Clinical trial NCT03144687
Conditions: MPN (Myeloproliferative Neoplasms)
Keywords: Myelofibrosis Janus kinase (JAK) inhibitor itacitinib ruxolitinib
Sponsor: Incyte Corporation
Start date: 2018-01-26; Completion date: 2021-06-01
Enrollment: 23 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of itacitinib combined with low-dose ruxolitinib or itacitinib alone in participants with myelofibrosis (MF).

Detailed description:

Arms: arm 1: Participants with MF who were tolerating a ruxolitinib dose of less than 20 milligrams (mg) daily with no dose increase or no dose modification in the 8 weeks before screening visit received a combination of the itacitinib at the dose of 200 mg, orally, once daily (QD) and ruxolitinib, orally, twice daily (BID) at their previous stable dose (must had been \< 20 mg daily). Participants continued study treatment until disease progression, unacceptable toxicity, withdrawal of consent, or other Protocol-specified criteria to stop treatment are met. arm 2: Participants with MF who progressed after initial reduction in spleen with ruxolitinib treatment, progressed or discontinued for hematologic toxicities received treatment with itacitinib alone at the dose of 600 mg QD. Participants continued study treatment until disease progression, unacceptable toxicity, withdrawal of consent, or other Protocol-specified criteria to stop treatment are met.
Interventions: intervention 1: Itacitinib intervention 2: Ruxolitinib
Intervention descriptions: intervention 1: Itacitinib self-administered orally once daily . intervention 2: Ruxolitinib self-administered orally at the stable dose of \< 20 mg daily established before entering the study.

Protocol documents:
Prot_000.pdf: 
 
Offici al Titl e:  
A n O p e n -L a b el P h as e 2 St u d y of It aciti ni b (I N C B 0 3 9 1 1 0) i n C o m bi n ati o n 
Wit h  L o w -D os e  R u x oliti ni b  or  It aciti ni b  Al o n e  F oll o wi n g  R u x oliti ni b  i n  
S u bj ects Wit h M y el ofi br osis  
N C T N u m b er:  
N C T 0 3 1 4 4 6 8 7  
 
D oc u m e nt  D at e : 
 
Cli nic al St u dy Pr ot oc ol : 1 4  A u g ust 2 0 1 7  
 
 
 
 
 
 
 
 


I nc yte C or p orati o n 
P a ge 1 of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4  A U G 2 0 1 7  
C O N FI D E N TI A L  
 
Cli nic al St u d y Pr ot oc ol 
 
I N C B 3 9 1 1 0 -2 0 9  
A n O pe n - L a bel P h ase 2 St u d y of It aciti ni b (I N CB 0 3 9 1 1 0 ) i n 
C o m bi n ati o n Wit h L o w -D ose R u x oliti ni b or It aciti ni b Al o ne 
F oll o wi n g R u x oliti ni b i n S u bje cts Wit h M yel ofi b r osis  
 
 
 
 
 
P r o d uct:  
It aciti ni b (I N C B 03 9 1 1 0) 
I N D N um ber:  
 
P h ase of S t u d y: 
2 
S p o ns or:  
I nc yte C or p or ati o n 
1 8 0 1 A u g usti ne C ut - Off 
Wil mi n gt o n, D E 1 9 8 0 3 
D ate of P r ot oc ol:  
2 2 M A R 2 0 1 7 
D ate of A me n de me nt  1:  
1 4 A U G 2 0 1 7 
 
 
 
T his  st u d y will be perf or me d i n acc or da nce wit h et hical pri nci ples t hat ha ve t heir ori gi n i n t he Declarati o n of 
Helsi n ki a n d c o n d ucte d i n a d here nce t o t he st u d y Pr ot oc ol , G o o d Cli nical Practices  as defi ne d i n Title 2 1 of t he 
U S  C o de of Fe deral Re g ulati o ns P arts 1 1, 5 0, 5 4 , 5 6, a n d 3 1 2 , as well as I C H G C P c o ns oli date d g ui deli nes ( E 6) a n d 
a p plica ble re g ulat or y re q uire me nts. 
 
T he i nf or mati o n i n t his d oc u me nt is  c o nfi de ntial.  N o part of t his i nf or mati o n ma y be d u plicate d, refere nce d, or 
tra ns mitte d i n a n y f or m or b y a n y mea ns (electr o nic, mec ha nical, p h ot oc o p y, rec or di n g, or ot her wise) wi t h o ut t he pri or 
writte n c o nse nt of I nc yte C or p orati o n.  


I nc yte C or p orati o n 
P a ge 2 of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4  A U G 2 0 1 7  
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 ve r ea d t he I N C B 3 9 1 1 0- 2 0 9 Pr ot oc ol A me n d me nt 1 ( date d 1 4 A U G  2 0 1 7) a n d a gree t o 
c o n d uct t he st u d y as o utli ne d.  I a gr ee t o mai ntai n t he c o nfi de ntialit y of all i nf or mati o n recei ve d 
or de vel o pe d i n c o n n ecti o n wit h t his Pr ot oc ol. 
 
 
 
 
 
( Pri nte d Na me of I n vesti gat or) 
 
 
 
 
 
 
 
 
( Si g nat ur e of I n v esti gat or) 
 
( Date) 


I nc yte C or p orati o n 
P a ge 3 of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4  A U G 2 0 1 7  
C O N FI D E N TI A L  
S Y N O P SI S  
N a me of I n vesti g ati o n al Pr o d uct:   Itaciti ni b (I N C B 0 3 9 1 1 0) 
Title of St u d y:   A n O pe n -La bel  P hase 2 St u d y of Itaciti ni b (I N CB 0 3 9 1 1 0) i n C o m bi nati o n Wit h 
L o w - D ose R u x oliti ni b or Itaciti ni b Al o ne F oll o wi n g R u x oliti ni b i n S u bjects Wit h M yel ofi br osis  
P r ot oc ol N u m ber:   I N CB 3 9 1 1 0 - 2 0 9 
St u d y P h ase:   2 
I n dic ati o n:  Pri mar y a n d sec o n dar y m yel ofi br osis ( M F) 
 
Pri m ar y O bjecti ve  
Pri m ar y E n d p oi nt  
T o e val uate preli mi nar y effica c y of itaciti ni b 
(I N C B 0 3 9 1 1 0) o n s plee n v ol u me re d ucti o n ( S V R) 
fr o m baseli ne at W ee k 2 4 i n t he 2 f oll o wi n g c o h orts 
of M F  s u bj ects: 
•  C o h ort A :  i n c o m bi nati o n i n s u bj ects wit h 
r u x oliti ni b l o w d ose (less t ha n 2 0 m g dail y). 
•  C o h ort B :  as m o n ot hera p y i n s u bj ects w h o 
pr o gresse d ( per re vise d E ur o pea n Le u ke mia Net 
[E L N ] 2 0 1 3 res p o nse criteria f or M F) after i nitial 
re d ucti o n i n s plee n o n r u x oliti ni b or disc o nti n ue d 
f or he mat ol o gic t o xicities. 
C ha n ge a n d p erce ntage c ha n ge  i n S V R as meas ure d b y 
ma g netic res o na nce i ma gi n g [ M RI] (c o m p ute d 
t o m o gra p h y [ C T] sca n i n s u bj ects w h o are n ot ca n di dates 
f or M RI or w he n M RI is n ot r ea dil y a vaila ble) at 
W ee k 2 4 w he n c o m pare d wit h  baseli ne.  
Sec o n d ar y O bjecti ve s ( C o h orts A a n d B) 
Sec o n d ar y E n d p oi nt s 
T o e val uate preli mi nar y safet y a n d t olera bilit y of 
itaciti ni b al o ne. 
Safet y a n d t olera bilit y t hr o u g h assess me nt of fre q ue nc y, 
se verit y, a n d d urati o n of a d verse e ve nts ( A Es ); c ha n ges 
i n cli nical safet y assess me nts; a n d c ha n ges i n cli nical 
la b orat or y para meters. 
T o e val uate preli mi nar y safet y a n d t olera bilit y of 
itaciti ni b i n c o m bi nati o n wit h r u x oliti ni b. 
T o e val uate preli mi nar y effica c y of itaciti ni b al o ne or 
i n c o m bi nati o n wit h r u x oliti ni b o n S V R  fr o m 
baseli ne at W ee k 1 2.  
C ha n ge a n d  perce nta ge i n S V R fr o m baseli ne t hr o u g h 
W ee k 1 2 as meas ure d b y M RI ( or C T sca n i n a p plica ble 
s u bj ects). 
T o e val uate preli mi nar y effica c y of itaciti ni b al o ne or 
i n c o m bi nati o n wit h r u x oliti ni b o n s plee n le n gt h 
re d ucti o n fr o m baseli ne at W e e k 1 2 a n d W ee k 24.  
C ha n ge  a n d perce nta ge c ha n ge o n s plee n le n gt h 
re d ucti o n fr o m baseli ne t hr o u g h W ee k 1 2 a n d W ee k 2 4 
as meas ure d b y pal pati o n.  
T o e val uate preli mi nar y effica c y of itaciti ni b al o ne or 
i n c o m bi nati o n wit h r u x oliti ni b wit h res pect t o M F 
s y m pt o ms at W ee k 1 2 an d W ee k 2 4.  
C ha n ge a n d perce nta ge c ha n ge i n T otal S y m pt o m Sc ore 
(T S S ) fr o m baseli ne t hr o u g h W ee k 1 2 a n d W ee k 2 4 as 
meas ure d b y t he M yel ofi br osis S y m pt o m Assess me nt 
F or m versi o n 2. 0 ( M F S A F v 2. 0) s y m pt o m diar y a n d b y 
t he M yel o pr oliferati ve Ne o plas ms S y m pt o m Assess me nt 
F or m ( M P N -S A F).  
P atie nt Gl o bal I m pressi o n of C ha n ge sc ore at eac h visit 
w here t he varia ble is meas ure d.  
T o e val uate preli mi nar y effica c y of itaciti ni b usi n g 
I nter nati o nal W or ki n g Gr o u p-M yel o pr oliferati ve 
Ne o plas ms Researc h a n d Treat me nt (I W G-M R T)  
criteria.  
N u m ber of s u bj ects wit h res p o nses acc or di n g t o t he 2 0 1 3 
I W G-M R T c o nse ns us c riteria f or treat me nt res p o nse. 
 


I nc yte C or p orati o n 
P a ge 4 of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4  A U G 2 0 1 7  
C O N FI D E N TI A L  
 
Sec o n d ar y O bjecti ve s ( C o h orts A a n d B) ( C o nt' d) 
Sec o n d ar y E n d p oi nts ( C o nt' d)  
T o assess t he p har mac o ki netics ( P K) of itaciti ni b a n d  
r u x oliti ni b. 
Calc ulati o n of t he P K para met ers s uc h as A U C, C L/ F, 
C ma x , a n d tma x  al o n g wit h s u m marizati o n of t he o bser ve d 
c o nce ntrati o n data b y ti me p oi nt will be perf or me d f or 
b ot h r u x oliti ni b a n d itaciti ni b. 
 
O ver all S t u d y Desi g n: 
T his is a n o pe n-la bel P hase 2 st u d y wit h 2 c o h orts: 
•  C o h ort A :  M F  s u bjects w h o are t olerati n g a r u x oliti ni b d ose of less t ha n 2 0 m g dail y will recei ve a  
c o m bi nati o n of t he J A K 1 i n hi bit or itaciti ni b at t he d ose of 2 0 0 m g o nce dail y ( Q D ) a n d t he J A K 1/ 2 
i n hi bit or r u x oliti ni b. 
•  C o h ort B :  M F  s u bjects w h o pr o gresse d after i nitial re d ucti o n i n s plee n wit h  r u x oliti ni b treat me nt or 
disc o nti n ue d f or he mat ol o gic t o x icities will recei ve treat me nt wit h J A K 1 i n hi bit or itaciti ni b  al o ne at t he 
d ose of 6 0 0 m g Q D.  
S u bj ects will c o nti n ue st u d y treat me nt u ntil disease pr o gressi o n, u nacce pta ble t o xicit y, wit h dra wal of 
c o nse nt, or ot her Pr ot oc ol -s pecifie d criteria t o st o p treatme nt are met.  S u bj ects w h o are recei vi n g be nefit 
will c o nti n ue recei vi n g st u d y treat me nt u ntil wit h dra wal criteria are met . 
All s u bj ects will be f oll o we d f or safet y (e g, re p orti n g of A Es a n d seri o us A Es) 3 0 t o 3 5 da ys after last 
d ose of st u d y treat me nt. 
St u d y P o p ul ati o n:   
Male or fe male s u bjects a ge d 1 8 years or ol der w h o ha ve bee n dia g n ose d wit h M F (eit her pri mar y 
m yel ofi br osis [ P M F ] or sec o n dar y M F [ p ost –p ol yc yt he mia vera m yel ofi br osis { P P V -M F } or p ost –
esse ntial t hr o m b oc yt he mia m yel ofi br osis { P E T -M F }] ) a n d w h o ca n t olerate o nl y less t ha n 2 0 m g dail y 
d ose of r u x oliti ni b or s u bjects w h o eit her disc o nti n ue d f or he mat ol o gical t o xicities or pr o gresse d o n 
r u x oliti ni b after i nitial re d ucti o n i n s plee n. 


I nc yte C or p orati o n 
P a ge 5 of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4  A U G 2 0 1 7  
C O N FI D E N TI A L  
Ke y I ncl usi o n Criteri a: 
C o h ort A o nl y 
•  Recei vi n g r u x oliti nib d ose of less t ha n 2 0  m g dail y wit h n o d ose i ncrease or n o d ose m o dificati o n i n t he 
last 8 wee ks bef ore scree ni n g visit. 
C o h ort B o nl y  
•  M ust ha ve ha d i nitial re d ucti o n i n s plee n o n r u x oliti ni b treat me nt ( res p o nse is defi ne d b y a n y s plee n 
le n gt h or v ol u me re d ucti o n, b y pal pati o n or M RI/ C T assess me nt, fr o m baseli ne w hile o n pre vi o us 
r u x oliti ni b treat me nt per I W G-M R T E L N 2 0 1 3 g ui deli nes): 
-  F oll o we d b y d oc u me nte d e vi de nce of pr o gressi o n i n s plee n le n gt h or v ol u me O R  
-  Disc o nti n ue d r u x oliti ni b f or he mat ol o gic t o xic ities, after t he i nitial re d ucti o n i n s plee n le n gt h or 
v ol u me. 
All s u bj ects  
•  Me n a n d w o me n, a ge d 1 8 years or ol der. 
•  C o nfir me d dia g n osis of P M F, P P V -M F, or P E T -M F  acc or di n g t o re vise d W H O 2 0 1 6 criteria . 
•  M ust ha ve pal pa ble s plee n of ≥ 5 c m bel o w t he left s u bc ostal mar gi n o n p h ysical e xa mi nati o n at t he 
scree ni n g visit.  (If s plee n is n ot pal pa ble d ue t o b o d y ha bit us, s plee n e nlar ge me nt m ust be d oc u me nte d 
b y ot her mea ns [ e g, ultras o u n d or M RI ] a n d st u d y s p o ns or me dical m o nit or be c o ntacte d f or 
acce pta nce). 
•  E C O G perf or ma nce stat us of 0, 1, or 2.  
•  Scree ni n g b o ne marr o w bi o ps y s peci me n a vaila ble or willi n g ness t o u n der g o a b o ne marr o w bi o ps y at 
scree ni n g/ baseli ne; willi n g ness t o u n der g o b o ne marr o w bi o ps y at Wee k 2 4. 
•  Life e x pecta nc y of at least 2 4 wee ks.  
•  Willi n g ness t o a v oi d pre g na nc y or fat heri n g c hil dre n base d o n t he f oll o wi n g criteria : 
-  W o ma n of n o nc hil d beari n g p ote ntial (ie, s ur gicall y sterile wit h a h ysterect o m y a n d/ or bilateral 
o o p h orect o m y O R ≥ 1 2 m o nt hs of a me n orr hea a n d at least 5 0 years of a ge). 
-  W o ma n of c hil d beari n g p ote ntial w h o has a ne gati ve ser u m pre g na nc y test at scree ni n g a n d ne gati ve 
uri nar y test bef ore t he first d ose o n Da y 1 a n d w h o a grees t o ta ke a p pr o priate preca uti o ns t o a v oi d 
pre g na nc y ( wit h at least 9 9 % certai nt y) fr o m scree ni n g t hr o u g h safet y f oll o w - u p.  Per mitte d met h o ds 
t hat are at least 9 9 % effecti ve i n pre ve nti n g pre g na nc y s h o ul d be c o m m u nicate d t o t he s u bject a n d 
t heir u n dersta n di n g c o nfir me d. 
-  Ma n w h o a grees t o ta ke a p pr o priate preca uti o ns t o a v oi d fat heri n g c hil dre n ( wit h at least 9 9 % 
certai nt y) fr o m scree ni n g t hr o u g h safet y f oll o w- u p.  Per mitte d met h o ds t hat are at least 9 9 % effecti ve 
i n pre ve nti n g pre g na nc y s h o ul d be c o m m u nicate d t o t he s u bject a n d t heir u n dersta n di n g c o nfir me d. 
Ke y E xcl usi o n Criteri a:  
All s u bj ects  
•  L ac k of rec o ver y fr o m a ll t o xicities fr o m pre vi o us t hera p y (e xce pt r u x oliti ni b) t o Gra de 1 or better. 
•  Pre vi o us treat me nt wit h itaciti ni b or J A K 1 i n hi bit ors (J A K 1/J A K 2 i n hi bit or r u x oliti ni b is per mitte d). 
•  I na bilit y t o s wall o w f o o d or a n y c o n diti o n of t he u p per gastr oi ntesti nal tract t hat precl u des 
a d mi nistrati o n of oral me dicati o ns. 
•  U n willi n g ness t o be tra nsf use d wit h bl o o d c o m p o ne nts. 
•  Rece nt hist or y of i na de q uate b o ne marr o w reser ve as de m o nstrate d b y t he f oll o wi n g:  
-  Platelet c o u nt < 5 0 × 1 0 9/ L i n t he 4 wee ks bef ore scree ni n g or platelet tra nsf usi o n wit hi n 8 wee ks 
bef ore scree ni n g.  
-  A bs ol ute ne utr o p hil c o u nt le vels < 0. 5 × 1 0 9/ L i n t he 4 wee ks bef ore scree ni n g. 
-  Peri p heral bl o o d blast c o u nt of > 1 0 % at t he scree ni n g or baseli ne he mat ol o g y assess me nts.  


I nc yte C or p orati o n 
P a ge 6 of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4  A U G 2 0 1 7  
C O N FI D E N TI A L  
•  I na de q uate li ver f u ncti o n at scree ni n g a n d baseli ne visits as  de m o nstrate d b y t he f oll o wi n g:  
-  Direct bilir u bi n ≥ 2. 0 × t he u p per li mit of la b orat or y n or mal ( U L N).  ( N O T E:  direct bilir u bi n ma y be 
ass u me d t o be wit hi n li mits if t otal bilir u bi n is ≤ 2. 0 × U L N).  
-  Ala ni ne a mi n otra nsferase  or as partate a mi n otra nsferase > 2. 5 × U L N. 
•  I na de q uate re nal f u ncti o n at scree ni n g a n d baseli ne visits as de m o nstrate d b y creati ni ne cleara nce 
< 4 0 m L/ mi n meas ure d or calc ulate d b y C oc kr oft - Ga ult e q uati o n, or gl o mer ular filtrati o n rate 
< 4 0 m L/ mi n/ 1. 7 3 m 2 as calc ulate d usi n g t he M o dificati o n of Diet i n Re nal Disease f or m ula. 
•  Acti ve bacterial, f u n gal, parasitic, or viral i nfecti o n t hat re q uires t hera p y.  S u bjects wit h ac ute 
i nfecti o ns re q uiri n g treat me nt s h o ul d dela y scree ni n g/e nr oll me nt u ntil t he c o urse of t hera p y has bee n 
c o m plete d a n d t he e ve nt is c o nsi dere d res ol ve d.  Pr o p h ylactic a nti bi otics will be per mitte d.  
•  E vi de nce of he patitis B vir us ( H B V) or he patitis C vir us ( H C V) i nfecti o n or ris k of reacti vati o n:  H B V 
D N A a n d H C V R N A m ust be u n detecta ble.  S u bjects ca n n ot be p ositi ve f or he patitis B s urface a nti ge n 
or a nti – he patitis B c ore a nti b o dies.  S u bjects w h o ha ve p ositi ve a nti- H Bs as t he o nl y e vi de nce of pri or 
e x p os ure ma y partici pate i n t he st u d y pr o vi de d t hat t here is b ot h 1) n o k n o w n hist or y of H B V i nfecti o n 
a n d 2) verifie d recei pt of he patitis B vacci ne.  
•  K n o w n h u ma n i m m u n o deficie nc y vir us i nfecti o n. 
•  Cli nicall y si g nifica nt or u nc o ntr olle d car diac disease , i ncl u di n g u nsta ble a n gi na; ac ute m y ocar dial 
i nfarcti o n wit hi n 6 m o nt hs of Da y 1 of st u d y dr u g a d mi nistrati o n; Ne w Y or k Heart Ass ociati o n 
Class  III or I V c o n gesti ve heart fail ure; a n d arr h yt h mia re q uiri n g t hera p y u nless a p pr o ve d b y me dical 
m o nit or/s p o ns or. 
•  Acti ve i n vasi ve mali g na nc y o ver t he pre vi o us 2 years e xce pt treate d basal or s q ua m o us carci n o mas of 
t he s ki n, c o m pletel y resecte d i ntrae pit helial carci n o ma of t he cer vi x, a n d c o m pletel y resecte d pa pillar y 
t h yr oi d a n d f ollic ular t h yr oi d ca ncers.  S u bjects wit h mali g na ncies wit h i n d ole nt be ha vi or s uc h as 
pr ostate ca ncer treate d wit h ra diati o n or s ur ger y ma y be  e nr olle d as l o n g as t he y ha ve a reas o na ble 
e x pectati o n t o ha ve bee n c ure d wit h t he treat me nt m o dalit y recei ve d.  
•  S ple nic irra diati o n wit hi n 6 m o nt hs bef ore recei vi n g t he first d ose of itaciti ni b . 
•  Use of a n y pr o hi bite d c o nc o mita nt me dicati o ns. 
•  Acti ve alc o h o l or dr u g a d dicti o n t hat w o ul d i nterfere wit h t heir a bilit y t o c o m pl y wit h t he st u d y 
re q uire me nts. 
•  Use of a n y p ote nt/str o n g c yt oc hr o me P 4 5 0 3 A 4 i n hi bit ors wit hi n 1 4 da ys or 5 half- li ves ( w hic he ver is 
l o n ger) bef ore t he first d ose of itaciti ni b or a ntici pat e d d uri n g t he st u d y. 
•  Use of c o nc o mita nt treat me nt of fl uc o naz ole at a d ose >  2 0 0 m g (f or r u x oliti ni b s u bj ects treate d i n 
C o h ort A o nl y) . 
•  I na de q uate rec o ver y fr o m t o xicit y a n d/ or c o m plicati o ns fr o m a maj or s ur ger y bef ore starti n g t hera p y. 
•  C urre ntl y breastfe e di n g or pre g na nt. 
•  I na bilit y t o c o m pre he n d or u n willi n g t o si g n t he i nf or me d c o nse nt f or m. 
•  A n y c o n diti o n t hat w o ul d, i n t he i n vesti gat or's j u d g me nt, i nterfere wit h f ull partici pati o n i n t he st u d y, 
i ncl u di n g a d mi nistrati o n of st u d y dr u g a n d atte n di n g re q uire d st u d y visits; p ose a si g nifica nt ris k t o t he 
s u bj ect; or i nterfere wit h i nter pretati o n of st u d y data. 
It aciti ni b/ St u d y Dr u g, D os a ge, a n d M o de of A d mi nistr ati o n:  
Itaciti ni b is f or m ulate d as 1 0 0 m g s ustai ne d-release ta blet.  Itaciti ni b will be a d mi niste re d orall y Q D  i n 
t he m or ni n g o n a n o ut patie nt basis as f oll o ws: 
•  C o h ort A o nl y :  2 0 0 m g Q D, wit h o ut re gar d t o f o o d, f or t he c o m bi nati o n treat me nt wit h r u x oliti ni b.  
•  C o h ort B o nl y :  6 0 0 m g Q D, wit h o ut re gar d t o f o o d, f or t he m o n ot hera p y treat me nt. 


I nc yte C or p orati o n 
P a ge 7 of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4  A U G 2 0 1 7  
C O N FI D E N TI A L  
Ref ere nce  T her a p y, D os a ge , a n d M o de of A d mi nistr ati o n:   
•  C o h ort A o nl y :  R u x oliti ni b will be a d mi nistere d orall y, t wice dail y  ( BI D), a p pr o xi matel y 1 2 h o urs 
a part usi n g t he sta ble d ose of less t ha n 2 0 m g dail y esta blis he d bef ore e nteri n g t he st u d y. 
•  C o h ort B o nl y :  N o t a p plica ble. 
St u d y Sc he d ule/ P r oce d ures:  
S u bj ects will ha ve a re g ularl y sc he d ule d st u d y visit at scree ni n g, baseli ne, Da y 1, Wee k 2, Wee k 4, 
Wee k  8, Wee k 1 2, Wee k 1 6, Wee k 2 0, a n d Wee k 2 4 a n d e ver y 1 2 wee ks t hereafter if c o nti n ui n g o n 
treat me nt, w here assess me nts, i ncl u di n g bl o o d sa m ples a n d s plee n meas ure me nts, will be o btai ne d.  All 
la b orat or y para meters (ser ol o g y, li pi d pr ofile, uri nal ysis, bl o o d c he mistr y, he mat ol o g y, a n d c oa g ulati o n) 
will be assesse d usi n g l ocal la b orat ories.  Bl o o d 
 P K sa m ples will be c ollecte d a n d 
a nal yze d b y t he s p o ns or or s p o ns or' s desi g nee.  
A d diti o nal la b orat or y assess me nts ma y be perf or me d at i n vesti gat or 's discreti o n, i ncl u di n g f oll o wi n g 
c ha n ges i n d ose, or if la b orat or y para meters are at Gra de 3 or Gra de 4 le vels base d o n t he C T C A E v 4. 0 3.  
S u bj ects will ha ve a n M RI of t he u p per a n d l o wer a b d o me n a n d pel vis t o deter mi ne t he s plee n v ol u me at 
baseli ne, at Wee k 1 2 a n d Wee k 2 4, a n d e ver y 1 2 wee ks t hereafter.   C o m p ute d t o m o gra p h y sca n will be 
s u bstit ute d f or s u bj ects w h o are n ot ca n di dates f or M RI or w he n M RI is n ot rea dil y a vaila ble.  Patie nt 
Gl o bal I m pressi o n of C ha n ge q uesti o n naire will be c o m plete d at eac h st u d y visit fr o m Wee k 4.  
Deter mi nati o n of s plee n le n gt h bel o w t he left c ostal mar gi n will be meas ure d b y p al pati o n at eac h st u d y 
visit usi n g a fle xi ble r uler.  
S u bj ects will c o m plete a n electr o nic s y m pt o m diar y ( M F S A F v 2. 0) dail y fr o m baseli ne t hr o u g h t he 
Wee k  2 4 visit (t otal of 2 5 wee ks).  
S u bj ects will c o m plete t he M P N -S A F at baseli ne; at Wee ks 1 2 a n d 2 4; a n d e ver y 1 2 wee ks t hereafter.  
Esti m ate d D ur ati o n of P artici p ati o n:  
Scree ni n g :  U p t o 2 1 da ys.  
B aseli ne :  7 da ys bef ore first d ose of itaciti ni b.  
Tre at me nt :  Be gi ns wit h t he first d ose of itaciti ni b ( Da y 1).  Treat me nt will c o nti n ue as l o n g as t he 
re gi me n is t olerate d a n d t he s u bject d oes n ot meet disc o nti n uati o n criteria.  
S af et y f oll o w -u p :  3 0 da ys t o 3 5 da ys after t he last d ose of me dicati o n is ta ke n.  
It is esti mate d t hat a n i n di vi d ual s u bject will partici pate f or a p pr o xi matel y 3 2 wee ks . 
Esti m ate d  N u m ber of S u bjects:   
A p pr o xi matel y 2 1 s u bjects will be i ncl u de d i n eac h d ose c o h ort f or a t otal of 4 2 s u bj ects.  A p pr o xi matel y 
2 0 cli nical sites will be use d.  
P ri nci p al C o or di n ati n g I n vesti g at or:   T B D  
St atistic al Met h o ds:  
T he pri mar y e n d p oi nt of c ha n ge a n d perce nta ge c ha n ge of S V R  (as meas ure d b y M RI or C T ) fr o m 
baseli ne at Wee k 2 4  will be s u m marize d b y c o h ort.  Wit hi n eac h c o h ort, t he si g n test will be use d t o 
e val uate me dia n perce nta ge of S V R a n d a 9 0 % c o nfi de nce i nter val f or t he me dia n perce nta ge S V R will  
be calc ulate d usi n g t he e xact bi n o mi al c o nfi de nce i nter val met h o d .  If t he perce nta ge of S V R at Wee k 2 4  
is n or mall y distri b ute d wit h mea n 1 1. 4 a n d sta n dar d de viati o n 1 4. 5, t he test has 8 5 % p o wer t o i n dicate 
a d diti o nal de vel o p me nt is warra nte d wit h a sa m ple size of 2 1 s u bjects per c o h ort.  T he perce nta ge of  S V R  
will be s u m marize d descri pti vel y at Wee k 1 2 b y c o h ort. 
Safet y data, i ncl u di n g la b orat or y val ues, A E s, a n d vital si g ns, will be s u m marize d. A d verse e ve nts  of 
s pecial i nterest i ncl u de Gra de 4 t hr o m b oc yt o pe nia, Gra de 2 or hi g her a ne mia, a n d Gra de 2 or hi g her 
he m orr ha gic e ve n ts, as meas ure d b y C T C A E v 4. 0 3. 
Sec o n dar y efficac y e n d p oi nts f or perce nt a ge c ha n ge fr o m baseli ne i n 7 - da y M F S A F T S S a n d M P N -S A F 
T S S will be s u m marize d at Wee k 1 2 a n d Wee k 2 4 b y c o h ort , a n d 9 0 % c o nfi de nce i nter vals f or t he 




I nc yte C or p orati o n 
P a ge 9 of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4  A U G 2 0 1 7  
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 6  
1.  
I N T R O D U C TI O N ...................................................................................................... 1 9 
1. 1.  
Bac k gr o u n d a n d O v er vie w o n M yel ofi br osis ............................................................. 1 9  
1. 2.  
R ole of J A K Pat h wa y i n M yel ofi br osis ...................................................................... 2 0  
1. 3.  
Pr o d uct I nf or mati o n a n d O ver vie w of Itaciti ni b  ........................................................ 2 1 
1. 3. 1.  
P har mac ol o g y  ............................................................................................................. 2 1 
1. 3. 2.  
N o ncli nical Dr u g Met a b olis m a n d P har mac o ki netics  ................................................ 2 2 
1. 3. 3.  
Itaciti ni b Cli nical Safet y S u m mar y ............................................................................ 2 2 
1. 3. 3. 1.  
Cli nical St u dies i n Patie nts  ......................................................................................... 2 2 
1. 3. 4.  
R u x oliti ni b Cli nical Safet y S u m mar y  ......................................................................... 2 3 
1. 3. 4. 1.  
Cli nical Safet y D ata  .................................................................................................... 2 3 
1. 3. 4. 2.  
R u x oliti ni b I n dicati o ns ............................................................................................... 2 4  
1. 4.  
St u d y R ati o nale  ........................................................................................................... 2 4 
1. 5.  
P ote ntial Ris ks a n d Be nefits of t he Treat me nt Re gi me n  ............................................ 2 5 
1. 5. 1.  
Ris ks Relate d t o Itaciti ni b  ........................................................................................... 2 5 
1. 5. 2.  
Ris ks Relate d t o R u x oliti ni b  ....................................................................................... 2 6 
1. 5. 3.  
Ris ks f or t he C o m bi nati o n of It aciti ni b a n d R u x oliti ni b ............................................ 2 6 
1. 5. 4.  
P ote ntial Be nefits of It aciti ni b a n d R u x oliti ni b  .......................................................... 2 6 
1. 5. 4. 1.  
Itaciti ni b P ote ntial Be nefits ........................................................................................ 2 6 
1. 5. 4. 2.  
R u x oliti ni b P ote ntial Be nefit  ...................................................................................... 2 6 
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 7 
3.  
S U BJ E C T E LI GI BI LI T Y  ........................................................................................... 2 8 
3. 1.  
S u bject I n cl usi o n Criteria  ........................................................................................... 2 8 
3. 2.  
S u bject E x cl usi o n Criteria  .......................................................................................... 2 9 
3. 3.  
S u bjects W h o Fail t o Meet Scree ni n g Criteri a  ........................................................... 3 1 
4.  
I N V E S TI G A TI O N A L P L A N ..................................................................................... 3 2 
4. 1.  
O verall St u d y Desi g n  .................................................................................................. 3 2 
4. 2.  
Meas ures T a ke n t o A v oi d Bias ................................................................................... 3 3  
4. 3.  
N u m ber of S u bjects .................................................................................................... 3 3  
4. 4.  
D urati o n of Tr eat me nt a n d S u bject Partici pati o n  ....................................................... 3 3 


I nc yte C or p orati o n 
P a ge 1 0  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4  A U G 2 0 1 7  
C O N FI D E N TI A L  
4. 5.  
O verall St u d y D urati o n  ............................................................................................... 3 3 
4. 6.  
St u d y Ter mi nati o n  ...................................................................................................... 3 3 
5.  
T R E A T M E N T  ............................................................................................................ 3 4 
5. 1.  
Treat me nt Assi g n me nt  ................................................................................................ 3 4 
5. 1. 1.  
S u bject N u m beri n g a n d Treat me nt Assi g n me nt ......................................................... 3 4  
5. 1. 2.  
Ra n d o mizati o n a n d Bli n di n g ...................................................................................... 3 4  
5. 2.  
St u d y Dr u g  .................................................................................................................. 3 4 
5. 2. 1.  
Itaciti ni b ...................................................................................................................... 3 4 
5. 2. 1. 1.  
Descri pti o n a n d A d mi nistrati o n  .................................................................................. 3 4 
5. 2. 1. 2.  
S u p pl y, Pac ka gi n g, a n d La b eli n g ............................................................................... 3 5  
5. 2. 2.  
R u x oliti ni b  .................................................................................................................. 3 5 
5. 2. 2. 1.  
Descri pti o n a n d A d mi nistra ti o n .................................................................................. 3 5 
5. 2. 2. 2.  
S u p pl y, Pac ka gi n g, a n d La b elli n g .............................................................................. 3 5  
5. 2. 3.  
St ora ge  ........................................................................................................................ 3 5 
5. 3.  
Treat me nt C o m plia nce  ................................................................................................ 3 6 
5. 4.  
Treat me nt M o dificati o ns:  I ncreases, Decreases, a n d I nterr u pti o ns ........................... 3 6  
5. 4. 1.  
D ose I ncreas es f or I n a de q uate Efficac y  ..................................................................... 3 6 
5. 4. 2.  
D ose M o dificati o n f or T o xici t y .................................................................................. 3 6 
5. 4. 2. 1.  
La b orat or y Fi n di n gs T h at Re q uire D ose M o dificati o n .............................................. 3 6  
5. 4. 2. 2.  
Per mitte d D ose Le vels  ................................................................................................ 3 7 
5. 4. 2. 3.  
D ose A dj ust me nt G ui deli nes a n d Ma na gi n g T o xicit y ................................................ 3 7  
5. 4. 2. 4.  
G ui deli nes f or D ose R estart or Re- escalati o n  ............................................................. 3 9 
5. 4. 3.  
I nterr u pti o n of R u x oliti ni b ( C o h ort A O nl y) .............................................................. 3 9 
5. 5.  
Wit h dra wal of S u bjects Fr o m St u d y Treat me nt  ......................................................... 3 9 
5. 5. 1.  
Wit h dra wal Criteria  .................................................................................................... 3 9 
5. 5. 2.  
Wit h dra wal Pr oce d ures  ............................................................................................... 4 0 
5. 6.  
C o nc o mita nt Me dicati o ns ........................................................................................... 4 1  
5. 6. 1.  
Per mitte d Me dicati o ns  ................................................................................................ 4 1 
5. 6. 2.  
Restricte d Me dicati o ns  ............................................................................................... 4 1 
5. 6. 3.  
Pr o hi bite d Me dicati o ns ............................................................................................... 4 2  
6.  
S T U D Y A S S E S S M E N T S  .......................................................................................... 4 2 
6. 1.  
Scree ni n g  .................................................................................................................... 4 8 
6. 2.  
Baseli ne  ....................................................................................................................... 4 9 


I nc yte C or p orati o n 
P a ge 1 1  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4  A U G 2 0 1 7  
C O N FI D E N TI A L  
6. 3.  
Treat me nt  .................................................................................................................... 5 0 
6. 4.  
E n d of Treat me nt ........................................................................................................ 5 0  
6. 5.  
F oll o w- U p  ................................................................................................................... 5 1 
6. 5. 1.  
Safet y F oll o w -U p  ........................................................................................................ 5 1 
6. 6.  
E n d of St u d y ............................................................................................................... 5 1  
6. 7.  
U nsc he d ule d Visits ..................................................................................................... 5 1  
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  ........................... 5 1 
7. 1.  
A d mi nistrati o n of I nf or m e d C o nse nt F or m ................................................................ 5 1  
7. 2.  
I nteracti ve Res p o nse Tec h n ol o g y Pr oce d ure .............................................................. 5 1 
7. 3.  
De m o gra p h y a n d Me dical Hist or y .............................................................................. 5 2  
7. 4.  
Pri or a n d C o nc o mita nt Me dicati o ns a n d Pr oce d ures .................................................. 5 2  
7. 5.  
Safet y Assess me nts  ..................................................................................................... 5 2 
7. 5. 1.  
Re vie w I ncl usi o n a n d E x cl usi o n Criteria  ................................................................... 5 2 
7. 5. 2.  
A d verse E v e nts  ........................................................................................................... 5 2 
7. 5. 3.  
P h ysical E x a mi nati o ns  ................................................................................................ 5 2 
7. 5. 3. 1.  
C o m pre he nsi ve P h ysical E x a mi nati o n  ....................................................................... 5 2 
7. 5. 3. 2.  
Tar gete d P h ysical E x a mi nati o ns  ................................................................................. 5 3 
7. 5. 4.  
Vital Si g ns  .................................................................................................................. 5 3 
7. 5. 5.  
Electr ocar di o gra ms  ..................................................................................................... 5 3 
7. 5. 6.  
La b orat or y Ass ess me nts  ............................................................................................. 5 3 
7. 5. 6. 1.  
Pre g n a nc y T esti n g  ...................................................................................................... 5 3 
7. 6.  
Efficac y Assess me nts  ................................................................................................. 5 4 
7. 6. 1.  
B o ne Marr o w Bi o ps y .................................................................................................. 5 4  
7. 6. 2.  
S plee n a n d Li v er Pal pati o n  ......................................................................................... 5 4 
7. 6. 3.  
I ma gi n g ....................................................................................................................... 5 4 
7. 6. 4.  
S y m pt o m Diar y  ........................................................................................................... 5 5 
7. 7.  
Perf or ma nce a n d Q ualit y - of-Life Assess me nts  .......................................................... 5 5 
7. 7. 1.  
Easter n C o o per ati ve O nc ol o g y Gr o u p Perf or ma n ce Stat us ........................................ 5 5  
7. 7. 2.  
Patie nt Gl o bal I m pr essi o n of C ha n ge ......................................................................... 5 5  
7. 7. 3.  
M yel o pr olif erati ve Ne o plas ms S y m pt o m Assess m e nt F or m  ..................................... 5 5 
7. 8.  
I W G-M R T Assess me nt  .............................................................................................. 5 5 
7. 9.  
P har mac o ki netic Assess me nts  .................................................................................... 5 6 
7. 9. 1.  
Bl o o d Sa m ple C ollecti o n  ............................................................................................ 5 6 


I nc yte C or p orati o n 
P a ge 1 2  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4  A U G 2 0 1 7  
C O N FI D E N TI A L  
7. 9. 2.  
Bi oa nal ytical M et h o d ol o g y a n d A nal ysis ................................................................... 5 6  
 
5 6  
 
5 6  
 
5 6  
 
5 7  
7. 1 1.  
Ot her St u d y Pr oce d ur es .............................................................................................. 5 7  
7. 1 1. 1.  
A d mi nistrati o n of St u d y Treat me nt  ............................................................................ 5 7 
7. 1 1. 2.  
Dis pe nsati o n of St u d y Tr eat me nt ............................................................................... 5 7  
7. 1 1. 3.  
Assess me nt of C o m plia nce Wit h St u d y Dr u g  ............................................................ 5 7 
7. 1 1. 4.  
Distri b uti o n of S u bject Re mi n der Car ds ..................................................................... 5 7  
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 8 
8. 1.  
A d verse E v e nts  ........................................................................................................... 5 8 
8. 1. 1.  
Defi niti o ns  .................................................................................................................. 5 8 
8. 1. 2.  
Re p orti n g .................................................................................................................... 5 8  
8. 2.  
La b orat or y T est A b n or m alities  ................................................................................... 5 9 
8. 3.  
Seri o us A d verse E v e nts .............................................................................................. 6 0  
8. 3. 1.  
Defi niti o ns  .................................................................................................................. 6 0 
8. 3. 2.  
Re p orti n g .................................................................................................................... 6 0  
8. 4.  
E mer ge nc y U n bli n di n g of Treat me nt Assi g n me nt ..................................................... 6 1  
8. 5.  
Pre g n a nc y  ................................................................................................................... 6 1 
8. 6.  
War ni n gs a n d Pr eca uti o ns .......................................................................................... 6 2  
8. 7.  
Data M o nit ori n g C o m mittee  ....................................................................................... 6 2 
8. 8.  
A d verse E v e nts of S peci al I nt erest  ............................................................................. 6 2 
8. 9.  
Pr o d uct C o m plai nts .................................................................................................... 6 2  
9.  
S T A TI S TI C S  .............................................................................................................. 6 3 
9. 1.  
St u d y P o p ulati o ns ....................................................................................................... 6 3  
9. 2.  
Selecti o n of Sa m ple Size  ............................................................................................ 6 3 
9. 3.  
Le v el of Si g nifi ca nce  .................................................................................................. 6 3 
9. 4.  
Statistical A nal yses  ..................................................................................................... 6 3 
9. 4. 1.  
Efficac y A nal yses  ....................................................................................................... 6 3 
9. 4. 1. 1.  
Pri mar y Efficac y A nal ys es  ......................................................................................... 6 3 
9. 4. 1. 2.  
Sec o n dar y Efficac y A nal ys es  ..................................................................................... 6 4 
9. 4. 2.  
Safet y A nal yses  .......................................................................................................... 6 4 


I nc yte C or p orati o n 
P a ge 1 3  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4  A U G 2 0 1 7  
C O N FI D E N TI A L  
9. 4. 2. 1.  
A d verse E v e nts  ........................................................................................................... 6 5 
9. 4. 2. 2.  
Cli nical La b or at or y Tests  ........................................................................................... 6 5 
9. 4. 2. 3.  
Vital Si g n s .................................................................................................................. 6 5 
9. 4. 2. 4.  
Electr ocar di o gra ms  ..................................................................................................... 6 5 
9. 4. 2. 5.  
A d verse E v e nts of S peci al I nt erest  ............................................................................. 6 6 
9. 4. 3.  
P har mac o ki netic A n al ys es  .......................................................................................... 6 6 
 
6 6  
9. 5.  
A nal ys es f or t he Data M o nit ori n g C o m mittee  ............................................................ 6 6 
9. 6.  
I nteri m A nal ysis .......................................................................................................... 6 6 
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 7 
1 0. 1.  
I n v esti gat or Res p o nsi bilities ....................................................................................... 6 7 
1 0. 2.  
Acc o u nta bilit y, Ha n dli n g, a n d Dis p osal of St u d y Dr u g ............................................. 6 8  
1 0. 3.  
Data Ma na ge me nt  ....................................................................................................... 6 9 
1 0. 3. 1.  
Data C ollecti o n  ........................................................................................................... 6 9 
1 0. 3. 2.  
Data Ma na ge me nt  ....................................................................................................... 6 9 
1 0. 4.  
St u d y M o nit ori n g ........................................................................................................ 6 9  
1 0. 5.  
Pr ot oc ol A d here n ce .................................................................................................... 7 0  
1 0. 6.  
Data Pri vac y a n d C o nfi de ntialit y of St u d y R ec or ds ................................................... 7 0  
1 0. 7.  
Fi na ncial Discl os ur e  ................................................................................................... 7 1 
1 0. 8.  
Q ualit y C o ntr ol a n d Q u alit y Ass ura n ce  ...................................................................... 7 1 
1 0. 8. 1.  
S p o ns or A u dits............................................................................................................ 7 1  
1 0. 8. 2.  
I ns p ecti o n b y Re g ulat or y A ut h orities ......................................................................... 7 1 
1 0. 9.  
Data Ha n dli n g a n d Rec or d kee pi n g ............................................................................. 7 2  
1 0. 9. 1.  
I ns p ecti o n of Rec or ds ................................................................................................. 7 2 
1 0. 9. 2.  
Rete nti o n of Rec or ds .................................................................................................. 7 2  
1 0. 9. 3.  
C o nfi de ntialit y  ............................................................................................................ 7 2 
1 0. 1 0.  
P u blicati o n P olic y  ....................................................................................................... 7 3 
1 1.  
R E F E R E N C E S  ........................................................................................................... 7 4 
A P P E N DI X  A. R E VI S E D W H O 2 0 1 6 C RI T E RI A F O R M Y E L O FI B R O SI S  .......................... 7 6 
A P P E N DI X  B.  I N T E R N A TI O N A L W O R KI NG G R O U P – M Y E L O P R O LI F E R A TI V E 
N E O P L A S M S R E S E A R C H A N D T R E A T M E N T C RI T E RI A  ................................ 7 8 


I nc yte C or p orati o n 
P a ge 1 4  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4  A U G 2 0 1 7  
C O N FI D E N TI A L  
A P P E N DI X  C.  E A S T E R N C O O P E R A TI V E O N C O L O G Y G R O U P 
P E R F O R M A N C E S T A T U S  ....................................................................................... 8 0 
A P P E N DI X  D.  M O DI FI E D M Y E L O FI B R O S I S S Y M P T O M A S S E S S M E NT S F O R M 
V E R SI O N 2. 0  ............................................................................................................. 8 1 
A P P E N DI X  E.  M Y E L O P R O LI F E R A TI V E N E O P L A S M S S Y M P T O M 
A S S E S S M E N T F O R M  .............................................................................................. 8 2 
A P P E N DI X  F.  P A TI E N T G L O B A L I M P R E S SI O N O F C H A N G E  ......................................... 8 3 
A P P E N DI X  G.  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 ............................................................................... 8 4  
A P P E N DI X  H.  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  ................................................................ 8 5 
 


I nc yte C or p orati o n 
P a ge 1 5  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4  A U G 2 0 1 7  
C O N FI D E N TI A L  
LI S T O F T A B L E S  
Ta ble  1: 
Ris k Cate g ories  ........................................................................................................... 2 0 
Ta ble  2: 
St u d y O bjecti ves a n d E n d p oi nts  ................................................................................. 2 7 
Ta ble  3: 
Per m itte d D ose Le vels b y C o h ort ............................................................................... 3 7 
Ta ble  4: 
D ose I nterr u pti o ns or Re d ucti o ns f or T o xicit y ........................................................... 3 8  
Ta ble  5: 
Sc he d ule of Assess me nts f or C o h ort A a n d B ( Scree ni n g T hr o u g h Wee k 1 2) .......... 4 3  
Ta ble  6: 
Sc he d ule of Assess me nts f or C o h ort A a n d B ( Wee k 1 6 T hr o u g h 
F oll o w- U p)  ................................................................................................................. 4 4 
Ta ble  7: 
Sc he d ule of La b orat or y Assess me nts f or C o h ort A a n d B ( Scree ni n g 
T hr o u g h Wee k 1 2) ...................................................................................................... 4 5  
Ta ble  8: 
Sc he d ule of La b orat or y Assess me nts f or C o h ort A a n d B ( Wee k 1 6 T hr o u g h 
F oll o w- U p)  ................................................................................................................. 4 6 
Ta ble  9: 
L ocal La b or at or y Tests:  Re q uire d A n al ytes  .............................................................. 4 7 
Ta ble  1 0: Sc he d ule of P har mac o ki netic Sa m pli n g f or C o h ort A (It aciti ni b a n d 
R u x oliti ni b) ................................................................................................................. 4 8  
Ta ble  1 1: Sc he d ule of P har mac o ki netic Sa m pli n g f or C o h ort B (Itaciti ni b Al o ne) ................... 4 8  
Ta ble  1 2: Criteria f or Cli nicall y N ota ble Vital Si g n A b n or m alities  ........................................... 6 5 
Ta ble  1 3: W H O Pre – Pri mar y M yel ofi br osis Criteria  ................................................................. 7 6 
Ta bl e 1 4:  W H O O vert Pri mar y M yel ofi br osis Criteria  .............................................................. 7 6 
Ta ble  1 5: M yel ofi br osis Gra di n g  ................................................................................................ 7 7 
 
LI S T O F FI G U R E S  
Fi g ure  1: 
St u d y Desi g n  ............................................................................................................... 3 2 
 


I nc yte C or p orati o n 
P a ge 1 6  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4  A U G 2 0 1 7  
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 he f oll o wi n g a b bre vi ati o ns a n d s pecial ter ms are use d i n t his cli nical st u d y Pr ot oc ol. 
A b bre vi ati o n  
Defi niti o n  
A E  
ad verse  eve nt  
A L T  
ala ni ne a mi n otra nsferase 
A N C  
abs ol ute  ne utr o p hil c o u nt  
A S T  
as partate a mi n otra nsferase 
A U C  
area u n der t he c ur ve 
B A T  
best  a vaila ble t hera p y 
BI D  
twice  dail y  
 
 
C F R  
C o de of Fe deral Re g ulati o ns 
CI  
cli nical i m pr o ve me nt  
C ma x  
ma xi m u m  plas ma c o nce ntrati o n  
C M L  
c hr o nic m yel oi d le u ke mia 
C R  
c o m plete re missi o n 
C T  
c o m p ute d t o m o gra p h y 
C T C A E  
C o m m o n T er mi n ol o g y Criteria f o r A d verse E ve nts 
C Y P  
c yt oc hr o me P 4 5 0 
DI P S S  
D y na mic I nter nati o nal Pr o g n ostic Sc ori n g S yste m  
D N A  
de o x yri b o n ucleic aci d 
E C G  
electr ocar di o gra m 
E C O G  
Easter n C o o perati ve O nc ol o g y Gr o u p 
e C R F 
electr o nic case re p ort f or m 
E L N  
E ur o pea n Le u ke mia Net 
E O T  
e n d of treat me nt 
E T  
esse ntial thr o m b oc yt h e mia 
F A S  
F ull A nal ysis Set  
F D A  
F o o d a n d Dr u g A d mi nistrati o n 
F S H  
f ollicle-sti m ulati n g h or m o ne 
G C P  
G o o d Cli nical Practice  
 
 
H B V  
he patitis  B vir us  
H C V  
he patitis  C vir us  
H D L  
hi g h - de nsit y li p o pr otei n 
HI P A A 
Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act  of 1 9 9 6 


I nc yte C or p orati o n 
P a ge 1 7  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4  A U G 2 0 1 7  
C O N FI D E N TI A L  
A b bre vi ati o n  
Defi niti o n  
H U  
h y dr o x y urea 
I B 
I n vesti gat or's Br oc h ure 
I C F 
inf or me d  co nse nt f or m  
I C H 
I nter nati o nal C o nfere nce o n Har m o nisati o n 
I E C 
in de pe n de nt et hics co m mittee  
 
 
I N 
I n vesti gat or N otificati o n 
I NR 
i nter nati o nal n or malize d rati o 
I P S S 
I nter nati o nal Pr o g n ostic Sc ori n g S yste m 
I R B 
i nstit uti o nal re vie w b oar d  
I W G-M R T  
I nter nati o nal W or ki n g Gr o u p-M yel o pr oliferati ve Ne o plas ms Researc h a n d 
Treat me nt  
I X R S 
interacti ve  v oice/ we b res p o nse s yste m  
J A K 
Ja n us ki nase 
L D L  
l o w- de nsit y li p o pr otei n 
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
M F  
m yel ofi br osis 
M F S A F v 2. 0  
M yel ofi br osis S y m pt o m Assess me nt F or m versi o n 2. 0  
M P N  
m yel o pr oliferati ve  ne o plas m 
M P N -S A F  
M yel o p r oliferati ve Ne o plas m– S y m pt o m Assess me nt F or m  
M RI  
ma g netic res o na nce i ma gi n g  
N A  
n ot a p plica ble 
N CI  
Nati o nal Ca ncer I nstit ute  
N S AI D  
n o nster oi dal a nti-i nfla m mat or y dr u g 
 
  
P E T -M F  
p ost –esse ntial t hr o m b oc yt he mia m yel ofi br osis 
P GI C  
P atient G l o bal Im pressi o n of C ha n ge  
P K  
p har mac o ki netic  
P M F  
pri mar y  m yel ofi br osis 
P P V -M F  
p ost – p ol yc yt he mia vera m yel ofi br osis 
P R  
partial  res p o nse 
P R B C  
pac ke d re d bl o o d cell 
P T  
pr ot hr o m bi n ti me 
P T T  
partial t hr o m b o plasti n ti me  
P V  
p ol yc yt he mia  vera  
Q D  
o nce dail y  


I nc yte C or p orati o n 
P a ge 1 8  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4  A U G 2 0 1 7  
C O N FI D E N TI A L  
A b bre vi ati o n  
Defi niti o n  
R A  
r he u mat oi d art hritis 
R B C  
re d bl o o d cell 
R N A  
ri b o n ucleic aci d 
S A E  
seri o us a d verse eve nt  
S A P  
Statistical A nal ysis Pla n  
S T A T  
si g nal tra ns d ucer a n d acti vat or of tra nscri pti o n 
S U S A R  
s us pecte d u ne x pecte d seri o us a d verse reacti o n  
S V R  
s plee n v ol u me re d ucti o n 
T E A E  
treat me nt-e mer ge nt  a d verse e ve nt 
 
 
 
 
T P O  
t hr o m b o p oieti n 
T S S  
T otal S y m pt o m Sc ore 
T Y K 2 
t yr osi ne ki nase 2  
U L N  
u p per li mit of n or mal 
W B C  
w hite  bl o o d cells 


I nc yte C or p orati o n 
P a ge 1 9  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4  A U G 2 0 1 7  
C O N FI D E N TI A L  
1.  
I N T R O D U C TI O N 
Itaciti ni b (I N C B 0 3 9 1 1 0) re pres e nts a n o vel, p ote nt, a n d selecti ve i n hi bit or of t he J A Ks wit h 
selecti vit y f or J A K 1 wit h l o w i n vitr o affi nit y f or J A K 2 a n d is pr o p ose d f or i n vesti gati o n a n d 
de vel o p me nt f or t he tr eat me nt of M F .  F or a t h or o u g h disc ussi o n of t he p h ar mac ol o g y of 
itaciti ni b, refer t o t he I n v esti gat or's Br o c h ure (I B). 
R u x oliti ni b, a p ote nt a n d selecti ve i n hi bit or of t he J A K fa mil y of pr otei n t yr osi ne ki nases, J A K 1 
a n d J A K 2, is a p pr o ve d i n m ulti ple j uris dicti o ns f or M F, wit h variati o ns o n t he s pecific i n dicati o n 
la n g u a ge, a n d is c urre ntl y i n de v el o p me nt f or t he treat me nt of M P Ns , he m at ol o gic mali g na n cies, 
a n d s oli d t u m ors.  F or a t h or o u g h disc ussi o n of t h e p har mac ol o g y of r u x oliti ni b (I N C B 0 1 8 4 2 4), 
refer t o t he r u x oliti ni b prescri bi n g i nf or mati o n. 
1. 1.  
B ac k gr o u n d  a n d O ver vie w o n M yel ofi br osis  
T he classic M P Ns i ncl u d e C M L, P V , E T, a n d P M F.  M yel ofi br osis ca n prese nt as a de n o v o  
dis or der ( P M F) or e v ol ve sec o n daril y fr o m pre vi o us P V or E T ( P P V -M F or P E T -M F).  
Re gar dless of w h et her M F is a pri mar y or sec o n d ar y dis or d er, it is c haracterize d b y a cl o nal ste m 
cell pr olifer ati o n ass ociat e d wit h pr o d ucti o n of ele vate d ser u m le v els of m ulti ple i nfla m mat or y 
a n d pr oa n gi o ge nic c yt o ki nes, a c haracteristic b o ne marr o w str o mal patter n t hat i ncl u des var yi n g 
de grees of c olla ge n fi br osis, oste oscler osis a n d a n gi o ge n esis , a n d a peri p heral bl o o d s mear 
s h o wi n g a l e u k oer yt hr o bl astic patter n wit h var yi n g de grees of circ ulati n g pr o ge nit or cells.  
Cli nicall y, M F is c haracterize d b y pr o gressi ve a ne mia , le u k o pe nia or le u k o c yt osis, 
t hr o m b oc yt o pe ni a or t hr o m b oc yt he mia, a n d m ulti or ga n e xtra me d ullar y he mat o p oiesis m ost 
pr o mi ne ntl y i n v ol vi n g t h e li ver a n d s plee n.  Patie nts ma y e x perie n ce de bilitati n g s y m pt o ms 
(Mesa  et al 2 0 0 7 , M esa  et al 2 0 1 3a), se q uel ae of massi ve s ple n o me gal y ( p ai n, li mitati o ns of 
m o ve me nt, earl y satiet y a n d s h ort ness of breat h, he patic o bstr ucti o n, a n d s ple nic i nfarcti o n), a 
h y per meta b olic state wit h cac h e xia, pr o gre ssi ve h e mat o p oietic fail ure, pr o gressi o n t o le u ke mia, 
a n d pre mat ur e deat h. 
T he me dia n a ge at dia g n osis of M F is a p pr o xi matel y 6 0 t o 6 5 years, a n d t h e i nci de nce of P M F 
has bee n esti mate d at 4 t o 6 cases per 1 0 0, 0 0 0 pe o ple i n t he U nite d States  (Stei n  et al 2 0 1 5).  
S ur vi val i n M F varies wit h t he prese nce or a bs e nce of s pecifi c ris k fact ors.  A nal ysis of ris k 
fact ors o ver t he past 2 0 years has res ulte d i n a n u m ber of pr o g n ostic sc ori n g s yste ms (f or a 
re vie w, r efer t o B os e  a n d Verst o vse k 2 0 1 5).  A pr o g n ostic sc ori n g s yste m base d o n a 
ti me- de pe n de nt ris k e v al uati o n has bee n de v el o pe d:  t he DI P S S f or P M F (Passa m o nti  et al 
2 0 1 0 ).  A ge of great er t h a n 6 5 years, prese n ce of c o nstit uti o nal s y m pt o ms, a ne mia ( he m o gl o bi n 
less t ha n 1 0 0 g/ L), l e u k o c yt osis ( W B C c o u nt > 2 5 × 1 09/ L), a n d a circ ulati n g blast perce nt a ge of 
1 % or hi g h er w ere assess e d f or t heir i m pact o n s ur vi val w he n a nal yze d as ti me- de pe n d e nt 
c o variates i n a m ulti variate C o x pr o p orti o nal hazar ds m o del.  T he a p pr o ac h s h o we d t hat 
ac q uisiti o n of a ne mia o v er ti me aff ects s ur vi val wit h a hazar d rati o r o u g hl y d o u ble t hat of ot her 
para meters, a n d t heref ore a ne mia was assi g n e d a s c ore of 2, w hile t he ot her 4 fact ors w ere 
assi g ne d s c ores of 1.  F o ur ris k cate g ories wit h n o n o verla p pi n g s ur vi val c ur ves ha ve b ee n 
descri be d  (Ta ble  1). 


I nc yte C or p orati o n 
P a ge 2 0  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4  A U G 2 0 1 7  
C O N FI D E N TI A L  
T a ble 1: 
Ris k C ate g ories  
T ot al Ris k Sc ore 
Ris k C a te g or y 
Me di a n S ur vi v al ( ye ars ) 
0 
L o w  
n ot reac he d 
1 or 2 
I nter me diate- 1 
1 4. 2 
3 or 4 
I nter me diate- 2 
4 
5 or 6 
Hi g h  
1. 4 
Alt h o u g h n ot i ncl u de d i n t he DI P S S, c yt o ge n etic a b n or malities i n P M F, J A K V 6 1 7 F allele 
b ur de n, m utati o ns i n e x o n 9 of t he ge ne e nc o di n g C A L R a n d m utati o ns i n t he ge ne e nc o di n g t he 
T P O  rece pt or ( M P L) ha v e bee n e x a mi ne d f or i m pact o n DI P S S sc ore, t hr o m b otic ris k, a n d 
o verall s ur vi val a n d t o get her ar e gr o u pe d as " dri ver" m utat i o ns.  T hese m ut ati o ns ofte n c oe xist 
wit h se veral s o matic m ut ati o n s:  ge nes f or t he e pi ge n etic re g ul at ors E Z H 2 (e n ha ncer of zeste 2 
p ol yc o m b r e pressi ve c o m ple x 2 s u b u nit), A S X L 1 (a d diti o nal se x c o m bs- li ke 1 tra nscri pti o nal 
re g ulat or, t he s plici n g ge ne S R S F 2 (seri ne/ar gi ni ne-ric h s plici n g fact or), a n d t he ge nes e n c o di n g 
the Kre bs c ycle e nz y mes is ocitrate de h y dr o ge nase 1 a n d 2 (I D H 1 a n d I D H 2).  T hese fact ors are 
c o m bi ne d i nt o t he ne west pr o g n ostic sc ori n g s yste m, t he ge n etics- bas e d pr o g n ostic sc ori n g 
s yste m, w hic h is c urre ntl y bei n g v ali date d.  
F or t he s u bset of p atie nts w h o are y o u n ger ( ge nerall y < 6 5 years), ot her wise healt h y, a n d ha v e a 
hist oc o m pati ble d o n or, all o ge n eic ste m cell tra ns pl a ntati o n ma y pr o vi de a c urati ve o pti o n, 
alt h o u g h wit h s u bsta ntial ( 1 0 %- 2 0 %) ris ks of m ortalit y ( Dee g  et al 2 0 0 3 ).  Dr u g t hera pi es use d 
i n M F, i ncl u di n g H U , b us ulfa n, 6- mer ca pt o p uri ne, a na greli de, t h ali d o mi de, le nali d o mi de, 
i nterfer o n, c ortic oster oi ds, a n d er yt hr o p oiesis-sti m ulati n g a ge nts or gr o wt h fact ors, ha v e n ot 
bee n s h o w n t o i m pr o ve s ur vi val.  S o me c a n i ncrease t he ris k of le u ke mic tra nsf or mati o n, ca n b e 
p o orl y t oler ate d, a n d all ha ve li mite d effecti ve ness i n i m pr o vi n g s ple n o me gal y a n d c o nstit uti o nal 
s y m pt o ms.  S ple nic irra diati o n is als o e m pl o ye d t o re d uce s y m pt o ms sec o n dar y t o s ple n o me gal y, 
b ut s y m pt o matic i m pr o ve me nt is varia ble a n d s h ort-li ve d; m ore o ver, tra nsi e nt a n d 
life-t hreat e ni n g p a nc yt o p e nia a n d a n a p pr o xi mate 2 0 % treat me nt-relate d m ortalit y ha v e bee n 
n ote d.  S ple nect o m y, p erf or me d i n a p pr o xi matel y 1 0 % of t he patie nt c o h ort re p orte d b y 
Cer va ntes  et al (2 0 0 9 ), is ass ociate d wit h si g nifica nt m or bi dit y a n d m ortalit y. 
1. 2.  
R ole of J A K P at h w a y i n M yel ofi br osis  
Wit hi n t he rece nt years , it was disc o vere d t hat a p pr o xi matel y 9 5 % of patie nts wit h P V a n d 
a p pr o xi matel y 5 0 % of p atie nts wit h P M F a n d E T ha ve a s o matic gai n- of-f u ncti o n m utati o n i n 
t he J A K 2 ge ne res ulti n g i n s u bstit uti o n of p he n yl ala ni ne f or v ali ne at p ositi o n 6 1 7 (J A K 2 
V 6 1 7 F) wit hi n t he pse u d o ki nase d o mai n of t he e n c o de d pr otei n.  J a n us ki nase 2 is o ne of 
4 me m bers of t he J A K fa mil y al o n g wit h J A K 1, J A K3, a n d T Y K 2.  T h e J A Ks are res p o nsi ble 
f or tra ns d ucti o n of cell si g nali n g fr o m T y p e I a n d II c yt o ki ne rece pt ors fa milies, beca use t hes e 
rece pt ors d o n ot p ossess i ntri nsic ki nase acti vit y t o acti vate d o w nstrea m si g nal tra ns d ucti o n.  
U n der p h ysi ol o gi c c o n diti o ns, t he J A Ks ass ociate wit h t he i ntracell ular d o mai n of t he c yt o ki ne 
rece pt ors i n res p o nse t o c yt o ki ne bi n di n g.  T he y t h e n u n der g o a ut o p h os p h or yl ati o n, res ulti n g i n 
c o nf or mati o nal c h a n ges t hat e na ble t he m t o  tra ns d uce i ntracell ular si g nali n g b y p h os p h or ylati n g 
a n d acti vati n g tra ns cri pti o n fact ors calle d S T A T pr otei ns.  T he acti vat e d S T A Ts tra nsl ocate t o 
t he n ucle us w here t he y r e g ulate tr a nscri pti o n of a n u m ber of ge n es i n v ol ve d i n cell ular 






I nc yte C or p orati o n 
P a ge 2 3  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4  A U G 2 0 1 7  
C O N FI D E N TI A L  
•  Itaciti ni b i n c o m bi nati o n wit h I N C B 0 5 0 4 6 5 f or t h e treat me nt of s oli d t u m ors. 
•  Itaciti ni b i n c o m bi nati o n wit h pe m br oliz u ma b f or t he treat me nt of s oli d t u m ors. 
•  Itaciti ni b i n c o m bi nati o n wit h e paca d ostat f or t he treat me nt of s oli d t u m ors. 
•  Itaciti ni b i n c o m bi nati o n wit h c ortic oster oi ds f or t he treat me nt of ac ute G V H D. 
Of t he s u bjects e x p ose d t o itaciti ni b, 4 9 3 s u bjects ha ve bee n e x p ose d t o itaciti ni b m o n ot hera p y:  
2 8 4 of t hese s u bjects w er e healt h y v ol u nteers a n d 2 0 9 s u bjects ha d u n derl yi n g diseas e, s uc h as 
R A ( St u d y I N C B 3 9 1 1 0- 2 0 1), c hr o nic pla q u e ps oriasis ( St u d y I N C B 3 9 1 1 0- 2 5 0), or M F ( St u d y 
I N C B 3 9 1 1 0- 2 3 0).  Ni ne  P hase 1 , 3 P hase 1/ 2, a n d 5 P hase 2 cli nical st u dies wit h itaciti ni b , 
i ncl u di n g st u dies of itaciti ni b i n c o m bi nati o n wit h PI 3 K δ i n hi bit ors I N C B 0 4 0 0 9 3 a n d 
I N C B 0 5 0 4 6 5, ha v e eit her bee n c o m plet e d or are o n g oi n g.  A d diti o nal details re gar di n g t he st u d y 
desi g ns a n d pri mar y e n d p oi nts of t hese st u dies are s u m marize d i n t he itaciti ni b I B. 
I n t he o p e n -la b el P hase 2 st u d y I N C B 3 9 1 1 0- 2 3 0 , t he efficac y a n d safet y of 3 d ose le vels of 
itaciti ni b, a p ote nt a n d selecti ve oral J A K 1 i n hi bit or, were e val u ate d i n pati e nts wit h 
i nter me diate- or hi g h-ris k M F a n d a pl atelet c o u nt ≥ 5 0 × 1 09/ L.  Of 1 0, 4 5, a n d 3 2 s u bjects 
e nr olle d i n t he 1 0 0 m g BI D , 2 0 0 m g BI D , a n d 6 0 0 m g Q D  c o h orts, res p ecti vel y, 5 0. 0 %, 6 4. 4 %, 
a n d 6 8. 8 % c o m plete d W ee k 2 4.  A ≥ 5 0 % re d ucti o n i n T S S  was ac hie ve d b y 3 5. 7 % a n d 2 8. 6 % 
of s u bjects i n t he 2 0 0 m g BI D  c o h ort a n d 3 2. 3 % a n d 3 5. 5 % i n t he 6 0 0 m g Q D  c o h ort at Wee k 1 2 
( pri mar y e n dp oi nt) a n d Wee k 2 4, res pecti vel y.  B y c o ntrast, 2 s u bjects ( 2 0 %) i n t he 1 0 0 m g BI D  
c o h ort ha d ≥ 5 0 % T S S  re d ucti o n at Wee ks 1 2 a n d 2 4.  F or t he 2 0 0 m g BI D  a n d 6 0 0 m g Q D  
c o h orts, t he me dia n S V R  at Wee k 1 2 were 1 4. 2 % a n d 1 7. 4 %, res p ecti vel y. F urt her m ore, 2 1 of 
3 9 s u bjects ( 5 3. 8 %) w h o re q uire d R B C  tra nsf usi o ns d uri n g t he 1 2 w ee ks prece di n g treat me nt 
i nitiati o n ac hie ve d a ≥ 5 0 % re d ucti o n i n t he n u m b er of R B C u nits tra nsf us e d d uri n g st u d y 
W ee ks 1 t hr o u g h 2 4.  O nl y 1 s u bject disc o nti n ue d f or Gra de 3 t hr o m b oc yt o pe nia.  
N o n he mat ol o gi c A Es  were lar gel y Gra d e 1 or 2; t he m ost c o m m o n was fati g ue.  Treat me nt wit h 
itaciti ni b res ulte d i n cli nicall y m ea ni n gf ul s y m pt o m relief, m o dest S V R , a n d li mite d 
m yel os u p pr essi o n ( Mascare n has  et al 2 0 1 6).  Alt h o u g h t he pri mar y efficac y e n d p oi nts w ere at 
1 2 a n d 2 4 wee ks p oste nr oll me nt, s u bjects were all o we d t o c o nti n ue i n t he st u d y as l o n g as t he y 
are e x perie n ci n g cli nical be nefit i n t he i n vesti gat or 's o pi ni o n.  As of t he d at a c ut off, 1 4 s u bjects 
are still recei vi n g t he st u d y dr u g.  
1. 3. 4.  
R u x oliti ni b Cli nic al S afet y  S u m m ar y  
1. 3. 4. 1.  
Cli nic al S af et y D at a  
Base d o n t h e ra n d o mize d P hase 3 C O M F O R T  I a n d II a n d R E S P O N S E st u dies, ru x oliti ni b is 
i n dicate d f or t he tr eat me nt of i nter me diate or hi g h-ris k M F , i ncl u di n g P M F, P P V -M F , P E T-M F,  
a n d P V patie nts. 
T he m ost c o m m o n he mat ol o gical a d vers e reacti o ns base d o n t hese st u dies are m yel os u p pressi o n 
(t hr o m b oc yt o p e nia, a n e mia , a n d ne utr o pe nia) a n d i ncreas e of A L T/ A S T, h y perc h olester ole mia 
a n d h y p ertri gl yceri de mia.  N o n he mat ol o gi c a d verse reacti o ns are br uisi n g, dizzi ness, hea dac h e, 
uri nar y tract i nfecti o n , a n d wei g ht gai n. 
T he A E pr ofile of t he c o m p o u n d has bee n ass esse d i n m ore t ha n 3 7 0 healt h y v ol u nteers, i n 
s u bjects wit h vari o us de grees of re nal ( n = 3 2) or he patic ( n = 2 4) i m pair m e nt, a n d i n s u bjects 




I nc yte C or p orati o n 
P a ge 2 5  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4  A U G 2 0 1 7  
C O N FI D E N TI A L  
efficac y o n S V R  a n d so me de gree of s y m pt o ms i m pr o ve me nt wit h li mite d he mat ol o gical a n d 
n o n he mat ol o gical A E  r ate, alt h o u g h t his d ose w as n ot ma xi mall y effecti ve.  
S o me patie nts treate d wit h r u x olit i ni b ha ve re q uire d i nterr u pti o ns i n t hera p y f or eit her 
he mat ol o gical t o xicities o r ha ve e x perie n ce d a n o n d ura ble s plee n res p o nse a n d disc o nti n ue d 
r u x oliti ni b d ue t o disease pr o gressi o n.  Itaciti ni b ma y re prese nt a sec o n d -li ne t hera p y o pti o n f or 
t hese patie nts wit h g o o d perf or ma n ce stat us .  It aciti ni b at t he d ose of 6 0 0 m g Q D m a y 
de m o ns trate g o o d t olera bilit y a n d efficac y o n s y m pt o ms i m pr o ve me nt a n d s o me S V R  f or t hese 
patie nts.  
T h us, t his st u d y is pr o p osi n g t o a d mi nister itaciti ni b i n 2 disti nct c o h orts:  
− C o h ort A s u bjects will recei ve a c o m bi nati o n of t he J A K 1 i n hi bit or itaciti ni b at 
t he d ose of 2 0 0 m g Q D a n d t he J A K 1/ 2 i n hi bit or r u x oliti ni b, a n d 
− C o h ort B s u bjects will recei ve t he J A K 1 i n hi bit or itaciti ni b as m o n ot hera p y at t he 
d ose of 6 0 0 m g Q D. 
T he st u d y will t h us e val u ate t he effects of selecti v e J A K 1 i n hi biti o n i n M F , i n c o m bi nati o n wit h 
a l o w d ose of r u x oliti ni b (less t ha n 2 0 m g d ail y ) or as a m o n ot hera p y aft er r u x oliti ni b treat me nt  
i n s u bjects w h o i nitiall y ha d s o me re d u cti o n i n s plee n f oll o we d b y pr o gressi o n or disc o nti n ue d 
f or he mat ol o gic t o xicities.  T he  i m pact o n s plee n size a nd M F s y m pt o m s (usi n g pal pati o n a n d 
M RI  or C T a n d usi n g s y m pt o m diar y, res pecti vel y) al o n g wit h t he p ossi ble be nefits of l o w ere d 
a ne mia a n d t hr o m b oc yt o pe nia i nci de nce will be assesse d. 
1. 5.  
P ote nti al Ris ks a n d Be nefits of t he Tre at me nt Re gi me n  
1. 5. 1.  
Ris ks R el ate d t o It aciti ni b 
Cli nical e x perie nce wit h itaciti ni b as of 1 3 D E C 2 0 1 6 is base d o n a d mi nistrati o n t o 7 7 7 safet y 
e val ua ble s u bjects.  T his p o p ulati o n i ncl u des 4 9 3 s u bjects w h o recei ve d itaciti ni b as 
m o n ot hera p y, i ncl u di n g healt h y s u bjects ( n = 2 8 4) a n d s u bjects wit h M F ( n = 8 7), c hr o ni c pla q ue 
ps oriasis ( n = 3 8), a n d R A ( n = 8 4).  Als o, 6 4 s u bjects wit h s oli d t u m ors recei ve d itaciti ni b i n 
c o m bi nati o n wit h c he m ot hera p y; 7 8 s u bjects wit h l y m p h oi d mali g n a ncies recei ve d itaciti ni b i n 
c o m bi nati o n wit h t he PI 3 K δ i n hi bit o r, I N C B 0 4 0 0 9 3; 3 8 s u bjects wit h s oli d t u m ors or l y m p h oi d 
mali g na n cies recei ve d itaciti ni b i n c o m bi nati o n wit h pe m br oliz u ma b ; 4 0 s u bjects wit h s oli d 
t u m ors recei ve d itaciti ni b i n c o m bi nati o n wit h e paca d ostat; a n d 2 9 s u bjects wit h a G V H D disease 
recei v e d itaciti ni b i n c o m bi nati o n wit h c ortic oster oi ds.  A d diti o nal details o n eac h of t h ese 
st u dies ca n be f o u n d i n t he itaciti ni b I B. 
A d verse e ve nts t hat ha ve bee n re p orte d b y m ore t ha n 5 % of healt h y s u bjects recei vi n g itaciti ni b 
i n a n i n di vi d ual st u d y i n cl u de d fati g u e, hea dac h e, ne utr o pe nia, na us ea, c o ntact der matitis, 
ecc h y m osis, retic ul oc yt e c o u nt decr ease d, e x c oriati o n, a n d nasal c o n gesti o n . 
Beca use of t h e p ote ntial f or m yel os u p pressi o n, s u bjects will ha ve he mat ol o gic p ara met ers  
cl osel y m o nit ore d d uri n g cli nical st u dies.  If t here are cli nicall y rele va nt d ecli nes i n he mat ol o g y 
para meters, t he n t her a p y ma y b e i nterr u pte d u ntil res ol uti o n or disc o nti n uati o n.  As itaciti ni b 
als o has t he p ote ntial t o ca use W B C mar gi nati o n (ie, a tra n sie nt decrease i n A N C), assess me nt of 
he mat ol o g y p ara met ers s h o ul d be perf or me d bef ore st u d y dr u g a d mi nistrati o n a n d at all 
a p plica ble st u d y visits.  


I nc yte C or p orati o n 
P a ge 2 6  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4  A U G 2 0 1 7  
C O N FI D E N TI A L  
A d verse e ve nts re p orte d b y m ore t h a n 1 0 % of s u bjects i n t he M F st u d y i n cl u de d a ne mia, fati g u e, 
t hr o m b oc yt o pe ni a/ platelet c o u nt decrease d , u p p er res pirat or y tract i nfecti o n, na usea, 
c o nsti pati o n, diarr hea, c o u g h, peri p heral e de ma, p yre xia, d ys p nea, dizzi ness, pai n i n e xtre mit y, 
ni g ht s weats, a b d o mi nal pai n, art hral gia, c o nt usi o n, hea dac he, pr urit us, a n d v o miti n g.  T he o nl y 
a d verse e ve nt r e p orte d b y m ore t h a n 1 0 % of itaciti ni b-treate d s u bjects wit h a n i nfla m mat or y 
c o n diti o n was nas o p har y n gitis i n a ps oriasis st u d y ; t here were n o T E A Es re p orte d b y m ore t ha n 
1 0 % of s u bjects wit h R A. 
1. 5. 2.  
Ris ks R el ate d t o R u x oliti ni b  
T he safet y of r u x oliti ni b was assesse d i n 6 1 7 s u bj ects i n 6 cli nical st u dies wit h a me dia n d urati o n 
of f oll o w- u p of 1 0. 9 m o nt hs, i ncl u di n g 3 0 1 s u bjects wit h M F  i n 2 P hase 3 st u dies.  I n a 
d o u ble- bli n d ra n d o mize d, place b o c o ntr olle d st u d y of r u x oliti ni b, a m o n g t he 1 5 5 s u bjects treat e d 
wit h r u x oliti ni b, t he m ost fre q ue nt a d vers e dr u g reacti o ns were t hr o m b oc yt o pe nia a n d a n e mia.  
T hr o m b oc yt o p e nia, a n e mia, a n d ne utr o pe nia are d ose-relat e d effects.  T h e m ost fre q ue nt 
n o n he mat ol o gic a d vers e reacti o ns w ere br uisi n g, di zzi ness, a n d hea dac he.  
S o me s y m pt o ms s uc h as i nfecti o ns wit h her pes z oster or m ultif ocal le u k oe nce p hal o pat h y ( P M L), 
s y m pt o m e x acer b ati o n f oll o wi n g i nterr u pti o n or disc o nti n uati o n of treat me nt wit h r u x oliti ni b, 
a n d n o nmela n o ma s ki n ca ncer  h a ve o cc urre d.  
F or  a d escri pti o n of t he f ull ris ks of r u x oliti ni b, refer t o t he prescri bi n g i nf or mati o n. 
1. 5. 3.  
Ris ks f or t he C o m bi n ati o n of I t aciti ni b a n d R u x oliti ni b  
I n hi biti o n of J A K 1 a n d J A K 2 b y r u x oliti ni b is ass ociate d wit h a p ote ntial ris k of de vel o pi n g 
seri o us bacterial, myc o bacterial, f u n gal, a n d viral i nfecti o ns.  It is n ot k n o w n w het her  i n hi biti o n 
pri maril y of J A K 1, s uc h as wit h itaciti ni b, will be ass ociate d wit h i ncrease d ris k of i nfecti o ns.  
S u bjects wit h acti ve seri o us i nfecti o ns will n ot be all o we d t o e nr oll i n t he st u d y.  I n v esti gat ors 
s h o ul d caref ull y o bser ve s u bjects recei vi n g itaciti ni b f or si g ns a n d s y m pt o ms of i nfecti o ns a n d 
i nitiate a p pr o priate tr eat me nt. 
1. 5. 4.  
P ot e nti al B e nefits  of It aciti ni b a n d R u x oliti ni b  
1. 5. 4. 1.  
It aciti ni b P ote nti al B e n efits 
J a n us ki nase i n hi biti o n b y itaciti ni b ma y res ult i n re d ucti o ns i n s plee n size a n d s y m pt o ms.   
1. 5. 4. 2.  
R u x oliti ni b P ote nti al B e nefit 
T he cli nical efficac y res ults of r u x oliti ni b t hat ha ve e mer ge d fr o m t he o n g oi n g st u dies a n d 
P hase  3 st u dies are n ota ble, i ncl u di n g mar k e d re d ucti o n i n s ple n o me gal y, i m pr o ve me nt i n 
s y m pt o ms, perf or ma nce stat us a n d acti vit y le v el, a n d re d ucti o n i n plas ma l e vels of 
i nfla m mat or y, pr ot hr o m b otic, a n d a n gi o ge nic c yt o ki nes.  I n t h os e s u bjects wit h pr ol o n ge d 
e x p os ure t o r u x oliti ni b ( me dia n of 5 years t hera p y), t hes e p osi ti ve effects ha ve bee n mai ntai ne d, 
gi ve n t he cl osel y rel ate d pat h o p h ysi ol o g y of M P Ns. 


I nc yte C or p orati o n 
P a ge 2 7  of 8 5 
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4  A U G 2 0 1 7  
C O N FI D E N TI A L  
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  
St u d y o bj ecti ves a n d e n d p oi nts are pres e nte d i n T a ble  2. 
T a ble 2: 
St u d y O bjecti ves a n d E n d p oi nts  
Pri m ar y O bjecti ve  
Pri m ar y E n d p oi nt  
T o e val uate preli mi nar y effica c y of itaciti ni b o n S V R 
fr o m baseli ne at W ee k 2 4 i n t he 2 f oll o wi n g c o h orts of 
M F  s u bj ects: 
•  C o h ort A :  i n c o m bi nati o n i n s u bj ects wit h 
r u x oliti ni b l o w dose (less t ha n 2 0 m g dail y) . 
•  C o h ort B :  as m o n ot hera p y i n s u bj ects w h o 
pr o gresse d ( per re vise d E L N 2 0 1 3 res p o nse criteria 
f or M F) after i nitial re d u cti o n i n s plee n o n 
r u x oliti ni b or disc o nti n ue d f or he mat ol o gic 
t o xicities. 
C ha n ge a n d p erce nta ge c ha n ge  i n S V R as meas ure d b y 
M RI ( C T sca n i n s u bj ects w h o are n ot ca n di dates f or M RI 
or w he n M RI is n ot rea dil y a vaila ble) at W ee k  2 4 w he n 
c o m pare d wit h  baseli ne.  
Sec o n d ar y O bjecti ve s ( C o h orts A a n d B) 
Sec o n d ar y E n d p oi nt s 
T o e val uate preli mi nar y safet y a n d t olera bil it y of 
itaciti ni b al o ne.  
Safet y a n d t olera bilit y t hr o u g h assess me nt of fre q ue nc y, 
se verit y, a n d d urati o n of A Es; c ha n ges i n cli nical safet y 
assess me nts; a n d c ha n ges i n cl i nical la b orat or y 
para meters.  
T o e val uate preli mi nar y safet y a n d t olera bilit y of 
itaciti ni b i n c o m bi nati o n wit h r u x oliti ni b. 
T o e val uate preli mi nar y effica c y of itaciti ni b al o ne or 
i n c o m bi nati o n wit h r u x oliti ni b o n S V R  fr o m baseli ne 
at W ee k 1 2. 
C ha n ge a n d p erce nta ge i n S V R fr o m baseli ne t hr o u g h 
W ee k 1 2 as meas ure d b y M RI ( or C T sca n i n a p plica ble 
s u bj ects).  
T o e val uate preli mi nar y effica c y of itaciti ni b al o ne or 
i n c o m bi nati o n wit h r u x oliti ni b o n s plee n le n gt h 
re d ucti o n fr o m baseli ne at W e e k 1 2 a n d W ee k 2 4.  
C ha n ge a n d p erce nta ge c ha n ge o n s plee n le n gt h re d ucti o n 
fr o m baseli ne t hr o u g h Wee k 1 2 a n d W ee k 2 4 as meas ure d 
b y pal pati o n.  
T o e val uate preli mi nar y effica c y of itaciti ni b al o ne or 
i n c o m bi nati o n wit h r u x oliti ni b wit h res pect t o M F 
s y m pt o ms at W ee k 1 2 a n d W ee k 2 4. 
C ha n ge a n d perce nta ge c ha n ge i n T S S  fr o m baseli ne 
t hr o u g h W ee k 1 2 a n d W ee k 2 4 as meas ure d b y t he 
M F S A F v 2. 0 s y m pt o m diar y a n d b y t he M P N -S A F.  
P GI C  sc ore at eac h visit w her e t he varia ble is meas ure d. 
T o e val uate preli mi nar y effica c y of itaciti ni b usi n g 
I W G-M R T  criteria.  
N u m ber of s u bj ects wit h res p o nses acc or di n g t o t he 
2 0 1 3  I W G-M R T  c o nse ns us criteria f or treat me nt res p o nse.  
T o assess t he P K of itaciti ni b a n d r u x oliti ni b.  
Calc ulati o n of t he P K para met ers s uc h as A U C, C L/ F, 
C ma x , a n d tma x  al o n g wit h s u m marizati o n of t he o bser ve d 
c o nce ntrati o n data b y ti me p oi nt will be perf o r me d f or b ot h 
r u x oliti ni b a n d itaciti ni b. 


I nc yte C or p orati o n 
P a ge 2 8  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4  A U G 2 0 1 7  
C O N FI D E N TI A L  
T a ble 2: 
St u d y O bjecti ves a n d E n d p oi nts ( C o nti n ue d)  
3.  
S U B J E C T E LI GI BI LI T Y  
De viati o ns fr o m eli gi bilit y criteria are n ot all o w e d beca use t h e y ca n p ot e ntiall y je o p ar dize t he 
scie ntific i nte grit y of t he st u d y, re g ul at or y acce pta bilit y, a n d/ or s u bject safet y.  T heref ore, 
a d here n ce t o t he criteria as s pecifie d i n t he P r ot oc ol is esse ntial. 
3. 1.  
S u bject I ncl usi o n Criteri a  
A s u bject  w h o meet s all of t he f oll o wi n g criteri a ma y b e i ncl u de d i n t he st u d y:  
C o h ort A o nl y  
1.  Recei vi n g  r u x oliti ni b d ose of less t ha n 2 0 m g dail y wit h n o d ose i ncreas e or n o d ose 
m o difica ti o n i n t he last 8 wee ks bef ore s cree ni n g visit. 
C o h ort B o nl y  
2.  M ust ha ve ha d i nitial re d ucti o n i n s plee n o n r u x oliti ni b treat me nt (res p o nse is defi ne d b y 
a n y s plee n le n gt h or v ol u me re d ucti o n, b y pal pati o n or M RI/ C T assess me nt, fr o m 
baseli ne w hile o n pr e vi o us r u x oliti ni b treat me nt per I W G-M R T E L N 2 0 1 3 g ui deli nes, 
A p pe n di x B ): 
a. F oll o we d b y d oc u me nt e d e vi de nce of pr o gressi o n i n s plee n le n gt h or v ol u me O R   
b.  Disc o nti n ue d r u x oliti ni b f or he mat ol o gic t o xicities, after t he i nitial re d u ct i o n i n 
s plee n le n gt h or v ol u me. 
All s u bjects  
3.  Me n a n d w o me n, a ge d 1 8 years or ol d er.  
4.  C o nfir me d dia g n osis of P M F, P P V- M F, or P E T- M F acc or di n g t o re vise d W H O 2 0 1 6 
criteria (A p pe n di x A ). 


I nc yte C or p orati o n 
P a ge 2 9  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4  A U G 2 0 1 7  
C O N FI D E N TI A L  
5.  M ust ha ve pal pa ble s plee n of ≥ 5 c m bel o w t h e left s u bc ostal mar gi n o n p h ysical 
e x a mi nati o n at t he scree ni n g visit  (if s plee n is n ot pal pa ble d ue t o b o d y ha bit us, s plee n 
e nlar ge me nt m ust be d o c u me nte d b y ot h er mea ns [e g, ultras o u n d or M RI] a n d st u dy 
s p o ns or me dical m o nit or be c o ntact e d f or acce pta n ce). 
6.  E C O G perf or ma nce stat us of 0, 1, or 2.  
7.  Scree ni n g b o ne marr o w bi o ps y s peci me n a vaila bl e or willi n g ness t o u n der g o a b o n e 
marr o w bi o ps y at scree ni n g/ baseli ne; willi n g ness t o u n der g o b o ne marr o w bi o ps y at 
Wee k 2 4. 
8.  Lif e e x pecta nc y of at least 2 4 wee ks.  
9.  Willi n g ness t o a v oi d pre g na n c y or fat heri n g c hil dre n base d o n t h e f oll o wi n g criteria 
(A p pe n di x G ): 
a. W o ma n of n o nc hil d beari n g p ote ntial (ie, s ur gicall y sterile wit h a h yst erect o m y a n d/ or 
bilateral o o p h orect o m y O R ≥ 1 2 m o nt hs of a me n orr hea a n d at least 5 0 years of a ge). 
b.  W o ma n of c hil d beari n g p ote ntial w h o has a ne gati ve ser u m pre g n a nc y test at 
scree ni n g a n d ne gati ve uri nar y test bef ore t he first d ose o n Da y 1 a n d w h o a grees t o 
ta ke a p pr o priate pr eca uti o ns t o a v oi d preg na nc y ( wit h at least 9 9 % certai nt y) fr o m 
scree ni n g t hr o u g h s afet y f oll o w-u p.  Per mitte d met h o ds t hat are at least 9 9 % effecti ve 
i n pre ve nti n g pre g n a nc y s h o ul d be c o m m u nicate d t o t he s u bject a n d t heir 
u n dersta n di n g c o nfir m e d. 
c. Ma n w h o a gr ees t o ta ke a p pr o pr iate preca uti o ns t o a v oi d fat heri n g c hil dre n ( wit h at 
least 9 9 % certai nt y) fr o m scree ni n g t hr o u g h s afet y f oll o w- u p.  Per mitte d met h o ds t hat 
are at least 9 9 % effecti ve i n pre ve nti n g pre g n a nc y s h o ul d be c o m m u nicate d t o t he 
s u bject a n d t heir u n dersta n di n g c o nfir me d. 
3. 2.  
S u bject E xcl usi o n Criteri a  
A s u bject  w h o meet s a n y of t he f oll o wi n g criteri a will be e x cl u de d fr o m t he st u d y: 
1.  Lac k of r ec o v er y fr o m all t o xicities fr o m pre vi o us t hera p y (e x ce pt r u x oliti ni b) t o Gra de 1 
or better.  
2.  Pre vi o us treat me nt wit h itaciti ni b  or J A K 1 i n hi bit ors (J A K 1/J A K 2 i n hi bit or r u x oliti ni b is 
per mitte d ). 
3.  I n a bilit y t o s wall o w f o o d or a n y c o n diti o n of t he u p per gastr oi ntesti nal tract t hat 
precl u des a d mi nistrati o n of oral me dicati o ns.  
4.  U n willi n g ness t o be tra nsf use d wit h bl o o d c o m p o ne nts. 
5.  Rece nt hist or y of i na de q uate b o ne marr o w reser v e as de m o nstrate d b y t h e f oll o wi n g:  
a. Platelet c o u nt < 5 0 × 1 0 9/ L i n t he 4 w ee ks bef ore s cree ni n g or platelet tra nsf usi o n 
wit hi n 8 wee ks bef ore scree ni n g.  
b.  A N C  le vels < 0. 5 × 1 09/ L i n t he 4 w ee ks bef ore s cree ni n g.  
c. Peri p heral bl o o d blast c o u nt of > 1 0 % at t he scree ni n g or b aseli ne he mat ol o g y 
assess me nts.  


I nc yte C or p orati o n 
P a ge 3 0  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4  A U G 2 0 1 7  
C O N FI D E N TI A L  
6.  I n a de q uat e li ver f u n cti o n at scree ni n g a n d baseli n e visits as de m o nstrate d b y t he 
f oll o wi n g:  
a. Direct bilir u bi n ≥ 2. 0 × U L N.  ( N O T E:  direct bilir u bi n ma y be ass u me d  t o be wit hi n 
li mits if t otal bilir u bi n is ≤ 2. 0 × U L N).  
b.  A L T or A S T > 2. 5 × U L N.  
7.  I n a de q uat e re n al f u ncti o n at scree ni n g a n d baseli n e visits as de m o nstrate d b y creati ni ne 
clear a nce < 4 0 m L/ mi n meas ure d or calc ul ate d b y C oc kr oft -Ga ult e q u ati o n , or 
gl o mer ula r filtrati o n rat e < 4 0 m L/ mi n/ 1. 7 3 m2 as calc ulate d usi n g t he M o dificati o n of 
Diet i n Re nal Disease f or m ula . 
8.  Acti ve bact erial, f u n gal, parasitic, or viral i nfecti o n t hat re q uires t hera p y.  S u bjects wit h 
ac ute i nfecti o ns re q uiri n g treat me nt s h o ul d dela y s cr ee ni n g/e nr oll me nt u ntil t he c o urse of 
t hera p y has b ee n c o m plet e d a n d t he e v e nt is c o nsi dere d res ol ve d.  Pr o p h ylactic 
a nti bi otics will be per mitte d.  
9.  E vi de nce of H B V or H C V i nfecti o n or ris k of reacti vati o n:  H B V D N A a n d H C V R N A 
m ust be u n detecta ble.  S u bjects ca n n ot be p ositi v e f or he p atitis B s urface a nti ge n or  
a nti– he patitis B c or e a nti b o dies.  S u bjects w h o ha ve p ositi ve a nti- H Bs as t he o nl y 
e vi de nce of pri or e x p os ure ma y partici pate i n t he st u d y pr o vi de d t hat t here is b ot h 1) n o 
k n o w n hist or y of H B V i nfe cti o n a n d 2) v erifie d recei pt of he patitis B v acci ne.  
1 0.  K n o w n h u ma n i m m u n o deficie nc y vir us i nfecti o n. 
1 1.  Cli nicall y si g nifica nt or  u nc o ntr olle d car diac disease, i ncl u di n g u nst a ble a n gi na; ac ute 
m y ocar dial i nfarcti o n wit hi n 6 m o nt hs of Da y 1 of st u d y dr u g a d mi ni strati o n; Ne w Y or k 
Heart Ass o ciati o n Class III or I V c o n gesti ve h eart fail ure; a n d arr h yt h mia re q uiri n g 
t hera p y u nless a p pr o ve d b y me dical m o nit or/s p o ns or.   
1 2.  Acti ve i n vasi ve mali g na n c y o v er t he pre vi o us 2 years e x ce pt treat e d basal or s q ua m o us 
carci n o mas of t he s ki n, c o m pletel y resecte d i ntrae pit helial carci n o ma of t h e cer vi x, a n d 
c o m pletel y resecte d pa pillar y t h yr oi d a n d f ollic ular t h yr oi d ca ncers.  S u bjects wit h 
mali g na n cies wit h i n d ole nt be ha vi or s uc h as pr ostate ca n cer treate d wit h ra diati o n or 
s ur ger y ma y b e e nr olle d as l o n g as t h e y ha ve a reas o na ble e x pectati o n t o ha ve bee n c ure d 
wit h t he treat me nt m o dalit y recei ve d . 
1 3.  S ple nic irra diati o n wit hi n 6 m o nt hs bef ore recei vi n g t he first d ose of itaciti ni b. 
1 4.  Use of a n y pr o hi bite d c o nc o mita nt  me dicati o ns . 
1 5.  Acti ve alc o h ol or dr u g a d dicti o n t hat w o ul d i nterfere wit h t heir a bilit y t o c o m pl y wit h t he 
st u d y re q uire me nts. 
1 6.  Use of a n y p ote nt /str o n g c yt o c hr o me P 4 5 0 3 A 4 i n hi bit ors wit hi n 1 4 da ys or 5 half -li ves 
( w hic he ver is l o n ger) b ef ore t he first d ose of itaciti ni b or a ntici pate d d uri n g t he st u d y. 
1 7.  Use of c o n c o mita nt treat me nt of fl uc o naz ole at a d ose >  2 0 0 m g ( o nl y f or s u bjects treate d 
i n C o h ort A wit h r u x oliti ni b ). 
1 8.  I n a de q uat e rec o ver y fr o m t o xicit y a n d/ or c o m pli cati o ns fr o m a maj or s ur ger y bef ore 
starti n g t her a p y. 
1 9.  C urre nt l y breastf ee di n g or pre g na nt. 


I nc yte C or p orati o n 
P a ge 3 1  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4  A U G 2 0 1 7  
C O N FI D E N TI A L  
2 0.  I n a bilit y t o c o m pr e he n d or u n willi n g t o si g n t he I C F. 
2 1.  Hist or y or prese n ce of a n a b n or mal E C G  t hat, i n t he i n vesti gat or's o pi ni o n, is cli nicall y 
mea ni n gf ul. 
2 2.  A n y c o n diti o n t hat w o ul d, i n t he i n vesti gat or' s j u d g me nt, i nterfere wit h f ull partici pati o n 
i n t he st u d y, i ncl u di n g a d mi nistrati o n of st u d y dr u g a n d atte n di n g re q uire d st u d y visits; 
p ose a si g nifica nt ris k t o t he s u bject; or i nterfere wit h i nter pretati o n of st u d y dat a.  
3. 3.  
S u bjects W h o F ail t o Meet Scree ni n g Criteri a  
A s u bject w h o has a l a b orat or y test res ult, vital si g n assess me nt , or E C G fi n di n g t hat d oes n ot 
satisf y t he e ntra n ce criteria ma y h a ve t he tests re p eate d o nce.  T hes e tests ma y b e re p eate d as 
s o o n as t he i n vesti gat or b elie ves t hat t he ret est res ult is li kel y t o be wit hi n t he acce pta ble ra n ge t o 
satisf y t he e ntra n ce criteria, b ut t he y m ust be c o m plete d wit hi n t he 3- wee k scree ni n g p eri o d  
( Da ys - 2 8 t o - 8).  I n t his case, t he s u bject will n ot be re q uire d t o si g n a n ot h er I C F, a n d t he 
ori gi nal s u bject i de ntificati o n n u m ber will be use d.  If t he la b orat or y tests ca n n ot be perf or m e d 
wit hi n t he scree ni n g peri o d, if t he retests d o n ot meet t he e ntra nce criteri a, or if t he s u bject's 
me dical c o n diti o n has c h a n ge d si g nifica ntl y d uri n g t he scree ni n g p eri o d  s u c h t hat 
i ncl usi o n/e x cl usi o n criteria are n o l o n ger met, t he s u bject will be c o nsi dere d a scree n fail ure a n d 
m ust be wit h dra w n fr o m t he st u d y.  T heref ore, sites s h o ul d c o nsi der t he testi n g sc he d ule 
caref ull y s o t hat a n y p ote ntial retests are acc o m plis he d wit h i n t he 3-wee k ti me fra me.  If t he 
s u bject a n d i n vesti gat or a gr ee t o r escr ee ni n g, t he n t he s u bject m ust si g n a n e w I C F, a ne w 
s u bject i de ntificati o n n u m ber will be assi g n e d, a n d all re q uire d scree ni n g acti vities m ust be 
perf or me d w he n t he s u bj ect is re scree n e d f or p arti ci pati o n in t he st u d y (e x ce pt b o ne marr o w 
bi o ps y if alr ea d y perf or m e d at scr ee ni n g).  A n  i n di vi d ual s u bject ma y o nl y rescree n o nce f or t he 
st u d y. 
If all scr ee ni n g acti vities ca n n ot be c o m plet e d d uri n g t he scree ni n g p eri o d  b eca use of a n e ve nt 
u nrelate d t o a me di cal fi n di n g (f or e x a m ple, sc he d uli n g diffic ulties f or M RI), t he n t he 2 1-da y 
scree ni n g p eri o d ma y be e xte n de d t o as m uc h as 4 2 da ys, wit h t he s u bject retai ni n g t he ori gi n al 
s u bject n u m ber.  A r e peat of scree ni n g  tests f or he mat ol o g y a n d bl o o d c h e mistr y ma y be 
ne cessar y t o deter mi ne eli gi bilit y. 


I nc yte C or p orati o n 
P a ge 3 2  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4  A U G 2 0 1 7  
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 ver all St u d y Desi g n  
T his is a n o pe n-la bel P hase 2 st u d y wit h 2 c o h orts: 
•  C o h ort A :  M F  s u bjects w h o are t olerati n g a r u x oliti ni b d ose of less t ha n 2 0 m g dail y 
wit h n o d ose i ncreas e or n o d ose m o dificat i o n i n t he last 8 wee ks b ef ore scree ni n g 
visit  will recei ve a c o m bi nati o n of t he J A K 1 i n hi bit or itaciti ni b at t he d ose of 2 0 0 m g 
Q D a n d t he J A K 1/ 2 i n hi bit or r u x oliti ni b. 
•  C o h ort B :  M F  s u bjects w h o, after a n i nitial re d u cti o n i n s plee n wit h r u x oliti ni b 
treat me nt, pr o gr esse d or disc o nti n ue d f or he mat ol o gic t o xicities, will recei ve 
treat me nt wit h J A K 1 i n hi bit or itaciti ni b al o ne at t he d ose of 6 0 0 m g Q D.  
S u bjects will c o nti n ue st u d y treat me nt u ntil disease pr o gressi o n, u nacce pta ble t o xicit y, 
wit h dra wal of c o nse nt, or ot her Pr ot oc ol- s pecifi e d criteria t o st o p treat me nt are met.  S u bjects 
w h o are recei vi n g b e nefit fr o m t he t hera p y will c o nti n ue recei vi n g st u d y treat me nt u ntil 
wit h dra wal criteria are m et . 
All s u bjects will be f oll o we d f or s afet y 3 0 t o 3 5 d a ys afte r t h e last d ose of st u d y treat me nt (e g, 
re p orti n g of A Es a n d S A Es). 
T he o ver all st u d y desi g n is s h o w n i n Fi g ure  1. 
Fi g ure  1: 
St u d y Desi g n   
 


I nc yte C or p orati o n 
P a ge 3 3  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4  A U G 2 0 1 7  
C O N FI D E N TI A L  
4. 2.  
Me as ures T a ke n t o A v oi d Bi as  
T his is a n o pe n-la bel st u d y; n o c o m paris o ns will be ma de bet w ee n s u bjects or a gai nst hist orical 
c o ntr ols.  Meas ur e me nts of safet y a n d effi cac y are o bjecti ve meas ure me nts, a n d o nl y 
c o m paris o ns t o pretreat me nt c o n diti o ns will be ma de. 
4. 3.  
N u m ber of S u bjects  
A p pr o xi ma tel y 2 1 s u bj ects will be i ncl u de d i n eac h d ose c o h ort f or a t otal of 4 2 s u bjects. 
4. 4.  
D ur ati o n of Tre at me nt a n d S u bject P artici p ati o n  
After si g ni n g t he I C F, s u bject st u d y partici pati o n is esti mate d t o a vera ge a p pr o xi matel y 
3 2 wee ks  per i n di vi d ual s u bject, e x clusi ve of l o n g- ter m f oll o w- u p peri o d:  
•  Scree ni n g  peri o d  ( Da y - 2 8 t o Da y - 8):  U p t o 2 1 da ys.  
•  B aseli ne ( p retre at me nt) peri o d  ( Da y - 7 t o Da y -1):  7 da ys b ef ore t he  first d ose of 
itaciti ni b (re q uired f or all eli gi ble s u bjects t o c o m plete t he dail y s y m pt o m di a r y f or 
7 da ys b ef or e t he  first d ose of st u d y m e dicati o n). 
•  Tre at me nt peri o d  (starts at Da y 1 t hr o u g h E O T ):  Be gi ns wit h t he first d ose of 
itaciti ni b ( Da y 1).  Tr eat me nt will c o nti n ue as l o n g as t he re gi me n is t olerate d a n d t he 
s u bject d oes n ot meet disc o nti n uati o n criteria.  
•  S af et y f oll o w -u p  peri o d :  3 0 t o 3 5 da ys after t he l ast d ose of itaciti ni b is ta ke n. 
4. 5.  
O ver all St u d y D ur ati o n  
T he st u d y will be gi n w h e n t he first s u bject e nters s cree ni n g, a n d t he  e n d of t he st u d y will occ ur  
w he n all s u bjects ha v e c o m plete d treat me nt or disc o nti n ue d st u d y dr u g a n d ha ve c o m plete d 
a p plica ble f oll o w- u p assess me nts .  I n di vi d ual s u bj ect partici pati o n is e x pecte d t o a vera ge 
3 2 wee ks per i n di vi d ual s u bject. 
4. 6.  
St u d y Ter mi n ati o n  
T he in vesti gat or ret ai ns t he ri g ht t o ter mi nate st u d y partici pati o n at a n y ti me, acc or di n g t o t he 
ter ms s pecifie d i n t he st u d y c o ntr act.  T h e i n vesti gat or is t o n otif y t he i nstit uti o nal re vie w b oar d 
(I R B)/i n de p e n de nt et hics c o m mittee (I E C) i n writi n g of t he st u d y's c o m pleti o n or earl y 
ter mi nati o n, se n d a c o p y of t he n otificati o n t o t he s p o ns or or s p o ns or's desi g nee, a n d retai n 
1 c o p y f or t he site st u d y r e g ul at or y file.  
T he s p o ns or ma y ter mi nate t he st u d y el ecti vel y, if re q uire d b y re g ulat or y d ecisi o n.  If t he st u d y 
is ter mi nate d pre mat ur el y, t he n t he s p o ns or will n otif y t he i n vesti gat ors, t h e I R Bs a n d IE C s, a n d 
re g ulat or y b o dies of t h e decisi o n a n d reas o n f or t er mi nati o n of t he st u d y. 


I nc yte C or p orati o n 
P a ge 3 4  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4  A U G 2 0 1 7  
C O N FI D E N TI A L  
5.  
T R E A T M E N T  
5. 1.  
Tre at me nt Assi g n me nt  
5. 1. 1.  
S u bject N u m beri n g a n d Tre at me nt Assi g n me nt  
Eac h s u bject will be i de ntifie d i n t he st u d y b y a s u bject I D n u m ber, w hic h is a c o m bi nati o n of 
the site I D a n d s u bject n u m ber (see Secti o n 7. 2 ). 
E nr oll me nt will be c o ntr olle d b y a n I X R S .   
St u d y sites will re gister st u d y s u bjects i n t he I X R S i n or der t o recei ve a s u bject n u m ber a n d 
treat me nt all ocati o n. 
All s u bject n u m bers will be 6 di gits; t he first 3 di gits will be t he site n u m ber , a n d t he last 3 di gits 
will be t he s u bject 's n u m ber.  T his s u bject n u m ber will be mai ntai ne d t hr o u g h o ut t he st u d y a n d 
will n ot be reassi g n e d .  S u bjects w h o wit h dra w c o nse nt or disc o nti n ue fr o m t he st u d y aft er bei n g 
assi g ne d a s u bject n u m ber will retai n t heir i nitial n u m ber.  
Site staff will c o ntact t he I X R S t o o btai n t he i nitial st u d y dr u g assi g n me nt.  Refer t o t he I X R S 
ma n ual f or det aile d i nf o r mati o n. 
If a s u bject is mista ke nl y gi ve n a b ottle of st u d y dr u g t hat is n ot t he b ottle assi g ne d b y t he I X R S, 
t he n t he I X R S hel p des k m ust be n otifie d i m me diatel y.  T h e reas o n f or t h e misall ocati o n of t he 
st u d y dr u g m ust be d oc u me nte d b y t h e st u d y site a n d re p ort e d t o t he I R B/I E C. 
F or s u bjects w h o si g ne d a n I C F b ut are n ot all ocat e d a n d f or s u bj ects w h o are all ocat e d b ut were 
n ot treate d, r efer t o t he e C R F C o m pleti o n G ui deli nes f or i nstr ucti o n o n w hic h e C R Fs t o 
c o m plete.  
5. 1. 2.  
R a n d o miz ati o n a n d Bli n di n g  
N ot a p plica ble.  
5. 2.  
St u d y Dr u g   
5. 2. 1.  
It aciti ni b 
5. 2. 1. 1.  
Descri pti o n a n d A d mi nistr ati o n   
5. 2. 1. 1. 1.  C o h ort A s u bjects  
Itaciti ni b will be self-a d mi nistere d  as a 2 0 0 m g Q D oral treat me nt i n t he f or m of 1 0 0 m g ta blets , 
i n a d diti o n t o t heir c urre nt r u x oliti ni b treat me nt.  D oses of itaciti ni b s h o uld be self -a d mi nistere d 
wit h o ut re gar ds t o f o o d.  N ote t hat s u bjects m ust be i nstr u cte d t o wit h h ol d t he m or ni n g d os e of 
itaciti ni b u ntil reac hi n g t he cli nic f or eac h st u d y visit w here d ose a d mi nistrati o n  will occ ur.   


I nc yte C or p orati o n 
P a ge 3 5  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4  A U G 2 0 1 7  
C O N FI D E N TI A L  
5. 2. 1. 1. 2.  C o h ort B s u bjects  
Itaciti ni b will be self-a d mi nistere d  as a 6 0 0 m g Q D oral treat me nt i n t he f or m of 1 0 0 m g ta blets .  
N ote t hat s u bjects m ust be i nstr u cte d t o wit h h ol d t he m or ni n g d os e of itaciti ni b u ntil reac hi n g t he 
cli nic f or eac h st u d y visit w here d os e a d mi nistrati o n  will occ ur.   
5. 2. 1. 2.  
S u p pl y, P a c k a gi n g, a n d L a beli n g  
Itaciti ni b will be pr o vi de d as 1 0 0 m g S R  ta blets p acka ge d i n hi g h -d e nsit y p ol yet h yle n e  b ottles.   
All I nc yt e i n vesti gati o nal pr o d uct la bels will be i n t he l ocal la n g ua ge a n d will c o m pl y wit h t he 
le gal re q uir e me nts of eac h c o u ntr y. 
5. 2. 2.  
R u x o liti ni b 
5. 2. 2. 1.  
Descri pti o n a n d A d mi nistr ati o n  
5. 2. 2. 1. 1.  C o h ort A s u bjects  
R u x oliti ni b will be self-a d mi nistere d  as a n oral treat me nt at t he sta ble d ose of less t ha n 2 0 m g  
dail y esta blis he d b ef or e e nteri n g t he st u d y. 
D oses of r u x oliti ni b s h o ul d be self- a d mi nistere d a p pr o xi m atel y 1 2 h o urs a part wit h o ut re gar d t o 
f o o d. 
N ote t hat s u bjects m ust be i nstr ucte d t o wit h h ol d t he m or ni n g d os e of r u x oliti ni b u ntil reac hi n g 
t he cli nic f or eac h st u d y visit w here d ose a d mi nistrati o n will occ ur (see Secti o n  6. 3 ). 
5. 2. 2. 1. 2.  C o h ort B s u bjects 
N ot a p plica ble.  
5. 2. 2. 2.  
S u p pl y, P ac k a gi n g, a n d L a belli n g  
Refer t o t h e r u x oliti ni b prescri bi n g i nf or mati o n  f or s u p pl y, pac ka gi n g, a n d la beli n g i nf or mati o n.  
5. 2. 3.  
 St or a ge 
T he b ottles of ta blets s h o ul d be st ore d at r o o m te m perat ure, 1 5° C t o 3 0° C ( 5 9° F t o 8 6° F). 
T he s u bject m ust be i nstr ucte d i n t he ha n dli n g of st u d y dr u gs as f oll o ws: 
•  T o st ore s t u d y dr u gs at r o o m te m perat ure. 
•  T o o nl y r e m o ve fr o m t he b ottle of itaciti ni b or r u x oliti ni b t he n u m ber of ta blets 
nee de d at t he ti me of a d mi nistrati o n.  
•  N ot t o re m o ve d oses i n a d va nce of t h e ne xt sc he d ule d a d mi nistrati o n. 
•  T o ma ke e ver y e ff ort t o ta ke d oses o n sc h e d ule. 
•  T o re p ort a n y misse d d os es at t he ne xt st u d y visit.  
•  If t he s u bject v o mits after ta ki n g st u d y dr u g(s), t h e n t he s u bject s h o ul d n ot ta ke 
a n ot her d os e.  


I nc yte C or p orati o n 
P a ge 3 6  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4  A U G 2 0 1 7  
C O N FI D E N TI A L  
•  If a d ose of st u d y dr u g itaciti ni b is misse d b y m ore t ha n 8 h o urs, t he n t hat d ose s h o ul d 
be s ki p pe d, a n d t he ne xt sc he d ule d d ose ta k e n at t he us ual ti me, e x ce pt o n Wee k 2 
Da y 8 f or P K sa m ple m a na ge me nt.  ( F or C o h ort A s u bjects, r u x oliti ni b s h o ul d be 
ta ke n BI D  e v er y 1 2 h o urs b ut n o less t ha n 8 h o urs a part). 
•  T o  kee p st u d y dr u g i n a s afe place a n d o ut of reac h of c hil dre n. 
•  T o bri n g all use d a n d u n use d st u d y dr u g kits t o t he site at eac h visit. 
5. 3.  
Tre at me nt C o m pli a nce  
C o m plia nce wit h all st u d y -r elate d tr eat me nts s h o ul d be e m p hasize d t o t he s u bject b y t h e site 
pers o n nel, a n d a p pr o priat e ste ps s h o ul d be ta ke n t o o pti mize c o m plia nce d uri n g t he st u d y.  
C o m plia nce wit h itaciti ni b  will be calc ulate d b y t h e s p o ns or base d o n t he dr u g acc o u nta bilit y 
d oc u me nte d b y t he site st aff a n d m o nit ore d b y t h e s p o ns or/ desi g nee (ta blet c o u nts).  S u bjects 
will be i nstr ucte d t o bri n g all st u d y  dr u gs  wit h t he m t o t he st u d y visits i n or der f or site p ers o n nel 
t o c o n d uct ta blet c o u nts t o assess st u d y dr u g acc o u nta bilit y.  T h e dr u g acc o u nta bilit y 
d oc u me ntati o n will be use d b y t h e s p o ns or t o calc ulate treat me nt c o m plia n ce.   
5. 4.  
Tre at me nt M o dific ati o ns :  I ncre ases, Decre ases , a n d I nterr u pti o ns  
5. 4. 1.  
D ose Incre as es f or In a de q u ate E ffic ac y  
F or C o h ort A a n d C o h ort B, itaciti ni b will be gi ve n at a fi x e d starti n g d ose ( 2 0 0  m g or 6 0 0 m g 
Q D) , a n d n o i ncreas e will be all o we d f or i n a de q uate efficac y . 
5. 4. 2.  
D os e M o dific ati o n f or T o xicit y 
A d verse e ve nt data a n d l a b orat or y d ata s h o ul d be re vie we d b y t h e i n vesti gat or wit h t he s u bject 
(eit her i n pers o n or b y tel e p h o ne or em ail) at least wee kl y.  Dat a will als o be m o nit ore d b y t h e 
s p o ns or o n a n o n g oi n g b asis i n or der t o o bser v e a n y e m er gi n g tre n ds.  La b orat or y data s h o ul d be 
use d t o g ui de d os e m o dificati o ns f or i n di vi d ual s u bjects as descri be d i n t his secti o n.  
5. 4. 2. 1.  
L a b or at or y Fi n di n gs T h at Re q uire D ose M o dific ati o n  
T he g o al of t he d ose titr ati o n is t o a d mi nister t he hi g hest d ose t hat ca n be t olerate d w hile 
mai ntai ni n g t he f oll o wi n g s pecific safet y para met ers: 
1.  Platelet c o u nts s h o ul d re mai n a b o ve 3 5 ×  1 0 9/ L ( 5 0 × 1 0 9/ L is desira ble). 
2.  A N C s h o ul d re mai n ≥ 0. 5 × 1 0 9/ L. 
3.  A L T, A S T, bilir u bi n, a n d creati ni ne v al ues s h o ul d n ot e x cee d Gra d e 3 . 
4.  T he s u bject s h o ul d n ot e x perie nce ne w or w orse ni n g a n e mia.  F or t h e p ur p oses of t his 
Pr ot oc ol, ne w or w ors e ni n g a n e mia is defi ne d as f oll o ws: 
a. F or s u bj ects w h o are tra nsf usi o n - de pe n de nt * at baseli ne:  
− R ecei ve d t he s a me t otal n u m ber of pac ke d R B C ( P R B C ) u nits tra nsf use d b et wee n 
st u d y start Da y 1 t hr o u g h Da y 4 2 as w as o bser ve d d uri n g t he 1 2 wee ks b ef ore 
st u d y start; O R 


I nc yte C or p orati o n 
P a ge 3 7  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4  A U G 2 0 1 7  
C O N FI D E N TI A L  
− A n i ncreas e b y m ore t ha n 5 0 % i n t otal n u m ber of P R B C  u nits c o m pare d wit h t he 
1 2 wee ks bef ore t h e st u d y start. 
b.  F or s u bjects w h o are tra nsf usi o n-i n de pe n de nt * * at b aseli ne: 
− A decli ne i n he m o gl o bi n of at least 2 g/ d L t o a le v el < 8. 0 g/ d L ( n ot res ulti n g 
fr o m a blee d ca use d b y ac ute tra u ma), if c o nfir m e d b y a re peat la b orat or y 
assess me nt wit hi n 7 da ys wit h o ut i nter ve ni n g c h a n ge i n d os e, use of a n 
er yt hr o p oiesis sti m ula nt , or recei pt of a tra nsf usi o n. 
* B aseli ne tra nsf usi o n -de pe n d e n t is defi ne d as tra nsf usi o ns of at least 6 u nits of P R B Cs  i n t he 1 2 wee ks 
bef ore  st u d y e nr oll me nt, or a he m o gl o bi n le vel of < 8.5 g/ d L, i n t he a bse nce of blee di n g or treat me nt -
i n d uce d a ne mia.  I n a d diti o n, t he m ost rece nt tra nsf usi o n e pis o de m ust ha ve occ urre d i n t he 2 8 da ys 
bef ore  st u d y e nr oll me nt. 
* *  S u bj ects n ot meeti n g t he defi niti o n of tra nsf usi o n -de pe n de nt at baseli ne are c o nsi dere d tra nsf usi o n -
i n de pe n de nt. 
5.  A d diti o nall y, si g nifi ca nt A Es  or la b orat or y a b n or malities ot her t ha n t h ose s pecifie d ma y 
preci pitate a d os e a dj ust me nt or i nterr u pti o n if j u d ge d b y t h e i n vesti gat or t o be at least 
p ossi bl y relate d t o st u d y dr u g.  
5. 4. 2. 2.  
Per mitte d D ose Le v els  
Per mitte d d ose le vels ar e o nl y t h ose s h o w n i n Ta ble  3.  
T a ble 3: 
Per mitte d D ose Le v els b y C o h ort  
 
D ose Le v el 1 
D ose Le vel 2  
D ose Le vel 3  
D ose Le vel 4  
C o h ort A 
2 0 0 m g Q D 
1 0 0 m g Q D 
I nterr u pt 
N/ A  
C o h ort B 
6 0 0 m g Q D 
3 0 0 m g Q D 
2 0 0 m g Q D 
I nterr u pt 
5. 4. 2. 3.  
D ose A dj ust me nt G ui deli nes a n d M a n a gi n g T o xicit y  
He mat ol o gi c or bl o o d c h e mistr y fi n di n gs ma y res ult i n ma n dat or y re d ucti o ns or i nterr u pti o ns i n 
itaciti ni b a d mi nistrati o n as s h o w n i n Ta ble  4.  G ui deli nes are pr o vi d e d f or d ose re d ucti o ns, 
i nterr u pti o ns, restarts, a n d re-es calati o ns i n or der t o pr o vi de c o nsiste nc y i n t he d ose titrati o n 
strate g y; h o we ver, n ot all p ossi ble cases ma y be a ntici pate d b y t h ese g ui deli nes.  T he  
i n vesti gat or ma y us e a m ore ca uti o us a p pr oac h t o d ose i nterr u pti o n, restart, or re-escal ati o n if 
dee me d i n t he s u bject 's b est i nterest, b ut ma y n ot use d oses t hat e x cee d t he g ui deli nes des cri be d 
here u nless a p pr o ve d b y t he me dical m o nit or. 
I n ge ner al, t o xicities are t o be ma na ge d b y d os e re d ucti o ns or i nterr u pti o ns.  Me dicati o ns ma y be 
use d t o ma na ge e m er gi n g t o xicities if nee de d ; h o we ver , please see Secti o ns  5. 6. 2  a n d 5. 6. 3  f or 
restricte d a n d pr o hi bite d me dicati o ns.  Er yt hr o p oi eti n is n ot all o we d d uri n g t he st u d y.  
Gra n ul oc yte gr o wt h fact ors are n ot all o w e d w hile st u d y me di cati o n is bei n g  a d mi nistere d b ut 
ma y b e use d f or se vere n e utr o pe nia at t he i n v esti gat or' s dis creti o n w hile st u d y me dicati o n is 
i nterr u pte d. 
D ose decisi o ns s h o ul d be ma de i n c o nj u ncti o n wit h t he s p o ns or' s me di cal m o nit or w he n s pecial 
cases e xist.  T hese g ui deli nes c o ul d be re vise d b as e d o n e mer gi n g safet y data.  T he s p o ns or will 
pr o vi de a n y r ele va nt safet y u p dates t o t he i n vesti gat or. 


I nc yte C or p orati o n 
P a ge 3 8  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4  A U G 2 0 1 7  
C O N FI D E N TI A L  
T a ble 4: 
D ose I nterr u pti o ns or Re d ucti o ns f or T o xicit y  
L a b or at or y Fi n di n g or 
A d verse E ve nt  
Act i o n T a ke n wit h It aciti ni b D ose 
Re q uire d D ur ati o n of  
D ose Re d ucti o n or I nterr u pti o n  
C O H O R T A  
Restart or re -escalati o n is per mitte d after 
≥ 2 wee ks I F:   
 
St art:  D ose Le vel 1  
First Re d ucti o n:   D ose Le vel 2  
↓ 
P latelet c o u nt  
2 5 t o <  3 5 × 1 0 9/ L 
Re d uce t o or mai ntai n D ose Le vel 2 . 
Platelets rec o ver t o ≥ 5 0  × 1 0 9/ L o n 
2 c o nsec uti ve meas ures ≥ 7 da ys a part . 
Platelet c o u nt  
< 2 5  × 1 0 9/ L 
I nterr u pt d ose. 
Platelets sta bilize at ≥ 3 5 -5 0 × 1 0 9/ L o n 
2 c o nsec uti ve meas ures ≥ 7 da ys a part  
(restart all o we d o nl y at D ose Le vel 2) 
O R  
Platelets rec o ver t o 5 0 × 1 0 9/ L o n 
2 c o nsec uti ve meas ures ≥ 7 da ys a part . 
A N C < 0. 5 × 1 0 9/L 
I nterr u pt d ose.  
A N C rec o vers t o  ≥ 0. 5 × 1 0 9/ L o n 
2 c o nsec uti ve meas ures ≥ 7 da ys a part . 
Pr ot oc ol -defi ne d a ne mia  
Re d uce 1 le vel fr o m c urre nt d ose. 
H e m o gl o bi n sta bilize d f or at l east 4 wee ks 
at ≥ 9 g/ d L . 
C o nfir me d Gra de 4 a 
i ncrease i n A L T, A S T, 
bilir u bi n, or creati ni ne  
I nterr u pt d ose. 
La b orat or y a b n or malit y res ol ves t o Gra de 2 
or  better . 
Ot her n o n he mat ol o gic 
t o xicities 
St u d y dr u g ma y be i nterr u pte d at t he 
discreti o n of t he i n vesti gat or.  
C o ns ult s p o ns or 's me dical m o nit or bef ore 
restarti n g. 
C O H O R T B  
Restart or re -escalati o n is per mitte d after 
≥ 2 wee ks I F:   
 
St art:  D ose Le vel 1  
First Re d ucti o n:  D ose Le vel 2  
Sec o n d Re d ucti o n:  D ose Le vel 3  
↓ 
P latelet c o u nt  
2 5 t o <  3 5 × 1 0 9/ L 
Re d uce 1 le vel fr o m c urre nt d ose 
O R mai ntai n d ose if at D ose L e vel 3. 
Platelets rec o ver t o ≥ 5 0 ×  1 0 9/ L o n 
2 c o nsec uti ve meas ures ≥ 7 da ys a part . 
Platelet c o u nt  
< 2 5 × 1 0 9/ L 
I nterr u pt d ose. 
Platelets sta bilize at ≥ 3 5 -5 0 × 1 0 9/ L o n 
2 c o nsec uti ve meas ures ≥ 7 da ys a part  
(restart per mitte d o nl y at Dose L e vel 3)  
O R  
Platelets  rec o ver t o ≥ 5 0 ×  1 0 9/ L o n 
2 c o nsec uti ve meas ures ≥ 7 da ys a part . 
A N C < 0. 5 × 1 0 9/L 
I nterr u pt d ose. 
A N C rec o vers t o ≥ 0. 5 ×  1 0 9/ L o n 
2 c o nsec uti ve meas ures ≥ 7 da ys a part . 
Pr ot oc ol -defi ne d a ne mia  
Re d uce 1 le vel fr o m c urre nt d ose. 
H e m o gl o bi n sta bilize d f or at l east 4 wee ks at 
≥ 9 g/ d L.  
C o nfir me d Gra de 4 a 
i ncrease i n A L T, A S T, 
bilir u bi n, or creati ni ne  
I nterr u pt d ose. 
La b orat or y a b n or malit y res ol ves t o Gra de 2 or 
better . 
Ot her n o n he mat ol o gic 
t o xicities 
St u d y dr u g ma y be i nterr u pte d at t he 
discreti o n of t he i n vesti gat or.   
C o ns ult s p o ns or 's me dical m o nit or bef ore 
restarti n g. 
a Ac c or di n g t o t h e C T C A E v 4. 0 3.  


I nc yte C or p orati o n 
P a ge 3 9  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4  A U G 2 0 1 7  
C O N FI D E N TI A L  
5. 4. 2. 4.  
G ui deli nes f or D ose Rest art o r Re-esc al ati o n 
It is rec o m me n de d t hat a n y la b or at or y fi n di n gs or A Es preci pitati n g a d ose decrease or 
i nterr u pti o n be m o nit ore d at least t wice w ee kl y u ntil rec o vere d.  T he d ose i nterr u pti o n or 
re d ucti o n s h o ul d be at least 2 wee ks i n d urati o n, after w hic h st u d y dr u g ma y be rec h alle n ge d 
(ie, restarte d or r e-es calat e d) I F t he criteri o n s h o w n i n Ta ble  4 has bee n met.  
T he rec halle n ge ma y  utli ze t he d ose t hat preci pitat e d t he re d u cti o n or i nterr u pti o n, u nless 
ot her wise specifie d  i n Ta ble  4.  If rec o ver y is pr ol o n ge d or t he a b n or malit y is ver y pr o n o u nce d, 
c o nsi der rec halle n gi n g at t he ne xt l o wer d ose , if o ne is a vaila ble.  T h e decisi o n t o rec halle n ge at 
t he d ose preci pitati n g t he e ve nt or at a l o w er a vail a ble d ose le vel  s h o ul d de pe n d o n t he d urati o n 
a n d se verit y of t he a b n or malit y; disc ussi o n wit h t he me dical m o nit or is rec o m me n de d.  I n t he 
case t hat r ec h alle n ge is c o n d ucte d at a d ecrease d d ose, t he d ose ma y be re -escalate d 
s u bse q ue ntl y (after ≥ 2 w ee ks) if safet y para meters per mit. 
A n y  gi ve n  d os e ma y be r ec halle n ge d a ma xi m u m of t wice.  S u bse q ue ntl y, a n y rec h alle n ge m ust 
utilize t he ne xt l o wer d ose f or t hat c o h ort ( Ta ble  3).   (E x ce pti o n s ma y b e gra nte d b y t he 
s p o ns or's me dical m o nit or if t he preci pitati n g e v e nts are se parate d b y l o n g p eri o ds of sta ble 
c o u nts.)  If t he l o w est all o wa ble d ose h as bee n rec halle n ge d t wice a n d is f o u n d t o be n ot 
t olerate d, O R if t he st u d y dr u g ca n n ot safel y be resta rte d at t he l o west a v aila ble d ose le vel wit hi n 
2 1 da ys, t h e s u bject s h o ul d be wit h dra w n fr o m t he st u d y ( see Secti o n  5. 5. 1 )  
5. 4. 3.  
I nterr u pti o n of R u x oliti ni b  ( C o h ort A O nl y ) 
D ose re d u cti o ns of r u x oliti ni b t o dail y d ose s b el o w 5 m g BI D are n ot p er mitte d a n d will res ult i n 
t he disc o nti n uati o n of t he s u bject fr o m t he st u d y.  All c ha n ges i n d ose s h o ul d be rec or de d i n t he 
e C R F, a n d t he s u bject s h o ul d be n otifie d b y p h o n e wit h writte n f oll o w- u p i n cases w here 
la b orat or y dat a s u bse q ue nt t o a st u d y visit i n dicate t hat a d ose c h a n ge is re q uire d.  
D ose m o dificati o n or te m p orar y i nterr u pti o n (f or n o m ore t ha n 8 wee ks) of r u x oliti ni b f or safet y 
reas o ns is at t he discr eti o n of t he i n vesti gat or wit h a p pr o val fr o m t he m e dical m o nit or. 
5. 5.  
W it h dr a w al of S u bjects Fr o m St u d y Tre at me nt  
5. 5. 1.  
Wit h dr a w al Criteri a  
S u bjects m ust  be wit h dr a w n fr o m st u d y treat me nt f or t he f oll o wi n g reas o ns: 
•  If t o xicit y r e q uiri n g itaciti ni b interr u pti o n is n ot res ol ve d s ufficie ntl y t o per mit st u d y 
dr u g a d mi nistrati o n t o res ume wit h 2 1 da ys.  
•  Treat me nt wit h itaciti ni b is i nterr u pte d f or m ore t ha n 2 1  da ys f or a n y reas o n ot her 
t ha n t o xicit y. 
•  If t he l o west all o wa bl e d ose ( base d o n c o h ort) h as been rec halle n ge d t wice a n d was 
n ot t olerate d. 
•  C o h ort A:  Treat me nt wit h r u x oliti ni b is i nterr u pte d f or ≥ 8 wee ks, u nless a p pr o ve d 
b y t he me di cal m o nit or, or if r u x oliti ni b is re d uce d t o a d ose bel o w 5 m g Q D.  
•  T he s u bject re q uires s ple nic irra diati o n. 


I nc yte C or p orati o n 
P a ge 4 0  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4  A U G 2 0 1 7  
C O N FI D E N TI A L  
•  T he s u bject e x hi bits le u ke mic tra nsf or m ati o n (as e vi de nce d b y b o ne m arr o w blast 
c o u nts of at least 2 0 %, or peri p heral blast c o u nts of at least 2 0 %, lasti n g at l east 
8 c o nsec uti ve w ee ks ). 
•  T he s u bject bec o mes pre g na nt ( p ositi ve uri n e pre g na n c y test, c o nfir m e d b y p ositi ve 
ser u m pre g na nc y [ser u m h u ma n c h ori o nic g o na d otr o pi n] test res ults). 
•  C o nse nt is wit h dra w n. 
•  F urt her p artici pati o n w o ul d be i nj uri o us t o t he s u bject' s healt h or w ell- bei n g, i n t he 
i n vesti gat or's me dical j u d g me nt. 
•  T he st u d y is t er mi nat e d  b y t he s p o ns or. 
•  T he st u d y is t er mi nat e d  b y t he l o cal healt h a ut h orit y, I R B, or I E C. 
A s u bject  m a y  be disc o nti n ue d fr o m st u d y treat me nt as f oll o ws: 
•  S u bjects ma y c h o os e t o wit h dra w fr o m t he st u d y at a n y ti me wit h o ut pe nalt y of 
je o par dizi n g t heir h ealt h care or l oss of be n efits t o w hic h t he s u bject is ot her wise 
e ntitle d.  E ver y reas o na bl e eff ort s h o ul d be ma d e t o deter mi ne t he reas o n  t h at a 
s u bject wit h dra ws pr e mat urel y, a n d t his i nf or mati o n s h o ul d be rec or de d i n t he e C R F.  
•  If, d uri n g t he c o urse of t h e st u d y, a s u bject is f o u n d n ot t o ha ve met eli gi bilit y 
criteria, t he n t he m e dical m o nit or, i n c olla b orati o n wit h t he i n vesti gat or, will 
deter mi ne w het h er t he s u bject s h o ul d be wit h dra w n fr o m t he st u d y (see Secti o n 1 0. 5 , 
Pr ot oc ol A d here n ce).  
•  A s u bject ma y be wit h dr a w n fr o m t he st u d y if, i n t he i n vesti gat or' s e x pert me dical 
j u d g me nt, t he s u bject is n o nc o m plia nt wit h t he st u d y re q uire me nts.  T h e s p o ns or 
s h o ul d be c o ns ulte d f or i nstr ucti o n o n ha n dli n g t h e s u bject.  S u bjects ma y be 
wit h dra w n at t he discr eti o n of t he h ealt h a ut h oriti es  or t he i n vesti gat or. 
5. 5. 2.  
Wit h dr a w al Pr oce d ures  
I n t he e ve nt t hat t he d ecisi o n is ma de t o per ma ne ntl y disc o nti n ue t he st u d y treat me nt (itaciti ni b) 
t he E O T visit s h o ul d be c o n d ucte d.  Reas o na bl e eff orts s h o ul d be ma de t o h a ve t he s u bject ret ur n 
f or a f oll o w- u p visit.   T h ese visits are des cri be d i n Secti o n 6 .  T he last date of t he last d ose of 
st u d y treat me nt a n d t he r eas o n f or s u bject wit h dra wal will be rec or de d i n t he eC R F . 
If a s u bject is wit h dr a w n f r o m t he st u d y tre at me nts: 
•  T he st u d y m o nit or or s p o ns or m ust be n otifie d. 
•  T he reas o n(s) f or wit h dra wal m ust be d oc u me nte d i n t he s u bject's me di cal rec or d a n d 
i n t he eC R F.  
•  T he E O T  visit s h o ul d be perf or me d, i n cl u di n g diar y c o m pleti o n. 
•  T he date of t h e E O T visit s h o ul d be rec or de d i n t he I X R S. 
•  I n t he e ve nt t hat a d ecisi o n is ma de t o per ma ne ntl y disc o nti n ue t he st u d y treat me nt, 
reas o na bl e eff orts s h o ul d be ma de t o ha v e t he su bject  ret ur n f or a f oll o w- u p visit f or 
safet y a n d, if p ossi ble, s h o ul d be f oll o we d u ntil st u d y treat me nt -relate d t o xicities 
res ol ve, ret ur n t o baseli n e , or are dee me d irre versi ble, w hic he ver is l o n gest. 


I nc yte C or p orati o n 
P a ge 4 1  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4  A U G 2 0 1 7  
C O N FI D E N TI A L  
5. 6.  
C o nc o mit a nt Me dic ati o ns  
5. 6. 1.  
Per mitte d Me dic ati o ns  
All c o nc o mita nt me dicati o ns a n d treat me nts m ust be rec or de d i n t he e C R F.  A n y pri or 
me dicati o n recei ve d u p t o 3 0 da ys b ef ore e nr ol me nt will be rec or d e d i n t he e C R F.  C o nc o mita nt 
treat me nts or pr o ce d ur es t hat are r e q uire d t o ma n a ge a s u bject's me dical c o n diti o n d uri n g t he 
st u d y will als o be rec or d e d i n t he e C R F. 
A nti bi otic pr o p h yla xis f or c hr o nic tr eat me nt is per mitte d; s u bjects re q uiri n g ac ute a nti bi otic 
treat me nt at t he ti me of s cree ni n g m ust dela y s cree ni n g/e nr oll me nt u ntil t he c o urse of a nti bi otic 
t hera p y is c o m plete d.  
T he s u bject nee ds t o n otif y t he i n v esti gati o nal site a b o ut a n y ne w me di cati o ns he/s he ta kes after 
t he start of t he st u d y dr u g.  All me dicati o ns ( ot her t ha n st u d y dr u g) a n d si g nifica nt n o n dr u g 
t hera pies (i ncl u di n g p h ysical t hera p y a n d bl o o d tra nsf usi o ns) a d mi nistere d after t he s u bject starts 
treat me nt wit h st u d y dr u g m ust be liste d o n t he C o nc o mita nt Me dicati o ns/ Si g nifica nt N o n dr u g 
T hera pies A fter Start of St u d y Dr u g e C R F.   
5. 6. 2.  
Restricte d Me dic ati o ns  
T he f oll o wi n g m e dicati o ns are pr o hi bite d d uri n g t he st u d y: 
1.  As piri n i n d oses e x cee di n g 8 1 m g per da y i n t he U nite d States, 1 2 5 m g i n E ur o pe or 
sta n dar d d ose f or pr o p h yla xis is n ot per mitte d.  L o w- d ose as piri n is per mitte d.  
2.  Aceta mi n o p he n a n d N S AI Ds  (e g, i b u pr ofe n) m a y be us e d at o ver-t he-c o u nter d oses.  
S u bjects recei vi n g o ver -t he-c o u nter N S AI Ds s h o ul d n ot e x cee d t he rec o m me n de d d ose 
a n d s h o ul d be e nc o ura ge d t o use gastr o pr otecti ve a ge nts (a ntaci ds, H 2 a nta g o nists, or 
pr ot o n p u m p i n hi bit ors). 
3.  I n d u cers of C Y P 3 A 4 (A p pe n di x H ) ma y be us e d wit h ca uti o n, a n d i n vesti gat ors s h o ul d 
see k ot her o pti o ns if a v aila ble. 
4.  Mil d/ m o derate C Y P 3 A 4 i n hi bit ors ( A p pe n di x H ) ma y b e use d wit h ca uti o n.  Differe nces 
i n i n di vi d ual se nsiti vit y a n d variati o n i n p ote nc y of i n hi biti o n of vari o us C Y P e nz y m es 
ma y r es ult i n t he nee d f or a re d u ce d d ose of r u x oliti ni b / or itaciti ni b d uri n g a peri o d of 
c o nc o m ita nt me dicati o n use.  If re q uire d f or safet y,  r u x oliti ni b d ose ma y be re d uce d 
fr o m BI D  t o Q D  i n t hese circ u msta nces.  T he s p o ns or's me di cal m o nit or ma y be 
c o ns ulte d f or a d vice w he n usi n g t hese a ge nts. 
5.  If c o nc o mita nt a d mi nistr ati o n of a n a ntic oa g ul a nt/a nti platelet me dicati o n is i n dicate d, 
t he n ca uti o n a n d e n h a nce d m o nit ori n g is re q uire d.  Hist or y of t hr o m b o c yt o p e nia a n d a n y 
c o nc urr e nt r u x oliti ni b-relate d t hr o m b oc yt o pe nia s h o ul d be a fact or i n t he c h oice of 
a ntic oa g ula nt a n d d ose.   
6.  Gra n ul oc yte gr o wt h fact o rs are n ot all o w e d w hile st u d y me dicati o n is bei n g a d mi nistere d 
b ut ma y be us e d f or s e vere ne utr o p e nia at t he i n vesti gat or's discreti o n w hile st u d y 
me dicati o n is i nterr u pte d  
7.  If a s u bject re q uires ster oi ds f or a c o m or bi d c o n diti o n d uri n g st u d y partici p ati o n, t he n 
c o nti n uati o n i n t he st u d y will be c o nsi dere d o n a n i n di vi d ual basis b y t he s p o ns or a n d t he 
i n vesti gat or. 


I nc yte C or p orati o n 
P a ge 4 2  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4  A U G 2 0 1 7  
C O N FI D E N TI A L  
5. 6. 3.  
Pr o hi bite d Me dic ati o ns  
1.  A n y i n vesti gati o nal me di cati o n ( a dr u g t h at is n ot a p pr o ve d f or a n y i n dicati o n) ot her t ha n 
t he st u d y dr u g is pr o hi bit e d.  Use of s u c h me dicati o ns wit hi n 3 0 da ys or 5 h alf-li ves, 
w hic he ver is l o n ger, bef ore t he first d ose of st u d y dr u g a n d d uri n g t he st u d y t hr o u g h t he 
safet y f oll o w- u p visit is pr o hi bite d.  
2.  Use of a n y me di cati o n use d t o treat M F ( e g, H U , i nterfer o n, t h ali d o mi de, b us ulfa n, 
le nali d o mi de, a na gr eli de, ot her c yt ot o xics or i m m u ne m o d ulat ors, ot her J A K 1 i n hi bit ors, 
or a n y i n vesti gati o nal a ge nt) is n ot per mitte d at a n y ti me be gi n ni n g at D a y 1 u p u ntil t he 
ti me t hat itaciti ni b t hera p y is per m a ne ntl y disc o nti n ue d.  I n vesti gat ors m ust deter mi ne 
t hat t he s u bject is a ble t o wit h dra w c urre nt t hera p y wit h o ut it bei n g li kel y t o lea d t o 
si g nifica nt d eteri or ati o n of t he s u bject's c o n diti o n i n or der f or t h e s u bject t o q ualif y f or 
t he st u d y. 
3.  Use of T P O  rece pt or a g o nists (r o mi pl osti m, eltr o m b o pa g) is n ot per mitte d fr o m scree ni n g 
t o t he safet y foll o w- u p visit. 
4.  Us e of er yt hr o p oieti n  is n ot per mitte d fr o m scree ni n g. 
5.  Use of rif a m pi n a n d St J o h n' s W ort, is n ot per mitte d at a n y ti me d uri n g partici pati o n i n 
t he st u d y fr o m scree ni n g t o safet y foll o w- u p visit. 
6.  Use of p ote nt /str o n g C Y P 3 A 4 i n hi bit ors ( b oce pre vir, clarit hr o m yci n, c o ni v a pta n, 
i n di na vir, itrac o naz ole, k et oc o naz ole, l o pi na vir/rit o na vir, rit o na vir, mi befra dil, 
nefaz o d o ne, nelfi n a vir, p osac o naz ole, sa q ui na vir, tela pre vir, telit hr o m yc i n, v oric o naz ole) 
is pr o hi bite d.  Base d o n t he l o w o verall bi oa v aila bilit y of t o pical ket oc o n az ole, t here are 
n o restricti o ns o n t o pical ket oc o naz ole i n t he st u d y. 
See A p pe n di x H  f or a list of C Y P  i n hi bit ors a n d i n d ucers. 
6.  
S T U D Y A S S E S S M E N T S  
All st u d y assess me nts will be perf or me d as i n dicat e d i n t he sc he d ule of assess me nts (see Ta ble  5 
a n d Ta ble  6), a n d all la b orat or y assess me nts will b e perf or me d as i n dicate d i n Ta ble  7 a n d 
Ta ble  8.  Re q uire d la b orat or y a n al yt es are liste d i n Ta ble  9.  T he or d er of assess me nts is 
s u g geste d b y t h e or der of me nti o n wit hi n t he sc he d ule.  See Secti o n 7  f or i nstr ucti o ns o n eac h 
assess me nt.  F urt h er details of st u d y pr oce d ures a n d assess me nts ca n b e f o u n d i n t he st u d y 
refere nce ma n ual.


I nc yte C or p orati o n 
P a ge 4 3  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4 A U G 2 0 1 7  
 
C O N FI D E N TI A L  
T a ble 5: 
Sc he d ule of Assess me nts  f or C o h ort A a n d B ( Scree ni n g T hr o u g h Wee k 1 2) 
Visit D a y ( R a n g e)  
Secti o n  
Scree ni n g  
D a y -2 8 t o 
D a y - 8 
B aseli ne  
D a y -7 t o  
D a y - 1 
D 1  
W 2 
( D 8) 
W 4 ( D 2 9), 
W 8 ( D 5 7)  
W 1 2 
( D 8 5) 
N otes  
± 5 d  
± 5 d  
I nf or me d c o nse nt 
7. 1  
X 
 
 
 
 
 
 
C o ntact I X R S  
7. 1  
X 
 
X 
 
X 
X 
 
I ncl usi o n/e xcl usi o n criteria 
3  
X 
X 
 
 
 
 
 
Pri or me dical a n d  me dica ti o n hist or y  
7. 3  
X 
X 
 
 
 
 
 
C o nc o mita nt me dicati o n re vie w  
7. 4  
 
X 
X 
 
X 
X 
 
Tra nsf usi o n hist or y/stat us  
7. 3  
X 
X 
X 
 
X 
X 
 
Rec or d  A Es  
7. 5. 2  
X 
X 
X 
X 
X 
X 
 
C o m pre he nsi ve p h ysic al e xa mi n ati o n  
7. 5. 3. 1  
X * 
 
X 
 
 
 
*I ncl u des hei g ht (scree ni n g o nl y).  
Tar gete d p h ysical e xa mi n ati o n  
7. 5. 3. 2  
 
 
 
 
X 
X 
 
S plee n pal pati o n a n d meas ure /li v er 
pal pati o n  
7. 6. 2  
X 
X 
 
 
X 
X 
 
Vital si g ns  
7. 5. 4  
X 
X 
X 
X 
X 
X 
 
1 2 -lea d E C G 
 7. 5. 5   
X 
 
 
 
 
 
 
M RI/ C T of t he u p p er a n d l o wer 
a b d o me n a n d pel vis  
7. 6. 3  
 
X 
 
 
 
X 
 
E C O G stat us  
7. 7. 1  
X 
 
 
 
 
 
 
P GI C ( A p pe n di x  F) 
7. 7. 2  
 
 
 
 
X 
X 
 
I W G-M R T assess me nt * 
7. 8  
 
 
 
 
 
 
* R es p o nse assess me nt starts at Wee k 2 4  
Dis pe nse a n d/ or bri n g M F S A F v 2. 0 
diar y t o visit  
7. 6. 4  
 
X 
X 
X 
X 
X 
 
M o difie d M F S A F v 2. 0 diar y 
(A p pe n di x  D) 
7. 6. 4  
 
C o m plete d e ver y e ve ni n g fr o m b aseli n e t hr o u g h Wee k 2 4 
( 2 5 wee k s i n t otal) 
 
M P N -S A F ( A p p e n di x  E) 
7. 7. 3  
 
X 
 
 
 
X 
 
La b orat or y assess me nts *  
7. 5. 6  
X 
X 
X 
X 
X 
X 
* S ee Ta ble  7 a n d Ta ble  8. 
Dis pe nse re mi n d er car d  
7. 1 1. 4  
 
X 
X 
 
X 
X 
 
A d mi nister st u d y dr u g d uri n g visit  
7. 1 1. 1  
 
 
X 
X 
X 
X 
 
Di s pe nse st u d y dr u g 
7. 1 1. 2  
 
 
X 
 
X 
X 
 
Dr u g acc o u nta bilit y assess me nt  
7. 1 1. 3  
 
 
 
X 
X 
X 
 


I nc yte C or p orati o n 
P a ge 4 4  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4 A U G 2 0 1 7  
 
C O N FI D E N TI A L  
T a ble 6: 
Sc he d ule of Assess me nts  f or C o h ort A a n d B  (Wee k 1 6  T hr o u g h F oll o w-U p)  
Visit D a y ( R a n g e)  
Secti o n  
W 1 6 ( D 1 1 3), 
W 2 0 ( D 1 4 1)  
W 2 4 ( D 1 6 9)  
E xte nsi o n 
Visits ( Q 1 2 W 
A fter W 2 4) 
E O T /E arl y 
Ter m i n. Visit  
+ 7 d  of disc o n.  
S afet y F oll o w -U p  
3 0 -3 5 d After L ast 
D ose of It aciti ni b 
N otes  
± 5 d  
± 5 d  
± 7 d  
I nf or me d c o nse nt 
7. 1  
 
 
 
 
 
 
C o ntact I X R S  
7. 1  
X 
X 
X 
X 
 
 
I ncl usi o n/e xcl usi o n criteria 
3  
 
 
 
 
 
 
Pri or me dical a n d me dicati o n hist o r y  
7. 3  
 
 
 
 
 
 
C o nc o mita nt me dicati o n re vie w  
7. 4  
X  
X  
X  
X  
X  
 
Tra nsf usi o n hist or y/stat us  
7. 3  
X  
X  
X  
X  
X  
 
Rec or d A Es  
7. 5. 2  
X  
X  
X  
X  
X  
 
C o m pre he nsi ve p h ysic al e xa mi n ati o n  
7. 5. 3. 1  
 
X 
 
 
X 
 
Tar gete d p h ysical e xa mi n ati o n  
7. 5. 3. 2  
X 
 
X 
X 
 
 
S plee n pal pati o n a n d meas ure /li v er 
pal pati o n  
7. 6. 2  
X 
X 
X 
X 
X 
 
Vital si g ns  
7. 5. 4  
X 
X 
X 
X 
X 
 
1 2 -lea d E C G 
7. 5. 5  
 
 
 
X 
 
 
M RI/ C T of t he u p p er a n d l o wer 
a b d o me n a n d pel vis  
7. 6. 3  
 
X 
X 
 
 
 
E C O G stat us  
7. 7. 1  
 
X  
 
 
X  
 
P GI C ( A p pe n di x  F ) 
7. 7. 2  
X  
X  
X  
X  
 
 
I W G-M R T assess me nt  
7. 8  
 
X *  
X *  
 
 
* Q 2 4 W   
Dis pe nse a n d/ or bri n g M F S A F v 2. 0 
diar y t o visit  
7. 6. 4  
X 
X 
 
 
 
 
M o difie d M F S A F v 2. 0 diar y 
(A p pe n di x  D) 
7. 6. 4  
C o m plete d e ver y e ve ni n g fr o m 
b aseli n e t hr o u g h Wee k  2 4 
( 2 5 wee k s i n t otal) 
 
 
 
 
M P N -S A F ( A p p e n di x  E) 
7. 7. 3  
 
X 
X * 
 
 
* Q 1 2 W  
La b orat or y assess me nts *  
7. 5. 6  
X 
X 
X 
X 
X 
* S ee Ta ble  7 a n d Ta ble  8. 
Dis pe nse re mi n d e r car d 
7. 1 1. 4  
X  
X  
X  
 
 
 
A d mi nister st u d y dr u g d uri n g visit  
7. 1 1. 1  
X 
X 
 
 
 
 
Dis pe nse st u d y dr u g  
7. 1 1. 2  
X  
X  
X  
 
 
 
Dr u g acc o u nt a bilit y assess me nt  
7. 1 1. 3  
X  
X  
X  
X  
 
 


I nc yte C or p orati o n 
P a ge 4 5  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4 A U G 2 0 1 7  
 
C O N FI D E N TI A L  
T a ble 7: 
Sc he d ule of L a b or at or y Assess me nts  f or C o h ort A a n d B ( Scree ni n g T hr o u g h Wee k 1 2) 
 
Secti o n  
Scree ni n g  
D a y -2 8 t o 
D a y - 8 
B aseli ne  
D a y -7 t o 
D a y - 1 
D 1  
W 2 
( D 8) 
W 4 ( D 2 9), 
W 8 ( D 5 7)  
W 1 2 
( D 8 5) 
N otes  
Wi n d o w  
 
T he wi n d o w f or l a b or at or y visits is ± 3 d a ys  
 
L oc al L a b or at or y Assess me nts  
 
Bl o o d c he mistries  
7. 5. 6  
X  
X *  
X *  
 
X  
X  
* S h o ul d be ta k e n as cl ose as p ossi ble t o Da y 1 b ut ma y be 
dra w n u p t o 3 da ys bef ore first d ose.  O nl y 1 sa m ple f or 
b aseli ne/ Da y 1 is re q uire d.  
He mat ol o g y  
7. 5. 6  
X  
X *  
X *  
 
X  
X  
* S h o ul d be ta ke n as cl ose as p ossi ble t o Da y  1 b ut m a y be 
dra w n u p t o 3 da ys bef ore first d ose.  O nl y 1 sa m ple f or 
b aseli ne/ Da y 1 is re q uire d.  
C oa g ulati o n pa nel  
7. 5. 6  
X  
 
 
 
 
X  
 
Uri ne pre g na nc y test *  
7. 5. 6. 1  
 
 
X * *  
 
 
 
* Al l fe male s u bjects of c hil d beari n g p ote ntial. 
* * Pre g na nc y tests s h o ul d be c o n d ucte d m ore ofte n if 
re q uire d b y l ocal re g ulati o ns. 
B o ne marr o w bi o ps y/as pirate  
a n d a nal ysis  
7. 5. 6  
 
X *  
 
 
 
 
* R e q uire me nt f or baseli ne bi o ps y/as pirate ma y be f ulfille d 
b y pri or sta n dar d -of -care assess me nt wit hi n 2 m o nt hs of 
D a y 1 if data are ma de a vaila ble t o t he i n vesti gat or a n d 
s p o ns or. 
Li pi d pa nel (re q uires 
o ver ni g ht fast)  
7. 5. 6  
X  
 
 
 
 
X  
 
Ser o l o g y - he patitis *  
7. 5. 6  
X  
 
 
 
 
 
* H B V, H C V  
Uri nal ysis  
7. 5. 6  
X  
 
 
 
 
X  
 
Ser u m pre g na nc y *  
7. 5. 6. 1  
X  
 
 
 
 
 
* All fe male s u bjects of  c hil d beari n g p ote ntial. 
F S H *  
7. 5. 6. 1  
X  
 
 
 
 
 
* T o d oc u me nt h or m o nal me n o pa use.  
Ce ntr al L a b or at or y Assess me nts *  
* T he ce ntral la b orat or y is t he s p o ns or or s p o ns or's desi g nee.  
C o h ort A a n d B *  
P K sa m ples  
7. 9  
 
 
 
X * *  
X * * *  
 
* C o h ort A, see Ta ble  1 0 .  C o h ort B, see Ta ble  1 1 . 
* * F or C o h ort A , itaciti ni b s h o ul d be a d mi nistere d  after last 
P K c ollecti o n ; see Ta ble  1 0 . 
* * * We e k 4 o nl y.  
C orrelati ve p las ma 
7. 1 0. 2  
 
 
X  
X  
X *  
X  
* We e k 4 o nl y  


I nc yte C or p orati o n 
P a ge 4 6  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4 A U G 2 0 1 7  
 
C O N FI D E N TI A L  
T a ble 8: 
Sc he d ule of L a b or at or y Assess me nts  f or C o h ort A a n d B ( Wee k 1 6 T hr o u g h F oll o w-U p ) 
 
Secti o n  
W 1 6 
( D1 1 3) , 
W 2 0 
( D 1 4 1) 
W 2 4 
( D 1 6 9) 
E xte nsi o n 
Visits ( Q 1 2 W 
After W 2 4)  
E O T /E arl y 
Ter m i n. Visit  
+ 7 d  of disc o n.  
S afet y F oll o w -U p  
3 0 -3 5 d After L ast 
D ose of It aciti ni b 
N otes  
Wi n d o w  
 
T he wi n d o w f or l a b or at or y visits is ± 3 d a ys  
 
L oc al L a b or at or y Assess me nts  
 
Bl o o d c he mistries  
7. 5. 6  
X 
X 
X 
X 
X 
 
He mat ol o g y  
7. 5. 6  
X 
X 
X 
X 
X 
 
C oa g ulati o n pa nel  
7. 5. 6  
 
X 
X 
X 
X 
 
Uri ne pre g na nc y test *  
7. 5. 6. 1  
 
 
 
 
 
* All fe male s u bjects of c hil d beari n g p o te ntial. 
B o ne marr o w 
bi o ps y/as pirate, a n d a n al ysis  
7. 5. 6  
 
X 
X *  
 
 
* R e q uire d Q 2 4 W.  
Li pi d pa nel (re q uires 
o ver ni g ht fast)  
7. 5. 6  
 
X 
X *  
X 
X 
* R e q uire d Q 1 2 W.  
Ser ol o g y * - he p atitis  
7. 5. 6  
 
 
 
 
 
* H B V, H C V  
Uri nal ysis  
7. 5. 6  
 
X 
X *  
 
X 
* R e q uire d Q 1 2 W.  
Ser u m pre g na nc y *  
7. 5. 6. 1  
 
 
 
X 
 
* All fe male s u bject s of c hil d beari n g p ote ntial. 
F S H *  
7. 5. 6. 1  
 
 
 
 
 
* T o d oc u me nt h or m o nal me n o pa use.  
Ce ntr al L a b or at or y * Assess me nts  
* T he ce ntral la b orat or y is t he s p o ns or or s p o ns or 's 
desi g nee.  
C o h ort A a n d B *  
P K sa m ples  
7. 9  
 
 
 
 
 
* C o h ort A, see Ta ble  1 0 .  C o h ort B, see Ta ble  1 1 . 
C orrelati ve plas ma  
7. 1 0. 2  
 
X 
X * *  
 
 
* * Wee k 3 6 a n d 4 8 o nl y  
 


I nc yte C or p orati o n 
P a ge 4 7  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4 A U G 2 0 1 7  
 
C O N FI D E N TI A L  
T a ble 9:  
L oc al L a b or at or y Tests:  Re q uire d A n al ytes 
Bl o o d C he mistr y  
He m at ol o g y  
Uri n al ysis  Wit h 
Micr osc o pic E x a mi n ati o n  
He p atitis Scree ni n g  
C o a g ul ati o n  
Al b u mi n  
Al kali ne p h os p hatase  
A L T  
A S T  
Bicar b o nate  
Bl o o d urea nitr o ge n  
Calci u m  
C hl ori de  
Creati ni ne  
Ferriti n  
Gl uc ose  
Lactate de h y dr o ge nase  
P h os p hate  
P otassi u m  
S o di u m  
T otal bilir u bi n  
Direct bilir u bi n (if t otal bilir u bi n is 
ele vate d a b o ve U L N)  
T otal pr otei n  
Uric aci d  
C o m plete bl o o d c o u nt , 
i ncl u di n g re p orti n g of % 
blasts  
He m o gl o bi n  
He mat ocrit  
Platelet c o u nt  
R B C  c o u nt  
W B C  c o u nt  
 
Differe ntial c o u nt, i ncl u di n g:  
B as o p hils  
E osi n o p hils  
L y m p h oc ytes  
M o n oc y tes 
Ne utr o p hils  
 
A bs ol ute val ues m ust be 
pr o vi de d f or:  
W B C differe ntial la b orat or y 
res ults: 
L y m p h oc ytes  
Ne utr o p hils  
 
C ol or a n d a p peara nce  
p H a n d s pecific gra vit y  
Bilir u bi n  
Gl uc ose  
Ket o nes  
Le u k oc ytes  
Nitrite  
Occ ult bl o o d  
Pr otei n  
Ur o bili n o ge n  
He patitis B s u rface a nti ge n 
He patitis  B s urface a nti ge n 
a nti b o d y 
He patitis A , B c ore a nti b o d y  
H B V -D N A  
H C V a nti b o d y  
H C V -R N A  
P T  
P T T  
I N R 
Li pi d P a nel  
Pre g n a nc y Testi n g  
T otal ch olester ol  
Tri gl yceri des  
L D L  
H D L  
Fe male s u bj ects of 
c hil d beari n g p ote ntial 
o nl y re q uire a ser u m test 
at scree ni n g a n d E O T a n d 
a uri ne pre g na nc y test 
bef ore t he first d ose o n 
C ycle 1 Da y  1.  
Pre g na nc y tests (ser u m or 
uri ne) s h o ul d be re peate d 
if re q uire d b y l ocal 
re g ulati o ns. 
F S H  
H D L = hi g h -de nsit y li p o pr otei n; I N R = i nter n ati o nal n or malize d rati o; L D L = l o w -d e nsit y li p o pr otei n ; P T = pr ot hr o m bi n ti me; P T T = partial t hr o m b o plasti n ti me. 
N ote:  A d diti o nal tests ma y b e re q uire d, as a gree d b y i n vesti g at or a n d s p o ns or, b ase d o n e mer gi n g safet y d ata . 


I nc yte C or p orati o n 
P a ge 4 8  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4 A U G 2 0 1 7  
C O N FI D E N TI A L  
T a ble 1 0: 
Sc he d ule of P h ar m a c o ki netic S a m pli n g f or C o h ort A ( It a citi ni b a n d 
R u x oliti ni b)  
Wee k 2  ( D a y 8) 
Wee k 4 
S u bj ect arri ves ha vi n g wit h hel d b ot h itaciti ni b a n d 
r u x oliti ni b 
Pre d ose sa m ple = Ti me 0 sa m ple  
A d mi nister ru x oliti ni b  
Ti me d sa m ples:  
1 h o ur p ost d ose  ( ± 1 5  mi n) 
2 h o ur s p ost d ose  ( ± 3 0  mi n)  
5 h o ur s p ost d ose  ( ± 6 0  mi n)  
8 h o ur s p ost d ose ( ±  6 0  mi n) a 
A d mi nister itaciti ni b  
S u bj ect arri ves ha vi n g wit h hel d b ot h itaciti ni b a n d 
r u x oliti ni b 
Pre d ose sa m ple = Ti me 0 sa m ple  
A d mi nis ter itaciti ni b pl us r u x oliti ni b  
Ti me d sa m ples:  
1 h o ur p ost d ose  ( ± 1 5  mi n)  
2 h o ur s p ost d ose  ( ± 3 0  mi n)  
5 h o ur s p ost d ose  ( ± 6 0  mi n)  
8 h o ur s p ost d ose ( ±  6 0  mi n)  
a Ei g ht -h o ur p ost d ose sa m ples o n Wee k 2 s h o ul d o nl y b e c ollecte d if t h e s u bject is still i n cli nic at t h e sc h e d ule d ti me of 
c ollecti o n (ie,  at least 7 h p ost d ose).  If t h e s u bject will b e release d b ef ore t h e start of t h e c ollecti o n wi n d o w ( 7 h p ost d ose) , t he 
sa m ple is n ot re q uire d.  T h e s u bject s h o ul d recei ve itaciti ni b Wee k 2 after c ollecti o n of t h e last P K sa m ple at eit h er 5 or 8  h o urs 
p ost d ose.  T he Wee k 4 ei g ht -h o ur p ost d ose sa m ple is re q uire d.  
T a ble 1 1: 
Sc he d ule of P h ar m a c o ki netic S a m pli n g f or C o h o rt B (It aciti ni b Al o ne) 
Wee k 2 ( D a y 8)  
Wee k 4  
S u bj ect arri ves ha vi n g wit h hel d  itaciti ni b  
Pre d ose sa m ple = Ti me 0 sa m ple  
A d mi nister itaciti ni b  
Ti me d sa m ples:  
1 h o ur p ost d ose  ( ± 1 5  mi n)  
2 h o ur s p ost d ose  ( ± 3 0  mi n)  
5 h o ur s p ost d ose  ( ± 6 0  mi n)  
8 h o ur s p ost d o se ( ± 6 0  mi n) a 
S u bj ect arri ves ha vi n g wit h hel d itaciti ni b  
Pre d ose sa m ple = Ti me 0 sa m ple  
A d mi nister itaciti ni b   
Ti me d sa m ples:  
1 h o ur p ost d ose  ( ± 1 5 mi n)  
2 h o ur s p ost d ose  ( ± 3 0 mi n)  
5 h o ur s p ost d ose  ( ± 6 0 mi n)  
8 h o u rs p ost d ose ( ±  6 0 mi n)  
a Ei g ht -h o ur p ost d ose sa m ples o n Wee k 2 s h o ul d o nl y b e c ollecte d if t h e s u bject is still i n cli nic at t h e sch e d ule d ti me of 
c ollecti o n (ie,  at least 7 h p ost d ose).  If t h e s u bject will b e release d b ef ore  t h e start of t h e c ollecti o n wi n d o w ( 7 h p ost d ose) , t he 
sa m ple is n ot re q uire d.  T h e Wee k 4 ei g ht-h o ur p ost d ose sa m ple is re q uire d.  
6. 1.  
Scree ni n g  
Scree ni n g is t he i nter val bet wee n si g ni n g t he I C F a n d t he be gi n ni n g of t he 7- da y ba seli ne p eri o d 
(ie, Da y - 2 8 t o D a y - 7).  Scree ni n g ma y n ot e x cee d 2 1 da ys.  Assess me nts t hat are re q uire d t o 
de m o nstrate eli gi bilit y ma y b e perf or me d o v er t he c o urse of 1 or m ore d a ys d uri n g t he s cree ni n g 
pr ocess.  
S u bjects s h o ul d arri ve f or t he scree ni n g visit after a n o ver ni g ht fast of at least 8 h o urs or si nce 
mi d ni g ht.  A s u bject w h o has n ot faste d s h o ul d be sc he d ule d f or t h e scree ni n g ass ess me nt bl o o d 
dra ws o n a m or ni n g w h e n he/s he ca n arri ve after a n o ver ni g ht fast of at least 8 h o urs or si nce 
mi d ni g ht.  
Pr oce d ures  c o n d ucte d as part of t he s u bject's r o uti ne cli nical ma na ge me nt (e g, bl o o d c o u nt, b o ne 
marr o w bi o ps y) a n d o bt ai ne d bef or e si g ni n g of i nf or me d c o nse nt ma y b e us e d f or scree ni n g 
p ur p oses pr o vi de d t hat t h e pr oce d ure meets t he Pr ot oc ol- defi ne d crite ria a n d has bee n perf or m e d 


I nc yte C or p orati o n 
P a ge 4 9  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4 A U G 2 0 1 7  
C O N FI D E N TI A L  
i n t he ti mefra me of t he st u d y (ie, wit hi n 2 8 da ys  of C ycl e 1 Da y 1) .  All i nf or mati o n ass ociate d 
wit h eli gi bilit y re q uir e me nts  m ust be e ntere d i nt o t he a p pr o pri ate eC R F p a ges.  
B o ne marr o w bi o ps y ( a n d a d diti o nal as pirate c oll ecti o n) f or c o nfir mati o n of M F dia g n osis a n d 
de gree of fi br osis m ust be perf or me d at t he s cree ni n g or bas eli ne visit i nter vals.  N O T E:  
S u bjects wit h o ut circ ulati n g blasts at t he scree ni n g he mat ol o g y assess me nt ma y use a hist orical 
bi o ps y o btai ne d wit hi n 2 m o nt hs bef ore scree ni n g if all data a n d re p orts are a vaila ble f or 
i n vesti gat or's r e vie w.  S u bjects wit h o ut a pri or bi o ps y re p ort as i n dicat e d a b o ve m ust ha ve a 
bi o ps y at scree ni n g or b aseli ne or will n ot be a ble t o e nr oll i n t he st u d y.  T h e pri or data will nee d 
t o be e ntere d i nt o t he e C R F f or t his st u d y, wit h e x pla nati o n as t o t he ori gi n of t he data ( d ate of 
bi o ps y/as pirate). 
Res ults fr o m t he scree ni n g v isit e val uati o ns will be re vie w e d t o c o nfir m s u bject eli gi bilit y b ef ore  
e nr oll me nt.   
6. 2.  
B aseli ne  
S u bjects w h o h a ve si g ne d t he I C F a n d meet all t he e ntr y criteria (s ee Secti o n  3 ) ma y be eli gi ble 
in t he st u d y a n d will be c o ntacte d b y cli nical site staff t o sc he d ule t h e baseli ne visit.  T he 
baseli ne i nter val c orres p o n ds t o t he 7 da ys b ef ore i nitiati n g treat me nt wit h itaciti ni b  a n d d uri n g 
w hic h t he baseli ne M RI ( or C T sca n i n a p plica bl e s u bjects) a n d s y m pt o m diar y will be i nitiate d. 
•  S u bjects w h o meet all eli gi bilit y criteria ma y b e gi n t he baseli ne peri o d of t his st u d y 
( 7 da ys bef ore D a y 1 st u d y start).  D uri n g t he bas eli ne peri o d, all eli gi ble s u bjects 
will be iss ue d a ha n d hel d de vice (e Diar y) o n w hic h t o rec or d s y m pt o ms of M F  i n t he 
M F -S A F diar y (see A p pe n di x D ).  S u bjects will recei ve trai ni n g o n t he d e vice b y 
st u d y site staff b ef or e lea vi n g t he site.  T he i n v esti gati ve site staff m ust e ns ure t hat 
t he diar y is c o m plete d eac h ni g ht be gi n ni n g o n at least Da y - 7 i n or d er t o pr o vi de 
1 c o m plete wee k  of data e ntries bef ore t he D a y 1 visit.   S u bjects will bri n g t he de vice 
al o n g t o t he D a y 1 visit t o c o nfir m t hat at t he diar y e ntri es ha ve b ee n c o m plete d.  T he 
Da y 1 visit s h o ul d n ot be sc he d ule d f or a n y s u bject w h o has n ot c o m plete d at least 
4 da ys of diar y e ntries.  T he s u bjects will als o bri n g t he d e vice al o n g t o e v er y st u d y 
visit t o verif y t he de vi ce c har gi n g a n d t o d o w nl oa d acc u m ulate d d ata.  T he de vice 
will t he n be ret ur ne d t o t he s u bject u p o n visit c o m pleti o n f or c o nti n ue d use eac h 
ni g ht.  S u bjects will ret ur n t he de vice a n d its d oc ki n g s tati o n f or t he fi nal ti me at t he 
E O T visit s o t hat all data ca n be arc hi ve d.  N O T E:   T he diar y ma y b e distri b ute d as 
earl y as t he s cree ni n g visit i n or der t o acc o m m o date s u bject visit sc he d ules d uri n g t he 
baseli ne peri o d. 
•  T he M RI ( or C T sca n i n a p plica ble s u bjects) s h o ul d be c o n d ucte d o n t he first or 
sec o n d da y of t h e baseli n e i nter val t o all o w a m ple ti me t o verif y s ca n q ualit y.   
•  Bl o o d sa m ples f or h e mat ol o g y a n d c he mistr y a nal ys es s h o ul d be t a ke n as cl ose as 
p ossi ble t o Da y 1 b ut ma y be dra w n u p t o 3 d a ys bef ore t h e first d ose of it aciti ni b.  
T his bl o o d sa m ple will ser ve as t h e pre -itaciti ni b baseli ne sa m ple; a D a y 1 sa m ple is 
n ot re q uire d if t he b aseli ne sa m ple is wit hi n 3 da ys of t he first d ose of itaciti ni b. 


I nc yte C or p orati o n 
P a ge 5 0  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4 A U G 2 0 1 7  
C O N FI D E N TI A L  
6. 3.  
Tre at me nt  
T he treat me nt peri o d be gi ns wit h t he first d ose of itaciti ni b ( Da y 1) t hr o u g h t he p oi nt at w hic h 
t he i n vesti gat or d eter mi n es t he s u bject will be per ma ne ntl y disc o nti n ue d fr o m st u d y dr u g. 
T here will be st u d y visits wit h  la b orat or y assess m e nts  i n t he st u d y.  Ta ble  5, Ta ble  6, Ta ble  7, 
a n d Ta ble  8 pr o vi d e t he s c he d ule d a ss ess me nts f or eac h st u d y visit. 
S u bjects will ha ve a re g ularl y s c he d ule d st u d y visit at scree ni n g , b aseli ne, Da y 1, Wee k 4, 
Wee k  8, Wee k 1 2, Wee k 1 6, Wee k 2 0, a n d Wee k 2 4 a n d e ver y 1 2 wee ks t hereafter if c o nti n ui n g 
o n treat me nt, w here bl o o d sa m ples, s plee n meas ure me nts, a n d ot her assess me nts will be 
o btai ne d.  T her e is als o a st u d y visit at Wee k 2  f or P K sa m pli n g, A E assess me nt, a n d he mat ol o g y 
bl o o d dra ws.  T he visit wi n d o w is ± 5 da ys f or visits t hr o u g h Wee k 2 4 a n d ± 7 da ys f or visits 
t hereafter.  T h e ti mi n g f or st u d y visits will be base d o n t he date of t he D a y 1 visit w he n treat me nt 
wit h itaciti ni b  is i nitiate d. 
Bl o o d 
 P K sa m ples will be c ollecte d a n d a nal yz e d b y t he s p o ns or or 
s p o ns or's desi g n ee.  S u bjects will arri ve f or all st u d y visits ha vi n g wit h hel d t he m or ni n g d ose of 
itaciti ni b a n d r u x oliti nib if a p plica ble  a n d i n t he faste d state; a d mi nistrati o n will occ ur i n t he 
cli nic.  S u bjects s h o ul d be t ol d t o bri n g a s n ac k or s mall meal t o t he st u d y visits, as t he y will 
arri ve f or t he visits i n t he faste d state.  
S u bjects will ha ve la b orat or y ass ess me nt s perf or m e d d uri n g st u d y visits t o c ollect he mat ol o g y 
la b sa m ples as n ote d i n T a ble  7 a n d Ta bl e  8.  T he wi n d o w f or la b orat or y visits is ± 3 da ys.  
A d diti o nal la b orat or y ass es s me nts ma y b e perf or me d at t he i n vesti gat or's discreti o n, i ncl u di n g 
f oll o wi n g c h a n ges i n d os e, or if la b or at or y para meters are at Gra de 3 or Gra de 4 le vels base d o n 
t he C T C A E v 4. 0 3. 
S u bjects will c o m plete a n el ectr o nic s y m pt o m diar y ( M F S A F v 2. 0) dail y fr o m baseli ne t hr o u g h 
t he Wee k 2 4 visit (t otal of 2 5 wee ks; A p p e n di x D ). 
S u bjects will c o m plete t he M P N -S A F  i n a e-diar y  (A p pe n di x E ) at visits n ote d i n Ta ble  5 a n d 
Ta ble  6. 
6. 4.  
E n d of Tre at me nt 
T here is n ot a pr e defi n e d E O T.  If a d ecisi o n is ma de t hat t he s u bject will wit h dra w fr o m st u d y 
partici pati o n, t he n a n E O T visit s h o ul d be c o n d ucte d wit hi n 7 da ys after t h e last d ose of st u d y 
treat me nt.  If t he E O T visit c oi nci des wit h a re g ul ar st u d y visit, t he n t he E O T e val uati o ns will 
s u perse de t h ose of t hat sc he d ule d visit, a n d t he dat a s h o ul d be e ntere d i n t he E O T visit i n t he 
e C R F.  T he s u bject s h o ul d be e nc o ur a ge d t o ret ur n f or t he f oll o w- u p visit.   
If a st u d y wit h dra w al occ urs, or if t he s u bject fails t o ret ur n f or visits, t he n t he i n vesti gat or m ust 
deter mi ne t he pri mar y reas o n f or a s u bject's pre m at ure wit h dra wal fr o m t h e st u d y a n d rec or d t his 
i nf ormati o n i n t he e C R F.  
T he i n vesti gat or m ust c o ntact t he I X R S s yste m t o re gister t he s u bject's disc o nti n uati o n. 


I nc yte C or p orati o n 
P a ge 5 1  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4 A U G 2 0 1 7  
C O N FI D E N TI A L  
6. 5.  
F oll o w - U p 
6. 5. 1.  
S af et y F oll o w- U p  
T he safet y f oll o w- u p peri o d is t he i nter val bet wee n t he E O T visit a n d t he sc he d ule d f oll o w- u p 
visit, w hic h s h o ul d occ ur 3 0 t o 3 5 da ys after t he E O T visit ( or after t h e last d ose of st u d y 
treat me nt if t he E O T visit was n ot perf or m e d).  A d verse e v e nts a n d S A Es m ust be re p orte d u p 
u ntil 3 0 da ys aft er t he last d ose of st u d y treat me nt, t he date of t he f oll o w- u p visit, or u ntil st u d y 
treat me nt– relat e d t o xicities res ol ve, r et ur n t o baseli ne, or are dee m e d irre v ersi ble, w hic he ver is 
l o n ger.  R eas o na ble eff orts s h o ul d be ma de t o ha v e t he s u bject ret ur n f or t h e f oll o w- u p visit a n d 
re p ort a n y A Es t h at ma y occ ur d uri n g t his peri o d.  If t he s u bject ca n n ot ret ur n t o t he site f or t he 
safet y f oll o w- u p visit (e g, li ves far a w a y), t he n t h e s u bject s h o ul d be c o ntacte d b y tel e p h o ne f or 
assessi n g A Es a n d S A Es.  Sites s h o ul d d oc u me nt t his c o ntact i n t he s o urce. 
6. 6.  
E n d o f St u d y 
T he e n d of st u d y f or eac h s u bject is c o nsi dere d t o ha ve occ urre d w he n t he s u bject is decease d, 
w he n t he st u d y is c o m plete d, or w he n t he s u bject is per ma ne ntl y l ost t o f oll o w u p.   
6. 7.  
U nsc he d ule d Visits  
U nsc he d ule d st u d y visits ma y o cc ur at a n y ti me if me dicall y warra nte d.  A n y ass ess me nts 
perf or me d (e g, la b orat or y or cli nical assess me nts) at t h ose visits s h o ul d be rec or d e d i n t he eC R F.  
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  
Pr os pecti ve partici pa nts will be sc he d ule d f or a scree ni n g visit b y site staff.  A s u bject n u m ber 
will b e assi g ne d b y a n I X R S.  All pr oce d ures f or s cree ni n g a n d baseli ne m ust be c o m plete d 
wit hi n t he 2 1- da y s cree ni n g + 7 -da y b aseli ne peri o d , e x ce pt as n ote d i n Secti o n  6. 1 ).  T he 
pr oce d ur es i n t his secti o n will be perf or me d. 
7. 1.  
A d mi nistr ati o n of I nf or me d C o nse nt F or m  
Vali d i nf or me d c o nse nt m ust be o btai ne d fr o m t he st u d y s u bject bef ore c o n d ucti n g a n y 
st u d y-s pecific pr o ce d ur es usi n g a n I C F a p pr o v e d b y t he l ocal I R B/I E C t hat c o ntai ns all ele me nts 
re q uire d b y I C H E 6 a n d descri bes t he n at ure, sc o pe, a n d p os si ble c o nse q u e nces of t h e st u d y i n a 
f or m u n dersta n d a ble t o t he st u d y s u bject.  L o cal a n d i nstit uti o nal g ui deli nes f or I C F c o nte nt a n d 
a d mi nistrati o n m ust be f oll o we d; t he ori gi nal si g ne d I C F m ust be retai ne d b y t he i n vestigat or , 
a n d a c o p y of t h e si g n e d I C F m ust be pr o vi de d t o t he st u d y s u bject.  T h e i nf or me d c o nse nt 
pr ocess f or eac h s u bject m ust be d oc u me nte d i n writi n g wit hi n t he s u bject s o urce d oc u me nt ati o n. 
7. 2.  
I nter acti ve Res p o nse Tec h n ol o g y Pr oce d ure  
T he I X R S will be c o ntact e d t o o btai n a s u bject I D n u m ber w he n a s u bject e nters t he scree ni n g 
peri o d.  U p o n deter mi ni n g t hat t he s u bject is eli gi ble , t he I X R S will be c o ntacte d t o o btai n  t he 
treat me nt c o h ort assi g n m e nt.   A d diti o nall y, t he I X R S will be c o ntacte d at eac h re g ul ar st u d y v isit 
t o u p date t he st u d y tr eat me nt s u p pl y a n d at t he E O T visit t o rec or d s u bject disc o nti n uati o n fr o m 
t he st u d y treat me nt (see Secti o n  5. 1. 1 ). 


I nc yte C or p orati o n 
P a ge 5 2  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4 A U G 2 0 1 7  
C O N FI D E N TI A L  
7. 3.  
De m o gr a p h y a n d Me di cal Hist or y  
De m o gra p hic d ata a n d a c o m plete  me dical a n d m e dicati o n hist or y will be c ollecte d at scree ni n g.  
T he s u bject 's date of birt h, race, et h nicit y, m e dical a n d s ur gi cal hist or y, a n d c o nc urrent ill nesses 
assesse d usi n g C T C A E v 4. 0 3 ( N CI  2 0 1 0) will be rec or de d .  D oc u me ntati o n of disease hist or y, 
i ncl u di n g details of M F  dia g n osis, a n d pri or b o ne marr o w bi o ps y data wit h res pect  t o fi br osis 
sta ge will be rec or de d.  All treat me nts f or M F, i n cl u di n g a c o m plete hist or y of r u x oliti ni b usa ge, 
p hle b ot o m y hist or y, a n d all tra nsf usi o ns of R B C pr o d ucts or platelets fr o m at least 1 2 wee ks 
bef ore t h e scr ee ni n g visit will als o be c ollecte d . 
7. 4.  
Pri or  a n d C o nc o mit a nt Me dic ati o n s a n d Pr oce d ures  
Pri or  a n d c o nc o mita nt m e dicati o ns a n d pr o ce d ures will be re vie we d t o d eter mi ne s u bject 
eli gi bilit y.  All c o nc o mit a nt me dicati o ns a n d meas ures  m ust be rec or de d i n t he eC R F , a n d an y 
me dicati o n recei ve d  or pr oce d ur e perf or me d wit hi n 3 0 da ys b ef ore  e nr ollm e nt  a n d u p t o t he 
safet y f oll o w- u p ( 3 0-3 5 da ys after E O T ) will be rec or de d i n t he eC R F.  T h e me dicati o n rec or d 
will be mai ntai ne d  after si g ni n g t he I C F t o d o c u me nt c o nc o mita nt me dicati o ns, i ncl u di n g a n y 
c ha n ges t o t he d ose or re gi me n.  C o nc o mita nt me dicati o ns i ncl u de a n y prescri pti o n, 
o ver-t he- c o u nter, or nat ural/ her bal pr e parati o ns ta ke n or a d mi nistere d d uri n g t he st u d y peri o d.  
C o nc o mita nt treat me nts  a n d/ or pr oce d ures t hat are re q uire d t o ma na ge a s u bject's me di cal 
c o n diti o n d uri n g t he st u d y will als o be rec or d e d i n t he eC R F.   Tra nsf usi o ns of PR B Cs , platelets, 
or ot her bl o o d pr o d uct m ust be rec or d e d i n t he e C R F.   
7. 5.  
S afet y Assess me nts  
Safet y e x a mi nati o ns m ust be perf or m e d b y a s uita bl y trai ne d, m e dicall y q u alifie d i n di vi d ual s uc h 
as a lice nse d p h ysici a n, p h ysicia n 's assista nt, or a n a d va nce d r e gistere d n urs e p ractiti o ner, as 
l ocal la w per mits. 
7. 5. 1.  
Re vie w I ncl usi o n a n d E xcl usi o n C riteri a 
All safet y data a n d ot her eli gi bilit y ass ess me nts m ust be re vie w e d d uri n g t he scree ni n g peri o d t o 
c o nfir m t he s u bject's eli gi bilit y.  
7. 5. 2.  
A d verse E ve nts  
A d verse e ve nts will be m o nit ore d fr o m t he ti me t he s u bject si g ns t he I C F.  S u bjects will be 
i nstr ucte d t o re p ort all A Es d uri n g t he st u d y a n d will be assesse d f or t h e o cc urre nce of A Es 
t hr o u g h o ut t he st u d y.  I n or der t o a v oi d bias i n eliciti n g A Es, s u bjects will be as ke d ge n eral, 
n o nlea di n g q u esti o ns s uc h as "H o w ar e y o u feeli n g? "  All A Es (seri o us a n d n o nseri o us) m ust be 
rec or d e d o n t he s o ur ce d oc u me nts a n d eC R Fs  re gar dless of t he ass u m pti o n of a ca us al 
relati o ns hi p wit h t he st u d y treat me nt.  T he d efi niti o n, re p orti n g, a n d rec or di n g re q uire me nts f or 
A Es are d escri be d i n Secti o n  8 . 
7. 5. 3.  
P h ysic al E x a mi n ati o ns 
7. 5. 3. 1.  
C o m pre he nsi ve P h ysic al E x a mi n ati o n 
T he c o m pre h e nsi ve p h ysical e x a mi nati o n will i ncl u de hei g ht (at scree ni n g) a n d b o d y wei g ht, a n d 
assess me nt(s) of t he f oll o wi n g or ga n or b o d y s yste ms:  s ki n; hea d, e yes, ears, n ose, a n d t hr oat; 


I nc yte C or p orati o n 
P a ge 5 3  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4 A U G 2 0 1 7  
C O N FI D E N TI A L  
t h yr oi d; l u n gs; car di o vas c ular s yste m; a b d o me n (li ver, s plee n); e xtre mities; a n d l y m p h n o des, as 
well as a brief ne ur ol o gical e x a mi nati o n.   T he c o m pre he nsi ve p h ysical e x a mi nati o n s h o ul d als o 
i ncl u de a n assess me nt of b o d y fl ui d a b n or malities , i ncl u di n g ascites a n d e d e ma. 
7. 5. 3. 2.  
 T ar gete d P h ysic al E x a mi n ati o ns 
A tar gete d p h ysical e x a mi nati o n will be a s y m pt o m - directe d e val uati o n a n d will i ncl u de 
assess me nt(s) of t he b o d y s yste ms or or ga ns, as i n dicate d b y s u bject s y m pt o ms, A Es, or ot her 
fi n di n gs as d eter mi ne d b y t he i n vesti gat or or desi g nee.  A tar gete d p h ysical e x a mi nati o n m ust 
i ncl u de a meas ure me nt of t he s u bject's b o d y wei g ht ( wit hi n 1 l b. or 0. 5 k g), a n assess me nt of 
b o d y fl ui d a b n or malities of e de ma a n d ascites, a n d a n e v al uati o n of a n y A Es or s y m pt o ms t hat 
t he s u bject has ha d pr e vi o usl y.  
7. 5. 4.  
Vit al Si g ns  
Vital si g n meas ur e me nts i ncl u de bl o o d press ure, p ulse, res pirat or y rate, a n d b o d y te m perat ure.  
Bl o o d press ur e a n d p ulse will be ta ke n wit h t he s u bject i n t he rec u m b e nt, se mi rec u m be nt, or 
sitti n g p ositi o n after 5 mi n utes of rest.   Cli nicall y n ota ble a b n or malities t hat are c o nsi dere d 
cli nicall y si g nifica nt i n t he j u d g me nt of t h e i n vesti gat or are t o b e re p orte d as A Es . 
7. 5. 5.  
Electr oc a r di o gr a ms  
All 1 2 -lea d E C Gs will be perf or me d wit h the s u bject i n a rec u m be nt or se mirec u m be nt p ositi o n 
after 5 mi n utes of r est.  
T he 1 2- lea d E C Gs will be i nter pret e d b y t he in vesti gat or at t he site  t o be us e d f or i m me diate 
s u bject ma na ge me nt.  T h e decisi o n t o i ncl u de or e x cl u de a s u bject or wit h dra w a s u bje ct fr o m 
t he st u d y bas e d o n a n E C G fla g ge d as "A b n or mal, Cli nicall y Si g nifica nt " is t he res p o nsi bilit y of 
t he i n vesti gat or, i n c o ns ultati o n wit h t he s p o ns or's m e dical m o nit or, as a p pr o priate.  C li nicall y 
n ota ble a b n or malities t hat are c o nsi dere d cli nicall y si g nifica nt i n t he j u d g me nt of t he i n vesti gat or 
are t o be re p orte d as A E s. 
7. 5. 6.  
L a b or at or y Assess me nts 
All he mat ol o g y la b or at or y ass ess me nt s, bl o o d c he mistries , c oa g ul ati o n , li pi d pa nel, ser ol o g y, 
a n d uri nal ysis para m eters will be a nal yze d b y l o cal la b orat ories .  Sa m ples f or he mat ol o g y, bl o o d 
c he mistr y, s er ol o g y, c o a g ulati o n tests, pre g n a nc y, a n d F S H tests a n d uri n al ysis  will be pre p are d 
usi n g sta n dar d pr oce d ures.  A c o m plete list of la b orat or y assess me nts is s h o w n i n Ta ble  7 a n d 
Ta ble  8.  Refer t o t he La b orat or y Ma n u al f or f urt her details a n d s pecificati o ns f or sa m ple 
ha n dli n g, pr o cessi n g, a n d s hi p pi n g.  A d diti o nal la b orat or y assess me nts ma y be c o n d ucte d at 
i n vesti gat or's discr eti on t o u n dersta n d safet y fi n di n gs or t o s u p p ort d ose m o dificati o ns   
7. 5. 6. 1.  
Pre g n a nc y Testi n g  
A ser u m pre g n a nc y test will be re q uire d f or all w o me n  of c hil d beari n g p ot e ntial at scree ni n g  a n d 
at t he E O T  visit .  A n F S H test will be perf or m e d o n fe males w h o h a ve bee n a me n orr h eic f or 
≥ 1 year.  If F S H le v els are ele v ate d t o p ost me n o p a usal ra n ge, n o pre g n a nc y testi n g is re q uire d 
f or t hese f e male s u bjects.  Uri ne pre g n a nc y tests will be c o n d ucte d  as o utli ne d i n Ta ble  7, as 
me dicall y i n dicate d , or p er c o u ntr y-s p ecific re q uire me nt.  Uri ne pre g na n c y tests will be 
perf or me d  l o call y. 




I nc yte C or p orati o n 
P a ge 5 5  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4 A U G 2 0 1 7  
C O N FI D E N TI A L  
A n M RI is t he pr eferre d met h o d f or o btai ni n g s pl ee n v ol u me data.  H o we v er, C T sca ns ma y b e 
perf or me d at t he visits w here M RI is desi g nate d if t he s u bject is n ot a ca n di date f or M RI (e g, 
beca use of t he pr ese nce of metal cli ps i n t he b o d y, beca use of cla ustr o p h o bi a) or if M RI is n ot 
rea dil y a vaila bl e.  C o m p ute d t o m o gra p h y s ca ns will be si milarl y pr ocess e d b y t he sa m e ce ntral 
la b orat or y as us e d f or M RIs.  Pr oce d ure-s pecifi c trai ni n g f or sca n ni n g a n d i ma ge ca pt ure will be 
pr o vi de d b y t he ve n d or.  N O T E:  T he sa me m et h o d ( M RI vs C T) m ust be use d f or all visits f or a 
gi ve n s u bject u nless a ne w c o ntrai n dicati o n t o t he use of M RI occ urs (e g, p ace ma k er i nserti o n). 
7. 6. 4.  
S y m pt o m Di a r y  
S y m pt o ms of M F will be assesse d usi n g a s y m pt o m diar y ( m o difie d M F S A F v 2. 0 diar y; 
A p pe n di x D ).  S u bjects will be iss ue d a ha n d- hel d de vice o n w hic h t o rec or d a ns wers t o q ueries 
re gar di n g M F s y m pt o ms.  S y m pt o ms ass esse d will i ncl u de filli n g u p q uic kl y/ earl y satiet y, 
a b d o mi nal disc o mf ort, a b d o mi nal pai n, i nacti vit y, ni g ht s weats, itc hi n g, a n d b o ne/ m us cle pai n.  
T he m o di fie d M F S A F v 2. 0 diar y will be c o m plete d b y s u bjects eac h ni g ht be gi n ni n g at D a y - 7 
(first da y of b aseli ne) a n d c o nti n ui n g t o t he Wee k 2 4 visit ( 2 5 wee ks t otal).  S u bjects will bri n g 
t he de vice t o t he st u d y site at st u d y visits as o utli ne d i n Ta ble  5 a n d T a ble  6 s o t hat t he de vice 
c har gi n g ca n be verifie d a n d t he acc u m ulate d data ca n be d o w nl o a de d.  N O T E:  S u bjects w h o 
will ha ve o ver ni g ht sta ys ass ociate d wit h t heir st u d y visit  m ust als o bri n g t heir d oc ki n g stati o n s o 
t hat t heir de vice ca n be f ull y c har ge d at all ti mes a n d s o t hat t he y ca n c o m plete t he e ve ni n g diar y 
e ntries.  T he de vi ce will t he n be ret ur ne d t o t he s u bject at t hese sa m e visits f or c o nti n ue d use 
eac h ni g ht.  T he s u bject will ret ur n t he de vice a n d t he d oc ki n g stati o n f or t he fi nal ti me at t he 
Wee k 2 4 visit s o t hat t he data ca n b e ar c hi ve d.  D etaile d directi o ns f or t he a d mi nistrati o n of t he 
m o difie d M F S A F v 2. 0 di ar y will be pr o vi de d i n a refere nce ma n ual.  Fre nc h a n d S pa nis h 
tra nslati o ns of t he m o difie d M F S A F v 2. 0 di ar y will be a vaila ble. 
7. 7.  
Perf or m a nce a n d Q u alit y -of -Life  Assess me nts  
7. 7. 1.  
E aster n C o o per ati ve O nc ol o g y Gr o u p Perf or m a nce St at us  
T he E C O G perf or ma n ce stat us will be assesse d as s h o w n i n Ta ble  5 a n d Ta ble  6 (A p pe n di x C ).   
7. 7. 2.  
P ati e nt Gl o b al I m pressi o n of C h a n ge 
S u bjects will c o m plete t he 1 - q uesti o n assess me nt f or m (A p pe n di x F ) at st u d y visits s h o w n i n  
Ta ble  5 a n d T a ble  6.  I nstr ucti o ns will be pro vi de d as a se parate d o c u me nt.  
7. 7. 3.  
M yel o pr olif er ati ve Ne o pl as ms S y m pt o m Assess me n t F or m  
T he M P N -S A F q uesti o n naire (see A p pe n di x E ) will be c o m plete d at b aseli ne; at Wee ks 1 2 a n d 
2 4 ; a n d at e ver y 1 2- wee k visit t hereafter  s o t hat t h e o verall s y m pt o ms res p o nse assess me nt ca n 
be deter mi ne d a n d re p orte d. 
7. 8.  
I W G-M R T Assess me nt  
O verall r es p o nse assess m e nt will be gr a de d acc or di n g t o t he I W G c o nse ns us criteria f or 
treat me nt res p o ns e i n P M F a n d P P V/ E T -M F ( A p pe n di x B , Tefferi  et al 2 0 1 3). 




I nc yte C or p orati o n 
P a ge 5 7  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4 A U G 2 0 1 7  
C O N FI D E N TI A L  
7. 1 1.  
Ot her St u d y Pr oce d ures  
7. 1 1. 1.  
A d mi nistr ati o n of St u d y T re at me nt  
C o h ort A a n d B :  S u bjects will ta ke t heir d ose of  itaciti ni b i n t he m or ni n g. 
C o h ort A o nl y :  Ru x oliti ni b will be a d mi nistere d orall y as direct e d b y t he l ocal pres cri bi n g 
i nf or mati o n.  I n t h e U nite d States, u p date d i nf or m ati o n ca n be f o u n d at 
htt p:// dail y me d. nl m. ni h. g o v/ dail y me d/a b o ut.cf m. 
7. 1 1. 2.  
Dis pe ns ati o n of S t u d y T re at me nt  
Site staff will c o ntact t he I X R S t o o btai n t he i nitial s u bject st u d y treat me nt assi g n me nt, as well 
as f or s u bse q u e nt dis pe nsati o ns of st u d y treat me nt.  T he i n vesti gat or or desi g nee will select t he 
assi g ne d st u d y dr u g b ottl es fr o m t heir st oc k t hat c orres p o n d wit h  t he n u m b er pr o vi de d b y I X R S 
a n d dis pe nse t he me dicati o n.  T he i n vesti gat or will e nter t he b ottle n u m bers i n t he e C R F.  F ull 
details will be pr o vi de d i n t he I X R S Ma n ual.  
7. 1 1. 3.  
Assess me nt of C o m pli a nce Wit h St u d y Dr u g  
C o m plia nce will be calc ulate d b y t h e s p o ns or base d o n t he dr u g acc o u nta bilit y d oc u me nte d b y 
t he site staff a n d m o nit or e d b y t h e s p o ns or/ desi g n ee (ta blet c o u nts).  T he o bjecti ve is 1 0 0 % 
c o m plia nce, a n d i n v esti gat ors a n d t heir staff s h o ul d e val uate c o m plia nce at eac h visit a n d ta ke 
a p pr o priate ste ps t o o pti mize c o m plia n ce. 
7. 1 1. 4.  
Distri b uti o n of  S u bject Re mi n der C ar ds  
S u bjects will be pr o vi de d wit h re mi n der car ds at eac h visit.  T he s u bject re mi n der car ds will 
i n dicate t he date/ti me of t he ne xt visit a n d i ncl u de a n y s p ecial i nstr ucti o ns f or t hat visit.  T his 
car d will ha ve a n area f or t he s u bject t o rec or d  t he date a n d ti me of t he last d ose ta ke n bef ore  t he 
st u d y visit a n d t he ti me of t heir last m eal (re q uire d f or P K visits).   O n da ys w he n st u d y dr u g is 
N O T t o be ta ke n at h o me i n a d va nce of t he st u d y cli nic, re mi n der car ds will i n dicate t his.  


I nc yte C or p orati o n 
P a ge 5 8  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4 A U G 2 0 1 7  
C O N FI D E N TI A L  
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 verse E ve nts  
8. 1. 1.  
Defi niti o ns  
F or t he p ur p os es of t his Pr ot oc ol, a n a d vers e e ve nt ( A E) is defi ne d as a n y u nt o war d me dical 
occ urr e nce ass ociat e d wit h t he use of a dr u g i n h u ma ns, w het her or n ot c o nsi dere d dr u g r elate d, 
t hat occ urs after a s u bject pr o vi des i nf or me d c o ns e nt.  A b n or mal la b orat or y val ues or test res ults 
occ urri n g after i nf or me d c o nse nt c o nstit ute A Es o nl y if t he y i n d uce cli nical si g ns or s y m pt o ms, 
are c o nsi d ere d cli nicall y mea ni n gf ul, re q uire t hera p y  (e g, he mat ol o gic a b n or malit y t hat re q uires 
tra nsf usi o n), or r e q uire c ha n ges i n t he st u d y dr u g(s). 
8. 1. 2.  
Re p orti n g  
A d verse e ve nts t hat be gi n or w orse n after i nf or me d c o nse nt s h o ul d be rec or de d o n t he A d verse 
E ve nts f or m of t he e C R F.  C o n diti o ns t hat were alrea d y prese nt at t he ti me of i nf or me d c o ns e nt 
s h o ul d be rec or de d o n t h e Me dical Hist or y f or m i n t he e C R F.  M o nit ori n g f or t he occ urre nce of 
ne w A Es s h o ul d be c o nti n ue d f or at least 3 0 da ys after t he l ast d ose of st u d y dr u g  A d vers e 
e ve nts (i ncl u di n g la b orat or y a b n or malities t hat c o nstit ute A Es) s h o ul d be descri be d usi n g a 
dia g n osis w he n e ver p ossi ble rat her t h a n b y i n di vi d ual u n derl yi n g si g ns a n d s y m pt o ms.  W he n a 
clear dia g n osis ca n n ot be i de ntifie d, eac h si g n or s y m pt o m s h o ul d be re p ort e d as a se p arat e A E. 
T he ter m "disease pr o gressi o n " s h o ul d be rec or de d as a n A E/ S A E o nl y if t here are n o ot her 
i de ntifia ble A Es/ S A Es ass ociate d wit h t he disease pr o gressi o n at t he ti me of re p orti n g.  F or 
e ve nts ass ociate d wit h disease pr o gressi o n, t he rele va nt si g ns a n d s y m pt o ms s h o ul d be re p orte d 
usi n g a dia g n osis w h e ne ver p ossi ble rat her t ha n i n di vi d ual u n derl yi n g si g ns a n d s y m pt o ms.  
W he n a clear di a g n osis ca n n ot be i de ntifie d, eac h si g n or s y m pt o m s h o ul d be re p ort e d as a 
se parat e A E.  If t h e e ve nts res ulti n g fr o m disease pr o gressi o n meet t he criteria f or a n S A E (e g, 
res ulte d i n h os pitalizati o n, a life-t hreate ni n g e v e nt, or deat h), t he s pecific e ve nt(s) s h o ul d be 
re p orte d as a n S A E(s) as descri be d i n Secti o n 8. 3. 2 .  I n b ot h cases (i e, AEs or S A Es relate d t o 
disease pr o gr essi o n), it s h o ul d be i n dicate d t hat eac h e v e nt (re p orte d as a dia g n osis or as si g ns 
a n d s y m pt o ms) is relat e d t o disease pr o gressi o n o n t he A d verse E ve nts f or m of t he e C R F. 
T he se verit y of A Es will be assesse d usi n g C T C A E  v 4. 0 3 Gra des 1 t hr o u g h 5.  If a n e v e nt is n ot 
classifie d b y C T C A E, t he se verit y of t he A E will be gra de d acc or di n g t o t he scale b el o w t o 
esti mate t he gra de of se v erit y:  
Gr a de  1 
Mil d; as y m pt o matic or mil d s y m pt o ms; cli nical or dia g n ostic o bser vati o ns o nl y;  
i nter ve nti o n n ot i n dicate d. 
Gr a de 2  
M o derate; mi ni mal, l ocal, or n o ni n vasi ve i nter ve nti o n i n dicate d; li miti n g 
a ge -a p pr o priate acti vities of dail y li vi n g.  
Gr a de 3  
Se vere or me dical l y si g nifica nt b ut n ot i m me diatel y life-t hreate ni n g; h os pitalizati o n 
or pr ol o n gati o n of h os pitalizati o n i n dicate d; disa bli n g; li miti n g self -care acti vities of 
dail y li vi n g.  
Gr a de 4  
Life -t hreate ni n g c o nse q ue nces; ur ge nt i nter ve nti o n i n dicate d. 
Gr a de 5  
Deat h d ue t o A E. 


I nc yte C or p orati o n 
P a ge 5 9  of 8 5 
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4 A U G 2 0 1 7  
C O N FI D E N TI A L  
T he occ urre n ce of A Es s h o ul d be s o u g ht b y n o n directi ve q uesti o ni n g of t he s u bject d uri n g t h e 
scree ni n g pr o cess after si g ni n g t he I C F a n d at eac h visit d uri n g t he st u d y.  A d verse e ve nts ma y 
als o be detect e d w he n t h e y are v ol u nteere d b y t he s u bject d uri n g t h e scree ni n g pr ocess or 
bet wee n visits, or t hr o u g h p h ysical e x a mi nati o n, la b orat or y test, or ot h er assess me nts.  T o t he 
e xte nt p ossi ble, eac h A E s h o ul d be e val uate d t o deter mi ne: 
•  T he se verit y gr a de ( C T C A E Gra d e  1 t o 5). 
•  W het her t here is at least a reas o n a ble p ossi bilit y t hat t he A E is relate d t o t h e st u d y 
treat me nt:  s us pecte d ( yes) or n ot s us pecte d ( n o). 
•  T he start a n d e n d d ates, u nless u nres ol ve d at fi nal f oll o w- u p. 
•  T he acti o n ta ke n wit h re gar d t o st u d y dr u g. 
•  T he e ve nt o utc o me (e g, n ot rec o vere d/ n ot res ol ve d, rec o vere d/res ol ve d, 
rec o veri n g/res ol vi n g, rec o vere d/res ol ve d wit h se q uelae, fatal, u n k n o w n). 
•  T he seri o us ness, as p er s eri o us a d vers e e v e nt ( S A E) defi niti o n pr o vi de d i n 
Secti o n  8. 3. 1 . 
U nli ke r o uti ne safet y assess me nts, S A Es are m o nit ore d c o nti n u o usl y a n d h a ve s peci al re p orti n g 
re q uire me nts (s ee Secti o n  8. 3. 2 ). 
All A Es s h o ul d be treate d a p pr o priatel y.  If a n A E is treate d wit h a c o n c o mita nt me dicati o n or 
n o n dr u g t h era p y, t his acti o n s h o ul d be rec or de d o n A d verse E v e nt f or m a n d t he treat me nt s h o ul d 
be s pecifie d o n t h e Pri or/ C o nc o mita nt Me dicati o ns or Pr oce d ures a n d N o n- Dr u g T hera p y f or m 
i n t he e C R F. 
O nce a n A E is detect e d, it s h o ul d be f oll o we d u ntil it has res ol ve d or u ntil it is j u d ge d t o be 
per ma ne nt; assess me nt s h o ul d be ma de at eac h visit ( or m ore fre q ue ntl y if necessar y) of a n y 
c ha n ges i n se v erit y, t h e s us pecte d r elati o ns hi p t o t he st u d y dr u g, t h e i nter ve nti o ns re q uire d t o 
treat t he e v e nt, a n d t he o utc o me. 
W he n t he se verit y of a n A E c ha n ges o v er ti me f or a re p orti n g p eri o d ( e g, bet wee n visits), eac h 
c ha n ge i n se v erit y will be re p ort e d as a s e parate A E u ntil t he e ve nt res ol v es.  F or e x a m ple, 
2 se parat e A Es will be re p orte d if a s u bject h as Gra de 1 diarr hea, m eeti n g t he defi niti o n of a n A E 
t hat lasts f or 3 da ys bef or e w orse ni n g t o a Gra d e 3 se verit y.  T he Gra de  1 e ve nt will be re p orte d 
as a n A E wit h a start date e q ual t o t he da y t he e ve nt met t he Gra de  1 A E defi niti o n a n d a st o p 
date e q ual t o t he d a y t hat t he e ve nt i ncrease d i n se verit y fr o m Gra de  1 t o Gra de 3.  T h e Gra d e  3 
e ve nt will als o be re p orte d as a n A E, wit h t he start date e q ual t o t he d a y t he e ve nt c ha n ge d i n 
i nte nsit y fr o m Gr a de 1 t o Gra de 3 a n d a st o p date e q ual t o t he da y t hat t he e ve nt eit her c ha n ge d 
se verit y a gai n or res ol ve d. 
8. 2.  
L a b or at or y Test A b n or m alities  
La b orat or y a b n or malities t hat c o nstit ute a n A E i n t heir o w n ri g ht (c o nsi dere d cli nicall y 
mea ni n gf ul, i n d uce cli nical si g ns or s y m pt o ms, re q uire c o nc o mita nt t hera p y, or re q uire c ha n ges 
i n st u d y dr u g) s h o ul d be rec or d e d o n t he A d v erse E ve nt f or m i n t he e C R F.  W he ne ver p ossi ble, a 
dia g n osis r at her t ha n a s y m pt o m s h o ul d be pr o vi de d (e g, " a n e mia" i nstea d of "l o w h e m o gl o bi n").  
La b orat or y a b n or malities t hat meet t he criteri a f or A Es s h o ul d be f oll o we d u ntil t he y ha ve 
ret ur ne d t o n or mal or a n a de q uate e x pla nati o n of t he a b n or malit y is f o u n d.  W he n a n a b n or mal 


I nc yte C or p orati o n 
P a ge 6 0  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4 A U G 2 0 1 7  
C O N FI D E N TI A L  
la b orat or y test 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 pre vi o usl y re p orte d A E, it is n ot 
necessar y t o se par atel y r ec or d t he la b orat or y test res ult as a n a d diti o nal e v e nt.  
La b orat or y a b n or malities t hat d o n ot meet t he defi niti o n of a n A E s h o ul d n ot be re p orte d as A Es.  
A Gra d e  3 a n d Gr a de 4  A E d oes n ot a ut o maticall y i n dicat e a n S A E u nless it meets t he defi niti o n 
of seri o us, as defi ne d i n Secti o n  8. 3. 1 .  A d ose m o dificati o n f or t he la b orat or y a b n or malit y m a y 
be re q uir e d (see Secti o n  5. 4 ) a n d s h o ul d n ot c o ntri b ute t o t he desi g nati o n of a la b orat or y test 
a b n or malit y as a n S A E.  
8. 3.  
Seri o us A d verse E ve nts  
8. 3. 1.  
Defi niti o ns  
A n S A E is defi ne d as a n e ve nt t hat meets at least 1 of t he f oll o wi n g criteri a:  
•  Is fatal or life-t hreate ni n g. 
•  Re q uires i n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n, u nless 
h os pitalizati o n is a res ult of:  
− A r o uti ne treat me nt or m o nit ori n g of t he st u die d i n dicati o n n ot ass ociate d wit h 
a n y d eteri or ati o n i n c o n diti o n. 
− A n electi ve s ur ger y or pre pla n ne d treat me nt f or a pre- e xisti n g c o n diti o n t hat is 
u nrelate d t o t he i n dicati o n u n der st u d y a n d has n ot w orse ne d si nce si g ni n g t he 
I C F. 
− A treat me nt o n a n e mer ge nc y o ut patie nt basis f or a n e ve nt n ot f ulfilli n g a n y of t he 
defi niti o ns of a S A E a n d n ot res ulti n g i n h os pital a d missi o n. 
− A n y s o cial reas o ns a n d res pite care, i n t he a bse n ce of a n y det eri orati o n i n t he 
s u bject's ge ner al c o n diti o n. 
•  Res ults i n persiste nt or si g nifica nt disa bilit y, i nca p acit y, or a s u bsta ntial disr u pti o n of 
a pers o n 's a bilit y t o c o n d uct n or mal life f u ncti o ns. 
•  C o nstit utes a c o n ge nital a n o mal y or birt h defect. 
•  Is c o nsi dere d t o b e a n i m p orta nt me dical e v e nt or a me dicall y si g nifica nt e ve nt t hat 
ma y n ot r es ult i n deat h, b e i m me diatel y life -t hreat e ni n g, or re q uire h os pitalizati o n b ut 
ma y b e c o nsi der e d seri o us w he n, base d o n a p pr o priate me dical j u d g me nt, t he e ve nt 
ma y je o p ar dize t he s u bject or ma y re q uire me dical or s ur gi cal i nter ve nti o n t o pre ve nt 
1 of t he o utc o mes liste d a b o ve. 
8. 3. 2.  
Re p orti n g  
E ver y S A E, re gar dless of s us pecte d ca usalit y (e g, relati o ns hi p t o st u d y dr u g(s) or st u d y 
pr oce d ur e or disease pr o gr essi o n), occ urri n g after t he s u bject has si g n e d t h e I C F t hr o u g h t he last 
st u d y visit ( or 3 0 da ys after t he last d ose of st u d y dr u g, w hic he ver is later) m ust be re p orte d t o 
t he s p o ns or ( or desi g nee) wit hi n 2 4 h o urs  of lear ni n g of its occ urre n ce, u nl ess ot her wise 
s pecifie d b y t he Pr ot oc ol.  A n y S A Es occ urri n g m ore t ha n 3 0 da ys after t h e last d ose of st u d y 
dr u g s h o ul d be re p ort e d t o t he s p o ns or or its desi g nee o nl y if t he i n vesti gat or s us pects a ca usal 
relati o ns hi p t o t he st u d y dr u g.   


I nc yte C or p orati o n 
P a ge 6 1  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4 A U G 2 0 1 7  
C O N FI D E N TI A L  
I nf or mati o n a b o ut all S A Es is c ollecte d a n d rec or de d o n t he A d verse E ve nt f or m of t he e C R F.  
T he i n vesti gat or m ust assess a n d rec or d t he ca usal relati o ns hi p of eac h S A E t o t he st u d y 
treat me nt.  
T he i n vesti gat or m ust als o c o m plete t he I nc yt e Seri o us A d verse E ve nt Re p ort F or m, i n E n glis h, 
a n d se n d t he c o m plete d a n d si g ne d f or m t o t he s p o ns or or desi g nee wit hi n 2 4 h o urs of bec o mi n g 
a war e of t he S A E.  T h e i n vesti gat or m ust pr o vi de a ca usalit y assess me nt, t h at is, assess w het her 
t here is at least a reas o n a ble p ossi bilit y t hat t he S A E is relate d t o t he st u d y treat me nt:  s us pecte d 
( yes) or n ot s us pecte d ( n o).  Refer t o t he I nc yte R efere nce G ui de f or C o m pleti n g t he Seri o us 
A d verse E v e nt Re p ort F or m. 
T he c o ntact i nf or mati o n of t he s p o ns or' s st u d y-s p ecific re pres e ntati ves is liste d i n t he 
i n vesti gat or ma n u al pr o vi de d t o eac h site.  T h e ori gi nal c o p y of t he S A E Re p ort F or m a n d t he 
c o nfir mati o n s heet m ust be ke pt at t he st u d y site. 
I n v esti gati o nal site pers o n nel m ust re p ort a n y ne w i nf or mati o n re gar di n g t h e S A E wit hi n 
2 4 h o urs of bec o mi n g a w are of t h e i nf or mati o n i n t he sa me ma n ner t hat t he i nitial S A E Re p ort 
F or m was s e nt.  F oll o w- u p i nf or mati o n is rec or d e d o n a n a me n de d or ne w S A E Re p ort F or m, 
wit h a n i n dicati o n t hat it is f oll o w - u p t o t he pre vi o usl y re p orte d S A E a n d t h e date of t he ori gi nal 
re p ort.  T he f oll o w- u p re p ort s h o ul d i ncl u de i nf or mati o n t hat was n ot pr o vi de d o n t he pre vi o us 
S A E Re p ort F or m, s uc h as t he o utc o me of t he e ve nt (e g, res ol ve d or o n g oi n g), treat me nt 
pr o vi de d, acti o n ta ke n wit h st u d y dr u g beca use of t he S A E (e g, d ose re d uce d, i nterr u pte d, or 
disc o nti n ue d), or s u bject dis p ositi o n (e g, c o nti n ue d or wit h dre w fr o m st u d y partici pati o n).  Eac h 
rec urre nce, c o m plicati o n, or pr o gressi o n of t he ori gi nal e v e nt s h o ul d be re p orte d as f oll o w- u p t o 
t hat e ve nt, re gar dless of w he n it occ urs. 
If t he S A E is n ot d oc u me nte d i n t he I B f or t he st u d y dr u g ( ne w o cc urre nce) a n d is t h o u g ht t o be 
relate d t o t he s p o ns or's st u d y dr u g, t h e s p o ns or or its desi g nee m a y ur ge ntl y re q uire f urt her 
i nf or mati o n fr o m t he i n v esti gat or f or re p orti n g t o healt h a ut h orities.  T he s p o ns or or its desi g n ee 
ma y n ee d t o iss ue a n I n v esti gat or N otificati o n (I N) t o i nf or m all i n ve sti gat ors i n v ol ve d i n a n y 
st u d y wit h t he sa me dr u g t hat t his S A E has bee n re p orte d.  S us pecte d U ne x pecte d Seri o us 
A d verse Reacti o ns ( S U S A Rs) will be c ollecte d a n d re p orte d t o t he c o m pete nt a ut h orities a n d 
rele va nt et hics c o m mittees i n acc or da nce wit h Directi ve 2 0 0 1/ 2 0/ E C, or as per nati o nal 
re g ulat or y r e q uire me nts i n partici pati n g c o u ntries. 
8. 4.  
E mer ge nc y U n bli n di n g of Tre at me nt Assi g n me nt  
N ot a p plica ble.  
8. 5.  
Pre g n a nc y  
Pre g n a nc y, i n a n d of itself, is n ot re gar d e d as a n A E u nless t here is s us pici o n t hat st u d y dr u g m a y 
ha ve i nterf ere d wit h t he effecti ve n ess of a c o ntrace pti ve me dicati o n or met h o d.  W he n a 
pre g na nc y h as bee n c o nfir me d i n a s u bject d uri n g mater nal or p ater nal e x p os ure t o st u d y dr u g, 
t he f oll o wi n g pr o ce d ur es s h o ul d be f oll o we d i n or der t o e ns ure s u bj ect safet y: 
•  T he st u d y dr u g m ust be disc o nti n ue d i m me diatel y (fe male s u bjects o nl y; see 
Secti o n  5. 5. 1  f or t he ma xi m u m per mitte d d urati o n of st u d y dr u g i nterr u pti o n). 
•  T he i n vesti gat or m ust c o m plete a n d s u b mit t he I n c yt e Cli nical Trial Pre g n a nc y f or m 
t o t he s p o ns or or its desi g nee wit hi n 2 4 h o urs  of lear ni n g of t he pre g na n c y. 


I nc yte C or p orati o n 
P a ge 6 2  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4 A U G 2 0 1 7  
C O N FI D E N TI A L  
Data o n fet al o utc o me a n d breastfee di n g are c ollecte d f or re g ulat or y re p orti n g a n d dr u g safet y 
e val uati o n.  F oll o w- u p s h o ul d be c o n d ucte d f or eac h pre g na n c y t o deter mi ne o utc o me, i ncl u di n g 
s p o nta ne o us or v ol u ntar y ter mi nati o n, details of t he birt h, a n d t he prese nce or a bse nce of a n y 
birt h defects, c o n ge nital a b n or malities, or mater n al a n d/ or ne w b or n c o m plicati o ns, b y f oll o wi n g 
u ntil t he first well - ba b y visit.  Pre g na nc y s h o ul d b e rec or de d o n a Cli nical Trial Pre g na nc y f or m 
a n d re p ort e d b y t he i n vesti gat or t o t he s p o ns or or its desi g nee.  Pre g na n c y f oll o w- u p i nf or mati o n 
s h o ul d be rec or de d o n t h e sa me f or m a n d s h o ul d i ncl u de a n ass ess me nt of t he p ossi ble ca usal 
relati o ns hi p t o t he s p o ns or's st u d y dr u g t o a n y pre g na n c y o utc o me, as well as f oll o w- u p t o t he 
first well- ba b y visit or t he d urati o n s pecifi e d i n l ocal re g ulati o ns, w hic h e ver is later.  Refer t o t he 
I n c yt e Ref ere n ce G ui d e f or C o m pleti n g t he Cli nical Trial Pre g na n c y F or m.  
A n y S A E occ urri n g d uri n g pre g n a nc y m ust be rec o r de d o n t he S A E re p ort f or m a n d 
s u b mitte d t o t he s p o ns o r or desi g nee. 
8. 6.  
W ar ni n gs a n d Prec a uti o ns  
S pecial war ni n gs or preca uti o ns f or t he st u d y dr u g, deri ve d fr o m s afet y i nf or mati o n c olle cte d b y 
t he s p o ns or or its desi g n ee, are prese nt e d i n t he itaciti ni b I n vesti gat or's Br o c h ure (I B) a n d 
r u x oliti ni b prescri bi n g i nf or mati o n.  A d diti o nal safet y i nf or mati o n c ollect e d bet wee n I B u p d ates 
will be c o m m u nicate d i n t he f or m of I n v esti gat or N otificati o ns (I Ns).  A n y i m p orta nt ne w safet y 
i nf or mati o n s h o ul d be disc usse d wit h t he s u bject d uri n g t he st u d y, as n ecessar y.  If n e w 
si g nifica nt ris ks are i de ntifie d, t he y will be a d de d t o t he I C F. 
8. 7.  
D at a M o nit ori n g C o m mittee  
N o t a p plica ble. 
8. 8.  
A d verse E ve nts of S peci al I nterest  
All re p orte d A Es will be c ollecte d.  T he i n ci de nce of s pecific s afet y  e v e nts i ncl u di n g maj or 
t hr o m b osis, he m orr ha gic e ve nts, le u ke mia, or m yel oi d tra nsf or mati o n will be ta b ulate d.  
8. 9.  
Pr o d uct C o m pl ai nts  
T he s p o ns or c ollects pr o d uct c o m plai nts o n st u d y dr u gs a n d dr u g deli ver y s yste ms use d i n 
cli nical st u dies i n or der t o e ns ure t he s afet y of st u d y partici pa nts, m o nit or q ualit y, a n d facilitate 
pr ocess a n d pr o d uct i m pr o ve me nts. 
All pr o d uct c o m plai nts ass ociate d wit h  material p ac ka ge d, la bele d, a n d rel ease d b y t he s p o ns or 
or its desi g nee will be re p orte d t o t he s p o ns or.  All pr o d uct c o m plai nts ass ociate d wit h ot her 
st u d y materi al will be re p orte d directl y t o t he res pecti ve ma n ufact urer. 
T he i n vesti gat or or his/ her desi g nee is res p o nsi ble f or re p orti n g a c o m plet e descri pti o n of t he 
pr o d uct c o m plai nt via e mail or ot her writte n c o m m u nicati o n t o t he s p o ns or c o ntact or res pecti ve 
ma n ufact ur er as n ot e d i n t he pac ka gi n g i nf or mati o n.  A n y A E ass ociat e d wit h a pr o d uct 
c o m plai nt s h o ul d be re p orte d as descri be d i n Secti o n 8. 1. 2  of t his Pr ot oc ol. 
If t he i n vesti gat or is as ke d t o ret ur n t he pr o d uct f or i n vesti gati o n, he/s he will ret ur n a c o p y of t h e 
pr o d uct c o m plai nt c o m m u nicati o n wit h t he pr o d uct. 


I nc yte C or p orati o n 
P a ge 6 3  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4 A U G 2 0 1 7  
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 n s 
T he F A S i ncl u des all s u bjects e nr olle d i n t h e st u d y w h o recei ve d at least 1  d ose of st u d y dr u g 
(itaciti ni b).  T he F A S  will be use d i n t he a nal yses of de m o gra p hic, b aseli ne, a n d effi cac y d ata.  
T he safet y p o p ulati o n i ncl u des all e nr olle d  s u bjects w h o recei ve d at least 1 d ose of st u d y dr u g.   
T he per pr ot o c ol p o p ulati o n i ncl u des all e nr olle d s u bjects w h o were s uffi cie ntl y c o m plia nt wit h 
t he Pr ot oc ol.  S pecific criteria f or t his p o p ulati o n will be defi ne d i n t he S A P.  
T he P K /P D  e val ua ble p o p ulati o n i ncl u des all s u bjects w h o recei ve d at least 1 d ose of st u d y dr u g 
a n d pr o vi de d at least 1 sa m ple f or P K /P D .   
9. 2.  
Selecti o n of S a m ple S ize 
U p t o 2 1 s u bjects will be e nr olle d i n eac h of t he 2 d ose c o h orts ( C o h ort A a n d C o h ort B) f or a 
t otal of 4 2 s u bjects o verall.  T he si g n test will be use d t o e val uate p erce nt a ge c ha n ge fr o m 
baseli ne i n s plee n v ol u m e b y M RI or C T at Wee k 2 4 i n a p plica ble s u bjects  wit h a 1-si de d T y pe I 
err or of 0. 0 5.  If 1 5 or m ore o ut of 2 1 s u bjects o bser ve a > 0 % S V R at Wee k 2 4, t he n f urt her 
de vel o p me nt of itaciti ni b as m o n ot hera p y or i n c o m bi nati o n wit h r u x oliti ni b ma y b e c o nsi dere d.  
If t he per ce nta ge of S V R at Wee k 2 4 is n or mall y distri b ute d wit h mea n 1 1. 4 a n d sta n dar d 
de viati o n 1 4. 5, t he test has 8 5 % p o wer t o i n dicat e t hat a d diti o nal de vel o p me nt is warra nt e d.   
9. 3.  
Le vel of Si g nific a nce  
T he le vel of si g nifica nce f or detecti n g a differe nce  fr o m a 0 % me dia n p erce nta ge S V R i n eac h 
c o h ort is 5 % ( 1-si de d).  I n ot her w or ds, u n der t he n ull h y p ot hesis of s u bjects recei vi n g itaciti ni b 
ha vi n g a tr ue me dia n p er ce nta ge S V R of 0 %, t here is a 5 % c h a nce of decl ari n g a gi v e n c o h ort as 
ha vi n g a me dia n perce nt a ge S V R > 0 %.  N ote t h at t his le vel of si g nifica n ce d oes n ot acc o u nt f or 
testi n g of m ulti ple c o h orts. 
9. 4.  
St atistic al A n al yses  
A f ull descri pti o n of all a nal yses will be i ncl u de d i n t he S A P d oc u me nt. 
9. 4. 1.  
Effic ac y A n al yses 
9. 4. 1. 1.  
Pri m ar y Effic ac y A n al yses  
T he pri mar y e n d p oi nt of c ha n ge a n d perce nt a ge of S V R (as meas ure d b y M RI or C T ) at 
Wee k  2 4 will be s u m marize d b y c o h ort.  Wit hi n eac h c o h ort, t he si gn test will be use d t o 
e val uate me dia n p er ce nta ge of S V R , a n d a 9 0 % c o nfi de nce i nter val f or t h e me dia n perce nta ge 
S V R will be calc ulate d  usi n g t he e x act bi n o mial c o nfi de nce i nter val met h o d.  Perce nta ge S V R 
will be s u m marize d descri pti vel y at Wee k 1 2 b y c o h ort.  


I nc yte C or p orati o n 
P a ge 6 4  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4 A U G 2 0 1 7  
C O N FI D E N TI A L  
9. 4. 1. 2.  
Sec o n d ar y Effic ac y A n al yses 
Sec o n dar y efficac y a n al yses will be c o n d ucte d f or t he F A S  p o p ulati o n.  C ha n ge a n d p erce nta ge 
c ha n ge fr o m baseli ne i n q ua ntitati ve varia bles will be s u m marize d  b y c o h ort usi n g des cri pti ve 
statistics.  Fre q ue n cies a n d perce nt a ges f or cat e g orical varia bles will be pr o vi de d b y c o h ort.  
C ha n ge a n d perce nt a ge c ha n ge i n s plee n le n gt h fr o m baseli ne as meas ure d b y pal p ati o n at eac h 
visit w here t he par a meter is assesse d t hr o u g h Wee k 2 4 will be ta b ulate d b y c o h ort wit h s u m mar y 
statistics.  
Perce nt a ge c ha n ge fr o m baseli ne i n 7 -da y M F S A F T S S a n d M P N -S A F T S S will be s u m marize d 
at Wee k 1 2 a n d Wee k 2 4 b y c o h ort, a n d 9 0 % c o nfi de nce i nter v al s f or t he m e dia n perce nta ge 
c ha n ge will be esti mate d.  
Patie nt Gl o bal I m pr essi o n of C ha n ge will be s u m mari ze d b y visit.  S u bject data will be 
s u m marize d b y c o h ort a n d fi nal titrate d d ose of itaciti ni b. 
T he n u m ber of s u bjects wit h res p o nses acc or di n g t o t he 2 0 1 3 I W G c o ns e ns us criteria will be 
ta b ulate d. 
9. 4. 1. 2. 1.  Deri v ati o n of M F S A F T S S  
T he T S S f or t he M F S A F v 2. 0 diar y w ill be deter mi ne d as f oll o ws ( N O T E:  sc ores f or i nacti vit y 
a n d fati g ue will n ot be i n cl u de d i n T S S  deter mi nati o ns):  
•  T he Dail y T otal Sc ore will be defi ne d as t he s u m of 6 i n di vi d ual s y m pt o m sc ores 
( ni g hts s weats, itc hi ness, a b d o mi nal disc o mf ort, pai n u n der left ri bs, earl y s atiet y, 
b o ne/ m uscle pai n, eac h wit h a 0 t o 1 0 p oi nt scale) c ollecte d o n t he s a me d a y; t he 
sc ore will be missi n g if t here are a n y missi n g i n di vi d ual sc ores.  N ote t hat t he diar y is 
c o m plete d at t he e n d of eac h da y.  
•  T he Baseli ne T otal Sc or e will be defi ne d as t he a v era ge of Dail y T otal Sc ores fr o m 
t he baseli ne peri o d.  If t h ere are m ore t ha n 7 da ys of b aseli ne s y m pt o m data rec or de d 
( beca us e of a d ela y i n treat me nt start), t he last 7 d a ys b ef ore e nr oll me nt will be use d.  
T he Baseli ne T otal S c or e will be missi n g if t here are fe wer t ha n 4 d a ys of Baseli ne 
Dail y T otal Sc ore s. 
•  T he Wee k 1 2 ( 2 4) T ot al Sc ore will be defi n e d as t he a vera ge of Dail y T otal Sc ores 
fr o m t he last 7 da ys of s y m pt o m sc ores bef ore t he Wee k 1 2 ( 2 4) visits.  T he Wee k 1 2 
( 2 4) Total Sc ore will be missi n g if t here are fe w er t ha n 4 da ys of Wee k 1 2 ( 2 4) Dail y 
T otal Sc ores.  
•  T he per ce nt a ge c ha n ge will be calc ulate d as f oll o ws:   
% C ha n ge = 1 0 0 × ( Wee k 1 2 T otal Sc ore – Baseli ne T otal Sc ore) / Bas eli ne T otal 
Sc ore  
9. 4. 2.  
S af et y A n al yses 
T he sa fet y a nal yses will be c o n d ucte d f or t he safet y e v al ua ble p o p ulati o n. 


I nc yte C or p orati o n 
P a ge 6 5  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4 A U G 2 0 1 7  
C O N FI D E N TI A L  
9. 4. 2. 1.  
A d verse E ve nts  
A T E A E is a n y A E eit her re p orte d f or t he first ti me or w orse ni n g of a pre- e xisti n g e ve nt after 
first d ose of st u d y dr u g.  A nal ysis of A Es will be li mite d t o T E A Es, b ut data listi n gs will i ncl u de 
all A Es re gar dless of t heir ti mi n g t o st u d y dr u g a d mi nistrati o n.  A d verse e v e nts will be ta b ulate d 
b y t he M e d D R A preferre d ter m a n d s yste m or ga n class.  Se verit y of A Es will be base d o n t he 
N CI C T C A E v 4. 0 3 usi n g Gra des 1 t hr o u g h 5. 
T he s u bset of A Es c o nsi d ere d b y t he i n vesti gat or t o ha ve a relati o ns hi p t o st u d y dr u g will be 
c o nsi dere d t o be tr eat me nt-relate d A Es.  If t he i n v esti gat or d o es n ot s pecif y t he relati o ns hi p of 
t he A E t o st u d y dr u g, t he n t he A E will be c o nsi dere d treat me nt-relate d.  T h e i nci de nce of A Es 
a n d treat me nt -relate d A Es will be ta b ulate d. 
9. 4. 2. 2.  
Cli nic al L a b or at or y Tests 
La b orat or y test v al ues o utsi de t he n or mal ra n ge will be assesse d f or s e verit y base d o n t he n or mal 
ra n ges f or t he cli nical r ef ere nce la b or at or y.  T he i nci de nce of a b n or m al la b orat or y val ues a n d 
s hift ta bles relati ve t o bas eli ne will be ta b ulate d. 
La b orat or y d ata will be classifie d i nt o G ra des 1 t hr o u g h 5 usi n g C T C A E v 4. 0 3 or si milar criteria 
w here cli nical i nter ve nti o n is re q uire d f or C T C A E gra di n g.  S hift ta bles fr o m baseli ne t o t he 
w orst p ost baseli ne C T C A E gra de will be pr o vi de d f or la b orat ories usi n g C T C A E gra di n g 
criteria.  F or la b orat or y p ara meters w here C T C A E gra des are n ot defi ne d, s hift ta bles t o t he 
w orst p ost baseli ne val ue usi n g t he l o w/ n or mal/ hi g h cl assificati o ns base d o n la b orat or y refere nce 
ra n ges will be pr o vi de d.  
9. 4. 2. 3.  
Vit al Si g ns  
Descri pti ve statistics a n d mea n c ha n ge fr o m b aseli ne will be deter mi ne d f or vital si g ns ( bl o o d 
press ure, p ulse , res pirat or y rate, a n d b o d y te m perat ure) at eac h assess me nt ti me.  Vital si g n 
res ults will be re vie w e d f or cli nicall y n ot a ble a b n or malities (see Ta bl e  1 2), a n d s u bjects 
e x hi biti n g cli nicall y n ota ble vital si g n a b n or m alities will be liste d.  A val ue will be c o nsi dere d a n 
"alert" v al ue if it is o utsi de t he esta blis he d ra n ge a n d s h o ws a > 2 5 % c ha n ge fr o m baseli ne.  
T a ble 1 2: 
Criteri a f or Cli nic all y N ot a ble Vit al Si g n A b n or m alities  
P ar a meter  
Hi g h T hres h ol d  
L o w T hres h ol d  
S yst olic bl o o d press ure  
> 1 5 5  m m H g  
< 8 5 m m H g  
Diast olic bl o o d press ure  
> 1 0 0 m m H g  
< 4 0 m m H g  
P ulse  
> 1 0 0 b p m  
< 4 0 b p m  
T e m perat ure  
> 3 8º C  
< 3 5. 5º C  
Res pirat or y rate  
> 2 4/ mi n  
< 8/ mi n  
9. 4. 2. 4.  
Electr oc a r di o gr a ms  
Electr ocar di o gra m a b n or malities, b ot h at baseli ne a n d p ost baseli ne visits, wil l be ta b ulate d b y 
treat me nt gr o u p.  S u bjects e x hi biti n g cli nicall y n ota ble E C G a b n or malities will be liste d.  




I nc yte C or p orati o n 
P a ge 6 7  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4 A U G 2 0 1 7  
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 vesti g at or Res p o nsi bilities 
T his st u d y will be perf or me d i n acc or d a nce wit h et hical pri nci ples t hat ori gi nate i n t he 
Declar ati o n of Helsi n ki a n d c o n d ucte d i n a d h ere n ce t o t he st u d y Pr ot o c ol; G C Ps as defi ne d i n 
Title  2 1 of t he U S C F R Parts 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 date d g ui deli nes; a n d 
l ocal re g ulat or y re q uir e me nts as a p plica ble t o t he st u d y l ocati o ns. 
T he i n vesti gat or will be r es p o nsi ble f or: 
•  P er mitti n g st u d y-related m o nit ori n g , s p o ns or a u dits, I R B/I E C re vie w, a n d re g ul at or y 
i ns pecti o ns b y pr o vi di n g direct access t o s o urce data a n d ot her rele va nt cli ni cal st u d y 
d oc u me nts. 
− M o nit ori n g:  Q ualifie d r e prese ntati ves of t h e s p o ns or or its desi g n ee , st u d y 
m o nit ors, will m o ni t or t he st u d y acc or di n g t o a pre deter mi ne d pla n.  T he 
i n vesti gat or m ust all o w t he st u d y m o nit ors t o re vi e w a n y st u d y materi als a n d 
s u bject rec or ds at eac h m o nit ori n g visit. 
− A u diti n g:  Q ualifie d r e prese ntati ves of t he s p o ns or or its desi g n ee ma y a u dit t he 
cli nical st u d y site a n d st u d y dat a t o e val uat e c o m plia nce wit h t he Pr ot oc ol, 
a p plica ble l ocal cli nical st u d y re g ul ati o ns, a n d o verall st u d y c o n d u ct.  T he 
i n vesti gat or m ust all o w t he a u dit ors t o re vie w ori gi nal s o urce rec or ds a n d st u d y 
d oc u me ntati o n f or all s u bjects. 
− Re g ulat or y i ns pecti o n:  Re g ulat or y a ut h orities ma y c o n d uct a n i ns pecti o n of t he 
st u d y a n d t he site at a n y ti me d uri n g t he d e vel o p m e nt of a n i n vesti gati o nal 
pr o d uct .  T he i n vesti gat or a n d staff are e x pecte d t o c o o perat e wit h t he i ns pect ors 
a n d allo w access t o all s o urce d oc u m e nts s u p p orti n g t he e C R Fs a n d ot her 
st u d y-r elate d d oc u m e nts.  T he i n vesti gat or m ust i m me diatel y n otif y t he s p o ns or 
w he n c o ntacte d b y a n y re g ulat or y a ut h orit y f or t he p ur p oses of c o n d u cti n g a n 
i ns pecti o n. 
•  O btai ni n g i nf or m e d c o ns e nt a n d e ns uri n g t hat t he st u d y s u bjects' q uesti o ns ha ve bee n 
a ns wer e d a n d t he s u bjects f ull y u n dersta n d st u d y pr oce d ures: 
− I nf or me d c o ns e nt m ust be o btai ne d bef ore  a n y st u d y-relate d pr oce d ures are 
c o n d ucte d, u nless ot her wise s pecifie d b y t he Pr ot o c ol. 
− I nf or me d c o ns e nt m ust be o btai ne d usi n g t h e I R B/I E C-a p pr o ve d versi o n i n a 
la n g u a ge t hat is nati ve a n d u n dersta n da ble t o t he s u bject.  A te m plate will be 
pr o vi de d b y t he s p o ns or or its desi g nee.  T he s p o ns or or its desi g n ee m ust re vie w 
a n d ac k n o wl e d ge t he site-s pecific c ha n ges t o t he I C F te m plate.  T he I C F m ust 
i ncl u de a state me nt t hat t he s p o ns or or its desi g n ee a n d re g ul at or y a ut h oriti es ha ve 
direct access t o s u bject rec or ds.  


I nc yte C or p orati o n 
P a ge 6 8  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4 A U G 2 0 1 7  
C O N FI D E N TI A L  
•  O btai ni n g a p pr o val fr o m t he I R B/I E C bef ore t he  st art of t he st u d y a n d f or a n y 
c ha n ges  t o t he cli nical st u d y Pr ot oc ol, i m p orta nt Pr ot oc ol de viati o ns, r o uti ne u p dates, 
a n d safet y i nf or mati o n i n acc or d a nce wit h i nstit uti o nal re q uire m e nts a n d l ocal la w. 
− T he  i n vesti gat or is res p o nsi ble f or e ns uri n g t hat t he safet y re p orts pr o vi de d b y t he 
s p o ns or are re vie w e d a n d pr ocesse d i n acc or da nce wit h re g ul at or y re q uire m e nts 
a n d wit h t he p olicies a n d pr oce d ures esta blis he d b y t he I R B /I E C. 
•  A d heri n g t o t he Pr ot oc ol as descri be d i n t his d oc u me nt a n d a gree i n g t hat c ha n ges t o 
t he Pr ot oc ol pr oce d ur es, wit h t he e x ce pti o n of me dical e mer ge ncies, m ust be 
disc usse d a n d a p pr o v e d, first, b y t he s p o ns or or its desi g nee a n d, s ec o n d, b y t he 
I R B/IE C.  Eac h i n v esti gat or is res p o nsi ble f or e nr olli n g s u bjects w h o ha v e met t he 
s pecifie d eli gi bilit y criteria. 
T he I R B/I E C t hat g r a nte d ori gi nal a p pr o val, or t h e I R B/I E C c urre ntl y res p o nsi ble f or 
o verseei n g t he c o n d uct of t he st u d y, m ust be n otifie d of all c ha n ges i n a n d de viati o ns 
fr o m t he P r ot oc ol t hat ma y i n crease ris k t o t he s u bject a n d/ or t hat ma y a d v ersel y 
affect t he ri g hts of  t he s u bject or vali dit y of t he i n vesti gati o n.  T he i n v esti gat or m ust 
se n d a c o p y of t h e a p pr o val letter fr o m t he I R B/I E C t o t he s p o ns or or C R O a n d retai n 
t he ori gi nal i n t he site st u d y re g ulat or y file. 
Maj or eli gi bilit y d e viati o ns m ust be re p orte d t o t h e I R B/I E C i n acc or d a nce wit h t he 
I R B/I E C re q uir e me nts.  D uri n g t h e c o urs e of t he st u d y, t he m o nit or m ust n otif y t he 
s p o ns or of s u bjects f o u n d n ot t o ha ve met eli gi bilit y criteria.  T he me di cal m o nit or, i n 
c olla b orati o n wit h t he i n vesti gat or, will deter mi ne w het her  t h e s u bject s h o ul d be 
wit h dra w n fr o m t he st u d y. 
•  Retai n i n g r ec or ds i n acc or da nce wit h all l ocal, nati o nal, a n d re g ulat or y la ws, b ut f or a 
mi ni m u m peri o d of at least 2  years aft er t he last m ar keti n g a p plicati o n a p pr o val i n a n 
I C H re gi o n a n d u ntil t her e are n o p e n di n g or c o nt e m plate d mar keti n g a p plicati o ns i n 
a n I C H re gi o n, or if n ot a p pr o ve d, 2 years aft er t he ter mi nati o n of t he test article f or 
i n vesti gati o n t o e ns ure t h at t he a vaila bilit y of st u d y d oc u m e ntati o n s h o ul d it bec o me 
necessar y f or t he s p o ns or or a re g ul at or y a ut h orit y t o re vie w. 
− T he i n vesti gat or m ust n ot destr o y a n y rec or ds ass ociate d wit h t he st u d y wit h o ut 
recei vi n g a p pr o val fr o m t he s p o ns or.  T he i n vesti gat or m ust n otif y t he s p o ns or or 
its desi g nee i n t he e ve nt of acci d e ntal l oss or destructi o n of a n y st u d y rec or ds.  If 
t he i n vesti gat or l ea ves t h e i nstit uti o n w here t he st u d y w as c o n d uct e d, t he s p o ns or 
or its desi g nee m ust be c o ntacte d t o arra n ge alter n ati ve rec or d st ora ge o pti o ns. 
− All eC R F data e ntere d b y t he site (i ncl u di n g a u dit trail), as well as c o m p uter 
har d ware a n d s oft war e (f or accessi n g t h e data), will be mai ntai ne d or ma de 
a vaila ble at t he site i n c o m plia nce wit h a p plica ble rec or d rete nti o n re g ulati o ns.  
T he s p o ns or will retai n t he ori gi n al e C R F data a n d a u dit trail.  
1 0. 2.  
Acc 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 
T he i n vesti gat or is res p o nsi ble f or dr u g acc o u nta bilit y at t he st u d y site; h o we ver, t he i n v esti gat or 
ma y assi g n s o me of t he dr u g acc o u nt a bilit y d uties t o a n a p pr o priat e p har macist or desi g n ee.  
I n v e nt or y a n d acc o u nt a bilit y rec or ds m ust be mai ntai ne d a n d rea dil y a vaila ble f or i ns pecti o n b y 
t he st u d y m o nit or a n d are o pe n t o i ns pecti o n at a n y ti me b y a n y a p plica ble re g ulat or y a ut h orities. 


I nc yte C or p orati o n 
P a ge 6 9  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4 A U G 2 0 1 7  
C O N FI D E N TI A L  
T he i n vesti gat or or desi g nee will be e x pecte d t o c ollect a n d retai n all use d, u n use d, a n d partiall y 
use d c o ntai ners of st u d y dr u g u ntil t he e n d of t he st u d y.  T he i n vesti gat or or desi g n ee m ust 
mai ntai n rec or ds t hat d o c u me nt: 
•  I n v esti gati o nal pr o d uct d eli ver y t o t he st u d y site 
•  T he i n ve nt or y at t he site 
•  Use b y eac h s u bject i ncl u di n g pill/ u ni t c o u nts fr o m eac h s u p pl y dis pe nse d 
•  Ret ur n t o t he i n vesti gat or or desi g n ee  
T hese rec or ds s h o ul d i ncl u de dates, q ua ntities, bat c h/serial n u m bers (if a vaila ble), a n d t he u ni q ue 
c o de n u m bers (if a vaila bl e) assi g ne d t o t he i n vesti gati o nal pr o d u ct a n d st u d y s u b jects. 
T he i n vesti gati o nal pr o d uct m ust be use d o nl y i n acc or d a nce wit h t he pr ot oc ol.  T he i n vesti gat or 
will als o mai ntai n rec or ds a de q uatel y d oc u m e nti n g t hat t he s u bjects were pr o vi de d t he c orrect 
st u d y dr u g s pecifie d. 
C o m plete d acc o u nta bilit y r ec or ds wil l be arc hi v e d b y t he site.  At t he c o m pleti o n of t he st u d y, 
t he i n vesti gat or or desi g n ee will o versee s hi p me nt of a n y re m ai ni n g st u d y dr u g b ac k t o t he 
s p o ns or or s p o ns or's desi g nee f or d estr ucti o n acc or di n g t o i nstit uti o nal sta n dar d o perati n g 
pr oce d ur es.  If l ocal pr oce d ures ma n d ate site destr ucti o n of i n vesti gati o nal s u p pl y, pri or writte n 
a p pr o val m ust be o btai ne d fr o m t he s p o ns or. 
1 0. 3.  
D at a M a n a ge me nt  
1 0. 3. 1.  
D at a C ollecti o n 
T he i n vesti gat or will be pr o vi de d wit h a n e C R F f or eac h s u bj ect.  E ntries ma de i n t he e C R F m us t 
be verifia bl e a gai nst s o ur ce d oc u me nts; a n y discre pa ncies s h o ul d be e x plai ne d a n d d oc u me nt e d.  
T he i n vesti gat or will be r es p o nsi ble f or re vie wi n g all data a n d e C R F e ntries a n d will si g n a n d 
date t he desi g nate d p a ges i n eac h s u bject 's e C R F, verif yi n g t hat t he i nf or m ati o n is tr ue a n d 
c orrect.  T he i n vesti gat or is res p o nsi ble f or t he re vie w a n d a p pr o val of all res p o nses.   
1 0. 3. 2.  
D at a M a n a ge me nt 
Data ma na ge me nt will be perf or me d i n a vali dat e d data base via a n Electr o nic Data Ca pt ure 
( E D C) s yst e m.  All data e ntr y, verificati o n, a n d v ali dati o n will be perf or m e d i n acc or da nce wit h 
t he c urr e nt sta n dar d o p er ati n g pr o ce d ures of t he D ata Ma na ge me nt De p art me nt at t he s p o ns or or 
its desi g nee.  T h e data b ase will be a ut h orize d f or l oc k o nce all defi ne d pr o ce d ures are c o m plete d. 
1 0. 4.  
St u d y M o nit ori n g  
Q ualifie d re prese nt ati ves of t he s p o ns or or s p o ns or desi g n ees, "st u d y m o nit ors," will m o nit or t he 
st u d y acc or di n g t o a pr e d eter mi ne d m o nit ori n g pla n.  M o nit ori n g visits pr o vi de t he s p o ns or wit h 
t he o p p ort u nit y t o: 
•  E val uate t he pr o gress of t he st u d y  
•  Verif y t he acc urac y a n d c o m plete ness of e C R Fs  


I nc yte C or p orati o n 
P a ge 7 0  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4 A U G 2 0 1 7  
C O N FI D E N TI A L  
•  Ass ure t hat all pr ot oc ol r e q uire me nts, a p plica ble la ws a n d/ or re g ulati o ns, a n d 
i n vesti gat or's o bli gati o ns are bei n g f ulfille d 
•  Res ol ve a n y i nc o nsiste ncies i n t he st u d y rec or ds. 
T he i n vesti gat or m ust all o w t he st u d y m o nit ors t o peri o dicall y re vie w, at m ut uall y c o n v e nie nt 
ti mes, d uri n g t he st u d y a n d after t he st u d y has b ee n c o m plete d, all e C R Fs a n d office, h os pital, 
a n d la b orat or y rec or ds s u p p orti n g t he partici pati o n of eac h s u bj ect i n t he st u d y.  T he e C R Fs a n d 
ot her d oc u me ntati o n s u p p orti n g t he st u d y m ust be ke pt u p- t o-date b y t he i n vesti gat or a n d t he 
researc h staff at t he i n vesti gati ve site.  T hes e st u d y materials m ust be a vaila ble f or re vi e w b y t he 
st u d y m o nit or, a n d/ or ot h er q ualifie d r e prese ntati v es of t he s p o ns or, at eac h m o nit ori n g visit. 
T he st u d y m o nit or will re vie w t he vari o us rec or ds of t he st u d y (e C R Fs, s u bj ect me dical a n d 
la b orat or y r ec or ds, a n d ot her perti ne nt data).  T he st u d y m o nit or will verif y t he e C R F data 
a gai nst ori gi n al s o urce d oc u me ntati o n f or acc urac y a n d c o m plete ness.  T h e st u d y m o nit or will 
i de ntif y dat a discre p a nci es a n d c olla b orate wit h t he i n vesti gat or a n d researc h staff t o res ol ve t he 
discre pa n cies i n a ti mel y ma n ner.  Pr ot oc ol de viati o ns will als o be i de ntifie d a n d rec or de d o n a 
" Pr ot oc ol De vi ati o n L o g."  T he st u d y m o nit or will f oll o w a n "Iss ue Escalati o n" pla n i n or d er t o 
e ns ure t hat eac h iss ue i de ntifie d d uri n g a m o nit ori n g visit is a p pr o priatel y d oc u me nte d, re p orte d, 
a n d res ol ve d i n a ti mel y ma n ner i n acc or d a nce wit h t he pla n 's re q uire me nts. 
1 0. 5.  
Pr ot oc ol A d here nce  
T he Pri nci pal I n vesti gat or m ust o btai n I R B a p pr o v al f or t he i n vesti gati o n.  I nitial I R B a p pr o val, 
a n d all materials a p pr o ve d b y t he I R B f or t his st u d y i ncl u di n g t he s u bject I C F a n d recr uit me nt 
materials m ust be mai nta i ne d b y t he i n v esti gat or a n d ma de a vaila ble f or i ns pecti o n. 
Eac h i n vesti gat or m ust a d here t o t he pr ot o c ol as d escri be d i n t his d oc u me nt a n d a gree t hat 
c ha n ges t o t he pr ot o c ol, wit h t he e x ce pti o n of me dical e mer ge ncies, m ust be disc usse d a n d 
a p pr o ve d, firstl y, b y t he s p o ns or a n d, sec o n dl y, b y t he I R B/I E C.  Eac h i n vesti gat or is res p o nsi ble 
f or e nr olli n g s u bjects w h o ha ve met t he pr ot oc ol i ncl usi o n a n d e x cl usi o n criteria.  T he I R B/I E C 
t hat gr a nte d ori gi nal a p pr o val, or t he I R B/I E C c urre ntl y res p o nsi ble f or o verseei n g t he c o n d u ct 
of t he st u d y m ust be n otifie d of all c h a n ges i n a n d de viati o ns fr o m t he pr ot oc ol t hat ma y i n crease 
ris k t o t he s u bject, a n d/ or t hat ma y a d vers el y affect t he ri g hts of t he s u bject or vali dit y of t he 
i n vesti gati o n.  T he i n vesti gat or m ust se n d a c o p y of t he a p pr o v al letter fr o m t he I R B/I E C t o t he 
s p o ns or or C R O a n d retai n t he ori gi nal i n t he site st u d y re g ul at or y file. 
Maj or eli gi bilit y d e viati o ns m ust be re p orte d t o t h e I R B/I E C i n acc or d a nce wit h t he I R B/I E C 
re q uire me nts.  D uri n g t h e c o urse of t he st u d y, t he m o nit or m ust n otif y t he s p o ns or of s u bjects 
f o u n d n ot t o ha ve met eli gi bilit y criteria.  T h e me dical m o nit or, i n c olla b orati o n wit h t he 
i n vesti gat or, will deter mi ne if t he s u bject s h o ul d b e wit h dra w n fr o m t he st u d y. 
1 0. 6.  
D at a Pri v ac y a n d C o n fi de nti alit y of St u d y Rec or ds  
T he i n vesti gat or a n d t he s p o ns or or its desi g nee m ust a d here t o a p plica ble d ata pri vac y l a ws a n d 
re g ulati o ns.  T he i n vesti gat or a n d t he s p o ns or or its desi g nee are res p o nsi ble f or e ns uri n g t h at 
se nsiti ve i nf or mati o n is ha n dle d i n acc or da n ce wit h l ocal re q uire me nts (e g, HI P A A).  
A p pr o priate c o nse nt a n d a ut h orizati o ns f or use a n d discl os ure a n d/ or tra nsfer (if a p plica ble) of 
pr otecte d i nf or m ati o n m ust be o btai ne d. 


I nc yte C or p orati o n 
P a ge 7 1  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4 A U G 2 0 1 7  
C O N FI D E N TI A L  
S u bject na mes will n ot be s u p plie d t o t he s p o ns or or its desi g nee, if a p plica ble.  O nl y t he s u bject 
n u m ber a n d s u bject' s i nitials (s u bject's i nitials will o nl y be rec or de d if all o wa ble b y l ocal 
re g ulati o ns) will be rec or de d i n t he eC R F , w here p er mitte d; if t he s u bject 's na me a p pears o n a n y 
ot her d oc u me nt ( e g, la b orat or y re p ort), it m ust be o bliterate d o n t he c o p y of t he d oc u me nt t o be 
s u p plie d t o t he s p o ns or or its desi g nee.  St u d y fi n di n gs st ore d o n a c o m p uter will be st ore d i n 
acc or d a nce wit h l ocal dat a pr otecti o n la ws.  T h e s u bjects will be i nf or me d t hat re pres e ntati ve s of 
t he s p o ns or or its desi g n ee, I R B or I E C, or re g ulat or y a ut h orities ma y i ns pect t heir me dical 
rec or ds t o verif y t he i nf or mati o n c ollecte d, a n d t h at all pers o nal i nf or m ati o n ma de a vaila ble f or 
i ns pecti o n will be ha n dle d i n strictest c o nfi de nce a n d i n acc or d a nce wit h l ocal data pr ot ecti o n 
la ws. 
1 0. 7.  
Fi n a nci al Discl os ure  
All cli nical i n vesti gat ors partici pati n g i n cli nical st u dies s u bject t o F D A Re g ulati o n Title 2 1 
C o de of Fe d er al Re g ul ati o ns ( C F R) Part 5 4 – Fi na ncial Discl os ure b y Cli nical I n vesti gat ors, are 
re q uire d pri or t o st u d y i nitiati o n t o s u b mit a c o m plete d Cli nical I n v esti gat or Fi na nci al Discl os ure 
Re q uest F or m t hat s uffi cie ntl y det ails a n y fi na ncial i nterests a n d arra n ge me nts t hat a p pl y.  F or 
t he p ur p ose of t his re g ulati o n, cli nical i n vesti gat or is defi ne d as a n y i n vesti gat or or 
s u bi n vesti gat or w h o is directl y i n v ol ve d i n t he treat me nt or e val uati o n of researc h s u bjects, 
i ncl u di n g t he s p o use a n d eac h d e pe n de nt c hil d of t he cli nical i n vesti gat or.  T hese re q uire me nts 
a p pl y t o b ot h U S a n d f or ei g n cli nical i n vesti gat ors c o n d ucti n g c o vere d cli nical st u dies. 
A n y n e w i n vesti gat ors or s u b- i n vesti gat ors a d de d t o t he c o vere d cli nical st u d y d uri n g its c o n d uct 
m ust als o s u b mit a c o m plete d Cli nical I n vesti gat or Fi na ncial Discl os ure Re q uest F or m.  D uri n g a 
c o vere d cli nical st u d y, a n y c h a n ges t o t he fi n a ncial i nf or mati o n pre vi o usl y re p orte d b y a cli nical 
i n vesti gat or m ust be r e p orte d t o t he s p o ns or/ desi g nee.  At t he c o n cl usi o n of t he c o vere d cli nical 
st u d y, t he cli nical i n vesti gat ors will be re mi n de d of t heir o bli gati o n t o re p ort t o t he 
s p o ns or/ desi g nee a n y c ha n ges t o t he fi na ncial i nf or mati o n pre vi o usl y re p ort e d.  T he cli nical 
i n vesti gat ors will als o be re mi n de d t hat t he y m ust re p ort a n y c ha n ges i n t heir fi na ncial 
i nf or mati o n f or a p eri o d of 1 year after c o m pleti o n of t he c o vere d cli nical st u d y. 
1 0. 8.  
Q u alit y C o ntr ol a n d Q u alit y Ass ur a nce  
1 0. 8. 1.  
S p o ns or A u dits  
At s o me p oi nt d uri n g t he st u d y, i n di vi d uals fr o m t he s p o ns or' s Q ualit y Ass ura nce d e part me nt 
a n d/ or t heir a ut h orize d r e prese ntati ve ma y visit t he i n vesti gat or 's site t o c o n d uct a n a u dit of t he 
st u d y.  T he p ur p ose of t his visit will be t o deter mi ne t he i n vesti gat or's a d here nce t o t he pr ot oc ol, 
a p plica ble r e g ulati o ns, a n d t he s p o ns or' s pr oce d ures, i n a d diti o n t o assessi n g t he acc urac y of t he 
st u d y data.  Bef ore i nitiati n g t his a u dit, t he i n vesti gat or will be c o ntact e d b y t he s p o ns or t o 
arra n ge a c o n ve nie nt ti me f or t his visit.  T he i n vesti gat or a n d st aff are e x pecte d t o c o o perate wit h 
t he a u dit ors a n d all o w access t o all s u bject rec or ds s u p p orti n g t he e C R Fs a n d ot her st u d y-relat e d 
d oc u me nts. 
1 0. 8. 2.  
I ns pecti o n b y Re g ul at or y A ut h orities 
At s o me p oi nt d uri n g t he i n vesti gati o nal pr o d u ct's de vel o p me nt pr o gra m, a re g ulat or y a ut h orit y 
ma y visit t he i n vesti gat or t o c o n d uct a n i ns pecti o n of t he st u d y a n d t he site.  T he i n vesti gat or a n d 


I nc yte C or p orati o n 
P a ge 7 2  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4 A U G 2 0 1 7  
C O N FI D E N TI A L  
staff ar e e x pecte d t o c o o perate wit h t he i ns pect ors a n d all o w access t o all s o urce d oc u m e nts 
s u p p orti n g t he e C R Fs a n d ot her st u d y-relat e d d oc u me nts.  T he i n vesti gat or m ust i m me diatel y 
n otif y t he s p o ns or w h e n c o ntacte d b y a n y re g ulat or y a ut h orit y f or p ur p os es of c o n d uct i n g a n 
i ns pecti o n. 
1 0. 9.  
D at a H a n dli n g a n d Rec or d kee pi n g  
1 0. 9. 1.  
I ns pecti o n of Rec or ds 
T he s p o ns or will be all o we d t o c o n d uct site visits t o t he i n vesti gati o n facilities f or t he p ur p ose of 
m o nit ori n g a n y as p ect of t he st u d y.  T he i n v esti gat or a grees t o all o w t he m o nit or  t o i ns pect t he 
dr u g st or a ge area, st u d y dr u g st oc ks, dr u g acc o u nta bilit y rec or ds, s u bject c harts a n d st u d y s o urce 
d oc u me nts, a n d ot her r ec or ds relati ve t o st u d y c o n d uct. 
T he i n vesti gat or m ust e ns ure t hat all rec or ds pertai ni n g t o t he c o n d uct of t h e cli nic al st u d y (as 
liste d a b o ve) ar e a d e q uat el y mai ntai ne d f or a peri o d of 2 years after t he last a p pr o val of a 
mar keti n g a p plicati o n i n a n I C H re gi o n a n d u ntil t here are n o p e n di n g or c o nte m plate d mar keti n g 
a p plicati o ns i n a n I C H re gi o n, or at least 2 years h a v e ela ps e d si nce t he f or mal ter mi nati o n of 
cli nical de vel o p me nt of t he i n vesti gati o nal pr o d uct. 
1 0. 9. 2.  
Rete nti o n of Rec or ds  
T he Pri nci pal I n vesti gat or m ust mai ntai n all d oc u me ntati o n relati n g t o t he st u d y f or a peri o d of 
2 years after t he l ast mar keti n g a p plicati o n a p pr o v al, or if n ot a p pr o ve d, 2 years after t he 
ter mi nati o n of t he test article f or i n vesti gati o n.  If it bec o mes necessar y f or t he s p o ns or or t he 
Re g ulat or y A ut h orit y t o r e vie w a n y d o c u me ntati o n relati n g t o t he st u d y, t h e i n vesti gat or m ust 
per mit access  t o s uc h rec or ds. 
T he i n vesti gat or m ust n ot destr o y a n y rec or ds ass ociate d wit h t he st u d y wit h o ut recei vi n g 
a p pr o val fr o m t he s p o ns or.  T he i n vesti gat or m ust n otif y t he s p o ns or i n t he e ve nt of acci de ntal 
l oss or destr ucti o n of a n y st u d y rec or ds.  If t he i nv esti gat or l ea ves t he i nstit uti o n w here t he st u d y 
was c o n d ucte d, t he s p o ns or m ust be c o ntacte d t o arra n ge alter nati ve rec or d st ora ge o pti o ns. 
W he ne ver p ossi ble, a n ori gi nal rec or di n g of a n o bser vati o n m ust be retai n e d as t he s o urce 
d oc u me nt.  H o we v er, a p h ot oc o p y of a rec or d is acce pta bl e, pr o vi de d it is le gi ble a n d is a 
verifie d c o p y of t he ori gi nal d oc u me nt. 
All e C R F data e ntere d b y t he site (i ncl u di n g a u dit trail), as well as c o m p uter har d w are a n d 
s oft ware (f or accessi n g t he data), will be mai ntai n e d or ma de a vaila ble at t he site i n c o m plia nce 
wit h a p plica ble rec or d r ete nti o n re g ul ati o ns.  T he s p o ns or will retai n t he ori gi nal e C R F d ata a n d 
a u dit trail. 
1 0. 9. 3.  
C o nfi de nti alit y  
S u bject na mes will n ot be s u p plie d t o t he s p o ns or.  O nl y t he s u bject n u m ber a n d s u bject i nitials 
will be rec or d e d i n t he e C R F, a n d if t he s u bject n a me a p pears o n a n y ot h er d oc u me nt (e g, 
la b orat or y r e p ort), it m ust be o bliterate d o n t he c o p y of t he d oc u me nt t o be s u p plie d t o t he 
s p o ns or.  St u d y fi n di n gs st ore d o n a c o m p uter will be st ore d i n acc or da n ce wit h l ocal data 
pr otecti o n la ws.  T he s u bjects will be i nf or me d t hat re prese nt ati ves of t he s p o ns or, I R B/I E C, or 
re g ulat or y a ut h orities ma y i ns pect t heir me dical rec or ds t o verif y t he i nf or mati o n c ollecte d, a n d 


I nc yte C or p orati o n 
P a ge 7 3  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4 A U G 2 0 1 7  
C O N FI D E N TI A L  
t hat all pers o nal i nf or mati o n ma de a vaila ble f or i ns pecti o n will be ha n dle d i n strictest c o nfi de nce 
a n d i n acc or da nce wit h l ocal data pr ot ecti o n la ws.  
1 0. 1 0.  
P u blic ati o n P olic y  
B y si g ni n g t he st u d y Pr ot oc ol, t he i n vesti gat or a n d his or her i nstit uti o n a gree t hat t he res ults of 
t he st u d y ma y be us e d b y t he s p o ns or, I nc yte C or p orati o n (I nc yte), f or t h e p ur p oses of nati o nal 
a n d i nter nati o nal r e gistrati o n, p u blicati o n, a n d i nf or mati o n f or me dical a n d p har mace utical 
pr ofessi o nals.  St u d y r es ults will be p u blis he d i n acc or d a nce wit h a p plica ble l ocal a n d nati o nal 
re g ulati o ns.  If necessar y, t he a ut h orities will be n otifie d of t he i n vesti gat or's na m e, a d dress, 
q ualificati o ns, a n d e xte nt of i n v ol ve me nt.  T he ter ms re gar di n g t he p u blicati o n of st u d y res ults 
are c o nt ai ned i n t he a gree me nt si g ne d wit h t he s p o ns or or its desi g n ee.  A si g ne d a gree me nt will 
be retai ne d b y t h e s p o ns or or its desi g n ee. 


I nc yte C or p orati o n 
P a ge 7 4  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4 A U G 2 0 1 7  
C O N FI D E N TI A L  
1 1.  
R E F E R E N C E S  
Ar ber D A, Or azi A, Hasserjia n R, et al . T he 2 0 1 6 re visi o n t o t he W orl d Healt h Or ga nizati o n 
classificati o n of m yel oi d ne o plas ms a n d ac ut e le u ke mia . Bl o o d 2 0 1 6; 1 2 7: 2 3 9 1- 2 4 0 5. 
B ose P , Verst o vse k S. T he e v ol uti o n a n d cli nical rele va nce of pr o g n ostic classificati o n s yste ms 
i n m yel ofi br osis. Ca ncer 2 0 1 6; 1 2 2: 6 8 1- 6 9 2. 
Cer va ntes  F,  D u preiz B, Pereira A , et al. N e w pr o g n ostic sc ori n g s yste m f or pri mar y 
m yel ofi br osis bas e d o n a st u d y of t he I nter nati o nal w or ki n g Gr o u p f or M yel ofi br osis Researc h 
a n d Treat me nt.  Bl o o d 2 0 0 9; 1 1 3: 2 8 9 5- 2 9 0 1. 
Cer va ntes  F, Va n n u cc hi A M, Kila djia n JJ, et al. T hree-year effi cac y, s afet y, a n d s ur vi val 
fi n di n gs fr o m C O M F O R T-II, a p h ase 3 st u d y c o m pari n g r u x oliti ni b wit h best a vaila ble t hera p y 
f or m yel ofi br osis. Bl o o d 2 0 1 3; 1 2 2: 4 0 4 7- 4 0 5 3. 
Cli nical Trial  Facilitati o n Gr o u p ( C T F G) . Rec o m me n dati o ns relate d t o c o ntrace pti o n a n d 
pre g na nc y t esti n g i n cli ni cal trials. 2 0 1 4. htt p:// w w w. h ma.e u/ctf g. ht ml . Accesse d J ul y 1 5, 2 0 1 6. 
Dee g HJ, G o ole y T A, Fl o wers M E , et al. All o ge nic he mat o p oietic ste m cell tra ns pla ntati o n f or 
m yel ofi br osis. Bl o o d 2 0 0 3; 1 0 2: 3 9 1 2- 3 9 1 8. 
Harris o n C, Kila djia n JJ, Al- Ali H K, et al. J A K i n hi biti o n wit h r u x oliti ni b vers us best a vaila bl e 
t hera p y f or m yel ofi br osis. N E n gl J Me d 2 0 1 2; 3 6 6: 7 8 7- 7 9 8. 
I N C 4 2 4 (I N C B 0 1 8 4 2 4) R u x oliti ni b I n vesti gat or's Br oc h ure (I B). Basel, S witzerla n d : N o vartis. 
I N C B 0 3 9 1 1 0 I n v esti gat or's Br o c h ure (I B). Wil mi n gt o n, D E: I n c yt e C or p orati o n. 
Mascar e n has J O, Tal paz M, G u pta V, e t al. Pri mar y a n al ysis of a p has e II o pe n -la bel trial of 
I N C B0 3 9 1 1 0, a s electi ve J A K 1 i n hi bit or, i n patie nts wit h m yel ofi br osis, H ae mat ol o gica 
2 0 1 6; 1 5 1 1 2 6. 
Mesa R A, Ni blac k J, Wa dlei g h M, et al. T h e b ur d e n of fati g ue a n d q ualit y of life i n 
m yel o pr olif erati ve dis or d ers ( M P Ds): a n i nter n ati o nal I nt er net- b ase d s ur v e y of 1 1 7 9 M P D 
patie nts. Ca ncer 2 0 0 7; 1 0 9: 6 8- 7 6. 
Mesa R A, G otli b J, G u pta V, et al. Effect of r u x oliti ni b t hera p y o n m yel ofi br osis- relate d 
s y m pt o ms a n d ot her pati e nt-re p ort e d o utc o mes i n C O M F O R T-I: a ra n d o mize d, d o u ble bli n d, 
place b o -c o ntr olle d trial.  J Cli n O nc ol 2 0 1 3a; 3 1: 1 2 8 5- 1 2 9 2. 
Mesa R A, S hiel ds A, Har e T, et al . Pr o gressi ve b ur de n of m yel ofi br osis i n u ntreate d patie nts: 
assess me nt of patie nt -r e p orte d o utc o mes i n patie nts ra n d o mize d t o place b o i n t he C O M F O R T- 1 
st u d y. Le u k Res 2 0 1 3 b; 3 7: 9 1 1- 9 1 6. 
Nati o nal Ca ncer I nstit ute ( N CI) . C o m m o n Ter mi n ol o g y Criteria f or A d vers e E ve nts versi o n 
4. 0 3. 2 0 1 0. htt p://cte p.ca ncer. g o v/r e p orti n g/ ctc. ht ml. Accesse d J ul y 1 5, 2 0 1 6. 
O ke n M M, Creec h R H, T or me y D C. T o xicit y a n d res p o nse criteria of t h e Easter n C o o perati ve 
O nc ol o g y Gr o u p.  J Cli n O nc ol 1 9 8 2; 5: 6 4 9- 6 5 5. 
Passa m o nti F, Cer va ntes F, Va n n u c hi A M, et al. A d y na mic pr o g n ostic m o del t o pre dict s ur vi val 
i n pri mar y m yel ofi br osis: a st u d y b y t he I W G-M R T. Bl o o d 2 0 1 0; 1 1 5: 2 7 0 3- 1 7 0 8. 


I nc yte C or p orati o n 
P a ge 7 5  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4 A U G 2 0 1 7  
C O N FI D E N TI A L  
Stei n B L, G otli b J, Arcas o y M, et al. Hist orical vie ws, c o n ve nti o nal a p pr oac hes, a n d e v ol vi n g 
ma na ge me nt strat e gies f or m yel o pr oliferati ve ne o plas ms.  J Natl C o m pr Ca nc  Net w  
2 0 1 5; 1 3: 4 2 4- 4 3 4. 
Tefferi A, Cer v a ntes F, Mesa R , et al. Re vise d res p o nse criteria f or m yel ofi br osis: I nter nati o nal 
W or ki n g Gr o u p- M yel o pr oliferati ve N e o plas ms R esearc h a n d T reat me nt (I W G- M R T) a n d 
E ur o pea n Le u ke mia N et ( E L N) c o nse ns us re p ort. Bl o o d 2 0 1 3; 1 2 2: 1 3 9 5- 1 3 9 8. 
T hiele J, K vas nic ka H M, Facc hetti F , Fra n c o V, v a n der Walt J, Ora zi A. E ur o pea n c o ns e ns us o n 
gr a di n g b o ne marr o w fi br osis a n d assess me nt of cell ularit y. H ae mat ol o gica 2 0 0 5; 9 0: 1 1 2 8- 1 1 3 2. 
Va n n ucc hi A M, Ka ntarji a n H M, Kila djia n JJ, et al. A p o ole d a nal ysis of o verall s ur vi val i n 
C O M F O R T - 1 a n d C O M F O R T-II, 2 ra n d o mize d p hase III trials of r u x oliti ni b f or t he treat me nt of 
m yel ofi br osis. H ae mat ol o gica 2 0 1 5; 1 0 0: 1 1 3 9- 1 1 4 5. 
Verst o vse k S, Mesa R A, G otli b J, et al. A d o u ble- bli n d, place b o-c o ntr olle d trial of r u x oliti ni b f or 
m yel ofi br osis. N E n gl J Me d 2 0 1 2; 3 6 6: 7 9 9- 8 0 7. 
Verst o vse k S, Mesa R A, G otli b J, et al. T he cli nical be nefit of r u x oliti ni b acr oss patie nt 
s u b gr o u ps: a n al ysis of a place b o- c o ntr olle d, P has e III st u d y i n patie nts wit h m yel ofi br osis. Br J 
Hae mat ol 2 0 1 3; 1 6 1: 5 0 8- 5 1 6. 
Verst o vse k S, Mesa R A, G otli b J, et al. Efficac y, safet y , a n d s ur vi val wit h r u x oliti ni b i n patie nts 
wit h m yel ofi br osis: res ults of a me dia n 3 -year f oll o w - u p of C O M F O R T -I. Hae mat ol o gica 
2 0 1 5; 1 0 0: 4 7 9- 4 8 8. 


I nc yte C or p orati o n 
P a ge 7 6  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4 A U G 2 0 1 7  
C O N FI D E N TI A L  
A P P E N DI X  A.  R E VI S E D W H O 2 0 1 6 C RI T E RI A F O R M Y E L O FI B R O SI S 
T a ble 1 3: 
W H O Pre – Pri m a r y M y el ofi br osis Criteri a  
M aj or Criteri a  
1.  Me ga kar y oc ytic pr oliferati o n a n d at y pia, wit h o ut retic uli n fi br osis > gra de 1
a, acc o m pa nie d b y i ncrease d 
a ge-a dj uste d B M cell ularit y, gra n ul oc ytic pr oliferati o n, a n d ofte n decrease d er yt hr o p oiesis  
2.  N ot meeti n g t he W H O criteria f or B C R -A B L 1 +  C M L, P V, E T, m yel o d ys plastic s y n dr o mes, or ot her m yel oi d 
ne o plas ms  
3.  Prese nce of J A K 2 , C A L R , or M P L  m utati o n or i n t he a bse nce of t hese m utati o ns, prese nc e of a n ot her cl o nal 
mar ker, b or a bse nce of mi n or reacti ve B M retic uli n fi br osis c 
Mi n or Criteri a  
Prese nce of at least 1 of t he f oll o wi n g, c o nfir me d i n 2 c o nse c uti ve deter mi nati o ns:  
a. A ne mia n ot attri b ute d t o a c o m or bi d c o n diti o n  
b.  Le u k oc yt osis ≥1 1 × 1 0 9/ L 
c. P al pa ble s ple n o me gal y  
d.  L D H i ncrease d t o a b o ve u p per n or mal li mit of i nstit uti o nal r efere nce ra n ge  
Dia g n osis of pre P M F re q uires meeti n g all 3 maj or criteria, a n d at least 1 mi n or criteri o n  
a See Ta ble  1 5 . 
b I n t he a bse nce of a n y of t h e 3 maj or cl o n al m utati o ns, t h e searc h f or t h e m ost fre q u e nt acc o m p a n yi n g m utati o ns (e g, A S X L 1, 
E Z H 2, T E T 2, I D H 1/I D H 2, S R S F 2, S F 3 B 1) are of h el p i n d eter mi ni n g t h e cl o n al n at ure of t h e disease.  
c B M fi br osis sec o n d ar y t o i nfecti o n, a ut oi m m u n e dis or d er, or ot h er c hr o nic  i nfla m mat or y c o n diti o ns, h air y cell le u ke mi a or 
ot her l y m p h oi d n e o plas m, metast atic mali g n a n c y, or t o xic (c hr o nic) m yel o p at hies.  
T a ble 1 4: 
W H O O vert Pri m ar y M yel ofi br osis Criteri a  
M aj or Criteri a  
1. Prese nce of me ga k ar y oc ytic pr oliferati o n a n d at y pia, acc o m pa nie d b y eit her retic uli n a n d/ or c olla ge n fi br osis 
gra des 2 or 3 a 
2. N ot meeti n g W H O criteria f or E T, P V, B C R -A B L 1 + C M L, m yel o d ys plastic s y n dr o mes, or ot her m yel oi d 
ne o pla s ms 
3. Prese nce of J A K 2, C A L R, or M P L m utati o n or i n t he a bs e nce of t hese m utati o ns, prese nce of a n ot her cl o nal 
mar ker, b or a bse nce of reacti ve m yel ofi br osis c 
Mi n or Criteri a  
Prese nce of at least 1 of t he f oll o wi n g, c o nfir me d i n 2 c o nse c uti ve deter mi nati o ns:  
 a. A ne mia n ot attri b ute d t o a c o m or bi d c o n diti o n  
 b. Le u k oc yt osis ≥1 1 × 1 0 9/ L 
 c. P al pa ble s ple n o me gal y  
 d. L D H i ncrease d t o a b o ve u p per n or mal li mit of i nstit uti o nal refere nce ra n ge  
 e. Le u k oer yt hr o blast osis  
Dia g n osis of o vert P M F re q uires meeti n g all 3  maj or criteria, a n d at least 1 mi n or criteri o n  
a See Ta ble  1 5 . 
b I n t he a bse nce of a n y of t h e 3 maj or cl o n al m utati o ns, t h e searc h f or t h e m ost fre q u e nt acc o m p a n yi n g m utati o ns (e g, A S X L 1, 
E Z H 2, T E T 2, I D H 1/I D H 2, S R S F 2, S F 3 B 1) are of h el p i n d eter mi ni n g t h e cl o n al n at ure of t h e disease.  
c B M fi br osis sec o n d ar y t o i nfecti o n, a ut oi m m u n e dis or d er, or ot h er c hr o nic i nfla m mat or y c o n diti o ns, h air y cell le u ke mi a or 
ot her l y m p h oi d n e o plas m, metast atic mali g n a n c y, or t o xic (c hr o nic) m yel o p at hies.  


I nc yte C or p orati o n 
P a ge 7 7  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4 A U G 2 0 1 7  
C O N FI D E N TI A L  
T a ble 1 5: 
M y el ofi br osis Gr a di n g  
M yel ofi br osis Gr a di n g  
M F - 0 
Scattere d li near retic uli n wit h n o i ntersecti o ns (cr oss o vers) c orres p o n di n g t o n or mal B M  
M F - 1 
L o ose net w or k of retic uli n wit h ma n y i ntersecti o ns, es peciall y i n peri vasc ular areas  
M F - 2 
Diff use a n d de nse i ncrease i n retic uli n wit h e xte nsi ve i nters ecti o ns, occasi o nall y wit h f oc al b u n dles of 
t hic k fi bers m ostl y c o nsiste nt wit h c olla ge n, a n d/ or f ocal oste oscler osisa 
M F - 3 
Diff use a n d de nse i ncrease i n retic uli n wit h e xte nsi ve i nters ecti o ns a n d c oarse b u n dles of t hic k fi bers 
c o nsiste nt wit h c olla ge n, us uall y ass ociate d wit h oste oscler osis a 
a I n gra des M F -2 or M F -3 a n a d diti o n al tric hr o me stai n is rec o m me n d e d.  
S o urce:  Ar ber  et al 2 0 1 6 . 


I nc yte C or p orati o n 
P a ge 7 8  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4 A U G 2 0 1 7  
C O N FI D E N TI A L  
A P P E N DI X  B. I N T E R N A TI O N A L W O R KI NG G R O U P –
M Y E L O P R O LI F E R A TI V E N E O P L A S M S R E S E A R C H 
A N D T R E A T M E N T C RI T E R I A 
Res p o nse 
C ate g ories  
Re q uire d Criteri a (f or All Res p o nse C ate g ories, B e nefit M ust L ast f or ≥ 1 2 Wee ks t o 
Q u alif y as a Res p o nse)  
C R  
B o ne marr o w a:  A ge -a dj uste d n or m ocell ularit y; < 5 % blasts; ≤ Gra de 1 M F b a n d  
P eri p heral bl o o d:  He m o gl o bi n ≥ 1 0 0 g/ L a n d < U N L; ne utr o p hil c o u nt ≥ 1 × 1 0 9/ L a n d 
< U N L;  
Platelet c o u nt ≥ 1 0 0 × 1 0 9/ L a n d < U N L; < 2 % i m mat ure m yel oi d cellsc a n d  
Cli nical:  Res ol uti o n of diseas e s y m pt o ms; s plee n a n d li ver n o t pal pa ble; n o e vi de nce of 
E M H  
P R  
P eri p heral bl o o d:   He m o gl o bi n ≥ 1 0 0 g/ L a n d <  U N L; ne utr o p hil c o u nt ≥ 1 × 1 0 9/ L a n d 
< U N L; platelet c o u nt ≥ 1 0 0 × 1 0 9/ L a n d < U N L; <  2 % i m mat ure m yel oi d cells c a n d  
Cli nical:  Res ol uti o n of diseas e s y m pt o ms; s plee n a n d li ver n ot pal pa ble; n o e vi de nce of 
E M H or  
B o ne marr o w: a  A ge -a dj uste d n or m ocell ularit y; <  5 % blasts; ≤ Gra de 1 M Fb; a n d peri p heral 
bl o o d:  he m o gl o bi n ≥ 8 5 g/ L b ut <  1 0 0 g/ L a n d <  U N L; ne utr o p hil c o u nt ≥ 1 × 1 0 9/ L a n d 
< U N L; platelet c o u nt ≥ 5 0  × 1 0 9/ L b ut < 1 0 0 × 1 0 9/ L a n d < U N L; <  2 % i m mat ure m yel oi d 
cells c a n d  
Cli nical:  Res ol uti o n of diseas e s y m pt o ms; s plee n a n d li ver n ot pal pa ble; n o e vi de nce of 
E M H  
CI  
T he ac hie ve me nt of a ne mia, s plee n or s y m pt o ms res p o nse wit h o ut pr o gressi ve disease or 
i ncrease i n se verit y of a ne mia, t hr o m b oc yt o pe nia, or ne utr o pe nia d 
A ne mia res p o nse  
Tra nsf usi o n -i n de pe n de nt patie nts:  a ≥ 2 0 g/ L i ncrease i n he m o gl o bi n le vel e 
Tra nsf usi o n -de pe n de nt patie nts:   bec o mi n g tra nsf usi o n -i n de pe n de ntf 
S plee n res p o nse g 
A basel i ne s ple n o me gal y t hat is pal pa ble at 5-1 0 c m, bel o w t he L C M, bec o mes n ot pal pa ble h 
or  
A baseli ne s ple n o me gal y t hat is pal pa ble at >  1 0 c m, bel o w t he L C M, decreases b y ≥ 5 0 % h 
A baseli ne s ple n o me gal y t hat is pal pa ble at <  5 c m, bel o w t he L C M, is n ot eli gi ble f or s pl ee n 
res p o nse 
A s plee n res p o nse re q uires c o nfir mati o n b y M RI or C T  s h o wi n g ≥ 3 5 % s plee n v ol u me 
re d ucti o n 
S y m pt o ms 
res p o nse 
A ≥ 5 0 % re d ucti o n i n t he M P N-S A F T S S i 
Pr o gressi ve disease j 
A p peara nce of a ne w s ple n o me gal y t hat is pal pa ble at least 5 c m bel o w t he L C M or  
A ≥ 1 0 0 % i ncrease i n pal pa bl e dista nce, bel o w L C M, f or baseli ne s ple n o me gal y of 5 -1 0 c m 
or  
A 5 0 % i ncrease i n pal pa ble dista nce, bel o w L C M, f or baseli ne s ple n o me gal y of >  1 0 c m or  
Le u ke mic tra nsf or mati o n c o nfir me d b y a b o ne marr o w blast c o u nt of ≥ 2 0 % or  


I nc yte C or p orati o n 
P a ge 7 9  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4 A U G 2 0 1 7  
C O N FI D E N TI A L  
Res p o nse 
C ate g ories  
Re q uire d Criteri a (f or All Res p o nse C ate g ories, B e nefit M ust L ast f or ≥ 1 2 Wee ks t o 
Q u alif y as a Res p o nse)  
A peri p heral bl o o d blast c o nte nt of ≥ 2 0 % ass oc iate d wit h a n a bs ol ute blast c o u nt of 
≥ 1 × 1 0 9/ L t hat lasts f or at least 2 wee ks 
Sta ble disease  
B el o n gi n g t o n o ne of t he a b o ve -liste d res p o nse cate g ories 
Rela pse  
N o l o n ger meeti n g criteria f or at least CI after ac hie vi n g C R, P R, or CI, or  
L oss of a ne m ia res p o nse persisti n g f or at least 1 m o nt h or 
L oss of s plee n res p o nse persisti n g f or at least 1 m o nt h  
CI = cli nical i m pr o ve me nt; C R = c o m plete res p o nse; C T = c o m p ute d t o m o gra p h y; E M H = e xtra me d ullar y h e mat o p oiesis ; L C M 
= left c ostal mar gi n; M F = m yel of i br osis; M P N-S A F T S S = M yel o pr oliferati ve Ne o plas m S y m pt o m Assess me nt F or m T otal 
S y m pt o m Sc ore; M RI = ma g n etic res o n a n ce i ma gi n g; P R = p artial res p o nse; P R B C = p ac ke d re d bl o o d cell; U N L = u p per 
n or mal li mit.  
a Baseli ne a n d p ost -treat me nt b o n e marr o w sli d es are t o b e i nter prete d at 1 sitti n g b y a ce ntral re vie w pr o cess.  
 
 
b Gra di n g of M F is acc or di n g t o t he E ur o p ea n classificati o n ( T hiele  et al 2 0 0 5 ).  It is u n d ersc ore d t h at t h e c o nse ns us d efi niti o n 
of a C R b o ne marr o w is t o b e use d o nl y i n t h ose p atie nts i n w hic h all ot h er criter ia are met, i n cl u di n g res ol uti o n of 
le u k oer yt hr o blast osis.  It s h o ul d als o b e n ote d t h at it was a p artic ularl y diffic ult tas k f or t h e w or ki n g gr o u p t o reac h a c onse ns us 
re gar di n g w hat re prese nts a c o m plete hist ol o gic re missi o n. 
c I m mat ure m yel oi d cells c o nstit ute blasts + pr o m yel o c ytes + m yel o c yt es + meta m yel o c ytes + n u cleate d re d bl o o d cells.  I n 
s ple nect o mize d p atie nts, < 5 % i m mat ure m yel oi d cells is all o we d.  
d See a b o ve f or d efi niti o ns of a n e mia res p o nse, s plee n res p o nse, a n d pr o gressi ve disease.  I n crease i n se verit y of a n e mia 
c o nstit utes t he o cc urre n ce of n e w tra nsf usi o n d e p e n d e n c y or a ≥ 2 0 g/ L d ecre ase i n h e m o gl o bi n le vel fr o m pret reat me nt 
baseli ne t hat lasts f or at least 1 2 we e ks.  I n creas e i n se verit y of t hr o m b o c yt o p e nia or n e utr o p e nia is d efi n e d as a 2-gra d e 
decli ne, fr o m pretreat me nt b aseli n e, i n platelet c o u nt or a bs ol ute ne utr o p hil c o u nt, acc or di n g t o t h e C T C A E versi o n 4. 0.  In 
a d diti o n, assi g n me nt t o CI re q uires a mi ni m u m platelet c o u nt of ≥ 2 5 ,0 0 0 × 1 0 9/ L a n d a bs ol ute n e utr o p hil c o u nt of 
≥ 0. 5  × 1 0 9/ L. 
e A p plica ble o nl y t o p atie nts wit h baseli n e h e m o gl o bi n of <  1 0 0 g/ L.   I n p atie nts n ot meeti n g t h e strict criteria f or tra nsf usi o n 
de pe n de nc y at t h e ti me of st u d y e nr oll me nt (see as f oll o ws), b ut h a ve recei ve d tra nsf usi o ns wit hi n t he pre vi o us m o nt h, t he 
pretra nsf usi o n h e m o gl o bi n le vel s h o ul d b e use d as t h e b aseli n e.  
f Tra nsf usi o n de p e n d e n c y b ef ore st u d y e nr oll me nt is d efi n e d as tra nsf usi o ns of at least 6 u nits of P R B C s, i n t h e 1 2 wee ks pri or 
t o st u d y e nr oll me nt, f or a h e m o gl o bi n le vel of < 8 5 g/ L, i n t h e a bse n c e of blee di n g or treat me nt -i n d uce d a n e mia.  I n a d diti o n, 
t he m ost rece nt tra nsf usi o n e pis o d e m ust h a ve o cc urre d i n t h e 2 8 da ys pri or t o st u d y e nr oll me nt.  Res p o nse i n 
tra nsf usi o n-de p e n d e nt p atie nts re q uires a bse n ce of a n y P R B C tra nsf usi o ns d uri n g a n y c o nse c uti ve "r olli n g" 1 2 -wee k i nter val 
d uri n g t he treat me nt p h ase, ca p p e d b y a h e m o gl o bi n le vel of ≥ 8 5 g/ L.  
g I n s ple nect o mize d p atie nts, p al p a ble h e p at o me g al y is s u bstit ute d wit h t h e sa me meas ure me nt strate g y. 
h S plee n or li ver res p o nses m ust b e c o nfir me d b y i ma gi n g st u dies w h ere a ≥ 3 5 % re d u cti o n i n s plee n v ol u me, as assesse d b y 
M RI or C T, is re q uire d.  F urt h er m ore, a ≥ 3 5 % v ol u me re d u cti o n i n t h e s plee n or li ver, b y M RI or C T, c o nstit utes a res p o nse 
re gar dless of w h at is re p orte d wit h p h ysical e xa mi n ati o n. 
i S y m pt o ms are e val u ate d b y t h e M P N -S A F T S S.   T h e M P N -S A F T S S is assesse d b y t h e p atie nts t he msel v es a n d t his i n cl u des 
fati g ue, c o nce ntrati o n, earl y s atiet y, i n acti vit y, ni g ht s we ats, itc hi n g, b o n e p ai n, a b d o mi n al disc o mf ort, wei g ht l oss, a n d fe vers.  
Sc ori n g is fr o m 0 (a bse nt/as g o o d as it ca n b e) t o 1 0 ( w orst i ma gi n a ble/as b a d as it ca n b e) f or eac h ite m. T h e M P N -S A F T S S 
is t he s u m mati o n of all t h e i n di vi d u al sc ores ( 0-1 0 0 scale).   S y m pt o ms res p o nse re q uires ≥ 5 0 % re d u cti o n i n t h e M P N -S A F 
T S S.  
j Pr o gressi ve disease assi g n me nt f or s pl en o me gal y re q uires c o nfir mati o n b y M RI or C T s h o wi n g a ≥ 2 5 % i n crease i n s plee n 
v ol u me fr o m b aseli n e.   Baseli n e val u es f or b ot h p h ysical e xa mi n ati o n a n d i ma gi n g st u dies refer t o pretreat me nt b aseli n e a n d 
n ot t o p osttreat me nt me as ure me nts.  
S o urce:  Tefferi   et al 2 0 1 3 . 


I nc yte C or p orati o n 
P a ge 8 0  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4 A U G 2 0 1 7  
C O N FI D E N TI A L  
A P P E N DI X  C.  E A S T E R N C O O P E R A TI V E O N C O L O G Y G R O U P  
P E R F O R M A N C E S T A T U S  
Gr a de  
P erf or m a nce St at us  
0 
F ull y a cti ve, a ble t o carr y o n all pre disease perf or ma nce wit h o ut restricti o n. 
1 
Restricte d i n p h ysicall y stre n u o us acti vit y b ut a m b ulat or y a n d a ble t o carr y o ut w or k of a 
li g ht or se de ntar y nat ure, e g, li g ht h o use w or k, office w or k. 
2 
A m b ulat or y a n d ca pa ble of all self -care b ut u na ble t o carr y o ut a n y w or k acti vities .  U p 
a n d a b o ut m ore t ha n 5 0 % of wa ki n g h o urs. 
3 
Ca pa ble of o nl y li mite d self- care, c o nfi ne d t o be d or c hai r m ore t ha n 5 0 % of wa ki n g 
h o urs. 
4 
C o m pletel y disa ble d.  Ca n n ot carr y o n a n y self -care.  T otall y c o nfi ne d t o be d or c hair. 
5 
Dea d.  
S o urce :  O ke n  et al 1 9 8 2 . 


I nc yte C or p orati o n 
P a ge 8 1  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4 A U G 2 0 1 7  
C O N FI D E N TI A L  
A P P E N DI X  D.  M O DI FI E D M Y E L O FI B R O SI S  S Y M P T O M 
A S S E S S M E N T S F O R M V E R SI O N 2 . 0 
Please c o m plete t his diar y at ni g ht bef ore b e dti me.  T he diar y as ks a b o ut y o ur M F s y m pt o ms 
d uri n g t he p ast 2 4 h o urs.  T here is n o ri g ht or wr o n g a ns wer.  Pleas e gi ve t he a ns wer t hat best 
reflects y o ur o pi ni o n. 
1. D uri n g t he past 2 4 h o urs, h o w se vere 
were y o ur w orst ni g ht s weats ( or feeli n g 
h ot or fl us he d) d ue t o M F?  
0 ( A bse nt)  1    2    3    4    5    6    7    8    9    1 0 ( W orst I ma gi na ble)  
2. D uri n g t he past 2 4 h o urs , h o w se vere 
was y o ur w orst itc hi n ess d ue t o M F?  
0 ( A bse nt)  1    2    3    4    5    6    7    8    9    1 0 ( W orst I ma gi na ble)  
3. D uri n g t he past 2 4 h o urs , h o w se vere 
was y o ur w orst a b d o mi nal dis c o mf ort 
(feel u nc o mf orta ble, press ure or 
bl oati n g) d ue t o M F?  
0 ( A bse nt)  1    2    3    4    5    6    7    8    9    1 0 ( W orst I ma gi na ble)  
4. D uri n g t he past 2 4 h o urs , h o w se vere 
was y o ur w orst pai n u n der t he ri bs o n 
t he left si de d ue t o M F? 
0 ( A bse nt)  1    2    3    4    5    6    7    8    9   1 0 ( W orst I ma gi na ble)  
5. D uri n g t he past 2 4 h o u rs, w hat was 
t he w orst feeli n g of f ull ness (e arl y 
satiet y) y o u ha d after be gi n ni n g t o eat, 
d ue t o M F?  
0 ( A bse nt)  1    2    3    4    5    6    7    8    9   1 0 ( W orst I ma gi na ble)  
6. D uri n g t he past 2 4 h o urs , h o w se vere 
was y o ur w orst b o ne or m uscl e pai n d ue 
t o M F ( diff use, n ot  j oi nt or art hritis 
pai n)?  
0 ( A bse nt)  1    2    3    4    5    6    7    8    9   1 0 ( W orst I ma gi na ble)  
7. D uri n g t he past 2 4 h o urs , w hat was 
t he w orst de gree of i nacti vit y (i ncl u di n g 
w or k a n d s ocial acti vities) y o u ha d d ue 
t o M F? 
0 ( A bse nt)  1    2     3    4    5    6    7    8    9   1 0 ( W orst I ma gi na ble)  
 


I nc yte C or p orati o n 
P a ge 8 2  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4 A U G 2 0 1 7  
C O N FI D E N TI A L  
A P P E N DI X  E. M Y E L O P R O LI F E R A TI V E N E O P L A S M S S Y M P T O M 
A S S E S S M E N T F O R M  
S u bj ect 
N u m ber 
 
 
 
 
 
S y m pt o m  
1 t o 1 0 ( 0 if a bse nt) r a n ki n g - 1 is m ost  
 f a v or a ble a n d 1 0 le ast f a v or a ble 
Please rate y o ur fati g ue ( weari ness, tire d ness) b y 
circli n g t he o ne n u m ber t hat best descri bes y o ur 
W O R S T le vel of fati g ue d uri n g t he past 2 4 h o urs.  
0 ( A bse nt)   1  2  3  4  5  6  7  8  9     1 0 ( W orst I ma gi na ble)  
Circle t he o ne n u m ber t h at descri bes, d uri n g t he p ast we e k, h o w m uc h diffic ult y y o u h a d wit h e ac h 
of t he f oll o wi n g s y m pt o ms  
Ni g ht s weats  
0 ( A bse nt)   1  2  3  4  5  6  7  8  9     1 0 ( W orst I ma gi na ble)  
Itc hi n g ( pr urit us) 
0 ( A bse nt)   1  2  3  4  5  6  7  8  9     1 0 ( W orst I ma gi na ble)  
B o ne pai n ( diff use, n ot  j oi nt pai n or art hritis) 
0 ( A bse nt)   1  2  3  4  5  6  7  8  9     1 0 ( W orst I ma gi na ble)  
Fe ver ( > 1 0 0° F)  
0 ( A bse nt)   1  2  3  4  5  6  7  8  9     1 0 ( W orst I ma gi na ble)  
U ni nte nti o nal wei g ht l oss i n t he last 6 m o nt hs  
0 ( A bse nt)   1  2  3  4  5  6  7  8   9     1 0 ( W orst I ma gi na ble)  
Filli n g u p q uic kl y w he n y o u e at (earl y satiet y)  
0 ( A bse nt)   1  2  3  4  5  6  7  8  9     1 0 ( W orst I ma gi na ble)  
A b d o mi nal disc o mf ort  
0 ( A bse nt)   1  2  3  4  5  6  7  8  9     1 0 ( W orst I ma gi na ble)  
I nacti vit y 
0 ( A bse nt)   1  2  3  4  5  6  7  8  9     1 0 ( W orst I ma gi na ble)  
Pr o ble ms wit h c o nce ntrati o n - 
 c o m pare d t o pri or t o m y M P D  
0 ( A bse nt)   1  2  3  4  5  6  7  8  9     1 0 ( W orst I ma gi na ble)  
 
 
 
 
 
T S S:    _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
M D Si g nat ure/ Date  
P er I W G -M R T 2 0 1 3 Criteri a: T S S t o i ncl u de fati g ue, 
c o nce ntrati o n, earl y satiet y, i nacti vit y, ni g ht s weats, 
itc hi n g, b o ne pai n, a b d o mi nal disc o mf ort, wei g ht l oss, a n d 
fe vers. 
 
Staff Si g nat ure/ Date  
 
 
 
 


I nc yte C or p orati o n 
P a ge 8 3  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4 A U G 2 0 1 7  
C O N FI D E N TI A L  
A P P E N DI X  F.  P A TI E N T G L O B A L I M P R E S SI O N O F C H A N G E  
I nstr ucti o ns:  C ircle t he a ns w er t h at is m ost a p pr o pri ate. 
Si nce t he start of t he tr eat me nt y o u ' ve recei ve d i n t his st u d y, y o ur m yel ofi br osis s y m pt o ms are: 
1.  Ver y m uc h i m pr o ve d 
2.  M uc h i m pr o ve d 
3.  Mi ni mall y i m pr o v e d  
4.  N o c ha n ge  
5.  Mi ni mall y w orse  
6.  M uc h w orse 
7.  Ver y m uc h w orse  


I nc yte C or p orati o n 
P a ge 8 4  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4 A U G 2 0 1 7  
C O N FI D E N TI A L  
A P P E N DI X  G. I N F O R M A TI O N R E G A R DI NG 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 or S u bjects P arti ci p ati n g i n t he St u d y:  
T he f oll o wi n g m et h o ds t hat ca n ac hie ve a fail ure rate of less t ha n 1 % per year w h e n use d 
c o nsiste ntl y a n d c orr ectl y are c o nsi d ere d as hi g hl y effecti ve birt h c o ntr ol met h o ds.  
S uc h met h o ds i ncl u de: 
•  C o m bi ne d (estr o ge n a n d pr o gest o ge n c o ntai ni n g) h or m o nal c o ntrace pti o n ass ociate d 
wit h i n hi biti o n of o v ulati o n 1 
− oral  
− i ntra va gi nal 
− tra ns der mal 
•  Pr o gest o ge n - o nl y h or m o nal c o ntrace pti o n ass ociate d wit h i n hi biti o n of o v ulati o n1 
− oral  
− i njectable 
− i m pla nta ble2 
•  I ntr a uteri ne d e vice (I U D)2 
•  I ntr a uteri ne h or m o ne-rel easi n g s yst e m (I U S)2 
•  Bilater al t u bal occl usi o n 2 
•  Vasect o mise d  part ner2, 3 
•  Se x ual a bsti ne nce 4 
 
1  H or m o nal  c o ntrace pti o n ma y be s usce pti ble t o i nteracti o n wit h t he I M P, w hic h ma y re d uce t he efficac y of t he 
c o ntrace pti o n met h o d.  
2  C o ntrace pti o n  met h o ds t hat i n t he c o nte xt of t his g ui da nce are  c o nsi dere d t o ha ve l o w us er de pe n de nc y.  
3  Vasect o mise d  part ner is a hi g hl y effecti ve met h o d pr o vi de d of a v oi di n g pre g na nc y  t hat p art ner is t he s ole se x ual 
part ner of t he W O C B P trial partici pa nt a n d t hat t he vasect o mise d  part ner has recei ve d me di cal assess me nt of t he 
s ur gical s uccess.  
4  I n t he c o nte xt of t his g ui da nce, se x ual a bsti ne nce is c o nsi d ere d a hi g hl y effecti ve met h o d o nl y if defi ne d as 
refrai ni ng fr o m heter ose x ual i nterc o urse d uri n g t he e ntire peri o d of ris k ass ociate d wit h t he st u d y treat me nts.  T he 
relia bilit y of se x ual a bsti ne nce nee ds t o be e val uate d i n relati o n t o t he d urati o n of t he cli nic al trial a n d t he 
preferre d a n d us ual lifest yle of t he s u bj ect.  
S o urce :  C T F G  2 0 1 4 . 


I nc yte C or p orati o n 
P a ge 8 5  of 8 5  
Pr ot oc ol I N C B  3 9 1 1 0 -2 0 9 A me n d me nt 1  
1 4 A U G 2 0 1 7  
C O N FI D E N TI A L  
A P P E N DI X  H. 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 
I n cli nical st u dies wit h C Y P 3 A 4 i n hi bit ors, ele vate d le vels of I N C B 0 1 8 4 2 4 of a p pr o xi matel y 
2-f ol d ha ve b ee n o bser ve d a fter or al a d mi nistrati o n.  A d diti o nall y, si m ulati o ns usi n g 
p h ysi ol o gicall y base d p h ar mac o ki netic m o d els s u g geste d t h at fl uc o naz ole (a d ual C Y P 3 A 4 a n d 
C Y P 2 C 9 i n hi bit or) i ncreases stea d y- st ate r u x oliti ni b A U C b y a p pr o xi matel y 1- t o 3-f ol d after 
oral a d mi nist rati o n.  T h us, t hese c o nc o mita nt me dicati o ns s h o ul d n ot be ta ke n b y s u bj ects 
be gi n ni n g 2 w ee ks or 5 h alf-li ves ( w hic h e ver is l o n ger) bef ore t h e first a p plicati o n of st u d y dr u g 
u ntil t he last a d mi nistrati o n (eit her Wee k 2 4 or W ee k 4 8); h o we ver, t o pical use of t hese a ge nts if 
t he s yste mic bi oa v aila bilit y is l o w ma y be per mitte d o n a case-b y -case b asis.  T he f oll o wi n g is a 
list of p ote nt C Y P 3 A 4 i n hi bit ors a n d fl uc o naz ole.  T he s p o ns or s h o ul d be c o ntacte d wit h a n y 
q uesti o ns re gar di n g c o n c o mita nt me dicati o ns t hat mi g ht be c o nsi dere d p ote nt C Y P 3 A 4 i n hi bit ors 
b ut are n ot o n t his list. 
b oce pre vir 
clarit hr o m yci n  
c o bicistat  
c o ni va pta n 
da n o pre vir 
el vite gr a vir  
fl uc o naz ole 
gr a pefr uit j uice  
i delalisi b 
i n di na vir 
itrac o naz ole 
ket oc o naz ole 
L C L 1 6 1  
l o pi na vir 
mi befra dil  
nefaz o d o ne 
nelfi na vir 
p osac o naz ole 
rit o na vir 
sa q ui na vir 

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