Conditions: All Malignancies Advanced Malignancies Hematologic Malignancy Solid Tumor Follicular Lymphoma (FL) Non-Hodgkin Lymphoma (NHL) Diffuse Large B-Cell Lymphoma (DLBCL) Epithelioid Sarcoma (ES) Synovial Sarcoma Renal Medullary Carcinoma Mesothelioma Rhabdoid Tumor
Keywords: Epizyme Tazverik Tazemetostat (EPZ-6438) Itraconazole CYP3A4 inhibitor Rifampin CYP3A4 inducer Drug-Drug Interaction (DDI) Pharmacokinetics (PK)
Allocation: NON_RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 42
Healthy volunteers: no

Brief summary:
The participants of this study will have advanced malignancies (also known as advanced cancer). The main aim of this trial will be to study the blood levels (known as pharmacokinetics) of the tazemtostat (the study drug) when administered in combination with another drug.

Part 1 of the study will evaluate the interaction between the drugs tazemetostat and itraconazole.

Part 2 of the study will evaluate the interaction between the drugs tazemetostat and rifampin

For both Parts 1 and 2, safety and the level that effects of the study drug can be tolerated (known as tolerability) will be assessed throughout.

Detailed description:
This two-part study is designed to characterize the steady-state PK of oral tazemetostat and its metabolite EPZ 6930 when administered as a single and twice daily dose in subjects with advanced malignancies while taken alone or in combination with either itraconazole or rifampin.

Part 1: tazemetostat and Itraconazole Drug Interaction Part 1 of the study will evaluate the drug-drug interaction between tazemetostat and itraconazole in an open-label, fixed sequential cross over design.

Part 2: tazemetostat and Rifampin Drug Interaction Part 2 of the study will evaluate the drug-drug interaction between tazemetostat and rifampin in an open-label, fixed sequential cross over design.

For both Parts 1 and 2, safety and tolerability will be assessed throughout the subject's participation. Subjects must have an end of study visit after 30 days of the last dose of tazemetostat for safety assessment.

Arms:
arm 1: Participants in Part 1 of the study will receive a single oral, 400 mg dose of tazemetostat on Day 1, 15, and Day 36.

The study participants will receive tazemetostat (oral 400 mg) tablets to be taken twice daily on Days 3 - 14 and Days 21 - 35. In addition, the participants will receive oral 200 mg itraconazole once daily on Days 18 - 38.

Study participants may continue tazemetostat from Day 40+ at the recommended therapeutic dose (oral 800 mg twice daily) in 28-day cycles. arm 2: Participants in Part 2 of the study will receive a single oral, 800 mg dose of tazemetostat on Days 1, 15, and Day 36.

The study participants will receive tazemetostat (oral 800 mg dose) tablets to be taken twice daily on Days 3 - 14 and Days 17 - 23. In addition, the participants will receive oral 200 mg rifampin once daily on Days 17 - 25.

Study participants may continue tazemetostat from Day 27+ at the recommended therapeutic dose (oral 800 mg twice daily) in 28-day cycles.

Interventions: intervention 1: Tazemetostat intervention 2: Itraconazole intervention 3: Tazemetostat intervention 4: Rifampin
Intervention descriptions: intervention 1: A single, oral, 400 mg dose of tazemetostat on Day 1, Day 15, and Day 36; and tazemetostat (oral 400 mg) tablets twice daily on Days 3 - 14 and Days 21 - 35. intervention 2: Oral 200 mg itraconazole once daily on Days 18 - 38 intervention 3: A single, oral, 800 mg dose of tazemetostat on Days 1, 15, and Day 24 ; and tazemetostat (oral 800 mg) twice daily on Days 3 - 14 and on Days 17 - 23. intervention 4: Oral 600 mg rifampin once daily on Days 17 - 25.

Protocol document:
Prot_000.pdf: 
Clinical Study Protocol 
 
EZH-108 
Tazemetostat 
 
Amendment 2.0
 
 
31 August 2021 
Epizyme, Inc. 
Confidential 
 
 
 
 
 
EZH-108 
 
A PHASE I, OPEN-LABEL MULTI-DOSE TWO-PART 
STUDY TO CHARACTERIZE THE EFFECTS OF A 
STRONG CYP3A4 INHIBITOR ON THE STEADY-
STATE PHARMACOKINETICS OF TAZEMETOSTAT 
(EPZ-6438), AND THE EFFECTS OF A STRONG CYP3A4 
INDUCER ON THE STEADY-STATE 
PHARMACOKINETICS OF TAZEMETOSTAT IN 
SUBJECTS WITH ADVANCED MALIGNANCIES 
 
 
 
Amendment 2.0: 31 August 2021 
Amendment 1.0: 08 April 2020 
Original Protocol: 03 March 2020  
 
 
 
 
 
 
GCP Statement: This study is to be performed in full compliance with International Council for Harmonisation of 
Technical Requirements for 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, Inc. (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. 


Cli nical St u d y Pr ot oc ol  
E Z H- 1 0 8  
Taze met ostat  
A me n d me nt 2. 0
3 1  A u g ust 2 0 2 1  
E piz y me, I nc.  
C o nfi de n tial 
SI G N A T U R E P A G E  
S p o ns or’s A p pr o v al  
T he pr ot oc ol has bee n a p pr o ve d b y E piz y me, I n c. 
S p o ns or’s A ut h orize d Officer:  
E piz y me, I nc.  
4 0 0 Tec h n ol o g y S q uare, 4t h Fl o or 
Ca m bri d ge, M A 0 2 1 3 9, U S A 
Tele p h o ne: 
 
Date  
Res p o nsi ble Me dic al Officer:  
E piz y me, I nc.  
4 0 0 Tec h n ol o g y S q uare, 4t h Fl o or 
Ca m bri d ge, M A 0 2 1 3 9, U S A 
P h o ne:
 
Date  
3 0- A u g- 2 0 2 1 | 0 6: 1 2 E D T
3 1- A u g- 2 0 2 1 | 1 0: 4 5 E D T
P P D
P P D
P P D
P P D


Clinical Study Protocol 
 
EZH-108 
Tazemetostat 
 
Amendment 2.0
 
 
31 August 2021 
Epizyme, Inc. 
Confidential 
INVESTIGATOR’S AGREEMENT 
 
Protocol Title: A Phase I, Open-label Multi-dose Two-Part Study to Characterize the Effects of 
a Strong CYP3A4 Inhibitor on the Steady-State Pharmacokinetics of Tazemetostat (EPZ-6438), 
and the Effects of a Strong CYP3A4 Inducer on the Steady-State Pharmacokinetics of 
Tazemetostat in Subjects with Advanced Malignancies 
 
Protocol Number: EZH-108 
 
 
I have read the EZH-108 protocol and agree to conduct the study as outlined. I agree to maintain 
the confidentiality of all information received or developed in connection with this protocol. 
 
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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 




Clinical Study Protocol 
 
EZH-108 
Tazemetostat 
 
Amendment 2.0
 
 
31 August 2021 
Epizyme, Inc. 
Confidential 
PROTOCOL AMENDMENT AND SUMMARY OF CHANGES 
DOCUMENT HISTORY 
Document 
Date 
Amendment 2.0 
31 August 2021 
Amendment 1.0 
08 April 2020 
Original Protocol 
03 March 2020 
Amendment 2.0 
Overall Rationale for the Amendment: 
This amendment is being made to:  
• Update inclusion/exclusion criteria. 
• Update clinical experience with tazemetostat and benefit:risk assessment. 
• Update dose modifications for tazemetostat treatment-related toxicities. 
• Update schedule of assessments. 
• Update medications to be used with caution. 
• Update special situations: overdose, misuse, abuse, and medication error. 
• Update information regarding study drug approval by the FDA. 
• Update contraception language. 
• Update safety-related information. 
• Include benefit:risk assessment during COVID-19. 
In addition, minor editorial, and document formatting revisions (eg, typos, deletion of repeated 
information, addition of abbreviations to tabular footnotes, etc) were made. All changes are 
visible in the tracked version. Details of important changes are given below. 
Details of substantial changes to the protocol include: 
 
Section # and Name 
Description of Substantial 
Changes 
Brief Rationale 
Synopsis, Section 8.1: Subject 
Inclusion Criteria, and 
Section 12.3.11: Pregnancy 
Updated contraception language 
for female and male subjects. 
Updated to be consistent with 
Epizyme policy on 
contraception for female and 
male subjects. 
Synopsis and Section 8.2: 
Subject exclusion Criteria 
Criterion #6 has been updated to 
include further information on 
subjects with hepatitis B and 
Hepatitis C infection.  
Updated for more clarity. 
Section 5.4: Clinical Experience 
and Section 5.5: Benefit:Risk 
Assessment 
Further information regarding 
clinical experience and the 
benefit:risk assessment for 
tazemetostat has been included. 
Updated to be consistent with 
the current investigators 
brochure (IB). 


Clinical Study Protocol 
 
EZH-108 
Tazemetostat 
 
Amendment 2.0
 
 
31 August 2021 
Epizyme, Inc. 
Confidential 
Section # and Name 
Description of Substantial 
Changes 
Brief Rationale 
Table 2: Dose Modifications for 
Tazemetostat Treatment-Related 
Toxicities 
Updated dose modification for 
Grade 3 neutropenia, 
thrombocytopenia, and Grade 4. 
Updated to align with 
TAZVERIK label. 
Section 7.5.3: Continuation of 
Treatment 
Updated language for 
continuation of treatment for 
subjects who experience clinical 
progression at the end of Cycle 
1. 
Subjects deriving clinical 
benefit, in the opinion of the 
Investigator, may be allowed to 
continue treatment despite 
clinical progression upon 
consideration of risk:benefit. 
Table 3: Schedule of 
Assessments (Part 1: 
Tazemetostat and Itraconazole) 
and Table 4: Schedule of 
Assessments (Part 2: 
Tazemetostat and Rifampin) 
Removed annual assessments 
and optional chest ultrasound. 
Removed annual assessment 
since annual PK assessment 
would not yield enough 
additional data to characterize 
safety and efficacy of 
tazemetostat. AESI and tumor 
response assessments performed 
routinely at other timepoints. 
 
Optional chest ultrasound 
(previously Section 12.3.6) was 
removed since evaluation for T-
LBL/T-ALL will be at 
Investigator’s discretion as 
clinically indicated. 
Section 9.3.1: Special 
Situations: Overdose, Misuse, 
Abuse and Medication Error and 
Section 12.11: Reporting of 
Special Situations: Overdose, 
Misuse, Abuse and Medication 
Error 
Included separate sections to 
include information on the 
definition and reporting of 
special situations such as 
overdose, misuse, abuse, and 
medication error. 
Updated to be consistent on 
Epizyme policy for special 
situations such as overdose, 
misuse, abuse, and medication 
error. 
Section 10.1: Study Drug 
Updated to include information 
on tazemetostat approval by the 
FDA. 
Updated to provide information 
on approval status. 
Section 12.4.2.2: 
Myelodysplastic 
Syndrome/Acute Myeloid 
Leukemia/ Other Malignancies 
Like Myeloproliferative 
Neoplasms 
Updated this section with the 
current number of 
MDS/AML/MPN cases. 
Updated to be consistent with 
the current safety information 
and the current IB. 
Section 12.4.2.4: Quarterly and 
External Safety Review: The 
Tazemetostat Safety 
Committees 
Updated to include a new 
section on safety monitoring by 
tazemetostat safety committees. 
Updated to reflect the current 
Epizyme standard on safety 
monitoring. 
Section 12.4.3: Potential Safety 
Signal Under Evaluation: B-cell 
Acute Lymphoblastic Leukemia 
(B-ALL) 
Updated to include a new 
section on B-ALL. 
Updated to include current 
information on potential safety 
signal under evaluation. 


Clinical Study Protocol 
 
EZH-108 
Tazemetostat 
 
Amendment 2.0
 
 
31 August 2021 
Epizyme, Inc. 
Confidential 
Section # and Name 
Description of Substantial 
Changes 
Brief Rationale 
Appendix 4: Benefit:Risk 
Assessment During COVID-19 
Included a separate section on 
the benefit:risk assessment 
during COVID-19. 
Included to ensure the safety of 
the study subjects. 
 
Details of non-substantial changes to the protocol include: 
 
Section # and Name 
Description of Substantial 
Changes 
Brief Rationale 
Synopsis and Section 7.1: 
Overall Study Design 
Updated language regarding 
admitting eligible subjects in the 
to the clinical study center. 
Updated to provide clarity. 
Synopsis, Section 7.2: Number 
of Subjects, Section 7.5.1: Dose 
Modification, and 
Section 8.2.4: Replacement of 
Subjects 
Updated language regarding 
replacement of subjects due to 
interruption of 
tazemetostat/itraconazole/rifampin 
doses. 
Updated to provide clarity. 
Table 1 and Table 5: 
Laboratory Values for Hepatic, 
Hematologic and Renal 
Function 
Updated absolute neutrophil count 
(ANC), hematologic factors, and 
hepatic function parameters 
Updated for clarity and to be 
consistent with the ANC values 
in TAZVERIK label and to be 
consistent with NCI-ODWG 
criteria for hepatic function. 
Synopsis and Section 8.2: 
Subject exclusion Criteria 
Criterion #10 has been updated to 
include AML and MPN. 
Criterion #13 has been updated to 
include further information 
regarding alcohol consumption. 
 
Updated to provide clarity. 
Figure 1: Study Design, 
Figure 2: Study Schema (Part 1: 
Tazemetostat and Itraconazole), 
and Figure 3:  Study Schema 
(Part 2: Tazemetostat and 
Rifampin) 
Updated study design schema.  
Updated for more clarity. 
Section 9.1: Description of 
Study Drug 
Description of tazemetostat has 
been removed.  
Updated since it has already 
been described in Section 10.1: 
Study Drug 
Section 9.2.2: Medications to 
be Used with Caution 
Included further information 
regarding medications to be 
administered concomitantly with 
tazemetostat, itraconazole or 
rifampin. 
Updated for more clarity. 
Section 9.5: Treatment of 
Overdose 
Removed the sentence “A subject 
suspected of overdose should be 
monitored until tazemetostat can 
no longer be detected 
systemically”. 
Tazemetostat titers are not 
conducted, and subjects will be 
monitored clinically. 


Clinical Study Protocol 
 
EZH-108 
Tazemetostat 
 
Amendment 2.0
 
 
31 August 2021 
Epizyme, Inc. 
Confidential 
Section # and Name 
Description of Substantial 
Changes 
Brief Rationale 
Section 11.1: Blood Sample 
Collection 
Updated information on PK blood 
collection timeline and timing 
tolerance window for ECG 
Updated for more clarity. 
Section 12.3.7: Laboratory 
Assessments 
Updated to include MDS/AML or 
MPN and cytogenetic testing 
using next generation sequencing 
(NGS). 
Updated for more clarity. 
Section 18: Publication 
Policy 
Updated the publication policy. 
Updated to be consistent on 
Epizyme policy for 
publications. 
 


Cli nical St u d y Pr ot oc ol  
 
E Z H- 1 0 8  
Taze met ostat  
 
A me n d me nt 2. 0
 
 
3 1  A u g ust 2 0 2 1  
E piz y me, I nc.  
C o nfi de n tial 
2.  
S Y N O P SI S  
N a me of S p o ns or/ C o m p a n y:  
E piz y me, I nc.  
N a me of I n vesti g ati o n al Pr o d uct:  
Taze met ostat ( E P Z -6 4 3 8)  
N a me of Acti ve I n gre die nt:  
Taze met ostat h y dr o br o mi de  
Pr ot oc ol N u m ber: E Z H- 1 0 8  
P h ase: I  
C o u ntr y: Gl o b al  
Title of St u d y: A P hase I, O pe n -la bel M ulti-d ose T w o -Part St u d y t o C haracterize t he Effects of a 
Str o n g C Y P 3 A 4 I n hi bit or o n t he Stea d y -State P har mac o ki netics of Taze met ostat ( E P Z -6 4 3 8), a n d t he 
Effects of a Str o n g C Y P 3 A 4 I n d ucer o n t he Stea d y -State P har mac o ki netics of Taze met ostat i n 
S u bjects wit h A d va nce d Mali g na ncies  
St u d y ce nter(s): ~ 2 4  
Pri nci p al I n vesti g at or: 
 
I n vesti g at ors: T B D  
St u die d peri o d ( ye ars):  
Esti mate d date first patie nt e nr olle d: Q 2 2 0 2 0  
Esti mate d date last patie nt c o m plete d: Q 4 2 0 2 0  
P h ase of de vel o p me nt: I 
 
O bjecti ves:  
P art 1: T aze met ost at a n d Itr ac o n az ole Dr u g I nter a cti o n 
Pri m ar y  
•  
T o e val uate t he effect of C Y P 3 A 4 i n hi biti o n b y itrac o naz ole o n t he stea d y -state 
p har mac o ki netics ( P K) of taze met ostat w he n a d mi nistere d as a si n gle a n d t wice dail y oral 
d ose i n s u bjects wit h a d va nce d mali g na ncies.  
Sec o n d ar y  
•  
T o e val uate t he stea d y -state safet y pr ofile of taze met ostat w he n c o-a d mi nistere d as a 
si n gle a n d t wice dail y oral d ose wit h itrac o naz ole i n s u bjects wit h a d va nce d 
mali g na ncies.  
•  
T o e val uate t he stea d y -state P K of taze met ostat a n d its meta b olites after a d mi nistrati o n 
al o ne a n d wit h itrac o naz ole.  
•  
T o e val uate t he effect of itrac o naz ole o n P K of a si n gle 4 0 0 m g oral d ose of taze met ostat.  
P art 2: T aze met ost at a n d Rif a m pi n  Dr u g I nter acti o n  
Pri m ar y  
•  
T o e val uate t he effect of C Y P 3 A 4 i n d ucti o n  b y rifa m pi n o n t he stea d y -state P K of 
taze met ostat w he n a d mi nistere d as a si n gle a n d t wice dail y oral d ose i n s u bjects wit h 
a d va nce d mali g na ncies.  
 
P P D


Clinical Study Protocol 
 
EZH-108 
Tazemetostat 
 
Amendment 2.0
 
 
31 August 2021 
Epizyme, Inc. 
Confidential 
Secondary: 
• 
To evaluate the steady-state safety profile of tazemetostat when co-administered as a 
single and twice daily oral dose with rifampin in subjects with advanced malignancies. 
• 
To evaluate the steady-state PK of tazemetostat and its metabolites after administration 
alone and with rifampin. 
Study Design: 
This is a phase 1, 2-part, multi-center, open-label, PK, and safety study. 
Methodology:  
This two-part study is designed to characterize the steady-state PK of oral tazemetostat and its 
metabolite EPZ 6930 when administered as a single and twice daily dose in subjects with advanced 
malignancies while taken alone or in combination with either itraconazole or rifampin (Figure 1).  
Part 1: Tazemetostat and Itraconazole Drug Interaction  
Part 1 of the study will evaluate the drug-drug interaction between tazemetostat and itraconazole in an 
open-label, fixed sequential cross over design (Figure 2).  
A screening visit will occur within 30 days of signing an informed consent form (ICF). During the 
screening phase, subjects will be evaluated for eligibility to participate in the study. Subjects who 
meet the protocol criteria may be admitted in the evening to the clinical study center, or visit the 
clinic if staying locally, on day -1. For Cycle 1, subjects may be admitted to the clinical study center 
during PK sampling periods or must agree to stay locally with frequent clinic visits as required and 
optional admission to the center, if available. Prior to dosing on day 1 of Cycle 1, subject eligibility 
will be reconfirmed. On day 1, a single oral dose of 400 mg tazemetostat will be administered in the 
morning (eg, 7 – 9 am) followed by 2 days of multiple blood sampling (day 1 – 3). From day 3 – 14, 
subjects will receive an oral 400 mg dose of tazemetostat twice daily (12 hours apart, once in the 
morning [eg, 7 – 9 am] and once in the evening [eg, 7 – 9 pm]). In the evening of day 14, subjects 
may be admitted to the clinical study center. On day 15, a single oral dose of 400 mg tazemetostat 
will be administered in the morning (eg, 7 – 9 am) followed by 3 days of multiple blood sampling 
(day 15 – 18). From day 18 – 20, a single dose of oral 200 mg itraconazole will be administered daily 
in the morning (eg, 7 – 9 am) after a meal. In the evening of day 20, subjects may be admitted to the 
clinical study unit. From day 21 – 35, subjects will receive an oral 400 mg dose of tazemetostat twice 
daily, once in the morning (eg, 7 – 9 am) and once in the evening (eg, 7 – 9 pm), co-administered in 
the morning (eg, 7 – 9 am) after a meal with a single dose of oral 200 mg itraconazole followed by 1 
day of multiple blood sampling (day 21 – 22). In the evening of day 35, subjects may be admitted to 
the clinical study center. On day 36, subjects will receive a single oral dose of 400 mg tazemetostat 
co-administered in the morning (eg, 7 – 9 am) after a meal with a single dose of oral 200 mg 
itraconazole followed by 3 days of multiple blood sampling (day 36 – 39). Itraconazole will also be 
administered on day 37 and 38 as a single oral 200 mg daily dose in the morning (eg, 7 – 9 am) after a 
meal. Note: Tazemetostat will not be administered on day 37 and 38. After the 72-hour PK sample 
collection, safety assessments will be conducted on day 39. Sparse PK samples will be collected pre-
dose (0 hour) and 2 hours post-dose on day 25, 28, 31, and 34. 
Subjects may discontinue from the study after completion of Cycle 1 or can continue treatment (Cycle 
2+ onwards) until Investigator-assessed clinical progression per standard practice, or unacceptable 
toxicity, or until another discontinuation criterion is met. For subjects continuing tazemetostat 
treatment at the recommended therapeutic dose (oral 800 mg tazemetostat twice daily [12 hours 
apart]), Cycle 2 will begin on day 40 (Cycle 2 Day 1) and each subsequent cycle from Cycle 2+ 
onwards will be of 28-day duration. Safety and tolerability will be assessed throughout the subject’s 
participation. Subjects will be instructed to report any adverse events that occur up to 30 days after 


Cli nical St u d y Pr ot oc ol  
 
E Z H- 1 0 8  
Taze met ostat  
 
A me n d me nt 2. 0
 
 
3 1  A u g ust 2 0 2 1  
E piz y me, I nc.  
C o nfi de n tial 
t he last d ose of taze met ostat. S u bjects m ust ha ve a n e n d of st u d y visit 3 0 da ys after t he last d ose of 
taze met ostat f or safet y assess me nt. 
P art 2: T aze met ost at a n d Rif a m pi n Dr u g I nter acti o n  
Part 2 of t he st u d y will e val uate t he dr u g -dr u g i nt eracti o n bet wee n taze met ostat a n d rifa m pi n i n a n 
o pe n -la bel, fi xe d se q ue ntial cr oss o ver desi g n (Fi g ure  3). 
A scr ee ni n g visit will occ ur wit hi n 3 0 da ys of si g ni n g a n i nf or me d c o nse nt f or m (I C F). D uri n g t he 
scree ni n g p hase, s u bjects will be e val uate d f or eli gi bilit y t o partici pate i n t he st u d y. S u bjects w h o 
meet t he pr ot oc ol criteria m a y be a d mitte d i n t he e ve ni n g t o t he cli nical st u d y ce nter, or visit t he 
cli nic if sta yi n g l ocall y, o n da y -1. F or C ycle 1, s u bjects ma y be a d mitte d t o t he cli nical st u d y ce nter 
d uri n g P K sa m pli n g peri o ds or  m ust a gree t o sta y l ocall y wit h fre q ue nt cli nic visits as re q uire d a n d 
o pti o nal a d missi o n t o t he ce nter, if a vaila ble. Pri or t o d osi n g o n da y 1 of C ycle 1, s u bject eli gi bilit y 
will be rec o nfir me d. O n da y 1, a si n gle oral d ose of 8 0 0 m g taze met ostat will be a d mi nistere d i n t he 
m or ni n g (e g, 7 – 9 a m) f oll o we d b y 2 da ys of m ulti ple bl o o d sa m pli n g ( da y 1 – 3). Fr o m da y 3 – 1 4, 
s u bjects will recei ve a n oral 8 0 0 m g d ose of taze met ostat t wice dail y ( 1 2 h o urs a part o nce i n t he 
m or ni n g [e g, 7 – 9 a m] a n d o nce i n t he e ve ni n g [e g, 7 – 9 p m]). I n t he e ve ni n g of da y 1 4, s u bjects 
ma y be a d mitte d t o t he cli nical st u d y ce nter. O n da y 1 5, a si n gle oral d ose of 8 0 0 m g taze met ostat 
will be a d mi nistere d i n t he m or ni n g (e g, 7 – 9 a m) f oll o we d b y 2 da ys of m ulti ple bl o o d sa m pli n g 
( da y 1 5 – 1 7). Fr o m da y 1 7 – 2 3, s u bjects will recei v e a n oral 8 0 0 m g d ose of taze met ostat t wice 
dail y, o nce i n t he m or ni n g (e g, 7 – 9 a m) a n d o nce i n t he e ve ni n g (e g, 7 – 9 p m), c o -a d mi nistere d i n 
t he m or ni n g (e g, 7 – 9 a m) o ne h o ur bef ore a meal wit h a si n gle d ose of oral 6 0 0 m g rifa m pi n. I n t he 
e ve ni n g of da y 2 3, s u bjects ma y be a d mitte d t o t he cli nical st u d y ce nter. O n da y 2 4, s u bjects will 
recei ve a si n gle oral d ose of 8 0 0 m g taze met ostat c o-a d mi nistere d i n t he m or ni n g (e g, 7 – 9 a m) o ne 
h o ur bef ore a meal wit h a si n gle d ose of oral 6 0 0 m g rifa m pi n  f oll o we d b y 2 da ys of m ulti ple bl o o d 
sa m pli n g ( da y 2 4 – 2 6). Rifa m pi n will als o be a d mi nistere d o n da y 2 5 as a si n gle oral 6 0 0 m g d ose i n 
t he m or ni n g (e g, 7 – 9 a m) o ne h o ur bef ore a meal. N ote:  Taze met ostat will n ot be a d mi nistere d o n 
da y 2 5. After t he 4 8- h o ur P K sa m ple c ollecti o n, safet y assess me nts will be c o n d ucte d o n da y 2 6. 
S parse P K sa m ples will be c ollecte d pre -d ose ( 0 h o ur) a n d 2 h o urs p ost -d ose o n da y 1 9 a n d 2 1.  
S u bjects ma y disc o nti n ue fr o m t he st u d y after c o m pleti o n of C ycle 1 or ca n c o nti n ue t reat me nt ( Cycle 
2 + o n war ds) u ntil I n vesti gat or -assesse d cli nical pr o gressi o n per sta n dar d practice, or u nacce pta ble 
t o xicit y, or u ntil a n ot her disc o nti n uati o n criteri o n is met. F or s u bjects c o nti n ui n g taze met ostat 
treat me nt at t he rec o m me n de d t hera pe utic dose ( 8 0 0 m g taze met ostat t wice dail y [ 1 2 h o urs a part]), 
C ycle 2 will be gi n o n da y 2 7 ( C ycle 2 Da y 1) a n d eac h s u bse q ue nt c ycle fr o m C ycle 2 + o n war ds will 
be of 2 8 -da y d urati o n. Safet y a n d t olera bilit y will be assesse d t hr o u g h o ut t he s u bject ’s partici pati o n. 
S u bjects will be i nstr ucte d t o re p ort a n y a d verse e ve nts t hat occ ur u p t o 3 0 da ys after t he last d ose of 
taze met ostat. S u bjects m ust ha ve a n e n d of st u d y visit 3 0 da ys after t he last d ose of taze met ostat f or 
safet y assess me nt. 
R oll o ver St u d y  
All s u bjects w h o recei ve t he rec o m me n de d t hera pe utic d ose of 8 0 0 m g taze met ostat t wice dail y [ 1 2 
h o urs a part ] f or 9 C ycles or l o n ger, a n d are eli gi ble t o c o nti n ue recei vi n g taze met ostat, will tra nsfer t o 
a R oll o ver St u d y  
 f or m o nit ori n g a n d c o nti n ue d st u d y d r u g at t he I n vesti gat or a n d Me dical 
M o nit or ’s discreti o n. 
N u m ber of s u bjects ( pl a n ne d):  
A p pr o xi matel y 4 0 s u bjects will be e nr olle d i n t he st u d y ass u mi n g a b o ut a 4 0 % dr o p o ut rate t o 
ac hie ve 1 2 s u b jects w h o will c o m plete eac h part of t he st u d y f or a t otal of 2 4 c o m plete d s u bjects. 
S u bjects will c o m plete eit h er Part 1 or Part 2.  
S u bjects w h o re q uire a taze met ostat d ose i nterr u pti o n or re d ucti o n d uri n g C ycle 1 of eit her Part 1 or 
Part 2 will be re place d. D uri n g C ycle 1, s u bjects w h o miss t w o or m ore c o nsec uti ve 
taze met ostat/itrac o naz ole/rifa m pi n d oses or m ore t ha n t hree taze met ostat/itrac o naz ole/rifa m pi n d oses 
C CI


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in total will be replaced. Subjects who miss two or more consecutive PK blood sample collections 
during either part of Cycle 1 will be replaced. Subjects that require replacement will be discontinued 
from study treatment. 
Diagnosis and main criteria for inclusion:  
Inclusion Criteria:  
1. Male or female ≥ 18 years age at the time of consent. 
2. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2. 
3. Has the ability to understand informed consent and provide signed written informed consent. 
4. Life expectancy of > 3 months. 
5. Histologically and/or cytologically confirmed advanced metastatic or unresectable solid 
tumors has progressed after treatment for which there are no standard therapies available OR 
histologically and/or cytologically confirmed hematologic malignancies that have relapsed, or 
refractory disease, following at least 2 standard lines of systemic therapy for which there are 
no standard therapies available. 
Note: Subjects with prior radiotherapy will be included; however, radiotherapy alone will not 
be considered a separate systemic treatment regimen. 
6. Must have evaluable or measurable disease.  
7. Has all prior treatment (ie, chemotherapy, immunotherapy, radiotherapy) related clinically 
significant toxicities resolve to ≤ Grade 1 per National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.0 or are clinically stable 
and not clinically significant, at time of consent.  
8. All subjects must have completed any prior chemotherapy, targeted therapy and major 
surgery ≥ 28 days before study entry. For daily or weekly chemotherapy without the potential 
for delayed toxicity, a washout period of 14 days or 5 half-lives, whichever is shorter may be 
acceptable, and questions related to this can be discussed with the Medical Monitor. 
9. Has normal hepatic function as well as adequate hematologic (bone marrow [BM] and 
coagulation factors) and renal function (Table 1). 
Table 1: 
Laboratory Values for Hepatic, Hematologic and Renal Function 
System 
Laboratory Value 
Hematologic (BM Function) 
Hemoglobina 
≥9 g/dL (90 g/L) 
Plateletsb 
 ≥75,000/mm3 (≥75 × 109/L) 
ANCc 
Hematologic malignancy subjects: ≥1,000/mm3 (≥1.0 × 109/L) 
Solid tumor subjects: ≥1,500/mm3 (≥1.5 x 109/L) 
Hematologic (Coagulation Factors) 
PT/INR 
<1.5 ULN 
aPTT 
<1.5 ULN 
Renal Function 
Serum creatinined 
≤1.5 × ULN 
Normal Hepatic Function (Per NCI-ODWG criteria) 
Total bilirubin, AST, and ALT 
≤ ULN 


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Abbreviations: ANC = absolute neutrophil count; AST = aspartate aminotransferase; ALT = alanine 
aminotransferase; BM = bone marrow; eGFR = estimated glomerular filtration rate; INR = international 
normalized ratio; PT = prothrombin time; aPTT = activated partial thromboplastin time; ULN = upper limit of 
normal. 
a May receive transfusion. 
b Should be evaluated after at least 7 days since last platelet transfusion. 
c Without growth factor support (filgrastim or pegfilgrastim) for at least 14 days. 
d If serum creatinine is not ≤1.5 × ULN, then calculate eGFR by Chronic Kidney Disease Epidemiology 
Collaboration (CKD-EPI) Creatinine Equation (2009) (Appendix 3). eGFR must be ≥50 mL/min/1.73 m2. 
 
Note: Laboratory results obtained during screening should be used to determine eligibility criteria. In 
situations where laboratory results are outside the permitted range, the Investigator may retest the 
subject and the subsequent within range screening result may be used to determine the subject’s 
eligibility. Subjects may be retested once within 2 weeks of the screening test. Samples must be 
reanalyzed at the local laboratory. 
 
10. Able to swallow and retain orally-administered medication and without clinically significant 
gastrointestinal abnormalities that could alter absorption such as malabsorption syndrome or 
major resection of the stomach or bowels.  
11. Manual differential with no significant morphologic abnormalities other than those associated 
with the subject’s diagnosed type of advanced malignancy on complete blood count (CBC) 
testing. 
12. Females of childbearing potential (FCBP) must have a negative serum pregnancy test (beta-
human chorionic gonadotropin [β-hCG] test with a minimum sensitivity of 25 mIU/mL or 
equivalent units of β-hCG) at screening and within 24 hours prior to the first dose of study 
drug. All females will be considered to be of childbearing potential unless they are naturally 
postmenopausal (at least 12 months consecutively amenorrhoeic [amenorrhea following 
cancer therapy does not rule out childbearing potential] and without other known or suspected 
cause) or have been sterilized surgically (ie, total hysterectomy and/or bilateral 
oophorectomy, with surgery completed at least 28 days prior to the first dose of study drug). 
13. Females of childbearing potential (FCBP) must either practice complete abstinence or agree 
to use a highly effective method of contraception beginning at least 28 days prior to the first 
dose of study drug, during study treatment (including during dose interruptions), and for 6 
months after study drug discontinuation. If the below contraception methods are not 
appropriate for the FCBP, she must be referred to a qualified contraception provider to 
determine the medically effective contraception method appropriate for the subject. The 
following are examples of highly effective methods of contraception (result in a failure rate of 
<1% per year when used consistently and correctly): 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
• 
Hormonal (ovulation inhibitory combined [estrogen and progesterone]: oral, intravaginal, 
or transdermal; ovulation inhibitory progesterone-only: oral, injectable, or implantable) 
NOTE: Due to the potential of enzyme induction with tazemetostat, hormonal 
contraception methods must be supplemented with a barrier method of contraception 
(preferably male condom) 
• 
Bilateral tubal ligation 
• 
Partner’s vasectomy (if medically confirmed [azoospermia] and sole sexual partner) 


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NOTE: Female subjects of childbearing potential exempt from these contraception 
requirements are subjects who practice complete abstinence from heterosexual sexual contact. 
True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, or post-ovulation 
methods) and withdrawal are not acceptable methods of contraception. 
14. Male subjects must have had a successful vasectomy (with medically confirmed 
azoospermia) OR must either practice complete abstinence or agree to use a latex or synthetic 
condom during sexual contact with a female of childbearing potential (FCBP) from the first 
dose of study drug, during study treatment (including during dose interruptions), and for 3 
months after study drug discontinuation. 
NOTE: Male subjects must not donate sperm from the first dose of study drug, during study 
treatment (including during dose interruptions), and for 3 months after study drug 
discontinuation. 
15. Has a QT interval corrected by Fridericia’s formula (QTcF) ≤450 msec. 
16. Subjects with diagnosed human immunodeficiency virus (HIV) are eligible to participate in 
the study if they meet the following criteria: 
a. No history of AIDS-defining opportunistic infections or have not had an 
opportunistic infection within the past 12 months prior to enrollment. 
b. No history of AIDS-defining cancers (eg, Kaposi’s sarcoma, aggressive B-cell 
lymphoma, and invasive cervical cancer). 
c. Subjects may take prophylactic antimicrobials, however subjects that are taking 
specific antimicrobial drugs where there may be drug-drug interaction or overlapping 
toxicities should be excluded from study participation (Table 7 and Table 8).  
d. Subjects should be on established anti-retroviral therapy for at least 4 weeks and have 
an HIV viral load of < 400 copies/mL prior to enrollment. 
 
Exclusion Criteria: 
Subjects meeting ANY of the following criteria must NOT be enrolled in this study: 
1. Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression as 
documented by CT or MRI scan, analysis of cerebrospinal fluid or neurological exam. 
Subjects with primary glioblastoma multiforme are excluded. 
Note: Subjects with clinically stable brain metastases are eligible to enroll in the study. 
2. Clinically significant bleeding diathesis or coagulopathy, including known platelet function 
disorders. Subjects on anticoagulation with low molecular weight heparin are allowed. 
3. Known hypersensitivity to any of the components of tazemetostat, itraconazole or rifampin. 
4. Use of concurrent investigational agent or anticancer therapy. 
Note: megestrol (Megace) if used as an appetite stimulant is allowed. 
a. Concurrent treatment with bisphosphonates is permitted; however, treatment must be 
initiated prior to the first dose of tazemetostat. Prophylactic use of bisphosphonates in 
subjects without bone disease is not permitted, except for the treatment of 
osteoporosis. 
b. The concurrent use of all herbal supplements is prohibited during the study as the 
composition, PK, and metabolism of many herbal supplements are unknown. 
5. Uncontrolled concurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, clinically significant cardiac 
arrhythmias, or psychiatric illness/social situations that would limit compliance with study 
requirements. 


Clinical Study Protocol 
 
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6. Have a known active infection with hepatitis B virus (HBV), as measured by positive 
hepatitis B surface antigen; hepatitis C virus (HCV), as measured by positive hepatitis C 
antibody; AND/OR human T-cell lymphotropic virus 1, as measured by positive HTLV-1 
antibody. 
Exceptions: Subjects with a history of hepatitis B or C who have normal alanine 
aminotransferase (ALT) values and are hepatitis B surface antigen negative with undetectable 
HBV DNA and/or have undetectable HCV RNA if hepatitis C antibody positive. 
7. Subjects taking medications that are known CYP3A4 inducers or inhibitors (including St. 
John’s Wort) (Table 7 and Table 8). 
8. Is unwilling to exclude grapefruit juice, Seville oranges and grapefruit from the diet and all 
foods that contain those fruits from 24 hours prior to the first dose of study drug until the last 
dose of study drug. 
9. Any condition or medical problem in addition to the underlying malignancy and organ 
dysfunction that the Investigator feels would pose unacceptable risk. 
10. Has thrombocytopenia, neutropenia, or anemia of grade ≥3 (per CTCAE v5.0 criteria) or any 
prior history of myeloid malignancies, including myelodysplastic syndrome (MDS)/acute 
myeloid leukemia (AML) or myeloproliferative neoplasm (MPN). 
11. Has cytogenetic abnormalities known to be associated with myeloid malignancies, such as 
those for MDS (eg, del 5q, chr 7, abn) or MPN (eg, JAK2 V617F). 
12. Has a prior history of T-cell lymphoblastic lymphoma (T-LBL)/T-cell acute lymphoblastic 
leukemia (T-ALL). 
13. Ingestion of alcohol within 72 hours prior to day 1 of Cycle 1 until the end of Cycle 1 (Day 
39 for Part 1 and Day 26 for Part 2). Regular alcohol consumption must not exceed 16 units 
for males and 7 units for females per week (2 units equals 440 mL [a can] of beer, 175 mL [a 
standard glass] of wine, or 50 mL [2 small shots] of spirits) after Cycle 1 until the end of 
treatment. 
14. Any form of marijuana use. 
15. History of drug abuse (including alcohol) within the last 6 months prior to screening. 
Study drug, dosage, and mode of administration:  
Part 1: Tazemetostat and itraconazole 
Subjects in Part 1 of the study will receive a single oral dose of 400 mg tazemetostat on day 1, 15, and 
day 36. The subjects will receive tazemetostat (oral 400 mg dose) tablets to be taken twice daily from 
day 3 – 14 and day 21 – 35.  
Part 2: Tazemetostat and rifampin 
Subjects in Part 2 of the study will receive a single oral dose of 800 mg tazemetostat on day 1, 15 and 
day 24. The subjects will receive tazemetostat (oral 800 mg dose) tablets to be taken twice daily from 
day 3 – 14 and day 17 – 23.  
The subjects will be requested to maintain a medication diary of each dose of tazemetostat. The 
dosing diary must be returned to the site staff at each visit. 
Other medications, dose, and mode of administration: Itraconazole and Rifampin  
Part 1: Tazemetostat and Itraconazole 
Subjects will receive itraconazole (oral 200 mg dose) to be taken daily from day 18 – 38.  
Part 2: Tazemetostat and Rifampin  
Subjects will receive rifampin (oral 600 mg dose) to be taken daily on day 17 – 25. 
Duration of treatment for tazemetostat:  
Part 1: Tazemetostat and Itraconazole 


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Epizyme, Inc. 
Confidential 
Subjects in Cycle 1 Part 1 of the study will be treated for 39 days. On day 1, 15, and 36, subjects will 
receive a single dose of 400 mg tazemetostat. On day 3 – 14, and from 21 – 35, subjects will receive a 
twice daily dose of 400 mg tazemetostat.  
Part 2: Tazemetostat and Rifampin 
Subjects in Cycle 1 Part 2 of the study will be treated for 26 days. On day 1, 15, and 24 subjects will 
receive a single dose of 800 mg tazemetostat. On day 3 – 14, and from 17 – 23, subjects will receive a 
twice daily dose of 800 mg tazemetostat.  
Criteria for evaluation: 
Pharmacokinetics: Plasma tazemetostat and EPZ 6930 concentrations will be determined for both 
single and multi-dose and the following parameters will be calculated, as data permit: 
• 
AUC0–t: area under the plasma concentration-time curve from time 0 to the time of the 
last quantifiable concentration 
• 
AUC0-24: area under the plasma concentration-time curve from time 0 to 24 hours post-
dose 
• 
AUC0-48: area under the plasma concentration-time curve from time 0 to 48 hours post-
dose 
• 
AUC0-72: area under the plasma concentration-time curve from time 0 to 72 hours post-
dose 
• 
Cmax: observed maximum plasma concentration 
• 
Tmax: observed time at Cmax 
• 
 λz: terminal phase elimination rate constant 
• 
t1/2: terminal elimination half-life 
Safety: The following safety parameters will be recorded during the study: 
• 
Adverse event and serious adverse event assessment 
• 
Physical examination 
• 
Vital signs (blood pressure, heart rate, body temperature) 
• 
12-lead ECG 
• 
Clinical laboratory tests (hematology including coagulation profile, serum chemistries, 
urinalysis) 
• 
ECOG performance status 
• 
Concomitant medication monitoring 
Statistical methods: 
PK analyses: 
Plasma concentrations of tazemetostat and its metabolite (EPZ6930) will be determined by validated 
bioanalytical methods. Plasma concentrations of tazemetostat and its metabolite (EPZ6930) will be 
listed for each subject and summarized by study part, treatment, day, and nominal time. Standard 
summary statistics will be calculated (ie, arithmetic mean, geometric mean, standard deviation, 
median, minimum, and maximum) for each endpoint.  


Clinical Study Protocol 
 
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Epizyme, Inc. 
Confidential 
All PK parameters will be calculated with noncompartmental methods using actual times. The 
following PK parameters will be determined as data permit: 
Part 1: Plasma AUC0-72, Cmax, Tmax, and t½ for tazemetostat alone on day 15 – 18, and in the presence 
of itraconazole on day 36 – 39.  
Part 2: Plasma AUC0-48, Cmax, Tmax, and t½ for tazemetostat alone on day 15 – 17, and in the 
presence of rifampin on day 24 – 26. 
Safety analyses: Safety analyses will be based on all subjects who receive at least 1 dose or partial 
dose of study drugs (Safety population). Drug exposure will be summarized using descriptive 
statistics. The severity of all adverse events is to be evaluated by the Investigator based on the 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 and verbatim terms will be coded to the preferred term (PT), higher level term (HLT), and system 
organ class (SOC) using the Medical Dictionary for Regulatory Activities (MedDRA) version in use 
at the time of the analysis. The number and percentage of subjects with adverse events will be 
presented by MedDRA SOC and PT, relationship to study treatment, and severity. Laboratory values 
also will be classified by toxicity grade based on the NCI’s CTCAE, version 5.0. Laboratory shift 
tables from baseline result to the worst post-baseline result will be provided. AEs will be summarized 
overall and separately for: serious AEs, AEs leading to discontinuation, AEs leading to death, Grade 
3, or higher AEs (per NCI CTCAE Version 5.0). Vital signs and ECG will be descriptively 
summarized based on marked abnormality criteria. 
Analyses will be done separately for each study part and overall. 
Efficacy analysis:  
 No efficacy analysis will be performed. 


Clinical Study Protocol 
EZH-108 
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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF
FIGURES 
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1
SIGNATURE PAGE .......................................................................................................................2 
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
PROCEDURES IN CASE OF EMERGENCY ...............................................................................4 
PROTOCOL AMENDMENT AND SUMMARY OF CHANGES ................................................5 
Details of substantial changes to the protocol include: ....................................................................5 
Details of non-substantial changes to the protocol include: ............................................................7 
2. 
SYNOPSIS ...................................................................................................................9
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............18
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................23
5. 
INTRODUCTION ......................................................................................................26
5.1. 
Background .................................................................................................................26 
5.1.1. 
Hematologic Malignancies .........................................................................................26 
5.1.2. 
Solid Tumors ..............................................................................................................27 
5.2. 
Tazemetostat ...............................................................................................................27 
5.2.1. 
Nonclinical Pharmacology ..........................................................................................27 
5.2.2. 
Pharmacokinetics ........................................................................................................27 
5.2.3. 
Pharmacodynamics .....................................................................................................28 
5.2.4. 
Effect of Other Drugs on Exposure to Tazemetostat ..................................................28 
5.2.5. 
Effect of Tazemetostat on Exposure to Other Drugs ..................................................29 
5.3. 
Study Rationale ...........................................................................................................29 
5.4. 
Clinical Experience .....................................................................................................29 
5.5. 
Benefit:Risk Assessment ............................................................................................30 
5.5.1. 
Clinical and Nonclinical Safety Profile ......................................................................30 
5.5.2. 
Conclusion ..................................................................................................................31 
6. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................32
6.1. 
Study Objectives and Endpoints .................................................................................32 
7. 
INVESTIGATIONAL PLAN .....................................................................................34
7.1. 
Overall Study Design ..................................................................................................34 


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7.2. 
Number of Subjects ....................................................................................................36 
7.3. 
Treatment Assignment ................................................................................................36 
7.4. 
Restrictions During Study Treatment .........................................................................36 
7.5. 
Dose Adjustment Criteria ...........................................................................................37 
7.5.1. 
Dose Modification ......................................................................................................37 
7.5.2. 
Dose Modification due to Treatment-Related Toxicity ..............................................37 
7.5.3. 
Continuation of Treatment ..........................................................................................39 
7.5.4. 
Rules for Suspension of Enrollment ...........................................................................39 
7.6. 
Criteria for Study Termination ...................................................................................39 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................50 
8.1. 
Subject Inclusion Criteria ...........................................................................................50 
8.2. 
Subject Exclusion Criteria ..........................................................................................52 
8.2.1. 
Subject Withdrawal Criteria .......................................................................................54 
8.2.2. 
Withdrawal of Subjects from Treatment/Procedures .................................................54 
8.2.3. 
Withdrawal of Subjects from Study ...........................................................................54 
8.2.4. 
Replacement of Subjects .............................................................................................54 
9. 
TREATMENT OF SUBJECTS ..................................................................................56 
9.1. 
Description of Study Drug ..........................................................................................56 
9.2. 
Concomitant Medications ...........................................................................................56 
9.2.1. 
Permitted Medications ................................................................................................57 
9.2.2. 
Medications to be Used with Caution .........................................................................57 
9.2.3. 
Prohibited Medications ...............................................................................................57 
9.2.4. 
Non-Drug Therapies ...................................................................................................60 
9.3. 
Treatment Compliance ................................................................................................60 
9.3.1. 
Special Situations: Overdose, Misuse, Abuse and Medication Error .........................60 
9.4. 
Randomization and Blinding ......................................................................................61 
9.5. 
Treatment of Overdose ...............................................................................................61 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................62 
10.1. 
Study Drug ..................................................................................................................62 
10.2. 
Study Drug Packaging and Labeling ..........................................................................62 
10.3. 
Study Drug Storage .....................................................................................................62 
10.4. 
Study Drug Preparation ..............................................................................................62 
10.5. 
Study Drug Administration .........................................................................................63 


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10.5.1. 
Missed Doses ..............................................................................................................65 
10.6. 
Study Drug Accountability .........................................................................................65 
10.7. 
Study Drug Handling and Disposal ............................................................................65 
11. 
PHARMACOKINETIC ASSESSMENTS .................................................................66 
11.1. 
Blood Sample Collection ............................................................................................66 
11.2. 
Sample Analysis .........................................................................................................66 
12. 
ASSESSMENT OF SAFETY .....................................................................................67 
12.1. 
Consent .......................................................................................................................67 
12.2. 
Screening Assessments ...............................................................................................67 
12.2.1. 
Demographic/Medical History ...................................................................................67 
12.3. 
Safety Parameters .......................................................................................................67 
12.3.1. 
Vital Signs ..................................................................................................................67 
12.3.2. 
Weight and Height ......................................................................................................68 
12.3.3. 
Physical Examination .................................................................................................68 
12.3.4. 
Electrocardiogram (ECG) ...........................................................................................68 
12.3.5. 
Disease Assessment ....................................................................................................69 
12.3.6. 
End of Study Pharmacokinetics ..................................................................................69 
12.3.7. 
Laboratory Assessments .............................................................................................69 
12.3.7.1. 
Estimated Glomerular Filtration Rate .........................................................................70 
12.3.8. 
ECOG Performance Status .........................................................................................70 
12.3.9. 
Drug and Alcohol Screen ............................................................................................70 
12.3.10. 
Pregnancy/Post-Menopausal Testing ..........................................................................70 
12.3.11. 
Pregnancy ...................................................................................................................70 
12.3.11.1. Definition of Childbearing Potential: Female Subjects ..............................................70 
12.3.11.2. Definition of Childbearing Potential: Male Subjects ..................................................71 
12.3.11.3. Pregnancy Prevention .................................................................................................71 
12.3.12. 
Unscheduled Visits .....................................................................................................72 
12.4. 
Adverse and Serious Adverse Events .........................................................................73 
12.4.1. 
Definition of Adverse Events .....................................................................................73 
12.4.1.1. 
Adverse Event (AE) ....................................................................................................73 
12.4.1.2. 
Serious Adverse Event (SAE) ....................................................................................73 
12.4.1.3. 
Laboratory Abnormalities ...........................................................................................74 
12.4.1.4. 
Other Safety Assessment Abnormalities ....................................................................74 


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12.4.1.5. 
Disease-Related Events ..............................................................................................75 
12.4.1.6. 
Other Adverse Event (OAE) .......................................................................................75 
12.4.2. 
Adverse Events of Special Interest (AESIs) ...............................................................75 
12.4.2.1. 
T-Cell Lymphoblastic Lymphoma/T-Cell Acute Lymphoblastic Leukemia .............75 
12.4.2.2. 
Myelodysplastic Syndrome/Acute Myeloid Leukemia/ Other Malignancies 
Like Myeloproliferative Neoplasms ...........................................................................76 
12.4.2.3. 
Dose Modification for Occurrence of Myeloid Dysplastic Syndrome/Acute 
Myeloid Leukemia or Other Malignancies Like Myeloproliferative 
Neoplasms ...................................................................................................................76 
12.4.2.4. 
Quarterly and External Safety Review: The Tazemetostat Safety Committees .........77 
12.4.3. 
Potential Safety Signal Under Evaluation: B-cell Acute Lymphoblastic 
Leukemia (B-ALL) .....................................................................................................77 
12.4.4. 
Grading and Severity ..................................................................................................78 
12.5. 
Relationship to Study Drug ........................................................................................79 
12.6. 
Recording Adverse Events .........................................................................................80 
12.7. 
Reporting Adverse Events ..........................................................................................80 
12.8. 
Reporting of Serious Adverse Events .........................................................................81 
12.9. 
Reporting of Pregnancy ..............................................................................................81 
12.10. 
Reporting of Adverse Events of Special Interest ........................................................82 
12.11. 
Reporting of Special Situations: Overdose, Misuse, Abuse, or Medication 
Error ............................................................................................................................82 
13. 
STATISTICS ..............................................................................................................83 
13.1. 
Study Design Considerations ......................................................................................83 
13.1.1. 
Determination of Sample Size ....................................................................................83 
13.2. 
PK analyses .................................................................................................................83 
13.3. 
Safety analyses ............................................................................................................84 
13.4. 
Efficacy analysis .........................................................................................................84 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .........................................85 
14.1. 
Study Monitoring ........................................................................................................85 
14.2. 
Audits and Inspections ................................................................................................85 
14.3. 
Institutional Review Board (IRB) ...............................................................................86 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................87 
16. 
ETHICS ......................................................................................................................88 
16.1. 
Ethics Review .............................................................................................................88 


Cli nical St u d y Pr ot oc ol  
 
E Z H- 1 0 8  
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A me n d me nt 2. 0
 
 
3 1  A u g ust 2 0 2 1  
E piz y me, I nc.  
C o nfi de n tial 
1 6. 2.  
Et hical C o n d uct of t he St u d y  ...................................................................................... 8 8 
1 6. 3.  
Writte n I nf or me d C o nse nt  .......................................................................................... 8 8 
1 7.  
D A T A H A N D LI N G A N D R E C O R D K E E PI N G  ....................................................... 8 9 
1 7. 1.  
I ns pecti o n of Rec or ds ................................................................................................. 8 9 
1 7. 2.  
Rete nti o n of Rec or ds  .................................................................................................. 8 9 
1 8.  
P U B LI C A TI O N P O LI C Y  .......................................................................................... 9 0 
1 9.  
LI S T O F R E F E R E N C E S  ............................................................................................ 9 1 
 
 
 
 
LI S T O F T A B L E S  
Ta ble  1: 
La b orat or y Val ues f or He patic, He mat ol o gic a n d Re nal F u ncti o n  ............................ 1 2 
Ta ble  2: 
D ose M o dificati o ns f or Taze met ostat Treat me nt -Relate d T o xicities ( C ycle 
2 +)  ............................................................................................................................... 3 8 
Ta ble  3: 
Sc he d ule of Assess me nts ( Part 1: Taze met ostat a n d Itrac o naz ole)  ............................ 4 4 
Ta ble  4: 
Sc he d ule of Assess me nts ( Part 2: Taze met ostat a n d Rifa m pi n)  ................................ 4 7 
Ta ble  5: 
La b orat or y Val ues f or He patic, He mat ol o gic a n d Re nal F u ncti o n  ............................ 5 0 
Ta ble 6:  
St u d y Dr u gs  ................................................................................................................ 5 6 
Ta ble  7: 
E xa m ples of cli nical i n hi bit ors f or P 4 5 0 -me diate d meta b olis ms a n d 
tra ns p orter ................................................................................................................... 5 8 
Ta ble  8: 
E xa m ples of cli nical i n d ucers f or P 4 5 0 -me diate d meta b olis ms a n d s u bstrate  ........... 5 9 
Ta ble  9: 
Ti mi n g All o wa nce Wi n d o ws f or Vital Si g n Meas ure me nts, E C G 
Assess me nts a n d P har mac o ki netic Sa m pli n g  ............................................................. 6 6 
 
LI S T O F FI G U R E S  
Fi g ure 1:  
St u d y Desi g n  ............................................................................................................... 4 1 
Fi g ure 2:  
St u d y Sc he ma ( Part 1: Taze met ostat a n d Itrac o naz ole)  ............................................. 4 2 
Fi g ure 3:  
St u d y Sc he ma ( Part 2: Taze met ostat a n d Rifa m pi n)  .................................................. 4 3 
 
C CI
C CI
C CI
C CI
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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Abbreviation or Specialist Term 
Explanation 
AE 
Adverse event 
AESIs 
Adverse Events of Special Interest 
AIDS 
acquired immunodeficiency syndrome 
ALT 
Alanine aminotransferase 
AML 
Acute myeloid leukemia 
ANC 
Absolute neutrophil count 
AUC 
Area under the concentration-time curve 
β-hCG 
beta-human chorionic gonadotropin 
B-ALL 
B-cell Acute Lymphoblastic Leukemia 
B-LBL 
B-cell lymphoblastic lymphoma 
BM 
Bone marrow 
BP 
Blood pressure 
CBC 
Complete blood count 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
Cmax 
Curve [AUC] and maximum concentration 
CR 
Complete response 
CRF 
Case report form 
CSR 
Clinical study report 
CT 
Computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DDI 
Drug-drug interactions 
DLBCL 
Diffuse large B-cell lymphoma 
DNA 
deoxyribonucleic acid 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
ES 
Epithelioid sarcoma 
ESC 
External Safety Committee 
EZH2 
Enhancer of zeste homologue 2 
FCBP 
Females of childbearing potential 
FL 
Follicular lymphoma 
FSH 
Follicle-stimulating hormone 


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Abbreviation or Specialist Term 
Explanation 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
GOF 
Gain-of-function 
H3K27 
Histone 3 lysine 27 
H3K27me3 
Trimethylated state of histone 3 lysine 27 
HATs 
Histone acetyl transferases 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HMTs 
Histone methyltransferases 
HR 
Heart rate 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
INI1 
Integrase interactor 1 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone-releasing system 
MDS 
Myelodysplastic syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
Min 
Metastasis in prostate cancer 
MLL2 
Mixed lineage leukemia protein 2 
MPN 
Myeloproliferative neoplasms 
MRI 
Magnetic resonance imaging 
NCI  
National Cancer Institute  
NCI CTCAE 
National Cancer Institute Common Terminology 
Criteria for Adverse Events 
NGS 
next generation sequencing 
NHL 
Non-Hodgkin lymphoma 
P-gp 
P-glycoprotein 
PK 
Pharmacokinetics 
QSR 
Quarterly Safety Review 
QTcF 
QT interval corrected by Fridericia’s formula 
R/R 
relapsed or refractory 


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Abbreviation or Specialist Term 
Explanation 
RNA 
ribonucleic acid 
SAE 
Serious adverse event 
SD 
Standard deviation 
SET 
Sun(var)3-9, enhancer-of-zeste and trithorax 
SMARCA4 
SMARC, subfamily A, member 4 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reaction 
T 
Temperature 
t½ 
half-life 
T-ALL 
T-cell acute lymphoblastic leukemia 
TEAE 
Treatment-emergent adverse event 
TESAE 
Treatment-emergent serious adverse event 
T-LBL 
T-cell lymphoblastic lymphoma 
Tmax 
To maximum plasma concentration 
ULN 
Upper limit of normal 
WBC 
White blood cell 
WT 
Wild-type 
 
 


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5. 
INTRODUCTION 
This document is a protocol for a human research study. This study is to be conducted according 
to: United States and international standards of GCPs, FDA Title 21 Part 312, and International 
Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use 
(ICH) guidelines; applicable government regulations; and institutional research policies and 
procedures. 
5.1. 
Background 
Post-translational modifications of histones, the core proteins of chromatin, play an important 
role in controlling the fidelity of cellular gene transcription patterns. One of the critical 
transcription-controlling histone modifications is methylation of specific lysine and arginine 
residues, catalyzed by histone methyltransferases (HMTs) which all use S-adenosyl methionine 
(SAM) as a co-factor for the methylation reaction (Copeland, 2013). Genetic alterations in a 
number of HMTs or associated regulatory proteins have been identified in several human cancers 
where they are purported to be oncogenic. Enhancer of zeste homolog 2 (EZH2) is the catalytic 
subunit of the multi-protein polycomb repressive complex 2 (PRC2) that catalyzes the mono-, di, 
and trimethylation of lysine 27 of histone H3 (H3K27) (Margueron, 2011).  
Enhancer of zeste homolog-2 mutation and/or over-expression has been observed in several 
cancer types, leading to an aberrant H3K27 trimethylation (H3K27me3) state which is oncogenic 
(Chase, 2011). For instance, somatic EZH2 gain-of-function (GOF) mutations at three hotspots 
(Y646, A682, and A692 [NM_001203247]) are found in 10% to 20% of follicular lymphoma 
(FL) and diffuse large B-cell lymphoma (DLBCL). These GOF mutations result in an oncogenic 
dependency on EZH2 production of abnormally high H3K27me3 levels, and resultant 
transcriptional reprogramming of the cell (Morin, 2010). 
5.1.1. 
Hematologic Malignancies 
Somatic mutations within the EZH2 gene on 3 hotspots (Y646, A682, and A692 
[NM_001203247]) are present in follicular lymphoma (FL) and diffuse large B-cell lymphoma 
(DLBCL) and lead to high levels of H3K27 trimethylation (H3K27me3) in these lymphomas. 
Those mutations of EZH2, therefore, have been proposed to be required for the development and 
maintenance of the 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 mixed lineage leukemia protein 2 (MLL2) and histone acetyl transferases (HATs) 
may generate abnormal methylation states of H3K27, potentially leading to a dependency 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 are growth inhibited with EZH2 inhibition in vitro, only mutant bearing cells undergo cell 
death in culture (Beguelin, 2013; Knutson, 2014). 
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, 


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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 wild-type cases could also be affected through 
tumor cell autonomous mechanisms (mutations in MLL2, HATs, ubiquitously transcribed 
tetratricopeptide repeat, X chromosome [UTX], etc) and/or effects of EZH2 inhibitors on the 
tumor microenvironment. 
5.1.2. 
 Solid Tumors 
In addition to the EZH2 GOF activation mutations described above, overexpression or 
amplification of EZH2 has been described in numerous tumor types, including but not limited to 
bladder, breast cancer, colorectal, lung, pancreatic, ovarian, prostate, mesothelioma, uveal 
melanoma, renal carcinoma, cholangiocarcinoma, and stomach cancer (Kuroki, 2014; LaFave, 
2015; Comet, 2016). This is partially explained by the regulation of EZH2 gene expression by 
the pRB-E2F pathway, which is dysregulated in many tumor types (Bracken, 2003). In many of 
these tumors, EZH2 has been demonstrated to function as an oncogene (Comet, 2016). For 
instance, EZH2 overexpression promotes anchorage-independent growth and cell invasion in 
breast cancer (Kleer, 2003), proliferation and epithelial-mesenchymal transition in lung cancer 
(Takawa, 2011; Tiwari, 2013), and tumorigenesis and metastasis in prostate cancer (Min, 2010).  
These data suggest that inhibition of EZH2 might also be beneficial in solid tumors that 
overexpress EZH2 or contain amplifications of the EZH2 gene.  
5.2. 
Tazemetostat 
5.2.1. 
Nonclinical Pharmacology 
Tazemetostat (EPZ-6438) is a highly selective small molecule inhibitor of the histone-lysine 
methyltransferase EZH2 gene. Tazemetostat inhibits both wild-type (WT) and mutant EZH2 
mutated at residues Y641, A677G and A687 with half maximal inhibitory concentrations (IC50) 
ranging from 2-38 nmol/L. The compound shows a 36-fold selectivity over the most closely 
related HMT, EZH1, and greater than a 4500-fold selectivity over other HMTs. It selectively 
inhibits intracellular H3K27 methylation in a concentration- and time- dependent manner in all 
cell lines tested in vitro to date.  
Additional details are provided in the current tazemetostat Investigator’s Brochure (IB). 
5.2.2. 
Pharmacokinetics  
Tazemetostat is orally bioavailable in subjects with hematologic and solid tumor malignancies. 
The absorption is rapid with a median time to maximum plasma concentration (tmax) of 1 to 2 
hours. The mean absolute bioavailability was approximately 33% (Study EZH-103). In dose 
escalation studies in subjects with hematologic and solid tumor malignancies, tazemetostat 
exhibited a more than dose-proportional increase in exposure (area under the concentration-time 
curve [AUC] and maximum concentration [Cmax]). At the recommended therapeutic dose of 800 
mg twice daily, the mean steady state Cmax was 829 ng/mL and AUC from 0 to 12 hours (AUC0-
12) was 3340 ng•hr/mL. The consistent tmax and apparent elimination half-life (t1/2) across the 


Cli nical St u d y Pr ot oc ol  
 
E Z H- 1 0 8  
Taze met ostat  
 
A me n d me nt 2. 0
 
 
3 1  A u g ust 2 0 2 1  
E piz y me, I nc.  
C o nfi de n tial 
ra n ge of d oses e val uate d ( 1 0 0 t o 1 6 0 0 m g t wice dail y) s u g gest o verall d ose-i n de pe n de nt 
a bs or pti o n a n d cleara nce. 
T here was n o differe nce i n relati ve bi oa vaila bilit y bet wee n l o w -fat a n d hig h- fat meal c o n diti o ns. 
A hi g h- fat meal e x hi bite d a ne gli gi ble effect o n t he e xte nt a n d rate of a bs or pti o n. A hi g h- fat 
meal s h o we d a 2 4 % a n d 1 8 % decrease i n taze met ostat C
ma x a n d A U C e x p os ures, w hile t he 
ge o metric mea n rati os f or C ma x  a n d A U C f or t he maj or meta b olite E P Z - 6 9 3 0 were cl ose t o 1, 
t here b y de m o nstrati n g t hat a si milar o verall s yste mic e x p os ure was see n after a hi g h-fat meal 
c o m pare d t o d osi n g i n t he faste d state.  
T here was little t o n o acc u m ulati o n ( C ma x  a n d A U C) of plas ma taze met ostat f oll o wi n g re peat 
d osi n g, li kel y d ue t o a ut o- i n d ucti o n. T he metab olite E P Z - 6 9 3 0 ha d mi ni mal acc u m ulati o n 
f oll o wi n g m ulti ple d osi n g. Taze met ostat is eli mi nate d pri maril y via he patic meta b olis m i n 
h u ma ns, wit h a p pr o xi matel y 8 8 % b o u n d t o plas ma pr otei ns. F oll o wi n g a d mi nistrati o n of a si n gle 
oral 8 0 0 m g d ose of ra di ola bele d taze met ostat, t he a vera ge perce nt rec o ver y of t he a d mi nistere d 
d ose was 1 5. 4 % i n uri ne a n d 8 7. 8 % i n feces. U nc ha n ge d taze met ostat acc o u nte d f or 1. 3 9 % of 
t he a d mi nistere d d ose rec o vere d i n uri ne a n d was n ot detecte d i n feces. 
5. 2. 3.  
P h ar m ac o d y n a mics  
Pre d ose a n d  p ost d ose s ki n p u nc h bi o psies were s uccessf ull y c ollecte d i n 3 2 s u bjects e nr olle d i n 
t he d ose-escalati o n part of St u d y E 7 4 3 8- G 0 0 0- 1 0 1. A d ose-de pe n de nt re d ucti o n i n tri -
met h ylati o n of l ysi ne 2 7 o n hist o ne H 3 ( H 3 K 2 7 me 3) was o bser ve d acr oss t he strat u m s pi n os u m 
la yer of t he s ki n, wit h a mar ke d decrease i n H 3 K 2 7 me 3 as taze met ostat A U C0- 1 2 i ncrease d after 
a d mi nistrati o n of d oses ra n gi n g fr o m 1 0 0 t o 8 0 0 m g t wice dail y. T he re d ucti o n i n H 3 K 2 7 me 3 
a p peare d t o reac h a platea u i n t he A U C 0- 1 2  o bser ve d i n t he 8 0 0 m g t wice dail y d ose c o h ort. A n 
i n hi bit or y ma xi m u m effect ( Ema x ) m o del– pre dicte d decrease i n H 3 K 2 7 me 3 at t he o bser ve d mea n 
A U C 0- 1 2 o n Da y 1 5 i n t he 8 0 0 m g t wice- dail y d ose c o h ort was m ore t ha n 8 0 % of t he ma xi m u m 
effect, i n dicati n g t hat tar get i n hi biti o n i n t he s ki n was near ma xi mal a n d t hat d o u bli n g t he d ose t o 
1 6 0 0 m g t wice dail y res ulte d i n o nl y a m o dest i ncre me ntal i ncrease i n t he i n hi biti o n of H 3 K 2 7 
met h ylati o n. T hese p har mac o d y na mic res ults i nf or me d t he deter mi nati o n of 8 0 0 m g t wice dail y 
as t he taze met ostat  rec o m me n de d p hase 2 d ose ( R P 2 D). 
5. 2. 4.  
Effect of Ot her Dr u gs o n E x p os ure t o T aze met ost at  
A t h or o u g h i n vesti gati o n f or dr u g i nteracti o n p ote ntial was d o ne b y c o n d ucti n g a series of i n 
vitr o st u dies w hic h i ncl u de d C Y P p he n ot y pi n g, meta b olic sta bilit y, s u bstrate a n d i n hi biti o n 
assess me nt of meta b olic tra ns p orters, a n d i n hi biti o n of maj or h u ma n C Y P e nz y mes. Base d o n 
t he res ults fr o m t he p o p ulati o n P K a nal yses, t he i m pact of c o nc o mita nt dr u gs o n taze met ostat 
e x p os ure was e val uate d. T hese res ults de m o nstrate t hat C Y P 3 A 4 i n hi bit ors, C Y P 3 A 4 i n d ucers, 
C Y P 2 D 6 i n hi bit ors, C Y P 2 D 6 i n d ucers a n d p H m o difiers ha d n o cli nicall y si g nifica nt effect o n 
taze met ostat e x p os ure s u g gesti n g t hat t hese dr u gs ma y be c o-a d mi nistere d wit h taze met ostat 
. Wit h res pect t o p ote ntial dr u g-dr u g i nteracti o ns ( D DI) ass ociate d wit h dr u g 
tra ns p orters, taze met ostat is a P- gl yc o pr otei n ( P- g p) s u bstrate b ut n ot a s u bstrate f or ot her dr u g 
tra ns p orters st u die d, i ncl u di n g breast ca ncer resista nce pr otei n, or ga nic a ni o n tra ns p orti n g 
p ol y pe pti de ( O A T P ) 1 B 1 a n d 1 B 3, or ga nic a ni o n tra ns p orters 1 a n d 3, or ga nic cati o n 
tra ns p orter 2, a n d m ulti dr u g a n d t o xi n e xtr usi o n 1. H o we ver, P- g p d oes n ot see m t o li mit 
taze met ostat a bs or pti o n i n s u bjects, pres u ma bl y d ue t o t he relati vel y g o o d passi ve per mea bilit y 
C CI




Cli nical St u d y Pr ot oc ol  
 
E Z H- 1 0 8  
Taze met ostat  
 
A me n d me nt 2. 0
 
 
3 1  A u g ust 2 0 2 1  
E piz y me, I nc.  
C o nfi de n tial 
•  Pr ostate ca nce r 
•  
 
•  
 
•  
 
5. 5.  
Be nefit: Ris k Assess me nt  
5. 5. 1.  
Cli nic al a n d N o ncli nic al S afet y Pr ofile  
Base d o n n o ncli nical t o xic ol o g y st u dies a n d t he cli nical e x perie nce as of 1 2 A pril 2 0 2 1, t his 
secti o n s u m marizes t he a ntici pate d safet y pr ofile f or taze met ostat.  
A m o n g t he 8 9 5 a d ult a n d pe diatric s u bjects treate d wit h taze met ostat m o n ot hera p y, 8 5 7 ( 9 6 %) 
su bjects e x p erie nce d at least 1 treat me nt -e mer ge nt a d verse e ve nt ( T E A E), wit h 5 9 7 ( 7 0 %) 
s u bjects e x perie nce d T E A Es assesse d as relate d  t o t he st u d y dr u g b y t he I n vesti gat or. Of s u bjects 
wit h T E A Es, 4 6 9 ( 5 5 %) s u bjects ha d T E A Es of Gra de 3 or 4 se verit y. Trea t me nt-relate d g ra de 3 
or 4 T E A Es occ urre d i n 1 6 1 ( 3 4 %) of s u bjects wit h gra de 3 or 4 T E A Es.  
T he f oll o wi n g treat me nt -e mer ge nt AEs, re gar dless of ca usalit y, ha ve bee n o bser ve d i n ≥1 0 % of 
a d ult s u bjects acr oss cli nical st u dies: na usea, fati g ue, v o miti n g, diarr hea, a ne mia, decrease d 
a p petite, ast he nia, d ys p nea, c o nsti pati o n, t hr o m b oc yt o pe nia, a n d a b d o mi nal pai n.  
T he m ost c o m m o n treat me nt-relate d treat ment -e mer ge nt A Es i n t he a d ult s u bjects acr oss cli nical 
st u dies i ncl u de: na usea, fati g ue, ast he nia, a ne mia, diarr hea, v o miti n g, t hr o m b oc yt o pe nia, 
decrease d a p petite, ne utr o pe nia, a n d al o pecia.  
Of t he 7 7 9 a d ult s u bjects recei vi n g taze met ostat m o n ot hera p y, 3 2 6 ( 4 2 %) e x perie nce d at least 
o ne treat m e nt-e mer ge nt seri o us a d verse e ve nt ( T E S A E). Treat me nt -relate d S A Es were re p orte d 
i n 5 8 ( 7 %) of s u bjects. Of t he 1 0 9 pe diatric s u bjects, 5 2 ( 4 8 %) e x perie nce d a T E S A E, a n d 1 0 
pe diatric s u bjects ( 9 %) e x perie nce d a T E S A E t hat was assesse d as relate d  b y t he I n vesti gat or. 
Of t he 8 9 5 a d ult a n d pe diatric s u bjects, 1 4 4 ( 1 6 %) s u bjects die d wit hi n 3 0 da ys of last d ose of 
taze met ostat. Of t he 1 4 4 deat hs, 1 3 5 ( 9 4 %) of t he deat hs were d ue t o disease  pr o gressi o n. I n 
a d diti o n, 2 deat hs, o ne t hat was d ue t o i ntesti nal o bstr ucti o n a n d o ne wit h a n u n k n o w n ca use, 
were assesse d as p ossi bl y treat me nt relate d b y t he I n vesti gat or. 
Of t he 1 0 9 pe diatric s u bjects, 3 0 ( 2 8 %) die d o n st u d y wit hi n 3 0 da ys of last d ose a n d 2 8 ( 9 3 %) 
of t h ose deat hs were d ue t o disease pr o gressi o n. 
T he m ost c o m m o n T E A Es le a di n g t o taze met ostat d ose i nterr u pti o n i n t he a d ult p o p ulati o n were 
t hr o m b oc yt o pe nia ( 5 %), ne utr o pe nia ( 3 %), a n d a ne mia a n d diarr hea (eac h 2 %). T he m ost 
c o m m o n T E A Es lea di n g t o taze met ostat d ose re d ucti o n acr oss all p o p ulati o ns were 
t hr o m b oc yt o pe nia, ne utr o pe nia a n d diarr hea re p orte d i n < 1 % of a d ult s u bjects.  
As of 1 2 A pril 2 0 2 1, 7 ( 0. 5 %) m yel oi d A E SI ha ve bee n re p orte d i n a n esti mate d c u m ulati ve 
e x p os ure of 1, 5 2 1 pa tie nts fr o m b ot h cli nical a n d p ost- mar keti n g s o urces. T he ris k of m yel oi d 
ne o plasia as a res ult of E Z H 2 i n hi biti o n is c o nsi dere d u ncertai n base d o n a vaila ble literat ure a n d 
E piz y me cli nical data. A ris k miti gati o n pla n is i n place t o e xcl u de p ote ntial s u bjects w h o ma y 
be pre dis p ose d t o de vel o pi n g a m yel oi d ne o plasia a n d f or earl y i de ntificati o n a n d m o nit ori n g of 
s u bjects w h o ma y be de vel o pi n g a m yel oi d ne o plasia.  
C CI
C CI
C CI


Clinical Study Protocol 
 
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Amendment 2.0
 
 
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Epizyme, Inc. 
Confidential 
In addition, as described in Section 5.4 and more extensively in Section 12.4.2 AESIs identified 
for the tazemetostat development program include: T-LBL/T-ALL, MDS, AML, and other 
myeloid malignancies like MPN. Epizyme considers the risk for T-LBL/T-ALL in tazemetostat 
clinical trials to be largely concentrated in pediatric subjects. One event of T-LBL has occurred 
in pediatric subjects (n=109). 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. As of 12 
April 2021, over 954 subjects (adults and pediatric) have been treated with tazemetostat as 
monotherapy and in combination with no other reported cases of T-LBL/T-ALL.  
As tazemetostat is a bromide salt, bromide levels were measured in the phase 1 study of 
tazemetostat in adults (Study E7438-G000-101) and pediatric subjects (Study EZH-102). As of 
12 April 2021, bromide elevation was reported in 5 (5%) of 109 pediatric subjects, all of which 
were considered to be related to tazemetostat treatment, but there were no associated AEs 
suggestive of bromide toxicity.  
Additionally, there are unknown risks of abnormal pregnancy outcomes and drug-drug 
interactions. Based on the nonclinical toxicology of tazemetostat, the potential risks associated 
with treatment include: T-LBL, bone changes, bile duct hyperplasia, lymphoid depletion, 
teratogenicity and phototoxicity.  
Further details of study designs, tazemetostat exposure, and AESI are outlined in the current IB.  
5.5.2. 
Conclusion 
Tazemetostat is a clinically active drug that has the potential to benefit both adult and pediatric 
subjects across different tumor types, including non-Hodgkin’s lymphoma (NHL) and INI1-
negative solid tumors where there are unmet medical needs. The safety of tazemetostat has 
remained favorable across the clinical development program in more than 895 subjects. See 
Appendix 4 for details regarding benefit/risk assessment during the COVID-19 pandemic. 




Clinical Study Protocol 
 
EZH-108 
Tazemetostat 
 
Amendment 2.0
 
 
31 August 2021 
Epizyme, Inc. 
Confidential 
Objective 
Endpoint 
Secondary 
• To evaluate the steady-state safety 
profile of tazemetostat when co-
administered as a single and twice daily 
oral dose with rifampin in subjects with 
advanced malignancies. 
 
• Safety parameters: Adverse event 
assessment, physical examination, vital 
signs (blood pressure, heart rate, body 
temperature), 12-lead ECG, clinical 
laboratory tests (hematology including 
coagulation profile, serum chemistries, 
urinalysis), ECOG performance status, 
and concomitant medication monitoring 
• To evaluate the steady-state PK of 
tazemetostat and its metabolites after 
administration alone and with rifampin. 
• AUC0–t: area under the plasma 
concentration-time curve from time 0 to 
the time of the last quantifiable 
concentration 
• Cmax: observed maximum plasma 
concentration 
• Tmax: observed time at Cmax 
•  λz: terminal phase elimination rate 
constant 
• t1/2: terminal elimination half-life 
 


Clinical Study Protocol 
 
EZH-108 
Tazemetostat 
 
Amendment 2.0
 
 
31 August 2021 
Epizyme, Inc. 
Confidential 
7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This two-part study is designed to characterize the steady-state PK of oral tazemetostat and its 
metabolite EPZ 6930 when administered as a single and twice daily dose in subjects with 
advanced malignancies while taken alone or in combination with either itraconazole or rifampin 
(Figure 1).  
Part 1: Tazemetostat and Itraconazole Drug Interaction  
Part 1 of the study will evaluate the drug-drug interaction between tazemetostat and itraconazole 
in an open-label, fixed sequential cross over design (Figure 2).  
A screening visit will occur within 30 days of signing an informed consent form (ICF). During 
the screening phase, subjects will be evaluated for eligibility to participate in the study. Subjects 
who meet the protocol criteria may be admitted in the evening to the clinical study center, or visit 
the clinic if staying locally, on day -1. For Cycle 1, subjects may be admitted to the clinical study 
center during PK sampling periods or must agree to stay locally with frequent clinic visits as 
required and, optional admission to the center, if available. Prior to dosing on day 1 of Cycle 1, 
subject eligibility will be reconfirmed. On day 1, a single oral dose of 400 mg tazemetostat will 
be administered in the morning (eg, 7 – 9 am) followed by 2 days of multiple blood sampling 
(day 1 – 3). From day 3 – 14, subjects will receive an oral 400 mg dose of tazemetostat twice 
daily (12 hours apart, once in the morning [eg, 7 – 9 am] and once in the evening [eg, 7 – 9 pm]). 
In the evening of day 14, subjects may be admitted to the clinical study center. On day 15, a 
single oral dose of 400 mg tazemetostat will be administered in the morning (eg, 7 – 9 am) 
followed by 3 days of multiple blood sampling (day 15 – 18). From day 18 – 20, a single dose of 
oral 200 mg itraconazole will be administered daily in the morning (eg, 7 – 9 am) after a meal. In 
the evening of day 20, subjects may be admitted to the clinical study unit. From day 21 – 35, 
subjects will receive an oral 400 mg dose of tazemetostat twice daily, once in the morning (eg, 7 
– 9 am) and once in the evening (eg, 7 – 9 pm), co-administered in the morning (eg, 7 – 9 am) 
after a meal with a single dose of oral 200 mg itraconazole followed by 1 day of multiple blood 
sampling (day 21 – 22). In the evening of day 35, subjects may be admitted to the clinical study 
center. On day 36, subjects will receive a single oral dose of 400 mg tazemetostat co-
administered in the morning (eg, 7 – 9 am) after a meal with a single dose of oral 200 mg 
itraconazole followed by 3 days of multiple blood sampling (day 36 – 39). Itraconazole will also 
be administered on day 37 and 38 as a single oral 200 mg daily dose in the morning (eg, 7 – 9 
am) after a meal. Note: Tazemetostat will not be administered on day 37 and 38. After the 72-
hour PK sample collection, safety assessments will be conducted on day 39. Sparse PK samples 
will be collected pre-dose (0 hour) and 2 hours post-dose on day 25, 28, 31, and 34. 
Subjects may discontinue from the study after completion of Cycle 1 or can continue treatment 
(Cycle 2+ onwards) until Investigator-assessed clinical progression per standard practice, or 
unacceptable toxicity, or until another discontinuation criterion is met. For subjects continuing 
tazemetostat treatment at the recommended therapeutic dose (oral 800 mg tazemetostat twice 
daily [12 hours apart]), Cycle 2 will begin on day 40 (Cycle 2 Day 1) and each subsequent cycle 
from Cycle 2+ onwards will be of 28-day duration. Safety and tolerability will be assessed 
throughout the subject’s participation. Subjects will be instructed to report any adverse events 


Cli nical St u d y Pr ot oc ol  
 
E Z H- 1 0 8  
Taze met ostat  
 
A me n d me nt 2. 0
 
 
3 1  A u g ust 2 0 2 1  
E piz y me, I nc.  
C o nfi de n tial 
t hat occ ur u p t o 3 0 da ys after t he last d ose of taze met ostat. S u bjects m ust ha ve a n e n d of st u d y 
visit 3 0 da ys after t he last d ose of taze met ostat f or safet y assess me nt.  
P art 2: T aze met ost at a n d Rif a m pi n Dr u g I nter acti o n  
Part 2 of t he st u d y will e val uate t he dr u g- dr u g i nteracti o n bet wee n taze met ostat a n d rifa m pi n i n 
a n o pe n- la bel, fi xe d se q ue ntial cr oss o ver desi g n (Fi g ure 3 ). 
A scree ni n g visit will occ ur wit hi n 3 0 da ys of si g ni n g a n i nf or me d c o nse nt f or m (I C F). D uri n g 
t he screeni n g p hase, s u bjects will be e val uate d f or eli gi bilit y t o partici pate i n t he st u d y. S u bjects 
w h o meet t he pr ot oc ol criteria ma y be a d mitte d i n t he e ve ni n g t o t he cli nical st u d y ce nter,  or visit 
t he cli nic if sta yi n g l ocall y, o n da y - 1. F or C ycle 1 s u bjects ma y be a d mitte d t o t he cli nical st u d y 
ce nter d uri n g P K sa m pli n g peri o ds or m ust a gree t o sta y l ocall y wit h fre q ue nt cli nic visits as 
re q uire d a n d o pti o nal a d missi o n t o t he ce nter if a vaila ble. Pri or t o d osi n g o n da y 1 of C ycle 1, 
s ubject eli gi bilit y will be rec o nfir me d. O n da y 1, a si n gle oral d ose of 8 0 0 m g taze met ostat will 
be a d mi nistere d i n t he m or ni n g (e g, 7 – 9 a m) f oll o we d b y 2 da ys of m ulti ple bl o o d sa m pli n g 
( da y 1 – 3). Fr o m da y 3 – 1 4, s u bjects will recei ve a n oral 8 0 0 m g dose of taze met ostat t wice 
dail y ( 1 2 h o urs a part o nce i n t he m or ni n g [e g, 7 – 9 a m] a n d o nce i n t he e ve ni n g [e g, 7 – 9 p m]). 
I n t he e ve ni n g of da y 1 4, s u bjects ma y be a d mitte d t o t he cli nical st u d y ce nter. O n da y 1 5, a 
si n gle oral d ose of 8 0 0 m g taze met ostat will be a d mi nistere d i n t he m or ni n g (e g, 7 – 9 a m) 
f oll o we d b y 2 da ys of m ulti ple bl o o d sa m pli n g ( da y 1 5 – 1 7). Fr o m da y 1 7 – 2 3, s u bjects will 
recei ve a n oral 8 0 0 m g d ose of taze met ostat t wice dail y, o nce i n t he m or ni n g (e g, 7 – 9 a m) a n d 
o nce i n t he e v e ni n g (e g, 7 – 9 p m), c o-a d mi nistere d i n t he m or ni n g (e g, 7 – 9 a m) o ne h o ur 
bef ore a meal wit h a si n gle d ose of oral 6 0 0 m g rifa m pi n. I n t he e ve ni n g of da y 2 3, s u bjects ma y 
be a d mitte d t o t he cli nical st u d y ce nter. O n da y 2 4, s u bjects will recei ve a si n gle oral d ose of 8 0 0 
m g taze met ostat c o -a d mi nistere d i n t he m or ni n g (e g, 7 – 9 a m) o ne h o ur bef ore a meal wit h a 
si n gle d ose of oral 6 0 0 m g rifa m pi n f oll o we d b y 2 da ys of m ulti ple bl o o d sa m pli n g ( da y 2 4 – 
2 6). Rifa m pi n will als o be a d mi nistere d o n da y 2 5 as a si n gle oral 6 0 0 m g d ose i n t he m or ni n g 
(e g, 7 – 9 a m) o ne h o ur bef ore a meal. N ote:  Taze met ostat will n ot be a d mi nistere d o n da y 2 5. 
After t he 4 8 - h o ur P K sa m ple c ollecti o n, safet y assess me nts will be c o n d ucte d o n da y 2 6. S parse 
P K sa m ples will be c ollect e d pre- d ose ( 0 h o ur) a n d 2 h o urs p ost- d ose o n da y 1 9 a n d 2 1. 
S u bjects ma y disc o nti n ue fr o m t he st u d y after c o m pleti o n of C ycle 1 or ca n c o nti n ue treat me nt 
( C ycle 2 + on war ds) u ntil I n vesti gat or- assesse d cli nical pr o gressi o n per sta n dar d practice, or 
u nacce p ta ble t o xicit y, or u ntil a n ot her disc o nti n uati o n criteri o n is met. F or s u bjects c o nti n ui n g 
taze met ostat treat me nt at t he rec o m me n de d t hera pe utic d ose ( 8 0 0 m g taze met ostat t wice dail y 
[ 1 2 h o urs a part]), C ycle 2 will be gi n o n da y 2 7 ( C ycle 2 Da y 1) a n d eac h s u bse q ue nt c ycle fr o m 
C ycle 2 + o n war ds will be of 2 8- da y d urati o n. Safet y a n d t olera bilit y will be assesse d t hr o u g h o ut 
t he s u bject’s partici pati o n. S u bjects will be i nstr ucte d t o re p ort a n y a d verse e ve nts t hat occ ur u p 
t o 3 0 da ys after t he last d ose of taze met ostat. S u bjects m ust ha ve a n e n d of st u d y visit 3 0 da ys 
after t he last d ose of taze met ostat f or safet y assess me nt.  
R oll o ver St u d y  
All s u bjects w h o recei ve t he rec o m me n de d t hera pe utic d ose of 8 0 0 m g taze met ostat t wice dail y 
[ 1 2 h o urs apart] f or 9 C ycle s or l o n ger, a n d are eli gi ble t o c o nti n ue recei vi n g taze met ostat, will 
tra nsfer t o a R oll o ver St u d y 
 f or m o nit ori n g a n d c o nti n ue d st u d y dr u g at t he 
I n vesti gat or a n d Me dical M o nit or’s discreti o n. 
C CI


Clinical Study Protocol 
 
EZH-108 
Tazemetostat 
 
Amendment 2.0
 
 
31 August 2021 
Epizyme, Inc. 
Confidential 
7.2. 
Number of Subjects 
Approximately 40 subjects will be enrolled in the study assuming about a 40% drop out rate to 
achieve 12 subjects who complete each part of the study for a total of 24 completed subjects. 
Subjects will complete either Part 1 or Part 2, but not both. 
Subjects who require a tazemetostat dose interruption or reduction during Cycle 1 of either Part 1 
or Part 2 will be replaced. During Cycle 1, subjects who miss two or more consecutive 
tazemetostat/itraconazole/rifampin doses or more than three tazemetostat/itraconazole/rifampin 
doses in total will be replaced. Subjects who miss two or more consecutive PK blood sample 
collections during either part of Cycle 1 will be replaced. Subjects that require replacement will 
be discontinued from study treatment. 
7.3. 
Treatment Assignment 
After obtaining written, informed consent, subjects with advanced malignancies will be screened 
according to the exclusion and inclusion criteria. Subjects who have complied with all selection 
criteria will receive a unique subject number upon enrollment in the study. Subject numbers will 
be allocated sequentially in the order in which subjects are enrolled. The Investigator or designee 
will enter the corresponding subject number and complete each eCRF. 
Subjects will be assigned to the study as follows: 
Part 1: Tazemetostat and Itraconazole Drug Interaction (Figure 2) 
Part 2: Tazemetostat and Rifampin Drug Interaction (Figure 3) 
Part 1: Tazemetostat and Itraconazole Drug Interaction 
Subjects in Part 1 of the study will receive a single oral, 400 mg dose of tazemetostat on Day 1, 
15, and Day 36. The subjects will receive tazemetostat (oral 400 mg dose) tablets to be taken 
twice daily from Day 3 – 14 and Day 21 – 35. In addition, the subjects will receive oral 200 mg 
itraconazole once daily from Day 18 – 38. Detailed schedule of assessments is provided in 
Table 3.  
Note: Subjects will not be dosed with tazemetostat on day 2, from day 16 – 20, 37, and 38.  
Part 2: Tazemetostat and Rifampin Drug Interaction 
Subjects in Part 2 of the study will receive a single, oral, 800 mg dose of tazemetostat on Day 1, 
15 and Day 24. The subjects will receive tazemetostat (oral 800 mg dose) tablets to be taken 
twice daily from Day 3 – 14 and Day 17 – 23. In addition, the subjects will receive oral 600 mg 
rifampin once daily from Day 17 – 25. Detailed schedule of assessments is provided in Table 4.  
Note: Subjects will not be dosed with tazemetostat on day 2, 16, and 25. 
7.4. 
Restrictions During Study Treatment 
Subjects will abstain from ingesting Seville oranges, grapefruit or grapefruit juice, and 
foods/beverages that contain those, for 24 hours prior to the first dose of study treatment until the 
last dose of study treatment. 


Clinical Study Protocol 
 
EZH-108 
Tazemetostat 
 
Amendment 2.0
 
 
31 August 2021 
Epizyme, Inc. 
Confidential 
Subjects should avoid prolonged exposure to sunlight while receiving study treatment. In 
addition, subjects should take other measures to avoid ultraviolet exposure including tanning 
beds. Use sunscreen, sunglasses, and protective clothing whenever outside. 
7.5. 
Dose Adjustment Criteria 
7.5.1. 
Dose Modification 
Tazemetostat dose interruptions and reductions will not be allowed in Cycle 1 (both Part 1 and 
Part 2). Dose modification only applies to Cycle 2 and beyond. If a dose interruption or reduction 
is required during Cycle 1, the subject will be discontinued from study treatment and replaced. 
For Cycle 2 and beyond, an interruption in the administration of tazemetostat for more than 14 
days must be discussed with the Medical Monitor before treatment can be resumed. Dose-
limiting toxicities are covered in Section 7.5.2.  
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 instructions in Table 2. 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. For any MDS/AML or other myeloid malignancies like MPN, tazemetostat will be 
discontinued.  
For subjects who require dose interruption due to tazemetostat-related toxicity after Cycle 1 of 
the study, the treatment may re-start once the toxicity has been resolved to Grade ≤ 1 or baseline, 
unless otherwise noted, according to the instructions in Table 2.  
For continuation of treatment for Cycle 2 and beyond, subjects must meet the following 
retreatment criteria: 
• Platelet count must be ≥ 75 × 109/L 
• Absolute neutrophil count (ANC) must be ≥1,000/mm3 (≥ 1.0 × 109/L) for 
hematologic malignancy subjects and ANC must be ≥1,500/mm3 (≥1.5 x 109/L) for 
solid tumor subjects. 
• Any Grade 3 or higher toxicity must have resolved to at least Grade 1 or baseline, 
unless otherwise noted. 
7.5.2. 
Dose Modification due to Treatment-Related Toxicity 
In Cycle 2 and beyond for tazemetostat, other toxicities that, in the opinion of the Investigator 
are possibly, probably, or definitely related to study treatment, should be managed per Table 2. 
Toxicities that are felt by the Investigator to be unrelated to tazemetostat but clinically significant 
should be discussed with the Medical Monitor. In the event of an urgent unrelated toxicity, study 
treatment should be interrupted as per Table 2. Dose re-escalation is not permitted. 


Clinical Study Protocol 
 
EZH-108 
Tazemetostat 
 
Amendment 2.0
 
 
31 August 2021 
Epizyme, Inc. 
Confidential 
Table 2: 
Dose Modifications for Tazemetostat Treatment-Related Toxicities (Cycle 
2+) 
Toxicitya 
During Therapy 
Approximate Dose 
Adjustmentb 
Grade 1 
All occurrences 
Continue tazemetostat 
Maintain dose level 
Grade 2c, d 
1st occurrence 
Interrupt tazemetostat until resolved to Grade ≤ 1 or 
baselineb 
Maintain dose level 
2nd occurrence  
(same or new toxicity) 
Restart at 600 mg twice daily 
3rd occurrence  
(same or new toxicity) 
Restart at 400 mg twice daily 
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 twice daily 
2nd occurrence  
(same or new toxicity) 
Restart at 400 mg twice daily 
3rd occurrence  
(same or new toxicity) 
Discontinue tazemetostat 
Not applicable 
Grade 3 Neutropenia (ANC: <1.0 – 0.5 × 109/L) 
ANC < 1.0 × 109/L 
1st occurrence 
Interrupt tazemetostat until resolved to ANC ≥ 1.0 × 
109/Lb 
 
Maintain dose level 
2nd occurrence  
Restart at 600 mg twice daily 
3rd occurrence  
Restart at 400 mg twice daily 
4th occurrence 
Discontinue tazemetostat 
Not applicable 
Grade 3 Thrombocytopenia 
1st occurrence  
Interrupt tazemetostat until resolved to Grade ≤ 1 or 
baselineb 
Restart at 600 mg twice daily 
2nd occurrence  
Restart at 400 mg twice daily 
3rd occurrence  
Discontinue tazemetostat 
Not applicable 
Grade 4 
1st occurrence 
Interrupt tazemetostat until resolved to Grade ≤ 1 or 
baselineb 
Restart at 600 mg twice daily 
2nd occurrence  
(same or new toxicity) 
Discontinue tazemetostat 
Not applicable 
Abbreviations: ANC = absolute neutrophil count 
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 Medical 
Monitor 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  


Cli nical St u d y Pr ot oc ol  
 
E Z H- 1 0 8  
Taze met ostat  
 
A me n d me nt 2. 0
 
 
3 1  A u g ust 2 0 2 1  
E piz y me, I nc.  
C o nfi de n tial 
d  E xcl u di n g Gra de 2 ne utr o pe nia a n d t hr o m b oc yt o pe nia  
7. 5. 3.  
C o nti n u ati o n of Tre at me nt  
After s uccessf ul c o m pleti o n of C ycle 1 ( b ot h Part 1 a n d Part 2), s u bjects w h o ha ve n ot 
e x perie nce d u nacce pta ble t o xici t y a n d ha ve n o si g ns or s y m pt o ms of pr o gressi ve disease per 
sta n dar d practice ma y c o nti n ue treat me nt ( C ycle 2 + o n war ds) wit h taze met ostat at t he 
rec o m me n de d t hera pe utic d ose ( oral 8 0 0 m g taze met ostat t wice dail y [ 1 2 h o urs a part]) u ntil 
I n vesti gat or-assesse d cli nical disease pr o gressi o n, u nacce pta ble t o xicit y, wit h dra wal of c o nse nt, 
or ter mi nati o n of t he st u d y b y t he S p o ns or. 
S u bjects w h o e x perie nce cli nical pr o gressi o n at t he e n d of C ycle 1, as assesse d b y I n vesti gat or 
per c urre nt  sta n dar ds of care i n t he abse nce of cli nical deteri orati o n, ma y be per mitte d t o 
c o nti n ue st u d y treat me nt ( C ycle 2 a n d be y o n d) if t he s u bject is recei vi n g cli nical be nefit i n t he 
o pi ni o n of t he I n vesti gat or. I n t he e ve nt of s uc h a sit uati o n, t he I n vesti gat or m ust c o ntact t he 
Me dical  M o nit or t o disc uss t he assess me nt of ris k: be nefit of mai ntai ni n g t he s u bject o n st u d y.  
All s u bjects w h o recei ve t he rec o m me n de d t hera pe utic d ose of 8 0 0 m g taze met ostat t wice dail y 
( 1 2 h o urs a part) f or 9 C ycles or l o n ger, a n d are eli gi ble t o c o nti n ue receivi n g taze met ostat, will 
tra nsfer t o a R oll o ver St u d y 
 f or m o nit ori n g a n d c o nti n ue d st u d y dr u g at t he 
I n vesti gat or a n d Me dical M o nit or’s discreti o n. 
7. 5. 4.  
R ules f or  S us pe nsi o n of E nr oll me nt 
T he I n vesti gat ors, I R Bs/ E Cs, a n d re g ulat or y a ge ncies will be ur ge ntl y i nf or me d if o ne or m ore 
s u bjects devel o p a n y of t he f oll o wi n g c o n diti o ns: 
•  Deat h  
•  A na p h yla xi s (a n gi oe de ma, h y p ote nsi o n, s h oc k, br o nc h os pas m, h y p o xia, or 
res pirat or y distress) 
•  T- L B L/ T -A L L  
S h o ul d st u d y e nr oll me nt or d osi n g be s us pe n de d, t he st u d y will n ot be restarte d u ntil all parties 
ha ve a gree d t o t he c o urse of acti o n t o be ta ke n a n d t he I R Bs/ E Cs ha ve bee n n otifie d. 
If a case of a d ult T-L B L/ T - A L L occ urs, e nr oll me nt will be s us pe n de d, a n d t he be nefit-ris k of t he 
dr u g will be assesse d b y t he Taze m et ostat Safet y C o m mittee a n d will be c o m m u nicate d t o all 
Healt h A ut h orities a n d Et hics C o m mittees ( Secti o n  1 2. 4. 2. 4  ). F or a n y T-L B L/ T -A L L, 
M D S/ A M L,  or ot her m yel oi d mali g na ncies li ke M P N, taze met ostat will be disc o nti n ue d.  
7. 6.  
Criteri a f or St u d y Ter mi n ati o n  
S h o ul d c o n diti o ns re q uiri n g f urt her clarificati o n arise bef ore t he decisi o n t o pr ocee d wit h or 
ter mi nate t he st u d y ca n be reac he d, t he st u d y will be sus pe n de d u ntil t he sit uati o n has bee n 
res ol ve d.  
T he S p o ns or has t he ri g ht t o ter mi nate t his st u d y a n d re m o ve all st u d y material fr o m t he site at 
a n y ti me. Exa m ples of w here t his mi g ht occ ur i ncl u de, b ut are n ot li mite d t o:  
C CI


Clinical Study Protocol 
 
EZH-108 
Tazemetostat 
 
Amendment 2.0
 
 
31 August 2021 
Epizyme, Inc. 
Confidential 
• When it becomes apparent that subject enrollment is unsatisfactory with respect to 
quality and/or quantity or data recording is inaccurate and/or incomplete on a chronic 
basis.  
• When the incidence and/or severity of AEs in this study indicates a potential health 
hazard caused by treatment with tazemetostat. 
 


Clinical Study Protocol
EZH-108
Tazemetostat
Amendment 2.0
31 August 2021
Epizyme, Inc.
Confidential
Figure 1: 
Study Design 


Clinical Study Protocol
EZH-108
Tazemetostat
Amendment 2.0
31 August 2021
Epizyme, Inc.
Confidential
Figure 2: 
Study Schema (Part 1: Tazemetostat and Itraconazole)


Clinical Study Protocol
EZH-108
Tazemetostat
Amendment 2.0
31 August 2021
Epizyme, Inc.
Confidential
Figure 3: 
Study Schema (Part 2: Tazemetostat and Rifampin)


Clinical Study Protocol 
 
EZH-108 
Tazemetostat 
 
Amendment 2.0
 
 
31 August 2021 
Epizyme, Inc. 
Confidential 
Table 3: Schedule of Assessments (Part 1: Tazemetostat and Itraconazole)  
 
Assessment 
Screeninga 
Baseline 
Cycle 1 
Cycle 
2+ 
End of 
Studyb 
Study Day 
Within 30 
days 
before day 
1 
-1 c, d 
1 
2 
3 
3 
to 
14 d 
15 
16 
17 
18 
18 
to 
20 d 
21 
 
21 
to 
35 d 
36 
37 
38 
39 
Every 
28 
days 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinic Visite 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Medical Historyf 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographicsg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and concomitant medicationsh 
Record from signing of informed consent through end of study 
Drug and alcohol screen 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
 
 
 
 
Pregnancy/Post-Menopausal testingi 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Vital signsj 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination (Complete) 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
 
 
 
X 
Physical Examination (Symptom-directed) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
ECOG Performance Status 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
 
 
X 
X 
12-lead ECGk 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
 
X 
 
X 
X 
PK Blood Samplel 
 
 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
AEs/SAEsm 
Record from signing of informed consent through end of study 
Laboratory Assessmentsn 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
 
 
X 
X 
X 
Tazemetostat Administration (QD)o 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
Tazemetostat Administration (twice daily)p  
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
Itraconazole Administration (QD)q  
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
 
 
 
Body Weight 
X 
 
X 
 
 
 
X 
 
 
 
 
X 
 
X 
 
 
 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease Assessmentr 
X 
According to standard-of-care until PD or EOS 
X 


Clinical Study Protocol 
 
EZH-108 
Tazemetostat 
 
Amendment 2.0
 
 
31 August 2021 
Epizyme, Inc. 
Confidential 
Assessment 
Screeninga 
Baseline 
Cycle 1 
Cycle 
2+ 
End of 
Studyb 
Study Day 
Within 30 
days 
before day 
1 
-1 c, d 
1 
2 
3 
3 
to 
14 d 
15 
16 
17 
18 
18 
to 
20 d 
21 
 
21 
to 
35 d 
36 
37 
38 
39 
Every 
28 
days 
 
HIV, HBV, HCV, HTLV-1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: AE = adverse event; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOS = End of study; HBV = hepatitis B virus; 
HCV = hepatitis C virus; HIV = human immunodeficiency virus; HTLV-1 = human T-cell lymphotropic virus 1; PD = disease progression; PK = 
pharmacokinetics; SAE = serious adverse event 
 
a Screening: Screening should be performed within 30 days before day 1. 
b End of Study: Subjects will have a safety follow-up visit, including disease assessment, 30 (±3) days after the last dose of tazemetostat, or prior to initiation of 
an investigational agent or cytotoxic chemotherapy, whichever occurs first. A blood sample will also be required for PK assessment. 
 c Prior to dosing, assessments must be performed to determine if subject continues to meet eligibility criteria. If screening assessments are preformed within 24 
hours prior to day -1 (baseline assessments), ie, day -2, they do not need to be repeated on day -1. 
 d For Cycle 1 subjects may be admitted to the clinical study center during PK sampling periods or must agree to stay locally with frequent clinic visits as required 
and optional admission to the center if available. Subjects may have the option to be admitted to the clinical study center in the evening of day -1, 14, 20, and 
35. During these admissions, laboratory assessments may be performed within 24 hours prior to when required on day 1, 15, 21, and 36. 
e Clinic Visit: Subjects will visit the clinical study unit from day -1 to day 3, from day 15 to 18, 21 to 22, 25, 28, 31, 34, and from day 36 to day 39 (Cycle 1). 
Cycle 2 day 1 will begin on day 40 (+ 3 days) and for subsequent cycles, clinic visit will be on day 1 (± 3 days). There will be a final clinic visit at the end of 
study. 
f Medical History/Current Medical Conditions: General and disease-specific medical history including a history of past and current medical conditions will be 
recorded during screening. Current medical conditions will be updated on day -1. 
g Demographics: Date of birth, gender, ethnicity, and race must be recorded. 
h Prior and Concomitant Medications: All prior medications administered 30 days before study drug administration will be recorded. Concomitant 
medications will be recorded throughout the study. 
i Pregnancy/Post-Menopausal Testing: For all FCBP, a serum pregnancy test must be performed at screening and within 24 hours (day -1) of the first dose of 
study drug in Cycle 1. For Cycle 2+, pregnancy testing to be performed on day 1 of each cycle prior to dosing of study drug. Subsequent testing at Cycle 2+ 
and at the end of study visit can be either urine or serum. Any positive urine pregnancy test must be confirmed with a serum test. Postmenopausal females: 
defined as 12 months with no menses prior to screening and a serum follicle-stimulating hormone (FSH) >40 IU/L at screening only. 
j Vital signs: Blood pressure (BP), heart rate (HR), and temperature (T) must always be measured after the subject has been sitting for 5 minutes. Vital signs will 
be assessed at screening and during each clinic visit. See Table 9 for timing window allowances. When vital signs are to be obtained concurrently with PK or 
other blood samples, the vital sign measurements will be performed before blood samples are collected in order to maximize the accuracy of blood sampling 
times while minimizing the potential effects of blood collection on other safety assessments. 
k ECG: ECG collection will occur after a 10-minute rest and with the subject in a supine position. A 12-lead ECG will be performed at screening, prior to dosing 
and 2 hours post-tazemetostat dose (Cycle 1 day 1, 15, 21, 25, 28, 31, 34, and day 36), prior to dosing at 24 hours post-tazemetostat BID dose (Cycle 1 day 22), 


Clinical Study Protocol 
 
EZH-108 
Tazemetostat 
 
Amendment 2.0
 
 
31 August 2021 
Epizyme, Inc. 
Confidential 
prior to dosing at 48 hours post-tazemetostat QD dose (Cycle 1 day 3, 17 and day 38), beginning of each cycle (day 1) from Cycle 2 onwards, and at the end of 
study visit. As no study drugs are administered on day 17 of Cycle 1, perform ECG per 48-hour timepoint timing tolerance window in Table 9 prior to 
collection of 48 hour PK sample. A single ECG will be recorded unless there is an abnormality, such as prolonged QT interval corrected for heart rate using 
Fridericia’s formula (QTcF) >450 msec, new arrhythmia, or other clinically significant findings. If an abnormality is observed, the ECG is to be performed in 
triplicate at least 2 minutes apart. See Table 9 for timing window allowances. When dosing is to occur, ECGs are performed pre-dose unless otherwise 
specified as 2 hours post-dose. On days when an ECG assessment and a PK blood sample collection are scheduled at the same time, the ECG assessment will 
be performed prior to collection of the PK blood sample. 
l PK Blood Sample: Blood samples for PK analysis will be obtained pre-dose (0 hour), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24 (day 21 – 22), 36, 48 (day 1 – 3), and up to 
72 hours post-dose (day 15 – 18 and day 36 – 39). Sparse PK samples will be collected pre-dose (0 hours) and 2 hours post-dose on day 25, 28, 31, and 34. See 
Table 9 for timing window allowances. All dosing and PK sampling times will be recorded. PK blood samples at post-dose timepoints that coincide with 
dosing of study drug(s) (ie, 12, 24, 36, 48, and 72 hour) must be collected prior to dosing of the subject at that timepoint. 
m AEs/SAEs: AEs/SAEs and non-serious adverse events will be collected from the time the subject signs the consent form until the end of the safety reporting 
period (or until screen failure). The safety reporting period ends 30 days after the last dose of study drug, or initiation of an investigational agent or cytotoxic 
chemotherapy, whichever occurs first. 
n Laboratory Assessments: Lab assessments for Cycle 1 will be performed at screening, day 1, 3, 15, 18, 21, 22, 36, and day 39. For all subjects, laboratory 
assessments may be performed within 24 hours prior to the day on which they are required (ie, day -1, 2, 14, 17, 20, 21, 35, and 38) to ensure results are 
available for review prior to dosing of study drug(s) the following day. For Cycle 2+, laboratory assessments will be performed at the beginning of each cycle 
on day 1 and at the end of study. Refer to Appendix 2 for a complete list of the clinical laboratory tests to be conducted. In addition, a complete peripheral 
blood smear morphology assessment (see Blood Smear Guidance in laboratory manual) will be performed manually or automated along with routine 
hematology testing at screening and during the study by the local laboratory. If the peripheral blood smear morphology results are abnormal and suggestive of 
MDS/AML or MPN, the subject will undergo a bone marrow aspirate/biopsy procedure. The bone marrow aspirate/biopsy sample will then be analyzed by 
cytogenetic testing at the local laboratory to closely monitor subjects for abnormalities known to be associated with MDS (eg, del 5q, chr 7, abn) and MPN (eg, 
JAK2 V617F). Additional local laboratory testing of genetic aberrations associated with MDS/AML or MPN can be conducted using targeted next generation 
sequencing (NGS) of known disease genes, as necessary. If local testing is unavailable or if results are inconclusive/indeterminate, the site will be required to 
ship samples for central laboratory testing. If the cytogenetic testing and, if conducted, DNA sequencing by NGS results are abnormal and associated with 
myeloid malignancies, tazemetostat will be discontinued. See Section 12.3.7 for further details. 
o Tazemetostat Administration (QD): During Cycle 1, subjects will receive a single oral dose of 400 mg tazemetostat on day 1, 15, and day 36 in the morning 
(eg, 7 – 9 am).  
p Tazemetostat Administration (multi-dose): Subjects will receive an oral 400 mg dose of tazemetostat twice daily during Cycle 1 from day 3 –14 and day 21 
– day 35. During subsequent cycles (Cycle 2+), dosing will begin on day 1 whereby subjects will receive 800 mg tazemetostat twice daily. Tazemetostat is to 
be taken twice daily 12 hours apart, once in the morning (eg, 7 – 9 am) and once in the evening (eg, 7 – 9 pm). 
q Itraconazole Administration (QD): During Cycle, subjects will receive oral 200 mg itraconazole once daily from day 18 to 38 in the morning (eg, 7 – 9 am) 
after a meal.  
r Disease Assessment: Disease progression (PD) will be determined through Investigator assessed review of clinical status. 
 


Clinical Study Protocol 
 
EZH-108 
Tazemetostat 
 
Amendment 2.0
 
 
31 August 2021 
Epizyme, Inc. 
Confidential 
Table 4: 
Schedule of Assessments (Part 2: Tazemetostat and Rifampin) 
Assessment 
Screeninga 
Baseline 
Cycle 1 
Cycle 2+ 
End of 
Studyb 
Study Day 
Within 30 
days 
before day 
1 
-1 c, d 
1 
2 
3 
3 - 14 d 
15 
16 
17 
17 - 23 d 
24 
25 
26 
Every 
28 days 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinic Visite 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical Historyf 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographicsg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and concomitant medicationsh 
Record from signing of informed consent through end of study 
Drug and alcohol screen 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
Pregnancy/Post-Menopausal testingi 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Vital signsj 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination (Complete) 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Physical Examination (Symptom-directed) 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
ECOG Performance Status 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
12-lead ECGk 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
X 
X 
X 
PK Blood Samplel 
 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
AEs/SAEsm 
Record from signing of informed consent through end of study 
Laboratory Assessmentsn 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Tazemetostat Administration (QD)o  
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
Tazemetostat Administration (twice daily)p  
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Rifampin Administration (QD)q  
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
 
 
Body Weight 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
X 


Clinical Study Protocol 
 
EZH-108 
Tazemetostat 
 
Amendment 2.0
 
 
31 August 2021 
Epizyme, Inc. 
Confidential 
Assessment 
Screeninga 
Baseline 
Cycle 1 
Cycle 2+ 
End of 
Studyb 
Study Day 
Within 30 
days 
before day 
1 
-1 c, d 
1 
2 
3 
3 - 14 d 
15 
16 
17 
17 - 23 d 
24 
25 
26 
Every 
28 days 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease Assessmentr 
X 
According to standard-of-care until PD or EOS 
X 
HIV, HBV, HCV, HTLV-1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: AE = adverse event; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOS = End of study; HBV = hepatitis B virus; 
HCV = hepatitis C virus; HIV = human immunodeficiency virus; HTLV-1 = human T-cell lymphotropic virus 1; PD = disease progression; PK = 
pharmacokinetics; SAE = serious adverse event 
  
 
a Screening: Screening should be performed within 30 days before day 1. 
b End of Study: Subjects will have a safety follow-up visit, including disease assessment, 30 (±3) days after the last dose of tazemetostat, or prior to initiation of 
an investigational agent or cytotoxic chemotherapy, whichever occurs first. A blood sample will also be required for PK assessment. 
 c Prior to dosing, assessments must be performed to determine if subject continues to meet eligibility criteria. If screening assessments are preformed within 24 
hours prior to day -1 (baseline assessments), ie, day -2, they do not need to be repeated on day -1. 
 d For Cycle 1 subjects may be admitted to the clinical study center during PK sampling periods or must agree to stay locally with frequent clinic visits as required 
and optional admission to the center if available. Subjects may have the option to be admitted to the clinical study center in the evening of day -1, 14, and 23. 
During these admissions, laboratory assessments may be performed within 24 hours prior to when required on day 1, 15 and 24. 
e Clinic Visit: Subjects will visit the clinical study unit from day -1 to day 3, from day 15 to 17, 19, 21, and from day 24 to day 26 (Cycle 1). Cycle 2 day 1 will 
begin on day 27 (+ 3 days) and for subsequent cycles, clinical visit will be on day 1 (± 3 days). There will be a final clinic visit at the end of study. 
f Medical History/Current Medical Conditions: General and disease-specific medical history including a history of past and current medical conditions will be 
recorded during screening. Current medical conditions will be updated on day -1. 
g Demographics: Date of birth, gender, ethnicity, and race must be recorded. 
h Prior and Concomitant Medications: All prior medications administered 30 days before study drug will be recorded. Concomitant medications will be 
recorded throughout the study. 
i Pregnancy/Post-Menopausal Testing: For all FCBP, a serum pregnancy test must be performed at screening and within 24 hours (day -1) of the first dose of 
study drug in Cycle 1. For Cycle 2+, pregnancy testing to be performed on day 1 of each cycle prior to dosing of study drug. Subsequent testing at Cycle 2+ 
and at the end of study visit can be either urine or serum. Any positive urine pregnancy test must be confirmed with a serum test. Postmenopausal females: 
defined as 12 months with no menses prior to screening and a serum follicle-stimulating hormone (FSH) >40 IU/L at screening only. 
j Vital signs: Blood pressure (BP), heart rate (HR), and temperature (T) must always be measured after the subject has been sitting for 5 minutes. Vital signs will 
be assessed at screening and during each clinic visit. See Table 9 for timing window allowances. When vital signs are to be obtained concurrently with PK or 


Clinical Study Protocol 
 
EZH-108 
Tazemetostat 
 
Amendment 2.0
 
 
31 August 2021 
Epizyme, Inc. 
Confidential 
other blood samples, the vital sign measurements will be performed before blood samples are collected in order to maximize the accuracy of blood sampling 
times while minimizing the potential effects of blood collection on other safety assessments. 
k ECG: ECG collection will occur after a 10-minute rest and with the subject in a supine position. A 12-lead ECG will be performed at screening, prior to dosing 
and 2 hours post-tazemetostat dose (Cycle 1 day 1, 15, 17, 19, 21, and day 24), prior to dosing at 48 hours post-tazemetostat QD dose (Cycle 1 day 3 and 26), 
beginning of each cycle (day 1) from Cycle 2 onwards, and at the end of study visit. As no study drugs are administered on day 26 of Cycle 1, perform ECG 
per 48-hour timepoint timing tolerance window in Table 9 prior to collection of 48 hour PK sample. A single ECG will be recorded unless there is an 
abnormality, such as prolonged QT interval corrected for heart rate using Fridericia’s formula (QTcF) >450 msec, new arrhythmia, or other clinically 
significant findings. If an abnormality is observed, the ECG is to be performed in triplicate at least 2 minutes apart. See Table 9 for timing window allowances. 
When dosing is to occur, ECGs are performed pre-dose unless otherwise specified as 2 hours post-dose. On days when an ECG assessment and a PK blood 
sample collection are scheduled at the same time, the ECG assessment will be performed prior to collection of the PK blood sample. 
l PK Blood Samples: Blood samples for PK analysis will be obtained pre-dose (0 hour), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 36, and 48 hours post-dose (day 1 – 3, day 
15 – 17 and day 24 – 26). Sparse PK samples collected pre-dose and 2 hours post-dose on day 19 and 21. See Table 9 for timing window allowances. All 
dosing and PK sampling times will be recorded. PK blood samples at post-dose timepoints that coincide with dosing of study drug(s) (ie, 12, 24, 36, and 48 
hour) must be collected prior to dosing of the subject at that timepoint. 
m AEs/SAEs: AEs/SAEs and non-serious adverse events will be collected from the time the subject signs the consent form until the end of the safety reporting 
period (or until screen failure). The safety reporting period ends 30 days after the last dose of study drug, or initiation of an investigational agent or cytotoxic 
chemotherapy, whichever occurs first. 
n Laboratory Assessments: Lab assessments for Cycle 1 will be performed at screening, day 1, 3, 15, 17, 24, and 26. For all subjects, laboratory assessments 
may be performed within 24 hours prior to the day on which they are required (ie, day -1, 2, 14, 16, 23, and 25) to ensure results are available for review prior 
to dosing of study drug(s) the following day. For Cycle 2+, laboratory assessments will be performed at the beginning of each cycle on day 1 and at the end of 
study. Refer to Appendix 2 for a complete list of the clinical laboratory tests to be conducted. In addition, a complete peripheral blood smear morphology 
assessment (see Blood Smear Guidance in laboratory manual) will be performed manually or automated along with routine hematology testing at screening and 
during the study by the local laboratory. If the peripheral blood smear morphology results are abnormal and suggestive of MDS/AML or MPN, the subject will 
undergo a bone marrow aspirate/biopsy procedure. The bone marrow aspirate/biopsy sample will then be analyzed by cytogenetic testing at the local laboratory 
to closely monitor subjects for abnormalities known to be associated with MDS (eg, del 5q, chr 7, abn) and MPN (eg, JAK2 V617F). Additional local 
laboratory testing of genetic aberrations associated with MDS/AML or MPN can be conducted using targeted next generation sequencing (NGS) of known 
disease genes, as necessary. If local testing is unavailable or if results are inconclusive/indeterminate, the site will be required to ship samples for central 
laboratory testing. If the cytogenetic testing and, if conducted, DNA sequencing by NGS results are abnormal and associated with myeloid malignancies, 
tazemetostat will be discontinued. See Section 12.3.7 for further details. 
o Tazemetostat Administration (QD): During Cycle 1, subjects will receive a single oral dose of 800 mg tazemetostat on day 1, 15, and day 24 in the morning 
(eg, 7 – 9 am).  
p Tazemetostat Administration (multi-dose): Subjects will receive an oral 800 mg dose of tazemetostat twice daily during Cycle 1 from day 3 – 14 and day 17 
– 23. During subsequent cycles (Cycle 2+), dosing will begin on day 1 whereby subjects will receive 800 mg tazemetostat twice daily. Tazemetostat is to be 
taken twice daily 12 hours apart once in the morning (eg, 7 – 9 am) and once in the evening (eg, 7 – 9 pm). 
q Rifampin Administration (QD): During Cycle 1, subjects will receive oral 600 mg rifampin once daily from day 17 to 25 in the morning (eg, 7 – 9 am) one 
hour before a meal.  
r Disease Assessment: Disease progression (PD) will be determined through Investigator assessed review of clinical status.  


Clinical Study Protocol 
 
EZH-108 
Tazemetostat 
 
Amendment 2.0
 
 
31 August 2021 
Epizyme, Inc. 
Confidential 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. 
Subject Inclusion Criteria 
1. Male or female ≥ 18 years age at the time of consent. 
2. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2. 
3. Has the ability to understand informed consent and provide signed written informed 
consent. 
4. Life expectancy of > 3 months. 
5. Histologically and/or cytologically confirmed advanced metastatic or unresectable solid 
tumors has progressed after treatment for which there are no standard therapies available 
OR histologically and/or cytologically confirmed hematologic malignancies that have 
relapsed, or refractory disease, following at least 2 standard lines of systemic therapy for 
which there are no standard therapies available. 
Note: Subjects with prior radiotherapy will be included; however, radiotherapy alone will 
not be considered a separate systemic treatment regimen. 
6. Must have evaluable or measurable disease.  
7. Has all prior treatment (ie, chemotherapy, immunotherapy, radiotherapy) related 
clinically significant toxicities resolve to ≤ Grade 1 per National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.0 or are 
clinically stable and not clinically significant, at time of consent.  
8. All subjects must have completed any prior chemotherapy, targeted therapy and major 
surgery ≥ 28 days before study entry. For daily or weekly chemotherapy without the 
potential for delayed toxicity, a washout period of 14 days or 5 half-lives, whichever is 
shorter may be acceptable, and questions related to this can be discussed with the 
Medical Monitor. 
9. Has normal hepatic function as well as adequate hematologic (bone marrow [BM] and 
coagulation factors) and renal function (Table 5). 
 
Table 5: 
Laboratory Values for Hepatic, Hematologic and Renal Function  
System 
Laboratory Value 
Hematologic (BM Function) 
Hemoglobina 
≥9 g/dL (90 g/L) 
Plateletsb 
 ≥75,000/mm3 (≥75 × 109/L) 
ANCc 
Hematologic malignancy subjects: ≥1,000/mm3 (≥1.0 × 109/L) 
Solid tumor subjects: ≥1,500/mm3 (≥1.5 x 109/L) 
Hematologic (Coagulation Factors) 
PT/INR 
<1.5 ULN 
aPTT 
<1.5 ULN 
Renal Function 
Serum creatinined 
≤1.5 × ULN 


Clinical Study Protocol 
 
EZH-108 
Tazemetostat 
 
Amendment 2.0
 
 
31 August 2021 
Epizyme, Inc. 
Confidential 
System 
Laboratory Value 
Normal Hepatic Function (per NCI-ODWG criteria) 
Total bilirubin, AST, and ALT 
≤ ULN 
Abbreviations: ANC = absolute neutrophil count; AST = aspartate aminotransferase; ALT = alanine 
aminotransferase; BM = bone marrow; eGFR = estimated glomerular filtration rate; INR = international normalized 
ratio; PT = prothrombin time; aPTT = activated partial thromboplastin time; ULN = upper limit of normal 
a May receive transfusion. 
b Should be evaluated after at least 7 days since last platelet transfusion. 
c Without growth factor support (filgrastim or pegfilgrastim) for at least 14 days. 
d If serum creatinine is not ≤1.5 × ULN, then calculate eGFR by Chronic Kidney Disease Epidemiology 
Collaboration (CKD-EPI) Creatinine Equation (2009) (Appendix 3). eGFR must be ≥50 mL/min/1.73 m2. 
 
Note: Laboratory results obtained during screening should be used to determine eligibility 
criteria. In situations where laboratory results are outside the permitted range, the Investigator 
may retest the subject and the subsequent within range screening result may be used to determine 
the subject’s eligibility. Subjects may be retested once within 2 weeks of the screening test. 
Samples must be reanalyzed at the local laboratory. 
 
10. Able to swallow and retain orally-administered medication and without clinically 
significant gastrointestinal abnormalities that could alter absorption such as 
malabsorption syndrome or major resection of the stomach or bowels.  
11. Manual differential with no significant morphologic abnormalities other than those 
associated with the subject’s diagnosed type of advanced malignancy on complete blood 
count (CBC) testing. 
12. Females of childbearing potential (FCBP) must have a negative serum pregnancy test 
(beta-human chorionic gonadotropin [β-hCG] test with a minimum sensitivity of 25 
mIU/mL or equivalent units of β-hCG) at screening and within 24 hours prior to the first 
dose of study drug. All females will be considered to be of childbearing potential unless 
they are naturally postmenopausal (at least 12 months consecutively amenorrhoeic 
[amenorrhea following cancer therapy does not rule out childbearing potential] and 
without other known or suspected cause) or have been sterilized surgically (ie, total 
hysterectomy and/or bilateral oophorectomy, with surgery completed at least 28 days 
prior to the first dose of study drug). 
13. Females of childbearing potential (FCBP) must either practice complete abstinence or 
agree to use a highly effective method of contraception beginning at least 28 days prior to 
the first dose of study drug, during study treatment (including during dose interruptions), 
and for 6 months after study drug discontinuation. If the below contraception methods are 
not appropriate for the FCBP, she must be referred to a qualified contraception provider 
to determine the medically effective contraception method appropriate for the subject. 
The following are examples of highly effective methods of contraception (result in a 
failure rate of <1% per year when used consistently and correctly): 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 


Clinical Study Protocol 
 
EZH-108 
Tazemetostat 
 
Amendment 2.0
 
 
31 August 2021 
Epizyme, Inc. 
Confidential 
• Hormonal (ovulation inhibitory combined [estrogen and progesterone]: oral, 
intravaginal, or transdermal; ovulation inhibitory progesterone-only: oral, injectable, 
or implantable)  
NOTE: Due to the potential of enzyme induction with tazemetostat, hormonal 
contraception methods must be supplemented with a barrier method of contraception 
(preferably male condom) 
• Bilateral tubal ligation 
• Partner’s vasectomy (if medically confirmed [azoospermia] and sole sexual partner) 
NOTE: Female subjects of childbearing potential exempt from these contraception 
requirements are subjects who practice complete abstinence from heterosexual sexual 
contact. True abstinence is acceptable when this is in line with the preferred and usual 
lifestyle of the subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, or 
post-ovulation methods) and withdrawal are not acceptable methods of contraception.  
14. Male subjects must have had a successful vasectomy (with medically confirmed 
azoospermia) OR must either practice complete abstinence or agree to use a latex or 
synthetic condom during sexual contact with a female of childbearing potential (FCBP) 
from the first dose of study drug, during study treatment (including during dose 
interruptions), and for 3 months after study drug discontinuation. 
NOTE: Male subjects must not donate sperm from the first dose of study drug, during 
study treatment (including during dose interruptions), and for 3 months after study drug 
discontinuation. 
15. Has a QT interval corrected by Fridericia’s formula (QTcF) ≤450 msec. 
16. Subjects with diagnosed human immunodeficiency virus (HIV) are eligible to participate 
in the study if they meet the following criteria: 
a. No history of AIDS-defining opportunistic infections or have not had an 
opportunistic infection within the past 12 months prior to enrollment. 
b. No history of AIDS-defining cancers (eg, Kaposi’s sarcoma, aggressive B-cell 
lymphoma, and invasive cervical cancer). 
c. Subjects may take prophylactic antimicrobials, however subjects that are taking 
specific antimicrobial drugs where there may be drug-drug interaction or 
overlapping toxicities should be excluded from study participation (Table 7 and 
Table 8).  
d. Subjects should be on established anti-retroviral therapy for at least 4 weeks and 
have an HIV viral load of < 400 copies/mL prior to enrollment. 
8.2. 
Subject Exclusion Criteria 
Subjects meeting ANY of the following criteria must NOT be enrolled in this study: 
1. Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression 
as documented by CT or MRI scan, analysis of cerebrospinal fluid or neurological exam. 
Subjects with primary glioblastoma multiforme are excluded. 
Note: Subjects with clinically stable brain metastases are eligible to enroll in the study. 
2. Clinically significant bleeding diathesis or coagulopathy, including known platelet 
function disorders. Subjects on anticoagulation with low molecular weight heparin are 
allowed. 


Clinical Study Protocol 
 
EZH-108 
Tazemetostat 
 
Amendment 2.0
 
 
31 August 2021 
Epizyme, Inc. 
Confidential 
3. Known hypersensitivity to any of the components of tazemetostat, itraconazole or 
rifampin. 
4. Use of concurrent investigational agent or anticancer therapy. 
 
Note: megestrol (Megace) if used as an appetite stimulant is allowed. 
a. Concurrent treatment with bisphosphonates is permitted; however, treatment must 
be initiated prior to the first dose of tazemetostat. Prophylactic use of 
bisphosphonates in subjects without bone disease is not permitted, except for the 
treatment of osteoporosis. 
b. The concurrent use of all herbal supplements is prohibited during the study as the 
composition, PK, and metabolism of many herbal supplements are unknown. 
5. Uncontrolled concurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, clinically significant 
cardiac arrhythmias, or psychiatric illness/social situations that would limit compliance 
with study requirements. 
6. Have a known active infection with hepatitis B virus (HBV), as measured by positive 
hepatitis B surface antigen; hepatitis C virus (HCV), as measured by positive hepatitis C 
antibody; AND/OR human T-cell lymphotropic virus 1, as measured by positive HTLV-1 
antibody. 
Exceptions: Subjects with a history of hepatitis B or C who have normal alanine 
aminotransferase (ALT) values and are hepatitis B surface antigen negative with 
undetectable HBV DNA and/or have undetectable HCV RNA if hepatitis C antibody 
positive. 
7. Subjects taking medications that are known CYP3A4 inducers or inhibitors (including St. 
John’s Wort) (Table 7 and Table 8). 
8. Is unwilling to exclude grapefruit juice, Seville oranges and grapefruit from the diet and 
all foods that contain those fruits from 24 hours prior to the first dose of study drug until 
the last dose of study drug. 
9. Any condition or medical problem in addition to the underlying malignancy and organ 
dysfunction that the Investigator feels would pose unacceptable risk. 
10. Has thrombocytopenia, neutropenia, or anemia of grade ≥3 (per CTCAE v5.0 criteria) or 
any prior history of myeloid malignancies, including myelodysplastic syndrome 
(MDS)/acute myeloid leukemia (AML) or myeloproliferative neoplasm (MPN). 
11. Has cytogenetic abnormalities known to be associated with myeloid malignancies, such 
as those for MDS (eg, del 5q, chr 7 abn) or MPN (eg, JAK2 V617F). 
12. Has a prior history of T-cell lymphoblastic lymphoma (T-LBL)/T-cell acute 
lymphoblastic leukemia (T-ALL). 
13. Ingestion of alcohol within 72 hours prior to day 1 of Cycle 1 until the end of Cycle 1 
(Day 39 for Part 1 and Day 26 for Part 2). Regular alcohol consumption must not exceed 
16 units for males and 7 units for females per week (2 units equals 440mL [a can] of 
beer, 175mL [a standard glass] of wine, or 50 mL [2 small shots] of spirits) after Cycle 1 
until the end of treatment. 
14. Any form of marijuana use. 
15. History of drug abuse (including alcohol) within the last 6 months prior to screening. 


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8.2.1. 
Subject Withdrawal Criteria 
8.2.2. 
Withdrawal of Subjects from Treatment/Procedures 
Subjects have the right to withdraw from the study treatment at any time and for any reason 
without prejudice to future medical care by the physician or institution. 
Subjects (or legally authorized representatives) can decline to continue receiving tazemetostat 
and/or other protocol-required procedures at any time during the study but can continue 
participation in the study (eg, for follow-up information). If this occurs the Investigator is to 
discuss with the subject appropriate processes for discontinuation and the options for procedures 
that may continue such as collection of data, including endpoints and AEs. The Investigator must 
document the agreement in the procedures that the subject will continue with and the level of 
follow-up that is agreed to by the subject (eg, in person, by telephone/mail, through 
family/friends, in correspondence/communication with other physicians, from review of the 
medical records). 
Reasons for removal from protocol-required treatment or procedures might include the 
following: 
• Disease progression 
• Subject request to end study treatment and/or procedures 
• Safety concern (eg, AE, failure to follow contraception or pregnancy, excluded 
medication required). 
8.2.3. 
Withdrawal of Subjects from Study 
Withdrawal of full consent from the study means that the subject does not wish to receive further 
protocol-required treatment or procedures and does not wish to or is unable to continue further 
study participation. Subject data up to withdrawal of consent will be included in the analysis of 
the study, and where permitted, publicly available data can be included after withdrawal of 
consent (eg, death records). The Investigator must document this agreement regarding 
withdrawal of full consent as well as discuss appropriate procedures for withdrawal from the 
study. 
Reasons for removal of a subject from the study might include the following: 
• Death 
• Decision by Sponsor to terminate the study 
• Subject request to withdraw from study 
• Lost to follow-up. 
8.2.4. 
Replacement of Subjects 
Subjects who require a tazemetostat dose interruption or reduction during Cycle 1 of either Part 1 
or Part 2 will be replaced. During Cycle 1, subjects who miss two or more consecutive 
tazemetostat/itraconazole/rifampin doses or more than three tazemetostat/itraconazole/rifampin 
doses in total will be replaced. Subjects who miss two or more consecutive PK blood sample 


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collections during either part of Cycle 1 will be replaced. Subjects that require replacement will 
be discontinued from study treatment. 
Subjects in Cycle 2+ will not be replaced in this study. 
 


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9. 
TREATMENT OF SUBJECTS 
9.1. 
Description of Study Drug 
A description of the study drugs is provided in Table 6 and further information pertaining to 
tazemetostat in Section 10.1. 
Table 6: 
Study Drugs 
Product name: 
Study Drug 
(Tazemetostat) 
  
Itraconazole 
Rifampin 
Formulation 
description: 
200 mg tablet 
100 mg capsule 
150 mg and 300 mg 
capsules 
Dosage form: 
Tablet 
Capsule 
Capsule 
Physical description:  
Red, round, and biconvex 
film-coated tablets 
packaged in white high-
density polyethylene 
bottle with a child 
resistant, tamper-evident 
polypropylene screw cap. 
Capsules contain 100 mg 
of itraconazole coated on 
sugar spheres (composed 
of sucrose, maize starch, 
and purified water), with 
a blue opaque cap and 
pink transparent body, 
imprinted with 
“JANSSEN” and 
“SPORANOZ 100”. The 
capsules are supplied in 
unit-dose blister packs of 
3 × 10 capsules,  
bottles of 30 capsules, and 
in the PulsePak® 
containing 7 blister 
packs × 4 capsules each.  
150 mg maroon and 
scarlet capsules imprinted 
“RIFADIN 150” in 
bottles of 30. 300 mg 
maroon and scarlet 
capsules imprinted 
“RIFADIN 300” in 
bottles of 60. 
Manufacturer: 
Epizyme 
Janssen Pharmaceuticals, 
Inc. 
Sanofi-Aventis U.S. LLC 
 
Refer to the current manufacturer’s prescribing information for tazemetostat (Tazverik, 2020), 
itraconazole (Sporanox, 2018) and rifampin (Rifadin, 2019). Information regarding brand 
itraconazole (Sporanox) and brand rifampin (Rifadin) is provided here as an example only. 
During this study, the use of either brand or generic forms of itraconazole and rifampin is 
acceptable. Please refer to manufacturer’s prescribing information for drug form selected prior to 
administration. 
9.2. 
Concomitant Medications 
Documentation of all concomitant medication administered during study treatment will be 
recorded in the eCRF at each visit. 
Because there is a potential for interaction of tazemetostat, itraconazole and rifampin with other 
concomitantly administered drugs through the CYP450 system, over-the-counter medications, or 
alternative therapies must be recorded in the eCRF. The Investigator should be alerted if the 
subject is taking any agent known to affect or with the potential to affect selected CYP450 
isoenzymes. 


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9.2.1. 
Permitted Medications 
• Supportive care measures and symptomatic treatment for any treatment-related 
toxicity, including short courses of glucocorticoids, if clinically indicated. 
• Glucocorticoids may be taken by subjects with CNS tumors, under the following 
conditions: 
− For control of neurological symptoms that may continue at a tapering dose  
− Intermittent use for control of nausea (not to exceed 0.3 mg/kg/dose 
dexamethasone, maximum of 20 mg) every 12 hours as needed. 
• Non-enzyme inducing anti-epileptic drugs. 
• Prophylactic use of standard anti-emetics. 
• Blood and platelet transfusions, as needed per the judgment of the Investigator. 
• Initiation of bisphosphonates or other approved bone targeting agents if prior to the 
first dose of tazemetostat is allowed and should not result in discontinuation of study 
drug therapy. Prophylactic use of bisphosphonates in subjects without bone disease is 
not permitted, except for the treatment of osteoporosis. 
9.2.2. 
Medications to be Used with Caution 
Substrates of P-gp, CYP3A, CYP2C8, CYP2C9, CYP2C19, and CYP2D6 should be used with 
caution. Medications that are substrates of CYP3A, CYP2C8, CYP2C9, CYP2C19, and CYP2D6 
should be avoided, if possible, especially substrates of CYP3A. 
Medications to be administered concomitantly with tazemetostat, itraconazole or rifampin 
require consideration for potential interactions and may need to be avoided. Follow the 
manufacturer’s prescribing information for itraconazole and rifampin when considering the use 
of concomitant medications. After Cycle 1, the manufacturer’s prescribing information for 
TAZVERIK (tazemetostat) may be followed in regard to concomitantly administered 
medications. Contact the Medical Monitor with any additional questions. 
NOTE: A link to a listing of CYP inhibitors, inducers, and substrates can be found in the 
reference section of this protocol (U. S. Food and Drug Administration, March 2020). 
9.2.3. 
Prohibited Medications 
Prohibited medications include: 
• Antineoplastic therapy or other investigational therapy for the treatment of cancer. 
• Prophylactic use of hematopoietic colony stimulating factors. 
NOTE: Therapeutic use of hematopoietic colony stimulating factors is discouraged and should 
be discussed with the Medical Monitor and should be conducted according to the 2006 American 
Society for Clinical Oncology Guideline for use of white blood cell (WBC) growth factors 
(Smith, 2006). 
• Subjects must not receive other antitumor therapies while on study. Prohibited 
medications during this study are any other experimental or unapproved drugs, other 


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anticancer therapies unless otherwise stated, and known CYP3A4 inhibitors and 
inducers within 14 days prior to the first dose of tazemetostat and concomitantly with 
tazemetostat or in the absence of tazemetostat during the duration of the study. 
Medications that are CYP inhibitors and inducers include but are not limited to those 
listed in Table 7 and Table 8. The list of medications in Table 7 and Table 8 is not 
exhaustive, refer to the FDA website (U. S. Food and Drug Administration, March 
2020) for the most up-to-date information.  
Table 7: 
Examples of clinical inhibitors for P450-mediated metabolisms and 
transporter 
CYP Enzyme 
Strong inhibitors 
Moderate inhibitors 
Weak inhibitors 
CYP1A2 
ciprofloxacin, enoxacin, 
fluvoxamine(a) 
methoxsalen, mexiletine, 
oral contraceptives 
acyclovir, allopurinol, 
cimetidine, peginterferon 
alpha-2a, piperine, 
zileuton 
CYP2B6 
N/A 
N/A 
clopidogrel(b), tenofovir, 
ticlopidine(c), 
voriconazole(d) 
CYP2C8 
gemfibrozil(e) 
clopidogrel(b), 
deferasirox, teriflunomide 
trimethoprim 
CYP2C9 
 
N/A 
amiodarone, 
fluconazole(f), 
miconazole, piperine 
diosmin, disulfiram, 
fluvastatin, 
fluvoxamine(a), 
voriconazole 
CYP2C19 
fluconazole(f), 
fluoxetine(g), 
fluvoxamine(a), 
ticlopidine 
felbamate 
omeprazole, voriconazole 
CYP2D6 
bupropion, fluoxetine(g), 
paroxetine, quinidine(h), 
terbinafine 
cimetidine, cinacalcet, 
duloxetine, 
fluvoxamine(a), 
mirabegron 
abiraterone, amiodarone, 
celecoxib, cimetidine, 
clobazam, cobicistat, 
desvenlafaxine, 
escitalopram, labetalol, 
lorcaserin, ritonavir(h,i,j), 
sertraline, vemurafenib 
CYP3A4 
boceprevir, cobicistat(h), 
danoprevir and 
ritonavir(j), elvitegravir 
and ritonavir(j), grapefruit 
juice(k), indinavir and 
ritonavir(j), 
itraconazole(h), 
ketoconazole, lopinavir 
and ritonavir(h,j), 
paritaprevir and ritonavir 
and (ombitasvir and/or 
aprepitant, ciprofloxacin, 
conivaptan(l), crizotinib, 
cyclosporine, 
diltiazem(m), 
dronedarone(h), 
erythromycin, 
fluconazole(f), 
fluvoxamine(a), imatinib, 
tofisopam, verapamil(h) 
chlorzoxazone, cilostazol, 
cimetidine, clotrimazole, 
fosaprepitant, 
istradefylline, 
ivacaftor(h), lomitapide, 
ranitidine, ranolazine(h), 
ticagrelor(h) 


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CYP Enzyme 
Strong inhibitors 
Moderate inhibitors 
Weak inhibitors 
dasabuvir)(j), 
posaconazole, 
ritonavir(h,j), saquinavir 
and ritonavir(h,j), 
telaprevir(h), tipranavir 
and ritonavir(h,j), 
telithromycin, 
troleandomycin, 
voriconazole 
 
clarithromycin(h), 
idelalisib, nefazodone, 
nelfinavir(h) 
Transporter 
Inhibitor 
P-gp(a) 
amiodarone, carvedilol, clarithromycin, dronedarone, itraconazole, lapatinib, 
lopinavir and ritonavir, propafenone, quinidine, ranolazine, ritonavir, saquinavir and 
ritonavir, telaprevir, tipranavir and ritonavir, verapamil 
Abbreviations: CYP = cytochrome p450; P-gp = permeability glycoprotein 
 
Table 8: 
Examples of clinical inducers for P450-mediated metabolisms and substrate 
CYP Enzyme 
Strong inducers 
Moderate inducers 
Weak inducers 
CYP1A2 
N/A 
phenytoin(a) 
rifampin(b), 
ritonavir(c,d), smoking, 
teriflunomide 
N/A 
CYP2B6 
carbamazepine(e) 
efavirenz(e), 
rifampin(a) 
nevirapine, ritonavir(c, 
d) 
CYP2C8 
N/A 
rifampin(a) 
N/A 
CYP2C9 
N/A 
enzalutamide(g), 
rifampin(a) 
apalutamide, aprepitant, 
carbamazepine(e), 
ritonavir(c, d) 
CYP2C19 
rifampin(a) 
apalutamide, 
efavirenz(e,f), 
enzalutamide(g), 
phenytoin(b) 
ritonavir(c, d) 
CYP3A 
apalutamide, 
carbamazepine(e), 
enzalutamide(g), 
mitotane, phenytoin(b), 
rifampin(a), St. John’s 
wort(h) 
bosentan, efavirenz(f), 
etravirine, 
phenobarbital, 
primidone 
armodafinil, 
modafinil(i), 
rufinamide 
Abbreviations: CYP = cytochrome p450 
 


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• Enzyme inducing anti-epileptic drug(s) including, but not limited to, carbamazepine, 
phenobarbital, phenytoin, and barbiturates, should not be taken within 14 days prior 
to the first dose of study treatment and for the duration of study treatment. 
• All herbal remedies (including remedies in the form of herbal teas/infusions and 
marijuana) are excluded while enrolled in the study. 
• Medicinal food supplements such as calcium, folic acid, vitamin D, multi-vitamin, 
etc, which have been taken under the advice from a physician, should be continued at 
the same dose and regimen during the study provided there are no contraindication as 
above. These should be listed as concomitant medications in the CRF. 
• Any other supplements or alternative therapies should be discussed with the medical 
monitor prior to enrollment in the study or prior to initiating them during the study. 
9.2.4. 
Non-Drug Therapies 
Radiation Therapy: Localized, palliative radiation therapy and potential concurrent dose 
interruptions will be permitted for pain or severe symptom control after discussion with the 
Medical Monitor. Radiation will be limited to non-target lesions only and documented in the 
eCRF. 
Other Palliative Procedures: Other procedures intended for symptom control and potential 
concurrent dose interruptions may be permitted after discussion with the Medical Monitor. These 
procedures will be limited to non-target lesions only and documented in the eCRF. 
9.3. 
Treatment Compliance 
The subject will be requested to maintain a medication diary documenting each dose of 
tazemetostat as well as itraconazole or rifampin. The dosing diary will need to be returned to the 
site staff at each clinic visit. 
9.3.1. 
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. 
• Overdose: An overdose is defined, regardless of any associated AEs or sequelae, as: 
− 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. 
− On a schedule or frequency basis, anything taken more frequently than the 
protocol-required schedule or frequency. 
• Misuse: Intentional and inappropriate use of study drug not in accordance with the 
protocol. 
• Abuse: Sporadic or persistent intentional excessive use of study drug accompanied 
by harmful physical or psychological effects. 


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• 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 12.11 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 Sponsor’s or 
Designee Medical Monitor or their designee and closely monitor the subject for AEs/SAEs and 
laboratory abnormalities. 
 
Compliance for doses taken outside of the clinic may be assessed by a count of the tablets 
returned to the study site by the subject and review of doses taken with the subject that have been 
recorded in the medication diary. This will be recorded in the source documents, which may 
include the use of a subject medication diary per institutional practice. 
9.4. 
Randomization and Blinding 
This is an open-label study; subjects will not be randomized or blinded to treatment. 
9.5. 
Treatment of Overdose 
In the event of an overdose of tazemetostat (defined as administration of more than the protocol-
specified dose), the Investigator should contact the Medical Monitor, or their designee 
immediately and closely monitor the subject for AEs/SAE and laboratory abnormalities. 
For reference, five half-lives of tazemetostat would be at minimum 25 hours, longer in subject 
with delayed clearance. Decisions regarding dose interruptions or modifications will be made by 
the Investigator in consultation with the Medical Monitor or their designee based on the subject’s 
clinical evaluation. 
A plasma sample for PK analysis may be requested on a case-by-case basis. If requested, the 
plasma sample should be collected at least within 7 days from the date of the last dose of study 
treatment. 
The quantity of the excess dose as well as the duration of the overdosing should be documented 
in the eCRF. Refer to section 12.1 for details of recording and reporting overdose, medication 
errors, misuse, and abuse. 


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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug 
In June 2020, the US Food and Drug Administration (FDA) granted accelerated approval of 
TAZVERIK (tazemetostat) in the US for the treatment of adult patients with relapsed or 
refractory (R/R) follicular lymphoma (FL) whose tumors are positive for an EZH2 mutation as 
detected by an FDA-approved test and who have received at least 2 prior systemic therapies, and 
for the treatment of adult patients with R/R FL who have no satisfactory alternative treatment 
options. 
Earlier, in January 2020, the US FDA granted accelerated approval to TAZVERIK for adults and 
pediatric patients aged 16 years and older with metastatic or locally advanced epithelioid 
sarcoma not eligible for complete resection.  
Tazemetostat (EPZ-6438) is an Epizyme IP and is defined as an Investigational Medicinal 
Product (IMP) under the European Union Clinical Trials Directive (EU CT Dir). The contents of 
the package label will be in accordance with all applicable regulatory requirements. The expiry 
date will be printed on the label. 
 
Investigational Product 
Product Name: 
Tazemetostat (EPZ-6438) 
Formulation Description: 
200 mg tablets 
Dosage Form: 
Tablet 
Physical Description: 
Round, red, biconvex, film-coated tablets  
Dose/Route/Schedule/Duration: Oral/twice daily/continuousa 
a Until Investigator-assessed disease progression, or unacceptable toxicity or until another discontinuation criterion 
is met. 
10.2. 
Study Drug Packaging and Labeling 
Tazemetostat tablets are packaged in a white high- density polyethylene bottle with a child 
resistant, tamper-evident polypropylene screw cap. The contents of the package label will be in 
accordance with all applicable regulatory requirements. The expiry date will be printed on the 
container label. 
10.3. 
Study Drug Storage 
Tazemetostat must be stored in a secure area, in compliance with storage requirements listed on 
the label, with access limited to the Investigator and authorized site staff only. 
10.4. 
Study Drug Preparation 
No preparation for tazemetostat is needed. 


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10.5. 
Study Drug Administration 
Tazemetostat must be dispensed or administered only to subjects enrolled in the study and in 
accordance with the protocol. Standard institutional procedures for administering an oral agent 
will be followed. An adequate supply will be provided with instructions on home administration. 
Tazemetostat (400 mg for Part 1 and 800 mg for Part 2) doses must be taken at least 12 hours 
apart at approximately the same time each day, for example between 7 – 9 am for the morning 
dose and 7 – 9 pm for the evening dose. Administration of itraconazole, whether alone or 
concomitantly with tazemetostat, must be after a meal. Rifampin dosing, whether alone or co-
administered with tazemetostat, must be one hour before a meal. 
Part 1: Tazemetostat and Itraconazole Drug Interaction  
Part 1 of the study will evaluate the drug-drug interaction between tazemetostat and itraconazole 
in an open-label, fixed sequential cross over design (Figure 2).  
A screening visit will occur within 30 days of signing an informed consent form (ICF). During 
the screening phase, subjects will be evaluated for eligibility to participate in the study. Subjects 
who meet the protocol criteria will be admitted in the evening to the clinical study center, or visit 
the clinic if staying locally, on day -1. Subjects may be admitted to the clinical study center for 
the entirely of Cycle 1 or must agree to stay locally, with optional admission to the center when 
necessary, during their study participation. Prior to dosing on day 1 of Cycle 1, subject eligibility 
will be reconfirmed. On day 1, a single oral dose of 400 mg tazemetostat will be administered in 
the morning (eg, 7 – 9 am) followed by 2 days of multiple blood sampling (day 1 – 3). From day 
3 – 14, subjects will receive an oral 400 mg dose of tazemetostat twice daily (12 hours apart, 
once in the morning [eg, 7 – 9 am] and once in the evening [eg, 7 – 9 pm]). In the evening of day 
14, subjects may be admitted to the clinical study center. On day 15, a single oral dose of 400 mg 
tazemetostat will be administered in the morning (eg, 7 – 9 am) followed by 3 days of multiple 
blood sampling (day 15 – 18). From day 18 – 20, a single dose of oral 200 mg itraconazole will 
be administered daily in the morning (eg, 7 – 9 am) after a meal. In the evening of day 20, 
subjects may be admitted to the clinical study unit. From day 21 – 35, subjects will receive an 
oral 400 mg dose of tazemetostat twice daily, once in the morning (eg, 7 – 9 am) and once in the 
evening (eg, 7 – 9 pm), co-administered in the morning (eg, 7 – 9 am) after a meal with a single 
dose of oral 200 mg itraconazole followed by 1 day of multiple blood sampling (day 21 – 22). In 
the evening of day 35, subjects may be admitted to the clinical study center. On day 36, subjects 
will receive a single oral dose of 400 mg tazemetostat co-administered in the morning (eg, 7 – 9 
am) after a meal with a single dose of oral 200 mg itraconazole followed by 3 days of multiple 
blood sampling (day 36 – 39). Itraconazole will also be administered on day 37 and 38 as a 
single oral 200 mg daily dose in the morning (eg, 7 – 9 am) after a meal. Note: Tazemetostat will 
not be administered on day 37 and 38. After the 72-hour PK sample collection, safety 
assessments will be conducted on day 39. Sparse PK samples will be collected pre-dose (0 hour) 
and 2 hours post-dose on day 25, 28, 31, and 34. 
Subjects may discontinue from the study after completion of Cycle 1 or can continue treatment 
(Cycle 2+ onwards) until Investigator-assessed clinical progression per standard practice, or 
unacceptable toxicity, or until another discontinuation criterion is met. For subjects continuing 
tazemetostat treatment at the recommended therapeutic dose (oral 800 mg tazemetostat twice 
daily [12 hours apart]), Cycle 2 will begin on day 40 (Cycle 2 Day 1) and each subsequent cycle 
from Cycle 2+ onwards will be of 28-day duration. Safety and tolerability will be assessed 


Cli nical St u d y Pr ot oc ol  
 
E Z H- 1 0 8  
Taze met ostat  
 
A me n d me nt 2. 0
 
 
3 1  A u g ust 2 0 2 1  
E piz y me, I nc.  
C o nfi de n tial 
t hr o u g h o ut t he s u bject’s partici pati o n. S u bjects will be i nstr ucte d t o re p ort a n y a d verse e ve nts 
t hat occ ur u p t o 3 0 da ys after t he last d ose of taze met ostat. S u bjects m ust ha ve a n e n d of st u d y 
visit 3 0 da ys after t he last d ose of taze met o stat f or safet y assess me nt. 
P art 2: T aze met ost at a n d Rif a m pi n Dr u g I nter acti o n  
Part 2 of t he st u d y will e val uate t he dr u g- dr u g i nteracti o n bet wee n taze met ostat a n d rifa m pi n i n 
a n o pe n- la bel, fi xe d se q ue ntial cr oss o ver desi g n (Fi g ure 3 ). 
A scree ni n g visit will occ ur wit hi n 3 0 da ys of si g ni n g a n i nf or me d c o nse nt f or m (I C F). D uri n g 
t he scree ni n g p hase, s u bjects will be e val uate d f or eli gi bilit y t o partici pate i n t he st u d y. S u bjects 
w h o meet t he pr ot oc ol criteria will be a d mitte d i n t he e ve ni n g t o t he cli nical st u d y ce nter, or visit 
t he cli nic if sta yi n g l ocall y, o n da y - 1. S u bjects ma y be a d mitte d t o t he cli nical st u d y ce nter f or 
t he e ntirel y of C ycle 1 or m ust a gree t o sta y l ocall y, wit h o pti o nal a d missi o n t o t he ce nter w he n 
necessar y, d uri n g t heir st u d y partici pati o n. Pri or t o d osi n g o n da y 1 of C ycle 1, s u bject eli gi bilit y 
will be rec o nfir me d. O n da y 1, a si n gle oral d ose of 8 0 0 m g taze met ostat will be a d mi nistere d i n 
t he m or ni n g (e g, 7 – 9 a m) f oll o we d b y 2 da ys of m ulti ple bl o o d sa m pli n g ( da y 1 – 3). Fr o m da y 
3 – 1 4, s u bjects will recei ve a n oral 8 0 0 m g d ose of taze met ostat t wice dail y ( 1 2 h o urs a part o nce 
i n t he m or ni n g [e g, 7 – 9 a m] a n d o nce i n t he e ve ni n g [e g, 7 – 9 p m]). I n t he e ve ni n g of da y 1 4, 
s u bjects ma y be a d mitte d t o t he cli nical st u d y ce nter. O n da y 1 5, a si n gle oral d ose of 8 0 0 m g 
taze met ostat will be a d mi nistere d i n t he m or ni n g (e g, 7 – 9 a m) f oll o we d b y 2 da ys of m ulti ple 
bl o o d sa m pli n g ( da y 1 5 – 1 7). Fr o m da y 1 7 – 2 3, s u bjects will recei ve a n oral 8 0 0 m g d ose of 
taze met ostat t wice dail y, o nce i n t he m or ni n g (e g, 7 – 9 a m) a n d o nce i n t he e ve ni n g (e g, 7 – 9 
p m), c o-a d mi nistere d i n t he m or ni n g (e g, 7 – 9 a m) o ne h o ur bef ore a meal wit h a si n gle d ose of 
oral 6 0 0 m g rifa m pi n. I n t he e ve ni n g of da y 2 3, s u bjects ma y be a d mitte d t o t he cli nical st u d y 
ce nter. O n da y 2 4, s u bjects will recei ve a si n gle oral d ose of 8 0 0 m g taze met ostat c o -
a d mi nistere d i n t he m or ni n g (e g, 7 – 9 a m) o ne h o ur bef ore a meal wit h a si n gle d ose of oral 6 0 0 
m g rifa m pi n f oll o we d b y 2 da ys of m ulti ple bl o o d sa m pli n g ( da y 2 4 – 2 6). Rifa m pi n will als o be 
a d mi nistere d o n da y 2 5 as a si n gle oral 6 0 0 m g d ose i n t he m or ni n g (e g, 7 – 9 a m) o ne h o ur 
bef ore a meal. N ote:  Taze met ostat will n ot be a d mi nistere d o n da y 2 5. After t he 4 8 - h o ur P K 
sa m ple c ollecti o n, safet y assess me nts will be c o n d ucte d o n da y 2 6. S parse P K sa m ples will be 
c ollecte d pre - d ose ( 0 h o ur) a n d 2 h o urs p ost- d ose o n da y 1 9 a n d 2 1. 
S u bjects ma y disc o nt i nue fr o m t he st u d y after c o m pleti o n of C ycle 1 or ca n c o nti n ue treat me nt 
( C ycle 2 + o n war ds) u ntil I n vesti gat or-assesse d cli nical pr o gressi o n per sta n dar d practice, or 
u nacce pta ble t o xicit y, or u ntil a n ot her disc o nti n uati o n criteri o n is met. F or s u bjects c o nti n ui n g 
taze met ostat treat me nt at t he rec o m me n de d t hera pe utic d ose ( 8 0 0 m g taze met ostat t wice dail y 
[ 1 2 h o urs a part]), C ycle 2 will be gi n o n da y 2 7 ( C ycle 2 Da y 1) a n d eac h s u bse q ue nt c ycle fr o m 
C ycle 2 + o n war ds will be of 2 8- da y d urati o n. Safet y a n d t olera bilit y will be assesse d t hr o u g h o ut 
t he s u bject’s partici pati o n. S u bjects will be i nstr ucte d t o re p ort a n y a d verse e ve nts t hat occ ur u p 
t o 3 0 da ys after t he last d ose of taze met ostat. S u bjects m ust ha ve a n e n d of st u d y visit 3 0 da ys 
after t he last d ose of taze met ostat f or safet y assess me nt.  
R oll o ver St u d y  
All s u bjects w h o recei ve t he rec o m me n de d t hera pe utic d ose of 8 0 0 m g taze met ostat t wice dail y 
[ 1 2 h o urs a part] f or 9 C ycles or l o n ger, a n d are eli gi ble t o c o nti n ue recei vi n g taze met ostat, will 
tra nsfer t o a R oll o ver St u d y 
 f or m o nit ori n g a n d c o nti n ue d st u d y dr u g at t he 
I n vesti gat or a n d Me dical M o nit or’s discreti o n. 
C CI


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10.5.1. 
Missed Doses 
Tazemetostat doses must be taken 12 hours apart at approximately the same time each day, for 
example between 7 – 9 am for the morning dose and 7 – 9 pm for the evening dose. If a dose of 
any study drug (tazemetostat, itraconazole or rifampin) is missed, then that drug should be 
administered at the next dosing time point. 
Vomiting: If the subject vomits after study drug administration, then that study drug 
(tazemetostat, itraconazole or rifampin) should be administered at the next dosing time point. All 
doses given, missed, and vomited, should be recorded. 
10.6. 
Study Drug Accountability 
The Investigator/designee will be responsible for taking an inventory of each shipment of all 
study drugs (tazemetostat, itraconazole and rifampin) received and comparing it with the 
accompanying shipment form. The Investigator/designee will verify the accuracy of the 
information on the form, sign, and date it, and acknowledge the shipment receipt according to the 
instructions provided. 
The Investigator/designee must keep accurate written records of all tazemetostat, itraconazole 
and rifampin received from the Sponsor. Additionally, the Investigator/designee must keep 
accurate records of the tazemetostat, itraconazole and rifampin dispensed to subjects enrolled in 
this study including the quantity of tablets, lot number, date dispensed, subject initials and 
identification number, dose administered, balance forward, and the initials of the person 
dispensing the study drug. Based on the entries in the site accountability forms, it must be 
possible to reconcile study drugs delivered with that used and returned. All study drugs must be 
accounted for, and all discrepancies investigated and documented appropriately. 
Tazemetostat, itraconazole and rifampin stock may not be removed from the investigative site 
where originally shipped without prior knowledge and consent of the Sponsor or its designee. 
When authorized, all applicable local, state, and national laws must be adhered to for the 
transfer. 
10.7. 
Study Drug Handling and Disposal 
At the end of the study, all unused tazemetostat, itraconazole and rifampin will be destroyed by 
the investigative site or sent to a designated contractor for disposal on behalf of the Sponsor, per 
the instructions at that time. Any study drugs returned to the Sponsor-designated contractors 
must be counted and verified by site personnel and the Sponsor or its designee. All certificates of 
delivery/receipts and/or return forms must be signed prior to shipment. The study drugs for 
return must be packed in a tamper-evident manner to ensure integrity is maintained during 
return. All study drugs returned must be in accordance with local, state, and national laws and 
must first be authorized by the Sponsor prior to shipment. 


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11. 
PHARMACOKINETIC ASSESSMENTS 
11.1. 
Blood Sample Collection 
PK blood samples will be collected at steady-state dosing intervals following multi-dose 
administration of tazemetostat (Table 9). All dosing and PK sampling times will be recorded. PK 
blood samples at post-dose timepoints that coincide with dosing of study drug(s) (ie, 12, 24, 36, 
48, and 72 [Part 1 only] hour) must be collected prior to dosing of the subject at that timepoint. A 
laboratory manual detailing the PK sample collection, preparation, storage, and shipping process 
will be provided to Investigators.  
Table 9: 
Timing Allowance Windows for Vital Sign Measurements, ECG Assessments 
and Pharmacokinetic Sampling 
Measurement 
Time Point (hours) 
Timing Tolerance Window 
Vital signs  
0 (pre-dose) 
-60 min to 0 hour 
ECG 
0 (pre-dose) 
-60 min to 0 hour 
 
2 
-10 min prior to 2 hours post-
tazemetostat dose 
 
24a 
-60 min prior to 24 hours post-
tazemetostat dose 
 
48a, b 
-60 min prior to 48 hours post-
tazemetostat dose 
PK blood sampling 
0 (pre-dose) 
-60 min to 0 hour 
 
>0 to 3  
-5 min to +5 min 
 
4 – 12 
-15 min to +15 min 
 
24 and >24 
-60 min to +60 min 
Abbreviations: ECG= electrocardiogram, PK= pharmacokinetics. 
a ECGs performed at 24 (Part 1 only) or 48 hours post-tazemetostat administration are to be performed prior to 
dosing of any study drugs on that day 
b No study drugs administered on Cycle 1 day 17 in Part 1 or Cycle 1 day 26 in Part 2 at 48 hours post-tazemetostat 
administration. Perform ECG per timing tolerance window prior to collection of 48 hour PK sample 
11.2. 
Sample Analysis 
Samples taken for PK analysis will be shipped to a central lab for analysis. 


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12. 
ASSESSMENT OF SAFETY 
Study assessments and their timing are summarized in the Schedule of Assessment and 
Procedures. The following safety parameters will be collected for subjects enrolled in Part 1 
(Table 3) and Part 2 (Table 4) of the study. 
12.1. 
Consent 
All subjects must take part in the informed consent process. Adequate time must be allowed for 
the subject to ask questions and make a voluntary decision. No protocol-specific procedures, 
including screening procedures are to be performed until the subject has signed and dated an 
IRB/IEC-approved informed consent form (ICF). 
12.2. 
Screening Assessments 
A signed, written informed consent must be obtained prior to any study-specific assessments or 
procedures being performed. 
All screening assessments, including tumor assessment, must be performed within 30 days of 
enrollment. Subjects may undergo a second laboratory test only once within 2 weeks of the 
initial test if deemed necessary by the Investigator. All samples must be retested at the local 
laboratory. 
12.2.1. 
Demographic/Medical History 
The following demographic information will be collected: date of birth, race, gender, ethnicity. 
The ECOG performance status will also be collected. These will be documented in source 
documents and captured in the relevant eCRF. 
The Investigator or designee will obtain detailed information regarding all past medical history 
and surgical events. The dates and descriptions of past history and events will be documented in 
source documents and captured in the relevant eCRF. Current medical conditions will be updated 
on admission to the clinical research unit. 
12.3. 
Safety Parameters 
12.3.1. 
Vital Signs 
Vital signs will be performed after the subject is seated for 5 minutes and will include the 
following: 
• Systolic BP 
• Diastolic BP 
• Heart rate 
• Temperature 
Vital signs will be documented in source documents and captured in the relevant eCRF. Any 
clinically significant changes noted by the Investigator should be reported as an AE. Vital signs 
will be assessed at screening and during each clinic visit as indicated in the Schedule of 
Assessments and Procedures (Table 3 and Table 4). See Table 9 for timing window allowances. 


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When vital signs are to be obtained concurrently with PK or other blood samples, the vital sign 
measurements will be performed before blood samples are collected in order to maximize the 
accuracy of blood sampling times while minimizing the potential effects of blood collection on 
other safety assessments. 
12.3.2. 
Weight and Height 
Weight is required to be measured at screening, on day 1, 15, 21, and 36 of Cycle 1 for 
itraconazole (Table 3), day 1, 15, and 24 of Cycle 1 for rifampin (Table 4), day 1 (±3 days) of 
each cycle from Cycle 2+ onwards, and at the end of study. 
Height measurement is required at screening only. 
12.3.3. 
Physical Examination 
A complete physical examination is required at screening, on day -1, 15, 21, and 36 of Cycle 1 
for itraconazole (Table 3), day -1, 15, and 24 of Cycle 1 for rifampin (Table 4) and at the end of 
study. Symptom-directed physical examination is required on day 1 (±3 days) of each cycle from 
cycle 2+ onwards. 
A complete physical examination of all body systems must be performed at screening by a 
qualified licensed individual. A review of body systems will include the following: 
• General appearance 
• Skin 
• Head, Ears, Eyes, Nose, Throat (HEENT) 
• Respiratory 
• Cardiovascular 
• Abdomen (including liver and kidneys) 
• Neurological examination with sensory testing and seizure status, if applicable 
• Musculoskeletal 
Any abnormalities or changes in intensity noted during the review of body systems should be 
documented in the source document and reported appropriately in the eCRF. If a new clinically 
significant finding (eg, not noted at screening) occurs from the initial tazemetostat administration 
until the end of the study, an AE must be documented. In addition, resolution of any abnormal 
findings during the study will be noted in source document and the eCRF if clinically significant. 
These assessments will be completed as indicated in the Schedule of Assessments and 
Procedures for Part 1: tazemetostat and itraconazole (Table 3) and Part 2: tazemetostat and 
rifampin (Table 4). 
12.3.4. 
Electrocardiogram (ECG) 
A standard 12 lead ECG will be performed. ECG collection will occur after a 10-minute rest and 
with the subject in a supine position. ECGs will be collected prior to any blood sample 
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The ECGs will be performed as indicated in the Schedule of Assessments and Procedures 
(Table 3 and Table 4). A single ECG will be recorded unless there is an abnormality, such as 
prolonged QT interval corrected for heart rate using Fridericia’s formula (QTcF) >450 msec, 
new arrhythmia, or other clinically significant findings. If an abnormality is observed, the ECG 
is to be performed in triplicate at least 2 minutes apart. Machine read ECGs should be reviewed 
by the Investigator at the time of assessment. ECGs will be read locally within 72 business hours 
and data entered in the clinical database. See Table 9 for timing window allowances. On days 
when an ECG assessment and a PK blood sample collection are scheduled at the same time (see 
Table 3 and Table 4), the ECG assessment should be performed immediately prior to collection 
of the PK blood sample, if possible. 
12.3.5. 
Disease Assessment 
Disease assessment will be performed as indicated in the Schedule of Assessments and 
Procedures (Table 3 and Table 4). 
12.3.6. 
End of Study Pharmacokinetics 
A blood sample for PK analysis will be required at the end of study. A laboratory manual 
detailing the PK sample collection, preparation, storage, and shipping process will be provided.  
12.3.7. 
Laboratory Assessments  
Lab assessments will be performed as indicated in the Schedule of Assessments and Procedures 
(Table 3 and Table 4). Safety laboratory testing at screening and during study will be performed 
at local labs according to institutional procedures. Reference ranges will be supplied by the 
laboratory and used to assess the laboratory data for clinical significance and out of range 
pathological changes. Abnormal laboratory values which are unexpected or not explained by the 
subject’s clinical condition should be repeated until confirmed, explained, or resolved. 
Laboratory value changes starting from the initial tazemetostat exposure will be recorded in the 
eCRF as an AE if clinically significant.  
In addition, a complete peripheral blood smear morphology assessment (see Blood Smear 
Guidance in laboratory manual) will be performed manually or automated along with routine 
hematology testing at screening and during the study by the local laboratory. If the peripheral 
blood smear morphology results are abnormal and suggestive of MDS/AML or MPN, the subject 
will undergo a bone marrow aspirate/biopsy procedure. The bone marrow aspirate/biopsy sample 
will then be analyzed by cytogenetic testing at the local laboratory to closely monitor subjects for 
abnormalities known to be associated with MDS (eg, del 5q, chr 7, abn) and MPN (eg, JAK2 
V617F). Additional local laboratory testing of genetic aberrations associated with MDS/AML or 
MPN can be conducted using targeted next generation sequencing (NGS) of known disease 
genes, as necessary. If local testing is unavailable or if results are inconclusive/indeterminate, the 
site will be required to ship samples for central laboratory testing.  
If the cytogenetic testing and, if conducted, DNA sequencing by NGS results are abnormal and 
associated with myeloid malignancies, tazemetostat will be discontinued. 
Specific clinical laboratory tests for hematology including coagulation profile, serum 
chemistries, urinalysis, and viral serology are detailed in Appendix 2. 


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12.3.7.1. Estimated Glomerular Filtration Rate 
Estimated glomerular filtration rate (eGFR) is only required if serum creatinine is >1.5 × upper 
limit of normal (ULN). If necessary, eGFR should be calculated by the Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) Creatinine Equation (2009) (Appendix 3) and must be 
≥50 mL/min/1.73 m2. 
12.3.8. 
ECOG Performance Status 
Assessment of ECOG Performance Status should be performed according to the table in 
Appendix 1.  
12.3.9. 
Drug and Alcohol Screen 
A blood ethanol test and urine drug screening will be performed at screening, day -1, 15, 21, and, 
36 in Part 1, day -1, 15, and 24 in Part 2. 
12.3.10. 
Pregnancy/Post-Menopausal Testing 
For all FCBP, a serum pregnancy test must be performed at screening and within 24 hours (day -
1) of the first dose of study drug in Cycle 1. For Cycle 2+, pregnancy testing to be performed on 
day 1 of each cycle prior to dosing of study drug. Subsequent testing at Cycle 2+ and at the end 
of study visit can be either urine or serum. Any positive urine pregnancy test must be confirmed 
with a serum test. Post-menopausal females: defined as 12 months with no menses prior to 
screening and a serum FSH >40 IU/L at screening only. 
12.3.11. 
Pregnancy 
Based on findings from animal studies, tazemetostat may cause fetal harm when administered to 
a pregnant woman. There are no available data on the use of tazemetostat in pregnant and 
lactating women to inform a drug-associated risk. In rat and rabbit embryofetal development 
studies, evidence of a higher incidence of skeletal developmental abnormalities in fetuses from 
the pregnant animals relative to fetuses from the control animals were observed in both species, 
while tazemetostat-related visceral findings were noted only in rabbits. Because there is potential 
risk for teratogenicity, tazemetostat should not be used during pregnancy or lactation. 
12.3.11.1. Definition of Childbearing Potential: Female Subjects 
A female subject is considered of childbearing potential if she: 
• Is anatomically and physiologically capable of becoming pregnant, and 
• Will be or could possibly be sexually active with a male while undergoing study 
treatment 
A female subject is considered to be of non-childbearing potential (ie, physiologically incapable 
of becoming pregnant) if she: 
• Is naturally postmenopausal (at least 12 months consecutive amenorrheic 
[amenorrhea following cancer therapy does not rule out childbearing potential] and 
without other known or suspected cause) 


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• Is surgically sterilized (ie, total hysterectomy and/or bilateral oophorectomy) with 
surgery completed at least 1 month before the first dose of study drug 
• Has a documented congenital or acquired disorder that is incompatible with 
pregnancy 
12.3.11.2. Definition of Childbearing Potential: Male Subjects 
A male subject is considered of childbearing potential if he: 
• Is anatomically and physiologically capable of causing a pregnancy in a female 
partner, AND 
• Will be or could possibly be sexually active with a female (who is or may become 
pregnant) while undergoing study treatment 
A male subject is considered to be of non-childbearing potential if he: 
• Has a documented successful vasectomy (with medically confirmed azoospermia). 
However, even with a successful vasectomy, male subjects must either practice 
complete abstinence or agree to use a latex or synthetic condom during sexual contact 
with a pregnant female or FCBP from first dose of study drug, during study treatment 
(including during dose interruptions), and for 3 months after study drug 
discontinuation. 
12.3.11.3. Pregnancy Prevention  
12.3.11.3.1. 
Female Subjects  
Females of childbearing potential (FCBP) must either practice complete abstinence or agree to 
use a highly effective method of contraception beginning at least 28 days prior to the first dose of 
study drug, during study treatment (including during dose interruptions), and for 6 months after 
study drug discontinuation. If the below contraception methods are not appropriate for the FCBP, 
she must be referred to a qualified contraception provider to determine the medically effective 
contraception method appropriate for the subject. The following are examples of highly effective 
methods of contraception (result in a failure rate of <1% per year when used consistently and 
correctly): 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• Hormonal (ovulation inhibitory combined [estrogen and progesterone]: oral, 
intravaginal, or transdermal; ovulation inhibitory progesterone-only: oral, injectable, 
or implantable) 
NOTE: Due to the potential of enzyme induction with tazemetostat, hormonal contraception 
methods must be supplemented with a barrier method of contraception (preferably male 
condom) 
• Bilateral tubal ligation 
• Partner’s vasectomy (if medically confirmed [azoospermia] and sole sexual partner) 


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NOTE: Female subjects of childbearing potential exempt from these contraception 
requirements are subjects who practice complete abstinence from heterosexual sexual 
contact. True abstinence is acceptable when this is in line with the preferred and usual 
lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-
ovulation methods) and withdrawal are not acceptable methods of contraception. 
12.3.11.3.2. 
Male Subjects 
Male subjects must have had a successful vasectomy (with medically confirmed azoospermia) 
OR must either practice complete abstinence or agree to use a latex or synthetic condom during 
sexual contact with a female of childbearing potential (FCBP) from the first dose of study drug, 
during study treatment (including during dose interruptions), and for 3 months after study drug 
discontinuation. 
NOTE: Male subjects must not donate sperm from the first dose of study drug, during study 
treatment (including during dose interruptions), and for 3 months after study drug 
discontinuation. 
12.3.12. 
Unscheduled Visits 
A patient may require unscheduled visits to assess safety outside of the protocol Schedule of 
Assessments. Any procedures/assessments performed at an unscheduled time point are at the 
discretion of the Investigator and corresponding results/data for the unscheduled visit should be 
reported on the eCRF. Adverse Events should always be assessed and reported regardless if the 
visit is schedule or unscheduled. The following assessments will also be available to be reported 
as unscheduled visits:  
• Drug and Alcohol Screen 
• Pregnancy Test 
• Vital Signs 
• Physical Examination 
• ECOG Performance Status 
• 12-lead ECG 
• PK Blood Sample 
• Laboratory Assessments 
• Estimated GFR 
• Disease Assessment 
• Optional Chest Ultrasound 


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12.4. 
Adverse and Serious Adverse Events 
12.4.1. 
Definition of Adverse Events 
12.4.1.1. Adverse Event (AE) 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a medicinal product and which does not necessarily have to have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a study drug, whether or not related to the study drug. 
Worsening of a pre-treatment event, after initiation of any study drugs, must be recorded as a 
new AE. For example, if a subject experiences mild intermittent dyspepsia prior to dosing of 
study drug, but the dyspepsia becomes severe and more frequent after the first dose of study 
drug, a new AE of severe worsening dyspepsia (with the appropriate date of onset) should be 
recorded in the eCRF. 
“Lack of efficacy” or “failure of an expected pharmacological action” per se is not to be reported 
as an AE or SAE. However, any signs and symptoms and/or clinical sequelae resulting from 
“lack of efficacy” will be reported as an AE or SAE, if they fulfill the definition of an AE or 
SAE. 
Events that do not meet the definition of an AE include: 
Medical or surgical procedure (eg, endoscopy, appendectomy); the condition that leads to the 
procedure is an AE. 
Situations where an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital). 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected 
at the start of the study that do not worsen. 
12.4.1.2. Serious Adverse Event (SAE) 
An SAE is an AE occurring during any study phase (ie, baseline, treatment, washout, or follow-
up), and at any dose of the study drug, comparator, or placebo, that fulfils one or more of the 
following: 
• Results in death 
• Is life-threatening 
• NOTE: The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in 
which the subject was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe. 
• Requires hospitalization or prolongation of existing hospitalization. 
• NOTE: In general, hospitalization signifies that the subject has been detained 
(usually involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 


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office or out-patient setting. Complications that occur during hospitalization are AEs. 
If a complication prolongs hospitalization or fulfills any other serious criteria, the 
event is serious. When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious. 
• Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
• Results in disability or incapacity. 
• NOTE: The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (eg, sprained ankle) which may 
interfere or prevent everyday life functions but do not constitute a substantial 
disruption. 
• Is a congenital abnormality or birth defect. 
• It is an important medical event that may jeopardize the subject or may require 
medical intervention to prevent one of the outcomes listed above. Examples of such 
events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions (in subjects without pre-existing 
seizure disorder) that do not result in hospitalization, or development of drug 
dependency or drug abuse. 
12.4.1.3. Laboratory Abnormalities 
A clinical laboratory AE is any laboratory value that is considered clinically significant by the 
Investigator and requires a medical intervention or is accompanied by clinical symptoms. 
Laboratory abnormalities that have not required medical intervention should not be recorded as 
AEs and will be captured and reported in the laboratory section of the clinical study report 
(CSR). If a medical intervention occurs, it should be recorded as a treatment with the abnormal 
laboratory finding as the AE (eg, anemia with treatment required and blood transfusion recorded 
as a procedure, hyperglycemia with treatment required and change in insulin dose recorded on 
concomitant medications). 
All clinically significant lab values should be followed and recorded in the eCRF until return to 
baseline.  
12.4.1.4. Other Safety Assessment Abnormalities 
Other safety assessments (eg, ECGs, radiological scans, vital signs measurements), including 
those that worsen from baseline and/or those considered to be clinically significant, are to be 
recorded as an AE or SAE, in accordance with the definitions provided in Section 12.4.1.1 and 
Section 12.4.1.2, respectively. 
Any other safety assessment that led to an intervention, including permanent discontinuation of 
study treatment, dose reduction, and/or dose interruption/delay is also to be recorded as an AE or 
SAE. 


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12.4.1.5. Disease-Related Events 
Disease progression is not a SAE per se as it is an efficacy criterion. However, events that are 
associated with progression but are untoward (for a given patient or for the disease) and meet the 
criteria for seriousness should still be reported as SAEs.  
NOTE: Disease progression should not be reported as an SAE event term. 
12.4.1.6. Other Adverse Event (OAE) 
Adverse events associated with study drug overdose, misuse, abuse, and medication error refer to 
AEs associated with uses of the study drug outside of that specified by the protocol. Overdose, 
misuse, abuse, and medication error are defined as follows:  
• Overdose: Accidental or intentional use of the study drug in an amount higher than 
the protocol-defined dose  
• Misuse: Intentional and inappropriate use of study drug not in accordance with the 
protocol  
• Abuse: Sporadic or persistent intentional excessive use of study drug accompanied 
by harmful physical or psychological effects  
• Medication error: Any unintentional event that causes or leads to inappropriate 
study drug use or subject harm while the study drug is in the control of site personnel 
or the subject.  
All AEs associated with an overdose, misuse, abuse, or medication error should be captured on 
the AE eCRF. Both the adverse event (if any) and the dosing details should be reported using the 
procedures for reporting SAEs (Section 12.7). This process should be followed even if the there 
are no associated AE of if the associated AE does not meet serious criteria. Non-serious 
associated AE should be noted as non-serious on the SAE form and on the AE eCRF.  
12.4.2. 
Adverse Events of Special Interest (AESIs) 
The following AESIs have been identified as requiring mitigation steps and monitoring to 
minimize the risk for the occurrence of these events. 
12.4.2.1. T-Cell Lymphoblastic Lymphoma/T-Cell Acute Lymphoblastic Leukemia 
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 non-Hodgkin lymphoma with a median age at diagnosis of 25 years (Lones, 
2007; Lai, 2013; Cortelazzo, 2017). 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 subjects tend to have less 
thymic disease and greater lymph node disease and bone marrow involvement (Baleydier, 2008; 






Cli nical St u d y Pr ot oc ol  
 
E Z H- 1 0 8  
Taze met ostat  
 
A me n d me nt 2. 0
 
 
3 1  A u g ust 2 0 2 1  
E piz y me, I nc.  
C o nfi de n tial 
 t he patie nt recei ve d taze met ostat f or 2 6 c ycles a n d ac hie ve d a n 
o bjecti ve P R at wee k 1 6 t hat was mai ntai ne d t hr o u g h wee k 1 0 4.  
T he patie nt was s u bse q ue ntl y e nr olle d o nt o t he  
mai nte na nce st u d y a n d recei ve d t he 
first d ose of taze met ostat o n 2 1 Ja n 2 0 1 9. T he last d ose of taze met ostat occ urre d o n 0 5 N o v 
2 0 2 0. O n st u d y 
 t he patie nt ac hie ve d a n i n vesti gat or-re p orte d C R t hr o u g h wee k 8 3. 
O n 0 5 N o v 2 0 2 0, la b orat or y testi n g re veale d a W B C c o u nt of 2, 8 0 0/ m m 3 wit h 1, 5 0 0 
ne utr o p hils / m m3 a n d 2 8 0 circ ulati n g blasts, H g b 1 2. 7 g/ d L, a n d platelets 9 2, 0 0 0/ m m 3. 
C he mistr y la b orat ories were creati ni ne 1 1 m g/ L, urea 0. 3 3 g/ L, n o electr ol yte i m bala nce, 
calci u m 1. 1 7 m g/ L, p h os p h or us 3 4 m g/ L, n o c yt ol ysis or c h olestasis, C R P 9 m g/ L, a n d L D H 
1, 5 6 2 U/ L. 
M olec ular bi ol o g y a nal ysis  of b o ne marr o w o n 0 5 N o v 2 0 2 0 re p orte d n o B C R- A B L f usi o n 
tra nscri pt, I K A R O S stat us ne gati ve, rearra n ge me nt of i m m u n o gl o b uli n hea v y c hai n P C R F R 1, 
rearra n ge me nt of i m m u n o gl o b uli n ka p pa li g ht c hai n I g k A V k-J k p ositi ve a n d I g k B p ositi ve, 
T C R ga m m a a n d delta c hai n rearra n ge me nt p ositi ve f or T C R ga m ma V G 9J 1J 2, V G 1 0J 1J 2, 
V G 1 0J P 1/ 2, a n d T C R delta D D 2 D D 3. 
O n 1 4 N o v 2 0 2 0, t he patie nt was wit h dra w n fr o m st u d y  
 a n d be ga n n o n- e mer ge nt 
treat me nt f or B- A L L wit h i dar u bici n, vi ncristi ne, a n d de xa met has o ne.  
O n 1 1 Dec 2 0 2 0, la b orat or y a plasia was de m o nstrate d a n d assesse d as a partial res p o nse b y t he 
i n vesti gat or. 
T here ha ve bee n n o e ve nts of B- cell ac ute l y m p h o blastic le u ke mia ( B - A L L) or B -cell 
l y m p h o blastic l y m p h o ma ( B- L B L) o bser ve d i n a n y n o ncli nical safet y st u dies perf or me d at 
E piz y me wit h E Z H 2 i n hi biti o n. A d diti o nall y, n o e ve nts of B- A L L or B - L B L occ urre d i n 
precli nical efficac y st u dies usi n g m o use m o dels wit h a n i ntact B cell c o m part me nt. O n t he 
c o ntrar y, E Z H 2 i n hi biti o n wit h taze met ostat i n vitr o i n a d ult a n d pe diatric B- A L L cell li nes di d 
n ot e n ha nce pr oliferati o n a n d i n fact ca use d m o dest decreases i n pr oliferati o n i n a s u bset of cell 
li nes. 
 e x perie nce d B cell ac ute l y m p h o blastic le u ke mia, 
t y pe B-I a p pr oxi matel y 6 5 5 da ys after i nitial st u d y dr u g a d mi nistrati o n o n St u d y  
. T otal 
e x p os ure 
 t o taze met ostat is a p pr o xi matel y 4 6 m o nt hs. 
Ot her p ossi ble eti ol o gies/ris k fact ors i ncl u de ge netic pre dis p ositi o n t o l y m p h oi d mali g na ncies 
lea di n g t o t he e ve nt as a n e v ol uti o n of t he u n derl yi n g l y m p h o ma a n d p ossi bl y i n d uce d b y 
pre vi o us a g gressi ve c he m ot hera p y.  
Base d u p o n me dical re vie w of t he bi ol o g y, n o ncli nical data, a n d literat ure of t his is olate d case of 
B- A L L, E p iz y me belie ves t he e ve nt is u nli kel y relate d t o taze met ostat e x p os ure. H o we ver, 
E piz y me will c o nti n ue t o m o nit or patie nt safet y wit h re gar d t o sec o n dar y mali g na nc y a n d all 
he mat ol o gical sec o n dar y mali g na ncies will be assesse d b y t he taze met ostat Q S R a n d E S C as 
detaile d i n Secti o n  1 2. 4. 2. 4 .  
1 2. 4. 4.  
Gr a di n g a n d Se verit y  
T he se verit y of all A Es a n d S A Es, i ncl u di n g a p pr o priate la b orat or y val ues, will be gra de d 
utilizi n g t he  C T C A E v 5. 0 (Nati o nal I nstit utes of Healt h, N o ve m ber 2 7, 2 0 1 7 ). 
C CI
C CI
C CI
C CI
C CI
P P D
C CI


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In the event that an AE is not covered by the CTCAE, the assessment of severity will be 
determined by using the CTCAE general guideline, as follows: 
Grade 1:  Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.  
Grade 2:  Moderate; minimal, local, or noninvasive intervention indicated; limiting age- appropriate 
instrumental ADL.a  
Grade 3:  Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL.b  
Grade 4:  Life-threatening consequences; urgent intervention indicated.  
Grade 5:  Death related to AE.  
Abbreviations: ADL = activities of daily living; AE = adverse event. 
a Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc  
b Self-care ADL refer to bathing, dressing, and undressing, feeding self, using the toilet, taking medications, and not 
bedridden.  
An AE that is assessed as severe should not be confused with an SAE. Severity is a category 
used for rating the intensity of an event (as in ‘mild’, ‘moderate’, or ‘severe’); both AEs and 
SAEs can be assessed as severe. An event is described as ‘serious’ when it meets one of the pre-
defined outcomes as described in Section 12.4.1.2 which are based on patient/event outcome or 
action criteria associated with events that pose a threat to a subject’s life or functioning. 
12.5. 
Relationship to Study Drug 
A qualified Investigator must make the determination of relationship to study drug for each AE. 
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. 
The following should be considered when assessing the relationship of an AE to study treatment: 
• Temporal relationship of the onset of the event to the first dose of study drug 
• The course of the event, considering especially the effect of discontinuation of study 
• treatment or the reintroduction of study treatment, as applicable 
• Whether the event is known to be associated with the study treatment or with other 
similar treatments 
• The presence of risk factors in the study subject known to increase the occurrence of 
the event 
• The presence of non-study treatment-related factors that are known to be associated 
with the occurrence of the event. 
Investigators must also systematically assess the causal relationship of AEs to the study drug 
using the following definitions (the decisive factor being the temporal relationship between the 
AE and administration of the study drug): 


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• Probable: A causal relationship is clinically/biologically highly plausible, there is a 
plausible time sequence between onset of the AE and administration of the study 
drug, and there is a reasonable response on withdrawal. 
• Possible: A causal relationship is clinically/biologically plausible and there is a 
plausible time sequence between onset of the AE and administration of the study 
drug. 
• Unlikely: A causal relationship is improbable, and another documented cause of the 
AE is most plausible. 
• Unrelated: A causal relationship can be definitively excluded, and another 
documented cause of the AE is most plausible. 
12.6. 
Recording Adverse Events 
Adverse events spontaneously reported by the subject and/or in response to an open question 
from the study personnel or revealed by observation will be recorded during the study at the 
investigational site. Clinically insignificant changes in laboratory values, BP, and pulse need not 
be reported as AEs. However, abnormal values that constitute an SAE or lead to discontinuation 
of administration of study drug must be reported and recorded as an AE. Information about AEs 
will be collected from signing of the consent form until the end of the study. Serious Adverse 
Event information will be collected from signing of the informed consent until 30 days following 
the last dose of study drug and for related SAEs, until resolution. The AE term should be 
reported in standard medical terminology when possible. For each AE, the Investigator will 
evaluate and report the onset (date and time), resolution (date and time), intensity, causality, 
action taken, serious outcome (if applicable), and whether or not it caused the subject to 
discontinue the study. 
Intensity will be assessed according to the CTCAE v5.0 or Section 12.4.4.  
Should a pregnancy occur, it must be reported and recorded on the Sponsor’s pregnancy form. 
Pregnancy in itself is not regarded as an AE unless there is a suspicion that a study drug may 
have interfered with the effectiveness of a contraceptive medication. Study IMP will stop 
immediately for female subjects who become pregnant.  
The outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth, or 
congenital abnormality) will be followed up (assuming consent) and documented even if the 
subject was discontinued from the study. 
All reports of congenital abnormalities/birth defects are SAEs. Spontaneous miscarriages should 
also be reported and handled as SAEs. Elective abortions without complications should not be 
handled as AEs. 
12.7. 
Reporting Adverse Events 
All AE and SAEs (related and unrelated) will be recorded from the signing of consent form until 
the end of the safety reporting period (or until screen failure, 30 days following the end of 
treatment exposure or initiation of an investigational agent or cytotoxic chemotherapy, 
whichever occurs first). Any SAEs considered possibly or probably related to the study drug and 
discovered by the Investigator at any time after the study should be reported. All SAEs must be 


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reported to the Sponsor within 24 hours of the first Investigator awareness of the event. The 
Investigator must complete, sign and date the SAE pages, verify the accuracy of the information 
recorded on the SAE pages with the corresponding source documents, and send a copy to the 
Sponsor.  
Additional follow-up information, if required or available, should all be reported to the Sponsor. 
Epizyme, Inc. following the same reporting timeline as the initial report, and this should be 
completed on a follow-up SAE form and placed with the original SAE information and kept with 
the appropriate section of the eCRF and/or study file. 
12.8. 
Reporting of Serious Adverse Events 
All SAEs will be reported to the Sponsor within 24 hours of the Investigator becoming aware of 
the event. The Investigator must promptly notify the Sponsor or its designee of all SAEs in order 
that the legal obligations and ethical responsibilities of the sponsor or its designee are met. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of the study drug under clinical investigation. The Sponsor 
and its designee will comply with country specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRB/EC/CEC, and Investigators. 
Any SAE that is unexpected (not consistent with the applicable product information) and 
considered related to the study treatment by the Investigator-or the Sponsor, meets the definition 
of a SUSAR. SUSARs are prepared for expedited reporting according to local regulatory 
requirements and are forwarded to Investigators as necessary. The Sponsor is legally obligated to 
report SUSARs to the regulatory authorities within 7 days for fatal or life-threatening events or 
15 days for all other events. 
An Investigator who receives an Investigator safety report describing a SAE(s) or other specific 
safety information (eg, summary or listing of SAEs) from the sponsor will file it with the IB and 
will notify the IRB/EC/CEC, if appropriate according to local requirements. 
12.9. 
Reporting of Pregnancy 
Pregnancy will not be considered an SAE. Any report of pregnancy recorded for any female 
subject, or a female partner of a male subject should be reported. To ensure subject safety, each 
pregnancy must be reported to the Sponsor or its designee within 2 weeks of learning of its 
occurrence using a clinical trial Pregnancy Report Form. A Pregnancy Report Form should be 
completed and submitted by email and/or fax to the Sponsor or its designee.  
The pregnant female subject must be withdrawn from the study. Every effort should be made to 
gather information regarding the pregnancy outcome until 8 weeks post-partum. It is the 
responsibility of the Investigator to obtain all pregnancy information. 
Pregnancy complications and elective terminations for medical reasons must be reported as an 
AE or SAE. Spontaneous abortions must be reported as an SAE. 
Any SAE occurring in association with a pregnancy brought to the Investigator’s attention after 
the subject has completed the study and considered by the Investigator as possibly related to the 
study treatment, must be promptly reported to the Sponsor. 


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The Investigator also must attempt to collect and report to the Sponsor or its designee pregnancy 
information on any female partner of male study subjects who become pregnant while the subject 
is enrolled in the study. 
12.10. 
Reporting of Adverse Events of Special Interest 
All potential and identified AESIs, irrespective of their relationship to study treatment, must be 
reported as soon as possible, but no later than 24 hours from when the Investigator becomes 
aware of the event.  
12.11. 
Reporting of Special Situations: Overdose, Misuse, Abuse, or 
Medication Error  
Report the special situation(s) of overdose, misuse, abuse, and/or medication error (described in 
Section 9.3.1) 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): 
• Report to Epizyme using a paper Special Situations Form following the procedures for 
reporting SAE (Section 12.8).   
Special situation(s) with an associated non-serious AE: 
• Enter the non-serious event on the AE eCRF and mark the SAE field, “no”. SAE related 
narrative fields should not be completed. 
• Report to Epizyme using a paper Special Situations Form following the procedures for 
reporting SAE (Section 12.8).  
Special situation(s) with an associated SAE: 
• 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. 
• Report to Epizyme using both a paper Special Situations Form and a paper Serious 
Adverse Event Form following the procedures for reporting SAE (Section 12.8).  
 
 
 


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13. 
STATISTICS 
Summaries of continuous variables will present the number of subjects included in the analysis 
(N), the mean and standard deviation (SD), the median, the minimum, and the maximum 
statistics. Counts and percentages will be presented in summaries of categorical variables. The 
denominator for each percentage will be the number of subjects in the population unless 
otherwise specified. In general, missing data will not be imputed unless otherwise specified. 
All disposition, baseline demographics and disease characteristics will be descriptively 
summarized for the Safety population 
Analyses will be done separately for each study part and overall. 
13.1. 
Study Design Considerations 
13.1.1. 
Determination of Sample Size 
A total of 12 subjects per study part is adequate to describe the effect of CYP3A4 inhibition by 
itraconazole or induction by rifampin on the steady state PK of tazemetostat. 
A point estimate and associated 90% confidence interval on the magnitude of the effect of the 
perpetrator drugs on the PK of the victim drugs will be provided. The default no effect boundary 
of 80 – 125% for the 90% confidence interval for an effect size will be used as a reference. This 
is equivalent to a hypothesis test with a null hypothesis that there is a nonzero effect and 
alternative of no effect. If the 90% confidence interval for any effect tested in this study falls 
completely within 80 – 125%, it will be concluded that no significant differences are present.  
The sample size calculation is based on the underlying assumption that the within subject 
coefficient of variation (CV) is 30%, a two-sided alpha level of 0.05, the underlying within-
subject correlation of subsequent measurements of the same PK parameter and geometric mean 
ratio. If the geometric mean ratio of itraconazole is 1.06 or the geometric mean ratio for rifampin 
is 0.94 and subsequent measurements of tazemetostat AUC have a correlation of at least 0.80, 
this test is powered at 88% or higher.  
Calculations were performed using the Paired t-test for the Equivalence of Log-Normal Means 
(Multiplicative Model) in nQuery version 8.0. 
13.2. 
PK analyses 
Plasma concentrations of tazemetostat and its metabolite (EPZ6930) will be determined by 
validated bioanalytical methods. Plasma concentrations of tazemetostat and its metabolite 
(EPZ6930) will be listed for each subject and summarized by study part, treatment, day, and 
nominal time. Standard summary statistics will be calculated (ie, arithmetic mean, geometric 
mean, standard deviation, median, minimum, and maximum) for each endpoint.  
All PK parameters will be calculated with noncompartmental methods using actual times. The 
following PK parameters will be determined as data permit: 
Part 1: Plasma AUC0-72, Cmax, Tmax, and t½ for tazemetostat alone on Day 15 – 18, and in the 
presence of itraconazole on Day 36 – 39.  


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Part 2: Plasma AUC0-48, Cmax, Tmax, and t½ for tazemetostat alone on Day 15 – 17, and in the 
presence of rifampin on Day 24 – 26. 
13.3. 
Safety analyses 
Safety analyses will be based on all subjects who receive at least 1 dose or partial dose of study 
drugs (Safety population). Drug exposure will be summarized using descriptive statistics. The 
severity of all adverse events is to be evaluated by the Investigator based on the National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 and 
verbatim terms will be coded to the preferred term (PT), higher level term (HLT), and system 
organ class (SOC) using the Medical Dictionary for Regulatory Activities (MedDRA) version in 
use at the time of the analysis. The number and percentage of subjects with adverse events will 
be presented by MedDRA SOC and PT, relationship to study treatment, and severity. Clinical 
laboratory values also will be classified by toxicity grade based on the NCI CTCAE, version 5.0. 
Laboratory shift tables from baseline result to the worst post-baseline result will be provided. 
AEs will be summarized separately for: AEs, serious AEs, AEs leading to discontinuation, AEs 
leading to death, Grade 3, or higher AEs (per NCI CTCAE Version 5.0). Physical examination, 
vital signs, 12-lead ECG, and ECOG performance status will be descriptively summarized based 
on marked abnormality criteria. 
Analyses will be done separately for each study part and overall. 
Complete details of the safety analysis will be provided in the statistical analysis plan (SAP). 
13.4. 
Efficacy analysis  
No efficacy analysis will be performed. 


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14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
14.1. 
Study Monitoring 
Before an investigational site can enter a patient into the study, a representative of Epizyme, Inc. 
will visit the investigational study site to: 
• Determine the adequacy of the facilities 
• Discuss with the Investigator(s) and other personnel their responsibilities with regard 
to protocol adherence, and the responsibilities of Epizyme, Inc. or its representatives. 
This will be documented in a Clinical Study Agreement between Epizyme, Inc. and 
the Investigator. 
During the study, a monitor from Epizyme, Inc. or representative will have regular contacts with 
the investigational site, for the following: 
• Provide information and support to the Investigator(s) 
• Confirm that facilities remain acceptable 
• Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the case report forms, and that investigational product 
accountability checks are being performed 
• Perform source data verification. This includes a comparison of the data in the case 
report forms with the patient’s medical records at the hospital or practice, and other 
records relevant to the study. This will require direct access to all original records for 
each patient (eg, clinic charts). 
• Record and report any protocol deviations not previously sent to Epizyme, Inc. 
• Confirm AEs and SAEs have been properly documented on CRFs and confirm any 
SAEs have been forwarded to Epizyme, Inc. and those SAEs that met criteria for 
reporting have been forwarded to the IRB. 
The monitor will be available between visits if the Investigator(s) or other staff needs 
information or advice. 
14.2. 
Audits and Inspections 
Authorized representatives of Epizyme, Inc., a regulatory authority, an Independent Ethics 
Committee or an Institutional Review Board may visit the site to perform audits or inspections, 
including source data verification. The purpose of an Epizyme, Inc. audit or inspection is to 
systematically and independently examine all study-related activities and documents to 
determine whether these activities were conducted, and data were recorded, analyzed, and 
accurately reported according to the protocol, Good Clinical Practice guidelines of the 
International Conference on Harmonization, and any applicable regulatory requirements. The 
Investigator should contact Epizyme, Inc. immediately if contacted by a regulatory agency about 
an inspection. 
 


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14.3. 
Institutional Review Board (IRB) 
The Principal Investigator must obtain IRB approval for the investigation. Initial IRB approval, 
and all materials approved by the IRB for this study including the patient consent form and 
recruitment materials must be maintained by the Investigator and made available for inspection. 
 


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15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with Good Clinical Practices and all applicable regulatory requirements, 
Epizyme, Inc. may conduct a quality assurance audit. Please see Section 14.2 for more details 
regarding the audit process. 
 


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16. 
ETHICS 
16.1. 
Ethics Review 
The final study protocol, including the final version of the Informed Consent Form, must be 
approved, or given a favorable opinion in writing by an IRB or IEC as appropriate. The 
Investigator must submit written approval to Epizyme, Inc. before he or she can enroll any 
patient/subject into the study. 
The Principal Investigator is responsible for informing the IRB or IEC of any amendment to the 
protocol in accordance with local requirements. In addition, the IRB or IEC must approve all 
advertising used to recruit subjects for the study. The protocol must be re-approved by the IRB 
or IEC upon receipt of amendments and annually, as local regulations require. 
The Principal Investigator is also responsible for providing the IRB with reports of any 
reportable serious adverse drug reactions from any other study conducted with the investigational 
product. Epizyme, Inc. will provide this information to the Principal Investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines. 
16.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, applicable 
regulatory requirements and Epizyme, Inc.’s policy on Bioethics. 
16.3. 
Written Informed Consent 
The Principal Investigator(s) at each center will ensure that the patient is given full and adequate 
oral and written information about the nature, purpose, possible risk, and benefit of the study. 
Subjects must also be notified that they are free to discontinue from the study at any time. The 
patient should be given the opportunity to ask questions and allowed time to consider the 
information provided. 
The patient’s signed and dated informed consent must be obtained before conducting any study 
procedures. 
The Principal Investigator(s) must maintain the original, signed Informed Consent Form. A copy 
of the signed Informed Consent Form must be given to the patient. 
 


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17. 
DATA HANDLING AND RECORDKEEPING 
17.1. 
Inspection of Records 
Epizyme, Inc. will be allowed to conduct site visits to the investigation facilities for the purpose 
of monitoring any aspect of the study. The Investigator agrees to allow the monitor to inspect the 
drug storage area, study drug stocks, drug accountability records, subject charts and study source 
documents, and other records relative to study conduct. 
17.2. 
Retention of Records 
The Principal Investigator must maintain all documentation relating to the study for a period of 2 
years after the last marketing application approval, or if not approved 2 years following the 
discontinuance of the test article for investigation. If it becomes necessary for Epizyme, Inc. or 
the Regulatory Authority to review any documentation relating to the study, the Investigator 
must permit access to such records. 
 


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18. 
PUBLICATION POLICY 
Clinical study results will be made publicly available in compliance with local legislation and 
guidelines. 
If a manuscript is published in a peer-reviewed journal, then that initial release may be an 
abstract that meets the requirements of the International Committee of Medical Journal Editors. 
All manuscripts, abstracts or other modes of presentation arising from the results of the study 
must be reviewed and approved in writing by Epizyme, Inc., in advance of submission. The 
review is aimed at protecting the Sponsor’s proprietary information existing either at the date of 
the commencement of the study or generated during the study. 
The detailed obligations regarding the publication of any data, material results, or other 
information, generated or created in relation to the study shall be set out in the agreement 
between each Investigator and the Sponsor. 


Clinical Study Protocol 
 
EZH-108 
Tazemetostat 
 
Amendment 2.0
 
 
31 August 2021 
Epizyme, Inc. 
Confidential 
19. 
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Bracken AP, Pasini D, Capra M, et al. EZH2 is downstream of the pRB-E2F pathway, essential 
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Cortelazzo S, Ferreri A, Hoelzer D, et al. Lymphoblastic lymphoma. Crit Rev Oncol Hematol. 
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DuPage M, Chopra G, Quiros J, et al. The chromatin-modifying enzyme Ezh2 is critical for the 
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Kleer CG, Cao Q, Varambally S, et al. EZH2 is a marker of aggressive breast cancer and 
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Knutson SK, Kawano S, Minoshima Y, et al. Selective inhibition of EZH2 by EPZ-6438 leads to 
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Kuroki H, Hayashi H, Okabe H, et al. EZH2 is associated with malignant behavior in pancreatic 
IPMN via p27Kip1 downregulation. PLoS One. 2014;9(8):e100904. 
LaFave LM, Beguelin W, Koche R, et al. Loss of BAP1 function leads to EZH2-dependent 
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Lones MA, Heerema NA, Le Beau MM, et al. Chromosome abnormalities in advanced stage 
lymphoblastic lymphoma of children and adolescents: a report from CCG-E08. Cancer Genet 
Cytogenet. 2007;172(1):1-11. 


Clinical Study Protocol 
 
EZH-108 
Tazemetostat 
 
Amendment 2.0
 
 
31 August 2021 
Epizyme, Inc. 
Confidential 
Margueron R, Reinberg D. The Polycomb complex PRC2 and its mark in life. Nature. 
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Morin RD, Johnson NA, Severson TM, et al. Somatic mutations altering EZH2 (Tyr641) in 
follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat Genet. 
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National Institutes of Health. Common Terminology Criteria for Adverse Events (CTCAE), 
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Rifadin (rifampin, USP) [package insert]. Bridgewater, NJ: Sanofi-Aventis U.S. LLC; 2019. 
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Wrangle J, Wang W, Koch A, et al. Alterations of immune response of Non-Small Cell Lung 
Cancer with Azacytidine. Oncotarget. 2013;4(11):2067-2079. 
Yang XP, Jiang K, Hirahara K, et al. EZH2 is crucial for both differentiation of regulatory T 
cells and T effector cell expansion. Sci Rep. 2015;5:10643. 

SAP_001.pdf: 
N u m b er: 
St at us: Iss u e d
Pr ot oc ol E Z H- 1 0 8
V 2. 0, 3 1 A u g ust 2 0 2 1
Statistical A nal ysis Pla n
V 2. 1, 2 1  N o v, 2 0 2 2
E pi z y m e, I n c.
C O N FI D E N TI A L I N F O R M A TI O N
P a g e 1 of 3 1
St atistic al A n al ysis Pl a n
Pr ot oc ol E Z H- 1 0 8
A  P h ase  I,  O pe n-l a bel  M ulti- d ose  T w o- P art  St u d y  t o  
C h ar acterize t he Effects of a Str o n g C Y P 3 A 4 I n hi bit or o n 
t he  Ste a d y- St ate  P h ar m ac o ki netics  of  T aze met ost at  ( E pz-
6 4 3 8), a n d t he Effects of a Str o n g C Y P 3 A 4 I n d ucer o n t he 
Ste a d y- St ate P h ar m ac o ki netics of T aze met ost at i n S u bjects 
wit h A d v a nce d M ali g n a ncies
Pre p are d B y: E PI Z Y M E, I N C.
4 0 0 Tec h n ol o g y S q uar e, 4 t h 
Fl o or Ca m bri d ge, M A 0 2 1 3 9
Versi o n N u m b er a n d D ate: V 2. 1, 2 1  N o ve m ber 2 0 2 2
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C O N FI D E N TI A L I N F O R M A TI O N 
P a g e 3 of 3 1 
 
 
 
 
M O DI FI C A TI O N H I S T O R Y 
After a p pr o val of versi o n 1. 0 of t he statistical a nal ysis p la n, s u bse q ue nt versi o ns s h o ul d be d oc u me nte d bel o w wit h 
a brief descri pti o n of t he c ha n ge fr o m t he pre vi o us versi o n as well as t he rati o nale f or t he c ha n ge. 
 
Versi o n, D ate 
A ut h or 
Brief Descri pti o n of C h a n ge a n d R ati o n ale 
V 2. 0, 0 7/ 2 9/ 2 0 2 2 
 
 Secti o n 1 4. 1 : U p date d t he defi niti o n of a vera ge d ose i nte nsit y i n c ycle 1 f or 
m ore clarit y a n d m o difie d t he t hres h ol d of s u m mar y statistics f or t he t otal 
a m o u nt of itrac o naz ole/ rifa m pi n recei ve d t o be c o nsiste nt wit h st u d y d ose 
sc he d ule i n c ycle 1. 
 Secti o n 1 4. 2 : U p date d dr u g c o m plia nce f or m ula i n c ycle 1 f or m ore clarit y. 
 
V 2. 1, 1 1/ 2 1/ 2 0 2 2  
 
A p pe n di x 1 : Al g orit h m f or pri or a n d c o nc o mita nt me dicati o ns is re vise d t o 
ali g n wit h t he defi niti o n: Me di cati o ns t h at starte d pri or t o t he first d ose of 
st u d y dr u g a n d c o nti n ue d i nt o st u dy treat me nt p eri o d are c o nsi dere d  as b ot h 
pri or a n d c o nc o mita nt i n Secti o n 1 3. 2 . 
 
 
 
 
 
 
 
 
 
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T A B L E O F C O N T E N T S  
T a ble of C o nte nts ............................................................................................................. .......................................... 4 
List of T a bles ................................................................................................................ .............................................. 5 
List of Fi g ures ............................................................................................................... ............................................. 5 
1.  
I ntr o d ucti o n........................................................................................................................................ 9 
2.  
St u d y O bj ecti v es a n d E n d p oi n ts ......................................................................................................... 9 
2. 1.  
Pri m ar y a n d Sec o n d ar y O bject i ves  a n d  E n d p oi nts .............................................................................. 9 
3.  
St u d y D esi g n .................................................................................................................. ................... 1 1 
3. 1.  
Ge ner al Descri pti o n ........................................................................................................... .................... 1 1 
3. 2.  
C h a n ges t o A n al yses fr o m P r ot oc ol ............................................................................................. ......... 1 4 
4.  
Pl a n n e d A n al ys es a n d S a m pl e Siz e .............................................................................................. ..... 1 5 
4. 1.  
Pl a n ne d A n al yses .............................................................................................................. ..................... 1 5 
4. 1. 1.  
I nteri m A nal ysis .................................................................................................................. 1 5 
4. 1. 2.  
Pri mar y A nal ysis .............................................................................................................. ... 1 5 
4. 2.  
S a m ple Size ................................................................................................................... .......................... 1 5 
5.  
A n al ysis P o p ul ati o ns .......................................................................................................... ............... 1 6 
6.  
G e n er al C o nsi d er ati o ns ........................................................................................................ ............ 1 6 
6. 1.  
Gr o u pi n g of S u bjects .......................................................................................................... ................... 1 6 
6. 2.  
Ti me P oi nt C o n ve nti o ns ........................................................................................................ ................ 1 6 
6. 2. 1.  
Start of Treat me nt C o n ve nti o ns ........................................................................................... 1 6  
6. 2. 2.  
Baseli ne Assess me nts ..........................................................................................................  1 7 
6. 2. 3.  
Visit Assess me nts a n d St u d y Da y C o n ve nti o ns .................................................................. 1 7  
6. 2. 4.  
E n d of Treat me nt Assess me nt ............................................................................................. 1 7  
6. 2. 5.  
Missi n g Data .................................................................................................................. ...... 1 7 
6. 2. 6.  
Partial/ Missi n g Dates ......................................................................................................... .. 1 7 
6. 3.  
U nit C o n ve nti o ns .............................................................................................................. ..................... 1 8 
7.  
St atistic al C o nsi d er ati o ns .................................................................................................... ............. 1 8 
8.  
S u m m ar y of A n al ysis P o p ul ati o ns a n d E nr oll m e nt ............................................................................ 1 9  
9.  
Dis p ositi o n ................................................................................................................... ..................... 1 9 
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1 0.  
M aj or Pr ot oc ol D e vi ati o ns ..................................................................................................... ........... 1 9 
1 1.  
D e m o gr a p hic a n d Ot h er B as eli n e C h ar act eristics ............................................................................. 2 0  
1 2.  
S ur gic al a n d M e dic al Hist or y................................................................................................... .......... 2 0 
1 3.  
M e dic ati o ns ................................................................................................................... ................... 2 0 
1 3. 1.  
Pre vi o us A ntic a ncer T her a pies ................................................................................................. ............ 2 0 
1 3. 2.  
Pri or a n d C o nc o mit a nt M e dic ati o ns ............................................................................................. ....... 2 1 
1 4.  
St u d y Dr u g E x p os ur e a n d C o m pli a nc e ............................................................................................ .. 2 1 
1 4. 1.  
St u d y Dr u g E x p os ure ........................................................................................................... ................. 2 1 
1 4. 2.  
St u d y Dr u g C o m pli a nce ......................................................................................................... ............... 2 3 
1 5.  
Effic ac y a n al ysis ............................................................................................................. ................... 2 4 
1 6.  
S af et y O utc o m es a n d A n al ysis .................................................................................................. ........ 2 4 
1 6. 1.  
A d verse E ve nts ................................................................................................................ ....................... 2 4 
1 6. 2.  
L a b or at or y E v al u ati o ns ........................................................................................................ ................ 2 5 
1 6. 3.  
Perf or m a nce st at us a n al ysis ................................................................................................... ............... 2 5 
1 6. 4.  
E C G E v al u ati o ns ............................................................................................................... .................... 2 5 
1 6. 5.  
Vit al Si g ns a n d Ot her Cli nic al St at us M e as ures ................................................................................ . 2 6 
1 7.  
P h ar m ac o ki n etic a n d P h ar m ac o d y n a mic A n al ys es ........................................................................... 2 7  
1 7. 1.  
P h ar m ac o ki netic ( P K) A n al yses ................................................................................................. .......... 2 7 
1 7. 2.  
P h ar m ac o d y n a mic ( P D) A n al yses ................................................................................................. ....... 2 7 
1 8.  
R ef er e nc es .................................................................................................................... .................... 2 7 
A P P E N DI X 1.  
P arti al a n d Missi n g D at es C o n v e nti o ns ................................................................................... 2 8  
Al g orit h m f or Tre at me nt E mer ge nce of A d verse E ve nts ........................................................................... .......... 2 8 
Al g orit h m f or Pri or a n d C o nc o mit a nt M e dic ati o ns ............................................................................... .............. 2 9 
 
L I S T O F T A B L E S  
T a bl e 1. Vit al Si g ns a n d A b n or m al Crit eri a 
2 6  
T a bl e 2. Tr e at m e nt- e m er g e nt A d v ers e E v e nts 
2 8  
T a bl e 3. Pri or a n d C o nc o mit a nt m e dic ati o ns 
2 9  
 
L I S T O F F I G U R E S 
Fi g ur e 1:  
St u d y D esi g n 
1 1  
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Fi g ur e 2:  
St u d y Sc h e m a ( P art 1: T az e m et ost at a n d Itr ac o n az ol e) 
1 2  
Fi g ur e 3:  
St u d y Sc h e m a ( P art 2: T az e m et ost at a n d Rif a m pi n) 
1 4  
 
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P a g e 7 of 3 1 
 
 
 
 
List of A b bre vi ati o ns a n d Defi niti o ns 
A b bre viati o n  
T er m 
A E 
a d verse e ve nt 
A T C 
a nat o mic t hera pe utic c he mical (classificati o n s yste m) 
A U C 
area u n der t he c o nce ntrati o n-ti me c ur ve 
A U C 0-t, A U Clast 
area u n der t he c o nce ntrati o n-ti me c ur ve fr o m ti me 0 t o t he last q ua ntifia ble 
c o ncertati o n  
A U C 0-  
area u n der t he c o nce ntrati o n-ti me c ur ve fr o m ti me 0 e xtra p olate d t o i nfi nit y 
BI D 
t wice dail y 
CI 
c o nfi de nce i nter val 
C ma x  
ma xi m u m plas ma c o nce ntrati o n 
C R 
c o m plete res p o nse 
C T C A E 
C o m m o n T er mi n ol o g y Criteri a f or A d verse E ve nts 
C Y P 
c yt oc hr o me 
D C R 
disease c o ntr ol rate 
D DI 
dr u g – dr u g i nteracti o n 
D L B C L 
diff use lar ge B cell l y m p h o ma 
D O R 
d urati o n of res p o nse 
E C G 
electr ocar di o gra m 
E C O G 
Easter n C o o perati ve O nc ol o g y Gr o u p 
E P Z- 6 4 3 8 
taze met ostat 
F L 
f ollic ular l y m p h o ma 
H L G T 
hi g h-le vel gr o u p ter m 
I P 
i n vesti gati o nal pr o d uct 
I S S 
i nte grate d s u m mar y of safet y 
I T T 
I nte nt-t o- Treat 
Me d D R A 
Me dical Dicti o nar y f or Re g ul at or y Acti vities 
M C L 
ma ntel cell l y m p h o ma 
M Z L 
mar gi nal z o ne l y m p h o ma 
N CI 
Nati o nal Ca ncer I nstit ute 
O R R 
o bj ecti ve res p o nse rate 
P D 
pr o gressi ve disease 
P G x 
p har mac o ge n o mics 
P K 
p har mac o ki netics 
P M B C L 
pri mar y me diasti nal B-cell l y m p h o ma 
P R 
partial res p o nse 
P T 
preferre d ter m 
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Q T c F 
Fri dericia c orrecti o n of Q T i nter val f or heart rate 
S A P 
statistical a nal ysis pla n 
S D 
sta ble disease, i n t he c o nte xt of cli nical res p o nse of a s u bj ect’s t u m ors t o dr u g 
t hera p y 
sta n dar d de viati o n, i n t he c o nt e xt of statistical s u m mar y statistics 
S O C 
s yste m or ga n class 
t1/ 2 
a p pare nt eli mi nati o n half li ve 
T E A E 
treat me nt-e mer ge nt a d verse e ve nt 
T ma x  
ti me t o ma xi m u m c o nce ntrati o n 
W H O 
W orl d Healt h Or ga nizati o n 
 
 
 
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P a g e 1 0 of 3 1 
 
 
 
O bjecti ves 
E n d p oi nts 
 
 C ma x : o bser ve d ma xi m u m plas ma 
c o nce ntrati o n 
Sec o n d ar y: 
 T o e val uate t he stea d y- state safet y pr ofile of 
taze met ostat w he n c o-a d mi nistere d as a si n gle 
a n d t wice dail y oral d ose wit h rifa m pi n i n 
s u bj ects wit h a d va nce d mali g na ncies 
 Safet y para meters: A d verse e ve nt assess me nt, 
p h ysical e xa mi nati o n, vital si g ns ( bl o o d 
press ure, heart rate, b o d y te m perat ure), 1 2 -
lea d E C G, cli nical la b orat or y tests 
( he mat ol o g y i ncl u di n g c oa g ulati o n pr ofile, 
ser u m c he mistries, uri nal ysis), E C O G 
perf or ma nce stat us, a n d c o nc o mita nt 
me dicati o n m o nit ori n g 
 T o e val uate t he stea d y-state P K of taze met ostat 
a n d its meta b olites after a d mi nistrati o n al o n e 
a n d wit h rifa m pi n. 
 
 A U C 0 – t: area u n der t he plas ma c o nce ntrati o n-
ti me c ur ve fr o m ti me 0 t o t he ti me of t he last 
q ua ntifia ble c o nce ntrati o n 
 C ma x : o bser ve d ma xi m u m plas ma 
c o nce ntrati o n 
 T ma x : o bser ve d ti me at C ma x 
  λ z: ter mi nal p hase eli mi nati o n rate c o nsta nt 
 t1/ 2: ter mi nal eli mi nati o n half-life 
 
 
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3. 
S T U D Y D E SI G N
3. 1.  
G E N E R A L D E S C RI P TI O N
T his is a P hase 1, o pe n-la bel, m ulti- d ose t w o- part st u d y  desi g ne d t o c haracterize t he effcts of a str o n g 
C Y P 3 A 4 i n hi bit or o n t he stea d y-state P K of oral taze met ostat ( E P Z- 6 4 3 8) a n d its meta b olite E P Z 6 9 3 0, 
a n d t he effcts of a str o n g C Y P 3 A 4 i n d ucer o n t he stea d y-state P K of taze met ostat a n d its meta b olite E P Z 
6 9 3 0 w he n a d mi nistere d as a si n gle a n d t wice dail y d ose i n s u bjects wit h a d va nce d mali g na ncies, w hile 
ta ke n al o ne or i n c o m bi nati o n wit h eit her itrac o naz ole or rifa m pi n ( Fi g ure 1 ).
Fi g ure 1:
St u d y Desi g n
P art 1. T aze met ost at a n d Itr ac o n az ole Dr u g I nter acti o n
Part 1 of t he st u d y will e val uate t he dr u g- dr u g i nteracti o n bet wee n taze met ostat a n d itrac o naz ole i n a n 
o pe n-la bel, fi xe d se q ue ntial cr oss o ver desi g n ( Fi g ure 2 ). 
A  scree ni n g  visit  will  occ ur  wit hi n  3 0  da ys  of  si g ni n g  a n  i nf or me d  c o nse nt  f or m (I C F).  D uri n g  t he  
scree ni n g p hase, s u bj ects will be e val uate d f or eli gi bilit y t o partici pate i n t he st u d y. S u bj ects w h o meet t he 
pr ot oc ol criteria ma y be a d mitte d i n t he e ve ni n g t o t he cli nical st u d y ce nter, or visit t he cli nic if sta yi n g 
l ocall y, o n da y - 1. F or C ycle 1, s u bj ects ma y be a d mitted t o t he cli nical st u d y ce nter d uri n g P K sa m pli n g 
peri o ds or m ust a gree t o sta y l ocall y wit h fre q ue nt cl i nic visits as re q uire d a n d, o pti o nal a d missi o n t o t he 
ce nter, if a vaila ble. Pri or t o d osi n g o n da y 1 of C ycle 1, s u bj ect eli gi bilit y will be rec o nfir me d. O n da y 1, a 
si n gle oral d ose of 4 0 0 m g taze met ostat will be a d mi nistere d i n t he m or ni n g (e g, 7 – 9 a m) f oll o we d b y 2 
da ys of m ulti ple bl o o d sa m pli n g ( da y 1 – 3). Fr o m da y 3 – 1 4, s u bjects will recei ve a n oral 4 0 0 m g d ose of 
taze met ostat t wice dail y ( 1 2 h o urs a part, o nce i n t he m or ni n g [e g, 7 – 9 a m] a n d o nce i n t he e ve ni n g [e g, 7 
– 9 p m]). I n t he e ve ni n g of da y 1 4, s u bjects ma y be a d mitte d t o t he cli nical st u d y ce nter. O n da y 1 5, a 
C CI


N u m b er: 
St at us: Iss u e d
Pr ot oc ol E Z H- 1 0 8
V 2. 0, 3 1 A u g ust 2 0 2 1
Statistical A nal ysis Pla n
V 2. 1, 2 1  N o v, 2 0 2 2
E pi z y m e, I n c.
C O N FI D E N TI A L I N F O R M A TI O N
P a g e 1 2 of 3 1
si n gle oral d ose of 4 0 0 m g taze met ostat will be a d mi nistere d i n t he m or ni n g (e g, 7 – 9 a m) f oll o we d b y 3 
da ys  of  m ulti ple  bl o o d  sa m pli n g  ( da y  1 5  – 1 8).  Fr o m  da y  1 8  – 2 0,  a  si n gle  d ose  of  oral  2 0 0  m g  
itrac o naz ole will be a d mi nistere d dail y i n t he m or ni n g (e g, 7 – 9 a m) after a meal. I n t he e ve ni n g of da y 
2 0, s u bjects ma y be a d mitte d t o t he cli nical st u d y u nit. Fr o m da y 2 1 – 3 5, s u bj ects will recei ve a n oral 4 0 0 
m g d ose of taze met ostat t wice dai l y, o nce i n t he m or ni n g (e g, 7 – 9 a m) a n d o nce i n t he e ve ni n g (e g, 7 – 9 
p m), c o-a d mi nistere d i n t he m or ni n g (e g, 7 – 9 a m) after a meal wit h a si n gle d ose of oral 2 0 0 m g 
itrac o naz ole f oll o we d b y 1 da y of m ulti ple bl o o d sa m pli n g ( da y 2 1 – 2 2). I n t he e ve ni n g of da y 3 5, 
s u bj ects ma y be a d mitte d t o t he cli nical st u d y ce nter. O n da y 3 6, s u bjects will recei ve a si n gle oral d ose of 
4 0 0 m g taze met ostat c o-a d mi nistere d i n t he m or ni n g (e g, 7 – 9 a m) after a meal wit h a si n gle d ose of oral 
2 0 0 m g itrac o naz ole f oll o we d b y 3 da ys of m ulti ple bl o o d sa m pli n g ( da y 3 6 – 3 9). Itrac o naz ole will als o 
be a d mi nistere d o n da y 3 7 a n d 3 8 as a si n gle oral 2 0 0 m g dail y d ose i n t he m or ni n g (e g, 7 – 9 a m) after a 
meal. 
N ote: Taze met ostat will n ot be a d mi nistere d o n da y 3 7 a n d 3 8. After t he 7 2- h o ur P K sa m ple c ollecti o n, 
safet y assess me nts will be c o n d ucte d o n da y 3 9. S parse P K sa m ples will be c ollecte d pre- d ose ( 0 h o ur) 
a n d 2 h o urs p ost- d ose o n da y 2 5, 2 8, 3 1, a n d 3 4.
Fi g ure 2: 
St u d y Sc he m a ( P art 1: T aze met ost at a n d Itr ac o n az ole)
S u bj ects ma y disc o nti n ue fr o m t he st u d y after c o m pleti o n of C ycle 1 or ca n c o nti n ue treat me nt ( C ycle 2 + 
o n war ds) u ntil I n vesti gat or-assesse d cli nical pr o gressi o n per sta n dar d practice, or u nacce pta ble t o xicit y, or 
u ntil  a n ot her  disc o nti n uati o n  criteri o n  is  met.  F or  s u bj ects  c o nti n ui n g  taze met ostat  treat me nt  at  t he  
rec o m me n de d t hera pe utic d ose ( oral 8 0 0 m g taze met ostat t wice dail y [ 1 2 h o urs a part]), C ycle 2 will be gi n 
o n da y 4 0 ( C ycle 2 Da y 1) a n d eac h s u bse q ue nt c ycl e fr o m C ycle 2 + o n war ds will be of 2 8- da y d urati o n. 
Safet y a n d t olera bilit y will be assesse d t hr o u g h o ut t he s u bject’s partici pati o n. S u bj ects will be i nstr ucte d 
t o re p ort a n y a d verse e ve nts t hat occ ur u p t o 3 0 da ys after t he last d ose of taze met ostat. S u bje cts m ust 
C CI


N u m b er: 
 
 
St at us: Iss u e d  
 
Pr ot oc ol E Z H- 1 0 8 
V 2. 0, 3 1 A u g ust 2 0 2 1 
Statistical A nal ysis Pla n 
V 2. 1, 2 1 N o v, 2 0 2 2 
E pi z y m e, I n c. 
C O N FI D E N TI A L I N F O R M A TI O N 
P a g e 1 3 of 3 1 
 
 
 
ha ve a n e n d of st u d y visit 3 0 da ys after t he last d ose of taze met ostat f or safet y assess me nt.  
 
P art 2: T aze met ost at a n d Rif a m pi n Dr u g I nter acti o n 
Part 2 of t he st u d y will e val uate t he dr u g- dr u g i nteracti o n bet wee n taze met ostat a n d rifa m pi n i n a n o pe n-
la bel, fi xe d se q ue ntial cr oss o ver desi g n (Fi g ure  3). 
A  scree ni n g  visit  will  occ ur  wit hi n  3 0  da ys  of  si g ni n g  a n  i nf or me d  c o nse nt  f or m (I C F).  D uri n g  t he  
scree ni n g p hase, s u bj ects will be e val uate d f or eli gi bilit y t o partici pate i n t he st u d y. S u bj ects w h o meet t he 
pr ot oc ol criteria ma y be a d mitte d i n t he e ve ni n g t o t he cli nical st u d y ce nter, or visit t he cli nic if sta yi n g 
l ocall y, o n da y - 1. F or C ycle 1 s u bjects ma y be a d mitted t o t he cli nical st u d y ce nter d uri n g P K sa m pli n g 
peri o ds or m ust a gree t o sta y l ocall y wit h fre q ue nt cli nic visits as re q uire d a n d o pti o n al a d missi o n t o t he 
ce nter if a vaila ble. Pri or t o d osi n g o n da y 1 of C ycle 1, s u bject eli gi bilit y will be rec o nfir me d. O n da y 1, a 
si n gle oral d ose of 8 0 0 m g taze met ostat will be a d mi nistere d i n t he m or ni n g (e g, 7 –  9 a m) f oll o we d b y 2 
da ys of m ulti ple bl o o d sa m pli n g ( da y 1 –  3). Fr o m da y 3 –  1 4, s u bjects will recei ve a n oral 8 0 0 m g d ose of 
taze met ostat t wice dail y ( 1 2 h o urs a part o nce i n t he m or ni n g [e g, 7 –  9 a m] a n d o nce i n t he e ve ni n g [e g, 7 
–  9 p m]). I n t he e ve ni n g of da y 1 4, s u bjects ma y be a d mitte d t o t he cli nical st u d y ce nter. O n da y 1 5, a 
si n gle oral d ose of 8 0 0 m g taze met ostat will be a d mi nistere d i n t he m or ni n g (e g, 7 –  9 a m) f oll o we d b y 2 
da ys of m ulti ple bl o o d sa m pli n g ( da y 1 5 –  1 7). Fr o m da y 1 7 –  2 3, s u bjects will recei ve a n oral 8 0 0 m g 
d ose of taze met ostat t wice dail y, o nce i n t he m or ni n g (e g, 7 –  9 a m) a n d o nce i n t he e ve ni n g (e g, 7 –  9 
p m), c o-a d mi nistere d i n t he m or ni n g (e g, 7 –  9 a m) o ne h o ur bef ore a meal wit h a si n gle d ose of oral 6 0 0 
m g rifa m pi n. I n t he e ve ni n g of da y 2 3, s u bj ects ma y be a d mitte d t o t he cli nical st u d y ce nter. O n da y 2 4, 
s u bj ects will recei ve a si n gle oral d ose of 8 0 0 m g taze met ostat c o-a d mi nistere d i n t he m or ni n g (e g, 7 –  9 
a m) o ne h o ur bef ore a meal wit h a si n gle d ose of oral 6 0 0 m g rifa m pi n f oll o we d b y 2 da ys of m ulti pl e 
bl o o d sa m pli n g ( da y 2 4 –  2 6). Rifa m pi n will als o be a d mi nistere d o n da y 2 5 as a si n gle oral 6 0 0 m g d ose 
i n t he m or ni n g (e g, 7 –  9 a m) o ne h o ur bef ore a meal. 
N ote:  T aze met ostat will n ot be a d mi nistere d o n da y 2 5. After t he 4 8- h o ur P K sa m ple c ollecti o n, s afet y 
assess me nts will be c o n d ucte d o n da y 2 6. S parse P K sa m ples will be c ollecte d pre- d ose ( 0 h o ur) a n d 2 
h o urs p ost- d ose o n da y 1 9 a n d 2 1. 
S u bj ects ma y disc o nti n ue fr o m t he st u d y after c o m pleti o n of C ycle 1 or ca n c o nti n ue treat me nt ( C ycle 2 + 
o n war ds) u ntil I n vesti gat or-assesse d cli nical pr o gressi o n per sta n dar d practice, or u nacce pta ble t o xicit y, or 
u ntil  a n ot her  disc o nti n uati o n  criteri o n  is  met.  F or  s u bj ects  c o nti n ui n g  taze met ostat  treat me nt  at  t he  
rec o m me n de d t hera pe utic d ose ( 8 0 0 m g taze met ostat t wice dail y [ 1 2 h o urs a part]), C ycle 2 will be gi n o n 
da y 2 7 ( C ycle 2 Da y 1) a n d eac h s u bse q ue nt c ycle fr o m C ycle 2 + o n war ds will be of 2 8- da y d urati o n. 
Safet y a n d t olera bilit y will be assesse d t hr o u g h o ut t he s u bject’s partici pati o n. S u bj ects will be i nstr ucte d 
t o re p ort a n y a d verse e ve nts t hat occ ur u p t o 3 0 da ys after t he last d ose of taze met ostat. S u bjects m ust 
ha ve a n e n d of st u d y visit 3 0 da ys after t he last d ose of taze met ostat f or safet y assess me nt. 
C CI


N u m b er: 
St at us: Iss u e d
Pr ot oc ol E Z H- 1 0 8
V 2. 0, 3 1 A u g ust 2 0 2 1
Statistical A nal ysis Pla n
V 2. 1, 2 1  N o v, 2 0 2 2
E pi z y m e, I n c.
C O N FI D E N TI A L I N F O R M A TI O N
P a g e 1 4 of 3 1
Fi g ure 3: 
St u d y Sc he m a ( P art 2: T aze met ost at a n d Rif a m pi n)
R oll o ver St u d y 
All s u bjects w h o recei ve t he rec o m me n de d t hera pe utic d ose of 8 0 0 m g taze met ostat t wice dail y [ 1 2 h o urs 
a part]  f or  9  C ycles  or  l o n ger,  a n d  are  eli gi ble  t o  c o nti n ue  recei vi n g  taze met ostat,  will  tra nsfer  t o  a  
R oll o ver  St u d y   
 f or  m o nit ori n g  a n d  c o nti n ue d  st u d y  dr u g  at  t he  I n vesti gat or  a n d  Me dical 
M o nit or’s discreti o n .
3. 2.  
C H A N G E S T O A N A L Y S E S F R O M P R O T O C O L
Acc or di n g t o Secti o n 1 3. 3 of t he pr ot oc ol (a me n d me nt 2. 0), la b orat or y a nal ytes will be 
s u m marize d  descri pti vel y  as  val ue  a n d  c ha n ge fr o m  bas eli ne,  as  well  as  s hifts  fr o m  
baseli ne ( base d o n l o w, n or mal, hi g h cate g oriz ati o n) at eac h visit. T o all o w f or m ore 
f oc use d  pres e ntati o n  of  val ues  m ost  li kel y  t o  re pres e nt  a  safet y  c o n cer n,  la b orat or y  
a nal yt es will be s u m mari ze d as s hift fr o m t h e bas eli ne t o t he w orst p ost- baseli ne cat e g or y 
( base d o n Nati o nal Ca ncer I nstit ute [ N CI] C o m m o n Ter mi n ol o g y Criteria f or A d verse 
E ve nts [ C T C A E v 5. 0] se verit y gra des). 
If warra nte d, a d diti o nal e x pl orat or y a nal yses of safet y e n d p oi nts ma y be perf or me d. 
T o be c o nsiste nt wit h t he a nal ysis d o ne i n ot her st u dies a n d i n t he I nte grate d S u m mar y of 
Safet y (I S S), T E A Es wit h missi n g C T C A E gra des will be treate d as missi n g.
C CI
C CI


N u m b er: 
 
 
St at us: Iss u e d  
 
Pr ot oc ol E Z H- 1 0 8 
V 2. 0, 3 1 A u g ust 2 0 2 1 
Statistical A nal ysis Pla n 
V 2. 1, 2 1 N o v, 2 0 2 2 
E pi z y m e, I n c. 
C O N FI D E N TI A L I N F O R M A TI O N 
P a g e 1 5 of 3 1 
 
 
 
4.  
P L A N N E D A N A L Y S E S A N D S A M P L E S I Z E 
4. 1.  
P L A N N E D A N A L Y S E S  
4. 1. 1.  
IN T E RI M A N A L Y SI S  
N o i nteri m a nal yses are pla n ne d f or t his st u d y. 
4. 1. 2.  
P RI M A R Y A N A L Y SI S  
T he pri mar y a nal ys es will occ ur w he n t he fi nal p har mac o ki netic para meters are a vaila ble.  I ncl usi o n of t he 
safet y data c ollecte d o ver all c ycles of treat me nt wit hi n t he cli ni cal st u d y re p ort or as a n a d de n d u m will be 
de pe n de nt u p o n t he a vaila bilit y of t he data at t he ti me t he pri mar y a nal yses are c o m plete d. 
4. 2.  
S A M P L E S I Z E 
T he sa m ple size was deter mi ne d base d o n feasi bilit y c o nsi derati o ns. A p pr o xi matel y 4 0 s u bj ects will be 
e nr olle d i n t he st u d y ass u mi n g a b o ut a 4 0 % dr o p o ut rate t o ac hie ve 1 2 s u bjects per st u d y part f or a t otal 
of 2 4 c o m plete d s u bjects. S u bj ects will c o m plete eit her Part 1 or Part 2, b ut n ot b ot h.  
S u bj ects w h o re q uire a taze met ostat d ose i nterr u pti o n or  re d ucti o n d uri n g C ycle 1 of eit her Part 1 or Part 2 
will
 be
 re place d.
 D uri n g
 C ycle
 1,
 s u bj ects
 w h o
 miss
 t w o
 or
 m ore
 c o nsec uti ve
 
taze met ostat/itrac o naz ole/rifa m pi n d oses or m ore t ha n t hree taze met ostat/itrac o naz ole/rifa m pi n d oses i n 
t otal will be re place d. S u bjects w h o miss t w o or m ore c o nsec uti ve P K bl o o d sa m ple c ollecti o ns d uri n g 
eit her part of C ycle 1 will be re place d. S u bjects t h at re q uire re place me nt will be disc o nti n ue d fr o m st u d y 
treat me nt. 
A  t otal  of  1 2  s u bjects  per  st u d y  part  is  a de q uate  t o  descri be  t he  effect  of  C Y P 3 A 4  i n hi biti o n  b y  
itrac o naz ole or i n d ucti o n b y rifa m pi n o n t he stea d y state P K of taze met ostat. 
A p oi nt esti mate a n d ass ociate d 9 0 % c o nfi de nce i nter val o n t he ma g nit u de of t he effect of t he per petrat or 
dr u gs o n t he P K of t he victi m dr u gs will be pr o vi de d. T he defa ult n o effect b o u n dar y of 8 0 –  1 2 5 % f or t he 
9 0 % c o nfi de nce i nter val f or a n effect size will be use d as a refere nce. T his is e q ui vale nt t o a h y p ot hesis 
test wit h a n ull h y p ot hesis t hat t here is a n o nzer o effect a n d alter nati ve of n o effect. If t he 9 0 % c o nfi de nce 
i nter val f or a n y effect teste d i n t his st u d y falls c o m pletel y wit hi n 8 0 –  1 2 5 %, it will be c o ncl u de d t hat n o 
si g nifica nt differe nces are prese nt.  
T he sa m ple size calc ulati o n is base d o n t he u n derl yi n g  ass u m pti o n t hat t he wit hi n s u bje ct c oefficie nt of 
variati o n  ( C V)  is  3 0 %,  a  t w o-si de d  al p ha  le vel  of  0. 0 5,  t he  u n derl yi n g  wit hi n-s u bj ect  c orrelati o n  of  
s u bse q ue nt meas ure me nts of t he sa me P K para meter a n d ge o metric mea n rati o.  If t he ge o metric mea n 
rati o of itrac o naz ole is 1. 0 6 or t he ge o metric mea n rati o f or rifa m pi n is 0. 9 4 a n d s u bse q ue nt meas ure me nts 
of taze met ostat A U C ha ve a c orrelati o n of at leas t 0. 8 0, t his test is p o were d at 8 8 % or hi g her.  
Calc ulati o ns  were  perf or me d  usi n g  t he  Paire d  t-test  f or  t he  E q ui vale nce  of  L o g- N or mal  Mea ns  
( M ulti plicati ve M o del) i n n Q uer y versi o n 8. 0. 
C CI


N u m b er: 
 
 
St at us: Iss u e d  
 
Pr ot oc ol E Z H- 1 0 8 
V 2. 0, 3 1 A u g ust 2 0 2 1 
Statistical A nal ysis Pla n 
V 2. 1, 2 1 N o v, 2 0 2 2 
E pi z y m e, I n c. 
C O N FI D E N TI A L I N F O R M A TI O N 
P a g e 1 6 of 3 1 
 
 
 
5.  
A N A L Y SI S P O P U L A TI O N S  
T he a gree me nt a n d a p pr o val of s u bj ects t o be i ncl u de d/e xcl u de d fr o m eac h a nal ysis p o p ulati o n will be 
esta blis he d pri or t o data base l oc k. T he p o p ulati o n defi niti o ns are as f oll o ws: 
 
E nr olle d p o p ul ati o n  will i ncl u de all s u bjects w h o si g ne d i nf or me d c o nse nt a n d met all scree ni n g 
criteria. T he E nr olle d p o p ulati o n will be use d f or s u m maries of de m o gra p hic a n d baseli ne disease 
c haracteristic. 
 
S af et y p o p ul ati o n  will c o nsist of all s u bjects i n t he E nr olle d p o p ulati o n w h o recei ve at least o ne 
d ose or partial d ose of st u d y dr u gs a n d ha ve at least o ne p ost- d ose safet y o bser vati o n rec or de d. 
T he Safet y p o p ulati o n will be use d f or s u m maries a n d a nal yses of t he safet y a n d t olera bilit y. 
 
P h ar m ac o ki netic ( P K) p o p ul ati o n will i ncl u de all s u bjects i n t he Safet y p o p ulati o n w h o 
ha ve at least o ne p ost- d ose sa m ple c ollec te d t o all o w esti mati o n of t he P K para meters. 
T he P K p o p ulati o n will be use d f or P K data a n al ysis.  
6.  
G E N E R A L C O N SI D E R A TI O N S  
6. 1.  
G R O U PI N G O F S U B J E C T S  
U nless state d ot her wise, s u bj ects will be gr o u pe d a n d prese nte d acc or di n g t o t he st u d y part a n d o verall. 
6. 2.  
T I M E P OI N T C O N V E N TI O N S  
6. 2. 1.  
S T A R T O F T R E A T M E N T C O N V E N TI O N S  
S u bj ects e nr olle d i n Part 1 of t he st u d y will recei ve a si n gle oral, 4 0 0 m g d ose of taze met ostat o n Da y 1. 
S u bj ects e nr olle d i n Part 2 of t he st u d y will recei ve a si n gle, oral, 8 0 0 m g d ose of taze met ostat o n Da y 1. 
Calc ulati o ns relati ve t o start of st u d y treat me nt wi ll de pe n d o n t he c o nte xt of t he a nal ysis. T he f oll o wi n g 
r ules will a p pl y: 
 
A nal ysis Cate g or y 
Refere nce Start Date 
De m o gra p hics, Baseli ne C har acteristics, a n d 
Me dical Hist or y 
Date of first d ose of a n y st u d y dr u g 
Safet y Meas ures a n d N o n- St u d y Me dicati o ns 
U nless n ote d ot her wise, date of first d ose of a n y 
st u d y dr u g 
T aze met ostat E x p os ure a n d C o m plia nce  
Date of first d ose of taze met ostat 
 
De pe n di n g o n t he c o nte xt, listi n gs ma y prese nt assess me nts i n ter ms of ‘ St u d y Da y’.  F or c o nsiste nc y wit h 
t he pr ot oc ol, t he first da y of a n y st u d y treat me nt will be i de ntifie d as ‘ D a y 1’.  Assess me nts perf or me d t he 
da y pri or t o t he first da y of st u d y treat me nt will be i de ntifie d as ‘ Da y -1’ ( wit h n o i nter ve ni n g 0).  St u d y 
Da y will be calc ulate d as f oll o ws: 
 
Assess me nt date is o n/after first d ose date of st u d y dr u g: 
  
St u d y Da y = ( date of e ve nt –  first d ose date of st u d y dr u g) + 1   
C CI


N u m b er: 
 
 
St at us: Iss u e d  
 
Pr ot oc ol E Z H- 1 0 8 
V 2. 0, 3 1 A u g ust 2 0 2 1 
Statistical A nal ysis Pla n 
V 2. 1, 2 1 N o v, 2 0 2 2 
E pi z y m e, I n c. 
C O N FI D E N TI A L I N F O R M A TI O N 
P a g e 1 7 of 3 1 
 
 
 
 
Assess me nt date is pri or t o first d ose date of st u d y dr u g: 
  
St u d y Da y = ( date of e ve nt –  first d ose date of st u d y dr u g)  
 
 
T he assess me nt date is greater t ha n last date of st u d y dr u g: 
P ost T x St u d y Da y = ( date of e ve nt –  last d ose date) 
In t hese cases, St u d y Da y will be dis pla ye d as “ # # da ys p ost t x”.  
F or partial dates, St u d y Da y will be missi n g i n t he listi n gs.  F urt her i nf or mati o n a b o ut partial date 
c o n ve nti o ns is descri be d i n  A p pe n di x 1 . 
6. 2. 2.  
B A S E LI N E A S S E S S M E N T S  
Baseli ne data are defi ne d as t he last n o n- missi n g asse ss me nt (i ncl u di n g u nsc he d ule d assess me nts) pri or t o 
starti n g treat me nt. If t here is m ore t ha n o ne val ue o n or pri or t o starti n g treat me nt, t he val ue cl osest t o a n d 
pri or t o t he recei pt of t he first d ose, w het her sc he d ule d or u nsc he d ule d, will be use d as t he baseli ne val ue. 
U nless t he c ollecti o n ti me or la bel i n dicates ot her wis e, assess me nts perf or me d o n t he sa me da y as t he first 
d ose of st u d y dr u g will be c o nsi dere d perf or me d pr i or t o t he start of treat m e nt. A Es a n d me dicati o ns 
re p orte d wit h a start date o n t he date of first d ose will be c o nsi dere d t o ha ve occ urre d after t he start of 
treat me nt.  F or  vital  si g ns  (e xcl u di n g wei g ht  a n d  hei g ht)  a n d  E C G meas ures,  baseli ne  res ults  will  be 
i de ntifie d f or t he set.   
F or la b orat or y para meters, t he baseli ne ti me p oi nt will be deter mi ne d se paratel y f or eac h para meter.   
6. 2. 3.  
V I SI T A S S E S S M E N T S A N D S T U D Y D A Y C O N V E N TI O N S  
F or b y visit s u m maries, n o mi nal visits will be prese n te d (i.e. visit wi n d o wi n g will n ot be a p plie d). U nless 
ot her wise  s pecifie d,  u nsc he d ule d  meas ure me nts  wi ll  n ot  be  i ncl u de d  i n  b y- visit  s u m maries  b ut  will  
c o ntri b ute t o w orst-case val ues w here re q uire d ( e g . s hift ta ble).  Listi n gs will i ncl u de b ot h sc he d ule d a n d 
u nsc he d ule d data. 
6. 2. 4.  
E N D O F T R E A T M E N T A S S E S S M E N T  
W here ver a n e n d- of-treat me nt assess me nt res ult is re q uire d f or a nal ysis, t he last n o n- missi n g assess me nt 
res ult wit hi n 3 0 da ys after t he fi nal d ose of st u d y dr u g or u ntil t he start of a s u bse q ue nt a ntica ncer t hera p y, 
w hic he ver is earlier, will be use d.   
6. 2. 5.  
M
I S SI N G D A T A  
U nless  ot her wise  s pecifie d,  missi n g data  will  be  treate d  as  missi n g,  i.e.,  n o  s pecial  ha n dli n g will  be 
perf or me d. Details of safet y data ha n dli n g will be d oc u me nte d i n safet y a nal yses secti o n.  
6. 2. 6.  
P A R TI A L / MI S SI N G D A T E S  
F or  partial  dates,  t he  al g orit h ms  f or  i m p utati o n  wi ll  var y  de pe n di n g  u p o n  t he  para meter;  missi n g  or  
i nc o m plete me dicati o ns start a n d st o p dates will be i m p ute d t o deter mi ne w het her t he me dicati o ns are 
ta ke n pri or t o t he st u d y dr u g or c o nc o mita ntl y. Missi n g a d verse e ve nt ( A E) start dates will be i m p ute d t o 
deter mi ne w het her t he A Es are treat me nt e mer ge nt. I n  listi n gs, all dates will be liste d as rec or de d. T he 
details of i m p utati o n al g orit h m r ules ca n be f o u n d i n  A p pe n di x 1 . 
C CI


N u m b er: 
 
 
St at us: Iss u e d  
 
Pr ot oc ol E Z H- 1 0 8 
V 2. 0, 3 1 A u g ust 2 0 2 1 
Statistical A nal ysis Pla n 
V 2. 1, 2 1 N o v, 2 0 2 2 
E pi z y m e, I n c. 
C O N FI D E N TI A L I N F O R M A TI O N 
P a g e 1 8 of 3 1 
 
 
 
6. 3.  
U NI T C O N V E N TI O N S  
 
1 year = 3 6 5. 2 5 da ys. Year is calc ulate d as ( da ys/ 3 6 5. 2 5) a n d will be r o u n de d t o 1 di git after t he 
deci mal p oi nt (te nt hs) f or prese ntati o n p ur p oses. 
 
1 m o nt h = 3 0. 4 3 7 5 da ys. M o nt h is calc ulate d as ( da ys/ 3 0. 4 3 7 5) a n d will be r o u n de d t o 1 di git 
after t he deci mal p oi nt (te nt hs) f or prese ntati o n p ur p oses. 
 
1 p o u n d = 0. 4 5 4 k g a n d 1 k g = 2. 2 p o u n ds. 
 
1 i nc h = 2. 5 4 c m a n d 1 c m = 0. 3 9 3 7 i nc hes. 
 
B o d y mass i n de x ( B MI) calc ulate d as [ wei g ht ( k g)/ hei g ht ( m) 2]  
 
B MI calc ulate d as [ wei g ht (l b) / hei g ht (i n) 2] x 7 0 3 
 
U nless ot her wise s pecifie d, perce nta ges will be c alc ulate d base d o n t he n u m ber of s u bj ects 
s pecifie d b y t he a p pr o priate a nal ysis p o p ulati o n defi niti o n.  
 
All ta bles, listi n gs, fi g ures will be pr o d uce d i n la n dsca pe orie ntati o n usi n g t he defa ult C o urier 
Ne w 9- p oi nt f o nt w he ne ver feasi ble. O ut p ut files will be create d i n ric h te xt file ( R T F) f or mat. 
7.  
S T A TI S TI C A L C O N SI D E R A TI O N S  
U nless n ote d ot her wise, t he statistical c o nsi derati o ns bel o w will be a p plie d a n d use d f or b ot h st u d y parts. 
 
As t his is a p hase I st u d y, data fr o m all ce nters will be p o ole d f or a nal yses. 
 
U nless ot her wise n ote d, ta ble s u m maries will be prese nte d b y st u d y part a n d o verall. 
 
T he iss ue of m ulti plicit y will n ot a p pl y t o t he e n d p oi nts f or t his st u d y.  
 
E xce pt f or  i nc o m plete  dates  ass ociate d wit h  A Es a n d  me dicati o ns  (r ules i n  A p pe n di x 1 )  a n d  
missi n g se verit y or relati o ns hi p (r ules i n Secti o n  1 6. 1), ot her missi n g safet y data will n ot be 
i m p ute d. 
 
S u m mar y statistics will c o nsist of t he n u m ber a n d perce nta ge of s u bjects i n eac h cate g or y f or 
discrete varia bles, a n d t he n u m ber of s u bj ects wit h n o n- missi n g val ues, mea n, me dia n, sta n dar d 
de viati o n ( S D), mi ni m u m, a n d ma xi m u m f or c o nti n u o us varia bles. 
 
W he n t he de n o mi nat or i ncl u des s u bjects wit h missi n g val ues, a “ missi n g” cate g or y ma y be a d de d 
f or c o m plete ness.  
 
I n s u m mar y ta bles of c o nti n u o us varia bles (e xce pt f or wei g ht, hei g ht a n d B MI), t he mi ni m u m a n d 
ma xi m u m val ues will be dis pla ye d t o t he sa me n u m ber of deci mal places as t he ra w data; all 
mea n,  me dia n,  a n d  perce ntile  val ues  will  be  f or matte d  t o  o ne  m ore  deci mal  place  t ha n  t he  
meas ure d val ue.  S D val ues will be f or matte d t o t w o m ore deci mal places t ha n t he meas ure d 
val ue, u nless ot her wise s pecifie d. T he ma xi m u m n u m ber of deci mal places is 3 a n d val ues will be 
tr u ncate d t o 3 deci mal places i n sit uati o ns w here t here are m ore t ha n 3 deci mal places. W here ver 
p ossi ble data will be deci mal ali g ne d. F or wei g ht, hei g ht a n d B MI, o nl y o ne deci mal place will be 
ke pt f or s u m mar y res ults (e xce pt N). 
C CI


N u m b er: 
 
 
St at us: Iss u e d  
 
Pr ot oc ol E Z H- 1 0 8 
V 2. 0, 3 1 A u g ust 2 0 2 1 
Statistical A nal ysis Pla n 
V 2. 1, 2 1 N o v, 2 0 2 2 
E pi z y m e, I n c. 
C O N FI D E N TI A L I N F O R M A TI O N 
P a g e 1 9 of 3 1 
 
 
 
 
All perce nta ges will be r o u n de d t o o ne deci mal place.  T he n u m ber a n d perce nta ge of res p o nses 
will be prese nte d i n t he f or m X X ( X X. X %). 
 
C ha n ge fr o m baseli ne = test val ue at t he p ost- baseli ne visit –  baseli ne val ue. T he perce nta ge 
c ha n ge  fr o m  baseli ne  will  be  calc ulate d  as  (test  val ue  at  t he  p ost- baseli ne  visit  -  baseli ne  
val ue)/ baseli ne val ue x 1 0 0. Perce nt of baseli ne is calc ulate d as test val ue at t he p ost- baseli ne 
visit/ baseli ne val ue × 1 0 0. If eit her t he baseli ne or t he p ost- baseli ne val ue is missi n g, t he c ha n ge 
fr o m baseli ne, perce nta ge c ha n ge fr o m baseli ne, a nd perce nt of baseli ne are set t o missi n g. If 
baseli ne is 0, t he n perce nta ge of baseli ne a n d perce nta ge c ha n ge fr o m baseli ne are set t o missi n g. 
 
P ost Baseli ne D urati o n i n da ys = e n d date –  start date + 1 ( di vi de b y 7 t o c o n vert t o wee ks, di vi de 
b y 3 0. 4 3 7 5 t o c o n vert t o m o nt hs, a n d di vi de b y  3 6 5. 2 5 t o c o n vert t o years; r o u n d res ult t o 1 
deci mal place) 
 
Listi n gs t y picall y will be s orte d b y st u d y part, s u bject i de ntificati o n n u m ber (c o ncate nate d site a n d 
s u bj ect n u m ber), visit, date, a n d ti me, if c ollecte d. 
 
P- val ues, if a p plica ble, will be prese nte d t o 3 deci mal places. If t he r o u n de d res ult is a val ue of 
1. 0 0 0, it will be dis pla ye d as > 0. 9 9 9.  
 
A n y date i n t he listi n gs will use t he d ate 9.  f or mat, f or e xa m ple, 0 7 M A Y 2 0 0 2.  
 
All a nal yses will be c o n d ucte d wit h S A S versi o n 9. 4 or hi g her. 
8.  
S U M M A R Y O F A N A L Y SI S P O P U L A TI O N S A N D E N R O L L M E N T  
T he  n u m ber  of  s u bjects  i n  eac h  a nal ysis  p o p ulati o n  ( E nr olle d,  Safet y  a n d  P K  p o p ulati o ns)  will  be  
s u m marize d b y st u d y part a n d o verall o n t he E nr olle d p o p ulati o n.  
A s u bj ect listi n g i n dicati n g a nal ysis p o p ulati o n, st u d y part, a n d site of e nr oll me nt will be prese nte d.  
9.  
D I S P O SI TI O N 
St u d y dis p ositi o n will be s u m marize d b y st u d y part a n d o verall. A s u m mar y of s u bj ect dis p ositi o n will 
i ncl u de n u m ber a n d perce nta ges f or t he f oll o wi n g cate g ories: 
 
S u bj ects i n eac h defi ne d a nal ysis p o p ulati o n 
 
S u bj ects w h o disc o nti n ue d st u d y treat me nt a n d reas o n f or disc o nti n uati o n 
 
S u bj ects w h o wit h dra w fr o m st u d y a n d reas o ns f or wit h dra wal 
 
S u bj ect re place me nts a n d reas o ns f or re place me nts, if a n y. 
1 0.  
M A J O R P R O T O C O L D E VI A TI O N S  
All pr ot oc ol de viati o ns will be liste d f or t he safet y p o p ulati o n. Pr ot oc ol de viati o ns will be s u m marize d b y 
maj or a n d mi n or cate g or y a n d b y st u d y part. Pre defi ne d cate g ories of maj or pr ot oc ol de viati o ns will 
i ncl u de: 
 
Vi olati o n of i ncl usi o n/e xcl usi o n criteria 
C CI


N u m b er: 
 
 
St at us: Iss u e d  
 
Pr ot oc ol E Z H- 1 0 8 
V 2. 0, 3 1 A u g ust 2 0 2 1 
Statistical A nal ysis Pla n 
V 2. 1, 2 1 N o v, 2 0 2 2 
E pi z y m e, I n c. 
C O N FI D E N TI A L I N F O R M A TI O N 
P a g e 2 0 of 3 1 
 
 
 
 
Pr o hi bite d me dicati o ns 
 
St u d y dr u g c o m plia nce 
A d diti o nal cate g ories ma y be a d de d d uri n g t he c o urse of t he st u d y b ut will be deter mi ne d pri or t o data base 
l oc k. 
1 1.  
D E M O G R A P HI C A N D O T H E R B A S E LI N E C H A R A C T E RI S TI C S  
De m o gra p hic data a n d ot her baseli ne c haracteristics will be s u m marize d b y st u d y part a n d o verall, a n d 
liste d f or t he E nr olle d p o p ulati o n.  De m o gra p hics will i ncl u de a ge ( deri ve d, i n years), se x, race, et h nicit y, 
a n d baseli ne c haracteristics will i ncl u de, b ut n ot li mite d t o, Easter n C o o perati ve O nc ol o g y Gr o u p ( E C O G) 
perf or ma nce stat us, c o m plete p h ysical e xa mi nati o n, vital si g ns a n d dr u g/alc o h ol scree ni n g details. 
Baseli ne disease c haracteristics will i ncl u de t u m or dia g n osis ( T D), pri or a ntica ncer t hera p y ( yes/ n o), pri or 
ra di ot hera p y  ( yes/ n o),  pri or  ca ncer  relate d  s ur ger y  ( yes/ n o),  pr o gressi ve  disease  pri or  t o  st u d y  e ntr y  
( yes/ n o), pri or disease pr o gressi o n date of last pr o gressi o n pri or t o t he st u d y e nr oll me nt, bl o o d s mear 
( B S), B o ne Marr o w As pirate/ Bi o ps y ( BM) a n d ti me fr o m d ate of last disease pr o gressi o n t o st u d y e ntr y 
(i n m o nt hs). 
1 2.  
S U R GI C A L A N D M
E DI C A L H I S T O R Y 
S ur gical a n d me dical hist or y occ urri n g pri or t o start of  st u d y treat me nt will be s u m marize d a n d liste d f or 
t he E nr olle d p o p ulati o n. 
Me dical  a n d  s ur gical  hist or y  will  be  c o de d  usi n g  t he  Me dical  Dicti o nar y  f or  Re g ulat or y  Acti vities  
( Me d D R A) v 2 3. 1. T he n u m ber a n d perce nta ge of s u bj ects wit h a n y s ur gical a n d me dical hist or y will be 
s u m marize d.   Me dic al  hist or y  als o  will  be  s u m marize d  b y  Me d D R A  s yste m or ga n  class  ( S O C)  a n d  
preferre d ter m ( P T).  S ur gical hist or y will be s u m m arize d b y t he Me d D R A hi g h-l e vel gr o u p ter m ( H L G T) 
a n d P T.  Listi n gs will i ncl u de start date a n d st o p date  or n otati o n of o n g oi n g f or c o n diti o ns c o nti n ui n g i nt o 
t he st u d y treat me nt peri o d. 
1 3.  
M E DI C A TI O N S  
Me dicati o ns will be c o de d usi n g W orl d Healt h Or ga nizati o n ( W H O) Dr u g Dict i o nar y versi o n Se pte m ber 
2 0 2 0. F or i nci de nce s u m maries of me dicati o ns c o de d b y W H O A nat o mical T hera pe utic C he mical ( A T C) 
cate g or y, a s u bject will be c o u nte d o nce e ve n if t h e s u bject t o o k m ore t ha n o ne me dicati o n wit hi n a 
s pecific A T C cate g or y (li ke wise f or P T). 
1 3. 1.  
P R E VI O U S A N TI C A N C E R T H E R A PI E S  
Pre vi o us a ntica ncer t hera p y a n d ra di ot hera p y will be  s u m marize d a n d liste d f or t he E nr olle d p o p ulati o n. 
T he s u m mar y f or pre vi o us a ntica ncer t hera pies will i ncl u de: 
 
N u m ber of re gi me ns ( descri pti vel y a n d b y cate g or y ( 1, 2, 3, 4, or m ore t ha n 4 pri or re gi me ns)) 
 
Hist or y of a n y pri or t hera p y b y setti n g ( Ne oa dj u va nt, A dj u va nt, T hera pe utic f or 
C CI


N u m b er: 
 
 
St at us: Iss u e d  
 
Pr ot oc ol E Z H- 1 0 8 
V 2. 0, 3 1 A u g ust 2 0 2 1 
Statistical A nal ysis Pla n 
V 2. 1, 2 1 N o v, 2 0 2 2 
E pi z y m e, I n c. 
C O N FI D E N TI A L I N F O R M A TI O N 
P a g e 2 1 of 3 1 
 
 
 
A d va nce d/ Metastatic Disease, C o ns oli dati o n, Ma i nte na nce, Palliati o n, or U n k n o w n); A s u bj ect 
ma y be c o u nte d i n m ulti ple cate g ories 
 
I nci de nce of pri or a ntica ncer t hera pies b y W H O Dr u g A T C le vel 4 a n d P T 
T he s u m mar y f or t he pre vi o us ra di ot hera p y will i ncl u de: 
 
N u m ber of pri or c o urses ( 0, 1, or 2 or m ore c o urses) 
 
Maj or sites of pri or ra di ot hera p y (s u b di visi o ns of t h ose sites will be liste d); A s u bject ma y be 
c o u nte d i n m ulti ple cate g ories 
T he s u m mar y f or pri or tra ns pla nt will i ncl u de: 
 
I nci de nce of pri or tra ns pla nt (a ut ol o g o us or all o ge nic) 
 
T y pe of pri or a ut ol o g o us tra ns pla nt ( b o ne marr o w, peri p heral bl o o d ste m cell, or b ot h) 
1 3. 2.  
P RI O R A N D C O N C O MI T A N T M
E DI C A TI O N S  
Me dicati o ns  will  be  s u m marize d  a n d  liste d  f or  t he  Safet y  p o p ulati o n.  S u m mar y  ta bles  will  i ncl u de  
i nci de nce  ( n u m ber  a n d  perce nta ge)  of  s u bjects  recei vi n g  a n y  me dicati o n  a n d  i nci de nce  of  s pecific  
me dicati o ns b y W H O Dr u g A T C le vel 4 a n d P T. 
Pri or  a n d  c o nc o mita nt  me dicati o ns  will  be  s u m marize d  se paratel y.  Cate g orizati o n  will  be  defi ne d  as  
f oll o ws: 
 
Pri or me dicati o ns will i ncl u de me dicati o ns w hic h st o p pe d pri or t o t he first d ose of st u d y dr u g. 
 
C o nc o mita nt me dicati o ns are defi ne d as me dicati o ns t hat were starte d at a n y ti me after t he start of 
first d ose of st u d y dr u g a n d st o p pe d pri or t o t he e n d of st u d y treat me nt or t he disc o nti n uati o n of 
st u d y dr u g, w hic he ver is earlier.  
 
Me dicati o ns t hat starte d pri or t o t he first d ose of st u d y dr u g a n d c o nti n ue d i nt o st u d y treat me nt 
peri o d u ntil t he e n d of st u d y treat me nt or t he disc o nti n uati o n of st u d y dr u g, w hic he ver is earlier,  
are c o nsi dere d as b ot h pri or a n d c o nc o mita nt. 
 P ost-treat me nt me dicati o ns will i ncl u de a ntica ncer t hera pies w hi c h starte d after 
disc o nti n uati o n of st u d y dr u g.  
Me dicati o ns  wit h  missi n g  or  partiall y  missi n g  start  or  e n d  dates  will  be  ha n dle d  acc or di n g  t o  t he  
c o n ve nti o ns  descri be d  i n  A p pe n di x  1.  If  it  ca n n ot  be  deter mi ne d  w het her  a  me dicati o n  was  a  pri or  
me dicati o n d ue t o partial me dicati o n start date or e n d date, t he me dicati o n will be c o nsi dere d c o nc o mita nt. 
If  me dicati o n  start  date  a n d  e n d  date  are  missi n g,  t he  me dicati o n  will  be  c o nsi dere d  c o nc o mita nt.  
Pr o hi bite d me dicati o ns, as defi ne d i n Secti o n 9. 3 of t he pr ot oc ol, will be i de ntifie d wit h a ‘ *’ i n t he listi n g.  
1 4.  
S T U D Y D R U G E X P O S U R E A N D C O M P LI A N C E  
St u d y dr u g e x p os ure a n d c o m plia nce will be s u m marize d a n d liste d f or t he Safet y p o p ulati o n.   
1 4. 1.  
S T U D Y D R U G E X P O S U R E  
T he f oll o wi n g s u m maries of st u d y dr u g e x p os ure will be prese nte d: 
St u d y P arts 1 a n d 2: 
 
D urati o n of taze met ostat e x p os ure ( wee ks)  
C CI




N u m b er: 
 
 
St at us: Iss u e d  
 
Pr ot oc ol E Z H- 1 0 8 
V 2. 0, 3 1 A u g ust 2 0 2 1 
Statistical A nal ysis Pla n 
V 2. 1, 2 1 N o v, 2 0 2 2 
E pi z y m e, I n c. 
C O N FI D E N TI A L I N F O R M A TI O N 
P a g e 2 3 of 3 1 
 
 
 
A vera ge d ose i nte nsit y ( m g BI D/ da y) = t otal a m o u nt of taze met ostat ta ke n ( m g) / [ 2 * d urati o n of 
  e x p os ure ( da ys)] ( m g BI D/ da y) 
w here d urati o n of e x p os ure ( da ys) = [( date of last act ual d ose of taze met ostat –  date of first d ose of 
taze met ostat) + 1] ( da ys) 
P art 2: 
1)  F or C ycle 1 ( Da ys 1- 2 6): 
 
A vera ge d ose i nte nsit y ( m g BI D/ da y) = t otal a m o u nt of taze met ostat ta ke n ( m g) / ( 2 * 2 2) 
( da ys) ( m g BI D/ da y) 
 
Pla n ne d a vera ge d ose i nte nsit y ( m g BI D/ da y) = [ 8 0 0 * 3 + 8 0 0 * 2 *( 1 2 + 7)]/( 2 * 2 2) = 3 2, 8 0 0 
/( 2 * 2 2) = 7 4 5. 4 5 ( m g BI D/ da y) 
2)  F or C ycle 2 + o n war ds 
A vera ge d ose i nte nsit y ( m g BI D/ da y) = t otal a m o u nt of taze met ostat ta ke n ( m g) / [ 2 * d urati o n of 
e x p os ure ( da ys)] ( m g BI D/ da y) 
w here d urati o n of e x p os ure ( da ys) = [( date of last act ual d ose of taze met ostat –  date of first d ose of 
taze met ostat) + 1] ( da ys) 
 
 
F or assess me nt of t olera bilit y, n u m bers of s u bj ects re q uiri n g d ose re d ucti o ns, treat me nt 
i nterr u pti o n or treat me nt disc o nti n uati o n i n res p o nse t o A Es ( base d o n acti o n ta ke n f or re p orte d 
A Es) 
T he f oll o wi n g s u m maries of st u d y dr u gs itrac o naz ole i n part 1 a n d rifa m pi n i n part 2 will be prese nte d. 
St u d y P art 1: 
 
S u m mar y statistics f or t he t otal a m o u nt of itrac o naz ole recei ve d ( m g) 
 
N u m ber ( %) of s u bjects w h o recei ve d < 4 2 0 0 m g, 4 2 0 0 m g a n d > 4 2 0 0 m g of itrac o naz ole 
St u d y P art 2: 
 
S u m mar y statistics f or t he t otal a m o u nt of rifa m pi n recei ve d ( m g) 
 
N u m ber ( %) of s u bjects w h o recei ve d < 5 4 0 0 m g, 5 4 0 0 m g a n d > 5 4 0 0 m g of rifa m pi n 
1 4. 2.  
S T U D Y D R U G C O M P LI A N C E  
T he f oll o wi n g s u m maries of st u d y dr u g c o m plia nce will be prese nte d f or C ycle 1 a n d all s u bse q ue nt 
c ycles, se paratel y: 
 
Perce nta ge taze met ostat ta ke n (s u m marize d as a c o nti n u o us varia ble). 
St u d y P art  1:  
C ycle 1: Perce nta ge of taze met ostat ta ke n = 1 0 0 % × A vera ge d ose i nte nsit y ( m g BI D/ da y) / 
Pla n ne d a vera ge d ose i nte nsit y ( m g BI D/ da y). 
C ycle 2 +: Perce nta ge of taze met ostat ta ke n = 1 0 0 % × A vera ge d ose i nte nsit y ( m g BI D/ da y) / 8 0 0 
m g BI D/ da y. 
St u d y P art  2:  
C ycle 1: Perce nta ge of taze met ostat ta ke n = 1 0 0 % × A vera ge d ose i nte nsit y ( m g BI D/ da y) / 
Pla n ne d a vera ge d ose i nte nsit y ( m g BI D/ da y). 
C ycle 2 +: Perce nta ge of taze met ostat ta ke n = 1 0 0 % × A vera ge d ose i nte nsit y ( m g BI D/ da y) / 8 0 0 
m g BI D/ da y. 
 
Cate g or y of perce nta ge of taze met ostat ta ke n ( usi n g cate g ories ≥ 9 0 %, 8 0 % t o < 9 0 %, 7 0 % t o 
C CI


N u m b er: 
 
 
St at us: Iss u e d  
 
Pr ot oc ol E Z H- 1 0 8 
V 2. 0, 3 1 A u g ust 2 0 2 1 
Statistical A nal ysis Pla n 
V 2. 1, 2 1 N o v, 2 0 2 2 
E pi z y m e, I n c. 
C O N FI D E N TI A L I N F O R M A TI O N 
P a g e 2 4 of 3 1 
 
 
 
< 8 0 %, a n d < 7 0 %). 
1 5.  
E F FI C A C Y A N A L Y SI S  
N o efficac y a nal ysis will be perf or me d. Listi n g f or efficac y res p o nses s uc h as C R/ P R/ P D a n d o verall 
s ur vi val will be pr o vi de d if data are c ollecte d.  
1 6.  
S A F E T Y O U T C O M E S A N D A N A L Y SI S  
All safet y s u m maries will be base d o n t he Safet y p o p ulati o n. 
1 6. 1.  
A D V E R S E E V E N T S  
A Es will be c o de d usi n g Me d D R A v 2 3. 1. S u m mar y ta bles will be base d o n treat me nt e mer ge nt a d verse 
e ve nts ( T E A Es) w hic h are defi ne d as A Es t hat starte d or w orse ne d i n se verit y o n or after t he da y of t he 
first  d ose  of  st u d y dr u g t hr o u g h  3 0  da ys  after  t he  e n d  of  st u d y dr u g or  t he  i nitiati o n  of  s u bse q ue nt 
a ntica ncer t hera p y, w hic he ver is earlier. All A Es, treat me nt e mer ge nt or ot her wise, will be prese nte d i n 
A E listi n gs. 
Eac h s u m mar y ta ble will i ncl u de t he i nci de nce ( n u m ber a n d perce nta ge) of s u bjects re p orti n g a n y T E A E, 
as well as, b y S O C a n d P T.  A s u bject will be c o u nte d o nl y o nce wit h a n S O C, e ve n if t he s u bj ect 
e x perie nce d m ore t ha n o ne T E A Es wit hi n t hat s pecific S O C (li ke wise f or P T).  
I n vesti gat or assesse d se verit y gra de will be base d o n t he Nati o nal Ca ncer I nstit ute C T C A E v 5. 0. A s u bject 
will be c o u nte d o nl y o nce wit h t he w orst se verit y gra de wit hi n a S O C a n d/ or P T.   
I n vesti gat or  assesse d  ca usalit y  t o  st u d y  dr u g  will  be  cate g orize d  as  “ n ot  relate d,”  “ u nli kel y  relate d,”  
“ p ossi bl y relate d,” or “pr o ba bl y relate d” t o st u d y dr u g.  F or s u m mar y p ur p oses, treat me nt-relate d T E A Es 
will i ncl u de e ve nts wit h relati o ns hi p t o st u d y dr u g classifie d as “ n ot relate d” i ncl u di n g b ot h “ n ot relate d” 
a n d “ u nli kel y relate d” or “relate d” i n v ol vi n g b ot h “ p ossi bl y relate d” a n d “ pr o ba bl y relate d”. A T E A E wit h 
a missi n g ca usalit y will be classifie d as “relate d” t o st u d y dr u g.  A s u bject will be c o u nte d o nl y o nce at t he 
str o n gest ca usalit y wit hi n a S O C a n d/ or P T (relate d o ver n ot relate d).   
T E A Es of s pecial i nterest are defi ne d i n Se cti o n 1 2. 4. 2 of t he pr ot oc ol.  
I n acc or da nce wit h t he T E A E ta ble prese ntati o n descri be d a b o ve, A Es will be s u m mari ze d as f oll o ws: 
 
T E A Es 
 
T E A Es of gra de 3 or 3 
 
Treat me nt-relate d T E A Es 
 
Treat me nt-relate d T E A Es of gra de 3 or 4 
 
T E A Es lea di n g t o d ose i nterr u pti o n 
 
T E A Es lea di n g t o d ose re d ucti o n 
 
T E A Es lea di n g t o disc o nti n uati o n of st u d y dr u g 
 
Seri o us a d verse e ve nts ( S A Es) 
 
Treat me nt-relate d S A Es 
C CI


N u m b er: 
 
 
St at us: Iss u e d  
 
Pr ot oc ol E Z H- 1 0 8 
V 2. 0, 3 1 A u g ust 2 0 2 1 
Statistical A nal ysis Pla n 
V 2. 1, 2 1 N o v, 2 0 2 2 
E pi z y m e, I n c. 
C O N FI D E N TI A L I N F O R M A TI O N 
P a g e 2 5 of 3 1 
 
 
 
 
T E A Es lea di n g t o deat h 
 
T E A Es of s pecial i nterest  
F or treat me nt-relate d s u m maries, relati o ns hi p will be s u m marize d b y eac h st u d y dr u g ( Part 1: t aze met ostat 
or itrac o naz ole; Part 2: taze met ostat or rifa m pi n).  
Se parate  listi n gs  of  S A Es,  T E A Es  lea di n g  t o  disc o nti n uati o n  of  st u d y  dr u g,  T E A Es  lea di n g  t o  d ose  
m o dificati o ns, a n d T E A Es wit h a n o utc o me of deat h will be pr o vi de d. A listi n g of T E A Es of s pecial 
i nterest will als o be pr o vi de d. 
1 6. 2.  
L A B O R A T O R Y E V A L U A TI O N S  
T he  s pecific  he mat ol o g y,  c he mistr y,  a n d  uri nal ysis  a nal ytes  c ollecte d  f or  t he  st u d y  are  descri be d  i n  
A p pe n di x 2 of t he pr ot oc ol. S u m mar y ta bles a n d listi n gs of l ocal la b orat or y data will be re prese nte d i n SI 
u nits, w here a p plica ble. La b orat or y val ues t hat are re p orte d as ‘ bel o w t he detecta ble li mit’ of a n assa y will 
be a nal yze d as half t he detecta ble li mit f or q ua ntita ti ve a nal ysis b ut liste d as ori gi nall y re p orte d. T he 
f oll o wi n g s u m maries will be pr o vi de d f or la b orat or y data: 
 
S hift fr o m baseli ne gra de t o w orst p ost- baseli ne gra de base d o n N CI C T C A E v 5. 0 (f or a nal ytes 
w here C T C A E gra di n g a p plies). A missi n g b aseli ne  gra de will be ass u me d t o be gra de 0.  F or 
la b orat or y tests wit h b ot h l o w a n d hi g h val ues, s u m maries will be pr o vi de d se paratel y. 
 
S hift fr o m baseli ne t o w orst p ost- baseli ne val ue t hat is < 0. 2 5 x L L N or > 2. 5 x U L N (f or a nal ytes 
n ot gra da ble b y N CI C T C A E v 5. 0). 
All la b data will be liste d.  A n a d diti o nal listi n g will be prese nte d f or s u bjects wit h a p ost- baseli ne a nal yte 
t hat is gra de 3 or hi g her ( per N CI C T C A E) or t hat is < 0. 2 5 x L L N or > 2. 5 x U L N (f or a nal ytes n ot 
gra da ble b y N CI C T C A E).  F or t he later listi n g, all val ues f or t hat a nal yte will be liste d.  
1 6. 3.  
P E R F O R M A N C E S T A T U S A N A L Y SI S  
E C O G  perf or ma nce  stat us  sc ore  will  be  s u m marize d  a n d  liste d  f or  t he  E nr olle d  p o p ulati o n.  E C O G  
perf or ma nce stat us will be s u m marize d cate g oricall y at  baseli ne, best p ost- baseli ne val ue, a n d w orst p ost-
baseli ne val ue.  A s u m mar y of s hift fr o m baseli ne (i m pr o ve d, n o c ha n ge, deteri orate d) will be perf or me d 
f or t he best p ost- baseli ne val ue a n d t he w orst p ost- baseli ne val ue d uri n g t he st u d y. Best a n d w orst p ost-
baseli ne val ues will be fla g ge d i n t he listi n g. 
1 6. 4.  
E C G  E V A L U A TI O N S  
1 2- Lea d  ec h ocar di o gra m ( E C G)  meas ures  (si n glets  a n d  tri plicates)  will  be c ollecte d  acc or di n g t o  t he 
sc he d ule of e ve nts, w hic h varies b y st u d y part. W he n tri plicates are c ollecte d, t he a vera ges will be use d i n 
t he s u m maries. 
T he i n vesti gat or will pr o vi de a n o verall i nter pretati o n of t he E C G (i.e. cli nicall y si g nifica nt, yes or n o).  
F or t he Fri dericia c orrecti o n of Q T i nter val f or heart rate ( Q T c F), mar ke dl y a b n or mal criteria will be 
defi ne d as descri be d i n t he ta ble bel o w. 
C CI


N u m b er: 
 
 
St at us: Iss u e d  
 
Pr ot oc ol E Z H- 1 0 8 
V 2. 0, 3 1 A u g ust 2 0 2 1 
Statistical A nal ysis Pla n 
V 2. 1, 2 1 N o v, 2 0 2 2 
E pi z y m e, I n c. 
C O N FI D E N TI A L I N F O R M A TI O N 
P a g e 2 6 of 3 1 
 
 
 
E C G val ues , t he i n vesti gat or’s i nter pretati o n of t he E C G, a n d ot her i nf or mati o n c ollecte d will be liste d.  
Q T c F val ues meeti n g mar ke dl y a b n or mal crit eria will be fla g ge d. 
T he f oll o wi n g ta bles will be pr o vi de d f or t he Q T c F: 
 
Q ua ntitati ve 1 2-lea d E C G meas ure me nts:  S hift fr o m baseli ne t o w orst p ost- baseli ne i n Q T c F 
stat us cate g orize d as mar ke dl y a b n or mal or n ot ( defi ne d i n t he ta ble bel o w)  
 
Q ua ntitati ve 1 2-lea d E C G Q T c F meas ure me nts: C o u nts a n d perce nta ges of s u bjects w h ose w orst-
case c ha n ges fr o m baseli ne i n Q T c F meas ure me nts  meet mar ke dl y a b n or mal criteria ( descri be d i n 
t he ta ble bel o w f or c ha n ges fr o m baseli ne).   
Q T c F Meas ure 
Mar ke dl y A b n or mal Criteria 
O bser ve d  Meas ures 
4 5 0 – 4 8 0 msec, i ncl usi ve [ C T C A E gra de 1] 
4 8 1 – 5 0 0 msec, i ncl usi ve [ C T C A E gra de 2] 
> 5 0 0 msec  [ C T C A E gra de 3 or hi g her] 
O bser ve d  C ha n ges 
fr o m Baseli ne 
> 3 0 msec i ncrease fr o m baseli ne  
> 6 0 msec i ncrease fr o m baseli ne  
1 6. 5.  
V I T A L S I G N S A N D O T H E R C LI NI C A L S T A T U S M
E A S U R E S  
Wei g ht ( k g) a n d hei g ht at scree ni n g (c m), as well as vital si g ns f or sitti n g s yst olic bl o o d press ure ( m m H g), 
sitti n g diast olic bl o o d press ure ( m m H g), sitti n g heart rate ( b p m), sitti n g res pirat or y rate ( breat hs/ mi n), a n d 
te m perat ure  (⁰C)  will  be  c ollecte d  a n d  liste d.  S u m maries  of  heart  rate,  te m perat ure,  s yst olic  bl o o d  
press ure, a n d diast olic bl o o d press ure will be base d o n mar ke dl y a b n or mal criteria defi ne d bel o w: 
T a ble 1. Vit al Si g ns a n d A b n or m al Criteri a 
Vit al Si g n  
A b n or m al Criteri a  
Heart rate ( b p m) 
< 6 0 b p m  
> 1 0 0 b p m  
T e m perat ure ( ⁰C) 
≤ 3 5 ⁰C 
≥ 3 8 ⁰C 
S yst olic
 bl o o d
 press ure
 
( m m H g) 
1 2 0 - 1 3 9 m m H g, i ncl usi ve ( C T C A E gra de 1) 
1 4 0 – 1 5 9 m m H g, i ncl usi ve ( C T C A E gra de 2) 
≥ 1 6 0 m m H g ( C T C A E Gra de 3) 
Diast olic  bl o o d  press ure  
( m m H g) 
8 0 – 8 9 m m H g, i ncl usi ve ( C T C A E gra d e 1) 
9 0 – 9 9 m m H g, i ncl usi ve ( C T C A E gra d e 2) 
≥ 1 0 0 m m H g ( C T C A E gra de 3) 
 
C CI


N u m b er: 
 
 
St at us: Iss u e d  
 
Pr ot oc ol E Z H- 1 0 8 
V 2. 0, 3 1 A u g ust 2 0 2 1 
Statistical A nal ysis Pla n 
V 2. 1, 2 1 N o v, 2 0 2 2 
E pi z y m e, I n c. 
C O N FI D E N TI A L I N F O R M A TI O N 
P a g e 2 7 of 3 1 
 
 
 
I nci de nce of a b n or mal w orst-case val ues will be prese nte d.  F or heart rate a n d te m perat ure, b ot h hi g h a n d 
l o w val ues will be prese nte d se paratel y s uc h t hat s u bjects ca n be c o u nte d i n b ot h cate g ories. A b n or mal 
vital si g n val ues will be fla g ge d as s uc h o n a vital si g n listi n g. 
1 7.  
P H A R M A C O KI N E TI C A N D P H A R M A C O D Y N A MI C A N A L Y S E S  
1 7. 1.  
P H A R M A C O KI N E TI C ( P K) A N A L Y S E S  
All p har mac o ki netic a nal yses will be perf or me d base d o n t he P K p o p ulati o n.  
Plas ma c o nce ntrati o ns will be s u m marize d usi n g descri pti ve statistics ( n, mea n, sta n d ar d de viati o n ( S D), 
c oefficie nt of variati o n ( C V %), sta n dar d err or ( S E)  of t he mea n, me dia n, ma xi m u m, a n d mi ni m u m) at 
eac h sc he d ule d e val uati o n ti me p oi nt. T he mea n P K c o nce ntrati o ns will be pl otte d o ver ti me si nce last 
d ose a n d ti me si nce first d ose. P K c o nce ntrati o n data will be liste d. 
 
All P K a nal yses will be descri be d i n a se parate P h ar mac o ki netic A nal ysis Pla n ( P K A P). Res ults fr o m P K 
a nal yses will be re p orte d i n a P K re p ort, a n d t he ke y messa ges will be s u m marize d i n t he C S R, or i n 
se parate p u blicati o ns. 
1 7. 2.  
P H A R M A C O D Y N A MI C ( P D) A N A L Y S E S  
N o P D a nal ysis will be perf or me d. 
1 8.  
R E F E R E N C E S  
1.  Br o o k me yer  R,  Cr o wle y  JJ.  ( 1 9 8 2).  A  c o nfi de nce  i nter val  f or  t he  me dia n  s ur vi val  ti me.  
Bi o metrics . 3 8( 1), 2 9- 4 1 
2.  C hes o n B D, Fis her RI, Barri n gt o n S F, et al. Rec o m me n dati o ns f or I nitial E val uati o n, Sta gi n g, 
a n d Res p o nse Assess me nt of H o d g ki n a n d N o n- H o d g ki n L y m p h o ma: T he L u ga n o Classificati o n. 
J Cli n O nc ol. 2 0 1 4; 3( 3 2) ( C hes o n B D e. a., 2 0 1 4) 2 7: 3 0 5 9- 3 0 6 7 
 
 
C CI






N u m b er: 
 
 
St at us: Iss u e d  
 
Pr ot oc ol E Z H- 1 0 8 
V 2. 0, 3 1 A u g ust 2 0 2 1 
Statistical A nal ysis Pla n 
V 2. 1, 2 1 N o v, 2 0 2 2 
E pi z y m e, I n c. 
C O N FI D E N TI A L I N F O R M A TI O N 
P a g e 3 0 of 3 1 
 
 
 
S T A R T D A T E 
S T O P D A T E 
A C TI O N 
 
P artial 
I m p ute st o p date as latest p ossi ble date (i.e. last da y of m o nt h if da y 
u n k n o w n or 3 1 st Dece m ber if da y a n d m o nt h are u n k n o w n), t he n: 
 
If st o p date < st u d y dr u g start date, assi g n as pri or . 
 
If st o p date > = st u d y dr u g start d ate, assi g n as c o nc o mit a nt. 
 
Missi n g 
Assi g n as c o nc o mita nt. 
 
 
C CI


 
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E L E C T R O NI C R E C O R D A N D SI G N A T U R E DI S C L O S U R E  
Fr o m ti me t o ti me, E piz y me I n c. ( we, us or C o m p a n y) ma y be re q uire d b y la w t o pr o vi de t o y o u 
certai n writte n n otices or discl os ures. Please rea d t he i nf or mati o n bel o w caref ull y a n d 
t h or o u g hl y, a n d if y o u ca n access t his i nf or mati o n electr o nicall y t o y o ur s atisfacti o n a n d a gree t o 
t his Electr o nic Rec or d a n d Si g nat ure Discl os ure ( E R S D), please c o nfir m y o ur a gree me nt b y 
selecti n g t h e c hec k-b o x ne xt t o ‘I a gree t o use electr o nic rec or ds a n d si g nat ures’ bef ore clic ki n g 
‘ C O N TI N U E’ wit hi n t he D oc u Si g n s yste m. 
  
Use of 2 1 C F R P a rt 1 1 Electr o nic Si g n at ures  
As a n E piz y me D o c u Si g n user, y o u u n dersta n d a n d a gree t h at b y a d o pti n g a n d a p pl yi n g y o ur 
electr o nic si g nat ur e t o d o c u me nts, t he si g n at ure is t he le gall y bi n di n g e q ui v ale nt of y o ur 
tra diti o nal ha n d writte n si g nat ur e. A d diti o nall y, y ou affir m t hat t he el ectr o ni c si g nat ure is u ni q ue 
t o y o u a n d ma y o nl y b e use d b y y o u t o si g n d oc u me nts. 
Please refer t o t he free a v aila ble D oc u Si g n trai ni n g f or a p pl yi n g y o ur ele ctr o nic si g nat ur e at 
htt ps://s u p p ort. d oc usi g n.c o m/e n/ vi de os/ Si g n-a- C F R- Part- 1 1 . 
  
Ac k n o wle d gi n g y o ur access a n d c o nse nt t o recei ve a n d si g n d oc u me nts electr o nic all y  
B y sele cti n g t he c hec k- b o x ne xt t o ‘I a gree t o use electr o nic rec or ds a n d si g nat ur es’, y o u c o nfir m 
t hat: 
 
Y o u ca n access a n d rea d t his Electr o nic Rec or d a n d Si g nat ure Discl os ure; a n d 
 
Y o u ca n pri nt o n pa per t his Electr o nic Rec or d a n d Si g nat ure Discl os ure, or sa ve or s e n d 
t his Electr o nic Rec or d a n d Discl os ure t o a l ocati o n w here y o u ca n pri nt it, f or f ut ure 
refere nce a n d access; a n d 
 
Y o u u n dersta n d t hat y o ur electr o nic si g nat ur e is a le gall y bi n di n g e q ui vale nt t o y o ur 
ha n d writte n si g n at ure. 
P P D