Phase 2 Study Using Tazemetostat in Patients With Recurrent/Refractory and/or Metastatic Malignant Peripheral Nerve Sheath Tumors (MPNST)
Phase: PHASE2
Conditions: Peripheral Nerve Sheath Tumor
Sponsor: University of Florida

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2024-Aug-12 
 
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Phase 2 study using Tazemetostat in patients with recurrent/refractory and/or metastatic 
malignant peripheral nerve sheath tumors (MPNST) 
 
Protocol Number: 
UF-SC-001  
 
Protocol Version Number: 
1.7 
 
Coordinating Center:  
 
University of Florida 
 
Principal Investigator:   
 
Joanne P. Lagmay, MD 
University of Florida 
1600 SW Archer Road HD204 
Gainesville, FL 32610 
Telephone: (352) 273-9120 
Email: jplagmay@ufl.edu   
 
 
 
  
Statistician: 
 
 
 
Ji-Hyun Lee, DrPH 
University of Florida Health Cancer Center 
 
Protocol Manager: 
 
           CRO Project Management Office 
pmo@cancer.ufl.edu  
 
Clinical Phase: 
Phase II 
 
NCT#: 
NCT04917042 
 
IND Status: 
159759 
 
Investigational Agent(s): 
 
Tazemetostat (Tazverik, Epizyme)  
 
 
Keywords: 
 Metastatic malignant peripheral nerve sheath tumors (MPNST), Enhancer of zeste 
homolog 2 (EZH2) inhibition, Sarcoma, Pediatric, Tazemetostat  
 
 
 
CONFIDENTIAL 
This protocol was designed and developed by the University of Florida Health Cancer Center.  The information contained in this document is regarded as confidential and, except to 
the extent necessary to obtain informed consent, may not be disclosed to another party unless law or regulations require such disclosure.  Persons to whom the information is 
disclosed must be informed that the information is confidential and may not be further disclosed by them. 
 

 
 
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TABLE OF CONTENTS 
Page 
STUDY SCHEMA – single arm ................................................................................................................. 11 
PROTOCOL SYNOPSIS ............................................................................................................................... 12 
1. 
BACKGROUND .................................................................................................................................... 18 
1.1 
MPNST in neurofibromatosis type 1 (NF1) ......................................................................... 18 
1.2 
Malignant peripheral nerve sheath tumor systemic therapy ........................................ 19 
1.3 
Overview of Pre-clinical Studies ............................................................................................. 20 
1.3.1 
EZH2 in sarcomas ........................................................................................................... 22 
1.4 
Overview of Clinical Studies .................................................................................................... 23 
1.4.1 
Hematologic malignancies ......................................................................................... 23 
1.4.2 
Solid tumors ..................................................................................................................... 25 
1.4.3 
Pediatrics ........................................................................................................................... 27 
1.5 
Rationale for Regimen/Doses/Schedule .............................................................................. 27 
1.5.1 
Rationale for Doses Indicated in Current Study ................................................. 28 
2. 
OBJECTIVES AND ENDPOINTS ...................................................................................................... 28 
2.1 
Primary ............................................................................................................................................ 28 
2.1.1 Primary Objective: ................................................................................................................... 28 
2.1.2  Primary Endpoint: ................................................................................................................... 28 
2.2 
Secondary ...................................................................................................................................... 28 
2.2.1 Secondary Objectives: ............................................................................................................ 28 
2.2.2 Secondary Endpoints: ............................................................................................................ 29 
2.3 
Exploratory .................................................................................................................................... 29 
3. 
STUDY DESIGN .................................................................................................................................... 29 
3.1 
Study Overview ............................................................................................................................ 29 
4. 
SELECTION OF SUBJECTS ................................................................................................................ 30 
4.1 
Number of Subjects.................................................................................................................... 30 
4.2 
Inclusion Criteria .......................................................................................................................... 30 
4.3 
Exclusion Criteria ......................................................................................................................... 32 
4.4 
Inclusion of Women and Minorities ...................................................................................... 34 
5. 
REGISTRATION PROCEDURES ....................................................................................................... 34 

 
 
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6. 
STUDY PROCEDURES ........................................................................................................................ 34 
6.1 
Schedule of Events ...................................................................................................................... 36 
6.2 
Allowable Visit Windows .......................................................................................................... 38 
6.3 
End of Treatment Evaluations ................................................................................................. 39 
6.4 
Follow up/ Evaluations .............................................................................................................. 39 
7. 
STUDY TREATMENT .......................................................................................................................... 39 
7.1 
Treatment Schedule/Administration ..................................................................................... 39 
7.2 
Overview of treatment plan ..................................................................................................... 40 
7.3 
Criteria for Starting Subsequent Cycles ............................................................................... 40 
7.4 
Grading of Adverse Events ....................................................................................................... 41 
7.5 
Supportive Care and other concomitant therapy ............................................................. 41 
7.5.1 
Supportive Care Guidelines ........................................................................................ 41 
7.5.2 
Concomitant Therapy ................................................................................................... 41 
7.5.3 
Prohibited Concomitant Therapy ............................................................................. 42 
7.6 
Dose Modifications ..................................................................................................................... 43 
7.6.1 
Non- Hematologic Toxicity ........................................................................................ 43 
7.6.2 
Dose Modifications for Non-Hematological Toxicity ....................................... 43 
7.6.3 
Hematologic Toxicity .................................................................................................... 44 
7.6.4 
Dose Modifications for Hematological Toxicity .................................................. 44 
7.6.5 
Dose Modification Tables ........................................................................................... 45 
8. 
TREATMENT DISCONTINUATION ................................................................................................ 45 
8.1 
Screen Failures ............................................................................................................................. 45 
8.2 
Criteria For Study Treatment Discontinuation ................................................................... 45 
8.3 
Replacement of Subjects .......................................................................................................... 46 
9. 
BIOLOGICAL SPECIMENS AND CORRELATIVES ...................................................................... 47 
9.1 
Preparation, Shipment and Storage of Specimens .......................................................... 47 
10. 
STUDY DRUG INFORMATION .................................................................................................... 47 
10.1 Study Drug Name ....................................................................................................................... 47 
10.1.1 
Identification .................................................................................................................... 47 
10.1.2 
Packaging and Labeling .............................................................................................. 48 
10.1.3 
Drug Supply ..................................................................................................................... 48 

 
 
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10.1.4 
Storage, Handling and Dispensing .......................................................................... 48 
10.1.5 
Contraindications ........................................................................................................... 50 
10.1.6 
Special Warnings and Precautions for Use ........................................................... 50 
10.1.7 
Adverse Event Profile .................................................................................................... 50 
10.1.8 
Drug Interactions ........................................................................................................... 50 
11. 
ADVERSE EVENTS ........................................................................................................................... 50 
11.1 Definitions ..................................................................................................................................... 50 
11.1.1 
Adverse Event .................................................................................................................. 51 
11.1.2 
Serious Adverse Event .................................................................................................. 52 
11.1.3 
Non-Serious Adverse Event ....................................................................................... 53 
11.2 Period of Observation................................................................................................................ 53 
11.3 Documenting and Reporting of Adverse Events by Investigator ................................ 54 
11.3.1 
Assessment of Causal Relationship of Study Drug ............................................ 54 
11.3.2 
Intensity of Adverse Events ........................................................................................ 55 
11.3.3 
Action Taken with Study Drug .................................................................................. 56 
11.3.4 
Definition of Outcome ................................................................................................. 56 
11.4 Immediately Reportable Events .............................................................................................. 56 
11.4.1 
Serious Adverse Events ................................................................................................ 56 
11.4.2 
Other Events Requiring Immediate Reporting .................................................... 57 
11.4.3 
Reporting to Epizyme ................................................................................................... 58 
12. 
STATISTICAL METHODS ............................................................................................................... 58 
12.1 Data collection and management plan................................................................................ 58 
12.2 Sample Size Justification ........................................................................................................... 58 
12.3 Analysis of Primary Endpoint .................................................................................................. 59 
12.4 Analysis of Secondary Endpoints ........................................................................................... 59 
12.5 Analysis of Exploratory Endpoints ......................................................................................... 59 
12.6 Analysis of Safety Data ................................................................................................................ 60 
12.7 Interim Analysis for Efficacy ..................................................................................................... 60 
12.8 Data Integrity and Safety Committee ................................................................................... 60 
12.9 Data Monitoring .......................................................................................................................... 61 
12.10 Principal Investigator Responsibilities .................................................................................. 62 

 
 
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13. 
EMERGENCY PROCEDURES ........................................................................................................ 62 
13.1 Emergency Contact .................................................................................................................... 62 
13.2 Emergency Treatment ............................................................................................................... 62 
14. 
ADMINISTRATIVE, ETHICAL, and REGULATORY CONSIDERATIONS ........................... 63 
14.1 Good Clinical Practice ................................................................................................................ 63 
14.2 Institutional Review Board ....................................................................................................... 63 
14.3 Compliance with Laws and Regulations .............................................................................. 63 
14.4 Delegation of Investigator Responsibilities ........................................................................ 64 
14.5 Subject Information and Informed Consent ...................................................................... 64 
14.6 Confidentiality .............................................................................................................................. 65 
14.7 Protocol Amendments .............................................................................................................. 65 
14.8 Case Report Forms ..................................................................................................................... 66 
14.9 Record Retention ........................................................................................................................ 66 
15. 
REFERENCES ..................................................................................................................................... 67 
16. 
APPENDICES ..................................................................................................................................... 71 
Appendix A: PROTOCOL VERSION HISTORY / SUMMARY OF CHANGES ............................ 72 
Appendix B: PERFORMANCE STATUS CRITERIA ........................................................................... 74 
Appendix C: RECIST GUIDELINES (VERSION 1.1) .......................................................................... 75 
Appendix D: SUBJECT TREATMENT DIARY ..................................................................................... 82 
Appendix E: ORAL MEDICATION ACCOUNTABILITY LOG ......................................................... 88 
Appendix F: CYP3A4 SUSBTRATES, INDUCERS AND INHIBITORS .......................................... 90 
Appendix G: NUMBERED PAIN RATING SCALE 11 ....................................................................... 93 
Appendix H: ADEQUATE RENAL FUNCTION .................................................................................. 94 
 

 
 
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ABBREVIATIONS  
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine transaminase (also SGPT) 
ANC 
absolute neutrophil count 
AST 
aspartate transaminase (also SGOT) 
AUC 
BID 
area under curve 
twice daily 
BAP1 
Breast cancer gene 1 (BRCA1)-associated protein 1 
BM 
bone marrow 
BSA 
body surface area 
BUN 
blood urea nitrogen 
CBC 
CBR 
complete blood count 
Clinical Benefit Rate 
CL 
clearance 
CNS 
Central nervous system 
CR 
complete remission 
CRF 
case report form 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTMS 
clinical trials management system 
CRO 
Clinical Research Office 
CTO 
Clinical Trials Office 
DCR 
Disease Control Rate 
DISC 
Data Integrity and Safety Committee 
DLBCL 
diffuse large B-cell lymphoma 
DLI 
Donor lymphocyte infusion 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
DOR 
Duration of Response 
DTR 
decreased tendon reflex 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EED 
embryonic ectoderm development 
EFS 
Event Free Survival 

 
 
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EMT 
epithelial-mesenchymal transition 
EOT 
EZH2 
End of Treatment 
Enhancer of zeste homolog 2 
EPSGG 
European Pediatric Soft Tissue Sarcoma Group 
FDG 
fluorodeoxyglucose positron emission 
FSH 
follicle stimulating hormone 
GAP 
GTPase-activating protein 
GCB 
germinal center B-cell 
GCP 
Good Clinical Practice  
GFR 
glomerular filtration rate 
GVHD 
Graft vs. Host Disease 
HMT 
histone methyltransferase 
HRT 
hormone replacement therapy 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
INI1 
integrase interactor 1 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IV 
intravenous 
kg  
kilogram(s) 
KPMB1 
Karyopherin β1 
LDH 
lactic dehydrogenase 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
MPNST 
mean corpuscular volume 
Malignant Peripheral Nerve Sheath Tumors 
Mg 
milligrams 
MDS 
myelodysplastic syndromes 
miRNA 
micro RNA 
MPN  
myeloproliferative neoplasms 
MRI 
magnetic resonance imaging 
MRT 
malignant rhabdoid tumors 
MT 
Mutant type 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 

 
 
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NF1 
Neurofibromatosis type 1 
NHL 
Non-Hodgkin’s Lymphoma 
NK 
Natural killer 
NSAE 
non-serious adverse event 
ORR 
overall response rate 
OS 
overall survival 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PET 
positron emission tomography 
PFS 
progression free survival 
PMO 
Project Management Office 
PI 
principal investigator 
PK 
pharmacokinetics 
PR 
PRC2 
PRO 
partial remission 
polycomb repressive complex 2 
Subject Reported Outcome 
PS 
performance status 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
RBC 
red blood cells 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RNA 
ribonucleic acid 
RP2D 
Recommended Phase II Dose 
R/R 
Relapsed or Refractory 
SAE 
serious adverse event 
SC 
subcutaneous 
SCCOHT 
small cell carcinoma of the ovary of the hypercalcemic type 
SD 
stable disease 
SGOT 
serum glutamic oxaloacetic transaminase (also AST) 
SGPT 
serum glutamic pyruvate transaminase (also ALT) 
SMARCA4 
SWI/SNF Related, Matrix Associated, Actin Dependent Regulator of 
Chromatin, Subfamily A, Member 4 
STS 
Soft tissue sarcoma 
SUZ12 
suppressor of zeste 12 
SWI/SNF 
SWItch/Sucrose Non-Fermentable 

 
 
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T-ALL 
T-cell acute lymphoblastic leukemia 
TBI 
Traumatic brain injury  
T-LBL 
T-cell lymphoblastic lymphoma 
Tmax 
TTP 
time to maximum plasma concentration 
Time to Progression 
UF 
University of Florida 
UFHCC 
University of Florida Health Cancer Center 
ULN 
upper limit of normal 
US 
United States 
WBC 
white blood cell  
WHO 
World Health Organization 
WOCBP 
women of childbearing potential 
WT 
Wild type 
XRT 
Radiation therapy 
ZH2 
zeste homolog 2 
 

 
 
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Protocol Signature Page 
 
Phase 2 study using Tazemetostat in patients with recurrent/refractory and/or metastatic 
malignant peripheral nerve sheath tumors (MPNST) 
 
 
Study Principal Investigator:  
 
 
 
 
 
Signature of Investigator 
 
Date 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
Name of Facility 
 
 
 
 
 
Location of Facility (City/State) 
 
 
 
By my signature, I agree to personally supervise the 
conduct of this study and to ensure its conduct in 
compliance with the protocol, informed consent, IRB 
procedures, the Declaration of Helsinki, ICH Good Clinical 
Practices guidelines, and the applicable parts of the United 
States Code of Federal Regulations or local regulations 
governing the conduct of clinical studies. 
 
 
 

 
 
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STUDY SCHEMA – SINGLE ARM 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
Cycle = 28 days 
Accrual Goal: 29 evaluable subjects (Up to 50 total accrued) 
 
 
 
Screening 
Assessments via scans every 2 cycles 
Tazemetostat (28-day cycles) 
Pediatric Dose (12 - <18y): 520mg/m2/dose orally BID 
Adult Dose: (>18y): 800 mg orally BID 
CR, PR, stable disease 
Progressive disease 
Continue Tazemetostat 
up to 2 years  
or until disease 
progression or toxicity 
STOP Tazemetostat 
OFF study 

 
 
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PROTOCOL SYNOPSIS 
 
Title: 
Phase 2 study using Tazemetostat in patients with recurrent/refractory 
and/or metastatic malignant peripheral nerve sheath tumors (MPNST) 
Funding 
Source(s): 
Epizyme, University of Florida 
Investigational 
Agent Source: 
Epizyme                                                                       
Rationale: 
Enhancer of zeste homolog 2 (EZH2) is a critical component of 
polycomb repressive complex 2 (PRC2), a multimeric protein complex 
which plays an essential role in the epigenetic maintenance. EZH2 has 
been shown to be a critical regulator of epithelial-mesenchymal 
transition, which is a critical step for initiation of cancer invasion and 
metastasis.  
Recent research showed that EZH2 expression is significantly higher in 
MPNST than in neurofibromas and normal nerve tissues.  EZH2 
knockdown by RNA interference in MPNST cell lines induces MPNST 
cell apoptosis in vitro and inhibits MPNST tumor growth in vivo.  
Pharmacological inhibition of EZH2 has been shown to inhibit MPNST 
cell growth and induce apoptosis in vivo, in vitro and in mouse 
xenograft models. In addition, inhibition of EZH2 has been shown to 
ameliorate MPNST invasion and metastasis. These preclinical data 
suggest that EZH2 is a potential therapeutic target in MPNST.       
Objectives: 
Primary:    
To assess the objective response rate of Tazemetostat in subjects with 
recurrent/refractory and/or metastatic MPNST. 
Secondary:  
• To determine the progression free survival (PFS) in subjects with 
recurrent/refractory and/or metastatic MPNST. 
• To determine the time to progression (TTP) in subjects with 
recurrent/refractory and/or metastatic MPNST. 
• To determine the clinical benefit using subject reported outcome 
(PRO)  
• To assess the clinical benefit rate (CBR). 
 
 

 
 
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Exploratory aims:  
• Assess circulating tumor DNA (ctDNA) as a potential treatment 
response tool  
• Correlate clinical data, outcomes and toxicity with biomarkers of 
EZH2 inhibition and resistance, potentially including but not 
limited to circulating or tumor molecular profiling, epigenetics, and 
immune system activity. 
Study Design: 
This is a single institution, single-arm, open label phase 2 study. 
Accrual Goal: 
Up to 50 people will be enrolled in this study to achieve 29 evaluable 
subjects. 
Inclusion Criteria: 
Individuals eligible for study participation must meet the following 
criteria at enrollment:  
A. A histologic confirmation of recurrent/refractory and/or 
metastatic MPNST with RECIST measurable disease.  
B. Subjects > 12 years of age at the time of enrollment. 
C. Performance status:  
• 12-15 years old- Lansky > 50    
• 16-17 years old- Karnofsky > 50 
• >18 years old- ECOG score 0-2 
D. Subjects must have adequately recovered from the acute toxic 
effects of all prior anti-cancer therapy per enrolling physician and 
must meet the following minimum duration from prior anti-
cancer directed therapy prior to enrollment.  
• Anti-cancer agents known to be Myelosuppressive: ≥ 28 days 
after the last dose of agent. 
• Anti-cancer agents not known to be myelosuppressive: > 7 
days after the last dose of agent.  
• Antibodies: > 21 days must have elapsed from infusion of last 
dose of antibody, and toxicity related to prior antibody therapy 
must be recovered to Grade < 1.  
• Systemic Corticosteroids: if related to prior therapy > 14 days 
must have elapsed, or on stable dose for treatment of CNS 
disease.  

 
 
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• Hematopoietic growth factors: > 14 days after the last dose of 
a long-acting growth factor.  
• Interleukins, Interferons, and Cytokines (other than 
hematopoietic growth factors): > 21 days after the completion 
of interleukins, interferon or cytokines (other than 
hematopoietic growth factors).  
• XRT/External Beam Irradiation including Protons: > 14 days 
after local XRT; > 150 days after TBI, craniospinal XRT or if 
radiation to > 50% of the pelvis; > 42 days if other substantial 
BM radiation.  
• Radiopharmaceutical therapy: > 42 days after systemically 
administered radiopharmaceutical therapy. 
• Major Surgery: > 14 days prior, with evidence of wound healing 
and no active surgical complications.  
E. Subjects must not have had prior exposure to Tazemetostat or 
other inhibitor(s) of EZH2.  
F. Adequate laboratory values of organ function, defined as:  
• Peripheral absolute neutrophil count (ANC) > 1000/mm3.  
• Platelet count > 100,000/mm3 (transfusion independent, 
defined as not receiving platelet transfusions for at least 7 days 
prior to enrollment).  
• Hemoglobin > 8.0 g/dL at baseline (may receive RBC 
transfusions). 
• Creatinine clearance or radioisotope GFR > 70 ml/min/1.73 m2, 
or serum creatinine based on age/gender as followed in 
Appendix H.  
• Total bilirubin < 1.5 ULN or direct bilirubin < 1 x ULN. 
• Aspartate aminotransferase (AST) and alanine aminotransferase 
(ALT) < 2.5 x ULN; if liver metastases present, then AST and ALT 
must be < 5 x ULN.  Serum albumin ≥ 2 g/dL. 
• Coagulation INR < 1.5, if on anti-coagulation INR < 2.5. 
G. Nervous system disorders (CTCAE v5.0) resulting from prior 
therapy must be < Grade 2, with the exception of decreased 
tendon reflex (DTR). Any grade of DTR is eligible.  
H. Subjects must not have more than one active malignancy at the 
time of enrollment (Subjects with a prior or concurrent 

 
 
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malignancy whose natural history or treatment does not have the 
potential to interfere with the safety or efficacy assessment of the 
investigational regimen [as determined by the treating physician 
and approved by the PI] may be included).  
I. Written informed consent obtained from the subject and the 
subject agrees to comply with all the study-related procedures. All 
subjects and/or their parents or legally authorized representatives 
must sign a written informed consent. Assent, when appropriate, 
will be obtained according to institutional standard practice. 
J. Use of contraception: 
• Women of childbearing potential (WOCBP) who are 
heterosexually active must be using two highly effective 
methods of contraception to avoid pregnancy throughout the 
study and for at least 6 months after the last dose of study 
drug to minimize the risk of pregnancy as Tazemetostat might 
counteract the effects of hormonal contraceptives.  Birth 
control methods that can be used while in this study include: 
established use of oral, injected or implanted hormonal birth 
control or placement of an intrauterine device [IUD] or 
intrauterine system [IUS]. They or their partner must also use a 
second method, (e.g., condom with spermicidal 
foam/gel/film/cream/suppository or occlusive cap [diaphragm 
or cervical/vault caps] with spermicidal 
foam/gel/film/cream/suppository.  If their male partner is 
vasectomized, they do not need to use any of the birth control 
methods listed above. The type of birth control they use must 
be discussed with the study doctor before beginning the 
study.  The study doctor must approve the method you use 
before they can enter the study. Prior to study enrollment, 
women of childbearing potential must be advised of the 
importance of avoiding pregnancy during trial participation 
and the potential risk factors for an unintentional pregnancy.   
• Males with female partners of child-bearing potential must 
agree to use physician-approved contraceptive methods (e.g., 
abstinence, condoms, vasectomy) throughout the study and 

 
 
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should avoid donating sperm, for 90 days following the last 
dose of study drug. 
Exclusion Criteria: 
Subjects with any of the following present at time of enrollment will not 
be eligible for study participation:  
A. Subjects who are currently taking the following concomitant 
medications:  
• Anti-cancer Agents: Subjects who are currently receiving other 
anti-cancer agents are not eligible.  
• CYP3A4 Agents:  Subjects who are currently receiving drugs 
that are strong inducers or strong inhibitors of CYP3A4 are not 
eligible. Strong inducers or inhibitors of CYP3A4 are prohibited 
from 14 days prior to the first dose of Tazemetostat to the end 
of the study. Note: Dexamethasone for CNS tumors or 
metastases, on a stable dose, is allowed. 
• Grapefruit, grapefruit juice, Seville oranges and food/drinks 
containing them should be avoided one week before the first 
dose of the study intervention  
B. Subjects who are acutely ill with an uncontrolled active infection 
on systemic anti-infective agents are not eligible.  
C. Subjects with a prior history of T-LBL/T-ALL, myelodysplastic 
syndrome (MDS), acute myeloid leukemia (AML), B-cell acute 
lymphoblastic leukemia (B-ALL) or other myeloproliferative 
neoplasm (MPN).  
D. Subjects who have any of the following underlying major cardiac 
issues or conditions: 
• Known QTc prolongation or documentation  
• Documented New York Heart Association (NYHA) Class III or IV 
congestive heart failure. 
• Myocardial infarction within 6 months prior to registration. 
• Unstable angina within 6 months prior to registration. 
• Symptomatic arrhythmia. 

 
 
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E. Subjects who in the opinion of the investigator may be high risk 
for treatment complications or unable to comply with the safety 
monitoring requirements of the study are not eligible.  
F. Heterosexually active males or females of reproductive potential 
may not participate unless they have agreed to use two highly 
effective contraceptive methods for the duration of study 
treatment as Tazemetostat might counteract the effects of 
hormonal contraceptives. Female subjects of childbearing 
potential should agree to remain abstinent or use adequate 
contraceptive methods for 6 months after the last dose of 
Tazemetostat. Male subjects should agree to remain abstinent or 
use adequate contraceptive methods, and agree to refrain from 
donating sperm, and for 90 days after the last dose of 
Tazemetostat.  
G. Females who are pregnant or breastfeeding will not be entered on 
this study because there is currently no available information 
regarding human fetal or teratogenic toxicities. Pregnancy tests 
must be obtained in girls who are post-menarchal.  
H. Administration of a vaccine containing live virus within 30 days 
prior to the first dose of trial treatment.  For examples, see Section 
7.3.3: Prohibited Concomitant Therapy.  Note: Most flu vaccines 
are killed viruses, with the exception of the intra-nasal vainer (Flu-
Mist) which is an attenuated live virus and therefore prohibited for 
30 days prior to first dose. Non-live versions of the COVID-19 
vaccine are allowed. 
I. Prisoners or subjects who are involuntarily incarcerated, or 
subjects who are compulsorily detained for treatment of either a 
psychiatric or physical illness. 
J. Known hypersensitivity to tazmetostat or any component of the 
formulation of tazmetostat 
K. 
Inability to take oral medication OR have malabsorption 
syndrome or any other uncontrolled gastrointestinal condition (eg, 
nausea, diarrhea, vomiting) that might impair the bioavailability of 
tazmetostat 
Efficacy 
Assessments: 
RECIST (Version 1.1) 

 
 
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1. BACKGROUND 
1.1 
MPNST in neurofibromatosis type 1 (NF1) 
NF1 is an autosomal-dominant cancer predisposition syndrome afflicting 1 in 3500 
individuals worldwide, making it one of the most common genetic disorders, and a 
de novo incidence rate of 1 in 3000.  NF1 subjects have up to 60% lifetime 
predisposition to cancer.  NF1 gene is a tumor suppressor gene in chromosome 
17q11.2 which codes for neurofibromin, a GTPase-activating protein (GAP) which 
negatively regulates Ras signaling keeping cell proliferation in check.  All NF1 
tumors show biallelic inactivation of NF1 gene and activated Ras pathway driving 
cancer formation. 1,2  
 
Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive sarcomas 
that frequently develop in the context of NF1 and represent the leading cause of 
death in individuals with this disease.  The lifetime risk of development of MPNST 
in individuals with NF1 is 8-13%3, with a 1000-fold higher risk than the general 
population. 4,5 MPNST constitute 10% of all malignant sarcomas overall, with highly 
aggressive clinical behavior characterized by high local recurrence rates and early 
metastases.  The cornerstone of MPNST treatment is surgical resection, but is often 
not possible due to large lesions at presentation, and at sites adjacent to 
neurovascular bundles and vital organs.  Thus, unresectable and metastatic tumors 
are considered incurable. MPNSTs rapidly develop resistance to chemotherapy. 
Sample Size 
Justification 
Simon's two-stage Optimum design will be used for the study to 
evaluate the primary endpoint of objective response rate (ORR, 
defined as CR+PR) of Tazemetostat.  
Assuming that with current treatment (chemotherapy with 
doxorubicin and ifosfamide), the null hypothesis that the true ORR is 
21% (Kroep JR et al, 2011) will be tested against a one-sided 
alternative. In the first stage, 9 patients will be accrued. If there are 2 
or fewer responses in these 9 patients, the study will be stopped. 
Otherwise, 20 additional patients will be accrued for a total of 29. The 
null hypothesis will be rejected if 10 or more responses are observed 
in 29 patients.   This design yields a type I error rate of 5% and power 
of 80% when the ORR is 45%. 
Estimated 
Enrollment 
Period: 
24 months 
Estimated Study 
Duration: 
36 months 

 
 
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Even with aggressive surgery and chemotherapy, MPNST subjects have a 5-year 
survival rate of just 35%– 50%. 3, 4  
 
1.2 
Malignant peripheral nerve sheath tumor systemic therapy 
The role of adjuvant therapies in unresectable MPNST has recently been 
investigated in both pediatric and adult trials.   A large adult soft tissue sarcoma 
(STS) study evaluated the chemosensitivity of advanced MPNST and compared 
these results with other advanced soft tissue sarcoma histologic subtypes. Out of 
2675 chemo naïve eligible STS, the outcome of 175 MPNST patients after a median 
follow up of 4.1 years showed response rate, median PFS and overall survival of 
21% (versus 22%), 17 weeks (versus 16 weeks) and 48 weeks (versus 51 weeks), 
respectively. Chemotherapy regimen was an independent prognostic factor for 
response (p < 0.0001) and PFS (p = 0.009). Compared with standard first-line 
doxorubicin, the doxorubicin–ifosfamide regimen had the best response, whereas 
ifosfamide had the worst prognosis.6  A prospective European Pediatric Soft Tissue 
Sarcoma Group (EpSGG) study of MPNST patients under 21 years old showed 5-
year event-free survival (EFS) and overall survival (OS) to be 52.9% (95% confidence 
interval, 38.1-65.8) and 62.1% (46.7-74.3), respectively.  Similar to the adult series, 
standard ifosfamide-doxorubicin chemotherapy for unresectable MPNST rendered 
the best reported outcome, with a response rate to chemotherapy (partial response 
+ complete response) in patients with measurable disease of 46%, higher than 
adults.7 
 
Preclinical studies have identified several novel candidate molecular targets for 
therapeutic intervention. Several early phase trials using these novel drugs have 
been conducted but to date, no targeted therapies have yet been proven effective 
(Table 1).8 Due to the limited number of therapeutic options in advanced MPNST, 
identification of novel drug targets and development of new treatment strategies 
are urgently needed. 
 

 
 
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Table 1.  Clinical trials of targeted therapied for MPNST8 
 
1.3 
Overview of Pre-clinical Studies 
The role of epigenetics in cancers has been well elucidated.   Post translational 
modifications of core histone proteins of chromatin are important in controlling 
the fidelity of gene transcription pattern in cells. Paramount among these 
transcription-controlling modifications are methylation events at lysine and 
arginine residues, catalyzed by histone methyltransferase (HMTs).9. Genetic 
alterations in a number of HMTs have been identified in human cancers where they 
are purported to play a causal role in malignancies.10 
 
Enhancer of zeste homolog 2 (EZH2), is the catalytic subunit of the multi-protein 
histone-lysine N-methyltransferase complex polycomb repressive complex 2 
(PRC2), involved in chromatin remodeling and transcriptional silencing11 (Figure 1). 
PRC2 plays an essential role in the epigenetic maintenance of the repressive 
H3K27me3 chromatin mark 12.  Trimethylation form H3K27Me3 is associated with 
repression of genes important for differentiation. WI/SNF is another multi-protein 
complex involved in chromatin remodeling. It antagonizes PRC2 activity in 
regulating self-renewal and differentiation of cells. In stem or progenitor cells, 
EZH2 activity is high, and the expression of PRC2 target genes is therefore 
repressed. When EZH2 activity is down-regulated, PRC2 target gene expression is 
increased through augmented SWI/SNF activity, and cells can differentiate and 
become quiescent13 (Figure 2).  
 

 
 
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Abnormal EZH2 expression has been associated with various human malignancies 
such as prostate, bladder, breast, endometrium, colorectal and melanoma 13.  In 
glioblastoma multiforme, EZH2 has been shown to be a functional oncogene, a 
prognostic factor, and a potential therapeutic target 14.  EZH2 overexpression is 
associated with adverse outcome, enhanced progression and advanced disease in 
cancers of the prostate, bladder, breast, and endometrium, as well as melanoma. 
High expression of EZH2, defined as greater than 10% in immunohistochemical 
analysis and up to 4-fold increased expression via real-time polymerase chain 
reaction testing, has been associated with increased disease aggressiveness. 12, 15, 16  
 
Several mechanisms have been implicated in overexpression of EZH2 in tumors. 
EZH2 overexpression as a result of gene amplification was identified in prostate 
cancer. Increased EZH2 expression can be also the result of various signals and 
pathways depending on the tumor type. For instance, Fujii et al (2011) 17 has 
demonstrated that MEK–ERK–Elk-1 pathway, which is one of the signal 
Figure 1.  EZH2, a core subunit of PRC2 regulates  
transcriptional activity and chromatin remodeling 
transcriptional activity.  The other subunits are embryonic 
ectoderm development (EED), suppressor of zeste 12 
(SUZ12) and retinoblastoma-associated protein 46v 
(RbAp46) (Adapted from Burns EM Targeted Oncology 6 
(11), 2017) 47. 
Figure 2. The SWI/SNF and the PRC2 complexes 
antagonistically regulate gene expression.  If the 
components of the SWI/SNF complex such as INI1 or 
SMARCA4 are mutated or deleted in certain cancers, 
PRC2-SWI/SNF1 antagonism is perturbed leading to 
hyperexpression of PRC2 targets, potentiation of stem cell 
programs and oncogenic transformation.  In normal stem 
cells, EZH2 is highly expressed in cancer stem cell 
populations and suppresses differentiation via repression 
of lineage-specific factors to maintain these populations. It 
has been hypothesized that EZH2 blocks differentiation, 
which facilitates cell transformation (Adapted from Italiano 
A J Pharm Therap 165(2016) 26-31).  

 
 
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transduction pathways that are upregulated in cancer cells, is linked to 
overexpression of EZH2 in triple-negative and ERBB2 overexpressing subtypes of 
breast cancer. EZH2 depletion has been shown to accelerate KRas (G12D)-driven 
neoplasia in a pancreatic cancer model, suggesting that its role is tumor context 
dependent. 18   
 
 
Several studies have shown that EZH2 expression can be negatively regulated by 
different miRNA, which are a class of small, non-coding RNA important in post-
transcriptional gene silencing. For instance, the upregulation of EZH2 has been 
linked to loss of expressions of miR-101, miR-26a, and miR-124 in different tumor 
types. 19-21 Conversely, EZH2 also epigenetically represses tumor suppressive 
miRNAs to facilitate tumor growth. EZH2 overexpression is mainly found in solid 
tumors, whereas missense mutations of EZH2 are identified in hematologic 
malignancies. In fact, gain-of-function missense mutations Y641 and A677 residues 
within the catalytic SET domain of EZH2 have been discovered in up to 25% of 
follicular lymphoma and diffuse large B-cell lymphoma. 22 These mutations result in 
an increased EZH2 stability and an increase in H3K27 trimethylation. 23 In mouse 
models of the germinal center B-cell-like (GCB) subtype of diffuse large B-cell 
lymphoma (DLBCL), EZH2 mutations induce differentiation arrest, resulting in 
germinal center hyperplasia, and accelerated lymphomagenesis in the presence of 
BCL2 overexpression. Interestingly, the small molecule inhibitor of EZH2 
methyltransferase activity are able to decreases global H3K27me3 levels, to 
reactivate silenced PRC2 target genes and to inhibit the proliferation of EZH2 
mutant DLBCL cells in vitro and in vivo.  
 
1.3.1 EZH2 in sarcomas 
INI1 is a potent tumor suppressor gene, a member of the SWI/SNF complex 
whose integrated functions control diverse cellular processes such as 
differentiation and proliferation.  Loss of INI1 function leads to elevated 
expression and recruitment of EZH2 to target genes that become 
trimethylated on H3K27 and repressed, which results in the upregulation of 
several oncogenic signaling pathways, including Sonic Hedgehog, Wnt/β-
Catenin, and MYC. 24 INI1 loss was first identified in malignant rhabdoid 
tumors (MRTs) which are rare and aggressive cancers that principally occur in 
childhood and can arise in various locations, mainly the kidney, brain, and 
soft tissues. MRTs harbor recurrent and specific biallelic-inactivating 
mutations or deletions of INI1 located in the 22q11.2 region. 25 Interestingly, 
apart from this specific alteration, MRTs have a remarkably low rate of 
mutations and no genomic instability, suggesting a potential oncogenic 
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with high frequency (50 to 80%) in epithelioid sarcomas or other sarcomas 
with epithelioid features such as malignant peripheral sheath tumors 
(MPNSTs). 26, 27 
 
EZH2 overexpression has been noted in MPNST, compared to normal nerves, 
and neurofibroma, and levels appear to be 8-fold higher compared to 
atypical plexiform neurofibromas. 28 It has shown that EZH2 directly inhibits 
miR-200b expression in MPNST, which may ultimately also contribute to 
epithelial-mesenchymal transition (EMT) progression, MPNST invasion and 
metastasis. 29 EZH2 has been shown to be a critical regulator of epithelial-
mesenchymal transition (EMT), which is a critical step for initiation of cancer 
invasion and metastasis. 30. EZH2 promotes EMT directly by inhibiting the 
expression of E-cadherin and indirectly through the NF-κB/Twist pathway. 31, 
32 Additionally, miR-200b is known to act as an inhibitor of EMT by targeting 
the transcription faction ZEB1/2 and then by activating E-cadherin. 33, 34 
MPNSTs typically have known mutations in SUZ12 (56%) and EED (32%). 
 
EZH2 knockdown by RNA interference in MPNST cell lines induced MPNST 
cell apoptosis in vitro and inhibits MPNST tumor growth in vivo, suggesting 
that EZH2 is a potential therapeutic target in MPNST. 35   Zhang et al 29, 35 
found that pharmacological inhibition of EZH2 by DZNep depleted EZH2 
expression, induced expression of miR-30a and miR-30d, and inhibited 
Karyopherin β1 (KPNB1) expression in MPNST cells. By impairing the 
EZH2/miR-30a,d/KPNB1 pathway, DNZep induced MPNST cell apoptosis and 
cell cycle arrest, which together decreased MPNST cell viability and 
suppressed cell survival in vitro. They also demonstrated that DZNep 
treatment inhibited MPNST tumor initiation and growth rates in a mouse 
xenograft model.  
 
1.4 
Overview of Clinical Studies 
 
Tazemetostat (EPZ-6438) is a potent and highly selective, first-in-class oral small 
molecule EZH2 inhibitor. Tazemetostat has been shown to have anti-tumour 
activity in in vitro and xenograph models of EZH2- mutant B-cell non-Hodgkin 
lymphoma, INI1-negative malignant rhabdoid tumor, and SMARCA4-negative 
malignant rhabdoid tumor of the ovary. 36-38  
 
1.4.1 Hematologic malignancies 
A Phase 1 study for relapsed/refractory solid tumors and B cell lymphoma 
(NCT01897571) was conducted with the primary endpoint being the 
maximum tolerated dose of Tazemetostat.  Tazemetostat was administered 

 
 
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orally from 100 mg twice daily to 1600 mg twice daily in 28-day cycles 
between June 13, 2013, and Sept 21, 2016.  64 patients (21 with B-cell non-
Hodgkin lymphoma, and 43 with advanced solid tumors) received 
Tazemetostat, the most common treatment-related adverse events were 
asthenia (21 [33%] of 64 treatment-related events), anemia (nine [14%]), 
anorexia (four [6%]), muscle spasms (nine [14%]), nausea (13 [20%]), and 
vomiting (six [9%]), usually grade 1 or 2 in severity. The recommended phase 
2 dose was determined to be 800 mg twice daily.  Durable objective 
responses, including complete responses, were observed in eight (38%) of 21 
patients with B-cell non-Hodgkin lymphoma and two (5%) of 43 patients with 
solid tumors. Tazemetostat showed a favorable safety profile and antitumor 
activity in patients with refractory B-cell non-Hodgkin lymphoma and 
advanced solid tumors, including epithelioid sarcoma. 39 
 
An interim update from a Phase 2 multicenter study using Tazemetostat in 
patients with relapsed or refractory follicular lymphoma showed that 
Tazemetostat was generally well tolerated, with 5% patients discontinued 
treatment due to a treatment-related AE, 9% patients needing a dose 
reduction due to a treatment-related AE, low rate of grade ≥3 treatment 
related AEs and no treatment related deaths.   This study demonstrated 
durable, single agent, antitumor activity in difficult-to-treat patients with 
relapsed / refractory follicular lymphoma with an ORR of 77% and 34% in MT 
(mutant type) and WT (wild type) EZH2, respectively.  All patients in the MT 
cohort and a majority of patients in WT cohort demonstrating a reduction in 
tumor volume.  There was durable clinical activity across both MT and WT 
cohorts, with patients on therapy up to 23 months, and responses continuing 
to deepen over time, with a PFS of 11.1 and 5.7 months in MT and WT EZH2, 
respectively. 40   
 
An open-label, single-arm, phase 2 trial done at 38 clinics or hospitals in 
France, the UK, Australia, Canada, Poland, Italy, Ukraine, Germany, and the 
USA using Tazemetostat 800 mg twice daily in patients with 
relapsed/refractory follicular lymphoma (NCT01897571). 41 This study showed 
meaningful clinical activity and durability of response in patients with 
recurrent/refractory follicular lymphoma, with ORR pronounced in patients 
with EZH2 activating mutations. Late onset responses have been reported on 
Tazemetostat. Tazemetostat was generally well tolerated in heavily 
pretreated patients with relapsed or refractory follicular lymphoma.  Between 
July 9, 2015, and May 24, 2019, 99 patients (45 in the EZH2mut cohort and 54 
in the EZH2WT cohort) were enrolled in the study with median follow-up of 

 
 
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22 months for the EZH2MT cohort and 35.9 months for the EZH2WT cohort. 
The objective response rate was 69% (95% CI  53–82; 31 of 45 patients) in the 
EZH2mut cohort and 35% (23–49; 19 of 54 patients) in the EZH2WT cohort. 
Median duration of response was 10.9 months (95% CI 7.22–not estimable 
[NE]) in the EZH2mut cohort and 13 months (5.6–NE) in the EZH2WT cohort; 
median progression-free survival was 13.8 months (10.7–22.0) and 11.1 
months (3.7–14.6).  Among all 99 patients, treatment-related grade 3 or 
worse adverse events included thrombocytopenia (3%), neutropenia (3%), 
and anemia (2%). Serious treatment-related adverse events were reported in 
four (4%) of 99 patients. There were no treatment-related deaths.  
 
In 2016, the Food and Drug Administration (FDA) granted Tazemetostat Fast 
Track status in 2016 for patients with relapsed/refractory DLBCL with EZH2-
activating mutations. On June 18, 2020, the Food and Drug Administration 
(FDA) granted accelerated approval to Tazemetostat for adult patients with 
relapsed or refractory (R/R) follicular lymphoma whose tumors are positive 
for an EZH2 mutation and who have received at least 2 prior systemic 
therapies, and for adult patients with R/R follicular lymphoma who have no 
satisfactory alternative treatment options. 
 
Tazemetostat is still being evaluated as a combination therapy in ongoing 
clinical trials. One study is evaluating Tazemetostat in combination with R-
CHOP (NCT02889523), a chemotherapy regimen, as a first-line treatment for 
newly diagnosed elderly, high-risk patients with diffuse large B-cell 
lymphoma (DLBCL), the most common type of NHL.  Another clinical trial 
(phase 1) is evaluating Tazemetostat in combination with Tecentriq™ 
(atezolizumab), in patients with relapsed or refractory DLBCL. Tecentriq is an 
anti-PD-L1 cancer immunotherapy approved by FDA, and in a phase 1b study 
as a combination therapy with prednisolone, in patients with relapsed or 
refractory DLBCL (NCT02220842, NCT01897571). 
 
1.4.2 Solid tumors 
There are preclinical data on impact of inhibition of EZH2 overexpression in 
various solid tumors, including MPNST, but degree of downstream effects is 
tumor dependent and overall clinical impact in terms of response rates in 
MPNST is unknown.  Tazemetostat has been shown to have antitumor 
activity in preclinical malignant rhabdoid tumor (MRT) models that were 
negative for the INI1 protein and in phase I trials of MRT and epithelioid 
sarcoma.43  In an open-label, phase 2 basket study, patients were enrolled 
from 32 hospitals and clinics in Australia, Belgium, Canada, France, Germany, 

 
 
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Italy, Taiwan, the USA, and the UK into seven cohorts of patients with 
different INI1-negative solid tumors or synovial sarcoma (NCT02601950). 
Patients eligible for the epithelioid sarcoma cohort (cohort 5) were aged 16 
years or older with histologically confirmed, locally advanced or metastatic 
epithelioid sarcoma; documented loss of INI1 expression by 
immunohistochemical analysis or biallelic SMARCB1 (the gene that encodes 
INI1) alterations, or both.  Patients received Tazemetostat 800 mg orally twice 
per day in continuous 28-day cycles and primary endpoint was objective 
response rate per RECIST 1.1.  Between Dec 22, 2015, and July 7, 2017, 62 
patients with epithelioid sarcoma were enrolled in the study.  Tazemetostat 
was well tolerated and showed clinical activity in this cohort of patients with 
advanced epithelioid sarcoma. Nine (15%) of 62 patients had an objective 
response at data cutoff (Sept 17, 2018). At a median follow-up of 13.8 
months, median duration of response was not reached (95% CI 9.2 -not 
estimable). 16 (26%) patients had disease control at 32 weeks. Median time 
to response was 3·9 months. Median progression-free survival was 5·5 
months (95% CI 3.4-5.9), and median overall survival was 19 months (11-not 
estimable). Grade 3 or worse treatment-related adverse events included 
anemia (6%) and weight loss (3%), without treatment-related deaths. 43 A 
phase 1b/3 trial of Tazemetostat plus doxorubicin in the front-line setting is 
currently underway (NCT04204941).  
 
Breast cancer gene 1 (BRCA1)-associated protein 1 (BAP1), a nuclear 
deubiquitinase, is commonly inactivated in malignant mesothelioma and 
preclinical data showed that BAP1 inactivation sensitizes mesothelial cells to 
inhibition of EZH2. A 2-part, open label phase 2 study evaluated the safety 
and efficacy of Tazemetostat in relapsed/refractory (R/R) malignant 
mesothelioma with BAP1-inactivation (NCT02860286).  Primary endpoints 
were PK profiling of Tazemetostat in all patients (part 1), and disease control 
rate (DCR) at week 12 in patients with BAP1-deficient R/R malignant 
mesothelioma (part 2). Secondary endpoints included safety, overall response 
rate (ORR), progression-free survival, overall survival, and duration of 
response (DOR). The study enrolled 74 patients with R/R malignant 
mesothelioma, of which 70 (95%) were centrally confirmed to be BAP1-
deficient. Median prior lines of therapy were two. The 12-week DCR was 47% 
(n = 35). The ORR per RECIST version 1.1 was 3% [complete response: 0%; 
partial response (PR): 3% (n = 2)]. Of the 2 patients with PR, 1 had a duration 
of response (DOR) of 21 weeks and the other is ongoing (15.3 weeks at data 
cut off).  47 subjects (64%) and 21 subjects (28%) had stable disease (SD) and 
progressive disease, respectively. Overall, 91% of subjects discontinued, 

 
 
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either due to disease progression (n = 65), death (n = 5), or treatment 
discontinuation (n = 1). Grade ≥3 treatment-emergent adverse events 
occurred in ≤5% of patients, most commonly anemia (5%) and dyspnea (4%). 
No subjects discontinued due to treatment-emergent adverse events and 
there were no treatment-related deaths. Based on disease control rate and 
stable disease, Tazemetostat showed antitumor activity in patients with 
BAP1-deficient R/R malignant mesothelioma. 44  
 
Recent literature has described genomic features of small cell carcinoma of 
the ovary of the hypercalcemic type (SCCOHT), a rare highly aggressive 
tumor that affects young women. This cancer was found to have loss-of-
function mutations in SMARCA4 (Brahma-related gene 1, BRG1) as a highly 
recurrent event in SCCOHT. 45, 46. SMARCA4 encodes one of the two possible 
catalytic subunits of the Switch/Sucrose Non-Fermentable chromatin-
remodeling complex. Others have since confirmed this finding, with 
SMARCA4 mutations being found in over 90% of cases.  
 
1.4.3 Pediatrics 
Tazemetostat is among the first investigational therapies to be tested in 
the multicenter, phase II Pediatric MATCH trial, which is being sponsored 
by the National Cancer Institute. The trial is examining targeted agents in 
children with advanced metastatic/recurrent tumors that are refractory and 
have EZH2, SMARCA4, or SMARCB1 gene mutations. The primary endpoint 
is ORR, with a secondary endpoint of PFS and additional evaluations of 
biomarker predictors of treatment response and change in tumor 
dynamics (NCT03213665, NCT03155620). 
 
1.5 
Rationale for Regimen/Doses/Schedule 
EPZ-6438 (Tazemetostat) is a selective small molecule inhibitor of the histone 
methyltransferase EZH2.  Tazemetostat is an inhibitor of both wild type and 
mutated EZH2 containing residues Y646, A682G and A692 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 selectivity over other HMTs. It selectively inhibits H3K27 methylation in 
a concentration and time dependent manner leading to selective killing of cell 
lines, specifically, human lymphoma cell lines with mutant or wildtype EZH2, 
SMARCB1-deficient malignant rhabdoid tumor (MRT) cell lines, and SMARCA2/A4 
negative SCCOHT cell lines with IC50 in the nanomolar range. Tazemetostat 
administered orally has demonstrated antitumor activity in vivo against several 
EZH2 wild type and mutant human lymphoma xenograft murine models. 36 

 
 
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SMARCB1 mutant MRT xenografts treated for 21-28 days demonstrated near 
elimination of the tumors with no regrowth observed. The MRT tumors 
demonstrated strong inhibition of H3K27Me3 which correlated with anti-tumor 
activity. 37  
 
1.5.1 Rationale for Doses Indicated in Current Study 
The first pediatric phase 1 study of Tazemetostat (EZH-102, NCT02601937) 
for children with relapsed/refractory MRT including CNS ATRT and other INI-
deficient tumors and synovial sarcoma enrolled its first patient in January 
2016 and completed the dose escalation phase of the trial (dose expansion is 
ongoing). As of July 2017, the RP2D was determined to be 1200 mg/m2 twice 
daily (for CNS primary tumors).  The dose that will be utilized in the current 
protocol for children is lower (520mg/m2 twice daily, up to a maximum of 
800 mg per dose), due to the non-CNS MPSNT subjects under study. 
 
For adults, the current study proposes 800mg twice daily, which is the dose 
studied in the previous described hematologic and solid tumor trials. 39, 41, 
43 
 
Additional information, including animal toxicology data, is provided in the 
Investigator’s Brochure (IB) for Tazemetostat. 
 
2. OBJECTIVES AND ENDPOINTS 
 
2.1 
Primary  
2.1.1 Primary Objective:  
To assess the objective response rate of Tazemetostat in subjects with 
recurrent/refractory and/or metastatic MPNST 
 
2.1.2  Primary Endpoint: 
Objective response rate (ORR, defined as proportion of subjects who achieve 
complete response CR or partial response PR) based on radiographic evaluation of 
treatment response via RECIST1.1.  
 
2.2 
Secondary 
2.2.1 Secondary Objectives: 
• To determine the progression free survival (PFS) in subjects with 
recurrent/refractory and/or metastatic MPNST. 
• To determine the time to progression (TTP) in subjects with recurrent/refractory 
and/or metastatic MPNST. 

 
 
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• To determine the clinical benefit using subject reported outcome (PRO)  
• To assess the clinical benefit rate (CBR). 
 
2.2.2 Secondary Endpoints: 
• PFS, defined as the duration of time from start of treatment to time of 
progression (RECIST 1.1 criteria) or death, whichever occurs first.  
• TTP, defined as the length of time from the start of treatment until the evidence 
of disease progression, as defined by RECIST 1.1 criteria.  
• Patient Reported Outcome (PRO) Numbered Pain Rating Scale 11 pain score 
mean (Appendix I). 
• Clinical Benefit Rate (CBR), defined as the proportion of subjects with objective 
response (CR or PR) or stable disease (SD) lasting ≥ 4 months. 
 
2.3 
Exploratory 
• Assess circulating tumor DNA (ctDNA) as a potential treatment response tool.  
• Correlate clinical data, outcomes and toxicity with biomarkers of EZH2 
inhibition and resistance - potentially including but not limited to circulating or 
tumor molecular profiling, epigenetics, and immune system activity. 
 
3. 
STUDY DESIGN 
 
3.1 
Study Overview 
This is a single institution, open label, single-arm phase 2 trial. We plan to accrue 
up to 50 subjects in order to meet our goal of 29 evaluable subjects.  Each subject 
will be administered Tazemetostat orally twice daily for subjects with recurrent 
and/or metastatic MPNST.  Subjects will be dosed in continuous 28 day cycles, and 
as follows:  
• 
Pediatric (12y- <18y): 520 mg/m2/dose orally BID, not to exceed 800 mg 
orally twice daily 
• 
Adult: (>18y): 800 mg orally BID (flat dose for adults) 
 
Surveillance imaging of primary and metastatic sites will be performed every 2 
cycles, +/- 7 days after Cycle 1 Day 1, until disease progression or death. ctDNA 
testing results will be collected whenever performed per standard of care. 
Response to treatment will be evaluated via RECIST 1.1. Treatment with 
Tazemetostat will continue until disease progression, unacceptable toxicity or 
withdrawal of consent or termination of study.   Screening data will be reviewed to 
determine subject eligibility.  Subjects who meet all inclusion criteria and none of 
the exclusion criteria will be entered into the study.  
 
 

 
 
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Total duration of subject participation will be 24 months.  Total duration of the 
study is expected to be 36 months. 
 
4. SELECTION OF SUBJECTS 
 
Subjects with a clinical diagnosis of recurrent and/or metastatic MPNST who meet 
the following inclusion and exclusion criteria at study enrollment will be eligible for 
participation in this study.  Per UFHCC guidelines, exceptions to inclusion and 
exclusion criteria are not permitted.  For questions concerning eligibility, please 
contact the PMO (pmo@cancer.ufl.edu). 
 
4.1 
Number of Subjects 
Up to 50 people will be enrolled in this study to achieve 29 evaluable subjects. 
 
4.2 
Inclusion Criteria  
Individuals eligible for study participation must meet the following criteria at 
enrollment:  
A. A histologic confirmation of recurrent/refractory and/or metastatic MPNST 
with RECIST measurable disease.  
B. Subjects ≥ 12 years of age at the time of enrollment 
C. Performance status: 
• 
12-15 years old- Lansky > 50    
• 
16-17 years old- Karnofsky > 50 
• 
>18 years old- ECOG score 0-2 
D. Subjects must have adequately recovered from the acute toxic effects of all 
prior anti-cancer therapy per enrolling physician and must meet the 
following minimum duration from prior anti-cancer directed therapy prior to 
enrollment. Subjects who have not received any anti-cancer treatment prior 
to study treatment are also eligible to enroll. 
• Anti-cancer agents known to be Myelosuppressive: ≥ 28 days after the 
last dose of agent. 
• Anti-cancer agents not known to be myelosuppressive: > 7 days after the 
last dose of agent.  
• Antibodies: > 21 days must have elapsed from infusion of last dose of 
antibody, and toxicity related to prior antibody therapy must be 
recovered to Grade < 1.  
• Systemic Corticosteroids: if related to prior therapy > 14 days must have 
elapsed, or on stable dose for treatment of CNS disease. 
• Hematopoietic growth factors: > 14 days after the last dose of a long-
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• Interleukins, Interferons, and Cytokines (other than hematopoietic growth 
factors): > 21 days after the completion of interleukins, interferon or 
cytokines (other than hematopoietic growth factors). 
• XRT/External Beam Irradiation including Protons: > 14 days after local 
XRT; > 150 days after TBI, craniospinal XRT or if radiation to > 50% of the 
pelvis; > 42 days if other substantial BM radiation. 
• Radiopharmaceutical therapy: > 42 days after systemically administered 
radiopharmaceutical therapy. 
• Major surgery > 14 days prior, with evidence of wound healing and no 
active surgical complications 
E. Subjects must not have had prior exposure to Tazemetostat or other 
inhibitor(s) of EZH2.  
F. Adequate laboratory values of organ function, defined as:  
• Peripheral absolute neutrophil count (ANC) > 1000/mm3. 
• Platelet count > 100,000/mm2 (transfusion independent, defined as not 
receiving platelet transfusions for at least 7 days prior to enrollment). 
• Hemoglobin > 8.0 g/dL at baseline (may receive RBC transfusions).  
• Creatinine clearance or radioisotope GFR > 70 ml/min/1.73 m2, or serum 
creatinine based on age/gender as followed in Appendix H.  
• Total bilirubin < 1.5 ULN or direct bilirubin < 1 x ULN. 
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 
2.5 x ULN; if liver metastases present, then AST and ALT must be < 5 x 
ULN. 
• Serum albumin > 2 g/dL. 
• Coagulation INR < 1.5, while on anti-coagulation INR < 2.5. 
G. Nervous system disorders (CTCAE v5.0) resulting from prior therapy must be 
< Grade 2, with the exception of decreased tendon reflex (DTR). Any grade of 
DTR is eligible.  
H. Subjects must not have more than one active malignancy at the time of 
enrollment (Subjects with a prior or concurrent malignancy whose natural 
history or treatment does not have the potential to interfere with the safety 
or efficacy assessment of the investigational regimen [as determined by the 
treating physician and approved by the PI] may be included).  
I. Written informed consent obtained from the subject and the subject agrees 
to comply with all the study-related procedures. All subjects and/or their 
parents or legally authorized representatives must sign a written informed 
consent. Assent, when appropriate, will be obtained according to institutional 
standard practice. 
J. Use of contraception: 

 
 
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• Women of childbearing potential (WOCBP) who are heterosexually active 
must be using two highly effective methods of contraception to avoid 
pregnancy throughout the study and for at least 6 months after the last 
dose of study drug to minimize the risk of pregnancy as Tazemetostat 
might counteract the effects of hormonal contraceptives.  Birth control 
methods that can be used while in this study include: established use of 
oral, injected or implanted hormonal birth control or placement of an 
intrauterine device [IUD] or intrauterine system [IUS]. They or their partner 
must also use a second method, (e.g., condom with spermicidal 
foam/gel/film/cream/suppository or occlusive cap [diaphragm or 
cervical/vault caps] with spermicidal foam/gel/film/cream/suppository.  If 
their male partner is vasectomized, they do not need to use any of the 
birth control methods listed above. The type of birth control they use 
must be discussed with the study doctor before beginning the study.  The 
study doctor must approve the method you use before they can enter the 
study. Prior to study enrollment, women of childbearing potential must 
be advised of the importance of avoiding pregnancy during trial 
participation and the potential risk factors for an unintentional pregnancy.   
• Males with female partners of child-bearing potential must agree to use 
physician-approved contraceptive methods (e.g., abstinence, condoms, 
vasectomy) throughout the study and should avoid donating sperm, for 
90 days following the last dose of study drug. 
 
4.3 
Exclusion Criteria 
Subjects with any of the following present at time of enrollment will not be eligible 
for study participation: 
A. Subjects who are currently taking the following concomitant medications:  
• Anti-cancer Agents: Subjects who are currently receiving other anti-cancer 
agents are not eligible.  
• CYP3A4 Agents:  Subjects who are currently receiving drugs that are 
strong inducers or strong inhibitors of CYP3A4 are not eligible. Strong 
inducers or inhibitors of CYP3A4 are prohibited from 14 days prior to the 
first dose of Tazemetostat to the end of the study. Note: Dexamethasone 
for CNS tumors or metastases, on a stable dose, is allowed. 
• Grapefruit, grapefruit juice, Seville oranges and food/drinks containing 
them should be avoided one week before the first dose of the study 
intervention  
 
B. Subjects who are acutely ill with an uncontrolled active infection on systemic 
anti-infective agents are not eligible.  

 
 
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C. Subjects with a prior history of T-LBL/T-ALL, myelodysplastic syndrome 
(MDS), acute myeloid leukemia (AML), B-cell acute lymphoblastic leukemia 
(B-ALL), or other myeloproliferative neoplasm (MPN). 
D. Subjects who have any of the following underlying major cardiac issues or 
conditions: 
• Known QTc prolongation or documentation  
• Documented New York Heart Association (NYHA) Class III or IV 
congestive heart failure. 
• Myocardial infarction within 6 months prior to registration. 
• Unstable angina within 6 months prior to registration. 
• Symptomatic arrhythmia. 
E. Subjects who in the opinion of the investigator may be high risk for 
treatment complications or unable to comply with the safety monitoring 
requirements of the study are not eligible.  
F. Heterosexually active males or females of reproductive potential may not 
participate unless they have agreed to use two highly effective contraceptive 
methods for the duration of study treatment as Tazemetostat might 
counteract the effects of hormonal contraceptives. Female subjects of 
childbearing potential should agree to remain abstinent or use adequate 
contraceptive methods for 6 months after the last dose of Tazemetostat. 
Male subjects should agree to remain abstinent or use adequate 
contraceptive methods, and agree to refrain from donating sperm, and for 90 
days after the last dose of Tazemetostat.  
G. Females who are pregnant or breastfeeding will not be entered on this study 
because there is currently no available information regarding human fetal or 
teratogenic toxicities. Pregnancy tests must be obtained in girls who are 
post-menarchal.  
H. Administration of a vaccine containing live virus within 30 days prior to the 
first dose of trial treatment.  For examples, See Section 7.3.3: Prohibited 
Concomitant Therapy. Note: Most flu vaccines are killed viruses, with the 
exception of the intra-nasal vainer (Flu-Mist) which is an attenuated live virus 
and therefore prohibited for 30 days prior to first dose. Patients may receive 
non-live versions of the COVID-19 vaccine. 
I. Prisoners or subjects who are involuntarily incarcerated, or subjects who are 
compulsorily detained for treatment of either a psychiatric or physical illness. 

 
 
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4.4 
Inclusion of Women and Minorities 
Any subjects who meet eligibility criteria may enroll in this trial. 
 
5. REGISTRATION PROCEDURES 
 
All consented subjects must be entered into the University of Florida’s Clinical Trial 
Management System (OnCore) prior to assignment of a subject identification 
number.  The study team must submit the completed study specific eligibility 
checklist, supporting source documentation and a copy of the signed informed 
consent document(s) to the UFHCC Project Management Office (PMO; 
PMO@cancer.ufl.edu) or their assigned Project Manager.  Upon receipt of a 
completed eligibility packet, the designated Project Manager will review the source 
to verify eligibility and assign a subject number.  No subject may be enrolled until 
his/her eligibility packet is complete and eligibility is verified by PMO.  If eligibility 
cannot be confirmed, the project manager will query the site for clarification or 
additional documents as needed. Subjects failing to meet all study eligibility 
requirements will not be able to participate in the trial. 
 
All eligible and enrolled subjects will receive a unique subject number. This number 
will be used to identify the subject throughout the study. Subjects withdrawn from 
the study will retain their subject number.   
 
6. STUDY PROCEDURES 
 
Written informed consent must be obtained prior to performing any study-specific 
evaluations or tests. Tests or evaluations performed as standard of care within the 
specified screening period, but prior to informed consent, may be accepted for this 
study and need not be repeated.  All clinical and laboratory studies to determine 
eligibility must be performed within 7 days prior to enrollment unless otherwise 
indicated in Section 6.2. Laboratory tests need not be repeated at the baseline visit 
(C1D1) if therapy starts within 72 hours of obtaining screening labs to assess 
eligibility. If a post-enrollment lab value is outside the limits of eligibility, then the 
following laboratory evaluations must be re-checked within 48 hours prior to 
initiating therapy: CBC with differential, bilirubin, ALT (SGPT) and serum creatinine. If 
J. Known hypersensitivity to tazmetostat or any component of the formulation 
of tazmetostat 
K. Inability to take oral medication OR have malabsorption syndrome or any 
other uncontrolled gastrointestinal condition (eg, nausea, diarrhea, vomiting) 
that might impair the bioavailability of tazmetostat 

 
 
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the recheck is outside the limits of eligibility, the patient may not receive protocol 
therapy and will be considered off protocol therapy. Imaging studies must be 
obtained within 30 days prior to start of protocol therapy. 

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6.1 
Schedule of Events 
 
                                    Visit: 
 
Procedure: 
SCREENING 
(Windows 
outlined in 
Section 6.2) 
 
CYCLE 1 
CYCLES 2 AND 
BEYOND 
(WITHIN 72 HRS 
PRIOR) 
END OF TREATMENT 
(WITHIN 14 DAYS OF 
LAST STUDY DRUG 
ADMINISTRATION) 
FOLLOW UP (28 +/- 
7 DAYS AFTER LAST 
DOSE OF 
TREATMENT) 
SURVIVAL 
FOLLOW UP 
EVERY 90 +/- 
14 DAYS 
AFTER LAST 
DOSE 
Informed Consent 
X 
 
 
 
 
 
Medical History, Demographic 
Information 
X 
 
 
 
 
 
Clinical Exam 
X 
X 
X 
X 
 
 
Performance status (PS)1 
X 
X 
X 
X 
 
 
Vital Signs (VS) including height8, weight, 
and BSA8 
X 
X 
X 
X 
 
 
Numbered Pain Rating Scale 2  
 
X 
X 
X 
 
 
Labs (CBC diff, CMP) 3,9 
X 
WEEKLY  3 
X 
 
 
X12 
Pregnancy Test (Urine or Serum) 4 
X 
X 
X 
 
 
 
INR 
X 
 
 
 
 
 
Tibial x-ray10 
X 
 
X11 
 
 
 
Provide Study Drug for home 
administration 
 
X 
X 
 
 
 
Tumor disease evaluation5 
X 
 
EVERY 2 CYCLES5  
 X 
 
 
Tumor NGS6 
X 
 
 
 
 
 
Circulating tumor DNA (ctDNA) 7 
 
 
X 
X 
 
 
Provide and/or Review Subject Diary  
 
X 
X 
X 
 
 
Concomitant Medication Review9 
X 
X 
X 
X 
 
 
Adverse Event Review9 
 
X 
X 
X 
X 
 
Survival Assessment 
 
 
 
 
 
X 
Abbreviations: VS=vital signs (blood pressure, temperature, pulse and respiratory rates, weight and height); CBC/diff=complete blood count and white blood cell differential; 
CMP = complete metabolic profile (sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, glucose, alkaline phosphatase, AST, ALT, total bilirubin, protein), 
NGS Next Generation Sequencing 
1 
Performance status: Pediatric Karnofsky for subjects > 16 years of age and Lansky for subjects 12-15 years of age; Adult ECOG score (18+)  

 
 
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2 
Numbered Pain Rating Scale , refer to Appendix G. 
3 
Laboratory tests at baseline need not be repeated if therapy starts within 72 hours of obtaining labs to assess eligibility.  Labs are to be collected weekly for Cycle 1 (Days 
1, 8, 15, and 22) +/- 72 hours.   If patients have Grade 4 neutropenia then CBCs should be checked at least every other day until recovery to Grade 3 or until meeting the 
criteria for dose limiting toxicity. Automated differentials acceptable unless concern for blasts; then please obtain manual differential. 
4 
Female subjects of childbearing potential only. 
5 
Patients must have either CT or MRI of primary and metastatic tumors, as well as whole body 18F-FDG PET/CT.  Radiographic Tumor Assessment using RECIST 1.1 
criteria.  Imaging to be obtained every 2 cycles +/- 7 days from Cycle 1 Day 1 until disease progression or death.  Screening imaging studies must be obtained within 30 
days prior to start of protocol therapy. 
6 
Tumor NGS will be sent as part of standard of care, if not already done.  If already done, results will be recorded as part of medical history review. 
7 
Circulating tumor DNA (ctDNA) results will be collected whenever obtained per standard of care. 
8 
Height and BSA only collected for pediatric subjects.   
9 
Adverse events, conmed collection, and all sample collections, should be performed pre-dose at every cycle. The study drug will be provided at study visits, but self-
administered at home throughout the trial. Cycles may be repeated for up to a total duration of therapy of 2 years (maximum 26 cycles), provided the patient meets the 
criteria for starting subsequent cycles and does not meet any of the criteria for removal from protocol therapy criteria. 
10 
Only to be completed for subjects <18 years of age. Screening tibial x-ray may have been performed within the past 6 months (180 days) before treatment (C1D1). 
11 
Tibial x-rays to be completed every 180 +/- 30 days only for those with open growth plates at screening.  
12 
CBC only – at each survival follow-up visit for five years, then yearly (at least once per calendar year) up to 10 years. Once a subject begins new anti-cancer therapy, they 
will be followed for survival only.  
 

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6.2 
Allowable Visit Windows 
Visit Name 
Window 
Screening 
 
Informed Consent 
≤ 28 days prior to Cycle1 Day 1 (C1D1) 
Medical History, Physical examination, 
Performance Status, Concomitant 
Medications, and Labs (CBC Diff, CMP, 
INR, pregnancy test) 
≤ 28 days prior to Cycle1 Day 1 (C1D1) 
Tibial X-Ray 
≤ 180 days prior to Cycle1 Day 1 (C1D1) 
Imaging (CT and PET) 
≤ 30 days prior to Cycle1 Day 1 (C1D1) 
All other screening procedures 
≤ 7 days prior to C1D1 
Cycle 1 Day 1 
 
Labs  
Laboratory tests at screening need not be 
repeated if therapy starts within 72 hours 
of obtaining labs to assess eligibility.  All 
others to be done ≤ 72 hours of C1D1 
dosing.  Labs are to be collected weekly 
for Cycle 1 (Days 1, 8, 15, and 22) +/- 72 
hours 
All other baseline procedures (which 
include complete physical exam, 
performance status, vital signs, and 
concomitant medication review) 
Baseline procedures completed at 
screening need not be repeated if therapy 
starts within 72 hours of performing 
procedures to assess eligibility. All others 
to be done ≤ 72 hours of C1D1 dosing. 
Day 1 of subsequent cycles (after Cycle 1) 
 
Assessments 
Within 72 hours prior to dosing 
Study treatment administration (dosing) 
Every 28 days 
Tibial X-Ray 
Every 180 +/- 30 days 
Tumor Assessments 
Imaging every 2 cycles +/- 7 days from 
Cycle 1 Day 1 until disease progression or 
death.   
End of Treatment (EOT) Procedures 
Within 14 days of last dose of therapy 
28-Day Safety Follow-up  
28 +/- 7 days after last dose of treatment 

 
 
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Survival Follow-Up  
Every 90 +/- 14 days 
 
6.3 
End of Treatment Evaluations 
The end of treatment visit as well as evaluations will occur within 14 days following 
the last dose of therapy.  End of treatment evaluations will also be performed 
within 14 days if the subject is discontinued as per section 8.2. 
 
6.4 
Follow up/ Evaluations 
Subjects will have a follow-up visit for the evaluation of adverse events 28 days (± 
7 days) after the last dose of study medication. Any adverse events ongoing at the 
follow up visit will be followed until resolution or start of a new therapy.  If the 
subject is unavailable to travel to the institution, the visit may be made via 
telephone interview to review for adverse event resolution or the occurrence of any 
new adverse events.  Additionally, external or internal medical records may be 
consulted with permission of the subject to complete remote visit reporting. 
 
Subjects will continue to be contacted via telephone for survival approximately 
every 90 +/- 14 days until death.  Safety labs (CBC) will be performed as part of 
these visits for 5 years, then annually until 10 years (at least once per calendar year) 
after last dose of therapy.  Labs may be collected at an outside laboratory as 
standard of care.  If study therapy is discontinued for reasons other than 
progression, continue imaging/disease assessments per standard of care until 
progression or until start of another therapy or death. Following discontinuation of 
study therapy for any reason, report the date the first non-protocol anti-cancer 
therapy is administered. Once a subject begins new anti-cancer therapy, the 
subject will be followed for survival only.  
 
 
If a subject becomes unreachable during the course of the study, the investigator 
or study team will make a reasonable effort to contact the subject and document 
each attempt (in accordance with Section 4.3.4 of the ICH E-6 GCP).  If these 
attempts are not successful, the subject may be declared “lost to follow up.”  For 
subjects lost to follow-up, the termination date will be the date of last contact with 
the subject. 
 
7. STUDY TREATMENT 
 
7.1 
Treatment Schedule/Administration 
Tazemetostat will be administered orally twice daily with the dose beginning at the 
baseline visit (Cycle 1/Day 1) according to the Table 2 below. 

 
 
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Table 2: Tazemetostat Dosing 
Baseline Criteria (age at enrollment) 
Dose (continuous 28-day cycles) 
Pediatric (12y - < 18y) 
520 mg/m2/dose orally twice daily, not to 
exceed 800 mg orally twice daily, rounded 
up if between doses 
Adult (> 18y) 
800 mg orally twice daily (flat dose for 
adults) 
 
7.2 
Overview of treatment plan 
Tazemetostat will be administered at a dose of 520 mg/m2/dose for pediatric 
patients 12- <18 years of age (rounding up if between doses), and for adults > 18 
years of age, 800 mg, orally twice daily.  The powder for suspension must be 
reconstituted prior to administration. Patients can take Tazemetostat without 
regard to meals, with no less than 8 hours between each dose. The oral 
suspension should be given by mouth immediately after the dose is prepared in 
the oral syringe. Patients should drink additional water after administration (about 
4 ounces). For feeding tube dosing, administer directly into the feeding tube with 
the syringe. Rinsing with 10 mL of water for NG tubes and 40 mL of water for G-
tubes is recommended. If vomiting occurs after taking oral suspension 
formulation, the dose should NOT be repeated and the next dose should be 
administered at the regularly scheduled time.  
 
Therapy will be discontinued if there is evidence of progressive disease or drug 
related dose-limiting toxicity that requires removal from therapy (Section 7.6).  A 
cycle of therapy is considered to be 28 days. Cycles may be repeated for up to a 
total duration of therapy of 2 years (maximum 26 cycles), provided the patient 
meets the criteria for starting subsequent cycles and does not meet any of the 
criteria for removal from protocol therapy criteria.  
 
Pediatric drug dosages should be adjusted based on the BSA calculated from 
height and weight, measured within 7 days prior to the beginning of each cycle.  
Patients who experience dose-limiting toxicity should have their dose reduced by 
25% so that patients receive 75% of the original administered dose.  
 
7.3 
Criteria for Starting Subsequent Cycles 
A cycle may be repeated every 28 days if the patient has at least stable disease 
and has again met laboratory parameters as defined in the eligibility section 
(Section 4) and remains eligible to continue agent administration per the 

 
 
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requirements in the Investigator Brochure, package insert, and Sections 4 and 7 of 
this document.    
 
7.4 
Grading of Adverse Events 
Adverse events (toxicities) will be graded according to version 5.0 of the NCI 
Common Terminology Criteria for Adverse Events (CTCAE). All appropriate 
treatment areas should have access to a copy of version 5.0 of the CTCAE. A copy 
of the CTCAE v5 can be downloaded from the CTEP website 
(http://ctep.cancer.gov). Any suspected or confirmed dose-limiting toxicity should 
be reported immediately (within 24 hours) to the Project Management Office 
(PMO@cancer.ufl.edu) and the PI.  
 
7.5 
Supportive Care and other concomitant therapy 
 
7.5.1 Supportive Care Guidelines 
Subjects should receive full supportive care, including transfusions of blood 
and blood products, antibiotics, antiemetics, antidiarrheals, analgesics, etc., 
when appropriate. Bisphosphonates or denosumab are allowed for subjects 
with bone metastases. 
 
Growth factors that support platelet or white cell number or function can 
only be administered for culture proven bacteremia or invasive fungal 
infection when approved by the Principal Investigator.  
 
7.5.2 Concomitant Therapy  
Relevant medical history should be obtained at screening and include prior 
medications and treatment history.  All medications taken within 4 weeks 
prior to screening, regardless of indication, should be recorded. 
 
Any therapy or medication (except study drugs), administered from screening 
until thirty days after the last dose of either study drug, is considered a 
concomitant therapy or medication. However, if another course of anti-
cancer therapy is initiated prior to the thirty-day follow-up period visit, a 
record of concomitant medications will no longer be performed. If the use of 
any concomitant treatments (medications or procedures) becomes necessary, 
the treatment must be recorded, including the name of the drug or 
treatment, dose, route, date, indication for use, expected duration, and 
frequency of treatment.  
 

 
 
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Assessment and documentation of concomitant medications will be done at 
each visit. 
 
7.5.3 Prohibited Concomitant Therapy 
Supportive care measures consistent with optimal subject care will be 
permitted throughout the study, as long as the therapy is not included in this 
section as prohibited. 
 
Subjects are prohibited from receiving the following therapies during the 
Screening and Treatment Phase of this trial:  
  
• Concurrent cancer therapy, including chemotherapy, radiation therapy, 
immunotherapy, or biologic therapy may NOT be administered to 
patients receiving study drug. If these treatments are administered the 
patient will be removed from protocol therapy.  
• Investigational agents other than the study drug in this trial.  
• Radiation therapy (allowed if ≥ 14 days prior to study registration). 
• Cancer-Related Surgery (allowed if ≥ 14 days prior to study 
registration). 
• Strong inhibitors and inducers of CYP2C8, CYP2D6, and P-glycoprotein 
(P-gp) should be used with caution.  
• Medications that are sensitive or narrow therapeutic range substrates of 
CYP3A, CYP2C8, CYP2C9, CYP2C19, CYP2D6 should be avoided if 
possible. Other substrates of CYP2C8, 2C9, 2C19, 2D6, 3A, P-gp, 
OATP1B1, OATP1B3, OAT3, MATE1, and MATE2K should be used with 
caution.  
• CYP3A4/5 inhibitors or inducers: Strong CYP3A4/5 inhibitors or inducers 
are prohibited from 14 days prior to the first dose of Tazemetostat to 
the end of the study (Appendix F). Note: Dexamethasone for CNS 
tumors or metastases, on a stable dose, is allowed.  
• Live vaccines within 30 days prior to the first dose of trial treatment and 
while participating in the trial. Examples of live vaccines include, but are 
not limited to, the following: measles, mumps, rubella, chicken pox, 
yellow fever, rabies, BCG, and typhoid (oral) vaccine. Seasonal influenza 
vaccines for injection are generally killed virus vaccines and are allowed. 
However, intranasal influenza vaccines (e.g. Flu - Mist®) are live 
attenuated vaccines, and are not allowed. Patients may receive non-live 
versions of the COVID-19 vaccine. 
 

 
 
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7.6 
Dose Modifications 
The National Cancer Institute (NCI) Common Toxicity Criteria (CTCAE Version 5.0) 
for Adverse Events (CTCAE) will be used to grade toxicity 
(http://evs.nci.nih.gov/ftp1/CTCAE/About.html).   See Table 3 for Dose 
Modification Tables for children and adults. 
 
7.6.1 Non- Hematologic Toxicity 
Non- Hematological dose limiting toxicity is defined as any Grade 3 or 
greater non-hematological toxicity attributable to the investigational drug 
with the specific exclusion of:  
• Grade 3 nausea and vomiting of less < 3 days duration. 
• Grade 3 liver enzyme elevation, including ALT/AST/GGT that returns 
to levels that meet initial eligibility criteria or baseline within 7 days.  
• Grade 3 or 4 fever < 5 days duration.  
• Grade 3 infection < 5 days duration.  
• Grade 3 hypophosphatemia, hypokalemia, hypocalcemia or 
hypomagnesemia responsive to supplementation.  
• Any Grade 2 non-hematological toxicity that persists for ≥ 7 days and 
is considered sufficiently medically significant or sufficiently 
intolerable by patients that it requires treatment interruption.  
• Note: Allergic reactions that necessitate discontinuation of study drug 
will not be considered a dose-limiting toxicity.  
 
7.6.2 Dose Modifications for Non-Hematological Toxicity  
If a patient experiences non-hematological dose-limiting toxicity as 
defined in Section 7.6.1, treatment will be held. When the toxicity resolves 
to meet eligibility parameters or baseline within 14 days of drug 
discontinuation, the patient may resume treatment at a reduced dose as 
below. 
 
Patients who experience dose-limiting toxicity should have their dose 
reduced by 25% so that patients receive 75% of the original administered 
dose. For subjects taking 800 mg twice daily (dispensed as 4, 200-mg 
tablets twice daily), dosage should be reduced to 600 mg, dispensed as 3, 
200mg tablets twice daily.  
 
Doses reduced for toxicity will not be re-escalated, even if there is minimal 
or no toxicity with the reduced dose.  
 

 
 
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If toxicity does not resolve to meet eligibility or baseline parameters within 
14 days of drug discontinuation, the patient must be removed from 
protocol therapy.   If dose-limiting toxicity recurs in a patient who has 
resumed treatment, the patient must be removed from protocol therapy.  
 
7.6.3 Hematologic Toxicity 
Hematological dose limiting toxicity is defined as:  
• Grade 4 thrombocytopenia or neutropenia, not due to malignant 
infiltration. 
• Grade 3 thrombocytopenia that persists for > 7 days. 
• Grade 3 thrombocytopenia requiring a platelet transfusion on two 
separate days, within a 7-day period.  
• Grade 3 thrombocytopenia with clinically significant bleeding.  
• Neutropenia or thrombocytopenia that causes a delay of > 14 days 
between treatment cycles (e.g. platelets < 100K or ANC < 1000).  
• NOTE: Grade 3 or 4 febrile neutropenia will not be considered a 
dose-limiting toxicity. 
 
7.6.4 Dose Modifications for Hematological Toxicity  
If a patient experiences hematological dose-limiting toxicity as defined in 
Section 7.6.3, treatment will be held.  
 
Counts should be checked every 3-4 days for thrombocytopenia and every 
other day for neutropenia during this time. If the toxicity resolves to meet 
eligibility parameters within 14 days of drug discontinuation, the patient may 
resume treatment at a reduced dose. The dose will be reduced by 25% so 
that patients receive 75% of the original administered dose. For subjects 
taking 800 mg twice daily (dispensed as 4, 200-mg tablets twice daily), 
dosage should be reduced to 600 mg, dispensed as 3, 200-mg tablets twice 
daily. 
 
Doses reduced for toxicity will not be re-escalated, even if there is minimal or 
no toxicity with the reduced dose.  
 
If toxicity does not resolve to meet eligibility parameters within 14 days of 
drug discontinuation, the patient must be removed from protocol therapy.  
If hematological dose-limiting toxicity recurs in a patient who has resumed 
treatment at the reduced dose, the patient must be removed from protocol 
therapy.  
 

 
 
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7.6.5 Dose Modification Tables  
 
The table in this section (Table 3) should be used for dose modifications as a 
result of toxicities outlined in section 7.6.  
 
Table 3: Tazemetostat Dose Modifications for Adverse Reactions 
Adults 
Dose level 
Initial Dose: 8 capsules per day 
Starting Dose 
Four 200-mg capsules twice daily (1600 
mg/day) 
Dose Reduction (by 25%) 
Three 200-mg capsules twice daily (1200 
mg/day) 
 
Children 
Dose level 
Initial Dose: 8 capsules per day 
Starting Dose 
520 mg/m2/dose orally twice daily (up to 1600 
mg/day) 
Dose Reduction (by 25%) 
390 mg/m2/dose orally twice daily (up to 1200 
mg/day) 
 
8. TREATMENT DISCONTINUATION 
 
8.1 
Screen Failures  
Subjects who sign informed consent, but do not meet eligibility criteria, or 
withdraw prior to eligibility being verified, and undergo at least some of the 
screening procedures will be considered screening failures. Subjects who sign 
informed consent and are verified as eligible, but do not proceed to formal 
registration will be considered “unregistered.”  A record of screen failures and 
unregistered subjects will be maintained by the study site. 
 
8.2 
Criteria For Study Treatment Discontinuation 
Subjects who discontinue participation in the clinical study on their own or subjects 
who are withdrawn by the investigator, for reasons other than completion of 
treatment, disease progression or toxicity, will be defined as premature 
withdrawals.   
 
A subject will be discontinued from protocol therapy under the following 
circumstances: 

 
 
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• Any adverse event which, in the Investigator’s opinion, requires termination 
of the study medication. 
• Disease progression, unless at the discretion of the principal investigator (in 
collaboration with any co-sponsors or collaborators) continued treatment 
with study drug is appropriate. 
• The subject becomes pregnant.  Pregnancy will be reported along the same 
timelines as a serious adverse event. 
• The subject uses illicit drugs or other substances, or takes part in activities 
that may, in the opinion of the Investigator, have a reasonable chance of 
contributing to toxicity or otherwise interfering with results. 
• The development of a second malignancy that requires treatment, which 
would interfere with this study. 
• The subject is lost to follow-up. 
• Development of an intercurrent illness or situation which would, in the 
judgment of the investigator, affect assessments of clinical status and study 
endpoints to a significant degree. 
• If subject desires to discontinue. 
 
The Investigator will make every reasonable effort to keep each subject in the 
study unless it is in the subject’s best interests to discontinue participation.  If a 
subject is removed from the study or declines further participation, all EOT 
evaluations should be performed if the subject is willing and able to be assessed.  
A description of the reason(s) for withdrawal from the study must be recorded on 
the case report form (CRF).  The Investigator should also ensure that all subjects 
are followed up for survival status after the Final Visit. 
 
Relevant visit data should be entered on the CRF and any unused study 
medication will be accounted for and returned for all subjects participating in the 
study, even for a brief period of time.  Subjects who discontinue following entry 
will have relevant information completed and recorded on the CRF.  All subjects 
who discontinue because of adverse events or clinically significant laboratory 
abnormalities should be followed up until they recover or stabilize, and the 
subsequent outcome will be recorded.  If any subject should experience a serious 
adverse event during the trial or within 30 days of stopping study treatment, the 
Investigator will inform the UF Health Data Integrity and Safety Committee.   
 
8.3 
Replacement of Subjects 
Subjects may be replaced if they are not screen failures, have not completed at 
least 75% of intended doses in the first cycle, or are not discontinued for disease 
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Subjects who receive at least 75% of the intended doses in their first cycle will be 
evaluable for clinical response. Additionally, subjects who receive any dose will be 
evaluable for toxicity.         
                                                                                   
9. BIOLOGICAL SPECIMENS AND CORRELATIVES 
 
 
9.1 
Preparation, Shipment and Storage of Specimens 
See Study Procedure Manual for collection, processing and shipping instructions 
for all tissue and blood specimens. 
 
10. STUDY DRUG INFORMATION 
 
10.1 Study Drug Name 
Tazemetostat (Tazverik, Epizyme) 
 
10.1.1 Identification 
Tazverik is a methyltransferase inhibitor indicated for the treatment of adults 
and pediatric subjects aged 16 years and older with metastatic or locally 
advanced epithelioid sarcoma, a rare slow-growing type of soft tissue cancer, 
who are not eligible for complete resection. Tazemetostat is taken orally, with 
or without food. Swallow the tablet whole and do not crush, chew or break it. 
 
 
Chemical Name: [1,1’-Biphenyl]-3-carboxamide, N-[(1,2-dihydro-4,6-
dimethyl-2-oxo-3-pyridinyl)methyl]-5-[ethyl(tetrahydro-2H-pyran-4-
yl)amino]-4-methyl-4’-(4-morpholinylmethyl)-,hydrobromide(1:1). 
 
Chemical Structure:  
 
Molecular Formula: C34H44N4O4·HBr 
Molecular Weight: 653.66 g/mol 

 
 
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Physical Description:  Tazemetostat hydrobromide is a white to off-white 
solid that is slightly soluble in water. Tazemetostat tablets contains 200 mg 
Tazemetostat, equivalent to 228 mg Tazemetostat hydrobromide. Each 
Tazemetostat tablet is film-coated, red, round, biconvex shape, and debossed 
with “EZM 200” on one side and plain on the other.  
 
10.1.2 Packaging and Labeling 
Study drug is provided in bottles of 240 tablets with a desiccant; NDC 72607-
100-00. 
 
All study treatment supplies must be stored in accordance with the storage 
and handling manual instructions and package labeling. Until dispensed to 
subjects, the study treatment will be stored in a securely locked area, 
accessible to authorized staff only. 
 
10.1.3 Drug Supply 
The Sponsor Epizyme (or designee) will ship Study Drug to the 
investigational site, University of Florida.  The initial study drug shipment will 
be shipped after site activation (i.e., all required regulatory documentation 
has been received by the Sponsor and a contract has been executed). 
Subsequent study drug shipments will be made after site request for 
resupply. 
 
10.1.4 Storage, Handling and Dispensing 
 
Tablets  
Do not store Tazverik tablets above 86°F (30°C). Drug is administered orally, 
with or without food. Swallow tablets whole; do not cut, crush, or chew. Store 
at room temperature away from moisture and heat. Keep the tablets in their 
original container, along with the packet or canister of moisture-absorbing 
preservative.  
 
Powder suspension 
Do not store above 25°C (77°F). Protect from light. Once oral suspension is 
prepared, store refrigerated between 2-8 °C (36-46 °F) and protect from light. 
Brief excursion (less than 4 hours) up to 30°C is allowable for transfer from 
the clinic to home, but bottles must be immediately refrigerated upon arrival. 
A cold pack may be provided to the patient as required.  
 

 
 
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If a storage temperature excursion is identified, promptly return tazemetostat 
un-reconstituted powder for oral suspension to below 25°C (77°F) and 
prepared oral suspension to 2-8°C (36-46 °F) and quarantine the supplies.  
 
Drug doses should be adjusted based on the BSA calculated from height and 
weight measured within 7 days prior to the beginning of each cycle. Shake 
the bottle for one minute before you take tazemetostat; do not shake too 
much (if there are bubbles wait for them to dissipate before measuring the 
dose). Note: If multiple bottles are dispensed, daily shaking of all bottles is 
required to ensure the suspension stays properly suspended. Store your oral 
suspension in the refrigerator.  
 
Table 4. Suspension preparation guidance table 
Total tazemetostat 
required 
2 gm 
bottles 
7 gm 
bottles 
Ora-Sweet® volume* 
(mL) 
Allowable medication bottle 
size** (mL) 
< 2 grams 
1 
0 
65 
100-150 
2 to < 4 grams 
2 
0 
130 
200-300 
4 to < 6 grams 
3 
0 
195 
250-500 
6 to < 7 grams 
0 
1 
228 
250-500 
7 to < 9 grams 
1 
1 
293 
400-700 
9 to < 11 grams 
2 
1 
358 
400-800 
11 to < 12 grams 
3 
1 
423 
600-1000 
12 to < 14 grams 
0 
2 
455 
600-1100 
14 to < 16 grams 
1 
2 
520 
600-1200 
18 to < 20 grams 
3 
2 
650 
750-1500 
20 to < 21 grams 
0 
3 
683 
850-1600 
21 to < 23 grams 
1 
3 
748 
1000-1800 
23 to < 25 grams 
2 
3 
813 
1000-2000 
25 to < 27 grams 
3 
3 
878 
1100-2100 
27 to < 28 grams 
0 
4 
910 
1200-2400 

 
 
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28 to < 30 grams 
1 
4 
975 
1300-2500 
30 to < 32 grams 
2 
4 
1040 
1400-2600 
32 to < 34 grams 
3 
4 
1105 
1500-2800 
This table is for guidance purposes only, larger volumes should be calculated using the 
Tazemetostat Oral Suspension Preparation Worksheet.  
*The volume of Ora-Sweet® to obtain a concentration of 30 mg tazemetostat/mL of suspension 
accounts for the volume of tazemetostat in the solution. 
** Total volume listed may require more than one medication bottle to accommodate. Each 
medication bottle must be prepared separately but multiple whole bottles of tazemetostat powder 
for oral suspension can be combined into one medication bottle. 
 
10.1.5 Contraindications 
None 
 
10.1.6 Special Warnings and Precautions for Use 
Secondary Malignancies: TAZVERIK increases the risk of developing 
secondary malignancies, including T-cell lymphoblastic lymphoma, 
myelodysplastic syndrome, and acute myeloid leukemia.  
 
Embryo-Fetal Toxicity: Can cause fetal harm. Advise subjects of potential risk 
to a fetus and to use effective non-hormonal contraception.  
 
10.1.7 Adverse Event Profile 
The most common (≥20%) adverse reactions are pain, fatigue, nausea, 
decreased appetite, vomiting, and constipation.  
 
10.1.8 Drug Interactions 
Strong and Moderate Cytochrome P450 (CYP)3A Inhibitors: Avoid 
coadministration of strong and moderate CYP3A inhibitors with TAZVERIK. 
Reduce the dose of TAZVERIK if coadministration of moderate CYP3A 
inhibitors cannot be avoided. 
Strong and Moderate CYP3A Inducers: Avoid coadministration with 
TAZVERIK.  
 
11. ADVERSE EVENTS 
 
11.1 Definitions 
 

 
 
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11.1.1 Adverse Event 
The term “adverse event” (AE) includes any sign, symptom, syndrome, or 
illness that appears or worsens in a subject during the period of observation 
in the clinical study and that may impair the wellbeing of the subject. The 
term also covers laboratory findings or results of other diagnostic procedures 
that are considered to be clinically significant (e.g., that requires unscheduled 
diagnostic procedures or treatment measures, or result in withdrawal from 
the study).  An abnormal lab value or test results constitute an adverse event 
if they are considered clinically significant or require therapy. An AE is 
therefore any unfavorable and unintended symptom or disease temporally 
associated with the administration of an investigational product, whether or 
not related to that investigational product. 
 
The adverse event may be: 
• A new illness/condition; 
• Worsening of a sign or symptom of the condition under treatment, or of 
a concomitant illness/condition; 
• An effect of the study drug; or 
• A combination of 2 or more of these factors. 
 
 No causal relationship with the study drug or with the clinical study itself is 
implied by the use of the term “adverse event.” 
 
The Investigator or his/her designee will probe, via discussion with the 
subject, for the occurrence of AEs during each subject visit and record the 
information in the site’s source documents.  AEs will be recorded in the 
subject CRF.  AEs will be described by duration (start and stop dates and 
times), severity, outcome, treatment and relation to study drug, or if 
unrelated, the cause. 
 
Surgical procedures themselves are not adverse events; they are therapeutic 
measures for conditions that require surgery. The condition(s) for which the 
surgery is required may be an adverse event. Planned surgical measures 
permitted by the clinical study protocol and the condition(s) leading to these 
measures are not adverse events. 
 
When a clear diagnosis is available that explains the abnormal objective 
findings, this diagnosis will be recorded as an adverse event and not the 
abnormal objective findings (e.g., viral hepatitis will be recorded as the 
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not available, then the sign(s) (e.g., clinically significant elevation of 
transaminase levels) or symptom(s) (e.g., abdominal pain) will be recorded as 
the adverse event. 
 
Adverse events fall into the categories “serious” and “non-serious.” 
 
11.1.2 Serious Adverse Event 
A serious adverse event is one that at any dose of the study drug or at any 
time during the period of observation: 
• Results in death; 
• Is life-threatening (defined as an event in which the subject was at risk of 
death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe); 
• Requires inpatient hospitalization or causes prolongation of existing 
hospitalization (see note below for exceptions); 
• Results in persistent or significant disability/incapacity; 
• Is a congenital anomaly/birth defect; or 
• Is an important medical event, defined as a medical event that may not 
be immediately life-threatening or result in death or hospitalization but, 
based on appropriate medical and scientific judgment, may jeopardize 
the subject or may require intervention (e.g., medical, surgical) to prevent 
one of the other serious outcomes listed above. Examples of such events 
include but are not limited to intensive treatment in an emergency 
department or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization. “Medically important” 
should be marked only if no other serious criteria are met. 
 
An “unexpected SAE” is any SAE for which the nature, specificity or severity 
is not consistent with the currently known adverse event profile of the 
investigational agent(s). 
 
NOTE: The following hospitalizations are not considered SAEs in UFHCC 
clinical studies: 
• a visit to the emergency room or other hospital department lasting less 
than 24 hours that does not result in admission (unless considered an 
“important medical event” or a life-threatening event). 
• elective surgery planned before signing consent. 
• admissions as per protocol for a planned medical/surgical procedure. 
• routine health assessment requiring admission for baseline/trending of 
health status (e.g., routine colonoscopy). 

 
 
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• medical/surgical admission for purpose other than remedying ill health 
state that was planned before study entry. Appropriate documentation is 
required in these cases. 
• admission encountered for another life circumstance that carries no 
bearing on health status and requires no medical/surgical intervention 
(e.g., lack of housing, economic inadequacy, caregiver respite, family 
circumstances, administrative). 
 
Clarification of the difference in meaning between “severe” and “serious” 
The term “severe” is often used to describe the intensity (severity) of a 
specific event (as in mild, moderate, or severe myocardial infarction); the 
event itself, however, may be of relatively minor medical significance (such 
as severe headache). Any grade ≥ 3 adverse event per CTCAE is generally 
considered severe AE. This is not the same as “serious,” which is based on 
the outcome or action criteria usually associated with events that pose a 
threat to life or functioning. Seriousness (not severity) serves as a guide for 
defining regulatory reporting obligations. 
 
11.1.3 Non-Serious Adverse Event 
A non-serious adverse event is any adverse event not meeting any of the 
serious adverse event criteria. 
 
11.2 Period of Observation 
Following the subject’s written consent to participate in the study, all SAEs must be 
collected, including those thought to be associated with protocol-specified 
procedures. Collection of all SAEs must continue for 30 days after the last 
administration of the investigational product. If applicable, SAEs must be collected 
that relate to any later protocol-specified procedure (e.g., a follow-up skin biopsy). 
The investigator should notify the DISC of any SAE occurring after this time period 
that is believed to be related to the investigational product or protocol-specified 
procedure. 
 
The investigator will begin collecting non-serious adverse event (NSAE) information 
once administration of the investigational product is initiated. This NSAE 
information should also be collected from the start of a placebo lead-in period or 
other observational period intended to establish a baseline status for the subjects.  
Treated subjects, including those who were prematurely discontinued from the 
study, will be followed for any adverse events that occur during the study until 30 
days following the last dose of study treatment (i.e., the Follow-up Visit).  However, 
if another course of anti-cancer therapy is initiated prior to the 30-day follow-up 

 
 
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period visit, collection of adverse events will no longer be performed, with the 
exception of events that may be possibly, probably, or definitely related to the 
investigational agent or are clinically significant.  
 
11.3 Documenting and Reporting of Adverse Events by Investigator 
All adverse events must be fully recorded in the subject’s case record form.  
Documentation must be supported by an entry in the subject’s file.  A laboratory 
test abnormality considered clinically relevant, e.g., causing the subject to withdraw 
from the study, requiring treatment or causing apparent clinical manifestations, or 
judged relevant by the investigator, should be reported as an adverse event.  Each 
event should be described in detail along with start and stop dates, severity, 
relationship to investigational product, action taken and outcome. 
 
Every attempt should be made to describe the adverse event in terms of a 
diagnosis that encompasses the component signs and symptoms. If only 
nonspecific signs or symptoms are present, then these should be recorded as 
separate diagnoses on the pages of the case report form. 
 
 
All subjects who have adverse events, whether considered associated with the use 
of study drug or not, must be monitored to determine the outcome. The clinical 
course of the adverse event will be followed according to accepted standards of 
medical practice, even after the end of the period of observation, until a 
satisfactory explanation is found or the Principal Investigator considers it medically 
justifiable to terminate follow-up. Should the adverse event result in death, a full 
pathologist’s report should be supplied, if possible. 
 
11.3.1 Assessment of Causal Relationship of Study Drug 
The Investigator will provide an assessment of the potential causal 
relationship between adverse events and study medication by determining 
whether or not there is a reasonable possibility that the event was caused by 
the study medication. The relationship or association of the adverse event to 
the study medication will be characterized as not related, unlikely related, 
possibly related, probably related, or related:   
 
Not Related: There is not a temporal relationship to the study drug 
administration or the adverse event is clearly due only to the progression of 
the underlying disease state, intercurrent illness, concomitant medication, 
concurrent therapy or other known cause. 
 
Unlikely Related: There is little or no chance that the study drug 

 
 
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administration caused the adverse event; the event is most likely due to 
another competing cause, including intercurrent illness, progression or 
expression of the disease state, or a reaction to a concomitant medication or 
concurrent therapy appearing to explain the reported adverse event.  
 
Possibly Related: The association of the adverse event with the study drug 
administration is unknown; however, the adverse event is not reasonably 
attributed to any other condition.  
 
Probably Related: When a reasonable temporal relationship exists between 
the adverse event and the study drug administration; significant symptoms 
abate upon discontinuation of the study drug and there is a reasonable 
explanation based on known characteristics of the study drug and there is no 
clear association with preexisting disease or therapy, intercurrent illness, 
concurrent therapy or other factor(s). 
 
Related: When the adverse event is a known side effect of the study drug or 
there is a temporal relationship to the administration of the study drug; or 
the adverse event reappears upon re-administration of the study drug 
(rechallenge); or the significant symptoms of the adverse event abate upon 
discontinuation of the study drug (dechallenge). 
 
11.3.2 Intensity of Adverse Events 
The intensity of adverse changes in physical signs or symptoms will be 
graded according to the most up-to-date CTCAE version. For all other 
adverse events not described in the CTCAE, the intensity will be assessed by 
the Investigator using the following categories: 
 
Mild (Grade 1) – transient or mild discomfort; no limitation in activity; no 
medical intervention/therapy required. 
 
Moderate (Grade 2) – mild to moderate limitation in activity, some assistance 
may be needed; no or minimal medical intervention/therapy required. 
 
Severe (Grade 3) – marked limitation in activity, some assistance usually 
required; medical intervention/therapy required, hospitalization is possible. 
 
Life-threatening (Grade 4) – extreme limitation in activity, significant 
assistance required; significant medical intervention/therapy required, 
hospitalization or hospice care probable. 

 
 
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Death (Grade 5) – the event resulted in death. 
 
11.3.3 Action Taken with Study Drug 
 
The action the Investigator took with study drug as a result of the event 
should be recorded as one of the following: 
 
None – No action was taken with regard to the study drug as a result of the 
adverse event. 
 
Interrupted – Study drug was stopped due to the adverse event, but was later 
resumed at the same dose. 
Dose decreased – The dose of study drug was decreased as a result of the 
adverse event. 
 
Permanently discontinued – The subject was withdrawn from the study due to 
the adverse event. 
 
Only one item should be chosen. If multiple actions apply, the following 
“worst case” scenario hierarchy should be used to determine the preferred 
entry: permanently discontinued > dose decreased > interrupted. 
 
11.3.4 Definition of Outcome 
The outcome of the AE should be recorded as one of the following: 
 
Resolved without sequelae – The subject fully recovered from the adverse 
event with no observable residual effects. 
 
Resolved with sequelae – The subject recovered from the adverse event with 
observable residual effects. 
 
Not resolved – The adverse event was present at the time of last observation. 
 
Death – The subject died as a result of the adverse event. 
 
11.4 Immediately Reportable Events 
 
11.4.1 Serious Adverse Events 
Serious adverse events (SAE's) must be reported to the UFHCC CRO Project 

 
 
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Management Office (PMO; pmo@cancer.ufl.edu), and entered into OnCore, 
within 24 hours of discovery of the event. The FDA MEDWATCH 3500 form 
must be completed and sent to Epizyme within 7 business days.  If only 
limited details are known, these should be reported within that time frame 
and follow up reports can be submitted for elaboration, clarifications, or 
corrections.  Any email correspondence must be kept in the trial file at the 
study site. The site investigator is responsible for informing the IRB and/or 
the Regulatory Authority of the SAE as per local requirements.   
 
Follow-up information will be submitted to the UFHCC CRO PMO 
(pmo@cancer.ufl.edu), stating that this is a follow-up to a previously 
reported SAE and giving the date of the original report. Each re-occurrence, 
complication, or progression of the original event should be reported as a 
follow-up to that event regardless of when it occurs. The follow-up 
information should describe whether the event has resolved or continues, if 
and how it was treated, and whether the participant continued or withdrew 
from study participation.  PMO will confirm that the event and any necessary 
follow-ups are reported to the UFHCC Data and Safety Integrity Committee 
(DISC), the sponsor, and any other regulatory authorities as required (FDA, 
etc.)  
 
11.4.2 Other Events Requiring Immediate Reporting  
All pregnancies, regardless of outcome, must be reported to the UFHCC 
CRO Project Management Office (PMO; pmo@cancer.ufl.edu), including 
pregnancies that occur in the female partner of a male study subject. All 
pregnancies must be followed to outcome.  Pregnancies and follow-ups 
will be submitted by PMO to DISC, the sponsor if required, and any other 
regulatory authorities required. 
 
Although overdose and cancer are not always serious by regulatory 
definition, these events should also be reported to the UFHCC CRO Project 
Management Office (PMO; pmo@cancer.ufl.edu) in an expedited manner.  
In case the overdose did not result in any adverse event, the Investigator 
should report this as “overdose, no adverse event” and provide the 
intended amount, as well as the actual amount, of drug administered.  In 
the event of overdose or exaggerated response, appropriate supportive 
measures should be employed.  Actual treatment should depend on the 
severity of the clinical situation and the judgment and experience of the 
treating physician.  Overdose events and follow-ups will be submitted by 
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authorities required. 
 
Pregnancies and overdoses should be documented and reported per the 
reporting guidelines below. 
 
 
Institution Immediate Reporting Information 
 
SAEs and pregnancies must be reported to the UFHCC CRO Project 
Management Office (PMO), or assigned designee at: 
  
Email: pmo@cancer.ufl.edu  
As well as entered in OnCore, the study CTMS. 
 
11.4.3 Reporting to Epizyme 
 
The UFHCC CRO Project Management Office (PMO) will forward any SAE, 
AESI, or pregnancy to Epizyme as agreed upon in the contract.  PMO will 
forward both initial and follow-up versions of each report.   
 
Epizyme AE and Pregnancy Reporting Information 
 
Email: drugsafety.USA@ipsen.com AND pharmacovigilance@ipsen.com 
12. STATISTICAL METHODS 
The sections below provide an overview of the statistical considerations and 
analyses. 
 
12.1 Data collection and management plan  
Data will be collected via paper source documents and the medical record, and will 
subsequently be entered into a validated Electronic Data Capture (EDC), REDCap, 
which will be monitored and audited on a regular basis to ensure accuracy.  Data 
will be accessible only to certified members of the research team, under the 
supervision of the PI, and will be fully de-identified prior to analysis.  All paper 
records will be archived for a pre-specified length of time as per applicable 
regulations and federal laws. 
 
12.2 Sample Size Justification 
Simon's two-stage Optimum design will be used for the study to evaluate the 
primary endpoint of objective response rate (ORR, defined as CR+PR) of 
Tazemetostat.  Assuming that with current treatment (traditional chemotherapy 
with doxorubicin and ifosfamide), ORR is 21% for the target study subjects (Kroep 

 
 
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JR et al Annals Oncol 22:207-214, 2011), the null hypothesis that the true ORR is 
21% and this will be tested against a one-sided alternative.  In the first stage, 9 
patients will be accrued. If there are 2 or fewer responses in these 9 patients, the 
study will be stopped. Otherwise, 20 additional patients will be accrued for a total 
of 29. The null hypothesis will be rejected if 10 or more responses are observed in 
29 subjects. This design yields a type I error rate of 5% and power of 80% when the 
true ORR is 45%. 
 
Assuming an enrollment rate of 6-12 subjects per year per institutional experience, 
this protocol is expected to accrue within 2-4 years.  
 
12.3 Analysis of Primary Endpoint 
The analysis for the primary endpoint, ORR, is based on the intent-to-treat 
approach. ORR will be calculated as the proportion of the patients with objective 
response divided by the total number of the study patients. The 95% confidence 
interval for ORR will be calculated based on the exact binomial distribution. 
 
12.4 Analysis of Secondary Endpoints 
Secondary endpoints include PFS, TTP, PRO and CBR.  PFS is defined as the 
duration of time from start of treatment to time of progression or death, whichever 
occurs first. Development of new disease or progression in any established lesions 
is considered progressive disease, regardless of response in other lesions. All 
subjects surviving at the time of analyses without events will be censored at their 
last follow-up date. PFS along with the confidence intervals will be estimated using 
the Kaplan-Meier method. TTP will be reported as the length of time from the start 
of treatment until the evidence of disease progression. Clinical benefit will be 
described using subject reported outcomes using PRO Numerical Rating Scale 11 
as well as reporting the clinical benefit rate (CBR), defined as the proportion of 
subjects experiencing of objective response (CR+PR) or stable disease ≥ 4months.  
 
12.5 Analysis of Exploratory Endpoints 
Exploratory studies will be performed post hoc, in a pre-planned manner, and will 
include measurement of immune correlate T cell receptor beta chain V gene family 
(TCRVB) for patients who underwent radiation therapy to primary or metastatic 
sites.  All data will be summarized using descriptive statistics along with graphical 
illustrations.   Exploratory studies will also examine circulating tumor DNA (ctDNA) 
when performed as standard of care.  
 

 
 
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12.6 Analysis of Safety Data 
The incidence, severity and reversibility of toxicities will be performed on all 
subjects who receive any dose of study medication. Non-serious adverse events 
that occur more than 30 days after the administration of the last dose of treatment 
will not be included. The safety and tolerability of treatment is determined by 
reported AEs, physical examinations, and laboratory tests.. AEs will be summarized 
with the incidence and percentage of subjects with at least one occurrence of a 
preferred term (NCI - CTCAE Version 5 grade) will be included. The number of AEs 
reported will also be summarized. Causality (relationship to study drug) will be 
summarized separately. Duration of AE will be determined and included in listings 
along with action taken and outcome.  
 
Laboratory results will be classified according to NCI-CTCAE, Version 5.0. Incidence 
of laboratory abnormalities will be summarized; laboratory results not 
corresponding to an NCI- CTCAE Version 5.0 term will not be graded. Laboratory 
toxicity shifts from baseline to worst grade will also be provided. The results from 
physical examination and vital sign measurement will be tabulated.  
 
12.7 Interim Analysis for Efficacy 
According to the two-stage design, an interim analysis will be performed after the 
first 9 subjects are enrolled in the trial and have response data available for analysis 
of the primary endpoint.  If there are 2 or fewer responses in these 9 subjects, the 
study will be stopped. Otherwise, 20 additional subjects will be accrued for a total 
of 29. The study will stay open to enrollment during the interim analysis due to the 
rareness of the disease and lack of available treatment options, barring any 
unexpected safety concerns. 
 
12.8 Data Integrity and Safety Committee 
This protocol will be reviewed and monitored by the University of Florida Health 
Cancer Center Data Integrity and Safety Committee (UFHCC DISC) in accordance 
with their policies and procedures.  They will review and monitor study progress, 
toxicity, safety and other data from this trial. Questions about subject safety or 
protocol performance will be addressed with the sponsor-investigator, statistician 
and study team members. Should any major concerns arise, the DISC will offer 
recommendations regarding whether or not to suspend the trial. 
 
UFHCC DISC data and safety monitoring activities include:  
• Review of clinical trial conducted for progress and safety.  
• Review of all adverse events requiring expedited reporting as defined in the 
protocol.  

 
 
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• Review of reports generated by data quality control review process.  
• Notification of the sponsor-investigator of recommended action.  
• Notification of sites coordinated by the UFHCC of adverse events requiring 
expedited reporting and subsequent committee recommendations for study 
modifications. 
 
In compliance with the UFHCC data and safety monitoring plan, the PI will provide 
a Data Integrity and Safety Committee Report to DISC at the predetermined 
timelines for the level of risk category assigned during the initial SRMC (Scientific 
Review and Monitoring Committee) review, which occurs prior to initial IRB 
approval. 
 
UFHCC investigator-initiated protocols will be classified into one of the following 
categories of risk by the SRMC (see SRMC manual for further details): 
 
 
Level 1 – Low risk Investigator Initiated interventional trials. 
 
Level 2 – Moderate risk Investigator Initiated or externally sponsored 
interventional (such as drug, biologic or device) trials using FDA approved or 
commercially available compounds or interventions. 
Level 3 –  High risk Investigator Initiated or externally sponsored interventional 
trials (such as investigator-sponsored INDs, Phase I trials, studies requiring 
biosafety approval, or other areas that may be designated by NIH as high risk). 
Level 4 – Complex trials involving very high risk to subjects and a high level of 
complexity such as first in human or gene transfer studies. 
 
 
The risk level assigned by SRMC will determine the appropriate level of DISC 
monitoring required, with increased monitoring required for higher-risk trials.  
 
12.9 Data Monitoring 
UFHCC (University of Florida Health Cancer Center) Quality Assurance team and/or 
project management officers will perform remote monitoring and may make 
monitoring visits to the trial sites periodically during the trial to confirm that all 
sites are complying with the protocol. Source documents will be reviewed for 
completion and validated against data submitted electronically via Electronic Data 
Capture. The site investigator/institution guarantee access to source documents by 
UFHCC or its designee and appropriate regulatory agencies.  As part of the 
responsibilities assumed by conducting this study, the Principal Investigator (PI) 
agrees to maintain and have available for monitoring adequate case records 
(accurate source documents and CRFs) for the subjects treated under this protocol. 
 

 
 
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The trial site may also be subject to quality assurance audit by any collaborating 
sponsors or their designee as well as inspection by appropriate regulatory 
agencies.  
 
It is important for the site investigator and their relevant personnel to be available 
during the monitoring visits and possible audits and for sufficient time to be 
devoted to the process. 
 
12.10 Principal Investigator Responsibilities 
Per UF IRB requirements, the PI is personally responsible for conducting and 
supervising the conduct of human subjects research by “protecting the rights, 
safety, and welfare of subjects under the investigator’s care.” The PI also must 
ensure that all the research conducted is done so in an ethical manner and in 
accordance with all federal, state, and local laws and regulations, institutional 
policies, and the requirements of the IRB. 
Oversight is defined as “management by overseeing the performance or operation 
of a person or group; watchful care, superintendence, general supervision”. Any 
person serving as a PI has voluntarily accepted these responsibilities and is 
expected to fully comply with these requirements, as outlined in the UFHCC 
Guidance: Principal Investigator Responsibilities and Oversight. 
 
The PI will be primarily responsible for continuous monitoring of adverse events, 
protocol violations, and other immediate protocol issues. The study coordinator 
will collect information on subjects enrolled through the use of electronic or paper 
adverse event (AE) forms, CRFs, and Informed Consent forms.  
 
13. EMERGENCY PROCEDURES 
 
13.1 Emergency Contact 
In emergency situations, the treating physician should contact the Principal 
Investigator by telephone at the number listed on the title page of the protocol. 
 
13.2 Emergency Treatment 
During and following a subject’s participation in the study, the treating physician 
and/or institution should ensure that adequate medical care is provided to a 
subject for any adverse events, including clinically significant laboratory values, 
related to the study. 
 

 
 
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14. ADMINISTRATIVE, ETHICAL, AND REGULATORY CONSIDERATIONS 
 
14.1 Good Clinical Practice 
The procedures set out in this study protocol pertaining to the conduct, evaluation, 
and documentation of this study are designed to ensure that the Principal 
Investigator and Co-Investigators abide by Good Clinical Practice (GCP), as 
described in International Conference on Harmonization (ICH) Guideline E6 and in 
accordance with the general ethical principles outlined in the Declaration of 
Helsinki.  
 
The study will be conducted in compliance with the protocol. The protocol, any 
amendments, and the subject informed consent will receive Institutional Review 
Board (IRB) approval before initiation of the study.  
 
The Principal Investigator will conduct all aspects of this study in accordance with 
applicable national, state, and local laws of the pertinent regulatory authorities. 
All potential serious breaches must be reported immediately to the UFHCC Project 
Management Office (PMO, pmo@cancer.ufl.edu, who will then report the breach to 
UFHCC DISC) and the IRB of record, if applicable. A serious breach is a breach of 
the conditions and principles of GCP in connection with the study or the protocol, 
which is likely to affect, to a significant degree, the safety or physical or mental 
integrity of the subjects of the study or the scientific value of the study. 
 
14.2 Institutional Review Board 
Before study initiation, the investigator must have written and dated approval from 
the IRB for the protocol, consent form, subject recruitment materials/process (e.g., 
advertisements), and any other written information to be provided to subjects. The 
investigator should also provide the IRB with a copy of the Investigator Brochure or 
product labeling, information to be provided to subjects, and any updates. The 
investigator should provide the IRB with reports, updates, and other information 
(e.g., amendments, and administrative letters) according to regulatory 
requirements or institution procedures. 
 
14.3 Compliance with Laws and Regulations 
It is intended that the proposed study be conducted according to the International 
Conference on Harmonization E6 Guideline for Good Clinical Practice (GCP) and the 
Declaration of Helsinki.  Please refer to the following references. 
 
International Conference on Harmonization and GCP:  
https://www.fda.gov/media/93884/download 

 
 
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Declaration of Helsinki:   
https://www.wma.net/what-we-do/medical-ethics/declaration-of-helsinki/ 
 
Code of Federal Regulations, Title 21: 
https://www.ecfr.gov/cgi-bin/text-
idx?gp=&SID=2fa30a11d9a46ebee8122c33aefd684c&mc=true&tpl=/ecfrbrowse/T
itle21/21tab_02.tpl 
  
All UF Health Cancer Center investigator-initiated trials, meeting the criteria of the 
FDAAA’s applicable clinical trials, will be registered with ClinicalTrials.gov by the 
Project Management Officer (PMO) or assigned designee.  All studies must be 
registered prior to enrollment of the first participant.  The Project Management 
Officer or assigned designee will maintain the responsibility of updating trials 
registered with ClinicalTrials.gov.  Per FDA requirement, information must be 
updated at least every twelve months and the registry must be updated within 
thirty days of any changes in recruitment status or completion of the study. The 
PMO will determine if registration and updates to the NCI CTRP are required. 
 
14.4 Delegation of Investigator Responsibilities 
The Principal Investigator will ensure that all persons assisting with the study are 
adequately informed about the protocol, any amendments to the protocol, the 
study treatments, and their study-related duties and functions. The Principal 
Investigator will maintain a list of Co-Investigators and other appropriately 
qualified persons to whom s/he has delegated significant study-related duties.  
 
 
Study personnel involved in conducting this study will be qualified by education, 
training, and experience to perform their respective tasks. This study will not use 
the services of study personnel where sanctions have been invoked or where there 
has been scientific misconduct or fraud (e.g., loss of medical licensure; debarment). 
Systems with procedures that ensure the quality of every aspect of the study will be 
implemented. 
 
14.5 Subject Information and Informed Consent 
Before being enrolled in this clinical trial, the subject must consent to participate 
after the nature, scope, and possible consequences of the clinical study have been 
explained in a form understandable to him or her. An informed consent document 
that includes both information about the study and the consent form will be 
prepared and given to the subject. This document will contain all ICH, GCP, and 
locally required regulatory elements. The document must be in a language 

 
 
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understandable to the subject and must specify the person who obtained informed 
consent. 
 
After reading the informed consent document, the subject must give consent in 
writing. The written informed consent will be obtained prior to conducting any 
study-related procedures or tests. The subject’s consent must be confirmed at the 
time of consent by the personally dated signature of the person conducting the 
informed consent discussions and a copy of the consent form (preferably signed) 
must be given to the subject for their records.  
 
 
The PI will retain the original signed consent document. The PI will not undertake 
any measures specifically required only for the clinical study until valid consent has 
been obtained. 
 
14.6 Confidentiality 
All records identifying the subject will be kept confidential and, to the extent 
permitted by the applicable laws and/or regulations, will not be made publicly 
available. 
 
Should direct access to medical records require a waiver or authorization separate 
from the subject’s statement of informed consent, it is the responsibility of the 
Investigator to obtain such permission in writing from the appropriate individual.   
 
Subjects will be told that the IRB, UF Health DISC, or regulatory authorities may 
inspect their medical records to verify the information collected, and that all 
personal information made available for inspection will be handled in strictest 
confidence and in accordance with local data protection law. 
 
14.7 Protocol Amendments 
Once the study has started, amendments should be made only in exceptional 
cases.  Protocol amendments will not be implemented without prior written IRB 
approval. All amendments will be submitted to the IRB and SRMC (as applicable), 
and written verification that the amendment was submitted and subsequently 
approved is to be obtained, and notification will sent out to the applicable study 
teams, prior to implementing the amendment.   
 
On an emergency-basis, to eliminate an immediate safety hazard to a subject, a 
protocol deviation may be implemented immediately, provided the IRB and UFHCC 
CRO PMO (pmo@cancer.ufl.edu) are notified within 5 business days with a full 
justification and description of the event.    

 
 
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14.8 Case Report Forms 
The Principal Investigator and/or his/her designee, will prepare and maintain 
adequate and accurate participant case histories with observations and data 
pertinent to the study.  Study specific Case Report Forms (CRFs) will document 
protocol-required outcomes for safety monitoring and data analysis.  All study data 
will be entered electronically in an Electronic Data Capture system in accordance 
with the protocol schedule of events and guidelines developed in the Data 
Management Plan for the study, using a secure access account.   
 
All protocol data is the sole property of UFHCC and should not be made available 
in any form to third parties, except for authorized representatives of appropriate 
Health/Regulatory Authorities, without written permission from UFHCC. 
 
14.9 Record Retention 
Study documentation includes all eCRFs, data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and 
regulatory documents (e.g., protocol and amendments, IRB correspondence and 
approval, signed subject consent forms). 
Source documents include all recordings of observations or notations of clinical 
activities and all reports and records necessary for the evaluation and 
reconstruction of the clinical research study. 
 
Government agency regulations and directives require that all study 
documentation pertaining to the conduct of a clinical trial must be retained by the 
study investigator. In the case of a study with a drug seeking regulatory approval 
and marketing, these documents shall be retained for at least two years after the 
last approval of marketing application in an International Conference on 
Harmonization (ICH) region.  In all other cases, study documents should be kept on 
file until three years after the completion and final study report of this 
investigational study. 
 
 
UF Health Cancer Center requires that all study documentation be maintained for 
at least 6 years from the date of final study publication.  No study records may be 
destroyed without prior authorization from UF. 
 
 

 
 
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M. A. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell 
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28. Amirnasr A, Verdijk RM, van Kuijk PF, Taal W, Sleijfer S, Wiemer EAC. Expression and 
inhibition of BRD4, EZH2 and TOP2A in neurofibromas and malignant peripheral 
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37. Knutson SK, Kawano S, Minoshima Y, et al. Selective inhibition of EZH2 by EPZ-6438 
leads to potent antitumor activity in EZH2-mutant non-Hodgkin lymphoma. Mol 
Cancer Ther 2014;13: 842–54.  
38. Chan-Penebre E, Armstrong K, Drew A, et al. Selective killing of SMARCA2- and 
SMARCA4-deficient small cell carcinoma of the ovary, hypercalcemic type cells by 
inhibition of EZH2: in vitro and in vivo preclinical models. Mol Cancer Ther 2017; 16: 
850–60.  
39. Italiano A, Soria JC, Toulmonde M, Michot JM, Lucchesi C, Varga A, Coindre JM, 
Blakemore SJ, Clawson A, Suttle B, McDonald AA, Woodruff M, Ribich S, Hedrick E, 
Keilhack H, Thomson B, Owa T, Copeland RA, Ho PTC, Ribrag V.  Tazemetostat, an 
EZH2 inhibitor, in relapsed or refractory B-cell non-Hodgkin lymphoma and 
advanced solid tumours: a first-in-human, open-label, phase 1 study.  Lancet Oncol. 
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40. Morschhauser F, Salles G, McKay P, et al. Interim report from a phase 2 multicenter 
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41. Morschhauser F, Tilly H, Chaidos A, McKay P, Phillips T, Assouline S, Batlevi CL, 
Campbell P, Ribrag V, Damaj GL, Dickinson M, Jurczak W, Kazmierczak M, Opat S, 
Radford J, Schmitt A, Yang J, Whalen J, Agarwal S, Adib D, Salles G.Tazemetostat for 
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multicentre, phase 2 trial. Lancet Oncol. 2020 Nov;21(11):1433-1442.  
42. Gounder MM, Stacchiotti S, Sch&ouml;ffski P, et al. Phase 2 multicenter study of the 
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43. Gounder M, Schöffski P, Jones RL, Agulnik M, Cote GM, Villalobos VM, Attia S, Chugh 
R, Chen TW, Jahan T, Loggers ET, Gupta A, Italiano A, Demetri GD, Ratan R, Davis LE, 
Mir O, Dileo P, Van Tine BA, Pressey JG, Lingaraj T, Rajarethinam A, Sierra L, Agarwal 
S, Stacchiotti S.  Tazemetostat in advanced epithelioid sarcoma with loss of 
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44. Zauderer MG, Szlosarek PW, Le Moulec S, Popat S, Taylor P, Planchard D, Scherpereel 
A, Jahan TM, Koczywas M, Forster M, Cameron R, Peikert T, Kocabas Argon 
E,  Michaud N, Yang J, Kansra V, and Fennell DA.   Safety and efficacy of 
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45. Lin DI, Chudnovsky, Y, Duggan, B,  Zajchowski, D, Greenbowe, J,  Ross JS,  Gay  LM, 
Ali SM,  Elvin JA. Comprehensive genomic profiling reveals inactivating SMARCA4 
mutations and low tumor mutational burden in small cell carcinoma of the ovary, 
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46. Witkowski L, Carrot-Zhangv J,  Albrecht S. Germline and somatic SMARCA4 
mutations characterize small cell carcinoma of the ovary, hypercalcemic type. Nat. 
Genet. 2014, 46, 438–443 
47. Burns EM.   Targeted Oncology Volume 6, Issue 11, December 21, 2017. EZH2 
Targetability Demonstrated Across Cancer Types.   
 
 

 
 
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16. APPENDICES 
 
 
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Appendix A: PROTOCOL VERSION HISTORY / SUMMARY OF CHANGES 
Protocol 
Version 
Number 
Protocol Version Date 
Affected Section(s) 
Summary of Revisions Made 
1.0 
June 15, 2021 
N/A- Initial protocol 
1.1 
August 6, 2021 
Added Epizyme reporting information and email; Removed 
repeated exclusion criteria (inclusion I) 
1.2 
September 22, 2021 
Clarified amount of time between screening and baseline 
procedures needing to be repeated; Added language regarding 
abnormal lab values as AEs; Added clarifying language to 
appendix E so study team can use a comparable drug 
accountability log. 
1.3 
January 10, 2022 
Removed Phos, Mag, and Uric Acid from labs to be done at each 
cycle and weekly for cycle 1. Removed ECG and urinalysis from 
screening and eligibility criteria (exclusion D). Modified inclusion 
criteria D to include washout period for prior myelosuppressive 
chemotherapy. Clarified section 3.1 ctDNA testing to be 
collected whenever obtained per SOC.  
1.4 
May 3, 2022 
Added tibial x-rays for pediatric subjects. Added surveillance 
CBCs with every surveillance visit until 5 years, then yearly until 
10 years.  Expanded screening visit windows to accommodate 
subject schedules and standard of care. Changed wording of 
“physical” exam to “clinical” exam. Removed research 
blood section 9.1 as it was not being collected per 
protocol before but there was one sentence not removed. 
1.5 
October 27, 2023 
Sample Size 
Justification 
 
Interim Analysis 
for Efficacy 
 
Exclusion Criteria 
 
Section 11.4.3 
Changed statistical design from Simon’s 
two-stage Minimax to Simon’s two-stage 
Optimum.  
 
 
Clarified Exclusion Criteria A and D 
Added Exclusion Criteria J and K.  
 
Updated safety reporting email address. 
1.6 
December 8, 2023 
Section 6.1 
Section 6.4 
 
 
Section 6.2 
Clarified that subjects who begin new 
anti-cancer therapy while in follow up will 
be followed for survival only.  
 
Added 72 hour window for weekly labs. 
1.7 
August 12, 2024 
Section 6.2 
 
 
Corrected typo in the Allowable Visit 
Window Table, which was previously IRB 
approved with Protocol v1.6. 

 
 
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Exclusion Criteria 
 
Added B-cell acute lymphoblastic 
leukemia (B-ALL) to exclusionary medical 
history in Exclusion Criteria C, per sponsor 
request. 

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Appendix B: PERFORMANCE STATUS CRITERIA 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
 
Lansky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
Description 
0 
Normal activity 
Fully active, able to carry on all 
pre-disease performance 
without restriction 
100 
Normal, no complaints, no 
evidence of disease 
Fully active, normal. 
90 
Able to carry on normal 
activity; minor signs or 
symptoms of disease 
Minor restrictions in physically 
strenuous activity. 
1 
Symptoms, but ambulatory 
Restricted in physically 
strenuous activity, but 
ambulatory and able to carry 
out work of a light or sedentary 
nature (e.g., light housework, 
office work) 
80 
Normal activity with effort; 
some signs or symptoms 
of disease 
Active, but tires more quickly. 
70 
Cares for self, unable to 
carry on normal activity or 
to do active work 
Both greater restriction of and 
less time spent in play activity. 
2 
In bed < 50% of the time 
Ambulatory and capable of all 
self-care, but unable to carry 
out any work activities 
Up and about more than 50% 
of waking hours 
60 
Requires occasional 
assistance, but is able to 
care for most of his/her 
needs 
Up and around, but minimal 
active play; keeps busy with 
quieter activities. 
50 
Requires considerable 
assistance and frequent 
medical care 
Gets dressed, but lies around 
much of the day; no active 
play, able to participate in all 
quiet play and activities.  
3 
In bed > 50% of the time 
Capable of only limited self-
care, confined to bed or chair 
more than 50% of waking 
hours 
40 
Disabled, requires special 
care and assistance 
Mostly in bed; participates in 
quiet activities. 
30 
Severely disabled, 
hospitalization indicated 
Death not imminent 
In bed; needs assistance even 
for quiet play. 
4 
100% bedridden 
Completely disabled 
Cannot carry on any self-care 
Totally confined to bed or chair 
20 
Very sick, hospitalization 
indicated 
Death not imminent 
Often sleeping; play entirely 
limited to very passive 
activities. 
10 
Moribund, fatal processes 
progressing rapidly 
No play; does not get out of 
bed. 
5 
Dead 
0 
Dead 
 
 
 

 
 
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Appendix C: RECIST GUIDELINES (VERSION 1.1) 
 
Response and progression will be evaluated in this study using the international criteria 
proposed by the New Response Evaluation Criteria in Solid Tumors (RECIST): Revised 
RECIST Guideline (version 1.1). 
 
Measurability of Tumor at Baseline 
Tumor lesions/lymph nodes will be categorized at baseline as measurable or non-
measurable.  Measurable disease is defined by the presence of at least 1 measurable 
lesion. 
 
Measurable 
Tumor lesions: Measured in at least 1 dimension (longest diameter in the plane of 
measurement is to be recorded) with a minimum size of: 
• 10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan 
(slice thickness ≤5 mm). 
• 10 mm caliper measurement by clinical exam (non-measurable lesions if cannot be 
accurately measured with calipers). 
• 20 mm by chest X-ray. 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm in short axis when assessed by CT scan (CT scan thickness 
recommended to be ≤5 mm). 
 
Non-measurable 
All other lesions, including small lesions (longest diameter < 10 mm or pathological lymph 
nodes with > 10 to < 15 mm short axis) as well as truly non-measurable lesions. Lesions 
considered truly non-measurable include: leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, 
lymphangitis involvement of skin or lung, abdominal masses/abdominal organomegaly 
identified by physical exam that is not measureable by reproducible imaging techniques. 
 
Special Considerations for Lesion Measurability 
Bone Lesions: 
• Bone scan, PET scan or plain films are not considered adequate imaging techniques 
to measure bone lesions. 
• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as 
CT or MRI, can be considered measurable lesions if the soft tissue component 
meets the definition of measurability. 
• Blastic bone lesions are non-measurable. 

 
 
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Cystic Lesions: 
• Simple cysts should not be considered as malignant lesions (neither measurable 
nor non-measurable). 
• Cystic lesions thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability. If non-cystic 
lesions are presented in the same subjects, these are preferred for selection as 
target lesions. 
 
Lesions with Prior Local Treatment: 
• Tumor lesions situated at a previously irradiated area, or in an area subjected to 
other loco-regional therapy, are non-measurable unless there has been 
demonstrated progression in the lesion. 
 
Baseline Documentation of Target and Non-Target Lesion 
 
Target Lesions 
When more than 1 measurable lesion is present at baseline, all lesions up to a maximum 
of 5 lesions total (and a maximum of 2 lesions per organ) representative of all involved 
organs should be identified as target lesions and will be recorded and measured at 
baseline. Non-nodal target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, and can be 
reproduced in repeated measurements.  Measurable lymph nodes are target lesions if 
they meet the criteria of a short axis of ≥15 mm by CT scan. All measurements are to be 
recorded in the CRF in millimeters (or decimal fractions of centimeters). 
 
Non-target Lesions 
All other lesions (or sites of disease) are identified as non-target lesions (chosen based on 
the representativeness of involved organs and the ability to be reproduced in repeated 
measurements) and should be recorded at baseline. Measurement of these lesions are not 
required but should be followed as ‘present,’ ‘absent,’ or in rare cases ‘unequivocal 
progression.’ In addition, it is possible to record multiple non-target lesions involving the 
same organ as a single item on the CRF (for example, multiple liver metastases recorded 
as 1 liver lesion).  Lymph nodes with short axis > 10 mm but < 15 mm should be 
considered non-target lesions.  Nodes that have a short axis < 10 mm are considered 
non-pathological and are not recorded or followed. 
 
Specifications by Methods of Measurement 
 
All measurements should be recorded in metric notation, using a ruler or calipers if 
clinically assessed. All baseline evaluations should be performed as closely as possible to 

 
 
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the beginning of treatment and never more than 4 weeks before the beginning of the 
treatment.  The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation should always be done rather than clinical examination unless 
the lesion(s) being followed cannot be imaged but are assessed by clinical exam. 
 
An adequate volume of a suitable contrast agent should be given so that the metastases 
are demonstrated to best effect and a consistent method is used on subsequent 
examinations for any given subject. If prior to enrollment it is known a subject is not able 
to undergo CT scans with intravenous contrast due to allergy or renal insufficiency, the 
decision as to whether a non-contrast. 
 
CT or MRI (with or without intravenous contrast) should be used to evaluate the subject at 
baseline and follow-up should be guided by the tumor type under investigation and the 
anatomic location of the disease. 
 
Clinical Lesions: Clinical lesions will be considered measurable only when they are 
superficial and > 10 mm diameter as assessed using calipers (for example, skin nodules). 
For the case of skin lesions, documentation by color photography, including a ruler to 
estimate the size of the lesion is recommended. When lesions can be evaluated by both 
clinical exam and imaging, imaging evaluation should be undertaken since it is more 
objective and may be reviewed at the end of the study. 
 
Chest X-ray: Chest CT is preferred over chest X-ray when progression is an important 
endpoint.  lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung. 
 
CT and MRI: CT scan is the best currently available and reproducible method to measure 
lesions selected for response assessment. Measurability of lesions on CT scan is based on 
the assumption that CT slice thickness is < 5 mm. When CT scans have slice thickness > 5 
mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is 
also acceptable in certain situations (for example, for body scans). If there is concern 
about radiation exposure at CT, MRI may be used instead of CT in selected instances. 
 
Ultrasound: Ultrasound should not be used to measure lesion size. Ultrasound 
examinations cannot be reproduced in their entirety for independent review at a later 
date and, because they are operator dependent, it cannot be guaranteed that the same 
technique and measurements will be taken from one assessment to the next. If new 
lesions are identified by ultrasound in the course of the study, confirmation by CT or MRI 
is advised. 

 
 
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Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised. However, such techniques can be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response or surgical resection is an endpoint. 
 
Tumor Markers: Tumor markers alone cannot be used to assess tumor response. If 
markers are initially above the upper normal limit, they must normalize for a subject to be 
considered in complete response (CR). 
 
Cytology, Histology: These techniques can be used to differentiate between partial 
responses (PR) and complete response (CR) in rare cases if required by protocol (for 
example, residual lesions in tumor types such as germ cell tumors, where known residual 
benign tumors can remain). When effusions are known to be a potential adverse effect of 
treatment (for example, with certain taxane compounds or angiogenesis inhibitors), the 
cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment can be considered if the measurable tumor has met criteria for response 
or stable disease (SD) in order to differentiate between response (or SD) and progressive 
disease (PD). 
 
PET Scan (FDG-PET, PET CT): PET is not recommended for lesion assessment. If a new 
lesion is found by PET, another assessment must be done by CT, unless the PET CT is of 
diagnostic quality. If CT is done to confirm the results of the earlier PET scan, the date of 
progression must be reported as the earlier date of the PET scan. 
 
Bone Scan: If lesions measured by bone scan are reported at baseline, it is necessary to 
repeat the bone scan when trying to identify a complete response (CR) or partial response 
(PR) in target disease or when progression in bone is suspected. 
 
Response Criteria 
 
Evaluation of Target Lesions 
 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to < 10 mm. 
Tumor marker results must have normalized. 
 
Partial Response (PR): At least a 30% decrease in the sum of diameter of target lesions, 
taking as reference the baseline sum diameters. 
 

 
 
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Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (including the baseline sum if that 
is the smallest).  In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. The appearance of 1 or more new 
lesions is also considered progression. For equivocal findings of progression (for example, 
very small and uncertain new lesions; cystic changes or necrosis in existing lesions), 
treatment may continue until the next scheduled assessment. If at the next scheduled 
assessment, progression is confirmed, the date of progression should be the earlier date 
when progression was suspected. 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
 
Not Evaluable (NE): When an incomplete radiologic assessment of target lesions is 
performed or there is a change in the method of measurement from baseline that impacts 
the ability to make a reliable evaluation of response. 
 
Evaluation of Non-target Lesions 
 
Complete Response: Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological or normal in size (< 10 mm short 
axis). 
 
Non-CR/ non-PD: Persistence of 1 or more non-target lesions and/or maintenance of 
tumor marker level above the normal limits. 
 
Progressive Disease: Unequivocal progression of existing non-target lesions. The 
appearance of 1 or more new lesions is also considered progression. 
 
Not Evaluable: When a change in method of measurement from baseline occurs and 
impacts the ability to make a reliable evaluation of response. 
 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the study 
treatment until the earliest of objective progression or start of new anticancer therapy, 
taking into account any requirement for confirmation. The subject’s best overall response 
assignment will depend on the findings of both target and non-target disease and will 
also take into consideration the appearance of new lesions. The best overall response will 

 
 
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be calculated via an algorithm using the assessment responses provided by the 
investigator over the course of the trial. 
 
Time Point Response 
It is assumed that at each protocol-specified time point, a response assessment occurs. 
(When no imaging/measurement is done at all at a particular time point, the subject is not 
evaluable (NE) at that time point.) Table 17.2.1 provides a summary of the overall 
response status calculation at each time point for subjects who have measurable disease 
at baseline. 
 
Table 17.2.1- Time Point Response: Subjects with Target or Measurable Disease 
 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all Evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Abbreviations: CR = complete response; NE = not evaluable; PD = progressive disease;  
PR = partial response; SD = stable disease. 
 
Table 17.2.2 is to be used when subjects have non-measurable disease only. 
 
Table 17.2.2- Time Point Response: Subjects with Non-Target or Non-Measurable Disease 
 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PDa 
Not all evaluable 
No 
NE 
Unequivocal 
Yes or No 
PD 
Any 
Yes 
PD 
Abbreviations: CR = complete response; NE = not evaluable; PD = progressive disease;  
SD = stable disease.   a non-CR/non-PD is preferred over SD for non-target disease due to 
SD being increasingly used as an endpoint for assessment in trials; to assign this category 
when no lesions can be measured is not advised. 

 
 
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Frequency of Tumor Re-Evaluation 
A baseline tumor evaluation must be performed within 4 weeks before a subject begins 
study treatment. Frequency of tumor re-evaluation while on and adapted to treatment 
should be protocol-specific and adapted to the type and schedule of treatment. Normally, 
all target and non-target sites are evaluated at each assessment using the same method. 
However, bone scans may need to be repeated only when CR is identified in target 
disease or when progression in bone is suspected. 
 
Duration of Response 
Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are first 
met for CR or PR (whichever is first recorded) until the first date that disease is recurrent 
or objective progression is observed (taking as reference for PD the smallest 
measurements recorded on study). 
 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that recurrent disease is objectively documented. 
 
Duration of Stable Disease 
Stable disease is measured from the start of the treatment (in randomized trials, from date 
of randomization) until the criteria for objective progression are met, taking as reference 
the smallest sum on study (if the baseline sum is the smallest, that is the reference for 
calculation of PD). 
 
 

 
 
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Appendix D: SUBJECT TREATMENT DIARY  
TABLET MEDICATION DIARY FOR TAZEMETOSTAT 
Subject ID:  
 
 
 
Protocol ID#: 
UF-SC-001 
Study Site: 
University of Florida  
Study MD:  
 
Study 
Coordinator:  
 
__________________________ 
Prescribed 
Dose:  
              mg, twice daily  
# Tablets to be taken at each dose: __________ 
 
Swallow tablets whole, with or without food. Do not store Tazemetostat above 86°F (30°C).   
 
NOTE: Avoid eating grapefruit or drinking grapefruit juice during treatment with Tazemetostat. 
Avoid taking St. John’s Wort during treatment with Tazemetostat. Do not take an additional dose 
if a dose is missed or vomiting occurs after Tazemetostat, but continue with the next scheduled 
dose. 
 
WHEN TO CONTACT THE STUDY TEAM AND/OR YOUR PROVIDER:  
Contact your health care provider immediately or seek emergency medical treatment if you 
experience any of the following symptoms (also alert the Study Team within 24 hours):  
• 
Fever of 100.4ο F (38ο C) or higher, chills (possible signs of infection) 
• 
Shortness of breath 
• 
Have persistent pain or pressure in your chest 
• 
Develop new confusion 
• 
Are unable to wake up or stay awake 
• 
Have bluish lips or face 
Contact the Study Team and/or your health care provider within 24 hours of noticing any of the 
following:  
• 
Nausea (interferes with ability to eat and unrelieved with prescribed medication) 
• 
Feel feverish 
• 
Develop a cough  
• 
Develop mild symptoms like sore throat, muscle aches, tiredness, or diarrhea 
• 
Vomiting (vomiting more than 4-5 times in a 24-hour period) 
• 
Diarrhea (4-6 episodes in a 24-hour period) 
• 
Unusual bleeding or bruising 
• 
Black or tarry stools, or blood in your stools 
• 
Blood in the urine 
• 
Pain or burning with urination 
• 
Extreme fatigue (unable to carry on self-care activities) 
• 
Mouth sores (painful redness, swelling or ulcers) 

 
 
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TABLET DIARY INSTRUCTIONS:  Please complete each day with the time and dose given for 
Tazemetostat. If a dose is not due or is missed, leave that day blank.   Please bring this diary, 
along with any remaining medication and medication bottles to your next clinical visit.  
 
EXAMPLE:  
 
 
 
 
Date  
Time  
Number of tablets 
taken 
Comments 
Day 1 
01/01/2020 
8:30 
AM 
1 
Felt nauseated an hour after taking, 
did not vomit, took a Zofran  
 
PM 
 
CYCLE # 
 
Cycle Start 
Date: 
 
Dose:  
 
 
 
Cycle End 
Date: 
______________ 
 
Week 1 
Date  
Time  
Number of tablets  
Prescribed 
 
AM#:        PM# 
 
Comments 
(Describe any missed or extra 
doses, vomiting and/or 
bothersome side effects)  
Number of tablets  
taken 
Day 1 
 
 
AM 
 
 
 
PM 
 
 
Day 2 
 
 
AM 
 
 
 
PM 
 
 
Day 3 
 
 
AM 
 
 
 
PM 
 
 
Day 4 
 
 
AM 
 
 
 
PM 
 
 
Day 5 
 
 
AM 
 
 
 
PM 
 
 
Day 6 
 
 
AM 
 
 
 
PM 
 
 
Day 7 
 
 
AM 
 
 
 
PM 
 
 
Day 8 
 
 
AM 
 
 
 
PM 
 
 
Day 9 
 
 
AM 
 
 
 
PM 
 
 
Day 10 
 
 
AM 
 
 
 
PM 
 
 
Day 11 
 
 
AM 
 
 

 
 
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PM 
 
 
Day 12 
 
 
AM 
 
 
 
PM 
 
 
Day 13 
 
 
AM 
 
 
 
PM 
 
 
Day 14 
 
 
AM 
 
 
 
PM 
 
 
Day 15 
 
 
AM 
 
 
 
PM 
 
 
Day 16 
 
 
AM 
 
 
 
PM 
 
 
Day 17 
 
 
AM 
 
 
 
PM 
 
 
Day 18 
 
 
AM 
 
 
 
PM 
 
 
Day 19 
 
 
AM 
 
 
 
PM 
 
 
Day 20 
 
 
AM 
 
 
 
PM 
 
 
Day 21 
 
 
AM 
 
 
 
PM 
 
 
Day 22 
 
 
AM 
 
 
 
PM 
 
 
Day 23 
 
 
AM 
 
 
 
PM 
 
 
Day 24 
 
 
AM 
 
 
 
PM 
 
 
Day 25 
 
 
AM 
 
 
 
PM 
 
 
Day 26 
 
 
AM 
 
 
 
PM 
 
 
Day 27 
 
 
AM 
 
 
 
PM 
 
 
Day 28 
 
 
AM 
 
 
 
PM 
 
 
 
 
[STUDY STAFF VERIFYING SIGNATURE &  DATE] 
 
 

 
 
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LIQUID MEDICATION DIARY FOR TAZEMETOSTAT 
Subject ID:  
 
 
 
Protocol ID#: 
UF-SC-001 
Study Site: 
University of Florida  
Study MD:  
 
Study 
Coordinator:  
 
__________________________ 
Prescribed 
Dose:  
             mg/mL, twice daily  # mL to be taken at each dose: ________________ 
 
Shake the bottle for one minute before you take Tazemetostat; do not shake too much (if there 
are bubbles, wait for them to settle before measuring the dose).  Daily shaking of all bottles is 
required to ensure the liquid stays properly mixed. Store your medication in the refrigerator. 
 
NOTE: Avoid eating grapefruit or drinking grapefruit juice during treatment with Tazemetostat. 
Avoid taking St. John’s Wort during treatment with Tazemetostat. Do not take an additional dose 
if a dose is missed or vomiting occurs after Tazemetostat, but continue with the next scheduled 
dose. 
 
WHEN TO CONTACT THE STUDY TEAM AND/OR YOUR PROVIDER:  
Contact your health care provider immediately or seek emergency medical treatment if you 
experience any of the following symptoms (also alert the Study Team within 24 hours):  
• 
Fever of 100.4ο F (38ο C) or higher, chills (possible signs of infection) 
• 
Shortness of breath 
• 
Have persistent pain or pressure in your chest 
• 
Develop new confusion 
• 
Are unable to wake up or stay awake 
• 
Have bluish lips or face 
Contact the Study Team and/or your health care provider within 24 hours of noticing any of the 
following:  
• 
Nausea (interferes with ability to eat and unrelieved with prescribed medication) 
• 
Feel feverish 
• 
Develop a cough  
• 
Develop mild symptoms like sore throat, muscle aches, tiredness, or diarrhea 
• 
Vomiting (vomiting more than 4-5 times in a 24-hour period) 
• 
Diarrhea (4-6 episodes in a 24-hour period) 
• 
Unusual bleeding or bruising 
• 
Black or tarry stools, or blood in your stools 
• 
Blood in the urine 
• 
Pain or burning with urination 
• 
Extreme fatigue (unable to carry on self-care activities) 
• 
Mouth sores (painful redness, swelling or ulcers) 

 
 
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LIQUID DOSING DIARY INSTRUCTIONS:  Please complete each day with the time and dose given 
for Tazemetostat. If a dose is not due or is missed, leave that day blank.   Please bring this diary, 
along with any remaining medication and medication bottles to your next clinical visit.  
 
EXAMPLE:  
 
 
 
 
Date  
Time  
Dose taken (in mL) 
Comments 
Day 1 
01/01/2020 
8:30 
AM 
XX mL 
Felt nauseated an hour after taking, 
did not vomit, took a Zofran  
 
PM 
 
CYCLE # 
 
Cycle Start 
Date: 
 
Dose 
(mg/mL):  
 
 
 
Cycle End 
Date: 
 
________________ 
 
Week 1 
Date  
Time  
Prescribed Dose (in mL) 
____________________ 
 
Comments 
(Describe any missed or extra 
doses, vomiting and/or 
bothersome side effects)  
Dose taken (in mL) 
Day 1 
 
 
AM 
 
 
 
PM 
 
 
Day 2 
 
 
AM 
 
 
 
PM 
 
 
Day 3 
 
 
AM 
 
 
 
PM 
 
 
Day 4 
 
 
AM 
 
 
 
PM 
 
 
Day 5 
 
 
AM 
 
 
 
PM 
 
 
Day 6 
 
 
AM 
 
 
 
PM 
 
 
Day 7 
 
 
AM 
 
 
 
PM 
 
 
Day 8 
 
 
AM 
 
 
 
PM 
 
 
Day 9 
 
 
AM 
 
 
 
PM 
 
 
Day 10 
 
 
AM 
 
 
 
PM 
 
 
Day 11 
 
 
AM 
 
 
 
PM 
 
 
Day 12 
 
 
AM 
 
 
 
PM 
 
 
Day 13 
 
 
AM 
 
 

 
 
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PM 
 
 
Day 14 
 
 
AM 
 
 
 
PM 
 
 
Day 15 
 
 
AM 
 
 
 
PM 
 
 
Day 16 
 
 
AM 
 
 
 
PM 
 
 
Day 17 
 
 
AM 
 
 
 
PM 
 
 
Day 18 
 
 
AM 
 
 
 
PM 
 
 
Day 19 
 
 
AM 
 
 
 
PM 
 
 
Day 20 
 
 
AM 
 
 
 
PM 
 
 
Day 21 
 
 
AM 
 
 
 
PM 
 
 
Day 22 
 
 
AM 
 
 
 
PM 
 
 
Day 23 
 
 
AM 
 
 
 
PM 
 
 
Day 24 
 
 
AM 
 
 
 
PM 
 
 
Day 25 
 
 
AM 
 
 
 
PM 
 
 
Day 26 
 
 
AM 
 
 
 
PM 
 
 
Day 27 
 
 
AM 
 
 
 
PM 
 
 
Day 28 
 
 
AM 
 
 
 
PM 
 
 
 
 
 
 
[STUDY STAFF VERIFYING SIGNATURE &  DATE] 
 

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Appendix E: ORAL MEDICATION ACCOUNTABILITY LOG 
Date 
MMDDYYYY 
Dispensed 
or 
Received 
# of 
tablets 
Compliance 
(Express as 
%) 
Lot # 
Exp. Date 
Comments 
Staff 
initials 
 
Dispensed       
 
 
 
 
 
 
 
 
Received 
 
 
 
 
 
 
 
 
Dispensed       
 
 
 
 
 
 
 
 
Received 
 
 
 
 
 
 
 
 
Dispensed       
 
 
 
 
 
 
 
 
Received 
 
 
 
 
 
 
 
 
Dispensed       
 
 
 
 
 
 
 
 
Received 
 
 
 
 
 
 
 
**The study team may use a comparable internal form in place of this form regarding drug accountability, provided all the same data is captured and recorded in EDC.  
 
Subject Name: 
MRN: 
Subject ID#: 
Protocol #: UF-SC-001 
IRB #:  
PI Name:  
Product Name:  TAZEMETOSTAT 
Oral Medication Accountability Log (Tablets) 

 
 
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Date 
MMDDYYYY 
Dispensed 
or 
Received  
# mL 
Compliance 
(Express as 
%) 
Lot # 
Exp. Date 
Comments 
Staff 
initials 
 
Dispensed       
 
 
 
 
 
 
 
 
Received 
 
 
 
 
 
 
 
 
Dispensed       
 
 
 
 
 
 
 
 
Received 
 
 
 
 
 
 
 
 
Dispensed       
 
 
 
 
 
 
 
 
Received 
 
 
 
 
 
 
 
 
Dispensed       
 
 
 
 
 
 
 
 
Received 
 
 
 
 
 
 
 
Subject Name: 
MRN: 
Subject ID#: 
Protocol #: UF-SC-001 
IRB #:  
PI Name:  
Product Name:  TAZEMETOSTAT 
Oral Medication Accountability Log (Liquid) 

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Appendix F: CYP3A4 SUSBTRATES, INDUCERS AND INHIBITORS 
This is not an inclusive list. Because the lists of these agents are constantly changing, it is 
important to regularly consult frequently updated medical references. 
 
CYP3A4 substrates 
Strong Inhibitors1 
Moderate 
Inhibitors 
Strong 
Inducers 
Moderate 
Inducers 
acalabrutinib5  
alfentanil4,5  
amiodarone4  
aprepitant/fosaprepitant  
atorvastatin  
axitinib  
bortezomib  
bosutinib5  
budesonide5  
buspirone5  
cabozantinib  
calcium channel blockers  
cisapride  
citalopram/escitalopram  
cobimetinib5  
conivaptan5  
copanlisib  
crizotinib  
cyclosporine4  
dabrafenib  
dapsone  
darifenacin5  
darunavir5  
dasatinib5  
dexamethasone2  
diazepam  
dihydroergotamine  
docetaxel  
doxorubicin  
dronedarone5  
eletriptan5  
eplerenone5  
ergotamine4  
erlotinib  
estrogens  
etoposide  
everolimus5  
atazanavir  
boceprevir  
clarithromycin  
cobicistat  
darunavir  
delavirdine  
grapefruit3  
grapefruit juice3  
idelalisib  
indinavir  
itraconazole  
ketoconazole  
lopinavir/ritonavir  
nefazodone  
nelfinavir  
posaconazole  
ritonavir  
saquinavir  
telaprevir  
telithromycin  
voriconazole  
aprepitant  
conivaptan  
crizotinib  
diltiazem  
dronedarone  
erythromycin  
fluconazole  
fosamprenavir  
grapefruit3  
grapefruit 
juice3  
imatinib  
isavuconazole  
mifepristone  
nilotinib  
verapamil  
barbiturates  
carbamazepine  
enzalutamide  
fosphenytoin  
phenobarbital  
phenytoin  
primidone  
rifampin  
St. John’s wort  
bosentan  
dabrafenib  
efavirenz  
etravirine  
modafinil  
nafcillin  
rifapentin 

 
 
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CYP3A4 substrates 
Strong Inhibitors1 
Moderate 
Inhibitors 
Strong 
Inducers 
Moderate 
Inducers 
fentanyl4  
gefitinib  
haloperidol  
ibrutinib5  
idelalisib  
imatinib  
indinavir5  
irinotecan  
isavuconazole5  
itraconazole  
ivacaftor  
ketoconazole  
lansoprazole  
lapatinib  
losartan  
lovastatin5  
lurasidone5  
macrolide antibiotics  
maraviroc5  
medroxyprogesterone  
methadone  
midazolam5  
midostaurin5  
modafinil  
nefazodone  
nilotinib  
olaparib  
ondansetron  
osimertinib  
paclitaxel  
palbociclib  
pazopanib  
quetiapine5  
quinidine4  
regorafenib  
romidepsin  
saquinavir5  
sildenafil5  
simvastatin5  
sirolimus4,5  
sonidegib  

 
 
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CYP3A4 substrates 
Strong Inhibitors1 
Moderate 
Inhibitors 
Strong 
Inducers 
Moderate 
Inducers 
sunitinib  
tacrolimus4,5  
tamoxifen  
telaprevir  
temsirolimus  
teniposide  
tetracycline  
tipranavir5  
tolvaptan5  
triazolam5  
trimethoprim  
vardenafil5  
vemurafenib  
venetoclax5  
vinca alkaloids  
zolpidem  
 
1 Certain fruits, fruit juices and herbal supplements (star fruit, Seville oranges, pomegranate, gingko, 
goldenseal) may inhibit CYP 3A4 isozyme, however, the degree of that inhibition is unknown.  
2Refer to Section 4.3 regarding use of corticosteroids.  
3The effect of grapefruit juice (strong vs moderate CYP3A4 inhibition) varies widely among brands and is 
concentration-, dose-, and preparation-dependent.  
4Narrow therapeutic range substrates.  
5Sensitive substrates (drugs that demonstrate an increase in AUC of ≥ 5-fold with strong inhibitors). 
 
 

 
 
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Appendix G: NUMBERED PAIN RATING SCALE 11 
 
 
 
 

 
 
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Appendix H: ADEQUATE RENAL FUNCTION 
 
Adequate Renal Function Defined as: Creatinine clearance or radioisotope GFR > 70 
ml/min/1.73 m2 or serum creatinine based on age/gender as follows: