Conditions: Relapsed or Refractory B-cell Non-Hodgkin's Lymphoma
Keywords: relapsed or refractory B-cell non-Hodgkin's lymphoma tazemetostat Japan E7438
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 7
Healthy volunteers: no

Brief summary:
This is a multicenter, single-arm, open-label, Phase 1 study to assess the tolerability, safety, pharmacokinetics, and preliminary anti-tumor activity of tazemetostat in participants with relapsed or refractory B-cell non-Hodgkin's lymphoma (NHL).

Detailed description:

Arms:
arm 1: Participants will receive oral tazemetostat at a starting dose of 800 milligrams (mg) as a single dose (Cycle 0) and 800 mg twice a day as continuous dosing (Cycle 1 and later) (Cycle 0 duration=4 days) (Cycle 1 and later duration= 28 days).

Interventions: intervention 1: Tazemetostat
Intervention descriptions: intervention 1: Tazemetostat tablets.

Protocol document:
Prot_000.pdf: 
Clinical Study Protocol incorporating Amendment 04 
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FINAL:  18 Oct 2018 
Confidential 
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1 
TITLE PAGE 
 
Clinical Study Protocol 
Study Protocol 
Number: 
E7438-J081-106 (EZH-106) 
Study Protocol 
Title: 
A Phase 1 Study of Tazemetostat in Patients With Relapsed or 
Refractory B-cell Non-Hodgkin’s Lymphoma 
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: 
1 
Approval Date: 
V5.0 
18 Oct 2018 
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. 
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 1 Study of Tazemetostat in Patients With Relapsed or Refractory B-cell Non-Hodgkin’s 
Lymphoma 
Investigators 
See the Attachment separately provided to each site.   
Sites 
Study centers: 2 sites (planned) 
Study location: Japan 
Study Period and Phase of Development 
Study period: 24 months (planned)   
Phase of development: Phase 1 
Objectives 
Primary objective: 
To assess the tolerability of tazemetostat in patients with B-cell non-Hodgkin’s lymphoma (NHL). 
Secondary objectives: 
(1)To assess the safety of tazemetostat. 
(2)To assess the pharmacokinetics (PK) profile of tazemetostat. 
(3)To assess the preliminary anti-tumor activity of tazemetostat. 
Exploratory objectives: 
Study Design 
This is a multicenter, single-arm, phase 1 study to assess tolerability, safety, PK and preliminary anti-
tumor activity of tazemetostat in patients with relapsed or refractory B-cell NHL. 
This study will be conducted in the following 4 phases: Pre-treatment Phase, Treatment Phase, 
Extension Phase, and Follow-up Phase. 
The Pre-treatment Phase will last no longer than 28 days and include a period to obtain informed 
consent, screening, enrollment and a baseline assessment.  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 Cycle 0 (4 days) for tazemetostat single-dose oral administration and 
Cycle 1 of 28 days for tazemetostat twice daily (BID) oral administration on a continuous basis.   
Considering visit schedule and safety, subjects will be hospitalized from Cycle 0/Day 1 (C0D1) to 
Cycle 1/Day 15 (C1D15).  Based on the thorough evaluation of the data obtained on C1D15 and all 
safety data available, the investigator or subinvestigator will determine whether subjects can be 
treated on an outpatient basis.  When subjects are considered to require extended hospitalization to 
ensure subject safety, they will be hospitalized from C1D15 onwards. 
The Extension Phase consists of Cycle 2 of 28 days and later for tazemetostat BID oral administration 
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on a continuous basis and lasts until discontinuation of study drug.  
Subjects will discontinue study drug at the time of disease progression, 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. 
The starting dose of tazemetostat is 800 mg as a single dose (Cycle 0) and 800 mg BID as continuous 
dosing (Cycle 1 and later).  Three subjects will be enrolled and ensure that they are evaluable for 
dose-limiting toxicities (DLTs) at the end of Cycle 1 of the cohort.  When a DLT is observed in 0 or 1 
of 3 subjects at a given dose level, 3 additional subjects would be treated at the same dose level.   
When 2 of 3 subjects at a given dose level experience DLTs, enrollment of additional subjects will be 
discussed jointly by the investigator and sponsor.  The opinion of Independent Data Monitoring 
Advisor should be also obtained.  When additional subjects are to be enrolled, they will be monitored 
individually.  When no DLTs are observed, up to 3 additional subjects will be enrolled.  When no 
additional subjects are accrued or 3 subjects in total experienced DLTs, the enrollment in the cohort 
will be discontinued and the lower dose level of tazemetostat cohort will be considered jointly by the 
investigator and sponsor.  The opinion of Independent Data Monitoring Advisor can be obtained if 
needed. 
If the subject is regarded as DLT non-evaluable (eg, early discontinuation due to non-DLT, 
medication compliance with < 75% in Cycle 1 as a result of the reason other than treatment related 
toxicity), another subject will be added for replacement.  
 
Dose-Limiting Toxicities (DLT) 
A DLT is defined as toxicity related to study drug in Table below.  The tolerability of tazemetostat 
will be determined based on the incidence of DLTs in Cycles 0 and 1.  If DLTs occurs in 0 or 1 of 6 
subjects, this dose level is considered tolerable.  If DLTs occur in 2 of 6 subjects, the tolerability of 
this dose level will be determined jointly by the investigator and sponsor.  The opinion of 
Independent Data Monitoring Advisor should be also obtained.  In the case of difficulty of 
determination of whether a subject should be counted as having experienced a DLT and/or not for 
tolerability assessment, the final determination will be made jointly by the investigator and sponsor.  
The opinion of Independent Data Monitoring Advisor can be obtained if needed. 
 
Table  Dose-Limiting Toxicities (DLT) 
Toxicity Category 
Toxicity/CTCAE Grade 
Hematological Toxicity 
• Grade 4 neutropenia for > 7 days or neutropenia requiring 
hematopoietic growth factors 
• ≥ Grade 3 febrile neutropenia 
• Grade 4 thrombocytopenia, Grade 3 thrombocytopenia with 
bleeding, or thrombocytopenia requiring platelet transfusion 
• Grade 4 anemia or anemia requiring erythrocyte transfusion  
Non-hematological 
Toxicity 
• ≥ Grade 3 nausea, vomiting, or diarrhea that persists > 7 days 
despite maximal medical therapy 
• ≥ Grade 3 non-hematological laboratory abnormalities with 
clinical symptoms that persists > 7 days 
• Other Grade 3 toxicity lasting > 7 days or Grade 4 non-
hematological toxicity of any duration 
Medication compliance 
• Failure to administer ≥ 75% (≥ 42/56 doses) of the planned 
administration number of study drug in Cycle 1 as a result of 
treatment-related toxicity 
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Number of Subjects 
Six DLT evaluable patients with relapsed or refractory B-cell NHL.  Add 6 patients per cohort when 
additional lower dose level examined. 
Inclusion Criteria 
(1) Patients with histological diagnosis of B-cell NHL (except transformed lymphoma) as 
follows: 
· Diffuse large B-cell lymphoma (DLBCL) 
· Follicular lymphoma (FL) 
(2) 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. 
(3) Patient who had previous therapy with systemic chemotherapy and/or antibody therapy 
and for which no standard therapy exists. 
(4) Patient who was 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. 
(5) Patient with Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 
1 
(6) Patient with life expectancy of ≥3 months from starting study drug administration. 
(7) Patient with adequate renal function: 
· Serum creatinine ≤1.5× upper limit of normal (ULN) 
(8) Patient with adequate liver function: 
· Total bilirubin ≤1.5×ULN 
· Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3.0×ULN 
(9) 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 
(10) Patient with left ventricular ejection fraction (LVEF) >50% on echocardiography or 
multiple gate acquisition (MUGA) scan. 
(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 medical need for the continued use of potent or moderate inhibitors of CYP3A or P-
gp, or potent or moderate 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 achlorhydria or use of H2 blockers or proton-pump inhibitors within 2 weeks before 
study drug administration. 
(8) Patient with inability to take oral medication, or malabsorption syndrome or any other 
uncontrolled gastrointestinal condition (eg, nausea, diarrhea, or vomiting) that might impair the 
bioavailability of study drug. 
(9) Patient with significant cardiovascular impairment 
· History of congestive heart failure ≥ New York Heart Association (NYHA) Class III 
· Uncontrolled arterial hypertension, unstable angina, myocardial infarction, or stroke within 6 
months of the first dose of study drug 
· Ischaemic heart disease, cardiac arrhythmia requiring medical treatment 
(10) Patient with prolongation of corrected QT interval using Fridericia’s formula (QTcF) to > 
480 msec. 
(11) Patient with venous thrombosis or pulmonary embolism within the last 3 months before starting 
study drug. 
(12) Patient with complications of hepatic cirrhosis, interstitial pneumonia or pulmonary fibrosis. 
(13) Patient with active infection requiring systemic therapy.  
(14) Patient with known hypersensitivity to any component of study drug.  
(15) Patient who is positive for HIV antibody, HCV antibody, or HBs antigen.  Patient who is positive 
for HBs or HBc antibody and showing DNA more than sensitivity in HBV-DNA assay. 
(16) 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). 
(17) 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 below) 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.   
(18) Woman with pregnant or breastfeeding (not eligible even if she discontinues breastfeeding).  
(19) Patient who was decided as inappropriate to participate in the study by the investigator or sub-
investigator. 
 
Note: Condom*, contraceptive sponge**, foam**, jelly**, diaphragm*, intrauterine device (IUD) *, or use 
of oral contraception* 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) 
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Study Treatment 
Tazemetostat 800 mg will be administered orally by single dose in Cycle 0/Day 1 (C0D1) and 
continuous BID (1600 mg total daily dose, no less than 8 hours between doses except C1D15 that 
requires 12 hours or more) in Cycle 1 and later, in a fasted state on C0D1 and at the first 
administration of C1D15 defined as ≥2 hours before and ≥2 hours after a meal (only water is 
allowed). Tazemetostat will be provided as 200 mg tablet. 
 
Tazemetostat Dose Reduction and Interruption Instructions 
1. Cycles 0 and 1 
a. If DLT occurs: 
Tazemetostat administration should be interrupted immediately.  Treatment may be resumed in 
Cycle 2 at 600 mg BID (1200 mg total daily dose) if toxicity is resolved to Grade ≤ 1 or baseline 
and the investigator or subinvestigator decides to continue the study. 
b. No DLT 
Tazemetostat administration will be interrupted if judged to be clinically needed by investigator 
or subinvestigator, and may be resumed at the same dose level at appropriate timing.   
2. Cycle 2 and later 
Dose reduction and interruption for subjects who experience tazemetostat-related toxicity will 
follow the instructions shown in the 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, also 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 as had been administered before the interruption. 
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Table 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 sponsor 
or discontinue tazemetostat 
ANC = absolute neutrophil count. 
a: Tolerability of Grade 2 toxicities will be judged by the study investigators. 
b: Dose interruption and reduction is 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. 
c: Laboratory abnormalities judged to be non-life threatening, will be 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 must be discussed with the sponsor 
before treatment can be resumed. 
 
Duration of Treatment 
Treatment will continue until disease progression, development of unacceptable toxicity, subject 
requests to discontinue, withdrawal of consent, or study termination by the sponsor. 
Concomitant Drug/Therapy 
The following drugs and therapies are prohibited: 
1. 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.  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 
2. Cycles 0 and 1 
· To start or change the drugs for prophylactic use to prevent adverse event (AE) occurrence 
(continuous or treatment use is allowed).  
· Any agent that moderately inhibits or induces CYP3A or inhibits P- gp 
· H2 blockers, proton-pump inhibitors 
· Any antacids or other drugs known to raise gastric pH (C0D1 and C1D15 only).  These drugs 
should be administered ≥2 hours before study drug administration and 2 hours after study drug 
administration if used in Cycle 1. 
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Assessments 
Efficacy Assessments: 
Tumor assessment will be performed by investigator or subinvestigator using “The Lugano 
Classification (CT-Based Response)” (Cheson, et al., 2014).  Overall response and best overall 
response (BOR) (best response recorded at the designated visits during the study) will be assessed.  
Perform CT scans at Screening, every 8 weeks (starting at Cycle 1/Day1) during Cycles 2-6, every 
12 weeks starting at Cycle 7 (Cycle 7/Day 1) and beyond, and discontinuation.  
A bone marrow aspiration or biopsy will be performed at screening for evaluation of bone marrow 
infiltration of tumor.  After the study drug administration, perform bone marrow aspiration or biopsy 
if the result of screening was positive or unconfirmed and when to confirm CR as best of response, or 
if clinically indicated. 
Preliminary anti-tumor activity will be objective response rate (ORR) as defined by “The Lugano 
Classification (CT-Based Response)” (Cheson, et al., 2014).  ORR is defined as the proportion of 
subjects who have a BOR of CR or PR. 
 
Pharmacokinetics Assessments: 
Plasma and urine concentrations of tazemetostat and plasma concentrations of its metabolite, 
ER-897387, and PK parameters. 
 
Tolerability and Safety Assessments: 
Safety assessments will consist of monitoring and recording all AEs, including all grading of 
Common Terminology Criteria for Adverse Events (CTCAE v4.03), and serious adverse events 
(SAEs); regular laboratory evaluation for hematology, blood chemistry, and urine values; and 
periodic measurement of vital signs, electrocardiograms (ECGs), echocardiograms/MUGA scans to 
assess LVEF, ECOG-PS, and physical examinations. 
Bioanalytical Methods 
Plasma concentrations of tazemetostat and ER-897387 and urine tazemetostat concentrations will be 
measured by validated methods using liquid chromatography with tandem mass spectrometry (LC-
MS/MS). 
Statistical Methods 
Definitions of Analysis Sets 
DLT Analysis Set will include all subjects who have completed treatment Cycles 0 and 1 without 
major protocol deviations with at least 75% of treatment compliance in Cycle 1 and were assessed for 
DLT, and subjects who have experienced DLT during Cycles 0 and 1.  Subjects with less than 75% 
treatment compliance in Cycle 1 due to a reason other than toxicity up to Cycle 1/Day 28 will not be 
included in this analysis set. 
 
Safety/Efficacy Analysis Set will include all subjects who received at least 1 administration of the 
study drug.  This will be the analysis set for all safety and efficacy evaluations, as well as for 
demographic and baseline characteristics. 
 
Pharmacokinetic Analysis Set will include all subjects who have received at least 1 administration 
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of the study drug and had sufficient PK data to derive at least 1 PK parameter. 
Efficacy Analyses  
BOR will be summarized in whole or each disease (DLBCL, FL).  The assessment of the ORR (CR + 
PR) in subjects with B cell lymphomas will be based on “The Lugano Classification (CT-Based 
Response)” (Cheson, et al., 2014) response criteria. 
ORR will be presented with corresponding 2-sided Clopper–Pearson exact 95% confidence intervals 
(CIs).  This analysis will be performed on the Efficacy Analysis Set.  If applicable, a waterfall plot 
will be presented for the percent changes from baseline in the sum of the diameters of target lesions at 
post-baseline nadir. 
 
Pharmacokinetic Analysis: 
The PK Analysis Set will be used for all PK analyses including summaries of plasma and urine 
concentrations of tazemetostat and plasma concentrations of ER-897387.  Plasma concentration-time 
profiles of tazemetostat and ER-897387 will be plotted.  Using non-compartmental analysis methods, 
plasma concentrations of tazemetostat and ER-897387 will be calculated to determine the PK 
parameters including Cmax, tmax, AUC at the first administration (Cycle 0/Day 1) and repeated 
administration (Cycle 1/Day 15). 
 
 
Tolerability and Safety Analysis: 
All tolerability analyses will be performed on the DLT Analysis Set.  The number and percentage of 
subjects with DLT will be calculated.  DLT will also be summarized per type of toxicity.  The Safety 
Analysis Set will be used for all other safety analyses. 
The number and percentage of subjects with all AEs and SAEs observed after the first administration 
of study drug will be summarized and listed by SOC, PT, and severity.  Summary statistics will be 
presented for laboratory test values, vital signs, 12-lead ECG, LVEF parameters, and ECOG-PS.  If 
needed, the changes from baseline will also be summarized. 
Sample Size Rationale 
The primary objective of this study is to investigate the tolerability of tazemetostat.  Hence neither 
clinical hypothesis nor judgment criteria are set, the sample size is not based on statistical 
consideration.  The sample size of 6 patients is considered adequate for the purpose to evaluate the 
tolerability of each cohort. 
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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 ...................................................................................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 
Diffuse Large B-cell Lymphoma and Follicular Lymphoma and Current 
Therapeutic Options ...............................................................................................20 
7.1.1 
Malignant Lymphoma ..................................................................................20 
7.1.2 
Diffuse Large B-Cell Lymphoma ................................................................20 
7.1.3 
Current Therapeutic Options for Diffuse Large B-Cell Lymphoma ...........20 
7.1.4 
Follicular Lymphoma (FL) ..........................................................................21 
7.1.5 
Current Therapeutic Options for Follicular Lymphoma ..............................21 
7.2 
EZH2 (Enhancer of Zeste Homolog 2) ..................................................................22 
7.3 
Tazemetostat (E7438) ............................................................................................23 
7.3.1 
Physical, Chemical, and Pharmaceutical Properties and Formulations .......24 
7.3.2 
Nonclinical Studies ......................................................................................24 
7.3.2.1 
Pharmacology ......................................................................................24 
7.3.2.1.1 
Primary Pharmacodynamics ..........................................................24 
7.3.2.1.2 
Secondary Pharmacodynamics ......................................................25 
7.3.2.2 
Safety Pharmacology ...........................................................................25 
7.3.2.3 
Pharmacokinetics and Drug Metabolism .............................................25 
7.3.2.4 
Toxicology ...........................................................................................26 
7.3.3 
Clinical Studies ............................................................................................29 
7.4 
Study Rationale ......................................................................................................30 
8 
STUDY OBJECTIVES ....................................................................................................32 
8.1 
Primary Objective ..................................................................................................32 
8.2 
Secondary Objectives.............................................................................................32 
8.3 
Exploratory Objectives ..........................................................................................32 
9 
INVESTIGATIONAL PLAN ..........................................................................................33 
9.1 
Overall Study Design and Plan ..............................................................................33 
9.1.1 
Study Design ................................................................................................33 
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9.1.1.1 
Pre-treatment Phase .............................................................................33 
9.1.1.2 
Treatment Phase ...................................................................................34 
9.1.1.3 
Extension Phase ...................................................................................34 
9.1.1.4 
Follow-Up Phase ..................................................................................34 
9.1.2 
Dose-Limiting Toxicities (DLT).................................................................34 
9.2 
Discussion of Study Design, Including Choice of Control Groups .......................35 
9.3 
Selection of Study Population ................................................................................36 
9.3.1 
Inclusion Criteria .........................................................................................36 
9.3.2 
Exclusion Criteria ........................................................................................37 
9.3.3 
Removal of Subjects From Therapy or Assessment ....................................38 
9.3.3.1 
Discontinuation Criteria by Subject .....................................................38 
9.4 
Treatment ...............................................................................................................39 
9.4.1 
Treatment Administered ..............................................................................39 
9.4.1.1 
Tazemetostat Dose Reduction and Interruption Instructions ...............39 
9.4.1.1.1 
Cycles 0 and 1 ................................................................................39 
9.4.1.1.2 
Cycle 2 and later ............................................................................39 
9.4.2 
Identity of Investigational Product...............................................................40 
9.4.2.1 
Chemical Name, Structural Formula of Tazemetostat .........................40 
9.4.2.2 
Comparator Drug .................................................................................41 
9.4.2.3 
Labeling for Study Drug ......................................................................41 
9.4.2.4 
Storage Conditions ...............................................................................41 
9.4.3 
Method of Assigning Subjects to Treatment Groups ...................................41 
9.4.4 
Selection of Doses in the Study ...................................................................42 
9.4.5 
Selection and Timing of Dose for Each Subject ..........................................42 
9.4.6 
Blinding........................................................................................................42 
9.4.7 
Prior and Concomitant Therapy ...................................................................42 
9.4.7.1 
Prohibited Concomitant Therapies and Drugs .....................................43 
9.4.7.2 
Concomitant Drugs to be Used with Caution ......................................43 
9.4.8 
Prohibitions and Restrictions during Study Period ......................................44 
9.4.9 
Treatment Compliance .................................................................................44 
9.4.10 
Drug Supplies and Accountability ...............................................................44 
9.5 
Study Assessments .................................................................................................45 
9.5.1 
Assessments .................................................................................................45 
9.5.1.1 
Demography .........................................................................................45 
9.5.1.2 
Pre-treatment Assessments ..................................................................45 
9.5.1.2.1 
Medical History and Current Medical Conditions .........................45 
9.5.1.3 
Efficacy Assessments...........................................................................46 
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9.5.1.4 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments .............................................................46 
9.5.1.4.1 
Pharmacokinetic Assessments .......................................................46 
9.5.1.4.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Assessments ...................................................................................47 
9.5.1.5 
Safety Assessments ..............................................................................49 
9.5.1.5.1 
Adverse Events and Events Associated with Special Situations ...49 
9.5.1.5.2 
Serious Adverse Events and Events Associated with Special 
Situations........................................................................................51 
9.5.1.5.3 
Laboratory Measurements .............................................................52 
9.5.1.5.4 
Vital Signs and Weight Measurements ..........................................53 
9.5.1.5.5 
Physical Examinations ...................................................................53 
9.5.1.5.6 
Electrocardiograms ........................................................................53 
9.5.1.5.7 
Other Safety Assessments ..............................................................54 
9.5.2 
Schedule of Procedures/Assessments ..........................................................55 
9.5.2.1 
Schedule of Procedures/Assessments of the Study ..............................55 
9.5.3 
Appropriateness of Measurements ...............................................................58 
9.5.4 
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations ..............................................................58 
9.5.4.1 
Reporting of Serious Adverse Events ..................................................58 
9.5.4.2 
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding .......................................................................................59 
9.5.4.3 
Reporting of Events Associated with Special Situations .....................59 
9.5.4.3.1 
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error ............................59 
9.5.4.3.2 
Reporting of Study-Specific Events...............................................60 
9.5.4.4 
Expedited Reporting ............................................................................60 
9.5.4.5 
Breaking the Blind ...............................................................................60 
9.5.4.6 
Regulatory Reporting of Adverse Events ............................................60 
9.5.5 
Completion/Discontinuation of Subjects .....................................................61 
9.5.6 
Abuse or Diversion of Study Drug ..............................................................61 
9.5.7 
Confirmation of Medical Care by Another Physician .................................61 
9.6 
Data Quality Assurance .........................................................................................61 
9.6.1 
Data Collection ............................................................................................61 
9.6.2 
Clinical Data Management ..........................................................................62 
9.7 
Statistical Methods .................................................................................................62 
9.7.1 
Statistical and Analytical Plans ....................................................................62 
9.7.1.1 
Study Endpoints ...................................................................................62 
9.7.1.1.1 
Primary Endpoint ...........................................................................62 
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9.7.1.1.2 
Secondary Endpoints .....................................................................62 
9.7.1.1.3 
Exploratory Endpoints ...................................................................62 
9.7.1.2 
Definitions of Analysis Sets.................................................................63 
9.7.1.3 
Subject Disposition ..............................................................................63 
9.7.1.4 
Demographic and Other Baseline Characteristics ...............................63 
9.7.1.5 
Prior and Concomitant Therapy ...........................................................63 
9.7.1.6 
Efficacy Analyses ................................................................................63 
9.7.1.7 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses ...................................................................64 
9.7.1.7.1 
Pharmacokinetic Analyses .............................................................64 
9.7.1.7.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses .........................................................................................64 
9.7.1.8 
Safety Analyses ....................................................................................64 
9.7.1.8.1 
Extent of Exposure .........................................................................64 
9.7.1.8.2 
Dose Limiting Toxicities ...............................................................64 
9.7.1.8.3 
Adverse Events ..............................................................................64 
9.7.1.8.4 
Laboratory Values ..........................................................................65 
9.7.1.8.5 
Vital Signs ......................................................................................65 
9.7.1.8.6 
Electrocardiograms ........................................................................65 
9.7.1.8.7 
Other Safety Analyses....................................................................66 
9.7.2 
Determination of Sample Size .....................................................................66 
9.7.3 
Interim Analysis ...........................................................................................66 
9.7.4 
Other Statistical/Analytical Issues ...............................................................66 
9.7.5 
Procedure for Revising the Statistical Analysis Plan ...................................66 
10 REFERENCE LIST .........................................................................................................67 
11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES) .......71 
11.1 
Changes to the Protocol .........................................................................................71 
11.2 
Adherence to the Protocol ......................................................................................71 
11.3 
Monitoring Procedures...........................................................................................71 
11.4 
Recording of Data ..................................................................................................72 
11.5 
Identification of Source Data .................................................................................72 
11.6 
Retention of Records..............................................................................................73 
11.7 
Auditing Procedures and Inspection ......................................................................73 
11.8 
Handling of Study Drug .........................................................................................74 
11.9 
Publication of Results ............................................................................................74 
11.10 Disclosure and Confidentiality ..............................................................................74 
11.11 Discontinuation of Study .......................................................................................75 
11.12 Subject Insurance and Indemnity ...........................................................................75 
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LIST OF IN-TEXT TABLES 
Table 1 
Dose-Limiting Toxicities (DLT)................................................................35 
Table 2 
Tazemetostat Dose Reduction and Interruption Instructions .....................40 
Table 3 
Blood Sampling Schedule for Pharmacokinetic Assessment ....................47 
Table 4 
Urine Sampling Schedule for Pharmacokinetic Assessment .....................47 
Table 5 
Clinical Laboratory Tests ...........................................................................53 
Table 6 
Schedule of Procedures/Assessments in Study E7438-J081-106 (EZH-
106) ............................................................................................................56 
 
LIST OF IN-TEXT FIGURES 
Figure 1 
Study Design ..............................................................................................33 
 
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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 
AUC 
area under the plasma concentration-time curve 
β-hCG 
beta-human chorionic gonadotropin 
BID 
twice daily 
BOR 
best overall response 
BUN 
blood urea nitrogen 
C#/D# 
Cycle#/Day# 
Cmax 
maximum observed concentration 
 
CR 
complete response 
CRA 
clinical research associate 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DLBCL 
diffuse large B-cell lymphoma 
DLT 
dose limiting toxicity 
ECOG 
Eastern Cooperative Oncology Group 
EZH2 
enhancer of zeste homolog 2 
FL 
follicular lymphoma 
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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Abbreviation 
Term 
HL 
Hodgkin lymphoma 
HMT 
histone methyltransferase 
ICF 
informed consent form 
INN 
International Nonproprietary Name 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
LC-MS/MS 
liquid chromatography with tandem mass spectrometry 
LDH 
lactate dehydrogenase 
LLT 
lower level term 
LVEF 
left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
MUGA 
multigated acquisition 
NCCN 
National Comprehensive Cancer Network 
NHL 
Non-Hodgkin’s lymphoma 
NYHA 
New York Heart Association 
ORR 
objective response rate 
PD 
progressive disease 
P-gp 
P-glycoprotein 
PK 
pharmacokinetics 
PR 
partial response 
PS 
performance status 
PT 
preferred term 
R 
Rituximab 
tmax 
time at which the highest drug concentration occurs 
QOL 
quality of life 
QTc 
QT interval corrected for heart rate 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
RP2D 
recommended Phase 2 dose 
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Abbreviation 
Term 
SD 
Sprague Dawley 
SOC 
system organ class 
SOP 
standard operating procedure 
TEAE 
treatment-emergent adverse event 
TEMAV 
treatment-emergent markedly abnormal laboratory values 
ULN 
upper limit of normal 
UV 
Ultraviolet 
 
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5 
ETHICS 
5.1 
Institutional Review Boards 
The protocol, informed consent form (ICF), and appropriate related documents must be 
reviewed and approved by an Institutional Review Board (IRB) constituted and functioning 
in accordance with Good Clinical Practice (GCP).  Any protocol amendment or revision to 
the ICF will be resubmitted to the IRB for review and approval, except for changes involving 
only administrative aspects of the study (eg, change in 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 and the 
relevant IRB via the head of the medical institution of any reportable adverse events (AEs) 
per GCP guidelines and local IRB standards of practice.  Upon completion of the study, the 
investigator will provide the IRB and sponsor via the head of the medical institution with a 
brief report of the outcome of the study. 
5.2 
Ethical Conduct of the Study 
This study will be conducted in accordance with standard operating procedures (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 
• 
Article 14, Paragraph 3, and Article 80-2 of the Pharmaceuticals, Medical devices and 
Other Therapeutic Products Act (Law No. 145, 1960) 
5.3 
Subject Information and Informed Consent 
As part of administering the informed consent document, the investigator must explain to 
each subject the nature of the study, its purpose, the procedures involved, the expected 
duration, the potential risks and benefits involved, any potential discomfort, potential 
alternative procedure(s) or course(s) of treatment available to the subject, and the extent of 
maintaining confidentiality of the subject’s records.  Each subject must be informed that 
participation in the study is voluntary, that he/she may withdraw from the study at any time, 
and that withdrawal of consent will not affect his/her subsequent medical treatment or 
relationship with the treating physician. 
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This informed consent should be given by means of a standard written statement, written in 
nontechnical language.  The subject should understand the statement before signing and 
dating it and will be given a copy of the signed document.  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 by the investigator in 
accordance with GCP and all applicable local regulations with the cooperation of the 
sponsor.  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 ICF for genomic test will be prepared separately from the study ICF.  Genetic testing 
will be performed only on subjects who provided their consent to the planned genetic 
analysis.  Subjects can participate in this study even if they do not provide tumor samples or 
do not agree to undergo genetic test using their tumor samples (see Section 9.5.1.4.2). 
6 
INVESTIGATORS AND STUDY PERSONNEL 
This study will be conducted by qualified investigators under the sponsor at approximately 2 
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 
Diffuse Large B-cell Lymphoma and Follicular Lymphoma and 
Current Therapeutic Options 
7.1.1 
Malignant Lymphoma 
The nationwide survey by the Ministry of Labor, Health, and Welfare (2014) has reported 
that 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, diffuse large 
B-cell lymphoma (DLBCL) and follicular lymphoma (FL), are subtypes of B-cell NHL.  
7.1.2 
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.  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 7.1.1 Malignant Lymphoma and 
these reports, it is estimated that approximately 29,000 people are diagnosed with DLBCL 
and DLBCL is prevalent in approximately 12,000 patients per year.   
7.1.3 
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, which is a combination of several 
chemotherapy drugs (cyclophosphamide, doxorubicin, vincristine, and prednisone) and 
rituximab (R).  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 chemotherapies in current use are the R-
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DHAP (dexamethasone, cisplatin, and cytosine arabinoside), 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.  
7.1.4 
Follicular Lymphoma (FL) 
FL is the most common type of the indolent B-cell lymphoma, which progress in yearly term.  
FL has a structure basis that histologically mimics germinal center.  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 7.1.1 Malignant Lymphoma and these reports, it is estimated that 
approximately 8,600 people are diagnosed with FL and FL is prevalent in approximately 
3,600 patients per year.   
7.1.5 
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).  The standard therapy for advanced-stage primary FL that requires 
treatment is the R-CHOP regimen or the non-doxorubicin-containing R-CVP regimen.  
Rituximab monotherapy or chemotherapy alone approach should also be considered based on 
the patient’s 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’s 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 
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above, therapeutic options and outcomes, particularly in patients with relapsed or refractory 
FL are limited, thus a new therapeutic option is anticipated.  
7.2 
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 stem cells such as hematopoieticis 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 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 
DLBCL, FL, 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 DLBCL and FL lead to 
increased activity of trimethylation of EZH2 and produces hypertrimethylation on H3K27 
(H3K27Me3), resulting in 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 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 an 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-cell acute lymphoblastic 
leukemia, medulloblastoma, mesothelioma, and others) (Plass 2013, LaFave 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 in 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 
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others (Kadoch and Crabtree, 2013, Kadoch, et al., 2016).  INI1 or SMARCA4 deficiency 
promotes 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 an 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. 
7.3 
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 the 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 
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 Nov 2012.  Phase 1 data were reviewed by an 
Independent Data Monitoring Committee on 12 Nov 2014.  The committee agreed that the 
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recommended Phase 2 dose be 800 mg BID based on evaluation of safety, pharmacokinetics 
(PK), biomarker, antitumor activity. 
Tazemetostat is currently under investigation for the treatment of DLBCL, FL, and INI1- or 
SMARCA4-negative tumors outside Japan. 
7.3.1 
Physical, Chemical, and Pharmaceutical Properties and Formulations 
Tazemetostat (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) is an organonitrogen compound with molecular weight of 
653.65.  Drug product of tazemetostat is a red, film-coated tablet with a diameter of 
10.1 mm.  Tazemetostat tablets contain 200 mg of drug substance as the free base.  
Tazemetostat film-coated tablets should be stored at room temperature.   
7.3.2 
Nonclinical Studies 
7.3.2.1 
Pharmacology 
7.3.2.1.1 PRIMARY PHARMACODYNAMICS 
Cell-free biochemical assays showed that E7438 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.  E7438 specifically inhibited histone H3K27 methylation across different cell 
lines.  This result indicates E7438 also specifically inhibit EZH2 in cell lines.  Incubation 
with E7438 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.  
E7438-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.  E7438 incubation in INI1-negative MRT cell lines 
induced changes in gene expression together with the expression of the neuronal 
differentiation markers.  E7438-induced cell death occurring through G1 cell cycle arrest and 
genetic alterations occurred Day 3 of culture or later, consistent with elimination of 
intracellular H3K27Me3 requiring 3 days. 
An oral administration of E7438 to human xenograft models in mice including DLBCL cell 
lines with EZH2 mutations (WSU-DLCL2, KARPAS-422, and Pfeiffer) induces significant 
antitumor effects, ranging from tumor growth inhibition to complete and durable tumor 
regressions.  E7438 exposure led to dose- and time-dependent decreases in intracellular 
H3K27Me3 in both tumor and selected non-tumor tissues.  An oral administration of E7438 
demonstrated significant antitumor activity against 4 of 6 xenograft models of INI-deficient 
tumors (INI1-negative G401 MRT cell line, INI1 levels reduced Fuji synovial sarcoma cell 
line, patient-derived CTG-0331 and CTG-0771). 
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7.3.2.1.2 SECONDARY PHARMACODYNAMICS 
E7438 dose-dependently inhibited H3K27Me3 in skin in mice and peripheral blood 
mononuclear cells, bone marrow, spleen, and skin in rats and cynomolgus monkeys.  Bone 
marrow showed the highest degree of H3K27Me3 inhibition.  While H3K27Me3 changes in 
skin in rats are observed after 7 days of dosing, longer dosing periods (22–28 days) are 
necessary to detect H3K27Me3 significant reduction. 
E7438 did not significantly inhibit a panel of G-protein-coupled receptors, transporters, and 
ion channels, and had no effect on the activity of 40 kinases. 
7.3.2.2 
Safety Pharmacology 
The effects of E7438 on the cardiovascular system were examined in in vitro 
electrophysiology study assessing effects on the human ether-à-go-go related gene (hERG) in 
human embryonic kidney cells (HEK293), ex vivo rabbit ventricular wedge evaluations, and 
an oral-dose safety study in conscious, telemetered cynomolgus monkeys.  The effects on the 
central nervous system and respiratory systems were evaluated in neurological examinations 
and respiratory function tests performed in the repeated-dose oral toxicity study in 
cynomolgus monkey. 
E7438 inhibited hERG potassium current by 15.1% at 10 μmol/L in cell lines expressing 
hERG channels.  While E7438 had no effects on QRS duration at concentrations up to 
20 μmol/L, E7438 decreased QRS duration at 20 μmol/L and Tp-e interval at 7 and 
20 μmol/L, however, E7438 did not cause any pro-arrhythmic events.  Additionally, E7438 
had no effects on cardiovascular parameters in conscious, telemetered cynomolgus monkeys 
at single oral doses up to 1000 mg/kg.  Neurological examination was conducted in the 
repeated-dose oral toxicity study in cynomolgus monkeys.  Monkeys showed a decrease in 
muscle tone in both legs at 1000 mg/kg/day.  No abnormality in neuromuscular function was 
observed at lower doses (≤ 300 mg/kg). E7438 did not affect respiratory function at up to 
1000 mg/kg/day in cynomolgus monkeys.  Based on the above results, no notable 
cardiovascular, central nervous system, or respiratory risks were identified. 
7.3.2.3 
Pharmacokinetics and Drug Metabolism 
The plasma PK following E7438 administration to Sprague-Dawley (SD) rats and 
cynomolgus monkeys was characterized by high-to-moderate clearance (3.5 and 1.4 L/h/kg 
respectively), moderate-to-large volume of distribution (1.8 and 2.0 L/kg respectively), and a 
short half-life (t1/2) (0.4 and 1.6 hours, respectively).   The absolute bioavailability of 
tazemetostat was < 4% at a dose of 5 mg/kg in rats and monkeys, and approximately 40% at 
a dose of 10 mg/kg in mice.   
[14C] E7438-derived radioactivity was rapidly absorbed and widely distributed in SD rats 
following a single oral administration of [14C] E7438 (50 mg/kg).  Elimination of the 
radioactivity was completed in the majority of tissues up to 168 hours postdose.  The primary 
route of elimination of radioactivity after a single oral dose of [14C] E7438 in rats was in the 
feces (86% of the dose), with low renal excretion (8% of the dose).  The primary route of 
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elimination of radioactivity in bile duct cannulated rats was in the bile (54% of the dose).  
[14C] E7438-derived radioactivity was widely distributed in Long-Evans (LE) rats similar to 
SD rats following a single oral administration of [14C]E7438 (50 mg/kg).  Radioactivity 
concentrations observed in melanin-containing tissues in LE rats were notably higher than 
those in SD rats, which indicated that there was a specific association of [14C] E7438-derived 
radioactivity with melanin.  Association with melanin was considered to be reversible. 
Protein binding of tazemetostat at a concentration of 1000 ng/mL was 96.4%, 88.3%, 85.6%, 
81.8%, and 83.4% in mouse, rat, dog, monkey, and human plasma, respectively.  There was 
minimal difference among species (mouse, rat, monkey, and human) or concentrations (50–
50000 ng/mL) in the blood/plasma concentration ratios (RB) (ratios between 0.53 and 1.06). 
In vitro, cytochrome P450 (CYP) 3A was the predominant enzyme responsible for the 
hepatic metabolism of E7438.  ER-897387-00, the N-desethylated metabolite (EPZ-6930; 
M5), was the major metabolite formed in vitro and there was no metabolite observed unique 
to humans. 
E7438 directly inhibited CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A activities in 
vitro with IC50 values of 4 to 19 µmol/L. E7438 showed time-dependent inhibition of 
CYP3A.  E7438 induced CYP3A4 messenger ribonucleic acid (mRNA) in vitro, with a 
potency similar to the positive control, 10 µmol/L of rifampicin. 
Results from in vitro studies demonstrated that E7438 was a substrate for P-glycoprotein (P-
gp), but not a substrate for breast cancer resistance protein (BCRP). E7438 inhibited P-gp 
and BCRP with IC50 values of 5.9 and 34.1 µmol/L, respectively.  E7438 was not a substrate 
for organic anion transporting polypeptiden (OATP), 1B1, OATP1B3, organic anion 
transporter (OAT) 1, OAT3, organic cation transporter (OCT) 2.  E7438 inhibited OATPB1, 
OATP1B3, OCT2, and OAT3 with IC50 values of 19.7, 14.4, 14.7, and 10.0 µmol/L, 
respectively.  E7438 hardly inhibited OAT1 with IC50 values of >100 µmol/L.  E7438 
inhibited bile salt export pump (BSEP) with IC50 values of 20.0 µmol/L (for reference 
purpose only).   
7.3.2.4 
Toxicology 
Single oral administration of E7438 up to 1000 mg/kg was tolerated in SD rats and 
cynomolgus monkeys. 
In a 4-week repeated-dose toxicity study in rats, a number of animals were found dead 
possibly due to the gastrointestinal tract toxicity at a dose of 1000 mg/kg/day between Day 7 
and Day 21.  Pathological changes were found in these animals in the gastrointestinal tract 
(glandular stomach mucosa erosion/ulceration and glandular stomach and gastrointestinal 
epithelia degeneration/necrosis) and other organs such as kidney (eosinophilic droplets and 
necrosis in epithelial cells), bone marrow (slight-to-moderate hypocellularity), lymphoid 
tissues (lymphoid depletion), and new trabecular bone formation in the medullary cavity of 
the sternum and femur.  In some rats at 1000 mg/kg/day, there were secondary clinical 
laboratory changes or changes possibly due to general deterioration.  Reversibility or 
recovery trend of all adverse findings observed at 1000 mg/kg/day was demonstrated after a 
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2-week off-dose period subsequent to cessation of dosing in surviving animals at 
1000 mg/kg/day on Day 21 or later.  While a drop of urinary sediment was observed at doses 
of 100 and 300 mg/kg, no pathological changes were found in the urinary system.  In the 13-
week repeated-dose toxicity study, there was an occurrence of lymphoblastic lymphoma 
originated from the thymus in the 300 mg/kg group or higher doses.  Lymphoma was the 
cause of death or moribundity after Day 65.  A total of 3/20 males and 8/20 females at 300 
mg/kg, and 1/20 male and 0/20 female at 600 mg/kg developed lymphoblastic lymphoma in 
the study.  Metastases to various tissues and organs included.  At 600 mg/kg, findings other 
than lymphoma were lymphoid depletion, shortening of the lower incisor, trabecular 
formation in the femur and sternum, erosion/ulcer and regenerative changes in the upper 
gastrointestinal tract, and granular materials in the renal pelvis.  Changes at 300 mg/kg/day 
were similar to but less severe than those observed at 600 mg/kg/day.  At 100 mg/kg/day, 
there were no significant changes except for labial abscess observed at 300 mg/kg/day or 
higher doses in one male rat.  For the recovery evaluation, primary non-neoplastic changes 
were generally reversible with the exception of splenic lymphoid depletion and changes in 
the bone and incisors after the 4-week recovery period.   
In a 4-week repeated-dose toxicity study in cynomolgus monkeys, the 1000-mg/kg dose was 
discontinued on Day 8 or Day 9 of dosing due to adverse clinical observations, which 
resulted in the euthanasia of 3 moribund animals.  On Day 11 or Day 12, dosing was re-
initiated at a lower dose of 600 mg/kg/day for surviving animals.  During the dosing period, 
1000 mg/kg/day caused infrequent and intermittent emesis on Day 6 after the morning dose 
only.  There were no test article-related effects on heart rate or electrocardiograms (ECGs) 
observed in this study.  In moribund animals at 1000 mg/kg/day, there were adverse clinical 
signs and associated decreased muscle tone on Day 7, clinical pathology abnormalities, and 
changes in the gastrointestinal tract and liver, however, the cause of morbidity in these 
animals was not clearly identified.  In both the moribund animals at 1000 mg/kg and the 
remaining high-dose animals that had their dose reduced to 600 mg/kg, there were test 
article-related changes in the liver  and kidney as well as an increase in alanine 
aminotransferase (ALT) and triglycerides.  At 300 mg/kg and above, lymphoid depletion, 
that was dose-dependent in incidence and severity was observed.  Reversibility or a trend 
towards reversibility for toxicity was demonstrated in one 1000-mg/kg/day animal after a 21-
day recovery period.  In the 13-week cynomolgus monkey study, the principal clinical and 
necropsy findings in the 13-week monkey study were similar to those observed in a 4-week 
study, although more pronounced.  Moribundity occurred in a single female animal at 
600 mg/kg/day on Day 83 following severe clinical signs (decreased activity, cold to touch, 
hunched posture, and shivering/tremor).  While the cause of moribundity was not clearly 
explained by histopathology, E7438-related significant changes in this animal were similar to 
those observed in terminal sacrificed animals as below.  E7438-related clinical observations 
included emesis and abnormal feces. The incidence of emesis and/or fecal changes was 
sporadic in all tazemetostat-treated groups; however, the incidence of emesis was dose 
related.  At 300 mg/kg/day and above there was a mild shortening of the RR interval, which 
was not statistically significant.  Dose-dependent lymphoid depletion in the spleen, lymph 
nodes, and thymus, increases in ALT and AST, hepatocyte hypertrophy, Kupffer cell 
hypertrophy/pigmentation, and bile duct hyperplasia in the liver were observed.  At 
600 mg/kg/day there were increases in ALP and glomerulopathy and tubular pigmentation in 
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the kidney.  No toxicologically significant changes were observed at 100 mg/kg/day.  After a 
4-week recovery, there was a trend toward reversibility in most parameters; however, the 4-
week recovery period was not sufficient for complete assessment of reversibility for some 
changes.  
E7438 was not genotoxic in an in vitro bacterial reverse mutation assay, in vitro micronuclei 
assay, and in vivo rat micronuclei studies. 
In a repeated-dose, range-finding study in juvenile SD rats, E7438 was initiated at Post-Natal 
Day 7 and repeatedly administered for 4 weeks.  All male and female animals treated at 500 
and 1000 mg/kg euthanized following clinical signs of hypoactivity and a cool and/or pale 
body after first or second dosing.  Histopathological changes were limited to the stomach, 
hematopoietic and lymphoid tissues, and kidney.  The gastric toxicity was considered to be 
the cause of moribundity.  No toxicologically significant changes were found at 50 and 150 
mg/kg/day.   
The ultraviolet (UV) absorption spectrum of E7438 showed absorption maxima at 302 nm 
and 265 nm was observed.  Thus, an in vitro phototoxicity study of E7438 in 3T3 cells was 
performed.  E7438 showed phototoxic potential because Mean Photo Effect, known as 
phototoxicity index, was more than the criterion for phototoxic, 0.15 (0.270 and 0.347) when 
examined up to the solubility limit of 100 µg/mL. 
In a 13-week repeated-dose rat toxicity study with a 4-week recovery period, there was an 
occurrence of lymphoblastic lymphoma originated from the thymus.  To investigate further 
the mechanism of lymphomagenesis noted in this study, additional 13-week rat studies were 
completed using two structurally similar, but chemically distinct EZH2 inhibitors, EPZ-
10961 and EPZ011989.  They have similar specificity and mechanism of inhibition and 
inhibit cellular H3K27Me3 with 3 to 4-fold higher potency than E7438.  Non-dose dependent 
incidence of lymphoma was observed in studies for EPZ-10961 and EPZ011989 in 
approximately the same time frame that it was seen in the 13-week rat study with E7438 
(after 8-10 weeks of dosing).  Immunophenotyping of cells isolated from the thymus, bone 
marrow, and spleen samples showed higher percentages of CD8+ T-cells and αβ TCR+T-
cells and lower percentage of CD4+ T-cells and γδ TCR+ T-cells in thymus derived samples.  
In contrast, immunophenotyping of cells isolated from the thymus, bone marrow, and spleen 
samples from rats without lymphoma showed lower percentages of αβ TCR+ T-cells and 
concurrent higher percentage of γδ TCR+ T-cells.  The similar results were obtained with 
EPZ-10961.  Notch-mediated transcription was studied in thymus samples from E7438 or the 
EPZ011989 study.  The mechanism of lymphomagenesis in these rats does not appear to be 
related to E7438-mediated alterations in the Notch signaling pathway or effects on retroviral 
reintegration of the Rat Leukemia virus (RaLV).  Gene expression and whole transcriptome 
analysis from thymus tissue isolated during studies with EPZ011989 revealed elevated 
expression of Myc in rats with lymphoma, but otherwise, no similarities to genetic and 
transcriptional abnormalities related to mechanism of occurrence and immunophenotyping in 
human T-cell acute lymphoblastic leukemia were seen. 
An additional 4-week oral study in rats was performed with E7438 to assess the toxicologic 
impact of the presence of new impurities in the lot to be used in the clinical study of 
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tazemetostat in tablet form.  No notable changes attributable to new impurities were 
observed. 
7.3.3 
Clinical Studies 
As of the cutoff date of 15 Jan 2016, the following 3 studies are ongoing outside Japan. 
• 
Study E7438-G000-101, “An Open-Label, Multicenter, Phase 1/2 Study of E7438 
(EZH2 Histone Methyl Transferase [HMT] Inhibitor) as a Single Agent in Subjects with 
Advanced Solid Tumors or with B-cell Lymphomas” 
• 
Study EZH-102 “A Phase 1 Study of the EZH2 Inhibitor Tazemetostat in Pediatric 
Subjects with Relapsed or Refractory INI1-Negative Tumors or Synovial Sarcoma” 
• 
Study EZH-202 “A Phase 2, Multicenter Study of the EZH2 Inhibitor Tazemetostat in 
Adult Subjects with INI1-Negative Tumors or Relapsed/Refractory Synovial Sarcoma” 
Eighty-eight subjects had been enrolled in Study E7438-G000-101 and 1 subject in study 
EZH-202, all of whom, a total of 89 subjects, had been exposed to tazemetostat. 
Seventy-eight of 89 (87.6%) subjects experienced at least 1 AE and 51 of 89 (57.3%) 
subjects experienced AEs that were considered related to tazemetostat by the investigator.  
AEs occurring in ≥ 5% of subjects and in descending order of frequency were asthenia 
(34.8%), nausea (15.7%), thrombocytopenia (14.6%), decreased appetite (13.5%), anemia 
(12.4%), constipation (12.4%), dysgeusia (7.9%), vomiting (7.9%), diarrhea (6.7%), dry skin 
(6.7%), dyspnea (6.7%), muscle spasms (6.7%), abdominal pain (5.6%), and neutropenia 
(5.6%).  Of the subjects who experienced related AEs, the majority reported Grade 1 or 2 
events.  Seven subjects (7.9%) experienced Grade 3 or 4 AEs and 5 subjects (5.6%) 
discontinued study drug due to AEs.   
One subject experienced Grade 4 thrombocytopenia during the dose-escalation group of 
Study E7438-G000-101 at the dose level of 1600 mg BID; this event was also considered to 
be a DLT.  The protocol-defined MTD was not reached.  No other DLTs were observed.   
Twenty-two of 89 subjects experienced 31 serious adverse events (SAEs).  Of these, 4 SAEs 
occurring in 3 subjects were considered possibly related to study drug (anemia, 
thrombocytopenia, and 2 events of neutropenia).  In Study E7438-G000-101, 11 subjects 
died.  For 9 subjects, the cause of death was progressive disease, 1 was due to an AE, and 1 
was noted as being not due to progressive disease (no further information was available at the 
time of data cutoff [15 Jan 2016]).   
The clinical PK characteristics of tazemetostat are derived from Study E7438-G000-101 in 
which tazemetostat was administered at doses of 100 mg BID as a suspension or tablet 
formulation and 200, 400, 800, and 1600 mg BID as a tablet formulation.  Tazemetostat was 
rapidly absorbed with a time to the maximum plasma concentration (tmax) of approximately 1 
to 2 hours postdose and a mean t1/2 of approximately 3 to 5 hours.  After multiple dosing, 
there was a dose-dependent decrease in tazemetostat systemic exposure relative to Day1.  
However, no further reduction in systemic exposure was observed beyond Day 15. 
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Administration of tazemetostat with a high-fat meal decreased geometric mean AUC(0-inf) and 
Cmax values approximately 7% and 28%, respectively, relative to administration in the fasted 
state.   Administration of tazemetostat with a high-fat meal also resulted in a 4-fold increase 
in median tmax relative to administration in the fasted state.  All individual Cmax and AUC(0-inf) 
values observed after administration of tazemetostat following a high-fat meal were within 
the range of the respective values observed after administration in the fasted state.  The 
decrease in systemic exposure is not clinically significant, and therefore tazemetostat can be 
taken without regard to meals. 
Tazemetostat antitumor activity has been evaluated in Phase 1 part of Study E7438-G000-
101.  As of 07 Nov 2015, tazemetostat has demonstrated antitumor activity in subjects with 
B-cell lymphomas and INI1- and SMRCA4-negative cancers.  Objective responses (2 CRs 
and 7 PRs) have been observed in 9 of 16 response evaluable subjects (DLBCL [5 of 12]; FL 
[3 of 4]; and marginal zone lymphoma [1 of 1]).  Objective responses (1 CR and 3 PRs) were 
also observed in 4 of 11 response evaluable subjects with INI1- and SMARCA4-negative 
cancers (MRT) [2 of 5]; epithelioid sarcoma (ES) [1 of 3]; malignant rhabdoid tumor of the 
ovary (MRTO) [1 of 2]). 
Phase 1 data were reviewed by an Independent Data Monitoring Committee on 12 Nov 2014.  
The committee agreed that the recommended Phase 2 dose be 800 mg BID based on 
evaluation of safety, PK, biomarker, and antitumor activity. 
7.4 
Study Rationale 
This study is the Japan Phase 1 study to investigate the tolerability, safety, PK, and 
preliminary antitumor activity of tazemetostat in patients with relapsed or refractory B-cell 
NHL.  The tolerability and safety of tazemetostat in Japanese patients has not yet been 
investigated; therefore, this study was planned. 
Tazemetostat 800 mg will be administered orally by single dose in Cycle 0 and by 
continuous 800 mg BID in Cycle 1 and later in 28-day cycles.  Tazemetostat treatment will 
continue until disease progression, development of unacceptable toxicity, subject requests to 
discontinue, withdrawal of consent, or study termination by the sponsor. 
In the Phase 1 part of the Study E7438-G000-101, a Phase 1/2 study currently ongoing 
outside Japan, the recommended dose of tazemetostat has been determined to be 800 mg 
BID.  The Phase 2 part of the study is ongoing at this dose level.  Safety and tolerability of 
tazemetostat for subjects enrolled in Study E7438-G000-101 was assessed as of 15 Jan 2016.  
Tazemetostat was administered twice daily in 6 subjects for100 mg, 3 subjects for 200 mg, 
16 subjects for 400 mg, 46 subjects for 800 mg (including 1 subject from Study EZH-202), 
and 18 subjects for 1600 mg.  One subject experienced treatment-related Grade 4 
thrombocytopenia at the dose level of 1600 mg BID; this event was also considered to be a 
DLT.  The protocol-defined MTD was not reached.  Treatment-related Grade 3 or 4 AEs 
observed at 800 mg BID were thrombocytopenia (2 subjects, 4.3%) and Grade 3 
hepatocellular injury and Grade 3 hypertension (1 subject each, 2.2%) while no treatment-
related Grade 3 or 4 AEs occurred at the dose level of 400 mg BID or lower doses.  Based on 
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the current clinical data, the starting dose of 800 mg, half of the maximum single dose of 
1600 mg established outside Japan, was considered as suitable for this study whereas clinical 
data in Japanese subjects are not available. 
Tazemetostat has demonstrated antitumor activity in subjects with B-cell lymphomas in 
Study E7438-G000-101.  As of 07 Nov 2015, objective responses (2 CRs and 7 PRs) have 
been observed in 9 of 16 response evaluable subjects.  Therefore, the target population of this 
study is considered to be relapsed or refractory B-cell NHL, in which preliminary efficacy is 
expected. 
With these reasons, the Phase 1 study was designed to investigate the tolerability, safety, PK, 
and preliminary anti-tumor activity of tazemetostat in Japanese patients with relapsed or 
refractory B-cell NHL, and the current study is rationalized. 
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8 
STUDY OBJECTIVES 
8.1 
Primary Objective 
To assess the tolerability of tazemetostat in patients with B-cell non-Hodgkin’s lymphoma 
(NHL). 
8.2 
Secondary Objectives 
(1)To assess the safety of tazemetostat. 
(2)To assess the PK profile of tazemetostat. 
(3)To assess the preliminary anti-tumor activity of tazemetostat. 
 
8.3 
Exploratory Objectives 
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9 
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan 
This is a multicenter, single-arm, phase 1 study to assess the tolerability, safety, PK and 
preliminary anti-tumor activity of tazemetostat in patients with relapsed or refractory B-cell 
NHL. 
9.1.1 
Study Design 
The study design of this study is presented in Figure 1.  This study will be conducted in the 
following 4 phases: Pre-treatment Phase, Treatment Phase, Extension Phase, and Follow-up 
Phase. 
 
 
 
 
 
 
 
 
 
 
Figure 1 
Study Design 
BID = twice daily, DLT = dose limiting toxicity. 
 
9.1.1.1 
Pre-treatment Phase 
The Pre-treatment Phase will last no longer than 28 days and include a period to obtain 
informed consent, screening, enrollment, and a baseline assessment.  Informed consent will 
be obtained after the study has been fully explained to each subject and before the conduct of 
any screening procedures or assessments.  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 
Pre-treatment Phase 
Treatment Phase 
Extension Phase 
Screening 
Baseline 
Cycle 0 
Cycle 2 and later 
Follow-up Phase 
Cycle 1 
DLT evaluation 
Within 28 days 
Informed consent 
Treatment initiated 
Registration 
Discontinuation 
Last dose 
Final observation 
Within  
3 days 
28-day cycles 
30 days (+7 days)  
after last dose  
4 days  
(+5 days) 
Tazemetostat 800 mg BID continuously 
800 mg 
Single dose 
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that the patient continues to meet the inclusion criteria and does not meet the exclusion 
criteria before moving to the Treatment Phase. 
The CRF must be completed to indicate whether the subject is eligible to participate in the 
study and to provide reasons for screen failure, if applicable. 
9.1.1.2 
Treatment Phase 
The Treatment Phase consists of Cycle 0 (4 days) for tazemetostat single-dose oral 
administration and Cycle 1 of 28 days for tazemetostat twice daily (BID) oral administration 
on a continuous basis.  The subject who discontinues study drug during the Treatment Phase 
will have a discontinuation visit of the Follow-up Phase.  The subject who completes the 
Treatment Phase will enter the Extension Phase. 
Considering visit schedule and safety, subjects will be hospitalized from Cycle 0/Day 1 
(C0D1) to Cycle 1/Day 15 (C1D15).  Based on the thorough evaluation of the data obtained 
on C1D15 and all safety data available, the investigator or subinvestigator will determine 
whether subjects can be treated on an outpatient basis.  When subjects are considered to 
require extended hospitalization to ensure subject safety, they will be hospitalized from 
C1D15 onwards. 
9.1.1.3 
Extension Phase 
The Extension Phase consists of Cycle 2 of 28 days and later for tazemetostat BID oral 
administration on a continuous basis and lasts until discontinuation of study drug.  Informed 
consent should be obtained before initiating the study or before entering the Extension Phase 
when Cycle 2 or later administrations will be continued.  Subjects will discontinue study 
drug at the time of disease progression, 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 Extension Phase will have a discontinuation 
visit of the Follow-up Phase. 
9.1.1.4 
Follow-Up Phase 
The 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. 
9.1.2 
Dose-Limiting Toxicities (DLT) 
The starting dose of tazemetostat is 800 mg as a single dose (Cycle 0) and 800 mg BID as 
continuous dosing (Cycle 1 and later).  Three subjects will be enrolled and ensure that they 
are evaluable for dose-limiting toxicities (DLTs) at the end of Cycle 1 of the cohort.  When a 
DLT is observed in 0 or 1 of 3 subjects at a given dose level, 3 additional subjects would be 
treated at the same dose level.   When 2 of 3 subjects at a given dose level experience DLTs, 
enrollment of additional subjects will be discussed jointly by the investigator and sponsor.  
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The opinion of Independent Data Monitoring Advisor should be also obtained.  When 
additional subjects are to be enrolled, they will be monitored individually.  When no DLTs 
are observed, up to 3 additional subjects will be enrolled.  When no additional subjects are 
accrued or 3 subjects in total experienced DLTs, the enrollment in the cohort will be 
discontinued and the lower dose level of tazemetostat cohort will be considered jointly by the 
investigator and sponsor.  The opinion of Independent Data Monitoring Advisor can be 
obtained if needed. 
If the subject is regarded as DLT non-evaluable (eg, early discontinuation due to non-DLT, 
medication compliance with <75% in Cycle 1 as a result of the reason other than treatment 
related toxicity), another subject will be added for replacement.  
A DLT is defined as toxicity related to study drug in Table 1 below.  The tolerability of 
tazemetostat will be determined based on the incidence of DLTs in Cycles 0 and 1.  If DLTs 
occur in 0 or 1 of 6 subjects, this dose level is considered tolerable.  If DLTs occurs in 2 of 6 
subjects, the tolerability of this dose level will be determined jointly by the investigator and 
sponsor.  The opinion of Independent Data Monitoring Advisor should be also obtained.  In 
the case of difficulty of determination of whether a subject should be counted as having 
experienced a DLT and/or not for tolerability assessment, the final determination will be 
made jointly by the investigator and sponsor.  The opinion of Independent Data Monitoring 
Advisor can be obtained if needed. 
Table 1 
Dose-Limiting Toxicities (DLT) 
Toxicity Category 
Toxicity/CTCAE Grade 
Hematological Toxicity 
• Grade 4 neutropenia for > 7 days or neutropenia requiring 
hematopoietic growth factors 
• ≥ Grade 3 febrile neutropenia 
• Grade 4 thrombocytopenia, Grade 3 thrombocytopenia with 
bleeding, or thrombocytopenia requiring platelet transfusion 
• Grade 4 anemia or anemia requiring erythrocyte transfusion  
Non-hematological 
Toxicity 
• ≥ Grade 3 nausea, vomiting, or diarrhea that persists > 7 days 
despite maximal medical therapy 
• ≥ Grade 3 non-hematological laboratory abnormalities with 
clinical symptoms that persists > 7 days 
• Other Grade 3 toxicity lasting > 7 days or Grade 4 non-
hematological toxicity of any duration 
Medication compliance 
• Failure to administer ≥ 75% (≥ 42/56 doses) of the planned 
administration number of study drug in Cycle 1 as a result of 
treatment-related toxicity 
 
9.2 
Discussion of Study Design, Including Choice of Control Groups 
This study was designed according to “The Guidelines for Clinical Evaluation of Anti-
Cancer Drugs in Japan (Notification No. 1101001 issued on 01 Nov, 2005).” 
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9.3 
Selection of Study Population 
Approximately 6 subjects will be enrolled at approximately 2 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. 
9.3.1 
Inclusion Criteria 
Subjects must meet all of the following criteria to be included in this study: 
(1)Patients with histological diagnosis of B-cell NHL (except transformed 
lymphoma) as follows:  
· Diffuse large B-cell lymphoma (DLBCL) 
· Follicular lymphoma (FL) 
(2)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. 
(3)Patient who had previous therapy with systemic chemotherapy and/or antibody 
therapy and for which no standard therapy exists. 
(4)Patient who was 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. 
(5)Patient with Eastern Cooperative Oncology Group (ECOG) performance status 
of 0 to 1 
(6)Patient with life expectancy of ≥3 months from starting study drug 
administration. 
(7)Patient with adequate renal function: 
· Serum creatinine ≤1.5× upper limit of normal (ULN) 
(8)Patient with adequate liver function: 
· Total bilirubin ≤1.5×ULN 
· Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3.0×ULN 
(9)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 
(10)Patient with left ventricular ejection fraction (LVEF) >50% on echocardiography 
or multiple gate acquisition (MUGA) scan. 
(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 medical need for the continued use of potent or moderate inhibitors of 
CYP3A or P-gp, or potent or moderate 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 achlorhydria or use of H2 blockers or proton-pump inhibitors within 2 
weeks before study drug administration. 
(8)Patient with inability to take oral medication, or malabsorption syndrome or any other 
uncontrolled gastrointestinal condition (eg, nausea, diarrhea, or vomiting) that might 
impair the bioavailability of study drug. 
(9)Patient with significant cardiovascular impairment 
· History of congestive heart failure ≥ New York Heart Association (NYHA) Class III 
· Uncontrolled arterial hypertension, unstable angina, myocardial infarction, or stroke 
within 6 months of the first dose of study drug 
· Ischaemic heart disease, cardiac arrhythmia requiring medical treatment 
(10)Patient with prolongation of corrected QT interval using Fridericia’s formula (QTcF) to 
> 480 msec. 
(11)Patient with venous thrombosis or pulmonary embolism within the last 3 months before 
starting study drug. 
(12)Patient with complications of hepatic cirrhosis, interstitial pneumonia or pulmonary 
fibrosis. 
(13)Patient with active infection requiring systemic therapy.  
(14)Patient with known hypersensitivity to any component of study drug.  
(15)Patient who is positive for HIV antibody, HCV antibody, or HBs antigen.  Patient who is 
positive for HBs or HBc antibody and showing DNA more than sensitivity in HBV-DNA 
assay. 
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(16)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). 
(17)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 below) 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.   
(18)Woman with pregnant or breastfeeding (not eligible even if she discontinues 
breastfeeding).  
(19)Patient who was decided as inappropriate to participate in the study by the investigator 
or subinvestigator. 
Note:  Condom*, contraceptive sponge**, foam**, jelly**, diaphragm*, intrauterine device (IUD) *, or 
use of oral contraception* 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.  The CRF will be 
completed indicating the primary reason for discontinuation.  In addition, the date of last 
dose of study drug will be documented on the CRF. 
9.3.3.1 
Discontinuation Criteria by Subject 
If a subject meet 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 the subject 
(2) Major violation of inclusion or exclusion criteria are found.   
(3) Presence of adverse event that is judged by the investigator or subinvestigator to prohibit 
continuation with therapy 
(4) Pregnancy 
(5) Evidence of disease progression.  Subjects will be allowed to be treated with study drug 
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if the investigator judges that the 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 will be administered orally by single dose in Cycle 0/Day 1 (C0D1) 
and continuous BID (1600 mg total daily dose, no less than 8 hours between doses except 
C1D15 that requires 12 hours or more) in Cycle 1 and later, in a fasted state on C0D1 and at 
the first administration of C1D15 defined as either ≥2 hours before and ≥2 hours after a meal 
(only water is allowed).  
9.4.1.1 
Tazemetostat Dose Reduction and Interruption Instructions 
9.4.1.1.1 CYCLES 0 AND 1 
If DLT occurs: 
Tazemetostat administration should be interrupted immediately.  Treatment may be resumed 
in Cycle 2 at 600 mg BID (1200 mg total daily dose) if toxicity is resolved to Grade ≤ 1 or 
baseline and the investigator or subinvestigator decides to continue the study. 
No DLT: 
Tazemetostat administration will be interrupted if judged to be clinically needed by 
investigator or subinvestigator, and may be resumed at the same dose level at appropriate 
timing.   
9.4.1.1.2 
CYCLE 2 AND LATER 
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 
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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, also 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 as had been administered 
before the interruption. 
 
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 sponsor 
or discontinue tazemetostat 
ANC = absolute neutrophil count. 
a: Tolerability of Grade 2 toxicities will be judged by the study investigators. 
b: Dose interruption and reduction is 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. 
c: Laboratory abnormalities judged to be non-life threatening, will be 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 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, 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:  C34H44N4O4Br 
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N
Me
O
HN
O
Me
N
O
HN
Me
O
Me
HBr
• 
Molecular weight:  653.65 
• 
Structural formula:   
 
 
 
 
9.4.2.2 
Comparator Drug 
Not applicable. 
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. 
(1)The investigator, subinvestigator, or clinical research coordinator will issue the Subject 
ID Number to individual subjects who provide signed informed consent for study entry 
and record it in “Subject Screening Log.” 
(2)The investigator, subinvestigator, or clinical research coordinator will screen the subjects 
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and determine subject eligibility based on the inclusion and exclusion criteria.  The 
investigator, subinvestigator, or clinical research coordinator will record the decision on 
the subject eligibility in the “Subject Screening Log.”  
(3)The investigator, subinvestigator, or clinical research coordinator will notify the sponsor 
of date of informed consent, date of screening initiation, and eligibility decision by email 
or fax immediately after the investigator or subinvestigator determines the subject 
eligibility. 
(4)After the sponsor confirms the subject eligibility, the investigator or subinvestigator will 
be informed of the date of registration and dose to be administered by email or fax 
(subject registration).   
(5)The investigator or subinvestigator will confirm the subject registration and then confirm 
the subject eligibility based on the results of screening 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, a Phase 1/2 study currently ongoing 
outside Japan, the recommended dose of tazemetostat has been determined to be 800 mg 
BID.  The Phase 2 part of the study is ongoing at this dose level.  Safety and tolerability of 
tazemetostat for subjects enrolled in Study E7438-G000-101 was assessed as of 15 Jan 2016.  
Tazemetostat was administered twice daily in 6 subjects for 100 mg, 3 subjects for 200 mg, 
16 subjects for 400 mg, 46 subjects for 800 mg (including 1 subject from Study EZH-202), 
and 18 subjects for 1600 mg.  One subject experienced Grade 4 thrombocytopenia at the dose 
level of 1600 mg BID; this event was also considered to be a DLT.  The protocol-defined 
MTD was not reached.  Treatment-related Grade 3 or 4 AEs observed at 800 mg BID were 
thrombocytopenia (2 subjects, 4.3%) and Grade 3 hepatocellular injury and Grade 3 
hypertension (1 subject each, 2.2%) while no treatment-related Grade 3 or 4 AEs occurred at 
the dose level of 400 mg BID or lower doses.  Based on the current clinical data, the starting 
dose of 800 mg, half of the maximum single dose of 1600 mg established outside Japan, was 
considered as suitable for this study whereas clinical data in Japanese subjects are not 
available. 
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 until the final observation) 
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will be recorded on the CRF.  For all drugs, the name, treatment start dates (or timing of 
starting treatment), treatment end dates, and reason for use will be recorded on the CRF.  
Concomitant drugs such as premedication, 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 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: 
(1)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.  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 (see the Attachment separately 
provided to each site) 
· Other investigational agents 
 
(2)Cycles 0 and 1 
· To start or change the drugs for prophylactic use to prevent AE occurrence (continuous 
or treatment use is allowed).  
· Any agent that moderately inhibits or induces CYP3A or inhibits P- gp 
· H2 blockers, proton-pump inhibitors 
· Any antacids or other drugs known to raise gastric pH (C0D1 and C1D15 only).  These 
drugs should be administered ≥2 hours before study drug administration and ≥2 hours 
after study drug administration if used in Cycle 1. 
 
When anti-tumor therapies are implemented, study drug administration should be 
discontinued and protocol-specified off-treatment visits and procedures will be completed.  
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. 
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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, 
which has not been observed in clinical studies.  Skin-related AEs include dry skin, pruritus, 
rash, and eczema.  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.  
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 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, and second administration on C1D15] as shown in Table 6) and meal time 
before and after the first administration on C0D1 and C1D15 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 or (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 dispensing/return reconciliation 
log and documentation of returns to the sponsor by the assigned pharmacist (or designee), all 
unused study drugs and empty bottles are to be returned to the sponsor.  Unused study drugs 
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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. 
9.5 
Study Assessments 
9.5.1 
Assessments 
9.5.1.1 
Demography 
Subject demography information will be collected at Screening.  Demography information 
includes Subject ID Number, date of written informed consent, date of birth (or age), sex, 
race, and ethnicity. 
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.  
All medical history that is considered to have effects on safety, efficacy, or PK by the 
investigator or subinvestigator, and medical conditions that are identified at Screening must 
be noted on the CRF.   
The following information on primary disease and its prior therapies will be collected at 
Screening and noted on the CRF. 
(1)Primary disease 
- 
Date of diagnosis 
- 
Diagnosis 
- 
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) 
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9.5.1.3 
Efficacy Assessments 
Tumor assessment will be performed by investigator or subinvestigator using “The Lugano 
Classification (CT-Based Response)” (Cheson, et al., 2014).  Overall response and best 
overall response (BOR) (best response recorded at the designated visits during the study) will 
be assessed.  Perform CT scans at Screening, every 8 weeks (starting at Cycle 1/Day 1) 
during Cycles 2-6, every 12 weeks starting at Cycle 7 (Cycle 7/Day 1) and beyond, and 
discontinuation.  
A bone marrow aspiration or biopsy will be performed at screening for evaluation of bone 
marrow infiltration of tumor.  After the study drug administration, perform bone marrow 
aspiration or biopsy if the result of screening was positive or unconfirmed and when to 
confirm CR as best of response or if clinically indicated. 
Preliminary anti-tumor activity will be objective response rate (ORR) as defined by “The 
Lugano Classification (CT-Based Response)” (Cheson, et al., 2014).  ORR is defined as the 
proportion of subjects who have a BOR of CR or PR. 
Details of procedure of efficacy assessments will be provided in the Attachment “Overall 
response evaluation criteria” separately provided to each site. 
9.5.1.4 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Assessments 
The sampling schedule of PK, pharmacogenomics, and other biomarker assessments of 
tazemetostat is shown in Table 6 and below. 
9.5.1.4.1 PHARMACOKINETIC ASSESSMENTS 
Plasma and urine concentrations of tazemetostat and plasma concentrations of its metabolite, 
ER–897387 will be measured to evaluate pharmacokinetics in all of the registered subjects.  
Blood samples and urine samples will be collected at the time points designated in Table 6.  
Detailed blood and urine sampling schedules for PK assessment are shown in Table 3 and 
Table 4, respectively.  Procedures for collection, handling, and shipping for PK samples will 
be provided in a separate manual.   
Plasma concentrations of tazemetostat and ER-897387 and urine tazemetostat concentrations 
will be measured by validated methods using liquid chromatography with tandem mass 
spectrometry (LC-MS/MS).   
For PK assessment, actual time and date of PK blood samplings, starting time of urine 
collection (defined as the time of first administration of study drug), ending time of urine 
collection, urine volume, and tween80 volume will be recorded in the CRF. 
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Table 3 
Blood Sampling Schedule for Pharmacokinetic Assessment 
Tazemetostat and ER-897387 
Day 
Sampling Time 
Allowance (as a Target) 
C0D1 
Predose 
Within 180 minutes before dosing 
 
0.5 hours postdose 
±10 minutes 
 
1 hour postdose 
±10 minutes 
 
2 hours postdose 
±10 minutes 
 
4 hours postdose 
±10 minutes 
 
6 hours postdose 
±10 minutes 
 
8 hours postdose 
±10 minutes 
 
10 hours postdose 
±10 minutes 
 
12 hours postdose 
±10 minutes 
C0D2 
24 hours postdose 
±60 minutes 
C0D3 
48 hours postdose 
±60 minutes 
C0D4 
72 hours postdose 
±60 minutes 
C1D3 
Predose of first administration 
Within 120 minutes before dosing 
C1D8 
Predose of first administration 
Within 120 minutes before dosing 
C1D15 
Predose of first administration 
Within 60 minutes before dosing 
(Blood sampling after 
first administration of 
study drug should be 
performed before second 
administration) 
0.5 hours postdose of first administration 
±10 minutes 
1 hour postdose of first administration 
±10 minutes 
2 hours postdose of first administration 
±10 minutes 
4 hours postdose of first administration 
±10 minutes 
6 hours postdose of first administration 
±10 minutes 
8 hours postdose of first administration 
±10 minutes 
10 hours postdose of first administration 
±10 minutes 
12 hours postdose of first administration 
±10 minutes 
C1D22 
Predose of first administration 
Within 120 minutes before dosing 
C2D1 
Predose of first administration 
Within 120 minutes before dosing 
C#D# = Cycle #/Day #. 
 
Table 4 
Urine Sampling Schedule for Pharmacokinetic Assessment 
Tazemetostat 
 
Day 
Sampling Time 
Allowance (as a Target) 
C0D1 
Predose (urine sampling) 
From the time of wake-up to 
just before dosing 
C0D2 
0–24 hours postdose (urine collection) 
– 
C0D3 
24–48 hours postdose (urine collection) 
– 
C0D4 
48–72 hours postdose (urine collection) 
– 
C1D15 
0–12 hours postdose of first administration 
(urine collection) (should be ended before 
second administration) 
– 
C#D# = Cycle #/Day #. 
 
 
9.5.1.4.2 PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ASSESSMENTS 
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9.5.1.5 
Safety Assessments 
Safety assessments are shown in Table 6 (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 
laboratory evaluation for hematology, blood chemistry, and urine values; and periodic 
measurement of vital signs, ECGs, echocardiograms/MUGA scans to assess LVEF, ECOG-
PS, and physical examinations.  
9.5.1.5.1 ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS 
An AE is any untoward medical occurrence in a subject.  An AE does not necessarily have a 
causal relationship with the medicinal product.  For this study, the study drug is 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 
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related to the investigational product (Note:  Every sign or symptom should not be listed 
as a separate AE if the applicable disease [diagnosis] is being reported as an AE) 
• 
Any new disease or exacerbation of an existing disease.  However, worsening of the 
primary disease should be captured under efficacy assessments as disease progression 
rather than as an AE. 
• 
Any deterioration in nonprotocol-required measurements of a laboratory value or other 
clinical test (eg, ECG or x-ray) that results in symptoms, a change in treatment, or 
discontinuation of study drug 
• 
Recurrence of an intermittent medical condition (eg, headache) not present pretreatment 
(Baseline) 
• 
An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, withdrawal of study drug, or withholding 
of study drug, whether prescribed in the protocol or not 
All AEs observed during the study will be reported on the CRF.  All AEs, regardless of 
relationship to study drug or procedure, should be collected beginning from the time the 
subject signs the study ICF through the final observation visit.  SAEs will be collected until 
the final observation visit.  Subjects who fail screening primarily due to AE(s) must have the 
AE(s) leading to screen failure and its seriousness reported on the CRF.   
Any laboratory abnormality considered to constitute an AE should be reported on the CRF.  
Abnormal laboratory values should not be listed as separate AEs if they are considered to be 
part of the clinical syndrome that is being reported as an AE.  It is the responsibility of the 
investigator 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 (QTc) results, if not otherwise considered part of a clinical symptom that is 
being reported as an AE, should be considered an AE if the QTc interval is more than 450 ms 
and there is an increase of more than 60 ms from baseline.  Any ECG abnormality that the 
investigator or subinvestigator considers as an AE should be reported as such. 
All AEs must be followed until last visit for final observation or until resolution, whichever 
comes first.  However, if other anticancer treatments should be implemented as soon as 
possible considering the deterioration of subject’s physical condition, the last visit will be 
allowed within 30 days after the last dose (ie, before the start of other anticancer treatments).  
All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization.   
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 v 4.03.  Investigators 
will report CTCAE grades for all AEs (for both increasing and decreasing severity).  
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Assessing Relationship to Study Treatment 
Items to be considered when assessing the relationship of an AE to the study treatment are: 
• 
Temporal relationship of the onset of the event to the initiation of the study treatment 
• 
The course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable 
• 
Whether the event is known to be associated with the study treatment or with other 
similar treatments 
• 
The presence of risk factors in the study subject known to increase the occurrence of the 
event 
• 
The presence of nonstudy, treatment-related factors that are known to be associated with 
the occurrence of the event 
Classification of Causality 
Yes (related) 
A causal relationship between the study drug and the AE is a reasonable 
possibility. 
No (not related) A causal relationship between the study drug and the AE is not a 
reasonable possibility. 
9.5.1.5.2 SERIOUS ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS 
An SAE is any untoward medical occurrence that at any dose: 
• 
Results in death 
• 
Is life-threatening (ie, the subject was at immediate risk of death from the adverse event 
as it occurred; this does not include an event that, had it occurred in a more severe form 
or was allowed to continue, might have caused death) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly/birth defect (in the child of a subject who was exposed to the 
study drug) 
Other important medical events that may not be immediately life-threatening or result in 
death or hospitalization but, when based on appropriate medical judgment, may jeopardize 
the subject or may require intervention to prevent one of the outcomes in the definition of 
SAE listed above should also be considered SAEs.  Medical and scientific judgment should 
be exercised in deciding whether expedited reporting is appropriate in such situations.  
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.   
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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 Section 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” associated with the hospitalization: 
• 
Hospitalizations for respite care  
• 
Planned hospitalizations required by the protocol 
• 
Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed after study drug administration) 
• 
Hospitalization for administration of study drug or insertion of access for administration 
of study drug 
• 
Hospitalization for routine maintenance of a device (eg, battery replacement) that was in 
place before study entry 
 
9.5.1.5.3 LABORATORY MEASUREMENTS 
Clinical laboratory tests to be performed, including hematology, chemistry, and urinalysis, 
are summarized in Table 5.  The Schedule of Procedures/Assessments (Table 6) shows the 
visits and time points at which blood for clinical laboratory tests and urine for urinalysis will 
be collected in the study.  Clinical laboratory tests will be performed at each site.  
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Table 5 
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, globulin, LDH, creatine phosphokinase, 
amylase, uric acid, glucose, triglycerides, cholesterol, INR, sodium, 
chloride, potassium, calcium, phosphorus 
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. 
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).   
 
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 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 6) by a validated 
method.  Blood pressure and pulse will be measured after the subject has rested.  
9.5.1.5.5 PHYSICAL EXAMINATIONS 
Physical examinations will be performed as designated in the Schedule of 
Procedures/Assessments (Table 6).  Documentation of the physical examination will be 
included in the source documentation at the site.  Only changes from screening 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 6).  
Standardized, 12-lead ECG recordings that permit all 12 leads to be displayed on a single 
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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 Echocardiograms and MUGA scan 
An echocardiogram or a MUGA scan (using technetium-99m-pertechnetate) to assess LVEF 
will be performed as designated in the Schedule of Procedures/Assessments (Table 6).  
Echocardiograms or MUGA scans and should be performed locally in accordance with the 
institution’s standard practice.  Either an echocardiogram or a MUGA scan which is used for 
an individual subject at baseline should be repeated for all subsequent LVEF assessments for 
that subject.  LVEFs as assessed by the institution will be entered into the CRF.  
9.5.1.5.7.2 ECOG PS 
An ECOG performance status (ECOG-PS) should be done at each visit as designated in the 
Schedule of Procedures/Assessments (Table 6). 
9.5.1.5.7.3 Pregnancy Test 
An hCG or β-hCG test will be performed for women of childbearing potential.  A serum or 
urine sample will be taken at visits as designated in the Schedule of Procedures/Assessments 
(Table 6). 
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). 
9.5.1.5.7.4 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.  
When subjects have HBs antibody or HBc antibody positive results, HBV-DNA tests will be 
performed.   
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9.5.2 
Schedule of Procedures/Assessments 
9.5.2.1 
Schedule of Procedures/Assessments of the Study 
Table 6 presents the schedule of procedures/assessments for the study. 
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Table 6 
Schedule of Procedures/Assessments in Study E7438-J081-106 (EZH-106) 
Phase 
Pre-treatment 
Treatment 
Extension 
Follow-up 
Period 
Screeninga 
Baseline 
Cycle 0 
Cycle 1 
Cycle 2 and later 
Discontinuation 
Final observation 
Day 
Within 28 
days 
before 
administration 
Within 3 days 
before 
administration 
1 
1b 
3 
8 
(±1) 
15 
(±1) 
22 
(±1) 
1 
(±3)c 
15 
(±3)n 
(+7) 
30 days after last dosing 
(+7)d 
Informed Consent 
X 
 
 
 
 
 
 
 
[X]m 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
Medical history/Current medical condition 
X 
 
 
 
 
 
 
 
 
 
 
 
Previous therapy 
X 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
Body weight 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Physical examination 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
ECOG-PS 
X 
X 
 
X 
 
 
 
 
X 
 
X 
 
12-lead ECGse 
X 
 
X 
X 
 
 
X 
 
X 
X 
X 
 
Echocardiogram or MUGA scanf 
X 
 
 
 
 
 
 
 
[X] 
 
 
 
Pregnancy test (if applicable) 
X 
 
 
 
 
 
 
 
 
 
X 
 
Virus test 
X 
 
 
 
 
 
 
 
 
 
 
 
Hematologyo 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Blood chemistry 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
PK (blood) g 
 
 
X 
 
X 
X 
X 
X 
[X] 
 
 
 
PK (urine) h 
 
 
X 
 
 
 
X 
 
 
 
 
 
Tumor assessments (CT) i 
X 
 
 
 
 
 
 
 
[X] 
X 
 
Bone marrow aspiration or biopsyj 
X 
 
 
 
 
 
 
 
[X] 
 
 
Tazemetostat administrationk 
 
 
X 
Continuous 28-day cycle of tazemetostat twice daily. 
 
 
Archival tumor sample submissionl 
X 
Adverse events 
From informed consent to final observation 
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Note, [X]: In case to perform. 
C#/D# = Cycle #/Day #, CR = complete response, CT = computed tomography, ECG = electrocardiogram, ECOG-PS = Eastern Cooperative Oncology Group-Performance Status, MUGA 
= multigated acquisition, PK = pharmacokinetics. 
a: Screening assessments may be used as baseline assessments if performed within 3 days of the first administration of study drug. 
b: To start C1D1 on Cycle 0 Days 4-9. 
c:  +1 day for C2D1. 
d: When subject needs to receive other anti-tumor therapy due to deterioration of the disease 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. . 
e: 12-Lead ECGs on C0D1, C1D1, and C2D1 will be collected at pre-dose and 0.5-2 hours post dose of first administration.  
f: Echocardiogram or MUGA scan will be performed at screening, every 16 weeks (ie, Day 1 of every 4 cycles [± 1 week]) from C2D1. Additional assessments may be performed if clinically 
indicated. 
g: Blood samples for PK analyses of tazemetostat and metabolites will be collected in C0D1 at predose, 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 48 and 72 hours postdose; C1D3 and C1D8 at predose of 
first administration; C1D15 at predose of first administration, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose (postdose blood samples should be collected before the second administration of 
study drug); C1D22 and C2D1 predose of first administration. 
h: Urine samples for PK analyses of tazemetostat will be collected in C0D1 at predose, 0-24, 24-48 and 48-72 hours postdose; C1D15 at 0-12 hours postdose of first administration. 
i: The data of tumor assessments before informed consent within 28 days from study drug administration can be used as screening data if it meets the requirement of the protocol.  Perform 
tumor assessment at screening, every 8 weeks [±1 week] (starting at Cycle 1 Day 1) during Cycles 2-6, every 12 weeks [± 1 week] starting at Cycle 7 and beyond, and discontinuation. The 
data within 28 days can be used as discontinuation data. 
j: The data of bone marrow aspiration or biopsy before informed consent within 42 days from study drug administration can be used as screening data if it meets the requirement of the 
protocol.  After the study drug dosing, perform bone marrow aspiration or biopsy if the result of screening was positive or unconfirmed and when to confirm CR as best of response or if 
clinically indicated. 
k: Subjects should not take study drug before evaluations are performed (except tumor assessments and peripheral blood smear morphology assessment), unless specified. 
l: Submit pre-study drug treated tumor sample to central laboratory before final observation, as far as possible. 
m: Informed consent should be obtained before initiating the study or before entering the Extension Phase when Cycle 2 or later administrations will be continued. 
n: 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. 
o: 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. 
 
 
Concomitant drug/therapies 
From informed consent to final observation 
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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, echocardiograms/MUGA scans, 
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 
The investigator must report SAEs to the sponsor according to the following procedure: 
(1)Initial report (when the investigator becomes aware of the event) 
All SAEs regardless of the causal relationship to the study drug must be reported to the sponsor 
by telephone, fax, or email within 24 hours after obtaining the information.  However, the 
following events must be reported immediately by telephone or other means: 
• 
“Unexpected fatal events” (ie, treatment-related events are not listed in the investigator 
brochure or periodic safety report)  
• 
The terms of treatment-related “unexpected fatal events” that are already reported are 
changed to the new term of “unexpected fatal events.” 
(2)Completed SAE report  
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 drug or any 
protocol-required procedure should be reported to the sponsor regardless of the length of 
time that has passed since study completion. 
The detailed contact information for reporting of SAEs is provided in the 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 or subinvestigator’s assessment of 
causality. 
Any follow-up information received on SAEs should be forwarded from the investigator 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. 
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Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents 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 
treatment, or any exposure to study drug through breastfeeding during study treatment or 
within 30 days of last study treatment, must be reported. 
If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment. 
A congenital anomaly, death during perinatal period, an induced abortion, or a spontaneous 
abortion are considered to be an SAE and should be reported in the same time frame and in 
the same format as all other SAEs (see Reporting of Serious Adverse Events 
[Section 9.5.4.1]). 
Pregnancies or exposure to study drug through breastfeeding must be reported by fax or 
email as soon as possible but no later than 1 business day from the date the investigator 
becomes aware of the pregnancy 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  
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Abuse 
Sporadic or persistent intentional excessive use of study drug 
accompanied by harmful physical or psychological effects 
Medication error 
Any unintentional event that causes or leads to inappropriate study 
drug use or subject harm while the study drug is in the control of site 
personnel or the subject.   
All AEs associated with 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 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.  Events of interest should be considered as 
serious only if the events meet the serious criteria.  These events should be entered on the 
CRF even if the events do not meet serious criteria.   
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 the 
investigator or subinvestigator provides complete SAE information in the manner described 
above (Section 9.5.4.1). 
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. 
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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 6). 
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 
failure to return, the status of treatment compliance, the presence or absence of AEs, and 
clinical courses of signs and symptoms.   
Subjects who discontinue early from the study will be discontinued for 1 of primary reasons.  
Study disposition information will be collected on the CRF.   
If the subject is regarded as DLT non-evaluable, he/she is not considered as DLT evaluable 
subjects.  The sponsor can enroll additional subjects. 
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 the 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 
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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. 
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 after the study is completed and the database is 
locked.  Statistical analyses will be performed using SAS software or other validated 
statistical software as required.  Details of the statistical analyses will be included in a 
separate statistical analysis plan (SAP). 
9.7.1 
Statistical and Analytical Plans 
The statistical analyses of 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 
• 
DLTs 
 
9.7.1.1.2 SECONDARY ENDPOINTS 
• 
Safety assessments (AEs, clinical laboratory tests, vital signs, body weight, 12-lead 
ECGs, echocardiograms/MUGA scans to assess LVEF, ECOG-PS, and physical 
examinations) 
• 
PK parameters 
• 
ORR of BOR 
 
9.7.1.1.3 EXPLORATORY ENDPOINTS  
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9.7.1.2 
Definitions of Analysis Sets 
DLT Analysis Set will include all subjects who have completed treatment Cycles 0 and 1 
without major protocol deviations with at least 75% of treatment compliance in Cycle 1 and 
were assessed for DLT, and subjects who have experienced DLT during Cycles 0 and 1.  
Subjects with less than 75% treatment compliance in Cycle 1 due to a reason other than 
toxicity up to Cycle 1/Day 28 will not be included in this analysis set. 
Safety/Efficacy Analysis Set will include all subjects who received at least 1 administration 
of the study drug.  This will be the analysis set for all safety and efficacy evaluations, as well 
as for demographic and baseline characteristics. 
Pharmacokinetic Analysis Set will include all subjects who have received at least 1 
administration of the study drug and had sufficient PK data to derive at least 1 PK parameter. 
9.7.1.3 
Subject Disposition 
Subjects who signed informed consent, were registered in the study, and failed screening 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 (DLBCL, FL).  Continuous demographic and baseline 
variables include age, height, and body weight; categorical variables include sex, age group, 
race, ethnics, ECOG-PS, and prior therapies for primary disease (chemotherapy, 
radiotherapy, and other therapies).   
9.7.1.5 
Prior and Concomitant Therapy 
All investigator terms for medications recorded in the CRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary (WHO DD) 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 
BOR will be summarized in whole or each disease (DLBCL, FL).  The assessment of the 
ORR (CR + PR) in subjects with B cell lymphomas will be based on “The Lugano 
Classification (CT-Based Response)” (Cheson, et al., 2014) response criteria. 
ORR will be presented with corresponding 2-sided Clopper–Pearson exact 95% confidence 
intervals (CIs).  This analysis will be performed on the Efficacy Analysis Set.  If applicable, 
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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. 
9.7.1.7 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses 
9.7.1.7.1 PHARMACOKINETIC ANALYSES 
The PK Analysis Set will be used for all PK analyses including summaries of plasma and 
urine concentrations of tazemetostat and plasma concentrations of ER-897387.  Plasma 
concentration-time profiles of tazemetostat and ER-897387 will be plotted.  Using non-
compartmental analysis methods, plasma concentrations of tazemetostat and ER-897387 will 
be calculated to determine the PK parameters including Cmax, tmax, AUC at the first 
administration (Cycle 0/Day 1) and repeated administration (Cycle 1/Day 15). 
9.7.1.7.2 PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ANALYSES 
9.7.1.8 
Safety Analyses 
All tolerability analyses will be performed on the DLT Analysis Set.  The Safety Analysis 
Set will be used for all other safety analyses.   
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 DOSE LIMITING TOXICITIES 
The number and percentage of subjects with DLT will be calculated.  DLT will also be 
summarized per type of toxicity.   
9.7.1.8.3 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  
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• 
Worsens in severity during treatment relative to the pretreatment state, when the AE is 
continuous. 
Only those AEs that are treatment-emergent will be included in summary tables.  All AEs, 
treatment-emergent or otherwise, will be presented in subject data listings. 
The TEAEs will be summarized.  The 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 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. 
9.7.1.8.4 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 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. 
9.7.1.8.5 VITAL SIGNS 
Descriptive statistics for vital signs parameters (ie, systolic and diastolic blood pressure, 
pulse rate, body temperature) and body weight and changes from baseline will be presented 
by visit. 
9.7.1.8.6 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.  
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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: 
Absolute QTcF interval prolongation: 
• 
QTcF interval >450 ms 
• 
QTcF interval >480 ms 
• 
QTcF interval >500 ms 
Change from baseline in QTcF interval: 
• 
QTcF interval increases from baseline >30 ms 
• 
QTcF interval increases from baseline >60 ms 
9.7.1.8.7 OTHER SAFETY ANALYSES 
Descriptive statistics for LVEF and LVEF changes from baseline using MUGA scans or 
echocardiograms will be calculated. 
ECOG-PS will be summarized by the scale at each visit and by highest postbaseline scale. 
9.7.2 
Determination of Sample Size 
The primary objective of this study is to investigate the tolerability of tazemetostat.  Hence 
neither clinical hypothesis nor judgment criteria are set, the sample size is not based on 
statistical consideration.  The sample size of 6 patients is considered adequate for the purpose 
to evaluate the tolerability of each cohort. 
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 statistical analysis plan 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. 
Béguelin W, Popovic R, Teater M, Jiang Y, Bunting KL, Rosen M, et al. EZH2 is 
required for germinal center formation and somatic EZH2 mutations promote lymphoid 
transformation. Cancer Cell. 2013 May 13;23(5):677-92. 
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. 
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. 
Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, et al. 
Recommendations for initial evaluation, staging, and response assessment of Hodgkin 
and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014 Sep 
20;32(27):3059-68. 
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. 
Margueron R, Reinberg D. The Polycomb complex PRC2 and its mark in life. Nature. 
2011 Jan 20;469(7330):343-9. 
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. 
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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. 
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, The Japanese Society of Hematology. Guideline for 
management of hematopoietic tumor, 2013. 
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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 or 
subinvestigator 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 or subinvestigator will conduct the study in strict accordance with the 
protocol. 
11.3 Monitoring Procedures 
The CRA will maintain contact with the investigator or subinvestigator 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, x-rays, and other imaging reports 
(eg, sonograms, CT scans, magnetic resonance images, radioactive images, ECGs, EEGs, 
pulmonary function tests, microfiche and photographic negatives) regardless of how 
these images are stored, including microfiche and photographic negatives 
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• 
Pain, quality of life, or medical history questionnaires completed by subjects 
• 
Records of telephone contacts 
• 
Diaries or evaluation checklists 
• 
Drug distribution and accountability logs maintained in pharmacies or by research 
personnel 
• 
Laboratory results and other laboratory test outputs (eg, urine pregnancy test result 
documentation and urine dip-sticks) 
• 
Correspondence regarding a study subject’s treatment between physicians or memoranda 
sent to the IRBs 
• 
CRF components (eg, questionnaires) that are completed directly by subjects and serve as 
their own source 
11.4 Recording of Data 
A CRF is required and must be completed for each subject by qualified and authorized 
personnel.  All data on the CRF must reflect the corresponding source document, except 
when a section of the CRF itself is used as the source document.  Any correction to entries 
made on the CRF must be documented in a valid audit trail where the correction is dated, the 
individual making the correction is identified, the reason for the change is stated, and the 
original data are not obscured.  Only data required by the protocol for the purposes of the 
study should be collected. 
The investigator must sign each CRF.  The investigator will report the CRFs to the sponsor 
and retain a copy of the CRFs. 
11.5 Identification of Source Data 
All data to be recorded on the CRF must reflect the corresponding source documents.  For 
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, 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, meal 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, new 
lesions) 
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- 
Comments 
(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, as 
directed by the sponsor, for at least 3 years after the approval of a marketing application and 
until there are no pending or contemplated marketing applications or at least 3 years have 
elapsed since the formal discontinuation of clinical development of the investigational 
product, whichever occurs later. 
It is requested that at the completion of the required retention period the medical institution 
contact the sponsor, allowing the sponsor the option of permanently retaining the study 
records. 
11.7 Auditing Procedures and Inspection 
In addition to routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the sponsor’s 
SOPs to evaluate compliance with the GCP and all applicable local regulations.  Government 
regulatory authority may request an inspection during the study or after its completion. 
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Clinical Study Protocol incorporating Amendment 04 
E7438-J081-106 (EZH-106) 
 
Eisai 
FINAL:  18 Oct 2018 
Confidential 
Page 74 of 75  
 
11.8 Handling of Study Drug 
All study drug will be supplied to the assigned pharmacist (or designee) by the sponsor.  
Drug supplies must be kept in an appropriate secure area (eg, locked cabinet) and stored 
according to the conditions specified on the drug labels.  The assigned pharmacist (or 
designee) must maintain an accurate record of the shipment and dispensing of the study drug 
in a drug accountability ledger.  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. 
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. 
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Eisai 
FINAL:  18 Oct 2018 
Confidential 
Page 75 of 75  
 
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 investigator/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/institution, as specified by the 
applicable regulatory requirement(s). 
The investigator reserves the right to discontinue the study should his/her judgment so 
dictate.  If the investigator terminates or suspends a study without prior agreement of the 
sponsor, the investigator should inform the institution where applicable, and the 
investigator/the head of medical institution should promptly inform the sponsor and the IRB 
and provide 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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E7438-J081-106 (EZH-106) 
 
 
Date:  21 Oct 2016 
Confidential 
Page 1 of 9 
 
Protocol Amendment 
Study Protocol Title: 
A Phase 1 Study of Tazemetostat in Patients With Relapsed or Refractory B-cell Non-Hodgkin’s 
Lymphoma 
Study Protocol Number: 
E7438-J081-106 (EZH-106) 
 
Protocol 
Pages 
Protocol V1.0, 20 Sep 2016 
Protocol V2.0, 21 Oct 2016 
Rationale 
Footer in 
all pages 
Date:  20 Sep 2016 
Date:  21 Oct 2016 
Changed with the 
protocol updated.   
1 
Approval Date:  V1.0, 20 Sep 2016 
Approval Date:  V2.0, 21 Oct 2016 
Changed with the 
protocol updated.   
2 
26 
9.1.1.2 Treatment Phase 
Considering visit schedule and safety, subjects will be 
hospitalized from Cycle 0 Day 1 (C0D1) to Cycle 1 
Day 15 (C1D15), in principle.   
9.1.1.2 Treatment Phase 
Considering visit schedule and safety, subjects will be 
hospitalized from Cycle 0/Day 1 (C0D1) to Cycle 
1/Day 15 (C1D15).  Based on the thorough evaluation 
of the data obtained on C1D15 and all safety data 
available, the investigator or subinvestigator will 
determine whether subjects can be treated on an 
outpatient basis.  When subjects are considered to 
require extended hospitalization to ensure subject 
safety, they will be hospitalized from C1D15 onwards.   
To allow subjects 
to continue 
hospitalization 
after C1D15, 
considering the 
safety of subjects.  
27 
9.1.1.3 Extension Phase 
The Extension Phase consists of Cycle 2 of 28 days 
and later for tazemetostat BID oral administration on a 
9.1.1.3 Extension Phase 
The Extension Phase consists of Cycle 2 of 28 days 
and later for tazemetostat BID oral administration on a 
To clarify that 
informed consent 
should be 
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Protocol 
Pages 
Protocol V1.0, 20 Sep 2016 
Protocol V2.0, 21 Oct 2016 
Rationale 
continuous basis and lasts until discontinuation of 
study drug.   
continuous basis and lasts until discontinuation of 
study drug.  Informed consent should be obtained 
before initiating the study or before entering the 
Extension Phase when Cycle 2 or later administrations 
will be continued.   
obtained when 
Cycle 2 or later 
administrations 
will be continued.  
3 
27 
9.1.2 
Dose-Limiting Toxicities (DLT) 
Three subjects will be enrolled and ensure that they are 
evaluable for dose-limiting toxicities (DLTs) at the end 
of Cycle 1 of the cohort.  When a DLT is observed in 0 
to 2 of 3 subjects at a given dose level, 3 additional 
subjects would be treated at the same dose level.   
When 3 subjects at a given dose level experience 
DLTs, the enrollment in the cohort will be 
discontinued and the lower dose level of tazemetostat 
cohort will be considered jointly by the investigator 
and sponsor.  The opinion of Independent Data 
Monitoring Advisor can be obtained if needed.   
9.1.2 
Dose-Limiting Toxicities (DLT) 
Three subjects will be enrolled and ensure that they are 
evaluable for dose-limiting toxicities (DLTs) at the end 
of Cycle 1 of the cohort.  When a DLT is observed in 0 
or 1 of 3 subjects at a given dose level, 3 additional 
subjects would be treated at the same dose level.   
When 2 of 3 subjects at a given dose level experience 
DLTs, enrollment of additional subjects will be 
discussed jointly by the investigator and sponsor.  The 
opinion of Independent Data Monitoring Advisor 
should be also obtained.  When additional subjects are 
to be enrolled, they will be monitored individually.  
When no DLTs are observed, up to 3 additional 
subjects will be enrolled.  When no additional subjects 
are accrued or 3 subjects in total experienced DLTs, 
the enrollment in the cohort will be discontinued and 
the lower dose level of tazemetostat cohort will be 
considered jointly by the investigator and sponsor.  The 
opinion of Independent Data Monitoring Advisor can 
be obtained if needed.   
To clarify the 
procedure of 
enrollment of 
additional 
subjects to avoid 
more than 3 
subjects to have 
DLTs when 2 of 
3 subjects at a 
given dose level 
experience DLTs.  
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Protocol 
Pages 
Protocol V1.0, 20 Sep 2016 
Protocol V2.0, 21 Oct 2016 
Rationale 
3 
27 
9.1.2 
Dose-Limiting Toxicities (DLT) 
The tolerability of tazemetostat will be determined 
based on the incidence of DLTs in Cycles 0 and 1.  If 
DLTs occur in 0 to 2 of 6 subjects, this dose level is 
considered tolerable.   
9.1.2 
Dose-Limiting Toxicities (DLT) 
The tolerability of tazemetostat will be determined 
based on the incidence of DLTs in Cycles 0 and 1.  If 
DLTs occur in 0 or 1 of 6 subjects, this dose level is 
considered tolerable.  If DLTs occurs in 2 of 6 subjects, 
the tolerability of this dose level will be determined 
jointly by the investigator and sponsor.  The opinion of 
Independent Data Monitoring Advisor should be also 
obtained.   
To clarify that the 
tolerability of the 
dose level will be 
determined with 
discussion if 
DLTs occurs in 2 
of 6 subjects.   
3 
27 
9.1.2 
Dose-Limiting Toxicities (DLT) 
Table 1  Dose-Limiting Toxicities (DLT) 
Toxicity Category 
Toxicity/CTCAE Grade 
Hematological 
Toxicity 
• Grade 4 neutropenia for > 7 days 
• ≥ Grade 3 febrile neutropenia 
• Grade 4 thrombocytopenia 
• Grade 3 thrombocytopenia with bleeding or 
requiring platelet transfusion 
Non-
hematological 
Toxicity 
• ≥ Grade 3 nausea, vomiting, or diarrhea that 
persists > 7 days despite maximal medical 
therapy 
• ≥ Grade 3 non-hematological laboratory 
abnormalities with clinical symptoms that persists 
> 7 days 
• Other Grade 3 toxicity lasting > 7 days or Grade 
4 non-hematological toxicity of any duration 
Medication 
compliance 
• Failure to administer ≥ 75% (≥ 42/56 doses) of 
the planned administration number of study drug 
in Cycle 1 as a result of treatment-related toxicity 
 
9.1.2 
Dose-Limiting Toxicities (DLT) 
Table 1  Dose-Limiting Toxicities (DLT) 
Toxicity Category 
Toxicity/CTCAE Grade 
Hematological 
Toxicity 
• Grade 4 neutropenia for > 7 days or neutropenia 
requiring hematopoietic growth factors 
• ≥ Grade 3 febrile neutropenia 
• Grade 4 thrombocytopenia, Grade 3 
thrombocytopenia with bleeding, or 
thrombocytopenia requiring platelet transfusion 
• Grade 4 anemia or anemia requiring erythrocyte 
transfusion  
Non-
hematological 
Toxicity 
• ≥ Grade 3 nausea, vomiting, or diarrhea that 
persists > 7 days despite maximal medical 
therapy 
• ≥ Grade 3 non-hematological laboratory 
abnormalities with clinical symptoms that persists 
> 7 days 
• Other Grade 3 toxicity lasting > 7 days or Grade 
4 non-hematological toxicity of any duration 
Medication 
compliance 
• Failure to administer ≥ 75% (≥ 42/56 doses) of 
the planned administration number of study drug 
in Cycle 1 as a result of treatment-related toxicity 
Added DLTs.   
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Protocol 
Pages 
Protocol V1.0, 20 Sep 2016 
Protocol V2.0, 21 Oct 2016 
Rationale 
4 
28 
9.3.1 
Inclusion Criteria 
(3)Patient who had previous therapy with systemic 
chemotherapy and/or antibody therapy.   
9.3.1 
Inclusion Criteria 
(3)Patient who had previous therapy with systemic 
chemotherapy and/or antibody therapy and for 
which no standard therapy exists.   
To clarify that the 
patients for 
which no 
standard therapy 
exists should be 
enrolled.   
5 
29 
9.3.2 
Exclusion Criteria 
(17)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 below) 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.   
Note:  Condom, contraceptive sponge, foam, jelly, 
diaphragm, intrauterine device (IUD), or use of oral, 
transdermal, or transvaginal contraception 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) 
9.3.2 
Exclusion Criteria 
(17)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 below) 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.   
Note:  Condom*, contraceptive sponge**, foam**, 
jelly**, diaphragm*, intrauterine device (IUD)*, or 
use of oral contraception* 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) 
To clarify 
whether the 
medically 
effective methods 
for contraception 
are approved or 
certified.   
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Protocol 
Pages 
Protocol V1.0, 20 Sep 2016 
Protocol V2.0, 21 Oct 2016 
Rationale 
36 
9.5.1.4.1 
Pharmacokinetic Assessments 
Table 3  Blood Sampling Schedule for Pharmacokinetic 
Assessment 
Tazemetostat and ER-897387 
Day 
Sampling Time 
Allowance (as a 
Target) 
C0D1 
Predose 
Within 60 minutes 
before dosing 
 
0.5 hours postdose 
±10 minutes 
 
1 hour postdose 
±10 minutes 
 
2 hours postdose 
±10 minutes 
 
4 hours postdose 
±10 minutes 
 
6 hours postdose 
±10 minutes 
 
8 hours postdose 
±10 minutes 
 
10 hours postdose 
±10 minutes 
 
12 hours postdose 
±10 minutes 
C0D2 
24 hours postdose 
±60 minutes 
C0D3 
48 hours postdose 
±60 minutes 
C0D4 
72 hours postdose 
±60 minutes 
C1D3 
Predose of first administration 
Within 60 minutes 
before dosing 
C1D8 
Predose of first administration 
Within 60 minutes 
before dosing 
C1D15 
Predose of first administration 
Within 60 minutes 
before dosing 
(Blood 
sampling after 
first 
administration 
should 
be 
performed 
before second 
administration) 
0.5 hours postdose of first administration
±10 minutes 
1 hour postdose of first administration 
±10 minutes 
2 hours postdose of first administration 
±10 minutes 
4 hours postdose of first administration 
±10 minutes 
6 hours postdose of first administration 
±10 minutes 
8 hours postdose of first administration 
±10 minutes 
10 hours postdose of first administration 
±10 minutes 
12 hours postdose of first administration 
±10 minutes 
C1D22 
Predose of first administration 
Within 60 minutes 
before dosing 
C2D1 
Predose of first administration 
Within 60 minutes 
before dosing 
C#D# = Cycle #/Day #. 
9.5.1.4.1 
Pharmacokinetic Assessments 
Table 3  Blood Sampling Schedule for Pharmacokinetic 
Assessment 
Tazemetostat and ER-897387 
Day 
Sampling Time 
Allowance (as a 
Target) 
C0D1 
Predose 
Within 180 minutes 
before dosing 
 
0.5 hours postdose 
±10 minutes 
 
1 hour postdose 
±10 minutes 
 
2 hours postdose 
±10 minutes 
 
4 hours postdose 
±10 minutes 
 
6 hours postdose 
±10 minutes 
 
8 hours postdose 
±10 minutes 
 
10 hours postdose 
±10 minutes 
 
12 hours postdose 
±10 minutes 
C0D2 
24 hours postdose 
±60 minutes 
C0D3 
48 hours postdose 
±60 minutes 
C0D4 
72 hours postdose 
±60 minutes 
C1D3 
Predose of first administration 
Within 120 minutes 
before dosing 
C1D8 
Predose of first administration 
Within 120 minutes 
before dosing 
C1D15 
Predose of first administration 
Within 60 minutes 
before dosing 
(Blood 
sampling after 
first 
administration 
should 
be 
performed 
before second 
administration
) 
0.5 hours postdose of first administration 
±10 minutes 
1 hour postdose of first administration 
±10 minutes 
2 hours postdose of first administration 
±10 minutes 
4 hours postdose of first administration 
±10 minutes 
6 hours postdose of first administration 
±10 minutes 
8 hours postdose of first administration 
±10 minutes 
10 hours postdose of first administration 
±10 minutes 
12 hours postdose of first administration 
±10 minutes 
C1D22 
Predose of first administration 
Within 120 minutes 
before dosing 
C2D1 
Predose of first administration 
Within 120 minutes 
before dosing 
C#D# = Cycle #/Day #. 
To extend 
allowance of 
sampling time 
considering 
feasibility of the 
blood sampling 
schedule.   
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Page 6 of 9 
 
Protocol 
Pages 
Protocol V1.0, 20 Sep 2016 
Protocol V2.0, 21 Oct 2016 
Rationale 
37 
9.5.1.4.2 
Pharmacodynamic, Pharmacogenomic, 
And Other Biomarker Assessments 
Details of sample collection, handling, and shipping 
will be provided in a separate manual.  Sample 
security, use, retention and subject privacy are 
provided below.   
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, 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 destroyed at the finalization of the 
analytical report at the central laboratory.  
9.5.1.4.2 
Pharmacodynamic, Pharmacogenomic, 
And Other Biomarker Assessments 
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, 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. 
To clarify the 
sample 
collection, 
timing, and 
storage method 
and period.   
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Protocol 
Pages 
Protocol V1.0, 20 Sep 2016 
Protocol V2.0, 21 Oct 2016 
Rationale 
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.   
42 
9.5.1.5.7.3  Pregnancy Test 
An hCG or β-hCG test will be performed for 
premenopausal women and postmenopausal women 
who have been amenorrheic for less than 12 months.  
A serum or urine sample will be taken at visits as 
designated in the Schedule of Procedures/Assessments 
(Table 6).  
9.5.1.5.7.3  Pregnancy Test 
An hCG or β-hCG test will be performed for women of 
childbearing potential.  A serum or urine sample will 
be taken at visits as designated in the Schedule of 
Procedures/Assessments (Table 6). 
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).  
To clarify the 
definition of 
women of 
childbearing 
potential and 
postmenopausal 
women.   
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Protocol 
Pages 
Protocol V1.0, 20 Sep 2016 
Protocol V2.0, 21 Oct 2016 
Rationale 
43 
9.5.2.1 Schedule of Procedures/Assessments of the 
Study 
Table 6 Schedule of Procedures/Assessments in Study E7438-
J081-106 (EZH-106) 
 
Phase 
Pre-treatment 
Treatment 
Extensio
n 
Follow-up 
Period 
Screen
inga 
Baseli
ne 
Cyc
le 0 
Cycle 1 
Cycle 2 
and later 
Disco
ntinu
ation 
Final 
observ
ation 
Day 
Within 
28 days 
before 
admin. 
Within 
3 days  
before 
admin. 
1 
1b 3 
8 
(±1
) 
15 
(±1
) 
22 
(±1
) 
1 
(±3)c 
15 
(±3
) 
(+7) 
30 
days 
after 
last 
dosing 
(+7)d 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
9.5.2.1 Schedule of Procedures/Assessments of the 
Study 
Table 6 Schedule of Procedures/Assessments in Study E7438-
J081-106 (EZH-106) 
m: Informed consent should be obtained before initiating the study or before 
entering the Extension Phase when Cycle 2 or later administrations will be 
continued. 
Phase 
Pre-treatment 
Treatment 
Extensio
n 
Follow-up 
Period 
Screen
inga 
Baseli
ne 
Cyc
le 0 
Cycle 1 
Cycle 2 
and later 
Disco
ntinu
ation 
Final 
observ
ation 
Day 
Within 
28 days 
before 
admin. 
Within 
3 days  
before 
admin. 
1 
1b 3 
8 
(±1
) 
15 
(±1
) 
22 
(±1
) 
1 
(±3)c 
15 
(±3
) 
(+7) 
30 
days 
after 
last 
dosing 
(+7)d 
Informed 
Consent 
X 
 
 
 
 
 
 
 
[X]m 
 
 
 
To stipulate that 
informed consent 
for entering the 
Extension Phase 
will be obtained 
if subjects enter 
the Extension 
Phase.   
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Protocol 
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Protocol V1.0, 20 Sep 2016 
Protocol V2.0, 21 Oct 2016 
Rationale 
45 
9.5.4 
Reporting of Serious Adverse Events, 
Pregnancy, and Events Associated with Special 
Situations 
9.5.4.1 Reporting of Serious Adverse Events 
The investigator must report SAEs to the sponsor 
according to the following procedure: 
(1)Initial report (when the investigator becomes aware 
of the event) 
All SAEs regardless of the causal relationship to the 
study drug must be reported to the sponsor by 
telephone, fax, or email as soon as possible but no later 
than 1 business day after obtaining the information.  
However, the following events must be reported within 
24 hours (no later than 1 calendar day) by telephone or 
other means: 
• “Unexpected fatal events” (ie, treatment-related 
events are not listed in the investigator brochure or 
periodic safety report)  
• The terms of treatment-related “unexpected fatal 
events” that are already reported are changed to the 
new term of “unexpected fatal events.”  
9.5.4 
Reporting of Serious Adverse Events, 
Pregnancy, and Events Associated with Special 
Situations 
9.5.4.1 Reporting of Serious Adverse Events 
The investigator must report SAEs to the sponsor 
according to the following procedure: 
(1)Initial report (when the investigator becomes aware 
of the event) 
All SAEs regardless of the causal relationship to the 
study drug must be reported to the sponsor by 
telephone, fax, or email within 24 hours after obtaining 
the information.  However, the following events must 
be reported immediately by telephone or other means: 
• “Unexpected fatal events” (ie, treatment-related 
events are not listed in the investigator brochure or 
periodic safety report)  
• The terms of treatment-related “unexpected fatal 
events” that are already reported are changed to the 
new term of “unexpected fatal events.”  
To stipulate that 
all SAEs must be 
reported within 
24 hours after 
obtaining the 
information.   
 
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E7438-J081-106 (EZH-106) 
 
 
Date:  15 Dec 2016 
Confidential 
Page 1 of 2 
 
Protocol Amendment 
Study Protocol Title: 
A Phase 1 Study of Tazemetostat in Patients With Relapsed or Refractory B-cell Non-Hodgkin’s 
Lymphoma 
Study Protocol Number: 
E7438-J081-106 (EZH-106) 
 
Protocol 
Pages 
Protocol V2.0, 21 Oct 2016 
Protocol V3.0, 15 Dec 2016 
Rationale 
Footer in 
all pages 
Date:  21 Oct 2016 
Date:  15 Dec 2016 
Changed with the 
protocol updated.   
1 
Approval Date:  V2.0, 21 Oct 2016 
Approval Date:  V3.0, 15 Dec 2016 
Changed with the 
protocol updated.   
3 
27 
9.1.1.4 Follow-Up Phase 
The Follow-up Phase consists of the evaluation at 
discontinuation which is performed within 7 days after 
final administration of tazemetostat and a final 
observation which occurs 30 days (+7 days) after final 
administration or initiation of a new anti-tumor 
therapy, whichever occurs early. 
9.1.1.4 Follow-Up Phase 
The 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. 
Revised the 
timing of the 
evaluation at 
discontinuation to 
be performed 
appropriately.   
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Protocol 
Pages 
Protocol V2.0, 21 Oct 2016 
Protocol V3.0, 15 Dec 2016 
Rationale 
6 
31 
9.4.1 
Treatment Administered 
Tazemetostat 800 mg will be administered orally by 
single dose in Cycle 0/Day 1 (C0D1) and continuous 
BID (1600 mg total daily dose, no less than 8 hours 
between doses except C1D15 that requires 12 hours or 
more) in Cycle 1 and later, in a fasted state on C0D1 
and at the first administration of C1D15 defined as 
either ≥2 hours before or ≥2 hours after a meal (only 
water is allowed). 
9.4.1 
Treatment Administered 
Tazemetostat 800 mg will be administered orally by 
single dose in Cycle 0/Day 1 (C0D1) and continuous 
BID (1600 mg total daily dose, no less than 8 hours 
between doses except C1D15 that requires 12 hours or 
more) in Cycle 1 and later, in a fasted state on C0D1 
and at the first administration of C1D15 defined as ≥2 
hours before and ≥2 hours after a meal (only water is 
allowed). 
Revised the 
definition of 
fasted state 
appropriately.   
7 
35 
9.4.7.1 Prohibited Concomitant Therapies and 
Drugs 
(2)Cycles 0 and 1 
• Any antacids or other drugs known to raise gastric 
pH (C0D1 and C1D15 only).  These drugs should be 
administered ≥2 hours before study drug 
administration or ≥2 hours after study drug 
administration if used in Cycle 1.  
9.4.7.1 Prohibited Concomitant Therapies and 
Drugs 
(2)Cycles 0 and 1 
• Any antacids or other drugs known to raise gastric 
pH (C0D1 and C1D15 only).  These drugs should be 
administered ≥2 hours before study drug 
administration and ≥2 hours after study drug 
administration if used in Cycle 1.  
Revised 
appropriately the 
available timing 
of receiving the 
concomitant 
drug.   
 
Page 86 of 167


 
 
E7438-J081-106 (EZH-106) 
 
 
Date:  23 Mar 2018 
Confidential 
Page 1 of 1 
 
Protocol Amendment 
Study Protocol Title: 
A Phase 1 Study of Tazemetostat in Patients With Relapsed or Refractory B-cell Non-Hodgkin’s 
Lymphoma 
Study Protocol Number: 
E7438-J081-106 (EZH-106) 
 
Protocol 
Pages 
Protocol V3.0, 15 Dec 2016 
Protocol V4.0, 23 Mar 2018 
Rationale 
Footer in 
all pages 
Date:  15 Dec 2016 
Date:  23 Mar 2018 
Changed with the 
protocol updated.   
1 
Approval Date:  V3.0, 15 Dec 2016 
Approval Date:  V4.0, 23 Mar 2018 
Changed with the 
protocol updated.   
2 
Investigators 
To be determined.    
Investigators 
See the Attachment separately provided to each site.   
Updated the 
reference of the 
investigators.  
45 
46 
9.5.2.1 Schedule of Procedures/Assessments of the 
Study 
Table 6, Cycle 2 and later, Day 15 (±3) 
Footnote:   
(Not included) 
9.5.2.1 Schedule of Procedures/Assessments of the 
Study 
Table 6, Cycle 2 and later, Day 15 (±3)n 
Footnote:   
n: 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. 
To reduce the 
burden on 
subjects. 
 
Page 87 of 167


 
 
E7438-J081-106 (EZH-106) 
 
 
Date:  18 Oct 2018 
Confidential 
Page 1 of 5 
 
Protocol Amendment 
Study Protocol Title: 
A Phase 1 Study of Tazemetostat in Patients With Relapsed or Refractory B-cell Non-Hodgkin’s 
Lymphoma 
Study Protocol Number: 
E7438-J081-106 (EZH-106) 
 
Protocol 
Pages 
Protocol V4.0, 23 Mar 2018 
Protocol V5.0, 18 Oct 2018 
Rationale 
Footer in 
all pages 
Date:  23 Mar 2018 
Date:  18 Oct 2018 
Changed with the 
protocol updated.   
1 
Approval Date:  V4.0, 23 Mar 2018 
Approval Date:  V5.0, 18 Oct 2018 
Changed with the 
protocol updated.   
6 
Tazemetostat Dose Reduction and Interruption 
Instructions 
(Not included) 
Tazemetostat Dose Reduction and Interruption 
Instructions 
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.   
Updated based on 
the latest protocol 
text provided by 
Epizyme to 
ensure the safety 
of subjects.   
Page 88 of 167


 
 
E7438-J081-106 (EZH-106) 
 
 
Date:  18 Oct 2018 
Confidential 
Page 2 of 5 
 
Protocol 
Pages 
Protocol V4.0, 23 Mar 2018 
Protocol V5.0, 18 Oct 2018 
Rationale 
14 
4 
LIST OF ABBREVIATIONS AND 
DEFINITIONS OF TERMS 
T-ALL:  T-cell acute lymphoblastic leukemia 
4 
LIST OF ABBREVIATIONS AND 
DEFINITIONS OF TERMS 
(Deleted) 
– 
32 
9.3.3.1 Discontinuation Criteria by Subject 
If a subject meet any of the following criteria, the 
investigator or subinvestigator will discontinue treating 
the subject with study treatment.   
9.3.3.1 Discontinuation Criteria by Subject 
If a subject meet 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.   
(8)Subject experiences T-cell lymphoblastic 
lymphoma/T-cell acute lymphoblastic leukemia.   
Updated based on 
the latest protocol 
text provided by 
Epizyme to 
ensure the safety 
of subjects.   
33 
9.4.1.1 Tazemetostat Dose Reduction and 
Interruption Instructions 
9.4.1.1.2 
Cycle 2 And Later 
(Not included) 
9.4.1.1 Tazemetostat Dose Reduction and 
Interruption Instructions 
9.4.1.1.2 
Cycle 2 And Later 
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 
Updated based on 
the latest protocol 
text provided by 
Epizyme to 
ensure the safety 
of subjects.   
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E7438-J081-106 (EZH-106) 
 
 
Date:  18 Oct 2018 
Confidential 
Page 3 of 5 
 
Protocol 
Pages 
Protocol V4.0, 23 Mar 2018 
Protocol V5.0, 18 Oct 2018 
Rationale 
experiences T-cell lymphoblastic lymphoma/T-cell 
acute lymphoblastic leukemia, study treatment should 
be discontinued and other actions should be discussed 
with the sponsor.   
43 
9.5.1.5.2 
Serious Adverse Events And Events 
Associated With Special Situations 
For this study, occurrence of lymphoblastic 
lymphoma/T-ALL and abnormal bone formation* 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.   
*Definition of signs and symptoms for abnormal bone 
formation:  unexplained localized bone pain, 
neuropathy, nerve compression and symptomatic 
skeletal events.  Symptomatic skeletal events are 
defined as pathological fracture not related to 
metastases, spinal cord compression, or external beam 
radiotherapy or surgery to the bone. 
9.5.1.5.2 
Serious Adverse Events And Events 
Associated With Special 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.   
Updated based on 
the latest protocol 
text provided by 
Epizyme to 
ensure the safety 
of subjects.   
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E7438-J081-106 (EZH-106) 
 
 
Date:  18 Oct 2018 
Confidential 
Page 4 of 5 
 
Protocol 
Pages 
Protocol V4.0, 23 Mar 2018 
Protocol V5.0, 18 Oct 2018 
Rationale 
44 
9.5.1.5.3 
Laboratory Measurements 
Table 5  Clinical Laboratory Tests  
Hematology:  (Not included) 
9.5.1.5.3 
Laboratory Measurements 
Table 5  Clinical Laboratory Tests 
Hematology:  Peripheral blood smear morphology 
assessmenta 
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).   
Updated based on 
the latest protocol 
text provided by 
Epizyme to 
ensure the safety 
of subjects.   
46 
47 
9.5.2.1 Schedule of Procedures/Assessments of the 
Study 
Table 6  Schedule of Procedures/Assessments in 
Study E7438-J081-106 (EZH-106) 
Hematology 
k:  Subjects should not take study drug before evaluations 
are performed (except tumor assessments), unless specified. 
9.5.2.1 Schedule of Procedures/Assessments of the 
Study 
Table 6  Schedule of Procedures/Assessments in 
Study E7438-J081-106 (EZH-106) 
Hematologyo 
k:  Subjects should not take study drug before evaluations 
are performed (except tumor assessments and peripheral 
blood smear morphology assessment), unless specified. 
o:  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. 
Updated based on 
the latest protocol 
text provided by 
Epizyme to 
ensure the safety 
of subjects.   
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E7438-J081-106 (EZH-106) 
 
 
Date:  18 Oct 2018 
Confidential 
Page 5 of 5 
 
Protocol 
Pages 
Protocol V4.0, 23 Mar 2018 
Protocol V5.0, 18 Oct 2018 
Rationale 
49 
9.5.4.3.2 
Reporting Of Study-Specific Events 
Occurrence of lymphoblastic lymphoma/T-ALL and 
abnormal bone formation will be considered events of 
interest for this study.  These events should be directly 
reported to the sponsor or by fax with completed SAE 
report as soon as the investigator becomes aware of the 
event.  The faxed report should be followed up by the 
original SAE report.  Study-specific events must be 
followed to resolution or, if resolution is unlikely, to 
stabilization.  Study-specific events should be 
considered as serious only if the events meet the 
serious criteria.  These events should be entered on the 
CRF even if the events do not meet serious criteria.   
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 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.  Events of interest 
should be considered as serious only if the events meet 
the serious criteria.  These events should be entered on 
the CRF even if the events do not meet serious criteria.   
Updated based on 
the latest protocol 
text provided by 
Epizyme to 
ensure the safety 
of subjects.   
 
Page 92 of 167


Page 93 of 167
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SAP_001.pdf: 
Statistical Analysis Plan 
E7438-J081-106(EZH-106) 
 
 
Eisai 
Version 2.0:  18 JUL 2019 
Confidential 
Page 1 of 25 
 
 
STATISTICAL ANALYSIS PLAN 
Study Protocol 
Number: 
E7438-J081-106(EZH-106) 
Study Protocol 
Title: 
A Phase 1 Study of Tazemetostat in Patients With Relapsed or 
Refractory B-cell Non-Hodgkin’s Lymphoma  
 
Date: 
18 JUL 2019 
Version: 
Version 2.0 
 


Statistical Analysis Plan 
E7438-J081°106(EZH-106) 
SIGNATURE PAGE 
Author: 
2...:~ )vl "ol~ 
Date 
Medicine Development Center, · 
Eisai Co., Ltd. 
Approval: 
2) JLA-l 26( ~ 
Date 
Medicine Development Center, 
Eisai Co., Ltd. 
2~ 1~1 
z_ o I q 
Date 
Oncology Business Group 
Eisai Co., Ltd. 
23 J~I 
2- 019 
Date 
Medicine Development Center, 
Eisai Co., Ltd. 
. 
Eisai 
Confidential 
Page 2 of25 
Version 2.0: 18 JUL 2019 
PPD
PPD
PPD
PPD


Statistical Analysis Plan 
E7438-J081-106(EZH-106) 
 
 
Eisai 
Version 2.0:  18 JUL 2019 
Confidential 
Page 3 of 25 
 
1 TABLE OF CONTENTS 
1 
TABLE OF CONTENTS ...................................................................................................3 
2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................5 
3 
INTRODUCTION .............................................................................................................7 
3.1 
Study Objectives ......................................................................................................7 
3.1.1 
Primary Objective ..........................................................................................7 
3.1.2 
Secondary Objectives.....................................................................................7 
3.1.3 
Exploratory Objectives ..................................................................................7 
3.2 
Overall Study Design and Plan ................................................................................7 
4 
DETERMINATION OF SAMPLE SIZE ..........................................................................9 
5 
STATISTICAL METHODS ..............................................................................................9 
5.1 
Study Endpoints .......................................................................................................9 
5.1.1 
Primary Endpoint ...........................................................................................9 
5.1.2 
Secondary Endpoints .....................................................................................9 
5.1.2.1 
Pharmacokinetic (PK) Endpoints ....................................................9 
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 .....................................12 
5.4 
Efficacy Analyses ..................................................................................................12 
5.5 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Analyses ...............................................................................................13 
5.5.1 
Pharmacokinetic Analyses ...........................................................................13 
5.5.1.1 
Plasma Concentration and its PK Parameter Analysis .............13 
5.5.1.2 
Urine Concentration and its PK Parameter Analysis .................14 
5.5.1.3 
Pharmacokinetic Data Figures ......................................................14 
5.5.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses ....15 
5.5.3 
Pharmacokinetic/Pharmacodynamic Analyses ....................................15 
5.6 
Safety Analyses ......................................................................................................15 


Statistical Analysis Plan 
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5.6.1 
Extent of Exposure .......................................................................................15 
5.6.2 
Dose Limiting Toxicities .............................................................................15 
5.6.3 
Adverse Events ............................................................................................15 
5.6.4 
Laboratory Values ........................................................................................16 
5.6.5 
Vital Signs ....................................................................................................17 
5.6.6 
Electrocardiograms ......................................................................................17 
5.6.7 
Other Safety Analyses..................................................................................18 
5.7 
Exploratory Analyses .............................................................................................18 
6 
INTERIM ANALYSES ...................................................................................................18 
7 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING...............................18 
7.1 
PHARMACOKINETIC DATA HANDLING .......................................................18 
7.1.1 
Lower Limit of Quantification of tazemetostat and ER-897387 Plasma 
Concentration ...............................................................................................18 
7.1.2 
BLQ Handling for Calculation of PK Parameters .................................18 
8 
CHANGES IN THE PLANNED ANALYSES ...............................................................18 
8.1.1 
BLQ Handling for Developing Concentration-Time Profiles ...............19 
8.1.2 
Handling of Anomalous Concentration Values .....................................19 
8.1.3 
General Rules for Presentation of Drug Concentrations and PK 
Parameters .................................................................................................19 
8.2 
OTHER DATA HANDLING ................................................................................20 
9 
PROGRAMMING SPECIFICATIONS ..........................................................................21 
10 STATISTICAL SOFTWARE ..........................................................................................21 
11 MOCK TABLES, LISTINGS, AND GRAPHS ..............................................................21 
12 REFERENCES ................................................................................................................21 
13 APPENDICES .................................................................................................................22 
13.1 
Table For CTCAE version 4.03 .............................................................................22 
 


Statistical Analysis Plan 
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2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation 
Term 
AE 
adverse event 
Ae 
amount of unchanged drug excreted in urine 
AUC(0-12h) 
area under the concentration–time curve 
from zero time to 12 h 
AUC(0-t) 
area under the concentration–time curve 
from zero time to time of last quantifiable 
concentration 
AUC(0-τ) 
area under the concentration–time curve 
over the dosing interval on multiple dosing 
AUC(0-inf) 
area under the concentration–time curve 
from zero time extrapolated to infinite time 
BID 
twice daily 
BOR 
best overall response 
CI 
confidence interval 
CL/F 
apparent total clearance following oral 
administration 
CLR 
renal clearance 
CLss/F 
apparent total clearance following oral 
administration at steady state 
Cmax 
maximum observed concentration 
 
 
CR 
complete response 
CRF 
case report form 
Css,av 
average steady state concentration 
Css,max 
maximum observed concentration at steady 
state 
Css,min 
minimum observed concentration at steady 
state 
CTCAE 
Common Terminology Criteria for Adverse 
Events  
CCI
CCI


Statistical Analysis Plan 
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DLBCL 
diffuse large B-cell lymphoma 
DLTs 
dose-limiting toxicities 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group  
 
  
Fe 
fraction of dose excreted in urine 
FL 
follicular lymphoma  
LVEF 
left ventricular ejection fraction  
λz 
terminal phase rate constant 
MRT 
mean residence time 
MUGA 
multigated acquisition  
MedDRA 
Medical Dictionary for Regulatory 
Activities 
NHL 
Non-Hodgkin’s lymphoma 
ORR 
objective response rate 
PK 
pharmacokinetic 
PR 
partial response  
PS 
Performance Status 
PT 
preferred term 
PTF 
peak–trough fluctuation 
QTcF 
QT interval corrected for heart rate using 
Fridericia’s formula  
Rac 
accumulation ratio 
Rss 
time and concentration dependency 
accumulation ratio 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SI 
Système International 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TEMAV 
treatment-emergent markedly abnormal 
laboratory value 
CCI
CCI


Statistical Analysis Plan 
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Confidential 
Page 7 of 25 
 
TLG 
tables, listings, and graphs 
tmax 
time at which the highest drug concentration 
occurs 
tss,max 
time at which the highest drug concentration 
occurs at steady state 
t½ 
terminal elimination phase half-life 
Vz/F 
apparent volume of distribution at terminal 
phase 
WHO DD 
World Health Organization Drug Dictionary 
 
3 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the procedures, the statistical 
methods and pharmacokinetics (PK) analysis methods that will be used to analyze and report 
results for Eisai Protocol E7438-J081-106. 
3.1 
Study Objectives 
3.1.1 
Primary Objective 
To assess the tolerability of tazemetostat in patients with B-cell non-Hodgkin’s lymphoma 
(NHL).  
 
3.1.2 
Secondary Objectives 
 (1)To assess the safety of tazemetostat.  
 (2)To assess the PK profile of tazemetostat.  
 (3)To assess the preliminary anti-tumor activity of tazemetostat. 
 
3.1.3 
Exploratory Objectives 
 
3.2 
Overall Study Design and Plan 
This is a multicenter, single-arm, phase 1 study to assess tolerability, safety, PK and 
preliminary anti-tumor activity of tazemetostat in patients with relapsed or refractory B-cell 
CCI


Statistical Analysis Plan 
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NHL.  
This study will be conducted in the following 4 phases: Pre-treatment Phase, Treatment 
Phase, Extension Phase, and Follow-up Phase.  
The Pre-treatment Phase will last no longer than 28 days and include a period to obtain 
informed consent, screening, enrollment and a baseline assessment. 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 continue to meet the inclusion criteria and does 
not meet the exclusion criteria before moving to the Treatment Phase.  
The Treatment Phase consists of Cycle 0 (4 days) for tazemetostat single-dose oral 
administration and Cycle 1 of 28 days for tazemetostat twice daily (BID) oral administration 
on a continuous basis.  
Considering visit schedule and safety, subjects will be hospitalized from Cycle 0/Day 1 
(C0D1) to Cycle 1/Day 15 (C1D15). Based on the thorough evaluation of the data obtained 
on C1D15 and all safety data available, the investigator or subinvestigator will determine 
whether subjects can be treated on an outpatient basis. When subjects are considered to 
require extended hospitalization to ensure subject safety, they will be hospitalized from 
C1D15 onwards.  
The Extension Phase consists of Cycle 2 of 28 days and later for tazemetostat BID oral 
administration on a continuous basis and lasts until discontinuation of study drug.  
Subjects will discontinue study drug at the time of disease progression, development of 
unacceptable toxicity, subject’s request to discontinue, withdrawal of consent, or study 
termination by 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.  
The starting dose of tazemetostat is 800 mg as a single dose (Cycle 0) and 800 mg BID as 
continuous dosing (Cycle 1 and later). Three subjects will be enrolled and ensure that 3 
subjects are evaluable for dose-limiting toxicities (DLTs) at the end of Cycle 1 of the cohort. 
When a DLT is observed in 0 or 1 of 3 subjects at a given dose level, 3 additional subjects 
would be treated at the same dose level. When 2 of 3 subjects at a given dose level 
experience DLTs, enrollment of additional subjects will be discussed jointly by the 
investigator and sponsor. The opinion of Independent Data Monitoring Advisor should be 
also obtained. When additional subjects are to be enrolled, they will be monitored 
individually. When no DLTs are observed, up to 3 additional subjects will be enrolled. When 
no additional subjects are accrued or 3 subjects in total experienced DLTs, the enrollment in 
the cohort will be discontinued and the lower dose level of tazemetostat cohort will be 
considered jointly by the investigator and sponsor. The opinion of Independent Data 
Monitoring Advisor can be obtained, if needed.  
If the subject is regarded as DLT non-evaluable (eg, early discontinuation due to non-DLT, 
medication compliance with < 75% in Cycle 1 as a result of the reason other than treatment 
related toxicity), another subject will be added for replacement. 


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4 
DETERMINATION OF SAMPLE SIZE 
The primary objective of this study is to investigate the tolerability of tazemetostat. Hence 
neither clinical hypothesis nor judgment criteria are set, the sample size is not based on 
statistical consideration. The sample size of 6 patients is considered adequate for the purpose 
to evaluate tolerability of each cohort.  
 
5 
STATISTICAL METHODS 
All descriptive statistics for continuous variables will be reported using mean, standard 
deviation, median, minimum and maximum.  Categorical variables will be summarized as 
number (percentage) of subjects. 
5.1 
Study Endpoints 
5.1.1 
Primary Endpoint 
• DLTs  
 
5.1.2 
Secondary Endpoints 
• Safety assessments (adverse events (AEs), clinical laboratory tests, vital signs, body 
weight, 12-lead electrocardiograms (ECGs), echocardiograms/ multigated acquisition  
(MUGA) scans to assess left ventricular ejection fraction (LVEF), Eastern Cooperative 
Oncology Group - Performance Status (ECOG-PS), and physical examinations)  
• PK parameters  
• Objective response rate (ORR) of best overall response (BOR)  
 
5.1.2.1 
Pharmacokinetic (PK) Endpoints 
PK parameters derived by non-compartmental analysis using plasma concentrations of 
tazemetostat and ER-897387 which include, but are not limited to, are shown as below: 
Cycle 0 Day 1: 
• maximum observed concentration (Cmax) 
• time at which the highest drug concentration occurs (tmax) 
• area under the concentration–time curve from zero time to 12 h (AUC(0-12h)) 
• area under the concentration–time curve from zero time to time of last quantifiable 
concentration (AUC(0-t))  
• area under the concentration–time curve from zero time extrapolated to infinite time 
(AUC(0-inf))  


Statistical Analysis Plan 
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• terminal phase rate constant (λz) 
• terminal elimination phase half-life (t½) 
• apparent total clearance following oral administration (CL/F) (tazemetostat only) 
• apparent volume of distribution at terminal phase (Vz/F) (tazemetostat only) 
• mean residence time (MRT) 
 
Cycle 1 Day 15: 
• area under the concentration–time curve over the dosing interval on multiple dosing 
(AUC(0-τ)) 
• average steady state concentration (Css,av) 
• maximum observed concentration at steady state (Css,max) 
• minimum observed concentration at steady state (Css,min) 
• peak–trough fluctuation (PTF) 
• time at which the highest drug concentration occurs at steady state (tss,max) 
• terminal elimination phase half-life (t½) 
• apparent total clearance following oral administration at steady state (CLss/F) 
(tazemetostat only) 
• apparent volume of distribution at terminal phase (Vz/F) (tazemetostat only) 
• accumulation ratio (Rac) 
 
 
Urine PK parameters will be calculated using urine concentrations of tazemetostat are shown 
as below: 
Cycle 0 Day 1 and Cycle 1 Day 15: 
• amount of unchanged drug excreted in urine (Ae) 
• fraction of dose excreted in urine (Fe) 
• renal clearance (CLR) 
 
5.1.3 
Exploratory Endpoints  
CCI


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5.2 
Study Subjects 
5.2.1 
Definitions of Analysis Sets 
DLT Analysis Set will include all subjects who have completed treatment Cycle 0 and 1 
without major protocol deviations with at least 75% of treatment compliance in Cycle 1 and 
were assessed for DLT, and subjects who have experienced DLT during Cycle 0 and 1. 
Subjects with less than 75% treatment compliance in Cycle 1 due to a reason other than 
toxicity up to Cycle 1/Day 28 will not be included in this analysis set. 
Safety/Efficacy Analysis Set will include all subjects who received at least 1 administration 
of the study drug. This will be the analysis set for all safety and efficacy evaluations, as well 
as for demographic and baseline characteristics.  
Pharmacokinetic Analysis Set will include all subjects who have received at least 1 
administration of the study drug and had sufficient PK data to derive at least 1 PK parameter. 
 
5.2.2 
Subject Disposition 
Subjects who signed informed consent, were registered in the study, and failed screening 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. 
 
5.2.3 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics for the Safety/Efficacy Analysis Set will be 
summarized in whole or each disease (DLBCL, follicular lymphoma (FL)). Continuous 
demographic and baseline variables include age, height, and body weight; categorical variables 
include sex, age group (<65, 65<=), race, ethnicity, ECOG-PS, Ann Arbor Staging at 
Screening, prior therapies for primary disease (chemotherapy, radiotherapy, Autologous Stem-
Cell Transplantation and other therapies), B Symptoms and Disease diagnosis (DLBCL, FL). 
 
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 
All investigator terms for medications recorded in the case report form (CRF) will be coded to 
an 11-digit code using the World Health Organization Drug Dictionary (WHO DD) 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 


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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 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 
All efficacy analyses will be conducted in whole or each disease (DLBCL, FL). 
 
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 
BOR will be summarized in whole or each disease (DLBCL, FL). The assessment of the 
ORR (complete response (CR) + partial response (PR)) in subjects with B cell lymphomas 
will be based on “The Lugano Classification (CT-Based Response)” (Cheson, et al., 2014) 
response criteria.  
ORR will be presented with corresponding 2-sided Clopper–Pearson exact 95% confidence 
intervals (CIs). This analysis will be performed on the Efficacy Analysis Set. If applicable, a 
waterfall plot will be presented for the percent changes from baseline in the sum of the 
diameters of target lesions at post-baseline nadir. 


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5.5 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses 
5.5.1 
Pharmacokinetic Analyses 
The Safety Analysis Set will be used for individual listings of tazemetostat and its metabolite 
(ER-897387) plasma concentrations and urine tazemetostat concentrations.  The PK Analysis 
Set will be used for the summaries of tazemetostat and ER-897387 plasma concentrations 
and urine tazemetostat concentrations and for summaries and listings of PK parameters. 
When necessary, molecular weight (free base) 572.74 for the parent and 544.68 for ER-
897387 will be used.  The data in patient with dose-reduction/interruption will not be 
included on calculation of summary statistics. 
5.5.1.1 
Plasma Concentration and its PK Parameter Analysis 
<Plasma Concentration> 
Plasma concentrations for tazemetostat and ER-897387 will be summarized using summary 
statistics (n, mean, standard deviation [SD], median, minimum, and maximum) by nominal 
time points. 
Plasma concentrations of tazemetostat and ER-897387 will be listed for each subject by 
nominal time points with actual sampling time. 
<Plasma PK Parameter> 
PK parameters will be derived by noncompartmental analysis using Phoenix WinNonlin 
software (version 6.2.1 or later) according to Eisai Non-compartmental Pharmacokinetic 
Analysis Manual (302-104.00-MNL) (NCA-MNL, hereafter). 
The following PK parameters for tazemetostat and ER-897387 will be calculated.  
After Cycle 0 Day 1 dosing (single dosing)  
Cmax, tmax, AUC(0-12h), AUC(0-t), AUC(0-inf), λz, t½, MRT, metabolite to parent AUC(0-inf) ratio 
with and without molecular weight correction 
The following PK parameters will be calculated for tazemetostat only: CL/F and Vz/F. 
After Cycle 1 Day 15 dosing (multiple dosing) 
Css,max, Css,min, tss,max, Css,av, AUC(0-τ), AUC(0-t), t½, λz, MRT, PTF, Rac(Cmax), Rac(AUC), Rss, 
and metabolite to parent AUC(0-t) ratio with and without molecular weight correction 
The following PK parameters will be calculated for tazemetostat only: CLss/F and Vz/F. 
Other PK parameters may be calculated as appropriate. 


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Summary statistics will be tabulated for the PK parameters of tazemetostat and ER-897387.  
Summary statistics (n, mean, SD, median, minimum and maximum) will be presented for all 
parameters (apart from tmax and tss,max where mean and SD are not required).  In addition, 
geometric mean and %CV will also be presented for all parameters apart from tmax and tss,max.  
PK parameters of tazemetostat and ER-897387 for each subject will be listed. 
5.5.1.2 
Urine Concentration and its PK Parameter Analysis 
Urine volume and urinary concentrations of tazemetostat will be listed for each subject by 
nominal collection periods. 
The following urinary PK parameters will be derived by SAS and/or Phoenix WinNonlin 
according to NCA-MNL. 
After Cycle 0 Day 1 dosing and Cycle 1 Day 15 dosing 
• Amount of tazemetostat recovered in urine (Ae(t1-t2)) by each collection interval 
• Cumulative amount of tazemetostat excreted in urine through total collection period (Ae) 
• Cumulative fraction of dose excreted in urine until end of collection interval 
• Renal clearance (CLR) [CLR will be obtained as CLR = Ae(0-t)/AUC(0-t)] 
 
Summary statistics (n, mean, SD, median, minimum and maximum) will be tabulated for the 
Ae(t1-t2) and urinary PK parameters of tazemetostat by collection period. 
Urinary PK parameters of tazemetostat for each subject will be listed.   
5.5.1.3 
Pharmacokinetic Data Figures 
The mean plasma concentrations of tazemetostat and ER-897387 after Cycle 0 Day 1 dosing 
and Cycle 1 Day 15 dosing will be displayed on one figure in linear scale and semi-log scale 
using nominal time with SD (tazemetostat and ER-897387, respectively). 
The mean plasma concentrations of tazemetostat and ER-897387 will be displayed 
respectively on one figure in linear scale and semi-log scale using nominal time with SD 
after Cycle 0 Day 1 dosing and Cycle 1 Day 15 dosing, after Cycle 0 Day 1, and after Cycle 
1 Day 15 respectively. 
The individual and mean plasma trough concentrations (Cycle 1 Day 3, Cycle 1 Day 8, Cycle 
1 Day 15, Cycle 1 Day 22, and Cycle 2 Day 1) and concentrations of 12 h after dosing (Cycle 
0 Day 1 and Cycle 1 Day 15) of tazemetostat will be displayed using the nominal day in linear 
scale. 


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Individual plasma concentration of tazemetostat or ER-897387 for all subjects after Cycle 0 
Day 1 dosing or Cycle 1 Day 15 dosing will be displayed on the same figure in linear and 
semi-log scale using actual time respectively. 
Plasma concentration of tazemetostat and ER-897387 after Cycle 0 Day 1 and Cycle 1 Day 
15 dosing, after Cycle 0 Day 1, or Cycle 1 Day 15 dosing will be displayed on one figure for 
each subject in linear and semi-log scale using actual time respectively. 
 
5.5.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses 
 
5.5.3 
Pharmacokinetic/Pharmacodynamic Analyses 
Not applicable  
 
5.6 
Safety Analyses 
All tolerability analyses will be performed on the DLT Analysis Set. The Safety Analysis Set 
will be used for all other safety analyses. 
 
5.6.1 
Extent of Exposure 
The number of cycles/days on treatment, quantity of study drug administered will be 
summarized. Number of subjects with dose reductions and dose interruptions will be 
summarized. 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 
Dose Limiting Toxicities 
For the analysis set for DLT evaluation, The number and percentage of subjects with DLT 
will be calculated. DLT will also be summarized by Medical Dictionary for Regulatory 
Activities (MedDRA) preferred term (PT). 
 
5.6.3 
Adverse Events 
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using the MedDRA. Adverse events will be coded to the 
CCI


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MedDRA lower level term (LLT) closest to the verbatim term. The linked MedDRA 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 time 
from the first dose of study drug to 37 days after the subject’s last dose,, having been absent 
at pretreatment (Baseline) or  
• Reemerges during treatment, having been present at pretreatment (Baseline) but stopped 
before treatment, or  
• Worsens in severity during treatment relative to the pretreatment state, when the AE is 
continuous. 
Only those AEs that are treatment-emergent will be included in summary tables. All AEs, 
treatment-emergent or otherwise, will be presented in subject data listings.  
 
The TEAEs will be summarized. The 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 Common 
Terminology Criteria for Adverse Events (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 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. 
The number (percentage) of subjects with TEAEs and treatment-related TEAEs will be 
summarized by SOC, PT and CTCAE Grade in Decreasing Frequency. 
 
5.6.4 
Laboratory Values 
Laboratory results will be summarized using Système International (SI) units, as appropriate. 
For all quantitative parameters listed in Section 9.5.1.5.3 Safety Assessments (Laboratory 
Measurements), 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 listed in Section 9.5.1.5.3 will be summarized using frequencies (number and 
percentage of subjects), and changes from baseline to each postbaseline visit and 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). Except for phosphate, a TEMAV is defined as a post baseline 


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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 bystudy overall. 
The following combination of abnormal laboratory tests will be presented in listing. 
•  Elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal   
AND 
• Elevated total bilirubin lab value that is greater than or equal to 2X the upper limit of 
normal   
AND AT THE SAME TIME  
• Alkaline phosphatase lab value that is less than 2X the upper limit of normal 
 
The measured values for quantitative data will be displayed over time using Box plot. 
  
5.6.5 
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. 
The measured values will be displayed over time using Box plot. 
 
5.6.6 
Electrocardiograms 
ECG assessments were performed at each visit. Descriptive statistics for ECG parameters and 
changes from baseline will be presented by visit.  
Shift tables will present changes from baseline in ECG parameters and ECG findings.  
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: 
Absolute QTcF interval prolongation:  
• QTcF interval >450 ms  
• QTcF interval >480 ms  
• QTcF interval >500 ms  
 
Change from baseline in QTcF interval:  
• QTcF interval increases from baseline >30 ms  
• QTcF interval increases from baseline >60 ms  


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5.6.7 
Other Safety Analyses 
Descriptive statistics for LVEF and LVEF changes from baseline using MUGA scans or 
echocardiograms will be calculated.  
ECOG-PS will be summarized by scale at each visit and by highest postbaseline scale. 
 
5.7 
Exploratory Analyses 
No exploratory analyses are planned for this study. 
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 analysis is planned for this study. 
 
7 
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. 
 
7.1 
PHARMACOKINETIC DATA HANDLING 
7.1.1 
  Lower Limit of Quantification of tazemetostat and ER-897387 Plasma 
Concentration 
The LLOQ of tazemetostat and ER-897387 plasma concentration is 1.00 ng/mL.  
The LLOQ of tazemetostat urine concentration is 1.00 ng/mL.  
7.1.2 
BLQ Handling for Calculation of PK Parameters 
While calculating PK parameters in WinNonlin, BLQ values will be handled according to the 
NCA-MNL.  
8 
CHANGES IN THE PLANNED ANALYSES 
Changes in the planned analyses for protocol are as follows: 
• Extent of Exposure 


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• Swimmer plot will be created. 
• Number of subjects with drug withdraw will not be summarized. 
• Listing for the combination of abnormal laboratory tests will be created. 
 
• PK parameter 
• Calculation and summarization of “Ae and Fe until end of each collection interval” has 
been deleted.  
• PK parameter name ‘AUC(0-12h)’ was revised to ‘AUC(0-τ)’ for Cycle 1 Day 15. 
• The calculation of metabolite to parent AUC ratio with and without molecular weight 
correction was changed from using AUC(0-12h) to using AUC(0-t). 
 
8.1.1 
BLQ Handling for Developing Concentration-Time Profiles 
When developing individual concentration-time profiles, BLQ values will be handled 
according to the NCA-MNL.  
8.1.2 
Handling of Anomalous Concentration Values 
The handling of anomalous concentration values will follow the guidance in the NCA-MNL. 
8.1.3 
General Rules for Presentation of Drug Concentrations and PK Parameters 
When presenting individual/raw (raw, hereafter) values and summary statistics, the following 
rule will be applied: for drug concentrations and concentration-dependent pharmacokinetic 
parameters, all summary statistics (mean, median, geometric mean, SD, and CV) will have 3 
significant digits.  For tmax and tss,max, raw values and median have fixed 2 decimal places. 
Typical variable 
Standard 
Unit 
N 
Digit rule 
Raw 
Minimum 
Maximum 
Mean 
Median 
S
D 
Geometric  
Mean 
CV 
(%) 
tazemetostat and 
ER-897387 
concentration 
ng/mL 
X 
Significant digits 
3 
3 
3 
- 
- 
Cmax, Css,max, 
Css,min, Css,av  
ng/mL 
X 
Significant digits 
3 
3 
3 
3 
3 
tmax, tss,maxa 
h 
X 
Fixed decimal 
places 
2 
2 
- 
- 
- 
λz 
1/h 
X 
Significant digits 
3 
3 
3 
3 
3 
t1/2 
h 
X 
Significant digits 
3 
3 
3 
3 
3 
AUC 
ng·h/mL 
X 
Significant digits 
3 
3 
3 
3 
3 
%AUCex 
% 
X 
Significant digits 
3 
- 
- 
- 
- 


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Typical variable 
Standard 
Unit 
N 
Digit rule 
Raw 
Minimum 
Maximum 
Mean 
Median 
S
D 
Geometric  
Mean 
CV 
(%) 
CL/F, CLss/F 
L/h 
X 
Significant digits 
3 
3 
3 
3 
3 
Vｚ/F 
L 
X 
Significant digits 
3 
3 
3 
3 
3 
MRT 
h 
X 
Significant digits 
3 
3 
3 
3 
3 
AUC ratio 
% 
X 
Significant digits 
3 
3 
3 
3 
3 
Rac, Rss 
– 
X 
Significant digits 
3 
3 
3 
3 
3 
PTF 
% 
X 
Significant digits 
3 
3 
3 
3 
3 
Ae 
mg 
X 
Significant digits 
3 
3 
3 
3 
3 
Fe 
% 
X 
Significant digits 
3 
3 
3 
3 
3 
CLR 
L/h 
X 
Significant digits 
3 
3 
3 
3 
3 
a:  Mean, SD, geometric mean and CV will not be calculated for tmax and tss,max. 
CV(%) = sqrt(exp[SD2 of log transformed data]-1)×100 
NOTE 
The following parameters are reported in the CSR, but appear in Listings only.  They are 
important information to confirm that individual t1/2 and its related parameters such as 
AUC(0-inf) are appropriately derived and allow those PK parameters to be reproduced when 
necessary. 
a. Time points used for estimation of λz (lower and upper) 
b. Number of the time points used for λz 
c. Adjusted regression coefficient (R2adj) 
d. Percentage of AUC(0-inf) obtained by extrapolation (%AUCex) 
In Listings, a) are shown in same digits as actual sampling time after dosing used for 
calculation of PK parameters.  For b), integer number is used in Listings.  For c) and d), 
significant 3 digits are used in Listing. 
 
8.2 
OTHER DATA HANDLING 
Baseline 
Baseline is defined as the last non-missing value observed prior to the first dose of study 
drug for a given parameter. For any Baseline value of 0, the subject’s corresponding 
Percent Change from Baseline will not be included in the summary statistics tables. 
Handling of Missing data 
No imputation will be performed for missing data. 


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9 
PROGRAMMING SPECIFICATIONS 
The rules for programming derivations and dataset specifications are provided in separate 
documents. 
10 STATISTICAL SOFTWARE 
PK Analysis will be performed using SAS for Windows (ver.9.2 or later), WinNonlin (version 
7.0 or later), Microsoft Excel (97 or later) and S-PLUS (6.1J or later for Windows).  
Statistical analyses and summaries will be performed by Takumi Information Technology 
using SAS for Windows (ver.9.2 or later), and Microsoft Excel (2003 or later). Analyses will 
be conducted by using validated standard programs or double programming. For analyses 
needed in data review, single programming will be used.  
 
11 MOCK TABLES, LISTINGS, AND GRAPHS 
The study tables, listings, and graphs (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 Table For CTCAE version 4.03   
Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0  
Published: May 28, 2009 (v4.03: June 14, 2010) 
Adverse event 
Grade 
1 
2 
3 
4 
5 
Blood and lymphatic system disorders 
Anemia 
Hemoglobin 
(Hgb) <LLN - 
10.0 g/dL;  
<LLN - 6.2 
mmol/L; 
<LLN - 100 g/L 
Hgb <10.0 - 8.0 
g/dL; 
<6.2 - 4.9 
mmol/L;  
<100 - 80g/L 
Hgb <8.0 g/dL;  
<4.9 mmol/L; 
<80 g/L;  
transfusion 
indicated 
Life-
threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Leukocytosis 
- 
- 
＞100,000 
/mm3 
Clinical 
manifestations 
of leucostasis;  
urgent 
intervention 
indicated 
Death 
Investigations 
Alanine 
aminotransfera
se increased 
＞ULN - 3.0 × 
ULN 
＞3.0 - 5.0 × 
ULN 
＞5.0 - 20.0 × 
ULN 
＞20.0 × ULN 
- 
Alkaline 
phosphatase 
increased 
＞ULN - 2.5 × 
ULN 
＞2.5 - 5.0 × 
ULN 
＞5.0 - 20.0 × 
ULN 
＞20.0 × ULN 
- 
Aspartate 
aminotransfera
se increased 
＞ULN - 3.0 × 
ULN 
＞3.0 - 5.0 × 
ULN 
＞5.0 - 20.0 × 
ULN 
＞20.0 × ULN 
- 
Blood bilirubin 
increased 
＞ULN - 1.5 × 
ULN 
＞1.5 - 3.0 × 
ULN 
＞3.0 - 10.0 × 
ULN 
＞10.0 × ULN 
- 
Cholesterol 
high 
＞ULN - 300 
mg/dL; 
＞ULN - 7.75 
mmol/L 
＞300 - 400 
mg/dL; 
＞7.75 - 10.34 
mmol/L 
＞400 - 500 
mg/dL; 
＞10.34 - 12.92 
mmol/L 
＞500 mg/dL; 
＞12.92 
mmol/L 
- 
Creatinine 
increased 
＞1 - 1.5 × 
baseline;      
＞ULN - 1.5 × 
ULN 
＞1.5 - 3.0 × 
baseline; 
＞1.5 - 3.0 × 
ULN 
＞3.0 × 
baseline; 
＞3.0 - 6.0 × 
ULN 
＞6.0 × ULN 
- 
Hemoglobin 
increased 
Increase in >0 - 
2 gm/dL above 
ULN or above 
baseline if 
Increase in >2 - 
4 gm/dL above 
ULN or above 
baseline if 
Increase in >4 
gm/dL above 
ULN or above 
baseline if 
- 
- 


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baseline is 
above ULN 
baseline is 
above ULN 
baseline is 
above ULN 
INR increased 
>1 - 1.5 x ULN; 
>1 - 1.5 times 
above baseline 
if on 
anticoagulation 
>1.5 - 2.5 x 
ULN; >1.5 - 2.5 
times above 
baseline if on 
anticoagulation 
>2.5 x ULN; 
>2.5 times 
above baseline 
if on 
anticoagulation 
- 
- 
Lipase 
increased 
 
＞ULN - 1.5 × 
ULN 
＞1.5 - 2.0 × 
ULN 
＞2.0 - 5.0 × 
ULN 
＞5.0 × ULN 
- 
Lymphocyte 
count 
decreased 
＜LLN - 
800/mm3;  
＜LLN - 0.8 × 
10e9 /L 
＜800 - 
500/mm3;  
＜0.8 - 0.5 × 
10e9 /L 
＜500 - 
200/mm3;  
＜0.5 - 0.2 × 
10e9 /L 
＜200/mm3;  
＜0.2 × 10e9 /L 
- 
Lymphocyte 
count increased 
- 
＞4,000 - 
20,000/mm3 
＞20,000/mm3 
- 
- 
Neutrophil 
count 
decreased 
＜LLN - 
1,500/mm3;  
＜LLN – 1.5 × 
10e9 /L 
＜1,500 - 
1,000/mm3;  
＜1.5 - 1.0 × 
10e9 /L 
＜1,000 - 
500/mm3;  
＜1.0 - 0.5 × 
10e9 /L 
＜500/mm3;  
＜0.5 × 10e9 /L 
- 
Platelet count 
decreased 
＜LLN - 
75,000/mm3; 
＜LLN - 75.0 × 
10e9 /L 
＜75,000 - 
50,000/mm3; 
＜75.0 - 50.0 × 
10e9 /L 
＜50,000 - 
25,000/mm3; 
＜50.0 - 25.0 × 
10e9 /L 
＜25,000/mm3; 
＜25.0 × 10e9 
/L 
- 
Serum amylase 
increased 
＞ULN - 1.5 × 
ULN 
＞1.5 - 2.0 × 
ULN 
＞2.0 - 5.0 × 
ULN 
＞5.0 × ULN 
- 
White blood cell 
decreased 
＜LLN - 
3,000/mm3;  
＜LLN - 3.0 × 
10e9 /L 
＜3,000 - 
2,000/mm3;  
＜3.0 - 2.0 × 
10e9 /L 
＜2,000 －
1,000/mm3; ＜
2.0 - 1.0 × 
10e9 /L 
＜1,000/mm3;  
＜1.0 × 10e9 /L 
- 
CPK increased 
>ULN - 2.5 x 
ULN 
>2.5 x ULN - 5 
x ULN 
>5 x ULN - 10 
x ULN 
>10 x ULN 
- 
Metabolism and nutrition disorders 
Hypercalcemia 
Corrected 
serum calcium 
of 
>ULN - 11.5 
mg/dL;  
>ULN - 2.9 
mmol/L; 
Ionized calcium 
>ULN 
- 1.5 mmol/L 
Corrected 
serum calcium 
of 
>11.5 - 12.5 
mg/dL;  
>2.9 - 3.1 
mmol/L;  
Ionized calcium 
>1.5 - 1.6 
mmol/L;  
symptomatic 
Corrected 
serum calcium 
of 
>12.5 - 13.5 
mg/dL;  
>3.1 - 3.4 
mmol/L; 
Ionized calcium 
>1.6 - 1.8 
mmol/L; 
hospitalization 
indicated 
Corrected 
serum calcium 
of 
>13.5 mg/dL;  
>3.4 mmol/L; 
Ionized calcium 
>1.8 mmol/L; 
life-threatening 
consequences 
Death 
Hyperglycemia 
 
Fasting 
glucose value 
Fasting 
glucose value 
>250 - 500 
mg/dL;  
>500 mg/dL;  
>27.8 mmol/L; 
Death 


Statistical Analysis Plan 
E7438-J081-106(EZH-106) 
 
 
Eisai 
Version 2.0:  18 JUL 2019 
Confidential 
Page 24 of 25 
 
 
 
 
>ULN - 160 
mg/dL; 
Fasting 
glucose value 
>ULN - 8.9 
mmol/L 
>160 - 250 
mg/dL;  
Fasting 
glucose value 
>8.9 - 13.9 
mmol/L 
>13.9 - 27.8 
mmol/L; 
hospitalization 
indicated 
Lifethreatening 
consequences 
Hyperkalemia 
 
 
 
＞ULN - 5.5 
mmol/L 
＞5.5 - 6.0 
mmol/L 
>6.0 - 7.0 
mmol/L; 
hospitalization 
indicated 
>7.0 mmol/L; 
life-threatening 
consequences 
Death 
Hypernatremia 
＞ULN - 150 
mmol/L 
＞150 - 155 
mmol/L 
>155 - 160 
mmol/L; 
hospitalization 
indicated 
>160 mmol/L; 
life-threatening 
consequences 
Death 
Hypertriglycerid
emia 
 
 
 
 
150 mg/dL - 
300 mg/dL;  
1.71 mmol/L - 
3.42 mmol/L 
>300 mg/dL – 
500 mg/dL;  
>3.42 mmol/L - 
5.7 mmol/L 
>500 mg/dL - 
1000 mg/dL; 
>5.7 mmol/L - 
11.4 mmol/L 
>1000 mg/dL;  
>11.4 mmol/L; 
life-threatening 
consequences 
Death 
Hypoalbumine
mia 
 
 
 
 
＜LLN - 3 g/dL;  
＜LLN - 30 g/L 
＜3 - 2 g/dL;  
＜30 - 20 g/L 
＜2 g/dL;  
＜20 g/L 
Life-
threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Hypocalcemia 
 
 
 
 
 
 
 
Corrected 
serum calcium 
of <LLN - 8.0 
mg/dL;  
<LLN - 2.0 
mmol/L; 
Ionized calcium 
<LLN - 
1.0 mmol/L 
Corrected 
serum calcium 
of <8.0 - 7.0 
mg/dL;  
<2.0 - 1.75 
mmol/L; 
Ionized calcium 
<1.0 - 
0.9 mmol/L;  
symptomatic 
Corrected 
serum calcium 
of <7.0 - 6.0 
mg/dL;  
<1.75 - 1.5 
mmol/L; 
Ionized calcium 
<0.9 - 
0.8 mmol/L; 
Hospitalization 
indicated 
Corrected 
serum calcium 
of <6.0 mg/dL; 
<1.5 mmol/L; 
Ionized calcium 
<0.8 mmol/L; 
life-threatening 
consequences 
Death 
Hypoglycemia 
＜LLN - 55 
mg/dL;  
＜LLN - 3.0 
mmol/L 
＜55 - 40 
mg/dL; 
＜3.0 - 2.2 
mmol/L 
＜40 - 30 
mg/dL;  
＜2.2 - 1.7 
mmol/L 
＜30 mg/dL;  
＜1.7 mmol/L;  
lifethreatening 
consequences; 
seizures 
Death 
Hypokalemia 
＜LLN - 3.0 
mmol/L 
NA 
indicated 
＜3.0 - 2.5 
mmol/L; 
＜2.5 mmol/L; 
 
Death 


Statistical Analysis Plan 
E7438-J081-106(EZH-106) 
 
 
Eisai 
Version 2.0:  18 JUL 2019 
Confidential 
Page 25 of 25 
 
Hyponatremia 
 
 
 
＜LLN - 130 
mmol/L 
- 
＜130 - 120 
mmol/L 
＜120 mmol/L; 
life-threatening 
consequences 
Death 
Hyperuricemia 
>ULN - 10 
mg/dL (0.59 
mmol/L) 
NA 
-NA 
>10 mg/dL; 
>0.59 mmol/L 
Death 
Renal and urinary disorders 
Proteinuria 
1+ proteinuria; 
urinary protein 
<1.0 g/24 hrs 
Adults: 2+ 
proteinuria;  
urinary protein  
1.0 - 3.4 g/24 
hrs; 
Pediatric: urine 
P/C 
(Protein/Creati
nine) ratio 0.5 - 
1.9 
Adults: urinary 
protein >=3.5 
g/24 hrs; 
Pediatric: urine 
P/C >1.9 
- 
 -