Conditions: Chronic Graft Versus Host Disease
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 50
Healthy volunteers: no

Brief summary:
This phase II trial studies how well ixazomib citrate works in treating patients with chronic graft-versus-host disease. Chronic graft-versus-host disease is a complication of a donor bone marrow or blood cell transplant, usually occurring more than three months after transplant, in which donor cells damage the host tissue. Ixazomib citrate may be an effective treatment for chronic graft-versus-host disease.

Detailed description:
PRIMARY OBJECTIVES:

I. Determine the proportion of subjects with treatment failure by 6 months of ixazomib (ixazomib citrate) treatment for chronic graft-versus-host disease (GVHD).

SECONDARY OBJECTIVES:

I. Determine 3 month overall (complete + partial), and complete response rate.

II. Determine 6 month overall (complete + partial), and complete response rate.

III. Report overall survival, non-relapse mortality, primary malignancy relapse, failure-free survival, treatment success, and discontinuation of immune-suppressive therapy at 6 months and 1 year.

IV. Examine functional outcome (2-minute walk test) and patient-reported outcomes (Lee Chronic GVHD Symptom Scale, quality of life \[Short Form Health Survey (SF)-36, Functional Assessment of Cancer Therapy Bone Marrow Transplant (FACT-BMT)\], Human Activity Profile \[HAP\]) at study enrollment, 6 months, and 1 year.

V. Study biologic effects of proteasome inhibition.

OUTLINE:

Patients receive ixazomib citrate orally (PO) once weekly on days 1, 8, and 15. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients with complete response, partial response, or stable disease may receive an additional 6 courses of ixazomib citrate.

After completion of study treatment, patients are followed up for 6 months.

Arms:
arm 1: Patients receive ixazomib citrate PO once weekly on days 1, 8, and 15. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients with complete response, partial response, or stable disease may receive an additional 6 courses of ixazomib citrate.

Interventions: intervention 1: Ixazomib Citrate intervention 2: Laboratory Biomarker Analysis intervention 3: Quality-of-Life Assessment intervention 4: Questionnaire Administration
Intervention descriptions: intervention 1: Given PO intervention 2: Correlative studies intervention 3: Ancillary studies intervention 4: Ancillary studies

Protocol document:
Prot_SAP_000.pdf: 
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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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 
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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
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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 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
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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


•  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
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•  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
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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


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
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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


•  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   
 
 
 
 
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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.   
 
 
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•  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 
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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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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  
 
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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 
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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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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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- 
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
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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


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 
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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
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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 
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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. 
 
 
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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 
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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 
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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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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
 
-
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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 
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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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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 
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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 .
 
 
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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