Clinical trial NCT02953678
Conditions: Graft-versus-host Disease (GVHD)
Keywords: Graft-versus-host disease (GVHD) acute GVHD steroid-refractory ruxolitinib Janus kinase inhibitor
Sponsor: Incyte Corporation
Start date: 2016-12-30; Completion date: 2019-08-14
Enrollment: 71 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study was to assess the efficacy of ruxolitinib in combination with corticosteroids in subjects with Grades II to IV steroid-refractory acute graft-versus-host disease (GVHD).

Detailed description:

Arms: arm 1: Participants began oral administration of ruxolitinib at 5 mg twice daily (BID); if stable after the first 3 days of treatment, the dose could be increased to 10 mg BID.
Interventions: intervention 1: Ruxolitinib intervention 2: Prednisone or methylprednisolone
Intervention descriptions: intervention 1: None intervention 2: Either oral prednisone or IV methylprednisolone may be used to begin corticosteroid treatment at the investigator's discretion.

Protocol documents:
Prot_000.pdf: 
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) 
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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

SAP_001.pdf: 
Incyte Corporation 
Page 1 of 34 
INCB 18424-271 SAP Amendment 3 
24 JUL 2017 
CONFIDENTIAL 
STATISTICAL ANALYSIS PLAN 
INCB 18424-271 / NCT02953678 
A Single-Cohort, Phase 2 Study of Ruxolitinib in Combination With 
Corticosteroids for the Treatment of Steroid-Refractory Acute 
Graft-Versus-Host Disease
IND Number: 
77456 
Sponsor: 
Incyte Corporation 
1801 Augustine Cut-Off 
Wilmington, DE 19803 
Protocol Version: 
Protocol Amendment 2 (dated 04 OCT 2016) 
CRF Approval Date: 
15 NOV 2016 
SAP Version: 
Amendment 3 
SAP Author: 
 
, Biostatistics 
Date of Plan: 
24 JUL 2017 
This study is being conducted in compliance with good clinical practice, 
including the archiving of essential documents. 


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Page 2 of 34 
INCB 18424-271 SAP Amendment 3 
24 JUL 2017 
CONFIDENTIAL 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..........................................................................................................5 
1. 
INTRODUCTION ........................................................................................................6 
2. 
STUDY INFORMATION, OBJECTIVES, AND ENDPOINTS.................................6 
2.1. 
Protocol and Case Report Form Version ......................................................................6 
2.2. 
Study Objectives ...........................................................................................................6 
2.2.1. 
Primary Objectives .......................................................................................................6 
2.2.2. 
Secondary Objectives ...................................................................................................6 
 
6 
2.3. 
Study Endpoints ............................................................................................................7 
2.3.1. 
Primary Endpoint ..........................................................................................................7 
2.3.2. 
Secondary Endpoints ....................................................................................................7 
 
8 
3. 
STUDY DESIGN .........................................................................................................8 
3.1. 
Control of Type I Error .................................................................................................8 
3.2. 
Sample Size Considerations .........................................................................................9 
3.3. 
Schedule of Assessments ..............................................................................................9 
4. 
DATA HANDLING DEFINITIONS AND CONVENTIONS ....................................9 
4.1. 
Scheduled Study Evaluations and Study Periods .........................................................9 
4.1.1. 
Day 1 .............................................................................................................................9 
4.1.2. 
Study Day .....................................................................................................................9 
4.1.3. 
Baseline Value ............................................................................................................10 
4.1.4. 
Last Available Value ..................................................................................................10 
4.2. 
Variable Definitions ....................................................................................................10 
4.2.1. 
Age ..............................................................................................................................10 
4.2.2. 
Body Mass Index ........................................................................................................10 
4.2.3. 
Body Surface Area ......................................................................................................10 
4.2.4. 
Prior and Concomitant Medication .............................................................................10 
5. 
STATISTICAL METHODOLOGY ...........................................................................11 
5.1. 
General Methodology .................................................................................................11 
5.2. 
Treatment Groups .......................................................................................................11 
5.3. 
Analysis Populations ..................................................................................................12 


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INCB 18424-271 SAP Amendment 3 
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CONFIDENTIAL 
5.3.1. 
Efficacy Evaluable Population ...................................................................................12 
5.3.2. 
Safety Evaluable Population .......................................................................................12 
5.3.3. 
Pharmacokinetic Evaluable Population ......................................................................12 
6. 
BASELINE, EXPOSURE, AND DISPOSITION VARIABLES AND 
ANALYSES ...............................................................................................................12 
6.1. 
Baseline and Demographics, Physical Characteristics, and Disease History .............12 
6.1.1. 
Demographics and Baseline Characteristics ...............................................................12 
6.1.2. 
Disease History ...........................................................................................................12 
6.1.3. 
Prior Therapy ..............................................................................................................12 
6.1.4. 
Medical History ..........................................................................................................13 
6.2. 
Disposition of Subjects ...............................................................................................13 
6.3. 
Protocol Deviations ....................................................................................................13 
6.4. 
Exposure .....................................................................................................................13 
6.5. 
Study Drug Compliance .............................................................................................13 
6.6. 
Prior and Concomitant Medication .............................................................................14 
7. 
EFFICACY .................................................................................................................14 
7.1. 
General Considerations ...............................................................................................14 
7.2. 
Efficacy Hypotheses ...................................................................................................14 
7.3. 
Analyses of the Efficacy Parameters ..........................................................................14 
7.3.1. 
Primary Efficacy Analysis ..........................................................................................14 
7.3.2. 
Secondary and Efficacy Analysis ...............................................................................14 
7.3.2.1. 
Duration of Response .................................................................................................14 
7.3.2.2. 
Overall Response Rate ................................................................................................15 
7.3.2.3. 
Nonrelapse Mortality ..................................................................................................15 
7.3.2.4. 
Relapse Rate ...............................................................................................................15 
7.3.2.5. 
Relapse-Related Mortality Rate ..................................................................................15 
7.3.2.6. 
Failure-Free Survival ..................................................................................................15 
7.3.2.7. 
Overall Survival ..........................................................................................................16 
 
16 
7.4. 
Pharmacokinetic Analyses ..........................................................................................16 
 
17 
8. 
SAFETY AND TOLERABILITY ..............................................................................18 
8.1. 
General Considerations ...............................................................................................18 


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CONFIDENTIAL 
8.2. 
Adverse Events ...........................................................................................................18 
8.2.1. 
Adverse Event Definitions ..........................................................................................18 
8.2.2. 
Adverse Event Summaries ..........................................................................................19 
8.3. 
Clinical Laboratory Tests ...........................................................................................20 
8.3.1. 
Laboratory Value Definitions .....................................................................................20 
8.3.2. 
Laboratory Value Summaries .....................................................................................20 
8.4. 
Vital Signs ..................................................................................................................21 
8.5. 
Electrocardiograms .....................................................................................................21 
8.6. 
Analyses for the Data Monitoring Committee ............................................................21 
9. 
INTERIM ANALYSES ..............................................................................................21 
10. 
CHANGES AND MODIFICATIONS TO THE ANALYSIS PLAN ........................22 
10.1. 
Changes to Protocol-Defined Analyses ......................................................................22 
10.2. 
Changes to the Statistical Analysis Plan .....................................................................22 
11. 
REFERENCES ...........................................................................................................24 
APPENDIX A. PLANNED TABLES, FIGURES, AND LISTINGS ........................................25 
APPENDIX B. MAGIC GUIDELINES FOR STAGING AND GRADING ACUTE 
GVHD .........................................................................................................................29 
APPENDIX C. SCHEDULE OF ASSESSMENTS ....................................................................31 
APPENDIX D. PLANNED TABLES AND FIGURES FOR PK ANALYSES ........................34 
 
LIST OF TABLES 
Table 1: 
Criteria for Clinically Notable Vital Sign Abnormalities ...........................................21 
Table 2: 
Statistical Analysis Plan Versions ..............................................................................22 
 


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Page 5 of 34 
INCB 18424-271 SAP Amendment 3 
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CONFIDENTIAL 
LIST OF ABBREVIATIONS 
Abbreviation 
Term 
AE 
adverse event 
BID 
twice daily 
BMI 
body mass index 
BMT CTN 
Bone Marrow Transplant Clinical Trials Network 
BSA 
body surface area 
CI 
confidence interval 
CR 
complete response 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events (v4.03) 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
case report form 
EOT 
end of treatment 
FDA 
Food and Drug Administration 
FFS 
failure-free survival 
GVHD 
graft-versus-host disease 
IVRS 
interactive voice response system 
JAK 
Janus kinase 
MAGIC 
Mount Sinai Acute GHVD International Consortium 
MedDRA 
Medical Dictionary for Regulatory Activities 
MF 
myelofibrosis 
MN-CIBMTR 
Minnesota-Center for International Bone Marrow Transplant Research 
NCI 
National Cancer Institute 
NRM 
nonrelapse mortality 
ORR 
overall response rate 
OS 
overall survival 
PK 
pharmacokinetic 
PR 
partial response 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
TEAE 
treatment-emergent adverse event 
VGPR 
very good partial response 
WHO 
World Health Organization  


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1. 
INTRODUCTION 
Ruxolitinib is a novel, potent, and selective inhibitor of the Janus kinases (JAKs) with selectivity 
for JAK1 and JAK2 (Quintás-Cardama et al 2010).  Ruxolitinib potently inhibits JAK1 and 
JAK2 (IC50 < 5 nM), yet it does not significantly inhibit a broad panel of 28 kinases 
(< 30% inhibition) when tested at 200 nM (approximately 100 × the average IC50 value for JAK1 
and JAK2 enzyme inhibition. 
Section 1 of the Protocol provides a detailed description of the investigational products, target 
patient population, and the potential risks and benefits from the combination treatments.  The 
purpose of this document is to provide a detailed Statistical Analysis Plan (SAP). 
2. 
STUDY INFORMATION, OBJECTIVES, AND ENDPOINTS 
2.1. 
Protocol and Case Report Form Version 
This SAP is based on INCB 18424-271 Protocol Amendment 2 dated 04 OCT 2016 and case 
report form (CRF) approved 15 NOV 2016.  Unless superseded by an amendment, this SAP will 
be effective for all subsequent Protocol amendments and electronic case report form (eCRF) 
versions. 
2.2. 
Study Objectives 
2.2.1. 
Primary Objectives 
Assess the efficacy of ruxolitinib in combination with corticosteroids in subjects with Grades II 
to IV steroid-refractory acute graft-versus-host disease (GVHD). 
2.2.2. 
Secondary Objectives 
Secondary objectives include the following: 
• Assess additional response and longer-term efficacy outcomes in the study 
population. 
• Assess the incidence and severity of adverse events (AEs) and serious adverse events 
(SAEs). 
• Evaluate the pharmacokinetics (PK) of ruxolitinib when administered in combination 
with corticosteroids. 


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2.3. 
Study Endpoints 
2.3.1. 
Primary Endpoint 
Overall response rate (ORR) at Day 28, defined as the proportion of subjects demonstrating a 
complete response (CR), very good partial response (VGPR), or partial response (PR). 
2.3.2. 
Secondary Endpoints 
Key secondary endpoint and other secondary endpoints are included in the following:  
• Key secondary endpoint:  Six-month duration of response (DOR), defined as the time 
from first response until GVHD progression or death.  DOR will be assessed when all 
subjects complete the Day 180 visit.  
• ORR, defined as the proportion of subjects demonstrating a CR, VGPR, or PR at 
Days 14, 56, and 100. 
• Three-month DOR, defined as the time from first response until GVHD progression 
or death, when all subjects complete the Day 84 visit. 
• Nonrelapse mortality (NRM), defined as the proportions of subjects who died due to 
causes other than malignancy relapse at Months 6, 9, 12, and 24. 
• Relapse rate, defined as the proportion of subjects whose underlying malignancy 
relapses. 
• Relapse-related mortality rate, defined as the proportion of subjects whose 
malignancy relapses and has a fatal outcome. 
• Failure-free survival (FFS), defined as the proportion of subjects who are still alive, 
have not relapsed, have not required additional therapy for acute GVHD, and have 
not demonstrated signs or symptoms of chronic GVHD, at Month 6. 
• Overall survival (OS), defined as the time from study enrollment (first day of 
ruxolitinib treatment) to death due to any cause. 
• Summary of clinical safety data (eg, AEs, infections) will be tabulated and listed. 
• Maximum observed plasma drug concentration (Cmax), minimum observed plasma 
drug concentration (Cmin), time of maximum observed plasma drug concentration 
(tmax), area under the plasma drug concentration versus time curve (AUC), and 
apparent clearance of study drug from plasma (CL/F). 


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3. 
STUDY DESIGN 
This is an open-label, single-cohort, multicenter Phase 2 study of ruxolitinib in combination with 
corticosteroids for the treatment of steroid-refractory Grades II to IV acute GVHD.  Eligible 
subjects will begin treatment at 5 mg twice daily (BID) ruxolitinib; if hematologic parameters are 
stable and no treatment-related toxicity is observed after the first 3 days of treatment, the dose 
may be increased to 10 mg BID.  Ruxolitinib may be tapered after Day 180 provided the subject 
has achieved CR or VGPR and corticosteroids have been discontinued for at least 8 weeks.  
Corticosteroids will be administered at a starting dose of 2.0 mg/kg per day (unless otherwise 
indicated) on Day 1 and will be tapered as appropriate.  Subjects will receive study treatment 
until treatment failure (progression of GVHD, no response, or requiring additional systemic 
therapy), unacceptable toxicity, or death.  Continued use of anti-infective medications, GVHD 
prophylaxis medications (including calcineurin inhibitors), transfusion support, and topical 
steroid therapy is permitted. 
Severity of GVHD will be assessed from screening through end of treatment (EOT) using the 
Mount Sinai Acute GHVD International Consortium (MAGIC) guidelines.  Adverse events and 
SAEs will be assessed from the time of consent through 30 to 35 days after the EOT as per 
National Cancer Institute CTCAE v4.03.  Subjects will be assessed for efficacy (including 
overall response, NRM, FFS, DOR, relapse rate, relapse-related mortality rates, and OS), safety 
(including AEs, SAEs, and clinical/laboratory assessments),
 
 
3.1. 
Control of Type I Error 
No formal statistical tests will be performed.  All confidence intervals (CIs) will be 95%. 


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3.2. 
Sample Size Considerations 
Approximately 70 subjects are planned for the final analysis of the primary endpoint of ORR.  A 
second-line treatment demonstrating a true ORR of 60% would be considered clinically 
meaningful.  With the assumed true rate of 60%, a sample size of 70 subjects would provide 
> 90% probability to have a 95% CI with lower limit of ≥ 40%. 
An interim analysis will be conducted once 35 subjects complete the Day 28 visit.  In this interim 
analysis, only futility will be assessed, and the trial will be terminated if the lower boundary is 
crossed. 
A group sequential design method for 1 sample binary outcome data will be used to calculate the 
lower boundary of futility.  The spending function of HSD(-4) will be used.  For H0:  p = 0.4, 
Ha:  p = 0.6, and a 1-sided binomial test with alpha of 0.025, if ≤ 15 subjects respond at the time 
of the interim analysis, the study will be terminated.  This will provide 70.03% probability for 
the response rate of 40% at the interim analysis. 
If ≥ 37 subjects respond at the time of final analysis, the study outcome will be considered 
positive.  These assumptions will provide 89.88% power for the response rate of 60% in the final 
analysis with Type I error of 0.0189. 
3.3. 
Schedule of Assessments 
See Appendix C for assessment schedules for this study. 
4. 
DATA HANDLING DEFINITIONS AND CONVENTIONS 
4.1. 
Scheduled Study Evaluations and Study Periods 
4.1.1. 
Day 1 
Day 1 is the date of first dose of ruxolitinib.  For patients who started corticosteroids before 
ruxolitinib, all study visits will be counted based on Day 1 of study. 
4.1.2. 
Study Day 
If a visit/reporting date is on or after Day 1, then the study day at the visit/reporting date will be 
calculated as follows: 
Day # = [Visit/Reporting Date – Day 1 date + 1] 
If the visit/reporting date is before Day 1, then the study day at the visit/reporting date will be 
calculated as follows: 
Day # = [Visit/Reporting Date – Day 1 date] 
A study day of -1 indicates 1 day before Day 1. 


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4.1.3. 
Baseline Value 
Baseline is the last nonmissing measurement obtained on or before the day of the first 
administration of study drug.  When scheduled assessments and unscheduled assessments occur 
on the same day and time of the assessment or first dose is not available, use the following 
convention to determine baseline: 
• If both a scheduled and an unscheduled visit are available on the day of the first dose 
and the time is missing, use the scheduled assessment as baseline. 
• If all scheduled assessments are missing on the day of the first dose and an 
unscheduled assessment is available, use the unscheduled assessment as baseline. 
4.1.4. 
Last Available Value 
The last available value is the last nonmissing measurement obtained after starting study drug. 
4.2. 
Variable Definitions 
4.2.1. 
Age 
Subject age will be calculated as the integer part of the number of years from date of birth to the 
date of signing the informed consent form, using the following formula: 
Age = integer part of (date of informed consent – date of birth + 1) / 365.25 
4.2.2. 
Body Mass Index 
Body mass index (BMI) will be calculated as follows: 
BMI (kg/m2) = [weight (kg)] / [height (m)]2 
4.2.3. 
Body Surface Area 
Body surface area (BSA) will be calculated based on the Mosteller (1987) formula as follows: 
BSA (m2) = {[weight (kg) × height (cm)] / 3600}½ 
Sites will also record the BSA calculated per institutional standards. 
4.2.4. 
Prior and Concomitant Medication 
Prior medication is defined as any nonstudy medication started before the first dose of study 
drug. 
Concomitant medication is defined as any nonstudy medication that is started accordingly: 
• Before the date of first administration of study drug and is ongoing throughout the 
study or ends on/after the date of first study drug administration. 
• On/after the date of first administration of study drug and is ongoing or ends during 
the course of study drug. 


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A prior medication could also be classified as "both prior and concomitant medication" if the end 
date is on or after first dose of study drug.  In the listing, it will be indicated whether a 
medication is prior only, concomitant only, or both prior and concomitant. 
For the purposes of analysis, all medications will be considered concomitant medications unless 
the medications can unequivocally be defined as not concomitant. 
The start/stop dates recorded in the eCRF by the investigator and his or her research staff will be 
used to identify when a concomitant medication was taken during the study.  Unresolved missing 
start dates will be handled as follows: 
• For the starting date, impute as follows: 
− If the day is missing, then impute as the first day of the month. 
− If the month is missing, then impute as the first day of the year. 
− If the year is missing, then the medication will be considered both prior and 
concomitant. 
• For the ending date, impute as follows: 
− If the day is missing, then impute as the last day of the month. 
− If the month is missing, then impute as the last day of the year. 
− If the year is missing, then the medication will be considered as ongoing until the 
end of the study. 
5. 
STATISTICAL METHODOLOGY 
5.1. 
General Methodology 
Unless otherwise noted, SAS® software (SAS Institute Inc., Cary, NC; v9 or later) will be used 
for the generation of all tables, graphs, and statistical analyses.  Descriptive summaries for 
continuous variables will include, but not be limited to, the number of observations, mean, 
standard deviation, median, minimum, and maximum.  Descriptive summaries for categorical 
variables will include the number and percentage of subjects in each category. 
5.2. 
Treatment Groups 
This is a single-cohort study.  Eligible subjects will begin treatment at ruxolitinib 5 mg BID; if 
hematologic parameters are stable and no treatment-related toxicity is observed after the first 
3 days of treatment, the dose may be increased to 10 mg BID.  Corticosteroids will be 
administered at a starting dose of 2.0 mg/kg per day (unless otherwise indicated) on Day 1 and 
will be tapered as appropriate. 


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5.3. 
Analysis Populations 
5.3.1. 
Efficacy Evaluable Population 
The efficacy evaluable population includes all subjects enrolled in the study.  Demographics, 
baseline characteristics, subject disposition, and all efficacy analyses will be conducted using the 
efficacy evaluable population. 
5.3.2. 
Safety Evaluable Population 
The safety evaluable population includes all subjects enrolled in the study who received at least 
1 dose of study drug.  Treatment groups for this population will be determined according to the 
actual treatment that the subject received on Day 1.  All safety analyses will be conducted using 
the safety evaluable population. 
5.3.3. 
Pharmacokinetic Evaluable Population 
The pharmacokinetic evaluable population includes subjects who receive at least 1 dose of study 
drug and provide at least 1 plasma sample (1 PK measurement) after study drug administration.  
The study pharmacokineticist will review data listings of study drug administration and sample 
records to identify subjects to be excluded from analyses of PK data. 
6. 
BASELINE, EXPOSURE, AND DISPOSITION VARIABLES AND 
ANALYSES 
6.1. 
Baseline and Demographics, Physical Characteristics, and Disease 
History 
Demographic and baseline characteristics, disease history, and prior therapy will be summarized 
for the efficacy evaluable population and listed. 
6.1.1. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics include the following:  age, sex, race, ethnicity, 
weight, height, BMI, BSA, and ECOG performance status. 
6.1.2. 
Disease History 
Cancer type, time since initial diagnosis, stage at diagnosis, current stage, disease histology, 
primary site of disease, mutation status, and site of metastatic disease at baseline will be 
summarized. 
Time since diagnosis will be calculated as follows: 
Time since diagnosis (years) = [Day 1 – date of diagnosis + 1] / 365.25 
6.1.3. 
Prior Therapy 
Number of subjects who received prior systemic therapy will be summarized for the efficacy 
evaluable population.  Regimen name, component drugs, start and stop dates, purpose of the 
regimen, best response, reason for discontinuation, and date of relapse/progression will be listed.  


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Number of subjects who received prior radiation will be summarized for the efficacy evaluable 
population.  Radiotherapy type, body site, start and stop dates, total dose, and best response will 
be listed. 
Number of subjects who had prior surgery or surgical procedure for the malignancies under 
study will be summarized for the efficacy evaluable population.  Date and description of the 
surgery/procedure will be listed. 
6.1.4. 
Medical History 
For subjects in the efficacy evaluable population, medical history will be summarized by 
system-organ class and preferred term and will be listed. 
6.2. 
Disposition of Subjects 
The number and percentage of subjects who were treated, discontinued study treatment with a 
primary reason for discontinuation, and discontinued from the study with a primary reason for 
withdrawal will be summarized for the efficacy evaluable population. 
6.3. 
Protocol Deviations 
Protocol deviations and violations collected on eCRF will be presented in the subject data 
listings. 
6.4. 
Exposure 
For subjects in the safety evaluable population, exposure to study drug (INCB018424) will be 
summarized descriptively as follows: 
• Duration of treatment with study drug: 
Duration of treatment (days) = Date of last dose of study drug – Date of first dose of 
study drug + 1 
• Average daily dose of study drug: 
Average daily dose of study drug (mg/day) = [total actual study drug dose taken 
(mg)] / [duration of treatment with study drug] 
Summary for the planned exposure of corticosteroids will be provided. 
6.5. 
Study Drug Compliance 
For subjects in the safety evaluable population, overall compliance (%) for study drug 
(ruxolitinib) will be calculated for all subjects as follows: 
Overall compliance (%) = 100 × [total dose actually taken (mg)] / [total prescribed 
dose (mg)] 
The total prescribed dose is defined as the sum of the doses prescribed by the investigator 
accounting for dose modifications. 
Compliance of study drug will be summarized descriptively and listed. 


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6.6. 
Prior and Concomitant Medication 
Prior medications and concomitant medications will be coded using the WHO Drug Dictionary.  
For subjects in the safety population, the number and percentage of subjects with prior and 
concomitant medications will be summarized by WHO drug class and WHO drug term.  In the 
data listing, each medication will be recorded as prior, concomitant, or both prior and 
concomitant. 
7. 
EFFICACY 
Planned tables, figures, and listings are provided in Appendix A.  All efficacy analyses will be 
performed using the efficacy evaluable population. 
7.1. 
General Considerations 
Missing observations will be handled for specific endpoints as detailed in the sections addressing 
each analysis. 
7.2. 
Efficacy Hypotheses 
No formal statistical tests will be performed.   
7.3. 
Analyses of the Efficacy Parameters 
7.3.1. 
Primary Efficacy Analysis 
Overall response rate at Day 28 is defined as the proportion of subjects demonstrating a CR, 
VGPR, or PR as per standard criteria (see Appendix B). 
The proportion of responders will be estimated with 95% CIs for the efficacy evaluable 
population.  Confidence intervals will be calculated based on the exact method for binomial 
distributions.  Summary statistics will be provided. 
Subjects who have missing response data at Day 28 (includes withdrawal or death before 
Day 28) will be considered nonresponders.  The primary analysis will be conducted when all 
subjects have completed Day 28 response assessments or discontinued. 
7.3.2. 
Secondary and Efficacy Analysis 
7.3.2.1. 
Duration of Response 
Duration of response at Month 6 is the key secondary endpoint.  For responders, the DOR is 
defined as the difference of the end of response and the start of response for subjects who have at 
least 1 response measurement.  The start of a response will be the first visit where the subject 
achieves PR or better based on response criteria in Appendix B (MAGIC guidelines).  The end 
of response will be the first visit after GVHD progression based on response criteria in 
Appendix B or death.  Duration of response will be assessed using the Kaplan-Meier method for 
subjects who achieve a response.  Median duration and 95% CI will be estimated.  Subjects who 
are still responding at the time of database lock or discontinuation will be right-censored at the 


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time of last valid response assessment.  Six-month DOR will be assessed when all subjects 
complete the Day 180 visit. 
In addition, 3-month DOR will be assessed.  Three-month DOR is defined as the time from first 
response until GVHD progression or death, when all subjects complete the Day 84 visit.  
Duration of response will be assessed using the Kaplan-Meier method for subjects who achieve a 
response. 
7.3.2.2. 
Overall Response Rate 
Overall response rate at Days 14, 56, and 100 is defined as the proportion of subjects 
demonstrating a CR, VGPR, or PR based on the MAGIC guidelines. 
Subjects who have missing response data at Days 14, 56, and 100 (includes withdraw or death 
before these days) will be considered as nonresponders.  The ORR on Days 14, 56, and 100 will 
be estimated with a 95% CI.  The proportion of responders will be estimated with 95% CIs.  
Confidence intervals will be calculated based on the exact method for binomial distributions.  
Summary statistics will be provided. 
7.3.2.3. 
Nonrelapse Mortality 
Nonrelapse mortality is defined as the proportion of subjects who died due to causes other than 
malignancy relapse at Months 6, 9, 12, and 24. 
Cumulative incidence functions of NRM will be estimated using Gray's method, and subjects 
with relapse-related mortality will be treated as competing risk and no observed mortality as 
censored at their last date known to be alive.  Cumulative incidence rates of NRM at Months 6, 
9, 12, and 24 will be estimated with 95% CI.  Confidence intervals will be calculated based on 
the exact method for binomial distributions.  Summary statistics will be provided. 
7.3.2.4. 
Relapse Rate 
Relapse rate is defined as the proportion of subjects whose underlying malignancy relapses.  
Primary disease relapse rate at Month 6 will be estimated with 95% CI.  Confidence intervals 
will be calculated based on the exact method for binomial distributions.  Cumulative incidence 
rate and summary statistics will be provided. 
7.3.2.5. 
Relapse-Related Mortality Rate 
Relapse-related mortality rate is defined as the proportion of subjects whose malignancy relapses 
and has a fatal outcome at Month 6.  Relapse mortality rate will be provided with 95% CI.  
Confidence interval will be calculated based on the exact method for binomial distributions.  
Cumulative incidence rate and summary statistics will be provided. 
7.3.2.6. 
Failure-Free Survival 
Failure-free survival, defined as the proportion of subjects who are still alive, have not relapsed, 
have not required additional therapy for acute GVHD, and have not demonstrated signs or 
symptoms of chronic GVHD, at Month 6.  The Kaplan-Meier method will be used to estimate 
the FFS time distribution and the median survival.  Subjects with no observed death or loss to 
follow-up or have not relapsed, have not required additional therapy for acute GVHD, and have 


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not demonstrated signs or symptoms of chronic GVHD, at Month 6 will be treated as censored at 
Month 6.  Survival rate at Month 6 will be estimated with 95% CI.  The 95% CI will be 
calculated using the Brookmeyer and Crowley's method (Brookmeyer and Crowley 1982).  
Summary statistics will be provided. 
7.3.2.7. 
Overall Survival 
Overall survival is defined as the time from study enrollment (first date of ruxolitinib treatment) 
to death due to any cause.  The Kaplan-Meier method will be used to estimate the survival time 
distribution and the median survival.  Subjects with no observed death or loss to follow-up will 
be treated as censored at their last date known to be alive.  Survival rate at Month 6 will be 
estimated with 95% CI.  The 95% CI will be calculated using the Brookmeyer and Crowley's 
method (Brookmeyer and Crowley 1982).  Summary statistics will be provided. 
7.4. 
Pharmacokinetic Analyses 
Noncompartmental analysis of the observed PK concentration data will be performed, and PK 
parameters, such as Cmax, tmax, AUC, and t½, will be generated and summarized wherever 
possible.  Planned tables, listings, and figures are listed in Appendix B. 
The population PK of ruxolitinib in subjects with myelofibrosis (MF) has been established in the 
previous MF New Drug Application.  First, the PK data from this study will be applied to 
validate the final PK model established in the MF population.  If significant biases are observed 
in this validation process, then a new population PK model may be generated based on the data 
from this study, and the model development process will follow the methods below.  The data 
from this study may be combined with data from other clinical studies to improve parameter 
estimation. 


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The model development process consists of base pharmacokinetic model development and 
covariate analysis.  In the base model development, compartment models with first-order 
absorption and linear elimination will be tested for their ability to characterize the PK of 
ruxolitinib in combination with corticosteroids for the treatment of steroid-refractory acute 
GVHD.  Interindividual variability will be modeled using an exponential error model and 
explored for each PK parameter.  Proportional, additive, and mixed error (additive plus 
proportional) models will be individually evaluated for their ability to describe the magnitude of 
residual variability.  The first-order conditional estimation method with the interaction option 
will be used. 
After a final base model is identified, covariates will be tested as predictors of PK variability.  A 
generalized additive model analysis will be used as a screening tool to initially identify 
covariates to be formally tested for statistical significance in NONMEM.  The candidate 
covariates will be incorporated into the PK model as fixed-effect parameters by making the 
typical values of the structural PK parameters a function of the covariate.  NONMEM regression 
analysis will be performed on the model, with covariate parameters being added in a stepwise 
univariate fashion during the forward selection process and removed in the model reduction 
(backward elimination) process.  The likelihood ratio test will be used to evaluate the 
significance of incorporating parameters into or removing parameters from the population model.  
The accuracy and robustness of the final population PK model will be investigated using a visual 
predictive check method. 
The population PK data preparation will be performed using SAS v9.1 or later (SAS Institute 
Inc, Cary, NC).  
 
 
  The PK analyses will use NONMEM v7.1.0 or later (ICON 
Development Solutions, Dublin, Ireland). 


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8. 
SAFETY AND TOLERABILITY 
8.1. 
General Considerations 
The analyses for this section will be provided for the safety evaluable population.  Summary 
tables may be replaced with listings when appropriate.  For instance, an AE frequency table may 
be replaced with a listing if it only contains a few unique preferred terms reported on relatively 
few subjects. 
8.2. 
Adverse Events 
8.2.1. 
Adverse Event Definitions 
A treatment-emergent adverse event (TEAE) is any AE either reported for the first time or the 
worsening of a pre-existing event after the first dose of study drug until 30 days after the last 
dose of study drug.  Analysis of AEs (as discussed below) will be limited to TEAEs, but data 
listings will include all AEs regardless of their timing to study drug administration. 
Adverse events will be tabulated by MedDRA preferred term and system organ class.  Severity 
of AEs will be described and graded using the National Cancer Institute (NCI) CTCAE v4.03 
(NCI 2010).  The CTCAE reporting guidelines and grading details are available on the Cancer 
Therapy Evaluation Program website. 
A grading (severity) scale is provided for each AE term.  If the toxicity is not included in the 
CTCAE v4.03 criteria, then it will be rated on a scale of 1 to 4 as follows:  1 = mild, 
2 = moderate, 3 = severe, and 4 = life-threatening.  All toxicities will be graded based on the 
worst level reached, not the level they may have reached if they had not been treated.  When the 
intensity of an AE changes over time for a reporting period (eg, between visits), then each 
change in intensity will be reported as an AE until the event resolves. 
The subset of AEs considered by the investigator to be related to study drug will be considered to 
be treatment-related AEs.  If the investigator does not specify the relationship of the AE to study 
drug, then the AE will be considered to be treatment-related.  The incidence of AEs and 
treatment-related AEs will be tabulated.  Serious AEs will also be tabulated.  
Any missing onset date, causality, or severity must be queried for resolution.  Unsolved missing 
values will be handled according to the following rules: 
• An unsolved missing causality will be considered treatment-related. 
• An unsolved missing severity will be identified as an unknown severity. 
For purposes of analysis, all AEs will be considered TEAEs unless the AE can unequivocally be 
defined as not treatment-emergent. 


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8.2.2. 
Adverse Event Summaries 
An overall summary of AEs will include the following: 
• Number (%) of subjects reporting any TEAEs 
• Number (%) of subjects reporting any SAEs 
• Number (%) of subjects reporting any Grade 3 or 4 TEAEs 
• Number (%) of subjects reporting any TEAEs related to ruxolitinib 
• Number (%) of subjects reporting any TEAEs related to corticosteroids 
• Number (%) of subjects who temporarily interrupted ruxolitinib because of a TEAE 
• Number (%) of subjects with ruxolitinib dose reductions because of TEAEs  
• Number (%) of subjects who permanently discontinued ruxolitinib because of a 
TEAE 
• Number (%) of subjects who permanently discontinued ruxolitinib or corticosteroids 
because of a TEAE 
• Number (%) of subjects who withdrew from the study because of a TEAE   
• Number (%) of subjects who had a fatal TEAE 
• Number (%) of subjects who had a TEAE of special interest 
The following summaries will be produced by MedDRA term (if 10 or fewer subjects appear in a 
table, a listing may be appropriate): 
• Number (%) of subjects reporting TEAEs by system organ class and preferred term 
• Number (%) of subjects reporting TEAEs by preferred term in decreasing order of 
frequency 
• Number (%) of subjects reporting TEAEs by system organ class, preferred term, and 
highest CTCAE grade 
• Number (%) of subjects reporting any Grade 3 or 4 TEAEs by system organ class and 
preferred term 
• Number (%) of subjects reporting treatment-related AEs by system organ class and 
preferred term 
• Number (%) of subjects reporting treatment-related AEs by preferred term in 
decreasing order of frequency 
• Number (%) of subjects reporting treatment-related AEs by system organ class, 
preferred term, and highest CTCAE grade 
• Number (%) of subjects reporting fatal TEAEs by system organ class and preferred 
term 
• Number (%) of subjects reporting treatment-emergent SAEs by system organ class 
and preferred term 


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• Number (%) of subjects reporting treatment-related SAEs by system organ class and 
preferred term 
• Number (%) of subjects reporting TEAEs leading to dose reduction of ruxolitinib by 
system organ class and preferred term 
• Number (%) of subjects reporting TEAEs leading to discontinuation of ruxolitinib by 
system organ class and preferred term 
• Number (%) of subjects reporting treatment-emergent non-SAE by system organ 
class and preferred term 
8.3. 
Clinical Laboratory Tests 
8.3.1. 
Laboratory Value Definitions 
Laboratory values and change from baseline values will be summarized descriptively by visit.  
The baseline value will be determined using the last nonmissing values collected before the first 
dose. 
Laboratory test values outside the normal range will be assessed for severity based on 
CTCAE v4.03 grade or similar criteria where clinical intervention is required for CTCAE 
grading.  The incidence of abnormal laboratory values and shift tables relative to baseline will be 
tabulated. 
8.3.2. 
Laboratory Value Summaries 
All test results and associated normal ranges from central laboratories will be reported in SI 
units.  All tests with numeric values will have a unique unit per test.  Any laboratory test results 
and associated normal ranges from local laboratories will be converted to SI units.  For the 
limited number of cases where the associated normal ranges from a local laboratory cannot be 
obtained despite due diligence, associated central laboratory normal ranges will be applied.  In 
the event that central laboratory normal ranges are not available, a set of standard normal ranges 
based on documented reference ranges will be applied to facilitate reporting the test results. 
For numeric laboratory values, baseline value, postbaseline value, change from baseline, and 
percent change from baseline will be summarized by visit.  In addition, mean change from 
baseline will be plotted over time for selected laboratory parameters. 
Shift summaries will be presented showing the number and percentage of subjects with 
laboratory values of low, normal, and high at baseline along with change to the worst 
postbaseline visits.  The denominator for the percentage calculation will use the number of 
subjects in the baseline category (ie, low, high, normal, missing). 
For the laboratory parameters that have CTCAE grading, shift tables will also be presented 
showing change in CTCAE severity grade from baseline to worst grade postbaseline.  Separate 
tables will be provided for selected laboratory tests that have grading criteria in both high and 
low directions.  The denominator for the percentage calculation will be the number of subjects in 
the baseline category. 
Categorical laboratory data will be tabulated by visit at baseline and postbaseline visits where 
appropriate. 


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8.4. 
Vital Signs 
Values at each scheduled visit, change, and percentage change from baseline for vital signs, 
including systolic blood pressure, diastolic blood pressure, pulse, respiration rate, and body 
temperature, will be summarized descriptively.   
Criteria for clinically notable vital sign abnormalities are defined in Table 1.  The abnormal 
values for subjects exhibiting clinically notable vital sign abnormalities will be listed.  Alert vital 
signs are defined as an absolute value outside the defined range and percentage change from 
baseline greater than 25%.  The abnormal values for subjects exhibiting alert vital sign 
abnormalities will also be listed. 
Table 1: 
Criteria for Clinically Notable Vital Sign Abnormalities 
Parameter 
High Threshold 
Low Threshold 
Systolic blood pressure 
> 155 mmHg 
< 85 mmHg 
Diastolic blood pressure 
> 100 mmHg 
< 40 mmHg 
Pulse 
> 100 bpm 
< 45 bpm 
Temperature 
> 38ºC 
< 35.5ºC 
Respiratory rate 
> 24/min 
< 8/min 
8.5. 
Electrocardiograms 
Normal or abnormal 12-lead electrocardiograms (ECGs) will be collected and listed for each 
scheduled visit. 
8.6. 
Analyses for the Data Monitoring Committee 
No Data Monitoring Committee is planned. 
9. 
INTERIM ANALYSES 
An interim analysis will be conducted when 35 subjects complete the Day 28 visit.  In this 
interim analysis, only futility will be assessed, and the study will be terminated if the lower 
boundary is crossed. 
A group sequential design method for 1 sample binary outcome data will be used to calculate the 
lower boundary of futility.  The spending function of HSD(-4) will be used.  For H0:  p = 0.4, 
Ha:  p = 0.6, and a 1-sided binomial test with alpha of 0.025, if ≤ 15 subjects respond at the time 
of the interim analysis, the study will be terminated.  This will provide 70.03% probability for 
the response rate of 40% at the interim analysis. 
If ≥ 37 subjects respond at the time of final analysis, the study outcome will be considered 
positive.  These assumptions will provide 89.88% power for the response rate of 60% in the final 
analysis with Type I error of 0.0189. 


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10. 
CHANGES AND MODIFICATIONS TO THE ANALYSIS PLAN 
All versions of the SAP are listed in Table 2. 
Table 2: 
Statistical Analysis Plan Versions 
SAP Version 
Date 
Original 
15 JUN 2016 
Amendment 1 
13 SEP 2016 
Amendment 2 
09 OCT 2016 
Amendment 3 
24 JUL 2017 
10.1. 
Changes to Protocol-Defined Analyses 
1. Key secondary endpoint:  6-month DOR. 
2. Updated interim analysis for futility. 
3. Removed ECG analysis. 
10.2. 
Changes to the Statistical Analysis Plan 
SAP Amendment 1: 
1. Sections 2.3.2 and 7.3.2.1:  Key secondary endpoint was changed to 6-month DOR, and 
3-month DOR was added as a secondary endpoint; duration of response analysis 
description was updated accordingly. 
2. Sections 3.2 and 9:  Modified language to reflect planned interim analysis for futility. 
3. Section 3:  Updated text regarding guidance on tapering of ruxolitinib to align with 
revisions made in Protocol Amendment 2. 
SAP Amendment 2: 
1. Section 7.3.1:  Revised to indicate that if subjects have response assessments before 
Day 28 and discontinue the study, then the response assessments before Day 28 will be 
used for the overall responses rate at Day 28. 
2. Section 7.3.2.2:  Revised to indicate that if subjects have response assessments before 
scheduled visits and discontinue the study, the response assessments before the scheduled 
visits will be used for the overall responses rate at the next closest scheduled visits.  
SAP Amendment 3: 
1. Section 4.1.1:  Revised definition of Day 1 to be based on first day of treatment of 
ruxolitinib. 
2. Section 2.3.2 and 7.3.2.7:  Clarified that study enrollment refers to the first date of 
ruxolitinib treatment (Day 1) for the overall survival definition. 


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3. Section 7.3.1:  Revised to indicate that if subjects have response assessments before 
Day 28 and discontinue the study, then the subject will be considered as non-responder 
for the overall responses rate at Day 28. 
4. Section 7.3.2.2:  Revised to indicate that if subjects have response assessments before 
scheduled visits and discontinue the study, the subject will be considered as non-
responder at that scheduled visit. 
5. Section 7.3.3:  Revised to include more detail on the summary statistics to be provided 
for other efficacy analyses.  Modified to indicate that summary statistics will not be 
provided for chronic GVHD. 
6. Section 8.2.2: Updated planed AE related outputs 
7. Section 8.5:  Revised to indicate that there will not be any ECG analysis; instead 
normal/abnormal status will be listed per CRF collection. 
8. Appendix A:  Updated the planned tables, listings, and figures as a result of the other 
changes to this SAP.  Numbering was modified as necessary as a result of the 
modifications. 


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11. 
REFERENCES 
Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics 
1982;38:29-41. 
Center for International Blood and Marrow Transplant Research (CIBMTR). Clinical trial 
endpoints for patients with acute GVHD. 2009. 
https://www.cibmtr.org/Meetings/Materials/GVHDworkshop/pages/index.aspx. Accessed 
February 5, 2015. 
Harris AC, Young R, Devine S, et al. International, Multicenter Standardization of Acute Graft 
versus-Host Disease Clinical Data Collection: A Report from the Mount Sinai Acute GVHD 
International Consortium. Biol Blood Marrow Transplant 2016;22:4-10. 
Martin PJ, Bachier CR, Klingemann HG, et al. Endpoints for clinical trials testing treatment of 
acute graft-versus-host disease: a joint statement. Biol Blood Marrow Transplant 2009;15:777 
784. 
Mosteller RD. Simplified calculation of body-surface area. N Engl J Med 1987;317:1098. 
National Cancer Institute (NCI). Common Terminology Criteria for Adverse Events v4.03. 2010. 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html. Accessed June 13, 2016. 
Quintás-Cardama A, Vaddi K, Liu P, et al. Preclinical characterization of the selective JAK1/2 
inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative 
neoplasms. Blood 2010;115:3109-3117. 


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APPENDIX A. PLANNED TABLES, FIGURES, AND LISTINGS 
This appendix provides a list of the planned tables, figures, and listings for the Clinical Study 
Report.  Standard tables will follow the conventions in the Standard Safety Tables initial version.  
In-text tables are identical in structure and content as appendix tables, but follow a Rich Text 
Format. 
Tables 
Table No. 
Title 
Population 
In-Text 
1.1.1 
Analysis Population 
Enrolled 
X 
1.1.2 
Summary of Subject Disposition 
Enrolled 
X 
1.2.1 
Summary of Demographic and Baseline Characteristics 
Efficacy 
X 
1.2.2 
Summary of Baseline Disease Characteristics 
Efficacy 
X 
1.3.1 
Summary of Medical History 
Efficacy 
 
1.3.2 
Summary of Cancer History 
Efficacy 
 
1.3.3 
Summary of Allogeneic Hematopoietic Stem Cell Transplant History 
Efficacy 
 
1.4.1 
Summary of Prior Medications 
Efficacy 
 
1.4.2 
Summary of Concomitant Medications 
Efficacy 
 
1.4.3 
Summary of Prior Anti-Cancer Therapy 
Efficacy 
X 
1.4.4 
Summary of Prior Anti-GVHD Therapy 
Efficacy 
 
1.4.5 
Summary of Prior Radiotherapy 
Efficacy 
 
2.1.1 
Summary of Overall Response Rate at Day 28 
Efficacy 
X 
2.1.2  
Summary of Overall Response Rate at Days 14, 56, and 100 
Efficacy 
X 
2.1.3 
Summary of Overall Response Rate at Interim Analysis 
Efficacy 
X 
2.2.1 
Summary of Duration of Response 
Efficacy 
X 
2.2.2 
Summary of Nonrelapse Mortality Rate 
Efficacy 
X 
2.2.3 
Summary of Relapse Rate and Relapse Mortality Rate 
Efficacy 
X 
2.2.4 
Kaplan-Meier Analysis of Failure-Free Survival 
Efficacy 
X 
2.2.5 
Kaplan-Meier Analysis of Overall Survival 
Efficacy 
X 
2.3.5 
Summary of Stages of GVHD by Organ 
Efficacy 
 
2.3.8 
Summary of Body Weight 
Efficacy 
 
2.3.9 
Summary of ECOG Status 
Efficacy 
 
2.3.10 
Summary of Correlative Study Parameters 
Efficacy 
 
3.1.1 
Summary of Ruxolitinib Exposure and Compliance 
Safety 
X 
3.1.2 
Summary of Corticosteroid Exposure 
Safety 
X 
3.2.1 
Overall Summary of Treatment-Emergent Adverse Events  
Safety 
X 
3.2.2 
Summary of Treatment-Emergent Adverse Events by MedDRA 
System Organ Class and Preferred Term  
Safety 
 
3.2.3 
Summary of Treatment-Emergent Adverse Events by MedDRA 
Preferred Term in Decreasing Order of Frequency 
Safety 
X 
3.2.4 
Summary of Treatment-Emergent Adverse Events by MedDRA 
System Organ Class, Preferred Term, and Highest Grade 
Safety 
 


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Table No. 
Title 
Population 
In-Text 
3.2.5 
Summary of Ruxolitinib Treatment-Related, Treatment-Emergent 
Adverse Events by MedDRA System Organ Class and Preferred Term 
Safety 
 
3.2.6 
Summary of Ruxolitinib Treatment-Related, Treatment-Emergent 
Adverse Events by MedDRA Preferred Term in Decreasing Order of 
Frequency 
Safety 
X 
3.2.7 
Summary of Ruxolitinib Treatment-Related, Treatment-Emergent 
Adverse Events by MedDRA System Organ Class, Preferred Term, 
and Highest Grade 
Safety 
 
3.2.8 
Summary of Treatment-Emergent Fatal Adverse Events by MedDRA 
System Organ Class and Preferred Term  
Safety 
X 
3.2.9 
Summary of Treatment-Emergent Serious Adverse Events by 
MedDRA System Organ Class and Preferred Term  
Safety 
X 
3.2.10 
Summary of Ruxolitinib Treatment-Related, Treatment-Emergent 
Serious Adverse Events by MedDRA System Organ Class and 
Preferred Term  
Safety 
 
3.2.11 
Summary of Treatment-Emergent Adverse Events Leading to 
Ruxolitinib Dose Interruption By MedDRA System Organ Class and 
Preferred Term 
Safety 
 
3.2.12 
Summary of Treatment-Emergent Adverse Events Leading to 
Ruxolitinib Dose Reduction By MedDRA System Organ Class and 
Preferred Term 
Safety 
 
3.2.13 
Summary of Treatment-Emergent Adverse Events Leading to 
Discontinuation of Ruxolitinib by MedDRA System Organ Class and 
Preferred Term 
Safety 
X 
3.2.14 
Summary of  Corticosteroids Treatment-Related, Treatment-Emergent 
Adverse Events by MedDRA System Organ Class and Preferred Term 
Safety 
 
3.2.15 
Summary of Corticosteroids Treatment-Related, Treatment-Emergent 
Adverse Events by MedDRA Preferred Term in Decreasing Order of 
Frequency 
Safety 
X 
3.2.16 
Summary of  Corticosteroids Treatment-Related, Treatment-Emergent 
Adverse Events by MedDRA System Organ Class, Preferred Term, 
and Highest Grade 
Safety 
 
3.2.17 
Summary of Corticosteroids Treatment-Related, Treatment-Emergent 
Serious Adverse Events By MedDRA System Organ Class and 
Preferred Term  
Safety 
X 
3.2.18 
Summary of Treatment-Emergent Adverse Events Leading to 
Corticosteroids Dose Interruption by MedDRA System Organ Class 
and Preferred Term 
Safety 
 
3.2.19 
Summary of Treatment-Emergent Adverse Events Leading to 
Corticosteroids Dose Reduction by MedDRA System Organ Class 
and Preferred Term 
Safety 
 
3.2.20 
Summary of Treatment-Emergent Adverse Events Leading to 
Discontinuation of Corticosteroids by MedDRA System Organ Class 
and Preferred Term 
Safety 
X 
3.2.21 
Summary of Treatment-Emergent Adverse Events Leading to 
Withdrawal From the Study By MedDRA System Organ Class and 
Preferred Term  
Safety 
 
3.2.22 
Summary of Treatment-Emergent Grade 3 or Higher Adverse Events 
By MedDRA System Organ Class and Preferred Term 
Safety 
 
3.2.23 
Summary of Treatment-Emergent Adverse Events of Special Interest 
Safety 
X 
3.3.1 
Summary of Laboratory Values – Hematology 
Safety 
 
3.3.2 
Shift Summary of Hematology Values – to the Worst Abnormal 
Value 
Safety 
 


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Table No. 
Title 
Population 
In-Text 
3.3.3 
Shift Summary of Hematology Values in CTC Grade – to the Worst 
Abnormal Value 
Safety 
 
3.3.4 
Summary of Laboratory Values – Chemistry 
Safety 
 
3.3.5 
Shift Summary of Chemistry Values – to the Worst Abnormal Value 
Safety 
 
3.3.6 
Shift Summary of Chemistry Values in CTC Grade – to the Worst 
Abnormal Value 
Safety 
 
3.4.1 
Summary of Systolic Blood Pressure 
Safety 
 
3.4.2 
Summary of Diastolic Blood Pressure 
Safety 
 
3.4.3 
Summary of Pulse 
Safety 
 
3.4.4 
Summary of Body Temperature 
Safety 
 
3.4.5 
Summary of Respiratory Rate 
Safety 
 
Figures 
Figure No. 
Title 
4.2.1 
Kaplan-Meier Estimate of Duration of Response 
4.2.2 
Kaplan-Meier Estimate of Overall Survival 
4.2.3 
Kaplan-Meier Estimate of Failure-Free Survival 
4.2.4 
Body Weight Over Time 
Listings 
Listing No. 
Title 
2.1.1 
Subject Enrollment and Disposition Status 
2.1.2 
Subject Inclusion and Exclusion Criteria 
2.2 
Protocol Deviations/Violations 
2.4.1 
Demographic and Baseline Characteristics 
2.4.2 
Medical History 
2.4.3 
GVHD and Cancer History 
2.4.4 
Prior and Concomitant Drug Treatments 
2.4.5 
Allogeneic Hematopoietic Stem Cell Transplant History 
2.4.6 
Prior Anti-GVHD Medication 
2.4.7 
Prior Radiotherapy 
2.4.8 
Prior Anti-Cancer Therapy 
2.4.9 
Immunosuppressive Medication 
2.5.1 
Ruxolitinib Exposure and Compliance 
2.5.2 
Corticosteroid Exposure 
2.6.1 
GVHD Symptoms and Response Assessment 
2.6.2 
Overall Survival Events and Assessment 
2.6.3 
Failure-Free Survival Events and Assessment 
2.6.4 
ECOG Performance Status 
2.6.5 
Duration of Response 
2.6.6 
Acute GVHD Staging and Grading 
2.7.1 
Adverse Events  
2.7.2 
Serious Adverse Events 
2.7.3 
Grade 3 or 4 Adverse Events 
2.7.4 
Adverse Events Leading to Interruption, Dose Reduction or Discontinuation of Ruxolitinib 
2.7.5 
Adverse Events Leading to Interruption, Dose Reduction or Discontinuation of Corticosteroids 
2.7.6 
Fatal Adverse Events 
2.8.1 
Clinical Laboratory Values – Hematology 
2.8.2 
Clinical Laboratory Values – Chemistry 


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Listing No. 
Title 
2.8.3 
Abnormal Clinical Laboratory Values – Hematology 
2.8.4 
Abnormal Clinical Laboratory Values – Chemistry 
2.8.5 
PK Blood Sampling Times 
2.9.1 
Vital Signs 
2.9.2 
Abnormal Vital Signs 
2.10.1 
12-Lead ECG 


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APPENDIX B. MAGIC GUIDELINES FOR STAGING AND GRADING 
ACUTE GVHD 
Acute GVHD Staging and Grading, MAGIC Guidelines 
Stage 
Skin 
(Active Erythema Only) 
Liver 
(bilirubin) 
Upper GI 
Lower GI 
(stool output/day) 
0 
No active (erythematous) 
GVHD rash 
< 2 mg/dL 
No or intermittent 
nausea, vomiting, or 
anorexia 
Adult:  < 500 mL/day or 
< 3 episodes/day. 
Child:  < 10 mL/kg per day 
or < 4 episodes/day. 
1 
Maculopapular rash 
< 25% BSA 
2-3 mg/dL 
Persistent nausea, 
vomiting, or anorexia 
Adult:  500-999 mL/day or 
3-4 episodes/day. 
Child:  10-19.9 mL/kg per 
day or 4-6 episodes/day. 
2 
Maculopapular rash 
25%-50% BSA 
3.1-6 mg/dL 
– 
Adult:  1000-1500 mL/day or 
5-7 episodes/day. 
Child:  20-30 mL/kg per day 
or 7-10 episodes/day. 
3 
Maculopapular rash 
> 50% BSA 
6.1-15 mg/dL 
– 
Adult:  > 1500 mL/day or 
> 7 episodes/day. 
Child: > 30 mL/kg per day or 
> 10 episodes/day. 
4 
Generalized erythroderma 
(> 50%) with bullae 
> 15 mg/dL 
– 
Severe abdominal pain with 
or without ileus or grossly 
bloody stool (regardless of 
stool volume). 
Overall clinical grade (based on most severe target organ involvement): 
Grade 0:  No stage 1-4 of any organ. 
Grade I:  Stage 1-2 skin without liver, upper GI, or lower GI involvement. 
Grade II:  Stage 3 rash and/or stage 1 liver and/or stage 1 upper GI and/or stage 1 lower GI. 
Grade III:  Stage 2-3 liver and/or stage 2-3 lower GI, with stage 0-3 skin and/or stage 0-1 upper GI. 
Grade IV:  Stage 4 skin, liver, or lower GI involvement, with stage 0-1 upper GI. 


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Response Definitions: 
GVHD response assessments will be made with respect to changes in the organ stage relative to 
Study Day 1. 
• Complete response (CR) is defined as a score of 0 for the GVHD grading in all 
evaluable organs.  For a response to be scored as CR at Day 28 or later, the 
participant must still be in CR on that day and have had no intervening additional 
therapy for an earlier progression, mixed response (MR), or no response (NR). 
• Very good partial response (VGPR) is defined as follows: 
− Skin:  No rash, or residual erythematous rash involving < 25% of the body 
surface, without bullae (residual faint erythema and hyperpigmentation do not 
count). 
− Liver:  Total serum bilirubin concentration < 2 mg/dL or < 25% of baseline at 
enrollment. 
− Gut: 
o Tolerating food or enteral feeding. 
o Predominantly formed stools. 
o No overt gastrointestinal bleeding or abdominal cramping. 
o No more than occasional nausea or vomiting. 
• Partial response (PR) is defined as improvement in 1 stage in 1 or more organs 
involved with GVHD symptoms without progression in others.  For a response to be 
scored as PR at Day 28 or later, the participant must still be in PR on that day and 
have had no intervening additional therapy for an earlier progression, MR, or NR. 
• Mixed response is defined as improvement in 1 or more organs with deterioration in 
another organ manifesting symptoms of GVHD or development of symptoms of 
GVHD in a new organ. 
• Progression of disease is defined as deterioration in at least 1 organ without any 
improvement in others. 
• No response is defined as absence of any improvement or progression as defined.  
Subjects receiving secondary therapy (including need to re-escalate steroid dose to 
greater than the Day 1 dose), will be classified as nonresponders. 
Source:  CIBMTR 2009, Martin et al 2009, Harris et al 2016. 


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APPENDIX C. SCHEDULE OF ASSESSMENTS 
Schedule of Assessments 
Item 
Protocol 
Section 
Screening 
Phase 
Treatment 
Phasea 
EOT 
Follow-Up Phase 
D -28 to -1 
D1 
D3 
D7 
D14 
D21 
D28 
D35 
D42 
D49 
D56b 
D100 
D180 
D365c 
Safetyd 
Survival 
Informed consent 
7.1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Contact IVRS 
7.2 
X 
X 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
X 
 
X 
Demography/disease 
history 
7.3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant 
medications 
7.4 
X 
X 
X 
X 
 
Supportive care 
medications 
5.2.2.4 
X 
X 
X 
X 
 
AE assessment 
7.5.1 
X 
X 
X 
X 
 
Physical examination 
7.5.2 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Vital signs 
7.5.3 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
ECOG performance 
status 
7.5.4 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
12-lead ECG 
7.5.5 
X 
As indicated 
X 
 
 
Acute GVHD grading 
and response 
assessment 
7.6.1 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Chimerism 
assessment 
7.6.3 
X 
As indicated 
 
 
 
PTLD assessment 
7.6.4 
 
As indicated 
 
 
 


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Schedule of Assessments (Continued) 
Item 
Protocol 
Section 
Screening 
Phase 
Treatment 
Phasea 
EOT 
Follow-Up Phase 
D -28 to -1 
D1 
D3 
D7 
D14 
D21 
D28 
D35 
D42 
D49 
D56b 
D100 
D180 
D365c 
Safetyd Survival 
Dispense study drug 
5.1 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
Study drug 
compliance 
5.3 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
 
 
Steroid dose 
monitoring 
5.3 
 
X 
X 
 
 
Survival follow-up 
6.4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xe 
ECG = electrocardiogram; PTLD = post-transplant lymphoproliferative disorder. 
a A ± 2-day window is permitted to facilitate scheduling during the treatment phase. 
b After Day 56, visits will occur every 28 days and will include all Day 56 assessments. 
c The Day 365 visit will also serve as the regularly scheduled visit occurring every 28 days after Day 56 (ie, Day 364). 
d Thirty to 35 days after EOT.  For subjects withdrawing due to reasons other than GVHD progression, GVHD status should be assessed every 28 days. 
e Every 8 weeks ± 7 days. 


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Laboratory Assessments 
Item 
Protocol 
Section 
Screening 
Phase 
Treatment 
Phasea 
EOT 
Safety 
Follow-Up 
D -28 to -1 
D1b 
D3 
D7 
D14 
D21 
D28 
D35 
D42 
D49 
D56c 
D100 
D180 
D365d 
Chemistry panel 
7.5.6.1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Hematology 
7.5.6.2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Hepatitis screening 
7.5.6.4 
X 
 
 
 
Serum pregnancy test 
(childbearing females 
only) 
7.5.6.3 
X 
 
X 
 
Urine pregnancy teste
(childbearing females 
only) 
7.5.6.3 
 
X 
 
 
PK assessmentf 
7.7 
 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Correlative study blood 
collection 
7.8 
X 
X 
 
X 
X 
 
X 
 
 
 
Xg 
X 
X 
X 
X 
 
a A ± 2-day window is permitted to facilitate scheduling during the treatment phase. 
b Day 1 laboratory assessments do not need to be repeated if screening assessments were performed in preceding 7 days. 
c After Day 56, visits will occur every 28 days and will include all Day 56 assessments. 
d The Day 365 visit will also serve as the regularly scheduled visit occurring every 28 days after Day 56 (ie, Day 364). 
e Urine pregnancy tests are only required if medically indicated and should be confirmed with a serum pregnancy test. 
f Samples to be collected at predose and at 1 hour ± 15 minutes, at 2 hours ± 30 minutes, and between 4 and 8 hours postdose. 
g Day 56 only.


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APPENDIX D. PLANNED TABLES AND FIGURES FOR PK ANALYSES 
Tables 
Table No. 
Title 
Table 1 
Randomization of the Study 
Table 2 
Accuracy and Precision of the Plasma Assay Quality Control Samples 
Table 3 
Plasma Sample Collections Times With Deviations 
Table 4 
Summary of INCB018424 Pharmacokinetic Parameters From Observed Concentration Data 
Table 5 
Estimation of INCB018424 Population Pharmacokinetic Model Parameters 
Table 6 
Summary of INCB018424 Pharmacokinetic Parameters From Predicted Concentration Data 
Table 7 
Observed INCB018424 Plasma Concentrations for Individual Subjects 
Table 8 
INCB018424 Pharmacokinetic Parameters for Individual Subjects From Observed 
Concentration Data 
Table 9 
Predicted INCB018424 Plasma Concentrations for Individual Subjects From Final PK Model 
Table 10 
INCB018424 Pharmacokinetic Parameters for Individual Subjects From Predicted 
Concentration Data 
Figures 
Figure No. 
Title 
Figure 1 
INCB 018424 Plasma Concentrations (Mean ± SE) Profile from Observed Concentration Data 
Figure 2 
Basic Goodness of fit diagnostic plots for population PK model 
Figure 3 
Additional Goodness of fit diagnostic plots for population PK model (optional) 
Figure 4 
Visual Predictive Check Plot 
Figure 5 
Individual Plot for Final PK