Ixazomib for Treatment of Chronic Graft vs. Host Disease
Phase: PHASE2
Conditions: Chronic Graft Versus Host Disease
Sponsor: Fred Hutchinson Cancer Center

C LI NI C A L S T U D Y P R O T O C O L   
Pr ot oc ol n u m ber: X 1 6 0 3 2  
I xaz o mi b f or Treat me nt of C hr o nic Graft vs. H ost Disease 
 
 
 
 
I n dic ati o n: 
Treat me nt of C hr o nic G V H D  
P h ase:  
P hase II  
 
 
 
Pr ot oc ol Hist or y  
Ori gi nal  
 
3 0  A pril  2 0 1 5  
M o dificati o n  
 
1 3 N o ve m ber 2 0 1 5  
M o dificati o n  
 
1 0 Fe br uar y 2 0 1 6  
M o dificati o n  
 
6 Ma y 2 0 1 6  
M o dificati o n  
 
1 7 Oct o ber 2 0 1 6  
M o dificati o n  
 
4 A pril 2 0 1 7  
 
 
Pri nci pal I n vesti gat or: 
 
Ste p ha nie J. Lee, M D, M P H  
Fre d H utc hi ns o n Ca ncer Researc h Ce nter  
1 1 0 0 Fair vie w A ve. N o., Seattle, W A 9 8 1 0 9 -1 0 2 4  
sjlee @fre dh utc h. or g  
 
 
 
St u d y C hair : 
 
J ose p h Pi dala, M D, P h D  
Bl o o d a n d Marr o w Tra ns pla ntati o n  
M offitt Ca ncer Ce nter  
Ta m pa, F L 3 3 6 1 2  
J ose p h. pi dala @ m offitt. or g 
8 1 3 -7 4 5 -2 5 5 6  
 
 
 
T his is a n i n vesti gat or -i nitiate d st u d y.  T he pri nci pal i n vesti gat or , Ste p ha nie J. Lee, M D, 
M P H  ( w h o ma y als o be referre d t o as t he s p o ns or-i n vesti gat or), is c o n d ucti n g t he st u d y a n d 
acti n g as t he s p o ns or.  T heref ore, t he le gal/et hical o bli gati o ns of t he pri nci pal i n vesti gat or 
i ncl u de b ot h t h ose of a s p o ns or a n d t h ose of a n i n vesti gat or.
 
 
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P R O T O C O L S U M M A R Y   
St u d y Title:   I xaz o mi b f or Treat me nt of C hr o nic Graft vs. H ost Disease 
P h ase :  P hase II, si n gle ar m, o pe n la bel, m ulti -ce nter trial  
N u m ber of P atie nts:   5 0 t otal patie nts  
St u d y O bjecti ves   
 
Pri m a r y O bj ecti ve:  
Deter mi ne t he pr o p orti o n of s u bjects wit h treat me nt fail ure b y 6 m o nt hs of I xaz o mi b treat me nt f or 
c hr o nic G V H D.  
Sec o n d ar y O bjecti ves:  
 
1.  
Deter mi ne 3 m o nt h o verall (c o m plete + partial), a n d c o m plete res p o nse rate  
2.  
Deter mi ne 6 m o nt h o verall (c o m plete + partial), a n d c o m plete res p o nse rate 
3.  
Re p ort o verall s ur vi val, n o n -rela pse m ortalit y, pri mar y mali g na nc y rela pse, fail ure-
free s ur vi val, treat me nt s uccess, a n d disc o nti n uati o n of i m m u ne-s u p pressi ve t hera p y at 6 
m o nt hs a n d 1 year  
4.  
E xa mi ne f u ncti o nal o utc o me ( 2 -mi n ute wal k test) a n d patie nt -re p orte d o utc o mes 
( Lee C hr o nic G V H D S y m pt o m Scale, q ualit y of life ( S F-3 6, F A C T -B M T), H u ma n Acti vit y 
Pr ofile ( H A P)) at st u d y e nr oll me nt, 6 m o nt hs a n d 1 year  
5.  
St u d y bi ol o gic effects of pr oteas o me i n hi biti o n  
 
O ver vie w of St u d y Desi g n:    
 
T his p hase II trial will e xa mi ne t he efficac y of I xaz o mi b i n c hr o nic G V H D treat me nt. T he 
pri mar y e n d p oi nt is 6 m o nt h treat me nt fail ure.  
St u d y P o p ul ati o n:    
Patie nts wit h c hr o nic G V H D ( dia g n ose d acc or di n g t o NI H C o nse ns us  Criteria) w h o ha ve 
faile d at least o ne pri or li ne of s yste mic i m m u ne-s u p pressi ve t hera p y. 
D ur ati o n of St u d y:   Patie nts will c o m plete u p t o 6 c y cles of I xaz o mi b t hera p y a n d will c o m plete 1 2 
m o nt hs of cli nical f oll o w u p o n st u d y. At t he 6 m o nt h ti me p oi nt,  p atie nts w h o ha ve ac hie ve d a 
c o m plete or partial res p o nse, or ha ve sta ble disease , will ha ve t he o pti o n of recei vi n g  u p t o  a n 
a d diti o nal 6 m o nt hs of I xaz o mi b t hera p y.   
 
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T A B L E O F C O N T E N T S  
P R O T O C O L S U M M A R Y  ........................................................................................................2  
T A B L E O F C O N T E N T S  .........................................................................................................3  
LI S T O F A B B R E VI A TI O N S A N D G L O S S A R Y O F T E R M S  ..............................................5  
1. B A C K G R O U N D A N D S T U D Y R A TI O N A L E  ..................................................................7  
1. 1 Scie ntific Bac k gr o u n d  ....................................................................................................7  
1. 1. 1  Disease U n der Treat me nt  .........................................................................................7  
1. 1. 2  I xaz o mi b (I xaz o mi b)..............................................................................................1 2  
1. 2 Precli nical E x perie nce  ..................................................................................................1 2  
1. 3 Cli nical E x perie nce  .......................................................................................................1 2  
1. 4  P har mac o ki netics a n d Dr u g Meta b olis m  ......................................................................1 2  
1. 5 Cli nical Trial E x perie nce Usi n g t he Oral F or m ulati o n of I xaz o mi b ............................1 3  
1. 6 Rela pse d a n d/ or Refract or y M ulti ple M yel o ma  ...........................................................1 7  
1. 7 Ne wl y Dia g n ose d M ulti ple M yel o ma ( N D M M)  ..........................................................2 1  
1. 8 St u d y Rati o nale  .............................................................................................................2 3  
1. 9 P ote ntial Ris ks a n d Be nefits  .........................................................................................2 3  
2. S T U D Y O BJ E C TI V E S  ......................................................................................................2 4  
2. 1  Pri ma r y O bjecti ves .......................................................................................................2 4  
3. S T U D Y E N D P OI N T S  ........................................................................................................2 5  
3. 1 Pri mar y E n d p oi nts  ........................................................................................................2 5  
3. 2 Sec o n dar y E n d p oi nts  ....................................................................................................2 7  
4. S T U D Y D E SI G N  ...............................................................................................................2 9  
4. 1 O ver vie w of St u d y Desi g n  ...........................................................................................2 9  
4. 2 N u m ber of Patie nts  .......................................................................................................2 9  
4. 3 D urati o n of St u d y  .........................................................................................................2 9  
5. S T U D Y P O P U L A TI O N  .....................................................................................................3 0  
5. 1 I ncl usi o n Criteria  ..........................................................................................................3 0  
5. 2 E xcl usi o n Criteria  .........................................................................................................3 1  
6. S T U D Y D R U G  ...................................................................................................................3 3  
6. 1 St u d y Dr u g A d mi nistrati o n  ..........................................................................................3 3  
6. 2 D ose -M o dificati o n G ui deli nes  .....................................................................................3 4  
6. 2. 1  Rec o m me n de d I xaz o mi b Criteria f or Be gi n ni n g or Dela yi n g a S u bse q ue nt 
Treat me nt C ycle & D ose M o dificati o ns f or Treat me nt Ass ociate d 
T o xicit y  ...........................................................................................................3 4  
6. 2. 2  Rec o m me n de d D ose M o dificati o ns f or < ot her dr u g(s) > Treat me nt 
Ass o ciate d T o xicit y  ........................................................................................3 8  
6. 3 E xcl u de d C o nc o mita nt Me dicati o ns  .............................................................................3 8  
6. 4 Per mitte d C o nc o mita nt Me dicati o ns a n d Pr oce d ures  ...................................................3 9  
6. 5 Preca uti o ns a n d Restricti o ns  .........................................................................................3 9  
6. 6 Ma na ge me nt of Cli nical E ve nts  ...................................................................................4 0  
6. 7 Pre parati o n, Rec o nstit uti o n, a n d Dis pe nsi n g  ................................................................4 2  
6. 8 Pac ka gi n g a n d La beli n g  ................................................................................................4 2  
6. 9 St ora ge, Ha n dli n g, a n d Acc o u n ta bilit y .........................................................................4 2  
6. 1 0 St u d y C o m plia nce  .......................................................................................................4 3  
6. 1 1 Disc o nti n uati o n of I xaz o mi b t hera p y .........................................................................4 4
 
 
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6. 1 2 Ter mi nati o n of st u d y partici pati o n  .............................................................................4 4  
7. S T A TI S TI C A L A N D Q U A N TI T A TI V E A N A L Y S E S  .....................................................4 5  
7. 1 Statistical Met h o ds  .......................................................................................................4 5  
7. 1. 1  Deter mi nati o n of Sa m ple Size a n d pla n ne d met h o ds of a nal ysis  ..........................4 5  
7. 1. 2  S T U D Y S T O P PI N G R U L E S  ................................................................................4 6  
8. A D V E R S E E V E N T S  ..........................................................................................................4 8  
8. 1 Defi niti o ns  ....................................................................................................................4 8  
8. 2   Rec or di n g of A d verse E ve nts  .....................................................................................5 1  
8. 3  I N D Safet y Re p orti n g ...................................................................................................5 2  
8. 4   Re p orti n g t o Mille n ni u m  ............................................................................................5 3  
8. 5   Pr oce d ures f or Re p orti n g A Es  ....................................................................................5 6  
8. 6   Pr oce d ures f or Re p orti n g Dr u g E x p os ure D uri n g Pre g na nc y a n d Birt h E ve nts  ........5 6  
9. A D MI NI S T R A TI V E R E Q UI R E M E N T S  ..........................................................................5 6  
9. 1 Pr o d uct C o m plai nts  ......................................................................................................5 6  
1 0.  R E F E R E N C E S  .................................................................................................................5 8  
1 1. A P P E N DI C E S  ..................................................................................................................6 1  
1 1. 1 St u d y Cale n dar  ...........................................................................................................6 1  
1 1. 2 C oc kcr oft -Ga ult E q uati o n  ...........................................................................................6 3  
 
 
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LI S T O F A B B R E VI A TI O N S A N D G L O S S A R Y O F T E R M S  
C o m m o n a b brevi ati o ns use d i n  o nc ol o gy  pr ot oc ols are pr ovi de d bel o w.  Pr o gr a m -s pecific 
or pr ot oc ol -s pecific a b brevi ati o ns m ust be a d de d t o t his list, a n d un necess ary a b brevi ati o ns 
re m ove d, as a p plic a ble.  A b brevi ati o ns t h at are ret ai ne d s h o ul d n ot be c h a n ge d.  
A b bre vi ati o n  
Ter m  
 
 
A E  
a d verse e ve nt  
A L P  
al kali ne p h os p hatase 
A L T  
ala ni ne a mi n otra nsferase  
A N C  
a bs ol ute ne utr o p hil c o u nt  
A S T  
as partate a mi n otra n sferase 
A U C  
area u n der t he plas ma c o nce ntrati o n vers us ti me c ur ve  
BI D  
bis i n die; t wice a da y  
B M  
b o ne marr o w  
B S A  
b o d y s urface area  
B U N  
bl o o d urea nitr o ge n  
C B C  
c o m plete bl o o d c o u nt  
C F R  
C o de of Fe deral Re g ulati o ns  
C R  
c o m plete res p o nse  
C Y P  
c yt oc hr o me P 4 5 0 
D L T  
d ose -li miti n g t o xicit y 
E C G  
E lectr ocar di o gra m 
F D A  
U nite d States F o o d a n d Dr u g A d mi nistrati o n  
G C P  
G o o d Cli nical Practice  
G M P  
G o o d Ma n ufact uri n g Practice  
H b  
H e m o gl o bi n 
Hct  
H e mat ocrit  
I B 
I n vesti gat or’s Br oc h ure 
I C F 
i nf or me d c o nse nt f or m 
I RB  
i nstit uti o nal re vie w b oar d 
I V 
i ntra ve n o us; i ntra ve n o usl y 
K P S  
Kar n ofs k y Perf or ma nce Stat us  
L D H  
lactate de h y dr o ge nase 
L F T  
li ver f u ncti o n test(s) 
 
 
 
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A b bre vi ati o n  
Ter m  
Mille n ni u m  
Mille n ni u m P har mace uticals, I nc., a n d its affiliates  
M T D  
ma xi m u m t olerate d d ose  
N CI C T C A E  
Nati o nal Ca ncer I nstit ute C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts  
P B M C  
peri p heral bl o o d m o n o n uclear cell  
P C R  
p ol y merase c hai n reacti o n  
P g p  
P -gl yc o pr otei n  
P K  
p har mac o ki netic(s)  
P O  
per os ; b y m o ut h ( orall y) 
P R  
partial res p o nse  
P R O  
patie nt -re p orte d o utc o me 
Q D  
q u a q ue die ; eac h da y; o nce dail y 
QI D  
q u ater i n die;  4 ti mes a da y  
Q O D  
q u a q ue alter a die ; e ver y ot her da y 
Q O L  
q ualit y of life  
Q Tc  
rate-c orrecte d Q T i nter val ( millisec) of electr ocar di o gra p h  
R B C  
re d bl o o d cell 
S A E  
seri o us a d verse e ve nt 
S C  
S u bc uta ne o us  
S D  
sta ble disease 
T ma x  
si n gle-d ose ti me t o reac h ma xi m u m ( pea k) c o nce ntrati o n  
U L N  
u p per li mit of t he n or mal ra n ge  
U S  
U nite d States  
W B C  
w hite bl o o d cell  
 
 
 
 
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1.     
B A C K G R O U N D A N D S T U D Y  R A TI O N A L E  
1. 1     Scie ntific B ac k gr o u n d  
1. 1. 1    Dise ase U n de r Tre at me nt  
 
C hr o nic gr aft vs. h ost dise ase  
C hr o nic graft vs. h ost disease (c hr o nic G V H D) is a maj or late c o m plicati o n of all o ge neic 
he mat o p oietic cell tra ns pla ntati o n ( H C T) t hat affects u p t o 7 0 % of H C T s ur vi v ors. T he 
s y n dr o me is ass ociate d wit h maj or trans pla nt -relate d m or bi dit y, m ortalit y, i nfecti o us 
c o m plicati o ns, pr ol o n ge d d urati o n of i m m u ne s u p pressi o n, a n d i m paire d patie nt -re p orte d 
q ualit y of life. 1 -8  T h us,  it re prese nts a maj or o bstacle t o rec o ver y a n d s ur vi val f oll o wi n g 
H C T, a n d its pre ve nti o n a n d treat me nt are of si g nifica nt i m p orta nce. T he s y n dr o me is 
c haracterize d b y di verse cli nical ma nifestati o ns, b ut t he m ost c o m m o nl y affecte d or ga ns are 
t he s ki n, e yes, m o ut h, a n d li ver. H o we ver, m ost or ga ns ca n be i n v ol ve d, wit h parallels t o 
ot her s yste mic i m m u ne -me diate d dis or ders.   
 
 
C hr o nic G V H D di a g n osis a n d cl assific ati o n  
 
Dia g n osis a n d classificati o n of t he s y n dr o me has u n der g o ne maj or re visi o n f oll o wi n g t he 
2 0 0 5 NI H C o nse ns us C o nfere nce o n C hr o nic G V H D.  Acc or di n g t o t he hist orical 
classificati o n, ac ute a n d c hr o nic G V H D were disti n g uis he d b y t he occ urre nce of 
ma nifestati o ns bef ore or f oll o wi n g da y 1 0 0 p ost -H C T. 9  Acc or di n g t o t he pr o p ose d NI H 
C o nse ns us defi niti o ns, t he dia g n osis of c hr o nic G V H D is base d o n t he prese nce of 
dia g n ostic ma nifestati o ns of t he s y n dr o me, rat her t ha n t he ti me of o nset f oll o wi n g H C T. 
Classic c h r o nic G V H D is defi ne d b y t he defi niti ve ma nifestati o ns of t he s y n dr o me i n t he 
a bse nce of c o nc urre nt ac ute G V H D ma nifestati o ns. Prese nce of b ot h c hr o nic a n d ac ute 
G V H D ma nifestati o ns defi nes t he o verla p s u bt y pe of c hr o nic G V H D. C hr o nic G V H D 
se verit y is sc ore d acc or di n g t o o bjecti ve criteria f or eac h or ga n i n v ol ve d, w hic h is 
s u m marize d f or a n o verall gl o bal se verit y sc ore of mil d, m o derate, or se vere. 1 0 
 
 
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T her a p y of est a blis he d c hr o nic G V H D  
 
Acce pte d sta n dar d pri mar y t hera p y f or c hr o nic G V H D i ncl u des 1 m g/ k g or greater of 
pre d nis o ne or e q ui vale nt wit h or wit h o ut a calci ne uri n i n hi bit or. 2 ,1 1 T he a d diti o n of ot her 
s yste mic i m m u ne-s u p pressi ve a ge nts t o i nitial t hera p y has n ot pr o vi de d be nefit, as 
e vi de nce d b y trials a d di n g azat hi o pri ne, t hali d o mi de, or h y dr o x yc hl or o q ui ne t o i niti al 
treat me nt wit h ster oi ds,1 2 -1 4 or t he m ore rece nt ra n d o mize d trial e val uati n g t he c o m bi nati o n 
of ster oi ds a n d m yc o p he n olate m ofetil. 1 5  P u blis he d pri mar y c hr o nic G V H D t hera p y trials 
de m o nstrate t hat o n a vera ge 2 7 % will ac hie ve c o m plete res p o nse, a n d 6 0 % will ac hie ve 
o verall res p o nse (c o m plete + partial res p o nse) b y 6 -9 m o nt hs after starti n g i nitial t hera p y. 1 1 -
1 6  
Base d o n i ns ufficie nt res p o nse t o pri mar y t hera p y or a flare of c hr o nic G V H D after ta peri n g 
of i nitial t hera p y, ma n y wil l g o o n t o re q uire a d diti o nal i m m u ne-s u p pressi ve a ge nts f or 
c hr o nic G V H D c o ntr ol. “ Ster oi d -refract or y” c hr o nic G V H D has m ost c o m m o nl y bee n 
defi ne d as eit her pr o gressi ve ma nifestati o ns des pite o ne m o nt h of treat me nt, or i nc o m plete 
res p o nse des pite t w o m o nt hs of 1-2 m g/ k g of pre d nis o ne or e q ui vale nt. 2 I n a d diti o n t o 
ster oi d-refract ori ness, ot her cli nical i n dicati o ns f or a d diti o nal li nes of s yste mic i m m u ne 
s u p pressi ve t hera p y i ncl u de ster oi d de pe n de nce a n d ster oi d i nt olera nce. Patie nts wit h 
ster oi d-de pe n de nt c hr o nic G V H D ca n’t t olerate ta peri n g pre d nis o ne d ue t o rec urre nt c hr o nic 
G V H D ma nifestati o ns. Ster oi d i nt olera nt pat ie nts ha ve me dical c o m plicati o ns of ster oi d 
t hera p y (e. g. h y per gl yce mia, e de ma, ps yc h osis, oste o p or osis), a n d t h us re q uire a d diti o nal 
i m m u ne-s u p pressi ve a ge nts t o c o ntr ol G V H D a n d facilitate ta per of pre d nis o ne. M ulti ple 
i m m u ne-s u p pressi ve t hera pies, i ncl udi n g p har mac ol o gic a ge nts, m o n ocl o nal a nti b o dies, a n d 
strate gies s uc h as e xtrac or p oreal p h ot o p heresis ha ve de m o nstrate d m o derate acti vit y i n t his 
setti n g, b ot h a meli orati n g o bjecti ve c hr o nic G V H D ma nifestati o ns, as well as facilitati n g 
ta per of s yste mic ster oi ds. 1 7 T heir effecti ve ness is s u b o pti mal, h o we ver, a n d ma n y patie nts 
will re q uire m ulti ple a ge nts t o ac hie ve disease c o ntr ol. 
 
 
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T he o verall b ur de n of c hr o nic G V H D des pite r o uti ne p har mac ol o gic G V H D pr o p h yla xis, 
li mite d res p o nse t o pri mar y a n d sec o n dar y t hera p y, a n d t he atte n da nt m or bi dit y a n d 
m ortalit y all s u p p ort t he nee d f or n o vel a p pr oac hes i n c hr o nic G V H D treat me nt.  
 
Assess me nt of t her a pe utic res p o nse i n c hr o nic G V H D  
 
T he esta blis he d met h o d f or res p o nse deter mi nati o n i n t he m aj orit y of c hr o nic G V H D 
t hera p y trials is cli nicia n-deter mi ne d res p o nse. T his met h o d relies o n t he treati n g cli nicia n’s 
i nte grati o n of d y na mic c hr o nic G V H D ma nifestati o ns f or a s u m mar y res p o nse 
cate g orizati o n of c o m plete res p o nse ( C R), partial res p o nse ( P R ), sta ble disease ( S D), or 
pr o gressi ve disease ( P D). C R i n dicates c o m plete res ol uti o n of all c hr o nic G V H D 
ma nifestati o ns; P R si g nifies re d ucti o n i n disease acti vit y c o m pare d wit h pre -treat me nt 
le vels, b ut wit h o ut c o m plete res ol uti o n; S D i n dicates n o res p o nse a n d n o pr o gressi o n; a n d 
P D i n dicates pr o gressi ve c hr o nic G V H D ma nifestati o ns fr o m baseli ne.  
F oll o wi n g a 2 0 0 5 NI H C o nse ns us C o nfere nce f or C hr o nic G V H D, se veral a d diti o nal mea ns 
of res p o nse assess me nt i n c hr o nic G V H D t hera pe utic trials ha ve bee n pr o p ose d. T hese 
i ncl u de c ha n ge i n o verall NI H se verit y cate g ories, pr o p ose d NI H res p o nse criteria, 0-4 a n d 
0 -1 0 or di nal scales t hat rel y o n cli nicia n assess me nt, or ga n -s pecific t o ols s uc h as t he Vie n na 
s ki n scale, as well as patie nt-deter mi ne d c ha n ge i n c hr o nic G V H D acti vit y, c hr o nic G V H D -
ass ociate d s y m pt o m b ur de n, f u ncti o nal li mitati o ns, a n d c ha n ge i n q ualit y of life. T he 
C hr o nic G V H D C o ns orti u m is c urre ntl y assessi n g t hese c o m peti n g meas ures of disease 
acti vit y a n d t heir relati o ns hi p t o l o n ger -reac hi n g o utc o mes i n dicati n g cli nical be nefit, s uc h 
as fail ure -free s ur vi val, disc o nti n uati o n of all i m m u ne s u p pressi o n, o verall s ur vi val, or 
patie nt -re p orte d be nefit. 
 
I nter pretati o n of pre vi o usl y p u blis he d trials f or sec o n dar y c hr o nic G V H D treat me nt is 
li mite d b y a n u m ber of fact ors, m ost n ota bl y heter o ge neit y i n res p o nse deter mi nati o n. A 
rece ntl y p u blis he d lar ge a nal ysis has e xa mi ne d fail ure-free s ur vi val ( F F S) as a pr o p ose d 
o utc o me a m o n g c hr o nic G V H D patie nts treate d wit h sec o n d -
 
li ne s yste mic treat me nt. It 
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i ncl u de d  3 1 2 patie nts w h o met t he f oll o wi n g criteria: ( 1) Ha d alrea d y recei ve d s yste mic 
ster oi d treat me nt f or c hr o nic G V H D at a pre d nis o ne-e q ui vale nt d ose of at least 0. 5 
m g/ k g/ da y, ( 2) als o o n a n a d diti o nal s yste mic i m m u n os u p pressi ve treat me nt w he n sec o n d -
li ne treat ment was starte d, a n d ( 3) recei ve d sec o n d -li ne treat me nt beca use of pr o gressi ve 
G V H D ma nifestati o ns after at least 1 wee k of i nitial treat me nt or beca use of lac k of 
i m pr o ve me nt after at least 2 wee ks of i nitial treat me nt. C o m m o nl y use d sec o n d-li ne 
treat me nts i ncl u de d m yc o p he n olate m ofetil, tacr oli m us, sir oli m us, e xtrac or p oreal 
p h ot o p heresis, c ycl os p ori ne, met h otre xate, or ot her a ge nts. B y 6 m o nt hs of sec o n d -li ne 
t hera p y, 4 4 % ha d e x perie nce d treat me nt fail ure (c o m p osite of re q uire me nt of a d diti o nal 
s yste mic i mm u ne s u p pressi o n be y o n d sec o n d -li ne t hera p y, deat h, a n d mali g na nc y rela pse),1 8 
a n d t h us 6 m o nt h fail ure -free s ur vi val ( F F S) was 5 6 %. I n m ulti variate a nal ysis, t hree fact ors 
were si g nifica nt deter mi na nts of treat me nt fail ure: hi g h -ris k disease at tra ns pla ntati o n 
( defi ne d as diseases ot her t ha n l o w ris k; l o w-ris k disease cate g ories i ncl u de d c hr o nic 
m yel oi d le u ke mia i n c hr o nic p hase, ac ute le u ke mia i n first c o m plete re missi o n, 
m yel o d ys plastic s y n dr o me wit h o ut e xcess blasts, a n d n o n -mali g na nt diseases), l o wer 
gastr oi ntesti nal i n v ol ve me nt  as sec o n d -li ne treat me nt was a d de d, a n d se vere NI H gl o bal 
sc ore as sec o n d-li ne treat me nt was a d de d.  T hese t hree fact ors were use d t o defi ne ris k 
gr o u ps: l o w -ris k ha d n o ris k fact ors, i nter me diate-ris k i ncl u de d t h ose wit h 1 ris k fact or, a n d 
hi g h -ris k i ncl u de d t h ose wit h 2 -3 ris k fact ors. T he c u m ulati ve i nci de nce of 6 m o nt h 
treat me nt fail ure was 3 3 % f or l o w-ris k, 4 1 % f or i nter me diate ris k, a n d 5 6 % f or hi g h ris k.  
 
I m m u ne m o d ul ati o n f oll o wi n g pr ote as o me i n hi biti o n 
 
Pr oteas o me i n hi biti o n e xerts p o werf ul effects o n i m m u ne cel ls i m plicate d i n G V H D 
pat h o ge nesis. Pre -cli nical a n d cli nical data pr o vi de r o b ust s u p p ort f or t his c o nce pt. 1 9 ,2 0 
Pr oteas o me i n hi bit ors i nterfere wit h a nti ge n pr ocessi n g a n d prese ntati o n, as well as 
si g nali n g casca des i n v ol ve d i n i m m u ne cell f u ncti o n a n d s ur vi val: I n de n dritic cells ( D C), 
t here is i m paire d mat urati o n, c o-sti m ulat or y m olec ule e x pressi o n, a n d re d ucti o n of pr o -
i nfla m mat or y c yt o ki nes. T l y m p h oc ytes de m o nstrate a p o pt osis, re d uce d pr oliferati o n, 
i m paire d pr o-i nfla m mat or y c yt o ki ne pr o d ucti o n, as well as e x pa nsi o n of re g ulat or y T cells 
( Tre g). B cell pr oliferati o n is decrease d, a n d re d uce d a nti b o d y pr o d ucti o n 
 
is o bser ve d 
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a m o n g plas ma cells. T h us, pr oteas o me i n hi biti o n tar gets ke y me diat ors esta blis he d t o be 
rele va nt i n G V H D pat h o ge nesis. I n a m uri ne G V H D m o del, b ortez o mi b i n hi bite d 
all oreacti ve T cells a n d pr otecte d fr o m G V H D, di d n ot a d versel y affect d o n or re c o nstit uti o n, 
a n d di d n ot i m pair c yt ot o xic T cell killi n g of t u m or. 2 1  
 
 
Effect of pr ote as o me i n hi biti o n o n c hr o nic G V H D i n t he cli nic al setti n g  
 
W hile p u blis he d cl i nical trials de m o nstrate t he acti vit y of pr oteas o me i n hi biti o n i n t he 
pri mar y pre ve nti o n of G V H D, 2 2 ,2 3 less is k n o w n i n t he setti n g of c hr o nic G V H D treat me nt. 
E mer gi n g cli nical data s u g gest t hat pr oteas o me i n hi biti o n ma y c o ntr ol c hr o nic G V H D: I n a 
case re p ort, a patie nt wit h rela pse d m ulti ple m yel o ma after H C T was s uccessf ull y treate d 
wit h b ortez o mi b f or oral l ic he n pla n us a n d bi o ps y-c o nfir me d he patic c hr o nic G V H D. 2 4 I n a 
case series ( n = 8), m ulti ple m yel o ma patie nts were treate d wit h b ortez o mi b f or rela pse d 
disease af ter H C T, a n d t h ose wit h c hr o nic G V H D ( n = 4) e x perie nce d i m pr o ve me nt.2 5  T hree 
ha d re missi o n of c hr o nic G V H D at a me dia n of 1 5 0 da ys after b ortez o mi b disc o nt i n uati o n, 
a n d o ne ha d rec urre nt oc ular ma nifestati o ns of c hr o nic G V H D.  Fi nall y, i n a lar ger series, 3 7 
m ulti ple m yel o ma patie nts wit h pr o gressi ve or resi d ual disease after H C T were treate d wit h 
b ortez o mi b. Of t hese, 8 patie nts ha d li mite d c hr o nic G V H D, a n d 3 ha d e xte nsi ve c hr o nic 
G V H D. Patie nts were treate d wit h a me dia n of 6 c ycles of b ortez o mi b, a n d t his was 
t olerate d well. C o m m o n a d verse e ve nts i ncl u de d peri p heral ne ur o pat h y, mil d 
t hr o m b oc yt o pe nia n ot re q uiri n g tra nsf usi o n, a n d fati g ue, a n d t here were no treat me nt relate d 
deat hs. Of t he 3 e xte nsi ve c hr o nic G V H D cases, 2 res p o n de d a n d were d o w n -gra de d t o 
li mite d disease at last e val uati o n. Of t he 8 wit h li mite d c hr o nic G V H D, n o ne re q uire d 
a d diti o nal i m m u ne s u p pressi ve t hera p y, a n d o ne ha d res ol uti o n of c h r o nic G V H D.2 6 
Beca use t hese li mite d data are of i nterest b ut diffic ult t o i nter pret i n t he setti n g of m yel o ma 
rela pse or persiste nce, a d diti o nal i nsi g ht s h o uld arise fr o m a n e xisti n g c hr o nic G V H D 
pri mar y t hera p y trial ( N C T 0 0 8 1 5 9 1 9) testi n g t he c o m bi nati o n of pre d nis o ne a n d 
b ortez o mi b.  
 
 
 
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1. 1. 2     I x az o mi b 
1. 2     Precli nic al E x perie nce  
Please refer t o t he c urre nt I xaz o mi b I n vesti gat or’s Br oc h ure (I B). 
1. 3     Cli nic al E x p erie nce 
As of 3 0 A pril 2 0 1 2 , 3 8 2  patie nts ha ve bee n treate d wit h I xaz o mi b acr oss 9  e nr olli n g, 
s p o ns or-le d p hase 1 or p hase 1/ 2 st u dies e val uati n g b ot h t wice-wee kl y a n d wee kl y d osi n g 
sc he d ules.  I xaz o mi b is a vaila ble as a n i ntra ve n o us a n d oral f or m ulati o n. Re gar dless of t he 
r o ute of a d mi nistrati o n i n t he t wice-wee kl y d osi n g sc he d ule, I xaz o mi b is gi ve n o n Da ys 1, 4, 
8, a n d 1 1 of a 2 1 -da y c ycle; i n t he wee kl y d osi n g sc he d ule, t he dr u g is gi ve n o n Da ys 1, 8, 
a n d 1 5 of a 2 8 -da y c ycle.  T o date, t he de vel o p me nt of  oral I xaz o mi b has f oc use d o n 
m ulti ple m yel o ma [rela pse d a n d/ or refract or y a n d ne wl y dia g n ose d] a n d a differe nt yet 
relate d plas ma cell d yscrasia, s yste mic li g ht c hai n ( A L) a m yl oi d osis. A cli nical 
p har mac ol o g y st u d y l o o ki n g at dr u g -dr u g i nteracti o ns, t he e ffect of f o o d, a n d bi oa vaila bilit y 
als o uses t he oral f or m ulati o n. Details of t hese trials ca n be f o u n d i n Cli nical Trials. g o v a n d 
t he I xaz o mi b I B.   
1. 4    P h ar m ac o ki netics a n d Dr u g Met a b olis m  
Cli nical I V a n d P O p har mac o ki netic ( P K) data s h o w t hat I xaz o mi b ( meas ure d as t he 
bi ol o gicall y acti ve b or o nic aci d f or m of I xaz o mi b [ M L N 2 2 3 8]) has m ulti-e x p o ne ntial 
dis p ositi o n wit h a ra pi d i nitial p hase t hat is lar gel y o ver b y 4 h o urs.  Oral I xaz o mi b is 
ra pi dl y a bs or be d wit h a me dia n ti me t o first ma xi m u m plas ma c o nce ntrati o n ( Tma x ) of 
a p pr o xi matel y 0. 5 t o 2. 0 h o urs a n d ter mi nal t 1/ 2 after m ulti ple d osi n g of a p pr o xi matel y 5 t o 7 
da ys. [ 1]  Res ults of a p o p ulati o n P K a nal ysis ( N = 1 3 7) s h o w t hat t here is n o relati o ns hi p 
bet wee n b o d y s urface area ( B S A) or b o d y wei g ht a n d clea ra nce ( C L).  Als o, base d o n 
st oc hastic si m ulati o ns f or fi xe d d ose, e x p os ures are i n de pe n de nt of t he i n di vi d ual patie nt’s 
B S A. [ 2]  Base d o n t hese data, a rec o m me n dati o n was ma de f or fi xe d d osi n g i n cli nical 
trials.  A n a bs ol ute bi oa vaila bilit y of 6 7 % was deter mi ne d f or I xaz o mi b usi n g t he p o p ulati o n 
P K a nal ysis.  Please refer t o  t he c urre nt  I B f or i nf or mati o n o n t he P K f or I V d oses of 
I xaz o mi b. 
Meta b olis m a p pears t o be t he maj or r o ute of eli mi nati o n f or I xaz o mi b, wit h ne gli gi ble 
uri nar y e xcreti o n of t he pare n t dr u g ( < 
 
3 % of d ose).  I n vitr o st u dies of li ver micr os o mes 
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D o c u m e nt R el e a s e D at e: 0 8/ 1 1/ 2 0 1 7
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s h o w t hat I xaz o mi b is meta b olize d b y m ulti ple c yt oc hr o me P 4 5 0 e nz y mes ( C Y Ps) a n d n o n-
C Y P e nz y mes/ pr otei ns.  T he ra n k or der of relati ve bi otra nsf or mati o n acti vit y of t he 5 maj or 
h u ma n C Y P is oz y mes  is 3 A 4 ( 3 4. 2 %) > 1 A 2 ( 3 0. 7 %) > 2 D 6 ( 1 4. 7 %) >  2 C 9 ( 1 2. 1 %) 
>  2 C 1 9 ( <  1 %).  I xaz o mi b is n ot a n i n hi bit or of C Y Ps 1 A 2, 2 C 9, 2 C 1 9, 2 D 6, or 3 A 4, n or is 
it a ti me-de pe n de nt i n hi bit or of C Y P 3 A 4/ 5.  T he p ote ntial f or I xaz o mi b treat me nt t o 
pr o d uce D DIs via C Y P i n hi biti o n is i nferre d t o be l o w; h o we ver, t here ma y be a p ote ntial 
f or D DIs wit h a c o nc o mita nt str o n g C Y P 3 A 4 or C Y P 1 A 2 i n hi bit or beca use of t he p ote ntial 
f or first-pass meta b olis m w he n I xaz o mi b is a d mi nistere d via t he P O r o ute a n d beca use of 
t he m o derate c o ntri b uti o n of C Y P 3 A 4- a n d C Y P 1 A 2 -me diate d meta b olis m of I xaz o mi b i n 
h u ma n li ver micr os o mes.  I xaz o mi b ma y be a wea k s u bstrate of P -gl yc o pr otei n ( P -g p), 
breast ca ncer resista nce pr otei n ( B C R P), a n d m ulti dr u g resista nce ass ociate d pr otei n 
( M R P 2) effl u x p u m p tra ns p orters.  I xaz o mi b is n ot a n i n hi bit or of P-g p, B C R P, a n d M R P 2.  
T he p ote ntial f or D DIs wit h s u bstrates or i n hi bit ors of P -g p, B C R P, a n d M R P 2 is, t heref ore, 
i nferre d t o be l o w. 
1. 5     Cli nic al Tri al E x perie nce Usi n g t he Or al F or m ul ati o n of I x az o mi b 
I n t he 7 st u dies acti vel y e nr olli n g patie nts t o i n vesti gate oral I xaz o mi b i n patie nts wit h 
differi n g mali g na ncies ( m ulti ple m yel o ma, A L a m yl oi d osis, n o n he mat ol o gic ca ncers, a n d 
l y m p h o ma), a t otal of 2 4 2 patie nts ha ve bee n treate d as of 3 0 A pril 2 0 1 2. T hese patie nts 
ha ve bee n treate d wit h differe nt d oses of I xaz o mi b, eit her as a si n gle a ge nt treat me nt or i n 
c o m bi nati o n wit h c urre ntl y cli nicall y a vaila ble treat me nts. I nf or mati o n re gar di n g t he 
o n g oi n g st u dies, patie nt p o p ulati o ns, a n d d oses i n vesti gate d are i ncl u de d  i n Ta ble 1 -1 .
 
 
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T a ble  1 -1    
O n g oi n g St u dies of Or al I x az o mi b 
Trial/  
P o p ulati o n  
Descri pti o n  
D oses I n vesti gate d  
C 1 6 0 0 3  
R R M M  
N = 5 8  
P O, t wice wee kl y ( T W), si n gle a ge nt  
0. 2 4 -2. 2 3 m g/ m 2, T W 
M T D:  2. 0 m g/ m
2 
D L T:  ras h, t hr o m b oc yt o pe nia  
C 1 6 0 0 4  
R R M M  
N = 5 2  
P O, we e kl y ( W), si n gle a ge nt  
0. 2 4 -3. 9 5 m g/ m 2, W 
M T D:  2. 9 7 m g/ m
2 
D L T:  ras h, na usea, v o miti n g , diarr hea 
C 1 6 0 0 5  
N D M M  
N = 6 5  
P O, W, c o m bi nati o n wit h Le n De x  
2 8 da y c ycle  
1. 6 8 -3. 9 5 m g/ m 2, W 
M T D:  2. 9 7 m g/ m
2 
D L T:  na usea, v o miti n g, diarr hea, s y nc o pe  
R P 2 D *:  4. 0 m g f i xe d (s witc he d t o fi xe d d osi n g i n 
p hase 2 , rele va nt t o 2. 2 3 m g/ m2) 
C 1 6 0 0 6  
N D M M  
N = 2 8  
P O, T W ( Ar m A - 4 2 da y c ycle ) a n d W 
( Ar m B- 2 8 da y c ycle ), c o m bi nati o n 
wit h mel p hala n a n d pre d nis o ne  
Ar m A *:  3 -3. 7 m g, fi xe d d ose, T W  
D L T: ras h, t hr o m b oc yt o pe nia, s u bile us  
Ar m B *:  5. 5 m g , fi xe d d ose, W 
D L T: Es o p ha geal ulcer  
C 1 6 0 0 7  
R R -A L  
N = 6  
P O, W, si n gle a ge nt  
4 -5. 5 m g, fi xe d d ose *, W  
M T D: 4 m g  
D L T: t hr o m b oc yt o pe nia, dirr hea, d ys p nea, ac ute 
rise i n creati ni ne, car diac arrest 
 
C 1 6 0 0 8  
N D M M  
N = 1 1  
P O, T W, c o m bi nati o n wit h  Le n De x 2 1 
da y c ycle  
3. 0 -3. 7 m g fi xe d d ose * W  
M T D: 4 m g  
D L T:  
C 1 6 0 0 9  
S oli d 
t u m ors, 
L y m p h o mas  
N = 2 2  
P O, W, si n gle a ge nt  
5. 5 m g fi xe d d ose * W  
C 1 6 0 1 0  
R R M M  
N = 1  
P O, W, c o m bi nati o n wit h Le n De x  
4. 0 m g fi xe d d ose * W  
T B -
M C 0 1 0 0 3 4  
R R M M  
N = 5  
P O, W, si n gle a ge nt i n 1s part of st u d y 
t he n i n c o m bi nati o n wit h Le n De x i n 2n d 
part  
3. 0 m g fi xe d d ose * W  
D L T: t hr o m b oc yt o pe nia, na usea, h y perte nsi o n, 
diarr hea  
A b bre viati o ns:  R R A L = Rela pse d or refract or y Pri mar y s yste mic li g ht c hai n ( A L) a m yl oi d osis; B S A = b o d y 
s urface area ; D L T = d ose-li miti n g t o xicit y; I V = i ntra ve n u o usl y; Le n De x = le nali d o mi de pl us 
de xa met has o ne; M T D = ma xi m u m t olerate d d ose; N D M M = ne wl y dia g n ose d m ulti ple m yel o ma; P O = 
orall y; R R M M = rela pse d a n d/ or refract or y m ulti ple m yel o ma ; R P h 2 D = rec o m me n de d p hase 2 d ose 
*  A p pr o xi mate b o d y s urface area ( B S A) a n d fi xe d d osi n g e q ui vale nce:  3 m g ~ e q ui vale nt t o 1. 6 8 m g/ m 2 
B S A d osi n g; 4. 0 m g ~ e q ui vale nt t o 2. 2 3 m g/ m 2 B S A d osi n g; a n d 5. 5 m g ~ e q ui vale nt t o 2. 9 7 m g/ m 2 B S A 
d osi n g.  
 
 
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O ver vie w of t he Or al F or m ul ati o n of I x az o mi b 
T he e mer gi n g safet y pr ofile i n dicates t hat oral I xaz o mi b is ge nerall y well t olerate d wit h 
pre d o mi na nt t o xicities lar gel y re versi ble, a ble t o be m o nit ore d b y r o uti ne cli nical 
e xa mi nati o ns a n d ma na gea ble b y d ose re d ucti o ns, disc o nti n uati o n, or sta n d ar d s u p p orti ve 
care. Fr o m e x perie nce fr o m p hase 1 t hr o u g h 2 st u dies t he maj or t o xicities ca n be ma na ge d 
t o all o w re peat treat me nt c ycles o ver peri o ds e xte n di n g be y o n d 2 4 m o nt hs.  
I n t he 4 o n g oi n g st u dies ( C 1 6 0 0 3, C 1 6 0 0 4, C 1 6 0 0 7, a n d C 1 6 0 0 9) i n vesti gati n g si n gle-a ge nt 
oral I xaz o mi b i n patie nts wit h differi n g mali g na ncies ( m ulti ple m yel o ma, A L a m yl oi d osis, 
n o n he mat ol o gic ca ncers, a n d l y m p h o ma), a t otal of 1 4 6 patie nts ha ve bee n treate d as of 3 0 
A pril 2 0 1 2. T hese patie nts ha ve bee n treate d wit h differe nt d oses  of I xaz o mi b as t he y are all 
p hase 1 trials. A n o ver vie w of t he m ost fre q ue nt (at least 1 0 %) A Es occ urri n g i n t he p o ole d 
safet y  p o p ulati o n fr o m si n gle-a ge nt oral I xaz o mi b St u dies ( C 1 6 0 0 3, C 1 6 0 0 4, C 1 6 0 0 7, a n d 
C 1 6 0 0 9) i s s h o w n i n Ta ble 1-2.  
T a ble 1 -2  
S u m m ar y of M ost C o m m o n ( At Le ast 1 0 % of T ot al) All Gr a de 
Tre at me nt -E mer ge nt A d verse E ve nts ( Or al I x az o mi b Si n gle -A ge nt 
[ C 1 6 0 0 3/ 4/ 7/ 9] S afet y P o p ul ati o n) 
Pri m ar y S yste m Or g a n Cl ass  
Preferre d Ter m a n d I nci de nce  
N = 1 4 6  
n ( %)  
S u bjects wit h at Least O ne A d verse E ve n t 1 3 5 ( 9 2) 
 
Gastr oi ntesti nal dis or ders 1 0 2 ( 7 0)  
Na usea 6 8 ( 4 7); Diarr h oea 5 5 ( 3 8); V o miti n g 5 1 ( 3 5); 
A b d o mi nal pai n 2 1 ( 1 4); C o nsti pati o n 2 1 ( 1 4)  
Ge neral dis or ders a n d a d mi nistrati o n site c o n diti o ns 
9 8 ( 6 7)  
Fati g ue 7 1 ( 4 9); P yre xia 3 1 ( 2 1); Oe de ma peri p h eral 
1 5 ( 1 0)  
Bl o o d a n d l y m p hatic s yste m dis or ders 7 7 ( 5 3)  
T hr o m b oc yt o pe nia 6 0 ( 4 1); A nae mia 3 0 ( 2 1); 
Ne utr o pe nia 2 3 ( 1 6); Le u k o pe nia 1 5 ( 1 0)  
Ner v o us s yste m dis or ders 6 3 ( 4 3)  
Hea dac he 2 0 ( 1 4); Dizzi ness 1 8 ( 1 2)  
Meta b olis m a n d n utriti o n dis or ders 6 0 ( 4 1)  
Decrease d a p petite 3 9 ( 2 7) De h y drati o n 2 1 ( 1 4)  
Res pirat or y, t h oracic a n d me diasti nal dis or ders 6 0 
( 4 1) 
C o u g h 2 2 ( 1 5); D ys p n oea 2 1 ( 1 4)  
S ki n a n d s u bc uta ne o us tiss ue dis or ders 6 0 ( 4 1)  
Ras h mac ular 1 7 ( 1 2)  
M usc ul os keletal a n d c o n necti ve tiss ue dis or ders 5 6  
( 3 8) 
Art hral gia 2 0 ( 1 4); Bac k pai n 1 7 ( 1 2)  
I nfecti o ns a n d i nfestati o ns 5 4 ( 3 7) 
U p per res pirat or y tract i nfecti o n 2 1 ( 1 4)  
S o urce: I xaz o mi b I n vesti gat or’s Br oc h ure E diti o n 6 
Treat me nt e mer ge nt is defi ne d as a n y A E t hat occ urs after a d mi nistrati o n of t he f irst d ose of a n y st u d y dr u g 
t hr o u g h 3 0 da ys after t he last d ose of a n y st u d y dr u g, a n y e ve nt t hat is c o nsi dere d dr u g-relate d re gar dless 
of t he start date of t he e ve nt, or a n y e ve nt t hat is prese nt at baseli ne b ut w orse ns i n i nte nsit y or is 
s u bse q ue ntl y c o nsi dere d b y t he i n vesti gat or t o be dr u g-relate d.  
 
S u bject I nci de nce: A s u bject c o u nts o nce f or eac h preferre d ter m. Perce nta ges use t he n u m ber of treate d 
9 2 9 2
I R B A p pr o v e d 
D o c u m e nt R el e a s e D at e: 0 8/ 1 1/ 2 0 1 7
Pri nte d o n 1 2/ 4/ 2 0 1 8

s u bjects as t he de n o mi nat or 
 
I n t he 3 st u dies acti vel y e nr olli n g patie nts t o i n vesti gate oral I xaz o mi b i n c o m bi nati o n wit h 
sta n dar d c o m bi nati o n re gi me ns i n patie nts wit h ne wl y dia g n ose d m ulti ple m yel o ma, a t otal 
of 9 6 patie nts ha ve bee n treate d as of 3 0 A pril 2 0 1 2. T hese patie nts ha ve bee n treate d wit h 
differe nt d oses of I xaz o mi b i n c o m bi nati o n wit h le nali do mi de a n d de xa met has o ne i n 2 trials 
( C 1 6 0 0 5 a n d C 1 6 0 0 8) a n d wit h mel p hala n a n d pre d nis o ne i n 1 trial ( C 1 6 0 0 6). T he m ost 
fre q ue nt (at least 1 0 %) a d verse e ve nts occ urri n g i n t he p o ole d safet y p o p ulati o n fr o m 
St u dies C 1 6 0 0 5, C 1 6 0 0 6, a n d C 1 6 0 0 8 is s h o w n i n Ta b le 1-3. I n c o m bi nati o ns trials, relate d 
is defi ne d as p ossi bl y relate d t o a n y dr u g i n t he c o m bi nati o n re gi me n, n ot j ust s pecificall y 
relate d t o I xaz o mi b. 
 
T a ble 1 -3  
S u m m ar y of M ost C o m m o n ( At Le ast 1 0 % of T ot al) Tre at me nt - 
E mer ge nt A d verse E ve nts ( Or al I x az o mi b C o m bi n ati o n A ge nt 
[ C 1 6 0 0 5/ 6/ 8] S afet y P o p ul ati o n) 
 
Pri m ar y S yste m Or g a n Cl ass  
Preferre d Ter m a n d I nci de nce  
N =  9 6  
n ( %)  
S u bjects wit h at Least O ne A d verse E ve nt 1 3 5 ( 9 2)  
 
 
Gastr oi ntesti nal dis or ders 7 0 ( 7 3)  
Na usea 3 2 ( 3 3); C o nsti pati o n 2 9 ( 3 0); V o m iti n g 2 5 
( 2 6) 
Diarr h oea 2 2 ( 2 3)  
Ge neral dis or ders a n d a d mi nistrati o n site c o n diti o ns 
6 4 ( 6 7)  
Fati g ue 3 7 ( 3 9); Oe de ma peri p heral 2 0 ( 2 1); P yre xia 
1 9 ( 2 0)  
S ki n a n d s u bc uta ne o us tiss ue dis or ders 5 7 ( 5 9)  
Ras h 1 3 ( 1 4)  
Ner v o us s yste m dis or ders 4 6 ( 4 8)  
Ne ur o pa t h y peri p heral 1 3 ( 1 4); D ys ge usia 1 2 ( 1 3) 
Dizzi ness 1 1 ( 1 1)  
M usc ul os keletal a n d c o n necti ve tiss ue dis or ders 4 5 
( 4 7) 
Bac k pai n 1 8 ( 1 9); M uscle s pas ms 1 0 ( 1 0)  
Bl o o d a n d l y m p hatic s yste m dis or ders 4 2 ( 4 4)  
T hr o m b oc yt o pe nia 2 8 ( 2 9); A nae mia 2 2 ( 2 3);  
Ne utr o pe nia 1 9 ( 2 0)  
I nfecti o ns a n d i nfestati o ns 4 0 ( 4 2) 
U p per res pirat or y tract i nfecti o n 1 7 ( 1 8);  
Meta b olis m a n d n utriti o n dis or ders 3 8 ( 4 0)  
Decrease d a p petite 1 1 ( 1 1)  
Res pirat or y, t h oracic a n d me diasti nal dis or ders 3 4 
( 3 5) 
D ys p n oea 1 3 ( 1 4); C o u g h 1 1 ( 1 1)  
Ps yc hiatric dis or ders 2 3 ( 2 4)  
I ns o m nia 1 5 ( 1 6) 
S o urce: I xaz o mi b I n vesti gat or’s Br oc h ure E diti o n 6. 
Treat me nt e mer ge nt is defi ne d as a n y A E t hat occ urs after a d mi nistrati o n of t he first d ose of a n y st u d y dr u g  
t hr o u g h 3 0 da ys after t he last d ose of a n y st u d y dr u g, a n y e ve nt t hat is c o nsi dere d dr u g -relate d re gar dless 
of  t he start date of t he e ve nt, or a n y e ve nt t hat is prese nt at baseli ne b ut w orse ns i n i nte nsit y or is 
s u bse q ue ntl y c o nsi dere d b y t he i n vesti gat or t o be dr u g -relate d. 
S u bject I nci de nce: A s u bject c o u nts o nce f or eac h preferre d ter m. Perce nta ges use t he n u m ber of treate d  
s u bjects as t he de n o mi nat or. 
 
 
 
9 2 9 2
I R B A p pr o v e d 
D o c u m e nt R el e a s e D at e: 0 8/ 1 1/ 2 0 1 7
Pri nte d o n 1 2/ 4/ 2 0 1 8

 
 
T he cli nical e x perie nce wit h I xaz o mi b als o s h o ws earl y si g ns of a ntit u m or acti vit y as  
e vi de nce d b y at least a 5 0 % re d ucti o n i n disease b ur de n i n s o m e patie nts a n d pr ol o n ge d  
disease sta bilizati o n i n ot hers acr oss all o n g oi n g trials. T he a ntit u m or acti vit y has bee n see n  
wit h si n gle -a ge nt I xaz o mi b, w he n c o m bi ne d wit h esta blis he d t hera pies, a n d acr oss t he 
mali g na ncies st u die d (a d va nce d s oli d t u m ors  [ 3], no n -H o d g ki n ’s disease, H o d g ki n’s disease 
[ 4], rela pse d a n d/ or refract or y m ulti ple m yel o ma [ R R M M; 5; 6], rela pse d or refract or y 
s yste mic li g ht c hai n a m yl oi d osis [ R R A L ; 7], a n d ne wl y dia g n ose d m ulti ple m yel o ma 
[ N D M M; 8; 9; 1 0]) t o date. 
 
T h o u g h a d diti o nal dat a are nee de d t o c haracterize t he cli nical be nefit of t his dr u g, t he  
e mer gi n g data s u p p orts t he o n g oi n g de vel o p me nt of I xaz o mi b. 
 
Of partic ular rele va nce t o t his st u d y ( C 1 6 0 1 1) is t he cli nical e x perie nce fr o m St u dies  
C 1 6 0 0 4 a n d C 1 6 0 0 7 i n w hic h si n gle -a ge nt I xaz o mi b is a d mi nistere d wee kl y i n patie nts wit h 
R R M M or R R A L, res pecti vel y.  
 
1. 6     Rel a pse d a n d/ or Refr act or y M ulti ple M yel o m a  
St u d y C 1 6 0 0 4 is a n o pe n -la bel, d ose-escalati o n, p hase 1 st u d y of I xaz o mi b a d mi nistere d  
wee kl y o n Da ys 1, 8, a n d 1 5 of a 2 8 -da y c y cle i n a d ult patie nts wit h R R M M. Patie nts wit h  
M M e nr olle d i n t he d ose -escalati o n c o m p o ne nt of t he st u d y ha ve rela pse d f oll o wi n g at least  
2 li nes  o f t hera p y, w hic h m ust ha ve i ncl u de d b ortez o mi b, t hali d o mi de ( or le nali d o mi de), 
a n d c ortic oster oi ds. T he d ose -escalati o n p hase of t he trial has c o m plete d. I n t his st u d y, 2 of 
3  patie nts e x perie nce d pr ot oc ol -defi ne d D L Ts ( Gra de 3 ras h a n d Gra de 3 na usea, v o miti n g, 
a n d diarr hea) at a d ose of 3. 9 5 m g/ m 2. As per pr ot oc ol, s u bse q ue nt patie nts were treate d at  1 
d ose le vel bel o w ( 2. 9 7 m g/ m 2) w here 1 of 6 patie nts e x perie nce d a D L T ( Gra de 3 na usea,  
v o miti n g, a n d diarr hea). T he M T D of wee kl y oral I xaz o mi b was deter mi ne d t o be  2. 9 7 
m g/ m 2.  
O nce t he M T D was esta blis he d, c o h orts of patie nts re prese nti n g t he heter o ge ne o us patie n t 
p o p ulati o n c urre ntl y see n i n cli nical practice were e nr olle d i n or der t o f urt her e val uate t he 
safet y, t olera bilit y, efficac y, P K, a n d p har mac o d y na mics of oral I xaz o mi b. T he M T D 
e x pa nsi o n c o h orts e nr olli n g are:  
1. Rela pse d a n d Refract or y e x pa nsi o n c o h ort [refract or y is defi ne d as disease pr o gressi o n 
w hile o n t hera p y or wit hi n 6 0 da ys after t he last d ose of t hera p y];
 
 
9 2 9 2
I R B A p pr o v e d 
D o c u m e nt R el e a s e D at e: 0 8/ 1 1/ 2 0 1 7
Pri nte d o n 1 2/ 4/ 2 0 1 8

2. Carfilz o mi b e x pa nsi o n c o h ort  
3. Pr oteas o me I n hi bit or -Naï ve e x pa nsi o n c o h ort  
4. V E L C A D E -Rela pse d e x pa nsi o n c o h ort  
Fi nal st u d y res ults are n o t a vaila ble f or t his o n g oi n g trial, b ut preli mi nar y data s u g gest 
I xaz o mi b has a ntit u m or acti vit y i n hea vil y pretr eate d M M patie nts, wit h d ura ble 
res p o nses/ disease c o ntr ol, a n d is ge nerall y well t olerate d.[ 1 1, 1 2] 
As of t he 3 0 A pril 2 0 1 2 data c ut, t hese pati e nts are c o nsi dere d hea vil y pretreate d as 
e vi de nce d b y a me dia n n u m ber of 4 (ra n ge 1 – 1 3) pri or li nes of t hera p y, wit h 6 6 % refract or y 
t o t he last li ne of t hera p y. Patie nts ha ve recei ve d a me dia n of 2 c ycles of t hera p y (ra n ge, 1- 
1 1). Fi ve patie nts ha ve ac hi e ve d o bjecti ve res p o nse: 1 patie nt ac hie ve d a V G P R a n d 4 
patie nts ac hie ve d a P R. A d diti o nall y, 1 5 patie nts ac hie ve d d ura ble disease sta bilizati o n f or 
u p t o 9. 5 m o nt hs. At data c ut -off, 1 5 patie nts re mai n o n treat me nt; disc o nti n uati o n of 
treat me nt was pri maril y d ue t o pr o gressi ve disease ( 6 9 %). 
 
A s u m mar y of t he safet y pr ofile of patie nts treate d i n St u d y C 1 6 0 0 4 is o utli ne d i n Ta ble 1 -4 . 
O verall, 9 2 % of patie nts e x perie nce d a T E A E of a n y gra de a n d of a n y ca use. Peri p heral  
ne ur o pat h y was li mite d t o Gra de 1/ 2  i n 6 patie nts, wit h 3 patie nts re p orti n g baseli ne Gra de 
1 P N at st u d y e ntr y.  
 
T a ble 1 -4     
St u d y C 1 6 0 0 4 , Or al I x az o mi b, Si n gle A ge nt, Gi ve n Wee kl y:  M ost 
C o m m o n T E A Es as of 3 0 A pril 1 2  ( N = 5 2 ) 
M ost C o m m o n ( > 2 0 %) A n y Gra de a n d Irres pecti ve 
of Ca use  
T hr o m b oc yt o pe nia ( 5 4 %)  
Fati g ue ( 4 8 %)  
Na usea ( 4 4 %), diarr hea ( 4 4 %)  
V o miti n g ( 3 7 %)  
Decrease d a p petite  (3 3 %)  
Ras h * ( 3 1 %)  
A ne mia  ( 25 %)  
Ne utr o pe nia ( 2 3 %)  
Dr u g -Relate d Gra de  3 i n > 5 % of patie nts  
 
T hr o m b oc yt o pe nia ( 3 8 % ) 
Diarr hea a n d ne utr o pe nia 1 7 % (eac h), fati g ue  a n d 
l y m p h o pe nia 1 0 % (eac h), na usea a n d decrease d 
a p petite 8 % (eac h) a n d v o miti n g 6 %  
 
S o urce: I xaz o mi b I n vesti gat or’s Br oc h ure E diti o n 6 
* Ras h i ncl u des preferre d ter ms of ras h mac ular, ras h, mac ul o -pa p ular, ras h m or billif or m, ras h pr uritic,  
 
9 2 9 2
I R B A p pr o v e d 
D o c u m e nt R el e a s e D at e: 0 8/ 1 1/ 2 0 1 7
Pri nte d o n 1 2/ 4/ 2 0 1 8

pr urit us,, ra s h er yt he mat o us, e xf oliati ve ras h, a n d ras h p o p ular 
 
 
D ose re d ucti o ns re q uire d were d ue t o A Es t hat i ncl u de d ras h, ne utr o pe nia, 
t hr o m b oc yt o pe nia, diarr hea, na usea, v o miti n g, de h y drati o n, h y p ote nsi o n, i ncrease i n ser u m 
creati ni ne, a b d o mi nal pai n, ile us, fa ti g ue, a n d p ne u m o nia. T he A Es re p orte d f or t he 5 
patie nts w h o were re q uire d t o disc o nti n ue treat me nt i ncl u de d Gra de 2 I xaz o mi b-relate d 
na usea/ v o miti n g i n 1 patie nt treate d a b o ve t he M T D, Gra de 3 I xaz o mi b-relate d diarr hea i n a 
sec o n d patie nt, relate d Gra de 3 t hr o m b oc yt o pe nia, relate d Gra de 2 d ys p nea, a n d n otrelate d 
Gra de 4 ele vati o n i n creati ni ne( 1 patie nt eac h). T here were n o o n -st u d y deat hs.  
St u d y C 1 6 0 0 7 is e val uati n g si n gle a ge nt wee kl y , Da y 1, 8, a n d 1 5 of a 2 8 -da y c ycle, oral 
d osi n g i n patie nts wit h R R A L after at least 1 pri or t hera p y. T he o bjecti ves of t his st u d y are 
t o deter mi ne t he safet y, t olera bilit y, a n d M T D, as well as t o deter mi ne he mat ol o gic a n d 
or ga n res p o nse rates i n t his patie nt p o p ulati o n. T he starti n g d ose le vel was selecte d fr o m 
St u d y C 1 6 0 0 4 as pre vi o usl y descri be d. I n St u d y C 1 6 0 0 7 t he d ose was s witc he d fr o m t he 
B S A -base d d osi n g t o t he fi xe d d ose, t here b y t he 4. 0 m g fi xe d starti n g d ose i n St u d y C 1 6 0 0 7 
c orres p o n ds t o t he 2. 2 3 m g/ m 2 d ose ( o ne d ose le vel bel o w M T D) fr o m St u d y C 1 6 0 0 4. T his 
stu d y is c urre ntl y e nr olli n g patie nts i n t he d ose -e x pa nsi o n p orti o n of t he trial.  
As of 3 0 A pril 2 0 1 2, 1 4 patie nts ha ve bee n treate d i n t his st u d y. At t he first d ose le vel of 4. 0 
m g, 1 of 6 patie nts e x perie nce d a pr ot oc ol -defi ne d D L T (t hat is, t hr o m b oc yt o pe n ia t hat 
laste d m ore t ha n 2 wee ks, w hic h met t he defi niti o n of a D L T d ue t o t he dela y i n starti n g 
C ycle 2). As per pr ot oc ol, t he d ose was escalate d t o 5. 5 m g f or t he ne xt c o h ort of patie nts 
w here 2 of 5 patie nts e x perie nce d a D L T ( Gra de 3 diarr hea, n = 1; a n d  Gra de 2 d ys p nea, 
Gra de 2 ac ute rise i n ser u m creati ni ne, a n d Gra de 4 car diac arrest, n = 1). T he latter patie nt 
di d n ot a p pear t o ha ve car diac A L a m yl oi d osis b y ec h ocar di o gra m o n st u d y e ntr y, b ut di d 
ha ve s u bsta ntial re nal i n v ol ve me nt. After t he occ urre nce of t his D L T, dia g n oses i ncl u de d 
car diac i n v ol ve me nt a n d C H F. T he M T D of wee kl y oral I xaz o mi b was deter mi ne d t o be 4. 0 
m g. F oll o wi n g t he esta blis h me nt of t he M T D, patie nts are c urre ntl y bei n g e nr olle d i n t o 1 of 
2 c o h orts: pr oteas o me i n hi bit or naï ve or pr ot eas o me i n hi bit or e x p ose d.[ 1 3]  
As of t he 3 0 A pril 2 0 1 2 data c ut, t he patie nts e nr olle d i n t he st u d y are c o nsi dere d hea vil y 
pretreate d, as e vi de nce d b y a me dia n n u m ber of 3 pri or li nes of t hera p y (ra n ge 1 – 7), wit h 
3 8 % a n d 4 6 % of patie nts ha vi n g bee n pre vi o us l y treate d wit h b ortez o mi b a n d le nali d o mi de, 
 
res pecti vel y. T o be eli gi ble f or t he st u d y, patie nts m ust ha ve a m yl oi d i n v ol ve me nt of t he 
9 2 9 2
I R B A p pr o v e d 
D o c u m e nt R el e a s e D at e: 0 8/ 1 1/ 2 0 1 7
Pri nte d o n 1 2/ 4/ 2 0 1 8

heart, ki d ne y, or b ot h; at t he data c ut t he or ga n i n v ol ve me nt distri b uti o n was 6, 4, a n d 4 
patie nts, res pecti vel y. Patie n ts ha ve recei ve d a me dia n of 2. 5 c ycles of t hera p y (ra n ge, 1-1 2). 
Ei g ht patie nts re mai n o n treat me nt. Earl y si g ns of acti vit y ha ve bee n re p orte d. T here were 
1 1 patie nts w h o ha ve recei ve d at least 1 c ycle of t hera p y wit h c o m plete d res p o nse 
assess me nts ( 9 i n  t he 4. 0 m g [ M T D] c o h ort a n d 2 i n t he 5. 5 m g c o h ort). T he o verall 
he mat ol o gic res p o nse rate at M T D is 5 6 % ( 5 patie nts ac hie ve d a he mat ol o gic res p o nse [ 4 
V G P R a n d 1 P R]; 3 patie nts s h o we d n o c ha n ge, a n d 1 patie nt ha d a n earl y pr o gressi o n.  
A s u m mar y of t he safet y pr ofile of patie nts treate d i n St u d y C 1 6 0 0 7 is o utli ne d i n Ta ble 1-5. 
O verall, 8 6 % of patie nts e x perie nce d a T E A E of a n y gra de a n d of a n y ca use.  
T a ble 1 -5     
St u d y C 1 6 0 0 7 , Or al I x az o mi b, Si n gle A ge nt Gi ve n Wee kl y  M ost 
C o m m o n T E A Es  as of 3 0 A pril 1 2  ( N = 1 4 ) 
M ost C o m m o n ( > 2 0 %)  
A n y Gra de a n d Irres pecti ve of Ca use  
Na usea ( 5 0 %)  
Fati g ue ( 3 6 %)  
T hr o m b oc yt o pe nia ( 2 9 %)  
D iarr hea (2 9 %)  
Decrease d A p petite ( 2 1 %)  
Peri p heral E de ma ( 2 1 %)  
D ys p nea ( 2 1 %)  
A b d o mi nal pai n ( 2 1 %)  
Dr u g -Relate d Gra de  3 i n m ore t ha n 3  Pat ie nts  
T hr o m b oc yt o pe nia 5 patie nts, ras h 3 patie nts, 
de h y drati o n 2 patie nts, fati g ue 2 patie nts  
 
S o urce: I xaz o mi b I n vesti gat or’s Br oc h ure E diti o n 6 
 
O ne patie nt disc o nti n ue d st u d y dr u g a d mi nistrati o n d ue t o a T E A E ( patie nt wit h D L T of 
ac ute rise i n ser u m creati ni ne, d ys p nea, a n d car diac arrest treate d at 5. 5 m g, as n ote d a b o ve). 
N o deat h has bee n re p orte d.  
T he p ote ntial ris ks re p orte d wit h I xaz o mi b use, p o ole d fr o m all st u dies usi n g t he oral 
f or m ulati o ns, were a ntici pate d base d o n precli nical data a n d pre vi o us e x perie nce wit h 
V E L C A D E a n d are n ote d i n t he I xaz o mi b I B, S M A, a n d I C F d oc u me nts. Re gar dless of 
w het her I xaz o mi b is a d mi nistere d o n t he o nce wee kl y or t wice wee kl y d osi n g sc he d ule, 
t here is c o nsiste nc y a m o n g t he t y pe of T E A Es re p orte d, des pite s o me differe nces i n t he 
fre q ue nc y a n d se verit y of t he re p orte d e ve nts. W hile t he pre d o mi na nt p ote ntial t o xicities 
 
ma y be se vere i n s o me cases, t he y are lar gel y re versi ble, a n d ca n be ma na ge d b y r o uti ne 
9 2 9 2
I R B A p pr o v e d 
D o c u m e nt R el e a s e D at e: 0 8/ 1 1/ 2 0 1 7
Pri nte d o n 1 2/ 4/ 2 0 1 8

cli nical m o nit ori n g a n d sta n dar d me dical i nter ve nti o ns, w hic h  ma y i ncl u de d ose re d ucti o ns 
a n d s u p p orti ve care. Please refer t o t he I xaz o mi b I B a n d S M A f or f urt her i nf or mati o n. 
1. 7     Ne wl y Di a g n ose d M ulti ple M yel o m a ( N D M M)  
I n St u d y C 1 6 0 0 5, I xaz o mi b is gi ve n wee kl y ( Da ys 1, 8, a n d 1 5), i n c o m bi nati o n wit h 
le nali d o mi de (Da ys 1 -2 1), a n d de xa met has o ne ( Da ys 1, 8, 1 5, a n d 2 2) i n a 2 8 -da y c ycle.  
E nr oll me nt t o t his st u d y is cl ose d.   
Cli nical data as of 3 0 A pril 2 0 1 2 is a vaila ble.  T he M T D i n St u d y C 1 6 0 0 5 was deter mi ne d 
t o be 2. 9 7  m g/ m 2 gi ve n wee kl y i n a 2 8 -da y c ycle wit h Le n De x.  T he D L Ts were urticarial 
ras h, dizzi ness, na usea, ort h ostatic h y p ote nsi o n, v o miti n g, diarr h oea , a n d s y nc o pe.  T he 
rec o m me n de d phase 2 d ose ( R P 2 D) esti mati o n was esta blis he d f oll o wi n g e val uati o n of t he 
a vaila ble data fr o m t he p hase 1 p orti o n of t he tr ial w hic h i ncl u de d, b ut was n ot li mite d t o, 
a nal yses of efficac y res ults a n d a d verse e ve nts ( Gra de 3/ 4 A Es, S A Es, all gra des peri p heral 
ne ur o pat h y, a n d treat me nt disc o nti n uati o n).  Gi ve n t hat t he d ose of I xaz o mi b at 2. 9 7 m g/ m 2  
c o m pr o mise d t he ma xi mal d osi n g of le nali d o mi de a n d t hat t he d ose of 2. 2 3 m g/ m 2  is ver y 
t olera ble a n d cli nicall y acti ve, Mille n ni u m desi g nate d 2. 2 3 m g/ m2  as t he R P 2 D after 
e val uati o n of t he data a n d disc ussi o n wit h i n vesti gat ors.  T he R P 2 D of 2. 2 3 m g/ m 2  has bee n 
tra nslate d i nt o a fi xe d d ose of 4. 0 m g base d o n t he res ults fr o m t he p o p ulati o n P K a nal ysis.   
E nr oll me nt i n t his st u d y has bee n c o m plete d; fi nal st u d y res ults are n ot a vaila ble, b ut 
preli mi nar y data s u g gests oral I xaz o mi b gi ve n wee kl y pl us le nali d o mi de a n d de xa met has o ne 
i n a 2 8-da y c ycle a p pears well t olerate d wit h ma na gea ble t o xicit y a n d e nc o ura gi n g 
a ntit u m or acti vit y.   
I n St u d y C 1 6 0 0 5, 1 5 of 1 5 ( 1 0 0 %) patie nts i n t he d ose escalati o n p orti o n of t he st u d y 
e x perie nce d at least 1 T E A E irres pecti ve of gra de or ca usalit y.  At t he M T D acr oss all d ose 
e x pa nsi o n c o h orts 4 9 of 5 3 patie nts (i ncl u di n g 3 patie nts fr o m t he d ose escalati o n c o h ort 
[ 9 2 %]) re p orte d at least 1 T E A E irres pecti ve of gra de or ca usalit y.  I n t he M T D c o h orts, 
fati g ue was t he m ost c o m m o n A E re p orte d ( 3 8 %).  Ot her c o m m on A Es re p orte d i ncl u de 
na usea ( 3 2 %), c o nsti pati o n ( 3 0 %), u p per res pirat or y i nfecti o n ( 2 3 %), a n d peri p heral 
oe de ma  ( 2 1 %).  S ki n t o xicit y, pri maril y er yt he mat o us ras h, occ urre d i n 6 2 % of patie nts ( of 
n ote, ras h is a n o verla p pi n g t o xicit y wit h I xaz o mi b a n d le nali d o mi de).  Peri p heral 
ne ur o pat h y was re p orte d i n 1 3 % of patie nts; Gra de 3 i n 1 patie nt.   
A s u m mar y of t he o verall safet y pr ofile of patie nts treate d i n St u d y C 1 6 0 0 5 is o utli ne d i n  
Ta ble 1 -6 .  O verall, 1 0 0 % of 6 5 patie nts e x perie nce d at least o ne T E A E o f a n y gra de a n d of 
a n y ca use.  
 
 
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T a ble 1 -6     
St u d y C 1 6 0 0 5:  Or al I x az o mi b Gi ve n Wee kl y i n C o m bi n ati o n Wit h 
Le n ali d o mi de a n d De x a met h as o ne, M ost C o m m o n T E A Es as of 3 0 
A pril 2 0 1 2  
M ost C o m m o n ( >  2 0 %) A n y Gra de a n d Irres pecti ve of 
Ca use  
Fati g ue ( 3 7 %)  
Na usea ( 3 4 %)  
C o nsti pati o n ( 3 1 %)  
V o miti n g ( 2 8 %)  
Diarr h oea ( 2 6 %)  
T hr o m b oc yt o pe nia ( 2 3 %)  
U p per res pirat or y tract i nfecti o n ( 2 2 %)  
A nae mia a n d oe de ma peri p heral ( 2 0 % eac h)  
Dr u g -Relate d a Gra de  3 i n  2 Patie nts  
Na usea, v o miti n g ( n = 3 eac h)  
T hr o m b oc yt o pe nia, l y m p h o p e nia, ras h pr uritic ( n = 2 eac h )  
 
S o urce: I xaz o mi b I n vesti gat or’s Br oc h ure E diti o n 6. 
a 
Relate d mea ns t o A N Y dr u g i n t he st u d y dr u g c o m bi nati o n.  
 
T he m ost c o m m o n dr u g -relate d S A Es re p orte d i n St u d y C 1 6 0 0 5 as of 3 0 A pril 2 0 1 2 i ncl u de 
p ne u m o nia, i nfecti o n, d i vertic ulitis, localise d i nfecti o n , g astr oi ntesti nal hae m orr ha ge , 
res pirat or y s y nc ytial vir us ( R S V) p ne u m o nia f aecal o ma , p yre xia, p ne u m o nia res pirat or y 
s y nc ytial viral, n o n -car diac c hest pai n, peri p heral oe d ma, ast he nia, h y p o natrae mia v o miti n g, 
diarr h oea , na usea, c hest pai n, de h y drati o n, a ne mia, dizzi ness, peri p heral se ns or y 
ne ur o pat h y, ort h ostatic h y p ote nsi o n, e m b olis m, m usc ular wea k ness, ac ute re nal fail ure, 
bl o o d creati ni ne i ncrease d, mac ul o pa p ular ras h, atrial fi brillati o n, s y nc o pe, h y p ote nsi o n, a n d 
de e p vei n t hr o m b osis, a n d bac k pai n.   
As of t he cli nical data c ut off, 4 patie nts ha ve disc o nti n ue d treat me nt d ue t o T E A Es 
i ncl u di n g gastr oi ntesti nal hae m orr ha ge , a n gi oe de ma , s y nc o pe, a n d R S V p ne u m o nia. O ne 
deat h was re p orte d f or a patie nt wit h R S V p ne u m o nia;  t he e ve nt was dee me d b y t he 
i n vesti gat or t o be relate d t o treat me nt wit h I xaz o mi b. 
    
 
 
 
 
 
 
 
 
 
 
 
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1. 8  
St u d y R ati o n ale  
T he maj orit y of patie nts wit h c hr o nic G V H D will re q uire a d diti o nal treat me nt  be y o n d first -
li ne t hera p y, a n d n o vel t hera pies are nee de d i n t his setti n g t o i m pr o ve o utc o mes. Pre-cli nical 
a n d cli nical data de m o nstrate t hat pr oteas o me i n hi biti o n pr o d uces a n i m m u n o m o d ulat or y 
effect rele va nt t o G V H D c o ntr ol. I xaz o mi b is a n oral pr oteas o me i n hi bit or t hat has 
de m o nstrate d a n e nc o ura gi n g safet y pr ofile a n d efficac y i n mali g na nc y treat me nt i n cli nical 
trials. We pr o p ose a p hase II trial of I xaz o mi b t o e xa mi ne its cli nical a n d bi ol o gic acti vit y i n 
t he treat me nt of a d va nce d c hr o nic G V H D. 
 
1. 9     P ote nti al Ris ks a n d Be nefits  
Please refer t o t he c urre nt I xaz o mi b I n vesti gat or’s Br oc h ure (I B). 
I xaz o mi b is a m o difie d di pe pti de b or o nic aci d pr oteas o me i n hi bit or si milar t o V E L C A D E, 
w hic h has a k n o w n safet y pr ofile  [ V E L C A D E PI]. T he m ost fre q ue nt A Es re p orte d t o date 
i n t he o n g oi n g I xaz o mi b p hase 1 st u dies were a ntici p ate d base d o n precli nical data a n d 
pre vi o us  e x perie nce wit h V E L C A D E, a n d are n ote d i n t he I B  a n d t he i nf or me d c o nse nt 
d oc u me nts. H o we ver, it is p ossi ble t hat I xaz o mi b will ha ve  t o xicities t hat were n ot 
pre vi o usl y o bser ve d i n or pre dicte d fr o m s uc h s o urces.  Patie nts will  be m o nit ore d cl osel y 
f or t o xicities.  
T his st u d y will be c o n d ucte d i n c o m plia nce wit h t he pr ot oc ol, g o o d cli nical practice ( G C P),  
a p plica ble re g ulat or y re q uire me nts, a n d I nter nati o nal C o nfere nce o n Har m o nisati o n (I C H) 
g ui deli nes.  
 
 
 
 
 
 
 
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2.     
S T U D Y O B J E C TI V E S  
2. 1     Pri m ar y O bjecti ves  
 
Deter mi ne t he pr o p orti o n of s u bjects wit h treat me nt fail ure b y 6 m o nt hs of  I xaz o mi b 
treat me nt f or c hr o nic G V H D.    
 
2. 2    Sec o n d ar y O bjecti ves  
 
1.  
Deter mi ne 3 m o nt h o verall (c o m plete + partial), a n d c o m plete res p o ns e rate 
2.  
Deter mi ne 6 m o nt h o verall (c o m plete + partial), a n d c o m plete res p o nse rate  
3.  
Re p ort o verall s ur vi val, n o n -rela pse m ortalit y, pri mar y mali g na nc y rela pse, fail ure-
free s ur vi val, treat me nt s uccess, a n d disc o nti n uati o n of i m m u ne-s u p pressi ve t hera p y at 6 
m o nt hs a n d 1 year  
4.  
E xa mi ne f u ncti o nal o utc o me ( 2 -mi n ute wal k test) a n d patie nt -re p orte d o utc o mes 
( Lee C hr o nic G V H D S y m pt o m Scale, q ualit y of life ( S F-3 6, F A C T -B M T), H u ma n Acti vit y 
Pr ofile ( H A P)) at st u d y e nr oll me nt, 6 m o nt hs a n d 1 year  
5.  
St u d y bi o l o gic effects of pr oteas o me i n hi biti o n
 
 
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3.     
S T U D Y E N D P OI N T S  
3. 1     Pri m ar y E n d p oi nts   
6 m o nt h tre at me nt f ail ure:  
Defi ne d b y re q uire me nt f or a n a d diti o nal li ne of s yste mic i m m u ne -s u p pressi ve t hera p y, 
rec urre nt mali g na nc y, or deat h. Detaile d defi niti o ns f or s yst e mic i m m u ne s u p pressi ve 
t hera p y a n d rec urre nt mali g na nc y are pr o vi de d bel o w: 
S yste mic i m m u ne s u p pressi ve t hera p y:  
It is e x pecte d t hat patie nts will be o n a d diti o nal s yste mic i m m u ne-s u p pressi ve a ge nts at t he 
ti me of e nr oll me nt, a n d ma na ge me nt of t h ose a ge nts is n ot ma n date d b y t his pr ot oc ol. Ot her 
a ge nts ca n be ta pere d or disc o nti n ue d as directe d b y t he treati n g cli nicia n.  
A d diti o n of ne w s yste mic i m m u ne -s u p pressi ve a ge nts w hile o n trial c o nstit utes treat me nt 
fail ure, re gar dless of t he i n dicati o n f or t he a ge nt. S yste mic i m m u ne -s u p pressi ve a ge nts 
i ncl u de orall y or i ntra ve n o usl y a d mi nistere d s yste micall y acti ve i m m u ne-s u p pressi ve dr u gs, 
as well as pr oce d ures i ncl u di n g e xtra -c or p oreal p h ot o p heresis ( E C P).  
Treat me nt fail ure d oes n ot  i ncl u de t he f oll o wi n g: 
1.  A dj us t me nt of d osi n g of e xisti n g i m m u ne s u p pressi ve a ge nts t o mai ntai n t hera pe utic 
dr u g le vels (e. g. tacr oli m us, c ycl os p ori ne, sir oli m us), as t his is sta n dar d practice.  
2.  A dj ust me nt of pre d nis o ne d ose u p or d o w n acc or di n g t o cli nical j u d g me nt base d o n 
cli nical ma nifestati o ns of c hr o nic G V H D a n d patie nt t olera nce of ster oi d treat me nt.  
T he ma na ge me nt of pre d nis o ne will be directe d b y t he treati n g cli nicia n, a n d 
d ose/ d urati o n of pre d nis o ne t hera p y is n ot ma n date d b y t his pr ot oc ol.  
3.  Use of t o pical t hera pies, i ncl u di n g:  
a. oc ular dr o ps or p h ysical i nter ve nti o ns (e. g. m oist urizi n g e ye dr o ps, oc ular 
c ycl os p ori ne dr o ps, p u nctal pl u gs, scleral le nses, etc)  
b.  oral ri nses or a ge nts (e. g. oral ster oi d ri nse, oral t o pical i m m u ne s u p pressi ve 
a ge nts) 
c. n o n -a bs or ba ble gastr oi ntesti nal ste r oi d a ge nts (e. g. becl o met has o ne, 
b u des o ni de)
 
 
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d.  t o pical a ge nts a p plie d t o t he s ki n (e. g. t o pical ster oi d crea ms, m oist urizi n g 
l oti o n, t o pical i m m u ne s u p pressi ve a ge nts s uc h as tacr oli m us) 
e. t o pical a ge nts a p plie d t o t he va gi nal m uc osa (e. g. t o pical ster oi d crea ms or 
t o pical i m m u ne s u p pressi ve a ge nts s uc h as tacr oli m us) 
4.  P U V A  
5.  Fl uticas o ne, azit hr o m yci n, or m o ntele u kast  
 
Rec urre nt mali g na nc y:  
Defi ne d as he mat ol o gic rela pse or a n y u n pla n ne d i nter ve nti o n (i ncl u di n g wit h dra wal of 
i m m u ne s u p pressi o n) t o pre ve nt pr o gressi o n of disease i n patie nts wit h e vi de nce ( m olec ular, 
c yt o ge netic, fl o w c yt o metric, ra di o gra p hic) of mali g na nt disease after tra ns pla ntati o n.  
1.  T he date of t his e ve nt will be t he earlier date of t he f oll o wi n g:  
a. E vi de nce of rela pse  
b.  I nitiati o n date of i nter ve nti o n f or treat me nt or 
pre ve nti o n of rela pse
 
 
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3. 2     Sec o n d ar y E n d p oi nts  
F ail ure -free s ur vi v al 
T his ti me -t o-e ve nt o utc o me will be esti mate d wit h t he c o m p osite e ve nt of deat h fr o m a n y 
ca use, rela pse or a d diti o n of sec o n dar y i m m u ne s u p pressi ve a ge nts.  T his will be  esti mate d at 
6 m o nt hs a n d 1 year.  
 
O ver all res p o nse r ate  
O verall res p o nse rate ( O R R) at 3 a n d 6 m o nt hs f oll o wi n g i nitiati o n of I xaz o mi b re prese nts 
t he c o m p osite o utc o me of c o m plete a n d partial res p o nse ( C R + P R). O R R will be 
deter mi ne d b y cli nicia n -defi ne d cate g ories of C R a n d P R, a n d se paratel y calc ulate d 
acc or di n g t o t he pr o p ose d res p o nse defi niti o ns of t he NI H C o nse ns us C o nfere nce.  
 
C o m plete res p o nse r ate  
C o m plete res p o nse ( C R) at 3 a n d 6 m o nt hs f oll o wi n g i nitiati o n of t hera p y will be 
deter mi ne d b y cli n icia n-defi ne d C R, a n d se paratel y calc ulate d acc or di n g t o t he pr o p ose d 
res p o nse defi niti o ns of t he NI H C o nse ns us C o nfere nce. 
 
C u m ul ati ve i nci de nce of n o n -rel a pse m ort alit y a n d pri m ar y m ali g n a nc y rel a pse  
T he c u m ulati ve i nci de nce of n o n -rela pse m ortalit y ( defi ne d as deat h i n t he a bse nce of 
pri mar y mali g na nc y rela pse after tra ns pla nt) a n d rela pse ( defi ne d as he mat ol o gic rela pse or 
a n y u n pla n ne d i nter ve nti o n t o pre ve nt pr o gressi o n of disease i n patie nts wit h e vi de nce 
( m olec ular, c yt o ge netic, fl o w c yt o metric, ra di o gra p hic) of mali g na nt disease after 
tra ns pla ntati o n) will be esti mate d fr o m ti me of I xaz o mi b i nitiati o n. T hese will be treate d as 
c o m peti n g -ris k e ve nts, a n d esti mate d at 6 m o nt hs a n d 1 year. 
 
 
 
 
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O ver all s ur vi v al  
O verall s ur vi val will be deter mi ne d fr o m da te of I xaz o mi b i nitiati o n, wit h deat h fr o m a n y 
ca use as t he e ve nt of i nterest, a n d ce ns ori n g at last f oll o w u p date f or t h ose wit h i nc o m plete 
o bser vati o ns. T his will be deter mi ne d at 6 m o nt hs a n d 1 year.  
 
Use of a d diti o n al s yste mic i m m u ne s u p pressi ve t her a pies  
T he use of a d diti o nal s yste mic i m m u ne s u p pressi ve a ge nts will be ca pt ure d at eac h st u d y 
visit, as t his c o nstit utes treat me nt fail ure.  
 
Disc o nti n u ati o n of all s yste mic i m m u ne s u p pressi ve t her a pies  
T he i nci de nce of c o m plete disc o nti n uati o n of all s yste mic i m m u ne -s u p pressi ve t hera pies 
will be deter mi ne d at 6 m o nt hs a n d 1 year.  
 
Tre at me nt s uccess  
T his e n d p oi nt will be esti mate d at 6 m o nt hs a n d 1 year wit h a c o m p osite o utc o me of 
c o m plete res ol uti o n of all re versi ble c hr o nic G V H D ma nifestati o ns, disc o nti n u ati o n of all 
s yste mic i m m u ne-s u p pressi ve a ge nts, a n d free d o m fr o m deat h or pri mar y mali g na nc y 
rela pse after tra ns pla nt.  
 
P atie nt -re p orte d o utc o mes a n d f u ncti o n al me as ures  
Patie nts will pr o vi de assess me nts of t heir f u ncti o nal a bilit y ( 2 -mi n ute wal k test), s y m pt o m 
b ur de n, a n d q ualit y of life usi n g vali date d i nstr u me nts rec o m me n de d b y t he NI H C o nse ns us 
De vel o p me nt Pr oject o n C hr o nic G V H D ( Lee C hr o nic G V H D S y m pt o m Scale, H A P 
f u ncti o nal scale, S F-3 6, a n d F A C T -B M T). T hese will be st u die d at baseli ne, 6 m o nt hs, a n d 
1 year.  
 
 
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Bi ol o gic st u dies  
T hese st u dies ai m t o discer n t he bi ol o gic i m pact of pr oteas o me i n hi biti o n i n t he treat me nt of 
c hr o nic G V H D. Peri p heral bl o o d sa m ples will be o btai ne d at baseli ne (st u d y e nr oll me nt pre -
treat me nt), a n d t he n at t he 3 a n d 6 m o nt h ti me p oi nts. A n a d diti o nal e ve nt-dri ve n bl o o d 
sa m ple will be o btai ne d w he n a ne w s yste mic i m m u ne s u p pressi ve t hera p y is a d de d 
(treat me nt fail ure of I xaz o mi b). F or eac h ti me p oi nt, w h ole bl o o d will be c ollecte d i n 2 
Pa x Ge ne t u bes f or s u bse q ue nt R N A e xtracti o n. A d diti o nall y, o ne 1 0cc he pari n t u be will be 
c ollecte d f or pr ocessi n g of plas ma . T hese starti n g materials will i nf or m res pecti vel y (a) 
differe ntial ge ne e x pressi o n st u dies a n d ( b) E LI S A assa ys as pre dicti ve bi o mar kers of 
c hr o nic G V H D t hera pe utic res p o nse .  
 
4.     
S T U D Y D E SI G N  
4. 1     O ver vie w of St u d y Desi g n  
Si n gle ar m, p hase II trial e xa mi ni n g t he efficac y of I xaz o mi b f or treat me nt of c hr o nic 
G V H D.  
 
4. 2     N u m ber of P atie nt s 
A t otal of 5 0 patie nts will be e nr olle d. A patie nt is c o nsi dere d e nr olle d t he da y t he i n f or me d 
c o nse nt f or m is si g ne d.  I n or der t o c o ntr ol t he s pee d of e nr oll me nt a n d e ns ure t hat n o m ore 
t ha n 5 0 s u bjects are e nr olle d acr oss t he st u d y, eac h partici pa nt m ust be a p pr o ve d b y t he 
c o or di nati n g ce nter at Fre d H utc hi ns o n pri or t o e nr oll me nt.  
 
4. 3     D ur ati o n of St u d y  
Eli gi ble patie nts will be e nr olle d, a n d u n der g o u p t o 6 c ycles of st u d y t hera p y. Cli nical 
f oll o w u p will c o nti n ue t hr o u g h o ne year after e nr oll me nt. Patie nts e x perie nci n g a C R, P R, 
or sta ble disease at 6 m o nt hs will be gi ve n t he o pti o n t o c o nti n ue o n i xaz o mi b f or a n 
a d diti o nal 6 c ycles (f or a t otal of 1 2 c ycles, or ma xi m u m 3 6 d oses). T hese patie nts will 
ret ur n f or a st u d y assess me nt at 9 m o nt hs, i n a d diti o n t o t he 1 2 m o nt h visit f or all patie nts. 
T he y will c o nti n ue t o c o m plete St u d y Me dicati o n Diaries t o trac k t heir d oses, a n d will be 
re q uire d t o c o nti n ue t o ha ve a C B C c hec ke d bef ore eac h c ycle is dis pe nse d. Patie nts w h o 
ha ve a C R, P R or sta ble  G V H D, a n d w h o ha ve n ot starte d a n a d diti o nal s yste mic treat me nt 
f or G V H D, ca n ha ve a ga p of u p t o t wo m o nt hs bet wee n t heir 6 t h a n d 7 t h c ycles of i xaz o mi b. 
Patie nts w h o st o p i xaz o mi b after 6 c ycles a n d t he n e x perie nce a fl are 
 
of t heir c hr o nic 
9 2 9 2
I R B A p pr o v e d 
D o c u m e nt R el e a s e D at e: 0 8/ 1 1/ 2 0 1 7
Pri nte d o n 1 2/ 4/ 2 0 1 8

G V H D ma y re -start i xaz o mi b as l o n g as it has n ot bee n m ore t ha n 1 m o nt h si nce t heir m ost 
rece nt d ose of i xaz o mi b, a n d as l o n g as t he y ha ve n ot starte d a n a d diti o nal s yste mic 
treat me nt f or G V H D. N o patie nt will re mai n o n i xaz o mi b past t he 1 2  m o nt h ti me p oi nt; t his 
mea ns t hat s o me patie nts w h o elect t o c o nti n ue o n i xaz o mi b ma y n ot recei ve all si x 
a d diti o nal c ycles.  
 
5.     
S T U D Y P O P U L A TI O N  
5. 1     I ncl usi o n Criteri a 
Eac h patie nt  m ust meet all of t he f oll o wi n g i ncl usi o n criteria t o be e nr olle d i n t he st u d y:  
1.  A ge 1 8 years or ol der .  
2.  V ol u ntar y writte n c o nse nt m ust be gi ve n bef ore perf or ma nce of a n y st u d y  relate d 
pr oce d ure n ot part of sta n dar d me dical care, wit h t he u n dersta n di n g t hat c o nse nt ma y 
be wit h dra w n b y t he patie nt at a n y ti me wit h o ut prej u dice t o f ut ure me dical care.  
3.   Fe male patie nts w h o:  
•  Are p ost me n o pa usal f or at least 1 year bef ore t he scree ni n g visit, O R  
•  Are s ur gicall y s terile, O R 
•  If t he y are of c hil d beari n g p ote ntial, a gree t o practice 2 effecti ve met h o ds of 
c o ntrace pti o n, at t he sa me ti me, fr o m t he ti me of si g ni n g t he i nf or me d c o nse nt 
f or m t hr o u g h 9 0 da ys after t he last d ose of st u d y dr u g,  O R  
•  A gree t o practice tr ue a bst i ne nce or e xcl usi vel y n o n -heter ose x ual acti vit y w he n 
t his is i n li ne wit h t he preferre d a n d us ual lifest yle of t he s u bject.  ( Peri o dic 
a bsti ne nce [e g, cale n dar, o v ulati o n, s y m pt ot her mal, p ost -o v ulati o n met h o ds] a n d 
wit h dra wal are n ot acce pta ble met h o ds of c o ntrace pti o n.)  
Male patie nts, e ve n if s ur gicall y sterilize d (ie, stat us p ost -vasect o m y), m ust a gree t o 
o ne of t he f oll o wi n g : 
•  A gree t o practice t w o effecti ve c o ntrace pti o n meas ures d uri n g t he e ntire st u d y 
treat me nt peri o d a n d t hr o u g h 9 0 da ys  after t he last  d ose of st u d y dr u g, O R
 
 
9 2 9 2
I R B A p pr o v e d 
D o c u m e nt R el e a s e D at e: 0 8/ 1 1/ 2 0 1 7
Pri nte d o n 1 2/ 4/ 2 0 1 8

•  A gree t o practice tr ue a bsti ne nce  or e xcl usi vel y n o n -heter ose x ual acti vit y  w he n 
t his is i n li ne wit h t he preferre d a n d us ual lifest yle of t he s u bject.  ( Peri o dic 
a bsti ne nce (e g, cale n dar, o v ulati o n, s y m pt ot her mal, p ost -o v ulati o n met h o ds] a n d 
wit h dra wal are n ot acce pta ble met h o ds of c o ntrace pti o n.)  
4.  Patie nts m ust ha ve a d ia g n osis of a c hr o nic G V H D acc or di n g t o t he NI H C o nse ns us 
Criteria .1 0  
5.  Patie nts m ust  ha ve faile d at least o ne pri or li ne of s yste mic i m m u ne s u p pressi ve 
t hera p y f or ma na ge me nt of c hr o nic G V H D. 
6.  Patie nts m ust meet t he f oll o wi n g cli nical la b orat or y criteria:  
•  A bs ol ute ne utr o p hil c o u nt ( A N C)  1, 0 0 0/ m m 3 a n d platelet c o u nt  7 5, 0 0 0/ m m 3.  
Platelet tra nsf usi o ns are n ot all o we d  wit hi n 3 da ys bef ore st u d y e nr oll me nt.  
•  T otal bilir u bi n  1. 5   t he u p per li mit of t he n or mal ra n ge ( U L N). 
•  Ala ni ne a mi n otra nsferase ( A L T) a n d as partate a mi n otra nsferase 
( A S T)  3   U L N.  
•  Calc ulate d creati ni ne cle ara nce  3 0 m L/ mi n (see S ecti o n 1 1. 2 ). 
 
 
5. 2     E xcl usi o n Criteri a  
Patie nt s meeti n g a n y of t he f oll o wi n g e xcl usi o n criteria are n ot t o be e nr olle d i n t he st u d y : 
1.  Fe male patie nts w h o are  lactati n g or ha ve a p ositi ve ser u m pre g na nc y test d uri n g t he 
scree ni n g peri o d.  
2.  Maj or s ur ger y wit hi n 1 4  da ys bef ore e nr oll me nt.  
•  D oes n ot i ncl u de place me nt of ve n o us access de vice, b o ne marr o w bi o ps y, 
G V H D dia g n ostic bi o ps y, or ot her r o uti ne pr oce d ures i n c hr o nic G V H D or 
p ost -tra ns pla ntati o n care. 
 
3.  U nc o ntr olle d i nfecti o n wit hi n 1 4  da ys bef ore  st u d y e nr oll me nt.
 
 
9 2 9 2
I R B A p pr o v e d 
D o c u m e nt R el e a s e D at e: 0 8/ 1 1/ 2 0 1 7
Pri nte d o n 1 2/ 4/ 2 0 1 8

•  I nfecti o n treate d wit h a p pr o priate a nti micr o bial t hera p y a n d wit h o ut si g ns of 
pr o gressi o n/treat me nt fail ure d oes n ot c o nstit ute a n e xcl usi o n criteri o n  
 
4.  E vi de nce of c urre nt u nc o ntr olle d car di o vasc ular c o n diti o ns, i ncl u di n g u n c o ntr olle d 
h y perte nsi o n, u nc o ntr olle d car diac arr h yt h mias, s y m pt o matic c o n gesti ve heart 
fail ure, u nsta ble a n gi na, or m y ocar dial i nfarcti o n wit hi n t he past 6 m o nt hs.  
•  C hr o nic h y perte nsi o n o n me dical t hera p y d oes n ot c o nstit ute a n e xcl usi o n 
criteri o n. 
5.  S yste mi c treat me nt, wit hi n 1 4 da ys bef ore t he first d ose of I xaz o mi b, wit h str o n g 
i n hi bit ors of C Y P 1 A 2 (fl u v o xa mi ne, e n o xaci n, ci pr ofl o xaci n), str o n g i n hi bit ors of 
C Y P 3 A (clarit hr o m yci n, telit hr o m yci n, itrac o naz ole, v oric o naz ole, ket oc o naz ole, 
nefaz o d o ne, p osac o n az ole) or str o n g C Y P 3 A i n d ucers (rifa m pi n, rifa pe nti ne, 
rifa b uti n, car ba maze pi ne, p he n yt oi n, p he n o bar bital), or use of Gi n k g o bil o ba or St. 
J o h n’s w ort. 
6.  A cti ve he patitis B or C vir us i nfecti o n, or k n o w n h u ma n i m m u n o deficie nc y vir us 
( HI V) p ositi ve. 
7.  A n y seri o us me dical or ps yc hiatric ill ness t hat c o ul d, i n t he i n vesti gat or’s o pi ni o n, 
p ote ntiall y i nterfere wit h t he c o m pleti o n of treat me nt acc or di n g t o t his pr ot oc ol . 
8.  K n o w n aller g y t o a n y of t he st u d y me dicati o ns, t heir a nal o g ues, or e xci pie nts i n t he 
vari o us f o r m ulati o ns of a n y a ge nt. 
9.  N o n -he mat ol o gic mali g na nc y wit hi n t he past 2 years wit h t he e xce pti o n of:  
•  a de q uatel y treate d basal cell carci n o ma, s q ua m o us cell s ki n ca ncer, or t h yr oi d 
ca ncer 
•  carci n o ma i n sit u of t he cer vi x or breast  
•  pr ostate ca ncer of Gleas o n Gr a de 6 or less wit h sta ble pr ostate -s pecific 
a nti ge n le vels 
•  ca ncer c o nsi dere d c ure d b y s ur gical resecti o n or u nli kel y t o i m pact s ur vi val 
d uri n g t he d urati o n of t he st u d y
 
 
9 2 9 2
I R B A p pr o v e d 
D o c u m e nt R el e a s e D at e: 0 8/ 1 1/ 2 0 1 7
Pri nte d o n 1 2/ 4/ 2 0 1 8

1 0.  Patie nt has  Gra de  3  peri p heral ne ur o pat h y , or Gra de 2 wit h pai n o n cli nical 
e xa mi nati o n d uri n g t he scree ni n g peri o d . 
1 1.  Treat me nt wit h n o n -F D A a p pr o ve d dr u g wit hi n 2 1 da ys of start of t his trial  
1 2.  Ne w s yste mic i m m u ne s u p pressi ve a ge nt a d de d f or t he treat me nt of c hr o nic G V H D 
wit hi n 2 wee ks pri or t o e nr oll me nt  
•  A d diti o n of a ne w s yste mic i m m u ne s u p pressi ve treat me nt si m ulta ne o usl y 
wit h i xaz o mi b is als o pr o hi bite d.  
1 3.  E vi de nce of rec urre nt or pr o gressi ve u n derl yi n g mali g na nt disease.  
1 4.  Kar n ofs k y perf or ma nce stat us < 7 0 %  
1 5.  Life e x pecta nc y less t ha n 6 m o nt hs  
 
 
 
6.     
S T U D Y D R U G  
6. 1     St u d y Dr u g A d mi nistr ati o n  
 
Ixaz o mi b will be a d mi nistere d at 4 m g oral d ose o nce wee kl y o n d a ys 1, 8, a n d 1 5 of a 2 8 -
da y c ycle . U p t o 6 t otal c ycles of t hera p y will be deli vere d o n trial, a n d patie nts will be 
f oll o we d t hr o u g h 1 year of t otal cli nical f oll o w u p f or st u d y e n d p oi nts.  
Pat ie nts e x perie nci n g a C R, P R, or sta ble disease at 6 m o nt hs will be gi ve n t he o pti o n t o 
c o nti n ue o n i xaz o mi b f or  u p t o  a n a d diti o nal 6 c ycles (f or a t otal of  u p t o  1 2 c ycles, or 
ma xi m u m 3 6 d oses).  See secti o n 4. 3 f or a d diti o nal details.  
 
S ufficie nt st u d y dr u g will be dis pe nse d at eac h st u d y visit t o c o ver o ne 2 8 da y treat me nt 
c ycle . St u d y patie nts will d oc u me nt t heir c o m plia nce t hr o u g h me dicati o n l o gs. 
 
 
I xaz o mi b A d mi nistrati o n  
All pr ot oc ol -s pecific criteria f or a d mi nistrati o n of st u d y dr u g m ust be met a n d doc u me nte d 
bef ore dr u g a d mi nistrati o n.  St u d y dr u g will be a d mi nistere d  or dis pe nse d  
 
o nl y t o eli gi ble 
9 2 9 2
I R B A p pr o v e d 
D o c u m e nt R el e a s e D at e: 0 8/ 1 1/ 2 0 1 7
Pri nte d o n 1 2/ 4/ 2 0 1 8

patie nts u n der t he s u per visi o n of t he i n vesti gat or or i de ntifie d s u bi n vesti gat or(s).  Patie nts 
s h o ul d be m o nit ore d f or t o xicit y, as necessar y, a n d d oses of I xaz o mi b s h o ul d be m o difie d as 
nee de d t o acc o m m o date patie nt t olera nce t o treat me nt; t his ma y i ncl u de s y m pt o matic 
treat me nt, d ose i nterr u pti o ns, a n d a dj ust me nts of I xaz o mi b d ose (see Secti o n 6. 2 ). D ue t o 
t he c o m m o n si de effect of na usea, it is rec o m me n de d ( b ut n ot re q uire d) t hat partici pa nts ta ke 
Z ofra n ( o n da nsetr o n) 8 m g P O, 3 0 -6 0 mi n utes pri or t o eac h d ose, a n d 8 h o urs after eac h 
d ose. A d diti o nal d oses of Z ofra n ma y be ta ke n as nee de d , u p t o 2 4 m g i n a 2 4-h o ur peri o d . 
T he prescri be d a d mi nistrati o n of I xaz o mi b d oses i n t his st u d y is 4 m g oral d ose o nce wee kl y 
o n da ys 1, 8, a n d 1 5 of a 2 8 -da y c ycle.  Patie nts s h o ul d be i nstr ucte d t o s wall o w I xaz o mi b 
ca ps ules w h ole, wit h water, a n d n ot t o brea k, c he w, or o pe n t he ca ps ules.  St u d y dr u g s h o ul d 
be ta ke n o n a n e m p t y st o mac h. Patie nts s h o ul d n ot ha ve a n y f o o d or dri n k ( ot her t ha n water) 
f or at least 2 h o urs bef ore ta ki n g dr u g, a n d f or at least 1 h o ur after ta ki n g dr u g.   A t otal of 
a p pr o xi matel y 8 o u nces ( 2 4 0 m L) of water s h o ul d be ta ke n wit h t he ca ps ule.   
Misse d d oses ca n be ta ke n as s o o n as t he patie nt re me m bers if t he ne xt sc he d ule d d ose is 
7 2  h o urs or m ore a wa y.  A d o u ble d ose s h o ul d n ot be ta ke n t o ma ke u p f or a misse d d ose.  If 
t he patie nt v o mits after ta ki n g a d ose, t he patie nt s h o ul d n ot re peat t he d ose b ut s h o ul d 
res u me d osi n g at t he ti me of t he ne xt sc he d ule d d ose. 
I xaz o mi b Destr ucti o n  
I n vesti gati o nal I xaz o mi b (e x pire d or e n d of st u d y) s h o ul d be destr o ye d o n site acc or di n g t o 
t he i nstit uti o n’s sta n dar d o perati n g pr oce d ure, a n d re m o val a n d destr ucti o n will be 
d oc u me nte d o n dr u g acc o u nta bilit y l o gs .   
6. 2     D ose -M o dific ati o n G ui deli nes   
 
6. 2. 1  
Rec o m me n de d I x az o mi b Criteri a f or Be gi n ni n g or Del a yi n g a S u bse q ue nt 
Tre at me nt C ycle &  D ose M o dific ati o ns f or T re at me nt A ss oci ate d T o xicit y 
Treat me nt wit h I xaz o mi b will use a c ycle le n gt h of 2 8  da ys. T he ne xt c ycle s h o ul d be gi n as 
s o o n as p ossi ble, b ut n o later t ha n 1 4 da ys after t he e n d of t he pre vi o us c ycle. U na v oi da ble 
de viati o ns fr o m t his sc he d ule will be per missi ble wit h pri or a p pr o val b y t he Pri nci pal 
I n vesti gat or or St u d y C hair.  F or a ne w c ycle of treat me nt t o be gi n, t he patie nt m ust meet t he 
f oll o wi n g criteria wit hi n 3 da ys pri or t o dr u g bei n g dis pe nse d : 
 
•  A N C m ust be ≥ 1, 0 0 0/ m m 3.
 
 
9 2 9 2
I R B A p pr o v e d 
D o c u m e nt R el e a s e D at e: 0 8/ 1 1/ 2 0 1 7
Pri nte d o n 1 2/ 4/ 2 0 1 8

•  Platelet c o u nt m ust be ≥ 7 5, 0 0 0/ m m 3. 
•  All ot her n o n -he mat ol o gic t o xicit y (e xce pt f or al o pecia) m ust ha ve res ol ve d t o ≤ 
Gra de 1 or t o t he patie nt’s baseli ne c o n diti o n  
 
T hese la b orat or y tests s h o ul d be perf or me d a n d re vie we d at t he st u d y site.  
 
If t he patie nt fails t o meet t he a b o ve-cite d criteria f or i nitiati o n of t he ne xt c ycle of 
treat me nt, d osi n g s h o ul d be dela ye d f or 1 wee k. At t he e n d of t hat ti me, t he patie nt s h o ul d 
be re -e val uate d t o deter mi ne w het her t he criteria ha ve bee n met . If t he patie nt c o nti n ues t o 
fail t o meet t he a b o ve-cite d criteria, dela y t hera p y a n d c o nti n ue t o re -e val uate. T he 
ma xi m u m dela y bef ore treat me nt s h o ul d be disc o nti n ue d will be 3 wee ks or at t he discreti o n 
of t he Pri nci pal I n vesti gat or.  
 
I xaz o mi b d ose a dj ust me nts are descri be d i n ta ble 6 -1. F or d osi n g rec o m me n dati o ns f or 
he mat ol o gic t o xicities a n d n o n -he mat ol o gic t o xicities, see  Ta ble 6 -2 a n d Ta ble 6 -3  
res pecti vel y. 
 
 
T a ble 6 -1 I x az o mi b D ose A dj ust me nts  
 
D ose Le vel  
D ose ( m g)  
Starti n g D ose  
4. 0 m g  
-1  
3. 0 m g  
-2  
2. 3 m g  
-3  
Disc o nti n ue  
 
9 2 9 2
I R B A p pr o v e d 
D o c u m e nt R el e a s e D at e: 0 8/ 1 1/ 2 0 1 7
Pri nte d o n 1 2/ 4/ 2 0 1 8

T a ble 6 -2    
I x az o mi b D ose A dj ust me nts f or He m at ol o gic 
T o xicities  
Criteria  
Acti o n  
Wit hi n -C ycle D ose M o dificati o ns  
 
•  
If platelet c o u nt  3 0  1 0 9/ L 
or A N C ≤ 0. 5 0   1 0 9/ L o n a 
I xaz o mi b d osi n g da y ( ot her 
t ha n Da y 1) 
•  
I xaz o mi b d ose s h o ul d be wit h hel d.   
•  
C o m plete bl o o d c o u nt ( C B C) wit h 
differe ntial s h o ul d be re peate d u ntil 
t he A N C a n d/ or platelet c o u nts 
ha ve e xcee de d t he pres pecifie d 
val ues (see Secti o n  6. 2 . 1)  
•  
U p o n rec o ver y, I xaz o mi b ma y be 
rei nitiate d wit h 1 d ose le vel 
re d ucti o n.  
D ose M o dificati o ns f or 
S u bse q ue nt Treat me nt C ycles  
 
 
•  
A N C < 1. 0  1 0 9/ L, platelet 
c o u nt < 7 5  1 0 9/ L, or ot her 
n o n -he mat ol o gic t o xicities 
> Gra de 1 or n ot t o t he 
patie nt’s b aseli ne c o n diti o n  
•  
H ol d I xaz o mi b u ntil res ol uti o n as 
per criteria Secti o n  6. 2 . 
•  
U p o n rec o ver y, re d uce I xaz o mi b 1 
d ose le vel.  
•  
T he ma xi m u m dela y bef ore 
treat me nt s h o ul d be disc o nti n ue d 
will be 3 wee ks or at t he discreti o n 
of t he PI.  
D ose M o dificati o ns f or 
S u b se q ue nt Treat me nt C ycles 
 
•  
All he mat ol o gic t o xicities  
•  
F or he mat ol o gic t o xicit y t hat 
occ urs d uri n g a c ycle b ut rec o ver 
i n ti me f or t he start of t he ne xt 
c ycle: 
o   If d ose was re d uce d 
wit hi n t he c ycle, start 
t he ne xt c ycle at t hat 
sa me d ose. 
o  If d ue t o t o xicit y 
ti mi n g, ie, after Da y 
1 5 d osi n g t h us a d ose 
re d ucti o n was n ot 
re q uire d at t hat p oi nt 
i n t he c ycle, re d uce 
I xaz o mi b b y 1 d ose 
le vel at t he start of 
t hat c ycle. 
o  D o n ot re d uce t he 
d ose b ot h wit hi n a 
c ycle a n d at t he start 
of t he c ycle f or t he 
sa me m ost se vere 
t o xicit y.
 
 
9 2 9 2
I R B A p pr o v e d 
D o c u m e nt R el e a s e D at e: 0 8/ 1 1/ 2 0 1 7
Pri nte d o n 1 2/ 4/ 2 0 1 8

 
 
 
 
 
T a ble 6 -3    
I x az o mi b Tre at me nt M o dific ati o n ( Del a ys, Re d ucti o ns, a n d 
Disc o nti n u ati o ns) D ue t o A d verse E ve nts ( N o n -He m at ol o gic T o xicities)  
A d verse E ve nt ( Se verit y)  
Acti o n o n St u d y Dr u g  
F urt her C o nsi derati o ns  
Peri p her al Ne ur o p at h y : 
Gra de 1 peri p heral ne ur o pat h y  
 
•  N o acti o n  
 
Gra de 1 si g ns a n d s y m pt o ms :  
as y m pt o matic; wit h o ut pai n or l oss 
of f u ncti o n; cli nical or dia g n ostic 
o bser vati o ns o nl y [ 1 4 ] 
 
 
Ne w or w orse ni n g Gra de 1 
peri p heral ne ur o pat h y wit h pai n or 
Gra de 2  
•  H ol d st u d y dr u g u ntil 
res ol uti o n t o Gra de ≤ 1 or 
baseli ne  
•  Res u me at sa me d ose le vel  
Gra de 2 si g ns a n d s y m pt o ms :  
M o derate s y m pt o ms; li miti n g 
i nstr u me ntal acti vities of dail y 
li vi n g ( A D L) [ 14 ] 
 
 
Ne w or w orse ni n g Gra de 2 
peri p heral ne ur o pat h y wit h pai n or 
Gra de 3  
•  H ol d st u d y dr u g u ntil 
res ol uti o n t o Gra de ≤ 1 or 
baseli ne  
•  Re d uce st u d y dr u g t o ne xt 
l o wer d ose u p o n rec o ver y 
 
Gra de 3 si g ns a n d s y m pt o ms :  
se vere s y m pt o ms; li miti n g self-
care A D L; assisti ve de vice 
i n dicated [ 1 4 ] 
Ne w or w orse ni n g Gra de 4 
peri p heral ne ur o pat h y  
•  Disc o nti n ue st u d y dr u g 
 
 
 
Gra de 2 Ras h  
S y m pt o matic 
rec o m me n dati o ns as per 
secti o n 6. 6 
T he i n vesti gat or a n d pr oject 
cli nicia n ma y disc uss 
c o nsi derati o ns f or d ose 
m o dificati o ns a n d s y m pt o m 
ma na ge me nt.   
 
Ot her  Gra de 3 n o n -he mat ol o gic 
t o xicit y j u d ge d t o be relate d t o 
st u d y dr u g 
 
•  H ol d st u d y dr u g u ntil 
res ol uti o n t o Gra de < 1 or 
baseli ne  
 
S y m pt o matic rec o m me n dati o ns 
n ote d i n Secti o n  6. 6  
 
If rec o vere d t o < Gra de 1 
or baseli ne wit hi n 4 
wee ks  
 
 
 
Re d uce st u d y dr u g 1  t o ne xt 
l o wer d ose u p o n ret ur n t o 
<  Gra de 1 or baseli ne   
 
 
 
 
9 2 9 2
I R B A p pr o v e d 
D o c u m e nt R el e a s e D at e: 0 8/ 1 1/ 2 0 1 7
Pri nte d o n 1 2/ 4/ 2 0 1 8

T a ble 6 -3    
I x az o mi b Tre at me nt M o dific ati o n ( Del a ys, Re d ucti o ns, a n d 
Disc o nti n u ati o ns) D ue t o A d verse E ve nts ( N o n -He m at ol o gic T o xicities)  
A d verse E ve nt ( Se verit y)  
Acti o n o n St u d y Dr u g  
F urt her C o nsi derati o ns  
 
If n ot rec o vere d t o 
<  Gra de 1 or baseli ne 
wit hi n 4 wee ks  
 
 
•  Re d uce st u d y dr u g 1  t o ne xt 
l o wer d ose u p o n ret ur n t o 
<  Gra de 1 or baseli ne  
S u bse q ue nt rec urre nce  
 
 
 
Gra de 3 t hat d oes n ot 
rec o ver t o < Gra de 1 or 
baseli ne wit hi n 4 wee ks  
•  F oll o w a b o ve ma na ge me n t 
g ui deli nes  
 
 
•  Re d uce st u d y dr u g t o ne xt 
l o wer d ose  
M o nit or cl osel y, ta ke a p pr o priate 
me dical preca uti o ns, a n d pr o vi de 
a p pr o priate s y m pt o matic care  
 
Gra de 4 n o n he mat ol o gic t o xicities 
j u d ge d t o be relate d t o st u d y dr u g 
 
C o nsi der per ma ne ntl y 
disc o nti n ui n g st u d y dr u g 
 
E xce pti o ns are cases i n w hic h t he 
i n vesti gat or deter mi nes t he patie nt 
is o btai ni n g a cli nical be nefit  
 
O nce I xaz o mi b is re d uce d f or a n y t o xicit y, t he d ose ma y n ot be re-escalate d. 
 
6. 2. 2  
Rec o m me n de d D ose M o dific ati o ns f or < ot her dr u g(s) > Tre at me nt  Ass oci ate d 
T o xicit y  
 
6. 3     E xcl u de d C o nc o mit a nt Me dic ati o ns  
T he f oll o wi n g me dicati o ns are pr o hi bite d d uri n g t he st u d y:  
S yste mic treat me nt wit h a n y of t he f oll o wi n g meta b olizi n g e nz y me i n hi bit ors is n ot 
per mitte d d uri n g t his st u d y.  A Dr u g -Dr u g I nteracti o n (D DI ) wit h a str o n g i n hi bit or w o ul d 
i ncrease M L N 2 2 3 8 e x p os ure.  
•  Str o n g i n hi bit ors of C Y P 1 A 2:  fl u v o xa mi ne, e n o xaci n, ci pr ofl o xaci n  
•  Str o n g i n hi bit ors of C Y P 3 A:  clarit hr o m yci n, telit hr o m yci n, itrac o naz ole, 
v oric o naz ole, ket oc o naz ole, nefaz o d o ne, a n d p osac o n az ole 
S yste mic treat me nt wit h a n y of t he f oll o wi n g meta b olizi n g e nz y me i n d ucers s h o ul d 
be a v oi de d A D DI wit h a str o n g i n d ucer w o ul d decrease M L N 2 2 3 8 e x p os ure.   
 
 
9 2 9 2
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D o c u m e nt R el e a s e D at e: 0 8/ 1 1/ 2 0 1 7
Pri nte d o n 1 2/ 4/ 2 0 1 8

•  Str o n g C Y P 3 A i n d ucers:  rifa m pi n, rifa pe nti ne, rifa b uti n, car ba maze pi ne, p he n yt oi n, 
a n d p he n o ba r bital 
•  T he dietar y s u p ple me nts St J o h n’s w ort a n d Gi n k g o bil o ba .  
6. 4     Per mitte d C o nc o mit a nt Me dic ati o ns a n d Pr oce d ures  
T he f oll o wi n g me dicati o ns a n d pr oce d ures are per mitte d d uri n g t he st u d y:  
•  A ntie metics, i ncl u di n g 5 -H T 3 ser ot o ni n rece pt or a nta g o nists, ma y be use d at t he 
discreti o n of t he i n vesti gat or.  
•  L o pera mi de or ot her a nti diarr heal s h o ul d be use d f or s y m pt o matic diarr hea at 
discreti o n of t he i n vesti gat or. T he d ose a n d re gi me n will be acc or di n g t o i nstit uti o nal 
g ui deli nes.  
•  Gr o wt h fact ors (e g, gra n ul oc y te c ol o n y sti m ulati n g fact or [ G-C S F], gra n ul oc yte 
macr o p ha ge -c ol o n y sti m ulati n g fact or [ G M -C S F], rec o m bi na nt er yt hr o p oieti n) are 
per mitte d. T heir use s h o ul d f oll o w p u blis he d g ui deli nes a n d/ or i nstit uti o nal practice .  
•  Patie nts s h o ul d be tra nsf use d wit h re d cells a n d platelets as cli nicall y i n dicate d  a n d 
acc or di n g t o i nstit uti o nal g ui deli nes . 
•  A nti viral t hera p y s uc h as ac ycl o vir ma y be a d mi nistere d if me dicall y a p pr o priate.   
 
6. 5     Prec a uti o ns a n d Restricti o ns  
Fl ui d deficits s h o ul d be c orrecte d bef ore a n d t hr o u g h o ut treat me nt.  
N S AI Ds s h o ul d be a v oi de d i n patie nts wit h i m paire d re nal f u ncti o n gi ve n re p orte d N S AI D -
i n d uce d re nal fail ure i n patie nts wit h decrease d re nal f u ncti o n.  
 
Pre g n a nc y  
It is n ot k n o w n w hat effects I xaz o mi b has o n h u ma n pre g na nc y or de vel o p me nt  of t he 
e m br y o or fet us .  F e male patie nts partici pati n g i n t his st u d y s h o ul d a v oi d bec o mi n g 
pre g na nt, a n d male patie nts s h o ul d a v oi d i m pre g nati n g a fe male part ner.  N o n -
 
sterilize d 
9 2 9 2
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D o c u m e nt R el e a s e D at e: 0 8/ 1 1/ 2 0 1 7
Pri nte d o n 1 2/ 4/ 2 0 1 8

fe male patie nts of re pr o d ucti ve a ge gr o u p a n d male patie nts s h o ul d use effecti ve met h o ds of 
c o ntrace pti o n t hr o u g h defi ne d peri o ds d uri n g a n d after st u d y treat me nt as s pecifie d bel o w.  
Fe male patie nts m ust meet 1 of t he f oll o wi n g  criteria :  
•  P ost me n o pa usal f or at least 1 year bef ore t he scree ni n g visit, O R  
•  S ur gicall y sterile, O R  
•  If the y are of c hil d beari n g p ote ntial, a gree t o practice 2 effecti ve met h o ds of 
c o ntrace pti o n, at t he sa me ti me, fr o m t he ti me of si g ni n g t he i nf or me d c o nse nt f or m 
t hr o u g h 9 0 da ys after t he last d ose of st u d y dr u g, O R  
•  A gree t o practice tr ue a bsti ne nce  or e xcl u si vel y n o n-heter ose x ual acti vit y  w he n t his 
is i n li ne wit h t he preferre d a n d us ual lifest yle of t he s u bject.  ( Peri o dic a bsti ne nce 
[e g, cale n dar, o v ulati o n, s y m pt ot her mal, p ost-o v ulati o n met h o ds] a n d wit h dra wal are 
n ot acce pta ble met h o ds of c o ntrace pti o n.)  
Male patie nts, e ve n if s ur gicall y sterilize d (ie, stat us p ost vasect o m y), m ust a gree t o 1 of t he 
f oll o wi n g: 
•  A gree t o practice t w o effecti ve c o ntrace pti o n  meas ures  d uri n g t he e ntire st u d y 
treat me nt peri o d a n d t hr o u g h 9 0 da ys  after t he last d ose of st u d y dr u g, O R  
•  A gree t o practice tr ue a bsti ne nce  or e xcl usi vel y n o n -heter ose x ual acti vit y  w he n t his 
is i n li ne wit h t he preferre d a n d us ual lifest yle of t he s u bject.  ( Peri o dic a bsti ne nce 
(e g, cale n dar, o v ulati o n, s y m pt ot her mal, p ost-o v ulati o n met h o ds] a n d wit h dra w al are 
n ot acce pta ble met h o ds of c o ntrace pti o n.)  
 
 
6. 6    M a n a ge me nt of Cli nic al E ve nts  
A d verse dr u g reacti o ns s uc h as t hr o m b oc yt o pe nia, diarr hea, fati g ue, na usea, v o miti n g, a n d 
ras h ha ve bee n ass ociate d wit h I xaz o mi b treat me nt. Ma na ge me nt g ui deli nes re gar di ng t hese 
e ve nts are o utli ne d bel o w. F urt her details of ma na ge me nt of I xaz o mi b A Es are descri be d i n 
Secti o n 6 of t he I xaz o mi b I B. 
Pr o p h yla xis A gai nst Ris k of I nfecti o n  
I nfecti o n pr o p h yla xis s h o ul d f oll o w i nstit uti o nal sta n dar ds.
 
 
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D o c u m e nt R el e a s e D at e: 0 8/ 1 1/ 2 0 1 7
Pri nte d o n 1 2/ 4/ 2 0 1 8

Na usea a n d/ or V o miti n g  
Sta n da r d a nti-e metics  ma y be use d f or pr o p h yla xis a n d treat me nt of na usea or v o miti n g.   
Diarr hea  
Diarr hea s h o ul d be ma na ge d acc or di n g t o cli nical practice, i ncl u di n g t he a d mi nistrati o n of 
a nti diarr heals.  Fl ui d i nta ke s h o ul d be mai ntai ne d t o a v oi d de h y drati o n.   
Er yt he mat o us Ras h Wit h or Wit h o ut Pr urit us  
Ras h s h o ul d be ma na ge d s y m pt o maticall y acc or di n g t o sta n dar d me dical practice , i ncl u di n g 
s u p p orti ve care, oral or t o pical ster oi ds, a n d/ or a nti-hista mi nes.  
T hr o m b oc yt o pe nia  
Bl o o d c o u nts s h o ul d be m o nit ore d re g ul arl y as o utli ne d i n t he pr ot oc ol wit h a d diti o nal 
testi n g o btai ne d acc or di n g t o sta n dar d cli nical practice. I xaz o mi b a d mi nistrati o n s h o ul d be 
m o difie d as n ote d as per d ose m o dificati o n rec o m me n dati o ns i n Ta ble 6 -2  w he n 
t hr o m b oc yt o pe nia occ urs.  T hera p y ca n be rei nitiate d at a re d uce d le vel u p o n rec o ver y of 
platelet c o u nts.   
Ne utr o pe nia  
Bl o o d c o u nts s h o ul d be m o nit ore d re g ularl y as o utli ne d i n t he pr ot oc ol wit h a d diti o nal 
testi n g o btai ne d acc or di n g t o sta n dar d cli nical practice.  I xaz o mi b a d mi nistrati o n s h o ul d be 
m o difie d w he n ne utr o pe nia occ urs, as n ote d i n t he d ose m o dificati o n rec o m me n dati o ns i n 
Ta ble 6 -2.  T hera p y ca n be rei nitiate d at a re d uce d le vel u p o n rec o ver y of a bs ol ute 
ne utr o p hil c o u nts . T he use of gr o wt h fact ors (e. g. G -C S F) is per mitte d.  
Fl ui d De ficits 
Fl ui d deficits s h o ul d be c orrecte d bef ore i nitiati o n of st u d y dr u g  a n d d uri n g treat me nt  a n d as 
nee de d d uri n g t hera p y .   
H y p ote nsi o n  
Bl o o d press ure s h o ul d be cl osel y m o nit ore d w hile t he patie nt is o n st u d y treat me nt a n d fl ui d 
deficit s h o ul d be c orrec te d as nee de d.  
P osteri or Re versi ble E nce p hal o pat h y S y n dr o me  
 
9 2 9 2
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D o c u m e nt R el e a s e D at e: 0 8/ 1 1/ 2 0 1 7
Pri nte d o n 1 2/ 4/ 2 0 1 8

O ne case of p osteri or re versi ble e nce p hal o pat h y s y n dr o me ( P R E S) has bee n re p orte d wit h 
I xaz o mi b.  W hile t his case ulti matel y res ol ve d, P R E S has als o bee n re p orte d rarel y wit h 
a n ot her pr oteas o me i n hi bit or, V E L C A D E.  P R E S is c haracterize d b y hea dac he, seiz ures a n d 
vis ual l oss, as well as a br u pt i ncrease i n bl o o d press ure.  Pr o m pt dia g n osis a n d i nitiati o n of 
a nti h y perte nsi ve a n d a ntic o n v ulsa nt t hera p y are i m p orta nt t o pre ve nt irre versi ble e n d -or ga n 
da ma ge.  
Tra ns verse M yelitis  
Tra ns verse m yelitis has als o bee n re p orte d wit h I xaz o mi b. It is n ot k n o w n if I xaz o mi b 
ca uses tra ns verse  m yelitis; h o we ver, beca use it ha p pe ne d t o a patie nt recei vi n g I xaz o mi b, 
t he p ossi bilit y t hat I xaz o mi b ma y ha ve c o ntri b ute d t o tra ns verse m yelitis ca n n ot be  
e xcl u de d. 
 
 
6. 7   Pre p ar ati o n, Rec o nstit uti o n, a n d Dis pe ns i n g 
I xaz o mi b is a n a ntica ncer dr u g a n d as wit h ot her p ote ntiall y t o xic c o m p o u n ds ca uti o n s h o ul d 
be e xercise d w he n ha n dli n g I xaz o mi b ca ps ules. 
Mille n ni u m will s hi p  st u d y me dicati o n directl y t o partici pati n g sites, a n d n otif y Dr. 
Ste p ha nie Lee w he n eac h s hi p me nt is ma de. See t he Ma n ual of O perati o ns  f or m ore details. 
6. 8   P ac k a gi n g a n d L a beli n g  
T he st u d y dr u g I xaz o mi b ca ps ules will be pr o vi de d b y Mille n ni u m.  T he st u d y dr u g wil l be 
la bele d a n d ha n dle d as o pe n-la bel material, a n d pac ka gi n g la bels will f ulfill all re q uire me nts 
s pecifie d b y g o ver ni n g re g ulati o ns.   
I xaz o mi b ca ps ules s h o ul d be st ore d u n o pe ne d at 2° C t o 8° C ( 3 6° F -4 6° F).  T he ca ps ules are 
i n di vi d uall y pac ka ge d i n c ol d f or m f oil-f oil blisters i n a c hil d-resista nt pac ka ge. T he 2. 3 -, 
3. 0 -, a n d 4. 0 m g  ca ps ules are s u p plie d as a 1 x 3 blister car d i n a c hil d -resista nt car d b oar d 
wallet.  
6. 9   St or a ge, H a n dli n g, a n d Acc o u nt a bilit y  
U p o n recei pt at t he i n vesti gati ve site, I xaz o mi b s h o ul d re mai n i n t he blister a n d cart o n 
 
pr o vi de d u ntil use or u ntil dr u g is dis pe nse d. T he c o ntai ner s h o ul d be st ore d at t he 
9 2 9 2
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D o c u m e nt R el e a s e D at e: 0 8/ 1 1/ 2 0 1 7
Pri nte d o n 1 2/ 4/ 2 0 1 8

i n vesti gati ve site refri gerate d ( 3 6° F t o 4 6° F, 2° C t o 8° C). E ns ure t hat t he dr u g is use d bef ore 
t he retest e x pir y date pr o vi de d b y Mille n ni u m. E x pir y e xte nsi o ns will be c o m m u nicate d 
acc or di n gl y wit h u p date d d oc u me ntati o n t o s u p p ort t he e xte n de d s helf life.  
I xaz o mi b ca ps ules dis pe nse d t o t he patie nt f or ta ke -h o me d osi n g s h o ul d re mai n i n t he blister 
pac ka gi n g a n d refri gerate d as n ote d a b o ve u ntil t he p oi nt of use. T he i n vesti gati ve site is 
res p o nsi ble f or pr o vi di n g t he me dicati o n t o t he patie nt i n t he c orrect dail y d ose 
c o nfi g urati o ns. C o m pre he nsi ve i nstr ucti o ns s h o ul d be pr o vi de d t o t he patie nt i n or der t o 
e ns ure c o m plia nce wit h d osi n g pr oce d ures. Patie nts w h o are recei vi n g ta ke -h o me 
me dicati o n s h o ul d be gi ve n o nl y 1 c ycle of me dicati o n at a ti me. Patie nts s h o ul d be 
i nstr ucte d t o st ore t he me dicati o n refri gerate d ( 3 6° F t o 4 6° F, 2° C t o 8° C) f or t he d urati o n of 
eac h c ycle. Patie nts s h o ul d be i nstr ucte d t o ret ur n t heir e m pt y blister pac ks t o t he 
i n vesti gati ve site, rat her t ha n discar di n g t he m. Rec o nciliati o n will occ ur acc or di n gl y w he n 
t he patie nt ret ur ns f or t heir ne xt c ycle of ta ke-h o me me dicati o n. A n y e xtre me i n te m perat ure 
s h o ul d be re p orte d as a n e xc ursi o n a n d s h o ul d be dealt wit h o n a case-b y -case basis.   
Beca use I xaz o mi b is a n i n vesti gati o nal a ge nt, it s h o ul d be ha n dle d wit h d ue care. Patie nts 
s h o ul d be i nstr ucte d n ot t o c he w, brea k, or o pe n ca ps ules. I n case of c o ntact wit h br o ke n 
ca ps ules, raisi n g d ust s h o ul d be a v oi de d d uri n g t he clea n-u p o perati o n. T he pr o d uct ma y be 
har mf ul b y i n halati o n, i n gesti o n, or s ki n a bs or pti o n. Gl o ves a n d pr otecti ve cl ot hi n g s h o ul d 
be w or n d uri n g clea n u p a n d ret ur n of br o ke n ca ps ules a n d p o w der t o mi ni mize s ki n c o ntact. 
T he area s h o ul d be ve ntilate d a n d t he site was he d wit h s oa p a n d water after material pic k -u p 
is c o m plete. T he material s h o ul d be dis p ose d of as hazar d o us me dical waste i n c o m plia nce 
wit h fe deral, state, a n d l ocal re g ulati o ns.  
I n case of c o ntact wit h t he p o w der (e g, fr o m a br o ke n ca ps ule), s ki n s h o ul d be was he d 
i m me diatel y wit h s oa p a n d c o pi o us a m o u nts of water f or at least 1 5 mi n utes. I n case of 
c o ntact wit h t he e yes, c o pi o us a m o u nts of water s h o ul d be use d t o fl us h t he e yes f or at least 
1 5 mi n utes. Me dical pers o n nel s h o ul d be n otifie d. Patie nts are t o be i nstr ucte d o n pr o per 
st ora ge, acc o u nta bilit y, a n d a d mi nistrati o n of I xaz o mi b, i ncl u di n g t hat I xaz o mi b is t o be 
ta ke n as i ntact ca ps ules. 
6. 1 0       St u d y C o m pli a nce  
St u d y dr u g will be a d mi nistere d or dis pe nse d o nl y t o eli gi ble patie nts u n der t he s u per visi o n 
of t he i n vesti gat or or i de ntifie d s u b -i n vesti gat or(s).  T he a p pr o priate st u d y pers o n nel will 
mai ntai n rec or ds of st u d y dr u g recei pt a n d dis pe nsi n g.
 
 
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D o c u m e nt R el e a s e D at e: 0 8/ 1 1/ 2 0 1 7
Pri nte d o n 1 2/ 4/ 2 0 1 8

 
6. 1 1    
Disc o nti n u ati o n of I x az o mi b t her a p y 
 
Patie n ts will be i nf or me d t hat t he y ha ve t he ri g ht t o wit h dra w fr o m t he st u d y at a n y ti me f or 
a n y reas o n, wit h o ut prej u dice t o t heir me dical care.  I n t he f oll o wi n g circ u msta nces, 
I xaz o mi b t hera p y will be disc o nti n ue d, h o we ver acti ve st u d y f oll o w u p will c o nti n ue u ntil 
st u d y-defi ne d treat me nt fail ure occ urs (i.e. deat h, rela pse, or  a d diti o n of a ne w s yste mic 
i m m u ne s u p pressi ve t hera p y). T he E n d of Treat me nt visit s h o ul d occ ur as s o o n as p ossi ble 
after i xaz o mi b is st o p pe d. : 
- 
T he treati n g cli nicia n deter mi nes t hat t h e patie nt has res p o n de d t o t hera p y a n d 
d oes n ot re q uire a n y a d diti o nal I xaz o mi b t hera p y 
- 
I xaz o mi b t hera p y is disc o nti n ue d d ue t o u nres ol ve d t o xicit y 
- 
I xaz o mi b t hera p y is disc o nti n ue d d ue t o patie nt n o n-a d here nce t o t hera p y  
 
 
 
 
6. 1 2    Ter mi n ati o n of st u d y p articip ati o n  
 
T he f oll o wi n g c o n diti o ns re q uire disc o nti n uati o n of I xaz o mi b t hera p y a n d/ or 
ter mi nati o n of acti ve st u d y f oll o w u p: 
- 
Patie nt decisi o n t o wit h dra w fr o m t he st u d y  
o  At t he ti me of wit h dra wal, all st u d y pr oce d ures o utli ne d f or t he E n d of 
Treat me nt visit s h o ul d be c o m plete d. T he pri mar y reas o n f or patie nt’s 
wit h dra wal fr o m t he st u d y s h o ul d be rec or de d i n t he s o urce d oc u me nts 
a n d C R F.
 
 
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D o c u m e nt R el e a s e D at e: 0 8/ 1 1/ 2 0 1 7
Pri nte d o n 1 2/ 4/ 2 0 1 8

- 
I xaz o mi b t hera p y is disc o nti n ue d d ue t o t he a d diti o n of ( or pla n ne d a d diti o n of) 
a n ot her li ne of s yste mic i m m u ne s u p pressi ve t hera p y 
o  T he E n d of Treat me nt visit s h o ul d be c o m plete d as cl ose as p ossi ble t o 
t he date t hat i xaz o mi b is st o p pe d. T he date t hat t he ne w s yste mic 
treat me nt is starte d s h o ul d be rec or de d. 
- 
T he patie nt has rela pse of t heir he mat ol o gic dis or der or mali g na nc y af ter 
tra ns pla nt 
o  T he E n d of Treat me nt visit s h o ul d be c o m plete d if p ossi ble.  
- 
Deat h  
- 
C o m pleti o n of all st u d y f oll o w u p  
 
 
7.     
S T A TI S TI C A L A N D Q U A N TI T A TI V E A N A L Y S E S  
7. 1     St atistic al Met h o ds  
7. 1. 1      
Deter mi n ati o n of S a m ple Size  a n d pl a n ne d met h o ds of a n al ysis  
 
T he pr i mar y e n d p oi nt is o verall treat me nt fail ure at 6 m o nt hs fr o m st u d y e nr oll me nt. 
Treat me nt fail ure re prese nts t he c o m p osite i ncl u di n g a d diti o n of ne w li ne of s yste mic 
i m m u ne s u p pressi ve t hera p y be y o n d I xaz o mi b ( o bjecti ve si g nal of fail ure t o c o ntr ol G V H D 
wit h I xaz o mi b), n o n-rela pse deat h, a n d pri mar y mali g na nc y rela pse.2 9 T he hist orical 
be nc h mar k f or t his o utc o me base d o n t his a nal ysis of 3 1 2 c hr o nic G V H D patie nts is a 6 
m o nt h treat me nt fail ure rate of 4 4 %. Wit h 5 0 patie nts, t he sta n dar d err or of t he esti mate d 
fail ure rate will be a p pr o xi matel y 7 perce nta ge p oi nts.   
 
Wit h 5 0 s u bjects a n d a 1 -si de d al p ha of 0. 1, t here will be 8 2 % p o wer t o detect a 1 5 
perce nta ge p oi nt re d ucti o n i n t he 6 m o nt h treat me nt  fail ure rate, relati ve t o t he refere nce rate 
of 4 4 %. , base d o n a n e xact bi n o mial calc ulati o n usi n g t hat o pti o n i n n Q uer y T his re d ucti o n 
is dee me d feasi ble base d o n t he f oll o wi n g: T he maj or c o ntri b uti o n t o t he o bser ve d treat me nt 
fail ure rate was 3 4 % re q uiri n g a d diti o nal i m m u ne s u p pressi ve t hera p y be y o n d sec o n d-
 
li ne 
9 2 9 2
I R B A p pr o v e d 
D o c u m e nt R el e a s e D at e: 0 8/ 1 1/ 2 0 1 7
Pri nte d o n 1 2/ 4/ 2 0 1 8

t hera p y. Ass u mi n g effecti ve t hera p y wit h o n g oi n g I xaz o mi b o ver t he treat me nt peri o d c o ul d 
re d uce t his ris k b y 5 0 % (i.e. t o 1 7 %) wit h little or n o i ncrease d ris k f or rela pse ( 3 % i n t his 
p u blis he d a nal ysis) or n o n -rela pse deat h ( 7 % i n t his a nal ysis), t he o verall i m pr o ve me nt i n 
t he 6 m o nt h treat me nt fail ure rate c o ul d be 1 5 %. Patie nts w h o are l ost t o f oll o w u p or 
ot her wise n ot e val ua ble will n ot be re place d.  
Alt h o u g h t he o verall 6 m o nt h fail ure rate i n t he hist orical be nc h mar k st u d y was 4 4 %, t his 
varie d fr o m 3 3 % t o 4 1 % t o 5 6 % f or patie nts t hat were classifie d as l o w, i nter me diate a n d 
hi g h ris k, res pecti vel y.  T h us t he relati ve pr o p orti o ns of patie nts i n t he differe nt ris k 
cate g ories will nee d t o be c o nsi dere d i n or der t o i nter pret t he p ossi ble be nefit of I xaz o mi b 
t hera p y. 
Ti me -t o-e ve nt e n d p oi nts will be e val uate d usi n g Ka pla n -Meier a n d c u m ulati ve i nci de nce 
met h o ds; res p o nse e n d p oi nts will be e val uate d as pr o p orti o ns; patie nt -re p orte d o utc o mes 
will be s u m marize d as fre q ue ncies, or wit h mea n a n d S D, as a p pr o priate.   T he o nl y 
c o m parati ve a nal ysis will i n v ol ve t he bi ol o gic e n d p oi nts, w here res p o n ders at 3 a n d 6 
m o nt hs will be c o m pare d t o n o nres p o n ders, base d o n baseli ne val ues a n d o n c ha n ges fr o m 
baseli ne.   T his will i n v ol ve sta n dar d para metric or n o n -para metric met h o ds, de pe n di n g o n 
t he o bser ve d distri b uti o n of t hese e n d p oi nts. 
I n t he a nal ysis of sec o n dar y o bjecti ves, we will st u d y t he 3 a n d 6 m o nt h o verall (c o m plete + 
partial) res p o nse a n d c o m plete res p o n se rates, ot her efficac y meas ures liste d a b o ve, patie nt 
re p orte d o utc o mes, a n d bi ol o gic o utc o me meas ures. We will st u d y ass ociati o n bet wee n 
bi ol o gic o utc o me meas ures a n d cli nical para meters (res p o nse, treat me nt fail ure, m ortalit y).  
 
7. 1. 2        S T U D Y S T O P PI N G R U L E S  
 
W hile I xaz o mi b has de m o nstrate d safet y, it has n ot bee n pre vi o usl y st u die d i n c hr o nic 
G V H D t hera p y after all o ge neic he mat o p oietic cell tra ns pla ntati o n. C urre nt e vi de nce 
s u g gests t hat m ortalit y after i nitiati o n of c hr o nic G V H D t hera p y ma y be as hi g h as 2 0 % at 
5 6 da ys i n s o me hi g h-ris k patie nt gr o u ps ( Bl o o d a n d Marr o w Tra ns pla nt Cli nical Trial 
Net w or k Pr ot oc ol 0 8 0 1) . I n o ur c urre nt trial, we will i m ple me nt a st o p pi n g r ule base d o n a 
t hres h ol d rate of 1 0 % treat me nt-relate d m ortalit y occ urri n g wit hi n 5 6 da ys ( 2 c ycles) of 
starti n g treat me nt.  If reas o na ble e vi de nce e xists t hat 
 
t he rate o n t his trial e xcee ds t his 
9 2 9 2
I R B A p pr o v e d 
D o c u m e nt R el e a s e D at e: 0 8/ 1 1/ 2 0 1 7
Pri nte d o n 1 2/ 4/ 2 0 1 8

t hres h ol d, t he n e nr oll me nt t o t he trial will be halte d w hile data are re vie we d. Reas o na ble 
e vi de nce will be ta ke n t o mea n  t hat t he l o wer b o u n d of a n e xact 1 -si de d 8 0 % c o nfi de nce 
i nter val f or t he tr ue n o n-rela pse m ortalit y rate e xcee ds 1 0 %. T he data will be e val uate d at 
least e ver y 1 0 patie nts, a n d will be tri g gere d if 3  or m ore of 1 0,  4  or m ore of 2 0, 5  or m ore 
of 3 0, or 7  or m ore of 4 0 patie nts e x perie nce n o n -rela pse m ortalit y wit hi n t he first 5 6 da ys .  
F urt her details of t he st o p pi n g r ule i ncl u de t he f oll o wi n g:  
(a) Treat me nt -relate d m ortalit y is a n y deat h occ urri n g w hile recei vi n g st u d y dr u g, or 
wit hi n 3 0 da ys after disc o nti n uati o n of st u d y dr u g, t ha t is p ossi bl y, pr o ba bl y or 
defi nitel y relate d t o t he dr u g  
( b) Rela pse or pr o gressi ve disease will fact or i nt o t he attri b uti o n of ca use, b ut will n ot 
a ut o maticall y pre ve nt a deat h fr o m bei n g classifie d as treat me nt -relate d 
(c) F or p ur p oses of t his st o p pi n g r ule, t h e c o u nt of patie nts ( 1 0, 2 0, etc) will reflect t he 
or der i n w hic h patie nts start treat me nt  
( d) If a D S M B re vie w is re q uire d beca use t he st o p pi n g r ule is tri g gere d, patie nts w h o are 
alrea d y e nr olle d a n d ta ki n g i xaz o mi b ma y c o nti n ue treat me nt, pe n di n g t he o utc o m e 
of t hat re vie w. A n y e nr olle d patie nt w h o has c o nse nte d b ut n ot starte d st u d y dr u g 
ma y n ot start i xaz o mi b treat me nt, pe n di n g t he o utc o me of t hat re vie w.  
I n a d diti o n t o t his st o p pi n g r ule, we will als o i m ple me nt a pre-a p pr o val pr ocess t hr o u g h t he 
C o or di nat i n g Ce nter at Fre d H utc hi ns o n t o c o ntr ol t he rate of e nr oll me nt o n t he trial a n d 
re p ort t o t he D S M B all deat hs t hat occ ur t hr o u g h 6 m o nt hs of f oll o w-u p f or all patie nts o n 
trial ( 7 m o nt hs f or patie nts w h o c o m plete t he f ull 6 m o nt hs of st u d y treat me nt), s o t hat t hese 
e ve nts ca n be re vie we d a n d disc usse d b y t he D S M B if nee d be. F or a n y D S M B re vie w, we 
will pr o vi de a n u p date d esti mate of t he c u m ulati ve i nci de nce of treat me nt -relate d m ortalit y 
f or t he e ntire trial. 
 
T he o perati n g c haracteristics of t his st o p pi n g r ule are pr o vi de d bel o w:  
Tr u e r at e of e v e nt  Pr o b a bilit y of st o p pi n g * 
A v er a g e N at st o p pi n g * 
0. 0 5  
3 5  
4 9  
0. 1 0  
2 5 %  
4 3  
 
9 2 9 2
I R B A p pr o v e d 
D o c u m e nt R el e a s e D at e: 0 8/ 1 1/ 2 0 1 7
Pri nte d o n 1 2/ 4/ 2 0 1 8

0. 1 5  
6 2 %  
3 4  
0. 2 0  
8 7 %  
2 5  
0. 2 5  
9 7 %  
1 9  
* B a s e d o n 1 0, 0 0 0 M o nt e C arl o si m ul ati o n s 
 
8.         A D V E R S E E V E N T S  
 
8. 1   Defi niti o ns  
•  Pretre at me nt E ve nt Defi niti o n  
A pretreat me nt  e ve nt is a n y u nt o war d me dical occ urre nce i n a patie nt or s u bject w h o has 
si g ne d i nf or me d c o nse nt t o partici pate i n a st u d y b ut bef ore a d mi nistrati o n of a n y st u d y 
me dicati o n; it d oes n ot necessaril y ha ve t o ha ve a ca usal relati o ns hi p wit h st u d y 
partici pati o n .  
 
 
•  A d verse E ve nt  
 
A n a d verse e ve nt is a n y u nt o war d me dical occ urre nce ass ociate 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 relate d. It ca n be a n y u nfa v ora ble a n d u ni nte n de d 
si g n (e. g., a n a b n or mal la b orat or y fi n di n g), s y m pt o m, or disease, te m p orall y ass ociate d wit h 
t he use of a dr u g w het her or n ot it is relate d t o t he dr u g.  T his i ncl u des a n y ne wl y occ urri n g 
e ve nt, or a pre vi o us c o n diti o n t hat has i ncrease d i n se verit y or fre q ue nc y si nce t he 
a d mi nistrat i o n of st u d y dr u g. 
A n a b n or mal la b orat or y val ue will n ot be assesse d as a n A E u nless t hat val ue lea ds t o 
disc o nti n uati o n or dela y i n treat me nt, d ose m o dificati o n, t hera pe utic i nter ve nti o n, or is 
c o nsi dere d b y t he i n vesti gat or t o be a cli nicall y si g nifica nt  c ha n ge fr o m baseli ne . 
 
 
 
 
A E Gra di n g Criteria:  
 
T he st u d y site will gra de t he se verit y of a d verse e ve nts e x perie nce d b y st u d y partici pa nts o n 
 
a scale fr o m 1 t o 5 acc or di n g t o N CI C T C A E v 4. 0 or c urre nt versi o n. Gra de 1 a n d gra de 2 
9 2 9 2
I R B A p pr o v e d 
D o c u m e nt R el e a s e D at e: 0 8/ 1 1/ 2 0 1 7
Pri nte d o n 1 2/ 4/ 2 0 1 8

a d verse e ve nts d o n ot re q uire re p orti n g. A d verse e ve nts n ot i ncl u de d i n t he N CI C T C A E 
s h o ul d be rec or de d a n d gra de d acc or di n g t o t he Ge neral Gra de Defi niti o n pr o vi de d bel o w:  
 
 
 
A D V E R S E E V E N T G E N E R A L G R A D E D E FI NI TI O N S  
 
 
Gra 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 o stic o bser vati o ns o nl y; i nter ve nti o n n ot 
i n dicate d 
Gra de 2  
M o derate  
Mi ni mal, l ocal or n o n -i n vasi ve i nter ve nti o n 
i n dicate d; li miti n g a ge-a p pr o priate i nstr u me ntal 
A D L *  
Gra de 3  
Se vere  
Se vere or me dicall y si g nifica nt, b ut n ot i m me diatel y 
life-t hreate ni n g; h os pitalizati o n or pr ol o n gati o n of 
h os pitalizati o n i n dicate d; disa bli n g; li miti n g self -
care A D L * *  
Gra de 4  
Life -t hreate ni n g 
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 
Gra de 5  
Deat h relate d t o A E  
Deat h relate d t o A E  
 
*I nstr u me ntal A D L: Pre pari n g meals, s h o p pi n g f or gr oceries or cl ot hes, usi n g t he tele p h o ne, 
ma na gi n g m o ne y, etc.  
* * Self -care A D L: Bat hi n g, dressi n g a n d u n dressi n g, fee di n g self, usi n g t he t oilet, ta ki n g 
me dicati o ns, a n d n ot be dri d de n.  
 
 
 
 
 
 
○S us pecte d A d verse Re acti o ns  –  a s u b set of A d verse E ve nts b ase d o n c a us alit y 
       
  
A s us pecte d a d verse reacti o n is a n y a d verse e ve nt f or w hic h t here is a re as o n a ble p ossi bility 
t hat t he dr u g ca use d t he e ve nt. Re as o n a ble p ossi bility  mea ns t here is e vi de nce t o s u g gest a 
ca usal relati o ns hi p bet wee n t he dr u g a n d t he e ve nt.  S o me e xa m ples are:  
- 
A si n gle occ urre nce of a n e ve nt t hat is u nc o m m o n a n d k n o w n t o be str o n gl y 
ass ociate d wit h dr u g e x p os ure.  
- 
O ne or m ore occ urre nces of a n e ve nt t hat is n ot c o m m o nl y ass ociate d wit h dr u g 
e x p os ure, b ut is ot h er wise u nc o m m o n i n t he p o p ulati o n e x p ose d t o t he dr u g. If 
t he e ve nt occ urs i n ass ociati o n wit h ot her fact ors str o n gl y s u g gesti n g ca usati o n 
(e. g., str o n g te m p oral ass ociati o n, e ve nt rec urs o n re-c halle n ge), a si n gle case 
ma y be s ufficie ntl y pers uasi ve.  Oft e n, m ore t ha n o ne occ urre nce is nee de d 
bef ore t he s p o ns or -i n vesti gat or ca n deter mi ne t hat t here is a reas o na ble 
p ossi bilit y t hat t he dr u g ca use d t he e ve nt. 
 
 
9 2 9 2
I R B A p pr o v e d 
D o c u m e nt R el e a s e D at e: 0 8/ 1 1/ 2 0 1 7
Pri nte d o n 1 2/ 4/ 2 0 1 8

- 
A n a g gre gate a nal ysis of e ve nts o bser ve d i n a cli nical trial t hat i n dicates t h ose 
e ve nts occ ur m ore  fre q ue ntl y i n t he dr u g treat me nt gr o u p t ha n i n a si milar 
p o p ulati o n n ot recei vi n g t he st u d y dr u g.  
 
If t here is reas o n t o c o ncl u de wit h certai nt y t hat t he dr u g ca use d t he e ve nt, t he e ve nt is                  
classifie d as a n A d verse Re acti o n . 
 
 
o  U ne x pecte d  
 
A n a d verse e ve nt is c o nsi dere d u ne x pecte d if it is n ot liste d i n t he i nvesti g at or br oc h ure, or 
is n ot liste d at t he s pecificity or severity t h at h as bee n o bserve d i n t he eve nt.  “ U ne x pecte d” 
als o refers t o a d verse e ve nts t hat are me nti o ne d i n t he i n vesti gat or br oc h ure as occ urri n g 
wit h a class of dr u gs or as a ntici pate d fr o m t he p har mac ol o gical pr o perties of t he dr u g, b ut 
are n ot s pecificall y me nti o ne d as occ urri n g wit h t he partic ular dr u g u n der i n vesti gati o n.  
 
 
o  Seri o us  
 
A n a d verse e ve nt is c o nsi dere d “s eri o us” if, i n t he vie w of eit her t he i n vesti gat or or t he 
s p o ns or, it res ults i n a n y of t he f oll o wi n g o utc o mes: 
1.  Deat h  
2.  A life -t hreate ni n g a d verse e ve nt ( places t he s u bject at a n i m me diate ris k of 
deat h)  
3.  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  
4.  A persiste nt or si g nifica nt disa bilit y or i nca pacitati o n  
5.  A c o n ge nital a n o mal y or birt h defect  
6.  Is a me dic all y i m p ort a nt e ve nt .  T his refers t o a n A E t hat ma y n ot res ult i n 
deat h, be i m me diatel y life t hreate ni n g, or re q uire h os pitalizati o n, b ut ma y be 
c o nsi dere d seri o us w he n, base d o n a p pr o priate me dical j u d g me nt, ma y 
je o par dize t he patie nt, re q uire me dical or s ur gical 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, or i n v ol ves s us pecte d tra ns missi o n via a me dici nal 
pr o d uct of a n i nfec ti o us a ge nt.   E xa m ples of s uc h me dical e ve nts i ncl u de 
aller gic br o nc h os pas m re q uiri n g i nte nsi ve treat me nt i n a n e mer ge nc y r o o m or at 
h o me, bl o o d d yscrasias or c o n v ulsi o ns t hat d o n ot res ult i n i n patie nt 
h os pitalizati o n, or t he de vel o p me nt of dr u g de pe n de n c y or dr u g a b use; a n y 
or ga nis m, vir us, or i nfecti o us particle (e g, pri o n pr otei n tra ns mitti n g 
T ra ns missi ble S p o n gif or m E nce p hal o pat h y), pat h o ge nic or n o n pat h o ge nic, is 
c o nsi dere d a n i nfecti o us a ge nt.    
Clarificati o n s h o ul d be ma de bet wee n a seri o us A E ( S A E) a n d a n A E t hat is c o nsi dere d 
 
se vere i n i nte nsit y ( Gra de 3 or 4), beca use t he ter ms seri o us a n d se vere are N O T 
9 2 9 2
I R B A p pr o v e d 
D o c u m e nt R el e a s e D at e: 0 8/ 1 1/ 2 0 1 7
Pri nte d o n 1 2/ 4/ 2 0 1 8

s y n o n y m o us.  T he ge neral ter m severe is ofte n use d t o descri be t he i nte nsit y (se verit y) of a 
s pecific e ve nt; t he e ve nt itself, h o we ver, ma y be of relati vel y mi n or me dical si g nifica nce 
(s uc h as a Gra de 3 hea dac he).  T his is N O T t he sa me as seri o us, w hic h is base d o n 
patie nt/e ve nt o utc o me or acti o n criteria descri be d a b o ve, a n d is us uall y ass ociate d wit h 
e ve nts t hat p ose a t hreat t o a patie nt’s lif e or a bilit y t o f u ncti o n.  A se vere A E ( Gra de 3 or 4) 
d oes n ot necessaril y nee d t o be c o nsi dere d seri o us.  F or e xa m ple, a w hite bl o o d cell c o u nt of 
1 0 0 0/ m m 3 t o less t ha n 2 0 0 0 is c o nsi dere d Gra de 3 (se vere) b ut ma y n ot be c o nsi dere d 
seri o us.  Seri o us ness ( not i nte nsit y) ser ves as a g ui de f or defi ni n g re g ulat or y re p orti n g 
o bli gati o ns.   
 
8. 2   Rec or di n g of A d verse E ve nts  
 
 
T he st u d y will c ollect all Gra de 3 a n d a b o ve a d verse e ve nts  (exce pt  a b n or mal la bs as 
o utli ne d i n secti o n 8. 1, a n d t he e xce pti o ns liste d bel o w) , re gar dless of relati o ns hi p t o st u d y 
t hera p y or st u d y pr oce d ures.  Se verit y gra di n g will be base d o n t he c urre nt versi o n of t he 
C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts ( C T C A E).  Gra de 1 a n d 2 e ve nts will n ot 
be c ollecte d.  
 
A d verse e ve nts will be c ol lecte d fr o m t he ti me t he patie nt si g ns t he i nf or me d c o nse nt u ntil 
3 0 da ys after t he last d ose of I xaz o mi b.  E ve nts t hat occ ur after t his ti me will be rec or de d 
o nl y if t here is a reas o na ble p ossi bilit y t hat t he e ve nt was ca use d b y a st u d y pr oce d ure or 
I xaz omi b .  All rec or da ble a d verse e ve nts will be f oll o we d u ntil res ol uti o n. 
 
 
 
 
Re p orti n g pr oce d ures:  
 
o  All n o n -seri o us, Gra de 3 a n d a b o ve a d verse e ve nts m ust be rec or de d i n t he data base 
wit hi n 2 0 da ys of bec o mi n g a ware of t he e ve nt.  
 
o  E xce pti o ns:  
 
T he f oll o wi n g  are fre q ue nt e ve nts i n t he c hr o nic G V H D p o p ulati o n a n d will n ot  be rec or de d 
as a d verse e ve nts as l o n g as t hey are n ot seri o us : 
•  A b n or malities prese nt at st u d y e nr oll me nt: Will n ot be c o nsi dere d a d verse e ve nts, 
u nless s uc h a b n or malities w orse n (i.e. i ncreas e i n fre q ue nc y, i nte nsit y, or prese nt 
ne w c o m plicati o ns or u nt o war d e ve nts) d uri n g st u d y f oll o w u p  
•  Electr ol yte a b n or malities: I ncrease or decrease i n s o di u m, p otassi u m, c hl ori de, 
 
bicar b o nate, p h os p h or us, ma g nesi u m, calci u m, h y per gl yce mia f oll o wi n g ster oi d 
9 2 9 2
I R B A p pr o v e d 
D o c u m e nt R el e a s e D at e: 0 8/ 1 1/ 2 0 1 7
Pri nte d o n 1 2/ 4/ 2 0 1 8

t hera p y 
•  Oc ular: G V H D relate d e ye dr y ness, disc o mf ort, re q uire me nt f or m oist urizi n g e ye 
dr o ps or ot her t o pical G V H D oc ular t hera pies or i nter ve nti o ns (e. g. p u nctal pl u gs, 
scleral le nses), c ha n ges i n vis ual ac uit y. 
•  Der mat ol o g y: Nail c ha n ges, G V H D ras h (t o i n cl u de er yt he ma, scler o der ma, 
ulcerati o n, lic he n oi d c ha n ges, h y per - or h y p o -pi g me ntati o n, dr y s ki n a n d al o pecia) or 
c us hi n g oi d a p peara nce d ue t o ster oi d t hera p y.  
•  Gastr oi ntesti nal: Xer ost o mia, oral ulcers or ot her G V H D ass ociate d lesi o ns, oral pai n 
or se nsit i vit y, a n ore xia, diffic ult y s wall o wi n g d ue t o es o p ha geal strict ure or 
narr o wi n g, na usea/ v o miti n g, sali var y gla n d c ha n ges, G V H D ass ociate d a b d o mi nal 
pai n, bl oati n g, diarr hea, wei g ht l oss  
•  Res pirat or y: s h ort ness of breat h, c o u g h, or o x y ge n re q uire me nt ass ocia te d wit h 
p ul m o nar y c hr o nic G V H D i n v ol ve me nt  
•  Gr o wt h a n d De vel o p me nt: Re d uce d gr o wt h vel ocit y, dela ye d p u bert y.  
•  M usc ul os keletal c ha n ges: A vasc ular necr osis, fract ure, art hritis, oste o p or osis, 
decrease i n ra n ge of m oti o n ass ociate d wit h j oi nt or fascial G V H D i n v ol ve me nt 
•  Se x ual F u ncti o n: Erectile d ysf u ncti o n, i nfertilit y, a me n orr hea, va gi nal ste n osis, 
va gi nal dr y ness or disc o mf ort.  
•  E ve nts sec o n dar y t o r o uti ne pr oce d ures perf or me d f or c hr o nic G V H D t hera pies: 
E xtrac or p oreal p h ot o p heresis, P U V A t hera p y.  
 
 
 
N o n -seri o us a d verse e ve nts c ollecte d i n t he data base will be c o m pile d b y t he c o or di nati n g 
ce nter a n d re p orte d t o t he D S M B a p pr o xi matel y e ver y 6 m o nt hs.  
 
All seri o us a d verse e ve nts m ust be re p orte d i n t he data base wit hi n 2 4 h o urs of bec o mi n g 
a ware of t he e ve nt.  Si g nifica nt a n d rele va nt f oll o w -u p i nf or mati o n s h o ul d als o be re p orte d 
as s o o n as p ossi ble.  
 
 
o  E xce pti o n:  
▪ H os pitalizati o n f or electi ve treat me nt of a pre -e xisti n g c o n diti o n t hat di d n ot 
w orse n fr o m baseli ne is n ot c o nsi dere d a n S A E.  
 
T he data base will n otif y t he c o or di nati n g ce nter a n d s p o ns or -i n vesti gat or w he n a seri o us 
a d verse e ve nt has bee n e ntere d.  T he s p o ns or -i n vesti gat or will t he n deter mi ne w het her t he 
e ve nt meets t he criteria f or e x pe dite d re p orti n g (see bel o w) a n d will w or k wit h t he 
c o or di nati n g ce n ter t o pre pare t he I N D Safet y Re p ort. 
 
8. 3    I N D Safet y Re p orti n g 
 
 
A n e ve nt m ust meet all t hree of t he f oll o wi n g criteria i n or der t o q ualif y f or e x pe dite d 
re p orti n g t o t he F D A i n a n I N D Safet y Re p ort:
 
 
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Pri nte d o n 1 2/ 4/ 2 0 1 8

1)  Seri o us  
2)  U ne x pecte d  
3)  S us pecte d a d verse reacti o n (i.e. t her e is a reas o na ble p ossi bilit y t hat t he dr u g ca use d 
t he e ve nt) 
 
T he s p o ns or -i n vesti gat or is ulti matel y res p o nsi ble f or deter mi ni n g w het her all criteria are 
met. Details are as f oll o ws:  
 
•  Seri o us ness:  If eit her t he s p o ns or-i n vesti gat or or l ocal i n vesti gat or belie ves t hat a n 
e ve nt is seri o us, it m ust be c o nsi dere d seri o us a n d e val uate d b y t he s p o ns or -i n vesti gat or 
f or e x pe dite d re p orti n g. Si milarl y, if eit her t he s p o ns or-i n vesti gat or or l ocal i n vesti gat or 
belie ves t hat a n e ve nt is life t hreate ni n g, it m ust be c o nsi dere d life t hreate ni n g f or 
re p orti n g p ur p oses. 
 
•  E x pecte d ness:  T he s p o ns or -i n vesti gat or is res p o nsi ble f or deter mi ni n g w het her a n e ve nt 
is u ne x pecte d. 
 
•  C a us alit y:  Alt h o u g h l ocal i n vesti gat ors are re q uire d t o pr o vi de a ca usalit y assess me nt 
f or eac h seri o us a d verse e ve nt ori gi nati n g fr o m t heir sites, it is ulti matel y t he s p o ns or-
i n vesti gat or w h o deci des w het her t he e ve nt meets t he defi niti o n of a s us pecte d a d verse 
reacti o n.  
 
I N D Safet y re p orts will be s u b mitte d o n a Me d Watc h 3 5 0 0 A f or m t o t he F D A a n d all 
pa rtici pati n g i n vesti gat ors n o later t ha n 1 5 da ys after t he s p o ns or-i n vesti gat or deter mi nes 
t hat t he e ve nt q ualifies f or re p orti n g.  
•  E xce pti o n: Fatal or life -t hreate ni n g e ve nts will be re p orte d wit hi n 7 da ys of w he n t he 
s p o ns or-i n vesti gat or recei ves n otificati o n of t he e ve nt.  
 
Rele va nt a d diti o nal i nf or mati o n s h o ul d be s u b mitte d i n a f oll o w -u p re p ort as s o o n as 
p ossi ble, b ut n o later t ha n 1 5 da ys after t he s p o ns or -i n vesti gat or recei ves t he i nf or mati o n.  
All ot her a d verse e ve nts t hat are c ollecte d b y t he st u d y  b ut d o n ot meet t he criteria f or 
e x pe dite d re p orti n g will be re p orte d t o t he F D A i n t he I N D A n n ual Re p ort.  
 
N otificati o n of S A E t hat meet re q uire me nt f or e x pe dite d re p orti n g will als o be pr o vi de d t o 
i n di vi d ual site pri nci pal i n vesti gat ors of t his trial. 
 
 
 
8. 4   Re p orti n g t o  Mille n n i u m 
 
A Es w hic h are seri o us m ust be re p orte d t o Mille n ni u m P har mac o vi gila nce ( or desi g nee) 
fr o m t he date t he partici pa nt si g ns I nf or me d C o nse nt t hr o u g h 3 0 da ys after a d mi nistrati o n of 
t he last d ose of I xaz o mi b. A n y S A E t hat occ urs at  a n y ti me after c o m pleti o n of  I xaz o mi b 
treat me nt or after t he desi g nate d f oll o w-u p peri o d t hat t he s p o ns or -i n vesti gat or a n d/ or s u b
 
-
9 2 9 2
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D o c u m e nt R el e a s e D at e: 0 8/ 1 1/ 2 0 1 7
Pri nte d o n 1 2/ 4/ 2 0 1 8

i n vesti gat or c o nsi ders t o be relate d t o a n y st u d y dr u g m ust be re p orte d t o Mille n ni u m 
P har mac o vi gila nce ( or desi g nee).  I n a dditi o n, ne w pri mar y mali g na ncies t hat occ ur d uri n g 
t he f oll o w-u p peri o d m ust be re p orte d, re gar dless of ca usalit y t o st u d y re gi me n . 
A d diti o nall y, if t he i n vesti gat or lear ns of a ne w pri mar y mali g na nc y occ urri n g i n a st u d y 
partici pa nt wit hi n 3 years after t he last d ose of st u d y dr u g, it m ust be re p orte d t o Mille ni u m 
P har mac o vi gila nce.     
Pla n ne d h os pital a d missi o ns or s ur gical pr oce d ures f or a n ill ness or disease t hat e xiste d 
bef ore t he patie nt was e nr olle d i n t he trial are n ot t o be c o nsi dere d A Es u nless t h e c o n diti o n 
deteri orate d i n a n u ne x pecte d ma n ner d uri n g t he trial (e. g., s ur ger y was perf or me d earlier or 
later t ha n pla n ne d).  All S A Es s h o ul d be m o nit ore d u ntil t he y are res ol ve d or are clearl y 
deter mi ne d t o be d ue t o a patie nt’s sta ble or c hr o nic c o n dit i o n or i nterc urre nt ill ness(es). 
Si nce t his is a n i n vesti gat or -i nitiate d st u d y, t he pri nci pal i n vesti gat or als o referre d t o as t he 
s p o ns or-i n vesti gat or, is res p o nsi ble f or re p orti n g seri o us a d verse e ve nts ( S A Es) t o a n y 
re g ulat or y a ge nc y a n d t o t he s p o ns or- i n vesti gat or’s E C or I R B.    
Re gar dless of e x pecte d ness or ca usalit y, all S A Es  (i ncl u di n g seri o us pretreat me nt e ve nts) 
m ust als o be re p orte d t o Mille n ni u m P har mac o vi gila nce :  
 
F at al a n d Life T hre ate ni n g S A Es wit hi n 2 4 h o urs of t he s p o ns or -i n vesti gat or’s 
o bser vati o n or a ware ness of t he e ve nt  
 
All ot her seri o us ( n o n -f at al/ n o n life t hre ate ni n g) e ve nts wit hi n 4 cale n dar da ys of t he 
s p o ns or-i n vesti gat or’s o bser vati o n or a ware ness of t he e ve nt 
 
See bel o w  f or c o ntact i nf or mati o n f or t he re p orti n g of S A Es t o Millen ni u m 
P har mac o vi gila nce .   
T h e s p o ns or -i n vesti gat or m ust fa x t he S A E F or m per t he ti meli nes a b o ve .  A sa m ple of a n 
S A E F or m will be pr o vi de d.   
T he S A E re p ort m ust i ncl u de at mi ni m u m:  
•  E ve nt ter m(s)  
•  Seri o us criteri a  
•  I nte nsit y of t he e ve nt(s): S p o ns or -i n vesti gat or’s or s u b-i n vesti gat or’s 
deter mi nati o n.   I nte nsit y f or eac h S A E, i ncl u di n g a n y la b a b n or malities, will 
 
be deter mi ne d b y usi n g t he N CI C T C A E versi o n s pecifie d i n t he pr ot oc ol, as a 
9 2 9 2
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D o c u m e nt R el e a s e D at e: 0 8/ 1 1/ 2 0 1 7
Pri nte d o n 1 2/ 4/ 2 0 1 8

g ui deli ne, w he ne ver p ossi ble.   T he criteria are a vaila ble o nli ne at 
htt p://cte p.ca ncer. g o v/re p orti n g/ctc. ht ml . 
•  C a us alit y of t he e ve nt(s): S p o ns or -i n vesti gat or’s or s u b-i n vesti gat or’s 
deter mi nati o n of t he relati o ns hi p of t he e ve nt(s) t o st u d y dr u g a d mi nistrati o n.  
F oll o w -u p i nf or mati o n o n t he S A E ma y be re q ueste d b y Mille n ni u m.    
I nte nsit y f or eac h S A E, i ncl u di n g a n y la b a b n or malities, will be deter mi ne d b y usi n g t he 
N CI C T C A E versi o n use d at y o ur i nstit uti o n, as a g ui deli ne, w he ne ver p ossi ble.  T he criteria 
are a vaila b le o nli ne at htt p://cte p.ca ncer. g o v/re p orti n g/ctc. ht ml. 
I n t he e ve nt t hat t his is a m ultisite st u d y, t he s p o ns or-i n vesti gat or is res p o nsi ble t o e ns ure 
t hat t he S A E re p orts are se nt t o Mille n ni u m P har mac o vi gila nce ( or desi g nee) fr o m all sites 
partici pati n g i n t he st u d y.  S u b-i n vesti gat ors m ust re p ort all S A Es t o t he s p o ns or-
i n vesti gat or s o t hat t he s p o ns or-i n vesti gat or ca n meet his/ her f ore g oi n g re p orti n g o bli gati o ns 
t o t he re q uire d re g ulat or y a ge ncies a n d t o Mille n ni u m P har mac o vi gila nce, u nless ot her wise 
a gree d bet wee n t he s p o ns or-i n vesti gat or a n d s u b-i n vesti gat or(s).   
Relati o ns hi p t o all st u d y dr u gs f or eac h S A E will be deter mi ne d b y t he i n vesti gat or or s u b -
i n vesti gat or b y res p o n di n g yes or n o t o t he q uesti o n: Is t here a reas o na ble p ossi bilit y t hat t he 
A E is ass ociate d wit h t he st u d y dr u g(s)? 
S p o ns or -i n vesti gat or m ust als o pr o vi de Mille n ni u m P har mac o vi gila nce wit h a c o p y of all 
c o m m u nicati o ns wit h a p plica ble re g ulat or y a ut h orities relate d t o t he st u d y pr o d uct (s), as 
s o o n as p ossi ble b ut n o later t ha n 4 calen dar da ys of s uc h c o m m u nicati o n.   
S A E a n d Pre g n a nc y Re p orti n g C o nt act I nf or m ati o n  
S A E a n d Pre g n a nc y Re p orti n g C o nt act I nf or m ati o n  
 
Fa x N u m ber: 1 -8 0 0 -9 6 3 -6 2 9 0  
E mail: Ta ke da O nc o Cases @c o g niza nt.c o m   
S u g gest e d Re p orti n g F or m:   
• 
O nc ol o g y Electr o nic S A E F or m wit h S A E N otificati o n F or m C o ver S heet (pr o vi de d 
b y Mille n ni u m )
 
 
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Pri nte d o n 1 2/ 4/ 2 0 1 8

8. 5   Pr oce d ures f or Re p orti n g A Es  
A Es ma y be s p o nta ne o usl y re p orte d b y t he patie nt a n d/ or i n res p o nse t o a n o pe n q uesti o n 
fr o m st u d y pers o n nel or re veale d b y o bser vati o n, p h ysical e xa mi nati o n, or ot her dia g n ostic 
pr oce d ures .  A n y cli nicall y rele va nt deteri orati o n i n la b orat or y assess me nts or ot her cli nical 
fi n di n g is c o nsi dere d a n A E.  W he n p ossi ble, si g ns a n d s y m pt o ms i n dicati n g a c o m m o n 
u n derl y i n g pat h ol o g y s h o ul d be n ote d as o ne  c o m pre he nsi ve e ve nt.   F or n o nseri o us A Es  , 
t he i n vesti gat or m ust deter mi ne b ot h t he i nte nsit y of t he e ve nt a n d t he relati o ns hi p of t he 
e ve nt t o st u d y dr u g  a d mi nistrati o n. 
 
8. 6   Pr oce d ures f or Re p orti n g Dr u g E x p os ure D uri n g  Pre g n a nc y a n d Birt h 
E ve nts  
If a w o ma n bec o mes pre g na nt or s us pects t hat s he is pre g na nt w hile partici pati n g i n t his 
st u d y, s he m ust i nf or m t he i n vesti gat or i m me diatel y a n d per ma ne ntl y disc o nti n ue st u d y 
dr u g.  T he s p o ns or -i n vesti gat or m ust i m me diatel y fa x a c o m plete d Pre g na nc y F or m t o t he 
Mille n ni u m De part me nt of P har mac o vi gila nce or desi g nee  (pr o vi de d b y Mille n ni u m ).  T he 
pre g na nc y m ust be f oll o we d f or t he fi nal pre g na nc y o utc o me.  
If a fe male part ner of a male patie nt bec o mes pre g na nt d uri n g t he male patient’s 
partici pati o n i n t his st u d y, t he s p o ns or-i n vesti gat or m ust als o i m me diatel y fa x a c o m plete d 
Pre g na nc y F or m t o t he Mille n ni u m De part me nt of P har mac o vi gila nce or desi g nee  ).  E ver y 
eff ort s h o ul d be ma de t o f oll o w t he pre g na nc y f or t he fi nal pre g na nc y o u tc o me. 
S u g geste d Pre g na nc y Re p orti n g F or m:  
•  Pre g na nc y Re p ort F or m ( pr o vi de d b y Mille n ni u m )   
 
 
9.     
A D MI NI S T R A TI V E R E Q UI R E M E N T S  
9. 1     Pr o d uct C o m pl ai nts    
A pr o d uct c o m plai nt is a ver bal, writte n, or electr o nic e x pressi o n t hat i m plies dissatisfacti o n 
re gar di n g t he i de ntit y, stre n gt h, p urit y, q ualit y, or sta bilit y of a dr u g pr o d uct.  I n di vi d uals 
w h o i de ntif y a p ote ntial pr o d uct c o m plai nt sit uati o n s h o ul d i m me diatel y c o ntact Me d C o m m 
S ol uti o ns (see bel o w) a n d re p ort t he e ve nt.  W he ne ver p ossi ble, t he ass ociate d pr
 
o d uct 
9 2 9 2
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D o c u m e nt R el e a s e D at e: 0 8/ 1 1/ 2 0 1 7
Pri nte d o n 1 2/ 4/ 2 0 1 8

s h o ul d be mai ntai ne d i n acc or da nce wit h t he la bel i nstr ucti o ns pe n di n g f urt her g ui da nce 
fr o m a Mille n ni u m Q ualit y re prese ntati ve. 
F or Pr o d uct C o m pl ai nts,  
call Me d C o m m S ol uti o ns at  
8 7 7 -6 7 4 -3 7 8 4 ( 8 7 7 M PI D R U G)   
( U S a n d I nter nati o nal) 
 
Pr o d uct c o m plai nt s i n a n d of t he msel ves are n ot A Es.  If a pr o d uct c o m plai nt res ults i n a n 
S A E, a n S A E f or m s h o ul d be c o m plete d a n d se nt t o P P D .
 
 
9 2 9 2
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Pri nte d o n 1 2/ 4/ 2 0 1 8

1 0.     R E F E R E N C E S     
1.  
Fl o wers M E, Par ker P M, J o h nst o n LJ, Mat os A V, St orer B, Be nsi n ger WI, St or b R, 
A p pel ba u m F R, F or ma n SJ, Bl u me K G, Marti n PJ. C o m paris o n of c hr o nic graft -vers us -h ost 
disease after tra ns pla ntati o n of peri p heral bl o o d ste m cells vers us b o ne marr o w i n all o ge neic 
reci pie nts: l o n g-ter m f oll o w-u p of a ra n d o mize d trial. Bl o o d. 2 0 0 2; 1 0 0: 4 1 5 -4 1 9.  
2.  
L ee SJ, Fl o wers M E. Rec o g nizi n g a n d ma na gi n g c hr o nic graft -vers us -h ost disease. 
He mat ol o g y A m S oc He mat ol E d uc Pr o gra m. 2 0 0 8: 1 3 4 -1 4 1.  
3.  
Lee SJ, V o gelsa n g G, Fl o wers M E. C hr o nic graft -vers us -h ost disease. Bi ol Bl o o d 
Marr o w Tra ns pla nt. 2 0 0 3; 9: 2 1 5 -2 3 3.  
4.  
Lee  SJ, Klei n J P, Barrett AJ, Ri n g de n O, A nti n J H, Ca h n J Y, Cara basi M H, Gale R P, 
Giralt S, Hale G A, Il ha n O, Mc Cart h y P L, S ocie G, Ver d o nc k L F, Weis d orf DJ, H or o witz 
M M. Se verit y of c hr o nic graft -vers us -h ost disease: ass ociati o n wit h treat me nt -relate d 
m ortal it y a n d rela pse. Bl o o d. 2 0 0 2; 1 0 0: 4 0 6-4 1 4.  
5.  
S ocie G, St o ne J V, Wi n gar d J R, Weis d orf D, He nslee -D o w ne y PJ, Bre des o n C, 
Ca h n J Y, Pass we g J R, R o wli n gs P A, Sc h o ute n H C, K ol b HJ, Klei n J P. L o n g -ter m s ur vi val 
a n d late deat hs after all o ge neic b o ne marr o w tra ns pl a ntati o n. Late Effects W or ki n g 
C o m mittee of t he I nter nati o nal B o ne Marr o w Tra ns pla nt Re gistr y. N E n gl J Me d. 
1 9 9 9; 3 4 1: 1 4 -2 1.  
6.  
Fraser CJ, B hatia S, Ness K, Carter A, Fra ncisc o L, Ar ora M, Par ker P, F or ma n S, 
Weis d orf D, G ur ne y J G, Ba ker K S. I m pact of c hr o nic graft -vers us -h ost disease o n t he healt h 
stat us of he mat o p oietic cell tra ns pla ntati o n s ur vi v ors: a re p ort fr o m t he B o ne Marr o w 
Tra ns pla nt S ur vi v or St u d y. Bl o o d. 2 0 0 6; 1 0 8: 2 8 6 7 -2 8 7 3.  
7.  
Pi dala J, A nasetti C, Ji m H. Q ualit y of life after all o ge neic he mat o p oietic cell 
tra ns pla ntati o n. Bl o o d. 2 0 0 9; 1 1 4: 7-1 9.  
8.  
Pi dala J, K urla n d B, C hai X, Maj hail N, Weis d orf DJ, Pa vletic S, C utler C, 
Jac o bs o h n D, Pal mer J, Arai S, Ja gasia M, Lee SJ. Patie nt-re p orte d q ualit y of life is 
ass ociate d wit h se verit y of c hr o nic graft -vers us -h ost disease as meas ure d b y NI H criteria: 
re p ort o n baseli ne data fr o m t he C hr o nic G V H D C o ns orti u m. Bl o o d; 1 1 7: 4 6 5 1-4 6 5 7.  
9.  
S h ul ma n H M, S ulli va n K M, Wei de n P L, Mc D o nal d G B, Stri ker G E, Sale G E, 
Hac k ma n R, Ts oi M S, St or b R, T h o mas E D. C hr o nic graft -vers us -h ost s y n dr o me i n ma n. A 
l o n g-ter m cli nic o pat h ol o gic st u d y of 2 0 Seattle patie nts. A m J Me d. 1 9 8 0; 6 9: 2 0 4-2 1 7.  
1 0.  
Fili p o vic h A H, Weis d orf D, Pa vletic S, S ocie G, Wi n gar d J R, Lee SJ, Marti n P, 
C hie n J, Prze pi or ka D, C o uriel D, C o we n E W, Di n n d orf P, Fa rrell A, Hartz ma n R, He nslee-
D o w ne y J, Jac o bs o h n D, Mc D o nal d G, Mittle ma n B, Rizz o J D, R o bi ns o n M, Sc h u bert M, 
Sc h ultz K, S h ul ma n H, T ur ner M, V o gelsa n g G, Fl o wers M E. Nati o nal I nstit utes of Healt h 
c o nse ns us de vel o p me nt pr oject o n criteria f or cli nical tri als i n c hr o nic graft -vers us -h ost 
disease: I. Dia g n osis a n d sta gi n g w or ki n g gr o u p re p ort. Bi ol Bl o o d Marr o w Tra ns pla nt. 
2 0 0 5; 1 1: 9 4 5 -9 5 6.  
1 1.  
K oc S, Leise nri n g W, Fl o wers M E, A nasetti C, Dee g HJ, Nas h R A, Sa n ders J E, 
Wit hers p o o n R P, St or b R, A p pel ba u m F R, Ma rti n PJ. T hera p y f or c hr o nic graft-vers us -
 
h ost 
9 2 9 2
I R B A p pr o v e d 
D o c u m e nt R el e a s e D at e: 0 8/ 1 1/ 2 0 1 7
Pri nte d o n 1 2/ 4/ 2 0 1 8

disease: a ra n d o mize d trial c o m pari n g c ycl os p ori ne pl us pre d nis o ne vers us pre d nis o ne 
al o ne. Bl o o d. 2 0 0 2; 1 0 0: 4 8 -5 1.  
1 2.  
S ulli va n K M, Wit hers p o o n R P, St or b R, Wei de n P, Fl o ur n o y N, Da hl ber g S, Dee g 
HJ, Sa n ders J E, D o ne y K C, A p pel ba u m F R, et al. Pre d nis o ne a n d azat hi o pri ne c o m pare d 
wit h pre d nis o ne a n d place b o f or treat me nt of c hr o nic graft -v -h ost disease: pr o g n ostic 
i nfl ue nce of pr ol o n ge d t hr o m b oc yt o pe nia after all o ge neic marr o w tra ns pla ntati o n. Bl o o d. 
1 9 8 8; 7 2: 5 4 6 -5 5 4.  
1 3.  
Ar ora M, Wa g ner J E, Da vies S M, Blazar B R, Def or T, E nri g ht H, Miller WJ, 
Weis d orf D F. Ra n d o mize d cli nical trial of t hali d o mi de, c ycl os p ori ne, a n d pre d nis o ne vers us 
c ycl os p ori ne a n d pre d nis o ne as i nitial t hera p y f or c hr o nic graft -vers us -h ost disea se. Bi ol 
Bl o o d Marr o w Tra ns pla nt. 2 0 0 1; 7: 2 6 5 -2 7 3.  
1 4.  
Gil ma n A L, Sc h ultz K R, G ol d ma n F D, Sale G E, Krail o M D, C he n Z, La n g h olz B, 
Jac o bs o h n D A, C ha n K W, R ya n R E, Kellic k M, Ne u d orf S M, G o d der K, Sa n dler E S, 
Sa h de v I, Gr u p p S A, Sa n ders J E, Wall D A. Ra n d o mize d Trial of H y dr o x yc hl or o q ui ne f or 
Ne wl y Dia g n ose d C hr o nic Graft -vers us -H ost Disease i n C hil dre n: A C hil dre n's O nc ol o g y 
Gr o u p St u d y. Bi ol Bl o o d Marr o w Tra ns pla nt.  
1 5.  
Marti n PJ, St orer B E, R o wle y S D, Fl o wers M E, Lee SJ, Car pe nter P A, Wi n gar d J R, 
S ha u g h ness y  PJ, De Vette n M P, Ja gasia M, Fa y J W, va n Besie n K, G u pta V, Kit k o C, 
J o h nst o n LJ, Maziarz R T, Ar ora M, Jac o bs o n P A, Weis d orf D. E val uati o n of 
m yc o p he n olate m ofetil f or i nitial treat me nt of c hr o nic graft -vers us -h ost disease. Bl o o d. 
2 0 0 9; 1 1 3: 5 0 7 4 -5 0 8 2.  
1 6.  
K oc S, Leise nri n g W, Fl o wers M E, A nasetti C, Dee g HJ, Nas h R A, Sa n ders J E, 
Wit hers p o o n R P, A p pel ba u m F R, St or b R, Marti n PJ. T hali d o mi de f or treat me nt of patie nts 
wit h c hr o nic graft -vers us -h ost disease. Bl o o d. 2 0 0 0; 9 6: 3 9 9 5 -3 9 9 6.  
1 7.  
W olff D, Sc hle u ni n g M, v o n Hars d orf S, Bac her U, Ger bitz A, Sta dler M, A y u k F, 
Kia ni A, Sc h wer dtfe ger R, V o gelsa n g G B, K o b be G, Gra matz ki M, La witsc h ka A, M o ht y 
M, Pa vletic S Z, Grei ni x H, H oller E. C o nse ns us C o nfere nce o n Cli nical Practice i n C hr o nic 
G V H D: Sec o n d -Li ne Treat me nt o f C hr o nic Graft-vers us -H ost Disease. Bi ol Bl o o d Marr o w 
Tra ns pla nt. 2 0 1 1; 1 7: 1 -1 7.  
1 8.  
I na m ot o Y, St orer B E, Lee SJ, Car pe nter P A, Sa n d maier B M, Fl o wers M E, Marti n 
PJ. Fail ure -free s ur vi val after sec o n d-li ne s yste mic treat me nt of c hr o nic graft-vers us -h ost 
di sease. Bl o o d. 
1 9.  
M ora n E, Car b o ne F, A u g usti V, Patr o ne F, Ballestrer o A, Ne nci o ni A. Pr oteas o me 
i n hi bit ors as i m m u n os u p pressa nts: bi ol o gical rati o nale a n d cli nical e x perie nce. Se mi n 
He mat ol; 4 9: 2 7 0 -2 7 6.  
2 0.  
K oret h J, Al yea E P, M ur p h y WJ, Wel nia k L A. Pr ote as o me i n hi biti o n a n d all o ge neic 
he mat o p oietic ste m cell tra ns pla ntati o n: a re vie w. Bi ol Bl o o d Marr o w Tra ns pla nt. 
2 0 0 9; 1 5: 1 5 0 2 -1 5 1 2.  
2 1.  
S u n K, Wel nia k L A, Pa n os kaltsis -M ortari A, O' S ha u g h ness y MJ, Li u H, Bara o I, 
Ri or da n W, Sitc hera n R, W ys oc ki C, Ser o d y J S, Blazar B R, Sa yers TJ, M ur p h y WJ. 
I n hi biti o n of ac ute graft-vers us -h ost disease wit h rete nti o n of graft -vers us -t u m or effects b y 
t he pr oteas o me i n hi bit or b ortez o mi b. Pr oc Natl Aca d Sci U S A. 2 0 0 4; 1 0 1: 8 1 2 0-8 1 2 5.
 
 
9 2 9 2
I R B A p pr o v e d 
D o c u m e nt R el e a s e D at e: 0 8/ 1 1/ 2 0 1 7
Pri nte d o n 1 2/ 4/ 2 0 1 8

2 2.  
K oret h J, Ste ve ns o n K E, Ki m H T, Garcia M, H o V T, Ar ma n d P, C utler C, Ritz J, 
A nti n J H, S oiffer RJ, Al yea E P, 3r d. B ortez o mi b, tacr oli m us, a n d met h otre xate f or 
pr o p h yla xis of graft -vers us -h ost disease after re d uce d -i nte nsit y c o n diti o ni n g all o ge neic ste m 
cell tra ns pla ntati o n fr o m H L A -mis matc he d u nrelate d d o n ors. Bl o o d. 2 0 0 9; 1 1 4: 3 9 5 6 -3 9 5 9.  
2 3.  
K oret h J, Ste ve ns o n K E, Ki m H T, Mc D o n o u g h S M, Bi n dra B, Ar ma n d P, H o V T, 
C utler C, Blazar B R, A nti n J H, S oiffer RJ, Ritz J, Al yea E P, 3r d. B ortez o mi b -base d graft -
vers us -h ost disease pr o p h yla xis i n H L A -mis matc he d u nrelate d d o n or tra ns pla ntati o n. J Cli n 
O nc ol. 2 0 1 2; 3 0: 3 2 0 2 -3 2 0 8.  
2 4.  
T o disc o E, Sari na B, Casta g na L, Mazza R, Ra hal D, N ozza A, Sa nt or o A. I n hi biti o n 
of c hr o nic graft -vs -h ost disease wit h rete nti o n of a nti -m yel o ma effects b y t he pr oteas o me 
i n hi bit or b ortez o mi b. Le u k L y m p h o ma. 2 0 0 7; 4 8: 1 0 1 5 -1 0 1 8.  
2 5.  
Mate os -Maz o n J, Perez -Si m o n J A, L o pez O, Her na n dez E, Et xe barria J, Sa n Mi g uel 
J F. Use of b ortez o mi b i n t he ma na ge me nt of c hr o nic graft-vers us -h ost disease a m o n g 
m ulti ple m yel o ma patie nts rela psi n g after al l o ge neic tra ns pla ntati o n. Hae mat ol o gica. 
2 0 0 7; 9 2: 1 2 9 5 -1 2 9 6.  
2 6.  
El -C hei k h J, Mic hallet M, Na gler A, de La valla de H, Nic oli ni F E, S hi m o ni A, 
Fa uc her C, S o b h M, Re vesz D, Har da n I, F urst S, Blaise D, M o ht y M. Hi g h res p o nse rate 
a n d i m pr o ve d graft -vers us -h ost  disease f oll o wi n g b ortez o mi b as sal va ge t hera p y after 
re d uce d i nte nsit y c o n diti o ni n g all o ge neic ste m cell tra ns pla ntati o n f or m ulti ple m yel o ma. 
Hae mat ol o gica. 2 0 0 8; 9 3: 4 5 5 -4 5 8.  
2 7.  
G u pta N, et al. Cli nical p har mac o ki netics of i ntra ve n o us a n d oral M L N 9 7 0 8, a n 
i n vesti gati o nal pr oteas o me i n hi bit or: A n a nal ysis of data fr o m f o ur P hase I m o n ot hera p y 
st u dies. A S H A n n ual Meeti n g A bstracts; 2 0 1 0: 1 8 1 3. 
2 8.  
G u pta N, Sale h, M., Ve n kata kris h na n, K. Flat -d osi n g vers us B S A -base d d osi n g f or 
M L N 9 7 0 8, a n i n vesti gati o nal pr o teas o me i n hi bit or: P o p ulati o n p har mac o ki netic ( P K) 
a nal ysis of p o ole d data fr o m f o ur p hase I st u dies. A S H A n n ual Meeti n g a n d E x p ositi o n. Sa n 
Die g o, C A; 2 0 1 1.  
2 9.  
I na m ot o Y, St orer B E, Lee SJ, Car pe nter P A, Sa n d maier B M, Fl o wers M E, Marti n 
PJ. Fail ure -free s ur vi val after sec o n d-li ne s yste mic treat me nt of c hr o nic graft-vers us -h ost 
disease. Bl o o d. 2 0 1 3; 1 2 1: 2 3 4 0 -2 3 4 6.  
 
 
 
9 2 9 2
I R B A p pr o v e d 
D o c u m e nt R el e a s e D at e: 0 8/ 1 1/ 2 0 1 7
Pri nte d o n 1 2/ 4/ 2 0 1 8

1 1.     A P P E N DI C E S  
1 1. 1    St u d y C ale n d ar  
Pr o c e d ur e  
S cr e e ni n g  
B a s eli n e  
 
St u d y t h er a p y ( 2 8 d a y c y cl e s)  
 
 
 
 
1  
2  
3  
4  
5  
6  
7  
8  
9  
1 0  
1 1  
1 2  
 
I x a z o mi b 
a d mi ni str ati o n*  
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
 
F oll o w U p****  
 
 
 
3 m o nt h s  
6 m o nt h s  
9 m o nt h s ▲ 
1 2 m o nt h s  
E n d of 
Tr e at -
m e nt  
S cr e e ni n g Pr o c e d ur e s  
 
 
 
 
 
 
 
Eli gi bilit y crit eri a ** 
X  
 
 
 
 
 
 
I nf or m e d c o n s e nt 
X  
 
 
 
 
 
 
Effi c a c y A s s e s s m e nt s  
 
 
 
 
 
 
 
C hr o ni c G V H D a cti vit y  
- N I H s c or e  
- cli ni ci a n s e v erit y 
a s s e s s m e nt s  
- cli ni ci a n r e s p o n s e 
a s s e s s m e nt s  
 
 
X  
X  
X  
X  
X  
 
 
 
 
X  
P ati e nt - r e p ort e d 
o ut c o m e s  
- Q O L  
- H A P  
- L e e s y m pt o m s c al e  
-P ati e nt -r e p ort e d 
s e v erit y  
 
X  
 
X  
X  
X  
 
 
 
X  
Li v er f u n cti o n t e st s  
 
X  
X  
X  
X  
X  
X  
 F u n cti o n al m e a s ur e s  
- 2  mi n ut e w al k t e st  
 
X  
 
X  
 
X  
 
R e c or d s y st e mi c 
i m m u n e s u p pr e s si v e 
a g e nt s  
 
X  
X  
X  
X  
X  
 
X  
Bl o o d  s a m pl e s  ( T w o 
P a x g e n e t u b e s a n d o n e 
1 0 m L h e p ari n t u b e ) 
 
X  
X  
X  
 
 
 
X  
S ur vi v al a n d 
m ali g n a n c y r el a p s e  
 
 
X  
X  
X  
X  
X  
S af et y A s s e s s m e nt s  
 
 
 
 
 
 
 
Pr e g n a n c y t e st  
 
X  
 
 
 
 
 
 
C B C  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
P h y si c al e x a m  
 
X  
X  
X  
X  
X  
X  
A d v er s e e v e nt s** * 
 
X  
X  
X  
X  
X  
 
 
9 2 9 2
I R B A p pr o v e d 
D o c u m e nt R el e a s e D at e: 0 8/ 1 1/ 2 0 1 7
Pri nte d o n 1 2/ 4/ 2 0 1 8

 
* I xaz o mi b a d mi nistrati o n: Wee kl y f or 3 wee ks ( da y 1, 8, 1 5) o ut of eac h 2 8 da y c ycle f or u p 
t o a t otal of 6 c ycles  of t hera p y  ( or 1 2 c ycles if patie nt has C R/ P R or sta ble disease at 6 
m o nt hs a n d c h o oses t o c o nti n ue o n i xaz o mi b) . Acce pta ble wi n d o w f or eac h pla n ne d 
I xaz o mi b a d mi nistrati o n date is +/ - 3 da ys , base d o n t he da y of t he pre vi o us d ose i n t he 
c ycle . U na v oi da ble de viati o ns fr o m t his d osi n g sc he d ule m ust be a p pr o ve d b y t he Pri nci pal 
I n vesti gat or or St u d y C hair.  M o nit ori n g of r o uti ne la b orat or y tests ( C B C, c he mistr y, L F T) 
are per i nstit uti o nal sta n dar ds.  
 
* * Eli gi bilit y i ncl u des t he f oll o wi n g:  
- 
Re vie w of patie nt rec or ds f or c o m plia nce wit h all liste d i ncl usi o n a n d e xcl usi o n 
criteria 
- 
La b orat or y st u dies re q uire d t o meet la b orat or y criteria  
o  C B C, c he mistr y, li ver f u ncti o n tests  
- 
C o nfir mati o n of n o hist or y of HI V or he patitis B/ C  
o  If HI V a n d he patitis B/ C testi n g has bee n pre vi o usl y d o ne a n d d oc u me nte d i n 
t he patie nt rec or d, ne w testi n g at ti me of eli gi bilit y scree ni n g f or t his st u d y is 
n ot necessar y  
▪ If HI V +, t he patie nt is e xcl u de d 
o  If He patitis B ser ol o g y i n dicates pri or i nfecti o n (i.e. c ore A b p ositi ve, or 
s urface a nti ge n p ositi ve), he patitis B P C R testi n g o n peri p heral bl o o d s h o ul d 
be d o ne.  
▪ If P C R ne gati ve, t he patie nt is eli gi ble, b ut if p ositi ve, i neli gi ble. 
o  If he patitis C a nti b o d y testi n g is p ositi ve, he patitis C P C R s h o ul d be teste d i n 
peri p heral bl o o d.  
▪ If P C R ne gati ve, t he patie nt is eli gi ble, b ut if p ositi ve, i neli gi ble. 
 
* * * A E/ S A E are m o nit ore d fr o m t he ti me t he patie nt si g ns t he c o nse nt d oc u me nt t hr o u g h 3 0 
da ys f oll o wi n g t he fi nal d ose of st u d y t hera p y  
 
* * * * Acce pta ble wi n d o w f or st u d y visits at 3 , 6 , a n d 9 m o nt hs is +/ - 1 4 da ys, a n d acce pta ble wi n d o w f or 
t he 1 2 m o nt h st u d y visit is +/ - 1 m o nt h.  St u d y visit d ue dates are calc ulate d base d o n t he date of baseli ne 
visit, a n d 1 m o nt h = 2 8 da ys.  
 
▲F or patie nts w h o ha ve a C R/ P R or sta ble disease at 6 m o nt hs, a n d w h o elect t o c o nti n ue o n i xaz o mi b f or 
a n a d diti o nal 6 c ycles, t here will be a n a d diti o nal st u d y visit at 9 m o nt hs.  T his visit will occ ur at 9 m o nt hs 
re gar dless of w he n t he a d diti o nal c ycles of i xaz o mi b are starte d.  
 
 
 
 
9 2 9 2
I R B A p pr o v e d 
D o c u m e nt R el e a s e D at e: 0 8/ 1 1/ 2 0 1 7
Pri nte d o n 1 2/ 4/ 2 0 1 8

1 1. 2    
C oc kcr oft -G a ult E q u ati o n  
F or males:  
Creati ni ne Cleara nce = ( 1 4 0-a ge[ y ears]  wei g ht [ k g])  O R  
( 1 4 0– a ge[ y ears]  wei g ht [ k g])  
7 2  (ser u m creati ni ne[ m g/ d L])  
0. 8 1  (ser u m creati ni ne[m ol/ L])  
 
F or fe males:  
Creati ni ne Cleara nce  = 0. 8 5 ( 1 4 0 -a ge[ y ears]  wei g ht [ k g])  O R  0. 8 5 ( 1 4 0 -a ge[ y ears]  wei g ht [ k g])  
7 2  (ser u m creati ni ne[ m g/ d L])  
0. 8 1  (ser u m creati ni ne[m ol/ L])  
 
S o urce:  C oc kcr oft D W, Ga ult M H. Pre dicti o n of creati ni ne cleara nce fr o m ser u m creati ni ne. Ne p hr o n 
1 9 7 6; 1 6( 1): 3 1 -4 1.  
 
 
 
 
 
 
9 2 9 2
I R B A p pr o v e d 
D o c u m e nt R el e a s e D at e: 0 8/ 1 1/ 2 0 1 7
Pri nte d o n 1 2/ 4/ 2 0 1 8

9 2 9 2
 
I R B A p pr o v e d 
D o c u m e nt R el e a s e D at e: 0 8/ 1 1/ 2 0 1 7