Conditions: Persistent or Recurrent Cutaneous T-Cell Lymphoma
Keywords: Persistent or Recurrent Cutaneous T-Cell Lymphoma E7777
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 112
Healthy volunteers: no

Brief summary:
The purpose of this trial is to assess the efficacy of E7777 in participants with recurrent or persistent Cutaneous T-Cell Lymphoma (CTCL) in Stage I - III participants as assessed by objective response rate (ORR). A lead-in dose-finding part was used to determine dose level 9 microgram per kilogram (mcg/kg) E7777 that is being used to test efficacy and safety.

Detailed description:
This is a multicenter, open-label study of E7777 in participants with recurrent or persistent CTCL. The study consists of an initial Lead-in part (to select recommended dose of E7777 for Main part), followed by the Main part (to test efficacy). Participants will move through three phases while on study: Pretreatment Phase, Treatment Phase, and Extension Phase and a Follow-up Period.

Arms:
arm 1: None

Interventions: intervention 1: E7777 9 mcg/kg
Intervention descriptions: intervention 1: administered by intravenous (i.v.) infusion over 60 minutes (+/-10 minutes) on 5 consecutive days during every cycle of 21 days

Protocol document:
Prot_000.pdf: 
Clinical Study Protocol 
Amendment 06 
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FINAL:  29 Oct 2019 
Confidential 
Page 1 of 113 
REVISION HISTORY 
DATE 
Version 
Number 
Highlights of Major Changes  
SECTION/CHANGE 
05 Sep 2012 
v1.0 
Original protocol 
17 Apr 2013 v2.0 
Amendment 01:   

Addition of a non-formal interim analysis to ensure that an
acceptably safe dose was established and at least one
objective response was recorded in the Lead-In part before
proceeding into the Main Study where larger numbers of
subjects will be studied.

An addition to the text was made allowing subjects with
visceral involvement into the Lead-In part of the study, to
correct an error in the original protocol.

The process and data flow for the reviewing committee in
Section 9.5.2.1 were clarified for comprehension.

The process for the mSWAT score, collection of data for skin
lesion measurements for supplemental response assessment,
and an addition of required photographic views in Section
9.5.2.2 for skin disease were explained in greater detail for
comprehension.

The assessment of visceral involvement in Section 9.5.2.2
was explained in greater detail for comprehension.

The Schedule of Assessments (Table 4) was updated to clarify
the flexibility in visit windows, to correct the timing of urine
pregnancy testing, the duration of collection of adverse events
and concomitant medications, lymph node biopsy processes,
thyroid testing processes, and to confirm timing of
confirmatory 
response 
assessments 
for 
improved
comprehension and consistency among sites.

Appendix 4 was revised to describe assessments of mSWAT
scoring and visceral disease measurements for greater
comprehension and consistency among sites.


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DATE 
Version 
Number 
Highlights of Major Changes  
SECTION/CHANGE 
22 Apr 2014 v3.0 
Amendment 02:   
 Dose limiting toxicity (DLT) definition for “serious infusion 
reaction” has been revised to allow an opportunity to assess if 
steroid premedication will be effective in managing Grade 3 
infusion reaction. 
 Dose limiting toxicity (DLT) definition for “capillary leak 
syndrome” (CLS) has been changed to be based on CTCAE 
grading, to promote consistency in assessment of DLT, and to 
take into consideration current standard practices enabling 
medically managing this toxicity. 
 Investigator-assessed tumor responses will be used for 
decision-making on initiating the Main Study. 
 A longer time period of 8 weeks is now allowed from the time 
of signing informed consent to start of treatment, to enable 
central laboratory testing of CD25 expression (for Inclusion) 
to be performed within the Screening period. 
 Results obtained at Screening of from an archival skin biopsy 
can be used as long as the test was performed by the study-
designated central laboratory. 
 Exclusion criterion “Need for treatment with a drug that 
contains a warning for hepatotoxicity or nephrotoxicity in its 
labeling.” has been removed; it is a carry-over from a 
historical ONTAK protocol. 
 Instructions for premedication have been additionally 
clarified to be consistent with change in DLT definition for 
infusion reaction, and to allow more flexibility in timing and 
type of premedication as individual situations vary. 
 Dose interruption and dose modification instructions have 
been revised to be consistent with changes in DLT definitions. 
 Repeat procedures close in time are now not necessary, e.g. 
chemistry and hematology labs at Screening may count as 
Baseline assessments if they were performed within one week 
of start of treatment. 
 Addition of an analysis set in the Statistical section, “All 
enrolled subjects”.   


Clinical Study Protocol 
Amendment 06 
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DATE 
Version 
Number 
Highlights of Major Changes  
SECTION/CHANGE 
20 Apr 2016 v4.0 
Amendment 03:   
 E7777 is no longer being referred to as “denileukin diftitox” 
as Sponsor may apply for a new proprietary name. 
 The dose of E7777 for the Main Study is now stated in the 
protocol, following completion of the Lead-In part.  The 
Protocol Steering Committee has selected 9 µg/kg as the dose 
of E7777 to move forward with, in the Main Study. 
 CTCL disease stage for subject inclusion in the Main Study 
now allows Stage IVA1 but excludes lymph node disease N2, 
N3; this is to align with subject population in the reference 
ONTAK study (L4389-11). 
 Pharmacokinetic sampling schedule revised and the number 
of samples taken has been reduced. 
 The Study Phases have been clarified such that Extension 
Phase occurs after data cutoff for primary analysis. 
 Drug administration instructions for a new lyophilized 
formulation is added. 
 Tumor assessment method description and schedules revised 
to align with changes in CTCL disease stage included 
 


Clinical Study Protocol 
Amendment 06 
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FINAL:  29 Oct 2019 
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Page 4 of 113  
 
The table below describes revisions in Amendment 04 per the new protocol template (Nov 
2016). 
Revisions per Amendment 04 (Version 5.0) 
Date: 26 Jun 2017 
Change 
Rationale 
Affected Protocol Sections 
Inclusion Criteria 4:  
CTCL disease stage for subject 
inclusion in the Main Study now 
allows Stage IA- IVA2 including 
lymph node disease N2 and N3. 
Advised by Protocol Steering 
Committee to include N2, N3 
patients as this patient population 
is expected to benefit from E7777, 
based on their clinical experience 
with ONTAK and E7777.  
Synopsis – Inclusion Criteria 
Section 9.3.1 
Inclusion Criteria 4:  
Removed exclusion of “ known 
CTCL involvement of the bone 
marrow” from Main Study 
eligibility.  
Bone marrow disease exclusion 
was following old ONTAK 
protocol (L4389-11). With 
updated ISCL/EORTC criteria, 
bone marrow involvement is 
considered as M1/ stage IVB, 
which is not included. 
Therefore, it is not necessary to 
state bone marrow disease 
exclusion anymore.  
Synopsis – Inclusion Criteria 
Section 9.3.1 
Inclusion Criteria 6:  
Definition of recovery from 
adverse effects from any previous 
CTCL therapy added as “to 
CTCAE Grade <2”.  
Added clarification 
Synopsis – Inclusion Criteria 
Section 9.3.1 
Exclusion Criteria 1:  
“CTCL disease with CNS 
involvement” removed. 
 
Redundant with exclusion criteria 
8 “active central nervous system 
disease” 
Synopsis – Exclusion Criteria 
Section 9.3.2 
Exclusion Criteria 3: 
Active malignancy other than 
CTCL is now excluded within 2 
years instead of 5 years.  
Updated criteria and language 
Synopsis – Exclusion Criteria 
Section 9.3.2 
Exclusion Criteria 9: 
Significant or uncontrolled 
infections requiring systemic anti-
infective therapy. 
 
Added clarification, updated term 
“specific” to “systemic” 
Synopsis – Exclusion Criteria 
Section 9.3.2 
Biopsy and histologic 
characterization requirement 
during screening updated:  
In the Main Study, biopsy and 
histologic characterization is 
strongly recommended if an 
Advised by Protocol Steering 
Committee for disease staging of 
subjects with N2/ N3, which are 
now included in the study.  
 
 
Section 9.5.2.2 


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Change 
Rationale 
Affected Protocol Sections 
abnormal peripheral node 
suspicious for CTCL is detected 
by CT scans during Screening.   
Schedule of CT Scans modified: 
Additional CT scans are now 
required every 3 cycles (±1 week) 
during treatment for subjects with 
N2, N3, and Nx. 18FDG-PET-CT 
scans may also be acquired during 
screening. 
Advised by Protocol Steering 
Committee for monitoring nodal 
disease and response assessment 
Section 9.5.2.2 
Secondary Efficacy Variables:  
Skin response will be calculated 
with a 2-sided, exact 95% 
confidence interval (CI), using the 
Clopper-Pearson method.  Skin 
response, duration of skin 
response, and time to skin 
response are added, which will be 
calculated based on mSWAT 
score. 
Definition DOR updated as “time 
from the date when criteria for 
response (CR or PR) based on 
GRS was first met until the date 
when the response was first 
lost (date of loss is date when 
first meets criteria for PD)”.  
Removed “or relapse” from the 
date of loss. 
These efficacy variables for skin 
disease are also relevant. 
 
 
 
 
 
 
Advised by Protocol Steering 
Committee to avoid scenario 
where a relapse may not reflect 
disease progression.  
Synopsis-  
Objectives  
Criteria for Evaluation,  
Statistical Methods 
Section 9.7.1.2 
Section 9.7.1.7 
Section 8.2 
Treatment continuation beyond 8 
cycles is now allowed for subjects 
with skin tumor response and 
deriving clinical benefit from 
E7777 treatment instead of 
objective tumor response.  
Advised by Protocol Steering 
Committee that in this disease, 
subjects with skin response are 
considered to have had clinical 
benefit.  
Synopsis – Study Design 
Section 9.1.1 
Section 9.1.4 
Section 9.4.1 
Removed requirement of visual 
acuity tests.  
Section 9.5.4.7 is removed. 
Data from lead-in part should be 
sufficient for analysis.  
Severe grade loss of visual acuity 
was not reported during lead-in 
part.  
Synopsis (Safety Analysis) 
Section 9.5.4 
Section 9.5.4.7 
Section 9.5.5.1 
Section 9.5.5.2 
Appendix 5 
Charter for Lymph Node Disease 
Assessment is added. 
Added clarification 
Appendix 5 
 


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Change 
Rationale 
Affected Protocol Sections 
Appendix 4 – Global Response 
Score 
Added “Only N3 is considered as 
nodal disease (nodal involvement) 
for Global Response Score 
assessment.” 
Advised by Protocol Steering 
Committee – only N3 is 
considered as CTCL nodal 
involvement.  
Per ISCL/EORTC Staging, N0 to 
N2 is included from stage IIA to 
IVA1 and does not change the 
disease stage, whereas N3 is stage 
IVA2. 
Appendix 4, Table 5 
Appendix 5 
The table below describes revisions in Amendment 05 per the new protocol template (Nov 
2016). 
Revisions per Amendment 05 (Version 6.0) 
Date: 03 May 2018 
Change 
Rationale 
Affected Protocol Sections 
Updated Principles of the World 
Medical Association Declaration 
of Helsinki from 2008 to 2013.  
2013 is the current version.   
5.2  
Inclusion Criteria 3; Other 
Screening Assessments; Tumor 
Assessment Methods and 
Schedule:  
Deleted specific references to 
“skin” (in the context of CD25 
detection on lymphoid infiltrate in 
biopsied lesions by 
immunohistochemistry), and 
replaced with general reference to 
“tumor”. 
There is no rationale to limit 
assessment of CD25 expression 
only in “skin” biopsies.  CD25 
expression can be detected by the 
same central laboratory IHC-
based assessment in malignant 
cells within the skin biopsies or in 
other tumor lesions, e.g. in lymph 
node biopsies.   
 
Synopsis – Inclusion Criteria 
Section 9.3.1 
Section 9.5.1.2 
Section 9.5.5.1, Table 4 
Included creatine phosphokinase 
(CPK) testing as a monitoring 
procedure. 
CPK testing was included as a 
monitoring procedure as requested 
by FDA in response to a safety 
report (fatal AE rhabdomyolysis) 
under IND 110489 (SD 51/SN 
0050).   
Section 9.4.1.3 
Section 9.5.4.3, Table 3 
Section 9.5.5.1, Table 4 (footnote 
h) 
 
Updated CTCAE from v4.03 to 
v5.0.  
v5.0 CTCAE is the current 
version. 
9.5.4.1, 9.7.1.9, 10, 12 (Appendix 
6) 
Revised guidelines for ECG 
monitoring as follows: 
 
Triplicate ECGs are no longer 
required  
 
QT/QTcF interval will no 
longer be assessed by a central 
laboratory 
 
Single 12-Lead ECGs will be 
performed during Screening, 
Rationale: 
Reduce ECG monitoring based on 
Lead-in part ECG data analysis, 
ONTAK safety profile and E7777 
clinical experience.  
 
Section 9.5.4.6 
Section 9.5.5.1, Table 4 (footnote 
f) 


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Change 
Rationale 
Affected Protocol Sections 
Day 1 of each cycle and End 
of Treatment 
 
The table below describes revisions in Amendment 06 per the previous protocol template 
(Nov 2016). 
Revisions per Amendment 06 (Version 7.0) 
Date:  29 Oct 2019 
Change 
Rationale 
Affected Protocol 
Sections 
Removed ‘registration of’ from 
GCP statement 
ICH updated its formal title in 2018. 
Title page 
Section 4 
Investigator signature page 
Updated exploratory objective 
quality of life (QoL) to include 
Stage I-III subjects.   
QoL will be assessed in Stage I – III Main 
Study subjects and Stage I – III Lead-In 
subjects from the 9µg/kg/day dose group 
combined.  
Synopsis 
Section 8.2 
9.5.5.1, Table 4 (footnote 
p) 
Included Stage I – III subjects in 
evaluation of efficacy and safety 
for the Main Study and Stage I 
– III Lead-In subjects from the 
9µg/kg/day dose group.  Stage I 
– III subjects will be used for 
the primary efficacy analysis.  
ONTAK study L4389-11 is the reference 
study from which this current study (E7777-
G000-302) derives the statistical basis to 
calculate the sample size and the lower 
bound criteria for the 95% confidence 
interval (25%) for the objective response 
rate.  ONTAK study L4389-11 was 
conducted in subjects with Stage I-III 
cutaneous T-cell lymphoma (CTCL).  To 
align with that study population, the 
primary analysis of the current study will be 
conducted in Stage I – III Main Study 
subjects and Stage I – III Lead-In subjects 
from the 9µg/kg/day dose group combined. 
Subjects with Stage IVA1 and IVA2 CTCL 
will no longer be eligible to participate in 
the study.   
Synopsis 
Section 8.2 
Section 9.3Section 9.5.2.1 
 
Updated the target number of 
Stage I – III study subjects. 
A sufficient number of subjects will be 
treated for a total of approximately 70 Stage 
I – III subjects from the Lead-In and Main 
parts of the study combined. 
Synopsis 
Section 9.1.1 
Section 9.1.3 
Section 9.3 
Section 9.7.2 
Updated number of study sites. 
The number of study sites was updated to 
provide flexibility in accommodating the 
updated number of subjects for the study 
(approximately 115 subjects total). 
Synopsis 
Section 9.3 
Corrected the scale and score 
for assessment of pruritus.  
Updated to show the correct scale (100 
indicates worst possible itch); updated 
baseline score to be ≥20.   
Synopsis 
9.5.2.3 


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Change 
Rationale 
Affected Protocol 
Sections 
Updated immunogenicity 
assessments.  
Evaluation of positive anti-IL-2 
immunogenicity samples after treatment 
with E7777 will be carried out for 3 years or 
until samples are negative.  
Synopsis 
9.5.3.2 
9.5.5.1, Table 4 (footnote 
i) 
Updated definitions of analysis 
sets. 
Stage I – III subjects will be used for the 
primary efficacy analysis. 
Synopsis 
Section 9.7.1.3 
Updated the planned efficacy 
analyses.  
Stage I – III subjects will be used for the 
primary efficacy analysis. 
Synopsis 
Section 9.7.1.7 
Updated the planned safety 
analyses.  
Safety analyses for the main part of the 
study will be performed in all subjects, and 
Stage I – III subjects separately. 
Synopsis 
Section 9.7.1.9 
Clarified criteria for follow-up 
of subjects with 
immunogenicity.  
Immunogenicity should be followed up in 
subjects who develop progressive disease 
since they are exposed to E7777.  
Section 9.5.5.1, Table 4 
(footnote q) 
 
 


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1 
TITLE PAGE 
 
Clinical Study Protocol 
Study Protocol 
Number: 
E7777-G000-302 
Study Protocol 
Title: 
A Clinical Study to Demonstrate Safety and Efficacy of E7777 in 
Persistent or Recurrent Cutaneous T-Cell Lymphoma 
Sponsor 
Eisai Inc. 
100 Tice Boulevard 
Woodcliff Lake,  
New Jersey 07677 
US 
Investigational 
Product Name: 
E7777 
Indication: 
Cutaneous T-Cell Lymphoma 
Phase: 
3 
Approval Date:  
V1.0 
05 Sep 2012 (Original Protocol) 
 
V2.0 
17 Apr 2013 (Protocol Amendment 01) 
 
V3.0 
22 Apr 2014 (Protocol Amendment 02) 
 
V4.0 
20 Apr 2016 (Protocol Amendment 03) 
 
V5.0 
26 Jun 2017 (Protocol Amendment 04) 
 
V6.0 
03 May 2018 (Protocol Amendment 05) 
 
V7.0 
29 Oct 2019 (Protocol Amendment 06) 
GCP Statement: 
This study is to be performed in full compliance with International 
Conference on Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) and all applicable local 
Good Clinical Practice (GCP) and regulations.  All required study 
documentation will be archived as required by regulatory 
authorities. 
Confidentiality 
Statement: 
This document is confidential.  It contains proprietary information 
of Eisai (the sponsor).  Any viewing or disclosure of such 
information that is not authorized in writing by the sponsor is 


Clinical Study Protocol 
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strictly prohibited.  Such information may be used solely for the 
purpose of reviewing or performing this study. 


Clinical Study Protocol 
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2 
CLINICAL PROTOCOL SYNOPSIS 
Compound No.:  E7777 
Name of Active Ingredient:  Recombinant fusion protein composed of the amino acid sequences for 
diphtheria toxin fragments A and B (Met1-Thr387)-His and for human interleukin-2 (Ala1-Thr133) 
Study Protocol Title: 
A Clinical Study to Demonstrate Safety and Efficacy of E7777 in Persistent or Recurrent Cutaneous T-Cell 
Lymphoma  
Investigator(s) 
Multiple Investigators 
Site(s) 
Approximately 20 centers globally 
Study Period and Phase of Development 
Approximately 12 months for the Lead-In 
Approximately 30 months for the Main Study (from first subject in  to data cutoff) 
Registrational study 
Objectives 
Lead-In Objectives  
 
Primary objectives: Establish the maximum tolerated dose (MTD) of E7777 and to select the dose of E7777 
to be used in the Main Study 
 
Secondary objectives: Assess safety, tumor response, pharmacokinetics (PK) and immunogenicity after 
treatment with E7777 
Main Study Objectives 
All Main Study efficacy analyses will be performed primarily in the Stage I – III Main Study subjects plus the 
Stage I – III Lead-In subjects from the 9µg/kg/day dose group, as well as additionally in all subjects from the 
Main Study. 
Primary Objective: 
 
 
To demonstrate efficacy of E7777 in subjects with recurrent or persistent cutaneous T-cell lymphoma 
(CTCL) in Stage I – III subjects as assessed by objective response rate (ORR) (Objective Response is 
Complete Response and Partial Response, according to the ISCL/EORTC* Global Response Score [Olsen 
2011]) 
 
Secondary Objectives: 
 
To determine Duration of Response (DOR) for E7777  
 
To determine Time to Response (TTR) after E7777 treatment 
 
To determine skin response after E7777 treatment 
 
To determine duration of skin response after E7777 treatment 
 
To determine time to skin response after E7777 treatment 
 
To assess ORR for E7777 using the alternate response assessment criteria of Prince (2010)   
 
To evaluate safety and tolerability of E7777 in all subjects  
 
To evaluate safety and tolerability of E7777 in the Stage I – III Main Study subjects plus the Stage I – III 
Lead-In subjects from the 9µg/kg/day dose group combined  


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 
To characterize the pharmacokinetics (PK) of E7777 and immunogenicity after treatment with E7777      
Exploratory Objectives: 
 
To assess the following efficacy endpoints for subjects treated with E7777:  progression free survival (PFS), 
and time to progression (TTP) (using Global Response Score)  
 
To assess pruritus improvement reported by subjects treated with E7777 
 
To assess Quality of Life (QoL) for (1) all subjects treated in the Lead-In part, (2) all subjects treated in the 
Main Study, (3)  Stage I – III Main Study subjects plus Stage I – III Lead-In subjects from the 9µg/kg/day 
dose group combined 
* International Society for Cutaneous Lymphomas/European Org of Research and Treatment of Cancer  
Study Design  
This will be a multicenter open-label single-arm study of E7777 in subjects with recurrent or persistent CTCL. 
The study will consist of an initial Lead-In part followed by the Main Study: 
Lead-In:  A Continuous Reassessment Method (CRM) will be employed to establish the MTD of E7777 and to 
select the dose of E7777 to be used in the Main Study.  Approximately 20 subjects will be treated. 
Main Study:  A sufficient number of subjects in the Main Study will be recruited so that approximately 70 
Stage I – III subjects from both the Main Study and from the Lead-In subjects in the 9µg/kg/day dose group 
with recurrent or persistent CTCL will be treated with E7777 to assess efficacy.  Safety will be evaluated in all 
subjects from the Main Study, and in the Stage I – III Lead-In subjects from the 9µg/kg/day dose group.  The 
dose of E7777 in the Main Study will be the dose selected in the Lead-In part of the study.  The primary 
efficacy analysis will be based on Stage I – III subjects from both the Main Study plus from the Lead-In 
9µg/kg/day dose group combined. 
Lead-In 
A Continual Reassessment Method (CRM) will be employed to determine the maximum tolerated dose (MTD) 
of E7777, targeting a rate of dose-limiting toxicity (DLT) of approximately 20%. 
Subjects will be treated with E7777 using the regimen described under “Study Treatment”.  The doses of E7777 
that may be used are 3, 6, 9, 12, 15, or 18 µg/kg/d, with 6 µg/kg/d specified as the starting dose.  Each subject 
will be assigned a dose of E7777 in accordance with the rules of the CRM design.  The CRM design is described 
under “Statistical Methods”. 
Dose-limiting toxicities (DLTs) are based on known toxicities of ONTAK as described in the US product label.  
A DLT will be any of the following occurring within the first cycle of therapy: 
 
Serious infusion reaction, defined as CTCAE Grade 4 adverse event of “Infusion related reaction”, or 
recurrent CTCAE Grade 3 despite administration of systemic steroid premedication after initial occurrence.  
Infusion reactions are defined as symptoms (e.g., fatigue, nausea, vomiting, arthralgia, myalgia, pyrexia, 
chills, rigors) occurring within 24 hours of E7777 infusion.  
 
Capillary leak syndrome (CLS) CTCAE Grade 4 or Grade 3 (with exceptions). 
The CTCAE definitions are broad and general, therefore, the following guidance is provided: 
o Grade 4 is severity such as subjects experiencing hypovolemic shock or renal failure, or who need 
treatment with vasopressors or oxygen. 
o Grade 3 is severe symptoms (less severe than the Grade 4 symptoms above) that may or may not be 
dose-limiting.  For example, severe symptoms requiring hospitalization for acute intervention would 
be a DLT, whereas less severe symptoms leading to hospitalization for prophylactic treatment with 
fluids or diuretics would not be a DLT.  Hospitalization or medical intervention to prevent 
hospitalization is not in itself a DLT as the threshold for hospitalization may differ by doctor and region.   
CLS is defined as the noted occurrence of at least 2 of the following:  hypotension, edema, or serum albumin 
< 3.0 g/dL.  These are not required to occur simultaneously to be characterized as CLS. 
 
Loss of visual acuity.  This could be with loss of color vision, with or without retinal pigment mottling. 
 
Any CTCAE ≥ Grade 4 adverse event that may represent an infusion reaction 


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 
Any CTCAE Grade 3 adverse event that may represent an infusion reaction that prevents the entire dose of 
E7777 from being administered despite appropriate treatment 
 
Any other Grade 3 or greater toxicity assessed as related to E7777 treatment, and which in the opinion of a 
safety consultancy investigator panel constitutes a dose-limiting toxicity. 
Determination as to whether a subject has experienced a DLT will be made by the treating physician in 
consultation, as needed, with the medical monitor and investigator(s) on the Protocol Steering Committee 
(PSC) who are experienced in the use of denileukin diftitox. 
Subjects who are not evaluable for DLT in Cycle 1 should be replaced. 
If, during the course of the Lead-In, a trend is noted by the PSC where the E7777 toxicities described above are 
observed beyond the first cycle but not in Cycle 1, the definition of DLT may be amended to reflect that. 
Selection of the dose of E7777 that will be used in the Main Study was made in consultation with the PSC, based 
on review of the full output of the CRM data. 
Main Study 
Enrollment in the Main Study will commence after an acceptably safe dose has been established in the Lead-In 
part (as described above), and there is at least one objective response by investigator assessment recorded in the 
Lead-In. 
The objectives of the Main Study are to assess efficacy and safety of E7777 in Stage I - III subjects with recurrent 
and persistent CTCL.  A sufficient number of subjects in the Main Study will be treated for an approximate total 
of 70 Stage I – III subjects from both the Main Study and from Lead-In subjects from the 9µg/kg/day dose group 
combined. 
Study Phases for Each Subject 
All subjects in the study will move through three Phases while on study. 
 Pre-Treatment Phase,  consists of two Periods: 
o Screening 
o Baseline 
 Treatment Phase, consists of the following Periods: 
o Treatment with E7777 for up to 8 Cycles; each Cycle of 21 days is one Period. Subjects who have 
attained skin tumor response and are deriving clinical benefit from E7777 treatment may continue 
receiving treatment beyond 8 cycles, at the discretion of the treating physicians. 
o Follow-up: Tumor assessment until discontinuation of treatment due to PD; immunogenicity, and 
survival follow-up until relapse or initiation of new systemic anti-cancer therapy.  All Follow-up 
assessments performed for up to 3 years after end of treatment, or until sponsor termination of the study. 
After data cutoff for the primary analysis in the Main Study, the study moves to the Extension Phase. 
 Extension Phase, consists of the following Periods: 
o Treatment, for continued treatment of subjects with ongoing treatment at data cutoff.  Subjects will be 
treated for up to 8 cycles. Subjects who have attained skin tumor response and are deriving clinical benefit 
from E7777 treatment may continue receiving treatment beyond 8 cycles, at the discretion of the treating 
physicians. 
o Follow-up: Tumor assessment until discontinuation of treatment due to PD; immunogenicity, and 
survival follow-up until relapse or initiation of new systemic anti-cancer therapy.  All Follow-up 
assessments performed for up to 3 years after end of treatment, or until sponsor termination of the study. 
Pharmacokinetic (PK) assessment of E7777 will be performed in all subjects in the Lead-In part and in the first 
12 subjects in the Main Study, using serial blood PK sampling on Day 1 in Cycles 1, 3, and 5, with sparse 
sampling in Cycle 8.  In addition, sparse sampling will be performed in the Main Study in the rest of the subjects 
on Day 1 of Cycle 1. 


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Immunogenicity (formation of antibodies to E7777 or IL-2) will be assessed in all subjects in both the Lead-In 
part and the Main Study.  A predose blood sample for immunogenicity assessment will be collected prior to Day1 
dosing in Cycles 1, 2, 3, 5, and 8; after that, all subjects will be followed up for immunogenicity testing for anti-
IL2 on a 6-month schedule for one year and every year thereafter until antibody titers decrease to baseline level 
or upon study termination. 
The primary analysis will be performed after data cut-off which will be either of the following two events, 
whichever occurs later: (1) when all subjects in the Main Study have either completed Cycle 8 or are off 
treatment, or (2) when all subjects with at least one documented timepoint response of PR or better have 
undergone the subsequent tumor assessments necessary for confirmation of response (unless subject had disease 
progression or discontinued from study before that).   
Number of Subjects 
Approximately 20 subjects will be treated in the Lead-In part.  A sufficient number of subjects in the Main 
Study will be treated for an approximate total of 70 Stage I – III subjects from both the Main Study and from 
Lead-In subjects from the 9µg/kg/day dose group combined.  The study total will be approximately 
115 subjects with recurrent or persistent CTCL. 
Inclusion Criteria 
 Subjects must meet all of the following criteria to be included in the study: 
1. Age ≥18 years. 
2. Histopathologic diagnosis of CTCL (mycosis fungoides or Sezary Syndrome), confirmed by skin biopsy, 
or lymph node, or blood assessment, of current disease. 
3. CD25 assay-positive tumor, defined as detectable CD25 on ≥ 20% of total lymphoid infiltrate in biopsied 
lesions by immunohistochemistry, assessed by central pathology laboratory.  Results obtained at Screening 
or from an archival tumor biopsy (≤ 6 months) can be used as long as the test was performed by the study-
designated central laboratory.  Re-biopsy is required if the subject had disease progression or relapse since 
the last biopsy, or had received anti-cancer therapy since the last biopsy.  
4. CTCL disease at study entry according to ISCL/EORTC (Olsen 2011). 
 
Lead-in part: Stage IA – IV, except subjects with CNS involvement 
 
Main Study: Stage I – III 
5. History of prior therapies for CTCL as follows: must have had prior therapy; any number of prior therapies 
allowed.  
Topical treatments (except topical chemotherapy) and steroids are not considered as prior therapies. 
Prior therapies include: cytotoxic chemotherapy, combination cytotoxic chemotherapy, electron beam 
radiotherapy (EBRT), phototherapy (e.g., PUVA or UVB), photophoresis, interferon, topical 
chemotherapy (e.g., carmustine, nitrogen mustard), systemic retinoids, cyclosporin A (≥4 mg/kg/d for 
≥1 month), or histone deacetylase inhibitors. 
Repeated use of the same agent counts as one therapy, unless part of a different combination regimen. 
6. A minimum wash-out period of 4 weeks after previous CTCL therapy is recommended before the first dose 
of E7777.  Subjects must have recovered from any adverse effects from any previous CTCL therapy to 
CTCAE Grade <2 before starting study drug.  A shorter washout may be allowed if subject is experiencing 
progressive disease despite ongoing treatment. 
7. 
Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2 in the Lead-in part, and 
performance status 0 or 1 in the Main Study. 
8. 
Life expectancy ≥3 months in the Lead-in part, and ≥12 months in the Main Study. 
9. 
Adequate bone marrow reserve as evidenced by: 
o platelets ≥ 100,000/mm3 (100x109/L) 
o clinically stable hemoglobin ≥ 9 g/dL (90 g/L) and hematocrit ≥27% without transfusion support. 
10. Normal hepatic function as evidenced by: 
o bilirubin ≤ 1.5 × ULN and alkaline phosphatase ≤3.0 × ULN 


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o aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 × ULN 
o albumin ≥ 3.0 g/dL (30 g/L) 
If AST or ALT values are elevated, a second determination may be done ≥ 4 days later; if the values 
obtained upon the retest meet the above criteria, then the subject is considered to have met this criteria for 
entry 
11. Adequate renal function as evidenced by serum creatinine ≤ 1.8 mg/dL (158 µmol/L) OR calculated 
creatinine clearance ≥ 50 mL/min (per the Cockcroft-Gault formula) with < 2+ protein OR 24-hour urine 
creatinine clearance ≥ 50 mL/minute with 24-hour urine protein < 1g. 
12. Willing and able to comply with all aspects of the protocol. 
13. Provide written informed consent prior to any study-specific screening procedures. 
14. Females may not be lactating or pregnant at Screening or Baseline (as documented by a negative beta-
human chorionic gonadotropin [ß-hCG] test with a minimum sensitivity of 25 IU/L or equivalent units of 
ß-hCG).  A separate baseline assessment is required if a negative screening pregnancy test was obtained 
more than 72 hours before the first dose of study drug. 
15. All females will be considered to be of childbearing potential unless they are postmenopausal (amenorrheic 
for at least 12 consecutive months, in the appropriate age group, and without other known or suspected 
cause) or have been sterilized surgically (i.e., bilateral tubal ligation, total hysterectomy, or bilateral 
oophorectomy, all with surgery at least 1 month before dosing). 
16. Females of childbearing potential must agree to use a highly effective method of contraception (e.g., total 
abstinence, an intrauterine device, a double-barrier method [such as condom plus diaphragm with 
spermicide], a contraceptive implant, an oral contraceptive, or have a vasectomized partner with confirmed 
azoospermia) throughout the entire study period and for 30 days after study drug discontinuation.  If 
currently abstinent, the subject must agree to use a double-barrier method as described above if she 
becomes sexually active during the study period or for 30 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 4 weeks prior to dosing and must continue to use the same contraceptive 
during the study and for 30 days after study drug discontinuation. 
17. Male subjects must have had a successful vasectomy (confirmed azoospermia) or they and their female 
partner must meet the criteria above (i.e., not of childbearing potential or practicing highly effective 
contraception throughout the study period and for 30 days after study drug discontinuation). 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from the study: 
1. 
Prior denileukin diftitox therapy. 
2. 
Use of topical steroids within 14 days of Day 1 of initial therapy is not allowed, with the following 
exception: 
Topical steroids or systemic low dose steroids (≤10 mg/day prednisone) are allowed in subjects with 
erythroderma who have been on corticosteroids for a prolonged period of time and where discontinuation 
may lead to rebound flare in disease.  The concomitant steroid medication is allowed as long as the type 
of steroid, route of administration, and steroid dose remain the same as the subject had been receiving for 
a prolonged period of time 
3. 
Active malignancy (except for CTCL, definitively treated basal or squamous cell carcinoma of the skin, 
and carcinoma in-situ of the cervix) within the past 24 months. 
4. 
Serious intercurrent illness. 
5. 
Significant cardiac disease requiring ongoing treatment, including congestive heart failure (CHF), severe 
coronary artery disease (CAD), cardiomyopathy, uncontrolled cardiac arrhythmia, unstable angina 
pectoris, or myocardial infarction (MI) (within 6 months of study enrollment). 
6. 
Significant pulmonary symptoms or disease. 
7. 
History of uncontrolled seizure disorder or active central nervous system disease. 
8. 
Major surgery within 2 weeks of study enrollment. 


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9. 
Significant or uncontrolled infections requiring systemic anti-infective therapy. 
10. Known human immunodeficiency virus (HIV) infection; known active hepatitis B or hepatitis C infection. 
11. Females who are pregnant (positive urine test) or breastfeeding. 
12. 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. 
Study Treatment(s) 
E7777 administered by intravenous (i.v.) infusion over 60 minutes on 5 consecutive days every cycle of 21 days. 
 Premedication regimen for all subjects: 
Premedication for E7777 is required in Cycles 1 to 3, and is optional from Cycle 4 onward.  The following 
should be administered approximately 30 minutes prior to each E7777 drug infusion: 
o Acetaminophen 650 mg by mouth (or per local institutional guideline [eg, paracetamol 500 mg by mouth]) 
to prevent fever and chills 
o Diphenhydramine 25 mg intravenous push or other antihistamine per local institutional guideline, to 
prevent hives, itching, rash, shortness of breath, and chills 
o Antiemetic agents per institutional standard 
o Hydration with 250 to 500 mL normal saline i.v. (or other amount of fluid considered to be most 
appropriate for the subject’s condition, according to the judgment of the treating physician) before and 
after each E7777 infusion 
 Premedication with systemic steroids: 
o Lead-In part. Subjects should not receive premedication with systemic steroids with the following 
exception: 
- In the event that a subject experiences an infusion reaction (i.e. within 24 hours of infusion) CTCAE 
(grade 2 or 3) after the first administration of E7777 on Cycle 1 Day 1, the premedication regimen for 
that subject must be supplemented during the rest of Cycle 1 (Days 2-5) with systemic corticosteroids 
(see below).  Steroid premedication may be administered during subsequent treatment cycles at the 
discretion of the treating physician 
- In the event that a subject experiences an infusion related reaction at any time during any treatment 
cycle, the premedication regimen for that subject may be supplemented with systemic corticosteroids 
during the remainder of treatment days for that cycle (if event occurred before completion of cycle 
treatment) and/or in subsequent treatment cycles, at the discretion of the treating physician 
- Systemic corticosteroid premedication should be dexamethasone 4 mg, slow intravenous push OR 
equivalent corticosteroid dose according to institutional guidance. 
o Main Study.  Same guidance as for the Lead-In. 
Duration of Treatment 
Study duration for each subject is as follows: 
 
Pre-treatment (screening and baseline):  4 weeks 
 
Treatment:  up to 24 weeks (8 cycles) 
 
Extension:  follow-up only, for up to 3 years after the end of study treatment 
Treatment will stop upon completion of 8 cycles or disease progression* or unacceptable toxicity.  The 
investigator or subject may also stop study treatment at any time for safety or personal reasons; however subject 
should remain on study, if possible, for follow-up. 
* Treatment may continue after first notation of disease progression (PD) if the investigator is of the opinion 
that PD needs to be confirmed, e.g. in cases where (a) the apparent increased tumor burden in the skin or lymph 
nodes may reflect immune reaction/flare, or (b) the subject shows improvement or stable disease in the skin but 
increase in lymph node size. 
Concomitant Drug/Therapy 
o Topical steroids or systemic low dose steroids (equivalent to ≤ 10 mg/day prednisone) may be considered 
in subjects with erythroderma who have been on corticosteroids for a prolonged period of time and where 


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discontinuation may lead to rebound flare in disease, adrenal insufficiency, and/or unnecessary suffering. 
The concomitant steroid medication is allowed as long as the type of steroid, route of administration, and 
steroid dose remain the same as what the subject had been receiving for the prolonged period. 
Medications allowed for relief of CTCL signs and symptoms are:  hydroxyzine (25 mg), or ointments/lotions as 
specified in the protocol. 
Assessments 
Analysis Sets: 
All Enrolled Subjects:  All subjects who signed informed consent, and at Screening were assessed as meeting 
all inclusion criteria and not meeting any exclusion criteria.  This will be the analysis set for demographics and 
baseline characteristics analyses. 
Dose-Finding Analysis Set: All subjects in the Lead-In Part who completed Cycle 1 treatment and were 
evaluated for DLT, and those who discontinued during Cycle 1 due to DLT.  This will be the analysis set for 
MTD determination in the Lead-In. 
Full Analysis Set:  All subjects who received study drug in the Main Study. 
Primary Efficacy Analysis Set:  All Stage I – III Main Study subjects who received study drug plus the Stage I 
– III Lead-In subjects from the 9µg/kg/day dose group.  
Safety Analysis Set:  All subjects who received study drug.  This will be the analysis set for all safety analyses. 
Stage I-III Safety Analysis Set:  All Stage I – III Main Study subjects who received study drug plus the Stage I 
– III Lead-In subjects from the 9µg/kg/day dose group treated with E7777.  
Per Protocol Set:  All subjects in the Primary Efficacy Analysis and Full Analysis Sets who received study drug, 
and had a baseline and at least one post-dose tumor assessment and had no major protocol deviations.  The per 
protocol analysis set will be identified prior to database lock.  Full criteria for exclusion from the analysis set will 
be detailed in the statistical Analysis Plan.  This will be the secondary analysis set for the efficacy analyses. 
PK Analysis Set:  All subjects from whom at least one valid E7777 pharmacokinetic parameter is obtained will 
comprise the analysis set for the PK and immunogenicity. 
Population PK Analysis Set:  All subjects from whom at least one quantifiable concentration of E7777 is 
available with a documented dosing history. 
Population PK/PD Analysis Set:  All subjects in the Population PK Analysis Set in whom efficacy and safety 
variables are also available. 
Efficacy Assessments:  
The ISCL/EORTC response criteria for mycosis fungoides and Sezary syndrome (Olsen 2011) will be used for 
efficacy analysis in the Lead-In as well as for primary efficacy analysis in the Main Study. 
Tumor responses will be assessed by an independent central Response Review Committee (IRC) (Imaging Core 
Laboratory) for primary efficacy analysis in the Main Study.  Tumor responses will also be assessed by the site 
investigator, and these site assessments will be used to make subject treatment decisions. 
The response criteria described in Prince (2010) will be used as a supplemental alternate method (SAM) for the 
secondary objective of ORR.  This supplemental assessment will be conducted by the IRC only. 
For both the Lead-In and Main Study, photographs and CT scans will be sent by the investigator site to an 
Independent Imaging Core Laboratory designated by the sponsor for analysis.  Laboratory results, including 
blood, as well as investigator skin assessments as entered in the CRF, will be sent to the Core Laboratory by the 
sponsor.  At the time of data cutoff for primary analysis of the Main Study, the sponsor may choose to discontinue 
sending data (including photographs and scans) to the Imaging Core Laboratory. 
Tumor assessment schedule (see protocol body for details): 
 
At screening, skin, lymph node assessment by palpation, blood assessment, and CT scan for assessment of 
nodal and visceral disease. 
 
During treatment: (1) skin and blood disease assessment, on Day 1 of every cycle, (2) lymph node 
assessment by palpation and CT scans of nodal disease (as needed) and visceral disease (as needed), and 
(3) lymph node biopsy is only recommended in situations where the histology would affect the Global 


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Response score.  End-of-treatment tumor assessments should be performed if required for Global Response 
Score determination. 
Follow-up: (1) skin and blood disease assessment to be performed every 4 weeks for 1 year after end of study 
treatment, then every 12 weeks thereafter for up to 3 years, or sooner if clinically indicated, (2) other 
assessments e.g. lymph node palpation, CT scans of nodal and visceral disease, or lymph node biopsy only if 
appropriate, as described in Section 9.5.2.2 of the protocol. 
Measurement of Tumor Burden (see protocol body for details) 
Tumor assessment and response criteria will be according ISCL/EORTC response criteria described in Olsen 
(2011).  This is a composite measure of Tumor Burden in skin, lymph node, blood, and viscera.  Briefly: 
 
Skin disease will be assessed by quantifying total body surface area (BSA) involvement using a modified 
Severity Weighted Assessment Tool (mSWAT).  Since the IRC will perform a supplemental analysis using 
alternate method described in Prince (2010), the investigator will identify, photograph, and measure up to 
five representative skin lesions for subjects with skin lesions comprising <10% of BSA at all mSWAT 
assessment timepoints. 
 
Lymph node disease will be monitored by palpation and assessed by CT scan and/or biopsy, as necessary 
for determination of GRS. 
 
Blood tumor burden will be assessed by quantifying CD4+CD26- cells by flow cytometry; CD4+CD7- cells 
may be used in CD26+ subjects 
 
Visceral disease will be assessed by CT scan as appropriate. 
Definitions of responses in skin, lymph node, blood, and viscera are provided in Appendix 4 of the protocol. 
 
Secondary Tumor Assessment Method (Independent Review only) 
The response criteria described in Prince (2010) will be used as a supplemental alternate method, for the 
secondary objective of ORR (IRC review only). 
Patient’s Pruritus Assessment 
Subjects will rate the severity of pruritus using a 100-mm visual analog scale (VAS), on which zero indicates no 
itch and 100 indicates worst possible itch.  A clinically significant improvement is defined as an absolute decrease 
of 20 mm from baseline maintained for ≥ 4 weeks; baseline score must be ≥ 20. 
Subjects will be asked to refrain from the use of topical medication for the relief of pruritus symptoms for at least 
12 hours prior to evaluation.  Assessments should be performed during treatment and follow-up at the same time 
as skin disease SWAT assessments are performed. 
Quality of Life assessments  
Quality of Life assessments will be performed using Skindex-29 and FACT-G tools. 
Efficacy Variables in the Main Study 
All efficacy variables will be analyzed primarily in the Stage I – III Main Study subjects and the Stage I – III 
Lead-In subjects from the 9µg/kg/day dose group combined, and additionally in all subjects from the Main 
Study. 
Primary Efficacy Variable: 
Objective response (OR); OR is defined as the proportion of subjects with best response of CR or PR, using the 
Global Response Score of Olsen (2011). 
Secondary Efficacy Variables: 
 
Duration of response (DOR) is defined as time from the date when criteria for response (CR or PR) based 
on GRS was first met until the date when the response was first lost (date of loss is date when first meets 
criteria for PD). 
 
Time to response (TTR) is defined as time from the date of first dosing to the date when criteria for 
response (CR or PR) based on GRS are first met.  


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 
Skin response based on the mSWAT score is defined as the proportion of subjects with best response of 
CR or PR in skin. 
 
Duration of skin response based on the mSWAT Score is defined as time from the date when criteria for 
response in skin (CR or PR) was first met until the date when the response was first lost (date of loss is 
date when first meets criteria for global response PD). 
 
Time to skin response based on the mSWAT Score is defined as time from the date of first dosing to the 
date when criteria for response in skin (CR or PR) are first met. 
 
Objective response as determined by the alternate criteria of Prince (2010) 
Exploratory Variables: 
 
Progression free survival (PFS) is defined as the date of first dosing to the first date that meets the criteria 
for PD or death as a result of any cause 
 
Time to Progression (TTP) is defined as time from the date of first dosing to the first date that meets the 
criteria for PD or death as a result of CTCL. 
 
Subject’s Pruritus improvement rate is defined as the proportion of subjects with a clinically significant 
improvement in pruritus 
Note:  The same efficacy variables apply to the Lead-In. 
Pharmacokinetics:  
Non-Compartmental PK: 
The following PK parameters will be determined from subjects with full PK profiles using noncompartmental 
methods: 
 
Cmax, AUC(0-t), AUC(0-inf), Tmax, t½, CL, Vdss 
Population PK: 
A population PK model for E7777 will be developed using non-linear mixed effect modeling.  The model will 
be parameterized in terms of clearance and volume of distribution.   
 
Population PK/PD: 
PK/PD relationships between exposure to E7777 and some efficacy and safety variables will be explored 
graphically and may be followed by model-based analysis.  
Further details of the population PK and PK/PD analyses will be documented separately in a stand-alone data 
analysis plan. 
Immunogenicity: 
Immune response to E7777 during the study treatment will be assessed by determining the anti-E7777 and anti-
IL2 antibodies in serum during the study treatment.  Additionally, neutralizing antibody assessment will also be 
performed in subjects who tested positive for anti-E7777 or anti-IL2 antibodies.  
Safety:  
Safety will be assessed by the regular monitoring and recording of all adverse events (AEs) and serious adverse 
events (SAEs), hematology, blood chemistry, and urine values, vital signs, electrocardiograms (ECGs) and the 
performance of physical examinations including body weight and height. 
Bioanalytical Methods 
Quantitation of E7777 and Immunogenicity Assessments (Anti- E7777, Anti-IL2, and Neutralizing antibody) 
E7777 will be measured in serum samples using validated bioanalytical methods. 
Immunogenicity assessment in serum will be performed using validated bioanalytical methods to screen, 
confirm, and characterize the presence of anti-E7777 and anti-IL2 antibodies and, as necessary, neutralizing 
antibodies. 
Statistical Methods 


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Statistical Design of Dose Escalation during the Lead-In Part: 
The Lead-In part will be a dose-finding study including approximately 20 subjects.  A CRM design will be used 
to determine the MTD of E7777.  The MTD is defined in this study as the highest dose that has a ≤ 20% rate of 
DLT. 
Six experimental doses are proposed and can be investigated: 3, 6, 9, 12, 15, and 18 µg/kg/d.  The starting dose 
will be 6 µg/kg/d.   
Starting with the 6 µg/kg/d dose, the prior distribution of the logistic parameters for PT will be updated by the 
accruing data on DLTs each time a subject completes evaluation for toxicity in Cycle 1.  Additional subjects will 
be allocated to the highest dose that has at least a 50% posterior probability of being tolerable (i.e., having a 
≤ 20% DLT rate); the next dose allocated may be modified upon consultation with the safety consultancy 
investigator panel that is reviewing DLTs, based on overall cumulative safety results from the current study 
and/or on any emerging data from other studies with E7777.  The first four subjects will be treated in series, i.e. 
each subject will be required to complete Cycle 1 before the next subject can be treated; open enrollment will 
start with the fifth subject.  Dose levels cannot be skipped when escalating.  The MTD will be determined when 
approximately 20 subjects have been tested, or when futility is declared.  Futility is defined as having a <25% 
probability that any of the doses is safe (i.e., the probability that none of the six doses have a ≤ 20% DLT rate is 
<25%).  
For additional details regarding the CRM, please refer to Sections 9.1.2 and 9.7.1 of the protocol. 
Lead in: 
The preliminary safety and efficacy endpoints will be summarized and listed for all subjects in the Safety Analysis 
Set. 
Main Study: 
All of the efficacy analyses for tumor assessment related endpoints will be performed using independent central 
review data as primary analyses.  In addition, similar analyses will be performed using investigator assessment 
data as the secondary analyses.  
All efficacy and Quality of Life (QoL) analyses will be performed primarily in Stage I – III Main Study 
subjects plus the Stage I – III Lead-In subjects from the 9µg/kg/day dose group combined, and additionally in 
all subjects from the Main Study. 
Primary Efficacy Analysis:  
ORR will be calculated in Stage I – III CTCL in subjects from the Main Study plus the Lead-In subjects from the 
9µg/kg/day dose group combined, using a 2-sided, exact 95% confidence interval (CI), using the Clopper-Pearson 
method.  The treatment will be considered efficacious and demonstrating clinical benefit of E7777 if the lower 
limit of the 2-sided 95% exact CI of the observed ORR exceeds 25%.  
Secondary Efficacy Analyses: 
 
Skin response will be calculated with a 2-sided, exact 95% confidence interval (CI), using the Clopper-
Pearson method. 
 
Duration of response (DOR), Time to Response (TTR), duration of skin response and time to skin response 
for E7777 will be calculated using Kaplan-Meier product-limit estimates and plotted over time.  The 
medians for these endpoints and their corresponding 2-sided 95% CIs will be provided. 
 
ORR (by Prince [2010] criteria) will be calculated with a 2-sided, exact 95% confidence interval (CI), using 
the Clopper-Pearson method.    
Exploratory Efficacy Analyses: 
 
Progression Free Survival (PFS) and Time to Progression (TTP) for E7777 will be calculated using Kaplan-
Meier product-limit estimates and plotted over time.  The medians for these endpoints and their 
corresponding 2-sided 95% CIs will be provided. 
 
Subject’s Pruritus Improvement Rate will be calculated with a 2-sided exact 95% CI using the Clopper-
Pearson method.  In addition, the percentages of subjects who have ≥ 20% and ≥ 50% improvements relative 
to baseline in each of the VAS-based assessment scores will be tabulated.  The frequency of use of rescue 


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medications will determined by comparing the number of packages dispensed and the number of packages 
returned. 
 
Sensitivity analyses for ORR in subjects receiving vs not receiving steroid premedication.  
 
QoL analyses will be performed.  
Pharmacokinetic and Immunogenicity Analyses 
Pharmacokinetics 
PK parameters will be summarized descriptively based on the PK analysis set, and will be compared between 
E7777-treated subjects.  Potential relationships between the E7777 serum concentration data and tumor response 
as well as adverse events will be explored. 
Immunogenicity 
The percentage of subjects testing positive for anti-E7777 and anti-IL-2 antibodies at baseline and during study 
treatment will be assessed. Potential relationships between presence of anti-E7777 antibodies and tumor response 
as well as adverse events will be explored. 
Safety Analyses 
Evaluation of safety will be performed on the Safety Analysis Set.  Safety analyses for the Lead-In part will be 
done using all the Safety Analysis Set subjects.  The safety analyses for the Main Study will be performed in all 
Safety Analysis Set subjects and all Safety Analysis Set Stage I – III subjects, separately.  Safety data to be 
evaluated include AEs, clinical laboratory results (including thyroid function assessments), vital signs, 
electrocardiograms (ECGs), and the results of physical examinations. 
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). 
Dose-limiting toxicities will be listed for each Lead-In dose cohort. DLT rates will be calculated. 
Sample Size Rationale 
Sample size for Lead-In Part 
The number of subjects in the Lead-in will be approximately 20, based on the CRM design requirements. 
Sample size for Main Study  
The sample size of approximately 70 Stage I – III subjects (including Stage I – III subjects from both the Main 
Study plus from the Lead-In part 9 µg/kg/day dose group combined) was estimated assuming that the lower limit 
of the 2-sided 95% CI of ORR exceeding 25% indicates clinical benefit in persistent and recurrent CTCL; and 
that in this population we can reasonably expect to observe an ORR ≥ 36%, i.e., at least 25 subjects with CR+PR 
among 70 subjects.   
With a sample size of approximately 70 Stage I – III subjects (including Stage I – III subjects from both the Main 
Study and from the Lead-In part 9 µg/kg/day dose group), the 2-sided 95% exact Clopper-Pearson confidence 
interval of an observed 36% ORR would range from 25% to 48%. Thus, an observed ORR that is ≥ 36% would 
be significantly higher than 25%, thereby demonstrating the presence of clinical benefit. 
Sample size estimates were calculated using PASS 2008. 


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3 
TABLE OF CONTENTS 
1 
TITLE PAGE .....................................................................................................................9 
2 
CLINICAL PROTOCOL SYNOPSIS .............................................................................11 
3 
TABLE OF CONTENTS .................................................................................................22 
4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................26 
5 
ETHICS............................................................................................................................30 
5.1 
Institutional Review Boards/Independent Ethics Committees ..............................30 
5.2 
Ethical Conduct of the Study .................................................................................30 
5.3 
Subject Information and Informed Consent ...........................................................31 
6 
INVESTIGATORS AND STUDY PERSONNEL ..........................................................32 
7 
INTRODUCTION ...........................................................................................................32 
7.1 
E7777 .....................................................................................................................32 
7.2 
Mechanism of Action of E7777 / Denileukin Diftitox ..........................................32 
7.3 
Clinical Experience With ONTAK and E7777 ......................................................32 
7.3.1 
Clinical Experience with ONTAK (Denileukin Diftitox) ............................32 
7.3.2 
Clinical Experience With E7777 .................................................................33 
7.4 
CTCL and Current Therapeutic Options ................................................................33 
7.5 
Study Rationale ......................................................................................................34 
8 
STUDY OBJECTIVES ....................................................................................................35 
8.1 
Lead-In Part ...........................................................................................................35 
8.2 
Main Study .............................................................................................................35 
9 
INVESTIGATIONAL PLAN ..........................................................................................36 
9.1 
Overall Study Design and Plan ..............................................................................36 
9.1.1 
Overall Design .............................................................................................36 
9.1.2 
Lead-In Part .................................................................................................37 
9.1.3 
Main Study ...................................................................................................39 
9.1.4 
Study Phases ................................................................................................40 
9.2 
Discussion of Study Design, Including Choice of Control Groups .......................41 
9.3 
Selection of Study Population ................................................................................41 
9.3.1 
Inclusion Criteria .........................................................................................42 
9.3.2 
Exclusion Criteria ........................................................................................44 
9.3.3 
Removal of Subjects From Therapy or Assessment ....................................45 
9.4 
Treatments..............................................................................................................45 
9.4.1 
Treatments Administered .............................................................................45 
9.4.1.1 
Premedication ......................................................................................46 
9.4.1.2 
Drug Preparation and Administration ..................................................47 
9.4.1.3 
Monitoring Procedures During Administration ...................................48 


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9.4.1.4 
Management of Acute Infusion Reaction and Hypersensitivity 
During Administration .........................................................................49 
9.4.1.5 
Dose Interruption or Modification .......................................................50 
9.4.2 
Identity of Investigational Products .............................................................53 
9.4.2.1 
Frozen Formulation (Lead-In only) .....................................................53 
9.4.2.2 
Lyophilized Formulation (Main Study only) .......................................53 
9.4.2.3 
Chemical Name, Structural Formula of E7777....................................53 
9.4.2.4 
Comparator Drug .................................................................................54 
9.4.2.5 
Labeling for Study Drug ......................................................................54 
9.4.2.6 
Storage Conditions ...............................................................................54 
9.4.3 
Method of Assigning Subjects to Treatment Groups ...................................54 
9.4.4 
Selection of Doses in the Study ...................................................................54 
9.4.5 
Selection and Timing of Dose for Each Subject ..........................................55 
9.4.6 
Blinding........................................................................................................55 
9.4.7 
Prior and Concomitant Therapy ...................................................................55 
9.4.8 
Treatment Compliance .................................................................................56 
9.4.9 
Drug Supplies and Accountability ...............................................................56 
9.5 
Study Assessments .................................................................................................58 
9.5.1 
Screening and Baseline Assessments ...........................................................58 
9.5.1.1 
Demography .........................................................................................58 
9.5.1.2 
Other Screening Assessments ..............................................................58 
9.5.2 
Efficacy Assessments ...................................................................................59 
9.5.2.1 
Overview ..............................................................................................59 
9.5.2.2 
Tumor Assessment Methods and Schedule .........................................59 
9.5.2.3 
Subject Assessment of Pruritus ............................................................65 
9.5.2.4 
Quality of Life Assessments ................................................................65 
9.5.3 
PK and Immunogenicity Assessments .........................................................65 
9.5.3.1 
PK Assessments ...................................................................................65 
9.5.3.2 
Immunogenicity Assessments ..............................................................67 
9.5.4 
Safety Assessments ......................................................................................67 
9.5.4.1 
AEs and Other Events of Interest .........................................................67 
9.5.4.2 
Serious Adverse Events and Other Events of Interest .........................69 
9.5.4.3 
Laboratory Measurements ...................................................................70 
9.5.4.4 
Vital Signs ............................................................................................72 
9.5.4.5 
Physical Examinations and Weight .....................................................72 
9.5.4.6 
Electrocardiograms ..............................................................................72 
9.5.5 
Schedule of Procedures/Assessments ..........................................................72 
9.5.5.1 
Schedule of Assessments .....................................................................72 


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9.5.5.2 
Description of Procedures/Assessments Schedule – Lead-In and 
Main Study ...........................................................................................78 
9.5.6 
Appropriateness of Measurements ...............................................................79 
9.5.7 
Reporting of SAEs, Pregnancy, and Other Events of Interest .....................79 
9.5.7.1 
Reporting of SAEs ...............................................................................79 
9.5.7.2 
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding .......................................................................................80 
9.5.7.3 
Reporting of Other Events of Interest ..................................................80 
9.5.7.4 
Expedited Reporting ............................................................................81 
9.5.7.5 
Regulatory Reporting of AEs ...............................................................81 
9.5.8 
Completion/Discontinuation of Subjects .....................................................82 
9.5.9 
Abuse or Diversion of Study Drug ..............................................................82 
9.5.10 
Confirmation of Medical Care by Another Physician .................................82 
9.6 
Data Quality Assurance .........................................................................................82 
9.6.1 
Data Collection ............................................................................................82 
9.6.2 
Clinical Data Management ..........................................................................83 
9.7 
Statistical Methods .................................................................................................83 
9.7.1 
Statistical and Analytical Plans ....................................................................83 
9.7.1.1 
Statistical Design in the Lead-In Part:  Continual Reassessment 
Method .................................................................................................83 
9.7.1.2 
Study Endpoints ...................................................................................84 
9.7.1.3 
Definitions of Analysis Sets.................................................................85 
9.7.1.4 
Subject Disposition ..............................................................................85 
9.7.1.5 
Demographic and Other Baseline Characteristics ...............................86 
9.7.1.6 
Prior and Concomitant Therapy ...........................................................86 
9.7.1.7 
Efficacy Analyses ................................................................................86 
9.7.1.8 
PK and Immunogenicity Analyses .......................................................87 
9.7.1.9 
Safety Analyses ....................................................................................87 
9.7.2 
Determination of Sample Size .....................................................................89 
9.7.3 
Interim Analysis ...........................................................................................90 
9.7.4 
Procedure for Revising the SAP ..................................................................90 
10 REFERENCE LIST .........................................................................................................91 
11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES) .......92 
11.1 
Changes to the Protocol .........................................................................................92 
11.2 
Adherence to the Protocol ......................................................................................92 
11.3 
Monitoring Procedures...........................................................................................92 
11.4 
Recording of Data ..................................................................................................93 
11.5 
Identification of Source Data .................................................................................93 


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11.6 
Retention of Records ..............................................................................................94 
11.7 
Auditing Procedures and Inspection ......................................................................94 
11.8 
Handling of Study Drug .........................................................................................94 
11.9 
Publication of Results ............................................................................................95 
11.10 Disclosure and Confidentiality ..............................................................................95 
11.11 Discontinuation of Study .......................................................................................95 
11.12 Subject Insurance and Indemnity ...........................................................................96 
12 APPENDICES .................................................................................................................97 
 
LIST OF IN-TEXT TABLES 
Table 1 
Dose Interruption and Modification During Treatment Period .................52 
Table 2 
PK Sampling Time Points ..........................................................................66 
Table 3 
Clinical Laboratory Tests ...........................................................................71 
Table 4 
Schedule of Assessments ...........................................................................73 
 
LIST OF IN-TEXT FIGURES 
Figure 1 
 Continual Reassessment Method ..............................................................39 
 
LIST OF APPENDICES 
Appendix 1 
Classification and Staging of Mycosis Fungoides and Sézary 
Syndrome ...................................................................................................98 
Appendix 2 
ECOG Performance Status Scale .............................................................100 
Appendix 3 
Cockcroft–Gault Calculation of Creatinine Clearance ............................101 
Appendix 4 
CTCL Tumor Response Criteria According to the ISCL/EORTC 
Consensus (Olsen 2011) ..........................................................................102 
Appendix 5 
Lymph Node Disease Assessment ...........................................................110 
Appendix 6 
CTCAE (v5.0) ..........................................................................................111 
 


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4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase  
ATC 
Anatomical-Therapeutic-Chemical  
AUC(0-t) 
area under the curve from time 0 to time t 
AUC(0-inf) 
area under the curve from time 0 to infinity 
β-hCG 
beta-human chorionic gonadatropin 
BP 
blood pressure 
bpm 
beats per minute 
BSA 
body surface area 
BUN 
blood urea nitrogen 
CA 
Competent Authority  
CAD 
severe coronary artery disease   
CBC 
complete blood count 
CD4 
cluster of differentiation 4, a marker antigen for helper T-cells  
CD7 
cluster of differentiation 7 
CD25 
cluster of differentiation 25, -chain subunit of the IL-2R  
CFR 
Code of Federal Regulations 
CDF 
cumulative distribution function 
CI 
confidence interval 
CL 
total body clearance 
CLS 
capillary leak syndrome  
Cmax 
maximum drug concentration 
CPK 
creatine phosphokinase 
CPMP 
Committee for Proprietary Medicinal Products 
CR 
complete response 
CRA 
clinical research associate 
CRF 
case report form  
CRM 
continual reassessment method  
CS 
color distortion 
CT 
computed tomography  
CTCAE 
Common Terminology Criteria for Adverse Events 
CTCL 
cutaneous T-cell lymphoma 


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CV 
curriculum vitae  
DAB389IL-2 
denileukin diftitox, ONTAK® 
DLT 
dose-limiting toxicity 
DOR 
duration of response  
EBRT 
electron beam radiotherapy 
ECG 
electrocardiagram 
ECOG 
Eastern Cooperative Oncology Group 
EDTA 
ethylenediaminetetraacetic acid 
EORTC 
European Organization for Research and Treatment of Cancer 
EOT 
end of treatment 
EU 
European Union  
FDA 
Food and Drug Administration 
18FDG-PET 
18fluorodeoxyglucose positron emission tomography 
FFPE 
formalin fixed paraffin embedded 
GCP 
Good Clinical Practice 
GRS 
Global Response Scoring 
HDI 
histone deacetylase inhibitor 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
informed consent form  
ICH 
International Conference on Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee  
IHC 
immunohistochemistry 
IL-2 
interleukin-2 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee 
ISCL 
International Society for Cutaneous Lymphomas 
IUD 
intrauterine device  
i.v. 
intravenous 
IxRS 
interactive voice and web response system 
LDi 
longest diameter 
LNH 
low/normal/high  
MedDRA 
Medical Dictionary for Regulatory Activities 
MF 
mycosis fungoides  


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MHRA 
Medicines and Healthcare Products Regulatory Agency 
MI 
myocardial infarction 
mmHg 
millimeters of mercury 
mSWAT 
modified Severity Weighted Assessment Tool 
MTD 
maximum tolerated dose 
N/A 
not applicable 
NI 
not involved 
ONTAK® 
DAB389IL-2, denileukin diftitox 
OR 
objective response 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PFS 
progression-free survival 
PI 
principal investigator  
PK 
pharmacokinetic(s) 
PR 
partial response 
PUVA 
psoralen ultraviolet light A 
QoL 
Quality of Life  
QT 
measure of the time between the start of the Q wave and the end
of the T wave in the heart's electrical cycle 
QTc 
QT interval corrected for heart rate  
QTcF 
QT interval corrected for heart rate using Fridericia’s correction
RBC 
red blood cells 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
stable disease 
SD 
standard deviation 
SDi 
short axis 
SOC 
system organ class 
SPD 
sum of the products of the perpendicular diameters  
SS 
Sézary syndrome 
SUSAR 
suspected unexpected serious adverse reaction 
t½ 
terminal elimination half-life 
T3 
triiodothyronine 
T4 
thyroxine 


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TEAE 
treatment-emergent adverse event 
Treg 
regulatory T-lymphocyte 
tmax 
time to reach maximum (peak) concentration following drug
administration 
TSH 
thyroid stimulating hormone 
TTP 
time to progression 
TTR 
time to response 
US 
United States 
USP 
United States Pharmacopoeia  
ULN 
upper limit of normal 
UVB 
ultraviolet light B 
VA 
visual acuity 
VAS 
visual analog scale  
Vdss 
volume of distribution at steady state 
WBC 
white blood cell 
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, 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 International Conference on Harmonisation 
(ICH) E6 (Good Clinical Practice [GCP]), Section 3, and any local regulations.  Any protocol 
amendment or revision to the informed consent form (ICF) will be resubmitted to the IRB/IEC 
for review and approval, except for changes involving only logistical or administrative aspects 
of the study (e.g., change in clinical research associate(s) [CRA(s), change of telephone 
number[s]).  Documentation of IRB/IEC compliance with the ICH 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 (PI) (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 the 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 end of the study will be the date of the last study visit for the last subject 
in the study.  The sponsor should also provide the IRB/IEC with a summary of the study’s 
outcome. 
In the case of early termination/temporary halt of the study, the investigator should notify the 
IRB/IEC within 15 calendar days, and a detailed written explanation of the reasons for the 
termination/halt should be given. 
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 


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 
ICH E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, 
International Conference on Harmonisation of Pharmaceuticals for Human Use 
 
Title 21 of the United States Code of Federal Regulations (US 21 CFR) regarding clinical 
studies, including Part 50 and Part 56 concerning informed subject consent and IRB 
regulations and applicable sections of US 21 CFR Part 312 
 
European Good Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 
2001/20/EC for studies conducted within any EU country.  All SUSARs will be reported, 
as required, to the Competent Authorities of all involved EU member states.  
 
Article 14, Paragraph 3, and Article 80-2 of the Pharmaceutical Affairs Law (Law No. 
145, 1960) for studies conducted in Japan, in addition to Japan’s GCP 
 
Other applicable regulatory authorities’ requirements or directives 
5.3 
Subject Information and Informed Consent 
As part of administering the informed consent document, the investigator must explain to each 
subject (or guardian/legally authorized representative) the nature of the study, its purpose, the 
procedures involved, the expected duration, the potential risks and benefits involved, any 
potential discomfort, potential alternative procedure(s) or course(s) of treatment available to 
the subject, and the extent of maintaining confidentiality of the subject’s records.  Each subject 
must be informed that participation in the study is voluntary, that he/she may withdraw from 
the study at any time, and that withdrawal of consent will not affect his/her subsequent medical 
treatment or relationship with the treating physician. 
This informed consent should be given by means of a standard written statement, written in 
nontechnical language.  The subject should understand the statement before signing and dating 
it and will be given a copy of the signed document.  If a subject is unable to read or if a legally 
acceptable representative is unable to read, an impartial witness should be present during the 
entire informed consent discussion.  After the ICF and any other written information to be 
provided to subjects is read and explained to the subject or the subject’s legally acceptable 
representative, and after the subject or the subject’s legally acceptable representative has orally 
consented to the subject’s participation in the study and, if capable of doing so, has signed and 
personally dated the informed consent form, the witness should sign and personally date the 
consent form.  The subject will be asked to sign an ICF at the Screening Visit before any study-
specific procedures are performed.  No subject can enter the study before his/her informed 
consent has been obtained. 
An unsigned copy of an IRB/IEC-approved ICF must be prepared in accordance with ICH E6, 
Section 4, and all applicable local regulations and provided to the sponsor.  Each subject must 
sign an approved ICF before study participation.  The form must be signed and dated by the 
appropriate parties.  The original signed ICF for each subject will be verified by the sponsor 
and kept on file according to local procedures at the site. 


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6 
INVESTIGATORS AND STUDY PERSONNEL 
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at approximately 15 global investigational sites. 
The name and telephone and fax numbers of the medical monitor and other contact personnel 
at the sponsor are listed in the Regulatory Binder provided to each site. 
7 
INTRODUCTION 
7.1 
E7777 
Denileukin diftitox is a recombinant cytotoxic fusion protein composed of the amino acid 
sequences for diphtheria toxin fragments A and B (Met1-Thr387)-His and for human 
interleukin-2 (Ala1-Thr133).  Denileukin diftitox has been marketed in the US as ONTAK® 
(Eisai code name E7272) since 1999 and is indicated for the treatment of patients with 
persistent or recurrent cutaneous T-cell lymphoma (CTCL) whose malignant cells express the 
CD25 component of the IL-2 receptor. 
ONTAK may exhibit antineoplastic action through a direct cytocidal action on IL-2-expressing 
tumors, or through its ability to deplete immunosuppressive regulatory T-lymphocytes (Tregs) 
that are recruited into tumor infiltrates to assist tumors in evading host immune surveillance. 
E7777 is the same recombinant protein as denileukin diftitox but has improved purity 
compared with ONTAK.  E7777 was developed as a result of a refined manufacturing process 
and has an increased percentage of protein monomer species, with a concomitant decrease in 
levels of misfolded protein and protein aggregates compared with ONTAK.  The increase in 
bioactivity per milligram of protein in the E7777 finished drug product has been confirmed in 
nonclinical studies. 
7.2 
Mechanism of Action of E7777 / Denileukin Diftitox 
Denileukin diftitox is a cytotoxic protein designed to direct the cytocidal action of diphtheria 
toxin to cells that express the IL-2 receptor.  The mechanism of action for E7777 is the same 
as for ONTAK, as both proteins comprise the same amino acid sequence and active domains.  
Upon binding to the IL-2 receptor on the cell surface, denileukin diftitox is internalized by 
receptor-mediated endocytosis.  The fusion protein is subsequently cleaved, releasing 
diphtheria toxin enzymatic and translocation domains from the IL-2 fragment, resulting in the 
inhibition of protein synthesis and, ultimately, cell death.  As a result, clinical antitumor 
activity against a range of tumor types expressing the IL-2 receptor (e.g., CTCL) has been 
observed with ONTAK.1  In addition, ONTAK has been reported to have antineoplastic effects 
against tumors in which IL-2R-expressing Tregs play a role in helping tumors escape host 
immunesurveillance.2  E7777 likely retains the activity of ONTAK against IL-2R-expressing 
Tregs. 
7.3 
Clinical Experience With ONTAK and E7777 
7.3.1 
Clinical Experience with ONTAK (Denileukin Diftitox) 


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Since E7777 and ONTAK have a common active moiety, clinical experience with ONTAK in 
T-cell lymphoma provides relevant background information.  The most extensive clinical 
experience for denileukin diftitox is in CTCL.  More than 300 subjects have been treated in 
Phase 3 and Phase 4 studies, including one randomized placebo-controlled trial.  Data on 
efficacy, safety, pharmacokinetics (PK), and immunogenicity are summarized below: 
 Efficacy:  ONTAK has shown clinical efficacy at doses of 9 or 18 µg/kg/day 
administered intravenously for 5 consecutive days every 3 weeks, with an objective 
response rate (ORR) of 38% in 263 subjects. 
 Safety:  ONTAK is generally well tolerated, with the most notable AEs being infusion 
reaction and capillary leak syndrome (CLS).  Please refer to the Investigator’s Brochure 
(IB) for details on the safety profile.3  
 PK:  After the first dose, ONTAK is rapidly distributed and has a terminal elimination 
half-life (t½) of 70 to 80 minutes.  No accumulation was apparent between Day 1 and 
Day 5 of dosing, and the clearance increased from Cycle 1 to Cycle 3 corresponding to 
a 75% decrease in exposure. 
 Immunogenicity:  Immune response to ONTAK was tested in the Phase 3 studies.  At 
baseline, 66% of subjects (N=95) tested positive for antibodies to denileukin diftitox; 
after 1, 2, or 3 cycles of treatment, 94%, 99%, and 100% of subjects tested positive, 
respectively.  Antibody titers increased after 2 cycles, with PK parameters indicating 
decreased systemic exposure to drug. 
Please refer to the Investigator’s Brochure for more detailed information on clinical experience 
with ONTAK. 
7.3.2 
Clinical Experience With E7777 
E7777 has been tested on one other study in addition to this protocol.  A Phase 1/1b 
first-in-human trial was conducted in Japan, with the objective to establish the maximum 
tolerated dose (MTD) and to assess tolerability of E7777 administered as a continuous 5-day 
schedule every 21 days.  As of Feb 2016, accrual was completed at 13 subjects and the MTD 
was determined to be 9 µg/kg/day. 
Please refer to the Investigator’s Brochure for more detailed information on clinical experience 
with E7777. 
7.4 
CTCL and Current Therapeutic Options 
Cutaneous T-cell lymphomas account for about 10 to 15 percent of all cases of non-Hodgkins 
lymphoma.  The most common variant of CTCL (about 50% of cases) is mycosis fungoides 
(MF).  Less common is Sézary syndrome (SS), a leukemic variant that affects about 5% of 
patients with CTCL.   
Typically, the natural history of MF is indolent, with cutaneous symptoms waxing and waning 
over a period of years.  Cutaneous disease progresses from an eczematous patch/plaque stage 
(T1) to plaque stage covering (T2), and finally to tumors (T3) that frequently undergo necrotic 


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ulceration.  SS is thought to be an advanced form of MF with generalized erythroderma (T4) 
and peripheral blood involvement at presentation.  The prognosis of patients with MF/SS is 
based on the extent of disease at presentation; patients with stage IA disease have a median 
survival of 20 or more years while patients with stage III through stage IV disease have a 
median survival of less than 5 years.  
A number of therapeutic options are available to treat CTCL; these include skin-directed 
therapies, phototherapies, radiation, and systemic therapies.  Often a combination of either 
sequential or concomitant therapies gives a higher rate of response, but patients with advanced 
disease often relapse and no therapy has been proven to be curative.  Extensive skin or blood 
involvement, tumors, or nodal disease require systemic therapy with biologic response 
modifiers, bexarotene, ONTAK (denileukin diftitox), skin radiation, and single- or multi-agent 
chemotherapy.  Over the past few years, the FDA has approved two histone deacetylase 
inhibitors (HDIs), vorinostat and romidepsin, for treatment of CTCL. 
7.5 
Study Rationale 
This study is intended to demonstrate the efficacy and safety of E7777 to support a marketing 
application. 
The rationale for developing E7777 for the indication of CTCL is based on the structure and 
preclinical activity of E7777.  E7777 is composed of the same amino acid sequences as 
ONTAK (i.e., has the same active moiety).  In addition, in preclinical studies ONTAK and 
E7777 have been shown to have cytocidal activity in a cell-based viability inhibition assay 
using the HH cell line, which was derived from a CTCL patient and expresses the intermediate 
affinity form of the IL-2 receptor, supporting the concept that E7777 will have a cytocidal 
activity against IL-2R-expressing CTCL tumor cells. 
E7777 is increased-purity ONTAK, with a higher proportion of active monomer species and a 
lower proportion of protein aggregates and misfolded proteins compared to ONTAK.  An 
increase in specific bioactivity (on a weight basis) of the E7777 finished drug product has been 
confirmed in nonclinical studies.  Due to the altered proportion of different protein species and 
the 1.5- to 2-fold increased potency of E7777 compared to commercial ONTAK, this clinical 
study is being conducted to establish the appropriate clinical dose of E7777 to administer and 
to confirm the safety and efficacy of E7777 in CTCL. 


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8 
STUDY OBJECTIVES 
8.1 
Lead-In Part 
Primary Objectives: 
 To establish the maximum tolerated dose (MTD) of E7777 and to select the dose of 
E7777 to be used in the Main Study. 
Secondary Objectives: 
 To assess safety, tumor response, pharmacokinetics (PK), and immunogenicity after 
treatment with E7777. 
8.2 
Main Study 
All Main Study efficacy analyses will be performed primarily in the Stage I – III Main Study 
subjects plus the Stage I – III Lead-In subjects from the 9µg/kg/day dose group, as well as 
additionally in all subjects from the Main Study.  
Primary Objective: 
 To demonstrate efficacy of E7777 in subjects with recurrent or persistent CTCL in 
Stage I – III subjects as assessed by ORR; Objective Response is Complete Response 
(CR) plus Partial Response (PR), according to ISCL/EORTC Global Response Score 
(Olsen 2011)6 
Secondary Objectives: 
 To determine Duration of Response (DOR) for E7777 
 To determine time to response after E7777 treatment  
 To determine skin response after E7777 treatment 
 To determine duration of skin Response after E7777 treatment 
 To determine time to skin response after E7777 treatment 
 To assess ORR for E7777 using the alternate response assessment criteria of Prince 
(2010)5 
 To evaluate safety and tolerability of E7777 in all subjects and in subjects 
 To evaluate safety and tolerability of E7777 in the Stage I – III Main Study subjects 
plus the Stage I – III Lead-In subjects from the 9µg/kg/day dose group combined  


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 To characterize the pharmacokinetics (PK) of E7777 and immunogenicity after 
treatment with E7777 
Exploratory Objectives: 
 To assess two efficacy endpoints for subjects treated with E7777:  progression-free 
survival (PFS) and time to progression (TTP) (using Global Response Score) 
 To assess pruritus improvement reported by subjects treated with E7777 
 To assess Quality of Life (QoL) for (1) all subjects treated in the Lead-In part, (2) all 
subjects treated in the Main Study part, and (3) Stage I – III Main Study subjectsplus 
Stage I – III Lead-In subjects from the 9µg/kg/day dose group combined. 
 
9 
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan 
9.1.1 
Overall Design 
This is a multicenter open-label, single-arm study of E7777 in subjects with recurrent or 
persistent CTCL. 
The study will consist of an initial Lead-In part followed by the Main Study: 
o Lead-In:  A Continual Reassessment Method (CRM) will be employed to establish the 
MTD of E7777 and to select the dose of E7777 to be used in the Main Study.  
Approximately 20 subjects will be treated. 
o Main Study:  A sufficient number of subjects in the Main Study will be recruited so 
that approximately 70 Stage I – III subjects from both the Main Study and from the 
Lead-In subjects in the 9µg/kg/day dose group with recurrent or persistent CTCL will 
be treated with E7777 to assess efficacy.  Safety will be evaluated in all subjects from 
the Main Study, and in the Stage I – III Lead-In subjects from the 9µg/kg/day dose 
group.  The dose of E7777 in the Main Study will be the dose selected in the Lead-In 
part of the study.  The primary efficacy analysis will be based on Stage I – III subjects 
from both the Main Study plus from the Lead-In 9µg/kg/day dose group combined. 
The Lead-In and Main Study designs are described in detail in Sections 9.1.2 and 9.1.3. 
Study Phases for Each Subject 
Subjects in the study will move through three phases while on study. 
 Pretreatment Phase, consisting of two Periods: 
o Screening 


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o Baseline 
 Treatment Phase, consisting of the following periods: 
o Treatment Period. Treatment with E7777 for up to 8 cycles; each cycle of 21 
days is one Period.  Subjects who have attained skin tumor response and are 
deriving clinical benefit from E7777 treatment may continue receiving 
treatment beyond 8 cycles, at the discretion of the treating physician. 
o Follow-Up Period, for follow-up of tumor assessment, with immunogenicity 
and survival follow-up as appropriate. 
After data cutoff for the primary analysis in the Main Study, the study moves to the Extension 
Phase. 
 Extension Phase, consisting of the following periods: 
o Treatment Period, for continued treatment of subjects with ongoing treatment 
at data cutoff. 
o Follow-Up Period, for follow-up of tumor assessment, with immunogenicity 
and survival follow-up as appropriate. 
The Study Phases are described in more detail in Section 9.1.4. 
Pharmacokinetics and Immunogenicity 
Serial PK assessment of E7777 will be performed on all subjects in the Lead-In part and on 
the first 12 subjects in the Main Study, using serial blood PK sampling on Day 1 in Cycles 1, 
3, and 5, with sparse sampling in Cycle 8.  In addition, sparse sampling will be performed in 
the Main Study on the rest of the subjects on Day 1 of Cycle 1. 
Immunogenicity (formation of antibodies to E7777 or IL-2, and of neutralizing antibodies) will 
be assessed in all subjects in both the Lead-In part and the Main Study.  A predose blood 
sample for immunogenicity assessment will be collected before Day 1 dosing in Cycles 1, 2, 
3, 5, and 8; after that, subjects who tested positive at any time for anti-IL2 will be followed up 
for immunogenicity testing for anti-IL2 on a 6-month schedule for one year and every year 
thereafter until antibody titers decrease to baseline level or upon study termination. 
Primary Analysis 
The primary analysis will be performed after data cutoff, which will be either of the following 
two events, whichever occurs later:  (1) when all subjects in the Main Study have either 
completed Cycle 8 or are off treatment, or (2) when all subjects with at least one documented 
time point response of PR or better have undergone the subsequent tumor assessments 
necessary for confirmation of response (unless the subject had disease progression or 
discontinued from study before then). 
9.1.2 
Lead-In Part 
A Continual Reassessment Method (CRM) will be employed to determine the MTD of E7777, 


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targeting a rate of dose-limiting toxicity (DLT) of approximately 20%. 
Subjects will be treated with E7777 for 5 consecutive days during every cycle of 21 days.  The 
doses of E7777 that may be used are 3, 6, 9, 12, 15, or 18 µg/kg/d, with 6 µg/kg/d specified as 
the starting dose.  Each subject will be assigned a dose of E7777 in accordance with the rules 
of the CRM design.  The CRM design is described under Section 9.7 “Statistical Methods.” 
Dose-limiting toxicities are based on known toxicities of ONTAK, as described in the US 
product label.  A DLT will be any of the following occurring within the first cycle of therapy:  
 Serious infusion reaction, defined as CTCAE Grade 4 adverse event of “Infusion 
related reaction”, or recurrent CTCAE Grade 3 despite administration of systemic 
steroid premedication after initial occurrence.  Infusion reactions are defined as 
symptoms (e.g., fatigue, nausea, vomiting, arthralgia, myalgia, pyrexia, chills, rigors) 
occurring within 24 hours of E7777 infusion.  
 Capillary leak syndrome (CLS) CTCAE Grade 4 or Grade 3 (with exceptions). 
The CTCAE definitions are broad and general, therefore the following guidance is 
provided: 
o Grade 4 is life-threatening severity such as subjects experiencing hypovolemic 
shock or renal failure, or who need treatment with vasopressors or oxygen 
o Grade 3 is severe symptoms (less severe than the Grade 4 symptoms above) that 
may or may not be dose-limiting.  For example, severe symptoms requiring 
hospitalization for acute intervention would be a DLT, whereas less severe 
symptoms leading to hospitalization for prophylactic treatment with fluids or 
diuretics would not be a DLT.  Hospitalization or medical intervention to prevent 
hospitalization is not in itself a DLT as the threshold for hospitalization may differ 
by doctor and region.   
CLS is defined as the noted occurrence of at least 2 of the following: hypotension, 
edema, or serum albumin < 3.0 g/dL.  These are not required to occur simultaneously 
to be characterized as CLS. 
 Clinical visual impairment.  This could be loss of visual acuity and/or color vision.   
 Any CTCAE ≥ Grade 4 adverse event that may represent an infusion reaction. 
 Any CTCAE Grade 3 adverse event that may represent an infusion reaction that 
prevents the entire dose of E7777 from being administered despite appropriate 
treatment. 
 Any other Grade 3 or greater toxicity assessed as related to E7777 treatment, and which 
in the opinion of a safety consultancy investigator panel constitutes a dose-limiting 
toxicity. 


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Determination as to whether a subject has experienced a DLT will be made by the treating 
physician in consultation, as needed, with the medical monitor and investigator(s) on the 
Protocol Steering Committee (PSC) who are experienced in the use of denileukin diftitox. 
Subjects who are not evaluable for DLT in Cycle 1 should be replaced. 
If, during the course of the Lead-In part, a trend is noted by the PSC (see DLT assessment 
above) where the E7777 toxicities described above are observed beyond the first cycle but not 
in Cycle 1, the definition of DLT may be amended to reflect that observation. 
Selection of the dose of E7777 that will be used in the Main Study will be made in consultation 
with the PSC based on review of the full output of the CRM data. 
The dose-finding steps of the CRM design are shown in Figure 1. 
Pre-Define 6 dose levels
Define the target toxicity rate ≤20%
Calculate the prior dose-toxicity curve
Treat 1st  patient at 6 mcg/kg
Record all DLT’s in Cycle 1
Update the dose-toxicity curve based on observed DLT’s and 
select the dose closest to the target toxicity (but never skip a dose 
when escalating)
≥20 Pts tested
OR: none of the  
doses are safe?
Treat next patient 
at the next 
suggested dose
Declare 
suggested dose 
as the MTD, 
OR: stop for 
futility
True
False
 
Figure 1 
 
Continual Reassessment Method 
9.1.3 
Main Study 
Enrollment in the Main Study will commence after an acceptably safe dose has been 
established in the Lead-In part, as described in Section 9.1.2, and there is at least one objective 
response by investigator assessment recorded in the Lead-In. 
The objectives of the Main Study are to assess the efficacy and safety of E7777 in Stage I - III 
subjects with recurrent and persistent CTCL.  A sufficient number of subjects in the Main 


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Study will be treated for an approximate total of 70 Stage I – III subjects combined from both 
the Main Study plus from the Lead-In subjects from the 9µg/kg/day dose group . 
9.1.4 
Study Phases 
Subjects in the study will move through study phases as described below. 
Pretreatment Phase 
The Pretreatment Phase includes a Screening Period and a Baseline Period. 
 The Screening Period is from Day -28 to the start of treatment (Cycle 1 Day 1) except 
for signing of the informed consent form (ICF) which may be up to 8 weeks before the 
first dose of study drug.  The purpose of the Screening Period is to obtain informed 
consent and to ensure that each subject will meet all the specified eligibility criteria. 
 The Baseline Period is from Day -7 to the start of treatment.  Subjects who complete 
Baseline assessments and meet the eligibility criteria will begin treatment in the 
Treatment Phase. 
Treatment Phase 
The Treatment Phase will consist of the following Periods: 
 Treatment Period.  Treatment with E7777 for up to 8 cycles.  Each cycle of 21 days 
is one Period.  Subjects who have attained skin tumor response and are deriving clinical 
benefit from E7777 treatment may continue receiving treatment beyond eight cycles, 
at the discretion of the treating physician. 
 Follow-up Period.  Tumor assessment until discontinuation of treatment due to 
progressive disease [PD]); immunogenicity, and survival follow-up until relapse or 
initiation of new systemic anti-cancer therapy.  All Follow-up assessments performed 
for up to 3 years after end of treatment, or until sponsor termination of the study. 
After data cutoff for the primary analysis in the Main Study, the study moves to the Extension 
Phase. 
Extension Phase 
The Extension Phase consists of the following Periods: 
 Treatment Period, for continued treatment of subjects with ongoing treatment at data 
cutoff.  Subjects will be treated for up to 8 cycles.  Subjects who have attained skin 
tumor response and are deriving clinical benefit from E7777 treatment may continue 
receiving treatment beyond 8 cycles, at the discretion of the treating physicians. 
 Follow-up Period.  Tumor assessment until discontinuation of treatment due to PD; 


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immunogenicity, and survival follow-up until relapse, or initiation of new systemic 
anticancer therapy.  All Follow-up assessments will be performed for up to 3 years after 
the end of treatment, or until sponsor termination of the study. 
9.2 
Discussion of Study Design, Including Choice of Control Groups 
The primary objective of the study is to confirm efficacy and safety of E7777.  This will be 
done using a single-arm design in the Main Study.  A single-arm design is considered 
appropriate since E7777 has the same active ingredient as ONTAK, and efficacy of ONTAK 
has already been demonstrated in multiple Phase 3 studies, including a randomized placebo-
controlled study. 
The Main Study is preceded by a Lead-In part to establish the maximum tolerated dose of 
E7777.  The MTD or a lower acceptably safe dose established in the Lead-In part will be used 
in the Main Study to assess the efficacy and safety of E7777.  Selection of the dose of E7777 
that will be used in the Main Study will be made in consultation with the safety consultancy 
investigator panel (comprised of selected investigators from this study), based on review of the 
full output of the CRM data.  Establishment of the dose of E7777 is necessary because E7777 
has increased potency compared with ONTAK, due to an increased proportion of active 
monomer species and a decrease in levels of misfolded protein and protein aggregates 
compared with ONTAK.  Safety, PK, and immunogenicity for E7777 will be established as 
well because of this increased potency. 
A CRM will be employed to determine the maximum tolerated dose for E7777.  This is an 
accepted adaptive design that is statistically more robust than the conventional 3+3 
dose-escalation method used in most Phase 1 studies.  Dose-limiting toxicities are defined 
based on known serious ONTAK toxicities, but also include any unexpected toxicities.  The 
selection of the < 20% DLT rate for MTD definition is based on the observed DLT level for 
ONTAK in previous Phase 3 studies. 
9.3 
Selection of Study Population 
Approximately 20 subjects will be treated in the Lead-In part. A sufficient number of subjects 
in the Main Study will be treated for an approximate total of 70 Stage I – III subjects from both 
the Main Study and from Lead-In subjects from the 9µg/kg/day dose group.  The study total 
will be approximately 115 subjects treated at approximately 20 global investigational sites.  
Subjects who do not meet all of the inclusion criteria or who meet any of the exclusion criteria 
will not be eligible to receive study drug. 
In the Main Study, the study population is defined so that it will match as closely as possible 
the study population of the pivotal ONTAK study L4389-11.  This is because the primary 
efficacy of objective response rate in this study is being compared to the historical response 
rates observed with treatment and placebo groups in the ONTAK study L4389-11.  The 
definition of CTCL disease stage and status at study entry in this study takes into account the 
new CTCL staging criteria that was published in 2007 (Olsen 2007). 


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9.3.1 
Inclusion Criteria 
Subjects must meet all of the following criteria to be included in this study: 
1. Age ≥ 18 years. 
2. Histopathologic diagnosis of CTCL (mycosis fungoides [MF] or Sézary Syndrome [SS]), 
confirmed by skin biopsy, or lymph node, or blood assessment, of current disease. 
3. CD25 assay-positive tumor, defined as detectable CD25 on ≥ 20% of total lymphoid 
infiltrate in biopsied lesions by immunohistochemistry, assessed by a central pathology 
laboratory.  Results obtained at Screening or from an archival tumor biopsy (≤ 6 months) 
can be used as long as the test was performed by the study-designated central laboratory.  
Re-biopsy is required if the subject had disease progression or relapse since the last biopsy 
or had received anticancer therapy since the last biopsy. 
4. CTCL disease at study entry according to ISCL/EORTC4,6 (see Appendix 1).  
 Lead-In part:  Stage IA – IV, except subjects with CNS involvement 
 Main Study:  Stage I – III 
5. History of prior therapies for CTCL as follows:  must have had prior therapy, any number 
of prior therapies allowed. 
Topical treatments (except topical chemotherapy) and steroids are not considered as prior 
therapies. 
Prior therapies allowed include: 
 Cytotoxic chemotherapy 
 Combination cytotoxic chemotherapy 
 Electron beam radiotherapy (EBRT) 
 Phototherapy (e.g., psoralen ultraviolet light A [PUVA] or ultraviolet light B 
[UVB]) 
 Photophoresis 
 Interferon 
 Topical chemotherapy (e.g., carmustine, nitrogen mustard) 
 Systemic retinoids  
 Cyclosporin A (≥ 4 mg/kg/d for ≥ 1 month)  
 Histone deacetylase inhibitors 
Repeated use of the same agent counts as one therapy, unless it is part of a different 
combination regimen. 
6. A minimum washout period of 4 weeks after previous CTCL therapy is recommended 
before the first dose of E7777.  Subjects must have recovered from any adverse effects 
from any previous CTCL therapy to CTCAE Grade <2 before starting study drug.  A 
shorter washout may be allowed if a subject is experiencing progressive disease despite 


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ongoing treatment. 
7. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2 in the Lead-In 
part, and performance status 0 or 1 in the Main Study (Appendix 2). 
8. Life expectancy ≥ 3 months in the Lead-In part and ≥ 12 months in the Main Study. 
9. Adequate bone marrow reserves as evidenced by: 
a. platelets ≥ 100,000/mm3 (100 × 109/L) 
b. clinically stable hemoglobin ≥ 9 g/dL (90 g/L) and hematocrit ≥27% without 
transfusion support 
10. Normal hepatic function as evidenced by: 
a. bilirubin ≤ 1.5 × the upper limit of normal (ULN) and alkaline phosphatase ≤3.0 × 
ULN 
b. aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 × 
ULN 
c. albumin ≥ 3.0 g/dL (30 g/L) 
If AST or ALT values are elevated, a second determination may be made ≥ 4 days later; if 
the values obtained upon the retest meet the above criteria, then the subject is considered 
to have met this criterion for entry. 
11. Adequate renal function as evidenced by serum creatinine ≤ 1.8 mg/dL (158 µmol/L) OR 
calculated creatinine clearance ≥ 50 mL/min (per the Cockcroft–Gault formula 
[Appendix 3]) with < 2+ protein OR 24-hour urine creatinine clearance ≥ 50 mL/minute 
with 24-hour urine protein < 1 g. 
12. Willing and able to comply with all aspects of the protocol. 
13. Provide written informed consent prior to any study-specific screening procedures. 
14. Females may not be lactating or pregnant at Screening or Baseline (as documented by a 
negative beta-human chorionic gonadotropin [ß-hCG] test with a minimum sensitivity of 
25 IU/L or equivalent units of ß-hCG).  A separate baseline assessment is required if a 
negative screening pregnancy test was obtained more than 72 hours before the first dose of 
study drug. 
15. All females will be considered to be of childbearing potential unless they are 
postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age 
group, and without other known or suspected cause) or have been sterilized surgically (i.e., 
bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at 
least 1 month before dosing). 


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16. Females of childbearing potential must agree to use a highly effective method of 
contraception (e.g., total abstinence, an intrauterine device [IUD], a double-barrier method 
[such as condom plus diaphragm with spermicide], a contraceptive implant, an oral 
contraceptive, or have a vasectomized partner with confirmed azoospermia) throughout the 
entire study period and for 30 days after study drug discontinuation.  If currently abstinent, 
the subject must agree to use a double-barrier method as described above if she becomes 
sexually active during the study period or for 30 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 4 weeks prior to dosing and must continue 
to use the same contraceptive during the study and for 30 days after study drug 
discontinuation. 
17. Male subjects must have had a successful vasectomy (confirmed azoospermia) or they and 
their female partner must meet the criteria above (i.e., not of childbearing potential or 
practicing highly effective contraception throughout the study period and for 30 days after 
study drug discontinuation). 
9.3.2 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from the study: 
1. Prior denileukin diftitox therapy. 
2. Use of topical steroids within 14 days of Day 1 of initial therapy is not allowed, with the 
following exception: 
Topical steroids or systemic low dose steroids (≤ 10 mg/day prednisone) are allowed 
in subjects with erythroderma who have been on corticosteroids for a prolonged period 
of time and where discontinuation may lead to rebound flare in disease.  The 
concomitant steroid medication is allowed as long as the type of steroid, route of 
administration, and steroid dose remain the same as what the subject had been receiving 
for a prolonged period of time. 
3. Active malignancy (except for CTCL, definitively treated basal or squamous cell 
carcinoma of the skin, and carcinoma in-situ of the cervix) within the past 24 months . 
4. Serious intercurrent illness. 
5. Significant cardiac disease requiring ongoing treatment, including congestive heart failure 
(CHF), severe coronary artery disease (CAD), cardiomyopathy, uncontrolled cardiac 
arrhythmia, unstable angina pectoris, or myocardial infarction (MI) (within 6 months of 
study enrollment). 
6. Significant pulmonary symptoms or disease. 
7. History of uncontrolled seizure disorder or active central nervous system disease. 
8. Major surgery within 2 weeks of study enrollment. 


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9. Significant or uncontrolled infections requiring systemic anti-infective therapy. 
10. Known human immunodeficiency virus (HIV) infection; known active hepatitis B or 
hepatitis C infection. 
11. Females who are pregnant (positive urine test) or breastfeeding. 
12. 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. 
9.3.3 
Removal of Subjects From Therapy or Assessment 
The investigator may discontinue treating a subject with study treatment or withdraw the 
subject from the study at any time for safety or administrative reasons.  The subject may decide 
to discontinue study treatment or withdraw from the study at any time for any reason; however, 
the subject should remain on study, if possible, for follow-up. 
If a subject discontinues early from study treatment, the subject will enter the Follow-Up 
Period and complete protocol-specified off-treatment visits, procedures, and survival follow-
up unless the subject withdraws consent. 
During the Lead-In part, subjects who are not evaluable for DLT in Cycle 1 should be replaced.  
In the Main Study, subjects who withdraw from treatment or study participation will not be 
replaced.  Treatment will stop upon disease progression, unacceptable toxicity, or death. 
During the Follow-Up Period, subjects who have discontinued study treatment without 
progression should have disease assessments as specified in Section 9.5.2.2 until disease 
progression is documented or another new systemic anti-cancer therapy is initiated. 
9.4 
Treatments 
9.4.1 
Treatments Administered 
E7777 will be administered by intravenous (i.v.) infusion over 60 minutes (± 10 minutes) on 
5 consecutive days in every 21-day cycle. 
The E7777 dose in the Lead-In will be as assigned by CRM. 
The E7777 dose in the Main Study will be 9 µg/kg. 
Treatment will stop upon completion of 8 cycles or disease progression* or unacceptable 
toxicity.  Subjects who have attained skin tumor response and are deriving clinical benefit from 
E7777 treatment may continue receiving treatment beyond 8 cycles, at the discretion of the 
treating physician. 
The investigator or subject may also stop study treatment at any time for safety or personal 
reasons; however subject should remain on study, if possible, for follow-up. 
*Treatment may continue after first notation of disease progression (PD) if the investigator 


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is of the opinion that PD needs to be confirmed, eg, in cases where (a) the apparent 
increased tumor burden in the skin or lymph nodes may reflect immune reaction/flare, or 
(b) the subject shows improvement or stable disease in the skin but increase in lymph node 
size.  In this case, treatment will stop after 2 successive notations of PD. 
9.4.1.1 
Premedication 
Premedication for All Subjects 
Premedication for E7777 is required in Cycles 1 to 3 and is optional from Cycle 4 onward.  
The following should be administered approximately 30 minutes before each E7777 drug 
infusion: 
 Acetaminophen 650 mg by mouth (or per local institutional guideline [e.g., paracetamol 
500 mg by mouth]) to prevent fever and chills 
 Diphenhydramine 25 mg i.v. push or other antihistamine per local institutional guideline 
to prevent hives, itching, rash, shortness of breath, and chills 
 Antiemetic agents per institutional standard 
 Hydration with 250 to 500 mL normal saline i.v. (or other amount of fluid considered to 
be most appropriate for the subject’s condition, according to the judgment of the treating 
investigator) before and after each E7777 infusion 
Premedication with Systemic Steroids 
 Lead-In part.  Subjects should not receive premedication with systemic steroids, with the 
following exceptions: 
o In the event that a subject experiences an infusion reaction (i.e. within 24 hours of 
infusion) CTCAE grade 2 or 3 after the first administration of E7777 on Cycle 1 
Day 1, the premedication regimen for that subject must be supplemented during the 
rest of Cycle 1 (Days 2-5) with systemic corticosteroids (see below). Steroid 
premedication may be administered during subsequent treatment cycles at the 
discretion of the treating physician 
o In the event that a subject experiences an infusion related reaction at any time 
during any treatment cycle, the premedication regimen for that subject may be 
supplemented with systemic corticosteroids during the remainder of treatment days 
for that cycle (if event occurred before completion of cycle treatment) and/or in 
subsequent treatment cycles, at the discretion of the treating physician 
o Systemic corticosteroid premedication should be dexamethasone 4 mg, slow 
intravenous push OR equivalent corticosteroid dose according institutional 
guidance. 
 Main Study.  Same guidance as for the Lead-In part. 


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9.4.1.2 
Drug Preparation and Administration  
Frozen Drug Formulation (Lead-In only) 
The instructions below should be followed for preparation and administration of the frozen 
formulation of E7777 which is used in the Lead-In part: 
 Thaw vials in the refrigerator at 2 to 8 °C (36 to 46 °F) for not more than 24 hours or 
at room temperature for 1 to 2 hours. 
 Bring E7777 to room temperature, before dose preparation. 
 Mix the solution in the vial by gentle swirling; do not shake. 
 Visually inspect for particulate matter and discoloration prior to administration, 
whenever solution and container permit.  Use only if the solution is clear, colorless, 
and without visible particulate matter.  After thawing, a haze may be visible which 
should clear when the solution is at room temperature. 
 Do not refreeze E7777 after thawing. 
 Prepare and hold diluted E7777 in plastic syringes or soft plastic i.v. bags.  Do not use 
glass containers. 
 Maintain concentration of E7777 at 15 µg/mL or higher during all steps in the 
preparation of the solution for i.v. infusion. 
 Withdraw the calculated dose from the vial(s) and inject it into an empty i.v. infusion 
bag.  Do not add more than 9 mL of sterile saline without preservative to the i.v. bag 
for each 1 mL of E7777. 
 Do not administer as bolus injection. 
 Do not mix E7777 with other drugs. 
 Do not administer E7777 through an in-line filter. 


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 Administer prepared solutions of E7777 within 6 hours, using a syringe pump or i.v. 
infusion bag. 
 Discard unused portions of E7777 immediately. 
Lyophilized Drug Formulation (Main Study only) 
The instructions below should be followed for preparation and administration of the 
lyophilized formulation of E7777 which is used in the Main Study only: 
 E7777 is reconstituted with 2.1 mL of sterile Water for Injection prior to administration.  
 Mix the solution in the vial by gentle swirling; do not shake. 
 Visually inspect all the vials reconstituted for particulate matter and discoloration prior 
to administration.  Use only if the solution is clear, colorless, and without visible 
particulate matter.  After reconstitution, a haze may be visible which should clear when 
the solution is allowed to stand for a while at room temperature. 
 Prepare and hold diluted E7777 in plastic syringes or soft plastic (except for 
polystyrene) i.v. bags.  Do not use glass containers. 
 Maintain concentration of E7777 at 15 µg/mL or higher during all steps in the 
preparation of the solution for i.v. infusion. 
 Withdraw the calculated dose from the vial(s) and inject it into an empty i.v. infusion 
bag.  Do not add more than 9 mL of sterile saline without preservative to the i.v. bag 
for each 1 mL of E7777. 
 Do not administer as bolus injection. 
 Do not mix E7777 with other drugs. 
 Do not administer E7777 through an in-line filter. 
 Administer prepared solutions of E7777 within 6 hours, using a syringe pump or i.v. 
infusion bag. 
 Discard unused portions of E7777 immediately. 
9.4.1.3 
Monitoring Procedures During Administration 
Prior to administering E7777:   
 Ensure the facility is equipped and staffed for cardiopulmonary resuscitation. 
 Monitor vital signs. 


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 Monitor the following protocol-specified tests to ensure criteria for treatment are met:  
liver function tests, complete blood count (CBC), albumin, creatine phosphokinase 
(CPK), and renal function (Day 1 only). 
 Assess neurological status prior to each infusion including memory, orientation, gait, 
and numbness in extremities. 
 Monitor body weight prior to each infusion. 
 Monitor blood pressure. 
 Perform medical exploration specifically addressed to detect early signs of peripheral 
edema. 
During administration of E7777, monitor as follows: 
 Ensure epinephrine (0.1 to 0.5 mL of 1:1000 solution subcutaneous), diphenhydramine 
(50-mg i.v. push), and methylprednisolone sodium succinate (250-mg/mL i.v. push) or 
other medical preparation per local institutional guidelines for the treatment of infusion 
reactions are at the bedside. 
 Monitor for allergic reaction. 
 Perform frequent respiratory assessments. 
 Monitor vital signs before and at the end of the infusion and at 30 minutes postinfusion. 
General recommendations for administration of E7777 are:  to minimize the risk or to reduce 
the intensity of acute infusion-related reactions (e.g., fever, chills, tachycardia, etc.) that may 
occur, the infusion may be slowed or stopped temporarily until symptoms resolve.  Withhold 
E7777 treatment if serum albumin levels are < 3.0 g/dL (CTCAE Grade ≥ 2) or if clear signs 
of CLS occur e.g. peripheral edema, with or without functional impairment, cardiopulmonary 
impairment, or hypotension.  CPK testing is required if CLS is suspected and it should be 
monitored frequently as clinically indicated until resolution of CLS. 
9.4.1.4 
Management of Acute Infusion Reaction and Hypersensitivity During 
Administration 
The administration of E7777 should be withheld if the subject develops any of the following: 
 
Diastolic pressure below 60 mmHg or above 100 mmHg 
 
Pulse rate faster than 130 beats per minute (bpm) 
 
Shaking chills, rigors 
 
Oral temperature higher than 39.4 °C 


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 
Respiratory distress 
Administration of E7777 can be resumed if the subject’s signs and symptoms return to 
baseline; E7777 administration will be withheld for that day if the condition does not resolve. 
In the event a hypersensitivity reaction occurs, the following medications should be readily 
available during each administration: 
 Diphenhydramine (50-mg i.v. push) or other antihistamine per local institutional 
guideline for hives, itching, rash, shortness of breath, and/or chills 
 Methylprednisolone sodium succinate (250-mg/mL i.v. push) or per local institutional 
guideline for decrease in blood pressure (BP) and/or respiratory distress 
 Epinephrine 0.1 to 0.5 mL of a 1:1000 solution subcutaneous for anaphylaxis 
 Prochlorperazine (10-mg i.v. push) or institutional antiemetic agent of choice.  Subjects 
may receive antiemetics, as needed, for the control of nausea and/or vomiting 
9.4.1.5 
Dose Interruption or Modification 
Dose Delays 
 Dose delays will be allowed for toxicities. Resumption of dosing will be according to 
the guidelines provided in Table 1. 
 The maximum delay is 21 days before the day the next course is scheduled to start. 
o A full dose will be given if toxicities are resolved within this 21-day period. 
o A dose delay lasting > 21 days will lead to permanent discontinuation of 
treatment. 
o If a cycle is not delivered in full, regardless of the reason, the missing doses 
will not be replaced and the cycle will be considered as complete.  The missing 
doses will be captured per dose intensity calculations. 
 Two consecutive dose delays due to toxicity will lead to a permanent dose reduction 
by 50% without possible reescalation. 
o Only one dose reduction to 50% will be allowed, regardless of the reason.  The 
requirement for additional dose reductions, as defined previously, will lead to 
permanent discontinuation of treatment. 
 The starting date of a new cycle will coincide with the date of treatment resumption 
following a dose delay or dose reduction. 
 Dose delays are also allowed for scheduling purposes and if in the subject’s best interest 
in the opinion of the investigator. The maximum delay for this is 42 days. 


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Study drug interruption and dose reduction instructions for subjects who experience an 
E7777-related toxicity are presented in Table 1. 


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Table 1 
Dose Interruption and Modification During Treatment Period 
Toxicity 
Dose Interruption 
Dose Modification 
Capillary leak syndromea Grade 4 
Discontinue study treatment 
permanently 
N/A 
Capillary leak syndrome Grade 3,  
2. assessed as dose-limiting, e.g. 
severe symptoms requiring 
hospitalization for acute 
intervention 
Interrupt dosing until resolved to 
≤ Grade 1 
Resume at 50% dose 
Capillary leak syndrome Grade 3,  
- assessed as not dose-limiting, e.g. 
less severe symptoms leading to 
hospitalization for prophylactic 
treatment with fluids or diuretics 
Interrupt dosing until resolved to 
≤ Grade 1 
Resume at full dose 
Infusion reactionb Grade 4 
or 
Recurrent infusion reaction Grade 3 
that recurs despite premedication 
with systemic steroids 
Discontinue study treatment 
permanently 
N/A 
Infusion reaction Grade 2 or 3, first 
occurrence 
None 
Continue at full dose, but add 
systemic steroid premedication  
Recurrent infusion reaction Grade 2 
that recurs despite premedication 
with systemic steroids 
Interrupt dosing until resolved to 
≤ Grade 1 
Resume at full dose, but may add 
systemic steroid premedicationf  
Infusion related reactionc Grade 2 or 
3 
Interrupt dosing until resolved to 
≤ Grade 1 
Resume at full dose, but may add 
systemic steroid premedicationf 
Visual lossd 
Discontinue study treatment 
permanently 
N/A 
Grade ≥ 3 hematological ≥ 7 days, 
or febrile neutropenia, or bleeding. 
Exception:  Grade 3 lymphopeniae 
Interrupt dosing until toxicity 
≤ Grade 1, or until clinical 
symptoms are resolved 
No change; 
Resume at full dose 
Grade 3 nonhematologic toxicity 
except nausea, vomiting, or 
elevation of liver enzymes. 
Interrupt dosing until toxicity 
≤ Grade 1 or baseline 
No change; 
Resume at full dose 
Grade 4 nonhematologic toxicity 
other than, nausea, and vomiting. 
Discontinue study treatment 
permanently 
N/A 


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Table 1 
Dose Interruption and Modification During Treatment Period 
Toxicity 
Dose Interruption 
Dose Modification 
CLS = capillary leak syndrome, CTCAE = Common Terminology Criteria for Adverse Events, IRR = infusion-related 
reaction, N/A = not applicable. 
a Refer to Section 9.1.2 for definition of capillary leak syndrome (CSL) and of DLT for CLS 
b Infusion reactions are infusion related reactions that occur within 24 hr of E7777 administration; see 
Section 9.1.2 definitions 
c Infusion related reactions can occur at any time during the treatment cycle 
d Visual loss is defined as visual acuity impairment, color or shape distortion, or blurred vision  
e These toxicities were observed for E7777 in a Phase 1 study and are expected toxicities. 
f See Section 9.4.1.1 for detailed instructions on systemic steroid premedication 
9.4.2 
Identity of Investigational Products 
E7777 is a recombinant fusion protein composed of the amino acid sequences for diphtheria 
toxin fragments A and B (Met1-Thr387)-His and for human IL-2 (Ala1-Thr133).  E7777 is 
improved purity ONTAK resulting from an improved manufacturing process for ONTAK. 
9.4.2.1 
Frozen Formulation (Lead-In only) 
E7777 is supplied in single-use vials as a sterile, frozen solution intended for i.v. 
administration.  Each 2-mL vial of E7777 contains approximately 300 µg (150 µg/mL) of 
recombinant E7777 in a sterile solution of citric acid (20 mM), ethylenediamine tetraacetic 
acid ([EDTA], 0.05 mM), and polysorbate 20 (< 1%) in Water for Injection, United States 
Pharmacopoeia (USP).  Please refer to the label for the exact drug concentration in each vial. 
9.4.2.2 
Lyophilized Formulation (Main Study only) 
E7777 is supplied in single-use vials as a sterile, white lyophilized cake intended for i.v. 
administration.  E7777 white lyophilized cake is reconstituted with 2.1 mL of sterile Water for 
Injection prior to  administration.  After that, each 5-mL vial contains approximately 300 µg 
(150 µg/mL) of recombinant E7777, 5% (w/v) trehalose, 10 mM citric acid, 10 mM methionine, 
0.05 mM EDTA, and 0.06% polysorbate 20, at a pH of approximately 7 in Water for Injection, 
United States Pharmacopoeia (USP). 
9.4.2.3 
Chemical Name, Structural Formula of E7777 
 Test drug code:  E7777 
 Generic name:  Not Applicable 
 Chemical name:  diphtheria fragment A and B (Met1-Thr387)-His-Interleukin-2 (Ala1-
Thr133) 
 Molecular weight:  ~58 kD 


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9.4.2.4 
Comparator Drug 
Not applicable. 
9.4.2.5 
Labeling for Study Drug 
E7777 will be labeled in accordance with text that is in full regulatory compliance with each 
participating country and is translated into the required language(s) for each of those countries. 
9.4.2.6 
Storage Conditions 
Frozen Formulation (Lead-In only) 
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 be monitored 
throughout the total duration of the trial and that records be 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. 
Lyophilized Formulation (Main Study only) 
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 be monitored 
throughout the total duration of the trial and that records be 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 
Subjects in the Lead-In part will be assigned a dose of E7777 in accordance with the rules of 
the CRM. 
Main Study:  Not applicable, as there is only one treatment group. 
9.4.4 
Selection of Doses in the Study 
Lead-In part 
The doses of E7777 planned for testing in the CRM design are 3, 6, 9, 12, 15, and 18 µg/kg/day.  
E7777 has a higher proportion of active monomer species compared to current commercial 


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ONTAK.  Consistent with this, the bioactivity of E7777 on a weight basis is approximately 
1.5- to 2-fold higher than ONTAK.  The range of E7777 doses that are selected for the Lead-
In part takes into account this increased potency so that E7777 will be tested at approximate 
dose equivalents of FDA-approved ONTAK doses, as well as at surrounding lower and higher 
dose levels.  The starting dose of 6 µg/kg/day corresponds approximately to a 9 to 12 µg/kg/day 
dose of ONTAK in terms of bioactivity; this represents a reasonable starting dose as the 
approved ONTAK doses are 9 and 18 µg/kg/day administered at the same schedule. 
Main Study 
The E7777 dose for the Main Study will be 9 µg/kg/day. 
9.4.5 
Selection and Timing of Dose for Each Subject 
Treatment with E7777 will be by i.v. infusion over 60 minutes, on 5 consecutive days during 
every 21-day cycle, for up to eight cycles.  This is the schedule approved for ONTAK in the 
US. 
9.4.6 
Blinding 
Not applicable. 
9.4.7 
Prior and Concomitant Therapy 
The following are allowed: 
 Required premedications as described in Section 9.4.1.1. 
 Except as otherwise stated in this section of the protocol, only those concomitant 
medications intended to alleviate the signs and symptoms of CTCL will be allowed.  
Examples of such medications are:  antihistamine agents such as hydroxyzine, 
cyclizine, meclizine, or cetirizine; topical anesthetics such as lidocaine or benzocaine; 
ointments and lotions such as menthol, camphor, or calamine. 
 Topical steroids or systemic low dose steroids (≤ 10 mg/day prednisone) may be 
considered in subjects with erythroderma who have been receiving corticosteroids for 
a prolonged period of time and where discontinuation may lead to rebound flare in 
disease, adrenal insufficiency, and/or unnecessary suffering.  The concomitant steroid 
medication is allowed as long as the type of steroid, route of administration, and steroid 
dose remain the same as what the subject had been receiving for the prolonged period. 
The following are not allowed: 
 Use of topical steroids within 14 days of Cycle 1 Day 1; exception is noted in the 
section above (bullet #3 of allowed Concomitant Therapy). 
 While the subject is receiving study drug:  other anticancer treatment for CTCL, 
including chemotherapy, radiation therapy, immunotherapy, phototherapy, hormonal 


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therapy (with the exception of contraceptives or hormonal replacement), or 
experimental/investigational. 
The investigator will record on the AE case report form (CRF) any AE for which the 
concomitant medication/therapy was administered. 
9.4.8 
Treatment Compliance 
Records of treatment compliance will be kept for each subject during the study.  CRAs will 
review treatment compliance during site visits and at the completion of the study. 
9.4.9 
Drug Supplies and Accountability 
In compliance with local regulatory requirements, drug supplies will not be sent to the 
investigator (or if regionally required, the head of the medical institution or the designated 
pharmacist) until the following documentation has been received by the sponsor: 
 
A signed and dated confidentiality agreement 
 
A copy of the final protocol signature page, signed and dated by both the sponsor and 
investigator 
 
Written proof of approval of the protocol, ICFs, and any other information provided to 
the subjects by the IRB/IEC for the institution where the study is to be conducted 
 
A copy of the IRB/IEC-approved ICF and any other documentation provided to the 
subjects to be used in this study 
 
The IRB/IEC membership list and statutes, or Health and Human Services Assurance 
number 
 
A copy of the certification and a table of the normal laboratory ranges for the reference 
laboratory conducting the clinical laboratory tests required by this protocol 
 
An investigator-signed and dated Food and Drug Administration (FDA) Form FDA 1572, 
where applicable 
 
Financial Disclosure form(s) for the PI and all subinvestigators listed on Form FDA 1572, 
where applicable 
 
A signed and dated curriculum vitae (CV) of the PI and a copy of the PI’s current medical 
license (required in the US), or medical registration number on the CV 
 
A signed and dated clinical trials agreement 
 
A copy of the regulatory authority approval for the country in which the study is being 
conducted (if required) and the Import License (if required) 


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The investigator and the study staff (or if regionally required, the head of the medical institution 
or the designated pharmacist) will be responsible for the accountability of all study drugs 
(dispensing, inventory, and record keeping), following the sponsor’s instructions as provided 
in the Pharmacy Manual, and adherence to GCP guidelines as well as to local or regional 
requirements. 
Under no circumstances will the investigator allow the study drugs to be used other than as 
directed by this protocol.  Study drugs 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, dispensing of study drugs to the subject, collection and reconciliation of unused study 
drugs that are either returned by the subjects or shipped to site but not dispensed to subjects, 
and return of reconciled study drugs to the sponsor or (where applicable) destruction of 
reconciled study drugs at the site.  This includes, but may not be limited to:  (a) documentation 
of receipt of study drugs, (b) a study drugs dispensing/return reconciliation log, (c) a study 
drugs accountability log, (d) all shipping service receipts, (e) documentation of returns to the 
sponsor, and (f) certificates of destruction for any destruction 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 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 (e.g., 
FDA, Medicines and Healthcare products Regulatory Authority [MHRA]).  As applicable, all 
unused study drugs and empty and partially empty containers from used study drugs are to be 
returned to the investigator (or if regionally required, the head of the medical institution or the 
designated pharmacist) by the subject.  Empty containers from the subjects, along with unused 
study drugs that were shipped to the site but not dispensed to subjects, are to be returned to the 
sponsor’s designated central or local depot(s) during the study or at the conclusion of the study, 
unless provision is made by the sponsor for destruction of study drugs and containers at the 
site.  Destruction at the site will occur only under circumstances where regulation or supply 
type prohibits the return of study drugs 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 that are to be returned to the sponsor’s 
designated central or local depot(s) must be boxed and sealed and shipped back to the central 
or local depot(s) following all local regulatory requirements.  In some regions, study drugs 
may be removed from the site and hand-delivered to the central or local depot by sponsor 
representatives.  Where study drugs are approved for destruction at the site, destruction will 
occur following the site’s standard procedures, and certificates of destruction will be provided 
to the sponsor. 
Drug accountability will be reviewed during site visits and at the completion of the study. 


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9.5 
Study Assessments 
9.5.1 
Screening and Baseline Assessments 
9.5.1.1 
Demography 
Subject demography will be collected at the Screening Visit.  Demographic information 
includes date of birth (or age), sex, and race/ethnicity (record in accordance with local 
regulations). 
Medical History and Physical Examination 
Medical and surgical history and current medical conditions will be recorded at the Screening 
Visit.  All pertinent medical and surgical history must be noted in the Medical History and 
Current Medical Conditions CRF. 
Standard comprehensive physical examinations will be performed as designated on the 
Schedule of Procedures/Assessments (Table 4).  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 AEs CRF. 
A serum β-hCG pregnancy test will be performed. 
9.5.1.2 
Other Screening Assessments 
Tumor Assessments 
 A biopsy sample will be sent to a central laboratory for testing of CD25 expression by 
IHC; the sample may be sent in formalin, or may be a formalin fixed paraffin embedded 
(FFPE) sample, or may be sent as slides (minimum of 5 slides). Results must be 
obtained before enrollment of the subject in the study.  Results obtained at Screening 
or from an archival tumor biopsy (≤ 6 months) can be used as long as the test was 
performed by the study-designated central laboratory.  Multiple lesions may be tested.  
Re-biopsy with selection of the most representative lesion is required if the subject had 
disease progression or relapse since the last biopsy. 
 A whole blood sample should be collected for flow cytometry analysis by a central 
laboratory. 
 A lymph node biopsy should be obtained only if required for CTCL diagnosis and/or 
staging (see Section 9.5.2.2); lymph node analysis is to be performed by a local 
laboratory. 
NOTE:  Subjects may be enrolled in the study only after they have been confirmed to have a 
CD25 assay-positive tumor biopsy based on results from the central laboratory. 


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9.5.2 
Efficacy Assessments 
9.5.2.1 
Overview 
Primary Method for Tumor Assessment (Site review plus Independent Central review) 
The ISCL/EORTC response criteria6 (Olsen 2011) will be used as the primary method for 
efficacy analysis.  This method will be used by both the Site investigator and the Independent 
Review Committee (IRC). 
The dataset from the Stage I – III Main Study subjects plus the Stage I – III Lead-In subjects 
from the 9µg/kg/day dose group combined as generated by the IRC will be the primary 
efficacy analysis dataset.  All subjects from the Main Study will be assessed for efficacy by 
the IRC. 
For both the Lead-In and the Main Study, the site will report on the CRF their 
local/investigator tumor response assessment; site assessments will be used to make subject 
treatment decisions. 
Tumor assessment methods and schedules are provided in Section 9.5.2.3.  
Tumor burden scoring and the ISCL/EORTC response criteria are described in Appendix 1. 
Supplemental Alternate Method (SAM) for Tumor Assessment (IRC only) 
The response criteria described in Prince (2010)5 will be used as a supplemental alternate 
method, for the secondary objective of ORR and will be conducted by the IRC only. 
Imaging Core Laboratory 
For both the Lead-In and the Main Study, photographs and CT scans will be sent by the 
investigator site to an independent imaging core laboratory designated by the sponsor for 
analysis.  Laboratory results, including blood, as well as investigator skin assessments as 
entered in the eCRF, will be sent to the core laboratory by the sponsor.  At the time of data 
cutoff for primary analysis of the Main Study, the sponsor may choose to discontinue sending 
data (including photographs and scans) to the imaging core laboratory. 
9.5.2.2 
Tumor Assessment Methods and Schedule 
In the ISCL/EORTC criteria, a composite measure of disease in skin, lymph node, blood, and 
viscera will be used to assess tumor burden.  A Global Response Score will indicate the overall 
response assessment based on the composite measure. 
1. Skin Disease Assessment 
Skin tumor burden will be quantified using a modified Severity Weighted Assessment 
Tool (mSWAT) that provides an mSWAT score.  The mSWAT score measures the body 
surface area (BSA) involved in skin disease with a weighting factor applied according to 
the severity of the type of skin lesion, which can be patch, plaque, or tumor.  The mSWAT 


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can be utilized to track erythroderma by the summation of BSA involved with patch 
disease (macular erythema) and plaque disease (erythema with induration/edema).  In 
addition, subject(s) should be evaluated for the appearance of new skin tumor lesion(s) at 
each time point after the initiation of treatment.  A sample of the worksheet for calculating 
the mSWAT score is provided in Appendix 4.  Note:  The worksheet for use at the site 
will be provided separately to each site. 
Supplemental Assessment Method (SAM) using Prince (2010) Criteria (only for 
subjects with skin lesions comprising < 10% of BSA) 
Since the IRC will perform a secondary analysis based upon the method of Prince 
(2010), a supplemental measurement will be made by the site investigator at the time 
of mSWAT assessment, for subjects with skin lesions comprising < 10% of BSA.  
The investigator will identify, photograph, and measure up to five representative skin 
lesions (generally the largest and most representative of different locations, such as 
chest, abdomen, leg, arm, head, neck, if applicable; measurements will be of 
two-dimensional perpendicular diameters).  These measurements will be collected on 
the eCRF and will be used only by the IRC.  These lesions (even if they have 
disappeared) should be evaluated and photographed at all mSWAT assessment time 
points.  A sample of the worksheet for collecting skin lesion data per supplemental 
assessment method (by Prince 2010) is shown in Appendix 4.  Note:  The worksheet 
for use at the site will be provided separately to each site. 
The assessment schedule is as follows: 
a. At Screening, assessment to determine study eligibility 
b. During treatment 
 Day 1 (-3 days)  of every treatment cycle (minus 3-day window allowed) 
c. At EOT, if required for Global Response Score determination 
d. During Follow-up:  every 4 weeks (± 1 week) for 1 year after end of study 
treatment, then every 12 weeks (± 3 weeks) thereafter for up to 3 years, or 
sooner if clinically indicated 
The mSWAT scoring and supplemental assessment method (SAM) scoring should be 
performed by the same investigator at all time points.  If the same investigator cannot 
perform all the assessments, then all personnel grading the same subject must have 
completed prior training, ideally before study initiation. 
Standardized photographs of the skin are required to document the presence of skin lesions 
at all assessment times.  If the Screening assessment is within 1 week prior to Cycle 1 Day 
1, photographs are not required on Cycle 1 Day 1 as long as, in the investigators judgment, 
there is not a significant enough change in the subject’s skin disease involvement to 
warrant repeat photographs on Cycle 1 Day 1. 
The required views are: 
 Head and neck anterior view 


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 Head and neck posterior view  
 Head and neck left profile 
 Head and neck right profile 
 Head top of scalp 
 Upper body anterior (includes arms and hands) 
 Upper body posterior (includes arms and hands) 
 Upper body left flank with arm raised 
 Upper body right flank with arm raised 
 Lower body anterior (includes feet) 
 Lower body posterior (includes feet) 
 Lower body left side (includes foot) 
 Lower body right side (includes foot) 
When scoring by supplemental assessment method is being made, close-up and localization 
photographs including a millimeter ruler of target lesions are also required. 
2. Lymph Node Disease Assessment 
Assessment Methods and Schedules 
Lymph node involvement (see Appendix 5) will be assessed at Screening (and serve as 
baseline) by CT scan.  Biopsy will be performed if necessary, as described below (Part a, 
iii). 
Nx status may be assigned if there is no histologic information available: 
 Nx may be considered non-involved if the node >1.5 cm diameter is clinically 
not suspicious for lymphoma (Reactive/Inflammatory OR Dermatopathic) 
according to judgement of the investigator. 
 Nx should be considered involved if clinically suspicious for lymphoma (High 
SUV/ increasing size on scan). 
Lymph node status will be monitored on study during scheduled physical examination by 
palpation of peripheral nodes.  CT assessment or biopsy will be performed if necessary, as 
described below. 
a. At Screening, to record lymph node involvement at study entry, for use as baseline 
reference values 
i. Physical examination by palpation 
ii. CT scan and/or 18FDG-PET-CT scan 
 To identify any abnormal nodes (i.e., >1.5 cm diameter) at study entry. 
 To document normal nodes that may be used as reference for any 
subsequent PD in these nodes 


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 Scans performed prior to Screening that are within 6 weeks prior to C1D1 
are acceptable as Screening/baseline scans as long as they meet the 
requirements of the Imaging Acquisition Guideline from the Imaging 
Core Laboratory. 
iii. Biopsy and histologic characterization (per guidelines in Olsen 2007) 
In the Main Study, biopsy and histologic characterization is strongly 
recommended if an abnormal peripheral node suspicious for CTCL is 
detected by CT scans during Screening.  The most recent biopsy of a 
representative abnormal peripheral lymph node may be used as long as there 
has been stable lymph node size since that biopsy.  No biopsy of abnormal 
central nodes is required even if detected as abnormal upon CT scan at 
Screening (Olsen 2007).  
b. Treatment Phase:  
i. 
Physical examination by palpation 
Lead-In Part (scheduled examination) 
 During treatment:  Day 1 (-3 days) of every cycle (minus 3-day window 
allowed) 
 At the end of treatment 
 During Follow-up:  every 4 weeks (± 1 week) for 1 year after end of study 
treatment, then every 12 weeks (± 3 weeks) thereafter for up to 3 years, or 
sooner if clinically indicated. 
Main Study 
To be performed as necessary for monitoring of lymph node disease, with 
frequency according to the judgment of the investigator. 
ii. 
CT Scan 
CT assessment if any of the following conditions are met, during Treatment or 
Follow-up in Lead-in part 
 In subjects with more advanced disease (maximum/current TNMB 
greater than T1-2N0M0B0-1) at study entry, the CT assessment is to be 
performed at the time of CR or PR in skin disease 
 In subjects with early disease (maximum/current T1-2N0M0B0-1) at study 
entry, the CT is to be performed at time of CR or PR in skin disease, 
only if this affects the GRS 
 In all subjects, the CT is to be performed any time there is suggestion of 
new or progressive disease/relapse in lymph nodes or viscera (by 


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palpation of lymph nodes, liver, and/or spleen) and only in the absence 
of PD by skin or blood 
 Exceptions:  the CT need not be performed under the above 
circumstances if the lymph node response is not needed for GRS, e.g., 
if CR or PR is in skin but PD is in blood. 
CT assessment in Main Study is as described in Appendix 5 Figure 1. 
 In subjects with N0 and N1 at study entry:  
- 
CT is to be performed at time of CR or PR in skin disease, only if 
this affects the GRS 
- 
CT is to be performed any time there is suggestion of new or 
progressive disease/relapse in lymph nodes or viscera (by palpation 
of lymph nodes, liver, and/or spleen) and only in the absence of PD 
by skin or blood  
  In subjects with N2, N3 and Nx at study entry: 
- 
CT scans of the affected/suspected area are required every 3 cycles 
beginning at Cycle 3 (±1 week) 
 Exceptions:  the CT need not be performed under the above 
circumstances if the lymph node response is not needed for GRS, e.g., 
if there is already a PD assessment in another disease site. 
iii. 
Lymph node biopsy:  A repeat peripheral lymph node biopsy during the study 
is recommended only in situations where the histology would affect the Global 
Response score.  A fine needle aspirate or core biopsy with supportive ancillary 
studies may be acceptable. 
3. Blood Disease Assessment 
Blood tumor burden will be assessed by quantifying CD4+CD26− cells by flow cytometry; 
CD4+CD7− cells may be used in CD26+ subjects. 
Assessment frequency 
a. At Screening 
b. During treatment 
i. Day 1 (-3 days) of every treatment cycle 
c. At EOT, if required for Global Response Score determination 
d. During Follow-up:  Every 4 weeks (± 1 week) for 1 year after end of study treatment, 
then every 12 weeks (± 3 weeks) thereafter for up to 3 years, or sooner if clinically 
indicated. 
4. Visceral Disease Assessment 
Subjects with visceral involvement at study entry are only allowed in the Lead-In part.  


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Subjects will be assessed at Screening by CT scan (if applicable).  Viscera status will be 
monitored on study during scheduled physical examination by palpation (if applicable).  
CT assessment will be performed if necessary for GRS, as described below. 
a. At Screening, to exclude viscera involvement at study entry (Lead-In only), or for 
use as baseline reference values 
i. Physical examination by palpation 
ii. CT scan 
 to identify any measurable nodules or other visceral disease of any organ 
at study entry.  Measurable lesions are a minimum size of 1.0 × 1.0 cm; 
lesions smaller than this will be considered non-measurable.  Measurable 
visceral disease will be used to calculate SPD for visceral response 
assessment 
 to document any enlargement of liver and/or spleen that may be used as 
reference for any subsequent confirmation of tumor response or PD/relapse 
 Scans performed prior to Screening that are within 6 weeks prior to C1D1 
are acceptable as Screening/baseline scans as long as they meet the 
requirements of the Imaging Acquisition Guideline from the Imaging Core 
Laboratory. 
b. Physical examination by palpation 
During the study, physical examination (by palpation of liver and spleen) will be 
used to monitor for potential visceral disease. 
Lead-In Part (scheduled examination) 
i. During treatment:  Day 1 of every cycle 
ii. At the end of treatment 
iii. During Follow-up:  every 4 weeks for 1 year after end of study treatment, then 
every 12 weeks thereafter for up to 3 years, or sooner if clinically indicated 
Main Study 
To be performed as necessary for monitoring of viscera status, with frequency 
according to the judgment of the investigator. 
c. CT assessments for subjects with no visceral disease at study entry 
During the study, physical examination (by palpation of liver and spleen) will be 
used to monitor for potential visceral disease. 
If there is suspicion of new visceral disease, a CT scan should be performed to 
confirm PD/relapse.  The confirmatory CT is not necessary for the purposes of the 
study if PD in other disease sites has already been noted, as the latter is sufficient 


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for assessing the Global Response score. 
The minimum size of a new visceral lesion by CT must be >1.0 × 1.0 cm. 
d. Lead-In Part only:  CT assessments for subjects with visceral disease at study entry 
(Stage IVB)  
CT assessment if any of the following conditions are met, during Treatment or 
Follow-up 
i. In subjects with visceral disease at study entry, the CT assessment is to be 
performed every 12 weeks and at the time of CR or PR in skin disease 
ii. In all subjects, the CT is to be performed any time there is suggestion of new or 
progressive disease/relapse in lymph nodes or viscera (by palpation of lymph 
nodes, liver, and/or spleen) and only in the absence of PD by skin or blood 
iii. Exceptions:  The CT need not be performed under the above circumstances if 
the visceral response is not needed for GRS, e.g., if CR or PR is in skin but PD 
is in blood 
The minimum size of a new visceral lesion by CT must be >1.0 × 1.0 cm. 
9.5.2.3 
Subject Assessment of Pruritus 
Subjects will rate the severity of pruritus using a 100-mm visual analog scale (VAS), on which 
zero indicates no itch and 100 indicates worst possible itch.  A clinically significant 
improvement is defined as an absolute decrease of 20 mm from baseline maintained for ≥ 4 
weeks; baseline score must be ≥ 20. 
9.5.2.4 
Quality of Life Assessments 
Two instruments will be used for QoL assessments: 
 Skindex-29 
 FACT-G 
QoL assessments will be performed at Baseline, Day 1 of each cycle during treatment, at end 
of treatment (EOT), and during every tumor assessment visit during the Extension Phase. 
For illiterate subjects, local practices or standards will be utilized to obtain QoL assessments. 
9.5.3 
PK and Immunogenicity Assessments 
9.5.3.1 
PK Assessments 
PK assessment of E7777 will be performed in all subjects in the Lead-In part and in the first 
12 subjects in the Main Study using serial blood PK sampling on Day 1 in Cycles 1, 3, and 5, 
with sparse sampling in Cycle 8.  In addition, sparse sampling will be performed in the Main 
Study in the remaining subjects on Day 1 of Cycle 1.  PK blood samples will be collected as 


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shown in Table 2.  E7777 will be measured in serum samples using validated bioanalytical 
methods. 
Table 2 
PK Sampling Time Points 
Type of 
Sampling 
Cycle/Day 
Time Points 
Serial Blood 
PK Sampling 
Cycles 1, 3, 5, Day 1a 
predose, 30 minutes after the start of the infusion, 
end-of-infusion, and 30, 60, 90, 120, 180, 240, and 
300 minutes postinfusion stop 
Sparse PK 
Sampling 
Cycle 8, Day 1a 
predose, end-of infusion, and between 60 and 180 
minutes postinfusion 
Cycle 1, Day 1b 
1 
PK = pharmacokinetic. 
2 
a:  All subjects in the Lead-In part and the first 12 subjects in the Main Study. 
3 
b:  In the remaining subjects in the Main Study. 
Instructions for the processing, storage, and shipping of PK samples will be provided in the 
Laboratory Manual. 
The following PK parameters will be determined after serial blood PK sampling using 
noncompartmental methods: 
 Maximum drug concentration (Cmax)  
 Area under the curve from time 0 to time t (AUC(0-t))  
 Area under the curve from time 0 to infinity (AUC(0-inf))  
 Time to reach maximum (peak) concentration after drug administration (tmax) 
 Terminal elimination half-life (t½) 
 Total body clearance (CL)  
 Volume of distribution at steady state (Vdss) 
Data will also be evaluated for correlation between selected PK parameters with AEs and with 
objective responses. 
Population PK: 
A population PK model for E7777 will be developed using nonlinear mixed effect modeling.  
The model will be parameterized in terms of clearance and volume of distribution. 
Population PK/PD 
Pharmacokinetic/PD relationships between exposure to E7777 and some efficacy and safety 
variables will be explored graphically and may be followed by model-based analysis.   
All the PK samples noted in Table 2 will be utilized for the population PK analysis. 


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9.5.3.2 
Immunogenicity Assessments 
Immunogenicity (formation of antibodies to E7777) will be assessed in all subjects in both the 
Lead-In part and the Main Study.  Immunogenicity assessment in serum will be performed 
using validated bioanalytical methods to screen, confirm, and characterize the presence of anti-
E7777, anti-IL-2, and neutralizing antibodies.  Only samples with confirmed positive 
antibodies to E7777 and/or IL-2 will be tested by a neutralizing antibody assay.  A predose 
blood sample for immunogenicity assessment will be collected prior to dosing on Day 1 in 
Cycles 1, 2, 3, 5, and 8.  After that, all subjects will be followed up for immunogenicity for 
anti-IL2  on a 6-month schedule for 1 year and every year thereafter until antibody titers 
decrease to baseline level or until study conclusion/termination.  Blood samples will be 
collected prior to study drug administration. 
9.5.4 
Safety Assessments 
Safety will be assessed by the regular monitoring and recording of all AEs and serious adverse 
events (SAEs), hematology, blood chemistry, and urine values, vital signs, electrocardiograms 
(ECGs), and the performance of physical examinations including body weight and height as 
detailed in Section 9.5.5. 
9.5.4.1 
AEs and Other Events of Interest 
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered an investigational product.  An AE does not necessarily have a causal relationship 
with the medicinal product.  For this study, the study drug is E7777. 
The criteria for identifying AEs 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. 
 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 (e.g., ECG or x-ray) that results in symptoms, a change in treatment, or 
discontinuation from study drug. 
 Recurrence of an intermittent medical condition (e.g., headache) not present at baseline. 
 An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, whether prescribed in the protocol or not. 


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A laboratory result should be considered by the investigator to be an AE if it: 
 Results in the withdrawal of study drug 
 Results in withholding of study drug pending some investigational outcome 
 Results in an intervention, based on medical evaluation (e.g., potassium supplement for 
hypokalemia) 
 Results in any out-of-range laboratory value that in the investigator’s judgment fulfills the 
definitions of an AE with regard to the subject’s medical profile 
 Worsens (increases) to Grade 2 or higher based on the Sponsor’s Grading for Laboratory 
Values 
 Increases in severity compared to Baseline by ≥ 2 CTCAE grades (see Appendix 6 for 
CTCAE v5.0), with the exception of lymphocytes, albumin, cholesterol, glucose, and 
phosphate.  For these tests, any change of ≥ 2 grades will be evaluated by the investigator 
to determine if it is of clinical significance and, if so, will be considered an AE. 
All AEs observed during the study will be reported on the CRF.  All AEs, regardless of 
relationship to study drug or procedure, should be collected beginning from the time the subject 
signs the study ICF through the last visit and for 30 days after the subject’s last dose.  Serious 
AEs (SAEs) will be collected for 30 days after the last dose.  Any SAE that the investigator 
considers related to a protocol-required procedure must also be reported, regardless of the 
length of time since study-drug discontinuation. 
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.  Any laboratory abnormality 
considered to constitute an AE should be reported on the AE CRF. 
It is the responsibility of the investigator to review all laboratory findings in all subjects and to 
determine whether they constitute an AE.  Medical and scientific judgment should be exercised 
in deciding whether an isolated laboratory abnormality should be classified as an AE. 
Abnormal ECG (QT interval corrected for heart rate [QTc]) results, if not otherwise considered 
part of a clinical symptom that is being reported as an AE, should be considered an AE if the 
QTc interval is > 450 ms or there is an increase of > 60 ms from baseline.  Any ECG 
abnormality that the investigator considers an AE should be reported as such. 
Progression of malignant disease will not be recorded as an AE.  If the progression leads to an 
untoward medical occurrence (increased pain, pleural effusion, etc.), then this medical 
occurrence will be recorded as an AE. 
All AEs must be followed for 30 days after the subject’s last dose, or until resolution, 
whichever comes first.   


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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 
AEs will be graded on a 5-point scale according to CTCAE v5.0.  Investigators will report all 
CTCAE grades for AEs (see Appendix 6). 
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 
Not Related 
A causal relationship between the study treatment and the AE is not a 
reasonable possibility. 
Related 
A causal relationship between the study treatment and the AE is a reasonable 
possibility.  The investigator must further qualify the degree of certainty as 
“possible” or “probable.” 
9.5.4.2 
Serious Adverse Events and Other Events of Interest 
An SAE is any untoward medical occurrence that at any dose: 
 Results in death 
 Is life-threatening (i.e., the subject was at immediate risk of death from the AE 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 


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 Is a congenital anomaly/birth defect (in the child of a subject who was exposed to the study 
drug) 
Other important medical events that may not be immediately life-threatening or result in death 
or hospitalization but, when based on appropriate medical judgment, may jeopardize the 
subject or may require intervention to prevent one of the outcomes in the definition of SAE 
listed above should also be considered SAEs.  Medical and scientific judgment should be 
exercised in deciding whether expedited reporting is appropriate in such situations. 
In addition to the above, other events of interest include pregnancy or exposure to study drug 
through breastfeeding; AEs associated with study drug overdose, misuse, abuse, or medication 
error; any treatment-emergent significant laboratory abnormality; and vision loss.  These 
events of interest 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 events of interest are to 
be reported on the CRF whether or not they meet the criteria for SAEs. 
The following hospitalizations are not considered to be SAEs because there is no “AE” (i.e., 
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 post-study-drug administration) 
 Hospitalization for administration of study drug or insertion of access for administration of 
study drug 
 Hospitalization for routine maintenance of a device (e.g., battery replacement) that was in 
place prior to study entry 
If possible, a blood sample for PK analysis should be drawn at the first report of an SAE or a 
severe unexpected AE and at its resolution. 
9.5.4.3 
Laboratory Measurements 
Clinical laboratory tests to be performed, including hematology, chemistry, and urinalysis, are 
summarized in Table 3.  Subjects should be in a seated or supine position during blood 
collection.  The Schedule of Assessments (Table 4) shows the visits and time points at which 
blood for clinical laboratory tests and urine for analysis will be collected in the study. 


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Table 3 
Clinical Laboratory Tests 
Category 
Parameters 
Hematology 
Hematocrit, hemoglobin, platelets, RBC count, WBC count with 
differential (bands, basophils, eosinophils, lymphocytes, monocytes, 
neutrophils), and ANC 
Chemistry 
Screening/Baseline/ 
End-of-Treatment Panel 
Pregnancy test (serum β-hCG), LDH, chloride, potassium, sodium, 
BUN, serum creatinine, phosphorus, calcium, albumin, total protein, 
alkaline phosphatase, ALT, AST, total bilirubin, CPK, TSH, and free 
T4 in the case of abnormal TSH 
Treatment Panel 
Chloride, potassium, sodium, BUN, serum creatinine, phosphorus, 
calcium, albumin, total protein, alkaline phosphatase, ALT, AST, 
total bilirubin, CPK 
Serum TSH, free T3, and free T4, and in the case of abnormal TSH:  
anti-thyroglobulin antibodies and anti-thyroid peroxidase antibodies  
Urinalysisa 
Glucose, protein, leukocytes, nitrites, ketones, bilirubin, blood, 
urobilinogen, pH, and specific gravity.  Microscopic examination of 
sediment to include:  bacteria, casts, crystals, epithelial cells, RBCs, 
and WBCs 
Urine pregnancy test (Cycle 1 Day 1 only) 
ALT = alanine aminotransferase, ANC = absolute neutrophil count, AST = aspartate aminotransferase, ß-hCG = beta 
human chorionic gonadotropin, BUN = blood urea nitrogen, LDH = lactate dehydrogenase, RBC = red blood cell, T3 = 
triiodothyronine, T4 = thyroxine, TSH = thyroid-stimulating hormone, WBC = white blood cell, CPK = creatine 
phosphokinase. 
a:  When a local laboratory is required for a urinalysis, a Urinalysis Reagent Test Strip (URS-10) may be used. 
Clinical laboratory tests will be performed by a central laboratory.  All blood and urine samples 
will be collected and sent to the central laboratory on the day of collection unless otherwise 
instructed.  In cases of a safety concern, blood samples will be split, or two samples drawn, to 
allow a local laboratory analysis in addition to the central laboratory. 
All hematology, blood chemistry (including pregnancy test, as applicable), and urinalysis 
samples are to be obtained before study drug administration and results reviewed before 
administration/dispensing of study drug at the beginning of each treatment cycle.  Refer to 
Table 1 for dose interruption and reduction instructions in the event of clinically significant 
laboratory abnormalities. 
A laboratory abnormality may meet the criteria to qualify as an AE as described in this protocol 
(see AEs and Other Events of Interest [Section 9.5.4.1]).  In these instances, the AE 
corresponding to the laboratory abnormality will be recorded on the AE CRF.  Assessment of 
what constitutes a laboratory abnormality will take the underlying disease into consideration. 
For laboratory abnormalities meeting the criteria of SAEs (see SAEs and Other Events of 
Interest [Section 9.5.4.2]), the site must fax or email the SAE report including the laboratory 
report (as regionally required) to the sponsor using the SAE form (see Reporting of SAEs 
[Section 9.5.7.1]). 


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9.5.4.4 
Vital Signs  
Vital sign measurements (i.e., systolic and diastolic BP [mmHg], pulse [bpm], respiratory rate 
[per minute], body temperature [in degrees centigrade]), will be measured as signals for 
potential vascular leak syndrome.  Measurements will be obtained before and at the end of the 
infusion and 30 minutes post-infusion on treatment days at the visits designated in the Schedule 
of Assessments (Table 4). 
9.5.4.5 
Physical Examinations and Weight 
A complete physical examination including weight will be performed at baseline, Day 1 of 
each cycle and at study termination as designated on the Schedule of Assessments (Table 4).  
Height should be collected as part of the physical exam at the baseline visit.  A 
symptom-directed examination will be performed on all other visit days.  Documentation of 
the physical examination will be included in the source documentation at the site.  Only 
changes from screening physical examination findings the meet the definition of an AE will 
be recorded on the AE CRF. 
9.5.4.6 
Electrocardiograms 
12-lead ECGs will be taken as designated on the Schedule of Assessments (Table 4).   
Complete, standardized, single 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 three 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 Adverse 
Events and Other Events of Interest [Section 9.5.4.1]) and the CRF Completion Guidelines.  In 
these instances, the AE corresponding to the ECG abnormality will be recorded on the Adverse 
Events CRF.  For ECG abnormalities meeting criteria of an SAE (see Serious Adverse Events 
and Other Events of Interest [Section 9.5.4.2]), the site must fax or email the SAE report 
including the ECG report to the sponsor using the SAE form (see Reporting of Serious Adverse 
Events [Section 9.5.7.1]). 
9.5.5 
Schedule of Procedures/Assessments  
9.5.5.1 
Schedule of Assessments 
 


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Table 4 
Schedule of Assessments 
PHASEa 
PRETREATMENT 
TREATMENT 
Perioda Screening 
Baseline 
Cycles 1 to 8 
(Cycle 9 and beyond, if applicable)a 
Follow-Up 
 Cycle Day 
Up to -
28 
Up to -7 
1 
2 
3 
4 
5 
8 
EOT a 
Procedures/Assessments 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
 
 
 
 
 
Tumor biopsy for CTCL diagnosis b 
X 
 
 
 
 
 
 
 
 
 
Blood sampling or lymph node biopsy for CTCL 
diagnosis c 
X 
 
 
 
 
 
 
 
 
 
Prior/concomitant medications d 
X 
X 
X 
[X] 
 
Vital signs e 
 
X 
X 
X 
X 
X 
X 
[X] 
[X] 
 
Physical examination and ECOG e 
 
X 
X 
 
 
 
 
 
[X] 
 
ECG f 
X 
 
X 
 
 
 
 
 
[X] 
 
Urine pregnancy testg 
 
 
X 
 
 
 
 
 
 
 
Urinalysis g 
 
X 
X 
 
 
 
 
[X] 
 
 
Serum -hCG pregnancy test h 
X 
X 
 
 
 
 
 
 
X 
 
Hematology laboratory tests h 
X 
X 
X 
 
 
 
 
[X] 
[X] 
 
Chemistry laboratory tests h 
X 
X 
X 
 
 
 
 
[X] 
[X] 
 
PK and Immunogenicity blood samples i 
 
 
[X] 
 
 
 
 
 
 
[X] 
Drug administration:  E7777 j 
 
 
X 
X 
X 
X 
X 
 
 
 
Tumor assessment:  skin mSWAT with photographyk 
X 
 
X 
 
 
 
 
 
[X] 
[X] 
Tumor assessment:  lymph node PEk 
X 
 
X 
 
 
 
 
 
[X] 
[X] 
Tumor assessment:  blood diseasek 
X 
 
X 
 
 
 
 
 
[X] 
[X] 
Patient-reported pruritus assessmentl 
X 
 
X 
 
 
 
 
 
[X] 
[X] 


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Table 4 
Schedule of Assessments 
PHASEa 
PRETREATMENT 
TREATMENT 
Perioda Screening 
Baseline 
Cycles 1 to 8 
(Cycle 9 and beyond, if applicable)a 
Follow-Up 
 Cycle Day 
Up to -
28 
Up to -7 
1 
2 
3 
4 
5 
8 
EOT a 
Procedures/Assessments 
 
 
 
 
 
 
 
 
 
 
CT scansm 
X 
 
[X] 
[X] 
 
Adverse eventn  
 
X 
X 
X 
 
Survivalo 
 
 
 
 
 
 
 
 
 
X 
QoLp 
 
X 
X 
 
 
 
 
 
X 
X 
 
Table 4 Schedule of Assessments (cont’d) 
PHASEa 
EXTENSION 
Perioda 
Treatment 
(Continued treatment after data cut-off )a 
Follow-Up q 
 Cycle Day 
1 
2 
3 
4 
5 
8 
EOT a 
 
Procedures/Assessments 
 
 
 
 
 
 
 
 
Prior/concomitant medications d 
X 
[X] 
 
Vital signs e 
X 
X 
X 
X 
X 
[X] 
[X] 
 
Physical examination and ECOG e 
X 
 
 
 
 
 
[X] 
 
ECG f 
X 
 
 
 
 
 
[X] 
 
Urine pregnancy testg 
X 
 
 
 
 
 
 
 
Urinalysis g 
X 
 
 
 
 
[X] 
 
 
Serum -hCG pregnancy test h 
 
 
 
 
 
 
X 
 
Hematology laboratory tests h 
X 
 
 
 
 
[X] 
[X] 
 
Chemistry laboratory tests h 
X 
 
 
 
 
[X] 
[X] 
 
PK and Immunogenicity blood samplesi 
[X] 
 
 
 
 
 
 
[X] 


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Table 4 Schedule of Assessments (cont’d) 
PHASEa 
EXTENSION 
Perioda 
Treatment 
(Continued treatment after data cut-off )a 
Follow-Up q 
 Cycle Day 
1 
2 
3 
4 
5 
8 
EOT a 
 
Procedures/Assessments 
 
 
 
 
 
 
 
 
Drug administration:  E7777j 
X 
X 
X 
X 
X 
 
 
 
Tumor assessment:  skin mSWAT with photographyk 
X 
 
 
 
 
 
[X] 
[X] 
Tumor assessment:  lymph node PEk 
X 
 
 
 
 
 
[X] 
[X] 
Tumor assessment:  blood diseasek 
X 
 
 
 
 
 
[X] 
[X] 
Patient-reported pruritus assessmentl 
X 
 
 
 
 
 
[X] 
[X] 
CT scansm 
[X] 
[X] 
[X] 
Adverse eventn  
X 
X 
X 
Survivalo 
 
 
 
 
 
 
 
X 
QoLp 
[X] 
 
 
 
 
 
X 
X 
 
ALT = alanine aminotransferase, ANC = absolute neutrophil count, AST = aspartate aminotransferase, β-hCG = beta-human chorionic gonadotropin, BUN = blood urea nitrogen, 
CR = complete response, CRM = Continual Reassessment Method, CS = Color Distortion test, CT = computed tomography, CTCL = cutaneous T-cell lymphoma,  
ECG = electrocardiogram, ECOG = Eastern Cooperative Oncology Group, EOT = End of Treatment, FFPE = formalin-fixed paraffin embedded, IHC = immunohistochemistry, i.v. 
= intravenous, LDH = lactate dehydrogenase, min = minutes, mSWAT = modified Severity Weighted Assessment Tool, N/A = Not applicable, PD = progressive disease,  
PE = physical examination, PR = partial response, QoL = quality of life, RBC = red blood cell, TSH = thyroid-stimulating hormone, WBC = white blood cell 
Note:  [X] = Either:  not required in all cycles, or not required in all subjects.  See footnotes. 
a:  Pretreatment:  Screening up to 28 days before start of treatment except for signing of the ICF which may be up to 8 weeks before the first dose of study drug; Baseline up to 7 days 
before start of treatment.  If Screening laboratory tests (Hematology, Chemistry, and serum pregnancy) are performed within 7 days prior to Cycle 1 Day 1, these tests may count 
as Baseline tests and need not be repeated at Baseline.  If Baseline central laboratory test results are not available in time to confirm eligibility, the local site laboratory results 
(including from Cycle 1 Day 1) may be used for this purpose.  
Treatment:  cycles of 21 days, up to 8 cycles; applicable to the Lead-in only, if subject is treated beyond Cycle 8 per protocol, the same assessments should be performed as for 
Cycles 1 to 8; however, no PK samples will be collected after Cycle 8. 
Extension:  Up to 3 years. 
Day 8 Assessments:  Day 8 assessments are required in cycles 1-3, and are optional on cycle 4 and beyond. 
EOT:  Tumor assessments are only required at EOT if they affect GRS. Other EOT tests (with the exception of serum pregnancy test, and QoL) need only be performed if the 
EOT visit is > 7 days from the most recent Cycle Day 1 visit.  


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b:  A biopsy sample will be  sent to a central laboratory for testing of CD25 expression by IHC.  The sample may be sent in formalin, or may be a formalin fixed paraffin embedded 
(FFPE) sample block, or may be sent as slides (minimum of five slides).  Results must be obtained before enrollment of subject in the study.  Results obtained at Screening or 
from an archival tumor biopsy (≤ 6 months) can be used as long as the test was performed by the study-designated central laboratory.  Multiple lesions may be tested.  Re-biopsy 
with selection of the most representative lesion is required if the subject had disease progression or relapse since the last biopsy, or had received anticancer therapy since the last 
biopsy. 
c:  Blood sampling, if blood assessment required for CTCL diagnosis; whole blood to be collected for flow cytometry analysis by central laboratory.  Lymph node biopsy (if required 
per Olsen 2011):  allow either fine needle aspirate or core biopsy; if additional lymph node analysis is required, surgical biopsy may follow, if required for CTCL diagnosis and/or 
staging; lymph node analysis to be performed by local site laboratory. 
d:  Concomitant medications to be reviewed at every visit, until 30 days after the last treatment dose.  Use of topical or systemic steroids within 14 days of Cycle 1 Day 1 is not 
allowed, with the exception noted under “Concomitant Medications” (see Section 9.4.7). 
e:  Vital signs measured at baseline and EOT (if necessary), and on drug treatment days and on Cycle Day 8 (± 1 day), before and at the end of the infusion and 30 minutes after 
infusion.  A complete physical examination will be performed at Baseline, Day 1 of each cycle, and at Study Termination (discontinuation from study).  A symptom-directed 
examination will be performed on all other visit days.  All physical examinations are to include monitoring of weight and blood pressure as signals for potential vascular leak 
syndrome. 
f:  Single 12-lead ECGs will be performed during Screening, on Day 1 of each cycle  and at End of Treatment.   
g:  On Cycle Day 1 (i.e. treatment day), urinalysis will be performed prior to study drug administration.  Urinalysis includes glucose, protein, leukocytes, nitrites, ketones, bilirubin, 
blood, urobilinogen, pH, and specific gravity.  Microscopic examination of sediment includes bacteria, casts, crystals, epithelial cells, RBCs, and WBCs.  When a local laboratory 
is required for a urinalysis, a Urinalysis Reagent Test Strip (URS-10) may be used.  On Cycle 1 Day 1 only:  a urine pregnancy test will be performed prior to study drug 
administration. 
h:  Chemistry laboratory tests should include the following thyroid function tests:  serum TSH, free T3, free T4, and if these are abnormal, then include anti-thyroglobulin antibodies 
and anti-thyroid peroxidase antibodies (reflex testing at central laboratory only).  Laboratory tests should also include serum ß-hCG and LDH (screening only), chloride, potassium, 
sodium, BUN, serum creatinine, phosphorus, calcium, albumin, total protein, alkaline phosphatase, ALT, AST, total bilirubin, and CPK.  Hematology laboratory tests include 
hematocrit, hemoglobin, platelets, RBC count, WBC count with differential (bands, basophils, eosinophils, lymphocytes, monocytes, neutrophils), and ANC. If Screening 
laboratory tests (Hematology, Chemistry, and serum pregnancy) are performed within 7 days prior to Cycle 1 Day 1, these tests may count as Baseline tests and need not be 
repeated at Baseline.  On Day 1 of each cycle, laboratory assessments (local site laboratory) must be reviewed prior to drug administration, in addition to submitting to the central 
lab.  For Cycle Day 8, a window of ±1 day is allowed. 
i:  Blood sampling for pharmacokinetic (PK) and immunogenicity (anti-E7777, anti-IL-2, and neutralizing antibodies) testing.  Sample volumes are 3 mL for PK assessments and 3 
mL for immunogenicity testing.  Pharmacokinetic assessment of E7777 will be performed in all subjects in the Lead-In part and in the first 12 subjects in Main Study.  Serial 
blood samples will be taken on Day 1 of Cycles 1, 3, and 5, with sparse sampling in Cycle 8.  Serial blood samples will be collected at predose, 30 min after the start of the 
infusion, end-of-infusion, and 30, 60, 90, 120, 180, 240, and 300 minutes after the end of the infusion.  Sparse samples will be collected at predose, end-of infusion and between 
60 and 180 min after the infusion ends.  For the remaining subjects in the Main Study, sparse blood samples will be taken on Day 1 of Cycle 1.  They will be collected at predose, 
end-of infusion and between 60 and 180 min after the end of the infusion.  Immunogenicity will be assessed in all subjects in both the Lead-In part and the Main Study.  A predose 
blood sample for immunogenicity assessment will be collected prior to dosing on Day 1 in Cycles 1, 2, 3, 5, and 8; after that, all subjects  will be followed up for immunogenicity 
testing for anti-IL2 at 6 months, one year and every year thereafter until antibody titers decrease to baseline level.  These blood samples will be collected before study drug 
administration.  
j:  E7777 by i.v. infusion over 60 minutes (±10 minutes).  Premedication required in Cycles 1 to 3 (see protocol).  Lead-In:  E7777 at a dose assigned according to the CRM; Main 
Study:  E7777 at a dose determined in the Lead-In.  A window of ±1 day is allowed for start of treatment cycle from Cycle 3 onward, inclusive. 
k:  Assessment of skin disease by mSWAT score, lymph node disease by physical examination, and blood disease by flow cytometry (central laboratory).  During the Extension 
phase, assessment is to be performed every 4 weeks (± 1 week) for 1 year after end of study treatment, then every 12 weeks (± 3 weeks) thereafter for up to 3 years, or sooner if 
clinically indicated.  In addition, skin assessments as needed for the supplemental alternate method for independent review using the method of Prince (2010) are to be performed 


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as indicated in Section 9.5.2.2 and Appendix 4 of the protocol.  The Day 1 assessments can be performed within a -3 day window, i.e., Day 1 (-3 days).  Standardized photographs 
of the skin are to be taken at all assessment time points.  The required views are listed in the protocol Section 9.5.2.2.  If the Screening assessment is within 1 week prior to Cycle 
1 Day 1, photographs are not required on Cycle 1 Day 1 as long as, in the investigators judgment, there is not a significant enough change in the subject’s skin disease involvement 
to warrant repeat photographs on Cycle 1 Day 1. 
l:   Patient-reported assessments of pruritus will be performed at the same visits as the mSWAT assessments. 
m: CT scanning of neck, chest, abdomen, and pelvis is required at Screening (unless scans were performed within 6 weeks prior to C1D1) to assess nodal and visceral disease   (scans 
within 6 weeks prior to C1D1 are acceptable as baseline scans as long as they meet the requirements of the Imaging Acquisition Guideline from the Imaging Core Laboratory). 
For subjects who failed screening because of lab results, and at re-screening the investigator believes that there is no new disease progression, new scans are not required and 
previous screening scans are acceptable as baseline if performed within 6 weeks prior to C1D1. 
     18FDG-PET-CT scans may be performed during screening for lymph node disease assessment. 
     For subjects with nodal disease N2, N3 and Nx at screening, CT scans of the affected/suspected area are required every 3 cycles beginning at Cycle 3 (±1 week) during treatment 
phase. For all other subjects during treatment phase, CT scans are required at the time of a documented CR or PR or as clinically indicated (eg, suspicion of PD) and at final 
treatment for responding subjects (PR or CR) during follow-up for responding subjects (PR or CR) who have had documented nodal involvement at baseline and currently there 
is no suspicion of nodal involvement after the final treatment, at 6 months, 12 months, and yearly for up to 3 years.  For subjects in the Lead-In with visceral involvement at 
screening, CT scans of the chest, abdomen, and pelvis are required every four cycles (±1 week) during treatment; and at the time of a documented CR or PR, and as clinically 
indicated (e.g., suspicion of PD or relapse) within 1 week after suspicion of response or progression/relapse. 
CT/18FDG-PET-CT scans of skin disease may be performed as necessary for response assessment if the CT acquisition is of diagnostic quality. 
n:  Adverse events will be assessed at every visit, until 30 days after the last treatment dose. 
o:  Survival follow-up performed every 3 months after discontinuation from study treatment, up to 3 years from end of study treatment. 
p:  QoL is to be performed at Baseline, on Day 1 of every cycle during Treatment, at EOT, and during every Tumor Assessment visit during Extension.  The QoL will be assessed 
in Stage I – III Main Study subjects plus the Stage I – III Lead-In subjects from the 9µg/kg/day dose group combined. 
q:  Follow-up tumor assessments (except in subjects who discontinued treatment due to PD), immunogenicity and survival follow-up until relapse, or  initiation of new systemic 
anti-cancer therapy, for up to 3 years after EOT. 


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9.5.5.2 
Description of Procedures/Assessments Schedule – Lead-In and Main Study 
PRETREATMENT PHASE ASSESSMENT SCHEDULE 
SCREENING PERIOD ASSESSMENTS 
Visit 1 (up to 28 days before start of study treatment) 
Prior to performing any procedures or assessments, the nature of the study and the potential 
risks associated with the study will be explained to all candidates and their respective partners, 
where applicable, and written informed consent obtained from both, if required.  Once 
informed consent has been obtained, the Screening Period procedures and evaluations will be 
performed. 
Refer to the Schedule of Assessments, Table 4, for a description and the schedule for all other 
screening assessments. 
BASELINE PERIOD ASSESSMENTS 
Visit 2 (up to 7 days before the start of study treatment) 
The results of all baseline assessments and evaluations must be completed and reviewed by the 
PI prior to the subject’s arrival for the visit.  Only those subjects who continue to meet all of 
the inclusion and none of the exclusion criteria are eligible to continue in the study. 
If Screening laboratory tests (Hematology, Chemistry, and serum pregnancy) are performed 
within 7 days prior to Cycle 1 Day 1, these tests may count as Baseline tests and need not be 
repeated at Baseline.  If Baseline central laboratory test results are not available in time to 
confirm eligibility, the local site laboratory results (including from Cycle 1 Day 1) may be used 
for this purpose. 
Reasonable efforts should be made to conduct all baseline assessments and subsequent 
evaluations in the same test order at each subject visit.  This is intended to minimize variability 
in subject response.  It is further recommended (whenever possible) that subjects be evaluated 
at approximately the same time period of the day (e.g., morning or afternoon) at each 
subsequent visit. 
During the Lead-In Period only, IxRS should be called for dose assignment according to CRM 
design method.  Refer to the Schedule of Assessments, Table 4, for a description and the 
schedule for all other Baseline Visit assessments. 
TREATMENT PHASE AND EXTENSION PHASE ASSESSMENT SCHEDULES 
Treatment Period: 
Refer to the Schedule of Assessments, Table 4, for a description and the schedule for all cycle 
day and EOT assessments. 
Day 8 assessments are required during Cycles 1-3 and are optional on Cycle 4 and beyond. 


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EOT:  Tumor assessments are only required at EOT if they affect GRS.  Other EOT tests (with 
the exception of serum pregnancy test, and QoL) need only be performed if the EOT visit is > 
7 days from the most recent Cycle Day 1 visit. 
Follow-up Period: 
Tumor assessments should be performed until PD.  Immunogenicity and survival assessments 
should be performed until discontinuation from study.  All assessments for up to 3 years from 
EOT.  Refer to the Schedule of Assessments, Table 4, for a description and the schedule for all 
other Follow-Up assessments. 
9.5.6 
Appropriateness of Measurements 
All clinical assessments are standard measurements commonly used in studies of treatment of 
CTCL. 
9.5.7 
Reporting of SAEs, Pregnancy, and Other Events of Interest 
9.5.7.1 
Reporting of SAEs 
All SAEs, 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. 
Deaths and life-threatening events should be reported immediately by telephone.  The 
immediate report should be followed up within 1 business day by emailing or faxing the 
completed SAE form. 
SAEs, regardless of causality assessment, must be collected through the last visit and for 
30 days after the subject’s last dose.  All SAEs must be followed to resolution or, if resolution 
is unlikely, to stabilization.  Any SAE judged by the investigator to be related to the study 
treatment should be reported to the sponsor regardless of the length of time that has passed 
since study completion. 
The detailed contact information for reporting of SAEs is provided in the Investigator Study 
File. 
For urgent safety issues, please ensure all appropriate medical care is administered to the 
subject and contact the appropriate study team member listed in the Investigator Study File. 
It is very important that the SAE report form be filled out as completely as possible at the time 
of the initial report.  This includes the investigator’s assessment of causality. 
Any follow-up information received on SAEs should be forwarded within 1 business day of 
its receipt.  If the follow-up information changes the investigator’s assessment of causality, 
this should also be noted on the follow-up SAE form. 


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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 the institution.  A copy of this communication must be forwarded to the sponsor 
to be filed in the sponsor’s Trial Master File. 
9.5.7.2 
Reporting of Pregnancy and Exposure to Study Drug Through Breastfeeding 
Any pregnancy in which the estimated date of conception is either before the last visit or within 
30 days of last study treatment or any exposure to study drug through breastfeeding during 
study treatment or within 30 days of last study treatment must be reported. 
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 the 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 SAEs [Section 9.5.7.1]). 
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. 
9.5.7.3 
Reporting of Other Events of Interest 
REPORTING OF STUDY DRUG OVERDOSE, MISUSE, ABUSE, OR MEDICATION ERROR 
AEs 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  


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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 an overdose should be captured on the Adverse Event CRF.  AEs 
associated with overdose, misuse, abuse, or medication error should be reported using the 
procedures detailed in Reporting of SAEs (Section 9.5.7.1) 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. 
Any study drug overdose, misuse, abuse, or medication error during the study should be noted 
on the Study Medication CRF. 
REPORTING OF STUDY-SPECIFIC EVENTS 
Study-specific events, i.e., vision loss, should be entered on the AE CRF and reported using 
the procedures detailed in Reporting of SAEs (Section 9.5.7.1), even if the study-specific event 
does not meet serious criteria.  If the event 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 AE CRF. 
9.5.7.4 
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 (i.e., within specific time frames).  For this 
reason, it is imperative that sites provide complete SAE information in the manner described 
above. 
9.5.7.5 
Regulatory Reporting of AEs 
AEs will be reported by the sponsor or a third party acting on behalf of the sponsor to regulatory 
authorities in compliance with local and regional law and established guidance.  The format of 
these reports will be dictated by the local and regional requirements. 
All studies that are conducted within any European country will comply with European Good 
Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC.  All SUSARs 
will be reported, as required, to the competent authorities of all involved European member 
states. 


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9.5.8 
Completion/Discontinuation of Subjects 
See Section 9.3.3, Removal of Subjects from Therapy or Assessment, for reasons allowed for 
discontinuation. 
All subjects who discontinue early from the study treatment are expected to complete the EOT 
procedures indicated on the Schedule of Procedures/Assessments (see Table 4), if possible. 
For all subjects who discontinue from the study, study disposition information will be collected 
on the appropriate eCRF. 
A subject who has ceased to return for visits will be followed up by mail, phone, or other means 
as much as possible to gather protocol-specified follow-up information. 
Subjects who are not evaluable for DLT in Cycle 1 should be replaced. 
9.5.9 
Abuse or Diversion of Study Drug 
Not applicable (N/A). 
9.5.10 
Confirmation of Medical Care by Another Physician 
The investigator will instruct subjects to inform site personnel when they are planning to 
receive medical care by another physician.  At each visit, the investigator will ask the subject 
whether he/she has received medical care by another physician since the last visit or is planning 
to do so in the future.  When the subject is going to receive medical care by another physician, 
the investigator, with the consent of the subject, will inform the other physician that the subject 
is participating in the clinical study. 
9.6 
Data Quality Assurance 
This study will be organized, performed, and reported in compliance with the protocol, SOPs, 
working practice documents, and applicable regulations and guidelines.  Site audits will be 
made periodically by the sponsor’s 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 his designee as identified on 
Form FDA 1572 (where applicable) must sign the CRF to attest to its accuracy, authenticity, 
and completeness. 


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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 (e.g., laboratory data), will be entered into a clinical system 
as specified in the Data Management Plan. 
9.7 
Statistical Methods 
All statistical analyses will be performed by the sponsor or designee after the study is 
completed and the database is locked.  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. 
9.7.1.1 
Statistical Design in the Lead-In Part:  Continual Reassessment Method 
The Lead-In part will be a dose-finding study including approximately 12 subjects.  A CRM 
design will be used to determine the MTD of E7777.  The MTD is defined in this study as the 
highest dose that has a ≤ 20% rate of DLT. 
Six experimental doses are proposed and can be investigated:  3, 6, 9, 12, 15, and 18 µg/kg.  
The starting dose will be 6 µg/kg.   
The probability of observing (PT) a DLT at each dose level will be estimated through a 
two-parameter logistic model: 





T
T
p
p
1
log
= 
d
2
1



 
The independent prior distributions for the two parameters are: 


)
25
.
0
,
05
.
0
(
~
1,
5
.
2
~
2
2
1
N
N



 
Starting with the 6 µg/kg dose, the prior distribution of the logistic parameters for PT will be 
updated by the accruing data on DLTs each time a subject completes evaluation for toxicity in 
Cycle 1.  Additional subjects will be allocated to the highest dose that has at least a 50% 
posterior probability of being tolerable (i.e., having a ≤ 20% DLT rate); the next dose allocated 
may be modified upon consultation with the safety consultancy investigator panel that is 
reviewing DLTs, based on overall cumulative safety results from the current study and/or on 
any emerging data from other studies with E7777.  The first four subjects will each be required 


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to complete Cycle 1 before the next subject can be treated, and open enrollment will start with 
the fifth subject.  It is further specified that dose levels cannot be skipped when escalating.  The 
MTD will be determined when approximately 20 subjects have been tested, or when futility is 
declared.  Futility is defined as having a < 25% probability that any of the doses is safe (i.e., 
the probability that none of the six doses have a ≤ 20% DLT rate is < 25%). 
The CRM dose-finding steps are illustrated in Figure 1. 
 
9.7.1.2 
Study Endpoints 
LEAD-IN PART  
The primary endpoints for the Lead-In part are: 
 Dose-limiting toxicities (DLTs) 
 Maximum tolerated dose (MTD). 
The secondary endpoints for the Lead-In part are: 
 Safety parameters 
 Efficacy parameters (e.g., objective response, duration of response, time to response) 
 PK parameters 
 Immunogenicity. 
MAIN STUDY  
The primary efficacy endpoint for the Main Study is objective response (OR) based on GRS. 
The secondary endpoints for the Main Study are: 
 Duration of response (DOR) based on GRS. 
 Time to response (TTR) based on GRS. 
 Objective response (OR) using Prince (2010)5 
 Skin response (according to mSWAT) 
 Duration of skin response  
 Time to skin response  
 Safety parameters 
 PK parameters 
 Immunogenicity 
Exploratory endpoints: 
 Progression-free survival (PFS) and time to progression (TTP) 


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 Pruritus improvement 
 QoL using Skindex-29 and the FACT-G Questionnaire 
9.7.1.3 
Definitions of Analysis Sets 
The definitions of the analysis sets are provided below: 
All Enrolled Subjects:  All subjects who signed informed consent, and at Screening were 
assessed as meeting all inclusion criteria and not meeting any exclusion criteria. This will be 
the analysis set for demographics and baseline characteristics analyses. 
Dose-Finding Analysis Set:  All subjects in the Lead-In part who completed Cycle 1 treatment 
and were evaluated for DLT, and those who discontinued during Cycle 1 due to DLT.  This 
will be the analysis set for MTD determination in the Lead-In part. 
Full Analysis Set:  All subjects who received study drug in the Main Study.   
Primary Efficacy Analysis Set:  All Stage I – III Main Study subjects who received study 
drug plus the Stage I – III Lead-In subjects from the 9µg/kg/day dose group.  
Safety Analysis Set:  All subjects who received study drug.  This will be the analysis set for 
all safety analyses. 
Stage I-III Safety Analysis Set:  All Stage I – III Main Study subjects who received study 
drug plus the Stage I – III Lead-In subjects from the 9µg/kg/day dose group treated with E7777. 
Per Protocol Set:  All subjects in the Primary Efficacy Analysis and Full Analysis Sets who 
received study drug, and had a baseline and at least one postdose tumor assessment and had no 
major protocol deviations.  The per protocol analysis set will be identified prior to database 
lock.  Full criteria for exclusion from the analysis set will be detailed in the SAP.  This will be 
the secondary analysis set for the efficacy analyses. 
PK Analysis Set:  All subjects from whom at least one valid E7777 PK parameter is obtained 
will comprise the analysis set for the PK and immunogenicity data. 
Population PK Analysis Set:  All subjects from whom at least one quantifiable concentration 
of E7777 is available with a documented dosing history. 
Population PK/PD Analysis Set:  All subjects in the Population PK analysis set for whom 
efficacy and safety variables are also available. 
9.7.1.4 
Subject Disposition 
The method for summarizing the number (percentage) of subjects who were screened for the 
study (enrolled subjects, i.e., those who signed informed consent) and reasons for screen failure 
is described in the SAP. 


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9.7.1.5 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics will be summarized and listed.  For continuous 
demographic/baseline variables including age, weight, and vital signs, results will be 
summarized and presented as N, mean, standard deviation (SD), median, and minimum and 
maximum values.  For categorical variables such as race/ethnicity, the number and percentage 
of subjects will be used. 
9.7.1.6 
Prior and Concomitant Therapy 
Concomitant medications will be assigned an 11-digit code using the World Health 
Organization Drug Dictionary (WHO DD) drug codes.  Concomitant medications will be 
further coded to the appropriate Anatomical-Therapeutic-Chemical (ATC) code indicating 
therapeutic classification.  Prior and concomitant medications will be summarized and listed 
by drug and drug class in the clinical study report for this protocol. 
9.7.1.7 
Efficacy Analyses 
All efficacy and QoL analyses will be performed primarily in the Stage I – III Main Study 
subjects plus the Stage I – III Lead-In subjects from the 9µg/kg/day dose group combined, and 
additionally in all subjects from the Main Study. 
The efficacy analyses in the Main Study, including primary efficacy analysis, will be 
performed by the Independent Review Committee (IRC) as detailed in a Tumor Assessment 
Charter. 
In addition, investigator-assessed response assessments will be recorded for all subjects. 
The primary analysis will be performed after data cutoff, which will be either of the following 
2 events, whichever occurs later:  (1) when all subjects in the Main Study have either completed 
Cycle 8 or are off treatment, or (2) when all subjects with at least one documented time point 
response of PR or better have undergone the subsequent tumor assessments necessary for 
confirmation of response (unless the subject had disease progression or discontinued from 
study before then). 
The efficacy and QoL endpoints in the Lead-In part will be summarized and listed by dose 
level based on the Safety Analysis Set.  No statistical analysis will be performed. 
PRIMARY EFFICACY ANALYSIS 
The primary endpoint ORR will be analyzed on the full analysis set.  ORR will be calculated 
in Stage I – III CTCL subjects from the Main Study plus the Lead-In subjects from the 
9µg/kg/day dose group combined, using a 2-sided, exact 95% confidence interval (CI), using 
the Clopper-Pearson method.  The treatment will be considered efficacious and demonstrating 
clinical benefit of E7777 if the lower limit of the 2-sided 95% exact CI of the observed ORR 
exceeds 25%. 


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SECONDARY EFFICACY ANALYSES 
Skin response will be calculated with a 2-sided, exact 95% confidence interval (CI), using the 
Clopper-Pearson method.  DOR, TTR, duration of skin response, and time to skin response for 
E7777 will be calculated using Kaplan–Meier product-limit estimates and plotted over time.  
The medians for these endpoints and their corresponding two-sided 95% CIs will be provided.   
ORR (by Prince criteria) will be calculated with a 2-sided, exact 95% CI, using the Clopper–
Pearson method.5 
EXPLORATORY EFFICACY ANALYSES 
PFS and TTP will be analyzed using Kaplan–Meier product limit estimate.  Median PFS and 
TTP time will be calculated using Kaplan–Meier product limit estimate and presented with 
corresponding two-sided 95% CIs.  The cumulative probabilities will be plotted over time. 
Pruritus Improvement Rate will be calculated with a two-sided exact 95% CI using the 
Clopper–Pearson method.  In addition, the percentages of subjects who have ≥ 20% and ≥ 50% 
improvements relative to baseline in each of the VAS-based assessment scores will be 
tabulated.  The frequency of use of rescue medications will be determined by comparing the 
number of packages dispensed and the number of packages returned. 
Sensitivity analyses for ORR in subjects receiving versus subjects not receiving steroid 
medication will be performed. 
QoL assessment scores, based on Skindex-29 and FACT-G, will be summarized through basic 
statistics. 
9.7.1.8 
PK and Immunogenicity Analyses 
PK ANALYSES 
PK parameters will be summarized based on the PK analysis set.  Potential relationships 
between the E7777/ONTAK serum concentration data and tumor response, as well as AEs, 
will be explored. 
IMMUNOGENICITY ANALYSES 
The percentage of subjects testing positive for anti-E7777 and anti-IL-2 antibodies at baseline 
and during study treatment will be assessed.  Potential relationships between presence of 
anti-E7777 antibodies and tumor response, as well as AEs, will be explored. 
9.7.1.9 
Safety Analyses 
Lead-In Part 
DLTs will be summarized and listed by dose for all subjects in the Dose Finding Analysis Set. 
The posterior summaries from the CRM will be presented. 


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Safety analyses for the Lead-In part will be done using all the Safety Analysis Set subjects.   
Main Study 
Evaluation of safety will be performed on the Safety Analysis Set.  The safety analyses for the 
Main Study will be performed in all Safety Analysis Set subjects and all Safety Analysis Set 
Stage I – III subjects, separately.  Safety data to be evaluated include AEs, clinical laboratory 
results, vital signs, ECGs, and the results of physical examinations. 
Safety parameters will be summarized using descriptive statistics (mean, SD, median, Q1, Q3, 
and range for continuous variables; numbers and percentages for categorical measures). 
EXTENT OF EXPOSURE 
The number of subjects in each study arm, the number of days/cycles on treatment, quantity of 
study drug administered, and the number of subjects requiring dose reductions, treatment 
interruption, and treatment discontinuation will be summarized by study arm. 
ADVERSE EVENTS 
AEs will be graded using CTCAE v5.0.  Investigators will collect all AE CTCAE grades (for 
both increasing and decreasing severity).  AEs will be classified into standardized medical 
terminology from the verbatim description (investigator term) using the Medical Dictionary 
for Regulatory Activities (MedDRA).  AEs will be presented by preferred term (PT) nested 
within system organ class (SOC).  Verbatim descriptions and MedDRA SOC PT for all AEs 
will be contained in the data listings of the clinical study report for this protocol. 
An overview table, including the incidence of and the number of subjects with 
treatment-emergent adverse events (TEAEs), SAEs, deaths, and those TEAEs that led to 
discontinuation, dose modification, or dose interruption, will be provided. 
The incidence of TEAEs will be summarized by SOC, PT, CTCAE grade, and relatedness to 
study drug.  Although a MedDRA term may be reported more than once for a subject, that 
subject will be counted only one time in the incidence count for that MedDRA term with the 
highest CTCAE grade (in the summary by CTCAE grade) or with the closest relationship to 
study treatment (in the summary by relatedness to study treatment). 
TEAEs will be analyzed.  AEs that are not treatment-emergent will be listed.  TEAEs are 
defined as AEs that emerge during treatment, having been absent at pretreatment (baseline), or 
those that: 
 Reemerge during treatment, having been present at baseline but stopped prior to 
treatment, or  
 Worsen in severity during treatment relative to the pretreatment state, when the AE is 
continuous. 
Separate summary tables will be provided for all TEAEs, treatment-emergent SAEs, TEAEs 


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reported as treatment-related, treatment-emergent SAEs reported as treatment-related, and 
TEAEs leading to treatment discontinuation. 
LABORATORY VALUES 
Clinical laboratory values will be evaluated for each laboratory parameter by subject.  
Abnormal laboratory values will be identified as those outside (above or below) the normal 
range.  Reference (normal) ranges for laboratory parameters will be included in the clinical 
study report for this protocol.  Descriptive summary statistics for laboratory parameters and 
their changes from baseline will be calculated. 
Laboratory parameters that are graded in CTCAE v5.0 will be summarized by CTCAE grade. 
Clinical laboratory results postbaseline will be evaluated for markedly abnormal values.  The 
National Cancer Institute’s CTCAE v5.0 will be used to identify subjects with markedly 
abnormal laboratory values.  The incidence of markedly abnormal values will be summarized 
by cycle.  For the incidence of markedly abnormal laboratory values, each subject may be 
counted once in the laboratory parameter value high category and once in the laboratory 
parameter low category, as applicable. 
VITAL SIGNS 
Descriptive statistics for vital signs parameters (i.e., sitting diastolic and systolic BP, sitting 
pulse rate, respiratory rate, temperature, weight, and changes from baseline) will be presented 
by visit. 
ECGS 
Analysis of any drug effect on QT/QTcF will be described in the SAP.  
9.7.2 
Determination of Sample Size 
LEAD-IN PART 
The number of subjects in the Lead-In part will be approximately 20, based on the CRM design 
requirements. 
 
MAIN STUDY 
The sample size of approximately 70 Stage I – III subjects (including Stage I – III subjects 
from both the Main Study plus from the Lead-In part 9 µg/kg/day dose group combined) was 
estimated assuming that a lower limit of the 2-sided 95% CI of ORR exceeding 25% indicates 
clinical benefit in persistent and recurrent CTCL.  It was also assumed that in this population 
we can reasonably expect to observe an ORR ≥ 36%, i.e., at least 25 subjects with CR+PR 
among 70 subjects. 
With a sample size of approximately 70 Stage I – III subjects (including Stage I – III subjects 
from both the Main Study plus from the Lead-In part 9 µg/kg/day dose group combined), the 
2-sided 95% exact Clopper–Pearson CI of an observed 36% ORR would range from 25% to 


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48%.  Thus, an observed ORR that is ≥ 36% would be significantly higher than 25%, thereby 
demonstrating the presence of clinical benefit. 
Sample size estimates were calculated using PASS 2008 software. 
9.7.3 
Interim Analysis 
At the end of the Lead-In part of the study, the objective response of all subjects will be 
evaluated.  The study will only continue to the Main Study if there is at least one subject in the 
Lead-In with a confirmed CR or PR by investigator assessment. 
9.7.4 
Procedure for Revising the SAP 
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 
1. Olsen E, Duvic M, Frankel A, Kim Y, Martin A, Vonderheid E, et al. Pivotal phase III 
trial of two dose levels of denileukin diftitox for the treatment of cutaneous T-cell 
lymphoma. J Clin Oncol. 2001;19(2):376-88. 
2. Rasku MA, Clem AL, Telang S, Taft B, Gettings K, Gragg H, et al. Transient T cell 
depletion causes regression of melanoma metastases. J Transl Med. 2008;6:12. 
3. Investigator’s Brochure E7777. Eisai Inc.  Edition 1. 2010. 
4. Olsen E, Vonderheid E, Pimpinelli N, Willemze R, Kim Y, Knobler R, et al. Revisions 
to the staging and classification of mycosis fungoides and Sézary syndrome:  a proposal 
of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous 
lymphoma task force of the European Organization of Research and Treatment of 
Cancer (EORTC). Blood. 2007;110(6):1713-22. 
5. Prince HM, Duvic M, Martin A, Sterry W, Assaf C, Sun Y, et al. Phase III placebo-
controlled trial of denileukin diftitox for patients with cutaneous T-cell lymphoma.  
J Clin Oncol. 2010;28(11):1870-7 
6. Olsen EA, Whittaker S, Kim YH, Duvic M, Prince HM, Lessin SR, et al. Clinical end 
points and response criteria in mycosis fungoides and Sézary syndrome:  a consensus 
statement of the International Society for Cutaneous Lymphomas, the United States 
Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the 
European Organisation for Research and Treatment of Cancer. J Clin Oncol. 
2011;29(18): 2598-607. 
7. Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse 
Events (CTCAE) version 5.0 (published 27 Nov 2017).  Available from:  
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_5.0/CTCAE_v5.0_2017-11-27.xlsx.  
8. Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The 
European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-
life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 
1993;85(5):365-76. 
9. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity 
and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 
1982;5(6):649-56. 
10. Berry SM, Carlin BP, Lee JJ, Muller P. 2010, Bayesian Adaptive Methods for Clinical 
Trials Boca Raton (FL): CRC Press; 2011 
11. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron. 1976;16(1):31-41. 


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11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE 
PROCEDURES) 
11.1 Changes to the Protocol 
Any change to the protocol requires a written protocol amendment or administrative change 
that must be approved by the sponsor before implementation.  Amendments specifically 
affecting the safety of subjects, the scope of the investigation, or the scientific quality of the 
study require submission to health or regulatory authorities as well as additional approval by 
the applicable IRBs/IECs.  These requirements should in no way prevent any immediate action 
from being taken by the investigator, or by the sponsor, in the interest of preserving the safety 
of all subjects included in the study.  If the investigator determines that an immediate change 
to or deviation from the protocol is necessary for safety reasons to eliminate an immediate 
hazard to the subjects, the sponsor’s medical monitor 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 CA (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 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 IRB/IEC review. 
In accordance with ICH E6, Section 1.52, source documents include, but are not limited to the 
following: 
 Clinic, office, or hospital charts 


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 Copies or transcribed health care provider notes which have been certified for accuracy 
after production 
 Recorded data from automated instruments such as IxRS, x-rays, and other imaging reports 
(e.g., sonograms, CT scans, magnetic resonance images, radioactive images, ECGs, rhythm 
strips, electroencephalograms, polysomnographs, pulmonary function tests), regardless of 
how these images are stored, including microfiche and photographic negatives 
 Pain, QoL, 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 (e.g., 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 (e.g., 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 correction is identified, the reason for the change is stated, and the original data are 
not obscured.  Only data required by the protocol for the purposes of the study should be 
collected. 
The investigator must sign each CRF.  The investigator will report the CRFs to the sponsor 
and retain a copy of the CRFs. 
11.5 
Identification of Source Data 
All data to be recorded on the CRF must reflect the corresponding source documents.  For the 
following items, the data recorded directly on the CRF are to be considered source data:  
 Study drug compliance (e.g., the reason for the change of dosing) 
 Information on the subject’s discontinuation (e.g., in the case of lost to follow-up due to 
the subject choice) 


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 PK sampling date and time 
 Clinical laboratory test sampling date 
 Comments and relevant information on the AEs (e.g., severity, relationship to study drug, 
outcome) 
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 IB, and regulatory agency registration documents (e.g., Form FDA 1572, 
ICFs, and IRB/IEC correspondence).  In addition, the sponsor will send a list of treatment 
codes by study subject to the investigator after the clinical database for this study has been 
locked.  The site should plan to retain study documents, as directed by the sponsor, for at least 
2 years after the last approval of a marketing application in an ICH region and until there are 
no pending or contemplated marketing applications in an ICH region or at least 3 years have 
elapsed since the formal discontinuation of clinical development of the investigational product. 
It is requested that at the completion of the required retention period, or should the investigator 
retire or relocate, the investigator contact the sponsor, allowing the sponsor the option of 
permanently retaining the study records. 
11.7 
Auditing Procedures and Inspection 
In addition to the routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the sponsor’s 
Standard Operating Procedures (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 drugs will be supplied to the investigator (or a designated pharmacist) by the sponsor.  
Drug supplies must be kept in an appropriate secure area (e.g., 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 prior to approval to do so by the sponsor.  At the conclusion of the study and as 


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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, 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 and the institution/investigator.  The review is aimed at protecting the sponsor's 
proprietary information existing either on the date of the commencement of the study or 
generated during the study. 
The detailed obligations regarding the publication of any data, material results, or other 
information, generated or created in relation to the study shall be set out in the agreement 
between each investigator and the sponsor. 
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 and the institution/PI. 
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/PI and the sponsor. 
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. 


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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 
Classification and Staging of Mycosis Fungoides and 
Sézary Syndrome 
Appendix 1 Table 1 
ISCL/EORTC Revisions to the TNMB Classification of 
MF/SS (from Olsen 2011) 
Area 
TNMB Stages 
Description of TNMB 
Skin* 
T1 
Limited patches, papules, and/or plaques covering < 10% of the skin surface; may 
further stratify into T1a (patch only) v T1b (plaque ± patch) 
 
T1a 
Patch only 
 
T1b 
Plaque± patch  
T2 
Patches, papules, and/or plaques covering ≥ 10% of the skin surface; may further 
stratify into T2a (patch only) v T2b (plaque ± patch) 
 
T2a 
Patch only  
 
T2b 
Plaque ± patch  
T3 
One or more tumors (≥ 1 cm diameter) 
T4 
Confluence of erythema covering ≥ 80% body surface area 
Node† 
No 
No clinically abnormal lymph nodes; biopsy not required 
N1 
Clinically abnormal lymph nodes; histopathology Dutch Grade 1 or NCI LN0-2 
 
N1a 
Clone negative 
 
N1b 
Clone positive 
N2 
Clinically abnormal lymph nodes; histopathology Dutch Grade 2 or NCI LN3 
 
N2a 
Clone negative 
 
N2b 
Clone positive 
N3 
Clinically abnormal lymph nodes; histopathology Dutch Grade 3-4 or NCI LN4; clone 
positive or negative 
Nx 
Clinically abnormal lymph nodes without histologic confirmation or inability to fully 
characterize the histologic subcategories 
Visceral 
M0 
No visceral organ involvement 
M1 
Visceral involvement (must have pathology confirmation and organ involved should be 
specified) 
Blood 
B0 
Absence of significant blood involvement: ≤ 5% of peripheral blood lymphocytes are 
atypical (Sézary) cells 
 
B0a 
Clone negative 
 
B0b 
Clone positive 
B1 
Low blood tumor burden: >5% of peripheral blood lymphocytes are atypical (Sézary) 
cells but does not meet the criteria of B2 
 
B1a 
Clone negative 
 
B1b 
Clone positive 
B2 
High blood tumor burden:  ≥ 1,000/µL Sézary cells with positive clonec; one of the 
following can be substituted for Sézary cells:  CD4/CD8 ≥ 10%, CD4+CD7- cells ≥ 
40% or CD4+CD26- cells ≥ 30% 
EORTC = European Organization for Research and Treatment of Cancer, ISCL = International Society for Cutaneous 
Lymphomas, MF = mycosis fungoides, SS = Sézary syndrome, TNMB = tumor-node-metastasis-blood. 
*Patch = any size lesion without induration or significant elevation above the surrounding uninvolved skin:  poikiloderma 
may be present. 
Plaque = any size lesion that is elevated or indurated:  crusting or poikiloderma may be present. 
Tumor = any solid or nodular lesion ≥1 cm in diameter with evidence of deep infiltration in the skin and/or vertical 
growth. 


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† Lymph node classification has been modified from 2007 ISCL/EORTC consensus revisions1 to include central nodes.  
Lymph nodes are qualified as abnormal if >1.5 cm in diameter. 
‡ The clone in the blood should match that of the skin.  The relevance of an isolated clone in the blood or a clone in the 
blood that does not match the clone in the skin remains to be determined. 
 
Appendix 1 Table 2 
Modified ISCL/EORTC Revisions to the Staging of 
MF/SS (from Olsen 2011) 
Stage 
T (Skin) 
N (Node) 
M (Visceral) 
B (Blood) 
1A 
1 
0 
0 
0, 1 
1B 
2 
0 
0 
0, 1 
IIA 
1-2 
1, 2, X 
0 
0, 1 
IIB 
3 
0-2, X 
0 
0, 1 
IIIA 
4 
0-2, X 
0 
0 
IIIB 
4 
0-2, X 
0 
1 
IVA1 
1-4 
0-2, X 
0 
2 
IVA2 
1-4 
3 
0 
0-2 
IVB 
1-4 
0-3, X 
1 
0-2 
EORTC = European Organization for Research and Treatment of Cancer, ISCL = International Society for Cutaneous 
Lymphomas, MF = mycosis fungoides, SS = Sézary syndrome, X = clinically abnormal lymph nodes without histologic 
confirmation or inability to fully characterize histologic subcategories. 
 


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Appendix 2 
ECOG Performance Status Scale 
Appendix 2 Table 1 
ECOG 
Grade 
ECOG Status 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature (e.g., light house work, office work) 
2 
Ambulatory and capable of all self care but unable to carry out any work 
activities.  Up and about more than 50% of waking hours 
3 
Capable of only limited self care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled.  Cannot carry on any self care.  Totally confined to bed or 
chair 
5 
Dead 
ECOG = Eastern Cooperative Oncology Group. 
Source:  Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and Response Criteria of 
The Eastern Cooperative Oncology Group.  Am J Clin Oncol. 1982;5(6):649-56.9  
 


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Appendix 3 
Cockcroft–Gault Calculation of Creatinine Clearance 
Subjects must have adequate renal function as evidenced by serum creatinine ≤ 1.8 mg/dL or 
calculated creatinine clearance ≥ 50 mL/min per the Cockcroft–Gault formula as defined 
below. 
Appendix 3 Table 1 
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-
41.11  
 


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Appendix 4 
CTCL Tumor Response Criteria According to the 
ISCL/EORTC Consensus (Olsen 2011) 
This CTCL tumor response criteria summary guide follows the recommendations in:  
Olsen EA, Whittaker S, Kim YH, Duvic M, Prince HM, Lessin SR, et al. Clinical end points and response 
criteria in mycosis fungoides and Sézary syndrome: a consensus statement of the International Society for 
Cutaneous Lymphomas, the United States Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma 
Task Force of the European Organisation for Research and Treatment of Cancer. J Clin Oncol. 
2011;29(18):2598-607. 
 
A composite measure of disease in skin, lymph node, blood, and viscera will be used to assess 
Tumor Burden.  A Global Response Score will indicate the overall response assessment based 
on the composite measure. 
 
1. Skin Disease Assessment, Scoring, and Definition of Response 
Skin tumor burden will be quantified using a modified Severity Weighted Assessment 
Tool (mSWAT) that provides an mSWAT score.  The mSWAT score measures the body 
surface area (BSA) involved in skin disease with a weighting factor applied according to 
the severity of the type of skin lesion, which can be patch, plaque, or tumor.  The mSWAT 
can be utilized to track erythroderma by the summation of BSA involved with patch 
disease (macular erythema) and plaque disease (erythema with induration/edema).  In 
addition, subject(s) should be evaluated for the appearance of new skin tumor lesion(s) at 
each time point.  The Day 1 assessments can be performed within a -3-day window, e.g., 
Day 1 (-3 days). 
A. Assessment Schedule 
See Section 9.5.2.2 
B. Scoring of Skin Tumor Burden 
Tumor burden is quantitated using the mSWAT score.  mSWAT measures the body 
surface area (BSA) involved in skin disease with a weighting factor applied according 
to the severity of the type of skin lesion. 
mSWAT score = (BSA patch disease × 1) + (BSA plaque × 2) + (BSA tumor × 4) 
The mSWAT score should be computed using the table below.  (Note:  this table is a 
sample.  The worksheet for use at the site will be provided separately to each site.)  
In this table, the percent BSA represented by body region is indicated.   
 
 
 
 
 


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Appendix 4 Table 1 
Scoring of Skin Tumor Burden and Calculation of 
mSWAT Score 
Body Region 
% BSA in Body Region 
Assessment of Involvement in Patient’s Skin 
Patch*  
Plaque†  
Tumor‡ 
Head 
7 
 
 
 
Neck 
2 
 
 
 
Anterior trunk 
13 
 
 
 
Arms 
8 
 
 
 
Forearms 
6 
 
 
 
Hands 
5 
 
 
 
Posterior trunk 
13 
 
 
 
Buttocks 
5 
 
 
 
Thighs 
19 
 
 
 
Legs 
14 
 
 
 
Feet 
7 
 
 
 
Groin 
1 
 
 
 
Subtotal of lesion BSA 
 
 
 
Weighting factor 
×1 
×2 
×4 
Subtotal lesion BSA × weighting factor 
A: ___ 
B: ___ 
C: ___ 
mSWAT (A+B+C) 
 
BSA = body surface area, mSWAT = modified Severity Weighted Assessment Tool 
*Any size lesion without induration or significant elevation above the surrounding uninvolved skin; poikiloderma may be 
present. 
†Any size lesion that is elevated or indurated; crusting, ulceration, or poikiloderma may be present. 
‡Any solid or nodular lesion ≥ 1 cm in shortest diameter with evidence of deep infiltration in the skin and/or vertical 
growth. 
Supplemental Assessment for Prince (2010) Analysis (only for subjects with skin lesions 
comprising < 10% of BSA at screening)  
Since the IRC will perform a secondary analysis based upon the method of Prince (2010), a 
supplemental measurement will be made by the site investigator at the time of mSWAT 
assessment, for subjects with skin lesions comprising < 10% of BSA at screening.  The 
investigator will identify, photograph, and measure up to five representative skin lesions 
(generally the largest and most representative of different locations, such as chest, abdomen, 
leg, arm, head, neck, if applicable); measurements will be of two-dimensional perpendicular 
diameters).  These measurements will be collected on the eCRF and will be used only by the 
IRC.  A sample of the worksheet for collecting skin lesion data is shown in the table below.  
Note:  The worksheet for use at the site will be provided separately to each site.  These lesions 
(even if they have disappeared) should be evaluated and photographed at all mSWAT 
assessment time points. 
 


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Lesion 
number 
Cycle 
(date) 
Location 
Patch (cm) * 
Plaque (cm) † 
Tumor (cm) ‡ 
Diameter 
Perpendicular 
Diameter 
Diameter 
Perpendicular 
Diameter 
Diameter 
Perpendicular 
Diameter 
1 
 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
 
*Any size lesion without induration or significant elevation above the surrounding uninvolved skin; poikiloderma may 
be present. 
†Any size lesion that is elevated or indurated; crusting, ulceration, or poikiloderma may be present. 
‡Any solid or nodular lesion ≥ 1 cm in shortest diameter with evidence of deep infiltration in the skin and/or vertical growth. 
 
C. Definition of Response in Skin 
The mSWAT score will be used to quantify tumor burden for determination of skin response.  
The score of Cycle 1 Day 1 will be used as the baseline reference value.  Refer to Appendix 4 
Table 2 below. 
Appendix 4 Table 2   Definition of Response in Skin 
Response 
Definition 
CR 
100% clearance of skin lesions* 
PR 
50%-99% clearance of skin disease from baseline without new tumors (T3) in patients with 
T1, T2 or T4 only skin disease 
SD 
< 25% increase to < 50% clearance in skin disease from baseline without new tumors (T3) in 
patients with T1, T2, or T4 only skin disease 
PD† 
≥ 25% increase in skin disease from baseline or 
New tumors (T3) in patients with T1, T2 or T4 only skin disease or 
Loss of response:  in those with complete or partial response, increase of skin score of 
greater than the sum of nadir plus 50% baseline score 
Relapse 
Any disease recurrence in those with complete response 
CR = complete response, PD = progressive disease, PR = partial response, SD = stable disease 
*A biopsy of normal appearing skin is unnecessary to assign CR.  However, a skin biopsy should be performed of a 
representative area of the skin if there is question of residual disease (persistent erythema or pigmentary change) where 
otherwise a CR would exit.  If histologic features are suspicious or suggestive of MF/SS, the response should be 
considered a PR only. 
†Whichever criterion occurs first 
2. Lymph Node Assessment and Definition of Response 
A. Assessment Methods and Schedules 
See Section 9.5.2.2 and Figure 1 in Appendix 5.  
B. Measurements for lymph node disease 
a. Palpation. Each palpable node will be assessed as “normal size” or 
“enlarged/abnormal” and recorded as such. 


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b. CT. 
i. 
The longest diameter (LDi) and the short axis (SDi) will be recorded for all 
lymph nodes.  
If target lymph node is visible but is too small to measure, a default value of 5 mm 
should be used for LDi and SDi.  If only the SDi is too small to measure, report 
LDi dimension and report default value of 5 mm for SDi 
ii. 
The SPD will be calculated for target lymph nodes; target nodes are abnormal 
nodes identified at Screening assessment.  Abnormal nodes are > 1.5 cm in the 
LDi or > 1.0 cm in the SDi. 
SPD = Sum of PPDs of all target nodes 
PPD (Product of the Perpendicular Diameter) for each target lymph node = 
LDi × SDi 
 
C. Definition of Response in Lymph Nodes 
Appendix 4 Table 3 
Definition of Response in Lymph Nodes 
Response 
Definition 
CR 
All lymph nodes are now ≤ 1.5 cm in greatest transverse (long axis) diameter by method used 
to assess lymph nodes at baseline or biopsy negative for lymphoma; in addition, lymph nodes 
that were N3 classification and ≤ 1.5 cm in their long axis and > 1 cm in their short axis at 
baseline, must now be ≤ 1 cm in their short axis or biopsy negative for lymphoma 
PR 
Cumulative reduction ≥ 50% of the SPD of target lymph nodes from baseline and no new 
lymph node > 1.5 cm in the diameter of the long axis or > 1.0 cm in the diameter of the short 
axis if the long axis is 1-1.5 cm diameter.  Non-target lesions not unequivocally increased. 
SD 
Fails to attain the criteria for CR, PR, and PD 
PD 
All Target nodes demonstrate a ≥ 50% increase in SPD from SPD nadir and at least one node 
is >1.5 cm in LDi. 
Any new node > 1.5 cm in the long axis or. >1 cm in the short axis if 1-1.5 cm in the long axis 
that is proven to be N3 histologically or 
Loss of response: > 50% increase from nadir in SPD of lymph nodes in those with PR 
Relapse 
Any new lymph node > 1.5 cm in the long axis in those with CR proven to be N3 
histologically 
NI 
Not involved.  Lymph nodes are normal at baseline. 
UNK 
Assessment is not possible due to image quality issues 
4 
CR = complete response, LDi = longest diameter, PD = progressive disease, PR = partial response, SD = 
stable disease, SPD = sum of the products of the perpendicular diameters. 


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3. Blood Disease Assessment and Definition of Response 
Blood tumor burden will be assessed by quantifying CD4+CD26− cells by flow cytometry; 
CD4+CD7− cells may be used in CD26+ subjects. 
A. Assessment frequency 
See Section 9.5.2.2. 
B. Quantitation of blood tumor burden 
The absolute number of CD4+CD26− cells will be used to quantify blood tumor 
burden.  This number will be obtained from flow cytometry analysis. 
 
C. Definition of Response in Blood 
The blood tumor burden of Cycle 1 Day 1 will be used as the baseline reference 
value. 
Appendix 4 Table 4 
Definition of Response in Blood 
Response 
Definition 
CR 
B0 
PR 
> 50% decrease in quantitative measurements of blood tumor burden from baseline in those 
with high tumor burden at baseline (B2) 
SD 
Fails to attain criteria for CR, PR, or PD 
PD 
B0 to B2 or 
> 50% increase from baseline and at least 5,000 neoplastic cells/µL or 
Loss of response:  in those with PR who were originally B2 at baseline, > 50% increase from 
nadir and at least 5,000 neoplastic cells/µL 
Relapse 
Increase of neoplastic blood lymphocytes to ≥ B1 in those with CR 
CR = complete response, PD = progressive disease, PR = partial response, SD = stable disease. 
B0 is ≤ 250/µL tumor cells. 
 
4. Visceral Disease Assessment and Definition of Response 
 
A. Assessment method and schedules 
See Section 9.5.2.2. 
B. Measurement for visceral disease  
a. CT Scan  
i. 
The longest diameter (LDi) and the short axis (SDi) will be recorded for 
all measurable disease.  
At screening, the minimum size for measurable visceral disease is 1.0 × 1.0 
cm; smaller than that will be recorded as non-measurable disease. 


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If a nodule is visible but is too small to measure, a default value of 5 
mm should be used for LDi and SDi.  If only the SDi is too small to 
measure, report LDi dimension and report a default value of 5 mm for 
SDi. 
For follow-up scans, both LDi and SDi will be recorded for all 
measurable disease identified at screening.  If a measurable disease 
becomes visible but is too small to measure, a default value of 5 mm 
should be used for LDi and SDi.  If only the one diameter is too small 
to measure, record the default value of 5 mm for that diameter and the 
measured diameter for the other dimension. 
ii. 
The Sum of the Products of the Perpendicular Diameters (SPD) will be 
calculated for visceral disease.   
SPD = Sum of PPDs of all visceral disease 
PPD is the Product of the Perpendicular Diameter; for each lesion PPD 
= LDi × SDi 
b. Physical Examination (by palpation of liver and spleen) will be used to 
monitor for enlargement and visceral disease. 
C. Definition of Response in Viscera  
The minimum size of a new visceral lesion by CT must be:  > 1.0 × 1.0 cm. 
Response in Viscera 
Response 
Definition 
CR 
Liver or spleen or any organ considered involved at baseline should not be 
enlarged on physical examination and should be considered normal by imaging; 
no nodules or other visceral disease should be present on imaging of liver or 
spleen or any organ; any posttreatment mass must be determined by biopsy to be 
negative for lymphoma 
PR 
≥ 50% regression (SPD) in any splenic or liver nodules, or in measureable disease 
in any organs abnormal at baseline; no increase in size of liver or spleen and no 
new sites of involvement; no unequivocal increase in size of non-measurable 
disease 
SD 
Fails to attain the criteria for CR, PR, or PD 
PD 
> 50% increase in size (SPD) from nadir of any visceral disease involved at 
baseline or unequivocal increase in size of non-measurable disease, or 
New visceral disease involvement, or 
Loss of response:  > 50% increase from nadir in the size (SPD) of any previous 
visceral disease involvement in those with PR 
 Relapse 
New visceral disease involvement in those with CR 
5 
CR = complete response, PD = progressive disease, PR = partial response, SD = stable 
disease. SPD = sum of the products of the perpendicular diameters. 


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5. Global Response Assessment 
Each component of the tumor-node-metastasis-blood (TNMB) staging (i.e., skin, nodes, 
viscera, and blood) has been given its own definition of response (see Tables in the sections 
above) and these definitions are incorporated in and used to define the Global Response 
score.  
Appendix 4 Table 5 
Definition of the Global Response Score 
Global Score 
Definition 
Skin 
Nodes/Blood/Viscera 
CR 
Complete 
disappearance of all 
clinical evidence of 
disease 
CR 
All categories have CR/NI 
PR 
Regression of 
measurable disease 
CR 
All categories do not have a CR/NI and no 
category has a PD 
 
 
PR 
No category has a PD and if any category 
involved at baseline, at least one has a CR or 
PR 
SD 
Failure to attain CR, 
PR, or PD 
representative of all 
disease 
PR 
No category has a PD and if any category 
involved at baseline, no CR or PR in any 
 
 
SD 
CR/NI, PR, SD in any category and no 
category has a PD 
PD 
Progressive disease 
PD in any category 
Relapse 
Recurrence disease in 
prior CR 
Relapse in any category 
CR = complete response, PD = progressive disease, NI = noninvolved, PR = partial response, SD = stable diseas
Notes: 
1. No Global Score of CR can be assigned if the subject received concomitant therapy of topical steroids 
or low dose systemic steroids; in such a case, the maximum response is PR. 
2. In cases where the definition of PD or relapse is met but the clinical impression is questionable, the PD 
should be confirmed after at least 4 weeks in order to avoid premature removal of the subject from the 
study. 
3. Only N3 is considered as nodal disease (nodal involvement) for Global Response Score assessment.  
6. Best Response (Objective Response) 
The Best Response or Objective Response for the subject is the best Global Response Score 
that is at least 3 weeks in duration. 
Please note the following: 
 Olsen (2011) states 4 weeks duration, but this was based on drugs that had 4-week 
treatment cycles.  The intent is that the response should last at least one treatment cycle 
(based on consult with study investigators who are also co-authors of Olsen (2011). 


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 Treatment may continue after first assessment of disease progression (PD) if the 
investigator is of the opinion that PD needs to be confirmed (see Section 9.4.1).  If PD is 
not confirmed and subject continues treatment, any subsequent time point assessment of 
CR/PR will be used in assessing Best Response. 
 
 
 


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Appendix 5 
Lymph Node Disease Assessment 
Lymph node assessment is according to Olsen 2007, with the following clarifications. 
Only N3 is considered as nodal disease (nodal involvement) for Global Response Score 
assessment. 
Nx status may be assigned if there is no histologic information available: 
 Nx may be considered non-involved if the node >1.5 cm diameter is clinically 
not suspicious for lymphoma (Reactive/Inflammatory OR Dermatopathic) 
according to judgement of the investigator. 
 Nx should be considered involved if clinically suspicious for lymphoma (High 
SUV/ increasing size on scan). 
A flow chart depicting lymph node evaluations/assessments on study according to lymph 
node status is provided below. 
Appendix 5 Figure 1  Nodal Disease Assessment 


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Appendix 6 
CTCAE (v5.0)  
The National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE 
v5.0 published 27 Nov 2017) provides descriptive terminology to be used for AE reporting in 
clinical trials.  A brief definition is provided to clarify the meaning of each AE term.  To 
increase the accuracy of AE reporting, all AE terms in CTCAE version 5.0 have been 
correlated with single-concept, Medical Dictionary for Regulatory Activities (MedDRA®) 
terms. 
CTCAE v5.0 grading refers to the severity of the AE.  CTCAE Grades 1 through 5, with unique 
clinical descriptions of severity for each AE, are based on this general guideline: 
Appendix 6 Table 1 
CTCAE v5.0 
Grade 
Status 
1 
Mild:  asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
2 
Moderate:  minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL).a 
3 
Severe or medically significant but not immediately life-threatening:  
hospitalization or prolongation of hospitalization indicated; disabling, 
limiting self-care ADL.b 
4 
Life-threatening consequences:  urgent intervention indicated. 
5 
Death related to adverse event. 
a: Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
b:  Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden. 
Source:  Cancer Therapy Evaluation Program, NCI.  CTCAE v5.0.  Available from 
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_5.0/CTCAE_v5.0_2017-11-27.xlsx. 
 
For 
further 
details 
regarding 
MedDRA, 
refer 
to 
the 
MedDRA 
website:  
http://www.meddramsso.com. 
CTCAE v5.0 (published 27 Nov 2017) is available online:  
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_5.0/CTCAE_v5.0_2017-11-27.xlsx.  


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PROTOCOL SIGNATURE PAGE 
Study Protocol Number: E7777-G000-302  
Study Protocol Title: 
A Clinical Study to Demonstrate Safety and Efficacy of E7777 
in Persistent or Recurrent Cutaneous T-Cell Lymphoma 
Investigational Product 
Name: 
E7777   
 
 
PPD
PPD
PPD
PPD


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INVESTIGATOR SIGNATURE PAGE 
Study Protocol Number: 
E7777-G000-302 
Study Protocol Title: 
A Clinical Study to Demonstrate Safety and Efficacy of E7777 
in Persistent or Recurrent Cutaneous T-Cell Lymphoma 
Investigational Product 
Name: 
E7777 
 
I have read this protocol and agree to conduct this study in accordance with all stipulations of 
the protocol and in accordance with International Conference on Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) and all applicable local Good 
Clinical Practice (GCP) guidelines, including the Declaration of Helsinki. 
 
Medical Institution 
 
 
  
  
Investigator 
 Signature 
 Date 
 
 

SAP_001.pdf: 
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1 
TITLE PAGE 
 
 
STATISTICAL ANALYSIS PLAN 
Study Protocol 
Number: 
E7777-G000-302 
Study Protocol 
Title: 
A Clinical Study to Demonstrate Safety and Efficacy of E7777 in 
Persistent or Recurrent Cutaneous T-Cell Lymphoma 
 
Date: 
25 February 2022 
 
Version: 
Final Version 2.0 






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REVISION HISTORY 
 
Revisions to Version 1.0 
Date: 25 February 2022 
Change  
Rational 
Affected Sections 
Objective for Quality of 
Life (QoL) analysis is 
updated. 
Addition of Lead-in subjects treated at 
the same dose provides a more 
complete population to assess QoL at 9 
μg/kg/day, therefore QoL is expanded 
to include Lead-In subjects. 
4.1.3 Exploratory 
Objective(s) 
 
Full Analysis Set (FAS) 
and Safety Analysis Set are 
updated. 
Addition of Lead-in subjects treated at 
the same dose provides a more 
complete population to assess safety at 
9 μg/kg/day, therefore Safety Analysis 
Set is expanded to include Lead-In 
subjects. For completeness, the same 
additional subjects are included in FAS 
as well. The FAS and Safety Analysis 
Set now include all subjects in the 
Primary Efficacy Population. 
6.2.1 Analysis Sets 
8.1 Changes in the 
Planned Analyses 
from those in the 
Protocol 
 
Analysis Set for 
Immunogenicity is 
updated.  
To include all available data points for 
Immunogenicity analysis per protocol 
(Safety Analysis Set).  
6.2.1, Table 1 
Pharmacokinetic (PK) 
Analysis Set is updated. 
The PK Analysis Set is expanded to 
include Lead-In subjects as well, so 
that all subjects treated at the 9 
μg/kg/day dose can be pooled for 
analysis. 
6.2.1 Analysis Sets 
6.6.1 
Pharmacokinetic 
Analyses 
 
Best Overall Response 
(BOR) derivation rules for 
Global Response Score 
(GRS) per Olsen criteria 
are updated. 
Additional details for derivation of 
BOR rule are inserted to provide 
clarification about additional scenarios 
of timepoint GRS responses. 
Clarification is also provided for: (1) 
rules on time interval needed for 
confirmation of response; (2) definition 
of date of response; (3) rules for 
handling missing/UNK GRS timepoint 
responses; and 4) rules for 2 
progressive diseases (PDs) within 7 
days being counted as a single PD 
event (which is based on a reasonable 
clinical picture of duration of disease 
flare and of how fast progression may 
occur). 
6.4.1 Best Overall 
Response (BOR) 
based on GRS 
 
 
“How to handle PD” for 
Prince criteria is added. 
Clarification. Same rationale as that for 
BOR GRS per Olsen criteria 
6.4.3 Best Overall 
Response (BOR) 


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using Prince 
(2010) 
Definition of Clinical 
Benefit Rate is updated. 
Clinical Benefit Rate is based on CR, 
PR, or Durable SD (≥ 23 weeks). 
6.5.3.1 Exploratory 
Efficacy Analyses 
 
8.1 Changes in the 
Planned Analyses 
from those in the 
Protocol 
Remove “pre” from 
wording “premedication in 
sensitivity analysis. 
Typo in protocol, should be “steroid 
medication” instead of “steroid 
premedication”. 
6.5.3.1 Exploratory 
Efficacy Analyses 
Two figures are removed.  
 
Figure “Semi-log box plot 
for Anti-E7777 and Anti-
IL-2 titers by cycle” is 
added. 
To clarify ADA data types by assays 
rather than confirmation rate; Semi-log 
box plot will be used to present titer 
data rather than semi-log plot of titers 
from individual. 
6.6.2 
Immunogenicity 
Analysis 
 
 
Dose intensity is removed.  
Definition for received 
dose as percentage of 
planned starting dose are 
updated. 
Relative dose intensity as a percentage 
of actual total dose over total planned 
dose is more meaningful than dose 
intensity (as average daily dose) since 
the drug is given 5 days per 21-day 
cycle.  
6.7.1 Extent of 
Exposure 
 
The version of CTCAE 
grade is added. 
To clarify that CTCAE version was 
upgraded from 4.03 to 5.0 in Protocol 
Amendment 05 (03 May 2018). 
6.7.2 Adverse 
Events 
 
 
QTc Bazett is removed. 
QTc Bazett was not included in 
Protocol. 
6.7.5 
Electrocardiograms 
 


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2 
TABLE OF CONTENTS 
1 
TITLE PAGE ...................................................................................................................1 
2 
TABLE OF CONTENTS ...................................................................................................4 
3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................6 
4 
INTRODUCTION .............................................................................................................9 
4.1 
Study Objectives ......................................................................................................9 
4.1.1 
Primary Objective(s) ......................................................................................9 
4.1.2 
Secondary Objective(s) ..................................................................................9 
4.1.3 
Exploratory Objective(s) ................................................................................9 
4.2 
Overall Study Design and Plan ..............................................................................10 
5 
DETERMINATION OF SAMPLE SIZE ........................................................................11 
6 
STATISTICAL METHODS ............................................................................................12 
6.1 
Study Endpoints .....................................................................................................12 
6.1.1 
Primary Endpoint(s) .....................................................................................12 
6.1.2 
Secondary Endpoint(s) .................................................................................12 
6.1.3 
Exploratory Endpoint(s)...............................................................................12 
6.2 
Study Subjects ........................................................................................................13 
6.2.1 
Analysis Sets ................................................................................................13 
6.2.2 
Subject Disposition ......................................................................................14 
6.2.3 
Protocol Deviations ......................................................................................15 
6.2.4 
Demographic and Other Baseline Characteristics .......................................15 
6.2.4.1 
Demography .......................................................................................15 
6.2.4.2 
Disease characteristics .......................................................................15 
6.2.5 
Medical history ............................................................................................16 
6.2.6 
Prior Anticancer Therapy .............................................................................16 
6.2.7 
Prior and Concomitant Medications ............................................................16 
6.3 
Data Analysis General Considerations ..................................................................16 
6.3.1 
Pooling of Centers........................................................................................16 
6.3.2 
Adjustments for Covariates..........................................................................17 
6.3.3 
Multiple Comparisons/Multiplicity .............................................................17 
6.3.4 
Examination of Subgroups ...........................................................................17 
6.3.5 
Handling of Missing Data, Dropouts, and Outliers .....................................17 
6.4 
Efficacy Assessments.............................................................................................18 
6.4.1 
Best Overall Response (BOR) based on GRS .............................................18 
6.4.2 
Best Overall Response (BOR) for Skin Response .......................................19 
6.4.3 
Best Overall Response (BOR) using Prince (2010)2 ...................................19 
6.5 
Efficacy Analyses ..................................................................................................19 
6.5.1 
Primary Efficacy Analysis ...........................................................................20 


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6.5.2 
Secondary Efficacy Analyses ......................................................................20 
6.5.2.1 
Duration of Response .........................................................................20 
6.5.2.2 
Time to Response ...............................................................................20 
6.5.2.3 
ORR Using Prince (2010)2.................................................................21 
6.5.2.4 
Skin Response (according to mSWAT) .............................................21 
6.5.2.5 
Duration of Skin Response ................................................................21 
6.5.2.6 
Time to Skin Response ......................................................................21 
6.5.3 
Other Efficacy Analyses ..............................................................................21 
6.5.3.1 
Exploratory Efficacy Analyses ..........................................................21 
6.6 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Analyses ...............................................................................................24 
6.6.1 
Pharmacokinetic Analyses ...........................................................................24 
6.6.2 
Immunogenicity Analysis ............................................................................25 
6.6.3 
Pharmacodynamics, Pharmacogenomic, and Other Biomarker Analyses ...26 
6.7 
Safety Analyses ......................................................................................................26 
6.7.1 
Extent of Exposure .......................................................................................26 
6.7.2 
Adverse Events ............................................................................................26 
6.7.2.1 
Treatment-Emergent Adverse Events of Clinical Interest .................28 
6.7.3 
Laboratory Values ........................................................................................28 
6.7.3.1 
Hematology and Clinical Chemistry ..................................................28 
6.7.3.2 
Urinalysis ...........................................................................................29 
6.7.4 
Vital Signs ....................................................................................................29 
6.7.5 
Electrocardiograms ......................................................................................29 
6.7.6 
Other Safety Analyses..................................................................................30 
6.8 
Other Analyses .......................................................................................................30 
6.8.1 
Quality of Life..............................................................................................30 
6.8.2 
COVID-19 Impact .......................................................................................30 
6.9 
Exploratory Analyses .............................................................................................30 
7 
INTERIM ANALYSES ...................................................................................................30 
8 
CHANGES IN THE PLANNED ANALYSES ...............................................................30 
8.1 
Changes in the Planned Analyses from those in the Protocol ...............................30 
9 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING...............................31 
10 PROGRAMMING SPECIFICATIONS ..........................................................................31 
11 STATISTICAL SOFTWARE ..........................................................................................31 
12 MOCK TABLES, LISTINGS, AND GRAPHS ..............................................................31 
13 REFERENCES ................................................................................................................32 
 


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3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
AE 
adverse event 
AUC(0-t) 
area under the curve from time 0 to time t 
AUC(0-inf) 
area under the curve from time 0 to infinity 
ADaM 
Analysis Data Model 
BP 
blood pressure 
BSA 
body surface area 
BOR 
Best Overall Response 
CBR 
Clinical Benefit Rate 
CRF 
case report form 
CI 
confidence interval 
Cmax 
maximum concentration 
COVID-19 
coronavirus disease 2019 
CR 
complete response 
CCR 
clinical complete response 
CTCAE 
common terminology criteria for adverse events 
CTCL 
cutaneous T-cell lymphoma 
CV 
coefficient of variation 
DOR 
Duration of Response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EORTC 
European Organization for Research and Treatment of Cancer 
FACT-G 
Functional Assessment of Cancer Therapy - General 
FAS 
Full Analysis Set 
FDA 
US Food and Drug Administration 
GRS 
Global Response Score 
ICF 
informed consent form 
IRC 
Independent Review Committee 
IL-2 
Interleukin-2 


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Abbreviation 
Term 
ISCL 
International Society for Cutaneous Lymphomas 
KM 
Kaplan-Meier 
MedDRA 
Medical Dictionary for Regulatory Activities 
mSWAT 
modified Severity Weighted Assessment Tool 
NE 
not evaluable 
ORR 
Objective Response Rate 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PR 
Partial Response 
PD 
Progression disease 
PT 
preferred term 
Q1 
first quartile 
Q3 
third quartile 
QoL 
Quality of Life 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
stable disease 
SE 
standard error  
SI 
Système International 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TLG 
tables, listings, and graphs 
t1/2 
Elimination half-life 
tmax 
Time to maximum concentration 
TTP 
Time to Progression 
TTR 
Time to Response 
TNMB 
tumor-node-metastasis-blood 
UNK 
unknown 
VAS 
visual analog scale 
Vdss 
Volume of distribution at steady state 


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Abbreviation 
Term 
WHO 
World Health Organization 
 


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4 
INTRODUCTION 
Protocol E7777-G000-302 consists of an initial Lead-In part followed by the Main Study.  
The Lead-In part was conducted between May 2013 and August 2015 and a clinical study 
report (CSR) for lead-in part was completed in January 2019. 
This statistical analysis plan (SAP) is to describe the procedures and the statistical methods 
that will be used to analyze and report results for the Main Study.  The primary efficacy 
population will include a subset of subjects from the Lead-in part as described in Protocol 
Amendment 06. 
4.1 
Study Objectives 
The efficacy analyses will be performed primarily in the Stage I – III subjects from Main 
Study (approximately 65) plus the Stage I – III subjects from the 9 μg/kg/day dose group in 
Lead-In Study (approximately 5), and additional analyses will be performed in all subjects 
(both Main Study and Lead-In) who received study drug at 9 μg/kg/day dose. 
4.1.1 
Primary Objective(s) 
To demonstrate efficacy of E7777 in subjects with recurrent or persistent cutaneous T-cell 
lymphoma (CTCL) in Stage I – III subjects as assessed by objective response rate (ORR); 
Objective response is complete response [CR] and partial response [PR], according to 
International Society for Cutaneous Lymphomas (ISCL)/ European Organization for 
Research and Treatment of Cancer (EORTC) Global Response Score (GRS) [Olsen 2011])1. 
4.1.2 
Secondary Objective(s) 
• 
To determine the duration of response (DOR) for E7777 
• 
To determine time to response (TTR) after E7777 treatment 
• 
To determine skin response after E7777 treatment 
• 
To determine duration of skin response after E7777 treatment 
• 
To determine time to skin response after E7777 treatment 
• 
To assess ORR for E7777 using the alternate response assessment criteria of Prince 
(2010)2 
• 
To evaluate safety and tolerability of E7777 in all subjects 
• 
To evaluate safety and tolerability of E7777 in the Stage I – III Main Study subjects plus 
the Stage I – III Lead-In subjects from the 9 μg/kg/day dose group  
• 
To characterize the pharmacokinetics (PK) of E7777 and immunogenicity after treatment 
with E7777 
4.1.3 
Exploratory Objective(s) 
• 
To assess the following efficacy endpoints for subjects treated with E7777: progression-
free survival (PFS) and time to progression (TTP) (using GRS) 
• 
To assess pruritus improvement reported by subjects treated with E7777 


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• 
To assess Quality of Life (QoL) for (1) all subjects (both Main Study and Lead-In) who 
received study drug at 9 μg/kg/day dose, (2) Stage I – III subjects from Main Study plus 
Stage I – III subjects from the 9 μg/kg/day dose group in Lead-In Study. 
  
4.2 
Overall Study Design and Plan 
This is a multicenter open-label, single-arm study of E7777 in subjects with recurrent or 
persistent CTCL. 
A sufficient number of subjects in the Main Study will be recruited so that approximately 70 
Stage I – III subjects from both the Main Study and the Lead-In Study in the 9 μg/kg/day dose 
group with recurrent or persistent CTCL are treated with E7777 to assess efficacy.  Safety will 
be evaluated in all subjects from the Main Study, and in Lead-In subjects from the 9μg/kg/day 
dose group.  The dose of E7777 in the Main Study is selected from results of the Lead-In part 
of the study.  The primary efficacy analysis will be based on Stage I – III subjects treated at 9 
μg/kg/day, which includes subjects from both the Main Study plus the Lead-In. 
Study Phases for Each Subject  
Subjects in the study will move through three phases while on study. 
• 
Pretreatment Phase includes a Screening Period and a Baseline Period: 
◦ 
Screening Period is from Day -28 to the start of treatment (Cycle 1 Day 1) except for 
signing of the informed consent form (ICF) which may have been up to 8 weeks 
before the first dose of study drug.  The purpose of the Screening Period is to obtain 
informed consent and to ensure that each subject met all the specified eligibility 
criteria. 
◦ 
Baseline Period is from Day -7 to the start of treatment. Subjects who completed the 
Baseline assessments and met the eligibility criteria began treatment in the Treatment 
Phase. 
• 
Treatment Phase consists of the following periods: 
◦ 
Treatment Period.  E7777 will be administered by intravenous (IV) infusion over 60 
minutes (± 10 minutes) on 5 consecutive days every cycle of 21 days.  Treatment with 
E7777 for up to 8 cycles; each cycle of 21 days is one Period.  Subjects who attained 
skin tumor response and derived clinical benefit from E7777 treatment could continue 
receiving treatment beyond 8 cycles, at the discretion of the treating physician. 
◦ 
Follow-Up Period.  Tumor assessment until discontinuation of treatment due to 
progressive disease (PD); immunogenicity, and survival follow-up until relapse or 
initiation of new systemic anti-cancer therapy.  All Follow-up assessments will be 
performed for up to 3 years after end of treatment, or until sponsor termination of the 
study. 
After data cutoff for the primary analysis in the Main Study, the study moved to the Extension 
Phase. 
• 
Extension Phase consists of the following periods: 


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◦ 
Treatment Period, for continued treatment of subjects with ongoing treatment at 
data cutoff.  Subjects will be treated for up to 8 cycles.  Subjects with attained skin 
tumor response and deriving clinical benefit from E7777 treatment may continue 
receiving treatment beyond 8 cycles, at the discretion of the treating physicians. 
◦ 
Follow-Up Period.  Tumor assessment until discontinuation of treatment due to PD; 
immunogenicity, and survival follow-up until relapse, or initiation of new systemic 
anticancer therapy.  All Follow-up assessments will be performed for up to 3 years 
after the end of treatment, or until sponsor termination of the study. 
Pharmacokinetics and Immunogenicity 
In the Lead-in, initial serial PK sampling at dose levels 6 to 15 μg/kg had been performed. 
Immunogenicity had also been assessed at these dose levels.  In the Main Study, limited serial 
and sparse PK samples will be used to characterize PK, and the relationship of 9 μg/kg/day 
exposure and primary efficacy. 
PK assessment of E7777 will be based on the first 12 subjects in the Main Study, using serial 
blood PK sampling on Day 1 in Cycles 1, 3, and 5, with sparse sampling in Cycle 8.  In addition, 
sparse sampling obtained in the Main Study on the rest of the subjects on Day 1 of Cycle 1 
will be assessed. 
Immunogenicity (formation of antibodies to E7777 or Interleukin-2 (IL-2), and of neutralizing 
antibodies) will be assessed in all subjects in the Main Study.  A predose blood sample for 
immunogenicity assessment will be collected before Day 1 dosing in Cycles 1, 2, 3, 5, and 8; 
after that, subjects tested positive at any time for anti-IL-2 will be followed up for 
immunogenicity testing for anti-IL-2 on a 6-month schedule for one year and every year 
thereafter until antibody titers decrease to baseline level or upon study termination. 
Please see Table 4 of the Protocol (Schedule of Assessments) for more details on study 
procedures. 
Timing of Primary Analysis for the Main Study  
The primary analysis will be performed after data cutoff, which will be either of the following 
two events, whichever occurs later:  (1) when all subjects in the Main Study have either 
completed Cycle 8 or are off treatment, or (2) when all subjects with at least one documented 
time point response of PR or better have undergone the subsequent tumor assessments 
necessary for confirmation of response (unless the subject had disease progression or 
discontinued from study before that).  
5 
DETERMINATION OF SAMPLE SIZE 
The sample size of approximately 70 Stage I ̽ III subjects (including Stage I ̽ III subjects 
from both the Main Study and the Lead-In part 9ug/kg/day dose group combined) was 
estimated assuming that the lower bound of the 2-sided 95% Confidence Interval (CI) of 
ORR exceeding 25% which indicates clinical benefit in persistent and recurrent CTCL. With 
a sample size of 70, the 2-sided 95% exact Clopper-Pearson confidence interval of an 


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observed 36% ORR (i.e., 25 subjects with CR+PR among 70 subjects) would be with lower 
bound of 25% and upper bound of 48%. 
Sample size estimates were calculated using PASS 2008 software. 
6 
STATISTICAL METHODS 
All descriptive statistics for continuous variables will be reported using mean, standard 
deviation (SD), median, first quartile (Q1), third quartile (Q3), minimum and maximum.  
Categorical variables will be summarized as number (percentage) of subjects. 
6.1 
Study Endpoints 
Tumor responses (based on the Olsen criteria) assessed by an Independent Review 
Committee (IRC) will be used in the evaluation of primary efficacy endpoint, and the 
associated secondary and exploratory efficacy endpoints.  In addition, the IRC will assess 
tumor responses using Prince criteria, which is a separate secondary endpoint. Investigator-
assessed tumor response (based on the Olsen criteria) and the associated secondary and 
exploratory response endpoints will also be reported. 
6.1.1 
Primary Endpoint(s) 
The primary efficacy endpoint is ORRassessed by IRC based on Global Response Score 
(GRS) (Olsen 2011)1.  
6.1.2 
Secondary Endpoint(s) 
• 
DOR based on GRS 
• 
TTR based on GRS 
• 
ORR assessed by investigator using GRS (Olsen 2011)1 
• 
Objective response assessed by IRC using Prince (2010)2 
• 
Skin response (according to modified Severity Weighted Assessment Tool 
(mSWAT)) 
• 
Duration of skin response 
• 
Time to skin response 
• 
Safety parameters 
• 
PK parameters 
• 
Immunogenicity 
6.1.3 
Exploratory Endpoint(s)  
• 
PFS and TTP 
• 
Clinical Benefit Rate (CBR) 
• 
Pruritus improvement 
• 
QoL using Skindex-29 and the FACT-G Questionnaire 


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6.2 
Study Subjects 
6.2.1 
Analysis Sets 
The definitions of the analysis sets are provided below: 
All Enrolled Subjects:  All subjects in Main Study who signed informed consent, and at 
Screening were assessed as meeting all inclusion criteria and not meeting any exclusion 
criteria.  
Full Analysis Set:  All subjects (both Main Study and Lead-In) who received study drug at 9 
μg/kg/day dose. 
Primary Efficacy Analysis Set:  All Stage I – III subjects (both Main Study and Lead-In) 
who received study drug at 9μg/kg/day dose.  
Safety Analysis Set:  All subjects dose (both Main Study and Lead-In) who received study 
drug at 9 μg/kg/day. This will be the analysis set for all safety analyses.  
Stage I-III Safety Analysis Set:  All Stage I – III subjects (both Main Study and Lead-In) 
who received study drug at 9μg/kg/day dose.  
Per Protocol Set:  All subjects had a baseline and at least one post-dose tumor assessment 
and had no major protocol deviations in either Primary Efficacy Analysis Set or Full 
Analysis Set. The per protocol analysis set will be the secondary analysis set for efficacy 
endpoints. 
PK Analysis Set:  All subjects from whom at least one quantifiable concentration of E7777 
was observed at 9 μg/kg/day dose (both Main Study and Lead-In) will comprise the analysis 
set for the PK data. 
Population PK Analysis Set:  All subjects from whom at least one quantifiable 
concentration of E7777 is available with a documented dosing history from both Lead-in and 
Main Study. 
Population PK/PD Analysis Set:  All subjects in the Population PK analysis set for whom 
efficacy and safety variables are also available from both Lead-in and Main Study. 
The number (percentage) of subjects included in each analysis set will be presented. 


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Table 1 summarizes which analyses each analysis set will be primarily used for. 
 
Full  
Primary 
Efficacy 
Safety 
Stage I-III 
Safety  
Per 
Protocol 
PK Analysis 
Set 
Disposition 
• 
• 
 
 
 
 
Demography & Baseline 
Characteristics  
• 
• 
 
 
 
 
Disease History  
• 
• 
 
 
 
 
Prior & Concomitant 
Medications  
• 
• 
 
 
 
 
Tumor Response per Olsen 
criteria by Investigator 
assessment 
• 
• 
 
 
 
 
Tumor Response per Olsen 
criteria by IRC review 
• 
• 
 
 
• 
 
Tumor Response per Prince 
criteria by IRC review 
 
• 
 
 
 
 
Skin Response 
• 
• 
 
 
 
 
Progression-Free Survival  
• 
• 
 
 
 
 
Time to Progression 
• 
• 
 
 
 
 
Patient Pruritus 
• 
• 
 
 
 
 
Drug Exposure  
 
 
• 
• 
 
 
Adverse Events  
 
 
• 
• 
 
 
Laboratory Tests  
 
 
• 
• 
 
 
Vital Signs  
 
 
• 
• 
 
 
ECGs  
 
 
• 
• 
 
 
Pharmacokinetic 
serum/parameter 
 
 
 
 
 
• 
Immunogenicity 
 
 
• 
 
 
 
 
6.2.2 
Subject Disposition 
Enrolled subjects include all subjects who signed informed consent forms in the Main Study.  The 
number of subjects screened, the number (percentage) of subjects who failed screening and the 
reasons for screen failure, will be summarized based on data reported on the Screening 
Disposition CRF. 
The disposition status of subjects for both the Primary Efficacy Analysis Set and Full 
Analysis Set will be summarized based on data reported on the Study Disposition Treatment 
Phase CRF.  Also, subjects discontinued from treatment but on survival follow-up at the data 
cutoff date will be summarized. In addition, subjects discontinued study and the reasons for 
discontinuation will also be summarized.  
A distribution of the number of subjects by each country and site will be provided.   


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6.2.3 
Protocol Deviations 
All protocol deviations will be identified by reviewing the data prior to database lock for 
primary analysis.  Major protocol deviations will be appropriately summarized by site and 
grouped into different categories.  All major protocol deviations identified according to study 
entry criteria and during treatment will be listed. All protocol deviations related to COVID-19 
will be listed. 
6.2.4 
Demographic and Other Baseline Characteristics 
Demographic and Baseline characteristics will be presented using summary statistics and 
listings for both the Primary Efficacy Analysis Set and Full Analysis Set.  
6.2.4.1 
Demography 
Continuous demographic and Baseline variables include:  
• 
Age (year)  
• 
Height (cm)  
• 
Weight (kg)  
• 
Body Surface Area (BSA)(m2): BSA = SQRT([Height(cm) x Weight(kg)]/ 3600) 
Categorical variables include: 
• 
Sex (male/female)  
• 
Age group (year): <65 years, ≥65 
• 
Ethnicity: Hispanic or Latino, Not Hispanic or Latino 
• 
Country: Australia and United States 
• 
Race 
◦ 
White 
◦ 
Black or African American 
◦ 
Asian 
- 
Japanese 
- 
Other Asian 
◦ 
American Indian or Alaska Native 
◦ 
Native Hawaiian or other Pacific Islander  
◦ 
Other 
• 
Race group: White, Asian and all others 
• 
ECOG performance status (0 to 2) 
6.2.4.2 
Disease characteristics 
Disease history and characteristics at study entry including type of CTCL (Mycosis Fungoides 
(MF)/Sezary Syndrome (SS)), CTCL disease stage at baseline, CTCL disease staging, tumor-


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node-metastasis-blood (TNMB) stage at study entry, mSWAT (modified Severity Weighted 
Assessment Tool) score at baseline and pruritus VAS at baseline will be summarized.  
6.2.5 
Medical history  
A subject data listing of medical and surgical history will be provided.  Medical history will 
be coded using Medical Dictionary for Regulatory Activities (MedDRA) (version 24.0 or 
most recent version).  
6.2.6 
Prior Anticancer Therapy 
Prior anticancer therapies tables will be presented for both Primary Efficacy Analysis Set and 
Full Analysis Set, also listings will be provided. 
Number of subjects with prior anti-cancer therapies, number of therapies (including 
medication and non-medication) and duration of last therapy, and best response to the last 
therapy, and non-medication therapy category will be summarized for prior anticancer 
therapies.  Prior anti-cancer medications and non-medication therapies will be summarized 
separately. 
6.2.7 
Prior and Concomitant Medications 
Prior and concomitant medications tables will be presented for both Primary Efficacy 
Analysis Set and Full Analysis Set, also listings will be provided. 
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 2021 or 
most recent version.  The number (percentage) of subjects who took prior and concomitant 
medications will be summarized by Anatomical Therapeutic Chemical (ATC) Classification 
and WHO drug preferred term.  Prior medications include medications that started prior to 
first dose of study drug.  Concomitant medications are 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 but within 30 days after 
the end date of exposure of study drug.  
Premedication for E7777 is required in cycles 1 to 3 and is optional from cycle 4 onward.  
Premedications will be listed based on an indication of "Premedication" on prior and 
concomitant CRF.  Steroid premedications during study will also be summarized by number 
(percentage) of subjects who took steroid premedication in total and during each cycle.  
6.3 
Data Analysis General Considerations 
6.3.1 
Pooling of Centers  
Subject data from all centers will be pooled for all analyses.  Center will not be considered as 
a factor in the analyses. 


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6.3.2 
Adjustments for Covariates 
No adjustment for covariates will be made for this study. 
6.3.3 
Multiple Comparisons/Multiplicity 
Not applicable. 
6.3.4 
Examination of Subgroups 
Baseline disease stage subgroup analysis for efficacy endpoints ORR, DOR, TTR, CBR, skin 
response, duration of skin response and time to skin response may be provided as 
appropriate.  
For Primary Analysis Set, disease stage subgroup categories may include IA/IB/IIA; IIB; and 
IIIA/IIIB as appropriate; for Full Analysis Set, disease stage grouping categories may include 
IA/IB/IIA; IIB; IIIA/IIIB; and IVA/IVA1/IVA2 as appropriate. 
Additional subgroup analyses may also be conducted, if deemed appropriate. 
6.3.5 
Handling of Missing Data, Dropouts, and Outliers 
Adverse Events with incomplete start dates will be considered treatment emergent 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;  
d) Year is missing; or  
e) Complete date is missing.  
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 incomplete dates involving efficacy and other safety data, a conservative imputation will 
be used for calculation if needed.  More details of imputation rules will be specified in study 
analysis dataset specification. 


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6.4 
Efficacy Assessments  
6.4.1 
Best Overall Response (BOR) based on GRS 
The best overall response (BOR) based on the GRS according to Olsen (2011)1 criteria is 
described as follows.  
Tumor assessment and response criteria will be according ISCL/EORTC response criteria 
described in Olsen (2011)1 criteria.  This is a composite measure of tumor burden in skin, 
lymph node, blood, and viscera.  The documented date of CR/PR/SD/PD for GRS will be based 
on the corresponding mSWAT score assessment date (implemented for IRC assessment by 
IRC and derived programmatically for Investigator assessment).  Assessments showing non-
PD after a single PD, or assessments showing non-PD after two consecutive PD evaluations 
within 7 days of each other, will be included in the determination of BOR. The key points of 
BOR derivation are described as follows. 
• 
Complete Response (CR). BOR of CR can be achieved by the following situations:   
◦ 
BOR is CR when the duration between the two CRs is ≥ 3 weeks for two 
consecutive CRs or two CRs with “unknown” or “missing” assessments in 
between. 
The documented start date of CR is defined as the date of mSWAT score assessment 
date corresponding to the initial CR. 
• 
Partial Response (PR).  When BOR of CR is not achieved, BOR of PR can be 
achieved by one of the following situations: 
◦ 
BOR is PR when the duration between the two responses (PR or CR) is ≥ 3 weeks 
for two consecutive PRs, the order of CR, PR, or the order of PR, CR, without 
intervening of SD/UNK or missing assessments. 
◦ 
BOR is PR when the duration between the two responses (PR or CR) is ≥ 3 weeks 
for two PRs, or the order of PR, CR, with up to two intervening SD assessments 
in between. 
◦ 
BOR is PR when the duration between the two responses (PR or CR) is ≥ 3 weeks 
for two PRs, the order of CR, PR, or the order of PR, CR, with “unknown” or 
“missing” assessments in between. 
The documented start date of PR is the date of mSWAT score assessment date 
corresponding to the initial PR or CR 
• 
Stable Disease (SD).  When BOR of CR/PR is not achieved, BOR of SD can be 
achieved by the following: 
If subject at least once had an overall timepoint evaluation of CR/PR/SD that was 
recorded ≥3 weeks after the first dose of study drug. 
• 
Progressive Disease (PD).  When BOR of CR/PR/SD is not achieved, if subject at 
least once had an overall time point evaluation of PD, then the BOR is PD. 
The date of documented PD is: 


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◦ 
If subject is not treated beyond the initial PD, date of PD should be used. 
◦ 
If subject is treated beyond the initial PD (per protocol), date of the initial PD 
should be used if consecutive PDs; if there are intervening SD/PR/CR between 
the two PDs, date of the later PD should be used. 
• 
Unknown (UNK).   
◦ 
No baseline assessment 
◦ 
No post-baseline evaluations GRS assessment 
◦ 
Early SD (SD <21 days from first dose date) 
◦ 
Subject has only UNK (assessment not possible) for Global Response Score for 
all postbaseline Tumor Timepoint Response Assessment. 
More details regarding BOR derivation can be found in the Analysis Data Model (ADaM) 
Data Specification document. 
6.4.2 
Best Overall Response (BOR) for Skin Response  
BOR for skin response will follow the same approach as described in section 6.4.1 based on 
timepoint skin response instead of GRS assessment. 
6.4.3 
Best Overall Response (BOR) using Prince (2010)2  
The IRC will also assess timepoint tumor responses using Prince (2010)2 criteria.  The BOR 
based on Prince criteria at subject level will be derived.  BOR will fall into the following 
categories:  CR+CCR (Clinical Complete Response), PR, SD, PD, and UNK. 
The key point regarding Prince (2010)2 criteria is that, according to Prince (2010)2 criteria, the 
documented response (i.e., CR, CCR, PR) required confirmation by two additional tumor 
burden assessments over a period of at least 6 weeks.  Documented responses for all end points 
had to be confirmed at three consecutive visits (i.e., maintained for 6 weeks after the initial 
documentation). 
Assessments showing non-PD after a single PD, or assessments showing non-PD after two 
consecutive PD evaluations within 7 days of each other, will be included in the determination 
of BOR.   
The details of derivation can be found in the ADaM Data Specification document. 
6.5 
Efficacy Analyses 
All efficacy analyses will be performed on the Primary Efficacy Analysis Set (i.e., in the 
Stage I – III subjects from Main Study plus the Stage I – III subjects from the 9 μg/kg/day 
dose group in Lead-In Study), and additionally on Full Analysis Set. Tumor response 
assessed by IRC based on Olsen (2011)1 criteria will also be summarized using the Per 
Protocol Set.  


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6.5.1 
Primary Efficacy Analysis 
The primary endpoint is the ORR based on Olsen (2011)1 criteria, using response assessment 
data by IRC. The ORR is the proportion of subjects achieving a BOR of confirmed CR or PR.  
The Primary Efficacy Analysis Set will be used for analysis. 
The 2-sided, exact 95% CI of ORR will be calculated using the Clopper-Pearson method.  The 
treatment will be considered efficacious and demonstrating the clinical benefit of E7777 if the 
lower bound of the 2-sided 95% exact CI of the observed ORR exceeds 25%. 
6.5.2 
Secondary Efficacy Analyses 
6.5.2.1 
Duration of Response 
The DOR is defined as the time from the date that a confirmed objective response (CR or 
PR) was first met until the date of documented PD or death due to any cause for those 
subjects with a confirmed PR or CR. For subjects who did not experience PD or death by the 
end of data cut off, censoring rules for DOR are the same as those of PFS.  
• 
Duration of objective response (months) = (Date of PD/Death or Censor Date – Date 
of first objective response+ 1) × 12/365.25, for subjects with objective response. 
For subjects with confirmed PR or CR, the DOR will be analyzed using Kaplan-Meier (KM) 
product-limit estimates.  Probabilities of DOR ≥ 6 and 12 months will be presented with 2-
sided 95% CIs as appropriate, if they can be estimated from the model.  The median and 
quartiles of DOR from KM estimation will be provided with 95% CIs if estimable.  The 
DOR curve from KM method will be provided.  
For subjects with confirmed PR or CR, the number and percentage of subjects with DOR ≥ 6 
and 12 months will also be summarized as descriptive statistics as appropriate.   
The swimmer plot will be plotted demonstrating the treatment duration and timepoint 
responses over time.  
6.5.2.2 
Time to Response 
The TTR is defined as the elapsed time from the date of the first study drug dose until the 
date of first documented confirmed CR or PR, whichever occurs first.  Summary statistics of 
TTR for subjects with confirmed CR or PR (objective response) will be presented. 
TTR will also be summarized by treatment cycles completed when the first documented 
response occurred. 
TTR for subjects with confirmed CR or PR will be analyzed using KM method.  The median 
and quartiles of TTR from KM estimation will be provided with 2-sided 95% CIs if 
estimable.  The cumulative probabilities will be plotted over time.  


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6.5.2.3 
ORR Using Prince (2010)2 
The ORR is the proportion of subjects achieving a BOR of confirmed CR+CCR or PR per 
Prince (2010)2 criteria.  The Primary Efficacy Analysis Set will be used for analysis.  See 
Section 6.4.3 for the derivation of BOR.  
The 2-sided, exact 95% CI of ORR will be calculated using the Clopper-Pearson method. 
6.5.2.4 
Skin Response (according to mSWAT) 
ORR for skin response based on the mSWAT score, is defined as the proportion of subjects 
with best skin response of CR or PR. See Section 6.4.2 for the derivation of the BOR for skin 
response. 
The 2-sided, exact 95% CI of ORR will be calculated using the Clopper-Pearson method. 
In addition, waterfall plot presenting each subject’s percentage change in mSWAT from 
baseline at postbaseline nadir before data cutoff will be provided. 
6.5.2.5 
Duration of Skin Response 
The duration of skin response based on the mSWAT score is defined as time from the date 
when criteria for confirmed skin response (CR or PR) was first met until the date of 
documented PD or death due to any cause for those subjects with a confirmed PR or CR.  For 
subjects who did not experience PD or death by the end of data cut off, censoring rules for 
duration of skin response are the same as those of PFS. 
Duration of skin response will be analyzed following the same approach in Section 6.5.2.1.  
6.5.2.6 
Time to Skin Response 
The time to skin response based on the mSWAT score is defined as time from the date of 
first dosing to the date when criteria for confirmed skin response (CR or PR) are first met.  
Time to skin response will be analyzed following the same approach in Section 6.5.2.2. 
6.5.3 
Other Efficacy Analyses 
6.5.3.1 
Exploratory Efficacy Analyses 
PROGRESSION FREE SURVIVAL 
The PFS is defined as the date of first dosing to the date of documented PD or death as a 
result of any cause (whichever occurs first).  
PFS will be analyzed for the Primary Efficacy Analysis Set and Full Analysis Set. 
PFS will be analyzed using KM method.  The median, quartiles and the PFS rates at 3, 6, 9, 
12 months and so on (depending on data adequacy) will be calculated using KM method and 


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presented with 2-sided 95% CIs if estimable.  The cumulative probabilities of PFS will be 
plotted over time.  
The PFS censoring rules in this SAP and definition of progression date will follow the Food 
and Drug Administration (FDA) “Guidance for Industry Clinical Trial Endpoints for the 
Approval of Cancer Drugs and Biologics (2007)” 
Table 2 Censoring Rules for Analysis of Progression-Free Survival 
No. Situation 
Date of Event (Progression/Death) 
or Censoring 
Outcome 
1 
No baseline tumor or postbaseline GRS 
assessments 
Date of first dose  
Censored 
2 
Progression documented between scheduled 
visits*  
Date of PD by GRS assessment 
Event 
3 
No progression at the time of data cutoff 
Date of last adequate 
GRS assessment prior to 
or on date of data cutoff 
Censored 
4 
New anticancer treatment started 
Date of last adequate GRS 
assessment prior to or on date 
of new anticancer treatment 
Censored 
5 
Death before first PD by GRS assessment 
Date of death 
Event 
6 
Death between adequate GRS assessment 
visits** 
Date of death 
Event 
7 
Death or progression after more than 
one missed visit/GRS assessment*** 
Date of last adequate 
GRS assessment before 
missed GRS assessments 
Censored 
CR = complete response, PD = progressive disease, PR = partial response, SD = stable disease.  
Any GRS assessments after new anticancer treatment starts will not be considered in the definition of PFS. 
*If subject is not treated beyond initial PD, date of PD should be used. If subject is treated beyond initial PD 
(per protocol), date of initial PD should be used if consecutive PDs; if there are intervening SD/PR/CR between 
two PDs, date of the later PD should be used.** Adequate GRS assessment is assessment of CR, PR, SD and 
PD at regular interval.  
***More than one missed visits is defined as having the duration between the last tumor assessment  and death 
or PD longer than 44 days which is (3) ×2×7+3-1days for subjects on every 3 weeks (-3 days window) for 
subjects on every 3 weeks tumor assessment schedule during treatment; after date of end of treatment date, 69 
days which is (4+1) ×2×7-1days for subjects on every 4 weeks (± 1 week) for 1 year after end of study 
treatment; 209 days which is (12+3) ×2×7-1 days for subjects on every 12 weeks (± 3 weeks) tumor assessment 
schedule from 1 year after end of study treatment up to 3 years. 
The priority of the censoring rules is as follows:  
1. If the subject had PD or death, the following sequence will be applied:  
• 
If a subject did not have a baseline tumor assessment (No. 1), the subject will be 
censored on the date of first dose.  However, if the subject died within 41 days (6 
weeks-1day) after first dose and did not receive a new anticancer treatment, it will be 


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counted as PFS event at the date of death.  If a subject had new anticancer treatment 
before PD or death (No. 4), the subject will be censored on the date of the last 
adequate GRS assessment prior to or on the date of new anticancer treatment.  
• 
If a subject missed two or more tumor assessments before PD or death (No. 7), the 
subject will be censored on the date of the last adequate GRS assessment before PD 
or death.  Note that if a subject is censored by both this criterion and the anticancer 
treatment criterion, the earliest censoring date will be used.  
• 
Otherwise, if a subject had an 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).  
TIME TO PROGRESSION (TTP) 
TTP is defined as the time from the date of first dosing to the date of documented PD or death 
as a result of CTCL.  The same censoring rules, except for death (other cause), as in the analysis 
of PFS will be applied in calculation of TTP.  
TTP will be analyzed following the same approach as for PFS in Section 6.5.3.1. 
CLINICAL BENEFIT RATE (CBR)  
The CBR is defined as the proportion of subjects who had best overall response of CR or PR 
or Durable SD by IRC or investigator assessment.  
Durable Stable disease must be achieved at ≥ 23 weeks after first dose of study drug to be 
considered best overall response based on Olsen (2011)1 criteria. 
The 2-sided, exact 95% CI of CBR will be calculated using the Clopper-Pearson method.  
PRURITUS IMPROVEMENT 
Subjects will rate the severity of pruritus using a 100-mm visual analog scale (VAS), on 
which zero indicates no itch and 100 indicates worst possible itch.  A clinically significant 
improvement is defined as an absolute decrease of 20 mm from baseline maintained for ≥ 4 
weeks; baseline score must be ≥ 20.  Subject’s pruritus improvement rate is defined as the 
proportion of subjects with a clinically significant improvement in pruritus.  The 2-sided, 
exact 95% CI of pruritus improvement rate will be calculated using the Clopper-Pearson 
method. 
In addition, the percentages of subjects who have ≥ 20% and ≥ 50% improvements 
(decreases) relative to baseline will be tabulated. 
SENSITIVITY ANALYSES 
Sensitivity analyses for ORR in subjects receiving versus subjects not receiving steroid 
medication for any cycle during the study will be performed.  ORR (the proportion of 


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subjects achieving a BOR of confirmed CR or PR) will be summarized along with the 2-
sided, exact 95% CI, using the Clopper-Pearson method. 
6.6 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Analyses 
6.6.1 
Pharmacokinetic Analyses 
Analyses will be based on the pharmacokinetic analysis set. 
The PK Analysis Set will be defined as: 
The PK Analysis Set includes subjects from whom at least one quantifiable concentration 
of E7777 was observed at 9 μg/kg/day dose (both Main Study and Lead-In).  
Serial PK assessment of E7777 will be performed on all subjects in the Lead-In and on the first 
12 subjects in the Main Study, using serial blood PK sampling on Day 1 in Cycles 1, 3, and 5, 
with sparse sampling in Cycle 8.  In addition, sparse sampling will be performed in the rest of 
the subjects on Day 1 of Cycle 1. 
The PK analysis will be done using PK Analysis Set. 
Serum concentration data for E7777 will be analyzed and summarized using descriptive 
statistics (n, mean, standard deviation (SD), median, minimum and maximum) by time point.  
PK parameters will be derived for subjects with serial blood PK sampling using non-
compartmental methods for E7777 on Day 1 of Cycles 1, 3 and 5.  These include as data permit: 
x Time to maximum concentration (tmax) 
x Maximum concentration (Cmax) 
x Area under the curve from 0 to t (AUC(0-t)) 
x Area under the curve from 0 to infinity (AUC(0-inf)) 
x Elimination half-life (t1/2) 
x Total body clearance (CL) 
x Volume of distribution at steady state (Vdss) 
Descriptive statistics (n, mean, standard deviation (SD), median, minimum and maximum, 
geometric mean (%CV)) will be used to summarize PK parameters.Geometric mean (%CV) 
will not be computed for tmax. 
When presenting individual/raw values and summary statistics, the following rule will be 
applied:  for drug concentrations and concentration-dependent pharmacokinetic parameters, all 
summary statistics (mean, standard deviation (SD), median, minimum and maximum, 
geometric mean) will have 3 significant digits.  For tmax, raw values and median have fixed 2 
decimal places. 
The following figures will be prepared: 


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x Linear and semi-log plots of individual E7777 serum concentration versus time at each 
cycle and day for subjects with serial blood PK sampling 
x Linear and semi-log plots of mean and SD for E7777 serum concentration versus time 
by cycle and day for subjects with serial blood PK sampling 
x Box plot of pharmacokinetic parameters (Cmax, AUC(0-t), and AUC(0-inf)) by cycle for 
subjects with serial blood PK sampling 
x Relationship of Drug Exposure on Cycles (Cmax, AUC(0-t), AUC(0-inf) (AbImpact = 0 
Only) if applicable 
Based on the immunogenicity (antibody positive, negative, etc.) additional PK analyses may 
be prepared. 
Serum concentration data from the sparse PK sampling time points and the intense PK 
sampling time points from both lead-in and main phase will be analyzed using a population 
PK approach incorporating data from all studies of the E7777 program.  The relationship of 
E7777 exposure and key efficacy and safety endpoints will also be assessed (as part of 
population PK/PD analyses).  Details concerning the objectives and methods of these 
exploratory analyses will not be described in this SAP but will be described in a separate 
population analysis plan (PAP) authored by Modeling and Simulation of Clinical 
Pharmacology Science (M&S, CPhS), Medicine Development Center (MDC)-Eisai. 
 
6.6.2 
Immunogenicity Analysis 
Analyses will be based on the safety analysis set.  
Immunogenicity (formation of antibodies to E7777 or IL-2, and of neutralizing antibodies) 
will be assessed in all subjects in both the Lead-In and the Main Study.  Immunogenicity 
assessment in serum will be performed using validated bioanalytical methods to screen, 
confirm, and characterize the presence of anti-E7777, anti- IL-2, and neutralizing antibodies.  
Only samples with confirmed positive antibodies to E7777 and/or IL-2 will be tested by a 
neutralizing antibody assay.  A predose blood sample for immunogenicity assessment will be 
collected prior to dosing on Day 1 in Cycles 1, 2, 3, 5, and 8.  After that, all subjects will be 
to be followed up for immunogenicity testing for anti- LI 2 on a 6-month schedule for 1 year 
and every year thereafter until antibody titers decrease to Baseline level or until study 
conclusion/termination.  Blood samples will be collected prior to study drug administration. 
Anti-E7777/IL-2 antibodies results (negative/positive) will be summarized by number of 
subjects and percentage by visit.  For subjects with positive anti-E7777/IL-2 antibodies, the 
titer levels will be summarized using descriptive statistics (n, mean (SD), Q1, Q3, median, 
minimum and maximum) by visit.  In addition, neutralizing anti-E7777/IL-2 antibodies 
results (negative/positive) will be summarized by visit. 
The following figures will be prepared: 
x Semi-log box plot of Anti-E7777 and Anti-Il-2 titers by cycle 
 


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6.6.3 
Pharmacodynamics, Pharmacogenomic, and Other Biomarker Analyses 
Not applicable. 
6.7 
Safety Analyses 
All safety analyses will be performed for the Safety Analysis Set and the Stage I-III Safety 
Analysis Set.  Safety data will be summarized using descriptive statistics (eg, n, mean, 
standard deviation (SD), median, Q1, Q3, minimum and maximum for continuous variables; 
number and percentage for categorical variables).  Safety data to be evaluated include 
adverse event (AEs), clinical laboratory results, vital signs, ECGs. 
6.7.1 
Extent of Exposure 
The number of cycles/infusions on treatment, quantity of study drug administered, and duration 
of study drug treatment will be presented.  The number of subjects requiring dose reductions, 
treatment interruption will be summarized. 
x The number of cycles received and the number of infusions by cycle and overall will 
be summarized with descriptive statistics.  Subject is considered to have received one 
cycle if the subject received at least one dose on any of days 1, 2, 3, 4 or 5 of a cycle 
during the cycle.  
x The duration of study drug in weeks will be (Date of the last dose – Date of the first 
dose + 1) / 7, including drug interruption days. 
x Total dose (ug/kg) of study drug is the summarization of all the actual doses received 
during study. Actual dose (ug/kg) is calculated using planned dose (ug/kg) × (actual 
volume(ml)/planned volume(ml)).  
x Received dose as percentage of planned starting dose (%) = total dose (ug/kg) / (number 
of cycles × 5 (day) ×9 (ug/kg/day)) ×100. 
x Number of subject weeks = summation over all subjects’ exposure durations. 
Subject data listings will be provided for all dosing records, and for the summary statistics 
calculated above. 
Study drug interruption and dose reduction instructions for subjects who experience an E7777-
related toxicity are presented in Table 1 per protocol amendment 6 section 9.4.1.5.  The number 
of subjects with dose reductions and treatment interruption will be summarized by counts and 
percentages.  
6.7.2 
Adverse Events 
Adverse events will be summarized for the Safety Analysis Set and Stage I-III Safety 
Analysis Set.  Adverse events were graded using Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03 or version 5.0. CTCAE version was upgraded from 4.03 to 5.0 
in Protocol Amendment 05 (03 May 2018). Investigators will collect all AE CTCAE grades 
(for both increasing and decreasing severity). AEs will be classified into standardized 


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medical terminology from the verbatim description using the Medical Dictionary for 
Regulatory Activities (MedDRA version 24.0 or most recent version).  AEs will be 
summarized by preferred term (PT) nested within system organ class (SOC).  All AEs will be 
listed. 
A TEAE is defined as an AE that emerged during treatment or up to 30 days (also 30 days 
for serious TEAEs) following last dose of study drug; AEs that emerge during study drug 
treatment, having been absent at pretreatment (Baseline), or those that: 
x Reemerge during study drug treatment, having been present at Baseline but stopped 
prior to study drug treatment, or  
x Worsen in severity during study drug 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. 
An overview table, including the incidence of and the number of subjects with treatment-
emergent adverse events (TEAEs), SAEs, deaths, and those TEAEs that led to 
discontinuation from study drug, dose reduction or drug interruption, will be provided.  The 
incidence of TEAEs will be summarized by SOC, PT, CTCAE grade, and relatedness to 
study drug (possibly related or probably related).  Although a MedDRA term may be 
reported more than once for a subject, that subject will be counted only one time in the 
incidence count for that MedDRA term with the highest CTCAE grade (in the summary by 
CTCAE grade) or with the closest relationship to study treatment (in the summary by 
relatedness to study treatment).  Treatment-related TEAEs includes TEAEs considered by the 
Investigator to be possibly or probably related to study drug or TEAEs with missing 
causality. 
Separate summary tables and listings will be provided for all TEAEs, treatment-emergent 
SAEs, TEAEs reported as treatment-related, treatment-emergent SAEs reported as treatment-
related, TEAEs by CTCAE grade, and TEAEs leading to treatment discontinuation.     
In summary, the following TEAE tables will be provided: 
x Overview of TEAEs 
x Overview of treatment-related TEAEs 
x TEAEs by SOC and PT and Worst CTCAE Grade 
x TEAEs by PT in decreasing frequency 
x Treatment-related TEAEs by SOC and PT and Worst CTCAE Grade 
x Treatment-related TEAEs by PT in decreasing frequency 
x  Treatment-emergent serious TEAEs by SOC and PT 
x Treatment-emergent serious TEAEs by PT in decreasing frequency 
x Treatment-related serious TEAEs by SOC and PT 
x Treatment-related serious TEAEs by PT in decreasing frequency 
x TEAEs leading to discontinuation from study drug by SOC and PT 


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x TEAEs Leading to dose reduction or drug interruption by SOC and PT 
x TEAEs leading to dose reduction by SOC and PT 
x TEAEs leading to drug interruption by SOC and PT 
The following listings of deaths and AEs will be prepared: 
x All AEs 
x Adverse events with CTCAE grade 3 or higher 
x All Serious adverse events 
x All deaths 
x Adverse Events leading to study drug discontinuation 
x Adverse Events leading to dose reduction or drug interruption 
Note that for summary tables, if data are not adequate for summary, only listings will be 
provided. 
 
6.7.2.1 
Treatment-Emergent Adverse Events of Clinical Interest  
TEAEs of special interest (AESI) for E7777 will be identified based on the review of safety 
data by Clinical and Pharmacovigilance.  
AESI will be summarized by preferred terms and worst CTCAE grade. 
6.7.3 
Laboratory Values 
Laboratory results will be summarized using Système International (SI) units, as appropriate. 
On-treatment laboratory tests will be defined as laboratory tests conducted from the start of 
treatment to no more than 30 days after the last dose of study treatment.  Central laboratory 
test results will be primary data source for laboratory analyses.  Only when the central 
laboratory tests results are missing, the local laboratory test results will be used as substitute.  
For all quantitative parameters listed in Table 3 (protocol Section 9.5.4.3) 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) will be summarized by visit using descriptive statistics.  Qualitative 
parameters listed in Table 3 (protocol Section 9.5.4.3) will be summarized using frequencies 
(number and percentage of subjects), and changes from baseline 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. 
6.7.3.1 
Hematology and Clinical Chemistry 
Laboratory parameters that are graded in CTCAE v5.0 will be summarized by CTCAE grade.  
In the summary of laboratory parameters by CTCAE grade, for parameters with CTCAE 
grading in both high and low direction, CTCAE in high and low directions will be 
summarized separately.  Subjects with treatment-emergent markedly abnormal laboratory 


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values (TEMAV) will also be summarized.  Markedly abnormal is defined as a value that is 
above or below the normal range and the CTCAE grade increased from baseline by 2 or more 
grades. 
Laboratory test results will be reported in the following methods: hematology and blood 
chemistry.  
x Summary of values at each visit and changes from baseline. 
x Shifts from baseline to the worst postbaseline CTCAE grade.  
x Summary of Treatment-emergent markedly abnormal laboratory results by cycle  
6.7.3.2 
Urinalysis 
A listing of urinalysis results will be provided. 
6.7.4 
Vital Signs 
Descriptive statistics for vital signs parameters (systolic and diastolic blood pressure (BP), 
heart rate, respiratory rate, body temperature and weight) and their change from baseline value 
will be presented by visit.   
6.7.5 
Electrocardiograms 
Prior to Amendment 05 ECG QT/QTcF interval was read centrally, and triplicate ECG 
measurements were required.  Amendment 05 resulted in the following changes for ECG 
monitoring: 
x Triplicate ECGs were no longer required 
x QT/QTcF interval was no longer be assessed by a central laboratory 
x Single 12-Lead ECGs will be performed during Screening, Day 1 of each cycle, and 
End of Treatment  
Shift tables for overall ECG findings categorized as normal and abnormal will be presented 
from baseline to worst postbaseline values by visit.  
In addition, the number (percentage) of subjects with at least one postbaseline abnormal ECG 
result in QTc Fridericia during the treatment phase will be summarized.  Centrally-read pre-
Amendment 05 data will be combined with post-Amendment 05 non-centrally-read data.  ECG 
results in QTc Fridericia will be categorized as follows: 
x Absolute QTc interval prolongation:  
o QTc interval >450 ms  
o QTc interval >480 ms  
o QTc interval >500 ms  
x Change from baseline in QTc interval:  
o QTc interval increases from baseline >30 ms  


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o QTc interval increases from baseline >60 ms 
6.7.6 
Other Safety Analyses 
No other safety analyses are planned for this study.  
6.8 
Other Analyses 
6.8.1 
Quality of Life 
QoL will be assessed using the Skindex-29 and FACT-G questionnaires.  Details of QoL 
analyses will be presented in a separate SAP.  
6.8.2 
COVID-19 Impact 
Protocol deviations and adverse events associated with COVID-19 (coronavirus disease 
2019) will be presented. 
6.9 
Exploratory Analyses 
See Section 6.5.3 Other Efficacy Analyses 
7 
INTERIM ANALYSES 
No interim analyses are planned for this study. 
8 
CHANGES IN THE PLANNED ANALYSES 
8.1 
Changes in the Planned Analyses from those in the Protocol 
Clinical Benefit Rate (CBR), defined as the proportion of subjects who have best overall 
response of Complete Response + Partial Response + Durable Stable Disease, will be an 
additional exploratory efficacy analysis. This was not specified in protocol.  
FAS and Safety Analysis Set are updated to include all 9 ug/kg/day Lead-In subjects in the 
analysis. 
Full Analysis Set:  All subjects who received study drug at 9 μg/kg/day dose (both Main Study 
and Lead-In).  
Safety Analysis Set:  All subjects who received study drug at 9 μg/kg/day dose (both Main 
Study and Lead-In). This will be the analysis set for all safety analyses.  
Changes were presented in revision history table. 
 


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9 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING 
Baseline 
Baseline is defined as the non-missing value most recently collected before the first dose of 
any study. 
In the analyses of ORR and CBR, subjects without baseline or postbaseline tumor assessment 
will be considered as non-responders and will be included in the denominator when 
calculating ORR and CBR.  Non-responders will be excluded in the analysis of DOR. 
Study Day 1 
Study Day 1 is defined as the day of the first dose of study drug administrated. 
By-visit analysis 
All by-visit analyses will be performed using assessment at corresponding scheduled visits 
recorded in the eCRF (not including unscheduled). 
The unscheduled visits will be included in the analyses that involve definition of worst post-
baseline assessment. 
Time Conversion Factors 
The following factors will be used to convert days to months or years: 
1 month = 30.4375 days; 1 year = 365.25 days. 
Missing/Partial Dates  
Refer to programming specifications for details to handle any missing or partial dates. 
10 PROGRAMMING SPECIFICATIONS 
The rules for programming derivations and dataset specifications are provided in separate 
documents. 
11 STATISTICAL SOFTWARE 
All statistical analyses will be performed using SAS v 9.4 or higher. 
12 MOCK TABLES, LISTINGS, AND GRAPHS 
The study TLG shells will be provided in a separate document, which will show the content 
and format of all tables, listings, and graphs in detail. 


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13 REFERENCES 
1. Olsen EA, Whittaker S, Kim YH, Duvic M, Prince HM, Lessin SR, et al.  Clinical 
end points and response criteria in mycosis fungoides and Sézary syndrome:  a 
consensus statement of the International Society for Cutaneous Lymphomas, the 
United States Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma 
Task Force of the European Organisation for Research and Treatment of Cancer. J 
Clin Oncol. 2011;29(18): 2598-607. 
2. Prince HM, Duvic M, Martin A, Sterry W, Assaf C, Sun Y, et al.  Phase III placebo-
controlled trial of denileukin diftitox for patients with cutaneous T-cell lymphoma.  
J Clin Oncol. 2010;28(11):1870-7. 


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 SIGNATURE PAGE 
Author:   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Oncology Business Group, Eisai Inc. 
 
Date 
Approval: 
 
 
 
  
 
 
 
 
 
 
 
  
Oncology Business Group, Eisai Inc.  
 
Date 
  
 
 
 
 
 
 
 
 
 
Oncology Business Group, Eisai Ltd.    
 
Date 
 
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