Conditions: Malignant Rhabdoid Tumors (MRT) Rhabdoid Tumors of the Kidney (RTK) Atypical Teratoid Rhabdoid Tumors (ATRT) Selected Tumors With Rhabdoid Features Synovial Sarcoma INI1-negative Tumors Malignant Rhabdoid Tumor of Ovary Renal Medullary Carcinoma Epithelioid Sarcoma Poorly Differentiated Chordoma (or Other Chordoma With Sponsor Approval) Any Solid Tumor With an EZH2 GOF Mutation
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 267
Healthy volunteers: no

Brief summary:
This study will include participants with various types of cancer known as soft-tissue sarcomas.

Tissues that can be affected by soft tissue sarcomas include fat, muscle, blood vessels, deep skin tissues, tendons and ligaments.

Soft tissue cancers are rare and can occur almost anywhere in the body.

Part 1 of this trial will study the safety and the level that adverse effects of the study drug tazemetostat in combination with doxorubicin (current front line treatment) can be tolerated (known as tolerability).

It is also designed to establish a recommended study drug dosage for the next part of the study.

Part 2 will evaluate and compare how long participants live without their disease getting worse when receiving the study drug plus doxorubicin versus doxorubicin plus placebo (dummy treatment).

Detailed description:
This is a Phase II, multicenter, open-label, single arm, 2-stage study of tazemetostat 800 mg BID (twice daily) and 1600 mg QD (once daily). Subjects will be screened for eligibility within 21 days of the planned date of the first dose of tazemetostat and enrolled into one of 8 cohorts:

Cohort using tazemetostat 800 mg BID

* Cohort 1 (Closed for enrollment): malignant rhabdoid tumor (MRT), rhabdoid tumor of the kidney (RTK), atypical teratoid rhabdoid tumor (ATRT), and selected tumors with rhabdoid features, including small cell carcinoma of the ovary hypercalcemic type (SCCOHT), also known as malignant rhaboid tumor of the ovary (MRTO)
* Cohort 2 (Closed for enrollment): Relapsed or refractory synovial sarcoma with SS18-SSX rearrangement
* Cohort 3 (Closed for enrollment): Other integrase interactor 1 (INI1) negative tumors or any solid tumor with an enhancer of zeste homologue-2 (EZH2) gain of function (GOF) mutation, including: epithelioid malignant peripheral nerve sheath tumor (EMPNST), extraskeletal myxoid chondrosarcoma (EMC), myoepithelial carcinoma, other INI1-negative malignant tumors with Sponsor approval (e.g., dedifferentiated chordoma) any solid tumor with an EZH2 GOF mutation including but not limited to Ewing's sarcoma and melanoma
* Cohort 4 (Closed for enrollment): Renal medullary carcinoma (RMC)
* Cohort 5 (Closed for enrollment): Epithelioid sarcoma (ES)
* Cohort 6 (Closed for enrollment): Epithelioid sarcoma (ES) undergoing mandatory tumor biopsy
* Cohort 7 (Closed for enrollment): Poorly differentiated chordoma (or other chordoma with Sponsor approval)

Cohort using tazemetostat 1600 mg QD

• Cohort 8 (Closed for enrollment): Epitheliod sarcoma

Participants will be dosed in continuous 28-day cycles. (Note: if treatment with study drug is discontinued prior to completing 2 years, subjects will be followed for a maximum duration of 2 years from start of study drug dosing.) Response assessment will be performed every 8 weeks while on study.

Treatment with tazemetostat will continue until disease progression, unacceptable toxicity or withdrawal of consent, or termination of the study.

Arms:
arm 1: All cohorts will receive 800 mg oral Tazemetostat twice a day in continuous 28-day cycles.

Interventions: intervention 1: Tazemetostat
Intervention descriptions: intervention 1: Tazemetostat (EPZ-6438) is a selective small molecule inhibitor of the histone-lysine methyltransferase EZH2 gene

Protocol document:
Prot_000.pdf: 
Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 1
 
E Z H- 2 0 2 
A P H A S E II, M U L TI C E N T E R S T U D Y O F T H E E Z H 2 
I N HI BI T O R T A Z E M E T O S T A T I N A D U L T S U B J E C T S 
WI T H I NI 1- N E G A TI V E T U M O R S O R 
R E L A P S E D/ R E F R A C T O R Y S Y N O VI A L S A R C O M A
Ori gi nal Pr ot oc ol:
1 3 J ul y 2 0 1 5 
Pr ot oc ol A me n d me nt 1. 0: 
2 4 A u g ust 2 0 1 5 
Pr ot oc ol A me n d me nt 2. 0: 
0 2 Oct o ber 2 0 1 5
Pr ot oc ol A me n d me nt 2. 1: 
0 3 Dece m ber 2 0 1 5 ( U nite d Ki n g d o m o nl y) 
Pr ot oc ol A me n d me nt 2. 2: 
1 7 Fe br uar y 2 0 1 6 ( Ger ma n y o nl y) 
Pr ot oc ol A me n d me nt 2. 3: 
1 2 Fe br uar y 2 0 1 6 ( Fra nce o nl y) 
Pr ot oc ol A me n d me nt 3. 0: 
0 2 Marc h 2 0 1 6 
Pr ot oc ol A me n d me nt 3. 1: 
1 1 J ul y 2 0 1 6 ( Ger ma n y o nl y) 
Pr ot oc ol A me n d me nt 4. 0: 
2 5 Oct o ber 2 0 1 6
Pr ot oc ol A me n d me nt 4. 1: 
0 5 Dece m ber 2 0 1 6 ( Ger ma n y o nl y) 
Pr ot oc ol A me n d me nt 5. 0: 
0 7 A u g ust 2 0 1 7 
Pr ot oc ol A me n d me nt 5. 1: 
0 3 Oct o ber 2 0 1 7 ( Ger ma n y o nl y) 
Pr ot oc ol A me n d me nt 6. 0: 
2 8 Se pte m ber 2 0 1 8 
Pr ot oc ol A me n d me nt 6. 1: 
1 8 Ja n uar y 2 0 1 9 ( Ger ma n y o nl y) 
Pr ot oc ol A me n d me nt 7. 0: 
1 2 Se pte m ber 2 0 1 9 
Pr ot oc ol A me n d me nt 8. 0: 
2 1 Oct o ber 2 0 1 9
Pr ot oc ol A me n d me nt 8. 2: 
1 4 Ja n uar y 2 0 2 0 ( Fra nce o nl y) 
Pr ot oc ol A me n d me nt 9. 0: 
1 7 Marc h 2 0 2 0 
Pr ot oc ol A me n d me nt 9. 1: 
1 7 A pril 2 0 2 0 ( Ger ma n y o nl y) 
Pr ot oc ol A me n d me nt 1 0. 0: 
2 3 J ul y 2 0 2 1 
Pr ot oc ol A me n d me nt 1 0. 1: 
2 3 J ul y 2 0 2 1 ( Fra nce o nl y) 
Pr ot oc ol A me n d me nt 1 1. 0: 
0 5 Oct o ber 2 0 2 2 
G C P St ate me nt:
T his st u d y is t o be perf or me d i n c o m plia nce wit h I nter nati o nal C o u ncil f or Har m o nisati o n of 
Tec h nical Re q uire me nts f or P har mace uticals f o r H u ma n Use (I C H) a n d a p plica ble l ocal G o o d 
Cli nical Practices ( G C P) a n d re g ulati o ns. Re q ui re d st u d y d oc u me ntati o n will be arc hi ve d as 
re q uire d by  reg ulat or y  a ut h orities.
C o nfi de nti alit y 
St ate me nt:
T his d oc u me nt is c o nfi de ntial. It c o ntai ns pr o prietar y i nf or mati o n of E piz y me, I nc. (t he 
S p o ns or). A n y vie wi n g or discl os ure of s uc h i nf or mati o n t hat is n ot a ut h orize d i n writi n g b y 
t he S p o ns or is strictl y pr o hi bite d. S uc h i nf or mati o n ma y be use d s olel y f or t he p ur p ose of 
re vie wi ng  or perf or mi ng  t his st u dy .


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


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 3
I N V E S TI G A T O R’ S A G R E E M E N T
I ha ve rea d t he E Z H- 2 0 2 pr ot oc ol a n d a gree t o c o n d uct t he st u d y as o utli ne d. I a gree t o mai ntai n 
t he c o nfi de ntialit y of all i nf or mati o n recei ve d or de vel o pe d i n c o n necti o n wit h t his pr ot oc ol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pri nte d Na me of I n vesti gat or
 
 
 
 
 
 
 
 
 
 
 
 
 
Si g nat ure of I n vesti gat or 
 
 
 
 
 
 
 
Date ( d d m m m y y y y) 


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 4
C LI NI C A L S T U D Y P R O T O C O L
Pr ot oc ol Title:
A P hase II, M ultice nter St u d y of t he E Z H 2 I n hi bit or Taze met ostat i n 
A d ult S u bjects wit h I N I 1- Ne gati ve T u m ors or Rela pse d/ Refract or y 
S y n o vial Sarc o ma
C o m p o u n d N a me ( N u m ber):
Taze met ostat ( E P Z- 6 4 3 8)
Pr ot oc ol N u m ber:
E Z H- 2 0 2
I N D N u m ber:
1 2 4 6 0 8
E u dr a C T N u m ber:
2 0 1 5- 0 0 2 4 6 9- 4 1
S p o ns or:
E piz y me, I nc.
4 0 0 Tec h n ol o g y S q uare, 4 t h Fl o or
Ca m bri d ge, M A 0 2 1 3 9 U S A
S p o ns or Me dic al M o nit or:
E piz y me, I nc.
4 0 0 Tec h n ol o g y S q uare, 4 t h Fl o or
Ca m bri d ge, M A 0 2 1 3 9 U S A
P h o ne
E mail:
N ort h A meric a Me dic al M o nit or:
Me d pace I nc.
5 3 7 5 Me d pace Wa y
Ci nci n nati, O H 4 5 2 2 7 U S A
P h o ne: 
E mail: 
S A E H otli ne f or N ort h 
A meric a n/ A ustr ali a n Sites o nl y:
P h o ne: 
 
Fa x:   
 
E mail: 
E U Me dic al M o nit or:
Me d pace I nc.
P h o ne: 
M o bile:
E mail:  
S A E H otli ne f or E U Sites O nl y:
P h o ne: 
Fa x:   
 
E mail: 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 5
P R O T O C O L A M E N D M E N T S U M M A R Y O F C H A N G E S
D O C U M E N T HI S T O R Y
D oc u me nt
D ate
A me n d me nt 1 1
0 5 Oct o ber 2 0 2 2
A me n d me nt 1 0. 1
2 3 J ul y  2 0 2 1 ( Fra nce o nly )
A me n d me nt 1 0
2 3 J ul y  2 0 2 1
A me n d me nt 9. 1
1 7 A pril 2 0 2 0 ( Ger ma n y  o nly )
A me n d me nt 9:
1 7 Marc h 2 0 2 0
A me n d me nt 8. 2:
1 4 Ja n uar y  2 0 2 0 ( Fra nce o nly )
A me n d me nt 8:
2 1 Oct o ber 2 0 1 9
A me n d me nt 7
1 2 Se pte m ber 2 0 1 9
A me n d me nt 6. 1
1 8 Ja n uar y  2 0 1 9 ( Ger ma ny  o nly )
A me n d me nt 6
2 8 Se pte m ber 2 0 1 8
A me n d me nt 5. 1
0 3 Oct o ber 2 0 1 7 ( Ger ma n y  o nly )
A me n d me nt 5
0 7 A u g ust 2 0 1 7
A me n d me nt 4. 1
0 5 Dece m ber 2 0 1 6 ( Ger ma n y  o nly )
A me n d me nt 4
2 5 Oct o ber 2 0 1 6
A me n d me nt 3. 1
1 1 J ul y  2 0 1 6 ( Ger ma ny  o nly )
A me n d me nt 3
0 2 Marc h 2 0 1 6
A me n d me nt 2. 3
1 2 Fe br uar y  2 0 1 6 ( Fra nce o nly )
A me n d me nt 2. 2
1 7 Fe br uar y  2 0 1 6 ( Ger ma ny  o nly )
A me n d me nt 2. 1
0 3 Dece m ber 2 0 1 5 ( U nite d Ki n g d o m o nl y )
A me n d me nt 2
0 2 Oct o ber 2 0 1 5
A me n d me nt 1
2 4 A u g ust 2 0 1 5
Ori g i nal Pr ot oc ol
1 3 J ul y  2 0 1 5
A me n d me nt 1 1 ( 0 5 Oct o ber 2 0 2 2) 
O ver all R ati o n ale f or t he A me n d me nt:
T his a me n d me nt is bei n g ma de pr i maril y f or t he f oll o wi n g reas o ns: 
T o u p date a n d ali g n bac k gr o u n d a n d cli nical i nf or mati o n a b o ut taze met ostat wit h t he 
u p date d I n vesti gat or Br oc h ure (I B)  f or taze met ostat (I B versi o n 1 2. 0)
T o u p date t he Me dical M o nit or 
T o u p date t he e x pl orat or y o bjecti ves a n d e n d p oi nts re gar di n g p har mac o d y na mics 
T o re m o ve t he re q uire me nt f or ce ntral E C G rea di n gs 
T o re m o ve t he re q uire me nts f or P K sa m pli n g f or s u bjects i n C o h ort 8 
T o u p date t he re q uire me nt s f or rec or d rete nti o n
I n a d diti o n, n o n-s u bsta ntial c ha n ges, mi n or e dit orial, a n d d oc u me nt f or matti n g re visi o ns were 
ma de. All c ha n ges are visi bl e i n t he trac ke d versi o n.


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 6
S u bst a nti al c h a n ges t o t he pr ot oc ol are det aile d i n t he t a ble bel o w:
Secti o n # a n d N a me  
Descri pti o n of S u bst a nti al C h a n ge
R ati o n ale
S p o ns or Pr ot oc ol A p pr o val 
Pa ge
Cli nical St u d y Pr ot oc ol 
U p date d t o pr o vi de t he ne w Me dical 
M o nit or.
T o e ns ure t he Me dical M o nit or 
i nf or mati o n is u p-t o- date a n d acc urate.
Secti o n 2 ( Pr ot oc ol S y n o psis) 
Secti o n 6 ( O bjecti ves a n d 
E n d p oi nts)
Secti o n 1 7. 4. 2 ( A nal ysis of 
Sec o n dar y Efficac y 
E n d p oi nts)
Secti o n 1 7. 7 ( E x pl orat or y 
A nal ysis) 
Re p hrase d o bjecti ves a n d e n d p oi nts f or 
clarit y.
U p date d t o ma ke i n vesti gati n g t he 
p har mac o d y na mic effects of 
taze met ostat i n t u m or tiss ue a n 
e x pl orat or y e n d p oi nt rat her t ha n a 
sec o n dar y e n d p oi nt.
T u m or tiss ue sa m pli n g was ma de 
o pti o nal i n A me n d me nt 9. 0 ( 1 7 Marc h 
2 0 2 0), t heref ore n ot all s u bjects will 
ha ve t he sa m ples nee de d f or 
p har mac o d y na mics t o be a sec o n dar y 
e n d p oi nt. T he S p o ns or will i nstea d 
a nal yze a vaila ble sa m ples c ollecte d f or 
p har mac o d y na mic a nal ysis as a n 
e x pl orat or y e n d p oi nt.
Secti o n 7. 1 ( O verall 
E x peri me ntal Pla n)
U p date d base d o n c urre nt st u d y. 
T o clarif y t he hist or y of eac h c o h ort.
Secti o n 1 2. 1 ( Sc he d ule of 
Assess me nts a n d Pr oce d ures)
Re m o ve d r o w f or a n n ual assess me nts
A n n ual P K assess me nts are n o l o n ger 
re q uire d t o be c ollecte d f or s u bjects as 
of Pr ot oc ol A me n d me nt 1 0 (J ul y 2 0 2 1)
Secti o n 1 2. 1 ( Sc he d ule of 
Assess me nts a n d Pr oce d ures)
A d de d r o w f or o verall s ur vi val 
T o  clarif y w hat assess me nts are 
perf or me d d uri n g s ur vi val f oll o w- u p.
Secti o n 1 2. 1 ( Sc he d ule of 
Assess me nts a n d Pr oce d ures)
Secti o n 1 2. 5. 4
( Electr ocar di o gra ms ( E C Gs))
U p dates t o re m o ve t he nee d f or ce ntral 
E C G rea di n gs.
L ocal rea ds are s ufficie nt a n d t o ali g n 
acr oss t he taze met ostat pr o gra m.
Secti o n 1 2. 1 ( Sc he d ule of 
Assess me nts a n d Pr oce d ures)
Secti o n 1 2. 5. 7
( P har mac o ki netics)
U p date t o re m o ve t he re q uire me nt f or 
c ollecti n g P K sa m ples fr o m s u bjects i n 
C o h ort 8.
Base d o n t he n u m ber of sa m ples alrea d y 
c ollecte d, t he S p o ns or feels c o nti n ue d 
c ollecti o n of P K sa m ple fr o m C o h ort 8 
s u bjects w o ul d be a n u n necessar y 
b ur de n f or s u bjects a n d sites. P K 
sa m pli n g was st o p pe d i n a me m o t o file 
date d 1 4 Fe br uar y 2 0 2 0.
Secti o n 1 4. 4. 2
( M D S/ A M L/ M P N)
Secti o n 1 4. 4. 3 ( Taze met ostat 
Q uarterl y Safet y Re vie w a n d 
E xter nal Safet y C o m mittee 
( E S C))
Secti o n 1 4. 4. 4 ( D ose 
M o dificati o n f or Occ urre nce 
of A E SI)
U p dates t o ali g n wit h t he c urre nt I B. 
T o pr o vi de m ore u p-t o- date i nf or mati o n
Secti o n 1 9. 1 ( Rec or di n g a n d 
Access t o St u d y Rec or ds)
U p dates t o t he re q uire me nts f or rec or d 
rete nti o n.
T o ali g n acr oss t he taze met ostat 
pr o gra m.


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 7
N o n-s u bst a nti al c h a n ges t o t he pr ot oc ol are det aile d i n t he t a ble bel o w:
Secti o n # a n d N a me
Descri pti o n of S u bst a nti al C h a n ge
R ati o n ale
Title Pa ge
Si g nat ure Pa ge
I n vesti gat or’s A gree me nt
Secti o n 2 ( Pr ot oc ol S y n o psis)
Ref or matte d a n d rearra n ge d i nf or mati o n. 
T o ali g n wit h a n u p date d 
te m plate.
Secti o n 2 ( Pr ot oc ol S y n o psis) 
Secti o n 6 ( O bjecti ves a n d 
E n d p oi nts)
Re p hrase d o bjecti ves a n d e n d p oi nts f or 
clarit y, rea da bilit y, a n d acc urac y.
T he o bjecti ves a n d e n d p oi nts of 
t his st u d y ha ve c ha n ge d si nce it 
be ga n i n 2 0 1 5. T hese e dit orial 
u p dates were ma de t o 
strea mli ne t he f ut ure o ut p uts 
nee de d f or t he cli nical st u d y 
re p ort.
Secti o n 8. 2 (I ncl usi o n Criteria)  
Mi n or e dits
T o ali g n  wit h t he i ncl usi o n 
criteria liste d i n t he s y n o psis
Secti o n 1 2. 2 ( Ti mi n g Wi n d o w 
All o wa nces f or E C Gs)
C ha n ge d “- 2 4 0 mi n utes” t o “- 4 h o urs.” 
F or clarit y
Secti o n 1 2. 5. 2  ( C o m pre he nsi ve 
P h ysical E xa mi nati o n) 
Clarifie d ge nit o uri nar y e xa ms are re q uire d 
o nl y if cli nicall y i n dicate d. 
F or clarit y.
Secti o n 1 7. 4  ( Efficac y 
A nal yses) 
C ha n ge d 9 0 % c o nfi de nce i nter val ( CI) t o 9 5 % 
T o ali g n wit h t he Statistical 
A nal ysis Pla n
T hr o u g h o ut pr ot oc ol
Re n u m bere d secti o ns
T o better ali g n wit h t he 
E piz y me pr ot oc ol te m plate.


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 8
2. 
P R O T O C O L S Y N O P SI S
N a me of S p o ns or/ C o m p a n y: E piz y me, I nc.
N a me of I n vesti g ati o n al Pr o d uct: Taze met ostat ( E P Z- 6 4 3 8)
N a me of Acti ve I n gre die nt: Taze met ostat
Pr ot oc ol N u m ber: E Z H- 2 0 2 
P h ase: II
C o u ntr y: Gl o b al
Title of St u d y: 
A P hase II, M ultice nter St u d y of t he E Z H 2 I n hi bit or T aze met ostat i n A d ult S u bj ects wit h I NI 1- Ne gati ve 
T u m ors or Rela pse d/ Re fract or y S y n o vial Sarc o ma
St u d y ce nters: A p pr o xi matel y 2 0- 3 0 sites i n E ur o pe, N ort h A merica, A ustralia, a n d Tai wa n
St u die d peri o d ( ye ars): 
Esti mate d date first s u bject e nr olle d: 3 Q 2 0 1 5
Esti mate d date last s u bject c o m plete d: 4 Q 2 0 2 2
P h ase of de vel o p me nt: II
O bjecti ves: 
Pri m ar y O bjecti ves:
C o h orts 1 (r h a b d oi d t u m ors), 3 ( ot her i nte gr ase i nter act or 1 [I NI 1]- ne g ati ve 
t u m ors or a n y s oli d t u m or wit h e n h a ncer of zeste h o m ol o g- 2 [ E Z H 2] g ai n of 
f u ncti o n [ G O F] m ut ati o n), 4 (re n al me d ull ar y c arci n o m a [ R M C]), 5 (e pit heli oi d 
s arc o m a [ E S]), C o h ort 6 ( E S wit h o pti o n al t u m or bi o ps y), a n d 7 (c h or d o m a):
T o assess t he o bjecti ve res p o nse rate ( O R R) f oll o wi n g oral a d mi nistrati o n of 
taze met ostat 8 0 0 m g t wice dail y ( BI D).
C o h ort 2 (rel a pse d/ refr act or y [ R/ R] s y n o vi al s arc o m a):
T o deter mi ne t he pr o gressi o n-free s ur vi val ( P F S) rate f oll o wi n g 1 6 wee ks of oral 
a d mi nistrati o n of taze met ostat 8 0 0 m g BI D.  
C o h ort 8 ( E S tre ate d wit h t aze met ost at 1 6 0 0 m g o nce d ail y [ Q D]):
T o assess t he safet y a n d t olera bili t y of taze met ostat 1 6 0 0 m g Q D.
Sec o n d ar y O bjecti ves:
T o e val uate t he d urati o n of res p o nse ( D O R) i n s u bjects wit h r ha b d oi d t u m ors 
( C o h ort 1), R/ R s y n o vial sarc o ma ( C o h ort 2), ot her I NI 1- ne gati ve t u m ors or a n y 
s oli d t u m or wit h E Z H 2 G O F m utati o n ( C o h ort 3), R M C ( C o h ort 4), a n d E S 
( C o h ort 5), E S u n der g oi n g o pti o nal bi o ps y ( C o h ort 6), c h or d o ma ( C o h ort 7), a n d 
E S recei vi n g 1 6 0 0 m g taze met ostat Q D ( C o h ort 8) a n d t o e val uate t he D O R i n 
C o h orts 1, 3, 4, 5, 6, a n d 7 c o m bi ne d.
T o assess t he disease c o ntr ol rate ( D C R) i n s u bjects wit h E S ( C o h ort 5) a n d E S 
u n der g oi n g o pti o nal bi o ps y ( C o h ort 6) f o ll o wi n g oral a d mi nistrati o n of 
taze met ostat 8 0 0  m g BI D, a n d i n s u bjects wit h E S ( C o h ort 8) f oll o wi n g oral 
a d mi nistrati o n of taze met ostat 1 6 0 0 m g Q D. 
T o assess t he O R R i n s u bjects wit h R/ R s y n o vial sarc o ma ( C o h ort 2) f oll o wi n g 
oral a d mi nistrati o n of taze met ostat 8 0 0 m g BI D, a n d i n s u bjects wit h E S 
( C o h ort 8) f oll o wi n g oral a d mi nistrati o n of taze met ostat 1 6 0 0 m g Q D.
T o deter mi ne t he P F S a n d o verall s ur vi val ( O S) at Wee ks 2 4, 3 2, a n d 5 6 a n d 
o verall i n s u bjects wit h r ha b d oi d t u m ors ( C o h ort 1), R/ R s y n o vial sarc o ma
( C o h ort 2), ot her I NI 1- ne gati ve t u m ors or a n y s oli d t u m or wit h E Z H 2 G O F 
m utati o n ( C o h ort 3), R M C ( C o h ort 4), E S  ( C o h ort 5), E S u n der g oi n g o pti o nal 
bi o ps y ( C o h ort 6), a n d c h or d o ma ( C o h ort 7) f oll o wi n g oral a d mi nistrati o n of 


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 9
taze met ostat 8 0 0 m g BI D, a n d i n s u bjects wit h E S ( C o h ort 8) f oll o wi n g oral 
a d mi nistrati o n of taze met ostat 1 6 0 0  m g Q D.
E x pl or at or y O bjecti ves:
T o e x pl ore t he relati o ns hi p bet wee n pl as ma P K a n d t u m or p har mac o d y na mic ( P D) 
mar kers as per mitte d b y t he data
T o assess t u m or tiss ue a n d bl o o d f or s o matic m utati o ns, ger mli ne varia nts, 
messe n ger ri b o n ucleic aci d ( m R N A), a n d/ or pr otei ns as ca n di date mar kers of 
res p o nse t o taze met ostat
C o h ort 6 o nl y: T o assess t he effects of taze met ostat o n t u m or i m m u ne pri mi n g 
(e. g., P D- L 1 a n d C D 8 I H C)
C o h ort 6 o nl y: T o i n vesti gate t he P D effects of taze met ostat i n t u m or tiss ue, if a 
p ost- d ose t u m or sa m ple is a vaila ble
St u d y Desi g n:
T his is a P hase II, m ultice nter, o pe n-la bel, si n gle-ar m, 2-sta ge st u d y wit h a n oral d ose of 
taze met ostat 8 0 0 m g BI D a n d 1 6 0 0 m g Q D. S u bjects will be scree ne d f or eli gi bilit y 
wit hi n 2 1 da ys of t he pla n ne d date of t he firs t d ose of taze met ostat a n d e nr olle d i nt o 1 of 
8 c o h orts base d o n t u m or t y pe: 
C o h orts usi n g t aze met ost at 8 0 0 m g BI D:
C o h ort 1: R ha b d oi d t u m ors ( mali g na nt r ha b d oi d t u m ors [ M R T], r ha b d oi d t u m ors of t he 
ki d ne y [ R T K], at y pical terat oi d r ha b d oi d t u m ors [ A T R T], a n d selecte d t u m ors wit h 
r ha b d oi d feat ures, i ncl u di n g s mall cell carci n o ma of t he o var y h y percalce mic t y pe 
[ S C C O H T], als o k n o w n as mali g na nt r ha b d oi d t u m or of t he o var y [ M R T O]) (cl ose d t o 
e nr oll me nt)
C o h ort 2: R/ R s y n o vial sarc o ma wit h S S 1 8- S S X rearra n ge me nt (cl ose d t o e nr oll me nt)
C o h ort 3: Ot her I NI 1- ne gati ve t u m ors or a n y s oli d t u m or wit h E Z H 2 G O F m utati o n: 
e pit heli oi d mali g na nt peri p heral ner ve s heat h t u m ors ( E M P N S T), e xtras keletal m y x oi d 
c h o n dr osarc o ma, m y oe pit helial carci n o ma, ot her I NI 1- ne gati ve t u m ors wit h S p o ns or 
a p pr o val, a n d a n y s oli d t u m ors i ncl u di n g b ut n ot li mite d t o E wi n g’s sarc o ma a n d 
mela n o ma (cl ose d t o e nr oll me nt). 
C o h ort 4: R M C (cl ose d t o e nr oll me nt)
C o h ort 5 : E S (cl ose d t o e nr oll me nt)
C o h ort 6: E S u n der g oi n g o pti o nal t u m or bi o ps y (cl ose d t o e nr oll me nt)
C o h ort 7: P o orl y differe ntiate d c h or d o ma ( or ot her c h or d o ma wit h S p o ns or a p pr o val) 
(cl ose d t o e nr oll me nt)
C o h orts usi n g t aze met ost at 1 6 0 0 m g Q D:
C o h ort 8: E S (cl ose d t o e nr oll me nt)
S u bjects  will recei ve taze met ostat i n c o nti n u o us 2 8- da y c ycles. S u bjects ma y 
disc o nti n ue st u d y treat me nt at a n y ti me d ue t o  disease pr o gressi o n, de vel o p me nt of a n 
u nacce pta ble t o xicit y, wit h dra wal of c o nse nt, or ter mi nati o n of t he st u d y.
S u bjects will ha ve a n E n d of Treat me nt ( E O T) visit u p t o 3 0 da ys after last d ose of 
treat me nt i n t his st u d y or pri or t o t he start of a ne w a ntica ncer t hera p y, w hic he ver occ urs 
first. All s u bjects will be f oll o we d f or s ur vi val. Res p o nse is defi ne d as ha vi n g 
d oc u me nte d e vi de nce of c o m plete res p o nse ( C R) or partial res p o nse ( P R). Res p o nse 
assess me nt will be perf or me d e ver y 8 wee ks w hile o n treat me nt a n d e ver y 8- 1 2 wee ks 
i n s ur vi val f oll o w- u p.


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 1 0
F or all c o h orts (e xce pt C o h orts 6 a n d 8), sta tistical a nal yses of t he pri mar y e n d p oi nt will 
be perf or me d at t he e n d of Sta ge 1 (first 1 5 s u bjects i n eac h c o h ort a n d e n d of Sta ge 2 
(all s u bjects e nr olle d i n eac h c o h ort). T he data c ut- off f or Sta ges 1 a n d 2 a nal yses will 
var y b y c o h ort:
F or C o h orts 1, 3, 4, a n d 7: T he data c ut- off f or t he a nal ysis of t he pri mar y 
e n d p oi nt will occ ur w he n s u bjects ha ve c o m plete d at least t he Wee k 2 4 
assess me nt, c o m plete d t he fi nal st u d y visit,  or ter mi nate d earl y fr o m t he st u d y, 
w hic he ver is s o o ner.
F or C o h ort 2: T he data c ut- off f or t he a nal ysis of t he pri mar y e n d p oi nt will occ ur 
w he n s u bjects ha ve c o m plete d at least t he Wee k 1 6 assess me nt, c o m plete d t he 
fi nal st u d y visit, or ter mi nate d early fr o m t he st u d y, w hic he ver is s o o ner.
F or C o h ort 5: T he data c ut- off f or t he a nal ysis of t he pri mar y e n d p oi nt will occ ur 
w he n s u bjects ha ve c o m plete d at least t he Wee k 2 4 assess me nt, c o m plete d t he 
fi nal st u d y visit, or ter mi nate d earl y fr o m t he st u d y, w hic he ver is s o o ner. 
N ote t he data c ut- off f or t he Sta ge 1 f uti lit y a nal ysis a n d t he Sta ge 2 a nal ysis 
o pe ni n g t he e x pa nsi o n c o h ort occ urre d w he n s u bjects c o m plete d at least t he Wee k 
2 4 assess me nt ( or Wee k 3 2 assess me nt, r es pecti vel y), c o m plete d t he fi nal st u d y 
visit, or ter mi nate d earl y fr o m t he st u d y, w hic he ver was s o o ner. 
F or C o h ort 6: T he data c ut- off f or t he a nal ysis of t he pri mar y e n d p oi nt will occ ur 
w he n s u bjects ha ve c o m plete d at least t he Wee k 2 4 assess me nt, c o m plete d t he 
fi nal st u d y visit, or ter mi nate d early fr o m t he st u d y, w hic he ver is s o o ner.
F or C o h ort 8: T he data c ut- off f or t he a nal ysis of t he pri mar y e n d p oi nt will occ ur 
w he n s u bjects ha ve c o m plete d at least  t he C ycle 2 Da y 1 assess me nt, c o m plete d 
t he fi nal st u d y visit, or ter mi nate d earl y fr o m t he st u d y, w hic he ver is s o o ner. 
R oll o ver St u d y 
All s u bjects w h o recei ve d taze met ostat i n t his st u d y ( E Z H- 2 0 2) a n d are eli gi ble t o 
c o nti n ue recei vi n g taze met ostat or t o c o nti n ue s ur vi val f oll o w- u p, ca n tra nsfer t o a 
R oll o ver St u d y ( E Z H- 5 0 1) f or c o nti n ue d st u d y dr u g a n d/ or c o nti n ue d m o nit ori n g at t he 
I n vesti gat or a n d Me dical M o nit or’s discreti o n.
N u m ber of 
S u bjects:
Eac h c o h ort (e xce pt C o h orts 6 a n d 8) will use a t w o-sta ge Gree n- Da hl ber g desi g n. T he 
n u m ber of s u bjects e x pecte d t o be e nr olle d i n eac h sta ge are pr o vi de d i n t he ta ble 
bel o w:
E ac h C o h ort Se p ar atel y:
C o h ort 1 ( R ha b d oi d t u m ors)
C o h ort 2 ( R/ R s y n o vial 
sarc o ma)
C o h ort 3 (I NI 1- ne gati ve/ 
E Z H 2 G O F m utati o n)
C o h ort 4 ( R M C)
C o h ort 7 ( C h or d o ma)
C o h ort 5
( E S; 
taze met ostat 
8 0 0 m g 
BI D)
C o h ort 6
( E S 
u n der g oi n g 
o pti o nal 
t u m or 
bi o ps y)
C o h ort 8
( E S; taze met ostat 
1 6 0 0 m g Q D)
Sta g e 1
1 5
1 5
N A
N A
Sta ge 2
1 5 ( N ote: C o h orts 4 a n d 7 
were cl ose d pri or t o Sta g e 2)
1 5  
N A
N A
E x pa nsi o n
N A
3 0
N A
N A
T ot al
3 0
6 0
6 5
1 6 ( N ote: C o h ort 8 
was cl ose d pri or t o 
reac hi n g t his 
e nr oll me nt g oal)
A b bre viati o ns: BI D   t wice dail y; E S   e pit helial sarc o ma; G O F   gai n of f u ncti o n; N A   n ot 
a p plica ble; Q D   o nce dail y ; R/ R   rela pse d/ refract ory ; R M C   re nal me d ullary  carci n o ma.


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 1 1
It is e x pecte d t hat a p pr o xi matel y 1 3 0- 2 9 1 s u bjects will be e nr olle d. 
Di a g n osis a n d 
M ai n Criteri a 
f or I ncl usi o n:
I ncl usi o n Criteri a
S u bjects m ust meet A L L of t he f oll o wi n g crite ria t o be eli gi ble f or e nr oll me nt i n t his 
st u d y.
1.  
A ge (at t he 
2.  
Has a n Easter n C o o perati ve O nc ol o g y Gr o u p ( E C O G) perf or ma n ce stat us of 0, 
1, or 2
N O T E: If s u bject is u na ble t o wal k d ue t o paral ysis, b ut is m o bile i n a 
w heelc hair, s u bject is c o nsi dere d t o be  a m b ulat or y f or t he p ur p ose of assessi n g 
t heir perf or ma nce stat us.
3.  
Has pr o vi de d si g ne d wr itte n i nf or me d c o nse nt
4.  
Has a life e x pecta nc y of > 3 m o nt hs
5.  
Has a mali g na nc y:
F or w hic h t here are n o sta n dar d t hera pies a vaila ble ( C o h orts 1, 3, 4 & 5)
T hat is rela pse d or refract or y, defi ne d as metastatic or n o n-resecta ble, 
l ocall y a d va nce d disease t hat has pre vi o usl y bee n treate d wit h a n d 
pr o gresse d f oll o wi n g a p pr o ve d t hera p y(ie s), if t hera p y(ies) e xists ( C o h ort 2)
T hat has pr o gresse d wit hi n 6 m o nt hs pri or t o st u d y e nr oll me nt ( C o h ort 5
E x pa nsi o n, C o h ort 6, a n d C o h ort 8 o nl y)
6.  
Has a d oc u me nte d l ocal dia g n ostic pat h ol o g y of ori gi nal bi o ps y c o nfir me d b y a 
Cli nical La b orat or y I m pr o ve me nt A me n d me nts ( C LI A)/ C olle ge of A merica n 
Pat h ol o gists ( C A P) or ot her S p o ns or -a p pr o ve d la b orat or y certificati o n
7.
F or C o h ort 1 (r h a b d oi d t u m ors) o nl y : T he f oll o wi n g test res ults m ust be 
a vaila ble b y l ocal la b orat or y:
M or p h ol o g y a n d i m m u n o p he n ot y pic pa nel c o nsiste nt wit h r ha b d oi d t u m ors, 
a n d
L oss of I NI 1 or S M A R C A 4 c o nfir me d b y I H C, or
M olec ular c o nfir mati o n of t u m or bi-allelic I NI 1 or S M A R C A 4 l oss or 
m utati o n w he n I NI 1 or S M A R C A 4 I H C is e q ui v ocal or u na vaila ble
8.
F or C o h ort 2 (s u bjects wit h rel a pse d/ refr act or y s y n o vi al s arc o m a) o nl y:
T he f oll o wi n g test res ults m ust be a vaila ble b y l ocal la b orat or y:
M or p h ol o g y c o nsiste nt wit h  s y n o vial sarc o mas, a n d
C yt o ge netics or fl u oresce nce i n sit u h y bri dizati o n ( FI S H) a n d/ or m olec ular 
c o nfir mati o n (e. g., D N A se q ue nc i n g) of S S 1 8 rearra n ge me nt 
t( X; 1 8)( p 1 1; q 1 1)
9.
F or C o h orts 3, 4, 5, 7, a n d 8 (s u bjects wit h I NI 1- n e g ati ve t u m ors or a n y 
s oli d t u m or wit h E Z H 2 G O F m ut ati o n) o nl y: T he f oll o wi n g test res ults m ust 
be a vaila ble b y l ocal la b orat or y:
M or p h ol o g y a n d i m m u n o p he n ot y pic pa nel c o nsiste nt wit h I NI 1- ne gati ve 
t u m ors ( n ot a p plica ble f or s oli d t u m ors wit h E Z H 2 G O F m utati o n), a n d
L oss of I NI 1 c o nfir me d b y I H C, or
M olec ular c o nfir mati o n of t u m or bi-alle lic I NI 1 l oss or m utati o n w he n I NI 1 
I H C is e q ui v ocal or u na vaila ble, or
M olec ular e vi de nce of E Z H 2 G O F m utati o n
1 0. F or C o h ort 6 (s u bjects wit h E S u n der g oi n g o pti o n al t u m or bi o ps y) o nl y:
M or p h ol o g y a n d i m m u n o p he n ot y pic pa nel c o nsiste nt wit h E S (e. g., C D 3 4, 


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 1 2
E M A, Kerati n, a n d I NI 1)
If pr o vi di n g o pti o nal bi o ps y: Willi n g ness t o pr o vi de i nf or me d c o nse nt t o 
u n der g o pre- a n d p ost- d ose bi o ps y 
1 1.  Has all pri or treat me nt (i.e., c he m ot hera p y, i m m u n ot hera p y, ra di ot hera p y) 
Gra de 1 per C T C A E,
versi o n 4. 0 3 or are cli nicall y sta ble a n d n ot cli nicall y si g nifica nt, at ti me of 
e nr oll me nt
1 2. Pri or a nti-ca ncer t hera p y(ies), if a p pli ca ble, m ust be c o m plete d acc or di n g t o t he 
criteria bel o w:
Pri or T her a p y
Ti me fr o m L ast Pri or T her a p y  Reg i me n
C he m ot hera p y: c yt ot o xic
At least 1 4 da ys si nce last d ose of 
c he m ot hera p y pri or t o first d ose of 
taze met ostat
C he m ot hera p y: nitr os o ureas
At least 6 wee ks si nce last d ose of 
nitr os o ureas pri or t o first d ose of 
taze met ostat
C he m ot hera p y: n o n-c yt ot o xic 
(e. g., s mall m olec ule i n hi bit or)
At least 1 4 da ys si nce last d ose of n o n-
c yt ot o xic c he m ot hera p y pri or t o first d ose of 
taze met ostat
M o n ocl o nal a nti b o d y(ies)
At least 2 8 da ys si nce t he last d ose of 
m o n ocl o nal a nti b o d y pri or t o first d ose of 
taze met ostat
I m m u n ot hera p y (e. g., t u m or vacci ne)
At least 4 2 da ys si nce last d ose of 
i m m u n ot hera p y a ge nt(s) pri or t o first d ose of 
taze met ostat
Ra di ot hera p y ( R T)
At least 1 4 da ys fr o m last l ocal site R T pri or 
t o first d ose of taze met ostat
At least 2 1 da ys fr o m stere otactic 
ra di os ur ger y pri or t o first d ose of 
taze met ostat
ra diati o n of pel vis, or t otal b o d y irra diati o n 
pri or t o first d ose of taze met ostat
Hi g h D ose T hera p y wit h a ut ol o g o us or 
all og e neic he mat o p oie tic cell i nf usi o n
At least 6 0 da ys fr o m last i nf usi o n pri or t o 
first d ose of taze met ostat
He mat o p oietic gr o wt h fact or i n s u p p ort of a nti-
ca ncer t hera p y
At least 1 4 da ys fr o m last d ose of 
he mat o p oietic gr o wt h fact or pri or t o first 
d ose of taze met ostat
1 3. Has s ufficie nt t u m or tiss ue (sli des or bl oc ks) a vaila ble f or ce ntral c o nfir mat or y 
testi n g of I H C a n d/ or c yt o ge netics/ FI S H a n d/ or D N A m utati o n a nal ysis 
(re q uire d f or st u d y e ntr y b ut e nr oll me nt base d o n l ocal res ults).
1 4. Has me as ur a ble disease b ase d o n eit her R E CI S T 1. 1 f or s oli d t u m ors or R A N O 
f or C N S t u m ors 
1 5. Has a de q uate he mat ol o gic ( b o ne marr o w a n d c oa g ulati o n fact ors), re nal a n d 
he patic f u ncti o n as defi ne d b y criteria bel o w:
S y ste m
L a b or at or y  V al ue
He m at ol o g ic ( B o ne M arr o w F u ncti o n)
He m o g l o bi na
g / d L
Platelets b
3
9/ L)
A N C c
3
9/ L)
He m at ol o g ic ( C o ag ul ati o n F act ors)
I N R/ P Td


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 1 3
P T T
Re n al F u ncti o n
Ser u m creati ni ne e
He p atic F u ncti o n
T otal bilir u bi n f
A S T g
A L T g, h
A b bre viati o ns: A L T   ala ni ne a mi n otra nsferase; A N C   a bs ol ute ne utr o p hil c o u nt; A S T   
as partate a mi n otra nsferase; Cr Cl   creati ni ne cleara nce; L L N   l o wer li mit of n or mal; P T   
pr ot hr o m bi n ti me; P T T  partial t hr o m b o plasti n ti me; U L N   u p per li mit of n or mal.
a.  
Ma y recei ve tra nsf usi o n
b. S h o ul d be e val uate d after at least 7 da ys si nce last platelet tra nsf usi o n
c.  
Wit h o ut gr o wt h fact or s u p p ort (fil grasti m or pe gfil grasti m) f or at least 1 4 da ys
d. I N R is t he preferre d val ue t o be meas ure d. H o we ver, if o nl y P T ca n be perf or me d i n t he 
testi n g la b orat or y t hat is acce pta ble
e. If creati ni ne is n ot < 1. 5 U L N t he n calc ula te b y C oc kcr oft- Ga ult met h o ds or l ocal 
i nstit uti o nal sta n dar d a n d Cr Cl m ust be > 5 0 m L/ k g/ 1. 7 3 m2
f. If attri b ute d t o 
be deter mi ne d b y c o nj u gate d or t otal bilir u bi n 
g.
1 6. S u bjects wit h a hist or y of he patitis ( E xcl usi o n Criteri o n N o.  1 3 ) m ust ha ve A L T 
wit hi n t he n or mal ra n ge
N O T E: La b orat or y res ults o btai ne d d uri n g scree ni n g s h o ul d be use d t o 
deter mi ne eli gi bilit y criteria. I n sit uati o ns w here la b orat or y res ults are o utsi de 
t he per mitte d ra n ge, t he I n vesti gat or ma y retest t he s u bject a n d t he s u bse q ue nt 
wit hi n ra n ge scree ni n g res ult ma y be use d  t o deter mi ne t he s u bject’s eli gi bilit y.
1 7. F or s u bjects wit h C N S t u m ors o nl y: S u bject m ust ha ve seiz ures t hat are 
sta ble, n ot i ncreasi n g i n fre q ue nc y or severit y a n d c o ntr olle d o n c urre nt a nti-
seiz ure me dicati o n(s) f or a mi ni m u m of 2 1 da ys pri or t o t he pla n ne d first d ose 
of taze met ostat
N O T E: S u bjects ma y recei ve gl uc oc ortic oi ds (at sta ble or ta peri n g d ose) t o 
c o ntr ol C N S s y m pt o ms pri or t o e nr oll m e nt; h o we ver, s h o ul d recei ve sta ble or 
ta peri n g d ose f or at least 7 da ys pri or t o pla n ne d first d ose of taze met ostat
1 8. Has a s h orte ni n g fracti o n o
ec h ocar di o gra m ( E C H O) or m ulti- gate d ac q uisiti o n ( M U G A) sca n a n d Ne w 
1 9.
msec
2 0. Fe m ale s u bjects of c hil d be ari n g p ote nti al m ust: 
Ha ve a ne gati ve beta-
- h C G) pre g na nc y 
test at ti me of scree ni n g a n d wit hi n 1 4 da ys pri or t o pla n ne d first d ose of 
taze met ostat ( uri ne or ser u m test is acce pta ble h o we ver, p ositi ve uri ne tests 
m ust be c o nfir me d wit h ser u m testi n g), a n d
A gree t o use effecti ve c o ntrace pti o n, as defi ne d i n Secti o n 1 2. 6. 1 , fr o m a 
mi ni m u m of 7 da ys pri or t o first d ose u ntil 6 m o nt hs f oll o wi n g t he last d ose 
of taze met ostat a n d ha ve a male part ner w h o uses a c o n d o m, or
Practice tr ue a bsti ne nce ( w he n t his is i n li ne wit h t he preferre d a n d us ual 
lifest yle of t he s u bject, see Secti o n 1 2. 6. 1 ), or
Ha ve a male part ner w h o is vasect o mize d 
2 1. M ale s u bjects wit h a fe m ale p art ner of c hil d be ari n g p ote nti al m ust: 


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 1 4
Be vasect o mize d, or
A gree t o use c o n d o ms as defi ne d i n Secti o n 1 2. 6. 2 , fr o m first d ose of 
taze met ostat u ntil 3 m o nt hs f oll o wi n g t he last d ose of taze met ostat, or
Ha ve a fe male part ner w h o is N O T of c hil d beari n g p ote ntial
E xcl usi o n Criteri a:
S u bjects meeti n g A N Y of t he f oll o wi n g criteri a m ust N O T be e nr olle d i n t his st u d y:
1.  
Has ha d pri or e x p os ure t o taze met ostat or ot her i n hi bit or(s) of e n ha ncer of zeste 
h o m ol o g ue- 2 ( E Z H 2) 
2.  
Has partici pate d i n a n ot her i nter v e nti o nal cli nical st u d y a n d recei ve d 
i n vesti gati o nal dr u g wit hi n 3 0 da ys or 5 half-li ves, w hic he ver is l o n ger, pri or t o 
t he pla n ne d first d ose of taze met ostat
3.  
Has k n o w n acti ve C N S or a n y le pt o me ni n geal metastasis of pri mar y 
e xtracra nial t u m or. S u bjects wit h pre v i o usl y treate d brai n metastases ma y 
partici pate pr o vi de d t he y are sta ble ( wit h o ut e vi de nce of pr o gressi o n b y 
i ma gi n g 4 wee ks pri or t o t he first d ose of st u d y dr u g a n d a n y ne ur ol o gic 
s y m pt o ms ha ve sta bilize d), ha ve n o e vi de nce of ne w or e nlar gi n g brai n 
metastases, a n d are o n sta ble or ta peri n g d oses of ster oi ds f or at least 7 da ys 
pri or t o first d ose of st u d y dr u g. 
N O T E: S u bjects wit h as y m pt o matic brai n metastases f o u n d o n scree ni n g M RI 
ma y be e ntere d i nt o t he st u d y wit h o ut pri or ra diati o n t hera p y t o t he brai n if t he y 
d o n ot re q uire i m me diate s ur gical or ra diati o n t hera p y i n t he o pi ni o n of t he 
treati n g I n vesti gat or a n d i n t he o pi ni o n of a ra diati o n t hera p y or ne ur os ur gical 
c o ns ulta nt. 
4.  
Has ha d a pri or mali g na nc y ot her t ha n t he mali g na ncies u n der st u d y 
E xce pti o n: A s u bject w h o has bee n disease-free f or 5 years, or a s u bject wit h a 
hist or y of a c o m pletel y resecte d n o n- mela n o ma s ki n ca ncer  or s uccessf ull y 
treate d i n sit u carci n o ma is eli gi ble.
5.  
Has ha d maj or s ur ger y wit hi n 3 wee ks pri or t o e nr oll me nt 
N O T E : Mi n or s ur ger y (e. g., mi n or bi o ps y of e xtracra nial site, ce ntral ve n o us 
cat heter place me nt, s h u nt re visi o n) is per mitte d wit hi n 3 wee ks pri or t o 
e nr oll me nt. 
6.
criteria) or a n y pri or hist or y of  m yel oi d mali g na ncies, i ncl u di n g 
m yel o d ys plastic s y n dr o me ( M D S). Has a b n or malities k n o w n t o be ass ociate d 
wit h M D S (e. g. del 5 q, c hr 7 a b n) a n d M P N (e. g. J A K 2 V 6 1 7 F) o bser ve d i n 
c yt o ge netic testi n g a n d D N A se q ue nci n g. 
N O T E: B o ne marr o w as pirate/ bi o ps y w ill be c o n d ucte d f oll o wi n g a b n or mal 
peri p heral bl o o d s mear m or p h ol o g y assess me nt c o n d ucte d b y ce ntral 
la b orat or y. C yt o ge netic testi n g an d D N A se q ue nci n g will be c o n d ucte d 
f oll o wi n g a n a b n or mal res ult of b o ne marr o w as pirate/ bi o ps y.
7.  
Has a pri or hist or y of T- L B L/ T- A L L.
8. Is u n willi n g t o e xcl u de gra pefr uit j uice,  Se ville ora n ges a n d gra pefr uit fr o m t he 
diet a n d all f o o ds t hat c o ntai n t h ose fr uits fr o m ti me of e nr oll me nt t o w hile o n 
st u d y.
9.  
Has car di o vasc ular i m pair me nt, hist or y of  c o n gesti ve heart fail ure greater t ha n 
N Y H A Class 2, u nc o ntr olle d arterial h y per te nsi o n, u nsta ble a n gi na, m y ocar dial 
i nfarcti o n, or str o ke wit hi n 6 m o nt hs pri or t o t he pla n ne d first d ose of 


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 1 5
taze met ostat; or ve ntric ular car diac arr h yt h mia re q uiri n g me dical treat me nt
1 0. Is c urre ntl y ta ki n g a n y pr o hi bite d me dicati o n(s)
1 1.  Has a n acti ve i nfecti o n re q uiri n g s yste mic treat me nt
1 2. Is i m m u n oc o m pr o mise d (i.e., has a c o n ge nital i m m u n o deficie nc y), i ncl u di n g 
s u bjects k n o w n hist or y of i nfecti o n wit h h u ma n i m m u n o deficie nc y vir us ( HI V)
1 3.  Has k n o w n acti ve i nfecti o n wit h he pa titis B vir us or he patitis C vir us 
N O T E: S u bjects wit h a hist or y of he patitis B or C wit h n or mal A L T a n d 
u n detecta ble H B V D N A or H C V R N A are eli gi ble f or t his st u d y
1 4.  Has ha d a s y m pt o matic ve n o us t hr o m b osis wit hi n t he 2 wee ks pri or t o st u d y 
e nr oll me nt.
N O T E: S u bjects wit h a hist or y of a dee p vei n t hr o m b osis > 2 wee ks pri or t o 
st u d y e nr oll me nt w h o are o n a ntic oa g ulati o n t hera p y wit h l o w m olec ular 
wei g ht he pari n are eli gi ble f or t his st u d y.
1 5. F or s u bjects wit h C N S i n v ol ve me nt ( pri m ar y t u m o r or met ast atic dise ase):
Ha ve a n y acti ve blee di n g, or ne w i ntr a-t u m oral he m orr ha ge of m ore t ha n 
p u nctate size o n scree ni n g M RI o btai ne d w it hi n 1 4 da ys of starti n g st u d y dr u g 
or k n o w n blee di n g diat hesis or treat me nt wit h a nti- platelet or a nti-t hr o m b otic 
a ge nts.
1 6.  Has k n o w n h y perse nsiti vit y t o a n y of t h e c o m p o ne nts of taze met ostat or ot her 
i n hi bit or(s) of E Z H 2
1 7. Is u na ble t o ta ke oral me dicati o ns, or has mala bs or pti o n s y n dr o me or a n y ot her 
u nc o ntr olle d gastr oi ntesti nal c o n diti o n (e . g., na usea, diarr hea or v o miti n g) t hat 
mi g ht i m pair t he bi oa va ila bilit y of taze met ostat
1 8.  Has a n u nc o ntr olle d i nterc urre nt ill ne ss i ncl u di n g, b ut n ot li mite d t o, 
u nc o ntr olle d i nfecti o n, or ps yc hiatric ill ness/s ocial sit uati o ns t hat w o ul d li mit 
c o m plia nce wit h st u d y re q uire me nts.
1 9. F or fe m ale s u bjects of c hil d be ari n g p ote nti al: Is pre g na nt or n ursi n g
2 0. F or m ale s u bjects: Is u n willi n g t o a d here t o c o ntrace pti o n criteria fr o m ti me of 
e nr oll me nt i n st u d y t o at least 3 m o nt hs after last d ose of taze met ostat.
D os a ge a n d 
A d mi nistr ati o
n f or 
T aze met ost at:
S u bjects will recei ve taze met ostat 8 0 0 m g BI D orall y o ver c o nti n u o us 2 8- da y c ycles. 
S u bjects i n C o h ort 8 o nl y, will recei ve taze met ostat 1 6 0 0 m g Q D orall y o ver c o nti n u o us 
2 8- da y c ycles. S u bjects ma y disc o nti n ue at a n y ti me d ue t o disease pr o gressi o n, 
de vel o p me nt of a n u nacce pta ble t o xicit y, wit h dra wal of c o nse nt, or ter mi nati o n of t he 
st u d y. 
Criteri a f or 
E v al u ati o n:
Pri m ar y E n d p oi nts:
C o h orts 1, 3, 4, 5, 6, a n d 7: O R R (c o nfir me d C R + P R) f or taze met ostat i n s u bjects 
wit h I NI 1- ne gati ve t u m ors usi n g disease-a p pr o priate sta n dar dize d res p o nse criteria 
( pri mar y C N S t u m ors: Res p o nse Assess me nt f or Ne ur o- O nc ol o g y [ R A N O] a n d all 
ot hers: R E CI S T 1. 1)
C o h ort 2: P F S rate after 1 6 wee ks of treat me nt wit h taze met ostat. T his is t he 
n u m ber of s u bjects wit h c o nfir me d C R or P R, or sta ble disease ( S D) at t he 
Wee k 1 6 assess me nt.
C o h ort 8: Safet y a n d t olera bilit y as assesse d b y A Es a n d cli nical la b orat or y tests
Sec o n d ar y E n d p oi nts:
D O R f or eac h c o h ort ( C o h orts 1- 8) a n d f or C o h orts 1, 3, 4, 5, 6, a n d 7 c o m bi ne d. 
D O R is defi n e d as t he ti me fr o m t he first d o c u me nte d e vi de nce of C R or P R t o t he 


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 1 6
ti me of first d oc u me nte d disease pr o gressi o n or deat h d ue t o a n y ca use, w hic he ver 
c o mes first, usi n g disease-a p pr o priate sta n dar dize d res p o nse criteria
C o h orts 5, 6, a n d 8 : D C R f or taze met ostat. T his is defi ne d as t he n u m ber of 
s u bjects w h o ac hie ve c o nfir me d res p o nse ( C R + P R) or w h o ha ve S D lasti n g at least 
3 2 wee ks.
C o h orts 2 a n d 8: O R R. T his is defi ne d as t he n u m ber of s u bjects w h o ac hie ve 
c o nfir me d res p o nse ( C R + P R) per R E CI S T 1. 1
P F S at Wee ks 2 4, 3 2, a n d 5 6 a n d o verall f or eac h c o h ort. P F S is defi ne d as t he ti me 
fr o m t he date of first d ose of st u d y treat me nt t o t he earlier of t he date of first 
d oc u me nte d disease pr o gressi o n or date of deat h d ue t o a n y ca use
O S at Wee ks 2 4, 3 2, a n d 5 6 a n d o verall f or eac h c o h ort. O S is defi ne d as t he ti me 
fr o m t he date of t he first d ose of st u d y treat me nt t o t he date of deat h d ue t o a n y 
ca use
E x pl or at or y E n d p oi nts:
T u m or tar get ge ne e x pressi o n a n d p he n ot y pic mar kers i ncl u di n g t h ose f or 
differe ntiati o n, a p o pt osis, i nfla m mati o n, a n d cell pr oliferati o n a n d t heir c orrelati o n 
wit h acti vit y
S o matic m utati o n a nal ysis of t u m or tiss ue a n d bl o o d deri ve d circ ulati n g D N A
Ger mli ne D N A a nal ysis f or I NI 1 a n d S M A R C A 4 varia nts
C o h ort 6: Assess me nt of pre- a n d p ost- d ose bi o psies f or i m m u ne pri mi n g (e. g., 
P D- L 1 a n d C D 8 I H C)
C o h ort 6: Assess me nt of pre- a n d p ost- d ose bi o psies f or H 3 K 2 7 me 3 a n d f or 
c ha n ges i n ge ne e x pressi o n.
St atistic al 
Met h o ds:
S a m ple Size R ati o n ale: F or all c o h orts e xce pt C o h orts 6 a n d 8 ( E S u n der g oi n g o pti o nal 
t u m or bi o ps y a n d E S 1 6 0 0 m g Q D, descri bed bel o w), eac h c o h ort will be e val uate d 
se paratel y usi n g a t w o-sta ge Gree n- Da hl ber g desi g n. T he sa m ple size of eac h c o h ort is 
calc ulate d o n t he pri mar y e n d p oi nt. Wit hi n eac h c o h ort t he h y p ot hesis will be teste d 
usi n g a o ne-
E ac h C o h ort Se p ar atel y:
C o h ort 1 a ( R ha b d oi d 
t u m ors)
C o h ort 3 a
( Ot her I NI 1- ne gati ve 
t u m ors or a n y s oli d t u m or 
wit h E Z H 2 G O F m utati o n)
C o h ort 4 a ( R M C)
C o h ort 7 a ( C h or d o ma)
C o h ort 2 a
( Rela pse d/ 
refract or y 
s y n o vial 
sarc o ma)
I niti al 
Desi g n:
C o h ort 5 a
( E S)
A me n de d 
Desi g n:
C o h ort 5 b
( E S)
Sta ge 1: N ull 
h y p ot hesis
C R + P R + 
S D at Wee k 
C R + P R 
Sta ge 1: 
Alter nati ve 
h y p ot hesis
C R + P R + 
S D at Wee k 
C R + P R 
Sta ge 1 sa m ple 
size ( n 1)c
1 5
1 5
1 5
Sta ge 1 rejecti o n 
of st u d y treat me nt 
(r 1)c
0
1
0
Sta ge 2 sa m ple 
size ( n 2)
1 5
1 5
1 5
1 5


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 1 7
Sta ge 2 rejecti o n 
of st u d y treat me nt 
(r)
4
8
4
4
T ot al s a m ple size 
( n)
3 0
3 0
3 0
3 0
E x pa nsi o n d
N A
N A  
N A 
3 0
a.  
All s u bjects will ha ve c o m plete d at least t he Wee k 2 4 ( Wee k 1 6 f or s y n o vial sarc o ma) 
assess me nt, c o m plete d t he fi nal st u d y visit, or ter mi nate d earl y fr o m t he st u d y, 
w hic he ver is s o o ner.
b.  
All s u bjects will ha ve c o m plete d at least t h e Wee k 3 2 assess me nt, c o m plete d t he fi nal 
st u d y visit, or ter mi nate d earl y fr o m t he st u d y, w hic he ver is s o o ner - base d o n 
A me n d me nt 4.
c.  
Wit hi n eac h c o h ort, t he i nteri m a nal ysis pla n ne d at t he e n d of Sta ge 1 ma y occ ur s o o ner 
if t he Sta ge 1 rejecti o n criteri o n is s ur passe d bef ore all 1 5 s u bjects are treate d a n d 
f oll o we d f or t he s pecifie d ti me. I n t his sce nari o, t he t otal sa m ple size ( Sta ge 1 + Sta ge 2) 
f or a c o h ort w o ul d still re mai n u nc ha n ge d at 3 0 s u bjects.
d.  
A n a d diti o nal 3 0 s u bjects ma y be e nr olle d f or e x pa n de d e val uati o n of efficac y a n d 
safet y. E nr oll me nt i n t he e x pa nsi o n sta ge ma y be o pe ne d o nce t he Sta ge 2 rejecti o n 
criteri o n has bee n s ur passe d. If t his occ urs pri or t o t he f ull e nr oll me nt of Sta ge 2, t he 
t otal c o h ort sa m ple size ( Sta ge 1 + Sta ge 2 + e x pa nsi o n) will re mai n u nc ha n ge d at 6 0 
s u bjects.
T he C o h ort 5 e x pa nsi o n sta ge was o pe ne d i n  Dece m ber 2 0 1 6 after t he Sta ge 2 D C R 
criteri o n was s ur passe d. I n Ma y 2 0 1 7, E piz y m e met wit h t he F D A re gar di n g f ut ure 
de vel o p me nt pla ns f or taze met ostat. Base d o n s pecific rec o m me n dati o ns fr o m F D A, 
wit h A me n d me nt 5, t he pri mar y e n d p oi nt f o r C o h ort 5 has bee n c ha n ge d t o O R R a n d 
d urati o n of res p o nse i n res p o n di n g s u bjects ha s bee n ele vate d t o t he m ost i m p orta nt 
sec o n dar y e n d p oi nt.
E x p a nsi o n: T he a d diti o nal 3 0 s u bjects e nr olle d i n C o h ort 5 will all o w f or i ncrease d 
precisi o n f or t he p oi nt esti mates of D C R a n d O R R. T he ta ble bel o w s h o ws t he 9 5 % 
e xact bi n o mial c o nfi de nce i nter val ( CI) f or p ote ntial p oi nt esti mates of D C R a n d/ or 
O R R: 
P ote nti al D C R or 
O R R
2 0 %
3 0 %
4 0 %
S u bjects meeti n g 
e n d p oi nt
1 2 of 6 0
1 8 of 6 0
2 4 of 6 0
9 5 % e x act bi n o mi al 
CI
1 0. 8 %- 3 2. 3 %
1 8. 8 %- 4 3. 2 % 
2 7. 6 %- 5 3. 5 %
S a m ple Size R ati o n ale f or C o h ort 6: 
C o h ort 6 was a d de d o utsi de of a 2-sta ge desi g n fra me w or k base d o n cli nical data 
de m o nstrati n g e nc o ura gi n g e vi de nce of a n tit u m or acti vit y, a n d n o c o ncer ni n g safet y 
si g nals i n E S s u bjects i n C o h ort 5. Preli mi nar y e vi de nce of t he i m m u ne- pri mi n g effect 
of taze met ostat e val uate d b y I H C pr o vi de d t h e rati o nal f or c ollecti n g ma n dat or y paire d 
t u m or bi o psies i n t his c o h ort. T we nt y ( 2 0) paire d t u m or bi o psies will aff or d s ufficie nt 
data t o q ua ntif y t he i m m u ne pri mi n g effects of taze met ostat. D ue t o t he e x pectati o n t hat
s o me s u bjects will wit h dra w c o nse nt after t he p ost-scree ni n g bi o ps y a n d ot her s u bjects 
ma y n ot be a ble t o pr o vi de a p ost-treat m e nt bi o ps y, C o h ort 6 will e nr oll u p t o 4 0 
s u bjects t o e ns ure t hat 2 0 paire d t u m or bi o psies are c ollecte d a n d a de q uate f or a nal ysis. 
I n Ja n uar y 2 0 2 0, taze met ostat was a p pr o ve d f or t he treat me nt of a d ults a n d pe diatric 
patie nts a ge d 1 6 years a n d ol der wit h metasta tic or l ocall y a d va nce d E S n ot eli gi ble f or 
c o m plete resecti o n. U n der t he c o n diti o ns of t he a p pr o val, E piz y me a gree d wit h t he F D A 
t o e nr oll a n a d diti o nal 2 5 s u bjects i n c o h ort 6 t o f urt her e val uate t he O R R i n s u bjects 


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 1 8
wit h metastatic or l ocall y a d va nce d E S. T he pri mar y e n d p oi nt of C o h ort 6 has bee n 
c ha n ge d t o O R R a n d t he effects of taze met ostat o n t u m or i m m u ne pri mi n g has bee n 
c ha n ge d t o a n e x pl orat or y e n d p oi nt. T he re q uire me nt f or ma n dat or y pre- a n d p ost- d ose 
t u m or bi o psies has bee n ma de o pti o nal i n a me n d me nt 9.
Wit h a sa m ple size of at least 4 0 s u bjects, t he st u d y has a p o wer of m ore t ha n 8 0 % t o 
test t he h y p ot hesis t hat t he o bjecti ve res p o nse rate w o ul d be 2 0 % or hi g her a gai nst t he 
n ull h y p ot hesis t hat it w o ul d be 5 % or l o we r at o ne-si de d si g nifica nce le vel of 0. 0 2 5.
S a m ple Size R ati o n ale f or C o h ort 8:   
As wit h C o h ort 6, C o h ort 8 was a d de d o utsi de of a 2-sta ge desi g n fra me w or k base d o n 
cli nical data i n E S s u bjects i n C o h ort 5 (s ee rati o nale a b o ve f or C o h ort 6). C o h ort 8 was 
a d de d t o e val uate safet y, P K, a n d efficac y  pr ofile of o nce dail y taze met ostat d osi n g; 
1 6 s u bjects will be e nr olle d f or e val uati o n of P K, efficac y, a n d safet y.


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 1 9
3. 
T A B L E O F C O N T E N T S
1.  
TI T L E P A G E ................................................................................................................ 1
SI G N A T U R E P A G E ....................................................................................................................... 2
I N V E S TI G A T O R’ S A G R E E M E N T ............................................................................................... 3
C LI NI C A L S T U D Y P R O T O C O L .................................................................................................. 4
P R O T O C O L A M E N D M E N T S U M M A R Y O F C H A N G E S .......................................................... 5
2.  
P R O T O C O L S Y N O P SI S ............................................................................................. 8
3.  
T A B L E  O F C O N T E N T S ........................................................................................... 1 9
3. 1. 
List of Fi g ures ............................................................................................................. 2 4
3. 2. 
List of Ta bles .............................................................................................................. 2 4
4.  
A B B R E VI A TI O N S .................................................................................................... 2 5
5.  
I N T R O D U C TI O N ...................................................................................................... 3 0
5. 1.
Bac k gr o u n d ................................................................................................................. 3 0
5. 2. 
Cli nical C haracteristics of Tar gete d T u m ors .............................................................. 3 2
5. 3.
Rati o nale f or Taze met ostat Treat me nt ........................................................................ 3 3
5. 4.
Taze met ostat ............................................................................................................... 3 4
5. 4. 1. 
I n vesti gati o nal Pr o d uct ............................................................................................... 3 4
5. 4. 2.
N o ncli nical P har mac ol o g y .......................................................................................... 3 4
5. 4. 3. 
P har mac o ki netics ( P K) ............................................................................................... 3 6
5. 4. 4.
Cli nical E x perie nce ..................................................................................................... 3 7
5. 4. 5. 
P har mac o d y na mics ( P D) ............................................................................................ 3 9
5. 4. 6.
C o h ort 8 D osi n g J ustificati o n: 1 6 0 0 m g Q D .............................................................. 4 0
5. 5. 
St u d y Rati o nale ........................................................................................................... 4 0
5. 6. 
Be nefit: Ris k Assess me nts .......................................................................................... 4 1
5. 6. 1.  
A ni mal T o xic ol o g y ..................................................................................................... 4 1
5. 6. 2. 
P h ot o- Reacti ve P ote ntial ............................................................................................ 4 1
5. 6. 3.
C Y P 3 A Meta b olis m .................................................................................................... 4 1
5. 6. 4.
A ntici pate d Safet y Pr ofile ........................................................................................... 4 2
5. 6. 5.
S u m mar y ..................................................................................................................... 4 2
6.  
O BJ E C TI V E S A N D E N D P OI N T S ............................................................................ 4 4
7.  
S T U D Y D E SI G N ....................................................................................................... 4 6


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 2 0
7. 1.  
O verall E x peri me ntal Pla n .......................................................................................... 4 6  
7. 2.  
Esti mate d St u d y D urati o n ........................................................................................... 4 9  
7. 2. 1.  
St u d y D urati o n f or Partici pa nts .................................................................................. 4 9  
7. 2. 2.  
E n d of St u d y ............................................................................................................... 4 9  
7. 3.  
R ules f or S us pe nsi o n of E nr oll me nt ........................................................................... 5 0  
8.  
S U BJ E C T P O P U L A TI O N ......................................................................................... 5 1  
8. 1.  
N u m ber of S u bjects .................................................................................................... 5 1  
8. 2.  
I ncl usi o n Criteria ........................................................................................................ 5 1 
8. 3.  
E xcl usi o n Criteria ....................................................................................................... 5 5  
9.  
I N V E S TI G A TI O N A L P R O D U C T ............................................................................ 5 8 
9. 1.  
Descri pti o n .................................................................................................................. 5 8  
9. 2.  
Pre parati o n, Ha n dli n g, a n d St ora g e of I n vesti gati o nal Pr o d uct ................................. 5 8  
9. 3.  
D osa ge a n d A d mi nistrati o n ........................................................................................ 5 9  
9. 3. 1.  
Misse d D oses .............................................................................................................. 5 9  
9. 3. 2.  
Pr oc ure me nt of I P ....................................................................................................... 5 9  
9. 4.  
Acc o u nta bilit y ............................................................................................................. 5 9  
1 0.  
S T U D Y T R E A T M E N T .............................................................................................. 6 1  
1 0. 1.  
Treat me nt Assi g n me nt ................................................................................................ 6 1  
1 0. 2.  
Restricti o ns D uri n g St u d y Treat me nt ......................................................................... 6 1  
1 0. 3.  
D ose M o dificati o n ...................................................................................................... 6 1  
1 0. 3. 1.  
D ose M o dificati o n d ue t o Treat me nt- Relate d T o xicit y .............................................. 6 1  
1 0. 4.  
C o nti n uati o n of Treat me nt .......................................................................................... 6 2  
1 0. 5.  
D urati o n of Taze met ostat Treat me nt .......................................................................... 6 3  
1 0. 6.  
Treat me nt C o m plia nce ................................................................................................ 6 3  
1 0. 7.  
Treat me nt of O ver d ose ............................................................................................... 6 4  
1 1.  
C O N C O MI T A N T M E DI C A TI O N S .......................................................................... 6 5  
1 1. 1.  
Per mitte d Me dicati o n(s) ............................................................................................. 6 5  
1 1. 2.  
Me dicati o ns t o be use d wit h Ca uti o n .......................................................................... 6 5  
1 1. 3.  
Pr o hi bite d Me dicati o n(s) ............................................................................................ 6 5  
1 1. 4.  
N o n- Dr u g T hera pies ................................................................................................... 6 6  
1 2.  
S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S ...................................................... 6 7  
1 2. 1.  
Sc he d ule of Assess me nts a n d Pr oce d ures .................................................................. 6 8  
1 2. 2.  
Ti mi n g Wi n d o w All o wa nces f or E C Gs ...................................................................... 7 3  


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 2 1
1 2. 3.  
C o nse nt ....................................................................................................................... 7 3  
1 2. 4.  
Scree ni n g Assess me nts ............................................................................................... 7 3  
1 2. 5.  
St u d y Assess me nts ...................................................................................................... 7 4  
1 2. 5. 1.  
P h ysical E xa mi nati o ns ................................................................................................ 7 4  
1 2. 5. 2.  
C o m pre he nsi ve P h ysical E xa mi nati o n ....................................................................... 7 4  
1 2. 5. 3.  
S y m pt o m- Directe d P h ysical E xa mi nati o n .................................................................. 7 4  
1 2. 5. 4.  
Electr ocar di o gra ms ( E C Gs) ........................................................................................ 7 5  
1 2. 5. 5.  
Disease Assess me nt .................................................................................................... 7 5  
1 2. 5. 6.  
O pti o nal C hest Ultras o u n d ......................................................................................... 7 5  
1 2. 5. 7.  
P har mac o ki netics ........................................................................................................ 7 5  
1 2. 5. 8.  
P har mac o ge n o mics ( P G x) .......................................................................................... 7 5  
1 2. 5. 9.  
T u m or Sa m pli n g ......................................................................................................... 7 6  
1 2. 5. 1 0.  
Arc hi ve T u m or or Bi o ps y at Scree ni n g ...................................................................... 7 6  
1 2. 5. 1 1.  
O pti o nal T u m or Bi o psies Ta ke n o n St u d y ( C o h orts 1 t hr o u g h 5, 7, a n d 8) ............... 7 6 
1 2. 5. 1 2.  
O pti o nal T u m or Bi o psies Ta ke n o n St u d y ( C o h ort 6 O nl y) ....................................... 7 6  
1 2. 5. 1 3.  
Circ ulati n g T u m or D N A ............................................................................................. 7 7  
1 2. 5. 1 4.  
Cli nical La b orat or y  Assess me nts ............................................................................... 7 7  
1 2. 5. 1 5.  
S ur vi val F oll o w- U p .................................................................................................... 7 8  
1 2. 5. 1 6.  
S u bse q ue nt T hera p y After Disc o nti n uati o n of St u d y Treat me nt ............................... 7 8  
1 2. 5. 1 7.  
E val uati o n of Res p o nse t o S u bse q ue nt A nti- Ca ncer T hera p y .................................... 7 8  
1 2. 5. 1 8.  
Pre g na nc y ................................................................................................................... 7 8  
1 2. 5. 1 9.  
Defi niti o n of C hil d beari n g P ote ntial: Fe male S u bjects .............................................. 7 9  
1 2. 5. 2 0.  
Defi niti o n of C hil d beari n g P ote ntial: Male S u bjects .................................................. 7 9  
1 2. 5. 2 1.  
Pre g na nc y Testi n g ...................................................................................................... 7 9  
1 2. 6.  
Pre ve nti o n ................................................................................................................... 7 9  
1 2. 6. 1.  
Fe male S u bjects .......................................................................................................... 7 9  
1 2. 6. 2.  
Male S u bjects .............................................................................................................. 8 0  
1 2. 6. 3.  
Re p orti n g of Pre g na nc y .............................................................................................. 8 0  
1 3.  
WI T H D R A W A L A N D R E P L A C E M E N T O F S U BJ E C T S ...................................... 8 1  
1 3. 1.  
Wit h dra wal of S u bjects fr o m Treat me nt/ Pr oce d ures ................................................. 8 1  
1 3. 2.  
Wit h dra wal of S u bjects fr o m St u d y ........................................................................... 8 1  
1 3. 3.  
Re place me nt of S u bjects ............................................................................................. 8 1  
1 4.  
A D V E R S E E V E N T S A N D S E RI O U S A D V E R S E E V E N T S .................................. 8 2  


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 2 2
1 4. 1.  
Defi niti o ns .................................................................................................................. 8 2  
1 4. 1. 1.  
A d verse E ve nt ( A E) .................................................................................................... 8 2  
1 4. 1. 2.  
A d verse E ve nts Ass ociate d  wit h T u m or Bi o psies ...................................................... 8 2 
1 4. 1. 3.  
Seri o us A d verse E ve nt ( S A E) .................................................................................... 8 2  
1 4. 1. 4.  
S pecial Sit uati o ns ........................................................................................................ 8 3  
1 4. 2.  
La b orat or y A b n or malities ........................................................................................... 8 4  
1 4. 3.  
Ot her Safet y Assess me nt A b n or malities .................................................................... 8 4  
1 4. 3. 1.  
Disease- Relate d E ve nts .............................................................................................. 8 4  
1 4. 4.  
A d verse E ve nts of S pec ial I nterest ( A E SIs) ............................................................... 8 5 
1 4. 4. 1.  
T- L y m p h o blastic L y m p h o ma/ T- Ac u te L y m p h o blastic Le u ke mia ............................. 8 5 
1 4. 4. 2.  
M D S/ A M L/ M P N ........................................................................................................ 8 6  
1 4. 4. 3.  
Taze met ostat Q uarterl y Safet y Re vi e w a n d E xter nal Safet y C o m mittee 
( E S C) .......................................................................................................................... 8 6 
1 4. 4. 4.  
D ose M o dificati o n f or Occ urre nce of A E SI ............................................................... 8 7  
1 4. 4. 5.  
Safet y Si g nal E ve nts U n der E val uati o n: B-cell Ac ute L y m p h o blastic 
Le u ke mia ( B- A L L) ..................................................................................................... 8 7  
1 4. 5.  
Ot her P ote ntial I de ntifie d Ris ks .................................................................................. 8 8  
1 4. 6.  
Gra di n g a n d Se verit y .................................................................................................. 8 8  
1 4. 7.  
Relati o ns hi p Cate g orizati o n ........................................................................................ 8 9  
1 4. 7. 1.  
Assessi n g Relati o ns hi p t o St u d y Treat me nt ............................................................... 8 9  
1 4. 8.  
O utc o me Cate g orizati o n ............................................................................................. 9 0  
1 4. 9.  
Ti mefra me f or Re p orti n g A Es a n d S A Es ................................................................... 9 0  
1 4. 1 0.  
Re p orti n g of S A Es ...................................................................................................... 9 0  
1 4. 1 1.  
Re p orti n g of A E SIs ..................................................................................................... 9 1  
1 4. 1 2.  
Re p orti n g of S pecial Sit uati o ns .................................................................................. 9 1  
1 4. 1 3.  
Re p orti n g t o Re g ulat or y A ut h oriti es, I R B/ E C a n d Ce ntral Et hics 
C o m mittees ( C E Cs) .................................................................................................... 9 2  
1 5.  
C O R R E L A TI V E A S S E S S M E N T S ............................................................................ 9 3  
1 5. 1.  
Bi o mar kers of Res p o nse Assess me nt ......................................................................... 9 3  
1 5. 2.  
Assess me nt of Rela pse/ Resista nce t o Taze met ostat ................................................... 9 3  
1 5. 3.  
F ut ure Use of Tiss ue Sa m ples .................................................................................... 9 3  
1 6.  
D A T A M A N A G E M E N T ........................................................................................... 9 4  
1 6. 1.  
C o di n g ........................................................................................................................ . 9 4 


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 2 3
1 7.  
S T A TI S TI C A L M E T H O D S ....................................................................................... 9 5  
1 7. 1.  
H y p ot heses .................................................................................................................. 9 5  
1 7. 2.  
St u d y Desi g n C o nsi derati o ns ...................................................................................... 9 6  
1 7. 2. 1.  
Deter mi nati o n of Sa m ple Size .................................................................................... 9 6  
1 7. 2. 2.  
Sa m ple Size Re- Esti mati o n ........................................................................................ 9 8  
1 7. 3.  
Data A nal ysis C o nsi derati o ns ..................................................................................... 9 8  
1 7. 3. 1.  
A nal ysis P o p ulati o ns .................................................................................................. 9 8  
1 7. 3. 2.  
I nteri m A nal yses ......................................................................................................... 9 9 
1 7. 3. 3.  
Ke y Ele me nts of t he A nal ysis Pla n .......................................................................... 1 0 0  
1 7. 4.  
Efficac y A nal yses ..................................................................................................... 1 0 0  
1 7. 4. 1.  
Fi nal A nal ysis of Pri mar y E n d p oi nt b y C o h ort ........................................................ 1 0 0  
1 7. 4. 2.  
A nal ysis of Sec o n dar y Efficac y E n d p oi nts .............................................................. 1 0 1  
1 7. 5.  
Safet y A nal yses ........................................................................................................ 1 0 3  
1 7. 5. 1.  
E xte nt of E x p os ure ................................................................................................... 1 0 3  
1 7. 5. 2.  
A d verse E ve nts ......................................................................................................... 1 0 3  
1 7. 5. 3.  
Cli nical La b orat or y E val uati o n ................................................................................. 1 0 4  
1 7. 5. 4.  
Ot her Safet y Meas ures .............................................................................................. 1 0 4  
1 7. 6.  
P har mac o ki netic A nal yses ........................................................................................ 1 0 4  
1 7. 7.  
E x pl orat or y A nal ysis ................................................................................................ 1 0 5  
1 7. 8.  
I n de pe n de nt Data M o nit ori n g C o m mittee (I D M C) .................................................. 1 0 5 
1 8.  
S T U D Y C O N D U C T C O N SI D E R A TI O N S ............................................................. 1 0 6  
1 8. 1.  
P osti n g of I nf or mati o n o n P u blicl y A v aila ble Cli nical Trial Re gisters .................... 1 0 6  
1 8. 2.  
Re g ulat or y a n d Et hical C o nsi derati o ns .................................................................... 1 0 6  
1 8. 2. 1.  
I nstit uti o nal Re vie w B oar d (IR B)/ Et hics C o m mittee ( E C) ..................................... 1 0 6  
1 8. 2. 2.  
I nf or me d C o nse nt Pr ocess ........................................................................................ 1 0 7 
1 8. 3.  
S u bject C o nfi de ntialit y a n d Access t o S o urce D oc u me nts/ Data .............................. 1 0 7  
1 8. 4.  
St u d y M o nit ori n g ...................................................................................................... 1 0 7  
1 8. 5.  
Pr ot oc ol De viati o ns .................................................................................................. 1 0 8  
1 8. 6.  
Pr ot oc ol A me n d me nt ................................................................................................ 1 0 8  
1 8. 7.  
S us pe nsi o n or Ter mi nati o n of St u d y ........................................................................ 1 0 8  
1 9.  
A D MI NI S T R A TI V E P R O C E D U R E S ..................................................................... 1 0 9  
1 9. 1.  
Rec or di n g a n d Access t o St u d y Rec or ds .................................................................. 1 0 9  
1 9. 2.  
Case Re p ort F or ms ................................................................................................... 1 0 9  


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 2 4
1 9. 3.  
Q ualit y Ass ura nce a n d Q ualit y C o ntr ol ( Q C) .......................................................... 1 1 0  
1 9. 4.  
Data Q ualit y Ass ura nce ............................................................................................ 1 1 0  
1 9. 5.  
C o nfi de ntialit y .......................................................................................................... 1 1 0  
1 9. 6.  
A u dit/I ns pecti o n ....................................................................................................... 1 1 0  
1 9. 7.  
Pr o visi o n of St u d y Res ults a n d P u blicati o n .............................................................. 1 1 1  
2 0.  
R E F E R E N C E S ......................................................................................................... 1 1 2  
3. 1. 
List of Fi g ures
Fi g ure 1  
Taze met ostat i n I NI 1 Delete d M R T Xe n o grafts i n S CI D Mice ................................. 3 5  
Fi g ure 2  
St u d y Sc he ma ............................................................................................................. 4 9  
3. 2. 
List of T a bles
Ta ble 1  
S u m mar y of Preli mi nar y Mi daz ola m P har mac o ki netic Para meters After 
A d mi nistrati o n Al o ne ( Da y - 1) or wit h Taze met ostat 8 0 0 m g BI D f or 1 5 
Da ys ( Da y 1 5) i n St u d y E 7 4 3 8- G 0 0 0- 1 0 1 ( n = 1 2) ..................................................... 3 7  
Ta ble 2  
D ose M o dificati o ns f or Treat me nt- Relate d T o xicities ............................................... 6 2  
Ta ble 3  
Sc he d ule of Assess me nts a n d Pr oce d ures .................................................................. 6 8  


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 2 5
4.  
A B B R E VI A TI O N S
A b bre vi ati o n  
Defi niti o n
A D M E
a bs or pti o n, distri b uti o n, meta b olis m, a n d e xcreti o n
A E
a d verse e ve nt
A E SI
a d verse e ve nt of s pecial i nterest
A L T
 ala ni ne
 
a mi n otra nsferase
A M L
ac ute m yel oi d le u ke mia
A N C
a bs ol ute ne utr o p hil c o u nt
A S C O
A merica n S ociet y of Cli nical O nc ol o g y
A S T
as partate a mi n otra nsferase
A T C
 A nat o mical- T hera pe utic- C he mical
A T R T
at y pical terat oi d r ha b d oi d t u m or
A U C
area u n der t he c o nce ntrati o n-ti me c ur ve
- h C G
beta- h u ma n c h ori o nic g o na d otr o pi n
BI D
t wice dail y
B M
b o ne marr o w
Br o o k me yer 
Br o o k me yer- Cr o wle y met h o d
C A P
C olle ge of A merica n Pat h ol o gists
C E C
ce ntral et hics c o m mittee
C F R
C o de of Fe deral Re g ulati o ns
CI
c o nfi de nce i nter val
C L/ F
oral cleara nce
C LI A
Cli nical La b orat or y I m pr o ve me nt A me n d me nts
c m
ce nti meter
C ma x
ma xi m u m plas ma c o nce ntrati o n
C N S
ce ntral ner v o us s yste m
C R
c o m plete res p o nse
C R F
case re p ort f or m
C S R
cli nical st u d y re p ort
C T
c o m p ute d t o m o gra p h y
C T C A E
C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts
C T D
cli nical trial directi ve
C tr o u g h
o bser ve d c o nce ntrati o n at t he e n d of a d osi n g i nter val, i m me diatel y bef ore t he ne xt d ose 
a d mi nistrati o n


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 2 6
A b bre vi ati o n  
Defi niti o n
C Y P
c yt oc hr o me
D C R
disease c o ntr ol rate
D DI
dr u g- dr u g i nteracti o n
De vi ne
De vi ne F or m ula
D L B C L
diff use lar ge B-cell l y m p h o ma
D L T
 d ose-li miti n g
 
t o xicit y
D O R
d urati o n of res p o nse
E C
 et hics
 
c o m mittee
E C G
electr ocar di o gra m
E C H O
ec h ocar di o gra m
E C O G
Easter n C o o perati ve O nc ol o g y Gr o u p
e C R F
electr o nic case re p ort f or m
E D C 
Electr o nic Data Ca pt ure
EI A E D 
e nz y me i n d uci n g a nti-e pile ptic dr u g
E M A
E ur o pea n Me dici nes A ge nc y
E M C 
e xtras keletal m y x oi d c h o n dr osarc o ma
E M P N S T
e pit heli oi d mali g na nt peri p heral ner ve s heat h t u m or
E R
 effl u x
 
rati o
E S
 e pit heli oi d
 
sarc o ma
E U C T Dir 
E ur o pea n U ni o n Cli nical Trial Directi ve
E Z H 2 
e n ha ncer of zeste h o m ol o g ue- 2 
F D G- P E T
Fl u or o de o x y gl uc ose- P ositr o n E missi o n T o m o gra p h y
F F P E
f or mali n fi xe d paraffi n- e m be d de d
FI S H
fl u oresce nce i n sit u h y bri dizati o n
F L
f ollic ular l y m p h o ma
F L AI R
fl ui d-atte n uate d i n versi o n rec o ver y
F TI H
first-ti me-i n- h u ma n
G C P
G o o d Cli nical Practice
G O F
gai n of f u ncti o n
H 3 K 2 7
l ysi ne 2 7 of hist o ne H 3
H 3 K 2 7 me 3  
H 3 K 2 7 tri met h ylati o n
H C V
he patitis C vir us
H E E N T
hea d, e yes, ears, n ose, a n d t hr oat
HI V
h u ma n i m m u n o deficie nc y vir us


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 2 7
A b bre vi ati o n  
Defi niti o n
H M T
hist o ne met h yltra nsferase
H R
heart rate
I B
I n vesti gat or’s Br oc h ure
I B W
i deal b o d y wei g ht
I C5 0
half ma xi mal i n hi bit or y c o nce ntrati o n
I C F
I nf or me d C o nse nt F or m
I C H
i nter nati o nal C o nfere nce o n Har m o nizati o n
I D M C
I n de pe n de nt Data M o nit ori n g C o m mittee
I H C
i m m u n o hist oc he mistr y
I M P
i n vesti gati o nal me dici nal pr o d uct
I NI 1
i nte grase i nteract or 1
I N R
i nter nati o nal n or malize d rati o
I P
I n vesti gati o nal pr o d uct
I R B
I nstit uti o nal Re vie w B oar d
I T T
 i nte nt-t o- Treat
I V
i ntra ve n o us
Ka
first- or der a bs or pti o n rate c o nsta nt
k g
kil o gra m
L
liter
L L N 
l o wer li mit of n or mal
L N
 l y m p h
 
n o de
L S L V 
last s u bject, last visit
m 2
s q uare d meter
M D S
m yel o d ys plastic s y n dr o me
Me d D R A
Me dical Dicti o nar y f or Re g ulat or y Acti vities
m g
milli gra m
m m
milli meter
m L
milliliter
M P N
m yel o pr oliferati ve dis or der
msec
millisec o n d
M RI
ma g netic res o na nce i ma gi n g
m R N A
messe n ger ri b o n ucleic aci d
M R T
mali g na nt r ha b d oi d t u m or
M R T O
mali g na nt r ha b d oi d t u m or of t he o var y


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 2 8
A b bre vi ati o n  
Defi niti o n
M S D S 
Material Safet y Data S heet
M T D
ma xi m u m t olerate d d ose
M U G A
m ulti- gate d ac q uisiti o n sca n
N A
n ot a p plica ble
N E
n ot e val ua ble
N H L
N o n- H o d g ki n’s l y m p h o ma
NI H
Nati o nal I nstit utes of Healt h
N Y H A
Ne w Y or k Heart Ass ociati o n
O R R
o bjecti ve res p o nse rate
O S
o verall s ur vi val
P C H
partial cli nical h ol d
P D
p har mac o d y na mic or pr o gressi ve disease
P D X
patie nt- deri ve d xe n o graft
P E T 
p ositr o n e missi o n t o m o gra p h y
P F S
pr o gressi o n-free s ur vi val
P- g p
P- gl yc o pr otei n
P G x
p har mac o ge netics
P K
p har mac o ki netics
P R
partial res p o nse
P R C 2
p ol yc o m b re pressi ve c o m ple x 2
P T
pr ot hr o m bi n ti me or preferre d ter m
P T T
 Partial
 
t hr o m b o plasti n
 
ti me
Q C
q ualit y c o ntr ol
Q D
o nce dail y
Q Tc F
Q T i nter val c orrecte d b y Fri dericia’s f or m ula
R A N O
Res p o nse Assess me nt i n Ne ur o- O nc ol o g y
R T K
r ha b d oi d t u m or of t he ki d ne y
R E CI S T
Res p o nse E val uati o n Criteria i n S oli d T u m ors
R P 2 D
Rec o m me n de d P hase II d ose
R M C
re nal me d ullar y carci n o ma
R T
ra diati o n t hera p y
S A E
seri o us a d verse e ve nt
S A M
S-a de n os yl met hi o ni ne
S A P
Statistical A nal ysis Pla n


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 2 9
A b bre vi ati o n  
Defi niti o n
S C C O H T
s mall cell carci n o ma of t he o var y, h y percalce mic t y pe
S D
sta ble disease or sta n dar d de viati o n
S E T 
s u n( var) 3- 9, e n ha ncer- of-zeste a n d trit h ora x
SI
I nter nati o nal S yste m of U nits
S M A R C A 4 
S WItc h/ S ucr ose n o n-fer me nta ble relate d, ma tri x ass ociate d, acti n de pe n de nt re g ulat or of 
c hr o mati n, s u bfa mil y a, me m ber 4
S O C
S yste m Or ga n Class
S U S A R
s us pecte d u ne x pecte d seri o us a d verse reacti o n
S WI/ S N F
S WItc h/ S ucr ose N o n- Fer me nta ble
T
te m perat ure
t1/ 2
a p pare nt eli mi nati o n half-life
T- A L L
T-cell ac ute l y m p h o blastic le u ke mia
T E A E 
treat me nt-e mer ge nt a d verse e ve nt
T E S S 
treat me nt-e mer ge nt si g ns a n d s y m pt o ms
T- L B L
T-cell l y m p h o blastic l y m p h o ma
T- L B L/ T- A L L
 T-cell
 
l y m p h o bl astic l y m p h o ma/ T-cell ac ut e l y m p h o blastic le u ke mia
T ma x
Ti me t o ma xi m u m c o nce ntrati o n
T R A E
Treat me nt-relate d a d verse e ve nt
U L N 
u p per li mit of n or mal
U V
ultra vi olet
V d/ F
oral v ol u me of distri b uti o n
W B C
w hite bl o o d cell
W E S
 w h ole-e x o me
 
se q ue nci n g
W H O
W orl d Healt h Or ga nizati o n


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 3 0
5. 
I N T R O D U C TI O N
5. 1. 
B ac k gr o u n d
P ost-tra nslati o nal m o dificati o ns of hist o nes, t he c ore pr otei ns of c hr o ma ti n, pla y a n i m p orta nt 
r ole i n c o ntr olli n g t he fi delit y of cell ular ge ne tra nscri pti o n patter ns. O ne of t he critical 
tra nscri pti o n-c o ntr olli n g hist o ne m o dificati o ns is met h ylati o n of s pecific l ysi ne a n d ar gi ni ne 
resi d ues, catal yze d b y hist o ne met h yl tra nsferases ( H M Ts)  w hic h all use S-a de n os yl met hi o ni ne 
( S A M) as a c o-fact or f or t he met h ylati o n reacti o n (C o pela n d, 2 0 1 3 ). Ge netic alterati o ns i n a 
n u m ber of H M Ts or ass ociate d re g ulat or y pr otei ns ha ve bee n i de ntifie d i n se veral h u ma n ca ncers 
w here t he y are p ur p orte d t o be o nc o ge nic. E n ha ncer of Zeste h o m ol o g ue 2 ( E Z H 2) is t he 
catal ytic s u b u nit of t he m ulti- pr otei n p ol yc o m b re pressi ve c o m p le x 2 ( P R C 2) t hat catal yzes t he 
m o n o-, di-, a n d tri met h ylati o n of l y si ne 2 7 of hist o ne H 3 ( H 3 K 2 7) (Mar g uer o n, 2 0 1 1 ).
E Z H 2 m utati o n a n d/ or o ver-e x pressi o n has bee n o b ser ve d i n se veral ca ncer t y pes, lea di n g t o a n 
a berra nt H 3 K 2 7 tri met h ylati o n ( H 3 K 2 7 me 3) state w hic h is o nc o ge nic (B ur k har dt, 2 0 0 9 ). F or 
i nsta nce, s o matic E Z H 2 gai n of f u ncti o n ( G O F) m utati o ns at t hree h ots p ots ( Y 6 4 6, A 6 8 2, a n d 
A 6 9 2 [ N M _ 0 0 1 2 0 3 2 4 7]) are f o u n d i n 1 0 % t o 2 0 % of f o llic ular l y m p h o ma ( F L) a n d diff use lar ge 
B-cell l y m p h o ma ( D L B C L). T hese G O F m utati o ns res ult i n a n o nc o ge nic de pe n de nc y o n E Z H 2 
pr o d ucti o n of a b n or mall y hi g h H 3 K 2 7 me 3 le vels, a n d res ulta nt tra nscri pti o nal re pr o gra m mi n g of 
t he cell (M ori n, 2 0 1 0 ).  
C o nse q ue ntl y, i n hi biti o n of E Z H 2 lea ds t o re d u cti o n i n H 3 K 2 7 me 3 a n d cell deat h i n l y m p h o ma 
cell li nes beari n g t he m utati o n. W h ile l y m p h o ma cells wit h wil d-ty pe E Z H 2 are gr o wt h i n hi bite d 
b y E Z H 2 i n hi biti o n, o nl y E Z H 2 G O F m utati o n- bea ri n g cells u n der g o cell deat h i n c ult ure 
(Be g ueli n, 2 0 1 3;  K n uts o n, 2 0 1 4 ).  
W hile u nc o m m o n, ot her s oli d t u m o rs are k n o w n t o har b or E Z H 2 G O F m utati o ns w hic h i ncl u de 
E wi n g’s sarc o ma ( 2. 7 %) a n d mela n o ma ( < 2 %) (Tir o de, 2 0 1 4; Zi n g g, 2 0 1 5 ).  O vere x pressi o n of 
E Z H 2 wit h a G O F m utati o n i n mela n oc ytes i n d u ces hi g h- pe netra nce mela n o ma i n c o o perati o n 
wit h Braf, c o nfir mi n g t he o nc o ge nic r ole of a b erra nt H 3 K 2 7 tri met h ylati o n i n t his i n dicati o n 
(S o ur o ullas, 2 0 1 6 ). E Z H 2 i nacti vati o n or res ulte d i n a re d ucti o n i n eit her mela n o ma gr o wt h or 
metastasis i n vi v o, s u g gesti n g t hat E Z H 2 i n hi bi ti o n ma y be a pr o misi n g treat me nt para di g m i n 
t he ma na ge me nt of a d va nce d mela n o ma (Zi n g g, 2 0 1 5; S o ur o ullas, 2 0 1 6 ).
I n a d diti o n t o ge netic alterati o ns i n E Z H 2 itself, ge netic c ha n ges i n ot her pr otei ns ca n lea d t o a n 
o nc o ge nic de pe n de nc y o n E Z H 2 acti vit y, s pecifi call y t h ose affecti n g pr otei ns of t he 
S WItc h/ S ucr ose N o n- Fer me nta ble ( S WI/ S N F) c hr o mati n re m o deli n g c o m ple x. At ma n y ge ne 
l oci, P R C 2 a n d S WI/ S N F a nta g o nize eac h ot her a n d l oss of t he S WI/ S N F c o m p o ne nt, i nte grase 
i nteract or 1 (I NI 1), has bee n de m o nstrate d t o generate o ver-acti vati o n of t he P R C 2 pat h wa y a n d 
t u m or cell pr oliferati o n (Wils o n, 2 0 1 0 ). Ge netic l oss of I NI 1 has bee n descri be d i n ma n y h u ma n 
mali g na ncies, e. g., r ha b d oi d t u m o rs, e pit heli oi d sarc o ma ( E S), e pit heli oi d mali g na nt peri p heral 
ner ve s heat h t u m or ( E M P N S T), e xtras keletal m y x oi d c h o n dr osarc o ma ( E M C), m y oe pit helial 
carci n o ma, p o orl y differe ntiate d c h or d o ma, a n d re nal me d ullar y carci n o ma ( R M C) (Mar g ol, 
2 0 1 4 ; M o ble y, 2 0 1 0 ). I n hi biti o n of E Z H 2 acti vit y b y eit her k n oc k- d o w n or s mall m olec ule 
i n hi biti o n i n d uces t u m or cell killi n g a n d d ura ble t u m or re gressi o ns i n n o ncli nical m o dels of 


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 3 1
r ha b d oi d t u m ors (Ali m o va, 2 0 1 3;  K n uts o n, 2 0 1 3 ). T h us, E Z H 2 i n hi biti o n re prese nts a via ble 
p ote ntial t hera pe utic strate g y f or ge neticall y defi ne d I NI 1- ne gati ve t u m ors.
Mali g na nt r ha b d oi d t u m ors ( M R Ts) arise i n t he brai n, ki d ne y, a n d ot her s oft tiss ues. T he 
pat h o g n o m o nic ge netic alterati o n c o nsists of bi -allelic i nacti vati o n of I NI 1, w hic h ca n be 
detecte d, i n nearl y all s uc h t u m ors. T he t u m or s u p press or r ole of I NI 1 has bee n c o nfir me d i n 
m uri ne st u dies. Mice lac ki n g o ne c o p y of I NI 1 de vel o p t u m ors c o nsiste nt wit h M R T as earl y as 
5 wee ks of a ge (R o berts, 2 0 0 0 ). Bi-allelic c o n diti o nal i nacti vati o n of I NI 1 i n t he T-cell li nea ge 
lea ds t o f ull y pe netra nt ca ncer f or matio n wit h a me dia n o n set of 1 1 wee ks (Wils o n, 2 0 1 0 ). I n 
h u ma ns, r ha b d oi d t u m ors i n c hil dre n ha ve bee n c haracterize d b y bi-allelic l oss of I NI 1 i n u p t o 
9 8 % of t u m ors a n d ofte n prese nt i n i nfa nc y (Jac ks o n, 2 0 0 9). T hese t u m ors are dia g n ose d i n 
c hil dre n e ve n at birt h, ha ve ra pi d o nset, are hi g hl y resista nt t o a ll treat me nt a n d are c haracterize d 
b y a berra nt c hr o mati n re m o deli n g a n d ass oci ate d de pe n de nc y o n E Z H 2, hi g hli g hti n g t he 
a nta g o nistic relati o ns hi p of P R C 2 a n d S WI/ S N F. I n a d diti o n, o ver-e x pressi o n of E Z H 2 has bee n 
re p orte d i n at y pical terat oi d r ha b d oi d t u m or ( A T R T) (ce ntral ner v o us s yste m [ C N S] f or m of 
M R T) patie nt sa m ples, a n d E Z H 2 i nacti vati o n b y eit her ri b o n ucleic aci d ( R N A) i n hi bit or or 
c he mical i n hi biti o n lea ds t o a p o pt osis a n d i ncrease d se nsiti vit y t o ra diati o n (Ali m o va, 2 0 1 3 ). 
Taze met ostat i n d uces a p o pt osis a n d differe ntia ti o n of I NI 1- ne gati ve M R T cells i n vitr o. 
Taze met ostat d osi n g of M R T xe n o graft beari n g mice i n d uces d ura ble t u m or re gressi o ns a n d 
t u m ors di d n ot re- gr o w after cessati o n of d osi n g (K n uts o n, 2 0 1 3 ).  
A n ot her rare t u m or, s mall cell carci n o ma of t he o var y, h y percal ce mic t y pe ( S C C O H T) has bee n 
descri be d t o ha ve i nacti vati n g m utati o ns i n t he c hr o mati n re m o deli n g ge ne S M A R C A 4 wit h l oss 
of S M A R C A 4 pr otei n, a n i m p orta nt c o m p o ne nt of t he S WI/ S N F c hr o mati n re m o deli n g c o m ple x 
(Jeli nic, 2 0 1 4; Ra m os, 2 0 1 4;  Wit k o ws ki, 2 0 1 4). Rece ntl y t he m or p h ol o gic si milarit y of 
S C C O H T t o M R T a n d A T R T has bee n descri be d (F o ul kes, 2 0 1 4 ). T he y descri be i n a maj orit y of 
t u m ors se q ue nce d wit h w h ole-e x o me se q ue nci n g ( W E S) a n d Sa n ger se q ue nci n g, deleteri o us 
m utati o ns i n S M A R C A 4.  F o ul kes n otes t hat virt uall y all M R Ts a n d A T R Ts ha ve m utati o ns i n 
t his ge ne as well as t he S M A R C B 1  ge ne a n d are m or p h ol o gicall y a n d m olec ularl y si milar t o 
r ha b d oi d t u m ors, t h us pr o p oses reclassif yi n g S C C O H T as a mali g nant r ha b d oi d t u m or of t he 
o var y ( M R T O).  
S M A R C A 4 l oss has als o bee n descri be d i n a s u b set of u n differe ntiate d t h oracic sarc o mas. T hese 
t u m ors w he n ge neticall y c haracterize d are relate d t o M R T a n d S C C O H T wit h T P 5 3 m utati o ns 
a n d S M A R C A 4 i nacti vati o n bei n g t he s ole rec urre nt alterati o ns. T he 1 9 cases e val uate d ha d 
c o nsiste nt pat h ol o gical feat ures t hat were r ha b d oi d i n m or p h ol o g y a n d h o m o ge ne o us i n 
prese nti n g cli nical feat ures (Le L oarer, 2 0 1 5 ).
S y n o vial sarc o ma is a hi g hl y a g gressi ve s oft tiss ue sarc o ma of c hil d h o o d a n d y o u n g a d ults, 
re prese nti n g 1 0 % of s oft tiss ue sarc o mas i n all a ge gr o u ps a n d 1 5- 2 0 % of y o u n g a d ult sarc o mas. 
I n t he metastatic setti n g res p o nses t o c he m othera p y are tra nsie nt a n d t his mali g na nc y is 
u ni versall y fatal. T he mec ha nis m of I NI 1 deficie nc y i n s y n o vial sar c o mas is disti nct c o m pare d t o 
M R T. T u m ors har b or c haracteristic tra nsl ocat i o ns of c hr o m os o me X a n d 1 8, res ulti n g i n t he 
f usi o n ge nes ( S S 1 8- S S X 1, 2, a n d 4). T he res ulti n g f usi o n pr otei ns i nte grate i nt o t he S WI/ S N F 
c o m ple x e victi n g wil d-t y pe S S 1 8 a n d I NI 1 lea d i n g t o pr ote ol ytic de gra dati o n of I NI 1 (Ka d oc h, 
2 0 1 3 ). T his creates a state of I NI deficie nc y wit h o ut a m utati o n or deleti o n of I NI 1 itself, a n d 
res ults i n a berra nt S WI/ S N F c o m ple x c hr o mati n rem o deli n g acti vit y at vari o us ge nes. It als o has 
bee n re p orte d t hat t he S S 1 8- S S X f u si o n pr otei ns recr uit re pressive c o m ple xes s uc h as P R C 2 t o 


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 3 2
A T F 2 tar get ge ne l oci, a b n or mall y re pressi n g t he m (S o ur o ullas, 2 0 1 6 ). E Z H 2 i n hi biti o n is 
h y p ot hesize d t o release t his a ber ra nt re pressi o n, lea di n g t o a nti- pr oliferati ve effects.  
5. 2.  
Cli nic al C h ar acterist ics of T ar gete d T u m ors 
M R Ts a n d t heir C N S c o u nter part, A T R T, are rare, ha ve hist oricall y p o or o verall s ur vi val ( O S) 
a n d i n c hil dre n a n d a d ults ha ve n o esta blis he d sta n dar d treat me nt a p pr oac hes (M o ble y, 2 0 1 0;
M or ge nster n, 2 0 1 0; S ulta n, 2 0 1 0 ). T he hist orical 5- year O S i n c hil dre n is esti mate d t o be 1 7-
3 3 % (Gi n n, 2 0 1 2 ). T he me dia n a ge at dia g n osis is 6 years; h o we ver, patie nts are dia g n ose d well 
i nt o a d ult h o o d. T he cli nical c o urse of t he disease is c haracterize d b y fre q ue nt a n d late l ocal or 
metastatic rec urre nce, res u lti n g i n p o or l o n g-ter m pr o g n osis. T h o u g h c urre nt treat me nt at 
prese ntati o n f or M R T c o nsists of atte m pte d s ur gical resecti o n, f oll o we d b y i nte nsi ve 
c he m ot hera p y a n d ra di ot hera p y (C hi, 2 0 0 9 ), at t he rece nt R ha b d oi d T u m or S y m p osi u m i n 2 0 1 4, 
t he a ut h ors c o ncl u de d “c urre ntl y, n o sta n dar d a p pr oac hes are a vaila ble f or t he treat me nt of 
r ha b d oi d t u m ors, re gar dless of t u m or l ocati o n” (B o ur dea ut, 2 0 1 4 ). At ti me of rec urre nce, 
treat me nt is base d u p o n a nec d otal re p orts of res p o nse t o c he m ot hera p y (C hi, 2 0 0 9;  We n, 2 0 1 0 ). 
M R T O is a hi g hl y a g gressi ve a n d let hal f or m of o varia n ca ncer prese nti n g i n y o u n g w o me n wit h 
a mea n a ge at dia g n osis of 2 4 years. F or b ot h patie nts wit h l ocal a n d a d va nce d disease, t he 
pr o g n osis is p o or. I n t he s mall n u m ber of case re vie w re p orts, a d va nce d t u m ors a n d l ocal disease 
ha ve a 6. 5 % a n d 3 0- 4 0 % s ur vi val res pecti vel y (Y o u n g, 1 9 9 4; Ree d, 2 0 1 4 ). T he c urre nt sta n dar d 
of care is u ncertai n d ue t o a lac k of pr os pecti v e st u dies gi ve n t he rarit y of t he disease. S ur ger y 
a n d m ulti-a ge nt plati n u m base d c he m ot hera p y, of te n wit h t he a d diti o n of ra di ot hera p y, is 
t y picall y utilize d (Harris o n, 2 0 0 6 ). Des pite a n a g gressi ve a p proac h, m ost w o me n will ha ve 
rec urre nce of disease d uri n g or s h ortl y after c o m pleti n g a dj u va nt c he m ot hera p y a n d 6 5 % will die 
fr o m t heir disease wit hi n t wo years of dia g n osis (Erric o, 2 0 1 4 ). U n differe ntiate d t h oracic 
sarc o mas wit h S M A R C A 4 a d diti o nall y ha ve a hi g hl y a g gressi ve cli nical prese ntati o n wit h lar ge 
masses at ti me of prese nt ati o n, y o u n g a ge of o nset ( me dia n 4 1 years) wit h li mite d res p o nse t o 
t hera p y a n d me dia n O S of se ve n m o nt hs (Le L oarer, 2 0 1 5 ).  
Ot her t u m ors wit h I NI 1 deficie nc y i ncl u de E S, E M P N S T, E M C, m y oe pit helial carci n o mas, 
p o orl y differe ntiate d c h or d o mas, a n d R M C. C urr e nt sta n dar d of care f or t hese ot her I NI 1-
ne gati ve t u m ors has n ot bee n well esta blis he d d ue t o t heir rarit y. T he i nci de nce of I NI 1- ne gati vit y 
i n patie nts wit h E S was rece ntl y re p orte d t o be 9 0 % wit h h o m oz y g o us deleti o n of t he I NI 1 ge ne 
f o u n d i n 8 3 % of t hese patie nts (S ulli va n, 2 0 1 3 ). E S is a rare s oft tiss ue sarc o ma ofte n f o u n d i n 
y o u n g a d ults a n d acc o u nts f or < 1 % of all s oft tiss ue sarc o mas (J o nes, 2 0 1 2). L ocal rec urre nce 
ofte n re q uires ra dical e xcisi o ns a n d a m p utati o ns wit h l ocal ra diati o n as t he t u m or has a 
pre dilecti o n f or e xtre mities wit h n o dal metastasis (C h ba ni, 2 0 0 9 ). At ti me of rec urre nce t here is 
n o sta n dar d of care. Li kel y, beca use of t he rarit y of t he disease, n o p u blis he d pr os pecti ve st u dies 
of patie nts wit h t his hist ol o gic s u bt y pe ha ve bee n i de ntifie d. Retr os pecti ve i nstit uti o nal 
e x perie nces ha ve bee n re p orte d. I n o ne s uc h re vie w, t he i nstit uti o nal e x perie nce of 2 1 patie nts 
wit h E S treate d wit h c he m ot hera p y fr o m 1 9 9 0 t o 2 0 0 9 was prese nte d. T he me dia n P F S was 
deter mi ne d t o be 2 9  wee ks, wit h me dia n o verall s ur vi val of 5 1 wee ks. T hree of t he patie nts 
ac hie ve d a partial res p o nse, all of w h o m were treate d i n t he first li ne setti n g; 1 2 ha d sta ble disease 
as best res p o nse; a n d 5 pr o gresse d. It s h o ul d be e m p hasize d t hat t his re vie w descri be d patie nts 
recei vi n g first ( N = 2 0), sec o n d ( N = 7) or t hir d ( N = 3) li ne c he m ot hera p y; h o we ver, t he maj orit y 
were treate d i n t he fr o ntli ne setti n g (J o nes, 2 0 1 2). A n ot her si milar st u d y re p orte d o n 2 8 patie nts 


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 3 3
wit h E S at o ne i nstit uti o n bet wee n 1 9 8 9 a n d 2 0 1 2, 1 2 of w h o m recei ve d treat me nt wit h 
ge mcita bi ne a n d d oceta xel. Me dia n P F S was 8 m o nt hs o verall, a n d 9 m o nt hs i n t h ose recei vi n g 
t his re gi me n as first-li ne treat me nt (Pi n k, 2 0 1 4 ).
C h or d o ma is a rare, sl o w gr o wi n g sarc o ma of t he s k ull base a n d s pi ne t hat is t y picall y b ul k y a n d 
a d va nce d at t he ti me of dia g n osis. C h or d o mas pre d o mi na ntl y occ ur i n a d ults wit h rela pse 
occ urri n g i n > 5 0 % of cases res ulti n g i n deat h fr o m l ocal a n d me tastatic disease (M o ble y, 2 0 1 0;
Stacc hi otti, 2 0 1 3 ). T he c urre nt sta n dar d of care c o nti n ues t o be s ur ger y f oll o we d b y 
ra di ot hera p y, w hile s yste mic c he m ot hera p y is ge nerall y re gar de d as i neffecti ve i n a d va nce d 
c h or d o ma (Le bellec, 2 0 1 5 ). Alt h o u g h, pri or t o metastasis, c h ord o ma is belie ve d t o be a n i n d ole nt 
disease, a s u bset of c h or d o mas referr e d t o as p o orl y differe ntiate d ar e cli nicall y m ore a g gressi ve. 
T his cli nicall y a g gressi ve s u bset of c h or d o mas h as bee n s h o w n t o ha ve a c haracteristic l oss of 
I NI 1 (Hassel blatt, 2 0 1 6 ). P hase 2 pr os pecti ve st u dies de dicate d t o c h or d o ma ha ve bee n 
c o m plete d l o o ki n g at si n gle a ge n t acti vit y of la pati ni b, i mati ni b, a n d s orafe ni b wit h best 
o bjecti ve res p o nse rates ( O R R) re p orte d as 0, 1. 7, a n d 3. 7 % wit h a P F S of 8. 2, 9, a n d u p t o 1 5 
m o nt hs, res pecti vel y (B o m pas, 2 0 1 5 ). 
E M P N S T is a n ot her rare s oft tiss ue sarc o ma t hat is  treate d wit h s ur ger y at ti me of dia g n osis a n d 
de m o nstrates varia ble re s p o nse t o c he m ot hera p y (Mi na ga wa, 2 0 1 1 ). A gai n, d ue t o t he rarit y a n d 
a g gressi ve nat ure of t he t u m ors at ti me of re c urre nce, t here are o nl y a n ec d otal re p orts of l o n g-
ter m treat me nt s uccess. E M C is an ot her s oft tiss ue sarc o ma of i n ter me diate mali g na nt p ote ntial 
a n d case re p orts disc uss treat me nt wit h wi de l ocal resecti o n (Ka wa g uc hi, 2 0 0 3 ). M y oe pit helial 
carci n o ma is yet a n ot her s oft tiss ue t u m or wit h a n  a g gressi ve c o urse wit h me dia n s ur vi val of 9 
m o nt hs (Ma h di, 2 0 1 4; Le L oarer, 2 0 1 5 ). Fi nall y, R M C is a hi g hl y a g gressi ve t u m or t hat ofte n 
affects y o u n ger patie nts wit h sic kle cell trait or disease a n d fatalit y a p pr oac hes 1 0 0 % wit hi n 
se veral wee ks t o m o nt hs of dia g n osis ( C he n g, 2 0 0 8). T hese t u m ors are ver y rare a n d t here are n o 
re p orte d c o ntr olle d cli nical trials s pecific t o t hese I NI 1- ne gati ve p o p ulati o ns.  
Treat me nt of s y n o vial sarc o ma i n v ol ves s ur gical  e xcisi o n of pri mar y an d metastatic t u m ors, 
irra diati o n, a n d a dj u va nt c he mot hera p y wit h if osfa mi de, d o x o r u bici n, a n d cis plati n- base d 
re gi me ns, alt h o u g h cli nical data o n t he be nefit of c he m ot hera p y i n t he a dj u va nt setti n g are 
c o nflicti n g (Fis her, 1 9 9 8;  G ua da g n ol o, 2 0 0 7; Erric o, 2 0 1 4 ). At ti me of rec urre nce, c o m bi nati o ns 
wit h ge mcita bi ne a n d d oceta xel, tra becte di n or  paz o pa ni b are use d wit h 4 0 % pr o gressi o n-free 
s ur vi val ( P F S) at 3 m o nt hs (Sleijfer, 2 0 0 9; va n der Graaf, 2 0 1 2 ). A d diti o nal t hera pe utic o pti o ns 
f or s u bjects wit h t hese selecte d a d va nce d t u m ors are nee de d. 
5. 3.  
R ati o n ale f or T aze met ost at Tre at me nt 
I n I NI 1- deficie nt t u m ors, E Z H 2 acti vit y is dere g ulate d, i n d uci n g a berra nt o nc o ge nic ge ne 
e x pressi o n (Wils o n, 2 0 1 0;  Ali m o va, 2 0 1 3 ). Taze met ostat has bee n s h o w n t o i n d uce a p o pt osis 
a n d differe ntiati o n i n I NI 1 - ne gati ve M R T cell li nes (K n uts o n, 2 0 1 3 ). I n xe n o graft beari n g mice, 
treat me nt wit h taze met ostat res ulte d i n d ose-de pe n de nt re gressi o n of M R Ts wit h c orrelate d 
di mi n uti o n of i ntra-t u m oral H 3 K 2 7 met h ylati o n a n d pre ve nti o n of t u m or re gr o wt h after d osi n g 
cessati o n. Data fr o m t he o n g oi n g P hase I st u d y E 7 4 3 8- G 0 0 0- 1 0 1 de m o nstrates earl y b ut 
c o m pelli n g cli nical acti vit y i n s u bj ects wit h I NI 1- ne gati ve t u m ors ( u n p u blis he d data). T o date, of 
t he 6 treate d s u bjects wit h I NI 1- ne gati ve t u m ors ( M R T a n d E S), t here ha ve bee n 3 s u bjects wit h 
o bjecti ve res p o nses ( 1 c o m plete res p o nse [ C R] a n d 2 partial res p o nses [ P Rs]). Wit h o ne M R T 
s u bject wit h pat h ol o gicall y c o nfir me d c o m plete re missi o n c o nti n ui n g o n treat me nt t hr o u g h Wee k 


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 3 4
4 4 o n st u d y a n d 2 s u bjects wit h E S re mai ni n g o n st u d y. A n a d diti o nal s u bject wit h M R T has 
sta ble disease ( S D) b y Res p o nse E val uati o n Criteria i n S oli d T u m ors ( R E CI S T) 1. 1, a n d 
e x hi bite d a 1 5 % t u m or re d ucti o n after 8 wee ks of  treat me nt. Of t w o treate d s u bjects wit h 
M R T O, o ne ha d a c o nfir me d P R at Wee k 8 a n d re mai ns o n st u d y f or 2 5 wee ks a n d o ne ha d S D 
a n d re mai ns o n st u d y f or 2 5 wee ks. Of t he 3 s u bjects  wit h s y n o vial sarc o ma treate d t h us far t here 
ha ve bee n n o res p o nses o bser ve d. All 3 s u bjects  wit h a d va nce d s y n o vial sarc o ma e x perie nce d 
pr o gressi ve disease, alt h o u g h o nl y o ne was treate d at t he re c o m me n de d P hase II d ose ( R P 2 D) 
( u n p u blis he d data).  
5. 4. 
T aze met ost at
5. 4. 1. 
I n vesti g ati o n al Pr o d uct 
I n J u ne 2 0 2 0, t he U S F o o d a n d Dr u g A d mi nistrati o n ( F D A) gra nte d accelerate d a p pr o val of 
Taz veri k ® (taze met ostat) i n t he U S f or t he treat me nt  of a d ult patie nts wit h rela pse d or refract or y 
( R/ R) f ollic ular l y m p h o ma ( F L) w h ose t u m ors are p ositi ve f or a n E Z H 2 m utati o n as detecte d b y 
a n F D A-a p pr o ve d test a n d w h o ha ve recei ve d at least 2 pri or s yste mic t hera pies, a n d f or t he 
treat me nt of a d ult patie nts wit h R/ R F L w h o ha ve n o satisfact or y alter nati ve treat me nt o pti o ns. 
I n Ja n uar y 2 0 2 0, t he U S F D A gra nte d accelerate d ap pr o val t o Taz veri k f or a d ults a n d pe diatric 
patie nts a ge d 1 6 years a n d ol der wit h metastatic  or l ocall y a d va nce d e pit heli oi d sarc o ma n ot 
eli gi ble f or c o m p lete resecti o n. 
I n J u ne 2 0 2 1, Ja pa n’s P har mace uticals a n d Me dical De vices A ge nc y ( P M D A) gra nte d a p pr o val 
of Taz veri k f or t he treat me nt of patie nts wit h rela pse d or  refract or y E Z H 2 ge ne m utati o n-
p ositi ve f ollic ular l y m p h o ma (li mite d t o use w he n diffic ult t o treat wit h sta n dar d treat me nts) t o 
E piz y me’s de vel o p me nt pa rt ner, Eisai C o., Li mite d. 
5. 4. 2.  
N o ncli nic al P h ar m ac ol o g y
Taze met ostat ( E P Z- 6 4 3 8) is a selecti ve s mall m olec ule i n hi bit or of t he hist o ne-l ysi ne
met h yltra nsferase E Z H 2  ge ne (K n uts o n, 2 0 1 3 ). Taze met ostat i n hi bits b ot h wil d-t y pe E Z H 2  a n d 
m utate d E Z H 2  resi d ues Y 6 4 1, A 6 7 7 G a n d A 6 8 7 wit h half ma xi mal i n hi bit or y c o nce ntrati o ns 
(I C5 0 ) ra n gi n g fr o m 2- 3 8 n m ol/ L. T he c o m p o u n d sh o ws a 3 5-f ol d selecti v it y o ver t he m ost 
cl osel y relate d H M T, E Z H 1 a n d greater t ha n a 4 5 0 0-f ol d selecti vit y o ver ot her H M Ts. It 
selecti vel y i n hi bits i ntracell ular H 3 K 2 7 met h ylati o n i n a c o nce ntrati o n- a n d ti me- de pe n de nt 
ma n ner, lea di n g t o selecti ve cell killi n g of cell li nes. Taze met ostat s pecificall y i n hi bits h u ma n 
l y m p h o ma cell li nes beari n g E Z H 2 p oi nt m utati o ns a n d I NI 1 u nit deficie nt (als o k n o w n as 
S N F 5, S M A R C B 1, or B A F T 4 7)  M R T cell li nes wit h I C5 0  i n t he na n o m olar ra n ge. A d diti o nall y, 
taze met ostat a d mi nistere d orall y has de m o nstrate d a ntit u m or acti vit y i n vi v o a gai nst se veral 
E Z H 2 m uta nt h u ma n l y m p h o ma xe n o graft m uri ne m o dels (K n uts o n, 2 0 1 4 ). I NI 1 m uta nt M R T 
xe n o grafts treate d f or 2 1- 2 8 da ys de m o nstrate d near eli m i nati o n of t he t u m ors wit h n o re gr o wt h 
o bser ve d. T he M R T t u m ors de m o nstrate d str o n g i n hi biti o n of H 3 K 2 7 me 3, w hic h c orrelate d wit h 
a ntit u m or acti vit y (Fi g ure 1 ) (K n uts o n, 2 0 1 3 ).


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 3 5
Fi g ure 1  
T aze met ost at i n I NI 1 Dele te d M R T Xe n o gr afts i n S CI D Mice
A b bre viati o ns  BI D  t wice dail y, D O C K  de dicat or of c yt o ki nesis, E P Z- 6 4 3 8  taze met ostat, G LI gli o ma-
ass ociate d o nc o ge ne, P T P R K  pr otei n t yr osi ne p h os p hatase rece pt or t y pe, k.
A) T u m or re gressi o ns wit h BI D a d mi nistrati o n f or 2 8 da ys; 
B) E Z H 2 tar get i n hi biti o n f o r mice e ut ha nize d at Da y 2 1; 
C) C ha n ge i n ge ne e x pressi o n i n G 4 0 1 mice f or mice treate d f or 2 1 da ys.
Taze met ostat has s h o w n e n ha nce d a ntit u m or acti v it y w he n a d mi nistere d i n c o m bi nati o n wit h 
c he m ot hera p y re gi me ns use d f or t he treat me nt  of N H L a n d sarc o mas, wit h or wit h o ut 
d o x or u bici n, i n a ni mal m o dels. Fi nall y, a d mi nistrati o n of taze met ostat le d t o d ose- a n d ti me-
de pe n de nt decreases i n i ntracell ular H 3 K 2 7 met h yl ati o n i n b ot h t u m or a n d selecte d n o n-t u m or 
tiss ues.
Preli mi nar y data wit h taze met ostat i n 2 D m o del i n vitr o pr oliferati o n assa ys has de m o nstrate d 
t hat all s y n o vial sarc o ma cell li nes teste d ( b ot h S S 1 8- S S X 1 a n d S S 1 8- S S X 2 f usi o n p ositi ve) are 
se nsiti ve t o E Z H 2 i n hi biti o n. I n vi v o, d ose- de pe n de nt t u m or gro wt h i n hi biti o n was o bser ve d 
wit h taze met ostat treat me nt i n t w o patie nt- de ri ve d xe n o graft ( P D X) m o dels, b ot h har b ori n g t he 
S S 1 8- S S X 2 f usi o n, a n d a cell li ne xe n o graft m o del usi n g t he F uji s y n o vial sarc o ma cell li ne, 
w hic h als o c o ntai ns t he S S 1 8- S S X 2 f usi o n. 
L oss of t he S WI/ S N F c o m p o ne nt S M A R C A 4 has bee n  descri be d t o be s pecific t o S C C O H T. A 
pa nel of o varia n ca ncer cell li nes of differe nt hist ol o gies wit h a n d wit h o ut S M A R C A 4 l oss was 
scree ne d usi n g a n E Z H 2 i n hi bit or i n 2 D tiss ue c ult ure proliferati o n assa ys f or 1 4 da ys. 
S M A R C A 4- ne gati ve ( S C C O H T) cell li nes were i de ntifi e d t o be t he m ost se nsiti ve i n res p o nse t o 


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 3 6
E Z H 2 i n hi biti o n, as de m o nstrate d b y decrease d pr oliferati o n a n d/ or m or p h ol o g y c ha n ges, at 
c o nce ntrati o ns t hat are cli nicall y ac hi e va ble [ E piz y me i nter nal c o m m u nicati o n].
5. 4. 3. 
P h ar m ac o ki netics ( P K)
T he P K of taze met ostat a n d deset h yl meta b olite, E R- 8 9 7 3 8 7, ha ve bee n c haracterize d f oll o wi n g 
si n gle ( Da y 1) a n d m ulti ple ( Da y 1 5) a d mi nistrati o n t o s u bjects w it h a d va nce d s oli d t u m ors or 
B-cell l y m p h o ma ( n = 3 6). D oses a d mi nistere d were  1 0 0 m g t wice dail y ( BI D) as a s us pe nsi o n 
( n = 3) or ta blet ( n = 3) f or mulati o n a n d 2 0 0, 4 0 0, 8 0 0, a n d 1 6 0 0 m g BI D as a ta blet f or m ulati o n. 
Taze met ostat was ra pi dl y a bs or be d wit h a t i me t o t he ma xi m u m plas ma c o nce ntrati o n (tma x ) of 
a p pr o xi matel y 1- 2 h o urs p ost- d ose. Plas ma c o nc e ntrati o ns decli ne d i n a m o n o-e x p o ne ntial 
ma n ner wit h a mea n t
1/ 2  of a p pr o xi matel y 3- 5 h o urs, a n d q uantifia ble plas ma c o nce ntrati o ns of 
b ot h taze met ostat a n d its meta b olite, E R- 8 9 7 3 8 7 were meas ura ble u p t o 1 2 h o urs p ost- d ose. T he 
taze met ostat ma xi m u m plas ma c o nce ntrati o n ( Cma x ) a n d area u n der t he c o nce ntrati o n-ti me c ur ve 
( A U C) i ncrease d i n a greater t ha n d ose- pr o p orti o nal fas hi o n after a si n gle d ose a n d i n a n 
a p pr o xi matel y a d ose- pr o p orti o nal fas hi o n at stea d y-state. After m ulti ple d osi n g, t here was a 
d ose- de pe n de nt decrease i n taze met ostat e x p os ure bet wee n Da ys 1 a n d 1 5. T he acc u m ulati o n 
rati o ( Rac = A U C D 1 5 / A U CD 1 ) at t he R P 2 D of 8 0 0 m g BI D was 0. 5 8. H o we ver, dr u g e x p os ure at 
stea d y-state di d n ot c ha n ge be y o n d Da y 1 5 as e vi de nce d b y t he C tr o u g h le vels fr o m Da ys 1 5 t o 2 9. 
T here was ne gli gi ble c ha n ge i n t ma x  or t1/ 2 o n m ulti ple d osi n g acr oss t he d ose ra n ge. Preli mi nar y 
res ults i n dicate t hat < 5 % of t he a d mi nistere d d ose was e xcrete d i n uri ne as u nc ha n ge d 
taze met ostat. T he tma x of taze met ostat was o bser ve d at 1- 2 h o urs p ost- d ose a n d its eli mi nati o n 
parallele d t hat of taze met ostat (t 1/ 2 = 3- 5 h o urs). Meta b olite pr ofi li n g a n d i de ntificati o n st u dies 
are pla n ne d t o assess taze met o stat meta b olis m i n h u ma ns.
T he effect of f o o d o n t he P K of taze met ostat wa s e val uate d i n s u bjects wit h a d va nce d s oli d 
t u m ors or B -cell l y m p h o ma ( n = 1 2) as part of st u d y E 7 4 3 8- G 0 0 0-1 0 1. A d mi nistrati o n of 
taze met ostat wit h a hi g h-fat meal decrease d geo metric mea n area u n der t he c o nce ntrati o n-ti me 
c ur ve fr o m zer o e xtra p olate d t o i nfi nit y ( A U C 0- ) a n d Cma x  val ues a p pr o xi matel y 6 % a n d 2 8 %, 
res pecti vel y, relati ve t o a d mi nistrati o n i n t he faste d state. H o we ver, f or b ot h Cma x a n d A U C 0- ,
all val ues o bser ve d after a d mi nistrati o n of taze me t ostat f oll o wi n g a hi g h-fat meal were wit hi n 
t he ra n ge of val ues o bser ve d after a d mi nistratio n i n t he faste d stat e. A d mi nistrati o n of 
taze met ostat wit h a hi g h-fat meal als o res ulte d i n a 4-f ol d i ncrease i n me dia n tma x relati ve t o 
a d mi nistrati o n i n t he faste d state. T he relati o ns hi p bet wee n taze met ostat A U C o n Da y 1 5 a n d 
i n hi biti o n of H 3 K 2 7 met h ylati o n i n s ki n o bser ve d i n t he d ose escalati o n part of 
St u d y E 7 4 3 8- G 0 0 0- 1 0 1 i n dicates t hat tar get i n hi biti o n is relate d t o A U C. T he decrease i n 
s yste mic e x p os ure as meas ure d b y A U C 0-
is n ot cli nicall y si g nifica nt, a n d t heref ore, 
taze met ostat ca n be ta ke n wit h o ut re gar ds t o meals. 
T he effect of taze met ostat o n t he P K of mi daz o la m als o was i n vesti gate d as part of St u d y E 7 4 3 8-
G 0 0 0- 1 0 1. S u bjects wit h s oli d t u m o rs recei ve d a si n gle oral d ose of 2 m g mi daz ola m o n Da y - 1 
a n d Da y 1 5. Taze met ostat 8 0 0 m g BI D was a d mi ni stere d c o nti n u o usl y starti n g o n Da y 1. Serial 
bl o o d sa m ples f or t he a nal ysis of plas ma mi d az ola m a n d meta b olites we re c ollecte d o ver 2 4 
h o urs o n Da y - 1 ( mi daz ola m al o ne) a n d Da y 1 5 ( mi daz ola m pl us taze met ostat).
A s u m mar y of preli mi nar y  mi daz ola m P K para mete rs after a d mi nistrati o n al o ne ( Da y - 1) a n d 
wit h taze met ostat 8 0 0 m g BI D ( Da y 1 5) i n s u bjects wit h s oli d t u m ors is prese nte d i n  Ta ble 1 .  


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 3 7
T a ble 1 
S u m m ar y of Preli mi n ar y Mi d az o l a m P h ar m ac o ki netic P ar a meters After 
A d mi nistr ati o n Al o ne ( D a y - 1) or wit h  T aze met ost at 8 0 0 m g BI D f or 1 5 D a ys 
( D a y 1 5) i n St u d y E 7 4 3 8- G 0 0 0- 1 0 1 ( n = 1 2) 
P ar a meter
D a y - 1
a
D a y 1 5 a
G L S M R
b
( 9 0 % CI)
A U C 0-
n g• h/ m L
5 1. 9 
( 8 7. 2)
3 1. 1
( 4 8. 1)
0. 6 0
( 0. 4 6, 0. 7 8)
C ma x
n g/ m L
1 6. 5
( 9 4. 3)
1 3. 0
( 4 8. 3)
0. 7 8
( 0. 5 7, 1. 0 8)
t1/ 2
h 
5. 6 7
( 3 4. 3)
4. 2 5
( 3 2. 4)
N C
A b bre viati o ns: A U C   area u n der t he c o nce n trati o n-ti me c ur ve N C   n ot calc ulate d
a Data prese nte d as ge o metric mea n ( % C V)
b G L S M R   ge o metric least s q uares mea n rati o
Plas ma mi daz ola m A U C 0-  a n d Cma x  decrease d a p pr o xi matel y 4 0 % a n d 2 2 %, res pecti vel y, after 
a d mi nistrati o n wit h taze met ostat 8 0 0 m g BI D relati ve t o a d mi nistrati o n of mi daz ola m al o ne. 
Ge o metric mea n t 1/ 2  f or mi daz ola m decrease d a p pr o xi matel y 2 5 %, after a d mi nistrati o n of 
mi daz ola m wit h taze met ostat 8 0 0 m g BI D relati v e t o a d mi nistrati o n of mi daz ola m al o ne. T hese 
res ults i n dicate t hat a d mi nistrati o n of taze met ostat 8 0 0 m g BI D res ulte d i n net i n d ucti o n of 
C Y P 3 A- me diate d meta b olis m i n s u bjects wit h s o li d t u m ors. T he decrease i n mi daz ola m A U C0-
ca use d b y c o nc o mita nt a d mi nistrati o n wit h ta ze met ostat 8 0 0 m g BI D was less t ha n 5 0 %. 
T heref ore, taze met ostat 8 0 0 m g a d mi nistere d BI D is a wea k i n d ucer of C Y P 3 A- me diate d 
meta b olis m.
5. 4. 4.  
Cli nic al E x perie nce
I n 2 0 1 3, t he first-ti me-i n- h u ma n ( F TI H), sin gle-a ge nt, P hase I/II safet y, a n d P K st u d y 
( E 7 4 3 8- G 0 0 0- 1 0 1) of taze met ostat i n a d ult s u bjects wit h a d va nce d B-cell l y m p h o mas a n d s oli d 
t u m ors was i nitiate d i n Fra nce b y Eisai. I n t he d ose escalati o n part of t he st u d y, s u bjects wit h 
a d va nce d s oli d t u m ors or B-cel l l y m p h o mas f or w hic h t here is n o k n o w n effecti ve t hera p y were 
recr uite d. All s u bjects recei ve d oral taze met ostat BI D u ntil disease pr o gressi o n or a d ose-li miti n g 
t o xicit y ( D L T). As of 0 1 A pril 2 0 1 5, 4 0 s u bjects ha ve bee n e nr olle d a n d treate d at 5 d ose le vels 
of 1 0 0, 2 0 0, 4 0 0, 8 0 0, a n d 1 6 0 0 m g BI D. T he dia g n oses f or t he 1 6 s u bjects wit h B-cell N H L 
i ncl u de d f ollic ular l y m p h o ma, diff use lar ge B-cell l y m p h o ma i nclu di n g o ne s u bject wit h pri mar y 
me diasti nal l y m p h o ma a n d o ne mar g i nal z o ne l y m p h o ma. S u bjects wit h s oli d t u m ors i ncl u de d 4 
s u bjects wit h M R T a n d 2 s u bjects wit h E S. T he me dia n a ge of s u bjects e nr olle d is 5 9 years 
(ra n ge: 1 9- 8 4 years). T he d ose escalati o n p orti on of E 7 4 3 8- G 0 0 0- 1 0 1 has bee n c o m plete d. T he 
pr ot oc ol- defi ne d ma xi m u m t olerate d d ose ( M T D ) was n ot reac he d. T he hi g hest e val uate d d ose 
of 1 6 0 0 m g BI D was safe wit h o nl y o ne D L T ( C o m m o n Ter mi n ol o g y Criteria f or A d verse 
E ve nts [ C T C A E] versi o n 4. 0 3 Gra de 4 t hr o m b oc yt o pe nia) o bser ve d i n 6 s u bjects. T here was o ne 
ot her Gra de 4 seri o us a d verse e ve nt ( S A E) of p o ssi ble treat me nt-relate d ne utr o pe nia re p orte d i n 
a s u bject i n t he e x pa nsi o n c o h ort. T he R P 2 D of 8 0 0 m g BI D re prese nts 5 0 % of t he hi g hest 
e val uate d safe d ose a n d was deter mi ne d b y t he S p o ns or a n d ratifie d b y t he I n de pe n de nt Data 
M o nit ori n g C o m mittee (I D M C) f or use i n t he pr o p ose d P hase II st u d y i n a d ults wit h 
I NI 1- ne gati ve t u m ors a n d t he P hase II st u d y i n N H L a d ult s u bj ects i n E ur o pe a n d A ustralia. 


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 3 8
Taze met ostat has s h o w n clear e vi d e nce of r o b ust cli nical acti vit y i n s u bjects wit h ge neticall y 
defi ne d I NI 1 ne gati ve t u m ors c o nsisti n g of 3 of  6 s u bjects s h o wi n g o bjecti ve res p o nse ( 1 C R + 2 
P Rs) wit hi n 8 wee ks of recei vi n g t he first d ose of st u d y treat me nt. A f o urt h I NI 1- ne gati ve 
s u bject has e x perie nce d t u m or re d ucti o n, b ut di d n ot meet R E CI S T 1. 1 criteria f or P R at t he first 
re-sta gi n g at 8 wee ks. Taze met ostat has als o de m o nstrate d acti vit y i n s u bjects wit h pre vi o usl y 
treate d B-cell l y m p h o mas wit h o bjecti ve res p o nses i n 7 of 1 6 s u bjects wit h 4 s u bjects re mai ni n g 
o n st u d y treat me nt f or 4 1 t o 6 8 wee ks.  
As of 0 9 Se pte m ber 2 0 1 6, 8 5 s u bjects were e n r olle d t o t he o n g oi n g St u d y E Z H- 2 0 2. T he safet y 
pr ofile of s u bjects i n t his st u d y was ge nerall y c o nsiste nt wit h t hat o bser ve d f or s u bjects i n t he 
P hase 1 St u d y E 7 4 3 8- G 0 0 0- 1 0 1 as re p orte d a b o ve.  T he I D M C f or t his st u d y c o n ve ne d o n 0 4 
Oct o ber 2 0 1 6 t o re vie w C o h orts 2 (rela pse d/refract or y s y n o vial sarc o ma) a n d 5 ( E S). Base d o n 
t he re vie w of safet y a n d efficac y data, t he I DM C c o ncl u de d t hat f utilit y h ur dles ha d bee n 
s ur passe d i n b ot h c o h orts a n d n o safet y iss ues were i de ntifie d. 
At t he re q uest of t he s p o ns or, t he I D M C re -c o n ve ne d o n 2 1 Oct o ber 2 0 1 6 t o disc uss a me n di n g 
t he cli nical be nefit e n d p oi nt i n C o h ort 5. Base d o n a m ore rece nt literat ure re vie w (Secti o n 5. 2 )
a n d a d diti o nal disc ussi o ns wit h i n vesti gat ors e x perie nce d i n treati n g E S, t he cli nical si g nifica nce 
of s u bjects w h o mai ntai n l o n g- ter m S D was u na d dresse d i n t he ori gi nal e n d p oi nt. T heref ore, a 
pr o p osal was set f ort h t o t he I D M C t o c ha n ge t he pri mar y e n d p oi nt fr o m O R R t o disease c o ntr ol 
rate ( D C R), defi ne d as s u bjects w h o ac hie ve c o nfir me d res p o nse ( C R + P R) or w h o ha ve S D 
lasti n g at least 3 2 wee ks. T his was base d u p o n cli nical acti vit y o bser ve d as of 0 4 Oct o ber 2 0 1 6 
w hic h i ncl u des l o n g-ter m disease c o ntr ol as well as c o nfir me d a n d u nc o nfir me d o n g oi n g 
res p o nses. Base d u p o n t he i nitial cli nical acti vit y a n d l o w t o xicit y pr ofile o bser ve d, t he I D M C 
e n d orse d e x pa n di n g C o h ort 5 b y a n a d diti o nal 3 0 s u bjects. T he a d diti o nal s u bjects will all o w f or 
i ncrease d precisi o n ar o u n d t he p oi nt esti mates of D C R a n d O R R, as well as, pr o vi de e x pa n de d 
safet y e x perie nce i n E S. If i n t he f ut ure, si milar si g nals of p ositi ve acti vit y are see n i n ot her 
c o h orts, e x pa nsi o n f or f urt her e val uati o n of effi cac y a n d safet y ma y be c o nsi dere d f or t h ose 
c o h orts as well.
T he C o h ort 5 e x pa nsi o n sta ge was o pe ne d i n  Dece m ber 2 0 1 6 after t he Sta ge 2 D C R criteri o n 
was s ur passe d. I n Ma y 2 0 1 7, E piz y me met wit h t h e F D A re gar di n g f ut ure de vel o p me nt pla ns f or 
taze met ostat. Base d o n s pecific rec o m me n dati o ns fr o m t he F D A, wit h A me n d me nt 5, t he 
pri mar y e n d p oi nt f or C o h ort 5 has bee n c ha n ge d t o O R R a n d d ur ati o n of res p o nse i n res p o n di n g 
s u bjects has bee n ele vate d t o t he m ost i m p orta nt sec o n dar y e n d p oi nt. 
T A Z V E RI K ® (taze met ostat) recei ve d accelerate d a p pr o val f or mar keti n g i n t he U S t o treat t he 
f oll o wi n g: 
A d ults a n d pe diatric patie nts a ge d 1 6 y ears a n d ol der wit h metastatic or l ocall y 
a d va nce d E S n ot eli gi ble f or c o m plete resecti o n.  
A d ult patie nts wit h rela pse d or refract or y f ollic ular l y m p h o m a w h ose t u m ors are 
p ositi ve f or a n E Z H 2 m utati o n as detecte d b y a n F D A-a p pr o ve d test a n d w h o ha ve 
recei ve d at least 2 pri or s yste mic t hera pies. 
A d ult patie nts wit h rela pse d or refr act or y f ollic ular l y m p h o ma w h o ha ve n o 
satisfact or y alter nati ve treat me nt o pti o ns.


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 3 9
I n Ja pa n, T A Z V E RI K has recei ve d a p pr o val f or t he treat me nt of s u bjects wit h rela pse d or 
refract or y E Z H 2 ge ne m utati o n p ositi ve F L (li mite d t o use w he n diffic ult t o treat  wit h sta n dar d 
treat me nts) b y E piz y me’s c o- de vel o p me nt part ner, Eisai.
U n der t he c o n diti o ns of t he a p pr o val, E piz y me a gree d wit h t he F D A t o e nr oll a n a d diti o nal 2 5 
s u bjects i n c o h ort 6 t o f urt her e val uate t he O R R i n s u bjects wit h metastatic or l ocall y a d va nce d 
e pit heli oi d sarc o ma. T he pri mar y e n d p oi nt of c o h ort 6 has bee n c ha n ge d t o O R R a n d t he effects 
of taze met ostat o n t u m or i m m u ne pri mi n g has bee n c ha n ge d t o a n e x pl orat or y e n d p oi nt. 
A d diti o nall y, t he ma n dat or y pre- a n d p ost- d ose t u m or bi o psies re q uire d f or C o h ort 6 ha ve bee n 
ma de o pti o nal. 
E nr oll me nt i n all c o h orts of t he st u d y was c o m plete d i n Se pte m ber of 2 0 2 1 a n d a t otal of 2 6 7 
s u bjects were e nr olle d t o recei ve treat me nt. Treat me nt a n d data c ollecti o n f or st u d y o bjecti ves 
a n d e n d p oi nts is o n g oi n g. 
5. 4. 5. 
P h ar m ac o d y n a mics ( P D) 
I n t he a d ult P hase I st u d y t he P D of H 3 K 2 7 met h ylati o n f oll o wi n g taze met ostat d osi n g was 
meas ure d i n s ki n t o pr o vi de e vi de nce f or o n-tar get  met h ylati o n i n hi biti o n i n a s urr o gate tiss ue. I n 
t hat st u d y, i m m u n o hist oc he mistr y (IH C) a nal ysis of s ki n bi o psies c ollecte d pre- d os e a n d after 2 8 
da ys of taze met ostat treat me nt re veale d a p os t- d ose decrease i n H 3 K 2 7Me 3- p ositi ve cells acr oss 
all d oses e x pl ore d ( 1 0 0- 1 6 0 0 m g BI D), wit h a ma xi m u m re d uc ti o n i n t he perce nta ge of 
H 3 K 2 7 Me 3- p ositi ve cells t o 5 0 % of baseli ne. I n teresti n gl y differe nces were o bser ve d i n t he 
taze met ostat i n d uce d re d ucti o n i n H 3 K 2 7 Me 3 le vels i n differe nt s ki n la yers p ote ntiall y p oi nti n g 
t o differe nt ki netics f or H 3 K 2 7Me 3 t ur n o ver i n t he cells t hat occ u p y differe nt s ki n la yers.  
I n t his st u d y, pre- a n d p ost-treat me nt t u m or bio psies will be e val uate d t o e na ble t he assess me nt 
of taze met ostat 8 0 0 m g BI D d osi n g o n H 3 K 2 7 Me 3 le vels i n t u m or tiss ue. H 3 K 2 7 Me 3 I H C data 
will pr o vi de mec ha nistic i nsi g ht i nt o t he i m pact of E Z H 2 i n hi biti o n o n H 3 K 2 7 Me 3 le vels i n cell 
p o p ulati o ns wit hi n t u m or. I n a d di ti o n, t hese data will be e val uate d i n t he c o nte xt of taze met ostat 
e x p os ure data t o e x pl or e P K- P D relati o ns hi ps.  
A r o b ust re d ucti o n i n H 3 K 2 7 me 3 b y I H C stai ni n g was o bser ve d i n  a li mite d n u m ber of paire d 
pre- a n d p ost- d ose t u m or bi o psies c ollecte d t h us far i n St u d y E Z H - 2 0 2. I n a d diti o n t o m o nit ori n g 
H 3 K 2 7 me 3, e x pressi o n pr ofiles of i m m u ne mar kers P D- L 1 a n d C D 8 als o were assesse d. T o 
date, t w o of si x s u bjects teste d ha d i ncr ease d t u m or P D- L 1 e x pressi o n w hile u n der g oi n g 
treat me nt wit h taze met ostat. T he i ncrease d e x pressi o n of t u m or P D- L 1 was ass ociate d wit h a n 
i ncrease d n u m ber of C D 8- p ositi ve cells i nfiltrati n g t he t u m or s tr o ma. T hese data are s u p p orti ve 
of a n o bser vati o n ma de i n t he P hase 1 trial E 7 4 3 8- G 0 0 0- 1 0 1 i n w hic h bi o psies fr o m a s u bject 
wit h E S de m o nstrate d i ncrease d P D- L 1 e x pressi o n a n d e vi de nce of T-cell i nfiltrati o n. Gi ve n t he 
li mite d n u m ber of t u m or bi o psies c ollecte d t o date a n d t he varia bilit y of ti me p oi nts assesse d, it 
is diffic ult t o dra w c o ncl usi o ns re gar di n g t he i m m u ne- pri mi n g effects of taze met ostat. T o f urt her 
e val uate t his i m m u ne sti m ulat or y effect a n d t o sta n dar dize t he c ollecti o n ti me p oi nt of p ost- d ose 
bi o psies, St u d y E Z H- 2 0 2 has bee n a me n de d t o i n cl u de ma n dat or y bi o psies i n C o h ort 6 t o hel p 
g ui de f ut ure c o m bi nati o n st u dies (e. g., i m m u ne c h ec k p oi nt i n hi bit ors). Wit h t he i m ple me ntati o n 
of a me n d me nt 9, t he ma n dat or y pre a n d p ost d ose bi o psies f or C o h ort 6 ha ve bee n ma de 
o pti o nal. 


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 4 0
5. 4. 6.  
C o h ort 8 D osi n g J ustific ati o n: 1 6 0 0 m g Q D 
T he c urre nt rec o m me n de d d ose of taze met ostat as m o n ot hera p y is 8 0 0 m g BI D. T his d ose is 
s u p p orte d pri maril y b y a vaila ble P K/ P D/safet y a n d efficac y data fr o m t he d ose escalati o n st u d y 
E 7 4 3 8- G 0 0 0- 1 0 1 ( P hase 1 P orti o n). Briefl y, i n t he d ose escalati o n part, s u bjects wit h a d va nce d 
s oli d t u m ors or B-cell l y m p h o mas recei ve d oral taze met ostat c o nti n u o usl y i n 2 8- da y c ycles. T he 
starti n g d ose was 1 0 0 m g BI D, wit h s u bse q ue nt d ose c o h orts e val uated at 2 0 0 m g, 4 0 0 m g, 8 0 0 
m g, a n d 1, 6 0 0 m g BI D. A m o n g s u bjects wit h a d va n ce d s oli d t u m ors, 2 ( 5 %) of t he 4 3 s u bjects 
ac hie ve d a n o bjecti ve res p o nse, i ncl u di n g C R i n 1 s u bject wit h I NI 1- ne gati ve mali g na nc y at t he 
taze met ostat 8 0 0 m g BI D d ose le vel a n d 1 P R i n a s u bject wit h S M A R C A 4- ne gati ve mali g na nc y 
at t he taze met ostat 1 6 0 0 m g BI D d ose. Of t h e 2 res p o n ders i n t he a d va nce d s oli d t u m or 
s u b gr o u p, t he D O R was 1 6. 1 wee ks f or t he s u bject wit h P R a n d 1 1 2. 1 + w ee ks f or t he s u bject 
wit h C R; t he latter s u bject was o n g oi n g i n res p o nse as of t he data c ut off date ( St u d y E 7 4 3 8-
G 0 0 0- 1 0 1). 
T he pre d o mi na nt e nz y me res p o nsi ble f or t he me ta b olis m of taze met ostat i n h u ma ns is C Y P 3 A 4. 
N ota bl y, t he effect of taze me t ostat o n C Y P 3 A 4 is c o m plicate d, wit h o p p osi n g i n d ucti o n a n d 
ti me- de pe n de nt i n hi biti o n of t he e nz y me. T he net cli nical D DI o utc o me is a n i n d ucti o n of 
C Y P 3 A 4, as i n dicate d b y a n a p pr o xi matel y  4 0 % re d ucti o n of mi daz ola m A U C f oll o wi n g 8 0 0 
m g BI D d osi n g f or 1 5 da ys ( St u d y E 7 4 3 8- G 0 0 0- 1 0 1). I n-a d diti o n, t he e x p os ure res p o nse 
efficac y a nal ysis c o n d ucte d i n C o h ort 5 of St u d y E Z H- 2 0 2 s h o we d a se parati o n of D O R base d 
o n t he ti me-a vera ge d A U C w he n bi n ne d i nt o  t w o gr o u ps ( p = 0. 0 3): ti me-a vera ge d A U C < 3 2 1 2 
vs ti me-
ti me a vera ge d A U C s h o we d a vis ual te n de nc y f or hi g her ti me a vera ge d A U C f or s u bjects t hat 
ha d D C R a n d O R R. Ta ke n t o get her, t hese res ults s u p p ort t he e x pl orati o n of a d osi n g re gi me n 
t hat w o ul d all o w f or ac hie vi n g a hi g her A U C w hile mai ntai ni n g a c o m para ble safet y/t olera bilit y 
pr ofile t o t he 8 0 0 m g BI D d ose. T he o bjecti v e of a d di n g a ne w d osi n g sc he d ule, 1 6 0 0 m g 
taze met ostat Q D ( C o h ort 8), i n A me n d me nt 7 is t o kee p t he c urre nt t otal dail y d ose of 
taze met ostat t he sa me (i.e., 1 6 0 0 m g), b ut a d mi nister t he d ose Q D as o p p ose d t o BI D, as t his will 
all o w f or ac hie ve me nt of p ote n tiall y hi g her A U C at stea d y-state of a p pr o xi matel y 7 0 0 0 n g * h/ m L 
d ue t o p ote ntiall y l o wer i n d ucti ve effect of t he C Y P 3 A 4 e nz y me.   
5. 5. 
St u d y R ati o n ale
I NI 1- ne gati ve t u m ors, S M A R C A 4- ne gati ve t u m ors, s oli d t u m ors wit h E Z H 2 G O F m utati o n, or 
rela pse d/refract or y s y n o vial sarc o ma. T his st u d y will c haracterize t he safet y, efficac y, a n d P K i n 
t his p o p ulati o n. As t here is a reas o na ble e x pectati o n base d u p o n n o ncli nical data a n d t he P hase 1 
e x perie nce i n a d ults t hat cli nical acti vit y ma y be  o bser ve d i n a d ults wit h I NI 1- ne gati ve t u m ors, 
S M A R C A 4- ne gati ve t u m ors, s oli d t u m ors wit h E Z H 2 G O F m utatio n, a n d s y n o vial sarc o ma. As 
ma n y of t he tar gete d t u m ors occ ur i n y o u n g a d ults, t he l o wer a ge li mit w o ul d e na ble 
partici pati o n of s u bjects w h o are hist orica ll y u n der-re prese nte d i n cli nical trials. 


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 4 1
5. 6. 
Be nefit: Ris k Assess me nts
5. 6. 1.  
A ni m al T o xic ol o g y 
N o ncli nical safet y assess me nts of taze met ost at i ncl u de d i n vitr o a n d m o n ke y safet y 
p har mac ol o g y st u dies, ge n ot o xicit y st u dies, a n d si n gle- a n d re peat- d ose t o xicit y st u dies i n 
S pra g ue- Da wle y rats a n d c y n o m ol g us m o n ke ys of 4- a n d 1 3- wee ks d urati o n. N o n ota ble 
car di o vasc ular, ce ntral ner v o us s yste m ( C N S), or re s pirat or y ris ks were i de ntifie d i n n o ncli nical 
safet y p har mac ol o g y assess me nts. Taze met ostat was n ot ge n ot o xic i n sta n dar d i n vitr o a n d 
i n vi v o assa ys. T he f oll o wi n g p ote ntial ris ks were i de ntifie d f or taze met ostat base d o n 
n o ncli nical safet y data: T- L B L (rat), i ncrease d  b o ne f or mati o n i n b o ne a n d teet h (rat), 
n o n- pr o gressi ve bile d uct h y per plasia ( m o n ke y), te rat o ge nicit y (rat a n d ra b bit), l y m p h oi d 
de pleti o n (rat a n d m o n ke y), a n d p h ot ot o xic p ote ntial (i n vitr o). Ot her effects at hi g h, 
n o n-t olerate d d oses, t o xicities i ncl u de d b o ne marr o w effects ( h y p ocell ularit y, rat), a n d
gastr oi ntesti nal t o xicit y ( diste n ti o n, ulcerati o n, a n d de ge nerati o n, rat). 
Stea d y-state e x p os ures (area u n der t he c o nce ntr ati o n –ti me c ur v e fr o m 0 t o 2 4 h o urs [ A U C 0- 2 4]) 
i n rats at t he l o west d ose ( 1 0 0 m g/ k g/ da y) at w hic h n o T- L B L occ urre d i n t he 1 3- wee k
a d olesce nt rat st u d y were 2. 5- t o 7. 5-f ol d grea ter t ha n t hat o bser ve d i n h u ma ns at t he 
rec o m me n de d P hase 2 d ose ( R P 2 D; 8 0 0 m g BI D) fr o m t he o n g oi n g P hase 1/ 2 St u d y E 7 4 3 8-
G 0 0 0- 1 0 1. N o i nci de nces of a b n or mal b o ne f or m ati o n ha ve bee n o bser ve d i n t he o n g oi n g 
cli nical st u d y. Fe male s u bjects of re pr o d ucti ve a ge will pr o vi de bl o o d a n d uri ne sa m ples f or 
pre g na nc y testi n g at scree ni n g. All s u bjects m ust a gree t o use a relia ble birt h c o ntr ol met h o d 
d uri n g t he st u d y, a n d f or 3 0 da ys after t he last taze met ostat d ose, a n d a d diti o nall y will be 
acti vel y m o nit ore d f or si g ns or s y m pt o ms of a b n o r mal b o ne f or mati o n.  
A d diti o nal a ni mal t o xic ol o g y is pr o vi de d i n t he I n vesti gat or’s  Br oc h ure (I B) f or taze met ostat.
5. 6. 2. 
P h ot o- Re acti ve P ote nti al 
T here are n o ncli nical data s u p p or ti n g a p ote ntial f or p h ot ot o xicity, w hic h has n ot bee n e val uate d 
i n h u ma ns. He nce, pr ol o n ge d e x p os ure t o s u nli g ht s h o ul d be a v oi de d d uri n g treat me nt. I n 
a d diti o n, s u bjects s h o ul d ta ke ot her meas ures t o a v oi d ultra vi olet ( U V) e x p os ure s uc h as weari n g 
s u n scree n a n d s u n glasses, wearin g pr otecti ve cl ot hi n g, a n d a v oi di n g ta n ni n g be ds. Refer t o t he 
taze met ostat I B f or details. 
5. 6. 3.  
C Y P 3 A Met a b olis m
Taze met ostat is meta b olize d pri maril y b y C Y P 3 A a n d is a s u bstrate f or P- gl yc o pr otei n ( P- g p). 
T heref ore, treat me nt wit h str o n g i n hi bit ors or str o n g i n d ucers of C Y P 3 A w it hi n 1 4 da ys pri or t o 
first d ose of taze met ostat a n d f or t he d urati o n of st u d y treat me nt is pr o hi bite d. Taze met ostat was 
als o s h o w n t o be a ti me- de pe n de nt C Y P 3 A i n hi bit or a n d a C Y P 3 A 4 i n d ucer ( E C 5 0  val ue = 2. 6 
L) as well as a n i n hi bit or of  P- g p, C Y P 2 D 6, a n d t he C Y P 2 C fa mil y i n vitr o. P- g p, C Y P 3 A, 
C Y P 2 C 8, C Y P 2 C 9, C Y P 2 C 1 9, a n d C Y P 2 D 6 s u bstra tes s h o ul d be use d wit h ca uti o n. 
Me dicati o ns t hat are s u bstrates f or C Y P 3 A, C Y P 2 C 8, C Y P 2 C 9, C Y P 2 C 1 9, a n d C Y P 2 D 6 s h o ul d 
be a v oi de d if p ossi ble.


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 4 2
5. 6. 4.  
A ntici p ate d S afet y Pr ofile
M ore t ha n 1 1 0 5 cli nical st u d y s u bjects ha ve r ecei ve d taze met ostat as m o n ot hera p y or i n 
c o m bi nati o n wit h ot her dr u gs i n E piz y me-s p o ns or e d trials. T he maj orit y  of a d verse e ve nts 
o bser ve d i n t hese st u dies are c o nsiste nt wit h k n o w n a d verse reacti o ns of t he dr u gs u n der 
i n vesti gati o n a n d/ or c o m or bi dit y, are ge nerall y mil d t o m o derate i n se verit y, res p o n d t o d ose 
m o dificati o n a n d res ol ve wit h o ut  se q uelae. T he safet y pr ofile of taze met ostat is well 
c haracterize d a n d sta ble. T he be nefit-ris k re mai ns p ositi ve. 
A d verse e ve nts of s pecial i nterest i ncl u de T- L B L/ T- A L L, A M L, M D S, a n d ot her m yel oi d 
mali g na ncies li ke M P N.
Taze met ostat is i n late-sta ge cl i nical de vel o p me nt a n d has s h o wn cli nical acti v it y i n s u bjects 
acr oss t he taze met ostat pr o gra m, i ncl u di n g o bj ecti ve res p o nses a n d s ustai ne d disease 
sta bilizati o n. Taze met ostat has recei ve d accelerate d a p pr o val i n t he U S f or E S a n d F L.
Taze met ostat is c o nsi dere d t o be a cli nicall y acti ve dr u g t hat has t he p ote ntial t o be nefit b ot h 
a d ult a n d pe diatric o nc ol o g y s u bjec ts acr oss differe nt t um or t y pes w here t here are u n met me dical 
nee ds.
T A Z V E RI K ® (taze met ostat) has rece i ve d accelerate d a p pr o val f or mar keti n g i n t he U S t o treat 
t he f oll o wi n g:
A d ults a n d pe diatric patie nts a ge d 1 6 years a n d ol der wit h metastatic or l ocall y 
a d va nce d e pit heli oi d sarc o ma n ot eli gi ble f or c o m plete resecti o n.
A d ult patie nts wit h rela pse d or refract or y f ollic ular l y m p h o m a w h ose t u m ors are 
p ositi ve f or a n E Z H 2 m utati o n as detecte d b y a n F D A-a p pr o ve d test a n d w h o ha ve 
recei ve d at least 2 pri or s yste mic t hera pies.
A d ult patie nts wit h rela pse d or refr act or y f ollic ular l y m p h o ma w h o ha ve n o 
satisfact or y alter nati ve treat me nt o pti o ns.
I n Ja pa n, T A Z V E RI K has recei ve d a p pr o val f or t he treat me nt of s u bjects wit h rela pse d or 
refract or y E Z H 2 ge ne m utati o n p ositi ve F L (li mite d t o use w he n diffic ult t o treat wit h sta n dar d 
treat me nts) b y E piz y me’s c o- de vel o p me nt part ner, Eisai.
F urt her details of st u d y desi g ns, taze met ostat e x p os ure, a n d treat me nt-e mer ge nt A Es re gar dless 
of ca usalit y are o utli ne d  i n t he c urre nt I B. 
5. 6. 5. 
S u m m ar y
Treat me nt wit h orall y a d mi nistere d taze met ostat le d t o cli nica ll y mea ni n gf ul efficac y i n s u bjects 
wit h E S a n d ot her I NI 1 ne gati v e t u m ors. O bjecti ve res p o nses were o bser ve d i n 1 5 % of E S 
s u bjects i n C o h ort 5. F urt her, t he res p o nses were d ura ble wit h ma n y s u bjects ha vi n g disease 
sta bilizati o n f or at least 3 2 wee ks.
T he safet y pr ofile of taze met ost at was fa v ora ble acr oss a br oa d p o p ulati o n of s u bjects wit h 
mali g na ncies, i ncl u di n g t h ose wit h E S. Taze met ostat was ge nerall y well t olerate d wit h fe w 
s u bjects re q uiri n g disc o nti n uati o n of treat me nt d ue t o dr u g-relate d t o xicit y all o wi n g f or 
c o nti n ue d treat me nt. T here were n o seri o us, treat me nt-relate d e ve nts of c yt o pe nias, fe brile 
ne utr o pe nia, he pat ot o xicit y, or car diac a b n or malities.


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 4 3
I n c o ncl usi o n, taze met ostat has le d t o d ura ble res p o nses a n d has s h o w n a fa v ora ble safet y pr ofile 
i n s u bjects wit h l ocall y a d va nce d or metastatic E S a n d ot her I NI 1 ne gati ve t u m ors, a p o p ulati o n 
wit h a n u n met nee d.  T heref ore, t here is a n a p pr o priate ris k be nefit t o c o nti n ue st u d y of 
taze met ostat i n s u bjects wit h S WI/ S N F deficie nt t u m ors.


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 4 4
6.  
O B J E C TI V E S A N D E N D P OI N T S
O bjecti ves
E n d p oi nts
Pri m ar y:
C o h orts 1 (r h a b d oi d t u m ors), 3 ( ot her I NI 1-
ne g ati ve t u m ors or a n y s oli d t u m or wit h E Z H 2 
G O F m ut ati o n), 4 ( R M C), 5 ( E S), C o h ort 6 ( E S 
wit h o pti o n al t u m or bi o ps y), a n d 7 (c h or d o m a):
T o assess t he O R R f oll o wi n g oral a d mi nistrati o n of 
taze met ostat 8 0 0 m g BI D.
O R R (c o nfir me d C R + P R) f or taze met ostat i n 
s u bjects wit h I NI 1- ne gati ve t u m ors usi n g disease-
a p pr o priate sta n dar dize d res p o nse criteria ( pri mar y 
C N S t u m ors: Res p o nse Assess me nt f or Ne ur o-
O nc ol o g y [ R A N O] a n d all ot hers: R E CI S T 1. 1)
C o h ort 2 (rel a pse d/ refr act or y [ R/ R] s y n o vi al 
s arc o m a):
T o deter mi ne t he pr o gressi o n-free s ur vi val ( P F S) 
rate f oll o wi n g 1 6 wee ks of oral a d mi nistrati o n of 
taze met ostat 8 0 0 m g BI D. 
P F S rate after 1 6 wee ks of treat me nt wit h 
taze met ostat. T his is t he n u m ber of s u bjects wit h 
c o nfir me d C R or P R, or sta ble disease ( S D) at t he 
Wee k 1 6 assess me nt.
C o h ort 8 ( E S tre ate d wit h t aze met ost at 1 6 0 0  m g 
o nce d ail y [ Q D]):
T o assess t he safet y a n d t olera bilit y of taze met ostat 
1 6 0 0 m g Q D.
A Es a n d cli nical la b orat or y tests
Sec o n d ar y:
T o e val uate t he d urati o n of res p o nse ( D O R) i n 
s u bjects wit h r ha b d oi d t u m ors ( C o h ort 1), R/ R 
s y n o vial sarc o ma ( C o h ort 2), ot her I NI 1- ne gati ve 
t u m ors or a n y s oli d t u m or wit h E Z H 2 G O F 
m utati o n ( C o h ort 3), R M C ( C o h ort 4), E S 
( C o h ort 5), E S u n der g oi n g o pti o nal bi o ps y ( C o h ort 
6), c h or d o ma ( C o h ort 7), a n d E S recei vi n g 1 6 0 0 
m g taze met ostat Q D ( C o h ort 8) a n d t o e val uate t he 
D O R i n C o h orts 1, 3, 4, 5, 6, a n d 7 c o m bi ne d.
D O R, defi ne d as t he ti me fr o m t he first 
d oc u me nte d e vi de nce of C R or P R t o t he ti me of 
first d oc u me nte d disease pr o gressi o n or deat h d ue 
t o a n y ca use, w hic he ver c o mes first, usi n g disease-
a p pr o priate sta n dar dize d res p o nse criteria
T o assess t he disease c o ntr ol rate ( D C R) i n s u bjects 
wit h E S ( C o h ort 5) a n d E S u n der g oi n g o pti o nal 
bi o ps y ( C o h ort 6) f oll o wi n g oral a d mi nistrati o n of 
taze met ostat 8 0 0  m g BI D, a n d i n s u bjects wit h E S 
( C o h ort 8) f oll o wi n g oral a d mi nistrati o n of 
taze met ostat 1 6 0 0 m g Q D. 
D C R f or taze met ostat ( defi ne d as t he n u m ber of 
s u bjects w h o ac hie ve c o nfir me d res p o nse [ C R + P R] 
or w h o ha ve S D lasti n g at least 3 2  wee ks)
T o assess t he O R R i n s u bjects wit h R/ R s y n o vial 
sarc o ma ( C o h ort 2) f oll o wi n g oral a d mi nistrati o n 
of taze met ostat 8 0 0 m g BI D, a n d i n s u bjects wit h 
E S ( C o h ort 8) f oll o wi n g oral a d mi nistrati o n of 
taze met ostat 1 6 0 0 m g Q D.
O R R ( defi ne d as t he n u m ber of s u bjects w h o 
ac hie ve c o nfir me d res p o nse [ C R + P R] p er R E CI S T 
1. 1) 
T o deter mi ne t he P F S a n d O S at Wee ks 2 4, 3 2, a n d
5 6 a n d o verall i n s u bjects wit h r ha b d oi d t u m ors 
( C o h ort 1), R/ R s y n o vial sarc o ma ( C o h ort 2), ot her 
P F S at Wee ks 2 4, 3 2, 5 6, a n d o verall f or eac h 
c o h ort. P F S is defi ne d as t he ti me fr o m t he date of 
first d ose of st u d y treat me nt t o t he earlier of t he 


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 4 5
O bjecti ves
E n d p oi nts
I NI 1- ne gati ve t u m ors or a n y s oli d t u m or wit h 
E Z H 2 G O F m utati o n ( C o h ort 3), R M C ( C o h ort 4), 
E S ( C o h ort 5), E S u n der g oi n g o pti o nal bi o ps y 
( C o h ort 6), a n d c h or d o ma ( C o h ort 7) f oll o wi n g oral 
a d mi nistrati o n of taze met ostat 8 0 0 m g BI D, a n d i n 
s u bjects wit h E S ( C o h ort 8) f oll o wi n g oral 
a d mi nistrati o n of taze met ostat 1 6 0 0 m g Q D.
date of first d oc u me nte d disease pr o gressi o n or 
date of deat h d ue t o a n y ca use
O S at Wee ks 2 4, 3 2, 5 6, a n d o verall f or eac h 
c o h ort. O S is defi ne d as t he ti me fr o m t he date of 
t he first d ose of st u d y treat me nt t o t he date of deat h 
d ue t o a n y ca use
E x pl or at or y:
T o e x pl ore t he relati o ns hi p bet wee n plas ma P K a n d 
t u m or p har mac o d y na mic ( P D) mar kers as 
per mitte d b y data
T u m or tar get ge ne e x pressi o n a n d p he n ot y pic 
mar kers i ncl u di n g t h ose f or differe ntiati o n, 
a p o pt osis, i nfla m mati o n a n d cell pr oliferati o n, a n d 
t heir c orrelati o n wit h acti vit y
T o assess t u m or tiss ue a n d bl o o d f or s o matic 
m utati o ns, ger mli ne varia nts, messe n ger 
ri b o n ucleic aci d ( m R N A), a n d/ or pr otei ns as 
ca n di date mar kers of res p o nse t o taze met ostat
S o matic m utati o n a nal ysis of t u m or tiss ue a n d 
bl o o d deri ve d circ ulati n g de o x yri b o n ucleic aci d 
( D N A)
Ger mli ne D N A a nal ysis f or I NI 1 or S M A R C A 4 
varia nts
C o h ort 6 o nl y: T o assess t he effects of 
taze met ostat o n t u m or i m m u ne pri mi n g 
Assess me nt of pre- a n d p ost- d ose bi o psies f or 
i m m u ne pri mi n g (e. g. P D- L 1 a n d C D 8 I H C)
C o h ort 6 o nl y: T o i n vesti gate t he P D effects of 
taze met ostat i n t u m or tiss ue, if a p ost- d ose t u m or 
sa m ple is a vaila ble
Assess me nt of pre- a n d p ost- d ose bi o psies f or 
H 3 K 2 7 me 3 a n d f or c ha n ges i n ge ne e x pressi o n.


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 4 6
7. 
S T U D Y D E SI G N
7. 1.  
O ver all E x peri me nt al Pl a n
T his is a P hase II, m ultice nter, o pe n-la bel, si n gle-ar m, 2-sta ge st u d y of  taze met ostat 8 0 0 m g BI D 
or 1 6 0 0 m g Q D ( C o h ort 8) a d mi nistere d orall y i n c o nti n u o us 2 8- da y c ycles. Scree ni n g of 
s u bjects t o deter mi ne eli gi bilit y f or t he st u d y will be perf or me d wit hi n 2 1 da ys of t he first 
pla n ne d d ose of taze met ostat. As s h o w n i n  Fi g ure 2, eli gi ble s u bjects will be e nr olle d i nt o o ne of 
ei g ht c o h orts base d o n t u m or t y pe: 
C o h orts usi n g t aze met ost at 8 0 0 m g BI D: 
C o h ort 1: R ha b d oi d t u m ors ( M R T, r ha b d oi d t u m o rs of t he ki d ne y [ R T K], A T R T, 
a n d selecte d t u m ors wit h r ha b d oi d feat ures, i ncl u di n g S C C O H T, als o k n o w n as 
M R T O) (cl ose d t o e nr oll me nt)
C o h ort 2: Rela pse d or refract or y s y n o vial sa rc o ma wit h S S 1 8- S S X rearra n ge me nt 
(cl ose d t o e nr oll me nt)
C o h ort 3: Ot her I NI 1- ne gati ve t u m ors or a n y s oli d t u m or wit h E Z H 2 G O F m utati o n 
(cl ose d t o e nr oll me nt), i ncl u di n g :
E M P N S T
E M C
M y oe pit helial carci n o ma
Ot her I NI 1- ne gati ve mali g na nt t u m ors wit h S p o ns or a p pr o val 
A n y s oli d t u m or wit h E Z H 2 G O F m utati o n i ncl u di n g b ut n ot li mite d t o E wi n g’s 
sarc o ma a n d mela n o ma
C o h ort 4: R M C (cl ose d t o e nr oll me nt)
C o h ort 5: E S (cl ose d t o e nr oll me nt)
C o h ort 6:  E S u n der g oi n g o pti o nal t u m or bio ps y (cl ose d t o e nr oll me nt) 
C o h ort 7:  P o orl y differe ntiate d c h or d o ma ( or ot her c h or d o ma wit h S p o ns or 
a p pr o val) (cl ose d t o e nr oll me nt) 
C o h orts usi n g t aze met ost at 1 6 0 0 m g Q D: 
C o h ort 8: E S (cl ose d t o e nr oll me nt)
N ote: C h a n ges t o C o h orts: 
C o h ort 3 was i nitiall y i nte n de d t o e nr oll vari o us  I NI 1- ne gati ve t u m ors, i ncl u di n g R M C a n d E S. 
I nitial scree ni n g a n d e nr oll me nt tre nds i n dicate d t hat C o h ort 3 w o ul d be hea vil y wei g hte d t o war d 
R M C a n d E S t u m or t y pes, t heref ore, l osi n g t he p ot e ntial t o e val uate ot her I NI 1- ne gati ve t u m ors. 
T h us, C o h ort 4 ( R M C) a n d C o h ort 5 ( E S) were a d de d as part of A me n d me nt 3. S u bjects wit h 
R M C a n d E S w h o were e nr olle d i n C o h ort 3 pri or t o A me n d me nt 3 were m o ve d t o t he 
a p pr o priate c o h ort base d o n t he s pecific disease t y pe d oc u me nte d pri or t o start of treat me nt. 


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 4 7
A me n d me nt 4 all o we d t he i ncl usi o n of s u bjects wit h s oli d t u m ors a n d E Z H 2 G O F m utati o ns i nt o 
C o h ort 3, base d u p o n o bser ve d c li nical acti vit y i n t he P hase 1 St u d y E 7 4 3 8- G 0 0 0- 1 0 1 i n 
s u bjects wit h E Z H 2- m uta nt n o n- H o d g ki n l y m p h o ma ( N H L).  
A me n d me nt 5 a d de d 2 a d diti o nal c o h orts: C o h ort 6 ( E S u n der g oi n g ma n dat or y bi o ps y) a n d 
C o h ort 7 (c h or d o ma). C o h ort 6 was a d de d t o f u rt her e x pl ore t he i m m u ne- pri mi n g effects of 
taze met ostat (see Secti o n 5. 4. 5 ). C o h ort 7 was a d de d t o all o w t he i ncl usi o n of s u bjects wit h 
c h or d o ma, a ver y rare sarc o ma wit h a lar ge pe rce nta ge of t he p o orl y differe ntiate d varia nts 
ha vi n g l oss of I NI 1, base d o n o bser ve d cli nical  acti vit y i n t he P hase 1 pe diatric St u d y E Z H- 1 0 2 
“ A P hase 1 St u d y of t he E Z H 2 I n hi bit or Taze met osta t i n Pe diatric S u bjects wit h Rela pse d or 
Refract or y I NI 1- Ne gati ve T u m ors or S y n o vial Sarc o ma.” S u bjects wit h c h or d o ma w h o were 
e nr olle d i n C o h ort 3 pri or t o A me n d me nt 5 were m o ve d t o C o h ort 7. 
A me n d me nt 7 a d de d C o h ort 8, w hic h uses a ne w d osi n g sc he d ule of taze met ostat 1 6 0 0 m g Q D 
i n E S s u bjects. It was h y p ot hesize d t hat 1 6 0 0 m g Q D ma y ac hie ve a hi g her A U C at stea d y-state 
of a p pr o xi matel y 7 0 0 0 n g * h/ m L (see d ose j ust ificati o n i n Secti o n 5. 4. 6 ).  
I nteri m A n al yses
F or eac h c o h ort (e xce pt C o h orts 6 a n d 8), a t w o- sta ge, Gree n- Da hl ber g desi g n was utilize d wit h 
a st o p pi n g r ule t o all o w f or earl y ter mi nati o n at t he e n d of Sta ge 1 if t here was str o n g e vi de nce of 
lac k of efficac y. If earl y st o p pin g criteria were met f or a c o h ort,  e nr oll me nt was t o be st o p pe d. 
T o a v oi d disr u pti o ns i n t he st u d y, e nr oll me nt a n d treat me nt of s u bj ects was n ot t o be halte d i n 
or der t o c o n d uct t he i nteri m a nal ysis at Sta ge 1. 
F or C o h orts 1, 3, 4, 5, a n d 7, t he Sta ge 1 i nteri m a n al ysis was pla n ne d t o be perf or me d after t he 
first 1 5 s u bjects e nr olle d ha d c o m plete d at least t he Wee k 2 4 assess me nt, c o m plete d t he fi nal 
st u d y visit, or ter mi nate d earl y fr o m t he st u d y, w hic he ver was so o ner. As it was desira ble t o 
perf or m t he i nteri m a nal ysis i n  a ti mel y ma n ner, b ot h c o nfir me d a n d u nc o nfir me d res p o nses 
were i ncl u de d. C o h ort 4 ( R M C) a n d C o h ort 7 (c h o r d o ma) were ter mi nate d base d o n t he Sta ge 1 
i nteri m a nal ysis. C o h ort 1 (r hab d oi d t u m ors), C o h ort 3 (I NI 1- ne gati ve/ E Z H 2 G O F m utati o n), 
a n d C o h ort 5 ( E S) c o nti n ue d i nt o Sta ge 2, t o e n r oll a n a d diti o nal 1 5 s u bjects eac h. A d diti o nall y, 
C o h ort 5 we nt o n t o e nr oll a n a d diti o nal 3 0 s u bjec ts wit h E S i nt o t he C o h ort 5 E x pa nsi o n starti n g 
i n 2 0 1 6. I n Ma y 2 0 1 7, E piz y me met wit h t he F D A re gar di n g f ut u re de vel o p me nt pla ns f or 
taze met ostat. Base d o n a s pecific re q uest fr o m t he F D A, wit h A me n d me nt 5, t he pri mar y 
e n d p oi nt f or C o h ort 5 has bee n c ha n ge d bac k t o O R R, a n d d urati o n of res p o nse i n res p o n di n g 
s u bjects has bee n ele vate d t o t he m ost i m p orta nt sec o n dar y e n d p oi nt. 
Gi ve n s ufficie nt e vi de nce of a ntit u m or acti vit y a n d n o c o ncer ni n g safet y si g nal o bser ve d d uri n g 
t he 2-sta ge desi g n f or C o h ort 5, C o h ort 6 a n d C oh ort 8 were a d de d o utsi de t he 2-sta ge desi g n 
fra me w or k. C o h ort 6 ( E S u n der g oi n g ma n dat or y t u m or bi o ps y) was a d de d t o f urt her e x pl ore t he 
i m m u ne- pri mi n g effects of taze met ostat. C o h ort 8 ( E S) was a d de d t o e val uate safet y a n d P K 
f oll o wi n g oral a d mi nistrati o n of 1 6 0 0 m g taze met ostat o nce dail y. 
I n Ja n uar y 2 0 2 0, taze met ostat was a p pr o ve d f or t he treat me nt of a d ults a n d pe diatric patie nts 
a ge d 1 6 years a n d ol der wit h me tastatic or l ocall y a d va nce d E S n ot eli gi ble f or c o m plete 
resecti o n. U n der t he c o n diti o ns of t he a p pr o val, E piz y me a gree d wit h t he F D A t o e nr oll a n 
a d diti o nal 2 5 s u bjects i n C o h ort 6 t o f urt her e val uate t he O R R i n s u bjects wit h metastatic or 
l ocall y a d va nce d E S. T he pri mar y e n d p oi nt of C o h ort 6 was c ha n ge d t o O R R. T he effects of 


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 4 8
taze met ostat o n t u m or i m m u ne pri mi n g were ma de a n e x pl orat or y e n d p oint a n d t u m or bi o psies 
were ma de o pti o nal f or t his c o h ort. 
F or C o h ort 2 (rela pse d or refract or y s y n o vial sarc o ma), t he Sta ge 1 i nteri m a nal ysis was 
perf or me d after t he first 1 5 s u bj ects e nr olle d ha d c o m plete d at  least t he Wee k 1 6 assess me nt, 
c o m plete d t he fi nal st u d y visit, or ter mi nate d  earl y fr o m t he st u d y, w hiche ver was s o o ner. C o h ort 
2 c o nti n ue d i nt o Sta ge 2, t o e n r oll a n a d diti o nal 1 5 s u bjects. 
Tre at me nt 
S u bjects will recei ve taze met ost at i n c o nti n u o us 2 8- da y c ycles.  S u bjects ma y disc o nti n ue st u d y 
treat me nt at a n y ti me d ue t o disease pr o gressi o n, de vel o p me nt of a n u nacce pta ble t o xicit y, 
wit h dra wal of c o nse nt, or ter mi nati o n of t he st u d y.  
S u bjects will ha ve a n E O T visit u p t o 3 0 da ys after last d ose of treat me nt i n t his st u d y or pri or t o 
t he start of a ne w a ntica ncer t hera p y, w hic he ver occ urs first. All s u bjects will be f oll o we d f or 
s ur vi val. Res p o nse is defi ne d as ha vi n g d oc u me nte d e vi de nce of c o m plete res p o nse ( C R) or 
partial res p o nse ( P R). Res p o nse assess me nt perf o r me d e ver y 8 wee ks w hile o n treat me nt a n d 
e ver y 8- 1 2 wee ks i n s ur vi val f oll o w- u p. 
R oll o ver St u d y  
All s u bjects w h o recei ve d taze met o stat i n t his st u d y ( E Z H- 2 0 2) a n d are eli gi ble t o c o nti n ue 
recei vi n g taze met ostat or t o c onti n ue s ur vi val f oll o w- u p, ca n tra nsfer t o a R oll o ver St u d y 
( E Z H- 5 0 1) f or c o nti n ue d st u d y dr u g a n d/ or c o nti n ue d m o nit ori n g at t he I n vesti gat or a n d Me dical 
M o nit or’s discreti o n. 


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 4 9
Fi g ure 2  
St u d y Sc he m a
N ote: A me n d me nt 9 all o we d f or t he e nr oll me nt of a n a d diti o nal 2 5 s u bjects i n C o h ort 6. I n a d diti o n, t he ma n dat or y 
t u m or bi o ps y was ma de o pti o nal.
7. 2. 
Esti m ate d St u d y D ur ati o n
7. 2. 1. 
St u d y D ur ati o n f or P artici p a nts
T he st u d y d urati o n is a p pr o xi matel y 2 4 m o nt hs f or eac h s u bject. T he d urati o n of scree ni n g f or 
eac h s u bject will be a p pr o xi matel y 2 1 da ys. T he s u bject accr ual peri o d is pla n ne d f or 
a p pr o xi matel y 1 5 m o nt hs. T he d urati o n of treat me nt will var y f or eac h s u bject. S u bjects will 
recei ve taze met ostat i n c o nti n u o us 2 8- da y c ycles. S u bjects ma y disc o nti n ue st u d y treat me nt at 
a n y ti me d ue t o disease pr o gressi o n, de vel o p me n t of a n u nacce pta ble t o xicit y, wit h dra wal of 
c o nse nt, or ter mi nati o n of t he st u d y. 
S u bjects will ha ve a n E O T visit u p t o 3 0 da ys after last d ose of treat me nt i n t his st u d y or pri or t o 
t he start of a ne w a ntica ncer t hera p y, w hic he ver occ urs first. All s u bjec ts will be f oll o we d f or 
s ur vi val.  
7. 2. 2. 
E n d of St u d y
Pri m ar y C o m pleti o n : T his i ncl u des ti me u ntil t he last s u bject is assesse d or recei ves a n 
i nter ve nti o n f or t he p ur p oses of fi nal c ollecti o n of data f or t he pri mar y a nal ysis of t he st u d y. T he 
pri mar y c o m pleti o n is e x pecte d t o occ ur a p pr o xi mate l y 6 m o nt hs after t he date t he last s u bject is 
e nr olle d t o treat me nt a n d e val uate d f or res p o nse. 


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 5 0
E n d of St u d y: T his i ncl u des ti me w he n t he last s u bject  is assesse d or recei ves a n i nter ve nti o n 
f or e val uati o n i n t he st u d y. T he e n d of st u d y will occ ur w he n t he last s u bject disc o nti n ues t he 
st u d y treat me nt a n d has ha d t he o p p ort u nit y t o c o m plete t he e n d of treat ment visit or t he l o n g-
ter m s ur vi val f oll o w- u p peri o d, w hic he ver is later. Please re vie w if t his la n g ua ge is still 
a p plica ble.  
7. 3.  
R ules f or S us pe nsi o n of E nr oll me nt
T he I n vesti gat ors, I nstit uti o nal Re vie w B o ar ds (I R B)/ Et hics C o m mittees ( E C), re g ulat or y 
a ge ncies a n d I D M C will be ur ge ntl y i nf or me d a n d t he I D M C c o n ve ne d t o re vie w t he data a n d t o 
ma ke rec o m me n dati o ns f or p ote ntial c ha n ges i n st u d y c o n d uct if o ne or m ore s u bjects de vel o p 
a n y of t he f oll o wi n g A Es dee me d t o be defi nitel y relate d t o st u d y treat me nt b y t he I n vesti gat or 
a n d/ or Me dical M o nit or, base d u p o n cl ose te m p oral relati o ns hi p or ot her fact ors:
Deat h
S y m pt o matic br o nc h os pas m, wit h or wit h o ut  urticaria; pare nteral i nter ve nti o n 
i n dicate d; aller g y-relate d e de ma/a n gi oe de ma; h y p ote nsi o n  
T- L B L/ T- A L L 
S h o ul d st u d y e nr oll me nt be s us pe n de d, t he st u d y will n ot be restarte d u n til all parties ha ve 
a gree d t o t he c o urse of acti o n t o be ta ke n a n d t he I R Bs/ E Cs ha ve bee n n otifie d. 
If a case of a d ult T- L B L/ T- A L L occ urs, e nr oll me nt will be s us pe n de d, a n d t he be nefit-ris k of t he 
dr u g will be assesse d b y t he Taze met ostat Safet y  C o m mittee a n d will be c o m m u nicate d t o all 
Healt h A ut h orities a n d Et hics C o m mittees ( Secti o n 1 4. 4. 3 ).


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 5 1
8. 
S U B J E C T P O P U L A TI O N
8. 1.  
N u m ber of S u bjects
It is e x pecte d t hat a p pr o xi matel y 1 3 0- 2 9 1 s u bjects will be e nr olle d. Eac h c o h ort (e xce pt C o h orts 
6 a n d 8) will use a t w o-sta ge Gree n- Da hl ber g desi g n. See Secti o n 1 7. 2. 1 f or sa m ple size 
ass u m pti o ns. T he n u m ber of s u bjects t o be e nr olle d i n eac h sta ge are pr o vi de d i n t he ta ble bel o w: 
E ac h C o h ort Se p ar atel y:
C o h ort 1 ( R h a b d oi d t u m ors)
C o h ort 2 ( Rel a pse d/refr a ct or y 
s y n o vi al s arc o m a)
C o h ort 3 (I NI 1- ne g ati ve/ E Z H 2 G O F 
m ut ati o n)
C o h ort 4 ( Re n al me d ull ar y 
c arci n o m a)
C o h ort 7 ( C h or d o m a)
C o h ort 5
( E S; 
t aze met ost at 
8 0 0 m g BI D)
C o h ort 6
( E S 
u n der g oi n g 
o pti o n al 
bi o ps y)
C o h ort 8
( E S; 
t aze met ost at 
1 6 0 0 m g Q D)
Sta ge 1
1 5
1 5
N A
N A
Sta ge 2
1 5
1 5
N A
N A
E x pa nsi o n
N A
3 0
N A
N A
T ot al
 3 0
6 0
6 5 
1 6 ( N ote: 
C o h ort 8 was 
cl ose d pri or 
t o reac hi n g 
t his 
e nr oll me nt 
g oal)
A b bre viati o ns: BI D   t wice dail y; E S   e pit helial sarc o ma; G O F   gai n of f u ncti o n; N A   n ot a p plica ble; Q D   
o nce dail y; R/ R   rela pse d/ refract or y; R M C   re nal me d ullar y carci n o ma.
8. 2. 
I ncl usi o n Criteri a
A s u bject m ust meet A L L of t he f oll o wi n g criteria t o be eli gi ble f or e nr o ll me nt i n t his st u d y:
1.  A ge (at t he ti me of c o nse nt/asse nt): 1 8 years of a ge 
2.  Has a n Easter n C o o perati ve O nc ol o g y Gr o u p ( E C O G) perf or ma nce stat us of 0, 1, or 2 
(A p pe n di x 1 ) 
N O T E: If s u bject is u na ble t o wal k d ue t o paral ysis, b ut is m o bile i n a w heelc hair, s u bject is 
c o nsi dere d t o be a m b ulat or y f or t he p ur p ose of assessi n g t heir perf or ma nce stat us.
3.  Has pr o vi de d si g ne d writte n i nf or me d c o nse nt 
4.  Has a life e x pecta nc y of > 3 m o nt hs
5.  Has a mali g na nc y:
F or w hic h t here are n o sta n dar d t hera p ies a vaila ble ( C o h orts 1, 3, 4, & 5) 


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 5 2
T hat is rela pse d or refr act or y, defi ne d as metastatic or n o n-resecta ble, l ocall y 
a d va nce d disease t hat has pre vi o usl y bee n  treate d wit h a n d pr o gresse d f oll o wi n g 
a p pr o ve d t hera p y(ies), if t her a p y(ies) e xists ( C o h ort 2)  
T hat has pr o gresse d wit hi n 6 m o nt hs pri o r t o st u d y e nr oll me nt ( C o h ort 5 E x pa nsi o n, 
C o h ort 6, a n d C o h ort 8 o nl y) 
6.  Has a d oc u me nte d l ocal dia g n ostic pat h ol o g y of  ori gi nal bi o ps y c o nfir me d b y a Cli nical 
La b orat or y I m pr o ve me nt A me n d me nts ( C LI A)/ C olle ge of A merica n Pat h ol o gists ( C A P) 
or ot her S p o ns or-a p pr o ve d la b orat or y certificati o n
7.
F or C o h ort 1 (r h a b d oi d t u m ors) o nl y: T he f oll o wi n g test res ults m ust be a vaila ble b y 
l ocal la b orat or y:
M or p h ol o g y a n d i m m u n o p he n ot y pic pa nel c o nsiste nt wit h r ha b d oi d t u m ors, a n d 
L oss of I NI 1 or S M A R C A 4 c o nfir me d b y I H C, or 
M olec ular c o nfir mati o n of t u m or bi-allelic I NI 1 or S M A R C A 4 l oss or m utati o n w he n 
I NI 1 or S M A R C A 4 I H C is e q ui v ocal or u na vaila ble 
8.
F or C o h ort 2 (s u bjects wit h rel a pse d/ refr act or y s y n o vi al s arc o m a) o nl y: T he 
f oll o wi n g test res ults m ust be a vaila ble b y l ocal la b orat or y:
M or p h ol o g y c o nsiste nt wit h s y n o vial sarc o ma, a n d 
C yt o ge netics or Fl u oresce nce i n sit u h y bri dizati o n ( FI S H) a n d/ or m olec ular 
c o nfir mati o n (e. g., D N A se q ue nci n g) of S S 1 8 rearra n ge me nt t( X; 1 8)( p 1 1; q 1 1) 
9.
F or C o h orts 3, 4, 5, 7, a n d 8 (s u bjects wit h I NI 1- ne g ati ve t u m ors or a n y s oli d t u m or 
wit h E Z H 2 G O F m ut ati o n) o nl y: T he f oll o wi n g test res ults m ust be a vaila ble b y l ocal 
la b orat or y:
M or p h ol o g y a n d i m m u n o p he n ot y pic pa nel c o nsis te nt wit h I NI 1- ne gati ve t u m ors ( n ot 
a p plica ble f or s oli d t u m ors wit h E Z H 2 G O F m utati o n), a n d 
L oss of I NI 1 c o nfir me d b y I H C, or 
M olec ular c o nfir mati o n of t u m or bi-allelic I NI 1 l oss or m utati o n w he n I NI 1 I H C is 
e q ui v ocal or u na vaila ble, or 
M olec ular e vi de nce of E Z H 2 G O F m utati o n
1 0. F or C o h ort 6 (s u bjects wit h E S u n d er g oi n g o pti o n al t u m or bi o ps y) o nl y: 
M or p h ol o g y a n d i m m u n o p he n ot y pic pa nel c o nsiste nt wit h E S (e. g., C D 3 4, E M A, 
Kerati n, a n d I NI 1)
If pr o vi di n g o pti o nal bi o ps y: Willi n g ness t o pr o vi de i nf or me d c o nse nt t o u n der g o 
pre- a n d p ost- d ose bi o ps y  
1 1.  Has all pri or treat me nt (i.e., c he m ot he ra p y, i m m u n ot hera p y, radi ot hera p y) relate d 
cli nicall y sta ble a n d n ot cli nicall y  si g nifica nt, at ti me of e nr oll me nt


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 5 3
1 2. Pri or a nti-ca ncer t hera p y(ies), if a p plica ble , m ust be c o m plete d acc or di n g t o t he criteria 
bel o w: 
Pri or T her a p y
Ti me fr o m L ast Pri or T her a p y 
C he m ot hera p y: c yt ot o xic
At least 1 4 da ys si nce last d ose of c he m ot hera p y pri or t o 
first d ose of taze met ostat
C he m ot hera p y: nitr os o ureas
At least 6 wee ks si nce last d ose of nitr os o ureas pri or t o 
first d ose of taze met ostat
C he m ot hera p y: n o n-c yt ot o xic 
(e. g., s mall m olec ule i n hi bit or)
At least 1 4 da ys si nce last d ose of n o n-c yt ot o xic 
c he m ot hera p y pri or t o first d ose of taze met ostat
M o n ocl o nal a nti b o d y (ies)
At least 2 8 da ys si nce t he last d ose of m o n ocl o nal a nti b o d y 
pri or t o first d ose of taze met ostat
I m m u n ot hera p y (e. g., t u m or vacci ne)  
At least 4 2 days si nce last d ose of i m m u n ot hera p y a ge nt(s) 
pri or t o first d ose of taze met ostat
Ra di ot hera p y ( R T)
At least 1 4 da ys fr o m last l ocal site R T pri or t o first d ose 
of taze met ostat
At least 2 1 da ys fr o m stere otactic ra di os ur ger y pri or t o first 
d ose of taze met ostat
pel vis, or t otal b o d y irra diati o n pri or t o first d ose of 
taze met ostat
Hi g h D ose T hera p y wit h a ut ol o g o us or 
all o ge neic he mat o p oi etic cell i nf usi o n
At least 6 0 da ys fr o m last i nf usi o n pri or t o first d ose of 
taze met ostat
He mat o p oietic gr o wt h fact or i n s u p p ort of 
a nti-ca ncer t h era p y
At least 1 4 da ys fr o m last d ose of he mat o p oietic gr o wt h 
fact or pri or t o first d ose of taze met ostat
1 3.  Has s ufficie nt t u m or tiss ue (sli des or bl oc ks ) a vaila ble f or ce ntral c o nfir mat or y testi n g of 
I H C a n d/ or c yt o ge netics/ FI S H a n d/ or D N A m utati o n a nal ysis (re q uire d f or st u d y e ntr y 
b ut e nr oll me nt base d o n l ocal res ults).
1 4.  Has me as ur a ble  disease base d o n eit her R E CI S T 1. 1 f or s oli d t u m ors or R A N O f or C N S 
t u m ors as defi ne d i n Secti o n 1 2. 5. 5 .
1 5.  Has a de q uate he mat ol o gic ( b o ne marr o w a n d c oa g ulati o n fact ors) , re nal a n d he patic 
f u ncti o n as defi ne d b y criteria bel o w: 
S yste m
L a b or at or y V al ue
He m at ol o gic ( B o ne M arr o w F u ncti o n)
He m o gl o bi n a 
Platelets b 
3
9/ L)
A N C c
3
9/ L)
He m at ol o gic ( C o a g ul ati o n F act ors)
I N R/ P Td
< 1. 5 U L N


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 5 4
S yste m
L a b or at or y V al ue
P T T
< 1. 5 U L N
Re n al F u ncti o n
Ser u m creati ni ne e
He p atic F u n cti o n
T otal f bilir u bi n
A S T g
A L T g 
A b bre viati o ns: A L T   ala ni ne a mi n otra nsferase; A N C   a bs ol ute ne utr o p hil c o u nt; A S T   as partate 
a mi n otra nsferase; Cr Cl   creati ni ne cleara nce; L L N   l o wer li mit of n or mal; P T   pr ot hr o m bi n ti me; P T T   partial 
t hr o m b o plasti n ti me; U L N   u p per li mit of n or mal
a
Ma y recei ve tra nsf usi o n
b 
S h o ul d be e val uate d after at least 7 da ys si nce last platelet tra nsf usi o n
c  
Wit h o ut gr o wt h fact or s u p p ort (fil grasti m or pe gfil grasti m) f or at least 1 4 da ys
d 
I N R is t he preferre d val ue t o be meas ure d. H o we ver, if o nl y P T ca n be perf or me d i n t he testi n g la b orat or y t hat 
is acce pta ble
e 
- Ga ult met h o ds or l ocal i nstit uti o nal 
sta n dar d a n d Cr Cl m ust be > 5 0  m L/ k g/ 1. 7 3 m 2 (see A p pe n di x 3 )
f
or c o nj u gate d bilir u bi n.
g
1 6. S u bjects a hist or y of he pati tis ( E xcl usi o n Criteri o n N o. 1 3 ) m ust ha ve A L T wit hi n t he 
n or mal ra n ge
N O T E:  La b orat or y res ults o btai ne d d uri n g scree ni n g s h o ul d be use d t o deter mi ne 
eli gi bilit y criteria. I n sit ua ti o ns w here la b orat or y res ults are o utsi de t he per mitte d 
ra n ge, t he I n vesti gat or ma y retest t he su bject a n d t he s u bse q ue nt wit hi n ra n ge 
scree ni n g res ult  ma y be use d t o deter mi ne t he s u bject’s eli gi bilit y.
1 7. F or s u bjects wit h C N S t u m ors o nl y: S u bject m ust ha ve seiz ures t hat are sta ble, n ot 
i ncreasi n g i n fre q ue nc y or se verit y a n d c o ntr olle d o n c urre nt a nti-seiz ure me dicati o n(s) 
f or a mi ni m u m of 2 1 da ys pri or t o t he pla n ne d first d ose of taze met ostat
N O T E: S u bjects ma y recei ve gl uc oc ortic oi ds (at sta ble or ta peri n g d ose) t o c o ntr ol 
C N S s y m pt o ms pri or t o e nr oll me nt; h o we v er, s u bjects s h o ul d recei ve a sta ble or 
ta peri n g d ose f or at least 7 da ys pri or t o pla n ne d first d ose of taze met ostat
1 8.
( E C H O) or m ulti- gate d ac q uisiti o n ( M U G A) sca n a n d Ne w Y or k Heart Ass ociati o n 
A p pe n di x 2 ) 
1 9.
msec
2 0. Fe m ale s u bjects of c hil d be ari n g p ote nti al m ust: 


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 5 5
Ha ve a ne gati ve beta-
- h C G) pre g na nc y test at ti me 
of scree ni n g a n d wit hi n 1 4 da ys pri or t o pla n ne d first d ose of taze met ostat ( uri ne or 
ser u m test is acce pta ble h o we ver, p ositi ve uri ne tests m ust be c o nfir me d wit h ser u m 
testi n g), a n d
A gree t o use effecti ve c o ntra ce pti o n, as defi ne d i n Secti o n  1 2. 6. 1 , fr o m a mi ni m u m of 
7 da ys pri or t o first d ose u n til 6 m o nt hs f oll o wi n g t he last d ose of taze met ostat a n d 
ha ve a male part ner w h o uses a c o n d o m, or
Practice tr ue a bsti ne nce, ( w he n t his is i n li n e wit h t he preferre d a n d us ual lifest yle of 
t he s u bject, see Secti o n 1 2. 6. 1)  or
Ha ve a male part ner w h o is vasect o mize d 
2 1. M ale s u bjects wit h a fe m ale p art ner of c hil d be ari n g p ote nti al m ust: 
Be vasect o mize d, or
A gree t o use c o n d o ms as defi ne d i n Secti o n  1 2. 6. 2 , fr o m first d ose of taze met ostat 
u ntil 3 m o nt hs f oll o wi n g t he last d ose of taze met ostat, or
Ha ve a fe male part ner w h o is N O T of c hil d beari n g p ote ntial 
8. 3. 
E xcl usi o n Criteri a
S u bjects meeti n g A N Y of t he f o ll o wi n g criteria m ust N O T be e nr olle d i n t his st u d y:
1.  Has ha d pri or e x p os ure t o taze met ostat or  ot her i n hi bit or(s) of e n ha ncer of zeste 
h o m ol o g ue- 2 ( E Z H 2)
2.  Has partici pate d i n a n ot her i nter ve nti o nal c li nical st u d y a n d recei ved i n vesti gati o nal dr u g 
wit hi n 3 0 da ys or 5 half-li ves, w hic he ver is  l o n ger, pri or t o t he pla n ne d first d ose of 
taze met ostat
3.  Has k n o w n acti ve C N S or a n y le pt o me ni n geal metastasis of pri mar y e xtracra nial t u m or. 
S u bjects wit h pre vi o usl y treate d brai n metastases ma y partici pate pr o vi de d t he y are sta ble 
( wit h o ut e vi de nce of pr o gressi o n b y i ma gi n g 4 wee ks pri or t o t he first d ose of st u d y dr u g 
a n d a n y ne ur ol o gic s y m pt o ms ha ve sta bilize d ), ha ve n o e vi de nce of ne w or e nlar gi n g 
brai n metastases, a n d are o n sta ble or ta peri n g d o ses of ster oi ds f or at least 7 da ys pri or t o 
first d ose of st u d y dr u g.  
N O T E: S u bjects wit h as y m pt o matic brai n metastases f o u n d o n scree ni n g M RI ma y 
be e ntere d i nt o t he st u d y wit h o ut pri or ra diati o n t hera p y t o t he brai n if t he y d o n ot 
re q uire i m me diate s ur gical or ra diati o n t hera p y i n t he o pi ni o n of t he treati n g 
I n vesti gat or a n d i n t he o pi ni o n of a ra diati o n t hera p y or ne ur os ur gical c o ns ulta nt. 
4.  Has ha d a pri or mali g na nc y ot her t ha n t he mali g na ncies u n der st u d y  
E xce pti o n:  S u bject w h o has bee n disease-free f or 5 years, or a s u bject wit h a hist or y 
of a c o m pletel y resecte d n o n- mela n o ma s ki n  ca ncer or s uccessf ull y treate d i n sit u 
carci n o ma is eli gi ble.
5.  Has ha d maj or s ur ger y wit hi n 3 wee ks pri or t o e nr oll me nt 


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 5 6
N O T E:  Mi n or s ur ger y (e. g., mi n or bi o ps y of e xtracra nial site, ce ntral ve n o us cat heter 
place me nt, s h u nt re visi o n) is per mitte d  wit hi n 3 wee ks pri or t o e nr oll me nt.
6.
per o or a n y pri or hist or y of  m yel oi d mali g na ncies, i ncl u di n g m yel o d ys plastic s y n dr o me 
( M D S). Has a b n or malities k n o w n t o be ass ociate d wit h M D S (e. g. del 5 q, c hr 7 a b n) a n d 
M P N (e. g. J A K 2 V 6 1 7 F) o bser ve d i n c yt o ge netic testi n g a n d D N A se q ue nci n g.  
N O T E: B o ne marr o w as pirate/ bi o ps y w ill be c o n d ucte d f oll o wi n g a b n or mal 
peri p heral bl o o d s mear m or p h ol o g y assess me nt  c o n d ucte d b y ce ntral la b orat or y. 
C yt o ge netic testi n g a n d D N A se q ue nci n g wi ll be c o n d ucte d f oll o wi n g a n a b n or mal 
res ult of b o ne marro w as pirate/ bi o ps y.
7.  Has a pri or hist or y of T- L B L/ T- A L L.
8. Is u n willi n g t o e xcl u de gra pef r uit j uice, Se ville ora n ges a n d gra pefr uit fr o m t he diet a n d 
all f o o ds t hat c o ntai n t h o se fr uits fr o m ti me of e nr oll me nt t o w hile o n st u d y.
9.  Has car di o vasc ular i m pair me nt, hist or y of c o n gesti ve heart fail ure greater t ha n N Y H A 
Class II, u nc o ntr olle d arterial h y perte nsi o n, u ns ta ble a n gi na, m y ocar dial i nfarcti o n, or 
str o ke wit hi n 6 m o nt hs pri or t o t he pla n ned first d ose of taze met ostat; or ve ntric ular 
car diac arr h yt h mia re q u iri n g me dical treat me nt
1 0. Is c urre ntl y ta ki n g a n y pr o hi bite d me dicati o n(s) as descri be d i n Secti o n 1 1. 3
1 1.  Has a n acti ve i nfecti o n re q uiri n g s yste mic treat me nt
1 2. Is i m m u n oc o m pr o mise d (i.e ., has a c o n ge nital i m m u n o deficie nc y), i ncl u di n g s u bjects 
k n o w n hist or y of i nfecti o n wit h h u m a n i m m u n o deficie nc y vir us ( HI V) 
1 3.  Has k n o w n acti ve i nfecti o n wit h he pati tis B vir us or he patitis C vir us  
N O T E:  S u bjects wit h a hist or y of he patitis B or C wit h n or mal A L T a n d u n detecta ble 
H B V D N A or H C V R N A are eli g i ble f or t his st u d y
1 4.  Has ha d a s y m pt o matic ve n o us t hr o m b osis wit hi n 2 wee ks pri or t o st u d y e nr oll me nt 
N O T E:  S u bjects wit h a hist or y of a dee p vei n t hr o m b osis > 2 wee ks pri or t o st u d y 
e nr oll me nt w h o are o n a ntic oa g ulati o n t hera p y wit h l o w m olec ular wei g ht he pari n are 
eli gi ble f or t his st u d y.
1 5. F or s u bjects wit h C N S i n v o l ve me nt ( pri m ar y t u m or or met ast atic dise ase): Ha ve a n y 
acti ve blee di n g, or ne w i ntra-t u m oral he m o rr ha ge of m ore t ha n p u nctate size o n 
scree ni n g M RI o btai ne d wit hi n 1 4 da ys of starti n g st u d y dr u g or k n o w n blee di n g 
diat hesis or treat me nt wit h a nti- platelet or a nti-t hr o m b otic a ge nts. 
1 6.  Has k n o w n h y perse nsiti vit y t o a n y of t he c o m p o n e nts of taze met ostat or ot her i n hi bit or(s) 
of E Z H 2
1 7. Is u na ble t o ta ke oral me dicati o ns, or has mala bs or p ti o n s y n dr o me or a n y ot her 
u nc o ntr olle d gastr oi ntesti nal c o n diti o n (e. g., na usea,  diarr hea or v o miti n g) t hat mi g ht 
i m pair t he bi oa vaila bilit y of taze met ostat


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 5 7
1 8.  Has a n u nc o ntr olle d i nterc urre nt ill ness i ncl u di n g, b ut n ot li mite d t o, u nc o ntr olle d 
i nfecti o n, or ps yc hiatric ill ness/s ocial sit uati o ns t hat w o ul d li mit c o m plia nce wit h st u d y 
re q uire me nts.
1 9. F or fe m ale s u bjects of c hil d be ari n g p ote nti al: Is pre g na nt or n ursi n g 
2 0. F or m ale s u bjects: Is u n willi n g t o a d here t o c o ntrace pti o n criteria fr o m ti me of 
e nr oll me nt i n st u d y t o at least 3 m o nt hs after last d ose of taze met ostat.


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 5 8
9. 
I N V E S TI G A TI O N A L P R O D U C T
9. 1.  
Descri pti o n
Taze met ostat ( E P Z- 6 4 3 8) is a n E p iz y me i n vesti gati o nal pr o d uct (I P) a n d is defi ne d as a n 
I n vesti gati o nal Me dici nal Pr o d uct (I M P) u n der t he E ur o pea n U ni o n Cli nical Trials Directi ve 
( E U C T Dir). Taze met ostat (tra de na me: T A Z VE RI K ®) has recei ve d accelerate d a p pr o val f or 
mar keti n g i n t he U S t o treat t he f oll o wi n g:
A d ults a n d pe diatric patie nts a ge d 1 6 y ears a n d ol der wit h metastatic or l ocall y 
a d va nce d e pit heli oi d sarc o ma n ot eli gi ble f or c o m plete resecti o n.
A d ult patie nts wit h rela pse d or refract or y f ollic ular l y m p h o m a w h ose t u m ors are 
p ositi ve f or a n E Z H 2 m utati o n as detecte d b y a n F D A-a p pr o ve d test a n d w h o ha ve 
recei ve d at least 2 pri or s yste mic t hera pies.
A d ult patie nts wit h rela pse d or refr act or y f ollic ular l y m p h o ma w h o ha ve n o 
satisfact or y alter nati ve treat me nt o pti o ns.
I n Ja pa n, T A Z V E RI K has recei ve d a p pr o val f or t he treat me nt of s u bjects wit h rela pse d or
refract or y E Z H 2 ge ne m utati o n p ositi ve F L (li mite d t o use w he n diffic ult t o treat wit h sta n dar d 
treat me nts) b y E piz y me’s c o- de vel o p me nt part ner, Eisai.
T he c o nte nts of t he pac ka ge la bel will be i n acc or da nce wit h all a p plica ble re g ulat or y 
re q uire me nts. T he e x pir y date will be pri nte d o n t he la bel. 
I n vesti g ati o n al Pr o d uct
Pr o d uct na me:
Taze met ostat ( E P Z- 6 4 3 8)
F or m ulati o n descri pti o n: 
2 0 0 m g ta blet
D osa ge f or m:
Ta blet
P h ysical descri pti o n: 
Re d, r o u n d, a n d bic o n ve x fil m-c oate d ta blets pac ka ge d i n w hite hi g h-
de nsit y p ol yet h yle ne b ottle wit h a c hil d resista nt, ta m p er-e vi de nt 
p ol y pr o p yle ne scre w ca p
D ose/ R o ute/ Sc he d ule/ D urati o n:
 8 0 0
 m g/ O ral/ BI D/ C o nti n u o us ( C o h orts 1- 7)
1 6 0 0 m g/ Oral/ Q D/ C o nti n u o us ( C o h ort 8 O nl y)
9. 2. 
Pre p ar ati o n, H a n dli n g, a n d St or a ge of I n vesti g ati o n al Pr o d uct
Pre p ar ati o n: N o pre parati o n is nee de d.  
H a n dli n g: T he occ u pati o nal hazar ds a n d rec o m me n de d ha n dli n g pr oce d ures are pr o vi de d i n t he 
Material Safet y Data S heet ( M S D S). A M S D S  descri bi n g t he occ u pati o nal hazar ds a n d 
rec o m me n de d ha n dli n g preca uti o ns will be pr o vi de d t o site staff if re q uire d b y l ocal la ws or will 
ot her wise be a vaila ble fr o m t he S p o ns or u p o n re q uest. 
St or a ge: Taze met ostat m ust be st ore d i n a sec ure area, i n c o m plia nce wit h st ora ge re q uire me nts 
liste d o n t he la bel, wit h access li mite d t o t he I n vesti gat or a n d a ut h orize d site staff o nl y. 


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 5 9
9. 3.  
D os a ge a n d A d mi nistr ati o n
Taze met ostat m ust be dis pe nse d or a d mi nistere d o nl y t o s u bjects e nr olle d i n t he st u d y a n d i n 
acc or da nce wit h t he pr ot oc ol. Sta n dar d i nstit uti o nal pr oce d ures f o r a d mi nisteri n g a n oral a ge nt 
via b y m o ut h will be f oll o we d. A n a de q uate s u p p l y will be pr o vi de d wit h i nstr ucti o ns o n h o me 
a d mi nistrati o n.
Taze met ostat will be a d mi nistere d at t he R P 2 D of 8 0 0 m g/ d ose gi ve n BI D (e xce pti o n: C o h ort 8). 
D oses m ust be a d mi nistere d at l east 8 h o urs a part. A n a de q uate s u p pl y will be pr o vi de d wit h 
i nstr ucti o ns o n h o me a d mi nistrati o n.
C o h ort 8:  Taze met ostat will be a d mi nistere d at 1 6 0 0 m g d ose gi ve n Q D. 
Taze met ostat will be a d mi niste re d wit h or wit h o ut f o o d. 
V o miti n g: If t he s u bject v o mits wit hi n 3 0 mi n utes of d osi n g, a nti-e metics s h o ul d be gi ve n a n d a 
sec o n d fres h d ose of st u d y treat me nt gi ve n. All d oses gi ve n, misse d, a n d v o mite d, s h o ul d be 
rec or de d.  
R oll o ver St u d y  
All s u bjects w h o recei ve d taze met o stat i n t his st u d y ( E Z H- 2 0 2) a n d are eli gi ble t o c o nti n ue 
recei vi n g taze met ostat or t o c onti n ue s ur vi val f oll o w- u p, ca n tra nsfer t o a R oll o ver St u d y 
( E Z H- 5 0 1) f or c o nti n ue d st u d y dr u g a n d/ or c o nti n ue d m o nit ori n g at t he I n vesti gat or a n d Me dical 
M o nit or’s discreti o n. 
9. 3. 1.  
Misse d D oses
Taze met ostat 8 0 0 m g d oses gi ve n BI D m ust be ta ke n at least 8 h o urs a part. If a d ose is misse d 
(e. g., misse d m or ni n g d ose or v o mite d a n d di d n ot re- d ose wit hi n a p pr o priate ti me) it s h o ul d n ot 
be ta ke n if it is less t ha n  8 h o urs u ntil t he ne xt d ose. 
F or s u bjects i n C o h ort 8 w h o recei ve taze met ostat 1 6 0 0 m g  Q D, d osi n g s h o ul d occ ur at 
a p pr o xi matel y t he sa me ti me e ac h da y. If a d ose is misse d, it s h o ul d be ta ke n t he f oll o wi n g da y 
at t he re g ularl y sc he d ule d ti me.
9. 3. 2. 
Pr oc ure me nt of I P
T he i nitial s hi p me nt of taze met os tat t o a cli nical site will occ ur after all esse ntial re g ulat or y 
d oc u me nts (i ncl u di n g, b ut n ot li mite d t o t he recei p t of t he si g ne d pr ot oc ol si g nat ure pa ge, si g ne d 
F or m F o o d a n d Dr u g A d mi nistrati o n ( F D A) 1 5 7 2 or State me nt of I n vesti gat or, c urric ul u m vitae 
( C V) of Pri nci pal I n vesti gat or ( PI) a n d desig nees, I R B/ E C a p pr o val letter, a n d a p pr o ve d 
i nf or me d c o nse nt f or m [I C F]) are c ollecte d.
Refer t o t he P har mac y Ma n ual f or d irecti o ns o n re-s u p pl y s hi p me nts. 
9. 4.  
Acc o u nt a bilit y
T he I n vesti gat or/ desi g nee will be  res p o nsi ble f or ta ki n g a n i n vent or y of eac h s hi p me nt of 
taze met ostat recei ve d a n d c o m pari n g it wit h t he acc o m pa n yi n g s hi p me nt f or m. T he 
I n vesti gat or/ desi g nee will verif y t he acc urac y of t he i nf or mati o n o n t he f or m, si g n, a n d date it, 
a n d ac k n o wle d ge t he s hi p me nt recei pt acc o r di n g t o t he i nstr ucti o ns pr o vi de d. 


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 6 0
T he I n vesti gat or/ desi g nee m ust kee p acc urate wr itte n rec or ds of all taze met ostat recei ve d fr o m 
t he S p o ns or. A d diti o nall y, t he I n vesti gat or/ desi g nee m ust kee p acc urate rec or ds of t he 
taze met ostat dis pe nse d t o s u bjects e nr olle d i n t his st u d y i ncl u di n g t he q ua ntit y of ta blets, l ot 
n u m ber, date dis pe nse d, s u bject i nitials a n d i d e ntificati o n n u m ber, d ose a d mi nistere d, bala nce 
f or war d, a n d t he i nitials of t he pers o n dis pe nsi n g t he I P. Base d o n t he e ntries i n t he site 
acc o u nta bilit y f or ms, it m ust be p ossi ble t o rec o ncile I P deli vere d  wit h t hat use d a n d ret ur ne d. 
All I P m ust be acc o u nte d f or a n d all discre pa ncies i n vesti gate d  a n d d oc u me nte d a p pr o priatel y. 
Taze met ostat st oc k ma y n ot be re m o ve d fr o m t he i n vesti gati ve site w here ori gi nall y s hi p pe d 
wit h o ut pri or k n o wle d ge a n d c o nse nt of t he S p o n s or or its desi g nee. W he n a ut h orize d, all 
a p plica ble l ocal, state, a n d nati o nal la ws m ust be a d here d t o f or t he tra nsfer. 
At t he e n d of t he st u d y, all u n use d taze met ostat will be destr o ye d b y t he i n vesti gati ve site or se nt 
t o a desi g nate d c o ntract or f or disp osal o n be half of t he S p o ns or, per t he i nstr ucti o ns at t hat ti me. 
A n y I P ret ur ne d t o t he S p o ns or- desi g nate d c o nt ract ors m ust be c o u nte d a n d verifie d b y site 
pers o n nel a n d t he S p o ns or or its desi g nee. All certificates of de li ver y/recei pts a n d/ or ret ur n 
f or ms m ust be si g ne d pri or t o s hi p me nt. T he I P f or ret ur n m ust be pac ke d i n a ta m per-e vi de nt 
ma n ner t o e ns ure i nte grit y is mai ntai ne d d uri n g ret ur n. All I P ret ur ne d m ust be i n acc or da nce 
wit h l ocal, state, a n d nati o nal la ws a n d m ust firs t be a ut h orize d b y t he S p o ns or pri or t o s hi p me nt. 


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 6 1
1 0. 
S T U D Y T R E A T M E N T
1 0. 1. 
Tre at me nt Assi g n me nt 
S u bjects will be i de ntifie d b y a u ni q ue s u bject n u m ber t hat will re mai n c o nsiste nt f or t he 
d urati o n of t he st u d y. 
1 0. 2.  
Restricti o ns D uri n g St u d y Tre at me nt
S u bjects will a bstai n fr o m i n ge sti n g Se ville ora n ges a n d gra pefr uit or gra pefr uit j uice a n d 
f o o ds/ be vera ges t hat c o ntai n t h ose, f or 2 4 h o urs pri or t o t he first d ose of st u d y treat me nt u ntil t he 
last d ose of st u d y treat me nt.
S u bjects s h o ul d a v oi d pr ol o n ge d e x p os ure t o s u nli g ht w hile recei vin g st u d y treat me nt. I n 
a d diti o n, s u bjects s h o ul d ta ke ot her meas ures t o  a v oi d U V e x p os ure s uc h as weari n g s u nscree n 
a n d s u n glasses, weari n g pr otecti ve cl ot hi n g, a n d a v oi di n g ta n ni n g be ds.
1 0. 3.  
D ose M o dific ati o n
N o m o dificati o n of d ose is re q uire d f or t he f oll o wi n g Gra de 3 or greater n o n- he mat ol o gic 
t o xicities:
Tra nsie nt fati g ue or ast he nia
Tra nsie nt m yal gia or art hral gia
Na usea t hat res ol ves t o < Gra de 2 wit hi n  7 da ys ( wit h or wit h o ut a nti-e metics)
V o miti n g t hat res ol ves t o < Gra de 2 wit hi n  4 8 h o urs ( wit h or wit h o ut a nti-e metics)
Diarr hea t hat res ol ves t o  < Gra de 2 wit hi n 4 8 h o urs 
1 0. 3. 1.  
D ose M o dific ati o n d ue t o Tre at me nt- Rel ate d T o xicit y
Ot her t o xicities t hat, i n t he o pi ni o n of t he I n vesti gat or are p ossi ble, pr o ba bl y, or defi nitel y 
relate d t o st u d y treat me nt, s h o ul d be ma na ge d per Ta ble 2. T o xicities t hat are felt b y t he 
I n vesti gat or t o be u nrelate d t o taze met ostat b ut cli nicall y si g nifica nt s h o ul d be disc usse d wit h t he 
Me dical M o nit or. I n t he e ve nt of a n ur ge nt u nrelate d t o xicit y, st u d y treat me nt s h o ul d be 
i nterr u pte d as per Ta ble 2 . F or a n y M D S/ A M L or ot her m yel oi d mali g na ncies li ke M P N, 
taze met ostat will be disc o nti n ue d. D ose re-escalati o n is n ot per mitte d. 


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 6 2
T a ble 2  
D ose M o dific ati o ns f or Tre at me nt- Rel ate d T o xicities
T o xicit y
a
D uri n g T her a p y
8 0 0 m g BI D 
t aze met ost at: D ose 
A dj ust me nt
b
1 6 0 0 m g Q D 
t aze met ost at: D ose 
A dj ust me nt b
Gr a de 1
All occ urre nces 
C o nti n ue st u d y treat me nt  
M ai ntai n d ose le vel  
Mai ntai n d ose le vel
Gr a de 2
c
All occ urre nces 
C o nti n ue st u d y treat me nt  
M ai ntai n d ose le vel  
Mai ntai n d ose le vel
Gr a de 3
d ( n ot i ncl u di n g ne utr o pe ni a)
1st occ urre nce
I nterr u pt st u d y treat me nt u ntil 
res ol ve d t o Gra de
b
Restart at 6 0 0 m g BI D 
Restart at 1 2 0 0  m g Q D
2 n d occ urre nce 
Restart at 4 0 0 m g BI D 
Restart at 8 0 0 m g Q D
3r d occ urre nce  
Disc o nti n ue st u d y treat me nt
N ot a p plica ble
Gr a de 3 ne utr o pe ni a ( A N C: < 1 – 0. 5 × 1 0 9/ L) 
1st occ urre nce
I nterr u pt st u d y treat me nt u ntil 
9/ L
Mai ntai n d ose le vel  
Mai ntai n d ose le vel
2 n d occ urre nce
Restart at 6 0 0 m g BI D 
Restart at 1 2 0 0  m g Q D
3r d occ urre nce 
Restart at 4 0 0 m g BI D 
Restart at 8 0 0 m g Q D
4t h occ urre nce 
Disc o nti n ue st u d y treat me nt
N ot a p plica ble
Gr a de 3 T hr o m b oc yt o pe ni a
1st occ urre nce
I nterr u pt taze met ostat u ntil 
b
Restart at 6 0 0 m g BI D 
Restart at 1 2 0 0  m g Q D
2 n d occ urre nce 
Restart at 4 0 0 m g BI D 
Restart at 8 0 0 m g Q D
3r d occ urre nce 
Disc o nti n ue taze met ostat
N ot a p plica ble
Gr a de 4
All occ urre nces 
I nterr u pt st u d y treat me nt u ntil 
a n d disc uss wit h Me dical M o nit or
Pe n di n g disc ussi o n 
wit h Me dical M o nit or
Pe n di n g disc ussi o n 
wit h Me dical M o nit or
A b bre viati o ns: A N C   a bs ol ute ne utr o p hil c o u nt; BI D   t wice dail y; Q D   o nce dail y
a E xcl u di n g al o pecia a n d na usea, v o miti n g or diarr hea n ot recei vi n g a de q uate treat me nt.
b A dela y of taze met ostat f or m ore t ha n 1 4 da ys d ue t o a n y t o xicit y m ust be disc usse d wit h t he Me dical M o nit or 
bef ore treat me nt ca n be res u me d.
c A n y case of Gra de 2 t o xicit y w hic h t he i n vesti gat or dee ms a n i nterr u pti o n or d ose m o dificati o n is warra nte d 
s h o ul d be disc usse d wit h t he Me dical M o nit or
d E xcl u de Gra de 3 a ne mia: S u bjects are all o we d t o c o nti n ue taze met ostat at t hei r c urre nt d ose le vel wit h tra nsf usi o n 
per I n vesti gat or discreti o n.
1 0. 4.  
C o nti n u ati o n of Tre at me nt
I n s u bjects t hat are p ote ntiall y be nefitti n g ( C R, P R, or S D per R E CI S T 1. 1 or R A N O) fr o m 
taze met ostat treat me nt a n d ha ve n ot i nc urre d u nacce pta ble t o xicit y, taze met ostat a d mi nistrati o n 


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 6 3
ma y be c o nti n ue d at t he I n vesti gat or’s discreti o n w it h t he s u bject’s or his/ her le gal re prese ntati ve 
c o nse nt. 
T here ma y be s o me i nsta nces w he n s u bjects are n ote d t o ha ve m o dest disease pr o gressi o n, f or 
e xa m ple a sli g ht i ncrease i n tar g et lesi o ns b ut wit h sta ble n o n-tar get lesi o ns, a n d i n t he a bse nce 
of cli nical deteri orati o n are recei vi n g c o nti n ue d c li nical be nefit i n t he o pi ni o n of t he I n vesti gat or. 
I n s uc h a sit uati o n, t he I n vesti gat or s h o ul d co ntact t he Me dical M o nit o r t o disc uss t he assess me nt 
of ris k: be nefit of kee pi n g t he s u bject o n st u d y.  
Pri or t o declari n g pr o gressi ve disease, t he I n vesti gat or s h o ul d be certai n t hat s pecial 
circ u msta nces o n pr o gressi o n defi ne d b y R E CI S T 1. 1 are n ot met. I n t hese sit uati o ns of 
e q ui v ocal fi n di n gs of pr o gressi o n, s u bjects ma y c o nti n ue treat ment u ntil t he ne xt sc he d ule d 
disease assess me nt. If pr o gressi o n is c o nfir me d, t he da te of t he pre vi o us assess me nt will be use d 
as t he date of disease pr o gressi o n.
St u d y treat me nt ma y c o nti n ue if t he f oll o wi n g para meters are met o n Da y 1 of eac h c ycle:
9/ L
9/ L, a n d  
A n y Gra de 3 or hi g her t o xicit y m ust ha ve res ol ve d t o Gra de 1 or baseli ne  
St u d y treat me nt ma y be i nterr u pte d  f or u p t o 1 4 da ys. Treat me nt i nterr u pti o ns l o n ger t ha n 
1 4 da ys nee d Me dical M o nit or a p pr o val t o pr ocee d.
R oll o ver St u d y  
All s u bjects w h o recei ve d taze met o stat i n t his st u d y ( E Z H- 2 0 2), a n d are eli gi ble t o c o nti n ue 
recei vi n g taze met ostat or t o c onti n ue s ur vi val f oll o w- u p, ca n tra nsfer t o a R oll o ver St u d y 
( E Z H- 5 0 1) f or c o nti n ue d st u d y dr u g a n d/ or c o nti n ue d m o nit ori n g at t he I n vesti gat or a n d Me dical 
M o nit or’s discreti o n. 
1 0. 5.  
D ur ati o n of T aze met ost at Tre at me nt
S u bjects ma y disc o nti n ue st u d y treat me nt at a n y ti me d ue t o disease pr o gressi o n, de vel o p me nt of 
a n u nacce pta ble t o xicit y, wit h dra wal of c o nse nt, or ter mi nati o n of t he st u d y.
S u bjects will ha ve a n E O T visit u p t o 3 0 da ys after last d ose of treat me nt i n t his st u d y or pri or t o 
t he start of a ne w a ntica ncer t hera p y, w hic he ver occ urs first. All s u bjec ts will be f oll o we d f or 
s ur vi val.  
1 0. 6. 
Tre at me nt C o m pli a nce
C o m plia nce f or d oses ta ke n o utsi de  of t he cli nic ma y be assesse d b y a c o u nt of t he ta blets 
ret ur ne d t o t he st u d y trial site b y t he s u bject a n d re vie w of d oses ta ke n wit h t he s u bject. T his will 
be rec or de d i n t he s o urce d oc u me nts, w hic h ma y i ncl u de t he use of a s u bject me dicati o n diar y 
per i nstit uti o nal practice.


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 6 4
1 0. 7. 
Tre at me nt of O ver d ose
I n t he e ve nt of a n o ver d ose of taze met ostat ( defi ne d i n Secti o n 1 4. 1. 4 ), t he I n vesti gat or s h o ul d 
c o ntact t he Me dical M o nit or or t heir desi g nee i mme diatel y a n d cl osel y m o nit or t he s u bject f or 
A Es/ S A E a n d la b orat or y a b n or malities.  
A s u bject s us pecte d of o ver d ose s h o ul d be m o nit ore d u ntil taze met ostat ca n n o l o n ger be 
detecte d s yste micall y. F or refere nce, fi ve half-li ves of taze met ostat w o ul d be at mi ni m u m 
2 5 h o urs, l o n ger i n s u bject wit h dela ye d cleara nce. Decisi o ns re gar di n g d ose i nterr u pti o ns or 
m o dificati o ns will be ma de b y t he I n vesti gat or i n  c o ns ultati o n wit h t he Me dical M o nit or or t heir 
desi g nee base d o n t he s u bject’s cli nical e val uati o n.
A plas ma sa m ple f or P K a nal ys is ma y be re q ueste d o n a case-b y-case basis. If re q ueste d, t he 
plas ma sa m ple s h o ul d be c ollecte d at  least wit hi n 7 da ys fr o m t he date of t he last d ose of st u d y 
treat me nt. 
T he q ua ntit y of t he e xcess d ose as well as t he d urati o n of t he o ve r d osi n g s h o ul d be d oc u me nte d 
i n t he e C R F.


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 6 5
1 1.  
C O N C O MI T A N T M E DI C A TI O N S
D oc u me ntati o n of all c o nc o mit a nt me dicati o n a d mi nistere d d u ri n g st u d y treat me nt will be 
rec or de d i n t he e C R F at eac h visit.
Beca use t here is a p ote ntial f or i n teracti o n of taze met ostat wit h ot her c o nc o mita ntl y a d mi nistere d 
dr u gs t hr o u g h t he c yt oc hr o me P 4 5 0 s yste m, o v er-t he-c o u nter me dicati o ns, or alter nati ve 
t hera pies m ust be rec or de d i n t he e C R F. T he I nvesti gat or s h o ul d be alerte d if t he s u bject is 
ta ki n g a n y a ge nt k n o w n t o affect or wit h t he p ote ntial t o affect selecte d C Y P 4 5 0 is oe nz y mes. 
1 1. 1. 
Per mitte d Me dic ati o n(s)
S u p p orti ve care meas ures a n d s y m pt o mati c treat me nt f or a n y treat me nt-relate d 
t o xicit y, i ncl u di n g s h ort c o urses of gl uc ocortic oi ds, if cli nicall y i n dicate d  
Gl uc oc ortic oi ds ma y be ta ke n b y s u bject s  wit h C N S t u m ors, u n der t he f oll o wi n g 
c o n diti o ns: 
F or c o ntr ol of ne ur ol o gi cal s y m pt o ms t hat ma y c o nti n ue at a ta peri n g d ose
I nter mitte nt use f or c o ntr ol of nausea ( n ot t o e xcee d 0. 3 m g/ k g/ d ose 
de xa met has o ne, ma xi m u m of 2 0 m g) e ver y 1 2 h o urs as nee de d  
N o n-e nz y me i n d uci n g a nti-e pile ptic dr u gs
Pr o p h ylactic use of st a n dar d a nti-e metics
Bl o o d a n d platelet tra nsf usi o ns, as nee de d  per t he j u d g me nt of t he I n vesti gat or 
1 1. 2.  
Me dic ati o ns t o be  use d wit h C a uti o n
S u bstrates of P- g p, C Y P 3 A, C Y P 2 C 8, C Y P 2 C 9, C Y P 2 C 1 9, a n d C Y P 2 D 6 s h o ul d be use d wit h 
ca uti o n. Me dicati o ns t hat are s u bstrates of C Y P 3 A, C Y P 2 C 8, C Y P 2 C 9, C Y P 2 C 1 9, a n d C Y P 2 D 6 
s h o ul d be a v oi de d if p ossi ble. 
N O T E: A listi n g of C Y P i n hi bit ors, i n d ucers, a n d s u bstrates ca n be f o u n d usi n g t he f oll o wi n g 
li n k: htt p:// me dici ne.i u p ui.e d u/ cli n p har m/ d dis/ta ble.as p x
A list of me dicati o ns t hat are P- g p s u bstrates a n d a list of me di cati o ns t hat are C Y P 3 A, C Y P 2 C 8, 
C Y P 2 C 9, C Y P 2 C 1 9, a n d C Y P 2 D 6 s u bstrates ca n be f o u n d wit h f oll o wi n g li n k: 
htt p:// w w w.f da. g o v/ Dr u gs/ De vel o p me nt A p pr o val Pr ocess/ De vel o p me nt Res o urces/ Dr u gI nteracti o
ns La beli n g/ uc m 0 9 3 6 6 4. ht m 
1 1. 3. 
Pr o hi bite d Me dic ati o n(s)
A nti ne o plastic t hera p y or ot her i n vesti gat i o nal t hera p y f or t he treat me nt of ca ncer
Pr o p h ylactic use of he mat o p oietic  c ol o n y sti m ulati n g fact ors 
N O T E: T hera pe utic use of he mat o p oietic c ol o n y sti m ulati n g fact ors is disc o ura ge d 
a n d s h o ul d be disc usse d wit h t he Me d ical M o nit or a n d s h o ul d be c o n d ucte d 


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 6 6
acc or di n g t o t he 2 0 0 6 A merica n S ociet y of C li nical O nc ol o g y ( A S C O) G ui deli ne f or 
use of w hite bl o o d cell ( W B C) gr o wt h fact ors (S mit h, 2 0 0 6 ).
Treat me nt  wit h str o n g i n hi bit ors or str o n g i n d ucers of C Y P 3 A 4 s h o ul d n ot be ta ke n 
wit hi n 1 4 da ys pri or t o first d ose of st u d y treat me nt a n d f or t he d urati o n of st u d y. 
N O T E:  A listi n g of C Y P i n hi bit ors, i n d ucers, a n d s u bstrates ca n be f o u n d usi n g t he 
f oll o wi n g li n k: htt p:// me dici ne.i u p ui.e d u/cli n p har m/ d dis/ta ble.as p x
E nz y me i n d uci n g a nti-e pile ptic dr u g(s) ( EI A E D) i ncl u di n g, b ut n ot li mite d t o, 
car ba maze pi ne, p he n o bar bital, p he n yt oi n, a n d bar bit urates, s h o ul d n ot be ta ke n 
wit hi n 1 4 da ys pri or t o t he first d ose of st u d y treat me nt a n d f or t he d urati o n of st u d y 
treat me nt
All her bal re me dies a n d (i ncl u di n g re me dies i n t he f or m of her bal teas/i nf usi o ns) are 
e xcl u de d w hile e nr olle d i n t he st u d y. 
Me dici nal f o o d s u p ple me nts s u c h as calci u m, f olic aci d, vita mi n D, m ulti- vita mi n, 
etc., w hic h ha ve bee n ta ke n u n der t he a d vi ce fr o m a p h ysicia n, s h o ul d be c o nti n ue d at 
t he sa me d ose a n d re gi me n d uri n g t he st u d y pr o vi de d t here are n o c o ntrai n dicati o n as 
a b o ve. T hese s h o ul d be liste d as c o nc o mita nt me dicati o ns i n t he C R F. 
A n y ot her s u p ple me nts or alte r nati ve t hera pies s h o ul d be disc usse d wit h t he me dical 
m o nit or pri or t o e nr oll me nt i n t he st u d y or pri or t o i nitiati n g t he m d uri n g t he st u d y.
1 1. 4.  
N o n- Dr u g T her a pies
R a di ati o n T her a p y: Palliati ve ra diati o n t hera p y a n d p ote nti al c o nc urre nt d ose i nterr u pti o ns will 
be per mitte d f or pai n or se vere s y m pt o m c o nt r ol after disc ussi o n wit h t he Me dical M o nit or. 
Ra diati o n will be li mite d t o n o n-tar get lesi o ns o nl y a n d d oc u me nte d i n t he e C R F. 
Ot her P alli ati ve Pr oce d ures : Ot her pr oce d ures i nte n de d f or s y m pt o m c o ntr ol a n d p ote ntial 
c o nc urre nt d ose i nterr u pti o ns ma y be per mitte d after disc ussi o n w it h t he Me dical M o nit or. T hese 
pr oce d ures will be li mite d t o  n o n-tar get lesi o ns o nl y a n d d oc u me nte d i n t he e C R F.  


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 6 7
1 2. 
S T U D Y  A S S E S S M E N T S A N D P R O C E D U R E S
I n vesti gat ors ma y be re q ueste d t o perf or m a d diti o nal safet y tests d uri ng t he c o urse of t he st u d y 
base d o n ne wl y a vaila ble data t o e ns ure a p pr o priate safet y m o nit o ri n g. A p pr o priate l ocal 
re g ulat or y a n d et hical a p pr o vals sh o ul d be o btai ne d bef ore a n y a d diti o nal testi n g is perf or me d. 








Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 7 1
h Vit al Si g ns: Bl o o d press ure ( B P), heart rate ( H R), a n d te m perat ure ( T) m ust be meas ure d after t he s u bject has bee n sitti n g f or fi ve mi n utes at scree ni n g a n d at 
re g ular i nter vals d uri n g treat me nt.
i E C G: 1 2-lea d E C G m ust be perf or me d at eac h visit pri or t o d osi n g. O n Da ys 1 a n d 1 5, a n a d diti o nal E C G s h o ul d be perf or me d at t he 1- h o ur p ost- d ose ti me. A 
si n gle E C G will be rec or de d u nless t her
a b n or malit y is o bser ve d, t he E C G is t o be perf or me d i n tri plicate at least 2 mi n utes a part. See Secti o n 1 2. 2 f or wi n d o w ti mi n g all o wa nces.
j E C H O: A n E C H O m ust be perf or me d at scree ni n g as part of t he scree ni n g car diac assess me nt f or st u d y e ntr y. If a n E C H O ca n n ot be perf or me d, a M U G A 
sca n is acce pta ble f or assess me nt of car diac f u ncti o n, b ut is n ot re q uire d.
k Pre g n a nc y Test: A ser u m or uri ne pre g na nc y test m ust be perf or me d at Scree ni n g f or all fe males w h o are of c hil d beari n g p ote ntial. A uri ne pre g n a nc y test 
s h o ul d be perf or me d bef ore t he first d ose of st u d y treat me nt if t he ne gati ve scree ni n g pre g na nc y test is > 7 2 h o urs pri or t o d os i n g. F or s u bse q ue nt testi n g, eit her 
a uri ne or ser u m pre g na nc y test is t o be perf or me d e ver y 4 wee k s ( m o nt hl y) after first d ose of stu d y treat me nt. P ositi ve uri ne tests s h o ul d be c o nfir me d wit h 
ser u m testi n g.
l L a b or at or y Tests: C he mistries i ncl u de: al kali ne p h os p hatase, A L T, A S T, bilir u bi n (c o nj u gate d bilir u bi n w he n p ossi ble or t otal bilir u bi n), electr o l ytes 
(i ncl u di n g s o di u m, p otassi u m, c hl ori de a n d bicar b o nate w he n p ossi ble), Bl o o d urea/ bl o o d urea nitr o ge n, creati ni ne, al b u mi n, calci u m, ma g nesi u m, gl uc ose, 
p h os p h or us, t otal pr otei n, a n d tri gl yceri des. A c o m plete peri p heral bl o o d s mear m or p h ol o g y assess me nt nee ds t o be c ollecte d al o n g wit h n or mal he mat ol o g y 
testi n g. If t he m or p h ol o g y res ults are a b n or mal, a b o ne marr o w as pirate/ bi o ps y will be re q uire d f or c yt o ge netic testi n g a n d D N A se q ue nci n g t o cl osel y m o nit or 
s u bjects f or a b n or malities ass ociate d wit h M D S/ A M L/ M P N. B o ne marr o w as pirate/ bi o ps y will be c o n d ucte d f oll o wi n g a n a b n or mal per i p heral bl o o d s mear 
m or p h ol o g y assess me nt c o n d ucte d b y t he ce ntral la b orat or y. C yt o ge netic testi n g a n d D N A se q ue nci n g will be c o n d ucte d f oll o wi n g a n  a b n or mal res ult of b o ne 
marr o w as pirate/ bi o ps y. See Secti o n 1 2. 5. 1 4 f or f urt her details. Creati ni ne cleara nce o nl y re q uire d if ser u m creati ni ne greater t ha n a g e a n d se x U L N. Creati ni ne 
cleara nce b y C oc kcr oft- Ga ult f or m ula ( A p pe n di x 3 ) or i nstit uti o nal sta n dar d. F or s u bjects wit h a hist or y of he patitis per E xcl usi o n Criteri o n N o. 1 1, he patitis 
titers s h o ul d be dra w n if A L T e xcee ds t he U L N at a n y ti me d uri n g  treat me nt wit h taze met ostat. 
m C o a g ul ati o n Pr ofile: C oa g ulati o ns tests i ncl u de: pr ot hr o m bi n ti me ( P T), partial t hr o m b o plasti n ti me ( P T T), a n d I N R.
n P G x: A si n gle 6 m L bl o o d sa m ple will be c ollecte d at Scree ni n g. D o n ot c ollect sa m ples f or P G x fr o m s u bjects e nr olle d after A me n d me n t 7.
o Circ ul ati n g D N A: 2 0 m L circ ulati n g t u m or D N A bl o o d sa m ples t o be o btai ne d at Scree ni n g a n d at ti me of eac h disease assess me nt i ncl u di n g at ti me of 
disease pr o gressi o n.
p T u m or Tiss ue: Arc hi val tiss ue ( bl oc k or sli des) will be re q ueste d f or ce ntral c o nfir mati o n of pat h ol o g y, I H C, a n d a d diti o nal m olec ular testi n g, e. g. detecti o n of 
s o matic m utati o ns a n d/ or ca n di date bi o mar kers of res p o nse. If arc hi ve d t u m or material is n ot a vaila ble t u m or bi o ps y o btai ne d d u ri n g Scree ni n g is als o 
acce pta ble.
q O pti o n al T u m or Bi o p s y f or T aze met ost at: A n o pti o nal t u m or bi o ps y is re q ueste d at scree ni n g a n d C 2 D 1 ( ± 7 da ys) t o assess t he i m m u ne pri mi n g effect of 
taze met ostat
r T u m or Bi o ps y f or T aze met ost at P D: A n o pti o nal t u m or bi o ps y t o assess H 3 K 2 7 is re q ueste d fr o m  all s u bjects, w he n me dicall y feasi ble, a n y ti me after 1 5 
da ys of c o nti n u o us d osi n g. T his ma y c oi nci de wit h t he Wee k 8 t u m or assess me nt.
s T u m or Bi o ps y at Dise ase Pr o gressi o n: A n o pti o nal T u m or bi o ps y is re q ueste d, w here me dicall y  feasi ble, at disease pr o gressi o n i n all s u bjects. 
t Disease Assess me nt: T u m or assess me nts b y dis ease-a p pr o priate sta n dar d criteria ( R E CI S T 1. 1 or R A N O) usi n g C T, M RI of k n o w n site s of disease as 
cli nicall y i n dicate d. F or s u bjects wit h b o ne disease or C N S disease at baseli ne, a b o ne or brai n sca n, res pecti vel y, is re q uire d  e ver y 8 wee ks or s o o ner, if 
cli nicall y i n dicate d. T u m or assess me nts m ust be perf or me d at Scree ni n g a n d e ver y ot her o d d n u m bere d c ycle be gi n ni n g at C ycle 3 Da y 1 ( ± 3 da ys) fr o m start 
of d osi n g (e ver y 8 wee ks a n d irres pecti ve of treat me nt dela ys) or s o o ner, if cli nicall y i n dicate d.
u Dise ase Assess me nt: 1 8 F D G- P E T sca n s h o ul d be perf or me d as cli nicall y i n dicate d at t he I n vesti gat or’s discreti o n, a n d is n ot a re q uire d t u m or assess me nt.
v O pti o n al C hest Ultr as o u n d: A n o pti o nal c hest ultras o u n d ma y be perf or me d e ver y 8 wee ks at t he I n vesti gat or’s discreti o n t o m o nit or f or earl y si g ns of T-
L B L/ T- A L L. 


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 7 2


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 7 3
1 2. 2. 
Ti mi n g Wi n d o w All o w a nces f or E C Gs 
E C G
Ti me p oi nt
T oler a nce Wi n d o w
pre- d ose
- 4 h o urs t o 0 h o ur
1- h o ur p ost- d ose
- 1 5 mi n utes/ + 1 5 mi n utes
1 2. 3.  
C o nse nt
A c hil d is a pers o n w h o has n ot attai ne d t he le gal a ge f or c o nse nt t o treat me nts or pr oce d ures 
i n v ol ve d i n researc h, u n der l ocal a n d/ or state la w.  
Asse nt mea ns a c hil d’s affir mati ve a gre e me nt t o partici pate i n researc h.
T he Nati o nal I nstit utes of Healt h ( NI H) i ncl u des i n di vi d uals u p t o t he a ge of 2 1 as mi n ors 
(c hil dre n); h o we ver, s o me l ocal a n d/ or state la ws ma y ha ve differe nt a ges or a ge ra n ges 
(i.e., s u bjects a ge d 1 5 t o 2 1 years) c o nsi dere d as a d ults f or t he p ur p oses of me dical decisi o n-
ma ki n g.  
T he l ocal I R B/ E C will deter mi ne if c o nse nt a n d/ or asse nt m ust be o btai ne d fr o m/f or eac h 
s u bject. T he I R B/ E C s h o ul d a p ply l ocal a n d/ or state la w(s) re late d t o t he a ge at w hic h a n 
i n di vi d ual is c o nsi dere d a mi n or (c hil d) or a n a d ult f or me di cal decisi o n- ma ki n g.  
W he n a c hil d ca n n ot le gall y gi ve c o nse nt, i nf or m e d c o nse nt m ust be o btai ne d fr o m o ne or b ot h 
of t heir ( bi ol o gical or a d o pti ve) pare nt(s) ( pare ntal c o nse nt) or t h e le gall y a p p oi nte d g uar dia n(s). 
Per missi o n fr o m pare nt(s) or g uar dia n(s) m ust be o btai ne d pri or t o e nr olli n g a c hil d i n a researc h 
st u d y. 
W he n, i n t he j u d g me nt of t he I R B/ E C, t he c hil d is ca pa ble of pr o vi di n g asse nt t he I R B/ E C ma y 
deter mi ne t hat asse nt is re q uire d. A de q uate pr o visi o ns s h o ul d be ma de f or s oliciti n g t he asse nt of 
t he c hil d, a n d w het her a n d h o w asse nt is o btai ne d m ust be d oc u me nte d.  
E m a nci p ate d Mi n ors: L ocal a n d/ or state la ws will deter mi n e t he a ge of e ma nci pati o n. Pare ntal 
c o nse nt is n ot necessar y if t he mi n or (c hil d) is e ma nci pate d.
M arrie d Mi n ors:
L ocal a n d/ or state la ws will deter mi ne if  a marrie d mi n or is c o nsi dere d t o be 
at t he a ge of maj orit y u p o n t heir bei n g marrie d a n d t h us pare ntal c o nse nt is n ot necessar y. Pr o of 
of marria ge is re q uire d.
1 2. 4. 
Scree ni n g Assess me nts
A si g ne d, writte n i nf or me d c o nse nt (a n d asse nt, if a p plica ble) m ust be o btai ne d pri or t o a n y 
st u d y-s pecific assess me nts or pr oce d ures bei n g perf or me d.
All scree ni n g assess me nts, i ncl u di n g t u m or assess m e nt, m ust be perf or me d wit hi n 2 1 da ys of 
e nr oll me nt.
Pr oce d ures c o n d ucte d as part of t he s u bject’s r o uti ne cli nical ma na ge me nt (e. g., bl o o d c o u nts, 
c he mistries, i ma gi n g st u dies) a n d o btai ne d pri or t o c o nse nt ma y be use d f or scree ni n g pr o vi de d 
t he pr oce d ure meets t he pr ot oc ol- defi ne d criteria a n d has bee n perf or me d i n t he ti mefra me of t he 
st u d y. 


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 7 4
1 2. 5. 
St u d y Assess me nts
F or st u d y assess me nts n ot i ncl u de d i n secti o ns bel o w (e. g., vital si g ns, perf or ma nce stat us, 
E C H O), refer t o t he Sc he d ule of  Assess me nts a n d Pr oce d ures i n Secti o n 1 2. 1 f or details.
1 2. 5. 1. 
P h ysic al E x a mi n ati o ns
1 2. 5. 2.  
C o m pre he nsi ve P h ysic al E x a mi n ati o n
A c o m pre he nsi ve p h ysical e xa mi nati o n of all b o d y s yste ms m ust be perf or me d at scree ni n g, 
Da y 1 of eac h C ycle t hereafter d ur i n g treat me nt b y a q ualifie d lice nse d i n di vi d ual. A re vie w of 
b o d y s yste ms will i ncl u de t he f oll o wi n g: 
Ge neral a p peara nce
S ki n
Hea d, Ears, E yes, N ose, T hr oat ( H E E N T)  
Res pirat or y
Car di o vasc ular
A b d o me n (i ncl u di n g li v er a n d ki d ne ys) 
Ne ur ol o gical e xa mi nati o n wit h se ns or y te sti n g a n d seiz ure stat us, if a p plica ble
M usc ul os keletal
Ge nit o uri nar y (re q uire d o nl y if cli nicall y i n dicate d) 
Wei g ht is re q uire d t o be meas ure d at scree ni n g, o n Da y 1 of eac h c ycle, a n d at t he E n d of 
Treat me nt visit. 
Hei g ht meas ure me nt is re q uire d at scree ni n g o nl y.
A n y a b n or malities or c ha n ges i n i nte nsit y n ote d  d uri n g t he re vie w of b o d y s yste ms s h o ul d be 
d oc u me nte d i n t he s o urce d oc u me nt a n d re p orte d a p pr o priatel y i n t he e C R F. If a ne w cli nicall y 
si g nifica nt fi n di n g (e. g., n ot n ote d at scree ni n g) occ urs fr o m t he i nitial taze met ostat 
a d mi nistrati o n u ntil t he e n d of t he st u d y, a n A E m u st be d oc u me nte d. I n a d diti o n, res ol uti o n of 
a n y a b n or mal fi n di n gs d uri n g t he st u d y will be n ote d i n s o urce d oc u me nt a n d t he e C R F if 
cli nicall y si g nifica nt.
T hese assess me nts will be c o m plete d as i n dicate d  i n t he Sc he d ule of Assess me nts a n d 
Pr oce d ures, refer t o Secti o n 1 2. 1 .
1 2. 5. 3. 
S y m pt o m- Directe d P h ysic al E x a mi n ati o n
A s y m pt o m- directe d p h ysical e xa mi nati o n m u st be perf or me d w he n a c o m plete p h ysical 
e xa mi nati o n is n ot re q uire d ( o n Da y 1 5 of C ycl es 1 a n d 2) b y a q ualifie d lice nse d i n di vi d ual. 
T his will c o nsist of a f oc use d re vie w of s y ste ms a n d p h ysical e xa mi nati o n a d dressi n g a n y ne w 
s y m pt o ms, A Es, or c o m plai nts.
T hese assess me nts will be c o m plete d as i n dicate d  i n t he Sc he d ule of Assess me nts a n d 
Pr oce d ures ( Secti o n 1 2. 1 ).


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 7 5
1 2. 5. 4. 
Electr oc ar di o gr a ms ( E C Gs)
T he E C Gs will be perf or me d as i n dicate d i n t he Sc he d ule of Assess me nts a n d Pr oce d ures 
( Secti o n 1 2. 1 ). Mac hi ne rea d E C Gs s h o ul d be re vie we d b y t he I n vesti gat or at t he ti me of 
assess me nt. A si n gle E C G will be re c or de d u nless t here is a n a b n or malit y, s uc h as pr ol o n ge d Q T 
msec, ne w arr h yt h mia, 
or ot her cli nicall y si g nifica nt fi n di n g. If a cli nicall y si g ni fica nt a b n or malit y is o bser ve d, t he E C G 
is t o be perf or me d i n tri plicate at least 2 mi n utes a part.
If car di ot o xicit y is s us pecte d, t he I n vesti gat or ma y c o n d uct a d diti o nal testi n g per i nstit uti o nal 
sta n dar d of care (e. g., car diac bi o mar kers i ncl u di n g B-t y pe na tri uretic pe pti de a n d car diac 
tr o p o ni n I or car diac tr o p o ni n T). 
1 2. 5. 5.  
Dise ase Assess me nt 
Disease assess me nt will be perf o r me d as i n dicate d i n t he Sc he d ule of Assess me nts a n d 
Pr oce d ures ( Secti o n 1 2. 1 ) a n d as descri be d i n A p pe n di x 5 a n d A p pe n di x 6 .
1 2. 5. 6.  
O pti o n al C hest Ultr as o u n d
A n o pti o nal c hest ultras o u n d ma y be perf or me d e ver y 8 wee ks al o n g wit h ot her ra di ol o gical 
assess me nts per t he pr ot oc ol. 
1 2. 5. 7. 
P h ar m ac o ki netics
N ote: A n n ual P K assess me nts are n o l o n ger re q uire d t o be c ollecte d f or s u bjects as of Pr ot oc ol 
A me n d me nt 1 0 (J ul y 2 0 2 1). A n n ual P K sa m ples c olle cte d fr o m s u bjects e nr olle d u n der pre vi o us 
versi o ns of t he pr ot oc ol will be a nal yze d as pla n ne d. H o we ver, ne w a n n ual P K sa m ples s h o ul d 
n ot be c ollecte d after J ul y 2 0 2 1, re gar dless of t he pr ot oc ol versi o n t he s u bject i nitiall y e nr olle d 
u n der. 
C o h ort 8 O nl y: 
Bl o o d sa m ples f or P K a nal yses are n o l o n ger re q uire d t o be c ollecte d fr o m s u bjects as of a 
Me m o t o File date d 1 4 Fe br uar y 2 0 2 0. Sa m ples pr e vi o usl y c ollecte d fr o m s u bjects will be 
a nal yze d as pla n ne d. 
Refer t o La b orat or y Ma n ual a n d see  Ta ble 3 f or a d diti o nal details.
1 2. 5. 8. 
P h ar m ac o ge n o mics ( P G x)
A si n gle w h ole bl o o d sa m ple is c ollecte d d ur i n g t he scree ni n g p hase t o pr o vi de D N A f or 
a nal ysis of ge nes i n v ol ve d i n dr u g dis p ositi o n (i.e., a bs or pti o n, distri b uti o n, meta b olis m, a n d 
e xcreti o n [ A D M E]). T his will s u p p ort i n vesti gati o n of w het her s u bject ge n ot y pe, s pecificall y of 
A D M E ge nes, is relate d t o t he P K of taze met ostat. N ote as of A me n d me nt 7 , s u bjects e nr olle d 
will n ot be teste d f or P G x; s uffic ie nt P K P G x data ha ve bee n c ollecte d t o deter mi ne t he r ole of 
ge netic varia bilit y o n t he di s p ositi o n of taze met ostat.
A la b orat or y ma n ual detaili n g t he P G x sa m ple c o llecti o n, pre parati o n, st ora ge, a n d s hi p pi n g 
pr ocess will be pr o vi de d.  


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 7 6
1 2. 5. 9. 
T u m or S a m pli n g
1 2. 5. 1 0.  
Arc hi ve T u m or or Bi o ps y at Scree ni n g
A n arc hi val t u m or bl oc k or bi o ps y is re q uire d at scree ni n g fr o m al l s u bjects e nr olle d i n t he st u d y. 
As a vaila ble, t he dia g n ostic pat h ol o g y bl oc k or t u m or tiss ue o btai n e d at t he ti me of t he s u bject's 
i nitial dia g n osis a n d/ or at t he ti me of s u bse q uent pr oce d ures is acce pta ble. T he S p o ns or or its 
desi g nee will ret ur n all bl oc ks t o t he ori gi nati n g site o n c o m pleti o n of t he ass ociate d a nal yses. If 
a t u m or bl oc k is n ot a vaila bl e, 1 0- 2 0 u nstai ne d, paraffi n-e m be d de d, t u m or-tiss ue c o ntai ni n g 
sli des ma y be pr o vi de d. Please see la b orat or y ma n ual f or details.
If arc hi ve t u m or material is n ot a vaila ble, t um or bi o ps y o btai ne d d uri n g scree ni n g als o is 
acce pta ble. Please see la b orat or y ma n ual f or details. 
I n de pe n de nt ce ntral c o nfir mati o n will n ot be re q uire d f or st u d y e ntr y. Ce ntral c o nfir mati o n of 
dia g n osis wit h a p pr o priate I H C, kar y ot y pi n g, a n d D N A se q ue nci n g as a p pr o priate will be 
perf or me d o n t he t u m or bl oc k or 1 0- 2 0 u nstai ne d sli des.
I n a d diti o n t o ce ntral c o nfir mati o n, f ull ge netic c haracterizati o n of t he S M A R C B 1 or S M A R C A 4 
l oc us will be perf or me d f or t h ose s u bjects deter mi ne d t o ha ve l oss of pr otei n e x pressi o n i n t heir 
t u m or. T hese st u dies nee d hi g h q ualit y D N A fr o m eit her fr oze n or f or mali n fi xe d paraffi n- 
e m be d de d ( F F P E) t u m or tiss ue. T heref ore, eit her  1 µ g of is olate d D N A, or fi ve 2 0 µ M t hic k 
secti o ns (scr olls) c ut fr o m t he F F P E bl oc ks are req ueste d. T his material is o pti o nal a n d is i n 
a d diti o n t o t he t u m or tiss ue pr o vi de d f or ce ntral c o nfir mati o n. T u m or tiss ue ma y be a nal yze d f or 
D N A, m R N A a n d/ or pr otei ns p ote ntiall y ass ociate d f or res p o nse t o taze met ostat u p t o a n d 
i ncl u di n g w h ole ge n o me se q ue nci n g. 
A la b orat or y ma n ual detaili n g t he t u m or sa m ple c o llecti o n, pre parati o n, st ora ge, a n d s hi p pi n g 
pr ocess will be pr o vi de d. 
1 2. 5. 1 1.  
O pti o n al T u m or Bi o psies T a ke n o n St u d y ( C o h orts 1 t hr o u g h 5, 7, a n d 8) 
A n o pti o nal t u m or bi o ps y f or P D a nal ysis is t o be re q ueste d fr o m all s u bjects, w he n me dicall y 
feasi ble, at a n y ti me f oll o wi n g 1 5 da ys of c o nti n u o us d osi n g. T his ma y c oi nci de wit h t he Wee k 8 
t u m or assess me nt. 
A n a d diti o nal t u m or bi o ps y is t o be re q ueste d fr o m all s u bjects, w he n me dicall y feasi ble, at 
disease pr o gressi o n t o e na ble assess me nt of  a da pti ve mec ha nis ms of resista nce.
A la b orat or y ma n ual detaili n g t he t u m or sa m ple c o llecti o n, pre parati o n, st ora ge, a n d s hi p pi n g 
pr ocess will be pr o vi de d.  
1 2. 5. 1 2.  
O pti o n al T u m or Bi o psies T a ke n o n St u d y ( C o h ort 6 O nl y)
O pti o nal t u m or bi o psies will be c ollecte d pre- d ose a n d at t he C ycle 2 Da y 1 visit ( ± 7 da ys) t o 
assess t he effects of taze met ostat o n i m m u ne pr i mi n g. T he bi o ps y s h o ul d o nl y be ta ke n w he n 
me dicall y safe a n d tec h nicall y feasi ble.
I n a d diti o n t o t he t w o o pti o nal bi o psies, a n a d diti o nal o pti o nal t hir d t u m or bi o ps y is t o be 
re q ueste d at disease pr o gressi o n fr o m all s u bject e nr olle d i n C o h ort 6. T he t hir d t u m or bi o ps y 
will be e xa mi ne d t o f urt her assess t he t u m or f o r i m m u ne pri mi n g a n d e na ble t he assess me nt of 
a da pti ve mec ha nis ms of resista nce.


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 7 7
A la b orat or y ma n ual detaili n g t he t u m or sa m ple c o llecti o n, pre parati o n, st ora ge, a n d s hi p pi n g 
pr ocess will be pr o vi de d.  
1 2. 5. 1 3.  
Circ ul ati n g T u m or D N A
Bl o o d sa m ples are c ollecte d at scr ee ni n g a n d at eac h res p o nse assess me nt t o pr o vi de circ ulati n g 
t u m or D N A t hat ca n be use d f or i de ntificati o n of ca n di date bi o mar kers of res p o nse t o 
taze met ostat.
A la b orat or y ma n ual detaili n g t he circ ulati n g t u m or D N A sa m ple c ollecti o n, pre parati o n, 
st ora ge, a n d s hi p pi n g process will be pr o vi de d. 
1 2. 5. 1 4.  
Cli nic al L a b or at or y Assess me nts
All cli nical la b orat or y assa ys will be perf or me d at l ocal la b orat ories acc or di n g t o t he la b orat or y’s 
n or mal pr oce d ures. Refere nce ra n ges will be s u p plie d b y t he la b orat or y a n d use d t o assess t he 
la b orat or y data f or cli nical si g nifica nce an d o ut of ra n ge pat h ol o gical c ha n ges. ( See  A p pe n di x 4
f or peri p heral bl o o d dra w n g ui deli nes). 
A b n or mal la b orat or y val ues w hic h are u ne x pecte d or n ot e x plai ne d b y t he s u bject’s cli nical 
c o n diti o n s h o ul d be re peate d u ntil c o nfir me d, e x pl ai ne d, or res ol ve d. La b orat or y val ue c ha n ges 
starti n g fr o m t he i nitial taze met ostat e x p os ure will be rec or de d i n t he e C R F  as a n A E if cli nicall y 
si g nifica nt. 
He m at ol o g y:  He m o gl o bi n, he mat ocrit, W B C, differe ntial bl o o d c o u nt wit h A N C, platelet c o u nt, 
a n d c o m plete peri p heral bl o o d s mear m or p h ol o g y assess me nt as c o n d ucte d b y t he l ocal 
la b orat or y are perf or me d at scree ni ng a n d at re g ular i nter vals.  
N ote: If t he peri p heral bl o o d s mear m or p h ol o g y assess me nts s h o w a b n or mal res ults, a b o ne 
marr o w as pirate/ bi o ps y will be re q uire d f or c y t o ge netic testi n g a n d D N A se q ue nci n g. T he 
c yt o ge netic testi n g a n d D N A se q ue nci n g will be c o n d ucte d b y t he ce ntral la b orat or y. 
C o a g ul ati o n Pr ofile: T his will i ncl u de: partial t hr o m b o plasti n ( P T), partial t hr o m b o plasti n ti me 
( P T T), a n d i nter nati o nal n or malize d rati o (I N R).
Ser u m C he mistr y: Ser u m c he mistries are perf or me d at Scree ni n g a n d at re g ular i nter vals. 
C he mistries (li ver f u ncti o n) i ncl u de al kali ne p h os p hatase, A L T, A S T, a n d bilir u bi n 
(c o nj u gate d bilir u bi n w he n p ossi ble or t otal bilir u bi n) 
C he mistries (re nal f u ncti o n) i ncl u de bl o o d urea nitr o ge n, creati ni ne, electr ol ytes 
(i ncl u di n g bicar b o nate w he n p ossi ble) 
C he mistries ( meta b olis m) i ncl u de al b u mi n, calci u m, ma g nesi u m, gl uc ose, 
p h os p h or us, t otal pr otei n,  a n d tri gl yceri des 
Uri n al ysis: Uri nal ysis testi n g t o i ncl u de at mi ni m u m gl uc ose, bl o o d, pr otei n, a n d p H, a n d is t o 
be perf or me d at scree ni n g, o n Da y 1 of eac h c y cle, a n d at t he E n d of Treat me nt visit. 
Cre ati ni ne Cle ar a nce: O nl y re q uire d if ser u m creati ni ne is  > 1. 5 u p per li mit of n or mal ( U L N). 
Creati ni ne cleara nce s h o ul d be calc ulate d b y C oc kcr oft- Ga ult f or m ula (A p pe n di x 3 ) or b y 
m L/ mi n/ 1. 7 3 m 2. 


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 7 8
B o ne M arr o w As pir ate/ Bi o ps y: At scree ni n g, a peri p heral bl o o d s mear will be c ollecte d al o n g 
wit h n or mal he mat ol o g y testi n g a n d assesse d f o r a b n or mal m or p h ol o g y. If res ults are a b n or mal 
t he n t he s u bject will be re q uire d t o u n der g o a b o ne marr o w as pirate / bi o ps y c o n d ucte d b y t he 
ce ntral la b orat or y. If m or p h ol o g y is  a b n or mal, t he n c yt o ge netic testi n g will be c o n d ucte d t o 
cl osel y m o nit or s u bjects wit h  c yt o ge netic testi n g a n d D N A se q ue nci n g f or a b n or malities k n o w n 
t o be ass ociate d wit h M D S (e. g. del 5 q, c hr 7 a b n) a n d M P N (e. g. J A K 2 V 6 1 7 F). If t he res ults 
are a b n or mal ( per t he ce ntral la b orat or y) a n d are ass ociate d wit h m yel oi d mali g na ncies, t he 
s u bject will be e xcl u de d fr o m t he st u d y. 
D uri n g t he st u d y, a d diti o nal te sts i ncl u di n g c o m plete perip heral bl o o d s mear m or p h ol o g y 
assess me nt al o n g wit h n or mal he mat ol o g y tes ti n g will be i ncl u de d. If t he m or p h ol o g y 
assess me nt s h o ws a b n or mal res ults a b o ne marr o w as pirate/ bi o ps y will be re q uire d f or 
c yt o ge netic testi n g a n d D N A se q ue nci n g as c o n d uc te d b y t he ce ntral la b orat or y. If c yt o ge netic 
testi n g a n d D N A se q ue nci n g s h o ws a b n or mal res ults, t he n taze met ostat will be hel d a n d after 
disc ussi o n wit h t he I n vesti gat or, d ose will be  m o difie d or dr u g will be disc o nti n ue d.  
1 2. 5. 1 5. 
S ur vi v al F oll o w- U p
S u bjects w h o per ma ne ntl y disc o nti n ue st u d y trea t me nt will be f oll o we d ( b y p h o ne, e mail or 
cli nic visit) f or s ur vi val e ver y 1 6 wee ks u ntil deat h, f ull wit h dra wal of c o nse nt, l ost t o f oll o w- u p, 
or u ntil t he s u bject has bee n f o ll o we d f or 2 years fr o m start of first d ose of st u d y treat me nt..
A E SI a n d s u bse q ue nt a nti-ca ncer  t hera p y i nf or mati o n will be c ollecte d t hr o u g h o ut t he s ur vi val 
f oll o w u p. 
1 2. 5. 1 6. 
S u bse q ue nt T her a p y After Disc o n ti n u ati o n of St u d y Tre at me nt
O nce a s u bject has per ma ne ntl y disc o nti n ue d st u d y treat me nt, e ver y eff ort s h o ul d be ma de t o 
ha ve t he s u bject c o m plete t he E n d of Treat me nt visit pri or t o i nitiati n g a n y s u bse q ue nt a nti-
ca ncer t hera p y (a p pr o ve d or i n ves ti gati o nal). P ost-st u d y a nti-ca ncer t hera p y will n ot be pr o vi de d 
as part of t his st u d y. T he s u bject ma y recei ve s u bse q ue nt a nti-ca ncer t hera p y at t he discreti o n of 
t he treati n g p h ysicia n. T he s u bse q uent a nti-ca ncer t hera p y s h o ul d be  d oc u me nte d o n t he e C R F.  
1 2. 5. 1 7. 
E v al u ati o n of Res p o nse t o S u bse q ue nt A nti- C a ncer T her a p y
T o i de ntif y a p ote ntial e pi ge net ic pri mi n g effect of taze met ostat, s u bjects w h o are wit h dra w n 
fr o m t his st u d y d ue t o disease pr o gressi o n a n d wh o g o o n t o recei ve s u bse q ue nt t hera p y s h o ul d 
be f oll o we d f or res p o nse w he ne ver p ossi ble. Data t o be rec or de d o n t he s u bse q ue nt re gi me n 
s h o ul d i ncl u de a ge nts recei ve d, best res p o nse, a n d d urati o n of res p o nse. 
Refer t o t he Sc he d ule of A ssess me nt a n d Pr oce d ures ( Secti o n 1 2. 1 ) f or a d diti o nal details.
1 2. 5. 1 8. 
Pre g n a nc y
T here has bee n n o e x perie nce t o date of t he use of  taze met ostat d uri n g pre g na nc y or lactati o n. I n 
a n o n g oi n g e m br y ofetal de vel o p me nt st u d y, e vi d e nce of i ncrease d s kel etal de vel o p me ntal 
a b n or malities i n fet uses fr o m t he pre g na nt rats relati ve t o fet uses fr o m c o ntr ol rats was o bser ve d. 
C o nse q ue ntl y, t here is a p ote ntial  ris k f or terat o ge nicit y, a n d preca uti o ns m ust be ta ke n t o a v oi d 
a n y pre g na nc y t hat c o ul d p ote ntiall y be c o ncei ve d d uri n g e x p os ure t o taze met ostat b y EI T H E R 
male O R fe male s u bjects.


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 7 9
1 2. 5. 1 9.  
Defi niti o n of C hil d be ari n g P ote nti al: Fe m ale S u bjects
A fe male s u bject is c o nsi dere d of c hil d beari n g p ote ntial if s he:
Is a nat o micall y a n d p h ysi ol o gicall y ca pa ble of bec o mi n g pre g na nt, a n d 
Will be or c o ul d p ossi bl y be se x uall y acti ve wit h a male w hile u n der g oi n g st u d y 
treat me nt wit h t he p ossi bilit y of p osi n g har m t o a fet us
A fe male s u bject is c o nsi dere d t o  be of n o n-c hil d bearin g p ote ntial (i.e ., p h ysi ol o gicall y i nca pa ble 
of bec o mi n g pre g na nt) if s he: 
Is p ost- me n o pa usal (at least 1 2 m o nt hs c o nsec uti ve a me n orr heic) 
Is s ur gicall y sterilize d (i.e., bilateral tu bal li gati o n, t otal h ysterect o m y, or bilateral 
o o p h orect o m y) wit h s ur ger y at least 1 m o nt h bef ore t he first d ose of st u d y treat me nt
Has a d oc u me nte d c o n ge nital or ac q uire d di s or der t hat is i nc o m pati ble wit h 
pre g na nc y 
1 2. 5. 2 0.  
Defi niti o n of C hil d be ari n g P ote nti al: M ale S u bjects
A male s u bject is c o nsi dere d of c hil d beari n g p ote ntial if he:
Is a nat o micall y a n d p h ysi ol o gicall y ca pa ble of ca usi n g a pre g na nc y i n a fe male 
part ner, a n d 
Will be or c o ul d p ossi bl y be se x uall y acti v e wit h a fe male ( w h o is or ma y bec o me 
pre g na nt) w hile u n der g oi n g st u d y treat me nt w it h t he p ossi bilit y of p osi n g har m t o a 
fet us
A male s u bject is c o nsi dere d t o be of n o n-c hil d beari n g p ote ntial if he:
Has a d oc u me nte d s uccessf ul vasect o m y ( wit h c o nfir me d az o os per mia)
1 2. 5. 2 1. 
Pre g n a nc y Testi n g 
All fe male s u bjects of c hil d beari n g p ote ntial m u st ha ve a ne gati ve pre g na nc y test ( uri ne or 
ser u m) at scree ni n g a n d wit hi n 1 4 da ys of t he first d ose of st u d y treat me nt. A se parate 
assess me nt is re q uire d if a ne gati ve scree ni n g pre g na nc y test w as o btai ne d m ore t ha n 7 2 h o urs 
bef ore t he first d ose of st u d y treat me nt. 
S u bse q ue nt pre g na nc y tests perf o r me d e ver y 4 wee ks after first d ose of st u d y treat me nt ma y be 
eit her uri ne or ser u m. 
P ositi ve uri ne tests are t o be c o nfir me d b y ser u m testi n g. 
1 2. 6. 
Pre ve nti o n 
1 2. 6. 1. 
Fe m ale S u bjects 
Fe males of c hil d beari n g p ote ntial  m ust a gree t o use a hi g hl y effecti ve met h o d of c o ntrace pti o n 
t hat res ults i n a fail ure rate of < 1 % per year w he n use d c o nsiste ntl y a n d c orrectl y, starti n g at 
scree ni n g, d uri n g st u d y treat me nt, a nd f or 6 m o nt hs after t he fi na l d ose of st u d y treat me nt, a n d 
ha ve a male part ner w h o uses a c o n d o m w he n usi n g h or m o nal c o ntrace pti ves.  


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 8 0
Acce pta ble hi g hl y effecti v e c o ntrace pti o n i ncl u des:
Place me nt of a n i ntra uteri ne de vice 
Esta blis he d h or m o nal c o n trace pti ve met h o ds: oral, i njecta ble, or i m pla nt. 
N O T E: Fe male s u bjects w h o are usi n g h or m o nal c o nt race pti ves m ust ha ve bee n o n a sta ble d ose 
of t he sa me h or m o nal c o ntrace p ti ve pr o d uct f or at least 4 wee ks pri or t o t he first d ose of st u d y 
treat me nt a n d m ust c o nti n ue t o use t he sa me c o ntrace pti ve d uri n g st u d y treat me nt a n d f or 6 
m o nt hs after disc o nti n ua ti o n of st u d y treat me nt. 
D ue t o t he p ote ntial of e nz y me i n d ucti o n wit h taze met ostat, fe male s u bjects w h o use h or m o nal 
c o ntrace pti ves s h o ul d use a n a d di ti o nal barrier met h o d of birt h c o ntr ol w hile o n st u d y treat me nt 
a n d f or 6 m o nt hs after disc o nti n uati o n of st u d y treat me nt. 
Fe male s u bjects e xe m pt fr o m t his re q uire me nt ar e s u bjects w h o practice tr ue a bsti ne nce w he n 
t his is i n li ne wit h t he preferre d a n d us ual lifest yle of t he s ubject ( peri o dic a bsti ne nce [e. g., 
cale n dar, o v ulati o n, s y m pt ot her ma l, p ost- o v ulati o n met h o ds], declarati o n of a bsti ne nce f or t he 
d urati o n of t he trial, a n d wit h dra wal are n ot acce pta ble met h o ds  of c o ntrace pti o n), or ha ve a 
male part ner w h o is vasect o mize d. If c urre ntl y a b sti ne nt, t he s u bject m ust a gree t o use a hi g hl y 
effecti ve met h o d of c o ntrace pti o n as descri be d a b o ve if t he y bec o me se x uall y acti ve d uri n g 
st u d y treat me nt, a n d f or 6 m o nt hs after disc o nti n uati o n of st u d y treat me nt. 
1 2. 6. 2.  
M ale S u bjects
Male s u bjects m ust a gree t o use c o n d o ms wit h t heir fe male part ner of c hil d beari n g p ote ntial 
fr o m first d ose of taze metostat u ntil 3 m o nt hs after t he fi nal d ose of taze met ostat. Males s h o ul d 
refrai n fr o m s per m d o nati o n f or 3 m o nt hs after t he fi nal d ose of taze met ostat.
1 2. 6. 3.  
Re p orti n g of Pre g n a nc y
Pre g na nc y will n ot be c o nsi dere d a n S A E. A n y re p ort of pre g na nc y rec or de d f or a n y fe male 
s u bject or a fe male part ner of a male s u bject s h o ul d be re p orte d. T o e ns ure s u bject safet y, eac h 
pre g na nc y m ust be re p orte d t o t he S p o ns or or its desi g nee wit hi n 2 wee ks of lear ni n g of its 
occ urre nce usi n g a cli nical t rial Pre g na nc y Re p ort F or m. A Pre g na nc y Re p ort F or m s h o ul d be 
c o m plete d a n d s u b mitte d b y e m ail a n d/ or fa x t o t he S p o ns or or its desi g nee.  
T he pre g na nt fe male s u bject m ust  be wit h dra w n fr o m t he st u d y. E ver y eff ort s h o ul d be ma de t o 
gat her i nf or mati o n re gar di n g t he pre g na nc y o utc o me u ntil 8 wee ks p os t- part u m. It is t he 
res p o nsi bilit y of t he I n vesti gat or t o o btai n all pre g na nc y i nf or mati o n.
Pre g na nc y c o m plicati o ns a n d electi ve ter mi nati o ns f or me dical reas o ns m ust be re p orte d as a n 
A E or S A E. S p o nta ne o us a b orti o ns  m ust be re p orte d as a n S A E. 
A n y S A E occ urri n g i n ass ociati o n wit h a pre g na nc y br o u g ht t o t he I n vesti g at or’s atte nti o n after 
t he s u bject has c o m plete d t he stu d y a n d c o nsi dere d b y t he I n vesti g at or as p ossi bl y relate d t o t he 
st u d y treat me nt, m ust be pr o m ptl y re p orte d t o t he S p o ns or. 
T he I n vesti gat or als o m ust atte m pt t o c ollect a n d re p o rt t o t he S p o ns or or its desi g nee pre g na nc y 
i nf or mati o n o n a n y fe male part ner of male st u d y s u bjects w h o bec o me pre g na nt w hile t he s u bject 
is e nr olle d i n t he st u d y. 


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 8 1
1 3.  
WI T H D R A W A L A N D R E P L A C E M E N T O F S U B J E C T S
1 3. 1.  
Wit h dr a w al of S u bjects fr o m Tre at me nt/ Pr oce d ures
S u bjects ha ve t he ri g ht t o wit h dra w fr o m t he st u d y at a n y ti me a n d f or a n y reas o n wit h o ut 
prej u dice t o f ut ure me dical ca re b y t he p h ysician or i nstit uti o n. 
S u bjects ( or le gall y a ut h orize d re prese ntati ves) ca n decli ne t o c o nti n ue recei vi n g taze met ostat 
a n d/ or ot her pr ot oc ol-re q uire d pr oce d ures at a n y ti me d uri n g t he st u d y b ut ca n c o nti n ue 
partici pati o n i n t he st u d y (e. g., f or f oll o w- u p i nf or mati o n). If t his occ urs t he I n vesti gat or is t o 
disc uss wit h t he s u bject a p pr o priate pr ocesses f o r disc o nti n uati o n a n d t he o pti o ns f or pr oce d ures 
t hat ma y c o nti n ue s uc h as c ollecti o n of data, i ncl u di n g e n d p oi nts an d A Es. T he I n vesti gat or m ust 
d oc u me nt t he a gree me nt i n t he pr oce d ures t hat t he s u bject will c o nti n ue wit h a n d t he le vel of 
f oll o w- u p t hat is a gree d t o b y t he s u bject (e. g., i n pers o n, b y tele p h o ne/ mail, t hr o u g h 
fa mil y/frie n ds, i n c orres p o n de nce/c o m m u nicati o n wit h ot her p h ysicia ns, fr o m re vie w of t he 
me dical rec or ds.) 
Reas o ns f or re m o val fr o m pr ot oc ol-re q uire d treat me nt or pr oce d ures mi g ht i ncl u de t he 
f oll o wi n g:
Disease pr o gressi o n
S u bject re q uest t o e n d st u d y tre at me nt a n d/ or pr oce d ures 
Safet y c o ncer n (e. g. A E, fail ure t o f o ll o w c o ntrace pti o n or pre g na nc y, e xcl u de d 
me dicati o n re q uire d)
1 3. 2.  
Wit h dr a w al of S u bjects fr o m St u d y
Wit h dra wal of f ull c o nse nt f or a st u d y mea ns t h at t he s u bjects d oes n ot wis h t o recei ve f urt her 
pr ot oc ol-re q uire d treat me nt, pr oc e d ures a n d d oes n ot wis h t o or is u na ble t o c o nti n ue f urt her 
st u d y partici pati o n. S u bject data u p t o wit h dra wal of c o nse nt will be i ncl u de d i n t he a nal ysis of 
t he st u d y, a n d w here per mitte d, p u blicl y a vaila ble data ca n be i ncl u de d after wit h dra wal of 
c o nse nt (e. g., deat h rec or ds). T he I n vesti gat or m ust d oc u me nt t his a gree me nt re gar di n g 
wit h dra wal of f ull c o nse nt as well as disc uss a p pr o priate pr oce d ures f or wit h dra wal fr o m t he 
st u d y.  
Reas o ns f or re m o val of a s u bject fr o m t he st u d y mi g ht i n cl u de t he f oll o wi n g:
Deat h
Decisi o n b y S p o ns or t o ter mi nate t he st u d y 
S u bject re q uest t o wit h dra w fr o m st u d y
L ost t o f oll o w- u p 
1 3. 3.  
Re pl ace me nt of S u bjects
S u bjects will n ot be re place d i n t his st u d y.


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 8 2
1 4.  
A D V E R S E E V E N T S A N D S E RI O U S A D V E R S E E V E N T S
1 4. 1.  
Defi niti o ns
1 4. 1. 1.  
A d verse E ve nt ( A E)
A n A E is a n y u nt o war d me dical occ urre nce i n a patie nt or cli nical i n vesti gati o n s u bject 
a d mi nistere d a me dici nal pr o d uct a n d w hic h d oes n ot necessaril y ha ve t o ha ve a ca usal 
relati o ns hi p wit h t his treat me nt. A n A E ca n t heref ore be a n y u nfa v ora ble a n d u ni nte n de d si g n 
(i ncl u di n g a n a b n or mal la b orat or y fi n di n g), s y m pt o m, or disease te m p orall y ass ociate d wit h t he 
use of a n i n vesti gati o nal pr o d uct (I P) , w het her or n ot relate d t o t he I P. 
W orse ni n g of a pre-treat me nt e ve nt, after i nitia ti o n of taze met ostat, m ust be rec or de d as a ne w 
A E. F or e xa m ple, if a s u bject e x perie nces mil d  i nter mitte nt d ys pe psia pri or t o d osi n g 
taze met ostat, b ut t he d ys pe psia bec o mes se vere a n d m ore freq ue nt after t he first d ose of 
taze met ostat, a ne w A E of se vere w orse ni n g d yspe psia ( wit h t he a p pr o priate date of o nset) 
s h o ul d be rec or de d i n t he e C R F. 
“ Lac k of efficac y” or “fail ure of a n e x pecte d p har mac ol o gical acti o n” per se is n ot t o be re p orte d 
as a n A E or S A E. H o we ver, a n y si g ns a n d s y m p t o ms a n d/ or cli nical se q uelae res ulti n g fr o m 
“lac k of efficac y” will be re p orte d as a n A E or S A E, if t he y f ulfill t he defi niti o n of a n A E or 
S A E. 
E ve nts t hat d o n ot  meet t he defi niti o n of a n A E i ncl u de: 
Me dical or s ur gical pr oce d ure (e. g., e n d osc o p y, a p pe n dect o m y); t he c o n diti o n t hat 
lea ds t o t he pr oce d ure is a n A E. 
Sit uati o ns w here a n u nt o war d me dical occ urre nce di d n ot oc c ur (s ocial a n d/ or 
c o n ve nie nce a d missi o n t o a h os pital). 
A ntici pate d da y-t o- da y fl uct uati o ns of pre-e xisti n g disease(s) or  c o n diti o n(s) prese nt 
or detecte d at t he start of  t he st u d y t hat d o n ot w orse n. 
1 4. 1. 2.  
A d verse E ve nts Ass oci ate d wit h T u m or Bi o psies
F or s u bjects u n der g oi n g bi o psies, site pers o n nel will rec or d t he occ urre nce a n d nat ure of eac h 
s u bject’s pre-e xisti n g c o n diti o n(s) pri or t o o btai ni n g a bi o ps y. If a pre-e xisti n g c o n diti o n w orse ns 
(i ncreases i n se verit y or fre q ue nc y) after t he bi o ps y, t he w orse ne d c o n diti o n is t o be c o nsi dere d 
as a n A E. T he I n vesti gat or will re p ort a n y A Es ass ociate d wit h t h e bi o ps y, i ncl u di n g a n y 
treat me nt(s) (e. g., a nti bi otics f or i nfecti o n). A d diti o nall y, t he In vesti gat ors will deter mi ne t he 
relati o ns hi p of eac h A E t o t he st u d y pr oce d ure of o btai ni n g a bi o ps y, seri o us ness a n d i nte nsit y, 
a n d w het her st u d y dr u g ha d bee n a d mi nistere d (i. e., di d A E occ ur d uri n g pre- d ose bi o ps y).  
1 4. 1. 3. 
Seri o us A d verse E ve nt ( S A E)
A n S A E is a n y u nt o war d me dical occ urre nce t hat, at a n y d ose: 
a. Res ults i n deat h
b. Is life t hreate ni n g


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N O T E:  T he ter m 'life t hreate ni n g' i n t he defi niti o n of 'seri o us' refers t o a n e ve nt i n 
w hic h t he s u bject was at ris k of deat h at t he ti me of t he e ve nt. It d oes n ot refer t o a n 
e ve nt, w hic h h y p ot heticall y mi g ht ha ve ca use d deat h, if it were m ore se vere. 
c. Re q uires h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n 
N O T E:  I n ge neral, h os pitalizati o n si g nifies t hat t he s u bject has bee n detai ne d 
( us uall y i n v ol vi n g at least a n o ver ni g ht sta y) at t he h os pital or e mer ge nc y war d f or 
o bser vati o n a n d/ or treat me nt t h at w o ul d n ot ha ve bee n a p pr o priate i n t he p h ysicia n’s 
office or o ut patie nt setti n g. C o m plicati o ns t hat occ ur d uri n g h os pitalizati o n are A Es. 
If a c o m plicati o n pr ol o n gs h os pitalizati o n or f ulfills a n y ot her seri o us criteria, t he 
e ve nt is seri o us. W he n i n d o u bt as t o w het her “ h os pitalizati o n” occ urre d or was 
necessar y, t he A E s h o ul d be c o nsi dere d seri o us. 
H os pitalizati o n f or electi ve treat me nt of a pr e-e xisti n g c o n diti o n t hat di d n ot w orse n 
fr o m baseli ne is n ot c o nsi dere d a n A E. 
d. Res ults i n disa bilit y/i nca pacit y, or
N O T E: T he ter m disa bilit y mea ns a s u bsta ntia l disr u pti o n of a pers o n’s a bilit y t o 
c o n d uct n or mal life f u ncti o ns. T his defi niti o n is n ot i nte n de d t o i ncl u de e x perie nces 
of relati vel y mi n or me dical si g nifica nce s uc h as u nc o m plicate d hea dac he, na usea, 
v o miti n g, diarr hea, i nfl ue nza, a n d acci de ntal tra u ma (e. g., s prai ne d a n kle) w hic h ma y 
i nterfere or pre ve nt e ver y da y life f u nctio ns b ut d o n ot c o nstit ute a s u bsta ntial 
disr u pti o n. 
e. Is a c o n ge nital a n o mal y/ birt h defect.  
f.  
Me dicall y si g nifica nt: i m p orta nt me dical e ve nts t hat ma y n ot be i m me diatel y life 
t hreate ni n g or res ult i n deat h or h os pitalizati o n b ut ma y je o par dize t he s u bject or ma y 
re q uire me dical or s ur gical i nter ve nti o n t o pre ve nt o ne of t he ot her o utc o mes liste d i n 
t he a b o ve defi niti o n. E xa m ples i ncl u de i nte nsi ve treat me nt i n a n e mer ge nc y r o o m or 
at h o me f or aller gic br o nc h os pas m, bl o o d d yscrasias or c o n v ulsi o ns (i n s u bjects 
wit h o ut pre-e xisti n g seiz ure dis or der).
1 4. 1. 4. 
S peci al Sit u ati o ns
A Es ass ociate d wit h st u d y dr u g o ver d ose, mis use,  a b use, a n d me dicati o n err or refer t o A Es 
ass ociate d wit h uses of t he st u d y dr u g o utsi de of t hat s pecifie d b y t he pr ot oc ol. O ver d ose, 
mis use, a b use, a n d me dicati o n err or are defi ne d as f oll o ws: 
O ver d ose: A n o ver d ose is defi ne d, re gar dless of a n y ass ociate d A Es or se q uelae, as:
O n a per d ose basis, a n y a m o u nt of t he orall y  a d mi nistere d dr u g(s) t hat is o ver t he 
pr ot oc ol-s pecifie d d ose assi g ne d t o a gi ve n s u bject. 
O n a sc he d ule or fre q ue nc y basis, a n yt hi n g ta ke n m ore fre q ue ntl y t ha n t he 
pr ot oc ol-re q uire d sc he d ule or fre q ue nc y.
Mis use:  I nte nti o nal a n d i na p pr o priate use of st u d y dr u g n ot i n acc or da nce wit h t he 
pr ot oc ol  
A b use:  S p ora dic or persiste nt i nte nti o nal e xcessi ve use of st u d y dr u g acc o m pa nie d 
b y har mf ul p h ysical or ps yc h ol o gical effects  


Cli nical St u d y Pr ot oc ol A me n d me nt
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Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 8 4
Me dic ati o n err or:
A n y u ni nte nti o nal e ve nt t hat ca u ses or lea ds t o i na p pr o priate 
st u d y dr u g use or s u bject har m w hile t he st u d y dr u g is i n t he c o ntr ol of site pers o n nel 
or t he s u bject.  
All i nsta nces of s pecial sit ua ti o ns m ust be re p orte d o n t he d osi n g a d mi nistrati o n e C R F. A Es 
ass ociate d wit h t hese occ urre nces are t o be ca pt ure d o n t he A E e C R F.
All i nsta nces of s pecial sit uati o ns are t o be re p orte d usi ng t he S A E f or m, re gar dless of prese nce 
or a bse nce of a n ass ociate d A E. Refer t o Secti o n 1 4. 1 2  f or detaile d i nstr ucti o ns o n h o w t o ha n dle 
t he re p orti n g of s pecial sit uati o ns.
I n t he e ve nt of a s pecial sit uati o n, t he I n vesti gat or s h o ul d i m me diatel y c o ntact t he Me dical 
M o nit or or t heir desi g nee a n d cl osel y m o nit o r t he s u bject f or A Es/S A Es a n d la b orat or y 
a b n or malities.
1 4. 2. 
L a b or at or y A b n or m alities
A cli nical la b orat or y A E is a n y la b orat or y val ue t hat is c o nsi dere d cli nicall y si g nifica nt b y t he 
I n vesti gat or a n d has ca use d a me dical i nter ve nti o n or acc o m pa nie d b y cli nical s y m pt o ms. 
La b orat or y a b n or malities t hat ha ve n ot re q uire d me dical i nter ve nti o n s h o ul d n ot be rec or de d as 
A Es a n d will be ca pt ure d a n d re p orte d i n t he La b orat or y secti o n of t h e cli nical st u d y re p ort 
( C S R). If a me dical i nter ve nti o n occ urs, it s h o ul d be rec or de d as a treat me nt wit h t he a b n or mal 
la b orat or y fi n di n g as t he A E (e. g., a ne mia wit h treat me nt re q uire d a n d bl o o d tra nsf usi o n 
rec or de d as a pr oce d ure, h y per gl yce mia wit h treat me nt re q uire d a n d c ha n ge i n i ns uli n d ose 
rec or de d o n c o nc o mita nt me dicati o ns).
T he I n vesti gat or s h o ul d deci de, base d u p o n t he A E criteria a n d t he cli n ical c o n diti o n of t he 
s u bject, w het her a c ha n ge i n a la b orat or y parameter is cli nicall y si g nifica nt a n d t heref ore 
re prese nts a n A E.
If, at t he e n d of t he treat me nt p hase wit h t he st u d y dr u g, t here are pat h ol o gical la b orat or y val ues 
w hic h were n ot prese nt at baseli ne, f urt her cli n ical or la b orat or y i n vesti gati o ns s h o ul d be 
perf or me d u ntil t he val ues ret ur n t o wit hi n refere nce ra n ge or u ntil a pla usi ble e x pla nati o n (i.e., 
c o nc o mita nt disease) is f o u n d f or t he pat h ol o gical la b orat or y val ues.
1 4. 3.  
Ot her S afet y Assess me nt A b n or m alities
Ot her safet y assess me nts (e. g., E C Gs, ra di ol o gical sca ns, vital si g ns meas ure me nts), i ncl u di n g 
t h ose t hat w orse n fr o m baseli ne a n d e ve nts i n t he me dical a n d scie ntific j u d g me nt of t he 
I n vesti gat or are c o nsi dere d t o be cli nicall y si g nifica nt, are t o be rec or de d as a n A E or S A E, i n 
acc or da nce wit h t he defi niti o ns pr o vi de d i n Secti o n 1 4. 1. 1  a n d Secti o n  1 4. 1. 3 , res pecti vel y.  
A n y ot her safet y assess me nt t hat le d t o a n i n ter ve nti o n, i ncl u di n g per ma ne nt disc o nti n uati o n of 
st u d y treat me nt, d ose re d ucti o n, a n d/ or d ose i nterr u pti o n/dela y is als o t o be rec or de d as a n A E or 
S A E. 
1 4. 3. 1.  
Dise ase- Rel ate d E ve nts
E ve nts t hat meet t he criteria f or seri o us ness b u t are t h o u g ht t o be ass ociate d wit h pr o gressi o n of 
t he disease u n der st u d y s h o ul d n ot be re p orte d as S AEs u nless t he y are u nt o war d f or t hat s u bject 
a n d/ or disease u n der i n vesti gati o n.  


Cli nical St u d y Pr ot oc ol A me n d me nt
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Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 8 5
N O T E: Disease pr o gressi o n s h o ul d n ot be re p orte d as a n S A E ter m.
1 4. 4.  
A d verse E ve nts of S peci al I nterest ( A E SIs)
A n A E SI (seri o us or n o n-seri o us) is o ne of scie ntific a n d me dical c o ncer n s pecific t o t he 
S p o ns or’s pr o d uct or pr o gra m, f or w hic h o n g oi n g m o nit ori n g a n d ra pi d c o m m u nicati o n b y t he 
I n vesti gat or t o t he S p o ns or ca n be a p pr o priate. S uc h a n e ve nt mi g ht warra nt f urt he r i n vesti gati o n 
i n or der t o c haracterize a n d u n dersta n d it. Depe n di n g o n t he nat ure of t he e ve nt, ra pi d 
c o m m u nicati o n b y t he trial S p o ns or t o ot her parties (e. g., re g ulat ors) mi g ht als o be warra nte d 
(C o u ncil f or I nter nati o nal Or ga niza ti o ns of Me dical Scie nces, 2 0 0 5).
T he f oll o wi n g A E SIs ha ve bee n i de ntifie d, re q uiri n g miti gati o n ste ps a n d m o nit ori n g t o 
mi ni mize t he ris k f or t he o cc urre nce of t hese e ve nts.
1 4. 4. 1. 
T- L y m p h o bl astic L y m p h o m a/ T- Ac ute L y m p h o bl astic Le u ke mi a 
L y m p h o blastic l y m p h o mas are c o nsi dere d t h y m us  deri ve d mali g na ncies t hat ha ve n ot yet 
c o m plete d T-cell mat urati o ns. A p pr o xi matel y 9 0 % of l y m p h o bl astic l y m p h o mas are t he T-cell 
p he n ot y pe a n d t y picall y occ ur i n  y o u n g a d ults a n d a d olesce nts, acc o u nti n g f or 2 9 % of pe diatric 
a n d 2 % of a d ult N H L wit h a me dia n  a ge at dia g n osis of 2 5 years (L o nes, 2 0 0 7; Lai, 2 0 1 3;
C ortelazz o, 2 0 1 7 ). T- L B L is m or p h ol o gicall y a n d i m m u n o p he n ot y picall y i n disti nct fr o m 
T- A L L, wit h b ot h diseases aris i n g fr o m prec urs or l y m p h oi d cells of t he T-cell li nea ge (P ortell, 
2 0 1 2; Patel, 2 0 1 4 ). Des pite t he si milarities of t he t w o diseases, si g nifica nt yet u n k n o w n 
c haracteristics lea d t o differe n ces i n cli nical prese ntati o ns (B ur k har dt, 2 0 0 9 ). I nitial cli nical 
ma nifestati o n of b ot h a d ult a n d pe diatric T- L B L i ncl u des a me diasti nal mass or 
l y m p ha de n o pat h y wit h < 2 5 % b o ne marr o w blasts. A d ult T- L B L patie nts te n d t o ha ve less 
t h y mic disease a n d greater l y m p h n o de disease a n d b o ne marr o w i n v ol ve me nt (Bale y dier, 2 0 0 8;
S wer dl o w, 2 0 0 8; Ca m p o, 2 0 1 1 ). I n c o ntrast, T- A L L cases pre d o mi na ntl y prese nt wit h b o ne 
marr o w a n d peri p heral bl o o d disease, a n d > 2 5 % b o ne marr o w blasts (S wer dl o w, 2 0 0 8; Ca m p o, 
2 0 1 1 ).
O n 0 6 A pril 2 0 1 8, a se nti nel e ve nt of T- L B L was o b ser ve d i n a pe diatric s u bject o n st u d y E Z H-
1 0 2. T his e ve nt was re p orte d t o re g ulat or y a ut h orities as a 7- day s us pecte d u ne x pecte d seri o us 
a d verse reacti o n ( S U S A R) o n 1 3 A pril 2 0 1 8 ( Case n u m ber 2 0 1 8 U S E P Z 6 4 3 8 0 2 9 9). 
F oll o wi n g t his re p ort, E piz y me c o n d ucte d a c o m pre he nsi ve e val uati o n, i ncl u di n g: 
Re vie w of literat ure a n d a vaila ble precli n ical/cli nical data t o better u n dersta n d t he 
e ve nt of T- L B L.
Re vie w of t he literat ure a n d a vaila ble precli n ical/cli nical data t o better u n dersta n d t he 
ris k of M D S/ A M L a n d m yel oi d mali g na ncies, a n d ot her s oli d t um or mali g na ncies. 
Assess me nt of safet y, P K at vari o us d oses te ste d, a n d be nefit-ris k acr oss t u m or t y pes 
i n a d ults a n d c hil dre n. 
C o ns ultati o n wit h well re c o g nize d e xter nal e x perts  i n T-cell l y m p h o ma a n d 
pe diatric/a d ult o nc ol o g y. 
Hei g hte ne d s ur veilla nce was i m ple me nte d al o n g w it h i ncl usi o n/e xcl usi o n a n d d ose m o dificati o n 
criteria t o m o nit or a n d i de ntif y earl y si g ns a n d s y m pt o ms ( per l ocal  practice/sta n dar d of care) of 


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
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T- L B L/ T- A L L s o t hat taze met ostat ma y be disc o nti n ue d i n t he s u bject a n d treat me nt ca n be 
i nitiate d f or t hese mali g na ncies. E piz y me c o nsi de
- A L L i n taze met ostat 
cli nical trials t o be lar gel y c o nce ntrate d i n pe diatric s u bjects. 
As of t he date of t his pr ot oc ol, t w o e ve nts  of T- L B L ha ve occ urre d i n a p pr o xi matel y 1 6 0 
pe diatric s u bjects. T otal e x p os ure t o taze met ostat i ncl u des m ore t ha n 1 1 0 5 s u bjects (a d ults a n d 
pe diatrics) i n cli nical tria ls a n d o ver 2, 2 8 0 s u bjects fr o m b oth cli nical a n d p ost- mar keti n g 
s o urces.
-relate d 
s e x pecte d t o be u nc o m m o n. T o date, t here ha ve bee n n o e ve nts of T-
L B L/ T- A L L i n a d ult patie nts. 
If a n a d ult case of T- L B L/ T- A L L occ urs i n t he st u d y, e nr oll me nt i n t he st u d y will be s us pe n de d. 
T he be nefit-ris k of t he dr u g will be assesse d a d h oc b y t he E piz y me Q uarterl y Safet y Re vie w 
( Q S R) C o m mittee a n d t he E xter nal Safet y C o mmittee ( E S C), a n d t he res ulti n g be nefit-ris k 
assess me nt will be c o m m u nicate d t o all Healt h A u t h orities a n d Et hics C o m mittees as a p plica ble. 
1 4. 4. 2.  
M D S/ A M L/ M P N
As per t he c urre nt taze met ostat I B, less t ha n 1 %  of m yel oi d mali g na ncies ha ve bee n re p orte d i n 
a n esti mate d c u m ulati ve e x p os ure of m ore t ha n 2, 2 8 0 s u bjects fr o m b ot h cli nical a n d p ost-
mar keti n g s o urces. All m yel oi d e ve nts were re p orte d i n a d ult cli nical trial s u bjects. Brief te xt ual 
s u m maries o n eac h m yel oi d malig na nc y are pr o vi de d i n t he c urre nt taze met ostat I B.
I n t he e ve nt of s us pici o n of t hese mali g na ncies or rela te d c o ncer ns, please co ntact t he S p o ns or’s 
or Desi g nee Me dical M o nit or f o r e val uati o n. Hei g hte ne d s ur veilla nce will be c o n d ucte d t o 
m o nit or a n d i de ntif y earl y si g ns a n d s y m pt o ms ( per  l ocal practice/sta n dar d of care) of a n y A M L, 
M D S, a n d ot her m yel oi d mali g na ncies li ke M P N. If  a case of A M L, M D S, or a n ot her m yel oi d 
mali g na nc y li ke M P N occ urs i n t he st u d y, taze met o stat treat me nt will be disc o nti n ue d f or t he 
s u bject. 
1 4. 4. 3. 
T aze met ost at Q u arterl y S afet y Re vie w  a n d E xter n al S afet y C o m mittee ( E S C)
M o nit ori n g of sec o n dar y pri mar y mali g na ncies is  a p har mac o vi gila nce f u ncti o n. All p ote ntial 
safet y si g nals a n d A E SIs will be f ull y e val uate d i n Q uarterl y Safet y Re vie w ( Q S R) meeti n gs a n d 
i n t he E xter nal Safet y C o m mittee ( E S C). M o nit ori n g f or p ote ntial safet y si g nals, A E SI a n d ot her 
safet y c o ncer ns will als o be e val uate d d uri n g S R C.  
T he Q S R is c o m p ose d of i nter nal E piz y me s u bject matter e x perts. It is a cr oss-f u ncti o nal 
w or k gr o u p w h ose missi o n is t o pr o vi de i nter nal re vie w of a g gre gate safet y data fr o m E piz y me 
gl o bal cli nical a n d safet y data bases. T he c ore c o m mittee is c o m p ose d of t he E piz y me C hief 
Me dical Officer ( C M O), Me dical M o nit or(s), He a d of  N o ncli nical Safet y, Vice Presi de nt ( V P) 
P har mac o vi gila nce, V P Cli nical O per ati o ns, a n d V P Re g ulat or y Affairs. 
T he pri mar y o bjecti ve of t he Q S R is t o pr o vi de a r o uti ne, s yste matic, i nter n al re vie w of ne w a n d 
a g gre gate safet y i nf or mati o n, a n d t o escalate ne wl y i de ntifie d c o n cer ns or iss ues t o e xec uti ve 
ma na ge me nt a n d re g ulat or y a u t h orities, as a p plica ble.  
T he Q S R als o ser ves i n t he re vie w a n d a dj u dica ti o n of ur ge nt safet y fi n di n gs i de ntifie d d uri n g 
t he c o urse of E piz y me cli nical trials a n d as t he escalati o n pat h, as a p plica ble. 


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 8 7
T he E S C is c o m p ose d of i n de pe n de nt o nc ol o g y me dical c o ns ulta nts; o ne of w hic h ser ves as 
C hair. T he E S C meets q uarterl y t o  re vie w ne w data, or a d h oc.
T he p ur p ose of t he E S C is t o pr o vi de i n de pe n de nt  re vie w of cli nical data f or t he p ur p oses of 
i de ntif yi n g a n d e val uati ng sec o n dar y mali g na nc y safet y si g nals fr o m E piz y me s p o ns ore d cli nical 
trials. T he E S C als o m o nit ors t he data of t h ose st u d y s u bjects w h o ha ve e x perie nce d t he 
taze met ostat A E SIs, na mel y T- L B L/ T- A L L, M D S, A M L, a n d ot her m yel o pr oliferati ve 
mali g na ncies s uc h as M P N.
O utc o mes fr o m E S C meeti n gs ma y i ncl u de, b ut ar e n ot li mite d t o, t he i de ntificati o n of ne w 
A E SI a n d/ or p ote ntial ris k fact ors, t he nee d f or a d diti o nal n o n-cli nical st u dies or data a nal yses, 
pr o p osals f or ris k miti gati o n meas ur es a n d c o nfir mati o n or re visi o n of t he taze met ostat be nefit-
ris k. T he E S C will ma ke rec o m me n dati o ns i n t he e ve nt of a n A E SI safet y c o ncer n. E piz y me will 
i m ple me nt rec o m me n dati o ns w hic h ma y i ncl u de s us pe nsi o n of e nr oll me nt, pr ot oc ol a me n d me nt 
a n d c o m m u nicati o n t o healt h a ut h orities.
1 4. 4. 4.  
D ose M o dific ati o n f or Occ urre nce of A E SI 
If a case of a d ult T- L B L/ T- A L L occ urs i n t his st u d y, t he s u bject will be per ma ne ntl y 
disc o nti n ue d fr o m t he st u d y. E nr oll me nt of ne w s u bjects a n d d osi n g of s u bjects o n st u d y will be 
pa use d w hile t he Q S R/ E S C assesses t he case; ne w e n r oll me nt a n d c o nti n ue d d osi n g will res u me 
pe n di n g a decisi o n b y t he Q S R/ E S C a n d c o m m u nicati o n wit h healt h a ut h orities.  
If a case of M D S/ A M L or ot her m yel oi d mali g na ncies li ke M P N occ urs i n t he st u d y, 
taze met ostat treat me nt will be disc o nti n ue d f or t he s u bject a n d t he Q S R will assess t he case, 
f oll o we d b y re vie w of t he E S C. 
Rec o m me n dati o ns f or ne xt ste ps i n t he e ve nt of  a n y A E SI will be c o m m u nicate d b y t he E piz y me 
C hief Me dical Officer.
1 4. 4. 5. 
S afet y Si g n al E ve nts U n der E v al u ati o n: B-cell Ac ute L y m p h o bl astic 
Le u ke mi a ( B- A L L)
A 7 3- year- ol d fe male s u bject e x perie nce d a n S A E of B- A L L w hile e nr olle d i n St u d y E Z H- 5 0 1. 
T he s u bject was dia g n ose d wit h  Gra de 2 f ollic ular l y m p h o ma ( F L) i n Oct 2 0 1 6 f oll o wi n g a n 
i nitial dia g n osis of diff use lar ge B-cell l y m p h o ma ( D L B C L) o n 1 4 A u g 2 0 0 6.  
T he s u bject was e nr olle d i n t he F L E Z H 2 m uta nt-t y pe c o h ort of t he p hase 2 E 7 4 3 8- G 0 0 0- 1 0 1 
st u d y a n d be ga n treat me nt wit h taze met ostat 8 0 0 m g BI D o n 0 4 Ja n 2 0 1 7.  
Pri or t o e nr oll me nt i n t he E 7 4 3 8- G 0 0 0- 1 0 1 st u d y, t he s u bject ha d recei ve d 2 pri or s yste mic 
t hera pe utic re gi me ns as f oll o ws: rit u xi ma b, c ycl o p h os p ha mi de, d o x or u bici n, vi ncristi ne, a n d 
pre d nis o ne ( 2 2 Se p 2 0 0 6 t o 2 1 Mar 2 0 0 7) wit h t h e a d diti o n of met h otre xate a n d de xa met has o ne 
0 4 Oct 2 0 0 6 t o 1 8 Ja n 2 0 0 7. U n der a n i n vesti gati o nal pr ot oc ol ( R O M U L U S), t he s u bject 
recei ve d treat me nt wit h Ma b T hera (rit u xi ma b) wit h pi nat uz u ma b ve d oti n ( 1 1 J u n 2 0 1 3 t o 1 7 Se p 
2 0 1 3 a n d 1 5 Oct 2 0 1 3 t o 1 7 Dec 2 0 1 3).  
O n t he E 7 4 3 8- G 0 0 0- 1 0 1 st u d y, t he s u bject recei ve d taze met ostat f or 2 6 c ycles a n d ac hie ve d a n 
o bjecti ve P R at wee k 1 6 t hat w as mai ntai ne d t hr o u g h wee k 1 0 4.  
T he s u bject was s u bse q ue ntl y e nr olle d o nt o t he E Z H- 5 0 1 mai nte na nce st u d y a n d recei ve d t he 
first d ose o n 2 1 Ja n 2 0 1 9.  


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 8 8
M olec ular c haracterizati o n of  t he B- A L L cl o ne f o u n d i n t he b o ne marr o w bi o ps y fr o m 
N o ve m ber 2 0 2 0 was c o n d ucte d f or c o m paris o n t o t he pri mar y F L t u m or sa m ple is olate d i n t he 
Oct o ber 2 0 1 6 l y m p h n o de bi o ps y. T h e m olec ular a nal ysis of t he B- A L L a n d F L cl o nes i n dicates 
t hat t he y are n ot relate d, a n d t hat t he B- A L L cl o ne is n ot deri ve d fr o m t he F L cl o ne t hr o u g h a 
cl o nal e v ol uti o n mec ha nis m. Base d u p o n me dical re vie w of t he bi ol o g y, n o ncli nical data, a n d 
literat ure wit h re gar d t o t his se nti nel case of B- A L L, E piz y me belie ves t he e ve nt is u nli kel y 
relate d t o taze met ostat e x p os ure.
T here ha ve bee n n o e ve nts of B- A L L or B-cel l l y m p h o blastic l y m p h o ma ( B- L B L) o bser ve d i n 
a n y n o ncli nical safet y st u dies perf or me d at E p iz y me wit h E Z H 2 i n hi biti o n. A d diti o nall y, n o 
e ve nts of B- A L L or B- L B L occ urre d i n precli nic al efficac y st u dies usi n g m o use m o dels wit h a n 
i ntact B cell c o m part me nt. O n t he c o ntrar y, E Z H 2 i nhi biti o n wit h taze met ostat i n vitr o i n a d ult 
a n d pe diatric B- A L L cell li nes di d n ot e n ha nce pr ol iferati o n a n d i n fact ca use d m o dest decreases 
i n pr oliferati o n i n a s u bset of cell li nes.
Base d u p o n me dical re vie w of t he bi ol o g y, n o ncli nica l data, a n d literat ure of t his case of B- A L L, 
E piz y me belie ves t he e ve nt is u nli kel y relate d t o taze met ostat e x p os ure. Re fer t o t he taze met ostat 
I B f or case detail.  H o we ver, E piz y me will c o nti n ue t o m o nit or s u bject safet y wit h re gar d t o 
sec o n dar y mali g na nc y a n d all he mat ol o gical sec o n dar y mali g na ncies will be assesse d b y t he 
taze met ostat E S C a n d Q S R ( Secti o n 1 4. 4. 3 ).  
1 4. 5.  
Ot her P ote nti al I de ntifie d Ris ks
F or t his st u d y, ot her p ote ntial i de ntifie d ris ks will i ncl u de:
E ve nts c o nsi dere d relate d t o a b n or mal b o ne  f or mati o n a n d c o nfir me d b y ra di ol o gic 
sca n
A Es ass ociate d wit h treat me nt o ver d ose,  mis use, a b use, or me dicati o n err or; 
A n d a n y treat me nt-e mer ge nt si g nifica nt la b orat or y a b n or malit y.  
T hese ris ks are t o be ca pt ure d usi n g t he S A E pr o ce d ures b ut are t o be c o nsi dere d as S A Es o nl y if 
t he y met o ne of t he a b o ve criteria. All a d verse e ve n ts/ris ks are t o be rep orte d o n t he e C R F 
w het her or n ot t he y meet  t he criteria f or a n S A E.
1 4. 6.  
Gr a di n g a n d Se verit y
T he se verit y of all A Es a n d S A Es, i ncl u di n g a p pr o priate la b orat or y val ues, will be gra de d 
utilizi n g t he C T C A E v 4. 0 3. T he li n k t o t he C T C A E Versi o n 4. 0 3 is: 
htt p://e vs. nci. ni h. g o v/ft p 1/ C T C A E/ C T C A E _ 4. 0 3 _ 2 0 1 0- 0 6- 1 4 _ Q uic k Refere nce _ 8. 5 x 1 1. p df


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 8 9
I n t he e ve nt t hat a n A E is n ot c o vere d b y t he C T C A E, t he assess me nt of se verit y will be 
deter mi ne d b y usi n g t he C T C A E ge neral g ui deli ne: 
Gr a de 1:
Mil d; as y m pt o matic or mil d s y m pt o ms; c li nical or dia g n ostic o bser vati o ns o nl y; 
i nter ve nti o n n ot i n dicate d.
Gr a de 2:
M o derate; mi ni mal, l ocal, or n o ni n vasi ve  i nter ve nti o n i n dicate d; li miti n g a ge-
a p pr o priate i nstr u me ntal A D L. a 
Gr a de 3:
Se vere or me dicall y si g nifica nt b ut n ot i m me diatel y life t hreate ni n g; h os pitalizati o n or 
pr ol o n gati o n of h os pitalizati o n i n dicate d; disa bli n g; li miti n g self-care A D L. b 
Gr a de 4:
Life-t hreate ni n g c o nse q ue nces; ur ge nt i nter ve nti o n i n dicate d.
Gr a de 5:
Deat h relate d t o A E.
A b bre viati o ns: A D L   Acti vities of Dail y  Li vi ng ; A E   a d verse e ve nt
a I nstr u me ntal A D L refer t o pre pari n g meals, s h o p pi n g f or gr oceries or cl ot hes, usi n g t he tele p h o ne, ma na gi n g 
m o ne y, etc.
b Self-care A D L refer t o bat hi n g, dressi n g, a n d u n dressi n g, fee di n g self, usi n g t he t oilet, ta ki n g me dicati o ns, a n d n ot 
be dri d de n.
A n A E t hat is assesse d as se vere s h o ul d n ot be c o nf use d wit h a n S A E. Se verit y is a cate g or y 
use d f or rati n g t he i nte nsit y of a n e ve nt (as i n  ‘ mil d’, ‘ m o derate’, or ‘se vere’); b ot h A Es a n d 
S A Es ca n be assesse d as se vere. A n e ve nt is descri b e d as ‘seri o us’ w he n it  meets o ne of t he pre-
defi ne d o utc o mes as descri be d i n Secti o n 1 4. 1. 3  w hic h are base d o n s u bject/e ve nt o utc o me or 
acti o n criteria ass ociate d wit h e ve nts t hat p o se a t hreat t o a s u bject’s life or f u ncti o ni n g.
1 4. 7.  
Rel ati o ns hi p C ate g oriz ati o n
A q ualifie d I n vesti gat or m ust ma ke t he deter mi nati o n of relati o ns hi p t o taze met ostat f or eac h A E 
or S A E. T he I n vesti gat or s h o ul d deci de w het her,  i n his or her me dical j u d g me nt t here is a 
reas o na ble p ossi bilit y t hat t he e ve nt may ha ve bee n ca use d b y taze met ostat.  
1 4. 7. 1.  
Assessi n g Rel ati o ns hi p t o St u d y Tre at me nt
T he f oll o wi n g s h o ul d be c o nsi dere d w he n assessi n g t he relati o ns hi p of a n A E t o st u d y treat me nt: 
Te m p oral relati o ns hi p of t he o nset of t h e e ve nt t o t he first d ose of taze met ostat
T he c o urse of t he e ve nt, c o ns i deri n g es peciall y t he effect of disc o nti n uati o n of st u d y 
treat me nt or t he rei ntr o d ucti o n of st u d y treat me nt, as a p plica ble
W het her t he e ve nt is k n o w n t o be ass ociate d wit h t he st u d y treat me nt or wit h ot her 
si milar treat me nts
T he prese nce of ris k fact ors i n t he st u d y s u bject k n o w n t o i ncrease t he occ urre nce of 
t he e ve nt
T he prese nce of n o n-st u d y treat me nt-relate d fact ors t hat are k n o w n t o be ass ociate d 
wit h t he occ urre nce of t he e ve nt. 
T he relati o ns hi p of a n A E t o st u d y tr eat me nt is t o be classifie d as f oll o ws:
N ot Rel ate d:
A ca usal relati o ns hi p bet wee n taze met ostat a n d t he A E is n ot a reas o na ble 
p ossi bilit y. 


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 9 0
Rel ate d: A ca usal relati o ns hi p bet wee n taze met ostat a n d t he A E is a reas o na ble p ossi bilit y 
(i ncl u des pr o ba bl y, p ossi bl y, a n d defi nitel y relate d).  
If t he ca usal relati o ns hi p bet wee n a n A E/ S A E a n d taze met ostat is relate d, t hat deter mi nati o n will 
be use d f or p ur p oses of e x pe dite d re g ulat or y re p orti n g. 
1 4. 8.  
O utc o me C ate g oriz ati o n
O utc o me of a n A E/ S A E ma y be classifie d as res ol ve d, res ol ve d wit h se q uelae, u nres ol ve d, or 
deat h. 
All treat me nt-relate d A Es/ S A Es will be f oll o we d t o res ol uti o n (t he s u bject’s healt h has ret ur ne d 
t o his/ her baseli ne stat us or all varia bles ha ve ret ur ne d t o n or mal),  or u ntil a n o utc o me is reac he d, 
sta bilizati o n occ urs (t he I n vesti gat or d oes n ot e x pect a n y f urt her i m pr o ve me nt or w orse ni n g of 
t he e ve nt), or t he e ve nt is ot her wise e x plai ned, re gar dless of w het her t he s u bject is still 
partici pati n g i n t he st u d y. W here a p pr o priate, me dical tests a n d e xa mi nati o ns will be perf or me d 
t o d oc u me nt res ol uti o n of t he e ve nt(s).
1 4. 9. 
Ti mefr a me f or Re p orti n g A Es a n d S A Es
A Es: A Es will be c ollecte d fr o m t he ti me t he first d ose of st u d y treat me nt is a d mi nistere d u ntil 
t he earlier of eit her 3 0 da ys after t he disc o nti n uati o n of st u d y treat me nt or u ntil t he i nitiati o n of 
s u bse q ue nt a nti-ca ncer t hera p y.
A Es Rel ate d t o Bi o ps y : A Es will be c ollecte d fr o m t he ti me of scree ni n g bi o ps y u ntil eit her 
3 0 da ys after t he disc o nti n uati o n of st u d y treat me nt  or u ntil t he i nitiati o n of s u bse q ue nt a nti-
ca ncer t hera p y ( w hic h e ver is earlier). 
S A Es: S A Es will be c ollecte d o ver t he sa me ti me pe ri o d as state d a b o ve f or A Es. I n a d diti o n, 
a n y S A E assesse d as rel ate d  t o st u d y partici pati o n (e. g., pr otoc ol- ma n date d pr oce d ures, i n vasi ve 
tests, or c ha n ge i n e xisti n g t hera p y), st u d y treat me nt m ust be rec or de d fr o m t he ti me a s u bject 
pr o vi des c o nse nt t o partici pate i n t he st u d y u p t o  a n d i ncl u di n g a n y f oll ow- u p c o ntact. All S A Es 
will be re p orte d t o t he S p o ns or wit hi n 2 4 h o urs.  
After Disc o nti n u ati o n of St u d y Tre at me nt : T he I n vesti gat or will m o nit or all o n g oi n g 
A Es/ S A Es u ntil res ol uti o n or sta bilizati o n of t he e ve n t or u ntil t he s u bject is l ost t o f oll o w- u p or 
has wit h dra w n c o nse nt. F or a peri o d of 3 0 da ys afte r t he last d ose of st u d y treat me nt or u ntil t he 
i nitiati o n of s u bse q ue nt a nti-ca ncer t hera p y, w hic he ver is earlier,  t he I n vesti gat or will re p ort a n y 
A E t hat t he y c o nsi der t o be p o ssi bl y relate d t o st u d y treat me nt.  
N ote t hat a n y i nci de nce of sec o n dar y mali g na nc y, e ve n if occ urri n g m ore t ha n 3 0 da ys after t he 
last d ose of st u d y dr u g, will be re p orte d t o t he S p o ns or as i n Secti o n 1 4. 4.
1 4. 1 0.  
Re p orti n g of S A Es
All S A Es will be re p orte d wit hi n 2 4 h o urs of t he I n vesti gat or  bec o mi n g a ware of t he e ve nt. T he 
I n vesti gat or m ust pr o m ptl y n otif y t he S p o ns or or its desi g nee of all S A Es i n or der t hat t he le gal 
o bli gati o ns a n d et hical res p o nsi bilities of  t he S p o ns or or its desi g nee are met. 
T he S p o ns or has a le gal res p o nsi bilit y t o n otif y b ot h t he l ocal re g ulat or y a ut h orit y a n d ot her 
re g ulat or y a ge ncies a b o ut t he safet y of t he I P u nder cli nical i n vesti gati o n. T he S p o ns or a n d its 


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 9 1
desi g nee will c o m pl y wit h c o u ntr y s pecific re g ulat or y re q uire me nts relati n g t o safet y re p orti n g t o 
t he re g ulat or y a ut h orit y, IR B/ E C a n d I n vesti gat ors. 
A n y A E t hat is b ot h u ne x pecte d ( n ot  c o nsiste nt wit h t he a p plica ble pr o d uct i nf or mati o n) a n d als o 
meets t he defi niti o n of a seri o us a d verse e ve nt/reacti o n w o ul d be c o nsi dere d a s us pecte d 
u ne x pecte d seri o us a d verse react i o n (“ S U S A R”). S U S A Rs are pre pare d f or e x pe dite d re p orti n g 
acc or di n g t o l ocal re g ulat or y re q uire me nts a n d ar e f or war de d t o I n vesti gat ors as necessar y. T he 
S p o ns or is le gall y o bli gate d t o re p ort t he e ve nt t o t he re g ulat or y a ut h orities wit hi n 7 da ys f or 
fatal or life-t hreate ni n g S U S A Rs or 1 5 da ys f or all ot hers. 
A n I n vesti gat or w h o recei ves a n I n vesti gat or sa fet y re p ort descri bi n g a S U S A R or ot her s pecific 
safet y i nf or mati o n (e. g., s u m mar y or listi n g of S AEs) fr o m t he S p o ns or will file it wit h t he I B 
a n d will n otif y t he I R B/ E C, if a p pr o priate acc or di n g t o l ocal re q uire me nts.
1 4. 1 1.  
Re p orti n g of A E SIs
A E SIs are t o be ca pt ure d usi n g t he S A E pr oce d ur es, b ut are t o be c o nsi dere d as S A Es o nl y if 
t he y meet o ne of t he a b o ve criteria. All A E SIs are t o be re p orte d w het her or n ot t he y meet t he 
criteria f or a n S A E.
All p ote ntial a n d i de ntifie d A E SIs m ust be disc usse d wit h t he Me dical M o nit or.
1 4. 1 2.  
Re p orti n g of S peci al Sit u ati o ns
Re p ort t he s pecial sit uati o n(s) of  o ver d ose, mis use, a b use, a n d/ or me dicati o n err or ( descri be d i n 
Secti o n 1 4. 1. 4 ) usi n g o ne of t he f oll o wi n g sets of i nstr ucti o ns acc or di n g t o w het her t he s pecial 
sit uati o n occ urre d wit h o ut a n y ass ociate d A Es, wit h a n ass ociate d n o n-seri o us A E, or wit h a n 
ass ociate d S A E:
S peci al sit u ati o n(s) wit h o ut ass oci ate d A E(s):
Re p ort t o E piz y me usi n g a pa per S pecial Sit uati o ns F or m f oll o wi n g t he pr oce d ures 
f or re p orti n g S A E ( Secti o n 1 4. 1 0 ).   
S peci al sit u ati o n(s) wit h a n ass oci ate d n o n-seri o us A E:
E nter t he n o n-seri o us e ve nt o n t he A E e C R F a n d mar k t he S A E fiel d, “ n o”. S A E 
relate d narrati ve fiel ds s h o ul d n ot be c o m plete d. 
Re p ort t o E piz y me usi n g a pa per S pecial Sit uati o ns F or m f oll o wi n g t he pr oce d ures 
f or re p orti n g S A E ( Secti o n 1 4. 1 0 ).  
S peci al sit u ati o n(s) wit h a n ass oci ate d S A E:
C o m plete t he A E e C R F per pr ot oc ol f o r t he ass ociate d S A E ter m O N L Y ( S pecial 
sit uati o ns are n ot A E ter ms i n a n d of t he msel ves); c o m plete e C R F S A E fiel ds.
Re p ort t o E piz y me usi n g b ot h a pa per S pecial  Sit uati o ns F or m a n d a pa per Seri o us 
A d verse E ve nt F or m f oll o wi n g t he pr oce d ures f or re p orti n g S A E ( Secti o n  1 4. 1 0 ).  


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 9 2
1 4. 1 3.  
Re p orti n g t o Re g ul at or y A ut h oritie s, I R B/ E C a n d Ce ntr al Et hics 
C o m mittees ( C E Cs)
T he S p o ns or or its desi g nee is res p o nsi ble f or n o tif yi n g t he i n vesti gati o nal sites of all e x pe dite d 
S A Es. T he S p o ns or or desi g nee s hall als o n otif y t he C E C of ne w seri o us, relate d, a n d 
u ne x pecte d A E(s) or si g nifica nt ris ks t o  s u bjects, per c o u ntr y re q uire me nts. 
T he I n vesti gat or will n otif y t he I R B/ E C of seri o us, relate d, a n d u ne x pecte d A E(s) or si g nifica nt 
ris ks t o s u bjects, per l ocal c o u ntr y re q uire me nts. T he I n vesti gat or m ust kee p c o pies of all A E 
i nf or mati o n, i ncl u di n g c orres p o n de nce wit h t he S p o ns or or l ocal I R B/ E Cs o n file. 
It is t he res p o nsi bilit y of t he Pri ncipal I n vesti gat or t o n otif y t he I R B/ E C of all S A Es t hat occ ur at 
his/ her site. I n vesti gat ors will be  n otifie d of all s us pecte d, u ne x pecte d S A Es ( 7/ 1 5- Da y Safet y 
Re p orts) t hat occ ur d uri n g a n y c li nical st u dies t hat are usi n g t he i n vesti gati ve c o m p o u n d. Eac h 
site is res p o nsi ble f or n otif yi n g t heir I R B/ E C of t hese a d diti o nal S A Es.
All st u dies t hat are c o n d ucte d wit hi n a n y E ur o pe a n c o u ntr y will c o m pl y wit h t he E ur o pea n C T D 
2 0 0 5/ 2 8/ E C a n d C T D 2 0 0 1/ 2 0/ E C. All S U S A Rs will be re p orte d as re q uire d t o t he C o m pete nt 
A ut h orities of all i n v ol ve d E ur o pea n me m ber states.
M E DI C A L M O NI T O R C O N T A C T I N F O R M A TI O N
N a me  
A d dress 
P h o ne/ M o bile/ F a x 
E m ail
N ort h 
A meric a/
A ustr ali a 
Me dic al 
M o nit or
Me d pace I nc.
5 3 7 5 Me d pace 
Wa y
Ci nci n nati, O H 
4 5 2 2 7
P: 
 
 
E U 
Me dic al 
M o nit or
P: 
M: 
S A E R E P O R TI N G H O T LI N E I N F O R M A TI O N
P h o ne
 F a x
E m ail
F or N ort h 
A meric a n a n d 
A ustr ali a n Cli nic al 
Sites o nl y
 
E xt. 
or
 
E xt. 
or
F or E U Cli nic al 
Sites o nl y
 
 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 9 3
1 5.  
C O R R E L A TI V E A S S E S S M E N T S
1 5. 1. 
Bi o m ar kers of Res p o nse Assess me nt
C orrelati o ns of tre n ds i n s u bjects’ cli nical res p o nse t o t he m olec ular c haracteristics of t heir 
t u m or (e. g., dia g n ostic m olec ular lesi o ns, s o matic m utati o ns) ma y pr o vi de e vi de nce of t he 
bi ol o gical basis f or res p o nse t o taze met ostat. S u c h i n vesti gati o ns are e mer gi n g as a n effecti ve 
strate g y t o i nf or m f ut ure cli nical de vel o p me nt. 
T u m or Tiss ue S a m ple(s): T u m or tiss ue will be assesse d t o ce ntrall y c o nfir m m olec ular data 
re q uire d f or e nr oll me nt a n d i de ntif y ca n di date bi o mar kers of res p o nse t o taze met ostat via 
met h o ds, w hic h ma y i ncl u de c harac terizati o n of s u bjects’ t u m or heter o ge neit y usi n g b ot h pr otei n 
a n d n ucleic aci d base d met h o d ol o gies u p t o a n d i ncl u di n g w h ole ge n o me se q ue nci n g of t u m or 
R N A/ D N A. L ocal pat h ol o g y res ults are acce pta ble f or e nr oll me nt a n d eli gi bilit y deter mi nati o n.
Bl o o d s a m ples: Bl o o d sa m ples will be c ollect e d at scree ni n g a n d at ea c h res p o nse assess me nt t o 
pr o vi de circ ulati n g t u m or D N A t hat ca n be use d f or i de ntificati o n of ca ndi date bi o mar kers of 
res p o nse t o taze met ostat. 
1 5. 2.  
Assess me nt of Rel a pse / Resist a nce t o T aze met ost at
S u bjects w h o i nitiall y res p o n d t o taze met ostat c o ul d s u bse q ue ntl y eit her rela pse or bec o me 
resista nt t o taze met ostat t hr o u g h as yet u ni de ntifie d mec ha nis ms s uc h as dr u g-i n d uce d de- n o v o 
m utati o n.  
T u m or Bi o ps y: A s u bse q ue nt t u m or bi o ps y, if me dicall y fe asi ble, at disease pr o gressi o n will be 
re q ueste d t o e na ble assess me nt of a da pti ve mec ha nis ms of resista nce. T u m or c haracterizati o n b y 
D N A, R N A, or pr otei n ma y be pe rf or me d t o defi ne m olec ular c ha n ges o bser ve d i n rela pse d 
t u m ors.
1 5. 3. 
F ut ure Use of Tiss ue S a m ples
N ot all of t he tiss ue a n d bl o o d c o m p o ne nts o btai ne d d uri n g t his st u d y ma y be re q uire d f or t he 
tests t hat are part of t he cli nical trial. F oll o wi n g t he c o ncl usi o n of t he st u d y, t he sa m ples ma y be 
use d f or a d diti o nal researc h. T hese sa m ples will be hel d f or a ma xi m u m of 1 5 years. T his 
researc h will hel p t o u n dersta n d disease s u bt y pes, dr u g res p o nse a n d t o xicit y, a n d p ossi bl y 
i de ntif y ne w dr u g tar gets or bi o mar kers t hat pre dict s u bject res p o nse t o treat me nt. T he use of t he 
sa m ples f or i nter nal researc h will be d o ne acc or di n g t o t he g ui deli nes defi ne d b y t he F D A 
g ui da nce f or I n Vitr o Dia g n ostic De vice St u dies Usi n g Left o ver H u ma n S peci me ns t hat are N ot 
I n di vi d ual I de ntifia ble (iss ue d 2 5 A pril 2 0 0 6) a n d t he E ur o pea n Me dici nes A ge nc y ( E M A) 
Reflecti o n Pa per o n P har mac o ge netic Sa m ples, Testi n g a n d Data Ha n dli n g 
( E M E A/ C H M P/ P G x W P/ 2 0 1 9 1 4/ 2 0 0 6). If a s u bject re q uests destr ucti o n of t heir tiss ue a n d bl o o d 
sa m ples a n d t he sa m ples ha ve n ot yet bee n de-i de ntifie d, t he S p o ns or will destr o y t he sa m ples as 
descri be d i n t his F D A g ui da nce. T he S p o ns or w ill n otif y t he I n vesti gator i n writi n g t hat t he 
sa m ples ha ve bee n destr o ye d.


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 9 4
1 6.  
D A T A M A N A G E M E N T
Data fr o m e C R Fs a n d ot her e xter nal data will be  e ntere d i nt o a n Electr o nic Data Ca pt ure ( E D C) 
cli nical data base. T hese data will  be electr o nicall y verifie d t hr o u g h t he use of real-ti me c hec ks 
pr ocesse d d uri n g data e ntr y, a n d t hr o u g h pr o gra m me d e dit c hec ks as s pecifie d i n t he data 
ma na ge me nt pla n. Discre pa ncies i n t he data will be br o u g ht t o t he atte nti o n of t he cli nical tea m 
a n d i n vesti gati o nal site perso n nel, if necessar y, i n t he f or m of a n electr o nic data q uer y. 
Res ol uti o ns t o t hese iss ues will be reflecte d i n t h e data base a n d a n a u dit trial wit hi n t he s yste m 
will trac k all q ueries a n d c ha n ges ma de t o t he da ta. Q ualit y c o ntr ol a u dit(s) will be perf or me d.
1 6. 1.  
C o di n g
C o nc o mita nt me dicati o ns will be assi g ne d a c o de usi n g t he versi o n of t he W orl d Healt h 
Or ga nizati o n ( W H O) dicti o nar y ( versi o n J u ne 2 0 1 5 or hi g her) dr u g c o des s pecifie d i n t he data 
ma na ge me nt pla n ( versi o n J u ne 2 0 1 5 or hi g her). C o nc o mita nt me dicati o ns will be f urt her c o de d 
t o t he a p pr o priate A nat o mical- T hera pe utic- Che mical ( A T C) c o de i n dicati n g t hera pe utic 
classificati o n. A listi n g of c o nc o mita nt me dicati o ns b y dr u g a n d dr u g class will be i ncl u de d i n 
t he C S R f or t his pr ot oc ol.
A Es will be classifie d i nt o sta n dar dize d ter mi n ol o g y fr o m t he ver bati m descri pti o n (I n vesti gat or 
ter m) acc or di n g t o t he versi o n of t he Me d D R A c o di n g dic ti o nar y ( versi o n 1 8. 0, or hi g her) 
s pecifie d i n t he data ma na ge me nt pla n. A Es will be prese nte d b y Preferre d Ter m ( P T) neste d 
wit hi n S yste m Or ga n Class ( S O C). Ver bati m descri pti o n a n d P T a n d S O C Me d D R A-le vel ter ms 
f or all A Es will be c o ntai ne d i n t he data listi n gs of t he C S R f or t his st u d y.


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 9 5
1 7. 
S T A TI S TI C A L M E T H O D S
1 7. 1.  
H y p ot heses
C o h ort 1 ( R h a b d oi d T u m ors), C o h ort 3 ( Ot her  I NI 1- Ne g ati ve T u m ors or a n y S oli d T u m or 
wit h E Z H 2 G O F M ut ati o n), C o h ort 4 ( Re n al Me d ull ar y C arci n o m a), a n d C o h ort 7 
( C h or d o m a) 
F or C o h orts 1, 3, 4, a n d 7, t he n ull h y p ot hesis is t hat t he O R R ( perce nta ge of s u bjects ac hie vi n g 
eit her a c o nfir me d C R or P R), as assesse d at t he St a ge 2 a nal ysis, is n ot cli nicall y mea ni n gf ul 
( < 5 %). T he alter nati ve h y p ot hesis is t hat t he O R R is c li nicall y mea ni n gf ul ( > 2 0 %) a n d, 
t heref ore, t he st u d y treat me nt warra nts f urt her de vel o p me nt. At t he Sta ge 2 a nal ysis, 3 0 s u bjects 
will be e nr olle d i n eac h c o h ort,  a n d t he a nal ysis a n d decisi o n r ules s pecifie d here are base d o n 3 0 
s u bjects. T he decisi o n r ule at t he Sta ge 2 a nal ysis will differ sli g htl y if t here are m ore t ha n 3 0 
s u bjects. F or t he Sta ge 2 a nal ysis wit h 3 0 s u bjects, at least 5 c o nfir me d C Rs pl us P Rs are nee de d 
f or t he c o h ort t o declare a s uccess i.e., t o ha ve de m o nstrate d s ufficie nt cli nical acti vit y.
C o h ort 2 ( Rel a pse d or Refr act or y S y n o vi al S arc o m a) 
F or C o h ort 2, t he n ull h y p ot hesis is t hat P F S rate after 1 6 w ee ks of treat me nt ( perce nta ge of 
s u bjects wit h a C R, P R or S D at t he Wee k 1 6 t u m or assess me nt), as assesse d at t he Sta ge 2 
a nal ysis, is n ot cli nicall y mea ni n gf ul (
P F S rate at 
1 6 wee ks 
de vel o p me nt. At t he Sta ge 2 a nal ysis, 3 0 s u bjects  will be e nr olle d i n Co h ort 2, a n d t he a nal ysis 
a n d decisi o n r ules s pecifie d here are base d o n 3 0 s u bjects. T he decisi o n r ule at t he Sta ge 2 
a nal ysis will differ sli g htl y if t h ere are m ore t ha n 3 0 s u bjects. F or t he Sta ge 2 a nal ysis wit h 3 0 
s u bjects, at least 9 C R + P R + S Ds are nee de d f or t he c o h ort t o declare a s uccess i.e., t o ha ve 
de m o nstrate d s ufficie nt cli nical acti vit y.
C o h ort 5 ( E S wit h T aze met ost at 8 0 0 m g BI D) 
F or C o h ort 5, t he n ull h y p ot hesis is t hat t he D C R ( perce nta ge of  s u bjects w h o ac hie ve eit her a 
c o nfir me d C R or P R or w h o ha ve S D lasti n g at least 3 2 wee ks), as as sesse d at t he Sta ge 2 
a nal ysis, is n ot cli nicall y mea ni n gf ul ( < 5 %).  T he alter nati ve h y p ot hesis is t hat t he D C R is 
cli nicall y mea ni n gf ul ( > 2 0 %) a n d, t heref ore, t h e st u d y treat me nt warra nts f urt her de vel o p me nt. 
At t he Sta ge 2 a nal ysis, 3 0 s u bjects will be e nr oll e d i n eac h c o h ort, a n d t he a nal ysis a n d decisi o n 
r ules s pecifie d here are base d o n 3 0 s u bjects. T he decisi o n r ule at t he Sta ge 2 a nal ysis will differ 
sli g htl y if t here are m ore t ha n 3 0 s u bjects. F or t he Sta ge 2 a nal ysis wit h 3 0 s u bjects, at least 5 
c o nfir me d C Rs pl us P Rs or S Ds lasti n g at least 3 2 wee ks are nee de d f or t he c o h ort t o declare a 
s uccess i.e., t o ha ve de m o nstrate d s ufficie nt cli nical acti vit y. If t he Sta ge 2 f utilit y criteri o n is 
s ur passe d, e nr oll me nt i n C o h ort 5 ma y be ex pa n de d t o i ncl u de 3 0 a d diti o nal s u bjects. 
C o h ort 6 ( E S U n der g oi n g O pti o n al T u m or Bi o ps y) 
F or C o h ort 6, t he n ull h y p ot hesis is t hat t he O R R ( perce nta ge of  s u bjects w h o ac hie ve eit her a 


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 9 6
C o h ort 8 ( E S wit h T aze met ost at 1 6 0 0 m g Q D) 
F or sec o n dar y e n d p oi nts of C o h ort 8 ( d urati o n of  res p o nse ( D O R), D C R, a n d O R R; p ote ntiall y 
P F S a n d O S, if s ufficie nt data a n d a nal ysis warra nte d) statistical a nal ysis will be perf or me d a n d 
a nal yze d as f or C o h ort 5.
1 7. 2. 
St u d y Desi g n C o nsi der ati o ns
1 7. 2. 1.  
Deter mi n ati o n of S a m ple Size 
Eac h c o h ort (e xce pti o n: C o h orts 6 a n d 8) will be  e val uate d se paratel y usi n g a Gree n- Da hl ber g 
t w o-sta ge desi g n, t o all o w earl y ter mi nati o n of t he c o h ort d ue t o t he lac k of efficac y. T he sa m ple 
size of eac h c o h ort is calc ulate d o n t he pri mary e n d p oi nt. Wit hi n eac h c o h ort, t he h y p ot hesis will 
be teste d usi n g a o ne-
T he n u m bers of s u bjects t o be e nr olle d i n eac h  sta ge of t he Gree n- Da hl ber g t w o-sta ge desi g n f or 
eac h c o h ort are liste d i n t he ta ble bel o w.
  
E ac h C o h ort Se p ar atel y:
C o h ort 1 a ( R h a b d oi d 
t u m ors)
C o h ort 3 a ( Ot her I NI 1-
ne g ati ve t u m ors or a n y 
s oli d t u m or wit h E Z H 2 
G O F m ut ati o n)
C o h ort 4 a ( R M C)
C o h ort 7 a ( C h or d o m a)
C o h ort 2 a
( R/ R s y n o vi al 
s arc o m a)
I niti al Desi g n:
C o h ort 5 a
( E S) 
A me n d e d 
Desi g n:
C o h ort 5 b
( E S) 
Sta ge 1: N ull 
h y p ot hesis
C R + P R + S D at 
Sta ge 1: Alter nati ve 
h y p ot hesis
C R + P R + S D at 
C R + P R 
Sta ge 1 sa m ple size 
( n 1)c
1 5
1 5
1 5
Sta ge 1 rejecti o n of 
st u d y treat me nt 
(r 1)d
0
 1
 
0
 
Sta ge 2 sa m ple size 
( n 2)
1 5
1 5
1 5
1 5
Sta ge 2 rejecti o n of 
st u d y treat me nt (r)
4
 8
 
4
 
4
 
T otal sa m ple size 
( n) 
3 0
3 0
3 0
3 0
A b bre viati o ns: BI D   t wice dail y; C R   c o m plete res p o nse; E S   e pit helial sarc o ma; G O F   gai n of f u ncti o n; N A   
n ot a p plica ble; P R   partial res p o nse; Q D   o nce dail y; R/ R   rela pse d/ refract or y; R M C   re nal me d ullar y 
carci n o ma; S D   sta ble disease. 
a All s u bjects will ha ve c o m plete d at least t he Wee k 2 4 ( W ee k 1 6 f or s y n o vial sarc o ma)  assess me nt, c o m plete d t he 
fi nal st u d y visit, or ter mi nate d earl y fr o m t he st u d y, w hic he ver is s o o ner


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 9 7
b All s u bjects will ha ve c o m plete d at least t he Wee k 3 2 assess me nt, c o m plete d t he fi nal st u d y visit, or ter mi nate d 
earl y fr o m t he st u d y, w hic he ver is s o o ner- base d o n A me n d me nt 4.
c Wit hi n eac h c o h ort, t he i nteri m a nal ysis pla n ne d at t he e n d of Sta ge 1 ma y occ ur s o o ner if t he Sta ge 1 rejecti o n 
criteri o n is s ur passe d bef ore all 1 5 s u bjects are treate d a n d f oll o we d f or t he s pecifie d ti me. I n t his sce nari o, t he 
t otal sa m ple size ( Sta ge 1 + Sta ge 2) f or a c o h ort w o ul d still re mai n u nc ha n ge d at 3 0 s u bjects.
d A n a d diti o nal 3 0 s u bjects ma y be e nr olle d f or e x pa n de d e val uati o n of efficac y a n d safet y. E nr oll me nt i n t he 
e x pa nsi o n sta ge ma y be o pe ne d o nce t he Sta ge 2 rejecti o n criteri o n has bee n s ur passe d. If t his occ urs pri or t o t he 
f ull e nr oll me nt of Sta ge 2, t he t otal c o h ort sa m ple size ( Sta ge 1 + Sta ge 2 + e x pa nsi o n) will re mai n u nc ha n ge d at 
6 0 s u bjects.
A c o h ort ma y be st o p pe d f or f utilit y at t he e n d of  Sta ge 1 base d o n t he res ults f or t he first 1 5 
treate d s u bjects. T o a v oi d disr u pti o ns i n t he st u d y, e nr oll me nt a n d treat me nt of s u bjects will n ot 
be halte d i n or der t o c o n d uct t he i nteri m a nal ysis. If e ver y c o h ort c o m pletes e nr oll me nt of Sta ge 
2 a t otal of 1 5 0 s u bjects will be e nr olle d i n t he e ntire st u d y.
F or C o h orts 1, 3, 4, a n d 5: 
T he pr o ba bilit y of earl y st o p pi n g u n der t he n ull h y p ot heses is 0. 4 6 3. 
T he pr o ba bilit y of earl y st o p pi n g u n der t he alter nati ve h y p ot heses is 0. 0 3 5. 
F or C o h ort 2: 
T he pr o ba bilit y of earl y st o p pi n g u n der t he n ull h y p ot heses is 0. 3 1 9. 
T he pr o ba bilit y of earl y st o p pi n g u n der t he alter nati ve h y p ot heses is 0. 0 1 4. 
T he e x p a n de d s a m ple size f or C o h ort 5:
A n a d diti o nal 3 0 s u bjects ma y be e nr olle d f or e x pa n de d e val uati o n of efficac y a n d safet y. 
E nr oll me nt i n t he e x pa nsi o n st a ge ma y be o pe ne d o nce t he Sta ge 2 rejecti o n criteri o n has bee n 
s ur passe d. If t his occ urs pri or t o t he f ull e nr oll me nt of Sta ge 2, t he t otal c o h ort sa m ple size 
( Sta ge 1 + Sta ge 2 + e x pa nsi o n) will re mai n u ncha n ge d at 6 0 s u bjects. T h e a d diti o nal 3 0 s u bjects 
will all o w f or i ncrease d precisi o n f or t he p oi nt esti mates of D C R a n d O R R. T he ta ble bel o w 
s h o ws t he 9 5 % e xact bi n o mial CI f or p ote ntial p oi nt esti mates of D C R a n d/ or O R R:
P ote nti al D C R or O R R
2 0 %
3 0 %
4 0 %
S u bjects meeti n g e n d p oi nt
1 2 of 6 0
1 8 of 6 0
2 4 of 6 0
9 5 % e x act bi n o mi al CI
1 0. 8 %- 3 2. 3 % 
1 8. 8 %- 4 3. 2 % 
2 7. 6 %- 5 3. 5 %
T he C o h ort 5 e x pa nsi o n sta ge was o pe ne d i n Dec. 2 0 1 6 after t he Sta g e 2 D C R criteri o n was 
s ur passe d. I n Ma y 2 0 1 7, E piz y me met wit h t he FD A re gar di n g f ut ure de vel o p me nt pla ns f or 
taze met ostat. Base d o n a s pecific re q uest fr o m t he F D A, wit h A me n d me nt 5, t he pri mar y 
e n d p oi nt f or C o h ort 5 has bee n c ha n ge d t o O R R a n d d urati o n of res p o nse i n  res p o n di n g s u bjects 
has bee n ele vate d t o t he m o st i m p orta nt sec o n dar y e n d p oi nt. 
C o h ort 6  ( E S u n der g oi n g o pti o nal t u m or bi o ps y) was a d de d o utsi de of a 2-sta ge desi g n 
fra me w or k base d o n cli nical data de m o nstrati n g e nc o ura gi n g e vi de nce of a ntit u m or acti vit y, a n d 
n o c o ncer ni n g safet y si g nals i n E S s u bjects i n C o h ort 5. Preli mi nar y e vi de nce of t he i m m u ne 
pri mi n g effect of taze met ostat  e val uate d b y I H C pr o vi de d t he rati o nal f or c ollecti n g ma n dat or y 
paire d t u m or bi o psies i n t his c o h ort. T we nt y ( 2 0) paire d t u m or bi o psies will aff or d s ufficie nt 
data t o q ua ntif y t he i m m u ne pri mi n g effects of taze met ostat. D ue t o t he e x pectati o n t hat s o me 


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 9 8
s u bjects will wit h dra w c o nse nt after t he p ost-scree ni n g bi o ps y a n d other s u bjects ma y n ot be a ble 
t o pr o vi de f or a p ost-treat me nt bi o ps y, C o h ort 6 will e nr oll u p t o 4 0 s u bjects t o e ns ure t hat 2 0 
paire d t u m or bi o psies are c ollecte d  a n d a de q uate f or a nal ysis.
I n Ja n uar y 2 0 2 0, taze met ostat was a p pr o ve d f or t he treat me nt of a d ults a n d pe di atric s u bjects 
a ge d 1 6 years a n d ol der wit h me tastatic or l ocall y a d va nce d E S n ot eli gi ble f or c o m plete 
resecti o n. U n der t he c o n diti o ns of t he a p pr o val, E piz y me a gree d wit h t he F D A t o e nr oll a n 
a d diti o nal 2 5 s u bjects i n c o h ort 6 t o f urt her e v al uate t he O R R i n s u bjects wit h metastatic or 
l ocall y a d va nce d E S. T he pri mar y e n d p oi nt of c oh ort 6 has bee n c ha n ge d t o O R R a n d t he effects 
of taze met ostat o n t u m or i m m u ne pri mi n g has bee n c ha n ge d t o a n e x pl orat or y e n d p oi nt. 
A d diti o nall y, t he re q uire me nt f or pre- a n d p ost- d ose t u m or bi o psi es f or C o h ort 6 has bee n ma de 
o pti o nal. 
Wit h a sa m ple size of at least 4 0 s u bjects, t he st u d y has a p o wer of m ore t ha n 8 0 % t o test t he 
h y p ot hesis t hat t he o bjecti ve res p o nse rate w o ul d be 2 0 % or hi g her a gai nst t he n ull h y p ot hesis 
t hat it w o ul d be 5 % or l o wer at o ne-si de d si g nific a nce le vel of 0. 0 2 5. 
C o h ort 8: As wit h C o h ort 6, C o h ort 8 was a d de d o utsi de of a 2-sta ge desi g n fra me w or k base d 
o n cli nical data i n E S s u bjects i n C o h ort 5 (s ee rati o nale a b o ve f or C o h ort 6). C o h ort 8 was 
a d de d t o e val uate safet y, P K, a n d efficac y pr ofile of o nce dail y taze met ostat d osi n g; 1 6 s u bjects 
will be e nr olle d f or e val uati o n of P K, efficac y, a n d safet y.
1 7. 2. 2. 
S a m ple Size Re- Esti m ati o n
T he sa m ple size will n ot be re- esti mate d d uri n g t his st u d y. 
1 7. 3.  
D at a A n al ysis C o nsi der ati o ns
1 7. 3. 1.  
A n al ysis P o p ul ati o ns
T he E nr olle d p o p ulati o n will c o nsis t of all s u bjects w h o si g n i nf or me d c o nse nt a n d were e ntere d 
i nt o t he electr o nic case re p ort f or m f or t he st u d y. T he E nr olle d set will be use d f or s u m maries of 
s u bject dis p ositi o n a n d pr ot oc ol de viati o ns.
T he I nte nt-t o- Tre at (I T T) p o p ulati o n will c o nsist of all s u bjec ts  w h o recei ve at least o ne d ose 
of taze met ostat. T he I T T p o p ulati o n set will be use d f or s u m maries a n d a nal ysis of t he efficac y 
e n d p oi nts. 
T he S afet y p o p ulati o n will c o nsist of all s u bjects i n t he I T T p o p ulati o n w h o ha ve at least o ne 
p ost- d ose safet y o bser vati o n rec o r de d. T he Safet y p o p ulati o n will be use d f or s u m maries a n d 
a nal ysis of t he saf et y a n d t olera bilit y.
P h ar m ac o ki netic ( P K) P o p ulati o n will i ncl u de all s u bjects  i n t he I T T p o p ulati o n w h o ha ve 
s ufficie nt p ost- d ose sa m ples c ollecte d t o all ow esti mati o n of t he P K para meters. T he P K 
p o p ulati o n will be use d f or p o p ulati o n- base d a nal ysis.
P h ar m ac o d y n a mic ( P D) P o p ulati o n will i ncl u de all s u bjects  i n t he I T T p o p ulati o n w h o ha ve 
s ufficie nt sa m ples c ollecte d t o all o w esti mati o n of t he P D para meters. T he P D p o p ulati o n will be 
use d f or s u m maries a n d gra p hs of P D data.


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 9 9
1 7. 3. 2. 
I nteri m A n al yses
E xce pt f or C o h orts 6 a n d 8, a n i nteri m a nal ysis f or f utilit y will be perf or me d f or eac h c o h ort 
se paratel y. T he decisi o n r ules f or eac h c o h ort at t he e n d of Sta ge 1 are list e d i n t he ta ble bel o w. 
F or E ac h C o h ort Se p ar atel y
C o h ort 1 ( R h a b d oi d T u m ors)
C o h ort 3 (I NI 1- Ne g ati ve/ E Z H 2 
G O F M ut ati o n)
C o h ort 4 ( R M C)
C o h ort 5 ( E S) 
C o h ort 7 ( C h or d o m a)
C o h ort 2
( R/ R S y n o vi al S arc o m a)
N ull h y p ot hesis
C R + P R + S D at Wee k
Alter nati ve h y p ot hesis
C R + P R + S D at Wee k
Sta ge 1 sa m ple size 
( n 1)
1 5
1 5
Sta ge 1 rejecti o n of 
st u d y treat me nt (r 1)
0
 1
 
A b bre viati o ns: BI D   t wice dail y; C R   c o m plete res p o nse; E S   e pit helial sarc o ma; G O F   gai n of f u ncti o n; P R   
partial res p o nse; R/ R   rela pse d/ refract or y; R M C 
 re nal me d ullar y carci n o ma; S D   sta ble disease.
F or C o h orts 1, 3, 4, 5, a n d 7, se paratel y, t he e n d of Sta ge 1 occ urs w he n t he first 1 5 s u bjects ha ve 
c o m plete d at least t he Wee k 2 4 assess me nt, c o m ple te d t he fi nal st u d y visit or ter mi nate d earl y 
fr o m t he st u d y, w hic he ver is s o o ner. As it is desira ble t o perf or m t he i nteri m a nal ysis i n a ti mel y 
ma n ner, b ot h c o nfir me d a n d u nc o nfir me d res p o nses will be i ncl u de d. T o a v oi d disr u pti o ns i n t he 
st u d y, e nr oll me nt a n d treat me nt of s u bjects will n ot be halte d i n or der t o c o n d uct t he i nteri m 
a nal ysis. F or C o h orts 1, 3, 4, 5, a n d 7, se p aratel y, at t he e n d of Sta ge 1: 
If t here are zer o C Rs + P Rs, t he taze metostat treat me nt will be rejecte d a n d 
e nr oll me nt i n t he c o h ort will be ter mi nate d f or f utilit y.
If t here are o ne or m ore C Rs + P Rs, c o h ort e nr oll me nt will c o nti n ue t o its ma xi m u m 
sa m ple size of 3 0 s u bjects.
F or C o h ort 2 (rela pse d/re fract or y s y n o vial sarc o ma), t he e n d of Sta ge 1 occ urs w he n t he first 
1 5 s u bjects ha ve c o m plete d at least t he Wee k 1 6 assess me nt, c o m plete d t he fi nal st u d y visit or 
ter mi nate d earl y fr o m t he st u d y, w hic he ver is s o o ner. F or C o h ort 2 at t he e n d of Sta ge 1: 
If t here is at m ost o ne C R + P R + S D at t he Wee k 1 6 assess me nt, t he taze met ostat 
treat me nt will be rejecte d a n d e nr oll me nt i n C o h ort 2 will be ter mi nate d f or f utilit y.
If t here are t w o or m ore C R + P R + S D at t he Wee k 1 6 assess me nt, C o h ort 2 
e nr oll me nt will c o nti n ue t o its ma xi m u m sa m ple size.
Wit hi n eac h c o h ort, t he i nteri m a nal ysis pla n ne d at t he e n d of Sta ge 1 ma y occ ur s o o ner if t he 
Sta ge 1 rejecti o n criteri o n is s ur passe d bef ore all 1 5 s u bjects are treate d a n d f oll o we d f or t he 
s pecifie d ti me. I n t his sce nario, t he t otal sa m ple size ( Sta ge 1 + Sta ge 2) f or a c o h ort w o ul d still 
re mai n u nc ha n ge d at 3 0 s u bjects.  


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 1 0 0
If e nr oll me nt i n a n y c o h ort is ter mi nate d f or f utilit y, t he fi nal re p orti n g f or t hat c o h ort will be 
base d o n all s u bject da ta i n t he data base.
1 7. 3. 3.  
Ke y Ele me nts of t he A n al ysis Pl a n
C o m plete details of t he a nal ysis pla n will be pr o vi de d i n t he Statistical A nal ysis Pla n ( S A P). A n y 
de viati o ns fr o m, or a d diti o ns t o, t he ori gi nal a nal ysis pla n i n t his pr ot oc ol will be d oc u me nte d i n 
t he S A P a n d t he C S R. 
Si nce it is a ntici pate d t hat accr ual will be s pre a d t hi nl y acr oss ce nters a n d s u m maries of data b y 
ce nter w o ul d be u nli kel y t o pr o vi de val ua ble i nf o r mati o n, data fr o m all partici pati n g ce nters will 
be p o ole d pri or t o a nal ysis. 
All data u p t o t he ti me of st u d y c o m pleti o n/ wit h dra wal fr o m t h e st u d y will be i ncl u de d i n t he 
a nal ysis, re gar dless of treat me nt d urati o n.
Si nce t he d urati o n of st u d y treat me nt f or a gi ve n s u bject will de pe n d o n efficac y a n d t olera bilit y, 
t he d urati o n of f oll o w- u p will var y a m o n g s u bjects. All a vaila ble ti me-t o-e ve nt data will be 
a nal yze d usi n g a p pr o priate stat istical met h o ds. S u bjects wit h sh orter treat me nt a n d f oll o w- u p 
will n ot be c o nsi dere d t o ha ve missi n g data. C o nse q ue ntl y, t here will be n o i m p utati o n f or 
missi n g ti me-t o-e ve nt data.
De m o gra p hics a n d baseli ne c haracteristics will be s u m marize d b y c o h ort a n d o verall. 
1 7. 4. 
Effic ac y A n al yses
1 7. 4. 1. 
Fi n al A n al ysis of Pri m ar y E n d p oi nt b y C o h ort
Wit hi n C o h orts 1, 3, 4, a n d 7 se paratel y, t he data c ut- off f or t he a nal ysis at t he e n d of Sta ge 2 
will occ ur after all e nr olle d s u bjects ha ve c o m plete d at least t he Wee k 2 4 assess me nt, c o m plete d 
t he fi nal st u d y visit or ter mi nate d earl y fr o m t he st u d y. Wit hi n eac h c o h ort, O R R is defi ne d as 
t he perce nta ge of s u bjects ac hie vi n g a c o nfir me d C R or P R fr o m t he start of treat me nt u ntil 
disease pr o gressi o n or t he start of s u bse q ue nt a nti-ca ncer t hera p y, as per R A N O criteria f or 
pri mar y brai n t u m ors or R E CI S T 1. 1 cr iteria f or all ot her s oli d t u m ors (A p pe n di x 5 ). S u bjects 
wit h a best res p o nse of u n k n o w n/ n o n-e val ua ble r es p o nse will be treate d as n o n-res p o n ders, i.e., 
t he y will be i ncl u de d i n t he de n o mi nat or w he n calc ulati n g t he per ce nta ge. A n e xact 9 5 % 
c o nfi de nce i nter val ( CI) f or O R R will be pr o vi de d. 
Wit hi n C o h ort 2, t he data c ut- off f or t he a nal ysis  at t he e n d of Sta ge 2 will occ ur after all 
e nr olle d s u bjects ha ve c o m plete d at least t h e Wee k 1 6 assess me nt, c o m plete d t he fi nal st u d y visit 
or ter mi nate d earl y fr o m t he st u d y. T he pr o gres si o n-free rate at Wee k 1 6 is defi ne d as t he 
perce nta ge of s u bjects wit h a res p o nse of C R, P R, or S D at t he Wee k 1 6 assess me nt, as per 
R E CI S T 1. 1 criteria. S u bjects wit h n o n-e val ua bl e or missi n g res p o nse will be treate d as n ot 
pr o gressi o n-free; i.e., t he y will be i ncl u de d i n t he de n o mi nat or w he n calc ulati n g t he pr o gressi o n-
free rate. As a s pecific e xa m ple, s u bjects wit h disease pr o gressio n or deat h pri or t o t he Wee k 1 6 
assess me nt will be i ncl u de d i n t h e de n o mi nat or. I n a d diti o n t o t he P F S rate at Wee k 1 6, a n e xact 
9 5 % CI f or t his rate  will be pr o vi de d.
Wit hi n C o h ort 5, t he data c ut- off f or t he a nal ysis  at t he e n d of Sta ge 2 will occ ur after all 
e nr olle d s u bjects ha ve c o m plete d at least t he Wee k 3 2 assess me nt, c o m plete d t he fi nal st u d y 
visit, or ter mi nate d earl y fr o m t he st u d y. D C R is defi ne d as t he perce nta ge of s u bjects w h o 


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 1 0 1
ac hie ve a c o nfir me d res p o nse ( C R or P R, as per R E CI S T 1. 1 criteria) or w h o ha ve S D lasti n g at 
least 3 2 wee ks fr o m t he start of treat me nt u ntil disease pr o gressi o n or t he start of s u bse q ue nt 
a nti-ca ncer t hera p y. F or s u bjects wit h a c o nf ir me d res p o nse, t he o nset a n d d urati o n of t he 
res p o nse ma y be of a n y le n gt h as l o n g as t he res p o nse is c o nfir me d per R E CI S T 1. 1. A n 
u nc o nfir me d res p o nse ( C R or P R) will be c o nsi dere d S D at t hat ti me p oi nt. S u bjects wit h a best 
res p o nse of u n k n o w n/ n o n-e val ua ble res p o nse will be treate d as n o n- d isease c o ntr ol, i.e., t he y 
will be i ncl u de d i n t he de n o mi nat or w he n calc ula ti n g t he perce nta ge. S u bjects wit h a ti me p oi nt 
res p o nse of u n k n o w n/ n o n-e val ua ble res p o nse o n or bef ore Wee k 3 2 will still be classifie d as 
ha vi n g disease c o ntr ol as l o n g as t here is a res p o nse of C R, P R, or S D o n or after Wee k 3 2.  
F or C o h ort 5, t he f utilit y cr iteri o n was s ur passe d o n 0 4-Oct. 2 0 1 6. T he I D M C e n d orse d 
c o nti n ui n g e nr oll me nt t o Sta ge 2 c o m pleti o n. O n 2 1- Oct. 2 0 1 6, t h e I D M C e n d orse d a c ha n ge i n 
t he pri mar y e n d p oi nt f or C o h ort 5 fr o m O R R t o D C R ( w hic h i ncl u des s u bjects w h o ac hie ve a 
c o nfir me d res p o nse [ C R + P R] or w h o mai ntai n S D f or at least 3 2 wee ks). I n Dec. 2 0 1 6, after t he 
Sta ge 2 D C R criteri o n was s ur passe d, e nr oll me nt was o pe ne d i n t he e xte nsi o n sta ge. I n Ma y 
2 0 1 7, E piz y me met wit h t he F D A re gar di n g f ut ure de vel o p me nt pla ns f or taze met ostat. Base d o n 
a s pecific re q uest b y F D A, wit h A me n d me nt 5, t he pri mar y e n d p oi nt f or C o h ort 5 has bee n 
c ha n ge d t o O R R a n d d urati o n of res p o nse i n res p o n di n g s u bjects has bee n ele vate d t o t he m ost 
i m p orta nt sec o n dar y e n d p oi nt. T he ti mi n g of t he fi nal a nal ysis will be after all e nr olle d s u bjects 
ha ve c o m plete d at least t he Wee k  2 4 assess me nt, c o m plete d t he fi nal st u d y visit or ter mi nate d 
earl y fr o m t he st u d y. A n e xact 9 5 % CI f or O R R a n d D C R will be pr o vi de d f or s u bjects e nr olle d 
t hr o u g h Sta ge 2. I n a d diti o n, a 9 5 % CI f or O R R a n d D C R will be pr o vi de d f or t he e ntire c o h ort 
(i.e., i ncl u di n g t he s u bjects e nr olle d as part of t he e x pa nsi o n). Als o, a 9 5 % CI f or O R R a n d D C R 
will be pr o vi de d f or t he e n tire C o h ort 5 a n d C o h ort 6. 
F or C o h ort 8, t he data c ut- off f or t he fi nal a nal ysis  will occ ur after all e nr olle d s u bjects ha ve 
c o m plete d at least t he C ycle 2 Da y 1 assess me nt, c o m plete d t he fi nal st u d y visit or ter mi nate d 
earl y fr o m t he st u d y.  
F or pri mar y e n d p oi nt ( O R R) a n d sec o n dar y e n d p oi nts of C o h ort 6 ( D O R, D C R, a n d O R R; 
p ote ntiall y P F S a n d O S, if s ufficie nt data a n d a nal ysis warra nte d) statistical a nal ysis will be 
perf or me d a n d a nal yze d as f or C o h ort 5. 
1 7. 4. 2.  
A n al ysis of Sec o n d ar y Effic ac y E n d p oi nts 
Wit hi n eac h c o h ort, t he data c ut- off f or t he W ee k 3 2 a n d Wee k 5 6 a nal yses  will occ ur after all 
s u bjects ha ve c o m plete d at least t he Wee k 3 2 a n d Wee k 5 6 assess me nts res pecti vel y, c o m plete d 
t he fi nal st u d y visit, or ter mi nate d earl y fr o m t he st u d y, w hic he ver is s o o ner. T he o verall a nal ysis 
of all fi ve c o h orts c o m bi ne d will occ ur after all c o h orts ha ve reac he d t heir i n di vi d ual data c ut-
offs.
D O R, f or t he s u bset of s u bjects wit h c o nfir me d C R or P R res p o nse, is defi ne d as t he ti me fr o m 
t he first d oc u me nte d e vi de nce of C R or P R t o t he ti me of first d oc u me nte d disease pr o gressi o n or 
deat h d ue t o a n y ca use, w hic he ver c o mes first, usi n g disease-a p pr o priate sta n dar dize d res p o nse 
criteria. Wit hi n eac h c o h ort a n d f or C o h orts 1, 3, 4, 5, 6, a n d 7 c o m bi ne d, t he d urati o n of 
res p o nse will be calc ulate d f or eac h s u bject wit h a c o nfir me d C R or P R. If sa m ple size per mits, 
t he me dia n d urati o n of res p o nse will be calc ulate d fr o m t he Ka pla n- Meier esti mates. First a n d 
t hir d q uartiles will als o be calc ulate d al o n g wit h ass ociate d 9 5 % CIs if t here are a s ufficie nt 


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 1 0 2
n u m ber of res p o n ders w h o s u bse q ue ntl y pr o gress or  die d ue t o a n y ca use. A listi n g of d urati o n of 
res p o nse will be pr o vi de d. 
D C R is defi ne d as t he perce nta ge of s u bjects wh o ac hie ve a c o nfir me d res p o nse ( C R or P R, as 
per R E CI S T 1. 1 criteria) or w h o ha ve S D lasti n g at least 3 2 wee ks fr o m t he start of treat me nt 
u ntil disease pr o gressi o n or t he start of s u bse q ue nt a nti-ca ncer t hera p y. F or s u bjects wit h a 
c o nfir me d res p o nse, t he o nset a n d d urati o n of t h e res p o nse ma y be of a n y le n gt h as l o n g as t he 
res p o nse is c o nfir me d per R E CI S T 1. 1. A n u nc o nfirme d res p o nse ( C R or P R) will be c o nsi dere d 
S D at t hat ti me p oi nt. S u bjects wit h a best res p o nse of u n k n o w n/ n o n-e val ua ble res p o nse will be 
treate d as n o n- disease c o ntr ol, i.e., t he y will be i ncl u de d i n t he de n o mi nat or w he n calc ulati n g t he 
perce nta ge. S u bjects wit h a ti me p oi nt res p o ns e of u n k n o w n/ n o n-e val ua ble res p o nse o n or bef ore 
Wee k 3 2 will still be classifie d as ha vi n g disease c o ntr ol as l o n g as t here is a res p o nse of C R, 
P R, or S D o n or after Wee k 3 2.  
P F S is defi ne d as t he i nter val of ti me bet wee n t he date of t he first d ose of st u d y dr u g a n d t he 
earliest date of disease pr o gressi o n or deat h d ue t o a n y ca use. 
F or s u bjects w h o pr o gresse d or die d after a n e xte n de d  peri o d wit h o ut a de q uate 
assess me nt, t he ti me of P F S will be ce ns ore d at  t heir date of last a de q uate assess me nt 
pri or t o pr o gressi o n or deat h e ve n if s u b se q ue nt i nf or mati o n is a vaila ble re gar di n g 
pr o gressi o n or deat h. A n a de q uate assess me n t is defi ne d as a n assess me nt w here t he 
I n vesti gat or deter mi ne d res p o nse is C R, P R, or S D. T he date of res p o nse at t hat 
assess me nt will be use d f or ce ns ori n g. S pecific r ules f or i de ntif yi n g e xte n de d l oss t o 
f oll o w- u p or e xte n de d ti me wit h o ut a n a deq uate assess me nt are pr o vi de d i n t he S A P.
F or s u bjects w h o recei ve s u bse q ue nt a nti -ca ncer t hera p y pri or t o t he date of 
d oc u me nte d pr o gressi o n or deat h, t he ti me of P F S will be ce ns ore d at t he last 
a de q uate assess me nt (i.e., last assess me nt of C R, P R or S D) pri or t o t he i nitiati o n of 
t hat a nti-ca ncer t hera p y.
F or ot her s u bjects w h o d o n ot pr o gress or die,  t he ti me of P F S will be ce ns ore d at t he 
date of t he last a d e q uate t u m or assess me nt.
O S  is defi ne d as t he i nter val of ti me bet wee n t he date of t he first d ose of st u d y dr u g a n d t he date 
of deat h d ue t o a n y ca use. F or s u bjects w h o d o n ot die, t he ti me of deat h will be ce ns ore d at t he 
date of last c o ntact. Deat h d ue t o a n y ca use will be i ncl u de d.
Wit hi n eac h c o h ort, P F S a n d O S will be calc ulate d usi n g t he Ka pla n- Meier met h o d. P F S a n d O S 
at 2 4, 3 2, a n d 5 6 wee ks a n d o verall al o n g wit h t he ass ociate d 9 5 % CIs will be pr o vi de d. If t here 
are a s ufficie nt n u m ber of P F S e ve nts (i.e., pr o g ressi o ns or deat hs), me dia n P F S, first a n d t hir d 
q uartiles a n d 9 5 % CI, will be esti mate d usi n g t he Br o o k me yer- Cr o wle y met h o d (Br o o k me yer, 
1 9 8 2 ). If t here are a s ufficie nt n u m ber of deat hs, me dia n O S, first a n d t hir d q uartiles a n d 
9 5 % CI, will be esti mate d us i n g t he Br o o k me yer- Cr o wle y meth o d. Fi g ures a n d listi n gs of P F S 
a n d O S will als o be pr o vi de d. 
Wit hi n eac h c o h ort a n d f or C o h orts 1, 3, 4, 5, 6, a n d 7 c o m bi ne d, t he O R R a n d a n e xact 9 5 % CI 
will be pr o vi de d. 


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 1 0 3
1 7. 5. 
S afet y A n al yses
1 7. 5. 1. 
E xte nt of E x p os ure 
T he data o n e x p os ure t o taze met ostat will be liste d b y c o h ort. Details pertai ni n g t o d ose 
i nterr u pti o n or d ose m o dificati o n will als o be liste d. D urati o n of e x p os ure a n d perce nta ge of 
treat me nt c o m plia nce will be s u m marize d b y c o h ort a n d o verall. 
1 7. 5. 2.  
A d verse E ve nts
T he data listi n gs of A Es i n t he C S R will c o ntai n t he ver bati m descri pti o n, P T a n d S O C 
Me d D R A-le vel ter ms.
Treat me nt-e mer ge nt A Es ( T E A Es) are defi ne d b y a p pl yi n g treat me nt -e mer ge nt si g ns a n d 
s y m pt o ms ( T E S S) p hil os o p h y. A Es will be re gar de d as T E A Es if o ne of t he f oll o wi n g c o n diti o ns 
is met:
E mer ge after t he ti me of first d ose a d mi nistra ti o n, ha vi n g bee n a bse nt pri or t o t he first 
d ose. 
Re-e mer ge, ha vi n g bee n prese nt b ut st o p pe d pri or t o t he ti me of first d ose 
a d mi nistrati o n.
W orse n i n se verit y after t h e ti me of first d ose a d mi nis trati o n relati ve t o t he pre-
treat me nt state, w he n t he A E is c o nti n u o us.
A n A E wit h partial or c o m ple tel y missi n g start date a n d/ or ti me will al wa ys be ass u me d as 
T E A E, u nless it ca n be deter mi ne d t o be “ pri or t o a d mi nistrati o n” fr o m t he i nc o m plete start 
date/ti me or res ol uti o n date/ti m e (e. g., m o nt h, year is bef ore  first a d mi nistrati o n date, or 
res ol uti o n date is bef ore first a d mi nistrati o n date).
Ot her t ha n bi o ps y-relate d A Es, o nl y T E A Es will be s u m marize d. S u m maries of T E A Es will 
c o nsist of t he n u m ber a n d per ce nta ge of s u bjects re p orti n g t he A E b y S O C a n d b y P T. T E A Es 
w hic h occ ur m ore t ha n o nce f or a s u bject will be  c o u nte d o nl y o nce i n t he s u bject fre q ue ncies. 
T E A Es wit h differe nt C T C A E gra des f or a s u bject will be c o u nte d at t he w orst ( hi g hest) gra de 
f or t he sa me S O C (li ke wise f or P T). T E A Es wit h differe nt dr u g relati o ns hi p f or a s u bject will be 
c o u nte d at str o n gest relati o ns hi p f or t he sa me S O C (li ke wise f or P T). T E A Es wit h missi n g 
relati o ns hi p t o st u d y treat me nt will be c o u nte d as “relate d”. T E A Es wit h missi n g C T C A E gra de 
will be c o u nte d as Gra de 3 (“se vere”).
S u m maries of A Es b y st u d y c o h ort a n d o verall w ill be pr o d uce d t o prese nt t he n u m ber a n d 
perce nta ge of s u bjects wit h: 
A n y T E A E
A n y treat me nt-relate d T E A E
A n y T E A E wit h C T C A E Gra de 3 or hi g her 
A n y T E A E lea di n g t o st u d y treat me nt disc o nti n uati o n 
A n y Seri o us T E A Es
A n y T E A E of s pecial i nterest


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 1 0 4
A n y bi o ps y-relate d A E
Listi n gs will be pr o vi de d f or t he f oll o wi n g:
A Es
T E A Es lea di n g t o st u d y treat me nt disc o nti n uati o n
Seri o us T E A Es
Fatal T E A Es
T E A Es of s pecial i nterest
Bi o ps y-relate d A Es
1 7. 5. 3.  
Cli nic al L a b or at or y E v al u ati o n 
All cli nical la b orat or y para meters will be sta n da r dize d acc or di n g t o t he I nter nati o nal S yste m of 
U nits ( SI) pri or t o s u m marizati o n. Se parate listi n gs a n d s u m mar y ta bles ( b y c o h ort a n d o verall) 
will be pr o d uce d f or eac h la b orat or y test gr o u p (c o m plete bl o o d c o u nts, ser u m c he mistries (li ver, 
re nal [ wit h creati ni ne cleara nce, if creati ni ne is a b n or mal] a n d meta b olis m), c oa g ulati o n pr ofile, 
a n d uri nal ysis). 
S hifts fr o m baseli ne i n C T C A E gra des f or eac h  para meter will be s u m marize d b y c o h ort a n d 
o verall. T he s u m mar y will i ncl u de t he w orst-c ase s hift fr o m baseli ne d uri n g t he p ost- baseli ne 
peri o d, w hic h will i ncl u de b ot h pla n ne d (sc he d ule d) a n d u nsc he d ule d visits after t he first d ose of 
st u d y dr u g. S u bjects wit h la b orat ory data o utsi de t he n or mal ra n ge  will be fla g ge d as “ L” ( L o w) 
or “ H” ( Hi g h) i n t he data listi n g.
1 7. 5. 4.  
Ot her S afet y Me as ures
T he res ults of sc he d ule d assess me nts of p h ysical  e xa mi nati o n, vital si g ns, E C G, E C H O, a n d 
E C O G perf or ma nce stat us will be s u m marize d b y st u d y part a n d o verall. S u m maries will i ncl u de 
data fr o m sc he d ule d visits. S hifts fr o m baseli n e will be s u m marize d w here a p pr o priate. All data 
will be liste d.
1 7. 6. 
P h ar m ac o ki netic A n al yses
Plas ma c o nce ntrati o ns of taze met ostat a n d it s meta b olite E R- 8 9 7 3 8 7 will be deter mi ne d b y a 
vali date d bi oa nal ytical met h o d. C o nce ntrati o ns of taze met ostat a n d its meta b olite will be liste d 
b y c o h ort a n d n o mi nal ti me. Sta n dar d s u m mar y st atistics will be calc u late d (i.e., mea n, S D, 
me dia n, mi ni m u m, a n d ma xi m u m). 
All P K para meters will be calc ulate d usi n g act ual  ti mes. P o p ulati o n esti mates of C L/ F, V d/ F, a n d 
Ka f or taze met ostat will be calc ulate d wit h a n o n-li near mi xe d-effects m o del usi n g N O N M E M 7 
s oft ware. T he effect of s u bject c haracteristics s uc h as a ge, wei g ht, b o d y s urface area, a n d ge n der 
o n t he P K para meters ma y be i n vesti gate d. T he P K data fr o m t his st u d y ma y be c o m bi ne d wit h 
data fr o m ot her st u dies t o deter mi ne t he fi na l p o p ulati o n P K m o del. T he fi nal p o p ulati o n P K 
m o del will be descri be d i n a se parate re p ort.


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 1 0 5
1 7. 7. 
E x pl or at or y A n al ysis
As data warra nt, e x pl orat or y a nal ysis ma y be  perf or me d o n eac h e x pl orat or y e n d p oi nt liste d 
bel o w. I n a d diti o n, e x pl orat or y a nal yses ma y be perf or me d t o e xa mi ne t he relati o ns hi p bet wee n 
e x p os ure t o taze met ostat a n d c li nical a n d safet y e n d p oi nts (i nclu di n g t u m or size or c ha n ge i n 
t u m or size fr o m baseli ne). T he res ults of t hese e x pl orat or y a nal yses ma y be re p orte d se paratel y 
fr o m t he cli nical st u d y re p ort ( C S R). 
T u m or tar get ge ne e x pressi o n a n d p h e n ot y pic mar kers i n cl u di n g t h ose f or 
differe ntiati o n, a p o pt osis, i nfla m mati o n a n d cell pr oliferati o n, a n d t heir c orrelati o n 
wit h acti vit y
S o matic m utati o n a nal ysis of t u m or tiss ue a n d bl o o d 
Ger mli ne D N A a nal ysis f or I NI 1 or S M A R C A 4 varia nts
F or C o h ort 6: Assess me nt of pre- a n d p ost- d ose bi o psies f or i m m u ne pri mi n g (e. g., 
P D- L 1 a n d C D 8 I H C)
F or C o h ort 6: Assess me nt of pre- a n d p ost- d ose bi o psies f or H 3 K 2 7 me 3 a n d f or 
c ha n ges i n ge ne e x pressi o n. 
1 7. 8. 
I n de pe n de nt D at a M o nit or i n g C o m mittee (I D M C)
A n I D M C will be utilize d i n t his st u d y t o e ns ure e xter nal o bjecti ve me dical a n d/ or statistical 
re vie w of: 
Safet y data at eac h pre deter mi ne d ( or a d h oc, if nee de d) a n d ma ke rec o m me n dati o ns 
t o t he S p o ns or t o c o nti n ue, m o dif y or ter mi nate a n y of t he c oh orts or t he st u d y 
C o h ort efficac y data at t he defi ne d sta ges t o deter mi ne if f utilit y has bee n reac he d or 
t he c o h ort s h o ul d pr ocee d t o s u bse q ue nt sta ge 
A rec o m me n dati o n of st u d y h ol d, d ose de-escalati o n, or st u d y ter mi nati o n w o ul d be ma de i n t he 
e ve nt of t he disc o ver y of a n u ne x pecte d, seri o us, or  u nacce pta ble ris k t o t he s u bjects i n t he st u d y. 
T he sc he d ule of a n y pla n ne d i nteri m a nal ysis a n d t h e a nal ysis pla n f or I D M C re vie w is descri be d 
i n a se parate c harter.


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 1 0 6
1 8. 
S T U D Y C O N D U C T C O N SI D E R A TI O N S 
1 8. 1. 
P osti n g of I nf or m ati o n o n P u blicl y A v ail a ble Cli nic al Tri al Re gisters
St u d y i nf or mati o n fr o m t his pr ot oc ol will be p oste d o n p u blicl y a vaila ble cli nical trial re gisters.
1 8. 2.  
Re g ul at or y a n d Et hic al C o nsi der ati o ns
T he pr oce d ures set o ut i n t his  st u d y pr ot oc ol, pertai ni n g t o t he c o n d uct, e val uati o n, a n d 
d oc u me ntati o n of t his st u d y, are desi g ne d t o e ns ure  t hat t he S p o ns or a n d I n vesti gat ors a bi de b y 
G o o d Cli nical Practice ( G C P) as descri be d i n t he I nter nati o na l C o nfere nce o n Har m o nizati o n 
(I C H) Tri partite G ui deli ne E 6 ( R 1): G C P: C o ns oli date d G ui deli ne, a n d f or U S I n vesti gat ors, 2 1 
C o de of Fe deral Re g ulati o ns ( C F R) Parts 5 0, 5 4,  5 6, a n d 3 1 2. C o m plia nce wit h t hese re g ulati o ns 
als o c o nstit utes c o m plia nce wit h t he et hical pri n ci ples descri be d i n t he c urre nt re visi o n of t he 
Declarati o n of Helsi n ki. T he st u d y will als o be carrie d o ut i n kee pi n g wit h l ocal le gal a n d 
re g ulat or y re q uire me nts.
It is t he I n vesti gat or’s res p o nsi bilit y t o e ns ure t hat a de q uate ti me a n d a p pr o priate res o urces are 
a vaila ble at t he st u d y site pri or t o c o m mit me nt t o partici pate i n t his st u d y. T he I n vesti gat or 
s h o ul d als o be a ble t o esti mate or de m o nstrate a p ote ntial f or recr uiti n g t he re q uire d n u m ber of 
s uita ble s u bjects wit hi n t he a gree d recr uit me nt peri o d.
T he I n vesti gat or will  mai ntai n a list of a p pr o priate l y q ualifie d pers o ns t o w h o m t he I n vesti gat or 
has dele gate d si g nifica nt st u d y-relate d tas ks. A n  u p-t o- date c o p y of t he c urric ul u m vitae f or t he 
I n vesti gat or, s u b-I n vesti gat or(s), a n d esse ntial st ud y staff will be pr o vi de d t o t he S p o ns or or its 
desi g nee bef ore starti n g t he st u d y. 
If t he s u bject has a pri mar y p h ysicia n t he I n vesti gator s h o ul d, wit h t he s u bj ect’s or his/ her le gal 
re prese ntati ve’s c o nse nt, i nf or m t he m of t he s u bject’s partici pati o n i n t he st u d y.
1 8. 2. 1. 
I nstit uti o n al Re vie w B o ar d (I R B)/ Et hics C o m mittee ( E C)
It is t he res p o nsi bilit y of t he I n vesti gat or t o s ub mit t his pr ot oc ol, t he i n f or me d c o nse nt d oc u me nt 
(a p pr o ve d b y t he S p o ns or or its desi g nate), rele va nt s u p p orti n g i nf or mati o n a n d all t y pes of 
s u bject recr uit me nt i nf or mati o n t o t he I R B/ E C f or re vie w. All m ust be a p pr o ve d pri or t o site 
i nitiati o n. Pri or t o i m pleme nti n g c ha n ges i n t he st u d y, t he S p o ns or a n d t he I R B/ E C m ust als o 
a p pr o ve a n y re vise d I C Fs a n d/ or pr ot oc ol a me n d me nts. 
O n t he I R B/ E C a p pr o val letter, t he st u d y refere nce,  t he date of re vie w, a n d acti o ns ta ke n s h o ul d 
be clearl y state d.
Cli nical s u p plies of taze met ostat will n ot be re lease d t o t he site a n d recr uit me nt of s u bjects will 
n ot be gi n u ntil t he I R B/ E C writte n a p pr o val has bee n recei ve d b y t he S p o ns or or its desi g nee.
T he I n vesti gat or is res p o nsi ble f or kee pi n g t he I R B/ E C a p prise d of t he pr o gress of t he st u d y a n d 
of a n y c ha n ges ma de t o t he pr ot oc ol a n d/ or I C F. T he I n vesti gat or m ust als o kee p t he I R B/ E C 
i nf or me d of a n y seri o us a n d si g nifica nt A Es. 


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 1 0 7
1 8. 2. 2. 
I nf or me d C o nse nt Pr ocess
It is t he res p o nsi bilit y of t he I n vesti gat or t o o btai n writte n i nf or me d c o nse nt fr o m eac h s u bject 
bef ore a n y pr ot oc ol-s pecifi c assess me nts a n d/ or pr oce d ur es are perf or me d. All c o nse nt 
d oc u me ntati o n m ust be i n acc or da nce wit h a p plica b le re g ulati o ns a n d G C P. Eac h s u bject or t he 
s u bject’s le gall y a ut h orize d re prese ntati ve is re q ueste d t o si g n  t he I C F after t he s u bject has 
recei ve d a n d rea d t he writte n s u bject i nf or mati o n a n d recei ve d a n e x pla nati o n of w hat t he st u d y 
i n v ol ves, i ncl u di n g b ut n ot li mited t o: t he o bjecti ves, p ote ntial be nefits a n d ris k, i nc o n ve nie nces, 
a n d t he s u bject’s ri g hts a n d res p o nsi bilities. A c o p y of t he I C F (s u bject i nf or mati o n s heet a n d t he 
I C F, as a p plica ble) m ust be gi ve n t o t he s u bject or t he s u bject’s le gall y a ut h orize d re prese ntati ve. 
If a p plica ble, it will be pr o vi de d i n a certifie d tra nslati o n of t he s u bject’s  l ocal la n g ua ge. Si g ne d 
I C Fs m ust re mai n i n eac h s u bject’s st u d y file a n d m ust be a vaila ble f or verificati o n b y St u d y 
M o nit ors at a n y ti me. 
Eac h I n vesti gat or will pr o vi de t he S p o ns or or its desi g nee wit h a c o p y of t he I R B/ E C a p pr o ve d 
I C F(s), a n d a c o p y of t he I R B/ E C writte n a p pr o val, pri or t o t he start of t he st u d y. A d diti o nall y, if 
t he I R B/ E C re q uires m o dificati o n of t he sa m ple s u bject i nf or mati o n a n d t he m o del I C F pr o vi de d 
b y t he S p o ns or, t he d oc u me ntati o n s u p p orti n g t his re q uire me nt m ust be pr o vi de d t o t he S p o ns or. 
T he S p o ns or reser ves t he ri g ht t o dela y i nitiati o n of t he st u d y at a site w here t he I C F(s) d o n ot 
meet t he sta n dar ds of a p pli ca ble re g ulati o ns a n d I C H  G C P.
1 8. 3. 
S u bject C o nfi de nti alit y a n d Ac cess t o S o urce D oc u me nts/ D at a
S u bject c o nfi de ntialit y is stri ctl y hel d i n tr ust b y t he S p o ns or a n d/ or t heir desi g nee(s), 
partici pati n g I n vesti gat ors, a n d a n y staff. T his  c o nfi de ntialit y i ncl u des t he cli nical i nf or mati o n 
relati n g t o partici pati n g s u bjects, as well as a n y ge netic or bi ol o gical testi n g.
T he st u d y pr ot oc ol, d oc u me ntati o n, data, a n d all ot her i nf or mati o n ge nerate d will be hel d i n 
strict c o nfi de nce. N o i nf or matio n c o ncer ni n g t he st u d y or t he data  will be release d t o a n y 
u na ut h orize d t hir d part y wit h o ut pri o r writte n a p pr o val of t he S p o ns or. 
T he St u d y M o nit or or ot her a ut h orize d re prese nta ti ves of t he S p o ns or  ma y i ns pect all d oc u me nts 
a n d rec or ds re q uire d t o be mai ntai ne d b y t he I n vesti gat or, i ncl u di n g b ut n ot li mite d t o, me dical 
rec or ds ( office, cli nic, or h os pital), a n d p har mac y rec or ds f or t he s u bjects i n t his st u d y. T he 
cli nical st u d y site will pe r mit access t o s uc h rec or ds.
1 8. 4. 
St u d y M o nit ori n g
M o nit ori n g of t he st u d y will be perf or me d b y t he S p o ns or or its desi g nee(s). At t he m o nit ori n g 
visits, t he pr o gress of t he st u d y will  be disc usse d wit h t he I n vesti gat or, or his/ her re prese ntati ve. 
T he I C Fs will be re vie we d f or si g nat ures a n d t he e C R Fs c hec ke d f or c o m plete ness a n d acc urac y. 
S u bject s o urce data m ust be a vaila ble f or re vie w. T he I n vesti gat or a n d his/ her staff are e x pecte d 
t o c o o perate wit h t he St u d y M o nit or a n d be a vaila ble d uri n g at least a p orti o n of t he m o nit ori n g 
visit t o re vie w t he e C R Fs a n d a n y q ueries/r es ol uti o ns, a ns wer q ues ti o ns, a n d pr o vi de a n y 
missi n g i nf or mati o n.
T he St u d y M o nit or will rec or d t he date of eac h vi sit t o get her wit h a s u m mar y of t he stat us a n d 
pr o gress of t he st u d y. Pr o p ose d acti o ns will be c o nfir me d wit h t he I n vesti gat or i n writi n g. 


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 1 0 8
Tele p h o ne c o ntact will be ma de wit h t he I n ves ti gat or as necessar y d uri n g t he data c ollecti o n 
peri o d a n d d uri n g t he data a n d re p ort writi n g peri o ds. 
1 8. 5. 
Pr ot oc ol De vi ati o ns
N o de viati o n ma y be ma de fr o m t he pr ot oc ol u nless a n a me n d me nt has bee n a gree d t o i n writi n g 
b y b ot h t he I n vesti gat or a n d t he S p o ns or a n d a p pr o ve d b y t he I R B/ E C. I n vesti gati ve sites will 
c o ntact t he Me dical M o nit or t o re q uest clarificati o ns re gar di n g a n y as pect of t he cli nical st u d y or 
eli gi bilit y of s u bjects.
W he n a n e mer ge nc y occ urs t hat re q uires a de viat i o n fr o m t he pr ot oc ol f or a n i n di vi d ual s u bject, 
t he de viati o n will be o nl y f or t hat s u bject. T he I n vesti gat or or ot her p h ysicia n i n atte n da nce i n 
s uc h a n e mer ge nc y will, if circ u msta nces a n d ti me per mit, c o ntact t he S p o ns or or t heir 
re prese ntati ve(s), i m me diatel y b y tele p h o ne. S uc h c o ntacts will be ma de as s o o n as p ossi ble t o 
per mit a decisi o n as t o w het her or n ot t he s u bject (f or w h o m t he pr ot oc ol de viati o n was affecte d) 
is t o c o nti n ue i n t he st u d y. T he s o urce d oc u me ntati o n will c o m pletel y descri be t he pr ot oc ol 
de viati o n a n d state t he reas o ns f or s uc h de viati o n. I n a d diti o n, t he I R B/ E C will be n otifie d i n 
writi n g of s uc h pr ot oc ol de viati o n. 
1 8. 6. 
Pr ot oc ol A me n d me nt
All a me n d me nts t o t he pr ot oc ol m ust be d oc u me nte d i n writi n g, re vie we d, a n d a p pr o ve d b y t he 
I n vesti gat or a n d t he S p o ns or, a n d s u b mitte d t o t he I R B/ E C f or a p pr o val pri o r t o i nitiati o n, e xce pt 
i n cases w here re q uire d f or s u bject safet y. If t he pr ot oc ol a me n d me nt s u bs ta ntiall y alters t he 
st u d y desi g n or p ote ntial ris k t o t he s u bject, a ne w writte n I C F f or c o nti n ue d partici pati o n i n t he 
st u d y m ust be o btai ne d fr o m eac h s u bject or his/ her le gal re prese ntati ve.
1 8. 7. 
S us pe nsi o n or Ter mi n ati o n of St u d y
S h o ul d c o n diti o ns re q uiri n g f urt he r clarificati o n arise bef ore t he decisi o n t o pr ocee d wit h or 
ter mi nate t he st u d y ca n be reac he d, t he st u d y will be s us pe n de d u ntil t he sit uati o n has bee n 
res ol ve d. 
T he S p o ns or has t he ri g ht t o ter mi nate t his st u d y a n d re m o ve all st u d y mate rial fr o m t he site at 
a n y ti me. E xa m ples of w here t his mi g ht  occ ur i ncl u de, b ut are n ot li mite d t o: 
W he n it bec o mes a p pare nt t hat s u bject e nr oll me nt is u nsatisfact or y wit h res pect t o 
q ualit y a n d/ or q ua ntit y or data rec or di n g is  i nacc urate a n d/ or i nc o m plete o n a c hr o nic 
basis.
W he n t he i nci de nce a n d/ or se v erit y of A Es i n t his st u d y i n dicates a p ote ntial healt h 
hazar d ca use d b y treat me nt wit h taze met ostat.


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 1 0 9
1 9.  
A D MI NI S T R A TI V E P R O C E D U R E S
1 9. 1.  
Rec or di n g a n d Access t o St u d y Rec or ds
T he circ u msta nces of c o m pleti o n or  ter mi nati o n of t he st u d y n ot wit hsta n di n g, t he I n vesti gat or (if 
re gi o nall y re q uire d, t he hea ds of t he me dical i nstit uti o ns) has t he res p o nsi bilit y t o  retai n all st u d y 
rec or ds, i ncl u di n g b ut n ot li mited t o t he pr ot oc ol, c o pies of e C R Fs, t he I B, re g ulat or y a ge nc y 
re q uire d d oc u me nts (e. g., F or m F D A 1 5 7 2/ State me nt of I n vesti gat or, fi na ncial discl os ures, etc.), 
I C Fs, a n d I R B/I E C c orres p o n de nce. T o e na ble e val uati o ns a n d/ or i ns pec ti o ns fr o m re g ulat or y 
a ut h orities or S p o ns or, t he I n vesti g at or a grees t o mai ntai n rec or ds,  i ncl u di n g t he i de ntit y of all 
partici pati n g s u bjects (s ufficie nt  i nf or mati o n t o li n k rec or ds, e. g., e C R Fs a n d h os pital rec or ds), 
all ori gi nal si g ne d I C Fs, e C R Fs, S A E f or ms, s o ur ce d oc u me nts, detaile d rec or ds of treat me nt 
dis p ositi o n, a n d a de q uate d oc u m e ntati o n of rele va nt c orres p o n de nce (e. g., letters, meeti n g 
mi n utes, tele p h o ne calls re p orts). T h e rec or ds m ust be re tai ne d b y t he I n vesti gat or acc or di n g t o 
I C H G C P a n d/ or a p plica ble l ocal re g ulat or y re g ulati o ns, w hic he ver is l o n gest, as s pecifie d i n t he 
Cli nical St u d y A gree me nt. It is re q ueste d t hat at t he c o m pleti o n of t he re q uire d rete nti o n peri o d 
or, s h o ul d t he I n vesti gat or wit h dra w fr o m t he res p o nsi bilit y of  mai ntai ni n g st u d y rec or d (e. g., 
retire, rel ocate, etc.), t he I n vesti gat or ( or if re gi o nall y re q uire d, t he hea ds of t he me dical 
i nstit uti o ns) will pr os pecti vel y n otif y t he S p o nsor. T he st u d y rec or ds m ust  be tra nsferre d t o a 
desi g nee acce pta ble t o t he S p o ns or, s uc h as a n ot he r I n vesti gat or at t he i nstit uti o n or t o t he 
S p o ns or. T he I n vesti gat or m ust o b tai n t he S p o ns or’s writte n per missi o n bef ore dis p osi n g of a n y 
rec or ds, e ve n if rete nti o n re q uire me nts ha ve bee n met.  
1 9. 2.  
C ase Re p ort F or ms
Electr o nic case re p ort f or ms (e C R F) will be use d f or data c ollecti o n f or t his st u d y.
T he I n vesti gat or is res p o nsi ble f or mai ntai ni n g a de q uate a n d acc urate s o urce d oc u me nts fr o m 
w hic h acc urate i nf or mati o n will be tra nscri be d i nt o  e C R Fs, w hic h ha ve bee n desi g ne d t o ca pt ure 
all o bser vati o ns a n d ot her data perti ne nt t o t he cli nical i n ve sti gati o n. T he e C R Fs s h o ul d be 
c o m plete d b y t he I n vesti gat or or dele gate as state d o n t he Dele gati o n of A ut h orit y L o g. 
O ver writi n g of i nf or mati o n or use of li q ui d c orr ecti n g fl ui d is n ot all o we d i n t he s o urce 
d oc u me nt. 
Eac h i n vesti gati ve site will be visite d as fre q u e ntl y as d oc u me nte d i n t he m o nit ori n g pla n b y t he 
S p o ns or or t heir desi g nee t o re vie w t he e C R Fs f or c o m plete ness a n d acc urac y. T he S p o ns or or 
t heir desi g nee will hi g hli g ht a n y discre pa ncies f o u n d bet wee n s o urce d oc u me nts a n d t he 
c o m plete d e C R Fs a n d e ns ure t hat a p pr o priate site pers o n nel a d dress t he discre pa ncies. W he n a 
discre pa nc y res ults i n c orrecte d e C R F data, t h e c orrecti o n will be re vie we d a gai n a gai nst t he 
c orrect s o urce d oc u me ntati o n. U nif or m pr oce d ures w ill be disc usse d at t he Site I nitiati o n Visit.
T he e C R Fs m ust be re vie we d a n d electr o nicall y  si g ne d a n d date d b y t he I n vesti gat or o nce all 
data ha ve bee n e ntere d a n d all q ueries res ol ve d. Q ueries ma y be ra ise d if t he data are u nclear or 
c o ntra dict or y. T he I n vesti gat or m ust a d dress all q ueries.


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 1 1 0
1 9. 3.  
Q u alit y Ass ur a nce a n d Q u alit y C o ntr ol ( Q C)
A site m o nit ori n g pla n will be de vel o pe d t o  e ns ure t he h u ma n s u bject pr otecti o n, st u d y 
pr oce d ures, la b orat or y, st u d y i nter ve nti o n a d mi nis trati o n, a n d data c ollecti o n pr ocesses are of 
hi g h q ualit y a n d meet t he S p o ns or's, I C H/ G C P, a n d ot her a p pli ca ble re g ulat or y g ui deli nes. 
T he I n vesti gat or will per mit a u t h orize d t he S p o ns or or its desi g nee(s), a n d t he res pecti ve 
re g ulat or y a ut h orities, t o i ns pect facilities a n d rec or ds rele va nt t o t his st u d y if nee de d.
I nitial site trai ni n g will be pr o vi de d b y t he S p o nsor or its desi g nee. Trai ni n g f or ne w site staff 
will be pr o vi de d b y pre vi o usl y trai ne d st u d y n urses, st u d y c o or di nat ors, or ot her q ualifie d staff 
u n der t he s u per visi o n of t he Pri mar y I n vesti gat or. A d diti o nal trai ni n g will be pr o vi de d b y t he 
S p o ns or or its desi g nee as nee de d. 
T he desi g nate d Data Ma na ge me nt Tea m will i m ple me nt Q C pr oce d ures be gi n ni n g wit h t he data 
e ntr y s yste m a n d ge nerate data Q C c hec ks t hat will be r u n o n t he data base. A n y missi n g data or 
data a n o malies will be c o m m u nicate d t o t he site(s) f or clarificati o n/res ol uti o n.
1 9. 4.  
D at a Q u alit y Ass ur a nce
T his st u d y will be or ga nize d, perf or me d, a n d re p o rte d i n c o m plia nce wit h t he S p o ns or or its 
desi g nee's Sta n dar d O perati n g Pr oce d ures, pr ot oc ols a n d w or ki n g practice d oc u me nts, a n d t he 
re q uire me nts of I C H/ G C P g ui deli nes. C o m plia nce will be ac hie ve d t hr o u g h a c o m bi nati o n of 
st u d y-s pecific a u dits of i n vesti gati ve sites a n d a u dits at re g ular i nter vals of t he S p o ns or or its 
desi g nee's s yste ms f or data ha n d li n g, a nal ysis, a n d re p orti n g.  
1 9. 5.  
C o nfi de nti alit y
Data c ollecte d d uri n g t his st u d y ma y be use d t o s u p p ort t he de vel o p me nt, re gistrati o n, or 
mar keti n g of taze met ostat. After a s u bject or his/ her le gal re prese n tati ve ha ve c o nse nte d t o ta ke 
part i n t he st u d y t heir me dical r ec or ds a n d t he data c ollecte d d u ri n g t he st u d y will be re vie we d 
b y t he S p o ns or a n d/ or its desi g nee. T hese rec or d s a n d data ma y be re vie we d b y t he f oll o wi n g: 
i n de pe n de nt a u dit ors w h o vali date t he data o n be half of t he S p o ns or: t hir d parties wit h w h o m t he 
S p o ns or ma y de vel o p, re gister, or  mar ket taze met ostat; nati o nal or l ocal reg ulat or y a ut h orities 
a n d t he I R B/ E C(s) w hic h ga ve its/t heir a p pr o val f or t his st u d y t o pr ocee d. 
Alt h o u g h s u bjects will be k n o w n b y a u ni q ue i de ntifier n u m ber, t heir year of birt h will als o be 
c ollecte d a n d use d t o assist t he S p o ns or a n d/ or its desi g nee t o ve rif y t he acc urac y of t he data, f or 
e xa m ple, t hat t he la b orat or y res ults are assi g ne d t o t he c orrect s u bject.
1 9. 6.  
A u dit/I ns pecti o n
T o e ns ure c o m plia nce wit h rele va nt re g ulati o ns, data ge nerate d b y t his st u d y will be a vaila ble f or 
i ns pecti o n u p o n re q uest b y re prese ntati ves of t he U S F D A as well as ot her nati o nal a n d l ocal 
re g ulat or y a ut h orities, t he S p o ns or a n d/ or its desi g nee, i ntereste d c o m mercial parties, a n d t he 
I R B/ E C f or eac h st u d y site.


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 1 1 1
1 9. 7. 
Pr o visi o n of St u d y Res ults a n d P u blic ati o n
A s u m mar y of t he st u d y res ults will  be ma de p u blicl y a vaila ble wit hi n 1 2 m o nt hs of reac hi n g t he 
e n d of t he st u d y, defi ne d as t he date of t he L S L V. A f ull C S R will be ma de p u blicl y a vaila ble n o 
later t ha n 1 8 m o nt hs after t he e n d of t he st u d y. 
If a ma n uscri pt is p u blis he d i n a peer-re vie we d j o ur nal, t he n t hat i nitial release ma y be a n 
a bstract t hat meets t he re q uire me nts of t he I nte r nati o nal C o m mittee of Me dical J o ur nal E dit ors. 
All ma n uscri pts, a bstracts or ot her m o des of prese ntati o n arisi n g fr o m t he res ults of t he st u d y 
m ust be re vie we d a n d a p pr o ve d i n writi n g b y t he S p o ns or, i n a d vance of s u b missi o n. T he re vie w 
is ai me d at pr otecti n g t he S p o ns or’s pr o prietar y i nf or mati o n e xisti n g eit her at t he date of t he 
c o m me nce me nt of t he st u d y or ge nerate d d uri n g t he st u d y. 
T he detaile d o bli gati o ns re gar di n g t he p u blica ti o n of a n y data, material res ults, or ot her 
i nf or mati o n, ge nerate d or create d i n relati o n t o t he st u d y s hall be set o ut i n t he a gree me nt 
bet wee n eac h I n vesti gat or a n d t he S p o ns or. 


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 1 1 2
2 0.  
R E F E R E N C E S
Ali m o va I, Bir ks D K, Harris P S, et al. I n hi biti o n of E Z H 2 s u p presses self-re ne wal a n d i n d uces 
ra diati o n se nsiti vit y i n at y pical r ha b d oi d terat oi d t u m or cells. Ne ur o O nc ol. 2 0 1 3; 1 5( 2): 1 4 9- 1 6 0. 
Bale y dier F, Dec o u velaere A V, Ber ger o n J, et  al. T cell rece pt or ge n ot y pi n g a n d H O X A/ T L X 1 
e x pressi o n defi ne t hree T l y m p h o bl astic l y m p h o ma s u bsets w hic h mi g ht affect cli nical o utc o me. 
Cli n C a ncer Res. 2 0 0 8; 1 4( 3): 6 9 2- 7 0 0. 
Be g ueli n W, P o p o vic R, Teater M, et al. E Z H 2 is re q uire d f or ger mi nal ce nter f or mati o n a n d 
s o matic E Z H 2 m utati o ns pr o mote l y m p h oi d tra nsf or mati o n. C a ncer Cell. 2 0 1 3; 2 3( 5): 6 7 7- 6 9 2. 
B o m pas E, Le Ces ne A, Tresc h- Br u neel E, et al. S orafe ni b i n patie nts wit h l ocall y a d va nce d a n d 
metastatic c h or d o mas: a p h ase II trial of t he Fre nc h Sarc o ma Gr o u p ( G S F/ G E T O). A n n O nc ol. 
2 0 1 5; 2 6( 1 0): 2 1 6 8- 2 1 7 3. 
B o ur dea ut F, C hi S N, Fr u h wal d M C. R ha b d oi d t u m o rs: i nte grati n g bi ol o gical i nsi g hts wit h 
cli nical s uccess: a re p ort fr o m t he S M A R C B 1 a n d R ha b d oi d T u m or S y m p osi u m, Paris, 
Dece m ber 1 2- 1 4, 2 0 1 3. C a ncer ge netics. 2 0 1 4; 2 0 7( 9): 3 4 6- 3 5 1. 
Br o o k me yer R, Cr o wle y J. A C o nfi de nce I n ter val f or t he Me dia n S ur vi val Ti me. Bi o metrics. 
1 9 8 2; 3 8( 1): 2 9- 4 1. 
B ur k har dt B, Reiter A, La n d ma n n E, et al. P o or o utc o me f or c hil dre n a n d a d olesce nts wit h 
pr o gressi ve disease or rela pse of  l y m p h o blastic l y m p h o ma: a rep ort fr o m t he berli n-fra n kf urt-
m ue nster gr o u p. J Cli n O nc ol. 2 0 0 9; 2 7( 2 0): 3 3 6 3- 3 3 6 9. 
Ca m p o E, S wer dl o w S H, Harris N L, et al. T he 2 0 0 8 W H O classificati o n of l y m p h oi d ne o plas ms 
a n d be y o n d: e v ol vi n g c o nce pts a n d practical a p plicati o ns. Bl o o d. 2 0 1 1; 1 1 7( 1 9): 5 0 1 9- 5 0 3 2. 
C h ba ni L, G uill o u L, Terrier P, et al. E p it heli oi d sarc o ma: a cli nic o pat h ol o gic a n d 
i m m u n o hist oc he mical a nal ysis of 1 0 6 cases fr o m t he Fre nc h sarc o ma gr o u p. A meric a n j o ur n al 
of cli nic al p at h ol o gy. 2 0 0 9; 1 3 1( 2): 2 2 2- 2 2 7. 
C he n g J X, Tretia k o va M, G o n g C, et al. Re nal me d ullar y carci n o ma: r ha b d oi d feat ures a n d t he 
a bse nce of I NI 1 e x pressi o n as mar kers of a g gressi ve be ha vi or. M o d P at h ol. 2 0 0 8; 2 1( 6): 6 4 7- 6 5 2. 
C hi S N, Zi m mer ma n M A, Ya o X, et al. I nte nsi ve m ulti m o dalit y treat me nt f or c hil dre n wit h 
ne wl y dia g n ose d C N S at y pical terat oi d r ha b d oi d t u m or. J Cli n O nc ol. 2 0 0 9; 2 7( 3): 3 8 5- 3 8 9. 
C o pela n d R A. M olec ular pat h wa ys: pr otei n met h yltra nsferases i n ca ncer. Cli n C a ncer Res. 
2 0 1 3; 1 9( 2 3): 6 3 4 4- 6 3 5 0. 
C ortelazz o S, Ferreri A, H oelzer D,  et al. L y m p h o blastic l y m p h o ma. Crit Rev O nc ol He m at ol. 
2 0 1 7; 1 1 3: 3 0 4- 3 1 7. 
C o u ncil f or I nter nati o nal Or ga niza ti o ns of Me dical Scie nces. Ma na ge me nt of Safet y I nf or mati o n 
Fr o m Cli nical Trials: Re p ort of CI O M S Gr o u p VI. I n: G or d o n AJ, e d. Ge ne va, S witzerla n d: 
C o u ncil f or I nter nati o nal Or ga niza ti o ns of Me dical Scie nces; 2 0 0 5. 
De vi ne BJ, Mc Carr o n M M. Cli nical P har m ac y: Case St u dies: Case N u m ber 2 5 Ge nta mici n 
T hera p y. Dr u g I ntelli ge nce & Cli nic al P h ar m acy. 1 9 7 4; 8( 1 1): 6 5 0- 6 5 5. 
Erric o A. Ge netics: S M A R C A 4 m utate d i n S C C O H T. N at Rev Cli n O nc ol. 2 0 1 4; 1 1( 6): 3 0 2. 
Fis her C. S y n o vial sarc o ma. A n n als of di a g n ostic p at h ol o gy. 1 9 9 8; 2( 6): 4 0 1- 4 2 1. 
F o ul kes W D, Clar ke B A, Hassel blatt M, et al. N o  s mall s ur prise - s mall cell carci n o ma of t he 
o var y, h y percalcae mic t y pe, is a mali g na nt r ha b d oi d t u m o ur. T he J o ur n al of p at h ol o gy. 
2 0 1 4; 2 3 3( 3): 2 0 9- 2 1 4. 
Gi n n K F, Gajjar A. At y pical tera t oi d r ha b d oi d t u m or: c urre nt t hera p y a n d f ut ure directi o ns. 
Fr o ntiers i n o nc ol o gy. 2 0 1 2; 2: 1 1 4. 


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 1 1 3
G ua da g n ol o B A, Za gars G K, Ball o M T, et al. L o n g-ter m o utc o mes f or s y n o vial sarc o ma treate d 
wit h c o nser vati o n s ur ger y a n d ra di ot hera p y. I nter n ati o n al j o ur n al of r a di ati o n o nc ol o gy, 
bi ol o gy, p hysics. 2 0 0 7; 6 9( 4): 1 1 7 3- 1 1 8 0. 
Harris o n M L, H os ki ns P, d u B ois A, et al. S mall cell of t he o var y, h y percalce mic t y pe -- a nal ysis 
of c o m bi ne d e x perie nce a n d rec o m me n dati o n f or ma na ge me nt. A G CI G st u d y. Gy nec ol o gic 
o nc ol o gy. 2 0 0 6; 1 0 0( 2): 2 3 3- 2 3 8. 
Hassel blatt M, T h o mas C, H o v esta dt V, et al. P o orl y differe ntiate d c h or d o ma wit h
S M A R C B 1/I NI 1 l oss: a dis ti nct m olec ular e ntit y wit h dis mal pr o g n osis. Act a Ne ur o p at h ol. 
2 0 1 6; 1 3 2( 1): 1 4 9- 1 5 1. 
Jac ks o n E M, Sie vert AJ, Gai X, et al. Ge n o mic a nal ysis usi n g hi g h- de nsit y si n gle n ucle oti de 
p ol y m or p his m- base d oli g o n ucle oti de arra ys a n d m ulti ple x li gati o n- de pe n de nt pr o be 
a m plificati o n pr o vi des a c o m pre he nsi ve a nal ysis  of I NI 1/ S M A R C B 1 i n mali g na nt r ha b d oi d 
t u m ors. Cli n C a ncer Res. 2 0 0 9; 1 5( 6): 1 9 2 3- 1 9 3 0. 
Jeli nic P, M ueller JJ, Ol vera N, et al. Rec urrent S M A R C A 4 m utati o ns i n s mall cell carci n o ma of 
t he o var y. N at Ge net. 2 0 1 4; 4 6( 5): 4 2 4- 4 2 6. 
J o nes R L, C o nsta nti ni d o u A, Ol m os D, et al. R ole of palliati ve c he m ot hera p y i n a d va nce d 
e pit heli oi d sarc o ma. A m J Cli n O nc ol. 2 0 1 2; 3 5( 4): 3 5 1- 3 5 7. 
Ka d oc h C, Cra btree G R. Re versi ble disr u pti o n of m S WI/ S N F ( B A F) c o m ple xes b y t he S S 1 8-
S S X o nc o ge nic f usi o n i n s y n o vial sarc o ma. Cell. 2 0 1 3; 1 5 3( 1): 7 1- 8 5. 
Ka wa g uc hi S, Wa da T, Na g o ya S, et al. E x tras keletal m y x oi d ch o n dr osarc o ma: a M ulti-
I nstit uti o nal St u d y of 4 2 Cases i n Ja pa n. C a ncer. 2 0 0 3; 9 7( 5): 1 2 8 5- 1 2 9 2. 
K n uts o n S K, Ka wa n o S, Mi n os hi ma Y, et al. Selecti ve i n hi biti o n of E Z H 2 b y E P Z- 6 4 3 8 lea ds t o 
p ote nt a ntit u m or acti v it y i n E Z H 2- m uta nt n o n- H o d g ki n l y m p h o ma. M ol C a ncer T her. 
2 0 1 4; 1 3( 4): 8 4 2- 8 5 4. 
K n uts o n S K, War h olic N M, Wi gle TJ, et al. D ura ble t u m or re gr essi o n i n ge neticall y altere d 
mali g na nt r ha b d oi d t u m ors b y i n hi biti o n of met h yl tra nsferase E Z H 2. Pr oc N atl Ac a d Sci U S A. 
2 0 1 3; 1 1 0( 1 9): 7 9 2 2- 7 9 2 7. 
Lai C, D u nlea v y K. N K/ T-cell l y m p h o mas i n c hil dre n. Best Pr act Res Cli n H ae m at ol. 
2 0 1 3; 2 6( 1): 3 3- 4 1. 
Le L oarer F, Wats o n S, Pierr o n G, et al. S M A R C A 4 i nacti vati o n defi nes a gr o u p of 
u n differe ntiate d t h oracic mali g na ncies tra nscri pti o nall y relate d t o B A F- deficie nt sarc o mas. N at 
Ge net. 2 0 1 5; 4 7( 1 0): 1 2 0 0- 1 2 0 5. 
Le bellec L, A u bert S, Zairi F, et al. M olec ular tar gete d t hera pies i n ad va nce d or metastatic 
c h or d o ma patie nts: facts a n d h y p ot heses. Crit Rev O nc ol He m at ol. 2 0 1 5; 9 5( 1): 1 2 5- 1 3 1. 
L o nes M A, Heere ma N A, Le Bea u M M, et al. C hr o m os o me a b n or malities i n a d va nce d sta ge 
l y m p h o blastic l y m p h o ma of c hil dre n an d a d olesce nts: a re p ort fr o m C C G- E 0 8. C a ncer Ge net 
Cyt o ge net. 2 0 0 7; 1 7 2( 1): 1- 1 1. 
Ma h di Y, Z o uai dia F, Z o u hair A, et al. C o m bi n e d m y oe pit helial carci n o ma a n d m y oe pit heli o ma 
i n s oft tiss ue: a case re p ort a n d re vie w of t he literat ure. J Me d C ase Re p. 2 0 1 4; 8( 1): 3 1 7. 
Mar g ol A S, J u d ki ns A R. Pat h ol o g y a n d dia g n osis of S M A R C B 1- deficie nt t u m ors. C a ncer 
ge netics. 2 0 1 4; 2 0 7( 9): 3 5 8- 3 6 4. 
Mar g uer o n R, Rei n ber g D. T he P ol yc o m b c o m ple x P R C 2 a n d its mar k i n life. N at ure. 
2 0 1 1; 4 6 9( 7 3 3 0): 3 4 3- 3 4 9. 
Mi na ga wa T, S hi o ya R, Sat o C, et al. A d va n ce d e pit heli oi d mali g na nt peri p heral ner ve s heat h 
t u m or s h o wi n g c o m plete resp o nse t o c o m bi ne d s ur ger y a n d c he m ot hera p y: a case re p ort. C ase 
Re p O nc ol Me d. 2 0 1 1; 2 0 1 1: 7 0 5 3 4 5. 


Cli nical St u d y Pr ot oc ol A me n d me nt
E Z H- 2 0 2
Taze met ostat
Pr ot oc ol A me n d me nt 1 1. 0
E piz y me, I nc.
C o nfi de ntial
Pa ge 1 1 4
M o ble y B C, Mc Ke n ne y J K, Ba n gs C D, et al . L oss of S M A R C B 1/I NI 1 e x pressi o n i n p o orl y 
differe ntiate d c h or d o mas. Act a Ne ur o p at h ol. 2 0 1 0; 1 2 0( 6): 7 4 5- 7 5 3. 
M or ge nster n D A, Gi bs o n S, Br o w n T, et al. Cl i nical a n d pat h ol o gical feat ures of pae diatric 
mali g na nt r ha b d oi d t u m o urs. Pe di atric bl o o d & c a ncer. 2 0 1 0; 5 4( 1): 2 9- 3 4. 
M ori n R D, J o h ns o n N A, Se vers o n T M, et al. S o matic m utati o ns alteri n g E Z H 2 ( T yr 6 4 1) i n 
f ollic ular a n d diff use lar ge B-cell l y m p h o mas of ger mi nal-ce nter ori gi n. N at Ge net. 
2 0 1 0; 4 2( 2): 1 8 1- 1 8 5. 
O ke n M M, Creec h R H, T or me y D C, et al. T o xici t y a n d res p o nse criteria of t he Easter n 
C o o perati ve O nc ol o g y Gr o u p. A m J Cli n O nc ol. 1 9 8 2; 5( 6): 6 4 9- 6 5 5. 
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Pi n k D, Ric hter S, Ger des S, et al. Ge mcita bi ne a n d d oceta xel f or e pit heli oi d sarc o ma: res ults 
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P ortell C A, S weete n ha m J W. A d ult l y m p h o blastic l y m p h o ma. C a ncer J. 2 0 1 2; 1 8( 5): 4 3 2- 4 3 8. 
Ra m os P, Kar nezis A N, Crai g D W, et al. S mall cell carci n o ma of t he o var y, h y percalce mic t y pe, 
dis pla ys fre q ue nt i nacti vati n g ger mli ne a n d s o matic m utati o ns i n S M A R C A 4. N at Ge net. 
2 0 1 4; 4 6( 5): 4 2 7- 4 2 9. 
Ree d N S, Pa utier P, A vall- L u n d q vist E, et al. G y nec ol o gic Ca ncer I nter Gr o u p ( G CI G) c o nse ns us 
re vie w f or o varia n s mall cell ca ncers. I nter n ati o n al j o ur n al of gy nec ol o gic al c a ncer : offici al 
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i nteract or 1) pre dis p oses t o mali g na nt r ha b d oi d t u m ors i n mice. Pr oc N atl Ac a d Sci U S A. 
2 0 0 0; 9 7( 2 5): 1 3 7 9 6- 1 3 8 0 0. 
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patie nts wit h rela pse d or refract or y a d va nce d  s oft tiss ue sarc o ma: a p hase II st u d y fr o m t he 
E ur o pea n or ga nisati o n f or rese arc h a n d treat me nt of ca ncer-s oft tiss ue a n d b o ne sarc o ma gr o u p 
( E O R T C st u d y 6 2 0 4 3). J Cli n O nc ol. 2 0 0 9; 2 7( 1 9): 3 1 2 6- 3 1 3 2. 
S mit h TJ, K hatc heressia n J, L y ma n G H, et al . 2 0 0 6 u p date of rec o m me n dati o ns f or t he use of 
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2 0 0 6; 2 4( 1 9): 3 1 8 7- 3 2 0 5. 
S o ur o ullas G P, Jec k W R, Par ker J S, et al. A n  o nc o ge nic Ez h 2 m utati o n i n d uces t u m ors t hr o u g h 
gl o bal re distri b uti o n of hist o ne  3 l ysi ne 2 7 tri met h ylati o n. N at Me d. 2 0 1 6; 2 2( 6): 6 3 2- 6 4 0. 
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t u m or site, affects t he o utc o me of patie nts wit h mali g na nt r ha b d oi d t u m ors. Pe di atric bl o o d & 
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4 4 3.
Y o u n g R H, Oli va E, Sc ull y R E . S mall cell carci n o ma of t he o var y, h y percalce mic t y pe. A 
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Zi n g g D, De b bac he J, Sc haefer S M, et al. T he e pi ge netic m o difier E Z H 2 c o ntr ols mela n o ma 
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2 0 1 5; 6: 6 0 5 1. 
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As pects. P h ar m ace utics. 2 0 1 0; 2( 4): 3 6 4- 3 8 8. 

SAP_001.pdf: 
Epizyme, an Ipsen Company 
Confidential 
 
Statistical Analysis Plan 
 
V 3.0, 30 NOV 2022 
 
 
 
 
 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
Protocol EZH-202 
 
 
A Phase II, Multicenter Study of the EZH2 Inhibitor 
Tazemetostat in Adult Subjects with INI1-Negative Tumors or 
Relapsed/Refractory Synovial Sarcoma 
 
 
 
Prepared By: Epizyme, an Ipsen Company 
 
Version Number and Date: V3.0, 30 NOV 2022 


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Statistical Analysis Plan 
 
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table presentation. 
 
Remove the text about the study day calculation when the assessment 
date is after the last dose date. 
 
Update the confidence interval calculation as 95% CI in the whole 
study. 
 
Add response evaluable population definition and defined the efficacy 
parameters to be analyzed in RE population. 
 
from date of last disease progression until the start of study 
 
 
medications will include medications taken any time from the start of 
the first dose of study drug through 30 days following end of study 
 
 
Update radiotherapy instead of palliative radiotherapy will be 
analyzed in the study. 
 
Update the definition of Best Overall Response (BOR), Stable Disease 
(SD), and Overall Response Rate definition.  
 
Update the censor rule for PFS and DOR: No progression (or death) 
and new anticancer treatment or cancer-related surgery documented 
on or prior to starting anti-cancer therapy or cancer-related surgery; 
Death or progression after two missed visit (with 2 week window) will 
to missed assessments 
 
Define the subgroup analyses for best overall response, objective 
response rate, and response duration. 
 
severity on or after the day of the first dose of study drug through 30 
 
 
Update the Adverse Event summary list, add the definition of 
cardiotoxicity of TEAEs.  
 
Remove the urinalysis shift tables. 
 
Clarify the Creatinine Clearance calculation formula and the criteria for 
subject with creatinine clearance rate. 
 
Add liver function analysis in laboratory evaluation 
 
The changes are based on FDA guidance and updated protocol 
 
 


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Statistical Analysis Plan 
 
V 3.0, 30 NOV 2022 
 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ..................................................................................................1 
SIGNATURE PAGE .........................................................................................................................2 
MODIFICATION HISTORY ............................................................................................................3 
TABLE OF CONTENTS ...................................................................................................................5 
LIST OF TABLES .............................................................................................................................6 
LIST OF FIGURES ...........................................................................................................................7 
LIST OF ABBREVIATIONS AND DEFINITIONS .........................................................................8 
1. 
INTRODUCTION ........................................................................................................10 
2. 
STUDY OBJECTIVES AND ENDPOINTS ................................................................10 
3. 
STUDY DESIGN ..........................................................................................................12 
3.1. 
General Description ......................................................................................................12 
3.2. 
Estimated Study Duration .............................................................................................15 
3.2.1. 
Study Duration for Participants ............................................................................................... 15 
3.2.2. 
End of Study ............................................................................................................................. 15 
3.3. 
Changes to Analyses from Protocol ..............................................................................15 
4. 
PLANNED ANALYSES AND SAMPLE SIZE ...........................................................16 
4.1. 
Interim Analysis ............................................................................................................16 
4.2. 
Primary Analysis ...........................................................................................................17 
4.3. 
Final Analysis of Progression-Free Survival (PFS) and Overall Survival (OS) ............17 
4.4. 
Determination of Sample Size ......................................................................................17 
4.5. 
Sample Size Re-estimation ...........................................................................................20 
5. 
ANALYSIS POPULATIONS .......................................................................................20 
6. 
GENERAL CONSIDERATIONS .................................................................................20 
6.1. 
Grouping of Subjects and Table Presentation ...............................................................20 
6.2. 
Time Point Conventions ................................................................................................21 
7. 
STATISTICAL CONSIDERATIONS ..........................................................................21 
7.1. 
Common Conventions ..................................................................................................21 
7.2. 
Missing Data .................................................................................................................22 
8. 
ANALYSIS POPULATIONS AND ENROLLMENT .................................................23 
9. 
DISPOSITION ..............................................................................................................23 
10. 
PROTOCOL DEVIATIONS ........................................................................................23 
11. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ........................29 
12. 
PRIOR SURGICAL AND MEDICAL HISTORY .......................................................29 
13. 
MEDICATIONS AND PROCEDURES .......................................................................30 


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Statistical Analysis Plan 
 
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13.1. 
Prior Anticancer Therapy and Radiotherapy .................................................................30 
13.2. 
Prior and Concomitant Medications ..............................................................................30 
13.3. 
Concurrent Surgery and Radiotherapy ..........................................................................31 
13.4. 
Post-Treatment Anticancer Therapy .............................................................................31 
14. 
STUDY DRUG EXPOSURE AND COMPLIANCE ...................................................31 
14.1. 
Study Drug Exposure ....................................................................................................31 
14.2. 
Study Drug Compliance ................................................................................................32 
15. 
EFFICACY ANALYSES..............................................................................................32 
15.1 
Primary and Secondary Endpoints ................................................................................33 
15.2 
Other Endpoints ............................................................................................................37 
15.3 
Subgroup Analysis ........................................................................................................37 
16. 
PERFORMANCE STATUS ANALYSIS .....................................................................38 
17. 
SAFETY OUTCOMES .................................................................................................38 
17.1. 
Adverse Events .............................................................................................................38 
17.2. 
Laboratory Evaluations .................................................................................................40 
17.3. 
Electrocardiogram Evaluations .....................................................................................41 
17.4. 
Vital Signs .....................................................................................................................42 
17.5. 
ECHO/MUGA ..............................................................................................................43 
18. 
REFERENCES..............................................................................................................43 
APPENDIX 1. 
PARTIAL DATES CONVENTIONS ..................................................................45 
Algorithm for Treatment Emergence of Adverse Events ............................................................................ 45 
Algorithm for Prior and Concomitant Medications .................................................................................... 46 
APPENDIX 2. 
SCHEDULE OF EVENTS .....................................................................................3 
APPENDIX 3. 
PHARMACODYNAMICS AND GENETICS ANALYSES ...............................52 
 
 
LIST OF TABLES 
Table 1: 
Decision Rules for Each Cohort at the End of Stage 1 .................................................16 
Table 2: 
Numbers of Subjects Enrolled in Each Stage ...............................................................17 
Table 3: 
95% exact binomial (CI) for potential point estimates of DCR and/or ORR ...............19 
Table 4: 
Number of subjects enrolled in each cohort .................................................................20 
Table 5: 
Date of Event or Censoring for PFS .............................................................................35 
Table 6: 
ECG Measures and Markedly Abnormal Criteria .........................................................42 
Table 7: 
Vital Signs and Markedly Abnormal Criteria ...............................................................43 
Table 8: 
Algorithm for Treatment Emergence of Adverse Events ..............................................45 
Table 9: 
Algorithm for Prior / Concomitant Medications ...........................................................46 


Epizyme, an Ipsen Company 
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Statistical Analysis Plan 
 
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Table 10: 
Schedule of Events .........................................................................................................3 
Table 11: 
Timing Window Allowances for ECGs and PK Collection ..........................................51 
 
LIST OF FIGURES 
Figure 1: 
Study Schema ...............................................................................................................13 
 
 


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Statistical Analysis Plan 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS 
 
Abbreviation 
Definition 
AEs 
Adverse Events 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
ATRT 
atypical teratoid rhabdoid tumors 
BID 
twice daily 
BOR 
Best Overall Response 
BP 
Blood pressure 
Brookmeyer 
Brookmeyer-Crowley method 
CI 
confidence interval 
CNS 
central nervous system 
CR 
complete response 
CrCl 
creatinine clearance 
CT 
computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCR 
disease control rate 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EMC 
Extraskeletal myxoid chondrosarcoma 
EMPNST 
Epithelioid malignant peripheral nerve sheath tumor 
ES 
epithelioid sarcoma 
EZH2 
enhancer of zeste homolog 2 
F 
absolute bioavailability 
GOF 
gain of function 
H3K27 
histone 3 lysine 27 
HLGT 
high-level group term 
HR 
heart rate 
IDMC 
Independent Data Monitoring Committee 
IHC 
Immunohistochemistry 
INI1 
integrase interactor 1 
ITT 
Intent-to-Treat 
IV 
intravenous 
LLN 
lower limit of normal 
MDS 
myelodysplastic syndrome 




Epizyme, an Ipsen Company 
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Statistical Analysis Plan 
 
V 3.0, 30 NOV 2022 
 
 
1. 
INTRODUCTION 
This statistical analysis plan (SAP) describes the planned analyses to be included in the Clinical 
Study Report for the phase 2 Protocol EZH-202.  This SAP is based on Protocol Amendment (PA) 
11.0, dated 05 October 2022. This SAP must be approved, the database locked, analysis 
populations defined, and protocol deviations identified prior to performing the primary analyses 
described in this document. 
Analyses of the Phase 2 pharmacokinetics (PK), pharmacodynamics (PD), genetics, and 
pharmacological data will be conducted under the auspices of Epizyme and will be governed by 
separate SAPs. 
 
2. 
STUDY OBJECTIVES AND ENDPOINTS 
 
Objective 
Endpoint 
Primary: 
Cohorts 1 (rhabdoid tumors), 3 (other integrase 
interactor 1 [INI1]-negative tumors or any solid tumor 
with enhancer of zeste homolog-2 [EZH2] gain of 
function [GOF] mutation), 4 (renal medullary 
carcinoma [RMC]), 5 (epithelioid sarcoma [ES]), 6 (ES 
with optional tumor biopsy), and 7 (chordoma): 
To assess the objective response rate (ORR) 
following oral administration of tazemetostat 800 mg 
twice daily (BID). 
ORR (confirmed complete response [CR] 
+ partial response [PR]) for tazemetostat in 
subjects with INI1-negative tumors using 
disease-appropriate standardized response 
criteria (primary CNS tumors: Response 
Assessment for Neuro-Oncology [RANO] 
and all others: RECIST 1.1) 
Cohort 2 (relapsed/ refractory [R/R] synovial sarcoma): 
To determine the progression-free survival (PFS) rate 
after 16 weeks of oral administration of tazemetostat 
800 mg BID 
PFS rate after 16 weeks of treatment with 
tazemetostat. This is the number of subjects 
with confirmed CR or PR, or stable disease 
(SD) at the Week 16 assessment. 
Cohort 8 (ES treated with tazemetostat 1600 mg once 
daily [QD]): 
To assess the safety and tolerability of tazemetostat 
1600 mg QD 
AEs and clinical laboratory test 
Secondary: 
To evaluate the duration of response (DOR) in 
subjects with rhabdoid tumors (Cohort 1), R/R 
synovial sarcoma (Cohort 2), other INI1-negative 
tumors or any solid tumor with EZH2 GOF mutation 
(Cohort 3), RMC (Cohort 4),  ES (Cohort 5), ES 
undergoing optional biopsy (Cohort 6), chordoma 
(Cohort 7), and ES receiving 1600 mg tazemetostat 
QD (Cohort 8) and to evaluate the DOR in Cohorts 1, 
3, 4, 5, 6, and 7 combined. 
DOR, defined as the time from the first 
documented evidence of CR or PR to the 
time of first documented disease progression 
or death due to any cause, whichever comes 
first, using disease-appropriate standardized 
response criteria 


Epizyme, Inc. 
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Statistical Analysis Plan 
 
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To assess the disease control rate (DCR) in subjects 
with ES (Cohort 5) and ES undergoing optional 
biopsy (Cohort 6) following oral administration of 
tazemetostat 800 mg BID, and in subjects with ES 
(Cohort 8) following oral administration of 
tazemetostat 1600 mg QD.  
DCR for tazemetostat (defined as the 
number of subjects who achieve confirmed 
response [CR+PR] or who have SD lasting 
at least 32 weeks) 
To assess the ORR in subjects with R/R synovial 
sarcoma (Cohort 2) following oral administration of 
tazemetostat 800 mg BID, and in subjects with ES 
(Cohort 8) following oral administration of 
tazemetostat 1600 mg QD. 
ORR (defined as the number of subjects 
who achieve confirmed response [CR+PR] 
per RECIST 1.1) 
To determine the PFS and overall survival (OS) at 
Weeks 24, 32, and 56 and overall in subjects with 
rhabdoid tumors (Cohort 1), R/R synovial sarcoma 
(Cohort 2), other INI1-negative tumors or any solid 
tumor with EZH2 GOF mutation (Cohort 3), RMC 
(Cohort 4), ES (Cohort 5), ES undergoing optional 
biopsy (Cohort 6), and chordoma (Cohort 7) 
following oral administration of tazemetostat 800 mg 
BID, and in subjects with ES (Cohort 8) following 
oral administration of tazemetostat 1600 mg QD. 
PFS at Weeks 24, 32, 56, and overall for 
each cohort. PFS is defined as the time from 
the date of first dose of study treatment to 
the earlier of the date of first documented 
disease progression or date of death due to 
any cause. 
OS at Weeks 24, 32, 56, and overall for each 
cohort. OS is defined as the time from the 
date of the first dose of study treatment to 
the date of death due to any cause. 
Exploratory: 
To explore the relationship between plasma PK and 
tumor pharmacodynamic (PD) markers as permitted 
by the data. 
Tumor target gene expression and 
phenotypic markers including those for 
differentiation, apoptosis, inflammation and 
cell proliferation, and their correlation with 
activity 
To assess tumor tissue and blood for somatic 
mutations, germline variants, messenger ribonucleic 
acid (mRNA), and/or proteins as candidate markers 
of response to tazemetostat. 
Somatic mutation analysis of tumor tissue 
and blood derived circulating 
deoxyribonucleic acid (DNA) 
Germline DNA analysis for INI1 or 
SMARCA4 variants 


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Statistical Analysis Plan 
 
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Cohort 6 only: To assess the effects of tazemetostat 
on tumor immune priming (e.g., PD-L1 and CD8 IHC) 
Assessment of pre- and post-dose biopsies 
for immune priming (e.g. PD-L1 and CD8 
IHC) 
Cohort 6 only: To investigate the PD effects of 
tazemetostat in tumor tissue, if a post-dose tumor 
sample is available. 
Assessment of pre- and post-dose biopsies 
for H3K27me3 and for changes in gene 
expression. 
 
 
3. 
STUDY DESIGN 
3.1. 
General Description 
This is a Phase II, multicenter, open-label, single-arm, 2-stage study of tazemetostat 800 mg BID 
or 1600 mg QD (Cohort 8) administered orally in continuous 28-day cycles. Screening of subjects 
to determine eligibility for the study will be performed within 21 days of the first planned dose of 
tazemetostat. As shown in Figure 1 below, eligible subjects will be enrolled into one of eight 
cohorts based on tumor type: 
Cohorts using tazemetostat 800 mg BID: 
 Cohort 1: Rhabdoid tumors (MRT, rhabdoid tumors of the kidney [RTK], ATRT, and 
selected tumors with rhabdoid features, including SCCOHT, also known as MRTO) (closed 
to enrollment) 
 Cohort 2: Relapsed or refractory synovial sarcoma with SS18-SSX rearrangement (closed 
to enrollment) 
 Cohort 3: Other INI1-negative tumors or any solid tumor with EZH2 GOF mutation 
(closed to enrollment), including: 
 EMPNST 
 EMC 
 Myoepithelial carcinoma 
 Other INI1-negative malignant tumors with Sponsor approval 
 
sarcoma and melanoma 
 Cohort 4: RMC (closed to enrollment) 
 Cohort 5: ES (closed to enrollment) 
 Cohort 6: ES undergoing optional tumor biopsy (closed to enrollment) 
 Cohort 7: Poorly differentiated chordoma (or other chordoma with Sponsor approval) 
(closed to enrollment) 
Cohort using tazemetostat 1600 mg QD: 
 
Cohort 8: ES (closed to enrollment). 


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Statistical Analysis Plan 
 
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Figure 1: 
Study Schema 
 
 
 
Note: PA 9 allowed for the enrollment of an additional 25 subjects in Cohort 6. In addition, the mandatory 
tumor biopsy was made optional. 
 
Response assessment was to be evaluated after 8 weeks of treatment and then every 8 weeks 
thereafter while on study. 
 
Note: Changes to Cohorts: 
Cohort 3 was initially intended to enroll various INI1-negative tumors, including RMC and ES. 
Initial screening and enrollment trends indicated that Cohort 3 would be heavily weighted toward 
RMC and ES tumor types, therefore, losing the potential to evaluate other INI1-negative tumors. 
Thus, Cohort 4 (RMC) and Cohort 5 (ES) were added as part of Amendment 3. Subjects with RMC 
and ES who were enrolled in Cohort 3 prior to Amendment 3 were moved to the appropriate cohort 
based on the specific disease type documented prior to start of treatment.  
Amendment 4 allowed the inclusion of subjects with solid tumors and EZH2 GOF mutations into 
Cohort 3, based upon observed clinical activity in the Phase 1 Study E7438-G000-101 in subjects 
with EZH2-mutant non-Hodgkin lymphoma (NHL).  
Amendment 5 added 2 additional cohorts: Cohort 6 (ES undergoing mandatory biopsy) and Cohort 
7 (chordoma). Cohort 6 was added to further explore the immune-priming effects of tazemetostat 
(see Section 5.4.5 of protocol amendment [PA] 11.0). Cohort 7 was added to allow the inclusion of 
subjects with chordoma, a very rare sarcoma with a large percentage of the poorly differentiated 
variants having loss of INI1, based on observed clinical activity in the Phase 1 pediatric dose-
escalation Study EZH-


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Subjects with Relapsed or Refractory INI1-
chordoma who were enrolled in Cohort 3 prior to Amendment 5 were moved to Cohort 7. 
Amendment 7 added Cohort 8, which uses a new dosing schedule of tazemetostat 1600 mg QD in 
ES subjects. It was hypothesized that 1600 mg QD may achieve a higher AUC at steady-state of 
approximately 7000 ng*h/mL (see dose justification in Section 5.4.6 of protocol v 11).  
Interim Analyses 
For each cohort (except Cohorts 6 and 8), a two-stage, Green-Dahlberg design was utilized with a 
stopping rule to allow for early termination at the end of Stage 1 if there was strong evidence of 
lack of efficacy. If early stopping criteria were met for a cohort, enrollment was to be stopped. To 
avoid disruptions in the study, enrollment and treatment of subjects was not to be halted in order to 
conduct the interim analysis at Stage 1.  
For Cohorts 1, 3, 4, 5, and 7, the Stage 1 interim analysis was planned to be performed after the 
first 15 subjects enrolled had completed at least the Week 24 assessment, completed the final study 
visit, or terminated early from the study, whichever was sooner. As it was desirable to perform the 
interim analysis in a timely manner, both confirmed and unconfirmed responses were included. 
Cohort 4 (RMC) and Cohort 7 (chordoma) were terminated based on the Stage 1 interim analysis. 
Cohort 1 (rhabdoid tumors), Cohort 3 (INI1-negative/EZH2 GOF mutation), and Cohort 5 (ES) 
continued into Stage 2, to enroll an additional 15 subjects each. Additionally, Cohort 5 went on to 
enroll an additional 30 subjects with ES into the Cohort 5 Expansion starting in 2016. In May 2017, 
Epizyme met with the FDA regarding future development plans for tazemetostat. Based on a 
specific request from the FDA, with Amendment 5, the primary endpoint for Cohort 5 has been 
changed back to ORR, and duration of response in responding subjects has been elevated to the 
most important secondary endpoint. 
Given sufficient evidence of antitumor activity and no concerning safety signal observed during the 
2-stage design for Cohort 5, Cohort 6 and Cohort 8 were added outside the 2-stage design 
framework. Cohort 6 (ES undergoing mandatory tumor biopsy) was added to further explore the 
immune-priming effects of tazemetostat. Cohort 8 (ES) was added to evaluate safety and PK 
following oral administration of 1600 mg tazemetostat once daily.  
In January 2020, tazemetostat was approved for the treatment of adults and pediatric patients aged 
16 years and older with metastatic or locally advanced ES not eligible for complete resection. 
Under the conditions of the approval, Epizyme agreed with the FDA to enroll an additional 25 
subjects in Cohort 6 to further evaluate the ORR in subjects with metastatic or locally advanced 
ES. The primary endpoint of Cohort 6 was changed to ORR. The effects of tazemetostat on tumor 
immune priming were made an exploratory endpoint and tumor biopsies were made optional for 
this cohort. 
For Cohort 2 (relapsed or refractory synovial sarcoma), the Stage 1 interim analysis was performed 
after the first 15 subjects enrolled had completed at least the Week 16 assessment, completed the 
final study visit, or terminated early from the study, whichever was sooner. Cohort 2 continued into 
Stage 2, to enroll an additional 15 subjects. 
Treatment 
Subjects will receive tazemetostat in continuous 28-day cycles. Subjects may discontinue study 
treatment at any time due to disease progression, development of an unacceptable toxicity, 
withdrawal of consent, or termination of the study.  


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Subjects will have an EOT visit up to 30 days after last dose of treatment in this study or prior to 
the start of a new anticancer therapy, whichever occurs first. All subjects will be followed for 
survival. Response is defined as having documented evidence of complete response (CR) or partial 
response (PR). Response assessment will be evaluated after 8 weeks of treatment and then every 8 
weeks thereafter while on treatment and in survival follow-up. 
Rollover Study  
All subjects who received tazemetostat in this study (EZH-202) and are eligible to continue 
receiving tazemetostat or to continue survival follow-up, can transfer to a Rollover Study (EZH-
501) for continued study drug and/or continued monitoring at the Investigator and Medical 
 
 
3.2. 
Estimated Study Duration 
3.2.1. 
Study Duration for Participants 
The study duration is approximately 24 months for each subject. The duration of screening for 
each subject will be approximately 21 days. The subject accrual period is planned for 
approximately 15 months. The duration of treatment will vary for each subject. Subjects will 
receive tazemetostat in continuous 28-day cycles. Subjects may discontinue study treatment at any 
time due to disease progression, development of an unacceptable toxicity, withdrawal of consent, 
termination of the study, or completion of treatment per protocol. 
Subjects will have an EOT visit up to 30 days after last dose of treatment in this study or prior to 
the start of a new anticancer therapy, whichever occurs first.  
3.2.2. 
End of Study  
Primary Completion: This includes time until the last subject is assessed or receives an 
intervention for the purposes of final collection of data for the primary analysis of the study. The 
primary completion is expected to occur approximately 6 months after the date the last subject is 
enrolled to treatment and evaluated for response. Response is defined as having documented 
evidence of CR or PR. 
End of Study: This includes time when the last subject is assessed or receives an intervention for 
evaluation in the study. The end of study will occur when the last subject discontinues the study 
treatment and has had the opportunity to complete the end of treatment visit or the long-term 
survival follow-up period, whichever is later.  
See Appendix 2 for the schedule of events. 
 
3.3. 
Changes to Analyses from Protocol 
Section 17.5.3 of PA 11.0 indicates that laboratory analytes will be summarized descriptively as 
value and change from baseline, as well as, shifts from baseline (based on low, normal, high 
categorization) at each visit.  To allow for more focused presentation of values most likely to 
represent a safety concern, laboratory analytes will be summarized as shift from the baseline to 
the worst post-baseline category (based on National Cancer Institute [NCI] Common Terminology 
Criteria for Adverse Events [CTCAE] severity grades).  When an NCI CTCAE category is 
undefined for an analyte, a multiple of the nearer normal limit will be used. 
Though not identified within the protocol, DCR at different time points (e.g. 24 weeks) may be 




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 If there is at most one CR+ PR+ SD at the Week 16 assessment, the tazemetostat 
treatment will be rejected and enrollment in Cohort 2 will be terminated for futility. 
 If there are two or more CR+ PR+ SD at the Week 16 assessment, Cohort 2 enrollment 
will continue to its maximum sample size. 
Within each cohort, the interim analysis planned at the end of Stage 1 may occur sooner if the 
Stage 1 rejection criterion is surpassed before all 15 subjects are treated and followed for the 
specified time. In this scenario, the total sample size (Stage 1 + Stage 2) for a cohort would still 
remain unchanged at 30 subjects. 
If enrollment in any cohort is terminated for futility, the final reporting for that cohort will be 
based on all subject data in the database. 
 
4.2. 
Primary Analysis 
The primary analysis for each cohort of the study may occur separately when each cohort has at 
least met its primary objective (further described in Section 15.1). Details regarding the timing of 
the PK, and cellular pharmacologic analyses will be described in detail under separate SAPs. 
Details regarding the timing of pharmacodynamics (PD) and genetics analyses will be in Appendix 
3 (which will be inserted into this SAP post finalization). 
 
4.3. 
Final Analysis of Progression-Free Survival (PFS) and Overall 
Survival (OS) 
Depending on the maturity of PFS and OS data at the time of the primary analysis, analyses of 
PFS and OS may be repeated when data are mature, i.e. not having high percentage of censoring 
(e.g. >50%) or having stable duration of response with estimable medians. 
 
4.4. 
Determination of Sample Size 
Each cohort (exception: Cohorts 6 and 8) will be evaluated separately using a Green-Dahlberg 
two-stage design, to allow early termination of the cohort due to the lack of efficacy. The sample 
size of each cohort is calculated on the primary endpoint. Within each cohort, the hypothesis will 
be tested using a one-
numbers of subjects to be enrolled in each stage of the Green-Dahlberg two-stage design for each 
cohort are listed in the Table 2 below. 
Typically, one tests the null hypothesis H0: p = p0 against the alternative HA: p = pA, where p is 
the probability of response, p0 is the response rate below which one considers the drug 
insufficiently active and pA is the assumed response rate of the new drug. In a well-known two- 
stage design, Simon proposed method of choosing n1, n, r1 and boundary at final analysis (r) via 
binomial distribution when p0, pA, type I and II errors (a and b) are specified. A number of 
extensions to Simon Two-Stage Design have been proposed. Green and Dahlberg (1992) proposed 
several approaches to adapting interim stopping rules when the actual sample size is not the 
planned size. The authors summarize the operating characteristic of the design comparing with 
others including 
 two stage design. 
 
Table 2: 
Numbers of Subjects Enrolled in Each Stage 
  
Each Cohort Separately: 
Cohort 1a (Rhabdoid tumors) 
Cohort 3a (Other INI1-negative 
Cohort 2a 
(R/R synovial 
sarcoma) 
Initial Design: 
Cohort 5a (ES) 
Amended 
Design: 
Cohort 5b (ES) 




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1 + Stage 2 + expansion) will remain unchanged at 60 subjects. The additional 30 subjects will 
allow for increased precision for the point estimates of DCR and ORR. The table below shows the 
95% exact binomial confidence interval (CI) for potential point estimates of DCR and/or ORR. 
The Cohort 5 expansion stage was opened in Dec. 2016 after the Stage 2 DCR criterion was 
surpassed. In May 2017, Epizyme met with the FDA regarding future development plans for 
tazemetostat. Based on a specific request from the FDA, with Amendment 5, the primary endpoint 
for Cohort 5 has been changed to ORR and duration of response in responding subjects has been 
elevated to the most important secondary endpoint. 
Table 3: 
95% exact binomial (CI) for potential point estimates of DCR and/or ORR 
Potential DCR or ORR 
20% 
30% 
40% 
Subjects meeting endpoint 
12 of 60 
18 of 60 
24 of 60 
95% exact binomial CI 
10.8%-32.3% 
18.8%-43.2% 
27.6%-53.5% 
 
For Cohort 6: 
Cohort 6 (ES undergoing optional tumor biopsy) was added outside of a 2-stage design framework 
based on clinical data demonstrating encouraging evidence of antitumor activity, and no 
concerning safety signals in ES subjects in Cohort 5. Preliminary evidence of the immune priming 
effect of tazemetostat evaluated by IHC provided the rational for collecting mandatory paired 
tumor biopsies in this cohort. Twenty (20) paired tumor biopsies will afford sufficient data to 
quantify the immune priming effects of tazemetostat. Due to the expectation that some subjects 
will withdraw consent after the post-screening biopsy and other subjects may not be able to 
provide for a post-treatment biopsy, Cohort 6 will enroll up to 40 subjects to ensure that 20 paired 
tumor biopsies are collected and adequate for analysis. 
In January 2020, tazemetostat was approved for the treatment of adults and pediatric subjects aged 
16 years and older with metastatic or locally advanced ES not eligible for complete resection. 
Under the conditions of the approval, Epizyme agreed with the FDA to enroll an additional 25 
subjects in cohort 6 to further evaluate the ORR in subjects with metastatic or locally advanced 
ES. The primary endpoint of cohort 6 has been changed to ORR and the effects of tazemetostat on 
tumor immune priming has been changed to an exploratory endpoint. Additionally, the 
requirement for pre- and post- dose tumor biopsies for Cohort 6 has been made optional. 
With a sample size of at least 40 subjects, the study has a power of more than 80% to test the 
hypothesis that the objective response rate would be 20% or higher against the null hypothesis that 
it would be 5% or lower at one-sided significance level of 0.025. 
For Cohort 8:  
As with Cohort 6, Cohort 8 was added outside of a 2-stage design framework based on clinical 
data in ES subjects in Cohort 5 (see rationale above for Cohort 6). Cohort 8 was added to evaluate 
safety, PK, and efficacy profile of once daily tazemetostat dosing; 16 subjects will be enrolled for 
evaluation of PK, efficacy, and safety. 
Total Sample Size: 
The total number of subjects to be enrolled for the entire study is approximately 291 (180 subjects 
in the 2-stage design with each cohort 30 subjects from Cohorts 1-5 and 7, respectively, 30 subjects 
from the Cohort 5 expansion, 65 subjects from Cohort 6, and 16 subjects from Cohort 8). The 
number of subjects to be enrolled in each stage are provided in the table below. 


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Table 4: 
Number of subjects enrolled in each cohort 
 
Each Cohort Separately: 
Cohort 1 (Rhabdoid tumors) 
Cohort 2 (R/R synovial sarcoma) 
Cohort 3 (INI1-negative/EZH2 GOF 
mutation) 
Cohort 4 (Renal medullary carcinoma) 
Cohort 7 (Chordoma) 
Cohort 5 
(ES; 
tazemetostat 
800 mg BID) 
Cohort 6 
(ES 
undergoing 
optional 
biopsy) 
Cohort 8 
(ES; 
tazemetostat 
1600 mg QD) 
Stage 1 
15 
15 
NA 
NA 
Stage 2 
15 (Note: Cohorts 4 and 7 were closed prior to Stage 2) 
15 
NA 
NA 
Expansion 
NA 
30 
NA 
NA 
Total 
30 
60 
65 
16 (Note: Cohort 
8 was closed prior 
to reaching this 
enrollment goal) 
Abbreviations: BID = twice daily; ES = epithelial sarcoma; GOF = gain of function; NA = not applicable; QD = once 
daily; R/R = relapsed/ refractory; RMC = renal medullary carcinoma 
 
4.5. 
Sample Size Re-estimation 
The sample size will not be re-estimated during this study. 
5. 
ANALYSIS POPULATIONS 
The agreement and approval of subjects to be included/excluded from each analysis population 
will be established prior to database lock. The analysis population definitions are as follows: 
 The Enrolled population will consist of all subjects who sign informed consent and were 
entered into the electronic case report form for the study.  The Enrolled population will be 
used for summaries of subject disposition and protocol deviations. 
 The Intent-to-Treat (ITT) population will consist of all subjects who receive at least one 
dose of tazemetostat. The ITT population will be used for summaries and analysis of the 
efficacy endpoints (excluding PK and PD). 
 The Safety population will consist of all subjects in the ITT population who have at least 
one post-dose safety observation recorded (safety observations are those identified in 
Section 17).  The Safety population will be used for summaries and analysis of the safety 
and tolerability. 
 The PK population will include all subjects in the ITT population who have sufficient 
post-dose samples collected to allow estimation of the PK parameters. The PK population 
will be used for population-based analysis. 
 The PD population will include all subjects in the ITT population who have sufficient 
samples collected to allow estimation of the PD parameters. The PD population will be 
used for summaries and graphs of PD data. 
6. 
GENERAL CONSIDERATIONS 
6.1. 
Grouping of Subjects and Table Presentation 
Subjects will be grouped and summarized by each cohort and overall in table presentations. 


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Epithelioid sarcoma (ES) subjects will be further summarized and presented by Cohorts 5 and 6 
combined. 
 
6.2. 
Time Point Conventions 
6.2.1. 
Study Day Conventions 
Start Day of study treatment will use the date of first dose of tazemetostat. 
Depending on the context, listings may present assessments in terms of 
 
 where 
the first day of treatment is identified as 
 
 and the day prior to the first day of treatment is 
identified as 
 -
(with no intervening 0). Study Day will be calculated as follows: 
 Study Day = (assessment date/event date  first dose date) + 1 if assessment date or event date 
first dose date of study drug. 
 Study Day = (assessment date/event date  first dose date of study drug) if assessment date or 
event date < first dose date of study drug. 
Study Day will appear as missing in the listings if the event date is partial. 
6.2.2. 
Baseline Assessments 
Baseline will be defined as the last non-missing (including unscheduled) assessment prior to 
starting study drug. Unless the collection time or label indicates otherwise, assessments performed 
on the same day as the first dose of tazemetostat will be considered as performed prior to 
treatment.  AEs and medications with a start date on the date of first dose of tazemetostat will be 
considered to have occurred after the start of treatment. Baseline will be determined separately for 
each laboratory analyte. 
 
6.2.3. 
Visit Assessments 
For by-visit summaries, nominal visits will be presented (i.e. visit windowing will not be applied). 
Unscheduled measurements will not be included in by-visit table summaries but will contribute to 
worst-case values table summaries.  Listings will include both scheduled and unscheduled data. 
 
7. 
STATISTICAL CONSIDERATIONS 
7.1. 
Common Conventions 
Unless noted otherwise, the statistical considerations below will be applied. 
 1 pound = 0.454 kg. 
 1 inch = 2.54 cm. 
 1 year = 365.25 days.  Year is calculated as (days / 365.25) and will be rounded up to 
1 significant digit for purposes of presentation. 
 1 month = 30.4375 days.  Month is calculated as (Days / 30.4375) and will be rounded up to 
1 significant digit for purposes of presentation. 
 Body mass index (BMI) calculated as [weight (kg)/height (m)2]. 
 Dates, time, and date/time fields will be displayed in data listings in ISO 8601 formats. 


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 Data from all centers within each cohort will be pooled for analyses. 
 The issue of statistical multiplicity will not apply to this study; therefore, all analyses will be 
conducted at the nominal 1-sided alpha 0.05 significance level. 
 Confidence interval (CI) will be presented as 2-sided 95% CI. 
 Safety data will not be imputed except for incomplete dates associated with AEs and 
medications (rules in Appendix 1) and missing severity or relationship (rules in Section 
17.1). 
 Missing response data will be handled as described in Section 15.1. 
 Summary statistics will include the number and percentage of subjects in each category for 
discrete variables and the sample size, mean, median, standard deviation (SD), minimum, 
and maximum for continuous variables. 
 When the denominator includes subjects with missing values, a 
category may be 
added for completeness and displayed last in the category summary. 
 Time-to-event statistics will include the minimum, 25th percentile, median, 75th percentile, 
and maximum, provided they are estimable. 
 In summary tables of continuous variables (except for weight, height and BMI), the 
minimum and maximum values will be displayed to the same number of decimal places as 
the raw data; all mean, median, and percentile values will be formatted to one more decimal 
place than the measured value.  SD values will be formatted to two more decimal places than 
the measured value, unless otherwise specified. The maximum number of decimal places is 3 
and values will be truncated to 3 decimal places in situations where there are more than 3 
decimal places. Wherever possible data will be decimal aligned. For weight, height and 
BMI, only one decimal place will be kept for summary results (except N). 
 The number and percentage of responses will be presented in the form XX (XX.X%) with 
percentage rounded to one decimal place. 
 Change from baseline = value (post-baseline visit)  value (baseline). 
 Percent change from baseline = 100 × [value (post-baseline visit)  value (baseline)]/ value 
(baseline). 
 Post Baseline Duration in days = end date  start date + 1 (divide by 7 to convert to weeks, 
divide by 30.4375 to convert to months, and divide by 365.25 to convert to years; Round 
result to 1 decimal place) 
 Listings typically will be sorted by cohort, subject identification number (concatenated site 
and subject number), date, and time, if collected. 
 P-values, if applicable, will be presented to 3 decimal places. If the rounded result is a value 
of 1.000, it will be displayed as > 0.999.  
 All analyses will be conducted using SAS version 9.4 or higher. Any date in the listings will 
use the date9. format, for example, 07MAY2002. 
7.2. 
Missing Data 


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Unless noted otherwise, missing data will not be imputed. All analyses will be based on observed 
data only. The effective sample size at each assessment visit will be based on the total number of 
subjects with non-missing data for the parameter of interest at that visit. 
Missing or partially missing start or end dates for adverse events (AEs) and medications will be 
imputed based on the conventions described in Appendix 1. The purpose of the imputation for AEs 
is to determine if an AE with an incomplete date is treatment-emergent, as defined in Section 17.1. 
Similarly, the purpose of the imputation for medications is to determine if a medication with an 
incomplete date was given concomitantly with study drug, as defined in Section 13.2. 
Missing or partially missing dates for initial disease diagnosis will be imputed. If the month and 
year of the diagnosis are provided but the day is missing, the missing day is imputed as 15. If only 
the year is provided, then the missing month and day are imputed as July 1st for the calculation.  
8. 
ANALYSIS POPULATIONS AND ENROLLMENT 
The number of subjects in each analysis population (Enrolled, ITT, and Safety populations) will 
be summarized on the Enrolled population. Similarly, the number of subjects enrolled will be also 
summarized by country and site. Subjects in the Enrolled population but not in the ITT 
population will be counted in a 
 
 column for table summaries on the Enrolled 
population. 
A subject listing indicating analysis population and country of enrollment will be presented for the 
Enrolled population. 
9. 
DISPOSITION 
Subject disposition, including reasons for study withdrawal, will be summarized and listed based 
on the Enrolled population. 
Cause of death during and until 30 days after the last dose of study drug will be summarized on 
the Safety population. The number of subjects who died due to Treatment Related Adverse Event 
during and until 30 days after the last dose of study drug will be summarized on the Enrolled 
population. The number of subjects who died due to Treatment Related Adverse Event after 30 
days after the last dose of study drug will be summarized on the Enrolled population. 
10. 
PROTOCOL DEVIATIONS 
Protocol deviation reports will be reviewed, and the severity of each protocol deviation will be 
assigned by the study team. A complete list of important protocol deviations in the following 
categories can be found in the CRO 
 Protocol Deviation Guidance Document.  
 Inclusion and exclusion criteria 
 Study drug 
 Assessment  safety 
 Lab/Endpoint data 
 Visit window 
 Informed consent 
 Prohibited Co-Medication 
 Overdose and/or Misuse 
 Other 
Below is a list (not exhaustive) of Inclusion and exclusion criteria for protocol deviations in 
general and refer to Section 4 of Protocol v 11 in detail. 


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Inclusion Criteria 
A subject must meet ALL of the following criteria to be eligible for enrollment in this study: 
1. Age (at the time of consent/assent): >18 years of age 
2. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 
(Appendix 1 of protocol) 
NOTE: If subject is unable to walk due to paralysis, but is mobile in a wheelchair, subject is 
considered to be ambulatory for the purpose of assessing their performance status. 
3. Has provided signed written informed consent 
4. Has a life expectancy of >3 months 
5. Has a malignancy: 
 For which there are no standard therapies available (Cohorts 1, 3, 4, & 5) 
 That is relapsed or refractory, defined as metastatic or non-resectable, locally advanced 
disease that has previously been treated with and progressed following approved 
therapy(ies), if therapy(ies) exists (Cohort 2)  
 That has progressed within 6 months prior to study enrollment (Cohort 5 Expansion, 
Cohort 6, and Cohort 8 only) 
6. Has a documented local diagnostic pathology of original biopsy confirmed by a Clinical 
Laboratory Improvement Amendments (CLIA)/College of American Pathologists (CAP) or 
other Sponsor-approved laboratory certification 
7. For Cohort 1 (rhabdoid tumors) only: The following test results must be available by local 
laboratory: 
 Morphology and immunophenotypic panel consistent with rhabdoid tumors, and 
 Loss of INI1 or SMARCA4 confirmed by IHC, or 
 Molecular confirmation of tumor bi-allelic INI1 or SMARCA4 loss or mutation when 
INI1 or SMARCA4 IHC is equivocal or unavailable 
8. For Cohort 2 (relapsed/refractory synovial sarcoma) only: The following test results must 
be available by local laboratory: 
 Morphology consistent with synovial sarcoma, and 
 Cytogenetics or Fluorescence in situ hybridization (FISH) and/or molecular confirmation 
(e.g., DNA sequencing) of SS18 rearrangement t(X;18)(p11;q11) 
9. For Cohorts 3, 4, 5, 7, and 8 (INI1-negative tumors or any solid tumor with EZH2 GOF 
mutation) only: The following test results must be available by local laboratory: 
 Morphology and immunophenotypic panel consistent with INI1-negative tumors (not 
applicable for solid tumors with EZH2 GOF mutation), and 
 Loss of INI1 confirmed by IHC, or 
 Molecular confirmation of tumor bi-allelic INI1 loss or mutation when INI1 IHC is 
equivocal or unavailable, or 
 Molecular evidence of EZH2 GOF mutation 






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Have a negative beta-
-hCG) pregnancy test at time of 
screening and within 14 days prior to planned first dose of tazemetostat (urine or serum 
test is acceptable however, positive urine tests must be confirmed with serum testing), 
and 
 
Agree to use effective contraception, as defined in Section 12.6.1 of PA 11.0, from a 
minimum of 7 days prior to first dose until 6 months following the last dose of 
tazemetostat and have a male partner who uses a condom, or 
 
Practice true abstinence, (when this is in line with the preferred and usual lifestyle of the 
subject, see Section 12.6.2 of PA 11.0) or 
 
Have a male partner who is vasectomized  
20. Male subjects with a female partner of childbearing potential must:  
 
Be vasectomized, or 
 
Agree to use condoms as defined in Section 12.6.2 of PA 11.0, from first dose of 
tazemetostat until 3 months following the last dose of tazemetostat, or 
 
Have a female partner who is NOT of childbearing potential 
 
Exclusion Criteria 
Subjects meeting ANY of the following criteria must NOT be enrolled in this study: 
1. Has had prior exposure to tazemetostat or other inhibitor(s) of enhancer of zeste homologue-2 
(EZH2) 
2. Has participated in another interventional clinical study and received investigational drug 
within 30 days or 5 half-lives, whichever is longer, prior to the planned first dose of 
tazemetostat 
3. Has known active CNS or any leptomeningeal metastasis of primary extracranial tumor. 
Subjects with previously treated brain metastases may participate provided they are stable 
(without evidence of progression by imaging 4 weeks prior to the first dose of study drug and 
any neurologic symptoms have stabilized), have no evidence of new or enlarging brain 
metastases, and are on stable or tapering doses of steroids for at least 7 days prior to first dose 
of study drug.  
NOTE: Subjects with asymptomatic brain metastases found on screening MRI may be entered 
into the study without prior radiation therapy to the brain if they do not require immediate 
surgical or radiation therapy in the opinion of the treating Investigator and in the opinion of a 
radiation therapy or neurosurgical consultant. 
4. Has had a prior malignancy other than the malignancies under study  
Exception: Subject who has been disease-free for 5 years, or a subject with a history of a 
completely resected non-melanoma skin cancer or successfully treated in situ carcinoma is 
eligible. 
5. Has had major surgery within 3 weeks prior to enrollment 
NOTE: Minor surgery (e.g., minor biopsy of extracranial site, central venous catheter 
placement, shunt revision) is permitted within 3 weeks prior to enrollment. 


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6. 
any prior history of myeloid malignancies, including myelodysplastic syndrome (MDS). Has 
abnormalities known to be associated with MDS (e.g. del 5q, chr 7 abn) and MPN (e.g. JAK2 
V617F) observed in cytogenetic testing and DNA sequencing.  
NOTE: Bone marrow aspirate/biopsy will be conducted following abnormal peripheral blood 
smear morphology assessment conducted by central laboratory. Cytogenetic testing and DNA 
sequencing will be conducted following an abnormal result of bone marrow aspirate/biopsy. 
7. Has a prior history of T-LBL/T-ALL. 
8. Is unwilling to exclude grapefruit juice, Seville oranges and grapefruit from the diet and all 
foods that contain those fruits from time of enrollment to while on study. 
9. Has cardiovascular impairment, history of congestive heart failure greater than NYHA Class 
II, uncontrolled arterial hypertension, unstable angina, myocardial infarction, or stroke within 
6 months prior to the planned first dose of tazemetostat; or ventricular cardiac arrhythmia 
requiring medical treatment 
10. Is currently taking any prohibited medication(s) as described in Section 11.3 of PA 11.0. 
11. Has an active infection requiring systemic treatment 
12. Is immunocompromised (i.e., has a congenital immunodeficiency), including subjects known 
history of infection with human immunodeficiency virus (HIV) 
13. Has known active infection with hepatitis B virus or hepatitis C virus  
NOTE: Subjects with a history of hepatitis B or C with normal ALT and undetectable HBV 
DNA or HCV RNA are eligible for this study 
14. Has had a symptomatic venous thrombosis within 2 weeks prior to study enrollment 
NOTE: Subjects with a history of a deep vein thrombosis >2 weeks prior to study enrollment 
who are on anticoagulation therapy with low molecular weight heparin are eligible for this 
study. 
15. For subjects with CNS involvement (primary tumor or metastatic disease): Have any 
active bleeding, or new intra-tumoral hemorrhage of more than punctate size on screening MRI 
obtained within 14 days of starting study drug or known bleeding diathesis or treatment with 
anti-platelet or anti-thrombotic agents. 
16. Has known hypersensitivity to any of the components of tazemetostat or other inhibitor(s) of 
EZH2 
17. Is unable to take oral medications, or has malabsorption syndrome or any other uncontrolled 
gastrointestinal condition (e.g., nausea, diarrhea or vomiting) that might impair the 
bioavailability of tazemetostat 
18. Has an uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, or 
psychiatric illness/social situations that would limit compliance with study requirements. 
19. For female subjects of childbearing potential: Is pregnant or nursing 
20. For male subjects: Is unwilling to adhere to contraception criteria from time of enrollment in 
study to at least 3 months after last dose of tazemetostat. 
Incidence of important protocol deviations will be summarized by deviation categories. A listing 
will be provided with protocol deviation details. None of the deviations will lead to subjects being 


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excluded from any analysis populations described in Section 5. If a deviation is serious enough to 
have a potential impact on the primary analysis, sensitivity analyses may be performed. 
Major protocol deviations will be listed for the Enrolled population.  Predefined categories of 
major protocol deviations will include: 
 Major violation of inclusion/exclusion criteria such as no baseline measurable disease per 
RECIST 1.1. 
 Prohibited medications, as defined in Section 7.3 of PA 11.0, while on tazemetostat 
(inclusive of the first and last days of treatment) 
Additional categories may be added during the course of the study but will be determined prior to 
the primary analysis. Sensitive analysis may be planned according to the final protocol deviation 
list, especially the major ones. 
 
11. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic data and other baseline characteristics will be summarized and listed for the ITT 
population.  Demographics will include age (in years), sex, race, ethnicity, hepatic impairment 
status, renal impairment status, and baseline Eastern Cooperative Oncology Group (ECOG) 
performance status. 
Baseline disease characteristics will include tumor type (Advanced solid tumor, ES), location of 
primary tumor at diagnosis, disease subtype (ES only; proximal vs. classic), and tumor stage (0, I, 
II, III, IV, or unknown). All cases of ES will be centrally reviewed for disease confirmation. 
Progressive disease (PD) prior to study entry (yes/no) and time (in months) from date of last 
disease progression until the start of study treatment, inclusive, will be summarized as a 
continuous measure.  Partial dates will be interpreted as July 1 when only a year is recorded and 
as the 15th of the month when only a month and year are recorded.  If this interpretation yields a 
date of last progression after the informed consent date, then the partial date of last progression 
will be interpreted as January 1 when only a year is provided and the 1st of the month when only a 
month and year are provided.  Other combinations of missing date elements will be handled as 
missing values. 
Baseline tumor burden will include descriptive statistics on the criteria used for response 
evaluation (RECIST or RANO), the sum of target lesion diameters (RECIST), the sum of target 
lesion cross products (RANO), as well as, presence of target lesions (RECIST or RANO; yes/no), 
presence of lymph node target lesions (RECIST; yes/no), presence of non-target lesions (RECIST 
or RANO; yes/no), and presence of non-target lesions evaluable by T2/FLAIR (RANO; yes/no). 
 
12. 
PRIOR SURGICAL AND MEDICAL HISTORY 
Significant prior surgical and medical history will be summarized and listed for the ITT 
population. 
Terms will be coded using Medical Dictionary for Regulatory Activities (MedDRA) version 23.1. 
The number and percentage of subjects with any significant surgical and medical history will be 
summarized.  Medical history will be summarized by MedDRA system organ class (SOC) and 
preferred term (PT). Surgical history will be summarized by the MedDRA high-level group term 
(HLGT) and PT.  Prior surgeries will be defined as surgeries performed on or prior to the date of 
first dose of study drug. Partial dates that cannot conclusively be identified as occurring after the 


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start of treatment will be assumed to have occurred prior to start of treatment. Listings will 
include start date and stop date or notation of ongoing for conditions continuing into treatment. 
 
13. 
MEDICATIONS AND PROCEDURES 
Medications will be coded using World Health Organization (WHO) Drug Dictionary (version 
September 2020). For incidence summaries of medications by coded WHO Anatomical 
Therapeutic Chemical (ATC) category, a subject will be counted once per specific ATC category 
(likewise for preferred drug name). 
 
13.1. 
Prior Anticancer Therapy and Radiotherapy 
Prior anticancer therapy and radiotherapy will be summarized and listed for the ITT population. 
The summary for prior anticancer therapies will include: 
 Number of regimens (0, 1, 2, 3, 4, or more than 4 prior regimens) 
 Number of regimens in the advanced/metastatic setting (0, 1, 2, 3, 4, or more than 4 prior 
regimens) 
 Number of prior anticancer therapies with progression 
 Therapy setting (Neoadjuvant, Adjuvant, Therapeutic for Advanced/Metastatic Disease, 
Consolidation, Maintenance, or Unknown); A subject may be counted in multiple 
categories 
 Incidence of prior anticancer therapies by WHO Drug ATC level 4 and preferred drug name 
The summary for the prior radiotherapy will include: 
 Number of prior lines (0, 1, or 2 or more lines) 
 Sites of prior radiotherapy (subdivisions of those sites will be listed); A subject may be 
counted in multiple categories 
Prior radiotherapy will be defined as radiotherapy performed on or prior to the date of first dose 
of study drug. Partial dates that cannot conclusively be identified as occurring after the start of 
treatment will be assumed to have occurred prior to start of treatment. 
 
13.2. 
Prior and Concomitant Medications 
Medications will be summarized and listed for the Safety population. Summary tables will include 
incidence (number and percentage) of subjects receiving any medication and incidence of specific 
medications by WHO Drug ATC level 4 and preferred drug name. 
Prior and concomitant medications will be summarized separately. Categorization will be defined 
as follows: 
 Prior medications will include medications which stopped prior to the first dose of study 
drug. 
 Concomitant medications are defined as medications that were started at any time after the 
start of first dose of any study drug through 30 days after the last dose of study drug 
administration or until the start of a subsequent anticancer therapy, whichever is earlier. 
 Medications that started prior to the first dose of study drug but continued into study 


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treatment period until the end of study treatment or the start of a subsequent anticancer 
therapy, whichever is earlier, are considered as both prior and concomitant. 
 Post-treatment anticancer therapies will include anticancer therapies which started after 
discontinuation of study drug. 
 
Medications with missing or partially missing start or end dates will be handled according to the 
conventions described in Appendix 1. If it cannot be determined whether a medication was a prior 
medication due to partial medication start date or end date, the medication will be considered 
concomitant. If medication  start date and end date are missing, the medication will be considered 
concomitant. 
 
13.3. 
Concurrent Surgery and Radiotherapy 
Concurrent anticancer surgery and radiotherapy will be summarized for coded terms in the same 
manner as prior surgeries and prior radiotherapy. Concurrent anticancer surgery and radiotherapy 
are those procedures that conclusively can be identified as occurring after the date of first dose of 
study drug up to, and including, the date of last dose of study drug. 
 
13.4. 
Post-Treatment Anticancer Therapy 
Post-treatment anticancer therapies will include anticancer therapies which started after 
discontinuation of study drug. The number and percentage of subjects with post-treatment 
anticancer therapy noted during survival follow up, as well as, the incidence (number and 
percentage) of anticancer therapies by WHO Drug ATC level 4 and preferred drug name will be 
summarized. 
 
14. 
STUDY DRUG EXPOSURE AND COMPLIANCE 
Study drug exposure and compliance will be summarized and listed for the Safety population. 
 
14.1. 
Study Drug Exposure 
The following summaries of study drug exposure will be presented: 
 
 Duration of exposure (weeks) = [(last dose date of tazemetostat  first dose date of 
tazemetostat) + 1]/7. Except for the first and last dose dates, this calculation is not 
adjusted for periods where dosing is interrupted or dose is recorded as 0. 
 Total number of cycles of study drug categorized as follows: 
 Cycle 1 (Days 1-28; weeks 1-4) 
 Cycle 2 (Days 29-56; weeks 5-8) 
 Cycle 3 (Days 57-84; weeks 9-12) 
 Cycle 4 (Days 85-112; weeks 13-16) 
 Cycle 5 (Days 113-140; weeks 17-20) 
 Cycle 6 (Days 141-168; weeks 21-24) 
 Cycle 7 (Days 169-196; weeks 25-28) 


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 Cycle 8 or more (Day 197 and beyond; week 29 and beyond) 
 Total amount of study drug taken (mg) 
 
Average dose intensity (mg BID/day) = total amount of study drug taken (mg) / [2 * 
duration of exposure (days)] (mg BID/day) 
where duration of exposure (days) = (last dose date of tazemetostat  first dose date of 
tazemetostat) + 1 
 For assessment of tolerability, numbers of subjects requiring dose reductions, treatment 
interruption or treatment discontinuation in response to AEs (based on action taken for 
reported AEs) 
 
14.2. 
Study Drug Compliance 
The following summaries of study drug compliance will be presented: 
 Percentage study drug taken (summarized as a continuous variable) = 100% * Average 
dose intensity (mg BID/day) / 800 (mg BID/day). 
 Category of percentage of study drug taken (using categories 
90%, 80% to < 90%, 70% 
to < 80%, and < 70%). 
15. 
EFFICACY ANALYSES 
Investigator assessments and Central imaging assessments of best overall response (BOR), Overall 
Response Rate (ORR), Duration of Response (DOR), and Disease Control Rate (DCR) will be 
summarized and listed for the ITT population. The results by investigator assessments will be 
considered as primary and those performed by central imaging assessment will be supportive. 
BOR, ORR, DOR, DCR, progression-free survival (PFS) and overall survival (OS) will be 
summarized and listed for the ITT population based on both investigator and central imaging 
assessments (only Cohort 5). 
PFS rate at week 16 will be summarized and listed for Cohort 2. Provided sufficient data exists, 
additional cohort summaries may be presented. All central imaging data will be listed for the ITT 
population. 
OS will be summarized by Kaplan-Meier method for the ITT population. The same analysis will 
be performed for Cohort 6 and combined Cohorts 5 and 6 (epithelioid sarcoma (ES) population) 
when Cohort 6 data is mature. 
Best Overall Response (BOR) 
BOR is defined as the best response designation (in the order of CR, PR, SD, PD) for each 
subject that is recorded between the date of the first dose of tazemetostat and the date of 
documented disease progression per RECIST 1.1 or RANO criteria or the date of subsequent 
anticancer therapy or cancer-related surgery (i.e., surgical resection of tumor) whichever occurs 
first. 
The summaries of BOR will include number and percentage of subjects in each of these 
categories: 
 Complete response (CR) 
 Partial response (PR) 


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 Stable disease (SD) (includes Non-CR/Non-PD for subjects with non-measurable disease 
only) 
 Progressive disease (PD) 
 Not Evaluable, Unknown, Missing 
Confirmation of CR/PR is required at least 28 days after the initial CR/PR was first met. 
Stable disease (SD) is required at least 4 weeks after the first dose of study drug for 
investigator assessments and central imaging assessments. Subjects will be evaluated for 
response based on the following disease appropriate criteria: 
 For primary brain tumors, response will be assessed based on RANO (Wen et al., 2010). 
Primary central nervous system tumors outside of the brain may use RECIST version 1.1. 
All other advanced solid tumors will be assessed based on RECIST version 1.1 (Eisenhauer et al., 
2009). 
 
15.1 
Primary and Secondary Endpoints 
Objective Response Rate (ORR) 
For Cohorts 1, 3, 4, and 7 separately, the data cut-off for the analysis at the end of Stage 2 will 
occur after all treated subjects have completed at least the Week 24 assessment, completed the 
final study visit or terminated early from the study. Within each cohort, ORR is defined as the 
percentage of subjects achieving a confirmed CR or PR from the start of treatment until PD or the 
start of subsequent anti-cancer therapy or cancer-related surgery, whichever is earlier, as per 
RANO criteria for primary brain tumors or RECIST 1.1 criteria for all other solid tumors. 
Subjects with a best response of unknown/non-evaluable response will be treated as non-
responders, i.e., they will be included in the denominator when calculating the percentage. An 
exact 95% confidence interval (CI) for ORR will be provided. 
Within Cohort 2, the data cut-off for the analysis at the end of Stage 2 will occur after all enrolled 
subjects have completed at least the Week 16 assessment, completed the final study visit or 
terminated early from the study. The progression-free rate at Week 16 is defined as the percentage 
of subjects with a response of CR, PR, or SD at the Week 16 assessment, as per RECIST 1.1 
criteria. Subjects with non-evaluable or missing response will be treated as not progression-free; 
i.e., they will be included in the denominator when calculating the progression-free rate. As a 
specific example, subjects with disease progression or death prior to the Week 16 assessment will 
be included in the denominator. In addition to the PFS rate at Week 16, an exact 95% CI for this 
rate will be provided. 
Within Cohort 5, the data cut-off for the analysis at the end of Stage 2 will occur after all enrolled 
subjects have completed at least the Week 32 assessment, completed the final study visit, or 
terminated early from the study. DCR is defined as the percentage of subjects who achieve a 
confirmed response (CR or PR, as per RECIST 1.1 criteria) or who have SD lasting at least 32 
weeks from the start of treatment until disease progression or the start of subsequent anti-cancer 
therapy. For subjects with a confirmed response, the onset and duration of the response may be of 
any length as long as the response is confirmed per RECIST 1.1. An unconfirmed response (CR or 
PR) will be considered SD at that time point. Subjects with a best response of unknown/non-
evaluable response will be treated as non-disease control, i.e., they will be included in the 
denominator when calculating the percentage. Subjects with a time point response of 


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unknown/non-evaluable response on or before Week 32 will still be classified as having disease 
control as long as there is a response of CR, PR, or SD on or after Week 32.  
For Cohort 5, the futility criterion was surpassed on 04-Oct. 2016. The IDMC endorsed 
continuing enrollment to Stage 2 completion. On 21-Oct. 2016, the IDMC endorsed a change in 
the primary endpoint for Cohort 5 from ORR to DCR (which includes subjects who achieve a 
confirmed response [CR+PR] or who maintain SD for at least 32 weeks). In Dec. 2016, after the 
Stage 2 DCR criterion was surpassed, enrollment was opened in the extension stage. In May 2017, 
Epizyme met with the FDA regarding future development plans for tazemetostat. Based on a 
specific request by FDA, with Amendment 5The primary endpoint for Cohort 5 has been changed 
to ORR and duration of response in responding subjects has been elevated to the most important 
secondary endpoint. The timing of the final analysis will be after all enrolled subjects have 
completed at least the Week 24 assessment, completed the final study visit or terminated early 
from the study. An exact 95% CI for ORR and DCR will be provided for subjects enrolled 
through Stage 2. In addition, a 95% CI for ORR and DCR will be provided for the entire cohort 
(i.e., including the subjects enrolled as part of the expansion). Also, a 95% CI for ORR and DCR 
will be provided for the entire Cohort 5 and Cohort 6. 
For Cohort 8, the data cut-off for the final analysis will occur after all enrolled subjects have 
completed at least the Cycle 2 Day 1 assessment, completed the final study visit or terminated 
early from the study.  
For primary endpoint (ORR) and secondary endpoints of Cohort 6 (DOR, DCR, and ORR; 
potentially PFS and OS, if sufficient data and analysis warranted) statistical analysis will be 
performed and analyzed as for Cohort 5. 
A plot of the maximum percent tumor reduction from baseline in target lesions for each subject 
will be provided by cohort. Each plot will be color coded for best overall response. 
Within each cohort and for Cohorts 1, 3, 4, 5, 6, and 7 combined, the ORR and an exact 95% CI 
will be provided. 
Duration of Response (DOR) 
DOR, for the subset of subjects with confirmed CR or PR response, is defined as the time from 
the first documented evidence of CR or PR to the time of first documented disease progression or 
death due to any cause, whichever comes first, using disease-appropriate standardized response 
criteria. Within each cohort and for Cohorts 1, 3, 4, 5, 6, and 7 combined, DOR will be calculated 
for subjects with a confirmed CR or PR. DOR is defined as the time from the first documented 
evidence of CR or PR to the time of first documented PD or death due to any cause, whichever 
occurs first, using disease-appropriate standardized response criteria. 
DOR censoring rules will follow those of the PFS analysis defined below. 
Provided there are a sufficient number of DOR events, DOR will be analyzed using Kaplan- 
Meier methods and the median DOR, first quartile, and third quartile will be presented for each 
group/cohort noted above. The associated 2-sided 95% CIs will be estimated using the 
Brookmeyer-Crowley method (Brookmeyer and Crowley, 1982). 
Disease Control Rate (DCR) 
DCR is defined as the percentage of subjects who achieve a confirmed response (CR or PR, as 
per RECIST 1.1 criteria) or who have SD lasting at least 32 weeks from the start of treatment until 
disease progression or the start of subsequent anti-cancer therapy. For Cohort 5 and Cohort 6, 
DCR at the specified time point (Week 12, Week 24, Week 32, and Week 48) is defined as the 






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As a secondary endpoint, PFS will be analyzed by cohort and listed for the ITT population. For 
Cohort 5, PFS also will be analyzed by prior systemic anticancer therapy (with, without), by adult 
subjects (age >= 18 years), and by prior systemic anticancer therapy (with, without) for adult 
subjects for investigator and central imaging assessments. 
Depending on the maturity of PFS data at the time of the primary analysis, the PFS analysis may be 
repeated when data are mature. 
Overall Survival (OS) 
OS is defined as the interval of time between the date of the first dose of study drug and the date of 
death due to any cause. For subjects who do not die, the time of death will be censored at the date 
of last contact. Death due to any cause will be included. 
OS will be analyzed by cohort and listed for the ITT population. For Cohort 5, OS also will be 
analyzed by DCR endpoint (i.e. subjects with disease control vs. non-disease control), by prior 
systemic anticancer therapy (with, without), by adult subjects (age >= 18 years), and by prior 
systemic anticancer therapy (with, without) for adult subjects. 
Within each cohort, OS will be calculated using the Kaplan-Meier method. OS rate at 24, 32, and 
56 weeks and overall, along with the associated 2-sided 95% CIs, will be provided. If there are a 
sufficient number of OS events (i.e., deaths), median OS, first and third quartiles and associated 
95% 2-sided CIs, will be estimated using the Brookmeyer-Crowley method (Brookmeyer and 
Crowley, 1982). Kaplan-Meier curves for OS also will be provided. Figures and listings of OS will 
also be provided. 
Depending on the maturity of OS data at the time of the primary analysis, OS may be repeated 
when data are mature. 
 
15.2 
Other Endpoints 
Time to Response (TTR) 
Defined only for subjects who have a response. Time to first response is defined as [(date of first 
response of confirmed CR or PR - first dose date of tazemetostat) + 1]/7, and will be calculated 
using the Kaplan-Meier method. The median, 25th percentile and 75th percentile and associated 
95% 2-sided CIs will be estimated using the Brookmeyer-Crowley method (Brookmeyer and 
Crowley, 1982). Response is based on RANO for primary CNS tumors and RECIST 1.1 for all 
other solid tumors. 
Time to Treatment Failure (TTF) 
Time to treatment failure is defined as [(last dose date of tazemetostat - first dose date of 
tazemetostat) + 1]/7 and will be calculated using the same method as for TTR. 
If the treatment is ongoing at the time of the analysis, the last visit date will be used as the last dose 
date and the subject will be censored at the last visit date. 
 
Concordance 
Concordance of investigator and central imaging assessments for BOR, ORR and DCR will be 
summarized for Cohorts 5 and 6 (and for other cohorts provided if sufficient data exists). 
 
15.3 
Subgroup Analysis 


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Subgroup Analysis will be performed for best overall response (BOR), Overall Response Rate 
(ORR), Duration of Response (DOR) for investigator and central imaging assessments. The 
following subgroup factors will be used:  
Prior systemic anticancer therapy (with, without) 
Prior systemic anticancer therapy (with, without) for adult subjects (age >= 18 years) 
Gender (Female, Male) 
Baseline ECOG 0 vs. 1 or 2 
Age (>= 18 years, < 18 years) 
Stage at disease diagnosis 
Baseline sum of target lesion by median 
 median, > median) 
Geographic region (US vs. Non-US) 
Geographic region (US vs. Non-US) for adult subjects (age >= 18 years) 
16. 
PERFORMANCE STATUS ANALYSIS
ECOG performance status score will be analyzed and listed for the ITT population. ECOG 
performance status will be summarized categorically at baseline, best post-baseline value, and 
worst post-baseline value. A summary of baseline, best post-baseline and worst post-baseline 
status as well as change from baseline (improved, no change, deteriorated) for the best post- 
baseline value and the worst post-baseline value during the study will be provided. Best and worst 
post-baseline values will be flagged in the listing. 
17. 
SAFETY OUTCOMES
Safety summaries will be based on the Safety population. 
17.1. 
Adverse Events 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), Version 
23.1. Summary tables will be based on treatment emergent adverse events (TEAEs) which are 
defined as AEs that started or worsened in severity on or after the day of the first dose of study 
drug through 30 days after the end of study drug. All AEs, treatment emergent or otherwise, will be 
presented in subject data listings. 
Missing or partially missing start and end dates for AEs and SAEs will be handled according to the 
conventions described in Appendix 1. For cases in which it is not possible to ascertain treatment-
emergence, the event will be classified as treatment-emergent. 
Each summary table will include the incidence (number and percentage) of subjects reporting any 
TEAE, as well as, by SOC and PT. A subject will be counted once within an SOC, even if the 
subject experienced more than one TEAE within a specific SOC (likewise for PT). 
Investigator assessed severity grade will be based on the National Cancer Institute CTCAE, 
version 5.0. A subject will be counted once at the worst severity grade within an SOC and/or PT. 
Investigator assessed causality to study drug will be categorized as 
or 
to study drug.  For summary purposes, treatment-related 
TEAEs will include events with relationship to study drug classified as 
 
or 


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  A TEAE with a missing causality will be classified as 
 
to study drug. 
A subject will be counted once at the strongest causality within an SOC and/or PT. 
TEAEs of special interest are defined in Section 14.4 of protocol amendment 11. In consultation 
with study clinicians, this subset of TEAEs will be identified using MedDRA terms. 
In accordance with the TEAE table presentation described above, AEs will be summarized as 
follows: 
 TEAEs 
 TEAEs with 
% incidence overall based on PT 
 TEAEs of grade 3 or higher 
 TEAEs of grade 3 or 4 
 Treatment-related TEAEs 
 Treatment-related TEAEs of grade 3 or higher 
 Treatment-related TEAEs of grade 3 or 4 
 TEAEs leading to dose interruption 
 TEAEs leading to dose reduction 
 TEAEs leading to discontinuation of study drug 
 TEAEs leading to discontinuation from study 
 Treatment-emergent serious adverse events (SAEs) 
 Treatment-related treatment emergent SAEs 
 TEAEs leading to death 
 Treatment-related TEAEs leading to death 
 TEAEs of special interest (provided a sufficient number of events occur) 
 TEAEs by Hepatic Impairment Status 
 TEAEs of grade 3 or higher by Hepatic Impairment Status 
 Treatment-related TEAEs by Hepatic Impairment Status 
 Treatment-emergent serious adverse events (SAEs) by Hepatic Impairment Status 
 Treatment-related treatment emergent SAEs by Hepatic Impairment Status 
 TEAEs by Potential Renal Impairment Status 
 TEAEs of grade 3 or higher by Potential Renal Impairment Status 
 Treatment-related TEAEs by Potential Renal Impairment Status 
 Treatment-emergent serious adverse events (SAEs) by Potential Renal Impairment 
Status 
 Treatment-related treatment emergent SAEs by Potential Renal Impairment Status 
 
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with an outcome of death will be provided. A listing of TEAEs of special interest will be provided. 
Adverse events with CTCAE Grade 5 or outcome of death are excluded from AE summary tables 
and summarized under death related tables. 
Subject deaths will be summarized and listed as follows: 
 Summary and listing of subjects who died during and till 30 days after last dose of study 
drug with the reason for death as follows. 
 Any AE (by MedDRA preferred Term) 
 Any treatment related TEAE 
 Progressive Disease 
 Disease under Study 
 Unknown/Other causes 
 Summary and listing of subjects who died during and till 30 days after last dose of study 
drug with treatment-related TEAEs 
 Summary and listing of subjects who died after 30 days after the last dose of study drug 
with treatment-related AEs. 
 
17.2. 
Laboratory Evaluations 
Section 12.5.14 of the protocol identifies the hematology, chemistry, and urinalysis analytes 
collected for the study. Laboratory evaluations will be performed by local laboratories. 
Summaries and listings of laboratory data will be represented in international system (SI) of units, 
where applicable. 
Laboratory values that are reported as 
 the detectable 
 of an assay will be analyzed as 
half the detectable limit when required for analysis purposes but listed as originally reported. The 
following summaries will be provided for selected hematology and chemistry data: 
 Shift from baseline grade to worst post-baseline grade based on NCI CTCAE v4.03 (for 
analytes where CTCAE grading applies). A missing baseline grade will be assumed to 
be grade 0. For laboratory tests with both low and high values, summaries will be 
provided separately. 
 Shift from baseline to worst post-baseline value that is < 0.25 x lower limit of normal 
(LLN) or > 2.5 x upper limit of normal (ULN) for analytes not gradable by NCI 
CTCAE v4.03. 
In addition to the analysis for serum creatinine, the number and percentage of subjects with 
creatinine clearance rate during the treatment period meeting the following categories will be 
presented: 
 Normal: Glomerular filtration rate (creatinine clearance [CrCl]) 
0 mL/min 
 Mild Impairment: CrCl 
- < 90 mL/min 
 Moderate Impairment: CrCl 
- < 60 mL/min 
 Severe Impairment: CrCl 
- < 30 mL/min 
 Kidney Failure: CrCl < 15 mL/min 


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Creatinine clearance rate will be calculated using serum creatinine and the Cockcroft-Gault 
formula. 
The number and percentage of subjects with the following potentially clinically significant 
abnormal liver function test will be summarized: 
 ALT 
 
 
 and 
 
 
 
 
 and 
 
 Total bilirubin 
 
 Potential 
 Law cases: ALT or AST 
xULN, total bilirubin 
 and ALP 
< 2xULN 
All above abnormal overlapping liver analytes have to be within a 7-day timeframe. All laboratory 
data will be listed.  Additional listings of grade 3 or higher (per NCI CTCAE) values and values < 
0.25 x LLN or > 2.5 x ULN for analytes not gradable by NCI CTCAE will be provided. For 
subjects with a post-baseline analyte that is grade 3 or higher, all values for that analyte will be 
listed. Similarly, for subjects with a post-baseline analyte value that is < 0.25 x LLN or > 2.5 x 
ULN, all values for that analyte will be listed. 
Special data handling rule for hematology and biochemistry: lab data are collected in different local 
laboratories with potential missing normal ranges and units. Two procedures have been applied to 
handle the issue: 1) conversion to standard international units and 2) Standard Lab Normal Ranges 
are used to replace missing ones. 
 
17.3. 
Electrocardiogram Evaluations 
Single electrocardiogram (ECG) measures will be collected according to the schedule of events in 
Appendix 2 unless there is an abnormality. Triplicates or additional unscheduled time points may be 
collected, if clinically indicated. When triplicates are collected, the averages (as calculated by the 
central ECG vendor ERT) will be used in the summaries. 
The following pre-dose and post-dose ECGs parameters will be collected at select scheduled time 
points and presented as continuous statistics: 
 PR Interval (msec) 
 RR Interval (msec) 
 QRS Interval (msec) 
 QT Interval (msec) 
 QTc Bazett [QTcF] Interval (mesc) 
 QTc, Fridericia [QTcF] Interval (msec) 
 HR (bpm) 
The QTcF interval will be the primary ECG measure of interest with other parameters as 
secondary. 
The following summaries will be provided for ECG measurements listed above: 
 ECG values and changes from baseline (and changes from pre-dose) by planned visit 
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abnormal or not (defined in the table below) 
 Number and percentage of subjects whose worst-case changes from baseline in QTcF 
measurements meet markedly abnormal criteria (described in the table below). 
Table 6: 
ECG Measures and Markedly Abnormal Criteria 
QTcF Measure 
Markedly Abnormal Criteria 
Observed 
450 480 msec, inclusive [CTCAE grade 1] 
481 500 msec, inclusive [CTCAE grade 2] 
> 500 msec [CTCAE grade 3 or higher] 
Change from 
Baseline 
31 60 msec, inclusive, increase from baseline 
>60 msec increase from baseline 
The listings will include the individual ECG values, the calculated averages, and other information 
collected from the ECG. QTcF measures meeting the markedly abnormal criteria as defined in the 
table above will be flagged on the listing. 
 
17.4. 
Vital Signs 
Weight (kg) and height at screening (cm). The following vital signs were measured following the 
initiation of study drug: 
 systolic and diastolic blood pressures (mmHg) 
 heart rate (bpm) 
 body temperature (degrees Celsius, C) 
Each of these vital signs will be summarized descriptively by calculating the mean, standard 
deviation, median, and range (minimum and maximum) of the following values that are derived 
for each subject: 
 baseline value 
 minimum post-baseline value and corresponding change from baseline 
 maximum post-baseline value and corresponding change from baseline 
 last post-baseline value and corresponding change from baseline 
In addition, summaries of heart rate, temperature, systolic blood pressure, and diastolic blood 
pressure will be based on markedly abnormal criteria defined below: 
 
 
 
 
 
 




Epizyme, Inc. 
Confidential 
 
 
Statistical Analysis Plan 
 
V 3.0, 30 NOV 2022 
 
Oncology 28(11), 1963-1972. 
8. Brookmeyer, R. and Crowley, J. (1982).  A confidence interval for the median survival time. 
Biometrics 38, 29-41. 
 
 
 
















Epizyme, Inc. 
Confidential 
 
 
 
 
Statistical Analysis Plan 
 
V 3.0, 15 NOV  2022 
APPENDIX 3. PHARMACODYNAMICS AND GENETICS ANALYSES 
 
The analysis will specify and will be provided in a separate report. 


C ertifi c at e Of C o m pl eti o n
E n v el o p e I d: 
St at u s: C o m pl et e d
S u bj e ct: C o m pl et e wit h D o c u Si g n: E Z H- 2 0 2 _ S A P _ V 3. 0 _ 3 0 N O V 2 0 2 2. p df
S o ur c e E n v el o p e: 
D o c u m e nt P a g e s: 5 2
Si g n at ur e s: 2
E n v el o p e Ori gi n at or: 
C ertifi c at e P a g e s: 3
I niti al s: 0
A ut o N a v: E n a bl e d
E n v el o p eI d St a m pi n g: Di s a bl e d
Ti m e Z o n e: ( U T C- 0 5: 0 0) E a st er n Ti m e ( U S & C a n a d a)
I P A d dr e s s: 
R e c or d Tr a c ki n g
St at u s: Ori gi n al
             9/ 1 2/ 2 0 2 3 1 1: 0 6: 2 8 A M
H ol d er: 
            
L o c ati o n: D o c u Si g n
Si g n er E v e nt s
Si g n at ur e
Ti m e st a m p
S e c urit y L e v el: E m ail, A c c o u nt A ut h e nti c ati o n 
( R e q uir e d)
Si g n at ur e A d o pti o n: Pr e- s el e ct e d St yl e
Si g n at ur e I D: 
U si n g I P A d dr e s s: 
Wit h Si g ni n g A ut h e nti c ati o n vi a D o c u Si g n p a s s w or d
Wit h Si g ni n g R e a s o n s ( o n e a c h t a b): 
   I a m t h e a ut h or of t hi s d o c u m e nt
S e nt: 9/ 1 2/ 2 0 2 3 1 1: 0 7: 4 4 A M
Vi e w e d: 9/ 1 2/ 2 0 2 3 1 1: 0 7: 5 3 A M 
Si g n e d: 9/ 1 2/ 2 0 2 3 1 1: 0 8: 2 6 A M
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e: 
      A c c e pt e d: 4/ 2 9/ 2 0 2 2 2: 5 6: 3 3 P M
      I D: 
S e c urit y L e v el: E m ail, A c c o u nt A ut h e nti c ati o n 
( R e q uir e d)
Si g n at ur e A d o pti o n: Pr e- s el e ct e d St yl e
Si g n at ur e I D: 
U si n g I P A d dr e s s: 
Wit h Si g ni n g A ut h e nti c ati o n vi a D o c u Si g n p a s s w or d
Wit h Si g ni n g R e a s o n s ( o n e a c h t a b): 
   I a p pr o v e t hi s d o c u m e nt
S e nt: 9/ 1 2/ 2 0 2 3 1 1: 0 7: 4 4 A M
Vi e w e d: 9/ 1 2/ 2 0 2 3 1 1: 1 2: 3 7 A M 
Si g n e d: 9/ 1 2/ 2 0 2 3 1 1: 1 3: 2 1 A M
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e: 
      A c c e pt e d: 9/ 1 2/ 2 0 2 3 1 1: 1 2: 3 7 A M
      I D: 
I n P er s o n Si g n er E v e nt s
Si g n at ur e
Ti m e st a m p
E dit or D eli v er y E v e nt s
St at u s
Ti m e st a m p
A g e nt D eli v er y E v e nt s
St at u s
Ti m e st a m p
I nt er m e di ar y D eli v er y E v e nt s
St at u s
Ti m e st a m p
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


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B y selecti n g t h e c hec k-
t hat: 
 
Y o u ca n access a n d rea d t his Electr o nic Rec or d a n d Si g nat ure Discl os ure; a n d 
 
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P P D