Clinical trial NCT03456726
Conditions: Relapsed or Refractory B-cell Non-Hodgkin's Lymphoma
Keywords: EZH2 gene mutation Tazemetostat Diffuse large B-cell lymphoma Follicular lymphoma
Sponsor: Eisai Co., Ltd.
Start date: 2018-04-09; Completion date: 2021-12-17
Enrollment: 20 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multicenter, open-label, Phase 2 study to assess the efficacy and safety of tazemetostat in participants with relapsed or refractory B-cell non-Hodgkin's lymphoma (NHL) with EZH2 gene mutation.

Detailed description:

Arms: arm 1: Participants with follicular lymphoma (FL) with the EZH2 gene mutation will receive oral tazemetostat at a starting dose of 800 milligrams (mg) twice daily (1600 mg total daily dose) by continuous regimen, no less than 8 hours between doses. arm 2: Participants with diffuse large B-cell lymphoma (DLBCL) with the EZH2 gene mutation will receive oral tazemetostat at a starting dose of 800 mg twice daily (1600 mg total daily dose) by continuous regimen, no less than 8 hours between doses.
Interventions: intervention 1: Tazemetostat
Intervention descriptions: intervention 1: Tazemetostat will be provided as a 200 mg oral tablet.

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol 
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1 
TITLE PAGE 
 
Clinical Study Protocol 
Study Protocol 
Number: 
E7438-J081-206 (EZH-206) 
Study Protocol 
Title: 
A Phase 2 Study of Tazemetostat in Relapsed or Refractory B-cell 
Non-Hodgkin’s Lymphoma with EZH2 Gene Mutation 
Sponsor: 
Eisai Co., Ltd.  
4-6-10 Koishikawa Bunkyo-Ku, Tokyo 112 8088 Japan 
Investigational 
Product Name: 
E7438/tazemetostat (INN) 
Indication: 
B-cell non-Hodgkin’s lymphoma 
Phase: 
2  
Approval Date: 
V1.0 
27 Dec 2017 (original protocol) 
 
V2.0 
18 Oct 2018 (per Amendment 01) 
 
V3.0 
15 Nov 2019 (per Amendment 02) 
 
V4.0 
29 Jan 2021 (per Amendment 03) 
GCP Statement: 
This study is to be performed in full compliance with all applicable 
local Good Clinical Practice (GCP) and regulations (Good Post-
marketing Study Practice [GPSP] in case of post-marketing study).  
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.:  E7438 
Name of Active Ingredient:  Tazemetostat (INN) 
Study Protocol Title 
A Phase 2 Study of Tazemetostat in Relapsed or Refractory B-cell Non-Hodgkin’s Lymphoma with 
EZH2 Gene Mutation 
Investigators 
Refer to the Attachment separately provided to each site.   
Sites 
Study centers:  Approximately 30 sites (planned) 
Study location:  Japan 
Study Period and Phase of Development 
Study period:  30 months (planned)   
Phase of development:  Phase 2 
(Note: subjects who meet approved indication of E7438 in Japan will continue this study as a post-
marketing study.) 
Objectives 
Primary objective 
To assess the efficacy of tazemetostat in patients with relapsed or refractory B-cell non-Hodgkin’s 
lymphoma (NHL) below by objective response rate (ORR). 
Cohort 1:  Follicular lymphoma (FL) with EZH2 gene mutation 
Cohort 2:  Diffuse large B-cell lymphoma (DLBCL) with EZH2 gene mutation  
Secondary objectives 
(1)To assess the efficacy of tazemetostat by the endpoints below. 
∙Progression-free survival (PFS) 
∙Duration of response (DOR) 
∙Time to response (TTR) 
(2)To assess the safety of tazemetostat. 
Exploratory objectives 
(1)To explore the pharmacokinetics (PK) of tazemetostat. 
(2)To explore the frequency of EZH2 gene mutation in B-cell NHL. 
Study Design 
This is a multicenter, open-label, phase 2 study in relapsed or refractory B-cell NHL patients with 
EZH2 gene mutation, consists with 2 cohorts.  The study will assess efficacy and safety of 
tazemetostat in FL patients with EZH2 gene mutation in cohort 1, and DLBCL (including primary 
mediastinal B-cell lymphoma and transformed FL) patients with EZH2 gene mutation in cohort 2.   
This study will be conducted in the following 3 phases:  Pre-treatment Phase, Treatment Phase, and 
Follow-up Phase.   
The Pre-treatment Phase consists of Screening 1, Screening 2, registration, and baseline assessment.  
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In Screening 1, the EZH2 gene mutation will be confirmed at central laboratory in patients with 
histologically diagnosed as FL (cohort 1) or DLBCL (cohort 2) who are available to provide archival 
tumor sample (Inclusion Criteria 1) and not apparent to conflict other eligible criteria to participate in 
the study.  The archival tumor samples will be submitted to the central laboratory, and then this will 
be reported to the sponsor.  If EZH2 gene mutation was confirmed, conduct Screening 2 to confirm 
the other eligibility for study treatment.  Obtain the written informed consent with regards to tumor 
EZH2 gene mutation test and study treatment respectively, before Screening 1 and Screening 2.  
Screening 2 will last no longer than 28 days before the start of study treatment.  After screening 
assessments, the patient who meets the inclusion criteria and does not meet the exclusion criteria will 
be enrolled.  The baseline assessment will be conducted within 3 days before the treatment in order to 
confirm that the patient continues to meet the inclusion criteria and does not meet the exclusion 
criteria before moving to the Treatment Phase. 
The Treatment Phase consists of 28 days/cycle for tazemetostat 800 mg twice daily (BID) oral 
administration (1600 mg total daily dose) on a continuous basis and lasts until discontinuation of 
study drug.  Subjects will discontinue study drug at the time of disease progression (site evaluation), 
development of unacceptable toxicity, subject’s request to discontinue, withdrawal of consent, or 
study termination by the sponsor.   
Follow-up Phase consists of the evaluation at discontinuation which is performed within 7 days after 
the discontinuation of the study and a final observation which occurs 30 days (+7 days) after final 
administration of tazemetostat or initiation of a new anti-tumor therapy, whichever occurs early. 
Number of Subjects 
Cohort 1:  FL with EZH2 gene mutation 
Eight efficacy evaluable patients (planned) 
Cohort 2:  DLBCL with EZH2 gene mutation 
Thirteen efficacy evaluable patients (planned) 
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Inclusion Criteria 
(1) Patient with histological diagnosis of B-cell NHL as follows, who has provided written 
consent to submit archival tumor sample to central laboratory to confirm the EZH2 gene 
mutation status in tumor: 
· Cohort 1:  Follicular lymphoma (FL) 
· Cohort 2:  Diffuse large B-cell lymphoma (DLBCL) (including primary mediastinal B-
cell lymphoma and transformed FL) 
(2) Patient who has confirmed EZH2 gene mutation of tumor in central laboratory 
(3) Patient who has measurable disease as below: 
· Lymph node or ex-nodal disease diagnosed 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 
(4) Patient who had previous therapy with systemic chemotherapy and/or antibody therapy 
and for which no standard therapy exists 
(5) Patient who was progressive disease (PD) or did not have response (complete response [CR] or 
partial response [PR]) in previous systemic therapy, or relapsed or progressed after previous 
systemic therapy 
(6) Patient with Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 
1 
(7) Patient with life expectancy of ≥3 months from starting study drug administration 
(8) Patient with adequate renal function: 
· Serum creatinine ≤1.5× upper limit of normal (ULN) 
(9) Patient with adequate liver function: 
· Total bilirubin ≤1.5×ULN 
· Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3.0×ULN 
(10) Patient with adequate bone marrow function: 
(confirm 2 weeks or later from last administration of granulocyte colony-stimulating factor [G-
CSF] and blood transfusion, if these are used) 
· Absolute neutrophil count ≥1.5×103/μL (≥1.5×109/L) 
· Platelet count ≥10.0× 104/μL  
· Hemoglobin ≥9.0 g/dL 
(11) Patient with time between prior anti-tumor therapy and first administration of study drug 
as below: 
· Cytotoxic chemotherapy – At least 3 weeks 
· Non-cytotoxic chemotherapy (eg, corticosteroids*, small molecule inhibitor) – At least 2weeks 
· Monoclonal antibody (ies) – At least 4 weeks 
· Radiotherapy  
-At least 3 weeks from radiation therapy 
-At least 6 weeks from prior radioisotope therapy  
· Autologous hematopoietic stem cell transplantation – At least 6 months  
*:  Patient may receive no more than 10 mg of prednisolone daily or equivalent corticosteroid 
when used for treatment of lymphoma-related symptoms. 
(12) Patient with no carry-over of ≥ Grade 2 adverse events of the prior treatment that may affect the 
safety evaluation of the investigational drug 
(13) Male and female patient ≥20 years of age at the time of informed consent 
(14) Patient who has provided written consent to participate in the study 
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Exclusion Criteria 
(1) Patient with prior exposure to EZH2 inhibitor 
(2) Patient with a history or a presence of central nerves invasion 
(3) Patient with malignant pleural effusion, cardiac effusion, or ascites retention 
(4) Patient with allogeneic stem cell transplantation 
(5) Patient with a medical need for the continued use of potent inhibitors of CYP3A, or potent 
inducer of CYP3A (including St. John’s wort).  Patient is eligible if 2 weeks or longer have 
passed since the last use of such agents prior to the first dose of study drug.   
(6) Patient unwilling to exclude grapefruit (juice) from the diet for 1 week prior to study drug 
administration and throughout the study 
(7) Patient with the inability to take oral medication, or malabsorption syndrome or any other 
uncontrolled gastrointestinal condition (eg, nausea, diarrhea, or vomiting) or medical history (eg, 
gastrectomy or enterectomy) that might impair the bioavailability of study drug 
(8) Patient with significant cardiovascular impairment 
1) History of congestive heart failure of ≥ New York Heart Association (NYHA) Class III 
2) Uncontrolled arterial hypertension, unstable angina, myocardial infarction, or stroke within 
6 months of the first dose of study drug 
3) Ischemic heart disease, cardiac arrhythmia requiring medical treatment 
(9) Patient with prolongation of corrected QT interval using Fridericia’s formula (QTcF) to 
>480 msec 
(10) Patient with venous thrombosis or pulmonary embolism within the last 3 months before starting 
study drug 
(11) Patient with complications of hepatic cirrhosis, interstitial pneumonia or pulmonary fibrosis 
(12) Patient with active infection requiring systemic therapy 
(13) Patient with known hypersensitivity to any component of study drug 
(14) Patient who is positive for HIV antibody, HCV antibody, and HCV-RNA, or HBs antigen.  
Patient who is positive for HBs or HBc antibody and showing DNA more than sensitivity in 
HBV-DNA assay 
(15) Patient with malignancy of activity other than B-cell NHL 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). 
(16) Women of childbearing potential or man of impregnate potential who don’t agree that both the 
patient and his/her partner will use a medically effective method for contraception (as the below 
note) for periods from before informed consent to during the clinical study and 30 days later (for 
males 90 days later) from last administration of study drug.   
(17) Woman who is pregnant or breastfeeding (not eligible even if she discontinues breastfeeding) 
(18) Patient who was decided as inappropriate for medical or other reasons to participate in the study 
by the investigator or sub-investigator 
(19) Patient who has a prior history of myeloid malignancy including T-cell lymphoblastic 
lymphoma, T-cell acute lymphoblastic leukemia or myelodysplastic syndrome 
 
Note:  Condom*, contraceptive sponge**, foam**, jelly**, diaphragm*, intrauterine device (IUD)*, or use 
of oral contraception* from at least 30 days before starting the study treatment 
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(*Approved drugs or certified medical devices in Japan, **Non-approved drugs or certified medical 
devices in Japan) 
Study Treatment 
Tazemetostat 800 mg BID (1600 mg total daily dose) will be administered orally by continuous 
regimen, no less than 8 hours between doses.   
Tazemetostat will be provided as 200 mg tablet. 
Tazemetostat Dose Reduction and Interruption Instructions 
Dose reduction and interruption for subjects who experience tazemetostat-related toxicity will follow 
the instructions shown in Table below.  Dose reductions will be based on the previous dose level in 
order of 600, 400 mg BID (1200 mg, 800 mg total daily dose, respectively).  Once the dose is 
reduced, it cannot be increased at a later date.  Any dose adjustment must be discussed with the 
sponsor or discontinue tazemetostat when toxicities requiring dose reduction occur at the dose of 
400 mg BID. 
If a subject experiences myeloid malignancy including myelodysplastic syndrome, study treatment 
should be interrupted and restart (including dose modification)/discontinuation of study treatment 
should be discussed with the sponsor. If a subject experiences T-cell lymphoblastic lymphoma/T-cell 
acute lymphoblastic leukemia, study treatment should be discontinued and other actions should be 
discussed with the sponsor. 
Study treatment may be interrupted, if it is required to ensure the safety of a subject experiencing an 
adverse event that is unrelated to the study drug.  In such cases, study treatment should be resumed as 
soon as possible, at the same dose. 
Tazemetostat Dose Reduction and Interruption Instructions 
Tazemetostat-related Toxicity 
During Therapyd 
Dose adjustmentd 
Grade 1 and Tolerable Grade 2a 
Continue tazemetostat  
Maintain dose level 
Intolerable Grade 2a and  
Grade 3b 
Interrupt tazemetostat until 
resolved to Grade ≤1 or 
baselinee 
Dose reduction by one dose 
level 
Grade 3 and 
Grade 4 
neutropenia 
ANC 
≥0.75×109/L 
Continue tazemetostat 
Maintain dose level 
ANC 
<0.75×109/L 
Interrupt tazemetostat until 
resolved to ANC≥0.75×109/Le 
Dose reduction by one dose 
level 
Grade 4c 
Interrupt tazemetostat until 
resolved to Grade ≤1 or 
baselinee 
Discuss with the sponsor 
or discontinue tazemetostat 
ANC = absolute neutrophil count. 
a:  Tolerability of Grade 2 toxicities will be judged by the investigator or subinvestigator. 
b:  Dose interruption and reduction are not necessary for Grade 3 thrombocytopenia, anemia and Grade 
3 or 4 leukopenia, lymphopenia and laboratory abnormalities that are not clinically relevant.  Initiate 
optimal medical management for nausea, vomiting, and/or diarrhea prior to any study treatment 
interruption or dose reduction and follow the dose reduction and interruption instructions when it 
cannot be controlled. 
c:  Laboratory abnormalities judged to be non-life threatening, will be excluded and managed as Grade 
3. 
d:  Discuss with the sponsor when to consider the dose interruption and adjustment other than the 
instructions. 
e:  To minimize the duration of interruption, assessment at least every 7 days is recommended.  A delay 
of tazemetostat for more than 28 days due to any toxicity that is related to the study treatment must 
be discussed with the sponsor before treatment can be resumed. 
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Duration of Treatment 
Treatment will continue until disease progression (site evaluation), development of unacceptable 
toxicity, subject’s requests to discontinue, withdrawal of consent, or study termination by the 
sponsor. 
[Subjects who meet approved indication of tazemetostat in Japan] 
As per regulatory requirements in Japan, from the time tazemetostat is approved by the regulatory 
authority, these subjects will continue this study as a post-marketing study.  Treatment will continue 
until tazemetostat is commercially available for individual subjects at each study site, at which time 
the subjects will be switched to commercial tazemetostat. 
Concomitant Drug/Therapy 
The following drugs and therapies are prohibited from the time of subject enrollment to final study 
drug administration: 
· Anti-tumor therapies (Subjects may receive corticosteroid for local or systemic symptom control 
prior to and while on study.  Starting study drug treatment however, subjects may receive no 
more than 10 mg of prednisolone daily or equivalent corticosteroid when used for treatment of 
lymphoma related symptoms) 
· Any agent that potently inhibits or induces CYP3A 
· Other investigational agents 
Assessments 
Efficacy Assessments 
Efficacy assessment will be performed by investigator or subinvestigator based on “Revised response 
criteria for malignant lymphoma (IWG-2007)” (Cheson, et al., 2007).  Overall response and best 
overall response (BOR) (best response recorded at the designated visits during the study) will be 
assessed.  Perform the assessment below for tumor assessment. 
CT scans will be performed at Screening 2, every 8 weeks from study drug administration up to first 
32 weeks, then every 12 weeks and at discontinuation. 
PET scans will be performed at Screening 2.  If positive, perform when it is required to confirm CR 
as soon as possible or when clinically indicated.   
If gastrointestinal disease is suspected, endoscopic examination will be performed at Screening 2.  If 
exists, perform when it is requested to confirm CR as soon as possible or when clinically indicated.   
To evaluate bone marrow infiltration, a bone marrow aspiration or biopsy will be performed at 
Screening 2.  If positive or indeterminate, perform when it is requested to confirm CR as soon as 
possible or when clinically indicated.   
Also, central review will be conducted by the Imaging Review Committee for CT and PET 
assessment which is obtained within 24 months after the last subject’s enrollment (cut-off date: 02 
Dec 2020).  In addition, Efficacy and Safety Evaluation Committee (ESEC) will conduct central 
evaluation based on the review of Imaging Review Committee and other assessment / bone marrow 
infiltration evaluated by the investigator or subinvestigator, to determine the overall responses and the 
best overall response. 
The primary endpoint and the secondary endpoint with regard to efficacy are defined as below, and 
will be evaluated by the result of ESEC review. 
• 
ORR: 
The rate of subjects whose BOR is CR or PR. 
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• 
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 whichever occurs first).  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. 
 
Pharmacokinetics Assessments 
To measure plasma trough concentrations of tazemetostat. 
 
Biomarker Assessments 
At Screening 1, archival tumor samples (formalin-fixed paraffin-embedded: FFPE) will be submitted 
to the central laboratory for detection of EZH2 gene mutation status in patients with written informed 
consent for tumor EZH2 gene mutation test. 
 
Safety Assessments 
Safety assessments will consist of monitoring and recording all adverse events (AEs) and serious 
adverse events (SAEs); periodic clinical laboratory assessment; measurement of vital signs, 12-lead 
electrocardiograms (ECGs), ECOG-PS, and physical examinations.  Severity will be evaluated by 
grading of Common Terminology Criteria for Adverse Events (CTCAE v4.03).   
Bioanalytical Methods 
Plasma concentrations of tazemetostat will be measured by validated methods using liquid 
chromatography with tandem mass spectrometry (LC-MS/MS).   
Statistical Methods 
Definitions of Analysis Sets 
Efficacy Analysis Set will include efficacy evaluable subjects who received at least 1 administration 
of the study drug and who has at least 1 appropriate tumor assessment data of Screening 2 and post-
baseline. 
Pharmacokinetic Analysis Set will include subjects who received at least 1 administration of the 
study drug and had at least 1 concentration data of tazemetostat. 
Biomarker Analysis Set will include subjects who have conducted EZH2 gene mutation assessment 
at Screening 1.   
Safety Analysis Set will include subjects who received at least 1 administration of the study drug.  
 
Efficacy Analyses 
This analysis will be performed on the Efficacy Analysis Set.  All summary of efficacy will be 
conducted for each disease (cohort). 
Primary Endpoint Analyses 
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BOR will be summarized.  The rate of subjects whose BOR is CR or PR is calculated as ORR, and its 
corresponding 2-sided exact 90% confidence intervals (CIs) using the method of Clopper–Pearson 
will also be calculated.  A waterfall plot will be presented for the percent changes from baseline in 
the sum of the diameters of target lesions at post-baseline nadir. 
Secondary Endpoint 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 in responders.   
• 
Analysis of TTR 
TTR will be summarized by descriptive statistics in responders.   
 
Pharmacokinetic Analyses 
This analysis will be performed on the Pharmacokinetic Analysis Set.  The plasma concentrations of 
tazemetostat will be summarized by timepoint.   
 
Biomarker Analysis 
This analysis will be performed on the Biomarker Analysis Set.  The rate of the tumor EZH2 gene 
mutation will be calculated in each disease. 
 
Safety Analyses 
This analysis will be performed on the Safety Analysis Set.  The number and percentage of subjects 
with all AEs and SAEs observed after first administration of study drug will be summarized and 
listed by system organ class (SOC), preferred term (PT), and severity in whole or each disease 
(cohort).  Summary statistics will be presented for laboratory test values, vital signs, 12-lead ECG, 
and ECOG-PS.  If needed, the changes from baseline will also be summarized.   
Sample Size Rationale 
In cohort 1, 8 efficacy evaluable FL patients with EZH2 mutation are required to detect lower limit of 
the 90% CI that exceed the 10% threshold in ORR, which is the primary endpoint of the study, with 
the expected ORR of 50% with power of approximately 80%.   
In cohort 2, 13 efficacy evaluable DLBCL patients with EZH2 mutation are required to detect lower 
limit of the 90% CI that exceed the 10% threshold in ORR, which is the primary endpoint of the 
study, with the expected ORR of 40% with power of approximately 80%.   
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3 
TABLE OF CONTENTS 
1 
TITLE PAGE .....................................................................................................................1 
2 
CLINICAL PROTOCOL SYNOPSIS ...............................................................................2 
3 
TABLE OF CONTENTS .................................................................................................10 
4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................15 
5 
ETHICS............................................................................................................................18 
5.1 
Institutional Review Boards/Independent Ethics Committees ..............................18 
5.2 
Ethical Conduct of the Study .................................................................................18 
5.3 
Subject Information and Informed Consent ...........................................................18 
6 
INVESTIGATORS AND STUDY PERSONNEL ..........................................................19 
7 
INTRODUCTION ...........................................................................................................20 
7.1 
EZH2 (Enhancer of Zeste Homolog 2) ..................................................................20 
7.2 
Epidemiology and Current Therapeutic Options of Follicular Lymphoma and 
Diffuse Large B-cell Lymphoma ...........................................................................21 
7.2.1 
Epidemiology of Malignant Lymphoma ......................................................21 
7.2.2 
Epidemiology of Follicular Lymphoma.......................................................21 
7.2.3 
Current Therapeutic Options for Follicular Lymphoma ..............................22 
7.2.4 
Diffuse Large B-Cell Lymphoma ................................................................22 
7.2.5 
Current Therapeutic Options for Diffuse Large B-Cell Lymphoma ...........23 
7.3 
Tazemetostat (E7438) ............................................................................................23 
7.4 
Clinical Studies ......................................................................................................24 
7.4.1 
Clinical Studies Conducted Outside Japan ..................................................24 
7.4.1.1 
Overview of Phase 1 Study Conducted Outside Japan ........................24 
7.4.1.2 
Overview of Phase 2 Study Conducted Outside Japan ........................25 
7.4.1.3 
Summary of Safety in Clinical Studies Conducted Outside Japan ......26 
7.4.1.4 
Summary of Efficacy in Clinical Studies Conducted Outside Japan ...28 
7.4.2 
Clinical Study Conducted in Japan ..............................................................28 
7.4.2.1 
Overview of Phase 1 Study Conducted in Japan .................................28 
7.4.2.2 
Summary of Safety in Clinical Study Conducted in Japan ..................28 
7.5 
Study Rationale ......................................................................................................29 
8 
STUDY OBJECTIVES ....................................................................................................30 
8.1 
Primary Objective ..................................................................................................30 
8.2 
Secondary Objectives.............................................................................................30 
8.3 
Exploratory Objectives ..........................................................................................30 
9 
INVESTIGATIONAL PLAN ..........................................................................................31 
9.1 
Overall Study Design and Plan ..............................................................................31 
9.1.1 
Study Design ................................................................................................31 
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9.1.1.1 
Pre-treatment Phase .............................................................................32 
9.1.1.2 
Treatment Phase ...................................................................................32 
9.1.1.3 
Follow-up Phase...................................................................................32 
9.2 
Discussion of Study Design, Including Choice of Control Groups .......................32 
9.3 
Selection of Study Population ................................................................................32 
9.3.1 
Inclusion Criteria .........................................................................................33 
9.3.2 
Exclusion Criteria ........................................................................................34 
9.3.3 
Removal of Subjects From Therapy or Assessment ....................................35 
9.3.3.1 
Discontinuation Criteria by Subject .....................................................35 
9.4 
Treatment ...............................................................................................................36 
9.4.1 
Treatment Administered ..............................................................................36 
9.4.1.1 
Tazemetostat Dose Reduction and Interruption Instructions ...............36 
9.4.2 
Identity of Investigational Product...............................................................37 
9.4.2.1 
Chemical Name and Structural Formula of Tazemetostat ...................37 
9.4.2.2 
Comparator Drug .................................................................................37 
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 
Prohibited Concomitant Therapies and Drugs .....................................40 
9.4.7.2 
Concomitant Drugs to be Used With Caution .....................................40 
9.4.8 
Prohibitions and Restrictions during Study Period ......................................40 
9.4.9 
Treatment Compliance .................................................................................41 
9.4.10 
Drug Supplies and Accountability ...............................................................41 
9.5 
Study Assessments .................................................................................................42 
9.5.1 
Assessments .................................................................................................42 
9.5.1.1 
Demography .........................................................................................42 
9.5.1.2 
Pre-treatment Assessments ..................................................................42 
9.5.1.2.1 
Medical History and Current Medical Conditions .........................42 
9.5.1.3 
Efficacy Assessments...........................................................................42 
9.5.1.4 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments .............................................................44 
9.5.1.4.1 
Pharmacokinetic Assessments .......................................................44 
9.5.1.4.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker, 
Assessments ...................................................................................44 
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9.5.1.5 
Safety Assessments ..............................................................................45 
9.5.1.5.1 
Adverse Events ..............................................................................46 
9.5.1.5.2 
Serious Adverse Events and Events Associated with Special 
Situations........................................................................................47 
9.5.1.5.3 
Laboratory Measurements .............................................................49 
9.5.1.5.4 
Vital Signs and Weight/Height Measurements ..............................49 
9.5.1.5.5 
Physical Examinations ...................................................................50 
9.5.1.5.6 
Electrocardiograms ........................................................................50 
9.5.1.5.7 
Other Safety Assessments ..............................................................50 
9.5.2 
Schedule of Procedures/Assessments ..........................................................51 
9.5.2.1 
Schedule of Procedures/Assessments ..................................................51 
9.5.3 
Appropriateness of Measurements ...............................................................54 
9.5.4 
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations ..............................................................54 
9.5.4.1 
Reporting of Serious Adverse Events ..................................................54 
9.5.4.2 
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding .......................................................................................54 
9.5.4.3 
Reporting of Events Associated with Special Situations .....................55 
9.5.4.3.1 
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error ............................55 
9.5.4.3.2 
Reporting of Study-Specific Events...............................................56 
9.5.4.4 
Expedited Reporting ............................................................................56 
9.5.4.5 
Breaking the Blind ...............................................................................56 
9.5.4.6 
Regulatory Reporting of Adverse Events ............................................56 
9.5.5 
Completion/Discontinuation of Subjects .....................................................56 
9.5.6 
Abuse or Diversion of Study Drug ..............................................................57 
9.5.7 
Confirmation of Medical Care by Another Physician .................................57 
9.6 
Data Quality Assurance .........................................................................................57 
9.6.1 
Data Collection ............................................................................................57 
9.6.2 
Clinical Data Management ..........................................................................58 
9.7 
Statistical Methods .................................................................................................58 
9.7.1 
Statistical and Analytical Plans ....................................................................58 
9.7.1.1 
Study Endpoints ...................................................................................58 
9.7.1.1.1 
Primary Endpoint ...........................................................................58 
9.7.1.1.2 
Secondary Endpoints .....................................................................58 
9.7.1.1.3 
Exploratory Endpoints ...................................................................58 
9.7.1.2 
Definitions of Analysis Sets.................................................................58 
9.7.1.3 
Subject Disposition ..............................................................................59 
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9.7.1.4 
Demographic and Other Baseline Characteristics ...............................59 
9.7.1.5 
Prior and Concomitant Therapy ...........................................................59 
9.7.1.6 
Efficacy Analyses ................................................................................59 
9.7.1.6.1 
Primary Efficacy Analysis .............................................................59 
9.7.1.6.2 
Secondary Efficacy Analyses ........................................................60 
9.7.1.7 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses ...................................................................60 
9.7.1.7.1 
Pharmacokinetic Analyses .............................................................60 
9.7.1.7.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses .........................................................................................60 
9.7.1.8 
Safety Analyses ....................................................................................60 
9.7.1.8.1 
Extent of Exposure .........................................................................60 
9.7.1.8.2 
Adverse Events ..............................................................................60 
9.7.1.8.3 
Laboratory Values ..........................................................................61 
9.7.1.8.4 
Vital Signs ......................................................................................61 
9.7.1.8.5 
Electrocardiograms ........................................................................61 
9.7.1.8.6 
Other Safety Analyses....................................................................62 
9.7.2 
Determination of Sample Size .....................................................................62 
9.7.3 
Interim Analysis ...........................................................................................62 
9.7.4 
Other Statistical/Analytical Issues ...............................................................62 
9.7.5 
Procedure for Revising the Statistical Analysis Plan ...................................62 
10 REFERENCE LIST .........................................................................................................63 
11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES) .......67 
11.1 
Changes to the Protocol .........................................................................................67 
11.2 
Adherence to the Protocol ......................................................................................67 
11.3 
Monitoring Procedures...........................................................................................67 
11.4 
Recording of Data ..................................................................................................68 
11.5 
Identification of Source Data .................................................................................68 
11.6 
Retention of Records..............................................................................................69 
11.7 
Auditing Procedures and Inspection ......................................................................70 
11.8 
Handling of Study Drug .........................................................................................70 
11.9 
Publication of Results ............................................................................................70 
11.10 Disclosure and Confidentiality ..............................................................................70 
11.11 Discontinuation of Study .......................................................................................71 
11.12 Subject Insurance and Indemnity ...........................................................................71 
 
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LIST OF IN-TEXT TABLES 
Table 1 
Summary of Treatment-Related Treatment-Emergent Adverse Events 
Occurring in ≥5% of Subjects in Phase 2 Studies with Tazemetostat .......27 
Table 2 
Tazemetostat Dose Reduction and Interruption Instructions .....................37 
Table 3 
Blood Sampling Schedule for Pharmacokinetic Assessment ....................44 
Table 4 
Clinical Laboratory Tests ...........................................................................49 
Table 5 
Schedule of Procedures/Assessments in Study E7438-J081-206 (EZH-
206) ............................................................................................................52 
 
LIST OF IN-TEXT FIGURES 
Figure 1 
Study Design ..............................................................................................31 
 
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4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
β-hCG 
beta-human chorionic gonadotropin 
BID 
twice daily 
BUN 
blood urea nitrogen 
C#D# 
Cycle# Day# 
CI 
confidence interval 
COO 
cell-of-origin 
CR 
complete response 
CRA 
clinical research associate 
CRF 
case report form 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DLBCL 
diffuse large B-cell lymphoma 
DLT 
dose limiting toxicity 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EFS 
event-free survival 
ESEC 
Efficacy and Safety Evaluation Committee 
EZH2 
enhancer of zeste homolog 2 
FFPE 
formalin-fixed paraffin-embedded 
FL 
follicular lymphoma 
GCB 
germinal center B-cell-like 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony-stimulating factor 
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Abbreviation 
Term 
GPSP 
Good Post-marketing Study Practice 
HBc 
hepatitis B virus core 
HBs 
hepatitis B virus surface 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HL 
Hodgkin lymphoma 
HMT 
histone methyltransferase 
ICF 
informed consent form 
ICML 
International Congress of Malignant Lymphoma 
IDMC 
Independent Data Monitoring Committee 
INN 
International Nonproprietary Name 
INR 
international normalized ratio 
IUD 
intrauterine device 
IxRS 
interactive voice/web response system 
LC-MS/MS 
liquid chromatography with tandem mass spectrometry 
LDH 
lactate dehydrogenase 
LLT 
lower level term 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
mRNA 
messenger ribonucleic acid 
MRT 
malignant rhabdoid tumor 
MTD 
maximum tolerated dose 
NCCN 
National Comprehensive Cancer Network 
NHL 
Non-Hodgkin’s lymphoma 
NYHA 
New York Heart Association 
ORR 
objective response rate 
PD 
progressive disease 
PET 
positron emission tomography 
PFS 
progression-free survival 
PK 
pharmacokinetics 
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Abbreviation 
Term 
PK/PD 
pharmacokinetic/pharmacodynamic 
PR 
partial response 
PRC2 
polycomb repressive complex 2 
PS 
performance status 
PT 
preferred term 
QOL 
quality of life 
QTc 
QT interval corrected for heart rate 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
R 
rituximab 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RP2D 
recommended Phase 2 dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
stable disease 
SOC 
system organ class 
SOP 
standard operating procedure 
TEAE 
treatment-emergent adverse event 
TEMAV 
treatment-emergent markedly abnormal laboratory values 
TTR 
time to response 
ULN 
upper limit of normal 
WHO DD 
World Health Organization Drug Dictionary 
 
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5 
ETHICS 
5.1 
Institutional Review Boards/Independent Ethics Committees 
The protocol, informed consent form (ICF), and appropriate related documents must be 
reviewed and approved by an Institutional Review Board (IRB) 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 administrative aspects of the study (eg, change in clinical research associates [CRAs], 
change of telephone numbers).  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 or the sponsor will 
submit, depending on local regulations, periodic reports and inform the investigator, the head 
of the medical institution, 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 the sponsor via the 
head of the medical institution with a brief report of the outcome of the study, if required. 
5.2 
Ethical Conduct of the Study 
This study will be conducted in accordance with standard operating procedures (SOPs) of the 
sponsor (or designee), which are designed to ensure adherence to GCP guidelines as required 
by the following: 
• 
Principles of the World Medical Association Declaration of Helsinki 
• 
GCP 
In addition, after tazemetostat is approved by the Japanese regulatory authority, the study 
will be conducted as a post-marketing study as per regulatory requirements of GPSP. 
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, 
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and that withdrawal of consent will not affect his/her subsequent medical treatment or 
relationship with the treating physician.   
This informed consent should be given by means of a standard written statement, written in 
nontechnical language.  The subject should understand the statement before signing and 
dating it and will be given a copy of the signed document.  If a subject is unable to read, an 
impartial witness should be present during the entire informed consent discussion.  After the 
ICF and any other written information to be provided to subjects is read and explained to the 
subject, and after the subject has orally consented to the subject’s participation in the study 
and, if capable of doing so, has signed and personally dated the ICF, the witness should sign 
and personally date the consent form.  The subject will be asked to sign an ICF before any 
study-specific procedures are performed.  No subject can enter the study before his/her 
informed consent has been obtained. 
An unsigned copy of an IRB-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.   
The written informed consent with regard to tumor EZH2 gene mutation test will be obtained 
from all patients who will participate in the study, followed by obtaining the written 
informed consent with regard to study treatment.  EZH2 gene mutation status will be 
detected using archival tumor samples in patients with written informed consent for tumor 
EZH2 gene mutation test.   
6 
INVESTIGATORS AND STUDY PERSONNEL 
This study will be conducted by qualified investigators under the sponsor at approximately 
30 investigational sites in Japan.   
The name and telephone and fax numbers of the sponsor are listed in the Attachment 
separately provided to each site.   
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7 
INTRODUCTION 
7.1 
EZH2 (Enhancer of Zeste Homolog 2) 
In epigenetic control of gene expression, post-translational modifications of histones 
(methylation, acetylation, ubiquitylation, and phosphorylation), the core proteins of 
chromatin, play an important role in controlling the occurrence of various cancers and 
malignant alteration.  Of these, trimethylation of lysine 27 on histone H3 (H3K27) is 
enhanced in most of the stem cells such as hematopoietic stem cells and chromatin in tumor 
cells.  H3K27 is also associated with suppression of genes involved in cell differentiation or 
tumor genes, cell growth-promotion activity (Margueron and Reinberg, 2011; Copeland, 
2013).   
EZH2 is the specific histone methyltransferase (HMT) that catalyzes the component of 
H3K27 and the mono-, di-, and trimethylation of H3K27 as a subunit of the multi-protein 
Polycomb Repressive Complex 2 (PRC2).  EZH2 gene mutation, amplification and/or 
overexpression, or increased activity has been observed in several cancer types including 
follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), malignant rhabdoid 
tumor (rhabdomyosarcoma), synovial sarcoma, breast cancer, prostate cancer, malignant 
melanoma or bladder cancer.  Therefore, drugs targeting EZH2 may become a new candidate 
for antitumor therapy (Chase and Cross, 2011; Kim, et al., 2016; Yoo and Hennighausen, 
2012; Varambally, et al., 2002; Zingg, et al., 2015; Arisan, et al., 2005).   
Mutations in the SET domain of EZH2 (Y646*) associated with FL and DLBCL lead to 
increased activity of trimethylation of EZH2 and produces hypertrimethylation on H3K27 
(H3K27Me3), resulting tumor proliferation depending on mutant EZH2 (Morin, et al., 2010; 
Sneeringer, et al., 2010).   In addition, germinal center lymphomas are likely to depend on 
EZH2 activity (Begeulin, et al., 2013).  In contrast, subsets of other malignancies such as T-
cell acute lymphoblastic leukemia (T-ALL) and myeloproliferative disorders show genetic 
loss of EZH2 components (Chase and Cross, 2011; Ntziachristos, et al., 2012).  Together this 
suggests that perturbing the correct balance of H3K27Me3 in a given cellular background in 
either direction can be oncogenic.   
In addition to genetic alterations in EZH2 itself, mutations in other chromatin modifying 
enzymes lead to imbalance of H3K27 methylation.  For instance, mutations in other 
chromatin modifying enzymes including HMTs (MLL family), histone demethylases 
(KDM6A), histone acetyltransferases (CREBBP, EP300), and histone deubquitinases (BAP1) 
are found in various tumor types (NHL, multiple myeloma, T-ALL, medulloblastoma, 
mesothelioma, and others) (Plass, et al., 2013; LaFave, et al., 2015).  These genetic lesions 
are hypothesized to perturb the methylation state of H3K27, leading to aberrant gene 
expression.  In addition to PRC2 that contains subunit of EZH2, subunits of the SWI/SNF 
complex play an important role on post-translational modifications of histones, and PRC2 
and SWI/SNF antagonize each other at many gene loci.  Approximately 20% of cancers carry 
genetic alteration or deletion in subunit of SWI/SNF, such as integrase interactor 1 (INI1, 
also known as SNF5, SMARCB1), SMARCB2, SMARCA4, ADRID1A, and others (Kadoch 
and Crabtree, 2013, Kadoch, et al., 2016).  INI1 or SMARCA4 deficiency promotes 
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inactivation of EZH2 blocks by SWI/SNF (Wilson, et al., 2010; Alimova, et al., 2013).  In 
synovial sarcoma, as gene transcription fuses SS18-SSX1/2 fusion protein, an imbalance in 
INI1 was observed and led to deregulate EZH2 activity.  This is because protease acts easily 
after SS18-SSX1/2 displaces SS18 from the SWI/SNF complex and INI1 is removed from 
SWI/SNF complex (Shen, et al., 2016; Kawano, et al., 2016).  As shown above, EZH2 gene 
mutation, INI1 deficiency, SMARCA4 deficiency, and SS18-SSX1/2 fusions drive 
deregulation of EZH2 activity, which means imbalance of H3K27 methylation, inducing 
oncogenesis and malignant alteration. 
*Amino acid sequence mutation is based on Genbank database EZH2 NM_004456.3.  This mutation 
is known as Y641. 
7.2 
Epidemiology and Current Therapeutic Options of Follicular 
Lymphoma and Diffuse Large B-cell Lymphoma 
7.2.1 
Epidemiology of Malignant Lymphoma 
The nationwide survey by the Ministry of Labor, Health, and Welfare (2014) has reported 
that approximately 64,000 people are diagnosed with malignant lymphoma per year in Japan.  
The survey, “Monitoring of Cancer Incidence in Japan” conducted by the Center for Cancer 
Control and Information Services at the National Cancer Center (2012) has also reported that 
malignant lymphoma is prevalent in approximately 26,600 patients per year.   
Malignant lymphoma is classified into various subtypes according to the antigen on the 
tumor cell surface and morphological characteristics, and each subtype has distinct prognosis 
and therapeutic treatment.  Malignant lymphoma is classified into Hodgkin’s lymphoma 
(HL) and non-Hodgkin’s lymphoma (NHL).  The target diseases of this study, FL and 
DLBCL, are subtypes of B-cell NHL.   
7.2.2 
Epidemiology of Follicular Lymphoma 
FL is the most common type of the indolent B-cell lymphoma, which progresses in yearly 
term.  FL has structure basis that histologically mimics germinal center.  Outside Japan, gain-
of-function mutation of EZH2 is reported in 7% to 27% of FL (Morin, et al., 2010; Bödör, et 
al., 2013).  The patient survey by the Ministry of Labor, Health, and Welfare (2014) has 
reported approximately 4,000 people are categorized as “International classification of 
disease C829: follicular non-Hodgkin's lymphoma, unspecified”.  This survey also indicates 
approximately 38,000 people are categorized as “International classification of disease C859: 
non-Hodgkin’s lymphoma, unspecified type” and some of them are thought to be FL.  The 
proportion of FL subtype among malignant lymphoma in Japan was 13.5% according to the 
survey of the incidence of malignant lymphoma encoded by classification of disease 
(Chihara, et al., 2014).  Based on the information on Section 7.2.1 Epidemiology of 
Malignant Lymphoma and these reports, it is estimated that approximately 600 to 2,300 
people are diagnosed as FL with EZH2 gene mutation and FL with EZH2 gene mutation is 
prevalent in approximately 250 to 970 patients per year.   
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7.2.3 
Current Therapeutic Options for Follicular Lymphoma 
In Japan, the guideline for management of hematopoietic tumor covering FL is established 
according to the US NCCN guidelines (general incorporated association, Japanese Society of 
Hematology, 2013).  In and outside Japan, the standard therapy for advanced-stage primary 
FL that requires treatment is the R-CHOP regimen, which is a combination of several 
chemotherapy drugs (cyclophosphamide, doxorubicin, vincristine, and prednisone) and 
rituximab (R), or the non-doxorubicin-containing R-CVP regimen.  Rituximab monotherapy 
or chemotherapy alone approach should also be considered based on the patient condition.  
The R-CHOP regimen showed a 3-year time to treatment failure rate of 62% and a 3-year 
overall survival rate of 95% (Federico, et al., 2013).   
The recommended therapy for relapsed or refractory FL is rituximab monotherapy, rituximab 
in combination with single- or multi-agent chemotherapy, or radioisotope therapy based on 
the patient condition.  In Japanese patients with relapsed or refractory indolent B-cell 
lymphoma, bendamustine monotherapy has demonstrated that the 1-year PFS rate was 70% 
(Ohmachi, et al., 2010) and a combination of rituximab and fludarabine has demonstrated 
that the median time to treatment failure was 8.6 months (Tobinai, et al., 2006).  While 
autologous stem-cell transplantation has been considered as consolidation therapy in younger 
patients who had a positive response, the increased risk of secondary malignancies has been 
reported (Deconinck, et al., 2005; Ladetto, et al., 2008; Gyan, et al., 2009).  As described 
above, therapeutic options and outcomes particularly in patients with relapsed or refractory 
FL are limited, thus a new therapeutic option is anticipated.   
7.2.4 
Diffuse Large B-Cell Lymphoma 
DLBCL is a B-cell type of lymphoma that derives from germinal center B-cells and is a 
diverse set of diseases that have various clinical features, immunophenotypes, genetic and 
chromosomal abnormalities.  DLBCL is classified to germinal center B-cell like (GCB) type 
and the others (non-GCB type including activated B-cell like type) based on gene expression 
profile, in approximately a half of proportion respectively (Lenz, et al., 2008).  Outside 
Japan, gain-of-function mutation of EZH2 is reported in 22% of GCB type while no 
activating mutation of EZH2 is reported in non-GCB type (Morin, et al., 2010).  The patient 
survey by the Ministry of Labor, Health, and Welfare (2014) has reported that approximately 
10,000 people are categorized as “international classification of disease C833: large cell 
(diffuse)”.  This survey also indicates approximately 38,000 people are categorized as 
“international classification of disease C859: non-Hodgkin’s lymphoma, unspecified type” 
and some of them are thought to be DLBCL.  The proportion of DLBCL subtype in Japan 
was 45.3% among malignant lymphoma according to the survey of the incidence of 
malignant lymphoma encoded by classification of disease (Chihara, et al., 2014).  Based on 
the information on Section 7.2.1 Epidemiology of Malignant Lymphoma and these reports, it 
is estimated that approximately 3,200 people are diagnosed as DLBCL with EZH2 gene 
mutation and DLBCL with EZH2 gene mutation is prevalent in approximately 1,300 patients 
per year.   
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7.2.5 
Current Therapeutic Options for Diffuse Large B-Cell Lymphoma 
In Japan, the guideline for management of hematopoietic tumor covering DLBCL is 
established according to the US NCCN guidelines (general incorporated association, 
Japanese Society of Hematology, 2013).  The standard therapy for advanced-stage primary 
DLBCL in and outside Japan is the R-CHOP regimen.  The R-CHOP regimen has shown a 5-
year event-free survival rate of 47% and a 5-year overall survival rate of 58% (Coiffier, et al., 
2002).   
The recommended therapy for relapsed or refractory DLBCL is rituximab-based multi-agent 
salvage chemotherapy.  The most common salvage chemotherapy in current use are the R-
DHAP (dexamethasone, cisplatin, and cytarabine), R-ICE (ifosfamide, carboplatin, and 
etoposide), and R-GDP (gemcitabine, dexamethasone, and cisplatin) regimens.  Comparable 
results are shown in patients treated with R-DHAP and R-ICE, both with a 3-year event-free 
survival rate of 31% and a 3-year overall survival rate of 50%.  In addition, no differences 
were identified among the effects of other regimens (Gisselbrecht, et al., 2010).  High-dose 
chemotherapy followed by autologous stem-cell transplantation was an effective therapeutic 
option before the rituximab era, and this is still an encouraging treatment option for the 
management of younger patients or other applicable patients (Philip, et al., 1995).  As 
described above, therapeutic options and outcomes particularly in patients with relapsed or 
refractory DLBCL are limited, thus a new therapeutic option is anticipated.   
7.3 
Tazemetostat (E7438) 
Tazemetostat (E7438) is a selective, reversible, small molecule inhibitor of EZH2, a histone 
methyltransferase (HMT).  EZH2 is a catalytic subunit of the polycomb repressive complex 2 
(PRC2) and is responsible for methylation of histone H3 lysine 27 (H3K27).  EZH2 plays a 
role in epigenetic regulation on various genes.  
Cell-free biochemical assays showed that tazemetostat inhibited wild-type and mutant EZH2 
in SET domain with IC50 values ranging from 2 to 38 nmol/L.  The compound showed 36-
fold selectivity over the closely related HMT, EZH1, and greater than 3000-fold selectivity 
over other HMTs.  Tazemetostat specifically inhibited histone H3K27 methylation across 
different cell lines.  Incubation with tazemetostat inhibited the proliferation of cancer cells, 
such as DLBCL lines bearing EZH2 mutations, INI1-negative MRT cell lines, and INI-
deficient synovial sarcoma cell lines (Knutson, et al., 2013; Knutson, et al., 2014).  
Tazemetostat-mediated cell death occurred through G1 cell cycle arrest and the subsequent 
induction of apoptosis.  G1 arrest was observed as of Day 3 to Day 7 and consistent with 
elimination of intracellular H3K27Me3.  Tazemetostat incubation in INI1-negative MRT cell 
lines induced changes in gene expression together with expression of the neuronal 
differentiation markers.  An oral administration of tazemetostat to human xenograft models 
in mice including DLBCL cell lines with EZH2 mutations induces significant antitumor 
effects, ranging from tumor growth inhibition to complete and durable tumor regressions.  
Tazemetostat exposure led to dose- and time-dependent decreases in intracellular H3K27Me3 
in both tumor and selected non-tumor tissues.  An oral administration of tazemetostat 
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demonstrated significant antitumor activity against 4 of 6 xenograft models of INI-deficient 
tumors.   
Therefore, based on the above results, a Phase 1/2 study of tazemetostat in patients with 
advanced solid tumors including INI1 or SMARCA4-negative tumors (including synovial 
sarcoma, malignant rhabdoid tumor, epithelioid sarcoma, and other INI1 or SMARCA4-
negative tumors) or with B-cell lymphomas including DLBCL and FL (E7438-G000-101) 
has been conducted outside Japan from November 2012.  Phase 1 data were reviewed by an 
Independent Data Monitoring Committee on 12 November 2014.  The committee agreed that 
the recommended Phase 2 dose be 800 mg BID based on the evaluation of safety, 
pharmacokinetics (PK), biomarker, and antitumor activity.   
Tazemetostat is currently under investigation for the treatment of FL, DLBCL, and INI1- or 
SMARCA4-negative tumors outside Japan.  In Japan, a Phase 1 study (E7438-J081-106) is 
ongoing in patients with B-cell non-Hodgkin’s lymphomas (NHLs) including FL and 
DLBCL.   
7.4 
Clinical Studies 
7.4.1 
Clinical Studies Conducted Outside Japan 
7.4.1.1 
Overview of Phase 1 Study Conducted Outside Japan 
As of 15 January 2017, a total of 64 subjects have received treatment with tazemetostat in a 
Phase 1 study (E7438-G000-101 [Phase 1 part]).  This study enrolled subjects with B-cell 
NHLs including FL and DLBCL, and solid tumors including INI1-negative tumors and 
synovial sarcoma.  Tazemetostat was administered as monotherapy at doses ranging from 
100 mg to 1600 mg BID.   
Study E7438-G000-101 (Phase 1 Part) 
Study E7438-G000-101 is a multicenter, open-label, first-in-human, Phase 1/2 study.  The 
Phase 1 part of this study enrolled subjects with advanced or metastatic solid tumors or B-
cell NHLs that have progressed after treatment with approved therapies or for which there are 
no standard therapies available.  The objectives of the Phase 1 part are to determine the 
recommended Phase 2 dose (RP2D) of tazemetostat as a single agent administered orally 
twice daily (BID) continuously in 28-day cycles and to assess the preliminary anti-tumor 
activity of tazemetostat.  Additionally, in separate 2 cohorts in Phase 1 of this study, clinical 
pharmacologic assessments were performed.   
The first subject was enrolled in June 2013, and subjects in all cohorts (dose escalation, food 
effect, drug-drug interaction [DDI]) have been enrolled in the Phase 1 part of this study.  
Tazemetostat 100, 200, 400, 800, and 1600 mg BID were administered in the Phase 1 dose 
escalation.  One dose-limiting toxicity (DLT) of Grade 4 thrombocytopenia was observed at 
the dose level of 1600 mg BID; thus, the protocol-defined maximum tolerated dose (MTD) 
was not reached.  Based on the safety, PK, biomarker, and antitumor activity observed, the 
RP2D of tazemetostat monotherapy was determined to be 800 mg BID.  The study of the 
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effect of food on the bioavailability of tazemetostat showed that the decrease in systemic 
exposure observed when tazemetostat was administered with a high-fat meal was not 
clinically significant.  Tazemetostat is moderately or weakly inhibitory to CYP3A activities 
and induced CYP3A messenger ribonucleic acid (mRNA) in human hepatocytes in vitro.  
The results from the DDI cohort demonstrated that tazemetostat is a net weak inducer of 
CYP3A-mediated metabolism. 
7.4.1.2 
Overview of Phase 2 Study Conducted Outside Japan 
As of 15 January 2017, a total of 266 subjects with FL, DLBCL, INI1-negative tumor, 
SMARCA4-negative tumor, synovial sarcoma, or malignant mesothelioma have received 
tazemetostat 800 mg BID in 3 ongoing Phase 2 studies (E7438-G000-101 [Phase 2 part], 
EZH-202, EZH-203).   
Study E7438-G000-101 (Phase 2 part) 
The Phase 2 part of this study is designed to assess the objective response rate of 
tazemetostat in patients with 1) EZH2 gene mutation-positive FL, 2) EZH2 gene mutation-
negative (wild-type) FL, 3) EZH2 gene mutation-positive DLBCL of germinal center origin 
subtype, 4) EZH2 gene mutation-negative (wild-type) DLBCL of germinal center origin 
subtype, or 5) DLBCL of non-germinal center origin subtype.  The primary objective of the 
Phase 2 part is to determine the objective response rate of tazemetostat.  The secondary 
objectives are to assess the effect of tazemetostat on duration of response (DOR), 
progression-free survival (PFS), and durable stable disease; the safety and tolerability of 
tazemetostat; and PK profile of tazemetostat.  The exploratory objectives are to explore the 
PK and pharmacodynamic (PD) relationship of tazemetostat; biomarkers and their correlation 
with biological activity for tazemetostat; the effects of tazemetostat on histone H3K27 
methylation, target gene expression, and phenotypic markers including those for 
differentiation, apoptosis, and cell proliferation; the role of DNA sequence variability on 
absorption, metabolism, excretion and susceptibility to adverse events (AEs) of tazemetostat.   
Upon review of the data available as of 06 September 2016, the Independent Data 
Monitoring Committee (IDMC) concluded that the futility hurdles have been surpassed in the 
last of all planned (5) monotherapy cohorts and that the safety profile of tazemetostat 
continued to be acceptable; therefore, the IDMC determined that enrollment should continue.  
A total of 151 subjects have been enrolled and the study is ongoing.   
Study EZH-202 
This study is enrolling subjects with histologically and/or cytologically confirmed advanced 
or metastatic INI1-deficient or SMARCA4-negative tumors, and is a multicenter, open-label, 
Phase 2 study, which has been conducted since December 2015.  Subjects aged more than 
16 years have been enrolled into disease-specific 5 cohorts which comprise of 1) malignant 
rhabdoid tumors, 2) synovial sarcoma, 3) other INI1-negative tumors, 4) renal medullary 
carcinoma, or 5) epithelioid sarcoma, and have received 800 mg BID tazemetostat.   
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The primary objective for Cohorts 1, 3, and 4 is to assess the objective response rate by 
Response Evaluation Criteria in Solid Tumors (RECIST) in patients with malignant rhabdoid 
tumors, other INI1-negative tumors, or renal medullary carcinoma.  The primary objective 
for Cohort 2 is to assess progression-free survival at Week 16 (as assessed by RECIST 1.1) 
in patients with synovial sarcoma.  The primary objective of Cohort 5 is to assess the disease 
control rate (complete response [CR] or partial response [PR] of any duration, or stable 
disease of >32 weeks’ duration) in patients with epithelioid sarcoma.   
Upon review of the data available on 04 October 2016, the IDMC concluded that futility 
hurdles in Cohorts 2 and 5 had been surpassed and that study should continue, as there were 
no safety concerns.  IDMC review of other cohorts will convene in the future based on 
enrollment and data maturation.  As of 15 January 2017, a total of 102 subjects have been 
enrolled and the study is ongoing.   
Study EZH-203 
This Phase 2 study is enrolling adult subjects with relapsed or refractory malignant 
mesothelioma and consists of Part 1 and Part 2.  The primary objective of Part 1 was to 
assess the PK and safety of tazemetostat administered orally in 400 mg tablet form at a total 
dose of 800 mg BID.  Part 2 uses a 2-stage design and is enrolling subjects with BAP1 loss of 
function.  The primary objective of Part 2 is to assess the disease control rate at 12 weeks.   
Thirteen subjects were enrolled in Part 1, irrespective of BAP1 status at data cut-off.  
7.4.1.3 
Summary of Safety in Clinical Studies Conducted Outside Japan 
As of 15 January 2017, 63 subjects (98%) enrolled in the Phase 1 part of E7438-G000-101 
(n=64) had experienced at least 1 treatment-emergent adverse event (TEAE) and 49 subjects 
(77%) experienced at least 1 TEAE that was considered by the investigator to be possibly 
related to tazemetostat.  TEAEs of Grade 3 or 4 severity were reported in 36% of subjects, 
and 9% of subjects experienced at least 1 Grade 3 or Grade 4 TEAE that was considered to 
be related to study drug.   
The most frequently reported treatment-related TEAEs that occurred in more than 5% of the 
subjects were asthenia (33%), nausea (20%), anemia, muscle spasms, and thrombocytopenia 
(14% each), dry skin (11%), vomiting (9%), dysgeusia (8%), decreased appetite, diarrhea, 
neutropenia, and night sweats (6% each), and abdominal pain (5%).  There were no Grade 3 
or Grade 4 treatment-related TEAEs that occurred in ≥5% of subjects.  Two subjects 
experienced Grade 4 treatment-related TEAEs, neutropenia and thrombocytopenia.  An event 
of Grade 4 thrombocytopenia occurred in a subject who experienced E. coli sepsis related to 
underlying disease with concurrent anemia and was considered a DLT.  Only 1 DLT (Grade 
4 thrombocytopenia) was observed at the dose level of 1600 mg BID; but, the protocol-
defined MTD was not reached.   
No clear pattern of dose-related increase in toxicity (AEs of all grades and Grade 3 and 4 
AEs) was identified in the dose-escalation part of Study E7438-G000-101.   
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As of 15 January 2017, of the 266 subjects enrolled in Phase 2 studies, 237 subjects (89%) 
experienced at least 1 TEAE and 157 subjects (59%) experienced a treatment-related TEAE.  
Grade 3 or Grade 4 events, regardless of causality, occurred in 40% of subjects, and 14% of 
subjects experienced a Grade 3 or Grade 4 TEAE deemed related to study treatment. 
The most frequently reported treatment-related TEAEs that occurred in more than 5% of 
subjects were nausea (14%), fatigue (13%), asthenia (8%), thrombocytopenia (7%), and 
anemia, diarrhea, and decreased appetite (6% each).  The only TEAE of Grade 3 or higher 
severity, regardless of assessed causality, to occur in ≥ 5% of subjects treated with 
tazemetostat monotherapy in the Phase 2 studies was anemia (17 subjects; 6%).  The reported 
Grade 4 treatment-related TEAEs were neutropenia (4 subjects, 2%), thrombocytopenia 
(2 subjects; 1%), pancytopenia and dyspnea (1 subject each; <1%).   
Table 1 presents the incidence of TEAEs determined to be related to study drug that occurred 
in ≥5% of subjects who received 800 mg BID tazemetostat monotherapy in the Phase 2 
studies.   
Table 1 
Summary of Treatment-Related Treatment-Emergent Adverse 
Events Occurring in ≥5% of Subjects in Phase 2 Studies with 
Tazemetostat 
 
 
MedDRA Preferred Term 
B-cell NHL 
N=151 
n (%) 
Solid Tumors 
N=115 
n (%) 
Overall 
N=266 
n (%) 
Subjects with at least 1 TEAE 
85 (56) 
72 (63) 
157 (59) 
Nausea 
20 (13) 
18 (16) 
38 (14) 
Fatigue 
11 (7) 
24 (21) 
35 (13) 
Asthenia 
14 (9) 
7 (6) 
21 (8) 
Thrombocytopenia 
19 (13) 
0 (0) 
19 (7) 
Anemia 
7 (5) 
10 (9) 
17 (6) 
Diarrhea 
11 (7) 
5 (4) 
16 (6) 
Decreased appetite 
6 (4) 
9 (8) 
15 (6) 
NHL=non Hodgkin lymphoma, TEAE=treatment-emergent adverse event.   
 
In the Phase 1 part of Study E7438-G000-101 (n=64), 19 subjects (30%) experienced at least 
1 treatment-emergent serious adverse event (SAE) of any assessed causality.  A total of 
2 subjects (3%) experienced an SAE that was assessed as possibly related to study drug; 
these SAEs included anemia and thrombocytopenia in 1 subject and neutropenia in 1 subject.   
SAEs of any causality occurred in 82 subjects (31%) in the Phase 2 studies (n=266); 
18 subjects (7%) experienced an SAE that was assessed as related to study drug.  SAEs 
assessed as related to tazemetostat that were experienced by more than 1 subject included 
neutropenia (3 subjects) and thrombocytopenia and constipation (2 subjects each).  All other 
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treatment-related SAEs occurred in no more than 1 subject (anemia, histiocytosis 
hematophagic, abdominal pain, gastric ulcer perforation, esophageal candidiasis, pneumonia, 
soft tissue infection, malaise, hyperbilirubinemia, hyponatremia, hemoptysis, and melaena).  
7.4.1.4 
Summary of Efficacy in Clinical Studies Conducted Outside Japan 
As of 01 June 2017, the efficacy of tazemetostat was reported as interim result of ongoing 
Phase 2 study (Study E7438-G000-101 [n=203]).  The ORR (primary endpoint) was 92% 
(12/13 subjects) in EZH2 gene mutation-positive FL, 26% (14/54 subjects) in EZH2 gene 
mutation-negative (wild-type) FL, 29% (5/17 subjects) in EZH2 gene mutation-positive 
DLBCL of germinal center origin subtype, and 15% (18/119 subjects) in EZH2 gene 
mutation-negative (wild-type) DLBCL of either germinal center origin or non-germinal 
center origin subtype.  Tazemetostat showed high efficacy in subjects with EZH2 gene 
mutation compared to subjects with wild type (Morschhauser, et al., 2017).  
7.4.2 
Clinical Study Conducted in Japan 
7.4.2.1 
Overview of Phase 1 Study Conducted in Japan 
As of 31 July 2017, a total of 7 subjects have received treatment with tazemetostat in a 
Phase 1 study (E7438-J081-106).  This study enrolled subjects with B-cell NHLs including 
FL and DLBCL, and the study is ongoing.   
Study E7438-J081-106 
This study is a multicenter, single-arm, Phase 1 study in Japan to assess the tolerability, 
safety, PK profile, and preliminary anti-tumor activity of tazemetostat in patients with 
relapsed or refractory B-cell NHL.  Tazemetostat 800 mg has been administered orally by 
single dose in Cycle 0 Day 1 and then continuous BID (1600 mg total daily dose).   
A total of 7 subjects have received tazemetostat, and 1 subject was excluded from DLT 
evaluation due to early disease progression.  No DLT was observed in 6 subjects; therefore, 
tazemetostat 800 mg BID, which is RP2D outside Japan, was confirmed to be well tolerated 
in Japanese subjects.   
7.4.2.2 
Summary of Safety in Clinical Study Conducted in Japan 
As of 31 July 2017, tazemetostat 800 mg has been administered orally by single dose in 
Cycle 0 Day 1 and then continuous BID to 7 subjects enrolled in the Japanese Phase 1 study.  
The most frequently reported treatment-related TEAEs were thrombocytopenia (3 subjects; 
43%), anemia, dry skin, rash, and dysgeusia (2 subjects each; 29%), constipation, fatigue, 
gastritis, hypoalbuminemia, insomnia, leukopenia, muscle spasms, nausea, neutropenia, and 
stomatitis (1 subject each; 14%).  The treatment-related TEAEs of Grade 3 or higher were 
thrombocytopenia (2 subjects; 29%) and anemia (1 subject; 14%).  There were no SAEs 
related to study drug.   
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7.5 
Study Rationale 
In the Phase 1 part of the Study E7438-G000-101 conducted outside Japan, the recommended 
Phase 2 dose of tazemetostat has been determined to be 800 mg BID.  As interim result of 
ongoing Phase 2 part of the study, encouraging efficacy of tazemetostat was reported in 
relapsed or refractory FL and DLBCL with EZH2 gene mutation.   
In the Phase 1 study of the Study E7438-J081-106 conducted in Japan, no DLT was observed 
in tazemetostat 800 mg BID by continuous regimen; therefore, tazemetostat 800 mg BID, 
which is RP2D outside Japan, was confirmed to be well tolerated in Japanese subjects.  Also, 
the favorable safety profile of tazemetostat has been shown in Japanese and non-Japanese 
subjects.   
Based on above, the Phase 2 study (E7438-J081-206) was planned to evaluate the efficacy 
and safety of tazemetostat in Japanese patients with relapsed or refractory B-cell NHL (FL 
and DLBCL) with EZH2 gene mutation.   
In this study, tazemetostat 800 mg BID (1600 mg total daily dose) will be administered orally 
in continuous cycles of 28 days each, and the treatment will continue until disease 
progression, development of unacceptable toxicity, subject’s requests to discontinue, 
withdrawal of consent, or study termination by the sponsor.   
As the patients eligible to this study are extremely few and standard therapy/treatment to 
prolong the overall survival for relapsed or refractory B-cell NHL has not been established 
yet, the response itself is considered to be clinically meaningful.  Therefore, the primary 
endpoint of the study was set as ORR, by referring the interim result of ongoing E7438-
G000-101 study outside of Japan.  Regarding sample size of this study, in cohort 1, 8 
efficacy evaluable FL patients with EZH2 mutation are required to detect lower limit of the 
90% CI that exceed the 10% threshold in ORR, which is the primary endpoint of the study, 
with the expected ORR of 50% with power of approximately 80%.  In cohort 2, 13 efficacy 
evaluable DLBCL patients with EZH2 mutation are required to detect lower limit of the 90% 
CI that exceed the 10% threshold in ORR, which is the primary endpoint of the study, with 
the expected ORR of 40% with power of approximately 80%.   
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8 
STUDY OBJECTIVES 
8.1 
Primary Objective 
The primary objective of the study is to assess the efficacy of tazemetostat in patients with 
relapsed or refractory B-cell non-Hodgkin’s lymphoma (NHL) below by objective response 
rate (ORR). 
Cohort 1:  Follicular lymphoma (FL) with EZH2 gene mutation 
Cohort 2:  Diffuse large B-cell lymphoma (DLBCL) with EZH2 gene mutation 
8.2 
Secondary Objectives 
(1)To assess the efficacy of tazemetostat by the endpoints below. 
∙Progression-free survival (PFS) 
∙Duration of response (DOR) 
∙Time to response (TTR) 
(2)To assess the safety of tazemetostat. 
8.3 
Exploratory Objectives 
(1)To explore the pharmacokinetics (PK) of tazemetostat. 
(2)To explore the frequency of EZH2 gene mutation in B-cell NHL. 
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9 
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan 
This is a multicenter, open-label, phase 2 study in relapsed or refractory B-cell NHL patients 
with EZH2 gene mutation, and consists with 2 cohorts.  The study will assess efficacy and 
safety of tazemetostat in FL patients with EZH2 gene mutation in cohort 1, and DLBCL 
(including primary mediastinal B-cell lymphoma and transformed FL) patients with EZH2 
gene mutation in cohort 2. 
Note:  As per regulatory requirements in Japan, from the time tazemetostat is approved by 
the regulatory authority, subjects who meet approved indication of tazemetostat will continue 
this study as a post-marketing study (clinical study shall be deemed to post-marketing study 
in this protocol) until tazemetostat is commercially available for individual subjects at each 
study site.  For these subjects, the end of the study will be the date of the last study treatment 
or evaluation at discontinuation, whichever comes later. 
9.1.1 
Study Design 
The study design of this study is presented in Figure 1.  This study will be conducted in the 
following 3 phases:  Pre-treatment Phase, Treatment Phase, and Follow-up Phase.   
 
 
 
 
 
 
 
 
 
Figure 1 
Study Design 
BID = twice daily.   
 
Pre-treatment 
Treatment 
Screening 2 
Baseline 
Cycle 2 and later 
Follow-up 
Cycle 1 
28-days cycles 
30 days (+7 days) 
after last dose 
Within 
3 days 
Informed consent for tumor 
EZH2 gene mutation test 
Treatment initiated 
Registration 
Discontinuation 
Last dose 
Any 
duration 
Final observation 
Informed consent for  
study treatment  
Tumor sample submitted and 
report to the sponsor 
Tazemetostat 800 mg BID continuously 
Screening 1 
Within 28 days 
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9.1.1.1 
Pre-treatment Phase 
The Pre-treatment Phase consists of Screening 1, Screening 2, registration, and baseline 
assessment.  In Screening 1, the EZH2 gene mutation will be confirmed at central laboratory 
in patients with histologically diagnosed as FL (cohort 1) or DLBCL (cohort 2) who are 
available to provide archival tumor sample (Inclusion Criteria 1) and not apparent to conflict 
other eligible criteria to participate in the study.  The archival tumor samples will be 
submitted to the central laboratory, and then this will be reported to the sponsor.  If EZH2 
gene mutation was confirmed, conduct Screening 2 to confirm the other eligibility for study 
treatment.  Obtain the written informed consent with regards to tumor EZH2 gene mutation 
test and study treatment respectively, before Screening 1 and Screening 2.  Screening 2 will 
last no longer than 28 days before the start of study treatment.  After screening assessments, 
the patient who meets the inclusion criteria and does not meet the exclusion criteria will be 
enrolled.  The baseline assessment will be conducted within 3 days before the treatment in 
order to confirm that the patient continues to meet the inclusion criteria and does not meet the 
exclusion criteria before moving to the Treatment Phase.   
9.1.1.2 
Treatment Phase 
The Treatment Phase consists of 28 days/cycle for tazemetostat 800 mg twice daily (BID) 
oral administration (1600 mg total daily dose) on a continuous basis and lasts until 
discontinuation of study drug.  Subjects will discontinue study drug at the time of disease 
progression (site evaluation), development of unacceptable toxicity, subject’s request to 
discontinue, withdrawal of consent, or study termination by the sponsor.  The subject who 
discontinues study drug during the Treatment Phase will have a discontinuation visit of the 
Follow-up Phase.   
9.1.1.3 
Follow-up Phase 
Follow-up Phase consists of the evaluation at discontinuation which is performed within 
7 days after the discontinuation of the study and a final observation which occurs 30 days 
(+7 days) after final administration of tazemetostat or initiation of a new anti-tumor therapy, 
whichever occurs early.  Final observation is unnecessary for subjects who withdraw from 
the study and continuously take commercial tazemetostat. 
9.2 
Discussion of Study Design, Including Choice of Control Groups 
Control groups are not set in this study.  This study was designed according to “The 
Guidelines for Clinical Evaluation of Anti-Cancer Drugs in Japan (Notification No. 1101001 
issued on 01 November, 2005).” 
9.3 
Selection of Study Population 
Eight efficacy evaluable FL patients with EZH2 mutation and 13 efficacy evaluable DLBCL 
patients with EZH2 mutation will be enrolled in cohort 1 and cohort 2, respectively, at 
approximately 30 sites in Japan.  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 B-cell NHL as follows, who has provided 
written consent to submit archival tumor sample to central laboratory to confirm the 
EZH2 gene mutation status in tumor: 
· Cohort 1:  Follicular lymphoma (FL) 
· Cohort 2:  Diffuse large B-cell lymphoma (DLBCL) (including primary 
mediastinal B-cell lymphoma and transformed FL) 
(2) Patient who has confirmed EZH2 gene mutation of tumor in central laboratory 
(3) Patient who has measurable disease as below: 
· Lymph node or ex-nodal disease diagnosed 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 
(4) Patient who had previous therapy with systemic chemotherapy and/or antibody 
therapy and for which no standard therapy exists 
(5) Patient who was progressive disease (PD) or did not have response (complete response 
[CR] or partial response [PR]) in previous systemic therapy, or relapsed or progressed 
after previous systemic therapy 
(6) Patient with Eastern Cooperative Oncology Group (ECOG) performance status 
of 0 to 1 
(7) Patient with life expectancy of ≥3 months from starting study drug administration 
(8) Patient with adequate renal function: 
· Serum creatinine ≤1.5× upper limit of normal (ULN) 
(9) Patient with adequate liver function: 
· Total bilirubin ≤1.5×ULN 
· Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3.0×ULN 
(10) Patient with adequate bone marrow function: 
(confirm 2 weeks or later from last administration of granulocyte colony-stimulating 
factor [G-CSF] and blood transfusion, if these are used) 
· Absolute neutrophil count ≥1.5×103/μL (≥1.5×109/L) 
· Platelet count ≥10.0× 104/μL  
· Hemoglobin ≥9.0 g/dL 
(11) Patient with time between prior anti-tumor therapy and first administration of 
study drug as below: 
· Cytotoxic chemotherapy – At least 3 weeks 
· Non-cytotoxic chemotherapy (eg, corticosteroids*, small molecule inhibitor) – At least 
2weeks 
· Monoclonal antibody (ies) – At least 4 weeks 
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· Radiotherapy  
-At least 3 weeks from radiation therapy 
-At least 6 weeks from prior radioisotope therapy  
· Autologous hematopoietic stem cell transplantation – At least 6 months  
*:  Patient may receive no more than 10 mg of prednisolone daily or equivalent 
corticosteroid when used for treatment of lymphoma-related symptoms. 
(12) Patient with no carry-over of ≥ Grade 2 adverse events of the prior treatment that may 
affect the safety evaluation of the investigational drug 
(13) Male and female patient ≥20 years of age at the time of informed consent 
(14) 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 prior exposure to EZH2 inhibitor 
(2) Patient with a history or a presence of central nerves invasion 
(3) Patient with malignant pleural effusion, cardiac effusion, or ascites retention 
(4) Patient with allogeneic stem cell transplantation 
(5) Patient with a medical need for the continued use of potent inhibitors of CYP3A, or 
potent inducer of CYP3A (including St. John’s wort).  Patient is eligible if 2 weeks or 
longer have passed since the last use of such agents prior to the first dose of study drug.   
(6) Patient unwilling to exclude grapefruit (juice) from the diet for 1 week prior to study 
drug administration and throughout the study 
(7) Patient with the inability to take oral medication, or malabsorption syndrome or any 
other uncontrolled gastrointestinal condition (eg, nausea, diarrhea, or vomiting) or 
medical history (eg, gastrectomy or enterectomy) that might impair the bioavailability of 
study drug 
(8) Patient with significant cardiovascular impairment 
1)History of congestive heart failure of ≥ New York Heart Association (NYHA) Class III 
2)Uncontrolled arterial hypertension, unstable angina, myocardial infarction, or stroke 
within 6 months of the first dose of study drug 
3)Ischemic heart disease, cardiac arrhythmia requiring medical treatment 
(9) Patient with prolongation of corrected QT interval using Fridericia’s formula (QTcF) to 
>480 msec 
(10) Patient with venous thrombosis or pulmonary embolism within the last 3 months before 
starting study drug 
(11) Patient with complications of hepatic cirrhosis, interstitial pneumonia or pulmonary 
fibrosis 
(12) Patient with active infection requiring systemic therapy 
(13) Patient with known hypersensitivity to any component of study drug 
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(14) Patient who is positive for HIV antibody, HCV antibody, and HCV-RNA, or HBs 
antigen.  Patient who is positive for HBs or HBc antibody and showing DNA more than 
sensitivity in HBV-DNA assay 
(15) Patient with malignancy of activity other than B-cell NHL 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). 
(16) Women of childbearing potential or man of impregnate potential who don’t agree that 
both the patient and his/her partner will use a medically effective method for 
contraception (as the below note) for periods from before informed consent to during the 
clinical study and 30 days later (for males 90 days later) from last administration of 
study drug.   
(17) Woman who is pregnant or breastfeeding (not eligible even if she discontinues 
breastfeeding) 
(18) Patient who was decided as inappropriate for medical or other reasons to participate in 
the study by the investigator or sub-investigator 
(19) Patient who has a prior history of myeloid malignancy including T-cell lymphoblastic 
lymphoma, T-cell acute lymphoblastic leukemia or myelodysplastic syndrome 
Note:  Condom*, contraceptive sponge**, foam**, jelly**, diaphragm*, intrauterine device (IUD)*, or 
use of oral contraception* from at least 30 days before starting the study treatment 
(*Approved drugs or certified medical devices in Japan, **Non-approved drugs or certified medical 
devices in Japan) 
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 
off-treatment visits and procedures unless the subject withdraws consent.  If a subject 
withdraws consent, the date will be documented in the source documents.   
9.3.3.1 
Discontinuation Criteria by Subject 
If a subject meets any of the following criteria, the investigator or subinvestigator will 
discontinue treating the subject with study treatment.  If a subject experiences myeloid 
malignancy including myelodysplastic syndrome, study treatment should be interrupted and 
restart (including dose modification)/discontinuation of study treatment should be discussed 
with the sponsor. If a subject experiences T-cell lymphoblastic lymphoma/T-cell acute 
lymphoblastic leukemia, study treatment should be discontinued and other actions should be 
discussed with the sponsor. 
(1) Withdrawal of consent or proposal to refuse continuation of participation by subject 
(2) Major violation of inclusion or exclusion criteria are found.   
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(3) Presence of adverse event that investigator or subinvestigator judged it is difficult to 
continue with therapy 
(4) Pregnancy 
(5) Evidence of disease progression.  Subjects will be allowed to be treated with study drug 
if the investigator or subinvestigator judges that administration of the study drug is 
clinically beneficial for the subject.   
(6) Subject is turned to be non-compliant with the protocol and ineligible in view of safety 
issue.   
(7) Study discontinuation is appropriate judged by the investigator or subinvestigator.   
(8) Subject experiences T-cell lymphoblastic lymphoma/T-cell acute lymphoblastic leukemia 
9.4 
Treatment 
9.4.1 
Treatment Administered 
Tazemetostat 800 mg BID (1600 mg total daily dose) will be administered orally by 
continuous regimen, no less than 8 hours between doses.   
Treatment will continue until disease progression (site evaluation), development of 
unacceptable toxicity, subject’s requests to discontinue, withdrawal of consent, or study 
termination by the sponsor.   
9.4.1.1 
Tazemetostat Dose Reduction and Interruption Instructions 
Dose reduction and interruption for subjects who experience tazemetostat-related toxicity 
will follow the instructions shown in Table 2.  Dose reductions will be based on the previous 
dose level in order of 600, 400 mg BID (1200 mg, 800 mg total daily dose, respectively).  
Once the dose is reduced, it cannot be increased at a later date.  Any dose adjustment must be 
discussed with the sponsor or discontinue tazemetostat when toxicities requiring dose 
reduction occur at the dose of 400 mg BID. 
If a subject experiences myeloid malignancy including myelodysplastic syndrome, study 
treatment should be interrupted and restart (including dose modification)/discontinuation of 
study treatment should be discussed with the sponsor.  If a subject experiences T-cell 
lymphoblastic lymphoma/T-cell acute lymphoblastic leukemia, study treatment should be 
discontinued and other actions should be discussed with the sponsor. 
Study treatment may be interrupted, if it is required to ensure the safety of a subject 
experiencing an adverse event that is unrelated to the study drug.  In such cases, study 
treatment should be resumed as soon as possible, at the same dose.   
 
 
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Table 2 
Tazemetostat Dose Reduction and Interruption Instructions 
Tazemetostat-related Toxicity 
During Therapyd 
Dose adjustmentd 
Grade 1 and Tolerable Grade 2a 
Continue tazemetostat  
Maintain dose level 
Intolerable Grade 2a and  
Grade 3b 
Interrupt tazemetostat until 
resolved to Grade ≤1 or 
baselinee 
Dose reduction by one dose 
level 
Grade 3 and 
Grade 4 
neutropenia 
ANC 
≥0.75×109/L 
Continue tazemetostat 
Maintain dose level 
ANC 
<0.75×109/L 
Interrupt tazemetostat until 
resolved to ANC≥0.75×109/Le 
Dose reduction by one dose 
level 
Grade 4c 
Interrupt tazemetostat until 
resolved to Grade ≤1 or 
baselinee 
Discuss with the sponsor 
or discontinue tazemetostat 
ANC = absolute neutrophil count. 
a:  Tolerability of Grade 2 toxicities will be judged by the investigator or subinvestigator. 
b:  Dose interruption and reduction are not necessary for Grade 3 thrombocytopenia, anemia and Grade 
3 or 4 leukopenia, lymphopenia and laboratory abnormalities that are not clinically relevant.  Initiate 
optimal medical management for nausea, vomiting, and/or diarrhea prior to any study treatment 
interruption or dose reduction and follow the dose reduction and interruption instructions when it 
cannot be controlled. 
c:  Laboratory abnormalities judged to be non-life threatening, will be excluded and managed as Grade 
3. 
d:  Discuss with the sponsor when to consider the dose interruption and adjustment other than 
instructions. 
e:  To minimize the duration of interruption, assessment at least every 7 days is recommended.  A delay 
of tazemetostat for more than 28 days due to any toxicity that is related to the study treatment must 
be discussed with the sponsor before treatment can be resumed. 
 
9.4.2 
Identity of Investigational Product 
Tazemetostat will be provided as 200 mg tablet by the sponsor.  Tazemetostat tablets contain 
200 mg of drug substance as the free base.   
9.4.2.1 
Chemical Name and Structural Formula of Tazemetostat 
• 
Test drug code:  E7438 
• 
Generic name:  tazemetostat (INN) 
• 
Chemical name:  N-[(4,6-Dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl]-5-
[ethyl(tetrahydro-2H-pyran-4-yl)amino]-4-methyl-4'-(morpholin-4-ylmethyl)biphenyl-3-
carboxamide hydrobromide 
• 
Molecular formula:  C34H44N4O4∙HBr 
• 
Molecular weight:  653.65 
9.4.2.2 
Comparator Drug 
Not applicable.   
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9.4.2.3 
Labeling for Study Drug 
The following information is provided on the study drug labeling.  Details on labeling and 
package are shown in the Attachment separately provided to each site.  
• 
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, that the study drug is maintained within an 
established temperature range, and that records are maintained; the temperature should be 
monitored continuously by using either an in-house data acquisition system, a mechanical 
recording device, such as a calibrated chart recorder, or by manual means, such that 
minimum and maximum thermometric values over a specific time period can be recorded 
and retrieved as required.   
9.4.3 
Method of Assigning Subjects to Treatment Groups 
This is an open-label, single-arm study.  All subjects who provide signed informed consent 
and satisfy all eligibility requirements (see Section 9.3) will receive study drug.  There is no 
randomization in this study.   
Screening 1 
(1) The investigator, subinvestigator, or clinical research coordinator will issue the Subject 
ID Number to individual subjects who provide signed informed consent for tumor EZH2 
gene mutation test and record the date of informed consent for the test in “Subject 
Screening Log.” 
(2) The archival tumor samples will be submitted to the central laboratory.   
(3) The sponsor will be notified by fax immediately after the archival tumor samples are 
submitted.   
(4) The result of the tumor EZH2 gene mutation test will be recorded in “Subject Screening 
Log.” 
Screening 2 
The same Subject ID Number will be used for the same subject in Screening 1 and 
Screening 2, in principle.   
(1) The investigator, subinvestigator, or clinical research coordinator will record the date of 
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informed consent for study treatment in “Subject Screening Log” for the subjects who 
were confirmed to have EZH2 gene mutation and have signed the consent. 
(2) The investigator or subinvestigator will screen the subjects and determine subject 
eligibility based on the inclusion and exclusion criteria.  The decision on the subject 
eligibility will be recorded in “Subject Screening Log.”  
(3) The sponsor will be notified of date of informed consent for study treatment, date of 
screening initiation, expected treatment start date, and eligibility decision by fax 
immediately after the investigator or subinvestigator determines the subject eligibility 
(registration to study).  
(4) The investigator or subinvestigator will reconfirm the subject eligibility based on the 
results of baseline assessment according to the inclusion and exclusion criteria.  The 
investigator or subinvestigator will record the subject eligibility in medical charts and 
initiate study drug administration.   
9.4.4 
Selection of Doses in the Study 
In the Phase 1 part of the Study E7438-G000-101 conducted outside Japan, the RP2D of 
tazemetostat has been determined to be 800 mg BID.  As interim result of ongoing Phase 2 
part of the study, encouraging efficacy of tazemetostat was reported in relapsed or refractory 
FL and DLBCL with EZH2 gene mutation.   
In the Phase 1 study of the Study E7438-J081-106 conducted in Japan, no DLT was observed 
in tazemetostat 800 mg BID by continuous regimen; therefore, tazemetostat 800 mg BID, 
which is RP2D outside Japan, was confirmed to be well tolerated in Japanese subjects.  Also, 
the favorable safety profile of tazemetostat has been shown in Japanese and non-Japanese 
subjects.   
Based on these results, tazemetostat 800 mg BID by continuous regimen was selected in this 
study, and the efficacy and safety of tazemetostat 800 mg BID will be assessed in patients 
with relapsed or refractory B-cell NHL (FL and DLBCL).   
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 Treatment 
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 for study treatment and until 
the final observation) will be recorded on the case report form (CRF).  For all drugs, the 
name, dose/frequency, route, treatment start dates (or timing of starting treatment), treatment 
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end dates, and reason for use will be recorded on the CRF.  Concomitant drugs such as 
premedications, diagnostic agents, solutions, or fluid transfusions provided for surgery, 
medical examinations, or administrations will be excepted.  For concomitant therapy, the 
name, treatment start dates (or timing of starting treatment), treatment end dates, and reason 
for use will be recorded on the CRF.   
Treatment of complications or adverse events (AEs), or therapy to ameliorate symptoms 
(including G-CSF, blood products, blood transfusions, fluid transfusions, antibiotics, 
steroids, antidiarrheal drugs, or tranquilizers) other than prohibited therapies and drugs may 
be given at the discretion of the investigator or subinvestigator, but these therapies or drugs 
should be used in caution. 
9.4.7.1 
Prohibited Concomitant Therapies and Drugs 
The following drugs and therapies are prohibited from the time of subject enrollment to final 
study drug administration: 
• 
Anti-tumor therapies (Subjects may receive corticosteroid for local or systemic symptom 
control prior to and while on study.  However, subjects may receive no more than 10 mg 
of prednisolone daily or equivalent corticosteroid when used for treatment of lymphoma 
related symptoms) 
• 
Any agent that potently inhibits or induces CYP3A 
• 
Other investigational agents 
When anti-tumor therapies are implemented, study drug administration should be 
discontinued and the subject will be moved to the Follow-up Phase.   
9.4.7.2 
Concomitant Drugs to be Used With Caution 
Medications that are substrates of CYP3A, CYP2C8, CYP2C9, CYP2C19, and CYP2D6 and 
have a narrow therapeutic range (as shown in the Attachment separately provided to each 
site) should be avoided if possible.   
9.4.8 
Prohibitions and Restrictions during Study Period 
Grapefruit and grapefruit juice-containing products are not permitted for 1 week prior to 
dosing and throughout the study. 
Phototoxic Potential:  There are nonclinical data supporting a potential for phototoxicity.  
Skin-related AEs including dry skin and rash have been reported in clinical studies.  Based 
on the current limited clinical data, subjects should be instructed to take measures to avoid 
prolonged exposure to sunlight such as wearing sun screen and sun glasses, wearing 
protective clothing.   
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9.4.9 
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 clinical 
research associate (CRA) will review the treatment compliance during site visits and at the 
completion of the study.   
Treatment compliance (date of administration, dose, time of administration [at second 
administration on the day before the PK sampling day, first administration on the PK 
sampling day] as shown in Table 5) will be collected and recorded on the CRF.   
9.4.10 
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 
and adherence to GCP guidelines as well as local or regional requirements. 
Under no circumstances will the investigator or subinvestigator 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, dispensing of study drugs to the subject, unused study 
drugs that are returned by the subjects (unused study drug-1), unused study drugs that are 
shipped to site but not dispensed to subjects (unused study drug-2), and return of reconciled 
study drugs to the sponsor (a sum of unused study drugs 1 and 2).  This includes, but may not 
be limited to:  (a) documentation of receipt of study drugs, (b) study drugs dispensing/return 
reconciliation log, (c) study drugs accountability log, (d) documentation of returns to the 
sponsor.   
The study drugs and inventory records must be made available, upon request, for inspection 
by a CRA or a representative of a health authority.  Upon completion of unused drug 
accountability procedures and documentation of study drugs return by the assigned 
pharmacist (or designee), all unused study drugs and empty bottles are to 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 during site visits and at the completion of 
the study, and throughout 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 and noted on the CRF.  The information to 
be collected at Screening 1 includes Subject ID Number, date of written informed consent for 
tumor EZH2 gene mutation test, date of birth (or age), sex, race, ethnicity, primary disease 
(date of diagnosis, disease diagnosis [see below]), and EZH2 gene mutation status (including 
known information of EZH2 gene mutation status, sampling date of tissues).  The 
information to be collected at Screening 2 includes date of written informed consent for study 
treatment, clinical staging, B symptoms, prior therapies for primary disease.   
(1) Primary disease 
・Date of diagnosis 
・Disease diagnosis (for DLBCL only:  Cell-of-origin [COO] and test method) 
・Clinical staging at Screening (Ann Arbor staging) (Carbone, et al., 1971) 
・B symptoms (unexplained fever more than 38 °C, drenching night sweats, 
unexplained weight loss of more than 10% of usual body weight over 6 months) 
(2) Prior therapies for primary disease 
1) Chemotherapy (type of therapy, best overall response, name of therapy/drug, start dates, 
end dates) 
2) Radiotherapy (site of radiation, deterioration after radiotherapy, first date of radiation, 
last date of radiation) 
3) Autologous stem cell transplantation (with or without autologous stem cell 
transplantation, date of transplantation) 
9.5.1.2 
Pre-treatment Assessments 
9.5.1.2.1 
MEDICAL HISTORY AND CURRENT MEDICAL CONDITIONS 
Medical and surgical history and current medical conditions will be recorded at Screening 2.  
All medical history that is considered to have effects on efficacy or safety by the investigator 
or subinvestigator and medical conditions that are identified at Screening 2 must be noted on 
the CRF.   
9.5.1.3 
Efficacy Assessments 
Efficacy assessment will be performed by investigator or subinvestigator based on “Revised 
response criteria for malignant lymphoma (IWG-2007)” (Cheson, et al., 2007).  Overall 
response and best overall response (BOR) (best response recorded at the designated visits 
during the study) will be assessed.  Perform the assessment below for tumor assessment. 
CT scans will be performed at Screening 2, every 8 weeks from study drug administration up 
to first 32 weeks, then every 12 weeks and at discontinuation. 
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PET scans will be performed at Screening 2.  If positive, perform when it is required to 
confirm CR as soon as possible or when clinically indicated.   
If gastrointestinal disease is suspected, endoscopic examination will be performed at 
Screening 2.  If exists, perform when it is required to confirm CR as soon as possible or when 
clinically indicated.   
To evaluate bone marrow infiltration, a bone marrow aspiration or biopsy will be performed 
at Screening 2.  If positive or indeterminate, perform when it is required to confirm CR as 
soon as possible or when clinically indicated.   
Also, central review will be conducted by the Imaging Review Committee for CT and PET 
assessment.  In addition, Efficacy and Safety Evaluation Committee (ESEC) will conduct 
central evaluation based on the review of Imaging Review Committee and other assessment / 
bone marrow infiltration evaluated by the investigator or subinvestigator, to determine the 
overall responses and the best overall response. 
The primary endpoint and the secondary endpoint with regard to efficacy are defined as 
below, and will be evaluated by the result of ESEC review. 
• 
ORR: 
The rate of subjects whose BOR is CR or PR. 
• 
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 whichever occurs first).  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. 
Details of procedure of efficacy assessments will be provided in the Attachment “Overall 
response evaluation criteria” separately provided to each site.   
Storage and provision of data 
In order to carry out central review by the Imaging Review Committee, CT/MRI images and 
PET images taken at Screening 2 and tumor evaluations will be stored at each site and 
provided to the imaging review vendor designated by the sponsor as electronic data after 
masking personal information of the subject. 
Refer to the procedure manual (defined separately) for the provision of data.   
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9.5.1.4 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Assessments 
9.5.1.4.1 
PHARMACOKINETIC ASSESSMENTS 
Plasma trough concentrations of tazemetostat will be measured to evaluate pharmacokinetics 
in all of registered subjects.  
Detailed blood sampling schedule for PK assessment is shown in Table 3.  Procedures for 
collection, handling, and shipping for PK samples will be provided in a separate manual.   
Plasma concentrations of tazemetostat will be measured by validated methods using liquid 
chromatography with tandem mass spectrometry (LC-MS/MS).   
Actual time and date of PK blood samplings will be recorded in the CRF. 
Table 3 
Blood Sampling Schedule for Pharmacokinetic Assessment 
Tazemetostat 
Day 
Sampling Time 
Allowance (as a Target) 
C1D15 
Predose of first administration 
Within 60 minutes before dosing 
C2D1 
Predose of first administration 
Within 120 minutes before dosing 
C#D# = Cycle # Day #. 
 
9.5.1.4.2 
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER, ASSESSMENTS 
For subjects who provided informed consent for tumor EZH2 gene mutation test, archival 
formalin fixed paraffin embedded (FFPE) tumor samples will be submitted to the central 
laboratory to determine an EZH2 gene mutation (codons* Y646, A682, and A692) at 
Screening 1.  Fresh biopsy of tumor is not available as the sample at Screening 1.  Sampling 
date of tissues will be noted on the CRF.   
* Y646F, Y646N, Y646S, Y646H, Y646C, A682G, A692V; results for codons Y646S, Y646H, and 
Y646C are not reported individually (grouped as Y646X). 
Sample collection, timing, storage, security, use, retention and subject privacy are provided 
below.  Details of sample collection, handling, and shipping will be provided in a separate 
manual.   
Sample Collection, Timing and Storage 
Five FFPE slides (5 μm) from the pre-study preserved tumor sample will be obtained 
according to the handling procedure at the site.  The slides should be stored at room 
temperature until the sponsor’s designated vender collects for sample shipping.   
Security of the Samples, Use of the Samples, Retention of the Samples 
Sample processing, for example DNA extraction, genotyping, sequencing, or other analysis 
will be performed by a laboratory under the direction of the sponsor.  Processing, analysis, 
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and storage will be performed at a secure laboratory facility to protect the validity of the data 
and maintain subject privacy.  
Samples will only be used for the purposes described in this protocol.  Laboratories 
contracted to perform the analysis on behalf of the sponsor will not retain rights to the 
samples beyond those necessary to perform the specified analysis and will not transfer or sell 
those samples.  The sponsor will not sell the samples to a third party. 
Samples will be stored until the finalization of the analytical report at the central laboratory.  
At the end of the storage period, samples will be destroyed.   
Right to Withdraw 
If, during the time the samples are stored, a participant would like to withdraw his/her 
consent for participation in this research, the sponsor will destroy the samples.  Information 
from any assays that have already been completed at the time of withdrawal of consent will 
continue to be used as the results of the research project. 
Subject Privacy and Disclosure of Data 
Samples will be single coded (Subject ID number).  No subject-identifying information (eg, 
initials, date of birth, government identifying number) will be associated with the sample.   
The sponsor will take steps to ensure that data are protected accordingly and confidentiality 
is maintained as far as possible.   
The sponsor and its representatives and agents may share coded data with persons and 
organizations involved in the conduct or oversight of this research.  These include:   
• 
Medical institutions 
• 
Clinical research organizations retained by the sponsor  
• 
Independent ethics committees or institutional review boards that have responsibility for 
this research study  
• 
National regulatory authorities or equivalent government agencies 
At the end of the analysis, results may be presented in the clinical study report which can 
include part or all of the coded data, in listing or summary format.  Other publication (eg, in 
peer-reviewed scientific journals) or public presentation of the study results will only include 
summaries of the population in the study, and no identified individual results will be 
disclosed.   
9.5.1.5 
Safety Assessments 
Safety assessments are shown in Table 5 (Schedule of Procedures/Assessments) and below. 
Safety assessments include monitoring and recording all AEs, including all grading of 
Common Terminology Criteria for Adverse Events (CTCAE) v4.03, and SAEs; regular 
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laboratory evaluation for hematology, blood chemistry, and urine values; and periodic 
measurement of vital signs, electrocardiograms (ECGs), ECOG-PS, and physical 
examinations.   
9.5.1.5.1 
ADVERSE EVENTS 
An AE is any untoward medical occurrence in a patient.  An AE does not necessarily have a 
causal relationship with the medicinal product.  For this study, the study drug is tazemetostat.   
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 protocol-required and nonprotocol-required measurements of a 
laboratory value or other clinical test (eg, ECG or x-ray) that results in symptoms, a 
change in treatment, or discontinuation of study drug 
• 
Recurrence of an intermittent medical condition (eg, headache) not present pretreatment 
(Baseline) 
• 
An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, withdrawal of study drug, or withholding 
of study drug, whether prescribed in the protocol or not 
All AEs, regardless of relationship to study drug or procedure, should be recorded beginning 
from the time the subject signs the study ICF through the final observation visit.  When 
subject needs to receive other anti-tumor therapy within 30 days after the final study drug 
administration, final observation must be conducted before initiation of other anti-tumor 
therapy.  SAEs will be collected until the final observation visit.   
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 or subinvestigator 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 (QTcF) results, if not otherwise considered part of a clinical symptom that is 
being reported as an AE, should be considered an AE if the QTcF interval is more than 
450 ms and there is an increase of more than 60 ms from baseline.  Any ECG abnormality 
that the investigator considers as an AE should be reported as such. 
All AEs must be followed until last visit for final observation or until resolution, whichever 
comes first.  When subject needs to receive other anti-tumor therapy within 30 days after the 
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final study drug administration considering the deterioration of subject’s physical condition, 
final observation must be conducted before initiation of other anti-tumor therapy.  All SAEs 
must be followed to resolution or, if resolution is unlikely, to stabilization.  For subjects who 
withdraw from the study and continuously use commercial tazemetostat, all AEs will be 
followed until discontinuation visit. 
Every effort must be made by the investigator or subinvestigator to categorize each AE 
according to its severity and its relationship to the study treatment.   
Assessing Severity of Adverse Events 
Adverse events will be graded on a 5-point scale according to CTCAE v4.03.  Investigators 
will report CTCAE grades for all AEs (for both increasing and decreasing 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 
The relationship of each AE to the study drug will be recorded on the CRF in response to the 
following question: 
Is there a reasonable possibility that the study drug caused the AE? 
Yes (related) 
A causal relationship between the study drug and the AE is a reasonable 
possibility. 
No (not related) A causal relationship between the study drug and the AE is not a 
reasonable possibility. 
9.5.1.5.2 
SERIOUS ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS 
An SAE is any untoward medical occurrence that at any dose: 
• 
Results in death 
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• 
Is life-threatening (ie, the subject was at immediate risk of death from the adverse event 
as it occurred; this does not include an event that, had it occurred in a more severe form 
or was allowed to continue, might have caused death) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly/birth defect (in the child of a subject who was exposed to the 
study drug) 
Other important medical events that may not be immediately life-threatening or result in 
death or hospitalization but, when based on appropriate medical judgment, may jeopardize 
the subject or may require intervention to prevent one of the outcomes in the definition of 
SAE listed above should also be considered SAEs.  Medical and scientific judgment should 
be exercised in deciding whether expedited reporting is appropriate in such situations.  
For this study, occurrence of T-cell lymphoblastic lymphoma/T-cell acute lymphoblastic 
leukemia or myeloid malignancy including myelodysplastic syndrome will be considered 
AEs of interest for this study.  These events should be reported to the sponsor by completed 
SAE report (see Section 9.5.4.3.2) and considered as serious only if events meet the serious 
criteria.  These AEs should be entered on the CRF even if the events do not meet serious 
criteria.  If subject experiences T-cell lymphoblastic lymphoma/T-cell acute lymphoblastic 
leukemia, enrollment of subject should be discontinued. 
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 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 
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9.5.1.5.3 
LABORATORY MEASUREMENTS 
Clinical laboratory tests to be performed, including hematology, chemistry, and urinalysis, 
are summarized in Table 4.  The Schedule of Procedures/Assessments (Table 5) shows the 
visits and time points at which blood for clinical laboratory tests and urine for urinalysis will 
be collected in the study.  Clinical laboratory tests will be performed at each site.   
Table 4 
Clinical Laboratory Tests 
Category 
Parameters 
Hematology 
WBC count with differential (basophils, eosinophils, lymphocytes, 
monocytes, neutrophils), RBC count, hemoglobin, hematocrit, and 
platelets  
Peripheral blood smear morphology assessmenta 
Chemistry 
 
 Liver function tests 
AST, ALT, ALP, total bilirubin, direct bilirubin 
 Renal function tests 
Creatinine, BUN 
 Other 
Total protein, albumin, LDH, creatine phosphokinase, amylase, uric 
acid, glucose, triglycerides, cholesterol, sodium, chloride, 
potassium, calcium, phosphorus, INRb 
Urinalysis 
Protein (qualitative), glucose (qualitative), occult blood 
ALP = alkaline phosphatase, ALT = alanine aminotransferase, AST = aspartate aminotransferase, BUN = blood 
urea nitrogen, INR = international normalized ratio, LDH = lactate dehydrogenase, RBC = red blood cell, WBC 
= white blood cell.   
a:  On Day 15 of each cycle, peripheral blood smear morphology assessment can be omitted at the discretion of 
the investigator or subinvestigator, if there was no concern for safety of the subject.  If peripheral blood smear 
morphology assessment is confirmed to be abnormal (eg, blood cell dysplasia, appearance of blast cells) and 
myeloid malignancy including myelodysplastic syndrome is suspected, then conduct bone marrow aspirate with 
cytogenic testing (eg, G-banding). 
b:  Screening 2 only. 
 
For the management of clinically significant laboratory abnormalities, refer to the 
Tazemetostat Dose Reduction and Interruption Instructions in Table 2.   
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. 
9.5.1.5.4 
VITAL SIGNS AND WEIGHT/HEIGHT MEASUREMENTS 
Vital sign measurements (ie, systolic and diastolic blood pressure [mmHg], pulse [beats per 
minute], temperature [in centigrade]), body weight (kg), and height (cm) will be obtained at 
the visits designated in the Schedule of Procedures/Assessments (Table 5) by a validated 
method.  Blood pressure and pulse will be measured after the subject has rested.  
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9.5.1.5.5 
PHYSICAL EXAMINATIONS 
Physical examinations will be performed as designated in the Schedule of 
Procedures/Assessments (Table 5).  Documentation of the physical examination will be 
included in the source documentation at the site.  Only changes from Screening 2 physical 
examination findings that meet the definition of an AE will be recorded on the CRF.   
9.5.1.5.6 
ELECTROCARDIOGRAMS 
ECGs will be obtained as designated in the Schedule of Procedures/Assessments (Table 5) at 
each site.  Standardized, 12-lead ECG recordings that permit all 12 leads to be displayed on a 
single page with an accompanying lead II rhythm strip below the customary 3×4 lead format 
are to be used.  In addition to a rhythm strip, a minimum of 3 full complexes should be 
recorded from each lead simultaneously.  ECGs will be obtained after the subject has rested.   
ECG parameters (heart rate, PR interval, QRS interval, QRS axis, QT interval, QTcF 
interval, RR interval) will be recorded on the CRF.  ECG findings (normal, abnormal not 
clinically significant, abnormal clinically significant) will also be recorded.  QTc will be 
corrected using Fridericia method (QTcF). 
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. 
9.5.1.5.7 
OTHER SAFETY ASSESSMENTS 
9.5.1.5.7.1 ECOG PS 
An ECOG performance status should be done at each visit as designated in the Schedule of 
Procedures/Assessments (Table 5). 
9.5.1.5.7.2 Pregnancy Test 
An hCG or β-hCG test will be performed for women of childbearing potential at each site.  A 
serum or urine sample will be taken at visits as designated in the Schedule of 
Procedures/Assessments (Table 5). 
All females will be considered to be of childbearing potential unless:  
• 
Postmenopausal (amenorrheic for at least 12 consecutive months without other known or 
suspected cause)  
• 
Sterilized surgically (bilateral tubal ligation at least 1 month before dosing, total 
hysterectomy, or bilateral oophorectomy at least 1 month before dosing). 
9.5.1.6.7.3 Viral Tests 
Hepatitis B surface (HBs) antigen, HBs antibody, hepatitis B virus core (HBc) antibody, 
hepatitis C virus (HCV) antibody, and HIV antibody tests will be performed at Screening 2.  
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When subjects have HBs antibody or HBc antibody positive results, HBV-DNA tests will be 
performed.  When subjects have HCV antibody positive results, HCV-RNA tests will be 
performed.  Viral tests will be performed at each site.   
9.5.2 
Schedule of Procedures/Assessments 
9.5.2.1 
Schedule of Procedures/Assessments 
Table 5 presents the schedule of procedures/assessments for the study. 
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Table 5 
Schedule of Procedures/Assessments in Study E7438-J081-206 (EZH-206) 
Phase 
Pre-treatment 
Treatment 
Follow-up 
Period 
Screening 1 
Screening 2a 
Baseline 
Cycle 1 
Cycle 2 and later 
Discontinuat
ion 
Final 
observation 
Day 
 
Within 28 
days 
before admin 
Within 3 days  
before admin 
1 
15 
(±3) 
1 
(±3) 
15k 
(±3) 
(+7) 
30 days after 
last dosing 
(+7)b, l 
IC for EZH2 gene mutation test  
X 
 
 
 
 
 
 
 
 
Archival tumor sample submission 
X 
 
 
 
 
 
 
 
 
IC for study treatmentc 
 
X 
 
 
 
 
 
 
 
Demographic data 
[X]d 
X 
 
 
 
 
 
 
 
Inclusion/exclusion Criteria 
 
X 
X 
 
 
 
 
 
 
Enrollment 
 
X 
 
 
 
 
 
 
 
Medical history/Current medical condition 
 
X 
 
 
 
 
 
 
 
Previous therapy 
 
X 
 
 
 
 
 
 
 
Height 
 
X 
 
 
 
 
 
 
 
Body weight 
 
X 
X 
 
X 
X 
X 
X 
X 
Physical examination 
 
X 
X 
 
X 
X 
X 
X 
X 
Vital signs 
 
X 
X 
 
X 
X 
X 
X 
X 
ECOG performance status 
 
X 
X 
 
 
X 
 
X 
 
12-lead ECGs 
 
X 
X 
 
X 
X 
X 
X 
 
Pregnancy test (if applicable) 
 
X 
 
 
 
 
 
X 
 
Virus test 
 
X 
 
 
 
 
 
 
 
Hematologyj 
 
X 
X 
 
X 
X 
X 
X 
X 
Blood chemistry 
 
X 
X 
 
X 
X 
X 
X 
X 
Urinalysis 
 
X 
X 
 
X 
X 
X 
X 
X 
PK blood samplinge 
 
 
 
 
X 
[X] 
 
 
 
Tumor assessments (CT/endoscopy)f 
 
X 
 
 
 
[X] 
X 
 
Tumor assessments (PET)g 
 
X 
 
 
 
[X] 
 
 
Bone marrow examination (bone marrow 
aspiration or biopsy)h 
 
X 
 
 
 
[X] 
 
 
Tazemetostat administrationi 
 
 
 
Continuous 28-day cycle of twice daily (BID) 
 
 
Adverse events 
 
From informed consent for study treatment to final observation 
Concomitant drug/therapies 
 
From informed consent for study treatment to final observation 
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Note, [X]:  In case to perform. 
admin = administration, BID = twice daily, C#D# = Cycle # Day #, CR = complete response, CT = computed tomography, ECG = electrocardiogram, ECOG-PS 
= Eastern Cooperative Oncology Group-Performance Status, IC = informed consent, PET = positron emission tomography, PK = pharmacokinetics. 
a:  Screening 2 assessments may be used as baseline assessments if performed within 3 days of the first administration of study drug. 
b:  When subject needs to receive other anti-tumor therapy within 30 days after the final study drug administration, final observation must be conducted before 
initiation of other anti-tumor therapy and the data within 7 days before next anti-tumor therapy can be used for final observation.  
c:  Obtain from the patients who has confirmed tumor EZH2 gene mutation in central laboratory. 
d:  Collect demography information described in Section 9.5.1.1.   
e:  Blood samples for PK analyses of tazemetostat will be collected in C1D15 and C2D1 predose of first administration. 
f:  The data of CT scan/endoscopy before informed consent within 28 days from study drug administration can be used as Screening 2 data if it meets the requirement 
of the protocol.  Perform tumor assessment at Screening 2, every 8 weeks from first study drug administration for first 32 weeks (±1 week, eg, C2D21 to C3D7, 
C4D21 to C5D7…C8D21 to C9D7), then every 12 weeks (±1 week, eg, C11D21 to C12D7, C14D21 to C15D7…) and discontinuation.  The data within 28 days 
can be used as discontinuation data.  If gastrointestinal disease were suspected, endoscopic examination will be performed at Screening 2.  If exists, perform 
when it is required to confirm CR as soon as possible or when clinically indicated.   
g:  The data of PET scan before informed consent within 28 days from study drug administration can be used as Screening 2 data if it meets the requirement of the 
protocol.  If positive, perform when it is required to confirm CR as soon as possible or when clinically indicated.   
h:  The data of bone marrow examination before informed consent within 42 days from study drug administration can be used as Screening 2 data if it meets the 
requirement of the protocol.  If positive or indeterminate, perform when it is required to confirm CR as soon as possible or when clinically indicated. 
i:  Subjects should not take study drug before evaluations are performed, unless specified (except tumor assessments and peripheral blood smear morphology 
assessment). 
j:  On Day 15 of each cycle, peripheral blood smear morphology assessment can be omitted at the discretion of the investigator or subinvestigator, if there was no 
concern for safety of the subject. 
k:  In Cycle 13 or later, visits and assessments on Day 15 can be omitted at the discretion of the investigator or subinvestigator, if there was no concern for safety 
of the subject. 
l:  Final observation is unnecessary for subjects who meet approved indication and receive commercial tazemetostat. 
 
 
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9.5.3 
Appropriateness of Measurements 
All clinical assessments were 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, ECGs, ECOG-PS, physical 
examinations, 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 SAEs, regardless of their relationship to study treatment, must be reported to the sponsor 
as soon as possible but no later than 1 business day from the date the investigator becomes 
aware of the event.  Completed SAE reports will be sent to the sponsor directly or by fax 
within 3 business days for fatal or life-threatening AEs and within 5 business days for other 
SAEs.  The faxed report should be followed up by the original SAE report.   
SAEs, regardless of causality assessment, must be collected through the final observation 
visit.  All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization.  
Any SAE judged by the investigator or subinvestigator to be related to the study treatment or 
any protocol-required procedure should be reported to the sponsor regardless of the length of 
time that has passed since study completion.  For subjects who withdraw from the study and 
continuously take commercial tazemetostat, all SAEs will be followed until discontinuation 
visit. 
The detailed contact information for reporting of SAEs is provided in the Attachment 
separately provided to each site.   
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 to the sponsor 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 if requested 
by the sponsor.   
9.5.4.2 
Reporting of Pregnancy and Exposure to Study Drug Through Breastfeeding 
Any pregnancy in which the estimated date of conception is either before the last visit or 
within 30 days of last study treatment, any partner’s pregnancy of male subjects in which the 
estimated date of conception is either before the last visit or within 90 days of last study 
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treatment, or any exposure to study drug through breastfeeding during study treatment or 
within 30 days of last study treatment, must be reported.  However, any pregnancy in which 
the estimated conception is after using commercial tazemetostat is not required to report, as 
these events are separately collected as spontaneous report. 
If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment.   
A congenital anomaly, death during perinatal period, an induced abortion, or a spontaneous 
abortion are considered to be an SAE and should be reported in the same time frame and in 
the same format as all other SAEs (see Reporting of Serious Adverse Events 
[Section 9.5.4.1]).   
Pregnancies or exposure to study drug through breastfeeding must be reported to the sponsor 
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 or breastfeeding.  The contact information for 
the reporting of pregnancies and exposure to study drug through breastfeeding is provided in 
the Attachment separately provided to each site.  The Pregnancy Report Form must be used 
for reporting.  All pregnancies must be followed to outcome.  The outcome of the pregnancy 
must be reported to the sponsor as soon as possible but no later than 1 business day from the 
date the investigator becomes aware of the outcome. 
A subject who becomes pregnant must be withdrawn from the study.   
9.5.4.3 
Reporting of Events Associated with Special Situations 
9.5.4.3.1 
REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE, 
MISUSE, ABUSE, OR MEDICATION ERROR 
Adverse events associated with study drug overdose, misuse, abuse, and medication error 
refer to AEs associated with uses of the study drug outside of that specified by the protocol.  
Overdose, misuse, abuse, and medication error are defined as follows:  
Overdose 
Accidental or intentional use of the study drug in an amount higher 
than the protocol-defined dose 
Misuse 
Intentional and inappropriate use of study drug not in accordance with 
the protocol 
Abuse 
Sporadic or persistent intentional excessive use of study drug 
accompanied by harmful physical or psychological effects 
Medication error 
Any unintentional event that causes or leads to inappropriate study 
drug use or subject harm while the study drug is in the control of site 
personnel or the subject. 
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All AEs associated with overdose, misuse, abuse, or medication error should be captured on 
the CRF and also reported using the procedures detailed in Reporting of Serious Adverse 
Events (Section 9.5.4.1) even if the AEs do not meet serious criteria.  Abuse is always to be 
captured as an AE.  If the AE associated with an overdose, misuse, abuse, or medication error 
does not meet serious criteria, it must still be reported using the SAE form and in an 
expedited manner but should be noted as nonserious on the SAE form and the CRF. 
9.5.4.3.2 
REPORTING OF STUDY-SPECIFIC EVENTS 
The occurrence of T-cell lymphoblastic lymphoma/T-cell acute lymphoblastic leukemia or 
myeloid malignancy including myelodysplastic syndrome will be considered events of 
interest for this study.  These events should be directly reported to the sponsor as soon as 
possible (no later than 1 business day) after obtaining the information.  In addition, these 
events should be directly reported to the sponsor or by fax with completed SAE report 
promptly. The faxed report should be followed up by the original SAE report.  Events of 
interest for this study must be followed to resolution or, if resolution is unlikely, to 
stabilization.  Any event of interest to be related to the study drug or any protocol-required 
procedure judged by the investigator or subinvestigator should be reported to the sponsor 
regardless of the length of time that has passed since study completion. 
9.5.4.4 
Expedited Reporting 
The sponsor must inform investigators, the head of the medical institution, and regulatory 
authorities of reportable events, in compliance with applicable regulatory requirements, on an 
expedited basis (ie, within specific time frames).  For this reason, it is imperative that sites 
provide complete SAE information in the manner described above. 
9.5.4.5 
Breaking the Blind 
Not applicable. 
9.5.4.6 
Regulatory Reporting of Adverse Events 
Adverse events will be reported by the sponsor 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 5).   
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 such as the reason for 
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failure to return, the status of treatment compliance, the presence or absence of AEs, and 
clinical courses of signs and symptoms.   
For subjects who discontinue the study early, 1 primary reason for discontinuation and study 
disposition information will be collected on the CRF.   
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 or subinvestigator, with the consent of the subject, will 
inform the other physician that the subject is participating in the clinical study. 
9.6 
Data Quality Assurance 
This study will be organized, performed, and reported in compliance with the protocol, 
SOPs, working practice documents, and applicable regulations and guidelines.  Site audits 
will be made periodically by the sponsor’s qualified compliance auditing team, which is an 
independent function from the study team responsible for conduct of the study.  
9.6.1 
Data Collection 
Data required by the protocol will be collected on the CRFs.  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 the sponsor, except for 
authorized representatives of the sponsor or appropriate regulatory authorities.   
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9.6.2 
Clinical Data Management 
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All 
data, both CRF and external data (eg, laboratory data), will be entered into a clinical system.   
9.7 
Statistical Methods 
All statistical analyses will be performed 1) after data cut-off for primary analysis or 2) after 
the study is completed and the database is locked and released.  Data cut-off will be 
performed at Week 56 (after more than 12 months from the start of treatment to all subjects), 
or after the discontinuation of treatment before 12 months.  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 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 
• 
ORR of BOR 
9.7.1.1.2 
SECONDARY ENDPOINTS 
• 
PFS 
• 
DOR 
• 
TTR 
• 
Safety assessments (AEs, clinical laboratory tests, vital signs, body weight, 12-lead 
ECGs, ECOG-PS, and physical examinations) 
9.7.1.1.3 
EXPLORATORY ENDPOINTS 
• 
Concentration of tazemetostat 
• 
Frequency of EZH2 gene mutation 
9.7.1.2 
Definitions of Analysis Sets 
Efficacy Analysis Set will include efficacy evaluable subjects who received at least 1 
administration of the study drug and who has at least 1 appropriate tumor assessment data of 
Screening 2 and post-baseline. 
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Pharmacokinetic Analysis Set will include subjects who received at least 1 administration 
of the study drug and had at least 1 concentration data of tazemetostat. 
Biomarker Analysis Set will include subjects who have conducted EZH2 gene mutation 
assessment at Screening.   
Safety Analysis Set will include subjects who received at least 1 administration of the study 
drug. 
9.7.1.3 
Subject Disposition 
Subjects who signed informed consent (for tumor EZH2 gene mutation test and study 
treatment), were registered in the study, and failed screening (Screening 1 and Screening 2) 
and the reason for screen failures will be presented.  Subjects who were treated, were not 
treated, were ongoing, and discontinued from study treatment and the reason for 
discontinuation will be presented.   
9.7.1.4 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics for the Safety/Efficacy Analysis Set will be 
summarized in whole or each disease (cohort).  Continuous demographic and baseline 
variables include age, height, and body weight; categorical variables include sex, age group, 
race, ethnics, ECOG-PS, diagnosis (including COO, as needed), clinical staging, 
B symptoms, and prior therapies for primary disease (chemotherapy, radiotherapy, and 
autologous stem cell transplantation, etc.).   
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) preferred name.  Prior 
medications will be defined as medications that stopped before the first dose of study drug.  
Concomitant medications will be defined as medications that started before the first dose of 
study drug and were continuing at the time of the first dose of study drug, or started on or 
after the date of the first dose of study drug up to the final observation.  All prior and 
concomitant medications will be presented in subject data listings. 
9.7.1.6 
Efficacy Analyses 
This analysis will be performed on the Efficacy Analysis Set.  All summary of efficacy will 
be conducted for each disease (cohort).   
9.7.1.6.1 
PRIMARY EFFICACY ANALYSIS 
BOR will be summarized.  The rate of subjects whose BOR is CR or PR is calculated as 
ORR, and its corresponding 2-sided exact 90% confidence intervals (CIs) using the method 
of Clopper–Pearson will also be calculated.  A waterfall plot will be presented for the percent 
changes from baseline in the sum of the diameters of target lesions at post-baseline nadir.   
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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 in responders.   
• 
Analysis of TTR 
TTR will be summarized by descriptive statistics in responders.   
9.7.1.7 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses 
9.7.1.7.1 
PHARMACOKINETIC ANALYSES 
This analysis will be performed on the Pharmacokinetic Analysis Set.  The plasma 
concentrations of tazemetostat will be summarized by timepoint.   
9.7.1.7.2 
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ANALYSES 
This analysis will be performed on the Biomarker Analysis Set.  The rate of the tumor EZH2 
gene mutation will be calculated in each disease.   
9.7.1.8 
Safety Analyses 
This analysis will be performed on the Safety Analysis Set in whole or each disease (cohort).   
9.7.1.8.1 
EXTENT OF EXPOSURE 
The number of cycles/days on treatment, quantity of study drug administered, and the 
number of subjects requiring study drug dose reductions, interruption, and discontinuation 
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 
(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. 
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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 number (percentage) of subjects with TEAEs will be summarized by SOC and PT.  A 
subject will be counted only once within an SOC and PT, even if the subject experienced 
more than 1 TEAE within a specific SOC and PT.  The number (percentage) of subjects with 
TEAEs will also be summarized by highest CTCAE grade.   
The number (percentage) of subjects with treatment-related TEAEs will be summarized by 
SOC and PT.  Treatment-related TEAEs include those events considered by the investigator 
to be related to study treatment.  The number (percentage) of subjects with treatment-related 
TEAEs will also be summarized by highest CTCAE grade.   
The number (percentage) of subjects with SAEs and TEAEs leading to death, discontinuation 
from study drug, study drug dose reduction or interruption will be summarized by SOC and 
PT.  Subject data listings of all SAEs and AEs leading to death, discontinuation from study 
drug, study drug dose reduction or interruption will be provided.   
9.7.1.8.3 
LABORATORY VALUES 
Laboratory results will be summarized using Système International (SI) units.  For all 
quantitative parameters listed in Section 9.5.1.5.3, the actual value and the change from 
baseline to each postbaseline visit and to the last observation will be summarized by visit 
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 the last observation will be reported using shift tables.  Percentages will be based on 
the number of subjects with both nonmissing baseline and relevant postbaseline results.   
CTCAE v4.03 will be used to identify subjects with treatment-emergent markedly abnormal 
laboratory values (TEMAVs).  The details of TEMAV definitions will be provided in the 
SAP.  TEMAVs will be summarized for overall visits. 
9.7.1.8.4 
VITAL SIGNS 
Descriptive statistics for vital signs parameters (ie, systolic and diastolic blood pressure, 
pulse, temperature) and body weight and changes from baseline will be presented by visit.   
9.7.1.8.5 
ELECTROCARDIOGRAMS 
ECG assessments will be 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 parameters.  
In addition, the number (percentage) of subjects with at least 1 postbaseline abnormal ECG 
result in QTcF will be summarized.  Clinically abnormal ECG results in QTcF will be 
categorized as follows: 
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Absolute QTcF interval prolongation: 
• 
QTcF interval >450 msec 
• 
QTcF interval >480 msec 
• 
QTcF interval >500 msec 
Change from baseline in QTcF interval: 
• 
QTcF interval increases from baseline >30 msec 
• 
QTcF interval increases from baseline >60 msec 
9.7.1.8.6 
OTHER SAFETY ANALYSES 
ECOG-PS will be summarized by scale at each visit and by highest postbaseline scale.   
9.7.2 
Determination of Sample Size 
In cohort 1, 8 efficacy evaluable FL patients with EZH2 mutation are required to detect lower 
limit of the 90% CI that exceed the 10% threshold in ORR, which is the primary endpoint of 
the study, with the expected ORR of 50% with power of approximately 80%.   
In cohort 2, 13 efficacy evaluable DLBCL patients with EZH2 mutation are required to 
detect lower limit of the 90% CI that exceed the 10% threshold in ORR, which is the primary 
endpoint of the study, with the expected ORR of 40% with power of approximately 80%.   
9.7.3 
Interim Analysis 
No interim analysis is planned for this study.   
9.7.4 
Other Statistical/Analytical Issues 
Not applicable. 
9.7.5 
Procedure for Revising the Statistical Analysis Plan 
If the SAP needs to be revised after the study starts, the sponsor will determine how the 
revision impacts the study and how the revision should be implemented.  The details of the 
revision will be documented and described in the clinical study report.   
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10 REFERENCE LIST 
Alimova I, Birks DK, Harris PS, Knipstein JA, Venkataraman S, Marquez VE, et al. 
Inhibition of EZH2 suppresses self-renewal and induces radiation sensitivity in atypical 
rhabdoid teratoid tumor cells. Neuro Oncol. 2013 Feb;15(2):149-60. 
Arisan S, Buyuktuncer ED, Palavan-Unsal N, Caşkurlu T, Cakir OO, Ergenekon E. Increased 
expression of EZH2, a polycomb group protein, in bladder carcinoma. Urol Int. 
2005;75(3):252-7. 
Bödör C, Grossmann V, Popov N, Okosun J, O'Riain C, Tan K, et al. EZH2 mutations are 
frequent and represent an early event in follicular lymphoma. Blood. 2013 Oct 
31;122(18):3165-8.  
Carbone PP, Kaplan HS, Musshoff K, Smithers DW, Tubiana M. Report of the Committee 
on Hodgkin's Disease Staging Classification. Cancer Res. 1971 Nov;31(11):1860-1. 
Chase A, Cross NC. Aberrations of EZH2 in cancer. Clin Cancer Res. 2011 May 
1;17(9):2613-8. 
Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, et al. Revised 
response criteria for malignant lymphoma. J Clin Oncol. 2007 Feb 10;25(5):579-86.  
Chihara D, Ito H, Matsuda T, Shibata A, Katsumi A, Nakamura S, et al. Differences in 
incidence and trends of haematological malignancies in Japan and the United States. Br J 
Haematol. 2014 Feb;164(4):536-45. 
Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, et al. CHOP 
chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse 
large-B-cell lymphoma. N Engl J Med. 2002 Jan 24;346(4):235-42. 
Copeland RA. Molecular pathways: protein methyltransferases in cancer. Clin Cancer Res. 
2013 Dec 1;19(23):6344-50. 
Deconinck E, Foussard C, Milpied N, Bertrand P, Michenet P, Cornillet-LeFebvre P, et al. 
High-dose therapy followed by autologous purged stem-cell transplantation and doxorubicin-
based chemotherapy in patients with advanced follicular lymphoma: a randomized 
multicenter study by GOELAMS. Blood. 2005 May 15;105(10):3817-23. 
Federico M, Luminari S, Dondi A, Tucci A, Vitolo U, Rigacci L, et al. R-CVP versus R-
CHOP versus R-FM for the initial treatment of patients with advanced-stage follicular 
lymphoma: results of the FOLL05 trial conducted by the Fondazione Italiana Linfomi. J Clin 
Oncol. 2013 Apr 20;31(12):1506-13. 
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Gisselbrecht C, Glass B, Mounier N, Singh Gill D, Linch DC, Trneny M, et al. Salvage 
regimens with autologous transplantation for relapsed large B-cell lymphoma in the 
rituximab era. J Clin Oncol. 2010 Sep 20;28(27):4184-90. 
Gyan E, Foussard C, Bertrand P, Michenet P, Le Gouill S, Berthou C, et al. High-dose 
therapy followed by autologous purged stem cell transplantation and doxorubicin-based 
chemotherapy in patients with advanced follicular lymphoma: a randomized multicenter 
study by the GOELAMS with final results after a median follow-up of 9 years. Blood. 2009 
Jan 29;113(5):995-1001. 
Kadoch C, Crabtree GR. Reversible disruption of mSWI/SNF (BAF) complexes by the 
SS18-SSX oncogenic fusion in synovial sarcoma. Cell. 2013 Mar 28;153(1):71-85. 
Kadoch C, Copeland RA, Keilhack H. PRC2 and SWI/SNF Chromatin Remodeling 
Complexes in Health and Disease. Biochemistry. 2016 Mar 22;55(11):1600-14. 
Kawano S, Grassian AR, Tsuda M, Knutson SK, Warholic NM, Kuznetsov G, et al. 
Preclinical Evidence of Anti-Tumor Activity Induced by EZH2 Inhibition in Human Models 
of Synovial Sarcoma. PLoS One. 2016 Jul 8;11(7):e0158888. 
Kim KH, Roberts CW, Targeting EZH2 in cancer. Nat Med. 2016 Feb;22(2):128-34. 
Knutson SK, Warholic NM, Wigle TJ, Klaus CR, Allain CJ, Raimondi A, et al. Durable 
tumor regression in genetically altered malignant rhabdoid tumors by inhibition of 
methyltransferase EZH2. Proc Natl Acad Sci U S A. 2013 May 7;110(19):7922-7. 
Knutson SK, Kawano S, Minoshima Y, Warholic NM, Huang KC, Xiao Y, et al. Selective 
inhibition of EZH2 by EPZ-6438 leads to potent antitumor activity in EZH2-mutant non-
Hodgkin lymphoma. Mol Cancer Ther. 2014 Apr;13(4):842-54. 
Ladetto M, De Marco F, Benedetti F, Vitolo U, Patti C, Rambaldi A, et al. Prospective, 
multicenter randomized GITMO/IIL trial comparing intensive (R-HDS) versus conventional 
(CHOP-R) chemoimmunotherapy in high-risk follicular lymphoma at diagnosis: the superior 
disease control of R-HDS does not translate into an overall survival advantage. Blood. 2008 
Apr 15;111(8):4004-13. 
LaFave LM, Béguelin W, Koche R, Teater M, Spitzer B, Chramiec A, et al. Loss of BAP1 
function leads to EZH2-dependent transformation. Nat Med. 2015 Nov;21(11):1344-9. 
Lenz G, Wright G, Dave SS, Xiao W, Powell J, Zhao H, et al. Stromal gene signatures in 
large-B-cell lymphomas. N Engl J Med. 2008 Nov 27;359(22):2313-23.  
Margueron R, Reinberg D. The Polycomb complex PRC2 and its mark in life. Nature. 2011 
Jan 20;469(7330):343-9. 
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Morin RD, Johnson NA, Severson TM, Mungall AJ, An J, Goya R, et al. Somatic mutations 
altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center 
origin. Nat Genet. 2010 Feb;42(2):181-5. 
Morschhauser F, Salles G, McKay P, Tilly H, Schmitt A, Gerecitano J, et al. Interim report 
from a phase 2 multicenter study of tazemetostat, an EZH2 inhibitor: clinical activity and 
favorable safety in patients with relapsed or refractory b-cell non-hodgkin lymphoma. 14th 
International Conference on Malignant Lymphoma 2017 Jun 14-17; Lugano, Switzerland.  
Ntziachristos P, Tsirigos A, Van Vlierberghe P, Nedjic J, Trimarchi T, Flaherty MS, et al. 
Genetic inactivation of the polycomb repressive complex 2 in T cell acute lymphoblastic 
leukemia. Nat Med. 2012 Feb 6;18(2):298-301. 
Ohmachi K, Ando K, Ogura M, Uchida T, Itoh K, Kubota N, et al. Multicenter phase II study 
of bendamustine for relapsed or refractory indolent B-cell non-Hodgkin lymphoma and 
mantle cell lymphoma. Cancer Sci. 2010 Sep;101(9):2059-64. 
Philip T, Guglielmi C, Hagenbeek A, Somers R, Van der Lelie H, Bron D, et al. Autologous 
bone marrow transplantation as compared with salvage chemotherapy in relapses of 
chemotherapy-sensitive non-Hodgkin's lymphoma. N Engl J Med. 1995 Dec 7;333(23):1540-
5.  
Plass C, Pfister SM, Lindroth AM, Bogatyrova O, Claus R, Lichter P. Mutations in regulators 
of the epigenome and their connections to global chromatin patterns in cancer. Nat Rev 
Genet. 2013 Nov;14(11):765-80. 
Shen JK, Cote GM, Gao Y, Choy E, Mankin HJ, Hornicek FJ, et al. Targeting EZH2-
mediated methylation of H3K27 inhibits proliferation and migration of Synovial Sarcoma in 
vitro. Sci Rep. 2016 Apr 29;6:25239. 
Sneeringer CJ, Scott MP, Kuntz KW, Knutson SK, Pollock RM, Richon VM, Copeland RA. 
Coordinated activities of wild-type plus mutant EZH2 drive tumor-associated 
hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell lymphomas. Proc 
Natl Acad Sci U S A. 2010 Dec 7;107(49):20980-5. 
Tobinai K, Watanabe T, Ogura M, Morishima Y, Ogawa Y, Ishizawa K, et al. Phase II study 
of oral fludarabine phosphate in relapsed indolent B-Cell non-Hodgkin's lymphoma. J Clin 
Oncol. 2006 Jan 1;24(1):174-80. 
Varambally S, Dhanasekaran SM, Zhou M, Barrette TR, Kumar-Sinha C, Sanda MG, et al. 
The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature. 
2002 Oct 10;419(6907):624-9. 
Wilson BG, Wang X, Shen X, McKenna ES, Lemieux ME, Cho YJ, et al. Epigenetic 
antagonism between polycomb and SWI/SNF complexes during oncogenic transformation. 
Cancer Cell. 2010 Oct 19;18(4):316-28. 
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Yoo KH, Hennighausen L. EZH2 methyltransferase and H3K27 methylation in breast cancer. 
Int J Biol Sci. 2012;8(1):59-65. 
Zingg D, Debbache J, Schaefer SM, Tuncer E, Frommel SC, Cheng P, et al. The epigenetic 
modifier EZH2 controls melanoma growth and metastasis through silencing of distinct 
tumour suppressors. Nat Commun. 2015 Jan 22;6:6051. 
General incorporated association, Japanese Society of Hematology. Guideline for 
management of hematopoietic tumor, 2013. 
CTCAE Reference 
Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 [published 28 May 2009 (v4.03: June 14, 2010)].  Available from: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-1 4_QuickReference_8.5x11.pdf.  
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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 IxRS, x-rays, and other imaging 
reports regardless of how these images are stored, including microfiche and photographic 
negatives 
• 
Questionnaires completed by subjects 
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• 
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 
• 
Correspondence regarding a study subject’s treatment between physicians or memoranda 
sent to the IRBs 
11.4 Recording of Data 
A CRF is required and must be completed for each subject who signed informed consent 
with regard to tumor EZH2 gene mutation test 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 
items other than the following items from 1 to 8, the data on medical records will be source 
data, but they can also be considered source data if appropriate records are available: 
(1)For items from below that are not documented in the medical records, including medical 
chart and worksheets, the data recorded directly on the CRF are source data: 
• 
Demography–race, ethnicity  
• 
Study drug administration (reason for treatment discontinuation, reason for dose 
modification, or others) 
• 
Reasons and dates for prior and concomitant therapy (including medications and 
therapies) 
• 
Discontinuation (reason for discontinuation, or others) 
• 
Sampling date and time for PK analysis, administration date and time 
• 
Sampling date for clinical laboratory tests 
• 
AEs (grade, relationship to study drug, outcome or others) 
• 
Tumor assessment (target lesions, non-target lesions, sites, tumor diameter, assessment 
date, new lesions) 
• 
Comments 
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(2)Source data of informed consent 
Signed ICF 
(3)Source data of relevant tests 
Clinical laboratory test chart including electronic data  
(4)Source data of histopathology 
Histopathology chart, patient referral document including electronic data  
(5)Source data of tumor assessment 
Films including electronic data  
Note that findings and measurement recorded on the CRF are source data. 
(6)Source data of ECGs 
• 
ECG charts including electronic data  
• 
Normal or abnormal findings recorded on the CRF 
(7)Record of sample shipment to external vender 
• 
Sample shipment slip 
(8)Source data of subject registration (subject eligibility determination) 
• 
Subject eligibility correspondence, email of subject registration correspondence 
(including printed email) or facsimile form 
11.6 Retention of Records 
The circumstances of completion or termination of the study notwithstanding, the 
investigator, 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).  The site should plan to retain study documents until the 
approval of a marketing application, until at least 3 years have elapsed since the formal 
discontinuation of clinical development of the investigational product as directed by the 
sponsor, or until at least 3 years have elapsed since the discontinuation or completion of this 
clinical study, whichever comes later. 
It is requested that at the completion of the required retention period the medical institution 
discuss with the sponsor if the relevant documents should be retained or not, as it may be 
necessary to retain the study records further period.  
Note:  The site should plan to retain all study documents of post-marketing study until the 
day of completion of the reexamination of Tazemetostat (the day of notification of the 
reexamination results). 
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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 drugs 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.  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 
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. 
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. 
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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 medical institution where applicable, and 
the investigator/the head of 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.   
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Date: 29 Jan 2021                                                Confidential                                               Page 1 of 6 
Protocol Amendment 
 
Study Protocol Title:  
A Phase 2 Study of Tazemetostat in Relapsed or Refractory B-cell Non-Hodgkin’s Lymphoma with EZH2 Gene Mutation 
Study Protocol Number:  E7438-J081-206 (EZH-206) 
 
Protocol 
Pages 
Before revision (Protocol V 3.0), 15 Nov 2019 
After revision (Protocol V 4.0), 29 Jan 2021 
Rationale 
1 
GCP Statement: 
This study is to be performed in full compliance with all 
applicable local Good Clinical Practice (GCP) and 
regulations.  All required study documentation will be 
archived as required by regulatory authorities. 
GCP Statement: 
This study is to be performed in full compliance with all 
applicable local Good Clinical Practice (GCP) and 
regulations (Good Post-marketing Study Practice [GPSP] in 
case of post-marketing study).  All required study 
documentation will be archived as required by regulatory 
authorities. 
Addition of the 
description for 
transition to a 
post-marketing 
study 
2 
Phase of development:  Phase 2 
Phase of development:  Phase 2 
(Note: subjects who meet approved indication of E7438 in 
Japan will continue this study as a post-marketing study.) 
The same as 
above 
7 
Duration of Treatment 
Treatment will continue until disease progression (site 
evaluation), development of unacceptable toxicity, subject’s 
requests to discontinue, withdrawal of consent, or study 
termination by the sponsor. 
Duration of Treatment 
Treatment will continue until disease progression (site 
evaluation), development of unacceptable toxicity, subject’s 
requests to discontinue, withdrawal of consent, or study 
termination by the sponsor. 
[Subjects who meet approved indication of tazemetostat in 
Japan] 
As per regulatory requirements in Japan, from the time 
tazemetostat is approved by the regulatory authority, these 
subjects will continue this study as a post-marketing study.  
Treatment will continue until tazemetostat is commercially 
The same as 
above 
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Protocol 
Pages 
Before revision (Protocol V 3.0), 15 Nov 2019 
After revision (Protocol V 4.0), 29 Jan 2021 
Rationale 
available for individual subjects at each study site, at which 
time the subjects will be switched to commercial 
tazemetostat. 
7 
Assessments 
Efficacy Assessments 
Efficacy assessment will be performed by investigator or 
subinvestigator based on “Revised response criteria for 
malignant lymphoma (IWG-2007)” (Cheson, et al., 2007).  
Overall response and best overall response (BOR) (best 
response recorded at the designated visits during the study) 
will be assessed. 
…. 
Also, central review will be conducted by the Imaging 
Review Committee for CT and PET assessment. 
Assessments 
Efficacy Assessments 
Efficacy assessment will be performed by investigator or 
subinvestigator based on “Revised response criteria for 
malignant lymphoma (IWG-2007)” (Cheson, et al., 2007).  
Overall response and best overall response (BOR) (best 
response recorded at the designated visits during the study) 
will be assessed. 
…. 
Also, central review will be conducted by the Imaging 
Review Committee for CT and PET assessment which is 
obtained within 24 months after the last subject’s enrollment 
(cut-off date: 02 Dec 2020). 
To clarify the 
rules about central 
review 
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Protocol 
Pages 
Before revision (Protocol V 3.0), 15 Nov 2019 
After revision (Protocol V 4.0), 29 Jan 2021 
Rationale 
16 
4 LIST OF ABBREVIATIONS AND DEFINITIONS 
OF TERMS 
No corresponding description 
4 LIST OF ABBREVIATIONS AND DEFINITIONS 
OF TERMS 
Added:  GPSP 
Good Post-marketing Study Practice 
Addition of the 
description for 
transition to a 
post-marketing 
study 
18 
5.2 
Ethical Conduct of the Study 
This study will be conducted in accordance with standard 
operating procedures (SOPs) of the sponsor (or designee), 
which are designed to ensure adherence to GCP guidelines as 
required by the following: 
 
Principles of the World Medical Association Declaration 
of Helsinki 
 
GCP 
5.2 
Ethical Conduct of the Study 
This study will be conducted in accordance with standard 
operating procedures (SOPs) of the sponsor (or designee), 
which are designed to ensure adherence to GCP guidelines as 
required by the following: 
 
Principles of the World Medical Association Declaration 
of Helsinki 
 
GCP 
In addition, after tazemetostat is approved by the Japanese 
regulatory authority, the study will be conducted as a post-
marketing study as per regulatory requirements of GPSP. 
The same as 
above 
31 
9.1 Overall Study Design and Plan 
The study will assess efficacy and safety of tazemetostat in 
FL patients with EZH2 gene mutation in cohort 1, and 
DLBCL (including primary mediastinal B-cell lymphoma 
and transformed FL) patients with EZH2 gene mutation in 
cohort 2. 
9.1 Overall Study Design and Plan 
The study will assess efficacy and safety of tazemetostat in 
FL patients with EZH2 gene mutation in cohort 1, and 
DLBCL (including primary mediastinal B-cell lymphoma 
and transformed FL) patients with EZH2 gene mutation in 
cohort 2. 
Note:  As per regulatory requirements in Japan, from the 
time tazemetostat is approved by the regulatory authority, 
The same as 
above 
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Date: 29 Jan 2021                                                Confidential                                               Page 4 of 6 
Protocol 
Pages 
Before revision (Protocol V 3.0), 15 Nov 2019 
After revision (Protocol V 4.0), 29 Jan 2021 
Rationale 
subjects who meet approved indication of tazemetostat will 
continue this study as a post-marketing study (clinical study 
shall be deemed to post-marketing study in this protocol) 
until tazemetostat is commercially available for individual 
subjects at each study site.  For these subjects, the end of the 
study will be the date of the last study treatment or evaluation 
at discontinuation, whichever comes later. 
 
32 
9.1.1.3 Follow-up Phase 
Follow-up Phase consists of the evaluation at discontinuation 
which is performed within 7 days after the discontinuation of 
the study and a final observation which occurs 30 days (+7 
days) after final administration of tazemetostat or initiation of 
a new anti-tumor therapy, whichever occurs early. 
9.1.1.3 Follow-up Phase 
Follow-up Phase consists of the evaluation at discontinuation 
which is performed within 7 days after the discontinuation of 
the study and a final observation which occurs 30 days 
(+7 days) after final administration of tazemetostat or 
initiation of a new anti-tumor therapy, whichever occurs 
early.  Final observation is unnecessary for subjects who 
withdraw from the study and continuously take commercial 
tazemetostat. 
 
The same as 
above 
47 
9.5.1.5.1 Adverse Events 
All SAEs must be followed to resolution or, if resolution is 
unlikely, to stabilization. 
9.5.1.5.1 Adverse Events 
All SAEs must be followed to resolution or, if resolution is 
unlikely, to stabilization.  For subjects who withdraw from 
the study and continuously use commercial tazemetostat, all 
AEs will be followed until discontinuation visit. 
The same as 
above 
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Protocol 
Pages 
Before revision (Protocol V 3.0), 15 Nov 2019 
After revision (Protocol V 4.0), 29 Jan 2021 
Rationale 
48 
9.5.1.5.2 Serious Adverse Events and Events 
Associated with Special Situations 
 
Requires inpatient hospitalization or prolongation of 
existing hospitalization for the purpose of therapy 
9.5.1.5.2 Serious Adverse Events and Events 
Associated with Special Situations 
 
Requires inpatient hospitalization or prolongation of 
existing hospitalization 
For the updated 
protocol template 
53 
9.5.2.1 Schedule of Procedures/Assessments 
No corresponding description 
9.5.2.1 Schedule of Procedures/Assessments 
Addition of the footnote l 
Additional 
description for 
transition to a 
post-marketing 
study 
54 
9.5.4.1 Reporting of Serious Adverse Events 
Any SAE judged by the investigator or subinvestigator to be 
related to the study treatment or any protocol-required 
procedure should be reported to the sponsor regardless of the 
length of time that has passed since study completion. 
9.5.4.1 Reporting of Serious Adverse Events 
Any SAE judged by the investigator or subinvestigator to be 
related to the study treatment or any protocol-required 
procedure should be reported to the sponsor regardless of the 
length of time that has passed since study completion.  For 
subjects who withdraw from the study and continuously take 
commercial tazemetostat, all SAEs will be followed until 
discontinuation visit. 
The same as 
above 
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Protocol 
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Before revision (Protocol V 3.0), 15 Nov 2019 
After revision (Protocol V 4.0), 29 Jan 2021 
Rationale 
54-55 
9.5.4.2 Reporting of Pregnancy and Exposure to 
Study Drug Through Breastfeeding 
Any pregnancy in which the estimated date of conception is 
either before the last visit or within 30 days of last study 
treatment, any partner’s pregnancy of male subjects in which 
the estimated date of conception is either before the last visit 
or within 90 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. 
9.5.4.2 Reporting of Pregnancy and Exposure to 
Study Drug Through Breastfeeding 
Any pregnancy in which the estimated date of conception is 
either before the last visit or within 30 days of last study 
treatment, any partner’s pregnancy of male subjects in which 
the estimated date of conception is either before the last visit 
or within 90 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.  
However, any pregnancy in which the estimated conception 
is after using commercial tazemetostat is not required to 
report, as these events are separately collected as spontaneous 
report. 
The same as 
above 
69 
11.6 Retention of Records 
It is requested that at the completion of the required retention 
period the medical institution discuss with the sponsor if the 
relevant documents should be retained or not, as it may be 
necessary to retain the study records further period. 
11.6 Retention of Records 
It is requested that at the completion of the required retention 
period the medical institution discuss with the sponsor if the 
relevant documents should be retained or not, as it may be 
necessary to retain the study records further period. 
Note:  The site should plan to retain all study documents of 
post-marketing study until the day of completion of the 
reexamination of Tazemetostat (the day of notification of the 
reexamination results). 
 
The same as 
above 
  
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Pages 79 to 167  removed – non-English text removed.

SAP_001.pdf: 
Statistical Analysis Plan 
E7438-J081-206 (EZH-206) 
 
 
Eisai 
Version 2.0:  31 May 2022 
Confidential 
Page 1 of 22 
 
 
STATISTICAL ANALYSIS PLAN 
Study Protocol 
Number: 
E7438-J081-206 (EZH-206) 
Study Protocol 
Title: 
A Phase 2 Study of Tazemetostat in Relapsed or Refractory B-cell Non-
Hodgkin’s Lymphoma with EZH2 Gene Mutation 
Date: 
31 May 2022 
Version: 
Version 2.0 
Page 2 of 23


Statistical Analysis Plan 
E7438-J081-206 (EZH-206) 
 
 
Eisai 
Version 2.0:  31 May 2022 
Confidential 
Page 2 of 22 
 
REVISION HISTORY 
Revisions to Version 2.0 
Date:  <31 May 2022> 
Change  
Rationale  
Affected Sections  
Added spider plot of the percent 
change from baseline in the sum 
of the diameters of target lesions 
To evaluate efficacy profile of 
E7438 
5.4.1 Primary Efficacy Analyses 
Added Treatment-Related 
Treatment-Emergent Adverse 
Events table (FL Cohort Subjects 
who Continued Study after Study 
Drug Approval Date)  
To evaluate safety profile of 
E7438  
5.6.2 Adverse Events  
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Statistical Analysis Plan 
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Version 2.0:  31 May 2022 
Confidential 
Page 3 of 22 
 
SIGNATURE PAGE 
Author:   
 
 
 
 
 
 
 
 
 
Medicine Development Center, 
Eisai Co., Ltd. 
 
 
Date 
Approval: 
 
 
 
 
 
 
 
 
 
 
Medicine Development Center, 
Eisai Co., Ltd. 
 
Date 
 
 
 
 
 
 
 
  
Oncology Business Group 
Eisai Co., Ltd. 
 
 
 
Date 
 
 
 
 
 
Medicine Development Center, 
Eisai Co., Ltd. 
 
 
Date 
Page 4 of 23
PPD
PPD
PPD
PPD
PPD
PPD
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Statistical Analysis Plan 
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Version 2.0:  31 May 2022 
Confidential 
Page 4 of 22 
 
1 
TABLE OF CONTENTS 
1 
TABLE OF CONTENTS ...................................................................................................4 
2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................6 
3 
INTRODUCTION .............................................................................................................9 
3.1 
Study Objectives ......................................................................................................9 
3.1.1 
Primary Objective ..........................................................................................9 
3.1.2 
Secondary Objectives .....................................................................................9 
3.1.3 
Exploratory Objectives ..................................................................................9 
3.2 
Overall Study Design and Plan ................................................................................9 
4 
DETERMINATION OF SAMPLE SIZE ........................................................................10 
5 
STATISTICAL METHODS ............................................................................................10 
5.1 
Study Endpoints .....................................................................................................10 
5.1.1 
Primary Endpoint .........................................................................................10 
5.1.2 
Secondary Endpoints ...................................................................................10 
5.1.3 
Exploratory Endpoints .................................................................................10 
5.2 
Study Subjects ........................................................................................................11 
5.2.1 
Definitions of Analysis Sets.........................................................................11 
5.2.2 
Subject Disposition ......................................................................................11 
5.2.3 
Demographic and Other Baseline Characteristics .......................................11 
5.2.4 
Prior and Concomitant Therapy ...................................................................11 
5.2.5 
Treatment Compliance .................................................................................12 
5.3 
Data Analysis General Considerations ..................................................................12 
5.3.1 
Pooling of Centers........................................................................................12 
5.3.2 
Adjustments for Covariates..........................................................................12 
5.3.3 
Multiple Comparisons/Multiplicity .............................................................12 
5.3.4 
Examination of Subgroups ...........................................................................12 
5.3.5 
Handling of Missing Data, Dropouts, and Outliers .....................................13 
5.4 
Efficacy Analyses ..................................................................................................13 
5.4.1 
Primary Efficacy Analyses ..........................................................................13 
5.4.2 
Secondary Efficacy Analyses ......................................................................13 
5.4.3 
Other Efficacy Analyses ..............................................................................15 
5.5 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Analyses ...............................................................................................15 
5.5.1 
Pharmacokinetic Analyses ...........................................................................15 
5.5.1.1 
Plasma Concentration Analysis .........................................................15 
5.5.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses ....15 
5.6 
Safety Analyses ......................................................................................................15 
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Statistical Analysis Plan 
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Confidential 
Page 5 of 22 
 
5.6.1 
Extent of Exposure .......................................................................................16 
5.6.2 
Adverse Events ............................................................................................16 
5.6.3 
Laboratory Values ........................................................................................17 
5.6.4 
Vital Signs ....................................................................................................18 
5.6.5 
12-lead ECGs ...............................................................................................18 
5.6.6 
Other Safety Analyses ..................................................................................18 
5.7 
Exploratory Analyses .............................................................................................19 
6 
INTERIM ANALYSES ...................................................................................................19 
7 
CHANGES IN THE PLANNED ANALYSES ...............................................................19 
8 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING ...............................19 
8.1 
PHARMACOKINETIC DATA HANDLING .......................................................19 
8.1.1 
Lower Limit of Quantification of Tazemetostat Plasma Concentration ......19 
8.1.2 
BLQ Handling for Calculation of PK Parameters .......................................19 
8.1.3 
BLQ Handling for Developing Concentration-Time Profiles .....................19 
8.1.4 
Handling of Anomalous Concentration Values ...........................................20 
8.1.5 
General Rules for Presentation of Drug Concentrations and PK 
Parameters ....................................................................................................20 
8.2 
OTHER DATA HANDLING ................................................................................20 
9 
PROGRAMMING SPECIFICATIONS ..........................................................................20 
10 STATISTICAL SOFTWARE ..........................................................................................20 
11 MOCK TABLES, LISTINGS, AND GRAPHS ..............................................................21 
12 REFERENCES ................................................................................................................21 
13 APPENDICES .................................................................................................................22 
13.1 
National Institute for Health: Common Terminology Criteria for Adverse 
Events (CTCAE) Version 4.03 ..............................................................................22 
 
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Statistical Analysis Plan 
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2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation 
Term 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
β-hCG 
beta-human chorionic gonadotropin 
BID 
twice daily 
BUN 
blood urea nitrogen 
C#D# 
Cycle# Day# 
COO 
cell-of-origin 
CR 
complete response 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DLBCL 
diffuse large B-cell lymphoma 
DLT 
dose limiting toxicity 
DOR 
duration of response 
ECOG 
Eastern Cooperative Oncology Group 
EFS 
event-free survival 
EZH2 
enhancer of zeste homolog 2 
FL 
follicular lymphoma 
GCB 
germinal center B-cell-like 
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 
HIV 
human immunodeficiency virus 
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Page 7 of 22 
 
HL 
Hodgkin lymphoma 
HMT 
histone methyltransferase 
INN 
International Nonproprietary Name 
INR 
international normalized ratio 
IUD 
intrauterine device 
LC-MS/MS 
liquid chromatography with tandem mass spectrometry 
LDH 
lactate dehydrogenase 
LLT 
lower level term 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCCN 
National Comprehensive Cancer Network 
NHL 
Non-Hodgkin’s lymphoma 
NYHA 
New York Heart Association 
ORR 
objective response rate 
PD 
progressive disease 
PET 
positron emission tomography 
PFS 
progression-free survival 
PK/PD 
pharmacokinetic/pharmacodynamic 
PR 
partial response 
PS 
performance status 
PT 
preferred term 
QOL 
quality of life 
QTc 
QT interval corrected for heart rate 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
R 
rituximab 
RP2D 
recommended Phase 2 dose 
SAE 
serious adverse event 
SD 
stable disease 
SOC 
system organ class 
SOP 
standard operating procedure 
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Confidential 
Page 8 of 22 
 
TEAE 
treatment-emergent adverse event 
TEMAV 
treatment-emergent markedly abnormal laboratory values 
TTR 
time to response 
ULN 
upper limit of normal 
WHO DD 
World Health Organization Drug Dictionary 
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Page 9 of 22 
 
3 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the procedures and the 
statistical methods that will be used to analyze and report results for Eisai Protocol E7438-
J081-206 (EZH-206). 
 
3.1 
Study Objectives 
3.1.1 
Primary Objective 
The primary objective of the study is to assess the efficacy of tazemetostat in patients with 
relapsed or refractory B-cell non-Hodgkin’s lymphoma (NHL) below by objective response 
rate (ORR). 
Cohort 1:  Follicular lymphoma (FL) with EZH2 gene mutation 
Cohort 2:  Diffuse large B-cell lymphoma (DLBCL) with EZH2 gene mutation 
 
3.1.2 
Secondary Objectives 
To assess the efficacy of tazemetostat by the endpoints below. 
∙Progression-free survival (PFS) 
∙Duration of response (DOR) 
∙Time to response (TTR) 
To assess the safety of tazemetostat. 
 
3.1.3 
Exploratory Objectives 
(1)To explore the pharmacokinetics (PK) of tazemetostat. 
(2)To explore the frequency of EZH2 gene mutation in B-cell NHL. 
 
3.2 
Overall Study Design and Plan 
This is a multicenter, open-label, phase 2 study in relapsed or refractory B-cell NHL patients 
with EZH2 gene mutation, consists with 2 cohorts.  The study will assess efficacy and safety 
of tazemetostat in FL patients with EZH2 gene mutation in cohort 1, and DLBCL (including 
primary mediastinal B-cell lymphoma and transformed FL) patients with EZH2 gene mutation 
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in cohort 2. 
 
4 
DETERMINATION OF SAMPLE SIZE 
In cohort 1, 8 efficacy evaluable FL patients with EZH2 mutation are required to detect lower 
limit of the 90% CI that exceed the 10% threshold in ORR, which is the primary endpoint of 
the study, with the expected ORR of 50% with power of approximately 80%.   
In cohort 2, 13 efficacy evaluable DLBCL patients with EZH2 mutation are required to detect 
lower limit of the 90% CI that exceed the 10% threshold in ORR, which is the primary endpoint 
of the study, with the expected ORR of 40% with power of approximately 80%. 
 
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 
• 
ORR of BOR 
5.1.2 
Secondary Endpoints 
 
PFS 
 
DOR 
 
TTR 
 
Safety assessments (AEs, clinical laboratory tests, vital signs, body weight, 12-lead ECGs, 
ECOG-PS, and physical examinations) 
 
5.1.3 
Exploratory Endpoints 
• 
Concentration of tazemetostat 
• 
Frequency of EZH2 gene mutation 
 
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5.2 
Study Subjects 
5.2.1 
Definitions of Analysis Sets 
Efficacy Analysis Set will include efficacy evaluable subjects who received at least 1 
administration of the study drug and who has appropriate tumor assessment data of Screening 
2 and post-baseline. 
Pharmacokinetic Analysis Set will include subjects who received at least 1 administration 
of the study drug and had at least 1 concentration data of tazemetostat. 
Biomarker Analysis Set will include subjects who have conducted EZH2 gene mutation 
assessment at Screening 1. 
Safety Analysis Set will include subjects who received at least 1 administration of the study 
drug. 
 
5.2.2 
Subject Disposition 
The number of subjects who signed informed consent (for tumor EZH2 gene mutation test 
and study treatment), were registered in the study, and failed screening (Screening 1 and 
Screening 2) and the primary reason for screen failures will be summarized for each disease 
(cohort).  The number and percentage of subjects who were treated, were not treated, were 
ongoing, and discontinued from studyand the primary reason for discontinuation will be 
summarized for each disease (cohort). 
5.2.3 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics for the Safety/Efficacy Analysis Set will be 
summarized for each disease (cohort) and overall.  Continuous demographic and baseline 
variables include age, body weight, height and Median time from initial diagnosis; 
categorical variables include age group(<65, 65<=), sex, race, ethnicity, ECOG-PS, Ann 
Arbor Staging at Screening, previous therapies (radiotherapy, chemotherapy, autologous 
stem cell transplantation and other medication for lymphoma), B symptoms, disease 
diagnosis (including COO) and Baseline Bone Marrow assessment. 
MEDICAL HISTORY AND CURRENT MEDICL CONDITION 
A subject data listing of medical history and current medical conditionswill be provided. 
  
5.2.4 
Prior and Concomitant Therapy 
For the Efficacy Analysis Set, the number and percentage of subjects with each previous 
therapies (radiotherapy, systemic chemotherapy, autologous stem-cell transplantation, other 
medication for lymphoma) will be provided for each disease (cohort) and overall. The 
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number and percentage of subject with each previous systemic chemotherapy will also be 
provided for each disease (cohort) and overall. 
 
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) preferred name.  Prior 
medications will be defined as medications that stopped before the first dose of study drug.  
Concomitant medications will be defined as medications that started before the first dose of 
study drug and were continuing at the time of the first dose of study drug, or started on or 
after the date of the first dose of study drug up to the final observation.  All prior and 
concomitant medications will be presented in subject data listings. 
 
5.2.5 
Treatment Compliance 
Not calculated.  
 
5.3 
Data Analysis General Considerations 
All efficacy analyses will be conducted based on the Efficacy Analysis Set. 
 
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. 
 
5.3.4 
Examination of Subgroups 
Subgroup analyses will be conducted for FL cohort. 
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For primary efficacy analysis based on the independent reviewer assessment, results will be 
summarized by subgroups defined by sex (Male/ Female), age group (<65/  >=65) and 
categories of previous chemotherapy(Bendamustine(Y/N), CHOP(Y/N), Rituximab(Y/N)), 
and lines of prior therapies(=<2/3=<, 2=</3=</4=<)  in order to assess whether the treatment 
effects are consistent across different subgroups. ORR, its corresponding 2-sided exact 90% 
confidence intervals (CIs) and 95% CIs using the method of Clopper–Pearson will be 
calculated. Additional subgroup analyses may also be conducted, if deemed appropriate. 
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 
All efficacy result will be summarized by disease (cohort) and overall. Results from central 
assessment by Efficacy and Safety Evaluation Committee and investigator assessment will be 
used.  
 
5.4.1 
Primary Efficacy Analyses 
BOR will be summarized. The rate of subjects whose BOR is CR or PR is calculated as 
ORR, and its corresponding 2-sided exact 90% confidence intervals (CIs) using the method 
of Clopper–Pearson will also be calculated. A waterfall plot will be presented for the percent 
changes from baseline in the sum of the product of diameters of target lesions at post-
baseline nadir. Also, percent change from baseline over time will be presented using spider 
plot. Regarding the ORR, 95% CIs will also be calculated. 
 
5.4.2 
Secondary Efficacy Analyses 
 Analysis of PFS 
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) and reasons of censor 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) and reasons of censor will be also summarized. 
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 Analysis of TTR 
TTR will be summarized using descriptive statistics in responders.  
 
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 
Treatment discontinuation without 
documented PD or death with post-
baseline tumor assessments 
Date of last tumor assessment before 
discontinuation 
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 
 
TTR will be calculated as: 
Date of first response – Date of administration of the first dose of study drug + 1 (day) 
 
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5.4.3 
Other Efficacy Analyses 
Not applicable. 
 
5.5 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses 
5.5.1 
Pharmacokinetic Analyses 
The Safety Analysis Set will be used for individual tazemetostat plasma concentration listings.  
The Pharmacokinetic Analysis Set will be used for summaries of tazemetostat plasma 
concentrations. The data in patient with dose-reduction/interruption will not be included on 
calculation of summary statistics.  If any subject forget the study drug administration within 3 
days before each blood collection for PK analysis, the data will not be included in the summary 
statistics. 
  
5.5.1.1 
Plasma Concentration Analysis 
<Concentration> 
Plasma concentrations of tazemetostat will be summarized using summary statistics (n, mean, 
SD, median, min and max) by timepoint in all subjects and subjects who collected blood 
sample for PK analysis within 8 to 16 hours after study drug administrationon respectively. 
Plasma concentrations of tazemetostat will be listed for each subject by actual sampling time. 
 
5.5.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses 
This analysis will be performed on the Biomarker Analysis Set. Calculate frequency and rate 
of the tumor EZH2 gene mutation in each disease. 
 
5.6 
Safety Analyses 
All safety analyses will be performed on the Safety Analysis Set. All safety result will be 
summarized for each disease (cohort) and overall. Safety variables include AEs, clinical 
laboratory parameters, vital signs, weight, ECOG PS, and 12-lead ECGs results. 
 
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5.6.1 
Extent of Exposure 
The number of cycles received, duration of treatment, total dose per subject, dose intensity 
per subject, received dose as percentage of planned starting will be summarized for each 
disease (cohort) and overall. Number of subjects with dose reductions and dose interruptions 
will be summarized for each disease (cohort) and overall. As for the subjects with any dose 
reduction, time to first dose reduction will also be summarized. 
The actual dosing transition and duration of both study drug with tumor response is presented 
using swimmer plot. 
 
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 22.0) 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 during time 
from the first dose of study drug to 37 days after the subject’s last dose, 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. 
The number and percentage of subjects with TEAEs will be calculated from the following 
viewpoints. 
 
All/Treatment-related Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term 
 
All/Treatment-Emergent Adverse Events by  Preferred Term in Decreasing Frequency 
 
All/Treatment-Emergent Adverse Events by System Organ Class, Preferred Term, and 
CTCAE Grade 
 
All/Treatment-Emergent Serious Adverse Events by System Organ Class, Preferred 
Term 
 
All/Treatment-Emergent Adverse Events Leading to Death by System Organ Class and 
Preferred Term  
 
All/Treatment-Emergent Adverse Events Leading to Study Drug Withdrawal by System 
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Organ Class and Preferred Term  
 
All/Treatment-Emergent Adverse Events Leading to Study Drug Dose Reduction by 
System Organ Class and Preferred Term  
 
All/Treatment-Emergent Adverse Events Leading to Study Drug Interruption by System 
Organ Class and Preferred Term  
 
All/Treatment-Emergent Adverse Events by System Organ Class, Preferred Term and 
Cycle 
 
All/Treatment-Emergent Adverse Events with Grade 3 or Higher by System Organ 
Class, Preferred Term and Cycle 
Also, the number and percentage of subjects with TEAEs that emerged during time from the 
study drug approval date to switching to commercial tazemostat will be calculated by System 
Organ Class and Preferred Term for FL Cohort Subjects who Continued Study after Study 
Drug Approval Date. 
In counting numbers of subjects by causal relationship or 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 (“related” > “not 
related”]) for the causal relationship and (“Grade 5” > “Grade 4” > “Grade 3” > “Grade 2” > 
“Grade 1”) for the severity. 
  
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 to the end of treatment will be summarized by visit using descriptive 
statistics. Qualitative parameters listed in protocol Section 9.5.1.5 will be summarized using 
frequencies (number and percentage of subjects), and changes from baseline to each post 
baseline visit and to end of treatment 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). Except for phosphate, a TEMAV is defined as a post 
baseline value with an increase from baseline to a grade of 2 or higher. For phosphate, a 
TEMAV is defined as a postbaseline value with an increase from baseline to a grade of 3 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. 
TEMAVs will be summarized for study overall. 
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, 
End of Treatment and Final Observation.  
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, End of Treatment and Final Observation. 
Shift tables will present changes from baseline in ECG interpretation (categorized as normal; 
abnormal, not clinically significant; and abnormal, clinically significant) to end of treatment 
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 : 
ECOG-PS will be summarized by scale at each visit and by highest postbaseline scale.  
 
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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. 
 
6 
INTERIM ANALYSES 
No interim analyses are planned for this study. 
 
7 
CHANGES IN THE PLANNED ANALYSES 
Changes in the planned analyses for protocol are as follows: 
 
Calculation of 95% CIs for ORR have been added (section 5.4.1).  
 
Subgroup analyses have been added. Both 90% CIs and 95% CIs for 
ORR(independent reviewer assessment) will be calculated for all and each subgroup 
(section 5.3.4). 
 
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 of Tazemetostat Plasma Concentration 
The LLOQ of tazemetostat plasma concentrations is 1.00 ng/mL. 
8.1.2 
BLQ Handling for Calculation of PK Parameters 
Not applicable 
8.1.3 
BLQ Handling for Developing Concentration-Time Profiles 
Not applicable 
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8.1.4 
Handling of Anomalous Concentration Values 
The handling of anomalous concentration values will follow the guidance in the Eisai manual 
302-104.01-MNL for non compartmental PK analysis (Version Date: 28 Jun 2018). 
8.1.5 
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, all summary statistics (mean, median, and 
standard deviation [SD]) will have 3 significant digits.   
Variable 
Unit 
N 
Digit rule 
Raw/ 
Minimum/ 
Maximum 
Mean 
Median 
SD 
 
Geometri
c  Mean 
CV 
(%) 
Tazemetostat 
concentration 
ng/mL 
X 
Significant 
digits 
3 
3 
3 
- 
- 
 
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).  
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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.  
 
11 MOCK TABLES, LISTINGS, AND GRAPHS 
The study table, listing and graph (TLG) shells will be provided in a separate document, 
which will show the content and format of all tables, listings, and graphs in detail. 
 
12 REFERENCES 
There is no reference. 
 
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13 APPENDICES 
13.1 National Institute for Health: Common Terminology Criteria for 
Adverse Events (CTCAE) Version 4.03  
National Cancer Institute (NCI) Cancer therapy evaluation program Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 May 2009 (v4.03 June 2010) is available 
online at: 
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf 
 
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