Clinical trial NCT04144140
Conditions: Lymphoma Advanced Solid Tumors
Keywords: Advanced Solid Tumors E7766 Intratumoral Injection Stimulator of Interferon Genes Agonist Interferons Antineoplastic Agents Lymphoma Melanoma Breast Cancer Colorectal Cancer Squamous Cell Carcinoma of the Head and Neck Oesophageal Squamous Cell Carcinoma Adenocarcinoma of the Gastroesophageal Junction or Gastric
Sponsor: Eisai Inc.
Start date: 2020-02-24; Completion date: 2022-07-26
Enrollment: 24 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is an open label, multicenter, phase 1/1b study to assess safety/tolerability and preliminary clinical activity of E7766 as a single agent administered intratumorally in participants with advanced solid tumors or lymphomas.

Detailed description:
The Phase 1/1b study consist of two parts: Dose Escalation and Dose Expansion. In the Dose Escalation Part, E7766 will be administered intratumorally in participants with advanced solid tumors or lymphomas to assess safety/tolerability profile of E7766 and to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of E7766. In the Dose Expansion Part, E7766 at RP2D will be administered to participants with melanoma, head and neck squamous cell carcinoma (HNSCC), breast cancer, colorectal cancer, and/or other tumors including lymphomas to confirm safety and assess preliminary clinical activity of E7766 as a single agent. Clinical activity will be evaluated by objective response rate (ORR), duration of response (DOR), and disease control rate (DCR) on treatment with E7766.

Arms: arm 1: None arm 2: Dose identified from dose escalation part for E7766 will be used in dose expansion part.
Interventions: intervention 1: E7766
Intervention descriptions: intervention 1: E7766, solution, intratumorally

Protocol documents:
Prot_000.pdf: 
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1
TITLE PAGE
Clinical Study Protocol
Study Protocol 
Number:
E7766-G000-101
Study Protocol 
Title:
An Open-Label, Multicenter Phase 1/1b Study of Intratumorally 
Administered STING Agonist E7766 in Subjects With Advanced 
Solid Tumors or Lymphomas – INSTAL-101
Sponsor:
Eisai Inc.
155 Tice Boulevard
Woodcliff Lake, 
New Jersey 07677, US
H3 Biomedicine Inc. 
300 Technology Square, FL 5, 
Cambridge, 
Massachusetts, 02139, US
Investigational 
Product Name:
E7766
Indication:
Advanced Solid Tumors or Lymphomas
Phase:
1/1b
Approval Date(s):
Original Protocol
Amendment 01
Amendment 02
21 June 2019
19 Aug 2019
04 Dec 2019
IND Number:
137834
EudraCT Number:
2019-000160-17
GCP Statement:
This study is to be performed in full compliance with International 
Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) and all applicable local 
Good Clinical Practice (GCP) and regulations.  All required study 
documentation will be archived as required by regulatory 
authorities.
Confidentiality 
Statement:
This document is confidential.  It contains proprietary information 
of the sponsors.  Any viewing or disclosure of such information that 
is not authorized in writing by the sponsors is strictly prohibited.  
Such information may be used solely for the purpose of reviewing 
or performing this study.


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REVISION HISTORY
Amendment 02
Date: 04 Dec 2019
Change
Rationale
Affected Protocol Sections
Safety pharmacology and toxicology section 
was updated to include additional data.
Updated for 
completeness and 
consistency with the 
Global Investigator’s 
Brochure and as per 
Medicines and 
Healthcare products 
Regulatory Agency 
(MHRA) request.

Section 7.1.3.3
Clarified that subjects with prior 
immunotherapy known to have experienced 
severe nontolerable toxicities attributed to 
drug should be excluded.
The text was updated
as per France Ethics 
Committee request.

Synopsis: Inclusion Criterion #6

Section 9.3.1: Inclusion 
Criterion #6
For Inclusion criterion#9, it was clarified 
that subjects with prior Hepatitis B or 
Hepatitis C are eligible if they have 
adequate liver function as described in 
Inclusion Criterion #13.  The additional 
wording “Exclusion criteria#4” was 
removed from “Inclusion criterion#9” to 
avoid confusion. Participants with active 
Hepatitis B or Hepatitis C infection will be 
excluded and participants who had prior 
Hepatitis B or Hepatitis C infection which is 
inactive at the time of screening and with 
normal liver function are eligible to the 
study.
The text was updated 
for further clarity.

Synopsis: Inclusion Criterion #9

Section 9.3.1: Inclusion 
Criterion #9
Additional guidance was added in the 
protocol for selection of lesions for 
intratumoral E7766 injection to minimize 
risk of hemorrhage and inadvertent risk of 
intravascular systemic injection.  
Also, recommendations for administering 
local analgesic (ie, at the site of injection) 
with or without systemic analgesic prior to 
initiation of the intratumoral injection, have 
been added to the protocol.
Further guidance was 
added for clarity and 
as per MHRA and 
France Ethics 
Committee request.

Synopsis: Study Treatments 

Section 9.4.1.3
Additional pregnancy testing added on Day 
1 of all cycles, ie, every 3 weeks (Q3W).
The change has been 
made per France 
health authority 
(ANSM) request. 

Section 9.5.2.1, Table 7, 
footnote f


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Amendment 01
Date: 19 Aug 2019
Change
Rationale
Affected Protocol Sections
Additional dose limiting toxicity 
criteria were added as follows:
-Any death not clearly due to the 
underlying disease or extraneous 
causes
-For patients with hepatic 
metastases, AST or ALT >8×ULN, 
or AST or ALT >5×ULN for 
≥14 days
-Hy’s Law cases
Removal from DLT exceptions of 
‘any laboratory abnormalities that 
are not clinically significant per 
investigator assessment’.
The change has been made per 
FDA requirement. 

Synopsis - Study Design

Section 9.1.1.2
Treatment is not allowed beyond 
confirmed disease progression per 
iRECIST or LYRIC.
The change has been made per 
FDA requirement. 

Synopsis – Study Treatment, 
Duration of treatment

Section 9.4.1.5 (deleted)

Appendix 2 (Appendix 
Table 2)
Selection of recommended Phase 2 
dose (RP2D) was updated to state 
that although decisions regarding 
dose escalation will be made based 
on review of data from Cycle 1, late 
immune-related observed toxicities 
occurring after Cycle 1 (DLT 
period) and up to 90 days after last 
dose of E7766, will also be used to 
inform corrections to the MTD and 
aid selection of the RP2D.
The change has been made per 
FDA requirement.

Synopsis: Study Design -
Definition of DLT, Selection 
of RP2D; Statistical methods

Section 9.1.1.1

Section 9.7.4.1
Clarified that investigators and 
sponsors will together conduct the 
evaluation and the recommended 
Phase 2 dose/doses and/or any 
modification to the dosing regimen 
will be agreed upon jointly.
The change has been made per 
FDA requirement

Synopsis:  Study design, 
Selection of RP2D

Section 9.1.1.3
Selection criterion for exclusion of 
subjects with prolongation of 
corrected QT interval (using 
Fridericia’s correction factor)
(QTcF) >480 msec was revised to 
exclude male and female subjects 
with prolongation >450 msec 
The change has been made per 
FDA and other health authority 
requirements. QTcF is clarified 
for consistency with the safety 
assessments section.

Synopsis:  Exclusion 
Criterion 8

Section 9.3.2, Exclusion 
Criterion 8


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AE and concomitant medications 
collection period was increased to 
90 days after last dose of study 
treatment from 30 days. If the
subject initiates new anticancer 
therapy within 30 days, then AEs 
and concomitant medications 
should be collected for 30 days 
following the last dose of E7766.
Definition for treatment-emergent 
adverse event (TEAE) was also 
updated to align with the above 
change.
The change has been made per 
FDA requirement to monitor all 
patients for approximately 90
days after treatment 
discontinuation for late immune-
related toxicities that have been 
associated with immunotherapy 
products.

Synopsis: Study design

Section 9.4.7

Section 9.5.2.1: Table 7 
(footnote w)

Section 9.5.1.5.1

Section 9.5.4.1

Section 9.7.1.5

Section 9.7.1.8.2 
Reporting period for SAEs was 
updated to 90 days after last dose of 
study treatment (previously 30 days 
after last dose). If the subject 
initiates new anticancer therapy 
within 30 days, then SAEs should 
be collected for 30 days following 
the last dose of E7766.
The change was made due to 
changes in AE collection period.

Section 9.5.1.5.1

Section 9.5.4.1


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2
CLINICAL PROTOCOL SYNOPSIS
Compound No.:  E7766
Name of Active Ingredient:  (1R,3R,15E,28R,29R,30R,31R,34R,36R,39S,41R)-29,41-Difluoro-34,39-
bis(sulfanyl)-2,33,35,38,40,42-hexaoxa-4,6,9,11,13,18,20,22,25,27-decaaza-34λ5,39λ5-diphosphaoctacyclo
[28.6.4.13,36.128,31.04,8.07,12.019,24.023,27]dotetraconta-5,7,9,11,15,19,21,23,25-nonaene-34,39-dione diammonia
Study Protocol Title
An Open-Label, Multicenter Phase 1/1b Study of Intratumorally Administered STING Agonist 
E7766 in Subjects With Advanced Solid Tumors or Lymphomas – INSTAL-101
Investigators
Multiple investigators
Sites
Approximately 4 sites globally for Dose Escalation part, additional sites planned for Dose Expansion 
part.
Study Period and Phase of Development
Total study period: Approximately 36 months 
Phase 1/1b
Objectives
Primary objectives
Dose Escalation part
•
Assess the safety/tolerability profile of E7766 administered intratumorally in subjects with 
advanced solid tumors or lymphomas
•
Determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of 
E7766 in subjects with advanced solid tumors or lymphomas
Dose Expansion part
•
Assess the safety/tolerability profile of E7766 administered intratumorally in cohorts of subjects 
with selected tumor types
•
Assess clinical activity of E7766 based on investigator assessment of objective response rate 
(ORR), duration of response (DOR), and disease control rate (DCR) according to modified 
Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 and modified RECIST 1.1 for 
immune-based therapeutics (iRECIST) for solid tumors, and for lymphoma (if included in Dose 
Expansion part), lymphoma response according to Lugano and LYmphoma Response to 
Immunomodulatory Therapy Criteria (LYRIC) criteria, in cohorts of subjects with selected tumor 
types 
Secondary objectives 
Dose Escalation part
•
Evaluate preliminary clinical activity of E7766 based on investigator assessment of ORR, DOR, 
and DCR according to modified RECIST 1.1 and iRECIST for solid tumors, and Lugano and 
LYRIC criteria for lymphoma 


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•
Evaluate the pharmacokinetic (PK) profile of E7766 and any metabolites in plasma, urine, and 
feces 
Dose Escalation and Dose Expansion parts
•
Evaluate the PK profile of E7766 and any metabolites in plasma
•
Evaluate progression-free survival (PFS) based on investigator assessment and overall survival 
(OS) in subjects treated with E7766 
•
Evaluate tumor size changes per investigator assessment in injected lesions and in non-injected 
lesions
Exploratory Objectives 
Dose Escalation and Dose Expansion parts
•
Evaluate changes in tumor size assessed by independent imaging review (IIR) using volumetric 
computed tomography (CT)/magnetic resonance imaging (MRI)
•
Evaluate immune pharmacodynamics effects of E7766 in the tumors and in peripheral blood
•
Explore PK/pharmacodynamics relationships (safety and efficacy endpoints) 
•
Explore correlation of baseline tumor and peripheral blood immune phenotypes and of STING 
genotypes with safety and/or efficacy endpoints
•
Evaluate pre-injection changes in size of injected lesion per investigator assessment in addition to 
the scheduled tumor assessments to characterize the kinetics of response, progression, or 
immune-induced flare in the injected lesion.
Study Design
This is an open label, multicenter, Phase 1/1b study to assess the safety and evaluate the clinical 
activity of E7766 administered intratumorally to subjects with advanced solid tumors or lymphomas.  
The study is a first-in-human (FIH) study for intratumoral administration route of E7766.  A Dose 
Escalation part will enable selection of a dose of E7766 to move forward with as the RP2D in the 
Dose Expansion part, where clinical activity in selected tumor types or populations will also be 
evaluated.  
Dose escalation will be conducted using an improved modified toxicity probability interval (mTPI) 
design (Guo, et al., 2017; Yan, et al., 2017) to determine the MTD for E7766.  Each subject will be 
assessed for tumor response (injected and non-injected lesions), PK, and pharmacodynamics (blood 
and tumor factors).  The RP2D will be selected based on integrating results of safety (including the 
MTD), clinical activity, PK, and pharmacodynamics.  During the Dose Escalation part, selected dose 
level cohorts may accrue additional subjects to provide further safety, drug administration-related, 
biomarker, and/or PK data needed for selection of the RP2D.  Intrapatient dose escalation of study 
drug will be allowed in the study.
The Dose Expansion part will be initiated when the RP2D and/or MTD is available from the Dose 
Escalation part.  In the Dose Expansion part, separate study arms will evaluate E7766 at the RP2D in 
selected tumor types and populations to confirm safety and assess clinical activity.  The study 
populations will be decided based on the emerging data from the Dose Escalation part. 
The overall study design is shown in Figure “Study Schematic for Dose Escalation and Dose 
Expansion parts.”




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Dose assignment of subjects will be done using the improved mTPI design in order to determine the 
MTD of E7766.  Each subject will be assigned a dose in accordance with the rules of the improved
mTPI design based on a target dose-limiting toxicity (DLT) rate of 25% and its equivalence interval 
(EI) of 20% to 30%. 
The dose assignment decision rule is pre-tabulated in the Table “Decision Rule for Dose 
Assignment.”  Two subjects will be enrolled for each tested dose level, and recruitment to the dose 
level will be expanded as required as described in the Table “Decision Rule for Dose Assignment.”
Based on the number of subjects with DLTs in each dose level, dose assignment for the next dose will 
be determined according to the Table “Method for Deciding the Dose of the Next Dose Group” after 
consultation between the investigators and the sponsor.  For the lowest dose, extra subjects may be 
added if a DLT develops in 1 of the 2 subjects, if deemed appropriate.  Subjects who are not 
evaluable for DLT (eg, those subjects who fail to complete at least 2 E7766 injections during Cycle 1 
for reasons other than DLT occurrence) should be replaced within their dose level, if at least 
2 subjects in total have not been tested at the dose level.  Subject enrollment will be closed when the 
DLT rate at the lowest dose level greatly exceeds the target DLT rate (25%) or when the RP2D has 
been determined.
Additional details of the improved mTPI design are in the statistical section.
Decision Rule for Dose Assignment
Number of Subjects Treated at Current Dose
2
4
6
8
10
12
Number of Subjects 
With DLTs
0
E
E
E
E
E
E
1
Da
S
E
E
E
E
2
D, U
D
D
S
S
E
3
D, U
D
D
D
S
4
D, U
D, U
D, U
D
D
5
D, U
D, U
D, U
D
≥6
D, U
D, U
D, U
D, U
Target DLT rate at MTD = 25% and its equivalence interval = 20% to 30%, Cohort size = 2 subjects.
Display for more than 12 subjects at the current dose is omitted. If the required rules are not available in the table, the 
decision will follow the rule determined by the improved mTPI design with the same settings above.
E = Escalate to the next higher dose, S = Stay at the current dose, D = De-escalate to the next lower dose, U = Current dose 
is unacceptably toxic (ie, Do not re-enter the current dose)
DLT = dose-limiting toxicity, MTD = maximum tolerated dose, mTPI = modified toxicity probability interval.
a:  Extra subjects may be added for the lowest dose, for example if the investigators and the sponsor determine that more 
subjects would be required to adequately evaluate that dose level and it is considered safe to do so.
Subjects will be assigned to a dose level in the order of study entry.  There should be at least 7 days 
between initiating treatment of the first and second subject in each new dose escalation.  This would 
provide enough safety margin in terms of safety evaluation for any acute serious toxicities arising 
from activation of the immune system, which would generally be expected to occur within the first 
hours or 1 to 3 days of drug exposure. In cohorts where the dose is de-escalated or re-escalated, a 
delay in administration of E7766 between the first subject and subsequent subjects in that cohort is 
not required if the same or a higher dose level has already been investigated in a previous cohort.
The first E7766 dose to be administered to subjects will be 75 µg, which is a calculated 
pharmacologically active dose (PAD) based on nonclinical studies. The dose of subsequent dose 
groups will be determined based on the E7766-related adverse events (AEs) that develop in subjects 
in the prior dose group during 3 weeks of Cycle 1 (see “Method for deciding the dose of the next dose 


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group”). When escalating or de-escalating the dose to the next dose level according to the improved
mTPI design, if there is a higher or lower dose level that has been tested previously, subjects should 
be enrolled to the previously tested dose and the “Method for deciding the dose of the next dose 
group” below shall not apply. In addition, intermediate doses can be further added if necessary based 
on the safety or PK of the previously tested dose. The addition of new dose levels will be decided 
based on discussions between the investigators and sponsor during dose escalation meetings.
Method for Deciding the Dose of the Next Dose Group
Dose Escalation Steps 
E7766-Related Toxicity During Cycle 1
Increase ~75% to 100%
Up to Grade 1
Increase ~30% to 60%
Grade 2 in 1 subject 
Increase ~10% to 30%
Grade 2 in 2 or more subjects and/or
Grade 3 or higher in 1 or more subject
Intrapatient dose escalation of study drug will be allowed in the study after a minimum of 3 cycles of 
study therapy at the designated dose and after there is sufficient information to ensure safety at the 
higher dose.  The decision for individual cases, if requested, will be made in agreement between the 
investigators and the sponsors.
Escalation of the E7766 dose will be achieved based on the concentrations and volumes administered 
according to the guidance in the table below entitled “Examples of Drug Dilutions and Volumes 
Administered.”
During the Dose Escalation part, selected dose level cohorts may accrue additional subjects to provide 
additional safety, drug administration-related, biomarker, and/or PK data needed for selection of the 
RP2D.
Definition of Dose-Limiting Toxicities 
DLTs are any of the following toxicities occurring during Cycle 1 and assessed by the investigator as 
related to study drug (any toxicities considered related to any degree to E7766): 
•
Clinically significant nonhematologic toxicity ≥ Grade 3 (National Cancer Institute [NCI]
Common Terminology Criteria for Adverse Events [CTCAE] v.5.0), except 
-
Grade 3 fatigue <5 days.
-
Asymptomatic Grade 3 or 4 laboratory abnormalities that are corrected within 72 hours.
-
≥ Grade 3 nausea, vomiting, and diarrhea unless lasting >48 hours despite optimal supportive 
care.
-
Other AEs that per investigator assessment are not dose limiting nor dose related.
•
CTCAE Grade 2 nonhematologic toxicities which, in the opinion of the investigator, require a 
dose reduction or discontinuation of study drug, or lead to the subject’s failure to complete at 
least 2 out of 3 scheduled injections of E7766 in Cycle 1, or be considered intolerable for any 
other reason by the investigator, may be deemed to be dose-limiting if agreed upon by 
participating investigators and the sponsors.
•
Nonhematologic laboratory findings of Grade ≥3 that were ≤ Grade 1 at baseline with the 
exception of abnormal Grade 3 laboratory values with no clinical significance that resolve within 
7 days (this includes electrolyte abnormalities which respond to medical intervention)
•
Hematologic toxicity:
-
Grade 4 neutropenia for >5 days, or febrile neutropenia.


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-
Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia with hemorrhage.
•
Any other toxicity assessed as related to E7766 treatment, and which in the opinion of the study 
investigator(s) and the study medical monitor constitutes a DLT
•
A delay of initiating Cycle 2 of 7 days or more due to toxicity.
•
Any death not clearly due to the underlying disease or extraneous causes
•
For patients with hepatic metastases, aspartate aminotransferase (AST) or alanine 
aminotransferase (ALT) >8×upper limit of normal (ULN), or AST or ALT >5×ULN for 
≥14 days.
•
For patients with normal ALT and AST and total bilirubin (TBIL) value at baseline:  AST or 
ALT >3.0×ULN combined with TBIL >2.0×ULN without evidence of cholestasis 
(ALP ≤2×ULN), with no alternative etiology (Hy’s law)
•
For patients with elevated AST or ALT or TBIL value at baseline: [AST or ALT >2×baseline 
and >3.0×ULN] OR [AST or ALT >8.0×ULN], whichever is lower, combined with 
[TBIL >2×baseline AND >2.0×ULN] without evidence of cholestasis (ALP ≤2×ULN)
A subject should have received at least 2 E7766 injections during the DLT period (Cycle 1) to be
considered evaluable for a DLT, unless the subject experienced a treatment-related toxicity 
preventing more than 1 administration of E7766.
If a subject at a given dose level receives fewer than 2 out of 3 planned E7766 intratumoral injections 
during the Induction cycle (DLT period/Cycle 1) because of E7766-related AEs, the subject should be 
considered as potentially experiencing a DLT by the Study Safety Committee, composed of 
investigators and representatives of the sponsor.
A subject experiencing a DLT may continue treatment at a reduced dose if the DLT has resolved and 
in the opinion of the investigator the subject is benefiting from treatment.  In case of recurrence of the 
DLT at a lower dose, E7766 treatment should be discontinued.  Late immune-related toxicities 
occurring after Cycle 1 (DLT period) and up to 90 days after last dose of E7766, will also be used to 
inform corrections to the MTD and aid selection of the RP2D.
SELECTION OF THE RP2D 
The RP2D of E7766 will be selected based on an integrated evaluation of safety, tolerability, clinical 
activity, PK data, and any available pharmacodynamics data for all dose levels or all available data 
according to the following guidelines:
•
The RP2D must not exceed the MTD, as defined in the Dose Escalation part.
•
Consideration will be given to other toxicities including:  AEs assessed as related to study drug 
treatment but not considered dose limiting, the nature and frequency of toxicities, late 
immune-related toxicities (up to 90 days after last dose of the study drug), and the emergence of 
any specific category of toxicities.
•
Consideration will be given to the tumor response(s) and antitumor activity.
•
Pharmacodynamic demonstration of biologic activity, including but not limited to:  activation of 
STING-mediated immune pathways and modulation of innate and adaptive immune response in 
the tumors and/or in the peripheral blood such as INFβ, CXCL10, and MCP1.
The investigators and sponsors will together conduct the evaluation, and the recommended Phase 2 
dose/doses and/or any modification to the dosing regimen will be agreed upon jointly.


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DOSE EXPANSION PART
Expansion arms shall be opened in specific tumor types and populations with treatment at the E7766 
RP2D.  Prioritized early indications, selected based on the preclinical finding and bioinformatics 
analysis of The Cancer Genome Atlas (TCGA) database, include melanoma, head and neck squamous 
cell carcinoma (HNSCC), breast cancer, colorectal cancer, and/or other tumors including lymphomas.
E7766 Expansion Arms
Safety and clinical activity of E7766 at the RP2D will be tested in separate Expansion arms with 
defined populations potentially including but not limited to: melanoma, HNSCC, breast cancer, 
colorectal cancer, and/or other tumors including lymphomas. About 40 patients will be recruited in 
each expansion arm.
Study Phases
There will be 4 phases for each subject in the Dose Escalation part and the Dose Expansion part: 
Pretreatment Phase, Treatment Phase, Extension Phase, and Follow-Up Phase.
Pretreatment Phase
This phase will last no longer than 28 days and includes:
•
A Screening Period to obtain informed consent and establish protocol eligibility
•
A Baseline Period to establish disease characteristics before treatment
Treatment Phase
The Treatment Phase will last for 1 treatment cycle of 21 days in the Dose Escalation part. In the 
Dose Expansion part, the Treatment Phase will last for 6 Cycles.  
Extension Phase
In the Extension Phase, subjects who are receiving study drug at the end of the Treatment Phase will 
continue to receive drug treatment at the same dose, and according to the Dosing Schedule described 
under “Study Treatment.”  
In the Treatment and Extension Phases, subjects will discontinue study drug at the time of confirmed 
disease progression (per iRECIST or LYRIC), disappearance or nonavailability of any injectable 
lesions, development of unacceptable toxicity, subject request, withdrawal of consent, termination of 
the study program, pregnancy, or investigator decision.
Follow-Up Phase:  The Follow-Up Phase will begin immediately after the off-treatment assessments 
have been completed and will continue for up to 2 years or until study subject is deceased, or until the 
completion of the primary analysis, whichever is earlier, unless the subject withdraws consent or until 
the sponsor terminates the study. Information on AEs and concomitant medications will be collected 
for 90 days after the last dose of study drug or start day of another anticancer therapy, whichever is 
earlier.  If the subject initiates new anticancer therapy within 30 days, then AEs and concomitant 
medications will be collected for 30 days following the last dose of E7766.
Subjects who discontinue study treatment before disease progression will continue to undergo disease 
assessment every 6 weeks in case of solid tumors and 12 weeks in case of lymphomas until 
documentation of disease progression or start of another anticancer therapy.
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 


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Extension Phase or when all subjects have discontinued study treatment.  Survival follow-up will be 
conducted in person or via phone call.
Study Assessments
Safety, tumor assessments, PK, and pharmacodynamic assessments will be performed on every 
subject; details are described under “Assessments” and in the Schedule of Visits and Procedures.
Number of Subjects
Approximately, 35 to 40 subjects will be enrolled in the Dose Escalation part and 80 subjects in the 
Dose Expansion part.
Inclusion Criteria
1.
Age ≥ 18 years.
2.
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
3.
Life expectancy ≥12 weeks.
4.
Subjects with solid tumors or lymphomas, confirmed by available histopathology records or 
current biopsy, that are advanced, nonresectable, or recurrent and progressing since last antitumor 
therapy, and for which no alternative standard therapy exists.
5.
Subjects must have a minimum of one injectable lesion which is also accessible for biopsy, and if 
available, one other measurable lesion also accessible for biopsy.
An injectable lesion is defined as being measureable (defined below) with a maximum of 3.0 cm 
longest diameter, accessible for injection as judged by the investigator, and has not been 
subjected to any prior intratumoral treatment or radiotherapy.  Lesions selected for injection must 
not be too close to a major vessel, as judged by the investigator, and not be associated with 
increased risk of bleeding, eg, subcapsular liver lesions or hypervascular tumors.  
Measurable lesions are:
a.
Solid tumors: At least 1 lesion of ≥1 cm by longest axial diameter or ≥1.5 cm short axis 
diameter if a nodal lesion, which is serially measurable according to modified RECIST 1.1
using CT/MRI or photography. Lesions that have had external beam radiotherapy or 
locoregional therapies such as radiofrequency (RF) ablation must show evidence of 
progression to be deemed a target lesion (Appendix 2).
b.
Lymphoma: At least 1 lymph node with a longest diameter >1.5 cm or an extranodal lesion 
with a longest diameter >1.0 cm (Appendix 3).
6.
Prior anticancer therapy such as chemotherapy, immunotherapy (eg, tumor vaccine, cytokine, 
checkpoint inhibitors), or investigational drugs, or any vaccine must have been completed at least
4 weeks before study drug administration, and all AEs must have either returned to baseline or 
stabilized. Subjects with prior immunotherapy known to have experienced severe nontolerable 
toxicities attributed to drug should be excluded.
7.
Prior definitive radiation therapy must have been completed at least 6 weeks and prior palliative 
radiotherapy at least 2 weeks before study drug administration. Radiopharmaceuticals (eg,
strontium, samarium) must be at least 8 weeks before study drug administration.
8.
Immunosuppressive doses of systemic medications, such as steroids or absorbed topical steroids 
(doses >10 mg/day prednisone or equivalent) must have been discontinued at least 4 weeks 
before study drug administration.


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9.
Subjects with prior Hepatitis B or C are eligible if they have adequate liver function as defined by 
Inclusion Criterion #13.
10. Left ventricular ejection fraction (LVEF) >50% or within normal limits per institutional practice,
on echocardiography or multigated acquisition (MUGA) scan.
11. 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 4).
12. Adequate bone marrow function: 
a.
Absolute neutrophil count (ANC) ≥1000/mm3 (≥1.0×103/μL)
b.
Platelets ≥75,000/mm3 (≥75×109/L)
c.
Hemoglobin ≥9.0 g/dL
13. Adequate liver function defined by: 
a.
Adequate blood coagulation function as evidenced by an International Normalized Ratio 
(INR) ≤1.5
b.
Total bilirubin ≤1.5 × ULN except for unconjugated hyperbilirubinemia or Gilbert’s 
syndrome
c.
Alkaline phosphatase (ALP), ALT, and AST ≤3 × ULN (in the case of liver metastasis ≤5 ×
ULN) unless there are bone metastases. Subjects with ALP values >3 × ULN and known to 
have bone metastases can be included.  
14. Willing and able to comply with all aspects of the protocol.
15. Provide written informed consent prior to any study-specific screening procedures.
Exclusion Criteria
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 5) or a documented history of 
autoimmune disease, except for subjects with vitiligo or resolved childhood asthma/atopy.
3.
Known human immunodeficiency virus (HIV) infection.
4.
Active infection requiring therapy, including known positive tests for Hepatitis B surface antigen 
or Hepatitis C ribonucleic acid (RNA).
5.
Major surgery within 4 weeks before the first dose of study drug.
6.
Concurrent medical condition requiring the use of immunosuppressive medications or 
immunosuppressive doses of systemic medications, such as steroids or absorbed topical steroids 
(doses >10 mg/day prednisone or equivalent).
7.
Brain metastases that are untreated or in the posterior fossa or involve the meninges.  Subjects 
with stable or progressing brain metastases (except in the posterior fossa or involving the 
meninges) previously treated with brain stereotactic radiotherapy (SRT), whole-brain 
radiotherapy (WBRT) and/or surgery are allowed as long as the subject is asymptomatic
neurologically and does not require immediate local intervention (radiotherapy and/or surgery).  
In addition, subjects must be off immunosuppressive doses of systemic steroids (>10 mg/day 
prednisone or equivalent) for at least 4 weeks before study drug administration.


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8.
Prolongation of corrected QT (QTcF) interval to >450 msec for males and females, when 
electrolytes balance is normal
9.
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).
10. Subjects on oral anticoagulants including low dose aspirin. To meet eligibility, these subjects can 
be switched to receive preventive dose of low molecular weight heparin (LMWH). It is 
recommended that their LMWH treatment is stopped 24 hours before the intratumoral injection 
and resumed again 24 hours after the injection.
11. 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.
12. Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive 
beta-human chorionic gonadotropin [ß-hCG] (or human chorionic gonadotropin [hCG]) test with 
a minimum sensitivity of 25 IU/L or equivalent units of ß-hCG [or 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.
13. Females of childbearing potential must not have had unprotected sexual intercourse within 
30 days before study entry and must agree to use a highly effective method of contraception (total 
abstinence [if it is their preferred and usual lifestyle], a contraceptive implant, an oral 
contraceptive, or have a vasectomized partner with confirmed azoospermia) throughout the entire 
study period and for 180 days after study drug discontinuation.  For sites outside of the EU, it is 
permissible that if a highly effective method of contraception is not appropriate or acceptable to 
the subject, then the subject must agree to use a medically acceptable method of contraception, ie, 
double barrier methods of contraception such as condom plus diaphragm or cervical/vault cap 
with spermicide. If currently abstinent, the subject must agree to use a highly effective method as 
described above if she becomes sexually active during the study period or for 180 days after study 
drug discontinuation.  Females who are using hormonal contraceptives must have been on a 
stable dose of the same hormonal contraceptive product for at least 28 days before dosing and 
must continue to use the same contraceptive during the study and for 180 days after study drug 
discontinuation.
14. Male subjects who are partners of women of childbearing potential must use a condom and 
spermicide and their female partners if of childbearing potential must use a highly effective 
method of contraception (see methods described above in Exclusion Criterion #13) beginning at 
least 1 menstrual cycle prior to starting study drug(s), throughout the entire study period, and for 
180 days after the last dose of study drug, unless the male subjects are totally sexually abstinent 
or have undergone a successful vasectomy with confirmed azoospermia or unless the female 
partners have been sterilized surgically or are otherwise proven sterile.  No sperm donation is 
allowed during the study period or for 180 days after study drug discontinuation.
15. Known hypersensitivity to E7766 or any of the excipients or prior therapy with E7766 or any 
other STING agonist.
16. Use of illegal recreational drugs.
17. Currently enrolled in another clinical study or used any investigational drug or device within 






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investigator after discussion with the sponsors.  Subject may be allowed to continue study drug 
at a reduced dose, if this is judged to be in their best interest.  E7766 dose reductions and 
interruptions should be carried out as outlined in “E7766 Dose Reduction and Interruption 
Instructions.”
Guidelines for dose adjustments after Cycle 1
E7766 dose reduction and interruption for subjects who experience therapy-related toxicity (as 
assessed by the investigator) will be in accordance with the dose modification guidelines described in 
the “E7766 Dose Reduction and Interruption Instructions.”

Subjects who experience toxicities that could have been qualified as DLTs may, at the discretion 
of the investigator and after discussion with the sponsor, be allowed to continue study drug at a 
reduced dose according to these dose modification guidelines, if this is judged to be in their best 
interest.
For subjects who require dose interruption due to E7766-related toxicity in Cycle 2 or beyond, the 
treatment may re-start once the toxicity has been resolved to Grade ≤1 or the baseline value according 
to the Dose Reduction and Interruption Instructions in the table below.”
E7766 Dose Reduction and Interruption Instructions
E7766-Related Toxicitya
During Therapy
Approximate Dose Adjustment
Grade 1
All occurrences
Continue E7766 treatment.  
If CRS, then interrupt E7766 
until Grade 0.
Maintain dose level.
Grade 2b
1st occurrence
Interrupt E7766 until resolved 
to Grade ≤1 or baseline. 
If CRS, then interrupt E7766 
until Grade 0c.
Maintain dose level. 
If CRS, consider dose reduction.
2nd occurrence 
(same toxicity)
Interrupt E7766 until resolved 
to Grade ≤1 or baseline.  
If CRS, then interrupt E7766 
until Grade 0c.
Consider reduction by 1 dose level of 
starting dose, if dose delayed.  
If CRS, then consider further dose reduction.
3rd occurrence 
(same toxicity)
Interrupt E7766 until resolved 
to Grade ≤1 or baselinec.  
If CRS, then discontinue 
E7766.
Reduce by 1 or 2 dose levels of starting dose, 
if appropriate.
4th occurrence 
(same toxicity)
Interrupt E7766 until resolved 
to Grade ≤1 or baselinec.
Discuss with sponsors.
Grade 3b
1st occurrence
Interrupt E7766 until resolved 
to Grade ≤1 or baselinec.  
If CRS, then discontinue 
E7766.
Reduce by 1 dose level of starting dose
2nd occurrence 
(same toxicity)
Interrupt E7766 until resolved 
to Grade ≤1 or baselinec.
Reduce by 2 dose levels of starting dose
3rd occurrence 
(same toxicity)
Discontinue E7766 treatment.
Not applicable
Grade 4d:  Discontinue E7766
CRS = cytokine release storm.
For grading, see Common Terminology Criteria for Adverse Events (CTCAE v. 5.0)


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a:  Excluding alopecia, anemia, lymphocytopenia, and asymptomatic neutropenia.  Initiate optimal medical 
management for nausea, vomiting, diarrhea, and/or fever before any E7766 interruption or dose reduction. 
b:  Applicable only to those Grade 2 toxicities judged by the subject and physician to be intolerable and to all 
Grade 3 toxicities.
c:  Interruption of E7766 treatment for more than 21 days (due to E7766-related toxicities) will require a 
discussion with the sponsors before treatment can be resumed.
d:  Excluding laboratory abnormalities judged to be non-life-threatening, in which case manage as Grade 3.
Management of Cytokine Release Storm
Cytokine release storm (CRS) has been identified as a potential safety risk in immunotherapies, 
especially drugs that act as agonists for immune activation.  A full guidance for identification and 
management of CRS is provided in the “Management of Cytokine Release Storm and Organ 
Toxicity” table below.  IL-6 levels will be assessed by the site as clinically indicated.  For E7766 dose 
adjustments and interruptions for the management of CRS, refer to “E7766 Dose Reduction and 
Interruption Instructions.” table.
Management of Cytokine Release Storm and Organ Toxicity
CRS Grade
(CTCAE)
Sign/Symptom
Management 
Grade 1
Fever or
Grade 1
organ toxicity
Acetaminophen and hypothermia blanket as needed for fever
Ibuprofen if fever is not controlled with above; use with caution 
or avoid if thrombocytopenic
Assess for infection with blood and urine cultures, and chest 
x-ray
Consider antibiotics and filgrastim (if neutropenic)
IV fluids as needed
Symptomatic management of constitutional symptoms and 
organ toxicities
Consider IL-6 antagonist1 for persistent (greater than 3 days) or 
refractory fever
Grade 2
Hypotension
IV fluid bolus of 500 – 1,000 mL normal saline; repeat as 
necessary to maintain SBP greater than 90 mmHg
Consider IL-6 antagonist1 for hypotension refractory to fluid 
boluses
If hypotension persists after two fluid boluses and IL-6 
antagonist1, start vasopressors, transfer patient to ICU, and 
obtain ECHO
In patients at high-risk for severe CRS2, if hypotension persists 
after IL-6 antagonist1, if there are signs of hypoperfusion3 or if 
there is rapid deterioration in the opinion of the clinician, may 
use dexamethasone 10 mg IV every 6 hours
Manage fever and constitutional symptoms as in Grade 1 CRS
Hypoxia
Use supplemental oxygen as needed
Use IL-6 antagonist1 with or without corticosteroids as in 
hypotension
Manage fever and constitutional symptoms as in Grade 1 CRS
Grade 2
organ toxicity
Manage organ toxicity as per standard guidelines 
Use IL-6 antagonist1 with or without corticosteroids as in 
hypotension


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Manage fever and constitutional symptoms as in Grade 1 CRS
Grade 3
Hypotension
IV fluid boluses as needed as in Grade 2 CRS 
IL-6 antagonist1 as in Grade 2 if not administered previously
Use vasopressors as needed 
Transfer patient to ICU and obtain ECHO if not performed 
already
Start dexamethasone 10 mg IV every 6 hours; increase to 20 mg 
IV every 6 hours if refractory
Manage fever and constitutional symptoms as in Grade 1 CRS
Hypoxia
Use supplemental oxygen including high-flow oxygen delivery 
and noninvasive positive pressure ventilation
Use IL-6 antagonist1, corticosteroids as above and supportive 
care
Grade 3
organ toxicity or 
Grade 4 increased 
transaminases
Manage organ toxicity as per standard guidelines 
Use IL-6 antagonist1, corticosteroids as above and supportive 
care 
Manage fever and constitutional symptoms as in Grade 1 CRS
Grade 4
Hypotension
IV fluids, IL-6 antagonist1, vasopressors, and hemodynamic 
monitoring as in Grade 3
High-dose methylprednisolone1
Manage fever and constitutional symptoms as in Grade 1
Hypoxia
Mechanical ventilation
Use IL-6 antagonist1, high-dose methylprednisolone1 and 
supportive care
Grade 4
organ toxicity, 
excluding increased 
transaminases
Symptomatic management of organ toxicity as per standard 
guidelines
Use IL-6 antagonist1, high-dose methylprednisolone1 and 
supportive care
CRS = cytokine release storm, CTCAE = Common Terminology Criteria for Adverse Events, ECHO = 
echocardiogram, ICU = intensive care unit, IL-6 = interleukin 6, IV = intravenous, SBP = systolic blood 
pressure.
1  See Appendix 6 for Interleukin-6 Antagonist and Corticosteroid Dosing Tables.
2  High risk for CRS includes any of the following:
-
High tumor burden 
-
Early onset CRS (less than 3 days from cell infusion)
-
Co-morbidities (a score of 3 or greater using the Hematopoietic Cell Transplantation Comorbidity 
Index; for solid tumor patients – prior solid tumor will not be counted)
3  Signs of hypoperfusion include:
-
Decreased urine output (less than 0.5 mL/kg/hour)
-
Lactate greater than or equal to 4 mmol/L, rising lactate, and/or poor lactate clearance (less than 
10%) despite adequate fluid resuscitation.
Source: Adapted from MD Anderson Cancer Center CAR cell therapy toxicity assessment and 
management protocol (Teachey et al., 2016; MD Anderson Cancer Center, 2017).
Duration of Treatment
A subject will remain on study treatment until 1 or more of the following events occur(s):

Confirmed progressive disease (PD) per iRECIST (iCPD)/LYRIC
Note: Subjects will be permitted to continue treatment beyond initial modified RECIST 1.1 (or Lugano)
defined progression as discussed further in Appendix Table 2




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new lesions if they meet the minimum size criteria for a measurable lesion.  Subjects with HNSCC
must also have head and neck scans performed.  Historical standard of care scans that are performed
with scanning parameters consistent with the requirements for this protocol within 28 days prior to 
dosing are acceptable.  A pretreatment biopsy will be obtained during the Screening Period (Day -28 
to Day -1) from the lesion selected for injection (mandatory) and, from one prespecified non-injected 
lesion, if available. If the non-injected lesion is not accessible for biopsy, the biopsy may be omitted
(Appendix 1). 
MRI scans may be used instead of CT scans for head, neck, abdomen and pelvis; however, chest 
lesions must be assessed using CT. Chest disease may not be followed using chest x-ray. The same 
method of assessment used at Screening must be used at all subsequent time points.  
For subjects with triple-negative breast cancer (TNBC) and non-small-cell lung carcinoma (NSCLC), 
or other tumor types where bone metastases are common, bone scans will be performed at Screening, 
every 24 weeks, or sooner if clinically indicated, and at confirmation of response. Lesions identified 
on bone scans must be verified with correlative cross-sectional imaging.  Cross sectional imaging will 
be used to follow response in target and nontarget lesions.
A brain MRI (pre- and post-gadolinium contrast) must be performed at Screening to assess potential 
central nervous system (CNS) disease and/or metastases.  For subjects with protocol-eligible treated 
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 to confirm a complete response (CR) within 
1 week following response confirmation, or if clinically indicated. 
Responses should be confirmed no less than 4 weeks following the initial response (generally at the 
next 6 weekly scheduled tumor assessment visit). 
Tumor assessments should initially proceed according to modified RECIST 1.1. 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).
Per iRECIST, disease progression should be confirmed by the site 4 to 8 weeks after site-assessed 
first radiologic evidence of progressive disease in clinically stable subjects.  Subjects who have 
unconfirmed disease progression per iRECIST (iUPD) may continue on treatment at the discretion of 
the investigator until progression is confirmed by the site, provided they have met the following 
conditions.
When clinically stable, participants should not be discontinued until progression is confirmed by the 
investigator, working with local radiology, according to the rules (Appendix 2). This allowance to 
continue treatment despite initial radiologic progressive disease takes into account the observation 
that some subjects can have a transient tumor flare in the first few months after the start of 
immunotherapy, and then experience subsequent disease response. These data will be captured in the 
clinical database.
Clinical stability is defined as the following:

Absence of symptoms and signs indicating clinically significant progression of disease

No decline in ECOG performance status

No requirements for intensified management, including increased analgesia, radiation, or other 
palliative care
Subjects who receive confirmatory imaging do not need to undergo the next scheduled tumor imaging 


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if it is scheduled less than 4 weeks later; tumor imaging should resume at the subsequent scheduled 
imaging time point, if clinically stable. Subjects who have confirmed disease progression by 
iRECIST or LYRIC, as assessed by the site, will discontinue study treatment. Exceptions may be 
discussed with the study medical monitor.
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.
Lymphoma
Tumor assessments will be performed based on Lugano (Cheson, et al, 2014) followed by LYRIC 
criteria (Cheson, et al., 2016) for confirmation of disease progression (Appendix 3).  Investigator-
determined response assessments will be performed at each assessment time point.
Tumor assessments will be carried out during the Pretreatment Phase, at Week 9 (during the 9th week 
counting from Cycle 1 Day 1), and then every 12 weeks during treatment cycles in both the 
Treatment Phase and the Extension Phase.  18Fluorodeoxyglucose-positron emission tomography 
(18FDG-PET)-CT (PET-CT) scans (contrast-enhanced diagnostic quality CT) of neck, 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. While diagnostic quality contrast-enhanced PET-CT is preferred, if contrast-enhanced 
images are not obtainable, noncontrast PET-CT will be acceptable. Historical standard of care scans 
that are performed with scanning parameters consistent with the requirements for this protocol within 
28 days prior to dosing are acceptable.
Tumor assessments should initially proceed according to Lugano criteria.
If the investigator believes that, at the time of Lugano progressive disease, a subject is experiencing 
clinical stability or improvement, they will be considered as having an immune response (IR), and 
continue to be followed according to LYRIC criteria. The subject must be considered likely to 
tolerate continued treatment and not at risk of serious complications should further tumor growth 
occur. For a subject categorized as having IR, repeat imaging is mandatory after an additional 
12 weeks (or sooner if clinically indicated) to assess whether they have true progressive disease.
All subjects
In additional to the individual lesion measurement data that will be collected for all lesions, the 
specific lesion injected at each time point/dose administration should be recorded. In addition, 
lesions that are biopsied should be recorded as such (at the time point) to allow evaluation of 
exploratory efficacy endpoints such as the effect on injected versus non-injected lesions.
Pharmacokinetic Assessments
Samples of blood, urine, and feces for PK analyses will be collected as described in the Schedule of 
Procedures/Assessments.
Blood, urine, and fecal samples may also be used for exploratory analysis of metabolites and 
pharmacodynamic assessments.
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Assessments
Pharmacodynamic Assessment
Pharmacodynamics biomarkers of E7766 include Proof of Mechanism (POM) biomarkers and Proof 
of Principle (POP) biomarkers, which will be measured to evaluate modulation of the STING 




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for STING genotype and gene expression analyses, respectively.  The DNA samples may be used also 
for PG analysis. The role of DNA sequence variability on the absorption, distribution, metabolism, 
and elimination (ADME) of E7766 may be evaluated in this study. Variation in E7766 exposure or 
the occurrence of AEs observed in the study population may be evaluated by correlation of single–
nucleotide polymorphisms with PK, safety, or pharmacodynamics data.
Instructions for the processing, storage, and shipping of samples will be provided in the Laboratory
Manual.
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs, including all CTCAE 5.0 AEs 
(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, safety ECGs, and physical examinations.
Additionally, QTc intervals will be evaluated in the Dose Escalation part only, unless a signal 
indicates the need for continued monitoring in the Dose Expansion part.  The effects of E7766 on 
cardiac repolarization will be evaluated via 24-hour, 12-lead continuous Holter/ECG monitoring 
during Baseline, Cycle 1 Day 1, Cycle 1 Day 14, and Cycle 1 Day 15 of the Dose Escalation part of 
the study only.  Replicate 12-lead ECGs will be extracted 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 correction factor (QTcF).  The primary QTc parameter 
will be QTcF.  Secondary parameters (heart rate, PR interval and QRS) and treatment emergent 
T wave abnormalities and U-waves will be evaluated.  Potential effects of E7766 will be evaluated as 
change-from predose baseline heart rate, PR interval, QRS and QTcF by postdosing time point.  For 
purposes of QT assessment, exposure response analysis will be performed of the relationship between 
E7766 plasma levels and ΔQTcF.
In preclinical studies, intratumorally or subcutaneously administered E7766 upregulated expression of 
certain cytokines in the blood suggesting a possibility of inducing CRS in patients who will receive 
E7766 treatment. In case a CRS-like symptom occurs, tocilizumab (anti-IL6R) and standard practice 
by clinical sites may be given to the subjects according to the “Management of Cytokine Release 
Storm and Organ Toxicity” table shown above.
Bioanalytical Methods
E7766 in plasma, urine, and feces will be determined using validated liquid chromatography–mass 
spectrometry (LC-MS/MS) assays.  If appropriate, assay of plasma, urine, and fecal samples for any 
metabolites of E7766 may be explored.
Gene expression, cytokine expression, immune cell phenotyping, and intratumoral cell phenotyping 
will be measured using qualified assays and appropriate technologies.
Statistical Methods
Improved Modified Toxicity Probability Interval Design in Dose Escalation Part
The improved mTPI design, which uses a Bayesian statistical framework and a beta-binomial 
hierarchical model, will be employed to determine the MTD and/or RP2D of E7766. 
Decision rules for dose assignment will be based on the improved mTPI design with the target DLT 
rate of 25% and its EI of 20% to 30%, and a set of equal-width intervals as EI below/above EI (ie, 
below EI: 0% to 10%, 10% to 20%; above EI: 30% to 40%, ... , 90% to 100%).  The posterior 


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probabilities of each interval will be calculated with non-informative beta prior distribution Beta 
(1, 1). The location of the interval with the largest posterior probability – below EI, EI, or above EI –
guides the decision for the next dose level to be assigned, ie, Dose Escalation (E), Staying at the 
current dose (S), or dose De-escalation (D), respectively.  This dose assignment rule minimizes the 
posterior expected penalty in the Bayes’ rule under a decision-theoretic framework with the equal 
prior expected penalties for E, S, and D.  The entire dose assignment decision rule can be 
pre-tabulated as presented above.
The subject enrollment will be closed when the lowest dose has a >95% posterior probability of being 
above the target DLT rate of 25% (ie, an unacceptable DLT rate beyond the target DLT rate) or when 
the RP2D has been determined.
MTD is defined as the dose with the smallest difference between the target DLT rate of 25% and an 
estimate of DLT rate at each dose among all the tested doses with a ≤95% posterior probability of 
being above target DLT rate of 25%. The isotonically transformed posterior mean under the beta 
posterior distribution with non-informative beta prior distribution Beta (0.005, 0.005) will be used to 
determine the estimate of DLT rates at each dose. The pooled adjacent violators algorithm (PAVA) 
will be used to maintain monotonically the increase of DLT rate with increasing dose level.  Late 
immune-related toxicities occurring after Cycle 1 (DLT period) and up to 90 days after last dose of 
E7766, will also be used to inform any corrections to the MTD and aid selection of the RP2D.
Primary Endpoints: 

Safety-related endpoints, including DLT

ORR according to modified RECIST 1.1 and iRECIST, or Lugano and LYRIC, defined as the 
proportion of subjects achieving a best overall response of confirmed partial or complete 
response (PR + CR).  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 (Dose Expansion part only)

DOR according to modified RECIST 1.1 and iRECIST, or Lugano and LYRIC, defined as the 
time from the date of first documented PR or CR until the first documentation of confirmed 
disease progression or death, whichever occurs first (Dose Expansion part only)

DCR according to modified RECIST 1.1 and iRECIST, or Lugano and LYRIC, defined as the 
proportion of subjects achieving PR or CR or stable disease (SD) (Dose Expansion part only).
Secondary Endpoints:

ORR, DOR, and DCR according to iRECIST and modified RECIST 1.1, or Lugano and LYRIC 
(Dose Escalation part only)

PK profile in plasma, urine, and feces (Dose Escalation part) and plasma only (in Dose 
Expansion part)  

PFS, defined as the time from the date of first dose to the date of the first documentation of 
confirmed disease progression or death, whichever occurs first

OS, defined as the time from the date of first dose to the date of death from any cause

Change in tumor size in injected lesions and in distant non-injected lesions
Exploratory Endpoints:

Changes in tumor size assessed by IIR using volumetric CT/MRI


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
Immune pharmacodynamics effects in the tumors and in the peripheral blood

PK/pharmacodynamic relationships (safety and efficacy endpoints)

Baseline immune phenotypes and its relationship with the response to E7766

STING genotypes and its relationship with the response to E7766

Changes in pre-injection size of injected lesion per investigator assessment
Analysis Sets
DLT Analysis Set is the group of subjects in the Dose Escalation part who have completed Cycle 1, 
without incurring certain major protocol deviation (for instance those related to dosing or others 
identified before database lock), with at least 2 E7766 injections during Cycle 1, and are evaluable for 
DLT, or subjects who have experienced a DLT during Cycle 1.  This will be the analysis set to 
evaluate tolerability. 
Full Analysis Set is the group of subjects who received at least 1 dose of study drug.  This will be the 
primary analysis set for efficacy evaluations, as well as for demographic and baseline characteristics. 
Safety Analysis Set is the same group as Full Analysis Set. This will be the analysis set for all safety 
evaluations except DLT results.
Efficacy Analysis Set is the group of subjects who received at least 1 dose of study drug and had a 
baseline tumor assessment.
Pharmacokinetic (PK) Analysis Set is the group of subjects who have received at least 1 dose of 
study drug and have at least 1 evaluable plasma concentration.
Pharmacodynamic Analysis Set is the group of subjects who have received at least 1 dose of study 
drug and have evaluable pharmacodynamic data.
Pharmacokinetic/Pharmacodynamic Analysis Set is the group of subjects in the Safety Analysis Set 
that also have evaluable serum PK and pharmacodynamics pretreatment assessment and at least one 
posttreatment assessment.
Efficacy Analyses
Evaluation of clinical activity will be primarily performed on the Full Analysis Set. Summary of 
clinical activity on the Efficacy Analysis Set will also be provided as needed. Objective response rate 
(ORR), DOR, DCR, PFS, assessed by the investigator, and OS will be listed and descriptively 
summarized as appropriate.  If applicable, a waterfall plot will be presented for the percent changes 
from baseline in the sum of the diameters of target lesions at post-baseline nadir (ie, maximum tumor 
shrinkage).

ORR will be calculated with exact 95% CI using the Clopper and Pearson method.  Summary 
of best overall response will also be presented. 

DOR will be summarized using Kaplan-Meier estimates as appropriate.  Median, Q1, Q3, and 
their 95% CIs will be presented and Kaplan-Meier estimates will be plotted over time.  The 
DOR will be based on subjects achieving a best overall response of confirmed PR + CR.  

DCR will be calculated with exact 95% CI using the Clopper and Pearson method.

PFS will be summarized using Kaplan-Meier estimates.  Median, Q1, Q3, and their 95% CIs 
will be presented and Kaplan-Meier estimates will be plotted over time. Subjects without 
progression of disease or death will be censored at the time of the last tumor assessment. 


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
OS will be summarized using Kaplan-Meier estimates.  Median, Q1, Q3, and their 95% CIs 
will be presented and Kaplan-Meier estimates will be plotted over time. Subjects who are lost 
to follow-up or withdrew consent will be censored at the last known alive date, or the data 
cutoff date, whichever occurs first.  Subjects who remained alive will be censored at the time of 
data cutoff.
The analysis using the tumor assessment by lesions, such as injected lesions and non-injected lesions,
will be collected and conducted separately. Time course changes in pre-injection size of injected 
lesion will also be provided separately.
Pharmacokinetic Analyses
Plasma concentrations of E7766 will be tabulated and summarized by dose level, day, and protocol 
time. E7766 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, terminal elimination half-life 
(t½), apparent body clearance (CL/F), apparent volume of distribution (Vd/F), renal clearance (CLr), 
accumulation ratio (R), and fraction excreted (fe).  Recovery of E7766 in urine and feces will be 
tabulated and summarized by dose level, day, and protocol time.
If exploratory characterization/identification of metabolites in plasma, urine, and feces are attempted 
after administration of E7766, the results will be presented in a separate report.
Pharmacokinetic/Pharmacodynamic Analyses
Exploratory/graphical analyses will be conducted for PK/pharmacodynamics evaluations and may be 
followed by model-based analyses. The analyses may be detailed and reported in a separate analysis 
plan.  
When conducting population analysis, the population PK analysis plan and its report will be made 
separately.
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses
Pharmacodynamics biomarkers of E7766 include POM biomarkers and POP biomarkers, which will 
be measured to evaluate modulation of the STING pathway and of both innate and adaptive immune 
response, respectively, by E7766 treatment in human patients.  To measure the STING pathway 
modulation, expression of a specific panel of STING pathway genes by E7766 will be examined as 
part of immune gene profiling in the tumor biopsies and in the blood.  To measure the innate and 
adaptive immune response, immune gene profiling will be performed for the available tumor biopsies 
and blood.  Immune cytokines and immune cell phenotyping will be analyzed in the blood as well.  
Results from the pharmacodynamic biomarker studies may be used to aid the selection for the RP2D 
and to monitor drug biological activity.  Blood and tumor tissue samples will be collected from study 
subjects at protocol-specified time points as indicated in the Schedule of Procedures/Assessments.
Tolerability/Safety Analyses
Evaluation of DLTs will be performed on the DLT Analysis Set.  The number and percentage of 
subjects with a DLT will be calculated. 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. QTc intervals will be evaluated in the Dose Escalation part 


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only.
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).
Interim Analyses
No formal interim analyses are planned.  Interim monitoring using a snapshot of the database will be 
conducted to determine the MTD and/or RP2D, or to confirm safety and detect efficacy signals in 
subjects with selected disease indications before the analysis for a clinical study report (CSR).
Database locks are not required to perform these interim evaluations.
The data cutoff date for the CSR will be after 6 months of the last subject in, and may be conducted
before the last subject discontinues study treatment in this study.
Sample Size Rationale
It is anticipated that selection of the RP2D will be based on integrated evaluation of safety, 
tolerability, clinical benefit, PK, and pharmacodynamic data.  The total number of subjects for the 
Dose Escalation part will depend on the observed data including safety profile, which will determine 
the number of subjects per dose level, as well as the number of dose levels tested before the RP2D is 
established.  Therefore, a formal statistical calculation of sample size is not applicable.  The 
anticipated sample size in the Dose Escalation part will be approximately 35 subjects, assuming 
approximately 10 dose levels and at least 2 subjects per dose level will be tested to achieve the MTD 
and then approximately 4 subjects for the selected 1 to 3 dose levels may be additionally enrolled for 
the RP2D selection. 
The total number of subjects for the Dose Expansion part will depend on the number of arms by the 
disease-specific indications, and the number of subjects per arm. The anticipated sample size for the 
Dose Expansion part will be approximately 80 subjects, assuming 2 arms, and a maximum of
40 subjects per arm will be enrolled.


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3
TABLE OF CONTENTS
1
TITLE PAGE ................................................................................................................1
2
CLINICAL PROTOCOL SYNOPSIS............................................................................5
3
TABLE OF CONTENTS.............................................................................................29
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................35
5
ETHICS.......................................................................................................................38
5.1
Institutional Review Boards/Independent Ethics Committees.............................38
5.2
Ethical Conduct of the Study..............................................................................39
5.3
Subject Information and Informed Consent ........................................................39
6
INVESTIGATORS AND STUDY PERSONNEL .......................................................40
7
INTRODUCTION.......................................................................................................40
7.1
E7766 Background.............................................................................................40
7.1.1
E7766 Mechanism of Action ....................................................................40
7.1.2
Therapeutic Indication..............................................................................41
7.1.3
Nonclinical Experience With E7766.........................................................42
7.1.3.1
Pharmacodynamics...........................................................................42
7.1.3.2
Pharmacokinetics..............................................................................43
7.1.3.3
Toxicology and Safety Pharmacology...............................................43
7.2
Study Rationale..................................................................................................46
8
STUDY OBJECTIVES................................................................................................48
8.1
Primary Objectives.............................................................................................48
8.2
Secondary Objectives.........................................................................................49
8.3
Exploratory Objectives.......................................................................................49
9
INVESTIGATIONAL PLAN ......................................................................................49
9.1
Overall Study Design and Plan...........................................................................49
9.1.1
Dose Escalation........................................................................................51
9.1.1.1
Dose Escalation Design ....................................................................51
9.1.1.2
Dose-Limiting Toxicities ..................................................................54
9.1.1.3
Selection of the RP2D.......................................................................55
9.1.2
Dose Expansion........................................................................................56
9.1.3
Study Phases ............................................................................................57
9.1.3.1
Pretreatment Phase ...........................................................................57
9.1.3.2
Treatment Phase ...............................................................................57
9.1.3.3
Extension Phase................................................................................58
9.1.3.4
Follow-Up Phase ..............................................................................58


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9.2
Discussion of Study Design, Including Choice of Control Groups......................59
9.3
Selection of Study Population ............................................................................60
9.3.1
Inclusion Criteria......................................................................................60
9.3.2
Exclusion Criteria.....................................................................................62
9.3.3
Removal of Subjects from Therapy or Assessment ...................................64
9.4
Treatments.........................................................................................................64
9.4.1
Treatments Administered..........................................................................64
9.4.1.1
Dosing Schedules .............................................................................65
9.4.1.2
Dose Adjustments.............................................................................66
9.4.1.3
Intratumoral Injection .......................................................................67
9.4.1.4
Management of Cytokine Release Storm ..........................................68
9.4.2
Identity of Investigational Product(s)........................................................69
9.4.2.1
Chemical Name, Structural Formula of E7766..................................69
9.4.2.2
Comparator Drug..............................................................................70
9.4.2.3
Labeling for Study Drug ...................................................................70
9.4.2.4
Storage Conditions ...........................................................................70
9.4.3
Method of Assigning Subjects to Treatment Groups.................................70
9.4.4
Selection of Doses in the Study ................................................................70
9.4.5
Selection and Timing of Dose for Each Subject........................................70
9.4.6
Blinding ...................................................................................................70
9.4.7
Prior and Concomitant Therapy................................................................71
9.4.7.1
Drug-Drug Interactions.....................................................................71
9.4.7.2
Prohibited Concomitant Therapies and Drugs ...................................71
9.4.8
Prohibitions and Restrictions During the Study Period..............................72
9.4.9
Treatment Compliance .............................................................................72
9.4.10
Drug Supplies and Accountability ............................................................72
9.5
Study Assessments.............................................................................................74
9.5.1
Assessments .............................................................................................74
9.5.1.1
Demography.....................................................................................74
9.5.1.2
Baseline Assessments .......................................................................74
9.5.1.2.1
Medical History and Physical Examinations................................74
9.5.1.2.2
Other baseline assessments .........................................................75
9.5.1.3
Efficacy Assessments .......................................................................75
9.5.1.3.1
Solid Tumors ..............................................................................75
9.5.1.3.2
Lymphoma..................................................................................78
9.5.1.3.3
All Subjects ................................................................................79


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9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments ..........................................................79
9.5.1.4.1
Pharmacokinetic Assessments.....................................................79
9.5.1.4.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Assessments................................................................................79
9.5.1.5
Safety Assessments...........................................................................81
9.5.1.5.1
Adverse Events...........................................................................82
9.5.1.5.2
Serious Adverse Events and Events Associated With Special 
Situations....................................................................................84
9.5.1.5.3
Laboratory Measurements...........................................................85
9.5.1.5.4
Vital Signs and Weight Measurements........................................85
9.5.1.5.5
Physical Examinations ................................................................86
9.5.1.5.6
Electrocardiograms .....................................................................86
9.5.1.5.7
ECHO/MUGA............................................................................87
9.5.1.5.8
Pregnancy Test ...........................................................................87
9.5.1.5.9
Assessment of Cytokines ............................................................87
9.5.2
Schedule of Procedures/Assessments........................................................87
9.5.2.1
Schedule of Procedures/Assessments................................................87
9.5.2.2
Description of Procedures/Assessments Schedule .............................95
9.5.3
Appropriateness of Measurements............................................................95
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations ...........................................................95
9.5.4.1
Reporting of Serious Adverse Events................................................95
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding....................................................................................96
9.5.4.3
Reporting of Events Associated With Special Situations...................97
9.5.4.3.1
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error...........................97
9.5.4.4
Expedited Reporting .........................................................................97
9.5.4.5
Breaking the Blind............................................................................97
9.5.4.6
Regulatory Reporting of Adverse Events ..........................................97
9.5.5
Completion/Discontinuation of Subjects...................................................98
9.5.6
Abuse or Diversion of Study Drug............................................................98
9.5.7
Confirmation of Medical Care by Another Physician................................98
9.6
Data Quality Assurance......................................................................................99
9.6.1
Data Collection.........................................................................................99
9.6.2
Clinical Data Management .......................................................................99


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9.7
Statistical Methods.............................................................................................99
9.7.1
Statistical and Analytical Plans.................................................................99
9.7.1.1
Study Endpoints..............................................................................100
9.7.1.1.1
Primary Endpoints ....................................................................100
9.7.1.1.2
Secondary Endpoints.................................................................100
9.7.1.1.3
Exploratory Endpoints ..............................................................100
9.7.1.2
Definitions of Analysis Sets............................................................100
9.7.1.3
Subject Disposition.........................................................................101
9.7.1.4
Demographic and Other Baseline Characteristics............................101
9.7.1.5
Prior and Concomitant Therapy ......................................................101
9.7.1.6
Efficacy Analyses...........................................................................102
9.7.1.6.1
Primary Efficacy Analysis.........................................................102
9.7.1.6.2
Secondary Efficacy Analyses....................................................103
9.7.1.6.3
Exploratory Efficacy Analyses..................................................103
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses..............................................................103
9.7.1.7.1
Pharmacokinetic Analyses ........................................................103
9.7.1.7.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses ...................................................................................104
9.7.1.8
Tolerability/Safety Analyses...........................................................104
9.7.1.8.1
Extent of Exposure....................................................................104
9.7.1.8.2
Adverse Events.........................................................................105
9.7.1.8.3
Laboratory Values.....................................................................106
9.7.1.8.4
Vital Signs ................................................................................106
9.7.1.8.5
Electrocardiograms ...................................................................106
9.7.1.8.6
Other Safety Analyses...............................................................107
9.7.2
Determination of Sample Size ................................................................107
9.7.3
Interim Analysis.....................................................................................107
9.7.4
Other Statistical/Analytical Issues ..........................................................107
9.7.4.1
Improved Modified Toxicity Probability Interval Design in Dose 
Escalation Part................................................................................107
9.7.5
Procedure for Revising the Statistical Analysis Plan...............................108
10
REFERENCE LIST...................................................................................................109
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).....111
11.1
Changes to the Protocol....................................................................................111
11.2
Adherence to the Protocol................................................................................111
11.3
Monitoring Procedures.....................................................................................111


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11.4
Recording of Data............................................................................................112
11.5
Identification of Source Data............................................................................112
11.6
Retention of Records........................................................................................112
11.7
Auditing Procedures and Inspection .................................................................113
11.8
Handling of Study Drug ...................................................................................113
11.9
Publication of Results ......................................................................................113
11.10 Disclosure and Confidentiality .........................................................................114
11.11 Discontinuation of Study..................................................................................114
11.12 Subject Insurance and Indemnity......................................................................114
12
APPENDICES...........................................................................................................115
LIST OF IN-TEXT TABLES
Table 1
Decision Rule for Dose Assignment .......................................................53
Table 2
Method for Deciding the Dose of the Next Dose Group..........................54
Table 3
Examples of Drug Dilutions and Volumes Administered........................65
Table 4
E7766 Dose Reduction and Interruption Instructions ..............................66
Table 5
Management of Cytokine Release Storm and Organ Toxicity .................68
Table 6
Clinical Laboratory Tests........................................................................85
Table 7
Schedule of Procedures/Assessments in Study E7766-G000-101 for 
Dose Escalation and Dose Expansion parts.............................................88
Appendix Table 1:  Target and Nontarget Lesion Definitions by LDi (Long Axis 
Diameter) and SDi (Short Axis Diameter) for Solid Tumors and 
Lymphoma ...........................................................................................118
Appendix Table 2:
Imaging and Treatment After First Radiologic Evidence of 
Progressive Disease..............................................................................123
Appendix Table 3:
Standard Definitions and Assessments Lugano Lexicon............124
Appendix Table 4:
Lugano Criteria for Response....................................................127
Appendix Table 5:
LYRIC PD Confirmation for Immunotherapy in Lymphomaa ...130
LIST OF IN-TEXT FIGURES
Figure 1
STING pathway activation .....................................................................41
Figure 2
Study Schematic for Dose Escalation and Dose Expansion parts.............51
Figure 3
Schematic for Dose Escalation................................................................52
Figure 4
Study Phases ..........................................................................................57


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LIST OF APPENDICES
Appendix 1
Identification and Documentation of Injectable and Biopsiable Lesions 
at Screening CT Scan ...........................................................................116
Appendix 2
Description of the iRECIST Process for Assessment of Disease 
Progression...........................................................................................119
Appendix 3
Description of the Lugano and LYRIC Assessment of Response in 
Lymphoma ...........................................................................................124
Appendix 4
Cockcroft–Gault Calculation of Creatinine Clearance...........................131
Appendix 5
Autoimmune-Related Diseases .............................................................132
Appendix 6
Interleukin-6 (IL-6) Antagonist and Corticosteroid Dosing Tables........133
Appendix 7
Appendix 8
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Research 135
CCI


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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AEs
adverse events 
ALP
alkaline phosphatase
ALT
alanine aminotransferase 
AST
aspartate aminotransferase 
BP
blood pressure
CA
Competent Authority 
CL/F
apparent body clearance 
CLr
renal clearance 
Cmax
maximum drug concentration
CNS
central nervous system
CR
complete response
CRA
clinical research associate 
CRF
case report form 
CRO
contract research organization
CRS
cytokine release storm 
CSR
clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P450 
DCR
disease control rate 
DLT
dose-limiting toxicity
DOR
duration of response 
EC50
50% effective concentrations 
ECOG
Eastern Cooperative Oncology Group 
eCRF
electronic case report form
EI
equivalence interval 
fe
fraction excreted 
FIH
first-in-human
FOB
functional observational battery
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
HNSCC
head and neck squamous cell carcinoma


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Abbreviation
Term
HNSTD
highest nonseverely toxic dose
ICF
informed consent form 
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
iCPD
confirmed progressive disease per iRECIST
IEC
Independent Ethics Committee 
IFN
interferon
IIR
independent imaging review
IR
immune response 
IRB
Institutional Review Board
iRECIST
modified RECIST 1.1 for immune-based therapeutics
iUPD
unconfirmed disease progression per iRECIST
Kd
dissociation constant 
LMWH
low molecular weight heparin
LVEF
left ventricular ejection fraction 
LYRIC
LYmphoma Response to Immunomodulatory Therapy Criteria
MABEL
minimally anticipated biological effect level
MRI
magnetic resonance imaging
MRP2
multidrug resistance-associated protein 2 
MTD
maximum tolerated dose
mTPI
modified toxicity probability interval 
MUGA
multigated acquisition 
OATP
organic anion transporting polypeptide 
ORR
objective response rate(s)
OS
overall survival 
PAD
pharmacologically active dose 
PD
progressive disease 
PET-CT
18fluorodeoxyglucose-positron emission tomography (18FDG-PET)-CT
PFS
progression-free survival 
PG
pharmacogenetic, pharmacogenomic
PK
pharmacokinetics
POM
Proof of Mechanism
POP
Proof of Principle
PR
partial response


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Abbreviation
Term
Q3W
once in 3 weeks (dosing)
QTc
corrected QTc interval
QTcF
corrected for QTc interval using Fridericia’s correction factors
R
accumulation ratio 
RECIST
Response Evaluation Criteria in Solid Tumours
RP2D
recommended Phase 2 dose 
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
SD
stable disease
STING
stimulator of interferon genes
t1/2
terminal elimination half-life
TBIL
total bilirubin 
tmax
time to reach maximum concentration
TNF
tumor necrosis factor
ULN
upper limit of normal 
Vd/F
apparent volume of distribution 
WHO DD
World Health Organization Drug Dictionary 


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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[s]).  Documentation of IRB/IEC 
compliance with the ICH E6 and any local regulations regarding constitution and review 
conduct will be provided to the sponsor.
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 adverse events (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 definition of the end of the study is the date of the data cutoff for 
the final analysis or last subject/last visit, including discontinuation from the study for any 
reason, whichever occurs later.  The sponsor should also provide the IRB/IEC with a 
summary of the study’s outcome.
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 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 2013

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 Council for Harmonisation of Technical Requirements for
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 suspected unexpected 
serious adverse reactions (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.  


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After the ICF and any other written information to be provided to subjects is read and 
explained to the subject or the subject’s legally acceptable representative, and after the 
subject or the subject’s legally acceptable representative has orally consented to the subject’s 
participation in the study and, if capable of doing so, has signed and personally dated the 
ICF, the witness should sign and personally date the consent form.  The subject will be asked 
to sign an ICF before any study-specific procedures are performed.  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.  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 or the subject’s legally authorized representative should be informed in a timely 
manner if new information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study.  The communication of this information 
should be documented.
6
INVESTIGATORS AND STUDY PERSONNEL
This study will be conducted by qualified investigators under the sponsorship of Eisai and 
H3biomedicine (the sponsors) at approximately 4 investigational sites globally for the Dose 
Escalation part with additional sites for the Dose Expansion part.
The name and telephone and fax numbers of the study medical monitor and other contact 
personnel at the sponsor and of the contract research organization(s) (CRO[s]) are listed in 
the Investigator Study File provided to each site.
7
INTRODUCTION
7.1
E7766 Background
7.1.1
E7766 Mechanism of Action
E7766 is a potent and specific agonist of stimulator of interferon genes (STING) that is being
investigated as an immunotherapy for cancer treatment.  STING is an important innate 
immune sensor that bridges the innate immune system and adaptive immunity and has been 
shown to play a critical role in controlling cancer progression by activating both type I IFN 
and canonical NF-kB pathways (Figure 1) (Woo, et al., 2014).  Intratumoral stimulation of 
STING by a synthetic STING agonist was shown to generate a potent antitumor response in 
multiple nonclinical models (Corrales, et al., 2015).  
As a potent STING agonist, E7766 is intended to be developed as a new cancer 
immunotherapy.  In this study it will be injected intratumorally, where it is hypothesized that 


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it will directly activate an antitumoral innate immune response in the injected tumor’s
microenvironment followed by inducing an adaptive tumor antigen-specific immune 
response to counter tumors systemically. It is believed that such intratumoral administration 
will reduce systemic drug exposure and nontumor-specific immune activation.  
Figure 1
STING pathway activation
ATP = adenosine triphosphate, cGAMP = cyclic GMP-AMP, cGAS = cyclic GMP-AMP 
synthase, IFN = interferon, IRF = interferon regulatory factor, STING = stimulator of 
interferon genes, TBK1 = tank-binding kinase 1.
Intratumorally injected E7766 demonstrated potent, immune-mediated, long lasting 
antitumor activity in multiple nonclinical tumor models of different tissue origins both 
locally (ie, injected sites) and systemically (non-injected sites), including in tumors in the 
brain (Section 7.1.3.1).
Further details of the mechanism of action of E7766 are provided in the Investigator’s
Brochure.
7.1.2
Therapeutic Indication
The initial clinical development of E7766 will be focused in selected tumor types with 
identified high unmet medical need, following scientific rationale and available emerging 
nonclinical information.  
Subjects with solid tumors or lymphomas that are advanced, nonresectable, or recurrent and 
progressing since last antitumor therapy, and for which no alternative standard therapy exists
will be enrolled in the Dose Escalation part.












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intratumoral injections into one of the tumors. Intratumoral injection of E7766 induced a 
robust and effective innate and adaptive immune response including but not limited to 
induction of type I IFN genes and activation of resident cytotoxic T cells, which led to 
antitumor activity in both the injected tumor and the nontreated distant tumor, including 
tumors in the brain (Section 7.1.3.1). Notably, most of the animals whose tumors were 
eradicated by E7766 treatment rejected re-challenge of the same tumor type without any 
further treatment, indicating development of a protective memory immune response. Thus, 
E7766 has the potential to produce clinical activity in a variety of human cancer types and 
stages of disease including early and advanced metastatic cancer.
Systemic administration of this potent agonist is likely to bring unwanted immune effects.  
E7766 administration directly to the tumor lesion may allow induction of tumor-specific 
immune response at both the local and systemic level while minimizing AEs and 
nontumor-specific immune responses.
Early clinical development will be focused in selected tumor types with identified high 
unmet medical need and the potential for response to a STING agonist.  As a result, advanced 
cancers including melanoma, HNSCC, breast cancer, and colorectal cancer will be prioritized 
initially.  New immunotherapeutic approaches exploring modalities that stimulate the human 
immune system to attack tumors in the brain have shown early but promising results in the 
clinic and could be of significant importance in patients with brain metastases (Venur and 
Ahluwalia, 2017). In this regard, E7766 may potentially have clinical activity against central 
nervous system (CNS) metastases as a result of its abscopal immunomodulatory action.  
Tumor-specific lymphocytes activated by injection of E7766 into tumors outside of the CNS 
are expected to migrate into the CNS and exert an antitumor effect. This hypothesis is 
supported by results from a nonclinical model in which an intracranial tumor was 
successfully eradicated by injecting E7766 into a concurrent subcutaneous tumor 
(Section 7.1.3.1).  Eisai thus plans to study E7766’s clinical activity in metastatic or 
advanced cancer in subjects who have limited treatment options, including those with brain 
metastasis.
Risk Benefit assessment
In the current study, E7766 is being evaluated for the treatment of solid tumors or 
lymphomas, that are advanced, nonresectable, or recurrent and progressing since last
antitumor therapy, and for which no alternative standard therapy exists.  E7766 is a new 
agent with a novel mechanism of action and has demonstrated a potent and long lasting 
antitumor activity in nonclinical tumor models with nonsevere toxicity through intratumoral 
administration.  Based on the antitumor activity of E7766 observed in nonclinical tumor 
models, E7766 is expected to demonstrate clinical activity and response in these subjects, for 
whom no alternative standard therapy exists and the prognosis is poor.


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Nonclinical safety assessments were conducted in mice and cynomolgus monkeys and they
showed adverse effects consistent with the pharmacologic activity.  Based on these studies, 
the following adverse effects may be anticipated in the FIH study:

Systemic inflammation, manifested as described in the next 2 bullets below 

Cytokine elevation, including of IL-6, IP-10, MCP-1, IFNβ, and TNF-α, peaking at 
approximately 8 hours postdose, and which is likely to be markedly lower after 
24 hours. The amplitude of cytokine response is not expected to change significantly 
upon repeated dosing.

Local injection site irritation including reddening, swelling, and ulceration.

Gastrointestinal signs, including diarrhea
Overall, considering the promising antitumor activity and limited toxicity of E7766 in 
nonclinical studies at the doses showing antitumor activity when administered via the 
intratumoral route, clinical evaluation of E7766 via the intratumoral route is planned in 
subjects with advanced solid tumors and lymphomas. 
8
STUDY OBJECTIVES
8.1
Primary Objectives
The primary objectives of the study are:
Dose Escalation part

Assess the safety/tolerability profile of E7766 administered intratumorally in subjects 
with advanced solid tumors or lymphomas

Determine the MTD and/or recommended Phase 2 dose (RP2D) of E7766 in subjects 
with advanced solid tumors or lymphomas
Dose Expansion part 

Assess the safety/tolerability profile of E7766 administered intratumorally in cohorts of 
subjects with selected tumor types

Assess clinical activity of E7766 based on investigator assessment of objective response 
rate (ORR), duration of response (DOR), and disease control rate (DCR) according to 
modified Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 and modified 
RECIST 1.1 for immune-based therapeutics (iRECIST) for solid tumors, and for 
lymphoma (if included in Dose Expansion part), lymphoma response according to 
Lugano and LYmphoma Response to Immunomodulatory Therapy Criteria (LYRIC) 
criteria, in cohorts of subjects with selected tumor types 


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8.2
Secondary Objectives
The secondary objectives of the study are:
Dose Escalation part

Evaluate preliminary clinical activity of E7766 based on investigator assessment of 
ORR, DOR, and DCR according to modified RECIST 1.1 and iRECIST for solid 
tumors, and Lugano and LYRIC criteria for lymphoma

Evaluate the pharmacokinetic (PK) profile of E7766 and any metabolites in plasma, 
urine, and feces 
Dose Escalation and Dose Expansion parts

Evaluate the PK profile of E7766 and any metabolites in plasma 

Evaluate progression-free survival (PFS) based on investigator assessment and overall 
survival (OS) in subjects treated with E7766 

Evaluate tumor size changes per investigator assessment in injected lesions and in 
non-injected lesions
8.3
Exploratory Objectives
The exploratory objectives of the study are:
Dose Escalation and Dose Expansion parts

Evaluate changes in tumor size assessed by independent imaging review (IIR) using 
volumetric computed tomography (CT)/magnetic resonance imaging (MRI)

Evaluate immune pharmacodynamics effects of E7766 in the tumors and in peripheral 
blood

Explore PK/pharmacodynamics relationships (safety and efficacy endpoints) 

Explore correlation of baseline tumor and peripheral blood immune phenotypes and of 
STING genotypes with safety and/or efficacy endpoints

Evaluate pre-injection changes in size of injected lesion per investigator assessment in 
addition to the scheduled tumor assessments to characterize the kinetics of response, 
progression, or immune-induced flare in the injected lesion.  
9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
This is an open label, multicenter, Phase 1/1b study to assess the safety and evaluate the 
clinical activity of E7766 administered intratumorally to subjects with advanced solid tumors 








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Table 1
Decision Rule for Dose Assignment
Number of Subjects Treated at Current Dose
2
4
6
8
10
12
Number of Subjects 
With DLTs
0
E
E
E
E
E
E
1
Da
S
E
E
E
E
2
D, U
D
D
S
S
E
3
D, U
D
D
D
S
4
D, U
D, U
D, U
D
D
5
D, U
D, U
D, U
D
≥6
D, U
D, U
D, U
D, U
Target DLT rate at MTD = 25% and its equivalence interval = 20% to 30%, Cohort size = 2 subjects.
Display for more than 12 subjects at the current dose is omitted.  If the required rules are not available in the 
table, the decision will follow the rule determined by the improved mTPI design with the same settings above.
E = Escalate to the next higher dose, S = Stay at the current dose, D = De-escalate to the next lower dose, U = 
Current dose is unacceptably toxic (ie, Do not re-enter the current dose).
DLT = dose-limiting toxicity, MTD = maximum tolerated dose, mTPI = modified toxicity probability interval.
a:  Extra subjects may be added for the lowest dose, for example if the investigators and the sponsor determine 
that more subjects would be required to adequately evaluate that dose level and it is considered safe to do so.
Subjects will be assigned to a dose level in the order of study entry.  There should be at least
7 days between initiating treatment of the first and second subject in each new dose 
escalation.  This would provide enough safety margin in terms of safety evaluation for any 
acute serious toxicities arising from activation of the immune system, which would generally 
be expected to occur within the first hours or 1 to 3 days of drug exposure. In cohorts where 
the dose is de-escalated or re-escalated, a delay in administration between the first subject 
and subsequent subjects in that cohort is not required if the same or a higher dose level has 
already been investigated in a previous cohort.
The first E7766 dose administered to the subjects will be 75 µg (refer to Section 9.2 for 
justification of starting dose).  The dose of subsequent dose groups will be determined based 
on the E7766-related AEs that develop in subjects in the prior dose group during the 3 weeks 
of Cycle 1 (see Table 2).  When escalating or de-escalating the dose to the next dose level 
according to the improved mTPI design, if there is a higher or lower dose level that has been 
tested previously, subjects should be enrolled to the previously tested dose and Table 2 below 
shall not apply.  In addition, intermediate doses can be further added if necessary based on 
the safety or PK of the previously tested dose.  The addition of new dose levels will be 
decided based on discussions between the investigators and sponsors during dose escalation 
meetings.


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Table 2
Method for Deciding the Dose of the Next Dose Group
Dose Escalation Steps 
E7766-Related Toxicity During Cycle 1
Increase ~75% to 100%
Up to Grade 1
Increase ~30% to 60%
Grade 2 in 1 subject 
Increase ~10% to 30%
Grade 2 in 2 or more subjects and/or
Grade 3 or higher in 1 or more subject
Intrapatient dose escalation of study drug will be allowed in the study after a minimum of 
3 cycles of study therapy at the designated dose and after there is sufficient information to 
ensure safety at the higher dose.  The decision for individual cases, if requested, will be made 
in agreement between the investigators and the sponsor. Subjects on the intrapatient dose 
escalation will be identified, but included in the evaluation of tolerability/safety and efficacy
at the dose level assigned in Cycle 1, instead of at the higher dose level.
Late immune-related toxicities occurring after Cycle 1 (DLT period) and up to 90 days after 
last dose of E7766, will also be considered to inform any corrections to the MTD and aid 
selection of the RP2D.
Escalation of E7766 dose will be achieved based on the concentrations and volumes 
administered according to the guidance in Table 3.
During the Dose Escalation part, selected dose level cohorts may accrue additional subjects 
to provide additional safety, drug administration-related, biomarker, and/or PK data needed 
for selection of the RP2D.
9.1.1.2
Dose-Limiting Toxicities
DLTs are any of the following toxicities occurring during Cycle 1 and assessed by the 
investigator as related to study drug (any toxicities considered related to any degree to 
E7766): 

Clinically significant nonhematologic toxicity ≥ Grade 3 (National Cancer Institute 
[NCI] Common Terminology Criteria for Adverse Events [CTCAE] v. 5.0), except
-
Grade 3 fatigue <5 days.
-
Asymptomatic Grade 3 or 4 laboratory abnormalities that are corrected within 
72 hours.
-
≥Grade 3 nausea, vomiting, and diarrhea unless lasting >48 hours despite optimal 
supportive care. 
-
Other AEs that per investigator assessment are not dose limiting nor dose related.

CTCAE Grade 2 nonhematologic toxicities which, in the opinion of the investigator, 
require a dose reduction or discontinuation of study drug, or lead to the subject’s failure 
to complete at least 2 out of 3 scheduled injections of E7766 in Cycle 1, or be 


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considered intolerable for any other reason by the investigator, may be deemed to be 
dose-limiting if agreed upon by participating investigators and the sponsors.

Nonhematologic laboratory findings of Grade ≥3 that were ≤ Grade 1 at baseline with 
the exception of abnormal Grade 3 laboratory values with no clinical significance that
resolve within 7 days (this includes electrolyte abnormalities which respond to medical 
intervention).  

Hematologic toxicity:
-
Grade 4 neutropenia for 5 days, or febrile neutropenia.
-
Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia with hemorrhage.

Any other toxicity assessed as related to E7766 treatment, and which in the opinion of
the study investigator(s) and the study medical monitor constitutes a DLT.

A delay of initiating Cycle 2 of 7 days or more due to toxicity.

Any death not clearly due to the underlying disease or extraneous causes

For patients with hepatic metastases, AST or ALT >8×upper limit of normal (ULN), or 
AST or ALT >5×ULN for ≥14 days.

For patients with normal ALT and AST and total bilirubin (TBIL) value at baseline: 
AST or ALT >3.0×ULN combined with TBIL >2.0×ULN without evidence of 
cholestasis (ALP ≤2×ULN), with no alternative etiology (Hy’s law)

For patients with elevated AST or ALT or TBIL value at baseline: [AST or ALT 
>2×baseline AND >3.0×ULN] OR [AST or ALT >8.0×ULN], whichever is lower, 
combined with [TBIL >2×baseline AND >2.0×ULN] without evidence of cholestasis
(ALP ≤2×ULN)
A subject should have received at least 2 E7766 injections during the DLT period (Cycle 1) 
to be considered evaluable for a DLT, unless the subject experienced a treatment-related
toxicity preventing more than 1 administration of E7766.
If a subject at a given dose level receives fewer than 2 out of the 3 planned E77766
intratumoral injections during the Induction cycle (ie, the DLT period/Cycle 1) because of 
E7766-related AEs, the subject should be considered as potentially experiencing a DLT by 
the Study Safety Committee, composed of investigators and representatives of the sponsor.
A subject experiencing a DLT may continue treatment at a reduced dose if the DLT has 
resolved and in the opinion of the investigator the subject is benefiting from treatment.  In 
case of recurrence of the DLT at a lower dose, E7766 treatment should be discontinued.
9.1.1.3
Selection of the RP2D
The RP2D of E7766 will be selected based on an integrated evaluation of safety, tolerability, 
clinical activity, PK data, and any available pharmacodynamics data for all dose levels or all 
available data according to the following guidelines:


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
The RP2D must not exceed the MTD, as defined in the Dose Escalation part of the 
study.

Consideration will be given to other toxicities including: AEs assessed as related to 
study drug treatment but not considered dose limiting, late immune-related toxicities 
(up to 90 days after last dose of the study drug), the nature and frequency of toxicities, 
and the emergence of any specific category of toxicities.

Consideration will be given to the tumor response(s) and antitumor activity.

Pharmacodynamic demonstration of biologic activity, including but not limited to: 
activation of STING-mediated immune pathways and modulation of innate and adaptive 
immune response in the tumors and/or in the peripheral blood such as INFβ, CXCL10, 
and MCP1.
The investigators and sponsors will together conduct the evaluation and the recommended 
Phase 2 dose/doses and/or any modification to the dosing regimen will be agreed upon 
jointly.
9.1.2
Dose Expansion
Expansion arms shall be opened in specific tumor types and populations with treatment at the 
E7766 RP2D.
Safety and clinical activity of E7766 at the RP2D will be tested in separate expansion arms 
with defined populations potentially including but not limited to melanoma, HNSCC, breast 
cancer, colorectal cancer, and/or other tumors. About 40 patients will be recruited in each 
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The Treatment Phase will extend from the start of study drug administration in Cycle 1 and 
will last for 1 treatment cycle of 21 days in the Dose Escalation part and 6 cycles in the Dose 
Expansion part.  At the end of the Treatment Phase subjects will continue to the Extension 
Phase.
9.1.3.3
Extension Phase 
In the Extension Phase, subjects who are receiving study drug at the end of the Treatment 
Phase will continue to receive drug treatment at the same dose and according to the Dosing 
Schedule described in Section 9.4.1.1.  
In the Treatment and Extension phases, subjects will undergo disease assessments every 
6 weeks in the case of solid tumors and 12 weeks in the case of lymphomas, and will 
discontinue study drug at the time of confirmed disease progression (per iRECIST or 
LYRIC), disappearance or nonavailability of any injectable lesions, development of 
unacceptable toxicity, subject request, withdrawal of consent, termination of the study 
program, pregnancy, or investigator decision.  
An off-treatment assessment should occur within 30 days after the final dose of study 
treatment.  
Subjects who are continuing to derive clinical benefit in the view of the investigator at the 
time of study termination by the sponsor, can continue to be treated with E7766 after 
discussion with the sponsors.
9.1.3.4
Follow-Up Phase
The Follow-Up Phase will begin immediately after the off-treatment assessments have been 
completed and will continue for up to 2 years or until study subject is deceased, or until the 
completion of the primary analysis, whichever is earlier, unless the subject withdraws 
consent or until the sponsor terminates the study. 
Subjects who discontinue study treatment before disease progression will continue to 
undergo disease assessment every 6 weeks in case of solid tumors and 12 weeks in case of 
lymphomas until documentation of disease progression or start of another anticancer therapy.
Subjects will be followed every 12 weeks (±1 week) 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.  
Survival follow-up will be conducted in person or via phone call.
In the Follow-Up Phase, subjects will be treated by the investigator according to the 
prevailing local standard of care.






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3. Life expectancy ≥12 weeks.
4. Subjects with solid tumors or lymphomas, confirmed by available histopathology records 
or current biopsy, that are advanced, nonresectable, or recurrent and progressing since 
last antitumor therapy, and for which no alternative standard therapy exists.
5. Subjects must have a minimum of one injectable lesion which is also accessible for 
biopsy, and if available, one other measurable lesion also accessible for biopsy.
An injectable lesion is defined as being measureable (defined below) with a maximum of 
3.0 cm longest diameter, accessible for injection as judged by the investigator, and has 
not been subjected to any prior intratumoral treatment or radiotherapy.  Lesions selected 
for injection must not be too close to a major vessel, as judged by the investigator, and 
not be associated with increased risk of bleeding, eg, subcapsular liver lesions or 
hypervascular tumors.  
Measurable lesions are:
a.
Solid tumors:  At least 1 lesion of ≥1 cm by longest axial diameter or ≥1.5 cm short 
axis diameter if a nodal lesion, which is serially measurable according to modified
RECIST 1.1 using CT/MRI or photography.  Lesions that have had external beam 
radiotherapy or locoregional therapies such as radiofrequency ablation must show 
evidence of progression to be deemed a target lesion (Appendix 1, Appendix 2).
b.
Lymphoma:  At least 1 lymph node with a longest diameter >1.5 cm or an extranodal 
lesion with a longest diameter >1.0 cm (Appendix 3).
6. Prior anticancer therapy such as chemotherapy, immunotherapy (eg, tumor vaccine, 
cytokine, checkpoint inhibitors), or investigational drugs, or any vaccine must have been 
completed at least 4 weeks before study drug administration, and all AEs must have 
either returned to baseline or stabilized.  Subjects with prior immunotherapy known to 
have experienced severe nontolerable toxicities attributed to drug should be excluded.
7. Prior definitive radiation therapy must have been completed at least 6 weeks and prior 
palliative radiotherapy at least 2 weeks before study drug administration. 
Radiopharmaceuticals (eg, strontium, samarium) must be at least 8 weeks before study 
drug administration.
8. Immunosuppressive doses of systemic medications, such as steroids or absorbed topical 
steroids (doses >10 mg/day prednisone or equivalent) must have been discontinued at 
least 4 weeks before study drug administration.
9. Subjects with prior Hepatitis B or C are eligible if they have adequate liver function as 
defined by Inclusion Criterion #13.
10. Left ventricular ejection fraction (LVEF) >50% or within normal limits per institutional 
practice, on echocardiography or multigated acquisition (MUGA) scan.
11. 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 4]).


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12. Adequate bone marrow function: 
a.
Absolute neutrophil count (ANC) ≥1000/mm3 (≥1.0 × 103/μL)
b. Platelets ≥75,000/mm3 (≥75 × 109/L)
c.
Hemoglobin ≥9.0 g/dL
13. Adequate liver function defined by: 
a.
Adequate blood coagulation function as evidenced by an International Normalized 
Ratio (INR) ≤1.5
b. Total bilirubin ≤1.5 × ULN except for unconjugated hyperbilirubinemia or Gilbert’s 
syndrome
c. Alkaline phosphatase (ALP), ALT, and AST ≤3 × ULN (in the case of liver 
metastasis ≤5 × ULN) unless there are bone metastases. Subjects with ALP values 
>3 × ULN and known to have bone metastases can be included.
14. Willing and able to comply with all aspects of the protocol.
15. Provide written informed consent prior to any study-specific screening procedures.
9.3.2
Exclusion Criteria
Subjects with 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 5) or a documented history of 
autoimmune disease, except for subjects with vitiligo or resolved childhood asthma/atopy.
3. Known human immunodeficiency virus (HIV) infection.
4. Active infection requiring therapy, including known positive tests for Hepatitis B surface 
antigen or Hepatitis C ribonucleic acid (RNA).
5. Major surgery within 4 weeks before the first dose of study drug.
6. Concurrent medical condition requiring the use of immunosuppressive medications or 
immunosuppressive doses of systemic medications, such as steroids or absorbed topical 
steroids (doses >10 mg/day prednisone or equivalent).
7. Brain metastases that are untreated or in the posterior fossa or involve the meninges.  
Subjects with stable or progressing brain metastases (except in the posterior fossa or 
involving the meninges) previously treated with brain stereotactic radiotherapy (SRT), 
whole-brain radiotherapy (WBRT) and/or surgery are allowed as long as the subject is 
asymptomatic neurologically and does not require immediate local intervention 
(radiotherapy and/or surgery).  In addition, subjects must be off immunosuppressive 
doses of systemic steroids (>10 mg/day prednisone or equivalent) for at least 4 weeks 
before study drug administration.
8. Prolongation of corrected QT (QTcF) interval to >450 msec for males and females, when 
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9. 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).
10. Subjects on oral anticoagulants including low dose aspirin.  To meet eligibility, these 
subjects can be switched to receive preventive dose of low molecular weight heparin 
(LMWH).  It is recommended that their LMWH treatment is stopped 24 hours before the 
intratumoral injection and resumed again 24 hours after the injection.
11. 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.
12. Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a 
positive beta-human chorionic gonadotropin [ß-hCG] (or human chorionic gonadotropin 
[hCG]) test with a minimum sensitivity of 25 IU/L or equivalent units of ß-hCG [or 
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.
13. Females of childbearing potential must not have had unprotected sexual intercourse 
within 30 days before study entry and must agree to use a highly effective method of 
contraception (total abstinence [if it is their preferred and usual lifestyle], a contraceptive 
implant, an oral contraceptive, or have a vasectomized partner with confirmed 
azoospermia) throughout the entire study period and for 180 days after study drug 
discontinuation. For sites outside of the EU, it is permissible that if a highly effective 
method of contraception is not appropriate or acceptable to the subject, then the subject 
must agree to use a medically acceptable method of contraception, ie, double barrier 
methods of contraception such as condom plus diaphragm or cervical/vault cap with 
spermicide. If currently abstinent, the subject must agree to use a highly effective 
method as described above if she becomes sexually active during the study period or for 
180 days after study drug discontinuation. Females who are using hormonal 
contraceptives must have been on a stable dose of the same hormonal contraceptive 
product for at least 28 days before dosing and must continue to use the same 
contraceptive during the study and for 180 days after study drug discontinuation.
14. Male subjects who are partners of women of childbearing potential must use a condom 
and spermicide and their female partners if of childbearing potential must use a highly 
effective method of contraception (see methods described above in Exclusion 
Criterion #13) beginning at least 1 menstrual cycle prior to starting study drug(s), 
throughout the entire study period, and for 180 days after the last dose of study drug, 
unless the male subjects are totally sexually abstinent or have undergone a successful 
vasectomy with confirmed azoospermia or unless the female partners have been sterilized 
surgically or are otherwise proven sterile.  No sperm donation is allowed during the study 
period or for 180 days after study drug discontinuation.






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9.4.1.2
Dose Adjustments
E7766 Dose Adjustments
In the Dose Escalation part, dose adjustments may be allowed at the discretion of the 
investigator after discussion with the sponsors.  Subject may be allowed to continue study 
drug at a reduced dose, if this is judged to be in their best interest.  E7766 dose reductions 
and interruptions should be carried out as outlined in Table 4.
Guidelines for dose adjustments after Cycle 1
E7766 dose reduction and interruption for subjects who experience therapy-related toxicity
(as assessed by the investigator) will be in accordance with the dose modification guidelines 
described in Table 4.  

Subjects who experience toxicities that could have been qualified as DLTs may, at the 
discretion of the investigator and after discussion with the sponsors, be allowed to 
continue study drug at a reduced dose according to these dose modification guidelines, 
if this is judged to be in their best interest.
For subjects who require dose interruption due to E7766-related toxicity in Cycle 2 or 
beyond, the treatment may re-start once the toxicity has been resolved to Grade ≤1 or 
baseline according to the dose reduction and interruption instructions in Table 4.
Table 4
E7766 Dose Reduction and Interruption Instructions
E7766-Related Toxicitya
During Therapy
Approximate Dose Adjustment
Grade 1
All occurrences
Continue E7766 treatment.  
If CRS, then interrupt E7766 
until Grade 0.
Maintain dose level.
Grade 2b
1st occurrence
Interrupt E7766 until resolved to 
Grade ≤1 or baseline.  
If CRS, then interrupt E7766 
until Grade 0c.
Maintain dose level.  
If CRS, consider dose reduction.
2nd occurrence 
(same toxicity)
Interrupt E7766 until resolved to 
Grade ≤1 or baseline.  
If CRS, then interrupt E7766 
until Grade 0c.
Consider reduction by 1 dose level of starting 
dose, if dose delayed.  
If CRS, then consider further dose reduction.
3rd occurrence 
(same toxicity)
Interrupt E7766 until resolved to 
Grade ≤1 or baselinec.  
If CRS, then discontinue E7766.
Reduce by 1 or 2 dose levels of starting dose, 
if appropriate.
4th occurrence 
(same toxicity)
Interrupt E7766 until resolved to 
Grade ≤1 or baselinec.
Discuss with sponsors.
Grade 3b
1st occurrence
Interrupt E7766 until resolved to 
Grade ≤1 or baselinec.  
If CRS, then discontinue E7766.
Reduce by 1 dose level of starting dose


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2nd occurrence 
(same toxicity)
Interrupt E7766 until resolved to 
Grade ≤1 or baselinec.
Reduce by 2 dose levels of starting dose
3rd occurrence 
(same toxicity)
Discontinue E7766 treatment
Not applicable
Grade 4d:  Discontinue E7766
For grading, see Common Terminology Criteria for Adverse Events (CTCAE v. 5.0)
a:  Excluding alopecia, anemia, lymphocytopenia, and asymptomatic neutropenia.  Initiate optimal medical 
management for nausea, vomiting, diarrhea, and/or fever before any E7766 interruption or dose reduction. 
b:  Applicable only to those Grade 2 toxicities judged by the subject and physician to be intolerable and to all 
Grade 3 toxicities.
c:  Interruption of E7766 treatment for more than 21 days (due to E7766-related toxicities) will require a 
discussion with the sponsors before treatment can be resumed.
d:  Excluding laboratory abnormalities judged to be non-life-threatening, in which case manage as Grade 3.
9.4.1.3
Intratumoral Injection
Lesions selected for injection must be at least 1.0 cm for solid tumors, and >1.5 cm for 
lymphoma in the longest diameter, so as to be measureable by RECIST (solid tumors) or 
Lugano criteria (lymphoma). The maximum size of any injected lesion is 3.0 cm in the 
longest diameter for both solid tumors and lymphoma.  Lymph nodes for injection must be at 
least 1.5 cm in the short axis for solid tumors and >1.5 cm in the longest diameter for 
lymphoma. 
Investigators will define which lesions are appropriate for E7766 injection.  Preference in the 
initial dose levels will be given to easier to access lesions.  Intratumoral injection approaches 
for lesions that are proximal to major vessels or those deemed to have a risk of bleeding 
should be discussed in a multidisciplinary setting with regards to safety of the approach in 
order to avoid a risk of vascular catastrophe and/or inadvertent risk of intravascular systemic 
injection.  Lesions in the vicinity of major vessels with a high risk of bleeding (eg, the 
common, internal or external carotid arteries or their branches), or other situations with a risk 
of vascular catastrophe such as tumor-encased large vessels, subcapsular liver lesions, 
hypervascular tumors, lesions that have been previously irradiated, lesions with macroscopic 
intravascular tumor invasion (eg, liver lesions with tumor infiltration into the main portal 
vein, hepatic vein or vena cava) should be excluded from intratumoral injection.  To avoid 
potential risk of bleeding and systemic exposure, Doppler ultrasound guidance is
recommended for intratumoral injections with E7766 to ensure that the injection is not 
carried out within a vessel (Marabelle, et al., 2018).  Lesions selected for injections must not 
have been subjected to any prior intratumoral therapy.
Local (at site of injection) plus or minus systemic analgesic treatments should be anticipated 
and are recommended to be initiated at least 30 minutes before undertaking intratumoral 
injection procedure. Skin analgesia at the site of injection can be administered using topical 
xylocaine (4%) or other local anaesthetic agents. The options for systemic analgesia are 
recommended to include the full range of analgesia from paracetamol/acetaminophen to 
opioids, depending on the precise details of the procedure and the subject’s underlying 
symptoms (Marabelle, et al., 2018).


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The same lesion will be injected at each administration.  In the event that the injected lesion 
shrinks and/or is no longer injectable (ie, no longer accessible, not appropriate for injection, 
or for other reasons), additional lesions may also be considered for injection and the same 
guidance for injection of these lesions will apply in terms of accessibility, injectability, and 
follow-up.  The sequence of lesion selection for injection should be agreed in advance by the 
investigator and treating team.  If no other injectable lesions are available, treatment will 
stop.
Additional guidance for direct and ultrasound/CT guided injection will be provided in a 
separate manual.
9.4.1.4
Management of Cytokine Release Storm 
Cytokine release storm (CRS) has been identified as a potential safety risk in 
immunotherapies, especially drugs that act as agonists for immune activation. Guidance for 
identification and management is provided in Table 5. IL-6 will be assessed by the site as 
clinically indicated. For E7766 dose adjustments and interruptions for the management of 
CRS, refer to Table 4.
Table 5
Management of Cytokine Release Storm and Organ Toxicity
CRS Grade
(CTCAE)
Sign/Symptom
Management 
Grade 1
Fever or Grade 1
organ toxicity
Acetaminophen and hypothermia blanket as needed for fever
Ibuprofen if fever is not controlled with above; use with caution or avoid if 
thrombocytopenic
Assess for infection with blood and urine cultures, and chest x-ray
Consider antibiotics and filgrastim (if neutropenic)
IV fluids as needed
Symptomatic management of constitutional symptoms and organ toxicities
Consider IL-6 antagonist1 for persistent (greater than 3 days) or refractory fever
Grade 2
Hypotension
IV fluid bolus of 500 – 1,000 mL normal saline; repeat as necessary to maintain 
SBP greater than 90 mmHg
Consider IL-6 antagonist1 for hypotension refractory to fluid boluses
If hypotension persists after two fluid boluses and IL-6 antagonist1, start 
vasopressors, transfer patient to ICU, and obtain ECHO
In patients at high-risk for severe CRS2, if hypotension persists after IL-6 
antagonist1, if there are signs of hypoperfusion3 or if there is rapid deterioration in 
the opinion of the clinician, may use dexamethasone 10 mg IV every 6 hours
Manage fever and constitutional symptoms as in Grade 1 CRS
Hypoxia
Use supplemental oxygen as needed
Use IL-6 antagonist1 with or without corticosteroids as in hypotension
Manage fever and constitutional symptoms as in Grade 1 CRS
Grade 2
organ toxicity
Manage organ toxicity as per standard guidelines 
Use IL-6 antagonist1 with or without corticosteroids as in hypotension
Manage fever and constitutional symptoms as in Grade 1 CRS
Grade 3
Hypotension
IV fluid boluses as needed as in Grade 2 CRS 
IL-6 antagonist1 as in Grade 2 if not administered previously
Use vasopressors as needed 
Transfer patient to ICU and obtain ECHO if not performed already
Start dexamethasone 10 mg IV every 6 hours; increase to 20 mg IV every 6 hours 


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if refractory
Manage fever and constitutional symptoms as in Grade 1 CRS
Hypoxia
Use supplemental oxygen including high-flow oxygen delivery and non-invasive 
positive pressure ventilation
Use IL-6 antagonist1, corticosteroids as above and supportive care
Grade 3
organ toxicity or 
Grade 4 increased 
transaminases
Manage organ toxicity as per standard guidelines 
Use IL-6 antagonist1, corticosteroids as above and supportive care 
Manage fever and constitutional symptoms as in Grade 1 CRS
Grade 4
Hypotension
IV fluids, IL-6 antagonist1, vasopressors, and hemodynamic monitoring as in 
Grade 3
High-dose methylprednisolone1
Manage fever and constitutional symptoms as in Grade 1
Hypoxia
Mechanical ventilation
Use IL-6 antagonist1, high-dose methylprednisolone1 and supportive care
Grade 4
organ toxicity,
excluding
increased 
transaminases
Symptomatic management of organ toxicity as per standard guidelines
Use IL-6 antagonist1, high-dose methylprednisolone1 and supportive care
CRS = cytokine release storm, CTCAE = Common Terminology Criteria for Adverse Events, ECHO = 
echocardiogram, ICU = intensive care unit, IL-6 = interleukin 6, IV = intravenous, SBP = systolic blood 
pressure.
1  See Appendix 6 for Interleukin-6 Antagonist and Corticosteroid Dosing Tables.
2  High risk for CRS includes any of the following:
-
High tumor burden 
-
Early onset CRS (less than 3 days from cell infusion)
-
Co-morbidities (a score of 3 or greater using the Hematopoietic Cell Transplantation Comorbidity 
Index; for solid tumor patients – prior solid tumor will not be counted)
3  Signs of hypoperfusion include:
-
Decreased urine output (less than 0.5 mL/kg/hour)
-
Lactate greater than or equal to 4 mmol/L, rising lactate, and/or poor lactate clearance (less than 10%) 
despite adequate fluid resuscitation.
Source: Adapted from MD Anderson Cancer Center CAR cell therapy toxicity assessment and management 
protocol (Teachey, et al., 2016; MD Anderson Cancer Center, 2017).
9.4.2
Identity of Investigational Product(s)
9.4.2.1
Chemical Name, Structural Formula of E7766
Standard Text

Test drug code:  E7766

Generic name:  N/A

Chemical name:  (1R,3R,15E,28R,29R,30R,31R,34R,36R,39S,41R)-29,41-Difluoro-
34,39-bis(sulfanyl)-2,33,35,38,40,42-hexaoxa-4,6,9,11,13,18,20,22,25,27-decaaza-
34λ5,39λ5-diphosphaoctacyclo [28.6.4.13,36.128,31.04,8.07,12.019,24.023,27]dotetraconta-
5,7,9,11,15,19,21,23,25-nonaene-34,39-dione diammonia 


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
Molecular formula:  C24H26F2N10O8P2S2･2NH3

Molecular weight:  780.66 (746.60, Free Acid)
9.4.2.2
Comparator Drug
Not applicable.
9.4.2.3
Labeling for Study Drug
E7766 will be labeled in accordance with text that is in full regulatory compliance with each 
participating country and will be 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.
9.4.3
Method of Assigning Subjects to Treatment Groups
This is an open-label, single-arm study.  All subjects who provide signed informed consent to 
participate in this study and satisfy all eligibility requirements (see Section 9.3) will be 
assigned to receive E7766.  There is no randomization in this study.
9.4.4
Selection of Doses in the Study
Refer to Section 9.2 for the rationale for FIH dose selection. 
9.4.5
Selection and Timing of Dose for Each Subject
Refer to Section 9.4.1.1 for dosing schedule for E7766.
9.4.6
Blinding
This is an open-label study; the treatment will not be blinded.




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
Systemic steroid therapy or any other form of immunosuppressive therapy.  Any such 
therapy should be stopped at least 7 days prior to the first dose of study treatment.  The 
use of physiologic doses of corticosteroids (up to 10 mg/d of prednisone or equivalent) 
may be approved after consultation with the sponsors.  

If subjects receive additional antitumor therapies, such as chemotherapy, hormone therapy, 
radiotherapy (with the exception of palliative radiotherapy as described above), or 
immunotherapy, this will be judged to represent evidence of disease progression, and study 
medication will be discontinued.  These subjects should complete all off-treatment 
assessments and continue to be followed for survival in the Follow-Up Phase.
9.4.8
Prohibitions and Restrictions During the Study Period
It is recommended that subjects should avoid prolonged exposure to sunlight, and use 
sunscreens, umbrellas, and protective long sleeved clothing to minimize sun exposure, 
pending completion of test to assess E7766’s phototoxicity potential.
Physical Activity Restrictions in subjects with Lymphoma (undergoing 18fluorodeoxyglucose
[18FDG] -positron emission tomography-CT [PET-CT] assessments):
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 with 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.  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 sponsors:

A signed and dated confidentiality agreement

A copy of the final protocol signature page, signed and dated by both the sponsors 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
CCI


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
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 Food and Drug Administration (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 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, and the Import License
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 
drugs/study supplies (dispensing, inventory, and record keeping) following the sponsors’
instructions and adherence to Good Clinical Practice (GCP) guidelines as well as local or 
regional requirements.
Under no circumstances will the investigator allow the study drugs/study supplies to be used 
other than as directed by this protocol.  Study drugs/study supplies 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 
drugs/study supplies, dispensing of study drugs/study supplies to the subject, collection and 
reconciliation of unused study drugs/study supplies that are either returned by the subjects or 
shipped to site but not dispensed to subjects, and return of reconciled study drugs/study 
supplies to the sponsor or (where applicable) destruction of reconciled study drugs/study 
supplies at the site.  This includes, but may not be limited to:  (a) documentation of receipt of 
study drugs/study supplies, (b) study drugs/study supplies dispensing/return reconciliation 
log, (c) study drugs/study supplies 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 drugs/study supplies 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 drugs/study supplies and 
empty and partially empty containers from used study drugs/study supplies 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 


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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 drugs/study supplies and containers 
at the site.  Destruction at the site will only occur under circumstances where regulation or 
supply type prohibits the return of study drugs/study supplies 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 drugs/study supplies that 
are to be returned to the sponsor’s designated central or local depot(s) must be boxed, sealed,
and shipped back to the central or local depot(s) following all local regulatory requirements. 
In some regions, study drugs/study supplies may be removed from the site and hand 
delivered to the central or local depot by sponsor representatives.  Where study drugs/study 
supplies 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.
9.5
Study Assessments
9.5.1
Assessments
9.5.1.1
Demography
Subject demography information will be collected at the Screening Visit.  Demography 
information includes date of birth (or age), sex, race/ethnicity.
9.5.1.2
Baseline Assessments
9.5.1.2.1
MEDICAL HISTORY AND PHYSICAL EXAMINATIONS
Medical and 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).
Physical examinations (comprehensive or symptom directed) will be performed as designated 
in the Schedule of Procedures/Assessments (Table 7).  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.  
A urogenital examination will only be required in the presence of clinical symptoms related 
to this region.  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 
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Information on history of current malignancy will be collected, including tumor type and 
prior therapy, with response and duration of response for each therapy.
9.5.1.2.2
OTHER BASELINE ASSESSMENTS
Assessment of prior and concomitant medications, ECOG performance status 
echocardiogram/MUGA, 12-lead ECG, ECG Holter monitoring, pregnancy test, vital signs, 
hematology, blood chemistry, and urinalysis will be performed per the Schedule of 
Procedures/Assessments (Table 7).
9.5.1.3
Efficacy Assessments
The schedule of assessments for efficacy analysis based on tumor imaging is presented in the 
Schedule of Procedures/Assessments (Table 7) and details are described below.
9.5.1.3.1
SOLID TUMORS
Tumor assessments will be performed according to modified RECIST 1.1, followed by 
iRECIST, if appropriate. Tumor assessments will follow Eisenhauer, et al. (2009) per a
modified RECIST 1.1.  The modification allows selection of up to 10 target lesions, with up 
to 5 per organ (as opposed to a maximum of 5 target lesions, up to 2 per organ in unmodified 
RECIST 1.1). Investigator-determined response assessments will be performed at each 
assessment time point.
All tumor assessment scans and photographs will be sent to an imaging core laboratory
designated by the sponsor for quality assessment, tumor lesions volumetric assessment, and 
archival for potential independent efficacy review.
Tumor assessments at Screening:

Tumor assessments:  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. Information from the baseline scans should be used to 
complete Appendix 1 for identification, categorization, and documentation of all target 
lesions, injectable lesions, and if available, non-injected biopsy lesion. This should be 
performed in a joint multidisciplinary team approach comprising of the radiologist, 
interventional radiologist, and oncologist.  Injectable lesions should be prioritized based 
on ease of accessibility and degree of risk (eg, bleeding) involved with administration of 
E7766.
Skin lesions may be considered as target lesions if documented with color photographs 
with a millimeter ruler in the same plane as the lesion, as nontarget lesions if
photographic and measurement documentation is not available, or as new lesions if they 
meet the minimum size criteria for a measurable lesion. 
MRI scans may be used instead of CT scans for head, neck, abdomen and pelvis; 
however, chest lesions must be assessed using CT. Chest disease may not be followed 


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using chest x-ray.  The same method of assessment used at Screening must be used at 
all time points.  
Subjects with HNSCC must also have head and neck scans performed.  Historical 
standard of care scans that are performed with scanning parameters consistent with the 
requirements for the protocol within 28 days prior to dosing are acceptable.
CT scans should be performed with oral and iodinated intravenous contrast and MRI 
scans with intravenous gadolinium chelate unless there is a medical contraindication to 
contrast.  If iodinated intravenous contrast is contraindicated, chest CT should be 
performed without intravenous contrast. The method of assessment must be consistent 
at all time points.

Bone scans:  For subjects with triple-negative breast cancer and non-small cell lung 
carcinoma, or other tumor types where bone metastases are common, bone scans will be 
performed at Screening.  Lesions identified on bone scans must be verified with 
correlative cross-sectional imaging.  Cross sectional imaging will be used to follow 
response in target and nontarget lesions.

Brain MRI:  A brain MRI (pre- and post-gadolinium contrast) must be performed at 
Screening to assess potential CNS disease and/or metastases.  Subjects with 
protocol-eligible treated bone metastasis (See Exclusion Criterion #7) will be followed 
up as described below.

Biopsy:  A pretreatment biopsy will be obtained during the Screening Period (Day ˗28 
to Day ˗1) from the lesion selected for injection (mandatory), and from one prespecified 
non-injected lesion, if available (Appendix 1).
Tumor assessments during study:

CT scans for head, neck, abdomen and pelvis will be carried out every 6 weeks 
(± 7 days) counting from Cycle 1 Day 1 during treatment cycles in the Treatment Phase,
the Extension Phase, and, if the subject has discontinued treatment without confirmed 
disease progression, the Follow-Up Phase.
MRI scans may be used instead of CT scans for head, neck, abdomen and pelvis; 
however, chest lesions must be assessed using CT.  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

Bone scans:  For subjects with triple-negative breast cancer and non-small-cell lung 
carcinoma, or other tumor types where bone metastases are common, bone scans will be 
performed every 24 weeks, or sooner if clinically indicated, and at confirmation of 
response.  Lesions identified on bone scans must be verified with correlative 
cross-sectional imaging.  Cross sectional imaging will be used to follow response in 
target and nontarget lesions.

Brain MRI:  


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-
For subjects with protocol-eligible treated brain metastases (See Exclusion 
Criterion #7) detected at the Screening MRI brain, a brain scan must be performed at 
all tumor assessment time points.  
-
For all subjects, a follow-up brain scan must be performed to confirm a CR within 
1 week following response confirmation, or if clinically indicated. 
For definitions of target and nontarget lesions at Baseline, assessment of target, nontarget, 
and new lesions after Baseline, and overall tumor assessment using iRECIST, refer to 
Appendix 1 and Appendix 2.
Responses should be confirmed no less than 4 weeks following the initial response (generally 
at the next 6 weekly scheduled tumor assessment visit). 
Tumor assessments should initially proceed according to modified RECIST 1.1. 
Per iRECIST, disease progression should be confirmed by the site 4 to 8 weeks after 
site-assessed first radiologic evidence of progressive disease in clinically stable subjects. 
Subjects who have unconfirmed progressive disease per iRECIST (iUPD) may continue on 
treatment at the discretion of the investigator until progression is confirmed by the site, 
provided they have met the following conditions.
When clinically stable, participants should not be discontinued until progression is confirmed 
by the investigator, working with local radiology, according to the rules (Appendix 2). This 
allowance to continue treatment despite initial radiologic progressive disease takes into 
account the observation that some subjects can have a transient tumor flare in the first few 
months after the start of immunotherapy, and then experience subsequent disease response. 
These data will be captured in the clinical database.
Clinical stability is defined as the following:

Absence of symptoms and signs indicating clinically significant progression of disease

No decline in ECOG performance status

No requirements for intensified management, including increased analgesia, radiation, 
or other palliative care
Subjects who receive confirmatory imaging do not need to undergo the next scheduled tumor 
imaging if it is less than 4 weeks later; tumor imaging should resume at the subsequent 
scheduled imaging time point, if clinically stable. Subjects who have confirmed disease 
progression by iRECIST (for solid tumors) or LYRIC (for lymphoma), as assessed by the 
site, will discontinue study treatment. Exceptions may be discussed with the study medical 
monitor.


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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.
9.5.1.3.2
LYMPHOMA
Tumor assessments will be performed based on Lugano (Cheson, et al., 2014) followed by 
LYRIC criteria (Cheson, et al., 2016) for confirmation of disease progression, if appropriate. 
Investigator-determined response assessments will be performed at each assessment time 
point.
Tumor assessments will be carried out during the Pretreatment Phase, at Week 9 (during the 
9th week counting from Cycle 1 Day 1), and then every 12 weeks during treatment cycles in 
both the Treatment Phase and the Extension Phase. 
An 18FDG-PET-CT scans (contrast-enhanced diagnostic quality CT) of neck, 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. While diagnostic quality contrast-enhanced PET-CT is preferred, if 
contrast-enhanced images are not obtainable, noncontrast PET-CT will be acceptable. 
Historical standard of care scans that are performed with scanning parameters consistent with 
the requirements for this protocol within 28 days prior to dosing are acceptable.
Information from the baseline scans should be used to complete Appendix 1 for 
identification, categorization, and documentation of all target lesions, injectable lesions, and, 
if available, the non-injected biopsy lesion.  This should be performed in a joint 
multidisciplinary team approach comprising of the radiologist, interventional radiologist, and 
oncologist.
A pretreatment biopsy will be obtained during the Screening Period (Day ˗28 to Day ˗1) from 
the lesion selected for injection (mandatory), and from one prespecified non-injected lesion,
if available (Appendix 1).
Tumor assessments should initially proceed according to Lugano criteria (Appendix 3).
If the investigator believes that, at the time of Lugano progressive disease, a subject is 
experiencing clinical stability or improvement, they will be considered as having an immune 
response (IR), and continue to be followed according to LYRIC criteria. The subject must be 
considered likely to tolerate continued treatment and not at risk of serious complications 
should further tumor growth occur. For a subject categorized as having IR, repeat imaging is 
mandatory after an additional 12 weeks (or sooner if clinically indicated) to assess whether 
they have true progressive disease.


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9.5.1.3.3
ALL SUBJECTS
In addition to the individual lesion measurement data that will be collected for all lesions, the 
specific lesion injected at each time point/dose administration should be recorded.  In 
addition, lesions that are biopsied should be recorded as such (at the time point) to allow 
evaluation of exploratory efficacy endpoints such as the effect on injected versus
non-injected lesions.
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Assessments
9.5.1.4.1
PHARMACOKINETIC ASSESSMENTS
Samples of blood, urine, and feces for PK analyses will be collected as described in the 
Schedule of Procedures/Assessments.
E7766 in plasma, urine, and feces will be determined using validated LC-MS/MS assays. If 
appropriate, assay of plasma, urine and feces samples for any metabolites of E7766 may be 
explored.  Instructions on PK sample collection, handling, storage, and shipment will be 
detailed in the study-specified Laboratory Manual to be provided to the site.
Blood, urine, and fecal samples may also be used for exploratory analysis of metabolites.
Blood will also be drawn where possible at the first report of a serious adverse event (SAE) 
or severe unexpected AE and at its resolution.
9.5.1.4.2
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ASSESSMENTS
Overview of Biomarker Approach
Pharmacodynamics biomarkers of E7766 include POM biomarkers and Proof of Principle 
(POP) biomarkers, which will be measured to evaluate modulation of the STING pathway 
and of both innate and adaptive immune response, respectively, by E7766 treatment in 
human subjects.  

To measure the STING pathway modulation, expression of a panel of STING pathway 
genes by E7766 will be examined as part of immune gene profiling in the tumor 
biopsies and in the blood.  

To measure the innate and adaptive immune response, immune gene profiling will be 
performed for the available tumor biopsies and for the blood.  Immune cytokines and 
immune cell phenotyping may be analyzed in the blood as well.  
Results from the pharmacodynamics biomarker studies may be used to aid the selection for 
the RP2D and to monitor drug biological activity.  Blood and tumor tissue samples will be 
collected from study subjects at protocol-specified time points as indicated in the Schedule of 
Procedures/Assessments (Table 7).  It is worthy to note that when new research results 


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emerge, the parameters and methods for the pharmacodynamics biomarker analysis may 
change. 
Instructions for the processing, storage, and shipping of samples will be provided in the 
Laboratory Manual.
Biomarker sample collection:
Mandatory paired pre- and on-treatment tumor biopsies will be obtained from injected and, if 
available, from one non-injected lesion, with appropriate subject consent, to examine the 
potential intratumoral STING pathway modulation and antitumor immune response 
enhancement upon E7766 treatment at both local and systemic levels. These markers may 
include a panel of E7766-regulated STING pathway genes, including IFN1, type I IFN 
genes, TNF, and IL6, and immune activation genes such as granzyme B, perforin, and 
IFNy. Immune cell infiltration and T-cell repertoire may also be investigated. Mandatory 
on-treatment tumor biopsy will be performed on Day 1 of Cycle 2, on the day of drug 
administration. Subjects should have the biopsy with the same image-guided procedure as 
E7766 injection.  The biopsy will be performed after the E7766 administration.  In the event 
that E7766 administration is delayed, the biopsy time will be moved as well, to coincide with 
drug administration.
In the event that a subject is required to have additional tumor biopsy(s) for medically 
indicated reasons while on study, formalin-fixed paraffin-embedded (FFPE) tissue will be 
requested for shipment for exploratory biomarker analysis.
Blood biomarkers:
Blood biomarker samples from study subjects may be analyzed for immune cytokine 
expression monitoring by ELISA, multiplex bead-based immunoassay, or other 
assays/methods and new technology. Whole blood (peripheral blood mononuclear cell 
[PBMC]) may be subjected to immune gene expression profiling and flow cytometric 
analysis as well. Blood biomarker samples will be collected both prior to the first 
administration and during the treatment process.
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 
their relationship with tumor response to E7766.
Pharmacogenetic (PG) Assessment:
Whole blood DNA and RNA samples will be collected for STING genotype and gene 
expression analyses, respectively. The DNA samples may be utilized also for PG analysis. 
The role of DNA sequence variability on the absorption, distribution, metabolism, and 


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elimination (ADME) of E7766 may be evaluated in this study. Variation in E7766 exposure 
or the occurrence of AEs observed in the study population may be evaluated by correlation of 
single–nucleotide polymorphisms with PK, safety, or pharmacodynamics data.
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 E7766 or cancers, and for potential diagnostic development.
Archived tumor tissue samples and blood samples for pharmacodynamics, 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 and/or validation to identify blood or tumor 
biomarkers that may be useful to predict treatment response (efficacy, pharmacodynamics), 
PK, and/or 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 may be based on the clinical outcome of the study and/or the 
signals observed in other clinical studies.
Further details are provided in Appendix 8.
Exploratory Imaging Biomarkers
Tumor volume (3-dimensional size as opposed to measuring a single diameter) changes (per 
independent imaging review) as assessed using all CT/MRI scans will also be explored as a 
continuous variable.
Time course changes in pre-injection sizes of injected lesions per investigator assessment 
will be evaluated.  The assessment should be performed using the same modality of 
radiological guidance that will be used for the E7766 injection (for example, USG, CT, or 
MRI, or for superficial lesions, photography, calipers, or ruler).  
9.5.1.5
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs, including all CTCAE 
v 5.0 grades (for both increasing and decreasing severity), and SAEs; regular monitoring of 
hematology, blood chemistry, and urine values; periodic measurement of vital signs, 
ECHO/MUGA scans, safety ECGs; and physical examinations.  The effects of E7766 on 
cardiac repolarization will be evaluated via continuous Holter/ECG monitoring.


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9.5.1.5.1
ADVERSE EVENTS
An adverse event (AE) is any untoward medical occurrence in a patient or clinical 
investigation subject administered an investigational product.  An AE does not necessarily 
have a causal relationship with the medicinal product.  For this study, the study drug is 
E7766.
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.

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, regardless of relationship to study drug or procedure, should be recorded beginning 
from the time the subject signs the study ICF through the last visit and for 90 days after the 
subject’s last dose or start day of another anticancer therapy, whichever is earlier.  If the 
subject initiates new anticancer therapy within 30 days, then AEs must be collected for 
30 days following the last dose of E7766.  SAEs will be collected for 90 days after the last 
dose or start day of another anticancer therapy, whichever is earlier.  If the subject initiates 
new anticancer therapy within 30 days, then SAEs must be collected for 30 days following 
the last dose of E7766.  All AEs should be recorded in the Adverse Event CRF.
Abnormal laboratory values should not be listed as separate AEs if they are considered to be 
part of the clinical syndrome that is being reported as an AE.  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. 


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Abnormal ECG (QTcF) results, if not otherwise considered part of a clinical symptom that is
being reported as an AE, should be considered an AE if the QTcF 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 90 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, 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 v 5.0.  Investigators 
will report CTCAE grades for all AEs (for both increasing and decreasing severity).  
The criteria for assessing severity are different than those used for seriousness (see
Section 9.5.1.5.2 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
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?


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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.
9.5.1.5.2
SERIOUS ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
An 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 inpatient 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. 
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.
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 for respite care 

Planned hospitalizations required by the protocol

Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed after 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 
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If possible, a blood sample for the measurement of study drug plasma concentration should 
be drawn at the first report of an SAE or a severe unexpected AE and at its resolution.
9.5.1.5.3
LABORATORY MEASUREMENTS
Clinical laboratory tests to be performed, including hematology, chemistry, and urinalysis, 
are summarized in Table 6.  Subjects should be in a seated or supine position during blood 
collection.  The Schedule of Procedures/Assessments (Table 7) shows the visits and time 
points at which blood for clinical laboratory tests and urine for urinalysis will be collected in 
the study.
Table 6
Clinical Laboratory Tests
Category
Parameters
Hematology
Hematocrit, hemoglobin, platelets, RBC count, and WBC count 
with differential (bands, basophils, eosinophils, lymphocytes, 
monocytes, neutrophils)
Chemistry
Electrolytes
Chloride, potassium, sodium 
Liver function tests
Alanine aminotransferase, alkaline phosphatase, aspartate 
aminotransferase, gamma glutamyl transpeptidase, direct bilirubin, 
total bilirubin, International Normalized Ratio (INR)
Renal function tests
Blood urea/blood urea nitrogen, creatinine
Other
Albumin, calcium, cholesterol, globulin, glucose, lactate 
dehydrogenase, phosphorus, total protein, triglycerides, uric acid
Urinalysis
Bacteria, casts, crystals, epithelial cells, glucose, ketones, occult 
blood, pH, protein, RBCs, specific gravity, WBCs
RBC = red blood cell, WBC = white blood cell.
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. Refer to 
Table 4 for the management of clinically significant laboratory abnormalities.
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 9.5.1.5.1 and the CRF Completion Guidelines).  In these instances, the 
AE corresponding to the laboratory abnormality will be recorded on the Adverse Event CRF.
9.5.1.5.4
VITAL SIGNS AND WEIGHT MEASUREMENTS
Vital sign measurements (ie, systolic and diastolic blood pressure [BP] [mmHg], pulse [beats 
per minute], respiratory rate [per minute], body temperature [in centigrade]), height, and 
weight (kg) will be obtained at the visits designated in the Schedule of Procedures/
Assessments (Table 7) by a validated method.  Blood pressure and pulse will be measured 


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after the subject has been sitting for 5 minutes.  All BP measurements should be performed 
on the same arm, preferably by the same person. 
For subjects with an elevated BP (≥140/90 mmHg), confirmation should be obtained by 
performing 3 measurements (at least 5 minutes apart) to yield a mean value.  Systolic BP
≥160 mmHg or diastolic BP ≥100 mmHg should be confirmed by repeat measurements after 
1 hour.
9.5.1.5.5
PHYSICAL EXAMINATIONS
Comprehensive or system-directed physical examination will be performed as designated in 
the Schedule of Procedures/Assessments (Table 7).  Documentation of the physical 
examination will be included in the source documentation at the site.  Only changes from 
screening physical examination findings that meet the definition of an AE will be recorded 
on the Adverse Event CRF.
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.  A urogenital examination will only be required in the presence of 
clinical symptoms related to this region.  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.
9.5.1.5.6
ELECTROCARDIOGRAMS
Electrocardiograms will be obtained as designated in the Schedule of Procedures
/Assessments (Table 7).  Complete, standardized, 12-lead ECG recordings that permit all 
12 leads to be displayed on a single page with an accompanying lead II rhythm strip below 
the customary 3 × 4 lead format are to be used.  In addition to a rhythm strip, a minimum of
3 full complexes should be recorded from each lead simultaneously.  Subjects must be in the 
recumbent position for a period of 5 minutes prior to the ECG.
An ECG abnormality may meet the criteria of an AE as described in this protocol (see
Section 9.5.1.5.1) and the CRF Completion Guidelines.  In these instances, the AE 
corresponding to the ECG abnormality will be recorded on the Adverse Event CRF.
Additionally, QTc intervals will be evaluated in the Dose Escalation part only, unless a signal
indicates the need for continued monitoring in the Dose Expansion part.  
The effects of E7766 on cardiac repolarization will be evaluated via 24-hour, 12-lead 
continuous Holter/ECG monitoring during Baseline, Cycle 1 Day 1, Cycle 1 Day 14, and 
Cycle 1 Day 15 in the Dose Escalation part of the study only. Additionally, cardiodynamic 
evaluation, including concentration-QTc (C-QTc) analysis will be performed in the Dose 
Escalation part only, unless a signal indicates the need for continued monitoring in the Dose 
Expansion part. For this purpose, replicate 12-lead ECGs will be extracted from 24-hour 


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continuous recordings (Holters) by a central ECG laboratory at time points, as detailed in the 
Schedule of Procedures/Assessments (Table 7). QT intervals will be measured from Lead II 
and will be corrected for QTc using Fridericia’s correction factors (QTcF). The primary QTc 
parameter will be QTcF. Secondary parameters (heart rate, PR interval and QRS) and 
treatment-emergent T wave abnormalities and U-waves will be evaluated.  Potential effects 
of E7766 will be evaluated as change-from predose baseline heart rate, PR interval, QRS,
and QTcF by postdosing time point. For purposes of QT assessment, concentration-QTc 
analysis will be performed of the relationship between E7766 plasma levels and ΔQTcF.
9.5.1.5.7
ECHO/MUGA
A MUGA scan (using technetium-99m-pertechnetate) or an ECHO to assess LVEF will be 
performed as indicated in Schedule of Procedures/Assessments (Table 7).  MUGA and 
ECHO scans should be performed locally in accordance with the institution’s standard 
practice.  MUGA scans are the preferred modality; however, whichever modality is used for 
an individual subject at Baseline should be repeated for all subsequent LVEF assessments for 
that subject. The LVEF as assessed by the institution will be entered onto the CRF.  
Investigator assessment will be based upon institutional reports.  
9.5.1.5.8
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 at Screening.  A 6-mL sample of 
blood will be taken at designated time points as specified in the Schedule of Procedures/
Assessments (Table 7).  Subsequent to the serum pregnancy test at Screening, a urine or 
serum pregnancy test can be performed at subsequent time points as specified in the Schedule 
of Procedures/Assessments (Table 7).
9.5.1.5.9
ASSESSMENT OF CYTOKINES
In preclinical studies, intratumorally or subcutaneously administered E7766 upregulated 
expression of certain cytokines in the blood, suggesting a possibility of inducing CRS in 
patients who will receive E7766 treatment. 
In case a CRS-like symptoms occur, tocilizumab (anti-IL6R) and other treatment as per 
standard practice at the study sites may be given to the subjects according to the recent 
successful outcome in the CART clinical study (Teachey, et al., 2016; MD Anderson Cancer 
Center, 2017) (Table 5).
9.5.2
Schedule of Procedures/Assessments 
9.5.2.1
Schedule of Procedures/Assessments
Table 7 presents the schedule of procedures and assessments for the E7766-G000-101 study.
















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9.5.2.2
Description of Procedures/Assessments Schedule
Refer to Schedule of Procedures/Assessments in Table 7 and footnotes therein for description 
of procedures.
9.5.3
Appropriateness of Measurements
All clinical assessments are standard measurements commonly used in studies of oncology 
studies.  
The safety assessments to be performed in this study, including hematology analyses, blood 
chemistry tests, urinalysis, and assessment of AEs, are standard evaluations to ensure subject 
safety.
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events Associated 
with Special Situations
9.5.4.1
Reporting of Serious Adverse Events
All SERIOUS ADVERSE EVENTS, regardless of their relationship to study treatment, 
must be reported on a completed SAE form by email or fax as soon as possible but no 
later than 1 business day from the date the investigator becomes aware of the event.
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 90 days after the subject’s last dose or start day of another anticancer therapy, 
whichever is earlier.  If the subject initiates new anticancer therapy within 30 days, then 
SAEs will be collected for 30 days following the last dose of E7766.  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.


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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 
sponsors or third party vendor acting on behalf of the sponsors to be filed in the sponsor’s 
Trial Master File.
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through Breastfeeding
Any pregnancy in a female subject (or partner of a male subject) in which the estimated date 
of conception is either before the last visit or within 30 days of last study treatment, or any 
exposure to study drug through breastfeeding during study treatment or within 30 days of last 
study treatment, must be reported.
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 (see Reporting of Serious Adverse Events 
[Section 9.5.4.1]).
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.


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9.5.4.3
Reporting of Events Associated With Special Situations
9.5.4.3.1
REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE,
MISUSE, ABUSE, OR MEDICATION ERROR
Adverse events associated with study drug overdose, misuse, abuse, and medication error 
refer to AEs associated with uses of the study drug outside of that specified by the protocol.  
Overdose, misuse, abuse, and medication error are defined as follows:
Overdose
Accidental or intentional use of the study drug in an amount higher 
than the protocol-defined dose
Misuse
Intentional and inappropriate use of study drug not in accordance with 
the protocol
Abuse
Sporadic or persistent intentional excessive use of study drug 
accompanied by harmful physical or psychological effects
Medication error
Any unintentional event that causes or leads to inappropriate study 
drug use or subject harm while the study drug is in the control of site
personnel or the subject
All AEs associated with overdose, misuse, abuse, or medication error should be captured on 
the Adverse Event CRF and also reported using the procedures detailed in Reporting of 
Serious Adverse Events (Section 9.5.4.1) even if the AEs do not meet serious criteria.  Abuse 
is always to be captured as an AE.  If the AE associated with an overdose, misuse, abuse, or 
medication error does not meet serious criteria, it must still be reported using the SAE form 
and in an expedited manner but should be noted as nonserious on the SAE form and the 
Adverse Event CRF.
9.5.4.4
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.
9.5.4.5
Breaking the Blind
Not applicable.
9.5.4.6
Regulatory Reporting of Adverse Events
Adverse events will be reported by the sponsor or a third party acting on behalf of the 
sponsor to regulatory authorities in compliance with local and regional law and established 


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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.
9.5.5
Completion/Discontinuation of Subjects
A subject may elect to discontinue the study at any time for any reason.  All subjects who 
discontinue the study are to complete the study’s early discontinuation procedures indicated 
in the Schedule of Procedures/Assessments (Table 7).
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, progression of disease, withdrawal of 
consent, pregnancy, study terminated by the sponsor, or other.  In addition to the primary 
reason, the subject may indicate 1 or more secondary reason(s) for discontinuation.  Study 
disposition information will be collected on the Subject Disposition CRF.
In the Dose Escalation part only, subjects who are not evaluable for DLT (eg, those subjects 
who fail to complete at least 2 E7766 injections during Cycle 1 for reasons other than DLT 
occurrence) should be replaced within their dose level, if at least 2 subjects in total have not 
been tested at the dose level.  
9.5.6
Abuse or Diversion of Study Drug
Not applicable.
9.5.7
Confirmation of Medical Care by Another Physician
The investigator will instruct subjects to inform site personnel when they are planning to 
receive medical care by another physician.  At each visit, the investigator will ask the subject 
whether he/she has received medical care by another physician since the last visit or is 
planning to do so in the future.  When the subject is going to receive medical care by another 
physician, the investigator, with the consent of the subject, will inform the other physician 
that the subject is participating in the clinical study.


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9.6
Data Quality Assurance
This study will be organized, performed, and reported in compliance with the protocol, 
SOPs, working practice documents, and applicable regulations and guidelines.  Site audits 
may 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.
9.7
Statistical Methods
All statistical analyses will be performed by the sponsor or designee after the data cutoff date 
for the clinical study report (CSR) or the study is completed and the database is locked and 
released.  Statistical analyses will be performed using SAS software or other validated 
statistical software as required.  Details of the statistical analyses will be included in a 
separate statistical analysis plan (SAP).
9.7.1
Statistical and Analytical Plans
The statistical analyses of 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.


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9.7.1.1
Study Endpoints
9.7.1.1.1
PRIMARY ENDPOINTS

Safety-related endpoints, including DLT

ORR according to modified RECIST 1.1 and iRECIST, or Lugano and LYRIC, defined 
as the proportion of subjects achieving a best overall response of confirmed partial or 
complete response (PR + CR).  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 (Dose Expansion part only)

DOR according to modified RECIST 1.1 and iRECIST, or Lugano and LYRIC, defined 
as the time from the date of first documented PR or CR until the first documentation of 
confirmed disease progression or death, whichever occurs first (Dose Expansion part 
only)

DCR according to modified RECIST 1.1 and iRECIST, or Lugano and LYRIC, defined 
as the proportion of subjects achieving PR or CR or stable disease (SD) (Dose 
Expansion part only).
9.7.1.1.2
SECONDARY ENDPOINTS

ORR, DOR, and DCR according to iRECIST and modified RECIST 1.1, or Lugano and 
LYRIC (Dose Escalation part only)

PK profile in plasma, urine, and feces (Dose Escalation part) and plasma only (in Dose 
Expansion part)

PFS, defined as the time from the date of first dose to the date of the first documentation 
of confirmed disease progression or death, whichever occurs first

OS, defined as the time from the date of first dose to the date of death from any cause

Change in tumor size in injected lesions and in distant non-injected lesions
9.7.1.1.3
EXPLORATORY ENDPOINTS

Changes in tumor size assessed by IIR using volumetric CT/MRI

Immune pharmacodynamics effects of E7766 in the tumors and in the peripheral blood

PK/pharmacodynamics relationships (safety and efficacy endpoints)

Baseline immune phenotypes and its relationship with the response to E7766

STING genotypes and its relationship with the response to E7766

Changes in pre-injection size of injected lesion per investigator assessment
9.7.1.2
Definitions of Analysis Sets
DLT Analysis Set is the group of subjects in the Dose Escalation part who have completed 
Cycle 1, without incurring certain major protocol deviation (for instance those related to 
dosing or others identified before database lock), with at least 2 E7766 injections during 


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Cycle 1, and are evaluable for DLT, or subjects who have experienced DLT during Cycle 1.  
This will be the analysis set to evaluate tolerability. 
Full Analysis Set is the group of subjects who received at least 1 dose of study drug.  This 
will be the primary analysis set for efficacy evaluations, as well as for demographic and 
baseline characteristics. 
Safety Analysis Set is the same group as Full Analysis Set. This will be the analysis set for 
all safety evaluations except DLT results.
Efficacy Analysis Set is the group of subjects who received at least 1 dose of study drug and 
had a baseline tumor assessment.
Pharmacokinetic (PK) Analysis Set is the group of subjects who have received at least 1
dose of study drug and have at least 1 evaluable plasma concentration.
Pharmacodynamic Analysis Set is the group of subjects who have received at least 1 dose 
of study drug and have evaluable pharmacodynamics data.
Pharmacokinetic/Pharmacodynamic Analysis Set is the group of subjects in the Safety 
Analysis Set that also have evaluable serum PK and pharmacodynamics pretreatment 
assessment and at least one posttreatment assessment.
9.7.1.3
Subject Disposition
The number (percentage) of enrolled and treated subjects will be summarized as well as 
subjects who completed the study or discontinued from the study, with reasons for 
discontinuation.  The number (percentage) of subjects who completed the study 
treatment/discontinued from the study treatment and reasons for discontinuation will also be 
summarized. The summary will be presented for each dose level/arm, total of each part, and 
overall.
9.7.1.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics for the Full Analysis Set will be summarized 
for each dose level/arm, total of each part, and overall using descriptive statistics.  
Continuous demographic and baseline variables including age, weight, and height will be 
summarized and presented as N, mean, standard deviation, median, Q1, Q3, minimum, and 
maximum values.  For categorical variables such as sex, age group, race, ethnicity, 
geographic region, ECOG PS, and NYHA cardiac disease classification, the number and 
percentage of subjects will be used.
9.7.1.5
Prior and Concomitant Therapy
All investigator terms for medications recorded in the CRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary (WHO DD).  The number 


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(percentage) of subjects who took prior and concomitant medications will be summarized on 
the Full Analysis Set by Anatomical Therapeutic Chemical (ATC) class (ie, Anatomical class, 
Pharmacological class), and WHO DD preferred term.  Prior medications will be defined as 
medications that were stopped before the first dose of study drug.  Concomitant medications 
will be defined as medications that were (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 90 days after the subject’s last dose, or start day of 
another anticancer therapy, whichever is earlier.  If the subject initiates new anticancer 
therapy within 30 days, then medications given concomitantly will be recorded for 30 days 
following the last dose of E7766.  The summary will be presented for each dose level/arm, 
total of each part, and overall as appropriate. All medications will be presented in subject 
data listings.
9.7.1.6
Efficacy Analyses
Evaluations of clinical activity will be performed primarily on the Full Analysis Set. A 
summary of clinical activity on the Efficacy Analysis Set will also be provided as needed.  
The ORR, DOR, DCR, PFS (as assessed by the investigator), and OS will be listed and 
descriptively summarized as appropriate. If applicable, a waterfall plot will be presented for 
the percent changes from baseline in the sum of the diameters of target lesions at 
postbaseline nadir (ie, maximum tumor shrinkage).  The summary will be presented for each
dose level/arm, total of each part, and overall as appropriate.
The analysis using the tumor assessment by lesions, such as injected lesions and non-injected 
lesions, will be conducted separately for the selected efficacy endpoints, if appropriate.
9.7.1.6.1
PRIMARY EFFICACY ANALYSIS
Dose Escalation part:
There will be no primary efficacy analysis since the primary objective of the Dose Escalation 
part is to assess the safety/tolerability and to determine the MTD and/or RP2D. Thus, the 
efficacy analyses are described in the subsequent sections according to the study endpoints.
Dose Expansion part:

ORR will be calculated with exact 95% confidence interval (CI) using the Clopper and 
Pearson method.  A summary of best overall response will also be presented. 

DOR will be summarized using Kaplan-Meier estimates as appropriate.  Median, Q1, 
Q3, and their 95% CIs will be presented and Kaplan-Meier estimates will be plotted 
over time.  The DOR will be based on subjects achieving a best overall response of 
confirmed PR + CR.  

DCR will be calculated with exact 95% CI using the Clopper and Pearson method.


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9.7.1.6.2
SECONDARY EFFICACY ANALYSES

ORR, DOR, and DCR for the Dose Escalation part will be evaluated using same
methodology for primary analysis in the Dose Expansion part.

PFS will be summarized using Kaplan-Meier estimates.  Median, Q1, Q3, and their 
95% CIs will be presented and Kaplan-Meier estimates will be plotted over time. 
Subjects without progression of disease or death will be censored at the time of the last 
tumor assessment. 

OS will be summarized using Kaplan-Meier estimates.  Median, Q1, Q3, and their 95% 
CIs will be presented and Kaplan-Meier estimates will be plotted over time. Subjects 
who are lost to follow-up or withdrew consent will be censored at the last known alive
date, or the data cutoff date, whichever occurs first.  Subjects who remained alive will 
be censored at the time of data cutoff.  

Change in tumor size in injected lesions and in distant non-injected lesions will be 
presented using plots, such as waterfall plots/spider plots, if appropriate. 
9.7.1.6.3
EXPLORATORY EFFICACY ANALYSES

Changes in tumor size assessed by IIR using volumetric CT/MRI will be provided.

Time course changes in pre-injection sizes of injected lesions per investigator 
assessment will be presented by injected lesion/subject, if appropriate.
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Analyses
9.7.1.7.1
PHARMACOKINETIC ANALYSES
Plasma concentrations of E7766 will be tabulated and summarized by dose level, day, and 
protocol-specified time.  Urine and fecal recovery (as µg as well as percentage of dose) of 
E7766 will be tabulated and summarized by dose level, day, and protocol-specified collection 
interval.  E7766 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, terminal elimination half-life (t½), apparent body clearance (CL/F), apparent 
volume of distribution (Vd/F), renal clearance (CLr), accumulation ratio (R), and fraction 
excreted (fe) in urine and feces. Exploratory characterization/identification of metabolites in 
urine and plasma will be attempted after administration of E7766. The results will be 
presented in a separate report. PK analyses may be supported by modeling. Details of the 
PK analyses will be provided in a separate analysis plan.
Analysis variable(s):
Plasma concentrations of E7766


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Analysis set:
The Safety Analysis Set will be used for individual plasma 
concentration listings.  The Pharmacokinetic Analysis Set will be 
used for all other analyses such as the summaries of plasma 
concentrations.
Analysis methods:
Summary statistics of plasma concentrations will be obtained by visit.  
E7766 concentration data will be used to build PK models to explain 
the observed concentration data using population approach.  
Additionally, the models may be used to explore the relationship 
between PK and select demographic variables.  The relationship 
between PK and pharmacodynamics parameters and efficacy/AE 
endpoints will also be investigated through population PK/
pharmacodynamics modeling.  For population PK and PK/
pharmacodynamics analysis, the details will be described in the 
separately prepared analysis plan and its report, and the results will 
not be included in the clinical study report.
9.7.1.7.2
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ANALYSES
The effect of E7766 treatment on blood and/or tissue biomarkers, and/or immune cell subsets 
will be summarized using descriptive statistics.  Pharmacodynamic, PG, and other biomarker 
analyses will be performed and reported separately.  Details of these analyses may be 
described in a separate analysis plan and reported separately.
9.7.1.8
Tolerability/Safety Analyses
Evaluation of DLTs will be performed on the DLT Analysis Set.  The number and percentage 
of subjects with DLT will be calculated.  
All safety analyses will be performed on the Safety Analysis Set.  Safety data, presented for 
each dose level/arm, total of each part, and overall as appropriate, will be summarized on an 
“as treated” basis using descriptive statistics (eg, n, mean, standard deviation, median, Q1, 
Q3, minimum, maximum for continuous variables; n [%] for categorical variables).  Safety 
variables include treatment-emergent adverse events (TEAEs), clinical laboratory 
parameters, vital signs, 12-lead ECG results, ECOG performance status, and ECHO/MUGA 
scans.  Study Day 1 for all safety analyses will be defined as the date of the first dose of 
study drug.
9.7.1.8.1
EXTENT OF EXPOSURE
The number of cycles/days on treatment, quantity of study drug administered, and the 
number of subjects requiring dose reductions and treatment interruption will be summarized.


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9.7.1.8.2
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 21.1 or higher) lower 
level term (LLT) closest to the verbatim term.  The linked MedDRA preferred term (PT) and 
primary system organ class (SOC) are also captured in the database.
A treatment-emergent adverse event (TEAE) is defined as an AE that emerges during 
treatment (on or after the first dose of study drug up to 90 days after the subject’s last dose)
or start day of another anticancer therapy, whichever is earlier; or in case subject has initiated 
new anticancer therapy within 30 days, then AEs occurring for 30 days following the last 
dose of E7766, 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 are 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.  The incidence of TEAEs will be reported as the number 
(percentage) of subjects with TEAEs by SOC and PT.  A subject will be counted only once 
within an SOC and PT, even if the subject experienced more than 1 TEAE within a specific 
SOC and PT.  The number (percentage) of subjects with TEAEs will also be summarized by 
highest CTCAE grade.
The number (percentage) of subjects with treatment-related TEAEs will be summarized by 
SOC and PT.  Treatment-related TEAEs include those events considered by the investigator 
to be related to study treatment.  The number (percentage) of subjects with treatment-related 
TEAEs will also be summarized by highest CTCAE grade.
The number (percentage) of subjects with TEAEs leading to death will be summarized by 
MedDRA SOC and PT.  A subject data listing of all AEs leading to death will be provided.
The number (percentage) of subjects with treatment-emergent serious adverse events (SAEs) 
will be summarized by MedDRA SOC and PT.  A subject data listing of all SAEs will be 
provided.
The number (percentage) of subjects with TEAEs leading to discontinuation from study drug 
will be summarized by MedDRA SOC and PT. A subject data listing of all AEs leading to 
discontinuation from study drug will be provided.


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9.7.1.8.3
LABORATORY VALUES
Laboratory results will be summarized using Système International (SI) units, as appropriate. 
For all quantitative parameters listed in Section 9.5.1.5.3, the actual value and the change 
from baseline to each postbaseline visit and to the end of treatment (defined as the last 
on-treatment value, including off treatment assessment) will be summarized by visit using 
descriptive statistics. Qualitative parameters listed in Section 9.5.1.5.3 will be summarized 
using frequencies (number and percentage of subjects) and change from baseline values to 
each postbaseline visit and to end of treatment will be reported using shift tables.  
Percentages will be based on the number of subjects with both nonmissing baseline and 
relevant postbaseline results.
Laboratory parameters will be categorized according to CTCAE v5.0, and shifts from 
baseline CTCAE grades to worst postbaseline grades will be assessed.  Number and 
percentage of subjects with postbaseline results of CTCAE grades 3 or 4 will also be 
presented.
9.7.1.8.4
VITAL SIGNS
Descriptive statistics for vital signs parameters (ie, systolic and diastolic BP, pulse, 
respiratory rate, temperature, weight) and changes from baseline will be presented by visit.
9.7.1.8.5
ELECTROCARDIOGRAMS
Descriptive statistics for ECG parameters and changes from baseline will be presented by 
visit.
For Dose Escalation part only, shift tables will present changes from baseline in ECG 
interpretation (categorized as normal; abnormal, not clinically significant; and abnormal, 
clinically significant) to worst postbaseline category. 
In addition, the number (percentage) of subjects with at least 1 postbaseline abnormal ECG 
result in QTc Fridericia (QTcF) during the treatment period will be summarized.  Clinically 
abnormal ECG results in QTcF will be categorized as follows:
Absolute QTcF interval prolongation:

QTcF interval >450 ms

QTcF interval >480 ms

QTcF interval >500 ms
Change from baseline in QTcF interval:

QTcF interval increases from baseline >30 ms

QTcF interval increases from baseline >60 ms


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9.7.1.8.6
OTHER SAFETY ANALYSES
Descriptive summary statistics for LVEF assessed on echocardiograms or MUGA scans and 
changes from baseline will be calculated.
Shift table for ECOG-PS will present change from baseline classification to worst 
postbaseline classification.
9.7.2
Determination of Sample Size
It is anticipated that selection of the RP2D will be based on integrated evaluation of safety, 
tolerability, clinical benefit, PK, and pharmacodynamics data.  The total number of subjects 
for the Dose Escalation part will depend on the observed data including safety profile, which 
will determine the number of subjects per dose level, as well as the number of dose levels 
tested before the RP2D is established.  Therefore, a formal statistical calculation of sample 
size is not applicable.  The anticipated sample size for E7766 in the Dose Escalation part will 
be approximately 35 subjects, assuming approximately 10 dose levels and at least 2 subjects 
per dose level will be tested to achieve the MTD and then approximately 4 subjects for the 
selected 1 to 3 dose levels may be additionally enrolled for the RP2D selection.  
The total number of subjects for the Dose Expansion part will depend on the number of arms 
by the disease-specific indications, and the number of subjects per arm.  The anticipated 
sample size for the Dose Expansion part will be approximately 80 subjects, assuming 2 arms, 
and a maximum of 40 subjects per arm will be enrolled.
9.7.3
Interim Analysis
No formal interim analyses are planned.  Interim monitoring using a snapshot of the database 
will be conducted to determine the MTD and/or RP2D, or to confirm safety and detect 
efficacy signals in subjects with selected disease indications before the analysis for CSR. 
Database locks are not required to perform these interim evaluations.  
The data cutoff date for the CSR will be done after 6 months after the last subject in, and may 
be conducted before the last subject discontinues study treatment in this study.
9.7.4
Other Statistical/Analytical Issues
9.7.4.1
Improved Modified Toxicity Probability Interval Design in Dose Escalation Part
The improved mTPI design, which uses a Bayesian statistical framework and a beta-binomial 
hierarchical model, will be employed to determine the MTD and/or RP2D of E7766. 
Decision rules for dose assignment will be based on the improved mTPI design with the 
target DLT rate of 25% and its equivalence interval (EI) of 20% to 30%, and a set of 
equal-width intervals as EI below/above EI (ie, below EI: 0% to 10%, 10% to 20%; above 


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EI: 30% to 40%, ... , 90% to 100%).  The posterior probabilities of each interval will be 
calculated with non-informative beta prior distribution Beta (1, 1). The location of the 
interval with the largest posterior probability—below EI, EI, or above EI—guides the 
decision for the next dose level to be assigned, ie, Dose Escalation (E), Staying at the current 
dose (S), or dose De-escalation (D), respectively.  This dose assignment rule minimizes the 
posterior expected penalty in the Bayes’ rule under a decision-theoretic framework with the 
equal prior expected penalties for E, S, and D.  The entire dose assignment decision rule can 
be pre-tabulated as presented in Table 1.
The subject enrollment will be closed when the lowest dose has a >95% posterior probability 
of being above the target DLT rate of 25% (ie, an unacceptable DLT rate beyond the target 
DLT rate) or when the RP2D has been determined.
The MTD is defined as the dose with the smallest difference between the target DLT rate of 
25% and an estimate of DLT rate at each dose among all the tested doses with a ≤95% 
posterior probability of being above the target DLT rate of 25%. The isotonically
transformed posterior mean under the beta posterior distribution with non-informative beta 
prior distribution Beta (0.005, 0.005) will be used to determine the estimate of DLT rates at 
each dose. The pooled adjacent violators algorithm (PAVA) will be used to maintain 
monotonically the increase of DLT rate with increasing dose level.  Late immune-related 
toxicities occurring after Cycle 1 (DLT period) and up to 90 days after last dose of E7766, 
will also be used to inform corrections to the MTD and aid selection of the RP2D.
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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10 REFERENCE LIST
Cancer Therapy Evaluation Program. Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0 [published 27 Nov 2017].  Available from: 
https://ctep.cancer.gov/protocoldevelopment/.../ctcae_v5_quick_reference_5x7.pdf.  
Accessed on 28 Jan 2018.
Cheson BD, Ansell S, Schwartz L, Gordon LI, Advani R, Jacene HA, Hoos A, et al. 
Refinement of the Lugano Classification lymphoma response criteria in the era of 
immunomodulatory therapy. Blood. 2016;128(21): 2489-96.
Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, et al.
Recommendations for initial evaluation, staging, and response assessment of Hodgkin and 
non-Hodgkin lymphoma: the Lugano Classification. J Clin Onc. 2014:32:3059-67.
Corrales L, Glickman LH, McWhirter SM, Kanne DB, Sivick KE, Katibah GE, et al. Direct 
activation of STING in the tumor microenvironment leads to potent and systemic tumor 
regression and immunity. Cell Rep. 2015. 11(7):1018-30.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J 
Cancer. 2009;45(2):228-47.
Guo W, Wang SJ, Yang S, Lynn H, Ji Y. A Bayesian interval dose-finding design addressing 
Ockham’s razor: mTPI-2. Contemp Clin Trials. 2017;58:23-33.
Marabelle A, Andtbacka R, Harrington K, Melero I, Leidner R, de Baere T, et al. Starting the 
fight in the tumor: expert recommendations for the development of human intratumoral 
immunotherapy (HIT-IT). Ann Oncol. 2018;29(11):2163-74.
MD Anderson Cancer Center. Chimeric antigen receptor (CAR) cell therapy toxicity 
assessment and management – adult [practice algorithm]. V2. Approved by the Executive 
Committee of the Medical Staff on 10/31/2017. 16 pages. Available from: 
https://www.mdanderson.org/documents/for-physicians/algorithms/clinical-
management/clin-management-cytokine-release-web-algorithm.pdf. Accessed on 19 Apr
2019.
Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, et al. iRECIST: guidelines for 
response criteria for use in trials testing immunotherapeutics. Lancet Oncol. 
2017:18(3):e143-e152.
Teachey DT, Lacey SF, Shaw PA, Melenhorst JJ, Maude SL, Frey N, et al. Identification of 
predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell 
therapy for acute lymphoblastic leukemia. Cancer Discov. 2016;6(6):664-79. 


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Venur VA, Ahluwalia MS. Novel therapeutic agents in the management of brain metastases. 
Curr Opin Oncol. 2017;29(5):395-9.
Woo SR, Fuertes MB, Corrales L, Spranger S, Furdyna MJ, Leung MY, et al. 
STING-dependent cytosolic DNA sensing mediates innate immune recognition of 
immunogenic tumors. Immunity. 2014;41(5):830-42.
Yan F, Mandrekar SJ, Yuan Y. Keyboard: a novel Bayesian toxicity probability interval 
design for phase I clinical trials. Clin Cancer Res. 2017;23(15):3994-4003.


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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 study 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 (or if regionally required, the head of the medical institution) should 
be kept informed of such changes as required by local regulations.  In these cases, the 
sponsor may be required to send a letter to the IRB/IEC and the Competent Authorities (or, if 
regionally required, the head of the medical institution) 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 (or if 
regionally required, the head of the medical institution) will allow the CRA to inspect the 
clinical, laboratory, and pharmacy facilities to assure compliance with GCP and local 
regulatory requirements.  The CRFs and subject’s corresponding original medical records 
(source documents) are to be fully available for review by the sponsor’s representatives at 
regular intervals.  These reviews verify adherence to study protocol and data accuracy in 
accordance with local regulations.  All records at the site are subject to inspection by the 
local auditing agency and to IRB/IEC review.
In accordance with ICH E6, Section 1.52, source documents include, but are not limited to,
the following:


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
Clinic, office, or hospital charts

Copies or transcribed health care provider notes that 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 the source document.  Any correction to entries 
made on the CRF must be documented in a valid audit trail where the correction is dated, the 
individual making the correct is identified, the reason for the change is stated, and the 
original data are not obscured.  Only data required by the protocol for the purposes of the 
study should be collected.
The investigator must sign each CRF.  The investigator will report the CRFs to the sponsor 
and retain a copy of the CRFs.
11.5
Identification of Source Data
All data to be recorded on the CRF must reflect the corresponding source documents.  
11.6
Retention of Records
The circumstances of completion or termination of the study notwithstanding, the 
investigator (or if regionally required, the head of the medical institution or the designated 
representative) 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).  The site should plan 


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to retain study documents, as directed by the sponsor, for at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 3 years have elapsed since 
the formal discontinuation of clinical development of the investigational product.
It is requested that at the completion of the required retention period, or should the 
investigator retire or relocate, the investigator contact the sponsor, allowing the sponsor the 
option of permanently retaining the study records.
11.7
Auditing Procedures and Inspection
In addition to routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the sponsor’s 
SOPs to evaluate compliance with the principles of ICH GCP and all applicable local 
regulations.  If a government regulatory authority requests an inspection during the study or 
after its completion, the investigator must inform the sponsor immediately.
11.8
Handling of Study Drug
All study drug will be supplied to the principal investigator (or a designated pharmacist) by 
the sponsor.  Drug supplies must be kept in an appropriate secure area (eg, locked cabinet) 
and stored according to the conditions specified on the drug labels.  The 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


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Appendix 1
Identification and Documentation of Injectable and Biopsiable Lesions at Screening CT 
Scan
#: An injectable lesion can also be the biopsiable lesion if it has not been injected and there are other lesions available to be targeted for injecting with E7766. 


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*At Screening, the investigator can identify more than 1 lesion for injection.  The sequence of lesion selection for injection should be agreed in advance by the 
investigator based on ease of accessibility and degree of risk (eg, bleeding) involved.  In case additional lesions are required for injection, additional forms can be 
filled during the study as required.
Lesion Assessment for Injection and Biopsy
Site Number:_________________        Subject ID:____________________          Date of Visit:______________________
Visit ID:_
        Investigator:_
_____________________________________________                                                _________________________________
                                    Signature                                                                                                     Date (MM/DD/YYYY)
_____________________________________________
                         Print Name and Title


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Appendix Table 1: Target and Nontarget Lesion Definitions by LDi (Long Axis 
Diameter) and SDi (Short Axis Diameter) for Solid Tumors 
and Lymphoma
Solid Tumor: Modified 
RECIST 1.1/iRECIST
Lymphoma: Lugano/LYRIC
Maximum number of target  
lesions
Up to 10 total Nodal/Extranodal 
Sites / max 5 per organa
Up to 6 Nodal/Extranodal Sites 
Target: Lymph Node
15 mm SDi
15 mm LDi
Target:  non-Lymph Node
10 mm LDi
10 mm LDi
Non-Target: Lymph Node
10 mm SDi (pathological)
10 mm LDi (pathological)
Non-Target : non-Lymph Node
NA
NA
NOTE:  An injectable lesion can also be selected as the lesion for biopsy if it has not been injected previously 
and there are other lesions available to be targeted for injecting with E7766. 
iRECIST = modified RECIST 1.1 for immune-based therapeutics, LYRIC = LYmphoma Response to 
Immunomodulatory Therapy Criteria, RECIST 1.1 = Response Evaluation Criteria in Solid Tumours
version 1.1.
a:  Lymph nodes are considered 1 organ system.


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Appendix 2
Description of the iRECIST Process for Assessment of 
Disease Progression
Assessment at Screening and Prior to modified RECIST 1.1 Progression
Until radiographic disease progression based on modified RECIST 1.1, there is no distinct 
iRECIST assessment.
Assessment and Decision at modified RECIST 1.1 Progression
For participants who show evidence of radiological PD by modified RECIST 1.1 as 
determined by the Investigator, the Investigator will decide whether to continue a participant 
on studytreatment until repeat imaging is obtained (using iRECIST for participant 
management (Appendix Table 2). This decision by the Investigator should be based on the 
participant’s overall clinical condition.
Clinical stability is defined as the following:

Absence of symptoms and signs indicating clinically significant progression of disease

No decline in ECOG performance status

No requirements for intensified management, including increased analgesia, radiation, 
or other palliative care
Any participant deemed clinically unstable should be discontinued from study treatment, 
and is not required to have repeat tumor imaging for confirmation of PD by iRECIST.
If the Investigator decides to continue treatment, the participant may continue to receive 
study treatment and the tumor assessment should be repeated 4 to 8 weeks later to confirm 
PD by iRECIST, per Investigator assessment. Images should continue to be sent in to the 
central imaging vendor for potential retrospective independent imaging review (IIR) and 
exploratory analysis of tumor volume
Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, 
including:

Increase in the sum of diameters of target lesion(s) identified at baseline to ≥20% and
≥5 mm from nadir
-
Note: The iRECIST publication uses the terminology “sum of measurements,” but 
“sum of diameters” will be used in this protocol, consistent with the original 
RECIST 1.1 terminology.

Unequivocal progression of nontarget lesion(s) identified at baseline

Development of new lesion(s)


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iRECIST defines new response categories, including iUPD (unconfirmed progressive disease
per iRECIST) and iCPD (confirmed progressive disease per iRECIST). For purposes of 
iRECIST assessment, the first visit showing progression according to modified RECIST 1.1 
will be assigned a visit (overall) response of iUPD, regardless of which factors caused the 
progression.
At this visit, target and nontarget lesions identified at baseline by modified RECIST 1.1 will 
be assessed as usual.
New lesions will be classified as measurable or nonmeasurable, using the same size 
thresholds and rules as for baseline lesion assessment in RECIST 1.1. From measurable new 
lesions, up to 5 lesions total (up to 2 per organ), may be selected as New Lesions – Target. 
The sum of diameters of these lesions will be calculated, and kept distinct from the sum of 
diameters for target lesions at baseline. All other new lesions will be followed qualitatively 
as New Lesions – Non-target.
Assessment at the Confirmatory Imaging
On the confirmatory imaging, the participant will be classified as progression confirmed 
(with an overall response of iCPD), or as showing persistent unconfirmed progression (with 
an overall response of iUPD), or as showing disease stability or response (iSD/iPR/iCR).
Confirmation of Progression
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the 
following occurs:

Any of the factors that were the basis for the iUPD at the previous visit show worsening
-
For target lesions, worsening is a further increase in the sum of diameters of
-
≥5 mm, compared to any prior iUPD time point
-
For nontarget lesions, worsening is any significant growth in lesions overall, 
compared to a prior iUPD time point; this does not have to meet the “unequivocal” 
standard of RECIST 1.1
-
For new lesions, worsening is any ofthese:
◦
An increase in the new lesion sum of diameters by ≥5 mm from a prior iUPD time 
point
◦
Visible growth of new nontarget lesions
◦
The appearance of additional newlesions

Any new factor appears that would have triggered PD by modified RECIST 1.1
Persistent iUPD
Progression is considered not confirmed, and the overall response remains iUPD, if:


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
None of the progression-confirming factors identified above occurs AND

The target lesion sum of diameters (initial target lesions) remains above the initial PD 
threshold (by modified RECIST 1.1)
Additional imaging for confirmation should be scheduled 4 to 8 weeks from the imaging on 
which the initial iUPD is seen. This may correspond to the next visit in the original visit 
schedule.
The assessment of the subsequent confirmation imaging proceeds in an identical 
manner, with possible outcomes of iCPD, iUPD, and iSD/iPR/iCR.
Resolution of iUPD
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if:

None of the progression-confirming factors identified above occurs, AND

The target lesion sum of diameters (initial target lesions) is not above the initial PD 
threshold.
The response is classified as iSD or iPR (depending on the sum of diameters of the target 
lesions), or iCR if all lesions resolve.
In this case, the initial iUPD is considered to be pseudo-progression, and the level of 
suspicion for progression is “reset.” This means that the next visit that shows radiographic 
progression, whenever it occurs, is again classified as iUPD by iRECIST, and the 
confirmation process is repeated before a response of iCPD can be assigned.
Management Following the Confirmatory Imaging
If repeat imaging does not confirm PD per iRECIST, as assessed by the Investigator, and the 
participant continues to be clinically stable, study treatment may continue and follow the 
regular imaging schedule. If PD is confirmed, participants will be discontinued from study 
treatment.
Detection of Progression at Visits After Pseudo-progression Resolves
After resolution of pseudo-progression (ie, achievement of iSD/iPR/iCR), iUPD is indicated 
by any of the following events:

Target lesions
-
Sum of diameters reaches the PD threshold (≥20% and ≥5 mm increase from nadir)
either for the first time, or after resolution of previous pseudo-progression. The nadir 
is always the smallest sum of diameters seen during the entire trial, either before or 
after an instance of pseudo-progression.

Non-target lesions


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-
If nontarget lesions have never shown unequivocal progression, their doing so for the 
first time results in iUPD.
-
If nontarget lesions have shown previous unequivocal progression, and this 
progression has not resolved, iUPD results from any significant further growth of 
nontarget lesions, taken as awhole.

New lesions
-
New lesions appear for the first time
-
Additional new lesions appear
-
Previously identified new target lesions show an increase of ≥5 mm in the new lesion 
sum of diameters, from the nadir value of that sum
-
Previously identified nontarget lesions show any significantgrowth
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process (see Assessment at the Confirmatory Imaging above) is repeated.
Progression must be confirmed before iCPD can occur.
The decision process is identical to the iUPD confirmation process for the initial PD, with 
one exception: if new lesions occurred at a prior instance of iUPD, and at the confirmatory 
imaging the burden of new lesions has increased from its smallest value (for new target 
lesions, the sum of diameters is ≥5 mm increased from its nadir), then iUPD cannot resolve 
to iSD or iPR. It will remain iUPD until either a decrease in the new lesion burden allows 
resolution to iSD or iPR, or until a confirmatory factor causes iCPD.
Additional details about iRECIST are provided in the iRECIST publication (Seymour, et al., 
2017).


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Appendix Table 2: Imaging and Treatment After First Radiologic Evidence of 
Progressive Disease
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
First radiologic
evidence of PD by
modified 
RECIST 1.1 
Repeat imaging 
at 4 to 8 weeks to
confirm PD.
May continue study
treatment 
Repeat imaging
at 4 to 8 weeks to
confirm PD per
investigator’s
discretion only.
Discontinue treatment.
Repeat tumor
imaging confirms
PD (iCPD) by
iRECIST per
investigator
assessment
No additional
imaging required.
Discontinue
treatment.
No additional
imaging required.
Not applicable
Repeat tumor
imaging shows
iUPD by iRECIST
per investigator
assessment
Repeat imaging
at 4 to 8 weeks to
confirm PD.
May occur at next
regularly
scheduled
imaging visit.
Continue study
treatment at the
investigator’s
discretion.
Repeat imaging
at 4 to 8 weeks to
confirm PD per
Investigator’s
discretion only.
Discontinue treatment.
Repeat tumor
imaging shows
iSD, iPR, or iCR
by iRECIST per
investigator
assessment.
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.  Next tumor
imaging should occur
according to the regular
imaging schedule.
iCPD = confirmed progressive disease per iRECIST, iCR = complete response per iRECIST, iRECIST = modified Response 
Evaluation Criteria in Solid Tumors 1.1 for immune-based therapeutics, iSD = stable disease per iRECIST, iUPD =
unconfirmed progressive disease per iRECIST, PD = progressive disease, RECIST 1.1 = Response Evaluation Criteria in 
Solid Tumors 1.1.


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Appendix 3
Description of the Lugano and LYRIC Assessment of 
Response in Lymphoma
The Lugano criteria is based on a combination of metabolic and radiographic responses to 
characterize several components of lymphoma involvement including: nodal disease, 
extranodal disease, bone marrow disease, spleen and liver involvement, and clinical 
assessment.  The standard assessment for tumor burden is CT for non-FDG avid lymphoma, 
and PET-CT for FDG-avid lymphoma.  Standard definitions associated with the Lugano 
assessment are summarized in Appendix Table 3.
Responses should be determined on the basis of radiographic and clinical evidence of 
disease. Assessment of PET-CT should follow the recommendations for initial evaluation, 
staging, and response assessment for Hodgkin and non-Hodgkin’s lymphoma; the Lugano 
classification described by Cheson (2014) is presented in the Revised Criteria for Response 
in Appendix Table 4. 
In the context of immunotherapy, once PD is indicated by the Lugano criteria, the time point
must then be confirmed as a true progression rather than an immune response by the LYRIC
described by Cheson (2016).  If the LYmphoma Response to Immunomodulatory Therapy 
Criteria (LYRIC) response does not qualify as true progression, it is called an Indeterminate 
Response (IR), which requires follow-up imaging as presented in Appendix Table 5.
Appendix Table 3: Standard Definitions and Assessments Lugano Lexicon
1.
Baseline Assessments
Lugano 
Measurement 
Terminology
Radiographic Measurement: Measureable lesions are characterized by the 
following radiographic parameters to describe lesion size by CT or MRI:

LDi: longest transverse diameter of a lesion

SDi: shortest axis perpendicular to the LDi

PPD: cross product of the LDi and perpendicular diameter

SPD: sum of the product of the perpendicular diameters for multiple lesions
FDG-PET Measurement:  Measureable FDG-avid lesions are characterized by the 
FDG-PET 5-point scale (5-PS) (recommended by visual inspection of SUV 
images):

Score 1: No uptake above background

Score 2: Uptake < mediastinum 

Score 3: Uptake > mediastinum, but < liver 

Score 4: Uptake moderately > liver at any site

Score 5:  Uptake markedly higher than liver at any site and/or new lesions
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 LDi for nodal 


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lesions

Identify up to 6 lesions including nodal masses or other lymphomatous disease 
including extranodal disease measureable in 2 diameters (LDi and SDi)

Likely to be reproducible across all time points

Representative of tumor burden
a. Nodes should preferably be from disparate regions of the body and should 
include, where applicable, mediastinal and retroperitoneal areas.
b. Non-nodal lesions include those in solid organs (eg, liver, spleen, kidneys, and 
lungs), gastrointestinal (GI) involvement, cutaneous lesions, or those noted on 
palpation.

For FDG-avid lesions, the target lesion should correlate with a co-registered 
FDG-PET lesion.

Product of perpendicular diameters (PPD) is used to characterize the size each 
lesion, PPD = LDi × SDi

Sum of product diameters (SPD) of all target lesions including nodal and 
non-nodal are reported as baseline SPD which is used for assessing tumor 
response at follow-up time points.   
Bone Marrow 
Involvement

Bone marrow biopsy no longer indicated for the routine staging of HL and most 
DLBC. FDG-PET imaging should be used instead.  Involvement determined by 
FDG avid disease in marrow.

For other lymphoma subtypes 2.5 cm unilateral bone marrow biopsy is 
recommended, along with immunohistochemistry and flow cytometry at 
screening/baseline
Spleen Involvement

Splenomegaly is characterized by a >13 cm vertical length, as measured from 
cranial to caudal aspects by CT.
Nonmeasurable 
(Nontarget) Lesions
Nontarget lesions will include:
Measurable lesions not selected as target lesions.  Up to 10 nontarget lesions can be 
recorded at baseline.
All other disease not selected as target lesions consistent with lymphoma
Abnormal nodes, extranodal sites, assessable sites*
(*Cutaneous, gastrointestinal, bone lesions, pleural or pericardial effusions, ascites)
For FDG-avid lesions, the nontarget lesion should correlate with a co-registered 
FDG-PET lesion.
Nontarget lesions should be reported as present at baseline
SPDbaseline
Sum of product diameters at baseline = sum of the perpendicular product diameters, 
PPD = LDi × SDi, of each nodal and nonnodal target lesion.  SPD = n (PPDn) where 
the subscript n denotes each target lesion.
Clinical Assessment
Comprehensive history including 

Absence/presence of fevers to >101 °F (38.3 °C)

Chills, drenching night sweats, or unexplained weight loss >10% of body mass 
over 6 months, and history of malignancy. 

Fatigue, pruritus, and alcohol-induced pain in patients with HL should also be 
noted.*
(*These factors rarely direct treatment, their recurrence may herald disease 


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relapse.)
2.
Time Point Assessments After Baseline
Target Lesion 
Measurements
Radiographic measurement:  Locate image that optimizes the LDi of the nodal and 
non-nodal target lesions.  There is no need to go to an identical slice from baseline.  
Measure the respective LDi and SDi for all target lesions and calculate time point sum of 
product diameters (SPDtimepoint).
Special consideration for target lesions:
If target lesion is too small to measure, a default value of 5 mm LDi and 5mm SDi 
should be entered on the eCRF.
When no longer visible, enter 0 x 0 mm.
For a node >5 mm × 5 mm, but smaller than normal, use actual measurement for 
calculation.
If target lesion is between 5 to 10 mm, actual diameter should be entered on the
eCRF.
If target lesion splits into 2 or more lesion then the LDi and SDi and PPD of the split 
lesions will be added to the SPD and entered in place of that lesion.
If 2 target lesion merged to form one lesion than the LDi and SDi of one should be 
entered as “0 x 0 mm” while the other lesion should have the LDi and SDi and PPD of 
the merged lesion 
FDG-PET metabolic measurement: Locate each target lesion that is co-registered with 
CT imaging (maximum of 6) and use 5 point scale with an additional parameters to 
describe nonlymphoma-related FDG-uptake and nonevaluable lesions:

Score 1: No uptake above background

Score 2: Uptake < mediastinum 

Score 3: Uptake > mediastinum, but < liver 

Score 4: Uptake moderately > liver at any site

Score 5:  Uptake markedly higher than liver at any site and/or new lesions

X         :  Area of new uptake unlikely to be related to lymphoma

NE      :  Not evaluable 
Nontarget Lesion 
Assessment
Nontarget lesions are evaluated by radiographic assessment qualitatively as present, 
regressed, absent, not evaluable (NE), or unequivocal progression. 
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 investigator.

May include a lesion in an anatomical location that was not scanned at baseline (ie, 
brain)

Should be unequivocal and not due to differences in scanning technique “x”
5-PS = 5-point scale, CT = computed tomography, DLBC = diffuse large B-cell lymphoma, eCRF = electronic 
case report form, FDG-PET = 18fluorodeoxyglucose-positron emission tomography, HL= Hodgkin’s lymphoma, 
MRI = magnetic resonance imaging, SUV = standardized uptake value.


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Appendix Table 4: Lugano Criteria for Response
Response
Site
PET-CTBased Response
CT-Based Response
Complete
Complete metabolic response
Complete radiologic response (all of the following)
Lymph nodes and
extralymphatic sites
Score 1, 2, or 3a with or without a residual mass on the 5-PSb
It is recognized that in Waldeyer’s ring or extranodal sites with 
high physiologic uptake or with activation within spleen or 
marrow (eg, with chemotherapy or myeloid colony-stimulating 
factors), uptake may be greater than normal mediastinum and/or 
liver. In this circumstance, complete metabolic response may be 
inferred if uptake at sites of initial involvement is no greater than 
surrounding normal tissue even if the tissue has high physiologic 
uptake.
Target nodes/nodal masses must regress to 1.5 cm in 
LDi. No extralymphatic sites of disease.
Nonmeasured lesion
Not applicable
Absent
Organ enlargement
Not applicable
Regress to normal
New lesions
None
None
Bone marrow
No evidence of FDG-avid disease in marrow.
If the bone marrow was involved by lymphoma prior to treatment, 
the infiltrate must have cleared on repeat bone marrow biopsy.
If the bone marrow was involved by lymphoma prior to 
treatment, the infiltrate must have cleared on repeat 
bone marrow biopsy.
Partial
Partial metabolic response
Partial remission (all of the following)
Nonmeasured lesion
Not applicable
Absent/normal, regressed, but no increase.
Organ enlargement
Not applicable
Spleen must have regressed by >50% in length beyond 
normal (>13cm).
New lesions
None
None
Bone marrow
Residual uptake higher than uptake in normal marrow but reduced 
compared with baseline (diffuse uptakecompatible with reactive 
changes from chemotherapy allowed).  If there are persistent focal 
changes in the marrow in the context of a nodal response, 
consideration should be given to further evaluation with MRI or 
biopsy or an intervalscan.
Not applicable
No Response or 
Stable Disease
No metabolic response
Stable disease
Lymph nodes and
extralymphatic sites
Score 4 or 5b with no significant change in FDG uptake from 
baseline at interim or end of treatment.
50% decrease from baseline in SPD for up to 6 
dominant, measurable nodes and extranodal sites; 
no criteria for progressive disease are met.
Nonmeasured lesion
Not applicable
No increase consistent with progression.
Organ enlargement
Not applicable
No increase consistent with progression. 


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Appendix Table 4: Lugano Criteria for Response
Response
Site
PET-CTBased Response
CT-Based Response
New lesions
None
None
Bone marrow
No change from baseline
Not applicable
Progressive 
Disease
Progressive metabolic disease
Progressive disease (requires at least 1 of the 
following)
Individual target 
nodes/nodal lesions
Score 4 or 5b with an increase in intensity of uptake from baseline
An individual node/lesion must be abnormal with:

LDi >1.5 cm AND

Increase by 50% from PPD nadir AND

An increase in LDi or SDi from nadir

0.5 cm for lesions 2 cm

1.0 cm for lesions 2 cm
Extranodal lesions
and/or
New FDG-avid foci consistent with lymphoma at interim or end-
of-treatment assessment.
An individual node/lesion must be abnormal with:

LDi >1.5 cm AND

Increase by 50% from PPD nadir AND

An increase in LDi or SDi from nadir

0.5 cm for lesions 2 cm

1.0 cm for lesions 2 cm
Nonmeasured lesion
New or clear progression of preexisting
Organ enlargement
In the setting of splenomegaly, the splenic length 
must increase by 50% of the extent of its prior 
increase beyond baseline (eg, 15 cm spleen must 
increase to 16 cm). If no prior splenomegaly, must 
increase by at least 2 cm from baseline.
New or recurrent splenomegaly.
New lesions
and/or
New FDG-avid foci consistent with lymphoma rather than another 
etiology (eg, infection, inflammation). If uncertain regarding 
etiology of new lesions, biopsy or interval scan may be 
considered.
Regrowth of previously resolved lesions.
A new node 1.5 cm in any axis.
A new extranodal site 1.0 cm in any axis; if 
1.0 cm in any axis, its presence must be 
unequivocal and must be attributable to lymphoma.


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Appendix Table 4: Lugano Criteria for Response
Response
Site
PET-CTBased Response
CT-Based Response
Assessable disease of any size unequivocally 
attributable to lymphoma.
Bone marrow
and/or
New or recurrent FDG-avid foci.
New or recurrent involvement
5-PS = 5-point scale, CR = complete response, CT = computed tomography, FDG = fluorodeoxyglucose, GI = gastrointestinal, LDi = longest transverse
diameter of a lesion, MRI = magnetic resonance imaging, PET = positron emission tomography, PPD = cross product of the LDi and perpendicular diameter,
PR = partial response, SDi = shortest axis perpendicular to the LDi, SPD = sum of the product of the perpendicular diameters for multiple lesions.
a
A score of 3 in many patients indicates a good prognosis with standard treatment, especially if scored at the time of an interim scan. However, in studies 
involving PET where de-escalation is investigated, it may be preferable to consider a score of 3 as inadequate response (to avoid under treatment).
b
PET 5-PS: 1, no uptake above background; 2, uptake ≤mediastinum; 3, uptake > mediastinum but ≤liver; 4, uptake moderately > liver; 5, uptake 
markedly higher than liver and/or new lesions; X, new areas of uptake unlikely to be related to lymphoma.
Source:  Cheson, et al., 2014.


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Appendix Table 5: LYRIC PD Confirmation for Immunotherapy in Lymphomaa
LYRIC Measurement 
Terminology
Indeterminate Response (IR): This modification retains the core concepts of immunotherapy response criteria, incorporating 
them into lymphoma-specific response criteria.  Responses that are potentially due to immune reactions and characterized as 
IR (as described below) require additional follow-up scanning to confirm disease progression.
LYRIC PD and IR definitions
PD is the same as Lugano with the following exceptions that will qualify as IR:

IR(1): ≥50% increase in SPD in first 12 weeks.

IR(2): <50% increase in SPD with
a.
  New lesions(s), or
b.
  ≥50% increase in PPD of a lesion or set of lesions (including non-TL) at any time during treatment.

IR(3): Increase in FDG uptake without a concomitant increase in lesion size meeting criteria for PD.
LYRIC follow-up after IR for 
PD confirmation
In patients categorized as having any of the above types of IR, it is mandatory to obtain a repeat imaging after an additional 
12 weeks (or earlier if clinically indicated). At that time, response should be re-evaluated, and the patient should be considered 
to have true PD if the SPD of target lesion has increased further, with the considerations below:

In the case of IR (1), the comparison should be between the first IR and the current overall tumor burden, with an 
increase of ≥10% constituting PD.  In addition there should be an increase of ≥5 mm for at least 1 lesions ≤2 cm,  and 
10 mm for lesions >2 cm (consistent with Lugano).

In the case of IR(2), the new or growing (including non-TL) lesion(s) (unless biopsy proven benign) should be added to 
the target lesion(s) up to a total of no more than 6 lesions. If the SPD of the newly defined set of target lesions has 
increased ≥50% from their nadir value (which may precede IR) this patient would be considered PD.

In the case of IR(3): Since inflammatory response may result in an increase in the standardized uptake value of a lesion, 
the patient will not be considered to have progressive disease unless there is evidence of progressive disease by an 
increase in lesion size or the development of a new lesions. 
Note on LYRIC PD time
point assignment
If a patient is evaluated as IR and then “true” PD at a subsequent time point (without an intervening objective response 
between IR and PD), the IR assessment should subsequently be corrected to PD for reporting purposes to the date of the prior 
designation of IR. We recognize that these lesions may remain stable during the time of observation, but, even if this is the
case, the initial designation of IR should be changed to PD.
a FDG = fluorodeoxyglucose, IR = Indeterminate Response, LYRIC = LYmphoma Response to Immunomodulatory Therapy Criteria, PD = progressive disease, 
PPD = product of perpendicular diameters, SPD = sum of product diameters, TL = target lesion.   
Source:  Cheson, et al. 2016.


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Appendix 4
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 5
Autoimmune-Related Diseases


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Appendix 6
Interleukin-6 (IL-6) Antagonist and Corticosteroid 
Dosing Tables
CRES = CAR-related encephalopathy syndrome, CRS = cytokine release storm.


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Appendix 7
CCI


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Appendix 8
Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Research
Objective
Subjects enrolled in this clinical study will have biologic samples collected for 
pharmacodynamic , pharmacogenomic (PG), and other biomarker analysis.  These samples 
may be used for discovery and validation to identify biomarkers that may be used for 
exploratory evaluation of response and/or safety-related outcomes as well as for use in 
diagnostic development.
The PG samples may be used to identify genetic factors that may influence a subject’s 
exposure to the study drug, as well as genetic factors that may have an effect on clinical 
response or potential adverse events related to study treatment, and to explore the role of 
genetic variability in response.  Samples may be analyzed to determine a subject’s genotypes 
or sequence for a number of genes or noncoding regulatory regions.  The research may 
include the investigation of polymorphisms in genes that are likely to influence the study 
drug pharmacokinetics or therapeutic response.
Collection of the pharmacodynamic, PG, and other biomarker samples will be bound by the 
sample principles and processes outlined in the main study protocol.  Sample collection for 
pharmacodynamic, PG, and other biomarker analysis is required as per the study protocol 
unless the collection and use of the samples is prohibited by specific country laws.
Sample Collection, Handling and Shipment
This information will be included in the laboratory manual.
Security of the Samples, Use of the Samples, Retention of the Samples
Sample processing, for example DNA and/or RNA extraction, genotyping, sequencing, or 
other analysis will be performed by a laboratory under the direction of the sponsor.  
Processing, analysis, and storage will be performed at a secure laboratory facility to protect 
the validity of the data and maintain subject privacy.
Samples will only be used for the purposes described in this protocol.  Laboratories will not 
retain rights to the samples beyond those necessary to perform the specified analysis and will 
not transfer or sell those samples.  The sponsor will not sell the samples to a third party.
Samples will be stored for up to 15 years after the completion of the study (defined as 
submission of the clinical study report to the appropriate regulatory agencies).  At the end of 
the storage period, samples will be destroyed.  Samples may be stored longer if a health 
authority (or medicinal product approval agency) has active questions about the study.  In 
this special circumstance, the samples will be stored until the questions have been adequately 
addressed.


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It is possible that future research and technological advances may identify genomic variants 
of interest, or allow alternative types of genomic analysis not foreseen at this time.  Because 
it is not possible to prospectively define every avenue of future testing, all samples collected 
will be single coded (subject ID) (according to the ICH E18 draft guidelines) in order to 
maintain subject privacy. 
Right to Withdraw
If, during the time the samples are stored, a participant would like to withdraw his/her 
consent for participation in this research, Eisai will destroy the samples.  Information from 
any assays that have already been completed at the time of withdrawal of consent will 
continue to be used as necessary to protect the integrity of the research project.
Subject Privacy and Return of Data
Samples will be single coded (subject ID).  No subject-identifying information (eg, initials, 
date of birth, government identifying number) will be associated with the sample.
At the end of the analysis, results may be presented in the clinical study report (or may be 
presented in the separately prepared report) which can include part or all of the coded data, in 
listing or summary format.  Other publication (eg, in peer-reviewed scientific journals) or 
public presentation of the study results will only include summaries of the population in the 
study, and no identified individual results will be disclosed.
Given the research nature of the pharmacodynamic, PG, and other biomarker analysis, it will 
not be possible to return individual data to subjects. The results that may be generated are 
not currently anticipated to have clinical relevance to the patients or their family members. 
Therefore, these results will not be disclosed to the patients.
If at any time, pharmacodynamic, PG, and/or other biomarker results are obtained that may 
have clinical relevance, IRB review and approval will be sought to determine the most 
appropriate manner of disclosure and to determine whether or not validation in a Clinical 
Laboratory Improvement Amendments (CLIA)-certified setting will be required.  Sharing of 
research data with individual patients should only occur when data have been validated by 
multiple studies and testing has been done in CLIA-approved laboratories.




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INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
E7766-G000-101
Study Protocol Title:
An Open-Label, Multicenter Phase 1/1b Study of Intratumorally 
Administered STING Agonist E7766 in Subjects With Advanced 
Solid Tumors or Lymphomas – INSTAL-101
Investigational Product
Name:
E7766
IND Number:
137834
EudraCT Number:
2019-000160-17
I have read this protocol and agree to conduct this study in accordance with all stipulations of 
the protocol and in accordance with International Council for Harmonisation of Technical 
Requirements for 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: 
Statistical Analysis Plan 
E7766-G000-101 
 
 
 
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STATISTICAL ANALYSIS PLAN 
Study Protocol 
Number: 
E7766-G000-101 
Study Protocol 
Title: 
An Open-Label, Multicenter Phase 1/1b Study of Intratumorally 
Administered STING Agonist E7766 in Subjects with Advanced 
Solid Tumors or Lymphomas – INSTAL-101 
Date: 
22 August 2022  
Version: 
Final Version 2.0 


Statistical Analysis Plan 
E7766-G000-101 
 
 
 
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FINAL Version 2.0  
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1 
TABLE OF CONTENTS 
1 
TABLE OF CONTENTS ...................................................................................................2 
2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................4 
3 
INTRODUCTION .............................................................................................................7 
3.1 
Study Objectives ......................................................................................................7 
3.1.1 
Primary Objectives .........................................................................................7 
3.1.2 
Secondary Objectives .....................................................................................7 
3.1.3 
Exploratory Objectives ..................................................................................8 
3.2 
Overall Study Design and Plan ................................................................................8 
3.2.1 
Dose Escalation ............................................................................................10 
3.2.1.1 
Dose Escalation Design .....................................................................10 
3.2.1.2 
Dose-Limiting Toxicities ...................................................................11 
3.2.1.3 
Selection of RP2D..............................................................................11 
3.2.2 
Dose Expansion ...........................................................................................12 
4 
DETERMINATION OF SAMPLE SIZE ........................................................................12 
5 
STATISTICAL METHODS ............................................................................................12 
5.1 
Study Endpoints .....................................................................................................13 
5.1.1 
Primary Endpoints .......................................................................................13 
5.1.2 
Secondary Endpoints ...................................................................................13 
5.1.3 
Exploratory Endpoints .................................................................................13 
5.2 
Study Subjects ........................................................................................................14 
5.2.1 
Definitions of Analysis Sets.........................................................................14 
5.2.2 
Subject Disposition ......................................................................................14 
5.2.3 
Protocol Deviations ......................................................................................15 
5.2.4 
Demographic and Other Baseline Characteristics .......................................15 
5.2.5 
Prior and Concomitant Therapy ...................................................................15 
5.2.6 
Treatment Compliance .................................................................................16 
5.3 
Data Analysis General Considerations ..................................................................16 
5.3.1 
Pooling of Centers........................................................................................16 
5.3.2 
Adjustments for Covariates..........................................................................16 
5.3.3 
Multiple Comparisons/Multiplicity .............................................................16 
5.3.4 
Examination of Subgroups ...........................................................................16 
5.3.5 
Handling of Missing Data, Dropouts, and Outliers .....................................16 
5.3.6 
Other Considerations ...................................................................................17 
5.4 
Efficacy Analyses ..................................................................................................17 
5.4.1 
Primary Efficacy Analyses ..........................................................................17 
5.4.1.1 
Dose Escalation Part ..........................................................................17 


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5.4.1.2 
Dose Expansion Part ..........................................................................18 
5.4.2 
Secondary Efficacy Analyses ......................................................................18 
5.4.2.1 
Objective Response Rate for Dose Escalation Part ...........................18 
5.4.2.2 
Duration of Response for Dose Escalation Part .................................18 
5.4.2.3 
Disease Control Rate for Dose Escalation Part ..................................18 
5.4.2.4 
Progression-free Survival...................................................................18 
5.4.2.5 
Overall Survival .................................................................................20 
5.4.2.6 
Change in Tumor Size in Injected Lesions ........................................20 
5.5 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Analyses ...............................................................................................21 
5.5.1 
Pharmacokinetic Analyses ...........................................................................21 
5.5.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses ....22 
5.6 
Safety/Tolerability Analyses ..................................................................................22 
5.6.1 
Extent of Exposure .......................................................................................22 
5.6.1.1 
Extent of Exposure to Study Drug .....................................................22 
5.6.1.2 
Study Drug Administered ..................................................................22 
5.6.1.3 
Study Drug Dose Modifications ........................................................23 
5.6.2 
Adverse Events ............................................................................................23 
5.6.2.1 
Dose Limiting Toxicity ......................................................................23 
5.6.2.2 
Adverse Events ..................................................................................23 
5.6.3 
Laboratory Values ........................................................................................25 
5.6.4 
Vital Signs ....................................................................................................26 
5.6.5 
Electrocardiograms ......................................................................................26 
5.6.6 
Other Safety Analyses ..................................................................................26 
5.6.6.1 
Left Ventricular Ejection Fraction .....................................................26 
5.6.6.2 
Eastern Cooperative Oncology Group Performance Status ...............27 
5.7 
Other Analyses .......................................................................................................27 
5.8 
Exploratory Analyses .............................................................................................27 
6 
INTERIM ANALYSES ...................................................................................................27 
7 
CHANGES IN THE PLANNED ANALYSES ...............................................................27 
8 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING ...............................28 
8.1 
Visit Windows .......................................................................................................28 
8.2 
Baseline Definitions ...............................................................................................28 
8.3 
Imputation of Missing Data ...................................................................................28 
9 
PROGRAMMING SPECIFICATIONS ..........................................................................28 
10 STATISTICAL SOFTWARE ..........................................................................................28 
11 MOCK TABLES, LISTINGS, AND GRAPHS ..............................................................29 
12 REFERENCES ................................................................................................................30 
 


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2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
AE 
adverse event 
ATC 
anatomical therapeutic class 
AUC 
area under the concentration-time curve 
CI 
confidence interval 
CL/F 
apparent total body clearance 
Cmax 
maximum observed concentration 
CR 
complete response 
CRC 
colorectal cancer 
CRF 
case report form 
CSR 
clinical study report 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
D 
dose de-escalation 
DCR 
disease control rate 
DLT 
dose limiting toxicity 
DOR 
duration of response  
E 
dose escalation 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EI 
equivalence interval 
HNSCC 
head and neck squamous cell carcinoma 
iCPD 
confirmed progressive disease per iRECIST 
iCR     
complete response per iRECIST 
IIR 
independent imaging review 
iRECIST 
modified Response Evaluation Criteria in Solid Tumors for 
immune-based therapeutics 
iSD  
stable disease per iRECIST 
iUPD  
unconfirmed progressive disease per iRECIST 


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Abbreviation 
Term 
LDi 
longest axis diameter of a lesion 
LLT 
lower level term  
LVEF 
left ventricular ejection fraction 
LYRIC 
Lymphoma Response to Immunomodulatory Therapy Criteria 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
mTPI-2 
improved modified toxicity probability interval 
MUGA 
multigated acquisition 
NYHA 
New York Heart Association  
ORR 
objective response rate 
OS 
overall survival 
PAVA 
pooled adjacent violators algorithm 
PD 
pharmacodynamic, progressive disease 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PR 
partial response 
PT 
preferred term 
Q1 
25th percentile  
Q3 
75th percentile 
Q3W 
once in 3 weeks 
QTc 
corrected QTc interval 
QTcF 
corrected for QTc interval using Frederica's correction factors 
R 
accumulation ratio 
RECIST 
Response Evaluation Criteria in Solid Tumors  
RP2D 
recommended Phase 2 dose 
S 
staying at the current dose 
SAP 
statistical analysis plan 
SD 
standard deviation or stable disease 


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Abbreviation 
Term 
SDi  
shortest axis perpendicular to the LDi 
STING 
stimulator of interferon genes 
SOC 
system organ class 
TL  
target lesion 
tmax 
time at which the highest drug concentration occurs 
t½ 
terminal elimination phase half-life 
TEAE 
treatment-emergent adverse event 
TLGs 
tables, listings, and graphs 
TNM 
tumor-node-metastasis  
Vd/F 
apparent volume of distribution 
WHO DD 
World Health Organization Drug Dictionary 
 


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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 Study E7766-G000-
101. 
3.1 
Study Objectives 
3.1.1 
Primary Objectives 
The primary objectives of the study are: 
Dose Escalation Part 
• Assess the safety/tolerability profile of E7766 administered intratumorally in subjects with 
advanced solid tumors or lymphomas 
• Determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) 
of E7766 in subjects with advanced solid tumors or lymphomas 
Dose Expansion Part 
• Assess the safety/tolerability profile of E7766 administered intratumorally in cohorts of 
subjects with selected tumor types 
• Assess clinical activity of E7766 based on investigator assessment of objective response 
rate (ORR), duration of response (DOR), and disease control rate (DCR) according to 
modified Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 and modified 
RECIST 1.1 for immune-based therapeutics (iRECIST) for solid tumors, in cohorts of 
subjects with selected tumor types 
3.1.2 
Secondary Objectives 
The secondary objectives of the study are: 
Dose Escalation part 
• Evaluate preliminary clinical activity of E7766 based on investigator assessment of 
ORR, DOR, and DCR according to modified RECIST 1.1 and iRECIST for solid 
tumors 
• Evaluate the pharmacokinetic (PK) profile of E7766 and any metabolites in plasma, 
urine, and feces  
Dose Escalation and Dose Expansion parts 
• Evaluate the PK profile of E7766 and any metabolites in plasma  


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• Evaluate progression-free survival (PFS) based on investigator assessment and overall 
survival (OS) in subjects treated with E7766  
• Evaluate tumor size changes per investigator assessment in injected lesions  
3.1.3 
Exploratory Objectives 
The exploratory objectives of the study are: 
Dose Escalation and Dose Expansion Parts 
• Evaluate changes in tumor size assessed by independent imaging review (IIR) using 
volumetric computed tomography (CT)/magnetic resonance imaging (MRI) 
• Evaluate immune pharmacodynamics effects of E7766 in the tumors and in peripheral 
blood 
• Explore PK/pharmacodynamics relationships (safety and efficacy endpoints) 
• Explore correlation of baseline tumor and peripheral blood immune phenotypes and of 
STING genotypes with safety and/or efficacy endpoints 
• Evaluate pre-injection changes in size of injected lesion per investigator assessment in 
addition to the scheduled tumor assessments to characterize the kinetics of response, 
progression, or immune-induced flare in the injected lesion 
3.2 
Overall Study Design and Plan 
This is an open label, multicenter, Phase 1/1b study to assess the safety and evaluate the clinical 
activity of E7766 administered intratumorally to subjects with advanced solid tumors or 
lymphomas. A Dose Escalation part will enable selection of a dose of E7766 to move forward 
with as the RP2D in the Dose Expansion part, where clinical activity in selected tumor types 
or populations will also be evaluated. 
Dose escalation will be conducted using an improved modified toxicity probability interval 
(i.e. mTPI-2) design (Guo et al., 2017; Yan et al., 2017) to determine the MTD for E7766.  
Each subject will be assessed for tumor response (injected and noninjected lesions), PK, and 
pharmacodynamics (blood and tumor factors). The RP2D will be selected based on integrating 
results of safety (including the MTD), clinical activity, PK, and pharmacodynamics. During 
the Dose Escalation part, selected dose level cohorts may accrue additional subjects to provide 
further safety, drug administration-related, biomarker, and/or PK data needed for selection of 
the RP2D. Intrapatient dose escalation of study drug will be allowed in the study. 
The Dose Expansion part will be initiated when the RP2D and/or MTD is available from the 
Dose Escalation part.  In the Dose Expansion part, separate study arms will evaluate E7766 at 
the RP2D in selected tumor types and populations to confirm safety and assess clinical activity.  
The study populations will be decided based on the emerging data from the Dose Escalation 
part.  


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The overall study design is shown in Figure 1. 
 
CRC = colorectal cancer, HNSCC = head and neck squamous cell carcinoma, RP2D = recommended Phase 2 
dose. 
Figure 1  
Study Schematic for Dose Escalation and Dose Expansion Parts 
 
A fixed E7766 dose will be administered for each subject. There will be no adjustments for 
subject weight.   
E7766 will be administered in cycles which are 3-weeks long, with treatment as follows: 
• Induction (Cycle 1): injection on Days 1, 8, and 15  
• Maintenance (Cycle 2 and after): injection on Day 1 of each cycle, once in 3 weeks 
(Q3W) 
Approximately 35 to 40 subjects will be enrolled in the Dose Escalation part and 80 subjects 
will be enrolled in the Dose Expansion part.  
The end of the study will be the date of data cutoff for the final analysis or last subject/last 
visit, whichever occurs later.  


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3.2.1 
Dose Escalation 
3.2.1.1 
Dose Escalation Design 
Dose assignment of subjects will be done using the improved mTPI (i.e mTPI-2) design in 
order to determine the MTD of E7766. Each subject will be assigned a dose in accordance with 
the rules of the mTPI-2 design based on a target dose-limiting toxicity (DLT) rate of 25% and 
its equivalence interval (EI) of 20% to 30%.  
The dose assignment decision rule is pre-tabulated in the Decision Rule for Dose Assignment 
(Table 1). Dose assignment for the next dose will be determined according to the Method for 
Deciding the Dose of the Next Dose Group (Table 2) after consultation between the 
investigators and the sponsor. Subjects who are not evaluable for DLT should be replaced 
within their dose level, if at least 2 subjects in total have not been tested at the dose level. 
Subject enrollment will be closed when the DLT rate at the lowest dose level greatly exceeds 
the target DLT rate (25%) or when the RP2D has been determined. 
Additional details of the mTPI-2 design are presented in Section 5.3.6. 
Table 1  
Decision Rule for Dose Assignment 
 
Number of Patients 
Number of Patients with DLTs 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
0 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
1 
D 
D 
D 
S 
S 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
2 
 
DU
* 
D 
D 
D 
D 
S 
S 
S 
S 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
3 
 
 
DU DU DU D 
D 
D 
D 
D 
S 
S 
S 
S 
S 
E 
E 
E 
E 
E 
4 
 
 
 
DU DU DU DU DU D 
D 
D 
D 
D 
S 
S 
S 
S 
S 
S 
S 
5 
 
 
 
 
DU DU DU DU DU DU D 
D 
D 
D 
D 
D 
S 
S 
S 
S 
6 
 
 
 
 
 
DU DU DU DU DU DU DU DU D 
D 
D 
D 
D 
D 
D 
7 
 
 
 
 
 
 
DU DU DU DU DU DU DU DU DU DU D 
D 
D 
D 
8 
 
 
 
 
 
 
 
DU DU DU DU DU DU DU DU DU DU DU DU D 
9 
 
 
 
 
 
 
 
 
DU DU DU DU DU DU DU DU DU DU DU DU 
10 
 
 
 
 
 
 
 
 
 
DU DU DU DU DU DU DU DU DU DU DU 
11 
 
 
 
 
 
 
 
 
 
 
DU DU DU DU DU DU DU DU DU DU 
12 
 
 
 
 
 
 
 
 
 
 
 
DU DU DU DU DU DU DU DU DU 
13 
 
 
 
 
 
 
 
 
 
 
 
 
DU DU DU DU DU DU DU DU 
14 
 
 
 
 
 
 
 
 
 
 
 
 
 
DU DU DU DU DU DU DU 
15 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DU DU DU DU DU DU 


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Number of Patients 
16 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DU DU DU DU DU 
17 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DU DU DU DU 
18 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DU DU DU 
19 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DU DU 
20 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DU 
 
Target DLT rate at MTD = 25% and its equivalence interval = 20% to 30%. 
Display for more than 20 subjects at the current dose is omitted. If the required rules are not available in the table, 
the decision will follow the rule determined by the improved mTPI (i.e. mTPI-2) design with the same settings 
above. 
Decision Table was calculated via East Bayes (EB 1.0.0). 
D = De-escalate to the next lower dose, DLT = dose-limiting toxicity, E = Escalate to the next higher dose,  
MTD = maximum tolerated dose, mTPI = modified toxicity probability interval, S = Stay at the current dose,  
U = Current dose is unacceptably toxic (ie, Do not re-enter the current dose). 
a:  Extra subjects may be added for the lowest dose, for example if the investigators and the sponsor determine 
that more subjects would be required to adequately evaluate that dose level and it is considered safe to do so. 
Table 2  
Method for Deciding the Dose of the Next Dose Group 
Dose Escalation Steps  
E7766-Related Toxicity During Cycle 1 
Increase ~75% to 100% 
Up to Grade 1 
Increase ~30% to 60% 
Grade 2 in 1 subject  
Increase ~10% to 30% 
Grade 2 in 2 or more subjects and/or 
Grade 3 or higher in 1 or more subject 
3.2.1.2 
Dose-Limiting Toxicities 
A subject should have received at least 2 E7766 injections during the DLT period (Cycle 1) to 
be considered evaluable for a DLT, unless the subject experienced a treatment-related toxicity 
preventing more than 1 administration of E7766. 
If a subject at a given dose level receives fewer than 2 out of the 3 planned E7766 intratumoral 
injections during the Induction cycle (ie, the DLT period/Cycle 1) because of E7766-related 
adverse events (AE), the subject should be considered as potentially experiencing a DLT by 
the Study Safety Committee, composed of investigators and representatives of the sponsor. 
3.2.1.3 
Selection of RP2D 
The RP2D of E7766 will be selected based on an integrated evaluation of safety, tolerability, 
clinical activity, PK data, and any available pharmacodynamics data for all dose levels or all 
available data.  
The investigators and sponsors will together conduct the evaluation and the recommended 
Phase 2 dose/doses and/or any modification to the dosing regimen will be agreed upon jointly. 


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3.2.2 
Dose Expansion 
Expansion arms shall be opened in specific tumor types and populations with treatment at the 
E7766 RP2D. 
Safety and clinical activity of E7766 at the RP2D will be tested in separate expansion arms 
with defined populations potentially including but not limited to melanoma, HNSCC, breast 
cancer, colorectal cancer, and/or other tumors. About 40 patients will be recruited in each 
expansion arm. 
Note that according to the corporate decision made on April 26, 2022, no subjects will be 
enrolled for dose expansion part. There will be no analysis for dose expansion part.  
 
4 
DETERMINATION OF SAMPLE SIZE 
It is anticipated that selection of the RP2D will be based on integrated evaluation of safety, 
tolerability, clinical benefit, PK, and pharmacodynamics data. The total number of subjects for 
the Dose Escalation part will depend on the observed data including safety profile, which will 
determine the number of subjects per dose level, as well as the number of dose levels tested 
before the RP2D is established. Therefore, a formal statistical calculation of sample size is not 
applicable. The anticipated sample size for E7766 in the Dose Escalation part will be 
approximately 35 subjects, assuming approximately 10 dose levels and at least 2 subjects per 
dose level will be tested to achieve the MTD and then approximately 4 subjects for the selected 
1 to 3 dose levels may be additionally enrolled for the RP2D selection.   
The total number of subjects for the Dose Expansion part will depend on the number of arms 
by the disease-specific indications, and the number of subjects per arm. The anticipated sample 
size for the Dose Expansion part will be approximately 80 subjects, assuming 2 arms, and a 
maximum of 40 subjects per arm will be enrolled. 
5 
STATISTICAL METHODS 
All statistical analyses will be performed by the sponsor or designee after the data cutoff for 
the abbreviated Clinical Study Report (CSR) or the study is completed and the database is 
locked and released. Statistical analyses will be performed using SAS® software or other 
validated statistical software as required.  
The data cutoff for the abbreviated CSR will be done after 6 months after the last subject in 
(i.e. last subject started treatment), and may be conducted before the last subject discontinues 
study treatment in this study.  
In general, continuous variables will be summarized using descriptive statistics such as 
mean, standard deviation (SD), median, 25th percentile (Q1), 75th percentile (Q3), minimum, 


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and maximum. Categorical variables will be summarized using frequency and percentage. 
For time-to-event variables, the Kaplan-Meier method will be used for descriptive summaries. 
Summary will be presented by initial dose level/arm and total for each part, and overall. Details 
will be provided in a separate Table Figure Listing document. 
  
5.1 
Study Endpoints 
5.1.1 
Primary Endpoints 
• Safety-related endpoints, including DLT 
• ORR according to modified RECIST 1.1 and iRECIST, defined as the proportion of 
subjects achieving a best overall response (BOR, see Appendix Error! Reference source 
not found.) of confirmed partial response (PR) or complete response (CR). 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 (Dose 
Expansion part only) 
• DOR according to modified RECIST 1.1 and iRECIST, defined as the time from the date 
of first documented and confirmed PR or CR until the first documentation of qualified 
disease progression (see Section 5.4.2.4) or death, whichever occurs first (Dose 
Expansion part only) 
• DCR according to modified RECIST 1.1 and iRECIST defined as the proportion of 
subjects achieving BOR as PR or CR or stable disease (SD) (Dose Expansion part only) 
5.1.2 
Secondary Endpoints 
• ORR, DOR, and DCR according to iRECIST and modified RECIST 1.1 (Dose Escalation 
part only) 
• PK profile in plasma, urine, and feces (Dose Escalation part) and plasma only (in Dose 
Expansion part) 
• PFS, defined as the time from the date of first dose to the date of the first documentation 
of qualified disease progression (see Section 5.4.2.4) or death, whichever occurs first 
• OS, defined as the time from the date of first dose to the date of death from any cause 
• Change in tumor size in injected lesions  
5.1.3 
Exploratory Endpoints 
• Changes in tumor size assessed by IIR using volumetric CT/MRI 


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• Immune pharmacodynamics effects of E7766 in the tumors and in the peripheral blood 
• PK/pharmacodynamics relationships (safety and efficacy endpoints) 
• Baseline immune phenotypes and its relationship with the response to E7766 
• STING genotypes and its relationship with the response to E7766 
• Changes in pre-injection size of injected lesion per investigator assessment 
5.2 
Study Subjects 
5.2.1 
Definitions of Analysis Sets 
DLT Analysis Set is the group of subjects in the Dose Escalation part who have completed 
Cycle 1, without incurring certain major protocol deviations (for instance those related to 
dosing or others identified before database lock), with at least 2 E7766 injections during Cycle 
1, and are evaluable for DLT, or subjects who have experienced DLT during Cycle 1. This will 
be the analysis set to evaluate tolerability. 
Full Analysis Set is the group of subjects who received at least 1 dose of study drug. This will 
be the primary analysis set for efficacy evaluations, as well as for demographic and baseline 
characteristics. 
Safety Analysis Set is the same group as Full Analysis Set. This will be the analysis set for all 
safety evaluations except DLT results. 
Efficacy Analysis Set is the group of subjects who received at least 1 dose of study drug and 
had a baseline tumor assessment. This will be used for supportive analysis of ORR. 
Pharmacodynamic Analysis Set and Pharmacokinetic/Pharmacodynamic Analysis Set are 
defined in separate PK or PK/PD analysis plan(s). 
5.2.2 
Subject Disposition 
The number (percentage) of enrolled (i.e., signed informed consent) and treated subjects will 
be summarized as well as subjects who completed the study or discontinued from the study, 
with reasons for discontinuation.  
The number (percentage) of subjects who completed the study treatment/discontinued from the 
study treatment and reasons for discontinuation will also be summarized.  
Subject data listings for the disposition of screening, treatment, and study will be provided. 


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5.2.3 
Protocol Deviations 
All major protocol deviations will be determined and documented based on the review of 
individual subject data prior to database lock.  
Major protocol deviations will be listed and summarized on Full Analysis Set. 
5.2.4 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics for the Full Analysis Set will be summarized 
using descriptive statistics. 
Continuous demographic and baseline variables including age, weight, height and time since 
first diagnosis (months) will be summarized and presented as N, mean, standard deviation, 
median, Q1, Q3, minimum and maximum values.  
For categorical variables such as sex, age group (e.g., <65, >=65), race, ethnicity, geographic 
region, Eastern Cooperative Oncology Group (ECOG) performance status, New York Heart 
Association (NYHA) cardiac disease classification, type of tumor diagnosis, location of 
primary tumor, histology/cytology of the primary tumor, and tumor staging (tumor-node-
metastasis [TNM] classification), the number and percentage of subjects will be presented. 
Previous therapies (anticancer medication, procedure, and radiotherapy) will also be listed and 
summarized. 
Medical History 
The history of any medical condition, as recorded on the case report form (CRF), will be listed.  
5.2.5 
Prior and Concomitant Therapy 
All investigator terms for medications recorded in the CRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary (WHO DD) Version of March 2019 or 
later.  
The number (percentage) of subjects who took prior and concomitant medications will be 
summarized on the Full Analysis Set by Anatomical Therapeutic Chemical (ATC) class (ie, 
Anatomical class, Pharmacological class) and WHO DD preferred term. Prior medications will 
be defined as medications that started 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 90 days after the subject’s last dose. Note that a 
medication can be classified as both prior and concomitant, if the medication started before the 
first dose of study drug and continued after the first dose. 
All medications will be presented in subject data listings. 


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Anticancer therapies (medication, procedure) received during survival follow-up will also be 
listed.  
5.2.6 
Treatment Compliance 
Treatment compliance related major protocol deviations will be presented as provided in 
Section 5.2.3. Information on subject exposure to study drug is described in Section 5.6.1. 
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 
No adjustment for covariates will be performed. 
5.3.3 
Multiple Comparisons/Multiplicity 
No statistical comparisons will be performed for this study. 
5.3.4 
Examination of Subgroups 
Subgroup analyses may be conducted, if deemed appropriate. 
5.3.5 
Handling of Missing Data, Dropouts, and Outliers 
Treatment Related TEAEs include TEAEs that were considered by the Investigator to be 
related to study drug or TEAEs with a missing causality. 
 
Medications will be considered concomitant if: 
a) Day and month are missing and the year is equal to or after the year of the first dose date;  
b) Day is missing, and the year is after the year of the first dose;  
c) Day is missing and 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; or  
d) Year is missing; or  
e) Complete date is missing.  
 
For efficacy endpoints, missing assessments will not be imputed. For incomplete dates 
involving efficacy and safety data such as adverse events, concomitant medications, laboratory 
assessments, vital signs, and echocardiogram/multigated acquisition (MUGA) data, a 
conservative imputation will be used for calculation if needed. The imputation rules will be 
specified in study analysis dataset specification with more details. 


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5.3.6 
Other Considerations 
Improved Modified Toxicity Probability Interval Design (mTPI-2) in Dose Escalation 
Part 
The mTPI-2 design, which uses a Bayesian statistical framework and a beta-binomial 
hierarchical model, will be employed to determine the MTD and/or RP2D of E7766.  
Decision rules for dose assignment will be based on the mTPI-2 design with the target DLT 
rate of 25% and its equivalence interval (EI) of 20% to 30%, and a set of equal-width intervals 
as EI below/above EI (ie, below EI:  0% to 10%, 10% to 20%; above EI:  30% to 40%, ... , 
90% to 100%). The posterior probabilities of each interval will be calculated with non-
informative beta prior distribution Beta (1, 1). The location of the interval with the largest 
posterior probability—below EI, EI, or above EI—guides the decision for the next dose level 
to be assigned, ie, Dose Escalation (E), Staying at the current dose (S), or dose De-escalation 
(D), respectively. This dose assignment rule minimizes the posterior expected penalty in the 
Bayes’ rule under a decision-theoretic framework with the equal prior expected penalties for 
E, S, and D. The entire dose assignment decision rule can be pre-tabulated as presented in 
Table 1. 
The subject enrollment will be closed when the lowest dose has a >95% posterior probability 
of being above the target DLT rate of 25% (ie, an unacceptable DLT rate beyond the target 
DLT rate) or when the RP2D has been determined. 
The MTD is defined as the dose with the smallest difference between the target DLT rate of 
25% and an estimate of DLT rate at each dose among all the tested doses with a ≤95% 
posterior probability of being above the target DLT rate of 25%. The isotonically 
transformed posterior mean under the beta posterior distribution with non-informative beta 
prior distribution Beta (0.005, 0.005) will be used to determine the estimate of DLT rates at 
each dose. The pooled adjacent violators algorithm (PAVA; Bartholomew et al., 1983) will 
be used to maintain monotonically the increase of DLT rate with increasing dose level. Late 
immune-related toxicities occurring after Cycle 1 (DLT period) and up to 90 days after last 
dose of E7766, will also be used to inform corrections to the MTD and aid selection of the 
RP2D. 
5.4 
Efficacy Analyses 
All efficacy analyses will be primarily performed on the Full Analysis Set. As supportive 
analysis, summary of ORR will also be performed on the Efficacy Analysis Set.  
5.4.1 
 Primary Efficacy Analyses 
5.4.1.1 
Dose Escalation Part 
There will be no primary efficacy analysis since the primary objective of the Dose Escalation 
part is to assess the safety/tolerability and to determine the MTD and/or RP2D. Thus, the 
efficacy analyses are described in the subsequent sections according to the study endpoints. 


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5.4.1.2 
Dose Expansion Part 
Objective Response Rate 
ORR will be calculated with exact 95% confidence interval (CI) using Clopper and Pearson 
method. Summary of best overall response will be provided.  
For subjects with solid tumors, swimmer plots based on modified RECIST 1.1 may also be 
presented as appropriate.  
 
Duration of Response 
DOR will be summarized using Kaplan-Meier estimates as appropriate. Median, Q1, Q3, and 
their 95% CIs estimated using generalized Brookmeyer and Crowley method will be presented. 
Kaplan-Meier estimates of DOR will be plotted over time.  The DOR will be based on subjects 
achieving a best overall response of confirmed PR or CR.  
Disease Control Rate  
DCR will be calculated with exact 95% CI using Clopper and Pearson method.  
5.4.2 
Secondary Efficacy Analyses 
5.4.2.1 
Objective Response Rate for Dose Escalation Part 
ORR for Dose Escalation part will be evaluated in the same manner as described in Section 
5.4.1.2 for Dose Expansion part. 
5.4.2.2 
Duration of Response for Dose Escalation Part 
DOR for Dose Escalation part will be evaluated in the same manner as described in Section 
5.4.1.2 for Dose Expansion part. 
5.4.2.3 
Disease Control Rate for Dose Escalation Part 
DCR for Dose Escalation part will be evaluated in the same manner as described in Section 
5.4.1.2 for Dose Expansion part. 
5.4.2.4 
Progression-free Survival  
In PFS analysis Subjects without disease progression or death will be censored at the time of 
the last tumor assessment. Subjects who started new anticancer therapies without documented 
progression of disease will be censored at the last adequate tumor assessment on or prior to the 
start of new anticancer therapies. Determination of the date of PFS event or censoring is 
summarized in Table 3 below. 


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Table 3  
PFS Event and Censoring Rules 
No. Situation 
Date of Progression or Censoring 
Outcome 
1 
No baseline or postbaseline 
adequate tumor assessments 
Date of first dose 
Censored 
 
2 
Progression documented 
between scheduled visits, on or 
prior to new anticancer therapy 
Date of first qualified*** PD assessment 
 
PFS Event 
 
3 
No progression at the time of data 
cutoff 
Date of last adequate assessment on or 
prior to data cutoff 
Censored 
4 
New anticancer therapy started 
Date of last adequate assessment on or 
prior to the start of new anticancer 
therapy  
Censored 
5 
Death before first PD assessment, 
on or prior to start of new 
anticancer therapy 
Date of death 
PFS Event 
6 
Death between adequate 
assessment* 
Date of death  
 
PFS Event 
 
7 
Death or progression after 
more than one missed 
visit/tumor assessment** 
Date of last adequate assessment before 
missed tumor assessments 
Censored 
CR = complete response, ic = iRECIST-confirmed, iu = iRECIST-unconfirmed, PD = progressive disease, 
PR = partial response, SD = stable disease. 
Note: 
* Adequate tumor assessment is radiologic assessment of CR, PR, SD, non-CR/non-PD or PD as determined 
by investigators at regular interval as defined in the protocol. Any tumor assessments after new anticancer 
therapy will not be considered in the definition of PFS. 
** More than one missed visit/adequate tumor assessment is defined as: 
• having the duration between two consecutive tumor assessments or the duration between the last 
adequate tumor assessment and death/PD being longer than (>) 97 days (for solid tumors because the 
scans are scheduled every 6 weeks ±7 days for this study). 
*** Qualified PD is defined as: 
• For modified RECIST: the documented PD per modified RECIST CRF page;  
• For iRECIST: in the order of 1) the documented iCPD per iRECIST CRF page, or 2) the iUPD that 
has not be reset by subsequent iCR/iPR/iSD 
NOTE: iCPD has to be within 8 weeks of iUPD, but not earlier than 4 weeks (i.e. >=28 days) of iUPD. 
 
1.  If the subject had PD or death, the following sequence will be applied: 
• If a subject did not have baseline or postbaseline adequate tumor assessments (No. 1), the subject will
be censored at the date of the first dose. However, if the subject died within 35 days after the first
dose date and did not receive any new anticancer therapy, it will be counted as a PFS event at the date
of death.  
• If subject has baseline tumor assessment but does not have any postbaseline adequate tumor
assessments, the subject will be censored at the date of the first dose. However, if the subject died 


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within 97 days after the first dose date and did not receive any new anticancer therapy, it will be counted
as a PFS event at the date of death. 
• If a subject has a baseline and at least one post-baseline adequate tumor assessment and had new
anticancer therapy before PD or death (No. 4), the subject will be censored at the date of the last
adequate tumor assessment on or prior to the date of new anticancer therapy 
• If a subject missed two or more tumor assessments (No. 7), the subject will be censored at the
date of the last adequate tumor assessment before the occurrence of more than one missing
assessment. Note that if a subject is censored by both of this criterion and start of new anticancer
therapy criterion, the earliest censoring date will be used. 
• Otherwise, if a subject had PFS event (No. 2, No. 5 or No. 6), the earliest event date will be used. 
2.  If a subject did not have PD or death, the censoring date will be the earliest censoring date if the subject 
met multiple censoring criteria (No. 1, No. 3, No. 4, No. 7). 
PFS will be presented in subject data listings. 
5.4.2.5 
Overall Survival 
OS is defined as the time from the date of first dose to the date of death from any cause.  
Subjects who are lost to follow up or withdrew consent will be censored at the date subject 
was last known to be alive, or the cutoff date, whichever occurs first. Subjects who remained 
alive will be censored at the time of data cutoff. Determination of the date of OS event or 
censoring is summarized in Table 4 below. 
Table 4  
OS Event and Censoring Rules 
Situation 
Date of Event or Censoring 
Outcome 
Death no later than data cut-off date 
Date of death 
OS Event 
Death after data cut-off  
Date of data cut-off 
Censored  
Subject still alive at data cut-off 
Date of data cut-off 
Censored  
Subject lost to follow-up or withdrawal of 
consent before data cut-off 
Date of last known to be alive  
Censored  
Note: date of subject disposition may be used as last known alive date if the disposition reason is 
Subject Choice, Withdrawal consent and Treatment ongoing at data cut-off.   
 
OS will be presented in subject data listings.  
5.4.2.6 
Change in Tumor Size in Injected Lesions  
For subjects with solid tumors based on modified RECIST 1.1 and iRECIST (if appropriate) 
assessments, a waterfall plot will be presented for the maximum percent change from baseline 


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in injected lesions. If a subject has multiple lesions injected, the first injected lesion will be 
included. 
5.5 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses 
5.5.1 
Pharmacokinetic Analyses 
Plasma concentrations of E7766 will be tabulated and summarized by dose level, day, and 
protocol specified time. Urine and fecal recovery of E7766 will be tabulated and summarized 
by dose level, day, and protocol specified collection interval.  
The Safety Analysis Set will be used for individual plasma concentration listings. The 
Pharmacokinetic Analysis Set will be used for all other analyses such as the summaries of 
plasma concentrations. 
E7766 PK parameters will be derived from plasma concentrations by noncompartmental 
analysis using actual times. Minimally, the following PK parameters will be calculated:  
• Cmax - Maximum drug concentration;  
• tmax - Time to reach Cmax following drug administration;  
• AUC - Area under the concentration-time curve;  
• t½ - apparent terminal half-life (if data permit);  
• CL/F - Apparent total body clearance;  
• Vd/F - Apparent volume of distribution;  
• R - Accumulation ratio post multiple doses;  
• fe - fraction of administered drug excreted/recovered in urine and feces.  
Details of the PK analyses will be described in a separate analysis plan and the results will be 
presented in a separate report. Metabolite PK will also be summarized in this report if 
exploratory characterization/identification of metabolites in urine and plasma is attempted 
depending on emerging nonclinical data.  
Any exploratory population PK or PK/PD modeling and simulation work, if done, will be 
described in details in a separate plan and a separate report.  
These plans and reports, if done, will be referenced and the high-level results and conclusions 
will be summarized in the clinical study report. 


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5.5.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses 
The effect of E7766 treatment on blood and/or tissue biomarkers, and/or immune cell subsets 
will be summarized using descriptive statistics. Pharmacodynamic, pharmacogenomic, and 
other biomarker analyses will be performed and reported separately.  
Details of these analyses will be described in a separate analysis plan and reported separately. 
5.6 
Safety/Tolerability Analyses 
Evaluation of DLTs will be performed on the DLT Analysis Set. The number and percentage 
of subjects with DLT will be calculated.  
All safety analyses will be performed on the Safety Analysis Set. Safety data will be 
summarized on an “as treated” basis using descriptive statistics.  
Safety variables include treatment-emergent AEs (TEAEs), clinical laboratory parameters, 
vital 
signs, 
12-lead 
electrocardiogram 
(ECG), 
ECOG 
performance 
status, 
echocardiogram/MUGA results including left ventricular ejection fraction (LVEF).  
Study Day 1 for all safety analyses will be defined as the date of the first dose of study drug. 
5.6.1 
Extent of Exposure 
The duration of treatment, number of study drug administered, and number of subjects 
requiring dose reductions and dose omission will be summarized. 
5.6.1.1 
Extent of Exposure to Study Drug 
The total number of treatment cycles for each subject is the largest cycle number in which a 
subject receives any non-zero dose of study drug. 
The treatment duration (days) will be calculated as the minimum of (day 1 of the last cycle 
with non-zero dose+21 days, or treatment disposition date) – date of the first non-zero dose. 
5.6.1.2 
Study Drug Administered  
The total number of dose administrations and total cumulative dose (µg) received per subject, 
and relative dose intensity will be summarized with descriptive statistics.    
The total number of doses received per subject will be calculated as the total number of 
injections with non-zero doses administered during the study per subject. The total cumulative 
dose per subject (µg) will be calculated as the sum of all doses (µg) that subject has actually 
received during the study. The relative dose intensity, which is defined as the ratio (%) of total 


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dose received and total planned dose (i.e., received dose as a percentage of sum of planned 
doses), will be calculated.  
Number of injected lesions per subject will also be summarized. 
5.6.1.3 
Study Drug Dose Modifications 
The guidance of E7766 dose modifications for Dose Escalation part and Dose Expansion part 
are outlined in protocol. 
Dose reduction refers to a situation that a planned dose level was reduced from the previous 
dose level without going back the previous dose level. Dose omission only refers to the 
scenario that the dose levels before and after omission period (defined as the period with 
planned dose=0) are the same. If the subject discontinued from treatment permanently after 
dose omission with planned dose=0, it should be counted as treatment discontinuation instead 
of dose omission. 
The number of subjects with dose reductions and dose omission will be summarized.  
Subject data listings will be provided for all dosing records. 
5.6.2 
Adverse Events 
5.6.2.1 
Dose Limiting Toxicity 
The number and percentage of subjects with DLT will be summarized for DLT Analysis Set.  
Subject data listing will be provided for DLT records. 
5.6.2.2 
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 21.1 or higher) lower level 
term (LLT) closest to the verbatim term. The linked MedDRA preferred term (PT) and primary 
system organ class (SOC) are also captured in the database.  
A TEAE is defined as an AE that emerges during treatment (on or after the first dose of study 
drug up to 90 days after the subject’s last dose) or start day of another anticancer therapy, 
whichever is earlier; or in case subject has initiated new anticancer therapy within 30 days, the 
AEs occurring for 30 days following the last dose of study drug, having been absent at 
pretreatment (baseline) or 
• Reemerges during treatment, having been present at pretreatment (baseline) but stopped 
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• Worsens in severity during treatment relative to the pretreatment state, when the AE is 
continuous, or 
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. 
Overview of TEAEs 
An overview of TEAEs reported through the study will be provided. Overall summary of 
TEAE will include the number and percentage of subjects with TEAEs, serious TEAEs, 
TEAEs of Grade 3 or higher, TEAEs leading to treatment discontinuation, TEAEs leading to 
dose reductions, TEAEs leading to dose interruptions, and TEAEs with fatal outcomes. Similar 
summaries for treatment-related TEAEs will also be provided. 
All TEAEs 
All TEAEs will be summarized by SOC and PT. A subject will be counted only once within 
an SOC and PT, even if the subject experienced more than 1 TEAE within a specific SOC and 
PT. The TEAEs will also be summarized by SOC, PT, and worst Common Terminology 
Criteria for Adverse Events (CTCAE) grade. 
Treatment-related TEAEs 
Treatment-related TEAEs will be summarized by SOC and PT. Treatment-related TEAEs 
include those events considered by the investigator to be related to study drug. Treatment-
related TEAEs will also be summarized by SOC, PT, and worst CTCAE grade. 
Grade 3 or higher TEAEs 
The grade 3 or higher TEAEs will be summarized by SOC and PT.  A subject data listing of 
grade 3 or higher AEs will be provided. 
Serious TEAEs 
Serious TEAEs will be summarized by SOC and PT. Similar summary for treatment-related 
serious TEAEs may also be presented. A subject data listing of all SAEs will be provided. 
TEAEs Leading to Treatment Discontinuation 
The TEAEs leading to discontinuation from study drug will be summarized by SOC and PT. 
A subject data listing of all AEs leading to discontinuation from study drug will be provided. 
TEAEs Leading to Dose Reductions and Dose Interruptions 


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The TEAEs leading to dose reductions and/or dose interruptions will be summarized by SOC 
and PT. A subject data listing of AEs leading to dose reductions and/or dose interruptions of 
study drug will be provided. 
TEAEs with Fatal Outcome 
The TEAEs with fatal outcome will be summarized by SOC and PT. Similar summary for 
treatment-related TEAEs with fatal outcome may also be presented.  
A subject data listing of AEs with fatal outcome will be provided. A listing of the AEs with 
fatal outcome not due to PD may also be provided. 
Deaths  
The number of subjects who died during the study will be summarized. In addition, the number 
of deaths within 90 days of last dose will also be presented. 
A listing of subjects who died during the study will be provided. 
5.6.3 
Laboratory Values 
Clinical laboratory tests to be performed for this study, including hematology, chemistry, and 
urinalysis. 
Laboratory results will be summarized using standard units, as appropriate.  
Laboratory parameters will be graded according to CTCAE Version 5.0. In the summary of 
laboratory parameters by CTCAE grade, for parameters with CTCAE grading in both high and 
low direction (eg, calcium, glucose, magnesium, potassium, sodium), CTCAE grades in both 
high and low directions will be summarized separately.  
Descriptive statistics for values and changes from baseline at each scheduled visit for 
quantitative hematology and chemistry laboratory parameters will be provided. Boxplots of 
laboratory values over time may be provided for selected hematology and chemistry 
parameters for subjects in the expansion cohort. 
In selected hematology and chemistry parameters, the worst CTCAE grade postbaseline and 
shift from baseline will be summarized in shift tables. Subject with nonmissing baseline and 
postbaseline results will be used as denominators in shift tables. 
Calcium corrected for albumin (mmol/L) will be calculated as: 
Calcium measured (mmol/L) + 0.025 (40 - Albumin (g/L)).  


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if result for Albumin is > 40 g/L, then calcium corrected for albumin (mmol/L) = Calcium 
measured (mmol/L). 
if albumin was missing, then calcium corrected for albumin is missing 
 
5.6.4 
Vital Signs 
Descriptive statistics for vital sign parameters (ie, systolic and diastolic blood pressure, pulse, 
respiratory rate, temperature, weight) and changes from baseline will be presented by visit.  
A subject data listing of vital signs will be provided. 
5.6.5 
Electrocardiograms 
ECG data includes 24 hour continuous Holter ECG, central and local 12-lead ECG data.  
Only local ECG data will be used for safety analysis. Descriptive statistics for ECG parameters 
and changes from baseline will be presented by visit. Shift tables will be presented for the 
changes from baseline in ECG interpretation (categorized as normal; abnormal, not clinically 
significant; and abnormal, clinically significant) to worst postbaseline category. 
In addition, the number (percentage) of subjects with at least 1 postbaseline abnormal ECG 
result in QTc Fridericia (QTcF) postbaseline will be summarized. Clinically abnormal ECG 
results in QTcF will be categorized as follows: 
Absolute QTcF interval prolongation: 
• QTcF interval >450 ms 
• QTcF interval >480 ms 
• QTcF interval >500 ms 
Change from baseline in QTcF interval: 
• QTcF interval increases from baseline >30 ms 
• QTcF interval increases from baseline >60 ms 
A subject data listing of local ECG only will also be provided. 
5.6.6 
Other Safety Analyses 
5.6.6.1 
Left Ventricular Ejection Fraction  
LVEF assessed on echocardiogram or MUGA scans will be listed.   


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5.6.6.2 
Eastern Cooperative Oncology Group Performance Status 
Shift table for ECOG performance status will be presented for the change from baseline 
classification to the worst postbaseline classification.   
A subject data listing of ECOG performance status will be provided. 
5.7 
Other Analyses 
No other analysis is planned. 
5.8 
Exploratory Analyses 
Exploratory analyses may be conducted as appropriate. Any exploratory analyses that are 
performed will be appropriately titled/labeled as exploratory and will be clearly distinguished 
from planned analyses when results are reported in abbreviated CSR. 
6 
INTERIM ANALYSES 
No formal interim analysis is planned for this study.  
Interim monitoring using a snapshot of the database will be conducted to determine the MTD 
and/or RP2D, or to confirm safety and detect efficacy signals in subjects with selected disease 
indications before the analysis for CSR. Database locks are not required to perform these 
interim evaluations.   
7 
CHANGES IN THE PLANNED ANALYSES     
MTD is not determined due to early termination of dose escalation part. As no subjects will 
be enrolled for dose expansion part, analysis for expansion arm will not be conducted. 
There will be an abbreviated CSR, the following analysis planned will be removed: 
• Protocol deviations 
• Medial history and Prior and concomitant medications 
• ECOG 
• Listings for tumor assessment 
• Efficacy analysis for efficacy analysis set 
• MUGA or Echocardiogram 


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8 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING 
8.1 
Visit Windows 
The purpose of this windowing is to provide a single record per subject per visit for the 
calculation of descriptive statistics per scheduled visit, and change from baseline per visit. In 
the calculation of by-visit analysis for laboratory values and vital signs, if multiple 
observations occurred on the same visit, the scheduled record will be used for summary tables. 
Other safety analyses (e.g., worst grade laboratory results and shift tables) will include all 
postbaseline assessments, including those scheduled and unscheduled visits. 
8.2 
Baseline Definitions 
In general, baseline value is defined as the last non-missing measurement taken on or prior to 
the first dose date. In particular, for laboratory assessments, vital signs and ECGs, the 
assessment collected pre-dose on the first dose date will be defined as baseline; other 
assessments, including unscheduled or postdose assessments on the first dose date will not be 
defined as baseline. 
Study day is defined as date of assessment – first dosing date + 1 for any assessment done on 
or after first dosing date; otherwise, study day is defined as date of assessment – first dosing 
date.  
8.3 
Imputation of Missing Data 
Unless specified otherwise, no data imputation will be applied for missing safety and 
efficacy evaluations. For analysis and reporting purpose, partial dates for adverse events, 
prior and concomitant therapies, disease diagnosis date, and start date of new anticancer 
therapy will be imputed if needed. Partial dates for laboratory values, vital signs, and ECGs 
will not be imputed. 
The imputation rules will be specified in study analysis dataset specification with more details. 
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 9.4 or higher, and/or other validated statistical software as required. 


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11 MOCK TABLES, LISTINGS, AND GRAPHS 
The study tables, listings, and graphs (TLGs) shells will be provided in a separate document, 
which will show the content and format of all the TLGs in details. 
 
 


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12 REFERENCES 
Bartholomew D. Isotonic inference. In: Samuel K, Norman LJ, editors. Encyclopedia of 
Statistical Science volume 4, New York: Wiley-Interscience. 1983;260-5. 
Guo W, Wang SJ, Yang S, Lynn H, Ji Y. A Bayesian interval dose-finding design addressing 
Ockham’s razor: mTPI-2. Contemp Clin Trials. 2017;58:23-33. 
Yan F, Mandrekar SJ, Yuan Y. Keyboard: a novel bayesian toxicity probability interval 
design for phase I clinical trials. Clin Cancer Res. 2017;23(15):3994-4003. 
 
 
 


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SIGNATURE PAGE
Author:
Oncology Business Group, Eisai Inc.
Date
Approval:
Oncology Business Group, Eisai Inc.
Date
Oncology Business Group, Eisai Inc.
 Clinical Pharmacology Science, Eisai Inc.
PPD
PPD
PPD
PPD
PPD