A Phase II, Multicenter Study of the EZH2 Inhibitor Tazemetostat in Adult Subjects With INI1-Negative Tumors or Relapsed/Refractory Synovial Sarcoma
Phase: PHASE2
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
Sponsor: Epizyme, Inc.

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

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 3
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
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 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
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 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
Pa ge 8 6
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. 
Patel B, Ka n g Y, C ui K, et al. A berra nt T A L 1  acti vati o n is me diate d b y a n i nterc hr o m os o mal 
i nteracti o n i n h u ma n T-cell ac ute l y m p h o blastic le u ke mia. Le uke mi a. 2 0 1 4; 2 8( 2): 3 4 9- 3 6 1. 
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 
fr o m a retr os pecti ve, m ulti-i nstit uti o nal a nal ysis. O nc ol o gy. 2 0 1 4; 8 7( 2): 9 5- 1 0 3. 
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 
j o ur n al of t he I nter n ati o n al Gy nec ol o gic al C a ncer S ociety. 2 0 1 4; 2 4( 9 S u p pl 3): S 3 0- 3 4.
R o berts C W, Gal us ha S A, Mc Me na mi n M E, et al. Ha pl oi ns ufficie nc y of S nf 5 (i nte grase 
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. 
Sleijfer S, Ra y- C o q uar d I, Pa pai Z, et al. Paz o pa ni b, a m ulti ki nase a n gi o ge nesis i n hi bit or, i n 
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 
w hite bl o o d cell gr o wt h fact ors: a n e vi d e nce- base d cli nical practice g ui deli ne. J Cli n O nc ol. 
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. 
Stacc hi otti S, Ta m b ori ni E, L o V ull o S, et al . P hase II st u d y o n la pati ni b i n a d va nce d E G F R-
p ositi ve c h or d o ma. A n n O nc ol. 2 0 1 3; 2 4( 7): 1 9 3 1- 1 9 3 6. 
S ulli va n L M, F ol pe A L, Pa wel B R, et al. E pit heli oi d sarc o ma is ass ociate d wit h a hi g h 
perce nta ge of S M A R C B 1 deleti o ns. M o d P at h ol. 2 0 1 3; 2 6( 3): 3 8 5- 3 9 2. 
S ulta n I, Qa d d o u mi I, R o dri g uez- Gali n d o C, et al. A ge, sta ge, a n d ra di ot hera p y, b ut n ot pri mar y 
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 & 
c a ncer. 2 0 1 0; 5 4( 1): 3 5- 4 0.
S wer dl o w S H, Ca m p o E, Harris N L, et al., e ds. W H O Cl assific ati o n of T u m o urs of 
H ae m at o p oietic a n d Ly m p h oi d Tiss ues. 4t h, V ol u me 2 e d. L y o n, Fra nce: I A R C Press; 2 0 0 8. 
T he Criteria C o m mittee of t he Ne w Y or k Heart Ass ociati o n. N o me nclat ure a n d Criteria f or 
Dia g n osis of Diseases of t he Heart a n d Great Ve ssels. I n: 9t h e d. B ost o n, M A: Little, Br o w n & 
C o.; 1 9 9 4: 2 5 3- 2 5 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 1 1 5
Tir o de F, S ur dez D, Ma X, et al. Ge n o mic la n dsca pe of E wi n g sarc o ma defi nes a n a g gressi ve 
s u bt y pe wit h c o-ass ociati o n of S T A G 2 a n d T P 5 3 m utati o ns. C a ncer Disc ov. 2 0 1 4; 4( 1 1): 1 3 4 2-
1 3 5 3.
va n der Graaf W T, Bla y J Y, C ha wla S P, et al . Paz o pa ni b f or metastatic s oft-tiss ue sarc o ma 
( P A L E T T E): a ra n d o mise d, d o u ble- bli n d, place b o-c o ntr olle d p hase 3 trial. L a ncet. 
2 0 1 2; 3 7 9( 9 8 2 9): 1 8 7 9- 1 8 8 6. 
We n P Y, Mac d o nal d D R, Rear d o n D A, et al. U p date d res p o nse assess me n t criteria f or hi g h-
gra de gli o mas: res p o nse assess me nt  i n ne ur o- o nc ol o g y w or ki n g gr o u p. J Cli n O nc ol. 
2 0 1 0; 2 8( 1 1): 1 9 6 3- 1 9 7 2. 
Wils o n B G, Wa n g X, S he n X, et al. E pi ge net ic a nta g o nis m bet wee n p ol yc o m b a n d S WI/ S N F 
c o m ple xes d uri n g o nc o ge nic tra nsf or mati o n. C a ncer Cell. 2 0 1 0; 1 8( 4): 3 1 6- 3 2 8. 
Wit k o ws ki L, Carr ot- Z ha n g J, Al brec ht S, et  al. Ger mli ne a n d s o matic S M A R C A 4 m utati o ns 
c haracterize s mall cell carci n o ma of t he o var y, h y percalce mic t y pe. N at Ge net. 2 0 1 4; 4 6( 5): 4 3 8-
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 
cli nic o pat h ol o gical a nal ysis of 1 5 0 cases. A m J S ur g P at h ol. 1 9 9 4; 1 8( 1 1): 1 1 0 2- 1 1 1 6. 
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 
gr o wt h a n d metastasis t hr o u g h sile nc i n g of disti nct t u m o ur s u p press ors. N at C o m m u n. 
2 0 1 5; 6: 6 0 5 1. 
Zis o ws k y J, Kra use A, Di n ge ma nse J. Dr u g De ve l o p me nt f or Pe diatric P o p ulati o ns: Re g ulat or y 
As pects. P h ar m ace utics. 2 0 1 0; 2( 4): 3 6 4- 3 8 8.