A Single-Cohort, Phase 2 Study of Ruxolitinib in Combination With Corticosteroids for the Treatment of Steroid-Refractory Acute Graft-Versus-Host Disease (REACH-1)
Phase: PHASE2
Conditions: Graft-versus-host Disease (GVHD)
Sponsor: Incyte Corporation

I n c yt e  C or p or ati o n 
P a g e  1  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
Cli ni c al  St u d y  P r ot o c ol 
I N C B 18 4 2 4 - 27 1  / N C T 0 2 9 5 3 6 7 8 
A Si n gle- C o h ort , P h ase 2 St u d y o f R u x olit i ni b i n C o m bi n ati o n Wit h 
C ortic oster oi ds f o r the T re at me nt o f St er oi d- Refr act or y Ac ut e 
Gr aft - Vers us-H ost Dis e ase 
P r o d u ct:  
I N C B 0 1 8 4 2 4 
I N D  N u m b e r: 
7 7 4 5 6 
P h as e  of  St u d y:   
2 
S p o ns o r:  
I n c yte  C o r p o r ati o n 
1 8 0 1  A u g usti n e  C ut- Off  
Wil mi n gt o n,  D E  1 9 8 0 3 
D at e  of  P r ot o c ol:   
1 4  J U N   2 0 1 6 
D at e  of  A m e n d m e nt  1:   
1 2  S E P  2 0 1 6  
D at e  of  A m e n d m e nt  2:   
0 4  O C T  2 0 1 6  
T his st u d y  will  b e  p erf or m e d i n  a c c or d a n c e  wit h  et hi c al  pri n ci pl es t h at  h a v e t h eir  ori gi n i n t h e  D e cl ar ati o n  of 
H elsi n ki  a n d  c o n d u ct e d i n  a d h er e n c e t o t h e st u d y  Pr ot o c ol,  G o o d  Cli ni c al  Pr a cti c es  as  d efi n e d i n  Titl e  2 1  of t h e 
U S  C o d e  of  F e d er al  R e g ul ati o ns  P arts  1 1,  5 0,  5 4 , 5 6,  a n d  3 1 2  as  w ell  a s I C H  G C P  c o ns oli d at e d  g ui d eli n e s ( E 6)  a n d 
a p pli c a bl e r e g ul at or y r e q uir e m e nts.  
T h e i nf or m ati o n i n t his  d o c u m e nt is  c o nfi d e nti al.   N o  p art  of t his i nf or m ati o n  m a y  b e  d u pli c at e d, r ef er e n c e d,  or 
tr a ns mitt e d i n  a n y f or m  or  b y  a n y  m e a ns ( el e ctr o ni c,  m e c h a ni c al,  p h ot o c o p y, r e c or di n g,  or  ot h er wis e)  wit h o ut t h e  pri or 
writt e n  c o ns e nt  of I n c yt e  C or p or ati o n.  

I n c yt e  C or p or ati o n 
P a g e  2  of  7 7 
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
I N V E S TI G A T O R' S  A G R E E M E N T  
I  h a v e r e a d t h e I N C B 1 8 4 2 4- 2 7 1  Pr ot o c ol  A m e n d m e nt  2  ( d at e d 0 4  O C T  2 0 1 6 )  an d  a gr e e t o 
c o n d u ct t h e st u d y  as  o utli n e d.  I  a gr e e t o  m ai nt ai n t h e  c o nfi d e nti alit y  of  all i nf or m ati o n r e c ei v e d 
or  d e v el o p e d i n  c o n n e cti o n  wit h t his  Pr ot o c ol. 
 
 
 
   
( Pri nt e d  N a m e  of I n v esti g at or) 
   
 
   
 
   
( Si g n at ur e  of I n v esti g at or) 
  ( D at e) 

I n c yt e  C or p or ati o n 
P a g e  3  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
S Y N O P SI S  
N a m e  of  I n v esti g ati o n al  Pr o d u ct :  I N C B 01 8 4 2 4 
Titl e  of  S t u d y:  A  Si n gl e - C o h ort,  P h as e  2  St u d y  of  R u x oliti ni b i n  C o m bi n atio n  Wit h  C orti c ost er oi ds f or 
t h e Tr e at m e nt  of  St er oi d -R efr a ct or y  A c ut e  Gr aft -V ers us -H ost  Dis e as e  
P r ot o c ol  N u m b e r:   I N C B 1 8 4 2 4- 2 7 1 
St u d y  P h as e :  2  
O bj e cti v es  a n d  E n d p oi nts:  
 
P ri m a r y  O bj e cti v e  
P ri m a r y  E n d p oi nt  
 
 
A ss ess t h e  effi c a c y  of r u x oliti ni b i n  c o m bi n ati o n 
wit h  c orti c ost er oi ds i n  s u bj e cts  wit h  Gr a d e II t o 
IV  st er oi d-r efr a ct or y a c ut e  gr aft -v er s us -h ost 
dis e as e ( G V H D).  
O v er all r es p o ns e r at e ( O R R ) at  D a y  2 8,  d efi n e d  as t h e 
pr o p orti o n  of s u bj e cts  d e m o nstr ati n g  a  c o m pl et e r es p o ns e 
( C R),  v er y  g o o d  p arti al r es p o ns e ( V G P R),  or  p arti al 
r es p o ns e ( P R). 
 
 
S e c o n d a r y  O bj e cti v es  
S e c o n d a r y  E n d p oi nts  
 
 
Ass ess  a d diti o n al r es p o ns e  a n d  l o n g er-t er m 
e ffi c a c y o ut c o m e s i n t h e st u d y  p o p ul ati o n.  
K e y s e c o n d ar y  e n d p oi nt:  
Si x -m o nt h  d ur ati o n  of r es p o ns e ( D O R ),  d efi n e d  as t h e 
ti m e fr o m first r es p o ns e  u ntil G V H D  pr o gr essi o n  or  d e at h.   
D O R  will  b e  ass ess e d  w h e n  all s u bj e cts  c o m pl et e  t h e 
D a y  1 8 0  visit . 
 
 
O R R,  d efi n e d  as t h e  pr o p orti o n  of s u bj e cts  d e m o nstr ati n g 
a  C R,  V G P R,  P R  at  D a ys  1 4,  5 6,  a n d  1 0 0.  
 
 
T hr e e -m o nt h  D O R,  d efi n e d  as t h e ti m e fr o m first r es p o ns e 
u ntil  G V H D  pr o gr essi o n  or  d e at h ,  w h e n all s u bj e cts 
c o m pl et e t h e  D a y  8 4  visit.  
 
 
N o nr el a ps e  m ort alit y ( N R M ),  d efi n e d  as t h e  pr o p orti o n  of 
s u bj e cts  w h o  di e d  d u e t o  c a us es  ot h er t h a n  m ali g n a n c y 
r el a ps e  at  M o nt hs  6,  9,  1 2, a n d  2 4. 
 
 
 
 
R el a ps e r at e,  d efi n e d  as t h e  pr o p orti o n  of s u bj e cts  w h os e 
u n d erl yi n g  m ali g n a n c y  r el a ps es. 
 
 
R el a ps e -r el at e d  m ort alit y r at e,  d efi n e d  as t h e  pr o p orti o n 
of s u bj e cts  w h o s e  m ali g n a n c y  r el a ps es  a n d  h a s  a f at al 
o ut c o m e.  
 
 
F ail ur e -fr e e s ur vi v al ( F F S),  d efi n e d  as t h e  pr o p orti o n  of 
s u bj e cts  w h o  ar e still  ali v e,  h a v e  n ot r el a ps e d,  h a v e  n ot 
r e q uir e d a d diti o n al t h er a p y f or  a c ut e  G V H D,  a n d  h a v e  n ot 
d e m o nstr at e d si g ns  or s y m pt o ms  of  c hr o ni c  G V H D,  at 
M o nt h  6.  
 
 
O v er all s ur vi v al  ( O S),  d efi n e d  as t h e ti m e fr o m st u d y 
e nr oll m e nt t o  d e at h  d u e t o  a n y  c a us e.  
 
 
Ass ess t h e i n ci d e n c e  a n d s e v erit y  of  a d v ers e 
e v e nts ( A Es)  a n d s eri o us  a d v ers e  e v e nt s ( S A Es). 
S u m m ari es  of  c li ni c al  s af et y  d at a (e g,  A E s, i nf e cti o ns) 
will  b e t a b ul at e d  a n d list e d.  
 
 
E v al u at e t h e  p h ar m a c o ki n eti c s  of  r u x oliti ni b 
w h e n  a d mi nist er e d i n  c o m bi n ati o n  wit h 
c orti c ost er oi ds. 
M a xi m u m  o bs er v e d  pl as m a  dr u g  c o n c e ntr ati o n ( C m a x ), 
mi ni m u m  o bs er v e d  pl as m a  dr u g  c o n c e ntr ati o n ( C
mi n ), 
ti m e  of  m a xi m u m  o bs er v e d  pl as m a  dr u g  c o n c e ntr ati o n 
(tm a x ), ar e a  u n d er t h e  pl as m a  dr u g  c o n c e ntr ati o n  v ers us 
ti m e  c ur v e ( A U C),  a n d  a p p ar e nt  cl e ar a n c e  of  st u d y  dr u g 
fr o m  pl as m a ( C L/ F). 
 
 
 
 
 

I n c yt e  C or p or ati o n 
P a g e  4  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
O v e r all  St u d y  D esi g n:  
T his is  a n  o p e n-l a b el, si n gl e- c o h ort,  m ulti c e nt er  P h as e  2 st u d y  of r u x oliti ni b i n  c o m bi n ati o n  wit h 
c orti c ost er oi ds f or t h e tr e at m e nt  of st er oi d -r efr a ct or y  Gr a d es II t o I V  a c ut e  G V H D.   Eli gi bl e s u bj e cts  will 
b e gi n tr e at m e nt  at  5  m g t wi c e  d ail y ( BI D) r u x olit i ni b; if  h e m at ol o gi c  p ar a m et ers  ar e st a bl e  a n d  n o 
tr e at m e nt-r el at e d t o xi cit y is  o bs er v e d  aft er t h e first  3  d a ys  of tr e at m e nt, t h e  d os e  m a y  b e i n cr e as e d t o 
1 0  m g  BI D.   R u x oliti ni b  m a y  b e t a p er e d  aft er  D a y  1 8 0  pr o vi d e d  t h e s u bj e ct  h as  a c hi e v e d  C R  or  V G P R  a n d 
c orti c ost er oi ds  h a v e  b e e n  dis c o nti n u e d f or  at l e ast  8  w e e ks.   C orti c ost er oi ds  will  b e  a d mi nist er e d  at  a 
st arti n g  d os e  of  2. 0  m g/ k g  p er  d a y ( u nl ess  ot h er wis e i n di c at e d)  o n  D a y  1  a n d  will  b e t a p er e d  as 
a p pr o pri at e.   S u bj e cts  will r e c ei v e st u d y tr e at m e nt  u nt il tr e at m e nt f ail ur e ( pr o gr essi o n  of  G V H D,  n o 
r es p o ns e,  or r e q uiri n g  a d diti o n al s yst e mi c t h er a p y),  u n a c c e pt a bl e t o xi cit y,  or  d e at h.   C o nti n u e d  us e  of  a nti-
i nf e cti v e  m e di c ati o ns,  G V H D  pr o p h yl a xis  m e di c ati o ns (i n cl u di n g  c al ci n e uri n i n hi bit ors), tr a nsf usi o n 
s u p p ort,  a n d t o pi c al st er oi d t h er a p y is  p er mitt e d. 
S e v erit y  of  G V H D  will  b e  ass ess e d fr o m s cr e e ni n g t hr o u g h  e n d  of tr e at m e nt ( E O T)  usi n g t h e  M o u nt  Si n ai 
A c ut e  G V H D I nt er n ati o n al  C o ns orti u m ( M A GI C)  g ui d eli n es.   A d v ers e  e v e nts  a n d  S A Es  will  b e  ass ess e d 
fr o m th e ti m e  of  c o ns e nt t hr o u g h  3 0 t o  3 5  d a ys  aft er t h e  E O T  as  p er  N ati o n al  C a n c er I nstit ut e  C T C A E 
v 4. 0 3.   S u bj e cts  will  b e  ass ess e d f or  effi c a c y (i n cl u di n g  o v er all r es p o ns e,  N R M,  F F S,  D O R, r el a ps e r at e, 
r el a ps e-r el at e d  m ort alit y r at es,  a n d  O S), s af et y (i n cl u di n g  A Es,  S A Es,  a n d  cli ni c al/l a b or at or y  ass ess m e nts), 
 
 
St u d y  P o p ul ati o n:    
S u bj e cts  w h o  h a v e  d e v el o p e d  Gr a d es  II t o I V st er oi d-r efr a ct or y  a c ut e  G V H D  m a y  b e  eli gi bl e  c a n di d at es 
f or t his st u d y. 
K e y I n cl usi o n  C rit e ri a:  
•  M al e  or f e m al e,  1 2  y e ars  of  a g e  or  ol d er.  
•  H a v e  u n d er g o n e first  all o g e n ei c  h e m at o p oi eti c st e m  c ell tr a ns pl a nt ati o n  ( all o-H S C T)  fr o m  a n y  d o n or 
s o ur c e  usi n g  b o n e  m arr o w,  p eri p h er al  bl o o d st e m  c ells,  or  c or d  bl o o d f or  h e m at ol o gi c  m ali g n a n ci es.  
R e ci pi e nts  of  n o n m y el o a bl ati v e  a n d  m y el o a bl ati v e  c o n diti o ni n g r e gi m e ns  ar e  eli gi bl e.  

I n c yt e  C or p or ati o n 
P a g e  5  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
•  Cli ni c all y s us p e ct e d  Gr a d es  II t o I V a c ut e  G V H D  as  p er  M A GI C  g ui d eli n es ,  o c c urri n g  aft er  all o g e n ei c 
h e m at o p oi eti c st e m  c ell tr a ns pl a nt  wit h  a n y  c o n diti o ni n g r e gi m e n  a n d  a n y  a nti- G V H D  pr o p h yl a cti c 
pr o gr a m.   Bi o psi es s h o ul d  b e  o bt ai n e d t o  p at h ol o gi c all y  c o nfir m  a c ut e  G V H D; i n  c as es  w h er e  a  bi o ps y 
is n e g ati v e, is  u n a bl e t o  b e  o bt ai n e d , or is  cli ni c all y  c o ntr ai n di c at e d,  cli ni c al s us pi ci o n  of  a c ut e  G V H D 
b y t h e tr e ati n g  p h ysi ci a n is s uffi ci e nt,   pr o vi d e d t h at  alt er n ati v e  di a g n os es  of  dr u g  eff e cts  or i nf e cti o n  ar e 
a d e q u at el y r ul e d  o ut. 
•  S u bj e cts  wit h st er oi d -r efr a ct or y  a c ut e  G V H D,  d efi n e d  as  a n y  of t h e f oll o wi n g:  
-  S u bj e cts  wit h  p r o gr essi v e G V H D  (i e, i n cr e as e i n st a g e i n  a n y  or g a n s yst e m  or  a n y  n e w  or g a n 
i n v ol v e m e nt)  aft er  3  d a ys  of  pri m ar y tr e at m e nt  wit h  m et h yl pr e d nis ol o n e ≥  2  m g/ k g  p er  d a y ( or 
e q ui v al e nt). 
-  S u bj e cts  wit h  G V H D t h at  h as  n ot i m pr o v e d  (i e,  d e cr e as e i n st a g e i n  at l e ast  1 i n v ol v e d  or g a n s yst e m) 
aft er  7  d a ys  of  pri m ar y tr e at m e nt  wit h  m et h yl pr e d nis ol o n e  ≥  2  m g/ k g  p er  d a y ( or  e q ui v al e nt). 
-  S u bj e cts  w h o  pr e vi o usl y  b e g a n  c orti c ost er oi d t h er a p y  at  a l o w er  d os e  ( at l e ast  1  m g/ k g  p er  d a y 
m et h yl pr e d nis ol o n e) f or tr e at m e nt  of s ki n  G V H D  or s ki n  G V H D  a c c o m p a ni e d  b y  u p p er 
g astr oi nt esti n al ( GI)  G V H D,  b ut  d e v el o p  n e w  G V H D i n  a n ot h er  or g a n  s yst e m. 
-  S u bj e cts  w h o  c a n n ot t ol er at e  a  c orti c ost er oi d t a p er, t h at is,  b e gi n  c orti c ost er oi ds  at  2. 0  m g/ k g  p er  d a y, 
d e m o nstr at e r es p o ns e,  b ut  pr o gr ess  b ef or e  a  5 0 %  d e cr e as e fr o m t h e i niti al st arti n g  d os e  of 
c orti c ost er oi ds is  a c hi e v e d.  
•  E vi d e n c e  of  m y el oi d  e n gr aft m e nt ( e g,  a bs ol ut e  n e utr o p hil  c o u nt  ≥  0. 5  ×  1 0 9/ L f or  3 c o ns e c uti v e  d a ys if 
a bl ati v e t h er a p y  w as  pr e vi o usl y  us e d).   Us e  of  gr o wt h f a c t or s u p pl e m e nt ati o n is  all o w e d. 
•  B e  willi n g t o  a v oi d  pr e g n a n c y  or f at h eri n g  c hil dr e n  b as e d  o n  1  of t h e f oll o wi n g  crit eri a: 
-  W o m e n  of  n o n c hil d b e ari n g  p ot e nti al (i e,  s ur gi c all y st erile  wit h  a  h yst er e ct o m y  a n d/ or  bil at er al 
o o p h or e ct o m y  O R   ≥  1 2  m o nt hs  of  a m e n orr h e a). 
-  W o m a n  of  c hil d b e ari n g  p ot e nti al  w h o  h as  a  n e g ati v e s er u m  pr e g n a n c y t est  at s cr e e ni n g  a n d  w h o 
a gr e es t o t a k e  a p pr o pri at e  pr e c a uti o ns t o  a v oi d  pr e g n a n c y ( wit h  at l e ast  9 9 %  c ert ai nt y) fr o m s cr e e ni n g 
t hr o u g h s af et y f oll o w-u p.   P er mitt e d  m et h o ds t h at  ar e  at l e ast  9 9 %  eff e cti v e i n  pr e v e nti n g  pr e g n a n c y 
s h o ul d  b e  c o m m u ni c at e d t o t h e s u bj e ct  a n d t h eir  u n d erst a n di n g  c o nfir m e d. 
-  M a n  w h o  a gr e es t o t a k e  a p pr o pri at e  pr e c a uti o ns t o  a v oi d f at h eri n g  c hil dr e n ( wit h  at l e ast  9 9 % 
c ert ai nt y) fr o m s cr e e ni n g t hr o u g h s af et y f oll o w -u p.   P er mitt e d  m et h o ds t h at  ar e  at l e ast  9 9 %  eff e cti v e 
i n  pr e v e nti n g  pr e g n a n c y s h o ul d  b e  c o m m u ni c at e d t o t h e s u bj e ct  a n d t h eir  u n d erst a n di n g  c o nfir m e d. 
•  Writt e n i nf or m e d  c o ns e nt  a n d/ or  ass e nt fr o m t h e s u bj e ct,  p ar e nt,  or  g u ar di a n. 
•  Willi n g n ess t o  c o m pl y  wit h  all st u d y  visits  a n d  pr o c e d ur es.  
K e y  E x cl usi o n  C rit e ri a:  
•  H as r e c ei v e d  m or e t h a n  1  all o -H S C T . 
•  H as r e c ei v e d  m or e t h a n  1 s yst e mi c tr e at m e nt  i n  a d diti o n t o  c orti c ost er oi ds f or a c ut e  G V H D.  
•  Pr es e n c e  of  G V H D  o v erl a p s y n dr o m e  as  p er  NI H  g ui d eli n es.  
•  Pr es e n c e  of  a n  a cti v e  u n c o ntr oll e d i nf e cti o n.   A n  a cti v e  u n c o ntr oll e d i nf e cti o n is  d efi n e d  as 
h e m o d y n a mi c  i nst a bilit y  attri b ut a bl e t o s e psis  or  n e w s y m pt o ms,  w ors e ni n g  p h ysi c al si g ns,  or 
r a di o gr a p hi c fi n di n gs  attri b ut a bl e t o i nf e cti o n.   P ersisti n g f e v er  wit h o ut si g ns  or s y m pt o ms  will  n ot  b e 
i nt er pr et e d  as  a n  a cti v e  u n c o ntr oll e d i nf e cti o n. 
•  K n o w n  h u m a n i m m u n o d ef i ci e n c y  vir us i nf e cti o n. 
•  A cti v e  h e p atitis  B  vir us ( H B V)  or  h e p atitis  C  vir us i nf e cti o n t h at r e q uir es tr e at m e nt  or  at ris k f or  H B V 
r e a cti v ati o n.   At ris k f or  H B V r e a cti v ati o n is  d efi n e d  as  h e p atitis  B s urf a c e  a nti g e n  p ositi v e  or  a nti–
h e p atitis  B  c or e  a nti b o d y  p ositi v e.   Pr e vi o us  t est r es ults  o bt ai n e d  as  p art  of st a n d ar d  of  c ar e b ef or e 
all o -H S C T t h at  c o nfir m  a s u bj e ct is i m m u n e  a n d  n ot  at ris k f or r e a cti v ati o n (i e,  h e p atitis  B s urf a c e 
a nti g e n  n e g ati v e, s urf a c e  a nti b o d y  p ositi v e)  m a y  b e  us e d f or  p ur p os es  of  el i gi bilit y  a n d t ests  d o  n ot  n e e d 
t o  b e r e p e at e d.   S u bj e cts  wit h pr e vi o us  p ositi v e s er ol o g y r es ults  m ust  h a v e  n e g ati v e  p ol y m er as e  c h ai n 

I n c yt e  C or p or ati o n 
P a g e  6  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
r e a cti o n r es ults.   S u bj e cts  w h os e i m m u n e st at us is  u n k n o w n  or  u n c ert ai n  m ust  h a v e r es ults  c o nfir mi n g 
i m m u n e st at us  b ef or e e nr oll m e nt.  
•  S er u m  cr e ati ni n e  >  2. 0  m g/ d L  or  cr e ati ni n e  cl e ar a n c e  <  4 0  m L/ mi n  m e a s ur e d  or  c al c ul at e d  b y 
C o c kr oft- G a ult  e q u ati o n. 
•  S u bj e cts  wit h  e vi d e n c e  of r el a ps e d  pri m ar y  dis e as e,  or s u bj e cts  w h o  h a v e  b e e n tr e at e d f or r el a ps e  aft er 
t h e  all o-H S C T  w as  p erf or m e d.  
•  U nr es ol v e d t o xi cit y  or  c o m pli c ati o ns ( ot h er t h a n  a c ut e  G V H D)  d u e t o  pr e vi o us  all o -H S C T.  
•  A n y  c orti c ost er oi d t h er a p y  f or i n di c ati o ns  ot h er t h a n  G V H D at  d os es  of  m et h yl pr e d nis ol o n e  or 
e q ui v al e nt  >  1  m g/ k g  p er  d a y  wit hi n  7  d a ys  of  e nr oll m e nt . 
•  S e v er e  or g a n   d ysf u n cti o n  u nr el at e d t o  u n d erl yi n g  G V H D, i n cl u di n g: 
-  C h ol est ati c  dis or d ers  or  u nr es ol v e d  v e n o- o c cl usi v e  dis e as e  of t h e li v er  (d efi n e d  as  p ersist e nt 
bilir u bi n  a b n or m aliti es  n ot  attri b ut a bl e t o  G V H D  a n d  o n g oi n g  or g a n  d ysf u n cti o n). 
-  Cli ni c all y si g nifi c a nt  or  u n c o ntr oll e d  c ar di a c  dis e as e , i n cl u di n g  u nst a bl e  a n gi n a,  a c ut e  m y o c ar di al 
i nf ar cti o n  wit hi n  6  m o nt hs fr o m  D a y  1  of st u d y  dr u g  a d mi nistr ati o n,  N e w  Y or k  H e art  Ass o ci ati o n 
Cl ass  III  or I V  c o n g esti v e  h e art f ail ur e, cir c ul at or y  c oll a ps e r e q uiri n g  v as o pr ess or  or  i n otr o pi c 
s u p p ort,  or  arr h yt h mi a  t h at r e q uir es t h er a p y. 
-  Cli ni c all y si g nifi c a nt r es pir at or y  dis e as e t h at r e q uir es  m e c h a ni c al  v e ntil ati o n s u p p ort  or  5 0 % 
o x y g e n. 
•  C urr e ntl y  br e ast f e e di n g.  
•  R e c ei v e d J a n us  ki n as e  (J A K) i n hi bit or t h er a p y aft er  all o -H S C T  f or  a n y i n di c ati o n.  Tr e at m e nt  wit h  a 
J A K i n hi bit or  b ef or e  all o -H S C T is  p er mitt e d.  
•  Tr e at m e nt  wit h  a n y  ot h er i n v esti g ati o n al  a g e nt,  d e vi c e,  or  pr o c e d ur e,  wit hi n  2 1  d a ys ( or  5  h alf- li v es, 
w hi c h e v er is  gr e at er)  of  e nr oll m e nt.   S u bj e cts  p arti ci p ati n g i n  a  G V H D  pr o p h yl a xis st u d y  or 
c o n diti o ni n g r e gi m e n s h o ul d  b e  dis c uss e d  wit h t h e s p o ns or' s  m e di c al  m o nit or b ef or e  e nr oll m e nt.  
•  A n y  c o n diti o n t h at  w o ul d, i n t h e i n v esti g at or's j u d g m e nt, i nt erf er e  wit h f ull  p arti ci p ati o n i n t h e st u d y, 
i n cl u di n g  a d mi nistr ati o n  of st u d y  dr u g  a nd  att e n di n g r e q uir e d st u d y  visits;  p os e  a si g nifi c a nt ris k t o t h e 
s u bj e ct;  or i nt erf er e  wit h i nt er pr et ati o n  of st u d y  d at a.  
•  K n o w n  all er gi es,  h y p ers e nsiti vit y,  or i nt ol er a n c e t o  a n y  of t h e st u d y  m e di c ati o ns,  e x ci pi e nts,  or si mil ar 
c o m p o u n ds.  
St u d y  D r u g,  D os a g e,  a n d  M o d e  of  A d mi nist r ati o n:  
S u bj e cts  will  b e gi n tr e at m e nt  at r u x oliti ni b  5  m g  BI D ; t h e d os e  m a y  b e  es c al at e d t o  1 0  m g  BI D  aft er  3  d a ys 
if  h e m at ol o gi c  p ar a m et ers  ar e st a bl e  a n d  n o tr e at m e nt-r el at e d t o xi cit y is  o bs er v e d.  S u bj e cts  m a y  h a v e  d os e 
r e d u cti o ns  d uri n g t h e  c o urs e  of tr e at m e nt  b as e d  o n s af et y  a n d l a b or at or y  ass ess m e nts.  T h e  d os e  of 
r u x oliti ni b  m a y  b e r e-es c al at e d if t o xi cit y  m a n a g e m e nt t hr es h ol ds  ar e  m et  or if  a s u bj e ct  e x p eri e n c es  a 
G V H D fl ar e  a n d  h as  a d e q u at e  h e m at ol o gi c  p ar a m et ers.   T h e  d os e  of r u x oliti ni b  m a y  n ot  e x c e e d  1 0  m g 
BI D.   T a p eri n g  of r u x oliti ni b is  p er mitt e d  pr o vi d e d t h e s u bj e ct  h as r e a c h e d t h e  D a y  1 8 0  visit,  a c hi e v e d  a 
C R  or  V G P R,  a n d  dis c o nti n u e d  c orti c ost er oi d t h er a p y f or  at l e ast  8  w e e ks.  
R ef e r e n c e  T h e r a p y,  D os a g e,  a n d  M o d e  of  A d mi nist r ati o n:  
S u bj e cts  will  b e gi n tr e at m e nt  at   pr e d nis o n e  2. 5  m g/ k g  p er  d a y  or all y ( P O)  or  m et h yl pr e d nis ol o n e 
2. 0  m g/ k g  p er  d a y i ntr a v e n o usl y  (I V).   S u bj e cts  w h o  pr e vi o usl y  b e g a n  c orti c ost er oi d t h er a p y  at  a  diff er e nt 
d os e  m a y r e m ai n  o n t h at  d os e if  c o nsi d er e d  a p pr o pri at e  b y t h e tr e ati n g  p h ysi ci a n.   C orti c ost er oi ds  s h o ul d 
b e t a p er e d  as  p er i nstit uti o n al  g ui d eli n es   at  a r at e t h at is  c o m m e ns ur at e  wit h r es ol uti o n  of  G V H D 
m a nif est ati o ns.  
If  G V H D fl ar es  d uri n g t h e t a p er  of c orti c ost er oi ds , t h e n t h e  d os e m a y   b e r e-es c al at e d  at t h e i n v esti g at or 's 
dis cr eti o n  a n d  will  n ot  b e  c o nsi d er e d tr e at m e nt f ail ur e,  as l o n g  as t h e  d os e  d o es  n ot  e x c e e d t h e  i niti al 
st arti n g  d os e.  If t h e  d os e r e q uir e d  e x c e e ds t his t hr es h ol d,  or if t h e fl ar e is  u nr es p o nsi v e t o i n cr e as e d 
c orti c ost er oi ds,  or if  m ulti pl e fl ar es  ar e  o bs er v e d, t h e n t h e s u bj e ct  will  b e  c o nsi d er e d t o  h a v e  e x p eri e n c e d 
tr e at m e nt f ail ur e. 

I n c yt e  C or p or ati o n 
P a g e  7  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
St u d y  S c h e d ul e/ K e y  St u d y  P r o c e d u r es:  
 
Ass ess m e nt  
F r e q u e n c y  
 
 
C o ns e nt,  m e di c al/ dis e as e  hist or y  
S cr e e ni n g  
 
 
G V H D  bi o ps y ( as  a p pr o pri at e)  
S cr e e ni n g  
 
 
Pr e g n a n c y t esti n g ( as  a p pr o pri at e)  
S cr e e ni n g  a n d  as i n di c at e d t hr o u g h  E O T  
 
 
El e ctr o c ar di o gr a m  
S cr e e ni n g  a n d  as i n di c at e d t hr o u g h  E O T  
 
 
P h ysi c al  e x a m/ vit als/ E C O G  
S cr e e ni n g ; w e e kl y t o  D a y  5 6, t h e n  e v er y  2 8  d a ys t hr o u g h 
E O T;  D a y  1 0 0 ; s af et y f oll o w-u p  
 
 
H e m at ol o g y/ c h e mistr y  p a n el  
S cr e e ni n g ; w e e kl y t o  D a y  5 6, t h e n  e v er y  2 8  d a ys t hr o u g h 
E O T;  D a y  1 0 0 ; s af et y f oll o w-u p  
 
 
A c ut e  G V H D st a gi n g  
S cr e e ni n g ; w e e kl y t o  D a y  5 6 , t h e n e v er y  2 8  d a ys t hr o u g h 
E O T;  D a ys  1 0 0,  1 8 0,  a n d  3 6 5 ; s af et y f oll o w-u p  
 
 
 
 
 
 
C hi m eris m  a ss e ss m e nt  
S cr e e ni n g,  as i n di c at e d  u p t o  E O T  
 
 
P T L D  ass ess m e nt  
As i n di c at e d  u p t o  E O T  
 
 
St er oi d  d os e  m o nit ori n g  
D a y  1  t hr o u g h  E O T 
 
 
C o n c o mit a nt/ pr o p h yl a cti c/s u p p orti v e  c ar e 
m e di c ati o ns  
S cr e e ni n g t hr o u g h  3 0  d a ys  aft er  E O T  
 
 
A E s 
S cr e e ni n g t hr o u g h  3 0  d a ys  aft er  E O T  
 
P T L D  =  p ost -tr e at m e nt l y m p h o pr olif er ati v e  dis or d er. 
A c ut e   G V H D  St a gi n g  a n d  G r a di n g,  M A GI C  G ui d eli n es 
St a g e  
S ki n  
( A cti v e  E r yt h e m a  O nl y) 
Li v e r  
( Bili r u bi n) 
U p p e r  GI  
L o w e r  GI  
( St o ol  O ut p ut/ D a y) 
0   
N o  a cti v e ( er yt h e m at o us) 
G V H D r as h  
<  2  m g/ d L   
N o  or i nt er mitt e nt 
n a us e a,  v o miti n g,  or 
a n or e xi a  
A d ult:   <  5 0 0 m L/ d a y  or 
<  3  e pis o d es/ d a y.  
C hil d:   <  1 0 m L/ k g  p er  d a y  or 
<  4  e pis o d es/ d a y.  
1   
M a c ul o p a p ul ar r as h  <  2 5 %  B S A   
2 -3  m g/ d L   
P ersist e nt  n a us e a, 
v o miti n g,  or  a n or e xi a  
A d ult:   5 0 0 -9 9 9  m L/ d a y  or  3 -4 
e pis o d es/ d a y.  
C hil d:   1 0 -1 9. 9  m L/ k g  p er  d a y 
or  4 -6  e pis o d es/ d a y.  
2   
M a c ul o p a p ul ar r as h  2 5 % -5 0 % 
B S A 
3. 1 -6  m g/ d L  
−  
A d ult:   1 0 0 0 -1 5 0 0  m L/ d a y  or  5 -
7  e pis o d es/ d a y.  
C hil d:   2 0 -3 0  m L/ k g  p er  d a y  or 
7 -1 0  e pis o d es/ d a y.  
3   
M a c ul o p a p ul ar r as h  >  5 0 %  B S A   
6. 1 -1 5  m g/ d L  
−  
A d ult:   >  1 5 0 0  m L/ d a y  or 
>  7  e pis o d es/ d a y.  
C hil d:   >  3 0  m L/ k g  p er  d a y  or 
>  1 0  e pis o d es/ d a y.  
4   
G e n er ali z e d  er yt hr o d er m a 
( > 5 0 %)  wit h  b ull a e  
>  1 5  m g/ d L  
−  
S e v er e  a b d o mi n al  p ai n  wit h  or 
wit h o ut il e us  or  gr ossl y  bl o o d y 
st o ol (r e g ar dl ess  of st o ol 
v ol u m e).  
B S A  =  b o d y s urf a c e  ar e a.  
O v er all  cli ni c al  gr a d e ( b as e d  o n  m ost s e v er e t ar g et  or g a n i n v ol v e m e nt):  
Gr a d e  0:   N o  St a g e  1 -4  of  a n y  or g a n.  
Gr a d e I:   St a g e  1 -2 s ki n  wit h o ut li v er,  u p p er  GI,  or l o w er  GI i n v ol v e m e nt.  
Gr a d e II:   St a g e  3 r as h  a n d/ or st a g e  1 li v er  a n d/ or st a g e  1  u p p er  GI  a n d/ or st a g e  1 l o w er  GI.  
Gr a d e III:   St a g e  2 -3 li v er  a n d/ or  St a g e  2 -3 l o w er  GI,  wit h  St a g e  0 -3 s ki n  a n d/ or  St a g e  0 -1  u p p er  GI.  
Gr a d e I V:   St a g e  4 s ki n, li v er,  or l o w er  GI i n v ol v e m e nt,  wit h  St a g e  0 -1  u p p er  GI.  
 
 

I n c yt e  C or p or ati o n 
P a g e  8  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
Esti m at e d  D u r ati o n  of  P a rti ci p ati o n:    S u bj e ct  p arti ci p ati o n is  e x p e ct e d t o  a v er a g e  1 2  m o nt hs,  w hi c h 
i n cl u d es t h e f oll o wi n g: 
•  A s cr e e ni n g  p eri o d l asti n g  u p t o  2 8  d a ys. 
•  A tr e at m e nt  p eri o d l asti n g  as l o n g  as t h e s u bj e ct  is  d eri vi n g  b e n efit ( esti m at e d  9  m o nt hs). 
•  A s af et y f oll o w- u p  p eri o d l asti n g  3 0 t o  3 5  d a ys  aft er tr e at m e nt  e n ds. 
•  A s ur vi v al f oll o w - u p  p eri o d l asti n g  u ntil  d e at h,  wit h dr a w al  of  c o ns e nt,  or t h e  e n d  of t h e st u d y,  w hi c h e v er 
o c c urs first . 
Esti m at e d  N u m b e r  of  S u bj e cts:    7 0 
Esti m at e d  N u m b e r  of  St u d y  Sit es:   4 0 
P ri n ci p al   C o o r di n ati n g I n v esti g at o r:  T B D  
St atisti c al  M et h o ds:  
A p pr o xi m at el y  7 0 s u bj e cts  ar e  pl a n n e d f or t h e fi n al  a n al ysis  of t h e  pri m ar y  e n d p oi nt.   A tr e at m e nt r e gi m e n 
f or st er oi d-r efr a ct or y  G V H D  d e m o nstr ati n g  a n  a bs ol ut e i m pr o v e m e nt  of  2 0 %  v ers us  hist ori c  d at a  w o ul d  b e 
c o nsi d er e d  cli ni c all y  m e a ni n gf ul.   Wit h t h e  as s u m e d tr u e r at e  of  6 0 %,  a s a m pl e si z e  of  7 0 s u bj e cts  w o ul d 
pr o vi d e  >  9 0 %  pr o b a bilit y t o  h a v e  a  9 5 %  c o nfi d e n c e i nt er v al  wit h l o w er li mit  of   ≥  4 0 %.  A n i nt eri m 
a n al ysis  will  b e  p erf or m e d f or f utilit y  o n c e  3 5 s u bj e cts  c o m pl et e t h e  D a y  2 8  visit; if t h e l o w er  b o u n d ar y is 
cr oss e d, t h e st u d y  will  b e t er mi n at e d. 

I n c yt e  C or p or ati o n 
P a g e  9  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
T A B L E  O F  C O N T E N T S  
S Y N O P SI S  ...................................................................................................................................... 3 
LI S T  O F  A B B R E VI A TI O N S ........................................................................................................ 1 5  
1.  
I N T R O D U C TI O N ...................................................................................................... 1 8 
1. 1.  
O v er vi e w  of  A c ut e  Gr aft -V ers us -H ost  Dis e as e  ......................................................... 1 8 
1. 1. 1.  
First -Li n e  Tr e at m e nt  of  A c ut e  G V H D  ....................................................................... 1 9 
1. 1. 2.  
Tr e at m e nt f or  St er oi d -R efr a ct or y  A c ut e  G V H D  ........................................................ 2 0 
1. 2.  
R u x oliti ni b  B a c k gr o u n d .............................................................................................. 2 1  
1. 2. 1.  
P h ar m a c ol o g y  ............................................................................................................. 2 1 
1. 2. 2.  
C li ni c al  St u di es ........................................................................................................... 2 2 
1. 3.  
St u d y  R ati o n al e  ........................................................................................................... 2 3 
1. 3. 1.  
A ni m al  St u di es i n  A c ut e  G V H D  M o d els  ................................................................... 2 3 
1. 3. 2.  
Cli ni c al  E x p eri e n c e  Wit h J A K I n hi bit ors f or t h e  Tr e at m e nt  of  A c ut e  G V H D  .......... 2 4 
1. 3. 3.  
R ati o n al e f or  C h os e n  E n d p oi nts ................................................................................. 2 5  
1. 4.  
P ot e nti al  Ris ks  a n d  B e n efits  of t h e  Tr e at m e nt  R e gi m e n  ............................................ 2 5 
2.  
S T U D Y  O BJ E C TI V E S  A N D  E N D P OI N T S  .............................................................. 2 6 
3.  
S U BJ E C T  E LI GI BI LI T Y  ........................................................................................... 2 7 
3. 1.  
S u bj e ct I n cl usi o n  Crit eri a  ........................................................................................... 2 7 
3. 2.  
S u bj e ct  E x cl usi o n  Crit eri a  .......................................................................................... 2 8 
4.  
I N V E S TI G A TI O N A L  P L A N ..................................................................................... 3 0 
4. 1.  
O v er all  St u d y  D esi g n  .................................................................................................. 3 0 
4. 2.  
M e as ur es  T a k e n t o  A v oi d  Bi as ................................................................................... 3 0  
4. 3.  
N u m b er  of  S u bj e cts .................................................................................................... 3 0  
4. 3. 1.  
Pl a n n e d  N u m b er  of  S u bj e cts ...................................................................................... 3 0  
4. 3. 2.  
R e pl a c e m e nt  of  S u bj e cts  ............................................................................................. 3 0 
4. 4.  
D ur ati o n  of  Tr e at m e nt  a n d  S u bj e ct  P arti ci p ati o n  ....................................................... 3 0 
4. 5.  
O v er all  St u d y  D ur ati o n  ............................................................................................... 3 1 
4. 6.  
St u d y  T er mi n ati o n  ...................................................................................................... 3 1 
5.  
T R E A T M E N T  ............................................................................................................ 3 1 
5. 1.  
Tr e at m e nt  Assi g n m e nt ................................................................................................ 3 1  
5. 1. 1.  
S u bj e ct  N u m b eri n g  a n d  Tr e at m e nt  Assi g n m e nt ......................................................... 3 1  
5. 1. 2.  
R a n d o mi z ati o n ............................................................................................................ 3 2  

I n c yt e  C or p or ati o n 
P a g e  1 0  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
5. 2.  
St u d y  Dr u gs  ................................................................................................................ 3 2 
5. 2. 1.  
R u x oliti ni b  .................................................................................................................. 3 2 
5. 2. 1. 1.  
D es cri pti o n  a n d  A d mi nistr ati o n  .................................................................................. 3 2 
5. 2. 1. 2.  
S u p pl y,  P a c k a gi n g,  a n d  L a b eli n g ............................................................................... 3 2  
5. 2. 1. 3.  
St or a g e  ........................................................................................................................ 3 2 
5. 2. 1. 4.  
I nstr u cti o n t o  S u bj e cts f or  H a n dli n g  R u x oliti ni b ........................................................ 3 3 
5. 2. 2.  
C orti c ost er oi ds ............................................................................................................ 3 3  
5. 2. 2. 1.  
Pr e d nis o n e ................................................................................................................... 3 3  
5. 2. 2. 2.  
M et h yl pr e d nis ol o n e .................................................................................................... 3 3  
5. 2. 2. 3.  
A d mi nistr ati o n  of  C orti c ost er oi ds  .............................................................................. 3 4 
5. 2. 2. 4.  
Pr o p h yl a cti c  a n d  S u p p orti v e  C ar e  M e di c ati o ns ......................................................... 3 5  
5. 3.  
Tr e at m e nt  C o m pli a n c e  ................................................................................................ 3 5 
5. 4.  
Tr e at m e nt I nt err u pti o ns  a n d  A dj ust m e nts .................................................................. 3 5  
5. 4. 1.  
D os e  M o difi c ati o ns ..................................................................................................... 3 5  
5. 4. 2.  
Crit eri a  a n d  Pr o c e d ur es f or  D os e I nt err u pti o ns  a n d  A dj ust m e nts  of 
R u x oliti ni b  .................................................................................................................. 3 5 
5. 4. 2. 1.  
D os e I nt err u pti o ns  a n d  R e d u cti o ns ............................................................................. 3 5  
5. 4. 2. 2.  
D os e  Es c al ati o n  of  R u x oliti ni b  ................................................................................... 3 8 
5. 4. 2. 3.  
T a p eri n g  of  R u x oliti ni b  .............................................................................................. 3 8 
5. 4. 3.  
Crit eri a  a n d  Pr o c e d ur es f or  D os e I nt err u pti o ns  or  A dj ust m e nts  of  
C orti c ost er oi ds ............................................................................................................ 3 9  
5. 4. 4.  
Crit eri a f or  P er m a n e nt  Dis c o nti n u ati o n  of  St u d y  Tr e at m e nt ...................................... 3 9  
5. 5.  
Wit h dr a w al  of  S u bj e cts  Fr o m  St u d y  Tr e at m e nt  ......................................................... 3 9 
5. 5. 1.  
Wit h dr a w al  Crit eri a  .................................................................................................... 3 9 
5. 5. 2.  
Wit h dr a w al  Pr o c e d ur es  ............................................................................................... 4 0 
5. 5. 3.  
St u d y  C o m pl eti o n  ....................................................................................................... 4 0 
5. 6.  
C o n c o mit a nt  M e di c ati o ns ........................................................................................... 4 1  
5. 6. 1.  
P er mitt e d  M e di c ati o ns  ................................................................................................ 4 1 
5. 6. 2.  
R estri ct e d  M e di c ati o ns  ............................................................................................... 4 1 
5. 6. 3.  
Pr o hi bit e d  M e di c ati o ns ............................................................................................... 4 1  
6.  
S T U D Y  A S S E S S M E N T S  .......................................................................................... 4 1 
6. 1.  
S cr e e ni n g  .................................................................................................................... 4 4 
6. 2.  
Tr e at m e nt  .................................................................................................................... 4 5 

I n c yt e  C or p or ati o n 
P a g e  1 1  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
6. 3.  
E n d  of  Tr e at m e nt ........................................................................................................ 4 5  
6. 4.  
F oll o w- U p  ................................................................................................................... 4 5 
6. 4. 1.  
S af et y  F oll o w- U p  ........................................................................................................ 4 5 
6. 4. 2.  
G V H D  Ass ess m e nt  F oll o w -U p  .................................................................................. 4 5 
6. 4. 3.  
S ur vi v al  F oll o w- U p  .................................................................................................... 4 5 
6. 5.  
U ns c h e d ul e d  Visits ..................................................................................................... 4 6  
7.  
C O N D U C T  O F  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  ........................... 4 6 
7. 1.  
A d mi nistr ati o n  of I nf or m e d  C o ns e nt  F or m ................................................................ 4 6  
7. 2.  
I nt er a cti v e  R es p o ns e  T e c h n ol o g y  Pr o c e d ur e .............................................................. 4 6 
7. 3.  
D e m o gr a p h y  a n d  M e di c al  Hist or y .............................................................................. 4 6  
7. 3. 1.  
D e m o gr a p hi cs  a n d  G e n er al  M e di c al  Hist or y  ............................................................. 4 6 
7. 3. 2.  
Dis e as e  C h ar a ct eristi cs  a n d  Tr e at m e nt  Hist or y  .......................................................... 4 6 
7. 4.  
Pri or  a n d  C o n c o mit a nt  M e di c ati o ns ........................................................................... 4 6  
7. 5.  
S af et y  Ass ess m e nts  ..................................................................................................... 4 7 
7. 5. 1.  
A d v ers e  E v e nts  ........................................................................................................... 4 7 
7. 5. 2.  
P h ysi c al  E x a mi n ati o n  ................................................................................................. 4 7 
7. 5. 3.  
Vit al  Si g ns  .................................................................................................................. 4 7 
7. 5. 4.  
E as t er n  C o o p er ati v e  O n c ol o g y  Gr o u p  P erf or m a n c e  St at us ........................................ 4 7 
7. 5. 5.  
T w el v e -L e a d  El e ctr o c ar di o gr a ms  ............................................................................... 4 8 
7. 5. 6.  
L a b or at or y  Ass ess m e nts  ............................................................................................. 4 8 
7. 5. 6. 1.  
C h e mistr y  .................................................................................................................... 4 8 
7. 5. 6. 2.  
H e m at ol o g y  ................................................................................................................. 4 8 
7. 5. 6. 3.  
Pr e g n a n c y  T esti n g  ...................................................................................................... 4 8 
7. 5. 6. 4.  
H e p atitis  S cr e e ni n g  ..................................................................................................... 4 9 
7. 6.  
Gr aft -V ers us -H ost  Dis e as e  Ass ess m e nts  .................................................................... 4 9 
7. 6. 1.  
Gr aft -V ers us -H ost  Dis e as e  St a gi n g  a n d  Gr a di n g  ....................................................... 4 9 
 
5 0  
7. 6. 3.  
D o n or  C hi m eris m ....................................................................................................... 5 0  
7. 6. 4.  
P ost- Tr a ns pl a nt  L y m p h o pr olif er ati v e  Dis or d er  Ass ess m e nt ...................................... 5 1  
7. 7.  
P h ar m a c o ki n eti c  Ass ess m e nts  .................................................................................... 5 1 
7. 7. 1.  
Bl o o d  S a m pl e  C oll e cti o n  ............................................................................................ 5 1 
7. 7. 2.  
Bi o a n al yti c al  M et h o d ol o g y  a n d  A n al ysis ................................................................... 5 1  
 
5 1  

I n c yt e  C or p or ati o n 
P a g e  1 2  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
7. 9.  
Ot h er  St u d y  Pr o c e d ur es .............................................................................................. 5 2  
7. 9. 1.  
Distri b uti o n  of  S u bj e ct  R e mi n d er  C ar ds ..................................................................... 5 2  
8.  
S A F E T Y  M O NI T O RI N G  A N D  R E P O R TI N G  ......................................................... 5 2 
8. 1.  
A d v ers e  E v e nts  ........................................................................................................... 5 2 
8. 1. 1.  
D efi niti o ns  .................................................................................................................. 5 2 
8. 1. 2.  
R e p orti n g .................................................................................................................... 5 2  
8. 2.  
L a b or at or y  T est  A b n or m aliti es  ................................................................................... 5 4 
8. 3.  
S eri o us  A d v ers e  E v e nts .............................................................................................. 5 4  
8. 3. 1.  
D efi niti o ns  .................................................................................................................. 5 4 
8. 3. 2.  
R e p orti n g .................................................................................................................... 5 5  
8. 4.  
E m er g e n c y  U n bli n di n g  of  Tr e at m e nt  Assi g n m e nt ..................................................... 5 6  
8. 5.  
Pr e g n a n c y  ................................................................................................................... 5 6 
8. 6.  
W ar ni n gs  a n d  Pr e c a uti o ns  .......................................................................................... 5 7 
8. 7.  
D at a  M o nit ori n g  C o m mitt e e  ....................................................................................... 5 7 
8. 8.  
Pr o d u ct  C o m pl ai nts .................................................................................................... 5 7  
9.  
S T A TI S TI C S  .............................................................................................................. 5 8 
9. 1.  
St u d y  P o p ul ati o ns ....................................................................................................... 5 8  
9. 2.  
S el e cti o n  of  S a m pl e  Si z e  ............................................................................................ 5 8 
9. 3.  
L e v el  of  Si g nifi c a n c e  .................................................................................................. 5 8 
9. 4.  
St atisti c al  A n al ys es  ..................................................................................................... 5 9 
9. 4. 1.  
Pri m ar y  A n al ys es  ........................................................................................................ 5 9 
9. 4. 2.  
S e c o n d ar y  A n al ys es  .................................................................................................... 5 9 
 
6 0  
9. 4. 4.  
S af et y  A n al ys es  .......................................................................................................... 6 0 
9. 4. 4. 1.  
A d v ers e  E v e nts  ........................................................................................................... 6 0 
9. 4. 4. 2.  
Cli ni c al  L a b or at or y  T ests  ........................................................................................... 6 0 
9. 4. 4. 3.  
Vit al  Si g ns  .................................................................................................................. 6 1 
9. 4. 4. 4.  
El e ctr o c ar di o gr a ms  ..................................................................................................... 6 1 
9. 4. 5.  
P h ar m a c o ki n eti c  A n al ysis  .......................................................................................... 6 1 
 
6 2  
9. 5.  
A n al ys es f or t h e  D at a  M o nit ori n g  C o m mitt e e  ............................................................ 6 2 
9. 6.  
I nt eri m  A n al ysis .......................................................................................................... 6 2 

I n c yt e  C or p or ati o n 
P a g e  1 3  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
1 0.  
E T HI C A L  C O N SI D E R A TI O N S  A N D  A D MI NI S T R A TI V E 
P R O C E D U R E S  .......................................................................................................... 6 3 
1 0. 1.  
I n v esti g at or  R es p o nsi biliti es ....................................................................................... 6 3 
1 0. 2.  
A c c o u nt a bilit y,  H a n dli n g,  a n d  Dis p os al  of  St u d y  Dr u g ............................................. 6 4  
1 0. 3.  
D at a  M a n a g e m e nt  ....................................................................................................... 6 5 
1 0. 4.  
D at a  Pri v a c y  a n d  C o nfi d e nti alit y  of  St u d y  R e c or ds ................................................... 6 5  
1 0. 5.  
Fi n a n ci al  Dis cl os ur e  ................................................................................................... 6 6 
1 0. 6.  
P u bli c ati o n  P oli c y  ....................................................................................................... 6 6 
1 1.  
R E F E R E N C E S  ........................................................................................................... 6 7 
A P P E N DI X  A.  I N F O R M A TI O N  R E G A R DI N G  E F F E C TI V E N E S S  O F 
C O N T R A C E P TI V E  M E T H O D S ............................................................................... 7 0  
A P P E N DI X  B.  M A GI C  G UI D E LI N E S  F O R  S T A GI N G  A N D  G R A DI N G  A C U T E 
G V H D  ......................................................................................................................... 7 1 
A P P E N DI X  C.  C Y T O C H R O M E  P 4 5 0  A N D  P- G L Y C O P R O T EI N I N HI BI T O R S 
A N D  C Y T O C H R O M E  P 4 5 0 I N D U C E R S  ................................................................ 7 3 
 

I n c yt e  C or p or ati o n 
P a g e  1 4  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
LI S T  O F  T A B L E S  
T a bl e   1: 
R e c o m m e n d e d  C orti c ost er oi d  A d mi nistr ati o n  T a bl e,  D a ys  1  T hr o u g h  2 8 ................ 3 4  
T a bl e   2: 
G ui d eli n es f or I nt err u pti o n  a n d  R est arti n g  of  R u x oliti ni b ......................................... 3 6  
T a bl e   3: 
D os e  R e d u cti o n  L e v els f or  R u x oliti ni b ...................................................................... 3 8  
T a bl e   4: 
D os e  Es c al ati o n  L e v els f or  R u x oliti ni b ...................................................................... 3 8  
T a bl e   5: 
S c h e d ul e  of  Ass ess m e nts  ............................................................................................ 4 2 
T a bl e   6: 
L a b or at or y  Ass ess m e nts  ............................................................................................. 4 3 
T a bl e   7: 
Cli ni c al  L a b or at or y  A n al yt es  ...................................................................................... 4 4 
T a bl e   8: 
E C O G  P erf or m a n c e  St at us  Gr a d es  ............................................................................. 4 7 
T a bl e   9: 
P h ar m a c o ki n eti c  S a m pl e  C oll e cti o n  Ti m e  a n d  Wi n d o ws  .......................................... 5 1 
T a bl e   1 0: Crit eri a f or  Cli ni c all y  N ot a bl e  Vit al  Si g n  A b n or m aliti es  ........................................... 6 1 
T a bl e   1 1: Crit eri a f or  Cli ni c all y  N ot a bl e  El e ctr o c ar di o gr a m  A b n or m aliti es  ............................. 6 1 
 
LI S T  O F  FI G U R E S  
Fi g ur e   1: 
S u m m ar y  of  St u di es  E v al u ati n g  A g e nts f or I niti al  T h er a p y  of  A c ut e  G V H D a .......... 2 0 
Fi g ur e   2: 
S u m m ar y  of  St u di es  E v al u ati n g  A g e nts f or  S e c o n d- Li n e  T h er a p y  of  A c ut e 
G V H D a ........................................................................................................................ 2 1 
Fi g ur e   3: 
Eff e ct  of  R u x oliti ni b  o n  S ur vi v al i n  Mi c e  Aft er  All o -H S C T  ..................................... 2 3 
Fi g ur e   4: 
R u x oliti ni b  M ai nt ai ns  a  B e n efi ci al  G V T  Eff e ct  as  D et er mi n e d  b y 
Bi ol u mi n es c e n c e I m a gi n g i n t h e  A 2 0  L e u k e mi a  M o d el ............................................ 2 4  
 

I n c yt e  C or p or ati o n 
P a g e  1 5  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
LI S T  O F  A B B R E VI A TI O N S  
T h e f oll o wi n g  a b br e vi ati o ns  a n d s p e ci al t er ms  ar e  us e d i n t his  cli ni c al  st u d y  Pr ot o c ol. 
A b b r e vi ati o n   
D efi niti o n  
A E  
a d v ers e  e v e nt  
a G V H D  
a c ut e  gr aft -v ers us -h ost  dis e as e  
AI H A  
a ut oi m m u n e  h e m ol yti c  a n e mi a  
all o -H S C T   
all o g e n ei c  h e m at o p oi eti c st e m  c ell tr a ns pl a nt ati o n  
A L P  
al k ali n e  p h os p h at as e 
A L T  
al a ni n e  a mi n otr a nsf er as e  
A N C  
a bs ol ut e  n e utr o p hil  c o u nt 
A S T  
as p art at e  a mi n otr a nsf er as e  
A T G  
a ntit h y m o c yt e  gl o b uli n 
BI D  
t wi c e  d ail y 
B M  
b o n e  m arr o w 
B O O P  
br o n c hi olitis  o blit er a ns- or g a ni zi n g  p n e u m o ni a 
B S A  
b o d y s urf a c e  ar e a 
CI  
c o nfi d e n c e i nt er v al  
CI B M T R   
C e nt er  f or I nt er n ati o n al  Bl o o d  a n d  M arr o w  Tr a ns pl a nt  R es e ar c h 
C F R  
C o d e  of  F e d er al  R e g ul ati o ns  
C M V  
c yt o m e g al o vir us  
C R  
c o m pl et e r es p o ns e  
C T C A E  
C o m m o n  T er mi n ol o g y  Crit eri a f or  A d v ers e  E v e nts 
C T F G  
Cli ni c al  Tri al  F a cilit ati o n  Gr o u p  
C Y P  
c yt o c hr o m e  P 4 5 0 
D N A  
d e o x yri b o n u cl ei c  a ci d 
D O R  
d ur ati o n  of r es p o ns e  
E C O G  
E ast er n  C o o p er ati v e  O n c ol o g y  Gr o u p  
E C G  
el e ctr o c ar di o gr a m  
E C P  
e xtr a c or p or e al  p h ot o p h er esis 
e C R F  
el e ctr o ni c  c as e r e p ort f or m  
E O T  
e n d  of tr e at m e nt  
F D A  
F o o d  a n d  Dr u g  A d mi nistr ati o n 
F F S  
f ail ur e-fr e e s ur vi v al 
G C P  
G o o d  Cli ni c al  Pr a cti c e  
G F P  
gr e e n fl u or es c e nt  pr ot ei n  
GI  
g astr oi nt esti n al 

I n c yt e  C or p or ati o n 
P a g e  1 6  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
A b b r e vi ati o n   
D efi niti o n  
G V H  
g r aft  v ers us h ost  
G V H D  
g r aft-v ers us - h ost  dis e as e 
G V T 
g r aft  v ers us t u m or 
H B V  
h e p atitis  B  v ir us 
H C V  
h e p atitis  C  v ir us 
HI P A A  
H e alt h I ns ur a n c e  P ort a bilit y  a n d  A c c o u nt a bilit y  A ct  of  1 9 9 6 
I B 
I n v esti g at or's  Br o c h ur e 
I C5 0 
h alf- m a xi m al i n hi bit or y  c o n c e ntr ati o n 
I C F 
i nf or m e d  c o ns e nt f or m  
I C H 
I nt er n ati o n al  C o nf er e n c e  o n  H ar m o nis ati o n 
I E C 
i n d e p e n d e nt  et hi cs  c o m mitt e e 
I F N- γ 
i nt erf er o n- γ 
I F N-γ R  
i nt erf er o n-γ  r e c e pt or 
I L 
i nt erl e u ki n 
I L- 2 R 
i nt erl e u ki n  2 r e c e pt or 
I N 
I n v esti g at or  N otifi c ati o n 
I R B 
i nstit uti o n al r e vi e w  b o ar d 
I T P 
i di o p at hi c t hr o m b o c yt o p e ni c  p ur p ur a 
I U D 
i ntr a ut eri n e  d e vi c es 
I U S 
i ntr a ut eri n e  h or m o n e-r el e asi n g s yst e m 
I V 
i ntr a v e n o usl y 
I V R S 
i nt er a cti v e  v oi c e r es p o ns e s yst e m 
J A K 
J a n us k i n as e 
M A GI C  
M o u nt  Si n ai  A c ut e  G V H D I nt er n ati o n al  C o ns orti u m  
M e d D R A   
M e di c al  Di cti o n ar y f or  R e g ul at or y  A cti viti es  
M H C  
m aj or  hist o c o m p ati bilit y 
M M F  
m y c o p h e n ol at e  m of etil 
M P N  
m y el o pr olif er ati v e  n e o pl as m 
N CI  
N ati o n al  C a n c er I nstit ut e  
NI H  
N ati o n al I nstit ut e s of  H e alt h  
N K  
n at ur al  kill er  
N R  
n o r es p o ns e 
N R M  
n o nr el a ps e  m ort alit y 
O R R  
o v er all r es p o ns e r at e  
O S  
o v er all s ur vi v al  
P B S  
p h os p h at e  b uff er e d s ali n e  

I n c yt e  C or p or ati o n 
P a g e  1 7  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
A b b r e vi ati o n   
D efi niti o n  
P F T  
p ul m o n ar y f u n cti o n t est  
P K  
p h ar m a c o ki n eti c 
P O  
or all y  
P R  
p arti al r es p o ns e  
P T L D  
p ost- tr a ns pl a nt l y m p h o pr olif er ati v e  dis or d er 
Q D  
o n c e  d ail y  
R A  
r h e u m at oi d  art hritis 
R etr o  
r etr os p e cti v e 
R N A  
ri b o n u cl ei c  a ci d 
S A E  
s eri o us  a d v ers e  e v e nt 
S T A T  
si g n al tr a ns d u c ers  a n d  a cti v at ors  of tr a ns cri pti o n  
S U S A R  
s us p e ct e d  u n e x p e ct e d s eri o us  a d v ers e r e a cti o n  
T E A E  
tr e at m e nt-e m er g e nt  a d v ers e  e v e nt  
T P O  
t hr o m b o p oi eti n 
Tr e g  
r e g ul at or y  T  c ell 
U L N  
u p p er li mit  of  n or m al 
V G P R  
v er y  g o o d  p arti al r es p o ns e  

I n c yt e  C or p or ati o n 
P a g e  1 8  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
1.   
I N T R O D U C TI O N 
1. 1.   
O v e r vi e w  of  A c ut e  G r aft- V e rs us - Host  D is e as e 
All o g e n ei c  h e m at o p oi eti c st e m  c ell tr a ns pl a nt ati o n ( all o -H S C T) is  a n  eff e cti v e i m m u n ot h er a p y 
f or  h u m a n  c a n c er (A p p el b a u m  2 0 0 7 ).   M or e t h a n  2 0, 0 0 0  all o-H S C Ts  ar e  p erf or m e d  e a c h  y e ar 
w orl d wi d e,  pri m aril y f or t h e tr e at m e nt  of  h e m at ol o gi c  m ali g n a n ci es  (P a vl eti c  a n d  F o wl er  2 0 1 2 ).  
A c ut e  gr aft - v ers us-h ost  dis e as e ( G V H D ) a n d  c hr o ni c  G V H D r e m ai n  m aj or  c o ntri b ut or s t o 
tr a ns pl a nt ati o n-r el at e d  d e at hs  a n d t h e  m ost si g nifi c a nt  b arri er t o s u c c essf ul all o - H SC T.  
Gr aft -v ers us - h ost  dis e as e o c c urs  w h e n i m m u n e  c ells tr a ns pl a nt e d fr o m  a  n o ni d e nti c al  d o n or (t h e 
gr aft) r e c o g ni z e t h e tr a ns pl a nt r e ci pi e nt (t h e  h ost)  as f or ei g n, t h er e b y i niti ati n g  a n i m m u n e 
r e a cti o n t h at  c a us es  dis e as e i n t h e tr a ns pl a nt r e ci pi e nt.  D es pit e  pr o p h yl a cti c tr e at m e nts  wit h 
i m m u n os u p pr essi v e  a g e nts,  a p pr o xi m at el y  5 0 %  of tr a ns pl a nt ati o n r e ci pi e nts  d e v el o p  G V H D.  
M ost  gr aft - v ers us- h ost ( G V H) r e a cti o ns  ar e  u n d esir a bl e  a n d  aff e ct  m ulti pl e  or g a ns;  h o w e v er, 
G V H r e a cti o ns  a g ai nst  h e m at o p oi eti c tiss u e t ar g ets  ar e  d esir a bl e  a n d  criti c al f or t h e  c ur e  of 
h e m at ol o gi c  m ali g n a n ci es (i e , t h e  gr aft- v ers us-t u m or [ G VT]  eff e ct )  a n d f or  d o n or 
i m m u n e-h e m at o p oi eti c s yst e m  e n gr aft m e nt .  T h es e  dis p ar at e  eff e cts  of  G V H  r e a cti o ns  ar e 
diffi c ult t o s e p ar at e , a n d  a n y str at e gi es  dir e ct e d  a g ai nst  G V H D  m a y  a d v ers el y  aff e ct s ur vi v al  b y 
i n cr e asi n g  m ali g n a n c y r el a ps e, gr aft r ej e cti o n,  a n d t h e fr e q u e n c y  a n d s e v erit y  of i nf e cti o ns  
(P a vl eti c  a n d  F o wl er  2 0 1 2 ). 
T h er e  ar e f e w t h er a p e uti c  st u di es f or  a c ut e  G V H D,  a n d  c urr e ntl y  n o  a g e nts  ar e  a p pr o v e d  b y t h e 
F D A f or  eit h er  pr e v e nti o n  or tr e at m e nt  of  a c ut e  G V H D  (M arti n  et  al  2 0 0 9 ).  I n r es p o ns e t o t his 
li mit ati o n,  a n  NI H- F D A  p u bli c  w or ks h o p  w as  c o n v e n e d i n  2 0 0 9 t o f a cilit at e cli ni c al 
d e v el o p m e nt  pr o gr a ms f or  pr o d u cts t o  pr e v e nt  or tr e at  a c ut e  G V H D.   A  m aj or t o pi c  of t his 
w or ks h o p  w as  d efi ni n g t h e  o pti m al  e n d p oi nt  a n d ti mi n g f or  e v al u ati n g  n e w t h er a p e uti cs f or 
a c ut e  G V H D .   Alt h o u g h  u ni v ers all y  a c c e pt e d  as  a s uit a bl e  en d p oi nt  f or r e g ul at or y  a p pr o v al i n 
o n c ol o g y  cli ni c al  st u di es, s ur vi v al is  n ot  al w a ys a  pr a cti c al  e n d p oi nt  f or d e v el o pi n g  G V H D 
t h er a p e uti cs,  o wi n g t o t h e  m ulti pl e  c o ntri b uti n g  c a us es  of  d e at h i n t h e  all o g e n ei c tr a ns pl a nt ati o n 
s etti n g (M arti n   2 0 0 8). 
Tr e at m e nt  o pti o ns f or  G V H D, i n cl u di n g  m o d ul ati o n  of  d o n or- all or e a cti v e  eff e ct or  T -c ells , 
r e m ai n  a  m aj or f o c us  of  c urr e nt t h er a pi es f or  a c ut e  G V H D.   Ot h er  c ell  p o p ul ati o ns, i n cl u di n g 
r e g ul at or y  T  c ells ( Tr e gs),  d e n driti c  c ells,  n at ur al  kill er ( N K) T  c ells,  a n d  B  c ells ,  or  ot h er 
m e c h a nis ms , s u c h  as  m o d ul ati o n  of tiss u e  or  v as c ul ar  e n d ot h eli u m  d a m a g e si g n als, m a y  als o 
r e pr es e nt t ar g ets f or  G V H D t h er a p y.   At  di a g n osis, t h e  e xt ent  of i n di vi d u al  or g a n i n v ol v e m e nt 
a n d  o v er all  gr a d e  of  a c ut e  G V H D s h o ul d  b e  d o c u m e nt e d, t a ki n g i nt o  a c c o u nt  all  or g a n 
i n v ol v e m e nt,  as t his  h as  pr o g n osti c si g nifi c a n c e.   A c ut e  G V H D  di a g n osis s h o ul d  b e  c o nfir m e d 
b y  bi o ps y  of  a n  aff e ct e d  or g a n if  p ossi bl e; i n  a d diti o n,  ot h er  n o n- G V H D  c o m pli c ati o ns i n v ol vi n g 
t h e s ki n, li v er,  a n d g astr oi nt esti n al  (GI ) tr a ct s h o ul d  b e r ul e d  o ut.   Alt h o u g h  di a g n osti c  bi o psi es 
ar e  hi g hl y s p e cifi c if  c urr e nt  hist o p at h ol o g y  crit eri a  ar e  us e d, t h e s e nsiti vit y  of t h es e  bi o psi es is 
o nl y  a p pr o xi m at el y  6 0 %; t h er ef or e, t h e  ulti m at e  a c ut e  G V H D  di a g n osis  a n d  d e cisi o n t o tr e at 
s yst e mi c all y is  b as e d  o n  c ar ef ul i nt e gr ati o n  of  all  a v ail a bl e  cli ni c al i nf or m ati o n ( W eis d orf  et  al 
2 0 0 3 ). 

I n c yt e  C or p or ati o n 
P a g e  1 9  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
T h e  cl assi c t ar g et  or g a ns f or  a c ut e  G V H D  ar e t h e s ki n (s e v erit y r a n gi n g fr o m  m a c ul o p a p ul ar 
r as h t o  er yt hr o d er m a  a n d  b ull a e f or m ati o n), t h e GI  tr a ct (r es ulti n g i n  n a us e a,  v o miti n g, 
a b d o mi n al  cr a m ps,  or  di arr h e a),  a n d t h e li v er (r es ulti n g i n  h y p er bilir u bi n e mi a, j a u n di c e,  or 
el e v at e d tr a ns a mi n as es).   T h e  h e m at o p oi eti c s yst e m  c a n  als o  b e t ar g et e d, r es ulti n g i n  c o m pl et e 
d o n or l y m p h o h e m at o p oi eti c  c hi m eris m  a n d t h e  G V T  r es p o ns e  a g ai nst  h e m at ol o gi c 
m ali g n a n ci es.    E n d ot h eli u m, l u n gs,  a n d  ot h er  or g a ns  c a n  als o  b e t ar g et e d,  alt h o u g h s ki n,  g ut, a n d 
li v er i n v ol v e m e nt  ar e t h e  o nl y  or g a ns s c or e d i n t h e  c urr e nt  gr a di n g s yst e m. 
T h e s e v erit y  of  a c ut e  G V H D is  gr a d e d  a c c or di n g t o t h e  d e gr e e  of i n v ol v e m e nt  of t h e s ki n, li v er, 
a n d  GI tr a ct.   T w o  of t h e  m or e  c o m m o nl y  us e d  gr a di n g s yst e ms  ar e t h e  Gl u c ks b er g s yst e m 
(I-I V)  a n d t h e I nt er n ati o n al  B o n e  M arr o w  Tr a ns pl a nt  R es e ar c h s yst e m ( A- D; Gl u c ks b er g  et  al 
1 9 7 4 , R o wli n gs  et  al  1 9 9 7 ).   T h es e  gr a di n g s yst e ms  h a v e  e v ol v e d  o v er ti m e,  w hi c h i n cl u d e d 
r efi n e m e nt  of t h e  Gl u c ks b er g s yst e m  b y  a n NI H   w or ki n g  gr o u p t o i n cl u d e  p ersist e nt  n a us e a  wit h 
hist ol o gi c  e vi d e n c e  of  G V H D  as  St a g e  1  u p p er  GI  a c ut e  G V H D ( Pr z e pi or k a  et  al  1 9 9 5 ).  T h e  
NI H  crit eri a  h a v e  b e e n f urt h er r efi n e d   b y t h e  M o u nt  Si n ai  A c ut e  G V H D  C o ns orti u m ( M A GI C) 
t o st a n d ar di z e t h e c oll e cti o n  of  c o m pl e x  cli ni c al  d at a fr o m  m ulti pl e  or g a n s yst e ms i n  m ulti c e nt er 
st u di es (H arris  et  al  2 0 1 6 ). 
T w o s u b c at e g ori es  h a v e  b e e n r e c o g ni z e d  wit hi n t h e  br o a d er  c at e g or y  of  a c ut e  G V H D :   1) cl assi c 
a c ut e  G V H D  (e g , m a c ul o p a p ul ar   er yt h e m at o us r as h, GI  s y m pt o ms,  c h ol est ati c  h e p atitis), 
o c c urri n g  wit hi n  1 0 0  d a ys  aft er tr a ns pl a nt ati o n  or  d o n or l e u k o c yt e i nf usi o n  a n d  2)  p ersist e nt, 
r e c urr e nt,  or l at e  a c ut e  G V H D,  o c c urri n g  b e y o n d  1 0 0  d a ys  aft er tr a ns pl a nt ati o n  or  d o n or 
l e u k o c yt e i nf usi o n.   B ot h  a c ut e  G V H D s u b e ntiti es  o c c ur  wit h o ut t h e  pr es e n c e  of  di a g n osti c  or 
disti n cti v e  c hr o ni c  G V H D  m a nif est ati o ns  (P a vl eti c  2 0 1 2 ).  T h e  c urr e nt  NI H  c o ns e ns us  crit eri a 
f or  ass ess m e nt  of  c hr o ni c  G V H D s u g g est t h at  cli ni c al  m a nif est ati o ns r at h er t h a n ti m e  aft er 
tr a ns pl a nt ati o n s h o ul d  d et er mi n e  w h et h er t h e  cli ni c al  G V H D s y n dr o m e is  c o nsi d er e d  a c ut e  or 
c hr o ni c ( J a g asi a et  al  2 0 1 5 ).   S o m e si g ns  a n d s y m pt o ms  ar e  c o m m o n t o  b ot h a c ut e  G V H D  a n d 
c hr o ni c  G V H D ( e g,  er yt h e m a,  m a c ul o p a p ul ar r as h,  n a us e a,  v o miti n g  or  di arr h e a,  a n d  el e v at e d 
li v er f u n cti o n t ests)  a n d t h us  ot h er  c h ar a ct eristi cs  m ust  b e  us e d t o  disti n g uis h  b et w e e n t h e 
2  c at e g ori es.  
1. 1. 1.   
Fi rst - Li n e  T r e at m e nt  of  A c ut e G V H D  
C orti c o st er oi ds  ar e us e d  as  c o n v e nti o n al first- li n e s yst e mi c t h er a p y, a n d r es p o ns e r at es  b et w e e n 
5 0 %  a n d  6 0 %  h a v e  b e e n  pr e vi o usl y r e p ort e d ( S ali b a  et  al  2 0 1 2,  M a c Mill a n  et  al  2 0 1 0, 
L e vi n e  et   al  2 0 1 0).  Tr e at m e nt  wit h  m et h yl pr e d nis o n e  at  2  m g / k g  p er  d a y ( or  a n  or al  pr e d nis o n e 
e q ui v al e nt)  h as  b e e n l o n g  a c c e pt e d  as st a n d ar d first -li n e t h er a p y f or  a c ut e  G V H D i n t h e  U nit e d 
St at es ( M arti n  et  al  2 0 1 2 )  a n d  E ur o p e (R u ut u  et  al  2 0 1 4).   I n st a n d ar d -ris k c as es  of  u p p er  GI 
G V H D,  r e d u c e d d os es  of  s yst e mi c  c orti c ost er oi ds ( e g,   1  m g/ k g  p er  d a y)  a n d t o pi c al st er oi ds 
h a v e  b e e n s h o w n t o  b e  e q u all y  eff e cti v e ( Mi el c ar e k  et  al  2 0 0 9 ).  N eit h er r es p o ns e r at e  n or 
o v er all  s ur vi v al (O S ) a d v a nt a g es  w er e  o bs er v e d i n  a c ut e  G V H D  p ati e nts tr e at e d  wit h 
c orti c ost er oi ds  at  d os es  hi g h er t h a n  2. 5  m g/ k g  p er  d a y  (V a n  Li nt   et  al  1 9 9 8). 
B e c a us e  o nl y  a p pr o xi m at el y  5 0 %  of  a c ut e  G V H D  p ati e nts r es p o n d t o s yst e mi c st er oi ds  a n d 
m a n y  of t h es e r es p o ns es  ar e  n ot  d ur a bl e,  att e m pts  h a v e  b e e n  m a d e t o  e v al u at e  ot h er  a g e nts i n 
a d diti o n t o  pr e d nis o n e  c o m p ar e d  wit h  pr e d nis o n e  al o n e f or i niti al t h er a p y, s u c h  as  a nti b o di es 
a g ai nst  i nt erl e u ki n  2 r e c e pt or (I L- 2 R),  hi g h- d os e st er oi ds,  h ors e  a ntit h y m o c yt e  gl o b uli n,  a nti –
t u m or  n e cr osis f a ct or  dr u gs,  m y c o p h e n ol at e  m of etil,  p e nt ost ati n,  a n d sir oli m us (Fi g ur e   1; 

I n c yt e  C or p or ati o n 
P a g e  2 0  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
C a h n  et  al  1 9 9 5 , L e e  et  al  2 0 0 4 , Cr a g g  et  al  2 0 0 0 , C o uri el  et  al  2 0 0 9 , L e vi n e  et  al  2 0 0 8 , 
Al o usi  et   al  2 0 0 9, Pi d al a  et  al  2 0 0 9 ).  I n  m ost  c as es, t h e s e c o n d  a g e nt  yi el d e d  m o d est b e n efit; 
h o w e v er,  a st u d y  of  d a cli z u m a b f o u n d t h e  a d diti o n al i nt er v e nti o n t o  b e  d etri m e nt al ( Fi g ur e   1). 
Fi g u r e   1:   
S u m m a r y  of  St u di es  E v al u ati n g  A g e nts f o r I niti al T h e r a p y  of  A c ut e  G V H D a 
 
S o ur c e:  M arti n  et  al  2 0 1 2 . 
1. 1. 2.   
T r e at m e nt f o r  St e r oi d -R ef r a ct o r y  A c ut e  G V H D  
If  a c ut e  G V H D  pr o gr ess es  wit hi n  3  d a ys  or  d o es  n ot i m pr o v e  aft er  5 t o  7  d a ys  of i niti al 
tr e at m e nt, it is  c o nsi d er e d t o  b e st er oi d refr a ct or y,  a n d s e c o n d -li n e t h er a p y is  w arr a nt e d 
(P a vl eti c  a n d  F o wl er  2 0 1 2 ).   T h er e  ar e  n o  F D A- a p pr o v e d  a g e nts f or st er oi d -r efr a ct or y  a c ut e 
G V H D;  n u m er o us  c o m bi n ati o n  a p pr o a c h es  h a v e  b e e n st u di e d,  b ut  d at a  d o  n ot s u p p ort  t h e 
r e c o m m e n d ati o n  or  e x cl usi o n  of  a n y  p arti c ul ar r e gi m e n.   V er y f e w  pr os p e cti v e st u di es  h a v e 
e v al u at e d s e c o n d -li n e t h er a p y f or  a c ut e  G V H D (Fi g ur e   2; M arti n  et  al  2 0 1 2 ),  a n d i nt er pr et ati o n 
of t h es e st u di es is  h a m p er e d  b y  h et er o g e n eit y  of s u bj e ct  p o p ul ati o n, s m all s a m pl e si z es,  a n d l a c k 
of st a n d ar di z ati o n i n t h e st u d y  d esi g n (i n cl u di n g ti mi n g  of t h e r es p o ns e,  diff er e nt r es p o ns e 
crit eri a,  a n d  a bs e n c e  of  v ali d at e d  e n d p oi nts).  I n  a d diti o n, tr e at m e nt  of st er oi d- r efr a ct or y  a c ut e 
G V H D is  ass o ci at e d  wit h si g nifi c a nt t o xi citi es,  hi g h f ail ur e r at es,  a n d  6 - m o nt h s ur vi v al r at e  of 
4 9 %.   A g e nts t h at  h a v e  b e e n i n v esti g at e d  o v er t h e l ast  2  d e c a d es i n t h es e st u di es i n cl u d e 
l o w- d os e  m et h otr e x at e,  m y c o p h e n ol at e  m of etil,  e xtr a c or p or e al  p h ot o p h er esis, I L-2 R t ar g eti n g 
(i e,  b asili xi m a b,  d a cli z u m a b,  d e nil e u ki n,  a n d  diftit o x),  al e mt u z u m a b,  h ors e  a ntit h y m o c yt e 
gl o b uli n,  et a n er c e pt, i nfli xi m a b,  a n d sir oli m us ( M arti n  et  al  2 0 1 2 ). 

I n c yt e  C or p or ati o n 
P a g e  2 1  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
Fi g u r e   2:   
S u m m a r y  of  St u di es  E v al u ati n g  A g e nts f o r  S e c o n d-Li n e  T h e r a p y  of  A c ut e 
G V H D a 
 
a G V H D  =  a c ut e  gr aft -v ers us -h ost  dis e as e;  A T G  =  a ntit h y m o c yt e  gl o b uli n;  C R  =  c o m pl et e r es p o ns e;  E C P  =  e xtr a c or p or e al 
p h ot o p h er esis;  M M F  =  m y c o p h e n ol at e  m of etil;  P R  =  p arti al r es p o ns e;  R etr o  = r etr os p e cti v e.  
a   Tr e at m e nt r es ults t h at f all  o utsi d e t h e  9 5 %  c o nfi d e n c e i nt er v al ( CI) f or t h e  a g gr e g at e d  o v er all  a v er a g e  of  all st u di es  ar e s h o w n 
i n  b ol d. 
b  T h e r e p ort  di d  n ot i n di c at e  w h et h er  a bs e n c e  of f urt h er s yst e mi c tr e at m e nt  w as  a  crit e ri o n f or r es p o ns e.  I n  all  ot h er r e p orts, 
s u bj e cts  w h o  h a d f urt h er s yst e mi c tr e at m e nt  w er e  cl assifi e d  as  n ot  h a vi n g  a  C R  or  P R.  
S o ur c e:   M arti n  et  al  2 0 1 2 . 
Gi v e n t h es e  d at a, t h e  c h oi c e  of  a s e c o n d -li n e r e gi m e n is  m a d e  b as e d  o n t h e  o ut c o m e  of  pri or 
tr e at m e nts,  d esir e d t o xi cit y  pr ofil e,  c o nsi d er ati o ns f or  dr u g i nt er a cti o ns, l o gisti c al  pr a cti c alit y, 
c osts,  a n d s u bj e ct  a n d  p h ysi ci a n  pr ef er e n c es.   S e c o n d- li n e tr e at m e nts,  es p e ci all y t h os e  ass o ci at e d 
wit h  s u p pr essi o n of  T  c ells,  ar e  ass o ci at e d  wit h i n cr e as e d i nf e cti o n  a n d  vir al r e a cti v ati o n 
(i n cl u di n g  c yt o m e g al o vir us [ C M V],  E pst ei n- B arr  vir us,  h u m a n  h er p es  vir us  6,  a d e n o vir us,  a n d 
p ol y o m a). 
1. 2.   
R u x oliti ni b  B a c k g r o u n d  
1. 2. 1.   
P h a r m a c ol o g y 
R u x oliti ni b is  a  n o v el,  p ot e nt  a n d s el e cti v e i n hi bit or  of t h e J a n us  ki n as es (J A Ks)  wit h s el e cti vit y 
f or J A K 1  a n d J A K 2 (Q ui nt ás- C ar d a m a  et  al  2 0 1 0 ).   R u x oliti ni b  p ot e ntl y i n hi bits J A K 1  a n d 
J A K 2 (I C 5 0  <  5  n M),  y et it  d o es  n ot si g nifi c a ntl y i n hi bit  a  br o a d  p a n el  of  2 8  ki n as es ( <  3 0 % 
i n hi biti o n)  w h e n t est e d  at  2 0 0  n M ( a p pr o xi m at el y  1 0 0  × t h e  a v er a g e I C5 0 v al u e f or J A K 1  a n d 
J A K 2  e n z y m e i n hi biti o n).   I n  c ell-b as e d  ass a ys r el e v a nt t o t h e  p at h o g e n esis  of 
m y el o pr olif er ati v e  n e o pl as ms ( M P Ns ), s u c h  as J A K/si g n al tr a ns d u c ers  a n d  a cti v at ors  of 

I n c yt e  C or p or ati o n 
P a g e  2 2  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
tr a ns cri pti o n (S T A T ) si g n ali n g  a n d t h e  gr o wt h  of  c yt o ki n e- d e p e n d e nt t u m or  c ell li n es, 
r u x oliti ni b  d e m o nstr at es I C5 0  v al u es  of  8 0 t o  3 0 0  n M.   T his  eff e ct is  n ot  d u e t o  g e n er al 
c yt ot o xi cit y,  b e c a us e r u x oliti ni b ( u p t o  2 5  μ M)  h a d  n o si g nifi c a nt  eff e ct  o n t h e  gr o wt h  of  a 
c yt o ki n e-i n d e p e n d e nt,  Br e a k p oi nt  cl ust er r e gi o n- A b els o n – dri v e n  c ell li n e.  I n  a d diti o n, 
r u x oliti ni b i n hi bit e d J A K/ S T A T si g n ali n g  a n d  gr o wt h  of  a  c ell li n e  e x pr essi n g t h e  c o nstit uti v el y 
a cti v e J A K 2  m ut a nt (J A K 2 V 6 1 7 F) t h at  h as  b e e n i m pli c at e d i n t h e  p at h o g e n esis  of t h e  m aj orit y 
of  P hil a d el p hi a  c hr o m os o m e  n e g ati v e  M P Ns.   R u x oliti ni b  w as  als o t est e d i n  c ell -b as e d  ass a ys 
r el e v a nt t o t h e i n cr e as e d i nfl a m m at or y  c yt o ki n e l e v els  o bs er v e d i n  M P Ns t h at  c o ntri b ut e t o 
M P N -r el at e d s yst e mi c s y m pt o ms.   R u x oliti ni b  p ot e ntl y i n hi bit e d i nt erl e u ki n (I L)- 2 3 –sti m ul at e d 
I L- 2 2  pr o d u cti o n i n  h u m a n  T  c ells (I C5 0  =  5 0  n M),  as  w ell  as I L-6,  gr a n ul o c yt e - m a cr o p h a g e 
c ol o n y – sti m ul ati n g f a ct or  a n d t hr o m b o p oi eti n ( T P O)-i n d u c e d  S T A T 3  p h os p h or yl ati o n i n  h u m a n 
p eri p h er al  bl o o d  m o n o n u cl e ar  c ells  wit h I C 5 0  v al u es  <  1 0 0  n M.   R u x oliti ni b  als o i n hi bit e d 
gr a n ul o c yt e  c ol o n y- sti m ul ati n g f a ct or–sti m ul at e d  S T A T 3  p h os p h or yl ati o n i n  h u m a n  n e utr o p hils 
(I C5 0  =  2 8  ±  9  n M),  as  w ell  as  T P O-i n d u c e d  S T A T 3  p h os p h or yl ati o n i n  h u m a n  w h ol e  bl o o d 
(I C5 0  =  2 8 1  ±  6 2  n M).   Fi n all y, r u x oliti ni b i n hi bit e d t h e  pr o d u cti o n  of I L- 1 7 i n r es p o ns e t o I L- 2 3 
i n  T  c ells  a n d t h e  pr o d u cti o n  of  m o n o c yt e  c h e m ot a cti c  pr ot ei n- 1 i n r es p o ns e t o I L- 6 i n p eri p h er al 
bl o o d  m o n o n u cl e ar  c ells  wit h I C 5 0  v al u es  of  ≤  1 2 0  n M (Fri d m a n  et  al  2 0 1 1 ). 
R u x oliti ni b i n hi bit e d s pl e n o m e g al y i n  mi c e r es ulti n g fr o m i ntr a v e n o us (I V) i n o c ul ati o n  of  c ells 
e x pr essi n g t h e  cli ni c all y r el e v a nt J A K 2 V 6 1 7 F  m ut ati o n ( Q ui nt ás- C ar d a m a  et  al  2 0 1 0 ).  Aft er 
3  w e e ks  of tr e at m e nt,  m or e t h a n  9 0 %  of  v e hi cl e- tr e at e d  mi c e  h a d s u c c u m b e d t o  dis e as e w hil e 
m or e t h a n  9 0 %  of r u x oliti ni b- tr e at e d  mi c e s ur vi v ed.   Tr e at m e nt  wit h r u x oliti ni b  als o  r e d u c e d 
i nfl a m m at or y  c yt o ki n e l e v els i n t h es e  mi c e.  T h e  eff e cts  of r u x oliti ni b  w er e  als o t est e d  i n  a 
m o us e  dis e as e  m o d el  of  p ol y c yt h e mi a  v er a –li k e  dis e as e,  b as e d  o n tr a ns pl a nt ati o n  of  a  1: 1  r ati o 
of J A K 2  wil d -t y p e  gr e e n fl u or es c e nt  pr ot ei n ( G F P) – e x pr essi n g  m uri n e  b o n e  m arr o w c ells  wit h 
J A K 2 V 6 1 7 F- p ositi v e  m uri n e  b o n e  m arr o w  c ells,  w hi c h  h a v e  a r e p o p ul ati o n  a d v a nt a g e.  I n t his 
m o d el,  or al r u x oliti ni b tr e at m e nt   at  d os es  of  3 0  or  9 0  m g/ k g t wi c e  d ail y (BI D ) f or  2 1  c o ns e c uti v e 
d a ys r e d u c e d l e v els  of  p h os p h or yl at e d  S T A T 5 ( p S T A T 5) i n t h e s pl e e n,  as  w ell  as  t h e s pl e e n 
si z e.  R u x oliti ni b  als o  eff e cti v el y r e d u c e d t h e r e d  c ell  p ar a m et ers ( r e d  bl o o d  c ell  c o u nt, 
h e m o gl o b uli n,  h e m at o crit ,  a n d r eti c ul o c yt e  c o u nt)  a n d  n e utr o p hil  c o u nt.   Th e tr e at m e nt  w as 
w ell -t ol er at e d  as  ass ess e d  b y  m o nit ori n g  b o d y  w ei g ht,  a n d  hist ol o gi c al  ass ess m e nts  of s pl e e n  a n d 
b o n e  m arr o w s a m pl es  p ost- t h er a p y r e v e al e d  a  d e cr e as e  of  h y p er c ell ul arit y ( er yt hr oi d  a n d 
m y el oi d li n e a g es) i n r u x oliti ni b -tr e at e d  gr o u ps  as  c o m p ar e d  wit h  v e hi cl e-tr e at e d  a ni m als.  
H o w e v er,  n o si g nifi c a nt  d e cr e as e i n t h e  m ut a nt  all el e  b ur d e n s urr o g at e r e a d o ut ( p er c e nt a g e  of 
G F P -n e g ati v e  c ells, i e,   c ells  e x pr essi n g J A K 2 V 6 1 7 F)  w as  o bs er v e d,  as  ass ess e d  b y fl o w 
c yt o m etr y.   Tr e at m e nt  of  mi c e  wit h r u x oliti ni b i n  a  c yt o ki n e - d e p e n d e nt m ulti pl e  m y el o m a  
x e n o gr aft  m o d el r es ult e d i n  a  d os e- d e p e n d e nt s u p pr essi o n  of  p h os p h or yl at e d  S T A T 3  a n d t u m or 
gr o wt h.    Effi c a c y  w as  als o  o bs er v e d i n  a d diti o n al  pr e cli ni c al t u m or  m o d els r e pr es e nti n g  b ot h 
h e m at ol o gi c  a n d s oli d t u m ors.   T a k e n t o g et h er, t h es e  d at a i n di c at e t h at r u x oliti ni b  will  b e  a bl e  t o 
i n hi bit  wil d-t y p e  a n d  m ut a nt J A Ks i n t h e  cli ni c al s etti n g  a n d  ar e  c o nsist e nt  wit h its  o bs er v e d 
effi c a c y i n  p ati e nts  wit h  M P Ns . 
1. 2. 2.   
Cli ni c al  St u di es  
As  of  2 2  F E B   2 0 1 6,  m or e t h a n  8 3 50  p ati e nts  h a v e r e c ei v e d  r u x oliti ni b i n  c o m p a n y-s p o ns or e d 
st u di es.  I n  a d diti o n,  m or e t h a n  7 0 i nt er v e nti o n al  or  o bs er v ati o n al st u di es s p o ns or e d  b y t hir d 

I n c yt e  C or p or ati o n 
P a g e  2 3  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
p arti es  ar e  o n g oi n g  or  c o m pl et e d.   A d diti o n al  d et ails r e g ar di n g t h e st u d y  d esi g ns  a n d  pri m ar y 
e n d p oi nts  of t h es e st u di es  ar e  s u m m ari z e d i n t h e r u x oliti ni b I n v esti g at or's  Br o c h ur e (I B). 
1. 3.   
St u d y  R ati o n al e  
1. 3. 1.   
A ni m al  St u di es i n  A c ut e  G V H D  M o d els  
T o  d et er mi n e t h e r ol e  of J A K/ S T A T si g n ali n g i n  G V H D,  m aj or  hist o c o m p ati bilit y 
(M H C )-mis m at c h e d  all o -H S C T  w as  p erf or m e d i n  mi c e [ B 6 ( H - 2b) t o B al b/ c( H - 2d)].  I n t his 
m o d el, i nt erf er o n  γ r e c e pt or ( I F N- γ R) si g n ali n g  w as s h o w n t o  pl a y  a  m aj or r ol e i n  T-c ell 
traffi c ki n g t o  G V H D t ar g et  or g a ns  vi a  C X C R 3.   Mi c e tr a ns pl a nt e d  wit h  I F N- γR  -/- T  c ells  h a d 
i m pr o v e d s ur vi v al  a n d l ess  cli ni c al  G V H D  c o m p ar e d  wit h  mi c e tr a ns pl a nt e d  wit h wil d -t y p e 
T  c ells .   F urt h erm or e ,  p h ar m a c ol o gi c i n hi biti o n  of i nt erf er o n si g n ali n g  wit h  a J A K/ S T A T 
si g n ali n g i n hi bit or, r u x oliti ni b, f or  2 0  d a ys r es ult e d i n t h e  d e cr e as e d  e x pr essi o n  of  C X C R 3, 
r e d u c e d  G V H D,  a n d i m pr o v e d s ur vi v al  aft er  all o-H S C T i n  mi c e ( Fi g ur e   3; C h oi  et  al  2 0 1 2 ). 
Fi g u r e   3:    
Eff e ct  of  R u x oliti ni b  o n  S u r vi v al i n  Mi c e  Aft e r  All o-H S C T  
 
B M  =  b o n e  m arr o w;  I N C B  = r u x oliti ni b (I N C B 0 1 8 4 2 4);  P B S  = p h os p h at e  b uff er e d s ali n e . 
S o ur c e:   C h oi  et  al  2 0 1 2 . 
T his  eff e ct  w as s h o w n t o  b e  m e di at e d  b y  alt e r e d tr affi c ki n g  of  T c ells t o  G V H D t ar g et  or g a ns.  
T h e  p h ar m a c ol o gi c  bl o c k a d e  of J A K/ S T A T si g n ali n g i n  wil d- t y p e  T-c ells  usi n g t h e 
J AK/ S T A T -si g n ali n g i n hi bit or, r u x oliti ni b, r es ult e d i n  a si mil ar  eff e ct t o I F N - γ R-/-  T  c ells  b ot h 
i n  vitr o (r e d u cti o n  of  C X C R 3  e x pr essi o n i n  T  c ells)  a n d i n  vi v o ( miti g ati o n  of  G V H D aft er 
all o - H S C T).   R u x oliti ni b  als o r e d u c e d  G V H D  a n d  pr es er v e d t h e  b e n efi ci al G V T  eff e ct i n 
2  diff er e nt  m o us e  M H C- mis m at c h e d  all o - H S C T  m o d els  a n d  2  diff er e nt  m o us e l e u k e mi a  m o d els 
(l y m p h oi d l e u k e mi a  a n d  m y el oi d l e u k e mi a; Fi g ur e   4; C h oi   et  al  2 0 1 4).   T his r es ult  w as  d u e t o  a n 
alt er ati o n i n  T -c ell tr affi c ki n g  wit h o ut  aff e cti n g  T - c ell  e x p a nsi o n.  I n  a d diti o n,  pr ol o n g e d 
a d mi nistr ati o n  of r u x oliti ni b f urt h er i m pr o v e d s ur vi v al  aft er  all o -H S C T.   T h es e  d at a s u g g est t h at 
p h ar m a c ol o gi c i n hi biti o n  of J A K/ S T A T si g n ali n g  mi g ht  b e  a  pr o misi n g t h er a p e uti c  a p pr o a c h t o 
a c hi e v e t h e  b e n efi ci al  a ntil e u k e mi a   eff e ct  a n d  o v er c o m e  h u m a n l e u k o c yt e  a nti g e n  b arri ers i n 
all o- H S C T.  

I n c yt e  C or p or ati o n 
P a g e  2 4  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
Fi g u r e   4:  
R u x oliti ni b  M ai nt ai ns  a  B e n efi ci al  G V T  Eff e ct  as  D et e r mi n e d  b y 
Bi ol u mi n es c e n c e I m a gi n g i n t h e  A 2 0  L e u k e mi a  M o d el  
 
B M  =  b o n e  m arr o w; I N C B   = r u x oliti ni b (I N C B 0 1 8 4 2 4). 
S o ur c e:   C h oi  et  al  2 0 1 4 . 
I n  a s e p ar at e st u d y, i n  vi v o J A K/ S T A T si g n ali n g i n hi biti o n i m pr o v e d s ur vi v al  of  mi c e 
d e v el o pi n g  a c ut e  G V H D  a n d r e d u c e d  hist o p at h ol o gi c al  G V H D  gr a di n g, s er u m l e v els  of 
pr oi nfl a m m at or y  c yt o ki n es,  a n d  e x p a nsi o n  of  all o r e a cti v e l u c-tr a ns g e ni c  T  c ells (C h oi  et  al 
2 0 1 2 ). 
It  w as s h o w n t h at t h e J A K 1/ 2 i n hi bit or r u x oliti ni b i m p air e d  diff er e nti ati o n  of  C D 4+  T  c ells i nt o 
i nt erf er o n  γ (I F N- γ) a n d I L - 1 7 A – pr o d u ci n g  c ells  a n d t h at  b ot h  T- c ell  p h e n ot y p es  ar e li n k e d t o 
G V H D.   A d diti o n all y, r u x oliti ni b tr e at m e nt i n  all o - H SC T r e ci pi e nts i n cr e as e d  F o x P 3 +  Tr e gs , 
w hi c h  ar e li n k e d t o i m m u n ol o gi c t ol er a n c e.  
1. 3. 2.   
Cli ni c al  E x p e ri e n c e  Wit h  J A K I n hi bit o rs  f o r t h e T r e at m e nt  of  A c ut e  G V H D  
Cli ni c al  e x p eri e n c e  wit h r u x oliti ni b i n  p ati e nts  wit h st er oi d -r efr a ct or y  G V H D  w as i niti all y 
r e p ort e d i n  6 p ati e nts   b as e d  o n  a  pr os p e cti v e  pr ot o c ol (S p o erl  et  al  2 0 1 4).   R es ults  w er e  u p d at e d 
i n  a r etr os p e cti v e  a n al ysis  of  9 5  p ati e nts  wit h st er oi d-r efr a ct or y  a c ut e  G V H D ( n  =  5 4,  all 
Gr a d e  III  or I V)  or st er oi d-r efr a ct or y  c hr o ni c  G V H D ( n  =  4 1,  all  m o d er at e  or s e v er e) w h o  w er e 
tr e at e d  wit h r u x oliti ni b  at  a  d os e  of  5 t o  1 0  m g  BI D (Z eis er  et  al   2 0 1 5).   Of t h e  4 5 p ati e nts  wit h 
a c ut e  G V H D ( all  of  w h o m  wit h  G r a d es  3  or  4  dis e as e),  a n  o v er all r es p o ns e r at e ( O R R)  of  81. 5 % 
w as r e p ort e d, i n cl u di n g  2 5  C Rs ( 4 6. 3 %).   T h e  m e di a n ti m e t o r es p o ns e  w as  1. 5  w e e ks 
(r a n g e  1- 1 1)  aft er i niti ati o n  of r u x oliti ni b t h er a p y.  I n  a d diti o n,  a  6-m o nt h s ur vi v al  esti m at e  of 
7 9 % ( 6 7. 3 %- 9 0. 7 %,  9 5 %  CI)  w as r e p ort e d,  wit h  a  m e di a n f oll o w- u p ti m e  of  2 6. 5  w e e ks.  
Gr aft -v ers us - h ost  dis e as e r el a ps es  w er e r e p ort e d i n  6. 8 % ( 3/ 4 4)  of  p ati e nts.   A si g nifi c a nt  d e cli n e 
i n l e v els  of I L- 6  a n d s ol u bl e I L- 2 r e c e pt or  w er e  o bs er v e d i n  1 2  of  2 5  e v al u a bl e  p ati e nts tr e at e d  at 
o n e  c e nt er.    C yt o m e g al o vir us r e a cti v ati o n  w as  o bs er v e d i n  3 3. 3 % ( 1 8/ 5 4)  a c ut e  G V H D  p ati e nts 
a n d  w as  c o ntr oll e d  usi n g  a nti vir al t h er a p y  w h il e r u x oliti ni b tr e at m e nt  c o nti n u e d.   C yt o p e ni as 
w er e  als o  o bs er v e d  d uri n g tr e at m e nt  wit h r u x oliti ni b i n  5 5. 5 % ( 3 0/ 5 4)  p ati e nts;  h o w e v er, 
c yt o p e ni as  w er e r e p ort e d  b ef or e  tr e at m e nt  wit h r u x oliti ni b i n  5 1. 7 % ( 2 8/ 5 4).   Mali g n a n c y 
r el a ps e  was r e p ort e d i n  9. 3 % ( 5/ 5 4). 
A  P h as e  1  cli ni c al  st u d y  e v al u ati n g I N C B 0 3 9 1 1 0,  a  p ot e nt, s el e cti v e i n hi bit or  of J A K 1, is 
c urr e ntl y  u n d er w a y. 

I n c yt e  C or p or ati o n 
P a g e  2 5  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
O v er all, t h es e r es ults  s u g g est t h at i n hi biti o n  of J A K/ S T A T si g n ali n g is  a  pr o misi n g  m e c h a nis m 
i n t h e tr e at m e nt  of  a c ut e  a n d  c hr o ni c G V H D .  N e w tr e at m e nts f or t h e t h er a p y  of  a c ut e  G V H D 
aft er  all o -H S C T  ar e  ur g e ntl y  n e e d e d.   N o v el tr e at m e nts  wit h  a g e nts t ar g eti n g t h e  J A K-S T A T 
p at h w a y  a p p e ar t o  d e cr e as e  a c ut e  G V H D  w hil e  pr es er vi n g  G V T i n  m uri n e  m o d els  b y t ar g eti n g 
t h e I F N- γ  p at h w a y i n  a cti v at e d  T  c ells r es p o nsi bl e f or  a c ut e  G V H D.   T h e  pr e cli ni c al  d at a  wit h 
cli ni c al  pr o of- of - pri n ci pl e fi n di n gs  wit h r u x oliti ni b  pr o vi d es  a str o n g r ati o n al e  a n d j ustifi c ati o n 
of f urt h er  i n v esti g ati n g r u x oliti ni b  wit h st a n d ar d  c orti c ost er oi d  d os es  as  a tr e at m e nt  o pti o n f or 
p ati e nts  wit h  a c ut e  G V H D.  
T his  st u d y will  i n cl u d e s u bj e cts  w h o  ar e  1 2  y e ars  a n d  ol d er  as  d at a fr o m  a  P h as e  1 st u d y i n 
p e di atri c s u bj e cts  s h o w e d t h at s af et y  of r u x oliti ni b  w as  g e n er all y f a v or a bl e  a n d  p h ar m a c o ki n eti c 
(P K ) d at a  w er e  c o m p ar a bl e t o  t h at i n a d ults ( L o h  et  al  2 0 1 5 ).   A d ol es c e nts b et w e e n t h e  a g es  of 
1 2  a n d  1 8  y e ars  c o m pris e  a p pr o xi m at el y  5 %  of t h e  a d ult  a G V H D  p o p ul ati o n,  a n d st a n d ar d 
tr eat m e nt  d o es  n ot  diff er  b et w e e n  a d ol es c e nts  a n d  a d ults.  
1. 3. 3.   
R ati o n al e f o r  C h os e n  E n d p oi nts  
As  pr e vi o usl y  d es cri b e d,  v er y f e w  pr os p e cti v e st u di es  h a v e  e v al u at e d s e c o n d -li n e t h er a p y f or 
G V H D,  a n d i nt er pr et ati o n  of t h es e st u di es is  h a m p er e d  b y  h et er o g e n eit y  of  p ati e nt  p o p ul ati o n 
a n d  l a c k  of st a n d ar di z ati o n i n t h e st u d y  d esi g n, i n cl u di n g ti mi n g  of t h e r es p o ns e,  a bs e n c e of 
v ali d at e d  e v al u ati o n  of  e n d p oi nts,  a n d s m all  n u m b ers  of  p ati e nts.   R es p o ns e r at es r a n g e  b et w e e n 
1 8 % t o  7 9 %,  a n d  tr e at m e nt  of st er oi d-r efr a ct or y a c ut e  G V H D  is  ass o ci at e d  wit h si g nifi c a nt 
t o xi citi es,  hi g h f ail ur e r at es,  a n d  6- m o nt h s ur vi v al r at e  of  4 9 % (M arti n  et  al   2 0 1 2). 
I n  or d er t o as s ess  w h et h er r es p o ns e i s a si g nifi c a nt  pr e di ct or t o l o n g- t er m  cli ni c al  b e n efit,  S ali b a 
et  al ( 2 0 1 2 ) r e p ort e d  D a y  2 8 r es p o ns e as   a n i n d e p e n d e nt  a n d str o n g est  pr e di ct or st atisti c all y  of 
n o nr el a ps e  m ort alit y ( N R M )  at  6  m o nt hs  a n d  at  2 4  m o nt hs.   P ati e nts  wit h  a  C R  or  P R  b y  D a y  2 8 
aft er i niti ati o n  of s yst e mi c t h er a p y  h a d  a si g nifi c a ntl y l o w er  6 - m o nt h  c u m ul ati v e i n ci d e n c e  of 
N R M ( 1 6 %) t h a n  p ati e nts  w h os e  a c ut e  G V H D  di d  n ot r es p o n d t o t h er a p y  b y  D a y  2 8 ( 4 8 %, 
P  =  0. 0 0 5).   T h e  i m p a ct  of  D a y  2 8 r es p o ns e  o n  6- m o nt h  N R M  w as i n d e p e n d e nt  of  a c ut e  G V H D 
s e v erit y.  L e vi n e  et  al  (2 0 0 8 ) r e p ort e d si mil ar fi n di n gs s h o wi n g  D a y  2 8 r es p o ns e  b ei n g  pr e di cti v e 
of  N R M  a n d s ur vi v al  at  6  a n d  9  m o nt hs.   T h es e fi n di n gs  w er e f urt h er s u p p ort e d  b y  M a c Mill a n 
et  al  (2 0 1 2 ) i n  a r etr os p e cti v e st u d y  of  8 6 4  p ati e nts t h at r e p ort e d  D a y  2 8  a n d  5 6 r es p o ns es  w er e 
si mil arl y  eff e cti v e i n  pr e di cti n g  2 -y e ar  N R M.  
1. 4.   
P ot e nti al  Ris ks  a n d  B e n efits  of t h e  T r e at m e nt  R e gi m e n  
T h e  pri m ar y  cli ni c al ris ks  wit h r u x oliti ni b tr e at m e nt  ar e t h e  p ot e nti al s e q u el a e  of  d e cr e as e d 
h e m at o p oi eti c  pr olif er ati o n  attri b ut a bl e t o t h e i n hi biti o n  of  gr o wt h f a ct or  p at h w a ys  ass o ci at e d 
wit h J A K i n hi biti o n.   D os e- d e p e n d e nt, r e v ersi bl e t hr o m b o c yt o p e ni a,  a n e mi a,  a n d  n e utr o p e ni a 
w er e t h e  m ost fr e q u e nt tr e at m e nt -e m er g e nt  a d v ers e  e v e nts  ( T E A Es)  o bs er v e d  d uri n g t h e  P h as e  3 
cli ni c al st u di es  of r u x oliti ni b i n  p ati e nts  wit h  m y el ofi br osis .  I n cr e as e d r at es  of i nf e cti o n  a n d 
a n e mi a  ar e  p ot e nti al ris ks  of  m y el os u p pr essi o n.  I n  h e alt h y  v ol u nt e ers,  r h e u m at oi d  art hritis 
p ati e nts,  a n d  p ati e nts  wit h  p a n cr e ati c  c a n c er  or  h or m o n e- r efr a ct or y  pr ost at e  c a n c er, t h e  eff e cts  o n 
h e m at o p oi eti c  pr olif er ati o n  ar e l ess  pr o n o u n c e d,  pr es u m a bl y  b e c a us e  of  gr e at er  b o n e  m arr o w 
r es er v e.   T he  m ost fr e q u e nt  n o n h e m at ol o gi c  a d v ers e  e v e nts ( A Es ) w er e  mil d, r e v ersi bl e 
i n cr e as es i n  al a ni n e  a mi n otr a nsf er as e (A L T ) a n d  as p art at e  a mi n otr a nsf er as e ( A S T ),  br uisi n g, 

I n c yt e  C or p or ati o n 
P a g e  2 6  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
h y p er c h ol est er ol e mi a,  di z zi n ess,  h e a d a c h e,  a n d  uri n ar y tr a ct i nf e cti o ns.   F or  a  c o m pr e h e nsi v e 
ass ess m e nt  of t h e ris ks  of r u x oliti ni b, r ef er t o t h e  I B. 
2.   
S T U D Y  O B J E C TI V E S  A N D  E N D P OI N T S  
P ri m a r y  O bj e cti v e  
P ri m a r y  E n d p oi nt  
A ss ess t h e  effi c a c y  of r u x oliti ni b i n 
c o m bi n ati o n  wit h  c orti c ost er oi ds i n s u bj e cts 
wit h  Gr a d e s II t o I V st er oi d-r efr a ct or y  ac ut e 
G V H D . 
O R R  at  D a y  2 8,  d efi n e d  as t h e  pr o p orti o n  of s u bj e cts 
d e m o nstr ati n g  a  C R,  v er y  g o o d  p arti al r es p o ns e ( V G P R), 
or  P R . 
S e c o n d a r y  O bj e cti v es  
S e c o n d a r y  E n d p oi nts  
Ass ess  a d diti o n al r es p o ns e  a n d l o n g er -t er m 
e ffi c a c y o ut c o m e s i n t h e st u d y  p o p ul ati o n.  
K e y s e c o n d ar y  e n d p oi nt:  
Si x -m o nt h  d ur ati o n  of r es p o ns e ( D O R),  d efi n e d  as t h e 
ti m e fr o m first r es p o ns e  u ntil  G V H D  pr o gr essi o n  or  d e at h.  
D O R  will  b e  ass ess e d  w h e n  all s u bj e cts  c o m pl et e t h e 
D a y  1 8 0  visit.  
O R R,  d efi n e d  as t h e  pr o p orti o n  of s u bj e cts  d e m o nstr ati n g 
a  C R,  V G P R,  or  P R  at  D a ys  1 4,  5 6,  a n d  1 0 0.  
T hr e e -m o nt h  D O R,  d efi n e d  as t h e ti m e fr o m first r es p o ns e 
u ntil  G V H D  pr o gr essi o n  or  d e at h ,  w h e n all s u bj e cts 
c o m pl et e t h e  D a y  8 4  visit.  
N R M,  d efi n e d  as t h e  pr o p orti o n  of s u bj e cts  w h o  di e d  d u e 
t o  ca us es  ot h er t h a n  m ali g n a n c y  r el a ps e  at  M o nt hs  6,  9, 
1 2 , a n d  2 4.  
R el a ps e r at e,  d efi n e d  as t h e  pr o p orti o n  of s u bj e cts  w h os e 
u n d erl yi n g  m ali g n a n c y  r el a ps es. 
R el a ps e -r el at e d  m ort alit y r at e,  d efi n e d  as t h e  pr o p orti o n  of 
s u bj e cts  w h os e  m ali g n a n c y  r el a ps es  a n d  h a s  a f at al 
o ut c o m e.  
F ail ur e -fr e e s ur vi v al ( F F S),  d efi n e d  as t h e  pr o p orti o n  of 
s u bj e cts  w h o  ar e still  ali v e,  h a v e  n ot r el a ps e d,  h a v e  n ot 
r e q uir e d  a d diti o n al t h er a p y f or  a c ut e  G V H D,  a n d  h a v e  n ot 
d e m o nstr at e d si g ns  or s y m pt o ms  of  c hr o ni c  G V H D ,  at 
M o nt h  6.  
O S ,  d efi n e d  as t h e ti m e fr o m st u d y  e nr oll m e nt t o  d e at h 
d u e t o  a n y  c a us e.  
Ass ess t h e i n ci d e n c e  a n d s e v erit y  of  A Es  a n d 
s eri o us  a d v ers e  e v e nts ( S A E s ). 
S u m m ari es  of  cli ni c al  s af et y  d at a ( e g,  A E s, i nf e cti o ns)  will 
b e t a b ul at e d  a n d list e d.  
E v al u at e t h e  P K  of  r u x oliti ni b  w h e n 
a d mi nist er e d i n  c o m bi n ati o n  wit h 
c orti c ost er oi ds.  
M a xi m u m  o bs er v e d  pl as m a  dr u g  c o n c e ntr ati o n ( C m a x ), 
mi ni m u m  o bs er v e d  pl as m a  dr u g  c o n c e ntr ati o n ( C
mi n ), ti m e 
of  m a xi m u m  o bs er v e d  pl as m a  dr u g  c o n c e ntr ati o n (t m a x ), 
ar e a  u n d er t h e  pl as m a  dr u g  c o n c e ntr ati o n  v er s us ti m e 
c ur v e ( A U C) , a n d  a p p ar e nt  cl e ar a n c e  of st u d y  dr u g fr o m 
pl as m a ( C L/ F).  

I n c yt e  C or p or ati o n 
P a g e  2 7  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
3.   
S U B J E C T  E LI GI BI LI T Y  
D e vi ati o ns fr o m  eli gi bilit y  crit eri a  ar e  n ot  all o w e d , b e c a us e t h e y  c a n  p ot e nti all y j e o p ar di z e t h e 
s ci e ntifi c i nt e grit y  of t h e st u d y, r e g ul at or y  a c c e pt a bilit y,  a n d/ or s u bj e ct s af et y.   T h er ef or e, 
a d h er e n c e t o t h e  crit eri a  as s p e cifi e d i n t h e  P r ot o c ol is  ess e nti al. 
3. 1.   
S u bj e ct I n cl usi o n  C rit e ri a  
A s u bj e ct  w h o  m e et s all  of t h e f oll o wi n g  crit eri a  m a y  b e i n cl u d e d i n t h e st u d y: 
1.   M al e  or f e m al e,  1 2  y e ars  of  a g e  or  ol d er.  
2.   H as   u n d er g o n e first all o -H S C T  fr o m  a n y  d o n or s o ur c e (m at c h e d  u nr el at e d  d o n or , si bli n g, 
h a pl oi d e nti c al)  usi n g  b o n e  m arr o w,  p eri p h er al  bl o o d st e m  c ells ,  or  c or d  bl o o d f or 
h e m at ol o gi c  m ali g n a n ci es.   R e ci pi e nts  of  n o n m y el o a bl ati v e  a n d  m y el o a bl ati v e 
tr a ns pl a nts  ar e  eli gi bl e. 
3.   Cli ni c all y s us p e ct e d  Gr a d e s II t o I V  a c ut e  G V H D  as  p er M A GI C  g ui d eli n es ,  o c c urri n g 
aft er  all o -H S C T   wit h  a n y  c o n diti o ni n g r e gi m e n  a n d  a n y  a nti-G V H D  pr o p h yl a cti c 
pr o gr a m.   Bi o psi es s h o ul d  b e  o bt ai n e d t o  p at h ol o gi c all y  c o nfir m  a c ut e  G V H D; i n  c as es 
w h er e  a  bi o ps y is  n e g ati v e, is  u n a bl e t o  b e  o bt ai n e d,  or is  cli ni c all y  c o ntr ai n di c at e d, 
cli ni c al s us pi ci o n  of  a c ut e  G V H D  b y t h e tr e ati n g  p h ysi ci a n is s uffi ci e nt ,  pr o vi d e d t h at 
alt er n ati v e  di a g n os es  of  dr u g  eff e cts  or i nf e cti o n  ar e  a d e q u at el y r ul e d  o ut. 
4.   S u bj e cts  wit h  st er oi d-r efr a ct or y  a c ut e  G V H D, d efi n e d  as   a n y  of t h e f oll o wi n g: 
a.   S u bj e cts  wit h  pr o gr essi v e  G V H D (i e , i n cr e as e i n st a g e i n  a n y  or g a n s yst e m or  a n y 
n e w  or g a n i n v ol v e m e nt )  aft er  3 d a ys  of  pri m ar y tr e at m e nt  wit h  m et h yl pr e d nis ol o n e 
≥  2  m g/ k g  p er  d a y ( or  e q ui v al e nt). 

I n c yt e  C or p or ati o n 
P a g e  2 8  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
b.   S u bj e cts  wit h  G V H D t h at  h as  n ot i m pr o v e d  (i e,  d e cr e as e i n st a g e i n  at l e ast 
1 i n v ol v e d  or g a n  s yst e m)  aft er  7  d a ys  of  pri m ar y tr e at m e nt  wit h  m et h yl pr e d nis ol o n e 
≥  2  m g/ k g  p er  d a y ( or  e q ui v al e nt). 
c.   S u bj e cts  w h o  pr e vi o usl y  b e g a n  c orti c ost er oi d t h er a p y  at  a l o w er  d os e  ( at l e ast 
1  m g/ k g  m et h yl pr e d nis ol o n e)  f or tr e at m e nt  of s ki n  G V H D  or s ki n  G V H D 
a c c o m p a ni e d  b y  u p p er  GI  G V H D,   b ut  d e v el o p  n e w  G V H D i n  a n ot h er  or g a n s yst e m. 
d.   S u bj e cts  w h o  c a n n ot t ol er at e  a  c orti c ost er oi d t a p er,  t h at is, b e gi n  c orti c ost er oi ds  at 
2. 0  m g/ k g  p er  d a y,  d e m o nstr at e r es p o ns e,  b ut  pr o gr ess  b ef or e  a  5 0 %  d e cr e as e fr o m 
t h e i niti al st arti n g  d os e  of  c orti c ost er oi ds is  a c hi e v e d. 
5.   E vi d e n c e  of  m y el oi d  e n gr aft m e nt ( e g ,  a bs ol ut e  n e utr o p hil  c o u nt [A N C ] ≥  0. 5   ×  1 09/ L f or 
3  c o ns e c uti v e  d a ys if  a bl ati v e t h er a p y  w as  pr e vi o usl y  us e d ).   Us e  of  gr o wt h f a ct or 
s u p pl e m e nt ati o n is  all o w e d. 
6.   B e  willi n g t o  a v oi d  pr e g n a n c y  or f at h eri n g  c hil dr e n  b as e d  o n  1  of t h e f oll o wi n g  crit eri a:  
a.   W o m e n  of  n o n c hil d b e ari n g  p ot e nti al (i e, s ur gi c all y st eril e  wit h  a  h yst er e ct o m y  a n d/ or 
bil at er al  o o p h or e ct o m y  O R  ≥  1 2  m o nt hs  of  a m e n orr h e a). 
b.   W o m a n  of  c hil d b e ari n g  p ot e nti al  w h o  h as  a  n e g ati v e s er u m  pr e g n a n c y t est  at 
s cr e e ni n g  a n d  w h o  a gr e es t o t a k e  a p pr o pri at e  pr e c a uti o ns t o  a v oi d  pr e g n a n c y ( wit h  at 
l e ast  9 9 %  c ert ai nt y) fr o m s cr e e ni n g t hr o u g h s af et y f oll o w- u p.   P er mitt e d  m et h o ds t h at 
ar e  at l e ast  9 9 %  eff e cti v e i n  pr e v e nti n g  pr e g n a n c y (s e e  A p p e n di x  A ) s h o ul d  b e 
c o m m u ni c at e d t o t h e s u bj e ct  a n d t h eir  u n d erst a n di n g  c o nfir m e d. 
c.   M a n  w h o  a gr e es t o t a k e  a p pr o pri at e  pr e c a uti o ns t o  a v oi d f at h eri n g  c hil dr e n ( wit h  at 
l e ast  9 9 %  c ert ai nt y) fr o m s cr e e ni n g t hr o u g h s af et y f oll o w- u p.   P er mitt e d  m et h o ds t h at 
ar e  at l e ast  9 9 %  eff e cti v e i n  pr e v e nti n g  pr e g n a n c y (s e e  A p p e n di x  A ) s h o ul d  b e 
c o m m u ni c at e d t o t h e s u bj e ct  a n d  t h eir  u n d erst a n di n g  c o nfir m e d. 
7.   Writt e n i nf or m e d  c o ns e nt  a n d/ or  ass e nt fr o m t h e s u bj e ct,  p ar e nt  or  g u ar di a n. 
8.   Willi n g n ess t o   c o m pl y  wit h  all st u d y  visits  a n d  pr o c e d ur es. 
3. 2.   
S u bj e ct  E x cl usi o n  C rit e ri a  
1.   H as r e c ei v e d  m or e t h a n  1  all o -H S C T . 
2.   H as r e c ei v e d  m or e t h a n  1  s yst e mi c tr e at m e nt i n  a d diti o n t o  c orti c ost er oi ds f or a c ut e  
G V H D.  
3.   Pr es e n c e  of  G V H D  o v erl a p s y n dr o m e  as  p er  NI H  g ui d eli n es  (J a gasi a   et  al  2 0 1 5). 
4.   S u bj e cts  w h o  h a v e  h a d  a s pl e n e ct o m y. 
5.   Pr es e n c e  of  a n  a cti v e  u n c o ntr oll e d i nf e cti o n.   A n  a cti v e  u n c o ntr oll e d i nf e cti o n is  d efi n e d 
as  h e m o d y n a mi c i nst a bilit y  attri b ut a b l e t o s e psis  or  n e w s y m pt o ms,  w ors e ni n g  p h ysi c al 
si g ns,  or r a di o gr a p hi c fi n di n gs  attri b ut a bl e t o i nf e cti o n.   P ersisti n g f e v er  wit h o ut si g ns  or 
s y m pt o ms  will  n ot  b e i nt er pr et e d  as  a n  a cti v e  u n c o ntr oll e d i nf e cti o n. 
6.   K n o w n  h u m a n i m m u n o d efi ci e n c y  vir us i nf e cti o n. 

I n c yt e  C or p or ati o n 
P a g e  2 9  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
7.   A cti v e  h e p atitis  B  vir us ( H B V)  or  h e p atitis  C  vir us ( H C V) i nf e cti o n t h at r e q uir es 
tr e at m e nt  or  at ris k f or  H B V r e a cti v ati o n.   At ris k f or  H B V r e a cti v ati o n is  d efi n e d  as 
h e p atitis  B s urf a c e  a nti g e n  p ositi v e  or  a nti – h e p atitis  B  c or e  a nti b o d y  p ositi v e.   Pr e vi o us 
t est r es ults  o bt ai n e d  as  p art  of st a n d ar d  of  c ar e  b ef or e all o -H S C T t h at  c o nfir m  a s u bj e ct is 
i m m u n e  a n d  n ot  at ris k f or r e a cti v ati o n (i e, h e p atitis  B s urf a c e  a nti g e n  n e g ati v e , s urf a c e 
a nti b o d y  p ositi v e)  m a y  b e  us e d f or  p ur p os es  of  eli gi bilit y,  a n d  t ests  d o  n ot  n e e d t o  b e 
r e p e at e d.   S u bj e cts  wit h pr e vi o us  p ositi v e s er ol o g y r es ults  m ust  h a v e  n e g ati v e 
p ol y m er as e  c h ai n r e a cti o n  r es ults.   S u bj e cts  w h os e i m m u n e st at us is  u n k n o w n  or 
u n c ert ai n  m ust  h a v e r es ults  c o nfir mi n g i m m u n e st at us  b ef or e  e nr oll m e nt.  
8.   S er u m  cr e ati ni n e  >  2. 0  m g/ d L  or  cr e ati ni n e  cl e ar a n c e  <  4 0  m L/ mi n  as  m e as ur e d  or 
c al c ul at e d  b y  C o c kr oft - G a ult  e q u ati o n. 
9.   S u bj e cts  wit h  e vi d e n c e  of r el a ps e d  pri m ar y  dis e as e,  or s u bj e cts  w h o  h a v e  b e e n tr e at e d f or 
r el a ps e  aft er t h e  all o-H S C T  w as  p erf or m e d.  
1 0.  U nr es ol v e d t o xi cit y  or  c o m pli c ati o ns ( ot h er t h a n  a c ut e  G V H D)  d u e t o  pr e vi o us 
all o -H S C T.  
1 1.  A n y  c orti c ost er oi d t h er a p y  f or i n di c ati o ns  ot h er t h a n  G V H D  at  d os es  of 
m et h yl pr e d nis ol o n e  or  e q ui v al e nt  >  1  m g/ k g  p er  d a y  wit hi n  7  d a ys  of  e nr oll m e nt. 
1 2.  S e v er e  or g a n  d ysf u n cti o n  u nr el at e d t o  u n d erl yi n g  G V H D, i n cl u di n g: 
a.   C h ol est ati c  dis or d ers  or  u nr es ol v e d  v e n o- o c cl usi v e  dis e as e  of t h e li v er  (d efi n e d  as 
p ersist e nt  bilir u bi n  a b n or m aliti es  n ot  attri b ut a bl e t o  G V H D  a n d  o n g oi n g  or g a n 
d ysf u n cti o n). 
b.   Cli ni c all y si g nifi c a nt  or  u n c o ntr oll e d  c ar di a c  dis e as e , i n cl u di n g  u nst a bl e  a n gi n a,  a c ut e 
m y o c ar di al i nf ar cti o n  wit hi n  6  m o nt hs fr o m  D a y  1  of st u d y  dr u g  a d mi nistr ati o n,  N e w 
Y or k  H e art  Ass o ci ati o n  Cl ass III  or I V  c o n g esti v e  h e art f ail ur e,  cir c ul at or y  c oll a ps e 
r e q uiri n g  v as o pr ess or  or i n otr o pi c s u p p ort,  or arr h yt h mi a t h at r e q uir es  t h er a p y. 
c.   Cli ni c all y si g nifi c a nt r es pir at or y  dis e as e t h at r e q uir es  m e c h a ni c al  v e ntil ati o n s u p p ort  
or  5 0 %  o x y g e n. 
1 3.  C urr e ntl y  br e ast f e e di n g.  
1 4.  R e c ei v e d J A K i n hi bit or t h er a p y  aft er  all o -H S C T  f or  a n y i n di c ati o n.  Tr e at m e nt  wit h  a  
J A K i n hi bit or b ef or e  all o -H S C T is  p er mitt e d.  
1 5.  Tr e at m e nt  wit h  a n y  ot h er i n v esti g ati o n al  a g e nt,  d e vi c e,  or  pr o c e d ur e,  wit hi n  2 1  d a ys ( or 
5  h alf -li v es,  w hi c h e v er is  gr e at er)  of e nr oll m e nt .   S u bj e cts  p arti ci p ati n g i n  a  G V H D 
pr o p h yl a xis st u d y  or  c o n diti o ni n g r e gi m e n s h o ul d  b e  dis c uss e d  wit h t h e s p o ns or' s 
m e di c al  m o nit or  b ef or e  e nr oll m e nt.  
1 6.  A n y  c o n diti o n t h at  w o ul d, i n t h e i n v esti g at or' s j u d g m e nt, i nt erf er e  wit h f ull  p arti ci p ati o n 
i n t h e st u d y, i n cl u di n g  a d mi nistr ati o n  of st u d y  dr u g  a n d  att e n di n g r e q uir e d stu d y  visits; 
p os e  a si g nifi c a nt ris k t o t h e s u bj e ct;  or i nt erf er e  wit h i nt er pr et ati o n  of st u d y  d at a.  
1 7.  K n o w n  all er gi es,  h y p ers e nsiti vit y,  or i nt ol er a n c e t o  a n y  of t h e st u d y  m e di c ati o ns, 
e x ci pi e nts,  or si mil ar  c o m p o u n ds. 

I n c yt e  C or p or ati o n 
P a g e  3 0  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
4.   
I N V E S TI G A TI O N A L  P L A N  
4. 1.   
O v e r all  St u d y  D esi g n  
T his is  a n  o p e n -l a b el, si n gl e- c o h ort,  m ulti c e nt er  P h as e  2 st u d y  of r u x oliti ni b i n  c o m bi n ati o n  wit h 
c orti c ost er oi ds f or t h e tr e at m e nt  of st er oi d -r efr a ct or y  Gr a d es II t o I V  a c ut e  G V H D.  Eli gi bl e 
s u bj e cts  will  b e gi n tr e at m e nt  at r u x oliti ni b  5  m g  BI D ; if h e m at ol o gi c  p ar a m et ers  ar e st a bl e  a n d 
n o tr e at m e nt -r el at e d t o xi cit y is  o bs er v e d  aft er t h e first  3  d a ys  of tr e at m e nt, t h e  d os e m a y  b e 
i n cr e as e d t o  1 0  m g  BI D.  R u x oliti ni b  m a y  b e t a p er e d  aft er  D a y  1 8 0  pr o vi d e d t h e s u bj e ct  h as 
a c hi e v e d  a  C R  or  V G P R  a n d  c orti c os t er oi ds  h a v e  b e e n  dis c o nti n u e d f or  at l e ast  8  w e e ks.   
S u bj e cts  w h o  ar e still r e c ei vi n g  c al ci n e uri n i n hi bit ors  or  ot h er  a g e nts f or  G V H D  pr o p h yl a xis  at 
t his ti m e  m a y  c o nti n u e t o  d o s o  at t h e tr e ati n g i n v esti g at or's  dis cr eti o n.  C orti c ost er oi ds  will  b e 
a d mi n ist er e d  at  a st arti n g  d os e  of  2. 0  m g/ k g  p er  d a y ( u nl ess  ot h er wis e i n di c at e d)  o n  D a y  1  a n d 
will  b e t a p er e d  as  a p pr o pri at e.   S u bj e cts  will r e c ei v e st u d y tr e at m e nt  u ntil tr e at m e nt f ail ur e 
( pr o gr essi o n  of G V H D ,  n o r es p o ns e,  or r e q uiri n g  a d diti o n al s yst e mi c t h er a p y),  u n a c c e pt a bl e 
t o xi cit y,  or  d e at h.   C o nti n u e d  us e  of  a nti-i nf e cti v e  m e di c ati o ns,  G V H D  pr o p h yl a xis  m e di c ati o ns 
(i n cl u di n g  c al ci n e uri n i n hi bit ors), tr a nsf usi o n s u p p ort,  a n d t o pi c al st er oi d t h er a p y is  p er mitt e d. 
S e v erit y  of  G V H D  will  b e  ass ess e d  fr o m s cr e e ni n g t hr o u g h  e n d  of tr e at m e nt ( E O T) usi n g  t h e 
M o u nt  Si n ai  A c ut e  G V H D I nt er n ati o n al  C o ns orti u m ( M A GI C)  g ui d eli n es.   A d v ers e  e v e nts  a n d 
S A Es   will  b e  ass ess e d fr o m t h e ti m e  of  c o ns e nt t hr o u g h  3 0 t o  3 5 d a ys  aft er t h e  E O T  as  p er 
N ati o n al  C a n c er I nstit ut e ( N CI )  C T C A E  v 4. 0 3.   S u bj e cts  will  b e  ass ess e d f or  effi c a c y (i n cl u di n g 
o v er all r es p o ns e,  N R M,  F F S,  D O R , r el a ps e r at e, r el a ps e-r el at e d  m ort alit y r at es,  a n d  O S), s af et y 
(i n cl u di n g  A Es,  S A Es,  a n d  cli ni c al/l a b or at or y  ass ess m e nts),
 
 
4. 2.   
M e as u r es  T a k e n t o  A v oi d  Bi as  
A c ut e  G V H D r es p o ns e   a n d A E s  will  b e  ass ess e d  u si n g st a n d ar di z e d  o bj e cti v e  crit eri a ( M A GI C 
g ui d eli n es [ A p p e n di x  B ] a n d  N CI  C T C A E  v 4. 0 3 [ 2 0 0 9 ], r es p e cti v el y). 
4. 3.   
N u m b e r  of  S u bj e cts  
4. 3. 1.   
Pl a n n e d  N u m b e r  of  S u bj e cts  
T his st u d y  will  e nr oll  a p pr o xi m at el y  7 0 s u bj e cts  wit h st er oi d -r efr a ct or y  a c ut e  G V H D fr o m 
a p pr o xi m at el y  4 0  st u d y sit es. 
4. 3. 2.   
R e pl a c e m e nt  of  S u bj e cts  
N ot  a p pli c a bl e.  
4. 4.   
D u r ati o n  of  T r e at m e nt  a n d  S u bj e ct  P a rti ci p ati o n  
Aft er si g ni n g t h e  i nf or m e d  c o ns e nt f or m (I C F), s cr e e ni n g  ass ess m e nts  m a y  b e  c o m pl et e d  o v er  a 
p eri o d  of  u p t o  2 8  d a ys.   E a c h s u bj e ct  e nr oll e d i n t h e st u d y  m a y  c o nti n u e t o r e c ei v e st u d y 
tr e at m e nt f or  as l o n g  as b e n efit is  o bs er v e d  a n d/ or tr e at m e nt  wit h dr a w al  crit eri a  ar e  n ot  m et .  If 

I n c yt e  C or p or ati o n 
P a g e  3 1  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
t h e s u bj e ct  dis c o nti n u es st u d y tr e at m e nt (i e, r u x oliti ni b  a n d  c orti c ost er oi ds), t h e n t h e tr e at m e nt 
p eri o d  will  e n d , a n d t h e s u bj e ct  will  e nt er  t h e f oll o w- u p  p eri o d (s e e S e cti o n  6. 4 ).  T h e s af et y 
f oll o w- u p  p eri o d  will l ast  3 0 t o  3 5  d a ys,  a n d t h e s ur vi v al f oll o w-u p  p eri o d  will l ast  u ntil  d e at h , 
wit h dr a w al  of  c o ns e nt,  or t h e  e n d  of t h e st u d y,  w hi c h e v er  o c c urs first.   St u d y  p arti ci p ati o n is 
e x p e ct e d t o  a v er a g e  a p pr o xi m at el y  1 2  m o nt hs  p er i n di vi d u al s u bj e ct. 
4. 5.   
O v e r all  St u d y  D u r ati o n  
T h e st u d y  b e gi ns  w h e n t h e first s u bj e ct si g ns t h e i nf or m e d  c o ns e nt.   S u bj e cts  w h o  ar e still 
r e c ei vi n g st u d y tr e at m e nt  at t h e ti m e  of t h e  pri m ar y  a nal ysis  will  b e  p er mitt e d t o  c o nti n u e  o n 
st u d y tr e at m e nt u ntil tr e at m e nt  wit h dr a w al  crit eri a  ar e  m et  (S e cti o n  5. 5 ).  All s u bj e cts  will  b e 
f oll o w e d f or s ur vi v al  u ntil d e at h ,  wit h dr a w al  of  c o ns e nt,  or t h e  e n d  of t h e st u d y,  w hi c h e v er 
o c c urs first .  T h e  st u d y  will  e n d  a n d t h e fi n al  a n al ysis  will  o c c ur  o n c e  7 5 %  of s u bj e cts  h a v e 
a c hi e v e d  2 -y e ar  N R M,  di e d  or  ar e l ost t o f oll o w- u p,  w hi c h e v er  o c c urs first. 
4. 6.   
St u d y  T e r mi n ati o n  
T h e  in v esti g at or r et ai ns t h e ri g ht t o t er mi n at e st u d y  p arti ci p ati o n  at  a n y ti m e,  a c c or di n g t o t h e 
t er ms s p e cifi e d i n t h e st u d y  c o ntr a ct.   T h e i n v esti g at or is t o  n otif y t h e i nstit uti o n al r e vi e w  b o ar d 
(I R B)/i n d e p e n d e nt  et hi cs  c o m mitt e e (I E C) i n  writi n g  of t h e st u d y's  c o m pl eti o n  or  e arl y 
t er mi n ati o n,  a n d s e n d  a  c o p y  of t h e  n otifi c ati o n t o t h e s p o ns or  or s p o ns or's  d esi g n e e  a n d r et ai n 
1  c o p y f or t h e sit e st u d y r e g ul at or y fil e.  
T h e  s p o ns or  m a y t er mi n at e t h e st u d y  el e cti v el y  or if r e q uir e d  b y r e g ul at or y  d e cisi o n.  If t h e st u d y 
is t er mi n at e d  pr e m at ur el y, t h e n t h e s p o ns or  will  n otif y t h e i n v esti g at ors, t h e I R Bs  a n d I E C s,  a n d 
t h e r e g ul at or y  b o di es  of t h e  d e cisi o n  a n d r e as o n f or t er mi n ati o n  of t h e st u d y. 
5.   
T R E A T M E N T  
5. 1.   
T r e at m e nt  Assi g n m e nt  
5. 1. 1.   
S u bj e ct  N u m b e ri n g  a n d  T r e at m e nt  Assi g n m e nt  
E a c h s u bj e ct  will  b e i d e ntifi e d i n t h e st u d y  b y  a s u bj e ct I D  n u m b er,  w hi c h is  a  c o m bi n ati o n  of 
t h e sit e I D  a n d s u bj e ct  n u m b er.   Sit e st aff s h o ul d  c o nt a ct t h e i nt er a cti v e  v oi c e r es p o ns e s yst e m 
(I V R S) t o  o bt ai n t h e s u bj e ct I D  n u m b er  d uri n g s cr e e ni n g. 
Sit e st aff  will  c o nt a ct t h e I V R S t o  e nr oll t h e s u bj e ct  a n d  o bt ai n t h e i niti al st u d y  dr u g  assi g n m e nt.  
T h e i n v esti g at or  or  d esi g n e e  will s el e ct t h e  assi g n e d  b ottl es  of st u d y  dr u g fr o m t h eir st o c k t h at 
c orr es p o n d t o t h e  n u m b er  pr o vi d e d  b y t h e I V R S, r e c or d t h e  b ottl e  n u m b ers i n t h e  el e ctr o ni c  c as e 
r e p ort f or m (e C R F ),  a n d  dis p e ns e t h e st u d y  dr u g t o t h e s u bj e ct.   All s u bs e q u e nt  dis p e nsi n g  of 
st u d y  dr u g s h o ul d f oll o w t his  pr o c ess.   F ull  d et ails  will  b e  pr o vi d e d i n t h e I V R S  m a n u al. 
All s u bj e ct  n u m b ers  will  b e  6  di gits; t h e first  3  di gits  will  b e t h e sit e  n u m b er ,  a n d t h e l ast  3  di gits 
will  b e t h e s u bj e ct 's  n u m b er.   T his s u bj e ct  n u m b er  will  b e  m ai nt ai n e d t hr o u g h o ut t h e st u d y  a n d 
will  n ot  b e r e assi g n e d .   S u bj e cts  w h o  wit h dr a w  c o ns e nt  or  dis c o nti n u e fr o m t h e st u d y  aft er  b ei n g 
assi g n e d  a s u bj e ct  n u m b er  will r et ai n t h eir i niti al  n u m b er.  

I n c yt e  C or p or ati o n 
P a g e  3 2  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
F or s u bj e cts  w h o si g n e d  a n I C F  b ut  ar e  n ot  all o c at e d  a n d f or s u bj e cts  w h o  ar e  all o c at e d  b ut  w er e 
n ot tr e at e d, r ef er t o t h e  e C R F  C o m pl eti o n  G ui d eli n es f or i nstr u cti o n  o n  w hi c h  e C R Fs t o 
c o m pl et e.  
5. 1. 2.   
R a n d o mi z ati o n 
N ot  a p pli c a bl e.  
5. 2.   
St u d y  D r u gs  
5. 2. 1.   
R u x oliti ni b  
5. 2. 1. 1.   
D es c ri pti o n  a n d  A d mi nist r ati o n  
R u x oliti ni b  5  m g t a bl ets  ar e r o u n d  a n d  w hit e t o  off- w hit e i n  c ol or. 
S u bj e cts  will  b e gi n tr e at m e nt  at  r u x oliti ni b  5 m g  BI D ; if h e m at ol o gi c  p ar a m et ers  ar e st a bl e  a n d 
n o tr e at m e nt -r el at e d t o xi cit y is  o bs er v e d  aft er t h e first  3  d a ys  of tr e at m e nt, t h e  d os e m a y  b e 
i n cr e as e d t o  1 0  m g  BI D.  St a bl e  h e m at ol o gi c  p ar a m et ers  ar e  d efi n e d  as t h e  a bs e n c e  of  a  ≥  5 0 % 
d e cr e as e  i n  pl at el et  c o u nts  a n d/ or A N C  r el ati v e to  D a y  1.   R u x oliti ni b  m a y  b e t a k e n  wit h o ut 
r e g ar d t o f o o d  e x c e pt  o n  d a ys  w h e n  P K s a m pl es  ar e  dr a w n;  o n t h os e  d a ys, s u bj e cts s h o ul d  b e 
i nstr u ct e d t o f ast  a n d r efr ai n fr o m t a ki n g r u x oliti ni b  u ntil  P K s a m pl es  ar e  c oll e ct e d.   S e e 
S e cti o n  7. 7. 1  f or  a d diti o n al i nf or m ati o n. 
S u bj e cts  m a y  h a v e  d os e r e d u cti o ns  or  m o difi c ati o ns  of r u x oliti ni b  d uri n g t h e  c o urs e  of  tr e at m e nt 
b as e d  o n  A E s,  cli ni c al  e v al u ati o n,  a n d l a b or at or y  ass ess m e nts.   S e e  S e cti o n  5. 4. 1  f or  d os e 
m o difi c ati o ns  of  r u x oliti ni b. 
S u bj e cts  ar e  p er mi tt e d t o r e m ai n  o n r u x oliti ni b tr e at m e nt  u ntil  wit h dr a w al fr o m st u d y tr e at m e nt 
is  c o nsi d er e d  n e c ess ar y  as  p er S e cti o n  5. 5 . 
5. 2. 1. 2.   
S u p pl y,  P a c k a gi n g,  a n d  L a b eli n g 
R u x oliti ni b  will  b e s u p pli e d  as  5  m g t a bl ets  p a c k a g e d i n  6 0- c o u nt  hi g h- d e nsit y  p ol y et h yl e n e 
b ottl es .   All t a bl et  e x ci pi e nts  c o m pl y  wit h t h e r e q uir e m e nts  of t he  a p pli c a bl e  c o m p e n di al 
m o n o gr a p hs. 
All I n c yt e i n v esti g ati o n al  pr o d u ct l a b els  will  b e i n t h e l o c al l a n g u a g e  a n d  will  c o m pl y  wit h t h e 
l e g al r e q uir e m e nts  of  e a c h  c o u ntr y  a n d  will st at e  "C a uti o n:  N e w  Dr u g --Li mit e d  b y  F e d er al ( or 
U nit e d  St at es) l a w t o i n v esti g ati o n al  us e. " 
5. 2. 1. 3.   
St o r a g e 
B ottl es  of r u x oliti ni b t a bl ets s h o ul d  b e st or e d  at r o o m t e m p er at ur e,  1 5° C t o  3 0° C ( 5 9 ° F t o  8 6° F).  

I n c yt e  C or p or ati o n 
P a g e  3 3  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
5. 2. 1. 4.   
I nst r u cti o n t o S u bj e cts  f o r  H a n dli n g R u x oliti ni b  
T h e s u bj e ct  m ust  b e i nstr u ct e d i n t h e  h a n dli n g  of st u d y  dr u g  as f oll o ws: 
•   T o st or e t h e  st u d y  dr u g  at r o o m t e m p er at ur e.  
•   T o  o nl y r e m o v e fr o m t h e st u d y  dr u g  b ottl e/ kit t h e  n u m b er  of t a bl ets  n e e d e d  at t h e 
ti m e  of  a d mi nistr ati o n. 
•   N ot t o r e m o v e  d os es i n  a d v a n c e  of t h e  n e xt s c h e d ul e d  a d mi nistr ati o n. 
•   T o  m a k e  e v er y  eff ort t o t a k e  d os es  o n s c h e d ul e. 
•   T o r e p ort  a n y  miss e d  d os es. 
•   T o t a k e st u d y  dr u g  wit hi n  1  h o ur  aft er  c o m pl eti n g  a  m e al ( m or ni n g  a n d  e v e ni n g  m e al) 
wit h  a  gl ass  of  w at er.  
•   N ot t o t a k e  a n ot h er  d os e i f v o miti n g  o c c urs  aft er t a ki n g st u d y  dr u g. 
•   T o  k e e p st u d y  dr u g i n  a s af e  pl a c e  a n d  o ut  of r e a c h  of  c hil dr e n. 
•   T o  bri n g  all  us e d  a n d  u n us e d st u d y  dr u g  kits t o t h e sit e  at  e a c h  visit.  
5. 2. 2.   
C o rti c ost e r oi ds  
Eit h er  or al  pr e d nis o n e  or  I V  m et h yl pr e d nis ol o n e  m a y  b e  us e d t o  b e gi n  c orti c ost er oid tr e at m e nt  at 
t h e i n v esti g at or's  dis cr eti o n. 
5. 2. 2. 1.   
P r e d nis o n e  
5. 2. 2. 1. 1.   D es c ri pti o n  
Pr e d nis o n e is  a  w hit e t o  off - w hit e,  o d orl ess,  cr yst alli n e  p o w d er.   T a bl ets  ar e t y pi c all y  w hit e i n 
c ol or  a n d  c o nt ai n l a ct os e  m o n o h y dr at e,  m a g n esi u m st e ar at e,  mi cr o cr yst alli n e  c ell ul os e, 
pr e g el ati ni z e d  st ar c h,  a n d s o di u m st ar c h  gl y c ol at e.  C o m m o nl y  a v ail a bl e   d os e str e n gt hs i n cl u d e 
1  m g,  2. 5  m g,  5  m g,  1 0  m g,  2 0  m g,  a n d  5 0  m g t a bl ets. 
5. 2. 2. 1. 2.   S u p pl y,  P a c k a gi n g,  a n d  L a b eli n g  
I n v esti g at ors  ar e r es p o nsi bl e f or  e ns uri n g t h at s u bj e cts r e c ei v e c o m m er ci all y  a v ail a bl e  s u p pli es 
of  pr e d nis o n e f or t h e  d ur ati o n  of t h e st u d y tr e at m e nt  p eri o d.  I n c yt e  m a y  pr o vi d e  pr e d nis o n e 
w h er e r e q uir e d  b y  a p pli c a bl e l a w  or r e g ul ati o n. 
5. 2. 2. 1. 3.   St o r a g e 
Pr e d nis o n e t a bl ets s h o ul d  b e st or e d i n  a c c or d a n c e  wit h l o c al  pr es cri bi n g i nf or m ati o n 
r e q uir e m e nts. 
5. 2. 2. 2.   
M et h yl p r e d nis ol o n e  
5. 2. 2. 2. 1.   D es c ri pti o n  
M et h yl pr e d nis ol o n e st eril e  p o w d er is  a n  a nti- i nfl a m m at or y  gl u c o c orti c oi d,  w hi c h  c o nt ai ns 
m et h yl pr e d nis ol o n e s o di u m s u c ci n at e  as t h e  a cti v e i n gr e di e nt.   M et h yl pr e d nis ol o n e s o di u m 

I n c yt e  C or p or ati o n 
P a g e  3 4  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
s u c ci n at e,  U S P, is t h e s o di u m s u c ci n at e  est er  of  m et h yl pr e d nis ol o n e,  a n d it  o c c urs  as  a  w hit e  or 
n e arl y  w hit e,  o d orl ess  h y gr os c o pi c,  a m or p h o us s oli d.  It is  v er y s ol u bl e i n  w at er  a n d i n  al c o h ol; 
it is i ns ol u bl e i n  c hl or of or m  a n d is  v er y sli g htl y s ol u bl e i n  a c et o n e. 
5. 2. 2. 2. 2.   S u p pl y,  P a c k a gi n g,  a n d  L a b eli n g 
I n v esti g at ors  ar e r es p o nsi bl e f or  e ns uri n g t h at s u bj e cts r e c ei v e c o m m er ci all y  a v ail a bl e  s u p pli es 
of  m et h yl pr e d nis ol o n e f or t h e  d ur ati o n  of t h e st u d y tr e at m e nt  p eri o d.  I n c yt e  m a y  pr o vi d e 
m et h yl pr e d nis ol o n e  w h er e r e q uir e d  b y  a p pli c a bl e l a w  or r e g ul ati o n. 
5. 2. 2. 2. 3.   St o r a g e 
M et h yl pr e d nis ol o n e ( u nr e c o nstit ut e d  pr o d u ct  or s ol uti o n) s h o ul d  b e st or e d i n  a c c or d a n c e  wit h 
l o c al  pr es cri bi n g i nf or m ati o n. 
5. 2. 2. 3.   
A d mi nist r ati o n  of  C o rti c ost e r oi ds 
S u bj e cts  will r e c ei v e  pr e d nis o n e  2. 5  m g/ k g  p er  d a y  or all y ( P O)  or  m et h yl pr e d nis ol o n e  2. 0  m g/ k g 
p er  d a y I V.   S u bj e cts  w h o  pr e vi o usl y  b e g a n  c orti c ost er oi d t h er a p y  at  a  diff er e nt  d os e  m a y r e m ai n 
o n t h at  d os e if  c o nsi d er e d  a p pr o pri at e  b y t h e tr e ati n g  p h ysi ci a n.   C orti c ost er oi ds s h o ul d  b e 
t a p er e d  as  p er i nstit uti o n al  g ui d eli n es at  a r at e t h at is  c o m m e n s ur at e  wit h r es ol uti o n  of  G V H D 
m a nif est ati o ns.  
A r e c o m m e n d e d t a p eri n g s c h e d ul e is  pr o vi d e d i n  T a bl e   1. 
T a bl e  1:  
R e c o m m e n d e d  C o rti c ost e r oi d  A d mi nist r ati o n  T a bl e,  D a ys  1  T h r o u g h  2 8 
St u d y  D a ys   
D os e  
D a ys  1 - 5  
Pr e d nis o n e  2. 5  m g/ k g  Q D  P O ( or  m et h yl pr e d nis ol o n e  2. 0  m g/ k g  p er  d a y I V) 
D a ys  6 - 1 0  
Pr e d nis o n e  2. 0  m g/ k g  Q D  P O ( or  m et h yl pr e d nis ol o n e  1. 6  m g/ k g  p er  d a y I V) 
D a ys  1 1- 1 5  
Pr e d nis o n e  1. 5  m g/ k g  Q D  P O ( or  m et h yl pr e d nis ol o n e  1. 2  m g/ k g  p er  d a y I V) 
D a ys  1 6 - 2 0  
Pr e d nis o n e  1. 0  m g/ k g  Q D  P O ( or  m et h yl pr e d nis ol o n e  0. 8  m g/ k g  p er  d a y I V) 
D a ys  2 1 - 2 5  
Pr e d nis o n e  0. 5  m g/ k g  Q D  P O ( or  m et h yl pr e d nis ol o n e  0. 4  m g/ k g  p er  d a y I V) 
D a ys  2 6- 2 8  
Pr e d nis o n e  0. 2 5  m g/ k g  Q D  P O ( or  m et h yl pr e d nis ol o n e  0. 2  m g/ k g  p er  d a y I V) 
Q D  =  o n c e  d ail y.  
If  G V H D fl ar es  d uri n g t h e t a p er  of  c orti c ost er oi ds, t h e n t h e  d os e  m a y  b e r e-es c al at e d  at t h e 
i n v esti g at or's  dis cr eti o n  a n d  will  n ot  b e  c o nsi d er e d tr e at m e nt f ail ur e,  as l o n g  as t h e  d os e  d o es  n ot 
e x c e e d t h e i niti al st arti n g  d os e.  If t h e  d os e r e q uir e d  e x c e e ds t his t hr es h ol d,  or if t h e fl ar e is 
u nr es p o nsi v e t o i n cr e as e d  c orti c ost er oi ds,  or if  m ulti pl e fl ar es  ar e   o bs er v e d, t h e n t h e s u bj e ct  will 
b e  c o nsi d er e d t o  h a v e  e x p eri e n c e d tr e at m e nt f ail ur e.  
C orti c ost er oi ds  m a y  b e t a k e n  or  a d mi nist er e d  wit h o ut r e g ar d t o f o o d  e x c e pt  o n  d a ys  w h e n  P K 
s a m pl es  ar e  dr a w n;  o n t h os e  d a ys, s u bj e cts s h o ul d  b e i nstr u ct e d t o f ast  a n d r efr ai n fr o m t a ki n g 
c orti c ost er oi ds  u ntil  aft er  P K s a m pl es  ar e  c oll e ct e d.   S e e  S e cti o n  7. 7. 1  f or  a d diti o n al i nf or m ati o n. 

I n c yt e  C or p or ati o n 
P a g e  3 5  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
5. 2. 2. 4.   
P r o p h yl a cti c  a n d  S u p p o rti v e  C a r e  M e di c ati o ns 
P a ti e nts  w h o  u n d er g o  all o-H S C T   ar e  at ris k f or  a  v ari et y  of i nf e cti o ns  b as e d  o n t h e  d e gr e e  of 
i m m u n os u p pr essi o n i n d u c e d  b y t h e  c o n diti o ni n g r e gi m e n b ef or e  tr a ns pl a nt.   As s u c h, it is 
c o nsi d er e d r o uti n e  pr a cti c e t o  us e  a nti bi oti cs,  a nti -i nf e cti v es,  a n d i m m u niz ati o ns  as  pr o p h yl a cti c 
t h er a pi es (T o m bl y n  et  al  2 0 0 9 ).  I n  c as es  w h er e  p ost-tr a ns pl a nt  a nti-i nf e cti v e  pr o p h yl a xis 
m e as ur es  ar e  n e c ess ar y,  o n g oi n g t h er a p y  m a y  c o nti n u e  at t h e i n v esti g at or 's  dis cr eti on  p er 
i nstit uti o n al  g ui d eli n es. 
S yst e mi c  a n d t o pi c al  G V H D  pr o p h yl a xis  m e di c ati o ns ( e g ,  c y cl os p ori n e,  m et h otr e x at e, 
t a cr oli m us)  m a y  b e  c o nti n u e d  at t h er a p e uti c  d os es  as  a p pr o pri at e  b as e d  o n st a g e  a n d sit es  of 
dis e as e.  
A d diti o n al s u p p orti v e  c ar e  m e as ur es ( e g ,  us e  of a nti m otilit y  a g e nts f or  di arr h e a  m a n a g e m e nt)  ar e 
p er mitt e d  at t h e i n v esti g at or 's  dis cr eti o n. 
5. 3.   
T r e at m e nt  C o m pli a n c e  
C o m pli a n c e  wit h  all st u d y -r el at e d  m e di c ati o ns s h o ul d  b e  e m p h asi z e d t o t h e s u bj e ct  b y t h e sit e 
p ers o n n el,  a n d  a p pr o pri at e st e ps s h o ul d  b e t a k e n t o  o pti mi z e  c o m pli a n c e  d uri n g t h e st u d y.  
C o m pli a n c e  wit h r u x oliti ni b  will  b e  c al c ul at e d   b y t h e s p o ns or  b as e d  o n t h e  dr u g  a c c o u nt a bilit y 
d o c u m e nt e d  b y t h e sit e st aff  a n d  m o nit or e d  b y t h e s p o ns or/ d esi g n e e (t a bl et  c o u nts).   S u bj e cts 
will  b e i nstr u ct e d t o  bri n g  all st u d y -r el at e d m e di c ati o ns  wit h t h e m t o t h e st u d y  visits i n  or d er f or 
sit e  p ers o n n el t o  c o n d u ct t a bl et  c o u nts t o  ass ess st u d y  dr u g  a c c o u nt a bilit y.   T h e  dr u g 
a c c o u nt a bilit y  d o c u m e nt ati o n  will  b e  us e d  b y t h e s p o ns or t o  c al c ul at e tr e at m e nt  c o m pli a n c e. 
Alt h o u g h  c o m m er ci al s u p pli es  of  c orti c ost er oi ds  will  b e  us e d ,  d os e  c h a n g es  a n d i nt err u pti o ns 
will  als o  b e  d o c u m e nt e d i n t h e  m e di c al r e c or d  a n d  m o nit or e d  b y t h e s p o ns or  or its  d esi g n e e.   As 
c orti c ost er oi d  d os e str e n gt hs  a n d  a d mi nistr ati o n t y p es  will  v ar y,  c o m pli a n c e  wit h  c orti c ost er oi ds 
will  n ot  b e  c al c ul at e d.  
5. 4.   
T r e at m e nt  I nt e r r u pti o ns  a n d  A dj ust m e nts  
5. 4. 1.   
D os e  M o difi c ati o ns 
D os e i nt err u pti o ns  a n d  m o difi c ati o ns  m a y  o c c ur f or i n di vi d u al st u d y s u bj e cts  b as e d  o n t h e 
pr es e n c e  or  a bs e n c e  of t o xi cit y.  
5. 4. 2.   
C rit e ri a  a n d  P r o c e d u r es f o r  D os e I nt e r r u pti o ns  a n d  A dj ust m e nts  of  R u x oliti ni b  
5. 4. 2. 1.   
D os e I nt e r r u pti o ns  a n d  R e d u cti o ns  
5. 4. 2. 1. 1.   T o xi cit y  M a n a g e m e nt 
Tr e at m e nt  wit h r u x oliti ni b  m a y  b e  d el a y e d  u p t o  1 4  d a ys t o  all o w f or r es ol uti o n  of t o xi cit y 
(T a bl e   2).  S u bj e cts  m a y r es u m e tr e at m e nt if  n o  m e di c al  c o n diti o n  or  ot h er  cir c u mst a n c e  e xists 
t h at, i n t h e  o pi ni o n  of t h e i n v esti g at or,  w o ul d  m a k e t h e s u bj e ct  u ns uit a bl e f or f urt h er 
p arti ci p ati o n i n t h e st u d y.   T h e i n v esti g at or s h o ul d  c o nt a ct t h e s p o ns or  m e di c al  m o nit or t o 
dis c uss  c as es  w h er e tr e at m e nt  h as  b e e n  d el a y e d f or  m or e t h a n  1 4  d a ys  b ef or e r est arti n g 
tr e at m e nt. 

I n c yt e  C or p or ati o n 
P a g e  3 6  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
B e c a us e s u bj e cts  m a y  e nt er t h e st u d y  wit h  c o m pr o mis e d  b o n e  m arr o w f u n cti o n, t h es e  d os e 
r e d u cti o ns  ar e  pr o vi d e d  as  g ui d eli n es; i n di vi d u al  d e cisi o ns r e g ar di n g  d os e r e d u cti o n s h o ul d  b e 
m a d e  usi n g  cli ni c al j u d g m e nt  a n d i n  c o ns ult ati o n  wit h t h e s p o ns or' s  m e di c al  m o nit or, t a ki n g i nt o 
a c c o u nt r el at e d n ess  of t h e  A E t o t h e st u d y  dr u g  a n d t h e s u bj e ct 's  u n d erl yi n g  c o n diti o n.   A d v ers e 
e v e nts t h at  h a v e  a  cl e ar  alt er n ati v e  e x pl a n ati o n  or tr a nsi e nt ( ≤  7 2  h o urs)  a b n or m al l a b or at or y 
v al u es  wit h o ut  ass o ci at e d  cli ni c all y si g nifi c a nt si g ns  or s y m pt o ms  m a y  b e  e x e m pt fr o m 
d os e-r e d u cti o n r ul es.  
S u bj e cts  w h o  ar e  c urr e ntl y r e c ei vi n g  r u x oliti ni b  1 0  m g  BI D  m a y  b e r e d u c e d t o  5  m g  BI D; 
s u bj e cts r e c ei vi n g  5  m g  BI D  m a y  b e r e d u c e d f urt h er t o  5  m g  Q D.   S u bj e cts w h o  ar e  u n a bl e  t o 
t ol er at e r u x oliti ni b at  a  d os e  of  5  m g  Q D  s h o ul d  b e  wit h dr a w n fr o m st u d y  tr e at m e nt (T a bl e   3). 
T a bl e  2:  
G ui d eli n es f o r I nt e r r u pti o n  a n d  R est a rti n g  of  R u x oliti ni b  
A D V E R S E  E V E N T  
A C TI O N  T A K E N 
C h e mist r y  
•   A S T  a n d/ or  A L T  >  3. 0  ×  U L N  i n s u bj e cts 
wit h  n or m al  A L T/ A S T  at  b as eli n e . 
St e p  1:   I nt err u pt st u d y tr e at m e nt u p t o  1 4  d a ys  u ntil t h e t o xi cit y  h a s 
r es ol v e d t o  ≤  Gr a d e  1.  E x c e pt i o ns r e q uir e s p o ns or  a p pr o v al. 
St e p  2:   R est art st u d y  tr e at m e nt at s a m e  d os e.  If  ass e ss e d  as r el at e d t o 
st u d y  tr e at m e nt, r est art st u d y tr e at m e nt at  n e xt l o w er  d os e  a n d  m o nit or 
as  cli ni c all y i n di c at e d.  
N O T E:   I n s u bj e cts  wit h  G V H D-r el at e d  c h e mistr y  el e v ati o ns  at 
b as eli n e,  c o nt a ct t h e s p o ns or  m e di c al  m o nit or t o  dis c uss  cli ni c al 
m a n a g e m e nt  a n d  p ossi bl e  d os e r e d u cti o ns.  
•   T ot al  bilir u bi n  el e v ati o ns  t h at  o c c ur i n t h e 
pr es e n c e  of  G V H D r es p o ns e t h at , i n t h e 
i n v e sti g at or's  o pi ni o n, c a n n ot  b e 
attri b ut e d t o  n e w li v er  G V H D  or 
c o n c o mit a nt t h er a p y . 
•   T ot al  b ilir u bi n 3. 0 − 5 . 0 ×  U L N : 
−  R e p e at  ass ess m e nt  wit hi n  7  d a ys .  If  el e v ati o n p ersist s: 
   R e d u c e  r u x oliti ni b d os e  b y  1  l e v el u ntil  bilir u bi n  ≤  1. 5  ×  U L N . 
   R es u m e  pr e vi o us  d os e if r es ol v e d i n  1 4  d a ys; if  >  1 4  d a ys, 
m ai nt ai n r e d u c e d  d os e . 
•   T ot al  b ilir u bi n > 5. 0 − 1 0. 0  ×  U L N:  
−  R e p e at  ass ess m e nt  wit hi n  7  d a ys.  If  el e v ati o n  p ersists:  
   H ol d  r u x oliti ni b u ntil  bilir u bi n  ≤  1. 5  ×  U L N . 
   M o nit o r  L F T s  w e e kl y  or  m or e fr e q u e ntl y  a s  a p pr o pri at e.  
   R es u m e  pr e vi o us  d os e if r es ol v e d i n  1 4  d a ys; if  >  1 4  d a ys, 
r es u m e  at r e d u c e d  d os e. 
•   T ot al  b ilir u bi n  > 1 0. 0  ×  U L N:  
−  R e p e at  ass ess m e nt  wit hi n  7  d a ys.  If  el e v ati o n  p ersists:  
   H ol d  r u x oliti ni b u ntil  bilir u bi n   ≤ 1. 5  ×  U L N . 
   R es u m e  at r e d u c e d  d os e  if r es ol v e d i n  1 4  d a ys; if  >  1 4  d a ys, 
dis c o nti n u e  r u x oliti ni b  a n d  m o nit or  as  a p pr o pri at e. 
•   T ot al  bilir u bi n  el e v ati o ns  t h at  o c c ur i n 
s u bj e cts  wit h  St a g e  1/ 2 li v er  G V H D  t h at, 
i n t h e i n v esti g at or's  o pi ni o n, c a n n ot  b e 
attri b ut e d t o  w ors e ni n g li v er  G V H D  or 
c o n c o mit a nt t h er a p y . 
•   T ot al  b ilir u bi n  > 3. 0  ×  U L N : 
−  R e p e at  ass ess m e nt  wit hi n  7  d a ys.  If  el e v ati o n  p ersists:  
   R e d u c e  r u x oliti ni b  d os e b y  1  d os e l e v el . 
•   If  bilir u bi n  ≤  3. 0 ×  U L N , m a y  r es u m e  pr e vi o us  d os e . 

I n c yt e  C or p or ati o n 
P a g e  3 7  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
T a bl e  2:  
G ui d eli n es f o r I nt e r r u pti o n  a n d  R est a rti n g  of  R u x oliti ni b  ( C o nti n u e d) 
A D V E R S E  E V E N T  
A C TI O N  T A K E N  
H e m at ol o g y  
•   A N C  <  1. 0  ×  1 0 9/ L, s us p e ct e d  as 
u nr el at e d t o st u d y tr e at m e nt ( e g,  G V H D, 
a cti v e  C M V  vir e mi a) . 
St e p  1:   R e d u c e  d os e  of r u x oliti ni b  b y  1  d os e l e v el.  
St e p  2:   M o nit or  A N C  c o u nt  a s  cli ni c all y i n di c at e d.  
St e p  3:   If  A N C  c o u nt is  ≥  1. 0 ×  1 0 9/L f or  m or e t h a n  7  d a ys, t h e n t h e 
pr e vi o us  d os e  of r u x oliti ni b  m a y  b e r es u m e d.  
•   A N C  <  1. 0  ×  1 0 9/ L, s us p e ct e d  as r el at e d 
t o st u d y tr e at m e nt. 
•   A N C  <  1. 0  ×  1 0 9/L,  wit h  a n  or al 
t e m p er at ur e  of  at l e a st  3 8. 5 ° C  O R  wit h 
≥  Gr a d e  3 i nf e cti o n.  
•   A N C  <  0. 5  ×  1 0 9/ L. 
St e p  1:   I nt err u pt st ud y tr e at m e nt f or  u p t o  1 4  d a ys.  
St e p  2:   M o nit or  A N C  c o u nt  a s  cli ni c all y i n di c at e d.  
St e p  3:   If  A N C  c o u nt is  ≥  1. 0 ×  1 0 9/L f or  m or e t h a n  7  d a ys,  t h e n 
r u x oliti ni b  m a y  b e r est art e d  at 1  d os e l e v el  b el o w t h e  c urr e nt  d os e.  
St e p  4:   If  A N C  c o u nt is  ≥  1. 0 ×  1 0 9/L f or  m or e t h a n  7  d a ys  aft er 
tr e at m e nt  at  a r e d u c e d  d os e, t h e pr e vi o us  d os e  l e v el of r u x oliti ni b  m a y 
b e r es u m e d . 
•   Pl at el et  c o u nt is  <  1 0  ×  1 0 9/L,  or  pl at el et 
c o u nt  h as  d e cr e as e d  b y  ≥  5 0 % fr o m 
b as eli n e , s us p e ct e d  as  u nr el at e d t o st u d y 
tr e at m e nt. 
St e p  1:   R e d u c e  d os e  of r u x oliti ni b  b y  1  d os e l e v el.  
St e p  2:   M o nit or  pl at el et  c o u nt  as  cli ni c all y i n di c at e d.  
St e p  3:   If  pl at el et  c o u nt r et ur ns t o  2 0 ×  1 0 9/L f or  m or e t h a n  7  d a ys, 
t h e n r u x oliti ni b  m a y  b e r est art e d  at 1  d os e l e v el  b el o w t h e  c urr e nt  d os e.  
•   Pl at el e t  c o u nt is  <  1 0 ×  1 0 9/L,  or  pl at el et 
c o u nt  h as  d e cr e as e d  b y  ≥  5 0 % fr o m 
b as eli n e , s us p e ct e d  as r el at e d t o st u d y 
tr e at m e nt. 
•   Pl at el ets  <  2 0  ×  1 0 9/L,  wit h  a n  or al 
t e m p er at ur e  of  at l e a st  3 8. 5 ° C. 
St e p  1:   I nt err u pt st u d y tr e at m e nt f or  u p t o  1 4  d a ys. 
St e p  2:   M o nit or  pl at el et  c o u nt  as  cli ni c all y i n di c at e d.  
St e p  3 a:   If  pl at el et  c o u nt r et ur ns t o  2 0 ×  1 0 9/L f or  m or e t h a n  1 4  d a ys, 
t h e n t h e  d os e  of r u x oliti ni b  m a y  b e r es u m e d. 
St e p  3 b:   If  pl at el et  c o u nt  d o es  n ot r et ur n t o  <  1 0 ×  1 0 9/L  a n d t h er e is 
n o  pl at el et  tr a nsf usi o n-i n d e p e n d e nt r e c o v er y t o  a b o v e  <  1 0 ×  1 0 9/L, 
t h e n a  b o n e  m arr o w  bi o ps y  s h o ul d  b e  p erf or m e d.  If  m e g a k ar y o c yti c 
h y p o pl asi a  a n d  n o  pl at el et tr a nsf usi o n -i n d e p e n d e nt r e c o v er y  ar e 
o bs er v e d  wit hi n  7 2  h o urs, t h e n  st u d y tr e at m e nt s h o ul d  b e  dis c o nti n u e d.  
St e p  4:   If  pl at el et  c o u nt r e m ai ns  ≥ 2 0  ×  1 0 9/L f or  m or e t h a n  7  d a ys 
aft er tr e at m e nt  at  a r e d u c e d  d os e,  t h e n t h e  pr e vi o us  d os e l e v el  of 
r u x oliti ni b  m a y  b e r es u m e d. 
Ot h e r t o xi citi es  
•   A n y  Gr a d e  1  or  Gr a d e  2 t o xi cit y . 
C o nti n u e  tr e at m e nt a n d tr e at t h e t o xi cit y;  m o nit or  as  cli ni c all y 
i n di c at e d. 
•   A n y  Gr a d e  3 t o xi cit y, if  cli ni c all y 
si g nifi c a nt  a n d  n ot  m a n a g e a bl e  b y 
s u p p orti v e  c ar e . 
St e p  1:   I nt err u pt st u d y tr e at m e nt u p t o  1 4  d a ys  u ntil t o xi cit y r es ol v es t o 
≤  Gr a d e  1.  
St e p  2:   R est art st u d y  tr e at m e nt at s a m e  d os e ; if  a ss ess e d  as r el at e d t o 
st u d y  tr e at m e nt, t h e n r est art st u d y tr e at m e nt at  n e xt l o w er  d os e , a n d 
m o nit or  as  cli ni c all y i n di c at e d.  
•   A n y r e c urr e nt  Gr a d e  3 t o xi cit y  at  5  m g 
Q D  d os e . 
Dis c o n ti n u e st u d y tr e at m e nt; f oll o w-u p  p er  P r ot o c ol.  E x c e pti o ns 
r e q uir e s p o ns or  a p pr o v al. 
•   A n y  ot h er  Gr a d e  4 t o xi cit y . 
Dis c o nti n u e st u d y  tr e at m e nt; f oll o w-u p  p er  P r ot o c ol. 
U L N  =  u p p er li mit  of  n or m al . 

I n c yt e  C or p or ati o n 
P a g e  3 8  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
T a bl e  3:  
D os e  R e d u cti o n  L e v els f o r  R u x oliti ni b  
C u r r e nt  D os e  
Fi rst  D os e  R e d u cti o n  
S e c o n d  D os e  R e d u cti o n  
1 0  m g  BI D  
5  m g  BI D  
5  m g  Q D  
5  m g  BI D  
5  m g  Q D  
Dis c o nti n u e  
5. 4. 2. 1. 2.   C o a d mi nist r ati o n  Wit h  St r o n g  C Y P 3 A 4 I n hi bit o rs  o r  D u al  C Y P 2 C 9/ C Y P 3 A 4 
I n hi bit o rs 
R u x oliti ni b is  m ai nl y  eli mi n at e d i n  h u m a ns  b y  o xi d ati v e  m et a b olis m  c at al y z e d  pr e d o mi n a ntl y  b y 
c yt o c hr o m e  P 4 5 0 ( C Y P ) 3 A 4  a n d  C Y P 2 C 9  a n d is  n ot  a s u bstr at e f or tr a ns p ort ers i n cl u di n g 
P- gl y c o pr ot ei n ( P- g p).   T h er ef or e,  c o n c o mit a nt  m e di c ati o ns t h at i n hi bit  C Y P 3 A 4  a n d  C Y P 2 C 9 
e n z y m es  mi g ht i n cr e as e  e x p os ur e t o r u x oliti ni b.   S e e  S e cti o n  5. 6  f or  a d diti o n al  d et ails. 
5. 4. 2. 2.   
D os e  Es c al ati o n  of  R u x oliti ni b 
S u bj e cts  will  b e gi n tr e at m e nt  at r u x oliti ni b  5  m g  BI D ; if h e m at ol o gi c  p ar a m et ers  ar e st a bl e  a n d 
n o tr e at m e nt -r el at e d t o xi cit y is  o bs er v e d  aft er t h e first  3  d a ys  of tr e at m e nt, t h e  d os e m a y  b e 
i n cr e as e d t o  1 0  m g  BI D.  St a bl e  h e m at ol o gi c  p ar a m et ers  ar e  d efi n e d  as t h e  a bs e n c e  of  a  ≥   5 0 % 
d e cr e as e i n  pl at el et  c o u nts  a n d / or  A N C r el ati v e t o D a y  1 . 
As  d es cri b e d i n  T a bl e   2, s u bj e cts  w h o  h a v e  h a d  a  d os e r e d u cti o n  of r u x oliti ni b i n  or d er t o 
m a n a g e t o xi cit y  m a y r es u m e tr e at m e nt  at t h e  pr e vi o us  d os e if  h e m at ol o gi c  p ar a m et ers  m e et t h e 
r e q uir e d t hr es h ol d(s). 
S u bj e cts   w h o  h a v e  pr e vi o usl y  h a d  a r e d u cti o n i n t h e  d os e  of r u x oliti ni b  m a y  h a v e t h eir  d os e 
r e-es c al at e d if  a  G V H D fl ar e is  e x p eri e n c e d,  pr o vi d e d t h at  h e m at ol o gi c t hr es h ol ds  ar e  d es cri b e d 
i n T a bl e   2 ar e  m et.   D os e r e -es c al ati o n l e v els  of r u x oliti ni b  ar e  d es cri b e d i n  T a bl e   4.  
D os e i n cr e as es  m a y  n ot  e x c e e d  1 0  m g  BI D.  
T a bl e  4:  
D os e  Es c al ati o n  L e v els f o r  R u x oliti ni b 
C u r r e nt  D os e  
Fi rst  D os e  Es c al ati o n  
S e c o n d  D os e  Es c al ati o n  
5  m g  Q D  
5  m g  BI D  
1 0  m g  BI D  
5  m g  BI D  
1 0  m g  BI D  
−  
5. 4. 2. 3.   
T a p e ri n g  of  R u x oliti ni b 
If  a s u bj e ct  h as  a c hi e v e d  C R  or V G P R  at  D a y  1 8 0 , i n v esti g at ors  m a y  b e gi n t o t a p er t h e  d os e  of 
r u x oliti ni b  b y  1  d os e l e v el  pr o vi d e d  c orti c ost er oi ds  h a v e  b e e n  dis c o nti n u e d f or  at l east   8 w e e ks  
f oll o wi n g i nstit uti o n al  g ui d eli n es.  S u bj e cts  w h o  ar e  still r e c ei vi n g  c al ci n e uri n i n hi bit ors  or  ot h er 
a g e nts f or  G V H D  pr o p h yl a xis  at t his ti m e  m a y  c o nti n u e t o  d o s o  at t h e tr e ati n g i n v esti g at or 's 
dis cr eti o n.  I n  a d diti o n, s u bj e cts  m ust  n ot  b e  e x p eri e n ci n g  a n y  Gr a d e  2  or  hi g h er  h e m at ol o gi c 
t o xi cit y r el at e d t o r u x oliti ni b  or s y m pt o ms  of  a n  a cti v e i nf e cti o n.   S u bs e q u e nt r e d u cti o ns t o t h e 
d os e  of r u x oliti ni b  m a y  o c c ur  aft er  a n  a d diti o n al  5 6  d a ys  h a v e  el a ps e d   pr o vi d e d t h e 
af or e m e nti o n e d r e q uir e m e nts  ar e still  b ei n g  m et . 
I n v esti g at ors  wis hi n g t o i niti at e  a t a p er  of r u x oliti ni b  at  a n  e arli er ti m e p oi nt  m a y  d o s o  u p o n 
c o ns ult ati o n  wit h  a n d  a p pr o v al fr o m t h e s p o ns or 's m e di c al  m o nit or.  

I n c yt e  C or p or ati o n 
P a g e  3 9  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
If  G V H D si g ns/s y m pt o ms  w ors e n  d uri n g t h e t a p er  of r u x oliti ni b, t h e  d os e  m a y  b e  es c al at e d  b y 
1  d os e l e v el  as i n di c at e d i n  T a bl e   4; if t h e s u bj e ct r e q uir es  a d diti o n al s yst e mi c t h er a p y (i n cl u d es 
r est arti n g  of  c orti c ost er oi ds), t h e n t h e s u bj e ct  w o ul d  b e  c o nsi d er e d  as  h a vi n g  pr o gr essi o n  of 
dis e as e  a n d  w o ul d  b e  wit h dr a w n fr o m st u d y tr e at m e nt.  
If s u bj e cts  c o m pl et el y t a p er  off r u x oliti ni b  a n d  G V H D si g ns/s y m pt o ms r e a p p e ar  at  a l at er ti m e, 
r u x oliti ni b t h er a p y  m a y  b e r est art e d  at t h e tr e ati n g i n v esti g at or's  dis cr eti o n,  a n d t h e s u bj e ct 
w o ul d r es u m e t h e  ass ess m e nt s c h e d ul e  usi n g t h e  ori gi n al  D a y  1  as  a r ef er e n c e  p oi nt. 
5. 4. 3.   
C rit e ri a  a n d  P r o c e d u r es f o r  D os e I nt e r r u pti o ns  o r  A dj ust m e nts  of  
C o rti c ost e r oi ds  
C orti c ost er oi d  d os es s h o ul d  b e t a p er e d  as  p er t h e r e c o m m e n d e d t a p eri n g s c h e d ul e i n  T a bl e   1 or 
as  p er  i nstit uti o n al g ui d eli n es;  f urt h er  d os e  m o difi c ati o ns  m a y  b e  m a d e  at t h e tr e ati n g 
i n v esti g at or's  dis cr eti o n. 
5. 4. 4.   
C rit e ri a f o r  P e r m a n e nt  Dis c o nti n u ati o n  of  St u d y  T r e at m e nt  
T h e  o c c urr e n c e  of  a n  u n a c c e pt a bl e t o xi cit y  n ot  c a us e d  b y t h e  u n d erl yi n g  dis e as e  will  b e 
pr es u m e d t o  b e  r el at e d t o st u d y  dr u g tr e at m e nt a n d  will r e q uir e t h at t h e st u d y  dr u g  b e 
p er m a n e ntl y  dis c o nti n u e d.   U n a c c e pt a bl e t o xi cit y is  d efi n e d  as f oll o ws: 
•   O c c urr e n c e  of  a n  A E t h at is r el at e d t o tr e at m e nt  wit h t h e st u d y  dr u g t h at , i n t h e 
j u d g m e nt  of t h e i n v esti g at or  or t h e s p o ns or's  m e di c al  m o nit or,  c o m pr o mis es t h e 
s u bj e ct's  a bilit y t o  c o nti n u e st u d y-s p e cifi c  pr o c e d ur es  or is  c o nsi d er e d t o  n ot  b e i n t h e 
s u bj e ct's  b est i nt er est.  
•   P ersist e nt  A E r e q uiri n g  a  d el a y  of t h er a p y f or  m or e t h a n  1 4  d a ys,  u nl ess  a  gr e at er 
d el a y  h as  b e e n  a p pr o v e d  b y t h e s p o ns or. 
5. 5.   
Wit h d r a w al  of  S u bj e cts  F r o m  St u d y  T r e at m e nt  
T h e  d e cisi o n t o  dis c o nti n u e st u d y tr e at m e nt  will  n ot  c o nstit ut e st u d y  c o m pl eti o n ( se e 
S e cti o n  5. 5. 3 ).  I n t h e  e v e nt t h at t h e  d e cisi o n is  m a d e t o  dis c o nti n u e st u d y tr e at m e nt, t h e 
tr e at m e nt p eri o d  will  b e  c o nsi d er e d  c o m pl et e ,  a n d t h e f oll o w- u p  p eri o d will  b e gi n.  
5. 5. 1.   
Wit h d r a w al  C rit e ri a  
S u bj e cts  m ust   b e  wit h dr a w n fr o m st u d y tr e at m e nt f or t h e f oll o wi n g r e as o ns: 
•   T h e s u bj e ct  h as  e x p eri e n c e d  a n  u n a c c e pt a bl e t o xi cit y . 
•   R el a ps e  of t h e  u n d erl yi n g  m ali g n a n c y. 
•   T h e s u bj e ct is  u n a bl e t o t ol er at e r u x oliti ni b  at  a  d os e  of  5  m g  Q D.  
•   A d diti o n al s yst e mi c t h er a p y is r e q uir e d f or  G V H D  pr o gr essi o n  or l a c k  of r es p o ns e, 
i n cl u di n g  c orti c ost er oi ds  e q u al t o  or  gr e at er t h a n t h e  d os e  us e d  o n  St u d y D a y  1 . 
•   F urt h er  p arti ci p ati o n  w o ul d  b e i nj uri o us t o t h e s u bj e ct' s  h e alt h  or  w ell- b ei n g, i n t h e 
i n v esti g at or's  m e di c al j u d g m e nt . 
•   T h e s u bj e ct  b e c o m es  pr e g n a nt. 

I n c yt e  C or p or ati o n 
P a g e  4 0  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
•   C o ns e nt is  wit h dr a w n. 
•   T h e st u d y is t er mi n at e d  b y t h e s p o ns or. 
•   T h e st u d y is t er mi n at e d  b y t h e l o c al  h e alt h  a ut h orit y , I R B,  or I E C. 
A s u bj e ct   m a y b e  wit h dr a w n fr o m st u d y tr e at m e nt  as f oll o ws:  
•   If,  d uri n g t h e  c o urs e  of t h e st u d y,  a s u bj e ct is f o u n d  n ot t o  h a v e  m et  eli gi bilit y 
crit eri a,  t h e n t h e m e di c al  m o nit or, i n  c oll a b or ati o n  wit h t h e i n v esti g at or,  will 
d et er mi n e  w h et h er t h e s u bj e ct s h o ul d  b e  wit h dr a w n fr o m t h e st u d y. 
•   If  a s u bj e ct is  n o n c o m pli a nt  wit h st u d y  pr o c e d ur es  or st u d y  dr u g  a d mi nistr ati o n i n t h e 
i n v esti g at or's  o pi ni o n, t h e n t h e s p o ns or s h o ul d  b e  c o ns ult e d f or i nstr u cti o n  o n 
h a n dli n g t h e s u bj e ct. 
5. 5. 2.   
Wit h d r a w al  P r o c e d u r es  
I n t h e  e v e nt t h at t h e  d e cisi o n is  m a d e t o  p er m a n e ntl y  dis c o nti n u e t h e st u d y  dr u g, t h e s u bj e ct  will 
b e  wit h dr a w n fr o m t h e st u d y,  a n d t h e  E O T   visit s h o ul d  b e  c o n d u ct e d.   R e as o n a bl e  eff orts s h o ul d 
b e  m a d e t o  h a v e t h e s u bj e ct r et ur n f or  a f oll o w- u p  visit.   T h es e  visits  ar e  d es cri b e d i n  S e cti o n  6 .  
T h e l ast  d at e  of t h e l ast   d os e  of st u d y  dr u g  a n d t h e r e as o n f or s u bj e ct  wit h dr a w al  will  b e r e c or d e d 
i n t h e  e C R F. 
If  a s u bj e ct is  wit h d r a w n f r o m st u d y t r e at m e nt:  
•   T h e st u d y  m o nit or  or s p o ns or  m ust  b e  n otifi e d. 
•   T h e r e as o n(s) f or  wit h dr a w al  m ust  b e  d o c u m e nt e d i n t h e s u bj e ct' s  m e di c al r e c or d  a n d 
i n t h e  e C R F. 
•   T h e  E O T  visit s h o ul d  b e  p erf or m e d. 
•   T h e  d at e  of t h e  E O T  visit s h o ul d  b e r e gist er e d i n t h e I V R S. 
•   S u bj e cts  m ust  b e f oll o w e d f or s af et y  u ntil t h e ti m e  of t h e f oll o w - u p  visit  or  u ntil 
st u d y  dr u g –r el at e d t o xi citi es r es ol v e, r et ur n t o  b as eli n e,  or  ar e  d e e m e d irr e v ersi bl e, 
w hi c h e v er is l o n g est.  
If t h e s u bj e ct  dis c o nti n u es st u d y tr e at m e nt  a n d  a cti v el y  wit h dr a ws  c o ns e nt f or  c oll e cti o n  of 
f oll o w- u p  d at a (s af et y f oll o w-u p  or  dis e as e  ass ess m e nt),  t h e n  n o  a d diti o n al  d at a  c oll e cti o n 
s h o ul d  o c c ur;  h o w e v er, s u bj e cts  will  h a v e t h e  o pti o n  of  wit h dr a wi n g  c o ns e nt f or st u d y tr e at m e nt 
b ut  c o nti n ui n g i n t h e f oll o w- u p  p eri o d  of t h e st u d y f or s af et y/ effi c a c y  ass ess m e nts. 
5. 5. 3.   
St u d y  C o m pl eti o n  
A s u bj e ct  will  b e  c o nsi d er e d  as  c o m pl eti n g t h e st u d y if t h e y  m e et  a n y  of t h e f oll o wi n g  crit eri a:  
•   S u bj e ct  di es  a n d  a  d at e  of  d e at h is  a v ail a bl e.  
•   S u bj e ct is  k n o w n t o  h a v e  di e d;  h o w e v er, t h e  d at e  of  d e at h  c a n n ot  b e  o bt ai n e d.  
( N O T E:   E v er y  eff ort  m ust  b e  m a d e t o  o bt ai n t h e  d at e  of  d e at h.) 
•   S u bj e ct  h as  dis c o nti n u e d st u d y tr e at m e nt  a n d  h as  wit h dr a w n  c o ns e nt f or  c oll e cti o n  of 
f oll o w- u p a nti c a n c er   a n d s ur vi v al  d at a. 

I n c yt e  C or p or ati o n 
P a g e  4 1  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
5. 6.   
C o n c o mit a nt  M e di c ati o ns  
5. 6. 1.   
P e r mitt e d  M e di c ati o ns  
C o n c o mit a nt tr e at m e nts  a n d/ or  pr o c e d ur es t h at  ar e r e q uir e d t o  m a n a g e  a s u bj e ct' s  m e di c al 
c o n diti o n (i n cl u di n g  pr o p h yl a cti c  a n d/ or s u p p orti v e  c ar e  m e di c ati o ns  as  d es cri b e d i n 
S e cti o n  5. 2. 2. 4 )  d uri n g t h e st u d y  will  als o  b e r e c or d e d i n t h e  eC R F.  
5. 6. 2.   
R est ri ct e d  M e di c ati o ns  
T h e f oll o wi n g  m e di c ati o ns  h a v e r estri cti o ns  o n  us e  d uri n g t h e tr e at m e nt  p eri o d  of t h e st u d y: 
•   As piri n i n  d os es  e x c e e di n g  1 2 5  m g   p er  d a y is  n ot  p er mitt e d.   L o w-d os e  as pi ri n 
( ≤  1 2 5 m g   p er  d a y) is  p er mitt e d  u nless  cli ni c all y  c o ntr ai n di c at e d. 
•   C o a d mi nistr ati o n   wit h str o n g  C Y P 3 A i n hi bit ors;  c o nsi d er  alt er n ati v e  a g e nts  wit h l ess 
C Y P 3 A i n hi biti o n ( A p p e n di x  C ).   Diff er e n c es i n i n di vi d u al s e nsiti vit y  a n d  v ari ati o n 
C Y P  e n z y m e i n hi biti o n  m a y r es ult i n t h e  n e e d f or  d os e r e d u cti o n  of r u x oliti ni b  a n d/ or 
c orti c ost er oi ds  as  a p pr o pri at e .   T h e s p o ns or  m e di c al  m o nit or  m a y  b e  c o ns ult e d f or 
a d vi c e  w h e n  usi n g t h es e  a g e nts.  
•   C o a d mi nistr ati o n   wit h  C Y P 3 A 4 i n d u c ers (A p p e n di x  C ). 
•   If  c o n c o mit a nt  a d mi nistr ati o n  of  a n  a nti c o a g ul a nt/ a nti pl at el et  m e di c ati o n is i n di c at e d, 
t h e n  c a uti o n  a n d  e n h a n c e d  m o nit ori n g is r e q uir e d.   Hist or y  of t hr o m b o c yt o p e ni a 
s h o ul d  b e  a f a ct or i n t h e  c h oi c e  of  a nti c o a g ul a nt  a n d  d os e. 
5. 6. 3.   
P r o hi bit e d  M e di c ati o ns  
T h e f oll o wi n g  m e di c ati o ns  ar e  pr o hi bit e d  d uri n g t h e tr e at m e nt  p eri o d  of t h e st u d y: 
•   A n y  c o n c urr e nt  a nti c a n c er t h er a p y ( e g ,  c h e m ot h er a p y, r a di ati o n t h er a p y, s ur g er y, 
i m m u n ot h er a p y,  bi ol o gi c t h er a p y,  h or m o n al t h er a p y,  or t u m or  e m b oli z ati o n).  Us e  of 
bi ol o gi c  a g e nts f or tr e at m e nt  of  n o n c a n c er i n di c ati o ns is  p er mitt e d.  
•   A n y s e c o n d ar y  G V H D t h er a p y  d u e t o i ns uffi ci e nt r es p o ns e/ pr o gr essi o n  o n st u d y 
tr e at m e nt. 
•   C o n c o mit a nt  us e  of  a J A K i n hi bit or. 
•   I niti ati n g t h er a p y  wit h  a n i n v esti g ati o n al  m e di c ati o n  u nl ess  ot h er wis e  a p pr o v e d  b y 
t h e  m e di c al  m o nit or. 
6.   
S T U D Y  A S S E S S M E N T S  
All st u d y  ass ess m e nts  will  b e  p erf or m e d  as i n di c at e d i n t h e s c h e d ul e  of  ass ess m e nts (s e e 
T a bl e   5), a n d  all l a b or at or y  ass ess m e nts  will  b e  p erf or m e d  as i n di c at e d i n  T a bl e   6.  T a bl e   7 
pr es e nts  a s u m m ar y  of  cli ni c al l a b or at or y  a n al yt es t o  b e  ass ess e d.   T h e  or d er  of  ass ess m e nts is 
s u g g est e d  b y t h e  or d er  of  m e nti o n  wit hi n t h e s c h e d ul e.   S e e  S e cti o n  7  f or i nstr u cti o ns  o n  e a c h 
ass ess m e nt.   F urt h er  d et ails  of st u d y  pr o c e d ur es  a n d  ass ess m e nts  c a n  b e f o u n d i n t h e st u d y 
r ef er e n c e  m a n u al. 

I n c yt e  C or p or ati o n 
P a g e  4 2  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
T a bl e  5:  
S c h e d ul e  of  Ass ess m e nts  
It e m 
S e cti o n  
S c r e e ni n g 
P h as e  
T r e at m e nt  
P h as e a 
E O T  
F oll o w -U p  P h as e  
-2 8 t o  -1   
D 1   
D 3   
D 7   
D 1 4   D 2 1   D 2 8   D 3 5   D 4 2   D 4 9  
D 5 6 b 
D 1 0 0   D 1 8 0  
D 3 6 5 c 
S af et y d   S u r vi v al  
I nf or m e d  c o ns e nt  
7. 1   
X   
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
I n cl usi o n/ e x cl usi o n 
crit eri a  
3   
X  
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
C o nt a ct I V R S  
7. 2   
X   
X   
  
  
  
  
X   
  
  
  
X   
X   
  
X   
X   
  
X  
D e m o gr a p h y/ dis e as e 
hist or y  
7. 3   
X  
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Pri or/ c o n c o mit a nt 
m e di c ati o ns  
7. 4   
X 
X 
X  
X  
 
S u p p orti v e  c ar e 
m e di c ati o ns  
5. 2. 2. 4    
X 
X 
X  
X  
 
A E  ass ess m e nt  
7. 5. 1   
X  
X  
X   
X   
 
P h ysi c al  e x a mi n ati o n   
7. 5. 2   
X   
X   
  
X   
X   
X   
X   
X   
X   
X   
X   
X   
  
X   
X   
X   
 
Vit al si g ns  
7. 5. 3   
X   
X   
  
X   
X   
X   
X   
X   
X   
X   
X   
X   
  
X   
X   
X   
 
E C O G  p erf or m a n c e 
st at us 
7. 5. 4   
X  
X 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
  
X  
X  
X  
 
1 2 -l e a d  E C G 
7. 5. 5   
X  
As i n di c at e d  
X   
  
 
A c ut e  G V H D  gr a di n g 
a n d r es p o ns e  ass ess m e nt  
7. 6. 1   
X  
X 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
C hi m eris m  ass ess m e nt   
7. 6. 3   
X  
As i n di c at e d  
  
  
 
P T L D  ass ess m e nt   
7. 6. 4   
 
As i n di c at e d  
  
  
 
Dis p e ns e st u d y  dr u g   
5. 1    
  
X   
  
  
  
  
X   
  
  
  
X   
  
  
X   
  
  
 
St u d y  dr u g  c o m pli a n c e   
5. 3   
  
X   
  
  
  
  
X   
  
  
  
X   
  
  
X   
X   
  
 
St er oi d  d os e  m o nit ori n g   
5. 3  
 
X  
X   
  
 
S ur vi v al f oll o w -u p   
6. 4   
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X e 
E C G  =  el e ctr o c ar di o gr a m;  P T L D  =  p ost -tr a ns pl a nt l y m p h o pr olif er ati v e  dis or d er. 
a  A  ±  2- d a y  wi n d o w is  p er mitt e d t o f a cilit at e s c h e d uli n g  d uri n g t h e tr e at m e nt  p h as e.  
b  Aft er  D a y  5 6,  visits  will  o c c ur  e v er y  2 8  d a ys  a n d  will i n cl u d e  all  D a y  5 6  ass ess m e nts.  
c  T h e  D a y  3 6 5  visit  will  als o s er v e  as t h e r e g ul arl y  s c h e d ul e d  visit  o c c urri n g  e v er y  2 8  d a ys  aft er  D a y  5 6 (i e,  D a y  3 6 4).  
d  T hirt y  t o  3 5  d a ys  aft er  E O T.   F or s u bj e cts  wit h dr a wi n g  d u e t o r e as o ns  ot h er t h a n  G V H D  pr o gr essi o n,  G V H D st at us s h o ul d  b e  ass ess e d  e v er y  2 8  d a ys. 
e  E v er y  8  w e e ks  ±  7  d a ys.  

I n c yt e  C or p or ati o n 
P a g e  4 3  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
T a bl e  6:    
L a b o r at o r y  Ass e ss m e nts 
It e m 
S e cti o n  
S c r e e ni n g 
P h as e  
T r e at m e nt  
P h as e a 
E O T  
S af et y 
F oll o w -U p  
-2 8 t o  - 1 
D 1 b 
D 3   
D 7   
D 1 4   
D 2 1   
D 2 8   
D 3 5   D 4 2   D 4 9  
D 5 6 c 
D 1 0 0   D 1 8 0   
D 3 6 5 d  
C h e mistr y  p a n el  
7. 5. 6. 1   
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
  
X  
X  
X 
H e m at ol o g y  
7. 5. 6. 2   
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
  
X  
X  
X 
H e p atitis s cr e e ni n g   
7. 5. 6. 4   
X 
 
  
 
S er u m  pr e g n a n c y t est 
( c hil d b e ari n g f e m al es o nl y)  
7. 5. 6. 3   
X 
 
X  
 
Uri n e  pr e g n a n c y t est e
( c hil d b e ari n g f e m al es  o nl y) 
7. 5. 6. 3   
 
X  
  
 
P K  ass ess m e nt f 
7. 7   
  
X  
  
X  
X  
  
  
  
  
  
  
  
  
  
  
 
C orr el ati v e st u d y  bl o o d 
c oll e cti o n  
7. 8   
X  
X  
  
X  
X  
  
X  
  
  
  
X g  
X  
X  
X  
X  
 
a  A  ±  2- d a y  wi n d o w is  p er mitt e d t o f a cilit at e s c h e d uli n g  d uri n g t h e tr e at m e nt  p h as e.  
b    Da y  1 l a b or at or y  ass ess m e nts  d o  n ot  n e e d t o  b e r e p e at e d if s cr e e ni n g  ass ess m e nts  w er e  p erf or m e d i n  pr e c e di n g  7  d a ys.  
c  Aft er  D a y  5 6,  visits  will  o c c ur  e v er y  2 8  d a ys  a n d  will i n cl u d e  all  D a y  5 6  ass ess m e nts.  
d T h e  D a y  3 6 5  visit  will  als o s er v e  as t h e r e g ul arl y  s c h e d ul e d  visit  o c c urri n g  e v er y  2 8  d a ys  aft er  D a y  5 6 (i e,  D a y  3 6 4). 
e    Uri n e  pr e g n a n c y t ests  ar e  o nl y r e q uir e d if  m e di c all y i n di c at e d a n d s h o ul d  b e  c o nfir m e d  wit h  a s er u m  pr e g n a n c y t est . 
f  S a m pl es t o  b e  c oll e ct e d  at  pr e d os e  a n d  at  1  h o ur  ±  1 5  mi n ut es,  at  2  h o urs  ±  3 0  mi n ut es,  a n d  b et w e e n  4  a n d  8  h o urs  p ost d os e.  
g  D a y  5 6  o nl y.  

I n c yt e  C or p or ati o n 
P a g e  4 4  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
T a bl e  7:    
Cli ni c al  L a b o r at o r y  A n al yt es 
S e r u m  C h e mist ri es  
H e m at ol o g y a 
Ot h e r  
Al b u mi n 
A L P  
A L T  
A S T  
Bi c ar b o n at e 
Bl o o d  ur e a  nitr o g e n  
C al ci u m  
C hl ori d e 
Cr e ati ni n e  
Gl u c os e 
L a ct at e  d e h y dr o g e n as e  
P h os p h or us 
P ot assi u m 
S o di u m 
T ot al  bilir u bi n  
T ot al  pr ot ei n  
H e m at o crit  
H e m o gl o bi n 
M e a n  c or p us c ul ar  v ol u m e  
Pl at el et  c o u nt 
R e d  bl o o d  c ell  c o u nt 
R eti c ul o c yt e  c o u nt  
W hit e  bl o o d  c ell  c o u nt 
W hit e  bl o o d  c ell  diff er e nti al ( 5  p arts):  
•  B as o p hils 
•  E osi n o p hils 
•  L y m p h o c yt es 
•  M o n o c yt es 
•  N e utr o p hils 
S er u m  p r e g n a n c y test  
Uri n e  pr e g n a n c y t est b 
H e p atitis   Sc r e e ni n g  T ests  
H e p atitis  B s urf a c e  a nti g e n  
H e p atitis  B s urf a c e  a nti g e n 
a nti b o d y 
H e p atitis  B  c or e  a nti b o d y 
H e p atitis  C  vir us  a nti b o d y  
H C V -R N A  
H B V -D N A  
A L P  =  al k ali n e  p h os p h at as e . 
a  H e m at ol o g y  a n d  c h e mistr y  a ss ess m e nts  will  b e  p erf or m e d l o c all y.  
b Uri n e  pr e g n a n c y t ests  ar e  o nl y r e q uir e d if  m e di c all y i n di c at e d.  
6. 1.   
S c r e e ni n g  
T h e s cr e e ni n g  p eri o d is t h e i nt er v al  b et w e e n si g ni n g t h e I C F  a n d t h e  d a y  t h at t h e s u bj e ct is 
e nr oll e d  i n t h e st u d y ( D a y  1).   T h e s cr e e ni n g p eri o d  m a y  n ot  e x c e e d  2 8  d a ys.  I nf or m e d  c o ns e nt 
m ust  b e  o bt ai n e d  b ef or e  p erf or mi n g  a n y st u d y- s p e cifi c  pr o c e d ur es t h at  ar e  n ot  c o nsi d er e d 
st a n d ar d  of  c ar e.   Ass ess m e nts t h at  ar e r e q uir e d t o  d e m o nstr at e  eli gi bilit y  m a y  b e  p erf or m e d  o v er 
t he  c o urs e  of  1  or  m or e  d a ys  d uri n g t his  p eri o d. 
Pr o c e d ur es  c o n d u ct e d  as  p art  of t h e s u bj e ct' s r o uti n e  cli ni c al  m a n a g e m e nt ( e g ,  bl o o d  c o u nt, 
i m a gi n g st u d y)  a n d  o bt ai n e d  b ef or e si g ni n g t h e I C F m a y  b e  us e d  f or s cr e e ni n g  or  b as eli n e 
p ur p os es,  pr o vi d e d  t h at t h e  pr o c e d ur e  m e ets t h e Pr ot o c ol- d efi n e d  crit eri a  a n d  h as  b e e n 
p erf or m e d i n t h e ti m efr a m e  of t h e st u d y.   R es ults fr o m t h e s cr e e ni n g  visit  e v al u ati o ns  will  b e 
r e vi e w e d t o  c o nfir m s u bj e ct  eli gi bilit y  b ef or e  e nr oll m e nt  or t h e  a d mi nistr ati o n  of st u d y  dr u g.  
T ests  wit h r es ults t h at f ail  eli gi bilit y r e q uir e m e nts  m a y  b e r e p e at e d  o n c e  d uri n g t h e s cr e e ni n g 
p eri o d if t h e i n v esti g at or  b eli e v es t h e r es ults t o  b e i n  err or.   F or s cr e e ni n g  ass ess m e nts t h at  ar e 
r e p e at e d, t h e  m ost r e c e nt  a v ail a bl e r es ult b ef or e   e nr oll m e nt will  b e  us e d t o  d et er mi n e s u bj e ct 
eli gi bilit y.   Tr e at m e nt s h o ul d st art  as s o o n  as  p ossi bl e,  b ut  wit hi n  2  d a ys  aft er t h e  d at e  of 
e nr oll m e nt.   A d diti o n all y,  a s u bj e ct  w h o f ails s cr e e ni n g  m a y r e p e at t h e s cr e e ni n g  pr o c ess  1  ti m e 
if t h e i n v esti g at or  b eli e v es t h at t her e  h as  b e e n  a  c h a n g e i n  eli gi bilit y st at us ( e g , f oll o wi n g 
r e c o v er y fr o m  a n i nf e cti o n). 

I n c yt e  C or p or ati o n 
P a g e  4 5  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
6. 2.   
T r e at m e nt  
T h e tr e at m e nt  p eri o d  b e gi ns  o n t h e  d a y  t h at t h e s u bj e ct r e c ei v es t h e first  d os e  of st u d y  dr u g 
t hr o u g h t h e  p oi nt  at  w hi c h t h e  pri n ci p al i n v esti g at or d et er mi n es  t h at t h e s u bj e ct  will  b e 
p er m a n e ntl y  dis c o nti n u e d fr o m  t h e st u d y  dr u g.   D at es f or s u bs e q u e nt st u d y  visits  will  b e 
d et er mi n e d  b as e d  o n t his  d a y  a n d s h o ul d  o c c ur  wit hi n  ±  2  d a ys  of t h e s c h e d ul e d  d at e  u nl ess 
d el a y e d f or s af et y r e as o ns.   D uri n g t h e  D a y  1  visit, r es ults fr o m s cr e e ni n g  visit  e v al u ati o ns 
s h o ul d  b e r e vi e w e d t o  d et er mi n e  w h et h er  t h e s u bj e ct  c o nti n u es t o  m e et t h e  eli gi bilit y 
r e q uir e m e nts  as s p e cifi e d i n t h e Pr ot o c ol. 
6. 3.   
E n d  of  T r e at m e nt  
If  a  d e cisi o n is  m a d e t h at t h e s u bj e ct  will  p er m a n e ntl y dis c o nti n u e  st u d y tr e at m e nt, t h e n t h e  E O T 
visit s h o ul d  b e  c o n d u ct e d.  If t h e  E O T  visit  c oi n ci d es  wit h  a r e g ul ar st u d y  visit, t h e n  t h e  E O T 
e v al u ati o ns  will s u p ers e d e t h os e  of t h at s c h e d ul e d  visit,  a n d t h e  d at a s h o ul d  b e  e nt er e d i n t h e 
E O T  visit i n t h e  e C R F.   T h e s u bj e ct s h o ul d  b e  e n c o ur a g e d t o r et ur n f or t h e f oll o w- u p  visit. 
6. 4.   
F oll o w -U p  
6. 4. 1.   
S af et y  F oll o w- U p  
T h e s af et y f oll o w - u p  p eri o d is t h e i nt er v al  b et w e e n t h e  E O T  visit  a n d t h e s c h e d ul e d f oll o w- u p 
visit,  w hi c h s h o ul d  o c c ur  3 0 t o  3 5  d a ys  aft er t h e  E O T  visit ( or  aft er  t h e l ast  d os e  of st u d y  dr u g if 
t h e  E O T  visit  w as  n ot p erf or m e d).   A d v ers e  e v e nts  a n d  S A Es  m ust  b e r e p ort e d  u p  u ntil  at l e ast 
3 0  aft er t h e l ast  d os e  of st u d y  dr u g, t h e  d at e  of t h e f oll o w- u p  visit,  or  u ntil t o xi citi es r es ol v e, 
r et ur n t o  b as eli n e,  or  ar e  d e e m e d irr ev ersi bl e,  w hi c h e v er is l o n g er. 
6. 4. 2.   
G V H D  Ass ess m e nt  F oll o w -U p  
S u bj e cts  w h o  dis c o nti n u e st u d y tr e at m e nt f or r e as o ns  ot h er t h a n  pr o gr essi o n  of  G V H D  will 
m o v e i nt o t h e  dis e as e st at us f oll o w- u p  p eri o d  a n d s h o ul d  b e  ass ess e d  e v er y  2 8  d a ys t o  m o nit or 
dis e as e st at us.   E v er y  eff ort s h o ul d  b e  m a d e t o  c oll e ct i nf or m ati o n r e g ar di n g  dis e as e st at us  u ntil 
o n e  of t h e f oll o wi n g  o c c urs: 
•   G V H D  pr o gr essi o n 
•   R el a ps e  of  m ali g n a n c y  
•   D e at h  
•   E n d  of st u d y 
6. 4. 3.   
S u r vi v al  F oll o w- U p  
O n c e  a s u bj e ct  h as  c o nfir m e d  G V H D  pr o gr essi o n  or st arts  a  n e w  G V H D t h er a p y, t h e s u bj e ct 
m o v es i nt o t h e s ur vi v al f oll o w- u p  p eri o d  a n d s h o ul d  b e  c o nt a ct e d  b y t el e p h o n e,  e m ail,  or  visit  at 
l e ast  e v er y  8  w e e ks ( ±  7  d a ys) t o  ass ess f or n e w  G V H D t h er a p y  a n d  s ur vi v al st at us  u ntil  d e at h, 
wit h dr a w al  of  c o ns e nt,  or t h e  e n d  of t h e st u d y,  w hi c h e v er  o c c urs first. 

I n c yt e  C or p or ati o n 
P a g e  4 6  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
6. 5.   
U ns c h e d ul e d  Visits  
U ns c h e d ul e d  visits  m a y  b e  h el d  at  a n y ti m e  at t h e i n v esti g at or 's  dis cr eti o n,  a n d  a p pr o pri at e 
cli ni c al  a n d l a b or at or y  m e as ur e m e nts  p erf or m e d  b as e d  o n  A Es  or  ot h er fi n di n gs. 
7.   
C O N D U C T  O F  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  
7. 1.   
A d mi nist r ati o n  of I nf o r m e d  C o ns e nt  F o r m  
V ali d i nf or m e d  c o ns e nt  m ust  b e  o bt ai n e d fr o m t h e st u d y s u bj e ct  b ef or e  c o n d u cti n g  a n y 
st u d y-s p e cifi c  pr o c e d ur es  usi n g  a n I C F  a p pr o v e d  b y  t h e l o c al I R B/I E C t h at  c o nt ai ns  all  el e m e nts 
r e q uir e d  b y I C H  E 6  a n d  d es cri b es t h e  n at ur e, s c o p e,  a n d  p ossi bl e  c o ns e q u e n c es  of t h e st u d y i n  a 
f or m  u n d erst a n d a bl e t o t h e st u d y s u bj e ct.   L o c al  a n d i nstit uti o n al  g ui d eli n es f or I C F  c o nt e nt  a n d 
a d mi nistr ati o n  m u st  b e f oll o w e d; t h e  ori gi n al si g n e d I C F  m ust  b e r et ai n e d  b y t h e i n v esti g at or, 
a n d  a  c o p y  of t h e si g n e d I C F  m ust  b e  pr o vi d e d t o t h e st u d y s u bj e ct.   T h e i nf or m e d  c o ns e nt 
pr o c ess f or  e a c h s u bj e ct  m ust  b e  d o c u m e nt e d i n  writi n g  wit hi n t h e s u bj e ct s o ur c e  d o c u m e nt ati o n.  
S u bj e cts  of  c hil d b e ari n g  p ot e nti al  m ust  a gr e e t o t a k e  a p pr o pri at e  m e as ur es t o  a v oi d  pr e g n a n c y i n 
or d er t o  p arti ci p at e i n t h e st u d y ( s e e A p p e n di x  A ). 
7. 2.   
I nt e r a cti v e  R es p o ns e  T e c h n ol o g y  P r o c e d u r e  
T h e I V R S  will  b e  c o nt a ct e d t o  o bt ai n  a s u bj e ct I D  n u m b er  w h e n  a s u bj e ct  e nt ers t h e s cr e e ni n g 
p h as e.   U p o n  d et er mi ni n g t h at t h e s u bj e ct is  eli gi bl e f or st u d y  e ntr y, t h e I V R S  will  b e  c o nt a ct e d 
t o  o bt ai n st u d y  dr u g  assi g n m e nt.   A d diti o n all y, t h e I V R S  will  b e  c o nt a ct e d  e v er y  2 8  d a ys t o 
u p d at e st u d y  dr u g s u p pl y.   S e e  S e cti o n  5. 1. 1  f or  a d diti o n al i nf or m ati o n. 
7. 3.   
D e m o g r a p h y  a n d  M e di c al  Hist o r y  
7. 3. 1.   
D e m o g r a p hi cs  a n d  G e n e r al  M e di c al  Hist o r y  
D e m o gr a p hi c  d at a  a n d  a  c o m pl et e  m e di c al  a n d  m e di c ati o n  hist or y  will  b e  c oll e ct e d  at s cr e e ni n g.  
7. 3. 2.   
Dis e as e  C h a r a ct e risti cs  a n d  T r e at m e nt  Hist o r y  
A  dis e as e -t ar g et e d  m e di c al  a n d  m e di c ati o n  hist or y i n cl u di n g  h e m at ol o gi c  m ali g n a n c y t y p e, 
c urr e nt  G V H D  st a gi n g,  d at e  of  di a g n osis, sit es  of  dis e as e,  pri or  a nti c a n c er  t h er a p y,  a bl ati o n 
t h er a p y, pr o p h yl a xis t h er a p y,  d o n or t y p e,  a n d  ot h er  d et ails r el at e d t o t h e  dis e as e  u n d e r st u d y  will 
b e  c oll e ct e d  at s cr e e ni n g.  
7. 4.   
P ri o r  a n d  C o n c o mit a nt  M e di c ati o ns   
Pri or  a n d  c o n c o mit a nt  m e di c ati o ns  will  b e r e vi e w e d t o  d et er mi n e s u bj e ct  eli gi bilit y.   All 
c o n c o mit a nt  m e di c ati o ns  a n d  m e as ur es  m ust  b e r e c or d e d i n t h e  e C R F,  a n d  a n y  m e di c ati o n 
r e c ei v e d  or  pr o c e d ur e  p erf or m e d  wit hi n  3 0 d a ys  b ef or e  e nr oll m e nt  a n d  u p t o t h e  e n d  of st u d y 
will  b e r e c or d e d i n t h e  e C R F.   T h e  m e di c ati o n r e c or d  will  b e  m ai nt ai n e d  aft er si g ni n g t h e I C F t o 
d o c u m e nt  c o n c o mit a nt  m e di c ati o ns, i n cl u di n g  a n y  c h a n g es t o t h e  d os e  or r e gi m e n.   C o n c o mit a nt 
m e di c ati o ns i n cl u d e  a n y  pr es cri pti o n,  o v er-t h e- c o u nt er,  or  n at ur al/ h er b al  pr e p ar ati o ns t a k e n  or 
a d mi nist er e d  d uri n g t h e st u d y  p eri o d.   C o n c o mit a nt tr e at m e nts  a n d/ or  pr o c e d ur es t h at  ar e 

I n c yt e  C or p or ati o n 
P a g e  4 7  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
r e q uir e d t o  m a n a g e  a s u bj e ct's  m e di c al  c o n diti o n  d uri n g t h e st u d y  will  als o  b e r e c or d e d i n t h e 
e C R F.  
7. 5.   
S af et y  Ass ess m e nts  
7. 5. 1.   
A d v e rs e  E v e nts  
A d v ers e  e v e nts  will  b e  m o nit or e d fr o m t h e ti m e t h e s u bj e ct si g ns t h e I C F.   S u bj e cts  will  b e 
i nstr u ct e d t o r e p ort  all  A Es  d uri n g t h e st u d y  a n d  will  b e  ass ess e d f or t h e  o c c urr e n c e  of  A Es 
t hr o u g h o ut t h e st u d y.  I n  or d er t o  a v oi d  bi as i n  eli citi n g  A Es, s u bj e cts  will  b e  as k e d  g e n er al, 
n o nl e a di n g  q u esti o ns s u c h  as  " H o w  ar e  y o u f e eli n g ? "   All  A Es (s eri o us  a n d  n o ns eri o us)  m ust  b e 
r e c or d e d  o n t h e s o ur c e  d o c u m e nts  a n d  e C R Fs r e g ar dl ess  of t h e  ass u m pti o n  of  a  c a us al 
r el ati o ns hi p  wit h t h e st u d y  dr u g.   T h e  d efi niti o n, r e p orti n g,  a n d r e c or di n g r e q uir e m e nts f or  A Es 
ar e  d es cri b e d i n  S e cti o n  8 . 
7. 5. 2.   
P h ysi c al  E x a mi n ati o n 
T h e t ar g et e d  p h ysi c al  e x a mi n ati o n  will  b e  a s y m pt o m - dir e ct e d  e v al u ati o n  c o n d u ct e d  b y t h e 
i n v esti g at or  or  a  m e di c all y  q u alifi e d  d esi g n e e.   T h e t ar g et e d  p h ysi c al  e x a mi n ati o n  will i n cl u d e 
ass ess m e nt(s)  of t h e  b o d y s yst e ms  or  or g a ns,  as i n di c at e d  b y s u bj e ct s y m pt o ms,  A Es,  or  ot h er 
fi n di n gs.  Cli ni c all y  n ot a bl e  a b n or m aliti es t h at  ar e  c o nsi d er e d  cli ni c all y si g nifi c a nt i n t h e 
j u d g m e nt  of t h e i n v esti g at or  ar e t o  b e r e p ort e d  as A E s. 
7. 5. 3.   
Vit al  Si g ns  
Vit al si g n  m e as ur e m e nts i n cl u d e  bl o o d  pr ess ur e,  p uls e, r es pir at or y r at e,  b o d y t e m p er at ur e,  a n d 
b o d y  w ei g ht.   Bl o o d  pr ess ur e  a n d  p uls e  will  b e t a k e n  wit h t h e s u bj e ct i n t h e r e c u m b e nt, 
s e mir e c u m b e nt ,  or sitti n g  p ositi o n.  Cli ni c all y  n ot a bl e  a b n or m aliti es t h a t  ar e  c o nsi d er e d 
cli ni c all y si g nifi c a nt i n t h e j u d g m e nt  of t h e i n v esti g at or  ar e t o  b e r e p ort e d  as  A E s. 
7. 5. 4.   
E ast e r n  C o o p e r ati v e  O n c ol o g y  G r o u p  P e rf o r m a n c e  St at us  
E ast er n  C o o p er ati v e  O n c ol o g y  Gr o u p  p erf or m a n c e st at us ( O k e n  et  al  1 9 8 2 ; T a bl e   8)  will  b e 
r e q uir e d  at s cr e e ni n g  a n d  will  b e  ass ess e d  at  ot h er stu d y  visits  p er  T a bl e   5.  P erf or m a n c e st at us 
m ust  b e  ass ess e d  b y  a  m e di c all y  q u alifi e d  i n di vi d u al  a n d r e c or d e d i n t h e  eC R F . 
T a bl e  8:  
E C O G  P e rf o r m a n c e  St at us  G r a d es  
G r a d e   
P e rf o r m a n c e  St at us  
0  
F ull y  a cti v e,  a bl e t o  c arr y  o n  all  pr e dis e as e  p erf or m a n c e  wit h o ut r estri cti o n . 
1 
R estri ct e d i n  p h ysi c all y str e n u o us  a cti vit y  b ut  a m b ul at or y  a n d  a bl e t o  c arr y  o ut  w or k  of  a 
li g ht  or s e d e nt ar y  n at ur e, e g , li g ht  h o us e  w or k,  offi c e  w or k. 
2 
A m b ul at or y  a n d  c a p a bl e  of  all s elf -c ar e  b ut  u n a bl e t o  c arr y  o ut  a n y  w or k  a cti viti es .  U p 
a n d  a b o ut  m or e t h a n  5 0 %  of  w a ki n g  h o urs. 
3  
C a p a bl e  of  o nl y li mit e d s elf- c ar e,  c o nfi n e d t o  b e d  or  c h air  m or e t h a n  5 0 %  of  w a ki n g  h o urs. 
4  
C o m pl et el y  dis a bl e d.   C a n n ot  c arr y  o n  a n y s elf -c ar e .   T ot all y  c o nfi n e d t o  b e d  or  c h air. 
5  
D e a d . 

I n c yt e  C or p or ati o n 
P a g e  4 8  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
7. 5. 5.   
T w el v e -L e a d  El e ct r o c a r di o g r a ms  
A  1 2 -l e a d  E C G will  b e  p erf or m e d  d uri n g s cr e e ni n g  wit h t h e s u bj e ct i n  a r e c u m b e nt  or 
s e mir e c u m b e nt   p ositi o n  aft er  5  mi n ut es  of r est. 
T h e  1 2- l e a d  E C G will  b e i nt er pr et e d  b y t h e i n v esti g at or  at t h e sit e  a n d  will  b e  us e d f or 
i m m e di at e s u bj e ct  m a n a g e m e nt.   T h e d e cisi o n t o i n cl u d e  or  e x cl u d e  a s u bj e ct  or  wit h dr a w  a 
s u bj e ct fr o m t h e st u d y  b as e d  o n  a n  E C G fl a g g e d  as  " A b n or m al,  Cli ni c all y  Si g nifi c a nt "  is t h e 
r es p o nsi bilit y  of t h e i n v esti g at or, i n  c o ns ult ati o n  wit h t h e s p o ns or's  m e di c al  m o nit or,  as 
a p pr o pri at e. 
El e ct r o c ar di o gr a ms t h at  ar e i d e ntifi e d  as  a b n or m al  a n d  cli ni c all y  m e a ni n gf ul  c o m p ar e d  wit h t h e 
s cr e e ni n g  ass ess m e nt s h o ul d  b e r e p ort e d  as  A Es.   F or s u c h  A Es, t h e fi n di n gs  of t h e  a b n or m al 
E C Gs  a n d t h e  c orr es p o n di n g  b as eli n e  E C G fi n di n gs  m ust  b e r e p ort e d i n t h e  e C R F . 
A n  a d diti o n al  E C G  will  b e  p erf or m e d  at t h e  E O T  visit;  a d diti o n al  E C Gs  m a y  b e  p erf or m e d  at t h e 
i n v esti g at or's  dis cr eti o n  as  cli ni c all y i n di c at e d.  
7. 5. 6.   
L a b o r at o r y  Ass ess m e nts 
Bl o o d  dr a ws f or l a b or at or y  ass ess m e nts  will  o c c ur  at st u d y  visits i n di c at e d i n  T a bl e   6.   Bl o o d 
dr a ws  will  b e  c o m pl et e d  b ef or e t h e s u bj e ct r e c ei v es t h e  m or ni n g  d os e  of  st u d y  dr u g.   S p e cifi c 
l a b or at or y  ass ess m e nts  ar e list e d i n T a bl e   7. 
All l a b or at or y  ass ess m e nts  will  b e  p erf or m e d  at  a l o c al (sit e) l a b or at or y  usi n g i nstit uti o n al  b est 
pr a cti c es.   R es ults  a n d  n or m al r ef er e n c e r a n g es  will  b e  e nt er e d  i nt o t h e  eC R F.  
7. 5. 6. 1.   
C h e mist r y  
All  c h e mistr y  ass ess m e nts  will  b e  p erf or m e d  at  a l o c al (sit e) l a b or at or y  fr o m  bl o o d s a m pl es 
c oll e ct e d  usi n g i nstit uti o n al  b est  pr a cti c es  b ef or e  a d mi nistr ati o n  of  st u d y  dr u g.   R es ults  a n d 
n or m al r ef er e n c e r a n g es  will  b e  e nt er e d  i nt o t h e  eC R F.  
7. 5. 6. 2.   
H e m at ol o g y 
H e m at ol o g y  ass ess m e nts, i n cl u di n g  c o m pl et e  bl o o d  c o u nt  wit h  diff er e nti al,  will  b e  p erf or m e d  at 
a l o c al (sit e) l a b or at or y  usi n g i nstit uti o n al  b est  pr a cti c es  b ef or e   a d mi nistr ati o n  of st u d y  dr u g.  
R es ults  a n d  n or m al  r ef er e n c e r a n g es  will  b e  e nt er e d i nt o t h e  eC R F.  
7. 5. 6. 3.   
P r e g n a n c y  T esti n g  
A s er u m  pr e g n a n c y t est  will  b e r e q uir e d f or  all  w o m e n  of  c hil d b e ari n g  p ot e nti al  d uri n g s cr e e ni n g 
a n d  at t h e  E O T   visit.   Uri n e  pr e g n a n c y t ests  will  b e  c o n d u ct e d  o nl y if  m e di c all y i n di c at e d.  Uri n e 
pr e g n a n c y t ests  will  b e  p erf or m e d  l o c all y.  If  a  uri n e  pr e g n a n c y t est is  p ositi v e, t h e n t h e r es ults 
s h o ul d  b e  c o nfir m e d  wit h  a s er u m  pr e g n a n c y t est. 
If t h e s er u m  pr e g n a n c y t est is  n e g ati v e  aft er  a  uri n e t est  w as  p ositi v e, t h e n th e i n v esti g at or  will 
a ss ess t h e  p ot e nti al  b e n efit/ris k t o t h e s u bj e ct  a n d  d et er mi n e  w h et h er  it is i n t h e s u bj e ct's  b est 
i nt er est t o r es u m e st u d y  dr u g  a n d  c o nti n u e  p arti ci p ati o n i n t h e st u d y. 

I n c yt e  C or p or ati o n 
P a g e  4 9  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
7. 5. 6. 4.   
H e p atitis  S c r e e ni n g  
S u bj e cts  wit h  a cti v e  H B V  or  H C V i nf e cti o n t h at r e q uir es tr e at m e nt  or  w h o  ar e  at ris k f or  H B V 
r e a cti v ati o n ar e  e x cl u d e d fr o m t h e  st u d y.   At ris k f or  H B V r e a cti v ati o n is  d efi n e d  as  h e p atitis  B 
s urf a c e  a nti g e n  p ositi v e  or  a nti – h e p atitis  B  c or e  a nti b o d y  p ositi v e.   Pri or t est  r es ults  o bt ai n e d  as 
p art  of st a n d ar d  of  c ar e  b ef or e  all o -H S C T  c o nfir mi n g t h at  a s u bj e ct is i m m u n e  a n d  n ot  at ris k f or 
r e a cti v ati o n (i e,  h e p atitis  B s urf a c e  a nti g e n  n e g ati v e, s urf a c e  a nti b o d y  p ositi v e)  m a y  b e  us e d f or 
p ur p os es  of  eli gi bilit y,  a n d t ests  d o  n ot  n e e d t o  b e r e p e at e d.   S u bj e cts  wit h  pri or  p ositi v e s er ol o g y 
r es ults  m ust  h a v e  n e g ati v e  p ol y m er as e  c h ai n r e a cti o n r es ults.   S u bj e cts  w h os e i m m u n e st at us is 
u n k n o w n  or  u n c ert ai n  m ust  h a v e r es ults  c o nfir mi n g  i m m u n e st at us  b ef or e  e nr oll m e nt  as  p er 
T a bl e   7. 
7. 6.   
G r aft- V e rs us -H ost  Dis e as e  Ass ess m e nts  
7. 6. 1.   
G r aft -V e rs us -H ost  Dis e as e   St a gi n g  a n d G r a di n g  
A c ut e  G V H D  gr a di n g  will  b e  p erf or m e d  b y t h e i n v esti g at or  o n  a  w e e k l y  b asis f or t h e first 
8  w e e ks  aft er  e nr oll m e nt , t h en  e v er y  2 8  d a ys  t h er e aft er.  Gr aft -v ers us -h ost  dis e as e  st a gi n g  a n d 
gr a di n g  will  als o  o c c ur  o n  D a y s  1 0 0,  1 8 0,  a n d  3 6 5  a n d  at t h e  E O T  visit.  If s u bj e cts  wit h dr e w 
d u e t o r e as o ns  ot h er t h a n  G V H D  pr o gr essi o n, t h e n  G V H D st a gi n g  a n d  gr a di n g  will  b e  ass ess e d 
at t h e s af et y f oll o w - u p  visit.  D at a r e g ar di n g t h e  q u a ntifi c ati o n  of  a G V H D s y m pt o ms ( e xt e nt  of 
s ki n r as h, t ot al  bilir u bi n l e v el,  v ol u m e  of  di arr h e a) s h o ul d  b e r e p ort e d  usi n g  M A GI C  g ui d eli n es 
(H arris  et  al  2 0 1 6 ); r es p o ns e  will  b e  ass ess e d  as  p er t h e C e nt er f or I nt er n ati o n al  Bl o o d  a n d 
M arr o w  Tr a ns pl a nt  R es e ar c h  (CI B M T R )  m o difi c ati o ns t o t h e I B M T R r es p o ns e i n d e x as 
i n di c at e d i n A p p e n di x  B  (CI B M T R  2 0 0 9 , M arti n  et  al  2 0 0 9 ). 
•   S ki n: 
−   O nl y  ar e as i n v ol v e d  wit h  a cti v e  er yt h e m a s h o ul d  b e  us e d f or  d et er mi ni n g   b o d y 
s urf a c e  ar e a st a gi n g  b as e d  o n t h e r ul e  of  ni n es. 
−   A  p orti o n  of  a  b o d y  ar e a s e g m e nt  m a y  b e  us e d f or t h e  q u a ntifi c ati o n. 
−   D es q u a m ati o n  or fl ui d-fill e d  b ull a e s h o ul d  b e r e p ort e d if  pr es e nt  as t h es e fi n di n gs 
ar e  h all m ar k s of  S t a g e  4 s ki n  G V H D. 
•   Li v er:  
−   Li v er  G V H D st a gi n g is  b as e d s ol el y  o n t ot al ( n ot  c o nj u g at e d/ dir e ct) s er u m 
bilir u bi n l e v els.  
−   Li v er  G V H D  m a nif esti n g  as tr a ns a mi nitis  wit h o ut  c o n c o mit a nt  el e v ati o n i n s er u m 
bilir u bi n s h o ul d  b e  di a g n os e d  w h e n t h e  pr es e n c e  of  G V H D is  c o nfir m e d  b y li v er 
bi o ps y  ( w h er e  a p pr o pri at e) a n d s c or e d  as  St a g e  0. 
−   If  bilir u bi n l e v els  w er e  el e v at e d  b ef or e t h e  di a g n osis  of  G V H D i n  a n ot h er t ar g et 
or g a n  a n d  d o  n ot i n cr e as e f urt h er,  t h e n li v er  G V H D s h o ul d  n ot  b e  di a g n os e d i n 
t h e  a bs e n c e  of  bi o ps y  c o nfir m ati o n.   H o w e v er, if  h y p er bilir u bi n e mi a  d e v el o ps  at 
t h e s a m e ti m e  or  aft er t h e  o ns et  of  G V H D i n  a n ot h er t ar g et  or g a n, t h e n li v er 
G V H D is  pr es u m e d t o  b e  pr es e nt i n t h e  a bs e n c e  of  a n i d e ntifi e d  alt er n ati v e  c a us e.  

I n c yt e  C or p or ati o n 
P a g e  5 0  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
•   U p p er  GI: 
−   S y m pt o ms  of  c o n c er n f or  u p p er  GI  G V H D i n cl u d e  a n or e xi a,  n a us e a,  v o miti n g, 
a n d  d ys p e psi a,  a n d  ass ess m e nt  d e p e n ds  o n  cl os e  att e nti o n t o  c al ori c i nt a k e  a n d 
s y m pt o m r e p orti n g.  
−   A n  u p p er  GI  e n d os c o p y s h o ul d  b e  p erf or m e d  w h e n e v er  p ossi bl e t o  c o nfir m  u p p er 
GI  G V H D;  h o w e v er, t h e  di a g n osis  m a y  b e  m a d e  wit h o ut  bi o ps y  c o nfir m ati o n. 
−   Gr aft -v ers us - h ost  dis e as e is t y pi c all y  n ot  c o nsi d er e d  as  a  p ossi bl e  eti ol o g y  w h e n 
n a us e a l asts f e w er t h a n  3  d a ys  or  wi t h f e w er t h a n  2  v o miti n g  e pis o d es  p er  d a y f or 
at l e ast  2  d a ys  or  a n or e xi a  wit h o ut  w ei g ht l oss.  
•   L o w er  GI:  
−   St a gi n g  of l o w er  GI  G V H D r eli es  o n  a c c ur at e  m e as ur e m e nt  of  d ail y st o ol 
v ol u m es  a n d  d o c u m e nt ati o n  of t h e  pr es e n c e  of  h e m at o c h e zi a  or s e v er e  a b d o mi n al 
p ai n. 
−   I n  c as es  w h e n st o ol  v ol u m e  c a n n ot  b e  cl os el y  m e as ur e d,  v ol u m e s h o ul d  b e 
c al c ul at e d  b as e d  o n  a n  a v er a g e  of  2 0 0  m L  p er  e pis o d e  m ulti pli e d  b y t h e  n u m b er 
of  e pis o d es i n  2 4- h o ur  p eri o d. 
−   At t h e ti m e  of  G V H D  o ns et, st a gi n g s h o ul d  b e  b as e d  o n t h e  hi g h est  d ail y  v ol u m e 
d uri n g t h e  3  d a ys  b ef or e  di a g n osis ( e x cl u di n g  v ol u m es  attri b ut a bl e t o  pr o c e d ur es 
s u c h  as  b o w el  pr e ps  or  e n d os c o p y). 
−   Aft er t h e i niti ati o n  of tr e at m e nt, l o w er  G V H D st a gi n g s h o ul d  b e  b as e d  o n t h e 
di arr h e a  v ol u m e  usi n g (i n t h e  or d er  of  pr ef er e n c e)  t h e f oll o wi n g  m e as ur e m e nts:  
1)  a v er a g e  of  3  c o ns e c uti v e  d a ys,  2)  a v er a g e  of  2  c o ns e c uti v e  d a ys,  or  3) t h e 
v ol u m e  o n  d a y  of  ass ess m e nt. 
−   S e v er e  a b d o mi n al  p ai n, il e us,  a n d/ or  gr ossl y  bl o o d y st o ol s h o ul d  b e  d o c u m e nt e d 
w h e n  pr es e nt,  b e c a us e  St a g e  4 l o w er  GI  G V H D i s st a g e d  b as e d  o n t h e  pr es e n c e  of 
t h es e s y m pt o ms  a n d is i n d e p e n d e nt  of  v ol u m e  of  di arr h e a. 
7. 6. 3.   
D o n o r  C hi m e ris m  
D o n or  c hi m eris m  aft er  a  h e m at o p oi eti c st e m  c ell tr a ns pl a nt i n v ol v es i d e ntif yi n g t h e  g e n eti c 
pr ofil es  of t h e r e ci pi e nt  a n d  of t h e  d o n or  a n d t h e n  e v al u ati n g t h e r ati o  of  d o n or t o r e ci pi e nt  c ells 
i n t h e r e ci pi e nt's  bl o o d,  b o n e  m arr o w,  or  ot h er tiss u e.   C hi m eris m t esti n g  usi n g  p eri p h er al  bl o o d 
or  b o n e  m arr o w  will  b e  p erf or m e d  at t h e tr e ati n g i n v esti g at or 's  dis cr eti o n a c c or di n g t o l o c al 
i nstit uti o n al  pr a cti c e as i n di c at e d i n  T a bl e   5.  I n  g e n er al,  g e n o mi c  p ol y m or p his ms s h o ul d  b e 
ass ess e d  vi a  p ol y m er as e  c h ai n r e a cti o n  a n al ysis  of  s h ort t a n d e m r e p e at l o ci fr o m is ol at e d 
l y m p h o c yt es  or  m y el oi d  c ells.  Fl u or es c e n c e  i n sit u h y bri di z ati o n   a n al ysis  m a y  als o  b e  us e d i n 
c as es  wit h s e x -mis m at c h e d tr a ns pl a nts ( M ats u d a  et  al  2 0 0 4 ). 

I n c yt e  C or p or ati o n 
P a g e  5 1  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
7. 6. 4.   
P ost - Tr a ns pl a nt  L y m p h o p r olif e r ati v e  Dis o r d e r  Ass ess m e nt  
St ai ni n g f or  E pst ei n -B arr  vir us  f or  P T L D t esti n g  will  b e  p erf or m e d  a c c or di n g t o l o c al 
i nstit uti o n al  pr a cti c e  at t h e tr e ati n g i n v esti g at or's  dis cr eti o n  as i n di c at e d i n T a bl e   5. 
7. 7.   
P h a r m a c o ki n eti c  Ass ess m e nts  
7. 7. 1.   
Bl o o d  S a m pl e  C oll e cti o n  
P h ar m a c o ki n e ti c s a m pl es  will  b e  o bt ai n e d  o n  D a ys  1,  7,  a n d  1 4.   O n  e a c h  of t h es e  d a ys,  a 
pr e d os e  bl o o d s a m pl e  will  b e  dr a w n, st u d y tr e at m e nt  will  b e  a d mi nist er e d,  a n d s eri al  bl o o d 
s a m pl es  will  b e t a k e n  at t h e i nt er v als s h o w n i n  T a bl e   9. 
T h e  e x a ct  d at e  a n d ti m e  of t h e  P K  bl o o d  dr a ws  will  b e r e c or d e d i n t h e  e C R F  al o n g  wit h t h e  d at e 
a n d ti m e  of t h e l ast  d os e  of st u d y  dr u g  pr e c e di n g t h e  bl o o d  dr a w (if  a p pli c a bl e)  a n d t h e ti m e  o f 
t h e  m ost r e c e nt  m e al.  I nstr u cti o ns f or s a m pl e  pr e p ar ati o n  a n d s hi p pi n g  will  b e  pr o vi d e d i n t h e 
L a b or at or y  M a n u al.   S u bj e cts  will r e c ei v e r e mi n d er  c ar ds i n  a d v a n c e  of t h e st u d y  visit  pr o vi di n g 
i nstr u cti o n t o  h ol d t h e  d os e  of st u d y  dr u g  o n t h e  d a y  of t h e visit,  as  w ell  as  a  pl a c e t o r e c or d t h e 
ti m e  of t h e pr e vi o us  d os e  of st u d y  dr u g  a n d ti m e  of t h e  m ost r e c e nt  m e al  or s n a c k  c o ns u m e d. 
If  P K s a m pl es  ar e  missi n g f or  a s u bj e ct,  P K s a m pl e  c oll e cti o n s h o ul d  b e  p erf or m e d  at t h e  n e xt 
visit .  O n  D a ys  1 ,  7, a n d  1 4,  s u bj e cts  m ust r efr ai n fr o m t a ki n g st u d y m e di c ati o n  b ef or e  arri vi n g 
f or t h e  visit.   S u bj e cts s h o ul d  n ot  h a v e  c o ns u m e d  a n y f o o d  wit hi n  8  h o urs  b ef or e  arri vi n g  at t h e 
cli ni c.   A tr o u g h ( pr e d os e)  P K s a m pl e ( 3 0- mi n ut e  wi n d o w) s h o ul d  b e  dr a w n  at  e a c h  of t h e  P K 
v isits.   F oll o wi n g t h e tr o u g h  P K s a m pl e, t h e s u bj e ct s h o ul d t a k e t h e  assi g n e d  d os e  of st u d y 
tr e at m e nt,  a n d s u bs e q u e nt ti m e d s a m pl es  will  b e t a k e n.   F o o d s h o ul d  b e  wit h h el d  u ntil  1  h o ur 
aft er st u d y  dr u g  a d mi nistr ati o n.  
T a bl e  9:  
P h a r m a c o ki n eti c  S a m pl e  C oll e cti o n  Ti m e  a n d  Wi n d o ws   
St u d y  D a y  
Ti mi n g  of  S a m pl e  R el ati v e t o I N C B 0 1 8 4 2 4  A d mi nist r ati o n  
D a y  1  
Pr e d os e  
1  h  
±  1 5  mi n  
2  h  
±  3 0  mi n  
4- 8  h 
D a y  7  
Pr e d os e  
1  h  
±  1 5  mi n  
2  h  
±  3 0  mi n  
4- 8  h 
D a y  1 4  
Pr e d os e  
1  h  
±  1 5  mi n  
2  h  
±  3 0  mi n  
4- 8  h  
7. 7. 2.   
Bi o a n al yti c al  M et h o d ol o g y  a n d  A n al ysis 
Pl as m a s a m pl es  will  b e  a n al y z e d f or  r u x oliti ni b  b y  a  v ali d at e d li q ui d  c hr o m at o gr a p h y –t a n d e m 
m ass s p e ctr o m etr y  ass a y.   T h es e s a m pl es  will  b e  a n al y z e d  b y I n c yt e  C or p or ati o n ( W il mi n gt o n, 
D E)  or its  d esi g n e e.  
P h ar m a c o ki n eti c  p ar a m et ers  will  b e  c al c ul at e d fr o m t h e  pl as m a  c o n c e ntr ati o ns  of  r u x oliti ni b 
a c c or di n g t o  a  m o d el -i n d e p e n d e nt  a p pr o a c h  or  p o p ul ati o n  P K  a p pr o a c h.  I nstr u cti o ns r e g ar di n g 
s a m pl e c oll e cti o n ,  h a n dli n g,  a n d s hi p pi n g  will  b e  pr o vi d e d i n t h e  L a b or at or y  Ma n u al.  

I n c yt e  C or p or ati o n 
P a g e  5 2  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
7. 9.   
Ot h e r  St u d y  P r o c e d u r es  
7. 9. 1.   
Dist ri b uti o n  of  S u bj e ct  R e mi n d e r  C a r ds  
S u bj e cts  will  b e  pr o vi d e d  wit h  a r e mi n d er  c ar d  at  e a c h  visit.   T h e s u bj e ct r e mi n d er  c ar d  will 
i n di c at e t h e  d at e/ti m e  of t h e  n e xt  visit  a n d  will  als o r e mi n d t h e s u bj e ct t o  n ot t a k e t h e st u d y dr u g 
o n  D a ys  1,  7,  a n d  1 4  u ntil  aft er  bl o o d  s a m pl es f or  P K  a n d s af et y  h a v e  b e e n  dr a w n i n t h e  cli ni c.  
T h e r e mi n d er  c ar ds f or  t h e  D a y  1,  7,  a n d  1 4 visits  will  h a v e  a n  ar e a  f or t h e s u bj e ct t o r e c or d t h e 
d at e  a n d ti m e  of t h e l ast  d os e t a k e n (fr o m t h e  pr e vi o us  d a y ) a n d t h e ti m e  of t h eir l ast  m e al  b ef o r e 
t h e  visit. 
8.   
S A F E T Y  M O NI T O RI N G  A N D  R E P O R TI N G  
8. 1.   
A d v e rs e  E v e nts  
8. 1. 1.   
D efi niti o ns  
F or t h e  p ur p os es  of t his  Pr ot o c ol,  a n  a d v ers e  e v e nt ( A E) is  d efi n e d  as  a n y  u nt o w ar d  m e di c al 
o c c urr e n c e  ass o ci at e d  wit h t h e  us e  of  a  dr u g i n  h u m a ns,  w h et h er  or  n ot  c o nsi d er e d  dr u g r el at e d 
t h at  o c c urs  aft er  a s u bj e ct  pr o vi d es i nf or m e d  c o ns e nt.   A b n or m al l a b or at or y  v al u es  or t est r es ults 
o c c urri n g  aft er i nf or m e d  c o ns e nt  c o nstit ut e  A Es  o nl y if t h e y i n d u c e  cli ni c al si g ns  or s y m pt o ms, 
ar e  c o nsi d er e d  cli ni c all y  m e a ni n gf ul, r e q uir e t h er a p y ( e g ,  h e m at ol o gi c  a b n or m alit y t h at r e q uir es 
tr a nsf usi o n),  or r e q uir e  c h a n g es i n t h e st u d y  dr u g(s). 
8. 1. 2.   
R e p o rti n g  
A d v ers e  e v e nts t h at  b e gi n  or  w ors e n  aft er i nf or m e d  c o ns e nt s h o ul d  b e r e c or d e d  o n t h e  A d v ers e 
E v e nts f or m  of t h e  e C R F.   C o n diti o ns t h at  w er e  alr e a d y  pr es e nt  at t h e ti m e  of i nf or m e d  c o ns e nt 
s h o ul d  b e r e c or d e d  o n t h e  M e di c al  Hist or y f or m i n t h e  e C R F.   M o nit ori n g  f or t h e  o c c urr e n c e of 
n e w   A Es s h o ul d  b e  c o nti n u e d f or  at l e ast  3 0  d a ys  aft er t h e l ast  d os e  of st u d y  dr u g.   A d v ers e 
e v e nts (i n cl u di n g l a b or at or y  a b n or m aliti es t h at  c o nstit ut e  A Es) s h o ul d  b e  d es cri b e d  usi n g  a 
di a g n osis  w h e n e v er  p ossi bl e r at h er t h a n  b y i n di vi d u al  u n d erl yi n g si g ns  a n d s y m pt o ms.   W h e n  a 
cl e ar  di a g n osis  c a n n ot  b e i d e ntifi e d,  e a c h si g n  or s y m pt o m s h o ul d  b e r e p ort e d  as  a s e p ar at e  A E.  

I n c yt e  C or p or ati o n 
P a g e  5 3  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
T h e t er m  "dis e as e  pr o gr essi o n " s h o ul d  b e r e c or d e d  as  a n  A E/ S A E its elf  o nl y if t h er e  ar e  n o  ot h er 
i d e ntifi a bl e  A Es/ S A Es  ass o ci at e d  wit h t h e  dis e as e  pr o gr essi o n  at t h e ti m e  of r e p orti n g.  F or 
e v e nts  ass o ci at e d  wit h  dis e as e  pr o gr e ssi o n, t h e r el e v a nt si g ns  a n d s y m pt o ms s h o ul d  b e r e p ort e d 
usi n g  a  di a g n osis  w h e n e v er  p ossi bl e r at h er t h a n i n di vi d u al  u n d erl yi n g si g ns  a n d s y m pt o ms.  
W h e n  a  cl e ar  di a g n osis  c a n n ot  b e i d e ntifi e d,  e a c h si g n  or s y m pt o m s h o ul d  b e r e p ort e d  as  a 
s e p ar at e  A E.  If t h e  e v e nts r es ulti n g fr o m  dis e as e  pr o gr essi o n  m e et t h e  crit eri a f or  a n  S A E ( e g, 
r es ult e d i n  h os pit ali z ati o n,  a lif e-t hr e at e ni n g  e v e nt,  or  d e at h), t h e s p e cifi c  e v e nt(s) s h o ul d  b e 
r e p ort e d  as  a n  S A E(s)  as  d es cri b e d i n S e cti o n  8. 3. 2 .  I n  b ot h  c as es (i e,  A Es  or  S A Es r el at e d t o 
dis e as e  pr o gr essi o n), f or  e a c h  e v e nt it s h o ul d  b e i n di c at e d  w h et h er t h e  e v e nt ( di a g n osis  or si g ns 
a n d s y m pt o ms) is r el at e d t o  dis e as e  pr o gr essi o n. 
T h e s e v erit y  of  A Es  will  b e  ass ess e d  usi n g  C T C A E  v 4. 0 3  Gr a d es  1 t hr o u g h  4.   T h e  C T C A E 
v 4. 0 3 s e v erit y  of  Gr a d e  5  will  n ot  b e  us e d;  A Es r es ulti n g i n  d e at h  will  b e  gr a d e d  a c c or di n gl y 
usi n g  Gr a d es  1 t hr o u g h  4  a n d  h a v e t h e  o ut c o m e  n ot e d  as f at al.  If  a n  e v e nt is  n ot  cl assifi e d  b y 
C T C A E, t h e s e v erit y  of t h e  A E  will  b e  gr a d e d  a c c or di n g t o t h e s c al e  b el o w t o  esti m at e t h e  gr a d e 
of s e v erit y:  
G r a d e   1 
Mil d;  as y m pt o m ati c  or  mil d s y m pt o ms;  cli ni c al  or  di a g n osti c  o bs er v ati o n s  o nl y; i nt er v e nti o n  n ot 
i n di c at e d. 
G r a d e  2  
M o d er at e;  mi ni m al l y, l o c al,  or  n o ni n v asi v e i nt er v e nti o n i n di c at e d; li miti n g  a g e- a p pr o pri at e 
a cti viti es  of  d ail y li vi n g.  
G r a d e  3  
S e v er e  or  m e di c al l y si g nifi c a nt  b ut  n ot i m m e di at el y lif e -t hr e at e ni n g;  h os pit ali z ati o n  or 
pr ol o n g ati o n  of  h os pit ali z ati o n i n di c at e d;  dis a bli n g; li miti n g s elf -c ar e  a cti viti es  of  d ail y li vi n g.  
G r a d e  4  
Lif e -t hr e at e ni n g  c o ns e q u e n c es;  ur g e nt i nt er v e nti o n i n di c at e d. 
T h e  o c c urr e n c e  of  A Es s h o ul d  b e s o u g ht  b y  n o n dir e cti v e  q u esti o ni n g  of t h e s u bj e ct  d uri n g t h e 
s cr e e ni n g  pr o c ess  aft er si g ni n g t h e I C F  a n d  at  e a c h  visit  d uri n g t h e st u d y.   A d v ers e  e v e nts  m a y 
als o  b e  d et e ct e d  w h e n t h e y  ar e  v ol u nt e er e d  b y t h e s u bj e ct  d uri n g t h e s cr e e ni n g  p r o c ess  or 
b et w e e n  visits,  or t hr o u g h  p h ysi c al  e x a mi n ati o n, l a b or at or y t est,  or  ot h er  ass ess m e nts.   T o t h e 
e xt e nt  p ossi bl e,  e a c h  A E s h o ul d  b e  e v al u at e d t o  d et er mi n e: 
•   T h e s e v erit y  gr a d e ( C T C A E  Gr a d e   1 t o 4).  
•   W h et h er t h er e is  at l e ast  a  r e as o n a bl e  p ossi bilit y t h at t h e  A E is r el at e d t o t h e st u d y 
tr e at m e nt:  s us p e ct e d ( y es)  or n ot s us p e ct e d  ( n o). 
•   T h e st art  a n d  e n d  d at es,  u nl ess  u nr es ol v e d  at fi n al f oll o w- u p. 
•   T h e  a cti o n t a k e n  wit h r e g ar d t o st u d y  dr u g. 
•   T h e  e v e nt  o ut c o m e ( e g ,  n ot r e c o v er e d/ n ot r es ol v e d, r e c o v er e d/r es ol v e d, 
r e c o v eri n g/r es ol vi n g, r e c o v er e d/r es ol v e d  wit h s e q u el a e, f at al,  u n k n o w n). 
•   T h e s eri o us n ess,  as  p er s eri o us  a d v ers e  e v e nt ( S A E)  d efi niti o n  pr o vi d e d i n 
S e cti o n  8. 3. 1 . 
U nli k e r o uti n e s af et y  ass ess m e nts,  S A Es  ar e  m o nit or e d  c o nti n u o usl y  a n d  h a v e s p e ci al r e p orti n g 
r e q uir e m e nts (s e e S e cti o n  8. 3. 2 ). 
All  A Es s h o ul d  b e tr e at e d  a p pr o pri at el y.  If  a n  A E is tr e at e d  wit h  a  c o n c o mit a nt  m e di c ati o n  or 
n o n dr u g t h er a p y, t his  a cti o n s h o ul d  b e r e c or d e d  o n  A d v ers e  E v e nt f or m  a n d t h e tr e at m e nt s h o ul d 

I n c yt e  C or p or ati o n 
P a g e  5 4  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
b e s p e cifi e d  o n t h e  P ri or/ C o n c o mit a nt  M e di c ati o ns  or  Pr o c e d ur es  a n d  N o n-Dr u g  T h er a p y f or m 
i n t h e  e C R F. 
O n c e  a n  A E is  d et e ct e d, it s h o ul d  b e f oll o w e d  u ntil it  h as r es ol v e d  or  u ntil it is j u d g e d t o  b e 
p er m a n e nt;  ass ess m e nt s h o ul d  b e  m a d e  at  e a c h  visit ( or  m or e fr e q u e ntl y if  n e c e ss ar y)  of  a n y 
c h a n g es i n s e v erit y, t h e s us p e ct e d r el ati o ns hi p t o t h e st u d y  dr u g, t h e i nt er v e nti o ns r e q uir e d t o 
tr e at t h e  e v e nt,  a n d t h e  o ut c o m e. 
W h e n t h e s e v erit y  of  a n  A E  c h a n g es  o v er ti m e f or  a r e p orti n g  p eri o d ( e g,  b et w e e n  visits),  e a c h 
c h a n g e i n s e v erit y  will  b e r e p ort e d  as  a s e p ar at e  A E  u ntil t h e  e v e nt r es ol v es.   F or  e x a m pl e, 
2  s e p ar at e  A Es  will  b e r e p ort e d if  a s u bj e ct  h as  Gr a d e  1  di arr h e a,  m e eti n g t h e  d efi niti o n  of  a n 
A E,  w hi c h l asts f or  3  d a ys  b ef or e  w ors e ni n g t o  a  Gr a d e  3 s e v erit y.   T h e  Gr a d e  1  e v e nt  will  b e 
r e p ort e d  as  a n  A E  wit h  a st art  d at e  e q u al t o t h e  d a y t h e  e v e nt  m et t h e  Gr a d e  1  A E  d efi niti o n  a n d 
a st o p  d at e  e q u al t o t h e  d a y t h at t h e  e v e nt i n cr e as e d i n s e v erit y fr o m  Gr a d e  1 t o  Gr a d e  3.   T h e 
Gr a d e  3  e v e nt  will  als o  b e r e p ort e d  as  a n  A E,  wit h t h e st art  d at e  e q u al t o t h e  d a y t h e  e v e nt 
c h a n g e d i n i nt e nsit y fr o m  Gr a d e  1 t o  Gr a d e  3  a n d  a st o p  d at e  e q u al t o t h e  d a y t h at t h e  e v e nt 
eit h er  c h a n g e d s e v erit y  a g ai n  or r es ol v e d.   F or  a n al ysis  p ur p os es, t his  will  b e  c o nsi d er e d  1  A E 
f or t his s u bj e ct,  a n d t h e hi g h est r e p ort e d s e v erit y  will  b e  us e d.  
8. 2.   
L a b o r at o r y  T est  A b n o r m aliti es  
L a b or at or y  a b n or m aliti es t h at  c o nstit ut e  a n  A E i n t h eir  o w n ri g ht ( c o nsi d er e d  cli ni c all y 
m e a ni n gf ul, i n d u c e  cli ni c al si g ns  or s y m pt o ms, r e q uir e  c o n c o mit a nt t h er a p y,  or r e q uir e  c h a n g es 
i n st u d y  dr u g) s h o ul d  b e r e c or d e d  o n t h e  A d v ers e  E v e nt f or m i n t h e  e C R F.   W h e n e v er  p ossi bl e,  a 
di a g n osis r at h er t h a n  a s y m pt o m s h o ul d  b e  pr o vi d e d ( e g,  " a n e mi a "  i nst e a d  of "l o w  h e m o gl o bi n " ).  
L a b or at or y  a b n or m aliti es t h at  m e et t h e  crit eri a f or  A Es s h o ul d  b e f oll o w e d  u ntil t h e y  h a v e 
r et ur n e d t o  n or m al  or  a n  a d e q u at e  e x pl a n ati o n  of t h e  a b n or m alit y is f o u n d.   W h e n  a n  a b n or m al 
l a b or at or y t est r es ult  c orr es p o n ds t o  a si g n  or s y m pt o m  of  a  pr e vi o usl y r e p ort e d  A E, it is  n ot 
n e c ess ar y t o s e p ar at el y r e c or d t h e l a b or at or y t est r es ult  as  a n  a d diti o n al  e v e nt.  
L a b or at or y  a b n or m aliti es t h at  d o  n ot  m e et t h e  d efi niti o n  of  a n  A E s h o ul d  n ot  b e r e p ort e d  as  A Es.  
A  Gr a d e   3  or  4 (s e v er e)  A E  d o es  n ot  a ut o m ati c all y i n di c at e  a n  S A E  u nl ess it  m e ets t h e  d efi niti o n 
of s eri o us,  as  d efi n e d i n  S e cti o n  8. 3. 1 ,  a n d/ or  p er t h e i n v esti g at or's  dis cr eti o n.   A  d os e 
m o difi c ati o n f or t h e l a b or at or y  a b n or m alit y  m a y  b e r e q uir e d (s e e  S e cti o n  5. 4. 2 )  a n d s h o ul d  n ot 
c o ntri b ut e t o t h e  d esi g n ati o n  of  a l a b or at or y t est  a b n or m alit y  as  a n  S A E. 
8. 3.   
S e ri o us  A d v e rs e  E v e nts  
8. 3. 1.   
D efi niti o ns  
A n  S A E is  d efi n e d  as  a n  e v e nt t h at  m e ets  at l e ast  1  of t h e f oll o wi n g  crit eri a:  
•   Is f at al  or lif e-t hr e at e ni n g. 
•   R e q uir es i n p ati e nt  h os pit ali z ati o n  or  pr ol o n g ati o n  of  e xisti n g  h os pit ali z ati o n,  u nl ess 
h os pit ali z ati o n is  a r es ult  of:  
−   A r o uti n e tr e at m e nt  or  m o nit ori n g  of t h e st u di e d i n di c ati o n  n ot  ass o ci at e d  wit h 
a n y  d et eri or ati o n i n  c o n diti o n. 

I n c yt e  C or p or ati o n 
P a g e  5 5  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
−   A n  el e cti v e  s ur g er y  or  pr e pl a n n e d tr e at m e nt f or  a  pr e- e xisti n g  c o n diti o n t h at is 
u nr el at e d t o t h e i n di c ati o n  u n d er st u d y  a n d  h as  n ot  w ors e n e d si n c e si g ni n g t h e 
I C F. 
−   A tr e at m e nt  o n  a n  e m er g e n c y  o ut p ati e nt  b asis f or  a n  e v e nt  n ot f ulfilli n g  a n y  of t h e 
d efi niti o ns  of  a  S A E  a n d  n ot r es ulti n g i n  h os pit al  a d missi o n. 
−   A n y s o ci al r e as o ns  a n d r es pit e  c ar e, i n t h e  a bs e n c e  of  a n y  d et eri or ati o n i n t h e 
s u bj e ct's  g e n er al  c o n diti o n. 
•   R es ults i n  p ersist e nt  or si g nifi c a nt  dis a bilit y, i n c a p a cit y,  or  a s u bst a nti al  disr u pti o n  of 
a  p ers o n 's  a bilit y t o  c o n d u ct  n or m al lif e f u n cti o ns. 
•   C o nstit ut es  a  c o n g e nit al  a n o m al y  or  birt h  d ef e ct. 
•   Is  c o nsi d er e d t o  b e  a n i m p ort a nt  m e di c al  e v e nt  or  a  m e di c all y si g nifi c a nt  e v e nt t h at 
m a y  n ot r es ult i n  d e at h,  b e i m m e di at el y lif e -t hr e at e ni n g,  or r e q uir e  h os pit ali z ati o n  b ut 
m a y  b e  c o nsi d er e d s eri o us  w h e n,  b as e d  u p o n  a p pr o pri at e  m e di c al j u d g m e nt, t h e  e v e nt 
m a y j e o p ar di z e t h e s u bj e ct  or  m a y r e q uir e  m e di c al  or s ur gi c al i nt er v e nti o n t o  pr e v e nt 
1  of t h e  o ut c o m es list e d  a b o v e. 
8. 3. 2.   
R e p o rti n g  
E v er y  S A E, r e g ar dl ess  of s us p e ct e d  c a us alit y ( e g, r el ati o ns hi p t o st u d y  dr u g(s)  or st u d y 
pr o c e d ur e  or  dis e as e  pr o gr essi o n),  o c c urri n g  aft er t h e s u bj e ct  h as si g n e d t h e I C F t hr o u g h t h e l ast 
st u d y  visit ( or  3 0  d a ys)  aft er t h e l ast  d os e  of st u d y  dr u g,  w hi c h e v e r is l at er)  m ust  b e r e p ort e d t o 
t h e s p o ns or ( or  d esi g n e e)  wit hi n 2 4  h o u rs  of l e ar ni n g  of its  o c c urr e n c e,  u nl ess  ot h er wis e 
s p e cifi e d  b y t h e  Pr ot o c ol.   A n y  S A Es  o c c urri n g  m or e t h a n  3 0  d a ys  aft er t h e l ast  d os e  of st u d y 
dr u g s h o ul d  b e r e p ort e d t o t h e s p o ns or  or its  d esi g n e e  o nl y if t h e i n v esti g at or s us p e cts  a  c a us al 
r el ati o ns hi p t o t h e st u d y  dr u g.   
I nf or m ati o n  a b o ut  all  S A Es is  c oll e ct e d  a n d r e c or d e d  o n t h e  A d v ers e  E v e nt f or m  of t h e  e C R F.  
T h e i n v esti g at or  m ust  ass ess  a n d r e c or d t h e  c a us al  r el ati o ns hi p  of  e a c h  S A E t o  e a c h s p e cifi c 
st u d y  dr u g (r u x oliti ni b  a n d  c orti c ost er oi ds)  d uri n g t h e ti m e it is  gi v e n. 
T h e i n v esti g at or  m ust  als o  c o m pl et e t h e I n c yt e  S eri o us  A d v ers e  E v e nt  R e p ort  F or m, i n  E n glis h, 
a n d s e n d t h e  c o m pl et e d  a n d si g n e d f or m t o t h e s p o ns or  or  d esi g n e e  wit hi n  2 4  h o urs  of  b e c o mi n g 
a w ar e  of t h e  S A E.   T h e i n v esti g at or  m ust  pr o vi d e  a  c a us alit y  ass ess m e nt, t h at is,  ass ess  w h et h er 
t h er e is  at l e ast  a r e as o n a bl e  p ossi bilit y t h at t h e  S A E is r el at e d t o t h e st u d y tr e at m e nt:  s us p e ct e d 
( y es)  or  n ot s us p e ct e d ( n o).  R ef er t o t h e I n c yt e  R ef er e n c e  G ui d e f or  C o m pl eti n g t h e  S eri o us 
A d v ers e  E v e nt  R e p ort  F or m. 
T h e  c o nt a ct i nf or m ati o n  of t h e s p o ns or' s st u d y-s p e cifi c r e pr es e nt ati v es is list e d i n t h e 
i n v esti g at or  m a n u al  pr o vi d e d t o  e a c h sit e.   T h e  ori gi n al  c o p y  of t h e  S A E  R e p ort  F or m  a n d t h e 
c o nfir m ati o n s h e et  m ust  b e  k e pt  at t h e st u d y sit e.  
I n v esti g ati o n al sit e  p ers o n n el  m ust r e p ort  a n y  n e w i nf or m ati o n r e g ar di n g t h e  S A E  wit hi n 
2 4  h o urs  of  b e c o mi n g  a w ar e  of t h e i nf or m ati o n i n t h e s a m e  m a n n er t h at t h e i niti al  S A E  R e p ort 
F or m  w as s e nt.   F oll o w- u p i nf or m ati o n is r e c or d e d  o n  a n  a m e n d e d  or  n e w  S A E  R e p ort  F or m, 
wit h  a n i n di c ati o n t h at it is f oll o w - u p t o t h e  pr e vi o usl y r e p ort e d  S A E  a n d t h e  d at e  of t h e  ori gi n al 
r e p ort.   T h e f oll o w- u p r e p ort s h o ul d i n cl u d e i nf or m ati o n t h at  w as  n ot  pr o vi d e d  o n t h e  pr e vi o us 

I n c yt e  C or p or ati o n 
P a g e  5 6  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
S A E  R e p ort  F or m, s u c h  as t h e  o ut c o m e  of t h e  e v e nt ( e g, r es ol v e d  or  o n g oi n g), tr e at m e nt 
pr o vi d e d,  a cti o n t a k e n  wit h st u d y  dr u g  b e c a us e  of t h e  S A E ( e g,  d os e r e d u c e d, i nt err u pt e d,  or 
dis c o nti n u e d),  or s u bj e ct  dis p ositi o n ( e g,  c o nti n u e d  or  wit h dr e w fr o m st u d y  p arti ci p ati o n).   E a c h 
r e c urr e n c e,  c o m pli c ati o n,  or  pr o gr essi o n  of t h e  ori gi n al  e v e nt s h o ul d  b e r e p ort e d  as f oll o w- u p t o 
t h at  e v e nt, r e g ar dl ess  of  w h e n it  o c c urs. 
If t h e  S A E is  n ot  d o c u m e nt e d i n t h e I B f or t h e st u d y  dr u g ( n e w  o c c urr e n c e)  a n d is t h o u g ht t o  b e 
r el at e d t o t h e s p o ns or's st u d y  dr u g, t h e s p o ns or  or its  d esi g n e e  m a y  ur g e ntl y r e q uir e f urt h er 
i nf or m ati o n fr o m t h e i n v esti g at or f or r e p orti n g t o  h e alt h  a ut h oriti es.   T h e s p o ns or  or its  d esi g n e e 
m a y  n e e d t o iss u e  a n I n v esti g at or  N otifi c ati o n (I N) t o i nf or m  all i n v esti g at ors i n v ol v e d i n  a n y 
st u d y  wit h t h e s a m e  dr u g t h at t his  S A E  h as  b e e n r e p ort e d.   S us p e ct e d  U n e x p e ct e d  S eri o us 
A d v ers e  R e a cti o ns ( S U S A Rs)  will  b e  c oll e ct e d  a n d r e p ort e d t o t h e  c o m p et e nt  a ut h oriti es  a n d 
r el e v a nt  et hi cs  c o m mitt e es i n  a c c or d a n c e  wit h  Dir e cti v e  2 0 0 1/ 2 0/ E C,  or  as  p er  n ati o n al 
r e g ul at or y r e q uir e m e nts i n  p arti ci p ati n g  c o u ntri es. 
8. 4.   
E m e r g e n c y  U n bli n di n g  of  T r e at m e nt  Assi g n m e nt  
N ot  a p pli c a bl e.  
8. 5.   
P r e g n a n c y  
Pr e g n a n c y, i n  a n d  of its elf, is  n ot r e g ar d e d  as  a n  A E  u nl ess t h er e is s us pi ci o n t h at st u d y  dr u g  m a y 
h a v e i nt erf er e d  wit h t h e  eff e cti v e n ess  of  a  c o ntr a c e pti v e  m e di c ati o n  or  m et h o d.   W h e n  a 
pr e g n a n c y  h as  b e e n  c o nfir m e d i n  a s u bj e ct  d uri n g  m at er n al  or  p at er n al  e x p os ur e t o st u d y  dr u g, 
t h e f oll o wi n g  pr o c e d ur es s h o ul d  b e f oll o wi n g i n  or d er t o  e ns ur e s u bj e ct s af et y: 
•   T h e st u d y  dr u g  m ust  b e  dis c o nti n u e d i m m e di at el y (f e m al e s u bj e cts  o nl y; s e e 
S e cti o n  5. 4. 1  f or t h e  m a xi m u m  p er mitt e d  d ur ati o n  of st u d y  dr u g i nt err u pti o n). 
•   T h e i n v esti g at or  m ust  c o m pl et e  a n d s u b mit t h e I n c yt e  Cli ni c al  Tri al  Pr e g n a n c y f or m 
t o t h e s p o ns or  or its  d esi g n e e  wit hi n 2 4  h o u rs   of l e ar ni n g  of t h e  pr e g n a n c y. 
D at a  o n f et al  o ut c o m e  a n d  br e astf e e di n g  ar e  c oll e ct e d f or r e g ul at or y r e p orti n g  a n d  dr u g s af et y 
e v al u ati o n.   F oll o w- u p s h o ul d  b e  c o n d u ct e d f or  e a c h  pr e g n a n c y t o  d et er mi n e  o ut c o m e, i n cl u di n g 
s p o nt a n e o us  or  v ol u nt ar y t er mi n ati o n,  d et ails  of t h e  birt h,  a n d t h e  pr es e n c e  or  a bs e n c e  of  a n y 
birt h  d ef e cts,  c o n g e nit al  a b n or m aliti es,  or  m at er n al  a n d/ or  n e w b or n  c o m pli c ati o ns,  b y f oll o wi n g 
u ntil t h e first  w ell - b a b y  visit.   Pr e g n a n c y s h o ul d  b e r e c or d e d  o n  a  Cli ni c al  Tri al  Pr e g n a n c y f or m 
a n d r e p ort e d  b y t h e i n v esti g at or t o t h e s p o ns or  or its  d esi g n e e.   Pr e g n a n c y f oll o w- u p i nf or m ati o n 
s h o ul d  b e r e c or d e d  o n t h e s a m e f or m  a n d s h o ul d i n cl u d e  a n  ass ess m e nt  of t h e  p ossi bl e  c a us al 
r el ati o ns hi p t o t h e s p o ns or's st u d y  dr u g t o  a n y  pr e g n a n c y  o ut c o m e,  as  w ell  as f oll o w- u p t o t h e 
first  w ell- b a b y  visit  or t h e  d ur ati o n s p e cifi e d i n l o c al r e g ul ati o ns,  w hi c h e v er is l at er.   R ef er t o t h e 
I n c yt e  R ef er e n c e  G ui d e f or  C o m pl eti n g t h e  Cli ni c al  Tri al  Pr e g n a n c y  F or m. 
A n y  S A E  o c c u r ri n g  d u ri n g  p r e g n a n c y  m ust  b e  r e c o r d e d  o n t h e  S A E  r e p o rt f o r m  a n d 
s u b mitt e d t o t h e s p o ns o r  o r  d esi g n e e . 

I n c yt e  C or p or ati o n 
P a g e  5 7  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
8. 6.   
W a r ni n gs  a n d  P r e c a uti o ns  
S p e ci al  w ar ni n gs  or  pr e c a uti o ns f or t h e st u d y  dr u g,  d eri v e d fr o m s af et y i nf or m ati o n  c oll e ct e d  b y 
t h e s p o ns or  or its  d esi g n e e,  ar e  pr es e nt e d i n t h e I n v esti g at or's  Br o c h ur e ( I B).   A d diti o n al s af et y 
i nf or m ati o n  c oll e ct e d  b et w e e n I B  u p d at es  will  b e  c o m m u ni c at e d i n t h e f or m  of I n v esti g at or 
N otifi c ati o ns (I Ns).   A n y i m p ort a nt  n e w s af et y i nf or m ati o n s h o ul d  b e  dis c uss e d  w it h t h e s u bj e ct 
d uri n g t h e st u d y,  as  n e c ess ar y.  If  n e w si g nifi c a nt ris ks  ar e i d e ntifi e d, t h e y  will  b e  a d d e d t o t h e 
I C F. 
8. 7.   
D at a  M o nit o ri n g  C o m mitt e e  
T h er e is  n o f or m al  D at a  M o nit ori n g  C o m mitt e e  r e vi e w. 
T h e s p o ns or  will  c o nti n u o usl y  m o nit or s af et y t hr o u g h fr e q u e nt  c o nt a ct  wit h t h e tr e ati n g 
i n v esti g at ors, r e vi e w  of t h e  cli ni c al  d at a,  a n d f or m al st u d y  m e eti n gs.   R o uti n e t el e c o nf er e n c es 
will  b e  h el d  a m o n g  p arti ci p ati n g st u d y sit es t o  pr o vi d e s u bj e ct -b y -s u bj e ct  u p d at es  o n  c urr e nt 
st u d y st at us, i nt eri m t o xi citi es r e p ort e d ,  a n d  a n y  ot h er  p erti n e nt i nf or m ati o n.   A d v ers e  e v e nt  a n d 
l a b or at or y  d at a  e nt er e d i nt o t h e  cli ni c al  d at a b as e  will  b e r e vi e w e d  p eri o di c all y f or tr e n ds  a n d 
e v ol vi n g s af et y si g n als. 
8. 8.   
P r o d u ct  C o m pl ai nts  
T h e s p o ns or  c oll e cts  pr o d u ct  c o m pl ai nts  o n st u d y  dr u gs  a n d  dr u g  d eli v er y s yst e ms  us e d i n 
cli ni c al st u di es i n  or d er t o  e ns ur e t h e s af et y  of st u d y  p arti ci p a nts,  m o nit or  q u alit y,  a n d f a cilit at e 
pr o c ess  a n d  pr o d u ct i m pr o v e m e nts. 
All  pr o d u ct  c o m pl ai nts  ass o ci at e d  wit h  m at eri al  p a c k a g e d, l a b el e d,  a n d r el e as e d  b y  t h e s p o ns or 
or its  d esi g n e e  will  b e r e p ort e d t o t h e s p o ns or.   All  pr o d u ct  c o m pl ai nts  ass o ci at e d  wit h  ot h er 
st u d y  m at eri al  will  b e r e p ort e d  dir e ctl y t o t h e r es p e cti v e  m a n uf a ct ur er.  
T h e i n v esti g at or  or  his/ h er  d esi g n e e is r es p o nsi bl e f or r e p orti n g  a  c o m pl et e  d es cri pti o n  of t h e 
pr o d u ct  c o m pl ai nt  vi a  e m ail  or  ot h er  writt e n  c o m m u ni c ati o n t o t h e s p o ns or  c o nt a ct  or r es p e cti v e 
m a n uf a ct ur er  as  n ot e d i n t h e  p a c k a gi n g i nf or m ati o n.   A n y  A E  ass o ci at e d  wit h  a  pr o d u ct 
c o m pl ai nt s h o ul d  b e r e p ort e d  as  d es cri b e d i n  S e cti o n  8. 1. 2   of t his  Pr ot o c ol. 
If t h e i n v esti g at or is  as k e d t o r et ur n t h e  pr o d u ct f or i n v esti g ati o n,  h e/s h e  will r et ur n  a  c o p y  of t h e 
pr o d u ct  c o m pl ai nt  c o m m u ni c ati o n  wit h t h e  pr o d u ct. 

I n c yt e  C or p or ati o n 
P a g e  5 8  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
9.   
S T A TI S TI C S  
9. 1.   
St u d y  P o p ul ati o ns  
S u bj e ct  e nr oll m e nt,  dis p ositi o n,  d e m o gr a p hi cs,  a n d  m e di c al  hist or y  will  b e s u m m ari z e d  at 
b as eli n e.   D os e  e x p os ur e  will  b e  c al c ul at e d f or  e a c h s u bj e ct.   S af et y  a n d  dis e as e r es p o ns e  d at a 
will  b e  c o m p ar e d  o v er ti m e t o  ass ess  c h a n g e fr o m  b as eli n e,  d uri n g tr e at m e nt,  a n d f oll o w- u p. 
T h e  p o p ul ati o ns t o  b e  a n al y z e d i n cl u d e t h e f oll o wi n g: 
•   Effi c a c y  E v al u a bl e  P o p ul ati o n:   S u bj e cts  e nr oll e d  i nt o t h e st u d y. 
•   S af et y  E v al u a bl e  P o p ul ati o n:   S u bj e cts  e nr oll e d  i nt o t h e st u d y  w h o r e c ei v e d  at l e ast 
1  d os e  of st u d y  dr u g. 
•   P h ar m a c o ki n eti c   E v al u a bl e  P o p ul ati o n:   S u bj e cts  w h o r e c ei v e  at l e ast  1  d os e  of st u d y 
dr u g  a n d  pr o vi d e  at l e ast  1  pl as m a s a m pl e ( 1  P K  m e as ur e m e nt)  aft er st u d y  dr u g 
a d mi nistr ati o n  will  b e  c o nsi d er e d  as  p o t e nti al  P K e v al u a bl e s u bj e cts .  T h e st u d y 
p h ar m a c o ki n eti cist  will r e vi e w  d at a listi n gs  of st u d y  dr u g  a d mi nistr ati o n  a n d s a m pl e 
r e c or ds t o i d e ntif y s u bj e cts t o  b e  e x cl u d e d fr o m  a n al ys es  of  P K d at a.  
9. 2.   
S el e cti o n  of  S a m pl e  Si z e  
A p pr o xi m at el y  7 0  s u bj e cts  ar e  pl a nn e d f or t h e fi n al  a n al ysis  of t h e  pri m ar y  e n d p oi nt  of  O R R.   A 
tr e at m e nt r e gi m e n f or st er oi d-r efr a ct or y  G V H D  d e m o nstr ati n g  a n  a bs ol ut e i m pr o v e m e nt  of  2 0 % 
v ers us  hist ori c  d at a  w o ul d  b e  c o nsi d er e d  cli ni c all y  m e a ni n gf ul.   Wit h t h e  ass u m e d tr u e r at e  of 
6 0 %,  a s a m pl e si z e  of  7 0 s u bj e cts  w o ul d  pr o vi d e  >  9 0 %  pr o b a bilit y t o  h a v e  a  9 5 %  CI  wit h l o w er 
li mit  of  ≥  4 0 %. 
A n i nt eri m  a n al ysis  will  b e  c o n d u ct e d  w h e n  3 5 s u bj e cts  c o m pl et e t h e  D a y  2 8  visit i n  or d er t o 
ass ess f or f utilit y; if t h e l o w er  b o u n d ar y is  cr oss e d, t h e  stu d y  will  b e t er mi n at e d.  
A  gr o u p s e q u e nti al  d esi g n  m et h o d f or  1  s a m pl e  bi n ar y  o ut c o m e  d at a  will  b e  us e d t o  c al c ul at e t h e 
l o w er  b o u n d ar y  of f utilit y.   T h e s p e n di n g f u n cti o n  of  H S D(- 4)  will  b e  us e d.   F or  H 0:   p  =  0. 4, 
H a:   p   =  0. 6,  a n d  a  1-si d e d  bi n o mi al t est   wit h  al p h a  of  0. 0 2 5, if  ≤  1 5 s u bj e cts r es p o n d  at t h e ti m e 
of t h e i nt eri m  a n al ysis, t h e st u d y  will  b e t er mi n at e d.   T his  will  pr o vi d e  7 0. 0 3 %  pr o b a bilit y f or 
t h e r es p o ns e r at e  of  4 0 %  at t h e i nt eri m  a n al ysis. 
If  ≥  3 7 s u bj e cts r es p o n d  at t h e ti m e  of fi n al  a n al ysis, t h e st u d y  o ut c o m e  will  b e  c o nsi d er e d 
p ositi v e.   T h es e  ass u m pti o ns  will  pr o vi d e  8 9. 8 8 %  p o w er f or t h e r es p o ns e r at e  of  6 0 % i n t h e fi n al 
a n al ysis  wit h  T y p e  I  err or  of  0. 0 1 8 9. 
9. 3.   
L e v el  of  Si g nifi c a n c e  
N o f or m al st atisti c al t ests  will  b e  p erf or m e d.   All  CIs  will  b e  9 5 %.  

I n c yt e  C or p or ati o n 
P a g e  5 9  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
9. 4.   
St atisti c al  A n al ys es  
9. 4. 1.   
P ri m a r y  A n al ys es 
T h e  pri m ar y  e n d p oi nt is  O R R  at  D a y  2 8,  d efi n e d  as t h e  pr o p orti o n  of s u bj e cts  d e m o nstr ati n g  a 
C R,  V G P R,  or  P R,  as  p er st a n d ar d  crit eri a  (A p p e n di x  B ).  T h e  pri m ar y  a n al ysis  will  b e 
c o n d u ct e d  o n c e t h e  l ast s u bj e ct  c o m pl et es t h e  D a y  2 8  visit  or  wit h dr a ws fr o m t h e st u d y. 
S u m m ar y st atisti cs  a n d  9 5 %  CI  will  b e  pr o vi d e d.  
9. 4. 2.   
S e c o n d a r y  A n al ys es 
T h e  k e y s e c o n d ar y  e n d p oi nt  is  6- m o nt h  D O R,  d efi n e d  as t h e ti m e fr o m first r es p o ns e  u ntil 
G V H D  pr o gr essi o n  or  d e at h.   Si x - m o nt h D O R  wi ll  b e  ass ess e d  w h e n  all s u bj e cts  c o m pl et e t h e 
t h e  D a y 1 8 0  visit.   T h e  d ur ati o n  of  dis e as e  c o ntr ol  will  b e  esti m at e d  b y t h e  K a pl a n -M ei er 
m et h o d. 
A d diti o n al s e c o n d ar y  e n d p oi nts  will  b e  a n al y z e d  as f oll o ws:  
•   O R R,  d efi n e d  as t h e  pr o p orti o n  of s u bj e cts  d e m o nstr ati n g  a  C R,  V G P R,  or  P R  at 
D a ys  1 4,  5 6,  a n d  1 0 0.   S u m m ar y st atisti cs  a n d  a p pli c a bl e  9 5 %  CI  will  b e  pr o vi d e d. 
•   T hr e e - m o nt h D O R ,  d efi n e d  as t h e ti m e fr o m first r es p o ns e  u ntil  G V H D  pr o gr essi o n 
or  d e at h,  w h e n  all s u bj e cts  c o m pl et e t h e  D a y  8 4  visit. 
•   N R M,  d efi n e d  as t h e  pr o p orti o n  of s u bj e cts  w h o  di e d  d u e t o  c a us es  ot h er t h a n 
m ali g n a n c y  r el a ps e  at  M o nt hs  6,  9,  1 2,  a n d  2 4.  C u m ul ati v e i n ci d e n c e r at es  w ill  b e 
pr o vi d e d.   S u m m ar y st atisti cs  a n d  a p pl i c a bl e  9 5 %  CI  will  b e  pr o vi d e d. 
•   R el a ps e r at e,  d efi n e d  as t h e  pr o p orti o n  of s u bj e cts  w h os e  u n d erl yi n g  m ali g n a n c y  
r el a ps es.  T h e  c u m ul ati v e i n ci d e n c e r at e  a n d s u m m ar y st atisti cs  will  b e  pr o vi d e d.  
•   R el a ps e -r el at e d  mort alit y r at e,  d efi n e d  as t h e  pr o p orti o n  of s u bj e cts  w h os e 
m ali g n a n c y  r el a ps es  a n d  h as  a f at al  o ut c o m e.  T h e  c u m ul ati v e i n ci d e n c e r at e  a n d 
su m m ar y st atisti cs  will  b e  pr o vi d e d.  
•   F F S,  d efi n e d  as t h e  pr o p orti o n  of s u bj e cts  w h o  ar e still  ali v e,  h a v e  n ot r el a ps e d,  h a v e 
n ot r e q uir e d  a d diti o n al t h er a p y f or  a c ut e  G V H D,  a n d  h a v e  n ot  d e m o nstr at e d si g ns  or 
s y m pt o ms  of  c hr o ni c  G V H D,  at  M o nt h  6.   T h e  K a pl a n -M ei er  m et h o d   will  b e  us e d.  
S u m m ar y st atisti cs  will  b e  pr o vi d e d.  
•   O v er all s ur vi v al,  d efi n e d  as t h e ti m e fr o m st u d y  e nr oll m e nt t o  d e at h  d u e t o  a n y  c a us e.  
T h e  K a pl a n -M ei er  m et h o d   will  b e  us e d.  S u m m ar y st atisti cs  will  b e  pr o vi d e d.  
•   Cli ni c al s af et y  d at a ( e g,  A Es, i nf e cti o ns)  will  b e t a b ul at e d  a n d list e d . 
•   T h e  pl as m a  P K  of  r u x oliti ni b will  b e  a n al y z e d  usi n g  a  m o d el -i n d e p e n d e nt  a p pr o a c h. 

I n c yt e  C or p or ati o n 
P a g e  6 0  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
9. 4. 4.   
S af e t y  A n al ys es 
9. 4. 4. 1.   
A d v e rs e  E v e nts  
A  T E A E is  eit h er  a n y  A E r e p ort e d f or t h e first ti m e  or  w ors e ni n g  of  a  pr e- e xisti n g  e v e nt  aft er 
first  d os e  of st u d y  dr u g.   A n al ysis  of  A Es  will  b e li mit e d t o  T E A Es,  b ut  d at a listi n gs  will i n cl u d e 
all  A Es , r e g ar dl ess  of t h eir ti mi n g t o st u d y  dr u g  a d mi nistr ati o n.   A d v ers e  e v e nts  will  b e t a b ul at e d 
b y t h e  M e d D R A  pr ef err e d t er m  a n d s yst e m  or g a n  cl ass.   S e v erit y  of  A Es  will  b e  b as e d  o n t h e 
N CI  C T C A E  v 4. 0 3. 
T h e s u bs et  of  A Es  c o nsi d er e d  b y t h e i n v esti g at or t o  h a v e  a r el ati o ns hi p t o st u d y  dr u g  will  b e 
c o nsi d er e d t o  b e tr e at m e nt-r el at e d  A Es.  If t h e i n v esti g at or  d o es  n ot s p e cif y t h e r el ati o ns hi p  of 
t h e  A E t o st u d y  dr u g, t h e n t h e  A E  will  b e  c o nsi d er e d tr e at m e nt-r el at e d.   T h e i n ci d e n c e  of  A Es 
a n d tr e at m e nt -r el at e d  A Es will  b e t a b ul at e d.  
9. 4. 4. 2.   
Cli ni c al  L a b o r at o r y  T ests 
L a b or at or y t est  v al u es  o utsi d e t h e  n or m al r a n g e  will  b e  ass ess e d f or s e v erit y  b as e d  o n t h e  n or m al 
r a n g es f or t h e  cli ni c al r ef er e n c e l a b or at or y.   T h e i n ci d e n c e  of  a b n or m al l a b or at or y  v al u es  a n d 
s hift t a bl es r el ati v e t o  b as eli n e  will  b e t a b ul at e d. 
L a b or at or y  d at a  will  b e  cl assifi e d i nt o  C T C  gr a d es f or  A Es ( C T C A E  v 4. 0 3).   T h e f oll o wi n g 
s u m m ari es  will  b e  pr o d u c e d f or t h e l a b or at or y  d at a:  
•   N u m b er  a n d  p er c e nt a g e  of s u bj e cts  wit h  w orst  p ost b as eli n e  C T C  gr a d e (r e g ar d l ess  of 
b as eli n e  v al u e)  will  b e s u m m ari z e d .   E a c h s u bj e ct  will  b e  c o u nt e d  o nl y f or t h e  w orst 
gr a d e  o bs er v e d  p ost b as eli n e. 

I n c yt e  C or p or ati o n 
P a g e  6 1  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
•   S hift t a bl es  usi n g  C T C  gr a d es t o  c o m p ar e  b as eli n e  wit h t h e  w orst  p ost b as eli n e  v al u e 
will  b e  pr o d u c e d  wit h  C T C  gr a d e. 
•   F or l a b or at or y  p a r a m et ers  w h er e  C T C  gr a d es  ar e  n ot  d efi n e d, s hift t a bl es t o t h e  w orst 
p ost b as eli n e  v al u e  will  b e  pr o d u c e d  usi n g t h e l o w/ n or m al/ hi g h  cl assifi c ati o ns  b as e d 
o n l a b or at or y r ef er e n c e r a n g es.  
9. 4. 4. 3.   
Vit al  Si g ns  
D es cri pti v e st atisti cs  a n d  m e a n  c h a n g e fr o m  b as eli n e  will  b e  d et er mi n e d f or  vit al si g ns ( bl o o d 
pr ess ur e,  p uls e , r es pir at or y r at e,  a n d  b o d y t e m p er at ur e)  at  e a c h  ass ess m e nt ti m e.   Vit al si g n 
r es ults  will  b e r e vi e w e d f or  cli ni c all y  n ot a bl e  a b n or m aliti es (s e e T a bl e   1 0),  a n d s u bj e cts 
e x hi biti n g  cli ni c all y  n ot a bl e  vit al si g n  a b n or m aliti es  will  b e list e d.   A  v al u e  will  b e  c o nsi d er e d  a n 
"al ert "  v al u e if it is  o utsi d e t h e  est a blis h e d r a n g e  a n d s h o ws  a  >  2 5 %  c h a n g e fr o m  b as eli n e.  
T a bl e  1 0:  
C rit e ri a f o r  Cli ni c all y  N ot a bl e  Vit al  Si g n  A b n o r m aliti es  
P a r a m et e r  
Hi g h  T h r es h ol d  
L o w  T h r es h ol d  
S yst oli c  bl o o d  pr ess ur e  
>  1 5 5  m m H g  
<  8 5  m m H g  
Di ast oli c  bl o o d  pr ess ur e  
>  1 0 0  m m H g  
<  4 0  m m H g  
P uls e  
>  1 0 0  b p m  
<  4 5  b p m  
T e m p er at ur e  
>  3 8º C  
<  3 5. 5º C  
R es pir at or y r at e  
>  2 4/ mi n  
<  8/ mi n  
9. 4. 4. 4.   
El e ct r o c a r di o g r a ms  
D es cri pti v e st atisti cs  a n d  m e a n  c h a n g e fr o m  b as eli n e  will  b e  d et er mi n e d f or  e a c h  E C G  p ar a m et er 
at  e a c h  ass ess m e nt ti m e.   El e ctr o c ar di o gr a m r es ults  will  b e  r e vi e w e d f or  cli ni c all y  n ot a bl e 
a b n or m aliti es  a c c or di n g t o  pr e d efi n e d  crit eri a ( T a bl e   1 1).   S u bj e cts  e x hi biti n g  cli ni c all y  n ot a bl e 
E C G  a b n or m aliti es  will  b e list e d.   A d v ers e  e v e nts  will  b e r e p ort e d f or  cli ni c all y  n ot a bl e 
a b n or m aliti es t h at  ar e  c o nsi d er e d  cli ni c all y si g nifi c a nt i n  t h e j u d g m e nt  of t h e i n v esti g at or. 
T a bl e  1 1:  
C rit e ri a f o r  Cli ni c all y  N ot a bl e  El e ct r o c a r di o g r a m  A b n o r m aliti es  
P a r a m et e r  
Hi g h  T h r es h ol d  
L o w  T h r es h ol d  
Q T c F  
>  4 6 0  ms e c  
<  2 9 5  ms e c  
P R  
>  2 2 0  ms e c  
<  7 5  ms e c  
Q R S  
>  1 2 0  ms e c  
<  5 0  ms e c  
Q T  
>  5 0 0  ms e c  
<  3 0 0  ms e c  
R R  
>  1 3 3 0  ms e c  
<  6 0 0  ms e c  
Q T c F  =  Fri d eri ci a  c orr e cti o n.  
9. 4. 5.   
P h a r m a c o ki n eti c  A n al ysis 
T h e  P K  p ar a m et ers  of  C m a x ,  Tm a x ,  Cmi n , A U C 0-t,  a n d  C L/ F  will  b e  c al c ul at e d fr o m t h e  bl o o d 
pl as m a  c o n c e ntr ati o ns  of  r u x oliti ni b  usi n g st a n d ar d  n o n c o m p art m e nt al ( m o d el-i n d e p e n d e nt)  P K 
m et h o ds.   P h ar m a c o ki n eti c  c al c ul ati o ns  will  b e  p erf or m e d, if  a p pr o pri at e,  usi n g  c o m m er ci al 
s oft w ar e s u c h  as  Wi n N o nli n ®  ( P h arsi g ht  C or p or ati o n,  M o u nt ai n  Vi e w,  C A).   N o mi n al ti m es  will 
b e  us e d i n  all  c a s es,  e x c e pt  w h e n t h e  diff er e n c e  b et w e e n t h e  a ct u al ti m e  a n d  n o mi n al ti m e is 
gr e at er t h a n  1 5  mi n ut es f or s a m pl es  c oll e ct e d  u p t o  4  h o urs  aft er  a d mi nistr ati o n  a n d  gr e at er t h a n 

I n c yt e  C or p or ati o n 
P a g e  6 2  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
3 0  mi n ut es f or s a m pl es  c oll e ct e d  m or e t h a n  4  h o urs  aft er  a d mi nistr ati o n; i n t h es e  c as es,  a ct u al 
ti m e  will  b e  us e d f or  P K  a n al ysis. 
If t h er e is  a s uffi ci e nt  a m o u nt  of  pl as m a  c o n c e ntr ati o n d at a fr o m t his st u d y,  t h e n t h e  d at a  will  b e 
a n al y z e d  b y st a n d ar d  p o p ul ati o n  P K  m et h o ds  usi n g  a p pr o pri at e s oft w ar e ( e g,  N O N M E M). 
9. 5.   
A n al ys es f o r t h e  D at a  M o nit o ri n g  C o m mitt e e  
N ot  a p pli c a bl e.  
9. 6.   
I nt e ri m  A n al ysis 
A n i nt eri m  a n al ysis  will  b e  c o n d u ct e d  w h e n  3 5 s u bj e cts  c o m pl et e  D a y  2 8  visit.   I n t his i nt eri m 
a n al ysis,  o nl y f utilit y  will  b e  ass ess e d , a n d t h e  st u d y will  b e t er mi n at e d if t h e l o w er  b o u n d ar y is 
cr oss e d.  
A  gr o u p s e q u e nti al  d esi g n  m et h o d f or  1  s a m pl e  bi n ar y  o ut c o m e  d at a  will  b e  us e d t o  c al c ul at e t h e 
l o w er  b o u n d ar y  of f utilit y.   T h e s p e n di n g f u n cti o n  of  H S D(- 4)  will  b e  us e d.   F or  H 0:   p  =  0. 4, 
H a:   p   =  0. 6,  a n d  a  1-si d e d  bi n o mi al t est  wit h  al p h a  of  0. 0 2 5, if  ≤  1 5 s u bj e cts r es p o n d  at t h e ti m e 
of  t h e i nt eri m  a n al ysis, t h e st u d y  will  b e t er mi n at e d.   T his  will  pr o vi d e  7 0. 0 3 %  pr o b a bilit y f or 
t h e r es p o ns e r at e  of  4 0 %  at t h e i nt eri m  a n al ysis. 
If  ≥  3 7 s u bj e cts r es p o n d  at t h e ti m e  of fi n al  a n al ysis, t h e st u d y  o ut c o m e  will  b e  c o nsi d er e d 
p ositi v e.   T h es e  ass u m pti o ns  will  pr o vi d e  8 9. 8 8 %  p o w er f or t h e r es p o ns e r at e  of  6 0 % i n t h e fi n al 
a n al ysis  wit h  T y p e  I  err or  of  0. 0 1 8 9. 

I n c yt e  C or p or ati o n 
P a g e  6 3  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
1 0.   
E T HI C A L  C O N SI D E R A TI O N S  A N D  A D MI NI S T R A TI V E 
P R O C E D U R E S  
1 0. 1.   
I n v esti g at o r  R es p o nsi biliti es  
T his st u d y  will  b e  p erf or m e d i n  a c c or d a n c e  wit h  et hi c al  pri n ci pl es t h at  ori gi n at e i n t h e 
D e cl ar ati o n  of  H elsi n ki  a n d  c o n d u ct e d i n  a d h er e n c e t o t h e st u d y  Pr ot o c ol;  G C Ps  as  d efi n e d i n 
Titl e   2 1  of t h e  U S  C F R  P arts  1 1,  5 0,  5 4,  5 6,  a n d  3 1 2; I C H  E 6  G C P  c o ns oli d at e d  g ui d eli n es;  a n d 
l o c al r e g ul at or y r e q uir e m e nts  as  a p pli c a bl e t o t h e st u d y l o c ati o ns. 
T h e i n v esti g at or  will  b e r es p o nsi bl e f or: 
•   P er mitti n g st u d y -r el at e d  m o nit ori n g, s p o ns or  a u dits, I R B/I E C r e vi e w,  a n d r e g ul at or y 
i ns p e cti o ns  b y  pr o vi di n g  dir e ct  a c c ess t o s o ur c e  d at a  a n d  ot h er r el e v a nt  cli ni c al st u d y 
d o c u m e nts. 
−   M o nit ori n g:   Q u alifi e d r e pr es e nt ati v es  of t h e s p o ns or  or its  d esi g n e e, st u d y 
m o nit ors,  will  m o nit or t h e st u d y  a c c or di n g t o  a  pr e d et er mi n e d  pl a n.   T h e 
i n v esti g at or  m ust  all o w t h e st u d y  m o nit ors t o r e vi e w  a n y st u d y  m at eri als  a n d 
s u bj e ct r e c or ds  at  e a c h  m o nit ori n g  visit.  
−   A u diti n g:   Q u alifi e d r e pr es e nt ati v es  of t h e s p o ns or  or its  d esi g n e e  m a y  a u dit t h e 
cli ni c al st u d y sit e  a n d st u d y  d at a t o  e v al u at e  c o m pli a n c e  wit h t h e  Pr ot o c ol, 
a p pli c a bl e l o c al  cli ni c al st u d y r e g ul ati o ns,  a n d  o v er all st u d y  c o n d u ct.   T h e 
i n v esti g at or  m ust  all o w t h e  a u dit ors t o r e vi e w  ori gi n al s o ur c e r e c or ds  a n d st u d y 
d o c u m e nt ati o n f or  all s u bj e cts. 
−   R e g ul at or y i ns p e cti o n:   R e g ul at or y  a ut h oriti es  m a y  c o n d u ct  a n i ns p e cti o n  of t h e 
st u d y  a n d t h e sit e  at  a n y ti m e  d uri n g t h e  d e v el o p m e nt  of  a n i n v esti g ati o n al 
pr o d u ct.   T h e i n v esti g at or  a n d st aff  ar e  e x p e ct e d t o  c o o p er at e  wit h t h e i ns p e ct ors 
a n d  all o w  a c c ess t o  all s o ur c e  d o c u m e nts s u p p orti n g t h e  e C R Fs  a n d  ot h er 
st u d y-r el at e d  d o c u m e nts.   T h e i n v esti g at or  m ust i m m e di at el y  n otif y t h e s p o ns or 
w h e n  c o nt a ct e d  b y  a n y r e g ul at or y  a ut h orit y f or t h e  p ur p os es  of  c o n d u cti n g  a n 
i ns p e cti o n. 
•   O bt ai ni n g i nf or m e d  c o ns e nt  a n d  e ns uri n g t h at t h e st u d y s u bj e cts'  q u esti o ns  h a v e  b e e n 
a ns w er e d  a n d t h e s u bj e cts f ull y  u n d erst a n d st u d y  pr o c e d ur es: 
−   I nf or m e d  c o ns e nt  m ust  b e  o bt ai n e d  b efor e  a n y st u d y -r el at e d  pr o c e d ur es  ar e 
c o n d u ct e d,  u nl ess  ot h er wis e s p e cifi e d  b y t h e  pr ot o c ol. 
−   I nf or m e d  c o ns e nt  m ust  b e  o bt ai n e d  usi n g t h e I R B/I E C- a p pr o v e d  v ersi o n i n  a 
l a n g u a g e t h at is  n ati v e  a n d  u n d erst a n d a bl e t o t h e s u bj e ct.   A t e m pl at e  will  b e 
pr o vi d e d  b y t h e s p o ns or  or its  d esi g n e e.   T h e s p o ns or  or its  d esi g n e e  m ust r e vi e w 
a n d  a c k n o wl e d g e t h e sit e -s p e cifi c  c h a n g es t o t h e I C F t e m pl at e.   T h e I C F  m ust 
i n cl u d e  a st at e m e nt t h at t h e s p o ns or  or its  d esi g n e e  a n d r e g ul at or y  a ut h oriti es  h a v e 
dir e ct  a c c ess t o s u bj e c t r e c or ds. 

I n c yt e  C or p or ati o n 
P a g e  6 4  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
•   O bt ai ni n g  a p pr o v al fr o m t h e I R B/I E C  b ef or e t h e st art  of t h e st u d y  a n d f or  a n y 
c h a n g es t o t h e  cli ni c al st u d y  Pr ot o c ol, i m p ort a nt  pr ot o c ol  d e vi ati o ns, r o uti n e  u p d at es, 
a n d s af et y i nf or m ati o n i n  a c c or d a n c e  wit h i nstit uti o n al r e q uir e m e nts  a n d l o c al  l a w. 
−   T h e i n v esti g at or is r es p o nsi bl e f or  e ns uri n g t h at t h e s af et y r e p orts  pr o vi d e d  b y t h e 
s p o ns or  ar e r e vi e w e d  a n d  pr o c ess e d i n  a c c or d a n c e  wit h r e g ul at or y r e q uir e m e nts 
a n d  wit h t h e  p oli ci es  a n d  pr o c e d ur es  est a blis h e d  b y t h e I R B/I E C. 
•   A d h eri n g t o t h e  Pr ot o c ol  as  d es cri b e d i n t his  d o c u m e nt  a n d  a gr e ei n g t h at  c h a n g es t o 
t h e  Pr ot o c ol  pr o c e d ur es,  wit h t h e  e x c e pti o n  of  m e di c al  e m er g e n ci es,  m ust  b e 
dis c uss e d  a n d  a p pr o v e d, first,  b y t h e s p o ns or  or its  d esi g n e e  a n d, s e c o n d,  b y t h e 
I R B/I E C.   E a c h i n v esti g at or is r es p o nsi bl e f or  e nr olli n g s u bj e cts  w h o  h a v e  m et t h e 
s p e cifi e d  eli gi bilit y  crit eri a.  
•   R et ai ni n g r e c or ds i n  a c c or d a n c e  wit h  all l o c al,  n ati o n al,  a n d r e g ul at or y l a ws,  b ut f or  a 
mi ni m u m  p eri o d  of  at l e ast  2  y e ars  aft er t h e l ast  m ar k eti n g  a p pli c ati o n  a p pr o v al i n  a n 
I CH r e gi o n  a n d  u ntil t h er e  ar e  n o  p e n di n g  or  c o nt e m pl at e d  m ar k eti n g  a p pli c ati o ns i n 
a n I C H r e gi o n,  or if  n ot  a p pr o v e d,  2  y e ars  aft er t h e t er mi n ati o n  of t h e t est  arti cl e f or 
i n v esti g ati o n t o  e ns ur e t h e  a v ail a bilit y  of st u d y  d o c u m e nt ati o n s h o ul d it  b e c o m e 
n e c e ss ar y f or t h e s p o ns or  or  a r e g ul at or y  a ut h orit y t o r e vi e w. 
−   T h e i n v esti g at or  m ust  n ot  d estr o y  a n y r e c or ds  ass o ci at e d  wit h t h e st u d y  wit h o ut 
r e c ei vi n g  a p pr o v al fr o m t h e s p o ns or.   T h e i n v esti g at or  m ust  n otif y t h e s p o ns or  or 
its  d esi g n e e i n t h e  e v e nt  of  a c ci d ent al l oss  or  d estr u cti o n  of  a n y st u d y r e c or ds.  If 
t h e i n v esti g at or l e a v es t h e i nstit uti o n  w h er e t h e st u d y  w as  c o n d u ct e d, t h e s p o ns or 
or its  d esi g n e e  m ust  b e  c o nt a ct e d t o  arr a n g e  alt er n ati v e r e c or d st or a g e  o pti o ns. 
−   All  e C R F  d at a  e nt er e d  b y t h e sit e (i n cl u di n g  a u dit tr ail),  as  w ell  as  c o m p ut er 
h ar d w ar e  a n d s oft w ar e (f or  a c c essi n g t h e  d at a),  will  b e  m ai nt ai n e d  or  m a d e 
a v ail a bl e  at t h e sit e i n  c o m pli a n c e  wit h  a p pli c a bl e r e c or d r et e nti o n r e g ul ati o ns.  
T h e s p o ns or  will r et ai n t h e  ori gi n al  e C R F  d at a  a n d  a u dit tr a il. 
1 0. 2.   
A c c o u nt a bilit y,  H a n dli n g,  a n d  Dis p os al  of  St u d y  D r u g  
T h e i n v esti g at or is r es p o nsi bl e f or  dr u g  a c c o u nt a bilit y  at t h e st u d y sit e;  h o w e v er, s o m e  of t h e 
dr u g  a c c o u nt a bilit y  d uti es  m a y  b e  assi g n e d t o  a n  a p pr o pri at e  p h ar m a cist  or  ot h er  d esi g n e e.  
I n v e nt or y  a n d  a c c o u nt a bilit y r e c or ds  m ust  b e  m ai nt ai n e d  a n d r e a dil y  a v ail a bl e f or i ns p e cti o n  b y 
t h e st u d y  m o nit or  a n d  ar e  o p e n t o i ns p e cti o n  at  a n y ti m e  b y  a n y  a p pli c a bl e r e g ul at or y  a ut h oriti es.  
T h e i n v esti g at or  or  d esi g n e e  m ust  m ai nt ai n r e c or ds t h at  d o c u m e nt: 
•   D eli v er y  of st u d y  dr u g t o t h e st u d y sit e.  
•   I n v e nt or y  of st u d y  dr u g  at t h e sit e. 
•   S u bj e ct  us e  of t h e st u d y  dr u g i n cl u di n g  pill  or  u nit  c o u nts fr o m  e a c h s u p pl y 
dis p e ns e d. 
•   R et ur n  of st u d y  dr u g t o t h e i n v esti g at or  or  d esi g n e e  b y s u bj e cts. 
T h e i n v esti g ati o n al  pr o d u ct  m ust  b e  us e d  o nl y i n  a c c or d a n c e  wit h t h e  Pr ot o c ol.   T h e i n v esti g at or 
will  als o  m ai nt ai n r e c or ds  a d e q u at el y  d o c u m e nti n g t h at t h e s u bj e cts  w er e  pr o vi d e d t h e s p e cifi e d 

I n c yt e  C or p or ati o n 
P a g e  6 5  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
st u d y  dr u g.   T h es e r e c or ds s h o ul d i n cl u d e  d at es,  q u a ntiti es,  a n d  a n y  a v ail a bl e  b at c h  or s eri al 
n u m b ers  or  u ni q u e  c o d e  n u m b ers  assi g n e d t o t h e i n v esti g ati o n al  pr o d u ct  a n d st u d y s u bj e cts. 
C o m pl et e d  a c c o u nt a bilit y r e c or ds  will  b e  ar c hi v e d  b y t h e sit e.   T h e i n v esti g at or  or  d esi g n e e  will 
b e  e x p e ct e d t o  c oll e ct  a n d r et ai n  a ll  us e d,  u n us e d,  a n d  p arti all y  us e d  c o nt ai n ers  of st u d y  dr u g 
u ntil  v erifi e d  b y t h e st u d y  m o nit or ( u nl ess  ot h er wis e  a gr e e d t o  b y t h e s p o ns or).   At t h e 
c o n cl usi o n  of t h e st u d y, t h e i n v esti g at or  or  d esi g n e e  will  o v ers e e s hi p m e nt  of  a n y r e m ai ni n g 
st u d y  dr u g  b a c k t o t h e s p o ns or  or its  d esi g n e e f or  d estr u cti o n  a c c or di n g t o i nstit uti o n al st a n d ar d 
o p er ati n g  pr o c e d ur es.  If l o c al  pr o c e d ur es  m a n d at e  o n-sit e  d estr u cti o n  of i n v esti g ati o n al s u p pl y, 
t h e sit e s h o ul d ( w h er e l o c al  pr o c e d ur es  all o w)  m ai nt ai n t h e i n v esti g ati on al s u p pl y  u ntil t h e st u d y 
m o nit or i ns p e cts t h e  a c c o u nt a bilit y r e c or ds i n  or d er t o  e v al u at e  c o m pli a n c e  a n d  a c c ur a c y  of 
a c c o u nt a bilit y  b y t h e i n v esti g ati v e sit e.   At sit es  w h er e t h e st u d y  dr u g is  d estr o y e d  b ef or e 
m o nit or i ns p e cti o n, t h e  m o nit ors r el y  o n  d o c u m e nt ati o n  of  d estr u cti o n  p er t h e sit e  S O P. 
1 0. 3.   
D at a  M a n a g e m e nt  
D at a  m a n a g e m e nt  will  b e  p erf or m e d i n  a  v ali d at e d  d at a b as e  vi a  a n  El e ctr o ni c  D at a  C a pt ur e 
( E D C) s yst e m.   All  d at a  e ntr y,  v erifi c ati o n,  a n d  v ali d ati o n  will  b e  p erf or m e d i n  a c c or d a n c e  wit h 
t h e  c urr e nt st a n d ar d  o p er ati n g  pr o c e d ur es  of t h e  D at a  M a n a g e m e nt  D e p art m e nt  at t h e s p o ns or  or 
its  d esi g n e e.   T h e  d at a b as e  will  b e  a ut h ori z e d f or l o c k  o n c e  all  d efi n e d  pr o c e d ur es  ar e  c o m pl et e d. 
T h e i n v esti g at or  will  b e  pr o vi d e d  wit h  a c c ess t o  a n  E D C s yst e m s o t h at  a n  e C R F  c a n  b e 
c o m pl et e d f or  e a c h s u bj e ct.   E ntri es  m a d e i n t h e  e C R F  m ust  b e  v erifi a bl e  a g ai nst s o ur c e 
d o c u m e nts; if  u p d at es t o t h e  d at a b as e  ar e  n ot  p ossi bl e,  a n y  dis cr e p a n ci es s h o ul d  b e  e x pl ai n e d 
a n d  d o c u m e nt e d.   T h e i n v esti g at or  will  b e r es p o nsi bl e f or r e v i e wi n g  all  d at a  a n d  e C R F  e ntri es 
a n d  will si g n  a n d  d at e t h e  d esi g n at e d f or ms i n  e a c h s u bj e ct's  e C R F,  v erif yi n g t h at t h e 
i nf or m ati o n is tr u e  a n d  c orr e ct.   T h e i n v esti g at or is r es p o nsi bl e f or t h e r e vi e w  a n d  a p pr o v al  of  all 
q u er y r es p o ns es. 
Pr ot o c ol  d e vi ati o ns  will  b e i d e ntifi e d  a n d r e c or d e d i n t h e  Pr ot o c ol  D e vi ati o n f or m  of t h e  e C R F.  
T h e st u d y  m o nit or  will r ef er e n c e t h e  M o nit ori n g  Pl a n i n  or d er t o  e ns ur e t h at  e a c h iss u e i d e ntifi e d 
is  a p pr o pri at el y  d o c u m e nt e d, r e p ort e d,  a n d r es ol v e d i n  a ti m el y  m a n n er i n  a c c or d a n c e  wit h t h e 
pl a n 's r e q uir e m e nts.  
1 0. 4.   
D at a  P ri v a c y  a n d  C o nfi d e nti alit y  of  St u d y  R e c o r ds  
T h e i n v esti g at or  a n d t h e s p o ns or,  or its  d esi g n e e,  m ust  a d h er e t o  d at a  pri v a c y l a ws  a n d 
r e g ul ati o ns.   T h e i n v esti g at or  a n d t h e s p o ns or,  or its  d esi g n e e,  ar e r es p o nsi bl e f or  e ns uri n g t h at 
s e nsiti v e i nf or m ati o n is  h a n dl e d i n  a c c or d a n c e  wit h l o c al r e q uir e m e nts ( e g,  HI P A A).  
A p pr o pri at e  c o ns e nt  a n d  a ut h ori z ati o ns f or  us e  a n d  dis cl os ur e  a n d/ or tr a nsf er (if  a p pli c a bl e)  of 
pr ot e ct e d i nf or m ati o n  m ust  b e  o bt ai n e d. 
S u bj e ct  n a m es  wi ll  n ot  b e s u p pli e d t o t h e s p o ns or  or its  d esi g n e e, if  a p pli c a bl e.   O nl y t h e s u bj e ct 
n u m b er  a n d s u bj e ct' s i niti als (s u bj e ct's i niti als  will  o nl y  b e r e c or d e d if  all o w a bl e  b y l o c al 
r e g ul ati o ns)  will  b e r e c or d e d i n t h e  e C R F,  w h er e  p er mitt e d; if t h e s u bj e ct's  na m e  a p p e ars  o n  a n y 
ot h er  d o c u m e nt ( e g, l a b or at or y r e p ort), it  m ust  b e  o blit er at e d  o n t h e  c o p y  of t h e  d o c u m e nt t o  b e 
s u p pli e d t o t h e s p o ns or  or its  d esi g n e e.   St u d y fi n di n gs st or e d  o n  a  c o m p ut er  will  b e st or e d i n 
a c c or d a n c e  wit h l o c al  d at a  pr ot e cti o n l a ws.   T h e s u bj e cts  will  b e i nf or m e d t h at r e pr es e nt ati v es  of 
t h e s p o ns or  or its  d esi g n e e, I R B  or I E C,  or r e g ul at or y  a ut h oriti es  m a y i ns p e ct t h eir  m e di c al 

I n c yt e  C or p or ati o n 
P a g e  6 6  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
r e c or ds t o  v erif y t h e i nf or m ati o n  c oll e ct e d,  a n d t h at  all  p ers o n al i nf or m ati o n  m a d e  a v ail a bl e f or 
i ns p e cti o n  will  b e  h a n dl e d i n stri ct est  c o nfi d e n c e  a n d i n  a c c or d a n c e  wit h l o c al  d at a  pr ot e cti o n 
l a ws. 
1 0. 5.   
Fi n a n ci al  Dis cl os u r e  
B ef or e st u d y i niti ati o n,  all  cli ni c al i n v esti g at ors  p arti ci p ati n g i n  cli ni c al st u di es s u bj e ct t o  F D A 
R e g ul ati o n  Titl e  2 1  C o d e  of  F e d er al  R e g ul ati o ns ( C F R)  P art  5 4  –  Fi n a n ci al  Dis cl os ur e  b y 
Cli ni c al I n v esti g at ors (i e,  "c o v er e d st u di es ")  ar e r e q uir e d t o s u b mit  a  c o m pl et e d  Cli ni c al 
I n v esti g at or  Fi n a n ci al  Dis cl os ur e f or m t h at s uffi ci e ntl y  d et ails  a n y fi n a n ci al i nt er ests  a n d 
arr a n g e m e nts t h at  a p pl y.   F or t h e  p ur p os e  of t his r e g ul ati o n,  " cli ni c al i n v esti g at or "  is  d efi n e d  as 
a n y i n v esti g at or  or s u bi n v esti g at or  w h o is  dir e ctl y i n v ol v e d i n t h e tr e at m e nt  or  e v al u ati o n  of 
r es e ar c h s u bj e cts, i n cl u di n g t h e s p o us e  a n d  e a c h  d e p e n d e nt  c hil d  of t h e  cli ni c al i n v esti g at or  or 
s u bi n v esti g at or.   T h es e r e q uir e m e nts  a p pl y t o  b ot h  U S  a n d f or ei g n  cli ni c al i n v esti g at ors 
c o n d u cti n g  c o v er e d  cli ni c al st u di es. 
A n y  n e w  cli ni c al i n v esti g at ors  a d d e d t o t h e  c o v er e d  cli ni c al st u d y  d uri n g its  c o n d u ct  m ust  als o 
s u b mit  a  c o m pl et e d I n v es ti g at or  Fi n a n ci al  Dis cl os ur e  F or m.   D uri n g  a  c o v er e d  cli ni c al st u d y, 
a n y  c h a n g es t o t h e fi n a n ci al i nf or m ati o n  pr e vi o usl y r e p ort e d  b y  a  cli ni c al i n v esti g at or  m ust  b e 
r e p ort e d t o t h e s p o ns or  or its  d esi g n e e.   At t h e  c o n cl usi o n  of t h e  c o v er e d  cli ni c al st u d y, t h e 
cli ni c al i n v esti g at ors  will  b e r e mi n d e d  of t h eir  o bli g ati o ns.  I n t h e  e v e nt t h at t h e  cli ni c al 
i n v esti g at or is  n ot r e mi n d e d, t h e y  n e v ert h el ess  will r e m ai n  o bli g at e d t o r e p ort t o t h e s p o ns or  or 
its  d esi g n e e  a n y  c h a n g es t o t h e fi n a n ci al i nf or m ati o n  pr e vi o usl y r e p ort e d,  as  w ell  as  a n y  c h a n g es 
i n t h eir fi n a n ci al i nf or m ati o n f or  a  p eri o d  of  1  y e ar  aft er  c o m pl eti o n  of t h e  c o v er e d  cli ni c al st u d y. 
1 0. 6.   
P u bli c ati o n  P oli c y  
B y si g ni n g t h e st u d y  Pr ot o c ol, t h e i n v esti g at or  a n d  his  or  h er i nstit uti o n  a gr e e t h at t h e r es ults  of 
t h e st u d y  m a y  b e  us e d  b y t h e s p o ns or, I n c yt e  C or p or ati o n (I n c yt e), f or t h e  p ur p os es  of  n ati o n al 
a n d i nt er n ati o n al r e gistr ati o n,  p u bli c ati o n,  a n d i nf or m ati o n f or  m e di c al  a n d  p h ar m a c e uti c al 
pr of essi o n als.   St u d y r es ults  will  b e  p u blis h e d i n  a c c or d a n c e  wi t h  a p pli c a bl e l o c al  a n d  n ati o n al 
r e g ul ati o ns.  If  n e c ess ar y, t h e  a ut h oriti es  will  b e  n otifi e d  of t h e i n v esti g at or's  n a m e,  a d dr ess, 
q u alifi c ati o ns,  a n d  e xt e nt  of i n v ol v e m e nt.   T h e t er ms r e g ar di n g t h e  p u bli c ati o n  of st u d y r es ults 
ar e  c o nt ai n e d i n t h e  a gr e e m e nt si g n e d  wit h t h e s p o ns or  or its  d esi g n e e.   A si g n e d  a gr e e m e nt  will 
b e r et ai n e d  b y t h e s p o ns or  or its  d esi g n e e. 

I n c yt e  C or p or ati o n 
P a g e  6 7  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
1 1.   
R E F E R E N C E S  
Al o usi  A M,  W eis d orf  DJ,  L o g a n  B R,  et  al.  Et a n er c e pt,  m y c o p h e n ol at e,  d e nil e u ki n,  or 
p e nt ost ati n  pl us  c orti c ost er oi ds f or  a c ut e  gr aft- v ers us- h ost  dis e as e:  a r a n d o mi z e d  p h as e  2 tri al 
fr o m t h e  Bl o o d  a n d  M arr o w  Tr a ns pl a nt  Cli ni c al  Tri als  N et w or k.  Bl o o d  2 0 0 9; 1 1 4: 5 1 1- 5 1 7. 
A p p el b a u m  F R.  H e m at o p oi eti c- c ell tr a ns pl a nt ati o n  at  5 0.  N  E n gl J  M e d  2 0 0 7; 3 5 7: 1 4 7 2- 1 4 7 5. 
C e nt er f or I nt er n ati o n al  Bl o o d  a n d  M arr o w  Tr a ns pl a nt  R es e ar c h ( CI B M T R ).  Cli ni c al tri al 
e n d p oi nts f or  p ati e nts  wit h  a c ut e  G V H D.  2 0 0 9. 
htt ps:// w w w. ci b mtr. or g/ M e eti n gs/ M at eri als/ G V H D w or ks h o p/ p a g es/i n d e x. as p x.  A c c ess e d 
F e br u ar y  5,  2 0 1 5. 
C h oi J,  C o o p er,  M L,  Al a h m ari  B,  et  al.  P h ar m a c ol o gi c  bl o c k a d e  of J A K 1/J A K 2 r e d u c es  G v H D 
a n d  pr es er v es t h e  gr aft- v ers us -l e u k e mi a  eff e ct.  Pl o S  O n e  2 0 1 4; 9: e 1 0 9 7 9 9. 
C h oi J,  Zi g a  E D,  Rit c h e y J,  et  al. I F N γ R si g n ali n g  m e di at es  all or e a cti v e  T -c ell tr affi c ki n g  a n d 
G V H D.  Bl o o d  2 0 1 2; 8: 4 0 9 3- 4 1 0 3. 
C a h n J Y,  B or di g o ni  P,  Ti b er g hi e n  P,  et  al.  Tr e at m e nt  of  a c ut e  gr aft - v ers us- h ost  dis e as e  wit h 
m et h yl pr e d nis ol o n e  a n d  c y cl os p ori n e  wit h  or  wit h o ut  a n  a nti- i nt erl e u ki n- 2 r e c e pt or  m o n o cl o n al 
a nti b o d y:  a  m ulti c e nt er  p h as e III st u d y.  T r a ns pl a nt ati o n  1 9 9 5; 6 0: 9 3 9- 9 4 2. 
Cli ni c al  Tri al  F a cilit ati o n  Gr o u p ( C T F G).  R e c o m m e n d ati o ns r el at e d t o  c o ntr a c e pti o n  a n d 
pr e g n a n c y t esti n g i n  cli ni c al tri als.  2 0 1 4.  htt p:// w w w. h m a. e u/ ctf g. ht ml.  A c c ess e d J u n e  8,  2 0 1 5. 
C o uri el  D R,  S ali b a  R,  d e  Li m a  M,  et  al.  A  p h as e III st u d y  of i nfli xi m a b  a n d  c orti c ost er oi ds f or 
t h e i niti al tr e at m e nt  of  a c ut e  gr aft-v ers us - h ost  dis e as e.  Bi ol  Bl o o d  M arr o w  Tr a ns pl a nt 
2 0 0 9; 1 5: 1 5 5 5- 1 5 6 2. 
Cr a g g  L,  Bl a z ar  B R,  D ef or  T,  et  al.  A r a n d o mi z e d tri al  c o m p ari n g  pr e d nis o n e  wit h 
a ntit h y m o c yt e  gl o b uli n/ pr e d nis o n e  as  a n i niti al s yst e mi c t h er a p y f or  m o d er at el y s e v er e  a c ut e 
gr aft - v ers us- h ost  dis e as e.  Bi ol  Bl o o d  M arr o w  Tr a ns pl a nt  2 0 0 0; 6: 4 4 1- 4 4 7. 
Fri d m a n J S,  S c h erl e  P A,  C olli ns  R,  et  al.  Pr e cli ni c al  e v al u ati o n  of l o c al J A K 1  a n d J A K 2 
i n hi biti o n i n  c ut a n e o us i nfl a m m ati o n. J I n v est  D er m at ol  2 0 1 1; 1 3 1: 1 8 3 8- 1 8 4 4. 
Gl u c ks b er g  H,  St or b  R,  F ef er  A,  et  al.  Cli ni c al  m a nif est ati o ns  of  gr aft- v ers us - h ost  dis e as e i n 
h u m a n r e ci pi e nts  of  m arr o w fr o m  H L- A- m at c h e d si bli n g  d o n ors.  Tr a ns pl a nt ati o n 
1 9 7 4; 1 8: 2 9 5- 3 0 4. 
H arris  A C,  Y o u n g  R,  D e vi n e  S,  et  al. I nt er n ati o n al,  M ulti c e nt er  St a n d ar di z ati o n  of  A c ut e 
Gr aft -v ers us - H ost  Dis e as e C li ni c al D at a  C oll e cti o n:  A  R e p ort fr o m t h e  M o u nt  Si n ai  A c ut e 
G V H D I nt er n ati o n al  C o ns orti u m.  Bi ol  Bl o o d  M arr o w  Tr a n s pl a nt  2 0 1 6; 2 2: 4- 1 0. 
I N CB 0 1 8 4 2 4 I n v esti g at or' s  Br o c h ur e (I B).  Wil mi n gt o n,  D E: I n c yt e  C or p or ati o n. 
J a g asi a  M H,  Gr ei ni x  H T,  Ar or a  M,  et  al.  N ati o n al I nstit ut es  of  H e alt h  C o ns e ns us  D e v el o p m e nt 
Pr oj e ct  o n  Crit eri a f or  Cli ni c al  Tri als i n  C hr o ni c  Gr aft -v ers us - H ost  Dis e as e: I.  T h e  2 0 1 4 
Di a g n osis  a n d  St a gi n g  W or ki n g  Gr o u p r e p ort.  Bi ol  Bl o o d  M arr o w  Tr a ns pl a nt  2 0 1 5; 2 1: 3 8 9- 4 0 1. 

I n c yt e  C or p or ati o n 
P a g e  6 8  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
L e e  SJ,  Z a hri e h  D,  A g ur a  E,  et  al.  Eff e ct  of  u p-fr o nt  d a cli z u m a b  w h e n  c o m bi n e d  wit h st er oi ds 
f or t h e tr e at m e nt  of  a c ut e  gr aft- v ers us- h ost  dis e as e: r es ults  of  a r a n d o mi z e d tri al.  Bl o o d 
2 0 0 4; 1 0 4: 1 5 5 9- 1 5 6 4. 
L e vi n e J E,  L o g a n  B,  W u J,  et  al.  Gr aft- v ers us- h ost  d is e as e tr e at m e nt: p r e di ct ors  of s ur vi v al.  Bi ol 
Bl o o d  M arr o w  Tr a ns pl a nt  2 0 1 0; 1 6: 1 6 9 3- 1 6 9 9. 
L e vi n e J E,  P a c z es n y  S,  Mi n eis hi  S,  et  al.  Et a n er c e pt  pl us  m et h yl pr e d nis ol o n e  as i niti al  t h er a p y 
f or  a c ut e  gr aft- v ers us- h ost  dis e as e.  Bl o o d  2 0 0 8; 1 1 1: 2 4 7 0- 2 4 7 5. 
L o h  M L,  T asi a n  S K,  R a bi n  K R,  et  al.  A  p h as e  1  d osi n g st u d y  of r u x oliti ni b i n  c hil dr e n  wit h 
r el a ps e d  or r efr a ct or y s oli d t u m ors, l e u k e mi as,  or  m y el o pr olif er ati v e  n e o pl as ms:  A  C hil dr e n's 
O n c ol o g y  Gr o u p  p h as e  1  c o ns orti u m st u d y ( A D V L 1 0 1 1).  P e di atr  Bl o o d  C a n c er  2 0 1 5; 6 2: 1 7 1 7-
1 7 2 4. 
M a c Mill a n  M L,  D e F or  T E,  W eis d orf  DJ.  T h e  b est  e n d p oi nt f or  a c ut e  G V H D tr e at m e nt tri als. 
Bl o o d  2 0 1 0; 1 1 5: 5 4 1 2- 5 4 1 7. 
M a c Mill a n  M L,  D e F or  T E,  W eis d orf  DJ.  W h at  pr e di cts  hi g h ris k  a c ut e  gr aft- v ers us- h ost  dis e as e 
( G V H D)  at  o ns et ?: i d e ntifi c ati o n  of t h os e  at  hi g h est ris k  b y  a  n o v el  a c ut e  G V H D ris k s c or e.  Br J 
H a e m at ol  2 0 1 2; 1 5 7: 7 3 2- 7 4 1. 
M a e c k er  H T ,  M c C o y J P,  N uss e n bl att  R.  St a n d ar di zi n g i m m u n o p h e n ot y pi n g f or t h e  H u m a n 
I m m u n ol o g y  Pr oj e ct.  N at  R e v I m m u n ol  2 0 1 2; 1 2: 1 9 1- 2 0 0. 
M a g e n a u J M,  Qi n  X,  T a w ar a I,  et  al.  Fr e q u e n c y  of  C D 4( +) C D 2 5( hi) F O X P 3( +) r e g ul at or y  T 
c ells  h as  di a g n osti c  a n d  pr o g n osti c  v al u e  as  a  bi o m ar k er f or  a c ut e  gr aft - v ers us- h ost-dis e as e.  Bi ol 
Bl o o d  M arr o w  Tr a ns pl a nt,  2 0 1 0; 1 6: 9 0 7- 9 1 4. 
M arti n   PJ.  St u d y  d esi g n  a n d  e n d p oi nts i n  gr aft-v ers us -h ost  dis e as e.  B est  Pr a ct  R es  Cli n 
H a e m at ol  2 0 0 8; 2 1: 3 5 7- 3 7 2. 
M arti n  PJ,  B a c hi er  C R,  Kli n g e m a n n  H G,  et  al.  E n d p oi nts f or  cli ni c al tri als t esti n g tr e at m e nt  of 
a c ut e  gr aft - v ers us-h ost  dis e as e:  a j oi nt st at e m e nt.  Bi ol  Bl o o d  M arr o w  Tr a ns pl a nt 
2 0 0 9; 1 5: 7 7 7- 7 8 4. 
M arti n  PJ,  Ri z z o J D,  Wi n g ar d J R,  et  al.  First-  a n d s e c o n d -li n e s yst e mi c tr e at m e nt  of  a c ut e 
gr aft - v ers us- h ost  dis e as e: r e c o m m e n d ati o ns  of t h e  A m eri c a n  S o ci et y  of  Bl o o d  a n d  M arr o w 
Tr a ns pl a nt ati o n.  Bi ol  Bl o o d  M arr o w  Tr a ns pl a nt  2 0 1 2; 1 8: 1 1 5 0- 1 1 6 3. 
M ats u d a  K,  Y a m a u c hi  K,  T o z u k a  M,  et  al.  M o nit ori n g  of  h e m at o p oi eti c  c hi m eris m  b y  s h ort 
ta n d e m  re p e ats ,  a n d t h e  eff e ct  of  C D s el e cti o n  o n i ts se nsiti vit y.  Cli n  C h e m  2 0 0 4; 5 0: 2 4 1 1- 2 4 1 4. 
Mi el c ar e k  M,  St or er  B E,  B o e c k h  M,  et  al.  I niti al t h er a p y  of  a c ut e  gr aft-v ers us - h ost  dis e as e  wit h 
l o w- d os e  pr e d nis o n e  d o es  n ot  c o m pr o mis e  p ati e nt  o ut c o m es.  Bl o o d  2 0 0 9; 1 1 3: 2 8 8 8- 2 8 9 4. 
Mi y ar a  M,  Y os hi o k a  Y,  Kit o h  A,  et  al.  F u n cti o n al  d eli n e ati o n  a n d  diff er e nti ati o n  d y n a mi cs  of 
h u m a n  C D 4 +  T  c ells  e x pr essi n g t h e  F o x P 3 tr a ns cri pti o n f a ct or. I m m u nit y  2 0 0 9; 3 0: 8 9 9- 9 1 1. 
N ati o n al  C a n c er I nstit ut e ( N CI).  C o m m o n  T er mi n ol o g y  Crit eri a f or  A d v ers e  E v e nts ( C T C A E) 
v 4. 0 3.  2 0 0 9.  htt p:// ct e p. c a n c er. g o v/r e p orti n g/ ct c. ht ml.  A c c ess e d J u n e  9,  2 0 1 6. 
O k e n  M M,  Cr e e c h  R H,  T or m e y  D C,  et  al.  T o xi cit y  a n d r es p o ns e  crit eri a  of t h e  E ast er n 
C o o p er ati v e  O n c ol o g y  Gr o u p.  A m J  Cli n  O n c ol  1 9 8 2; 5: 6 4 9- 6 5 5. 

I n c yt e  C or p or ati o n 
P a g e  6 9  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
P a vl eti c  S Z.  R es p o ns e  as  a n  e n d  p oi nt i n tr e at m e nt tri als f or  a c ut e  G V H D.  B o n e  M arr o w 
Tr a ns pl a nt  2 0 1 2; 4 7: 1 6 1- 1 6 3.  
P a vl eti c  S Z,  F o wl er  D H.  Ar e  w e  m a ki n g  pr o gr ess i n  G V H D  pr o p h yl a xis  a n d tr e at m e nt ? 
H e m at ol o g y  A m  S o c  H e m at ol  E d u c  Pr o gr a m  2 0 1 2; 2 5 1- 2 6 4. 
Pi d al a J,  Ki m J,  A n as etti  C.  Sir oli m us  as  pri m ar y tr e at m e nt  of  a c ut e  gr aft -v ers us -h ost  dis e as e 
f oll o wi n g  all o g e n ei c  h e m at o p oi eti c  c ell tr a ns pl a nt ati o n.  Bi ol  Bl o o d  M arr o w  Tr a ns pl a nt 
2 0 0 9; 1 5: 8 8 1- 8 8 5. 
Pr z e pi or k a  D,  W eis d orf  D,  M arti n  P,  et  al.  1 9 9 4  C o ns e ns us  C o nf er e n c e  o n  A c ut e  G V H D 
G r a di n g.  B o n e  M arr o w  Tr a ns pl a nt  1 9 9 5; 1 5: 8 2 5- 8 2 8. 
Q ui nt ás- C ar d a m a  A,  V a d di  K,  Li u  P,  et  al.  Pr e cli ni c al  c h ar a ct eri z ati o n  of t h e s el e cti v e J A K 1/ 2 
i n hi bit or I N C B 0 1 8 4 2 4: t h er a p e uti c i m pli c ati o ns f or t h e tr e at m e nt  of  m y el o pr olif er ati v e 
n e o pl as ms.  Bl o o d  2 0 1 0; 1 1 5: 3 1 0 9- 3 1 1 7. 
R o wli n gs  P A,  Pr z e pi or k a  D,  Kl ei n J P,  et  al. I B M T R  S e v erit y I n d e x f or  gr a di n g  a c ut e 
gr aft - v ers us-h ost  dis e as e: r etr os p e cti v e  c o m p aris o n  wit h  Gl u c ks b er g  gr a d e.  Br J  H a e m at ol 
1 9 9 7; 9 7: 8 5 5- 8 6 4. 
R u ut u  T,  Gr at w o hl  A,  d e  Witt e  T,  et  al.  Pr o p h yl a xis  a n d tr e at m e nt  of  G V H D:  E B M T – E L N 
w or ki n g  gr o u p r e c o m m e n d ati o ns f or  a st a n d ar di z e d  pr a cti c e.  B o n e  M arr o w  Tr a ns pl a nt 
2 0 1 4; 4 9: 1 6 8- 1 7 3. 
S a k a g u c hi  S,  Mi y ar a  M,  C o nst a nti n o  C M,  H afl er  D A .  F O X P 3 + r e g ul at or y  T  c ells i n t h e  h u m a n 
i m m u n e s yst e m.  N at  R e v I m m u n ol  2 0 1 0; 1 0: 4 9 0- 5 0 0. 
S ali b a  R M,  C o uri el  D R,  Gir alt  S,  et  al.  Pr o g n osti c  v al u e  of r es p o ns e  aft er  u pfr o nt t h er a p y f or 
a c ut e  G V H D.   B o n e  M arr o w  Tr a ns pl a nt  2 0 1 2; 4 7: 1 2 5- 1 3 1. 
S p o erl  S,  M a as - B a u er  K,  V er b e e k  M,  et  al.  R es p o ns e t o J A K  1/ 2 i n hi biti o n i n  p ati e nts  wit h 
c orti c ost er oi d -r efr a ct or y  a c ut e  gr aft- v ers us- h ost  dis e as e.  P ost er  pr es e nt e d  at:  5 6t h  A S H  A n n u al 
M e eti n g  a n d  E x p ositi o n;  D e c e m b er  6 - 9,  2 0 1 4;  S a n  Fr a n cis c o,  C A.  
T o m bl y n  M,  C hill er  T,  Ei ns el e  H,  et  al.  G ui d eli n es f or  pr e v e nti n g i nf e cti o us  c o m pli c ati o ns 
a m o n g  h e m at o p oi eti c  c ell tr a ns pl a nt ati o n r e ci pi e nts:  a  gl o b al  p ers p e cti v e.  Bi ol  Bl o o d  M arr o w 
Tr a ns pl a nt  2 0 0 9; 1 5: 1 1 4 3- 1 2 3 8. 
V a n  Li nt  M T,  U d er z o  C,  L o c as ci ulli  A,  et  al.  E arl y tr e at m e nt  of  a c ut e  gr aft - v ers us-h ost  dis e as e 
wit h  hi g h -  or l o w- d os e  6-m et h yl pr e d nis ol o n e:  a  m ulti c e nt er r a n d o mi z e d tri al fr o m t h e It ali a n 
Gr o u p f or  B o n e  M arr o w  Tr a ns pl a nt ati o n.  Bl o o d  1 9 9 8;  9 2: 2 2 8 8- 2 2 9 3. 
W eis d orf  DJ,  H ur d  D,  C art er  S,  et  al.  Pr os p e cti v e  gr a di n g  of  gr aft- v ers us- h ost  dis e as e  aft er 
u nr el at e d  d o n or  m arr o w tr a ns pl a nt ati o n:  a  gr a di n g  al g orit h m  v ers us  bli n d e d  e x p ert  p a n el r e vi e w. 
Bi ol  Bl o o d  M arr o w  Tr a ns pl a nt  2 0 0 3; 9: 5 1 2- 5 1 8. 
Z eis er  R,  B ur c h ert  A,  L e n g er k e  C,  et  al.  R u x oliti ni b i n  c orti c ost er oi d- r efr a ct or y  gr aft-v ers us - h ost 
dis e as e  aft er  all o g e n ei c st e m  c ell tr a ns pl a nt ati o n:  a  m ult i c e nt er s ur v e y.   L e u k e mi a 
2 0 1 5; 2 9: 2 0 6 2- 2 0 6 8. 

I n c yt e  C or p or ati o n 
P a g e  7 0  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
A P P E N DI X  A.   I N F O R M A TI O N  R E G A R DI N G  E F F E C TI V E N E S S  O F 
C O N T R A C E P TI V E  M E T H O D S  
F o r  S u bj e cts  P a rti ci p ati n g i n t h e  St u d y:  
T h e f oll o wi n g  m et h o ds t h at  c a n  a c hi e v e  a f ail ur e r at e  of l ess t h a n  1 %  p er  y e ar  w h e n  us e d 
c o nsist e ntl y  a n d  c orr e ctl y  ar e  c o nsi d er e d  as  h i g hl y  eff e cti v e  birt h  c o ntr ol  m et h o ds.  
S u c h  m et h o ds i n cl u d e: 
•   C o m bi n e d ( estr o g e n  a n d  pr o g est o g e n  c o nt ai ni n g)  h or m o n al  c o ntr a c e pti o n  ass o ci at e d 
wit h i n hi biti o n  of  o v ul ati o n 1 
−   or al  
−  i ntr a v a gi n al 
−  tr a ns d er m al 
•   Pr o g est o g e n - o nl y  h or m o n al  c o ntr a c e pti o n  ass o ci at e d  wit h i n hi biti o n  of  o v ul ati o n1 
−   or al  
−   i nj e ct a bl e 
−   i m pl a nt a bl e2 
•   I ntr a ut eri n e  d e vi c e (I U D)2 
•   I ntr a ut eri n e  h or m o n e-r el e asi n g s yst e m (I U S)2 
•   Bil at er al t u b al  o c cl usi o n 2 
•   V as e ct o mis e d  p art n er 2, 3 
•   S e x u al  a bsti n e n c e 4 
 
1  H or m o n al  c o ntr a c e pti o n  m a y  b e s us c e pti bl e t o i nt er a cti o n  wit h t h e I M P,  w hi c h  m a y r e d u c e t h e  effi c a c y  of t h e 
c o ntr a c e pti o n  m et h o d.  
2  C o ntr a c e pti o n  m et h o ds t h at i n t h e  c o nt e xt  of t his  g ui d a n c e  ar e  c o nsi d er e d t o  h a v e l o w  us er  d e p e n d e n c y.  
3  V as e ct o mis e d  p a rt n er is  a  hi g hl y  eff e cti v e  birt h  c o ntr ol  m et h o d  pr o vi d e d t h at  p art n er is t h e s ol e s e x u al  p art n er  of 
t h e  W O C B P tri al  p arti ci p a nt  a n d t h at t h e  v a s e ct o mis e d  p art n er  h as r e c ei v e d  m e di c al  a ss ess m e nt  of t h e s ur gi c al 
s u c c e ss.   
4  I n t h e  c o nt e xt  of t his  g ui d a n c e, s e x u al  a bsti n e n c e is  c o nsi d er e d  a  hi g hl y  eff e cti v e  m et h o d  o nl y if  d efi n e d  as 
r efr ai ni n g fr o m  h et er os e x u al i nt er c o urs e  d uri n g t h e  e ntir e  p eri o d  of ris k  ass o ci at e d  wit h t h e st u d y tr e at m e nts.   T h e 
r eli a bilit y  of  s e x u al  a bsti n e n c e  n e e ds t o  b e  e v al u at e d i n r elati o n t o t h e  d ur ati o n  of t h e  cli ni c al tri al  a n d t h e 
pr ef err e d  a n d  us u al lif e st yl e  of t h e s u bj e ct.  
S o ur c e:   C T F G  2 0 1 4 . 

I n c yt e  C or p or ati o n 
P a g e  7 1  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
A p p e n di x  B.   
M A GI C  G UI D E LI N E S  F O R  S T A GI N G  A N D  G R A DI N G 
A C U T E  G V H D  
A c ut e  G V H D  St a gi n g  a n d  G r a di n g,  M A GI C  G ui d eli n es  
St a g e  
S ki n  
( A cti v e  E r yt h e m a  O nl y) 
Li v e r  
( Bili r u bi n)  
U p p e r  GI  
L o w e r  GI  
( St o ol  O ut p ut/ D a y) 
0  
N o  a cti v e ( er yt h e m at o us) 
G V H D r as h  
<  2  m g/ d L   
N o  or i nt er mitt e nt 
n a us e a,  v o miti n g,  or 
a n or e xi a  
A d ult:    < 5 0 0  m L/ d a y  or 
<  3  e pis o d es/ d a y . 
C hil d:    < 1 0  m L/ k g  p er  d a y 
or  <  4  e pis o d es/ d a y .  
1  
M a c ul o p a p ul ar r as h 
<  2 5 %  B S A  
2- 3  m g/ d L   
P ersist e nt  n a us e a,  
v o miti n g , or  a n or e xi a  
A d ult:   5 0 0 -9 9 9  m L/ d a y  or 
3- 4  e pis o d es/ d a y . 
C hil d:   1 0 -1 9. 9  m L/ k g  p er 
d a y  or  4 -6  e pis o d es/ d a y . 
2  
M a c ul o p a p ul ar r as h  
2 5 %- 5 0 %  B S A  
3. 1 -6  m g/ d L  
−  
A d ult:   1 0 0 0 -1 5 0 0 m L/ d a y  or 
5- 7  e pis o d es/ d a y.  
C hil d:   2 0 -3 0  m L/ k g  p er  d a y 
or  7 -1 0  e pis o d es/ d a y . 
3  
M a c ul o p a p ul ar r as h  
>  5 0 %  B S A  
6. 1 -1 5  m g/ d L  
−  
A d ult:    > 1 5 0 0  m L/ d a y  or 
>  7  e pis o d es/ d a y . 
C hil d:    > 3 0  m L/ k g  p er  d a y  
or  >  1 0  e pis o d es/ d a y . 
4  
G e n er ali z e d  er yt hr o d er m a 
( > 5 0 %)  wit h  b ull a e 
>  1 5  m g/ d L  
−  
S e v er e  a b d o mi n al  p ai n  wit h 
or  wit h o ut il e us  or  gr ossl y 
bl o o d y st o ol (r e g ar dl ess  of 
st o ol  v ol u m e).  
O v er all  cli ni c al  gr a d e ( b as e d  o n  m ost s e v er e t ar g et  or g a n i n v ol v e m e nt):  
Gr a d e  0:   N o st a g e  1 -4  of  a n y  or g a n.  
Gr a d e I:   St a g e  1 -2 s ki n  wit h o ut li v er,  u p p er  GI,  or l o w er  GI i n v ol v e m e nt.  
Gr a d e II:   St a g e  3 r as h  a n d/ or st a g e  1 li v er  a n d/ or st a g e  1  u p p er  GI  a n d/ or st a g e  1 l o w er  GI.  
Gr a d e III:   St a g e  2 -3 li v er  a n d/ or st a g e  2 -3 l o w er  GI,  wit h st a g e  0 -3 s ki n  a n d/ or st a g e  0 -1  u p p er  GI.  
Gr a d e I V:   St a g e  4 s ki n, li v er,  or l o w er  GI i n v ol v e m e nt,  wit h st a g e  0 -1  u p p er  GI.  

I n c yt e  C or p or ati o n 
P a g e  7 2  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
R es p o ns e  D efi niti o ns:  
G V H D r es p o ns e  ass ess m e nts  will  b e  m a d e  wit h r es p e ct t o  c h a n g es i n t h e  or g a n st a g e r el ati v e t o 
St u d y  D a y  1.  
•   C o m pl et e r es p o ns e ( C R ) is  d efi n e d  as  a s c or e  of  0 f or t h e  G V H D  gr a di n g i n  all 
e v al u a bl e  or g a ns.   F or  a r es p o ns e t o  b e s c or e d  as  C R  at  D a y  2 8  or l at er, t h e 
p arti ci p a nt  m ust still  b e i n  C R  o n t h at  d a y  a n d  h a v e  h a d  n o i nt er v e ni n g  a d diti o n al 
t h er a p y f or  a n  e arli er  pr o gr essi o n, mi x e d  r es p o ns e ( MR) ,  or  n o r es p o ns e ( N R). 
•   V er y  g o o d  p arti al r es p o ns e ( V G P R ) is  d efi n e d  as f oll o ws: 
−   S ki n:   N o r as h,  or r esi d u al  er yt h e m at o us r as h i n v ol vi n g  <  2 5 %  of t h e  b o d y 
s urf a c e,  wit h o ut  b ull a e (r esi d u al f ai nt  er yt h e m a  a n d  h y p er pi g m e nt ati o n  d o  n ot 
c o u nt). 
−   Li v er:   T ot al s er u m  bilir u bi n  c o n c e ntr ati o n  <  2  m g/ d L  or  <  2 5 %  of  b as eli n e  at 
e nr oll m e nt. 
−   G ut:  
o   T ol er ati n g f o o d  or  e nt er al f e e di n g . 
o   Pr e d o mi n a ntl y f or m e d st o ols. 
o   N o  o v ert  g astr oi nt esti n al  bl e e di n g  or  a b d o mi n al  cr a m pi n g. 
o   N o  m or e t h a n  o c c asi o n al  n a us e a  or  v o miti n g. 
•   P arti al r es p o ns e  ( P R) is  d efi n e d  as i m pr o v e m e nt i n  1 st a g e i n  1 or  m or e  or g a ns 
i n v ol v e d  wit h  G V H D s y m pt o ms  wit h o ut  pr o gr essi o n i n  ot h ers.   F or  a r es p o ns e t o  b e 
s c or e d  as  P R  at  D a y  2 8  or l at er, t h e  p arti ci p a nt  m ust still  b e i n  P R  o n t h at  d a y  a n d 
h a v e  h a d  n o i nt er v e ni n g  a d diti o n al t h er a p y f or  a n  e arli er  pr o gr essi o n,  M R,  or  N R.  
•   Mi x e d r es p o ns e is  d efi n e d  as i m pr o v e m e nt i n  1  or  m or e  or g a ns  wit h  d et eri or ati o n i n 
a n ot h er  or g a n  m a nif esti n g s y m pt o ms  of  G V H D  or  d e v el o p m e nt  of s y m pt o ms  of 
G V H D i n  a  n e w  or g a n.  
•   Pr o gr essi o n  of  dis e as e is  d efi n e d  as  d et eri or ati o n i n  at l e ast  1  or g a n  wit h o ut  a n y 
i m pr o v e m e nt i n  ot h ers. 
•   N o r es p o ns e is  d efi n e d  as  a bs e n c e  of  a n y i m pr o v e m e nt  or  pr o gr essi o n  as  d efi n e d.  
S u bj e cts r e c ei vi n g s e c o n d ar y t h er a p y (i n cl u di n g  n e e d t o r e -es c al at e st er oi d  d os e t o 
gr e at er t h a n t h e  D a y  1  d os e)  will  b e  cl assifi e d  as  n o nr es p o n d ers. 
 
S o ur c e:   CI B M T R  2 0 0 9 , M arti n  et  al  2 0 0 9 , H arris  et  al  2 0 1 6 . 

I n c yt e  C or p or ati o n 
P a g e  7 3  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
A P P E N DI X  C.   C Y T O C H R O M E  P 4 5 0  A N D  P - G L Y C O P R O T EI N 
I N HI BI T OR S  A N D  C Y T O C H R O M E  P 4 5 0 I N D U C E R S  
U ni v ersit y  of  W as hi n gt o n  S c h o ol  of  P h ar m a c e uti cs:  Dr u g I nt er a cti o n  D at a b as e  Pr o gr a m.  2 0 0 2. 
htt p:/ / w w w. dr u gi nt er a cti o ni nf o. or g.  A c c ess e d  M a y  2 0 1 5.   Hi g hli g ht e d r o ws i n di c at e r e c e nt 
a d diti o ns t o t h e lists  at t h e ti m e t h e  d at a b as e s e ar c h  w as  p erf or m e d.  

I n c yt e  C or p or ati o n 
P a g e  7 4  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
I n  Vi v o C Y P 3 A  I n hi bit o rs 
 

I n c yt e  C or p or ati o n 
P a g e  7 5  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
 
 

I n c yt e  C or p or ati o n 
P a g e  7 6  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
I n  Vi v o C Y P 3 A I n d u c e rs  
 

I n c yt e  C or p or ati o n 
P a g e  7 7  of  7 7  
Pr ot o c ol I N C B  1 8 4 2 4 -2 7 1  A m e n d m e nt  2  
0 4  O C T  2 0 1 6  
C O N FI D E N TI A L  
 

Si g n at ur e M a nif e st
D o c u m e nt N u m b er: I C-D E V -P R O T -A M E N D -0 1 9 1
R e vi si o n: 0
Titl e: I N C B 1 8 4 2 4-2 7 1 Pr ot o c ol A m e n d m e nt 2
All d at e s a n d ti m e s ar e i n E a st er n St a n d ar d Ti m e.
A P P R O V A L: 1 8 4 2 4 -2 7 1 A m e n d m e nt 2
R ej e cti o n C oll a b or ati o n
N a m e/ Si g n at ur e
Titl e
D at e
M e a ni n g/ R e a s o n
 
0 6 O ct 2 0 1 6, 1 0: 1 9: 2 3 A M 
C o m pl et e
A p pr o v al a n d R el e a s e
N a m e/ Si g n at ur e
Titl e
D at e
M e a ni n g/ R e a s o n
0 6 O ct 2 0 1 6, 1 0: 2 1: 4 5 A M 
A p pr o v e d
0 6 O ct 2 0 1 6, 1 0: 3 5: 1 9 A M 
A p pr o v e d
 
0 6 O ct 2 0 1 6, 1 0: 4 2: 1 1 A M 
A p pr o v e d
0 6 O ct 2 0 1 6, 1 1: 4 8: 5 5 A M 
A p pr o v e d
Pa ge 1  of 1
Si g nat ure Ma nifest
1 0/ 6/ 2 0 1 6