Clinical trial NCT02860286
Conditions: Mesothelioma BAP1 Loss of Function
Sponsor: Epizyme, Inc.
Start date: 2016-07-01; Completion date: 2019-05-01
Enrollment: 74 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase 2, multicenter, open-label, 2-part, single-arm, 2-stage study of tazemetostat 800 mg two times a day (BID) administered orally. Screening of subjects to determine eligibility for the study will be performed within 21 days of the first planned dose of tazemetostat.

In Part 1: planned to enroll 12 subjects with relapsed or refractory malignant mesothelioma regardless of BAP1 status will be treated and undergo pharmacokinetics (PK) blood sample collection after a single tazemetostat 800 mg.

Part 2 plans to include 55 subjects with BAP1-deficient relapsed or refractory malignant mesothelioma.

Treatment with tazemetostat will continue until disease progression, unacceptable toxicity or withdrawal of consent, or termination of the study. Response assessment will be evaluated after 6 weeks of treatment and then every 12 weeks thereafter while on study.

Detailed description:

Arms: arm 1: Oral Tazemetostat 800mg BID
Interventions: intervention 1: Tazemetostat
Intervention descriptions: intervention 1: Tazemetostat (EPZ-6438) is a selective small molecule inhibitor of the histone-lysine methyltransferase EZH2 gene.

Protocol documents:
Prot_SAP_000.pdf: 
Epizyme, Inc. 
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NCT02860286 
Protocol Number: EZH-203 
Protocol Title: A Phase 2, Multicenter Study of the EZH2 Inhibitor Tazemetostat in Adult 
Subjects with Relapsed or Refractory Malignant Mesothelioma with BAP1 Loss of Function 
NCT Number: NCT02860286  
Protocol Amendment 3 Final: 27 November 2017 


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SPONSOR PROTOCOL APPROVAL PAGE 
Protocol Title: 
A Phase 2, Multicenter Study of the EZH2 Inhibitor Tazemetostat in Adult 
Subjects with Relapsed or Refractory Malignant Mesothelioma with BAP1 
Loss of Function 
Protocol 
Number: 
EZH-203 
Approved by: 
Responsible Sponsor Medical Officer: 
Signature: 
__________________________________________ Date: ________________ 
Peter Ho, MD, PhD 
Chief Medical Officer 
Epizyme, Inc. 
Responsible Sponsor Medical Monitor: 
Signature: 
__________________________________________ Date: ________________ 
Maria Roche, NP 
Medical Director, Clinical Research 
Epizyme, Inc. 
Version 1: 15 March 2016 
Amendment 1: 25 April 2016 
Amendment 2:  Final, 13 April 2017 
Amendment 3:  Final, 27 November 2017 


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INVESTIGATOR AGREEMENT PAGE 
 
Protocol Title: A Phase 2, Multicenter Study of the EZH2 Inhibitor Tazemetostat in Adult 
Subjects with Relapsed or Refractory Malignant Mesothelioma with BAP1 
Loss of Function 
 
Protocol Number: 
EZH-203 
 
By signature below, I agree to comply with the contents of this protocol and to conduct this study 
in compliance with Good Clinical Practices (GCP) and all applicable requirements. 
I acknowledge that I am responsible for the overall study conduct and that I agree to personally 
conduct or supervise the described clinical study. 
I agree to ensure that all associates, colleagues, and employees assisting in the conduct of this 
study are informed about their obligations.  Mechanisms are in place to ensure that site staff 
receives the appropriate information and training throughout the conduct of the study. 
I have read and agree to the following Confidentiality Statement: 
Confidentiality Statement:  This protocol and any related documents from Epizyme, Inc., 
contain privileged information that is confidential and may not be disclosed unless such 
disclosure is required by federal laws or regulations.  In any event, persons to whom the 
information is disclosed must be informed that it is privileged and/or confidential and may 
not be further disclosed by them.  Information from this study may not be reproduced in any 
form without the written permission of Epizyme, Inc.  
 
Principal Investigator: 
 
Name: _____________________________________________________________________ 
 
Title: ______________________________________________________________________ 
 
 
Signature: __________________________________________ 
Date: ________________ 
 
Name/Address of Institution: __________________________________________________ 
___________________________________________________________________________ 


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CLINICAL STUDY PROTOCOL 
 
Protocol title: 
A Phase 2, Multicenter Study of the EZH2 Inhibitor Tazemetostat in 
Adult Subjects with Relapsed or Refractory Malignant 
Mesothelioma with BAP1 Loss of Function 
Compound name (Number): 
Tazemetostat (EPZ-6438) 
Protocol number: 
EZH-203 
Effective date: 
27 November 2017 
IND number: 
129424 
EudraCT number: 
2016‐001139‐10 
Sponsor: 
Epizyme, Inc. 
400 Technology Square, 4th Floor 
Cambridge, MA  02139 USA 
Sponsor medical monitor: 
Maria Roche, NP 
Epizyme, Inc. 
400 Technology Square, 4th Floor 
Cambridge, MA  02139 USA 
Phone:  (617) 875-1329 
Fax:  
(617) 902-2645 
Global medical monitor: 
Franklin O. Smith, MD 
Medpace Inc. 
5375 Medpace Way 
Cincinnati, OH  45227 USA 
Phone:   (513) 579-9911, Ext. 2087 
Mobile:  (513) 659-8298       
Fax:  
(513) 579-0444      
Email:   f.smith@medpace.com 
SAE Hotline for North 
American: 
 
Phone:  +1-800-730-5779, ext. 2999 OR  
 
+1-513-579-9911, ext. 2999 
Fax:  
+1-866-336-5320 OR +1-513-579-0444 
Email:  medpace-safetynotification@medpace.com 
SAE Hotline for EU sites only: 
 
Phone:  +49 89 89 55 718 44 
Fax:  
+49 89 89 55 718 104 
Email:  medpace-safetynotification@medpace.com 
This protocol has been designed in accordance with the general ethical principles outlined in the Declaration of Helsinki.  The 
review of this protocol by an Institutional Review Board or Ethics Committee and the performance of all aspects of the study, 
including the methods used to obtain informed consent, must also be in accordance with the principles enunciated in the 
declaration, ICH E6 (R1) guidelines of Good Clinical Practice, US FDA CFR Part 50 Protection of Human Subjects and 21 CFR 
Part 56 Institutional Review Boards, and all applicable regulatory authority requirements. 
 


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1. 
SYNOPSIS 
Study title 
A Phase 2, Multicenter Study of the EZH2 Inhibitor Tazemetostat in Adult Subjects 
with Relapsed or Refractory Malignant Mesothelioma with BAP1 Loss of Function 
Clinical phase 
2 
Number of study 
centers 
6-10 centers in the US 
3-4 centers in each of France and the UK 
Investigational 
product 
Tazemetostat (EPZ-6438) 
Study objectives 
Primary objectives  
Part 1 (Pharmacokinetics) 
• 
To assess the pharmacokinetic (PK) and safety profile of single and repeated 
doses of 800 mg tazemetostat administered as 400 mg tablets in subjects with 
relapsed or refractory malignant mesothelioma regardless of BAP1 status  
Part 2 (Efficacy) 
• 
To assess disease control rate (DCR) at 12 weeks [consisting of complete 
response (CR), partial response (PR) or stable disease (SD)] according to 
modified RECIST [Nowak, 2005] for thoracic disease or RECIST 1.1 
elsewhere in subjects with relapsed or refractory BAP1-deficient malignant 
mesothelioma treated with tazemetostat 
 
Secondary objectives 
Parts 1 and 2 
• 
To assess the safety and tolerability of tazemetostat 
• 
To assess the overall response rate (ORR) in subjects with relapsed or 
refractory malignant mesothelioma treated with tazemetostat 
• 
To determine the progression-free survival (PFS) and overall survival (OS) at 
12 weeks, 24 weeks and overall in subjects with relapsed or refractory 
malignant mesothelioma treated with tazemetostat 
• 
 To evaluate the duration of response (DOR) in subjects with relapsed or 
refractory malignant mesothelioma achieving a CR or PR according to disease-
appropriate criteria treated with tazemetostat 
Part 1  
• 
To assess DCR at 12 weeks (consisting of CR, PR, and SD) in subjects with 
relapsed or refractory malignant mesothelioma treated with tazemetostat 
Part 2  
• 
To assess the population PK parameters of tazemetostat 
• 
To investigate the pharmacodynamic (PD) effects of tazemetostat in tumor 
tissue before and after treatment with tazemetostat (optional) 


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Exploratory objectives  
Parts 1 and 2 
• 
To explore the relationship between plasma PK and tumor PD markers  
• 
To assess tumor tissue and blood for somatic mutations, germline variants, 
messenger ribonucleic acid (mRNA), and/or proteins as candidate markers or 
response to tazemetostat 
Study endpoints 
Primary endpoints  
Part 1  
• 
Adverse events (AE) and clinical laboratory tests 
• 
Maximum plasma concentration (Cmax), time of Cmax (Tmax), area under the 
plasma concentration-time curve (AUC) from time 0 to the time of the last 
quantifiable concentration (AUC0-t), AUC from time 0 extrapolated to infinity 
(AUC0-∞) (single dose only), and the apparent terminal elimination half-life 
(t1/2) of tazemetostat after administration as 400-mg tablets. 
Part 2  
• 
DCR (CR+PR+SD) at Week 12 
Secondary endpoints  
Parts 1 and 2 
• 
AE and clinical laboratory tests 
• 
ORR (confirmed CR+PR) to tazemetostat in subjects with relapsed/refractory 
malignant mesothelioma using disease-appropriate standardized response 
criteria (modified RECIST or RECIST 1.1) 
• 
PFS at 12 weeks, 24 weeks, and overall (defined as the time from date of first 
dose of study treatment to the earlier of the date of first documented disease 
progression or date of death due to any cause) 
• 
OS at 12 weeks, 24 weeks, and overall (defined as the time from the date of the 
first dose of study treatment to the date of death due to any cause) 
• 
DOR, for the subset of subjects with a confirmed CR or PR (defined as the time 
from the first documented evidence of CR or PR to the time of first documented 
disease progression or death due to any cause, using disease-appropriate 
standardized response criteria) 
Part 1  
• 
DCR (CR+PR+SD) at Week 12 
Part 2  
• 
Population PK parameters oral clearance (CL/F), oral volume of distribution 
(Vd/F), and first-order absorption rate constant (Ka) for tazemetostat 
• 
Changes in H3K27me3 levels between pre- and post-dose tumor tissue 
 
 


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Exploratory endpoints  
Parts 1 and 2 
• 
Tumor target gene expression and phenotypic markers including those for 
differentiation, apoptosis, inflammation and cell proliferation and their 
correlation with activity 
• 
Somatic mutation analysis of tumor tissue and blood derived circulating 
deoxyribonucleic acid (DNA) 
Study design 
This is a Phase 2, multicenter, open-label, 2-part, single-arm, 2-stage study of 
continuous oral dosing with tazemetostat 800 mg BID.  Subjects will be screened 
for eligibility within 21 days of the planned date of the first dose of tazemetostat. 
Eligible subjects will be enrolled into two different parts: 
• 
Part 1 – Subjects with relapsed or refractory malignant mesothelioma regardless 
of BAP1 status 
• 
Part 2 – Subjects with relapsed or refractory BAP1-deficient malignant 
mesothelioma  
Part 1 
Subjects enrolled in Part 1 will receive a single 800-mg tazemetostat dose on 
Cycle 1 Day 1.  Starting on Cycle 1 Day 2, tazemetostat will be administered at a 
dose of 800 mg BID.  PK blood samples will be collected after the single 
tazemetostat 800 mg dose on Cycle 1 Day 1 and on Cycle 1 Day 15 after repeated 
BID doses of tazemetostat 800 mg.  Plasma samples will be analyzed for 
tazemetostat after each set of six subjects complete the PK sampling procedures 
on Cycle 1 Day 15.  In consultation with the investigators, the 400-mg tablets will 
be used in Part 2 if the PK and safety profiles of tazemetostat in Part 1 are 
acceptable. 
Part 2 
Subjects enrolled in Part 2 will receive tazemetostat 800 mg BID starting on Cycle 
1 Day 1.  PK blood samples will be collected on Days 1 and 15 of Cycle 1, and on 
Day 1 of Cycles 2, 3, and 4. 
A two-stage Green-Dahlberg design will be utilized for Part 2.  Statistical analyses 
of the primary endpoint in Part 2 will be performed when the first 30 subjects are 
enrolled (End of Stage 1 and after all subjects are enrolled [End of Stage 2]).   
Parts 1 and 2 
Response assessments will be performed every 6 weeks while on study.  Subjects 
will discontinue study treatment at the time of disease progression, development 
of an unacceptable toxicity, withdrawal of consent, or termination of the study. 
Subjects also will undergo physical examinations (PEs); vital sign measurements; 
ECOG assessments, blood sample collection for hematology, chemistry, PK, and 
PD markers; electrocardiograms (ECGs); adverse event (AE) assessments; 


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concomitant medication assessments; activity assessments, and pregnancy testing 
for females of childbearing potential. 
Study population/ 
Number of subjects 
Up to 67 subjects with relapsed or refractory malignant mesothelioma will be 
enrolled.  Part 1 will consist of 12 subjects with mesothelioma regardless of BAP1 
status.  Up to 55 subjects with BAP1-deficient mesothelioma will be enrolled in 
Part 2.  The number of subjects to be enrolled in Part 1 and in each stage of Part 2 
are provided in the table below: 
 
Number of Subjects 
BAP1 Status 
Part 1 
12 
Any 
Part 2 - Stage 1 
30 
Deficient 
Part 2 - Stage 2 
25 
Deficient 
Total 
67 
 
 
 
Diagnosis and 
criteria for 
inclusion 
Subjects must meet all criteria to be eligible for enrollment in this study. 
Inclusion criteria 
1. Age (at the time of consent) ≥18 years of age 
2. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 
0 or 1 
3. Has a life expectancy of >3 months 
4. Has mesothelioma (pleural, peritoneal, pericardial, tunica vaginalis) of any 
histology that is relapsed or refractory after treatment with at least one 
pemetrexed-containing regimen 
5. Has a documented local diagnostic pathology of original biopsy confirmed 
by a Clinical Laboratory Improvement Amendments (CLIA)/College of 
American Pathologists (CAP) or equivalent laboratory certification 
6. Part 2:  Molecular evidence of BAP1 loss of function present on local 
pathology, e.g., lack of nuclear BAP1 staining by immunohistochemistry 
(IHC)  
7. Has sufficient archival tumor tissue (a minimum of 10 slides or tumor block) 
available for central retrospective testing of BAP1 status  
8. Has all prior treatment (i.e., chemotherapy, immunotherapy, radiotherapy) 
related clinically significant toxicities resolve to ≤ Grade 1 per CTCAE, 
version 4.03 or are clinically stable and not clinically significant, at time of 
enrollment 
9. Prior therapy(ies), if applicable, must be completed according to the criteria 
below prior to first dose of tazemetostat: 
a. Cytotoxic chemotherapy; at least 21 days since last dose 
b. Non-cytotoxic chemotherapy (e.g., small molecule inhibitor); at least 
14 days since last dose 
c. Monoclonal antibody; at least 28 days since the last dose  
d. Non-antibody immunotherapy (e.g., tumor vaccine); at least 42 days 
since last dose 


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e. Radiotherapy, at least 14 days from last local site radiotherapy  
f. Hematopoietic growth factor; at least 14 days from last dose 
g. Investigational drug; 30 days or five half-lives, whichever is longer, 
from last dose 
10. Has measurable disease based on either modified RECIST [Nowak, 2005] 
for thoracic disease or RECIST 1.1 elsewhere 
11. Has adequate hematologic (bone marrow and coagulation factors), renal, and 
hepatic function as defined by criteria below: 
a. Hemoglobin ≥9 g/dL 
b. Platelets ≥100,000/mm3 (≥100 × 109/L) without platelet transfusion for 
7 days 
c. ANC ≥1000/mm3 (≥1.0 × 109/L) without growth factor support for 
14 days 
d. Coagulation: prothrombin time (PT) <1.5 × ULN and partial 
thromboplastin time (PTT) <1.5 × ULN 
e. Creatinine < 2.0 × ULN  
f. Hepatic function: Total bilirubin <1.5 × ULN and ALT and 
AST <3 × ULN 
12. Has a QT interval corrected by Fridericia's formula (QTcF) ≤480 msec 
13. Willing to allow tissue to be used for translational research 
14. Female subjects of childbearing potential must have a negative urine or 
serum pregnancy within 72 hours prior to receiving the first dose of study 
drug; if the urine test is positive or cannot be confirmed as negative, a serum 
pregnancy test will be required and subject also should agree to use an 
adequate method of contraception starting with screening through 30 days 
after the last dose of study therapy (if sexually active). 
15. Male subjects should agree to use condoms starting with the first dose of 
study therapy through 30 days after the last dose of study therapy if sexually 
active with a female partner of childbearing potential. 
 
Exclusion criteria 
1. Has had prior exposure to tazemetostat or other inhibitor(s) of enhancer of 
zeste homologue-2 (EZH2)  
2. Has a history of known central nervous system metastasis 
3. Has had a prior malignancy other than the malignancies under study  
Exception: A subject who has been disease-free for 5 years, or a subject 
with a history of a completely resected non-melanoma skin cancer or 
successfully treated in situ carcinoma is eligible. 
4. Has had major surgery within 3 weeks prior to enrollment (percutaneous 
biopsy, pleural catheter insertion, placement of central venous catheter, or 
other minor procedure are permitted) 
5. Is unwilling to exclude grapefruit juice, Seville oranges, and grapefruit from 
the diet and all foods that contain those fruits from time of enrollment 
throughout their time on study 


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6. Has cardiovascular impairment, history of congestive heart failure greater 
than NYHA Class II, uncontrolled arterial hypertension, unstable angina, 
myocardial infarction, or stroke within 6 months prior to the planned first 
dose of tazemetostat; or ventricular cardiac arrhythmia requiring medical 
treatment 
7. Is currently taking any prohibited medication(s) 
8. Has an active infection requiring systemic treatment 
9. Has a congenital or acquired immunodeficiency, including subjects with 
known history of infection with human immunodeficiency virus (HIV) 
NOTE: HIV-positive subjects who are taking antiretroviral therapy are 
ineligible due to potential PK interactions with tazemetostat.   
10. Has known history of chronic infection with hepatitis B virus (hepatitis B 
surface antigen positive) or hepatitis C virus (detectable anti-hepatitis C 
circulating viral RNA) 
11. Has had a deep venous thrombosis (DVT) or pulmonary embolism within the 
2 weeks prior to study enrollment. 
NOTE:  Subjects with a history of a DVT or pulmonary embolism > 2 weeks 
prior to study enrollment who are on anticoagulation therapy with low 
molecular weight heparin are eligible for this study 
12. Is pregnant or breastfeeding 
Dosage and 
administration 
Tazemetostat will be administered at the recommended Phase 2 dose (RP2D) of 
800 mg/dose. Tazemetostat will be administered BID with or without food with 
no less than 8 hours between doses. 
Statistical methods 
Sample size rationale:   The sample size of 12 subjects for Part 1 is sufficient for 
an initial assessment of the PK and safety profiles of the 400-mg tablet. The 
sample size in Part 2 is calculated on the primary endpoint using a two-stage 
Green-Dahlberg design.  The hypothesis will be tested using a one-sided test with 
α=0.05 and the type II error rate will be controlled at 0.2. 
Null Hypothesis: 
CR + PR + SD at 12 weeks ≤20% 
Alternative Hypothesis: CR + PR + SD at 12 weeks ≥35% 
 
Green-Dahlberg 
CR + PR + SD at 12 weeks 
Stage 1 Sample Size (n1)a 
30 
Stage 1 Rejection of Drug (r1)a 
4 
Maximum Sample Size (n) 
55 
Stage 2 Rejection of Drug (r) 
16 
a. The interim analysis planned at the end of Stage 1 may occur sooner if the Stage 
1 rejection criterion is surpassed before all 30 subjects are treated and followed for 
12 weeks.  In this scenario, the total sample size (Stage 1 + Stage 2) would still 
remain unchanged at 55 subjects. 
 


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• 
At the End of Stage 1, if there are ≤4 CR + PR + SD out of 30 subjects, then 
reject the new treatment and terminate the study for futility.  If there are 
≥5 CR + PR + SD out of 30 subjects, the study continues to Stage 2. 
• 
At the end of the study, if there are ≤16 CR + PR +SD out of 55 subjects, then 
reject the new treatment.  When there are ≥17 CR + PR + SD out of 55 
subjects, then the new treatment is accepted. 
• 
The probability of early stopping under the null hypotheses is 0.255. 
• 
The probability of early stopping under the alternative hypotheses is 0.008. 


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Table 1: 
Study Assessments  
 
Screeninga 
Cycle 1  
Cycle 1  
Cycles 2 − 8 
Cycles 9 +  
Post- 
Treatment/ 
Early 
Terminationq 
Follow-
upr 
Study Days Days -21 to 
-1 
Day 1 
Days 8 & 15 
(±1 day) 
Day 1 & every 21 
days (±3 days) 
Day 1 & every 42 
days (±3 days) 
(±3 days) 
 
Procedures/Assessmentsb 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
Inclusion/exclusion criteriac 
X 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Prior and concomitant medications 
Throughout the study 
Physical examination - Complete 
X 
X 
 
X 
X 
X 
 
Physical examination - Symptom 
directed 
 
 
X 
 
 
 
 
Weight 
X 
X 
 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
Vital signsd 
X 
X 
X 
X 
X 
X 
 
ECOG performance status 
X 
X 
X 
X 
X 
X 
 
12-lead ECGse 
X 
X 
X 
X 
X 
X 
 
Pregnancy testf 
X 
X 
 
X 
X 
X 
 
Hematologyg 
X 
X 
X 
X 
X 
X 
 
Blood chemistryg 
X 
X 
X 
X 
X 
X 
 
Coagulation profileh 
X 
If clinically indicated 
X 
 
PGx blood samplei 
X 
 
 
 
 
 
 
Circulating tumor DNA blood samplej 
X 
X (At the time of tumor assessment every 6 weeks) 
 
 
PK blood samples Part 1k 
 
X 
X 
 
 
 
 
PK blood samples Part 2k 
 
X 
X 
X 
 
 
 


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Screeninga 
Cycle 1  
Cycle 1  
Cycles 2 − 8 
Cycles 9 +  
Post- 
Treatment/ 
Early 
Terminationq 
Follow-
upr 
Study Days Days -21 to 
-1 
Day 1 
Days 8 & 15 
(±1 day) 
Day 1 & every 21 
days (±3 days) 
Day 1 & every 42 
days (±3 days) 
(±3 days) 
 
Procedures/Assessmentsb 
 
 
 
 
 
 
 
Archival tumor tissuel 
X 
 
 
 
 
 
 
Tumor biopsy for H3K27me3 PDm 
X 
 
 
X 
(At first or 
second tumor 
assessment) 
 
 
 
Tumor biopsy at disease progressionn 
 
At disease progression 
 
Tumor assessments: CT and/or MRIo 
X 
(Tumor assessments every 6 weeks) 
 
 
AEs/SAEs 
Throughout the study 
Tazemetostat administration 
 
Continuous dose of tazemetostat BID 
 
 
Disease assessment & survival statusp 
 
X 
X 
AE = adverse event; CT = computed tomography; ECOG = Eastern Cooperative Oncology Group; ECG = electrocardiogram; MRI = magnetic resonance imaging; PD = 
pharmacodynamic; PGx = pharmacogenomics; PK = pharmacokinetic; SAE = serious adverse event  
 
a. 
Screening:  Screening Period extends from Day -21 to Day -1.  Screening laboratory assessments may be used as Day 1 assessments if performed within 
72 hours of the first dose of study treatment. 
b. Subjects must continue to meet eligibility criteria prior to first dose of tazemetostat on Cycle 1 Day 1. 
c. 
Pre-study procedures and tumor assessment must be performed within 21 days before first dose of study treatment. 
d. Vital Signs:  Blood pressure (BP), heart rate (HR), temperature (T) and respiratory rate (RR) must be measured after the subject has been sitting for five 
minutes 
e. 
ECG:  12-lead ECG reading must be performed at screening, at Cycle 1 Days 1 and 15, approximately 1 hour after administration of tazemetostat.  A single 
ECG will be recorded unless there is an abnormality, such as prolonged QTc(F) ≥ 480 msec, new arrhythmia, or other clinically significant finding.  If an 
abnormality is observed, the ECG is to be performed in triplicate at least 2 minutes apart. Additional ECG readings will be performed prior to tazemetostat 
administration on Day 1 of each subsequent cycle.  On days when an ECG reading and a PK blood sample collection are scheduled at the same time (Cycle 1 
Days 1 and 15 and Day 1 of Cycles 2 through 4), the ECG reading should be performed immediately prior to collection of the PK blood sample, if possible.   
f. 
Pregnancy Test:  A serum or urine pregnancy test must be performed at screening and within 21 days of the first dose of study treatment for all females 
who are of childbearing potential.  A separate assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first 
dose of study treatment. Subsequent pregnancy tests should be performed on the first day of every cycle of study treatment and may be either urine or serum. 


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g. Laboratory Tests:  Clinical laboratory tests will be performed at local laboratories according to the laboratory’s normal procedures.  See Section 8.3.2 for a 
complete listing of laboratory tests to be performed.  
h. Coagulation Profile:  Coagulations tests include prothrombin time (PT) and partial thromboplastin time (PTT). 
i. 
PGx: A single 6-mL blood sample will be collected at screening. 
j. 
Circulating DNA:  20-mL circulating tumor DNA blood samples to be obtained at screening and at time of each tumor assessment including at time of 
disease progression. 
k. PK Part 1: The 12 subjects in Part 1 will have 2-mL blood samples for PK analysis collected at the following time points:  Cycle 1 Day 1: pre-dose, 0.5, 1, 
2, 4, 6, 8, 10, 12 and 24 hours post-dose; Cycle 1 Day 15: pre-dose, 0.5, 1, 2, 4, 6, 8, 10, and12 post-dose. 
PK Part 2:  The subjects in Part 2 will have 2-mL blood samples for PK analysis collected at the following time points: Cycle 1 Day 1: pre-dose, and 1, 3, 
and 6 hours post-dose; Cycle 1 Day 15: pre-dose, 1, 3, and 6 hours post-dose; Day 1 of Cycles 2 through Cycle 4: pre-dose.  All PK blood samples may be 
drawn from either a central venous catheter or a peripherally placed intravenous catheter. Exact time of draw must be recorded.  
l. 
Tumor Tissue:  Archival tissue (block or 10-15 slides) will be requested for central confirmation of pathology, IHC, and additional molecular testing, e.g., 
detection of somatic mutations and/or candidate biomarkers of response. If archived tumor material is not available, tumor biopsy obtained during screening 
is acceptable. 
m. Tumor Biopsy for Tazemetostat PD:  A minimum of 12 subjects will be required to provide pre-dose (to be collected at screening) and post-dose biopsies 
(formalin-fixed paraffin-embedded [FFPE] blocks) to assess H3K27me3 starting at or following the first or second tumor assessments (Cycle 3 or 5).  If 
the clinical study accrual has reached 75% and the goals for subjects undergoing tumor biopsy have not been met, only those subjects who can undergo 
tumor biopsy will be enrolled.  If the study subsequently completes accrual of 12 subjects with pre- and post-dose biopsies and the study accrual is still open, 
the study will then enroll all subjects irrespective of their ability to provide pre- and post-dose biopsies. 
n. Tumor Biopsy at Disease Progression:  An FFPE tumor biopsy is requested, where medically feasible, at disease progression in subjects who achieve a PR 
or better to tazemetostat. 
o. Tumor Assessment:  Tumor assessments by disease-appropriate standard criteria (modified RECIST for thoracic disease or RECIST 1.1 elsewhere) using 
CT/MRI of known sites of disease as clinically indicated.  Bone scan should be performed only if clinically indicated.  Tumor assessments must be 
performed at screening and every 6 weeks (±3 days) or sooner, if clinically indicated, from start of treatment.  18FDG-PET scan should be performed as 
clinically indicated at the investigator’s discretion, and is not a required tumor assessment. 
p. Disease Assessment and Survival Status:  Survival follow-up will be conducted approximately every 12 weeks on all subjects, unless the subject 
withdraws consent. 
q. Post-Treatment/Early Termination:  A Post-Treatment/Early Termination visit will be conducted within 30 days (±3 days) after the last dose of 
tazemetostat or prior to the start of a new treatment or therapy at the end of study or if the subject's participation is terminated early.  The post-
treatment/early termination assessments will be required and, in the event of a continuing AE, the subject will be asked to return for follow-up until the AE 
has resolved or is deemed to be continuing indefinitely.  
r. 
Follow-Up:  Survival follow-up will be conducted approximately every 12 weeks on all subjects, unless they withdraw consent. Information on all anti-
cancer therapies will be collected (the sponsor may choose to stop the collection of therapies after the first anti-cancer treatment following tazemetostat). 
This may be done by telephone contact.  
 
 


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Table 2: 
Timing Allowance Windows for Vital Sign Measurements, 
Pharmacokinetic Sampling, and ECG Measurements 
Vital Signs 
 
Timepoint 
Tolerance Window 
0 hour 
-60 min to 0 hour 
 
Pharmacokinetic Sampling 
 
Timepoint 
Tolerance Window 
0 hour 
-120 min to 0 hour 
>0 hour – 3 hour 
-5 minutes/+5 minutes 
4 hour – 8 hour 
-15 minutes/+15 minutes 
10 hour – 12 hour 
-30 min/+30 min 
24 hour  
-60 minutes/+60 minutes 
 
 
ECG 
 
Timepoint 
Tolerance Window 
0 hour 
-60 min to 0 hour 
>0 hour – 1 hour 
-10 minutes/+10 minutes 
 


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TABLE OF CONTENTS 
1. 
SYNOPSIS ............................................................................................................... 5 
TABLE OF CONTENTS .......................................................................................................... 16 
LIST OF TABLES .................................................................................................................... 20 
LIST OF ABBREVIATIONS.................................................................................................... 21 
2. 
BACKGROUND AND RATIONALE .................................................................... 25 
2.1. Introduction ............................................................................................................ 25 
2.2. Tazemetostat........................................................................................................... 26 
2.2.1 
Preclinical Pharmacology ............................................................................ 26 
2.2.2 
Clinical Pharmacokinetics (PK)................................................................... 28 
2.2.3 
Clinical Pharmacodynamics (PD) ................................................................ 29 
2.2.4 
Molecular Evidence of BAP1 Deficiency .................................................... 30 
2.2.5 
Clinical Safety and Efficacy ........................................................................ 30 
2.3. Benefit: Risk Assessments ...................................................................................... 31 
2.3.1 
Animal Toxicology ..................................................................................... 31 
2.3.2 
Photo-Reactive Potential ............................................................................. 32 
2.3.3 
CYP3A Metabolism .................................................................................... 32 
2.3.4 
Anticipated Safety Profile ........................................................................... 32 
2.4. Study and Dose Rationale ....................................................................................... 32 
2.4.1 
Study Rationale ........................................................................................... 32 
2.4.2 
Dosage Rationale ........................................................................................ 33 
2.5. Good Clinical Practice (GCP) ................................................................................. 33 
3. 
STUDY OBJECTIVES AND ENDPOINTS ........................................................... 35 
4. 
STUDY DESIGN ................................................................................................... 37 
4.1. Study Sites .............................................................................................................. 37 
4.2. Overview of Study Design ...................................................................................... 37 
4.3. Rules for Suspension of Enrollment ........................................................................ 38 
5. 
STUDY POPULATION ......................................................................................... 39 
5.1. Target Population ................................................................................................... 39 
5.2. Inclusion Criteria .................................................................................................... 39 
5.3. Exclusion Criteria ................................................................................................... 40 


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6. 
INVESTIGATIONAL PRODUCT ......................................................................... 42 
6.1. Description ............................................................................................................. 42 
6.2. Preparation, Handling and Storage of Investigational Product ................................. 42 
6.3. Dosage and Administration ..................................................................................... 43 
6.4. Procurement of IP ................................................................................................... 43 
6.5. Accountability ........................................................................................................ 43 
7. 
STUDY TREATMENT .......................................................................................... 45 
7.1. Treatment Assignment ............................................................................................ 45 
7.2. Restrictions During Study Treatment ...................................................................... 45 
7.3. Dose Modification .................................................................................................. 45 
7.4. Continuation of Treatment ...................................................................................... 46 
7.5. Treatment Compliance ............................................................................................ 47 
7.6. Treatment of Overdose ........................................................................................... 47 
7.7. Tazemetostat Duration of Treatment ....................................................................... 47 
8. 
STUDY ASSESSMENTS AND PROCEDURES ................................................... 49 
8.1. Consent .................................................................................................................. 49 
8.2. Screening Assessments ........................................................................................... 49 
8.2.1 
Demographics and Medical History ............................................................ 49 
8.3. Study Assessments ................................................................................................. 49 
8.3.1 
Physical Examinations ................................................................................ 49 
8.3.1.1. 
Comprehensive Physical Examination ............................................. 49 
8.3.1.2. 
Symptom-Directed Physical Examination ........................................ 50 
8.3.1.3. 
Vital Sign Measurements ................................................................. 50 
8.3.1.4. 
ECOG Performance Status .............................................................. 50 
8.3.2 
Clinical Laboratory Assessments ................................................................. 50 
8.3.3 
Pregnancy ................................................................................................... 51 
8.3.3.1. 
Definition of Childbearing Potential: Female Subjects ..................... 52 
8.3.3.2. 
Definition of Childbearing Potential: Male Subjects ........................ 52 
8.3.3.3. 
Pregnancy Testing ........................................................................... 52 
8.3.3.4. 
Prevention ....................................................................................... 53 
8.3.4 
Electrocardiograms (ECGs) ......................................................................... 53 
8.3.5 
Disease Assessment .................................................................................... 54 


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8.3.6 
Pharmacokinetics ........................................................................................ 54 
8.3.7 
Pharmacogenomics (PGx) ........................................................................... 54 
8.4. Correlative Assessments ......................................................................................... 55 
8.4.1 
Archive Tumor or Biopsy at Screening........................................................ 55 
8.4.2 
Paired Tumor Biopsies to Assess Tazemetostat PD ..................................... 55 
8.4.3 
Circulating Tumor DNA ............................................................................. 56 
8.4.4 
Biomarkers of Response Assessment........................................................... 56 
8.4.4.1. 
Tumor Tissue Sample(s) .................................................................. 56 
8.4.5 
Assessment of Relapse/Resistance to Tazemetostat ..................................... 56 
8.5. Future Use of Tissue Samples ................................................................................. 56 
9. 
CONCOMITANT MEDICATIONS ....................................................................... 58 
9.1. Permitted Medication(s).......................................................................................... 58 
9.2. Medications to be used with Caution ...................................................................... 58 
9.3. Prohibited Medication(s) ........................................................................................ 58 
9.4. Non-Drug Therapies ............................................................................................... 59 
10. 
WITHDRAWAL AND REPLACEMENT OF SUBJECTS ..................................... 60 
10.1. 
Withdrawal of Subjects from Treatment/Procedures .................................... 60 
10.2. 
Survival Follow-Up ..................................................................................... 60 
10.3. 
Subsequent Therapy After Discontinuation of Study Treatment .................. 60 
10.4. 
Evaluation of Response to Subsequent Anti-Cancer Therapy....................... 61 
10.5. 
Withdrawal of Subjects from Study ............................................................. 61 
10.6. 
Replacement of Subjects ............................................................................. 61 
10.7. 
Progression of Disease in Subjects Continuing to Receive Clinical 
Benefit ........................................................................................................ 61 
11. 
SAFETY ................................................................................................................ 63 
11.1. 
Safety Parameters ........................................................................................ 63 
11.2. 
Adverse Event Definition ............................................................................ 63 
11.2.1 
Adverse Events ........................................................................................... 63 
11.2.2 
Serious Adverse Events ............................................................................... 63 
11.3. 
Laboratory Abnormalities ........................................................................... 64 
11.4. 
Other Safety Assessment Abnormalities ...................................................... 65 
11.4.1 
Disease-Related Events ............................................................................... 65 
11.5. 
Adverse Events of Special Interest (AESIs) ................................................. 65 


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11.6. 
Relationship Categorization ........................................................................ 66 
11.6.1 
Assessing Relationship to Study Treatment ................................................. 66 
11.7. 
Outcome Categorization .............................................................................. 67 
11.8. 
Timeframe for Reporting AEs and SAEs ..................................................... 67 
11.9. 
Reporting of SAEs ...................................................................................... 68 
11.9.1 
Regulatory Authorities, IRB/EC, and CECs ................................................ 69 
12. 
DATA MANAGEMENT ........................................................................................ 70 
12.1. 
Coding ........................................................................................................ 70 
13. 
STATISTICAL METHODS ................................................................................... 71 
13.1. 
Hypotheses.................................................................................................. 71 
13.2. 
Study Design Considerations ....................................................................... 71 
13.2.1 
Determination of Sample Size ..................................................................... 71 
13.2.2 
Sample Size Re-Estimation ......................................................................... 72 
13.3. 
Data Analysis Considerations ...................................................................... 72 
13.3.1 
Analysis Populations ................................................................................... 72 
13.3.2 
Interim Analyses ......................................................................................... 72 
13.3.3 
Key Elements of the Analysis Plan .............................................................. 73 
13.4. 
Efficacy Analyses ....................................................................................... 73 
13.4.1 
Analysis of Primary Endpoint ..................................................................... 73 
13.4.2 
Analysis of Secondary Efficacy Endpoints .................................................. 74 
13.5. 
Safety Analyses ........................................................................................... 75 
13.5.1 
Extent of Exposure ...................................................................................... 75 
13.5.2 
Adverse Events ........................................................................................... 75 
13.5.3 
Clinical Laboratory Evaluation .................................................................... 76 
13.5.4 
Other Safety Measures ................................................................................ 77 
13.6. 
Pharmacokinetic Analyses........................................................................... 77 
13.7. 
Exploratory Analysis ................................................................................... 77 
14. 
INDEPENDENT DATA MONITORING COMMITTEE (IDMC).......................... 78 
15. 
STUDY CONDUCT CONSIDERATIONS ............................................................ 79 
15.1. 
Posting of Information on Publicly Available Clinical Trial Registers ......... 79 
15.2. 
Regulatory and Ethical Considerations ........................................................ 79 
15.2.1 
Institutional Review Board (IRB)/ Ethics Committee (EC)/Central 
Ethics Committee (CEC) ............................................................................. 79 


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15.2.2 
Informed Consent Process ........................................................................... 80 
15.3. 
Subject Confidentiality and Access to Source Documents/Data ................... 80 
15.4. 
Study Monitoring ........................................................................................ 81 
15.5. 
Protocol Deviations ..................................................................................... 81 
15.6. 
Protocol Amendment .................................................................................. 81 
15.7. 
Suspension or Termination of Study ............................................................ 82 
16. 
ADMINISTRATIVE PROCEDURES .................................................................... 83 
16.1. 
Recording and Access and to Study Records ............................................... 83 
16.2. 
Case Report Forms ...................................................................................... 83 
16.3. 
Quality Assurance and Quality Control ....................................................... 83 
16.4. 
Data Quality Assurance ............................................................................... 84 
16.5. 
Confidentiality ............................................................................................ 84 
16.6. 
Audit/Inspection .......................................................................................... 84 
16.7. 
Record Retention ........................................................................................ 85 
16.8. 
Provision of Study Results and Publication ................................................. 85 
17. 
REFERENCES ....................................................................................................... 86 
 
LIST OF TABLES 
Table 1: 
Study Assessments ................................................................................................. 12 
Table 2: 
Timing Allowance Windows for Vital Sign Measurements, Pharmacokinetic 
Sampling, and ECG Measurements ......................................................................... 15 
Table 3: 
Dose Modifications for Treatment-Related Toxicities ............................................. 46 
Table 4: 
Clinical Laboratory Panels ...................................................................................... 51 
 
 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ADME 
Absorption, Distribution, Metabolism and Excretion 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate aminotransferase 
ATC 
Anatomical-Therapeutic-Chemical 
AUC 
Area under the concentration-time curve 
AUC0-t 
Area under the concentration-time curve from time 0 to the last 
measurable plasma concentration 
AUC0-∞ 
Area under the concentration-time curve from time 0 extrapolated to 
infinity 
BAP1 
BRCA1 associated protein 1 
β-hCG 
Beta-human chorionic gonadotropin 
BID 
Twice daily 
BM 
Bone marrow 
BP 
Blood pressure 
°C 
Degrees Celsius 
CAP 
College of American Pathologists 
CEC 
Central Ethics Committee 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CL/F 
Oral clearance 
CLIA 
Clinical Laboratory Improvement Amendments 
Cmax 
Maximum plasma concentration 
CR 
Complete response 
CSR 
Clinical Study Report 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTD 
Clinical Trial Directive 
CYP 
Cytochrome 
DCR 
Disease control rate 
DLT 
Dose-limiting toxicity 
DOR 
Duration of response 
DNA 
Deoxyribonucleic acid 
DVT 
Deep vein thrombosis 
EC50 
Half maximal effective concentration 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EIAED 
Enzyme inducing anti-epileptic drug 


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Abbreviation 
Definition 
EMA 
European Medicines Agency 
Emax 
Maximum effect 
EPZ-6438, E7438 
Tazemetostat 
EPZ-6930, ER-897387 
Desethyl metabolite of tazemetostat 
EU CT Dir 
European Union Clinical Trial Directive 
EZH2 
Enhancer of zeste homologue-2 
FDA 
Food and Drug Administration 
FFPE 
Formalin-fixed paraffin-embedded 
FTIH 
First-time-in-human 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
H3K27 
Lysine 27 of histone H3 
H3K27me3 
H3K27 trimethylation 
HEENT 
Head, eyes, ears, nose and throat 
HIV 
Human immunodeficiency virus 
HMT 
Histone methyltransferase 
hr 
Hour 
HR 
Heart rate 
IB 
Investigator’s Brochure 
IC50 
Half maximal inhibitory concentration 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IDMC 
Independent Data Monitoring Committee 
IHC 
Immunohistochemistry 
IMP 
Investigational Medicinal Product 
INI1 
Integrase interactor 1 
IP 
Investigational product 
IRB 
Institutional Review Board 
ITT 
Intent-t- Treat 
Ka 
First-order absorption rate constant 
kg 
Kilogram 
L 
Liter 
LNH 
Low, normal, high 
m2 
Squared meter 
MCH 
Mean corpuscular hemoglobin 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mm 
Millimeter 
mL 
Milliliter 
msec 
Millisecond 
MRI 
Magnetic resonance imaging 
mRNA 
Messenger ribonucleic acid 
MRT 
Malignant rhabdoid tumor 
MRTO 
Malignant rhabdoid tumor of the ovary 


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Abbreviation 
Definition 
MSDS  
Material Safety Data Sheet 
MTD 
Maximum tolerated dose 
NA 
Not applicable 
NE 
Not evaluable 
NHL 
Non-Hodgkin’s lymphoma 
NYHA 
New York Heart Association 
ORR 
Overall response rate 
OS 
Overall survival 
PD 
Pharmacodynamic or progressive disease 
PE 
Physical examination 
PET 
Positron emission tomography 
PFS 
Progression-free survival 
PGx 
Pharmacogenetics 
PK 
Pharmacokinetics 
PR 
Partial response 
PRC2 
Polycomb repressive complex 2 
PT 
Prothrombin time when used in the context of coagulation 
Preferred term when used in the context of MedDRA coding of AEs 
PTT 
Partial thromboplastin time 
QC 
Quality control 
QTc 
Corrected QT interval 
QTcF 
QT interval corrected by Fridericia’s formula 
Rac 
Accumulation ratio 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
Recommended Phase II dose 
RNA 
Ribonucleic acid 
RR 
Respiration rate 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
S-D 
Sprague-Dawley 
SD 
Stable disease or standard deviation 
SI 
International System of Units 
SOC 
System Organ Class 
SSE 
Symptomatic skeletal events 
SUSAR 
Suspected unexpected serious adverse reaction 
SWI/SNF 
SWItch/Sucrose Non-Fermentable 
T 
Temperature 
t1/2 
Apparent elimination half-life 
TEAE 
Treatment-emergent adverse event 
TESS 
Treatment-emergent signs and symptoms 
Tmax 
Time to maximum concentration 
TRAE 
Treatment-related adverse event 
ULN 
Upper limit of normal 
US 
United States 
UV 
Ultraviolet 


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Abbreviation 
Definition 
Vd/F 
Oral volume of distribution 
WBC 
White blood cell 
WHO 
World Health Organization 


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2. 
BACKGROUND AND RATIONALE 
2.1. 
Introduction 
Malignant mesothelioma is an aggressive malignancy associated with asbestos exposure and 
carries a poor prognosis.  It was once thought to be rare but the incidence is increasing and will 
likely peak in the next 10 years in the US, UK and Europe, however the continued global use of 
asbestos threatens a worldwide epidemic in several developing economies [Robinson 2005; 
Ceresoli 2007; Fennell 2007].  At diagnosis patients usually have pleural involvement, 
presenting with chest wall pain, pleural effusions and dyspnea, but disease can also be found on 
other serosal surfaces such as the peritoneum [Robinson 2005].  Treatment consists of 
pemetrexed and platinum based chemotherapy, with or without surgery and radiation.  Despite 
treatment, outcomes are poor with median overall survival (OS) reported to be between 9 and 17 
months regardless of stage at diagnosis [Tsao 2009]. Currently, there is no standard of care in the 
relapsed setting after progression following pemetrexed and cisplatin, originally reported over a 
decade ago [Vogelzang 2003].  
To date there have been no genetically stratified therapies identified for the treatment of 
mesothelioma. However, in this patient population, BAP1 loss of function mutations, and protein 
loss determined by IHC are observed in up to 23% and 66%, respectively [Bott 2011; Bueno 
2016; Cigognetti 2015; Guo 2015].  Treatment of BAP1 mutant mesothelioma xenografts with 
EZH2 inhibitors significantly reduced BAP1 mutant tumor growth when compared to vehicle in 
two immunocompromised mouse models; see Figure 1 [LaFave, 2015 and Epizyme internal 
communication]. Thus, EZH2 inhibition represents a viable therapeutic strategy for BAP1-
deficient malignant mesothelioma patients.  A wild type BAP1 xenograft model exhibited 
variable in vivo efficacy when performed in two distinct immunocompromised backgrounds, 
suggesting a possible, though less compelling, role for EZH2 inhibition in the mesothelioma 
microenvironment; see Figure 2 [LaFave 2015 and Epizyme internal communication]. 
The cellular function of BAP1 is deubiquitination of specific nuclear proteins. Evidence exists 
for multiple genetic mechanisms that can lead to BAP1 loss of function, however, lack of BAP1 
expression in the nucleus (identified by immunohistochemistry; IHC) will be considered as a 
surrogate of BAP1 loss of function for the purposes of enrollment to this study and these subjects 
will be considered BAP1-deficient. 
Enhancer of Zeste homologue 2 (EZH2) is the catalytic subunit of the multi-protein polycomb 
repressive complex 2 (PRC2) that catalyzes the mono-, di-, and trimethylation of lysine 27 of 


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histone H3 (H3K27) [Margueron 2011].  EZH2 mutation and/or over-expression has been 
observed in several cancer types, leading to an aberrant H3K27 trimethylation (H3K27me3) state 
which is oncogenic [Chase 2011].  For instance, somatic gain-o- function mutations within 
EZH2, found within subsets of non-Hodgkin lymphoma (NHL), result in an oncogenic 
dependency on EZH2 production of abnormally high H3K27me3 levels, and resultant 
transcriptional reprogramming of the cell [Morin 2010].   
In addition to genetic alternations in EZH2 itself, genetic and/or protein loss of other proteins, 
such as BRACA1 associated protein 1 (BAP1), can lead to an oncogenic dependency on EZH2 
activity [LaFave 2015].  BAP1 is a nuclear deubiquitinase that removes monoubiquitin from 
Histone H2A lysine 119 (H2AK119), a histone mark which is catalyzed by the Polycomb 
Repressive Complex 1 (PRC1) [Wang 2004; Scheuermann 2010]. PRC1 dependent H2AK119 
ubiquitination can lead to recruitment of the PRC2 complex and induction of H3K27me3 
[Blackledge 2014].  Genetic and/or protein loss of BAP1 has been described in many human 
malignancies, such as mesothelioma, uveal melanoma, renal carcinoma, and cholangiocarcinoma 
[Testa 2015; Harbour 2010; Pena-Llopis 2012; Jiao 2013]. Germline mutations of BAP1, while 
rare, lead to a high familial incidence of mesothelioma and uveal melanoma in addition to other 
cancer types [Testa 2012, Carbone 2012].  Conditional loss of BAP1 in vivo leads to increased 
EZH2 expression in myeloid cells resulting in increased levels of H3K27me3 and repression of 
PRC2 targets.  These effects can be abrogated with concomitant conditional deletion of Ezh2 or 
treatment with an EZH2 inhibitor [LaFave 2015].    
2.2. 
Tazemetostat 
2.2.1 
Preclinical Pharmacology 
Tazemetostat (EPZ-6438) is a selective oral small molecule inhibitor of EZH2.  Tazemetostat 
inhibits both wild type EZH2 and mutated EZH2 residues Y641, A667G and A687 with half 
maximal inhibitory concentrations (IC50) ranging from 2-38 nmol/L.  The compound shows a 35-
fold selectivity over the most closely related HMT, EZH1, and greater than a 4500-fold 
selectively over other HMTs.  It selectively inhibits intracellular H3K27 methylation in a 
concentration- and time-dependent manner, leading to selective cell killing of cell lines with 
either EZH2 gain-of-function mutations or an acquired dependence on EZH2 activity due to 
other mutations [Knutson 2013].   
Oral administration of EZH2 inhibitors twice daily resulted in antitumor activity in vivo against 
two BAP1 mutant human mesothelioma xenograft murine models. BAP1 mutant mesothelioma 
xenografts treated with the EZH2 tool compound EPZ011989 (Figure 1a, b [LaFave 2015], and c 


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[Epizyme internal communications]) and tazemetostat (Figure 1c) demonstrated up to a four-fold 
reduction in tumor volume.  
NOD-SCID mice implanted with wild type BAP1 mesothelioma cell lines and treated with the 
EZH2 tool compound EPZ011989 twice daily (Figure 2a,b), did not demonstrate a significant 
reduction in tumor volume.  Interestingly, EZH2 inhibition in a MSTO-211H xenograft model in 
SCID mice treated with both the tool compound and tazemetostat (Figure 2c) did result in 
significant tumor reduction.  As SCID mice are more immunocompetent than NOD-SCID mice, 
this finding suggests a possible immune modulatory role for EZH2 in this setting.  
Figure 1: 
EZH2 Inhibition in BAP1 Mutant Xenografts 
 
Tumor fold change in mice dosed BID with vehicle or EZH2 inhibitors.  BAP1 mutant human mesothelioma lines 
were implanted in NOD-SCID (a, b) or BALB/c athymic (c) mice and dosed with 625 mg/kg EPZ011989 and 142.5, 
285, or 570 mg/kg EPZ-6438.  Data are represented as fold change of tumor volume over time for each dose group.  
Statistics were calculated for the last data point with Student t test; **P<0.01, ****P<0.0001. EPZ-6438 is 
expressed in terms of the hydrobromide salt form. The conversion factor for the dose of EPZ-6438 free base is 
0.8762. EPZ011989 is expressed in terms of the D-tartrate salt form. The conversion factor for the dose of 
EPZ011989 free base is 0.801. 
 
 
 


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Figure 2: 
EZH2 Inhibition in BAP1 Wild Type Xenografts 
 
Tumor fold change in mice dosed BID with vehicle or EZH2 inhibitors.  BAP1 wild-type human mesothelioma lines 
were implanted in NOD-SCID (a, b) or SCID (c) mice and dosed with 625 or 540 mg/kg EPZ011989, or 142.5, 285, 
or 570 mg/kg EPZ-6438.  Data are represented as fold change of tumor volume over time for each dose group.  
Statistics were calculated for the last data point with Student t test; ****P<0.0001. EPZ-6438 is expressed in terms 
of the hydrobromide salt form. The conversion factor for the dose of EPZ-6438 free base is 0.8762. EPZ011989 is 
expressed in terms of the D-tartrate salt form. The conversion factor for the dose of EPZ011989 free base is 0.801. 
2.2.2 
Clinical Pharmacokinetics (PK) 
The clinical PK of tazemetostat and desethyl metabolite, EPZ-6930, have been characterized 
following single (Day 1) and multiple (Day 15) administration to subjects with advanced solid 
tumors or B-cell lymphoma (n=36). Doses administered were 100 mg BID as a suspension (n=3) 
or tablet (n=3) 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 1-2 hours post-dose.  Plasma concentrations declined in a mono-exponential 
manner with a mean t1/2 of approximately 3-5 hours, and quantifiable plasma concentrations of 
both tazemetostat and its metabolite, EPZ-6930 were measurable up to 12 hours post-dose.  The 
tazemetostat maximum plasma concentration (Cmax) and area under the concentration-time curve 
(AUC) increased in a greater than dose-proportional fashion after a single dose and in an 
approximately a dose-proportional fashion at steady-state.  After multiple dosing, there was a 
dose-dependent decrease in tazemetostat exposure between Days 1 and 15.  The accumulation 
ratio (Rac = AUCD15/AUCD1) at the recommended Phase 2 dose (RP2D) of 800 mg BID was 
0.58.  However, drug exposure at steady-state did not change beyond Day 15 as evidenced by the 
Ctrough levels from Days 15 to 29.  There was negligible change in Tmax or t1/2 on multiple dosing 
across the dose range.  Preliminary results indicate that <5% of the administered dose was 
excreted in urine as unchanged tazemetostat. The Tmax of tazemetostat was observed at 1-2 hours 
post-dose and its elimination paralleled that of tazemetostat (t1/2 = 3-5 hours). Preliminary results 
indicate that <5% of the administered dose was excreted in urine as unchanged tazemetostat.  


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Metabolite profiling and identification studies are planned to assess tazemetostat metabolism in 
humans. 
The effect of food on the PK of tazemetostat was evaluated in in subjects with advanced solid 
tumors or B-cell lymphoma (n=12) as part of study E7438-G000-101. Administration of 
tazemetostat with a high-fat meal decreased geometric mean area under the concentration-time 
curve from zero extrapolated to infinity (AUC0-∞) and Cmax values approximately 6% and 28%, 
respectively, relative to administration in the fasted state. However, for both Cmax and AUC0-∞, 
all values observed after administration of tazemetostat following a high-fat meal were within 
the range of values observed after 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. The relationship between tazemetostat AUC on Day 15 and 
inhibition of H3K27 methylation in skin observed in the dose-escalation part of 
Study E7438-G000-101 indicates that target inhibition is related to AUC. The decrease in 
systemic exposure as measured by AUC0-∞ is not clinically significant, and therefore, 
tazemetostat can be taken without regards to meals. 
2.2.3 
Clinical Pharmacodynamics (PD) 
 
Inhibition of H3K27Me3 in skin was utilized as a measure of target engagement in Study 
E7438-G000-101.  IHC analysis of skin biopsies collected pre-dose and after 28 days of 
tazemetostat treatment revealed a post-dose decrease in H3K27Me3-positive cells across all 
doses explored (100−1600 mg BID). Interestingly, differences were observed in the 
tazemetostat-induced reduction in H3K27Me3 levels in different skin layers potentially pointing 
to different kinetics for H3K27Me3 turnover in the cells that occupy different skin layers. A 
relationship between tazemetostat AUC on Day 15 and inhibition of H3K27Me3 in the stratum 
spinosum was observed and described by an inhibitory Emax model. The tazemetostat AUC0-12 at 
which the H3K27Me3 inhibition was 50% of maximal (EC50) was 848 ng•h/mL and the 
maximum effect (Emax) was 51% inhibition. 
In this study pre- and post-treatment tumor biopsies will be evaluated to enable the assessment of 
tazemetostat dosing on H3K27Me3 levels in tumor tissue. H3K27Me3 IHC data will provide 
mechanistic insight into the impact of EZH2 inhibition on H3K27Me3 levels in cell populations 
within tumor. In addition, these data will be evaluated in the context of tazemetostat exposure 
data to explore PK-PD relationships.  


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2.2.4 
Molecular Evidence of BAP1 Deficiency 
BAP1 loss of function mutations and protein loss determined by IHC are observed in up to 23% 
and 66% of patients with malignant pleural mesothelioma, respectively [Bott 2011, Cigognetti 
2015].  For the purposes of this protocol BAP1 deficiency will be defined as locally determined 
lack of nuclear BAP1 positivity using IHC on archive tumor tissue (required for Part 2).  
Central retrospective analysis of BAP1 expression and DNA sequencing will be performed to 
assess the presence of either somatic and/or germline BAP1 mutations.  
2.2.5 
Clinical Safety and Efficacy 
In 2013, the first-time-in-human (FTIH), single-agent, Phase 1/2 safety and PK study (E7438 
G000-101) of tazemetostat in adult subjects with advanced B-cell lymphomas and solid tumors 
was initiated in France.  In the dose-escalation part of the study, subjects with advanced solid 
tumors or B-cell lymphomas for which there is no known effective therapy were recruited.  All 
subjects received oral tazemetostat twice daily (BID) until disease progression or a dose-limiting 
toxicity (DLT).  As of 07-Nov. 2015, 58 subjects have been enrolled and treated at five dose 
levels of 100, 200, 400, 800, and 1600 mg BID.  The diagnoses for the 21 subjects with B-cell 
NHL included follicular lymphoma, diffuse large B-cell lymphoma including one subject with 
primary mediastinal lymphoma and one marginal zone lymphoma.  The solid tumor cohort was 
enriched with subjects who were INI1 or SMARCA4-deficient with five subjects with malignant 
rhabdoid tumors (MRT), 3 subjects with epithelioid sarcoma and three subjects with 
SMARCA4-deficient tumors.  The median age of subjects enrolled is 59 years (range: 19 - 84 
years).  
The dose-escalation portion of E7438-G000-101 has been completed.  The protocol-defined 
maximum tolerated dose (MTD) was not reached.  The highest evaluated dose of 1600 mg BID 
was safe with only one DLT (Common Terminology Criteria for Adverse Events [CTCAE] 
version 4.03 Grade 4 thrombocytopenia) observed in 6 subjects.  There was one other Grade 4 
serious adverse event (SAE) of possible treatment-related neutropenia reported in a subject in the 
expansion cohort. The RP2D of 800 mg BID represents 50% of the highest evaluated safe dose 
and was determined by the sponsor and ratified by the Independent Data Monitoring Committee 
(IDMC) for use in the Phase 2 study in adults with INI1 negative tumors and the Phase 2 study in 
NHL adult subjects in Europe and Australia.  As of 07-Nov. 2015, the reported adverse events 
(AEs), regardless of attribution, occurring in >5% of subjects were:  asthenia, anorexia, 
thrombocytopenia, nausea, constipation, diarrhea, vomiting, anemia, dry skin, dysgeusia, 
dyspnea, muscle spasms, abdominal pain, hypophosphatemia, anxiety, depression, hypertension, 
influenza, insomnia, neutropenia, night sweats and peripheral edema. Only four Grade 3 or 


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greater treatment-related AEs (TRAEs) were observed in 58 subjects with no evidence of 
generation of secondary malignancies, and minimal hematologic toxicity.   
Tazemetostat has shown clear evidence of robust clinical activity in subjects with 9 of 16 
response evaluable subjects with previously treated B-cell lymphomas (2 CRs + 7 PRs) and in 
subjects with genetically-defined INI1 altered tumors consisting of 3 of 11 subjects showing 
clinical activity (1 CR, 2 PRs, and 1 SD with tumor reduction staying on study > 26 weeks).   
2.3. 
Benefit: Risk Assessments 
2.3.1 
Animal Toxicology 
Non-clinical repeated-dose oral toxicity studies in Sprague-Dawley (S-D) rats and cynomolgus 
monkeys, which may be relevant to human safety, revealed the following toxicities and target 
organs in the two species as follows: 
• In the gastrointestinal (GI) tract: ulcer/erosion in the stomach, duodenum, jejunum, 
and/or ileum 
• In lymphoid tissues: lymphoid depletion 
• In lymphoid tissues in S-D rats only: lymphoblastic lymphoma in a non-dose related 
fashion in 11 of 40 rats at 300 mg/kg (mid-dose) and in 1 of 40 animals at 600 mg/kg 
(high dose).  No cases of lymphoma were observed in the 100 mg/kg/day 
tazemetostat dose cohort in rats or at any dose cohort (100-600 mg/kg/day) in 
cynomolgus monkeys treated for 4 or 13 weeks.  The etiology and potential human 
relevance of the rat lymphoma is currently under continued laboratory investigation, 
but does not appear to be related to alterations in the Notch signaling pathway or 
endogenous rat leukemia virus reactivation. 
• In bone in S-D rats only:  there was trabecular bone formation in the femur and 
sternum in the 4- and 13-week studies 
• In the serum of monkeys only:  increase of chloride due to bromide derived from the 
tazemetostat bromide salt formulation (subsequent Phase 1 studies in humans have 
determined no detectable bromide levels) 
• In the liver of monkeys only: hepatocyte and Kupffer cell hypertrophy in the 4-week 
and 13-week studies, which was accompanied by pigmentation of Kupffer cells and 
bile duct hyperplasia in some cases in the 13-week study 
• In the kidney of monkeys only: glomerulopathy in the 13-week study 
Additional animal toxicology is provided in the Investigator’s Brochure (IB) for tazemetostat. 


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2.3.2 
Photo-Reactive Potential 
There are nonclinical data supporting a potential for phototoxicity, which has not been evaluated 
in humans. Hence, prolonged exposure to sunlight should be avoided during treatment. In 
addition, subjects should take other measures to avoid ultraviolet (UV) exposure such as wearing 
sun screen and sun glasses, wearing protective clothing, and avoiding tanning beds. Refer to the 
tazemetostat IB for details.  
2.3.3 
CYP3A Metabolism 
Tazemetostat is metabolized primarily by CYP3A.  Therefore, treatment with strong inhibitors or 
strong inducers of CYP3A within 14 days prior to first dose of tazemetostat and for the duration 
of study treatment is prohibited. Tazemetostat was also shown to be a time-dependent CYP3A 
inhibitor and a CYP3A4 inducer (EC50 value = 2.6 μmol/L) as well as an inhibitor of the CYP2C 
family in vitro.  CYP3A, CYP2C8, CYP2C9, and CYP2C19 substrates should be used with 
caution.  Medications that are substrates for CYP3A, CYP2C8, CYP2C9, and CYP2C19 and that 
have a narrow therapeutic range should be avoided if possible. 
2.3.4 
Anticipated Safety Profile 
Based on the ongoing Phase 1 study in adults, the AEs occurring in >5% of subjects regardless 
of attribution were asthenia, anorexia, thrombocytopenia, nausea, constipation, diarrhea, 
vomiting, anemia, dry skin, dysgeusia, dyspnea, muscle spasms, abdominal pain, 
hypophosphatemia, anxiety, depression, hypertension, influenza, insomnia, neutropenia, night 
sweats, and peripheral edema.  The possibly TRAEs seen in >5% of subjects included: asthenia, 
nausea, anemia, decreased appetite, muscle spasms, diarrhea, dry skin, dysgeusia, vomiting, and 
abnormal hair growth.  There have been only two Grade 4 TRAEs: thrombocytopenia and 
neutropenia. There has been no evidence of secondary lymphomas or other secondary cancers in 
subjects exposed to tazemetostat to date.  Additionally, there is the unknown risk of abnormal 
pregnancy outcomes and drug-drug interactions. Based on the preclinical toxicology of 
tazemetostat, the potential risks associated with treatment include GI AEs (nausea, vomiting, and 
diarrhea), lymphoid AEs (lymphoma in rats), liver AEs, renal AEs, bone AEs, and 
photosensitivity. 
2.4. 
Study and Dose Rationale 
2.4.1 
Study Rationale  
The preclinical antitumor activity of EZH2 inhibition in BAP1 mutant mesothelioma xenograft 
models highlights the potential clinical benefit of tazemetostat in BAP1 mutant mesothelioma.  
Given the available safety and initial activity data of tazemetostat in subjects with B-cell 
lymphoma and INI1-negative tumors in the Phase 1 FTIH study E7438-G000-101, non-clinical 


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safety profile, non-clinical efficacy data in xenograft models, and high unmet need in subjects 
with this poor prognosis cancer, especially in those with relapsed or refractory disease, there is 
an appropriate potential benefit to risk consideration to study tazemetostat in subjects with 
malignant mesothelioma. 
2.4.2 
Dosage Rationale  
The safety, tolerability, clinical activity, PK, and PD assessments from the subjects treated in the 
dose-escalation part of Study E7438-G000-101 were used to select the RP2D.  As of 07-Nov. 
2015, 58 subjects with advanced or metastatic solid tumors or B-cell lymphomas had been 
included in the Phase 1, dose-escalation part of the study. Clinical activity of EPZ-6438 was 
observed at dose levels of 100, 200, and 800 mg BID, including objective responses observed in 
9 of 16 response evaluable subjects with B-cell lymphoma who have had tumor assessments 
while on study drug. Objective responses were observed in 5/10 DLBCL, 3/5 FL, and 1/1 MZL 
subjects. A protocol-defined MTD was not established with EPZ-6438 doses of up to 1600 mg 
BID. 
A relationship between tazemetostat AUC on Day 15 and inhibition of H3K27Me3 in the stratum 
spinosum was observed and described by an inhibitory Emax model. The tazemetostat AUC0-12 at 
H3K27Me3 EC50 was 848 ng•h/mL and the Emax was 51% inhibition.  The predicted inhibition of 
H3K27Me3 in the stratum spinosum skin layer at the observed median Day 15 AUC0-12 in the 
800 mg twice daily dose cohort (3670 ng•h/mL) was over 80% of Emax.  These results suggest 
that target inhibition in the skin was near maximal at 800 mg tazemetostat twice daily and 
doubling the dose to 1600 mg twice daily results in only an incremental increase in the inhibition 
of the H3K27 methylation.  Furthermore, the greatest number of objective responses was 
observed in the 800 mg BID cohort during the dose-escalation part of the study.  Therefore, the 
RP2D of 800 mg BID was selected. This RP2D has been endorsed by the investigators and an 
IDMC. 
2.5. 
Good Clinical Practice (GCP) 
The principal investigator will ensure that the basic principles of GCP, as outlined in 21 Code of 
Federal Regulations (CFR) 312, subpart D, “Responsibilities of Sponsors and Investigators,” 21 
CFR, Part 50 (1998) and 21 CFR, Part 56, (1998) are followed.  
Since this is a covered clinical trial, the principal investigator is adhered to 21 CFR, Part 54, 
(1998).  A covered clinical trial is any “study of a drug or device in humans submitted in a 
marketing application or reclassification petition subject to this part that the applicant or FDA 
relies on to establish that the product is effective (including studies that show equivalence to an 


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effective product) or that make a significant contribution to the demonstration of safety.”  This 
requires that investigators and all sub-investigators must provide documentation of their financial 
interest or arrangements with Epizyme, Inc. or proprietary interests in the drug being studied. 
This documentation must be provided prior to the participation of the principal investigator and 
any sub-investigator. The principal investigator and sub-investigator agree to notify Epizyme, 
Inc. of any change in reportable interests during the study and for one year following completion 
of the study. Study completion is defined as the date that the last subject has completed the 
protocol-defined activities. 
 


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3. 
STUDY OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary  
 
Part 1 (Pharmacokinetics) 
• 
To assess the PK and safety profile of single and 
repeated doses of 800 mg tazemetostat 
administered as 400 mg tablets to subjects with 
relapsed or refractory malignant mesothelioma 
regardless of BAP1 status 
 
• 
AEs and clinical laboratory tests 
• 
Cmax, Tmax, AUC0-t, AUC0-∞ (single dose only), 
and t1/2 of tazemetostat after administration as 
400-mg tablets. 
 
Part 2 (Efficacy) 
• 
To assess disease control rate (DCR) at 12 weeks 
(consisting of complete response [CR], partial 
response [PR], or stable disease [SD]) according 
to modified RECIST [Nowak, 2005] for thoracic 
disease or RECIST 1.1 elsewhere in subjects 
with relapsed or refractory BAP1-deficient 
malignant mesothelioma treated with 
tazemetostat 
 
• 
DCR (CR+PR+SD) at Week 12 
 
Secondary  
 
Parts 1 and 2 
• 
To assess the safety and tolerability of 
tazemetostat 
 
• 
AEs and clinical laboratory tests 
• 
To assess the overall response rate (ORR) in 
subjects with relapsed or refractory malignant 
mesothelioma treated with tazemetostat 
• 
ORR (confirmed CR+PR) to tazemetostat in 
subjects with relapsed/refractory malignant 
mesothelioma using disease-appropriate 
standardized response criteria (modified RECIST 
or RECIST 1.1) 
• 
To determine the progression-free survival (PFS) 
and OS at 12 weeks, 24 weeks, and overall in 
subjects with relapsed or refractory malignant 
mesothelioma treated with tazemetostat 
• 
PFS at 12 weeks, 24 weeks, and overall (defined 
as the time from date of first dose of study 
treatment to the earlier of the date of first 
documented disease progression or date of death 
due to any cause) 
• 
OS at 12 weeks, 24 weeks, and overall (defined 
as the time from the date of the first dose of 
study treatment to the date of death due to any 
cause) 


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Objectives 
Endpoints 
• 
To evaluate the duration of response (DOR) in 
subjects with relapsed or refractory malignant 
mesothelioma treated with tazemetostat 
 
 
Part 1  
• 
To assess DCR at 12 weeks (consisting of CR, 
PR, and SD) in subjects with relapsed or 
refractory malignant mesothelioma treated with 
tazemetostat 
 
Part 2  
• 
To assess the population PK parameters of 
tazemetostat 
• 
To investigate the PD effects of tazemetostat in 
tumor tissue before and after treatment with 
tazemetostat (optional) 
 
• 
DOR, for the subset of subjects with a confirmed 
CR or PR (defined as the time from the first 
documented evidence of CR or PR to the time of 
first documented disease progression or death 
due to any cause, using disease-appropriate 
standardized response criteria) 
 
• 
DCR (CR+PR+SD) at Week 12 
 
 
 
 
 
• 
Population PK parameters oral clearance (CL/F), 
oral volume of distribution (Vd/F), and first-
order absorption rate constant (Ka) for 
tazemetostat 
• 
Changes in H3K27me3 levels between pre- and 
post-dose tumor tissue 
Exploratory  
 
Parts 1 and 2 
• 
To explore the relationship between plasma PK 
and tumor PD markers  
 
• 
Tumor target gene expression and phenotypic 
markers including those for differentiation, 
apoptosis, inflammation and cell proliferation 
and their correlation with activity 
• 
To assess tumor tissue and blood for somatic 
mutations, germline variants, messenger 
ribonucleic acid (mRNA), and/or proteins as 
candidate markers or response to tazemetostat 
• 
Somatic mutation analysis of tumor tissue and 
blood derived circulating deoxyribonucleic acid 
(DNA) 
 


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4. 
STUDY DESIGN 
4.1. 
 Study Sites 
This study will be conducted at 6 − 10 sites in the US and 3 − 4 sites each in France and the 
United Kingdom. 
4.2. 
Overview of Study Design 
This is a Phase 2, multicenter, open-label, 2-part, single-arm, 2-stage study of tazemetostat 
800 mg BID administered orally.  Screening of subjects to determine eligibility for the study will 
be performed within 21 days of the first planned dose of tazemetostat.   
In Part 1, 12 subjects with relapsed or refractory malignant mesothelioma regardless of BAP1 
status will be treated and undergo PK blood sample collection after a single tazemetostat 800 mg 
dose on Cycle 1 Day 1 and on Cycle 1 Day 15 after repeated BID doses of tazemetostat 800 mg.  
Subjects will receive a single oral 800-mg tazemetostat dose on Cycle 1 Day 1.  Starting on 
Cycle 1 Day 2, tazemetostat will be orally administered at a dose of 800 mg BID. 
Part 2 will include subjects with BAP1-deficient relapsed or refractory malignant mesothelioma. 
Subjects will receive orally administered tazemetostat 800 mg BID starting on Cycle 1 Day 1.  A 
two-stage Green-Dahlberg design will be utilized with a stopping rule to allow early termination 
at the end of Stage 1 if there is strong evidence of lack of efficacy based on results from the first 
30 treated subjects who meet the criteria outlined below.  If early stopping criteria are met, 
enrollment will be stopped.  To avoid disruptions in the study, enrollment and treatment of 
subjects will not be halted in order to conduct the interim analysis. 
The interim analysis will be performed after the first 30 treated subjects enrolled have completed 
at least the 12-week assessment, completed the final study visit or terminated early from the 
study, whichever is sooner.  This is to ensure subjects have adequate time to respond to 
treatment.  As it is desirable to perform the interim analysis in a timely manner, both confirmed 
and unconfirmed responses will be included. 
The interim analysis planned at the end of Stage 1 may occur sooner if the Stage 1 rejection 
criterion is surpassed before all 30 subjects are treated and followed for 12 weeks.  In this 
scenario, the total sample size (Stage 1 + Stage 2) would still remain unchanged at 55 subjects. 
Treatment with tazemetostat will continue until disease progression, unacceptable toxicity or 
withdrawal of consent, or termination of the study.  Response assessment will be evaluated after 
6 weeks of treatment and then every 6 weeks thereafter while on study. 


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Subjects also will undergo physical examinations (PEs); vital sign measurements; ECOG 
assessments, blood sample collection for hematology, chemistry, PK, and PD markers; 
electrocardiograms (ECGs); adverse event (AE) assessments; concomitant medication 
assessments; activity assessments, and pregnancy testing for females of childbearing potential. 
4.3. 
Rules for Suspension of Enrollment 
The investigators, IRBs/ECs, regulatory agencies and IDMC will be urgently informed and the 
IDMC convened to review the data and to make recommendations for potential changes in study 
conduct if one or more subjects develop any of the following AEs deemed to be definitely related 
to study treatment by the investigator and/or medical monitor, based upon close temporal 
relationship or other factors: 
• 
Death 
• 
Anaphylaxis (angioedema, hypotension, shock, bronchospasm, hypoxia or respiratory 
distress) 
• 
Secondary lymphoma 
Should study enrollment be suspended, the study will not be restarted until all parties have 
agreed to the course of action to be taken and the IRBs/ECs have been notified. 
 
 


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5. 
STUDY POPULATION 
5.1. 
Target Population 
This study will be conducted in up to 12 subjects (Part 1) and 55 subjects (Part 2) with malignant 
mesothelioma (pleural, peritoneal, pericardial, tunica vaginalis). 
5.2. 
Inclusion Criteria 
A subject must meet the following criteria to be eligible for entry into the study: 
1. Age (at the time of consent) ≥18 years of age 
2. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
3. Has a life expectancy of >3 months 
4. Has mesothelioma (pleural, peritoneal, pericardial, tunica vaginalis) of any histology that 
is relapsed or refractory after treatment with at least one pemetrexed-containing regimen 
5. Has a documented local diagnostic pathology of original biopsy confirmed by a Clinical 
Laboratory Improvement Amendments (CLIA)/College of American Pathologists (CAP) 
or equivalent laboratory certification 
6. Part 2:  Molecular evidence of BAP1 loss of function present on local pathology, 
e.g., lack of nuclear BAP1 staining by immunohistochemistry (IHC)  
7. Has sufficient archival tumor tissue (a minimum of 10 slides or tumor block) available 
for central retrospective testing of BAP1 status  
8. Has all prior treatment (i.e., chemotherapy, immunotherapy, radiotherapy) related 
clinically significant toxicities resolve to ≤ Grade 1 per CTCAE, version 4.03 or are 
clinically stable and not clinically significant, at time of enrollment 
9. Prior therapy(ies), if applicable, must be completed according to the criteria below prior 
to first dose of tazemetostat: 
a. Cytotoxic chemotherapy; at least 21 days since last dose 
b. Non-cytotoxic chemotherapy (e.g., small molecule inhibitor); at least 14 days 
since last dose 
c. Monoclonal antibody; at least 28 days since the last dose  
d. Non-antibody immunotherapy (e.g., tumor vaccine); at least 42 days since last 
dose 
e. Radiotherapy, at least 14 days from last local site radiotherapy  


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f. Hematopoietic growth factor; at least 14 days from last dose 
g. Investigational drug; 30 days or five half-lives, whichever is longer, from last 
dose 
10. Has measurable disease based on either modified RECIST [Nowak 2005] for thoracic 
disease or RECIST 1.1 elsewhere 
11. Has adequate hematologic (bone marrow and coagulation factors), renal, and hepatic 
function as defined by criteria below: 
a. Hemoglobin ≥9 g/dL 
b. Platelets ≥100,000/mm3 (≥100 × 109/L) without platelet transfusion for 7 days 
c. ANC ≥1000/mm3 (≥1.0 × 109/L) without growth factor support for 14 days 
d. Coagulation:  Prothrombin time (PT) <1.5 × ULN and partial thromboplastin time 
(PTT) <1.5 × ULN 
e. Creatinine < 2.0 × ULN  
f. Hepatic function: Total bilirubin <1.5 × ULN and ALT and AST <3 × ULN 
12. Has a QT interval corrected by Fridericia's formula (QTcF) ≤480 msec 
13. Willing to provide tissue for translational research 
14. Female subjects of childbearing potential must have a negative urine or serum pregnancy 
within 72 hours prior to receiving the first dose of study drug; if the urine test is positive 
or cannot be confirmed as negative, a serum pregnancy test will be required and subject 
also should agree to use an adequate method of contraception starting with screening 
through 30 days after the last dose of study therapy (if sexually active). 
15. Male subjects should agree to use condoms starting with the first dose of study therapy 
through 30 days after the last dose of study therapy if sexually active with a female of 
childbearing potential 
5.3. 
Exclusion Criteria 
A subject who meets any of the following criteria is ineligible for entry into the study: 
1. Has had prior exposure to tazemetostat or other inhibitor(s) of enhancer of zeste 
homologue-2 (EZH2)  
2. Has a history of known central nervous system metastasis 
3. Has had a prior malignancy other than the malignancies under study  


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Exception: A subject who has been disease-free for 5 years, or a subject with a history of 
a completely resected non-melanoma skin cancer or successfully treated in situ 
carcinoma is eligible. 
4. Has had major surgery within 3 weeks prior to enrollment (a percutaneous biopsy, pleural 
catheter insertion, placement of central venous catheter or other minor procedure are 
permitted) 
5. Is unwilling to exclude grapefruit juice, Seville oranges and grapefruit from the diet and 
all foods that contain those fruits from time of enrollment throughout their time on study 
6. Has cardiovascular impairment, history of congestive heart failure greater than NYHA 
Class II, uncontrolled arterial hypertension, unstable angina, myocardial infarction, or 
stroke within 6 months prior to the planned first dose of tazemetostat; or ventricular 
cardiac arrhythmia requiring medical treatment 
7. Is currently taking any prohibited medication(s) 
8. Has an active infection requiring systemic treatment 
9. Has a congenital or acquired immunodeficiency, including subjects with known history 
of infection with human immunodeficiency virus (HIV) 
NOTE: HIV-positive subjects who are taking antiretroviral therapy are ineligible due to 
potential PK interactions with tazemetostat.   
10. Has known history of chronic infection with hepatitis B virus (hepatitis B surface antigen 
positive) or hepatitis C virus (detectable anti-hepatitis C circulating viral RNA) 
11. Has had a deep venous thrombosis (DVT) or pulmonary embolism within the 2 weeks 
prior to study enrollment. 
NOTE: Subjects with a history of a DVT or pulmonary embolism > 2 weeks prior to 
study enrollment who are on anticoagulation therapy with low molecular weight heparin 
are eligible for this study. 
12.  Is pregnant of breastfeeding 


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6. 
INVESTIGATIONAL PRODUCT 
6.1. 
Description 
Tazemetostat (EPZ-6438) is an Epizyme investigational product (IP) and is defined as an 
Investigational Medicinal Product (IMP) under the European Union Clinical Trials Directive 
(EU CT Dir).    
The contents of the package label will be in accordance with all applicable regulatory 
requirements.  The expiry date will be printed on the label. 
Tablets will be provided in 200 mg and 400 mg strengths.  The 400-mg tablets will be used as 
primary treatment; however, if the median Cmax of the 400-mg tablets in Part 1 of the study is 
greater than twice the median Cmax observed with the 200-mg tablets used in the E7438-G000-
101 FIH study, the 200-mg tablets will be considered for use in Part 2 of the study.  The 200-mg 
tablets will be used when a dose reduction to 600 mg is required. 
 
Investigational Product 
Product name 
Tazemetostat (EPZ-6438) 
Formulation description 
200-mg tablet, 400-mg tablet 
Dosage form 
Tablet 
Physical description 
The 400-mg tablets are red, modified oval, biconvex, film-coated 
tablets with a length of approximately 18 mm.  The 200-mg tablets 
are red, round, biconvex, film-coated tablets with a diameter of 
approximately 10 mm.  Each strength is packaged in white high-
density polyethylene bottle with a child resistant, tamper-evident 
polypropylene screw cap. 
Dose/Route/Schedule/Duration  800 mg/Oral/ BID/Continuous 
 
6.2. 
Preparation, Handling and Storage of Investigational Product  
Preparation: No preparation is needed.    
Handling: The occupational hazards and recommended handling procedures are provided in the 
Material Safety Data Sheet (MSDS).  The MSDS describing the occupational hazards and 
recommended handling precautions will be provided to site staff if required by local laws or will 
otherwise be available from the sponsor upon request. 
Storage: Tazemetostat must be stored in a secure area with access limited to the investigator and 
authorized site staff.   


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6.3. 
Dosage and Administration 
Tazemetostat must be dispensed or administered only to subjects enrolled in the study and in 
accordance with the protocol.  Standard institutional procedures for administering an oral agent 
via by mouth will be followed.  An adequate supply will be provided with instructions on home 
administration. 
Tazemetostat will be orally administered at the RP2D of 800 mg/dose (two 400-mg tablets) 
given BID. In the event that PK results are not as expected in Part 1 of the study, four 200-mg 
tablets may be used in Part 2 of the study (see Section 6.1). An adequate supply will be provided 
with instructions on home administration. 
Tazemetostat will be administered BID with or without food.  Each dose of study drug should be 
given no sooner than 8 hours from the previous or next dose. If a dose is missed by over 4 hours, 
it should not be made up.  
Vomiting: If the subject vomits within 30 minutes of dosing, anti-emetics should be given and a 
second fresh dose of study treatment given.  All doses given, missed and vomited should be 
recorded in the dosing diary.   
6.4. 
Procurement of IP 
The initial shipment of tazemetostat to a clinical site will occur after all essential regulatory 
documents (including, but not limited to the receipt of the signed protocol signature page, signed 
Form Food and Drug Administration [FDA] 1572, curriculum vitae of principal investigator and 
designees, Institutional Review Board [IRB]/Ethics Committee (EC)/Central Ethics Committee 
[CEC] approval letter, and approved informed consent form [ICF]) are collected. 
Refer to the Pharmacy Manual for directions on re-supply shipments.  
6.5. 
Accountability 
The investigator/designee will be responsible for taking an inventory of each shipment of 
tazemetostat received and comparing it with the accompanying shipment form.  The 
investigator/designee will verify the accuracy of the information on the form, sign and date it, 
and acknowledge the shipment receipt according to the instructions provided. 
The investigator/designee must keep accurate written records of all tazemetostat received from 
the sponsor.  Additionally, the investigator/designee must keep accurate records of the 
tazemetostat dispensed to subjects enrolled in this study including the quantity of tablets, lot 
number, date dispensed, subject initials and identification number, dose administered, balance 


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forward, and the initials of the person dispensing the IP.  Based on the entries in the site 
accountability forms, it must be possible to reconcile IP delivered with that used and returned.  
All IP must be accounted for and all discrepancies investigated and documented appropriately. 
Tazemetostat stock may not be removed from the investigative site where originally shipped 
without prior knowledge and consent of the sponsor or its designee.  When authorized, all 
applicable local, state, and national laws must be adhered to for the transfer. 
At the end of the study, all unused tazemetostat will be destroyed by the investigative site or sent 
to a designated contractor for disposal on behalf of the sponsor, per the instructions at that time.  
Any IP returned to the sponsor-designated contractors must be counted and verified by site 
personnel and the sponsor or its designee.  All certificates of delivery/receipts and/or return 
forms must be signed prior to shipment.  The IP for return must be packed in a tamper-evident 
manner to ensure integrity is maintained during return.  All IP returned must be in accordance 
with local, state, and national laws and must first be authorized by the sponsor prior to shipment. 
 
 


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7. 
STUDY TREATMENT 
7.1. 
Treatment Assignment  
Subjects will be identified by a unique subject number that will remain consistent for the 
duration of the study. 
7.2. 
Restrictions During Study Treatment 
Subjects will abstain from ingesting Seville oranges and grapefruit or grapefruit juice and 
foods/beverages that contain those, for 24 hours prior to the first dose of study treatment until the 
last dose of study treatment.  Subjects should avoid prolonged exposure to sunlight while 
receiving study drug.  In addition, subjects should take other measures to avoid UV exposure 
such as wearing sun screen and sun glasses, wearing protective clothing, and avoiding tanning 
beds. 
7.3. 
Dose Modification 
No modification of dose is required for the following ≥ Grade 3 non-hematologic toxicities: 
• 
Transient fatigue or asthenia lasting < 24 hours 
• 
Transient myalgia or arthralgia lasting < 24 hours 
• 
Nausea that resolves to < Grade 2 within seven days (with or without anti-emetics) 
• 
Vomiting that resolves to < Grade 2 within 48 hours (with or without anti-emetics) 
• 
Diarrhea that resolves to < Grade 2 within 48 hours 
Other toxicities that, in the opinion of the investigator, are possible, probably or definitely related 
to study treatment, should be managed per Table 3. Toxicities that are felt by the investigator to 
be unrelated to tazemetostat but clinically significant should be discussed with the medical 
monitor. In the event of an urgent unrelated toxicity, study treatment should be interrupted as per 
Table 3.  Dose re-escalation is not permitted.  
Of note, in the event of an occurrence of a secondary neoplasm, including T-cell lymphoma, 
study treatment will be permanently discontinued.  See Sections 4.3 and 11.5 or further 
discussion. 


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Table 3: 
Dose Modifications for Treatment-Related Toxicities 
Toxicitya 
During Therapy 
Dose Adjustmentb 
Grade 1 
All occurrences 
Continue study treatment 
Maintain dose level 
Grade 2 
All occurrences 
Continue study treatment 
Maintain dose level 
Grade 3c (Not Including Neutropenia) 
1st occurrence 
Interrupt study treatment until 
resolved to Grade ≤1 or baselineb 
Restart at 600 mg BID 
2nd occurrence  
(same or new toxicity) 
Restart at 400 mg BID 
3rd occurrence  
(same or new toxicity) 
Discontinue study treatment  
Not applicable 
Grade 3 Neutropenia (ANC: <1 – 0.5 × 109/L) 
1st occurrence 
Interrupt study treatment until 
resolved to ANC ≥1.0 × 109/L 
Maintain dose level 
2nd occurrence  
Restart at 600 mg BID 
3rd occurrence  
Restart at 400 mg BID 
4th occurrence 
Discontinue study treatment 
Not applicable 
Grade 4d 
All occurrences 
Hold study treatment  
Resumption of dosing may 
occur only after discussion 
with medical monitor 
ANC = absolute neutrophil count; BID = twice daily 
a. 
Excluding alopecia and nausea, vomiting or diarrhea not receiving adequate treatment. 
b. 
A delay of tazemetostat for more than 14 days due to any toxicity may require permanent discontinuation of study 
treatment.  Study treatment may be resumed only after discussion with the medical monitor and a thorough assessment 
of the risk:benefit of resuming treatment. 
c. 
Exclude Grade 3 anemia: Subjects are allowed to continue tazemetostat at their current dose level with transfusion per 
investigator discretion. 
d. 
Grade 4 toxicity may require permanent discontinuation of study treatment.  Study treatment may only be resumed 
after discussion with medical monitor and a thorough assessment risk:benefit of resuming treatment at 600 mg BID.  
Toxicity must resolve to Grade ≤ 1or baseline before study treatment is restarted.  Should the same Grade 4 toxicity 
recur at 600 mg BID, study treatment will be held until the toxicity resolves to Grade ≤1 or baseline.  Study treatment 
will be discontinued or resumed at 400 mg BID following discussion with the medical monitor.  
 
 
7.4. 
Continuation of Treatment 
In subjects that are potentially benefitting (CR, PR, or SD per modified RECIST or RECIST 1.1) 
from tazemetostat treatment and that have not incurred unacceptable toxicity, tazemetostat 
administration may be continued.  Subjects will discontinue study treatment at the time of 
disease progression, development of an unacceptable toxicity, withdrawal of consent, or 
termination of the study. 


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Study treatment may continue if the following parameters are met on Day 1 of each cycle: 
• 
Platelet count must be ≥ 50 × 109/L; 
• 
ANC ≥ 1.0 × 109/L; and  
• 
Any Grade 3 or higher toxicity must have resolved to Grade 1 or baseline.   
Study treatment may be interrupted for up to 14 days.  Treatment interruptions longer than 
14 days need medical monitor approval to proceed. 
7.5. 
Treatment Compliance 
The subject will be requested to maintain a medication diary of each dose of tazemetostat.  The 
dosing diary will be returned to the site staff at each visit. 
7.6. 
Treatment of Overdose 
In the event of an overdose of tazemetostat (defined as administration of more than the protocol-
specified dose), the investigator should contact the medical monitor or their designee 
immediately and closely monitor the subject for AEs/SAEs and laboratory abnormalities.   
A subject suspected of overdose should be monitored until tazemetostat can no longer be 
detected systemically.  For reference, five half-lives of tazemetostat would be at minimum 
25 hours, longer in subject with delayed clearance.  Decisions regarding dose interruptions or 
modifications will be made by the investigator in consultation with the medical monitor or their 
designee based on the subject’s clinical evaluation. 
A plasma sample for PK analysis may be requested on a case-by-case basis.  If requested, the 
plasma sample should be collected at least within 7 days from the date of the last dose of study 
treatment.  
The quantity of the excess dose as well as the duration of the overdosing should be documented 
in the electronic case report form (eCRF). 
7.7. 
Tazemetostat Duration of Treatment 
Treatment with tazemetostat will continue until disease progression or unacceptable toxicity. 
Subjects may receive tazemetostat for an approximate duration of 12 months.  (Note:  If 
treatment is discontinued prior to completing 12 months, subjects will be followed for a 
maximum duration of 12 months from start of study drug dosing).  Those subjects who continue 
to derive clinical benefit from tazemetostat after 12 months of treatment may continue treatment 
on the current study as long as it is open and actively treating subjects. Once all subjects have 


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had the opportunity to receive 12 months of treatment, the active portion of the study may be 
closed per sponsor decision. Any subjects continuing to receive clinical benefit may rollover and 
continue to receive treatment on an extension study at the discretion of the investigator after 
discussion with the medical monitor.   


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8. 
STUDY ASSESSMENTS AND PROCEDURES 
Investigators may be requested to perform additional safety tests during the course of the study 
based on newly available data to ensure appropriate safety monitoring.  Appropriate local 
regulatory and ethical approvals should be obtained before any additional testing is performed. 
8.1. 
Consent 
All subjects must take part in the informed consent process.  Adequate time must be allowed for 
the subject to ask questions and make a voluntary decision.  No protocol-specific procedures, 
including screening procedures are to be performed until the subject has signed and dated an 
IRB/IEC/CEC-approved ICF.   
8.2. 
Screening Assessments 
A signed, written informed consent must be obtained prior to any study-specific assessments or 
procedures being performed. 
All screening assessments, including tumor assessment, must be performed within 21 days of 
enrollment. 
Procedures conducted as part of the subject’s routine clinical management (e.g., blood counts, 
chemistries, imaging studies) and obtained prior to consent may be used for screening provided 
the procedure meets the protocol-defined criteria and has been performed in the timeframe of the 
study. 
8.2.1 
Demographics and Medical History 
A complete medical history will be taken.  Information to be documented includes demographic 
information, prior medical illnesses and conditions, and surgical procedures. 
8.3. 
Study Assessments 
For study assessments not included in sections below (e.g., vital signs, ECOG performance 
status), refer to the Schedule of Assessments (Table 1) for details. 
8.3.1 
Physical Examinations 
8.3.1.1. 
Comprehensive Physical Examination 
A comprehensive physical examination (PE) of all body systems must be performed by a 
qualified licensed individual at screening, on Day 1 of each cycle through Cycle 8, and starting 
on Day 1 of Cycle 9, once every 6 weeks.  In addition, a complete PE is to be performed at the 
Post-Treatment/Early Termination visit.  A review of body systems will include the following: 
• 
General appearance 


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• 
Skin 
• 
Head, Ears, Eyes, Nose, Throat (HEENT)  
• 
Respiratory 
• 
Cardiovascular 
• 
Abdomen (including liver and kidneys) 
• 
Musculoskeletal 
Weight is required to be measured on Day 1 of each cycle.  Height measurement is required at 
screening only. 
Any abnormalities or changes in intensity noted during the review of body systems should be 
documented in the source document and reported appropriately in the eCRF.  If a new clinically 
significant finding (e.g., not noted at screening) occurs from the initial tazemetostat 
administration until the end of the study, an AE must be documented.  In addition, resolution of 
any abnormal findings during the study will be noted in source document and the eCRF if 
clinically significant. 
These assessments will be completed as indicated in the Schedule of Assessments (Table 1). 
8.3.1.2. 
Symptom-Directed Physical Examination 
A symptom-directed PE is to be performed on Days 8 and 15 of Cycle 1 by a qualified licensed 
individual.  This will consist of a focused review of systems and physical examination 
addressing any new symptoms, AEs, or complaints. 
These assessments will be completed as indicated in the Schedule of Assessments (Table 1). 
8.3.1.3. 
Vital Sign Measurements 
Blood pressure (BP), heart rate (HR), temperature (T) and respiratory rate (RR) must be 
measured after the subject has been sitting for five minutes. 
8.3.1.4. 
ECOG Performance Status 
Subject’s performance status will be assessed using the ECOG performance status tool. 
8.3.2 
Clinical Laboratory Assessments 
All clinical laboratory assessments (per Table 4, which follows) will be performed at local 
laboratories according to the laboratory’s normal procedures.  Reference ranges will be supplied 
by the laboratory and used to assess the laboratory data for out of range pathological changes and 
CTCAE grades, where applicable.   


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Table 4: 
Clinical Laboratory Panels 
Hematologya 
Serum Chemistry 
Coagulation 
• 
red blood cell count 
• 
WBC with differential 
(including neutrophils, 
basophils, eosinophils, 
lymphocytes, monocytes) 
• 
hemoglobin 
• 
hematocrit 
• 
platelet count 
• 
mean corpuscular volume 
(MCV) 
• 
mean corpuscular hemoglobin 
(MCH) 
• 
mean corpuscular hemoglobin 
concentration (MCHC) 
• 
albumin 
• 
amylase 
• 
alkaline phosphatase 
• 
ALT 
• 
AST 
• 
bicarbonate 
• 
BUN 
• 
calcium 
• 
chloride 
• 
creatinine 
• 
phosphorous 
• 
potassium 
• 
random glucose 
• 
sodium 
• 
total bilirubin   
• 
conjugated (direct) bilirubin (where possible) 
• 
total protein 
• 
magnesium 
• 
triglycerides 
• 
PT 
• 
PTT 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; PT = prothrombin time; PTT = 
partial thromboplastin time; WBC = white blood cell  
a. Differential should be recorded as absolute counts whenever possible. 
Starting from initial tazemetostat exposure, abnormalities in clinical laboratory tests that lead to a 
change in subject management (eg, dose delay, requirement for additional medication or 
monitoring) are considered clinically significant and will be recorded on the AE eCRF page. 
Abnormal laboratory values which are unexpected or not explained by the subject’s clinical 
condition should be repeated until confirmed, explained, or resolved.  If laboratory values 
constitute part of an event that meets criteria defining it as serious, the event (and associated lab 
values) must be reported as an SAE (see Section 11.2.1). 
8.3.3 
Pregnancy 
The effect of tazemetostat on fetal development has not been studied.  Consequently, precautions 
must be taken to avoid any pregnancy that could potentially be conceived during exposure to 
tazemetostat by EITHER male OR female subjects. 


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8.3.3.1. 
Definition of Childbearing Potential: Female Subjects 
A female subject is considered of childbearing potential if she: 
• Is anatomically and physiologically capable of becoming pregnant, and 
• Will be or could possibly be sexually active with a male while undergoing study 
treatment with the possibility of posing harm to a fetus 
A female subject is considered to be of non-childbearing potential (i.e., physiologically incapable 
of becoming pregnant) if she: 
• Is post-menopausal (at least 12 months consecutive amenorrheic), or 
• Is surgically sterilized (i.e., bilateral tubal ligation, total hysterectomy, or bilateral 
oophorectomy) with surgery at least 1 month before the first dose of study treatment 
• Has a documented congenital or acquired disorder that is incompatible with 
pregnancy 
8.3.3.2. 
Definition of Childbearing Potential: Male Subjects 
A male subject is considered of childbearing potential if he: 
• Is anatomically and physiologically capable of causing a pregnancy in a female 
partner 
 and 
• Will be or could possibly be sexually active with a female (who is or may become 
pregnant) while undergoing study treatment with the possibility of posing harm to a 
fetus 
A male subject is considered to be of non-childbearing potential if he: 
• Has a documented successful vasectomy  
8.3.3.3. 
Pregnancy Testing  
All female subjects of childbearing potential must have a negative pregnancy test (urine or 
serum) at screening and within 21 days of the first dose of study treatment.  A separate 
assessment is required if a negative screening pregnancy test was obtained more than 72 hours 
before the first dose of study treatment.  
Subsequent pregnancy tests should be performed on the first day of every cycle of study 
treatment and may be either urine or serum. 
Positive urine tests are to be confirmed by serum testing. 


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8.3.3.4. 
 Prevention  
8.3.3.4.1. Female Subjects  
Females of childbearing potential must agree to use a highly effective method of contraception, 
that results in a failure rate of < 1% per year when used consistently and correctly, starting at 
screening, during study treatment, and for 30 days after the final dose of study treatment, and 
have a male partner who uses a condom when using hormonal contraceptives.  
Acceptable highly effective contraception includes: 
• Placement of an intrauterine device 
• Established hormonal contraceptive methods: oral, injectable, or implant.  
NOTE: Female subjects who are using hormonal contraceptives must have been on a 
stable dose of the same hormonal contraceptive product for at least 4 weeks prior to the 
first dose of study treatment and must continue to use the same contraceptive during 
study treatment and for 30 days after discontinuation of study treatment.   
Due to the potential of enzyme induction with tazemetostat, female subjects who use 
hormonal contraceptives should use an additional barrier method of birth control while 
on study treatment and for 30 days after discontinuation of study treatment. 
Female subjects exempt from this requirement are subjects who practice true abstinence when 
this is in line with the preferred and usual lifestyle of the subject (periodic abstinence [e.g., 
calendar, ovulation, symptothermal, post-ovulation methods], declaration of abstinence for the 
duration of the trial, and withdrawal are not acceptable methods of contraception), or have a 
male partner who is vasectomized. If currently abstinent, the subject must agree to use a highly 
effective method of contraception as described above if they become sexually active during 
study treatment, and for 30 days after discontinuation of study treatment.  
8.3.3.4.2. Male Subjects 
Male subjects of childbearing potential must agree to use condoms with their female partner of 
childbearing potential prior to enrollment, during study treatment and for 30 days after the final 
dose of study treatment. 
8.3.4 
Electrocardiograms (ECGs) 
The ECGs will be performed as indicated in the Schedule of Assessments (Table 1).  Machine-
read ECGs should be reviewed by the investigator at the time of assessment. A single ECG will 
be recorded unless there is an abnormality, such as prolonged QTc(F) ≥ 480 msec, new 


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arrhythmia, or other clinically significant finding.  If such an abnormality is observed, the ECG 
is to be performed in triplicate at least 2 minutes apart. On days when an ECG reading and a PK 
blood sample collection are scheduled at the same time, the ECG reading should be performed 
immediately prior to collection of the PK blood sample, if possible.   
ECGs will be read by a Central Reader within 72 business hours and data from the Central 
Reader should be entered in the clinical database. 
8.3.5 
Disease Assessment  
Disease assessments will be performed as indicated in the Schedule of Assessments and 
Procedures (Table 1). 
Tumor assessments are to be performed by disease-appropriate standard criteria (modified 
RECIST for thoracic disease or RECIST 1.1 elsewhere) using CT/MRI of known sites of disease 
as clinically indicated.  Bone scan should be performed only if clinically indicated.  18FDG-PET 
scan should be performed as clinically indicated at the investigator’s discretion, and is not a 
required tumor assessment. 
8.3.6 
Pharmacokinetics 
The first 12 treated subjects in Part 1 of the study will undergo PK blood sampling.  A PK blood 
sampling scheme will be used in all subsequent subjects enrolled in Part 2 of the study.  Blood 
samples for PK analysis must be drawn per the Schedule of Assessments (Table 1).   
A separate Laboratory Manual detailing the PK sample collection, preparation, storage and 
shipping process will be provided.   
8.3.7 
Pharmacogenomics (PGx) 
A single whole blood sample is to be collected during the screening phase (this sample may be 
collected on Cycle 1 Day 1 if unable to collect during screening) to provide DNA for analysis of 
genes involved in drug disposition (i.e., absorption, distribution, metabolism and excretion 
[ADME]).  This will support investigation of whether subject genotype, specifically of ADME 
genes, is related to the PK of tazemetostat. In addition, DNA sequencing may be performed for 
determination of germline DNA variants in BAP1. 
A separate Laboratory Manual detailing the PGx sample collection, preparation, storage and 
shipping process will be provided.   


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8.4. 
Correlative Assessments 
8.4.1 
Archive Tumor or Biopsy at Screening 
An archival tumor block or biopsy is requested at screening from all subjects enrolled in the 
study.  The diagnostic pathology block or tumor tissue obtained at the time of the subject's initial 
diagnosis and/or at the time of subsequent procedures is acceptable.  The sponsor or its designee 
will return all blocks to the originating site on completion of the associated analyses.  If a tumor 
block is not available, 10-15 unstained paraffin-embedded tumor tissue containing slides may be 
provided.   
If archive tumor material is not available a tumor biopsy obtained during screening is also 
acceptable. 
Independent central confirmation will not be required for study entry (local pathology results 
showing BAP1-deficiency will be used for study entry). Central confirmation of diagnosis with 
appropriate IHC will be performed.  
Tumor tissue may be analyzed for DNA, mRNA and/or proteins potentially associated for 
response to tazemetostat up to and including whole genome sequencing. 
A Laboratory Manual detailing the tumor sample collection, preparation, storage and shipping 
process will be provided.  
8.4.2 
Paired Tumor Biopsies to Assess Tazemetostat PD 
A pre-dose tumor biopsy (to be collected during screening) and post-dose tumor biopsy for PD 
analysis is requested from all subjects, when medically feasible, at the first or second tumor 
assessment (Cycle 3 or 5) or any time between the two assessments.  A minimum of 12 patients 
will be required to provide pre- and post-dose biopsies.  If the clinical study accrual has reached 
75% and the goals for subjects undergoing tumor biopsy have not been met, only those 
subjects who can undergo tumor biopsy will be enrolled.  If the study subsequently completes 
accrual of 12 subjects with pre- and post-dose biopsies and the study accrual is still open, the 
study will then enroll all subjects irrespective of their ability to provide pre- and post-dose 
biopsies. 
A Laboratory Manual detailing the tumor sample collection, preparation, storage and shipping 
process will be provided.   


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8.4.3 
Circulating Tumor DNA 
Blood samples are collected at screening and at each response assessment to provide circulating 
tumor DNA that can be used for identification of candidate biomarkers of response to 
tazemetostat. 
A separate Laboratory Manual detailing the circulating tumor DNA sample collection, 
preparation, storage and shipping process will be provided.   
8.4.4 
Biomarkers of Response Assessment 
Correlations of trends in subjects’ clinical response to the molecular characteristics of their 
tumor (e.g., diagnostic molecular lesions, somatic mutations) may provide evidence of the 
biological basis for response to tazemetostat.  Such investigations are emerging as an effective 
strategy to inform future clinical development.   
8.4.4.1. 
Tumor Tissue Sample(s)   
Tumor tissue will be assessed to centrally confirm BAP1-deficiency that is required for 
enrollment.  These samples will be used to identify candidate biomarkers of response to 
tazemetostat via methods, which may include characterization of subjects’ tumor heterogeneity 
using both protein and nucleic acid based methodologies up to and including whole genome 
sequencing of tumor RNA/DNA. Local pathology results are acceptable for enrollment and 
eligibility determination. 
8.4.5 
Assessment of Relapse/Resistance to Tazemetostat 
Subjects who initially respond to tazemetostat could subsequently either relapse or become 
resistant to tazemetostat through as yet unidentified mechanisms such as drug-induced de-novo 
mutation.   
Tumor Biopsy:  A subsequent tumor biopsy, if medically feasible, at relapse in subjects who 
achieve a CR or PR to tazemetostat will be requested to enable assessment of adaptive 
mechanisms of resistance.  Tumor characterization by DNA, RNA, or protein may be performed 
to define molecular changes observed in relapsed tumors. 
8.5. 
Future Use of Tissue Samples 
Not all of the tissue and blood components obtained during this study may be required for the 
tests that are part of the clinical trial. Following the conclusion of the study, the samples may be 
used for additional research. These samples will be held for a maximum of 15 years. This 
research will help to understand disease subtypes, drug response and toxicity, and possibly 
identify new drug targets or biomarkers that predict subject response to treatment. The use of the 


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samples for internal research will be done according to the guidelines defined by the FDA 
guidance for In Vitro Diagnostic Device Studies Using Leftover Human Specimens that are Not 
Individual Identifiable (issued 25 April 25 2006) and the European Medicines Agency (EMA) 
Reflection Paper on Pharmacogenetic Samples, Testing and Data Handling 
(EMEA/CHMP/PGxWP/201914/2006). If a subject requests destruction of their tissue and blood 
samples and the samples have not yet been de-identified, the sponsor will destroy the samples as 
described in this FDA guidance. The sponsor will notify the investigator in writing that the 
samples have been destroyed. 


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9. 
CONCOMITANT MEDICATIONS 
Documentation of all concomitant medication administered during study treatment will be 
recorded in the eCRF at each visit. 
Because there is a potential for interaction of tazemetostat with other concomitantly administered 
drugs through the cytochrome P450 system, over-the-counter medications, or alternative 
therapies must be recorded in the eCRF.  The investigator should be alerted if the subject is 
taking any agent known to affect or with the potential to affect selected CYP450 isoenzymes. 
9.1. 
Permitted Medication(s) 
• Supportive care measures and symptomatic treatment for any treatment-related 
toxicity, including short courses of corticosteroids, if clinically indicated  
• Prophylactic use of standard anti-emetics 
• Intermittent use of dexamethasone is permitted as an antiemetic (not to exceed 
0.3 mg/kg/dose dexamethasone or maximum dose of 20 mg) every 12 hours as 
needed   
• Blood and platelet transfusions, as needed per the judgment of the investigator 
9.2. 
Medications to be used with Caution 
Substrates of P-gp, CYP3A, CYP2C8, CYP2C9, CYP2C19, and CYP2D6 should be used with 
caution.  Medications that are substrates of CYP3A, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 
and have a narrow therapeutic range should be avoided if possible 
NOTE: A listing of CYP substrates can be found using the following link: 
 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx 
A list of medications that are CYP3A, CYP2C8, CYP2C9, CYP2C19, and CYP2D6 substrates 
that have a narrow therapeutic range can be found with following link:  
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugIntera
ctionsLabeling/ucm093664.htm 
9.3. 
Prohibited Medication(s) 
• Antineoplastic therapy or other investigational therapy for the treatment of cancer 
• Prophylactic use of hematopoietic colony stimulating factors  


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NOTE:  Therapeutic use of hematopoietic colony stimulating factors is discouraged 
and should be discussed with the medical monitor and should be conducted 
according to the 2006 American Society for Clinical Oncology (ASCO) Guideline 
for use of white blood cell (WBC) growth factors [Smith, 2006]. 
• Treatment with strong inhibitors or strong inducers of CYP3A4 should not be taken 
within 14 days prior to first dose of study treatment and for the duration of study.   
NOTE: A listing of CYP inhibitors, inducers, and substrates can be found using the 
following link: http://medicine.iupui.edu/clinpharm/ddis/table.aspx 
• Enzyme inducing anti-epileptic drug(s) (EIAED) including, but not limited to, 
carbamazepine, phenobarbital, phenytoin and barbiturates, should not be taken within 
14 days prior to the first dose of study treatment and for the duration of study 
treatment 
• All herbal remedies and (including remedies in the form of herbal teas/infusions) are 
excluded while enrolled in the study 
• Medicinal food supplements such as calcium, folic acid, vitamin D, multi-vitamin, 
etc., which have been taken under the advice from a physician, should be continued at 
the same dose and regimen during the study provided there are no contraindication as 
above. These should be listed as concomitant medications in the CRF. 
• Any other supplements or alternative therapies should be discussed with the medical 
monitor prior to enrollment in the study or prior to initiating them during the study. 
9.4. 
Non-Drug Therapies 
Radiation Therapy:  Palliative radiation therapy and potential concurrent dose interruptions 
will be permitted for pain or severe symptom control after discussion with the medical monitor. 
Radiation will be limited to non-target lesions only and documented in the eCRF. 
Other Palliative Procedures: Other procedures intended for symptom control and potential 
concurrent dose interruptions may be permitted after discussion with the medical monitor.  These 
procedures will be limited to non-target lesions only and documented in the eCRF. 
 


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10. 
WITHDRAWAL AND REPLACEMENT OF SUBJECTS 
10.1. 
Withdrawal of Subjects from Treatment/Procedures 
Subjects have the right to withdraw from the study at any time and for any reason without 
prejudice to future medical care by the physician or institution.   
Subjects (or legally authorized representatives) can decline to continue receiving tazemetostat 
and/or other protocol-required procedures at any time during the study but can continue 
participation in the study (e.g., for follow-up information).  If this occurs the investigator is to 
discuss with the subject appropriate processes for discontinuation and the options for procedures 
that may continue such as collection of data, including endpoints and AEs.  The investigator 
must document the agreement in the procedures that the subject will continue with and the level 
of follow-up that is agreed to by the subject (e.g., in person, by telephone/mail, through 
family/friends, in correspondence/communication with other physicians, from review of the 
medical records.) 
Reasons for removal from protocol-required treatment or procedures might include the 
following: 
• Disease progression 
• Subject request to end study treatment and/or procedures 
• Safety concern (e.g., AE, failure to follow contraception or pregnancy, excluded 
medication required) 
10.2. 
Survival Follow-Up 
Subjects who permanently discontinue study treatment will be followed (by phone, email or 
clinic visit) for survival every 12 weeks until death, withdrawal of consent, or lost to follow-up.  
Survival follow-up will continue until 80% of treated subjects have died.  At such time, the 
subjects who are continuing on study treatment and have received 12 months of treatment on the 
current study will be followed and treated on a subsequent extension study.  
10.3. 
Subsequent Therapy After Discontinuation of Study Treatment 
Once a subject has permanently discontinued study treatment, every effort should be made to 
have the subject complete the post-treatment follow-up visit prior to initiating any subsequent 
anti-cancer therapy (approved or investigational).  Post-study anti-cancer therapy will not be 
provided as part of this study. The subject may receive subsequent anti-cancer therapy at the 


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discretion of the treating physician.  The subsequent anti-cancer therapy should be documented 
on the eCRF. 
10.4. 
Evaluation of Response to Subsequent Anti-Cancer Therapy 
To identify a potential epigenetic priming effect of tazemetostat, subjects who are withdrawn 
from this study due to disease progression and who go on to receive subsequent induction 
therapy should be followed for response whenever possible.  Data to be recorded on the 
subsequent regimen should include agents received, best response and DOR. 
10.5. 
 Withdrawal of Subjects from Study 
Withdrawal of full consent for a study means that the subjects does not wish to receive further 
protocol-required treatment, procedures and does not wish to or is unable to continue further 
study participation.  Subject data up to withdrawal of consent will be included in the analysis of 
the study, and where permitted, publicly available data can be included after withdrawal of 
consent (e.g., death records).  The investigator must document this agreement regarding 
withdrawal of full consent as well as discuss appropriate procedures for withdrawal from the 
study.   
Reasons for removal of a subject from the study might include the following: 
• Death 
• Decision by sponsor to terminate the study 
• Subject request to withdraw from study 
• Lost to follow-up 
10.6. 
Replacement of Subjects 
Subjects on Part 2 of the study will not be replaced.  Subjects on Part 1 of the study will be 
replaced if there are not a sufficient number of samples to calculate PK parameters. 
10.7. 
 Progression of Disease in Subjects Continuing to Receive Clinical Benefit 
There may be some instances when subjects are noted to have modest disease progression.  For 
example, a slight increase in target lesions but with stable non-target lesions, and in the absence 
of clinical deterioration are receiving continued clinical benefit in the opinion of the investigator.  
In such a situation, the investigator should contact the medical monitor to discuss the assessment 
of risk: benefit of keeping the subject on study.  


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Prior to declaring progressive disease, the investigator should be certain that special 
circumstances on progression defined by RECIST 1.1 are not met.  In these situations of 
equivocal findings of progression, subjects may continue treatment until the next scheduled 
disease assessment.  If progression is confirmed, the date of the previous assessment will be used 
as the date of disease progression. 
 
 


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11. 
SAFETY 
11.1. 
Safety Parameters 
11.2. 
Adverse Event Definition 
11.2.1 
Adverse Events 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a medicinal product and which does not necessarily have to have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of an IP, whether or not related to the IP.  
Worsening of a pre-treatment event, after initiation of tazemetostat, must be recorded as a new 
AE.  For example, if a subject experiences mild intermittent dyspepsia prior to dosing 
tazemetostat, but the dyspepsia becomes severe and more frequent after the first dose of 
tazemetostat, a new AE of severe worsening dyspepsia (with the appropriate date of onset) 
should be recorded in the eCRF. 
“Lack of efficacy” or “failure of an expected pharmacological action” per se is not to be reported 
as an AE or SAE.  However, any signs and symptoms and/or clinical sequelae resulting from 
“lack of efficacy” will be reported as an AE or SAE, if they fulfill the definition of an AE or 
SAE.  
Events that do not meet the definition of an AE include: 
• Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that 
leads to the procedure is an AE. 
• Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 
11.2.2 
Serious Adverse Events 
An SAE is any untoward medical occurrence that, at any dose: 
a. 
Results in death 
b. Is life-threatening 


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NOTE:  The term 'life-threatening' in the definition of 'serious' refers to an event in 
which the subject was at risk of death at the time of the event.  It does not refer to an 
event, which hypothetically might have caused death, if it were more severe. 
c. 
Requires hospitalization or prolongation of existing hospitalization 
NOTE:  In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
out-patient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious.  When in doubt as to whether “hospitalization” occurred or was necessary, the 
AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
d. Results in disability/incapacity, or 
NOTE:  The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions.  This definition is not intended to include experiences of 
relatively minor medical significance such as uncomplicated headache, nausea, vomiting, 
diarrhea, influenza, and accidental trauma (e.g., sprained ankle) which may interfere or 
prevent everyday life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect.  
Medical or scientific judgment should be exercised in deciding whether reporting is appropriate 
in other situations, such as important medical events that may not be immediately life threatening 
or result in death or hospitalization but may jeopardize the subject or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the above definition. These 
should also be considered serious. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions (in 
subjects without pre-existing seizure disorder) that do not result in hospitalization, or 
development of drug dependency or drug abuse. 
11.3. 
Laboratory Abnormalities 
A clinical laboratory AE is any laboratory value that is considered clinically significant by the 
investigator and has caused a medical intervention or is accompanied by clinical symptoms.  
Laboratory abnormalities that have not required medical intervention should not be recorded as 
AEs and will be captured and reported in the laboratory section of the clinical study report 
(CSR).  If a medical intervention occurs, it should be recorded as a treatment with the abnormal 


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laboratory finding as the AE (e.g., anemia with treatment required and blood transfusion 
recorded as a procedure, hyperglycemia with treatment required and change in insulin dose 
recorded on concomitant medications). 
The investigator should decide, based upon the AE criteria and the clinical condition of the 
patient, whether a change in a laboratory parameter is clinically significant and therefore 
represents an AE. 
If, at the end of the treatment phase with the study drug, there are pathological laboratory values 
which were not present at baseline, further clinical or laboratory investigations should be 
performed until the values return to within reference range or until a plausible explanation (i.e., 
concomitant disease) is found for the pathological laboratory values. 
11.4. 
Other Safety Assessment Abnormalities 
Other safety assessments (e.g., ECGs, radiological scans, vital signs measurements), including 
those that worsen from baseline and events in the medical and scientific judgment of the 
investigator are considered to be clinically significant, are to be recorded as an AE or SAE, in 
accordance with the definitions provided in Sections 11.2.1 and  11.2.2, respectively.   
Any other safety assessment that led to an intervention, including permanent discontinuation of 
study treatment, dose reduction, and/or dose interruption/delay is also to be recorded as an AE or 
SAE.   
11.4.1 
Disease-Related Events 
Events that meet the criteria for serious but are thought to be associated with progression of the 
disease under study should be reported as SAEs but will not typically be processed as expedited 
reports to regulatory authorities.  
NOTE:  Disease progression per se should not be reported as an SAE. 
11.5. 
Adverse Events of Special Interest (AESIs) 
For this study, AESIs will include: 
• Occurrence of T-cell lymphoma (refer to Section 11.10 for instructions on continued 
reporting of these events).  Refer to Section 4.3 for management of secondary 
lymphoma 
• Events considered related to abnormal bone formation and confirmed by radiologic 
scan.  


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• AEs associated with treatment overdose, misuse, abuse, or medication error; and any 
treatment-emergent significant laboratory abnormality.   
These AESIs are to be captured using the SAE procedures but are to be considered as SAEs only 
if they met one of the above criteria.   
11.6. 
Grading and Severity 
The severity of all AEs and SAEs, including appropriate laboratory values, will be graded 
utilizing the CTCAE v4.03.  The link to the CTCAE Version 4.03 is: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf 
In the event that an AE is not covered by the CTCAE, the assessment of severity will be 
determined by using the CTCAE general guideline: 
Grade 1: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2: 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL.a 
Grade 3: 
Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care ADL.b 
Grade 4: 
Life-threatening consequences; urgent intervention indicated. 
Grade 5: 
Death related to AE 
ADL = Activities of Daily Living; AE = adverse event 
Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. 
Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden. 
 
An AE that is assessed as severe should not be confused with an SAE.  Severity is a category 
used for rating the intensity of an event (as in ‘mild’, ‘moderate’, or ‘severe’); both AEs and 
SAEs can be assessed as severe.  An event is described as ‘serious’ when it meets one of the pre-
defined outcomes as described in Section 11.2.2 which are based on patient/event outcome or 
action criteria associated with events that pose a threat to a subject’s life or functioning 
11.7. 
Relationship Categorization 
A qualified investigator must make the determination of relationship to tazemetostat for each AE 
or SAE.  The investigator should decide whether, in his or her medical judgment there is a 
reasonable possibility that the event may have been caused by tazemetostat.   
11.7.1 
Assessing Relationship to Study Treatment 
The following should be considered when assessing the relationship of an AE to study treatment: 


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• Temporal relationship of the onset of the event to the first dose of tazemetostat 
• The course of the event, considering especially the effect of discontinuation of study 
treatment or the 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 non-study treatment-related factors that are known to be associated 
with the occurrence of the event. 
The relationship of an AE to study treatment is to be classified as follows: 
• Not Related: A causal relationship between tazemetostat and the AE is not a 
reasonable possibility. 
• Related:  A causal relationship between tazemetostat and the AE is a reasonable 
possibility (includes probably, possibly and definitely related).   
If the causal relationship between an AE/SAE and tazemetostat is related, that determination will 
be used for purposes of expedited regulatory reporting. 
11.8. 
Outcome Categorization 
Outcome of an AE/SAE may be classified as resolved, resolved with sequelae, unresolved or 
death. 
All treatment-related AEs/SAEs will be followed to resolution (the subject’s health has returned 
to his/her baseline status or all variables have returned to normal), or until an outcome is reached, 
stabilization occurs (the investigator does not expect any further improvement or worsening of 
the event), or the event is otherwise explained, regardless of whether the subject is still 
participating in the study.  Where appropriate, medical tests and examinations will be performed 
to document resolution of the event(s). 
11.9. 
Timeframe for Reporting AEs and SAEs 
AEs: AEs will be collected from the time the first dose of study treatment is administered until 
the earlier of either 30 days after the discontinuation of study treatment or until the initiation of 
subsequent anti-cancer therapy.  
SAEs: SAEs will be collected over the same time period as stated above for AEs.  In addition, 
any SAE assessed as related to study participation (e.g., protocol-mandated procedures, invasive 


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tests, or change in existing therapy), study treatment must be recorded from the time a subject 
provides consent to participate in the study up to and including any follow-up contact. All SAEs 
will be reported to the sponsor within 24 hours.    
After discontinuation of study treatment:  The investigator will monitor all ongoing 
AEs/SAEs until resolution or stabilization of the event or until the subject is lost to follow-up or 
has withdrawn consent.  Up until 30 days after the last dose of study treatment or until the 
initiation of subsequent anti-cancer therapy, whichever is earlier, the Investigator will report any 
AE that they consider to be possibly related to study treatment.    
Note that any incidence of secondary lymphoma, even if occurring more than 30 days after the last 
dose of study drug, will be reported to the Sponsor as an SAE. 
11.10. 
Reporting of SAEs 
All SAEs will be reported within 24 hours of the investigator becoming aware of the event.  The 
investigator must promptly notify the sponsor or its designee of all SAEs in order that the legal 
obligations and ethical responsibilities of the sponsor or its designee are met. 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of the IP under clinical investigation.  The sponsor and its 
designee will comply with country specific regulatory requirements relating to safety reporting to 
the regulatory authority, IRB/EC/CEC and investigators. 
Any AE that is both unexpected (not consistent with the applicable product information) and also 
meets the definition of a serious adverse event/reaction would be considered a suspected 
unexpected serious adverse reaction (“SUSAR”). All SUSARs will be reported within 24 hours 
of the Investigator becoming aware of the event. SUSARs are prepared for expedited reporting 
according to local regulatory requirements and are forwarded to Investigators as necessary. The 
Sponsor is legally obligated to report the event to the regulatory authorities within 7 days for 
fatal or life-threatening SUSARs or 15 days for all others. 
An investigator who receives an investigator safety report describing a SAE(s) or other specific 
safety information (e.g., summary or listing of SAEs) from the sponsor will file it with the IB 
and will notify the IRB/EC/CEC, if appropriate according to local requirements. 


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11.10.1 
Regulatory Authorities, IRB/EC, and CECs 
The sponsor or its designee is responsible for notifying the investigational sites of all expedited 
SAEs.  The sponsor or designee shall also notify Central Ethics Committees (CEC) of new 
serious, related, and unexpected AE(s) or significant risks to subjects, per country requirements. 
The investigator will notify the IRB/EC/CEC of serious, related, and unexpected AE(s) or 
significant risks to subjects, per local country requirements.  The investigator must keep copies 
of all AE information, including correspondence with the sponsor or local IRB/EC/CECs on file. 
It is the responsibility of the Principal investigator to notify the IRB/EC of all SAEs that occur at 
his/her site.  Investigators will be notified of all suspected, unexpected SAEs (7/15-Day Safety 
Reports) that occur during any clinical studies that are using the investigative compound.  Each 
site is responsible for notifying their IRB/EC/CEC of these additional SAEs. 
All studies that are conducted within any European country will comply with the European CTD 
2005/28/EC and CTD 2001/20/EC.  All SUSARs will be reported as required to the Competent 
Authorities of all involved European member states. 


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12. 
DATA MANAGEMENT 
Data from eCRFs and other external data will be entered into an Electronic Data Capture clinical 
database.  These data will be electronically verified through the use of real-time checks 
processed during data entry, and through programmed edit checks as specified in the data 
management plan.  Discrepancies in the data will be brought to the attention of the clinical team 
and investigational site personnel, if necessary, in the form of an electronic data query.  
Resolutions to these issues will be reflected in the database and an audit trial within the system 
will track all queries and changes made to the data.   Quality control audit(s) will be performed. 
12.1. 
Coding 
Concomitant medications will be assigned a code using the version of the World Health 
Organization (WHO) dictionary (version June 2015 or higher) drug codes specified in the data 
management plan (version June 2015 or higher).  Concomitant medications will be further coded 
to the appropriate Anatomical-Therapeutic-Chemical (ATC) code indicating therapeutic 
classification.  A listing of concomitant medications by drug and drug class will be included in 
the CSR for this protocol. 
AEs will be classified into standardized terminology from the verbatim description (investigator 
term) according to the version of the Medical Dictionary for Regulatory Activities (MedDRA) 
coding dictionary (version 18.0, or higher) specified in the data management plan. AEs will be 
presented by Preferred Term (PT) nested within System Organ Class (SOC).  Verbatim 
description and PT and SOC MedDRA-level terms for all AEs will be contained in the data 
listings of the CSR for this study. 


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13. 
STATISTICAL METHODS 
13.1. 
Hypotheses 
For Part 2 of the study, the null hypothesis is that DCR rate after 12 weeks of treatment 
(percentage of subjects with a CR, PR or SD at the Week 12 tumor assessment), as assessed at 
the Stage 2 analysis, is not clinically meaningful (≤20%).  The alternative hypothesis is that the 
DCR rate at 12 weeks is clinically meaningful (≥35%) and, therefore, the study treatment 
warrants further development.  At the Stage 1 analysis, 30 subjects will be enrolled and treated, 
and the analysis and decision rules specified here are based on 30 subjects.  For the Stage 1 
analysis with 30 treated subjects, at least five CR+PR+SDs are needed for the part to declare a 
success i.e., to have demonstrated sufficient clinical activity.  At the end of the study, if there are 
17 or more CR + PR +SDs out of 55 treated subjects, then the new treatment is accepted. 
13.2. 
Study Design Considerations 
13.2.1 
Determination of Sample Size 
The sample size of 12 subjects for Part 1 is sufficient for an initial assessment of the PK and 
safety profiles of the 400 mg tablet. 
For Part 2 of the study, evaluation will be done using a Green-Dahlberg two-stage design, to 
allow early termination of the study due to the lack of efficacy.  The sample size is calculated on 
the primary endpoint.  The hypothesis will be tested using a one-sided test with α=0.05 and the 
type II error rate will be controlled at 0.2.  The numbers of subjects to be enrolled using a Green-
Dahlberg two-stage design is listed in the table below. 
Green-Dahlberg 
CR + PR + SD 
at 12 Weeks 
Stage 1 Sample Size (n1) 
30 
Stage 1 Rejection of Drug (r1) 
4 
Maximum Sample Size (n)a 
55 
Stage 2 Rejection of Drug (r) 
16 
CR = complete response; PR = partial response; SD = stable disease 
a. The interim analysis planned at the end of Stage 1 may occur sooner if the 
Stage 1 rejection criterion is surpassed before all 30 subjects are treated and 
followed for 12 weeks.  In this scenario, the total sample size (Stage 1 + 
Stage 2) would still remain unchanged at 55 subjects.  
Approximately 30 subjects will be enrolled and treated in Stage 1 (see Section 13.3.2, Interim 
Analyses, for further details).  While evaluating the response for the first 30 treated subjects, the 
enrollment and treatment of subsequent subjects will be continued. If the study continues on to 
Stage 2, a total of 55 subjects will be enrolled in the entire study. 


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• The probability of early stopping under the null hypotheses is 0.255. 
• The probability of early stopping under the alternative hypotheses is 0.008. 
13.2.2 
Sample Size Re-Estimation 
The sample size will not be re-estimated during this study. 
13.3. 
Data Analysis Considerations 
13.3.1 
Analysis Populations 
The Intent-to-Treat (ITT) population will consist of all subjects who receive at least one dose of 
tazemetostat.  The ITT population will be used for summaries and analysis of the efficacy 
endpoints. 
The Safety Population will consist of all subjects in the ITT population who have at least one 
post-dose safety observation recorded.  The Safety Population will be used for summaries and 
analysis of the safety and tolerability. 
The Pharmacokinetic (PK) population set will include all subjects in the ITT population who 
have sufficient post-dose samples collected to allow estimation of the PK parameters.  The PK 
population will be used for PK analysis. 
The Pharmacodynamic (PD) population will include all subjects in the ITT population who 
have sufficient samples collected to allow estimation of the PD parameters.  The PD population 
will be used for summaries and graphs of PD data. 
13.3.2 
Interim Analyses 
If, in consultation with the investigators, the PK and safety profiles of tazemetostat in Part 1 are 
acceptable, then the 400 mg tablets will be used in Part 2. 
For Part 2, the decision rules at the end of Stage 1 are listed in the table below. 
 
Part 2 
(Relapsed/Refractory Synovial Sarcoma) 
Null Hypothesis 
CR+PR+SD at Week 12 <20% 
Alternative Hypothesis 
CR+PR+SD at Week 12 >35% 
Stage 1 Sample Size (n1) 
30 
Stage 1 Rejection of Study Treatment (r1) 
4 


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The end of Stage 1 occurs when the first 30 treated subjects have completed at least the Week 12 
assessment, completed the final study visit or terminated early from the study, whichever is 
sooner.   
• At the end of Stage 1, if there are ≤ 4 CR + PR + SD out of 30 subjects, then reject 
the new treatment and terminate the study for futility.  When there are ≥5 
CR + PR + SD out of 30 subjects, the study continues to Stage 2. 
• At the end of the study, if there are ≤16 CR + PR +SD out of 55 treated subjects, then 
reject the new treatment.  When there are ≥17 or more CR + PR +SD out of 55 
subjects, then the new treatment is accepted. 
The interim analysis planned at the end of Stage 1 may occur sooner if the Stage 1 rejection 
criterion is surpassed before all 30 subjects are treated and followed 12 weeks.  In this scenario, 
the total sample size (Stage 1 + Stage 2) would still remain unchanged at 55 subjects.   
13.3.3 
Key Elements of the Analysis Plan 
Complete details of the analysis plan will be provided in the Statistical Analysis Plan (SAP).  
Any deviations from, or additions to, the original analysis plan in this protocol will be 
documented in the SAP and the CSR. 
All data up to the time of study completion/withdrawal from the study will be included in the 
analysis, regardless of treatment duration. 
Since the duration of study treatment for a given subject will depend on efficacy and tolerability, 
the duration of follow-up will vary among subjects.  All available time-to-event data will be 
analyzed using appropriate statistical methods.  Subjects with shorter treatment and follow-up 
will not be considered to have missing data.  Consequently, there will be no imputation for 
missing time-to-event data. 
Demographics and baseline characteristics will be summarized by study part and overall. 
13.4. 
Efficacy Analyses 
13.4.1 
Analysis of Primary Endpoint  
The data cut-off for the Week 12 analysis at the end of the study will occur after all treated 
subjects have completed at least the Week 12 assessment; completed the final study visit; or 
terminated early from the study.  The DCR at Week 12 is defined as the percentage of subjects 
with a response of CR, PR or SD at the Week 12 assessment, as per modified RECIST [Nowak, 
2005] for thoracic disease or RECIST 1.1 elsewhere. 


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Subjects with non-evaluable or missing response will be treated as not having disease controlled; 
i.e., they will be included in the denominator when calculating the DCR.  As a specific example, 
subjects with disease progression or death prior to the Week 12 assessment will be included in 
the denominator.  In addition to the DCR at Week 12, an exact 90% CI for this rate will be 
provided. 
13.4.2 
Analysis of Secondary Efficacy Endpoints 
The ORR and an exact 90% CI will be provided. 
Data cut-off for Week 12 is defined in Section 13.4.1.  The data cut-off for the Week 24 analysis 
will occur after all subjects have completed at least the Week 24 assessment, completed the final 
study visit, or terminated early from the study, whichever is sooner.   
Progression-Free Survival (PFS) is defined as the interval of time between the date of the first 
dose of study drug and the earliest date of disease progression or death due to any cause. 
• For subjects who progressed or died after an extended period without adequate 
assessment, the time of PFS will be censored at their date of last adequate assessment 
prior to progression or death even if subsequent information is available regarding 
progression or death.  An adequate assessment is defined as an assessment where the 
investigator determined response is CR, PR, or SD.  The date of response at that 
assessment will be used for censoring.  Specific rules for identifying extended loss to 
follow-up or extended time without an adequate assessment are provided in the SAP. 
• For subjects who receive subsequent anti-cancer therapy prior to the date of documented 
progression or death, the time of PFS will be censored at the last adequate assessment 
(i.e., last assessment of CR, PR or SD) prior to the initiation of that anti-cancer therapy. 
• For other subjects who do not progress or die, the time of PFS will be censored at the 
date of the last adequate tumor assessment. 
Overall Survival (OS) is defined as the interval of time between the date of the first dose of 
study drug and the date of death due to any cause.  For subjects who do not die, the time of death 
will be censored at the date of last contact.  Death due to any cause will be included. 
Within each part and overall, PFS and OS will be calculated using the Kaplan-Meier method.  
PFS and OS at 12 weeks, 24 weeks, and overall along with the associated 90% CIs will be 
provided.  If there are a sufficient number of PFS events (i.e., progressions or deaths), median 
PFS, first and third quartiles and 90% CI, will be estimated using the Brookmeyer-Crowley 
method [Brookmeyer, 1982].  If there are a sufficient number of deaths, median OS, first and 


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third quartiles and 90% CI, will be estimated using the Brookmeyer-Crowley method.  Figures 
and listings of PFS and OS will also be provided. 
Response Duration, for the subset of subjects with confirmed CR or PR response, is defined as 
the interval of time from the first documented evidence of CR or PR until the first documented 
disease progression or death due to any cause, using disease-appropriate standardized response 
criteria. 
The DOR will be calculated for each subject with a confirmed CR or PR.  If sample size permits, 
the median DOR will be calculated from the Kaplan-Meier estimates.  First and third quartiles 
will also be calculated along with associated 90% CIs if there are a sufficient number of 
responders who subsequently progress or die due to any cause.  A listing of DOR will be 
provided. 
13.5. 
Safety Analyses 
13.5.1 
Extent of Exposure 
The data on exposure to tazemetostat will be listed.  Details pertaining to dose interruption or 
dose modification will also be listed.  Duration of exposure and percentage of treatment 
compliance will be summarized. 
13.5.2 
Adverse Events 
The data listings of AEs in the CSR will contain the verbatim description, PT and SOC 
MedDRA-level terms. 
Treatment-emergent AEs (TEAEs) are defined by applying treatment-emergent signs and 
symptoms (TESS) philosophy.  AEs will be regarded as TEAEs if one of the following 
conditions is met: 
• Emerge after the time of first dose administration, having been absent prior to the first dose. 
• Re-emerge, having been present but stopped prior to the time of first dose administration. 
• Worsen in severity after the time of first dose administration relative to the pre-treatment state, 
when the AE is continuous. 
An AE with partial or completely missing start date and/or time will always be assumed as 
TEAE, unless it can be determined to be “prior to administration” from the incomplete start 
date/time or resolution date/time (e.g., month, year is before first administration date, or 
resolution date is before first administration date). 


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Only TEAEs will be summarized.  Summaries of TEAEs will consist of the number and 
percentage of subjects reporting the AE by SOC and by PT.  TEAEs which occur more than once 
for a subject will be counted only once in the subject frequencies.  TEAEs with different CTCAE 
grades for a subject will be counted at the worst (highest) grade for the same SOC (likewise for 
PT).  TEAEs with different drug relationship for a subject will be counted at strongest 
relationship for the same SOC (likewise for PT).  TEAEs with missing relationship to study 
treatment will be counted as “related”.  TEAEs with missing CTCAE grade will be counted as 
Grade 3 (“severe”). 
Summaries of TEAEs by study part and overall will be produced to present the number and 
percentage of subjects with: 
• 
Any TEAE 
• 
Any treatment-related TEAE 
• 
Any TEAE with CTCAE Grade 3 or higher 
• 
Any TEAE leading to study treatment discontinuation 
• 
Any Serious TEAEs 
• 
Any TEAE of special interest 
Listings will be provided for the following: 
• 
AEs 
• 
TEAEs leading to study treatment discontinuation 
• 
Serious TEAEs 
• 
Fatal TEAEs 
• 
TEAEs of special interest 
13.5.3 
Clinical Laboratory Evaluation 
All clinical laboratory parameters will be standardized according to the International System of 
Units (SI) prior to summarization.  Separate listings and summary tables (by study part and 
overall) will be produced for each laboratory test group (complete blood counts, serum 
chemistries [liver, renal and metabolism] and coagulation profile). 
Low, normal, and high (LNH) classifications will be applied to determine whether the laboratory 
test value was below (L), within (N), or above (H) its reference range. Shifts from baseline in 
LNH classification and CTCAE grades for each parameter will be summarized by part and 
overall. The summary will include the worst case shift from baseline during the post-baseline 


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period, which will include both planned (scheduled) and unscheduled visits after the first dose of 
study drug.  Subjects with laboratory data outside the normal range will be flagged as “L” (Low) 
or “H” (High) in the data listing. 
13.5.4 
Other Safety Measures 
The results of scheduled assessments of physical examination, vital signs, ECG, and ECOG 
performance status will be summarized by study part and overall.  Summaries will include data 
from scheduled visits.  Shifts from baseline will be summarized where appropriate.  All data will 
be listed. 
13.6. 
Pharmacokinetic Analyses 
Plasma concentrations of tazemetostat and its metabolite EPZ-6930 will be determined by a 
validated bioanalytical method.  Concentrations of tazemetostat and its metabolite will be listed 
by study part and nominal time.  Standard summary statistics will be calculated (i.e., mean, SD, 
median, minimum and maximum).    
All PK parameters will be calculated using actual times.  Population estimates of CL/F, Vd/F, 
and Ka for tazemetostat will be calculated with a non-linear mixed-effects model using 
NONMEM 7 software.  The effect of subject characteristics such as age, weight, body surface 
area, and gender on the PK parameters may be investigated.  The PK data from this study may be 
combined with data from other studies to determine the final population PK model.  The final 
population PK model will be described in a separate report. 
13.7. 
Exploratory Analysis 
As data warrant, exploratory analysis may be performed on each exploratory endpoint listed 
below. In addition, exploratory analyses may be performed to examine the relationship between 
exposure to tazemetostat and clinical and safety endpoints (including tumor size or change in 
tumor size from baseline). The results of these exploratory analyses may be reported separately 
from the CSR.  
• Tumor target gene expression and phenotypic markers including those for differentiation, 
apoptosis, inflammation and cell proliferation, and their correlation with activity 
• Somatic mutation analysis of tumor tissue and blood 
• Germline analysis for BAP1 variants 


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14. 
INDEPENDENT DATA MONITORING COMMITTEE (IDMC) 
An IDMC will be utilized in this study to ensure external objective medical and/or statistical 
review of:  
• Safety data at each predetermined (or ad hoc, if needed) and make recommendations 
to the sponsor to continue, modify or terminate any of the parts or the study 
• Efficacy data at the end of Stage 1 in Part 2 to determine if futility has been reached 
or the study should proceed to subsequent stage 
A recommendation of study hold, dose de-escalation, or study termination would be made in the 
event of the discovery of an unexpected, serious, or unacceptable risk to the subjects in the study. 
The schedule of any planned interim analysis and the analysis plan for IDMC review is described 
in a separate charter. 
 


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15. 
STUDY CONDUCT CONSIDERATIONS  
15.1. 
Posting of Information on Publicly Available Clinical Trial Registers 
Study information from this protocol will be posted on publicly available clinical trial registers 
before subject enrollment begins. 
15.2. 
Regulatory and Ethical Considerations 
The procedures set out in this study protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the sponsor and investigators abide by 
GCP as described in the International Conference on Harmonization (ICH) Tripartite Guideline 
E6 (R1): GCP: Consolidated Guideline, and for US Investigators, 21 CFR Parts 50, 54, 56, and 
312.  Compliance with these regulations also constitutes compliance with the ethical principles 
described in the current revision of the Declaration of Helsinki.  The study will also be carried 
out in keeping with local legal and regulatory requirements. 
It is the investigator’s responsibility to ensure that adequate time and appropriate resources are 
available at the study site prior to commitment to participate in this study.  The investigator 
should also be able to estimate or demonstrate a potential for recruiting the required number of 
suitable subjects within the agreed recruitment period. 
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks.  An up-to-date copy of the curriculum vitae for the 
investigator, sub-investigator(s) and essential study staff will be provided to the sponsor or its 
designee before starting the study. 
If the subject has a primary physician the investigator should, with the subject’s or his/her legal 
representative’s consent, inform them of the subject’s participation in the study. 
15.2.1 
Institutional Review Board (IRB)/ Ethics Committee (EC)/Central Ethics 
Committee (CEC) 
It is the responsibility of the investigator to submit this protocol, the informed consent document 
(approved by the sponsor or its designate), relevant supporting information and all types of 
patient recruitment information to the IRB/EC/CEC for review.  All must be approved prior to 
site initiation.  Prior to implementing changes in the study, the sponsor and the IRB/EC/CEC 
must also approve any revised ICFs and/or protocol amendments. 
On the IRB/EC/CEC approval letter, the study reference, the date of review and actions taken 
should be clearly stated. 


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Clinical supplies of tazemetostat will not be released to the site and recruitment of subjects will 
not begin until the IRB/EC/CEC written approval has been received by the sponsor or its 
designee. 
The investigator is responsible for keeping the IRB/EC/CEC apprised of the progress of the 
study and of any changes made to the protocol and/or ICF.  The investigator must also keep the 
IRB/EC/CEC informed of any serious and significant AEs. 
15.2.2 
Informed Consent Process 
It is the responsibility of the investigator to obtain written informed consent from each subject 
before any protocol-specific assessments and/or procedures are performed.  All consent 
documentation must be in accordance with applicable regulations and GCP.  Each subject or the 
subject’s legally authorized representative is requested to sign the ICF after the subject has 
received and read the written subject information and received an explanation of what the study 
involves, including but not limited to: the objectives, potential benefits and risk, inconveniences 
and the subject’s rights and responsibilities.  A copy of the ICF (subject information sheet and 
the ICF, as applicable) must be given to the subject or the subject’s legally authorized 
representative.  If applicable, it will be provided in a certified translation of the subject’s local 
language.  Signed ICFs must remain in each subject’s study file and must be available for 
verification by study monitors at any time. 
Each investigator will provide the sponsor or its designee with a copy of the IRB/EC/CEC-
approved ICF(s), and a copy of the IRB/EC/CEC written approval, prior to the start of the study.  
Additionally, if the IRB/EC/CEC requires modification of the sample subject information and 
the model ICF provided by the sponsor, the documentation supporting this requirement must be 
provided to the sponsor. 
The sponsor reserves the right to delay initiation of the study at a site where the ICF(s) do not 
meet the standards of applicable regulations and ICH GCP. 
15.3. 
Subject Confidentiality and Access to Source Documents/Data 
Subject confidentiality is strictly held in trust by the sponsor and/or their designee(s), 
participating investigators, and any staff. This confidentiality includes the clinical information 
relating to participating subjects, as well as any genetic or biological testing. 
The study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the sponsor. 


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The study monitor or other authorized representatives of the sponsor may inspect all documents 
and records required to be maintained by the investigator, including but not limited to, medical 
records (office, clinic, or hospital) and pharmacy records for the subjects in this study. The 
clinical study site will permit access to such records. 
15.4. 
Study Monitoring 
Monitoring of the study will be performed by the sponsor or its designee(s).  At the monitoring 
visits, the progress of the study will be discussed with the investigator, or his/her representative.  
The ICFs will be reviewed for signatures and the eCRFs checked for completeness and accuracy.  
Subject source data must be available for review.  The investigator and his/her staff are expected 
to cooperate with the study monitor and be available during at least a portion of the monitoring 
visit to review the eCRFs and any queries/resolutions, answer questions, and provide any 
missing information. 
The study monitor will record the date of each visit together with a summary of the status and 
progress of the study.  Proposed actions will be confirmed with the investigator in writing. 
Telephone contact will be made with the investigator as necessary during the data collection 
period and during the data and report writing periods. 
15.5. 
Protocol Deviations 
Deviations from the protocol should not be made unless it has been agreed to in writing by both 
the investigator and the sponsor and approved by the IRB/EC/CEC.  Investigative sites will 
contact the medical monitor to request clarifications regarding any aspect of the clinical study or 
eligibility of subjects. 
When an emergency occurs that requires a deviation from the protocol for an individual subject, 
the deviation will be only for that subject.  The investigator or other physician in attendance in 
such an emergency will, if circumstances and time permit, contact the sponsor or their 
representative(s), immediately by telephone.  Such contacts will be made as soon as possible to 
permit a decision as to whether or not the subject (for whom the protocol deviation was affected) 
is to continue in the study.  The source documentation will completely describe the protocol 
deviation and state the reasons for such deviation.  In addition, the IRB/EC/CEC will be notified 
in writing of such protocol deviation. 
15.6. 
Protocol Amendment 
All amendments to the protocol must be documented in writing, reviewed, and approved by the 
investigator and the sponsor, and submitted to the IRB/EC/CEC for approval prior to initiation, 


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except in cases where required for subject safety.  If the protocol amendment substantially alters 
the study design or potential risk to the subject, a new written ICF for continued participation in 
the study must be obtained from each subject or his/her legal representative. 
15.7. 
Suspension or Termination of Study 
Should conditions requiring further clarification arise before the decision to proceed with or 
terminate the study can be reached, the study will be suspended until the situation has been 
resolved. 
The sponsor has the right to terminate this study and remove all study material from the site at 
any time.  Examples of where this might occur include, but are not limited to: 
• When it becomes apparent that subject enrollment is unsatisfactory with respect to 
quality and/or quantity or data recording is inaccurate and/or incomplete on a chronic 
basis. 
• When the incidence and/or severity of AEs in this study indicates a potential health 
hazard caused by treatment with tazemetostat. 


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16. 
ADMINISTRATIVE PROCEDURES 
16.1. 
Recording and Access and to Study Records 
As described in the ICH GCP Guidelines (ICH E6 Section 8.3), ‘essential documents’, including 
eCRFs, source documents, consent forms, laboratory test results and the IP inventory records 
must be maintained by the investigator. 
These records must be made available at reasonable times for inspection and duplication, if 
required, by a properly authorized representative of the US FDA in accordance with the US Code 
of Federal Regulations, 21 CFR 312.68, or other regulatory authorities in accordance with 
regulatory requirements. 
16.2. 
Case Report Forms 
eCRFs will be used for data collection for this study. 
The investigator is responsible for maintaining adequate and accurate source documents from 
which accurate information will be transcribed into eCRFs, which have been designed to capture 
all observations and other data pertinent to the clinical investigation.  The eCRFs should be 
completed by the investigator or delegate as stated on the Delegation of Authority Log.  
Overwriting of information or use of liquid correcting fluid is not allowed in the source 
document. 
Each investigative site will be visited as frequently as documented in the monitoring plan by the 
sponsor or their designee to review the eCRFs for completeness and accuracy.  The sponsor or 
their designee will highlight any discrepancies found between source documents and the 
completed eCRFs and ensure that appropriate site personnel address the discrepancies.  When a 
discrepancy results in corrected eCRF data, the correction will be reviewed again against the 
correct source documentation.  Uniform procedures will be discussed at the Site Initiation Visit. 
The eCRFs must be reviewed and electronically signed and dated by the investigator once all 
data has been entered and all queries resolved.  Once the study monitor has verified the contents 
of the completed eCRFs against the source data, queries may be raised if the data are unclear or 
contradictory.  The investigator must address all queries. 
16.3. 
Quality Assurance and Quality Control 
A site monitoring plan will be developed to ensure the human subject protection, study 
procedures, laboratory, study intervention administration, and data collection processes are of 
high quality and meet the sponsor's, ICH/GCP, and other applicable regulatory guidelines. 


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The investigator will permit authorized the sponsor or its designee(s) and the respective 
regulatory authorities to inspect facilities and records relevant to this study if needed. 
Initial site training will be provided by the sponsor or its designee.  Training for new site staff 
will be provided by previously trained study nurses, study coordinators or other qualified staff 
under the supervision of the primary investigator.  Additional training will be provided by the 
sponsor or its designee as needed. 
The designated Data Management Team will implement quality control (QC) procedures 
beginning with the data entry system and generate data QC checks that will be run on the 
database.  Any missing data or data anomalies will be communicated to the site(s) for 
clarification/resolution. 
16.4. 
Data Quality Assurance 
This study will be organized, performed, and reported in compliance with the sponsor or its 
designee's Standard Operating Procedures, protocols and working practice documents, and the 
requirements of ICH/GCP guidelines.  Compliance will be achieved through a combination of 
study-specific audits of investigative sites and audits at regular intervals of the sponsor or its 
designee's systems for data handling, analysis, and reporting.   
16.5. 
Confidentiality 
Data collected during this study may be used to support the development, registration, or 
marketing of tazemetostat.  After a subject or his/her legal representative have consented to take 
part in the study their medical records and the data collected during the study will be reviewed 
by the sponsor and/or its designee.  These records and data may be reviewed by the following: 
independent auditors who validate the data on behalf of the sponsor; third parties with whom the 
sponsor may develop, register or market tazemetostat; national or local regulatory authorities and 
the IRB/EC/CEC(s) which gave its/their approval for this study to proceed. 
Although subjects will be known by a unique identifier number, their year of birth will also be 
collected and used to assist the sponsor and/or its designee to verify the accuracy of the data, for 
example, that the laboratory results are assigned to the correct subject. 
16.6. 
Audit/Inspection 
To ensure compliance with relevant regulations, data generated by this study will be available for 
inspection upon request by representatives of the US FDA as well as other national and local 
regulatory authorities, the sponsor and/or its designee, interested commercial parties, and the 
IRB/EC/CEC for each study site. 


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16.7. 
Record Retention 
Essential documents should be retained by the investigator until at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the IP.  These documents should be retained 
for a longer period however if required by the applicable regulatory requirements or by an 
agreement with the sponsor or its designee.  It is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained.  The 
investigator must obtain written permission from the sponsor or its designee prior to the 
destruction of any study document. 
16.8. 
Provision of Study Results and Publication 
A summary of the study results will be made publicly available within 12 months of reaching the 
end of the study, defined as the date of the last subject’s last visit.  A full CSR will be made 
publicly available no later than 18 months after the end of the study. 
If a manuscript is published in a peer-reviewed journal, then that initial release may be an 
abstract that meets the requirements of the International Committee of Medical Journal Editors.  
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 investigator and the sponsor. 
 
 


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17. 
REFERENCES 
 
Blackledge NP, Farcas AM, Kondo T, King HW et al.  Variant PRC1 Complex DependentH2A 
Ubiquitylation Drives PRC2 Recruitment and Polycomb Domain Formation.  Cell. 2015; (157) 
1445–59. 
Bott M, Brevet M, Taylor BS, Shimizu S et al.  The nuclear deubiquitinase BAP1 is commonly 
inactivated by somatic mutations and 3p21.1 losses in malignant pleural mesothelioma.  Nat. 
Gen. 2011; (43);7 668-72. 
Brookmeyer R and Crowley JJ.  A confidence interval for the median survival time.  Biometrics. 
1982; 38:29-41. 
Bueno R, Stawiski EW, Goldstein LD, Durinck S, De Rienzo A, et al. Comprehensive genomic 
analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and 
splicing alterations. Nat Gen. 2016; Feb 29. doi: 10.1038/ng.3520. [Epub ahead of print] 
Carbone M, Ferris LK, Baumann F, Napolitano et al.  BAP1 cancer syndrome: malignant 
melanoma, uveal and cutaneous melanoma and MBAITs.  J of T Med 2012; (10):179. 
Ceresoli GL, Zucali PA, Gianoncelli L, Lorenzi E, Santoro A. Second-line treatment for 
malignant pleural mesothelioma.  Cancer Treatment Reviews 2010; 36:24–32. 
Chase A and Cross NC. Aberrations of EZH2 in cancer. Clin Cancer Res. 2011; 17(9):2613-
2618. 
Cigognetti M, Lonardi S, Fisogni S, Balzarini P et al.  BAP1 (BRACA1-associated protein 1) is a 
highly specific marker for differentiating mesothelioma from reactive mesothelial proliferations.  
Modern Path. 2015; (28)1043-1057. 
Fennell D, Gaudino G, O’Byrne K, et al.  Advances in the systemic therapy of malignant pleural 
mesothelioma.  Nat Clin Pract Oncol. 2008 Mar;5(3):136-47. 
Guo G, Chmielecki J, Goparaju C, Heguy A, Dolgalev I, et al. Whole-exome sequencing reveals 
frequent genetic alterations in BAP1, NF2, CDKN2A, and CUL1 in malignant pleural 
mesothelioma. Cancer Res. 2015 Jan 15; 75(2):264-95472. 
Harbour JW, Onken MD, Roberson EDO, Duan S, et al. Frequent Mutation of BAP1 in 


Tazemetostat 
Protocol Number EZH-203 
Amendment 3 
 
 
 
 
 
 
Epizyme, Inc. 
Page 87 of 88 
Confidential and Proprietary 
Final, 27 November 2017 
 
 
NCT02860286 
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Tazemetostat 
Protocol Number EZH-203 
Amendment 3 
 
 
 
 
 
 
Epizyme, Inc. 
Page 88 of 88 
Confidential and Proprietary 
Final, 27 November 2017 
 
 
NCT02860286 
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