Conditions: Diffuse Large B Cell Lymphoma Primary Mediastinal Lymphoma Mantle Cell Lymphoma Advanced Solid Tumor Marginal Zone Lymphoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 32
Healthy volunteers: no

Brief summary:
This is a Phase 1, open-label, two-part, safety, PK, and activity study designed to characterize the DDI potential of tazemetostat. Tazemetostat will be taken orally BID continuously in 28-day cycles in both study parts.

Detailed description:

Arms:
arm 1: Part A: Subjects enrolled in Part A will receive treatment with oral tazemetostat tablets 400 mg BID for 24 days beginning on Day 1. Subjects will receive fluconazole 400 mg once daily for 4 days starting on Day 16. Tazemetostat 400 mg BID will continue through Day 24. Subjects will then receive tazemetostat 800 mg BID starting on Day 25.

Part B: Subjects enrolled in Part B will receive single oral doses of repaglinide 0.25 mg and omeprazole 20 mg on Day 1. Administration of tazemetostat 800 mg BID will begin on Day 2. On Day 16, subjects again will receive single oral doses of repaglinide 0.25 mg and omeprazole 20 mg approximately 1 hour after the morning dose of tazemetostat. Subjects also will receive omeprazole 20 mg once daily in the morning on Days 16 through 19.

Interventions: intervention 1: Tazemetostat intervention 2: Fluconazole intervention 3: Omeprazole intervention 4: Repaglinide
Intervention descriptions: intervention 1: Tazemetostat is a selective oral small molecule inhibitor of EZH2 intervention 2: 200mg will be orally administered QD for 4 days in order to determine CYP3A4 inhibition when administered concomitantly with tazemetostat intervention 3: Using omeprazole as a probe substrate, 20mg will be orally administered for a total of 5 days in order to determine the potential of tazemetostat to inhibit or induce CYP2C19. Omeprazole is also being used to determine the effect of increased gastric pH on metabolism of tazemetostat. intervention 4: Using repaglinide as a probe substrate, 25mg will be orally administered for a total of 2 days in order to determine the potential of tazemetostat to inhibit or induce CYP2C8.

Protocol document:
Prot_SAP_000.pdf: 
                                 
 
 
Epizyme, Inc. 
Confidential and Proprietary 
NCT03028103 
28 September 2018 
 
 
 
Protocol Number: EZH-105 
 
Protocol Title: An Open-Label, Multicenter, Two-Part, Phase 1 Study to Characterize the 
Effects of a Moderate CYP3A Inhibitor on the Pharmacokinetics of Tazemetostat (EPZ-6438) 
(Part A), the Effects of Tazemetostat on the Pharmacokinetics of CYP2C8 and CYP2C19 
Substrates, and the Effect of Increased Gastric pH on the Pharmacokinetics of Tazemetostat (Part 
B) in Subjects with B-cell Lymphomas or Advanced Solid Tumors 
 
NCT Number: NCT03028103 
 
Protocol Amendment 4 Final: 28 September 2018 
 




Tazemetostat 
Protocol Number EZH-105 
Amendment 4.0 
 
 
 
                                 
 
 
Epizyme, Inc. 
Confidential  
28 September 2018 
 
 
INVESTIGATOR AGREEMENT PAGE 
 
Protocol Title: An Open-Label, Multicenter, Two-Part, Phase 1 Study to Characterize the 
Effects of a Moderate CYP3A Inhibitor on the Pharmacokinetics of 
Tazemetostat (EPZ-6438) (Part A), the Effects of Tazemetostat on the 
Pharmacokinetics of CYP2C8 and CYP2C19 Substrates, and the Effect of 
Increased Gastric pH on the Pharmacokinetics of Tazemetostat (Part B) in 
Subjects with B-cell Lymphomas or Advanced Solid Tumors 
 
Protocol Number: 
EZH-105 
 
By signature below, I agree to comply with the contents of this protocol and to conduct this study 
in compliance with Good Clinical Practices (GCP) and all applicable requirements.  I 
acknowledge that I am responsible for the overall study conduct and that I agree to personally 
conduct or supervise the described clinical study. 
I agree to ensure that all associates, colleagues, and employees assisting in the conduct of this 
study are informed about their obligations.  Mechanisms are in place to ensure that site staff 
receives the appropriate information and training throughout the conduct of the study. 
I have read and agree to the following Confidentiality Statement: 
Confidentiality Statement:  This protocol and any related documents from Epizyme, Inc., 
contain privileged information that is confidential and may not be disclosed unless such 
disclosure is required by federal laws or regulations.  In any event, persons to whom the 
information is disclosed must be informed that it is privileged and/or confidential and may 
not be further disclosed by them.  Information from this study may not be reproduced in any 
form without the written permission of Epizyme, Inc.  
Principal Investigator: 
Name: _____________________________________________________________________ 
 
Title: ______________________________________________________________________ 
 
 
Signature: __________________________________________ 
Date: ________________ 
 
Name/Address of Institution: __________________________________________________ 
___________________________________________________________________________ 


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CLINICAL STUDY PROTOCOL 
Protocol Title: 
An Open-Label, Multicenter, Two-Part, Phase 1 Study to Characterize the 
Effects of a Moderate CYP3A Inhibitor on the Pharmacokinetics of 
Tazemetostat (EPZ-6438) (Part A), the Effects of Tazemetostat on the 
Pharmacokinetics of CYP2C8 and CYP2C19 Substrates, and the Effect of 
Increased Gastric pH on the Pharmacokinetics of Tazemetostat (Part B) in 
Subjects with B-cell Lymphomas or Advanced Solid Tumors 
Compound Name (Number): 
Tazemetostat (EPZ-6438) 
Protocol Number: 
EZH-105 
Effective Date: 
03-Oct. 2016 
IND Number: 
124025 
Sponsor: 
Epizyme, Inc. 
400 Technology Square, 4th Floor 
Cambridge, MA  02139 USA 
Sponsor Medical Monitor: 
Deyaa Adib, MD 
Epizyme, Inc. 
400 Technology Square, 4th Floor 
Cambridge, MA  02139 USA 
Phone: (617) 674-1795 
Mobile: (617) 908-246-2899 
 
 
This protocol has been designed in accordance with the general ethical principles outlined in the Declaration of 
Helsinki.  The review of this protocol by an Institutional Review Board or Ethics Committee and the performance 
of all aspects of the study, including the methods used to obtain informed consent, must also be in accordance with 
the principles enunciated in the declaration, ICH E6 (R1) guidelines of Good Clinical Practice, US FDA CFR Part 
50 Protection of Human Subjects and 21 CFR Part 56 Institutional Review Boards, and all applicable regulatory 
authority requirements. 
 


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1. 
SYNOPSIS 
Study title 
An Open-Label, Multicenter, Two-Part, Phase 1 Study to Characterize the Effects of a 
Moderate CYP3A Inhibitor on the Pharmacokinetics of Tazemetostat (EPZ-6438) (Part 
A), the Effects of Tazemetostat on the Pharmacokinetics of CYP2C8 and CYP2C19 
Substrates, and the Effect of Increased Gastric pH on the Pharmacokinetics of 
Tazemetostat (Part B) in Subjects with B-cell Lymphomas or Advanced Solid Tumors 
Protocol number: 
EZH-105 
Clinical phase 
1 
Number of study 
centers 
3 centers in the US 
 
Investigational product 
Tazemetostat (EPZ-6438) 
Study objectives 
Primary objectives  
Part A: 
• 
To determine the effect of CYP3A inhibition by fluconazole on the 
pharmacokinetics (PK) of tazemetostat 
Part B: 
• 
To investigate the potential of tazemetostat to inhibit or induce CYP2C8 using 
repaglinide as a probe substrate 
• 
To investigate the potential of tazemetostat to inhibit or induce CYP2C19 using 
omeprazole as a probe substrate 
• 
To investigate the effect of increased gastric pH by omeprazole on the PK of 
tazemetostat 
 
Secondary objectives 
Part A 
• 
To investigate the safety profile of tazemetostat 400 mg twice daily (BID) after co-
administration with fluconazole 
• 
To determine the PK of tazemetostat and its metabolites after administration alone and 
with fluconazole 
• 
To determine the systemic exposure of fluconazole after administration of 400 mg 
once daily for 4 days 
Part B: 
• 
To investigate the safety profile of tazemetostat, repaglinide, and omeprazole after co-
administration 
• 
To determine the PK of repaglinide and its metabolites after administration with 
omeprazole and administration with omeprazole and tazemetostat 
• 
To determine the PK of omeprazole and its metabolites after administration with 
repaglinide and administration with repaglinide and tazemetostat 
• 
To determine the PK of tazemetostat and its metabolites after repeated dose of 
tazemetostat alone and with fluconazole 
Parts A and B: 
• 
To assess antitumor activity of tazemetostat in subjects with diffuse large B-cell 
lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), mantle cell 
lymphoma (MCL), marginal zone lymphoma (MZL), follicular lymphoma (FL), or 
advanced solid tumors 


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Exploratory objectives  
• 
To investigate the effects of variations in genes encoding for CYP enzymes and 
transporters on the potential drug-drug interaction profile of tazemetostat 
• 
To explore the effect of tazemetostat on overall survival (OS) 
Study design 
Phase 1, open-label, 2-part, pharmacokinetic, safety, and activity study 
Methodology 
This 2-part study is designed to characterize the drug-drug interaction (DDI) potential of 
tazemetostat.  Upon initiation of tazemetostat treatment, eligible subjects will receive 
tazemetostat BID continuously in 28-day cycles in both parts of the study.   
Part A.  Subjects enrolled in Part A will receive treatment with oral tazemetostat tablets 
400 mg BID for 24 days beginning on Day 1.  Blood samples for the analysis of plasma 
tazemetostat and its metabolites concentrations will be collected predose and over 8 hours 
after the morning dose of tazemetostat on Day 15.  Subjects will receive fluconazole 400 
mg once daily for 4 days starting on Day 16.  On Day 19, blood samples for the analysis 
of plasma tazemetostat, its metabolites, and fluconazole will be collected predose and 
over 8 hours after the morning tazemetostat dose.  Tazemetostat 400 mg BID will 
continue through Day 24.  Subjects will then receive tazemetostat 800 mg BID starting on 
Day 25. 
Part B.  Subjects enrolled in Part B will receive single oral doses of repaglinide 0.25 mg 
and omeprazole 20 mg on Day 1.  Administration of tazemetostat 800 mg BID will begin 
on Day 2.  On Day 16, subjects again will receive single oral doses of repaglinide 0.25 mg 
and omeprazole 20 mg approximately 1 hour after the morning dose of tazemetostat.  
Subjects also will receive omeprazole 20 mg once daily in the morning on Days 16 
through 19.  Blood samples for analysis of plasma repaglinide, repaglinide metabolites, 
omeprazole, 5-OH-omeprazole, and omeprazole sulfone will be collected predose and 
over 7 hours after administration on Day 1 and Day 16.  Blood samples for analysis of 
plasma tazemetostat and metabolites will be collected over 8 hours after administration of 
the morning dose on Day 16 and Day 19.   
Upon initiation of tazemetostat treatment, all subjects enrolled in this study will receive 
oral tazemetostat for up to 6 months (24 weeks) until they have an unacceptable toxicity, 
disease progression, or withdraw consent.  Subjects continuing to receive benefit from 
tazemetostat treatment can be transitioned to Study EZH-501 (a rollover study) upon 
completion of Study EZH-105, at the investigator’s discretion, and after completing all 
study assessments and receiving at least 6 months of treatment with tazemetostat.  
Subjects who are enrolled in the study and do not complete all study assessments, or who 
do not transition to Study EZH-501 must have a post-treatment follow-up visit within 30 
days  
of the last dose of tazemetostat.  Subjects who permanently discontinue treatment with 
tazemetostat and do not transition to the EZH-501 study, will be followed for OS.  
Number of subjects 
Approximately 32 subjects will be enrolled to achieve 12 subjects who complete each part 
of the study (total of 24 completed subjects).  Subjects will complete either Part A or Part 
B.   
Subjects (both parts of study) who require a dose reduction during the first 19 days of 
treatment may be replaced.  Subjects who miss 2 or more consecutive tazemetostat doses 
during the first 19 days of treatment or miss more than 3 tazemetostat doses during the 
first 19 days of treatment may be replaced.  Subjects who miss 2 or more PK blood 
sample collections may be replaced. 


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Diagnosis and criteria 
for inclusion 
Subjects must meet all criteria to be eligible for enrollment in this study. 
Inclusion criteria 
 Male or female ≥ 18 years of age at time of consent 
 Has an Eastern Cooperative Oncology Group (ECOG) performance status 
of 0, 1, or 2 (Appendix 3) 
 Has the ability to understand informed consent and provided signed written 
informed consent 
Must meet one of the following criteria: 
 Has histologically confirmed diffuse large B-cell lymphoma (DLBCL), 
primary mediastinal B-cell lymphoma (PMBCL), marginal zone lymphoma 
(MZL), or mantle cell lymphoma (MCL) and have relapsed or refractory 
disease following at least 2 standard lines of systemic therapy, including 
alkylator/anthracycline (unless anthracycline–based chemotherapy is 
contraindicated)/anti-CD20-based therapy (R-CHOP: rituximab, 
doxorubicin, cyclophosphamide, vincristine, and prednisolone or 
prednisone, or equivalent) AND must be considered unable to benefit from 
intensification treatment with autologous hematopoietic stem cell 
transplantation (ASCT), as defined by meeting at least 1 of the following 
criteria : 
a. 
Relapsed following, or refractory to, previous ASCT 
b. Did not achieve at least a partial response (PR) to a standard 
salvage regimen (e.g., R-ICE; rituximab, ifosfamide, carboplatin, 
etoposide, or R-DHAP; rituximab, dexamethasone, cytarabine, 
cisplatin) 
c. 
Ineligible for intensification treatment due to age or significant 
comorbidity 
d. Ineligible for intensification treatment due to failure to mobilize an 
acceptable number of hematopoietic stem cells 
e. 
Refused intensification treatment and/or ASCT  
 
Note: Subjects with prior radiotherapy will be included; however, 
radiotherapy alone will not be considered a separate systemic treatment 
regimen 
OR 
    Has histologically confirmed FL, all grades. Subjects must have 
relapsed/refractory disease following at least 2 standard lines of systemic 
therapy, including at least 1 anti-CD20-based regimen (eg, rituximab), as 
well as alkalating agents (eg, cyclophosphamide or bendamustine), and 
have no curative option with other available therapies OR have a contra-
indication to their use.  Subjects with prior ASCT may be included. 
Transformed disease is permitted. 
 
NOTE: Subjects with prior radiotherapy will be included; however, 
radiotherapy alone will not be considered a separate systemic treatment 
regimen 
 
OR 


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 Has histologically and/or cytologically confirmed advanced or metastatic 
solid tumor that has progressed after treatment with approved therapies or 
for which there are no standard therapies available. 
 Must have evaluable or measurable disease 
 Has all prior treatment (i.e., chemotherapy, immunotherapy, radiotherapy) 
related clinically significant toxicities resolve to ≤ Grade 1 per NCI 
CTCAE, Version 4.03 or are clinically stable and not clinically significant, 
at time of consent 
 
 
 Time required between the last dose of the latest therapy and the first dose of study 
drug: 
Prior Therapy 
Time from Last Prior Therapy 
Chemotherapy: cytotoxic 
At least 21 days  
Chemotherapy: nitrosoureas 
At least 6 weeks  
Chemotherapy: non-cytotoxic  
(e.g., small molecule inhibitor) 
At least 14 days  
Monoclonal antibody (ies) 
At least 28 days  
Non-antibody immunotherapy 
(e.g., tumor vaccine) 
At least 42 days  
Radiotherapy (RT) 
At least 14 days for stereotactic radiosurgery  
At least 12 weeks for craniospinal, ≥50% 
radiation of pelvis, or total body irradiation prior 
to first dose of study drug 
Autologous hematopoietic cell 
infusion after high dose 
therapy 
At least 60 days  
Hematopoietic growth factor 
At least 14 days  
 
 
 Has adequate hematologic (bone marrow [BM] and coagulation factors), renal and 
hepatic function as defined by criteria below: 
System 
Laboratory Value 
Hematologic (BM Function) 
Hemoglobina 
≥9 g/dL 
Plateletsb 
 ≥75,000/mm3 (≥75 × 109/L) 
 
ANCc 
Lymphoma subjects:  ≥750/mm3 
(≥0.75 × 109/L) 
Solid tumor subjects: ≥1,000/mm3 
(≥1.0 x 109/L) 
Hematologic (Coagulation Factors) 
PT 
<1.5 ULN 
PTT 
<1.5 ULN 
Renal Function 
eGFRd 
≥ 50 mL/min/1.73 m2 


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Hepatic Function 
Conjugated bilirubin 
<1.5 × ULN 
ASTe 
<3 × ULN 
ALTe 
<3 × ULN 
Abbreviations:  ALT = alanine aminotransferase; ANC = absolute neutrophil 
count; AST = aspartate aminotransferase; BM = bone marrow; eGFR = estimated 
glomerular filtration rate; PT = prothrombin time; PTT = 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. Calculate eGFR per institutional standard formula 
e.  If attributed to tumor involvement, AST and ALT <5×ULN 
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. 
 
 Has a QT interval corrected by Fridericia's formula (QTcF) ≤480 msec 
 Subjects with a history of Hepatitis B or C are eligible on the condition that subjects 
have adequate liver function as defined by Inclusion Criterion No. 10 and are 
hepatitis B surface antigen negative and/or have undetectable HCV RNA. 
 Male subjects must refrain from donating sperm starting at the planned first dose of 
investigational product (IP) until 30 days following the last dose of IP 
 Male subjects with a female partner of childbearing potential must:   
a. 
Be vasectomized, or 
b. Remain abstinent or use a condom as defined in Section 8.3.10.4.2, starting at 
the planned first dose of IP until 30 days following the last dose of IP.  The 
reliability of sexual abstinence should be evaluated in relation to the duration 
of the clinical trial and the preferred and usual lifestyle of the subject.  
Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, or post-
ovulation methods) and withdrawal are not acceptable methods of 
contraception. 
 Female partners of male subjects who are of childbearing potential must also adhere 
to one of the following: 
a. 
Placement of an intrauterine device or intrauterine system. 
b. Established use of oral, injected, or implanted hormonal methods of 
contraception plus an additional barrier method. 
c. 
Progesterone-only oral contraception, where inhibition of ovulation is not the 
primary mode of action. 
 Women of childbearing potential:   
a. 
A woman is considered to be of childbearing potential if she is post 
menarcheal, has not reached a postmenopausal state (≥ 12 continuous months 
of amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus). 
b. Must agree to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive methods that result in a failure rate of < 1% per year starting at 
the planned first dose of IP until 30 days following the last dose of IP. 


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c. 
Examples of contraceptive methods with a failure rate of < 1% per year 
include bilateral tubal ligation, male sterilization, established, proper use of 
hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine 
devices, and copper intrauterine devices. 
d. Due to the potential of enzyme induction with tazemetostat, female subjects 
who use hormonal contraceptives should use an additional barrier method of 
birth control while on study treatment and for 30 days after discontinuation of 
study treatment. 
e. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the 
subject.  Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, or 
post-ovulation methods) and withdrawal are not acceptable methods of 
contraception. 
f. 
Barrier methods must always be supplemented with the use of a spermicide.  
 
Exclusion criteria 
 Is pregnant or nursing 
 Has active central nervous system (CNS) or leptomeningeal metastasis  
 Has had a prior malignancy other than the malignancies under study  
Exception: Subject who has been disease-free for 3 years, or a subject with a 
history of a completely resected non-melanoma skin cancer or successfully treated 
in situ carcinoma are eligible. 
 Has thrombocytopenia, neutropenia, or anemia of Grade ≥3 (per CTCAE 4.03 
criteria) and any prior history of myeloid malignancies, including myelodysplastic 
syndrome (MDS). 
            NOTE: Bone marrow aspirate/biopsy will be conducted following abnormal 
peripheral blood smear morphology assessment conducted by the local laboratory. 
Cytogenetic testing and DNA sequencing will be conducted following an 
abnormal result of bone marrow aspirate/biopsy. 
 Has a prior history of T-LBL/T-ALL 
 
 Has had major surgery within 3 weeks prior to enrollment 
NOTE: Minor surgery (e.g., minor biopsy, central venous catheter placement) is 
permitted within 3 weeks prior to enrollment. 
 Is unwilling to exclude grapefruit juice, Seville oranges, and grapefruit from the diet 
and all foods that contain those fruits from time of enrollment to the last dose of 
tazemetostat 
 Has cardiovascular impairment, history of congestive heart failure greater than 
NYHA Class II (see Appendix 4), uncontrolled arterial hypertension, unstable 
angina, myocardial infarction, or stroke within 6 months prior to the planned first 
dose of tazemetostat; or ventricular cardiac arrhythmia requiring medical treatment 
 Subjects taking medications that are known potent or moderate inducers/ inhibitors 
of CYP3A4 (including St. John’s Wort) 
 Has an active infection or recent history (<30 days before study drug administration) 
requiring systemic treatment 
 Is immunocompromised, including subjects with known human immunodeficiency 
virus (HIV) infection 
 Has known hypersensitivity to any of the components of IP. 
 Is unable to take oral medications, has a history of surgery that would interfere with 
the administration or absorption of oral medication, has malabsorption syndrome or 
any other uncontrolled gastrointestinal condition (e.g., nausea, diarrhea or vomiting) 
that might impair the bioavailability of IP 


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 Has an uncontrolled intercurrent illness including, but not limited to, uncontrolled 
infection, or psychiatric illness/social situations that would limit compliance with 
study requirements. 
 Is unwilling to adhere to contraception criteria from time of enrollment in study to at 
least 30 days after last dose of IP. 
 A history of bleeding (i.e., hemoptysis, hematuria, gastrointestinal blood loss, 
epistaxis, or others with greater than Grade 1 according to NCI CTCAE Version 
4.03) within 1 month prior to beginning therapy or any clinical indications of current 
active bleeding. 
 Clinical history, current alcohol (ethanol), or illicit drug use which, in the judgment 
of the investigator, will interfere with the subject’s ability to comply with the dosing 
schedule and protocol-specified evaluations.   
 Regular alcohol consumption averaging more than 7 drinks/week for women and 14 
drinks/week for men within 6 months of screening.  A drink is defined as follows: 
Alcohol 
1 Drink 
(12 g alcohol) 
7 Drinks/week 
(84 g alcohol) 
14 Drinks/week 
(168 g alcohol) 
Wine 
150 mL (5 ounces) 
1050 mL (35 ounces) 
2100 mL (70 
ounces) 
Beer 
360 mL (12 
ounces) 
2520 mL (84 ounces) 
5040 mL (168 
ounces) 
Distilled 
spirits 
80 proof 
45 mL (1.5 ounces) 
315 mL (10.5 ounces) 
630 mL (21 ounces) 
Test article 
Tazemetostat will be provided as oral tablets. 
Epizyme will provide each investigator with adequate supplies of tazemetostat. 
Dosage and 
administration 
Part A:  Subjects in Part A will receive tazemetostat 400 mg orally BID for 24 days 
starting on Day 1.  Tazemetostat dose will be increased to 800 mg BID starting on Day 
25.   
Part B: Subjects in Part B will receive tazemetostat 800 mg BID starting on Day 2.   
Treatment with tazemetostat for both parts in this study may continue for up to 6 months 
(24 weeks) or until disease progression, unacceptable toxicity, withdrawal of consent, or 
termination of the study by the sponsor.   
Other medications 
Fluconazole, Repaglinide, and Omeprazole 
Part A:  Subjects in Part A will receive fluconazole 400 mg once daily for 4 days on 
Days 16 through 19, inclusive 
Part B: Subjects in Part B will receive single doses of repaglinide 0.25 mg orally in the 
morning on Day 1 and Day 16.  Subjects in Part B also will receive omeprazole 20 mg in 
the morning on Day 1 and Days 16 through 19, inclusive.   
Duration of subject 
participation and 
duration of study: 
Up to 30 weeks:  Up to 4 weeks screening; 24 weeks dosing; and 2 weeks follow-up. 
Subjects who discontinue treatment will be followed for survival via email, mail, phone 
contact, or clinic visit for up to 2 years after end of treatment. 
 
Concomitant 
medications 
Documentation of all concomitant medication administered during study treatment will be 
recorded in the eCRF at each visit. 
Because there is a potential for interaction of tazemetostat with other concomitantly 
administered drugs through the cytochrome P450 system, over-the-counter medications, 
or alternative therapies must be recorded in the eCRF.  The investigator should be alerted 


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if the subject is taking any agent known to affect or with the potential to affect selected 
CYP450 isoenzymes. 
See Section 9 for additional information. 
Safety assessments 
Safety assessments will include adverse events (AEs), serious adverse events (SAEs), 
physical examinations (PEs), vital sign measurements, clinical safety laboratory 
evaluations, electrocardiograms (ECGs), ECOG performance status, and reasons for 
treatment discontinuation due to toxicity.  
The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI 
CTCAE; Version 4.03) will be used for grading clinical and laboratory AEs.   
The AE reporting period for a subject enrolled in the study begins when the subject 
provides informed consent and continues through 14 days after the last dose of study drug.  
All AEs that occur in enrolled subjects during the AE reporting period must be recorded, 
regardless of the relationship of the AE to study drug.  Any known untoward event that 
occurs beyond the AE reporting period that the investigator assesses as possibly related to 
study drug also should be recorded. 
Pharmacokinetics 
Serial blood samples will be collected throughout the study. For PK analysis, 
approximately 24 mL of blood will be obtained in Part A and 56 mL of blood will be 
obtained in Part B. 
See Section 8.3.6 for specific collection timepoints for each part of the study. 
All PK blood samples may be drawn from either a central venous catheter or a 
peripherally placed intravenous catheter. 
Plasma concentrations of all analytes will be determined by validated bioanalytical 
methods.  Plasma concentrations of all analytes will be listed for each subject and 
summarized by study part, treatment, day, and nominal time.  Standard summary statistics 
will be calculated (i.e., arithmetic mean, standard deviation (STD), median, minimum, 
and maximum) for each endpoint.   
Activity 
Antitumor activity will be assessed using the Lugano Classification (Cheson 2014, 
Appendix 1) for subjects with lymphoma, or RECIST v1.1 (Appendix 2) for subjects with 
solid tumors.  Overall response rate (ORR: complete response [CR] or partial response 
[PR]) and disease control rate (DCR: any CR or PR, or stable disease [SD] lasting 24 
weeks or longer from start of treatment with tazemetostat) will be determined. 
Study endpoints 
Primary endpoints  
Part A  
• 
AUC0-t, AUC0-8, AUC0-12, and Cmax of tazemetostat on Day 15 and Day 19. 
Part B  
• 
AUC0-t, AUC0-∞, and Cmax of repaglinide on Day 1 and Day 16. 
• 
 AUC0-t, AUC0-∞, and Cmax of omeprazole on Day 1 and Day 16. 
• 
 AUC0-t, AUC0-8, AUC0-12, and Cmax of tazemetostat on Day 16 and Day 19 
 
Secondary endpoints  
Part A 
• 
Tmax, and t1/2 of tazemetostat and AUC0-t, AUC0-8, Cmax, Tmax, and t1/2 of 
tazemetostat metabolites on Day 15 and Day 19. 
• 
Safety and tolerability parameters including AEs, clinical laboratory assessments, 
and vital signs. 
• 
Plasma fluconazole AUC0-8, Cmax, and Tmax on Day 19 
Part B  


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Page 10 of 116 
Confidential and Proprietary 
28 September 2018 
 
 
• 
Tmax, and t1/2 of repaglinide and AUC0-t, AUC0-∞, Cmax, Tmax, and t1/2 of repaglinide 
metabolites on Day 1 and Day 16.  The metabolite to repaglinide ratio for AUC0-∞ 
and AUC0-t on Day 1 and Day 16.  The plasma metabolite to repaglinide 
concentration ratios at 1, 2, 3, 5, and 7 hours after administration of repaglinide on 
Day 1 and Day 16. 
• 
Tmax, and t1/2 of omeprazole on Day 1 and Day 16.  AUC0-t, AUC0-∞, Cmax, Tmax, 
and t1/2 of 5-hydroxyomeprazole (5-OH-omeprazole) and omeprazole sulfone.  The 
5-OH-omeprazole to omeprazole and the omeprazole sulfone to omeprazole ratios 
for AUC0-∞ and AUC0-t on Day 1 and Day 16.  The plasma 5-OH-omeprazole to 
omeprazole and omeprazole sulfone to omeprazole concentration ratios at 1, 2, 3, 
5, and 7 hours after administration of omeprazole on Day 1 and Day 16. 
• 
Tmax, and t1/2 of tazemetostat on Day 16 and Day 19.  AUC0-t, AUC0-8, Cmax, 
Tmax, and t1/2 of tazemetostat metabolites on Day 16 and Day 19 
• 
Safety and tolerability parameters including AEs, clinical laboratory 
assessments, and vital signs. 
Parts A and B  
• 
Overall response rate (ORR: CR or PR) and disease control rate (DCR: CR or PR, 
or SD lasting 24 weeks or longer from start of treatment with tazemetostat) using 
Lugano Classification (Cheson 2014, Appendix 1) for subjects with lymphoma, or 
RECIST v1.1 for subjects with solid tumors (Appendix 2).  
Exploratory endpoints  
• 
Genotyping data for genes encoding CYP enzymes and transporters 
• 
Overall survival (OS)  
 
Statistical methods 
Four populations will be employed in the analyses of the study data: 
• 
The Intent-to-Treat (ITT) population will consist of all subjects who receive at least 
one dose of tazemetostat.  The ITT population will be used for summaries and 
analyses of the efficacy endpoints. 
• 
The Safety population will consist of all subjects who receive at least one dose of IP 
who have at least one post dose safety observation recorded.  The Safety population 
will be used for summaries and analyses of the safety and tolerability. 
• 
Pharmacokinetic (PK) population will include all subjects in the Safety population 
who have sufficient postdose samples collected to allow estimation of the PK 
parameters.  The PK population will be used for PK summaries and analyses. 
• 
The Pharmacogenomic (PGx) population will include all subjects in the PK 
population from whom PGx results are available. The PGx population will be used 
for summary of PK parameters by presence or absence of polymorphic genetic 
markers. 
 
Log-transformed PK parameters will be analyzed by an analysis of variance (ANOVA).  
The geometric least squares (adjusted) mean and associated 90% confidence interval (CI) 
for the test treatment to reference treatment ratio of adjusted geometric means will be 
provided after transformation of the results from the log-transformed analysis back to the 
original scale. 
Part A 
Descriptive statistics will be calculated for plasma concentrations and PK parameters of 
tazemetostat and its metabolites and fluconazole.  To evaluate the effect of fluconazole on 
the PK of tazemetostat, the ratio of adjusted geometric means and 90% CI for the test 
treatment (tazemetostat administered in combination with fluconazole) to the reference 
treatment (tazemetostat alone) for tazemetostat PK parameters will be calculated.     
Part B 


tazemetostat 
Protocol Number EZH-105 
Amendment 4.0 
 
 
 
                                                             
 
 
Epizyme, Inc. 
Page 11 of 116 
Confidential and Proprietary 
28 September 2018 
 
 
Descriptive statistics will be calculated for plasma concentrations and PK parameters for 
repaglinide and its metabolites, omeprazole, 5-OH-omeprazole, omeprazole sulfone, and 
tazemetostat and its metabolites.  To evaluate the effect of tazemetostat on the PK of 
repaglinide and omeprazole, the ratio of adjusted geometric means and 90% CI for the test 
treatment (repaglinide administered with omeprazole and steady-state tazemetostat) to the 
reference treatment (repaglinide administered with omeprazole) for repaglinide and 
omeprazole PK parameters will be calculated.  To evaluate the effect of increased gastric 
pH on the PK of tazemetostat, the ratio of adjusted geometric means and 90% CI for the 
test treatment (tazemetostat administered after 4 days of treatment with omeprazole) to the 
reference treatment (tazemetostat administered 1 hour before administration of repaglinide 
and omeprazole) for tazemetostat PK parameters will be calculated. 
Treatment-emergent adverse events (TEAE) will be summarized. Summaries of TEAEs 
will consist of the number and percentage of subjects reporting the AE by System Organ 
Class (SOC) and by preferred term.  TEAEs which occur more than once for a subject will 
be counted only once in the subject frequencies.  TEAEs with different CTCAE grades for 
a subject will be counted at the worst (highest) grade for the same SOC (likewise for 
preferred term).  TEAEs with different drug relationship for a subject will be counted at 
strongest relationship for the same SOC (likewise for preferred term.  TEAEs with 
missing relationship to study treatment will be counted as “related”.  TEAEs with missing 
CTCAE grade will be counted as Grade 3 (“severe”). 
TEAEs, SAEs, related TEAEs, related SAEs, ≥ Grade 3 AEs, TEAEs leading to 
withdrawal or treatment discontinuation, and TEAEs of special interest will be 
summarized overall and by study part according to SOC and preferred terms.  TEAEs will 
also be summarized in listings.   
Shifts from baseline in low, normal, and high classification and clinically significant 
findings for each parameter will be summarized by study part and overall at each planned 
post-baseline visit. 
Physical examination, vital signs, ECG, and ECOG performance status will be 
summarized by study part and overall.   
Response will be based on Lugano Classification (Cheson 2014) for subjects with 
lymphoma, or RECIST v1.1 for subjects with solid tumors. ORR (CR or PR) will be 
summarized along with an exact 90% CI. DCR (CR or PR, or SD lasting 24 weeks or 
longer since start of treatment) will be summarized similarly. 
OS will be calculated using the Kaplan-Meier method. If there are a sufficient number of 
deaths at the time of the analysis, median OS, first and third quartiles, and 90% CI 
(Brookmeyer-Crowley method) will be summarized. 


tazemetostat 
Protocol Number EZH-105 
Amendment 4.0 
 
 
 
 
 
 
 
Epizyme, Inc. 
Page 12 of 116 
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Table 1: Schedule of Assessments and Procedures: Part A 
Visit Description / Study Period 
Screeninga,b 
Cycle 1c 
 
Cycle 2, 
Day 1 
Cycles  
2 – 6c 
End-of-
Studyd 
Study Days 
-28 to -1 
1 
2 ˗ 14 
15 
16 ˗ 18 
19 
25 
 
1 
 
Procedures/Assessments  
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
Demographicse 
X 
 
 
 
 
 
 
 
 
 
Medical History/Current Medical Conditionsf 
X 
 
 
 
 
 
 
 
 
X 
Prior & concomitant medications 
 
Throughout the study 
Complete PE 
X 
 
 
 
 
 
 
 
X 
X 
Symptom-directed PE 
 
X 
 
X 
 
X 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
Vital signsg 
X 
X 
 
X 
 
X 
 
 
X 
X 
ECOG performance status 
X 
X 
 
X 
 
X 
 
 
X 
X 
12-lead ECGsh 
X 
 
 
X 
 
X 
 
 
X 
X 
Safety laboratory testsi,j,t 
X 
 
 
X 
 
X 
 
 
X 
X 
Coagulation profilek 
X 
If clinically indicated 
 
 
X 
Pregnancy testingl 
X 
 
 
 
 
 
 
 
X 
X 
PGx blood samplem 
X 
 
 
 
 
 
 
 
 
 
PK blood samplesn 
 
 
 
X 
 
X 
 
 
 
X 
Archival tumor tissueo 
X 
 
 
 
 
 
 
 
 
 
Optional tumor tissue biopsyp 
X 
 
 
 
 
 
 
X 
 
 
Optional chest ultrasounds 
X 
 
 
 
 
 
 
 
X 
X 
Tumor assessments: PET, CT, bone marrow, or 
otherq,t 
X 
 
 
 
 
 
 
 
X 
 
AEs/SAEs 
 
Throughout the study 
Tazemetostat 400 mg BID 
 
X 
X 
X 
X 
Xq 
 
 
 
 
Fluconazole 400 mg  
 
 
 
 
X 
Xq 
 
 
 
 
Tazemetostat 800 mg BIDr 
 
 
 
 
 
 
X 
 
X 
 
Survival status and subsequent anti-cancer therapys 
 
 
 
 
 
 
 
 
 
X 
Abbreviations:  AE = adverse event; BID = twice daily; CT = computed tomography; ECG = electrocardiograms; ECOG = Eastern Cooperative Oncology Group; h = hour; HR = 
heart rate; PGx = pharmacogenomics; PE = physical examination; PET = positron emission tomography; PK = pharmacokinetic; SAE = serious adverse event 
  


tazemetostat 
Protocol Number EZH-105 
Amendment 4.0 
 
 
 
 
 
 
 
Epizyme, Inc. 
Page 13 of 116 
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a. 
Screening:  Screening Period extends from Day -28 to Day -1. 
b. Pre-Study Procedures and tumor assessment must be performed within 28 days before first dose of study treatment. 
c. 
Each cycle is 28 days in length. 
d. End of Study:  An End-of-Study visit will be conducted within 30 days (±3 days) after last dose of IP, prior to enrollment in Study EZH-501, or prior to the 
start of a new treatment or therapy, whichever occurs first.  The post-treatment assessments will be required and, in the event of a continuing AE, the subject 
will be asked to return for follow-up until the AE has resolved or is deemed to be continuing indefinitely. End of study assessments will be conducted 
including safety, PK and response. A 3 mL blood sample will be required for end of study PK assessments. 
e. 
Demographics:  Date of birth, gender, ethnicity, and race must be recorded.   
f. 
Medical History/Current Medical Conditions:  General and disease-specific medical history including a history of past and current medical conditions, 
full history of the course of the subject’s malignancy including primary diagnosis. Stage and date, and information on prior antitumor therapies including 
response to prior therapies must be recorded at Screening.   
g. Vital Signs:  Blood pressure (BP), heart rate (HR), and temperature (T) must be measured after the subject has been sitting for 5 minutes at screening and at 
regular intervals during treatment. 
h. ECG:  12-lead ECG reading must be performed at Screening and Days 15 and 19, Day 1 of Cycles 2 – 6, and End of Study.  A single ECG will be recorded 
unless there is an abnormality. If an abnormality is detected, then ECGs will be recorded in triplicate at least 2 minutes apart.   
i. 
Safety Laboratory Tests to include hematology and serum chemistry:  Hematology includes complete blood count with differential and absolute neutrophil 
count (differential values should be recorded as absolute counts whenever possible) and assessment of peripheral blood smear morphology. If peripheral 
blood smear morphology is abnormal, then conduct bone marrow aspirate with cytogenic testing to closely monitor patients with cytogenic abnormalities 
known to be associated with MDS (9del 5q, chr 7, abn, etc.) and MPN (e.g. JAK2 V617F, etc.) as observed with cytogenetic testing and DNA sequencing. 
Bone marrow aspirate/biopsy will be conducted following an abnormal peripheral blood smear morphology assessment conducted by the local laboratory. 
Cytogenetic testing and DNA sequencing will be conducted following an abnormal result of bone marrow aspirate/biopsy. See Section 8.3.9 for further 
details.  
j. 
Chemistries include: alkaline phosphatase, ALT, AST, conjugated (direct) bilirubin, and total bilirubin, electrolytes, Blood urea/blood urea nitrogen, 
creatinine, albumin, calcium, magnesium, glucose, phosphorus, triglycerides, and total protein.  
k. Coagulation Profile:  Coagulations tests include: prothrombin time (PT), partial thromboplastin time (PTT). 
l. 
Pregnancy Testing:  The screening test can be either urine or serum and must have been completed within 28 days of the first dose of study drug.  
Subsequent testing on the first day of each cycle (Cycles 2 – 6) 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. 
m. PGx:  A single 10 mL whole blood will be collected at any time during the screening period.   
n. PK:  Blood samples (1 mL) for analysis of tazemetostat and its metabolites will be collected at the following time points on Day 15: predose (within 30 
minutes prior to dose), 0.5, 1, 2, 3, 4, 6, and 8 hours postdose.  Blood samples (2 mL) for analysis of tazemetostat and its metabolites and fluconazole will be 
collected at the following time points on Day 19: predose (within 30 minutes prior to dose), 0.5, 1, 2, 3, 4, 6, and 8 hours postdose.  All PK blood samples 
may be drawn from either a central venous catheter or a peripherally placed intravenous catheter.  Allowable windows for collection of PK blood samples 
are ± 5 minutes for sample timepoints ≥ 0.5 and ≤ 4 and ± 30 minutes for sample timepoints > 5 hours. Subjects will check into the clinic on the morning of 
each PK sampling day and will be required to stay until the final sample is obtained and either tazemetostat and/or fluconazole have been dispensed.   
o. Archival tumor tissue (block or slides) is requested for molecular characterization, e.g., detection of somatic mutations and/or candidate biomarkers of 
response. 


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Protocol Number EZH-105 
Amendment 4.0 
 
 
 
 
 
 
 
Epizyme, Inc. 
Page 14 of 116 
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p. Optional tumor tissue biopsies may be obtained prior to and after initiation of treatment with tazemetostat.  An optional lymph node, core-needle biopsy, or 
bone marrow biopsy will be performed during the screening period and on Day 1 of Cycle 2,+ or - 14 days (must be done between Day 14 of Cycle 1 and 
Day 14 of Cycle 2).  
q. Disease (Tumor) Assessment:  Tumor assessments by disease-appropriate standard criteria (Lugano Classification [Cheson 2014, Appendix 1] for 
lymphoma or RECIST v1.1 [Appendix 2] for solid tumors) using PET (lymphoma only), CT, MRI of known sites of disease as clinically indicated.  
Assessments should be completed within 28 days of Study Day 1 and at the end of Cycle 2 (8 weeks), Cycle 4 (16 weeks), and Cycle 6 (24 weeks) (± 7 
days).   
r. 
Tazemetostat Administration:  On the morning of Day 19, tazemetostat and fluconazole will be taken together and no more than 5 minutes apart.  The 
tazemetostat dose will be increased to 800 mg BID administered continuously in 28-day cycles starting on Day 25, following sufficient wash-out of 
fluconazole.  An adequate supply of tazemetostat should be dispensed to subjects to take at home until the next scheduled clinic day. 
s. 
OS is to be assessed every 3 months following the end-of-treatment visit for up to 2 years (may be completed via phone, mail, email, or clinic visit).  All 
anti-cancer therapies will be collected.  
t. 
An optional chest ultrasound may be performed every 8 weeks at the Investigator’s discretion to monitor for early signs of T-LBL/T-ALL.


tazemetostat 
Protocol Number EZH-105 
Amendment 4.0 
 
 
 
 
 
 
 
Epizyme, Inc. 
Page 15 of 116 
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Table 2: Schedule of Assessments and Procedures: Part B 
Visit Description / Study Weeks 
Screeninga,b 
Cycle 1c 
Cycle  2, 
Day 1 
Cycles 2 – 
6c 
End-of-
Studyd 
Study Days 
-28 to -1 
1 
2 ˗15 
16 
17 & 
18 
19 
20 ˗ 
28 
 
1 
 
Procedures/Assessments 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
Demographicse 
X 
 
 
 
 
 
 
 
 
 
Medical History/Current Medical Conditionsf 
X 
 
 
 
 
 
 
 
 
X 
Prior and concomitant medications 
 
Throughout the study 
Complete PE 
X 
 
 
 
 
 
 
 
X 
X 
Symptom-directed PE 
 
X 
 
X 
 
X 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
Vital signsg 
X 
X 
 
X 
 
X 
 
 
X 
X 
ECOG performance status 
X 
X 
 
X 
 
X 
 
 
X 
X 
12-lead ECGsh 
X 
 
 
X 
 
X 
 
 
X 
X 
Safety Laboratory testsi 
X 
 
 
X 
 
X 
 
 
X 
X 
Coagulation profilej 
X 
If clinically indicated 
X 
Pregnancy testingk 
X 
 
 
 
 
 
 
 
X 
X 
PGx blood samplel 
 
X 
 
 
 
 
 
 
 
 
PK blood samplesm,d 
 
X 
 
X 
 
X 
 
 
 
X 
Archival tumor tissuen 
X 
 
 
 
 
 
 
 
 
 
Optional tumor tissue biopsyo 
X 
 
 
 
 
 
 
X 
 
 
Optional chest ultrasoundt 
X 
 
 
 
 
 
 
 
X 
X 
Tumor assessments: PET, CT, bone marrow, or 
otherp,d 
X 
 
 
 
 
 
 
 
X 
 
AEs/SAEs 
 
Throughout the study 
Tazemetostat 800 mg BIDr 
 
 
X 
X 
X 
X 
X 
 
X 
 
Repaglinide 0.25 mg 
 
Xq 
 
Xq 
 
 
 
 
 
 
Omeprazole 20 mg 
 
Xq 
 
Xq 
X 
X 
 
 
 
 


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Protocol Number EZH-105 
Amendment 4.0 
 
 
 
 
 
 
 
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Page 16 of 116 
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Visit Description / Study Weeks 
Screeninga,b 
Cycle 1c 
Cycle  2, 
Day 1 
Cycles 2 – 
6c 
End-of-
Studyd 
Study Days 
-28 to -1 
1 
2 ˗15 
16 
17 & 
18 
19 
20 ˗ 
28 
 
1 
 
Procedures/Assessments 
 
 
 
 
 
 
 
 
 
 
Survival status and subsequent anti-cancer 
therapys 
 
 
 
 
 
 
 
 
 
X 
Abbreviations:  AE = adverse event; BID = twice daily; CT = computed tomography; ECG = electrocardiograms; ECOG = Eastern Cooperative Oncology 
Group; h = hour; PGx = pharmacogenomics; PE = physical examination; PET = positron emission tomography; PK = pharmacokinetic; SAE = serious adverse 
event 
 
a. 
Screening:  Screening Period extends from Day -28 to Day -1. 
b. Pre-Study procedures and tumor assessment must be performed within 28 days before first dose of study treatment. 
c. 
Each cycle is 28 days in length 
d. End of Study:  An End-of-Study visit will be conducted within 30 days (±3 days) after last dose of IP, prior to enrollment in Study EZH-501, or prior to the 
start of a new treatment or therapy, whichever occurs first.  The post-treatment assessments will be required and, in the event of a continuing AE, the subject 
will be asked to return for follow-up until the AE has resolved or is deemed to be continuing indefinitely. End of study assessments will be conducted 
including safety, PK and response. A 3 mL blood sample will be required for end of study PK assessments. 
e. 
Demographics:  Date of birth, gender, ethnicity, and race must be recorded. 
f. 
Medical History/Current Medical Conditions:  General and disease-specific medical history including a history of past and current medical conditions, 
full history of the course of the subject’s malignancy including primary diagnosis. Stage and date, and information on prior antitumor therapies including 
response to prior therapies must be recorded at Screening. 
g. Vital Signs:  Blood pressure (BP), heart rate (HR), and temperature (T) must be measured after the subject has been sitting for 5 minutes at screening and at 
regular intervals during treatment. 
h. ECG:  12-lead ECG reading must be performed at Screening and Days 16 and 19, Day 1 of Cycles 2 – 6, and End of Study.  A single ECG will be recorded 
unless there is an abnormality. If an abnormality is detected then ECGs will be recorded in triplicate at least 2 minutes apart.   
i. 
Safety Laboratory Tests:  Hematology includes complete blood count with differential and absolute neutrophil count (differential values should be 
recorded as absolute counts whenever possible) and assessment of peripheral blood smear morphology. If peripheral blood smear morphology is abnormal, 
then conduct bone marrow aspirate with cytogenic testing to closely monitor patients with cytogenic abnormalities known to be associated with MDS (9del 
5q, chr 7, abn, etc.) and MPN (e.g. JAK2 V617F, etc.) observed with cytogenetic testing and DNA sequencing. Chemistries include: alkaline phosphatase, 
ALT, AST, conjugated (direct) bilirubin, and total bilirubin, electrolytes, Blood urea/blood urea nitrogen, creatinine, albumin, calcium, magnesium, glucose, 
phosphorus, triglycerides, and total protein. 
j. 
Coagulation Profile:  Coagulations tests include: prothrombin time (PT), partial thromboplastin time (PTT). 
k. Pregnancy Testing:  The screening test can be either urine or serum and must have been completed within 28 days of the first dose of study drug.  
Subsequent testing on the first day of each cycle (Cycles 2 – 6) 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. 
l. 
PGx:  A single 10 mL whole blood will be collected at any time during the screening period.   


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Protocol Number EZH-105 
Amendment 4.0 
 
 
 
 
 
 
 
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m. PK:  Day 1: Blood samples (2 mL) for analysis of plasma repaglinide and its metabolites, omeprazole, 5-OH-omeprazole, and omeprazole sulfone will be 
collected at the following time points on Day 1:  predose (within 90 minutes prior to dose) and 0.25, 0.5, 1, 2, 3, 5, and 7 hours postdose.  Day 16:  Blood 
samples (1 mL) for analysis of plasma tazemetostat and metabolites will be collected predose (within 30 minutes prior to dose) and 0.5, and 1 h after 
administration of tazemetostat.  Blood samples (2 mL) for analysis of repaglinide and its metabolites, omeprazole, 5-OH-omeprazole, and omeprazole 
sulfone will be collected predose (within 30 minutes prior to tazemetostat) and 1.25 and 1.5 h after tazemetostat administration (0.25 and 0.5 h after 
repaglinide and omeprazole administration).  Blood samples (3 mL) for analysis of tazemetostat and its metabolites, repaglinide and its metabolite, 
omeprazole, 5-OH-omeprazole, and omeprazole sulfone will be collected 2, 3, 4, 6, and 8 hours after tazemetostat administration (1, 2, 3, 5, and 7 hours after 
repaglinide and omeprazole administration).  Day 19:  Blood samples (1 mL) for analysis of tazemetostat and its metabolites will be collected predose 
(within 30 minutes prior to dose) and 0.5, 1, 2, 3, 4, 6, and 8 hour postdose.  All PK blood samples may be drawn from either a central venous catheter or a 
peripherally placed intravenous catheter.    Allowable windows for collection of PK blood samples are ± 5 minutes for sample timepoints ≥ 0.25 and ≤ 4 and 
± 30 minutes for sample timepoints > 5 hours. 
n. Archival tumor tissue (block or slides) is requested for molecular characterization, e.g., detection of somatic mutations and/or candidate biomarkers of 
response. 
o. 
Optional tumor tissue biopsies may be obtained before and after initiation of treatment with tazemetostat.  An optional lymph node, core-needle biopsy, or 
bone marrow biopsy will be performed during the screening period and on Day 1 of Cycle 2, + or – 14 days (must be done between Day 14 of Cycle 1 and 
Day 14 of Cycle 2).  
p. Disease (Tumor) Assessment:  Tumor assessments by disease-appropriate standard criteria (Lugano Classification [Cheson 2014, Appendix 1] for 
lymphoma or RECIST v1.1 (Appendix 2) for solid tumors) using PET (lymphoma only), CT, MRI of known sites of disease as clinically indicated. 
Assessments should be completed within 28 days of study Day 1 and at the end of Cycle 2 (8 weeks), Cycle 4 (16 weeks), and Cycle 6 (24 weeks) (± 7 
days).   
q. Repaglinide and omeprazole administration:  repaglinide and omeprazole will be taken together, no more than 5 minutes apart. 
r. 
Tazemetostat:  An adequate supply of tazemetostat should be dispensed to the subject to take at home until the next scheduled clinic day. 
s. 
OS is to be assessed every 3 months following the End-of-Treatment visit for up to 2 years (may be completed via phone, mail, email, or clinic visit). All 
anti-cancer therapies will be collected.  
t. 
An optional chest ultrasound may be performed every 8 weeks at the investigator’s discretion to monitor for early signs of T-LBL/T-ALL. 
 


tazemetostat 
Protocol Number EZH-105 
Amendment 4.0 
 
 
 
 
 
 
Epizyme, Inc. 
Page 18 of 116 
Confidential 
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Table 3: 
Timing Allowance Windows for Vital Sign and ECG Measurements 
Vital Signs 
 
Timepoint 
Tolerance Window 
0 hour 
-60 min to 0 hour 
 
Pharmacokinetic Sampling 
 
Timepoint 
Tolerance Window 
0 hour 
-90, 60, or 30 min to 0 hour (depending on Part A or 
Part B and day of sampling) 
>0 hour – 4 hour 
-5 minutes/+ 5 minutes 
5 hour – 8 hour 
-30 minutes/+ 30 minutes 
 
ECG 
 
Timepoint 
Tolerance Window 
0 hour 
-60 min to 0 hour 
 


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Protocol Number EZH-105 
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Epizyme, Inc. 
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TABLE OF CONTENTS 
 
1. 
SYNOPSIS ...................................................................................................................2 
TABLE OF CONTENTS ...............................................................................................................19 
LIST OF TABLES .........................................................................................................................23 
LIST OF FIGURES .......................................................................................................................24 
LIST OF ABBREVIATIONS ........................................................................................................25 
2. 
BACKGROUND AND RATIONALE .......................................................................28 
2.1. Background .................................................................................................................28 
2.2. Lymphoma ..................................................................................................................28 
2.3. Solid Tumors ..............................................................................................................29 
2.4. Tazemetostat ...............................................................................................................30 
2.4.1 
Preclinical Pharmacology ...............................................................................30 
2.4.2 
Lymphomas ....................................................................................................31 
2.4.3 
Solid Tumors ..................................................................................................33 
2.4.4 
In Vitro Aqueous Solubility............................................................................36 
2.4.5 
Nonclinical Pharmacokinetics ........................................................................36 
2.4.6 
Clinical Pharmacokinetics ..............................................................................37 
2.4.7 
Clinical Experience .........................................................................................40 
2.5. Study and Dose Rationale ...........................................................................................41 
2.5.1 
Study Rationale ...............................................................................................41 
2.5.2 
Dose Rationale ................................................................................................42 
2.6. Benefit: Risk Assessments ..........................................................................................43 
2.6.1 
Animal Toxicology .........................................................................................43 
2.6.2 
Photo-Reactive Potential ................................................................................44 
2.6.3 
Metabolism and Transporters .........................................................................44 
2.6.4 
Anticipated Safety Profile ...............................................................................44 
2.7. Good Clinical Practice (GCP) ....................................................................................45 
3. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................46 
4. 
STUDY DESIGN .......................................................................................................48 
4.1. Study Sites ..................................................................................................................48 
4.2. Overview of Study Design ..........................................................................................48 


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4.3. Study Schema for the First 28 Days of Treatment .....................................................50 
4.4. Rules for Suspension of Enrollment ...........................................................................51 
5. 
STUDY POPULATION .............................................................................................52 
5.1. Target Population ........................................................................................................52 
5.2. Inclusion Criteria ........................................................................................................52 
5.3. Exclusion Criteria .......................................................................................................56 
6. 
STUDY MEDICATIONS ..........................................................................................58 
6.1. Investigational Product - Tazemetostat ......................................................................58 
6.1.1 
Preparation, Handling and Storage of Investigational Product ......................58 
6.1.2 
Procurement of Investigational Product .........................................................58 
6.1.3 
Accountability .................................................................................................59 
6.2. Other Medications ......................................................................................................59 
6.2.1 
Fluconazole .....................................................................................................59 
6.2.2 
Repaglinide .....................................................................................................60 
6.2.3 
Omeprazole .....................................................................................................60 
6.2.4 
Procurement of Other Medications .................................................................60 
6.3. Dosage and Administration ........................................................................................60 
6.3.1 
Tazemetostat ...................................................................................................60 
6.3.2 
Fluconazole .....................................................................................................61 
6.3.3 
Repaglinide .....................................................................................................61 
6.3.4 
Omeprazole .....................................................................................................61 
7. 
STUDY TREATMENT ..............................................................................................62 
7.1. Treatment Assignment ................................................................................................62 
7.2. Restrictions During Study Treatment .........................................................................62 
7.3. Dose Modifications:  Criteria for Retreatment, Temporary Discontinuation 
of Treatment, Dose Reduction, and Resumption of Treatment ......................62 
7.4. Continuation of Treatment ..........................................................................................65 
7.5. Treatment Compliance ................................................................................................65 
7.6. Treatment of Overdose ...............................................................................................65 
7.7. Tazemetostat Duration of Treatment ..........................................................................65 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................66 
8.1. Consent .......................................................................................................................66 
8.2. Screening Assessments ...............................................................................................66 


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8.2.1 
Demographics and Medical History ...............................................................66 
8.3. Study Assessments......................................................................................................66 
8.3.1 
Physical Examinations ....................................................................................67 
8.3.2 
Electrocardiograms (ECGs) ............................................................................68 
8.3.3 
Optional Chest Ultrasound .............................................................................68 
8.3.4 
End of Study Assessments ..............................................................................68 
8.3.5 
Disease Assessment ........................................................................................68 
8.3.6 
Pharmacokinetics ............................................................................................68 
8.3.7 
Pharmacogenomics (PGx) ..............................................................................69 
8.3.8 
Tumor Tissue Collection ................................................................................70 
8.3.9 
Clinical Laboratory Assessments ...................................................................70 
8.3.10 
Pregnancy .......................................................................................................72 
9. 
CONCOMITANT MEDICATIONS ..........................................................................75 
9.1. Permitted Medication(s) .............................................................................................75 
9.2. Medications to be used with Caution ..........................................................................75 
9.3. Prohibited Medication(s) ............................................................................................76 
9.3.1 
All Subjects .....................................................................................................76 
9.3.2 
Part A ..............................................................................................................77 
9.3.3 
Part B ..............................................................................................................77 
9.4. Non-Drug Therapies ...................................................................................................78 
10. 
WITHDRAWAL AND REPLACEMENT OF SUBJECTS ......................................79 
10.1. 
Withdrawal from Treatment ...........................................................................79 
10.1.1 
Withdrawal of Subjects from Study ...............................................................79 
10.2. 
Survival Follow-Up ........................................................................................79 
10.3. 
Subsequent Therapy After Discontinuation of Study Treatment ...................80 
10.4. 
Evaluation of Response to Subsequent Anti-Cancer Therapy ........................80 
10.5. 
Replacement of Subjects .................................................................................80 
11. 
SAFETY .....................................................................................................................81 
11.1. 
Safety Monitoring ...........................................................................................81 
11.2. 
Adverse Event Definition ...............................................................................81 
11.2.1 
Adverse Events ...............................................................................................81 
11.2.2 
Serious Adverse Events ..................................................................................81 


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11.3. 
Laboratory Abnormalities ...............................................................................82 
11.4. 
Other Safety Assessment Abnormalities ........................................................83 
11.5. 
Adverse Events of Special Interest (AESIs) ...................................................83 
11.5.1 
T-LBL/T-ALL ................................................................................................83 
11.5.2 
MDS/AML/MPN ............................................................................................85 
11.5.3 
Other Identified Risks .....................................................................................86 
11.5.4 
Tazemetostat Safety Committee .....................................................................86 
11.6. 
Grading and Severity ......................................................................................86 
11.7. 
Relationship Categorization ............................................................................87 
11.7.1 
Assessing Relationship to Study Treatment ...................................................87 
11.8. 
Outcome Categorization .................................................................................88 
11.9. 
Timeframe for Reporting AEs and SAEs .......................................................88 
11.10. 
Reporting of SAEs ..........................................................................................89 
11.10.1 
Regulatory Authorities, IRB/EC, and Central Ethics Committees 
(CEC) ..............................................................................................................89 
12. 
DATA MANAGEMENT ...........................................................................................91 
12.1. 
Coding.............................................................................................................91 
13. 
STATISTICAL METHODS .......................................................................................92 
13.1. 
Hypotheses ......................................................................................................92 
13.2. 
Study Design Considerations ..........................................................................92 
13.2.1 
Determination of Sample Size ........................................................................92 
13.2.2 
Sample Size Re-Estimation ............................................................................92 
13.3. 
Data Analysis Considerations .........................................................................93 
13.3.1 
Analysis Populations ......................................................................................93 
13.3.2 
Interim Analyses .............................................................................................93 
13.3.3 
Key Elements of the Analysis Plan ................................................................93 
13.4. 
Pharmacogenomic Analyses (PGx) ................................................................95 
13.5. 
Efficacy Analyses ...........................................................................................95 
13.6. 
Safety Analyses ..............................................................................................96 
13.6.1 
Extent of Exposure .........................................................................................96 
13.6.2 
Adverse Events ...............................................................................................96 
13.6.3 
Clinical Laboratory Evaluation .......................................................................97 
13.6.4 
Other Safety Measures ....................................................................................98 


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13.7. 
Pharmacokinetic Analyses ..............................................................................98 
13.7.1 
Plasma Pharmacokinetics ...............................................................................98 
14. 
STUDY CONDUCT CONSIDERATIONS .............................................................100 
14.1. 
Posting of Information on Publicly Available Clinical Trial Registers ........100 
14.2. 
Regulatory and Ethical Considerations ........................................................100 
14.2.1 
Institutional Review Board (IRB)/ Ethics Committee (EC)/Central 
Ethics Committee (CEC) ..............................................................................100 
14.2.2 
Informed Consent Process ............................................................................101 
14.3. 
Subject Confidentiality and Access to Source Documents/Data ..................101 
14.4. 
Study Monitoring ..........................................................................................102 
14.5. 
Protocol Deviations ......................................................................................102 
14.6. 
Protocol Amendment ....................................................................................103 
14.7. 
Suspension or Termination of Study ............................................................103 
15. 
ADMINISTRATIVE PROCEDURES .....................................................................104 
15.1. 
Recording and Access and to Study Records ...............................................104 
15.2. 
Case Report Forms .......................................................................................104 
15.3. 
Quality Assurance and Quality Control ........................................................105 
15.4. 
Data Quality Assurance ................................................................................105 
15.5. 
Confidentiality ..............................................................................................105 
15.6. 
Audit/Inspection ...........................................................................................106 
15.7. 
Record Retention ..........................................................................................106 
15.8. 
Provision of Study Results and Publication..................................................106 
16. 
REFERENCES .........................................................................................................107 
APPENDIX 1:  LUGANO CLASSIFICATION FOR RESPONSE ASSESSMENT .................111 
APPENDIX 2:  RESPONSE EVALUATION CRITERIA IN SOLID TUMORS......................114 
APPENDIX 3: ECOG PERFORMANCE STATUS ...................................................................115 
APPENDIX 4: NYHA FUNCTIONAL CLASSIFICATION SYSTEM ....................................116 
 
LIST OF TABLES 
Table 1: 
Schedule of Assessments and Procedures: Part A ......................................................12 
Table 2: 
Schedule of Assessments and Procedures: Part B ......................................................15 
Table 3: 
Timing Allowance Windows for Vital Sign and ECG Measurements .......................18 


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Table 4:   Summary of Tazemetostat Pharmacokinetic Parameters After Administration 
Fasted or Immediately After a High-Fat Breakfast in Study E7438-G000-101 
(n=12) .........................................................................................................................38 
Table 5:   Fed: Fasted Geometric Mean Ratio and 90% Confidence Interval for 
Tazemetostat Cmax and AUC0-∞ in Study E7438-G000-101 .......................................38 
Table 6:  
Summary of Midazolam Pharmacokinetic Parameters After Administration 
Alone (Day -1) or with Tazemetostat 800 mg BID for 15 Days (Day 15) in 
Study E7438-G000-101 (n=12) ..................................................................................39 
Table 7: 
Tazemetostat Dose Reduction and Interruption Instructions ......................................64 
Table 8: 
Medications That Are Substrates for CYP3A, CYP2C8, CYP2C9, 
CYP2C19, and CYP2D6 That Have a Narrow Therapeutic Range ...........................76 
Table 9: 
Classification of Medications That Are Inhibitors or Inducers of CYP 
Enzymes ......................................................................................................................78 
 
LIST OF FIGURES 
Figure 1 
Antitumor Effects of Tazemetostat in KARPAS 422 Human DLBCL 
Xenograft Model in Athymic Mice ............................................................................32 
Figure 2 
H3K27Me3 Inhibition in KARPAS-422 Human DLBCL Xenografts in 
Athymic Mice Administered Tazemetostat EPZ-6438 for 7 Days .............................33 
Figure 3: 
Antitumor Effect of Tazemetostat Against 4 Human NSCLC Xenografts 
Models with SMARCA2/SMARCA4 Loss ................................................................34 
Figure 4 
Antitumor Effect of Tazemetostat (E7438) Against the G401 Human MRT 
Xenograft Model in SCID Mice .................................................................................35 
 
 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ADME 
Absorption, distribution, metabolism, and excretion 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
ANOVA 
Analysis of variance 
ASCO 
American Society of Clinical Oncology 
ASCT 
autologous hematopoietic stem cell transplantation 
AST 
Aspartate aminotransferase 
ATC 
Anatomical-Therapeutic-Chemical 
AUC 
Area under the concentration-time curve 
AUC0-8 
Area under the concentration-time curve from time 0 to 8 hours after administration 
AUC0-12 
Area under the concentration-time curve from time 0 to 12 hours after administration 
AUC0-t 
Area under the concentration-time curve from time 0 to the last quantifiable 
concentration 
AUC0-∞ 
Area under the concentration-time curve from time 0 extrapolated to infinity 
BAP1 
BRCA1 associated protein 1 
BID 
Twice daily 
BM 
Bone marrow 
CI 
Confidence interval 
Cmax 
Maximum plasma concentration 
CNS 
Central nervous system 
CR 
Complete response 
CSR 
Clinical Study Report 
CT 
Computed tomography 
CYP 
Cytochrome 
DCR 
Disease control rate 
DDI 
Drug-drug interaction 
DLBCL 
Diffuse large B-cell lymphoma 
DNA 
Deoxyribonucleic acid 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
eGFR 
Glomerular filtration rate 
Emax 
Maximum effect 
EPZ-6438, E7438 
Tazemetostat 
EPZ-6930, ER-897387 
Desethyl metabolite of tazemetostat 
EU CT Dir 
European Union Clinical Trial Directive 
EZH-2 
Enhancer of zeste homolog 
FDA 
Food and Drug Administration 
FL 
Follicular lymphoma 
GCP 
Good Clinical Practice 
H3K27 
Lysine 27 of histone H3 
H3K27me3 
H3K27 trimethylation 
HATs 
Histone acetyl transferases 
HbA1c 
Hemoglobin A1c 
H2AK119 
Histone H2A lysine 119 


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Abbreviation 
Definition 
HMT 
Histone methyl transferases 
hr 
Hour 
HR 
Heart rate 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
INI1 
Integrase interactor 1 
IP 
Investigational product 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
LNH 
Low, normal, high 
MCL 
Mantle cell lymphoma 
MDS 
Myelodysplastic syndrome 
MLL2 
Mixed lineage leukemia protein 2 
MPN 
Myeloproliferative disorder 
MRI 
Magnetic resonance imaging 
MSDS  
Material Safety Data Sheet 
MTD 
Maximum tolerated dose 
MZL 
Marginal zone lymphoma 
NA 
Not applicable 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NHL 
Non-Hodgkin lymphoma 
NYHA 
New York Heart Association 
ORR 
Overall response rate 
OS 
Overall survival 
PD 
Pharmacodynamic or progressive disease 
PE 
Physical exam 
PET 
Positron emission tomography 
PgP 
P-glycoprotein 
PGx 
Pharmacogenetics 
PK 
Pharmacokinetics 
PMBCL 
Primary mediastinal B-cell lymphoma 
PR 
Partial response 
PRC2 
Polycomb repressive complex 2 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
QC 
Quality control 
QTc 
Corrected QT interval 
R-CHOP 
Rituximab, doxorubicin, cyclophosphamide, vincristine, and prednisolone or 
prednisone 
R-DHAP 
Rituximab, dexamethasone, cytarabine, cisplatin 
RECIST 
Response Evaluation Criteria in Solid Tumors 
R-ICE 
Rituximab, ifosfamide, carboplatin, etoposide 
RP2D 
Recommended Phase II dose 
RNA 
Ribonucleic acid 
RT 
Radiotherapy 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SCID 
Severe combined immunodeficiency 
SD 
Stable disease  
SI 
International System of Units 
SOC 
System Organ Class 


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Abbreviation 
Definition 
STD 
Standard deviation 
t1/2 
Apparent elimination half-life 
TEAE 
Treatment-emergent adverse event 
T-LBL/T-ALL 
T-cell lymphoblastic leukemia/ T-cell acute lymphoblastic leukemia 
Tmax 
Time to maximum concentration 
ULN 
Upper limit of normal 
US 
United States 
UTX 
Ubiquitously transcribed tetratricopeptide repeat, X chromosome 
UV 
Ultraviolet 
WBC 
White blood cell 
WHO 
World Health Organization 
 
 
 


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2. 
BACKGROUND AND RATIONALE 
This document is a protocol for a human research study. This study is to be conducted according 
to United States (US) and international standards of Good Clinical Practice (GCP; Food and 
Drug Administration [FDA] Title 21 Part 312 and International Conference on Harmonization 
[ICH] guidelines), applicable government regulations, and institutional research policies and 
procedures.  
2.1. 
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 methyl transferases (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].  EZH2 mutation 
and/or over-expression has been observed in several cancer types, leading to an aberrant H3K27 
trimethylation (H3K27me3) state which is oncogenic [Chase, 2011].  For instance, somatic gain 
of function mutations within EZH2, found within subsets of non-Hodgkin lymphoma (NHL), 
result in an oncogenic dependency on EZH2 production of abnormally high H3K27me3 levels, 
and resultant transcriptional reprogramming of the cell. [Morin 2010] 
2.2. 
Lymphoma 
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 


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EZH2 are growth inhibited with EZH2 inhibition in vitro, only mutant bearing cells undergo cell 
death in culture [Béguelin 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 
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.   
2.3. 
Solid Tumors 
In addition to the EZH2 gain of function activation mutations described above, overexpression or 
amplification of EZH2 has been described in numerous tumor types, including not but limited to 
bladder, breast cancer, colorectal, lung, pancreatic, ovarian, prostate, mesothelioma, uveal 
melanoma, renal carcinoma, cholangiocarcinoma and stomach cancer [LaFave 2015, Comet 
2016, Kuroki 2014].  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. 
Genetic changes in other proteins in addition to genetic alterations in EZH2 itself, can lead to an 
oncogenic dependency on EZH2 activity, specifically those affecting proteins of the 
SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex.  At many gene 
loci, polycomb repressive complex (PRC2) and SWI/SNF antagonize each other and loss of the 


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SWI/SNF component, integrase interactor 1 (INI1), has been demonstrated to generate over-
activation of the PRC2 pathway and tumor cell proliferation [Wilson, 2010]. Genetic loss of INI1 
has been described in many human malignancies, e.g., rhabdoid tumors, epithelioid sarcoma, 
epithelioid malignant peripheral nerve sheath tumor, extraskeletal myxoid chondrosarcoma, 
myoepithelial carcinoma, and renal medullary carcinoma [Margol, 2014]. Inhibition of EZH2 
activity by either knock-down or small molecule inhibition induces tumor cell killing and 
durable tumor regressions in pre-clinical models of rhabdoid tumors [Alimova 2013; Knutson 
2013].  Genetic alterations in synovial sarcomas can create a state of INI1 deficiency and result 
in aberrant SWI/SNF complex chromatin remodeling activity at various genes [Kadoch, 2013], 
sensitizing these tumors to EZH2 inhibition [Kawano, 2016]. Loss of SMARCA2 and 
SMARCA4 protein, the redundant catalytic subunits of the SWI/SNF chromatin remodeling 
complex, have been described in small cell carcinoma of the ovary, hypercalcemic type [Jellinic 
2014; Ramos 2014; Witkowski 2014], and inhibition of EZH2 activity in in vivo preclinical 
models by a small molecule inhibitor results in dose dependent tumor growth inhibition and 
regressions [Penebre 2017]. It has additionally been postulated that additional tumor types with 
loss or mutation of SWI/SNF subunits, such as ovarian cancer with loss of ARID1A, would also 
be sensitive to EZH2 inhibition [Bitler 2015; Kim 2015]. Given that approximately 20% of 
tumors contain a mutation in one or more subunit of the SWI/SNF complex, this suggests that 
EZH2 inhibition might have therapeutic value in a diverse number of solid tumor types [Kadoch 
2016]. 
Finally, genetic and/or protein loss of chromatin remodelers other than SWI/SNF have been 
associated with sensitivity to EZH2 inhibition. For instance, BRACA1 associated protein 1 
(BAP1) can also lead to an oncogenic dependency on EZH2 activity [LaFave 2015]. This is 
clinically relevant as genetic and/or protein loss of BAP1 has also been described in multiple 
human malignancies including mesothelioma, uveal melanoma, renal carcinoma, and 
cholangiocarcinoma [Testa 2011; Harbour 2010; Pena-Llopis 2012; Jiao 2013]. 
2.4. 
Tazemetostat 
2.4.1 
Preclinical Pharmacology 
Tazemetostat (EPZ-6438) is a selective oral small molecule inhibitor of EZH2.  Tazemetostat 
inhibits both wild-type EZH2 and mutant bearingEZH2 residues with Y641, A667G and A687 
with half maximal inhibitory concentrations (IC50) ranging from 2-38 nmol/L.  The compound 
shows a 35-fold selectivity over the most closely related HMT, EZH1, and greater than a 4500-
fold selectively over other HMTs.  It selectively inhibits intracellular H3K27 methylation in a 
concentration- and time-dependent manner, leading to selective cell killing of cell lines.  


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Tazemetostat specifically inhibits human lymphoma cell lines bearing EZH2 point mutations and 
integrase interactor 1 (INI1) unit deficient (also known as SNF5, SMARCB1, or BAFT47) MRT 
cell lines with IC50 in the nanomolar range.  Additionally, tazemetostat administered orally has 
demonstrated antitumor activity in vivo against several EZH2 mutant human lymphoma 
xenograft murine models [Knutson, 2014].   
2.4.2 
Lymphomas 
Antitumor effects of oral tazemetostat dosing were evaluated in 3 EZH2 mutant DLBCL 
xenograft models; WSU-DLCL2 EZH2 Y646F, KARPAS-422 EZH2 Y646N, and Pfeiffer EZH2 
A682G.  In severe combined immunodeficiency (SCID) mice bearing WSU-DLCL2 EZH2 
Y646F mutant xenograft tumors, tazemetostat induced dose-dependent tumor growth inhibition, 
showing a maximum of 58% at the highest dose of 160 mg/kg 3 times daily.  A dose-dependent 
increase in plasma and tumor tissue exposure was observed.  ELISA analysis of histones from 
tumors collected on Day 28 indicated dose-dependent reduction in H3K27Me3 levels. 
In KARPAS-422 EZH2 Y646N mutant xenografts, 28-day dosing of tazemetostat on a twice 
daily (BID) schedule induced tumor growth inhibition at doses as low as 80.5 mg/kg BID, but all 
higher doses induced complete xenograft tumor regression (Figure 1A). When investigating 
intermittent dosing schedules in this model, tazemetostat showed significant dose-dependent 
antitumor effects with 2 cycles of 7-day on/7-day off and 21 day on/7 day off schedules 
(Figure 1B).  For all dosing schedules, tumor growth inhibition and complete regressions were 
observed at 90 and 361 mg/kg BID, respectively.  In a parallel study, the inhibition of 
H3K27Me3 by tazemetostat was evaluated in KARPAS-422 human DLBCL xenografts in 
athymic mice.  Tazemetostat induced a dose-dependent reduction of tumor H3K27Me3 levels 
with both regimens (Figure 2).   


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Figure 1 
Antitumor Effects of Tazemetostat in KARPAS 422 Human DLBCL 
Xenograft Model in Athymic Mice 
 
Abbreviations: DLBCL = diffuse large B-cell lymphoma, STD = standard deviation. 
A: Change of tumor volume from mice dosed BID at the indicated doses of tazemetostat. Data represent the mean 
± STD (n = 9). A dosage of 644 mg/kg was not plotted because it exceeded the maximum tolerated dose in the 
study. * P < 0.05 versus vehicle control on Day 29 (repeated measures analysis of variance followed by 
Dunnett’s multiple comparison test). Source: Study M11024. 
B: Change of tumor volume at 3 different dosing schedules of tazemetostat administered BID. Data represent the 
mean ± STD (n = 8 – 9). * P < 0.05 versus vehicle 28-day continuous dosing group on Day 29 (repeated 
measures analysis of variance followed by Dunnett’s multiple comparison test). Source: Study M12002. 
 
0
200
400
600
800
1000
1200
1400
1600
0
5
10
15
20
25
30
Tumor Volume (mm3)
Day
Vehicle
80.5 mg/kg
161 mg/kg
322 mg/kg
*
**
0
200
400
600
800
1000
1200
0
5
10
15
20
25
30
Tumor Volume (mm3)
Day
Vehicle; 28-day continuous
90 mg/kg; 28-day continuous
361 mg/kg; 28-day continuous
90 mg/kg; two cycles of 7-day on/7-day off
361 mg/kg; two cycles of 7-day on/7-day off
90 mg/kg; 21-day on/7-day off
361 mg/kg; 21-day on/7-day off
*
*
*
***
A
B


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Figure 2 
H3K27Me3 Inhibition in KARPAS-422 Human DLBCL Xenografts in 
Athymic Mice Administered Tazemetostat EPZ-6438 for 7 Days 
 
Source: Study W-20120483.  
Abbreviations: BID = twice daily, DLBCL = diffuse large B-cell lymphoma, H3K27 = lysine 27 
of histone H3, H3K27Me3 = trimethylated form of H3K27, STD = standard deviation, QD = once 
daily.  
Note: Each bar represents a mean ± STD (n = 6) of H3K27Me3 level in each group.  
* P < 0.05 versus vehicle control (one-way analysis of variance followed by the Dunnett’s multiple 
comparison test).  
 
The Pfeiffer EZH2 A682G mutant xenograft model was the most sensitive DLBCL tumor model.  
Complete tumor regressions were observed in all animals in the 114 mg/kg tazemetostat once 
daily and 342 mg/kg once daily dose groups. Tumor regrowth was not observed up to the end of 
the study (36 days after stopping tazemetostat administration).  
2.4.3 
Solid Tumors 
Oral administration of tazemetostat in 4 NSCLC cell line xenografts with dual SMARCA2/A4 
loss demonstrated inhibition of tumor growth or tumor regressions.  As shown in Figure 3, tumor 
regression was observed in the NCI H522 and NCI-H661 NSCLC xenograft models at ≥ 125  
mg/kg and ≥ 250 mg/kg, respectively.  Significant tumor growth inhibition but not tumor 
regressions was seen in the A427 and NCI-H1703 NSCLC xenografts at ≥ 250 mg/kg.  In 
addition, antitumor activity was observed in xenograft models of INI-1 deficient tumors.  The 
most robust antitumor activity was demonstrated in the G401 INI1-negative human malignant 
rhabdoid tumor (MRT) xenograft model following oral dosing with tazemetostat. Figure 4A and  
B shows significant and dose-dependent antitumor effects with tumor stasis and growth delay at 
143 mg/kg and tumor regression at 285 mg/kg and 571 mg/kg with no regrowth at study end.  A 
dose-dependent increase in plasma and tumor tazemetostat concentration and strong inhibition of 
H3K27Me3, which correlated with antitumor activity, are demonstrated in Figure 4C and D, 
Vehicle
75 mg/kg
150 mg/kg
301 mg/kg
602 mg/kg
0
50
100
Trimethylation Level of H3K27 (%)
Vehicle
150 mg/kg
301 mg/kg
602 mg/kg
1203 mg/kg
0
50
100
*
*
*
*
BID
QD
*
*
*
*


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respectively. Changes in expression of INI1-regulated genes are shown in Figure 4E (Study 
E7438-PD001).           
Figure 3: 
Antitumor Effect of Tazemetostat Against 4 Human NSCLC Xenografts 
Models with SMARCA2/SMARCA4 Loss  
 
Source: Chan-Penebre et al., AACR 2017. 
Abbreviations: BID= twice daily, EPZ006438= tazemetostat, SMARCA2= SWI/SNF Related, Matrix Associated, 
Actin Dependent Regulator Of Chromatin, PO= by mouth. 
Tumor volume (in mm3) in mice dosed BID with vehicle or tazemetostat (noted as EPZ-6438).  SMARCA2/A4-
negative NSCLC cell lines were implanted in Nude (NCI-H522), NOD-SCID (NCI-H661 and NCI-H1703) or SCID 
(A427) mice and dosed with 125, 250, and 500 mg/kg tazemetostat.  Data are displayed as mean ± SEM (n=10 per 
group).  Statistics were calculated for the last data point with two-way ANOVA followed by Bonferroni post-test; * 
P<0.05, ** P<0.01, ***P<0.001. 


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Figure 4 
Antitumor Effect of Tazemetostat (E7438) Against the G401 Human MRT 
Xenograft Model in SCID Mice 
 
Abbreviations: BID = twice daily, ELISA = enzyme-linked immunosorbent assay, H3 = histone H3, H3K27Me3 = 
trimethylated form of histone H3 lysine 27, MRT = malignant rhabdoid tumor, SCID = severe combined 
immunodeficiency, SEM = standard error of the mean.  
A: Change of tumor volume from mice dosed BID at the indicated doses for 28 days. Each point represents the mean ± SEM 
(n = 7 – 8, tumor growth delay cohort). * P < 0.05, ** P < 0.01 versus vehicle control on Day 21 (repeated measures 
analysis of variance and Dunnett’s posttest versus vehicle).  
B: Kaplan-Meier survival curve for the mice in the tumor growth delay cohort (n = 7 – 8). The tumor volume endpoint was 
2000 mm3. 
C: Tazemetostat concentration in plasma (closed circle: 5 minutes before dosing, closed square: 3 hours after dosing) or tumor 
(closed triangle) in mice on Day 21. Symbols represent values for the individual animals; horizontal lines represent group 
mean values. 
D: H3K27Me3/total H3 ratio in tumors on Day 21. Symbols represent values for the individual animals; horizontal lines 
represent group mean values. Symbols represented in gray are values that fell outside of the ELISA standard curve. 
E: Changes in gene expression in tumors on Day 21. Data are presented as fold change compared with vehicle ± SEM (n = 6, 
except for 571 mg/kg group [n = 4]). * P < 0.05, ** P < 0.01, **** P < 0.0001, versus vehicle (2-tailed t test). 


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2.4.4 
In Vitro Aqueous Solubility 
The solubility of tazemetostat was investigated in buffer systems of pH 1.0, 2.0, 3.0, 4.0, 5.5, and 
6.8.  Mean solubility of tazemetostat was approximately 7 mg/mL at pH values of 1.0 to 4.0.  
However, mean aqueous solubility of tazemetostat decreased to 0.508 mg/mL and 0.0333 
mg/mL at pH 5.5 and pH 6.8, respectively.  The pH values at which the aqueous solubility 
changes are similar to the pKa values for tazemetostat of 5.3 and 6.9. 
2.4.5 
Nonclinical Pharmacokinetics 
Sixteen metabolites of tazemetostat were identified from incubations of liver microsomes and 
hepatocytes from mouse, rat, dog, monkey, and human. The major metabolites in liver 
microsomal incubations were the result of N-deethylation (M5, EPZ-6930), oxidation of the 
pyridone (M7), and dual oxidation (M12). The major metabolites in hepatocyte incubations were 
the results of oxidation and dehydrogenation (M11), and N-dealkylation of the pyridone (M13). 
EPZ-6930 appeared to be the major metabolite formed in liver microsomes and hepatocytes from 
monkey and human. There was no metabolite observed that was considered to be unique to 
humans. 
Results from in vitro studies with human liver microsomes suggested that CYP3A, CYP2C8, and 
CYP2D6 were involved in the metabolism of tazemetostat. In experiments using recombinant 
human CYPs (SupersomesTM), CYP3A4 was the only isoform which caused detectable turnover 
of tazemetostat. Taken together, these results suggest that CYP3A4 is the predominant enzyme 
involved in tazemetostat metabolism with potentially lesser contributions from CYP2C8 and 
CYP2D6. 
Tazemetostat inhibited CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A (testosterone 6β-
hydroxylation) activities in vitro with Ki values of 1.3, 15.0, 6.7, 9.2, and 3.1 µmol/L, 
respectively.  The IC50 values for tazemetostat inhibition of CYP3A-mediated midazolam 1' 
hydroxylation and nifedipine dehydrogenation in vitro were 12.7 and 19.4 µmol/L, respectively.  
Tazemetostat demonstrated time-dependent inhibition of CYP3A with a half-maximum 
inactivation of 6.4 µmol/L and maximum rate constant of inactivation of 0.077 min-1.  
Tazemetostat induced CYP3A4 in human hepatocytes in vitro with concentration that achieved 
50% of the maximal effect values of 2.18 to 2.96 µmol/L, and maximum effect values of 15.62- 
to 103.5-fold increase in mRNA. Tazemetostat may induce other CYP isoforms, such as CYP1A, 
CYP2B6, and CYP2C9, but the effect is expected to be much weaker than that observed for 
induction of CYP3A4. 


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A physiologically-based pharmacokinetic (PBPK) model was developed based on in vitro and in 
vivo data to simulate the effect of tazemetostat on CYP probe substrates.  The model was used to 
predict the magnitude of interaction of tazemetostat with probe substrates for CYP2C8 
(repaglinide and rosiglitazone), CYP2C9 (S-warfarin), and CYP2C19 (omeprazole and S-
mephenytoin) based upon the in vitro Ki and protein binding values.  Simulations also were 
conducted to predict the magnitude of interaction of tazemetostat given a worst-case scenario 
with Ki values 10-fold lower than the observed in vitro values and a fraction unbound of 0.2.  
Results of the analysis indicated that interactions between tazemetostat and substrates for 
CYP2C8, CYP2C9, and CYP2C19 likely will be negligible based on observed in vitro estimates 
of Ki for tazemetostat.  However, the worst-case scenario for tazemetostat is to cause a 1.30- to 
1.55-fold and 1.39- to 2.40-fold increase in the exposure of CYP2C8 and CYP2C19 substrates, 
respectively, at tazemetostat doses ranging from 400 to 1600 mg BID. 
2.4.6 
Clinical Pharmacokinetics  
The PK of tazemetostat and the desethyl metabolite, EPZ-6930, have been characterized 
following single (Day 1) and multiple (Day 15) dose administration to subjects with advanced 
solid tumors or B-cell lymphoma (n=36). Doses administered were 100 mg BID as a suspension 
(n=3) or tablet (n=3) formulation and 200, 400, 800, and 1600 mg BID as a tablet formulation. 
Tazemetostat was absorbed rapidly with a time to the maximum plasma concentration (Tmax) of 
approximately 1-2 hours postdose.  Plasma concentrations declined in a mono-exponential 
manner with a mean t1/2 of approximately 3-5 hours, and quantifiable plasma concentrations of 
both tazemetostat and its metabolite, EPZ-6930, were observed up to 12 hours postdose.  The 
tazemetostat maximum plasma concentration (Cmax) and area under the concentration-time curve 
(AUC) increased in a greater than dose-proportional fashion after a single dose and in an 
approximately a dose-proportional fashion at steady-state.   
After multiple dosing, there was a dose-dependent decrease in tazemetostat exposure between 
Days 1 and 15.  Accumulation ratios (Rac = AUCD15/AUCD1) evaluated at Day 15 of dosing were 
0.89 at 100 mg BID (suspension) and 0.48 at 1600 mg BID.  The Rac at the RP2D of 800 mg BID 
was 0.58.  Further reduction in systemic exposure at steady-state was not observed beyond 
Day 15 as evidenced by predose Ctrough (observed concentration at the end of a dosing interval, 
immediately before the next administration) levels from Days 15 to 29.  There was negligible 
change in Tmax or t1/2 on multiple dosing across the dose range.     
The Tmax for the tazemetostat metabolite EPZ-6930 was observed at 1 to 2 hours after 
tazemetostat administration and its elimination paralleled that of tazemetostat (t1/2 = 3 – 5 hours).  


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In contrast to the parent compound, Cmax and AUC of the metabolite increased after multiple 
dosing.  Metabolite-to-parent AUC ratios (EPZ-6930 relative to tazemetostat) ranged from 
approximately 0.57 to 1.3 on Day 1 and from 1.1 to 2.1 on Day 15.  EPZ-6930 Tmax was 
observed at 1-2 hours postdose and its elimination paralleled that of tazemetostat (t½ =3-5 hours).  
The time-dependency in kinetics of both parent and the desethyl metabolite are consistent with 
induction of CYP3A-mediated metabolism by tazemetostat.   
The effect of food on the PK of tazemetostat was investigated as part of Study E7438-G000-101.  
Subjects with advanced solid tumors or B-cell lymphomas received 200 mg tazemetostat in 
either the fasted state or immediately after consuming a high-fat breakfast in a randomized, 
crossover fashion.  Serial blood samples for the analysis of plasma tazemetostat concentrations 
were collected over 24 hours after dosing.  A summary of the preliminary PK parameters from 
the food effect portion of Study E7438-G000-101 is displayed in Table 4. 
Table 4:   
Summary of Tazemetostat Pharmacokinetic Parameters After 
Administration Fasted or Immediately After a High-Fat Breakfast in Study 
E7438-G000-101 (n=12) 
Meal State 
Cmax 
ng/mL 
AUC0-t 
ng•h/mL 
AUC0-∞ 
ng•h/mL 
Tmaxa 
h 
t1/2 
h 
Fed 
170 
(232) 
(5.62 – 752) 
755 
(207) 
(25 – 2890) 
803 
(191) 
(32 – 3100) 
4.0 
(1.0 – 6.0) 
4.24 
(28.1) 
(2.63 – 6.22) 
Fasted 
276 
(151) 
(50.4 – 1470) 
944 
(155) 
(167 – 5990) 
1140 
(135) 
(179 – 6250) 
1.0 
(0.6 – 6.0) 
41.0 
(37.2) 
(1.80 – 7.18) 
a 
Data are presented as geometric mean [(%CV) (range)] 
b 
Tmax presented as median (range) 
 
 
The fed: fasted geometric mean ratios and 90% confidence intervals (CI) for log-transformed 
Cmax and AUC0-∞ were determined with a linear mixed-effects model.  Results are displayed in 
Table 5. 
Table 5:   
Fed: Fasted Geometric Mean Ratio and 90% Confidence Interval for 
Tazemetostat Cmax and AUC0-∞ in Study E7438-G000-101 
Parameter 
Fed: Fasted Ratio 
90% CI 
Cmax (ng/mL) 
0.62 
0.41, 0.93 
AUC0-∞ (ng•h/mL) 
0.82 
0.56, 1.90 
Abbreviations: AUC= area under concentration-time curve, Cmax= Maximum plasma concentration, CI= Confidence 
interval. 


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Administration of tazemetostat with a high-fat meal decreased geometric mean AUC0-∞ and Cmax 
values approximately 18% and 38%, respectively, relative to administration in the fasted state.  
However, the 90% CI for the fed: fasted geometric mean ratio for both Cmax and AUC0-∞ 
contained 1.  Administration of tazemetostat with a high-fat meal also resulted in a 4-fold 
increase in median Tmax relative to administration in the fasted state.  Geometric mean t1/2 values 
were nearly identical after administration in the fed and fasted state (4.24 h and 4.10 h, 
respectively).  These results indicate that administration of tazemetostat with a high-fat breakfast 
results in slower absorption into the systemic circulation with no effect on the systemic 
disposition or overall exposure to tazemetostat as measured by AUC.  The decrease in systemic 
exposure is not clinically significant, and therefore tazemetostat can be taken without regards to 
meals. 
The effect of tazemetostat on the PK of midazolam also was investigated as part of Study E7438-
G000-101.  Subjects with solid tumors (n=13) received a single oral dose of 2 mg midazolam on 
Day -1 and on Day 15.  Tazemetostat 800 mg BID was administered continuously starting on 
Day 1.  Serial blood samples for the analysis of plasma midazolam and metabolites were 
collected over 24 h on Day -1 (midazolam alone) and Day 15 (midazolam plus tazemetostat). 
A summary of preliminary midazolam PK parameters after administration alone (Day -1) and 
with tazemetostat 800 mg BID (Day 15) in subjects with solid tumors is presented in Table 6.     
Table 6:  
Summary of Midazolam Pharmacokinetic Parameters After Administration 
Alone (Day -1) or with Tazemetostat 800 mg BID for 15 Days (Day 15) in 
Study E7438-G000-101 (n=12) 
Parameter 
Day -1a 
Day 15a 
GLSMR 
(90% CI) 
AUC0-∞ 
ng•h/mL 
52.4 
(86.9) 
31.1 
(48.1) 
0.59 
(0.45, 0.78) 
Cmax 
ng/mL 
15.5 
(94.1) 
12.3 
(50.5)c 
0.79 
(0.59, 1.06) 
t1/2 
h 
5.69 
(34.6) 
4.12 
(33.8) 
NC 
Abbreviations: AUC= area under concentration-time curve, CI= confidence interval, GLSMR = geometric least 
squares mean ratio, NC = not calculated  Tmax = time to maximum concentration 
aData presented as geometric mean (%CV) 
 
cn=13 
 
 
Plasma midazolam AUC0-∞ and Cmax decreased approximately 40% and 20%, respectively, after 


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administration with tazemetostat 800 mg BID relative to administration of midazolam alone.  
Geometric mean t1/2 for midazolam decreased approximately 25%, after administration of 
midazolam with tazemetostat 800 mg BID relative to administration of midazolam alone.  These 
results indicate that administration of tazemetostat 800 mg BID resulted in net induction of 
CYP3A-mediated metabolism in subjects with solid tumors.  The decrease in midazolam AUC0-∞ 
caused by concomitant administration with tazemetostat 800 mg BID was less than 50%.  
Therefore, tazemetostat 800 mg administered BID is a weak inducer of CYP3A-mediated 
metabolism. 
2.4.7 
Clinical Experience 
In 2013, Study E7438-G000-101, a single-agent, Phase 1/2 study of tazemetostat in adult 
subjects with advanced B-cell lymphomas or advanced solid tumors for which there was no 
known effective therapy was initiated.  Enrollment in Phase 2 is continuing.  Three additional 
studies have also been initiated and are currently recruiting subjects:  
• EZH-102, A Phase 1 Study of the EZH2 Inhibitor Tazemetostat in Pediatric Subjects with 
Relapsed or Refractory INI1-Negative Tumors or Synovial Sarcoma 
• EZH-202 A Phase 2, Multicenter Study of the EZH2 Inhibitor Tazemetostat in Adult 
Subjects with INI1-Negative Tumors or Relapsed/Refractory Synovial Sarcoma   
• EZH-203, A Phase 2, Multicenter Study of the EZH2 Inhibitor Tazemetostat in Adult 
Subjects with Relapsed or Refractory Malignant Mesothelioma with BAP1 Loss of 
Function  
As of the cutoff date of 15-Jan. 2016, subjects with advanced solid tumors or B-cell lymphoma 
(N=88), or with INI-negative tumors (N=1) have been enrolled and exposed to tazemetostat in 
these 3 studies.  
As of the 15-Jan. 2016 cutoff date, 78 of 89 (87.6%) subjects experienced one or more treatment-
emergent adverse events (TEAEs) and 51 of 89 (57.3%) subjects experienced TEAEs that were 
considered by the investigator to be related to tazemetostat. The most common TEAEs, any 
grade, in descending order of frequency were asthenia, nausea, thrombocytopenia, decreased 
appetite, anemia, constipation, dysgeusia, vomiting, diarrhea, dry skin, dyspnea, muscle spasms, 
and abdominal pain. Twenty-two (22) of 89 (24.7%) subjects experienced Grade 3 or 4 AEs, 7 
(7.9%) of which were considered related to study drug. Five (5.6%) subjects in the study 
discontinued tazemetostat treatment due to AEs. 


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In addition, 22 subjects experienced a total of 31 serious adverse events (SAE). Of these, 
4 (12.9%) were considered possibly related to study drug (neutropenia [2], anemia [1], and 
thrombocytopenia [1]).  Eleven subjects died in Study E7438-G000-101.  Nine of the deaths 
were attributed to progressive disease, one event was attributed to an AE, and one death was 
reported as “not due to progressive disease” (no further information available at time of data 
cutoff date of 15-Jan. 2016).   
As of 07-Nov. 2015, antitumor activity has been noted (phase 1 part only) in subjects with B-cell 
lymphoma and with INI1-deficient tumors. Objective responses were demonstrated in 9 of 16 
subjects (5/10 with DLBCL, 3/5 with FL, and 1/1 with MZL) with B-cell lymphoma (2 complete 
responses [CR] and 7 partial responses [PR]) and in 4 of 11 subjects with INI1-deficiency (one 
CR and 3 PRs) who were evaluable for response per protocol (defined as having measurable 
disease, and least one post-baseline scan, and received at least one dose of study drug). Of the 9 
subjects with objective responses, 4 remained on study treatment for 41 to 68 weeks. 
Tazemetostat has shown clear evidence of robust clinical activity in subjects with genetically 
defined INI1 negative tumors consisting of 3 of 6 subjects showing objective response (1 CR + 2 
PRs) within 8 weeks of receiving the first dose of study treatment.  A fourth INI1-negative 
subject has experienced tumor reduction, but did not meet RECIST 1.1 criteria for PR at the first 
re-staging at 8 weeks.  Further information on clinical efficacy and safety can be found in the 
tazemetostat Investigator’s Brochure (IB), Version 8.0. 
2.5. 
Study and Dose Rationale 
2.5.1 
Study Rationale  
Tazemetostat is metabolized primarily by CYP3A4 in vitro.  Inhibition of CYP3A4/5 in vivo is 
expected to result in increased systemic exposure to tazemetostat.  Therefore, Part A of this study 
will determine the effect of a moderate CYP3A inhibitor, fluconazole, on tazemetostat PK.  
Tazemetostat inhibited multiple CYP isoforms in vitro.  The most potent inhibition (lowest Ki 
values) was for the CYP2C8 and CYP3A isoforms followed by CYP2C19.  The effect of 
tazemetostat on the PK of the sensitive CYP3A probe midazolam was determined in Study 
E7438-G000-101.  Therefore, Part B of this study will determine the effect of tazemetostat on 
the PK of the CYP2C8 probe medication repaglinide and the CYP2C19 probe medication 
omeprazole.   
The solubility of tazemetostat is pH dependent and an increase in gastric pH may alter the oral 
absorption of tazemetostat.  In addition to a CYP2C19 probe medication, omeprazole is a 


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medication that increases gastric pH.  The effect of increased gastric pH on the PK of 
tazemetostat will be determined in Part B by the concomitant administration of omeprazole for 4 
days.   
2.5.2 
Dose Rationale  
2.5.2.1. 
Tazemetostat 
The safety, tolerability, clinical activity, PK, and pharmacodynamic (PD) assessments from the 
subjects treated in the Dose Escalation part of Study E7438-G000-101 were used to select the 
recommended Phase 2 dose (RP2D).  As of 07-Nov. 2015, 58 subjects with advanced or 
metastatic solid tumors or B-cell lymphomas had been included in the Phase 1 Dose Escalation 
part of the study. Clinical activity of tazemetostat was observed at dose levels of 100, 200, 800, 
and 1600 mg BID, including objective responses observed in 9 of 16 response-evaluable subjects 
with B-cell lymphoma who have had tumor assessments while on study drug. Objective 
responses were observed in 5/10 DLBCL, 3/5 FL, and 1/1 MZL subjects. An MTD was not 
established with tazemetostat doses of up to 1600 mg BID. 
A relationship between tazemetostat AUC on Day 15 and inhibition of H3K27Me3 in the stratum 
spinosum was observed and described by an inhibitory Emax model. The tazemetostat AUC0-12 at 
which the H3K27Me3 inhibition was 50% of maximal (EC50) was 848 ng*h/mL and the 
maximum effect (Emax) was 51% inhibition.  The predicted inhibition of H3K27Me3 in the 
stratum spinosum skin layer at the observed median Day 15 AUC0-12 in the 800 mg BID dose 
cohort (3670 ng*h/mL) was over 80% of Emax.  These results suggest that target inhibition in the 
skin was near maximal at 800 mg tazemetostat BID and doubling the dose to 1600 mg BID 
results in only an incremental increase in the inhibition of the H3K27 methylation.  Furthermore, 
the greatest number of objective responses was observed in the 800 mg BID cohort during the 
Dose Escalation part of the study.  Therefore, 800 mg tazemetostat BID was selected as the 
RP2D.  The RP2D was selected to investigate the effect of tazemetostat on CYP2C8- and 
CYP2C19-mediated metabolism and the effect of increased gastric pH on the PK of tazemetostat 
in the current study.  
2.5.2.2. 
Fluconazole plus Tazemetostat 
Fluconazole doses up to 400 mg daily may be used to treat candida infections and for 
prophylaxis in patients undergoing bone marrow transplantation.  Administration of a single dose 
of 400 mg fluconazole followed by 200 mg fluconazole daily for 5 days increased midazolam (a 
sensitive CYP3A probe substrate) AUC and Cmax 259% and 150%, respectively, after oral 


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administration of 7.5 mg relative to administration of midazolam alone.  The highest dose of 
tazemetostat investigated in the Dose Escalation and Dose Expansion phases of Study E7438-
G000-101 was 1600 mg BID.  The results of the effect of fluconazole on systemic exposure to 
midazolam suggest that administration of tazemetostat 800 mg BID in the presence of CYP3A 
inhibition by 400 mg fluconazole once daily may result in systemic exposure to tazemetostat 
greater than that observed in the 1600 mg BID cohort in Study E7435-G000-101.  Therefore, 
tazemetostat 400 mg BID will be administered in Part A of the current study and continue 
through Day 24 to allow for sufficient wash-out of fluconazole.  The tazemetostat RP2D of 800 
mg BID will then be administered starting on Day 25, 6 days following the last dose of 
fluconazole. 
2.5.2.3. 
Repaglinide 
The starting dose for repaglinide in patients not previously treated or whose hemoglobin A1c 
(HbA1c) is < 8% is 0.5 mg administered with each meal.  A dose of 0.25 mg repaglinide was 
selected to minimize the effect on blood glucose in subjects in this study. 
2.5.2.4. 
Omeprazole 
The recommended dose of omeprazole to treat duodenal ulcers and gastro-esophageal reflux is 
20 mg once daily for 4 to 8 weeks.  A daily dose of 20 mg omeprazole was reported to maintain 
a median gastric pH of 4.5 over 24 hours [Houben, 1995].  Therefore, omeprazole 20 mg once 
daily was selected to determine the effect of tazemetostat on CYP2C19-mediated metabolism 
and to investigate the effect of increased gastric pH on the PK of tazemetostat.   
2.6. 
Benefit: Risk Assessments 
2.6.1 
Animal Toxicology 
Nonclinical safety assessments of tazemetostat included in vitro and monkey safety 
pharmacology studies, genotoxicity studies, and single- and repeat-dose toxicity studies in 
Sprague-Dawley rats and cynomolgus monkeys of 4- and 13 weeks duration. No notable 
cardiovascular, central nervous system (CNS), or respiratory risks were identified in nonclinical 
safety pharmacology assessments. Tazemetostat was not genotoxic in standard in vitro and in 
vivo assays. The following potential risks were identified for tazemetostat based on nonclinical 
safety data: T-LBL (rat), increased bone formation in bone and teeth (rat), non-progressive bile 
duct hyperplasia (monkey), teratogenicity (rat and rabbit), lymphoid depletion (rat and monkey), 
and phototoxic potential (in vitro). Other effects at high, non-tolerated doses, toxicities included 


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bone marrow effects (hypocellularity, rat), and gastrointestinal toxicity (distention, ulceration, 
and degeneration, rat).  
Steady-state exposures (area under the concentration–time curve from 0 to 24 hours [AUC0-24]) 
in rats at the lowest dose (100 mg/kg/day) at which no T-LBL occurred in the 13-week 
adolescent rat study were 2.5- to 7.5-fold greater than that observed in humans at the 
recommended Phase 2 dose (RP2D; 800 mg twice daily [BID]) from the ongoing Phase 1/2 
Study E7438-G000-101. No incidences of abnormal bone formation have been observed in the 
ongoing clinical study. Female subjects of reproductive age will provide blood and urine samples 
for pregnancy testing at screening. All subjects must agree to use a reliable birth control method 
during the study, and for 30 days after the last tazemetostat dose, and additionally will be 
actively monitored for signs or symptoms of abnormal bone formation.      
2.6.2 
Photo-Reactive Potential 
There are nonclinical data supporting a potential for phototoxicity, which has not been evaluated 
in humans. Hence, prolonged exposure to sunlight should be avoided during treatment. In 
addition, subjects should take other measures to avoid ultraviolet (UV) exposure such as wearing 
sun screen and sun glasses, wearing protective clothing, and avoiding tanning beds. Refer to the 
tazemetostat Investigator’s Brochure 8.0 for details. 
2.6.3 
Metabolism and Transporters 
Tazemetostat is metabolized primarily by CYP3A and is a substrate for P-glycoprotein (Pgp).  
Therefore, treatment with strong inhibitors or strong inducers of CYP3A within 7 days prior to 
the first dose of tazemetostat and for the duration of study treatment is prohibited. Treatment 
with moderate inhibitors, other than fluconazole administered in Part A of the current study, is 
prohibited within 7 days prior to the first dose of tazemetostat until after the final PK sample is 
drawn on Day 19. Tazemetostat also was shown to be a time-dependent CYP3A inhibitor and a 
CYP3A4 inducer as well as an inhibitor of Pgp, CYP2D6, and the CYP2C family in vitro.  Pgp, 
CYP3A, CYP2C8, CYP2C9, CYP2C19, and CYP2D6 substrates should be used with caution.  
Medications that are substrates for CYP3A, CYP2C8, CYP2C9, CYP2C19, or CYP2D6, and that 
have a narrow therapeutic range should be avoided if possible. 
2.6.4 
Anticipated Safety Profile 
In addition to the overall incidence of TEAEs as described in Section 2.2.5,  the most frequently 
reported TEAEs (all grades and in descending order) that occurred in ≥ 5% of subjects enrolled 
in the Phase 1 part of study  E7438-G000-101 included the following  (as of the 15-Jan.2016 
cutoff date, n = 62):  Asthenia (34.8%), nausea (15.7%), thrombocytopenia (14.6%), decreased 


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appetite (13.5%), anemia (12.4%), constipation (12.4%), dysgeusia (7.9%), vomiting (7.9%), 
diarrhea (6.7%), dry skin (6.7%), dyspnea (6.7%) muscle spasms (6.7%), abdominal pain (5.6%) 
and neutropenia (5.6%).  TEAEs did not appear to be dose dependent.  There have been 3 
Grade 4 TEAEs, which occurred in one subject each: thrombocytopenia (1 subject) and 
neutropenia (2 subjects).  All 3 events were considered related to study drug and required 
withdrawal of study drug.   For up-to date information on AESIs, see Section 11.5. Additionally, 
there is the unknown risk of abnormal pregnancy outcomes and drug-drug interactions (DDI). 
Based on the preclinical toxicology of tazemetostat, the potential risks associated with treatment 
include bone AEs and photosensitivity. 
2.7. 
Good Clinical Practice (GCP) 
The principal investigator will ensure that the basic principles of GCP, as outlined in 21 Code of 
Federal Regulations (CFR) 312, subpart D, “Responsibilities of Sponsors and Investigators,” 21 
CFR, Part 50 (1998) and 21 CFR, Part 56, (1998) are followed.  
Since this is a covered clinical trial, the principal investigator is adhered to 21 CFR, Part 54, 
(1998).  A covered clinical trial is any “study of a drug or device in humans submitted in a 
marketing application or reclassification petition subject to this part that the applicant or FDA 
relies on to establish that the product is effective (including studies that show equivalence to an 
effective product) or that make a significant contribution to the demonstration of safety.”  This 
requires that investigators and all sub-investigators must provide documentation of their financial 
interest or arrangements with Epizyme, Inc. or proprietary interests in the drug being studied. 
This documentation must be provided prior to the participation of the principal investigator and 
any sub-investigator. The principal investigator and sub-investigator agree to notify Epizyme, 
Inc. of any change in reportable interests during the study and for one year following completion 
of the study. Study completion is defined as the date that the last subject has completed the 
protocol-defined activities. 


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3. 
STUDY OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary:  
Part A   
• 
To determine the effect of CYP3A inhibition by 
fluconazole on the PK of tazemetostat 
Part A   
• 
AUC0-t, AUC0-8, AUC0-12, and Cmax of 
tazemetostat on Days 15 and 19 
Part B:   
• 
To investigate the potential of tazemetostat to inhibit or 
induce CYP2C8 using repaglinide as a probe substrate. 
Part B:   
• 
AUC0-t, AUC0-∞, and Cmax of repaglinide on Days 
1 and 16 
• 
To investigate the potential of tazemetostat to inhibit or 
induce CYP2C19 using omeprazole as probe a 
substrate. 
• 
AUC0-t, AUC0-∞, and Cmax of omeprazole on Days 
1 and 16  
• 
To investigate the effect of increased gastric pH by 
omeprazole on the PK of tazemetostat. 
• 
AUC0-t, AUC0-8, AUC0-12, and Cmax of 
tazemetostat on Days 16 and 19 
Secondary:  
Part A 
• 
To investigate the safety profile of tazemetostat 400 
mg BID after co-administration with fluconazole. 
Part A   
• 
Safety and tolerability parameters including AEs, 
clinical laboratory assessments, and vital signs 
• 
To determine the PK of tazemetostat and its 
metabolites after administration alone and with 
fluconazole. 
• 
Tmax, and t1/2 of tazemetostat and AUC0-t, AUC0-8, 
Cmax, Tmax, and t1/2 of tazemetostat metabolites on 
Days 15 and 19. 
• 
To determine the systemic exposure of fluconazole 
after administration of 400 mg once daily for 4 days. 
• 
Plasma fluconazole AUC0-8, Cmax, and Tmax on 
Day 19 
Part B 
• 
To investigate the safety profile of tazemetostat, 
repaglinide, and omeprazole after co-administration. 
Part B  
• 
Safety and tolerability parameters including AEs, 
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Objectives 
Endpoints 
• 
To determine the PK of repaglinide and its metabolites 
after administration with omeprazole and 
administration with omeprazole and tazemetostat 
• 
Tmax and t1/2 of repaglinide; AUC0-t, AUC0-∞, Cmax, 
Tmax, and t1/2 of repaglinide metabolites on Days 1 
and 16.  The metabolite to repaglinide ratio for 
AUC0-∞ and AUC0-t on Days 1 and 16. The plasma 
metabolite to repaglinide concentration ratios at 1, 
2, 3, 5, and 7 hours after administration of 
repaglinide on Days 1 and 16 
• 
To determine the PK of omeprazole and its metabolites 
after administration with repaglinide and 
administration with repaglinide and tazemetostat 
• 
Tmax and t1/2 of omeprazole on Days 1 and 16.  
AUC0-t, AUC0-∞, Cmax, Tmax, and t1/2 of 
5-hydroxyomeprazole (5-OH-omeprazole) and 
omeprazole sulfone.  The 5-OH-omeprazole to 
omeprazole and the omeprazole sulfone to 
omeprazole ratios for AUC0-∞ and AUC0-t on Day 1 
and Day 16.  The plasma 5-OH-omeprazole to 
omeprazole and omeprazole sulfone to omeprazole 
concentration ratios at 1, 2, 3, 5, and 7 hours after 
administration of omeprazole on Days 1 and 16 
• 
 
• 
 
Parts A and B: 
• 
To assess antitumor activity of tazemetostat in 
subjects with DLBCL, PMBCL, MCL, MZL, FL, 
or advanced solid tumors  
Parts A and B: 
• 
Overall response rate (ORR: CR or PR) and 
disease control rate (DCR: CR or PR, or SD 
lasting 24 weeks or longer from start of 
treatment with tazemetostat) using Lugano 
Classification [Cheson 2014] for subjects with 
lymphoma and RECIST 1.1 for subjects with 
solid tumors 
 
Exploratory: 
• 
To investigate the effects of variations in genes 
encoding for CYP enzymes and transporters on the 
potential DDI profile of tazemetostat 
• 
Genotype for genes encoding for CYP enzymes 
and transporters 
• 
To explore the effect of tazemetostat on OS 
• 
OS 
 
 
 


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4. 
STUDY DESIGN 
4.1. 
 Study Sites 
This study will be conducted at 3 sites in the US. 
4.2. 
Overview of Study Design 
This is a Phase 1, open-label, 2-part, safety, PK, and activity study designed to characterize the 
DDI potential of tazemetostat.  Tazemetostat will be taken orally BID continuously in 28-day 
cycles in both study parts.  Subjects in Part A will receive tazemetostat 400 mg BID 
continuously for 24 days starting on Day 1.  Tazemetostat 800 mg BID then will be administered 
continuously starting the morning of Day 25.  Subjects in Part B will receive tazemetostat 
800 mg BID continuously starting on Day 2.  Adequate supplies of tazemetostat to be taken at 
home will be dispensed to subjects on scheduled clinic days. On clinic days when blood samples 
are taken, subjects will be given morning tazemetostat doses at the clinic.   
Part A.  On the morning of Day 1, subjects will begin treatment with oral tazemetostat tablets 
400 mg BID.  Subjects will be given sufficient supply of tazemetostat to continue treatment 
through Day 14.  Subjects will check in to the clinic on the morning of Day 15 prior to the 
morning dose of 400 mg tazemetostat.  Blood samples for the analysis of tazemetostat and 
metabolites will be collected predose and over 8 hours after the morning dose of tazemetostat on 
Day 15.  Subjects will receive fluconazole 400 mg tablets, which will be taken once daily for 
4 days starting on Day 16.  On the morning of Day 19, subjects will check in to the clinic and 
serial blood samples for the analysis of tazemetostat and its metabolites, and fluconazole will be 
collected predose and over 8 hours after the morning tazemetostat dose.  Subjects will receive 
tazemetostat 400 mg BID until the evening dose on Day 24.  Tazemetostat 800 mg BID will be 
administered starting on Day 25 and continue until the subject withdraws from the study. 
Part B.  Subjects enrolled in Part B will check in to the clinic on the morning of Day 1 and will 
receive oral doses of repaglinide 0.25 mg and omeprazole 20 mg.  Blood samples for analysis of 
plasma repaglinide and its metabolites, omeprazole, 5-OH-omeprazole, and omeprazole sulfone 
will be collected over 7 hours after administration on Day 1.  Subjects will be able to leave the 
clinic after the last PK blood sample is collected and also will be given a sufficient supply of 
tazemetostat for home administration of tazemetostat 800 mg BID for 14 days starting on Day 2.  
Subjects will return to the clinic on Day 16, prior to the scheduled morning dose of tazemetostat.  
Subjects will receive the morning dose of tazemetostat, followed 1 hour (± 5 minutes) later by 
oral doses of repaglinide 0.25 mg and omeprazole 20 mg.  Blood samples for analysis of plasma 
tazemetostat and its metabolites, repaglinide and its metabolites, omeprazole, 5-OH-omeprazole, 
and omeprazole sulfone will be collected predose and over 8 hours after administration of 


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tazemetostat on Day 16.  Subjects will continue to receive omeprazole 20 mg once daily in the 
morning on Days 17 through 19, inclusive.  On Day 19, blood samples for analysis of plasma 
tazemetostat and its metabolites will be collected over 8 hours after the morning dose. Subjects 
will again be given an adequate supply of tazemetostat to last until the next scheduled clinic day.  
Upon initiation of tazemetostat treatment, all subjects enrolled in this study will receive oral 
tazemetostat for up to 6 months (24 weeks) or until they have an unacceptable toxicity, disease 
progression, or withdraw consent.  Subjects may be transitioned to Study EZH-501, at the 
investigator’s discretion, after completing all study assessments in EZH-105 and at least 6 
months of treatment with tazemetostat.  Subjects enrolling in the EZH-501 study will transition 
to 200 mg tazemetostat tablets from 400 mg tablets (as administered in EZH-105).  Subjects who 
are enrolled in the study and do not complete all study assessments, or who do not transition to 
Study EZH-501 must have a post-treatment follow-up visit within 30 days of the last dose of 
tazemetostat. In addition, subjects who discontinue treatment with tazemetostat and do not 
transition to the EZH-501 study, will be followed for OS.   
Supplementary study conduct information not mandated to be present in this protocol is provided 
in the accompanying procedure manuals (i.e., laboratory, pharmacy, ECG, and imaging 
manuals).  Such manuals will provide the site personnel with administrative and detailed 
technical information that does not impact subject safety. 


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4.3. 
Study Schema for the First 28 Days of Treatment 
Part A: 
 
 
 
 
 
Part B: 
 
 
 
BID = twice daily.   


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4.4. 
Rules for Suspension of Enrollment 
The investigators, IRBs/ECs, and regulatory agencies will be urgently informed and a Safety 
Review committee comprised of the investigators and Epizyme medical monitor convened to 
review the data and to make recommendations for potential changes in study conduct if one or 
more subjects develop any of the following AEs deemed to be definitely related to study 
treatment by the investigator and/or Medical Monitor, based upon close temporal relationship or 
other factors: 
• 
Death 
• 
Anaphylaxis (angioedema, hypotension, shock, bronchospasm, hypoxia, or respiratory 
distress) 
• 
Secondary lymphoma 
Should study enrollment be suspended, the study will not be restarted until all parties have 
agreed to the course of action to be taken and the IRBs/ECs have been notified. 


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5. 
STUDY POPULATION 
5.1. 
Target Population 
Approximately 32 subjects will be enrolled to achieve 12 subjects who complete each part of the 
study.  Subjects will complete either Part A or Part B. 
See Section 13.2.1 for sample size assumptions. 
5.2. 
Inclusion Criteria 
A subject must meet the following criteria to be eligible for entry into the study: 
 Male or female ≥ 18 years of age at time of consent 
 Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 (see 
Appendix 3) 
 Has the ability to understand informed consent and provided signed written informed 
consent 
Must meet one of the following criteria: 
 Has histologically confirmed diffuse large B-cell lymphoma (DLBCL),  primary mediastinal 
B-cell lymphoma (PMBCL), marginal zone lymphoma (MZL), or mantle cell lymphoma 
(MCL), and have relapsed or refractory disease following at least 2 standard lines of 
systemic therapy, including alkylator/anthracycline (unless anthracycline–based 
chemotherapy is contraindicated)/anti-CD20-based therapy (R-CHOP or equivalent) AND 
must be considered unable to benefit from intensification treatment with autologous 
hematopoietic stem cell transplantation (ASCT), as defined by meeting at least 1 of the 
following criteria: 
a. Relapsed following, or refractory to, previous ASCT 
b. Did not achieve at least a PR to a standard salvage regimen (e.g., R-ICE or R-
DHAP) 
c. Ineligible for intensification treatment due to age or significant comorbidity 
d. Ineligible for intensification treatment due to failure to mobilize an acceptable 
number of hematopoietic stem cells 
e. Refused intensification treatment and/or ASCT. 
 


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Note: Subjects with prior radiotherapy will be included; however, radiotherapy alone 
will not be considered a separate systemic treatment regimen. 
OR 
 Has histologically confirmed FL, all grades.  Subjects must have relapsed/refractory disease 
following at least 2 standard lines of systemic therapy, including at least 1 anti-CD20-based 
regimen (eg, rituximab), as well as alkalating agents (eg, cyclophosphamide or 
bendamustine), and have no curative option with other available therapies OR have a contra-
indication to their use.  Subjects with prior ASCT may be included. Transformed disease is 
permitted. 
Note: Subjects with prior radiotherapy will be included; however, radiotherapy alone will 
not be considered a separate systemic treatment regimen. 
OR 
 Histologically and/or cytologically confirmed advanced or metastatic solid tumor that has 
progressed after treatment with approved therapies or for which there are no standard 
therapies available 
 Must have evaluable or measurable disease 
 Has all prior treatment (i.e., chemotherapy, immunotherapy, radiotherapy) related clinically 
significant toxicities resolve to ≤ Grade 1 per NCI CTCAE, Version 4.03 or are clinically 
stable and not clinically significant, at time of consent 
 Time required between the last dose of the latest therapy and the first dose of study drug: 
Prior Therapy 
Time from Last Prior Therapy  
Chemotherapy: cytotoxic 
At least 21 days  
Chemotherapy: nitrosoureas 
At least 6 weeks   
Chemotherapy: non-cytotoxic  
(e.g., small molecule inhibitor) 
At least 14 days  
Monoclonal antibody (ies) 
At least 28 days  
Non-antibody immunotherapy (e.g., tumor vaccine) 
At least 42 days  
Radiotherapy (RT) 
At least 14 days for stereotactic radiosurgery  
At least 12 weeks for craniospinal, ≥50% radiation of 
pelvis, or total body irradiation  
Autologous hematopoietic cell infusion after high 
dose therapy 
At least 60 days  
Hematopoietic growth factor 
At least 14 days  
 


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 Has adequate hematologic (bone marrow [BM] and coagulation factors), renal and hepatic 
function as defined by criteria below: 
System 
Laboratory Value 
Hematologic (BM Function) 
Hemoglobina 
≥9 g/dL 
Plateletsb 
≥75,000/mm3 (≥75 × 109/L) 
ANCc 
Lymphoma subjects:  ≥750/mm3 (≥0.75 × 109/L) 
Solid tumor subjects:  ≥1,000/mm3 (≥1.0 x 109/L 
Hematologic (Coagulation Factors) 
PT 
<1.5 ULN 
PTT 
<1.5 ULN 
Renal Function 
eGFRd 
≥ 50 mL/min/1.73 m2 
Hepatic Function 
Conjugated bilirubin 
<1.5 × ULN 
ASTe 
<3 × ULN 
ALTe 
<3 × ULN 
Abbreviations:  ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate 
aminotransferase; BM = bone marrow; eCGR = estimated glomerular filtration rate; PT = prothrombin 
time; PTT = 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. Calculate eGFR per institutional standard formula 
e.  If attributed to tumor involvement, AST and ALT <5×ULN 
 
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. 
 
 Has a QT interval corrected by Fridericia's formula (QTcF) ≤480 msec 
  Subjects with a history of Hepatitis B or C are eligible on the condition that subjects have 
adequate liver function as defined by Inclusion Criterion No. 10 and are hepatitis B surface 
antigen negative and/or have undetectable HCV RNA. 
 Male subjects must refrain from donating sperm starting at the planned first dose of 
investigational product (IP) until 30 days following the last dose of IP. 
 Male subjects with a female partner of childbearing potential must:   
a. Be vasectomized, or 


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b. Remain abstinent or use a condom as defined in Section 8.3.10.4.2 starting at the 
planned first dose of IP until 30 days following the last dose of IP.  The reliability 
of sexual abstinence should be evaluated in relation to the duration of the clinical 
trial and the preferred and usual lifestyle of the subject.  Periodic abstinence (e.g., 
calendar, ovulation, sympto-thermal, or post-ovulation methods) and withdrawal are 
not acceptable methods of contraception. 
 Female partners of male subjects who are of childbearing potential must also adhere to 
one of the following: 
a. Placement of an intrauterine device or intrauterine system. 
b. Established use of oral, injected, or implanted hormonal methods of contraception 
plus an additional barrier method. 
c. Progesterone-only oral contraception, where inhibition of ovulation is not the 
primary mode of action. 
 Women of childbearing potential:   
a. A woman is considered to be of childbearing potential if she is post menarcheal, has 
not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus). 
b. Must agree to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive methods that result in a failure rate of < 1% per year starting at the 
planned first dose of IP until 30 days following the last dose of IP. 
c. Examples of contraceptive methods with a failure rate of < 1% per year include 
bilateral tubal ligation, male sterilization, established, proper use of hormonal 
contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and 
copper intrauterine devices. 
d. Due to the potential of enzyme induction with tazemetostat, female subjects who 
use hormonal contraceptives should use an additional barrier method of birth 
control while on study treatment and for 30 days after discontinuation of study 
treatment. 
e. The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the subject.  Periodic 
abstinence (e.g., calendar, ovulation, sympto-thermal, or post-ovulation methods) 
and withdrawal are not acceptable methods of contraception. 
f. Barrier methods must always be supplemented with the use of a spermicide.  


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5.3. 
Exclusion Criteria 
A subject who meets any of the following criteria is ineligible for entry into the study: 
 Is pregnant or nursing 
 Has active central nervous system (CNS) or leptomeningeal metastasis  
 Has had a prior malignancy other than the malignancies under study  
Exception: Subject who has been disease-free for 3 years, or a subject with a history of a 
completely resected non-melanoma skin cancer or successfully treated in situ 
carcinoma are eligible. 
 Has thrombocytopenia, neutropenia, or anemia of Grade ≥3 (per CTCAE 4.03 criteria) and 
any prior history of myeloid malignancies, including myelodysplastic syndrome (MDS). 
NOTE: 
 
Bone marrow aspirate/biopsy will be conducted following abnormal 
peripheral blood smear morphology assessment conducted by the local 
laboratory. Cytogenetic testing and DNA sequencing will be conducted 
following an abnormal result of bone marrow aspirate/biopsy. 
 Has a prior history of T-LBL/T-ALL. 
 Has had major surgery within 3 weeks prior to enrollment 
NOTE: 
 
Minor surgery (e.g., minor biopsy, central venous catheter placement) is 
permitted within 3 weeks prior to enrollment. 
 Is unwilling to exclude grapefruit juice, Seville oranges, and grapefruit from the diet and all 
foods that contain those fruits from time of enrollment to the last dose of tazemetostat 
 Has cardiovascular impairment, history of congestive heart failure greater than NYHA 
Class II (see Appendix 4), uncontrolled arterial hypertension, unstable angina, myocardial 
infarction, or stroke within 6 months prior to the planned first dose of tazemetostat; or 
ventricular cardiac arrhythmia requiring medical treatment 
 Subjects taking medications that are known potent or moderate inducers/inhibitors of 
CYP3A4 (including St. John’s Wort) 
 Has an active infection or recent history (<30 days before study drug administration) 
requiring systemic treatment 
 Is immunocompromised, including subjects with known human immunodeficiency virus 
(HIV) infection 
 Has known hypersensitivity to any of the components of IP 
 Is unable to take oral medications, has a history of surgery that would interfere with the 
administration or absorption of oral medication, has malabsorption syndrome or any other 


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uncontrolled gastrointestinal condition (e.g., nausea, diarrhea or vomiting) that might impair 
the bioavailability of IP 
 Has an uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, 
or psychiatric illness/social situations that would limit compliance with study requirements 
 Is unwilling to adhere to contraception criteria from time of enrollment in study to at least 
30 days after last dose of IP 
 A history of bleeding (i.e., hemoptysis, hematuria, GI blood loss, epistaxis, or others with 
greater than Grade 1 according to NCI CTCAE Version 4.03) within 1 month prior to 
beginning therapy or any clinical indications of current active bleeding 
 Clinical history, current alcohol (ethanol), or illicit drug use which, in the judgment of the 
investigator, will interfere with the subject’s ability to comply with the dosing schedule and 
protocol-specified evaluations 
 Regular alcohol consumption averaging more than 7 drinks/week for women and 
14 drinks/week for men within 6 months of screening.  A drink is defined as follows: 
Alcohol 
1 Drink 
(12 g alcohol) 
7 Drinks/week 
(84 g alcohol) 
14 Drinks/week 
(168 g alcohol) 
Wine 
150 mL (5 ounces) 
1050 mL (35 ounces) 
2100 mL (70 ounces) 
Beer 
360 mL (12 ounces) 
2520 mL (84 ounces) 
5040 mL (168 ounces) 
Distilled spirits 
80 proof 
45 mL (1.5 ounces) 
315 mL (10.5 ounces) 
630 mL (21 ounces) 
 


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6. 
STUDY MEDICATIONS 
6.1. 
Investigational Product - Tazemetostat 
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 
Formulation Description: 
200 and 400 mg tablets 
Dosage Form: 
Tablet 
Physical Description:  
The 400-mg tablets are red, modified oval, biconvex, film-coated tablets 
with a length of approximately 18 mm.  The 200-mg tablets are red, round, 
biconvex, film-coated tablets with a diameter of approximately 10 mm.  
Each strength is packaged in white high-density polyethylene bottle with a 
child resistant, tamper-evident polypropylene screw cap. 
Dose/Route/Schedule/Duration:  
400 mg or 800 mg / oral / BID / For up to 6 months 
Abbreviations: BID = twice daily. 
6.1.1 
Preparation, Handling and Storage of Investigational Product  
Preparation: No preparation is needed.    
Handling: The occupational hazards and recommended handling procedures are provided in the 
Material Safety Data Sheet (MSDS).  The MSDS describing the occupational hazards and 
recommended handling precautions will be provided to site staff if required by local laws or will 
otherwise be available from the sponsor upon request. Refer to Pharmacy Manual for additional 
details.  
Storage: IP must be stored at less than 25°C in a secure area with access limited to the 
investigator and authorized site staff.  Refer to study procedures manual for additional 
information on storage requirements.  Refer to Pharmacy Manual for additional details. 
6.1.2 
Procurement of Investigational Product 
The initial shipment of IP, tazemetostat, to a clinical site will occur after all essential regulatory 
documents (including, but not limited to the receipt of the signed protocol signature page, signed 
Form FDA 1572, curriculum vitae of principal investigator and designees, Institutional Review 
Board (IRB)/Ethics Committee (EC) approval letter, and approved informed consent form [ICF]) 
are collected. Refer to the Pharmacy Manual for directions on re-supply shipments.  


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6.1.3 
Accountability 
The investigator/designee will be responsible for taking an inventory of each shipment of IP 
received and comparing it with the accompanying accountability form.  The 
investigator/designee will verify the accuracy of the information on the form, sign and date it, 
and return it to the sponsor or its designee. 
The investigator/designee must keep accurate written records of all IP received from the sponsor.  
Additionally, the investigator/designee must keep accurate records of the IP 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 IP.  Based on the entries in the site accountability forms, it must be 
possible to reconcile IP delivered with that used and returned.  All IP must be accounted for and 
all discrepancies investigated and documented appropriately. 
IP stock may not be removed from the investigative site where originally shipped without prior 
knowledge and consent of the sponsor or its designee.  When authorized, all applicable local, 
state, and national laws must be adhered to for the transfer. 
At the end of the study, all unused vials of IP will be destroyed by the investigative site or sent to 
a designated contractor for disposal on behalf of the sponsor, per the instructions at that time.  
Any IP returned to the sponsor-designated contractors must be counted and verified by site 
personnel and the sponsor or its designee.  All certificates of delivery/receipts and/or return 
forms must be signed prior to shipment.  The receiving contractor must pack IP for return in a 
tamper-evident manner to ensure integrity.  All IP returned must be in accordance with local, 
state, and national laws, and must first be authorized by the sponsor prior to shipment. 
6.2. 
Other Medications  
6.2.1 
Fluconazole 
Product Name:  
Fluconazole  
Formulation Description: 
200 mg tablet 
Dosage Form: 
Immediate release tablet 
Dose/Route/Schedule/Duration:  
400 mg/oral /once daily/ Days 16 – 19 


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6.2.2 
Repaglinide 
Product Name:  
Repaglinide 
Formulation Description: 
 0.5 mg tablet 
Dosage Form: 
 Immediate release tablet 
Dose/Route/Schedule/Duration:  
0.25 mg/oral/single dose/Day 1 and Day 16 
 
6.2.3 
Omeprazole 
Product Name: 
Omeprazole 
Formulation Description: 
20 mg capsule 
Dosage Form: 
Delayed release capsule 
Dose/Route/Schedule/Duration:  
20 mg/oral/once daily/Day 1 and Days 16 −19 
 
6.2.4 
Procurement of Other Medications 
 
Fluconazole, repaglinide, and omeprazole will be locally supplied by each site. 
6.3. 
Dosage and Administration 
Tazemetostat must be dispensed or administered only to subjects enrolled in the study and in 
accordance with the protocol.   
6.3.1 
Tazemetostat 
Upon initiation of tazemetostat administration, tazemetostat will be administered BID (no less 
than 8 hours between doses) as 400 mg tablets for the duration of the study.  Tazemetostat 
400 mg BID administration will start on Day 1 and continue through Day 24 in Part A, and will 
increase to 800 mg BID, continuously, starting on Day 25.  Tazemetostat 800 mg BID 
administration will start on Day 2 in Part B.  Tazemetostat will be administered without regards 
to meals, with the exception of the morning doses on Day 15 and Day 19 in Part A and the 
morning doses on Day 16 and Day 19 of Part B when tazemetostat should be administered at 
least 1 hour before and 2 hours after a meal.  An adequate supply will be provided with 
instructions on home administration.   
Subjects who complete 6 cycles of treatment in the EZH-105 study and transition to the EZH-
501 study will be provided 200 mg tazemetostat tablets as part of the EZH-501 study.  


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6.3.2 
Fluconazole 
Subjects enrolled Part A of the study will receive fluconazole 400 mg orally once daily with 
tazemetostat on Days 16 through 19, inclusive.  Fluconazole can be administered without regards 
to meals.   
6.3.3 
Repaglinide 
Subjects enrolled in Part B of the study will receive a single oral dose of repaglinide 0.25 mg in 
the morning on Days 1 and 16.  Repaglinide administered on Day 16 should be administered 
1 hour (± 5 minutes) after the tazemetostat dose.  Repaglinide should be administered at least 1 
hour before and 2 hours after a meal. 
6.3.4 
Omeprazole 
Subjects enrolled in Part B of the study will receive a single oral dose of omeprazole 20 mg in 
the morning on Day 1.  Omeprazole 20 mg also will be administered once daily, in the morning, 
on Days 16 through 19, inclusive.  Omeprazole administered on Day 16 should be administered 
1 hour (± 5 minutes) after the tazemetostat dose.  Omeprazole should be administered at least 
1 hour before and 2 hours after a meal.   


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7. 
STUDY TREATMENT 
7.1. 
Treatment Assignment  
Subjects will be identified by a unique subject number that will remain consistent for the 
duration of the study. 
7.2. 
Restrictions During Study Treatment 
Subjects will abstain from ingesting Seville oranges and grapefruit or grapefruit juice and 
foods/beverages that contain those, for 24 hours prior to the first dose of study treatment until the 
last dose of study treatment.  Subjects should maintain their usual diet from 7 days prior to the 
first dose of study treatment until the last PK blood sample is collected.  Subjects should avoid 
prolonged exposure to sunlight while receiving study drug.  In addition, subjects should take 
other measures to avoid UV exposure such as wearing sun screen and sun glasses, wearing 
protective clothing, and avoiding tanning beds. 
7.3. 
Dose Modifications:  Criteria for Retreatment, Temporary Discontinuation of 
Treatment, Dose Reduction, and Resumption of Treatment 
Tazemetostat dose reductions and interruptions are not permitted during the first 19 days of 
treatment (both parts of the study).  However, subjects will be replaced if a dose reduction is 
necessary in order to manage toxicity within the first 19 days.  Subjects who miss 2 or more 
consecutive tazemetostat doses during the first 19 days of treatment or miss more than 3 
tazemetostat doses total during the first 19 days of treatment may be replaced. Tazemetostat dose 
reductions and interruptions will be allowed following the first 19 days. An interruption in the 
administration of tazemetostat for more than 14 days must be discussed with the medical monitor 
before treatment can be resumed.  
Toxicity will be managed by concomitant medication (as appropriate), treatment interruption, 
dose reduction, and treatment discontinuation, or a combination of these. During treatment with 
tazemetostat, dose interruption and reduction for subjects who experience tazemetostat-related 
toxicity will be in accordance with the Dose Reduction and Interruption Instructions in Table 7, 
which follows. For any case of T-LBL/T-ALL tazemetostat will be discontinued and patient will 
be followed until resolution of the event. For any case of MDS/MPN/AML or other myeloid 
malignancy, tazemetostat will be held and after discussion with the Investigator, dose modify or 
discontinue the drug. 


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For subjects who require dose interruption due to tazemetostat-related toxicity, the treatment 
may restart once the toxicity has been resolved to Grade ≤ 1 or baseline according to the Dose 
Reduction and Interruption Instructions in Table 7. 


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Table 7: 
Tazemetostat Dose Reduction and Interruption Instructions 
 
 
During Therapy 
Approximate Dose Adjustmentb 
Grade 1 
All occurrences 
Continue tazemetostat  
Maintain dose level 
Grade 2e 
1st occurrence 
Interrupt tazemetostat until 
resolved to Grade ≤ 1 or 
baselineb 
Maintain dose level 
2nd occurrence  
(same or new toxicity) 
Restart at 600 mg BID 
3rd occurrence  
(same or new toxicity) 
Restart at 400 mg BID 
4th occurrence  
(same or new toxicity) 
Discuss with medical monitor 
Grade 3c (not including neutropenia and thrombocytopenia) 
1st occurrence 
Interrupt tazemetostat until 
resolved to Grade ≤ 1 or 
baselineb 
Restart at 600 mg BID 
2nd occurrence  
(same or new toxicity) 
Restart at 400 mg BID 
3rd occurrence  
(same or new toxicity) 
Discontinue tazemetostat 
Not applicable 
Grade 3 Neutropenia (ANC: < 1 – 0.5 × 109/L) 
 
 
 
ANC < 0.75 × 109/L 1st occurrence 
Interrupt tazemetostat until 
resolved to ANC ≥ 0.75 × 
109/L 
Restart at 600 mg BID 
2nd occurrence 
Restart at 400 mg BID 
3rd occurrence 
Discontinue tazemetostat 
Not applicable 
Grade 3 Thrombocytopenia 
1st occurrence 
Interrupt tazemetostat until 
resolved to Grade ≤ 1 or 
baselineb 
Restart at 600 mg BID 
2nd occurrence 
Restart at 400mg BID 
3rd occurrence 
Discontinue tazemetostat 
Not applicable 
Grade 4  
Any occurrence 
Interrupt tazmetostat until 
resolved to Grade 2 or less 
Discuss with medical monitor 
Abbreviations: ANC = absolute neutrophil count, BID = twice daily 
a Excluding alopecia and nausea, vomiting, or diarrhea not receiving adequate treatment. 
b An interruption of tazemetostat for more than 14 days due to any toxicity must be discussed with the Sponsor 
before treatment can be resumed. 
c Excluding Grade 2 and 3 anemia: Subjects are allowed to continue tazemetostat at their current dose level with 
transfusion per investigator discretion. 
 


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7.4. 
Continuation of Treatment 
Subjects who are potentially benefitting (no signs or symptoms of progressive disease) from 
study treatment and have not incurred unacceptable toxicity, may continue treatment with 
tazemetostat by enrolling in Study EZH-501 at the investigator’s discretion with the subject’s or 
his/her legal representative consent after completion of all study procedures and at least 6 months 
of treatment with tazemetostat.   
7.5. 
Treatment Compliance 
The subject will be requested to maintain a medication diary of each dose of study treatment.  
The dosing diary will be returned to the site staff at each visit.  Tazemetostat will be self-
administered at home on non-clinic days. 
7.6. 
Treatment of Overdose 
In the event of an overdose of tazemetostat (defined as administration of more than the protocol-
specified dose), the investigator should contact the medical monitor or their designee 
immediately and closely monitor the subject for AEs/SAEs and laboratory abnormalities.   
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.  If tazemetostat treatment is interrupted or discontinued due to an overdose, the 
subject should be monitored closely until tazemetostat can no longer be detected systemically.  
For reference, 5 half-lives of tazemetostat would be at minimum 25 hours, longer in subject with 
delayed clearance.   
A plasma sample for PK analysis may be requested on a case-by-case basis.  If requested, the 
plasma sample should be collected at least within 7 days from the date of the last dose of study 
treatment.  
The quantity of the excess dose as well as the duration of the overdosing should be documented 
in the electronic case report form (eCRF). 
7.7. 
Tazemetostat Duration of Treatment 
Treatment with tazemetostat for both parts in this study may continue for up to 6 months 
(24 weeks) or until disease progression, unacceptable toxicity, withdrawal of consent, or 
termination of the study by the sponsor.   


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8. 
STUDY ASSESSMENTS AND PROCEDURES 
Investigators may be requested to perform additional safety tests during the course of the study 
based on newly available data to ensure appropriate safety monitoring.  Appropriate local 
regulatory and ethical approvals should be obtained before any additional testing is performed. 
8.1. 
Consent 
The local IRB/EC will determine if consent must be obtained from/for each subject.  The 
IRB/EC should apply local and/or state law(s) related to the age at which an individual is 
considered a minor (child) or an adult for medical decision-making.     
8.2. 
Screening Assessments 
A signed, written informed consent (and assent, if applicable) must be obtained prior to any 
study-specific assessments or procedures being performed. 
All screening assessments, including tumor assessment, must be performed within 28 days of 
enrollment. 
Procedures conducted as part of the subject’s routine clinical management (e.g., blood counts, 
chemistries, imaging studies) and obtained prior to consent may be used for screening provided 
the procedure meets the protocol-defined criteria and has been performed in the timeframe of the 
study. 
8.2.1 
Demographics and Medical History 
A complete medical history will be taken and is to include medical conditions at screening.  
Information to be documented includes demographic information, prior medical illnesses and 
conditions, and surgical procedures. 
8.3. 
Study Assessments 
For study assessments not included in sections below (e.g., vital signs, ECOG performance 
status), refer to the Schedule of Assessments and Procedures (Table 1 and Table 2) for details.  A 
cycle is defined as 28 days. 


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8.3.1 
Physical Examinations 
8.3.1.1. 
Comprehensive Physical Examination 
A comprehensive physical examination of all body systems must be performed at screening and 
on Day 1 of each treatment cycle starting with Cycle 2 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 
Weight is required to be measured at screening, on the first day of each cycle starting with 
Cycle 2 and at the post-treatment visit.  
Height measurement is required at screening only. 
Any abnormalities or changes in intensity noted during the review of body systems should be 
documented in the source document and reported appropriately in the eCRF.  If a new clinically 
significant finding (e.g., not noted at screening) occurs from the initial IP 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 (Table 1 and Table 2). 
8.3.1.2. 
Symptom-Directed Physical Examination 
A symptom-directed physical examination must be performed when a complete physical 
examination is not required by a qualified licensed individual.  This will consist of a focused 
review of systems and physical examination addressing any new symptoms, AEs, or complaints. 
These assessments will be completed as indicated in the Schedule of Assessments and 
Procedures (Table 1 and Table 2). 


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8.3.2 
Electrocardiograms (ECGs) 
The ECGs will be performed as indicated in the Schedule of Assessments and Procedures (Table 
1 and Table 2). Machine-read ECGs should be reviewed by the investigator at the time of the 
assessment.  A single ECG will be recorded unless there is an abnormality, such as prolonged 
QTc F > 480 msec, new arrhythmia, or other clinically significant finding.  If such an 
abnormality is detected, the ECG should be performed in triplicate at least 2 minutes apart.   
Data from ECGs will be entered in the appropriate eCRFs.   
8.3.3 
Optional Chest Ultrasound  
An optional chest ultrasound may be conducted every 8 weeks at the Investigator’s discretion 
while on study to identify early signs of T-LBL/T-ALL. 
8.3.4 
End of Study Assessments  
End of study assessments will be conducted to review AESIs, PK and tumor response. A 3 mL 
blood sample will be required for end of study PK assessments. 
8.3.5 
Disease Assessment  
Disease assessment will be performed as indicated in the Schedule of Assessments and 
Procedures (See Schedule of Events Table 1 and Table 2).  Investigator tumor assessments will 
be performed based on Lugano Classification (Cheson 2014, Appendix 1) for lymphoma and 
RECIST v1.1 (Appendix 2) for solid tumors at each assessment timepoint and entered into the 
appropriate eCRFs.  
8.3.6 
Pharmacokinetics 
All PK blood samples may be drawn from either a central venous catheter or a peripherally 
placed intravenous catheter.   
A separate laboratory manual detailing the PK sample collection, preparation, storage, and 
shipping process will be provided.   
8.3.6.1. 
Part A 
In Part A of the study, blood samples for analysis of plasma tazemetostat and metabolite 
concentrations will be collected on Study Days 15 and 19 and EOS: 


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Study  
Day 
Sample  
Size 
Collection  
Timepointsa 
15 
1 mL 
Predose (within 30 minutes prior to dose), 0.5, 1, 2, 3, 4, 6, and 8 hours postdose 
19 
2 mL 
Predose (within 30 minutes prior to dose), 0.5, 1, 2, 3, 4, 6, and 8 hours postdose 
EOS 
3 mL 
No specified timepoint 
a: Allowable windows for collection of PK blood samples are ± 5 minutes for sample timepoints ≥ 0.5 
 and ≤ 4 hours and ± 30 minutes sample timepoints > 5 hours. 
Approximately 24 mL of blood will be obtained for PK analysis in Part A. Subjects who miss 2 
or more PK blood sample collections may be replaced. 
8.3.6.2. 
Part B 
In Part B of the study, blood samples for analysis of plasma tazemetostat and metabolite 
concentrations will be collected on Study Days 1, 16, and 19 and EOS: 
Study  
Day 
Sample  
Size 
Collection  
Timepointsa 
1 
2 mL 
Predose (within 90 minutes prior to dose) and 0.25, 0.5, 1, 2, 3, 5, and 7 hours postdose 
16 
1 mL 
For analysis of plasma tazemetostat and metabolites:  Predose (within 30 minutes 
prior to dose) and 0.5, and 1 hours after administration of tazemetostat.   
2 mL 
For analysis of repaglinide and its metabolites, omeprazole, 5-OH-omeprazole, and 
omeprazole sulfone:  Predose (within 30 minutes prior to tazemetostat administration) 
and 1.25 and 1.5 h after tazemetostat administration (0.25 and 0.5 h after repaglinide 
and omeprazole administration).   
3 mL 
For analysis of tazemetostat and its metabolites, repaglinide and its metabolite, 
omeprazole, 5-OH-omeprazole, and omeprazole sulfone:  2, 3, 4, 6, and 8 hours after 
tazemetostat administration. 
 
19 
2 mL 
Predose (within 30 minutes prior to dose) and 0.5, 1, 2, 3, 4, 6, and 8 hour postdose 
EOS 
3 mL 
No specified timepoint 
a: Allowable windows for collection of PK blood samples are ± 5 minutes for sample timepoints ≥ 0.25 
 and ≤ 4 hour and ± 30 minutes sample timepoints > 5 hours. 
Approximately 56 mL of blood will be obtained for PK analysis in Part B. Subjects who miss 2 
or more PK blood sample collections may be replaced. 
8.3.7 
Pharmacogenomics (PGx) 
A single whole blood sample (10 mL) is to be collected during the screening phase to provide 
DNA for analysis of genes involved in drug disposition (i.e., absorption, distribution, 
metabolism, and excretion [ADME]).  This will support investigation of whether subject 
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8.3.8 
Tumor Tissue Collection 
Archive formalin-fixed tumor tissue block or 10-15 unstained slides are requested at screening 
from all subjects for molecular characterization, e.g., somatic mutation detection, gene 
expression profiling, and/or proteomic analysis. As available the diagnostic pathology block or 
slides obtained at the time of the subject’s diagnosis and/or time of subsequent procedures is 
acceptable. The sponsor or designee will return all blocks to the original site on completion of 
the planned analyses.  
An effort will be made to obtain paired tumor tissue biopsies before and after initiation of 
treatment with tazemetostat.  An optional lymph node, core-needle biopsy, or bone marrow 
biopsy will be performed during the screening period and on Day 1 of Cycle 2.  A window of 14 
days before and after Day 1 of Cycle 2 will be allowed (i.e., biopsy must be done between Day 
14 of Cycle 1 and Day 14 of Cycle 2).  Biopsies will be performed by a surgeon, if necessary, or 
by interventional radiology.  A cytopathologist will evaluate the biopsy microscopically for 
tumor cells at the time of the biopsy.  If multiple lymph nodes are available, the safest lymph 
node will be selected.  The choice of core biopsy versus incisional or excisional biopsy will be 
made based on safety, accessibility, and the likelihood of being pathologic.  If the subject has a 
single target lesion, this lesion will not be eligible for correlative biopsy.   
All subjects will indicate consent or denial for the optional studies within the main consent form 
for this study. 
Tumor tissue may be analyzed for DNA, mRNA and/or protein endpoints up to and including 
whole genome analysis. The data generated (from subjects who enroll in EZH-501) will be 
combined with equivalent data from additional tazemetostat single-agent studies of NHL 
subjects to determine candidate biomarkers of response to tazemetostat. The results of these 
analyses will be reported outside of this protocol. 
8.3.9 
Clinical Laboratory Assessments 
All clinical laboratory assays will be performed at local laboratories according to the laboratory’s 
normal procedures.  Reference ranges will be supplied by the laboratory and used to assess the 
laboratory data for 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. 


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Hematology:  Hemoglobin, hematocrit, WBC, differential blood count with ANC, platelet count 
and peripheral blood smear morphology are performed at screening and at regular intervals. 
Bone Marrow Aspirate/Biopsy: At screening, a peripheral blood smear will be collected along 
with normal hematology testing and assessed for abnormal morphology. If results are abnormal 
then the patient will be required to undergo a bone marrow aspirate/biopsy conducted by the 
local laboratory. If morphology is abnormal, then cytogenetic testing will be conducted to 
closely monitor patients with cytogenetic testing and DNA sequencing for abnormalities known 
to be associated with MDS (e.g. del 5q, chr 7 abn) and MPN (e.g. JAK2 V617F). If the results 
are abnormal (per the local laboratory) and are associated with myeloid malignancies, the patient 
will be excluded from the study. 
During the study, additional tests including complete peripheral blood smear morphology 
assessment along with normal hematology testing will be included. If the morphology 
assessment shows abnormal results a bone marrow aspirate/biopsy will be required for 
cytogenetic testing and DNA sequencing as conducted by the local laboratory. If cytogenetic 
testing and DNA sequencing shows abnormal results, then tazemetostat will be held and after 
discussion with the Investigator, dose will be modified or drug will be discontinued. 
Coagulation Profile:  This will include: partial thromboplastin (PT), partial thromboplastin time 
(PTT). 
Serum Chemistry:  Serum chemistries are performed at Screening and at regular intervals.   
• Chemistries (liver function) include alkaline phosphatase, ALT, AST, conjugated 
(direct) bilirubin, and total bilirubin 
• Chemistries (renal function) include blood urea nitrogen, creatinine, and electrolytes 
• Chemistries (metabolism) include albumin, calcium, magnesium, glucose, 
phosphorus, total protein, and triglycerides 
Refer to the Schedule of Assessment and Procedures (Tables 1 and 2) for additional details. 
8.3.9.1. 
Vital Sign Measurements 
Blood pressure (BP), heart rate (HR), and temperature must be measured after the subject has 
been sitting for 5 minutes. 


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8.3.9.2. 
ECOG Performance Status 
Subject’s performance status will be assessed using the ECOG performance status tool (see 
Appendix 3). 
8.3.10 
 Pregnancy 
There has been no experience to date of the use of tazemetostat during pregnancy or lactation. In 
an ongoing embryofetal development study, evidence of increased skeletal developmental 
abnormalities in fetuses from the pregnant rats relative to fetuses from control rats was observed. 
Consequently, there is a potential risk for teratogenicity, and precautions must be taken to avoid 
any pregnancy that could potentially be conceived during exposure to tazemetostat by EITHER 
male OR female subjects. 
8.3.10.1.    Definition of Childbearing Potential: Female Subjects 
A female subject is considered of childbearing potential if she: 
• Is anatomically and physiologically capable of becoming pregnant, and 
• Will be or could possibly be sexually active with a male while undergoing study 
treatment with the possibility of posing harm to a fetus 
A female subject is considered to be of non-childbearing potential (i.e., physiologically incapable 
of becoming pregnant) if she: 
• Is postmenopausal (at least 12 months consecutive amenorrheic, at least 45 years of 
age, and has a follicle stimulating hormone level of >40 mIU/mL), or 
• Is surgically sterilized (i.e., bilateral tubal ligation, total hysterectomy, or bilateral 
oophorectomy) with surgery at least 1 month before the first dose of study treatment 
• Has a documented congenital or acquired disorder that is incompatible with 
pregnancy 
8.3.10.2. Definition of Childbearing Potential: Male Subjects 
A male subject is considered of childbearing potential if he: 
• Is anatomically and physiologically capable of causing a pregnancy in a female 
partner, and, 
• Will be or could possibly be sexually active with a female (who is or may become 
pregnant) while undergoing study treatment with the possibility of posing harm to a 
fetus. 


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A male subject is considered to be of non-childbearing potential if he: 
• Has a documented successful vasectomy (with confirmed azoospermia) 
8.3.10.3. Pregnancy Testing  
All female subjects must have a negative pregnancy test (urine or serum) at screening within 28 
days of the first dose of study treatment.   
Subsequent pregnancy tests should be performed predose on the first day of each treatment 
cycle, beginning with Cycle 2, and can be either serum or urine.  Any positive urine pregnancy 
test must be confirmed with a serum test. 
8.3.10.4.  Prevention  
8.3.10.4.1. Female Subjects  
Females of childbearing potential must agree to use a highly effective method of contraception, 
that results in a failure rate of < 1% per year when used consistently and correctly, starting at 
screening, during study treatment, and for 30 days after the final dose of study treatment, and 
have a male partner who uses a condom when using hormonal contraceptives.  
Acceptable highly effective contraception includes: 
• Placement of an intrauterine device 
• Established hormonal contraceptive methods: oral, injectable, or implant, plus an 
additional barrier method.  
NOTE: Female subjects who are using hormonal contraceptives must have been on a 
stable dose of the same hormonal contraceptive product for at least 4 weeks prior to the 
first dose of study treatment and must continue to use the same contraceptive during 
study treatment and for 30 days after discontinuation of study treatment.   
Due to the potential of enzyme induction with tazemetostat, female subjects who use 
hormonal contraceptives should use an additional barrier method of birth control while 
on study treatment and for 30 days after discontinuation of study treatment. 
Female subjects exempt from this requirement are subjects who practice true abstinence when 
this is in line with the preferred and usual lifestyle of the subject (periodic abstinence [e.g., 
calendar, ovulation, sympto-thermal, post-ovulation methods], declaration of abstinence for the 
duration of the trial, and withdrawal are not acceptable methods of contraception), or have a 


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male partner who is vasectomized. If currently abstinent, the subject must agree to use a highly 
effective method of contraception as described above if they become sexually active during 
study treatment, and for 30 days after discontinuation of study treatment.  
8.3.10.4.2. Male Subjects 
Male subjects of childbearing potential must agree to use of condoms with their female partner 
prior to enrollment, during study treatment, and for 30 days after the final dose of study 
treatment. 
8.3.10.5. Reporting of Pregnancy 
The investigator must attempt to collect and report to the sponsor or its designee pregnancy 
information on any female subjects or female partner of male study subjects who became 
pregnant while the subject is enrolled in the study. Pregnancy will not be considered an SAE.  
Any incidence of pregnancy recorded for a female subject or 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.   
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 related 
information. 
Pregnancy complications must be reported as an AE or SAE in addition to 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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9. 
CONCOMITANT MEDICATIONS 
Documentation of all concomitant medication administered during study treatment will be 
recorded in the eCRF at each visit. 
Because there is a potential for interaction of tazemetostat with other concomitantly administered 
drugs through the cytochrome P450 system, over-the-counter medications, or alternative 
therapies must be recorded in the eCRF.  The investigator should be alerted if the subject is 
taking any agent known to affect or with the potential to affect selected CYP450 isoenzymes. 
9.1. 
Permitted Medication(s) 
• Supportive care measures and symptomatic treatment for any treatment-related 
toxicity, including short courses (≤ 5 days) of corticosteroids, if clinically indicated  
• Non-enzyme inducing anti-epileptic drugs 
• Prophylactic use of standard anti-emetics 
• Intermittent use of dexamethasone is permitted as an antiemetic (not to exceed 
0.3 mg/kg/dose dexamethasone or maximum dose of 10 mg/dose) every 12 hours as 
needed   
• Blood and platelet transfusions, as needed per the judgment of the investigator 
9.2. 
Medications to be used with Caution 
Substrates of Pgp, CYP3A, CYP2C8, CYP2C9, CYP2C19, and CYP2D6 should be used with 
caution.  Medications that are substrates of CYP3A, CYP2C8, CYP2C9, CYP2C19, or CYP2D6, 
and have a narrow therapeutic range should be avoided if possible.  Medications that are 
CYP3A, CYP2C8, CYP2C9, CYP2C19, and CYP2D6 substrates that have a narrow therapeutic 
range include, but are not limited to, medications listed in Table 8. 
 
 
 


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Table 8: 
Medications That Are Substrates for CYP3A, CYP2C8, CYP2C9, CYP2C19, 
and CYP2D6 That Have a Narrow Therapeutic Range 
CYP Enzymes 
Substrates with Narrow Therapeutic Range 
CYP2C8 
Paclitaxel 
CYP2C9 
Warfarin, phenytoin 
CYP2C19 
S-mephenytoin 
CYP3A 
Alfentanil, astemizole, cyclosporine, dihydroergotamine, ergotamine, fentanyl, 
pimozide, quinidine, sirolimus, tacrolimus 
CYP2D6 
Thioridazine 
Abbreviations: CYP= cytochrome 
This list is not exhaustive.  Please contact the medical monitor for additional questions. 
NOTE: A listing of CYP substrates can be found using the following link:  
http://medicine.iupui.edu/clinpharm/ddis/table.aspx 
9.3. 
Prohibited Medication(s) 
9.3.1 
All Subjects 
• 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 (ASCO) Guideline for use of white blood 
cell (WBC) growth factors [Smith, 2006]. 
• Treatment with strong inhibitors or inducers of CYP3A4 is prohibited within 7 days prior 
to first dose of study treatment and for the duration of study.  Medications that are strong 
inhibitors or strong inducers of CYP3A4 include, but are not limited to those listed in 
Table 9, which follows.   
• Treatment with moderate inhibitors or inducers of CYP3A4 are prohibited within 7 days 
of the first dose of study treatment until after the final PK blood sample is collected on 


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Day 19 with the exception of fluconazole administered as described in Part A.  
Medications that are moderate inhibitors or moderate inducers of CYP3A4 include, but 
are not limited to those listed in Table 9. 
• Non-approved herbal medications or supplements. 
9.3.2 
Part A 
• Medications that are substrates for CYP3A4 and have a narrow therapeutic range (see 
Table 8) are prohibited from 24 hours prior to the first dose of tazemetostat on Day 1 
until 5 days after the last dose of fluconazole.  
9.3.3 
Part B 
• Administration of repaglinide or omeprazole other than as part of this study is prohibited 
for 7 days prior to administration of the first study dose until the last PK blood sample is 
collected on Day 19.   
• Treatment with strong or moderate inhibitors or inducers of CYP2C8 or CYP2C19 
(including Ginkgo biloba and common sage) is prohibited within 7 days prior to first dose 
of study treatment until after the final PK blood sample is collected on Day 19.  
Medications that are strong or moderate inhibitors or inducers of CYP2C8 or CYP2C19 
include, but are not limited to, those listed in Table 9. 
• Treatment with other oral hypoglycemic medications is prohibited from 7 days prior to 
the first dose of study medication until after the final PK blood sample is collected on 
Day 19. 
• Treatment with medications that increase gastric pH, other than omeprazole as part of this 
study, is prohibited from 7 days prior to the first dose of study medication until after the 
final PK blood sample is collected on Day 19.  
• Concomitant administration of clopidogrel and omeprazole should be avoided.   
 
 


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Table 9: 
Classification of Medications That Are Inhibitors or Inducers of CYP Enzymes 
CYP Enzyme 
Strong Inhibitors 
Moderate Inhibitors 
Strong Inducers 
Moderate 
Inducers 
CYP3A 
Boceprevir, 
clarithromycin, 
conivaptan, grapefruit 
juice, indinavir, 
itraconazole, 
ketoconazole, 
lopinavir/ritonavir, 
mibefradil, nefazodone, 
nelfinavir, posaconazole, 
ritonavir, saquinavir, 
telaprevir, telithromycin, 
voriconazole 
Amprenavir, aprepitant, 
atazanavir, ciprofloxacin, 
darunavir/ritonavir, 
diltiazem, erythromycin, 
fluconazole, fosamprenavir, 
imatinib, verapamil 
Avasimibe, 
barbiturates, 
carbamazepine, 
phenobarbital, 
phenytoin, rifampin, 
St. John’s wort 
Bosentan, 
efavirenz, 
etravirine, 
modafinil, 
nafcillin 
CYP2C8 
Gemfibrozil 
 
 
Rifampin 
CYP2C9 
 
Amiodarone, fluconazole, 
miconazole, oxandrolone 
 
Carbamazepine, 
rifampin 
CYP2C19 
Fluconazole, fluvoxamine, 
ticlopidine 
Esomeprazole, fluoxetine, 
moclobemide, omeprazole, 
voriconazole 
 
Rifampin 
CYP2D6 
Bupropion, fluoxetine, 
paroxetine, quinidine 
Cinacalcet, duloxetine, 
terbinafine 
 
 
Transporter 
Inhibitors 
Inducers 
Pgp 
Amiodarone, azithromycin, captopril, carvedilol, 
clarithromycin, conivaptan, cyclosporine, diltiazem, 
dronedarone, erythromycin, felodipine, itraconazole, 
ketoconazole, lopinavir, ritonavir, quercetin, quinidine, 
ranolazine, verapamil 
Avasimibe, carbamazepine, phenytoin, 
rifampin, St John’s wort, 
tipranavir/ritonavir 
 
NOTE: The list of medications in Table 9 is not exhaustive.  A listing of CYP inhibitors, 
inducers, and substrates can be found using the following links:  
http://medicine.iupui.edu/clinpharm/ddis/table.aspx 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugIntera
ctionsLabeling/ucm093664.htm 
9.4. 
Non-Drug Therapies 
Radiation Therapy:  Palliative radiation therapy will be permitted for pain or severe symptom 
control after discussion with the medical monitor.  
 


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10. 
WITHDRAWAL AND REPLACEMENT OF SUBJECTS 
10.1. 
Withdrawal from Treatment 
The investigator or sponsor may withdraw the subject at any time in the interest of subject safety. 
Additionally, a subject is free to withdraw from treatment at any time for any reason without 
prejudice to future medical care by the physician or at the institution. When the subject 
withdraws from treatment, the reason for the withdrawal and date of last dose of tazemetostat (as 
well as the total treatment period) must be recorded in the eCRF and source documents.  
Similarly, if a subject has died on study, the cause and date of death must be reported as well. 
10.1.1 
Withdrawal of Subjects from Study 
Withdrawal of full consent for a study means that the subjects does not wish to receive further 
protocol-required treatment 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 (e.g., death records).  The investigator must document this agreement regarding 
withdrawal of full consent as well as discuss appropriate procedures for withdrawal from the 
study.   
Reasons for removal of a subject from the study might include the following: 
• Death 
• Decision by sponsor to terminate the study 
• Subject request to withdraw from study 
• Lost to follow-up 
10.2. 
Survival Follow-Up 
Subjects who permanently discontinue study treatment will be followed (by phone, email, or 
clinic visit) for survival every 12 weeks until death, withdrawal of consent, or lost to follow-up.  
Subjects will be followed for up to 2 years. 
Subjects who are continuing on study treatment and have received 6 months of treatment on the 
current study will be followed and treated on Study EZH-501.  


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10.3. 
Subsequent Therapy After Discontinuation of Study Treatment 
Once a subject has permanently discontinued study treatment, every effort should be made to 
have the subject complete the post-treatment follow-up visit prior to initiating any subsequent 
anti-cancer therapy (approved or investigational).  Post-study anti-cancer therapy will not be 
provided as part of this study. The subject may receive subsequent anti-cancer therapy at the 
discretion of the treating physician.  The subsequent anti-cancer therapy should be documented 
on the eCRF. 
10.4. 
Evaluation of Response to Subsequent Anti-Cancer Therapy 
To identify a potential epigenetic priming effect of tazemetostat, subjects who are withdrawn 
from this study due to disease progression and who go on to receive subsequent induction 
therapy should be followed for response whenever possible.  Data to be recorded on the 
subsequent regimen should include agents received, best response, and duration of response 
(DOR). 
10.5. 
Replacement of Subjects 
For both parts of the study, subjects who require a dose reduction of tazemetostat during the first 
19 days of treatment will be replaced.  Subjects who miss 2 or more consecutive tazemetostat 
doses during the first 19 days of treatment or miss more than 3 tazemetostat doses during the first 
19 days of treatment may be replaced.  Subjects who miss 2 or more PK blood sample 
collections may be replaced. 
  


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


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


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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 (e.g., anemia with treatment required and blood transfusion 
recorded as a procedure, hyperglycemia with treatment required and change in insulin dose 
recorded on concomitant medications). 
The investigator should decide, based upon the AE criteria and the clinical condition of the 
patient, whether a change in a laboratory parameter is clinically significant and therefore 
represents an AE. 
If, at the end of the treatment phase with the study drug, there are pathological laboratory values 
which were not present at baseline, further clinical or laboratory investigations should be 
performed until the values return to within reference range or until a plausible explanation (i.e., 
concomitant disease) is found for the pathological laboratory values. 
11.4. 
Other Safety Assessment Abnormalities 
Other safety assessments (e.g., ECGs, radiological scans, vital signs measurements), including 
those that worsen from baseline and events in the medical and scientific judgment of the 
investigator are considered to be clinically significant, are to be recorded as an AE or SAE, in 
accordance with the definitions provided in Sections 11.2.1 and  11.2.2, respectively.   
Any other safety assessment that led to an intervention, including permanent discontinuation of 
study treatment, dose reduction, and/or dose interruption/delay is also to be recorded as an AE or 
SAE.   
Events that meet the criteria for serious but are thought to be associated with progression of 
disease under study should be reported as SAEs but will not typically processed as an expedited 
report to regulatory authorities. 
NOTE: Disease progression per se should not be reported as an SAE. 
11.5. 
Adverse Events of Special Interest (AESIs) 
11.5.1 
T-LBL/T-ALL  
Lymphoblastic lymphomas are considered thymus derived malignancies that have not yet 
completed T-cell maturations. Approximately 90% of lymphoblastic lymphomas are the T-cell 
phenotype and typically occur in young adults and adolescents, accounting for 29% of pediatric 
and 2% of adult NHL with a median age at diagnosis of 25 years (Lai, 2013; Cortelazzo, 2017; 


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Lones, 2007). T-LBL is morphologically and immunophenotypically indistinct from T-ALL, with 
both diseases arising from precursor lymphoid cells of the T-cell lineage (Portell, 2012; Patel, 
2014). Despite the similarities of the two diseases, significant yet unknown characteristics lead to 
differences in clinical presentations (Burkhardt, 2009). Initial clinical manifestation of both adult 
and pediatric T-LBL includes a mediastinal mass or lymphadenopathy with <25% bone marrow 
blasts. Adult T-LBL patients tend to have less thymic disease and greater lymph node disease and 
bone marrow involvement (Baleydier, 2008; Swerdlow, 2008; Campo, 2011). In contrast, T-ALL 
cases predominantly present with bone marrow and peripheral blood disease, and >25% bone 
marrow blasts (Swerdlow, 2008; Campo, 2011). 
On 06 April 2018 an event of T-LBL was observed in a subject on study EZH-102. This event 
was reported to regulatory authorities as a 7-day SUSAR on 13 April 2018 (Case number 
2018USEPZ64380299).  
Following this report, Epizyme conducted a comprehensive evaluation, including:  
• Review of literature and available preclinical/clinical data to better understand event of 
T-LBL.  
• Review of the literature and available preclinical/clinical data to better understand the 
risk of MDS/AML and myeloid malignancies, and other solid tumor malignancies.  
• Assessment of safety, pharmacokinetics (PK) at various doses tested, benefit-risk across 
tumor types in adults and children. 
• Consultation with well recognized external experts in T-cell lymphoma and 
pediatric/adult oncology.  
Based on this evaluation, we continue to believe that tazemetostat is a clinically active drug and 
has the potential to benefit both adult and pediatric patients across different tumor types where 
there are unmet medical needs.  We also conclude that the risk assessment identifies a possible 
direct association between tazemetostat and T-LBL/T-ALL. Epizyme considers the risk for T-
LBL/T-ALL in tazemetostat clinical trials to be largely concentrated in pediatric patients based 
on 1) higher AUC0-24h exposures in pediatric patients and 2) increases over time in age-related 
thymic involution, and 3) the known epidemiology / pathophysiology of T-LBL/ALL. The risk 
of T-LBL/T-ALL in adults is not known, however the incidence of treatment-related T-LBL/T-
ALL in adults is expected to be uncommon. To date, over 702 adults have been treated with 
tazemetostat with no observed cased of T-LBL/ALL. 
 
T-LBL Case 


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The event of T-LBL in a 9-year-old (at the time of enrollment) female subject diagnosed with 
poorly differentiated chordoma occurred on Study Day 432 of treatment with tazemetostat 900 
mg/m2 BID. At the time of the event of T-LBL, the subject was in complete response of her 
target lesions of the disease under study, yet due to presence of 1 of 2 non-target lesion in her 
lung (1 lesion disappeared), was considered overall as a partial responder. The first response was 
observed and measured at Day 54 on treatment. The steady-state AUC0-24h at Cycle 1 Day 15 in 
this subject was 18,784 ng•h/mL and is similar to the mean AUC0-24h at Cycle 1 Day 15 for the 
900 mg/m2 dose group overall (21,000 ng•h/mL, n=5). The study medication was discontinued 
and the subject withdrawn from the study due to the event. 
 
Induction therapy was initiated on 06 April 2018 with the following regimen: cytrarabine, 
daunorubicin, dexamethasone, dexrazoxane. Methotrexate was subsequently started on 13 April 
2018. The 9-year-old subject has since experienced a partial clinical response following standard 
induction chemotherapy, and is expected to have a good overall prognosis as is typical of T-LBL 
in children when treated appropriately.  
The SUSAR of T-LBL resulted in the Sponsor initiating a temporary global halt in enrollment 
for the pediatric study EZH-102. In addition, this event led to a partial clinical hold (PCH) on 
new subject enrollment for tazemetostat by the U.S. (FDA), France (ANSM), and Germany 
(BfArM) across all studies of the Tazemetostat Development Program. For further details, see 
the Investigator’s Brochure, version 8.0. In the event of suspicion of T-LBL/T-ALL or related 
concerns, please refer to Section 7.3 for evaluation and dose adjustments.   
Heightened surveillance will be conducted to monitor and identify early signs and symptoms 
(per local practice/standard of care) of T-LBL/T-ALL so that tazemetostat may be discontinued 
in the subject and treatment can be initiated for these malignancies. If a case of adult T-LBL/T-
ALL occurs enrollment will be suspended and the benefit-risk of the drug will be assessed by the 
Tazemetostat Safety Committee and will be communicated to all Health Authorities and Ethics 
Committees. 
11.5.2 
MDS/AML/MPN 
As of the May 01 2018 data cut, 3 cases of MDS/AML/MPN have been reported. One case of 
MDS/MPN was in a subject with follicular lymphoma receiving 800 mg BID in the E7438-
G000-101 study. The second case of MDS was reported in the EZH-501 rollover study in a 
subject with DLBCL treated with 800 mg BID tazemetostat. A third case, a non-serious AE of 
myelofibrosis was reported in a subject with follicular lymphoma receiving 800 mg BID 
Tazemetostat in E7438-G000-101.  For all three cases, the causality assessment was confounded 
by the subject’s prior treatment history or the presence of the disease before starting 


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tazemetostat. A summary of these 3 cases please refer to the Investigator’s Brochure, Version 
8.0. In the event of suspicion of these malignancies or related concerns, please refer to Section 
6.5 for evaluation and dose adjustments.  Heightened surveillance will be conducted to monitor 
and identify early signs and symptoms (per local practice/standard of care) of any MDS/AML 
and other myeloid malignancies like MPN.  For any MDS/AML or other myeloid malignancies 
like MPN, tazemetostat will be held, and after discussion with the Investigator, tazemetostat will 
be modified or discontinued. All AESIs are to be reported on the eCRF whether or not they meet 
the criteria for an SAE. 
11.5.3 
Other Identified Risks 
• AEs considered related to abnormal bone formation and confirmed by a radiologic 
scan.  
• AEs associated with treatment overdose, misuse, abuse, or medication error; and any 
treatment-emergent significant laboratory abnormality.  
11.5.4 
Tazemetostat Safety Committee  
A safety monitoring committee composed of internal and external medical experts will review 
all AESI cases, including T-LBL/ALL, MDS/AML and other myeloid malignancies like MPN 
(both related and unrelated), and other solid tumor malignancies. Cases will be evaluated for 
suspected relationship to tazemetostat and adjudicated by the experts. Recommendations for next 
steps per the risk management plan will be communicated to the CMO.  
11.6. 
Grading and Severity 
The severity of all AEs and SAEs, including appropriate laboratory values, will be graded 
utilizing the NCI CTCAE Version 4.03.  The link to the NCI CTCAE Version 4.03 is: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf 
In the event that an AE is not covered by the CTCAE, the assessment of severity will be 
determined by using the CTCAE general guideline: 


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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 ADLa 
Grade 3: 
Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care ADLb 
Grade 4: 
Life-threatening consequences; urgent intervention indicated. 
Grade 5: 
Death related to AE. 
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 11.2.2 which are based on patient/event outcome or 
action criteria associated with events that pose a threat to a subject’s life or functioning 
11.7. 
Relationship Categorization 
A qualified investigator must make the determination of relationship to tazemetostat for each AE 
or SAE.  The investigator should decide whether, in his or her medical judgment there is a 
reasonable possibility that the event may have been caused by tazemetostat.   
11.7.1 
Assessing Relationship to Study Treatment 
The following should be considered when assessing the relationship of an AE to study treatment: 
• Temporal relationship of the onset of the event to the first dose of tazemetostat 
• The course of the event, considering especially the effect of discontinuation of study 
treatment or the reintroduction of study treatment, as applicable 
• Whether the event is known to be associated with the study treatment or with other 
similar treatments 
• The presence of risk factors in the study subject known to increase the occurrence of 
the event 
• The presence of non-study treatment-related factors that are known to be associated 
with the occurrence of the event. 


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The relationship of an AE to study treatment is to be classified as follows: 
• Not Related: A causal relationship between tazemetostat and the AE is not a 
reasonable possibility. 
• Related:  A causal relationship between tazemetostat and the AE is a reasonable 
possibility (includes probably, possibly, and definitely related).   
If the causal relationship between an AE/SAE and tazemetostat is related, that determination will 
be used for purposes of expedited regulatory reporting. 
11.8. 
Outcome Categorization 
Outcome of an AE/SAE may be classified as resolved, resolved with sequelae, unresolved, or 
death. 
All treatment-related AEs/SAEs will be followed to resolution (the subject’s health has returned 
to his/her baseline status or all variables have returned to normal), or until an outcome is reached, 
stabilization occurs (the investigator does not expect any further improvement or worsening of 
the event), or the event is otherwise explained, regardless of whether the subject is still 
participating in the study.  Where appropriate, medical tests and examinations will be performed 
to document resolution of the event(s). 
11.9. 
Timeframe for Reporting AEs and SAEs 
AEs: AEs will be collected from the time the first dose of study treatment is administered until 
the earlier of either 30 days after the discontinuation of study treatment or until the initiation of 
subsequent anti-cancer therapy.  
SAEs: SAEs will be collected over the same time period as stated above for AEs.  In addition, 
any SAE assessed as related to study participation (e.g., protocol-mandated procedures, invasive 
tests, or change in existing therapy), study treatment must be recorded from the time a subject 
provides consent to participate in the study up to and including any follow-up contact. All SAEs 
will be reported to the sponsor within 24 hours.   
After discontinuation of study treatment:  The investigator will monitor all ongoing 
AEs/SAEs until resolution or stabilization of the event or until the subject is lost to follow-up.  
Up until 30 days after the last dose of study treatment or until the initiation of subsequent anti-
cancer therapy, whichever is earlier, the investigator may report any AE that they consider to be 
possibly related to study treatment.   


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11.10. 
Reporting of SAEs 
All SAEs will be reported within 24 hours of the investigator becoming aware of the event.  The 
investigator must promptly notify the sponsor or its designee of all SAEs in order that the legal 
obligations and ethical responsibilities of the sponsor or its designee are met. 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of the IP under clinical investigation.  The sponsor and its 
designee will comply with country specific regulatory requirements relating to safety reporting to 
the regulatory authority, IRB/EC/CEC and investigators. 
Any AE that is both unexpected (not consistent with the applicable product information) and also 
meets the definition of a suspected unexpected serious adverse reaction (SUSAR). All SUSARs 
will be reported within 24 hours of the investigator becoming aware of the event.  Investigator 
safety reports are prepared for SUSARs according to local regulatory requirements and the 
sponsor policy and are forwarded to investigators as necessary.  The sponsor is legally obligated 
to report the event to the regulatory authorities within 7 days for fatal or life-threatening 
SUSARs or 15 days for all other SUSARs. 
An investigator who receives an investigator safety report describing a SAE(s) or other specific 
safety information (e.g., summary or listing of SAEs) from the sponsor will file it with the IB 
and will notify the IRB/EC/CEC, if appropriate according to local requirements. 
11.10.1 
Regulatory Authorities, IRB/EC, and Central Ethics Committees (CEC)  
The sponsor or its designee is responsible for notifying the investigational sites of all expedited 
SAEs.  The sponsor or designee shall also notify CEC of new serious, related, and unexpected 
AE(s) or significant risks to subjects, per country requirements. 
The investigator will notify the IRB/EC/CEC of serious, related, and unexpected AE(s) or 
significant risks to subjects, per local country requirements.  The investigator must keep copies 
of all AE information, including correspondence with the sponsor or local IRB/EC/CECs on file. 
It is the responsibility of the Principal investigator to notify the IRB/EC of all SAEs that occur at 
his/her site.  Investigators will be notified of all suspected, unexpected SAEs (7/15-Day Safety 
Reports) that occur during any clinical studies that are using the investigative compound.  Each 
site is responsible for notifying their IRB/EC/CEC of these additional SAEs. 


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All studies that are conducted within any European country will comply with the European CTD 
2005/28/EC and CTD 2001/20/EC.  All SUSARs will be reported as required to the Competent 
Authorities of all involved European member states. 


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


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13. 
STATISTICAL METHODS 
13.1. 
Hypotheses 
Results of this study will be descriptive and no hypothesis will be tested. 
13.2. 
Study Design Considerations 
13.2.1 
Determination of Sample Size 
The sample size was determined based on feasibility considerations.  A total of 12 subjects per 
part is adequate to describe the effect of CYP3A inhibition on the PK of tazemetostat, the effect 
of tazemetostat on the PK of repaglinide and omeprazole, and the effect of medications that 
increase gastric pH on tazemetostat PK. 
This study will provide a point estimate and associated 90% confidence intervals on the 
magnitude of the effect of the perpetrator drugs on the PK of the victim drugs.  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 clinically significant 
differences are present.  The operating characteristics of this hypothesis test depend on the 
underlying within-subject correlation of subsequent measurements of the same PK parameter. If 
subsequent measurements of tazemetostat AUC have a correlation of at least 0.885, this test is 
powered at 80% or higher (results from simulation assuming standard deviation of log AUC = 
0.5149 from the pilot study). Assuming the null hypothesis of this test is assumed to be >±5% 
effect, the simulated alpha level is 0.006. 
The precision in the confidence limits is difficult to succinctly characterize given the unknown 
intra-subject variability and the exponential transformation. The corresponding hypothesis test to 
the 90% CI has at least 93% power for the alternative of doubling (or halving) of the 
tazemetostat AUC, assuming within-subject correlation of at least 0.8. 
13.2.2 
Sample Size Re-Estimation 
The sample size will not be re-estimated during this study. 


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13.3. 
Data Analysis Considerations 
13.3.1 
Analysis Populations 
The Intent-to-Treat (ITT) population will consist of all subjects who receive at least one dose 
of tazemetostat. The ITT population will be used for summaries and analyses of the efficacy 
endpoints. 
The Safety population will consist of all subjects in the ITT population who receive at least one 
dose of IP and have at least one postdose safety observation recorded. The Safety population will 
be used for summaries and analyses of the safety and tolerability. 
The Pharmacokinetic (PK) population will include all subjects in the ITT population who have 
sufficient postdose samples collected to allow estimation of the PK parameters. The PK 
population will be used for PK summaries and analyses. 
The Pharmacogenomic (PGx) population will include all subjects in the PK population from 
whom PGx results are available. The PGx population will be used for summary of PK 
parameters by presence or absence of polymorphic genetic markers. 
13.3.2 
Interim Analyses 
Interim analyses will not be performed.   
13.3.3 
Key Elements of the Analysis Plan 
The statistical analyses will be performed on log-transformed PK parameters. The log-
transformed PK parameters will be analyzed by an analysis of variance (ANOVA). The ANOVA 
will use a mixed-effects model with treatment as a fixed effect and subject as a random effect. 
The anti-logs of the confidence limits of the 90% CI for the difference in the treatment means of 
the log-transformed data are a 90% CI for the ratio of geometric means between the test and 
reference treatment. The geometric least squares (adjusted) mean and associated 90% CI for the 
test treatment to reference treatment ratio of adjusted geometric means will be provided after 
transformation of the results from the log-transformed analysis back to the original scale. 
Complete details of the analysis plan will be provided in the Statistical Analysis Plan (SAP). Any 
deviations from, or additions to, the original analysis plan in this protocol will be documented in 
the SAP and the CSR. 


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13.3.3.1. Part A 
Descriptive statistics will be calculated. Plasma concentrations of tazemetostat and its 
metabolites will be listed for each subject and summarized by treatment (tazemetostat alone and 
tazemetostat plus fluconazole) and time point. PK parameters will be listed for each subject and 
summarized by treatment (tazemetostat alone and tazemetostat plus fluconazole). Plasma 
concentrations of fluconazole will be listed for each subject and summarized by time point. PK 
parameters for fluconazole will be listed for each subject and summarized. 
To evaluate the effect of fluconazole on the PK of tazemetostat, a 90% CI for the ratio of 
adjusted geometric means for the test treatment to the reference treatment for  tazemetostat Cmax 
and AUC will be calculated. Tazemetostat administered without fluconazole will be considered 
the reference treatment and tazemetostat administered in combination with fluconazole will be 
considered the test treatment.  
13.3.3.2. Part B 
Descriptive statistics will be calculated. Plasma concentrations of repaglinide and its metabolites, 
omeprazole, 5-OH-omeprazole, and omeprazole sulfone will be listed for each subject and 
summarized by treatment (repaglinide and omeprazole; repaglinide and omeprazole plus steady-
state tazemetostat) and time point. PK parameters will be listed for each subject and summarized 
by treatment (repaglinide and omeprazole; repaglinide and omeprazole plus steady-state 
tazemetostat). Plasma concentrations of tazemetostat will be listed for each subject and 
summarized by day (Day 16 and Day 19) and time point. PK parameters for tazemetostat will be 
listed for each subject and summarized by treatment (tazemetostat administered 1 h before 
repaglinide and omeprazole and tazemetostat administered after 4 days of omeprazole 
administration). 
To evaluate the effect of tazemetostat on the PK of repaglinide and omeprazole, a 90% CI for the 
ratio of adjusted geometric means for the test treatment to the reference treatment for repaglinide 
and omeprazole Cmax and AUC will be calculated. Repaglinide and omeprazole administered 
without tazemetostat will be considered the reference treatment. Repaglinide and omeprazole 
administered in combination with steady-state tazemetostat will be considered the test treatment.  
To evaluate the effect of omeprazole on the PK of tazemetostat, a 90% CI for the ratio of 
adjusted geometric means for the test treatment to the reference treatment for tazemetostat Cmax 
and AUC will be calculated. Tazemetostat administered 1 hour before repaglinide and 


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omeprazole on Day 16 will be considered the reference treatment. Tazemetostat administered 
after 4 days of omeprazole administration (Day 19) will be considered the test treatment 
13.4. 
Pharmacogenomic Analyses (PGx) 
Subjects who consent to PGx research will be genotyped for polymorphisms on genes for CYP 
enzymes. PGx parameters will be summarized by treatment and the presence or absence of 
polymorphic genetic markers. 
13.5. 
Efficacy Analyses 
Overall response rate is defined as the percentage of subjects achieving a CR or PR from the start 
of treatment until disease progression or the start of subsequent anti-cancer therapy, as per 
Lugano Classification [Cheson 2014] for subjects with lymphoma or RECIST v1.1 [Eisenhauer] 
for subjects with solid tumors. Subjects evaluated with RECIST require confirmation of CR or 
PR at least 28 days from the initial response assessment. Subjects with an unknown or missing 
response will be treated as non-responders, i.e., they will be included in the denominator when 
calculating the percentage. An exact 90% CI for the overall response rate will be provided.  
Response duration, for the subset of subjects with CR or PR response, is defined as the interval 
of time from the first documented evidence of CR or PR until the first documented disease 
progression or death due to any cause, using disease-appropriate standardized response criteria. 
The duration of response (DOR) will be calculated for each subject with a CR or PR (lymphoma) 
or confirmed CR or PR (solid tumors). A listing of DOR will be provided. 
Disease control rate (DCR) is defined as the percentage of subjects achieving CR or PR, or SD 
lasting 24 weeks since start of treatment until disease progression or the start of subsequent anti-
cancer therapy. The DCR will be summarized in a similar manner as overall response rate and 
duration.  
Overall survival (OS) is defined as the interval of time between the date of the first dose of 
tazemetostat and the date of death due to any cause. For subjects surviving at the time of the OS 
analysis, the time of death will be censored at the date of last contact. OS will be calculated using 
the Kaplan-Meier method. If there are a sufficient number of deaths at the time of the analysis, 
median OS, first and third quartiles, and 90% CI (Brookmeyer-Crowley method) will be 
summarized. A figure and listing of OS will also be provided.  


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Summaries will be presented by study part and overall. Data on disease status in subjects 
enrolled in this study will be listed. 
13.6. 
Safety Analyses 
13.6.1 
Extent of Exposure 
The data on exposure to tazemetostat will be listed. Details pertaining to dose interruption or 
dose modification will also be listed. 
13.6.2 
Adverse Events 
The data listings of AEs in the CSR will contain the verbatim description, preferred term, and 
SOC MedDRA-level terms. 
Treatment-emergent AEs (TEAEs) are defined by applying treatment-emergent signs and 
symptoms (TESS) philosophy. AEs will be regarded as TEAEs if one of the following conditions 
is met: 
• Emerge after the time of first dose administration, having been absent prior to the first 
dose. 
• Re-emerge, having been present but stopped prior to the time of first dose administration. 
• Worsen in severity after the time of first dose administration relative to the pre-treatment 
state, when the AE is continuous. 
An AE with partial or completely missing start date and/or time will always be assumed as 
TEAE, unless it can be determined to be “prior to administration” from the incomplete start 
date/time or resolution date/time (e.g., month, year is before first administration date, or 
resolution date is before first administration date). 
Only TEAEs will be summarized. Summaries of TEAEs will consist of the number and 
percentage of subjects reporting the AE by SOC and by preferred term. TEAEs which occur 
more than once for a subject will be counted only once in the subject frequencies. TEAEs with 
different CTCAE grades for a subject will be counted at the worst (highest) grade for the same 
SOC (likewise for preferred term). TEAEs with different drug relationship for a subject will be 
counted at strongest relationship for the same SOC (likewise for preferred term). TEAEs with 
missing relationship to study treatment will be counted as “related”. TEAEs with missing 
CTCAE grade will be counted as Grade 3 (“severe”). 


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Summaries of TEAEs by study part and overall will be produced to present the number and 
percentage of subjects with: 
• 
Any TEAE 
• 
Any treatment-related TEAE 
• 
Any TEAE with NCI CTCAE Grade 3 or higher 
• 
Any TEAE leading to study treatment discontinuation 
• 
Any Serious TEAEs 
• 
Any TEAE of special interest 
Listings will be provided for the following: 
• 
AEs 
• 
TEAEs leading to study treatment discontinuation 
• 
Serious TEAEs 
• 
Fatal TEAEs 
• 
TEAEs of special interest 
13.6.3 
Clinical Laboratory Evaluation 
All clinical laboratory parameters will be standardized according to the International System of 
Units (SI) prior to summarization. Separate listings and summary tables (by study part and 
overall) will be produced for each laboratory test group (complete blood counts, serum 
chemistries (liver, renal [with creatinine clearance, if creatinine is abnormal] and metabolism), 
coagulation profile, and urinalysis). 
Complete blood counts, serum chemistries and coagulation will be summarized at each planned 
visit assessment, and for change from baseline using descriptive statistics (mean, STD, median, 
minimum, and maximum). Categorical values will be summarized using number of observations 
and percentages (urinalysis assessment). 
Low, normal, and high (LNH) classifications will be applied to determine whether the laboratory 
test value was below (L), within (N), or above (H) its reference range. Shifts from baseline in 
LNH classification and clinically significant findings for each parameter will be summarized by 
study part and overall at each planned post-baseline visit. The summary will include the worst-
case shift from baseline during the post-baseline period, which will include both planned 
(scheduled) and unscheduled visits after the first dose of study drug. Subjects with laboratory 
data outside the normal range will be flagged as “L” (Low) or “H” (High) in the data listing. 


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The worst-case shift from baseline in terms of the clinically significant findings in each 
laboratory test group will be summarized separately. 
Unless otherwise specified, the denominator in percentage calculation at each visit will be based 
on the number of subjects with non-missing value at the specified visit. 
13.6.4 
Other Safety Measures 
The results of scheduled assessments of physical examination, vital signs, ECG, and ECOG 
performance status will be summarized by study part and overall. Summaries will include data 
from scheduled visits. Shifts from baseline will be summarized where appropriate. All data will 
be listed. 
13.7. 
Pharmacokinetic Analyses 
Plasma concentrations of all analytes will be determined by validated bioanalytical methods. 
Plasma concentrations of all analytes will be listed for each subject and summarized by study 
part, treatment, day, and nominal time. Standard summary statistics will be calculated 
(i.e., arithmetic mean, STD, median, minimum, and maximum) for each endpoint.   
13.7.1 
Plasma Pharmacokinetics  
All PK parameters will be calculated with noncompartmental methods using actual times. The 
following PK parameters will be determined as data permit: 
Part A: Plasma AUC0-8, Cmax, Tmax, and t1/2 for tazemetostat and tazemetostat metabolites on 
Day 15 and Day 19. Plasma AUC0-12 will be calculated for tazemetostat only on Day 15 and Day 
19. Plasma AUC0-8, Cmax, and Tmax for fluconazole on Day 19. 
Part B: Plasma AUC0-t, AUC0-∞, Cmax, Tmax, and t1/2 of repaglinide and its metabolites, 
omeprazole, 5-OH-omeprazole, and omeprazole sulfone on Days 1 and 16. The metabolite to 
repaglinide ratio for AUC0-∞ and AUC0-t after administration with omeprazole on Day 1 and after 
administration with omeprazole and tazemetostat on Day 16. The metabolite to repaglinide 
concentration ratio at 1, 2, 3, 5, and 7 hours after administration on Days 1 and 16. The 5-OH-
omeprazole to omeprazole ratio for AUC0-∞ and AUC0-t and the omeprazole sulfone to 
omeprazole ratio for AUC0-∞ and AUC0-t after administration with repaglinide on Day 1 and after 
administration with repaglinide and tazemetostat on Day 16. The 5-OH-omeprazole to 
omeprazole concentration ratio at 1, 2, 3, 5, and 7 hours after administration on Days 1 and 16. 
The omeprazole sulfone to omeprazole concentration ratio at 1, 2, 3, 5, and 7 hours after 
administration on Days 1 and 16. Plasma AUC0-8, AUC0-t, Cmax, Tmax, and t1/2 of tazemetostat on 
Days 16 and 19. 


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Plasma AUC0-8, Cmax, Tmax, and t1/2 for tazemetostat and tazemetostat metabolites on Day 16 and 
Day 19. Plasma AUC0-12 will be calculated for tazemetostat only on Day 16 and Day 19. 
 


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14. 
STUDY CONDUCT CONSIDERATIONS  
14.1. 
Posting of Information on Publicly Available Clinical Trial Registers 
Study information from this protocol will be posted on publicly available clinical trial registers 
before subject enrollment begins. 
14.2. 
Regulatory and Ethical Considerations 
The procedures set out in this study protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the sponsor and investigators abide by 
GCP as described in the ICH Tripartite Guideline E6 (R1): GCP: Consolidated Guideline, and 
for US Investigators, 21 CFR Parts 50, 54, 56, and 312. Compliance with these regulations also 
constitutes compliance with the ethical principles described in the current revision of the 
Declaration of Helsinki. The study will also be carried out in keeping with local legal and 
regulatory requirements. 
It is the investigator’s responsibility to ensure that adequate time and appropriate resources are 
available at the study site prior to commitment to participate in this study. The investigator 
should also be able to estimate or demonstrate a potential for recruiting the required number of 
suitable subjects within the agreed recruitment period. 
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks. An up-to-date copy of the curriculum vitae for the 
investigator, sub-investigator(s) and essential study staff will be provided to the sponsor or its 
designee before starting the study. 
If the subject has a primary physician the investigator should, with the subject’s or his/her legal 
representative’s consent, inform them of the subject’s participation in the study. 
14.2.1 
Institutional Review Board (IRB)/ Ethics Committee (EC)/Central Ethics 
Committee (CEC) 
It is the responsibility of the investigator to submit this protocol, the informed consent document 
(approved by the sponsor or its designate), relevant supporting information and all types of 
subject recruitment information to the IRB/EC for review. All must be approved prior to site 
initiation. Prior to implementing changes in the study, the sponsor and the IRB/EC must also 
approve any revised ICFs and/or protocol amendments. 


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On the IRB/EC approval letter, the study reference, the date of review, and actions taken should 
be clearly stated. 
Clinical supplies of IP will not be released to the site and recruitment of subjects will not begin 
until the IRB/EC written approval has been received by the sponsor or its designee. 
The investigator is responsible for keeping the IRB/EC apprised of the progress of the study and 
of any changes made to the protocol and/or ICF. The investigator must also keep the IRB/EC 
informed of any serious and significant AEs. 
14.2.2 
Informed Consent Process 
It is the responsibility of the investigator to obtain written informed consent from each subject 
before any protocol-specific assessments and/or procedures are performed. All consent 
documentation must be in accordance with applicable regulations and GCP. Each subject or the 
subject’s legally authorized representative is requested to sign the ICF after the subject has 
received and read the written subject information and received an explanation of what the study 
involves, including but not limited to: the objectives, potential benefits and risk, inconveniences, 
and the subject’s rights and responsibilities. A copy of the ICF (subject information sheet and the 
ICF, as applicable) must be given to the subject or the subject’s legally authorized representative. 
If applicable, it will be provided in a certified translation of the subject’s local language. Signed 
ICFs must remain in each subject’s study file and must be available for verification by study 
monitors at any time. 
Each investigator will provide the sponsor or its designee with a copy of the IRB/EC approved 
ICF(s), and a copy of the IRB/EC written approval, prior to the start of the study. Additionally, if 
the IRB/EC requires modification of the sample subject information and the model ICF provided 
by the sponsor, the documentation supporting this requirement must be provided to the sponsor. 
14.3. 
Subject Confidentiality and Access to Source Documents/Data 
Subject confidentiality is strictly held in trust by the sponsor and/or their designee(s), 
participating investigators, and any staff. This confidentiality includes the clinical information 
relating to participating subjects, as well as any genetic or biological testing. 
The study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the sponsor. 


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The study monitor or other authorized representatives of the sponsor may inspect all documents 
and records required to be maintained by the investigator, including but not limited to, medical 
records (office, clinic, or hospital) and pharmacy records for the subjects in this study. The 
clinical study site will permit access to such records. 
14.4. 
Study Monitoring 
Monitoring of the study will be performed by the sponsor or its designee(s). At the monitoring 
visits, the progress of the study will be discussed with the investigator, or his/her representative. 
The ICFs will be reviewed for signatures and the eCRFs checked for completeness and accuracy. 
Subject source data must be available for review. The investigator and his/her staff are expected 
to cooperate with the study monitor and be available during at least a portion of the monitoring 
visit to review the eCRFs and any queries/resolutions, answer questions, and provide any 
missing information. 
The study monitor will record the date of each visit together with a summary of the status and 
progress of the study. Proposed actions will be confirmed with the investigator in writing. 
Telephone contact will be made with the investigator as necessary during the data collection 
period and during the data and report writing periods. 
14.5. 
Protocol Deviations 
The clinical sites will adopt all reasonable measures to record data in accordance with the 
protocol. Under practical working conditions, however, some minor variations may occur due to 
circumstances beyond the control of the clinic. All such deviations will be documented in the 
study records, together with the reason for their occurrence; where appropriate, deviations will 
be detailed in the CSR. Investigative sites will contact the medical monitor to request 
clarifications regarding any aspect of the clinical study or eligibility of subjects. 
When an emergency occurs that requires a deviation from the protocol for an individual subject, 
the deviation will be only for that subject. The investigator or other physician in attendance in 
such an emergency will, if circumstances and time permit, contact the sponsor or their 
representative(s), immediately by telephone. Such contacts will be made as soon as possible to 
permit a decision as to whether or not the subject (for whom the protocol deviation was affected) 
is to continue in the study. The source documentation will completely describe the protocol 
deviation and state the reasons for such deviation. In addition, the IRB/EC/CEC will be notified 
in writing of such protocol deviation. 


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14.6. 
Protocol Amendment 
All amendments to the protocol must be documented in writing, reviewed, and approved by the 
investigator and the sponsor, and submitted to the IRB/EC/CEC for approval prior to initiation, 
except in cases where required for subject safety. If the protocol amendment substantially alters 
the study design or potential risk to the subject, a new written ICF for continued participation in 
the study must be obtained from each subject or his/her legal representative. 
14.7. 
Suspension or Termination of Study 
Should conditions requiring further clarification arise before the decision to proceed with or 
terminate the study can be reached, the study will be suspended until the situation has been 
resolved. 
The sponsor has the right to terminate this study and remove all study material from the site at 
any time. Examples of where this might occur include, but are not limited to: 
• When it becomes apparent that subject enrollment is unsatisfactory with respect to 
quality and/or quantity or data recording is inaccurate and/or incomplete on a chronic 
basis. 
• When the incidence and/or severity of AEs in this study indicates a potential health 
hazard caused by treatment with tazemetostat. 


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15. 
ADMINISTRATIVE PROCEDURES 
15.1. 
Recording and Access and to Study Records 
As described in the ICH GCP Guidelines, ‘essential documents’, including eCRFs, source 
documents, consent forms, laboratory test results, and the IP inventory records, should be 
retained by the investigator until at least 2 years after the last approval of a marketing application 
in an ICH region and until there are no pending or contemplated marketing applications in an 
ICH region or at least 2 years have elapsed since the formal discontinuation of clinical 
development of the IP. These documents should be retained for a longer period however if 
required by the applicable regulatory requirements or by an agreement with the sponsor or its 
designee. It is the responsibility of the sponsor to inform the investigator/institution as to when 
these documents no longer need to be retained. The investigator must obtain written permission 
from the sponsor or its designee prior to the destruction of any study document. 
These records must be made available at reasonable times for inspection and duplication, if 
required, by a properly authorized representative of the US FDA in accordance with the US Code 
of Federal Regulations, 21 CFR 312.68, or other regulatory authorities in accordance with 
regulatory requirements. 
15.2. 
Case Report Forms 
eCRFs will be used for data collection for this study. 
The investigator is responsible for maintaining adequate and accurate source documents from 
which accurate information will be transcribed into eCRFs, which have been designed to capture 
all observations and other data pertinent to the clinical investigation. The eCRFs should be 
completed by the investigator or delegate as stated on the Delegation of Authority Log. 
Overwriting of information or use of liquid correcting fluid is not allowed in the source 
document. 
Each investigative site will be visited as frequently as documented in the monitoring plan by the 
sponsor or their designee to review the eCRFs for completeness and accuracy. The sponsor or 
their designee will highlight any discrepancies found between source documents and the 
completed eCRFs and ensure that appropriate site personnel address the discrepancies. When a 
discrepancy results in corrected eCRF data, the correction will be reviewed again against the 
correct source documentation. Uniform procedures will be discussed at the Site Initiation Visit. 


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The eCRFs must be reviewed and electronically signed and dated by the investigator once all 
data has been entered and all queries resolved. Once the study monitor has verified the contents 
of the completed eCRFs against the source data, queries may be raised if the data are unclear or 
contradictory. The investigator must address all queries. 
15.3. 
Quality Assurance and Quality Control 
A site monitoring plan will be developed to ensure the human subject protection, study 
procedures, laboratory, study intervention administration, and data collection processes are of 
high quality and meet the sponsor's, ICH/GCP, and other applicable regulatory guidelines. 
The investigator will permit authorized the sponsor or its designee(s) and the respective 
regulatory authorities to inspect facilities and records relevant to this study if needed. 
Initial site training will be provided by the sponsor or its designee. Training for new site staff 
will be provided by current study nurses and study coordinators under the supervision of the 
primary investigator. Additional training will be provided by the sponsor or its designee as 
needed. 
The designated Data Management Team will implement quality control (QC) procedures 
beginning with the data entry system and generate data QC checks that will be run on the 
database. Any missing data or data anomalies will be communicated to the site(s) for 
clarification/resolution. 
15.4. 
Data Quality Assurance 
This study will be organized, performed, and reported in compliance with the sponsor or its 
designee's Standard Operating Procedures, protocols and working practice documents, and the 
requirements of ICH/GCP guidelines. Compliance will be achieved through a combination of 
study-specific audits of investigative sites and audits at regular intervals of the sponsor or its 
designee's systems for data handling, analysis, and reporting.  
15.5. 
Confidentiality 
Data collected during this study may be used to support the development, registration, or 
marketing of tazemetostat. After a subject or his/her legal representative have consented to take 
part in the study their medical records and the data collected during the study will be reviewed 
by the sponsor and/or its designee. These records and data may be reviewed by the following: 
independent auditors who validate the data on behalf of the sponsor; third parties with whom the 


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sponsor may develop, register, or market tazemetostat; national or local regulatory authorities, 
and the IRB/EC/CEC(s) which gave its/their approval for this study to proceed. 
Although subjects will be known by a unique identifier number, their year of birth will also be 
collected and used to assist the sponsor and/or its designee to verify the accuracy of the data, for 
example, that the laboratory results are assigned to the correct subject. 
15.6. 
Audit/Inspection 
To ensure compliance with relevant regulations, data generated by this study will be available for 
inspection upon request by representatives of the US FDA as well as other national and local 
regulatory authorities, the sponsor and/or its designee, interested commercial parties, and the 
IRB/EC/CEC for each study site. 
15.7. 
Record Retention 
As applicable, study records will be maintained a minimum of 5 years beyond (1) the publication 
of any abstract or manuscript reporting the results of the protocol; (2) the submission of any 
sponsored research final report; or (3) submission of a final report to clinicaltrials.gov. 
15.8. 
Provision of Study Results and Publication 
A summary of the study results will be made publicly available within 12 months of reaching the 
end of the study, defined as the date of the last subject’s last visit. A full CSR will be made 
publicly available no later than 18 months after the end of the study. 
If a manuscript is published in a peer-reviewed journal, then that initial release may be an 
abstract that meets the requirements of the International Committee of Medical Journal Editors. 
All manuscripts, abstracts or other modes of presentation arising from the results of the study 
must be reviewed and approved in writing by the sponsor, in advance of submission. The review 
is aimed at protecting the sponsor’s proprietary information existing either at the date of the 
commencement of the study or generated during the study. 
The detailed obligations regarding the publication of any data, material results, or other 
information, generated or created in relation to the study shall be set out in the agreement 
between each investigator and the sponsor. 
 
 


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16. 
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germinal center formation and somatic EZH2 mutations promote lymphoid transformation. 
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Copeland RA. Molecular pathways: protein methyltransferases in cancer. Clin Cancer Res. 
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Harbour JW, Onken MD, Roberson EDO, Duan S, et al. Frequent Mutation of BAP1 in 
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300 mg ranitidine b.d., 20 mg omeprazole o.m., 40 mg omeprazole o.m. vs. placebo. Aliment 
Pharmacol Ther. 1995;9:649-654 
Jellinic P, Mueller JJ, Olvera N, Dao F, Scott SN, Shah R, et al., Recurrent SMARCA4 
mutations in small cell carcinoma of the ovary. Nature Genetics 2014;46:424-426. 
Jiao Y, Pawlik TM, Anders RA, Selaru FM, et al. Exome sequencing identifies frequent 
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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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Lai C, Dunleavy K. NK/T-cell lymphomas in children. Best Pract Res Clin Haematol. 
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Study E7438-G000-101: An Open-Label, Multicenter, Phase 1/2 Study of E7438 (EZH2 Histone 
Methyl Transferase [HMT] Inhibitor) as a Single Agent in Subjects With Advanced Solid 
Tumors or With B cell Lymphomas. 
Study E7438-PD001: Antitumor Activity of Tazemetostat in Xenograft Models of INI-1 
Deficient Tumors. 
Study EZH-501, Tazemetostat Rollover Study (TRuST): An Open-Label, Rollover Study. 
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and Lymphoid Tissues. Lyon, France: IARC Press; 2008.  
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mesothelioma. Nat Genet. 2011;43:1022-5. 
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2010;18(4):316-328. 
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differentiation of regulatory T cells and T effector cell expansion. Sci Rep. 2015;5:10643. 


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APPENDIX 1:  LUGANO CLASSIFICATION FOR RESPONSE 
ASSESSMENT 
 
Revised Criteria for Response Assessment 
Response and Site 
PET-CT-Based Response 
CT-Based Response 
Complete 
Complete metabolic response 
Complete radiologic response (all 
Lymph nodes and 
extralymphatic sites 
 
Score 1, 2, or 3* with or without a residual 
mass on 5PS† 
It is recognized that in Waldeyer’s ring or 
extranodal sites with high physiologic uptake 
or with activation within spleen or marrow 
(eg, with chemotherapy or myeloid colony-
stimulating factors), uptake may be greater 
than normal mediastinum and/or liver. In this 
circumstance, complete metabolic response 
may be inferred if uptake at sites of initial 
involvement is no greater than surrounding 
normal tissue even if the tissue has high 
physiologic uptake 
 
Target nodes/nodal masses must 
regress to < 1.5 cm in LDi  
No extralymphatic sites of disease 
 
Nonmeasured lesion  
Not applicable  
Absent 
Organ enlargement  
Not applicable  
Regress to normal 
New lesions 
None 
None 
Bone marrow 
No evidence of FDG-avid disease in 
marrow 
Normal by morphology; if 
indeterminate, IHC negative 
Partial   
Partial metabolic response 
Partial remission (all of the 
Lymph nodes and 
extralymphatic sites 
 
Score 4 or 5† with reduced uptake compared 
with baseline and residual mass(es) of any 
size 
At interim, these findings suggest 
responding disease 
 
At end of treatment, these findings indicate 
residual disease 
> 50% decrease in SPD of up to 
6 target measurable nodes and 
extranodal sites 
When a lesion is too small to 
measure on CT, assign 5 mm x 5 mm 
as the default value 
When no longer visible, 0 x 0 mm 
For a node > 5 mm x 5 mm, but 
smaller than normal, use actual 
measurement for calculation 
 
Nonmeasured lesions 
Not applicable 
Absent/normal, regressed, but no 
increase 
 
Organ enlargement 
Not applicable 
Spleen must have regressed by > 
50% in length beyond normal 
 
New lesions 
None 
None 


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Revised Criteria for Response Assessment 
Response and Site 
PET-CT-Based Response 
CT-Based Response 
Bone marrow 
Residual uptake higher than uptake in 
normal marrow but reduced compared with 
baseline (diffuse uptake compatible with 
reactive changes from chemotherapy 
allowed). If there are persistent focal 
changes in the marrow in the context of a 
nodal response, consideration should be 
given to further evaluation with MRI or 
biopsy or an interval scan 
Not applicable 
No response or stable 
disease 
No metabolic response 
Stable disease 
Target nodes/nodal 
masses, extranodal 
lesions 
Score 4 or 5 with no significant change in 
FDG uptake from baseline at interim or 
end of treatment 
< 50% decrease from baseline in 
SPD of up to 6 dominant, 
measurable nodes and extranodal 
sites; no criteria for progressive 
disease are met 
Nonmeasured lesions 
Not applicable 
No increase consistent with 
progression 
Organ enlargement  
Not applicable 
No increase consistent with 
progression 
New lesions 
None 
None 
Bone marrow 
No change from baseline 
Not applicable 
Progressive disease 
Progressive metabolic disease 
Progressive disease requires at 
least 1 of the following:  
Individual target 
nodes/nodal masses 
Score 4 or 5 with an increase in intensity of 
uptake from baseline and/or 
PPD progression 
Extranodal lesions 
Score 4 or 5 with an increase in intensity of 
uptake from baseline and/o 
An individual node/lesion must be 
abnormal with: LDi > 1.5 cm and 
Increase by > 50% from PPD nadir 
and  
An increase in LDi or SDi from 
nadir 
0.5 cm for lesions ≤ 2 cm 
1.0 cm for lesions > 2 cm 
In the setting of splenomegaly, the 
splenic length must increase by > 
50% of the extent of its prior 
increase beyond baseline (eg, a 
15-cm spleen must increase to > 
16 cm). If no prior splenomegaly, 
must increase by at least 2 cm 
from baseline 
New or recurrent splenomegaly 
Nonmeasured lesions 
None 
New or clear progression of pre-
existing nonmeasured lesions 


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Revised Criteria for Response Assessment 
Response and Site 
PET-CT-Based Response 
CT-Based Response 
New lesions 
New FDG-avid foci consistent with 
lymphoma rather than another etiology 
(eg, infection, inflammation). If uncertain 
regarding etiology of new lesions, biopsy 
or interval scan may be considered 
 
Regrowth of previously resolved 
lesions  
A new node > 1.5 cm in any axis 
A new extranodal site > 1.0 cm in 
any axis; if < 1.0 cm in any axis, its 
presence must be unequivocal and 
must be attributable to lymphoma 
Assessable disease of any size 
unequivocally attributable to 
lymphoma 
 
Bone marrow 
New or recurrent FDG-avid foci 
New or recurrent involvement 
Abbreviations: 5PS = 5-point scale; CT = computed tomography; FDG = fluorodeoxyglucose; IHC = 
immunohistochemistry; LDi = longest transverse diameter of a lesion; MRI = magnetic resonance imaging; 
PET = positron emission tomography; PPD = cross product of the LDi and perpendicular diameter; SDi = 
shortest axis perpendicular to the LDi; SPD = sum of the product of the perpendicular diameters for 
multiple lesions. 
 
*A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an 
interim scan. However, in trials involving PET where de-escalation is investigated, it may be preferable to 
consider a score of 3 as inadequate response (to avoid undertreatment). Measured dominant lesions: Up to 6 of 
the largest dominant nodes, nodal masses, and extranodal lesions selected to be clearly measurable in 2 
diameters. Nodes should preferably be from disparate regions of the body and should include, where applicable, 
mediastinal and retroperitoneal areas. Non-nodal lesions include those in solid organs (eg, liver, spleen, kidneys, 
lungs), GI involvement, cutaneous lesions, or those noted on palpation. Nonmeasured lesions: Any disease not 
selected as measured, dominant disease and truly assessable disease should be considered not measured. These 
sites include any nodes, nodal masses, and extranodal sites not selected as dominant or measurable or that do not 
meet the requirements for measurability but are still considered abnormal, as well as truly assessable disease, 
which is any site of suspected disease that would be difficult to follow quantitatively with measurement, 
including pleural effusions, ascites, bone lesions, leptomeningeal disease, abdominal masses, and other lesions 
that cannot be confirmed and followed by imaging. In Waldeyer’s ring or in extranodal sites (eg, GI tract, liver, 
bone marrow), FDG uptake may be greater than in the mediastinum with complete metabolic response, but 
should be no higher than surrounding normal physiologic uptake (eg, with marrow activation as a result of 
chemotherapy or myeloid growth factors). 
†PET 5PS: 1 = no uptake above background; 2 = uptake < mediastinum; 3 = uptake > mediastinum but ≤ liver; 
4 = uptake moderately > liver; 5 =  uptake markedly higher than liver and/or new lesions; X = new areas of 
uptake unlikely to be related to lymphoma. 
 
 
Abstracted from: Cheson BC, Fisher RI, Barrington SF, et al. Recommendations for Initial 
Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin 
Lymphoma: The Lugano Classification. J Clin Oncol. 2014; 3(32)27:3059-
3067. 


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


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APPENDIX 3: ECOG PERFORMANCE STATUS 
Assessment of Eastern Cooperative Oncology Group (ECOG) performance status to evaluate 
daily living abilities is required at screening as well as routinely throughout the treatment and at 
treatment discontinuation. 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work  
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities; up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed or 
chair 
Reference:  Oken MM, Creech RH, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. American J of Clinical Oncology. 1982;5:649-655. 
 


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APPENDIX 4: NYHA FUNCTIONAL CLASSIFICATION SYSTEM 
 
The New York Heart Association (NYHA) Functional Classification: Class I, II, III, or IV 
Heart Failure provides a simple way of classifying the extent of heart failure. It places subjects 
in one of 4 categories based on the level of limitation experienced during physical activity.  
Class 
Symptoms 
Class I 
(Mild) 
No limitation of physical activity. Ordinary physical activity does not cause undue 
fatigue, palpitation, or dyspnea (shortness of breath). 
Class II 
(Mild) 
Slight limitation of physical activity. Comfortable at rest, but ordinary physical 
activity results in fatigue, palpitation, or dyspnea. 
Class III 
(Moderate) 
Marked limitation of physical activity. Comfortable at rest, but less than ordinary 
physical activity results in fatigue, palpitation, or dyspnea. 
Class IV 
(Severe) 
Unable to carry out any physical activity without discomfort. Symptoms of cardiac 
insufficiency at rest. If any physical activity is undertaken, discomfort is increased. 
 
Reference: The Criteria Committee of the New York Heart Association (NYHA). Nomenclature 
and Criteria for Diagnosis of Diseases of the Heart and Great Vessels. 9th Ed. Boston, Mass: 
Little, Brown & Co.; 1994:253-256.