Clinical trial NCT01897571
Conditions: B-cell Lymphomas (Phase 1) Advanced Solid Tumors (Phase 1) Diffuse Large B-cell Lymphoma (Phase 2) Follicular Lymphoma (Phase 2) Transformed Follicular Lymphoma Primary Mediastinal Large B-Cell Lymphoma
Keywords: Epizyme Tazverik Tazemetostat (EPZ-6438)
Sponsor: Epizyme, Inc.
Start date: 2013-06-13; Completion date: 2021-11-02
Enrollment: 400 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This is an open-label, multicenter, Phase 1/2 study of tazemetostat as a single agent in subjects with advanced solid tumors or with B-cell lymphomas and tazemetostat in combination with prednisolone in subjects with diffuse large B-cell lymphoma (DLBCL).

Detailed description:
This is a multicenter, open-label, Phase 1/2 study conducted in two parts: The Phase 1 part comprised dose escalation and expansion to establish the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D) when tazemetostat was given twice daily (BID) orally on a continuous basis. Additionally, in separate cohorts in Phase 1, the effect of food on the bioavailability of tazemetostat as well as the drug-drug interaction (DDI) potential of tazemetostat were evaluated. The Phase 2 part was initiated once the RP2D was established. Phase 2 enrolled subjects with relapsed/ refectory (R/R) DLBCL (Cohorts 1-3 and 6) and subjects with R/R FL (Cohorts 4 and 5) for the determination of efficacy and safety of tazemetostat monotherapy (Cohorts 1-5) and of tazemetostat in combination with prednisolone (Cohort 6) with placement determined by centrally confirmed histology, cell of origin (COO), and enhancer of zeste homologue 2 (EZH2) mutation status.

Arms: arm 1: Patients in the Phase 1 portion of the study. arm 2: Patients with R/R FL with mutant EZH2 treated with tazemetostat as a single agent in Phase 2 of the study. arm 3: Patients with R/R FL with wild-type EZH2 treated with tazemetostat as a single agent in Phase 2 of the study. arm 4: Patients with R/R DLBCL treated with tazemetostat as a single agent or tazemetostat in combination with prednisolone in Phase 2 of the study.
Interventions: intervention 1: Tazemetostat intervention 2: Prednisolone intervention 3: Tazemetostat
Intervention descriptions: intervention 1: Patients who received 800 mg of tazemetostat, BID, administered in continuous 28-day cycles. intervention 2: Patients who received 40 mg/m\^2 prednisolone once daily on Days 1-5 and 15-19 of Cycles 1-4. intervention 3: Patients who received 100 mg to 1600 mg of tazemetostat, BID, administered in continuous 28-day cycles.

Protocol documents:
Prot_000.pdf: 
Tazemetostat 
Protocol E7438-G000-101 
Protocol Amendment 
Amendment No. 13.0 
Epizyme, Inc. 
CONFIDENTIAL 
Page 1 of 119 
 
CLINICAL STUDY PROTOCOL 
Protocol Number: 
E7438-G000-101 
Study Protocol Title: 
An Open-Label, Multicenter, Phase 1/2 Study of Tazemetostat (EZH2 
Histone Methyl Transferase [HMT] Inhibitor) as a Single Agent in Subjects 
With Advanced Solid Tumors or With B Cell Lymphomas and 
Tazemetostat in Combination With Prednisolone in Subjects With Diffuse 
Large B Cell Lymphoma 
Sponsor: 
Epizyme, Inc. 
400 Technology Square – 4th Floor  
Cambridge, Massachusetts 02139 USA 
Investigational 
Product Name: 
Tazemetostat (formerly EPZ-6438 and E7438) 
Indication: 
Relapsed or refractory diffuse large B cell or follicular lymphoma 
Phase: 
1/2 
Approval Date:  
Original protocol: 
01 Nov 2012 
 
Amendment 1: 
11 Feb 2013 
Amendment 9.1 (US only): 
15 Apr 2016 
Amendment 2: 
24 Apr 2013 
Amendment 10: 
21 Nov 2016 
Amendment 3: 
19 Jun 2013 
Amendment 10.1 (US only): 
21 Nov 2016 
Amendment 4: 
22 Oct 2013 
Amendment 10.2 (UK only): 
28 Feb 2017 
Amendment 5: 
24 Feb 2014 
Amendment 11.0: 
24 Sep 2018 
Amendment 6: 
29 Aug 2014 
Amendment 11.1 (UK only): 
07 Nov 2018 
Amendment 6.1: 
14 Oct 2014 
Amendment 11.2 (Canada only): 
08 Nov 2018 
Amendment 7: 
19 Feb 2015 
Amendment 11.3 (France only): 
09 Dec 2019 
Amendment 7.1 (site-specific): 21 May 2015 
Amendment 12.0 (US only; not 
implemented): 
25 Aug 2020 
Amendment 8 (first US): 
15 Sep 2015 
Amendment 13.0: 
10 Aug 2021 
Amendment 8.1 (US only): 
03 Nov 2015 
Amendment 13.1 (UK only): 
10 Aug 2021 
Amendment 9: 
15 Apr 2016 
Amendment 13.2 (Canada only): 
10 Aug 2021 
 
 
Amendment 13.3 (France only): 
10 Aug 2021 
 
EudraCT Number: 
2012-004083-21 
IND Number: 
124025 
GCP Statement: 
This study is to be performed in full compliance with International 
Conference on Harmonisation of Technical Requirements for Registration 
of Pharmaceuticals for Human Use (ICH) and all applicable local Good 
Clinical Practices (GCP) and regulations. All required study documentation 
will be archived as required by regulatory authorities. 
Confidentiality 
Statement: 
This document is confidential. It contains proprietary information of 
Epizyme (the Sponsor). Any viewing or disclosure of such information that 
is not authorized in writing by the Sponsor is strictly prohibited. Such 
information may be used solely for the purpose of reviewing or performing 
this study. 


Tazemetostat 
Protocol E7438-G000-101 
Protocol Amendment 
Amendment No. 13.0 
Epizyme, Inc. 
CONFIDENTIAL 
Page 2 of 119 
SPONSOR PROTOCOL APPROVAL PAGE  
Protocol Title: 
An Open-Label, Multicenter, Phase 1/2 Study of Tazemetostat (EZH2 Histone Methyl 
Transferase [HMT] Inhibitor) as a Single Agent in Subjects With Advanced Solid 
Tumors or With B Cell Lymphoma and Tazemetostat in Combination With Prednisolone 
in Subjects With Diffuse Large B Cell Lymphoma 
 
 
 
Protocol Number: 
E7438-G000-101 
 
 
 
 
Approved by: 
 
 
 
Responsible Sponsor Medical Officer: 
 
 
 
 
Signature: 
Date: ________________
 
Epizyme, Inc. 
 
 
 
 
Responsible Sponsor Medical Monitor: 
 
 
 
 
Signature: 
Date: ________________
 
Epizyme, Inc. 
 

	

	
PPD
PPD


Tazemetostat 
Protocol E7438-G000-101 
Protocol Amendment 
Amendment No. 13.0 
Epizyme, Inc. 
CONFIDENTIAL 
Page 3 of 119 
INVESTIGATOR AGREEMENT PAGE 
 
Protocol Title: An Open-Label, Multicenter, Phase 1/2 Study of Tazemetostat (EZH2 Histone 
Methyl Transferase [HMT] Inhibitor) as a Single Agent in Subjects With 
Advanced Solid Tumors or With B Cell Lymphoma and Tazemetostat in 
Combination With Prednisolone in Subjects With Diffuse Large B Cell 
Lymphoma 
 
Protocol Number: 
E-7438-G000-101 
 
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: __________________________________________________ 
___________________________________________________________________________ 
 


Tazemetostat 
Protocol E7438-G000-101 
Protocol Amendment 
Amendment No. 13.0 
Epizyme, Inc. 
CONFIDENTIAL 
Page 4 of 119 
PROTOCOL AMENDMENT SUMMARY OF CHANGES 
DOCUMENT HISTORY 
Document 
Date 
Amendment 13.3 (France only) 
10 Aug 2021 
Amendment 13.2 (Canada only) 
10 Aug 2021 
Amendment 13.1 (UK only) 
10 Aug 2021 
Amendment 13.0 
10 Aug 2021 
Amendment 12.0 (US only; not implemented) 
25 Aug 2020 
Amendment 11.3 (France only) 
09 Dec 2019 
Amendment 11.2 (Canada only) 
08 Nov 2018 
Amendment 11.1 (UK only) 
07 Nov 2018 
Amendment 11.0 
24 Sep 2018 
Amendment 10 
21 Nov 2016 
Amendment 10.2 (UK only) 
28 Feb 2017 
Amendment 10.1 (US only) 
21 Nov 2016 
Amendment 09.1 (US only) 
15 Apr 2016 
Amendment 09 
15 Apr 2016 
Amendment 08.1 (US only) 
03 Nov 2015 
Amendment 08 (first in US) 
15 Sep 2015  
Amendment 07.1 (site-specific) 
21 May 2015 
Amendment 07 
19 Feb 2015 
Amendment 06.1 
14 Oct 2014 
Amendment 06 
29 Aug 2014 
Amendment 05 
24 Feb 2014 
Amendment 04 
22 Oct 2013 
Amendment 03 
19 Jun 2013 
Amendment 02 
24 Apr 2013 
Amendment 01 
11 Feb 2013 
Original protocol 
01 Nov 2012 
 
Amendment 13.0 (10 August 2021) 
Note: This amendment is considered to be substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the European 
Union. 
PLEASE NOTE: Because Protocol Amendment No 12.0 was specific to the US and was not 
implemented, this amendment describes changes from global Protocol Amendment 
No 11.0. 
Overall Rationale for the Amendment: 
This amendment is being made primarily for the following reasons: 
x To remove the requirement of survival follow-up globally, as the primary efficacy 
outcome assessment has been met. 
x To update contraception requirements for both male and female subjects, and to update 
prohibited medications and medications to be used with caution to ensure consistency 
with the US FDA approved tazemetostat label. 


Tazemetostat 
Protocol E7438-G000-101 
Protocol Amendment 
Amendment No. 13.0 
Epizyme, Inc. 
CONFIDENTIAL 
Page 5 of 119 
x To update the process for recording and reporting special situations, and to update the 
adverse event of special interest (AESI) assessment procedure and safety information to 
align with IBv11.0.  
x To adjust record retention requirements. 
Substantial changes to the protocol are detailed in the table below: 
Section # and Name 
Description of Substantial Change 
Rationale 
Section 1 Synopsis 
Section 7.1 Overall Study 
Design and Plan 
Section 7.3.4.4 Concomitant 
Medications to be Used with 
Caution 
Section 7.4.1.4 Exploratory 
Assessments 
Section7.4.2.2 Description of 
Assessment Schedule 
Section 7.4.5 
Completion/Discontinuation of 
Subjects 
Removed the requirement of overall survival 
(OS) follow-up, as of this protocol amendment. 
No further OS follow-up 
in FL cohorts is required 
because the primary 
efficacy outcome 
assessments for the study 
are met. 
Section 1 Synopsis 
Section 5.1.1.2 Nonclincal 
Experience with Tazemetostat 
Section 7.2.1 Inclusion Criteria 
Updated contraception requirement as follows:  
- 
For women of childbearing potential: 
for 6 months after study drug 
discontinuation. 
- 
For male subjects: for 3 months after 
study drug discontinuation. 
To ensure consistency 
with the US FDA 
approved tazemetostat 
label. 
Section 7.3.4.3 Prohibited 
Concomitant Therapies and 
Drugs 
Section 7.3.4.4 Concomitant 
Medications to be used with 
Caution 
Updated prohibited medications and medications 
to be used with caution with regard to CYP3A. 
To ensure consistency 
with the US FDA 
approved tazemetostat 
label.  
Section 7.3.2.2 Criteria for 
Retreatment, Temporary 
Discontinuation of Treatment, 
Dose Reduction, and 
Resumption of Treatment 
Updated procedures for AESI assessment by the 
Epizyme Quarterly Safety Review committee 
and discontinuing tazemetostat in subjects who 
experience an AESI of MDS/AML or other 
myeloid malignancies like MPN. 
To ensure consistent 
assessment of AESIs 
across Epizyme 
sponsored clinical trials 
and discontinuation of 
tazemetostat in subjects 
with MDS/AML or other 
myeloid malignancies like 
MPN. 
Section 7.4.4.9 Adverse Events 
of Special Interest 
Updated to align with tazemetostat IBv11.0 as 
follows: 
- 
Number of myeloid malignancy 
updated 
- 
Criteria of discontinuation for myeloid 
malignancy added 
To ensure consistency 
with the approved 
tazemetostat IB v11.0. 
Section 7.4.4.10.1 Special 
Situations: Overdose, Misuse, 
Abuse and Medication Error 
Updated process for recording and reporting 
abuse, medication error, and overdose as 
follows: 
To ensure consistent 
recording and reporting of 
special situations across 


Tazemetostat 
Protocol E7438-G000-101 
Protocol Amendment 
Amendment No. 13.0 
Epizyme, Inc. 
CONFIDENTIAL 
Page 6 of 119 
Section # and Name 
Description of Substantial Change 
Rationale 
Section 7.4.6.3 Reporting of 
Special Situations 
- 
Implemented a special situations form 
to capture these events in the safety 
database. 
- 
Provided clear steps for accurate 
recording of these events in the clinical 
and safety databases 
Epizyme sponsored 
clinical trials. 
Section 8.3.6 Retention of 
Records 
Adjusted record retention requirements. 
To ensure record retention 
for the full ICH retention 
period. 
Abbreviations: AML = acute myeloid leukemia; AESI = adverse event of special interest; FDA = Food and Drug 
Administration; FL = follicular lymphoma; IB = Investigator’s Brochure; ICH = International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use; MDS = myelodysplastic syndrome; 
MPN = myeloproliferative neoplasms; OS = overall survival. 
 
In addition, non-substantial changes as well as minor editorial and document formatting 
revisions were made. All changes are visible in the tracked version.  
Non-substantial changes to the protocol are detailed in the table below: 
Section # and Name 
Description of Non-Substantial Change 
Brief Rationale 
Title Page 
Corrected previous amendment descriptions on 
title page. Specified that amendment 12.0 (US 
only) was not implemented. 
To correct typographical 
errors. To add clarity 
concerning amendment 12.0. 
Section 1 Synopsis 
Section 7.1 Overall Study 
Design and Plan 
Specified “Enrollment Closed” for Phase 2. 
To update study status for 
phase 2. 
Section 5 Introduction  
More accurately defined “mutant” and “wild-
type” EZH2  
To add clarity. 
Section  7.6.1.1 Definition 
of Analysis Sets 
Added a definition for the PGx Analysis Set. 
To correct an error of 
omission in previous protocol 
versions. 
Section 1 Synopsis 
Section 7.4.1.8 Other 
Assements 
Section 7.4.2 Schedule of 
Procedures/Assessments 
As previously communicated to sites, removed 
the annual PK requirement.   
Also removed the redundant requirement of 
assessments to be performed annually while on 
study. 
To align with previous 
communication of 16 May 
2018 to sites that annual PK 
assessments were no longer 
required. 
To eliminate redundant 
assessments, as AESI and 
tumor response assessments 
are conducted at routine 
timepoints. 
Abbreviations: AESI = adverse event of special interest; EZH2 = enhancer of zeste homolog 2; PGx = 
pharmacogenomics. 
 


Tazemetostat 
Protocol E7438-G000-101 
Protocol Amendment 
Amendment No. 13.0 
Epizyme, Inc. 
CONFIDENTIAL 
Page 7 of 119 
1 CLINICAL PROTOCOL SYNOPSIS 
 
Compound Name 
Tazemetostat (formerly known as EPZ-6438 and E7438) 
Name of Active Ingredient 
N-[(4,6-Dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl]-5-[ethyl(tetrahydro-2H-pyran-4-yl)amino]-4-methyl-
4'-(morpholin-4-ylmethyl)biphenyl-3-carboxamide hydrobromide 
Study Protocol Title 
An Open-Label, Multicenter, Phase 1/2 Study of Tazemetostat (EZH2 Histone Methyl Transferase [HMT] 
Inhibitor) as a Single Agent in Subjects With Advanced Solid Tumors or With B Cell Lymphomas and 
Tazemetostat in Combination With Prednisolone in Subjects With Diffuse Large B Cell Lymphoma 
Sites 
Phase 1: 2 sites (Institut Bergonie [IB] and Institut Gustave Roussy [IGR] sites in France only) 
Phase 2: Up to 50 sites 
Study Period and Phase of Development 
Phase 1: First subject in 2Q2013; Last subject in 4Q2015. Enrollment closed. 
Phase 2: First subject in 3Q2015; Last subject in 4Q2019. Enrollment closed. 
Objectives 
Primary Objectives 
Phase 1 
x 
To determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of 
tazemetostat as a single agent administered orally twice daily (BID), continuously in 28-day cycles, 
in subjects with advanced solid tumors or with relapsed and/or refractory B cell lymphomas  
Phase 2 
x 
To determine the objective response rate (ORR; complete response + partial response [CR + PR]) of 
tazemetostat in subjects with enhancer of zeste homolog 2 (EZH2) gene mutation positive or 
negative (wild-type) with histologically confirmed diffuse large B cell lymphoma (DLBCL) or 
follicular lymphomas (FL), with relapsed or refractory disease and the ORR of tazemetostat in 
combination with prednisolone in subjects with EZH2 wild-type DLBCL 
Secondary Objectives 
Phase 1 
x 
To assess the effect of a high-fat meal on the bioavailability of tazemetostat 
x 
To assess the effect of tazemetostat on exposure of midazolam, a cytochrome P450 (CYP)3A4 
substrate 
x 
To assess the preliminary activity of tazemetostat 


Tazemetostat 
Protocol E7438-G000-101 
Protocol Amendment 
Amendment No. 13.0 
Epizyme, Inc. 
CONFIDENTIAL 
Page 8 of 119 
Phase 2 
x 
To assess the effect of tazemetostat monotherapy and tazemetostat in combination with prednisolone 
on progression-free survival (PFS) 
x 
To assess the effect of tazemetostat monotherapy and tazemetostat in combination with prednisolone 
on duration of response (DOR) 
All Phases and Cohorts 
x 
To assess the safety and tolerability of tazemetostat monotherapy and tazemetostat in combination 
with prednisolone 
x 
To assess the pharmacokinetic (PK) profile of tazemetostat monotherapy and tazemetostat in 
combination with prednisolone 
Exploratory Objectives 
All Phases and Cohorts 
x 
To explore the PK and pharmacodynamic (PD) relationship of tazemetostat 
x 
To identify and investigate biomarkers and their correlation with biological activity for tazemetostat 
x 
To explore the effects of tazemetostat on histone H3K27 methylation, target gene expression, and 
phenotypic markers including those for differentiation, apoptosis, cell proliferation, and changes in 
the tumor microenvironment 
x 
To explore the role of DNA sequence variability on absorption, metabolism, excretion, and 
susceptibility to adverse events of tazemetostat 
x 
To explore the effect of tazemetostat monotherapy and tazemetostat in combination with 
prednisolone on overall survival 
Study Design 
Overall Design: 
This is a multicenter, open-label, Phase 1/2 study that will be conducted in 2 parts. The Phase 1 part (dose 
escalation and expansion parts have completed enrollment) is comprised of dose escalation and expansion parts to 
establish the MTD and/or RP2D when tazemetostat is given BID orally on a continuous basis in subjects with 
histologically and/or cytologically confirmed advanced or metastatic solid tumors or B cell lymphomas that have 
progressed after treatment with approved therapies or for which there are no standard therapies available. 
Additionally, in separate cohorts in Phase 1, the effect of food on the bioavailability of tazemetostat will be 
evaluated as well as the drug-drug interaction (DDI) potential as evaluated by the effect of tazemetostat on the PK 
of midazolam, a CYP3A4 substrate. The effect of food on bioavailability cohort was initiated after safety of the 
200 mg tazemetostat dose (highest available tablet dosage strength) was evaluated. The DDI potential cohort was 
initiated at the RP2D of 800 mg BID. The Food Effect (FE) and DDI cohorts were performed once the dose 
escalation was completed. The Phase 2 part was initiated once the MTD and/or RP2D was established. Phase 2 
will enroll subjects with DLBCL (Cohorts 1-3 and 6) and FL (Cohorts 4 and 5) for the determination of efficacy 
and safety of tazemetostat monotherapy (Cohorts 1-5) and of tazemetostat in combination with prednisolone 
(Cohort 6) with placement determined by centrally confirmed histology, cell of origin (COO), and EZH2 
mutation status as shown in the schematic below.  


Tazemetostat 
Protocol E7438-G000-101 
Protocol Amendment 
Amendment No. 13.0 
Epizyme, Inc. 
CONFIDENTIAL 
Page 9 of 119 
Phase 1 
 
 
Subjects with 
advanced solid 
tumors or B 
cell 
lymphomas 
 
Food Effect Substudy 
(13 subjects enrolled) 
x Randomized to either fasted or fed tazemetostat treatment 
x 200 mg single dose on Day -8 and Day -1 
x Tazemetostat 400 mg BID beginning on Day 1 
Dose 
Escalation 
tazemetostat 
single agent 
 
DDI Substudy 
(13 subjects enrolled) 
x Midazolam single dose on Day -1 and 15 
x Tazemetostat (fasted) MTD/RP2D BID beginning on Day 1 
 
 
Phase 2 
Subjects with B cell lymphomas 
Tazemetostat Monotherapy Cohorts 
x Cohort 1: DLBCL (GCB subtype) EZH2 mutation positive (- 
enrollment closed)  
x Cohort 2: DLBCL (GCB subtype) EZH2 wild-type 
(enrollment closed) 
x Cohort 3: DLBCL non-GCB subtype (enrollment closed) 
Note: Upon cohort closure, up to 5 DLBCL non-GCB EZH2 
mutation positive subjects can be enrolled in Cohort 1  
x Cohort 4: FL (Grades 1 to 3) EZH2 mutation positive (up to 
45 subjects) (enrollment closed) 
x Cohort 5: FL (Grades 1 to 3) EZH2 wild-type (enrollment 
closed) 
Tazemetostat/Prednisolone Combination Cohort 
x Cohort 6: DLBCL GCB or non-GCB subtype EZH2 wild-type 
(enrollment closed) 
BID = twice daily, DDI = drug-drug interaction, DLBCL = diffuse large B cell lymphoma, EZH2 = enhancer of 
zeste- homolog 2, FL = follicular lymphoma, GCB = germinal-center B-cell-like, MTD = maximum tolerated 
dose, RP2D = recommended Phase 2 dose  
Number of Subjects 
Phase 1 (IB and IGR sites in France only): 
Dose Escalation (closed to enrollment) 
Thirty-eight subjects with advanced solid tumors or B cell lymphomas were enrolled.  
Food Effect and Drug-Drug Interaction (closed to enrollment): 
Thirteen evaluable subjects with advanced solid tumors or B cell lymphomas were enrolled in each FE and DDI 
cohort (for a total of 26 subjects). 
Phase 2: 
Up to 45 subjects will be enrolled in Cohort 4 FL (Grades 1-3) EZH2 mutation positive.  All other cohorts have 
completed enrollment. Approximately 420 subjects will be enrolled in the entire study. 


Tazemetostat 
Protocol E7438-G000-101 
Protocol Amendment 
Amendment No. 13.0 
Epizyme, Inc. 
CONFIDENTIAL 
Page 10 of 119 
Sample Size Rationale 
For Phase 1, the sample size of 6 to 45 subjects is considered adequate for the purposes of selecting a dose. Per 
Food and Drug Administration (FDA) guidance, 12 subjects are considered adequate to evaluate food effect. The 
sample size for the DDI cohort was not based on statistical considerations. 
For Phase 2, the original study design planned enrollment of up to 30 subjects in each cohort. The initial 
assessment of efficacy was to be conducted within each cohort when 10 subjects had been enrolled (stage 1). For 
each DLBCL cohort, if zero responders (with CR or PR) out of the initial 10 subjects was observed, further 
enrollment in the cohort was to be terminated for futility. This rule was based on the underlying assumption that 
the response rate is 30% and there is a 2.8% probability of observing no responders among 10 subjects. For each 
FL cohort, if 1 or zero responders (CR or PR) out of the initial 10 subjects was observed, further enrollment in 
the cohort was to be terminated for futility. This rule was based on the underlying assumption that the response 
rate LVDQGWKHUHLVDSUREDELOLW\RIREVHUYLQJUHVSRQGHUDPRQJ subjects. Subsequent to the 
futility analysis in the DLBCL cohorts, the Data Monitoring Committee (DMC) endorsed a study design change 
to a modified 2-stage Green-Dahlberg design. The resulting expanded sample size is shown in the table below. 
Up to 70 subjects with DLBCL (GCB or non-GCB, EZH2 wild-type) will be enrolled in an additional 
combination therapy cohort (tazemetostat and prednisolone), after completion of the accrual of the 
corresponding monotherapy cohort (2 or 3). A 2-stage Green-Dahlberg design will be used to terminate 
enrollment for futility. Prior to full enrollment of stage 1, initial tolerability of 800 mg BID tazemetostat in 
combination with prednisolone (40 mg/m2 once daily on Days 1 to 5 and Days 15 to 19 in a 28-day cycle for a 
total duration of 16 weeks) will be assessed in the first 6 subjects enrolled based on the same set of dose limiting 
toxicity (DLT) criteria used in Phase 1. If a DLT is observed in no more than 1 of the 6 subjects, enrollment will 
continue to the end of stage 1. If a DLT is observed in more than 1 of the 6 subjects, lower dose level(s) of 
prednisolone may be evaluated. Subjects treated at the dose found to be tolerable during the initial safety run-in 
assessment will be included as part of the 35 subjects enrolled for stage 1. 
 
 
Monotherapy 
Combination 
Therapy 
 
DLBCL 
GCB 
EZH2 
Mutant 
DLBCL 
GCB 
EZH2 Wild-
Type 
DLBCL 
non-GCB 
 
FL 
EZH2 
Mutant 
FL 
EZH2 
Wild-Type 
DLBCL 
GCB or 
non-GCB 
EZH2 
Wild-Type 
Stage 1 
10 
10 
10 
10 
10 
35 
Stage 2 
50 
50 
50 
35 
35 
35 
Total 
60 
60 
60 
45 
45 
70 
 
DLBCL = diffuse large B cell lymphoma, EZH2 = enhancer of zeste- homolog 2, FL = follicular lymphoma, 
GCB = germinal-center B-cell-like 
 
 
Inclusion Criteria 
All Subjects: 
1. Phase 1: Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Phase 2: ECOG 
performance status of 0 to 2 (Appendix 1). 
2. Life expectancy t 3 months before starting tazemetostat. 
3. Subjects with a history of hepatitis B or C are eligible on the condition that subjects have adequate liver 
function as defined by Inclusion Criterion #6 and are hepatitis B surface antigen negative and/or have 
undetectable hepatitis C virus (HCV) RNA. 
4. $GHTXDWHUHQDOIXQFWLRQGHILQHGDVFDOFXODWHGFUHDWLQLQHFOHDUDQFH 40 mL/min per the Cockcroft and Gault 
formula (Appendix 2) or local institutional standard formula. 


Tazemetostat 
Protocol E7438-G000-101 
Protocol Amendment 
Amendment No. 13.0 
Epizyme, Inc. 
CONFIDENTIAL 
Page 11 of 119 
5. Adequate bone marrow function:  
a. 
Absolute neutrophil count (ANC) t 750/mm3  0.75 × 109/L)  
x Without growth factor support (filgrastim or pegfilgrastim) for at least 14 days 
b. Platelets t 75,000/mm3  75 × 109/L) 
x Evaluated after at least 7 days since last platelet transfusion 
c. 
Hemoglobin t 9.0 g/dL  
x May receive transfusion 
6. Adequate liver function: 
a. 
Total bilirubin d 1.5 × the upper limit of normal (ULN) except for unconjugated hyperbilirubinemia of 
Gilbert’s syndrome 
b. Alkaline phosphatase (ALP) (in the absence of bone disease), alanine aminotransferase (ALT), and 
aspartate aminotransferase (AST) d 3 × ULN (d 5 × ULN if subject has liver metastases) 
7. Time between prior anticancer therapy and first dose of tazemetostat as below: 
x 
Cytotoxic chemotherapy – At least 21 days 
x 
Non-cytotoxic chemotherapy (eg, small molecule inhibitor) – At least 14 days 
x 
Nitrosoureas – At least 6 weeks 
x 
Monoclonal antibody(ies) – At least 28 days  
x 
Radiotherapy  
R 
At least 14 days from local site radiation therapy;  
R 
At least 6 weeks from prior radioisotope therapy; 
R 
At least 12 weeks from 50% pelvic or total body irradiation 
x 
High-dose therapy with autologous hematopoietic cell infusion – At least 60 days 
x 
High-dose therapy with allogeneic transplant – At least 90 days (if graft versus host disease [GVHD] is 
present, must be < Grade 2) and on no prohibited medications, per Exclusion Criterion #3) 
x 
NOTE: Starting at Cycle 1 Day 1, subjects may receive no more than 10 mg of prednisone daily (or 
equivalent corticosteroid, excluding protocol-defined prednisolone dosing for subjects enrolled in 
Cohort 6) when used for treatment of lymphoma-related symptoms, with the intent to taper by the 
end of Cycle 1. 
8. Males or females aged t 18 years at the time of informed consent (Phase 2). Males and females aged 16 
years of age at time of informed consent (Phase 1). 
9. Females must not be lactating or pregnant at Screening or Baseline (as documented by a negative beta-
human chorionic gonadotropin [ß-hCG] test with a minimum sensitivity of 25 IU/L or equivalent units of ß-
hCG). A separate baseline assessment is required if a negative screening pregnancy test was obtained more 
than 72 hours before the first dose of study drug. All females will be considered to be of childbearing 
potential unless they are postmenopausal (at least 12 months consecutively amenorrheic, in the appropriate 
age group, and without other known or suspected cause) or have been sterilized surgically (ie, bilateral tubal 
ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing). 
Females of childbearing potential must not have had unprotected sexual intercourse within 30 days prior to 
study entry and must agree to use a highly effective method of contraception, from the last menstrual period 
prior to randomization, during Treatment Cycles, and for 6 months after the final dose of study drug, and 
have a male partner who uses a condom. Highly effective contraception includes: 
a. 
Double barrier methods of contraception such as condom plus diaphragm or cervical/vault cap with 
spermicide. 
b. Placement of an intrauterine device. 
c. 
Established hormonal contraceptive methods: oral, injectable, or implant. Females who are using 
hormonal contraceptives must have been on a stable dose of the same hormonal contraceptive product 
for at least 4 weeks prior to dosing and must continue to use the same contraceptive during the study and 


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Epizyme, Inc. 
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for 6 months after study drug discontinuation. 
Female subjects exempt from this requirement are subjects who practice total abstinence 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 the Treatment Cycles, and for 6 
months after study drug discontinuation.  
10. Male subjects must have had either a successful vasectomy OR they and their female partner must meet the 
criteria above (ie, not of childbearing potential OR practicing highly effective contraception and use a 
condom throughout the study period and for 3 months after study drug discontinuation).  
11. Voluntary agreement to provide written informed consent and the willingness and ability to comply with all 
aspects of the protocol. 
Phase 1 only (IGR and IB sites in France only): 
12. Histologically and/or cytologically confirmed advanced or metastatic solid tumor or B cell lymphomas that 
have progressed after treatment with approved therapies or for which there are no standard therapies 
available. 
Phase 2: 
13. Subjects must satisfy all of the following criteria:  
a. 
Have histologically confirmed DLBCL (including primary mediastinal B cell lymphoma), with relapsed 
or refractory disease following at least 2 lines of prior standard therapy, including 
alkylator/anthracycline (unless anthracycline–based chemotherapy is contraindicated)/anti-CD20-based 
therapy (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP] or 
equivalent) AND must be considered unable to benefit from intensification treatment with autologous 
hematopoietic stem cell transplantation (ASCT), as defined by meeting at least 1 of the following 
criteria:  
x 
Relapsed following, or refractory to, previous ASCT 
x 
Did not achieve at least a partial response to a standard salvage regimen (eg, rituximab, 
ifosfamide, carboplatin, and etoposide phosphate [R-ICE] or rituximab, dexamethasone, 
cytarabine, and cisplatin [R-DHAP]) 
x 
Ineligible for intensification treatment due to age or significant comorbidity 
x 
Ineligible for intensification treatment due to failure to mobilize an acceptable number of 
hematopoietic stem cells 
x 
Refused intensification treatment and/or ASCT 
or  
b. Have histologically confirmed FL, all grades. Subjects may have relapsed/refractory disease following at 
least 2 standard prior systemic treatment regimens where at least 1 anti-CD20-based regimen was used. 
Subjects with prior radiotherapy will be included; however, radiotherapy alone will not be considered a 
separate systemic treatment regimen. 
c. 
Have provided sufficient archival tumor tissue that has been successfully tested for EZH2 mutation 
status and cell of origin (DLBCL only) at study specific laboratories allowing for allocation into an open 
cohort.  
d. Have measurable disease as defined by International Working Group-Non-Hodgkin’s Lymphoma (IWG-
NHL [Cheson, 2007]). 
Exclusion Criteria 
All Subjects: 
1. Prior exposure to tazemetostat or other inhibitor(s) of EZH2. 
2. Subjects with known leptomeningeal metastases or brain metastases or history of previously treated 
brain metastases. 
3. Has thrombocytopenia, QHXWURSHQLDRUDQHPLDRI*UDGHSHU&7&$(FULWHULDDQGDQ\SULRU
history of myeloid malignancies, including myelodysplastic syndrome (MDS). 
4. Has a prior history of T-LBL/T-ALL. 
5. Subjects taking medications that are known potent CYP3A4 inducers/inhibitors (including St. John’s 
wort) (see Section 7.3.4.3 and 


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http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabe
ling/ucm080499.htm; http://medicine.iupui.edu/clinpharm/ddis/). 
6. Subjects unwilling to exclude Seville oranges, grapefruit juice, and grapefruit from their diet. 
7. Any prior treatment-related (ie, chemotherapy, immunotherapy, radiotherapy), clinically significant 
toxicities have not resolved WR*UDGHSHU&7&$( version 4.03, or prior treatment-related toxicities 
are clinically unstable and clinically significant at time of enrollment. 
8. Major surgery within 4 weeks before the first dose of study drug. 
x 
NOTE: Minor surgery (eg, minor biopsy of extracranial site, central venous catheter placement, 
shunt revision) is permitted within 3 weeks prior to enrollment. 
9. Inability to take oral medication, or malabsorption syndrome or any other uncontrolled gastrointestinal 
condition (eg, nausea, diarrhea, or vomiting) that might impair the bioavailability of tazemetostat. 
10. Significant cardiovascular impairment: history of congestive heart failure greater than New York Heart 
Association (NYHA) Class II, uncontrolled arterial hypertension, unstable angina, myocardial infarction, 
or stroke within 6 months of the first dose of study drug; or cardiac ventricular arrhythmia (Appendix 3). 
11. Prolongation of corrected QT interval using Fridericia’s formula (QTcF) to > 480 msec. 
12. Venous thrombosis or pulmonary embolism within the last 3 months before starting tazemetostat. 
13. Active infection requiring systemic therapy. 
14. Known hypersensitivity to any component of tazemetostat, prednisolone/prednisone (combination cohort 
only), or inability to be treated with a Pneumocystis prophylaxis medication (combination cohort only). 
15. Immunocompromised subjects, including subjects known to be infected with human immunodeficiency 
virus (HIV). 
16. Any other major illness that, in the Investigator’s judgment, will substantially increase the risk 
associated with the subject’s participation in this study. 
17. Females who are pregnant or breastfeeding. 
18. Subjects who have undergone a solid organ transplant. 
Phase 2 only: 
19. Subjects with noncutaneous malignancies other than B cell lymphomas.  
x 
Exception: Subjects with another malignancy who have been disease-free for 5 years, or 
subjects with a history of a completely resected non-melanoma skin cancer or successfully 
treated in situ carcinoma are eligible. 
Study Drugs 
Study Drugs: Tazemetostat and Prednisolone (combination only) 
Tazemetostat is available as tablets in strengths of 100 (Phase 1 only) and 200 mg and supplied in white high-
density polyethylene bottles. 
Prednisolone will be sourced by the Investigator through the site pharmacy. In this study prednisolone is 
considered background therapy. 
Dosage and Administration: Tazemetostat and Prednisolone (combination only) 
Tazemetostat is administered orally with or without food. The doses being administered in each part of the study 
are as follows: 
Phase 1 Dose Escalation (closed to enrollment) – Five dose levels were explored: 100 mg BID, 200 mg BID, 
400 mg BID, 800 mg BID and 1600 mg BID starting on Cycle 1 Day 1. 
Phase 1 Food Effect (closed to enrollment) – A single 200 mg dose administered on Day -8 and Day -1. Starting 
on Cycle 1 Day 1 400 mg BID is administered. 
Phase 1 Drug-Drug Interaction (closed to enrollment) – Midazolam 2 mg is given orally on Day -1 and Day 15. 
Starting on Cycle 1 Day 1, tazemetostat 800 mg BID is administered. 


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Phase 2 – In the monotherapy cohorts, 800 mg BID is administered starting on Cycle 1 Day 1. In the combination 
cohort, tazemetostat is administered at 800 mg BID starting on Cycle 1 Day 1 continuously and prednisolone is 
administered at 40 mg/m2 (rounding can be done per local standard practice) once daily on Days 1 to 5 and Days 
15 to 19 in a 28-day cycle for a total duration of 16 weeks. After the combination treatment, tazemetostat will be 
continued as a monotherapy at 800 mg BID continuously. There will be a run-in of up to 6 subjects to evaluate 
the tolerability of the combination treatment. If the tolerability is not acceptable, lower dose(s) of prednisolone 
may be evaluated. 
Duration of Treatment 
The Treatment Phase for the Phase 1 Dose Escalation part will last for 1 cycle. In the Extension Phase, subjects 
may remain on study until they have disease progression, development of unacceptable toxicity that leads to 
tazemetostat treatment withdrawal, or withdrawal of consent.  
Food Effect and DDI cohorts were initiated as part of the Phase 1 study after safety of the 200 mg tazemetostat 
dose (highest available tablet dosage strength) was evaluated, and at the RP2D of 800 mg BID, respectively. The 
Treatment Phase for both cohorts will last until the end of Cycle 1. 
Subjects will continue to receive study treatment per study design until disease progression, development of 
unacceptable toxicity that leads to study treatment withdrawal, or withdrawal of consent. Investigators who note 
subjects with disease progression that are receiving continued clinical benefit without clinical deterioration 
should contact the Medical Monitor to discuss the assessment of risk/benefit of keeping the subject on study. 
As of Amendment 13.0, long-term survival follow-up is no longer required for subjects after 
discontinuation of study treatment. Also, annual PK sample collections for assessment were no longer 
required as of as of 16 May 2018. 
Rollover Study: All subjects in Phase 1 who remain on tazemetostat for 9 months or longer, and are eligible to 
continue receiving tazemetostat, will transfer to a Rollover Study for monitoring and continued study drug at the 
Investigator’s and the Medical Monitor’s discretion. All subjects in Phase 2 who remain on tazemetostat for 24 
months or longer, and are eligible to continue receiving tazemetostat, also will transfer to a Rollover Study for 
monitoring and continued access to study drug at the Investigator’s and the Medical Monitor’s discretion. 


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2 TABLE OF CONTENTS 
SPONSOR PROTOCOL APPROVAL PAGE 
2 
INVESTIGATOR AGREEMENT PAGE 
3 
PROTOCOL AMENDMENT SUMMARY OF CHANGES 
4 
1 
CLINICAL PROTOCOL SYNOPSIS 
7 
2 
TABLE OF CONTENTS 
15 
LIST OF IN-TEXT TABLES 
17 
3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
18 
4 
INVESTIGATORS AND STUDY PERSONNEL 
21 
5 
INTRODUCTION 
21 
5.1 
Investigational Product 
23 
5.1.1 
Tazemetostat 
23 
5.1.2 
Prednisolone 
26 
5.2 
Study Rationale 
26 
5.2.1 
Rationale for Dosage Selection 
27 
5.2.2 
Rationale for Phase 2 Dose 
29 
6 
STUDY OBJECTIVES 
31 
6.1 
Primary Objectives 
31 
6.2 
Secondary Objectives 
31 
6.3 
Exploratory Objectives 
32 
7 
INVESTIGATIONAL PLAN 
32 
7.1 
Overall Study Design and Plan 
32 
7.2 
Selection of Study Population 
37 
7.2.1 
Inclusion Criteria 
38 
7.2.2 
Exclusion Criteria 
41 
7.3 
Treatments 
42 
7.3.1 
Identity of Investigational Product 
42 
7.3.2 
Treatments Administered 
43 
7.3.3 
Method of Assigning Subjects to Treatment Groups 
49 
7.3.4 
Prior and Concomitant Therapy 
50 
7.3.5 
Prohibitions and Restrictions during Study Period 
53 
7.3.6 
Treatment Compliance 
53 
7.3.7 
Drug Supplies and Accountability 
53 
7.4 
Study Assessments 
55 
7.4.1 
Assessments 
55 
7.4.2 
Schedule of Procedures/Assessments 
66 
7.4.3 
Appropriateness of Measurements 
77 
7.4.4 
Adverse Events and Serious Adverse Events, Pregnancy, and Other 
Events of Interest 
77 
7.4.5 
Completion/Discontinuation of Subjects 
84 
7.4.6 
Reporting of Serious Adverse Events and Other Events of Interest 
85 
7.4.7 
Confirmation of Medical Care by Another Physician 
88 
7.5 
Data Quality Assurance 
88 


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7.5.1 
Data Management 
88 
7.5.2 
Database Quality Assurance 
89 
7.5.3 
Bioanalytical Data Management and Quality Control 
89 
7.6 
Statistical Methods 
89 
7.6.1 
Statistical and Analytical Plans 
89 
7.6.2 
Determination of Sample Size 
97 
7.6.3 
Interim Analyses 
99 
7.6.4 
Other Statistical/Analytical Issues 
99 
7.6.5 
Procedure for Revising the Statistical Analysis Plan 
99 
8 
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES) 
100 
8.1 
Changes to the Protocol 
100 
8.2 
Ethical Conduct of the Study 
100 
8.2.1 
Subject Information and Consent 
101 
8.3 
Administrative Procedures 
102 
8.3.1 
Changes to the Protocol 
102 
8.3.2 
Adherence to the Protocol 
102 
8.3.3 
Monitoring Procedures 
102 
8.3.4 
Recording of Data 
103 
8.3.5 
Identification of Source Data 
104 
8.3.6 
Retention of Records 
104 
8.3.7 
Auditing Procedures and Inspection 
104 
8.3.8 
Handling of Study Drug 
105 
8.3.9 
Publication of Results 
105 
8.3.10 
Disclosure and Confidentiality 
105 
8.3.11 
Discontinuation of Study 
106 
8.3.12 
Subject Insurance and Indemnity 
106 
9 
REFERENCE LIST 
107 
APPENDIX 1 
EASTERN COOPERATIVE ONCOLOGY GROUP 
PERFORMANCE STATUS 
111 
APPENDIX 2 
COCKCROFT AND GAULT FORMULA 
112 
APPENDIX 3 
NEW YORK HEART ASSOCIATION CARDIAC DISEASE 
CLASSIFICATION 
113 
APPENDIX 4 
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
114 
APPENDIX 5 
COMMON TERMINOLOGY CRITERIA FOR ADVERSE 
EVENTS 
115 
APPENDIX 6 
STANDARD HIGH-FAT BREAKFAST 
116 
APPENDIX 7 
PHARMACOGENOMICS/PHARMACODYNAMICS 
117 
 


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LIST OF IN-TEXT TABLES 
 
Table 1 
Geometric Mean [(%CV), (range)] for Preliminary Tazemetostat 
Pharmacokinetic Parameters after Administration Fasted or Immediately 
After a High-Fat Breakfast in Study E7438-G000-101 (n = 11) 
30 
Table 2 
Study Design for E7438-G000-101 
36 
Table 3 
Dose-Limiting Toxicities 
46 
Table 4 
Tazemetostat Dose Reduction and Interruption Instructions 
49 
Table 5 
Medications that are Potent Inhibitors and Inducers of CYP3A4 
52 
Table 6 
Tazemetostat Adjustment for Coadministration of a Moderate CYP3A 
Inhibitor 
52 
Table 7 
Clinical Laboratory Tests 
63 
Table 8 
Schedule of Visits and Procedures: Phase 1 Tazemetostat (all visits 
starting at Cycle 2 Day can have a +/- 3 day window) 
68 
Table 9 
Schedule of Visits and Procedures: Phase 2 (All Visits Starting at Cycle 1 
Day 15 Have ± 3-Day Window) 
72 
Table 10 
2-Stage Green Dahlberg Design 
98 
 
 


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3 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
18FDG-PET 
18fluorodeoxyglucose-positron emission tomography 
ABC 
activated B-cell-like 
ADL 
activities of daily living 
AE 
adverse event 
AESI 
adverse event of special interest 
ALL 
acute lymphoblastic leukemia 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase  
AML 
acute myeloid leukemia 
ANC 
absolute neutrophil count 
ASCO 
American Society of Clinical Oncology 
ASCT 
autologous hematopoietic stem cell transplantation 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC0-f 
area under the concentration-time curve from zero extrapolated to infinity 
AUC0-12 
area under the concentration-time curve from zero time to 12 hours 
AUC0-24 
area under the concentration-time curve from zero time to 24 hours 
ȕ-hCG 
beta-human chorionic gonadotropin 
BID 
twice daily 
BP 
blood pressure 
CHOP 
cyclophosphamide, doxorubicin, vincristine, and prednisone 
CI 
confidence interval 
Cmax 
maximum drug concentration 
CL 
total body clearance 
CLr 
renal clearance 
CNS 
central nervous system 
COO 
cell of origin 
COP 
CHOP without doxorubicin 
CR 
complete response 
CRA 
clinical research associate 
CRF 
case report form 
CRO 
contract research organization 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events  
CV 
coefficient of variation 
CYP 
cytochrome P450 
DDI 
drug-drug interaction 
DLBCL 
diffuse large B cell lymphoma 
DLT 
dose-limiting toxicity 
DMC 
Data Monitoring Committee 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EZH2 
enhancer of zeste homolog 2 
EU 
European Union 
FDA 
Food and Drug Administration 
fe 
fraction excreted 
FE 
food effect 
FFPE 
formalin fixed paraffin embedded 
FL 
follicular lymphoma 
GCB 
germinal-center B-cell-like 


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Abbreviation 
Term 
GCP 
Good Clinical Practice(s) 
GVHD 
graft versus host disease 
H3K27 
histone H3 lysine 27 
H3K27me3 
trimethylated state of histone H3 lysine 27 
HAT 
histone acetyltransferase 
HCV 
hepatitis C virus 
HDPE 
high-density polyethylene 
HIV 
human immunodeficiency virus 
HMT 
histone methyltransferase 
HR 
heart rate 
IB 
Institut Bergonie (when referring to study site in France) 
Investigator’s Brochure (when referring to document) 
IC90 
90% of the maximal inhibition 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation  
IEC 
Independent Ethics Committee 
IGR 
Institut Gustave Roussy 
IHC 
immunohistochemistry 
IRB 
Institutional Review Board 
IV 
intravenous 
IWG-NHL 
International Working Group-Non-Hodgkin’s Lymphoma 
LNH 
low/normal/high classification 
LVEF 
left ventricular ejection fraction 
MDS 
myelodysplastic syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
MPN 
myeloproliferative neoplasm 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
MUGA 
multiple-gated acquisition 
NE 
not evaluable 
NHL 
non-Hodgkin lymphoma 
NYHA 
New York Heart Association 
ORR 
objective response rate 
PCR 
polymerase chain reaction 
PD 
pharmacodynamic(s) or progressive disease 
PET 
positron-emission tomography 
PFS 
progression-free survival 
PI 
Principal Investigator 
PK 
pharmacokinetic(s) 
PK/PD 
pharmacokinetic(s)/pharmacodynamic(s) 
PMBCL 
primary mediastinal B cell lymphoma 
PR 
partial response 
PT 
preferred term 
QT 
the time interval from the beginning of the cardiac QRS complex to the end of the T 
wave 
QTc 
corrected QT interval 
QTcB 
QT interval corrected for heart rate using Bazett’s formula 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
R 
accumulation ratio 
R-CHOP 
rituximab plus CHOP 
R-DHAP 
rituximab, dexamethasone, cytarabine, and cisplatin 
RECIST 
Response Evaluation Criteria in Solid Tumors 
R-ICE 
rituximab, ifosfamide, carboplatin, and etoposide phosphate 
RP2D 
recommended Phase 2 dose 


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Abbreviation 
Term 
RR 
respiratory rate 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SmPC 
Summary of Product Characteristics 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
SOC 
system organ class  
SUSAR 
suspected unexpected serious adverse reaction 
t1/2 
elimination half-life 
tazemetostat (EPZ-6438 
and E7438) 
investigational study drug: N-[(4,6-Dimethyl-2-oxo-1,2-dihydropyridine-3-
yl)methyl]-5-[ethyl(tetrahydro-2H-pyran-4-yl)amino]-4-methyl-4'-(morpholin-4-
ylmethyl)biphenyl-3-carboxamide hydrobromide 
T-ALL 
T-cell acute lymphoblastic leukemia 
T-LBL 
T-cell lymphoblastic lymphoma 
TEAE 
treatment-emergent adverse event 
tmax 
time to reach maximum concentration (following drug administration) 
ULN 
upper limit of normal 
US/USA 
United States/United States of America 
UTX 
ubiquitously transcribed tetratricopeptide repeat, X chromosome 
UV 
ultraviolet 
Vd 
volume of distribution 


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4 INVESTIGATORS AND STUDY PERSONNEL 
This study will be conducted by qualified investigators under the sponsorship of Epizyme (the 
Sponsor) at up to 5 investigational sites in the European Union (EU) for the Phase 1 part of the 
study. Investigational sites for Phase 2 are being identified globally. 
The name of the Sponsor’s medical monitor, along with the telephone and fax numbers of the 
other contact persons at the Sponsor and, if applicable, any contract research organization 
(CRO), will be listed in the Investigator File provided to each site. 
5 INTRODUCTION 
Tazemetostat is a selective small molecule inhibitor of the histone lysine methyltransferase 
enhancer of zeste homolog 2 (EZH2). Posttranslational modifications of core histone proteins of 
chromatin play an important role in controlling the fidelity of gene transcription patterns in cells. 
Paramount among these transcription-controlling modifications is methylation events at lysine 
and arginine residues, catalyzed by histone methyltransferases (HMTs). Genetic alterations in a 
number of HMTs have been identified in human cancers where they are purported to play a 
causal role in malignancies. Of note, non-Hodgkin lymphoma (NHL) shows a high propensity in 
mutations in chromatin modifying enzymes, including HMTs (EZH2, MLL2), histone 
demethylases (for instance ubiquitously transcribed tetratricopeptide repeat, X chromosome, 
UTX) and histone acetyltransferases (HATs), perturbing the state of chromatin leading to 
aberrant gene expression (Morin, 2011). EZH2 is the catalytic subunit of the multi-protein HMT 
complex known as polycomb repressive complex 2, which is responsible for mono-, di-, and tri-
methylation of histone H3 lysine 27 (H3K27); hypertrimethylation of H3K27 is known to silence 
tumor suppressor genes and thus to be tumorigenic. MLL2, in contrast, methylates H3K4, a 
histone modification associated with actively transcribed chromatin (Milne, 2005). Loci of genes 
bivalently modified at H3K27 and H3K4 are poised for rapid expression regulation in either 
direction (Voigt, 2013), and perturbation of the correct methylation balance can lead to cancer 
(Béguelin, 2013). Multiple mechanisms have been shown to lead to hypertrimethylation of 
H3K27 in cancer, including mutation, amplification and overexpression of EZH2, and 
inactivating mutations of the H3K27 demethylase UTX. Somatic mutations in the catalytic SET 
(Su(var)3-9, Enhancer-of-zeste and Trithorax) domain of the EZH2 gene at 3 hotspot residues 
(Y646, A682, and A692 [NM_001203247]) are present in follicular and diffuse large B cell 
lymphomas (FL, DLBCL) and lead to high levels of H3K27 trimethylation (H3K27me3) in these 
lymphomas. These gain-of-function (GOF) mutations of EZH2 render the enzyme constitutively 
active and, therefore, have been proposed to be required for the development and maintenance of 
EZH2 mutation-bearing lymphomas. Inhibition of EZH2 leads to reduction in H3K27me3 and 
cell death in lymphoma cell lines bearing the mutation. In addition, loss of function of MLL2 and 
HATs may generate abnormal methylation states of H3K27, potentially leading to a dependency 


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on EZH2. In nonclinical models, inhibition of EZH2 leads to reduction in H3K27me3 in all 
lymphoma cell lines irrespective of their EZH2 mutation status. While cells with wild-type 
EZH2 (operationally defined here as lacking any of the GOF mutations within the SET domain 
that define “mutant” EZH2 [specifically, lacking any of the following mutations within codons 
Y646, A682, and A692 of the EZH2 gene: Y646F, Y646N, Y646S, Y646H, Y646C, A682G, 
and/or A692V (Bodor, 2013). While cells with wild-type EZH2 are growth inhibited with EZH2 
inhibition in vitro, only mutation bearing cells undergo cell death in culture (Béguelin, 2013; 
Knutson, 2014a).  
Changes to the tumor microenvironment, for instance those affecting antitumor immunity, are 
increasingly recognized as an important mechanism in lymphomagenesis, affecting all types of 
NHL (Scott, 2014). Epigenetic therapy has been suggested to release repression of molecules 
important for immune recognition on tumor cells (Wrangle, 2013), and EZH2 inhibition may 
induce similar effects. In addition, loss of EZH2 has been described as affecting T helper cell 
plasticity (Tumes, 2013) and is proposed to inhibit the function of regulatory T cells 
(Arvey, 2014; DuPage, 2015; Yang, 2015), suggesting that EZH2 inhibition may contribute to 
enhancing antitumor immunity. 
In summary, the available nonclinical data suggest that EZH2 mutant lymphomas should show 
the highest sensitivity to EZH2 inhibition, but cases lacking EZH2 GOF mutations (ie, wild-
type) could also be affected through tumor cell autonomous mechanisms (mutations in MLL2, 
HATs, UTX, etc.) and/or effects of EZH2 inhibitors on the tumor microenvironment. 
Diffuse large B cell lymphoma (DLBCL) and FL are the 2 most common lymphoid malignancies 
with annual incidences of 3.8 and 2.2/100,000, respectively, in Europe (Sant, 2010) and 6.9 and 
3.7/100,000, respectively, in the United States (US) (National Cancer Institute, 2014). For both 
DLBCL and advanced FL, chemoimmunotherapy with rituximab has substantially improved 
long-term disease control (Dreyling, 2014; Tilley, 2012). There are 3 histologically 
indistinguishable molecular subtypes of DLBCL: the activated B-cell-like (ABC) subtype, the 
germinal-center B-cell-like (GCB) subtype, and the primary mediastinal B cell lymphoma 
(PMBCL) subtype. These subtypes differ in terms of gene expression and are believed to 
originate in B cells at different stages of differentiation. In addition, the process of malignant 
transformation differs for each subtype, resulting in distinctive patterns of genetic abnormality. 
Clinical presentation and responsiveness to targeted therapies also vary across the subtypes 
(Foon, 2012). 
Gene expression in GCB lymphomas is characteristic for germinal-center B cells, with deletion 
of the tumor suppressor gene PTEN and p53 mutations being specific to GCB lymphomas. 
Genetic abnormalities that are characteristic for ABC DLBCL include deletion of the 
INK4ĮARF tumor suppressor locus on chromosome 9 and amplification of the 9-Mb region on 


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chromosome 19. Loss of these tumor suppressors impedes the action of chemotherapy and may 
contribute to the poor prognosis associated with this subtype. PMBCL may present with distinct 
clinical features, with disease thought to originate in the thymus, and often confined to the 
mediastinum. Gene expression profiling may provide additional information on characteristics of 
PMBCL such as deletion of SOCS1, a suppressor of JAK signaling, and gene profiling has 
identified similarities between PMBCL and classical Hodgkin’s lymphoma (Foon, 2012; 
Rosenwald, 2003). FL is thought to arise from germinal-center B cells, and the majority of 
subjects have a t(14:18) translocation at the site of the BCL-2 oncogene and 1 of the 3 
immunoglobulin genes. However, BCL-2 expression alone is not considered sufficient for FL 
development and other genetic mechanisms or host factors, such as epigenetic abnormalities, are 
considered required. FL is graded based on the proportion of centroblasts in the follicle with 
Grade 3b often being BCL-2 negative and displaying histological similarities to DLBCL. An 
integral part of the natural history of FL is progression to a higher grade histologic subtype such 
as DLBCL.  
Of note, in the Phase 1 Dose Escalation part of the present study, objective responses have been 
observed in both subjects lacking EZH2 GOF mutations (ie, wild-type) and subjects with mutant 
EZH2 NHL. In addition, objective responses have been noted in subjects with both GCB and 
non-GCB cell of origin (COO), determined by immunohistochemistry (IHC), including 1 subject 
with a classical clinical presentation of PMBCL. Based on these findings, the design of the 
Phase 2 part of this study has been modified to include a new cohort to evaluate the activity of 
tazemetostat in subjects with the non-GCB DLBCL subtype (inclusive of subjects with PMBCL), 
in addition to the previously described cohorts for mutation-bearing and non-mutation-bearing 
GCB DLBCL.  
5.1 Investigational Product 
Tazemetostat is under investigation as a treatment for subjects with relapsed or refractory 
DLBCL or FL for the Phase 2 portion of the protocol. Prednisolone in combination with 
tazemetostat will also be assessed as a treatment for subjects with relapsed or refractory DLBCL. 
5.1.1 Tazemetostat 
Active ingredient: N-[(4,6-Dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl]-5-
[ethyl(tetrahydro-2H-pyran-4-yl)amino]-4-methyl-4'-(morpholin-4-ylmethyl)biphenyl-3-
carboxamide hydrobromide 
5.1.1.1 Therapeutic Pathway or Mechanism of Action 
Tazemetostat inhibits EZH2, both wild-type  (ie, lacking EZH2 GOF mutations) and mutation-
bearing, with nanomolar affinity. The compound shows 36-fold selectivity over the closest 


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family member, EZH1, and greater than 4500-fold selectivity over other HMTs. It selectively 
inhibits intracellular histone H3K27 methylation in a concentration and time-dependent manner. 
Incubation with tazemetostat inhibits the proliferation of lymphoma cell lines, with those bearing 
EZH2 activating mutations being on average more sensitive. Administration of tazemetostat to 
mice bearing human DLBCL xenografts (4/5 EZH2 mutant DLBCL and 2/3 EZH2 wild-type 
DLBCL tested so far) induced significant antitumor effects, ranging from tumor growth 
inhibition to complete and durable tumor regressions (Knutson, 2014b; and unpublished). To 
determine the combination potential of tazemetostat with DLBCL standard of care, in vitro and 
in vivo studies of tazemetostat were performed with the constituent components or active 
metabolites of CHOP (Knutson, 2014b; and unpublished). In the in vitro studies, an additive or 
modest synergy benefit was seen for the DNA alkylating agent mafosfamide (a 
cyclophosphamide analogue), the DNA intercalating agent hyroxyldaunorubicin, and tubulin 
disrupting agent vincristine in DLBCL cell lines containing EZH2 GOF mutations at SET 
domain residues Y646, A682, or A692 that result in constitutive EZH2 activity and elevated 
levels of H3K27me3. Dramatic in vitro synergy was observed when tazemetostat was combined 
with glucocorticoid receptor agonist prednisolone (the active metabolite of prednisone) or 
dexamethasone in DLBCL cell lines containing either wild-type (ie, lacking EZH2 GOF 
mutations) or mutant EZH2. 
These in vitro results were extended into in vivo studies with 3 different EZH2 mutant 
lymphoma xenograft models. Combination treatments with CHOP or COP (CHOP without 
doxorubicin) were well-tolerated and significant synergy with regards to antitumor responses 
and/or tumor regressions were observed when tazemetostat was co-administered with either 
CHOP or COP. In line with the in vitro data, the combination benefit was also observed when 
tazemetostat was combined with prednisone alone. These in vitro and in vivo combination results 
provide a basis for investigating a new combination therapy in patients with DLBCL. 
5.1.1.2 Nonclinical Experience with Tazemetostat 
Nonclinical safety assessments of tazemetostat included in vitro and monkey safety 
pharmacology studies, genotoxicity studies, and single- and repeat-dose toxicity studies in 
Sprague-Dawley rats and cynomolgus monkeys of 4- and 13-weeks duration. No notable 
cardiovascular, central nervous system (CNS), or respiratory risks were identified in nonclinical 
safety pharmacology assessments. Tazemetostat was not genotoxic in standard in vitro and 
in vivo assays. The following potential risks were identified for tazemetostat based on 
nonclinical safety data: T-LBL (rat), increased bone formation in bone and teeth (rat), 
non-progressive bile duct hyperplasia (monkey), teratogenicity (rat and rabbit), lymphoid 
depletion (rat and monkey), and phototoxic potential (in vitro). Other effects at high, 


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non-tolerated doses, toxicities included bone marrow effects (hypocellularity, rat), and 
gastrointestinal toxicity (distention, ulceration, and degeneration, rat).  
Steady-state exposures (area under the concentration–time curve from 0 to 24 hours [AUC0-24]) 
in rats at the lowest dose (100 mg/kg/day) at which no T-LBL occurred in the 13-week 
adolescent rat study were 2.5- to 7.5-fold greater than that observed in humans at the 
recommended Phase 2 dose (RP2D; 800 mg twice daily [BID]) from the ongoing Phase 1/2 
Study E7438-G000-101. No incidences of abnormal bone formation have been observed in the 
ongoing clinical study. Female subjects of reproductive age will provide blood and urine samples 
for pregnancy testing at screening.  
All subjects must agree to use a reliable birth control method during the study, and for for 6 
months (female subjects) or 3 months (male subjects) after the last tazemetostat dose, and 
additionally will be actively monitored for signs or symptoms of abnormal bone formation.  
5.1.1.3 Clinical Experience with Tazemetostat 
This clinical study (Phase 1/2) is the first-in-human study with tazemetostat. The study parts and 
dose levels of the Phase 1 study are: Dose Escalation at 100 mg BID, Dose Escalation at 200 mg 
BID, Dose Escalation at 400 mg BID, Dose Escalation at 800 mg BID, Dose Escalation at 
1600 mg BID, Dose Expansion at 800 mg BID, Dose Expansion at 1600 mg BID, Food Effect 
(FE) at 400 mg BID, and Drug-Drug Interaction (DDI) at 800 mg BID. The Phase 1 dose 
escalation and expansion parts have been completed and the recommended Phase 2 dose (RP2D) 
was defined as 800 mg BID. The Phase 1 part also determined the relationship between exposure 
and H3K27me3 reduction in skin, and provided a preliminary assessment of activity.  
As of 7-Nov. 2015, 58 subjects were enrolled into the study (dose escalation, dose expansion, 
food effect, and drug-drug interaction), including 21 NHL subjects (14 DLBCL, 6 follicular 
lymphoma [FL], and 1 marginal zone lymphoma [MZL]). Adverse events (AE) occurring in 
 10% of the 58 subjects regardless of attribution were asthenia, anorexia, thrombocytopenia, 
nausea, diarrhea, and vomiting. There were 4 Grade  3 related AEs: thrombocytopenia, 
neutropenia, hypertension, and transaminase elevation. The median age of the NHL subjects 
enrolled was 63 years (range: 24-84) and 71% of subjects were male. Among the 16 response-
evaluable NHL subjects, objective responses were seen in 5/10 DLBCL, 3/5 FL and 1/1 MZL 
subjects.  
As of 19-Aug. 2016, 106 subjects were enrolled to the 5 monotherapy cohorts in the Phase 2 
portion of the study. The safety profile of subjects in Phase 2 was generally consistent with that 
observed for subjects in Phase 1. As part of safety surveillance reporting, 6% of subjects were 
observed to experience Grade 3 or higher infection/infestation in the entire study (n = 170, with 
64 subjects in Phase 1), of which only 1% experienced an opportunistic pneumonia 


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(Pneumocystis jirovecii pneumonia). Based on the review of safety and efficacy data, the DMC 
concluded on 6-Sep. 2016 that futility hurdles had been surpassed in all 5 monotherapy cohorts 
and no safety issues preclude the continued enrollment of study subjects. 
Further information on clinical efficacy and safety can be found in the tazemetostat 
Investigator’s Brochure (IB). 
5.1.1.4 Common Serious Adverse Events Expected to Occur 
in the Study Population Even in the Absence of Study 
Drug Exposure 
Lymphomatous meningitis, superior vena cava syndrome, compression syndromes, spinal cord 
compression, and pathologic fractures are known to occur in this study population. 
5.1.2 Prednisolone 
Prednisolone, an active metabolite of prednisone, is widely used for managing many types of 
disorders including aggressive lymphoma. Although its single-agent efficacy has been rarely 
documented, prednisolone has been integrated in important combination regimens in NHL, such 
as rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) 
(Cunningham, 2013). While prednisolone is generally well tolerated, chronic administration has 
been associated with adverse reactions including but not limited to fluid and electrolyte 
disturbances, muscle weakness, osteoporosis, peptic ulcer, pancreatitis, impaired wound healing, 
thin fragile skin, headache, convulsion, endocrine disorder (such as Cushingnoid state), etc. In 
this protocol, prednisolone will be administered in combination with tazemetostat to be assessed 
as a treatment for subjects with relapsed or refractory DLBCL. 
5.2 Study Rationale 
The proposed clinical study is a multicenter, open-label, Phase 1/2 study that will be conducted 
in 2 parts. 
The Phase 1 part (Institut Bergonie [IB] and Institut Gustave Roussy [IGR] sites in France only) 
will comprise dose escalation and establishment of the maximum tolerated dose (MTD) and/or 
RP2D when tazemetostat is given BID orally on a continuous basis in subjects with 
histologically and/or cytologically confirmed advanced or metastatic solid tumors or B cell 
lymphomas that have progressed after treatment with approved therapies or for which there are 
no standard therapies available. Additionally, in separate cohorts in Phase 1, the effect of food on 
the bioavailability of tazemetostat will be evaluated as well as the DDI potential as evaluated by 
the effect of tazemetostat on the pharmacokinetics (PK) of midazolam, a cytochrome P450 
(CYP)3A4 substrate. The effect of food on bioavailability will be initiated at 200 mg 
tazemetostat dose (highest available tablet dosage strength). DDI potential will be initiated at 


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800 mg BID (RP2D). The FE and DDI cohorts may be performed in parallel and may 
subsequently continue in parallel with Phase 2. 
The Phase 2 part will be initiated at a recommended dose of 800 mg BID. Based upon both the in 
vitro responses to tazemetostat of both EZH2 wild-type and mutant DLBCL cell lines and 
Phase 1 objective responses seen to date (Knutson, 2014a; Ribrag, 2015). Phase 2 will enroll 
subjects with DLBCL (Cohorts 1-3 and 6) or FL (Cohorts 4 and 5) for the determination of 
efficacy and safety of tazemetostat monotherapy (Cohorts 1-5) and of tazemetostat in 
combination with prednisolone (Cohort 6) with placement determined by centrally confirmed 
histology, COO, and EZH2 mutation status. 
There are a limited number of treatment options for patients with relapsed/refractory DLBCL 
who may have poor bone marrow reserve after multiple prior treatments with chemotherapy. 
This study will evaluate the activity of the combination of tazemetostat and prednisolone in these 
patients (see Section 5.1.1.1 for in vitro and in vivo data on this combination). The combination 
will first be tested in a safety evaluation (safety run-in) and then expanded to a larger cohort for 
further safety confirmation and efficacy futility assessment (stage 1). The safety data of 
tazemetostat and prednisolone were carefully reviewed to identify potential areas of overlap for 
the most commonly reported adverse events. Based on the mechanisms of action and safety 
profiles of tazemetostat and prednisolone, the likelihood of overlapping toxicities of tazemetostat 
and prednisolone is considered low, with the exception of infection given the potential for 
immune suppression with steroid therapy or the combination therapy. This potential risk will be 
mitigated by prophylactic treatment with sulfamethoxazole and trimethoprim. Investigators 
should monitor subjects for infections and administer necessary treatments per their medical 
judgment. Prednisolone has a half-life of ~2 hours and is a CYP3A substrate and inducer. The 
risk of decreased tazemetostat exposure by prednisolone is acceptable given the intermittent 
dosing schedule of prednisolone. It is also plausible that the prednisolone exposure may be 
decreased by tazemetostat. Nevertheless, study drug exposure will be monitored throughout the 
study to evaluate for a DDI effect, allowing for potential future dosing revisions. 
The preclinical demonstration of therapeutic synergy of tazemetostat and prednisolone, balanced 
with the implementation of protocol designated risk mitigation and safety monitoring for 
potential areas of overlapping toxicity support the rationale for the assessment of this treatment 
combination in patients with relapsed DLBCL. 
5.2.1 Rationale for Dosage Selection 
5.2.1.1 Tazemetostat 
The first-in-human dose selected for tazemetostat is 100 mg BID or 200 mg daily. This dose has 
been intentionally chosen as a conservative starting point to maximize safety margins since, 


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according to the standard DeGeorge method, 1/10 of the severely toxic dose in rats resulted in a 
suggested starting dose of 150 mg BID (300 mg/day) in humans. 
Twice-daily administration of tazemetostat was selected based on the nonclinical studies in nude 
and severe combined immunodeficiency mice xenograft models, wherein BID dosing resulted in 
maximal tumor growth inhibition and sustained inhibition of intratumoral H3K27me3.  
In a nonclinical study, the tazemetostat mean bioavailability in the fed state was roughly 5-fold 
lower than that in fasted state in cynomolgus monkeys. Thus, this study was originally designed 
to administer tazemetostat in the fasted state, defined as no food for 2 hours before and after 
study drug ingestion. The effect of food on tazemetostat bioavailability in humans was explored 
in the Phase 1 part of this study to inform tazemetostat dosing in the Phase 2 part. 
Tazemetostat is metabolized primarily by CYP3A4. Tazemetostat was also shown to be a time-
dependent CYP3A4 inhibitor and a CYP3A4 inducer. To assess the effect of tazemetostat 
coadministration on drugs metabolized by CYP3A4, a DDI cohort with midazolam, a probe 
CYP3A4 substrate, is included in this study. Assessment of the effect of tazemetostat on 
exposure to midazolam and its metabolites will be used to guide coadministration of tazemetostat 
with drugs metabolized by CYP3A4. 
Tazemetostat was initially supplied as an oral suspension. Tazemetostat was subsequently made 
available as tablets in strengths of 50, 100, and 200 mg and supplied in white high-density 
polyethylene (HDPE) bottles. The first cohort (100 mg BID) included 3 subjects dosed with 
tazemetostat suspension and 3 subjects dosed with the tazemetostat tablet formulation. Tablet 
strengths of 200 mg will be made available during the Phase 2 part of the study.  
Inclusion of subjects 16 years of age and older in Phase 1 (FE and DDI cohorts only):  
PK modeling has been conducted using a GastroPlus PBPKPlus module that is integrated with 
age-related population data for body weight, height, body mass index, and bioelectrical 
impedance resistance measured at 50 KHz for humans from the US population 0 to 85 years of 
age. Using tazemetostat concentration-time data from the completed Phase 1 Dose 
Escalation/Expansion part of the current study, the predicted mean steady-state AUC and steady-
state maximum drug concentration (Cmax) values were 4900 ng•h/mL and 1500 ng/mL, 
respectively, for subjects 12 to 18 years of age after administration of 800 mg BID. These 
predicted PK exposure values are within the range of observed values in subjects after 
administration of 800 or 1600 mg BID. The 1600 mg BID dose was tolerated without a MTD 
being reached. 


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5.2.1.2 Prednisolone 
Prednisolone (40 mg/m2 once daily) was a component of R-CHOP14 (Cunningham, 2013), a 
dose intense immunochemotherapy regimen which was administered once every 2 weeks for a 
total of 6 cycles (12 weeks). In a separate Phase 3 study (Delarue, 2013), prednisone was used in 
the R-CHOP14 regimen for a total duration of 8 cycles (16 weeks). There was no significant 
difference in the safety or efficacy profile when R-CHOP was administered every 2 weeks vs 
3 weeks, and no significant toxicity was associated with the glucocorticoid use in either of the 
R-CHOP regimens (Cunningham, 2013; Delarue, 2013). In addition, a Phase 1b/2 study 
(EudraCT 2016-001499-31) is being initiated by the French Lymphoma Study Association 
evaluating the combination treatment of tazemetostat with 8 cycles of R-CHOP in DLBCL 
subjects who have not received anticancer treatment. To synchronize with the current dosing 
schedule of tazemetostat (28-day cycle), prednisolone will be dosed for a total period of 
16 weeks in this proposed study.  
Prednisolone concentrations of 1 μM (~360 ng/mL) resulted in a 7-fold enhancement of the 
potency of tazemetostat against an EZH2-mutant cell line (Knutson, 2014b). Enhancement of the 
effect of tazemetostat on tumor growth in mice bearing an EZH2-mutant lymphoma xenograft 
was observed after oral administration of 0.15 mg/kg prednisone twice daily. El Dareer et al. 
(1977) demonstrated that a 10 mg/kg oral dose of prednisone to mice resulted in a mean serum 
prednisolone Cmax of approximately 3000 ng/mL. The estimated prednisolone Cmax after 
administration of 0.15 mg/kg to mice is approximately 45 ng/mL assuming that systemic 
exposure to prednisolone increases in proportion to the dose of prednisone. A single oral dose of 
50 mg (~30 mg/m2 in a 1.75 m2 subject) prednisolone administered to healthy volunteers resulted 
in a mean plasma Cmax of approximately 1000 ng/mL (Luippold, 2001). These results suggest 
that a dose of 40 mg/m2 in subjects with lymphoma will result in plasma concentrations greater 
than those that resulted in enhancement of tazemetostat activity in preclinical models. 
5.2.2 Rationale for Phase 2 Dose 
Oral tazemetostat doses of 100 mg to 1600 mg BID were investigated in the Dose Escalation part 
of this study. As of 09-Jul. 2015, 45 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 tazemetostat was observed at dose levels of 100, 200, and 800 mg BID, including objective 
responses observed in 9 of 15 evaluable subjects with B cell lymphoma who have had tumor 
assessments while on study drug. Objective responses were observed in 5/9 DLBCL, 3/5 FL, and 
1/1 MZL subjects. An MTD was not established with tazemetostat doses of up to 1600 mg BID. 
Inhibition of H3K27Me3 in skin was utilized as a measure of target engagement. A relationship 
between tazemetostat AUC on Day 15 and inhibition of H3K27 methylation in skin was 


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observed in the Dose Escalation part of Study E7438-G000-101. Results of preliminary 
pharmacokinetic/pharmacodynamic (PK/PD) modelling predicted that a tazemetostat Day 15 
AUC of approximately 4000 ng•h/mL will result in 90% of the maximal inhibition (IC90) of 
H3K27Me3 in the skin. The mean tazemetostat area under the concentration-time curve from 
zero time to 12 hours (AUC0-12) on Day 15 in the 800 mg BID cohort (n = 13) was 
3670 ng•h/mL, which is similar to the predicted IC90.  
The safety, tolerability, clinical activity, PK, and pharmacodynamic (PD) assessments from the 
subjects treated in the Dose Escalation part of the study were used to select the RP2D. The 
greatest number of objective responses was observed in the 800 mg BID cohort during the Dose 
Escalation part of the study. Administration of 800 mg tazemetostat BID also resulted in a mean 
AUC0-12 similar to the AUC predicted to result in 90% of the maximal inhibition of H3K27Me3 
in skin. Therefore, the RP2D of 800 mg BID was selected. This RP2D has been endorsed by the 
investigators and an independent Data Monitoring Committee (DMC). A summary of the 
preliminary PK parameters from the food effect portion of this study is displayed in Table 1. 
Table 1 
Geometric Mean [(%CV), (range)] for Preliminary Tazemetostat 
Pharmacokinetic Parameters after Administration Fasted or Immediately 
After a High-Fat Breakfast in Study E7438-G000-101 (n = 11) 
Meal State 
Cmax 
(ng/mL) 
AUC0- 
(ng*h/mL) 
tmaxa 
(h) 
Fed 
232 
(107) 
(65.7 – 752) 
1080 
(85.3) 
(317.7 – 3070) 
4.0 
(1.0 – 6.0) 
Fasted 
322 
(130) 
(59.6 – 1470) 
1140 
(135) 
(179.3 – 6251) 
1.0 
(0.5 – 6.0) 
AUC0- = area under the concentration-time curve from zero extrapolated to infinity, Cmax = maximum drug concentration, 
CV = coefficient of variation, n = number of subjects, tmax = time to reach maximum concentration (following drug 
administration) 
a 
tmax presented as median (range) 
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 
time to reach maximum concentration (following drug administration) (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 


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systemic exposure as measured by AUC0- is not clinically significant, and therefore, 
tazemetostat can be taken without regards to meals. 
Further information on the rationale for the RP2D can be found in the tazemetostat IB. 
6 STUDY OBJECTIVES 
6.1 Primary Objectives 
The primary objectives of this study are: 
Phase 1 
x To determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose 
(RP2D) of tazemetostat as a single agent administered orally twice daily (BID), 
continuously in 28-day cycles in subjects with advanced solid tumors or with relapsed 
and/or refractory B cell lymphomas  
Phase 2 
x To determine the objective response rate (ORR; complete response + partial response 
[CR + PR]) of tazemetostat in subjects with enhancer of zeste homolog 2 (EZH2) gene 
mutation positive or negative (wild-type) with histologically confirmed diffuse large 
B cell lymphoma (DLBCL) or follicular lymphomas (FL) with relapsed or refractory 
disease and the ORR of tazemetostat in combination with prednisolone in subjects with 
EZH2 wild-type DLBCL 
6.2 Secondary Objectives 
The secondary objectives of this study are: 
Phase 1 
x To assess the effect of a high-fat meal on the bioavailability of tazemetostat 
x To assess the effect of tazemetostat on exposure of midazolam, a cytochrome P450 
(CYP)3A4 substrate 
x To assess the preliminary activity of tazemetostat 
Phase 2 
x To assess the effect of tazemetostat monotherapy and tazemetostat in combination with 
prednisolone on progression-free survival (PFS) 
x To assess the effect of tazemetostat monotherapy and tazemetostat in combination with 
prednisolone on duration of response (DOR) 


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All Phases and Cohorts 
x To assess the safety and tolerability of tazemetostat monotherapy and tazemetostat in 
combination with prednisolone 
x To assess the pharmacokinetic (PK) profile of tazemetostat monotherapy and 
tazemetostat in combination with prednisolone 
6.3 Exploratory Objectives 
The exploratory objectives of this study are: 
All Phases and Cohorts 
x To explore the PK and pharmacodynamic (PD) relationship of tazemetostat 
x To identify and investigate biomarkers and their correlation with biological activity for 
tazemetostat 
x To explore the effects of tazemetostat on histone H3K27 methylation, target gene 
expression, and phenotypic markers including those for differentiation, apoptosis, and 
cell proliferation, and changes in the tumor microenvironment 
x To explore the role of DNA sequence variability on absorption, metabolism, excretion 
and susceptibility to adverse events of tazemetostat 
x To explore the effect of tazemetostat monotherapy and tazemetostat in combination with 
prednisolone on overall survival  
7 INVESTIGATIONAL PLAN 
7.1 Overall Study Design and Plan 
This is a multicenter, open-label, Phase 1/2 study that will be conducted in 2 parts (see 
Section 7.3.2). The Phase 1 part (dose escalation and expansion parts have completed 
enrollment) comprised of dose escalation and expansion to establish the MTD and/or RP2D 
when tazemetostat is given BID orally on a continuous basis in subjects with histologically 
and/or cytologically confirmed advanced or metastatic solid tumors or B cell lymphomas that 
have progressed after treatment with approved therapies or for which there are no standard 
therapies available. Additionally, in separate cohorts in Phase 1 (IB and IGR sites in France 
only), the effect of food on the bioavailability of tazemetostat will be evaluated as well as the 
DDI potential as evaluated by the effect of tazemetostat on the pharmacokinetics of midazolam, a 
CYP3A4 substrate. The effect of food on bioavailability was initiated after safety of the 200 mg 
tazemetostat dose (highest available tablet dosage strength) was evaluated. The DDI potential 
cohort was initiated at the RP2D of 800 mg BID. The FE and DDI cohorts were performed once 


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the dose escalation was completed. The Phase 2 part was initiated once the MTD and/or RP2D 
was established. Phase 2 will enroll subjects with DLBCL (Cohorts 1-3 and 6) and FL (Cohorts 4 
and 5) for the determination of efficacy and safety of tazemetostat monotherapy (Cohorts 1-5) 
and tazemetostat in combination with prednisolone (Cohort 6) with placement determined by 
centrally confirmed histology, COO, and EZH2 mutation status as described below: 
x Subjects with histologically confirmed DLBCL (including PMBCL and transformed 
FL) (all enrollment of these Cohorts is closed) 
o DLBCL Cohort 1: Subjects with GCB subtype and the following EZH2 mutations: 
Y646F, Y646N, Y646S, Y646H, Y646C, A682G, and/or A692V 
o DLBCL Cohort 2: Subjects with GCB subtype and EZH2 wild-type 
o DLBCL Cohort 3: Subjects with non-GCB subtype (including PMBCL) 
Note: Upon cohort closure, up to 5 non-GCB subtype EZH2 mutation positive 
subjects can be enrolled in Cohort 1 
o DLBCL Cohort 6: EZH2 wild-type DLBCL subjects (GCB and non-GCB subtypes) 
can be enrolled after the accrual of the corresponding monotherapy cohort (2 or 3) is 
completed 
or 
x Subjects with histologically confirmed FL, all grades  
o FL Cohort 4: Subjects with the following EZH2 mutations: Y646F, Y646N, Y646S, 
Y646H, Y646C, A682G, and/or A692V (enrollment closed) 
o FL Cohort 5: Subjects with EZH2 wild-type (enrollment closed) 
Subjects will be required to undergo EZH2 mutation testing of their tumor tissue. An EZH2 
mutation result will be determined at designated study laboratory testing sites using a cobas 
EZH2 Mutation Test (under development, Roche Molecular Systems, Inc.), which is a real-time 
allele-specific polymerase chain reaction (PCR) test to detect the following GOF mutations 
within codons Y646, A682, and A692 of the EZH2 gene (Bodor, 2013) in formalin fixed paraffin 
embedded (FFPE) NHL tumor tissue specimens: Y646F, Y646N, Y646S, Y646H, Y646C, 
A682G, and/or A692V; results for codons Y646S, Y646H, and Y646C are not reported 
individually (grouped as Y646X). For the purposes of this protocol, the term “wild-type” refers 
to the absence of detection of the above-specified mutations. Subjects with tumors that are wild-
type for EZH2 will be enrolled in the EZH2 wild-type cohort. The EZH2 mutation test is 
intended to be used as an Investigational Use Only assay.  
Cell-of-origin status will be determined for DLBCL subjects by the Hans method (Hans, 2004) 
using available tumor tissue at designated study laboratory testing sites. Further details of EZH2 
mutation and COO testing are provided in the Laboratory Manual. 


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The tumor tissue EZH2/COO testing can be performed prior to other screening procedures, for 
example, during wash-out of the second line anticancer therapy, after the subject is consented for 
the prescreening testing.  
This study will be conducted in 3 phases: a Pretreatment Phase, a Treatment Phase, and an 
Extension Phase. The Pretreatment Phase consists of Screening and Baseline Visits (see Table 8 
and Table 9). 
The Treatment Phase for the Phase 1 Dose Escalation and Expansion parts last for 1 cycle. 
Subjects were enrolled using a dose-escalation algorithm (3+3 subjects per dose level) to identify 
the MTD and/or RP2D. 
Each 28-day period will be considered 1 treatment cycle. PK sampling will be performed on 
every subject and samples will be collected predose and at protocol-defined intervals as 
described in the Schedule of Visits and Procedures (see Table 8 and Table 9). 
The treatment cycle will begin with the first dose of study drug administration and continue for 
1 cycle (28 days [4 weeks]). Treatment may continue in the Extension Phase with Cycle 2 and 
beyond until completion of the Off-Treatment Visit (30 days after the last study drug 
administration). 
The enrollment for the Phase 1 part of the study commenced in June 2013. Using a standard 
3+3 design and increasing in 100% increments, enrollment of 5 dose cohorts of 3 to 6 subjects 
was completed with tazemetostat at 100, 200, 400, 800, and 1600 mg BID, with 1 dose-limiting 
toxicity (DLT) reported at 1600 mg BID. As of 07-Nov. 2014, the maximum delivered dose was 
1600 mg BID, and hence, an MTD had not been reached. The RP2D was therefore 800 mg BID 
because of the safety, PK, biological activity, and responses at this dose.  
Dose escalation (complete): Dose escalation proceeded in 100% increments in subsequent 
cohorts unless 1 *UDGHQRQKHPDWRORJLFDOWR[LFLW\GXULQJ&\FOHwas assessed as related to 
the study drug in 2 or more subjects at a dose level. For dose escalation purposes, toxicities 
assigned as DLTs during the first cycle were assessed (see Table 4). After completion of Cycle 1 
in each cohort, all available safety data were reviewed jointly by the Sponsor and the 
investigators and the decision to proceed to the next dose cohort was made. If 0 of 3 or 1 of 6 
subjects demonstrated DLT(s), then enrollment proceeded to the next dose level. If 1 DLT was 
reported for the first 3 (or 4) subjects, the cohort expanded to a total of 6 subjects. If 2 subjects in 
any cohort demonstrate DLT(s) during Cycle 1, enrollment into that cohort stopped and a dose 
reduction took place. In the first and second cohorts only, the first subject in each dose level must 
have completed at least 2 weeks of treatment during Cycle 1 without experiencing any DLTs 
before additional subjects were treated at that dose level. A dose-escalation meeting occurred 
when 3 evaluable subjects (for DLTs) completed 1 cycle of treatment. If a fourth subject in this 


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cohort experienced a DLT after a decision had been made to escalate to the next dose level, then 
this dose cohort (of the fourth subject) was expanded to a total of 6 subjects. Any subject 
initiated at a higher dose level continued to receive the same dose. If 2 subjects in the expanded 
cohort experience a DLT(s), a dose reduction took place. Additionally, any subject being treated 
at a higher dose level had the dose reduced to below the dose level that exceeded the tolerable 
dose level. The highest dose level below the dose level that exceeds a tolerable dose level 
(ie, UHVXOWVLQRIVXEMHFWVZLWK'/7Vwas considered the MTD of Phase 1 and was used to 
determine the RP2D). Dose escalation continued until the MTD is reached, or up to a maximum 
feasible dose of 1600 mg BID, whichever comes first. If no DLTs are observed, the RP2D was 
determined based on safety, tolerability, activity, PK, and PD assessments. Two dose cohorts 
were expanded up to 12 subjects each in the Dose Expansion part. 
In the Extension Phase of the Dose Escalation and Expansion parts, subjects may remain on 
study until disease progression, development of unacceptable toxicity that leads to tazemetostat 
treatment withdrawal, or withdrawal of consent. Investigators who note subjects with disease 
progression that are receiving continued clinical benefit without clinical deterioration should 
contact the Medical Monitor to discuss the assessment of risk/benefit of keeping the subject on 
study. 
Food Effect and DDI cohorts were initiated as part of the Phase 1 study after safety of the 
200 mg tazemetostat dose (highest available tablet dosage strength) was evaluated, and at the 
RP2D of 800 mg BID, respectively. The Treatment Phase for both cohorts will last until the end 
of Cycle 1. In the Extension Phase, subjects may remain on study until disease progression, 
development of unacceptable toxicity that leads to tazemetostat treatment withdrawal, or 
withdrawal of consent.  
Randomization will be used in the Phase 1 FE cohort in this study.  
The Phase 2 study was initiated after a minimum of 6 subjects complete dosing at the RP2D. The 
RP2D has been determined as 800 mg BID. The Phase 2 proof-of-concept part of the study will 
enroll subjects with B cell lymphoma for the determination of efficacy and safety of tazemetostat 
in 5 separate cohorts determined by centrally confirmed histology, COO, and EZH2 mutation 
status. In addition, up to 70 subjects with DLBCL will be enrolled to a combination therapy 
cohort with a starting dose of tazemetostat 800 mg BID and prednisolone 40 mg/m2 once daily 
on Days 1-5 and 15-19 of Cycles 1-4. The tolerability of the combination treatment will be 
assessed in the first 6 subjects using the same DLT evaluation criteria as in Phase 1 (see Section 
7.3.2). In order to observe preliminary safety of the study drug combination, there will be at least 
a 2-week delay in start of treatment between the first and second subjects in the safety run-in. 
Provided there are no initial safety concerns, subsequent subjects in the safety run-in may be 
enrolled as available. If a DLT is observed in no more than 1 of the initial 6 subjects, enrollment 


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will continue to the end of stage 1. If a DLT is observed in more than 1 of the 6 subjects, lower 
dose level(s) of prednisolone may be evaluated using a similar approach. The Treatment Phase in 
Phase 2 will end when the last subject completes assessments following a minimum of 6 cycles 
or discontinues treatment due to disease progression, development of unacceptable toxicity that 
leads to tazemetostat treatment withdrawal, or withdrawal of consent. 
In the Extension Phase in both the Phase 1 and Phase 2, subjects will continue to receive study 
drug until disease progression, development of unacceptable toxicity that leads to study 
treatment withdrawal, or withdrawal of consent. An Off-Treatment Visit will occur up to 30 days 
after final administration of study drug, or initiation of a new anticancer treatment, whichever 
occurs earlier, after which subjects will enter the Follow-up Period.  
During the Follow-up Period, survival follow-up will be conducted approximately every 
12 weeks on all subjects, unless they withdraw consent.  As of Protocol Amendment 13.0, no 
further survival follow-up is necessary for remaining subjects because the primary outcome 
assessment for all subjects has been met. 
Rollover Study: All subjects in Phase 1 who receive tazemetostat for 9 months or longer, and 
are eligible to continue receiving tazemetostat, will transfer to a Rollover Study for monitoring 
and continued study drug at the Investigator’s and the Medical Monitor’s discretion. All subjects 
in Phase 2 who remain on tazemetostat for 24 months or longer, and are eligible to continue 
receiving tazemetostat, also will transfer to a Rollover Study for monitoring and continued study 
drug at the Investigator’s and the Medical Monitor’s discretion. 
This study will include PD assessments of the effects of tazemetostat in a variety of matrices, 
including plasma, PBMCs, skin, bone marrow, and malignant tissue as appropriate, which may 
help confirm the mechanism of action of tazemetostat, predict responses, and guide further 
development and optimize use of tazemetostat. See Section 7.4.1.6 for further information on PD 
assessments.  
An overview of the study design is presented in Table 2. 
Table 2 
Study Design for E7438-G000-101 
Phase 1 
 
 
 
Subjects with 
advanced solid 
tumors or B cell 
lymphomas 
 
Food Effect Substudy 
(13 subjects enrolled) 
x Randomized to either fasted or fed tazemetostat treatment 
x 200 mg single dose on Day -8 and Day -1 
x Tazemetostat 400 mg BID beginning on Day 1 
Dose Escalation 
tazemetostat single 
agent 
 
DDI Substudy 
(13 subjects enrolled) 
x Midazolam single dose on Day -1 and 15 
x Tazemetostat (fasted) MTD/RP2D BID beginning on Day 1 


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Phase 2 
Subjects with B cell lymphomas 
Tazemetostat Monotherapy Cohorts  
x Cohort 1: DLBCL (GCB subtype) EZH2 mutation positive 
(enrollment closed)  
x Cohort 2: DLBCL (GCB subtype) EZH2 wild-type (enrollment 
closed) 
x Cohort 3: DLBCL non-GCB subtype (enrollment closed)  
Note: Upon cohort closure, up to 5 DLBCL non-GCB EZH2 
mutation positive subjects can be enrolled in Cohort 1 
x Cohort 4: FL (Grades 1 to 3) EZH2 mutation positive (up to 45 
subjects) (enrollment closed) 
x Cohort 5: FL (Grades 1 to 3) EZH2 wild-type (up to 45 subjects) 
(enrollment closed) 
Tazemetostat/Prednisolone Combination Cohort 
x Cohort 6: DLBCL GCB or non-GCB subtype EZH2 wild-type 
(enrollment closed) 
BID = twice daily, DDI = drug-drug interaction, DLBCL = diffuse large B cell lymphoma, EZH2 = enhancer of zeste homolog 2, 
GCB = germinal-center B-cell-like, FL = follicular lymphoma, MTD = maximum tolerated dose, RP2D = recommended Phase 2 
dose 
 
The end of study is defined as last subject last follow-up visit or the last subject transferred to the 
Rollover Study (EZH-501). 
 
7.2 Selection of Study Population 
Approximately 420 subjects will be enrolled in the entire study. Subjects who do not meet all of 
the inclusion criteria or who meet any of the exclusion criteria will not be eligible to receive 
study drug. 
In Phase 1, a total of 64 subjects with advanced solid tumors or B cell lymphomas were enrolled. 
Two dose levels were expanded (to 14 subjects at 800 mg BID and 12 subjects at 1600 mg BID) 
to support the determination/confirmation of the RP2D per joint decision of the Sponsor and the 
investigators. 
Thirteen evaluable subjects with advanced solid tumors or B cell lymphomas were enrolled in 
each FE and DDI cohort (IB and IGR sites in France only). Enrollment is closed for both 
cohorts. 
In Phase 2, approximately 340 subjects with histologically confirmed DLBCL or FL with 
relapsed or refractory disease will be enrolled (monotherapy: up to 60 subjects in each of the 3 
DLBCL cohorts and up to 45 subjects in each of the 2 FL cohorts; combination therapy: up to 70 
subjects with relapsed or refractory DLBCL). 


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7.2.1 Inclusion Criteria 
Subjects must meet all of the following criteria to be included in this study: 
All Subjects: 
1. Phase 1: Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. 
Phase 2: Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 
(Appendix 1). 
2. Life expectancy t 3 months before starting tazemetostat. 
3. Subjects with a history of hepatitis B or C are eligible on the condition that subjects have 
adequate liver function as defined by Inclusion Criterion #6 and are hepatitis B surface 
antigen negative and/or have undetectable HCV RNA. 
4. $GHTXDWHUHQDOIXQFWLRQGHILQHGDVFDOFXODWHGFUHDWLQLQHFOHDUDQFH 40 mL/min per the 
Cockcroft and Gault formula (Appendix 2) or local institutional standard formula. 
5. Adequate bone marrow function:  
a. Absolute neutrophil count (ANC) t 750/mm3  0.75 × 109/L) 
x Without growth factor support (filgrastim or pegfilgrastim) for at least 14 days 
b. Platelets t 75,000/mm3  75 × 109/L) 
x Evaluated after at least 7 days since last platelet transfusion 
c. Hemoglobin t 9.0 g/dL  
x May receive transfusion 
6. Adequate liver function: 
a. Total bilirubin d 1.5 × the upper limit of normal (ULN) except for unconjugated 
hyperbilirubinemia of Gilbert’s syndrome  
b. Alkaline phosphatase (ALP) (in the absence of bone disease), alanine 
aminotransferase (ALT), and aspartate aminotransferase (AST) d 3 × ULN (d 5 × 
ULN if subject has liver metastases) 
7. Time between prior anticancer therapy and first dose of tazemetostat as below: 
x Cytotoxic chemotherapy – At least 21 days 
x Non-cytotoxic chemotherapy (eg small molecule inhibitor) – At least 14 days 
x Nitrosoureas – At least 6 weeks 


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x Monoclonal antibody(ies) – At least 28 days  
x Radiotherapy  
R At least 14 days from local site radiation therapy;  
R At least 6 weeks from prior radioisotope therapy; 
R At least 12 weeks from 50% pelvic or total body irradiation 
x High-dose therapy with autologous hematopoietic cell infusion – At least 60 days 
x High-dose therapy with allogeneic transplant – At least 90 days (if graft versus host 
disease [GVHD] is present, must be < Grade 2) and on no prohibited medications, per 
Exclusion Criterion #3) 
x NOTE: Starting at Cycle 1 Day 1, subjects may receive no more than 10 mg of 
prednisone daily (or equivalent corticosteroid, excluding protocol-defined 
prednisolone dosing for subjects enrolled in Cohort 6) when used for treatment of 
lymphoma related symptoms, with the intent to taper by the end of Cycle 1. 
8. Males or females aged t 18 years at the time of informed consent (Phase 2). Males or 
females aged t 16 years at the time of informed consent (Phase 1). 
9. Females must not be lactating or pregnant at Screening or Baseline (as documented by a 
negative beta-human chorionic gonadotropin [ß-hCG] test with a minimum sensitivity of 
25 IU/L or equivalent units of ß-hCG). A separate baseline assessment is required if a 
negative screening pregnancy test was obtained more than 72 hours before the first dose of 
study drug. All females will be considered to be of childbearing potential unless they are 
postmenopausal (at least 12 months consecutively amenorrheic, in the appropriate age group, 
and without other known or suspected cause) or have been sterilized surgically (ie, bilateral 
tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month 
before dosing). Females of childbearing potential must not have had unprotected sexual 
intercourse within 30 days prior to study entry and must agree to use a highly effective 
method of contraception, from the last menstrual period prior to randomization, during 
Treatment Cycles, and for 6 months after the final dose of study drug, and have a male 
partner who uses a condom. Highly effective contraception includes:  
a. Double barrier methods of contraception such as condom plus diaphragm or 
cervical/vault cap with spermicide.  
b. Placement of an intrauterine device. 
c. Established hormonal contraceptive methods: oral, injectable, or implant. Females 
who are using hormonal contraceptives must have been on a stable dose of the same 


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hormonal contraceptive product for at least 4 weeks prior to dosing and must continue 
to use the same contraceptive during the study and for 6 months after study drug 
discontinuation. 
Female subjects exempt from this requirement are subjects who practice total abstinence 
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 the Treatment Cycles, and for 6 months after study drug 
discontinuation. 
10. Male subjects must have had either a successful vasectomy OR they and their female partner 
must meet the criteria above (ie, not of childbearing potential OR practicing highly effective 
contraception and use a condom throughout the study period and for 3 months after study 
drug discontinuation). 
11. Voluntary agreement to provide written informed consent and the willingness and ability to 
comply with all aspects of the protocol. 
Phase 1 only (IB and IGR sites in France only): 
12. Histologically and/or cytologically confirmed advanced or metastatic solid tumor or B cell 
lymphomas that has progressed after treatment with approved therapies or for which there are 
no standard therapies available. 
Phase 2: 
13. Subjects must satisfy all of the following criteria:  
a. Have histologically confirmed DLBCL (including primary mediastinal B cell 
lymphoma), with relapsed or refractory disease following at least 2 lines of prior 
standard therapy, including alkylator/anthracycline (unless anthracycline –based 
chemotherapy is contraindicated)/ anti-CD20-based therapy (R-CHOP or equivalent) 
AND must be considered unable to benefit from intensification treatment with 
autologous hematopoietic stem cell transplantation (ASCT), as defined by meeting at 
least 1 of the following criteria:  
x Relapsed following, or refractory to, previous ASCT 
x Did not achieve at least a partial response to a standard salvage regimen 
(eg, rituximab, ifosfamide, carboplatin, and etoposide phosphate [R-ICE] or 
rituximab, dexamethasone, cytarabine, and cisplatin [R-DHAP]) 
x Ineligible for intensification treatment due to age or significant comorbidity 
x Ineligible for intensification treatment due to failure to mobilize an acceptable 


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number of hematopoietic stem cells 
x Refused intensification treatment and/or ASCT  
or  
b. Have histologically confirmed FL, all grades. Subjects may have relapsed/refractory 
disease following at least 2 standard prior systemic treatment regimens where at least 
1 anti-CD20-based regimen was used. Subjects with prior radiotherapy will be 
included; however, radiotherapy alone will not be considered a systemic treatment 
regimen. 
c. Have provided sufficient archival tumor tissue that has been successfully tested for 
EZH2 mutation status and cell of origin (DLBCL only) at study specific laboratories 
allowing for allocation into an open cohort.  
d. Have measurable disease as defined by International Working Group-Non-Hodgkin’s 
Lymphoma (IWG-NHL [Cheson, 2007]). 
7.2.2 Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from this study: 
All Subjects: 
1. Prior exposure to tazemetostat or other inhibitor(s) of EZH2. 
2. Subjects with known leptomeningeal metastases or brain metastases or history of previously 
treated brain metastases. 
3. +DVWKURPERF\WRSHQLDQHXWURSHQLDRUDQHPLDRI*UDGHSHU&7&$(FULWHULDDQG
any prior history of myeloid malignancies, including myelodysplastic syndrome (MDS). 
4. Has a prior history of T-Cell lymphoblastic lymphoma(T-LBL) or T-Cell lymphoblastic 
leukemia (T-ALL). 
5. Subjects taking medications that are known potent CYP3A4 inducers/inhibitors (including 
St. John’s wort) (see Section 7.3.4.3 and 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugIntera
ctionsLabeling/ucm080499.htm; http://medicine.iupui.edu/clinpharm/ddis/). 
6. Subjects unwilling to exclude Seville oranges, grapefruit juice, and grapefruit from their diet. 
7. Any prior treatment-related (ie, chemotherapy, immunotherapy, radiotherapy) clinically 
significant toxicities have not resolved WR*UDGHSHU&7&$(YHUVLRQRUSULRU
treatment-related toxicities are clinically unstable and clinically significant at time of 
enrollment. 
8. Major surgery within 4 weeks before the first dose of study drug.  


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x 
NOTE: Minor surgery (eg, minor biopsy of extracranial site, central venous catheter 
placement, shunt revision) is permitted within 3 weeks prior to enrollment. 
9. Inability to take oral medication, or malabsorption syndrome or any other uncontrolled 
gastrointestinal condition (eg, nausea, diarrhea, or vomiting) that might impair the 
bioavailability of tazemetostat. 
10. Significant cardiovascular impairment: history of congestive heart failure greater than New 
York Heart Association (NYHA) Class II, uncontrolled arterial hypertension, unstable angina, 
myocardial infarction, or stroke within 6 months of the first dose of study drug; or cardiac 
ventricular arrhythmia (Appendix 3). 
11. Prolongation of corrected QT interval using Fridericia’s formula (QTcF) to > 480 msec. 
12. Venous thrombosis or pulmonary embolism within the last 3 months before starting 
tazemetostat. 
13. Active infection requiring systemic therapy. 
14. Known hypersensitivity to any component of tazemetostat, prednisolone/prednisone 
(combination cohort only), or inability to be treated with a Pneumocystis prophylaxis 
medication (combination cohort only). 
15. Immunocompromised subjects, including subjects known to be infected with human 
immunodeficiency virus (HIV). 
16. Any other major illness that, in the Investigator’s judgment, will substantially increase the 
risk associated with the subject’s participation in this study. 
17. Females who are pregnant or breastfeeding. 
18. Subjects who have undergone a solid organ transplant. 
Phase 2 only: 
19. Subjects with noncutaneous malignancies other than B cell lymphomas. 
x 
Exception: Subjects with another malignancy who have been disease-free for 5 years, or 
subjects with a history of a completely resected non-melanoma skin cancer or 
successfully treated in situ carcinoma are eligible. 
7.3 Treatments 
7.3.1 Identity of Investigational Product 
Tazemetostat is available as tablets in strengths of 100 (Phase 1 only) and 200 mg and supplied 
in white HDPE bottles.  


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7.3.1.1 Chemical Name, Structural Formula of Tazemetostat 
Test drug code: EPZ-6438 (for free base) 
International non-proprietary name (INN) name: tazemetostat  
Chemical name: N-[(4,6-Dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl]-5-[ethyl(tetrahydro-
2H-pyran-4-yl)amino]-4-methyl-4'-(morpholin-4-ylmethyl)biphenyl-3-carboxamide 
hydrobromide 
Molecular formula: C34H45BrN4O4 (Hydrobromide salt) 
 
C34H44N4O4 (Free base) 
Molecular weight: 653.65 (Hydrobromide salt) 
 
572.74 (Free base) 
Structural formula:  
 
 
7.3.1.2 Labeling for Study Drug 
Tazemetostat will be labeled in accordance with text that is in full regulatory compliance with 
each participating country and is translated into the required language(s) for each of those 
countries. 
7.3.1.3 Storage Conditions 
Tablets: Tazemetostat tablets will be stored in accordance with the labeled storage conditions. 
See pharmacy manual. 
7.3.2 Treatments Administered 
Tazemetostat will be administered orally in Phase 1 and Phase 2.  
Midazolam will only be administered in the Phase 1 DDI cohort and will be administered orally 
according to the Summary of Product Characteristics (SmPC).  
N
Me
O
HN
O
Me
N
O
HN
Me
O
Me
HBr


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Phase 1 Dose Escalation and Expansion (closed to enrollment): In the Phase 1 Dose 
Escalation and Expansion parts, 38 subjects with advanced solid tumors or B cell lymphomas 
were given tazemetostat orally, starting at 100 mg BID (200 mg total daily dose) continuously 
starting Cycle 1 Day 1 in 28-day cycles. Dose escalation proceeded in 100% increments in 
subsequent cohorts unless 1 *UDGH 2 nonhematological toxicity during Cycle 1 was assessed as 
related to the study drug in 2 or more subjects at a dose level until the MTD and/or RP2D was 
established. Tazemetostat can be taken with or without food. 
Phase 1 Food Effect (IB and IGR sites in France only, closed to enrollment): In the Phase 1 
FE cohort, 13 subjects with advanced solid tumors or B cell lymphomas were randomized to 
receive the tazemetostat 200 mg as a single oral dose on Day -8 after fasting for 8 hours before 
dosing and immediately after consuming a high-fat breakfast (see Appendix 6). For 7 subjects, 
200 mg was dosed as a single dose on Day -8 after fasting for 8 hours before tazemetostat 
dosing, and for 6 subjects, 200 mg was dosed immediately after consuming a high-fat breakfast. 
Because tazemetostat was to be taken in a fasting state, subjects were required to record the time 
at which they ate food. Following a 7-day wash-out period subjects crossed over to receive the 
second tazemetostat 200 mg single oral dose on Day -1. Subjects consumed the high-fat 
breakfast within a 30-minute period before study drug administration. Each 28-day period was 
considered 1 treatment cycle.  
If a subject did not consume the full breakfast (when appropriate) and complete all PK 
assessments, this subject was replaced to ensure that there were 6 subjects in each sequence 
(fed/fasted and fasted/fed) with all PK assessments.  
Beginning on Day 1 of Cycle 1, tazemetostat 400 mg was administered BID for 28-day cycles 
and could be taken with or without food.  
Phase 1 CYP3A4 DDI with Midazolam (IB and IGR sites in France only, closed to 
enrollment): In the Phase 1 DDI cohort, 13 subjects with advanced solid tumors or B cell 
lymphoma were enrolled for a DDI study with midazolam to determine the effect of tazemetostat 
on CYP3A4. Subjects received 800 mg tazemetostat BID, continuously starting on Day 1. 
Subjects received a single oral dose of midazolam on Day -1 and Day 15. Subjects fasted 2 hours 
before and 1 hour after tazemetostat dosing. Once the DDI evaluation was completed in Cycle 1 
(after Day 15), continuous dosing of tazemetostat 800 mg BID continued, and tazemetostat was 
taken with or without food.  
Midazolam: Midazolam was administered only in the Phase 1 CYP3A4 DDI cohort of the study. 
A single 2-mg dose of midazolam was administered orally on Days -1 and Day 15, according to 
the instructions contained in the SmPC. On Day 15, midazolam was administered concurrently 
with tazemetostat administration. 


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Phase 2: Subjects with B cell lymphoma will be administered 800 mg BID of tazemetostat. 
Tazemetostat will be dosed BID beginning on Cycle 1 Day 1 for continuous 28-day cycles, with 
or without food.  
In the DLBCL tazemetostat and prednisolone combination cohort, prednisolone will be 
administered as open-label commercial product at a starting dose of 40 mg/m2 (rounding can be 
done per local standard practice) orally once daily on Days 1 to 5 and Days 15 to 19 of each 
28-day cycle for 4 cycles, without regard to food. Tazemetostat will be administered orally, 
continuously from Cycle Day 1 without break, at a starting dose of 800 mg BID. On days when 
both drugs are administered, prednisolone should be taken immediately after the morning dose of 
tazemetostat. 
Subjects enrolled in the cohort receiving the combination treatment of tazemetostat and 
prednisolone will receive a prophylaxis treatment for Pneumocystis jirovecii (eg, 
sulfamethoxazole 800 mg plus trimethoprim 160 mg 3 times a week or acceptable alternative) 
for a total of 24 weeks, starting on Cycle 1 Day 1. 
Each dose of tazemetostat should not be given any earlier than 8 hours after the previous dose or 
8 hours before the next dose. If a tazemetostat dose is missed (ie, not taken within 4 hours after 
the scheduled dosing time), that dose should not be made up and the subject should resume dose 
administration with the next scheduled dose. Each dose of prednisolone should not be given later 
than 12 hours before the next dose. If a prednisolone dose is missed (ie, not taken within 12 
hours after the scheduled dosing time), that dose should not be made up and the subject should 
resume dose administration with the next scheduled dose. 
If a subject vomits within 30 minutes of study treatment dose administration, anti-emetics should 
be given and a second dose of study treatment should be administered.  
Study treatment in Phase 2 will continue until disease progression, development of unacceptable 
toxicity, or withdrawal of consent. Subjects may be permitted to continue study treatment if they 
meet the IWG-NHL (Cheson, 2007) criteria for PD as well as the following criteria: 
x Absence of symptoms and signs (including worsening of laboratory values, eg, new or 
worsening hypercalcemia) that indicate unequivocal PD 
x No decline in ECOG performance status 
x Absence of tumor growth at critical anatomical sites (eg, leptomeningeal disease) that cannot 
be managed by protocol-allowed medical interventions 
At the time of apparent PD per the IWG 2007, subjects for whom approved treatment exists must 
provide written consent to acknowledge their choice to continue to receive study treatment. 


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Subjects whose radiographic PD is confirmed at a subsequent tumor assessment may be 
considered for continued study treatment at the discretion of the Investigator if they have 
evidence of clinical benefit and continue to meet the above criteria. Investigators who note 
subjects with disease progression that are receiving continued clinical benefit without clinical 
deterioration should contact the Medical Monitor to discuss the assessment of risk/benefit of 
keeping the subject on study. 
7.3.2.1 Dose-Limiting Toxicity 
Dose-limiting toxicities were assessed according to the Common Terminology Criteria for 
Adverse Events (CTCAE v4.03 [Cancer Therapy Evaluation Program, Common Terminology 
Criteria for Adverse Events, 2009], see Appendix 5) and are defined in Table 3. Final 
determination of whether a subject was counted as having experienced a DLT for dose escalation 
purposes or MTD and/or RP2D confirmation purposes, and whether the dose escalation 
proceeded in 100% increments, was made jointly by the Sponsor and the investigators.  
Table 3 
Dose-Limiting Toxicities 
Toxicity Category 
Toxicity/CTCAE Grade 
Hematological 
x Grade 4 neutropenia for t 7 days or Grade 3 neutropenia with fever 
(> 38.5 °C in axilla) 
x Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with 
bleeding or lasting > 7 days 
Other Nonhematological 
Toxicity 
x Grade 3 fatigue, or a 2-point decline in Eastern Cooperative Oncology 
Group (ECOG) performance status that persists for > 7 days 
x Grade 3 aspartate transaminase ([AST], also referred to as serum 
glutamic oxaloacetic transaminase [SGOT]) or Grade 3 alanine 
aminotransferase ([ALT], also referred to as serum glutamic pyruvic 
transaminase [SGPT]) elevation of > 7 days or Grade 4 AST or ALT of 
any duration 
x  Grade 2 neurotoxicity or cardiotoxicity 
x Grade 2 hypersensitivity reaction 
x Nausea, vomiting, or diarrhea that persists at Grade 3 or 4 despite 
maximal medical therapy 
x Any Grade 3 or higher nonhematological laboratory abnormalities that 
require hospitalization 
CTCAE = Common Terminology Criteria for Adverse Events 
 
The MTD and/or RP2D was determined based on the incidence of DLTs in Cycle 1, although 
toxicities occurring during subsequent cycles were also reviewed. If serious toxicities were 
observed at this dose level in later cycles, a reduction of the MTD and/or RP2D was to be 
considered.  


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For subjects who required a dose interruption due to tazemetostat-related toxicity during Cycle 1 
in the Dose Escalation part of the study, the treatment was re-started once the toxicity resolved to 
*UDGH 1 or baseline. Treatment was according to the criteria listed below: 
x If the observed toxicity was determined to be a DLT according to Table 3, the subject 
resumed treatment at the next lower dose level. 
x If the observed toxicity was not considered to be a DLT according to Table 3, the subject 
resumed treatment as described in the Dose Reduction and Interruption Instructions in 
Table 4.  
All available safety, PK and PD data were reviewed to decide whether to explore intermediate 
dose and/or alternative dose regimens. As PK were observed to be linear, the dosing schedule 
and dose escalation scheme was not modified during the dose escalation part of the study. 
Treatment will continue until disease progression, development of unacceptable toxicity, or 
withdrawal of consent.  
An independent DMC was established to review available safety data supporting the MTD 
and/or RP2D once a minimum of 6 subjects at the MTD or highest feasible dose complete 
1 cycle of treatment in Dose Escalation. The DMC reviewed safety data including, but not 
limited to, AEs, serious adverse events (SAEs), laboratory parameters, investigational product 
dosing records, treatment delays or reductions, and treatment discontinuation due to toxicity. One 
DLT was observed at the dose level of 1600 mg BID; thus, the protocol-defined MTD was not 
reached. Based on evaluation of safety, tolerability, activity, PK, and PD assessments from the 
24 subjects treated in the Dose Escalation part of the study, an RP2D of 800 mg BID has been 
determined. The RP2D has been endorsed by the investigators and a DMC. 
The rules listed in Table 3 will be applied to the safety run-in DLT assessment of the 
combination therapy of tazemetostat and prednisolone. In addition, any Grade 3 or higher 
non-hematological toxicities that require hospitalization will also be considered DLTs. For 
toxicities assessed by the Investigator to be attributed to prednisolone, the dose interruption and 
reduction of prednisolone should follow the same guidance above. The suggested dose reduction 
of prednisolone, if deemed necessary by the Investigator, is from 40 mg/m2 to 30 mg/m2. If 
further dose reduction of prednisolone is considered necessary to manage prednisolone-related 
toxicities, the recommended dose level is 22.5 mg/m2. A discussion with the Sponsor’s medical 
monitor is needed if further reduction is considered for prednisolone. A discussion with the 
Sponsor’s medical monitor is needed if dose interruption or reduction is considered for 
tazemetostat. 


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7.3.2.2 Criteria for Retreatment, Temporary Discontinuation 
of Treatment, Dose Reduction, and Resumption of 
Treatment 
Tazemetostat dose reductions and interruptions will be allowed in Phase 1 and Phase 2; however, 
an interruption in the administration of tazemetostat for more than 14 days must be discussed 
with the Medical Monitor before treatment can be resumed.  
Toxicity will be managed by concomitant medication (as appropriate), treatment interruption, 
dose reduction, and treatment discontinuation, or a combination of these. During treatment with 
tazemetostat, dose interruption and reduction for subjects who experience tazemetostat-related 
toxicity will be in accordance with the Dose Reduction and Interruption Instructions in Table 4.  
If a case of adult T-LBL/T-ALL occurs enrollment will be suspended and the benefit-risk of the 
drug will be assessed at an ad hoc Epizyme Quarterly Safety Review  Committee and the results 
will be communicated to all Health Authorities and Ethics Committees as applicable. For any 
MDS/AML or other myeloid malignancies like MPN, tazemetostat will be discontinued in that 
subject.  
 
For subjects who require dose interruption due to tazemetostat-related toxicity in Phase 1 or in 
Phase 2, the treatment may re-start once the toxicity has been resolved to Grade  1 or baseline 
according to the Dose Reduction and Interruption Instructions in Table 4. 
For continuation of treatment for Cycle 2 and beyond, subjects must meet the following 
retreatment criteria: 
x 3ODWHOHWFRXQWPXVWEH 75 × 109/L 
x ANC must be  0.75 × 109/L, and  
x Any Grade 3 or higher toxicity must have resolved to Grade 1 or baseline, unless 
otherwise noted. 
The same set of rules of treatment interruption and resumption will be applied to the cohort 
receiving combination therapy of tazemetostat and prednisolone. A discussion with the Sponsor’s 
medical monitor is needed if dose interruption or reduction is considered, either for both or only 
one of the drugs. The suggested initial dose reduction of prednisolone, if deemed necessary by 
the Investigator, is from 40 mg/m2 to 30 mg/m2. If further dose reduction of prednisolone is 
considered necessary, the recommended dose level is 22.5 mg/m2. A discussion with the 
Sponsor’s medical monitor is needed if further reduction is considered for prednisolone. Dose 
reduction of tazemetostat will follow the guidelines in Table 4. 
 


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Table 4 
Tazemetostat Dose Reduction and Interruption Instructions 
 
During Therapy 
Approximate Dose Adjustmentb 
Grade 1 
All occurrences 
Continue tazemetostat  
Maintain dose level 
Grade 2c 
1st occurrence 
Interrupt tazemetostat until 
resolved to Grade  1 or 
baselineb 
Maintain dose level 
2nd occurrence  
(same or new toxicity) 
Restart at 600 mg BID 
3rd occurrence  
(same or new toxicity) 
Restart at 400 mg BID 
4th occurrence  
(same or new toxicity) 
Discuss with medical monitor 
Grade 3c not including neutropenia and thrombocytopenia 
1st occurrence 
Interrupt tazemetostat 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 tazemetostat 
Not applicable 
Grade 3 Neutropenia (ANC: < 1 – 0.5 × 109/L) 
ANC < 0.75 × 109/L 
1st occurrence 
Interrupt tazemetostat until 
UHVROYHGWR$1&î
109/L 
Restart at 600 mg BID 
2nd occurrence  
Restart at 400 mg BID 
3rd occurrence  
Discontinue tazemetostat 
Not applicable 
Grade 3 Thrombocytopenia 
1st occurrence 
Interrupt tazemetostat until 
reVROYHGWR*UDGHRU
baselineb 
Restart at 600 mg BID 
2nd occurrence 
Restart at 400mg BID 
3rd occurrence 
Discontinue tazemetostat 
Not applicable 
Grade 4 
Any occurrence 
Interrupt study drug until 
resolved to Grade 2 or less 
Discuss with medical monitor 
ANC = absolute neutrophil count, BID = twice daily 
a 
Excluding alopecia and nausea, vomiting or diarrhea not receiving adequate treatment. 
b 
An interruption of tazemetostat for more than 14 days due to any toxicity must be discussed with the Sponsor before 
treatment can be resumed. 
c 
Excluding Grade 2 and 3 anemia: Subjects are allowed to continue tazemetostat at their current dose level with 
transfusion per investigator discretion. 
 
7.3.3 Method of Assigning Subjects to Treatment Groups 
For the Phase 1 Dose Escalation part, subjects with advanced solid tumors or B cell lymphoma 
were enrolled using a dose-escalation algorithm (3+3 subjects per dose level) to identify the 
MTD and/or RP2D. Food Effect cohort subjects with advanced solid tumors or B cell lymphoma 
were randomized to 1 of 2 treatment sequences (either fed/fasted or fasted/fed) according to a 


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randomization scheme. Subjects will be enrolled sequentially in the Dose Escalation component 
and DDI cohort. 
For Phase 2, DLBCL subjects will be allocated into cohorts (Cohorts 1-3 and 6) prior to 
tazemetostat dosing based on the results of the EZH2 mutation and COO testing. In Cohort 6, the 
safety run-in (DLT assessment) needs to be completed in the first 6 subject before other subjects 
can be enrolled. DLBCL subjects with wild-type EZH2 can be enrolled to Cohort 6 after the 
accrual of the Cohort 2 or 3 is completed. FL subjects will be allocated into cohorts (Cohorts 4 
and 5) prior to tazemetostat dosing based on the results of EZH2 mutation testing. The tumor 
tissue EZH2/COO testing can be performed prior to other screening procedures, for example, 
during wash-out of the second line anticancer therapy, after the subject is consented for the 
prescreening testing. 
7.3.4 Prior and Concomitant Therapy 
Prior and concomitant medications include all prescription and nonprescription medications, 
vitamins, herbals, and transfusions. 
All prior medications (including over-the-counter medications) administered 30 days before the 
first dose of study drug will be recorded. In the Phase 1 part of the study any concomitant 
therapy administered to the subject during the course of the study (starting at the date of 
informed consent) until 30 days after the final dose of study drug will be recorded. In the Phase 2 
part of the study any concomitant therapy administered to the subject during the course of the 
study (starting at the date of first dose of study drug) until 30 days after the final dose of study 
drug will be recorded. Additionally, all diagnostic, therapeutic, or surgical procedures relating to 
malignancy should be recorded. 
7.3.4.1 Permitted and Concomitant Medication 
Any medication that is considered necessary for the subject’s health and that is not expected to 
interfere with the evaluation of or interact with tazemetostat may be continued during the study. 
Subjects may receive prednisone (or equivalent corticosteroid) for systemic or local symptom 
control prior to and while on study. Starting at Cycle 1 Day 1 however, subjects may receive no 
more than 10 mg of prednisone daily (or equivalent corticosteroid, excluding protocol-defined 
prednisolone dosing for subjects enrolled in Cohort 6) when used for treatment of lymphoma 
related symptoms, with the intent to taper by the end of Cycle 1. 
Subjects enrolled in the cohort receiving the combination treatment of tazemetostat and 
prednisolone will receive a prophylaxis treatment for Pneumocystis jirovecii (eg, 
sulfamethoxazole 800 mg plus trimethoprim 160 mg 3 times a week or acceptable alternative) 
for a total of 24 weeks, starting on Cycle 1 Day 1. 


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Treatment of complications or AEs or therapy to ameliorate symptoms (including blood 
products, blood transfusions, fluid transfusions, antibiotics, and antidiarrheal drugs, etc.) may be 
given at the discretion of the Investigator, unless it is expected to interfere with the evaluation of 
(or to interact with) tazemetostat. The Investigator will record any AE on the AE case report form 
(CRF) for which the concomitant medication/therapy was administered. 
Over the counter medications, nutritional supplements, vitamins, and herbal preparations are 
permitted under physician recommendation only. Aspirin, nonsteroidal anti-inflammatory drugs, 
and low-molecular-weight heparin or prophylactic doses of heparin are permissible but should be 
used with caution. Granulocyte colony-stimulating factor or equivalent may be used in 
accordance with American Society of Clinical Oncology (ASCO), institutional, or national 
guidelines. Erythropoietin may be used according to ASCO, institutional, or national guidelines. 
7.3.4.2 Permitted Radiation Therapy 
Palliative radiotherapy may be given for the control of pain or for other reasons (ie, bronchial 
obstruction, ulcerating skin lesions) with no curative intent. The irradiated area should be as 
small as possible and should never involve more than 10% of the bone marrow in any given 
4-week period for distribution of active bone marrow). The irradiated area cannot be used as a 
parameter for response assessment. Treatment with tazemetostat should be delayed in subjects 
receiving palliative radiotherapy after discussion with the Medical Monitor. In addition, other 
palliative procedures intended for symptom control and concurrent dose interruptions may be 
permitted after discussion with the Medical Monitor. These procedures will be limited to non-
target lesions only. 
7.3.4.3 Prohibited Concomitant Therapies and Drugs 
Subjects must not receive other antitumor therapies while on study. Prohibited medications 
during this study are any other experimental or unapproved drugs, other anticancer therapies 
unless otherwise stated, and known strong CYP3A inhibitors and strong or moderate CYP3A 
inducers within 14 days prior to the first dose of tazemetostat and for the duration of the study.  
If subjects receive any of the prohibited antitumor medications, this will be judged as evidence of 
disease progression, and study drug will be discontinued. These subjects should complete all off-
treatment assessments and be followed for survival in the Follow-up Period.  (Note: As of 
Protocol Amendment 13.0, no further survival follow-up is necessary for remaining subjects 
because the primary outcome assessment for all subjects has been met.) 
 
Examples of medications that are strong inhibitors and strong or moderate inducers of CYP3A 
include, but are not limited to, those listed in Table 5.  


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Table 5 
Medications that are Potent Inhibitors and Inducers of CYP3A4 
CYP 
Enzymes 
Strong Inducers 
Strong Inhibitors 
CYP3A 
Avasimibe, 
carbamazepine, 
phenytoin, rifampin, St. 
John’s wort 
Boceprevir, clarithromycin, conivaptan, grapefruit juice, 
indinavir, itraconazole, ketoconazole, 
lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, 
posaconazole, ritonavir, saquinavir, elaprevir, 
telithromycin, voriconazole 
 
Please refer to the following websites for a comprehensive list of these medications or contact 
the Medical Monitor for additional questions: 
Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana 
University School of Medicine. 2020; https://drug-
interactions.medicine.iu.edu/MainTable.aspx 
US Food and Drug Administration. Drug Development and Drug Interactions: Table of 
Substrates, Inhibitors and Inducers. March 2020; https://www.fda.gov/drugs/drug-
interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-
and-inducers 
 
7.3.4.4 Concomitant Medications to be used with Caution 
The following medications are to be used with caution: 
• 
CYP3A sensitive substrates 
• 
Moderate CYP3A inhibitors. If coadministration with a moderate CYP3A inhibitor 
cannot be avoided, reduce the dose of tazemetostat as shown below. After discontinuation of the 
moderate CYP3A inhibitor for 3 elimination half-lives, resume the tazemetostat dose that was 
being taken prior to initiating the inhibitor, as listed in Table 6. 
Table 6 
Tazemetostat Adjustment for Coadministration of a Moderate CYP3A 
Inhibitor 
Current Dosage 
Adjusted Dosage 
800 mg twice daily 
400 mg twice daily 
600 mg twice daily 
400 mg for first dose and 200 mg for second dose 


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Current Dosage 
Adjusted Dosage 
400 mg twice daily 
200 mg twice daily 
  
Please refer to the following websites for a list of these medications or contact the medical 
monitor for additional questions: 
x Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana 
University School of Medicine. 2020; https://drug-
interactions.medicine.iu.edu/MainTable.aspx 
x US Food and Drug Administration. Drug Development and Drug Interactions: Table of 
Substrates, Inhibitors and Inducers. March 2020; https://www.fda.gov/drugs/drug-
interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-
and-inducers 
 
7.3.5 Prohibitions and Restrictions during Study Period 
Grapefruit and grapefruit juice-containing products and Seville oranges are not permitted for 
1 week before dosing and throughout the study. 
Phototoxic 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. 
7.3.6 Treatment Compliance 
 Compliance for doses taken outside of the clinic may be assessed by a count of the capsules 
returned to the study trial site by the subject and review of doses taken with the subject. This will 
be recorded in the source documents, which may include the use of a subject medication diary 
per institutional practice. 
7.3.7 Drug Supplies and Accountability 
In compliance with local regulatory requirements, drug supplies will not be sent to the 
Investigator until the following documentation has been received by the Sponsor: 
x A signed and dated confidentiality agreement 
x A copy of the final protocol signature page signed and dated by the Investigator 


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x Written proof of approval of the protocol, the informed consent form(s) (ICFs), and any 
other information provided to the subjects by the Institutional Review Board or 
Independent Ethics Committee (IRB/IEC) for the institution where the study is to be 
conducted 
x A copy of the IRB/IEC-approved ICF and any other documentation provided to the 
subjects to be used in this study 
x A copy of the regulatory authority approval for the country in which the study is being 
conducted (if required) and the Import License (if required) 
x An investigator-signed and dated Form Food and Drug Administration (FDA) 1572, a 
signed and dated curriculum vitae for the principal investigator (PI) including a copy of 
the PI’s current medical license (required in the US) or medical registration number on 
curriculum vitae 
x Financial Disclosure Form for the PI listed on Form FDA 1572 
x A signed and dated clinical trials agreement. 
The Investigator and study staff will be responsible for the accountability of all clinical supplies 
(dispensing, inventory, and record keeping) following the Sponsor’s instructions and adherence 
to Good Clinical Practice (GCP) guidelines as well as local and regional requirements. 
Under no circumstances will the Investigator allow the study drug to be used other than as 
directed by this protocol. Clinical supplies will not be dispensed to any individual who is not 
enrolled in the study. An accurate and timely record of the receipt of all clinical supplies, 
dispensing of study drug to the subject, collection and reconciliation of used and unused supplies 
that are either returned by the subject or shipped to the site but not used, subsequent return of 
unused study drug to the Sponsor or designated central or local depot, and (where applicable) 
destruction of study drug at the site must be maintained. This includes, but may not be limited to: 
(a) documentation of receipt of clinical supplies, (b) study drug dispensing/return reconciliation 
log, (c) study drug accountability log, (d) all shipping service receipts, (e) documentation of drug 
returned to the Sponsor, and (f) certificates of destruction for any destruction that occurs at site. 
All forms will be provided by the Sponsor. Any comparable forms that the investigational site 
wishes to use must be approved by the Sponsor. 
The supplies and inventory records must be made available, upon request, for inspection by the 
designated representative of the Sponsor or a representative of any national health authority. All 
used and unused study drugs, including empty containers, are to be returned to the Investigator 
by the subject and ultimately to the Sponsor’s designated contractor or depot by the conclusion 
of the study, unless approval is given by the Sponsor for destruction of supplies and containers at 


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the investigational site. Upon completion of drug accountability and reconciliation procedures by 
investigational site personnel and documentation procedures by the Sponsor’s personnel, study 
drug that is to be returned to the Sponsor’s approved contract vendor must be boxed and sealed 
and shipped back to the Sponsor’s approved contract vendor following all local regulatory 
requirements. In some regions, study drugs may be removed from the site and hand delivered to 
the Sponsor’s specified location by sponsor representatives. 
Drug accountability will be reviewed during investigational site visits and at the completion of 
the study. 
7.4 Study Assessments 
7.4.1 Assessments 
7.4.1.1 Screening Assessments and Demography 
Demographic information will be collected at the Screening Visit. Standard demography 
parameters include age, gender, and race/ethnicity (recorded in accordance with prevailing 
regulations). The Screening Visit will occur in the period specified in Table 8 and Table 9. The 
purpose of the Screening Period is to obtain informed consent and establish protocol eligibility. 
Informed consent will be obtained after the study has been fully explained to each subject and 
before the conduct of any screening procedures or assessments. Procedures to be followed when 
obtaining informed consent are detailed in Section 8.2.1. 
7.4.1.2 Medical History and Physical Examinations 
Medical and surgical histories will be obtained during the Pretreatment Phase, along with a 
record of prior and concomitant medications. Significant findings before the start of study drug 
will be recorded on the Medical History and Current Medical Conditions CRF. A standard-of-
care clinical examination for lymphoma, including assessment of B symptoms, will also be 
performed at the Screening Visit and at all disease assessments. 
Physical examinations (comprehensive or symptom-directed) will be performed as specified in 
the Schedule of Visits and Procedures (Table 8 and Table 9). Documentation of the physical 
examination will be included in the source documentation at the investigational site. Changes 
from screening physical examination findings that meet the definition of an AE will be recorded 
on the AE CRF. 
7.4.1.3 Tumor Assessments 
Solid tumors: Tumor assessment will be performed based on Response Evaluation Criteria in 
Solid Tumors (RECIST 1.1 [Eisenhauer, 2009]); see Appendix 4. Investigator-determined 
response assessments at each assessment time point will be entered onto the appropriate CRF. 


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B cell lymphoma: Tumor assessments will be performed based upon IWG-NHL (Cheson, 2007) 
criteria at each assessment time point and entered onto the appropriate CRF. Investigator-
determined response assessments at each assessment time point will be entered onto the 
appropriate CRF. For the Phase 2 part of the study, scans will be performed according to 
guidelines provided by the imaging core laboratory designated for this study (see Imaging 
Manual). All tumor assessment scans will be sent, as soon as they have been performed, to the 
imaging core laboratory for quality assessment and archival for potential independent imaging 
review. 
For additional tumor assessment details, see the Schedules of Procedures and Assessments 
(Table 8 and Table 9). 
During the Screening Period: 
All subjects: Computed tomography (CT) scans of the chest; and CT or magnetic resonance 
imaging (MRI) scans of the brain, abdomen, pelvis, and other known sites of disease (as well as 
photographs of skin lesions that will be followed as target and nontarget lesions), will be 
performed at Screening. Standard of care scans performed within 28 days before Cycle 1 Day 1 
using the protocol-specified parameters may be used as screening assessments.  
Solid tumor only: Bone scans will be performed as clinically indicated 
NHL only: An 18fluorodeoxyglucose-positron emission tomography (18FDG-PET) scan will be 
performed (NHL only). A bone marrow biopsy (including IHC) will be performed for all subjects 
with FL and if clinically indicated in subjects with DLBCL if these have not been performed 
within 42 days (an approval is needed from the Sponsor’s medical monitor if the window has 
been beyond 42 days) of Cycle 1 Day 1.  
During the Treatment Phase: 
All subjects: CT scans of the chest, and CT or MRI of the brain (if clinically indicated), 
abdomen, pelvis, and other known sites of disease will be performed every 8 weeks (starting 
from Cycle 1 Day 1 of continuous tazemetostat dosing), or sooner if clinically indicated. If local 
regulatory authorities mandate less frequent imaging, minimum frequency must be every 
12 weeks. Tumor assessments will be carried out every 8 weeks (or sooner, if clinically 
indicated) during treatment cycles in both the Treatment Phase and the Extension Phase. For 
subjects who remain on study drug for 24 weeks or more, radiologic disease assessments will be 
performed every 12 weeks.  
Solid tumor only: Possible PR and CR (according to RECIST 1.1 criteria) must be confirmed at 
least 4 weeks after the initial response assessment. 


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NHL only: At the first notation of possible PR and CR, a whole body 18FDG-PET scan should 
be performed. At the first notation of CR, a repeat bone marrow biopsy will be performed if 
lymphoma involvement in the bone marrow was reported at Screening. Repeat bone marrow 
biopsies will be performed if clinically indicated (if progressive disease or relapse is suspected). 
All Subjects: The CT scan should be a diagnostic quality spiral or multidetector CT with oral 
and iodinated intravenous (IV) contrast, and the MRI scan should be performed with IV 
gadolinium chelate. Scans of the neck, abdomen, pelvis, and other areas of the body may be 
performed with MRI instead of CT, but evaluation of the chest must be done with CT. If 
iodinated IV contrast is contraindicated, the chest evaluation should be done with noncontrast 
CT, and the abdomen and pelvis evaluation should be performed using either CT with oral 
contrast (without IV contrast) or MRI with gadolinium chelate IV contrast (the latter is 
preferred). Spiral/multidetector CT should be performed with a 5-mm contiguous slice 
reconstruction algorithm. If body MRI scans are performed, contiguous slices of 5 mm are also 
recommended. 
The same imaging modality and image-acquisition protocol (including use or nonuse of IV 
contrast) should be used consistently across all time points to allow consistent comparison of 
lesions. Low-dose noncontrast CT transmission scans from a positron emission tomography-CT 
(PET-CT) combination scanner are not acceptable. Ultrasound should not be used for 
radiographic tumor assessment. A chest x-ray or skeletal x-ray that clearly demonstrates a new 
metastatic lesion may be used to document progression in lieu of the CT or MRI scans. 
Brain scans should be performed by MRI pre- and post-contrast enhancement or CT with 
contrast enhancement, with 5-mm contiguous slices recommended (maximum inter-slice gap of 
1 mm on MRI). 
Solid tumor subjects only: The recommended bone scan technique is 99m-technetium 
methylene polyphosphonate (ie, methylene diphosphonate or hydroxymethylene diphosphonate 
scintigraphy or whole body-bone MRI, or 18F-sodium fluoride PET. The same methodology and 
scan acquisition techniques used at Screening should be used throughout the study to ensure 
comparability. If a bone lesion is to be followed as a nontarget lesion (RECIST 1.1 criteria), it is 
preferable that this be performed using CT or MRI. For bone nontarget lesions that can be 
followed only on bone scans, a time point response other than not evaluable (NE) will be 
allowed despite an individual lesion assessment of NE for weeks when bone scans are not 
required. 
Whole body 18FDG-PET scans should be performed using institutional guidelines for Phase 1 
and according to the imaging core laboratory guidelines for the Phase 2 part. 


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If subcutaneous masses or nodes are palpable (eg, bulky) and are assessable by both clinical and 
radiographic techniques, the radiographic (CT or MRI) technique should be used for the 
assessment of target and nontarget lesions. 
Assessments are to be performed at the site by appropriately qualified personnel and results of 
the site interpretation are to be recorded on the appropriate CRFs. 
7.4.1.4 Exploratory Assessments 
Overall survival 
Overall survival is the duration measured from the date of first dose until the date of death from 
any cause. Survival follow-up will be conducted approximately every 12 weeks on all subjects, 
unless they withdraw consent. Anti-cancer therapies and AESI information will also be collected 
at this time.  As of Protocol Amendment 13.0, no further survival follow-up is necessary for 
remaining subjects because the primary outcome assessment for all subjects has been met. 
7.4.1.5 Pharmacokinetic Assessments 
Phase 1: Blood samples for PK analyses will be collected during Cycle 1 in the Phase 1 Dose 
Escalation part, on Day -8 and Day -1 of the FE cohort, Day -1 and Day 15 of the DDI cohort, 
and Cycles 1 and 2 in the Phase 1 FE and DDI cohorts.  
Urine samples for PK analyses will be collected during the Phase 1 Dose Escalation part only 
during Cycle 1. 
Phase 2: Sparse PK blood samples will be collected during Cycle 1 and Cycle 2 of the Phase 2 
study until sample size needed for population PK analysis has been met.  
Refer to Laboratory Manual and see Table 8 and Table 9 for additional details. 
7.4.1.6 Biomarker and Pharmacogenomic Assessments 
Biomarker and Pharmacogenomic Assessments 
Biomarker discovery and validation may be performed through all phases of this clinical study. 
The goal of these studies is to assay biomarkers in blood, normal, and malignant tissue to 
confirm the mechanism of action of tazemetostat and discover biomarkers that may predict 
response to tazemetostat.  
Phase 1 Dose Escalation and Food Effect Cohort (Closed to Enrollment) 
Blood samples and skin punch biopsies (Dose Escalation only: closed), will be obtained predose 
and at various specified times postdose and may be assessed for molecular changes associated 
with exposure to tazemetostat, such as changes in histone methylation, gene expression (protein 


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and/or mRNA), or other markers with the potential to confirm the mechanism of action of 
tazemetostat (PD biomarker). Results will be correlated with PK and safety data. 
Archival, FFPE tumor tissue from all enrolled subjects will also be collected (if available) for 
assessment of EZH2 mutation status, for confirmation of COO in DLBCL cohorts, and for 
exploratory response biomarker analysis. Biomarker assays for analysis of markers identified in 
nonclinical studies and/or the scientific literature may include DNA mutation assessment, gene-
expression profiling, proteomics, or IHC analysis. Results may be correlated with efficacy data. 
During the FE cohort, paired tumor biopsies or bone marrow samples (for FL cases) may be 
obtained, with appropriate subject consent, to examine tumor tissue for molecular evidence of 
the downstream consequences of EZH2 inhibition (see below under Phase 2). 
For details regarding the Phase 1 PD analyses, see Schedule of Visits and Procedures (Table 8) 
and the Laboratory Manual. 
Phase 2 
Blood samples will be obtained predose and at various specified times postdose and assessed for 
molecular changes induced by exposure to tazemetostat, such as changes in histone methylation, 
gene expression (protein and/or mRNA), or other markers with the potential to elucidate or 
confirm the mechanism of action of tazemetostat. 
Paired tumor biopsies and/or bone marrow (FL cohorts) may be obtained, with appropriate 
subject consent, to examine tumor tissue for molecular evidence of the downstream 
consequences of EZH2 inhibition using relevant PD biomarkers such as H3K27 methylation 
status or others as assayed by appropriate methodologies. The aim is to obtain paired tumor 
tissue from a minimum of 4-6 subjects from each of the planned cohorts in Phase 2, FE, and 
Dose Expansion cohorts. Depending on tissue availability, assessment of the drug’s effect on 
both tumor and stromal cells is planned, as changes in 1 or both tissue types may predict tumor 
response. Lymphoma cell-specific markers can include, but are not limited to, differentiation 
markers, markers of immune cell recognition, and markers of proliferation and apoptosis. The 
general tumor/stromal architecture will be examined to study the drug’s effects on the interaction 
of lymphoma cells with the tumor microenvironment. Specific markers can include, but are not 
limited to, the presence and activation state of regulatory T cells, the Th1/Th2 profile of intra-
tumoral T helper cells, and expression of programmed death receptor 1 (PD1) and programmed 
death ligands (PDL1 and PDL2) on tumor and T cells. Refer to Section 7.4.1.8 for biopsy 
schedules.  
A plasma sample for cell-free nucleic acid analysis (circulating tumor DNA) will be obtained 
predose and at various time points as specified in the Schedule of Visits and Procedures (Phase 2 
only). Cell-free nucleic acid isolated from blood plasma samples may be used to explore tumor 


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genetic alterations, including mutations observed in archival tumor samples, mutations that may 
emerge with drug treatment, and candidate biomarkers of response to tazemetostat. 
Archival, FFPE tumor tissue from all enrolled subjects must be collected for prospective 
assessment of EZH2 mutation status, for confirmation of COO in DLBCL cohorts. Additional 
exploratory response biomarker analysis may be performed retrospectively. Gene-expression 
profiling, proteomics, DNA mutation analysis, or IHC analysis may be performed, based on the 
amount of tumor tissue available, for analysis of markers identified in preclinical studies and/or 
the scientific literature. Gene expression profiling may be performed and correlated with PK, PD, 
or safety data. 
An EZH2 mutation result will be determined at designated study laboratory testing sites using 
the cobas EZH2 Mutation Test, which is a real time allele-specific PCR test to detect mutations 
within codons Y646, A682, and A692 of the EZH2 gene in FFPE NHL tumor tissue specimens: 
Y646F, Y646N, Y646S, Y646H, Y646C, A682G, and/or A692V; results for Y646S, Y646H, and 
Y646C are not reported individually (grouped as Y646X). The EZH2 mutation test is an 
Investigational Use Only assay.  
COO will be determined for DLBCL subjects using the Hans method (Hans, 2004) at designated 
laboratory testing sites. Further details of EZH2 mutation and COO testing will be provided in 
the Laboratory Manual. 
Applicable to both Phase 1 and Phase 2 
Plasma samples from subjects receiving tazemetostat may undergo global proteomic and 
enzyme-linked immunosorbent assay-based analyses and multiplex bead-based immunoassay in 
an effort to identify protein markers.  
Genomic DNA samples may be used to examine the role of genetic variability in subjects’ 
absorption, distribution, metabolism, and excretion or the development of AEs. Variation in 
tazemetostat exposure or AEs may be evaluated by correlation of single-nucleotide 
polymorphisms with PK, safety, or PD data. Collection of Genomic DNA will cease when 
sample size has been met. 
Data obtained will be used only for research, to assist in developing safer and more effective 
treatments, and will not be used to change the diagnosis of the subject or alter the therapy of the 
subject. Biomarker specimens and any DNA, RNA, protein, or metabolites derived from the 
collected specimens may be stored for up to 15 years to assist in any research (eg, scientific 
questions related to tazemetostat, solid tumors, or B cell lymphoma) as well as for potential use 
in diagnostic development. 


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For additional information, see Appendix 7. Details of pharmacogenomic and biomarker 
sampling and analysis will be provided in the Laboratory Manual. 
PHARMACODYNAMIC ASSESSMENTS 
Blood samples, skin punch biopsies (for Dose Escalation only: closed), and optional tumor 
biopsies for PD assessments will be obtained predose and at various time points as specified in 
the Schedule of Visits and Procedures. Refer to Laboratory Manual and see Table 8 and Table 9 
for additional details. 
Pharmacokinetic/Pharmacodynamic Assessments 
The PK/PD relationship between exposure to tazemetostat and histone methylation will be 
explored graphically and any emergent relationship will be followed by model-based PK/PD 
analysis. 
PK/PD relationships will be assessed for exploratory biomarkers, safety, and preliminary 
efficacy. 
PK/PD analysis will be performed to correlate best overall response with tazemetostat exposure.  
The total volume of blood to be drawn per period or cycle can be found in the Laboratory 
Manual provided separately. Instructions for the processing, storage, and shipment of samples 
will be provided in a separate Laboratory Manual. 
7.4.1.7 Safety Assessments 
Safety assessments will consist of monitoring and recording all AEs, including all Common 
Terminology Criteria for Adverse Events (CTCAE v4.03 [Cancer Therapy Evaluation Program, 
Common Terminology Criteria for Adverse Events, 2009], see Appendix 5) (for both increasing 
and decreasing severity), and SAEs; regular laboratory evaluation for hematology, blood 
chemistry, and urine values; and periodic measurement of vital signs, echocardiograms/ multiple-
gated acquisition (MUGA) scans, electrocardiograms (ECGs), and physical examinations. 
Additionally, QT interval corrected for heart rate using Fridericia’s formula (QTcF) will be 
evaluated. 
For details, refer to the Schedule of Visits and Procedures (Table 8 and Table 9). 
LABORATORY MEASUREMENTS 
The clinical laboratory parameters that will be measured are detailed in Table 7. 
Phase 1 only: Clinical laboratory tests will be performed by a central laboratory. All blood 
samples will be collected and sent to the central laboratory on the day of collection unless 
otherwise instructed. In cases of a safety concern or to guide clinical dosing, a local laboratory 
may be used in addition to a central laboratory. If central laboratory results are not available 


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within the necessary time frame to allow the subject to be enrolled, local laboratories may be 
used to perform laboratory tests to qualify subjects for entry into the study. Urinalysis may be 
performed at the investigational site by dipstick or sent to the central laboratory.  
For the Phase 2 part of the study clinical laboratory tests will be performed locally. 
The Schedules of Visits and Procedures (Table 8 and Table 9) show the visits at which blood and 
urine will be collected for clinical laboratory tests. A Laboratory Manual will be provided to 
detail handling, processing, and shipping procedures. 
All hematology, blood chemistry (including pregnancy test, where applicable) samples are to be 
obtained before study drug administration and results reviewed before administration/dispensing 
of study drug at the beginning of each cycle. For the management of clinically significant 
laboratory abnormalities, refer to the Dose Reduction and Interruption Instructions for 
tazemetostat in Section 7.3.2.2 (Table 4). 
A laboratory abnormality may meet the criteria to qualify as an AE as described in this protocol 
(see Section 7.4.4.2) and the CRF Completion guidelines. In these instances, the AE 
corresponding to the laboratory abnormality will be recorded on the AE CRF. 
For laboratory abnormalities meeting criteria as SAEs (Section 7.4.4.2), the study site must send 
the SAE report including the laboratory report to the Sponsor using the SAE fax number or email 
address provided in the Investigator File. 


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Table 7 
Clinical Laboratory Tests 
Category 
Parameters 
Hematology 
x 
hematocrit, hemoglobin, red blood cell count (RBC), platelet 
count, white blood cell count (WBC) with differential (bands, 
basophils, eosinophils, lymphocytes, monocytes, neutrophils) 
x 
Peripheral blood smear morphology assessment (If peripheral 
blood smear morphology is abnormal, then conduct bone marrow 
aspirate with cytogenic testing to closely monitor subjects with 
cytogenic abnormalities known to be associated with 
myelodysplastic syndrome (MDS) 9del 5q, chr 7, abn, etc.) and 
myeloproliferative neoplasm (MPN) (e.g. JAK2 V617F, etc.)  
 
Chemistry 
 
 
Electrolytes 
x 
bicarbonate, chloride, potassium, sodium  
 
Liver function  
x 
alkaline phosphatase (ALP), alanine aminotransferase (ALT [or 
serum glutamic pyruvic transaminase (SGPT)]), aspartate 
aminotransferase (AST [or serum glutamic oxaloacetic 
transaminase (SGOT)]), conjugated (direct) bilirubina, total 
bilirubin 
 
Renal function 
x 
blood urea or blood urea nitrogen (BUN), creatinine 
 
Other 
x 
albumin, amylase, calcium, cholesterol, , creatine phosphokinase 
(CPK), glucose, International Normalized Ratio (INR), lactate 
dehydrogenase (LDH), phosphorous, total protein, triglycerides, 
uric acid 
a. The collection of conjugated bilirubin and globulin is not standard of care test across all institutions. Conjugated bilirubin 
should be collected whenever possible or if clinically indicated.  Globulin is no longer required. 
VITAL SIGNS AND WEIGHT MEASUREMENTS 
Vital signs and body weight (kg) will be collected at the visits designated in the Schedule of 
Visits and Procedures (Table 8 and Table 9) by a validated method. Vital sign measurements 
include blood pressure ([BP], systolic BP, diastolic BP), heart rate (HR, beats per minute), and 
body temperature (°C). Height will be measured at the Screening Visit only. Blood pressure and 
HR will be collected after subjects have been sitting for 5 minutes. 
When vital signs are to be obtained concurrently with PK or other blood samples, the vital sign 
measurements will be performed before drawing blood samples in order to maximize the 
accuracy of blood sampling times while minimizing the potential effects of blood drawing on 
recordings obtained during safety assessments. 
ECOG PERFORMANCE STATUS 
An ECOG performance status should be done at each visit as designated in the Schedule of Visits 
and Procedures (Table 8 and Table 9). 


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PHYSICAL EXAMINATIONS 
Comprehensive physical examinations and symptomatic physical examinations will be 
performed as designated in the Schedule of Visits and Procedures (Table 8 and Table 9). 
Documentation of the physical examination will be included in the source documentation at the 
investigational site. Only changes from screening physical examination findings that meet the 
definition of an AE will be recorded on the AE CRF. 
A comprehensive physical examination will include evaluation of the head, eyes, ears, nose, 
throat, neck, heart, chest, lungs, abdomen, extremities, skin, and neurological status. 
Symptom directed physical examination will include health status assessed by a brief evaluation 
of the head, eyes, ears, nose, throat, and other physical conditions of note. The subject must be 
queried regarding changes in physical status since the last examination. 
ELECTROCARDIOGRAMS 
Electrocardiograms will be complete, standardized, 12-lead recordings that permit all 12 leads to 
be displayed on a single page with an accompanying lead II rhythm strip below the customary 
3 × 4 lead format as designated in the Schedule of Visits and Procedures (Table 8 and Table 9). In 
addition to a rhythm strip, a minimum of 3 full complexes should be recorded from each lead 
simultaneously. Subjects must be in the recumbent position for a period of 5 minutes before the 
ECG. 
An ECG abnormality may meet the criteria of an AE as described in this protocol 
(Section 7.4.4.3) and the CRF instructions. In these instances, the AE corresponding to the ECG 
abnormality will be recorded on the AE CRF. 
For ECG abnormalities meeting criteria as SAEs (Section 7.4.6), the study site must send the 
SAE report including the ECG report to the number indicated in the Investigator File using the 
SAE reporting form. 
7.4.1.8 Other Assessments 
PREGNANCY TEST 
A serum ȕ-hCG test and/or urine ȕ-hCG test will be performed at Screening for all women of 
child bearing potential. A urine or serum pregnancy test will be performed before the first 
tazemetostat dose and prior to dosing on Day 1 of each cycle. For the serum ȕ-hCG test, a 6-mL 
sample of blood will be taken at designated time points on the Schedule of Visits and Procedures 
(Table 8 and Table 9). 
PAIRED TUMOR BIOPSIES 
Paired tumor biopsies (Phase 2 cohorts, Dose-Escalation cohorts, and FE cohort) and/or bone 
marrow biopsies (Phase 2 FL cohorts) may be obtained, with appropriate subject consent, from 


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4 to 6 subjects per cohort to examine tumor tissue for molecular evidence of the downstream 
consequences of EZH2 inhibition using relevant PD biomarkers assayed by appropriate 
methodologies. Paired tumor tissue will be obtained from the pool of subjects recruited to the 
Expansion Cohorts, FE cohort, and Phase 2 part. Tissue sample collection, for PD assessments 
will occur at the designated time point on the Schedule of Visits and Procedures (Table 9). 
Subjects should have the biopsy before administration of the first dose of tazemetostat and the 
second biopsy at Cycle 2 Day 1. 
TUMOR BIOPSY AT DISEASE PROGRESSION  
Tumor biopsy is requested, where medically feasible, at disease progression in subjects who 
achieve a PR or better with tazemetostat. 
BONE MARROW BIOPSY WITH IHC 
A bone marrow biopsy (including IHC) will be performed for all subjects with FL and in subjects 
with DLBCL if clinically indicated or if subject has history of bone marrow involvement if these 
have not been performed within 42 days (an approval is needed from the Sponsor’s medical 
monitor if the window has been beyond 42 days) of Cycle 1 Day 1. At the first notation of CR, a 
repeat bone marrow biopsy should be performed if lymphoma involvement in the bone marrow 
was reported at Screening.  For further details, see Table 9. 
PERIPHERAL BLOOD SMEAR/ BONE MARROW BIOPSY 
If peripheral blood smear morphology assessment is confirmed to be abnormal, the subject will 
be required to undergo bone marrow aspirate/biopsy for cytogenetic testing to closely monitor 
subjects with cytogenetic abnormalities known to be associated with MDS (9del 5q, chr 7, abn, 
etc.) and MPN (e.g. JAK2 V617F, etc.)  If abnormal results, pause tazemetostat and after 
discussion with the Investigator modify the dose or discontinue the drug. 
 
OPTIONAL CHEST ULTRASOUND 
An optional chest ultrasound may be performed at screening and every 8 weeks at the 
Investigator’s discretion to monitor for early signs of T-LBL/T-ALL. 
ANNUAL ASSESSMENTS 
Annual assessments will be conducted to review AESIs, PK and tumor response.  A 3 mL blood 
sample will be required for annual PK assessments. Note: Annual assessments are no longer 
required as of Amendment 13.0.  Annual PK sample collections that had been required in 
Cohorts 4 and 5 were no longer required as of 16 May 2018.   


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7.4.1.9 Safety Monitoring 
Completed: Final determination of whether a subject should be counted as having experienced a 
DLT for dose escalation purposes or MTD and/or RP2D confirmation purposes, and whether the 
dose escalation will proceed in 100% increments or smaller, will be made jointly by the Sponsor 
and investigators. For additional details, see Section  7.3.2.1. 
Completed: An independent DMC was established to review available safety data supporting the 
MTD and/or RP2D once a minimum of 6 subjects at the MTD or highest feasible dose complete 
1 cycle in Dose Escalation. The DMC reviewed safety data including, but not limited to, AEs, 
SAEs, laboratory parameters, investigational product dosing records, treatment delays or 
reductions, and treatment discontinuation due to toxicity. Based on all data reviews, the Sponsor 
and the DMC concurred on the dose for Phase 2. 
During Phase 2, in order to adequately monitor safety, data will be reviewed regularly by an 
independent DMC. The DMC Chair, in consultation with the Sponsor, will be responsible for 
determining the type and frequency of any additional DMC data review meetings. The DMC will 
review safety data including, but not limited to, AEs, SAEs, laboratory parameters, 
investigational product dosing records, treatment delays or reductions, and treatment 
discontinuations due to toxicity. Any treatment-related death will also trigger review by the 
DMC. The DMC will determine whether it is safe to proceed. 
A full description of the membership and roles and responsibilities of the DMC will be provided 
in the DMC charter, and its end of Phase 1 assessment report will be transmitted to the approving 
Ethics Committees and Competent Authorities for this study. 
Tazemetostat Safety Committee  
A safety monitoring committee composed of internal and external medical experts will review 
all AESI cases, including T-LBL/acute lymphoblastic leukemia (ALL), MDS/acute myeloid 
leukemia (AML) and other myeloid malignancies like MPN (both related and unrelated), and 
other solid tumor malignancies. Cases will be evaluated for suspected relationship 
to tazemetostat and adjudicated by the experts. Recommendations for next steps per the risk 
management plan will be communicated to the CMO 
 
7.4.2 Schedule of Procedures/Assessments 
7.4.2.1 Schedule of Procedures/Assessments 
Phase 1 Schedule of Visits and Procedures for assessments are presented in Table 8. 
Phase 2 Schedule of Visits and Procedures for assessments are presented in Table 9. 


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7.4.2.2 Description of Assessment Schedule 
Potential subjects will undergo a screening assessment within 28 days before the start of the 
study to evaluate their eligibility for the study. Before any procedures or assessments are 
performed, the nature of the study and the potential risks associated with the trial will be 
explained to all subject candidates, and written informed consent will be obtained. Once 
informed consent has been obtained, study procedures and evaluations will be performed. 
The tumor tissue EZH2/COO testing can be performed prior to other screening procedures, for 
example, during wash-out of the second line anticancer therapy, after the subject is consented for 
the prescreening testing. 
Efforts should be made to conduct study visits on the day scheduled (r 3 days). Clinical 
laboratory assessments (Table 7) may be conducted anytime within 72 hours before the 
scheduled visit, unless otherwise specified in the Schedule of Visits and Procedures. Whenever 
possible, subjects should be evaluated at approximately the same time of the day (eg, morning or 
afternoon) at each visit, and reasonable efforts should be made to conduct all evaluations in the 
same test order at each visit. Subjects on the Phase 1 part of the study who have completed at 
least 6 cycles of study drug and are considered clinically stable may, after prior agreement with 
the study medical monitor, have Day 15 assessments in additional cycles consisting of telephone 
contact to site and local clinical laboratory assessments. For the details of procedures, 
assessments, and timing of procedures and assessments that are to be conducted at each visit and 
cycle(s), refer to the Schedule of Visits and Procedures.


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Table 8 
Schedule of Visits and Procedures: Phase 1 Tazemetostat (all visits starting at Cycle 2 Day can have a +/- 3 
day window) 
Phase 
Pretreatment 
DDI 
only 
Treatment 
Extension 
Extension 
Off-
Treatmenta 
Follow-
upb 
Period 
Screening
c 
Baselinec 
 
Cycle 1 
Cycle 2 - 6 
Cycle 7 and Beyondd 
 
 
Day 
-28 to -4 
-3 to -1 
-1 
1 
15 
1 
15 
1 
 
 
Procedures/Assessment
s 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
 
Prior and concomitant 
medications 
 
 
Throughout study 
Comprehensive physical 
examination 
X 
 
 
 
 
 
 
 
X 
 
Symptom directed 
physical examination 
 
X 
 
X 
X 
X 
X 
X 
 
 
Pregnancy teste 
X 
X 
 
 
 
X 
 
X 
 
 
Body weight 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
Vital signsf 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
ECOG performance 
status 
X 
X 
 
 
 
X 
 
X 
X 
 
12-lead ECGsg 
X 
X 
 
X 
 
X 
X 
X 
X 
 
Hematology 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Blood chemistry 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Genomic DNAj 
 
X 
 
 
 
 
 
 
 
 
PK blood samplesk 
 
 
X 
 
X 
Xk 
 
 
 
 
PD blood samplesl 
 
 
 
X 
X 
Xl 
 
 
 
 
Paired tumor biopsym 
 
X 
 
 
 
X 
 
 
 
 
Archival tumor block or 
slidesn 
 
X 
 
 
 
 
 
 
 
 
Tumor assessments: CT 
(MRI)o 
X 
 
 
Tumor assessments must be performed every 8 weeks up 
to week 24 
Tumor assessments 
performed every 12 
weeks 
X 
 
Bone scans (solid tumor 
X 
 
 
X 
 
 
 


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Table 8 
Schedule of Visits and Procedures: Phase 1 Tazemetostat (all visits starting at Cycle 2 Day can have a +/- 3 
day window) 
Phase 
Pretreatment 
DDI 
only 
Treatment 
Extension 
Extension 
Off-
Treatmenta 
Follow-
upb 
Period 
Screening
c 
Baselinec 
 
Cycle 1 
Cycle 2 - 6 
Cycle 7 and Beyondd 
 
 
Day 
-28 to -4 
-3 to -1 
-1 
1 
15 
1 
15 
1 
 
 
Procedures/Assessment
s 
 
 
 
 
 
 
 
 
 
 
as indicated) 
18FDG-PET Scan 
(NHL)p 
X 
 
 
Repeat PET at PR or CR 
 
 
 
Bone Marrow Biopsy 
(NHL if indicated)q 
X 
 
 
 
 
 
 
CT or MRI of the brainr 
Brain scans should be performed if clinically indicated both NHL and solid tumor. 
AEs/SAEs 
 
 
Throughout study 
Tazemetostat 
administrations 
 
 
 
Continuous 28-day cycle of tazemetostat twice daily. 
Tazemetostat can be taken with or without food. 
 
 
 
Midazolam 
administration (DDI 
only)t 
 
 
X 
 
X 
 
 
 
 
 
Survival status and 
subsequent anticancer 
therapy 
 
 
 
 
 
 
 
 
X 
X 
AE = adverse event, BM = bone marrow, ȕ-hCG = beta-human chorionic gonadotropin, BP = blood pressure, CR = complete response, CT = computed tomography, DDI = 
drug-drug interaction, DNA = deoxyribonucleic acid, ECG = electrocardiogram, ECOG = Eastern Cooperative Oncology Group, 18FDG-PET = 18fluorodeoxyglucose-positron 
emission tomography, HR = heart rate, IV = intravenous, MRI = magnetic resonance imaging, NHL = non-Hodgkin lymphoma, PD = pharmacodynamic, PK = 
pharmacokinetic, PR = partial response, SAE = serious adverse event 
Note: All table footnotes are presented on the following 2 pages. 
PHASE 1 IS COMPLETED 
a 
Off-treatment assessment may occur at time of treatment discontinuation or up to 30 days after the final dose of study drug. AE and concomitant medication data must be 
collected for 30 days after the final dose of study drug, or until the start of new therapy. This may occur prior to 30 days if new therapy is started within 30 days of last 
dose of study drug.  
b 
Survival follow-up will be conducted approximately every 12 weeks on all subjects, unless they withdraw consent. Information on all anticancer therapies will be 
collected (the Sponsor may choose to stop the collection of therapies after the first anticancer treatment following tazemetostat). This may be done by telephone contact. 
c 
The Screening Period extends from Day -28 to Day -4, except for signing of the informed consent form, which may be up to 8 weeks before the first dose of study drug. 
The baseline assessments may be performed from Day -3 to Day -2 (before the first dose of tazemetostat). The screening assessments (except tumor assessment) must be 


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Table 8 
Schedule of Visits and Procedures: Phase 1 Tazemetostat (all visits starting at Cycle 2 Day can have a +/- 3 
day window) 
Phase 
Pretreatment 
DDI 
only 
Treatment 
Extension 
Extension 
Off-
Treatmenta 
Follow-
upb 
Period 
Screening
c 
Baselinec 
 
Cycle 1 
Cycle 2 - 6 
Cycle 7 and Beyondd 
 
 
Day 
-28 to -4 
-3 to -1 
-1 
1 
15 
1 
15 
1 
 
 
Procedures/Assessment
s 
 
 
 
 
 
 
 
 
 
 
performed within 28 days before the first dose of study drug and may be used as baseline assessments if performed within 72 hours of the first dose of study drug. Tumor 
assessment must occur within 28 days of CT or MRI or photographs and within 42 days of bone scans (if a bone scan is appropriate for a tumor type). 
d 
Starting at Cycle 7, a Day 15 visit is not required. On Day 15 of each cycle, subjects will have hematology and blood chemistry samples drawn at a local laboratory and 
telephone contact with the site to review AEs. 
e 
$VHUXPSUHJQDQF\WHVWȕ-hCG) will be performed at Screening for all women of childbearing potential. A urine or serum pregnancy test will be performed predose on 
Day 1 of each cycle. 
f 
Vital signs include BP, HR, and body temperature. BP and HR will be collected after the subject has been sitting for 5 minutes. 
g 
12-Lead ECGs will be collected at the following time points: Screening (single) and Baseline (single unless abnormalities are observed or if clinically indicated, then in 
triplicate at 2-minute intervals); Day 1 of all cycles (before and after morning dose of study drug administration); at Day 15 from Cycle 2 until Cycle 6; and at Off-
Treatment Visit. In case of any alteration, or if clinically necessary, an echocardiogram and/or cardiac enzymes should be performed. 
i 
[Procedure no longer being performed.] 
j 
Genomic DNA samples will be collected predose during Screening or Baseline. If it cannot be collected at the designated time point, it may be collected at a time point 
after baseline. 
k 
Blood samples for PK analysis in the DDI cohort will be collected in Cycle 1 on Days -1 and 15 at Predose (0 hours), 0.5, 1, 2, 4, 6, 8, 10, and 12 and 24 hours postdose; 
and on Cycle 2 Day 1 Predose (0 hours), 0.5 to 2 hours, and 3 to 6 hours postdose.  
l 
Blood samples for PD analysis will be collected at the following time points: Predose (0 hours) on Cycle 1 Days 1 and 15; and Predose (0 hours) on Cycle 2 Day 1. Blood 
samples should be collected on the day after Day 28 of Cycle 1, irrespective of the start of Cycle 2. 
m 
Paired tumor biopsies and/or bone marrow biopsies may be obtained, with appropriate subject consent, from at least 4 to 6 subjects per cohort to examine tissue target 
inhibition, relevant PD biomarkers, and potential markers of response. Subjects will have the biopsy before administration of the first dose of tazemetostat and on Cycle 2 
Day 1. 
n 
Subjects will have collection of archived, tumor-biopsy sections for identification of predictive biomarkers unless no such material is available. 
o 
Tumor assessments include CT scan of the chest, CT or MRI of abdomen, pelvis, and other known sites of disease or newly suspected disease (as well as photographs of 
skin lesions that will be followed as target and nontarget lesions) and should be performed at Screening and every 8 weeks (starting from Cycle 1 Day 1 through Cycle 6 
and every 12 weeks from Cycle 7 and beyond), and as clinically indicated. Subjects with B Cell Lymphoma should be assessed for B symptoms at these time points. See 
Section 7.4.1.3. CT scans should be performed with oral and iodinated IV contrast and MRI scans with IV gadolinium chelate unless there is a medical contraindication to 
contrast. If iodinated IV contrast is contraindicated, chest CT should be performed without IV contrast. 
p 
Subjects with B Cell Lymphoma should have 18FDG-PET Scan at Screening and at the first notation of possible PR or CR. 


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Table 8 
Schedule of Visits and Procedures: Phase 1 Tazemetostat (all visits starting at Cycle 2 Day can have a +/- 3 
day window) 
Phase 
Pretreatment 
DDI 
only 
Treatment 
Extension 
Extension 
Off-
Treatmenta 
Follow-
upb 
Period 
Screening
c 
Baselinec 
 
Cycle 1 
Cycle 2 - 6 
Cycle 7 and Beyondd 
 
 
Day 
-28 to -4 
-3 to -1 
-1 
1 
15 
1 
15 
1 
 
 
Procedures/Assessment
s 
 
 
 
 
 
 
 
 
 
 
q 
Subjects with B Cell Lymphoma should have a BM biopsy at Screening (unless performed within 42 days of Cycle 1 Day 1) and at first notation of CR if there was 
lymphoma involvement of BM at Screening. If a BM biopsy sample was provided for PD sample at Screening, subsequent BM biopsy samples will be requested for PD 
assessment. 
r 
CT or MRI of the brain should be performed if clinically indicated. The same methodology and scan acquisition techniques used at Screening should be used throughout 
the study to ensure comparability. 
s 
On visit days, subjects should not take study drug before evaluations are performed. 
t 
A single oral dose of midazolam 2 mg will be given on Day -1 and Day 15 for subjects in the DDI cohort of the study only. See Section 7.3.2 for additional details. 
 


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Table 9 
Schedule of Visits and Procedures: Phase 2 (All Visits Starting at Cycle 1 Day 15 Have ± 3-Day Window) 
Period 
Screeninga 
Cycles 1 and 2 
Cycle 3 and Beyond 
Off-
Treatmentb 
Follow-upc 
Day 
-28 to -1 
1 (± 3 days) 
15 (± 3 days) 
1 (± 3 days) 
15d (± 3 days) 
 
 
Procedures/Assessments 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Prior and concomitant medications 
Throughout study 
Comprehensive physical examination 
X 
 
 
 
 
X 
 
Symptom directed physical exam 
 
X 
X 
X 
 
 
 
Pregnancy teste 
X 
X 
 
X 
 
X 
 
Body weight 
X 
X 
X 
X 
 
X 
 
Height 
X 
 
 
 
 
 
 
Vital signsf 
X 
X 
X 
X 
 
X 
 
ECOG performance status 
X 
X 
 
X 
 
X 
 
12-lead ECGsg 
X 
X 
 
X 
 
X 
 
Hematologyu 
X 
X 
X 
X 
X 
X 
 
Blood chemistry 
X 
X 
X 
X 
X 
X 
 
Genomic DNAh, t 
 
 
 
 
 
 
 
PK blood samplesi, t, w 
 
Xi 
Xi 
 
 
 
 
PD blood samplesj 
 
Xj 
Xj 
 
 
 
 
PD blood sample for nucleic acidk 
 
X 
 
X 
 
X 
 
Sufficient tumor tissue availablel 
X 
 
 
 
Optional Paired tumor biopsiesm 
 
X 
 
 
 
 
 
Tumor biopsy at DPn 
 
 
 
 
 
X 
 
Tumor assessments: CT (MRI), and 
assessments of B symptomso,w 
X 
Radiologic tumor assessments (IWG-NHL [Cheson, 2007] criteria) 
must be performed every 8 weeks during Cycles 2-6, and every 
12 weeks starting at Cycle 7 and beyond 
X 
X 
Optional chest ultrasoundv,w 
X 
Every 8 weeks while subject is receiving study drug 
 
 
CT or MRI of the brainp 
Brain scans should be performed if clinically indicated. 
Bone marrow biopsy (with IHC)q 
X 
At first notation of CR if bone marrow involvement at Screening, and 
if clinically indicated (eg, suspicion of relapse or progressive disease) 
 
 


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Table 9 
Schedule of Visits and Procedures: Phase 2 (All Visits Starting at Cycle 1 Day 15 Have ± 3-Day Window) 
Period 
Screeninga 
Cycles 1 and 2 
Cycle 3 and Beyond 
Off-
Treatmentb 
Follow-upc 
Day 
-28 to -1 
1 (± 3 days) 
15 (± 3 days) 
1 (± 3 days) 
15d (± 3 days) 
 
 
Procedures/Assessments 
 
 
 
 
 
 
 
18FDG-PET scanr 
X 
Performed at first notation of possible PR or CR 
 
 
AEs/SAEsw 
Throughout study treatment and off-treatment periods 
 
Tazemetostat administrations  
 
Continuous 28-day cycle of tazemetostat twice daily. Tazemetostat can 
be taken with or without food.  
 
 
Prednisolone administration (Cohort 6 
only)s 
 
Prednisolone from Days 1 to 5 and Days 15 to 19 taken with or 
without food for a total of 4 cycles 
 
 
Survival status and subsequent 
anticancer therapy 
  
X 
X 
$( DGYHUVHHYHQWȕ-hCG = beta-human chorionic gonadotropin, BP = blood pressure, CR = complete response, CT = computed tomography, DLBCL = diffuse large B cell 
lymphoma, DNA = deoxyribonucleic acid, DP = disease progression, ECG = electrocardiogram, ECOG = Eastern Cooperative Oncology Group, EZH2 = enhancer of zeste 
homolog 2, 18FDG-PET = 18fluorodeoxyglucose-positron emission tomography, FL = follicular lymphoma, HR = heart rate, IHC = immunohistochemistry, IWG-NHL = 
International Working Group-Non-Hodgkin’s Lymphoma, MRI = magnetic resonance imaging, PD = pharmacodynamic, PK = pharmacokinetic, SAE = serious adverse event 
a. 
The Screening Period extends from Day -28 to Day -1, except for signing of the informed consent form, which may be up to 8 weeks before the first dose of study drug. 
Screening laboratory assessments may be used as Day 1 assessments if performed within 72 hours of the first dose of study treatment, however subjects must continue to meet 
eligibility criteria prior to first dose of tazemetostat on Cycle 1 Day 1. The screening assessments (except tumor assessment) must be performed within 28 days before the first 
dose of study drug.  
b. 
Off-treatment assessment may occur at time of treatment discontinuation (eg, at the visit at which the decision to discontinue treatment occurs) or up to 30 days after the final 
dose of study drug. AE and concomitant medication data must be collected for 30 days after the final dose of study drug, or until the start of new therapy. This may occur prior 
to 30 days if new therapy is started within 30 days of last dose of study drug. If subject is unable to return to the clinic for assessment of AEs this may be done by telephone. 
c. 
Survival follow-up will be conducted approximately every 12 weeks on all subjects, unless they withdraw consent.  Information on all subsequent anticancer therapies and 
AESIs will be collected throughout the survival follow up.  This may be done by telephone contact. NOTE:  As of Protocol Amendment 13.0, no further survival follow-up is 
necessary for remaining subjects because the primary outcome assessment for all subjects has been met. 
d. 
Starting at Cycle 3, a Day 15 laboratory assessments are not required, but the telephone contact is still required. Laboratory assessments are to be performed as medically 
needed and can be either at the clinic or at a local laboratory. Any abnormal laboratory test result collected at Day 15, Cycle 3 and beyond will only need to be entered into the 
clinical database if they are associated to an AE. These results will be reported as an unscheduled visit. 
e. 
$VHUXPSUHJQDQF\WHVWȕ-hCG) will be performed at Screening for all women of childbearing potential. A urine or serum pregnancy test will be performed predose on Day 1 
of each cycle starting at Cycle 2. 
f. 
Vital signs include BP, HR and body temperature. BP and HR will be collected after the subject has been sitting for 5 minutes. 
g. 
12-Lead ECGs will be collected at the following time points: Screening (triplicate), Cycles 1 and 2 Day 1 (predose and 0.5 – 2 hours post dose immediately before PK 
sample), Day 1 of all subsequent cycles (before the morning dose of study drug administration), and at the Off-Treatment Visit. In case of any alteration or if clinically 
necessary, additional ECGs, an echocardiogram, and/or testing of cardiac enzymes should be performed. 


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h. 
Genomic DNA samples will be collected predose at Screening. If it cannot be collected at the designated time point, it may be collected at a time point prior to first dose. 
i. 
Blood samples for PK analysis for tazemetostat (all cohorts) and prednisolone (Cohort 6 only) will be collected in Cycle 1 on Day 1 at 0.5 to 2 hours and 3 to 6 hours and 
Day 15 at predose (0 hours), 0.5 to 2 hours, and 3 to 6 hours; and Cycle 2 on Day 1 at predose (0 hours), 0.5 to 2 hours, and 3 to 6 hours. Blood samples should be collected on 
the day after Day 28 of Cycle 1, irrespective of start of Cycle 2. 
j. 
This sample is no longer required. 
k. 
Blood samples for nucleic acid analysis will be collected at the following time points: Predose (0 hours) on Cycle 1 Day 1, and Day 1 of every other cycle, and at the off-
treatment visit. 
l. 
Subjects will have collection of archived, tumor-biopsy sections for central testing of EZH2 mutation status (all subjects) and confirmation of cell of origin for DLBCL 
subjects. 
m. Paired tumor biopsies (DLBCL cohorts) and/or bone marrow biopsies (FL cohorts) are optional and may be obtained, with appropriate subject consent, from at least 4 to 
6 subjects per cohort to examine tissue target inhibition, relevant PD biomarkers, and potential markers of response. Subjects should have the biopsy before administration of 
the first dose of tazemetostat and the second biopsy on Cycle 2 Day 1. If sufficient tumor exists from archival, this could be considered the predose sample. 
n. 
Tumor biopsy is to be requested, where medically feasible, at disease progression in subjects who achieve a PR or better with tazemetostat.  
o. 
Tumor assessments include CT scan of the chest, CT or MRI of the abdomen, pelvis, and other areas of known disease or newly suspected disease and should be performed 
between Day -28 and Day -1 and every 8 weeks, irrespective of treatment delays, during Cycles 1 to 6, and every 12 weeks during Cycle 7 and beyond. If local regulatory 
authorities mandate less frequent imaging, minimum frequency must be every 12 weeks. For countries where CT scan of the chest, CT or MRI of abdomen, pelvis and other 
areas of known or newly suspected disease are part of Standard Of Care Assessment (SoC), the scan will be performed as per SoC schedule and evaluation of the result will be 
performed and reported as per the Protocol. The same parameters as the screening scans should be used. A standard-of-care clinical examination for lymphoma, including 
assessment of B symptoms, will also be performed at each visit. 
p. 
CT or MRI of the brain should be performed if clinically indicated.  
q. 
A bone marrow biopsy (including IHC) will be performed between Day -28 and Day -1 for all subjects with FL and in subjects with DLBCL if clinically indicated or if subject 
has history of bone marrow involvement if these have not been performed within 42 days (an approval is needed from the Sponsor’s medical monitor if the window has been 
beyond 42 days) of Cycle 1 Day 1. At the first notation of CR, a repeat bone marrow biopsy should be performed if lymphoma involvement in the bone marrow was reported 
at Screening. 
r. 
18FDG-PET scan should be performed at Screening and at the first notation of possible PR or CR. 
s. 
On visit days when PK samples are collected, study drug(s) should be administered in clinic. 
t. 
Effective 16 May 2018, the sample size for population PK and genomic DNA analysis has been met and additional samples are no longer being collected.  
u. 
If peripheral blood smear morphology is abnormal, then conduct bone marrow aspirate with cytogenic testing to closely monitor subjects with cytogenic abnormalities known 
to be associated with MDS 9del 5q, chr 7, abn, etc.) and MPN (e.g. JAK2 V617F, etc.)  
v. 
An optional chest ultrasound may be performed at the Investigator’s discretion to monitor for early signs of T-LBL/T-ALL. 
w. Annual assessments will be conducted to review AESIs, PK and tumor response. (Note: Annual assessments are no longer required as of Amendment 13.0.  Also, annual PK 
sample collections for assessment were no longer required as of as of 16 May 2018.) 
 


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OFF-TREATMENT PROCEDURES 
Off-treatment assessment may occur at time of treatment discontinuation or up to 30 days after 
the final dose of study drug or initiation of subsequent anticancer therapy. Adverse event and 
concomitant medication data must be collected for 30 days after the final dose of study drug, or 
until the start of new therapy. All subjects will be asked to return to the sites for discontinuation 
or off-treatment assessments, if possible. If a clinic visit is not feasible, follow up information 
may be obtained via telephone or written correspondence. This may occur prior to 30 days if new 
therapy is started within 30 days of last dose of study drug.  
If a subject fails to appear for a scheduled study visit, the Investigator will make every attempt to 
contact the subject and determine the reason(s) for the missed visit as completely and accurately 
as possible. Subjects will only be judged as lost to follow-up if they cannot be reached after 3 
documented attempts by the site to contact them (1 week apart). 
Whenever possible, the following assessments should be performed within 30 days after subjects 
have received the final dose of study drug: 
PHASE 1 
x Comprehensive physical examination 
x Body weight 
x Vital signs (BP, HR, body temperature) 
x ECOG performance status (Appendix 1) 
x 12-lead ECGs 
x Bone marrow biopsy, if clinically indicated 
x Collect blood samples for hematology and blood chemistry analysis (see Table 7 for the 
tests to be performed) 
x Tumor assessments: RECIST 1.1 criteria for solid tumors (Appendix 4) or IWG-NHL 
(Cheson, 2007) for B cell lymphoma  
x Record AEs and SAEs 
x Survival status and subsequent anticancer therapy  
For details, refer to the Schedule of Visits and Procedures (Table 8 and Table 9).  
PHASE 2 
x Comprehensive physical examination 
x Body weight 


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x Vital signs (BP, HR, body temperature) 
x ECOG performance status (Appendix 1) 
x 12-lead ECGs 
x Collect blood samples for hematology and blood chemistry analysis (see Table 7 for the 
tests to be performed) 
x Bone marrow biopsy for all FL subjects and if clinically indicated in DLBCL subjects 
with history of bone marrow involvement 
x Tumor assessments: IWG-NHL (Cheson, 2007) criteria 
x Record AEs and SAEs  
x Survival status subsequent anticancer therapy (no longer applicable after Amendment 
13.0) and AESI 
For details, refer to the Schedule of Visits and Procedures (Table 8 and Table 9). 
SURVIVAL STATUS AND SUBSEQUENT ANTICANCER THERAPY 
Survival status will be collected on all subjects every 12 weeks, unless they withdraw consent. 
Information about all subsequent anticancer therapies after study drug discontinuation will be 
collected (the Sponsor may choose to stop the collection of therapies after the first post study 
drug discontinuation anticancer treatment).  Note:  As of Protocol Amendment 13.0, no further 
survival follow-up is necessary for remaining subjects because the primary outcome assessment 
for all subjects has been met. 
TUMOR ASSESSMENTS DURING THE FOLLOW-UP PERIOD 
Where possible, for subjects who discontinue study drug for reasons other than disease 
progression, scans performed during the post study drug discontinuation follow-up period should 
be performed on the same schedule and using the same imaging modality as defined in the study 
protocol. 
7.4.2.3 Total Volume of Blood 
The total volume of blood drawn per period or cycle can be found in the Laboratory Manual 
provided separately. Additional samples may be taken at the discretion of the Investigator if the 
results of any tests fall outside reference ranges or if clinical symptoms necessitate testing to 
ensure subject safety. 


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7.4.3 Appropriateness of Measurements 
All clinical assessments are standard measurements commonly used in studies of solid tumors 
and hematological malignancies. The safety assessments to be performed in this study, including 
hematology analyses, blood chemistry tests, radiologic studies, and assessment of AEs, are 
standard International Conference on Harmonisation (ICH) GCP evaluations to ensure subject 
safety. The use of IWG-NHL (Cheson, 2007) for B cell lymphoma and RECIST 1.1 for solid 
tumor assessment and are widely accepted (Cheson, 2007; Eisenhauer, 2009). 
7.4.4 Adverse Events and Serious Adverse Events, Pregnancy, and Other 
Events of Interest 
7.4.4.1 Adverse Events and Other Events of Interest 
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered an investigational product. An AE does not necessarily have a causal relationship 
with the investigational product. 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 investigational product, whether or not related to the investigational product.  
In the Phase 1 part of the study all AEs, regardless of the relationship to the study drug or 
procedure, should be collected beginning from the time the subject signs the study consent. In 
the Phase 2 part of the study all AEs, regardless of the relationship to the study drug or procedure 
should be collected beginning from the time of first dose of the investigational product. 
Worsening of a pretreatment event, after initiation of investigational product, 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 or more frequent after the first dose of 
tazemetostat, a new AE of worsening or more frequent dyspepsia (with the appropriate date of 
onset and severity) 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: 
x 
Medical or surgical procedure (eg, endoscopy, appendectomy); the condition that leads to 
the procedure is an AE 
x 
Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital) 


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x 
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 
All AEs will be collected for 30 days after the final dose of study drug, or until the start of 
subsequent anticancer therapy, whichever happens first. If subject is unable to return to the clinic 
for assessment of AEs this may be done by telephone. 
7.4.4.2 Laboratory Abnormalities 
An abnormal laboratory test result may be considered as an AE if the identified laboratory 
abnormality leads to any type of intervention whether prescribed in the protocol or not. 
A laboratory result should be considered by the Investigator to be an AE if it: 
x Results in the withdrawal of study drug. 
x Results in withholding of study drug pending some investigational outcome. 
x Results in the initiation of an intervention, based on medical evaluation (eg, potassium 
supplement for hypokalemia). 
x Results in any out-of-range laboratory value that, in the Investigator’s judgment, fulfills 
the definition of an AE with regard to the subject’s medical profile. 
x ,QFUHDVHVLQVHYHULW\FRPSDUHGWREDVHOLQHE\ 2 CTCAE grades (see Appendix 5), with 
the exception of lymphocytes, albumin, cholesterol, glucose, and phosphate. For these 
WHVWVDFKDQJHRI 2 grades will be evaluated by the Investigator to determine if they are 
of clinical significance and, if so, will be considered AEs. 
Abnormal laboratory values should not be listed as separate AEs if they are considered to be part 
of the clinical syndrome that is being reported as an AE. Any laboratory abnormality considered 
to constitute an AE should be reported on the AE CRF. 
It is the responsibility of the Investigator to review all laboratory findings in all subjects and 
determine if they constitute AEs. Medical and scientific judgment should be exercised in 
deciding whether an isolated laboratory abnormality should be classified as an AE. 
7.4.4.3 Other Safety Assessment Abnormalities 
Abnormal ECG (QTc) results, if not otherwise considered part of a clinical symptom that is 
being reported as an AE, should be considered an AE if the QTc interval is > 450 ms and there is 
an increase of > 60 ms from baseline. Any ECG abnormality that the Investigator considers as an 
AE should be reported as such. 


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7.4.4.4 Assessing Severity of Adverse Events 
Adverse events will be graded on a 5-point scale according to CTCAE v4.03 (Appendix 5). 
Investigators will collect all CTCAE grades for AEs (for both increasing and decreasing 
severity). All AEs reported using CTCAE classification and graded as 4 or 5 are to be considered 
serious. Every effort must be made by the Investigator to categorize each AE according to its 
severity and its relationship to the study drug. In the event that an AE is not covered by the 
CTCAE, the assessment of severity will be determined by using the CTCAE general guidelines. 
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 activities of daily living (ADL). 
Grade 3 = Severe or medically significant but not immediately life-threatening: 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL. 
Grade 4 = Life-threatening consequences: urgent intervention indicated. 
Grade 5 = Death related to AE. 
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”). See 
Section 7.4.4.8 for the definition of an SAE. 
7.4.4.5 Assessing Relationship to Study Drug 
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.  
Items to be considered when assessing the relationship of an AE to the study drug are: 
x Temporal relationship of the onset of the event to the initiation of the study drug 
x The course of the event, considering especially the effect of discontinuation of study drug 
or reintroduction of study drug, as applicable 
x Whether the event is known to be associated with the study drug or with other similar 
treatments 
x The presence of risk factors in the study subject known to increase the occurrence of the 
event 


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x The presence of non-study drug-related factors which are known to be associated with the 
occurrence of the event. 
7.4.4.6 Classification of Causality 
Not Related: A causal relationship between the study drug and the AE is not a reasonable 
possibility. 
Related: 
A causal relationship between the study drug and the AE is a reasonable 
possibility. The Investigator must further qualify the degree of certainty as 
“possible” or “probable.” 
7.4.4.7 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). 
7.4.4.8 Serious Adverse Events 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
x Results in death 
x Is life-threatening (ie, the subject was at immediate risk of death from the AE as it 
occurred; this does not include an event that, had it occurred in a more severe form or 
was allowed to continue, might have caused death) 
x Requires inpatient hospitalization or prolongation of existing hospitalization 
x Results in persistent or significant disability/incapacity, or 
x Is a congenital anomaly/birth defect (in the child of a subject who was exposed to the 
study drug) 
Other important medical events that may not be immediately life-threatening or result in death or 
hospitalization, but when based on appropriate medical judgment, may jeopardize the subject or 
may require intervention to prevent 1 of the outcomes in the definition of an SAE listed above 
should also be considered serious SAEs. Medical and scientific judgment should be exercised in 
deciding whether expedited reporting is appropriate in such situations. 


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If possible, a blood sample for the measurement of study drug plasma concentration should be 
drawn at the first report of an SAE or a severe unexpected AE and at its resolution.  
The following hospitalizations are not considered to be SAEs because there is no “AE” (ie, there 
is no untoward medical occurrence) associated with the hospitalization: 
x Hospitalizations for respite care 
x Planned hospitalizations required by the protocol 
x Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed post study drug administration) 
x Hospitalization for administration of study drug or insertion of access for administration 
of study drug 
x Hospitalization for routine maintenance of a device (eg, battery replacement) that was in 
place before study entry 
x An emergency room visit lasting longer than 24 hours but not resulting in hospitalization 
Note: Disease progression is a study endpoint and should not be reported as an SAE term. 
However, AEs (eg, dyspnea) that meet seriousness criteria, although associated with disease 
progression, should be reported as SAE. 
7.4.4.9 Adverse Events of Special Interest 
The following AESIs have been identified, requiring mitigation steps and monitoring to 
minimize the risk for the occurrence of these events. 
7.4.4.9.1 T-LBL/T-ALL  
Lymphoblastic lymphomas are considered thymus derived malignancies that have not yet 
completed T-cell maturations. Approximately 90% of lymphoblastic lymphomas are the T-cell 
phenotype and typically occur in young adults and adolescents, accounting for 29% of pediatric 
and 2% of adult NHL with a median age at diagnosis of 25 years (Lai, 2013; Cortelazzo, 2017; 
Lones, 2007). T-LBL is morphologically and immunophenotypically indistinct from T-ALL, with 
both diseases arising from precursor lymphoid cells of the T-cell lineage (Portell, 2012; Patel, 
2014). Despite the similarities of the two diseases, significant yet unknown characteristics lead to 
differences in clinical presentations (Burkhardt, 2009). Initial clinical manifestation of both adult 
and pediatric T-LBL includes a mediastinal mass or lymphadenopathy with <25% bone marrow 
blasts. Adult T-LBL patients tend to have less thymic disease and greater lymph node disease and 
bone marrow involvement (Baleydier, 2008; Swerdlow, 2008; Campo, 2011). In contrast, T-ALL 
cases predominantly present with bone marrow and peripheral blood disease, and >25% bone 
marrow blasts (Swerdlow, 2008; Campo, 2011). 


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On 06 April 2018 an event of T-LBL was observed in a subject on study EZH-102. This event 
was reported to regulatory authorities as a 7-day SUSAR on 13 April 2018 (Case number 
2018USEPZ64380299).  
Following this report, Epizyme conducted a comprehensive evaluation, including:  
x Review of literature and available preclinical/clinical data to better understand event of 
T-LBL.  
x Review of the literature and available preclinical/clinical data to better understand the 
risk of MDS/AML and myeloid malignancies, and other solid tumor malignancies.  
x Assessment of safety, pharmacokinetics (PK) at various doses tested, benefit-risk across 
tumor types in adults and children. 
x Consultation with well recognized external experts in T-cell lymphoma and 
pediatric/adult oncology.  
Based on this evaluation, we continue to believe that tazemetostat is a clinically active drug and 
has the potential to benefit both adult and pediatric patients across different tumor types where 
there are unmet medical needs.  We also conclude that the risk assessment identifies a possible 
direct association between tazemetostat and T-LBL/T-ALL. Epizyme considers the risk for T-
LBL/T-ALL in tazemetostat clinical trials to be largely concentrated in pediatric patients based 
on 1) higher AUC0-24h exposures in pediatric patients and 2) increases over time in age-related 
thymic involution, and 3) the known epidemiology / pathophysiology of T-LBL/T-ALL. The risk 
of T-LBL/T-ALL in adults is not known, however the incidence of treatment-related T-LBL/T-
ALL in adults is expected to be uncommon. To date, over 958 subjects (adults and pediatric)  
have been treated with tazemetostat as monotherapy and in combination with other anti-
neoplastic therapies with no other observed cased of T-LBL/T-ALL. 
 
T-LBL Case 
The event of T-LBL in a 9-year-old (at the time of enrollment) female subject diagnosed with 
poorly differentiated chordoma occurred on Study Day 432 of treatment with tazemetostat 900 
mg/m2 BID. At the time of the event of T-LBL, the subject was in complete response of her 
target lesions of the disease under study, yet due to presence of 1 of 2 non-target lesion in her 
lung (1 lesion disappeared), was considered overall as a partial responder. The first response was 
observed and measured at Day 54 on treatment. The steady-state AUC0-24h at Cycle 1 Day 15 in 
this subject was 18,784 ng•h/mL and is similar to the mean AUC0-24h at Cycle 1 Day 15 for the 
900 mg/m2 dose group overall (21,000 ng•h/mL, n=5). The study medication was discontinued 
and the subject withdrawn from the study due to the event. 
 


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Induction therapy was initiated on 06 April 2018 with the following regimen: cytrarabine, 
daunorubicin, dexamethasone, dexrazoxane. Methotrexate was subsequently started on 13 April 
2018. The 9-year-old subject has since experienced a partial clinical response following standard 
induction chemotherapy, and is expected to have a good overall prognosis as is typical of T-LBL 
in children when treated appropriately.  
 
The SUSAR of T-LBL resulted in the Sponsor initiating a temporary global halt in enrollment 
for the pediatric study EZH-102. In addition, this event led to a partial clinical hold (PCH) on 
new subject enrollment for tazemetostat by the U.S. (FDA), France (ANSM), and Germany 
(BfArM) across all studies of the Tazemetostat Development Program. For further details, see 
the Investigator’s Brochure, version 8.0. In the event of suspicion of T-LBL/T-ALL or related 
concerns, please refer to Section 7.3.2.2 for evaluation and dose adjustments.   
 
Heightened surveillance will be conducted to monitor and identify early signs and symptoms 
(per local practice/standard of care) of T-LBL/T-ALL so that tazemetostat may be discontinued 
in the subject and treatment can be initiated for these malignancies. If a case of adult T-LBL/T-
ALL occurs enrollment will be suspended and the benefit-risk of the drug will be assessed by the 
Tazemetostat Safety Committee and will be communicated to all Health Authorities and Ethics 
Committees. 
 
7.4.4.9.2 MDS/AML/MPN 
As of the 12 April 2021, seven (7) cases of MDS/AMLhave been reported in tazemetostat 
clinical trials. A summary of these cases please refer to the Investigator’s Brochure, Version 
11.0. In the event of suspicion of these malignancies or related concerns, please refer to 
Section 6.5 for evaluation and dose adjustments.  Heightened surveillance will be conducted to 
monitor and identify early signs and symptoms (per local practice/standard of care) of any 
MDS/AML and other myeloid malignancies like MPN.  For any MDS/AML or other myeloid 
malignancies like MPN, tazemetostat will be held, and after discussion with the Investigator, 
tazemetostat will be discontinued.  
7.4.4.10 OTHER IDENTIFIED RISKS 
Further events of interest include pregnancy or exposure to study drug through breastfeeding;  
Laboratory abnormalities are not to be reported as AESI, laboratory abnormalities should be 
reported as standard AEs or SAEs if the seriousness criteria are met. These events of interest are 
to be captured using the SAE procedures but are to be considered as SAEs only if they met 1 of 


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the above criteria. All AEs associated with events of interest are to be reported on the CRF 
whether or not they meet the criteria for SAEs. 
7.4.4.10.1 Special Situations: Overdose, Misuse, Abuse and Medication Error 
Definitions, reporting, and management of overdose, misuse, abuse, and medication errors are 
presented below and refer to tazemetostat. 
x Overdose: An overdose is defined, regardless of any associated AEs or sequelae, as: 
o On a per dose basis, any amount of the orally administered drug(s) that is over the 
protocol-specified dose assigned to a given subject. 
o On a schedule or frequency basis, anything taken more frequently than the 
protocol-required schedule or frequency. 
x Misuse: Intentional and inappropriate use of study drug not in accordance with the 
protocol. 
x Abuse: Sporadic or persistent intentional excessive use of study drug accompanied by 
harmful physical or psychological effects. 
x Medication error: Any unintentional event that causes or leads to inappropriate study 
drug use or subject harm while the study drug is in the control of site personnel or the 
subject. 
These occurrences must be reported on the dosing administration eCRF. Adverse events 
associated with these occurrences are to be captured on the AE eCRF.  
All instances of special situations are to be reported using the SAE form regardless of presence 
or absence of an associated AE. Refer to Section 7.4.6.3 for detailed instructions on how to 
handle the reporting of special situations.  
In the event of a special situation, the Investigator should immediately contact the Medical 
Monitor or their designee and closely monitor the subject for AEs/SAEs and laboratory 
abnormalities. 
7.4.5 Completion/Discontinuation of Subjects 
The Investigator may permanently discontinue treating a subject with study drug or withdraw the 
subject from the study at any time for safety or administrative reasons. The subject may decide to 
permanently discontinue study drug or withdraw from the study at any time for any reason. The 
reason for discontinuation will be documented. The Study Disposition Treatment CRF page will 
be completed indicating the primary reason for discontinuation from treatment and the study 


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drug discontinuation procedures indicated in the Schedule of Visits and Procedures will be 
completed (if possible). 
If a subject discontinues study drug, the subject will have an Off-Treatment Visit with protocol-
specified procedures and enter the Survival Follow-up Period unless the subject or 
parent/guardian withdraws consent or is lost to follow-up.  
The Investigator should confirm whether a subject or parent/guardian will permanently 
discontinue study drug but agree to continue protocol-specified procedures at the Treatment Visit 
and Survival Follow-Up or whether the subject or parent/guardian will withdraw consent. If 
consent is withdrawn, the Investigator will promptly explain to the subject involved that the 
subject will be withdrawn from the study and provide appropriate medical treatment and other 
necessary measures for the subject. If a subject or parent/guardian withdraws consent, the date 
will be documented in the source documents.  
A subject who has ceased to return for visits will be followed up by mail, phone, or other means 
as much as possible to gather information such as the reason for failure to return and the status of 
treatment compliance, presence or absence of AEs, and clinical courses of signs and symptoms. 
This information will be recorded in the CRF.  
Note:  As of Protocol Amendment 13.0, no further survival follow-up is necessary for remaining 
subjects because the primary outcome assessment for all subjects has been met. 
A subject removed from the study for any reason may not be replaced, except if a subject is 
discontinued before completing the Treatment Phase, an additional subject should be enrolled in 
the Phase 1 Dose Escalation part, FE cohort, and DDI cohort in this study. 
7.4.6 Reporting of Serious Adverse Events and Other Events of Interest 
All serious adverse events, irrespective of their relationship to study drug, must be reported as 
soon as possible, but no later than 24 hours from when the Investigator becomes aware of the 
event. 
Deaths and life-threatening events should be reported immediately. The immediate report should 
be followed-up within 1 business day of report via CRF into the clinical database or with a 
completed SAE form in case of no access to clinical database. 
It is very important that the SAE is processed as completely as possible at the time of the initial 
report. This includes the Investigator’s assessment of causality. 
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by the 
Sponsor. 


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Any follow-up information received on SAEs should be forwarded within 1 business day of its 
receipt. If the follow-up information changes the Investigator’s assessment of causality, this 
should also be noted on the follow-up SAE form. 
The detailed contact information for reporting of SAEs is provided in the Investigator File. 
Serious adverse events, regardless of causality assessment, must be collected over the same time 
period as stated above for AEs through the last visit and for 30 days after last dose following 
study drug discontinuation.  
All SAEs must be followed to resolution, or if resolution is unlikely, to stabilization. 
Any SAE judged by the Investigator to be related to the study drug should be reported to the 
Sponsor regardless of the length of time that has passed since study completion. 
For urgent safety issues, please ensure that all appropriate medical care is administered to the 
subject and contact the appropriate study team member listed in the Investigator File. 
 
The Investigator should notify his/her IRB/IEC of the occurrence of the SAE, in writing, in 
accordance with local requirements. A copy of this communication must be forwarded to the 
Sponsor or CRO monitor and filed in the Trial Master File. 
7.4.6.1 Reporting of Adverse Events of Special Interest 
All potential and identified AESIs, irrespective of their relationship to study drug, must be 
reported as soon as possible, but no later than 24 hours from when the Investigator becomes 
aware of the event. 
 
All potential and identified AESIs must be discussed with the Medical Monitor. 
 
7.4.6.2 Reporting of Pregnancy 
Any pregnancy where the estimated date of conception occurs either before the last visit or 
within 30 days of the last study drug or any exposure to study drug through breastfeeding during 
study drug or within 30 days of last study drug must be reported. 
If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
drug. 
A congenital anomaly, death during perinatal period, an induced abortion, or a spontaneous 
abortion are considered to be an SAE and should be reported in the same time frame and in the 
same format as all other SAEs (see Reporting of Serious Adverse Events Section 7.4.6). 


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Pregnancies or exposure to study drug through breastfeeding must be reported as soon as 
possible but no later than 1 business day from the date the Investigator becomes aware of the 
pregnancy. 
The contact information for the reporting of pregnancies and exposure to study drug through 
breastfeeding is provided in the Investigator Study File. 
The Pregnancy Report Form must be used for reporting. All pregnancies must be followed to 
outcome. The outcome of the pregnancy must be reported as soon as possible but not later than 
1 business day from the date the Investigator becomes aware of the outcome. 
A subject who becomes pregnant must be withdrawn from the study. 
7.4.6.3 Reporting of Special Situations 
Report the special situation(s) of overdose, misuse, abuse, and/or medication error (described in 
Section 7.4.4.10.1) using one of the following sets of instructions according to whether the 
special situation occurred without any associated AEs, with an associated non-serious AE, or 
with an associated SAE: 
Special situation(s) without associated AE(s): 
x 
Report to Epizyme using a paper Special Situations Form following the procedures for 
reporting SAE (Section 7.4.6).   
Special situation(s) with an associated non-serious AE: 
x 
Enter the non-serious event on the AE eCRF and mark the SAE field, “no”. SAE 
related narrative fields should not be completed. 
x 
Report to Epizyme using a paper Special Situations Form following the procedures for 
reporting SAE (Section 7.4.6).  
Special situation(s) with an associated SAE: 
x 
Complete the AE eCRF per protocol for the associated SAE term ONLY (Special 
situations are not adverse event terms in and of themselves); complete eCRF SAE 
fields. 
x 
Report to Epizyme using both a paper Special Situations Form and a paper Serious 
Adverse Event Form following the procedures for reporting SAE (Section 7.4.6).  
Adverse events associated with overdose, misuse, abuse, or medication error should be reported 
using the procedures detailed in Reporting of Serious Adverse Events (Section 7.4.6) even if the 
AEs do not meet serious criteria.  
7.4.6.4 Expedited Reporting 
The Sponsor must inform investigators or, as regionally required, the head of the medical 
institution and regulatory authorities of reportable events, in compliance with applicable 
regulatory requirements, on an expedited basis (ie, within specific time frames). For this reason, 


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it is imperative that investigational sites provide complete SAE information in the manner 
described above. 
7.4.6.5 Regulatory Reporting of Adverse Events 
Adverse events will be reported by the Sponsor or a third party acting on behalf of the Sponsor to 
regulatory authorities in compliance with local and regional law and established guidance. The 
format of these reports will be dictated by the local and regional requirements. 
All studies that are conducted within any European country will comply with the European 
Clinical Trial Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC. All suspected 
unexpected serious adverse reactions (SUSARs) will be reported as required to the Competent 
Authorities of all involved European member states. 
7.4.7 Confirmation of Medical Care by Another Physician 
The Investigator will instruct the subject to inform beforehand when the subject is going to 
receive medical care by another physician. At each visit, the Investigator will ask the subject 
whether the subject has done so since the last visit or is planning to do so in the future. When the 
subject is going to receive medical care by another physician, the Investigator, with the consent 
of the subject, will inform the other physician that the subject is participating in the clinical 
study. 
7.5 Data Quality Assurance 
This study will be organized, performed, and reported in compliance with the protocol, standard 
operating practices, working practice documents, and applicable regulations and guidelines. Site 
visit audits will be made periodically by the Sponsor’s or CRO’s qualified compliance auditing 
team, which is an independent function from the study conduct team. 
7.5.1 Data Management 
Data required by the protocol will be collected on a CRF and entered into a validated Electronic 
Data Capture clinical database that is compliant with all regulatory requirements. Data collected 
on the CRF must follow the instructions described in the CRF Completion Guidelines.  
The Investigator has ultimate responsibility for the collection and reporting of all clinical, safety, 
and laboratory data entered on the CRF. The Investigator or designee as identified on Form FDA 
1572 must sign the CRF to attest to its accuracy, authenticity, and completeness. 
The completed, original CRF is the sole property of Epizyme and should not be made available 
in any form to third parties without written permission from Epizyme, except for authorized 
representatives of Epizyme or appropriate regulatory authorities. 


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The Data Management Plan defines and documents the procedures necessary to ensure data 
quality. These activities must be followed to ensure data are properly entered, validated, coded, 
integrated, reconciled, and reviewed. 
7.5.2 Database Quality Assurance 
The clinical database will be reviewed and checked for omissions, apparent errors, and values 
requiring further clarification using computerized and manual procedures. Data queries requiring 
clarification will be generated and addressed by the investigational site. Only authorized 
personnel will make corrections to the clinical database, and all corrections will be documented 
in an audit trail. 
7.5.3 Bioanalytical Data Management and Quality Control 
Samples will be shipped according to the Laboratory Manual. Tazemetostat will be quantified 
using a validated liquid chromatography/mass spectrometry/mass spectrometry method. Before 
the analysis of study samples, the assay sensitivity, specificity, linearity, and reproducibility will 
be documented. Details on the analytical methodology, the method of validation, and the 
analytical within-study quality control procedures will be included in the clinical study report for 
this protocol. 
7.6 Statistical Methods 
All statistical analyses will be performed by the Sponsor or designee after the study is completed 
and the database is locked and released, a snapshot of the database is obtained and released, and 
randomization codes have been released for the Phase 1 FE cohort. Phase 1 (Dose Escalation and 
Cohort Expansion), FE, and DDI cohorts may be analyzed separately upon completion (ie, at an 
earlier time point) from the Phase 2 analysis. Statistical analyses will be performed using SAS 
software or other validated statistical software as required. Details of the statistical analyses will 
be included in a separate statistical analysis plan (SAP). 
7.6.1 Statistical and Analytical Plans 
The statistical analyses described in this section will be performed as further outlined in the SAP, 
which will be finalized before database lock and included in the clinical study report for this 
protocol. 
Subjects are analyzed according to their initial dose level, with the exception of subjects in the 
FE cohort: 
x Subjects in the FE cohort who took only 200 mg doses and withdrew before Cycle 1 
Day 1 will be included in the 200 mg BID dosing level for analysis. 


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x Subjects in the FE cohort who completed both single 200 mg doses and started the 
400 mg BID dosing level on Cycle 1 Day 1 will be included in the 400 mg BID dosing 
level for analysis. 
7.6.1.1 Definitions of Analysis Sets 
The per protocol analysis sets will be defined as follows: 
x Full Analysis Set will include all subjects who received at least 1 dose of study drug. 
This will be the primary analysis set for efficacy evaluations, as well as for demographic 
and baseline characteristics. 
x Safety Analysis Set will include all subjects who received at least 1 dose of the study 
drug and have at least 1 post-baseline safety evaluation. This will be the analysis set for 
all safety evaluations, except for the DLT analysis. 
x Dose-Limiting Toxicity (DLT) Analysis Set will include all subjects in the Safety 
Analysis Set who: 
o Experience a DLT during Cycle 1 as defined in Section 7.3.2 
or 
o Are not removed from Cycle 1 for reasons other than toxicity. 
x Pharmacokinetic (PK) Analysis Set will include all subjects who have received at least 
1 dose of tazemetostat and have at least 1 evaluable plasma concentration. 
x Food Effect Analysis Set will include all subjects for whom a full PK profile of 
tazemetostat is available after study drug administration in both the fed and fasted state 
and who consumed the prescribed breakfast before treatment in the “fed” state. 
x Drug-Drug Interaction Analysis Set will include all subjects for whom a full PK profile 
of midazolam is available after midazolam administration.  
x Pharmacodynamic (PD) Analysis Set will include all subjects who have received at 
least 1 dose of study drug and have evaluable PD data. 
x Pharmacogenomic (PGx) Analysis Set will include all subjects who have received at 
least 1 dose of study drug and have evaluable PGx data. 
x Pharmacokinetic/Pharmacodynamic (PK/PD) Analysis Set will consist of all subjects 
in the Safety Analysis Set that also have evaluable serum PK and PD pretreatment 
assessment and at least 1 post treatment assessment. 
The SAP will outline which analysis sets are to be used for the Phase 1 part, FE cohort, and DDI 
cohort and Phase 2 analyses.  


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DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic and other baseline characteristics will be summarized and listed. For continuous 
demographic/baseline variables including age, weight, and vital signs, results will be 
summarized and presented as N, mean, standard deviation, median, and minimum and maximum 
values. For categorical variables such as race/ethnicity, the number and percentage of subjects 
will be used. 
PRIOR AND CONCOMITANT MEDICATIONS 
Concomitant medications will be assigned an 11-digit code using the World Health Organization 
Drug Dictionary drug codes. Concomitant medications will be further coded to the appropriate 
Anatomical-Therapeutic-Chemical code indicating therapeutic classification. Prior and 
concomitant medications will be summarized and listed by drug and drug class. 
7.6.1.2 Efficacy Analyses 
The efficacy endpoints in Phase 1 will be summarized and listed for each subject by the study 
part and initial dose level based upon the Full Analysis Set. No formal statistical comparison will 
be performed. 
PHASE 2 PRIMARY EFFICACY ANALYSES 
In Phase 2, the evaluation of the ORR (CR + PR) in subjects with B cell lymphomas will be 
based on IWG-NHL (Cheson, 2007) response criteria. 
ORR will be presented with corresponding 2-sided Clopper–Pearson exact 95% confidence 
intervals (CIs). For each cohort, this analysis will be performed on the Full Analysis Set. 
PHASE 2 SECONDARY EFFICACY ANALYSES 
PFS is defined as the time from the date of first dose to the date of first documentation of relapse, 
disease progression, or date of death, whichever occurs first. PFS will be estimated using 
Kaplan-Meier method. If there are a sufficient number of PFS events (ie, relapses, progressions 
or deaths), median PFS, first and third quartiles and 2-sided 95% CIs, will be estimated using the 
Brookmeyer-Crowley method (Brookmeyer, 1982) for each cohort. Figures and listings of PFS 
will also be provided. 
For each subject with a CR or PR, DOR is defined as time from the first date of response (CR or 
PR, whichever is first recorded) to recurrence, objectively documented disease progression, or 
death, whichever occurs first. If there are a sufficient number of responders who subsequently 
progress or die due to any cause, the median DOR, first and third quartiles, will be calculated 
from the Kaplan-Meier estimates for each cohort. The associated 2-sided 95% CIs will be 
estimated using the Brookmeyer-Crowley method for each cohort. A listing of DOR will be 
provided. 


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ALL PHASES EXPLORATORY EFFICACY ANALYSES 
Overall survival is the duration measured from the date of first dose until the date of death from 
any cause. The Kaplan-Meier estimate of the median survival time, first and third quartiles will 
be presented with 2-sided 95% CIs for each cohort.  
7.6.1.3 Pharmacokinetic, Pharmacodynamic, and 
Pharmacogenomic Analyses 
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
Pharmacokinetic 
Phase 1 
Plasma and urine concentrations of tazemetostat will be tabulated and summarized by dose level, 
day, and time. Tazemetostat PK parameters will be derived from plasma concentrations by 
noncompartmental analysis using actual times. 
Minimally, the following PK parameters will be calculated:  
x Maximum drug concentration (Cmax) 
x Time to reach maximum concentration (following drug administration) (tmax) 
x Area under the concentration time curve (AUC) 
If data permit: 
x Elimination half-life (t1/2) 
x Total body clearance (CL) 
x Volume of distribution (Vd) 
x Renal clearance (CLr) 
x Accumulation ratio (R) 
x Fraction excreted (fe) 
PK parameters (eg, Cmax, AUC) for tablet and suspension formulations will be compared within a 
dose cohort that comprises subjects receiving both tazemetostat formulations to assess the 
relative performance of each formulation. 
Pharmacokinetic parameters for midazolam and its metabolites, 1-OH-midazolam and 
4-OH midazolam, and 4ȕ-hydroxycholesterol will be derived from plasma concentrations by 
noncompartmental analysis using actual times. Minimally, the following PK parameters will be 
calculated: Cmax, tmax, and AUC. The effect of tazemetostat on AUC and Cmax of midazolam and 


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its metabolites will be evaluated using a mixed linear model of logarithmically transformed 
values of the primary PK parameters. Ratios of geometric means and associated 2-sided 90% CIs 
will be presented. Similar analyses will be conducted for the effect of food on the AUC and Cmax 
of tazemetostat (fed/fasted comparison). 
Phase 1 and Phase 2 
Combined PK data from Phase 1 and Phase 2 will be subjected to population PK analysis. The 
PK model will be parameterized for clearance and volume(s) and exposure parameters such as 
Cmax and AUC will be derived. 
Pharmacodynamic 
H3K27 trimethylation levels as measured in skin punch biopsies (Phase 1 Dose Escalation only) 
and tumor, bone marrow, and PBMCs using appropriate methodologies may be explored and 
summarized by dose for each time point. The effect of tazemetostat therapy on cytogenetic 
changes, changes in histone methylation or other soluble, tissue, genetic, and imaging 
biomarkers may be explored and summarized using descriptive statistics. 
The percentage change in the sum of the diameters of tumor target lesions based on investigator 
assessment may be summarized and correlated with tazemetostat exposure and PD markers. 
Pharmacokinetic/Pharmacodynamic Analyses: 
PK/PD relationships between exposure to tazemetostat and histone methylation status; exposure 
and exploratory biomarkers of safety; and exposure and best overall response will be explored 
graphically. Any emergent relationship might be followed by model based PK/PD analysis. 
Biomarker and Pharmacogenomics Analyses: 
Details of the biomarker and pharmacogenomics data analysis plan will be defined and reported 
separately. 
BIOANALYTICAL METHODS 
Plasma and urine concentrations of tazemetostat will be determined using a validated assay. If 
appropriate, assay of plasma and urine samples for any metabolites of tazemetostat may be 
explored in the future. 
Plasma concentrations of midazolam and its metabolites, 1-OH-midazolam and 
4-OH-midazolam, and 4ȕ-hydroxycholesterol will be determined using a validated assay. 
7.6.1.4 Safety Analyses 
All safety analyses, unless otherwise specified, will be performed on the Safety Analysis Set. 
ECG findings and the incidence of AEs and SAEs will be summarized. Laboratory test results, 
vital signs, bromide levels (bromide monitoring will not be prospectively conducted in the FE 


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and DDI cohorts in Phase 1 or Phase 2), and echocardiograms/MUGA scans (LVEFs), and their 
changes from baseline, will be summarized using descriptive statistics. Abnormal values will be 
flagged. 
The effects of tazemetostat on cardiovascular repolarization will be evaluated via 12-hour, 12-
lead continuous Holter/ECG monitoring on Day -1, and on Cycle 1 Day 1 (ie, amounting to a 
total of 24 hours continuous cardiac Holter monitoring around first dose administration on 
Cycle 1 Day 1) and Day 15 in the Dose Escalation part of the study only. Individual ECGs will 
be extracted in triplicate from the Holter recordings at specified time points and will be evaluated 
by a central laboratory. QT intervals will be measured from Lead II and will be corrected for HR 
(QTc) using Fridericia's (QTcF) correction factors. The primary QTc parameter will be QTcF. 
Secondary parameters (QT interval corrected for heart rate using Bazett’s formula [QTcB], QT, 
QRS, and HR) and waveforms (T waves) will be evaluated. 
EXTENT OF EXPOSURE 
The number of cycles/days on treatment, quantity of study drug administered, and the number of 
subjects requiring dose reductions, treatment interruption, and treatment discontinuation due to 
AEs will be summarized. 
ADVERSE EVENTS 
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA). Adverse events will be coded to the MedDRA (Version 15.1 or higher) lower level 
term closest to the verbatim term. The linked preferred term (PT) and primary system organ class 
(SOC) are also captured in the database. 
A treatment-emergent AE (TEAE) is defined as an AE that  
x Emerges during treatment, having been absent at Pretreatment (Baseline)  
x Reemerges during treatment, having been present at Pretreatment (Baseline) but stopped 
before treatment, or  
x Worsens in severity during treatment relative to the pretreatment state, when the AE is 
continuous. 
Only those AEs that were treatment-emergent and had a start date within the earlier of 30 days 
following study drug discontinuation or initiation of subsequent anticancer therapy 
(Section 7.4.4.1) will be included in summary tables. All AEs, treatment emergent or otherwise, 
will be presented in subject data listings. 
Treatment-emergent AEs will be summarized by treatment group. The incidence of TEAEs will 
be reported as the number (percentage) of subjects with TEAEs by SOC and PT. A subject will 


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be counted only once within an SOC and PT, even if the subject experienced more than 1 TEAE 
within a specific SOC and PT. The number (percentage) of subjects with TEAEs will also be 
summarized by maximum severity by highest CTCAE grade. 
The number (percentage) of subjects with TEAEs will also be summarized by relationship to 
study drug (possibly related, probably related, and not related). 
The number (percentage) of subjects with TEAEs leading to death will be summarized by 
MedDRA SOC and PT for each treatment group. A subject data listing of all AEs leading to 
death will be provided. 
The number (percentage) of subjects with treatment-emergent SAEs will be summarized by 
MedDRA SOC and PT for each treatment group. A subject data listing of all SAEs will be 
provided. 
The number (percentage) of subjects with TEAEs leading to discontinuation from study drug 
will be summarized by MedDRA SOC and PT for each treatment group. A subject data listing of 
all AEs leading to discontinuation from study drug will be provided.  
The number (percentage) of subjects in the DLT Analysis Set with TEAEs designated as DLTs in 
the CRF will be summarized by MedDRA SOC and PT for each treatment group in the Dose 
Escalation and Expansion parts. 
LABORATORY VALUES 
Laboratory results will be summarized using Système International units, as appropriate. For all 
quantitative parameters listed in Section 7.4.1.7 Safety Assessments (Laboratory Measurements), 
the actual value and the change from baseline to each postbaseline visit and to the end of 
treatment (defined as the last on-treatment value) will be summarized by visit and treatment 
group using descriptive statistics. Qualitative parameters listed in Section 7.4.1.7 will be 
summarized using frequencies (number and percentage of subjects), and changes from baseline 
to each postbaseline visit and to end of treatment will be reported using shift tables. Percentages 
will be based on the number of subjects with both nonmissing baseline and relevant postbaseline 
results. 
Laboratory test results will be assigned a low/normal/high (LNH) classification according to 
whether the value was below (L), within (N), or above (H) the laboratory parameter’s reference 
range. Within-treatment comparisons for each laboratory parameter will be based on 3-by-3 
tables (shift tables) that compare the baseline LNH classification to the LNH classification at 
each postbaseline visit and at the end of treatment. Similar shift tables will also compare the 
baseline LNH classification to the LNH classification for the highest and lowest value during the 
treatment period. 


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VITAL SIGNS 
Descriptive statistics for vital signs parameters (ie, diastolic and systolic BP, HR, RR, and body 
temperature) body weight, and changes from baseline will be presented by visit and treatment 
group.  
ELECTROCARDIOGRAM RESULTS 
Electrocardiogram assessments will be performed as specified in the Schedule of Assessments 
(Table 8 and Table 9). Time-matched, central-read ECGs will be performed to evaluate RR, PR, 
QRS, QT intervals, and QTc at various time points throughout the study. All 12-lead ECG and 
Holter-ECG data will be listed, and changes will be summarized by dose group, for each cohort 
using descriptive statistics. The number and percentage of subjects with abnormal ECG findings 
at each visit will be reported for each dosing cohort. Descriptive statistics will be used to present 
the abnormal ECG findings overall. Results will be tabulated and listed in the study report. 
MUGA SCANS AND ECHOCARDIOGRAMS 
MUGA scans and echocardiogram results will be evaluated on an individual basis by subject. 
Abnormal readings will be identified as those outside (above or below) the reference range. 
MUGA scans and echocardiogram findings will be summarized. 
OTHER SPECIAL TESTS 
SERUM BROMIDE LEVELS 
Clinical laboratory values will be evaluated for each laboratory parameter by subject. Abnormal 
laboratory values will be identified as those outside (above or below) the normal range. 
Reference (normal) ranges for laboratory parameters will be included in the clinical study report 
for this protocol. Serum bromide monitoring will not be prospectively conducted in the FE and 
DDI cohorts in Phase 1 or Phase 2. 
ELECTROCARDIOGRAM HOLTER MONITORING 
The effects of tazemetostat on cardiovascular repolarization will be evaluated via 12-hour, 12-
lead continuous Holter ECG monitoring in Cycle 1, Day 1 and Day 15 of the Dose Escalation 
part of the study. Individual ECGs will be extracted in triplicate from the Holter recordings at 
specified time points and will be evaluated by a central laboratory. QT intervals will be measured 
from Lead II and will be corrected for heart rate (QTc) using Fridericia's (QTcF) correction 
factors. The primary QTc parameter will be QTcF. Secondary parameters (QTcB, QT, QRS, and 
HR) and waveforms (T-waves) will be evaluated. 


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SKIN PUNCH BIOPSY 
Skin punch biopsy results will be evaluated on an individual basis by subject. Abnormal readings 
will be identified as those outside (above or below) the reference range. Skin punch biopsy 
findings will be summarized. 
PAIRED TUMOR BIOPSIES 
Paired tumor biopsy explorative analysis will be evaluated on an individual basis by subject. 
Paired tumor biopsy results will be summarized. 
BONE MARROW BIOPSY 
Bone marrow biopsy results will be evaluated on an individual basis by subject. Abnormal 
readings will be identified as those outside (above or below) the reference range. Bone marrow 
biopsy findings will be summarized. 
BONE MARROW BIOPSY (WITH IMMUNOHISTOCHEMISTRY) 
Bone marrow biopsy (with IHC) results will be evaluated on an individual basis by subject. 
Abnormal readings will be identified as those outside (above or below) the reference range. Bone 
marrow biopsy (with IHC) findings will be summarized. 
7.6.2 Determination of Sample Size 
For Phase 1, the sample size of 6 to 45 subjects is considered adequate for the purposes of 
selecting a dose. Per FDA guidance, 12 subjects are considered adequate to evaluate food effect. 
The sample size for the DDI cohort was not based on statistical considerations. A total of 64 
subjects were enrolled in Phase 1. 
For Phase 2, the original study design planned enrollment of up to 30 subjects enrolled in each 
cohort. The initial assessment of efficacy was to be conducted within each cohort when 
10 subjects had been enrolled (stage 1). For each DLBCL cohort, if zero responders (with CR or 
PR) out of the initial 10 subjects was observed, further enrollment in the cohort was to be 
terminated for futility. This rule was based on the underlying assumption that the response rate is 
30% and there is a 2.8% probability of observing no responders among 10 subjects. For each 
FL cohort, if 1 or zero responders (CR or PR) out of the initial 10 subjects was observed, further 
enrollment in the cohort was to be terminated for futility. This rule was based on the underlying 
DVVXPSWLRQWKDWWKHUHVSRQVHUDWHLVDQGWKHUHLVDSUREDELOLW\RIREVHUYLQJ
responder among 10 subjects. Subsequent to the futility analysis in the DLBCL cohorts, the 
DMC supported a study design change to a modified 2-stage Green-Dahlberg design for each 
cohort. The resulting expanded sample size is shown in Table 10. 
Up to 70 subjects with DLBCL (GCB or non-GCB, EZH2 wild-type) will be enrolled in an 
additional combination therapy cohort (tazemetostat and prednisolone). A 2-stage Green 


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Dahlberg design will be used to terminate enrollment for futility (Table 10). Prior to full 
enrollment of stage 1, initial tolerability of 800 mg BID tazemetostat in combination with 
prednisolone will be assessed in the first 6 subjects enrolled based on the same set of DLT 
criteria used in Phase 1 (see Section 7.3.2). If a DLT is observed in no more than 1 of the 6 
subjects, enrollment will continue to stage 1. If a DLT is observed in more than 1 of the 6 
subjects, lower dose level(s) of prednisolone may be evaluated. Subjects treated at the dose 
found to be tolerable during the initial safety run-in assessment will be included as part of the 35 
subjects enrolled for stage 1.  
 
Table 10 
2-Stage Green Dahlberg Design 
 
Monotherapy 
Combination 
Therapy 
 
DLBCL 
GCB EZH2 
Mutant 
DLBCL  
GCB EZH2 
Wild-Type 
DLBCL 
non-GCB  
 
FL 
EZH2 
Mutant 
FL 
EZH2 Wild-
Type 
DLBCL 
EZH2 Wild-
Type 
Ho: CR + PR 
 
 
 
 
 
 
Ha: CR + PR 
 
 
 
 
 
 
Stage 1 futility 
n 
10 
10 
10 
10 
10 
35b 
Stage 1 
rejection of 
treatment 
 
0a 
 
0a 
 
0a 
 
1a 
 
1a 
 
6c 
 
 
 
 
 
 
 
Stage 2 total n  
60 
60 
60 
45 
45 
70 
Stage 2 
rejection of 
treatment 
14 
14 
14 
13 
13 
19 
CR = complete response, DLBCL = diffuse large B cell lymphoma, EZH2 = enhancer of zeste homolog 2, FL = follicular lymphoma, GCB = 
germinal-center B-cell-like, Ha = Alternative Hypothesis, Ho = Null Hypothesis, n = sample size, PR = partial response 
Note: Approximate alpha=0.025 and power =0.80 
a. 
Stage 1 futility analysis has been conducted. Enrollment will continue to 60 subjects in each of the DLBCL arms and 45 
subjects in each of the FL arms.  
b. 
Includes subjects treated at the dose found to be tolerable during the initial safety run-in assessment. 
c. 
The interim analysis planned at the end of stage 1 may occur sooner if the stage 1 rejection criterion is surpassed before all 
35 subjects are treated and have completed at least the Week 24 assessment. In this scenario, the total sample size (stage 1 + 
stage 2) would still remain unchanged at 70 subjects. 
 
To avoid disruptions in the study, enrollment and treatment of subjects will not be halted in order 
to conduct the futility analysis. If every cohort completes enrollment of stage 2, a total of 340 
subjects will be enrolled in Phase 2. 
For the purpose of calculating an expanded cohort size, a modified 2-stage Green-Dahlberg 
design was used where the stage 1 futility sample size was set to the original protocol design 
sample size of 10 subjects per cohort (for Cohorts 1-5) and the stage 1 rejection criteria were set 
to the original protocol defined rejection criteria (0 for the DLBCL cohorts and 1 for the FL 
cohorts).  


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For the DLBCL Monotherapy Cohorts (futility analysis completed): 
x The probability of early stopping under the null hypothesis is 0.197. 
x The probability of stopping under the alternative hypothesis is 0.028. 
For the FL Monotherapy Cohorts (futility analysis completed): 
x The probability of early stopping under the null hypothesis is 0.376. 
x The probability of stopping under the alternative hypothesis is 0.046. 
A 2-stage Green-Dahlberg design will be used to assess futility in the DLBCL combination 
therapy cohort. The stage 1 rejection criterion will be 6 or fewer responders (CR + PR).  
x The probability of early stopping under the null hypothesis is 0.433. 
x The probability of stopping under the alternative hypothesis is 0.017. 
7.6.3 Interim Analyses 
Phase 1 Dose Escalation data will be summarized and reported. All available safety and PK data 
will be evaluated before Phase 2 initiation. 
At the end of the FE and DDI cohorts, the data may be analyzed. The results of these analyses 
will inform Phase 2 dosing. 
There will be an interim analysis for futility in each cohort in Phase 2. While evaluating the 
response for the stage 1 subjects in each cohort, the enrollment and treatment of subsequent 
subjects will be continued. Timing, sample size, and rejection criteria for the stage 1 futility 
interim of each cohort are described in Section 7.6.2. 
If enrollment in any cohort is terminated for futility, the final reporting for that cohort will be 
based on all subject data in the database. 
In the combination therapy cohort, tolerability of study therapy will be evaluated in the initial 6 
subjects based on the same set of DLT criteria used in Phase 1 (see Section 7.3.2). 
7.6.4 Other Statistical/Analytical Issues 
Not applicable. 
7.6.5 Procedure for Revising the Statistical Analysis Plan 
If the planned analysis needs to be revised after the study starts, the Sponsor will determine how 
the revision impacts the study and determine how the revision should be implemented. The 
details of the revision will be documented and described in the SAP and the clinical study report. 


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8 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE 
PROCEDURES) 
8.1 Changes to the Protocol 
The protocol, ICF, and appropriate related documents must be reviewed and approved by an IRB 
or IEC constituted and functioning in accordance with ICH E6, Section 3, and any local 
regulations, ie, Code of Federal Regulations, Title 21 CFR Part 56. Any protocol amendment 
and/or revision to the ICF will be resubmitted to the IRB/IEC for review and approval, except for 
changes involving only logistical or administrative aspects of the study (eg, change in clinical 
research associates [CRAs] or change of telephone number[s]). Documentation of IRB/IEC 
compliance with ICH and any local regulations regarding constitution and review conduct will 
be provided to the Sponsor. 
A signed letter of study approval from the IRB/IEC Chairman must be sent to the PI (if 
regionally required, the heads of the medical institutions) with a copy to the Sponsor before 
study start and the release of any study drug to the site by the Sponsor or its designee (ICH E6, 
Section 4.4). If the IRB/IEC decides to suspend or terminate the study, the Investigator (if 
regionally required, the heads of the medical institutions) will immediately send the notice of 
study suspension or termination by the IRB/IEC to the Sponsor. 
Study progress is to be reported to the IRB/IEC annually (or as required) by the Investigator or 
sponsor, depending on local regulatory obligations. If the Investigator is required to report to the 
IRB/IEC, he/she will forward a copy to the Sponsor at the time of each periodic report. The 
Investigator(s) or the Sponsor will submit, depending on local regulations, periodic reports and 
inform the IRB/IEC (if regionally required, the heads of the medical institutions) of any 
reportable AEs per ICH guidelines and local IRB/IEC standards of practice. Upon completion of 
the study, the Investigator will provide the IRB/IEC with a brief report of the outcome of the 
study, if required. 
8.2 Ethical Conduct of the Study 
This study will be conducted in accordance with the standard operating practices of the Sponsor 
(or designee), which are designed to ensure adherence to GCP guidelines as required by the 
following: 
x In accordance to the principle of World Medical Association Declaration of Helsinki, 
2008 
x ICH E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, 
International Conference on Harmonisation of Pharmaceuticals for Human Use 


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x US 21CFR, including parts 50 and 56 concerning Informed Patient Consent and IRB 
regulations, and applicable sections of US 21CFR Part 312 
x European Clinical Trial Directive 2005/28/EC, for studies conducted within any EU 
country. All SUSARs will be reported, as required, to the Competent Authorities of all 
involved EU member states 
x In accordance with Article 14, Paragraph 3, and Article 80-2 of the Pharmaceutical 
Affairs Law (Law No. 145, 1960) for studies conducted in Japan, in addition to Japan’s 
GCP 
x And other applicable regulatory authorities 
8.2.1 Subject Information and Consent 
As part of administering the ICF, the Investigator must explain to each subject (or 
guardian/legally authorized representative) the nature of the study, its purpose, the procedures 
involved, the expected duration, the potential risks and benefits involved, and any potential 
discomfort. Each subject must be informed that participation in the study is voluntary and that 
he/she may withdraw from the study at any time and that withdrawal of consent will not affect 
his/her subsequent medical treatment or relationship with the treating physician. 
This informed consent should be given by means of a standard written statement, written in 
nontechnical language. The subject should understand the statement before signing and dating it 
and will be given a copy of the signed document. If a subject is unable to read or if a legally 
acceptable representative is unable to read, an impartial witness should be present during the 
entire informed consent discussion. After the written ICF and any other written information to be 
provided to subjects is read and explained to the subject or the subject’s legally acceptable 
representative, and after the subject or the subject’s legally acceptable representative has orally 
consented to the subject’s participation in the trial and, if capable of doing so, has signed and 
personally dated the ICF, the witness should sign and personally date the consent form. The 
subject will be asked to sign an informed consent at the Screening Visit before any study-specific 
procedures being performed. No subject can enter the study before his/her informed consent has 
been obtained. 
An unsigned copy of an IRB/IEC and sponsor-approved written informed consent must be 
prepared in accordance with ICH E 6, Section 4, and all applicable local regulations (eg, Code of 
Federal Regulations, Title 21, CFR Part 50) and provided to the Sponsor. Each subject must sign 
an approved informed consent before study participation. The form must be signed and dated by 
the appropriate parties. The original, signed ICF for each subject will be verified by the Sponsor 
and kept on file, according to local procedure, at the study center. 


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The subject or the subject’s legally authorized representative should be informed in a timely 
manner if new information becomes available that may be relevant to the subject’s willingness to 
continue participation in the trial. The communication of this information should be documented. 
8.3 Administrative Procedures 
8.3.1 Changes to the Protocol 
There are to be no changes to the protocol without written approval from the Sponsor. Protocols 
will be followed as written. 
Any change to the protocol requires a written protocol amendment or administrative change that 
must be approved by the Sponsor before implementation. Amendments affecting the safety of 
subjects, the scope of the investigation, or the scientific quality of the study require submission 
to health or regulatory authorities as well as additional approval by the applicable IRB/IEC of all 
investigational sites and, in some countries, by the regulatory authority. These requirements 
should in no way prevent any immediate action from being taken by the Investigator, or by the 
Sponsor, in the interest of preserving the safety of all subjects included in the study. If an 
immediate change to the protocol is felt by the Investigator to be necessary for safety reasons, 
the Sponsor’s appropriate study team member must be notified promptly and the IRB/IEC for the 
site must be informed immediately. Per 21 CFR 312.30, a protocol change intended to eliminate 
an immediate hazard may be implemented immediately, provided FDA is subsequently notified 
by protocol amendment. 
Changes affecting only administrative aspects of the study do not require formal protocol 
amendments or IRB/IEC approval, but the IRB/IEC (if regionally required, the heads of the 
medical institutions) must be kept informed of such changes. In these cases, the Sponsor will 
send a letter to the IRB/IEC (if regionally required, the heads of the medical institutions) 
detailing such changes. 
8.3.2 Adherence to the Protocol 
The Investigator will conduct the study in strict accordance with the protocol (refer to ICH E6, 
Section 4.5). 
8.3.3 Monitoring Procedures 
The Sponsor’s or CRO’s CRA will maintain contact with the Investigator and designated staff by 
telephone, and/or letter, and/or email between study visits. Monitoring visits to each 
investigational site will be conducted by the assigned CRA as described in the monitoring plan. 
The Investigator (if regionally required, the heads of the medical institutions) will allow the CRA 
to inspect the clinical, laboratory, and pharmacy facilities to assure compliance with GCPs and 


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local regulatory requirements. The CRFs and subject’s corresponding original medical records 
(source documents) are to be fully available for review by the Sponsor’s representatives at 
regular intervals. These reviews verify adherence to the study protocol and data accuracy in 
accordance with federal regulations (or local regulations). All records at the investigational site 
are subject to inspection by the FDA or local regulatory agency. 
In accordance with ICH E6, Section 6.10, source documents include but are not limited to the 
following: 
x Clinic, office, hospital charts 
x Copies or transcribed healthcare provider notes which have been certified for accuracy 
after production 
x Recorded data from automated instruments such as IVRS/IWRS, x-rays, and other 
imaging reports: eg, sonograms, CT scans, MRIs, nuclear medicine scans, ECGs, rhythm 
strips, electroencephalograms, polysomnographs, and pulmonary function tests 
(regardless of how these images are stored, including microfiche and photographic 
negatives) 
x Pain, quality of life, medical history questionnaires completed by subjects 
x Records of telephone contacts 
x Diaries or evaluation checklists 
x Drug distribution and accountability logs maintained in pharmacies or by research 
personnel 
x Laboratory results and other laboratory test outputs: eg, urine pregnancy test result 
documentation 
x Correspondence regarding a study subject’s treatment between physicians or memoranda 
sent to the IRB/IEC 
x CRF components: eg, questionnaires that are completed directly by subjects and serve as 
their own source 
8.3.4 Recording of Data 
A CRF is required for each subject and must be completed by qualified and authorized personnel. 
Only data required by the protocol for the purposes of the study should be reported on the CRF. 
All data on the CRF must reflect the corresponding source document. Any corrections to entries 
made on the CRF must be documented in a valid audit trail. 


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8.3.5 Identification of Source Data 
The following items in the CRF will be handled as source data: 
x Study drug compliance (eg, the reason for dose increase/reduction) 
x Discontinuation information  
x Sampling date and time for the drug concentration 
x Sampling date and time for the clinical laboratory test 
x Comments and other information on AEs (eg, severity, relationship to study drug, 
outcome) 
8.3.6 Retention of Records 
The circumstances of completion or termination of the study notwithstanding, the Investigator (if 
regionally required, the heads of the medical institutions) has the responsibility to retain all study 
documents, including but not limited to the protocol, copies of CRFs, the IB, regulatory agency 
registration documents (eg, FDA 1572 form), ICFs, and IRB/IEC correspondence. To enable 
evaluations and/or audits from regulatory authorities or Sponsor, the Investigator agrees to keep 
records, including the identity of all participating subjects (sufficient information to link records, 
eg, eCRFs and hospital records), all original signed ICFs, eCRFs, SAE forms, source documents, 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, telephone calls reports). The records must be 
retained by the Investigator according to ICH GCP, local regulations, or as specified in the 
Clinical Study Agreement, whichever is longer. It is requested that at the completion of the 
required retention period or, should the Investigator retire or relocate, the Investigator (or if 
regionally required, the heads of the medical institutions) prospectively contact the Sponsor, 
allowing the Sponsor the option of permanently retaining the study records. The Investigator 
must obtain the Sponsor’s written permission before disposing of any records, even if retention 
requirements have been met. 
8.3.7 Auditing Procedures and Inspection 
In addition to routine monitoring procedures, the Sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the Sponsor’s 
standard operating procedures to evaluate compliance with the principles of ICH GCP and all 
applicable local regulations. A government regulatory authority may also wish to conduct an 
inspection (during the study or after its completion). If an inspection is requested by a regulatory 
authority, the Investigator must inform the Sponsor immediately that this request has been made. 


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8.3.8 Handling of Study Drug 
All study drug will be supplied to the PI (or a designated pharmacist) by the Sponsor. Drug 
supplies must be kept in an appropriate secure area (eg, locked cabinet) and stored according to 
the conditions specified on the drug label. The Investigator (or a designated pharmacist) must 
maintain an accurate record of the shipment and dispensing of the study drug in a drug 
accountability ledger, a copy of which must be given to the Sponsor at the end of the study. An 
accurate record of the date and amount of study drug dispensed to each subject must be available 
for inspection at any time. Once study drug has been received by the investigational site, the 
assigned CRA will review these documents along with all other study conduct documents at 
appropriate intervals during investigational site visits. 
All drug supplies are to be used only for this protocol and not for any other purpose. The 
Investigator (or a designated pharmacist) must not destroy any drug labels or any partly used or 
unused drug supply before approval to do so by the Sponsor. At the conclusion of the study and 
as appropriate during the course of the study, the Investigator (or a designated pharmacist) will 
either return all used and unused drug containers, drug labels, and a copy of the completed drug 
disposition form to the Sponsor’s designated contractor or, where approval is given by the 
Sponsor, will destroy supplies and containers at the investigational site. 
8.3.9 Publication of Results 
All manuscripts, abstracts, or other modes of presentation arising from the results of the study 
must be reviewed and approved in writing by the Sponsor in advance of submission. The review 
is aimed at protecting the Sponsor’s proprietary information existing either at the date of the 
commencement of the study or generated during the study. 
The detailed obligations regarding the publication of any data, material results or other 
information, generated or created in relation to the study shall be set out in the agreement 
between each investigator (or if regionally required, the heads of the medical institutions) and the 
CRO or the Sponsor, as appropriate. 
8.3.10 Disclosure and Confidentiality 
The contents of this protocol and any amendments and results obtained during the course of this 
study will be kept confidential by the Investigator, the Investigator’s staff, and the IRB/IEC and 
will not be disclosed in whole or in part to others or used for any purpose other than reviewing or 
performing the study without the written consent of the Sponsor. No data collected as part of this 
study will be utilized in any written work, including publications, without the written consent of 
the Sponsor. These obligations of confidentiality and non-use shall in no way diminish such 


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obligations as set forth in the Confidentiality Agreement between the Sponsor and the 
Investigator. 
All persons assisting in the performance of this study must be bound by the obligations of 
confidentiality and non-use set forth in the Confidentiality Agreement between the Investigator 
and the Sponsor (provided by the Sponsor). 
8.3.11 Discontinuation of Study 
The Sponsor reserves the right to discontinue the study for medical reasons or for any other 
reason at any time. If the study is prematurely terminated or suspended, the Sponsor will 
promptly inform the investigators/institutions and the regulatory authority(ies) of the termination 
or suspension and the reason(s) for the termination or suspension. The IRB/IEC should also be 
informed promptly and provided with the reason(s) for the termination or suspension by the 
Sponsor or by the Investigator/institution, as specified by the applicable regulatory 
requirement(s). 
The Investigator reserves the right to discontinue the study should his/her judgment so dictate. If 
the Investigator terminates or suspends a trial without prior agreement of the Sponsor, the 
Investigator should inform the institution where applicable, and the Investigator/institution 
should promptly inform the Sponsor and the IRB/IEC, and should provide the Sponsor and the 
IRB/IEC with a detailed written explanation of the termination or suspension. Study records 
must be retained as noted above. 
8.3.12 Subject Insurance and Indemnity 
The Sponsor will provide insurance in accordance with local guidelines and requirements as a 
minimum for the subjects participating in this study. 


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9 REFERENCE LIST 
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Inflammation-induced repression of chromatin bound by the transcription factor Foxp3 in 
regulatory T cells. Nat Immunol. 2014 Jun;15(6):580-7. 
Baleydier F, Decouvelaere AV, Bergeron J, et al. T cell receptor genotyping and HOXA/TLX1 
expression define three T lymphoblastic lymphoma subsets which might affect clinical outcome. 
Clin Cancer Res. 2008;14(3):692-700. 
Beccaria K, Sainte-Rose C, Zerah M, Puget S. Paediatric Chordomas. Orphanet J Rare Dis. 
2015;10:116. 
 
Béguelin W, Popovic R, Teater M, Jiang Y, Bunting KL, Rosen M, et al. EZH2 is required for 
germinal center formation and somatic EZH2 mutations promote lymphoid transformation. 
Cancer Cell. 2013 May 13;23(5):677-92. 
Bodor C, Grossmann V, Popov N, et al. EZH2 mutations are frequent and represent an early 
event in follicular lymphoma. Blood. 2013;122(18):3165-3168. 
Brookmeyer R, Crowley JJ. A confidence interval for the median survival time. Biometrics. 
1982;38(1):29-41. 
Burkhardt B, Reiter A, Landmann E, et al. Poor outcome for children and adolescents with 
progressive disease or relapse of lymphoblastic lymphoma: a report from the berlin-frankfurt-
muenster group. J Clin Oncol. 2009;27(20):3363-3369. 
 
Campo E, Swerdlow SH, Harris NL, Pileri S, Stein H, Jaffe ES. The 2008 WHO classification of 
lymphoid neoplasms and beyond: evolving concepts and practical applications. Blood. 
2011;117(19):5019-5032. 
 
Cortelazzo S, Ferreri A, Hoelzer D, Ponzoni M. Lymphoblastic lymphoma. Crit Rev Oncol 
Hematol. 2017;113:304-317. 
 
Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 [published 28 May 2009 (v4.03: June 14, 2010)]. Available from: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_ 8.5x11.pdf. 
Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, et al. Revised 
response criteria for malignant lymphoma. J Clin Oncol. 2007 Feb 10;25(5):579-86. 
Cunningham D, Hawkes EA, Jack A, Qian W, Smith P, Mouncey P, Pocock C, Ardeshna KM, 
Radford JA, McMillan A, Davies J, Turner D, Kruger A, Johnson P, Gambell J, Linch D. 
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newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: a phase 3 comparison of dose 
intensification with 14-day versus 21-day cycles. Lancet. 2013 May 25;381(9880):1817-26.  
Delarue R, Tilly H, Mounier N, Petrella T, Salles G, Thieblemont C, Bologna S, Ghesquières H, 
Hacini M, Fruchart C, Ysebaert L, Fermé C, Casasnovas O, Van Hoof A, Thyss A, Delmer A, 
Fitoussi O, Molina TJ, Haioun C, Bosly A. Dose-dense rituximab-CHOP compared with 
standard rituximab-CHOP in elderly patients with diffuse large B-cell lymphoma (the LNH03-
6B study): a randomised phase 3 trial. Lancet Oncol. 2013 May;14(6):525-33. 
Dreyling M, Geisler C, Hermine O, Kluin-Nelemans HC, Le Gouill S, Rule S, et al. ESMO 
Guidelines Working Group. Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical 
Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014 Sep;25 
Suppl 3:iii83-92. 
DuPage M, Chopra G, Quiros J, Rosenthal WL, Morar MM, Holohan D, et al. The chromatin-
modifying enzyme Ezh2 is critical for the maintenance of regulatory T cell identity after 
activation. Immunity. 2015 Feb 17;42(2):227-38. 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 
2009 Jan;45(2):228-47. 
El Dareer SM, Struck RF, White VM, Mellett B, Hill DL. Distribution and metabolism of 
prednisone in mice, dogs, and monkeys. Cancer Treat Rep. 1977 61:1279-1289. 
European Agency for the Evaluation of Medicinal Products. Committee for Veterinary Medicinal 
Products. Bromide, sodium salt. Summary Report. March 1997. Available from: 
http://www.ema.europa.eu/docs/en_GB/document_library/Maximum_Residue_Limits_-
_Report/2009/11/WC500011113.pdf. Accessed October 9, 2012. 
Foon KA, Takeshita K, Zinzani PL. Novel therapies for aggressive B-cell lymphoma. 
Adv Hematol. 2012; (article 302570). 
Hans CP, Weisenburger DD, Greiner TC, Gascoyne RD, Delabie J, Ott G, et al. Confirmation of 
the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a 
tissue microarray. Blood. 2004;103(1):275-82. 
Knutson SK, Kawano S, Minoshima Y, Warholic NM, Huang KC, Xiao Y, et al. Selective 
inhibition of EZH2 by EPZ-6438 leads to potent antitumor activity in EZH2-mutant non-
Hodgkin lymphoma. Mol Cancer Ther. 2014 Apr;13(4):842-54. 
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Keilhack H. Synergistic Anti-Tumor Activity of EZH2 Inhibitors and Glucocorticoid Receptor 
Agonists in Models of Germinal Center Non-Hodgkin Lymphomas. PLoS One. 2014 Dec 
10;9(12):e111840. 
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prednisolone tablet formulations in healthy volunteers. Arzneimittelforschung. 2001 Nov 
51(11):911-5. 
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2013;26(1):33-41. 
 
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lymphoblastic lymphoma of children and adolescents: a report from CCG-E08. Cancer Genet 
Cytogenet. 2007;172(1):1-11. 
 
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http://www.medicines.org.uk/emc/medicine/15432/SPC/mimpara/. Updated February 22, 2012. 
Accessed August 30, 2012. 
Milne TA, Dou Y, Martin ME, Brock HW, Roeder RG, Hess JL. MLL associates specifically 
with a subset of transcriptionally active target genes. Proc Natl Acad Sci U S A. 
2005 Oct 11;102(41):14765-70. 
Morin RD, Mendez-Lago M, Mungall AJ, Goya R, Mungall KL, Corbett RD, et al. Frequent 
mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature. 
2011;476(7360):298-03. 
National Cancer Institute. Surveillance, Epidemiology and End Results (SEER) Program 
(www.seer.cancer.gov) Research Data (1972-2011), Non-Hodgkins Lymphoma; 2014. Accessed 
19 Aug 2014.  
Patel B, Kang Y, Cui K, et al. Aberrant TAL1 activation is mediated by an interchromosomal 
interaction in human T-cell acute lymphoblastic leukemia. Leukemia. 2014;28(2):349-361. 
 
Portell CA, Sweetenham JW. Adult lymphoblastic lymphoma. Cancer J. 2012;18(5):432-438 
 
Ribrag V, Soria J, Reyderman L, et al. Phase 1 Study of E7438 (EPZ-6438), an Enhancer of 
Zeste-Homolog 2 (EZH2) Inhibitor: Dose Determination and Preliminary Activity in Non-
Hodgkin Lymphoma. Hematological Oncology, Volume 33, Issue Supplement S1, page 179, 
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Rosenwald A, Wright G, Leroy K, Yu X, Gaulard P, Gascoyne RD, et al. Molecular diagnosis of 
primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large 
B cell lymphoma related to Hodgkin lymphoma. J Exp Med. 2003;198(6):851-62. 
Sant M, Allemani C, Tereanu C, De Angelis R, Capocaccia R, Visser O, et al. Incidence of 
hematologic malignancies in Europe by morphologic subtype: results of the HAEMACARE 
project. Blood 2010;116(19):3724-34. 
Scott DW, Gascoyne RD. The tumour microenvironment in B cell lymphomas. Nat Rev Cancer. 
2014 Aug;14(8):517-34. 
Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoietic 
and Lymphoid Tissues. Lyon, France: IARC Press; 2008. 2. Harris NL 
 
Tilley H, Vitolo U, Walewski J, da Silva MG, Shpilberg O, Andre M, et al. Diffuse large B-cell 
lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-
up. Ann Oncol. 2012;23(suppl 7):vii78-82. 
Tumes DJ, Onodera A, Suzuki A, Shinoda K, Endo Y, Iwamura C, et al. The polycomb protein 
Ezh2 regulates differentiation and plasticity of CD4(+) T helper type 1 and type 2 cells. 
Immunity. 2013 Nov 14;39(5):819-32. 
Voigt P, Tee WW, Reinberg D. A double take on bivalent promoters. Genes Dev. 
2013 Jun 15;27(12):1318-38. 
Wrangle J, Wang W, Koch A, Easwaran H, Mohammad HP, Vendetti F, et al. Alterations of 
immune response of non-small cell lung cancer with azacytidine. Oncotarget. 
2013 Nov;4(11):2067-79. 
Yang XP, Jiang K, Hirahara K, Vahedi G, Afzali B, Sciume G, et al. EZH2 is crucial for both 
differentiation of regulatory T cells and T effector cell expansion. Sci Rep. 2015 Jun 19;5:10643. 
 


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APPENDIX 1 
EASTERN COOPERATIVE ONCOLOGY GROUP 
PERFORMANCE STATUS 
 
Scale 
ECOG Status 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature (eg, light house work, office work). 
2 
Ambulatory and capable of all self-care, but unable to carry out any work 
activities. Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair. 
5 
Dead. 
ECOG = Eastern Cooperative Oncology Group. 
Source: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response criteria of the 
Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-55. 


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APPENDIX 2 
COCKCROFT AND GAULT FORMULA 
 
Male 
(140-age) u weight (kg) 
= XX mL/min  
Serum creatinine (mg/dL) u 72 
 
 
 
 
Female 
(140-age) u weight (kg) 
= XX mL/min u 0.85 
Serum creatinine (mg/dL) u 72 
 
Source: Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 
1976;16(1):31-41. 
 
 
For serum creatinine measured in ȝmol/L: 
Male 
(140-age) u weight (kg) u 1.23 
 
Creatinine (μmol/L) 
 
 
 
Female 
(140-age) u weight (kg) u 1.23 u 0.85 
 
Creatinine (μmol/L) 
 


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APPENDIX 3 
NEW YORK HEART ASSOCIATION CARDIAC 
DISEASE CLASSIFICATION 
The New York Heart Association (NYHA) Cardiac Disease Classification provides a functional 
and therapeutic classification for the prescription of physical activity for cardiac subjects. Based 
on NYHA definitions, subjects are to be classified as follows: 
Class 
NYHA Status 
Class I: 
Subjects with no limitation of activities; they suffer no symptoms from 
ordinary activities. 
Class II: 
Subjects with slight, mild limitation of activity; they are comfortable with 
rest or with mild exertion. 
Class III: 
Subjects with marked limitation of activity; they are comfortable only at 
rest. 
Class IV: 
Subjects who should be at complete rest, confined to bed or chair; any 
physical activity brings on discomfort and symptoms occur at rest. 
NYHA = New York Heart Association. 
Source: The Criteria Committee of the New York Heart Association. Nomenclature and criteria for diagnosis of diseases of 
the heart and great vessels. 9th ed. NY: Little Brown;1994. p. 253-6. 


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APPENDIX 4 
RESPONSE EVALUATION CRITERIA IN SOLID 
TUMORS 
Tumor response assessments in this clinical trial will utilize Response Evaluation Criteria in 
Solid Tumors (RECIST 1.1) based on the following 2009 article: Eisenhauer EA, Therasse P, 
Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-47. 
The modifications to RECIST 1.1 to be implemented in this trial are: 1) chest x-rays may not be 
used to follow disease; only CT scans may be used to follow chest disease, and 2) the minimum 
duration of stable disease (or non-CR/non-PD for subjects with nontarget lesions only) is 
7 weeks following the date of first dose of study drug. 
The Eisenhauer article, published in the European Journal of Cancer, is available online at: 
http://linkinghub.elsevier.com/retrieve/pii/S0959804908008733. 


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APPENDIX 5 
COMMON TERMINOLOGY CRITERIA FOR ADVERSE 
EVENTS 
The National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE 
version 4.03 published 28 May 2009) provides descriptive terminology to be used for adverse 
event (AE) reporting in clinical trials. A brief definition is provided to clarify the meaning of 
each AE term. To increase the accuracy of AE reporting, all adverse event terms in CTCAE 4.03 
have been correlated with single-concept Medical Dictionary for Regulatory Activities 
(MedDRA) terms. 
For details regarding CTCAE v4.03, refer to Cancer Therapy Evaluation Program, Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03 [published 28 May 2009; 
v4.03: 14 June 2010], available from: http://ctep.cancer.gov/protocolDevelopment/electronic_ 
applications /docs/ctcaev4.pdf. 
For details regarding MedDRA, refer to the MedDRA website at: http://www.meddramsso.com. 


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APPENDIX 6 
STANDARD HIGH-FAT BREAKFAST 
Substitutions in this test meal can be made as long as the meal provides a similar amount of 
calories from protein, carbohydrate and fat, and has comparable meal volume and viscosity.  
Item 
Amount 
Calories 
Protein (g) 
Fat (g) 
Carbohydrate (g) 
Eggs (fried) 
2 
191 
14 
15 
- 
Bacon (strip) 
2 
96 
3.6 
8.8 
0.4 
Toast (slice) 
2 
136 
4 
- 
30 
Butter (pat) 
2 
90 
- 
10 
- 
Hash 
browned 
potatoes 
4 oz (100 g) 
156 
2 
10 
15 
Whole milk 
8 oz (200 
mL) 
170 
8 
10 
12 
Total  
841 
31.6 
53.8 
57.4 
 
As recommended by FDA Guidance: Guidance for industry. Food-effect in bioavailability and 
fed bioequivalence studies, p. 1-9. U.S. Department of Health and Human Services, Food and 
Drug Administration, Center for Drug Evaluation and Research, Rockville, MD, USA, 2002. 


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APPENDIX 7 
PHARMACOGENOMICS/PHARMACODYNAMICS 
Subjects enrolled in this clinical study will have samples collected for pharmacogenomic and 
biomarker analysis. The aim of the analysis is to identify genetic factors that may influence a 
subject’s exposure to the study drug, as well as genetic factors that may have an effect on clinical 
response or potential adverse events related to study drug, and to explore the role of genetic 
variability in response. Samples may be analyzed to determine a subject’s genotypes or sequence 
for a number of genes or non-coding regulatory regions. The research may include the 
investigation of polymorphisms in genes that are likely to influence the study drug 
pharmacokinetics or therapeutic response. 
Collection of the samples for pharmacogenomic analysis will be bound by the sample principles 
and processes outlined in the main study protocol. Sample collection for pharmacogenomic and 
biomarker analysis is required as per the study protocol unless the collection and use of the 
samples is prohibited by specific country laws. If regionally required, subjects’ consent form for 
collection of samples in which DNA will be analyzed will be prepared separately from the 
informed consent form for study participation. In these regions, subjects who do not consent to 
DNA sample collection can be enrolled without collection of these samples. 
SAMPLE COLLECTION AND HANDLING 
The samples will be collected according to the study flow chart and laboratory manual. 
SECURITY OF THE SAMPLES, USE OF THE SAMPLES, RETENTION OF THE SAMPLES 
Sample processing, including DNA extraction and genotyping, sequencing or other analysis will 
be performed by a laboratory under the direction of the Sponsor. Processing, analysis, and 
storage will be performed at a secure laboratory facility to protect the validity of the data and 
maintain subject privacy. 
Samples will only be used for the purposes described in this protocol by the Sponsor. 
Laboratories contracted to perform the analysis on behalf of the Sponsor will not retain rights to 
the samples beyond those necessary to perform the specified analysis and will not transfer or sell 
those samples. The Sponsor will not sell the samples to a third party. 
Samples will be stored for up to 15 years after the completion of the study (defined as 
submission of the clinical study report to the appropriate regulatory agencies). At the end of the 
storage period, samples will be destroyed. Samples may be stored longer if a Health Authority 
(or medicinal product approval agency) has active questions about the study. In this special 
circumstance, the samples will be stored until the questions have been adequately addressed. 
It is possible that future research and technological advances may identify genomic variants of 
interest, or allow alternative types of genomic analysis not foreseen at this time. Because it is not 


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possible to prospectively define every avenue of future testing, all samples collected will be 
single- or double-coded (according to the ICH15 guidelines) in order to maintain subject privacy. 
RIGHT TO WITHDRAW 
If, during the time the samples are stored, a participant would like to withdraw his/her consent 
for participation in this research, Eisai will destroy the samples, if they can still be identified (not 
anonymized). Once samples have been anonymized, it will not be possible to identify which 
samples have come from a particular individual. Therefore, it will not be possible to destroy 
subject samples after anonymization. Information from any assays that have already been 
completed at the time of withdrawal of consent will continue to be used as necessary to protect 
the integrity of the research project. 
SUBJECT PRIVACY AND RETURN OF DATA 
No subject-identifying information (eg, initials, date of birth, government identifying number) 
will be associated with the sample. Samples that are processed for analysis (DNA extracted) may 
be double-coded. Double-coding involves removing the initial code and replacing with another 
code such that the subject can be re-identified by use of 2 code keys. The code keys are usually 
held by different parties. The key linking the sample ID to the subject number will be maintained 
separately from the sample. At this point, the samples will be double-coded (the first code being 
the subject number) as long as the initial tube does not carry any personal identifiers or the 
random code assigned by the central laboratory or biorepository. Laboratory personnel 
performing genetic analysis will not have access to the “key.” Clinical data collected as part of 
the clinical trial will be cleaned of subject identifying information and linked by use of the 
sample ID “key.” 
Sample anonymization may occur by destruction of the “key.” Once the “key” is destroyed, it 
will not be possible to trace the pharmacogenomics assay results back to an individual. The 
Sponsor will take steps to ensure that data are protected accordingly and confidentiality is 
maintained as far as possible. Data from subjects enrolled in this study may be analyzed 
worldwide, regardless of location of collection. 
The Sponsor and its representatives and agents may share anonymized data with persons and 
organizations involved in the conduct or oversight of this research. These include: 
x Clinical research organizations retained by the Sponsor 
x Independent ethics committees or institutional review boards that have responsibility for 
this research study 
x National regulatory authorities or equivalent government agencies 


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At the end of the analysis, results may be presented in a final report that can include part or all of 
the anonymized data, in listing or summary format. Other publication (eg, in peer-reviewed 
scientific journals) or public presentation of the study results will only include summaries of the 
population in the study, and no identified individual results will be disclosed. 
Given the research nature of the planned analysis, it will not be possible to return individual data 
to subjects participating in the pharmacogenomics analysis. 

SAP_001.pdf: 
 
 
 
 
 
 
 
 
Epizyme, Inc 
 
 
STATISTICAL ANALYSIS PLAN 
 
An Open-Label, Multicenter, Phase 1/2 Study of Tazemetostat (EZH2 
Histone Methyl Transferase [HMT] Inhibitor) as a Single Agent in Subjects 
With Advanced Solid Tumors or With B Cell Lymphomas and 
Tazemetostat in Combination With Prednisolone in Subjects With Diffuse 
Large B Cell Lymphoma 
 
Protocol E7438-G000-101 
 
 
 
SAP Version: 
Date of Statistical Analysis Plan: 
 
 
Version 3.0 
20 April 2022 
 
 
 
.
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SIGNATURE PAGE 
Date 
  PROMETRIKA, LLC 
 
 
 
 
 
 
 
 
 
 
Date
 PROMETRIKA, LLC 
 
 
 
Date 
nc. 
 
 
 
 
Date 
 Epizyme Inc. 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
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Table of Contents 
1 
INTRODUCTION ................................................................................................ 9 
2 
STUDY SUMMARY............................................................................................ 9 
2.1 
STUDY OBJECTIVES .................................................................................. 9 
2.1.1 
Primary Objective ................................................................................... 9 
2.1.2 
Secondary Objectives............................................................................ 10 
2.1.3 
Exploratory Objectives ......................................................................... 10 
2.2 
STUDY DESIGN ......................................................................................... 10 
2.2.1 
Number of Patients ............................................................................... 12 
2.2.2 
Sample Size Determination................................................................... 12 
2.2.3 
Randomization and Blinding Procedures.............................................. 15 
2.2.4 
Data Monitoring Committee ................................................................. 15 
2.2.5 
Efficacy Assessments............................................................................ 15 
2.2.6 
Safety Assessments ............................................................................... 16 
2.2.7 
Other Assessments ................................................................................ 17 
3 
STATISTICAL METHODS ............................................................................... 18 
3.1 
General Methods .......................................................................................... 18 
3.1.1 
Computing Environment ....................................................................... 18 
3.1.2 
Reporting of Numerical Values ............................................................ 18 
3.1.3 
Study Day.............................................................................................. 19 
3.1.4 
Baseline Value and Change from Baseline ........................................... 19 
3.1.5 
Analysis Visits ...................................................................................... 19 
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3.1.6 
Handling of Missing/Incomplete Values .............................................. 19 
3.1.7 
Adjustments for Multiplicity................................................................. 19 
3.2 
Analysis Populations and Subgroups ........................................................... 20 
3.2.1 
Definition of Analysis Populations ....................................................... 20 
3.2.2 
Definition of Subgroups ........................................................................ 20 
3.3 
Efficacy Endpoints ....................................................................................... 21 
3.3.1 
Primary Efficacy Endpoint ................................................................... 21 
3.3.2 
Secondary Efficacy Endpoints .............................................................. 21 
3.3.3 
Exploratory Efficacy Endpoints ............................................................ 22 
3.4 
Safety Analyses ............................................................................................ 22 
3.5 
Subject Disposition and Evaluability ........................................................... 22 
3.5.1 
Subject Disposition ............................................................................... 22 
3.5.2 
Major Protocol Deviations .................................................................... 22 
3.6 
Demographics and Baseline Characteristics ................................................ 23 
3.6.1 
Demographics ....................................................................................... 23 
3.6.2 
Baseline Characteristics ........................................................................ 23 
3.7 
Medical and Surgical History ....................................................................... 24 
3.8 
Prior and Concomitant Medications ............................................................. 25 
3.8.1 
Previous Anticancer Therapies ............................................................. 25 
3.8.2 
Other Prior and Concomitant Medications ........................................... 25 
3.9 
Study Drug Exposure and Compliance ........................................................ 26 
3.9.1 
Exposure to Study Treatment................................................................ 26 
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3.9.2 
Study Drug Compliance ........................................................................ 27 
3.10 
Efficacy Analyses ..................................................................................... 27 
3.10.1 Primary Efficacy Endpoint ................................................................... 28 
3.10.2 Secondary Efficacy Endpoints .............................................................. 28 
3.10.3 Concordance ......................................................................................... 31 
3.10.4 Exploratory Efficacy Endpoints ............................................................ 31 
3.11 
Safety Analysis ......................................................................................... 32 
3.11.1 Adverse Events ..................................................................................... 32 
3.11.2 Clinical Laboratory Evaluation ............................................................. 34 
3.11.3 Vital Signs and Other Physical Findings .............................................. 36 
3.11.4 ECG....................................................................................................... 37 
3.11.5 MUGA Scans and Echocardiograms .................................................... 38 
3.11.6 Concurrent Nonpharmacological Procedures and Palliative 
Radiotherapy ....................................................................................................... 38 
3.12 
CHANGES TO ANALYSES FROM PROTOCOL ................................. 38 
4 
References ........................................................................................................... 39 
5 
Appendix ............................................................................................................. 39 
 
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LIST OF ABBREVIATIONS 
 
Abbreviation 
Full Term 
18FDG-PET 
18fluorodeoxyglucose-positron emission tomography 
AE 
Adverse Event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BID 
Twice daily 
COO  
Cell of origin 
CR  
Complete Response 
CRF 
Case Report Form 
CT  
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
DCR 
Disease control rate 
DLBCL 
Diffuse Large B-Cell Lymphoma 
DMC 
Data Monitoring Committee 
DOR 
Duration of response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EZH2 
Enhancer of zeste homolog 2 
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FL 
Follicular Lymphoma 
GCB  
Germinal-Center B-cell-like 
GELF 
Groupe d’Etude des Lymphomas Folliculaires 
HMT  
Histone Methyl Transferase 
ICH 
International Conference on Harmonisation 
IHC 
Immunohistochemistry  
IRC  
Independent Review Committee 
ITT 
Intent-to-Treat 
IWG  
International Work Group 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
MTD 
Maximum Tolerated Dose 
MUGA 
Multiple gated acquisition 
NHL 
Non-Hodgkin Lymphoma 
ORR  
Objective Response Rate 
PD  
Progressive disease 
PFS  
Progression-free survival 
PK 
Pharmacokinetic  
PT 
Preferred term 
QTc 
Corrected QT interval 
QTcB 
QT interval corrected for heart rate using Bazett’s 
formula 
QTcF 
QT interval corrected for heart rate using Fridericia’s 
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formula 
PFS 
Progression-free survival 
PK 
Pharmacokinetics 
POD24 
Progression or relapse within 24 months of diagnosis  
PR 
Partial Response 
RP2D  
Recommend Phase 2 Dose 
RR 
Respiratory rate 
SAE 
Serious adverse event 
SAP  
Statistical analysis plan 
SD 
Standard deviation 
SI  
Système International 
SOC 
System organ class 
 
 
 
 
 
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1 INTRODUCTION 
The clinical study, E7438-G000-101, is a Phase 1/2, open-label, multicenter study of 
tazemetostat. The Phase 1 portion is comprised of dose escalation and expansion parts 
to establish the maximum tolerated dose (MTD) and/or recommended phase 2 dose 
(RP2D) when tazemetostat is given twice daily (BID) orally on a continuous basis in 
subjects with histologically and/or cytologically confirmed advanced or metastatic 
solid tumors or B cell lymphomas that have progressed after treatment with approved 
therapies or for which there are no standard therapies available.  Additionally, in the 
Phase 1 portion of the study, which is completed, the effect of food on the 
bioavailability of tazemetostat was evaluated as well as the drug-drug interaction 
potential as evaluated by the effect of tazemetostat on the pharmacokinetics (PK) of 
midazolam, a cytochrome P450 (CYP) 3A4 substrate. Phase 2 enrolls subjects with 
Diffuse Large B-Cell Lymphoma (DLBCL) and Follicular Lymphoma (FL) for the 
determination of efficacy and safety of tazemetostat monotherapy and of tazemetostat 
in combination with prednisolone. 
This statistical analysis plan (SAP) describes the planned analyses to be included in 
the Clinical Study Report for the Phase 2 portion of Protocol E7438-G000-101. The 
efficacy analyses described in Version 2.0 of this SAP were performed for the FL 
cohorts of WT and MT only for analyses submitted in December 2019. This version 
of the SAP adds efficacy analyses for the DLBCL cohorts.  
This SAP is based on Amendment 13.0 of the protocol, dated 10 August 20121  Any 
changes made to the planned analyses after this document has been finalized will be 
noted in the final clinical study report.  This SAP was written in accordance with 
International Council on Harmonisation (ICH) Guideline E9.  
Analyses of the Phase 2 PK, pharmacodynamics, biomarker, and pharmacogenomics 
data will not be covered in this SAP. 
2 STUDY SUMMARY 
2.1 STUDY OBJECTIVES 
2.1.1 Primary Objective 
x For the Phase 2 portion of the study, the primary objective is to determine the 
objective response rate (ORR; complete response + partial response [CR + 
PR]) of tazemetostat in subjects with enhancer of zeste homolog 2 (EZH2) 
gene mutation positive or negative (wild-type) with histologically confirmed 
DLBCL or FL with relapsed or refractory disease and the ORR of 
tazemetostat in combination with prednisolone in subjects with EZH2 wild-
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type DLBCL. ORR will be assessed by the International Working Group-
Non-Hodgkin’s Lymphoma (IWG-NHL; Cheson 2007) criteria.  
2.1.2 Secondary Objectives 
For the Phase 2 portion of the study, the secondary objectives are as follows: 
x To assess the effect of tazemetostat monotherapy and tazemetostat in 
combination with prednisolone on progression-free survival (PFS) based on 
IWG-NHL (Cheson 2007) criteria 
x To assess the effect of tazemetostat monotherapy and tazemetostat in 
combination with prednisolone on duration of response (DOR) based on IWG-
NHL (Cheson 2007) criteria 
x To assess the safety and tolerability of tazemetostat monotherapy and 
tazemetostat in combination with prednisolone; 
x To assess the PK profile of tazemetostat monotherapy and tazemetostat in 
combination with prednisolone (covered in a separate SAP). 
2.1.3 Exploratory Objectives 
For the Phase 2 portion of the study, the exploratory objectives of the study are as 
follows: 
x To explore the effect of tazemetostat monotherapy and tazemetostat in 
combination with prednisolone on overall survival 
x To explore the PK and pharmacodynamic relationship of tazemetostat 
(covered in a separate SAP) 
x To identify and investigate biomarkers and their correlation with biological 
activity for tazemetostat (covered in a separate SAP) 
x To explore the effects of tazemetostat on histone H3K27 methylation, target 
gene expression, and phenotypic markers including those for differentiation, 
apoptosis, cell proliferation, and changes in the tumor microenvironment 
(covered in a separate SAP) 
x To explore the role of DNA sequence variability on absorption, metabolism, 
excretion and susceptibility to adverse events of tazemetostat (covered in a 
separate SAP)  
2.2 STUDY DESIGN 
The overall study design for both Phases 1 and 2 is displayed in Figure 1. 
Figure 1 
Schematic of the Study Design 
Phase 1 
 
 
Subjects with 
 
Food Effect Substudy 
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advanced solid 
tumors or B cell 
lymphomas 
(13 subjects enrolled) 
x Randomized to either fasted or fed EPZ-6438 treatment 
x 200 mg single dose on Day -8 and Day -1 
x EPZ-6438 400 mg BID beginning on Day 1 
Dose Escalation 
EPZ-6438 single agent 
 
DDI Substudy 
(13 subjects enrolled) 
x Midazolam single dose on Day -1 and 15 
x EPZ-6438 (fasted) MTD/RP2D BID beginning on Day 1 
 
 
Phase 2 
Subjects with B Cell lymphomas 
Cohorts 
x DLBCL EZH2 (GCB subtype) mutation positive (up to 60 subjects)  
x DLBCL EZH2 (GCB subtype) mutation negative (up to 60 subjects) 
x DLBCL EZH2 non-GCB subtype (up to 60 subjects) 
x FL (Grades 1 to 3) EZH2 mutation positive (up to 45 subjects) 
x FL (Grades 1 to 3) EZH2 mutation negative (up to 45 subjects) 
 
Phase 2 of the study is an open-label, multicenter study of tazemetostat that enrolls 
subjects with DLBCL (Cohorts 1-3 and 6) and FL (Cohorts 4 and 5) for the 
determination of efficacy and safety of tazemetostat monotherapy (Cohorts 1-5) and 
of tazemetostat in combination with prednisolone (Cohort 6) with placement 
determined by centrally confirmed histology, cell of origin, and EZH2 mutation status 
as shown below. 
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Table 1 
Phase 2 Cohorts 
Cohort 
Treatment 
Description  
Planned 
Enrollment 
1 
Tazemetostat Monotherapy 
DLBCL (GCB subtype) EZH2 mutation 
positive 
60 
2 
Tazemetostat Monotherapy 
DLBCL (GCB subtype) EZH2 wild-type 
60 
3 
Tazemetostat Monotherapy 
DLBCL non-GCB subtype 
60 
4 
Tazemetostat Monotherapy 
FL (Grades 1 to 3) EZH2 mutation 
positive 
45 
5 
Tazemetostat Monotherapy 
FL (Grades 1 to 3) EZH2 wild-type 
45 
6 
Tazemetostat/Prednisolone 
Combination 
DLBCL GCB or non-GCB subtype EZH2 
wild-type 
70 
DLBCL = diffuse large B cell lymphoma, EZH2 = enhancer of zeste- homolog 2, FL = follicular 
lymphoma, GCB = germinal-center B-cell-like 
2.2.1 Number of Patients 
Approximately 340 subjects were planned to be enrolled in the Phase 2 portion of the 
study with 60 subjects planned for each of the 3 DLBCL monotherapy cohorts, 45 for 
each of the 2 FL cohorts, and 70 for DLBCL combination therapy cohort. 
2.2.2 Sample Size Determination 
The original study design planned enrollment of up to 30 subjects enrolled in each 
monotherapy Cohort for Phase 2. The initial assessment of efficacy was to be 
conducted within each cohort when 10 subjects had been enrolled (stage 1). For each 
DLBCL cohort, if zero responders (with CR or PR) out of the initial 10 subjects was 
observed, further enrollment in the cohort was to be terminated for futility. This rule 
was based on the underlying assumption that the response rate is 30% and there is a 
2.8% probability of observing no responders among 10 subjects. For each FL cohort, 
if 1 or zero responders (CR or PR) out of the initial 10 subjects was observed, further 
enrollment in the cohort was to be terminated for futility. This rule was based on the 
underlying assumption that the response rate is 40% and there is a 4.6% probability of 
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REVHUYLQJUHVSRQGHUDPRQJVXEMHFWV6XEVHTXHQWWRWKHIXWLOLW\DQDO\VLVLQWKH
DLBCL cohorts, the Data Monitoring Committee (DMC) supported a study design 
change to a modified 2-stage Green-Dahlberg design [Green, 1992] for each cohort. 
Up to 70 subjects with DLBCL (GCB or non-GCB, EZH2 wild-type) was to be 
enrolled in an additional combination therapy cohort (tazemetostat and prednisolone). 
A 2-stage Green-Dahlberg design was used to terminate enrollment for futility. 
For the purpose of calculating an expanded cohort size, a modified 2-stage Green-
Dahlberg design was used where the stage 1 futility sample size was set to the 
original protocol design sample size of 10 subjects per cohort (for Cohorts 1-5) and 
the stage 1 rejection criteria was set to the original protocol defined rejection criteria 
(0 for the DLBCL cohorts and 1 for the FL cohorts). Final sample sizes are displayed 
in Table 2. 
For the DLBCL Monotherapy Cohorts (futility analysis completed): 
x The probability of early stopping under the null hypothesis is 0.197. 
x The probability of stopping under the alternative hypothesis is 0.028. 
For the FL Monotherapy Cohorts (futility analysis completed): 
x The probability of early stopping under the null hypothesis is 0.376.
x The probability of stopping under the alternative hypothesis is 0.046. 
A 2-stage Green-Dahlberg design was used to assess futility in the DLBCL 
combination therapy cohort. The stage 1 rejection criterion is 6 or fewer responders 
(CR + PR). 
x The probability of early stopping under the null hypothesis is 0.433. 
x The probability of stopping under the alternative hypothesis is 0.017. 
 
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Table 2 
2-Stage Green Dahlberg Design 
 
 
Monotherapy 
Combination therapy 
 
DLBCL GCB 
EZH2 Mutant 
DLBCL GCB 
EZH2 Wild-Type 
DLBCL 
non-GCB 
FL EZH2 
Mutant 
FL EZH2 
Wild-Type 
DLBCL EZH2 Wild-
Type 
Ho: CR + PR 
 
 
 
 
 
 
Ha: CR + PR 
 
 
 
 
 
 
Stage 1 
n 
10 
10 
10 
10 
10 
35a 
ORR events for declaring rejection 
of treatment 
0 
0 
0 
1 
1 
6 
Stage 2 
Total n 
60 
60 
60 
45 
45 
70 
ORR events for declaring rejection 
of treatment at end of Stage 2 
14 
14 
14 
13 
13 
19 
CR = complete response, DLBCL = diffuse large B cell lymphoma, EZH2 = enhancer of zeste homolog 2, FL = follicular lymphoma, GCB = germinal-center B-cell-like, Ha = Alternative Hypothesis, 
Ho = Null Hypothesis, n = sample size, PR = partial response 
Note: Approximate alpha=0.025 and power =0.80 
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2.2.3 Randomization and Blinding Procedures 
The Phase 2 portion of the study was not randomized and includes no blinding. 
2.2.4 Data Monitoring Committee 
An independent Phase 2 DMC performed futility analysis during three DMC 
meetings. The stopping boundaries detailed in Table 2 were utilized by the DMC to 
assess the futility of the study. Details governing the independent DMC review are 
covered in a separate Charter and DMC Reporting Plan. 
2.2.5 Efficacy Assessments 
Tumor assessments were performed based upon IWG-NHL (Cheson, 2007) criteria at 
each assessment time point and entered onto the appropriate CRF page. Investigator 
determined response assessments at each assessment time point were also entered 
onto the appropriate CRF page. Scans were performed according to guidelines 
provided by the imaging core laboratory designated for this study. For the FL cohorts 
only, all tumor assessment scans were sent, as soon as they had been performed, to 
the imaging core laboratory for quality assessment and an Independent Review 
Committee (IRC) provided an independent response assessment.  
During Screening:  
Computed tomography (CT) scans of the chest, and CT or magnetic resonance 
imaging (MRI) scans of the brain, abdomen, pelvis, and other known sites of disease 
(as well as photographs of skin lesions that were to be followed as target and 
nontarget lesions), were performed at Screening. Standard of care scans performed 
within 28 days before Cycle 1 Day 1 using the protocol-specified parameters could 
have been used as screening assessments. An 18fluorodeoxyglucose-positron emission 
tomography (18FDG-PET) scan was performed. A bone marrow biopsy (including 
IHC) was to be performed for all subjects with FL and if clinically indicated in 
subjects with DLBCL, if they were not performed within 42 days of Cycle 1 Day 1.  
During the Treatment Phase: 
 
CT scans of the chest, and CT or MRI of the brain (if clinically indicated), abdomen, 
pelvis, and other known sites of disease were to be performed every 8 weeks (starting 
from Cycle 1 Day 1 of continuous tazemetostat dosing), or sooner if clinically 
indicated. If local regulatory authorities mandate less frequent imaging, maximum 
frequency would be every 12 weeks. Tumor assessments was to be carried out every 
8 weeks (or sooner, if clinically indicated) during treatment cycles in the Treatment 
Phase. For subjects who remain on study drug for 24 weeks or more, radiologic 
disease assessments were to be performed every 12 weeks. At the first indication of 
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possible PR and CR, a whole body 18FDG-PET scan was to be performed. At the first 
indication of CR, a repeat bone marrow biopsy was to be performed if lymphoma 
involvement in the bone marrow was reported at Screening. Repeat bone marrow 
biopsies were to be performed if clinically indicated (if progressive disease or relapse 
is suspected). 
After the treatment phase, subjects were to be followed for overall survival every 12 
weeks unless they withdraw consent.  
2.2.6 Safety Assessments 
Safety assessments consisted of monitoring and recording all AEs, regular laboratory 
evaluation for hematology, blood chemistry, and urine values; and periodic 
measurement of vital signs, echocardiograms/ multiple gated acquisition (MUGA) 
scans, electrocardiograms (ECGs), and physical examinations. 
For details, refer to the Schedule of Visits and Procedures in appendix 1. 
2.2.6.1 Laboratory Measurements 
For the Phase 2 part of the study, clinical laboratory tests were performed locally. 
Blood samples were to be collected for clinical laboratory tests at Screening, Day 1 
and 15 of every cycle, and the End of Treatment visit. All hematology, blood 
chemistry (including pregnancy test, where applicable) samples were to be obtained 
before study drug administration and results reviewed before 
administration/dispensing of study drug at the beginning of each cycle. If a laboratory 
abnormality met the criteria to qualify as an AE as described in the protocol and the 
CRF Completion guidelines, the AE corresponding to the laboratory abnormality was 
to be recorded on the AE CRF page. 
2.2.6.2 Vital Signs and Weight Measurements 
Vital signs and body weight (kg) were to be collected at Screening, Day 1 and 15 of 
Cycles 1 and 2, Day 1 of every cycle starting with Cycle 3, and the End of Treatment 
visit. Vital sign measurements included systolic and diastolic blood pressure (BP, 
mmHg), heart rate (HR, beats per minute), and body temperature (°C). Height was to 
be measured at the Screening visit only. Blood pressure and HR were to be collected 
after subjects have been sitting for 5 minutes. 
2.2.6.3 ECOG Performance Status 
An Eastern Cooperative Oncology Group (ECOG) performance status was to be done 
at Screening, Day 1 of every cycle, and the End of Treatment visit. 
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2.2.6.4 Physical Examinations 
Comprehensive physical examinations were to be performed at Screening and the 
End of Treatment visit, and symptomatic physical examinations were to be performed 
on Day 1 and 15 of Cycles 1 and 2 and Day 1 of every cycle starting with Cycle 3. 
Documentation of the physical examination was to be included in the source 
documentation at the investigational site. Only changes from screening physical 
examination findings that meet the definition of an AE were to be recorded on the AE 
CRF.  
2.2.6.5 Electrocardiograms 
Electrocardiograms were to be complete, standardized, 12-lead recordings that permit 
all 12 leads to be displayed on a single page with an accompanying lead II rhythm 
strip below the customary 3 × 4 lead format at Screening, Day 1 of every cycle, and 
the End of Treatment visit.  In addition to a rhythm strip, a minimum of 3 full 
complexes were to be recorded from each lead simultaneously. Subjects were to be in 
the recumbent position for a period of 5 minutes before the ECG.  
If an ECG abnormality met the criteria to qualify as an AE as described in the study 
protocol and the CRF Completion guidelines, the AE corresponding to the ECG 
abnormality was to be recorded on the AE CRF page. 
2.2.6.6 MUGA Scans and Echocardiograms 
MUGA scan or an echocardiogram were to be performed at baseline and as clinically 
indicated. 
2.2.7 Other Assessments 
2.2.7.1 Pregnancy Test 
A serum ȕ-hCG test and/or urine ȕ-hCG test was to be performed at Screening for all 
women of child bearing potential. A urine or serum pregnancy test was to be 
performed before the first tazemetostat dose and prior to dosing on Day 1 of each 
cycle.  
2.2.7.2 Tumor Biopsy at Disease Progression 
Tumor biopsy was requested, where medically feasible, at disease progression in 
subjects who achieved a PR or better with tazemetostat. 
2.2.7.3 Bone Marrow Biopsy with IHC 
A bone marrow biopsy (including IHC) was to be performed for all subjects with FL 
and in subjects with DLBCL if clinically indicated or if subject has a history of bone 
marrow involvement, if these have not been performed within 42 days (an approval is 
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needed from the Sponsor’s medical monitor if the window has been beyond 42 days) 
of Cycle 1 Day 1. At the first notation of CR, a repeat bone marrow biopsy was to be 
performed if lymphoma involvement in the bone marrow was reported at Screening.  
2.2.7.4 Peripheral Blood Smear/ Bone Marrow Biopsy 
If peripheral blood smear morphology assessment was confirmed to be abnormal, the 
subject was required to undergo bone marrow aspirate/biopsy for cytogenetic/genetic 
testing to closely monitor the cytogenetic/genetic abnormalities known to be 
associated with MDS (9del 5q, chr 7, abn,etc.) and MPN (e.g. JAK2 V617F, etc.). If 
results were abnormal, treatment with tazemetostat was to be paused and after 
discussion with the Investigator, the dose was to be modified or the drug 
discontinued.  
2.2.7.5 Optional Chest Ultrasound 
An optional chest ultrasound could have been performed at screening and every 8 
weeks at the Investigator’s discretion to monitor for early signs of T-cell 
lymphoblastic lymphoma/T-cell acute lymphoblastic leukemia (T-LBL/T-ALL). 
3 STATISTICAL METHODS  
3.1 General Methods 
3.1.1 Computing Environment 
All statistical analyses will be performed using SAS® Version 9.4 or higher. 
3.1.2 Reporting of Numerical Values 
All clinical study data will be presented in patient data listings. Descriptive statistics 
(n, mean, standard deviation (SD), median, minimum, and maximum) will be 
calculated for continuous variables.   
Frequencies and percentages will be presented by treatment group for categorical and 
ordinal variables.  If there are missing values, the number and percent missing will be 
presented.  
Time-to-event statistics will include the 25th percentile, median, and 75th percentile, 
provided they are estimable.  Two-sided 95% CIs, will be estimated using the 
Brookmeyer-Crowley method (Brookmeyer and Crowley, 1982) 
Means, medians, and confidence intervals will be reported to one decimal place more 
than the data reported on the CRF or by the laboratory/vendor. Standard deviation 
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will be reported to two decimal places more than the data reported. Minimum and 
maximum will be reported to the same number of decimal places as the data reported.  
P-values will be reported to 3 decimal places. 
Start of study treatment will use the date of first dose of tazemetostat for cohorts 1-5 
and the first dose of tazemetostat or prednisolone for cohort 6. 
3.1.3 Study Day 
Study Day will be calculated as follows: 
• 
AssessmHQWGDWHILUVWGRVHGDWH6WXG\'D\ GDWH– first dose date) + 1 
• 
Assessment date < first dose date: Study Day = (date – first dose date) 
Study Day will appear as missing in the listings if the assessment date is partial. 
3.1.4 Baseline Value and Change from Baseline 
Baseline is defined as the last non-missing (including unscheduled) assessment prior 
to the first dose of study drug.  Unless the collection time or label indicates otherwise, 
assessments performed on the same day as the first dose of study drug will be 
considered as performed prior to treatment.  AEs and medications with a start date on 
the date of first dose of study drug will be considered to have occurred after the start 
of treatment.  
Change from baseline will be calculated by subtracting the baseline value from the 
post-dose value for each subject (i.e., post dose – baseline).  Percent change from 
baseline will be calculated by dividing the change value by the baseline value and 
multiplying the result by 100% (i.e., [{post dose value – baseline} / baseline] x 100).  
3.1.5 Analysis Visits 
For by-visit summaries, nominal visits will be presented (i.e. visit windowing will not 
be applied). Unscheduled measurements will not be included in by-visit table 
summaries but will contribute to worst-case values table summaries.  Listings will 
include both scheduled and unscheduled data. 
3.1.6 Handling of Missing/Incomplete Values 
Unless otherwise explicitly specified, missing data will not be imputed; observed data 
will be used in the analyses. 
3.1.7 Adjustments for Multiplicity  
There will be no adjustments for multiplicity.  
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3.2 Analysis Populations and Subgroups 
3.2.1 Definition of Analysis Populations 
The Enrolled population will consist of all subjects who sign informed consent and 
were entered into the electronic case report form (eCRF) for the study and were not 
screen failed. The Enrolled population will be used for summaries of analysis 
populations, inclusion and exclusion protocol deviations.   
The Intent-to-Treat (ITT) population will include all subjects who receive at least one 
dose of study treatment.  The ITT population will be used for summarizing subject 
disposition, demographic and baseline characteristics and will be used for the efficacy 
analysis.  
The Safety population will include all subjects who received at least one dose of 
study drug and have at least 1 post-baseline safety evaluation. The Safety population 
will be used for all safety analyses. 
3.2.2 Definition of Subgroups 
Refractory definitions. 
Treatment refractory:  
x No objective response to prior treatment or PD within 6 months of last dose of 
prior therapy 
 
Rituximab refractory: 
• 
No objective response to either rituximab monotherapy or rituximab-
containing therapy (e.g., R-CHOP) 
              OR 
• 
Progressive disease (loss of CR/PR) within 6 months of completion of R-
containing therapy.  
• 
Patient received at least 4 doses of rituximab for monotherapy or 5 
cycles of R+chemo 
Double refractory: 
• 
No objective response to any rituximab-containing therapy (monotherapy or 
in combination with chemotherapy) 
              AND  
• 
Relapsed within 6 months or refractory to any alkylator-based chemotherapy 
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• 
These can be given at the same time. For example, a patient who was 
relapsed within 6 months or refractory to R-CHOP would be 
considered “double refractory”. 
 
Early Relapse patients: (POD24)  
• 
Defined as disease progression within 2 years of first-line treatment. 
- 
Defined from the start date of first line systemic therapy. 
 
Where indicated, presentations of efficacy analyses for FL cohorts will be repeated 
for subgroups defined by the following parameters:  
x Treatment refractory 
x Rituximab refractory 
x Double refractory 
x POD24 
x Age group (<65 or >= 65)  
x Prior radiation (Yes or No) 
x Tumor burden (bulky disease [i.e., tumor > 10 cm in longest diameter or more 
than 1/3 of chest (as checked by the Investigator on the eCRF)]) (Yes or No) 
x Sex (Male or Female) 
x Lines of prior therapy (<=2 or >2) 
x 7LPHIURPODVWSULRUDQWLFDQFHUWKHUDS\WRILUVWGRVHPRQWK or > 1 month) 
x Region: North America/Europe/Rest of the World 
x GELF (Yes or No) 
3.3 Efficacy Endpoints 
3.3.1 Primary Efficacy Endpoint 
x Objective response rate based on IWG-NHL 
3.3.2 Secondary Efficacy Endpoints 
x Duration of response based on IWG-NHL 
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x Progression-free survival based on IWG-NHL 
3.3.3 Exploratory Efficacy Endpoints 
x Overall survival 
x Disease control rate 
x Time to first response 
x Time to first subsequent therapy 
3.4 Safety Analyses 
x Adverse events 
x Laboratory test results 
x Vital signs 
x Physical exams 
x Electrocardiograms 
x MUGA scans and echocardiograms 
3.5 Subject Disposition and Evaluability 
3.5.1 Subject Disposition 
Subject disposition, including reasons for treatment withdrawal and status at last 
contact, will be summarized and listed based on the ITT population.  The number of 
subjects in each analysis population will be summarized based on the Enrolled 
population.  
3.5.2 Major Protocol Deviations 
Major protocol deviations will be listed for the ITT population.  Predefined categories 
of major protocol deviations will include: 
x Violation of inclusion/exclusion criteria 
x Prohibited medications, as defined in section 7.3.4.3 of the protocol, while on 
tazemetostat (inclusive of the first and last days of treatment) 
x Failure to follow the radiological imaging procedures and schedule identified 
for the study which results in more than 1 unevaluable response assessment. 
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Additional categories may be added during the course of the study but will be 
determined prior to the database lock. 
3.6 Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be presented for the ITT population 
by FL (WT, MT and overall), by DLBCL, and by combined DLBCL and FL.   
3.6.1 Demographics 
Descriptive statistics will be provided for age (years) at screening, along with 
percentages for <65 and >= 65 years.  Frequencies and percentages will be tabulated 
for sex, race, ethnicity and region (North America/Europe/Rest of the World).  
3.6.2 Baseline Characteristics 
The following baseline disease characteristics will be summarized: 
x ECOG status (0, 1, or 2) 
x Location of primary tumor at diagnosis 
x Sum of target lesion diameters at baseline 
x Presence of lymph node target lesions at baseline (Yes, No) 
x Presence of non-lymph node target lesions at baseline (Yes, No) 
x Presence of non-target lesions at baseline (Yes, No) 
x Bulky disease (yes or no) 
x Any prior combination therapy (yes or no)  
x Any prior monotherapy (yes or no) 
x Number of prior therapies (categorical by 1, 2, >=3 and descriptive statistics) 
x Refractory to rituximab chemotherapy regimen  
x Refractory to last therapy (i.e., no objective response or PD after response 
within 6 months of completion of last therapy) 
x Last therapy contains an alkylating agent and is refractory (i.e., no objective 
response or PD after response within 6 months of completion of therapy) 
x POD24 status (yes or no) 
x Double refractory status (yes or no) 
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x FL staging (stage I, II, III and IV) 
x Myelosuppression (yes or no) (anemia, neutropenia or thrombocytopenia of 
JUDGHEDVHGRQEDVHOLQHODERUDWRU\GDWD) 
x Prior radiation 
x Prior stem cell transplant, including type of transplant (a subject with both 
allogenic and autologous stem cell transplants will be categorized as 
allogenic) 
x Groupe d’Etude des Lymphomas Folliculaires (GELF) criteria (yes or no) 
GELF is defined as meeting at least one of the following criteria: 
o A target lesion > 7 cm in diameter 
o 3 nodal target lesions > 3 cm diameter each 
o B symptoms at baseline  
o Serum LDH greater than normal 
o Hbg = 10 gm/dl or less 
o Neutrophil count 1500 /mm3 or less 
o Platelets 100,000 /microliter or less 
 
For the calculation of progression date and last date of prior therapy for refractory 
definitions, partial progression dates and end of therapy dates will be imputed as July 
1 of the year when only a year is recorded and as the 15th of the month when only a 
month and year are recorded.  If this imputation yields a date of last progression after 
the informed consent date, then the partial date of last progression will be imputed as 
January 1 of the year when only a year is provided and the 1st of the month when 
only a month and year are provided.  Other combinations of missing date elements 
will be treated as missing values. 
3.7 Medical and Surgical History 
All relevant medical history conditions will be coded using the Medical Dictionary of 
Regulatory Activities (MedDRA, Version 18.1) and will be classified by MedDRA 
system organ class (SOC) and preferred term (PT).  Medical history conditions will 
be tabulated by SOC and PT. Surgical history will be summarized by the MedDRA 
high-level group term (HLGT) and PT.  Listings will include start date and stop date 
or notation of ongoing for conditions continuing into treatment.  
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3.8 Prior and Concomitant Medications 
Medications will be coded using World Health Organization (WHO) Drug Dictionary 
(version March 2015).  Medications will be summarized and listed by Anatomical 
Therapeutic Chemical (ATC) level 4 and PT for the ITT population.  
3.8.1 Previous Anticancer Therapies 
Previous anticancer therapy and radiotherapy will be summarized and listed for the 
ITT population. The summary for previous anticancer therapies will include: 
x Number of regimens (1, 2, 3, 4, or more than 4 prior regimens) 
x Therapy setting (Neoadjuvant, Adjuvant, Therapeutic for 
Advanced/Metastatic Disease, Consolidation, Maintenance, or Unknown); a 
subject may be counted in multiple categories 
x Incidence of prior anticancer therapies by WHO Drug ATC level 4 and PT 
The summary for the previous radiotherapy will include: 
x Number of prior courses (0, 1, or 2 or more courses) 
x Major sites of prior radiotherapy (subdivisions of those sites will be listed); A 
subject may be counted in multiple categories 
x Progression at the site of the most recent radiotherapy (Yes, No, Not 
Evaluated) 
The summary for prior hematopoietic stem cell transplantation will include: 
x Incidence of prior hematopoietic stem cell transplantation 
x Type of hematopoietic stem cell transplantation (autologous, allogenic) 
3.8.2 Other Prior and Concomitant Medications 
Medications will be summarized and listed for the ITT population. Summary tables 
will include incidence (number and percentage) of subjects receiving any medication 
and incidence of specific medications by WHO Drug ATC level 4 and PT. 
Prior and concomitant medications will be summarized and listed separately.  
Prohibited medications, as defined in Section 7.3.4.3 of the protocol, will be 
identified with a ‘*’ in the listing. 
Prior and concomitant medications will be defined as follows: 
x Prior medications will include medications which started and stopped prior to 
the first dose of study drug. 
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x Concomitant medications will include medications taken any time from the 
start of the first dose of study drug through 30 days following end of study 
drug administration or until the start of a subsequent anticancer therapy, 
whichever is earlier. Medications that started prior to the first dose of study 
drug but continued into treatment are considered both concomitant and prior. 
For partial start dates, assume the earliest possible date (i.e., missing day will be set to 
the first day of the month and missing month will be set to January).  For partial end 
dates, assume the latest possible date (i.e., missing day will be set to the last day of 
the month and missing month will be set to December).  A completely missing start 
date will be assumed to have started prior to the first dose, and a completely missing 
end date will be assumed to have ended after the first dose.  
3.9 Study Drug Exposure and Compliance  
Study drug exposure and compliance will be summarized and listed for the Safety 
population.  
3.9.1 Exposure to Study Treatment 
The following summaries of study drug exposure will be presented: 
x Duration of exposure (weeks) = [(last dose date of tazemetostat – first dose 
date of tazemetostat) + 1]/7. Except for the first and last dose dates, this 
calculation is not adjusted for periods where dosing is interrupted or dose is 
recorded as 0. 
x Total number of cycles of study drug categorized as follows: 
- 
Cycle 1 (Days 1-28; weeks 1-4) 
- 
Cycle 2 (Days 29-56; weeks 5-8) 
- 
Cycle 3 (Days 57-84; weeks 9-12) 
- 
Cycle 4 (Days 85-112; weeks 13-16) 
- 
Cycle 5 (Days 113-140; weeks 17-20) 
- 
Cycle 6 (Days 141-168; weeks 21-24) 
- 
Cycle 7 (Days 169-196; weeks 25-28) 
- 
Cycle 8 or more (Day 197 and beyond; week 29 and beyond) 
x Total amount of study drug taken (mg)  
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x Average dose intensity (mg BID/day) where the average dose intensity (mg 
BID/day) = total amount of study drug taken (mg) / [2 * duration of exposure 
(days)] 
x Numbers of subjects requiring dose reductions, treatment interruption or 
treatment discontinuation in response to AEs (based on action taken for 
reported AEs). 
Duration of exposure for prednisolone exposure (cohort 6) will be summarized 
similarly. 
3.9.2 Study Drug Compliance 
The following summaries of study drug compliance will be presented: 
x Percentage of study drug taken = 100% * Average dose intensity (mg 
BID/day) / 800 mg BID/day. 
x &DWHJRU\RISHUFHQWDJHRIVWXG\GUXJWDNHQXVLQJFDWHJRULHVWR
< 90%, 70% to < 80%, and < 70%). 
3.10   Efficacy Analyses 
All efficacy analyses will be summarized by cohort and overall for the ITT 
population.  The primary analysis of the primary and secondary endpoints will be 
performed using the IRC response assessments for the FL subjects. The investigator 
response assessments will be analyzed as supportive evidence for the FL subjects. For 
the DLBCL subjects, IRC assessments were not performed. The DLBCL results will 
be presented by cohort and overall in analyses based on the investigator response 
assessments, including best overall response, objective response rate, duration of 
response, progression-free survival, disease control rate, and time to first response. 
The analyses of the primary and secondary efficacy endpoints by IRC will be 
repeated for the FL subjects for the subgroups defined in Section 3.2.2. The subgroup 
analysis will also be performed for the exploratory endpoint of overall survival. 
Subgroups for the investigator assessments for FL subjects will only be displayed in 
forest plots.  
No statistical hypothesis testing for comparison between cohorts will be performed. 
The issue of statistical multiplicity will not apply to this study, therefore, all analyses 
will be conducted at the nominal 2-sided alpha 0.05 significance level. 
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3.10.1 Primary Efficacy Endpoint 
Objective response rate (ORR; complete response or partial response [CR or PR]) 
will be summarized and listed for subjects - in the ITT population.  Evaluation of 
response for the subjects will be based on IWG-NHL (Cheson, 2007) response 
criteria.  
ORR is defined as the percentage of subjects achieving a CR or PR out of the total 
number of subjects included in the analysis population.  The CR or PR must occur 
prior to PD and the start of any subsequent anticancer therapy. Subjects with not 
evaluable, unknown or missing best response will be handled as non-responders; i.e. 
they will be included in the denominator when calculating the ORR.  
The summaries of ORR will include number and percentage of subjects in each best 
overall response (BOR) category: Complete response (CR), Partial response (PR), 
Stable disease (SD), Progressive disease (PD), and Not Evaluable, Missing, or 
Unknown. 
ORR will also be presented with corresponding 2-sided Clopper–Pearson exact 95% 
confidence intervals (CIs) for each cohort and overall. 
Waterfall plots of the best percentage change from baseline in sum of perpendicular 
diameters for target lesions for each subject will be provided by cohort using 
investigator and IRC reviews.  Each plot will be color coded for best overall response.  
Swim lane plots of subject response over time on treatment will also be provided by 
cohort using investigator and IRC reviews. 
Forest plots will present the ORR and 95% CI by subgroups. 
3.10.2 Secondary Efficacy Endpoints 
3.10.2.1 Duration of Response 
For each subject with a response, duration of response (DOR) is defined as the time 
(in months) from the date of first response (CR or PR, whichever is first recorded) to 
objectively documented disease progression or death whichever comes first. For 
patients with a response and no subsequent objectively documented disease 
progression or death, censoring rules for DOR will be same as for those PFS as 
detailed in Table 3. The number (%) of subjects with events and censored, as well the 
reason for censoring will be provided.  DOR will be estimated using the Kaplan-
Meier method. Median DOR, first and third quartiles and the associated 2-sided 95% 
CIs will be estimated using the Brookmeyer-Crowley method for each cohort and 
overall.  Figures displaying Kaplan-Meier curves of DOR by cohort will be provided.  
Kaplan-Meier estimates and 95% CIs will be presented at 6, 12, and 18months. Forest 
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plots will present the median DOR and 95% CI by subgroups. In addition, the number 
and percentage of subjects with duration of response > 6, >12, and >18 months will 
be presented.  A listing of DOR will be provided. 
3.10.2.2 Progression-Free Survival 
PFS is defined as the time from the date of first dose of study drug to the date of first 
documentation of disease progression, or death, whichever occurs first and will be 
presented. Subjects that do not die or progress on study will be censored at the last 
adequate assessment. Subjects who do not die on study and who do not have a 
baseline tumor assessment or at least one post-baseline tumor assessment will be 
censored at the first treatment day. Subjects who begin a new cancer therapy before 
documented progression will be censored at the date of the last adequate tumor 
assessment prior to the new cancer therapy, and subjects who progress or die 
immediately after one missed tumor assessment will be censored at the last adequate 
assessment prior to the missed assessment (See Table 3 for full details on PFS 
censoring).  Then number (%) of subjects with events and censored, as well as the 
reason for censoring, will be provided. PFS will be estimated using the Kaplan-Meier 
method. Median PFS, first and third quartiles and the associated 2-sided 95% CIs will 
be estimated using the Brookmeyer-Crowley method (Brookmeyer, 1982) for each 
cohort and overall. Figures displaying Kaplan-Meier curves of PFS by cohort will be 
provided.  Kaplan-Meier estimates and 95% CIs will be presented at 6, 12, 18, and 24 
months. Forest plots will present the median PFS and 95% CI by subgroups.  A 
listing of PFS will also be provided. 
Table 3 
Assignments for Progression and Censoring Dates for DOR and 
PFS Analysis 
Situation 
Date of Event (PD/Death) 
or Censoring  
Outcome: Event 
(PD/Death) or 
Censored 
No (or inadequate) baseline tumor 
assessments and the subject has 
not died  
Date of Study Day 1 
Censored 
No post-baseline assessments and 
the subject has not died  
Date of Study Day 1 
Censored 
No post-baseline disease assessments 
and death occurred prior to the first 
planned assessment 
Date of death 
Event 
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Situation 
Date of Event (PD/Death) 
or Censoring  
Outcome: Event 
(PD/Death) or 
Censored 
Progression documented between 
scheduled visits 
Date of assessment of 
progression1 
Event 
No progression (or death) and no 
new anticancer treatment 
documented 
Date of last ‘adequate’ 
assessment of response2  
Censored 
New anticancer treatment started 
during study treatment and prior to 
documented disease progression or 
death).3 
Date of last ‘adequate’ 
assessment of response2 on 
or prior to starting anti-
cancer therapy 
Censored 
New anticancer treatment started 
after study treatment end and prior 
to documented disease progression 
or death).3 
Date of last ‘adequate’ 
assessment of response2 on 
or prior to starting anti-
cancer therapy 
Censored 
Death between two planned 
assessment visits 
Date of death 
Event 
Death or progression after two 
missed visits (with 2 week 
window) 
Date of last ‘adequate’ 
assessment of response2 
prior to missed assessments 
Censored 
Alive and without documented 
disease progression 
Date of last ‘adequate’ 
assessment of response2 
Censored 
No documented disease 
progression or death and rolled 
over into Study 501 
Date of last ‘adequate’ 
assessment of response2 
Censored 
1 The earliest of (i) Date of radiological assessment showing new lesion (if 
progression is based on new lesion); or (ii) Date of radiological assessment showing 
unequivocal progression in non-target lesions, or (iii) Date of last radiological 
assessment of measured lesions (if progression is based on increase in sum of 
measured lesions) 
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2 An adequate assessment is defined as a radiological assessment where CR, PR, or 
SD was determined. 
3 If PD and subsequent anti-cancer therapy occur on the same day assume the 
progression was documented first, e.g., outcome is progression and the date is the 
date of the assessment of progression). If anti-cancer therapy is started prior to any 
adequate assessments, censoring date should be the date of Study Day 1. 
3.10.3 Concordance 
Concordance of the investigator and IRC assessments for BOR andORRwill be 
summarized by FL cohort and for all FL subjects.  
3.10.4 Exploratory Efficacy Endpoints 
3.10.4.1 Overall Survival (OS) 
Overall survival is the duration (in months) measured from the date of first dose of 
study drug until the date of death from any cause. Subjects who do not die will be 
censored at the time of the last contact. The Kaplan-Meier estimate of the 25th 
percentile, median, and 75th percentile, of survival times will be presented with the 
corresponding 2-sided 95% CIs for each cohort and overall. 
Figures displaying Kaplan-Meier curves of overall survival by cohort and overall will 
be provided.   
The analyses for OS will be repeated for the subgroups defined in Section 3.2.2. 
Forest plots will present the median OS time and 95% CI by subgroups. 
3.10.4.2 Disease Control Rate (DCR) 
DCR at the specified time point (month 12, month 18, and month 24) is defined as 
the percentage of subjects who achieve either confirmed CR or PR of any duration 
or who have SD lasting at least the number of months indicated from the start of 
study drug, according to the IWG-NHL (Cheson, 2007). Subjects with a best 
response of unknown/non-evaluable response will be handled as not achieving 
disease control, i.e., they will be included in the denominator when calculating the 
percentage.  Subjects with a time point response of unknown/non-evaluable 
response on or before the specified time point will still be classified as having 
disease control as long as there is a response of CR, PR, or SD on or after the 
specified time point. Disease control rate will be analyzed and summarized in the 
same manner as ORR except that forest plots by subgroup will not be produced for 
DCR.   
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3.10.4.3 Time to First Response 
For each subject with a response, the time to first response (months) is defined as 
time from the date of the first dose of study drug until the date of first response (CR 
or PR, whichever is first recorded).  Descriptive statistics (n, mean, SD, median, 
minimum, and maximum) will be presented for time to first response. 
3.10.4.4 Time to First Subsequent Therapy (TFST) 
TFST is defined as the time from the date of first dose of study drug to the date 
of start of the first subsequent anticancer therapy and will be summarized only 
for patients who started subsequent anticancer.  Descriptive statistics (n, mean, SD, 
median, minimum, and maximum) will be presented for TFST. 
3.11 Safety Analysis 
Safety analyses will be performed on the Safety population by FL (WT, MT and 
overall), by DLBCL (tazemetostat monotherapy, tazemetostat combination therapy, 
overall) and by combined FL and DLBCL. 
3.11.1 Adverse Events 
The AE verbatim description (investigator terms from the CRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory 
Activities (MedDRA) version 18.1. Adverse events will be coded to the MedDRA 
lower level term closest to the verbatim term, the associated preferred term (PT) and 
primary system organ class (SOC). AEs will be graded by severity using the Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03. 
A treatment-emergent AE (TEAE) is defined as an AE that: 
x Emerges during treatment, having been absent at Baseline 
x Reemerges during treatment, having been present at Baseline but stopped 
before treatment, or 
x Worsens in severity during treatment relative to baseline, when the AE is 
continuous. 
If there are missing or partial AE start and/or end dates that prevent the AE as being 
classified as a TEAE, the following imputation rules will be applied: 
1. If partial start date imputed to earliest possible date (i.e., missing day set to the 
first day of the month and missing month set to January) is on or after first 
dose date, then classify as a TEAE. 
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2. If partial start date imputed to latest possible date (i.e., missing day set to the 
last day of the month and missing month set to December) is before first dose 
date, then classify as not a TEAE. 
3. If partial stop date imputed to latest possible date (i.e., missing day set to the 
last day of the month and missing month set to December) is before first dose 
date, then classify as not a TEAE. 
4. Otherwise, assume the event was a TEAE. 
Only those AEs that are treatment-emergent and had a start date within the earlier of 
30 days following study drug discontinuation or initiation of subsequent anticancer 
therapy will be included in summary tables. All AEs, treatment emergent or 
otherwise, will be presented in subject data listings. 
Each summary table will include the incidence (number and percentage) of subjects 
reporting any TEAE, as well as, by SOC and PT.  A subject will be counted once 
within an SOC, even if the subject experienced more than one TEAE within a specific 
SOC (likewise for PT).  
Investigator assessed causality to study drug will be categorized as “not related,” 
“possibly related,” or “probably related”.  For summary purposes, treatment-related 
TEAEs will include events with relationship to study drug classified as “possibly 
related” or “probably related”.  A TEAE with a missing causality will be classified as 
“possibly related” to study drug.  A subject will be counted once at the strongest 
causality within a SOC and/or PT. 
Deaths due to progressive disease were not to be recorded in the AE CRF page for the 
study. Thus, fatal AEs (i.e., Grade 5 events) will be not be included in TEAE 
summaries but will be summarized in the summary of deaths.  
 
Events with a missing grade will not be summarized in “by grade” tables. In “by 
grade” tables, events will be summarized by Grade 3, Grade 4 and Grade 3 or 4.  A 
subject will be counted once at the worst severity grade within a SOC and/or PT. 
Adverse events of special interest (AESI) include T-LBL/T-ALL and 
MDS/AML/MPN and will be assessed by Sponsor pre-defined MedDRA PTs.  
 
AEs will be summarized with a separate table for each of the following: 
x TEAEs 
x TEAEs of grade 3 or 4 
x Treatment-related TEAEs 
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x Treatment-related TEAEs of grade 3 or 4 
x TEAEs leading to dose interruption 
x TEAEs leading to dose reduction 
x TEAEs leading to discontinuation of study drug 
x TEAEs leading to withdrawal from study 
x Serious adverse events (SAEs) 
x Treatment-related SAEs 
x AESIs 
 
Deaths 
x Summary and listing RIVXEMHFWVZKRGLHGGD\VDIWHUODVWGRVHRIVWXG\
drug, by cause as follows: 
- Any AE (by MedDRA preferred Term) 
- Any treatment related TEAE  
- Progressive Disease 
- Disease under Study 
- Unknown/Other causes 
x Summary and listing of subjects who died  30 days after last dose of study 
drug with treatment-related TEAEs 
x Summary and listing of subjects who died > 30 days after the last dose of 
study drug with treatment-related AEs 
Listings of all AEs, SAEs, AESIs, and TEAEs leading to discontinuation of study 
drug. 
3.11.2 Clinical Laboratory Evaluation 
Laboratory results will be summarized using Système International (SI) units, as 
appropriate. For all quantitative parameters, the actual value and the change from 
baseline to each post baseline visit and to the end of treatment (defined as the last on-
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treatment value) will be summarized by visit using descriptive statistics.  The 
summaries will include all laboratory parameters included in Table 4.  
In addition, creatinine clearance will be calculated by the Cockcroft-Gault formula. 
For males the creatinine clearance in mL/min will be calculated as (140-age) × weight 
(kg)/[serum creatinine (mg/dL) × 72]. For females, the creatinine clearance in 
mL/min will be calculated as 0.85 × (140-age) × weight (kg)/[serum creatinine 
(mg/dL) × 72]. 
Laboratory values that are reported as ‘below the detectable limit’ of an assay will be 
analyzed as half the detectable limit when required for analysis purposes but listed as 
originally reported. The following summaries will be provided for laboratory data: 
x For parameters graded by NCI CTCAE, shift from baseline grade to worst 
post-baseline grade based on NCI CTCAE v4.03). For laboratory tests with 
both low and high values, summaries will be provided separately. 
x For parameters not graded by NCI CTCAE, shift from baseline to worst post-
baseline value that is < 0.25 x LLN or > 2.5 x ULN. 
For subjects with a post-baseline parameter that is grade 3 or higher (per NCI 
CTCAE), all values for that parameter will be listed. Similarly, for parameters not 
gradable by NCI CTCAE for subjects with a post-baseline parameter value that is 
< 0.25 x LLN or > 2.5 x ULN, all values for that parameter will be listed.  
The number of subjects with potential Hy’s Law cases will be summarized, and all 
chemistry laboratory results will be summarized for any subjects meeting the criteria. 
Potential Hy’s Law cases require a concurrent $/7RU$67× ULN, total bilirubin 
î8/1and ALP < 2 × ULN. To count as concurrent, each of the laboratory 
parameters must be drawn within +/- 3 days. 
 
Table 4 
Laboratory Parameters 
Category 
Parameter 
Hematology 
x 
Hematocrit 
x 
Hemoglobin 
x 
Red blood cell count (RBC) 
x 
Platelet count 
x 
White blood cell count (WBC)  
x 
Differentials (bands, basophils, eosinophils, 
lymphocytes, monocytes, neutrophils) 
Chemistry 
 
Electrolytes 
x 
Bicarbonate 
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x 
Chloride 
x 
Potassium 
x 
Sodium 
Liver Function 
x 
Alkaline phosphatase (ALP) 
x 
Alanine aminotransferase (ALT) 
x 
Aspartate aminotransferase (AST) 
x 
Total bilirubin 
Renal Function 
x 
Blood urea or blood urea nitrogen (BUN) 
x 
Creatinine 
Other 
x 
Albumin 
x 
Amylase 
x 
Calcium 
x 
Cholesterol 
x 
Creatine phosphokinase (CPK) 
x 
Glucose 
x 
International Normalized Ratio (INR) 
x 
Lactate dehydrogenase (LDH) 
x 
Phosphorous 
x 
Total protein 
x 
Triglycerides 
x 
Uric acid 
3.11.3 Vital Signs and Other Physical Findings 
Weight (kg) as well as vital signs for sitting systolic blood pressure (mmHg), sitting 
diastolic blood pressure (mmHg), sitting heart rate (bpm), sitting respiratory rate 
(breaths/min), and temperature (ͼC) will be collected and listed. Summaries of heart 
rate, temperature, systolic blood pressure, and diastolic blood pressure will be based 
on markedly abnormal criteria defined below: 
Table 5 
Marked Abnormal Vital Signs Criteria 
Vital Sign 
Markedly Abnormal Criteria 
Heart rate (bpm) 
< 60 bpm 
> 100 bpm 
Temperature (ͼC) 
ͼC 
ͼC 
Systolic blood 
pressure (mmHg) 
120-139 mmHg, inclusive (CTCAE grade 1) 
140–159 mm Hg, inclusive (CTCAE grade 2) 
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 160 mmHg (CTCAE Grade 3) 
Diastolic blood 
pressure (mmHg) 
80–89 mmHg, inclusive (CTCAE grade 1) 
90–99 mm Hg, inclusive (CTCAE grade 2) 
 100 mmHg (CTCAE grade 3) 
Incidence of markedly abnormal worst-case values will be presented.  For heart rate 
and temperature, both high and low values will be presented separately such that 
subjects can be counted in both categories. Markedly abnormal vital sign values will 
be flagged as such on a vital signs listing. 
3.11.4 ECG 
Electrocardiogram assessments will be performed as specified in the Schedule of 
Assessments. Time-matched, central-read ECGs were performed to evaluate RR, PR, 
QRS, QT intervals, QTc, QTc Fridercia (QTcF), QTc Bazett (QTcB), and heart rate 
(HR) at various time points throughout the study. All 12-lead ECG data will be listed, 
and changes from baseline will be summarized using descriptive statistics.  When 
triplicates are collected, the averages (as calculated by the central ECG vendor) will 
be used in the summaries.  The number and percentage of subjects with abnormal 
ECG findings at each visit will be reported.  
The following summaries will be provided for 12-lead ECG assessments listed 
above: 
x Quantitative 12-lead ECG measurements: values and changes from baseline 
(and changes from pre dose) by planned visit  
x Investigator overall interpretation of the ECG: counts and percentages of 
subjects for each category 
x Quantitative 12-lead ECG:  Shift from baseline to worst post-baseline in 
QTcF status categorized as markedly abnormal or not (defined in the table 
below)  
x Quantitative 12-lead ECG measurements: Counts and percentages of 
subjects whose worst-case changes from baseline in QTcF measurements 
meet markedly abnormal criteria (described in the table below).  
Table 6 
Markedly Abnormal ECG Criteria 
QTcF Measure 
Markedly Abnormal Criteria 
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Observed 
450–480 msec, inclusive [CTCAE grade 1] 
481–500 msec, inclusive [CTCAE grade 2] 
> 500 msec [CTCAE grade 3 or higher] 
Change from 
Baseline 
31–60 msec, inclusive, increase from baseline 
>60 msec increase from baseline 
3.11.5 MUGA Scans and Echocardiograms 
The results of MUGA scans and echocardiograms at baseline and post-baseline visits 
will be listed along with the type of assessment (MUGA or echocardiogram). 
3.11.6 Concurrent Nonpharmacological Procedures and Palliative 
Radiotherapy 
Concurrent nonpharmacological anticancer procedures noted during survival follow 
up and palliative radiotherapy will be summarized and listed.  
The number and percentage of subjects with anticancer procedures noted during 
survival follow up and reason for the procedure (pre-existing condition, AE, or other) 
will be summarized. The incidence (number and percentage) of subjects undergoing 
each anticancer procedure will also be summarized by MedDRA HLGT and PT.  
The number and percentage of subjects receiving concurrent palliative radiotherapy 
will be summarized overall and by site of palliative radiotherapy.   
3.12 CHANGES TO ANALYSES FROM PROTOCOL 
x The primary analysis of the primary and secondary efficacy endpoints is based on 
the data assessed by IRC, which was requested by regulatory agency. As a result, 
concordance analysis was added for BOR and ORR. 
x TEAEs with a missing causality will be assumed to be “possibly related” to study 
drug. 
x Time to first response analysis was added as an exploratory endpoint. 
x Disease control rate added as an exploratory endpoint.  
x Time to first subsequent therapy added as an exploratory endpoint. 
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x Section 7.6.1.4 of the protocol indicates that laboratory parameters will be 
summarized descriptively as actual value and change from baseline, as well as, 
shifts from baseline (based on low, normal, high categorization) at each visit.  To 
allow for more focused presentation of values most likely to represent a safety 
concern, laboratory parameters will be summarized as shift from the baseline to 
the worst post-baseline severity (based on National Cancer Institute [NCI] 
Common Terminology Criteria for Adverse Events [CTCAE] severity grades).  
When an NCI CTCAE category is undefined for a parameter, a multiple of the 
nearer normal limit will be used. 
x The Full Analysis Set is relabeled as the Intent-to-Treat (ITT) population.  Other 
analysis sets are relabeled as the corresponding populations. 
x For vital signs, Section 7.6.1.4 of the protocol specifies summarizing the values 
and change from baseline for each vital sign by visit. The analysis of vital signs 
specified in the SAP will only present the number of subjects that have markedly 
abnormal vital signs as defined in Section 3.11.3 of the SAP. 
x For ECGs, markedly abnormal definitions have been added to the SAP, and the 
number of subjects meeting the markedly abnormal criteria will be summarized.  
x A summary of concurrent nonpharmacological anticancer procedures and 
palliative radiotherapy has been added to track other anticancer therapies given 
after the first dose of study drug for subjects. 
4 References 
Clopper, C. J., and Pearson, E. S. (1934), “The Use of Confidence or Fiducial Limits 
Illustrated in the Case of the Binomial,” Biometrika, 26, 404–413. 
Brookmeyer, R. and Crowley, J. (1982), “A Confidence Interval for the Median 
Survival Time,” Biometrics, 38, 29–41. 
Green S and Dahlberg S.  Planned versus attained design in Phase II Clinical Trials.  
Statistics and Medicine. 1992 Vol II:853-862. 
5 Appendix
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Appendix 1 
Schedule of Visits and Procedures: Phase 2 (All Visits Starting at Cycle 1 Day 15 Have ± 3-Day Window) 
Period 
Screeninga 
Cycles 1 and 2 
Cycle 3 and Beyond 
Off-
Treatmentb 
Follow-upc 
Day 
-28 to -1 
1 (± 3days) 
15 (± 3days) 
1 (± 3days) 
15d (± 3days) 
 
 
Procedures/Assessments 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Prior and concomitant medications 
Throughout study 
Comprehensive physical examination 
X 
 
 
 
 
X 
 
Symptom directed physical exam 
 
X 
X 
X 
 
 
 
Pregnancy teste 
X 
X 
 
X 
 
 
 
Body weight 
X 
X 
X 
X 
 
X 
 
Height 
X 
 
 
 
 
 
 
Vital signsf 
X 
X 
X 
X 
 
X 
 
ECOG performance status 
X 
X 
 
X 
 
X 
 
12-lead ECGsg 
X 
X 
 
X 
 
X 
 
Hematology 
X 
X 
X 
X 
 
X 
 
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Appendix 1 
Schedule of Visits and Procedures: Phase 2 (All Visits Starting at Cycle 1 Day 15 Have ± 3-Day Window) 
Period 
Screeninga 
Cycles 1 and 2 
Cycle 3 and Beyond 
Off-
Treatmentb 
Follow-upc 
Day 
-28 to -1 
1 (± 3days) 
15 (± 3days) 
1 (± 3days) 
15d (± 3days) 
 
 
Procedures/Assessments 
 
 
 
 
 
 
 
Blood chemistry 
X 
X 
X 
X 
X 
X 
 
Genomic DNAh 
 
 
 
 
 
 
 
PK blood samplesi 
 
Xi 
Xi 
 
 
 
 
PD blood samplesj 
 
Xj 
Xj 
 
 
 
 
PD blood sample for nucleic acidk 
 
X 
 
X 
 
X 
 
Sufficient tumor tissue availablel 
X 
 
 
 
Paired tumor biopsiesm 
 
X 
 
 
 
 
 
Optional tumor biopsy at DPn 
 
 
 
 
 
X 
 
Tumor assessments: CT (MRI), and 
assessments of B symptomso 
X 
Radiologic tumor assessments (IWG-NHL [Cheson 2007] criteria) 
must be performed every 8 weeks during Cycles 2-6, and every 
12 weeks starting at Cycle 7 and beyond 
X 
X 
CT or MRI of the brainp 
Brain scans should be performed if clinically indicated. 
Bone marrow biopsy (with IHC)q 
X 
At first notation of CR if bone marrow involvement at Screening, and if 
clinically indicated (eg, suspicion of relapse or progressive disease) 
 
 
18FDG-PET scanr 
X 
Performed at first notation of possible PR or CR 
 
 
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Appendix 1 
Schedule of Visits and Procedures: Phase 2 (All Visits Starting at Cycle 1 Day 15 Have ± 3-Day Window) 
Period 
Screeninga 
Cycles 1 and 2 
Cycle 3 and Beyond 
Off-
Treatmentb 
Follow-upc 
Day 
-28 to -1 
1 (± 3days) 
15 (± 3days) 
1 (± 3days) 
15d (± 3days) 
 
 
Procedures/Assessments 
 
 
 
 
 
 
 
AEs/SAEs 
Throughout study 
EPZ-6438 administrations 
 
Continuous 28-day cycle of EPZ-6438 twice daily. EPZ-6438 can be 
taken with or without food. 
 
 
Survival status and subsequent 
anticancer therapy 
 
X 
X 
$( DGYHUVHHYHQWȕ-hCG = beta-human chorionic gonadotropin, BP = blood pressure, CR = complete response, CT = computed tomography, DLBCL = diffuse large B cell 
lymphoma, DNA = deoxyribonucleic acid, DP = disease progression, ECG = electrocardiogram, ECOG = Eastern Cooperative Oncology Group, EZH2 = enhancer of zeste 
homolog 2, 18FDG-PET = 18fluorodeoxyglucose-positron emission tomography, FL = follicular lymphoma, HR = heart rate, IHC = immunohistochemistry, IWG-NHL = 
International Working Group-Non-Hodgkin’s Lymphoma, MRI = magnetic resonance imaging, PD = pharmacodynamic, PK = pharmacokinetic, SAE = serious adverse event. 
 
a. 
The Screening Period extends from Day -28 to Day -1, except for signing of the informed consent form, which may be up to 8 weeks before the first dose of study drug.  
Screening laboratory assessments may be used as Day 1 assessments if performed within 72 hours of the first dose of study treatment, however subjects must continue to meet 
eligibility criteria prior to first dose of tazemetostat on Cycle 1 Day 1.  The screening assessments (except tumor assessment) must be performed within 28 days before the first 
dose of study drug. Tumor assessment must occur within 28 days for CT or MRI or photographs. 
b. 
Off-treatment assessment may occur at time of treatment discontinuation (e.g., at the visit at which the decision to discontinue treatment occurs) or up to 30 days after the 
final dose of study drug. AE and concomitant medication data must be collected for 30 days after the final dose of study drug, or until the start of new therapy. This may occur 
prior to 30 days if new therapy is started within 30 days of last dose of study drug. If subject is unable to return to the clinic for assessment of AEs this may be done by 
telephone. 
c. 
Survival follow-up will be conducted approximately every 12 weeks on all subjects, unless they withdraw consent. Information on all anticancer therapies will be collected 
(the sponsor may choose to stop the collection of therapies after the first anticancer treatment following EPZ-6438). This may be done by telephone contact.  
d. 
Starting at Cycle 3, a Day 15 visit is not required. On Day 15 of each cycle, subjects will have hematology and blood chemistry samples drawn at a local laboratory and 
telephone contact with the site to review AEs. 
e. 
$VHUXPSUHJQDQF\WHVWȕ-hCG) will be performed at Screening for all women of childbearing potential. A urine or serum pregnancy test will be performed predose on Day 1 
of each cycle starting at Cycle 2. 
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f. 
Vital signs include BP, HR and body temperature. BP and HR will be collected after the subject has been sitting for 5 minutes. 
g. 
12-Lead ECGs will be collected at the following time points:  Screening (triplicate), Cycles 1 and 2 Day 1 (predose and 0.5 – 2 hours post dose immediately before PK 
sample), Day 1 of all subsequent cycles (before and after morning dose of study drug administration), and at the Off-Treatment Visit. In case of any alteration or if clinically 
necessary an echocardiogram and/or cardiac enzymes should be performed. 
h. 
Genomic DNA samples will be collected predose at Screening. If it cannot be collected at the designated time point, it may be collected at a time point after baseline. 
i. 
Blood samples for PK analysis will be collected in Cycle 1 on Day 1 at 0.5 to 2 hours and 3 to 6 hours and Day 15 at predose (0 hours), 0.5 to 2 hours, and 3 to 6 hours; and 
Cycle 2 on Day 1 at predose (0 hours), 0.5 to 2 hours, and 3 to 6 hours. Blood samples should be collected on the day after Day 28 of Cycle 1, irrespective of start of Cycle 2. 
j. 
Blood samples for PD analysis will be collected at the following time points: Predose (0 hours) on Cycle 1 Days 1 and 15; and Predose (0 h) on Cycle 2 Day 1. Blood samples 
should be collected on the day after Day 28 of Cycle 1, irrespective of the start of Cycle 2. 
k. 
Blood samples for nucleic acid analysis will be collected at the following time points: Predose (0 hours) on Cycle 1 Day 1, and Day 1 of every other cycle, and at the off-
treatment visit. 
l. 
Subjects will have collection of archived, tumor-biopsy sections for central testing of EZH2 mutation status (all subjects) and confirmation of cell of origin for DLBCL 
subjects. 
m. 
Paired tumor biopsies (DLBCL cohorts) and/or bone marrow biopsies (FL cohorts) are optional and may be obtained, with appropriate subject consent, from at least 4 to 
6 subjects per cohort to examine tissue target inhibition, relevant PD biomarkers, and potential markers of response. Subjects should have the biopsy before administration of 
the first dose of EPZ-6438 and the second biopsy at the time of first disease assessment.  If sufficient tumor exists from archival, this could be considered the predose sample. 
n. 
Tumor biopsy is to be requested, where medically feasible, at disease progression in subjects who achieve a PR or better with EPZ-6438.  
o. 
Tumor assessments include CT scan of the chest, CT or MRI of the neck, abdomen, pelvis, and other areas of known disease or newly suspected disease and should be 
performed between Day -28 and Day -14 and every 8 weeks, irrespective of treatment delays, during Cycles 1 to 6, and every 12 weeks during Cycle 7 and beyond. If local 
regulatory authorities mandate less frequent imaging, minimum frequency must be every 12 weeks. The same parameters as the screening scans should be used. A standard-of-
care clinical examination for lymphoma, including assessment of B symptoms, will also be performed at each visit. 
p. 
CT or MRI of the brain should be performed if clinically indicated.  
q. 
A bone marrow biopsy (including IHC) will be performed between Day -28 and Day -4, unless there is a report of bone marrow negative for lymphoma involvement within 
42 days before administration of the first dose of study drug. At the first notation of CR, a repeat bone marrow biopsy should be performed if lymphoma involvement in the 
bone marrow was reported at Screening.  
r. 
18FDG-PET scan should be performed at Screening and at the first notation of possible PR or CR. 
s. 
On visit days, subjects should not take study drug before evaluations are performed. 
 
 
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