter will be QTcF.  Secondary parameters (heart rate, PR and
QRS) and T wave morphology will be evaluated. Potential effects of E7046 will be evaluated as 
change-from predose baseline heart rate, PR, QRS and QTcF by post-dosing timepoint. For 
purposes of QT assessment, exposure response analysis will be performed of the relationship 
between E7046 plasma levels and ∆QTcF. 
Safety ECGs will be analyzed using descriptive statistics for ECG parameters and changes from 
baseline will be presented by treatment cohort abnormal readings will be identified as those 
outside (above or below) the reference range. ECG findings will be summarized.
9.7.1.10.1 EXTENT OF EXPOSURE
The number of cycles/days on treatment, quantity of study drug administered, and the number of
subjects requiring dose reductions, treatment interruption, and treatment discontinuation due to
AEs will be summarized.
9.7.1.10.2 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).  Adverse events will be coded to the MedDRA (Version 18.0 or higher) lower level 
term (LLT) closest to the verbatim term.  Adverse events will be presented by MedDRA 
preferred term (PT)  nested within primary system organ class (SOC).
A TEAE is defined as an AE that emerges during treatment, having been absent at pretreatment 
(Baseline), or 
•
Reemerges during treatment, having been present at pretreatment (Baseline) but stopped 
before treatment, or 
•
Worsens in severity during treatment relative to the pretreatment state, when the AE is 
continuous.
Only those AEs that were treatment emergent will be included in summary tables.  All AEs, 
treatment-emergent or otherwise, will be presented in subject data listings.
The TEAEs will be summarized by treatment cohort.  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 a 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 maximum severity (mild, moderate, or severe).and by relationship to study drug 
(Yes [related] and No [not related]), respectively.


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9.7.1.10.3 LABORATORY VALUES
Laboratory results will be summarized using Système International (SI) units, as appropriate.  
For all quantitative parameters listed in Section 9.5.5.3, the actual value and the change from 
baseline to each postbaseline visit and to the end of will be summarized by visit and treatment
cohort using descriptive statistics.  Qualitative parameters listed in Section 9.5.5.3 and change 
from baseline values will be summarized using frequencies (number and percentage of subjects).
9.7.1.10.4 VITAL SIGNS
Descriptive statistics for vital signs parameters (ie, diastolic and systolic BP, pulse, respiratory 
rate, temperature, weight and changes from baseline will be presented by day and time after 
dosing and treatment cohort. 
MUGA Scans: MUGA scans and/or echocardiograms will be assessed locally to determine 
LVEF. Summary statistics (standard deviation, median, and range) for LVEF changes from 
baseline will be calculated and summarized.
9.7.2
Determination of Sample Size
The sample size of 30 to 40 subjects is considered adequate for the purposes of selecting a dose. 
The expected sample size for the dose escalation part of this trial will be up to 24 subjects.  Per 
the dose escalation design adopted and modified from the traditional 3+3 design (Section 9.1.1.1), 
there will be a maximum of 4 planned cohorts and there will be 6 subjects each cohort to allow 
for adequate assessment of tolerability, clinical benefit, PK, PD data and integrated evaluation of 
safety so as to select RP2D.  Additional 6 to 16 subjects will be enrolled in the expansion cohort 
to confirm RP2D.
The dose escalation part and the extension part yield a total maximum sample size of 40 subjects. 
9.7.3
Interim Analysis
No interim analyses are planned.
9.7.4
Other Statistical/Analytical Issues
Not applicable.
9.7.5
Procedure 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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2010;141:39-51.
Robert C, Ribas A, Wolchok JD, Hodi FS, Hamid O, Kefford R, et al. Anti-programmed-death-
receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a 
randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014; ;384(9948):1109-17.
Rubinstein LV, Simon RM . Phase I clinical trial design. In: Budman DR, Calvert AH, Rowinsky 
EK (editors). Handbook of anticancer drug development. Philadelphia: Lippincott Williams & 
Wilkins; 2003. p. 297-308.


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Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity's roles in cancer 
suppression and promotion. Science. 2011;331(6024):1565-70.
The American College of Radiology (ACR). Uniform protocols for Imaging in Clinical Trials.
Philadelphia, PA: ACR; 2006.
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, 
activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 
2012;366(26):2443-54.
Wolchok JD, Hoos A, O'Day S, Weber JS, Hamid O, Lebbé C, et al. Guidelines for the 
evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin 
Cancer Res. 2009;15(23):7412-20.
Zhang QW, Liu L, Gong CY, Shi HS, Zeng YH, Wang XZ, et al. Prognostic significance of 
tumor-associated macrophages in solid tumor: a meta-analysis of the literature. PLoS One. 
2012;7(12):e50946.


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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 
submission to health or regulatory authorities as well as 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 (or appropriate study team member) 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 health or regulatory 
authority and IRB/IEC 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 Competent 
Authorities detailing such changes.
11.2
Adherence to the Protocol
The investigator will conduct the study in strict accordance with the protocol (refer to ICH E6, 
Section 4.5).
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 investigator 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 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 IRB/IEC review.
In accordance with ICH E6, Section 1.52, source documents include, but are not limited to the 
following:
•
Clinic, office, or hospital charts


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•
Copies or transcribed health care provider notes which have been certified for accuracy after 
production
•
Recorded data from automated instruments such as IxRS, x-rays, and other imaging reports, 
(eg, sonograms, CT scans, magnetic resonance images, radioactive images, ECGs, rhythm 
strips, EEGs, polysomnographs, pulmonary function tests) regardless of how these images 
are stored, including microfiche and photographic negatives
•
Pain, quality of life, or medical history questionnaires completed by subjects
•
Records of telephone contacts
•
Diaries or evaluation checklists
•
Drug distribution and accountability logs maintained in pharmacies or by research personnel
•
Laboratory results and other laboratory test outputs (eg, urine pregnancy test result 
documentation and urine dip-sticks)
•
Correspondence regarding a study subject’s treatment between physicians or memoranda sent 
to the IRBs/IECs
•
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 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.
11.6
Retention of Records
The circumstances of completion or termination of the study notwithstanding, the investigator is 
responsible for retaining all study documents, including but not limited to the protocol, copies of 
CRFs, the Investigator's Brochure, and regulatory agency registration documents (eg, Form FDA 
1572 ICFs, and IRB/IEC correspondence).  In addition, the sponsor will send a list of treatment 
codes by study subject to the investigator after the clinical database for this study has been 
locked.  The site should plan to retain study documents, as directed by the sponsor, for at least 2 


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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 the 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 the principal investigator (or a designated pharmacist) by the 
sponsor (this can be amended depending on the protocol).  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 investigator (or a designated pharmacist) 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 
investigator (or site personnel) 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 investigator (or a designated pharmacist) will return all used 
and unused drug containers, drug labels, and a copy of the completed drug disposition form to 
the sponsor’s CRA (or designated contractor) or, when approval is given by the sponsor, will 
destroy supplies and containers at the site.
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.


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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.
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 laws and regulations.


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12 APPENDICES
Appendix 1: Adaptation of RECIST for evaluation of immune therapy activity in 
solid tumors: Immune-Related Response Evaluation Criteria in Solid Tumors 
(irRECIST)
Investigators should follow the guidelines provided here which are an adaptation of RECIST 1.1 
and immume-related response criteria (irRC). The following guide represents a summary of 
irRECIST and is meant to help investigators in providing more objective and reproducible 
immune therapy related tumor response assessments in solid tumors.
The key changes for irRECIST are:
In contrast to RECIST 1.1, irRECIST allows the site to select up to ten (10) target lesions
at baseline, five (5) per organ, if clinically relevant via CT/MRI scans. Skin lesions are not 
permitted for selection as target lesions for this study.
The ability to continue treatment, if clinically stable, until repeat imaging scans ≥4 weeks 
later (in most cases at the next scanning timepoint 6 weeks later) to confirm Progressive 
Disease (irPD)


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irRECIST Lexicon
1. Baseline Assessments
Measurable 
(Target) lesions
Measurable lesions must be accurately measured in at least one dimension 
with a minimum size of:
10 mm in the longest diameter (LDi) by CT or MRI scan (or no less than
double the slice thickness) for non-nodal lesions and ≥15 mm in short axis
(SDi) for nodal lesions
Identify up to 10 lesions, not more than 5 from one organ system. Lymph 
nodes are considered one organ system
Likely to be reproducible across all timepoints
Representative of tumor burden
May include lesions in previously irradiated areas ONLY if there is 
demonstrated progression in that lesion after irradiation
Sum of diameters (SOD) of all target lesions including nodal and non-
nodal are reported as baseline SOD which is used for assessing tumor 
response at follow-up timepoints
Bone lesions
Regardless of the imaging modality, blastic bone lesions will not be selected
as target lesions. Lytic or mixed lytic-blastic lesions with a measurable soft 
tissue component ≥10 mm can be selected as target lesions.
Cystic and 
Necrotic 
Lesions as 
Target Lesions
Lesions that are partially cystic or necrotic can be selected as target lesions. 
The longest diameter of such a lesion will be added to the SOD of all target 
lesions at baseline. If other lesions with a non-liquid/non-necrotic component 
are present, those should be preferred.
Lesions with 
Prior Local 
Treatment
During target lesion selection the radiologist will consider information on the
anatomical sites of previous intervention (e.g. previous irradiation, RF-
ablation, TACE, surgery, etc.). Lesions undergoing prior intervention will not 
be selected as target lesions unless there has been a demonstration of 
progression in the lesion.
Nonmeasurable 
(Non-Target) 
lesions
Non-target lesions will include:
Measurable lesions not selected as target lesions. There is no limit to the 
number of non-target lesions that can be recorded at baseline
Other types of lesions that are confidently felt to represent neoplastic 
tissue, but are difficult to measure in a reproducible manner. These 
include bone metastases, leptomeningeal metastases, malignant ascites, 
pleural or pericardial effusions, ascites, inflammatory breast disease,
lymphangitis cutis/pulmonis, cystic lesions, ill-defined abdominal masses, 
skin lesions, etc.
Multiple non-target lesions from the same organ may be captured as a 
single item on the eCRF (e.g. multiple liver metastases)
Non-target lesions should be reported as present at baseline
SOD baseline
Sum of diameters at baseline = LDi of all non-nodal + SDi of all nodal target lesions


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2. Time Point Assessments After Baseline
Target lesion 
measurements
Locate image that optimizes the LDi of the non-nodal target lesion or short 
axis of target node(s). There is no need to go to an identical slice from 
baseline.
Measure the respective LDi and SDi for all target lesions and calculate 
timepoint SOD (SOD timepoint).
Special consideration for target lesions:
If target lesion is too small to measure, a default value of 5mm should be 
entered on eCRF.
If target lesion is between 5-10mm, actual diameter should be entered on 
eCRF 
If target lesion splits into 2 or more lesion then the LDi of split lesions will 
be added and entered in place of that lesion
If two target lesion merged to form one lesion than LDi of one should be 
entered as ‘0mm’ while the other lesion should have the diameter of the 
merged lesion
Non-Target 
Lesion 
Assessment
Non-target lesions are evaluated qualitatively as present, absent, not 
evaluable (NE) or unequivocal progression. The response of non-target 
lesions primarily contributes to the overall response assessments of irCR.
Non-target lesions do not affect irPR and irSD assessments. Only a massive 
and unequivocal worsening of non-target lesions alone, even in the presence 
of stable disease or a partial response in the target lesion is indicative of 
irPD. irCR is not possible unless all non-target lesions are absent.
Definition of 
New lesion
Any lesion which was not recorded at baseline. There is no minimum size 
criteria to identify a new lesion and clinical judgment must be used by the PI
May include a lesion in an anatomical location that was not scanned at 
baseline (i.e. brain)
Should be unequivocal and not due to differences in scanning technique
If equivocal, should be assessed at next timepoint; if present, PD is the 
date the lesion was first seen (not the date confirmed)
3. irRECIST Overall Tumor Assessment
irCR
Complete disappearance of all measurable and nonmeasurable lesions 
(from baseline) and there are no unequivocal new lesions (unconfirmed 
irCR).
Lymph nodes must decrease to < 10 mm in short axis.
Confirmation of response is required ≥ 4 weeks later, preferably at next 
timepoint, to be considered a confirmed irCR.
irPR
If the SODtimepoint of TLs decreases by ≥30 % compared to SODbaseline
and there are no unequivocal new lesions, and no progression of non-
target disease, it is an irPR (unconfirmed). 
Confirmation is required ≥ 4 weeks later, preferably at next timepoint, to 
be considered a confirmed irPR.


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irSD
Failure to meet criteria for irCR or irPR in the absence of irPD.
If the sum of the TLs and the status of the non-target lesions do not reach 
the criteria to meet irPR or irPD (increase ≥20% and at least 5 mm 
absolute increase in SOD compared to nadir†) the response is irSD.
irSD = neither 30% decrease compared to SODbaseline or 20% 
increase and at least 5 mm absolute change compared to nadir.
†SODnadir: Lowest measure SOD of TLs at any timepoint from baseline 
onward.
irPD
Minimum 20% increase and a minimum 5 mm absolute increase in SOD
compared to nadir, or irPD for non-target lesion(s) or unequivocal new 
lesion(s).
Confirmation of progression is recommended at a minimum of 4 weeks 
after the first irPD assessment (preferably at next tumor assessment 
timepoint).
The decision to continue study treatment after the first evidence of PD is at 
the Investigator’s discretion based on the clinical status of the subject as 
described in table below.
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
1st radiologic 
evidence of PD
Repeat 
imaging at > 4 
weeks (next 
TA timepoint) 
to confirm PD
May continue 
study treatment at 
the Investigator’s 
discretion while 
awaiting 
confirmatory scans 
Repeat imaging 
at > 4 weeks to 
confirm PD per 
physician 
discretion only
Discontinue 
treatment
Subsequent scan 
confirms PD
No additional 
imaging 
required
Discontinue 
treatment
No additional 
imaging 
required
N/A
Subsequent scan 
shows SD, PR 
or CR
Continue 
regularly 
scheduled 
imaging 
assessments 
Continue study 
treatment at the 
Investigator’s 
discretion
Continue 
regularly 
scheduled 
imaging 
assessments 
May restart study 
treatment if 
condition has 
improved and/or 
clinically stable 
per Investigator’s 
discretion
Subjects may continue receiving study treatment while waiting for 
confirmation of irPD if they are clinically stable as defined by the following 
criteria:
Absence of signs and symptoms (including worsening of laboratory 
values) indicating disease progression
No decline in ECOG performance status
Absence of rapid progression of disease 
Absence of progressive tumor at critical anatomical sites (e.g., cord 
compression) requiring urgent alternative medical intervention


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If irPD is confirmed and the subject is experiencing extraordinary clinical 
benefit, site must contact Sponsor to discuss continuing treatment
irNE
Used in exceptional cases where insufficient data exists due to poor quality 
of scans or missed scans or procedure
Derivation of irRECIST overall responses
Measurable response 
Nonmeasureable response
Target Lesions
(% change in SOD)*
Non-Target Lesions 
Status
New Lesions Status
Overall Response 
(irRECIST)
100
Absent
Absent
irCR¥
100
Present/NE
Absent
irPR¥
≥30
Present/Absent/NE
Absent
irPR¥
<30 to <20
Present/Absent/NE
Absent
irSD
100
≥30
<30 to <20
NE
Present/Absent/NE
Present
irPD¥
100
≥30
<30 to <20
NE
Unequivocal 
progression
Any
irPD¥
≥20 from nadir
Any
Any
irPD¥
NE
Present/Absent/NE
Absent
irNE¥
* Decreases assessed relative to baseline, including measureable lesions only.
¥ Assuming response (irCR) and progression (irPD) are confirmed by a second, consecutive assessment at least 4 
wk apart.


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Appendix 2: Pre-Existing Autoimmune Diseases
This list is from the study protocol provided as part of the publicationTopalian 2012.


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Appendix 3: Cockcroft–Gault Calculation of Creatinine Clearance
Subjects must have adequate renal function as evidenced by serum creatinine ≤1.8 mg/dL or 
calculated creatinine clearance ≥50 mL/min per the Cockcroft–Gault formula as defined below.
Cockcroft–Gault Calculation for Creatinine Clearance
Male
(140 - age) × weight (kg) × 1.23 = XX mL/min
serum creatinine (μmol/L)
Female
(140 - age) × weight (kg) × 1.23 × 0.85 = XX mL/min
serum creatinine (μmol/L)
Source:  Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine.  Nephron. 
1976;16(1):31-41.


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Appendix 4: Common Terminology Criteria for Adverse Events (v4.03)
The National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE 
v4.03 published 28 May 2009; v4.03: June 14, 2010) provides descriptive terminology to be 
used for AE reporting in clinical trials.  A brief definition is provided to clarify the meaning 
of each AE term.  To increase the accuracy of AE reporting, all AE terms in CTCAE version 
4.03 have been correlated with single-concept, Medical Dictionary for Regulatory Activities 
(MedDRA®) terms.
CTCAE v4.03 grading refers to the severity of the AE.  CTCAE Grades 1 through 5, with 
unique clinical descriptions of severity for each AE, are based on this general guideline:
Common Terminology Criteria for Adverse Events v4.03 Grading
Grade
Status
1
Mild: asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated.
2
Moderate: minimal, local, or noninvasive intervention indicated; 
limiting age-appropriate instrumental activities of daily living (ADL).a
3
Severe or medically significant but not immediately life-threatening: 
hospitalization or prolongation of hospitalization indicated; disabling, 
limiting self-care ADL.b
4
Life-threatening consequences: urgent intervention indicated.
5
Death related to adverse event.
a:
Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc.
b:
Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, 
and not bedridden.
Source:  Cancer Therapy Evaluation Program, NCI.  CTCAE v4.03.  Available from:
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev4.pdf.
For further details regarding MedDRA, refer to the MedDRA website: 
http://www.meddramsso.com.
CTCAE v4.03 is available online: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev4.pdf.


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PROTOCOL SIGNATURE PAGE
Study Protocol Number:
E7046-G000-101
Study Protocol Title:
An Open-Label Multicenter Phase 1 Study of E7046 in Subjects With 
Selected Advanced Malignancies
Investigational Product 
Name:
E7046
IND Number:
125272
EudraCT Number:
2014-004823-37
SIGNATURES
Authors:
Date
Date
Date
Date
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
E7046-G000-101
Study Protocol Title:
An Open-Label Multicenter Phase 1 Study of E7046 in Subjects With 
Selected Advanced Malignancies
Investigational Product 
Name:
E7046
IND Number:
125272
EudraCT Number:
2014-004823-37
I have read this protocol and agree to conduct this study in accordance with all stipulations of 
the protocol and in accordance with International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) and all applicable 
local Good Clinical Practice (GCP) guidelines, including the Declaration of Helsinki.
Medical Institution
Investigator
Signature
Date

SAP_001.pdf: 
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STATISTICAL ANALYSIS PLAN 
Study Protocol 
Number: 
E7046-G000-101 
Study Protocol 
Title: 
An Open-Label Multicenter Phase 1 Study of E7046 in Subjects With 
Selected Advanced Malignancies 
Date: 
25 January 2016 
Version: 
Final V1.0 


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SIGNATURE PAGE 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


 
Statistical Analysis Plan 
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1 
TABLE OF CONTENTS 
1 
TABLE OF CONTENTS 
3 
2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS (TO BE 
ADDED) 
5 
3 
INTRODUCTION 
7 
3.1 
Study Objectives 
7 
3.1.1 
Primary Objective(s) 
7 
3.1.2 
Secondary Objective(s) 
7 
3.1.3 
Exploratory Objective(s) 
7 
3.2 
Overall Study Design and Plan 
7 
4 
DETERMINATION OF SAMPLE SIZE 
8 
5 
STATISTICAL METHODS 
9 
5.1 
Study Endpoints 
9 
5.1.1 
Primary Endpoint(s) 
9 
5.1.2 
Secondary Endpoint(s) 
9 
5.1.3 
Exploratory Endpoint(s) 
10 
5.2 
Study Subjects 
10 
5.2.1 
Definitions of Analysis Sets 
10 
5.2.2 
Subject Disposition 
10 
5.2.3 
Protocol Deviations 
11 
5.2.4 
Demographic and Other Baseline Characteristics 
11 
5.2.5 
Prior and Concomitant Therapy 
11 
5.3 
Data Analysis General Considerations 
12 
5.3.1 
Pooling of Centers 
12 
5.3.2 
Adjustments for Covariates 
12 
5.3.3 
Multiple Comparisons/Multiplicity 
12 
5.3.4 
Examination of Subgroups 
12 
5.3.5 
Handling of Missing Data, Drop-outs, and Outliers 
12 
5.3.6 
Other Considerations 
13 
5.4 
Efficacy Analyses 
13 
5.4.1 
Efficacy Analyses According to immune-related RECIST 
(irRECIST) 
13 
5.4.2 
Efficacy Analyses According to Modified RECIST 1.1 
(mRECIST 1.1) 
17 
5.4.3 
Overall Survival (OS) Analyses 
17 
5.4.4 
FDG-PET Analyses 
17 
5.5 
Pharmacokinetic, Pharmacodynamic, and 
Pharmacogenomic/Pharmacogenetic Analyses 
18 
5.5.1 
Pharmacokinetic Analyses 
18 
5.5.2 
Pharmacodynamic and Pharmacogenomic Analyses 
19 
5.6 
Safety Analyses 
19 
5.6.1 
Extent of Exposure 
20 
5.6.2 
Dose Limiting Toxicity 
20 


 
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5.6.3 
Adverse Events 
20 
5.6.4 
Laboratory Values 
21 
5.6.5 
Vital Signs 
22 
5.6.6 
Electrocardiograms 
22 
5.6.7 
Other Safety Analyses 
22 
5.7 
Other Analyses 
22 
5.8 
Exploratory Analyses 
22 
6 
INTERIM ANALYSES 
22 
7 
CHANGES IN THE PLANNED ANALYSES 
22 
8 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING 
22 
9 
PROGRAMMING SPECIFICATIONS 
23 
10 
STATISTICAL SOFTWARE 
23 
11 
MOCK TABLES, LISTINGS AND GRAPHS (TLGS) 
23 
12 
REFERENCES 
23 
13 
APPENDICES 
24 
13.1 
Schedule of Procedures/Assessments 
25 
13.2 
Adaptation of RECIST for Evaluation of Immune Therapy Activity in 
Solid Tumors: Immune-Related Response Evalution Criteria in Solid 
Tumors (irRECIST) 
28 
13.3 
Dose-Limiting Toxicities 
32 
13.4 
Common Terminology Criteria for Adverse Events (v4.03) 
33 
 


 
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2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS (TO BE 
ADDED) 
Abbreviation 
Term 
AE 
adverse event 
ATC 
anatomical therapeutic class 
AUC 
area under the concentration-time curve 
BLQ 
below limit of quantification 
BMI 
body mass index 
BOR 
best overall response 
BSA 
body surface area 
CxDy 
Cycle x Day y 
CBR 
clinical benefit rate 
CI 
confidence interval 
CL 
total body clearance 
CLr 
renal clearance 
Cmax 
maximum observed plasma concentration 
CR 
complete response 
CRF 
case report form 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
DCR 
disease control rate 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EOT 
end of treatment 
FAS 
full analysis set 
fe 
fraction excreted 
18FDG-PET 
18fluorodeoxyglucose positron emission tomography 
irCR 
immune-related complete response 
irNE 
(immune-related) not evaluable 
irPD 
immune-related progressive disease 
irPR 
immune-related partial response 
irSD 
immune-related stable disease 
irRECIST 
immune-related RECIST 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTD 
maximum tolerated dose 
ORR 
overall response rate 
OS 
overall survival 
PD 
pharmacodynamic 
PFS 
progression-free survival 


 
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PK 
pharmacokinetic 
PR 
partially response 
PT 
preferred term 
Q1 
first quartile (25 percentile) 
Q3 
third quartile (75 percentile) 
R2PD 
recommended phase 2 dose 
Rac 
accumulation ratio 
RECIST 
Response Evaluation Criteria In Solid Tumors 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
stable disease or standard deviation 
SE 
standard error  
SI 
Système International 
SOC 
system organ class 
t1/2 
terminal elimination half-life 
TEAE 
treatment-emergent adverse event 
TLG 
tables, listings, and graphs 
tmax 
time to maximum concentration 
TTR 
time to response 
Vd 
volume of distribution 
WHO 
World Health Organization 
 
 


 
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3 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the procedures and the statistical 
methods that will be used to analyze and report results for Eisai Protocol E7046-G000-101 
Amendment 01 dated 30 December 2015.  
3.1 
STUDY OBJECTIVES 
3.1.1 
Primary Objective(s) 
The primary objectives of the study are to: 
 Assess the safety/tolerability profile of E7046 as a single agent administered orally once 
daily, continuously in 21-day cycles, in subjects with selected advanced and/or recurrent 
malignancies. 
 Determine the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose 
(RP2D) of E7046. 
3.1.2 
Secondary Objective(s) 
The secondary objectives of the study are to: 
• Evaluate the pharmacokinetic (PK) profile of E7046. 
 Evaluate the objective response rate (ORR) according to the immune-related RECIST 
(irRECIST) in subjects treated with E7046 with selected tumor types with high level of 
myeloid infiltrate. 
 Evaluate the following additional efficacy endpoints according to the irRECIST:  time to 
response (TTR), duration of response (DOR), progression-free survival (PFS), disease 
control rate (DCR), and clinical benefit rate (CBR).  
3.1.3 
Exploratory Objective(s) 
The exploratory objectives of the study are to: 
 Explore efficacy according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.1, 
using the following endpoints:  ORR, TTR, DOR, PFS, DCR, and CBR. 
 Assess overall survival (OS). 
 Explore the pharmacodynamic effect of E7046 on selected immune cell populations and 
selected biomarkers in tumor infiltrate and in peripheral blood. 
 Explore 18FDG-PET as a biomarker of response. 
 Explore the pharmacokinetic/pharmacodynamic (PK/PD) relationship. 
3.2 
OVERALL STUDY DESIGN AND PLAN 
This is an open label, multicenter, Phase 1 study that will be conducted in 2 parts: a dose 
escalation part and a cohort expansion part. The objective of the dose escalation part is to assess 
the safety and tolerability and determine the MTD and/or RP2D of E7046. In the cohort 


 
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expansion part an additional 6 to 16 subjects will be treated at the RP2D to further characterize 
safety, efficacy, PK, and PD. E7046 is a novel cancer immune therapy and as this is the first 
study in humans therefore a cautious approach in the first cohort of patients is prudent. Staggered 
start of dosing in the first cohort will thus be implemented to ensure exposure of a limited 
number of subjects in the initial dosing cohort. 
A major consideration was that the toxicities of E7046 are likely to be moderate in the dose 
range planned and an MTD may not be reached (according to preclinical results). It is anticipated 
that the RP2D will be selected based on integrated evaluation of safety, tolerability, clinical 
benefit, PK, and PD data, collected from all dose levels tested. Accordingly, a modification of 
the standard 3+3 design was selected, where dose cohorts of 6 subjects will be enrolled at each of 
the 4 dose levels to be tested so as to provide sufficient data for selecting RP2D in the absence of 
an MTD. 
The study will consist of three phases for each subject:  Pretreatment Phase, Treatment Phase, 
and Extension Phase. 
A schematic of the 3 Phases is shown in Figure 1. 
Figure 1 
Study Design 
PHASE 
 
Pretreatment 
Treatment 
Extension 
PERIOD Screening Baseline 
Treatment 
Cycle 1 
Treatment Continuation 
(Cycle 2 and beyond) 
EOT 
Follow
-Up 
Day 
–28 to –1 
-3 to -1 
D1 
D8 
D15 
D1 
D8 
(C2-6 only) 
 
 
VISIT 
1 
2 
3 
4 
5 
6, 8 etc 
7, 9 etc 
98 
99 
EOT = End of Treatment 
 
The schedule of procedures/assessments for the study is presented in Section 13.1. 
The study may be cut off for the data analysis and report when the study achieves its primary 
objective, i.e., the last subject completes his/her first cycle of study drug/treatment phase, or the 
sponsor and primary investigator of the study may determine the cutoff date for the analysis 
based on the enrollment and overall progress of the study. 
4 
DETERMINATION OF SAMPLE SIZE 
The sample size of approximately 40 subjects is considered adequate for the purposes of 
selecting a dose.  
The expected sample size for the dose escalation part of this trial will be up to 24 patients.  Per 
the dose escalation design adopted and modified from the traditional 3+3 design, there will be a 


 
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maximum of 4 planned cohorts and there will be 6 subjects each cohort to allow for adequate 
assessment in tolerability, clinical benefit, PK, PD data and integrated evaluation of safety so as 
to select RP2D.  Additional 6-16 subjects will be enrolled in the expansion cohort to confirm 
RP2D. 
The dose escalation part and the extension part yield a total maximum sample size of 40 subjects.  
5 
STATISTICAL METHODS 
All descriptive statistics for continuous variables will be reported using mean, standard deviation 
(SD), median, Q1, Q3, minimum and maximum; otherwise will be specified. Categorical 
variables will be summarized as number (percentage) of subjects.  
5.1 
STUDY ENDPOINTS 
5.1.1 
Primary Endpoint(s) 
Primary Endpoints (Dose Escalation Part): 
 Safety/tolerability profile of E7046.   
 MTD and/or the RP2D. 
5.1.2 
Secondary Endpoint(s) 
Secondary Efficacy Endpoints: 
 Objective response rate (ORR) 
The ORR is the proportion of patients achieving a best overall response (BOR) of confirmed 
partial or complete response (irPR + irCR), according to the irRECIST (Section 13.2) from 
first dose date until disease progression/recurrence.  Subjects who do not have a tumor 
response assessment for any reason will be considered nonresponders and will be included in 
the denominator when calculating the response rate.  
 Duration of response (DOR) 
The DOR is defined as the time from the date of first documented confirmed irCR/irPR until 
the first documentation of confirmed disease progression or death, whichever comes first.  
 Progression-free survival (PFS) 
The PFS is defined as the time from first dose date to the date of the first documentation of 
confirmed disease progression or death (whichever occurs first) using irRECIST.  The PFS is 
also defined as the event that a subject is alive without confirmed disease progression at a 
specific evaluation time point. The censoring rule for events will be defined in the SAP. 
 Disease control rate (DCR) 
The DCR is the proportion of patients achieving irPR + irCR + irSD from first dose date until 
disease progression/recurrence.  


 
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 Clinical benefit rate (CBR) 
The CBR is the proportion of patients achieving irPR + irCR + durable irSD [lasting at least 
24 weeks] from first dose date until disease progression/recurrence.  
5.1.3 
Exploratory Endpoint(s)  
Exploratory Endpoints: 
 ORR, TTR, DOR, PFS, DCR, and CBR according to RECIST 1.1 
 Assess overall survival (OS) 
 Explore the pharmacodynamic effect of E7046 on selected immune cell populations and 
selected biomarkers in tumor infiltrate and in peripheral blood 
 Explore 18FDG-PET as a biomarker of response 
 Explore the pharmacokinetic/pharmacodynamic (PK/PD) relationship 
5.2 
STUDY SUBJECTS 
5.2.1 
Definitions of Analysis Sets 
Full Analysis Set will include all subjects who received at least one dose of study drug.  This 
will be the primary analysis set for efficacy evaluations, as well as for demographic and baseline 
characteristics.  This analysis set will also constitute the Safety Analysis Set. 
DLT Evaluable Set will consist of those subjects who are evaluable for the DLTs (Section 13.3).  
This will be the analysis set for DLT analysis. 
Pharmacokinetic (PK) Analysis Set will include all subjects who have received at least one 
dose of study drug and have at least one evaluable plasma concentration. 
Pharmacodynamic (PD) Analysis Set will include all subjects who have received at least 1 
dose of study drug and have evaluable pharmacodynamic data. 
Pharmacokinetic/Pharmacodynamic (PK/PD) Analysis Set will consist of all subjects in the 
Safety Analysis Set that also have evaluable serum PK and PD pretreatment assessment and at 
least 1 post treatment assessment. 
Response Evaluable Set will consist of those subjects who have received at least 1 dose of study 
drug and have measurable disease at baseline and at least 1 post-baseline evaluation. This will be 
the primary analysis set for tumor response analysis. 
FDG-PET Analysis Set will include all subjects with a baseline and at least one post baseline 
evaluable FDG-PET/CT assessment. 
5.2.2 
Subject Disposition 
The number (percentage) of treated subjects will be summarized as well as subjects who 
completed the study/discontinued from the study and reasons for discontinuation by dose group.  


 
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The number (percentage) of subjects who completed the study treatment/discontinued from the 
study treatment and reasons for discontinuation will also be summarized by dose group. 
The number of subjects who signed informed consent and the number (percentage) of subjects 
who failed screening and the reasons for screen failure will be summarized, based on data 
reported on the Screening Disposition Case Report Forms (CRFs). Reasons for screen failure 
will also be listed.  
5.2.3 
Protocol Deviations 
Protocol deviations are based on the selected inclusion, exclusion, and on-treatment criteria.  
The major and minor protocol deviations will be finalized, documented and listed prior to 
database lock. 
5.2.4 
Demographic and Other Baseline Characteristics 
The demographic and baseline characteristics will be summarized using descriptive statistics by 
dose group. Subject demography information will be collected at the Screening Visit.   
Demographic and other baseline characteristics will be summarized using the Full Analysis Set, 
for each dose group and listed for each subject. For continuous demographic/baseline variables 
including age (year), height (cm), weight (kg), BMI (kg/m2: weight[kg]/{height[m]×height[m]}), 
and BSA (m2: height[cm]×weight[kg]/3600), results will be summarized and presented as n, 
mean, standard deviation, median, 25% percentile (Q1), 75% percentile (Q3), minimum and 
maximum values. For categorical variables, the number and percentage of subjects will be used. 
Categorical variables include age group (≤65, >65 years), race (White, Black or African 
American, Asian [Japanese, Chinese, Other Asian], American Indian or Alaska Native, Native 
Hawaiian or other Pacific Islander, and Other), ethnicity (Hispanic or Latino, not Hispanic or 
Latino), and Eastern Cooperative Oncology Group (ECOG) performance status grade (0 - 5). 
MEDICAL HISTORY 
The number (percentage) of subjects reporting a history of any medical condition, as recorded on 
the Case Report Form (CRF), will be summarized for each dose group and overall.  A subject 
data listing of medical and surgical history will be provided. 
5.2.5 
Prior and Concomitant Therapy 
All investigator terms for medications recorded on the CRF will be coded using the World 
Health Organization (WHO, Geneva, Switzerland) Drug Dictionary using the March 2015 
version or later. The number (percentage) of subjects who have taken prior and concomitant 
medications will be summarized on the Full Analysis Set, by Anatomical Therapeutic Chemical 
(ATC) Classification and WHO drug preferred term. Prior medications will be defined as 
medications that stopped prior to the first dose of study drug. Concomitant medications will be 
defined as medications that (i) have started before the first dose of study drug and are continuing 
at the time of the first dose of study drug, or (ii) have started on or after the date of the first dose 
of study drug up to 30 days following the last dose.  


 
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A medication that cannot be determined as prior/concomitant due to missing/incomplete dates 
will be regarded as a concomitant medication.  
Prior and concomitant medications will be summarized separately by anatomic class, 
pharmacological class, and WHO drug name (preferred term) by frequency counts and 
percentages.  
Subject data listings will be provided for medications recorded during the study.  
5.3 
DATA ANALYSIS GENERAL CONSIDERATIONS 
5.3.1 
Pooling of Centers  
Subjects from all centers will be pooled for all analyses. 
5.3.2 
Adjustments for Covariates 
Not applicable.   
5.3.3 
Multiple Comparisons/Multiplicity 
Not applicable.   
5.3.4 
Examination of Subgroups 
No subgroup analyses are planned for this study. 
5.3.5 
Handling of Missing Data, Drop-outs, and Outliers 
Adverse Events 
An adverse event is defined as “treatment emergent” if it starts on or after the first dose date. 
Adverse events with incomplete start dates will be considered treatment emergent if:  
a. Date is completely missing; or 
b. Year is missing; or 
c. Day and month are missing and the year is equal to or after the year of the first dose 
date; or 
d. Day is missing, and  
 the year is after the year of the first dose; or 
 the year is equal to the year of the first dose date and the month is equal to or after 
the month of the first dose date.  
 
Concomitant Medications  
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 30 days after the subject’s last dose. 


 
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Unless a medication is prior determined by the end date (i.e., end date is before the first dose) 
regardless the start date is partially or completely missing, medications with incomplete start 
and/or end date will be considered concomitant if:  
a. Date is completely missing; or 
b. Year is missing; or 
c. Day and month are missing and the year is equal to or after the year of the first dose 
date; or 
d. Day is missing, and  
 the year is after the year of the first dose; or 
 the year is equal to the year of the first dose date and the month is equal to or after 
the month of the first dose date.  
 
5.3.6 
Other Considerations 
There are no other specific considerations that are not covered in other relevant sections of this 
SAP. 
5.4 
EFFICACY ANALYSES 
Tumor response will be assessed by both immune-related RECIST [irRECIST] and modified 
version of RECIST 1.1 criteria [Eisenhauer, 2009]. All efficacy analyses will be performed on 
the Response Evaluable Set.  
5.4.1 
Efficacy Analyses According to immune-related RECIST (irRECIST) 
Tumor assessments and overall response to the treatment according to irRECIST are presented in 
Section 13.2. The confirmation of progressive disease (irPD) is required at least 4 weeks after the 
initial irPD. If irPD at two consecutive tumor assessment visits with less than 4 weeks, the 
additional confirmation of irPD visit is required. If irPD is confirmed, the documented start date 
of irPD is determined as follows: 
1. The date of the initial irPD if it is confirmed on consecutive tumor assessment visits. 
2. The date of the second irPD if the initial irPD is confirmed not on consecutive tumor 
assessment visits. 
The best overall response (BOR) is defined as follows: 
 irCR 
To achieve BOR of irCR, irCR must be observed at two consecutive tumor assessment visits 
with at least 4 weeks apart before the confirmed irPD, death, or end of study (whichever 
occurs first). If complete response at two consecutive tumor assessment visits with less than 
4 weeks, the confirmation of irCR at the next assessment visit is required. The documented 
start date of irCR is defined as the date of the initial irCR. 


 
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 irPR 
When BOR of irCR is not achieved, BOR of irPR can be achieved by that an initial irPR is 
confirmed by irPR or irCR at next consecutive visit (≥4weeks after the first irPR response). If 
irPR or irCR happens at two consecutive tumor assessment visits within 4 weeks, the 
additional confirmation of irPR (irPR or irCR in a later visit) is needed for BOR of irPR. The 
documented start date of irPR is the date of the initial irPR. 
 irSD 
If the documented start date of irPD is not the first evaluable tumor assessment visit after the 
first dose of study drug and the BOR is not a confirmed irCR/irPR, then the BOR is stable 
disease (irSD) when the duration of irSD is no less than 5 weeks. The duration of irSD is 
defined as the time from the first dose date to the documented start date of irPD, death, or the 
last evaluable tumor assessment (whichever occurs first).  
 irPD 
If the documented start date of irPD is the first evaluable tumor assessment visit after the first 
dose of study drug, then the BOR is irPD. 
Table 1 listed general rules in the derivation of BOR with two consecutive tumor response 
results. 
Table 1  
Derivation of BOR with Two Consecutive Tumor Response Results 
Timepoint 1 
Initial Response 
Timepoint 2 
Follow-up Response ≥ 4 weeks 
BOR 
irCR 
irCR 
irCR 
irCR 
irPR/irSD/irPD 
irSD/irPR* 
irPR 
irPR/irCR 
irPR 
irPR 
irSD 
irSD 
irPR 
irPD 
irSD 
irSD 
irSD 
irSD 
irSD 
irPD 
irSD, provided 
minimum irSD 
duration met 
irPD 
irPD 
irPD 
 *If an irCR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting irPR criteria 
relative to baseline, makes the disease irPD at that point (since disease must have reappeared after irCR). Best response would 
be irSD. However, sometimes ‘irCR’ may be claimed when subsequent scans suggest small lesions were likely still present and 
in fact the patient had irPR, not irCR at the first time point. Under these circumstances, the original irCR should be changed to 
irPR and the best response is irPR. 
 


 
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 irNE 
The BOR will be irNE in the following scenarios: 
o No evaluable tumor assessment 
o Only one evaluable tumor assessment with the result of either irPD or irCR/irPR/irSD 
but the duration of irSD is less than 5 weeks. 
 Handling of Missing /Not Evaluable Tumor Assessments 
The following rules will be used to handle missing and/or not evaluable tumor assessments: 
o One missing or not evaluable tumor assessment will be ignored if it is between two 
evaluable tumor assessments. 
o All the missing and/or not evaluable tumor assessments will be ignored if they are the 
only ones in between two irPDs. In this case, the irPD is confirmed and the 
documented start date of irPD is the date of the first irPD. 
o All the missing and/or not evaluable tumor assessments will be ignored if there is no 
evaluable tumor assessment after them.  
o Two irCRs, two irPR, or irPR and irCR with two or more missing and/or not 
evaluable tumor assessments in between will result in not evaluable result, i.e., irNE. 
Objective Response Rate (ORR) 
The objective response rate (ORR) is the proportion of patients achieving a best overall response 
of confirmed irPR or irCR according to irRECIST from first dose date until disease progression, 
death, or end of study (whichever occurs first).  Subjects who do not have a tumor response 
assessment for any reason will be considered nonresponders and will be included in the 
denominator when calculating the response rate. The count and percentage for the ORR will be 
summarized by dose group. 


 
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Time to Response (TTR) 
The time to response (TTR) is defined as the elapsed time (weeks) from the first dose date to the 
documented start date of confirmed irCR/irPR according to irRECIST. The descriptive statistics 
for the TTR will be summarized by dose group for the patients with the BOR of confirmed 
irCR/irPR.  
Duration of Response (DOR) 
The duration of response (DOR) is defined as the time (months) from the documented start date 
of confirmed irCR/irPR according to irRECIST until the documented start date of irPD or death 
(whichever occurs first).  
For subjects with the BOR of irCR/irPR who did not die and had no documented progression 
before the cut-off date for the end of the study, or before early discontinuation (including 
discontinuations due to toxicity, undocumented clinical progression, change of cancer treatment, 
or decreasing performance status), and who died or progressed after more than one missed visit, 
will be censored on the date of their last assessment with the BOR of irCR, irPR or irSD. 
The descriptive statistics (median and its standard error, Q1 and Q3) for the DOR will be 
summarized by dose group for the patients with the BOR of confirmed irCR/irPR using Kaplan-
Meier method. 
Progression-Free Survival (PFS) 
Progression-free survival is defined as alive without confirmed irPD using irRECIST at the end 
of study or certain evaluation time points such as 3 months, 6 months, etc. The time for PFS is 
defined as the elapsed time from first dose date to the documented start date of irPD or death 
(whichever occurs first).  
In analysis of PFS, the censoring rule is as follows: 
 Subjects who did not die and had no documented progression (confirmed irPD) before 
the cut-off date for the end of the study, or before early discontinuation (including 
discontinuations due to toxicity, undocumented clinical progression, change of cancer 
treatment, or decreasing performance status), PFS will be censored on the date of their 
last evaluable assessment. 
  Subjects who died or progressed after more than one missed visit, or non-evaluable 
assessment, or a combination of two, PFS will be censored on the date of their last 
evaluable assessment before the death or progression.   
The rate for PFS will be summarized by evaluation time point and dose group. The time curve 
and median of PFS will be estimated and reported by the Kaplan-Meier method.  


 
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Disease Control Rate (DCR) 
The disease control rate (DCR) is the proportion of patients achieving the BOR of confirmed 
irCR, confirmed irPR or irSD with the duration of at least 5 weeks. The count and percentage for 
the DCR will be summarized by dose group. 
Clinical Benefit Rate (CBR) 
The Clinical benefit rate (CBR) is the proportion of patients achieving the BOR of confirmed 
irCR, confirmed irPR or durable irSD (i.e., the duration of at least 24 weeks). The count and 
percentage for the CBR will be summarized by dose group. 
5.4.2 
Efficacy Analyses According to Modified RECIST 1.1 (mRECIST 1.1) 
Modified RECIST 1.1 is the same as the RECIST 1.1 but allow to choose up to ten (10) target 
lesions and five (5) per organ at baseline instead of 5 target lesion (and 2 per organ) if clinically 
relevant via CT/MRI scans. In contrast to irRECIST, Modified RECIST 1.1 does not require the 
confirmation of progressive disease (PD). 
The best overall response (BOR) based on mRECIST 1.1 is defined similarly as that according to 
the irRECIST (Section 5.4.1) except that the confirmation of PD is not required.    
Objective response rate, time to response (TTR), duration of response (DOR), progression-free 
survival (PFS), disease control rate (DCR), and clinical benefit rate (CBR) according to modified 
RECIST 1.1 will be analyzed similarly to those according to irRECIST (Section 5.4.1). 
5.4.3 
Overall Survival (OS) Analyses 
Overall survival rate will be presented at each evaluation visit by dose group. The survival 
(function) curve and median survival time will be estimated and reported by the Kaplan-Meier 
method. 
5.4.4 
FDG-PET Analyses 
The change from baseline at Week 6 and Week 12 will be summarized by the descriptive 
statistics for the following FDG-PET/CT measurements: 
 Sum of maximum for target lesions (Single pixel, unitless) 
 Maximum SUV (single pixel, unitless) 
 Maximum SUV (1 cm spot, unitless) 
 Average metabolic SUV (unitless) 
 Metabolic Volume (mm2) 
 Total Tumor Volume (mm2) 
The shift table from baseline for overall status of none-target lesions (present/absent) and status 
of new lesions (present/absent) will be tabulated at Week 6 and Week 12. 


 
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FDG-PET/CT as a biomarker of response analyses will be detailed in a separate biomarker 
analysis plan. 
5.5 
Pharmacokinetic, Pharmacodynamic, and Pharmacogenomic/Pharmacogenetic 
Analyses 
Plasma concentrations were obtained from blood samples drawn at each study visit during the 
treatment period (C1D1 and C1D8).  Details of the analysis methods for population PK/PD 
modeling will not be described in this SAP but will be described in a separate analysis plan. 
5.5.1 
Pharmacokinetic Analyses 
Blood samples for PK analyses will be collected during Cycle 1 on Day 1 and Day 8 at predose 
(0 h), 0.5, 1, 2, 4, 6, 8, and 10 and 24h postdose. Urine samples for PK analyses will be collected 
during the Dose Escalation part only Cycle 1. 
Concentration data for E7046 and its major metabolite M1 will be analyzed and summarized by 
time point and dose group, respectively. Linear/semi-log plots of individual concentration data 
and mean concentration with SD over time will be presented for E7046 and its major metabolite 
M1 by dose group based on the pharmacokinetic analysis set. 
For Cycle 1 on Day 1 and Day 8, PK parameters will be derived using non-compartmental 
methods for E7046 and its metabolite include, but are not limited to:  
 maximum concentration (Cmax),  
 time to maximum concentration (tmax),  
 area under the curve from 0 to 24 hours (AUC0-24),  
 area under the curve from 0 to infinity (AUC0-inf) , 
 elimination half life (t1/2); and if data permit,  
 total body clearance (CL), 
 volume of distribution (Vd), 
 renal clearance (CLr), 
 accumulation ratio (Rac), 
 fraction excreted (fe), 
 cumulative amount excreted in urine (Ae). 
Descriptive statistics will be used to summarize PK parameters for E7046 and its metabolite by 
dose group based on the pharmacokinetic analysis set. 
When presenting individual/raw values and summary statistics, the following rule will be 
applied:  for drug concentrations and concentration-dependent pharmacokinetic parameters, all 
summary statistics (mean, median, geometric mean, standard deviation [SD], and coefficient 
variation [CV]) will have 3 significant digits.  For t1/2, raw values and median have fixed 2 
decimal places. 


 
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In addition, plots of AUC, Cmax and CL versus dose as well as cumulative Ae versus time 
intervals (0-6 hours, 6-12 hours and 12-24 hours) will be presented for E7046 and its major 
metabolite M1 based on the pharmacokinetic analysis set. 
5.5.2 
Pharmacodynamic and Pharmacogenomic Analyses 
Pharmacodynamics (PD) biomarkers including Proof of Mechanism (POM) biomarkers to show 
target engagement and Proof of Principle (POP) biomarkers to show impact of E7046 treatment 
on disease will be evaluated from collected samples. 
Proof of Mechanism may be demonstrated by an alteration in expression of EP4 response genes 
and/or proteins, as EP4 is the molecular target of E7046. 
POP for E7046 could be a change in intratumoral immune cell populations consistent with 
inhibition of EP4 signaling such as a decrease in the ratio of M2/Total TAM or an increase in the 
number of CD8+ T cells.  POP could also be a decrease in the number or ratio of MDSC in 
circulation. 
Results from biomarker studies will be used to aid the selection of dose and for correlation with 
drug efficacy. The biomarker assessments planned for this study are summarized in Table 2.  
Table 2 
Biomarker assessments 
Biomarker sample 
Time points 
Analyses 
Potential Utility 
Serum protein  
C1D1 predose, 24hr after first dose, 
C1D8, C1D15 
TAM/MDSC-related cytokines, 
eg, PGE2, Renin) 
POM 
Serum mRNA 
C1D1 predose, 24hr after first dose, 
C1D8, C1D15 
Gene expression, eg, REN, EP4 
POM 
Paired tumor biopsy 
Predose and during Cycle 2 
T cell and macrophage 
infiltration 
POP 
Archived tumor 
Screening 
To be decided 
 
Whole blood 
Baseline, Predose on C1D1, C1D8, 
C1D15, C2D1, C3D1, and C5D1 
Circulating MDSC 
POP, POM, PS 
Blood plasma 
Baseline, time points for at each CT 
tumor assessment, and End of 
Treatment 
Cell-free nucleic acid 
 
Whole blood DNA 
Screening 
Pharmacogenomic analysis 
PG 
Urine 
Cycle 1 Day 1 pre-dose (0-hr) and 
Cycle 1 Day 1 and Day 8 post-dose to 
6hr, 6 to-12hr, 12 to 24hr. 
PGE2 metabolite 
POM 
C1D1 = Cycle 1 Day 1, MDSC = myeloid-derived suppressor cell, PG = prostaglandin, PGE =  prostaglandin e2,  POM = 
Proof of Mechanism, POP = Proof of Principle, PS = patient stratification, REN = renin, TAM = tumor-associated 
macrophages.  
Pharmacodynamic (PD), pharmacogenomic (PG) or other biomarker analyses will be detailed in 
a separate biomarker analysis plan.  
5.6 
SAFETY ANALYSES 
All safety analyses will be performed on the Safety Analysis Set. Safety data will be presented 
by dose group (although there will be no formal statistical comparison in the safety analysis) and 


 
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will be summarized on an “as treated” basis using descriptive statistics (e.g., n, mean, SD, 
median, Q1, Q3, minimum, maximum for continuous variables; n (%) for categorical variables). 
Study Day 1 for all safety analyses is defined as the date of the first dose of study drug.  
Safety variables include treatment-emergent adverse events (TEAEs), 12-lead ECG results, 
clinical laboratory tests and vital signs. The incidence of TEAEs, clinical laboratory parameters 
and vital signs as well as their changes from baseline will be summarized using descriptive 
statistics. Abnormal values will be flagged.  
5.6.1 
Extent of Exposure 
Number of cycles completed , duration of treatment and cumulative total dose will be 
summarized by dose group.  
5.6.2 
Dose Limiting Toxicity 
After all subjects in a dose level tested complete the first treatment cycle, safety information for 
those subjects will be reviewed by the Eisai clinical team together with the principal 
investigator/s and dose limiting toxicity (Yes/No) and reason(s) (see Section 13.3) for 
experiencing a dose limiting toxicity (DLT) as well as date and dosage of study drug when the 
DLT occurred will be determined for each subject. This result will be listed for the study report.   
5.6.3 
Adverse Events 
The adverse event verbatim descriptions (investigator terms from the eCRF) will be classified 
into standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA) version 18.0 or later. Adverse events will be coded to primary System Organ Class 
(SOC) and preferred term (PT) using MedDRA.  
A treatment-emergent AE (TEAE) is defined as an AE that emerged during treatment (from first 
dose to 30 days after last dose of study drug) and 
 had been absent at pretreatment (Baseline) or  
 reemerged during treatment, having been present at pretreatment (Baseline) but stopped 
before treatment, or  
 worsened in severity during treatment relative to the pretreatment state, when the AE was 
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 
within SOC and PT. Subjects will be counted only once within a SOC and PT, even if the subject 
experienced more than one TEAE within a specific SOC and PT, and the subject will be counted 
with the worst grade for that particular AE. The number (percentage) of subjects with TEAEs 
will also be summarized by highest Common Terminology Criteria for Adverse Events 
(CTCAE) grade. The number (percentage) of subjects with treatment-related TEAEs will also be 
summarized by SOC and PT. Treatment-related TEAEs include those events considered by the 
investigator to be possibly or probably related to study treatment. In summary, the following 
TEAE tables will be provided:  


 
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 Overview of TEAEs  
 TEAEs by SOC and PT  
 TEAEs by SOC, PT, and CTCAE grade  
 TEAEs with CTCAE grade 3 or 4 by SOC and PT  
 TEAEs that led to drug discontinuation by SOC and PT 
 TEAEs that led to dose reduction by SOC and PT 
 TEAEs that led to dose interruption by SOC and PT 
 Treatment-related TEAEs by SOC and PT  
 Treatment-related TEAEs with CTCAE grade 3 or 4 by SOC and PT  
 Treatment-emergent serious AEs by SOC and PT  
 Treatment-related treatment-emergent serious AEs by SOC and PT  
Subjects AE listings (treatment emergent or not) will be provided. In addition, the following 
subject AE listings will be provided:  
 All fatal adverse events.  
 All non-fatal serious adverse events (SAEs)  
 All non-fatal non-serious treatment-emergent adverse events that led to discontinuation of 
treatment 
5.6.4 
Laboratory Values 
Laboratory results will be summarized using the Système international (SI) units. Abnormal 
laboratory values will be identified as those outside the normal range. The abnormal values will 
be indicated in data listings.  
On-treatment laboratory tests are defined as laboratory tests conducted from the start of 
treatment to no more than 30 days after the last dose of study treatment. Descriptive statistics for 
laboratory test results as well as change from baseline at each visit will be produced by visit and 
dose group.  
Only laboratory parameters specified in the protocol will be summarized. Other laboratory 
parameters collected for some individual subjects will be presented in listings only. 
Laboratory test results will be assigned a low/normal/high (LNH) classification according to 
whether the value was below (L), within (N), or above (H) the laboratory parameter’s reference 
range. Within-treatment comparisons for each laboratory parameter will be based on 3-by-3 
tables (shift tables) that compare the baseline LNH classification to the LNH classification at 
each post-baseline visit.   


 
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5.6.5 
Vital Signs 
Descriptive statistics for vital signs parameters (diastolic and systolic blood pressure, pulse rate, 
respiratory rate, and body temperature) and changes from baseline will be presented by dose 
group for each cycle and visit.  
5.6.6 
Electrocardiograms 
The 12-lead ECG assessments were performed at specific visits (screening, baseline, Day 1 of 
each treatment cycle and off-treatment visit) as described in the protocol. Shift tables will present 
changes from baseline in ECG interpretation (categorized as normal; abnormal, not clinically 
significant; and abnormal, clinically significant) by visit and dose group. 
 
The left ventricular ejection fraction (LVEF) from MUGA or Echocardiogram will be evaluated 
at baseline (Screening) and off-treatment visit. Descriptive statistics for changes and % change at 
off-treatment visit from baseline will be presented by dose group for each cycle. 
Continuous Holter/ECGs will be collected during Cycle 1 on Day 1 and Day 8 at predose, and 
0.5, 1, 2, 4, 6, 8 and 10 hours post dose.  The analysis of continuous Holter/ECGs results will be 
included in a separate plan and therefore excluded in this plan. 
5.6.7 
Other Safety Analyses 
No other safety analyses are planned for this study.   
5.7 
OTHER ANALYSES 
Not applicable. 
5.8 
EXPLORATORY ANALYSES 
The planned exploratory analyses are defined in Section 5.1.3 and detained in sections 5.4.2, 
5.4.3 & 5.5.2. Additional exploratory analyses may be conducted if appropriate.  
6 
INTERIM ANALYSES 
Not applicable. 
7 
CHANGES IN THE PLANNED ANALYSES 
This SAP is in accordance with Clinical Study Protocol v1.0, dated 07 May 2015. No changes 
foe the planned analysis will be applied in this SAP.  
8 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING 
Baseline Value is defined as a Day 1 pre-dose, or the last observation before the start of drug, if 
the Day 1 pre-dose is missing.  
All by-visit analyses will be performed using assessments at corresponding scheduled visits 
recorded in the eCRF.  


 
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Partial dates for laboratory values, vital signs, and electrocardiograms (ECGs) will not be 
imputed.  
Details on calculating pharmacokinetics parameters and the method to handle below limit of 
quantification (BLQ) values will be detailed in a separate plan.  
When developing individual concentration-time profiles, BLQ values will be replaced with zero 
for the linear plot or missing for the semi-logarithm plot, respectively.  
When calculating the mean or median value for the concentration at a given time point, the BLQ 
values will be assigned as zero. If the proportion of values reported as BLQ is more than 50%, no 
summary statistics should be represented at that time point, and the value will be treated as 
missing in mean or median concentration profiles.  
More specific details, if any, are given with the discussion of analyses for each endpoint. 
9 
PROGRAMMING SPECIFICATIONS 
The rules for programming derivations and dataset specifications are provided in separate 
documents. 
10 
STATISTICAL SOFTWARE 
Statistical programming and analyses will be performed using SAS® (SAS Institute, Inc., Cary, 
NC, USA), version 9 or higher, and/or other validated statistical software as required.  
11 
MOCK TABLES, LISTINGS AND GRAPHS (TLGS) 
The study TLG shells will be provided in a separate document, which will show the content and 
format of all tables, listings, and graphs in detail. 
12 
REFERENCES 
1. Eisenhauer EA, et al. New response evaluation criteria in solid tumours: revised RECIST 
guideline (version 1.1). Eur J Cancer. 2009. 45(2): 228-47. 


 
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13 
APPENDICES 
 


 
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13.1 
Schedule of Procedures/Assessments  
Table 3 
Schedule of Procedures / Assessments in Study E7046-G000-101 
 
Phase 
Pretreatmenta 
Treatment 
Extension 
 
Period 
Screening 
Baseline 
Cycle 1 
Treatment Continuationb 
(Cycle 2 and beyond) 
Off-
Treatmentc 
Follow-
upc 
 
Visit 
1 
2 
3 
4 
5 
6, 8, etc. 
7, 9, etc. 
98 
99 
Day 
-28 to -1 
-3 to -1 
1 
8 
15 
1 
8 (C2-6 only) 
 
 
CRF 
Procedures/Assessments 
 
 
 
 
 
 
 
 
 
S 
Informed consent 
X 
 
 
 
 
 
 
 
 
S 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
S 
Medical history 
X 
 
 
 
 
 
 
 
 
S 
Prior and concomitant medications 
X 
 
X 
X 
X 
X 
X 
X 
 
S 
Physical examinationd and Vital signse 
X 
X 
X 
X 
X 
X 
 
X 
 
N 
Echocardiogram / MUGAf  
X 
 
 
 
 
 
 
X 
 
S 
Pregnancy testg 
X 
X 
X 
 
 
X 
 
 
 
S 
ECOG performance status 
X 
X 
X 
 
 
X 
 
X 
 
S 
12-lead ECGsh 
X 
X 
X 
 
 
X 
 
X 
 
S 
ECG Holter monitoringi 
 
 
X 
X 
 
 
 
 
 
S 
Hematology / Blood chemistryj 
X 
X 
X 
X 
X 
X 
X 
X 
 
S 
Urinalysisk 
X 
 
X 
X 
X 
X 
X 
X 
 
N 
Genomic DNAl 
X 
 
 
 
 
 
 
 
 
S 
PK and PD urine collectionm 
 
 
X 
X 
 
 
 
 
 
S 
PK blood samplesn 
 
 
X 
X 
 
 
 
 
 
N 
PD blood sampleso 
 
X o 
X 
Xo 
Xo 
Xo 
 
Xo 
 
N 
Paired tumor biopsy and archived tumorp 
X 
 
 
 
 
Xp 
 
 
 
N 
18FDG PET/CTq 
X 
 
 
 
 
Xq 
 
 
 
S 
Tumor assessments: CT or MRIr 
X 
 
Every 6 weeks or sooner if clinically indicated 
 
 
S 
CT or MRI of the brains 
 
 
X 
 
 
N 
Bone Scant 
X 
 
Every 24 wks, or sooner if clinically indicated, and at confirmation of irCR 
 
 
S 
E7046 administrationu 
 
 
Continuous daily dosing 
 
 
S 
Adverse Events 
X 
 
X 
X 
 
S 
Survival statusv 
 
 
 
 
X 
 
For CRF:  S = standard assessment, N = nonstandard assessment (study-specific), N/A = not applicable. 
AE = adverse event, β-hCG = beta-human chorionic gonadotropin, BP = blood pressure, C1D1 = Cycle 1 Day 1, CR = complete response, CRF = case report form, CT = 
computed tomography, CTCs = circulating tumor cells, DNA = deoxyribonucleic acid, ECG = electrocardiograms, ECOG = Eastern Cooperative Oncology Group, 18FDG-PET = 
18fluorodeoxyglucose-positron emission tomography, h = hour, HR = heart rate, irPR = immune-related partial response,  irRECIST = immune-related RECIST, IV = intravenous, 
MDSC = myeloid-derived suppressor cell(s), MRI = magnetic resonance imaging, myeloid-derived suppressor cell, MUGA = multiple gated acquisition, PD = 


 
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pharmacodynamic, PGE2 = prostaglandin e2, PK = pharmacokinetic, PR = partial response, RECIST = Response Evaluation Criteria In Solid Tumors, RR = respiratory rate, 
SCCHN = squamous cell carcinoma of head and neck, SAE = serious adverse event, TNBC = triple-negative breast cancer. 
a. The Screening Period extends from Day -28 to Day -1, except for signing of the informed consent form, which may be up to 8 weeks before the first dose of study drug.  The 
baseline assessments may be performed from Day -3 to Day -1 (before the first dose of E7046).  Screening assessments may be used as baseline assessments if performed 
within 72 hours of the first dose of study medication. 
b. The off-treatment assessment should occur within 30 days after the final dose of study treatment.  Subjects who discontinue study for reasons other than disease progression 
will be followed until disease progression or death.  All anticancer therapies will be collected (the sponsor may choose to stop the collection of therapies after the first 
anticancer treatment. 
c. Visit windows are allowed from Cycle 3 onwards as follows: Day 1 (±3 days), and Day 8 (±3 days).  There must be at least 5 days between the Day 1 and Day 8 visit for any 
given treatment cycle. 
d. A comprehensive physical examination will be performed at the Screening Visit and at the Off-Treatment Visit.  A symptom-directed physical examination will be 
performed on Day  1 of all treatment cycles and at any time during the study, as clinically indicated. 
e. Vital signs include BP, HR, RR, and body temperature, as well as weight and height.  BP, HR, and RR will be collected after the subject has been sitting for 5 minutes. 
Height will be measured at the Screening Visit only. 
f. MUGA scans or echocardiograms will be performed at Screening, during the Off-Treatment Visit (window of ±1 week), and if clinically indicated.  MUGA scans and 
echocardiograms will be performed locally in accordance with the institution’s standard practice. 
g. A serum pregnancy test (β-hCG) will be performed at screening for all premenopausal women and postmenopausal women who have been amenorrheic for less than 
12 months.  A urine pregnancy test will be performed at baseline before the first E7046 dose, and on Day 1 of every Cycle. 
h. 12-Lead ECGs will be collected at the following time points:  Screening (single) and Baseline (single unless abnormalities are observed or if clinically indicated, then in 
triplicate at 2-minute intervals); Day 1 of all cycles (before and after study drug administration); and at the Off-Treatment Visit.  In case of any alteration, or if clinically 
necessary, an echocardiogram and/or cardiac enzymes should be performed. 
i. Continuous Holter/ECGs (12-h/12-lead) to be collected during Cycle 1 on Day 1 and Day 8 at predose (3 timepoints within 45 minutes), and 0.5, 1, 2, 4, 6, 8, and 12 h 
postdose.  At each of these timepoints, patients should be supinely resting for at least 10 minutes prior to and 5 minutes after the nominal time. When coinciding, blood 
draws, vital signs and 12-lead safety ECGs should be performed immediately after the timewindow for ECG extraction.. 
j. Hematology and blood chemistry samples will be obtained before drug administration.  Screening assessments may be used as baseline assessments if performed within 
72 hours of the first dose of study medication. Before drug administration on Cycle 1, Days 1 and 8, a complete blood count should be drawn. 
k. Urine samples will be obtained before drug administration (either formal urinalysis or urine dipstick for protein and glucose are acceptable). 
l. Genomic DNA samples will be collected predose at baseline.  If it cannot be collected at the designated time point, it may be collected at a time point after baseline. 
m. In Cycle 1, Day 1 and Day 8 All urine excreted will be collected as follows: pre-dose (0 hr), post-dose to 6hr, 6 to 12hr, 12-24hr.  Total urine volume collected in each time 
interval will be recorded.Urine will be analyze for PK (E7046, M1 metabolite) and PD (PGE-M, metabolite of PGE2). 
n. Blood samples for PK analysis will be collected in Cycle 1 on Days 1 and 8 at predose (0 h), 0.5, 1, 2, 4, 6, 8, 10, and 24h postdose. 
o. Blood samples for PD mRNA and protein biomarker analysis (one red top serum tube and one PAX gene tube) will be collected at the following time points:  predose (0 h) 
on Cycle 1 Day 1, 24 h after first dose, Day 8, and Day 15.  Blood for cell free nucleic acid will be collected at C1D1 predose, at each tumor assessment, and at the end of 
treatment. Blood for MDSC in circulation will be collected at baseline, C1D1, C1D8, C1D15, C2D1, C3D1, and C5D1. 
p. Paired tumor biopsies will be obtained, with appropriate subject consent.  Subjects will have the biopsy before the first dose of E7046 and during Cycle 2, as long as the 
subject has had uninterrupted treatment at least 5 days prior to biopsy. In addition, archived fixed tumor tissue will be collected if available (instructions to be provided in a 
separate manual). 


 
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q. 18FDG PET/CT scans should be performed according to instructions provided by the imaging core lab and sent to the core lab for quantitative assessments.  Scans should be 
performed at baseline (within 7 days before C1D1) for all subejcts, Repeat scans in conjunction with the Week 6  and Week 12 tumor assessments timepoints only for 
subjects with evidence of evaluable FDG avid tumor lesion(s) at screening.  18FDG-PET/CT scan timepoints may be changed based on emergent data. 
Subjects must have a fasting serum glucose assessment performed before injection of the PET tracer for each scan.  FDG-PET/CT will not be performed if serum glucose is 
>120 mg/dl for nondiabetics or >200 mg/dl for diabetic subjects. 
r. Tumor assessments will be performed based on irRECIST and RECIST1.1. Treatment decisions will be based on irRECIST.  Tumor assessments will be carried out during 
the Pretreatment Phase and then every 6 weeks (during the 6th week; counting from C1D1) during treatment cycles in both the Treatment Phase and the Extension Phase. 
CT scans (with oral and intravenous contrast) of chest, abdomen, and pelvis and of other known sites of disease will be obtained at Screening (within 28 days prior to Cycle 
1/ Day 1), using the above tumor assessment schedule, and as indicated clinically.  Skin lesions may only be considered as non-index lesions (no photographs required) or as 
new lesions to add to the tumor burden sum.  Subjects with SCCHN must also have head and neck scans performed at all tumor assessment timepoints.   
MRI scans may be used instead of CT scans for (head, neck) abdomen and pelvis; however, chest must be assessed using CT.  Chest disease may not be followed using 
chest x-ray.    CT scans should be performed with oral and iodinated IV contrast and MRI scans with IV gadolinium chelate unless there is a medical contraindication to 
contrast.  If iodinated IV contrast is contraindicated, chest CT should be performed without IV contrast.  The same method of assessment must be used at all time points as 
used at Screening. 
s. Screening brain scans will be performed by MRI pre- and post- gadolinium or CT with contrast within 4 weeks prior to C1D1.  During the Treatment Phase, CT/MRI of the 
brain will be performed if clinically indicated, and within a target of 1 week after a subject achieves a irCR.  For subjects with history of treated brain metastases, brain scans 
will be performed at every tumor assessment time point. The same methodology and scan acquisition techniques used at screening should be used throughout the study to 
ensure comparability 
t. A bone scan (99m-technetium polyphosphonate scintigraphy, whole body bone MRI, or 18F-NaF) to assess bone metastases will be performed within 6 weeks prior to 
C1D1 (historical scans are acceptable) and then every 24 weeks (within that 24th week) from C1D1 for tumor types known to metastasize to bone (eg TNBC, NSCLC etc.), 
or sooner if clinically indicated.  In subjects whose body CT/MRI scans indicate irCR has been achieved, a bone scan will be required at confirmation of irCR to exclude 
new bone metastases.  The same methodology and acquisition techniques used at screening should be used throughout the study to ensure comparability.  If a non-target 
lesion is being followed by bone scan (not present on CT/MRI), and is not imaged at a follow-up time point because a bone scan is not required at that time point, the time 
point non-target lesion response will be based upon the other non-target lesions and will not be considered not evaluable (NE).   
u. E7046 should be taken daily at the dose assigned, with fasting 2 hours before and 2 hours after ingestion of E7046 capsules.  On visit days, subjects should not take study 
medication before evaluations are performed. 
v. Subjects who discontinue study will be followed for survival.  Survival follow-up will be conducted approximately every 12 weeks on all subjects, unless they withdraw 
consent.  Follow up on subsequent treatment and clinical response will be collected.   
 


 
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13.2 
Adaptation of RECIST for Evaluation of Immune Therapy Activity in Solid 
Tumors: Immune-Related Response Evalution Criteria in Solid Tumors (irRECIST) 
Investigators should follow the guidelines provided here which are an adaptation of RECIST 1.1 
and immume-related response criteria (irRC). The following guide represents a summary of 
irRECIST and is meant to help investigators in providing more objective and reproducible 
immune therapy related tumor response assessments in solid tumors. 
The key changes for irRECIST are: 
 In contrast to RECIST 1.1, irRECIST allows the site to select up to ten (10) target lesions 
at baseline, five (5) per organ, if clinically relevant via CT/MRI scans. Skin lesions are not 
permitted for selection as target lesions for this study. 
 The ability to continue treatment, if clinically stable, until repeat imaging scans ≥ 4 weeks 
later (in most cases at the next scanning timepoint 6 weeks later) to confirm Progressive 
Disease (irPD) 
Table 4  
Evaluation of Immune Therapy Activity in Solid Tumors: Immune-Related 
Response Evalution Criteria in Solid Tumors (irRECIST) 
irRECIST Lexicon 
1. Baseline Assessments 
Measurable 
(Target) lesions 
 
Measurable lesions must be accurately measured in at least one dimension 
with a minimum size of: 
 10 mm in the longest diameter (LDi) by CT or MRI scan (or no less than 
double the slice thickness) for non-nodal lesions and ≥15 mm in short axis 
(SDi) for nodal lesions 
 Identify up to 10 lesions, not more than 5 from one organ system. Lymph 
nodes are considered one organ system 
 Likely to be reproducible across all timepoints 
 Representative of tumor burden 
 May include lesions in previously irradiated areas ONLY if there is 
demonstrated progression in that lesion after irradiation 
 Sum of diameters (SOD) of all target lesions including nodal and non-
nodal are reported as baseline SOD which is used for assessing tumor 
response at follow-up timepoints 
Bone lesions 
 
Regardless of the imaging modality, blastic bone lesions will not be selected 
as target lesions. Lytic or mixed lytic-blastic lesions with a measurable soft 
tissue component ≥10 mm can be selected as target lesions. 
Cystic and 
Necrotic 
Lesions as 
Target Lesions 
Lesions that are partially cystic or necrotic can be selected as target lesions. 
The longest diameter of such a lesion will be added to the SOD of all target 
lesions at baseline. If other lesions with a non-liquid/non-necrotic component 
are present, those should be preferred. 
Lesions with 
Prior Local 
Treatment 
During target lesion selection the radiologist will consider information on the 
anatomical sites of previous intervention (e.g. previous irradiation, RF-
ablation, TACE, surgery, etc.). Lesions undergoing prior intervention will not 
be selected as target lesions unless there has been a demonstration of 


 
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progression in the lesion. 
Nonmeasurable 
(Non-Target) 
lesions 
 
Non-target lesions will include: 
 Measurable lesions not selected as target lesions. There is no limit to the 
number of non-target lesions that can be recorded at baseline 
 Other types of lesions that are confidently felt to represent neoplastic 
tissue, but are difficult to measure in a reproducible manner. These 
include bone metastases, leptomeningeal metastases, malignant ascites, 
pleural or pericardial effusions, ascites, inflammatory breast disease, 
lymphangitis cutis/pulmonis, cystic lesions, ill-defined abdominal masses, 
skin lesions, etc. 
 Multiple non-target lesions from the same organ may be captured as a 
single item on the eCRF (e.g. multiple liver metastases) 
Non-target lesions should be reported as present at baseline 
SOD baseline 
Sum of diameters at baseline = LDi of all non-nodal + SDi of all nodal target lesions 
2. Time Point Assessments After Baseline 
Target lesion 
measurements 
Locate image that optimizes the LDi of the non-nodal target lesion or short 
axis of target node(s). There is no need to go to an identical slice from 
baseline. 
Measure the respective LDi and SDi for all target lesions and calculate 
timepoint SOD (SOD timepoint). 
Special consideration for target lesions: 
 If target lesion is too small to measure, a default value of 5mm should be 
entered on eCRF. 
 If target lesion is between 5-10mm, actual diameter should be entered on 
eCRF  
 If target lesion splits into 2 or more lesion then the LDi of split lesions will 
be added and entered in place of that lesion 
 If two target lesion merged to form one lesion than LDi of one should be 
entered as ‘0mm’ while the other lesion should have the diameter of the 
merged lesion 
Non-Target 
Lesion 
Assessment 
 
Non-target lesions are evaluated qualitatively as present, absent, not 
evaluable (NE) or unequivocal progression. The response of non-target 
lesions primarily contributes to the overall response assessments of irCR. 
Non-target lesions do not affect irPR and irSD assessments. Only a massive 
and unequivocal worsening of non-target lesions alone, even in the presence 
of stable disease or a partial response in the target lesion is indicative of 
irPD. irCR is not possible unless all non-target lesions are absent. 


 
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Definition of 
New lesion 
Any lesion which was not recorded at baseline. There is no minimum size 
criteria to identify a new lesion  and clinical judgment must be used by the PI 
 May include a lesion in an anatomical location that was not scanned at 
baseline (i.e. brain) 
 Should be unequivocal and not due to differences in scanning technique 
 If equivocal, should be assessed at next timepoint; if present, PD is the 
date the lesion was first seen (not the date confirmed) 
3. irRECIST Overall Tumor Assessment 
irCR 
 Complete disappearance of all measurable and nonmeasurable lesions 
(from baseline) and there are no unequivocal new lesions (unconfirmed 
irCR). 
 Lymph nodes must decrease to < 10 mm in short axis. 
 Confirmation of response is required ≥ 4 weeks later, preferably at next 
timepoint, to be considered a confirmed irCR. 
irPR 
 If the SODtimepoint of TLs decreases by ≥ 30 % compared to SODbaseline 
and there are no unequivocal new lesions, and no progression of non- 
target disease, it is an irPR (unconfirmed).  
 Confirmation is required ≥ 4 weeks later, preferably at next timepoint, to 
be considered a confirmed irPR. 
irSD 
Failure to meet criteria for irCR or irPR in the absence of irPD. 
 If the sum of the TLs and the status of the non-target lesions do not reach 
the criteria to meet irPR or irPD (increase ≥20% and at least 5 mm 
absolute increase in SOD compared to nadir†) the response is irSD. 
 irSD = neither 30% decrease compared to SODbaseline or 20% 
increase  and at least 5 mm absolute change compared to nadir. 
 †SODnadir: Lowest measure SOD of TLs at any timepoint from baseline 
onward. 
irPD 
Minimum 20% increase and a minimum 5 mm absolute increase in SOD 
compared to nadir, or irPD for non-target lesion(s) or unequivocal new 
lesion(s). 
 Confirmation of progression is recommended at a  minimum of 4 weeks 
after the first irPD assessment (preferably at next tumor assessment 
timepoint). 
The decision to continue study treatment after the first evidence of PD is at 
the Investigator’s discretion based on the clinical status of the subject as 
described in table below. 
 
Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
1st radiologic 
evidence of PD 
Repeat 
imaging at > 4 
weeks (next 
TA timepoint) 
to confirm PD 
May continue 
study treatment at 
the Investigator’s 
discretion while 
awaiting 
confirmatory scans  
Repeat imaging 
at > 4 weeks to 
confirm PD per 
physician 
discretion only 
Discontinue 
treatment 


 
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Subsequent scan 
confirms PD 
No additional 
imaging 
required 
Discontinue 
treatment 
No additional 
imaging 
required 
N/A 
Subsequent scan 
shows SD, PR 
or CR 
Continue 
regularly 
scheduled 
imaging 
assessments  
Continue study 
treatment at the 
Investigator’s 
discretion 
Continue 
regularly 
scheduled 
imaging 
assessments  
May restart study 
treatment if 
condition has 
improved and/or 
clinically stable 
per Investigator’s 
discretion 
 
Subjects may continue receiving study treatment while waiting for 
confirmation of irPD if they are clinically stable as defined by the following 
criteria: 
 Absence of signs and symptoms (including worsening of laboratory 
values) indicating disease progression 
 No decline in ECOG performance status 
 Absence of rapid progression of disease  
 Absence of progressive tumor at critical anatomical sites (e.g., cord 
compression) requiring urgent alternative medical intervention 
If irPD is confirmed and the subject is experiencing extraordinary clinical 
benefit, site must contact Sponsor to discuss continuing treatment 
irNE 
Used in exceptional cases where insufficient data exists due to poor quality 
of scans or missed scans or procedure 
 
Derivation of irRECIST overall responses 
Measurable response  
Nonmeasureable response 
 
Target Lesions 
(% change in SOD)* 
Non-Target Lesions 
Status 
New Lesions Status 
Overall Response 
(irRECIST) 
100 
Absent 
Absent 
irCR¥ 
100 
Present/NE 
Absent 
irPR¥ 
≥30 
Present/Absent/NE 
Absent 
irPR¥ 
<30 to <20 
Present/Absent/NE 
Absent 
irSD 
100 
≥30 
<30 to <20 
NE 
Present/Absent/NE 
Present 
irPD¥ 
100 
Unequivocal 
Any 
irPD¥ 


 
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≥30 
<30 to <20 
NE 
progression 
≥20 from nadir 
Any 
Any 
irPD¥ 
NE 
Present/Absent/NE 
Absent 
irNE¥ 
* Decreases assessed relative to baseline, including measureable lesions only. 
¥ Assuming response (irCR) and progression (irPD) are confirmed by a second, consecutive assessment at least 4 
wk apart. 
13.3 
Dose-Limiting Toxicities 
Dose-limiting toxicities (DLTs) are any of the following drug related toxicities (any toxicities 
considered related, probably related, or possibly related to E7046) occurring during Cycle 1 as 
judged by the investigator. 
 Nonhematologic toxicity ≥ Grade 3 (except diarrhea, nausea and vomiting unless lasting >3 
days despite optimal supportive care) 
 Hematologic toxicity: 
o Grade 4 neutropenia for  5 days, or Grade 3 neutropenia with fever (fever is 38.4 
 ºC), 
o Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia with bleeding or lasting >7 
days 
 Any other toxicity assessed as related to E7046 treatment, and which in the opinion of a 
study investigator(s) the sponsor physician constitutes a dose-limiting toxicity 
 Subjects who have missed > 4 days of dosing in Cycle 1 due to drug-related toxicity (but 
not qualifying for a DLT) will be assessed as experiencing a DLT. 
Grading of toxicities is based on National Cancer Institute - Common Terminology Criteria for 
Adverse Events (NCI CTCAE) v4.03 (Section 13.4). 
Adverse events occurring after Cycle 1 may be considered DLTs upon discussion between the 
investigator and the sponsor physician.  
The following toxicities will not be considered DLTs: 
 Grade 3 adverse event of tumor flare (defined as local pain, irritation, or rash localized at 
sites of known or suspected tumor) 
 Grade 3 immune-related adverse event (irAE) that resolves to ≤ Grade 1 within 7 days 
o An irAE, a subset of AEs, is defined as a clinically significant adverse event of any 
organ that is associated with study drug exposure, of unknown etiology, and is 
consistent with an immune-mediated mechanism.  Serologic, immunologic, and 


 
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histologic (biopsy) data should be used to support an irAE diagnosis.  Appropriate 
efforts should be made to rule out neoplastic, infectious, metabolic, toxin, or other 
etiologic causes of the irAE. 
Subjects who do not complete at least 17 of 21 days of dosing in Cycle 1 due to reasons other 
than treatment related toxicity will be replaced for the purpose of DLT evaluation.  
Assessment of DLTs will be discussed and agreed to by investigator(s) and sponsor physician 
prior to proceeding to the next dose level, and the decision will be documented. 
13.4 
Common Terminology Criteria for Adverse Events (v4.03) 
The National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE 
v4.03 published 28 May 2009; v4.03: June 14, 2010) provides descriptive terminology to be used 
for AE reporting in clinical trials.  A brief definition is provided to clarify the meaning of each 
AE term.  To increase the accuracy of AE reporting, all AE terms in CTCAE version 4.03 have 
been correlated with single-concept, Medical Dictionary for Regulatory Activities (MedDRA®) 
terms. 
CTCAE v4.03 grading refers to the severity of the AE.  CTCAE Grades 1 through 5, with unique 
clinical descriptions of severity for each AE, are based on this general guideline: 
Table 5  
Common Terminology Criteria for Adverse Events v4.03 Grading 
Grade 
Status 
1 
Mild:  asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
2 
Moderate:  minimal, local, or noninvasive intervention indicated; 
limiting age-appropriate instrumental activities of daily living (ADL).a 
3 
Severe or medically significant but not immediately life-threatening:  
hospitalization or prolongation of hospitalization indicated; disabling, 
limiting self-care ADL.b 
4 
Life-threatening consequences:  urgent intervention indicated. 
5 
Death related to adverse event. 
a: Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
b:  Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and 
not bedridden. 
Source:  Cancer Therapy Evaluation Program, NCI.  CTCAE v4.03.  Available from: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf. 
 
For further details regarding MedDRA, refer to the MedDRA website:  
http://www.meddramsso.com. 
CTCAE v4.03 is available online:  
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf.