Clinical trial NCT02676778
Conditions: Peripheral T-cell Lymphoma Cutaneous T-cell Lymphoma
Keywords: Peripheral T-cell lymphoma Cutaneous T-cell lymphoma E7777 Phase 2
Sponsor: Eisai Co., Ltd.
Start date: 2016-03-28; Completion date: 2019-04-26
Enrollment: 45 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate the objective response rate (ORR) of E7777 in participants with relapsed or refractory peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL).

Detailed description:
This is a multicenter, single-arm, open label, Phase 2 to evaluate efficacy, safety, pharmacokinetics and immunogenicity of E7777 in participants with relapsed or refractory PTCL and CTCL.

Arms: arm 1: Participants with relapsed or refractory peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL) will receive 9 μg/kg/day of E7777, administered by intravenous drip infusion in 60 minutes (± 10 min) for Days 1 through 5 of each cycle in maximum of 8 cycles. Every cycle consists of 3 weeks.
Interventions: intervention 1: E7777
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_000.pdf: 
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1
TITLE PAGE
Clinical Study Protocol
Study Protocol 
Number:
E7777-J081-205
Study Protocol 
Title:
A Phase 2 study of E7777 in patients with relapsed or refractory 
peripheral T-cell lymphoma and cutaneous T-cell lymphoma
Sponsor:
Eisai Co., Ltd. 
4-6-10 Koishikawa, Bunkyo-Ku, Tokyo 112-8088, Japan
Investigational 
Product Name:
E7777/denileukin diftitox
Indication:
Patients with relapsed or refractory peripheral T-cell lymphoma and
cutaneous T-cell lymphoma
Phase:
2
Approval Date:
V2.0
19 Feb 2016
GCP Statement:
This study is to be performed in full compliance with Good Clinical 
Practice (GCP) and regulations.  All required study documentation 
will be archived as required by regulatory authorities.
Confidentiality 
Statement:
This document is confidential.  It contains proprietary information of 
Eisai (the sponsor).  Any viewing or disclosure of such information 
that is not authorized in writing by the sponsor is strictly prohibited.  
Such information may be used solely for the purpose of reviewing or 
performing this study.


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2
CLINICAL PROTOCOL SYNOPSIS
Compound No.:  E7777
Name of Active Ingredient:  denileukin diftitox
Study Protocol Title
A Phase 2 study of E7777 in patients with relapsed or refractory peripheral T-cell lymphoma and 
cutaneous T-cell lymphoma
Investigator(s)
Shown in the Attachment
Sites
Approximately 18 sites in Japan
Study Period and Phase of Development
Study period: 32 months (planned)
Phase of development: Phase 2
Objectives
Primary objective:
To evaluate the efficacy of E7777 with objective response rate (ORR) in patients with relapsed or
refractory peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL).
Secondary objectives:
1.
To evaluate the efficacy of E7777 below.

Progression-free survival (PFS)

Duration of response (DOR)

Time to response (TTR)

Complete response (CR) rate

Overall survival (OS)
2.
To evaluate the safety of E7777.
3.
To evaluate the pharmacokinetics (PK) and immunogenicity (anti-E7777 antibody, anti-IL-2
antibody and neutralizing activity of anti-E7777 antibody) of E7777.
Exploratory objectives:
To preliminarily explore the biomarkers in the tumor and blood below.
1.
To measure the rate of CD25+ cells in tumor by immunohistochemistry (IHC).
2.
To measure the serum soluble IL-2 receptor (sIL-2) and LDH levels.
3.
To measure the T-cell subsets in the peripheral blood.


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Study Design
This is a multicenter, single-arm, open-label, Phase 2 study to evaluate efficacy, safety, PK, and 
immunogenicity of E7777 in patients with relapsed or refractory PTCL and CTCL. This study will 
consist of the following 3 periods: Pretreatment, Treatment, and Follow-up Phases.
The Pretreatment Phase will include informed consent, screening, registration, and baseline 
assessments. Informed consent will be obtained within 28 days before the start of study drug 
administration. Subjects who meet all of the inclusion criteria and do not meet any of the exclusion 
criteria will be entered to this study. Baseline assessments will be performed within 7 days before the
study drug administration. Subjects will be confirmed to meet all of the inclusion criteria and not to 
meet any of the exclusion criteria prior to proceed to the Treatment Phase.
The Treatment Phase will start from the study drug administration on Cycle 1 Day 1 and will last
until meeting any of the discontinuation criteria for an individual subject (discontinuation) or Cycle 8 
Day 21 (completion), as 3 weeks per cycle. The evaluations at the discontinuation (completion) will 
be performed within 7 days after the discontinuation (completion).
Tumor evaluation:
In the Treatment Phase, tumor evaluation (nodal/extranodal lesion, liver/spleen enlargement, skin
lesion, and peripheral blood lesion) will be performed on screening, Days 15 to 22 (if postponed the
beginning of next cycle, by the beginning of next cycle or within 7 days at the time of completion of 
Cycle 8) of Cycles 2, 4, 6, 8, and at discontinuation. PET scan will be performed on screening, and if 
positive, Days 15 to 22 (if postponed the beginning of next cycle, by the beginning of next cycle, or
within 7 days at the time of completion of Cycle 8) of Cycles 4 and 8, and at discontinuation as 
possible.  Tumor evaluation will be performed in shorter period at confirmation of efficacy or if 
clinically indicated.
To evaluate bone marrow infiltration, bone marrow biopsy will be performed (if it is difficult, bone
marrow aspiration can be performed instead) at screening. If the result is positive or unconfirmed, or 
bone marrow biopsy is not performed (ie, bone marrow aspiration is performed instead) at screening, 
bone marrow biopsy will be performed when to confirm CR as best overall response.  In addition, 
bone marrow biopsy can be performed in any subject when clinically indicated.
B symptoms (fever of >38 °C with unknown reason, night sweat [requiring to change bedding], and 
>10% decrease of bodyweight with unknown reason within 6 months) will be evaluated at the same
timepoints with tumor evaluations.
The subjects who discontinued or completed the study drug administration will proceed to the 
Follow-up Phase. In the Follow-up Phase, the final observation will be performed on 30 days after 
the last dose of the study drug. Tumor evaluations (except PET and color photography of the skin 
lesion) will be performed on every 6 to 8 weeks (except the case of discontinuation by disease 
progression or starting treatment of a next antitumor drug) and survival investigations on every 12 to 
16 weeks from the discontinuation (or completion) of the study drug, unless the subject withdrew the 
informed consent or the sponsor decided to stop the investigation. In the Follow-up Phase, the 
information about next antitumor drugs/therapies (dosage period and best overall response of the 
treatment) will be collected as much as possible.
In all registered subjects, PK and immunogenicity (anti-E7777 antibody, anti-IL-2 antibody, and 
neutralizing activity of anti-E7777 antibody) will be evaluated and blood samples for the 
measurement of serum sIL-2R, LDH and T-cell subsets in the peripheral blood will be collected 
according to the specified schedule below.
The disease diagnosis by a central pathologist, and central evaluation of the rate of CD25+ cells in 


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tumor and CCR4 expression will be performed.
Pharmacokinetics:
Blood samples for non-compartment analysis will be collected at the following timepoints until
6 subjects continued the treatment for at least 5 cycles.
Day 1 of Cycles 1, 3, and 5; 
predose (within 180 minutes), 30 minutes after the start of infusion (±5 minutes), immediately 
after the end of infusion (within 5 minutes), and 30 (±5), 60 (±5), 90 (±5), 120 (±10), and 
*240 (±10) minutes after the end of infusion.  [*Only collected in Cycle 1]
As to subjects who start administrations of the study drug after 6 subjects continued the treatment for 
at least 5 cycles, blood samples for population PK analysis will be collected at the following
timepoints.
Day 1 of Cycles 1, 3, 5, and 8; 
predose (within 180 minutes), immediately after the end of infusion (within 5 minutes), 60 to 
180 minutes after the end of infusion.
Immunogenicity (anti-E7777 antibody, anti-IL-2 antibody, and neutralizing activity of anti-E7777
antibody):
Blood samples (3 samples each timepoint) will be collected at the following timepoints.
Day 1 of Cycles 1, 2, 3, 5, and 8; predose (within 180 minutes).
At the discontinuation or completion of the study drug.
Serum sIL-2R and LDH:
Blood samples will be collected at the following timepoints.
Day 1 of Cycles 1, 2, 3, 5, and 8; predose (within 180 minutes).
At the discontinuation or completion of the study drug.
T-cell subsets:
Blood samples will be collected at the following timepoints.
Cycles 1 and 2; predose (within 180 minutes) on Day 1, and on Days 8 and 15,
Cycles 3, 5, and 8; predose (within 180 minutes) on Day 1.
At the discontinuation or completion of the study drug.
Central disease diagnosis, the rate of CD25+ cells in tumor, and CCR4 expression by IHC:
For the evaluation of disease diagnosis by a central pathologist, measurement of the rate of CD25+ 
cells in tumor, and confirmation of CCR4 expression, tumor samples (fixed with formalin and 
embedded with paraffin) collected before the study drug administration will be submitted to the 
central measurement laboratory by the last observation. The submitted tumor samples may be used 
for the development of the diagnostic agent of E7777.
The disease diagnosis judged by the central pathological diagnosis committee will have priority, 
when it is different from the result of the investigational site.


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Number of Subjects
Total of 35 patients with relapsed or refractory PTCL and CTCL (at least 6 patients in CTCL).
Inclusion Criteria
1.
Patient with histological diagnosis of PTCL or CTCL as follows.

Peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS)

Angioimmunoblastic T-cell lymphoma (AITL)

Anaplastic large cell lymphoma, ALK positive (ALCL-ALK+)

Anaplastic large cell lymphoma, ALK negative (ALCL-ALK–)

Enteropathy-associated T-cell lymphoma (EATL)

Hepatosplenic T-cell lymphoma (HSTL)

Mycosis fungoides (MF)

Sézary syndrome (SS)

Primary cutaneous CD30＋T-cell lymphoproliferative disorders

Subcutaneous panniculitis-like T-cell lymphoma

Primary cutaneous γδT-cell lymphoma

Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma

Primary cutaneous CD4+ small/medium T-cell lymphoma
2.
Patient who has measurable lesion.
a. As to patients with PTCL, who have the lesion as all of below

Lymph node or extranodal lesion diagnosed as lymphoma by CT scan.

Clearly measurable in 2 orthogonal ways by CT scan.

≥1.5 cm in long axis or >1.0 cm in short axis, when long axis were <1.5 cm by CT scan.
b. As to patients with CTCL, who have the disease as skin lesion (patch, plaque, or tumor)
3.
Patient who has previous systemic chemotherapy (except monotherapy of corticosteroid,
psoralen and ultraviolet A [PUVA] therapy, interferon, and retinoid).
4.
As to patient with CD30+ anaplastic large cell lymphoma, who has received previous therapy of 
brentuximab vedotin or inappropriate for the drug.
5.
Patient who was PD or did not respond (CR or PR) during systemic chemotherapy, or who 
relapsed or progressed after systemic chemotherapy.
6.
Patient who can provide tumor samples for central review of disease diagnosis and CD25+ cell
expression.
7.
Patient with Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1.
8.
Patient with life expectancy of ≥3 months from starting study drug.
9.
Patient with no carry-over of adverse events with ≥Grade 2 of the prior treatment that may affect 
the safety evaluation of the investigational drug (excluding alopecia).
10. Patient with adequate renal function as below:

Serum creatinine ≤1.5×upper limit of normal (ULN).
11. Patient with adequate liver function as below:

Total bilirubin ≤1.5×ULN

Serum albumin ≥3.0 g/dL (confirm 2 weeks later from dosage of albumin product)


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
AST or ALT ≤3.0×ULN
12. Patient with adequate bone marrow function as below:
(confirm 2 weeks or later from last administration of granulocyte colony-stimulating factor 
[G-CSF] and blood transfusion)

Absolute neutrophil count ≥1.5×103/μL (1.5×109/L)

Platelet count ≥7.5×104/μL

Hemoglobin ≥8.0 g/dL
13. Patient who can be hospitalized from Days 1 to 8 of Cycle 1.
14. Male and female patient ≥20 years of age at the time of informed consent.
15. Patient who has provided written consent to participate in the study.
Exclusion Criteria
1.
Patient with central nerves invasion with clinical symptoms or which requires treatment.
2.
Patient with active infection requiring treatment.
3.
Patient with history of treatment with denileukin diftitox.
4.
Patient with history or plan to perform treatment below by starting study drug treatment.
a.
Blood transfusion, albumin product, G-CSF: within 2 weeks
b.
Chemotherapy including corticosteroid use (except continuous use of low amount [as equal as 
prednisolone 10 mg/day or low] before informed consent) as antitumor therapy, radiotherapy, 
electron beam therapy, photochemotherapy, systemic retinoid, interferon and histone 
deacetylase (HDAC) inhibitor: within 4 weeks
c.
Antibody therapy as antitumor therapy: within 12 weeks
5.
Patient who participates in other clinical study or ≤4 weeks from last administration of study
drug (≤12 weeks in case of antibody).
6.
Patient with serious complications or histories as below:
a.
History of myocardial infarction within 6 months before informed consent.
b.
Concurrent cardiac diseases require the treatment, such as ischemic heart disease and
arrhythmias etc.
c.
Complications of hepatic cirrhosis.
d.
Complications of interstitial pneumonia or pulmonary fibrosis.
e.
Complications of clinically significant bleeding events (eg, cerebral hemorrhage) or thrombotic 
events (eg, pulmonary embolism).
7.
Patient who has clinical abnormality in electrocardiography such as remarkable prolongation of
QT/QTc (eg, more than 500 ms in repeated measurements).
8.
Patient with history of hypersensitivity to protein therapeutics.
9.
Patient who is positive for HIV antibody, HCV antibody, or HBs antigen. Patient who is
positive for HBs or HBc antibody and showing DNA more than sensitivity in HBV-DNA assay.
10. Patient with malignancy of activity other than PTCL or CTCL within 36 months before informed 
consent (except treated non-invasive melanoma, basal cell carcinoma of the skin or squamous 
cell carcinoma, intraepithelial carcinoma such as uterine cervix).
11. Woman of childbearing potential or man of impregnate potential who do not agree to use a
medically effective method for contraception for periods from before informed consent to during 
the clinical trial and 30 days later from last administration of study drug.


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12. Woman with pregnant or breastfeeding.
13. Patient with allogeneic stem cell transplantation.
14. Patient with ≤6 months from autologous stem cell transplantation by starting study drug
treatment.
15. Patient who was decided as inappropriate to participate in the study by the investigator or
subinvestigator
Study Treatment(s)
E7777 (9 μg/kg/day) will be intravenously infused in 60 minutes (±10 minutes) once daily from 
Days 1 through 5 of each cycle in maximum of 8 cycles. Every cycle consists of 3 weeks.
Premedication:
The following premedication will be provided within approximately 120 minutes (within 
approximately 30 to 60 minutes for oral drugs) before infusion of E7777. 
The premedication must be provided in Cycles 1 to 3, but premedication in Cycle 4 and subsequent 
cycles may be omitted at the discretion of the investigator or subinvestigator.
Investigator or subinvestigator may use appropriate usage or dose, if they consider the same effect to 
be expected.  If adverse events occurred, the premedication regimen can be changed appropriately 
(eg. increase the dose, change drugs).

Acetaminophen: 500 mg, orally

Diphenhydramine: 20 mg, d-chlorpheniramine 5 mg, or chlorpheniramine 10 mg, 
intravenously

Dexamethasone: 4 to 8 mg, intravenously

An antiemetic agent according to the clinical practice of each investigational site.
Also, following procedures will be provided before and after E7777 administration.

Before and after each infusion of E7777, 250 to 500 mL of physiological saline (or an 
intravenous fluid preparation selected by the investigator or subinvestigator) will be 
intravenously infused.

For patients at risk for tumor lysis syndrome, prophylactic treatment (treatment of allopurinol
or rasburicase and intravenous fluids, etc.) should be considered.
Dose interruption criteria:
Administration of E7777 will be skipped on that day if ≥Grade 3 toxicity related to drug (except 
lymphopenia, Grade 3 abnormal electrolyte, or other abnormal clinical test result judged as not 
clinically significant) is observed before E7777 administration during Days 2 to 5. E7777 
administration may be interrupted if judged to be appropriate by investigator or subinvestigator.
To resume the E7777 administration at a later date, the tests related to the reason of dose-skipping
should be performed and recovery to ≤Grade 2 must be confirmed. Same dosage is allowed to 
resume administration in such case.
Criteria for initiating next cycle:
If any of the toxicities related to the study drug in below is observed, initiation of the next cycle must 
be postponed.

Serum albumin <3.0 g/dL

AST or ALT >3.0×ULN


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
Total bilirubin >1.5×ULN

≥Grade 3 toxicity (except lymphopenia, Grade 3 abnormal electrolyte, or the other abnormal 
clinical test result judged as not clinically significant)
Investigator or subinvestigator may postpone the initiation of next cycle by their own discretion. The 
initiation of the next cycle can be postponed for a maximum of 21 days after the planned date of 
administration.
Dose reduction criteria:
If a subject meets any of the criteria below, the dosage of E7777 must be decreased to 6 μg/kg/day. 
Dose increase is not allowed after the reduction.

Could not start next cycle at planned schedule (in principle, Day 22 of the previous cycle) in 
2 consequent cycles by the toxicity related to the study drug.

Investigator or subinvestigator considers that the dose reduction is needed.
The treatment will be discontinued if the subject meets the criteria above after the dose reduction. 
However, the continuous administrations of 6 μg/kg/day will be allowed, if the response is observed 
in the treatment period and the investigator or subinvestigator judges that the continuation of study 
drug treatment is possible and clinically valuable. 
Duration of the Study
Pretreatment Phase:
Informed consent and screening: within 28 days before starting the study drug administration
Baseline: within 7 days before starting the study drug administration
Treatment Phase:
Until meeting any of “Discontinuation criteria for each subject” or completion of Cycle 8 (ie, Cycle 8
Day 21).
The evaluations at discontinuation (or completion) will be performed within 7 days after 
discontinuation or completion of study treatment.
Follow-up Phase:
The final observation will be performed on 30 days (+7 days) after the last dose of E7777.
In the case of starting treatment of other antitumor drug before the final observation, the data 
collected within 7 days before starting the next antitumor drug can be used as the final observation 
data.  Tumor evaluation (except the case of discontinuation by disease progression and starting 
treatment of next antitumor drug) and survival investigations will be continued, unless the subject 
withdraws the informed consent or the sponsor determines to stop the investigation.
Discontinuation criteria for each subject:
1.
Disease progression (PD) is observed.
2.
A life-threatening, serious adverse event is observed. 
3.
The study treatment cannot be resumed within 21 days after the scheduled date of administration 
of E7777 (in principle, Day 22 of the previous cycle).
4.
The subject meets the discontinuation criterion specified in the dose reduction criteria. 
However, the continuous administrations of 6 μg/kg/day will be allowed, if the response is
observed in the treatment period and the investigator or subinvestigator judges that the 
continuation of study drug treatment is possible and clinically valuable.


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5.
The subject becomes pregnant or the partner of male subject desires pregnancy.
6.
The subject ascertained as inappropriate after the registration (possibilities of continuation of 
treatment will be discussed with the sponsor as needed).
7.
The subject wishes to decline participation in the study or withdraws consent.
8.
The subject cannot comply with the protocol-specified procedures, and the investigator or 
subinvestigator judges inappropriate to continue the study to maintain safety for the subject.
9.
The investigator or subinvestigator judges appropriate to discontinue the study for the subject by 
any other reason.
Concomitant Drug/Therapy
Concomitant use of chemotherapies (including corticosteroids), immunotherapies, radiotherapies, and 
other antitumor therapies are prohibited.
However, the use of topical corticosteroid (external use) or systemic use of low amount corticosteroid 
(equivalent to ≤ 10 mg/day prednisolone) is allowed, if it has been contentiously used before the 
study treatment and where the investigator or subinvestigator judged necessary to continue the drug. 
It is allowed to use drugs (other than antitumor drugs) intended to alleviate skin symptoms. 
Concomitant use of any other study drug is prohibited.
Assessments
Efficacy:
For antitumor activity, investigator or subinvestigator will evaluate overall response and best overall 
response (the best response among all timepoints) from the result of tumor lymph node (nodal lesion), 
non-lymph node tumor in viscera (extranodal lesion), liver/spleen enlargement, and bone marrow 
infiltration according to “Revised response criteria for malignant lymphoma (Cheson, et al., 2007)”, 
and skin lesion, peripheral blood lesion according to “Clinical endpoints and response criteria in 
mycosis fungoides and Sézary syndrome (Olsen, et al., 2011)”. Central review will be conducted by 
the Imaging Review Committee for nodal and extranodal lesions.  In addition, overall responses and 
the best overall response will be determined by the Efficacy and Safety Evaluation Committee based 
on the nodal and extranodal lesions reviewed by the Imaging Review Committee and responses on 
liver/spleen enlargement, bone marrow infiltration, skin lesion, and peripheral blood lesion evaluated 
by the investigator or subinvestigator. 
Primary endpoint of the study is ORR (rate of subjects whose best overall response is CR or PR) 
judged by the Efficacy and Safety Evaluation Committee.
The items below judged by efficacy judgement committee (except OS) are the secondary endpoint.

PFS:
Defined as the term between the date of administration of the first dose of the study drug and 
the date of the first event (PD or death whatever the reason is). The detail of the censoring 
rule for PFS will be described in the statistical analysis plan (SAP).

DOR:
Defined as the term between the date of confirmation of the first response and the date of 
confirmation of the PD. The detail of the censoring rule for DOR will be described in the 
SAP.

TTR:
Defined as the term between the date of administration of the first dose of the study drug and 
the date of confirmation of the first response.


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
CR rate:
Defined as the rate of subjects whose best overall response is CR.

OS:
Defined as the term between the date of administration of the first dose of the study drug and 
the date of death whatever the reason is. The subject who is not confirmed to die will be 
censored at the early date of either last confirmation of alive or at the cut-off date of the 
study.
Addition to the evaluation of the overall response described above, the efficacy according to 
“Revised response criteria for malignant lymphoma” for PTCL and “Clinical endpoints and response 
criteria in mycosis fungoides and Sézary syndrome” for CTCL will be evaluated and summarized. 
Pharmacokinetics (PK):
E7777 PK profile will be evaluated by serum concentration-time curves. 
Immunogenicity:
Anti-E7777 antibody, anti-IL-2 antibody, and neutralizing activity of anti-E7777 antibody in serum 
will be evaluated by qualitative analyses.
Pharmacodynamics (PD):
Serum sIL-2R and LDH will be explored.
PK/PD:
Not applicable.
Safety:
Safety evaluations will include: all adverse events (AEs), serious adverse events (SAEs), the results 
of hematological and biochemical examinations and urinalysis, ophthalmological test, vital signs, and 
electrocardiographic (ECG) findings obtained on a regular basis. Safety will be evaluated in 
accordance with the CTCAE v4.03.
IHC:
The CD25 positive cell rate and CCR4 expression in tumor will be measured for subjects with tumor 
tissue to be available.
T-cell subsets:
Subsets of T-cells in peripheral blood will be measured (actual counts and ratios of T-cells with 
CD4+, CD4+/CD25+, CD4+/CD25+/Foxp3+, CD4+/CD7–*, CD4+/CD26–*).
*Only for MF and SS
Bioanalytical Methods
Serum concentrations of E7777 will be measured by using a validated bioanalytical method.
Anti-E7777 antibodies, anti-IL-2 antibodies, and neutralizing activities of anti-E7777 antibody will 
be detected.


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Statistical Methods
The cut-off date of the study analyses will be the earlier date of either all subjects have discontinued 
or completed Cycle 8 of the study, or the best overall response of all subjects on treatments are
confirmed to be PR or better. All statistical analyses will be performed after the database is locked 
and released.
Analysis sets:
Full Analysis Set (FAS):
Defined as the group of subjects who registered in this study and received at least 1 dose of study 
drug.  This group will be the population for the evaluation of efficacy. 
Safety Analysis Set:
Defined as the group of subjects who received at least 1 dose of study drug and had at least 1 
evaluable post-baseline safety data.  This group will be the population for the evaluation of safety.
Pharmacokinetics Analysis Set:
Defined as the group of subjects who received at least 1 dose of study drug and had at least 1 
evaluable serum concentration data.
Pharmacodynamics Analysis Set:
Defined as the group of subjects who received at least 1 dose of study drug and had at least 1 each of 
evaluable pre- and post-baseline PD data.
Efficacy Analyses:
FAS will be the primary analysis population. All efficacy results will be summarized for each 
disease (PTCL, CTCL) and overall.
Primary Efficacy Analyses:
The rate of subjects whose best overall response is CR or PR is calculated as ORR, and its 
corresponding 2-sided exact 95% CI is also calculated. 
Secondary Efficacy Analyses:

Analysis of PFS
PFS will be summarized by Kaplan-Meier method using median with 95%CI. 

Analysis of DOR
DOR will be summarized by Kaplan-Meier method using median with 95% CI in responders. 

Analysis of TTR
TTR will be summarized by Kaplan-Meier method using median with 95% CI in responders. 

Analysis of CR rate
The number and percentage of subjects whose best overall response and its corresponding 
2-sided exact 95% CI will be provided.

Analysis of OS
OS will be summarized by Kaplan-Meier method using median with 95%CI.
Pharmacokinetic/Pharmacodynamic Analyses:
Pharmacokinetic Analyses:


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Plots of E7777 serum concentration versus actual time will be displayed for those samples collected 
for non-compartmental analysis.  PK parameters (including but not limited to the followings) will be 
derived by non-compartmental analysis of the serum concentration data;
Maximum observed concentration (Cmax), time at which the highest drug concentration occurs (tmax), 
area under the concentration-time curve (AUC), terminal elimination phase half-life (t1/2), volume 
of distribution at terminal phase (Vz), and total clearance (CL)
E7777 serum concentrations for population PK analyses will be listed.
Serum E7777 concentration data from this study and other studies will be integrated and used to build 
PK models to explain the observed concentration data using population approach.  Additionally, the 
models may be used to explore the relationship between PK and select demographic variables.  The 
relationship between PK parameters and efficacy/AE endpoints will also be investigated through 
population PK/PD modeling.  For population PK and PK/PD analysis, the details will be described in 
the separately prepared analysis plan and its report, and the results will not be included in the clinical 
study report.
Immunogenicity:
The measurement value will be listed for anti-E7777 antibody, anti-IL-2 antibody, and neutralizing 
activity of anti-E7777 antibody in the Safety Analysis Set.
Pharmacodynamics:
The measurement value (and the change from baseline, if necessary) for each evaluation period will 
be summarized using the number of subjects, mean, SD, median, minimum and maximum for each 
disease (PTCL, CTCL) and overall.  In addition, the individual plot over time will be prepared by 
subject.
Immunohistochemistry:
Frequency and percentage of the classified CD25 + cells rate will be calculated for each disease 
(PTCL, CTCL) and overall in subjects who submitted the tumor sample.
Safety Analysis:
All safety analyses will be performed on the Safety Analysis Set.  The TEAEs will be summarized for 
each disease (PTCL, CTCL) and overall.  TEAEs will also be summarized by system organ class 
(SOC) / preferred term (PT), causality, and severity. With respect to laboratory values, vital signs, 
and ECG parameters measured at each time point and changes from baseline in these parameters, the 
summary statistics, frequency, and incidence will be summarized for each disease (PTCL, CTCL) and 
overall.
Interim Analyses
No interim analysis is planned for this study.
Sample Size Rationale
Thirty-five patients are required to detect lower limit of the 95% confidence interval (CI) that exceed 
the 5% threshold in ORR, which is the primary endpoint of the study, with the expected ORR is 25% 
with a statistical power of 90%. In CTCL, 6 or more patient is targeted to evaluate the safety as 
specific disease.


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3
TABLE OF CONTENTS
1
TITLE PAGE.....................................................................................................................1
2
CLINICAL PROTOCOL SYNOPSIS...............................................................................2
3
TABLE OF CONTENTS.................................................................................................13
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..................................18
5
ETHICS............................................................................................................................20
5.1
Institutional Review Boards...................................................................................20
5.2
Ethical Conduct of the Study.................................................................................20
5.3
Subject Information and Informed Consent...........................................................20
6
INVESTIGATORS AND STUDY PERSONNEL..........................................................21
7
INTRODUCTION ...........................................................................................................22
7.1
Epidemiology and Treatment of the Cutaneous T-cell Lymphoma and 
Peripheral T-cell Lymphoma.................................................................................22
7.1.1
Epidemiology of the Malignant Lymphoma................................................22
7.1.2
Epidemiology of the Cutaneous T-cell Lymphoma (CTCL).......................22
7.1.3
Treatment of the Cutaneous T-cell Lymphoma (CTCL).............................23
7.1.4
Epidemiology of the Peripheral T-cell Lymphoma (PTCL)........................23
7.1.5
Treatment of the Peripheral T-cell Lymphoma (PTCL)..............................24
7.2
Denileukin diftitox（E7777，E7272）................................................................25
7.3
Origin/History of Development and Future Development Plan ............................26
7.4
Study Rationale......................................................................................................27
8
STUDY OBJECTIVES....................................................................................................29
8.1
Primary Objective..................................................................................................29
8.2
Secondary Objectives.............................................................................................29
8.3
Exploratory Objectives ..........................................................................................29
9
INVESTIGATIONAL PLAN..........................................................................................30
9.1
Overall Study Design and Plan..............................................................................30
9.1.1
Pretreatment Phase.......................................................................................30
9.1.1.1
Informed Consent, Screening, and Registration ..................................30
9.1.1.2
Baseline Assessments ..........................................................................31
9.1.2
Treatment Phase...........................................................................................31
9.1.3
Follow-up Phase...........................................................................................31
9.2
Discussion of Study Design, Including Choice of Control Groups.......................31
9.3
Selection of Study Population................................................................................31
9.3.1
Inclusion Criteria .........................................................................................32
9.3.2
Exclusion Criteria ........................................................................................33
9.3.3
Removal of Subjects from Therapy or Assessment.....................................34


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9.3.3.1
Discontinuation Criteria for Each Subject:..........................................34
9.4
Treatments..............................................................................................................35
9.4.1
Treatments Administered.............................................................................35
9.4.1.1
Dose, Dosing Method, and Duration of Dose......................................35
9.4.1.2
Premedication: .....................................................................................35
9.4.1.3
Preparation and Administration of the Study Drug .............................36
9.4.1.4
Control of Infusion Reactions During the Administration ..................36
9.4.1.5
Dose Interruption Criteria....................................................................37
9.4.1.6
Criteria for Initiating Next Cycle.........................................................37
9.4.1.7
Dose Reduction Criteria.......................................................................37
9.4.2
Identity of Investigational Product...............................................................37
9.4.2.1
Chemical Name, Structural Formula of E7777....................................37
9.4.2.2
Comparator Drug .................................................................................38
9.4.2.3
Labeling for Study Drug......................................................................38
9.4.2.4
Storage Conditions...............................................................................38
9.4.3
Method of Assigning Subjects to Treatment Groups...................................38
9.4.4
Selection of Doses in the Study...................................................................39
9.4.5
Selection and Timing of Dose for Each Subject..........................................39
9.4.6
Blinding........................................................................................................39
9.4.7
Prior and Concomitant Therapy...................................................................39
9.4.7.1
Drug-Drug Interactions........................................................................39
9.4.7.2
Prohibited Concomitant Therapies and Drugs.....................................39
9.4.8
Treatment Compliance.................................................................................40
9.4.9
Drug Supplies and Accountability...............................................................40
9.5
Study Assessments.................................................................................................41
9.5.1
Assessments.................................................................................................41
9.5.1.1
Demography.........................................................................................41
9.5.1.2
Assessments in the Pretreatment Phase ...............................................41
9.5.1.2.1
Medical History and Physical Examinations.................................41
9.5.1.3
Efficacy Assessments...........................................................................42
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments.............................................................44
9.5.1.4.1
Measurements of Drug Concentrations .........................................44
9.5.1.4.2
Immunogenicity (Anti-E7777 Antibody, Anti-IL-2 Antibody 
and Neutralizing Activity of Anti-E7777 Antibody).....................45
9.5.1.4.3
Measurements of Pharmacodynamics and Other Biomarkers.......46
9.5.1.5
Safety Assessments..............................................................................47
9.5.1.5.1
Adverse Events ..............................................................................47


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9.5.1.5.2
Serious Adverse Events and Events Associated with Special 
Situations........................................................................................49
9.5.1.5.3
Infusion Reactions .........................................................................50
9.5.1.5.4
Laboratory Measurements .............................................................50
9.5.1.5.5
Vital Signs, Weight, and Height Measurements............................51
9.5.1.5.6
Physical Examinations...................................................................51
9.5.1.5.7
ECOG-PS.......................................................................................52
9.5.1.5.8
Electrocardiograms ........................................................................52
9.5.1.5.9
Ophthalmological Examinations....................................................52
9.5.1.5.10
Pregnancy Tests .............................................................................52
9.5.1.5.11
Viral Tests......................................................................................52
9.5.1.6
Assessments on Treatment Compliance ..............................................52
9.5.1.7
Assessments of Prior and Concomitant Therapy.................................52
9.5.2
Schedule of Procedures/Assessments ..........................................................53
9.5.3
Appropriateness of Measurements...............................................................56
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations..............................................................56
9.5.4.1
Reporting of Serious Adverse Events..................................................56
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding .......................................................................................56
9.5.4.3
Reporting of Events Associated with Special Situations.....................57
9.5.4.3.1
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, or Medication Error.........................................57
9.5.4.4
Expedited Reporting ............................................................................57
9.5.4.5
Breaking the Blind...............................................................................58
9.5.4.6
Regulatory Reporting of Adverse Events ............................................58
9.5.5
Completion/Discontinuation of Subjects.....................................................58
9.5.6
Abuse or Diversion of Study Drug ..............................................................58
9.5.7
Confirmation of Medical Care by Another Physician .................................58
9.6
Data Quality Assurance .........................................................................................58
9.6.1
Data Collection ............................................................................................59
9.6.2
Clinical Data Management ..........................................................................59
9.7
Statistical Methods.................................................................................................59
9.7.1
Statistical and Analytical Plans....................................................................59
9.7.1.1
Study Endpoints...................................................................................59
9.7.1.1.1
Primary Endpoint...........................................................................59
9.7.1.1.2
Secondary Endpoints .....................................................................59
9.7.1.1.3
Exploratory Endpoints ...................................................................60


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9.7.1.2
Definitions of Analysis Sets.................................................................60
9.7.1.3
Subject Disposition..............................................................................60
9.7.1.4
Demographic and Other Baseline Characteristics ...............................60
9.7.1.5
Prior and Concomitant Therapy...........................................................60
9.7.1.6
Efficacy Analyses ................................................................................61
9.7.1.6.1
Primary Efficacy Analysis.............................................................61
9.7.1.6.2
Secondary Efficacy Analyses ........................................................61
9.7.1.6.3
Exploratory Efficacy Analyses ......................................................61
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses...................................................................61
9.7.1.7.1
Pharmacokinetic Analyses.............................................................61
9.7.1.7.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses.........................................................................................62
9.7.1.8
Safety Analyses....................................................................................62
9.7.1.8.1
Extent of Exposure.........................................................................62
9.7.1.8.2
Adverse Events ..............................................................................62
9.7.1.8.3
Laboratory Values..........................................................................63
9.7.1.8.4
Vital Signs......................................................................................64
9.7.1.8.5
Electrocardiograms ........................................................................64
9.7.1.8.6
Other Safety Analyses....................................................................64
9.7.2
Determination of Sample Size .....................................................................64
9.7.3
Interim Analysis...........................................................................................64
9.7.4
Other Statistical/Analytical Issues ...............................................................64
9.7.5
Procedure for Revising the Statistical Analysis Plan...................................65
10
REFERENCE LIST .........................................................................................................66
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).......69
11.1
Changes to the Protocol .........................................................................................69
11.2
Adherence to the Protocol......................................................................................69
11.3
Monitoring Procedures...........................................................................................69
11.4
Recording of Data..................................................................................................70
11.5
Identification of Source Data.................................................................................70
11.6
Retention of Records..............................................................................................70
11.7
Auditing Procedures and Inspection......................................................................71
11.8
Handling of Study Drug.........................................................................................71
11.9
Publication of Results ............................................................................................71
11.10 Disclosure and Confidentiality ..............................................................................72
11.11 Discontinuation of Study .......................................................................................72
11.12 Subject Insurance and Indemnity...........................................................................72


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LIST OF IN-TEXT TABLES
Table 1
Timepoints for Drug Concentration Measurements (For until 6 
Subjects Continued at Least 5 Cycles).......................................................45
Table 2
Timepoints for Drug Concentration Measurements (For after 6 
Subjects Continued at Least 5 Cycles).......................................................45
Table 3
Timepoints for Serum Antibodies and Neutralizing Activities .................46
Table 4
Timepoints for sIL-2R and LDH Measurements.......................................46
Table 5
Timepoints for T-cell Subsets Measurements............................................47
Table 6
Clinical Laboratory Tests...........................................................................51
Table 7
Schedule of Procedures/Assessments ........................................................54
LIST OF IN-TEXT FIGURES
Figure 1
Mechanism of Action for E7777 and E7272 .............................................26
Figure 2
Outline of the Study Design.......................................................................30


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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
ADP
adenosine diphosphate
AE
adverse event
AITL
angioimmunoblastic T-cell lymphoma
Ala
alanine 
ALCL
anaplastic large cell lymphoma
ALK
anaplastic lymphoma kinase
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the serum concentration-time curve
BUN
blood urea nitrogen
Ca
calcium
CCR4
CC chemokine receptor 4
CD122
β-chain, subunit of the IL-2R
CD132
γ-chain, subunit of the IL-2R
CD25
α-chain, subunit of the IL-2R
CHOP
CHOP therapy
CI
confidence interval
CL
total clearance
Cl
chloride
Cmax
maximum observed serum concentration
CR
complete response
CRF
case report form
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTCL
cutaneous T-cell lymphoma
DOR
duration of response
ECOG
Eastern Cooperative Oncology Group
GCP
Good Clinical Practice
G-CSF
granulocyte-colony stimulating factor
HBc
hepatitis B virus core
HBs
hepatitis B virus surface
HBV
hepatitis B virus
HCV
hepatitis C virus
His
histidine
HIV
human immunodeficiency virus
HL
Hodgkin’s lymphoma


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Abbreviation
Term
ICH
International Conference on Harmonisation
IL-2(R)
interleukin-2 (receptor)
K
potassium
LDH
lactate dehydrogenase
MedDRA
Medical Dictionary for Regulatory Activities
Met
methionine
MF
mycosis fungoides
Na
sodium
NHL
non-Hodgkin's lymphoma
ORR
objective response rate
OS
overall survival
PET
positron emission tomography
PFS
progression-free survival
PR
partial response
PS
performance status
PT
preferred term
PTCL
peripheral T-cell lymphoma
QTc(F)
QT interval corrected for heart rate (using Fridericia’s formula)
SAE
serious adverse event
SAS
statistical analysis system
SD
stable disease
sIL-2R
soluble interleukin-2 receptor
SOC
system organ class
SOP
standard operating procedures
SS
Sézary syndrome
t1/2
terminal phase half-life
TEAEs
treatment-emergent adverse events
Thr
threonine
tmax
time at which the highest drug concentration occurs
Treg
regulatory T-cell
TTR
time to response
ULN
upper limit of normal
VZ
volume of distribution at terminal phase
WHO DD
World Health Organization Drug Dictionary


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5
ETHICS
5.1
Institutional Review Boards
The protocol, informed consent form (ICF), and appropriate related documents must be 
reviewed and approved by an Institutional Review Board (IRB) constituted and functioning 
in accordance with Good Clinical Practice (GCP).  Any protocol amendment or revision to 
the ICF will be resubmitted to the IRB for review and approval, except for changes involving 
only logistical or administrative aspects of the study (eg, change in CRA[s], change of 
telephone number[s]).  Documentation of IRB compliance with the GCP regarding 
constitution and review conduct will be provided to the sponsor.
A signed letter of study approval from the IRB chairman must be sent to the head of the 
medical institution with a copy to the sponsor before study start and the release of any study 
drug to the site by the sponsor or its designee.  If the IRB decides to suspend or terminate the 
study, the head of the medical institution will immediately send the notice of study 
suspension or termination by the IRB to the sponsor.
Study progress is to be reported to IRBs annually (or as required) by the investigator via the 
head of the medical institution according to GCP.  The investigator(s) or the sponsor will 
submit, depending on local regulations, periodic reports and inform the investigator and the 
relevant IRB via the head of the medical institution of any reportable adverse events (AEs) 
per GCP guidelines and local IRB standards of practice.  Upon completion of the study, the 
investigator will provide the IRB and sponsor via the head of the medical institution with a 
brief report of the outcome of the study.
5.2
Ethical Conduct of the Study
This study will be conducted in accordance with standard operating procedures of the 
sponsor (or designee), which are designed to ensure adherence to GCP guidelines as required 
by the following:

Principles of the World Medical Association Declaration of Helsinki (Ethical Principles 
for Medical Research Involving Human Subjects)

GCP
5.3
Subject Information and Informed Consent
As part of administering the informed consent document, the investigator must explain to 
each subject 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.


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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. It will be confirmed that the 
subject has signed an informed consent before any tests or assessments relating to the study 
are performed (ie, before starting the screening).  No subject can enter the study before 
his/her informed consent has been obtained.
An unsigned copy of an IRB-approved ICF must be prepared in accordance with GCP and all 
applicable local regulations.  Each subject must sign an approved ICF before study 
participation.  The form must be signed and dated by the investigator or subinvestigator (and 
clinical research coordinator, if needed).  The original, signed ICF for each subject will be 
verified by the sponsor and kept on file according to local procedures at the site. 
The subject should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the study.  The 
communication of this information should be documented.
6
INVESTIGATORS AND STUDY PERSONNEL
This study will be conducted by qualified investigators under the sponsor at approximately 
18 investigational sites in Japan.
The name and telephone and fax numbers of the sponsor are listed in the Attachment.


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7
INTRODUCTION
7.1
Epidemiology and Treatment of the Cutaneous T-cell Lymphoma 
and Peripheral T-cell Lymphoma
7.1.1
Epidemiology of the Malignant Lymphoma
According to the Ministry of Health, Labor and Welfare Ministry’s 2011 patient survey, the 
total number of patients with malignant lymphoma in Japan was about 55000 per year.  
According to the “Monitoring of Cancer Incidence in Japan (2011)” of the National Cancer 
Center, Center for Cancer Control and Information Services, the number of incidence was 
reported to be about 24000 per year.
Malignant lymphoma is classified into various diseases depending on the surface antigen and 
morphological characteristics of tumor cells, and prognosis prediction and treatment method 
are different between the segmented diseases. Malignant lymphoma is classified into 
Hodgkin’s lymphoma (HL) and non-Hodgkin’s lymphoma (NHL).  Cutaneous T-cell 
lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL), the targets of E7777, are very 
rare diseases classified as the NHL (Vose, et al., 2008).
7.1.2
Epidemiology of the Cutaneous T-cell Lymphoma (CTCL)
CTCL is a T-cell derived NHL with the main lesion in skin and includes Mycosis fungoides 
(MF) and Sézary syndrome (SS) as major diseases.  The most frequent disease is MF, 
according to the Ministry of Health, Labor and Welfare Ministry’s 2011 patient survey, the 
number of patients with MF (as C84.0: Mycosis fungoides) was about 1000.  The number of 
patients with SS (as C84.1: Sézary syndrome) was reported to be less than 1000.  Also, 
according to a report on domestic frequencies of malignant lymphoma by disease 
classification, the proportion of MF and SS in malignant lymphoma was about 0.5% to 1% 
(Lymphoma Study Group of Japanese Pathologists, 2000; Aoki, et al., 2008), the total 
number of patients is from 275 to 500, and the number of incidence is considered to be 110 
to 220 per year.  Furthermore, according to “the results of case survey for skin lymphoma in 
2013”, the cumulative number of patients registered as MF or SS for 7 years was 1138 
patients (163 patients per year) (the Japanese Skin Cancer Society, 2013). Based on these 
reports, the number of CTCL patients is estimated to be about 1500 at the maximum and the 
number of incidence is less than 300 per year.
The prognosis of patients with MF and SS, the major diseases of CTCL, varies with stage.  
The 5-year survival rate was reported to be 94% and 84% in IA and IB (erythema stage), 
respectively, 78% and 47% in IIA and IIB (squamous infiltration stage), respectively, 47% 
and 40% in IIIA and IIIB (tumor stage), and 37%, 18%, and 18% in IVA1, IVA2, and IVV 
(visceral infiltration stage), respectively, and the prognosis of CTCL with IIB or later stage 
was reported to be particularly poor (Agar, et al., 2010).  Thus delaying disease progression 
by treatment is clinically meaningful.  As CTCL often shows symptoms of pain and/or 
pruritus, treatment not only improves prognosis but also improves quality of life is important.


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7.1.3
Treatment of the Cutaneous T-cell Lymphoma (CTCL)
Different treatment option is chosen depending on the stage of CTCL (Japanese Skin Cancer 
Society and Japanese Dermatological Association, 2010).  For early stages of MF (stage IA, 
IB, or IIA), local therapy such as external use of steroids, ultraviolet irradiation therapy, local 
radiation therapy, etc. is performed, however if it does not respond to local therapy, 
biological response modifiers (BRM) treatment including etretinate (not approved for CTCL
in Japan) and interferon and chemotherapy are considered.  For later stages of MF (stage IIB 
or later), electron beam irradiation therapy, radiation therapy, BRM treatment, and/or 
chemotherapy is selected.
Chemotherapy for CTCL is selected from drugs with indications of malignant lymphoma, but 
their effects are limited.  The duration of response of the combination therapy including 
doxorubicin was reported to be within 6 months in later stage of MF (Grozea, et al., 1979) 
and that of the recurrent or refractory MF or T-cell lymphoma with skin infiltration was 
reported to be within 15 months (Zinzani, et al., 2000).  Also, the molecular targeted drugs 
that have indications for CTCL are only vorinostat (histone deacetylase inhibitor) and 
mogamulizumab (anti-CCR4 antibody) in Japan, and the indication of mogamulizumab is 
limited to CCR4-positive CTCL.
In the National Comprehensive Cancer Network (NCCN) guidelines in the United States 
(US), treatment methods similar to those in Japan are generally recommended.  Interferon, 
retinoid, and deacetylase inhibitors are recommended as systemic drug treatment, although 
IFN-α, bexaroten, and romidepsin have not been approved in Japan.
Denileukin diftitox was recommended for drug treatment of CTCL (NCCN, 2012), but the 
description of denileukin diftitox has been deleted from V.1.2013 (NCCN, 2013) after it 
stopped marketing of denileukin diftitox (ONTAK®) in the US.*
As described above, the outcome of treatment for CTCL is not sufficient and the treatment 
options are limited in Japan compared with the US, so development of a new treatment 
method is required.
*Since the manufacturing company Lonza’s Hopkinson factory (Massachusetts, the US) was 
closed after GMP warning letter was issued from the FDA to the factory. 
7.1.4
Epidemiology of the Peripheral T-cell Lymphoma (PTCL)
PTCL is classified in NHLs, which derived from rear thymus originated T-cell.  According to 
the Ministry of Health, Labor and Welfare Ministry’s 2011 patient survey, the number of 
patients was reported to be less than 1000 and about 1000 in C84.4 (peripheral T-cell 
lymphoma) and C84.5 (other/unknown T-cell lymphoma), respectively.  
Also, according to a report on domestic frequencies of malignant lymphoma by disease 
classification, the proportion of PTCL-not otherwise specified (PTCL-nos), 
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(ALCL) in malignant lymphoma is about 10% to 11% (Lymphoma Study Group of Japanese 
Pathologists, 2000; Aoki, et al., 2008).  According to Section 7.1.1 “Epidemiology of the 
Malignant Lymphoma” and these reports, the total number of PTCL patients (excluding adult 
T-cell leukemia/lymphoma) is estimated to be about 5500 to 6000, and the number of 
incidence is estimated to be about 2200 to 2400 patients per year. 
The 5-year survival rate of PTCL is 32% for the major disease of PTCL nos and AITL, and 
49% for ALK negative (ALK–) ALCL.  It is reported that the prognosis of PTCL is generally 
poor, except 70% for ALK positive (ALK+) ALCL (Vose, et al., 2008).
7.1.5
Treatment of the Peripheral T-cell Lymphoma (PTCL)
In Japan, clinical practice guideline for hematologic malignancies including PTCL are issued
(the Japanese Society of Hematology, 2013) according to NCCN guidelines etc. in the US.  
The standard primary treatment of PTCL is combination chemotherapy including CHOP 
therapy (cyclophosphamide, doxorubicin, vincristine, and prednisolone) for both B-cell and 
T-cell NHL in Japan and other countries (Fisher, et al., 1993)
Primary combination therapy including anthracycline (such as CHOP therapy) respond to 
about 50% of PTCL patients (AbouYabis, et al., 2011), but for patients with relapsing or 
refractory after the first therapy, secondary and subsequent standard treatment have not been 
established. 
Hematopoietic stem cell transplantation will be considered for eligible patients, and treatment 
outcome of autologous hematopoietic stem cell transplantation after chemotherapy for PTCL 
(excluding ALK+ALCL) has been reported as 5-year survival rate of 51% (Yared and 
Kimball, 2013).  There is not enough evidence for allogeneic hematopoietic stem cell 
transplantation and its usefulness is not clear.  As other treatments, combination 
chemotherapies such as ICE therapy (ifosfamide, carboplatin, and etoposide) and GDP 
therapy (gemcitabine, dexamethasone, and cisplatin) and monotherapies as salvage 
chemotherapy are recommended.  However, progression free survival and overall survival of 
patients with relapsed or refractory PTCL were reported to be 3.7 months (median) and 
6.5 month (median), respectively, and it was reported that any treatment did not show 
superiority (Mak, et al., 2013). 
Recently, molecular targeted therapy is also considered, but molecular targeted drugs that 
have indications for relapsed or refractory PTCL are only brentuximab vedotin (limited to 
CD30 positive ALCL) and mogamulizumab (limited to CCR4 positive PTCL) in Japan. 
In the NCCN guidelines in the US, in addition to brentuximab vedotin, other molecular 
targeted drugs (pralatrexate, romidepsin, and belinostat) are recommended as second-line 
therapy for relapsed or refractory PTCL (NCCN, 2015), although those drugs have not been 
approved in Japan.
Denileukin diftitox was recommended for second-line therapy of PTCL which is not 
indicated for hematopoietic stem cell transplantation in the guideline V.3.2012 


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(NCCN, 2012), but the description of denileukin diftitox has been deleted from V.1.2013 
(NCCN, 2013) after it stopped marketing of denileukin diftitox (ONTAK®) in the US.
As described above, the outcome of treatment for PTCL is not sufficient and the treatment 
options are limited in Japan compared with the US, so development of a new treatment 
option is required.
7.2
Denileukin diftitox（E7777，E7272）
Denileukin diftitox (E7777 and E7272) 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 thought to have antitumor activities through specific binding to IL-2 
receptor (IL-2R) on malignant cells.  Once bound to the cell surface, the fusion protein is 
internalized by receptor-mediated endocytosis into an endosomal vesicle where it is cleaved 
by the serine endoprotease furin resulting in release of the diphtheria toxin enzymatic and 
translocation domains from the IL-2 domain.  Upon further cleavage, the enzymatic domain 
separates from the translocation domain, and moves into the cytoplasm, where it catalyzes 
the covalent linkage of ADP-ribose to elongation factor-2, resulting in the inhibition of 
protein synthesis and ultimately cell death (VanderSpek, et al., 1993).
T-cell activation and cellular immune responses are modulated by IL-2 through binding to its 
corresponding cell surface receptor.  These receptors are composed of up to three subunits 
α (CD25), β (CD122), and γ (CD132).  The high affinity receptor is a heterotrimer composed 
of α, β, and γ subunits, the intermidiate affinity receptor is a heterodimer composed of β and 
γ subunits, and the low affinity receptor is a monomer only composed of α subunit.
Antitumor activities of denileukin diftitox are expected on malignant cells with or without 
CD25 expression, since the α subunit is known to upregulate receptor sensitivity to IL2, 
while dimer of β and γ subunits mainly mediates internalization.  Mechanism of action for 
E7777 and E7272 is shown in Figure 1.


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Figure 1
Mechanism of Action for E7777 and E7272
ADP = adenosine diphosphate, DT = diphtheria toxin, IL2 and IL-2 = interleukin 2, and 
IL-2R = interleukin 2 receptor.
Denileukin diftitox is suggested to target and suppress CD4+CD25+Foxp3+ regulatory T  
cells (Treg) in nonclinical and clinical studies (Litzinger, et al., 2007, Morse, et al., 2008).
Tregs are immunosuppressive and when present in the tumor microenvironment can 
contribute to tumor escape from host tumor immune surveillance (Curiel, et al., 2004).  Thus 
suppression of Tregs is also considered to be a potential mechanism of antitumor activities of 
denileukin diftitox.
Efficacy of denileukin diftitox has been shown in 3 Phase 3 studies on CTCL and a Phase 1 
study of PTCL in foreign countries (Olsen, et al., 2001, Prince, et al., 2010, Prince, et al., 
2013, Dang, et al., 2007).
7.3
Origin/History of Development and Future Development Plan
E7272 (ONTAK®) was approved in 1999 by the FDA under the accelerated drug approval 
program for treatment of patients with persistent or recurrent cutaneous T-cell lymphoma 
(CTCL) whose malignant cells express the CD25 component of the IL-2 receptor at the dose 
of 9 or 18 μg/kg/day for 5 consecutive days every 21 days, based on Phase 1/2 study 
(92-04-01) in CTCL, the other NHL and HL, and Phase 3 study (93-04-10) in CTCL patients 
with CD25 positive.  At the time of approval, it is mentioned that granting of this approval is 
contingent upon completion of the placebo-controlled Phase 3 study and submission of the 
results and upon improvement of the purity of the drug product.


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In October 2008, E7272 was fully approved by the FDA based on the results of the 
placebo-controlled Phase 3 study (L4389-11) in CTCL patients with CD25 positive and 
another Phase 3 study (L4389-14) in CTCL patients who are not eligible to the L4389-11 
study (includes CTCL patients with CD25 negative).  However, the issue of low drug purity 
had not been solved yet, E7777, improved purity denileukin diftitox, was to be developed 
and manufactured.
E7777, improved purity denileukin diftitox, has an improved manufacturing process and 
therefore has a higher proportion of active monomer and a lower proportion of protein 
aggregates and misfolded proteins.
Currently, in order to replace E7272 with E7777, single-arm Phase 1/3 study 
(E7777-G000-302) of E7777 in persistent or recurrent CTCL patients with CD25 positive is 
ongoing in the United States and Australia.  The clinically recommended dose of E7777 in 
CTCL patients was determined to be 9 μg/kg/day for 5 consecutive days every 3 weeks based 
on the Lead-in part (Phase 1 part) of the study.
In Japan, Phase 1 study (E7777-J081-101) in CTCL and PTCL patients was completed on 
August 4, 2015, and the recommended dose of E7777 was determined to be 9 μg/kg/day for 5 
consecutive days every 3 weeks, which is the same as above.
7.4
Study Rationale
Since denileukin diftitox had an indication for CD25 positive CTCL in the US, development 
request for persistent or recurrent CTCL with CD25 (a component of IL-2R) positive 
malignant cells was issued in May 2010 from the Ministry of Health, Labor and Welfare 
based on the recommendation as an unapproved and highly required drug in Japan at the 3rd 
conference of evaluation committee on unapproved or off-labeled drugs with high medical 
needs (April 2010).  Also, E7777 has received orphan drug designation for treatment of 
PTCL (June 2011) and CTCL (July 2013) in the US.
Since recommended dosage and dose of E7777 in Japanese patients were determined in the 
domestic Phase 1 study (E7777-J081-101), domestic Phase 2 study in patients with CTCL 
and PTCL (E7777-J081-205) was planned.
No second-line or subsequent treatment has been established as showing prolongation of PFS 
or OS in CTCL or PTCL.  In addition, with the response to the drug, it is expected to lead to 
improve associated symptoms such as pain and pruritus with skin lesions in CTCL (Olsen, et 
al., 2011) and to recovery of B symptoms (fever, night sweat, weight decrease) and to 
improve the results of posttreatment therapy including transplantation of hematopoietic stem 
cell (Gouill, et al., 2008).  Thus the response itself is thought to be clinically meaningful, and 
primary endpoint of this study was determined to be objective response rate (ORR).
The evaluation criteria of this study is the overall response of lesions based on “Revised 
response criteria for malignant lymphoma (Cheson, et al., 2007)” which is the international 
evaluation criteria on NHL including PTCL and “Clinical endpoints and response criteria in 
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evaluation criteria on CTCL.  By using this criteria, the efficacy on both PTCL and CTCL 
patients is thought to be evaluable within the single study.
Both CTCL and PTCL are malignant lymphomas derived from mature T-cells, and 
expression of IL-2R has been reported in mature T-cells.  Since denileukin diftitox 
specifically binds to IL-2R and exerts cytotoxic effects, from the viewpoint of the mechanism 
of action, denileukin diftitox may also be effective in PTCL which is categorized as NHL as 
same as CTCL.
In addition, it is considered that the efficacy of this drug is not limited to CD25 positive cells 
from the viewpoint of the mechanism of action, and certain responses were observed also in 
CD25 negative patients in a foreign clinical study of E7272 (L4389-14) on CTCL patients 
including CD 25 negative ones and a foreign doctor-initiated study in PTCL patients 
(Dang, et al., 2007).  Thus patients with CD25 positive or negative PTCL and CTCL were to 
be eligible for this study.
As the patients eligible to this study are extremely few and standard second-line or later 
therapy has not been established yet, a single-arm clinical study without a control group is 
considered to be sufficient if the treatment group exceeds the 5% threshold in ORR.  
Thirty-five patients are required to detect lower limit of the 95% confidence interval (CI) that 
exceed the 5% threshold in ORR, which is the primary endpoint of the study, with the 
expected ORR is 25% with a statistical power of 90%.  For CTCL, 6 or more patients are 
minimally required to evaluate the safety as specific disease.
With the above reasons, it is reasonable to conduct the planned Phase 2 study 
(E7777-J081-205) which is designed to investigate the efficacy, safety, pharmacokinetics, 
and immunogenicity of E7777 in patients with relapsed or refractory PTCL and CTCL.


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8
STUDY OBJECTIVES
8.1
Primary Objective
To evaluate the efficacy of E7777 with objective response rate (ORR) in patients with 
relapsed or refractory peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma 
(CTCL).
8.2
Secondary Objectives
1. To evaluate the efficacy of E7777 below.

Progression-free survival (PFS)

Duration of response (DOR)

Time to response (TTR)

Complete response (CR) rate

Overall survival (OS)
2. To evaluate the safety of E7777.
3. To evaluate the pharmacokinetics (PK) and immunogenicity (anti-E7777 antibody, 
anti-IL-2 antibody and neutralizing activity of anti-E7777 antibody) of E7777.
8.3
Exploratory Objectives
To preliminarily explore the biomarkers in the tumor and blood below.
1. To measure the rate of CD25+ cells in tumor by immunohistochemistry (IHC).
2. To measure the serum soluble IL-2 receptor (sIL-2) and LDH levels.
3. To measure the T-cell subsets in the peripheral blood.


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9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
E7777-J081-205 study is a multicenter, single arm, Phase 2 study to evaluate efficacy, safety, 
PK, and immunogenicity of E7777 in patients with relapsed or refractory PTCL and CTCL.  
Study design of this study is shown in Figure 2. 
This study will consist of the following 3 phases: Pretreatment, Treatment, and Follow-up 
Phases.  
Figure 2
Outline of the Study Design
9.1.1
Pretreatment Phase
The Pretreatment Phase will include informed consent, screening, registration, and baseline 
assessments.  
9.1.1.1
Informed Consent, Screening, and Registration
Informed consent will be obtained within 28 days before the start of study drug
administration.  Screening assessments will be performed on subject who submitted written 
informed consent to enroll this study.  Subjects who meet all of the inclusion criteria and do 
not meet any of the exclusion criteria will be registered to this study.
Informed consent
Screening
Registration
First dose
Baseline assessments
Treatment Phase (8 cycles)
Pretreatment Phase
≤28 days
≤7 days
E7777 
administrations on 
Days 1 to 5
(3 weeks/Cycle)
Last dose
Discontinuation (Completion)
assessments
Final observation
30 days after 
the last dose
(+7 days)
Follow-up 
Phase
Follow-up assessments
Until meeting any of the 
discontinuation criteria for an 
individual subject or Cycle 8
Day 21


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9.1.1.2
Baseline Assessments
Baseline assessments will be performed within 7 days before the study drug administration.  
Subjects will be confirmed to meet all of the inclusion criteria and not to meet any of the 
exclusion criteria prior to proceed to the Treatment Phase.
9.1.2
Treatment Phase
The Treatment Phase will start from the study drug administration on Cycle 1 Day 1 and will 
last until meeting any of the discontinuation criteria for an individual subject 
(discontinuation) or Cycle 8 Day 21 (completion), as 3 weeks per cycle.  
The evaluations at the discontinuation (completion) will be performed within 7 days after the 
last dose of the study drug.  Subjects who discontinued or completed the study drug 
administration will be proceeded to the Follow-up Phase.  Subjects will be in hospitalized 
during Days 1 to 8 in Cycle 1.
9.1.3
Follow-up Phase
The final observation will be performed on 30 days (+7 days) after the last dose of the study 
drug.  If a subject start receiving a next anti-tumor therapy, etc. before that, any data 
collected within 7 days before starting such therapy can be considered as the final 
observation.  If the evaluations at the discontinuation is to be performed after 30 days of the 
last dose of the study drug, the data can be used as the final observation data.
Tumor evaluations (except PET) will be performed on every 6 to 8 weeks (except the case of 
discontinuation by disease progression or starting treatment of a next antitumor drug) and 
survival investigations on every 12 to 16 weeks from the discontinuation (or completion) of 
the study drug, except where a subject withdraws consent or the sponsor chooses to
discontinue the survival investigations.  In the Follow-up Phase, the information about next 
antitumor drugs/therapies (dosage period and best overall response of the treatment) will be 
collected as much as possible.
9.2
Discussion of Study Design, Including Choice of Control Groups
This study has no control groups.  This study was designed based on domestic Phase 1 study 
and “The Guidelines for Clinical Evaluation of Anticancer Drug in Japan (Notification No. 
1101001 issued on November 1, 2005)”.
9.3
Selection of Study Population
Total of 35 patients with relapsed or refractory PTCL and CTCL (at least 6 patients in 
CTCL) will be included in this study.  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.


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9.3.1
Inclusion Criteria
Subjects must meet all of the following criteria to be included in this study:
1. Patient with histological diagnosis of PTCL or CTCL as follows.

Peripheral T-cell lymphoma-not otherwise specified (PTCL NOS)

Angioimmunoblastic T-cell lymphoma (AITL)

Anaplastic large cell lymphoma, ALK positive (ALCL ALK+)

Anaplastic large cell lymphoma, ALK negative (ALCL ALK –)

Enteropathy-associated T-cell lymphoma (EATL)

Hepatosplenic T-cell lymphoma (HSTL)

Mycosis fungoides (MF)

Sézary syndrome (SS)

Primary cutaneous CD30+ T-cell lymphoproliferative disorders

Subcutaneous panniculitis-like T-cell lymphoma

Primary cutaneous γδT-cell lymphoma

Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma

Primary cutaneous CD4+ small/medium T-cell lymphoma
2. Patient who has measurable lesion.
a.
As to patients with PTCL, who have the lesion as all of below

Lymph node or extranodal lesion diagnosed as lymphoma by CT scan.

Clearly measurable in 2 orthogonal ways by CT scan.

≥1.5 cm in long axis or >1.0 cm in short axis, when long axis were <1.5 cm by CT 
scan.
b. As to patients with CTCL, who have the disease as skin lesion (patch, plaque, or 
tumor)
3. Patient who has previous systemic chemotherapy (except monotherapy of corticosteroid, 
psoralen and ultraviolet A [PUVA] therapy, interferon, and retinoid).
4. As to patient with CD30+ anaplastic large cell lymphoma, who has received previous
therapy of vedotin or inappropriate for the drug.
5. Patient who was PD or did not respond (CR or PR) during systemic chemotherapy, or 
who relapsed or progressed after systemic chemotherapy.
6. Patient who can provide tumor samples for central review of disease diagnosis and 
CD25+ cell expression.
7. Patient with Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 
1.
8. Patient with life expectancy of ≥3 months from starting study drug.
9. Patient with no carry-over of adverse events with ≥Grade 2 of the prior treatment that 
may affect the safety evaluation of the investigational drug (excluding alopecia).
10. Patient with adequate renal function as below:


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
Serum creatinine ≤1.5×upper limit of normal (ULN).
11. Patient with adequate liver function as below:

Total bilirubin ≤1.5×ULN

Serum albumin ≥3.0 g/dL (confirm 2 weeks later from dosage of albumin product)

AST or ALT ≤3.0×ULN
12. Patient with adequate bone marrow function as below:
(confirm 2 weeks or later from last administration of granulocyte colony-stimulating 
factor [G-CSF] and blood transfusion)

Absolute neutrophil count ≥1.5×103/μL (1.5×109/L)

Platelet count ≥7.5×104/μL

Hemoglobin ≥8.0 g/dL
13. Patient who can be hospitalized from Days 1 to 8 of Cycle 1.
14. Male and female patient ≥20 years of age at the time of informed consent.
15. Patient who has provided written consent to participate in the study.
9.3.2
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from this study:
1. Patient with central nerves invasion with clinical symptoms or which requires treatment.
2. Patient with active infection requiring treatment.
3. Patient with history of treatment with E7777.
4. Patient with history or plan to perform treatment below by starting study drug treatment.
a.
Blood transfusion, albumin product, G-CSF: within 2 weeks
b. Chemotherapy including corticosteroid use (except continuous use of low amount [as 
equal as prednisolone 10 mg/day or low] before informed consent) as antitumor 
therapy, radiotherapy, electron beam therapy, photochemotherapy, systemic retinoid, 
interferon and histone deacetylase (HDAC) inhibitor: within 4 weeks
c.
Antibody therapy as antitumor therapy: within 12 weeks
5. Patient who participates in other clinical study or ≤4 weeks from last administration of 
study drug (≤12 weeks in case of antibody).
6. Patient with serious complications or histories as below:
a.
History of myocardial infarction within 6 months before informed consent.
b. Concurrent cardiac diseases require the treatment, such as ischemic heart disease and 
arrhythmias etc.
c.
Complications of hepatic cirrhosis.
d. Complications of interstitial pneumonia or pulmonary fibrosis.
e.
Complications of clinically significant bleeding events (eg, cerebral hemorrhage) or 
thrombotic events (eg, pulmonary embolism).
7. Patient who has clinical abnormality in electrocardiography such as remarkable 
prolongation of QT/QTc (eg, more than 500 ms in repeated measurements).


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8. Patient with history of hypersensitivity to protein therapeutics.
9. Patient who is positive for HIV antibody, HCV antibody, or HBs antigen.  Patient who is 
positive for HBs or HBc antibody and showing DNA more than sensitivity in HBV-DNA 
assay.
10. Patient with malignancy of activity other than PTCL or CTCL within 36 months before 
informed consent (except treated non-invasive melanoma, basal cell carcinoma of the
skin or squamous cell carcinoma, intraepithelial carcinoma such as uterine cervix).
11. Woman of childbearing potential or man of impregnate potential who do not agree to use 
a medically effective method* for contraception for periods from before informed consent 
to during the clinical trial and 30 days later from last administration of study drug.
*Condom, contraceptive sponge, foam, jelly, diaphragm, intrauterine device (IUD), or use 
of oral contraception from at least 90 days before starting the study treatment
12. Woman with pregnant or breastfeeding.
13. Patient with allogeneic stem cell transplantation.
14. Patient with ≤6 months from autologous stem cell transplantation by starting study drug 
treatment.
15. Patient who was decided as inappropriate to participate in the study by the investigator or 
subinvestigator
9.3.3
Removal of Subjects from Therapy or Assessment
The investigator or subinvestigator 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.  The reason for discontinuation will be documented. If a subject discontinues 
study treatment, the subject will enter the Follow-up Phase and complete protocol-specified 
assessments, and survival investigations unless the subject withdraws consent.  If a subject 
withdraws consent, the date will be documented in the source documents.    The primary 
reason for discontinuation and all other reason(s) contributing to the subject’s discontinuation 
from study drug(s) should be reported on the CRF.   In addition, the date of last dose of study 
drug will be documented on the CRF.
Subjects who have discontinued or completed the study treatment without progression should 
have disease assessments (same assessments as the Follow-up Phase) every 6 to 8 weeks 
from the date of the discontinuation of completion until disease progression is documented or 
another antitumor therapy is initiated.
All subjects will be followed for survival until death, except where a subject withdraws 
consent or the sponsor chooses to discontinue the survival investigations, every 12 to 
16 weeks from the date of the discontinuation of completion.
9.3.3.1
Discontinuation Criteria for Each Subject:
1. Disease progression (PD) is observed.
2. A life-threatening, serious adverse event is observed. 


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3. The study treatment cannot be resumed within 21 days after the scheduled date of 
administration of E7777 (in principle, Day 22 of the previous cycle).
4. The subject meets the discontinuation criterion specified in the dose reduction criteria.  
However, the continuous administrations of 6 μg/kg/day will be allowed, if the response 
is observed in the treatment period and the investigator or subinvestigator judges that the 
continuation of study drug treatment is possible and clinically valuable.
5. The subject becomes pregnant or the partner of male subject desires pregnancy.
6. The subject ascertained as inappropriate after the registration (possibilities of 
continuation of treatment will be discussed with the sponsor as needed).
7. The subject wishes to decline participation in the study or withdraws consent.
8. The subject cannot comply with the protocol-specified procedures, and the investigator or 
subinvestigator judges inappropriate to continue the study to maintain safety for the 
subject.
9. The investigator or subinvestigator judges appropriate to discontinue the study for the 
subject by any other reason.
9.4
Treatments
9.4.1
Treatments Administered
9.4.1.1
Dose, Dosing Method, and Duration of Dose
E7777 (9 μg/kg/day) will be intravenously infused in 60 minutes (±10 minutes) once daily 
from Days 1 through 5 of each cycle in maximum of 8 cycles.  Every cycle consists of 
3 weeks.  
The same dose applied within a cycle.  Dose recalculation (μg/body) associated with body 
weight decrease will be allowed before initiating each cycle at the discretion of the
investigator or subinvestigator.
9.4.1.2
Premedication:
The following premedication will be provided within approximately 120 minutes (within 
approximately 30 to 60 minutes for oral drugs) before infusion of E7777. 
The premedication must be provided in Cycles 1 to 3, but premedication in Cycle 4 and 
subsequent cycles may be omitted at the discretion of the investigator or subinvestigator.
Investigator or subinvestigator may use appropriate usage or dose, if they consider the same 
effect to be expected.  If adverse events occurred, the premedication regimen can be changed 
appropriately (eg. increase the dose, change drugs).

Acetaminophen: 500 mg, orally

Diphenhydramine: 20 mg, d-chlorpheniramine 5 mg, or chlorpheniramine 10 mg, 
intravenously

Dexamethasone: 4 to 8 mg, intravenously


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
An antiemetic agent according to the clinical practice of each investigational site.
Also, following procedures will be provided before and after E7777 administration.

Before and after each infusion of E7777, 250 to 500 mL of physiological saline (or an 
intravenous fluid preparation selected by the investigator or subinvestigator) will be 
intravenously infused.

For patients at risk for tumor lysis syndrome, prophylactic treatment (treatment of 
allopurinol or rasburicase and intravenous fluids, etc.) should be considered.
9.4.1.3
Preparation and Administration of the Study Drug

Water for injection (2.1 mL) will be gently poured into the vial along its wall. ·Mix 
the solution by gentle swirling (be careful not to foam the contents) until completely 
resolved to get 2.2 mL of E7777 solution (0.15 mg/mL).  

When using multiple vials, E7777 will be completely resolved to the water in each 
vial before mixing the solution of multiple vials.

Haze due to microbubbles may be observed during dissolving, it may disappear by 
standing.  Use only if the solution is clear.  If the solution is not clear, colorless, or 
without visible particulate matter, the solution cannot be used.  Use of inline filter is 
prohibited.

Administer prepared solutions of E7777 immediately (within 24 hours at room 
temperature at the latest).

The E7777 solution can be diluted up to 50 times (3 μg/mL) by saline at room 
temperature.  However, it is not allowed to use a solution diluted to less than 
15 μg/mL (10-fold dilution) in plastic syringes.  For details of the materials of the 
equipment that can be used for preparation or administration and acceptable 
concentrations of E7777, refer to the study drug handling manual.

E7777 will be intravenously infused in 60 minutes (±10 minutes) once daily from 
Days 1 through 5 of each cycle.

Do not mix or simultaneously administer E7777 with other drugs.

Do not administer as bolus injection.

Discard unused portions of E7777 immediately
9.4.1.4
Control of Infusion Reactions During the Administration
E7777 can be cause infusion reactions during or after the administration.  Therefore, E7777 
will be administered under preparations of drugs and equipment, such as adrenaline 
antipyretic analgestics, antihistamine, corticosteroids, antiemetics, or other medical 
preparation per local institutional guidelines, which can be used for emergencies.
In the event an infusion reaction is suspected, the investigator or subinvestigator can decide 
to interrupt the administration of E7777.  Administration of E7777 can be resumed if the 
event returns to baseline under the judgment or investigator or subinvestigator.


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9.4.1.5
Dose Interruption Criteria
Administration of E7777 will be skipped on that day if ≥Grade 3 toxicity related to drug 
(except lymphopenia, Grade 3 abnormal electrolyte, or other abnormal clinical test result 
judged as not clinically significant) is observed before E7777 administration during Days 2 
to 5.  E7777 administration may be interrupted if judged to be appropriate by investigator or 
subinvestigator.
To resume the E7777 administration at a later date, the tests related to the reason of 
dose-skipping should be performed and recovery to ≤Grade 2 must be confirmed.  Same 
dosage is allowed to resume administration in such case.
9.4.1.6
Criteria for Initiating Next Cycle
If any of the toxicities related to the study drug in below is observed, initiation of the next 
cycle must be postponed.

Serum albumin <3.0 g/dL

AST or ALT >3.0×ULN

Total bilirubin >1.5×ULN

≥ Grade 3 toxicity (except lymphopenia, Grade 3 abnormal electrolyte, or the other 
abnormal clinical test result judged as not clinically significant)
Investigator or subinvestigator may postpone the initiation of next cycle by their own 
discretion.  The initiation of the next cycle can be postponed for a maximum of 21 days after 
the planned date of administration.
9.4.1.7
Dose Reduction Criteria
If a subject meets any of the criteria below, the dosage of E7777 must be decreased to 
6 μg/kg/day.  Dose increase is not allowed after the reduction.

Could not start next cycle at planned schedule (in principle, Day 22 of the previous cycle) 
in 2 consequent cycles by the toxicity related to the study drug.

Investigator or subinvestigator considers that the dose reduction is needed.
The treatment will be discontinued if the subject meets the criteria above after the dose 
reduction. However, the continuous administrations of 6 μg/kg/day will be allowed, if the 
response is observed in the treatment period and the investigator or subinvestigator judges 
that the continuation of study drug treatment is possible and clinically valuable.
9.4.2
Identity of Investigational Product
Study drug will be supplied by the sponsor in labeled containers. 
9.4.2.1
Chemical Name, Structural Formula of E7777

Test drug code:  E7777


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
Generic name:  denileukin diftitox

Chemical name:  1-388-Toxin (Corynebacterium diphtheriae strain C7), N-L-methionyl-
387-L-histidine-388-L5 alanine-, (388→2')-protein with 2-133-interleukin 2 (human 
clone pTIL2-21a)

Formulation:  freeze-dried formulation

Composition:  a vial contains 300 μg of E7777
9.4.2.2
Comparator Drug
Not applicable.
9.4.2.3
Labeling for Study Drug
The following information has to be provided.  Detailed information on the labeling and 
packaging of study drug will be included in an Attachment.

For clinical study use only

Name and address of the sponsor

Drug identifier

Lot number/batch number

Storage conditions
9.4.2.4
Storage Conditions
Study drug will be stored in accordance with the labeled storage conditions.  The assigned 
pharmacist or designee is responsible for ensuring that the temperature is monitored 
throughout the total duration of the study and that records are maintained by using either an 
in-house acquisition system, a mechanical recording device, such as a calibrated chart 
recorder, or by manual means.
9.4.3
Method of Assigning Subjects to Treatment Groups
This is an open-label, single-arm study.  All subjects who provide signed informed consent to 
participate in this study and satisfy all eligibility requirements (see Section 9.3) will receive
E7777.  There is no randomization in this study.  Procedure of the study registration is 
described below.
1. The investigator, subinvestigator, or clinical research coordinator will issue the Subject 
ID Number to individual subjects who provide signed informed consent for enrollment
and record it in “Subject Screening Log.”
2. The investigator, subinvestigator, or clinical research coordinator will screen the subjects 
and determine subject eligibility based on the inclusion and exclusion criteria.  The 
investigator, subinvestigator, or clinical research coordinator will record the decision on 
the subject eligibility in the “Subject Screening Log.” 


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3. For the eligible subjects, the investigator or subinvestigator will record the screening data 
and subject demography to the Subject Registration Form (an Attachment) and will 
inform the sponsor.  
9.4.4
Selection of Doses in the Study
Currently, single-arm Phase 1/3 study (E7777-G000-302) of E7777 in CTCL patients with 
CD25 positive is ongoing in abroad.  The clinically recommended dose of E7777 in CTCL 
patients was determined to be 9 μg/kg/day for 5 consecutive days every 3 weeks based on the 
Lead-in part (Phase 1 part) of the study.
In Japan, Phase 1 study (E7777-J081-101) in CTCL and PTCL patients was conducted and 
the recommended dose of E7777 was determined to be 9 μg/kg/day for 5 consecutive days 
every 3 weeks, which is the same as above.
Therefore, the above recommended dose which determined in the E7777-J081-101 study as 
well as the E7777-G000-302 study will be selected in this study.  Administrations of E7777 
at 6 μg/kg/day also seems to have efficacies in clinical studies conducted in Japan or other 
countries, dose reduction to 6 μg/kg/day is allowed in this study.
9.4.5
Selection and Timing of Dose for Each Subject
The selection and timing of the dose for each subject are provided in Section 9.4.1
Treatments Administered.
9.4.6
Blinding
The study will not be blinded.
9.4.7
Prior and Concomitant Therapy
Any medication (including over-the-counter medications) or therapy administered to the 
subject during the study (starting at the date of informed consent and until the final 
observation) will be recorded.  The adverse event or medical condition for which the 
concomitant medication or therapy was administered will be recorded.  Drugs used for other 
than treatments (such as contrast mediums, diagnostic agents, antiseptics, and infusion 
solution for flushing) will be excepted.  
9.4.7.1
Drug-Drug Interactions
No clinical study for drug-drug interaction has been conducted for E7777.
9.4.7.2
Prohibited Concomitant Therapies and Drugs
Concomitant use of other antitumor therapies for the primary disease such as chemotherapy 
(including corticosteroids), immunotherapy, and radiotherapy is not allowed.


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However, the use of topical corticosteroid (external use) or systemic use of low amount 
corticosteroid (equivalent to ≤ 10 mg/day prednisolone) is allowed, if it has been 
contentiously used before the study treatment and where the investigator or subinvestigator 
judged necessary to continue the drug.  In such a case, the concomitant steroid medication is 
allowed as long as the type of steroid, and steroid dose remain the same as what the subject 
had been receiving for the prolonged period (dose increase is not allowed).  It is allowed to 
use drugs (other than antitumor drugs) intended to alleviate skin symptoms.  Concomitant use 
of any other study drug is prohibited.
9.4.8
Treatment Compliance
The investigator, subinvestigator, or clinical research coordinator will instruct subjects to 
follow appropriate use of study drug and record the treatment compliance.  The CRA will 
review the treatment compliance during site visits and at the completion of the study.  
9.4.9
Drug Supplies and Accountability
The assigned pharmacist (or the designee) will be responsible for the accountability of all 
study drugs (dispensing, inventory, and record keeping) following the sponsor’s instructions 
“Instructions for Handling of Investigational Products and Trial-related Materials” and 
adherence to GCP guidelines as well as other 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 assigned pharmacist (or the designee) must maintain an accurate and timely record of the 
following:  receipt of all study drugs, administered study drugs to the subject, and return of 
reconciled study drugs to the sponsor.  This includes, but may not be limited to:  (a) 
documentation of receipt of study drugs, (b) study drugs administered/reconciliation log, (c) 
study drugs accountability log, and (d) documentation of returns to 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.  Upon 
completion of drug accountability and reconciliation procedures by the assigned pharmacist 
(or the designee) and documentation of study drugs return with the sponsor, all unused study 
drugs will be returned to the sponsor.  Unused study drugs that are returned from the site are 
hand-delivered to CRAs and to be returned to the sponsor’s designated depot.  
Drug accountability will be reviewed by the CRA throughout the study during site visits and 
at the completion of the study.


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9.5
Study Assessments
9.5.1
Assessments
9.5.1.1
Demography
Subject demography information will be collected at the screening.  Demography 
information includes Subject ID Number, date of written informed consent, date of birth (or 
age), sex, race/ethnicity.
The following information on primary disease and its prior therapies will be collected at 
Screening and recorded on the CRF.
1. Primary disease
-
Diagnosis (WHO classification)
-
Date of diagnosis
-
Disease stage at the screening
PTCL: Ann Arbor staging (Carbone, et al., 1971)
MF/SS: TNMB classification (Olsen, et al., 2007)
CTCL (except MF/SS): TNM classification (Kim, et al., 2007); TNMB classification 
will be employed for disease stage.
-
CCR4 expression (positive or negative)
(A tumor biopsy sample collected before study drug administration will be sent to the 
central laboratory until the last observation.  Results of IHC obtained in the past can 
be used.)
2. Prior therapies for primary disease
-
Anti-tumor therapy (name of therapy/drug, best overall response, start date, and end 
date)
9.5.1.2
Assessments in the Pretreatment Phase
9.5.1.2.1
MEDICAL HISTORY AND PHYSICAL EXAMINATIONS
Medical and surgical history and current medical conditions will be recorded at the 
screening.  All medical history that is considered to have effects on safety, efficacy, or PK by 
the investigator or subinvestigator and medical conditions that are identified at Screening 
must be recorded on the CRF.
Physical examinations will be performed as designated in the Schedule of 
Procedures/Assessments (Table 7).  Documentation of the physical examination will be 
included in the source documentation at the site.  Significant findings at the screening will be 
recorded on the CRF.  Changes from screening physical examination findings that meet the 
definition of an AE will be recorded on the CRF.


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9.5.1.3
Efficacy Assessments
For anti-tumor activity, investigator or subinvestigator will evaluate overall response and best 
overall response (the best response among all timepoints) from the result of tumor lymph 
node (nodal lesion), non-lymph node tumor in viscera (extranodal lesion), liver/spleen 
enlargement, and bone marrow infiltration according to “Revised response criteria for 
malignant lymphoma (Cheson, et al., 2007)”, and skin lesion, peripheral blood lesion
according to “Clinical endpoints and response criteria in mycosis fungoides and Sézary 
syndrome (Olsen, et al., 2011)” (see an Appendix “Overall Response Evaluation Criteria”).  
Central review will be conducted by the Imaging Review Committee for nodal and 
extranodal lesions.  In addition, overall responses and the best overall response will be 
determined by the Efficacy and Safety Evaluation Committee based on the nodal and 
extranodal lesions reviewed by the Imaging Review Committee and responses on liver/spleen 
enlargement, bone marrow infiltration, skin lesion, and peripheral blood lesion evaluated by 
the investigator or subinvestigator.
Primary endpoint of the study is ORR (rate of subjects whose best overall response is CR or 
PR) judged by Efficacy and Safety Evaluation Committee.
The items below judged by efficacy judgement committee (except OS) are the secondary 
endpoint.

PFS:
Defined as the term between the date of administration of the first dose of the study drug 
and the date of the first event (PD or death whatever the reason is).  The detail of the 
censoring rule for PFS will be described in the statistical analysis plan (SAP).

DOR:
Defined as the term between the date of confirmation of the first response and the date of 
confirmation of the PD.  The detail of the censoring rule for DOR will be described in the 
SAP.

TTR:
Defined as the term between the date of administration of the first dose of the study drug 
and the date of confirmation of the first response.

CR rate:
Defined as the rate of subjects whose best overall response is CR.

OS:
Defined as the term between the date of administration of the first dose of the study drug 
and the date of death whatever the reason is.  The subject who is not confirmed to die will 
be censored at the early date of either last confirmation of alive or at the cut-off date of 
the study.
Addition to the evaluation of the overall response described above, the efficacy according to 
“Revised response criteria for malignant lymphoma” for PTCL and “Clinical endpoints and 
response criteria in mycosis fungoides and Sézary syndrome” for CTCL will be evaluated 
and summarized.


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Tumor evaluation
Tumor evaluations of nodal/extranodal lesion (except skin lesion), imaging of liver/spleen 
enlargement (CT and PET [18F-FDG PET]), skin lesion (visual examination; color 
photograph will be taken if there are skin lesions), and lesion in the peripheral blood (count 
and percent of abnormal lymphocytes [lymphoma cells] among lymphocytes).  If 
astrointesitinal lesions are suspected, endoscopy (and biopsy, if necessary) will be performed
。
Tumor evaluation (nodal/extranodal lesion, liver/spleen enlargement, skin lesion, and 
peripheral blood lesion) will be performed on screening, Days 15 to 22 (if postponed the 
beginning of next cycle, by the beginning of next cycle or within 7 days at the time of 
completion of Cycle 8) of Cycles 2, 4, 6, 8, and at discontinuation.  PET scan will be 
performed on screening, and if positive, Days 15 to 22 (if postponed the beginning of next 
cycle, by the beginning of next cycle, or within 7 days at the time of completion of Cycle 8) 
of Cycles 4 and 8, and at discontinuation as possible.  Tumor evaluation will be performed in 
shorter period at confirmation of efficacy or if clinically indicated.
Tumor evaluations (except PET and color photography of the skin lesion) will be performed 
on every 6 to 8 weeks (except the case of discontinuation by disease progression or starting 
treatment of a next anti-tumor drug) from the discontinuation (or completion) of the study 
drug, unless the subject withdrew the informed consent or the sponsor decided to stop the 
investigation.  
Bone marrow biopsy
To evaluate bone marrow infiltration, bone marrow biopsy will be performed (if it is 
difficult, bone marrow aspiration can be performed instead) at screening.  If the result is 
positive or unconfirmed, or bone marrow biopsy is not performed (ie, bone marrow 
aspiration is performed instead) at screening, bone marrow biopsy will be performed when to 
confirm CR as best overall response.  In addition, bone marrow biopsy can be performed in 
any subject when clinically indicated.
B symptoms 
B symptoms (fever of >38 °C with unknown reason, night sweat [requiring to change
bedding], and >10% decrease of bodyweight with unknown reason within 6 months) will be 
evaluated at the same timepoints with tumor evaluations.
Items and methods for efficacy evaluation is provided in an Attachment ”Overall Response 
Evaluation Criteria”.
Survival investigations
Survival investigations on every 12 to 16 weeks from the discontinuation (or completion) of 
the study drug, unless the subject withdrew the informed consent or the sponsor decided to 
stop the investigation.  
Storage and provision of data


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In order to carry out central review, CT/MRI images, PET images, and color photographic 
images taken at the screening and tumor evaluations will be stored at the medical institution 
and provided to the sponsor as electronic data after masking personal information of the 
subject.
Regarding the evaluation of the skin lesions, a copy of the judgment record of the medical 
institution will be provided to the sponsor.
Submit the blood smear sample for evaluation of peripheral blood lesion and bone marrow 
sample (biopsy or puncture; if required), and a copy of the diagnosis report will be submitted 
to the central review committee.
Refer to the procedure manual (defined separately) for the provision of data and collection, 
handling, and transport procedures of samples.
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Assessments
In all registered subjects, PK and immunogenicity (anti-E7777 antibody, anti-IL-2 antibody, 
and neutralizing activity of anti-E7777 antibody) will be evaluated and blood samples for the 
measurement of serum sIL-2R, LDH and T-cell subsets (actual counts and ratios of T-cells 
with CD4+, CD4+/CD25+, CD4+/CD25+/Foxp3+, CD4+/CD7–*, CD4+/CD26–*; *Only for 
MF and SS) in the peripheral blood will be collected.
Pathological diagnosis of the primary disease and measurement of CD25 positive rate in the 
tumor cells will be conducted centrally.
9.5.1.4.1
MEASUREMENTS OF DRUG CONCENTRATIONS
Blood samples (6 mL each) will be collected for non-compartment analysis at the timepoints 
in Table 1 until 6 subjects continued the treatment for at least 5 cycles.


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Table 1
Timepoints for Drug Concentration Measurements (For until 6 
Subjects Continued at Least 5 Cycles)
Cycle
Day
Blood Collection Timepoint
Allowance (approximately)
Cycles 1, 3, 
and 5
Day 1
Predose
Within 180 minutes to administration
30 minutes after the start of infusion
± 5 minutes
Immediately after the end of infusion
Within 5 minutes after the end of infusion
30 minutes after the end of infusion
± 5 minutes
60 minutes after the end of infusion
± 5 minutes
90 minutes after the end of infusion
± 5 minutes
120 minutes after the end of infusion
± 10 minutes
240 minutes after the end of infusion *
± 10 minutes
*Cycle 1 only
Blood samples (6 mL each) will be collected in sparse sampling for pharmacokinetic analysis 
at the timepoints in Table 2 after 6 subjects continued the treatment for at least 5 cycles.
Table 2
Timepoints for Drug Concentration Measurements (For after 6 
Subjects Continued at Least 5 Cycles)
Cycle
Day
Blood Collection Timepoint
Allowance (approximately)
Cycles 1, 3, 
5,and 8
Day 1
Predose
Within 180 minutes to administration
Immediately after the end of infusion
Within 5 minutes after the end of infusion
30 to 180 minutes after the end of infusion
–
Refer to the procedure manual (defined separately) for collection, handling, and transport 
procedures of PK samples.
For samples collected from the treated subjects, serum concentrations of E7777 will be 
determined by a validated analytical method.  The pharmacokinetic parameters for E7777 
including the followings will be calculated: maximum observed concentration (Cmax), time at 
which the highest drug concentration occurs (tmax), area under the concentration-time curve 
(AUC), terminal elimination phase half-life (t1/2), volume of distribution at terminal phase 
(Vz), and total clearance (CL).
9.5.1.4.2
IMMUNOGENICITY (ANTI-E7777 ANTIBODY, ANTI-IL-2 ANTIBODY AND NEUTRALIZING 
ACTIVITY OF ANTI-E7777 ANTIBODY)
Blood samples (4 mL of peripheral blood × 3 samples per each timepoint) will be collected at 
the timepoints in Table 3.


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Table 3
Timepoints for Serum Antibodies and Neutralizing Activities
Cycle
Day
Blood Collection Timepoint
Allowance (approximately)
Cycles 1, 2, 
3, 5, and 8
Day 1
Predose
Within 180 minutes to administration
Discontinuation or completion of the study*
Date of discontinuation or completion + 7 days
*Perform depend on the subject’s condition, etc.
Refer to the procedure manual (defined separately) for collection, handling, and transport 
procedures of samples for immunogenicity assessments.
9.5.1.4.3
MEASUREMENTS OF PHARMACODYNAMICS AND OTHER BIOMARKERS
Serum sIL-2R and LDH levels
Blood samples (3 mL of peripheral blood for each timepoint) for sIL-2R and LDH 
measurements will be collected at the timepoints in Table 4.
Table 4
Timepoints for sIL-2R and LDH Measurements
Cycle
Day
Blood Collection Timepoint
Allowance (approximately)
Cycles 1, 2, 
3, 5, and 8
Day 1
Predose
Within 180 minutes to administration
Discontinuation or completion of the study*
Date of discontinuation or completion + 7 days
*Perform depend on the subject’s condition, etc.
Refer to the procedure manual (defined separately) for collection, handling, and transport 
procedures of samples for sIL-2R and LDH measurements.
T-cell subsets
Blood samples (4 mL of peripheral blood for each timepoint) will be collected at the 
timepoints in Table 5.


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Table 5
Timepoints for T-cell Subsets Measurements
Cycle
Day
Blood Collection Timepoint
Allowance (approximately)
Cycles 1
and 2
Day 1
Predose
Within 180 minutes to administration
Day 8
–
+ 3 days
Day 15
–
± 3 days
Cycles 3, 5,
and 8 
Day 1
Predose
Within 180 minutes to administration
Discontinuation or completion of the study*
Date of discontinuation or completion + 7 days
*Perform depend on the subject’s condition, etc.
Refer to the procedure manual (defined separately) for collection, handling, and transport 
procedures of peripheral blood samples for T-cell subset measurements
Central pathological diagnosis, CD25 positive rate in tumor cells by 
immunohistochemical staining, and CCR4 expression:
For central pathological diagnosis of the primary disease, measurement of CD25 positive rate 
in the tumor cells, and CCR4 expression, tumor samples (formalin-fixed paraffin-embedded 
tissue sample) before study drug administration will be collected and submitted to the central 
laboratory prior to the last observation.  The submitted tumor samples may also be used for 
development of diagnostic agent for E7777.
Central pathological diagnosis of the primary disease will be prioritized if it is different from 
that of the investigational site.
Refer to the procedure manual (defined separately) for handling and transport procedures of 
tumor samples.
9.5.1.5
Safety Assessments
Safety assessments are shown in Table 7 (Schedule of Procedures/Assessments).
Safety assessments will consist of monitoring and recording all AEs, including all Common 
Terminology Criteria for Adverse Events (CTCAE) v4.03 grades (for increasing severity), 
and SAEs; monitoring of hematology, blood chemistry, and urine values; measurement of 
vital signs and ECGs; and performance of ophthalmological and physical examinations.
9.5.1.5.1
ADVERSE EVENTS
An adverse event (AE) is any untoward medical occurrence in a subject.  An AE does not 
necessarily have a causal relationship with the medicinal product.  For this study, the study 
drug is E7777.


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The criteria for identifying AEs in this study are:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease found after the time of informed consent, whether or not considered 
related to the investigational product (Note:  Every sign or symptom should not be listed 
as a separate AE if the applicable disease [diagnosis] is being reported as an AE)

Any new disease or exacerbation of an existing disease.  However, worsening of the 
primary disease should be captured under efficacy assessments as disease progression 
rather than as an AE.

Any deterioration in nonprotocol-required measurements of a laboratory value or other 
clinical test (eg, ECG or x-ray) that results in symptoms, a change in treatment, or 
discontinuation of study drug

Recurrence of an intermittent medical condition (eg, headache) not present pretreatment 
(Baseline)

An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, withdrawal of study drug, or withholding 
of study drug, whether prescribed in the protocol or not
All AEs observed during the study will be recorded 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 final observation visit.  However, if other antitumor 
treatments should be implemented as soon as possible considering the deterioration of 
subject’s physical condition, the last visit will be allowed within 30 days after the last dose 
(ie, before the start of other antitumor treatments).  SAEs will be collected until the final 
observation visit.  Subjects who fail screening primarily due to AE(s) must have the AE(s) 
leading to screen failure and its seriousness reported on the CRF.  
Any laboratory abnormality considered to constitute an AE should be reported on the CRF.  
Abnormal laboratory values should not be listed as separate AEs if they are considered to be 
part of the clinical syndrome that is being reported as an AE.  It is the responsibility of the 
investigator to review all laboratory findings in all subjects and determine if they constitute 
an AE.  Medical and scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality should be classified as an AE.  
Abnormal ECG (QTc) results, if not otherwise considered part of a clinical symptom that is 
being reported as an AE, should be considered an AE if the QTc interval is more than 450 ms 
and there is an increase of more than 60 ms from baseline.  Any ECG abnormality that the 
investigator considers as an AE should be reported as such.
All AEs must be followed until last visit for final observation or until resolution, whichever 
comes first.  However, if other antitumor treatments should be implemented as soon as 
possible considering the deterioration of subject’s physical condition, the last visit will be 
allowed within 30 days after the last dose (ie, before the start of other antitumor treatments).  
All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization.  


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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
Adverse events will be graded on a 5-point scale according to Common Terminology Criteria 
for Adverse Event (CTCAE v4.03).  Investigators will report CTCAE grades for all AEs (for 
increasing severity).  
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
Yes (related)
A causal relationship between the study drug and the AE is a reasonable 
possibility.
No (not related) A causal relationship between the study drug and the AE is not a 
reasonable possibility.
9.5.1.5.2
SERIOUS ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
A serious adverse event (SAE) is any untoward medical occurrence that at any dose:

Results in death

Is life-threatening (ie, the subject was at immediate risk of death from the adverse event 
as it occurred; this does not include an event that, had it occurred in a more severe form 
or was allowed to continue, might have caused death)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect (in the child of a subject who was exposed to the 
study drug)
Other important medical events that may not be immediately life-threatening or result in 
death or hospitalization but, when based on appropriate medical judgment, may jeopardize 
the subject or may require intervention to prevent one of the outcomes in the definition of 


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SAE listed above should also be considered SAEs.  Medical and scientific judgment should 
be exercised in deciding whether expedited reporting is appropriate in such situations. 
In addition to the above, events associated with special situations include pregnancy or 
exposure to study drug through breastfeeding; AEs associated with study drug overdose, 
misuse, abuse, or medication error (see Sections 9.5.4.2 and 9.5.4.3).  These events
associated with special situations are to be captured using the SAE procedures but are to be 
considered as SAEs only if they meet one of the above criteria.  All AEs associated with
special situations (not including natural childbirth) are to be reported on the CRF whether or 
not they meet the criteria for SAEs.  
All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization.
The following hospitalizations are not considered to be SAEs because there is no “adverse 
event” (ie, there is no untoward medical occurrence) associated with the hospitalization:

Hospitalizations for respite care 

Planned hospitalizations required by the protocol

Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed after study drug administration)

Hospitalization for administration of study drug or insertion of access for administration 
of study drug

Hospitalization for routine maintenance of a device (eg, battery replacement) that was in 
place before study entry
9.5.1.5.3
INFUSION REACTIONS
In general, administration of a protein-derived drug has a possibility of causing an acute 
reaction called “infusion reactions”.
For TEAEs developed on the day of administration of the study drug or on the day after 
administration, the investigator or subinvestigator judged whether it is an infusion reaction or 
not and recorded on the CRF.
For each AE judged to be an infusion reaction, the times of onset and outcome will be 
recorded on the CRF (record of the time of outcome will not be required if it is on or after 
24 hours from the onset).
Examples of the infusion reactions include fatigue, nausea, vomiting, joint pain, muscle pain, 
fever, and chills.
9.5.1.5.4
LABORATORY MEASUREMENTS
Clinical laboratory tests to be performed, including hematology, chemistry, and urinalysis, 
are summarized in Table 6.  The Schedule of Procedures/Assessments (Table 7) shows the 
visits and time points at which blood for clinical laboratory tests and urine for urinalysis will 
be collected in the study.


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Table 6
Clinical Laboratory Tests
Category
Parameters
Hematology
RBC count, hemoglobin, hematocrit, platelets, and WBC count 
with differential (neutrophils, lymphocytes, monocytes, basophils, 
eosinophils,)
Chemistry
Liver function tests
Alkaline phosphatase, aspartate aminotransferase, alanine 
aminotransferase, gamma glutamyl transpeptidase, total bilirubin, 
cholinesterase
Renal function tests
Blood urea nitrogen, creatinine
Other
Glucose, albumin, cholesterol, triglycerides, lactate dehydrogenase, 
amylase, lipase, total protein, uric acid, sodium, potassium, 
chloride, calcium, C-reactive protein
Urinalysis
Protein (qualitative), glucose (qualitative), occult blood
RBC = red blood cell, WBC = white blood cell.
All hematology, blood chemistry and urinalysis samples are to be obtained prior to study 
drug administration and results reviewed prior to administration at the beginning of each 
treatment cycle.  When a clinically significant laboratory abnormality is observed and it is 
necessary to consider whether to continue the administration of study drug, refer to Dose 
Interruption Criteria (Section 9.4.1.5), Criteria for Initiating Next Cycle (Section 9.4.1.6), 
and Dose Reduction Criteria (Section 9.4.1.7).
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 9.5.1.5.1).  In these instances, the AE corresponding to the laboratory 
abnormality will be recorded on the CRF.
9.5.1.5.5
VITAL SIGNS, WEIGHT, AND HEIGHT MEASUREMENTS
Vital sign measurements (ie, systolic and diastolic blood pressure [BP] [mmHg], pulse [beats 
per minute], body temperature [in centigrade]), and weight (kg) and height (cm) will be 
obtained at the visits designated in the Schedule of Procedures/Assessments (Table 7) by 
predetermined methods.  Blood pressure and pulse will be measured after the subject has 
been resting.  
9.5.1.5.6
PHYSICAL EXAMINATIONS
Physical examinations will be performed as designated in the Schedule of 
Procedures/Assessments (Table 7).  Documentation of the physical examination will be 
included in the source documentation at the site.  Only changes from screening physical 
examination findings that meet the definition of an AE will be recorded on the CRF.


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9.5.1.5.7
ECOG-PS
ECOG-PS will be evaluated by the method described in the Attachment as designated in the 
Schedule of Procedures/Assessments (Table 7).
9.5.1.5.8
ELECTROCARDIOGRAMS
Electrocardiograms will be obtained as designated in the Schedule of 
Procedures/Assessments (Table 7).  Complete, standardized, 12-lead ECG recordings are to 
be used.  heart rate (bpm), QT (msec), and QTc (msec) will be recorded.  Fridericia’s 
correction (QTcF) will be employed for calculation of QTc. 
An ECG abnormality may meet the criteria of an AE as described in this protocol (see
Section 9.5.1.5.1).  In these instances, the AE corresponding to the ECG abnormality will be 
recorded on the CRF.
9.5.1.5.9
OPHTHALMOLOGICAL EXAMINATIONS
Ophthalmological examinations (visual test, color vision test as well as other tests judged to 
be necessary by the physician, such as visual field test, tonometry, and ophthalmoscopy) will 
be performed as designated in the Schedule of Procedures/Assessments (Table 7).
9.5.1.5.10 PREGNANCY TESTS
A serum or urine hCG test will be performed as designated in the Schedule of 
Procedures/Assessments (Table 7) for premenopausal women and postmenopausal women 
who have been amenorrheic for less than 12 months.
9.5.1.5.11 VIRAL TESTS
HBs antigen, HBs antibodies, HBc antibodies, HCV antibodies, and HIV antibodies will be 
measured at screening.  In case the results of HBs antibodies or HBc antibodies are positive, 
HBV-DNA will be quantitatively measured.
9.5.1.6
Assessments on Treatment Compliance
Treatment compliance (date and time of administration, dose [reason for dose change if 
applicable]) will be collected and recorded on the CRF.
9.5.1.7
Assessments of Prior and Concomitant Therapy
Any medication or therapy administered to the subject during the study (between at the date 
of informed consent and the date of final observation) will be recorded.  For all 
drugs/therapies, the name, reason for use, treatment start date, treatment end date will be 
collected and recorded on the CRF.  Treatment by another physician will be also collected 
from the physician if it is required.


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9.5.2
Schedule of Procedures/Assessments
Table 7 presents the schedule of procedures/assessments for the study.


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Table 7
Schedule of Procedures/Assessments
EOT: end of treatment (ie, discontinuation or completion), FU:  follow-up, LO:  last observation
Phase
Pretreatment Phase
Treatment Phase
Follow-up Phase
Period
IC
Screening Baseline p
Cycle 1 to 8
EOT
LO
FU
Day
–28 days
–7 days
1q
2
3
4
5
8
(+3)
15
(±3)
(+7)
30 (+7) days 
from last dose
Informed consent
X
Patient characteristic
X
Inclusion/Exclusion criteria
X
Registration
X
Prior therapy
X
Medical history/Complication
X
Height
X
Weight a, b
X
X
X
Physical exam
X
X
X
X
X
X
X
X
X
X
X
Vital signs b
X
X
X
X
X
X
X
X
X
X
ECOG PS a, b
X
X
X
X
X
Electrocardiogram (12-lead) b, c
X
X
X
X
Pregnancy test (if required)
X
X
Virus test
Hematology test a, b, d
X
X
X
X
X
X
X
Biochemistry test a, b, e
X
X
X
X
X
X
X
Urinalysis a, b
X
X
X
X
X
X
X
X
Ophthalmology test f
X
[X]
X
X
E7777 administration
X
X
X
X
X
Pharmacokinetics g
[X]
Anti-E7777 antibody, anti-IL-2 antibody, 
neutralizing activity h
[X]
X
Serum s-IL-2R and LDH h
[X]
X
T-cell subsets i
[X]
[X]
[X]
X
Tumor evaluation j
X
[X]
X
[X]
Bone marrow biopsy k
X
[X]
B symptoms l
X
[X]
X
Submission of tumor samples for central 
diagnosis, review of CD25 and CCR4 q m
Through all terms by the last observation
Concomitant drugs/therapies n
Through all terms by the last observation
[X]
Adverse events
Through all terms by the last observation
Survival investigations o
X


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Note：X indicates items to be perform on that timepoint, while [X] indicates items those may be performd on that timepoint.
a:
Baseline data can be employed on Cycle 1 Day 1.
b: It will be conducted before the administration.
c:
Perform immediately (approximately within 5 minutes) after the study drug administration on Cycle 1 Day 1.
d: Perform prior to the administration of study drug and confirm it meets the administration criteria (except differential white blood count).
e:
Perform prior to the administration of study drug and confirm it meets the administration criteria (Data of AST, ALT, total bilirubin, and albumin are mandately.  The other 
items will be also confirmed, if available). 
f:
Perform at screening, Day 15 of odd cycles, discontinuation (or completion) and the last observation.  Able to use any data at discontinuation (or completion) and within 14 
days from the last observation. Also perform when clinically indicated.
g: Blood samples will be collected for non-compartment analysis in schedule below (approximately) until 6 subjects continued the treatment for at least 5 cycles.
Day 1 in Cycles 1, 3, 5; at predose (within 180 minutes), 30 minutes after the start of infusion (±5 minutes), immediately after the end of infusion (within 5 minutes), 30 (±5), 
60 (±5), 90 (±5), 120 (±10), and 240 (±10)* minutes after the end of infusion (* Cycle 1 only).
After 6 subjects continued the treatment for at least 5 cycles, blood samples will be collected in sparse sampling schedule below.
Day 1 in Cycles 1, 3, 5, 8; at predose (within 180 minutes), immediately after the end of infusion (within 5 minutes), and 60 to 180 minutes after the end of infusion.
h: Blood samples will be collected at predose (within 180 minutes) of Day 1 in Cycles 1, 2, 3, 5, 8, and at discontinuation (or completion).
i:
Blood samples will be collected at predose (within 180 minutes) of Day 1, as well as Days 8 and 15 in Cycles 1 and 2, predose (within 180 min) of Cycles 3, 5, and 8, and at 
discontinuation (or completion).
j:
The tumor evaluation data within 28 days before the informed consent can be used as screening data if it meets the requirement of the protocol.  Tumor evaluation will be 
performed on screening, day 15-22 (if postponed the beginning of next cycle, by the beginning of next cycle) of cycle 2, 4, 6, 8 and discontinuation. PET scan will be 
performed on screening, and if positive, day 15-22 (if postponed the beginning of next cycle, by the beginning of next cycle) of cycle 4, 8 and discontinuation as possible. 
Perform tumor evaluation in short period at confirmation of efficacy or if clinically indicated. The data within 14 days can be used as discontinuation data. At the follow-up, 
tumor evaluation (except PET) will be performed on every 6-8 weeks (except the case of discontinuation by disease progression and starting treatment of next antitumor drug).
To be intravenously administered 60 minutes (±10 minutes) from days 1 through 5 of each cycle.
k: The data of bone marrow biopsy (if it is difficult, bone marrow aspiration can be performed instead) within 28 days before IC can be used as screening data if it meets the 
requirement of the protocol. Bone marrow re-biopsy is required to confirm CR as best overall response, for the patients who were positive or unconfirmed for infiltration at 
screening or who did not perform bone marrow biopsy (who performed bone marrow aspiration). If clinically indicated, all patients are able to perform bone marrow re-biopsy.
l:
Perform at the screening, Day 15 to 22 (if postponed the beginning of next cycle, by Day 42) of Cycles 2, 4, 6, and 8 and discontinuation.
m: Submit a tumor biopsy sample which collected before the study drug treatment to the central laboratory prior to the last observation. If there are immunohistochemical staining 
data on CCR4 expression, such data can be used for this study.
n: Only the antitumor drugs and therapies will be collected as concomitant drugs/therapies during the Follow-up Phase.  Information of the duration of treatment and best overall 
response will be collected as long as possible.
o: Conduct on every 12 to 16 weeks from the discontinuation (or completion).
p: Data collected at the screening can be used as the baseline data if the data are collected within 7 days before the study drug administration.
q: From Cycle 2 or later, the next cycle can start on ±1 day from the planned date. The data collected 1 day before Day 1 can be used as those on Day 1 (except vital signs and 
12-lead electrocardiogram data).  Subjects will be hospitalized during Cycle 1 Days 1 to 8. 


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9.5.3
Appropriateness of Measurements
All clinical assessments are standard measurements commonly used in studies of malignant 
lymphoma.
The safety assessments to be performed in this study, including hematology analyses, blood 
chemistry tests, urinalysis, vital signs, body weight, physical examinations, ECOG PS, 
ECGs, ophthalmologic tests, and assessment of AEs are standard evaluations to ensure 
subject safety.
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events Associated 
with Special Situations
9.5.4.1
Reporting of Serious Adverse Events
All SERIOUS ADVERSE EVENTS, regardless of their relationship to study treatment, must 
be reported on a completed SAE form by email or fax as soon as possible but no later than 1 
business day from the date the investigator becomes aware of the event.  The investigator 
must report SAEs to the sponsor promptly using the SAE report form.  The detailed contact 
information for reporting of SAEs is provided in the Attachment of this protocol.
It is very important that the SAE report form be filled out as completely as possible at the 
time of the initial report.  This includes the investigator’s assessment of causality.
Any follow-up information received on SAEs should be forwarded within 1 business day of 
its receipt.  If the follow-up information changes the investigator’s assessment of causality, 
this should also be noted on the follow-up SAE form.
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the sponsor.
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through Breastfeeding
Any pregnancy in a female subject in which the estimated date of conception is either before 
the last visit or within 30 days of last study treatment, or any exposure to study drug through 
breastfeeding during study treatment or within 30 days of last study treatment, must be 
reported.
If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment.
A congenital anomaly, death during perinatal period, an induced abortion, or a spontaneous 
abortion are considered to be an SAE and should be reported in the same time frame and in 
the same format as all other SAEs (see Reporting of Serious Adverse Events 
[Section 9.5.4.1]).


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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 Attachment of this 
protocol.  The Pregnancy Report Form (attached) must be used for reporting.  All 
pregnancies must be followed to outcome.  The outcome of the pregnancy must be reported 
using the Pregnancy Outcome Report Form (attached) as soon as possible but no later than 1 
business day from the date the investigator becomes aware of the outcome.  A subject who 
becomes pregnant must be withdrawn from the study.
9.5.4.3
Reporting of Events Associated with Special Situations
9.5.4.3.1
REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE,
MISUSE, OR MEDICATION ERROR
Adverse events associated with study drug overdose, misuse, and medication error refer to 
AEs associated with uses of the study drug outside of that specified by the protocol.  
Overdose, misuse, 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
Medication error
Any unintentional event that causes or leads to inappropriate study 
drug use or subject harm while the study drug is in the control of site
personnel or the subject. 
All AEs associated with overdose, misuse, or medication error should be captured on the 
Adverse Event CRF and also reported using the procedures detailed in Reporting of Serious 
Adverse Events (Section 9.5.4.1) even if the AEs do not meet serious criteria.  Abuse is 
always to be captured as an AE.  If the AE associated with an overdose, misuse, or 
medication error does not meet serious criteria, it must still be reported using the SAE form 
and in an expedited manner but should be noted as nonserious on the SAE form and the 
Adverse Event CRF.
9.5.4.4
Expedited Reporting
The sponsor must inform investigators, the head of the medical institution, and regulatory 
authorities of reportable events, in compliance with applicable regulatory requirements, on an 
expedited basis.  For this reason, it is imperative that investigator or subinvestigator provide 
complete SAE information in the manner described in Section 9.5.4.1 “Reporting of Serious 
Adverse Events”.


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9.5.4.5
Breaking the Blind
Not applicable.
9.5.4.6
Regulatory Reporting of Adverse Events
Adverse events will be reported by the sponsor to regulatory authorities in compliance with 
local and regional law and established guidance.  The format of these reports will be dictated 
by the local and regional requirements.
9.5.5
Completion/Discontinuation of Subjects
A subject may elect to discontinue the study at any time for any reason.  All subjects who 
discontinue the study are to complete the study’s early discontinuation procedures indicated 
in the Schedule of Procedures/Assessments (Table 7).
The investigator or subinvestigator will promptly explain to the subject involved that the 
study will be discontinued for that subject and provide appropriate medical treatment and 
other necessary measures for the subject.  A subject who has ceased to return for visits will 
be followed up by mail, phone, or other means to gather information.  
Subjects who discontinue early from the study will be discontinued for 1 of primary reasons.  
In addition to the primary reason, the subject may indicate 1 or more secondary reason(s) for 
discontinuation.  
9.5.6
Abuse or Diversion of Study Drug
Not applicable.
9.5.7
Confirmation of Medical Care by Another Physician
The investigator, subinvestigator, or clinical research coordinator will instruct subjects to 
inform site personnel when they are planning to receive medical care by another physician.  
At each visit, the investigator, subinvestigator, or clinical research coordinator 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, subinvestigator, or clinical research coordinator, 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.


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9.6.1
Data Collection
Data required by the protocol will be collected on the CRFs.  As defined by GCP, the CRF is 
a printed, optical, or electronic document designed to record all of the protocol-required 
information to be reported to the sponsor on each study subject.
Data collection on the CRF must follow the instructions described in the CRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the CRF.  The investigator must sign the completed CRF to attest to 
its accuracy, authenticity, and completeness.
Completed, original CRFs are the sole property of the sponsor and should not be made
available in any form to third parties without written permission from Eisai, except for 
authorized representatives of the sponsor or appropriate regulatory authorities.
9.6.2
Clinical Data Management
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All 
data, both CRF and external data (eg, laboratory data), will be entered into a clinical system.
9.7
Statistical Methods
The cut-off date of the study analyses will be the earlier date of either all subjects have 
discontinued or completed Cycle 8 of the study, or the best overall response of all subjects on 
treatments are confirmed to be PR or better.  All statistical analyses will be performed after 
the database is locked and released.  Statistical analyses will be performed using SAS 
software or other validated statistical software as required.  Details of the statistical analyses 
will be included in a separate statistical analysis plan (SAP).
9.7.1
Statistical and Analytical Plans
The statistical analyses of the study data are described in this section.  Further details of the 
analytical plan will be provided in the SAP, which will be finalized before database lock.
9.7.1.1
Study Endpoints
9.7.1.1.1
PRIMARY ENDPOINT
Objective response rate (ORR) of the best overall response.
9.7.1.1.2
SECONDARY ENDPOINTS

Progression-free survival (PFS)

Duration of response (DOR)

Time to response (TTR)

Complete response (CR) rate


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
Overall survival (OS)

Safety endpoints (AEs, clinical laboratory parameters, vital signs, weight, ECOG PS, 
12-lead ECGs results, and ophthalmologic test results)

PK parameters

Immunogenicity (anti-E7777 antibody, anti-IL-2 antibody, and neutralizing activity of 
anti-E7777 antibody)
9.7.1.1.3
EXPLORATORY ENDPOINTS
Biomarkers in the tumor and blood.
9.7.1.2
Definitions of Analysis Sets
Full Analysis Set (FAS) is the group of subjects who registered in this study and received at 
least 1 dose of study drug.  This group will be the population for the evaluation of efficacy. 
Safety Analysis Set is the group of subjects who received at least 1 dose of study drug and 
had at least 1 evaluable post-baseline safety data.  This group will be the population for the 
evaluation of safety.
Pharmacokinetics Analysis Set is the group of subjects who received at least 1 dose of 
study drug and had at least 1 evaluable serum concentration data.
Pharmacodynamics Analysis Set is the group of subjects who received at least 1 dose of 
study drug and had at least 1 each of evaluable pre- and post-baseline PD data. 
9.7.1.3
Subject Disposition
The number of subjects signed informed consent, continued in the study after screening and 
screen failures will be provided and primary reasons for screening failure will be 
summarized. The number of subjects treated, untreated, completed the study, discontinued 
the study and the primary reasons for study discontinuation will be summarized. The number 
of subjects completed the study treatment, discontinued the study treatment and the primary 
reasons for discontinuation of the study treatment will also be summarized.
9.7.1.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics for the FAS and the Safety Analysis Set will 
be summarized for each disease (PTCL, CTCL) and overall.  Continuous demographic and 
baseline variables include age, height, and weight.  Categorical variables include sex, age 
group, race, ethnicity, ECOG PS, and previous treatment for the primary disease 
(radiotherapy, chemotherapy, and other therapies).
9.7.1.5
Prior and Concomitant Therapy
All investigator terms for medications recorded in the CRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary (WHO DD).  Prior medications will be 


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defined as medications that stopped before the first dose of study drug.  Concomitant 
medications will be defined as medications that (1) started before the first dose of study drug 
and were continuing at the time of the first dose of study drug, or (2) started on or after the 
date of the first dose of study drug up to the subject’s last visit.  All medications will be 
presented in subject data listings.
9.7.1.6
Efficacy Analyses
All efficacy analyses will be performed on the FAS.  All efficacy results will be summarized 
for each disease (PTCL, CTCL) and overall.
9.7.1.6.1
PRIMARY EFFICACY ANALYSIS
The rate of subjects whose best overall response is CR or PR is calculated as ORR, and its 
corresponding 2-sided exact 95% CI is also calculated. 
9.7.1.6.2
SECONDARY EFFICACY ANALYSES

Analysis of PFS
PFS will be summarized by Kaplan-Meier method using median with 95%CI. 

Analysis of DOR
DOR will be summarized by Kaplan-Meier method using median with 95% CI in 
responders. 

Analysis of TTR
TTR will be summarized by Kaplan-Meier method using median with 95% CI in 
responders. 

Analysis of CR rate
The number and percentage of subjects whose best overall response and its corresponding 
2-sided exact 95% CI will be provided. 

Analysis of OS
OS will be summarized by Kaplan-Meier method using median with 95%CI. 
9.7.1.6.3
EXPLORATORY EFFICACY ANALYSES
Not applicable.
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Analyses
9.7.1.7.1
PHARMACOKINETIC ANALYSES
For the Pharmacokinetic Analysis Set, plots of E7777 serum concentration versus actual time 
will be displayed for those samples collected for non-compartmental analysis.  PK 
parameters will be derived by non-compartmental analysis of the serum concentration data.  


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The following pharmacokinetic parameters for E7777 will be calculated: maximum observed 
concentration (Cmax), time at which the highest drug concentration occurs (tmax), area under 
the concentration-time curve (AUC), terminal elimination phase half-life (t1/2), volume of 
distribution at terminal phase (Vz), and total clearance (CL).
E7777 serum concentrations for population PK analyses will be listed for each subject by 
actual sampling time.  
Serum E7777 concentration data will be used to build PK models to explain the observed 
concentration data using population approach.  Additionally, the models may be used to 
explore the relationship between PK and select demographic variables.  The relationship 
between PK parameters and efficacy/AE endpoints will also be investigated through 
population PK/PD modeling.  For population PK and PK/PD analysis, the details will be 
described in the separately prepared analysis plan and its report, and the results will not be 
included in the clinical study report.
9.7.1.7.2
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ANALYSES
Immunogenicity
The measurement value will be listed for anti-E7777 antibody, anti-IL-2 antibody, and 
neutralizing activity of anti-E7777 antibody in Safety Analysis Set.
Pharmacodynamics
The measurement value (and the change from baseline, if necessary) for each evaluation 
period will be summarized using the number of subjects, mean, SD, median, minimum and 
maximum for each disease (PTCL, CTCL) and overall.  In addition, the individual plot over 
time will be prepared by subject.
Immunohistochemistry
Classified frequency and percentage of the CD25+ cells will be calculated for each disease 
(PTCL, CTCL) and overall in subjects who submitted the tumor sample.
9.7.1.8
Safety Analyses
All safety analyses will be performed on the Safety Analysis Set.  All safety results will be 
summarized for each disease (PTCL, CTCL) and overall.
9.7.1.8.1
EXTENT OF EXPOSURE
Number of cycles received, duration of treatment, total number of doses, total doses and dose 
ratio (actual dose/planned dose) will be summarized.
9.7.1.8.2
ADVERSE EVENTS
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 


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(MedDRA).  Adverse events will be coded to the MedDRA lower level term (LLT) closest to 
the verbatim term.  The linked MedDRA preferred term (PT) and primary system organ class 
(SOC) are also captured in the database.
A treatment-emergent adverse event (TEAE) is defined as an AE that emerges during 
treatment, having been absent at pretreatment (baseline) or 

Reemerges during treatment, having been present at pretreatment (Baseline) but stopped 
before treatment, or 

Worsens in severity during treatment relative to the pretreatment state, when the AE is 
continuous.
Only those AEs that are treatment-emergent will be included in summary tables.  All AEs, 
treatment-emergent or otherwise, will be presented in subject data listings.
The TEAEs will be summarized for each disease (PTCL, CTCL) and overall.  The incidence 
of TEAEs will be reported as the number (percentage) of subjects with TEAEs by SOC and 
PT.  A subject will be counted only once within an SOC and PT, even if the subject 
experienced more than 1 TEAE within a specific SOC and PT.  The number (percentage) of 
subjects with TEAEs will also be summarized by highest CTCAE grade.
The number (percentage) of subjects with TEAEs will also be summarized by relationship to 
study drug (Yes [related] and No [not related]).
The number (percentage) of subjects with treatment-emergent serious adverse events (SAEs) 
will be summarized by MedDRA SOC and PT for each disease (PTCL, CTCL) and overall.  
The number (percentage) of subjects with TEAEs leading to discontinuation from study drug, 
leading to dose reduction or leading to dose interruption will be summarized by MedDRA 
SOC and PT for each disease (PTCL, CTCL) and overall.
9.7.1.8.3
LABORATORY VALUES
Laboratory results will be summarized using Système International (SI) units, as appropriate.  
For all quantitative parameters listed in Section 9.5.1.5.4, the actual value and the change 
from baseline to each postbaseline visit and to the end of treatment will be summarized by 
visit for each disease (PTCL, CTCL) and overall using descriptive statistics.  Qualitative 
parameters 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.
In addition, CTCAE v4.03 will be used to identify subjects with treatment-emergent 
markedly abnormal laboratory values (TEMAVs), if necessary.


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9.7.1.8.4
VITAL SIGNS
Descriptive statistics for vital signs parameters (ie, systolic and diastolic BP, pulse, and 
temperature) and weight and changes from baseline will be presented by visit for each 
disease (PTCL, CTCL) and overall.
9.7.1.8.5
ELECTROCARDIOGRAMS
ECG assessments were performed at each visit.  Descriptive statistics for ECG parameters 
and changes from baseline will be presented by visit for each disease (PTCL, CTCL) and 
overall.  Shift tables will present changes from baseline in ECG interpretation.  In addition, 
the number (percentage) of subjects with at least 1 postbaseline abnormal ECG result in QTc
Fridericia (QTcF) during the treatment period will be summarized.  Clinically abnormal ECG 
results in QTcF will be categorized as follows:
Absolute QTcF interval prolongation:

QTcF interval >450 ms

QTcF interval >480 ms

QTcF interval >500 ms
Change from baseline in QTcF interval:

QTcF interval increases from baseline >30 ms

QTcF interval increases from baseline >60 ms
9.7.1.8.6
OTHER SAFETY ANALYSES
ECOG PS
ECOG-PS will be summarized by scale at each visit and by highest postbaseline scale.
9.7.2
Determination of Sample Size
Thirty-five patients were required to detect lower limit of the 95% confidence interval (CI) 
that exceed the 5% threshold in ORR, which is the primary endpoint of the study, with the 
expected ORR is 25% with a statistical power of 90%. In CTCL, 6 or more patients are
targeted to evaluate the safety as specific disease.
9.7.3
Interim Analysis
No interim analysis is planned for this study.
9.7.4
Other Statistical/Analytical Issues
Not applicable.


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9.7.5
Procedure for Revising the Statistical Analysis Plan
If the SAP needs to be revised after the study starts, the sponsor will determine how the 
revision impacts the study and how the revision should be implemented.  The details of the 
revision will be documented and described in the clinical study report.


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10 REFERENCE LIST
AbouYabis AN, Shenoy PJ, Sinha R, Flowers CR, Lechowicz MJ. A systematic review and 
meta-analysis of front-line anthracycline-based chemotherapy regimens for peripheral T-cell 
lymphoma. ISRN Hematol. 2011; Article ID 623924: 14 pages
Agar NS, Wedgeworth E, Crichton S, Mitchell TJ, Cox M, Ferreira S, et al. Survival 
outcomes and prognostic factors in mycosis fungoides/Sézary syndrome: validation of the 
revised International Society for Cutaneous Lymphomas/European Organisation for Research 
and Treatment of Cancer staging proposal. J Clin Oncol. 2010; 28: 4730-9.
Aoki R, Karube K, Sugita Y, Nomura Y, Shimizu K, Kimura Y, et al. Distribution of 
malignant lymphoma in Japan: analysis of 2260 cases, 2001-2006. Pathol Int. 2008; 58: 
174-182.
Carbone PP, Kaplan HS, Musshoff K, Smithers DW, Tubiana M. Report of the Committee 
on Hodgkin's Disease Staging Classification. Cancer Res. 1971; 31: 1860-61.
Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, et al. Revised 
response criteria for malignant lymphoma. J Clin Oncol. 2007; 25: 579-86.
Clinical Practice Guideline of Hematological Malignancies. the Japanese Society of 
Hematology, 2013.
Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, et al. Specific recruitment of 
regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced 
survival. Nature Med. 2004; 10: 942-9.
Dang NH, Pro B, Hagemeister FB, Samaniego F, Jones D, et al. Phase II trial of denileukin 
diftitox for relapsed/refractory T-cell non-Hodgkin lymphoma. Br J Haematol. 2007; 136: 
439-47.
Fisher RI, Gaynor ER, Dahlberg S, Oken MM, Grogan TM, Mize EM, et al. Comparison of a 
standard regimen (CHOP) with three intensive chemotherapy regimens for advanced 
non-hodgkin’s lymphoma. NEJM. 1993; 328: 1002-6.
Grozea PN, Jones SE, McKelvey EM, Coltman CA Jr, Fisher R, et al. Combination 
chemotherapy for mycosis fungoides: a Southwest Oncology Group study. Cancer Treat Rep. 
1979; 63: 647-53.
Gouill SL, Milpied N, Buzyn A, Latour RPD, Vernant JP, Mohty M, et al. 
Graft-versus-lymphoma effect for aggressive T-cell lymphomas in adults: a study by the 
Société Francaise de Greffe de Moëlle et de Thérapie Cellulaire. J Clin Oncol. 2008; 26: 
2264-71.
Hamada T and Iwatsuki K. The results of case survey for skin lymphoma in 2013. The 
Japanese Skin Cancer Society. 2013


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Kim YH, Willemze R, Pimpinelli N, Whittaker S, Olsen EA, Ranki A, et al. TNM 
classification system for primary cutaneous lymphomas other than mycosis fungoides and 
Sezary 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: 479-84.
LeMaistre CF, Saleh MN, Kuzel TM, Foss F, Platanias LC, et al. Phase I trial of a ligand 
fusion-protein (DAB389IL-2) in lymphomas expressing the receptor for interkeukin-2. 
Blood. 1998; 91: 399 405.
Létourneau S, Krieg C, Pantaleo G, Boyman O. IL-2- and CD25-dependent 
immunoregulatory mechanisms in the homeostasis of T-cell subsets. J Allergy Clin Immunol. 
2009; 123: 758-62.
Litzinger MT, Fernando R, Curiel TJ, Grosenbach DW, Schlom J, Palena C. IL-2 
immunotoxin denileukin diftitox reduces regulatory T cells and enhances vaccine-mediated 
T-cell immunity. Blood. 2007; 110: 3192-3201.
Lymphoma Study Group of Japanese Pathologists. The world health organization 
classification of malignant lymphomas in Japan: incidence of recently recognized entities. 
Pathol Int. 2000; 50: 696 702.
Mak V, Hamm J, Chhanabhai M, Shenkier T, Klasa R, Sehn LH, et al. Survival of patients 
with peripheral T-cell lymphoma after first relapse or progression: spectrum of disease and 
rare long-term survivors. J Clin Oncol. 2013; 31:1970-6. 
Morris JC, Waldmann TA. Advances in interleukin 2 receptor targeted treatment. Ann 
Rheum Dis 2000; 59 (suppl I):i109-14.
Morse MA, Hobeika AC, Osada T, Serra D, Niedzwiecki D, Lyerly HK, et al. Depletion of 
human regulatory T cells specifically enhances antigen-specific immune responses to cancer 
vaccines. Blood. 2008; 112:610-8.
NCCN Clinical Practice Guidelines in Oncology non-Hodgkin’s Lymphomas. V.3.2012.
NCCN Clinical Practice Guidelines in Oncology non-Hodgkin’s Lymphomas. V.1.2013.
NCCN Clinical Practice Guidelines in Oncology non-Hodgkin’s Lymphomas. V.1.2015.
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: 376-88.
Olsen E, Vonderheid E, Pimpinelli N, Willemze R, Kim Y, Knobler R, et al. Revisions to the 
staging and classification of mycosis fungoides and Sezary syndrome: a proposal of the 
International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task 


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force of the European Organization of Research and Treatment of Cancer (EORTC). Blood. 
2007; 110: 1713-22.
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: 2598-607.
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; 28:1870-7.
Prince HM, Martin AG, Olsen EA, Fivenson DP, Duvic M. Denileukin diftitox for the 
treatment of CD25 low-expression mycosis fungoides and Sézary syndrome. Leuk 
Lymphoma. 2013; 54: 69-75.
Scientific Evidence-Based Clinical Practice Guideline on Skin Malignancies II (1st edition). 
2010
VanderSpek JC, Mindell JA, Finkelstein A, Murphy JR. Structure/function analysis of the 
transmembrane domain of DAB389-interleukin-2, an interleukin-2 receptor-targeted fusion 
toxin. J Biol Chem. 1993; 268: 12077-82.
Vose JM, Armitage J, Weisenburger D; International T-cell Lymphoma Project. International 
peripheral T-cell and natural killer/T-cell Lymphoma study: pathology findings and clinical 
outcomes. J Clin Oncol. 2008; 26: 4124-30.
Yared J, Kimball A. The role of high dose chemotherapy and autologous stem-cell 
transplantation in peripheral T-cell lymphoma: A review of the literature and new 
perspectives. Cancer Treat Rev. 2013; 39: 51-9.
Zinzani PL, Baliva G, Magagnoli M, Bendandi M, Modugno G, et al. Gemcitabine treatment 
in pretreated cutaneous T-cell lymohoma: Experience in 44 patients. J Clin Oncol. 2000; 18: 
2603-6.


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11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE 
PROCEDURES)
11.1
Changes to the Protocol
Any change to the protocol requires a written protocol amendment or administrative change 
that must be approved by the sponsor before implementation.  
Amendments specifically affecting the safety of subjects, the scope of the investigation, or 
the scientific quality of the study require additional approval by the applicable IRBs.  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, and the IRB 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 the IRB.  In these cases, the sponsor may be required to send a letter to 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.
11.3
Monitoring Procedures
The CRA will maintain contact with the investigator and designated staff by telephone, letter, 
or email between study visits.  Monitoring visits to each site will be conducted by the 
assigned CRA as described in the monitoring plan.  The head of the medical institution will 
allow the CRA to inspect the clinical, laboratory, and pharmacy facilities to assure 
compliance with GCP and local regulatory requirements.  The CRFs and subject’s 
corresponding original medical records (source documents) are to be fully available for 
review by the sponsor’s representatives at regular intervals.  These reviews verify adherence 
to study protocol and data accuracy in accordance with GCP.  All records at the site are 
subject to inspection by the local auditing agency and to IRB review.
In accordance with GCP, source documents include, but are not limited to, the following:

Clinic, office, or hospital charts

Copies or transcribed health care provider notes that have been certified for accuracy 
after production

Recorded data from automated instruments such as IVRS/IWRS, x-rays, and other 
imaging reports (eg, sonograms, CT scans, magnetic resonance images, radioactive 
images, ECGs, EEGs, polysomnographs, pulmonary function tests) regardless of how 
these images are stored, including microfiche and photographic negatives


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
Pain, quality of life, or medical history questionnaires completed by subjects

Records of telephone contacts

Diaries or evaluation checklists

Drug distribution and accountability logs maintained in pharmacies or by research 
personnel

Laboratory results and other laboratory test outputs (eg, urine pregnancy test result 
documentation and urine dip-sticks)

Correspondence regarding a study subject’s treatment between physicians or memoranda 
sent to the IRBs

CRF components (eg, questionnaires) that are completed directly by subjects and serve as 
their own source
11.4
Recording of Data
A CRF is required and must be completed for each subject by qualified and authorized 
personnel.  All data on the CRF must reflect the corresponding source document, except 
when a section of the CRF itself is used as the source document.  Any correction to entries 
made on the CRF must be documented in a valid audit trail where the correction is dated, the 
individual making the correct is identified, the reason for the change is stated, and the 
original data are not obscured.  Only data required by the protocol for the purposes of the 
study should be collected.
The investigator must sign each CRF.  The investigator will report the CRFs to the sponsor 
and retain a copy of the CRFs.
11.5
Identification of Source Data
All data to be recorded on the CRF must reflect the corresponding source documents.  For 
the following items, the data recorded directly on the CRF are to be considered source data:

Records of study drug administration (eg, reason for treatment discontinuation, reason for 
dose modification)

Reasons for prior and concomitant therapy (including medications and therapies)

Information on the discontinuation (eg, reason for discontinuation)

Sampling date and time for PK analysis

Sampling date for clinical laboratory tests

Information on AEs (eg, grade, relationship to study drug, outcome)
11.6
Retention of Records
The circumstances of completion or termination of the study notwithstanding, the head of the 
medical institution or the designated representative is responsible for retaining all study 
documents, including but not limited to the protocol, copies of CRFs, the Investigator's 
Brochure, and regulatory agency registration documents (eg, ICFs and IRB correspondence).  


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The site should plan to retain study documents, as directed by the sponsor, for at least 3 years 
after the last approval of a marketing application and until there are no pending or 
contemplated marketing applications 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 the medical institution 
contact the sponsor, allowing the sponsor the option of permanently retaining the study 
records.
11.7
Auditing Procedures and Inspection
In addition to routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the sponsor’s 
SOPs to evaluate compliance with the GCP and all applicable local regulations.  Government 
regulatory authority may request an inspection during the study or after its completion.
11.8
Handling of Study Drug
All study drug will be supplied to the assigned pharmacist (or designee) by the sponsor. 
Drug supplies must be kept in an appropriate secure area (eg, locked cabinet) and stored 
according to the conditions specified on the drug labels.  The assigned pharmacist (or 
designee) 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, if required.  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 the assigned pharmacist (or designee) must not destroy any drug labels or any 
partly used or unused drug supply before approval to do so by the sponsor.  At the conclusion 
of the study and as appropriate during the study, the assigned pharmacist (or designee) will 
return all used and unused drug containers, drug labels, and a copy of the completed drug 
disposition form to the sponsor, if required.
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.  
The review is aimed at protecting the sponsor's proprietary information existing either at the 
date of the commencement of the study or generated during the study.
The detailed obligations regarding the publication of any data, material results, or other 
information generated or created in relation to the study shall be set out in the agreement 
between each head of the medical institution and the sponsor.


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11.10 Disclosure and Confidentiality
The contents of this protocol and any amendments and results obtained during the study 
should be kept confidential by the investigator, the investigator’s staff, and the IRB 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 head of the medical institution.
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 sponsor and the head of the medical institution.
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, the head of the medical institution, and regulatory 
authorities of the termination or suspension and the reason(s) for the termination or 
suspension.  The IRB will also be informed promptly and provided the reason(s) for the 
termination or suspension by the sponsor or by the investigator/the head of the medical 
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 head of the medical institution where applicable, 
and the investigator/ the head of the medical institution should promptly inform the sponsor 
and the IRB and provide the sponsor and the IRB with a detailed written explanation of the 
termination or suspension.  Study records must be retained as noted above.
11.12 Subject Insurance and Indemnity
The sponsor will provide insurance for any subjects participating in the study in accordance 
with all applicable laws and regulations.

SAP_001.pdf: 
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STATISTICAL ANALYSIS PLAN 
Study Protocol 
Number: 
E7777-J081-205 
Study Protocol 
Title: 
A Phase 2 study of E7777 in patients with relapsed or refractory peripheral 
T-cell lymphoma and cutaneous T-cell lymphoma 
Date: 
29 Jul 2019 
Version: 
Version 2.0 


PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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1 
TABLE OF CONTENTS 
1 
TABLE OF CONTENTS ...................................................................................................3 
2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................5 
3 
INTRODUCTION .............................................................................................................7 
3.1 
Study Objectives ......................................................................................................7 
3.1.1 
Primary Objective ..........................................................................................7 
3.1.2 
Secondary Objectives.....................................................................................7 
3.1.3 
Exploratory Objectives ..................................................................................7 
3.2 
Overall Study Design and Plan ................................................................................7 
4 
DETERMINATION OF SAMPLE SIZE ..........................................................................8 
5 
STATISTICAL METHODS ..............................................................................................8 
5.1 
Study Endpoints .......................................................................................................8 
5.1.1 
Primary Endpoint ...........................................................................................8 
5.1.2 
Secondary Endpoints .....................................................................................8 
5.1.3 
Exploratory Endpoints ...................................................................................8 
5.2 
Study Subjects ..........................................................................................................9 
5.2.1 
Definitions of Analysis Sets...........................................................................9 
5.2.2 
Subject Disposition ........................................................................................9 
5.2.3 
Demographic and Other Baseline Characteristics .........................................9 
5.2.4 
Prior and Concomitant Therapy ...................................................................10 
5.2.5 
Treatment Compliance .................................................................................10 
5.3 
Data Analysis General Considerations ..................................................................10 
5.3.1 
Pooling of Centers........................................................................................10 
5.3.2 
Adjustments for Covariates..........................................................................10 
5.3.3 
Multiple Comparisons/Multiplicity .............................................................10 
5.3.4 
Examination of Subgroups ...........................................................................11 
5.3.5 
Handling of Missing Data, Dropouts, and Outliers .....................................11 
5.4 
Efficacy Analyses ..................................................................................................11 
5.4.1 
Primary Efficacy Analyses ..........................................................................11 
5.4.2 
Secondary Efficacy Analyses ......................................................................11 
5.4.3 
Other Efficacy Analyses ..............................................................................13 
5.5 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses 13 
5.5.1 
Pharmacokinetic Analyses ...........................................................................13 
5.5.1.1 
Serum Concentration and its PK Parameter Analysis........................13 
5.5.1.2 
Pharmacokinetic Data Figures ...........................................................14 
5.5.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses ....14 
5.6 
Safety Analyses ......................................................................................................15 
5.6.1 
Extent of Exposure .......................................................................................15 


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5.6.2 
Adverse Events ............................................................................................15 
5.6.3 
Laboratory Values ........................................................................................16 
5.6.4 
Vital Signs ....................................................................................................17 
5.6.5 
12-lead ECGs ...............................................................................................17 
5.6.6 
Other Safety Analyses..................................................................................17 
5.7 
Exploratory Analyses .............................................................................................17 
6 
INTERIM ANALYSES ...................................................................................................18 
7 
CHANGES IN THE PLANNED ANALYSES ...............................................................18 
8 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING...............................19 
8.1 
PHARMACOKINETIC DATA HANDLING .......................................................19 
8.1.1 
Lower Limit of Quantification (LLOQ) of E7777 Serum Concentration....19 
8.1.2 
Below the Limit of Quantification (BLQ) Handling for Calculation of PK Parameters 20 
8.1.3 
BLQ Handling for Developing Concentration-Time Profiles .....................20 
8.1.4 
Handling of Anomalous Concentration Values ...........................................20 
8.2 
OTHER DATA HANDLING ................................................................................21 
9 
PROGRAMMING SPECIFICATIONS ..........................................................................21 
10 STATISTICAL SOFTWARE ..........................................................................................21 
11 MOCK TABLES, LISTINGS, AND GRAPHS ..............................................................22 
12 REFERENCES ................................................................................................................22 
13 APPENDICES .................................................................................................................23 
13.1 
Table For Laboratory Result Grading Based on CTCAE version 4.03 .................23 
 


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2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation 
Term 
AE 
adverse event 
AUC(0-inf) 
area under the concentration-time curve from zero time 
extrapolated to infinite time 
AUC(0-t) 
area under the concentration-time curve from zero time to time of 
last quantifiable concentration 
BLQ 
below the limit of quantification 
CCR4 
CC chemokine receptor 4 
CI 
confidence interval 
CL 
total clearance 
CR 
complete response 
CRF 
case report form 
CTCAE 
common terminology criteria for adverse events 
CTCL 
cutaneous T-cell lymphoma 
CV 
coefficient of variation 
Cmax 
maximum observed concentration 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
FAS 
full analysis set 
IC 
informed consent 
IL-2 
interleukin-2 
LDH 
lactate dehydrogenase 
LLOQ 
lower limit of quantification 
MedDRA 
medical dictionary for regulatory activities 
ORR 
objective response rate 
OS 
overall survival 
PD 
Pharmacodynamics 
PD 
progression disease 


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PFS 
progression-free survival 
PK 
Pharmacokinetic 
PS 
performance status 
PT 
preferred term 
PTCL 
peripheral T-cell lymphoma 
QT 
ECG interval from the beginning of the Q wave to the end of the 
Twave 
QTc 
QT interval corrected for heart rate 
R2adj 
adjusted regression coefficient 
Rac 
accumulation index 
SD 
Standard deviation 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TEMAV 
treatment-emergent markedly abnormal laboratory value 
TTR 
time to response 
Vss 
volume of distribution at steady state 
Vz 
volume of distribution at terminal phase 
WHO DD 
World Health Organization Drug Dictionary 
sIL-2R 
soluble interleukin-2 receptor 
t1/2 
terminal elimination phase half-life 
tmax 
time at which the highest drug concentration occurs 
λz 
terminal phase rate constant 


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3 
INTRODUCTION 
The purpose of this statistical analysis plan is to describe the procedures and the statistical methods and 
pharmacokinetics (PK) analysis methods that will be used to analyze and report results for Eisai Protocol E7777-
J081-205. 
 
3.1 
Study Objectives 
3.1.1 
Primary Objective 
To evaluate the efficacy (objective response rate: ORR) of E7777 in patients with relapsed or refractory peripheral 
T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL). 
 
3.1.2 
Secondary Objectives 
(1)To evaluate the efficacy of E7777 below. 
•Progression-free survival (PFS) 
•Duration of response (DOR) 
•Time to response (TTR) 
•Complete response (CR) rate 
•Overall survival (OS) 
(2)To evaluate the safety of E7777. 
(3)To evaluate the PK and immunogenicity (anti-E7777 antibody, anti- interleukin-2 (IL-2) antibody and 
neutralizing activity of anti-E7777 antibody) of E7777. 
 
3.1.3 
Exploratory Objectives 
To preliminarily explore the biomarkers of tumor and the blood below. 
(1)To measure the rate of CD25+ cells in tumor by immunohistochemistry. 
(2)To measure the amount of serum soluble IL-2 receptor (sIL-2R) and lactate dehydrogenase (LDH). 
(3)To measure the T-cell subsets in the peripheral blood.  
 
3.2 
Overall Study Design and Plan 
This is a multicenter, single-arm, open label, Phase 2 to evaluate efficacy, safety, PK and immunogenicity of 
E7777 in patients with relapsed or refractory PTCL and CTCL. This study composed of the following 3 periods: 
preparation, treatment and follow-up periods. The preparation period consists of the following four procedures: 
informed consent (IC), screening, enrollment, and baseline assessment. Informed consent (IC) is able to obtain 28 
days before the treatment. Enroll the patient who meet the inclusion criteria and does not meet the exclusion 
criteria. Conduct the baseline assessment within 7 days before the treatment. Confirm that the patient continue to 
meet the inclusion criteria and does not meet the exclusion criteria before moving to the treatment period. The 


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treatment period consists of 1 cycle of 3 weeks and lasts until meet the “discontinuation criteria” or Day 21 of 
Cycle 8. The evaluation at discontinuation will be performed within 7 days after termination of study treatment. 
 
4 
DETERMINATION OF SAMPLE SIZE 
Thirty-five patients were required to detect lower limit of the 95% confidence interval (CI) that exceed the 5% 
threshold in ORR, which is the primary endpoint of the study, with the expected ORR is 25% with a statistical 
power of 90%. In CTCL, 6 or more patient is targeted to evaluate the safety as specific disease. 
 
5 
STATISTICAL METHODS 
All descriptive statistics for continuous variables will be reported using mean, standard deviation (SD), median, 
minimum and maximum. Categorical variables will be summarized as number (percentage) of subjects. 
 
5.1 
Study Endpoints 
5.1.1 
Primary Endpoint 
Objective response rate (ORR) of best overall response 
 
5.1.2 
Secondary Endpoints 
 
Progression-free survival (PFS) 
 
Duration of response (DOR) 
 
Time to response (TTR) 
 
Complete response (CR) rate 
 
Overall survival (OS) 
 
Safety endpoints (adverse events [AEs], clinical laboratory parameters, vital signs, weight, Eastern 
Cooperative Oncology Group [ECOG] performance status [PS], 12-lead electrocardiograms [ECGs] results, 
and ophthalmologic test results) 
 
Pharmacokinetic (PK) parameters 
 
Immunogenicity (anti-E7777 antibody, anti-IL-2 antibody and neutralizing activity of anti-E7777 antibody) 
 
5.1.3 
Exploratory Endpoints 
Biomarkers of tumor (CD25+, CC chemokine receptor 4 [CCR4] expression) and following Pharmacodynamics 
(PD) biomarkers from the blood. 
・sIL-2R, LDH 


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・T-cell subsets (CD4+, CD4+/CD25+, CD4+/CD25+/Foxp3+, *CD4+/CD7－, *CD4+/CD26－)(*Only for 
mycosis fungoides and Sézary syndrome) 
 
5.2 
Study Subjects 
5.2.1 
Definitions of Analysis Sets 
Full Analysis Set (FAS): 
Defined as a group of subjects who have received at least one dose of the study drug. This group will be the 
population for the evaluation of efficacy.  
 
Safety Analysis Set: 
Defined as a group of subjects who have received at least one dose of the study drug with at least one evaluable 
post- baseline safety data. This group will be the population for the evaluation of safety. 
 
Pharmacokinetics Analysis Set: 
Defined as a group of subjects in who have received at least one dose of the study drug with at least one serum 
concentration data. 
  
Pharmacodynamics Analysis Set: 
Defined as a group of subjects in who have received at least one dose of the study drug with at least one evaluable 
pre and post-baseline PD data.  
 
On eligibility-confirmed subjects, the number (percentage) of subjects included in each analysis set will be 
summarized. 
5.2.2 
Subject Disposition 
The number (and percentage as needed) of subjects signed IC, continued in the study after screening and screen 
failures will be provided and primary reasons for screening failure will be summarized for all subjects. The 
number and percentage of subjects treated, untreated, completed the study, discontinued the study and the primary 
reasons for study discontinuation will be summarized for each disease (PTCL, CTCL, Other, as appropriate, 
determined by central review) and overall.  
 
5.2.3 
Demographic and Other Baseline Characteristics 
Demographic and baseline characteristics for FAS and the safety analysis set (and the PK analysis set if any 
discrepancy) will be summarized for each disease and overall using descriptive statistics. Continuous 
demographic and baseline variables include Age, Height, and Weight. Categorical variables include Sex, Age 
group (<65, 65<=), Race, Ethnicity, ECOG PS, CCR4 Expression category, CD25+ Cell Rate category and 
Relapsed/Refractory status (Relapsed: BOR of CR or PR in last previous systemic chemotherapy, Refractory: 
BOR of SD or PD in last previous systemic chemotherapy, and Unknown). In addition, number and percentage 
of subjects with each disease histology and each stage will be summarized for each disease and overall. 


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5.2.4 
Prior and Concomitant Therapy 
For the FAS, the number and percentage of subjects with each prior treatment (systemic chemotherapy, 
systemic anti-neoplastic [except systemic chemotherapy], topical therapy, autologous stem-cell transplantation, 
extracorporeal therapy [except radiotherapy], radiotherapy, surgery[except biopsy]) will be provided. The 
number of previous systemic chemotherapy regimen will be summarized as categorical variable and continuous 
variable for each disease and overall. The number and percentage of subject with each previous systemic 
chemotherapy will be also provided for each disease and overall. 
 
All investigator terms for medications recorded in the case report form (CRF) will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary (WHO DD). Prior medications are defined as 
medications that stopped before the 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. Any subthequent anti-cancer 
therapies are not regared as concomitant but listed separately.  All medications will be presented in subject data 
listings.  
 
5.2.5 
Treatment Compliance 
For the Safety Analysis set, the number and percentage of subjects who experienced at least one dose skipping / 
delay of the start of the cycle / dose reduction will be provided for each cycle/all period for each disease and 
overall. Reasons of delay and reduction will also be summarized for each disease and overall.  
 
5.3 
Data Analysis General Considerations 
All efficacy analyses will be conducted based on FAS. 
 
5.3.1 
Pooling of Centers  
Subjects from all centers will be pooled for all analyses. 
 
5.3.2 
Adjustments for Covariates 
No adjustment for covariates will be performed. 
 
5.3.3 
Multiple Comparisons/Multiplicity 
No statistical comparison is planned in this study. 


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5.3.4 
Examination of Subgroups 
All efficacy analyses will be conducted for each disease and overall. 
Primary efficacy analysis based on the independent assessment results will be performed by the following 
subgroups: sex (Male/ Female) and age group (<65, >=65), ECOG PS (0/ 1), Baseline CCR4 Status (Postive/ 
Negative), CD25+ Cell Rate (category1: <1%, 1-<10%, 10-<20%, 20-<50%, >=50, category2: <20%, >=20%), 
Relapsed/ Refractory status, previous systemic chemotherapy regimen (<=2, >2) and prior use of newly 
approved agent (Yes/ No). 
Analysis of TEAEs by SOC and PT will be performed by the following subgroups: sex, age group and ECOG 
PS.  
5.3.5 
Handling of Missing Data, Dropouts, and Outliers 
No imputation will be performed for missing data. 
Data exceptions will be identified before data base lock based on discussion with medical experts if necessary. 
 
5.4 
Efficacy Analyses 
FAS will be the primary analysis population. All efficacy result will be summarized for each disease and overall. 
Results from central assessment by efficacy and safety evaluation committee and investigator assessment will be 
used, as applicable. If needed, efficacy analysis results per investigator assessment will also be summarized. 
Unless otherwise noted, overall response considering both “Revised Response Criteria for Malignant Lymphoma 
(Cheson, J Clin Oncol; 2007)” and “Clinical Endpoints and Response Criteria in Mycosis Fungoides and Sézary 
Syndrome (Olsen, J Clin Oncol; 2011)” will be used. 
For summarization of tumor assessment relevant analysis except PFS and DOR, assessment results until 
discontinuation from study treatment will be used.  
 
5.4.1 
Primary Efficacy Analyses 
The rate of subjects whose best overall response is CR or PR is calculated as ORR, and the Exact 95% CI is 
also calculated. Analysis based on central assessment by Efficacy and safety evaluation committee will be 
regarded as primary result.  
Additionally, For PTCL, best overall response and ORR using overall response evaluated according to “Revised 
response criteria for malignant lymphoma” will be summarized.  And for CTCL, best overall response and ORR 
based on global response score of  “Clinical end points and response criteria in mycosis fungoides and Sézary 
syndrome” will be summarized. 
5.4.2 
Secondary Efficacy Analyses 
 Analysis of PFS 


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PFS will be summarized by Kaplan-Meier method using median with 95% CI. Kaplan-Meier curve will be 
provided. The number of event/censor (percentage) will be also summarized. 
 Analysis of DOR 
DOR will be summarized by Kaplan-Meier method using median with 95% CI in responders. The number of 
event/censor (percentage) will be also summarized. 
 Analysis of TTR 
TTR will be summarized using descriptive statistics in responders.  
 Analysis of CR rate 
Best overall response will be summarized. For CR rate (the rate of subjects whose best overall response is CR) 
Exact 95% CI will also be provided.  
 Analysis of OS 
OS will be summarized by Kaplan-Meier method using median with 95% CI. Kaplan-Meier curve will be 
provided. The number of event/censor (percentage) will be also summarized. In addition, summarization for 
follow-up time will be provided using Kaplan-Meier method. 
 
PFS will be calculated as: 
End date for PFS – Date of administration of the first dose of study drug + 1 (day) 
DOR will be calculated as: 
End date for DOR – Date of the first response + 1 (day) 
 
End date of PFS and DOR is defined as the table below: 
Situation 
End Date for PFS and DOR 
Censored 
Documented progression disease (PD) during 
the study  
Date of the first assessment of the series of 
the tests that determined PD 
No 
Death during the study before PD 
Date of death 
No 
No baseline assessments  
Date of administration of the first dose of 
study drug 
Yes 
Treatment discontinuation without post-
baseline tumor assessments 
Date of administration of the first dose of 
study drug 
Yes 
New anticancer treatment started prior to 
disease progression 
Date of last tumor assessment before start of 
new treatment 
Yes 
Death or PD after more than one missed tumor 
assessments 
Date of the last tumor assessment before 
missed assessments 
Yes 
Subjects still on treatment without PD as of 
data cut-off 
Date of last tumor assessment 
Yes 


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TTR will be calculated as: 
Date of first response – Date of administration of the first dose of study drug + 1 (day) 
 
OS will be calculated as: 
End date for OS – Date of administration of the first dose of study drug + 1 (day) 
 
End date for OS is defined as the table below: 
Situation 
End Date for OS 
Censored 
Death during the study 
Date of death 
No 
Alive at cut-off  
Date of cut-off  
Yes 
Other than the above 
Last known alive date 
Yes 
 
5.4.3 
Other Efficacy Analyses 
Best overall response will be summarized and ORR will be provided for each disease histology. 
Best response (including CR+PR) will be summarized for each lesion (target lesion, skin lesion, and peripheral 
blood lesion). 
Waterfall plot of target lesions and mSWAT score for maximum tumor shrinkage as a percent change of target 
lesions will be provided. Also, percent change from baseline over time will be presented using spider plot.   
 
5.5 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses 
5.5.1 
Pharmacokinetic Analyses 
The Safety Analysis Set will be used for individual E7777 serum concentrations listings. The PK Analysis Set 
will be used for the summaries of E7777 serum concentrations and PK parameters. 
5.5.1.1 
Serum Concentration and its PK Parameter Analysis 
<Serum Concentration> 
E7777 serum concentrations for non-compartmental analysis will be summarized using summary statistics (n, 
mean, standard deviation [SD], median, minimum [min] and maximum [max]) by nominal time point. 
E7777 serum concentrations will be listed for each subject by actual sampling time. 
<PK Parameter> 
PK parameters will be derived by non-compartmental analysis using WinNonlin software (version 6.2.1 or 
later) according to 302-104.01-MNL. 


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The following pharmacokinetic parameters for E7777 will be calculated: maximum observed concentration 
(Cmax), time at which the highest drug concentration occurs (tmax), area under the concentration-time curve from 
zero time to time of last quantifiable concentration (AUC(0-t)), area under the concentration-time curve from 
zero time extrapolated to infinite time (AUC(0-inf)), terminal elimination phase half-life (t½), total clearance 
(CL), volume of distribution at terminal phase (Vz), volume of distribution at steady state (Vss), accumulation 
index (Rac) of Cmax (Rac(Cmax)), Rac(AUC). 
Other PK parameters may be calculated as appropriate. 
Summary statistics will be tabulated for the PK parameters of E7777.  Summary statistics (n, mean, SD, 
median, min, and max) will be presented for all parameters (apart from tmax where mean and SD are not 
required).  In addition, geometric mean and coefficient of variation (CV) will also be presented for all 
parameters apart from tmax.  
PK parameters of E7777 for each subject will be listed. 
5.5.1.2 
Pharmacokinetic Data Figures 
The linear and semi-log plots of E7777 serum concentration versus actual time will be displayed by individual 
subjects. The actual time will be plotted on the X axis and the concentrations of E7777 will be plotted on the Y 
axis. 
The linear and semi-log mean (+SD) plots of E7777 serum concentration versus nominal time will be displayed.  
The nominal time will be plotted on the X axis and the mean (+SD) will be plotted on the Y axis on the same 
graph by visit (Day 1 of Cycle 1, 3 and 5). 
 
5.5.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses 
Immunogenicity: 
 The measurement value will be listed for anti-E7777 antibody, anti-IL-2 antibody and neutralizing activity of 
anti-E7777 antibody in safety analysis set. 
 
If antibody production is observed, the frequency and percentage of all antibody and neutralization activity will 
be calculated by visit. Titers of antibody will be summarized using summary statistics (n, mean, SD, median, min 
and max) by visit. 
The semi-log mean plots of titer of antibody (anti-E7777 antibody and anti-IL-2 antibody) versus nominal time 
will be displayed.  The nominal time will be plotted on the X axis and the mean will be plotted on the Y axis on 
the same graph. 
   
 
Pharmacodynamics: 
 PD analysis will be performed on the PD analysis set. The measurement value (and the change from baseline, if necessary) of 
sIL-2R, LDH and T-cell subsets (CD4+, CD4+/CD25+, CD4+/CD25+/Foxp3+, *CD4+/CD7－, *CD4+/CD26－) (*Only for 
mycosis fungoides and Sézary syndrome) for each evaluation period will be summarized using the number of subjects, mean, SD, 


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median, minimum and maximum for each disease and overall. In addition, mean plot of recorded values over time will be created. 
 
5.6 
Safety Analyses 
All safety analyses will be performed on the safety analysis set. All safety result will be summarized for each 
disease and overall. Safety variables include AEs, clinical laboratory parameters, vital signs, weight, ECOG PS, 
12-lead ECGs results, and ophthalmologic test results. 
 
5.6.1 
Extent of Exposure 
Number of cycles received, duration of treatment, total number of doses, total doses (overall/ by cycle) and 
relative dose intensity will be summarized. Number and percentage of subject with each starting dose will be 
provided by cycle. 
 
5.6.2 
Adverse Events 
The AE verbatim descriptions (investigator terms from the CRF) will be classified into standardized medical 
terminology using the Medical Dictionary for Regulatory Activities (MedDRA). AEs will be coded to the 
MedDRA (Version 19.1 or higher) lower level term (LLT) closest to the verbatim term. The linked MedDRA 
preferred term (PT) and primary system organ class (SOC) will also be captured in the database.  
A treatment-emergent adverse event (TEAE) is defined as an AE that emerged on or after the date of first dose 
of study drug, having been absent at pretreatment (Baseline) or  
• Reemerged during treatment, having been present at pretreatment (Baseline) but stopped before treatment, or  
• Worsened in severity during treatment relative to the pretreatment state, when the AE was continuous.  
Only those AEs that are treatment emergent will be included in summary tables.  All AEs, treatment emergent 
or otherwise, will be presented in subject data listings. 
Over view of TEAEs and treatment-related TEAEs include the number and percentage of subjects with any 
TEAEs, treatment-related TEAE, TEAEs with grade 3 or higher, serious TEAEs (death, other SAEs) and 
TEAEs leading to study drug dose adjusment (study drug withdrawal, dose reduction, interruption). 
The number and percentage of subjects with TEAEs will be calculated from the following viewpoints. 
• All/Treatment-related TEAEs by PT 
• All/Treatment-related TEAEs by SOC/PT 
• All/Treatment-related TEAEs with Grade 3 or Higher by PT 
• All/Treatment-related TEAEs with Grade 3 or Higher by SOC/PT 
• All/Treatment-related TEAEs by SOC/PT and Grade 
• All/Treatment-related TEAEs with Grade 3 or Higher by SOC/PT and Grade 
• All/Treatment-related Serious TEAEs by PT 
• All/Treatment-related Serious TEAEs by SOC/PT 
• All/Treatment-related Serious TEAEs by SOC/PT and Grade 


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• All/Treatment-related TEAEs leading to withdrawal by SOC/PT 
• All/Treatment-related TEAEs leading to dose reduction by SOC/PT 
• All/Treatment-related TEAEs leading to dose interruption by SOC/PT 
• All/Treatment-related TEAEs leading to delay by SOC/PT 
• Specially grouped TEAE by SOC and PT 
• Specially grouped TEAE by SOC and PT and Cycle 
• Specially grouped TEAE with Grade 3 or Higher by SOC and PT 
• Specially grouped TEAE with Grade 3 or Higher by SOC and PT and Cycle 
 
Where Specially grouped TEAE includes Infusion reactuion, Capillary leak syndrome and related events, 
Vision disorders, Hepatobiliary disorders, Hematotoxicity, Infection, Skin disorders, Rhabdomyolysis and 
related events. 
In addition, the number and percentage of subjects with TEAEs of infision reaction will be summarized as 
follows. 
• TEAEs of Infusion reaction by SOC/PT and visit  
• Time to onset for initial TEAEs of infusion reaction 
• Time to onset for initial TEAEs of infusion reaction and visit 
• Time to recovery for TEAEs of infusion reaction 
• Time to recovery for TEAEs of infusion reaction and visit 
 
In counting numbers of subjects by severity, each subject will be counted only once for that categories. If a subject 
experienced relevant TEAEs more than once, the subject will be categorized according to the prioritizations of 
(“Grade 5” > “Grade 4” > “Grade 3” > “Grade 2” > “Grade 1”). 
 
Number of TEAEs and TEAE with grade 3 or higher devided by number of patients treated will be calculated per 
cycle and presented in figures.  
 
5.6.3 
Laboratory Values 
 
Laboratory results will be summarized using Système International (SI) units, as appropriate. 
For all quantitative parameters listed in protocol Section 9.5.1.5.4 Safety Assessments (Laboratory 
Measurements), the actual value and the change from baseline to each post baseline visit and final observation 
will be summarized by visit using descriptive statistics. Qualitative parameters listed in protocol Section 9.5.1.5.4 
will be summarized using frequencies (number and percentage of subjects), and changes from baseline to each 
post baseline visit and final observation will be reported using shift tables. Percentages will be based on the 
number of subjects with both non-missing baseline and relevant post baseline results. 
 
CTCAE ver.4.03 will be used to identify subjects with treatment-emergent markedly abnormal laboratory values 
(TEMAVs). TEMAV is defined as a post baseline value with an increase from baseline to a grade of 2 or higher. 
When displaying the incidence of TEMAVs, each subject will be counted once in the laboratory parameter high 
and in the laboratory parameter low categories, as applicable. 
The measured values for quantitative data will be displayed over time using Box plot. 
 


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5.6.4 
Vital Signs 
Descriptive statistics for vital signs parameters (diastolic and systolic blood pressure, pulse rate, body temperature 
and weight) and changes from baseline will be presented by visit.  
The measured values will be displayed over time using Box plot. 
 
5.6.5 
12-lead ECGs   
ECG assessments were performed at each visit. Descriptive statistics for ECG parameters and changes from 
baseline will be presented by visit. Shift tables will present changes from baseline in ECG interpretation 
(categorized as normal; abnormal, not clinically significant; and abnormal, clinically significant) by visit. In 
addition, the number (percentage) of subjects with at least 1 post baseline abnormal ECG result QTc Fridericia 
during the treatment period will be summarized. Clinically abnormal ECG results in QTc Fridericia will be 
categorized as follows: 
Absolute QTc interval prolongation: 
• QTc interval >450 ms 
• QTc interval >480 ms 
• QTc interval >500 ms 
Change from baseline in QTc interval: 
• QTc interval increases from baseline >30 ms 
• QTc interval increases from baseline >60 ms 
 
5.6.6 
Other Safety Analyses 
ECOG PS : 
The number and percentage of subjects included in each category will be cross tabulated based on baseline and 
each scheduled visit.  
 
Ophthalmologic test : 
The eye test result will be cross tabulated based on baseline and worst post-baseline. 
 
5.7 
Exploratory Analyses 
Exploratory analyses may be conducted as appropriate. Any exploratory analyses that are performed will be 
appropriate titled and labeled as exploratory and will be clearly distinguished from planned analyses when results 
are reported in the Clinical Study Report. 


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6 
INTERIM ANALYSES 
No interim analyses are planned for this study. 
 
7 
CHANGES IN THE PLANNED ANALYSES 
The list below includes both change from protocol and SAP version 1.0. 
 
Summarization of “Analysis Sets” has been added (section 5.2.1). 
 
Summarization of “Completion and discontinuation for treatment” has been deleted because the data is not 
collected (section 5.2.2). 
 
Summarization of  “CCR4 category”, “each disease histology and each stage” and “Relapsed/Refractory 
status” has been added (section 5.2.3). 
 
Summarization of  “Number of previous systemic chemotherapy regimen” and “each previous systemic 
chemotherapy” has been added (section 5.2.4). 
 
Summarization of  “prior medication” and “concomitant medication” has been deleted (section 5.2.4). 
 
Definition of concomitant medication has been changed (section 5.2.4). 
 
Summarization of “Treatment Compliance” has been added (section 5.2.5). 
 
Subgroup analyses for efficacy and safety have been added (section 5.3.4). 
 
Summarization of efficacy endpoints by investigator has been added (section 5.4). 
 
Handling rule of tumor assessment data has been clarified (section 5.4). 
 
Summarization of “BOR and ORR focused on PTCL/CTCL evaluation criteris” has been added (section 
5.4.1).  
 
Summarization of “Event/censor” for PFS, DOR and OS has been added (section 5.4.2). 
 
Kaplan-Meier curve for PFS, OS and OS has been added (section 5.4.2). 
 
Censoring rule for PFS and DOR has been changed (section 5.4.2).  
 
Summarization of TTR has been changed to not use Kaplan-Meier method because there is no need to use 
Kaplan-Meier method if the target is responder. (section 5.4.2). 
 
Summarization of “Best overall response” has been added (section 5.4.2). 


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 
Summarization of “Best overall response and ORR for each disease histology” has been added (section 
5.4.3). 
 
Summarization of “Best response for each lesion” has been added (section 5.4.3). 
 
Waterfall plot of “target lesions and mSWAT score” has been added (section 5.4.3). 
 
Spider plot of “target lesions and mSWAT score” has been added (section 5.4.3). 
 
Plotting individual values of immunogenity titer and PD markers on mean plot has been deleted (section 
5.5.2). 
 
Summarization of “dose ratio” has been changed to “relative dose intensity” (section 5.6.1). 
 
Definition of TEAEs has been changed to be conservative (section 5.6.1). 
 
Detailed listing of AE tables has been added (section 5.6.2). 
 
Some patterns of summazation on TEAEs has been added (section 5.6.2). 
 
Summarization of “Specially grouped TEAE” has been defined and added (section 5.6.2). 
 
Summarizations of “time to onset/recovery of infusion reaction” has been added (section 5.6.2). 
 
Summarization of “number of adverse events per subject” has been added (section 5.6.2). 
 
Boxplot of measured laboratory parameter values over time has been added (section 5.6.3). 
 
Boxplot of measured vital sign parameter values over time has been added (section 5.6.4). 
 
Summarization of “Ophthalmologic test” has been added (section 5.6.6). 
 
PK parameters have been added(section 8.2.5) 
 
CTCAE grading rules have been updated (section 13.1) 
 
8 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING 
The data will be handled as follows. The sponsor will determine how to handle all data prior to data base lock.  
 
8.1 
PHARMACOKINETIC DATA HANDLING 
8.1.1 
Lower Limit of Quantification (LLOQ) of E7777 Serum Concentration  
The LLOQ of E7777 serum concentrations is 5.00 ng/mL 


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8.1.2 
Below the Limit of Quantification (BLQ) Handling for Calculation of PK Parameters 
While calculating PK parameters in WinNonlin, BLQ values will be handled according to 302-104.01-MNL, 
for non-compartmental pharmacokinetic analysis. 
8.1.3 
BLQ Handling for Developing Concentration-Time Profiles 
When developing individual concentration-time profiles, BLQ values will be handled according to 302-104.01-
MNL for non-compartmental pharmacokinetic analysis. 
8.1.4 
Handling of Anomalous Concentration Values 
The handling of anomalous concentration values will follow the guidance in the SWP for non-compartmental 
pharmacokinetic analysis (302-104.01-MNL). 
8.2.5 General Rules for Presentation of Drug Concentrations and PK Parameters 
When presenting individual/raw (raw, hereafter) values and summary statistics, the following rule will be 
applied: for drug concentrations and concentration-dependent pharmacokinetic parameters, all summary 
statistics (mean, median, geometric mean, SD  and CV) will have 3 significant digits. For tmax, raw values and 
their median are shown in fixed 2 decimal places. 
Variable 
Unit 
N 
Digit rule 
Raw/ 
Minimum/ 
Maximum 
Mean 
Median 
SD 
 
Geometric  
Mean 
CV 
(%) 
drug concentration 
ng/mL 
X 
Significant 
digits 
3 
3 
3 
- 
- 
Cmax 
ng/mL 
X 
Significant 
digits 
3 
3 
3 
3 
3 
tmax 
min 
X 
Fixed decimal 
places 
2 
2 
- 
- 
- 
λz 
1/min 
X 
Significant 
digits 
3 
(Listing only) 
- 
- 
- 
- 
t1/2 
min 
X 
Significant 
digits 
3 
3 
3 
3 
3 
AUC(0-t),  
AUC(0-inf) 
ng•min/mL 
X 
Significant 
digits 
3 
3 
3 
3 
3 
%AUCex 
% 
X 
Significant 
digits 
3 
(Listing only) 
- 
- 
- 
- 
MRT 
min 
X 
Significant 
digits 
3 
3 
3 
3 
3 
CL 
mL/min/kg 
X 
Significant 
digits 
3 
3 
3 
3 
3 
Vz, Vss 
mL/kg 
X 
Significant 
digits 
3 
3 
3 
3 
3 
Rac(Cmax), 
Rac(AUC) 
 
X 
Significant 
digits 
3 
3 
3 
3 
3 
Mean, SD, geometric mean and CV will not be calculated for tmax. 
CV(%)= sqrt(exp[SD**2 of log transformed data]-1)*100 
 


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NOTE 
1. The following parameters are reported in the CSR, but appear in Listings only. They are important information to 
confirm that individual t½ and its related parameters such as AUC(0-inf) are appropriately derived and allow those PK 
parameters to be reproduced when necessary. 
a. Time points used for estimation of terminal phase rate constant (λz) (lower and upper) 
b. Number of the time points used for λz 
c. Adjusted regression coefficient (R2adj) 
d. Percentage of AUC(0-inf) obtained by extrapolation (%AUCex) 
 
In Listings, a) are shown in same digits as actual sampling time after dosing used for calculation of PK parameters. For b), 
integer number is used in Listings.  For c) and d), significant 3 digits are used in Listing. 
 
8.2 
OTHER DATA HANDLING 
Baseline 
Baseline is defined as the last non-missing value observed prior to the first dose of study 
drug for a given parameter. For any Baseline value of 0, the subject’s corresponding 
Percent Change from Baseline will not be included in the summary statistics tables. 
Handling of Missing data 
No imputation will be performed for missing data. 
 
9 
PROGRAMMING SPECIFICATIONS 
The rules for programing derivations and dataset specification are provided as separate documents. 
 
10 STATISTICAL SOFTWARE 
PK Analysis will be performed using SAS for Windows (ver.9.2 or later), WinNonlin (Professional version 6.2.1 
or later), Pharsight Knowledgebase Server (version 3.0 or later), Microsoft Excel (97 or later) and S-PLUS (6.1J 
or later for Windows).  
Statistical analyses and summaries will be performed by Takumi Information Technology using SAS for 
Windows (ver.9.2 or later), and Microsoft Excel (2003 or later). Analyses will be conducted by using validated 
standard programs or double programming. For analyses needed in data review, single programming will be used.  
 


Statistical Analysis Plan 
E7777-J081-205 
 
 
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Version 2.0 : 29 Jul 2019  
Confidential 
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11 MOCK TABLES, LISTINGS, AND GRAPHS 
The study table, listing and graph shells will be provided in a separate document, which will show the content 
and format of all tables, listings, and graphs in detail. 
 
12 REFERENCES 
There is no reference. 
 


Statistical Analysis Plan 
E7777-J081-205 
 
 
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Version 2.0 : 29 Jul 2019  
Confidential 
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13 APPENDICES 
13.1 Table For Laboratory Result Grading Based on CTCAE version 4.03  
This table is based on the CTCAE ver 4.03, but partially modified for the mathematical grading perpose. 
Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0  
Published: May 28, 2009 (v4.03: June 14, 2010) 
Adverse event 
Grade 
1 
2 
3 
4 
5 
Blood and lymphatic system disorders 
Anemia 
Hemoglobin (Hgb) 
<LLN - 10.0 g/dL;  
<LLN - 6.2 mmol/L; 
<LLN - 100 g/L 
Hgb <10.0 - 8.0 
g/dL; 
<6.2 - 4.9 mmol/L;  
<100 - 80g/L 
Hgb <8.0 g/dL;  
<4.9 mmol/L; 
<80 g/L;  
transfusion 
indicated 
Life-threatening 
consequences; 
urgent intervention 
indicated 
Death 
Leukocytosis 
- 
- 
＞100,000 /mm3 
Clinical 
manifestations of 
leucostasis;  
urgent intervention 
indicated 
Death 
Investigations 
Alanine 
aminotransferase 
increased 
＞ULN - 3.0 × ULN 
＞3.0 - 5.0 × ULN 
＞5.0 - 20.0 × ULN 
＞20.0 × ULN 
- 
Alkaline 
phosphatase 
increased 
＞ULN - 2.5 × ULN 
＞2.5 - 5.0 × ULN 
＞5.0 - 20.0 × ULN 
＞20.0 × ULN 
- 
Aspartate 
aminotransferase 
increased 
＞ULN - 3.0 × ULN 
＞3.0 - 5.0 × ULN 
＞5.0 - 20.0 × ULN 
＞20.0 × ULN 
- 
Blood bilirubin 
increased 
＞ULN - 1.5 × ULN 
＞1.5 - 3.0 × ULN 
＞3.0 - 10.0 × ULN 
＞10.0 × ULN 
- 
Cholesterol high 
＞ULN - 300 
mg/dL; 
＞ULN - 7.75 
mmol/L 
＞300 - 400 
mg/dL; 
＞7.75 - 10.34 
mmol/L 
＞400 - 500 
mg/dL; 
＞10.34 - 12.92 
mmol/L 
＞500 mg/dL; 
＞12.92 mmol/L 
- 
CPK increased 
＞ULN-2.5×ULN 
＞2.5×ULN-5×ULN 
＞5×ULN-10×ULN 
＞10×ULN 
- 
Creatinine 
increased 
＞1 - 1.5 × 
baseline;         
＞ULN - 1.5 × ULN 
＞1.5 - 3.0 × 
baseline; 
＞1.5 - 3.0 × ULN 
＞3.0 × baseline; 
＞3.0 - 6.0 × ULN 
＞6.0 × ULN 
- 
GGT increased 
 
＞ULN - 2.5 × ULN 
＞2.5 - 5.0 × ULN 
＞5.0 - 20.0 × ULN 
＞20.0 × ULN 
- 
Hemoglobin 
increased 
Increase in >0 - 2 
gm/dL above ULN 
or above baseline 
Increase in >2 - 4 
gm/dL above ULN 
or above baseline 
Increase in >4 
gm/dL above ULN 
or above baseline 
- 
- 


Statistical Analysis Plan 
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if baseline is above 
ULN 
if baseline is above 
ULN 
if baseline is above 
ULN 
Lipase increased 
 
＞ULN - 1.5 × ULN 
＞1.5 - 2.0 × ULN 
＞2.0 - 5.0 × ULN 
＞5.0 × ULN 
- 
Lymphocyte count 
decreased 
＜LLN - 800/mm3;  
＜LLN - 0.8 × 10e9 
/L 
＜800 - 500/mm3;  
＜0.8 - 0.5 × 10e9 
/L 
＜500 - 200/mm3;  
＜0.5 - 0.2 × 10e9 
/L 
＜200/mm3;  
＜0.2 × 10e9 /L 
- 
Lymphocyte count 
increased 
- 
＞4,000 - 
20,000/mm3 
＞20,000/mm3 
- 
- 
Neutrophil count 
decreased 
＜LLN - 
1,500/mm3;  
＜LLN – 1.5 × 
10e9 /L 
＜1,500 - 
1,000/mm3;  
＜1.5 - 1.0 × 10e9 
/L 
＜1,000 - 
500/mm3;  
＜1.0 - 0.5 × 10e9 
/L 
＜500/mm3;  
＜0.5 × 10e9 /L 
- 
Platelet count 
decreased 
＜LLN - 
75,000/mm3; 
＜LLN - 75.0 × 
10e9 /L 
＜75,000 - 
50,000/mm3; 
＜75.0 - 50.0 × 
10e9 /L 
＜50,000 - 
25,000/mm3; 
＜50.0 - 25.0 × 
10e9 /L 
＜25,000/mm3; 
＜25.0 × 10e9 /L 
- 
Serum amylase 
increased 
＞ULN - 1.5 × ULN 
＞1.5 - 2.0 × ULN 
＞2.0 - 5.0 × ULN 
＞5.0 × ULN 
- 
White blood cell 
decreased 
＜LLN - 
3,000/mm3;  
＜LLN - 3.0 × 10e9 
/L 
＜3,000 - 
2,000/mm3;  
＜3.0 - 2.0 × 10e9 
/L 
＜2,000 －
1,000/mm3; ＜2.0 - 
1.0 × 10e9 /L 
＜1,000/mm3;  
＜1.0 × 10e9 /L 
- 
Metabolism and nutrition disorders 
Hypercalcemia 
Corrected serum 
calcium of 
>ULN - 11.5 
mg/dL;  
>ULN - 2.9 
mmol/L; 
Ionized calcium 
>ULN 
- 1.5 mmol/L 
Corrected serum 
calcium of 
>11.5 - 12.5 
mg/dL;  
>2.9 - 3.1 mmol/L;  
Ionized calcium 
>1.5 - 1.6 mmol/L;  
symptomatic 
Corrected serum 
calcium of 
>12.5 - 13.5 
mg/dL;  
>3.1 - 3.4 mmol/L; 
Ionized calcium 
>1.6 - 1.8 mmol/L; 
hospitalization 
indicated 
Corrected serum 
calcium of 
>13.5 mg/dL;  
>3.4 mmol/L; 
Ionized calcium 
>1.8 mmol/L; 
life-threatening 
consequences 
Death 
Hyperglycemia 
 
 
 
 
Fasting glucose 
value >ULN - 160 
mg/dL; 
Fasting glucose 
value >ULN - 8.9 
mmol/L 
Fasting glucose 
value >160 - 250 
mg/dL;  
Fasting glucose 
value >8.9 - 13.9 
mmol/L 
>250 - 500 mg/dL;  
>13.9 - 27.8 
mmol/L; 
hospitalization 
indicated 
>500 mg/dL;  
>27.8 mmol/L; 
Lifethreatening 
consequences 
Death 
Hyperkalemia 
 
 
 
＞ULN - 5.5 
mmol/L 
＞5.5 - 6.0 mmol/L 
>6.0 - 7.0 mmol/L; 
hospitalization 
indicated 
>7.0 mmol/L; 
life-threatening 
consequences 
Death 
Hypernatremia 
＞ULN - 150 
mmol/L 
＞150 - 155 
mmol/L 
>155 - 160 
mmol/L; 
hospitalization 
indicated 
>160 mmol/L; life-
threatening 
consequences 
Death 


Statistical Analysis Plan 
E7777-J081-205 
 
 
Eisai 
Version 2.0 : 29 Jul 2019  
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Hypertriglyceridemi
a 
 
 
 
 
150 mg/dL - 300 
mg/dL;  
1.71 mmol/L - 3.42 
mmol/L 
>300 mg/dL – 500 
mg/dL;  
>3.42 mmol/L - 5.7 
mmol/L 
>500 mg/dL - 1000 
mg/dL; 
>5.7 mmol/L - 11.4 
mmol/L 
>1000 mg/dL;  
>11.4 mmol/L; 
life-threatening 
consequences 
Death 
Hyperuricemia 
 
 
 
 
- 
>ULN - 10 mg/dL 
(0.59 mmol/L) 
- 
>10 mg/dL; >0.59 
mmol/L; life-
threatening 
consequences 
Death 
Hypoalbuminemia 
 
 
 
 
＜LLN - 3 g/dL;  
＜LLN - 30 g/L 
＜3 - 2 g/dL;  
＜30 - 20 g/L 
＜2 g/dL;  
＜20 g/L 
Life-threatening 
consequences; 
urgent intervention 
indicated 
Death 
Hypocalcemia 
 
 
 
 
 
 
 
Corrected serum 
calcium of <LLN - 
8.0 mg/dL;  
<LLN - 2.0 mmol/L; 
Ionized calcium 
<LLN - 
1.0 mmol/L 
Corrected serum 
calcium of <8.0 - 
7.0 mg/dL;  
<2.0 - 1.75 
mmol/L; 
Ionized calcium 
<1.0 - 
0.9 mmol/L;  
symptomatic 
Corrected serum 
calcium of <7.0 - 
6.0 mg/dL;  
<1.75 - 1.5 
mmol/L; 
Ionized calcium 
<0.9 - 
0.8 mmol/L; 
Hospitalization 
indicated 
Corrected serum 
calcium of <6.0 
mg/dL; 
<1.5 mmol/L; 
Ionized calcium 
<0.8 mmol/L; 
life-threatening 
consequences 
Death 
Hypoglycemia 
＜LLN - 55 mg/dL;  
＜LLN - 3.0 
mmol/L 
＜55 - 40 mg/dL; 
＜3.0 - 2.2 mmol/L 
＜40 - 30 mg/dL;  
＜2.2 - 1.7 mmol/L 
＜30 mg/dL;  
＜1.7 mmol/L;  
lifethreatening 
consequences; 
seizures 
Death 
Hypokalemia 
- 
＜LLN - 3.0 
mmol/L; 
 
＜3.0 - 2.5 mmol/L; 
hospitalization 
indicated 
＜2.5 mmol/L; 
life-threatening 
consequences 
Death 
Hyponatremia 
 
 
 
＜LLN - 130 
mmol/L 
- 
＜130 - 120 
mmol/L 
＜120 mmol/L; 
life-threatening 
consequences 
Death 
Renal and urinary disorders 
Proteinuria 
1+ proteinuria; 
urinary protein 
<1.0 g/24 hrs 
Adults: 2+ 
proteinuria;  
urinary protein  
1.0 - 3.4 g/24 hrs; 
Pediatric: urine 
P/C 
Adults: urinary 
protein >=3.5 g/24 
hrs; 
Pediatric: urine 
P/C >1.9 
- 
 - 


Statistical Analysis Plan 
E7777-J081-205 
 
 
Eisai 
Version 2.0 : 29 Jul 2019  
Confidential 
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(Protein/Creatinine
) ratio 0.5 - 1.9