A Phase II, Open-Label Study of Bortezomib (Velcade), Cladribine and Rituximab (VCR) in Advanced, Newly Diagnosed and Relapsed/Refractory Mantle Cell and Indolent Lymphomas
Phase: PHASE2
Conditions: Lymphoma, Mantle Cell Lymphoma, Indolent Lymphoma, SLL
Sponsor: University of Arizona

Versi o n 7 :  0 8/ 1 5 / 2 0 1 7  
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S T U D Y P R O T O C O L  
Pr ot oc ol N u m ber X 0 5 2 6 0  
A P h ase II, O pe n -L a bel St u d y of B ortez o mi b( Velc a de ®), Cl a dri bi ne, a n d 
Rit u xi m a b ( V C R) i n A d v a nce d, Ne wl y Di a g n ose d a n d Rel a pse d/ Refr act or y 
M a n tle Cell a n d I n d ole nt L y m p h o m as  
Pr ot oc ol Versi o n : 
 
Date of Pr ot oc ol : 
Ori gi nal  
Versi o n # 2  
Versi o n # 3  
Versi o n # 4  
 
0 4/ 0 3 / 0 9 
0 3/ 0 8/ 1 0  
0 7/ 0 1/ 1 0  
0 6/ 2 0 / 1 2 
Versi o n # 5  
Versi o n # 6  
Versi o n # 7  
 
0 2/ 2 7/ 1 3  
0 3/ 3 0/ 1 7  
0 8/ 1 5/ 1 7  
 
 
 

Versi o n 7 :  0 8/ 1 5 / 2 0 1 7  
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I n vesti g at or & St u d y Ce nter: 
Pri nci pal I n vesti gat or:  
Da niel Pers k y, M D 
U ni versit y of Ariz o na Ca ncer Ce nter  
1 5 1 5 N. Ca m p bell A ve 
T ucs o n, A Z 8 5 7 2 4- 5 0 2 4 
Tele p h o ne: ( 5 2 0) 6 2 6 - 8 9 0 8 
 
C o -PI:  
Faiz A n wer , M D 
U ni versit y of Ariz o na Ca ncer Ce nter  
1 5 1 5 N. Ca m p bell A ve 
T ucs o n, A Z 8 5 7 2 4- 5 0 2 4 
Tele p h o ne:  ( 5 2 0)  6 2 6- 0 6 6 2 
 
 
 
 
 
 
 
* V E L C A D E is t he e xcl usi ve tra de mar k of Mille n ni u m P har mace uticals, I nc., re gistere d i n t he 
U nite d States a n d i nter nati o nall y.  
 

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P R O T O C O L S U M M A R Y  
Title: A P h ase II, O pe n -L a bel St u d y of B ortez o mi b( Velc a de ®), Cl a dri bi ne, a n d Rit u xi m a b 
( V C R) i n A d v a nce d, Ne wl y Di a g n ose d a n d Rel a pse d/ Refr act or y M a n tle Cell a n d I n d ole nt 
L y m p h o m as 
 
O bjecti ves  
T he pri mar y o bjecti ve of t his st u d y is t o:  
•  
Deter mi ne 2 -y ear P F S i n patie nts wit h ma ntle cell, mar gi nal z o ne, l y m p h o plas mac ytic, s mall 
l y m p h oc ytic, a n d rela psed f ollic ular l y m p h o mas  
T he sec o n dar y o bjecti ves of t his st u d y are t o:  
•  
Deter mi ne 2 -y ear O S;  
•  
Deter mi ne C R a n d O R R;  
•  
Descri be l o n g a n d s h ort -ter m t o xicit y; 
•  
C o n d uct c orrelati ve st u dies:  
o  Deter mi ne pr o g n ostic i m p orta nce of A ur ora ki nase A i n l y m p h o ma treate d w it h V C R;   
o  Deter mi ne t he c yt o ki ne pr ofiles of eac h l y m p h o ma s u bt y pe a n d h o w t he y c ha n ge wit h 
V C R; 
o  E val uate t he pr o g n ostic i m p orta nce of maj or o n co ge nic pat h wa ys i n l y m p h o ma treate d 
wit h V C R usi n g tiss ue micr oarra y ( T M A)  
P atie nt p o p ul ati o n  
Eli gi ble patie nt s m ust ha v e o ne of t he f oll o wi n g hist ol o gies: ma ntle cell l y m p h o ma, l y m p h o plas mac ytic 
l y m p h o ma  ( Wal de nstr o m’s  macr o gl o b uli ne mia),  mar gi nal  z o ne  l y m p h o ma,  s mall  l y m p h oc ytic  
l y m p h o ma, or rela pse d f ollic ular l y m p h o ma. T he y ma y or ma y n ot ha ve bee n treate d f or t heir l y m p h o ma.  
S pecific i ncl usi o n a n d e xcl usi o n criteria are detaile d i n secti o n 3. 2 . 
N u m ber of p atie nts  
3 9  
St u d y desi g n a n d met h o d ol o g y  
Pr os pecti ve o pe n -la bel p hase II trial 
Tre at me nts a d mi nistere d  
•  
Rit u xi ma b 3 7 5 m g/ m 2 I V da y 1  
•  
Cla dri bi ne 4 m g/ m 2 I V o ver 2 h o urs da ys 1 -5  
•  
B ortez o mi b 1. 3 m g/ m 2 I V da ys 1 a n d 4  
•  
Re peat e ver y 2 8 da ys f or a ma xi m u m of 6 c y cles  
 
Effic ac y d at a c ollecte d  
T he f oll o wi n g e val uati o ns will be c o n d ucte d t o assess t he efficac y of V E L C A D E -Cla dri bi ne -Rit u xi ma b : 
•  
Assess me nt of pr o gressi o n -free s ur vi val 
•  
Assess m e nt of o verall s ur vi val  
•  
Assess me nt of res p o nse acc or di n g t o t he I nter nati o nal W or ks h o p Gr o u p res p o nse criteria ( C hes o n 

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et al., 1 9 9 9). If P E T sca n is use d f or sta gi n g, re vise d res p o nse criteria s h o ul d be use d ( C hes o n et 
al., 2 0 0 7). F or Wal de nstr o m’s Macr o gl o b uli ne mia , res p o nse assess me nt s h o ul d a d diti o nall y be 
perf or me d acc or di n g t o t he T hir d I nter nati o nal W or ks h o p o n Wal de nstr o m’s Macr o gl o b uli ne mia 
( Tre o n et al., 2 0 0 6).  
P h ar m ac o ki netic/ P h ar m ac o d y n a mic/ P h ar m ac o ge n o mic / C orrel ati ve
 st u dies 
c ollecte d 
( o pti o n al) 
T he f oll o wi n g st u dies will be c o n d ucte d t o assess t he 
p har mac o ki netics/ p har mac o d y na mics/ p har mac o ge n o mics  of V E L C A D E -Cla dri bi ne -Rit u xi ma b : 
•  
N o ne  
T he f oll o wi n g st u dies will be perf or me d at Mille n ni u m:  
•  
N o ne  
T he f oll o wi n g c orrelati ve st u dies will be perf or me d  at t he Ariz o na Ca ncer Ce nter:  
•  
Ser u m c yt o ki ne pr ofile of > 1 7 5 ser u m c yt o ki nes utilizi n g a n a nti b o d y platf or m wit h n or mal 
c o ntr ols, t o e val uate maj or c yt o ki nes i n ma ntle cell l y m p h o ma, l y m p h o plas mac ytic l y m p h o ma 
( Wal de nstr o m’s macr o gl o b uli ne mia), s mall l y m ph oc ytic l y m p h o ma, a n d f ollic ular l y m p h o ma. 
T he c ha n ges i n c yt o ki ne le vels will be c o m pare d bet wee n l y m p h o ma s u bt y pes a n d bet wee n  
res p o n ders a n d n o n-res p o n ders. 
•  
Tiss ue micr o arra y ( T M A) t o e val uate maj or o nc o ge nic pat h wa ys i n l y m p h o ma. Se parate c o nse nt 
will be re q ueste d f or a n o pti o nal bi o ps y t o assess f or p ost -t hera p y c ha n ges at c y cle 2, da y 1. I n 
partic ular, t he i m p orta nce of A ur ora ki nase A will be e val uate d.  
S afet y d at a c ollecte d  
T he f oll o wi n g e val uati o ns  will be c o n d ucte d t o assess t he safet y of V E L C A D E -Cla dri bi ne -Rit u xi ma b : 
•  
T o xicit y assess me nt usi n g C T C A E, versi o n 3. 0  
St atistic al pr oce d ures  
T he pri mar y o utc o me meas ure of t his P hase II trial is pr o gressi o n -free s ur vi val ( P F S) at 2 y ears.  T his will 
be esti mate d f or t he c o h ort a n d prese nte d al o n g wit h a p pr o priate c o nfi de nce i nter vals.  T he Ka pla n -Meier 
pr o d uct -li mit met h o d will be use d t o esti mate pr o gressi o n-free s ur vi val i n t he prese nce of ce ns ori n g.  A 2-
y ear P F S of 7 0 % or m ore w o ul d be c o nsi dere d pr o misi n g, w hile a 2 -y ear P F S of less t ha n 5 0 % w o ul d be  
disa p p oi nti n g.  T h us we will test w het her we ca n reject t he n ull h y p ot hesis of 5 0 % or less vers us t he desire d 
alter nati ve rate of 7 0 % or m ore.  Base d o n a n e xact test f or a si n gle bi n o mial pr o p orti o n at t he o ne -si de d 
0. 1 0 si g nifica nce le vel, a sa m ple size  of 3 9 patie nts w o ul d pr o vi de a p o wer of 9 0 % (i.e., ma xi m u m fals e 
ne gati ve rate of 1 0 % a n d false p ositi ve rate of 1 0 %); t his calc ulati o n ass u mes t hat all patie nts w o ul d be 
f oll o we d u ntil pr o gressi o n or f or at least 2 y ears.  All patie nts e ntere d i nt o t he trial w h o recei ve at least o ne 
d ose of treat me nt will be i ncl u de d i n t he a nal ysis.  Wit h 3 9 patie nts, t here will be greater t ha n a 9 0 % 
pr o ba bilit y of o bser vi n g a n y s pecific t y pe of a d verse e ve nt w h ose tr ue i nci de nce rate is 6 % or hi g her.  

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T A B L E O F C O N T E N T S  
1 
I N T R O D U C TI O N A N D S T U D Y R A TI O N A L E ........................................................... 1 0 
1. 1 
O ver vie w of t he Disease  ...................................................................................... 1 0 
1. 2 
V E L C A D E ( b ortez o mi b) f or I njecti o n  ................................................................ 1 0 
1. 2. 1  Scie ntific Bac k gr o u n d .............................................................................. 1 0 
1. 2. 2 
N o ncli nical P har mac ol o g y  ....................................................................... 1 1 
1. 2. 3 
N o ncli nical T o xicit y  ................................................................................ 1 3  
1. 2. 4  Cli nical P har mac o ki netics a n d P har mac o d y na mics ................................ 1 3  
1. 2. 5 
Cli nical E x perie nce  .................................................................................. 1 4  
1. 2. 6 
P ote ntial Ris ks of V E L C A D E  ................................................................. 1 8  
1. 3  
C o m bi nati o n dr u g i nf or mati o n ............................................................................ 2 2 
1. 3. 1 
Scie ntific 
Bac k gr o u n d .............................................................................................. 2 2
......................................................................................................................  
1. 3. 2  Cli nical P har mac o ki netics a n d P har mac o d y na mics ................................ 2 4 
1. 3. 3 
Cli nical E x perie nce  .................................................................................. 2 6  
1. 3. 4  P ote ntial Ris ks of Cla dri bi ne a n d Rit u xi ma b........................................... 3 1 
1. 4  
St u d y rati o nale a n d selecti o n of dr u g d oses ......................................................... 4 0 
2 
S T U D Y O BJ E C TI V E S  .................................................................................................... 4 3 
2. 1 
Pri mar y O bjecti ve  ................................................................................................ 4 3 
2. 2 
Sec o n dar y O bjecti ves  ........................................................................................... 4 3 
3 
I N V E S TI G A TI O N A L P L A N .......................................................................................... 4 4 
3. 1  
O verall Desi g n a n d Pla n of t he St u d y .................................................................. 4 4 
3. 2 
Selecti o n of Patie nts  ............................................................................................. 4 5  
3. 2. 1 
I ncl usi o n Criteria ..................................................................................... 4 5  
3. 2. 2 
E xcl usi o n Criteria  .................................................................................... 4 6  
3. 3  
St u d y Treat me nts ................................................................................................. 4 7  
3. 3. 1 
Cli nical Trial Materials  ............................................................................ 4 7  
3. 3. 2  Pre parati o n, Ha n dli n g, a n d St ora ge of Dr u gs .......................................... 4 8  
3. 3. 4 
D ose M o dificati o n a n d Dela y  .................................................................. 5 1 
3. 3. 5  Treat me nt Assi g n me nt  ............................................................................. 5 7  
3. 3. 6  Bli n di n g, Pac ka gi n g, a n d La beli n g .......................................................... 5 7  
3. 3. 7  C o nc o mita nt Treat me nt  ........................................................................... 5 7  
3. 3. 8 
Treat me nt C o m plia nce  ............................................................................. 5 8  
3. 4 
D urati o n of Treat me nt a n d Patie nt Partici pati o n  ................................................. 5 8  
3. 5 
Ter mi nati o n of Treat me nt a n d/ or St u d y Partici pati o n  ......................................... 5 8  
3. 6 
Efficac y, P har mac o d y na mic/ P har mac o ge n o mic/ C orrelati ve st u dies, a n d  
Safet y  Meas ure me nts … … … … … … … … … … … … … … … … … … … … … … … 5 8  
3. 6. 1 
C orrelati ve St u d ies … … … … … … … … … … … … … … … … … … …........ 5 9 
4 
A D V E R S E E V E N T S  ....................................................................................................... 6 4 
4. 1 
Defi niti o ns ............................................................................................................ 6 4 
4. 1. 1  A d verse E ve nt Defi niti o n ........................................................................ 6 4 
4. 1. 2 
Seri o us A d verse E ve nt Defi niti o n  ........................................................... 6 4 
4. 2  
Pr oce d ures f or A E a n d S A E Re p orti n g ............................................................... 6 5 
4. 3  
M o nit ori n g of A d verse E ve nts a n d Peri o d of O bser vati o n .................................. 6 8  
  
  
4. 3. 1 I nteri m A nal ysis of Dr u g T o xicit y… … … … … … … … … … … … … …... 6 8 

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4. 4  
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 ................................................................................................................... 6 8  
5 
S T A TI S TI C A L P R O C E D U R E S  ..................................................................................... 6 9  
5. 1 
Sa m ple Size Esti mati o n  ....................................................................................... 6 9  
5. 2 
Ra n d o mizati o n a n d Stratificati o n  ........................................................................ 6 9  
5. 3 
P o p ulati o ns f or A nal ysis  ...................................................................................... 6 9  
5. 4  
Pr oce d ures f or Ha n dli n g Missi n g, U n use d, a n d S p uri o us Data........................... 6 9  
5. 5 
Statistical Met h o ds  ............................................................................................... 6 9  
5. 5. 1. I nteri m T o xicit y A nal ysis.. … … … … … … … … … … … … … … … … … … 6 9 
5. 5. 2. C orrelati ve St u d ies... … … … … … … … … … … … … … … … … … ….......... 7 0 
6 
A D MI NI S T R A TI V E R E Q UI R E M E N T S  ....................................................................... 7 1 
6. 1  
G o o d Cli nical P ractice ......................................................................................... 7 1 
6. 2 
Et hical C o nsi derati o ns  ......................................................................................... 7 1 
6. 3  
Patie nt I nf or mati o n a n d I nf or me d C o nse nt .......................................................... 7 1 
6. 4 
Patie nt C o nfi de ntialit y  ......................................................................................... 7 1 
6. 5  
Pr ot oc ol C o m plia nce ............................................................................................ 7 1 
6. 6 
Re gistrati o n Pr oce d ure … … … … … … … … … … … … … … … … … … … … …...... 7 2 
6. 7  
St u d y Data a n d Safet y M o nit ori n g … … … … … … … … … … … … … … … …....... 7 3 
6. 8  
Dr u g Acc o u nta bilit y............................................................................................. 7 7  
6. 9  
Pre mat ure Cl os ure of t he St u d y … … … … … … … … … … … … … … … … … … … 7 7 
6. 1 0  
Rec or d Rete nti o n … … … … … … … … … … … … … … … … … … … … … … … ….. 7 7 
6. 1 1  
Pr o d uct C o m plai nts … … … … … … … … … … … … … … … … … … … … … … ….. 7 7 
7 
R E F E R E N C E S  ................................................................................................................ 7 9  
8 
A P P E N DI C E S  ................................................................................................................. 8 4 
8. 1  
St u d y Fl o w C hart ................................................................................................. 8 4 
8. 2 
Kar n ofs k y Perf or ma nce Stat us Scale  ................................................................... 8 5 
8. 3 
B o d y S urface Area Calc ulati o n  ........................................................................... 8 6 
8. 4 
Ne w Y or k Heart Ass ociati o n Classificati o n of Car diac Disease  ......................... 8 7 
8. 5 
Declarati o n of Helsi n ki  ........................................................................................ 8 8 
8. 6 
F A C T/ G O G - Ne ur ot o xicit y Q uesti o n naire, Versi o n 4. 0 ...................................... 9 2 
  
8. 7  
A n n Ar b or Classificati o n … … … … … … … … … … … … … … … … … … … … ….. 9 3 
  
8. 8  
I nter nati o nal W or ki n g Gr o u p Res p o nse Criteria … … … … … … … … … … … ….. 9 4 
  
8. 9  
U p date d Res p o nse Criteria fr o m t he 3r d I nter nati o nal W or ks h o p o n  
Wal de nstr o m's Macr o g l o b uli ne mia … … … … … … … … … … … … … … … … ….. 9 5 
  
8. 1 0  
Pr ot oc ol Si g nat ure Pa ge … … … … … … … … … … … … … …. … … … … … … ….. 9 6 
  
8. 1 1  
Tiss ue a n d Ser u m Sa m ple S u b missi o n F or m … … … … … … … … … … … … ….. 9 7 
  
8. 1 2  
S u bject Re gistrati o n  F or m … … … …... … … … … … … … … … … … … … … … …. 9 8 
  
8. 1 3  
S u bject Eli gi bilit y F or m … … … … … … … … … … …... … … … … … … … … … … 9 9 
  
8. 1 4 
Pre g na nc y Re p orti n g F or m … … … … … … … … … … … … … … … … … … ….... 1 0 1  
 
 
 
 
 

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List of T a bles a n d Fi g ures i n t he Te xt  
T a ble 1  
K n o w n A ntici p ate d Ris ks of Velc a de b y Me d D R A S yste m Or g a n            
Cl ass, O bser ve d I nci de nce a n d Preferre d Ter m … … … … … … … … …. 1 8 
T a ble 2   
S u m m ar y of Rit u x a n D at a b y Sc he d ule a n d Cli nic al Setti n g … … … … 3 0 
T a ble 3  
T he Res ults f or P F S as Deter mi ne d b y a Bli n de d, I n de pe n de nt       
Assess me nt of  Pr o gressi o n … … … … … … … … … … … … … … … … … … 3 0 
T a ble 4 
M a n a ge me nt of P atie nts wit h Velc a de -Rel ate d Ne ur o p at hic P ai n           
a n d/ or Per hi p her al Se ns or y Ne ur o p at h y … … … … … … … … … … … … 5 6 
 

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8 
A B B R E VI A TI O N S LI S T  
 

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A b bre vi ati o n  
Defi niti o n  
°C  
de grees Celsi us  
µ M  
micr o m olar  
2 0 S  
2 0 S pr oteas o me s u b u nit  
A E  
a d verse e ve nt  
A N C  
a bs ol ute ne utr o p hil c o u nt  
Bc 1 -2  
B -cell l y m p h o ma -2; a ge ne t hat i n hi bits a p o pt osis  
B S A  
b o d y s urface area  
C A M  
cell a d hesi o n m olec ules  
c m 
ce nti meter 
C H O P  
C ycl o p h os p ha mi de, D o x or u bici n, Vi ncristi ne, Pre d nis o ne  
C R  
C o m plete Res p o nse  
C T C A E  
( N CI) C o m m o n Ter mi n ol o g y Criteria  f or A d verse E ve nts 
C T E P  
Ca ncer T hera p y E val uati o n Pr o gra m  
C V P  
C ycl o p h os p ha mi de, Vi ncristi ne, Pre d nis o ne  
d L  
deciliter  
D L T  
D ose Li miti n g T o xicit y  
D N A  
de o x yri b o n ucleic aci d  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
F L  
F ollic ular L y m p h o ma  
G C P  
G o o d Cli nical Practice  
G L P  
G o o d La b orat or y Practice  
ht  
hei g ht  
Iκ B  
I ka p pa B ki nase; c yt o ki ne res p o nse ki nase t hat acti vates 
tra nscri pti o n fact or N F- ka p pa b at seri ne 3 2 a n d 3 6 
I C A M-1  
i ntercell ular a d hesi o n m olec ule 1 
I C H 
I nter nati o nal C o nfere nce o n Har m o nisati o n  
I E C 
I n de pe n de nt Et hics C o m mittee 
I N D 
I n vesti gati o nal Ne w Dr u g 
I R B 
I nstit uti o nal Re vie w B oar d 
I V 
i ntra ve n o us 
Iκ B α  
I ka p pa B al p ha-ass ociate d pr otei n ki nase  
k g  
kil o gra m  
Ki  
i n hi bit or y c o nsta nt 
l bs 
p o u n ds  
L D H  
Lactate De h y dr o ge nase  
m 2 
s q uare meters 

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1 0  
A b bre vi ati o n  
Defi niti o n  
M C L  
Ma ntle Cell L y m p h o ma  
m g  
milli gra m  
mi n  
mi n ute  
m L  
milliliter  
m m 3 
c u bic milli meters 
m m ol  
milli m ole  
M T D  
Ma xi m u m T olerate d D ose  
N CI  
Nati o nal Ca ncer I nstit ute  
N F -κ B  
n uclear fact or -κ B  
N H L  
N o n -H o d g ki n’s L y m p h o ma  
n g  
na n o gra m  
n M  
na n o m ole  
O R R  
O verall Res p o nse Rate  
p 2 1  
p 2 1(ras) far nes yl -pr otei n tra nsferase  
p 2 7  
c ycli n- de pe n de nt ki nase i n hi bit or 
p 5 3  
t u m or s u p press or pr otei n wit h m olec ular wei g ht of 5 3 k Da 
P R  
Partial Res p o nse  
P S  
Perf or ma nce Stat us  
S A E  
seri o us a d verse e ve nt 
T M A  
Tiss ue Micr oarra y  
U S  
U nite d States  
U S P  
U nite d States P har mac o peia  
V C A M -1  
vasc ular cell a d hesi o n m olec ule 1  
w/ w  
wei g ht -t o-wei g ht rati o  
W M  
Wal de nstr o m’s macr o gl o b uli ne mia  
wt  
wei g ht  

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1 1  
1  I N T R O D U C TI O N A N D S T U D Y R A TI O N A L E 
1. 1  O ver vie w of t he Dise ase  
Ma ntle cell l y m p h o ma acc o u nts f or 6 % of all n o n -H o d g ki n’s l y m p h o mas ( N H L), dia g n ose d i n 
a p pr o xi matel y 3 8 0 0 patie nts eac h year i n t he U nite d States. It is a n i nc ura ble l y m p h o ma wit h a 
me dia n o verall s ur vi val of  3-5 years, b ut wit h great varia bilit y bet wee n t he patie nts. Ma ntle cell 
l y m p h o ma is c haracterize d b y i nitial se nsiti vit y t o b ot h c he m ot hera p y a n d ra diati o n b ut als o b y 
a n i n varia ble rela pse a n d e ve nt ual resista nce t o treat me nt. T here is n o esta blis he d sta n dar d of care. 
C urre ntl y use d re gi me ns s uc h as R- h y per- C V A D/ R - M-A a n d a ut ol o g o us ste m cell tra ns pla ntati o n 
( A S C T) i n first re missi o n are n ota ble f or t heir t o xicit y. V E L C A D E is  a p pr o ve d as a si n gle a ge nt 
f or rela pse d ma ntle cell l y m p h o ma a n d is bei n g acti vel y i n vesti gate d i n c o m bi nati o n t hera p y as 
part of i nitial t hera p y, w hic h is o ne of t he mai n o bjecti ves of t his trial as well.  
 
I n d ole nt  l y m p h o mas  s uc h  as  f ollic ular,  l y m p h o plas mac ytic,  mar gi nal  z o ne,  a n d  s mall  
l y m p h oc ytic l y m p h o mas re prese nt a p pr o xi matel y a t hir d of all N H L dia g n ose d i n t he U nite d 
Sta tes, or a b o ut 2 1, 0 0 0 patie nts  a year. T he y are i nc ura ble, wit h me dia n o verall s ur vi val of 8-1 0 
years t hat varies greatl y bet wee n t he patie nts. C urre nt sta n dar d of care is watc hf ul waiti n g u ntil 
certai n treat me nt criteria are met. O nce decisi o n t o treat is ma de, t here is n o sta n dar d treat me nt 
re gi me n. Se veral c o m bi nati o n t hera p y re gi me ns are c o nsi dere d, i nc or p orati n g rit u xi ma b, a n a nti-
C D 2 0 m o n ocl o nal a nti b o d y, i n c o m bi nati o n wit h a n al k ylat or, wit h a n a nt hrac ycli ne ( +/ - a n 
al k ylat or), or wit h a p uri ne a nal og ( +/- a n al k ylat or) . C o m bi nati o ns i ncl u di n g V E L C A D E are als o 
i n vesti gate d. T his pr ot oc ol will i n vesti gate c o m bi nati o n of V E L C A D E wi t h rit u xi ma b a n d a 
p uri ne a nal o g cla dri bi ne.  
 
T he me dia n  a ge  at  dia g n osis  of  b ot h  ma ntle  cell  a n d  i n d ole nt  l y m p h o mas  liste d  a b o ve  is  
a p pr o xi matel y 6 5 years, w hic h precl u des ma n y patie nts fr o m recei vi n g i nte nsi ve c he m ot hera p y.  
T heref ore,  it  is  partic ularl y  i m p orta nt  t o  de vel o p  a  n o n -t o xic  re gi me n  t o  i n d uce  d ura ble  
re missi o ns.  
 
1. 2  V E L C A D E  ( b ortez o mi b) f or I njecti o n 
1. 2. 1  Scie ntific B ac k gr o u n d 
V E L C A D E ™ ( b ortez o mi b) f or I njecti o n is a s mall m olec ule pr oteas o me i n hi bit or de vel o pe d b y 
Mille n ni u m P har mace uticals, I nc., ( Mille n ni u m) as a n o vel a ge nt t o treat h u ma n mali g na ncies.  
V E L C A D E is c urre ntl y a p pr o ve d b y t he U nite d States F o o d a n d D r u g A d mi nistrati o n (U S F D A )  
f or t he treat me nt of patie nts wit h m ulti ple m yel o ma ( M M).  It is als o i n dicate d f or t he treat me nt 
of patie nts wit h ma ntle cell l y m p h o ma ( M C L) w h o ha ve recei ve d at least 1 pri or t hera p y.  I n t he 
E ur o pea n U ni o n ( E U), V E L C A D E  i n c o m bi nati o n wit h mel p hala n a n d pre d nis o ne is i n dicate d 
f or t he treat me nt of patie nts wit h pre vi o usl y u ntreate d M M w h o are n ot eli gi ble f or hi g h- d ose 
c he m ot hera p y wit h b o ne marr o w tra ns pla nt.  V E L C A D E  is i n dicate d as m o n ot hera p y f or t he 
treat me nt of pr o gressi ve M M i n patie nts w h o ha ve recei ve d at least 1 pri or t hera p y a n d w h o ha ve 
alrea d y u n der g o ne or are u ns uita ble f or b o ne marr o w tra ns pla ntati o n.  

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B y i n hi biti n g a si n gle m olec ular tar get, t he pr oteas o me, b ortez o mi b affects m ulti ple si g nali n g 
pat h wa ys.  T he a n ti-ne o plastic effect of b ortez o mi b li kel y i n v ol ves se veral disti nct mec ha nis ms, 
i ncl u di n g i n hi biti o n of cell gr o wt h a n d s ur vi val pat h wa ys, i n d ucti o n of a p o pt osis, a n d i n hi biti o n 
of e x pressi o n of ge nes t hat c o ntr ol cell ular a d hesi o n, mi grati o n a n d a n gi o ge nesis.  T h us, t he 
mec ha nis ms b y w hic h b ortez o mi b elicits its a ntit u m or acti vit y ma y var y a m o n g t u m or t y pes, a n d 
t he e xte nt t o w hic h eac h affecte d pat h wa y is critical t o t he i n hi biti o n of t u m or gr o wt h c o ul d als o 
differ.  B ortez o mi b has a n o vel patter n of c yt o t o xicit y i n Nati o nal Ca ncer I nstit ute ( N CI) i n vitr o  
a n d i n vi v o assa ys (A da ms  et al., 1 9 9 9).  I n a d diti o n, b ortez o mi b has c yt ot o xic acti vit y i n a variet y 
of xe n o graft t u m or m o dels, b ot h as a si n gle a ge nt a n d i n c o m bi nati o n wit h c he m ot hera p y a n d 
ra diati o n (Stei ner et al ., 2 0 0 1; Teic her et al., 1 9 9 9; C usac k et al., 2 0 0 1; Le B la nc et al., 2 0 0 2; Pi n k 
et al., 2 0 0 2).  N ota bl y, b ortez o mi b i n d uces a p o pt osis i n cells t hat o ver e x press bcl-2, a ge netic 
trait  t hat  c o nfers  u nre g ulate d  gr o wt h  a n d  resista nce  t o  c o n ve nti onal c he m ot hera pe utics  
( Mc C o n ke y et al., 1 9 9 9). 
 
B ortez o mi b is t h o u g ht t o be efficaci o us i n m ulti ple m yel o ma via its i n hi biti o n of n uclear fact or 
κ B ( N F -κ B) acti vati o n, its atte n uati o n of i nterle u ki n -6 (I L - 6)-me diate d cell gr o wt h, a direct 
a p o pt otic effect,  a n d p ossi bl y a nti-a n gi o ge nic a n d ot her effects ( Hi des hi ma et al., 2 0 0 1). 
 
T he mec ha nis ms of acti o n lea di n g u p t o a p o pt osis ha ve bee n m ore clearl y defi ne d a n d i ncl u de 
i nitiati o n of t he u nf ol de d pr otei n res p o nse a n d direct/i n direct effects o n vari o us m olec ular tar gets 
i ncl u di n g  cell  c ycle  c o ntr ol  pr otei ns  p 2 7  a n d  p 2 1,  c ycli ns,  si g nal  tra ns d ucti o n  m olec ules,  
tra nscri pti o n fact ors c-j u n a n d HI F 1-α , t u m or s u p press or pr otei n p 5 3, a n gi o ge nesis fact ors, a n d 
ma n y ot hers.  B ortez o mi b is t h o u g ht t o be efficaci o us i n ma ntle cell l y m p h o ma b y i n hi biti n g p 2 7 
de gra dati o n, lea di n g t o cell c ycle arrest a n d a p o pt osis. I ncrease d pr oteas o me de gra dati o n of p 2 7 
has bee n ass ociate d wit h decrease d s ur vi val i n ma ntle cell l y m p h o ma ( C hiarle et al, 2 0 0 0). T he 
mec ha nis m of acti vit y i n ot her l y m p h o ma s u bt y pe has n ot bee n el uci date d, b ut ma y be relate d t o 
t he i n hi biti o n of n uclear fact or κ B ( N F -κ B) acti vati o n  ( O’ C o n n or et al, 2 0 0 5).  
1. 2. 2  N o ncli nic al P h ar m ac ol o g y  
P har mac o ki netic ( P K) a n d p har mac o d y na mic st u dies were c o n d ucte d i n t he rat a n d c y n o m ol g us 
m o n ke y.  U p o n i ntra ve n o us (I V) b ol us a d mi nistrati o n, b ortez o mi b dis pla ys a ra pi d distri b uti o n 
p hase (t ½ α  < 1 0 mi n utes) f oll o we d b y a l o n ger eli mi nati o n p hase (t ½ β  5 –1 5 h o urs).  B ortez o mi b 
has a lar ge v ol u me of distri b uti o n (ra n ge 5 – 5 0 L/ k g).  T he plas ma P K pr ofile is well descri be d b y 
a 2-c o m part me nt m o del.  
 
T he p har mac o d y na mic acti o n of b ortez o mi b is well esta blis he d a n d ca n be meas ure d t hr o u g h a n 
e x vi v o assa y ( 2 0 S pr oteas o me acti vit y) ( Li g htca p et al., 2 0 0 0).  T his assa y was use d t o deter mi ne 
t he d urati o n of dr u g effect i n lie u of t he P K data i n t he earl y precli nical t o xic ol o g y st u dies as well 
as t o set a g ui de f or d ose escalati o n i n h u ma ns.  F oll o wi n g d osi n g wit h b ortez o mi b i n t he rat a n d 
c y n o m ol g us m o n ke y, pr oteas o me i n hi biti o n i n peri p heral bl o o d ha d a half -life less t ha n 2 4 h o urs, 
wit h pr oteas o me acti vit y ret ur ni n g t o pretreat me nt baseli ne wit hi n 2 4 h o urs i n m o n ke y a n d wit hi n 
4 8 t o 7 2 h o urs i n rat after a si n gle d ose of b ortez o mi b.  F urt her, i nter mitte nt b ut hi g h i n hi biti o n 
( > 7 0 %) of pr oteas o me acti vit y was better t olerate d t ha n s ustai ne d i n hi biti o n.  T h us, a t wice -

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wee kl y cli nical d osi n g re gi me n was c h ose n i n or der t o all o w ret ur n of pr oteas o me acti vit y t o war ds 
baseli ne bet wee n d ose a d mi nistrati o ns.  
1. 2. 3  N o ncli nic al T o xic it y 
Si n gle- d ose I V t o xicit y st u dies were c o n d ucte d wit h b ortez o mi b i n t he m o use, rat, d o g, a n d 
m o n ke y t o esta blis h t he si n gle -d ose ma xi m u m t olerate d d ose ( M T D).  T he M T Ds were 0. 2 5 
m g/ k g ( 1. 5 m g/ m 2) a n d 0. 0 6 7 m g/ k g ( 0. 8 m g/ m2) i n t he 2 m ost se nsiti ve s pecies, rat a n d m o n ke y, 
res pectivel y. 
 
Re peat -d ose m ulti -c ycle t o xicit y st u dies of 3 a n d 6 m o nt hs i n t he rat a n d 9 m o nt hs i n t he m o n ke y, 
eac h  wit h  8-wee k  rec o ver y  peri o ds,  were  c o n d ucte d  t o  c haracterize  t he  c hr o nic  t o xicit y  of  
b ortez o mi b w he n a d mi nistere d b y t he cli nical r o ute a n d re gi me n of a d mi nistrati o n.  T he M T D i n 
t he  6-m o nt h  rat  st u d y  was  0. 1 0  m g/ k g  ( 0. 6  m g/ m 2)  a n d  t he  ke y  tar get  or ga ns  were  t he  
gastr oi ntesti nal ( GI) tract, he mat o p oietic a n d l y m p h oi d s yste ms.  T he M T D i n t he 9 - m o nt h 
m o n ke y  st u d y  was  0. 0 5  m g/ k g  ( 0. 6  m g/ m 2)  a n d  t he  key  tar get  or ga ns  were  t he  GI  tract,  
he mat o p oietic a n d l y m p h oi d s yste ms, peri p heral ner v o us s yste m, a n d ki d ne y.  F ull or partial 
re versi bilit y was o bser ve d f or eac h of t he t o xicities descri be d t o date.   
 
I n ge neral, t he nat ure of t he t o xicit y of b ortez o mi b is si milar acr oss s pecies, a n d tar get or ga ns of 
t o xicit y i n a ni mals ha ve bee n lar gel y pre dicti ve of h u ma n t o xicit y.  T he t o xicit y of b ortez o mi b i n 
a ni mals is c haracterize d b y a stee p d ose -res p o nse wit h m ortalit y see n at d osa ges a b o ve t he M T D.  
T he ca use of  deat h at ac utel y let hal d osa ges is c o nsi dere d t o be relate d t o i n direct car di o vasc ular 
( C V) effects of h y p ote nsi o n a n d vasc ular c ha n ges wit h sec o n dar y bra d ycar dia a n d t he ca use of 
deat h i n l o n g- ter m st u dies has bee n attri b ute d t o GI or he mat ol o gic t o xicit y.  T he p har mac ol o gic 
effects  of  b ortez o mi b  o n  t he  C V  s yste m  ha ve  bee n  e xte nsi vel y  c haracterize d  a n d  ha ve  
de m o nstrate d t hat i n direct effects o n C V f u ncti o n occ ur o nl y at ac utel y let hal d osa ges a n d are 
a br o gate d b y r o uti ne s u p p orti ve care. 
 
A d diti o nal  detai le d  i nf or mati o n  re gar di n g  t he  n o ncli nical  p har mac ol o g y  a n d  t o xic ol o g y  of  
b ortez o mi b ma y be f o u n d i n t he m ost rece nt I n vesti gat or’s Br oc h ure 
1. 2. 4  Cli nic al P h ar m ac o ki netics a n d P h ar m ac o d y n a mics  
T he cli nical p har mac ol o g y c haracterizati o n of b ortez o mi b has bee n deter mi ne d fr o m p hase  1 
st u dies i n s u bjects wit h s oli d t u m ors a n d he mat ol o gical mali g na ncies, a n d c o nfir me d i n p hase 2 
st u dies i n s u bjects wit h m ulti ple m yel o ma. 
 
B ortez o mi b  de m o nstrates  m ulti -c o m part me ntal  p har mac o ki netics.  F oll o wi n g  i ntra ve n o us  
a d mi nistratio n of 1. 0 m g/ m 2 a n d 1. 3 m g/ m 2 d ose, t he mea n first -d ose ma xi m u m o bser ve d plas ma 
c o nce ntrati o ns of b ortez o mi b were 5 7 a n d 1 1 2  n g/ m L, res pecti vel y i n 1 1 patie nts wit h m ulti ple 
m yel o ma a n d creati ni ne cleara nce val ues > 5 0 m L/ mi n partici pati n g i n a p har mac o ki netics st u d y.  
I n s u bse q ue nt d oses, mea n ma xi m u m o bser ve d plas ma c o nce ntrati o ns ra n ge d fr o m 6 7 t o 1 0 6 
n g/ m L f or t he 1. 0 m g/ m 2 d ose a n d 8 9 t o 1 2 0 n g/ m L f or t he 1. 3 m g/ m 2 d ose.  T he mea n eli mi nati o n 
half- life  of  b ortez o mi b  u p o n  m ulti ple  d osi n g  ra n ge d  fr o m  4 0  t o  1 9 3 h o urs.   B ortez o mi b  is  
eli mi nate d m ore ra pi dl y f oll o wi n g t he first d ose.  Mea n T otal B o d y Cleara nces were 1 0 2 a n d 1 1 2 

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L/ h f oll o wi n g t he first d ose f or d oses of 1 . 0 m g/ m2 a n d 1. 3 m g/ m 2, res pecti vel y, a n d ra n ge d fr o m 
1 5 t o 3 2 L/ h f oll o wi n g s u bse q ue nt d oses f or d oses of 1. 0 a n d 1. 3  m g/ m 2, res pecti vel y.  Cli nical 
e x perie nce  has  s h o w n  t hat  t he  c ha n ge  i n  cleara nce  d oes  n ot  res ult  i n  o vert  t o xicit y  fr o m  
acc u m ulati o n i n t his m ulti d ose re gi me n i n h u ma ns. 
 
I n s u bjects wit h a d va nce d mali g na ncies, t he ma xi m u m p har mac o d y na mic effect (i n hi biti o n of 
2 0 S acti vit y) occ urre d wit hi n 1 -h o ur p ost d ose.  At t he t hera pe utic d ose of 1. 3 m g/ m 2 i n s u bjects 
wit h m ulti ple m yel o ma, t he mea n pr oteas o me i n hi biti o n at 1 -h o ur p ost d ose was a p pr o xi matel y 
6 1 %. 
T he ti me c o urse of pr oteas o me i n hi biti o n i n s u bjects is c haracterize d b y ma xi m u m i n hi biti o n 
o bser ve d wit hi n t he first h o ur after a d mi nistrati o n, f oll o we d b y partial rec o ver y of pr oteas o me 
acti vit y o ver t he ne xt 6 t o 2 4 h o urs t o wit hi n 5 0 % of t he pretreat me nt acti vit y.  O n t he Da y 1, 4, 
8, a n d 1 1 sc he d ule, varia ble ( 1 0 % – 3 0 %) le vels of pr oteas o me i n hi biti o n ha ve bee n o bser ve d at 
ne xt sc he d ule d d osi n g.  I n t he or y, t his a d va nta ge all o ws cells t o rec o ver pr oteas o me acti vit y f or 
n or mal cell ular h o use kee pi n g f u ncti o ns bet wee n d oses. 
 
T he relati o ns hi p bet wee n b ortez o mi b plas ma c o nce ntrati o ns a n d pr oteas o me i n hi biti o n ca n be 
descri be d b y a ma xi m u m effect ( E ma x ) m o del.  T he E ma x  c ur ve is i nitiall y ver y ste e p, wit h s mall 
c ha n ges i n plas ma b ortez o mi b c o nce ntrati o n o ver t he ra n ge of 0. 5 t o 2. 0 n g/ m L relati n g t o lar ge 
i ncreases i n t he perce nt i n hi biti o n ( 0– 6 0 %).  After t hat, a platea u occ urs w here mar gi nal i ncreases 
of  pr oteas o me  i n hi biti o n  are  o bser ve d  i n  s pite  of  lar ge  c ha n ges  i n  plas ma  b ortez o mi b  
c o nce ntrati o ns.  
1. 2. 5  Cli nic al E x perie nce  
It is esti mate d t hat as of J u ne 2 0 1 1, m ore t ha n 3 0 0, 0 0 0 patie nts ha ve bee n  treate d wit h V E L C A D E, 
i ncl u di n g  patie nts  treate d  t hr o u g h  Mille n ni u m-s p o ns ore d  cli nical  trials,  I n vesti gat or-I nitiate d 
St u dies,  t he  U S  N CI  Ca ncer  T hera p y  E val uati o n  Pr o gra m  ( C T E P),  a n d  wit h  c o m merciall y  
a vaila ble dr u g.  V E L C A D E has bee n c o m merciall y a vaila ble si nce 1 3 Ma y 2 0 0 3. 
 
T he o verall g oal of t he Mille n ni u m p hase 1 pr o gra m was t o deter mi ne t he M T D a n d d ose -li miti n g 
t o xicit y ( D L T) of V E L C A D E i n a n u m ber of t hera pe utic setti n gs i n v ol vi n g s u bjects wit h vari o us 
a d va nce d mali g na ncies.  I n a P hase I trial i n patie nts wit h refract or y he mat ol o gic mali g na ncies, 
t he M T D f or a t wice wee kl y d osi n g f or 4 wee ks of a 4 2 da y c ycle was 1. 0 4 m g/ m2/d ose, wit h 
D L Ts of t hr o m b oc yt o pe nia, h y p o natre mia, h y p o kale mia, fati g ue, a n d malaise  ( Orl o ws ki et al., 
2 0 0 2).   T he t o xicit y was greatest d uri n g t he t hir d a n d f o urt h wee ks of t hera p y. I n t he 3-wee k 
sc he d ule of V E L C A D E m o n ot hera p y ( 4 d oses, gi ve n o n Da ys 1, 4, 8, a n d 1 1 of a 2 1-da y treat me nt 
c ycle), t he D L T occ urre d at 1. 5 6 m g/ m 2/ d ose ( 3 s u bjects wit h Gra de 3 diarr hea a n d 1 wit h 
peri p heral se ns or y ne ur o pat h y).  T heref ore, t he M T D at t his  sc he d ule was 1. 3 m g/ m 2/ d ose.  I n a 
3 5- da y treat me nt c ycle wit h 4 wee kl y d oses of V E L C A D E m o n ot hera p y, t he M T D was 1. 6 
m g/ m 2/ d ose a n d D L T i ncl u de d h y p ote nsi o n, tac h ycar dia, diarr hea, a n d s y nc o pe.   
 
I n p hase 1 cli nical st u dies, a nti-t u m or acti vit y was re p orte d i n s u bjects wit h N H L , m ulti ple 
m yel o ma, Wal de nstr ö m’s Macr o gl o b uli ne mia , s q ua m o us cell carci n o ma of t he nas o p har y n x, 
br o nc h oal ve olar carci n o ma of t he l u n g, re nal cell carci n o ma, a n d pr ostate ca ncer. 

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T he safet y a n d efficac y of V E L C A D E i n s u bjects wit h  m ulti ple m yel o ma were i n vesti gate d i n 
t w o p hase 2 cli nical st u dies, st u dies M 3 4 1 0 0-0 2 4 (s u bjects wit h first rela pse) (Ja ga n nat h et al, 
2 0 0 4 ) a n d M 3 4 1 0 0 -0 2 5 (s u bjects wit h sec o n d or greater rela pse a n d refract or y t o t heir last pri or 
t hera p y) ( Ric har ds o n  et al,  2 0 0 3).   I n  M 3 4 1 0 0 -0 2 5,  2 0 2  hea vil y  pre -treate d  s u bjects  wit h  
refract or y m ulti ple m yel o ma after at least 2 pre vi o us treat me nts recei ve d V E L C A D E, 1. 3 m g/ m2 
o n Da ys 1, 4, 8, a n d 1 1 of a 2 1- da y treat me nt c ycle. T he E ur o pea n Gr o u p f or Bl o o d a n d Marr o w 
Tra n s pla nt ( E B M T) res p o nse criteria, as descri be d b y Bla de ( Bla de et al., 1 9 9 8) were utilize d t o 
deter mi ne disease res p o nse.  C Rs were o bser ve d i n 4 % of s u bjects, wit h a n a d diti o nal 6 % of 
patie nts meeti n g all criteria f or C R b ut ha vi n g a p ositi ve i m m u n ofi xati o n test.  P R or better was 
o bser ve d i n 2 7 % of s u bjects, a n d t he o verall res p o nse rate ( C R, P R a n d mi n or res p o nse [M R ] 
c o m bi ne d) was 3 5 %.  Se ve nt y perce nt of s u bjects e x perie nce d sta ble disease or better.   
 
T he p hase 3 st u d y ( M 3 4 1 0 1 - 0 3 9) ( Ric har ds o n et al, 2 0 0 5), als o referre d t o as t he A P E X st u d y, 
was desi g ne d t o deter mi ne w het her V E L C A D E pr o vi de d be nefit (ti me t o pr o gressi o n [ T T P], 
res p o nse rate, a n d s ur vi val) t o patie nts wit h rela pse d or refract or y M M relati ve t o treat me nt wit h 
hi g h- d o se de xa met has o ne.  T he st u d y was als o desi g ne d t o deter mi ne t he safet y a n d t olera bilit y 
of V E L C A D E relati ve t o hi g h -d ose de xa met has o ne, a n d w het her treat me nt wit h V E L C A D E was 
ass ociate d wit h s u peri or cli nical be nefit a n d q ualit y of life relati ve t o hi g h - d ose de xa met has o ne. 
A t otal of 6 6 9 patie nts were e nr olle d a n d 6 6 3 patie nts recei ve d st u d y dr u g ( V E L C A D E: 3 3 1; 
de xa met has o ne: 3 3 2).  Patie nts ra n d o mize d t o V E L C A D E  recei ve d 1. 3 m g/ m2 I. V. p us h t wice 
wee kl y o n da ys 1, 4, 8, a n d 1 1 of a 3 -wee k c ycle f or u p t o e i g ht treat me nt c ycles as i n d ucti o n 
t hera p y, f oll o we d b y 1. 3 m g/ m2 V E L C A D E  wee kl y o n da ys 1, 8, 1 5, a n d 2 2 of a 5 -wee k c ycle 
f or t hree c ycles as mai nte na nce t hera p y. Patie nts ra n d o mize d t o de xa met has o ne recei ve d oral 
de xa met has o ne 4 0 m g o nce dail y o n da ys 1  t o 4, 9 t o 1 2, a n d 1 7 t o 2 0 of a 5-wee k c ycle f or u p t o 
f o ur treat me nt c ycles as i n d ucti o n t hera p y, f oll o we d b y de xa met has o ne 4 0 m g o nce dail y o n da ys 
1 t o 4 f oll o we d of a 4 -wee k c ycle f or fi ve c ycles as mai nte na nce t hera p y. T he E ur o pea n Gr o u p 
f or Bl o o d an d Marr o w Tra ns pla nt ( E B M T) res p o nse criteria, as descri be d b y Bla de ( Bla de et al., 
1 9 9 8) were utilize d t o deter mi ne disease res p o nse.  T here was a 7 8 % i ncrease i n T T P f or t he 
V E L C A D E  ar m. Me dia n T T P was 6. 2 m o nt hs f or t he V E L C A D E  ar m a n d 3. 5 m o nt hs f or t h e 
de xa met has o ne ar m ( P <. 0 0 0 1). C R (c o m plete res p o nse) + P R ( partial res p o nse) was 3 8 % wit h 
V E L C A D E  vs. 1 8 % wit h de xa met has o ne ( P < . 0 0 0 1). C R was 6 % wit h V E L C A D E  vs. < 1 % wit h 
de xa met has o ne  ( P <. 0 0 0 1).  T he  C R  +  n C R  rate  was 1 3 %  wit h  V E L C A D E  vs.  2 %  wit h  
de xa met h as o ne. I n patie nts w h o ha d recei ve d o nl y o ne pri or li ne of treat me nt ( V E L C A D E: 1 3 2; 
de xa met has o ne:  1 1 9) ,  C R  +  P R  was  4 5 %  wit h  V E L C A D E  vs.  2 6 %  wit h  de xa met has o ne  
(P =. 0 0 3 5). Wit h a me dia n 8. 3 m o nt hs of f oll o w -u p, o verall s ur vi val was si g nifica ntl y l o n ger 
(P = . 0 0 1 3)  f or  patie nts  o n  t he  V E L C A D E  ar m  vs.  patie nts  o n  t he de xa met has o ne  ar m.  T he  
pr o ba bilit y  of  s ur vi val  at  o ne  year  was  8 0 %  f or  t he  V E L C A D E  ar m  vs.  6 6 %  f or  t he  
de xa met has o ne ar m, w hic h re prese nte d a 4 1 % decrease d relati ve ris k of deat h i n t he first year 
wit h V E L C A D E  (P =. 0 0 0 5). I n patie nts w h o ha d recei ve d o nl y o ne pri or li ne of treat me nt, t he 
pr o ba bilit y  of  s ur vi val  at  o ne  year  was  8 9 %  f or  t he  V E L C A D E  ar m  vs.  7 2 %  f or  t he  
de xa met has o ne ar m, w hic h re prese nte d a 6 1 % decrease d relati ve ris k of deat h i n t he fi rst year 
wit h V E L C A D E  (P =. 0 0 9 8). U p date d res p o nse rates a n d s ur vi val data were re p orte d f or M 3 4 1 0 1-
0 3 9 ( Ric har ds o n A S H, 2 0 0 5 ). T he u p date d C R (c o m plete res p o nse) + P R ( partial res p o nse) rate 
was 4 3 % wit h V E L C A D E. T he C R + n C R rate was 1 6 % wit h V E L C A D E.  Wit h a me dia n 2 2 
m o nt hs of f oll o w -u p, o verall s ur vi val was si g nifica ntl y l o n ger f or patie nts o n t he V E L C A D E  ar m 

Versi o n 7 :  0 8/ 1 5 / 2 0 1 7  
1 6  
vs. patie nts o n t he de xa met has o ne ar m. T he me dia n o verall s ur vi val was 2 9. 8 m o nt hs ( 9 5 % CI: 
2 3. 2,  n ot  esti ma ble)  f or  t he  V E L C A D E  ar m vs  2 3. 7  m o nt hs  ( 9 5 %  CI:  1 8. 7,  2 9. 1)  f or  t he  
de xa met has o ne ar m  ( hazar d rati o = 0. 7 7, P = 0. 0 2 7 2). T he pr o ba bilit y of s ur vi val at o ne year was 
8 0 % f or t he V E L C A D E  ar m vs. vs 6 7 % f or t he de xa met has o ne ar m (P = 0. 0 0 0 2).    
 
T he safet y a n d efficac y of V E L C A D E i n rela pse d or  refract or y ma ntle cell l y m p h o ma ( M C L) 
were i n vesti gate d i n a n i nter nati o nal, p hase 2, m ultice nter st u d y M 3 4 1 0 3 -0 5 3, als o referre d t o as 
t he PI N N A C L E st u d y( Fis her et al, 2 0 0 6).  T he si n gle-ar m st u d y was desi g ne d t o e val uate t he 
res p o nse rates, d urati o n of res p o nse ( D O R), T T P, o verall s ur vi val ( O S), a n d safet y of V E L C A D E 
treat me nt i n patie nts wit h rela pse d or refract or y ma ntle cell l y m p h o ma.  F or 1 4 1 e val ua ble 
patie nts, t he res p o nse rate was 3 1 % ( 8 % C R/ u nc o nfir me d C R [ Cr u]).  Me dia n ti me t o res p o nse 
was 4 0 da ys (ra n ge 3 1 -2 0 4 da ys).  T he me dia n n u m ber of c ycles a d mi nistere d acr oss all patie nts 
was 4; i n res p o n di n g patie nts, t he me dia n n u m ber of c ycles was 8.  T he me dia n D O R b y al g orit h m 
was 9. 2 m o nt hs a n d 1 3. 5  m o nt hs i n patie nts wit h C R/ C R u.  Me dia n T T P f or b ot h gr o u ps was 6. 2 
m o nt hs.  Wit h a me dia n f oll o w -u p of 1 3. 4 m o nt hs, o verall s ur vi val ha d n ot bee n reac he d.  T he 
m ost  c o m m o nl y  re p orte d  a d verse  e ve nts  ( A Es)  were  fati g ue,  peri p heral  ne ur o pat h y,  a n d  
gastr oi ntesti nal e ve nts.  A ti me -t o-e ve nt u p date t o t he PI N N A C L E st u d y  ( G o y et al, 2 0 0 7) was 
re p orte d after a me dia n f oll o w-u p of 2 6. 4 m o nt hs.  T T P was 6. 7 m o nt hs f or all patie nts, 1 2. 4 
m o nt hs i n all res p o n ders.  T he me dia n D O R was 9. 2 m o nt hs i n all res p o n ders a n d ha d n ot bee n 
reac he d i n patie nts ac hie vi n g C R/ Cr u.  O verall s ur vi val was 2 3. 5  m o nt hs i n all patie nts a n d 3 6 
m o nt hs i n patie nts wit h C R/ Cr u.  S ur vi val at 1 2 m o nt hs was 6 9 % o verall a n d 9 1 % i n res p o n di n g 
patie nts.  
T he p hase 3 st u d y ( M M Y 3 0 0 2) k n o w n as t he VI S T A st u d y, e val uate d t he safet y a n d efficac y of 
t he c o m bi nati o n of V E L C A D E, mel p hala n, a n d pre d nis o ne i n pre vi o usl y u ntreate d m ulti ple 
m yel o ma patie nts w h o were n ot ca n di dates f or ste m cell tra ns pla nt  ( Sa n Mi g uel, 2 0 0 8).  T he st u d y 
was desi g ne d t o deter mi ne t he be nefit of a d di n g V E L C A D E t o M P ( mel p hala n a n d  pre d nis o ne) 
as assesse d b y T T P.  Patie nts ( 6 8 2) were ra n d o mize d t o recei ve ni ne 6 -wee k c ycles of mel p hala n 
9 m g/ m 2 a n d pre d nis o ne 6 0  m g/ m 2 o n Da ys 1 t o 4, al o ne or i n c o m bi nati o n wit h V E L C A D E 1. 3 
m g/ m 2 b y I V b ol us o n Da ys  1, 4, 8, 1 1, 2 2, 2 5, 2 9, a n d 3 2 d uri n g C ycles 1 t o 4, a n d o n Da ys 1, 8, 
2 2, a n d 2 9 d uri n g C ycles 5 t o 9.  Res p o nse was e val uate d e ver y 3 wee ks usi n g t he E B M T criteria.  
At a pre pla n ne d i nteri m a nal ysis, t he i n de pe n de nt data m o nit ori n g c o m mittee rec o m me n de d t hat 
t he st u d y be st o p pe d si nce t he pres pecifie d statistical b o u n dar y e n d p oi nt of T T P ha d bee n cr osse d.  
Res p o nse rates were 3 0 % wit h 4 % C R.  T he rates of partial res p o nse or better were 7 1 % i n t he 
V E L C A D E ( V M P) gr o u p c o m pare d t o 3 4 % i n t he M P gr o u p ( p  = 0. 0 0 1).  Wit h f oll o w -u p of 1 6. 3 
m o nt hs, t he T T P f or t he V M P gr o u p was 2 4 m o nt hs c o m pare d t o 1 6. 6 m o nt hs i n t he M P gr o u p 
( p = 0. 0 0 0 0 0 1) a n d was ass ociate d wit h a 5 2 % re d uce d ti me t o pr o gressi o n.  T he me dia n D O R 
was 1 9. 9 m o nt hs i n t he V M P gr o u p a n d 1 3. 1 m o nt hs i n t he M P gr o u p.  O verall s ur vi val ha d n ot 
bee n reac he d i n eit her gr o u p.  He mat ol o gic t o xicit y was si milar i n b ot h gr o u ps.  T he i nci de nce of 
peri p heral se ns or y ne ur o pat h y a n d gastr oi ntesti nal s y m pt o ms was hi g her i n t he V M P gr o u p.  T he 
i nci de nce  of  her pes  z oster was  3 %  i n  patie nts  i n  t h e  V M P  gr o u p  w h o  recei ve d  a nti viral  
pr o p h yla xis.  Fiftee n perce nt of patie nts i n t he V M P gr o u p disc o nti n ue d t hera p y d ue t o A Es 
c o m pare d t o 1 4 % i n t he M P gr o u p. 

Versi o n 7 :  0 8/ 1 5 / 2 0 1 7  
1 7  
T he VI S T A st u d y u p date after e xte n de d f oll o w -u p of 2 5. 9 m o nt hs,  ( Sa n Mi g uel et al, 2 0 0 8) 
c o nfir me d a s ur vi val be nefit f or t he V M P gr o u p.  O verall s ur vi val was n ot reac he d i n eit her gr o u p:  
V M P gr o u p ( 7 5) deat hs, 3 year O S 7 2 %; M P gr o u p ( 1 1 1) deat hs, 3 year O S 5 9 % ( p  = 0. 0 0 3 2).  
Patie nts o n V M P were less li kel y t o start sec o n d -li ne t hera p y ( V M P 3 8 % vs M P 5 7 % at t he ti me 
of data c ut -off) wit h a l o n ger ti me t o ne xt t hera p y ( T N T) a n d treat me nt free i nter val ( T FI).  Of 
t he M P patie nts w h o recei ve d s u bse q ue nt t hera p y, 4 3 % we nt o n t o recei ve V E L C A D E. 
Base d o n i n vesti gat or -re p orte d best res p o nses t o s u bse q ue nt t hera pies, patie nts rela psi n g after 
t hera p y wit h a n o vel a ge nt were n ot i ntri nsicall y m ore resista nt t ha n after recei vi n g a tra diti o nal 
a ge nt. 
I n t he VI S T A st u d y, V M P was ass ociate d wit h pr ol o n ge d T T P, T N T, T FI, a n d O S.  Patie nts were 
s uccessf ull y treate d wit h s u bse q ue nt I Mi D -base d t hera p y a n d retreate d wit h V E L C A D E.  After 
3 6. 7 m o nt hs f oll o w -u p, O S c o nti n ue d t o be s u peri or f or V M P.   T he O S f or V M P ha d n ot yet bee n 
reac he d c o m pare d t o M P ( 4 3. 1 m o nt hs) ( Mate os et al, 2 0 0 9). I n a n u p date d a nal ysis of o verall 
s ur vi val base d o n 3 8 7 deat hs ( me dia n f oll o w-u p 6 0. 1 m o nt hs), t he me dia n o verall s ur vi val f or 
V M P was 5 6. 4 m o nt hs a n d t he M P was 4 3. 1 m o nt hs, wit h a hazar d rati o n of 0. 6 9 5 ( 9 5 % CI: 0. 5 7, 
0. 8 5).  
 
V E L C A D E i n ma ntle cell a n d i n d ole nt l y m p h o mas  
 
V E L C A D E was i n vesti gate d i n t w o p hase II trials i n rela pse d/refract or y  N H L . O’ C o n n or et al 
( 2 0 0 5) f o u n d 5 8 % O R R wit h b ortez o mi b a d mi nistere d at 1. 5 m g/ m 2 o n Da ys 1, 4, 8, a n d 1 1 of a 
2 1- da y  treat me nt  c ycle.  Res p o nses  were  see n  i n  ma ntl e  cell,  f ollic ular a n d  mar gi nal  z o ne  
l y m p h o mas. G o y et al ( 2 0 0 5) teste d t he sa me d ose of b ortez o mi b i n a lar ger c o h ort of 6 0 patie nts 
a n d f o u n d 4 1 % O R R i n ma ntle cell l y m p h o mas a n d 1 9 % i n ot her N H L s u bt y pes. D ose of 1. 3  
m g/ m 2 o n Da ys 1, 4, 8, a n d 1 1 of a 2 1- da y treat me nt c ycle was e xa mi ne d i n a d diti o nal p hase II 
trials, a gai n s h o wi n g res p o nse i n ma ntle cell a n d i n d ole nt l y m p h o mas ( Stra uss et al, 2 0 0 6). A 
s mall p hase II trial j ust i n ma ntle cell l y m p h o ma, usi n g b ortez o mi b at t he d ose of 1. 3 m g/ m 2 o n 
Da ys 1, 4, 8, a n d 1 1 of a 2 1 -da y treat me nt c ycle, s h o we d a 4 6 % O R R a n d me dia n res p o nse 
d urati o n of 1 0 m o nt hs ( Belc h et al, 2 0 0 7). A lar ge p hase II st u d y ( PI N N A C L E trial) i n 1 5 5 patie nts 
wit h rela pse d/refract or y ma ntle cell l y m p h o ma, de m o nstrate d 3 1 % O R R wit h 8 % C R / Cr u, wit h 
me dia n d urati o n of res p o nse of 9 . 3 m o nt hs ( Fis her et al, 2 0 0 6).  Base d o n t his data, V E L C A D E 
was  a p pr o ve d  b y  t he  F D A  i n  Dece m ber  2 0 0 6  as  a  si n gle  a ge nt  i n  t he  treat me nt  of  
rela pse d/refract or y ma ntle cell l y m p h o ma.  
 
L y m p h o plas mac ytic  l y m p h o ma  ( Wa l der nstr o m’s  macr o gl o b uli ne mia)  ha d  de dicate d  trials 
de m o nstrati n g efficac y of b ortez o mi b. P hase II trial b y C he n et al ( 2 0 0 7) usi n g sta n dar d d osi n g 
of b ortez o mi b re veale d a 2 6 % O R R, all partial res p o nses b y c o m bi ne d I g M a n d bi di me ns i o nal 
meas ure me nt crite ria. Tre o n et al (2 0 0 7 ), o n t he ot her si de, de m o nstrate d a n 8 5 % O R R, b ut als o 
wit h o ut C Rs. Res p o nses i n S L L/ C L L are less r o b ust b ut prese nt, as i n dicate d b y p hase II trial i n 
fl u dara bi ne-refract or y C L L ( Fa derl et al, 2 0 0 6).  

Versi o n 7 :  0 8/ 1 5 / 2 0 1 7  
1 8  
1. 2. 6  P ote nti al Ris ks of V E L C A D E  
T o date, m ore t ha n 3 0 0, 0 0 0 patie nts ha ve bee n treate d wit h V E L C A D E  i n b ot h cli nical trials 
i n vesti gati n g its use i n he mat ol o gical mali g na ncies a n d s oli d t u m ors, a n d i n patie nts w h o were 
treate d wit h c o m merciall y a vaila ble V E L C A D E . 
Prescri bi n g p h ysicia ns a n d healt h care practiti o ners are referre d t o t heir l ocall y a p pr o ve d pr o d uct 
la bel  f or  V E L C A D E  re gar di n g  I n dicati o ns  a n d  Usa ge,  C o ntrai n dicati o ns,  War ni n gs,  a n d  
Preca uti o ns.  
T he k n o w n a ntici pate d ris ks of V E L C A D E t hera p y are prese nte d i n Ta ble 1 - 1 a n d Ta ble 1- 2 .  
T hese ris ks are gr o u pe d acc or di n g t o t he c o m bi ne d fre q ue nc y o bser ve d i n a n i nte grate d a nal ysis 
of A Es i n s p o ns ore d cli nical st u dies of si n gle -a gent V E L C A D E d ose d at 1. 3 m g/ m 2 t wice wee kl y 
o n a 2 1- da y sc he d ule, i n patie nts wit h m ulti ple m yel o ma a n d ma ntle cell l y m p h o ma. 
Preca uti o ns a n d Restricti o ns  
It is n ot k n o w n w hat effects V E L C A D E  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.  T heref ore, fe 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 nsterilize d fe male patie nts of 
re pr o d ucti ve a ge 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: 
•  P ost me n o pa usal f or at least 1 year bef ore t he scree ni n g visit, or  
•  S ur gicall y sterile, or 
•  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 
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 3 0 da ys after t he last d ose of 
V E L C A D E , or  a gree t o c o m pletel y a bstai n fr o m heter ose x ual i nterc o urse. 
It is str o n gl y rec o m me n de d t hat at least 1 of t hese 2 met h o ds be hi g hl y effecti ve (see e xa m ples 
bel o w). 
Hi g hl y effecti ve met h o ds  
Ot her effecti ve met h o ds ( barrier met h o ds)  
I ntra-uteri ne de vices (I U D)  
Late x c o n d o m  
H or m o nal c o ntrace pti ves ( birt h c o ntr ol pills/ oral 
c o ntrace pti ves, i njecta ble c o ntrace pti ves, 
c o ntrace pti ve patc hes, or c o ntrace pti ve i m pla nts)  
Dia p hra g m wit h s per mici de  
Cer vical ca p  
S p o n ge  
If o ne of t he hi g hl y effecti ve met h o ds ca n n ot be use d, usi n g 2 effecti ve met h o ds at t he sa me ti me is 
rec o m me n de d.  
 
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: 
•  Practice  effecti ve  barrier  c o ntrace pti o n  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 a mi ni m u m of 3 0 da ys after t he last d ose of st u d y dr u g, or c o m pletel y a bstai n 
fr o m heter ose x ual i nterc o urse. 

Versi o n 7 :  0 8/ 1 5 / 2 0 1 7  
1 9  
T a ble 1 -1     
K n o w n A ntici p ate d Ris ks of V E L C A D E b y Me d D R A S yste m Or g a n 
Cl ass, O bser ve d I nci de nce, a n d Preferre d Ter m  
S yste m Or g a n Cl ass  
O bser ve d I nci de nce  
Preferre d Ter m  
Bl o o d a n d L y m p h atic S yste m Dis or ders  
M ost c o m m o n  
T hr o m b oc yt o pe nia *, a nae mia *  
Ver y c o m m o n  
Ne utr o pe nia *  
C o m m o n  
L y m p h o pe nia, pa nc yt o pe nia *, le u k o pe nia *, fe brile 
ne utr o pe nia  
C ar di ac Dis or ders  
C o m m o n  
Tac h ycar dia, atrial fi brillati o n, pal pitati o ns, car diac 
fail ure c o n gesti ve * 
U nc o m m o n  
Car di o ge nic s h oc k *, atrial fl utter, car diac ta m p o na de * ± , 
bra d ycar dia, atri o ve ntric ular bl oc k c o m plete, arr h yt h mia, 
car diac arrest ∗, car diac fail ure, arr h yt h mia, pericar dial 
eff usi o n, pericar ditis, pericar dial disease ± , 
car di o pul m o nar y fail ure ±  
E ar a n d L a b yri nt h Dis or ders  
U nc o m m o n  
Deaf ness, heari n g i m paire d  
E ye Dis or ders  
C o m m o n  
Bl urre d visi o n, c o nj u ncti vitis, c o nj u ncti val hae m orr ha ge  
G astr oi ntesti n al Dis or ders  
M ost c o m m o n  
C o nsti pati o n, diarr h oea *, na usea, v o miti n g *  
Ver y c o m m o n  
a b d o mi nal pai n (e xcl u di n g oral a n d t hr oat)  
C o m m o n  
D ys pe psia, p har y n g olar y n geal pai n, gastr oes o p ha geal 
refl u x, a b d o mi nal diste nsi o n, gastritis, st o matitis, m o ut h 
ulcerati o n, d ys p ha gia, gastr oi ntesti nal hae m orr ha ge *, 
l o wer gastr oi ntesti nal haem orr ha ge * ± rectal 
hae m orr ha ge  
U nc o m m o n  
Er uctati o n, gastr oi ntesti nal pai n, t o n g ue ulcerati o n, 
retc hi n g, u p per gastr oi ntesti nal hae m orr ha ge *, 
hae mate mesis *, oral m uc osal petec hiae, ile us paral ytic *, 
ile us, o d y n o p ha gia, e nteritis, c olitis, oes o p ha gitis, 
e nter oc olitis, diarr h oea hae m orr ha gic, ac ute 
pa ncreatitis *, i ntesti nal o bstr ucti o n  
Ge ner al Dis or ders a n d A d mi nistr ati o n Site C o n diti o ns  
M ost c o m m o n  
Fati g ue, p yre xia  
Ver y c o m m o n  
C hills, oe de ma peri p heral, ast he nia  
C o m m o n  
Ne ural gia, let har g y, malaise, c hest pai n, m uc osal 
i nfla m mati o n * 
U nc o m m o n  
I njecti o n site pai n, i njecti o n site irritati o n, i njecti o n site 
p hle bitis, ge neral p h ysical healt h deteri orati o n *, 
cat heter -relate d c o m plicati o n 
He p at o bili ar y Dis or ders  
U nc o m m o n  
H y per bilir u bi nae mia, he patitis * ±  
I m m u ne S yste m Dis or ders 
U nc o m m o n  
Dr u g h y perse nsiti vit y, a n gi oe de ma  

Versi o n 7 :  0 8/ 1 5 / 2 0 1 7  
2 0  
T a ble 1 -1     
K n o w n A ntici p ate d Ris ks of V E L C A D E b y Me d D R A S yste m Or g a n 
Cl ass, O bser ve d I nci de nce, a n d Preferre d Ter m  
S yste m Or g a n Cl ass  
O bser ve d I nci de nce  
Preferre d Ter m  
I nfecti o ns a n d I nfest ati o ns 
Ver y c o m m o n  
U p per res pirat or y tract i nfecti o n, nas o p har y n gitis, 
p ne u m o nia *, Her pes z oster *  
C o m m o n  
L o wer res pirat or y tract i nfecti o n *, si n usitis, p har y n git is, 
oral ca n di diasis, uri nar y tract i nfecti o n *, se psis ∗, 
bactaere mia *, cell ulitis ∗, Her pes si m ple x, br o nc hitis, 
gastr oe nteritis *, i nfecti o n  
U nc o m m o n  
Se ptic s h oc k *, cat heter -relate d i nfecti o n *, s ki n 
i nfecti o n *, Her pes z oster disse mi nate d *, l u n g i nfecti o n∗, 
i nf usi o n site cell ulitis, cat heter site cell ulitis, i nf usi o n 
site i nfecti o n, ur ose psis *, As per gill osis *, ti nea i nfecti o n, 
Her pes z oster o p ht hal mic, Her pes si m ple x o p ht hal mic, 
me ni n g oe nce p halitis her petic ± , varicella, e m p ye ma± , 
f u n gal oes o p ha gitis±  
I nj ur y, P ois o ni n g, a n d Pr oce d ur al C o m plic ati o ns  
C o m m o n  
Fall  
U nc o m m o n  
S u b d ural hae mat o ma  
I n vesti g ati o ns 
C o m m o n  
Wei g ht decrease d, ala ni ne a mi n otra nsferase ( A L T) 
i ncrease d, as partate a mi n otra nsferase ( A S T) i ncrease d, 
bl o o d al kali ne p h os p hatase i ncrease d, li ve r f u ncti o n test 
a b n or mal, bl o o d creati ni ne i ncrease d *  
U nc o m m o n  
Ga m ma -gl uta m yltra nsferase ( G G T) i ncrease d, o x y ge n 
sat urati o n decrease d *, bl o o d al b u mi n decrease d, ejecti o n 
fracti o n decrease d * 
Met a b olis m a n d N utriti o n al Dis or ders  
Ver y c o m m o n  
Decrease d a p petite, a n ore xia, de h y drati o n *  
C o m m o n  
H y per gl ycae mia, h y p o gl ycae mia, h y p o natrae mia, 
h y p o kalae mia, h y percalcae mia *  
M usc ul os kelet al a n d C o n necti ve Tiss ue Dis or ders  
Ver y c o m m o n  
B o ne pai n, m yal gia, art hral gia, bac k pai n  
C o m m o n  
M usc ular wea k ness  
U nc o m m o n  
Li m b disc o mf ort  
Ne o pl as ms, Be ni g n, M ali g n a nt, a n d U ns pecifie d (i ncl u di n g c ysts a n d p ol y ps)  
U nc o m m o n  
T u m o ur l ysis s y n dr o me *  
Ner v o us S yste m Dis or ders  
M ost c o m m o n  
Peri p heral ne ur o pat h y (i ncl u di n g all preferre d ter ms 
u n der t he Me d D R A Hi g h -le vel ter m Peri p heral 
ne ur o pat h y N E C)  
Ver y c o m m o n  
Parest hesia, dizzi ness e xcl u di n g verti g o, hea dac he  
C o m m o n  
P ol y ne ur o pat h y, s y nc o pe, d ysest hesia, d ys ge usia, 
p ost her petic ne ural gia  

Versi o n 7 :  0 8/ 1 5 / 2 0 1 7  
2 1  
T a ble 1 -1     
K n o w n A ntici p ate d Ris ks of V E L C A D E b y Me d D R A S yste m Or g a n 
Cl ass, O bser ve d I nci de nce, a n d Preferre d Ter m  
S yste m Or g a n Cl ass  
O bser ve d I nci de nce  
Preferre d Ter m  
U nc o m m o n  
C o n v ulsi o n, l oss of c o nsci o us ness, a ge usia, 
e nce p hal o pat h y, paral ysis *,a ut o n o mic ne ur o pat h y, 
re versi ble p osteri or le u k oe nce p hal o pat h y s y n dr o me± , 
p osteri or re versi ble e nce p hal o pat h y s y n dr o me φ  
Ps yc hi atric Dis or ders  
Ver y c o m m o n  
A n xiet y, i ns o m nia  
C o m m o n  
C o nf usi o nal state  
U nc o m m o n  
Deliri u m  
Re n al a n d Uri n ar y Dis or ders  
C o m m o n  
Re nal i m pair me nt *, re nal fail ure *, hae mat uria  
U nc o m m o n  
Mict uriti o n dis or der  
Res pir at or y, T h or acic, a n d Me di asti n al Dis or ders  
Ver y c o m m o n  
C o u g h, d ys p n oea  
C o m m o n  
E pista xis, d ys p n oea e xerti o nal, ple ural eff usi o n *, 
r hi n orr hea, h y p o xia *, p ul m o nar y oe de ma ∗ 
U nc o m m o n  
He m o pt ysis *, ac ute res pirat or y distress s y n dr o me *, 
res pirat or y fail ure *, p ne u m o nitis *, l u n g i nfiltrati o n, 
p ul m o nar y al ve olar hae m orr ha ge *, i nterstitial l u n g 
disease *, p ul m o nar y h y perte nsi o n *, ple uris y, ple uritic 
pai n  
S ki n a n d S u bc ut a ne o us Tiss ue Dis or ders  
Ver y c o m m o n  
Ras h  
C o m m o n  
Ras h pr uritic, ras h er yt he mat o us, urticaria, petec hiae  
U nc o m m o n  
C uta ne o us vasc ulitis, le u k oc yt oclastic vasc ulitis ±   
V asc ul ar Dis or ders  
C o m m o n  
H y p ote nsi o n *, ort h ostatic h y p ote nsi o n  
U nc o m m o n  
Cere bral  hae m orr ha ge *  
S o urce:  V E L C A D E ®  I n vesti gat or’s Br oc h ure E diti o n 1 5 . 
M ost c o m m o n = ≥ 3 0 %, Ver y c o m m o n = 1 0 % t o 2 9 %, C o m m o n  = 1 % t o 9 %, U nc o m m o n  = < 1 %.  
* Fatal o utc o mes ha ve bee n re p orte d.  
±  I n dicates a Preferre d ter m n ot liste d i n t he s o urce ta ble, h o we ver t he e ve nt is dee me d me dicall y i m p orta nt 
a n d s o is i ncl u de d.  
φ  Effecti ve Me d D R A u p date t o versi o n 1 4. 0, t he ter m ‘re versi ble p osteri or le u k oe nce p hal o pat h y s y n dr o me’ 
u p date d t o ‘ p osteri or re versi ble e nce p hal o pat h y s y n dr o me ( P R E S)’.  
 

Versi o n 7 :  0 8/ 1 5 / 2 0 1 7  
2 2  
T a ble 1- 2    
Re p orts of A d verse Re acti o ns Fr o m 
P ost m ar keti n g E x perie nce  
S yste m Or g a n Cl ass  
 
Preferre d Ter m  
O bser ve d  
I nci de ncea 
Bl o o d a n d l y m p h atic s yste m dis or ders  
 
 
Disse mi n ate d i ntr av asc ul ar c o a g ul ati o n  
Rare  
C ar di ac Dis or ders  
 
 
Atri ove ntric ul ar bl ock c o m plete  
Rare  
 
C ar di ac t a m p o n a de  
Rare  
E ar a n d l a b yri nt h dis or ders  
 
 
De af ness bil ater al  
Rare  
E ye Dis or ders  
 
 
O p ht h al mic her pes  
Rare  
              O ptic ne ur o p at hy  
Rare  
              Bli n d ness  
Rare  
G astr oi ntesti n al Dis or ders  
 
 
Ac ute p a ncre atitis  
Rare  
 
Isc he mic c olitis 
Rare  
He p at o bili ar y dis or ders  
 
 
He p atitis  
U nc o m m o n  
 
Liver f ail ure  
U n k n o w n  
I nfecti o ns a n d i nfest ati o ns 
 
 
Her pes me ni n g oe nce p h alitis  
Rare  
 
Se ptic s h ock  
Rare  
Pr o gressive m ultif oc al le uk oe nce p h al o p at hy  
Ver y rare  
I m m u ne S yste m Dis or ders 
 
 
A n gi oe de m a  
Rare  
Ner v o us S yste m Dis or ders  
 
 
A ut o n o mic ne ur o p at hy  
Rare  
 
Dys a ut o n o mi a  
U n k n o w n  
 
E nce p h al o p at hy  
Rare  
Res pir at or y, t h or acic a n d me di asti n al dis or ders:  
 
 
Ac ute diff use i nfiltr ative p ul m o n ary dise ase b  
Rare  
 
Ac ute res pir at ory distress sy n dr o me ( A R D S)  
Rare  
 
I nterstiti al p ne u m o ni a 
Rare  
 
L u n g i nfiltr ati o n  
Rare  
 
P ne u m o nitis  
Rare  
 
P ul m o n ary hy perte nsi o n  
Rare  

Versi o n 7 :  0 8/ 1 5 / 2 0 1 7  
2 3  
T a ble 1- 2    
Re p orts of A d verse Re acti o ns Fr o m 
P ost m ar keti n g E x perie nce  
S yste m Or g a n Cl ass  
 
Preferre d Ter m  
O bser ve d  
I nci de ncea 
S ki n a n d s u bc ut a ne o us s yste m dis or ders  
 
 
Ac ute fe brile ne utr o p hilic der m at osis  
U n k n o w n  
 
T oxic e pi der m al necr olysis  
U n k n o w n  
S o urce:  V E L C A D E ®  I n vesti gat or’s Br oc h ure E diti o n 15 A d de n d u m 1 . 
a I nci de nce is assi g ne d usi n g t he f oll o wi n g c o n ve nti o n:  ver y c o m m o n 
(≥ 1/ 1 0); c o m m o n ( ≥ 1/ 1 0 0 a n d <  1/ 1 0); u nc o m m o n ( ≥ 1/ 1 0 0 0 a n d 
<  1/ 1 0 0); rare ( ≥ 1/ 1 0, 0 0 0 a n d <  1/ 1 0 0 0 ); ver y rare ( <  1/ 1 0, 0 0 0, 
i ncl u di n g is olate d re p orts). 
b Ac ute diff use i nfiltrati ve p ul m o nar y disease is a Me d D R A L o wer 
Le vel Ter m w hic h c orres p o n ds t o a Preferre d Ter m of I nterstitial l u n g 
disease.  
Ot her m e dical eve nts of interest t hat are co nsi dere d n ot ca usall y r elate d t o V E L C A D E  i ncl u de 
he patic fail ure a n d Q T pr ol o n gati o n.  Fatal o utc o mes ha ve bee n re p orte d. 
W o me n of c hil d beari n g p ote ntial  s h o ul d a v oi d bec o mi n g pre g na nt w hile bei n g treate d wit h 
V E L C A D E.   Ge n ot o xicit y testi n g has s h o w n t hat b ortez o mi b is ne gati ve i n t he i n vitr o A mes 
assa y a n d i n t he i n vi v o micr o n ucle us assa y, b ut it is a clast o ge n i n t he i n vitr o c hr o m os o mal 
a berrati o n assa y.    
A d diti o nal  details  o n  t he  p ote ntial  ris ks  of  V E L C A D E  ma y  be  f o u n d  i n  t he  I n vesti gat or’s  
Br oc h ure. 
1. 3  C o m bi n ati o n dr u g i nf or m ati o n  
1. 3. 1  Scie ntific B ac k gr o u n d   
Cl a dri bi ne  
Le ustati n (cla dri bi ne)  I njecti o n (als o c o m m o nl y k n o w n as 2-c hl or o-2’ - de o x y- B- D-a de n osi ne) is 
a s y nt hetic a nti ne o plastic a ge nt f or c o nti n u o us i ntra ve n o us i nf usi o n. It is a clear, c ol orless, sterile, 
preser vati ve -free, is ot o nic s ol uti o n. Le ustati n I njecti o n is a vaila ble i n si n gle- use vials c o ntai ni n g 
1 0  m g  ( 1  m g/ m L)  of  cla dri bi ne,  a  c hl ori nate d  p uri ne  n ucle osi de  a nal o g.  Eac h  milliliter  of  
Le ustati n I njecti o n c o ntai ns 1 m g of t he acti ve i n gre die nt a n d 9 m g ( 0. 1 5 m E q) of s o di u m c hl ori de 
as a n i nacti ve i n gre die nt. T he s ol uti o n has a p H ra n ge of 5. 5 t o 8. 0. P h os p h oric aci d a n d/ or dia betic 
s o di u m p h os p hate ma y ha ve bee n a d de d t o a dj ust t he p H t o 6. 3 + 0. 3. 
T he c he mical na me f or cla dri bi ne is 2 -c hl or o- 6-a mi n o- 9-( 2- de o x y- B- D-er yt hr o pe nt o-f ura n os yl) 
p uri ne. 
T he selecti ve t o xicit y of 2 -c hl or o- 2’- de o x y- b- D-a de n osi ne t o war ds certai n n or mal a n d mali g na nt 
l y m p h oc yte a n d m o n oc yte p o p ulati o ns is base d o n t he relati ve acti vities of de o x yc yti di ne ki nase 
a n d de o x y n ucle oti dase. Cla dri bi ne passi vel y cr osses t he cell me m bra ne. I n cells wit h a hi g h rati o 
of de o x yc yti di ne ki nase t o de o x y n ucle oti dase, it is p h os p h or ylate d b y de o x yc yti di ne ki nase t o 2 -

Versi o n 7 :  0 8/ 1 5 / 2 0 1 7  
2 4  
c hl or o- 2’ - de o x y- B- D-a de n osi ne  m o n o p h os p hate  ( 2 -C d A M P).  Si nce  2-c hl or o- 2’ de o x y- β - D-
a de n osi ne is resista nt t o dea mi nati o n b y a de n osi ne dea mi nase a n d t here is little de o x y n ucle oti de 
dea mi nase  i n  l y m p h oc ytes  a n d  m o n oc ytes,  2 -C d A M P  acc u m ulates  i ntracell ularl y  a n d  is  
s u bse q ue ntl y  c o n verte d  i nt o  t he acti ve  tri p h os p hate  de o x y n ucle oti de,  2-c hl or o- 2’ de o x y- β - D-
a de n osi ne tri p h os p hate ( 2- C d A T P). It is p ost ulate d t hat cells wit h hi g h de o x yc yti di ne ki nase a n d 
l o w de o x y n ucle oti dase acti vities will be selecti vel y kille d b y 2-c hl or o- 2’ de o x y- β - D-a de n osi ne as 
t o xic de o x y n ucle oti des acc u m ulates i ntracell ularl y. 
Cells c o ntai ni n g hi g h c o nce ntrati o ns of de o x y n ucle oti des are u na ble t o pr o perl y re pair si n gle -
stra n d D N A brea ks. T he br o ke n e n ds of D N A acti vate t he e nz y me p ol y ( A D P-ri b ose) p ol y merase 
res ulti n g i n N A D a nd A T P de pleti o n a n d disr u pti o n of cell ular meta b olis m. T here is e vi de nce, 
als o, t hat 2-C d A T P is i nc or p orate d i nt o t he D N A of di vi di n g cells, res ulti n g i n i m pair me nt of 
D N A  s y nt hesis.  T h us,  2 -c hl or o- 2’ de o x y-β - D-a de n osi ne  ca n  be  disti n g uis he d  fr o m  ot her  
c he mot hera pe utic a ge nts affecti n g p uri ne meta b olis m i n t hat it is c yt ot o xic t o b ot h acti vel y 
di vi di n g a n d q uiesce nt l y m p h oc ytes a n d m o n oc ytes, i n hi biti n g b ot h D N A s y nt hesis a n d re pair.  
Rit u xi m a b  
Rit u xi ma b  is a m o use/ h u ma n c hi meric m o n ocl o nal a nti b o d y c o nsisti n g of h u ma n I g G 1 hea v y a n d 
ka p pa li g ht c hai n c o nsta nt re gi o ns wit h m uri ne varia ble re gi o ns fr o m t he m uri ne I g G 1 ka p pa a nti -
h u ma n C D 2 0 m o n ocl o nal a nti b o d y rit u xi ma b.  T he rit u xi ma b a nti b o d y is pr o d uce d b y a C hi nese 
ha mster o var y tra nsfect o ma.   
Rit u xi ma b bi n ds s pecificall y t o t he a nti ge n C D 2 0 ( h u ma n B -l y m p h oc yte-restricte d differe ntiati o n 
a nti ge n, B p 3 5), a h y dr o p h o bic tra ns me m bra ne pr otei n wit h a m olec ular wei g ht of a p pr o xi matel y 
3 5 k D l ocate d o n pre -B a n d mat ure B l y m p h oc ytes. T he a nti ge n is e x presse d o n  >9 0 % of B -cell 
n o n- H o d g ki n’s l y m p h o mas ( N H L), b ut t he a nti ge n is n ot f o u n d o n he mat o p oietic ste m cells, pr o -
B- cells, n or mal plas ma cells or ot her n or mal tiss ues. C D 2 0 re g ulates a n earl y ste p(s) i n t he 
acti vati o n pr ocess f or cell c ycle i nitiati o n a n d differe ntiati o n, a n d p ossi bl y f u ncti o ns as a calci u m 
i o n c ha n nel. C D 2 0 is n ot s he d fr o m t he cell s urface a n d d oes n ot i nter nalize u p o n a nti b o d y 
bi n di n g. Free C D 2 0 a nti ge n is n ot f o u n d i n t he circ ulati o n.  
B- cells are belie ve d t o pla y a r ole i n t he pat h o ge nesis of  r he u mat oi d art hritis ( R A) a n d ass ociate d 
c hr o nic  s y n o vitis.  I n  t his  setti n g,  B -cells  ma y  be  acti n g  at  m ulti ple  sites  i n  t he  
a ut oi m m u ne/i nfla m mat or y pr ocess, i ncl u di n g t hr o u g h pr o d ucti o n of r he u mat oi d fact or ( R F) a n d 
ot her a ut oa nti b o dies, a nti ge n prese ntati o ns, T -cell acti vati o n, a n d/ or pr o -i nfla m mat or y c yt o ki ne 
pr o d ucti o n. 
Mec ha nis m of Acti o n: T he Fa b d o mai n of rit u xi ma b bi n ds t o t he C D 2 0 a nti ge n o n B l y m p h oc ytes, 
a n d t he Fc d o mai n recr uits i m m u ne effect or f u ncti o ns t o me diate B -cell l ysis i n vitr o. P ossi b le 
mec ha nis ms  of  cell  l ysis  i ncl u de  c o m ple me nt -de pe n de nt  c yt ot o xicit y  ( C D C)  a n d  a nti b o d y -
de pe n de nt cell me diate d c yt ot o xicit y ( A D C C). T he a nti b o d y has bee n s h o w n t o i n d uce a p o pt osis 
i n t he D H L- 4 h u ma n B-cell l y m p h o ma li ne.  
N or mal  Tiss ue  Cr oss -reacti vit y:  Rit u xi ma b  bi n di n g  was  o bser ve d  o n  l y m p h oi d  cells  i n  t he  
t h y m us, t he w hite p ul p of t he s plee n, a n d a maj orit y of B l y m p h oc ytes i n peri p heral bl o o d a n d 
l y m p h n o des. Little or n o bi n di n g was o bser ve d i n t he n o n-l y m p h oi d tiss ues e xa mi ne d. 

Versi o n 7 :  0 8/ 1 5 / 2 0 1 7  
2 5  
1. 3. 2  Cli nic al P h ar m ac o ki net ics a n d P h ar m ac o d y n a mics 
Cl a dri bi ne  
I n a cli nical i n vesti gati o n, 1 7 patie nts wit h Hair y Cell Le u ke mia a n d n or mal re nal f u ncti o n were 
treate d f or  7  da ys  wit h  t he  rec o m me n de d  treat me nt  re gi me n  of  Le ustati n  I njecti o n  ( 0. 0 9  
m g/ k g/ da y) b y c o nti n u o us i ntra ve n o us i nf usi o n. T he mea n stea d y -state ser u m c o nce ntrati o n was 
esti mate d t o be 5. 7 n g/ m L wit h a n esti mate d s yste mic cleara nce of 6 6 3. 5 m L/ h/ k g w he n  Le ustati n 
was gi ve n b y c o nti n u o us i nf usi o n o ver 7 da ys. I n Hair y Cell Le u ke mia patie nts, t here d oes n ot 
a p pear t o be a relati o ns hi p bet wee n ser u m c o nce ntrati o ns a n d ulti mate cli nical o utc o me.  
I n a n ot her st u d y, 8 patie nts wit h he mat ol o gical mali g na ncies recei ve d a t w o ( 2) h o ur i nf usi o n of 
Le ustati n I njecti o n ( 0. 1 2 m g/ k g). T he mea n e n d - of-i nf usi o n plas ma Le ustati n c o nce ntrati o n was 
4 8 + 1 9 n g/ m L. F or 5 of t hese patie nts, t he disa p peara nce of Le ustati n c o ul d be descri be d b y eit her 
a bi p hasic or tri p hasic decli ne. F or t hese patie nts wit h n or mal re nal f u ncti o n, t he mea n ter mi nal 
half- life was 5. 4 h o urs. Mea n val ues f or cleara nce  a n d stea d y -state v ol u me of distri b uti o n were 
9 7 8 + 4 2 2 m L/ h/ k g a n d 4. 5 + 2. 8 L/ k g, res pecti vel y. 
Cla dri bi ne plas ma c o nce ntrati o n after i ntra ve n o us a d mi nistrati o n decli nes m ulti -e x p o ne ntiall y 
wit h a n a vera ge half -life of 6. 7 + 2. 5 h o urs. I n ge neral, t he a p pare nt v ol u me of distri b uti o n of 
cla dri bi ne is a p pr o xi matel y 9 L/ k g, i n dicati n g a n e xte nsi ve distri b uti o n i n b o d y tiss ues. 
Cla dri bi ne  pe ne trates  i nt o  cere br os pi nal  fl ui d.  O ne  re p ort  i n dicates  t hat  c o nce ntrati o ns  are  
a p pr o xi matel y 2 5 % of t h ose i n plas ma. 
Le ustati n is b o u n d a p pr o xi matel y 2 0 % t o plas ma pr otei ns. 
E xce pt f or s o me u n dersta n di n g of t he mec ha nis m of cell ular t o xicit y, n o ot her i nf or mati o n is 
a vaila ble o n t he meta b olis m of Le ustati n i n h u ma ns. A n a vera ge of 1 8 % of t he a d mi nistere d d ose 
has bee n re p orte d t o be e xcrete d i n uri ne of patie nts wit h s oli d t u m ors d uri n g a 5 - da y c o nti n u o us 
i ntra ve n o us  i nf usi o n  of  3. 5-8. 1  m g/ m 2/ da y  of  Le ustati n.  T he  effect  of  re nal  a n d  he patic  
i m pair me nt o n t he eli mi nati o n of cla dri bi ne has n ot bee n i n vesti gate d i n h u ma ns. 
Rit u xi m a b  
P h ar m ac o d y n a mics:  A d mi nistrati o n of Rit u xa n res ulte d i n a ra pi d a n d s ustai ne d de pleti o n of 
circ ulati n g a n d tiss ue -base d B -cells. A m o n g 1 6 6 patie nts i n St u d y 1, circ ulati n g C D 1 9 - p ositi ve 
B- cells were de plete d wit hi n t he first t hree wee ks wit h s ustai ne d de pleti o n f or u p t o 6 t o 9 m o nt hs 
p ost- treat me nt i n 8 3 % of patie nts. B-cell rec o ver y be ga n at a p pr o xi matel y 6 m o nt hs a n d me dia n 
B- cell le vels ret ur ne d t o n or mal b y 1 2 m o nt hs f oll o wi n g c o m pleti o n of treat me nt. 
T here were s ustai ne d a n d statisticall y si g nifica nt re d ucti o ns i n b ot h I g M a n d I g G ser u m le vels 
o bser ve d fr o m 5 t hr o u g h 1 1 m o nt hs f oll o wi n g rit u xi ma b a d mi nistrati o n; 1 4 % of patie nts ha d I g M 
a n d/ or I g G ser u m le vels bel o w t he n or mal ra n ge. 
I n R A patie nts, treat me nt wit h Rit u xa n i n d uce d de pleti o n of peri p heral B l y m p h oc ytes, wit h all 
patie nts de m o nstrati n g near c o m plete de pleti o n wit hi n 2 wee ks after recei vi n g t he first d ose of 
Rit u xa n. T he maj orit y of patie nts s h o we d peri p heral B -cell de pleti o n f or at least 6 m o nt hs, 
f oll o we d b y s u bse q ue nt gra d ual rec o ver y after t hat ti me p oi nt. A s mall pr o p orti o n of patie nts ( 4 %) 
ha d pr ol o n ge d peri p heral B -cell de pleti o n lasti n g m ore t ha n 3 years after a si n gle c o urse of 
treat me nt. 

Versi o n 7 :  0 8/ 1 5 / 2 0 1 7  
2 6  
I n R A st u dies, t otal ser u m i m m u n o gl o b uli n le vels, I g M, I g G, a n d I g A were re d uce d at 6 m o nt hs 
wit h t he greatest c ha n ge o bser ve d i n I g M. H o we ver, mea n i m m u n o gl o b uli n le vels re mai ne d 
wit hi n  n or mal  le vels  o ver  t he  2 4 -wee k  peri o d.  S mall  pr o p orti o ns  of  patie nts  e x perie nce d  
decreases i n I g M ( 7 %), I g G ( 2 %), a n d I g A ( 1 %) le vels bel o w t he l o wer li mit of n or mal. T he 
cli nical c o nse q ue nces of decreases i n i m m u n o gl o b uli n le vels i n R A patie nts treate d wit h Rit u xa n 
are u nclear. 
Treat me nt wit h rit u xi ma b i n patie nts wit h R A was ass ociate d wit h re d ucti o n of certai n bi ol o gic 
mar kers of i nfla m mati o n s uc h as i nterle u ki n -6 (I L -6), C -reacti ve pr otei n ( C R P), ser u m a m yl oi d 
pr otei n ( S A A), s 1 0 0 A 8/ S 1 0 0 A 9 heter o di mer c o m ple x ( S 1 0 0 A 8/ 9), a nti -citr ulli nate d pe pti de 
(a nti-C C P) a n d R F.  
P h ar m ac o ki netics:  P har mac o ki netics were c haracterize d i n 2 0 3 N H L patie nts recei vi n g 3 7 5 
m g/ m 2 rit u xi ma b  wee kl y  b y  I V  i nf usi o n  f or  4  d oses.  T he  mea n  Cma x  i ncrease d  wit h  eac h  
s uccessi ve i nf usi o n a n d was 4 8 6 mc g/ m L (ra n ge, 7 8-9 9 7 mc g/ m L) f oll o wi n g t he f o urt h i nf usi o n. 
Pea k a n d tr o u g h ser u m le vels of rit u xi ma b were i n versel y c orrelate d wit h pretreat me nt circ ulati n g 
C D 1 9 -p ositi ve B -cells a n d t u m or b ur de n. Rit u xi ma b was detecta ble i n t he ser u m of patie nts 3 t o 
6 m o nt hs after c o m pleti o n of treat me nt.  
T he p har mac o ki netic pr ofile of rit u xi ma b w he n a d mi nistere d as 6 i nf usi o ns of 3 7 5 m g/ m 2 i n 
c o m bi nati o n wit h 6 c ycles of C H O P c he m ot hera p y was si milar t o t hat see n wit h rit u xi ma b al o ne.  
Base d o n a p o p ulati o n p har mac o ki netic a nal ysis of data fr o m 2 9 8 N H L patie nts w h o recei ve d 
rit u xi ma b o nce wee kl y or o nce e ver y t hree wee ks, t he esti mate d me dia n ter mi nal eli mi nati o n half-
life was 2 2 da ys (ra n ge, 6. 1 t o 5 2 da ys). Patie nts wit h hi g her C D 1 9-p ositi ve cell c o u nts or lar ger 
meas ura ble t u m or lesi o ns at pretreat me nt ha d a hi g her cleara nce. H o we ver d ose a dj ust me nt f or 
pretreat me nt C D 1 9 c o u nt or size of t u m or lesi o n is n ot necessar y. A ge a n d ge n der ha d n o effect 
o n t he p har mac o ki netics of rit u xi ma b.  
F oll o wi n g a d mi nistrati o n of 2 d oses of rit u xi ma b i n patie nts wit h r he u mat oi d art hritis, t he mea n 
C ma x  val ues were 1 8 3 mc g/ m L ( C V = 2 4 %) f or t he 2 X 5 0 0 m g d ose a n d 3 7 0 mc g/ m L ( C V = 2 5 %) 
f or t he 2 X 1 0 0 0 m g d ose, res pecti vel y. F oll o wi n g 2 X 1 0 0 0 m g rit u xi ma b d ose, mea n v ol u me of 
distri b uti o n at stea d y state was 4. 3 L  ( C V = 2 8 %). Mea n s yste mic cleara nce of rit u xi ma b was 0. 0 1 
L/ h ( C V = 3 8 %), a n d mea n ter mi nal eli mi nati o n half -life after  t he sec o n d d ose was 1 9 da ys 
( C V = 3 2 %). 
Fe male patie nts wit h R A ( n = 8 6) ha d a 3 7 % l o wer cleara nce of rit u xi ma b t ha n male patie nts wit h 
R A ( n = 2 5). T he ge n der differe nce i n rit u xi ma b cleara nce d oes n ot necessitate a n y d ose a dj ust me nt 
beca use safet y a n d efficac y of rit u xi ma b d o n ot a p pear t o be i nfl ue nce d b y ge n der. 
T he p har mac o ki netics of rit u xi ma b ha ve n ot bee n st u die d i n c hil dre n a n d a d olesce nts. N o f or mal 
st u dies were c o n d ucte d t o e xa mi ne t he effects of eit her re nal or he patic i m pair me nt o n t he 
p har mac o ki netics of rit u xi ma b. 
1. 3. 3  Cli nic al E x perie nce  
Cl a dri bi ne  
Cla dri bi ne  is  a  p uri ne  n ucle osi de  a nal o g effecti ve  i n  i n d ole n t  a n d  ma ntle  cell  l y m p h o mas. 
E x perie nce at t he Ma y o Cli nic a n d t he U ni versit y of Ariz o na Ca ncer Ce nter i n dicate cla dri bi ne 

Versi o n 7 :  0 8/ 1 5 / 2 0 1 7  
2 7  
t o be e xtre mel y effecti ve i n ma ntle cell l y m p h o mas wit h t olera ble t o xicit y, c o m plete res p o nse 
rates of 3 0-5 0 %, a n d d ura bilit y of res p o nses at 1 9 -2 4 m o nt hs i n ne wl y dia g n ose d patie nts, as 
c o m pare d t o 1 2 -1 5 m o nt hs wit h C H O P (I n war ds et al, 2 0 0 8 ; R u m mel et al., 1 9 9 9).  I n i n d ole nt 
l y m p h o mas, cla dri bi ne has res ulte d i n C R rates of u p t o 2 0 % i n rela pse d a n d u p t o 3 2 % i n 
u ntreate d setti n g ( Ka y et al ., 1 9 9 2; Fri dri k et al., 1 9 9 8). T he F D A a p pr o val f or cla dri bi ne is base d 
o n its efficac y i n treat me nt of hair y cell le u ke mia, a n i n d ole nt l y m p h oi d mali g na nc y.  
Cla dri bi ne i n hair y cell le u ke mia  
T w o si n gle-ce nter o pe n la bel st u dies of Le ustati n (cla dri bi ne) ha ve bee n c o n d ucte d  i n patie nts 
wit h  Hair y  Cell  Le u ke mia  wit h  e vi de nce  of  acti ve  disease  re q uiri n g  t hera p y.  I n  t he  st u d y  
c o n d ucte d at t he Scri p ps Cli nic a n d Researc h F o u n dati o n ( St u d y A, Sa ve n et al, 1 9 9 8 ), 8 9 patie nts 
were treate d wit h a si n gle c o urse of Le ustati n I njecti o n  gi ve n b y c o nti n u o us i nf usi o n f or 7 da ys 
at a d ose of 0. 0 9 m g/ k g/ da y. I n t he st u d y c o n d ucte d at t he M. D. A n ders o n Ca ncer Ce nter ( St u d y 
B , Este y et al., 1 9 9 2), 3 5 patie nts were treate d wit h a 7-da y c o nti n u o us i ntra ve n o us i nf usi o n of 
Le ustati n I njecti o n at a  c o m para ble d ose of 3. 6 m g/ m 2/ da y. A c o m plete res p o nse ( C R) re q uire d 
cleari n g of t he peri p heral bl o o d a n d b o ne marr o w of hair y cells a n d rec o ver y of t he he m o gl o bi n 
t o 1 2 g/ d L, platelet c o u nt t o 1 0 0 x 1 09/ L, a a bs ol ute ne utr o p hil c o u nt t o 1 5 0 0 x 1 06/ L. A g o o d 
partial res p o nse ( G P R) re q uire d t he sa me he mat ol o gic para meters as a c o m plete res p o nse, a n d 
t hat fe wer t ha n 5 % hair y cells re mai n i n t he b o ne marr o w. A partial res p o nse ( P R) re q uire d t hat 
hair y cells i n t he b o ne marr o w be decrease d b y at least 5 0 % fr o m baseli ne a n d t he sa me res p o nse 
f or he mat ol o gic para meters as f or c o m plete res p o nse. A pat h ol o gic rela pse was defi ne d as a n 
i ncrease i n b o ne marr o w hair y cells t o 3 5 % of pretreat me nt le vels. A cli nical rela pse was defi ne d 
as t he rec urre nce of c yt o pe nias, s pecificall y, decreases i n he m o gl o bi n > 2 g/ d L, A N C > 2 5 % or 
platelet c o u nts > 5 0, 0 0 0. Patie nts w h o met t he criteria fr o a c o m plete res p o nse b ut s u bse q ue ntl y 
were f o u n d t o  ha ve e vi de nce of b o ne marr o w hair y cells ( < 2 5 % of pretreat me nt le vels) were 
reclassifie d as partial res p o nses a n d were n ot c o nsi dere d t o be c o m plete res p o nses wit h rela pse.  
A m o n g patie nts e val ua ble f or efficac y ( N = 1 0 6), usi n g t he he mat ol o gic a n d b o ne marr o w res p o nse 
criteria descri be d a b o ve, t he c o m plete res p o nse rates i n patie nts treate d wit h Le ustati n I njecti o n 
were 6 5 % a n d 6 8 % f or St u d y A a n d St u d y B, res pecti vel y, yiel di n g a c o m bi ne d c o m plete res p o nse 
rate of 6 6 %. O verall res p o nse rates (i.e., C o m plete pl us G o o d Partial pl us Partial Res p o nses) were 
8 9 % a n d 8 6 % i n St u d y A a n d St u d y B, res pecti vel y, f or a c o m bi ne d o verall res p o nse rate of 8 8 % 
i n e val ua ble patie nts treate d wit h Le ustati n I njecti o n. 
Usi n g a n i nte nt -t o-treat a nal ysis ( N = 1 2 3) a n d f urt her re q uiri n g n o e vi de nce of s ple n o me gal y as a 
criteri o n f or C R (i.e., n o pal pa ble s plee n o n p h ysical e xa mi nati o n a n d < 1 3 c m o n C T sca n), t he 
c o m plete res p o nse rates f or St u d y A a n d St u d y B were 5 4 % a n d 5 3 %, res pecti vel y, gi vi n g a 
c o m bi ne d C R rate of 5 4 %. T he o verall res p o nse rates ( C R + G P R + P R)  were 9 0 % a n d 8 5 %, f or 
St u dies A a n d B, res pecti vel y, yiel di n g a c o m bi ne d o verall res p o nse rate of 8 9 %. I n t hese st u dies, 
6 0 %  of  t he  patie nts  ha d  n ot  recei ve d  pri or  c he m ot hera p y  f or  Hair y  Cell  Le u ke mia  or  ha d  
u n der g o ne  s ple nect o m y as  t he  pri or  treat me nt  a n d  were  recei vi n g  Le ustati n  as  a  first -li ne 
treat me nt. T he re mai ni n g 4 0 % of t he patie nts recei ve d Le ustati n as a sec o n d-li ne treat me nt, 
ha vi n g bee n treate d wit h ot he r a ge nts, i ncl u di n g α -i nterfer o n a n d/ or de o x yc of o m yci n. T he o verall 
res p o nse rate f or patie nts wit h o ut pri or c he m ot hera p y was 9 2 %, c o m pare d wit h s ple nect o m y or 
de o x yc of o m yci n a n d i n patie nts refract or y t o α -i nterfer o n.  

Versi o n 7 :  0 8/ 1 5 / 2 0 1 7  
2 8  
After a re versi ble decli ne, n or maliz ati o n of peri p heral bl o o d c o u nts ( He m o gl o bi n > 1 2. 0 g/ d L, 
Platelets > 1 0 0 x 1 0 9/ L, A bs ol ute Ne utr o p hil C o u nt ( A N C) > 1 5 0 0 x 1 06/ L) was ac hie ve d b y 9 2 % 
of e val ua ble patie nts. T he me dia n ti me t o n or malizati o n of peri p heral c o u nts was 9 wee ks fr o m 
t he start of treat me nt ( Ra n ge: 2 t o 7 2). T he me dia n ti me t o n or malizati o n of Platelet C o u nt was 2 
wee ks, t he me dia n ti me t o n or malizati o n of t he A N C was 5 wee ks a n d t he me dia n ti me t o 
n or malizati o n  of  He m o gl o bi n  was  8  wee ks.  Wit h  n or malizati o n  of  Platelet  C o u nt  a n d  
He m o gl o bi n, re q uire me nts f or platelet a n d R B C tra nsf usi o ns were a b olis he d after M o nt hs 1 a n d 
2, res pecti vel y, i n t h ose patie nts wit h c o m plete res p o nse. Platelet rec o ver y ma y be dela ye d i n a 
mi n orit y of patie nts wit h se ver e baseli ne t hr o m b oc yt o pe nia. C orres p o n di n g t o n or malizati o n of 
A N C, a tre n d t o war d a re d uce d i nci de nce of i nfecti o n was see n after t he t hir d m o nt h, w he n 
c o m pare d t o t he m o nt hs i m me diatel y prece di n g Le ustati n t hera p y.  
F or patie nts ac hie vi n g a c o m plete res p o nse, t he me dia n ti me t o res p o nse (i.e. , a bse nce of hair y 
cells  i n  b o ne  marr o w  a n d  peri p heral  bl o o d  t o get her  wit h n or malizati o n  of  peri p heral  bl o o d  
para meters), meas ure d fr o m treat me nt start, was a p pr o xi matel y 4 m o nt hs. Si nce b o ne marr o w 
as pirati o n a n d bi o ps y were fre q ue ntl y n ot perf or me d at t he ti me of peri p heral bl o o d n or malizati o n, 
t he me dia n ti me t o c o m plete res p o nse ma y act uall y be s h orter t ha n t hat w hic h was rec or de d. At 
t he ti me of data c ut-off, t he me dia n d urati o n of c o m plete res p o nse was greater t ha n 8 m o nt hs a n d 
ra n ge d t o 2 5 + m o nt hs. A m o n g 9 3 res p o n di n g patie nts, se ve n ha d s h o w n e vi de nce of disease 
pr o gressi o n at t he ti me of t he data c ut -off. I n f o ur of t hese patie nts, disease was li mite d t o t he 
b o ne marr o w wit h o ut peri p heral bl o o d a b n or malities ( pat h ol o gic pr o gressi o n), w hile i n t hree 
patie nts t here were als o peri p heral bl o o d a b n or malities (cli nical pr o gressi o n). Se ve n patie nts w h o 
di d n ot res p o n d t o a first c o urse of Le ustati n recei ve d a sec o n d c o urse of t hera p y. I n t he fi ve 
patie nts w h o ha d a de q uate f oll o w -u p, a d diti o nal c o urses di d n ot a p pear t o i m pr o ve t heir o verall 
res p o nse. 
Cla dri bi ne i n ma ntle cell l y m p h o ma  
Pri or t o realizati o n t hat ma ntle cell l y m p h o ma  has u ni q ue c haracteristics se parati n g it fr o m 
i n d ole nt l y m p h o mas, it was i ncl u de d i n t he sa me trials wit h o ut differe ntiati n g s ur vi val o utc o mes, 
alt h o u g h t he res p o nse rates were si milar. R u m mel et al ( 1 9 9 9) treate d 1 2 patie nts wit h ma ntle cell 
l y m p h o ma ( 7 u ntreate d, 5 rela pse d), wit h cla dri bi ne at 5 m g/ m 2 I V o ver 2 h o urs da ys 1-5 e ver y 
4- 5 wee ks f or 6 c ycles. C R rate was 2 5 % a n d P R was 3 3 %, wit h re missi o n d urati o n of 1 9 m o nt hs 
a n d  4-year  O S  of  5 8 %.  Gra de  3 -4  ne utr o pe nia  was  o bser ve d  i n  1 7 %  a n d  gra de  3 - 4 
t hr o m b oc yt o pe nia i n o nl y 2 %. I n war ds et al at t he Ma y o Cli nic c o n d ucte d a p hase II trial usi n g 
t he sa me a d mi nistrati o n sc he d ule i n 2 4 pre vi o usl y treate d patie nts, wit h C R/ CR u rate of 2 1 % a n d 
P R rate of 2 5 %, wit h me dia n P F S  of 5. 4 m o nt hs  a n d me dia n O S of 1. 9 years . I n u ntreate d patie nts, 
4 2 % C R a n d 3 9 % P R rates were see n, wit h me dia n P F S  of 1 3. 6 m o nt hs  a n d me dia n O S of 4. 7 
years . W he n cla dri bi ne was c o m bi ne d wit h rit u xi ma b  i n a f oll o w-u p st u d y of 2 9 patie nts  wit h 
me dia n a ge of 7 0, C R i ncrease d t o 5 2 % , P R was 1 4 %, me dia n P F S  was 1 2. 1 m o nt hs, a n d me dia n 
O S was n ot reac he d . Of 1 5 patie nts ac hie vi n g C R, o nl y  3 patie nt s rela pse d wit h t he me dia n 
f oll o w-u p of 2 1. 5 m o nt hs . Patie nts recei ve d a me dia n of 4 c ycles. C o m bi nati o n of cla dri bi ne a n d 
rit u xi ma b res ulte d i n 7 % gra de 3 a n d 2 4 % gra de 4 ne utr o pe nia, as well as 1 4 % gra de 3 a n d 3 % 
gra de 4 t hr o m b oc yt o pe nia. O ne patie nt die d d uri n g treat me nt fr o m a cere br o vasc ular i nci de nt  
f oll o wi n g a p ne u m o nia. (I n war ds et al, 2 0 0 8 ). Si milar if n ot m ore i m pressi ve res p o nses were see n 

Versi o n 7 :  0 8/ 1 5 / 2 0 1 7  
2 9  
at t he U ni versit y of Ariz o na Ca ncer Ce nter a n d Ore g o n Healt h a n d Scie nce U ni versit y ( pers o nal 
c o m m u nicati o n, Drs. Miller a n d E p ner).   
Cla dri bi ne i n i n d ole nt l y m p h o ma 
I nitial st u d y b y Ka y et al ( 1 9 9 2) i n 4 0 patie nts, 2 9 refract or y t o pri or t hera p y, usi n g 7- da y i nf usi o n 
sc he d ule s h o we d 2 0 % C R a n d 2 3 % P R wit h a me dia n d urati o n of res p o nse bei n g 5 m o nt hs. Gra de 
3- 4 ne utr o pe nia a n d t hr o m b oc yt o pe nia were o bser ve d i n 1 8 % a n d 3 0 %, res pecti vel y, wit h o nl y 
o ne patie nt wit h platelet c o u nt bel o w 2 0, 0 0 0/ µ L. T here was c u m ulati ve m yel os u p pressi o n a n d 
i ncrease d ris k of i nfecti o n, wit h 1 3 % bactere mia. F urt her st u dies i n rela pse d/refract or y i n d ole nt 
N H L c o nfir me d O R R of 3 6- 6 5 % a n d C R rates of 4- 2 0 % (re vie we d b y Zi nza ni, 2 0 0 2).  
I n u ntreate d i n d ole nt l y m p h o mas, cla dri bi ne was e ve n m ore effecti ve, wit h O R R 6 4-1 0 0 % a n d 
C R rates of 7 -3 2 % (re vie we d b y Zi nza ni, 2 0 0 2). T he lar gest was b y Fri dri k et al ( 1 9 9 8) i n 5 0 
patie nts, 6 of w h o m ha d ma ntle cell l y m p h o ma, usi n g 0. 1 2 m g/ k g I V 2 -h o ur i nf usi o n da ys 1 -5 of 
a 2 8 da y c ycle, f or 4 c ycles. O R R was 8 8 %, 2 8 % C R rate, wit h 2 1 -m o nt h O S of 9 1 % a n d 2 1 -
m o nt h ti me t o treat me nt fail ure of 5 1 % . O nl y 1 0 % gra de 3-4 ne utr o pe nia a n d 0 % gra de 3 -4 
t hr o m b oc yt o pe nia were see n, wit h o nl y 7 i nfecti o ns d uri n g treat me nt a n d 6 i nfecti o ns d uri n g t he 
o bser vati o n peri o d. All ma ntle cell l y m p h o ma patie nts res p o n de d ( 3 C Rs, 3 P Rs).   
Cla dri bi ne has bee n st u die d m uc h less t ha n fl u dara bi ne, a n ot her p uri ne a nal o g , a n d u ntil rece ntl y 
t here was n o hea d-t o-hea d c o m paris o n of t he t w o.  Rece nt p hase III trial i n u ntreate d s y m pt o matic 
C L L ra n d o mize d 2 2 9 patie nts fr o m Sca n di na via a n d A ustralia t o cla dri bi ne 5 m g/ m 2 I V o ver  2 
h o urs da ys 1 - 5; fl u dara bi ne 2 5 m g/ m 2 I V b ol us da ys 1-5; or c hl ora m b ucil 1 0 m g/ m 2 orall y da ys 
1- 1 0; o n a 2 8 da y c ycle.  Me dia n ti me t o pr o gressi o n was 2 5 m o nt hs f or cla dri bi ne, 1 0 m o nt hs f or 
fl u dara bi ne,  a n d  9  m o nt hs  f or  c hl ora m b ucil  ( p = 0. 0 0 0 3).  T he  tre n d f or  me dia n  O S  fa v ore d  
cla dri bi ne  ( 8 2  m o nt hs  vs.  6 8  m o nt hs  f or  fl u dara bi ne)  b ut  was  n ot  statisticall y  si g nifica nt.  
( Karlss o n et al., A S H 2 0 0 7). 
Rit u xi m a b  
Rit u xa n ®  ( Rit u xi ma b) is i n dicate d f or t he treat me nt of patie nts wit h rela pse d or refract or y, l o w-
gra de or f ollic ular, C D 2 0- p ositi ve, B -cell, n o n- H o d g ki n's l y m p h o ma. 
Rit u xa n ®  ( Rit u xi ma b) is i n dicate d f or t he first-li ne treat me nt of f ollic ular, C D 2 0-p ositi ve, B -cell 
n o n- H o d g ki n's l y m p h o ma i n c o m bi nati o n wit h C V P c he m ot hera p y. 
Rit u xa n ®  ( Rit u xi ma b) is i n dicate d f or t he treat me nt of l o w-gra de, C D 2 0 -p ositi ve, B -cell n o n-
H o d g ki n's l y m p h o ma i n patie nts wit h sta ble disease or w h o ac hie ve a partial or c o m plete res p o nse 
f oll o wi n g first-li ne treat me nt wit h C V P c he m ot hera p y. 
Rit u xa n ®  ( Rit u xi ma b) is i n dicate d f or t he first-li ne treat me nt of diff use lar ge B-cell, C D 2 0 -
p ositi ve, n o n -H o d g ki n's l y m p h o ma i n c o m bi nati o n wit h C H O P or ot her a nt hrac ycli ne -base d 
c he m ot hera p y re gi me ns. 
Rela pse d  or Refract or y, L o w - Gra de or F ollic ular, C D 2 0- P ositi ve, B-Cell N H L  
T he safet y a n d effecti ve ness of Rit u xa n i n rela pse d, refract or y C D 2 0 + N H L were de m o nstrate d 
i n 3 si n gle-ar m st u dies e nr olli n g 2 9 6 patie nts.  

Versi o n 7 :  0 8/ 1 5 / 2 0 1 7  
3 0  
St u d y 1 
A m ultice nter, o pe n -la bel, si n gle-ar m st u d y was c o n d ucte d i n 1 6 6 patie nts wit h rela pse d or 
refract or y, l o w-gra de or f ollic ular B -cell N H L w h o recei ve d 3 7 5 m g/ m 2 of Rit u xa n gi ve n as a n 
i ntra ve n o us i nf usi o n wee kl y f or 4 d oses ( Mc La u g hli n et al., 1 9 9 8). Patie nts wit h t u m or masses 
> 1 0c m or wit h > 5 0 0 0 l y m p h oc ytes/ µ L i n t he peri p heral bl o o d were e xcl u de d fr o m t he st u d y. 
Res ults are s u m marize d i n Ta ble # 1. T he me dia n ti me t o o nset of res p o nse was 5 0 da ys. Disease -
relate d si g ns a n d s y m pt o ms (i ncl u di n g B-s y m pt o ms) res ol ve d i n 6 4 % ( 2 5/ 3 9) of t h ose patie nts 
wit h s uc h s y m pt o ms at st u d y e ntr y. 
St u d y 2 
I n  a  m ultice nter,  si n gle-arm  st u d y,  3 7  patie nts  wit h  rela pse d  or  refract or y,  l o w -gra de  N H L  
recei ve d 3 7 5 m g/ m2 of R itu xa n wee kl y f or 8 d oses  ( Mal o ne y et al., 1 9 9 7). Res ults are s u m marize d 
i n Ta ble # 1. 
St u d y 3 
I n a m ultice nter, si n gle-ar m st u d y, 6 0 patie nts recei ve d 3 7 5 m g/ m 2 of Rit u x a n wee kl y f or 4 d oses. 
All patie nts ha d rela pse d or refract or y, l o w -gra de or f ollic ular B -cell N H L a n d ha d ac hie ve d a n 
o bjecti ve cli nical res p o nse t o Rit u xa n a d mi nistere d 3. 8 -3 5. 6 m o nt hs ( me dia n 1 4. 5 m o nt hs) pri or 
t o retreat me nt wit h Rit u xa n ( Da vis et al., 2 0 0 0). Of t hese 6 0 patie nts, 5 recei ve d m ore t ha n o ne 
a d diti o nal c o urse of Rit u xa n. Res ults are s u m marize d i n Ta ble # 1. 
B ul k y Disease 
I n p o ole d data  fr o m st u dies  o ne  a n d t hree, 3 9 patie nts wit h b ul k y (si n gle lesi o n > 1 0c m i n 
dia meter) a n d rela pse d or refract or y, l o w-gra de N H L recei ve d Rit u xa n 3 7 5 m g/ m 2 wee kl y f or 4 
d oses ( Da vis et al., 1 9 9 9) . Res ults are s u m marize d i n Ta ble 2. 
 
T a ble 2  
S u m mar y of Rit u xa n Data b y Sc he d ule a n d Cli nical Setti n g 
 
St u d y 1  
Wee kl y x 4  
N = 1 6 6  
St u d y 2  
Wee kl y x 8  
N = 3 7  
St u d y 1 a n d  3  
B ul k y disease  
Wee kl y x 4  
N = 3 9 a 
St u d y 3  
Retreat me nt,  
Wee kl y x 4  
N = 6 0  
O verall Res p o nse 
Rate  
4 8 %  
5 7 %  
3 6 %  
3 8 %  
C o m plete Res p o nse 
Rate  
6 %  
1 4 %  
3 %  
1 0 %  
Me dia n D urati o n of 
Res p o nse b,c, d 
( m o nt hs) [ Ra n ge] 
1 1. 2  
 
[ 1. 9 t o 4 2. 1 +] 
1 3. 4  
 
[ 2. 5 t o 3 6. 5 +] 
6. 9  
 
[ 2. 8 t o 2 5. 0 +]  
1 5. 0  
 
[ 3. 0 t o 2 5. 1 +] 
a   Si x of t hese pati e nts are i ncl u de d i n t he first c ol u m n. T h us, data fr o m 2 9 6 i nte nt t o treat patie nts are pr o vi de d i n t his ta ble.  
b  Ka pla n-Meier pr ojecte d wit h o bser ve d ra n ge.  
c “ +” i n dicates a n o n g oi n g res p o nse.  
d  D urati o n of res p o nse: i nter val fr o m t he o nset of res p o nse t o disease pr o gressi o n.      
 
St u d y 4 

Versi o n 7 :  0 8/ 1 5 / 2 0 1 7  
3 1  
A t otal of 3 2 2 patie nts wit h pre vi o usl y u ntreate d f ollic ular N H L were ra n d o mize d ( 1: 1) t o recei ve 
u p t o ei g ht 3 -wee k c ycles of C V P c he m ot hera p y al o ne ( C V P) or i n c o m bi nati o n wit h Rit u xa n 3 7 5 
m g/ m 2 o n Da y 1 of eac h c ycle ( R -C V P) i n a n o pe n -la bel, m ultice nter st u d y ( Marc us et al., 2 0 0 5). 
T he mai n o utc o me meas ure of t he st u d y was pr o gressi o n -free s ur vi val ( P F S) defi ne d as t he ti me 
fr o m ra n d o mizati o n t o t he first of pr o gressi o n, rela pse, or deat h. 
T we nt y -si x perce nt of t he st u d y p o p ulati o n was > 6 0 years of a ge, 9 9 % ha d Sta ge III or I V disease, 
a n d 5 0 % ha d a n I nter nati o nal Pr o g n ostic I n de x (I PI) sc ore > 2. T he res ults f o r P F S as deter mi ne d 
b y a bli n de d, i n de pe n de nt assess me nt of pr o gressi o n are prese nte d i n Ta ble 3 . T he p oi nt esti mates 
ma y be i nfl ue nce d b y t he prese nce of i nf or mati ve ce ns ori n g. T he P F S res ults base d o n i n vesti gat or 
assess me nt of pr o gressi o n were si milar t o t h ose o btai ne d b y t he i n de pe n de nt re vie w assess me n t. 
T a ble 3  
 
 
St u d y Ar m  
 
 
R -C V P  
N = 1 6 2  
 
C V P  
N = 1 6 0  
Me dia n P F S ( years)
a 
2. 4  
 
1. 4  
 
Hazar d rati o 
( 9 5 % CI)b 
 
0. 4 4 ( 0. 2 9, 0. 6 5)  
 
a  p < 0. 0 0 0 1, t w o -si de d stratifie d l o g-ra n k test. 
b  Esti mates of C o x re gressi o n stratifie d b y ce nter.  
 
N o n -Pr o gressi n g  L o w - Gra de. C D 2 0 -P ositi ve,  B -Cell  N H L  F oll o wi n g  First -Li ne  C V P  
C he m ot hera p y 
St u d y 5 
A t otal of 3 2 2 patie nts wit h pre vi o usl y u ntreate d l o w -gra de, B -cell N H L w h o di d n ot pr o gress 
after 6 or 8 c ycles of C V P c he m ot hera p y were e nr olle d i n a n o pe n -la bel, m ultice nter, ra n d o mize d 
trial. Patie nts were ra n d o mize d ( 1: 1) t o recei ve Rit u xa n, 3 7 5 m g/ m2 i ntra ve n o us i nf usi o n, o nce 
wee kl y f or 4 d oses e ver y 6 m o nt hs f or u p t o 1 6 d oses or n o f urt her t hera pe utic i nter ve nti o n  
( H oc hster et al., A S H 2 0 0 5). T he mai n o utc o me meas ure of t he st u d y was pr o gressi o n-free 
s ur vi val defi ne d as t he ti me fr o m ra n d o mizati o n t o pr o gressi o n, rela pse, or deat h. T hirt y -se ve n 
perce nt of t he st u d y p o p ulati o n was > 6 0 years of a ge, 8 8 % has Sta ge III or I V disease, a n d 6 3 % 
ha d a n I PI sc ore > 2. 
T here was a r e d ucti o n i n t he ris k of pr o gressi o n, rela pse, or deat h ( hazar d rati o esti mate i n t he 
ra n ge of 0. 3 6 t o 0. 4 9) f or patie nts ra n d o mize d t o Rit u xa n as c o m pare d t o t h ose w h o recei ve d n o 
a d diti o nal treat me nt.  
Rit u xi ma b i n ma ntle cell l y m p h o ma 
I n ma ntle cell l y m ph o ma, rit u xi ma b see ms t o e n ha nce t he effects of c o m bi nati o n c he m ot hera p y 
b ut has o nl y m o derate acti vit y as a si n gle a ge nt. S i n gle a ge nt rit u xi ma b gi ve n at 3 7 5 m g/ m 2 
wee kl y f or 4 d oses was e xa mi ne d i n 3 4 u ntreate d a n d 4 0 patie nts  wit h rela pse d M C L . F or 
u ntreate d patie nts, O R R was 3 8 %, C R rate was 1 6 %, w hile f or pre vi o usl y treate d patie nts O R R 
was 3 7 % a n d C R rate was 1 4 %. Ti me t o pr o gressi o n was 7 m o nt hs, wit h res p o nse d urati o n of 1 2 

Versi o n 7 :  0 8/ 1 5 / 2 0 1 7  
3 2  
m o nt hs ( F ora n et al, 2 0 0 0).  I n a pr os pecti ve p hase III trial, 1 2 2  patie nts wit h ne wl y dia g n ose d 
M C L were ra n d o mize d t o C H O P or C H O P c o m bi ne d wit h rit u xi ma b. A d diti o n of rit u xi ma b 
i m pr o ve d O R R fr o m 7 5 % t o 9 4 %, C R rate fr o m 7 % t o 3 4 %; a n d me dia n ti me t o treat me nt fail ure 
fr o m 1 4 t o 2 1 m o nt hs. H o we ver, t here was n o differe nce i n P F S or O S ( Le nz et al ., 2 0 0 5). O n t he 
ot her ha n d, w he n rit u xi ma b was a d de d t o a c o m bi nati o n of fl u dara bi ne, c ycl o p h os p ha mi de a n d 
mit o xa ntr o ne ( F C M) i n a ra n d o mize d pr os pecti ve trial of rela pse d M C L, it res ulte d i n i m pr o ve d 
O S ( n ot reac he d vs. 1 1 m o n t hs) ( F orst p oi nt ner et al., 2 0 0 4).   
1. 3. 4  P ote nti al Ris ks of Cl a dri bi ne a n d Rit u xi m a b  
Cl a dri bi ne  
Se vere b o ne marr o w s u p pressi o n , i ncl u di n g ne utr o pe nia, a ne mia a n d t hr o m b oc yt o pe nia, has bee n 
c o m m o nl y o bser ve d i n patie nts treate d wit h Le ustati n, es peciall y at h i g h d oses. At i nitiati o n of 
treat me nt, m ost patie nts i n t he cli nical st u dies ha d he mat ol o gical i m pair me nt as a ma nifestati o n 
of  acti ve  Hair y  Cell  Le u ke mia.  F oll o wi n g  treat me nt  wit h  Le ustati n,  f urt her  he mat ol o gic  
i m pair me nt occ urre d bef ore rec o ver y of peri p heral bl o o d c o u nts be ga n. D uri n g t he first t w o wee ks 
after treat me nt i nitiati o n, mea n Platelet C o u nt, A N C, a n d He m o gl o bi n c o nce ntrati o n decli ne d a n d 
s u bse q ue ntl y i ncrease d wit h n or malizati o n of mea n c o u nts b y Da y 1 2, Wee k 5 a n d Wee k 8, 
res pecti vel y. T he m yel os u p pressi ve effects of Le ustati n were m ost n ota ble d uri n g  t he first m o nt h 
f oll o wi n g treat me nt. F ort y-f o ur perce nt ( 4 4 %) of patie nts recei ve d tra nsf usi o ns wit h R B Cs a n d 
1 4 %  recei ve d  tra nsf usi o ns  wit h  platelets  d uri n g  M o nt h  1.  Caref ul  he mat ol o gic  m o nit ori n g, 
es peciall y d uri n g t he first 4 t o 8 wee ks after treat me nt wit h Le ustati n I njecti o n, is rec o m me n de d.  
Fe ver ( T > 1 0 0 oF) was ass ociate d wit h t he use of Le ustati n i n a p pr o xi matel y t w o -t hir ds of patie nts 
( 1 3 1/ 1 9 6) i n t he first m o nt h of t hera p y. Virt uall y all of t he ir patie nts were treate d e m piricall y wit h 
pare nteral a nti bi otics. O verall, 4 7 % ( 9 3/ 1 9 6) of all patie nts ha d fe ver i n t he setti n g of ne utr o pe nia 
( A N C < 1 0 0 0), i ncl u di n g 6 2 patie nts ( 3 2 %) wit h se vere ne utr o pe nia (i.e., A N C < 5 0 0). 
I n a P hase I i n vestigati o nal st u d y usi n g Le ustati n i n hi g h d oses ( 4 t o 9 ti mes t he rec o m me n de d 
d ose f or Hair y Cell Le u ke mia) as part of a b o ne marr o w tra ns pla nt c o n diti o ni n g re gi me n, w hic h 
als o i ncl u de d hi g h d ose c ycl o p h os p ha mi de a n d t otal b o d y irra diati o n, ac ute  ne p hr ot o xicit y a n d 
dela ye d o nset ne ur ot o xicit y were o bser ve d.  
T hirt y -o ne ( 3 1) p o or -ris k patie nts wit h dr u g-resista nt ac ute le u ke mia i n rela pse ( 2 9 cases) or n o n-
H o d g ki n’s  L y m p h o ma  ( 2  cases)  recei ve d  Le ustati n  f or  7  t o  1 4  da ys  pri or  t o  b o ne  marr o w  
tra ns pla ntati o n. D uri n g i nf usi o n, 8 patie nts e x perie nce d gastr oi ntesti nal s y m pt o ms. W hile t he 
b o ne marr o w was i nitiall y cleare d of all he mat o p oietic ele me nts, i ncl u di n g t u m or cells, le u ke mia 
e ve nt uall y rec urre d i n all treate d patie nts. Wit hi n 7 t o 1 3 da ys after starti n g treat me nt wit h 
Le ustati n, 6 patie nts ( 1 9 %) de vel o pe d ma nifestati o ns of re nal d ysf u ncti o n (e. g., aci d osis, a n uria, 
ele vate d ser u m creati ni ne, etc.) a n d 5 re q uire d d ialysis. Se veral of t hese patie nts were als o bei n g 
treate d  wit h  ot her  me dicati o ns  ha vi n g  k n o w n  ne p hr ot o xic  p ote ntial.  Re nal  d ysf u ncti o n  was  
re versi ble i n 2 of t hese patie nts. I n t he 4 patie nts  w h ose re nal f u ncti o n ha d n ot rec o vere d at t he 
ti me of deat h, a ut o psies were  perf or me d; i n 2 of t hese, e vi de nce of t u b ular da ma ge was n ote d. 
Ele ve n ( 1 1) patie nts ( 3 5 %) e x perie nce d dela ye d o nset ne ur ol o gic t o xicit y. I n t he maj orit y, t his 
was c haracterize d b y pr o gressi ve irre versi ble m ot or wea k ness ( para paresis/ q ua dri paresis) of t he  
u p per a n d/ or l o wer e xtre mities, first n ote d 3 5 t o 8 4 da ys after starti n g hi g h d ose t hera p y wit h 

Versi o n 7 :  0 8/ 1 5 / 2 0 1 7  
3 3  
Le ustati n. N o n -i n vasi ve testi n g (electr o m y o gra p h y a n d ner ve c o n d ucti o n st u dies) was c o nsiste nt 
wit h de m yeli nati n g disease. Se vere ne ur ol o gic t o xicit y has als o bee n n ote d wit h hi g h d oses of 
a n ot her dr u g i n t his class.  
A x o nal peri p heral p ol y ne ur o pat h y was o bser ve d i n a d ose fir Hair y Cell Le u ke mia) i n patie nts 
n ot recei vi n g c ycl o p h os p ha mi de or t otal b o d y irra diati o n. 
Se vere ne ur ol o gical t o xicit y has bee n re p orte d rarel y f oll o wi n g treat me nt wit h sta n dar d cla dri bi ne 
d osi n g re gi me ns. 
I n patie nts wit h Hair y Cell Le u ke mia treate d wit h t he rec o m me n de d treat me nt re gi me n ( 0. 0 9 
m g/ k g/ da y f or 7 c o nsec uti ve da ys), t here ha ve bee n n o re p orts of ne p hr ol o gic t o xicities. 
Of t he 1 9 6 Hair y Cell Le u ke mia patie nts e ntere d i n t he t w o trials, t here were 8 deat hs f oll o wi n g 
treat me nt. Of t hese, 6 were of i nfecti o us eti ol o g y, i ncl u di n g 3 p ne u m o nias, a n d 2 occ urre d i n t he 
first m o nt h f oll o wi n g Le ustati n  t hera p y. Of t he 8 deat hs, 6 occ urre d i n pre vi o usl y treate d patie nts 
w h o were refract or y t o α  i nterfer o n. 
Be nz yl alc o h ol is a c o nstit ue nt of t he rec o m me n de d dil ue nt f or t he 7 -da y i nf usi o n s ol uti o n. Be nz yl 
alc o h ol has bee n re p orte d t o be ass ociate d wit h a fatal “ Gas pi n g S y n dr o me” i n pre mat ure i nfa nts. 
Terat o ge nesis, Carci n o ge nesis, I m pair me nt of Fertilit y, Pre g na nc y, a n d N ursi n g: 
Le ustati n I njecti o n s h o ul d n ot be gi ve n d uri n g pre g na nc y. 
Cla dri bi ne is terat o ge nic i n mice a n d ra b bits a n d c o nse q ue ntl y has t he p ote ntial t o ca use fetal 
har m w he n a d mi nistere d t o a pre g na nt w o ma n. A si g nifica nt i ncrease i n fetal variati o ns was 
o bser ve d i n mice recei vi n g 1. 5 m g/ k g/ da y ( 4. 5 m g/ m 2) a n d i ncrease d  res or pti o ns, re d uce d litter 
size a n d i ncrease d fetal malf or mati o ns were o bser ve d w he n mice recei ve d 3. 0 m g/ k g/ d a y ( 9 
m g/ m 2). Fetal deat h a n d malf or mati o ns were o bser ve d i n ra b bits t hat recei ve d 3. 0 m g/ k g/ da y ( 3 3. 0 
m g/ m 2). N o fetal effects were see n i n mice at 0. 5 m g/ k g/ da y ( 1. 5 m g/ m2) or i n ra b bits at 1. 0 
m g/ k g/ da y ( 1 1. 0 m g/ m 2). 
Alt h o u g h t here is n o e vi de nce of terat o ge nicit y i n h u ma ns d ue t o Le ustati n, ot her dr u gs w hic h 
i n hi bit D N A s y nt hesis (e. g., met h otre xate a n d a mi n o pteri n) ha ve bee n re p orte d t o be terat o ge nic 
i n h u ma ns. Le ustati n has bee n s h o w n t o be e m br y ot o xic i n mice w he n gi ve n at d oses e q ui vale nt 
t o t he rec o m me n de d d ose. 
T here are n o a de q uate a n d well c o ntr olle d st u dies i n pre g na nt w o me n. If Le ustati n is use d d uri n g 
pre g na nc y, of if t he patie nt bec o mes pre g na nt w hile ta ki n g t his dr u g, t he patie nt s h o ul d be 
a p prise d of t he p ote ntial hazar d t o t he fet us. W o me n of c hil d beari n g p ote ntial s h o ul d be a d vise d 
t o a v oi d bec o mi n g pre g na nt. 
N o  a ni mal  carci n o ge nicit y  st u dies  ha ve  bee n  c o n d ucte d  wit h  cla dri bi ne.  H o we ver,  its  
carci n o ge nic p ote ntial ca n n ot be e xcl u de d base d o n de m o nstrate d ge n ot o xicit y of cla dri bi ne.  
Cla dr i bi ne was n ot m ut a ge nic i n vitr o ( A mes a n d C hi nese ha mster o var y cell ge ne m utati o n tests) 
a n d di d n ot i n d uce u nsc he d ule d D N A s y nt hesis i n pri mar y rat he pat oc yte c ult ures. H o we ver, 
cla dri bi ne was clast o ge nic b ot h i n vitr o (c hr o m os o me a berrati o ns i n C hi nese ha mster o var y cells) 
a n d i n viv o ( m o use b o ne marr o w micr o n ucle us test).   

Versi o n 7 :  0 8/ 1 5 / 2 0 1 7  
3 4  
W he n a d mi nistere d  i ntra ve n o usl y t o C y n o m ol g us m o n ke ys, cla dri bi ne has bee n s h o w n t o ca use 
s u p pressi o n of ra pi dl y ge nerati n g cells, i ncl u di n g testic ular cells. T he effect o n h u ma n fertilit y is 
u n k n o w n.  
It is n ot k n o w n w het her t his dr u g is e xcrete d i n h u ma n mil k. Beca use of t he p ote ntial f or seri o us 
a d verse reacti o ns i n n ursi n g i nfa nts, patie nts s h o ul d n ot be n ursi n g w hile recei vi n g cla dri bi ne.  
 
A d verse reacti o ns : 
 
Safet y data are base d o n 1 9 6 patie nts wit h Hair y cell Le u ke mia: t he ori gi nal c o h ort of 1 2 4 patie nts 
pl us a n a d diti o nal 7 2 patie nts e nr olle d at t he sa me t w o ce nters after t he ori gi nal e nr oll me nt c ut off. 
I n m o nt h 1 of Hair y cell Le u ke mia cli nical trials, se vere ne utr o pe nia was n ote d i n 7 0 % of patie nts, 
fe ver  i n  6 9 %,  a n d  i nfecti o n  was  d oc u me nte d  i n  2 8 %.  Ot her  a d verse  e x perie nces  re p orte d  
fre q ue ntl y d uri n g t he first 1 4 da ys after i nitiati n g treat me nt i ncl u de d: fati g ue ( 4 5 %), na usea 
( 2 8 %), ras h ( 2 7 %), hea dac he ( 2 2 %), a n d i njecti o ns site reacti o ns ( 1 9 %). M ost n o n - he mat ol o gic 
a d verse e x perie nces were mil d t o m o derate i n se verit y.  
M yel os u p pressi o n  was  fre q ue ntl y  o bser ve d  d uri n g  t he  first  m o nt h  after  starti n g  treat me nt.  
Ne utr o pe nia ( A N C < 5 0 0 x 1 0 6/ L) was n ote d i n 7 0 % of patie nts, c o m pare d wit h 2 6 % i n w h o m it 
was prese nt i nitiall y. Se vere a ne mia ( he m o gl o bi n < 8. 5 g/ d L) de vel o pe d i n 3 7 % of patie nts, 
c o m pare d wit h 1 0 % i nitiall y. T hr o m b oc yt o pe nia ( platelets < 2 0 x 1 0 9/ L) de vel o pe d i n 1 2 % of 
patie nts, c o m pare d t o 4 % i n w h o m it was n ote d i nitiall y.  
D uri n g t he first m o nt h, 5 4 of 1 9 6 patie nts ( 2 8 %) e x hi bite d d oc u me nte d e vi de nce of i nfecti o n. 
Seri o us i nfecti o ns (e. g., se ptice mia, p ne u m o nia) were re p orte d i n 6 % of all patie nts; t he re ma i ni n g 
i nfecti o ns  were mil d  or  m o derate.  Se veral  deat hs  were  attri b uta ble  t o  i nfecti o n  a n d/ or  
c o m plicati o ns relate d t o t he u n derl yi n g disease. D uri n g t he sec o n d m o nt h, t he o verall rate of 
d oc u me nte d i nfecti o n was 6 %; t hese i nfecti o ns w ere mil d t o m o derate a n d n o se vere s yste mic 
i nfecti ons were see n. After t he t hir d m o nt h, t he m o nt hl y i nci de nce of i nfecti o n was eit her less 
t ha n or e q ual t o t hat of t he m o nt hs i m me diatel y prece di n g Le ustati n t hera p y.  
D uri n g t he first m o nt h, 1 1 % of patie nts e x perie nce d se ver e fe ver (i.e., ≥ 1 0 4oF). D oc u me nt e d 
i nfecti o ns were n ote d i n fe wer t ha n o ne-t hir d of fe brile e pis o des.  Of t he 1 9 6 patie nts st u die d, 1 9 
were n ote d t o ha ve a d oc u me nte d i nfecti o n i n t he m o nt h pri or t o treat me nt. I n t he m o nt h f oll o wi n g 
treat me nt, t here were 5 4 e pis o des of d oc u me nte d i nfectio n: 2 3 ( 4 2 %) were bacterial, 1 1 ( 2 0 %) 
were viral a n d 1 1 ( 2 0 %) were f u n gal. Se ve n of 8 d oc u me nte d e pis o des of her pes z oster occ urre d 
d uri n g t he m o nt h f oll o wi n g treat me nt. Virt uall y all of t hese patie nts were treate d e m piricall y wit h 
a nti bi otics.  
A nal ysis  of  l y m p h oc yte  s u bsets  i n dicates  t hat  treat me nt  wit h  cla dri bi ne  is  ass ociate d  wit h  
pr ol o n ge d de pressi o n of t he C D 4 c o u nts. Pri or t o treat me nt, t he mea n C D 4 c o u nt was 7 6 6/ µl. T he 
mea n C D 4 c o u nt na dir, w hic h occ urre d 4 t o 6 m o nt hs f oll o wi n g treat me nt, was 2 7 2/ µl. Fiftee n 
m o nt hs after treat me nt, mea n C D 4 c o u nts re mai ne d bel o w 5 0 0/ µl. C D 8 c o u nts be ha ve d si milarl y, 
t h o u g h i ncreasi n g c o u nts were o bser ve d after 9 m o nt hs. T he cli nical si g nifica nce of t he pr ol o n ge d 
C D 4 l y m p h o pe nia is u nclear.  
A n ot her e ve nt of u n k n o w n  cli nical si g nifica nce i ncl u des t he o bser vati o n of pr ol o n ge d b o ne 
marr o w h y p ocell ularit y. B o ne marr o w cell ularit y of < 3 5 % was n ote d after 4 m o nt hs i n 4 2 of 1 2 4 

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3 5  
patie nts ( 3 4 %) treate d i n t he t w o pi v otal trials. T his h y p ocell ularit y was n ote d as late as da y  1 0 1 0. 
It is n ot k n o w n w het her t he h y p ocell ularit y is t he res ult of disease relate d marr o w fi br osis or if it 
is t he res ult of cla dri bi ne t o xicit y. T here was n o a p pare nt cli nical effect o n t he peri p heral bl o o d 
c o u nts.  
T he vast maj orit y of ras hes were mil d a n d occ urre d i n patie nts w h o were recei vi n g or ha d rece ntl y 
bee n treate d wit h ot her me dicati o ns (e. g., all o p uri n ol or a nti bi otics) k n o w n t o ca use ras h.  
M ost e pis o des of na usea were mil d, n ot acc o m pa nie d b y v o miti n g, a n d di d n ot re q uire treat me nt 
wit h a nti e metics. I n patie nts re q uiri n g a ntie metics, na usea was easil y c o ntr olle d, m ost fre q ue ntl y 
wit h c hl or pr o mazi ne.  
A d verse reacti o ns re p orte d d uri n g t he first 2 wee ks f oll o wi n g treat me nt i nitiati o n (re gar dless of 
relati o ns hi p t o dr u g) b y > 5 % of patie nts i ncl u de d: 
B o dy as a w h ole : fe ver ( 6 9 %), fati g ue ( 4 5 %), c hills ( 9 %), ast he nia ( 9 %), dia p h oresis ( 9 %), 
malaise ( 7 %) , tr u n k pai n ( 6 %) 
G astr oi ntesti n al :  na usea  ( 2 8 %),  decrease d  a p petite  ( 1 7 %),  v o miti n g  ( 1 3 %),  diarr hea  ( 1 0 %),  
c o nsti pati o n ( 9 %), a b d o mi nal pai n ( 6 %) 
He m at ol o gic/ Ly m p h atic : p ur p ura ( 1 0 %), petec hiae ( 8 %), e pista xis ( 5 %) 
Nerv o us Syste m : hea dac he ( 2 2 %), dizzi ness ( 9 %), i ns o m nia ( 7 %) 
C ar di ov asc ul ar Syste m : e de ma ( 6 %), tac h ycar dia ( 6 %) 
Res pir at ory Syste m : a b n or mal breat h s o u n ds ( 1 1 %), c o u g h ( 1 0 %), a b n or mal c hest s o u n ds ( 9 %), 
s h ort ness of breat h ( 7 %) 
Ski n/ S u bc ut a ne o us Tiss ue : ras h ( 2 7 %), i njecti o ns site reacti o n ( 1 9 %), pr urit us ( 6 %), pai n ( 6 %), 
er yt he ma ( 6 %)  
M usc ul oskelet al Syste m : m yal gia ( 7 %), art hral gia ( 5 %)  
A d verse reacti o ns relate d t o i ntra ve n o us a d mi nist rati o n i ncl u de d: i njecti o n site reacti o ns ( 9 %) 
(i.e., re d ness, s welli n g, pai n), t hr o m b osis ( 2 %), p hle bitis ( 2 %), a n d a br o ke n cat heter ( 1 %). T hese 
a p pear  t o  be  relate d  t o  t he  i nf usi o n  pr oce d ure  a n d/ or  i n d welli n g  cat heter,  rat her  t ha n  t he  
me dicati o n or t he ve hicle. Fr o m Da y 1 5 t o t he last f oll o w -u p visit, t he o nl y e ve nts re p orte d b y 
> 5 % of patie nts were: fati g ue ( 1 1 %), ras h ( 1 0 %), hea dac he ( 7 %), c o u g h ( 7 %), a n d malaise ( 5 %).  
T he f oll o wi n g a d diti o nal a d verse e ve nts s ha ve bee n re p orte d si nce t he dr u g beca me c o m merciall y 
a vaila ble. T hese a d verse e ve nts ha ve bee n re p orte d pri maril y i n patie nts w h o recei ve d m ulti ple 
c o urse of Le ustati n I njecti o n:  
He m at ol o gic : b o ne marr o w s u p pressi o n wit h pr ol o n ge d pa nc yt o pe nia, i ncl u di n g s o me re p orts of 
a plastic a ne mia; he m ol ytic a ne mia, w hic h was re p orte d i n patie nts wit h l y m p h oi d mali g na ncies, 
occ urri n g wit hi n t he first fe w wee ks f oll o wi n g treat me nt. Rare cases of m yel o d ys plastic s y n dr o me 
ha ve bee n re p orte d.  
He p atic : re versi ble, ge nerall y mil d i ncreases i n bilir u bi n a n d tra nsa mi nases.   
Nerv o us Syste m : Ne ur ol o gical t o xicit y; h o we ver, se vere ne ur ot o xicit y has bee n re p orte d rarel y 

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f oll o wi n g treat me nt wit h sta n dar d cla dri bi ne d osi n g re gi me ns. 
Res pir at ory Syste m : p ul m o nar y i nterstitial i nfiltrates; i n m ost cases, a n i nfecti o us eti ol o g y was 
i de ntifie d.  
Ski n/ S u bc ut a ne o us :  urticaria,  h y pere osi n o p hilia.  I n  is olate d cases  Ste ve ns-J o h ns o n a n d  t o xic  
e pi der mal necr ol ysis ha ve bee n re p orte d i n patie nt w h o were recei vi n g or ha d rece ntl y bee n 
treate d wit h ot her me dicati o ns (e. g., all o p uri n ol or a nti bi otics) k n o w n t o ca use t hese s y n dr o mes.  
O p p ort u nistic  i nfecti o ns  ha ve  occ urre d  i n  t he  ac ute  p hase  of  treat me nt  d ue  t o  t he  
i m m u n os u p pressi o n me diate b y Le ustati n I njecti o n.  
 
Rit u xi m a b  
 
H u ma n T o xi c ol o g y:  Si n gle d oses of u p t o 5 0 0 m g/ m 2 a n d wee kl y x 4 d oses of 3 7 5 m g/ m 2 ha ve 
bee n a d mi nistere d wit h o ut d ose li miti n g t o xicit y.  A d verse e ve nts are m ost c o m m o n d uri n g t he 
i nitial a nti b o d y i nf usi o n a n d us uall y c o nsist of Gra de I or 2 fe ver ( 7 3 %), ast he nia ( 1 6 %) c hills 
( 3 8 %) na usea ( 1 9 %), v o miti n g ( 1 1 %), ras h ( 1 4 %) a n d t u m or site pai n ( 3 %).  Gra de 1 or 2 
h y p ote nsi o n ( 8 %) ma y be treate d wit h I V fl ui ds.  He mat ol o gic t o xicit y is us uall y mil d a n d 
re versi ble.  Tra nsie nt decreases i n t he W B C or platelet c o u nt ha ve bee n o bser ve d - es peciall y i n 
patie nts wit h hi g h le vels of circ ulati n g t u m or cells or b o ne marr o w i n v ol ve me nt.  T w o patie nts 
ha ve ha d late -o nset Gra de 4 ne utr o pe nia at f o ur a n d te n m o nt hs t hat was attri b ute d t o a n u n k n o w n 
ca use, was tra nsie nt a n d res ol ve d.  I nfecti o ns ( Gra de 1 a n d 2) ha ve n ot bee n relate d t o d ose le vel.  
S y m pt o ms are ge nerall y ass ociate d wit h t he i nitial a nti b o d y i nf usi o ns a n d di mi nis h i n fre q ue nc y 
wit h eac h s uccessi ve i nf usi o n.  A re p ort i n t he literat ure descri be d a n i ncrease i n fatal i nfecti o n i n 
HI V -relate d  l y m p h o ma  patie nts  w he n  rit u xi ma b  was  use d  i n  c o m bi nati o n  wit h  C H O P  
c he m ot hera p y as c o m pare d t o C H O P al o ne.  I n patie nts wit h Wal de nstr o m’s macr o gl o b uli ne mia, 
f oll o wi n g i nitiati o n of rit u xi ma b t hera p y, tra nsie nt i ncreases in ser u m I g M le vels ha ve bee n 
o bser ve d w hic h ma y res ult i n h y per visc osit y s y n dr o me re q uiri n g plas ma p heresis. 
Se vere I nf usi o n a n d H y perse nsiti vit y Reacti o ns :  Rit u xi ma b has ca use d se vere i nf usi o n reacti o ns.  
I n s o me cases, t hese reacti o ns were fatal.  A n i nfusi o n- relate d s y m pt o m c o m ple x c o nsisti n g of 
fe ver a n d c hills/ri g ors has occ urre d i n t he maj orit y of patie nts d uri n g t he first rit u xi ma b i nf usi o n.  
Si g ns a n d s y m pt o ms of se vere i nf usi o n reacti o ns ma y i ncl u de urticaria, h y p ote nsi o n, a n gi oe de ma, 
h y p o xia, or b r o nc h os pas m.  T he m ost se vere ma nifestati o ns a n d se q uelae i ncl u de p ul m o nar y 
i nfiltrates, ac ute res pirat or y distress s y n dr o me, m y ocar dial i nfarcti o n, ve ntric ular fi brillati o n, 
car di o ge nic  s h oc k,  a n d  a na p h ylactic  a n d  a na p h ylact oi d  e ve nts.   T hese  reacti o ns  ge nerall y 
occ urre d wit hi n 3 0 mi n utes t o 2 h o urs of be gi n ni n g t he first i nf usi o n, a n d res ol ve d wit h sl o wi n g 
or i nterr u pti o n of t he rit u xi ma b i nf usi o n a n d wit h s u p p orti ve care (i ncl u di n g, b ut n ot li mite d t o 
I V sali ne, di p he n h y dra mi ne, a n d aceta mi n o p he n). 
T u m or  L ysis S y n dr o me:  Rit u xi ma b ra pi dl y decreases be ni g n a n d mali g na nt C D 2 0 p ositi ve cells.  
T u m or l ysis s y n dr o me has bee n re p orte d t o occ ur wit hi n 1 2 t o 2 4 h o urs after t he first rit u xi ma b 
i nf usi o n i n patie nts wit h hi g h n u m bers of circ ulati n g mali g na nt l y m p h ocytes.  Patie nts wit h hi g h 
t u m or b ur de n ( b ul k y lesi o ns) ma y als o be at ris k.  Patie nts at ris k f or de vel o pi n g t u m or l ysis 
s y n dr o me s h o ul d be f oll o we d cl osel y a n d a p pr o priate la b orat or y m o nit ori n g perf or me d. 

Versi o n 7 :  0 8/ 1 5 / 2 0 1 7  
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He patitis B Reacti vati o n wit h Relate d F ul mi na nt He patitis a n d Ot her Viral I nfecti o ns:   He patitis 
B vir us ( H B V) reacti vati o n wit h f ul mi na nt he patitis, he patic fail ure, a n d deat h has bee n re p orte d 
i n s o me patie nts wit h he mat ol o gic mali g na ncies treate d wit h rit u xi ma b.  T he maj orit y of patie nts 
recei ve d rit u xi ma b i n c o m bi nati o n wit h c he m ot hera p y.  T he me dia n ti me t o t he dia g n osis of 
he patitis was a p pr o xi matel y 4 m o nt hs after t he i nitiati o n of rit u xi ma b a n d a p pr o xi matel y o ne 
m o nt h after t he last d ose.  Pers o ns at hi g h ris k of H B V i nfecti o n s h o ul d be scree ne d bef ore 
i nitiati o n of rit u xi ma b.  Carriers of he patitis B s h o ul d be cl osel y m o nit ore d f or cli nical a n d 
la b orat or y si g ns of acti ve H B V i nfecti o n a n d f or si g ns of he patitis d uri n g a n d f or u p t o se veral 
m o nt hs f oll o wi n g rit u xi ma b t hera p y.  I n patie nts w h o de vel o p  viral he patitis, rit u xi ma b a n d a n y 
c o nc o mita nt c he m ot hera p y s h o ul d be disc o nti n ue d a n d a p pr o priate treat me nt i ncl u di n g a nti viral 
t hera p y i nitiate d.  T here are i ns ufficie nt data re gar di n g t he safet y of res u mi n g rit u xi ma b t hera p y 
i n patie nts w h o de vel o p he patitis s u bse q ue nt t o H B V reacti vati o n.   
T he f oll o wi n g a d diti o nal seri o us viral i nfecti o ns, eit her ne w, reacti vate d or e xacer bate d, ha ve 
bee n i de ntifie d i n cli nical st u dies or p ost mar keti n g re p orts.  T he maj orit y of patie nts recei ve d 
rit u xi ma b i n c o m bi natio n wit h c he m ot hera p y or as part of a he mat o p oietic ste m cell tra ns pla nt.  
T hese viral i nfecti o ns i ncl u de d J C vir us ( pr o gressi ve m ultif ocal le u k oe nce p hal o pat h y [ P M L]), 
c yt o me gal o vir us, her pes si m ple x vir us, par v o vir us B 1 9, varicella z oster vir us, West Nile vir us, 
a n d  he patitis  C.   I n  s o me  cases,  t he  viral  i nfecti o ns  occ urre d  u p  t o  o ne  year  f oll o wi n g  
disc o nti n uati o n of rit u xi ma b a n d ha ve res ulte d i n deat h.   
Se vere M uc oc uta ne o us Reacti o ns :  M uc oc uta ne o us reacti o ns, s o me wit h fatal o utc o me, ha ve bee n 
re p orte d i n patie nts treate d wit h rit u xi ma b.  T hese re p orts i ncl u de d para ne o plastic pe m p hi g us (a n 
u nc o m m o n dis or der w hic h is a ma nifestati o n of t he patie nt's u n derl yi n g mali g na nc y), Ste ve ns -
J o h ns o n  s y n dr o me,  lic he n oi d  der matitis,  vesic ul o b ull o us  der matitis,  a n d  t o xic  e pi der mal  
necr ol ysis.  T he o nset of t he reacti o n i n t he re p orte d cases has varie d fr o m 1 - 1 3 wee ks f oll o wi n g 
rit u xi ma b e x p os ure.  Patie nts e x perie nci n g a se vere m uc oc uta ne o us reacti o n s h o ul d n ot recei ve 
a n y f urt her i nf usi o ns a n d see k pr o m pt me dical e val uati o n.  S ki n bi o ps y ma y hel p t o disti n g uis h 
a m o n g  differe nt  m uc oc uta ne o us  reacti o ns  a n d  g ui de  s u bse q ue nt  treat me nt.   T he  safet y  of  
rea d mi nistrati o n of rit u xi ma b t o patie nts wit h a n y of t hese m uc oc uta ne o us reacti o ns has n ot bee n 
deter mi ne d.   
Pr o gressi ve  M u ltif ocal Le u k oe nce p hal o pat h y ( P M L): J o h n  C u n ni n g ha m  (J C)  vir us i nfecti o n 
res ulti n g i n P M L a n d deat h ca n occ ur i n Rit u xa n-treate d patie nts wit h he mat ol o gic mali g na ncies 
or wit h a ut oi m m u ne diseases f or w hic h Rit u xa n has n ot bee n a p pr o ve d. T he maj orit y of pat ie nts 
wit h  he mat ol o gic  mali g na ncies  dia g n ose d  wit h  P M L  recei ve d  Rit u xa n  i n  c o m bi nati o n  wit h  
c he m ot hera p y or as part of a he mat o p oietic ste m cell tra ns pla nt. T he patie nts wit h a ut oi m m u ne 
diseases ha d pri or or c o nc urre nt i m m u n os u p pressi ve t hera p y a n d were dia g n ose d wit h P M L 
wit hi n 1 2 m o nt hs of t heir last i nf usi o n of Rit u xa n. 
C o nsi der  t he  dia g n osis  of  P M L  i n  a n y  patie nt  prese nti n g  wit h  ne w  o nset  ne ur ol o gic  
ma nifestati o ns. E val uati o n of P M L i ncl u des, b ut is n ot li mite d t o, c o ns ultati o n wit h a ne ur ol o gist, 
brai n  M RI, a n d l u m bar p u nct ure. Disc o nti n ue Rit u xa n a n d c o nsi der disc o nti n uati o n or re d ucti o n 
of a n y c o nc o mita nt c he m ot hera p y or i m m u n os u p pressi ve t hera p y i n patie nts w h o de vel o p P M L.   
B o wel O bstr ucti o n a n d Perf orati o n:  A b d o mi nal pai n, b o wel o bstr ucti o n a n d perf orati o n, i n s o me 
cases  lea di n g  t o  deat h,  were  o bser ve d  i n  patie nts  recei vi n g  rit u xi ma b  i n  c o m bi nati o n  wit h  

Versi o n 7 :  0 8/ 1 5 / 2 0 1 7  
3 8  
c he m ot hera p y f or D L B C L.  I n p ost -mar keti n g re p orts, w hic h i ncl u de b ot h patie nts wit h l o w -gra de 
or f ollic ular N H L a n d D L B C L, t he mea n ti me t o o nset of s y m pt o ms was 6 da ys (ra n ge 1 -7 7) i n 
patie nts wit h d oc u me nte d gastr oi ntesti nal perf orati o n.  C o m plai nts of a b d o mi nal pai n, es peciall y 
earl y i n t he c o urse of treat me nt, s h o ul d pr o m pt a t h or o u g h dia g n ostic e val uati o n a n d a p pr o priate 
treat me nt.   
Car di o vasc ular :  T he i nci de nce of seri o us car di o vasc ular e ve nts i n t he d o u ble-bli n d cli nical trial 
f or r he u mat oi d art hritis ( R A) patie nts was 1. 7 % a n d 1. 3 % i n rit u xi ma b a n d place b o gr o u ps, 
res pecti vel y.  T hree car di o vasc ular deat hs occ urre d d uri n g t he d o u ble-bli n d peri o d of t he R A 
st u dies, i ncl u di n g all rit u xi ma b re gi me ns ( 3/ 7 5 9 = 0. 4 %) as c o m pare d t o n o ne i n t he place b o 
gr o u p ( 0/ 3 8 9).  Si nce patie nts wit h R A are at i ncrease d ris k f or car di o vasc ular e ve nts c o m pare d 
t o t he ge neral p o p ulati o n, patie nts wit h R A s h o ul d be m o nit ore d t hr o u g h o ut t he i nf usi o n a n d 
rit u xi ma b s h o ul d be disc o nti n ue d i n t he e ve nt of a seri o us or life-t hreate ni n g car diac e ve nt.   
Rit u xi ma b i nf usi o ns s h o ul d be disc o nti n ue d i n t he e ve nt of seri o us or life -t hreate ni n g car diac 
arr h yt h mias.  Patie nts w h o de vel o p cli nicall y si g nifica nt arr h yt h mias s h o ul d u n der g o car diac 
m o nit ori n g d uri n g a n d after s u bse q ue nt i nf usi o ns of rit u xi ma b.  Patie nts wit h pre -e xisti n g car diac 
c o n diti o ns  i ncl u di n g  arr h yt h mias  a n d  a n gi na  ha ve  ha d  rec urre nces  of  t hese  e ve nts  d uri n g  
rit u xi ma b t hera p y a n d s h o ul d be m o nit ore d t hr o u g h o ut t he i nf usi o n a n d i m me diate p ost-i nf usi o n 
peri o d.  
Re nal :  Rit u xi ma b a d mi nistrati o n has bee n ass ociate d wit h se vere re nal t o xicit y i ncl u di n g ac ute 
re nal fail ure re q uiri n g dial ysis a n d i n s o me cases, has led t o a fatal o utc o me i n he mat ol o gic 
mali g na nc y patie nts.  Re nal t o xicit y has occ urre d i n patie nts wit h hi g h n u m bers of circ ulati n g 
mali g na nt cells ( > 2 5, 0 0 0/ m m 3) or hi g h t u m or b ur de n w h o e x perie nce t u m or l ysis s y n dr o me a n d 
i n patie nts wit h N H L a d mi nistere d c o nc o mita nt cis plati n t hera p y d uri n g cli nical trials.  T he 
c o m bi nati o n of cis plati n a n d rit u xi ma b is n ot a n a p pr o ve d treat me nt re gi me n.  If t his c o m bi nati o n 
is use d i n cli nical trials e xtre me ca uti o n s h o ul d be e xercise d; patie nts s h o ul d be m o nit ore d cl osel y 
f or si g ns of r e nal fail ure.  Disc o nti n uati o n of rit u xi ma b s h o ul d be c o nsi dere d f or t h ose wit h risi n g 
ser u m creati ni ne or oli g uria.   
I m m u nizati o n:  T he safet y of i m m u nizati o n wit h li ve viral vacci nes f oll o wi n g rit u xi ma b t hera p y 
has n ot bee n st u die d a n d vacci nati o n wit h li ve vir us vacci nes is n ot rec o m me n de d.  T he a bilit y t o 
ge nerate a pri mar y or a na m nestic h u m oral res p o nse t o vacci nati o n is c urre ntl y bei n g st u dies.  F or 
patie nts wit h N H L, t he be nefits of pri mar y a n d/ or b o oster vacci nati o ns s h o ul d be wei g he d a gai nst 
t he ris ks of dela y i n i nitiati o n of rit u xi ma b t hera p y.   
Carci n o ge nesis, I m pair me nt of Fertilit y, Pre g na nc y, a n d N ursi n g:  N o l o n g -ter m a ni mal st u dies 
ha ve bee n perf or me d t o esta blis h t he carci n o ge nic p ote ntial of rit u xi ma b.  St u dies als o ha ve n ot 
bee n c o m plete d t o assess m uta ge nic p ote ntial of rit u xi ma b, or t o deter mi ne p ote ntial effects o n 
fertilit y  i n  males  or  fe males.   I n di vi d uals  of  c hil d beari n g  p ote ntial  s h o ul d  use  effecti ve  
c o ntrace pti ve met h o ds d uri n g treat me nt a n d f or u p t o 1 2 m o nt hs f oll o wi n g rit u xi ma b t hera p y.   
It is n ot k n o w n w het her rit u xi ma b is e xcrete d i n h u ma n mil k.  Beca use h u ma n I g G is e xcrete d i n 
h u ma n mil k a n d t he p ote ntial f or a bs or pti o n a n d i m m u n os u p pressi o n i n t he i nfa nt is u n k n o w n, 
w o me n s h o ul d be a d vise d t o disc o nti n ue n ursi n g u ntil circ ulati n g dr u g le vels are n o l o n ger 
detecta ble.   

Versi o n 7 :  0 8/ 1 5 / 2 0 1 7  
3 9  
T he f oll o wi n g ris ks were u p date d per t he Ca ncer T hera p y E val uati o n Pr o gra m’s ( C T E P), 
Nati o nal Ca ncer I nstit ute ( N CI) Acti o n Letter date d J u ne 1 6 t h, 2 0 1 0. 
Li kel y  
•  Fe ver  
•  Reacti o n t hat ca n occ ur d uri n g or f oll o wi n g i nf usi o n of t he dr u g.  T he reacti o n ma y i ncl u de 
fe ver, c hills, ras h, l o w bl o o d press ure, a n d diffic ult y breat hi n g. 
•  Decrease d n u m ber of a t y pe of w hite bl o o d cell (l y m p h oc yte) 
•  C hills  
 
Less Li kel y  
•  Lac k of e n o u g h re d bl o o d cells (a ne mia) 
•  T hic ke ni n g of bl o o d/ser u m as f o u n d i n Wal de nstr o m’s macr o gl o b uli ne mia (a ca ncer of 
certai n bl o o d cells)  
•  Fe ver ass ociate d wit h da n ger o usl y l o w le vels of a t y pe of w hite bl o o d cell ( ne utr o p hils) 
•  Heart attac k ca use d b y a bl oc ka ge of a bl o o d vessel s u p pl yi n g pa rt of t he heart 
•  Fast heart beat; re g ular r h yt h m  
•  Fast heart beat us uall y ori gi nati n g i n a n area l ocate d a b o ve t he ve ntricles 
•  Bell y Pai n  
•  Diarr hea  
•  Na usea or t he ur ge t o v o mit 
•  V o miti n g  
•  S welli n g of t he ar ms a n d/ or le gs 
•  Fati g ue or tire d ness  
•  Pai n  
•  Aller gic reacti o n b y y o ur b o d y t o t he dr u g pr o d uct t hat ca n occ ur i m me diatel y or ma y be 
dela ye d.  T he reacti o n ma y i ncl u de hi ves, l o w bl o o d press ure, w heezi n g, s welli n g of t he 
t hr oat a n d diffic ult y breat hi n g. 
•  I nfecti o n  
•  A wa ke ni n g of vir uses w hic h ha ve bee n late nt/ d or ma nt 
•  I nfecti o n i n HI V p ositi ve patie nts 
•  Decrease d n u m ber of a t y pe of w hite bl o o d cell ( ne utr o p hil/ gra n ul oc yte) 
•  Decrease d n u m ber of a t y pe of bl o o d cell t hat hel p t o cl ot bl o o d ( platelet) 
•  Decrease i n t he t otal n u m ber of w hite bl o o d cells (le u k oc ytes)  
•  I ncrease d bl o o d s u gar le vel 
•  Decrease d bl o o d le vel of calci u m  
•  Decrease d bl o o d le vel of p otassi u m  
•  J oi nt pai n 
•  Bac k pai n  
•  M uscle pai n  
•  Pai n i n t he area of t he t u m or  
•  Dizzi ness ( or se nsati o n of li g ht hea de d ness, u nstea di ness, or gi d di ness)  
•  Hea dac he or hea d pai n  
•  A b n or mal dr o wsi ness or sl u g gis h ness, a n u n us ual lac k of e ner g y 
•  C o n v ulsi o n or seiz ure  

Versi o n 7 :  0 8/ 1 5 / 2 0 1 7  
4 0  
•  S u d de n or tra u matic i nj ur y t o t he ki d ne y 
•  St uff y or r u n n y n ose, s neezi n g 
•  S u d de n c o nstricti o n of t he s mall air wa ys t o t he l u n g t hat ca n ca use w heezi n g a n d s h ort ness 
of breat h 
•  C o u g h 
•  S h ort ness of breat h 
•  Decrease i n t he o x y ge n s u p pl y t o a tiss ue 
•  I nfla m mati o n of t he l u n gs t hat ma y ca use diffic ult y breat hi n g a n d ca n be life t hreate ni n g 
•  S ore t hr oat 
•  E xcess s weati n g  
•  Itc hi n g 
•  S ki n ras h wit h t he prese nce of mac ules (flat disc ol ore d area) a n d pa p ules (raise d b u m p) 
•  S welli n g of b o d y tiss ue u n der neat h t he s ki n 
•  Hi ves  
•  S u d de n re d de ni n g of t he face a n d/ or nec k 
•  Hi g h bl o o d press ure 
•  L o w bl o o d press ure 
 
R are, b ut Seri o us 
Seri o us, life- t hreate ni n g aller gic reacti o n re q uiri n g i m me diate me dical treat me nt b y y o ur d oct or. 
T he reacti o n ma y i ncl u de e xtre mel y l o w bl o o d press ure, s welli n g of     t he t hr oat, diffic ult y 
breat hi n g, a n d l oss of c o nsci o us ness.  
•  Gr o u p of si g ns a n d s y m pt o ms d ue t o ra pi d brea k d o w n of t u m or t hat ca n occ ur after treat me nt 
of ca ncer has starte d t hat ca uses i ncrease d le vels of bl o o d p otassi u m, uric aci d, a n d p h os p hate, 
decrease d le vels of bl o o d calci u m, a n d ki d ne y fail ure. 
•  Disease affecti n g brai n tiss ue, ca use d  b y a vir us (s pecificall y t he J C vir us: Jac o b Cr uetzfel d 
vir us).  
•  Se vere p ote ntiall y life -t hreate ni n g da ma ge t o t he l u n gs w hic h ca n lea d t o fl ui d i n t he l u n gs. 
•  Se vere reacti o n of t he s ki n a n d g ut li ni n g t hat ma y i ncl u de ras h a n d s he d di n g or deat h of 
tiss ue. 
•  P ote ntiall y life -t hreate ni n g c o n diti o n affecti n g less t ha n 1 0 % of t he s ki n i n w hic h cell deat h 
ca uses t he e pi der mis ( o uter la yer) t o se parate fr o m t he der mis ( mi d dle la yer).  
•  Life -t hreate ni n g c o n diti o n affecti n g greater t ha n 3 0 % of t he s ki n i n w hic h cell deat h ca uses 
t he e pi der mis ( o uter la yer) t o se parate fr o m t he der mis ( mi d dle la yer). 
 
Refer  t o  t he  ' C T E P,  N CI  G ui deli nes:  A d verse  E ve nt  Re p orti n g  Re q uire me nts'  
htt p://cte p.ca ncer. g o v/re p orti n g/a deers. ht ml f or f urt her clarificati o n.  
N ote : Rit u xi ma b i n c o m bi nati o n wit h ot her a ge nts c o ul d ca use a n e xacer bati o n of a n y a d verse 
e ve nt c urre ntl y k n o w n t o be ca use d b y t he ot her a ge nt, or t he c o m bi nati o n ma y res ult i n e ve nts 
ne ver pre vi o usl y ass ociate d wit h eit her a ge nt.  
 
 
1. 4  St u d y r ati o n ale a n d selecti o n of dr u g d oses  
S y n er g y 

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T he s y ner g y of rit u xi ma b i n c o m bi nati o n w it h a p uri ne a nal o g is well descri be d i n pre-cli nical 
st u dies, wit h ra n d o mize d pr os pecti ve cli nical trials i n dicati n g t hat t he a d diti o n of rit u xi ma b t o 
fl u dara bi ne-base d  re gi me ns  i m pr o ves  O S  ( F orst p oint ner et  al.,  2 0 0 4). W he n  cla dri bi ne  was  
c o m bi ne d wit h rit u xi ma b i n a f oll o w -u p st u d y of 2 9 patie nts wit h me dia n a ge of 7 0, C R was 5 2 %, 
P R was 1 4 %, me dia n P F S was 1 2. 1 m o nt hs, a n d me dia n O S was n ot reac he d. Of 1 5 patie nts 
ac hie vi n g C R, o nl y 3 patie nts rela pse d w it h t he me dia n f oll o w-u p of 2 1. 5 m o nt hs. Patie nts 
recei ve d a me dia n of 4 c ycles. C o m bi nati o n of cla dri bi ne a n d rit u xi ma b res ulte d i n 7 % gra de 3 
a n d 2 4 % gra de 4 ne utr o pe nia, as well as 1 4 % gra de 3 a n d 3 % gra de 4 t hr o m b oc yt o pe nia. O ne 
patie nt die d d uri n g treat me nt fr o m a cere br o vasc ular i nci de nt f oll o wi n g a p ne u m o nia. (I n war ds 
et al, 2 0 0 8). Si milar if n ot m ore i m pressi ve res p o nses were see n at t he U ni versit y of Ariz o na 
Ca ncer Ce nter a n d Ore g o n Healt h a n d Scie nce U ni versit y ( pers o nal c o m m u nicati o n, Drs. Miller  
a n d E p ner).  
R o ba k et al ( 2 0 0 6) e nr olle d 5 4 patie nts wit h ma ntle cell a n d i n d ole nt l y m p h o mas/ C L L i n a trial 
c o m bi ni n g rit u xi ma b 3 7 5 m g/ m 2 o n da y 1 wit h cla dri bi ne at 0. 1 2 m g/ k g o ver 2 hrs o n da ys 2 -6, 
wit h a n d wit h o ut c ycl o p h os p ha mi de, o n a 2 8 -da y c ycle. N ota bl y, 4 2 ( 7 8 %) patie nts pre vi o usl y 
recei ve d cla dri bi ne. T he c o m bi nati o n of rit u xi ma b a n d cla dri bi ne res ulte d i n 5 8 % P R a n d 1 3 % 
C R , wit h si g nifica nt i m pr o ve me nt i n P F S a n d O S i n res p o n ders. Of 9 patie nts wit h M C L, 2 ( 2 2 %) 
ha d C R a n d 4 ( 4 4 %) ha d P R. T o xic ities were he mat ol o gic a n d i nfecti o us, i ncl u di n g 1 1 % gra de 3-
4 ne utr o pe nia, 7 % gra de 3 -4 t hr o m b oc yt o pe nia, 7 % gra de 3 a ne mia, 2 0 % gra de 3 -4 i nfecti o ns ( n o 
pr o p h yla xis was use d), a n d 9 % p ne u m o nias, incl u di n g o ne fatal p ne u m o nia wit h  se psis i n a 
patie nt w h o recei ve d rit u xi ma b, cla dri bi ne, c ycl o p h os p ha mi de. H y perse nsiti vit y reacti o n wit h 
rit u xi ma b occ urre d i n 3 5 % of patie nts.  
T he s y ner g y of rit u xi ma b wit h b ortez o mi b is descri be d m ore rece ntl y .  I n vitr o data s u g gests at 
least  a d diti ve  effect,  partic ularl y  wit h  rit u xi ma b  pretreat me nt  i n  a  st u d y  C L L  cell  li nes  
(S m ole ws ki et al ., 2 0 0 6) a n d i n M C L cell li nes  (Wa de hra et al., A S H 2 0 0 5 ). Se veral p hase II trials 
e xa mi ne d c o m bi nati o ns of rit u xi ma b a n d b ortez o mi b  ( gi ve n da ys 1, 4, 8, a n d 1 1, o n a 3-wee k 
c ycle) . Rit u xi ma b, b ortez o mi b, a n d de xa met has o ne i n rela pse d ma ntle cell l y m p h o ma s h o we d 3 
C Rs  a n d  6  P Rs  i n  1 6  e val ua ble  patie nts  ( Drac h  et  al .,  A S H  2 0 0 7),  w hile  i n  u ntr eate d 
Wal de nstr o m’s macr o gl o b uli ne mia, t his c o m bi nati o n res ulte d i n 5 mi n or a n d 5 maj or res p o nses  
(i.e., C R + P R) i n 1 0 patie nts (Tre o n e t al., A S H 2 0 0 6). P hase II st u d y of rit u xi ma b a n d b ortez o mi b 
i n rela pse d f ollic ular a n d mar gi nal z o ne l y m p h o mas de m o nstrate d 1 1 % C R a n d 3 5 % P R i n 3 7 
e val ua ble  patie nts  ( de  V os  et  al.,  A S H  2 0 0 6),  w hile  i n  rela pse d  Walde nstr o m’s 
macr o gl o b uli ne mia t his c o m bi nati o n res ulte d i n 7 mi ni mal res p o nses, 3 P Rs, a n d 1 C R, o ut of 1 3 
patie nts ( G h o brial et al ., A S H 2 0 0 7). A n ot her p hase II trial i n rela pse d f ollic ular a n d ma ntle cell 
l y m p h o mas  a n d  Wal de nstr o m’s  macr o gl o b uli ne mia  re veale d O R R  of  5 6 %  i n  3 9  e val ua ble  
patie nts, wit h F L  ha vi n g O R R of 4 4 %, M C L 4 6 %, a n d W M 9 0 % ( A gat h ocle o us et al., A S H 2 0 0 7 ).  
B ortez o mi b has a differe nt mec ha nis m of acti o n, a n o n -o verla p pi n g t o xicit y pr ofile efficac y i n 
ma ntle cell a n d i n d ole nt l y m p h o mas, a n d i n vitr o s y ner g y wit h p uri ne a nal o gs ( D uec hler et al., 
2 0 0 5). A n o n g oi n g p hase I trial i n rela pse d/refract or y i n d ole nt N H L/ C L L c o m bi nes escalati n g 
d oses of b ortez o mi b o n da ys 1,  4, 8, a n d 1 1, wit h fl u dara bi ne, a p uri ne a nal o g, at 2 5 m g/ m 2 da ys 
1- 3, wit h a d diti o n of rit u xi ma b at d ose le vel 5 , i n a 3-wee k c ycle. Preli mi nar y re p ort s h o we d t hat 
at 1. 3 m g/ m 2 of b ortez o mi b D L T has n ot bee n reac he d , b ut t he first patie nt at d ose le vel 5 
de vel o pe d gra de 4 ne utr o pe nia. Of 1 3 patie nts wit h me dia n of 3  pri or c ycles of treat me nt, 1 

Versi o n 7 :  0 8/ 1 5 / 2 0 1 7  
4 2  
ac hie ve d C R u (f ollic ular l y m p h o ma) a n d 1 ac hie ve d P R ( ma ntle cell l y m p h o ma), wit h 6 S D 
lasti n g 1. 5-3 m o nt hs a n d 1 pr o gressi o n ( C L L) (S nell et al ., A S C O 2 0 0 6). O ur trial will use 
cla dri bi ne o n a 4 -wee k c ycle, w hic h reflec ts he mat ol o gic rec o ver y wit h p uri ne a nal o gs better t ha n 
a 3-wee k c ycle , a n d will all o w ti me f or l o n g-acti n g gr o wt h fact or s u p p ort. T he d ose of cla dri bi ne 
will be re d uce d sli g htl y f or  t he c o m bi nati o n, si milarl y t o fl u dara bi ne-c o ntai ni n g c o m bi nati o n. T he 
d os e of b ortez o mi b will be re d uce d t o da ys 1 a n d 4, base d o n t he c o m bi nati o n data wit h R -C H O P 
( Le o nar d et al., A S C O 2 0 0 7) a n d R-h y per C V A D ( Ka hl  et al., A S C O 2 0 0 7).   
E x perie nce at t he U ni versit y of Ariz o na Ca ncer Ce nter i ncl u des c o m bi nati o n of b ortez o mi b wit h  
cla dri bi ne a n d rit u xi ma b, gi ve n t o 5 patie nts - 1 3  c ycles wit h b ortez o mi b  at 1. 6 m g/ m 2 o n da y 1 , 
a n d 4 c ycles wit h b ortez o mi b gi ve n at 1. 3 m g/ m 2 o n da ys 1 a n d 4. T w o patie nts ha d gra de 3 
ne utr o pe nia a n d a ne mia, a n d o ne patie nt ha d g ra de 3 t hr o m b oc yt o pe nia, wit h n o i nci de nce of 
ne ur o pat h y. F o ur patie nts ac hie ve d C R, 3 of w hic h are n o w 6 + m o nt hs i n d urati o n ; t here ha ve 
bee n n o h os pitalizati o ns ( Dr. Miller, pers o nal c o m m u nicati o n).  
 
St u d y h y p ot hesis 
O ur h y p ot hesis is t hat t he c o m bi nati o n of b ortez o mi b, cla dri bi ne, a n d rit u xi ma b will s y ner gize t o  
pr o d uce pr o gressi o n- free s ur vi val t hat is hi g her t ha n e x pecte d fr o m a vaila ble t hera p y o pti o ns i n 
ma ntle cell a n d i n d ole nt l y m p h o mas.  

Versi o n 7 :  0 8/ 1 5 / 2 0 1 7  
4 3  
2  S T U D Y O B J E C TI V E S  
2. 1  Pri m ar y O bjecti ve  
T he pri mar y o bjecti ve of t his st u d y is t o: 
•  Deter mi ne 2 -year P F S i n patie nts wit h ma ntle cell, mar gi nal z o ne, l y m p h o plas mac ytic, 
s mall l y m p h oc ytic, a n d rela pse d f ollic ular l y m p h o mas 
o  Sta n dar d defi niti o n of P F S will be use d: fr o m t he ti me of first dr u g d ose t o 
pr o gressi o n or deat h  fr o m a n y ca use  
2. 2  Sec o n d ar y O bjecti ves  
T he sec o n dar y o bjecti ves of t his st u d y are t o: 
•  Deter mi ne 2 -year O S;  
•  Deter mi ne C R a n d O R R;  
•  Descri be l o n g a n d s h ort- ter m t o xicit y; 
•  C o n d uct c orrelati ve st u dies:  
o  Deter mi ne pr o g n ostic i m p orta nce of A ur ora ki nase A i n l y m p h o ma treate d wit h 
V C R;   
o  Deter mi ne t he c yt o ki ne pr ofiles of eac h l y m p h o ma s u bt y pe a n d h o w t he y c ha n ge 
wit h V C R;  
o  E val uate t he pr o g n ostic i m p orta nce of maj or o nc o ge nic pat h wa ys i n l y m p h o ma 
treate d wit h V C R usi n g tiss ue micr oarra y ( T M A)  

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4 4  
3  I N V E S TI G A TI O N A L P L A N 
3. 1  O ver all Desi g n a n d Pl a n of t he St u d y  
 
Re gistrati o n: all patie nts m ust be re gistere d ce ntrall y b y t he s t u d y c o or di nat or at 5 2 0- 6 9 4- 9 0 5 3  
pri or t o i nitiati o n of t hera p y.  
 
Wit hi n 8 wee ks of re gistrati o n:  
•  B o ne marr o w bi o ps y (as pirate n ot ma n dat or y b ut s u g geste d as g o o d me dical practice) 
•  C o nfir mati o n of pat h ol o gic dia g n osis  (t o be perf or me d as sta n dar d of care f or eac h st u d y 
s u bject  e nr olle d  at  t heir  res pecti ve  i nstit uti o ns  (T he U ni versit y  of  Ariz o na  a n d  t he 
U ni versit y of Massac h usetts ) 
•  Pat h ol o g y bl oc k or 1 0 u nstai ne d sli des f or tiss ue micr oarra y c o nstr ucti o n (f or c orrelati ve 
st u dies)  
 
Wit hi n 4 wee ks of re gistrati o n:  
•  C T c hest/a b d o me n/ pel vis of dia g n ostic q ualit y; C T nec k o pt i o nal 
 
Wit hi n 2 wee ks of re gistrati o n:  
•  Hist or y a n d P h ysical  
•  Vital si g ns i ncl u di n g wei g ht, hei g ht, a n d perf or ma nce stat us 
•  C B C, c o m pre he nsi ve meta b olic pa nel  (i ncl u des s o di u m, p otassi u m, c hl ori de, bicar b o nate, 
urea nitr o ge n ( B U N), creati ni ne, gl uc ose, t otal pr otei n, al b u mi n, A S T, A L T, al k ali ne 
p h os p hatase, t otal bilir u bi n)  
•  L D H  
•  Ser u m Pre g na nc y test f or pre- me n o pa usal w o me n of c hil d beari n g a ge 
•  N ot ma n dat or y b ut  s u g geste d as g o o d me dical practice: beta 2-micr o gl o b uli n a n d he patitis 
B s urface a nti ge n  
•  Ser u m s peci me n  ( 5 ml) f or c yt o ki ne pr ofile (f or correlati ve st u dies)  
•  St u d y re gistrati o n ( O nce scree ni n g has bee n c o m plete  a n d e val uate d  a n d wit hi n 7 2 h o urs  
pri or t o Da y 1, C ycle 1) 
 
Wit hi n 2 da ys of da y 1 of c ycle 2 O N L Y: c orrelati ve st u dies  
•  Ser u m s peci me n  ( 5 ml) f or c yt o ki ne pr ofile (f or c orrelati ve st u dies) 
•  O pti o nal re -bi o ps y f or tiss ue micr oarra y (f or c orrelati ve st u dies)  Pat h ol o g y bl oc k or 1 0 
u nstai ne d sli des f or  tiss ue micr oarra y) 
 
Wit hi n 2 da ys of da y 1 of c ycles 2- 6: r o uti ne assess me nt  
•  Hist or y a n d P h ysical  
•  Vital si g ns i ncl u di n g wei g ht a n d perf or ma nce stat us  
•  T o xicit y assess me nt  
•  C B C, c o m pr e he nsi ve meta b olic pa nel 
 
Wit hi n 7  da ys of da y 1 of c ycles 3 a n d 5 (i.e., after c ycles 2 a n d 4): i nteri m cli nical resta gi n g 

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•  C T c hest/a b d o me n/ pel vis of dia g n ostic q ualit y 
•  L D H ( beta 2 - micr o gl o b uli n is n ot ma n dat or y b ut s u g geste d as g o o d me dical practice) 
 
4- 8 wee ks after  da y 1 of c ycle 6: f ull resta gi n g 
•  Hist or y a n d P h ysical  
•  Vital si g ns i ncl u di n g wei g ht a n d perf or ma nce stat us  
•  T o xicit y assess me nt  
•  C B C, c o m pr e he nsi ve meta b olic pa nel 
•  L D H ( beta 2 - micr o gl o b uli n is n ot ma n dat or y b ut s u g geste d as g o o d me dical practice) 
•  C T c hest/a b d o me n/ pel vis of dia g n ostic q ualit y 
•  B o ne marr o w bi o ps y (a n d as pirate, if perf or me d at baseli ne) if t here was b o ne marr o w 
i n v ol ve me nt o n i nitial bi o ps y 
•  A n y test perf or me d pre -treat me nt f or sta gi n g p ur p oses t hat was p ositi ve f or l y m p h o ma 
(e. g.,  c ol o n osc o p y  f or  ma ntle  cell  l y m p h o ma,  I g M  le vels  f or  l y m p h o plas mac ytic 
l y m p h o ma) s h o ul d be re peate d at resta gi n g.  
 
E ver y 3 m o nt hs f or 2 years or u ntil pr o gressi o n : cli nical resta gi n g  
•  Hist or y a n d P h ysical  
•  Vital si g ns i ncl u di n g wei g ht a n d perf or ma nce stat us  
•  T o xicit y assess me nt  
•  C B C, c o m pr e he nsi ve meta b olic pa nel 
•  L D H ( beta 2- micr o gl o b uli n is n ot ma n dat or y b ut s u g geste d as g o o d me dical practice) 
•  C T c hest/a b d o me n/ pel vis of dia g n ostic q ualit y 
 
F or Wal de nst o m’s macr o gl o b uli ne mia /l y m p h o plas mac ytic l y m p h o ma  o nl y: i nitial assess me nt, 
i nteri m cli nical resta gi n g, resta gi n g at t hera p y c o m pleti o n, a n d cli nical resta gi n g at f oll o w u p 
s h o ul d als o i ncl u de ser u m pr otei n electr o p h oresis wit h i m m u n ofi xati o n, I g M le vel , a n d ser u m 
visc osit y .   
 
A st u d y fl o w c hart is pr o vi de d i n secti o n 8. 1 . 
3. 2  Selecti o n of P atie nts  
T he t otal n u m ber of patie nts t o be re gistere d o n t his st u d y is 3 9. 
E nr oll me nt  is  def i ne d  as  t he  da y  of c o nse nt;  Re gistrati o n  is  t he  da y  t he  patie nt  has  bee n  
deter mi ne d t o be eli gi ble f or st u d y a n d is gi ve n a st u d y n u m ber.  
3. 2. 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 re gistere d i n t he st u d y: 
 
•  V ol u ntar y writte n i nf or me d c o nse nt bef ore perf or ma nce of a n y st u d y -relate d pr oce d ure n ot 
part of n or mal 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 
s u bject at a n y ti me wit h o ut prej u dice t o f ut ure me dical care. 
•  Fe male  s u bject  is  eit her  p ost -me n o pa usal  or  s ur gicall y  sterilize d  or  willi n g  t o  use  a n  
acce pta ble  met h o d  of  birt h  c o ntr ol  ( i.e.,  a  h or m o nal  c o ntrace pti ve,  i ntra-uteri ne  de vice,  

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dia p hra g m wit h s per mici de, c o n d o m wit h s per mici de, or a bsti ne nce) f or t he d urati o n of t he 
st u d y. 
•  Male s u bject a grees t o use a n acce pta ble met h o d f or c o ntrace pti o n f or t he d urati o n of  t he 
st u d y. 
•  Bi o ps y- pr o ve n  ma ntle  cell,  mar gi nal  z o ne,  l y m p h o plas mac ytic ,  s mall  l y m p h oc ytic  
l y m p h o ma, or f ollic ular l y m p h o ma 
•  C D 2 0 -p ositi ve disease  
•  F or  patie nts  wit h  mar gi nal  z o ne,  l y m p h o plas mac ytic,  s mall  l y m p h oc ytic,  or  f ollic ular  
l y m p h o ma – at least o ne criteri o n f or i nitiati o n of treat me nt m ust be met: 
o  S y m pt o matic disease  
o  C yt o pe nia relate d t o l y m p h o ma  
o  Le u ke mic p hase  ( > 5, 0 0 0 mali g na nt l y m p h oc ytes/ µl) 
o  Mass o ver 5  c m i n greatest dia meter   
o  F or  l y m p h o plas mac ytic  l y m p h o ma:  a d diti o nal  treat me nt  criteria  are  s er u m 
visc osit y ≥ 4  c p, ser u m m o n ocl o nal pr otei n > 5 g/ L, c o nc urre nt pri mar y s yste mic 
A L a m yl oi d osis, c ol d a g gl uti ni n disease   
•  A ge o ver 1 8 
•  Pri or treat me nt wit h b ortez o mi b a n d/ or rit u xi ma b is acce pta ble 
•  F or f ollic ular l y m p h o ma o nl y, at least o ne pri or treat me nt  
3. 2. 2  E xcl usi o n Criteri a  
Patie nts 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 re gistere d i n t he st u d y: 
 
•  Patie nt has a platelet c o u nt of < 1 0 0 ×  1 09/ L wit hi n 1 4  da ys bef ore e nr oll me nt, u nless d ue t o 
b o ne marr o w i nfiltrati o n wit h l y m p h o ma , or d ue t o a ut oi m m u ne t hr o m b oc yt o pe nia beca use 
of l y m p h o ma. 
•  Patie nt has a n a bs ol ute ne utr o p hil c o u nt of < 1. 0 ×  1 09/ L wit hi n 1 4  da ys bef ore re gistrati o n , 
u nless d ue t o b o ne marr o w i nfiltrati o n wit h l y m p h o ma. 
•  Patie nt has a calc ulate d or meas ure d creati ni ne c leara nce of < 2 0 m L/ mi n ute wit hi n 1 4  da ys 
bef ore re gistrati o n. ( Creati ni ne Cleara nce is i n dicate d t hr o u g h t he Ser u m Creati ni ne. If t he 
Ser u m Creati ni ne is a b n or mal, t he p h ysicia n ma y t he n d ue a  2 4 h o ur uri ne t o f urt her clarif y 
Creati ni ne Cleara nce. A 2 4 h o u r uri ne test is n ot re q uire d per st u d y.) 
•  Patie nt has ≥ Gra de  2 peri p heral ne ur o pat h y wit hi n 1 4 da ys bef ore  re gistrati o n. 
•  M y ocar dial  i nfarcti o n  wit hi n  6  m o nt hs  pri or  t o  re gistrati o n or  has  Ne w  Y or k  Heart  
Ass ociati o n ( N Y H A) Class III or I V  heart fail ure (see  secti o n 8. 4), u nc o ntr olle d a n gi na, 
se vere  u nc o ntr olle d  ve ntric ular  arr h yt h mias,  or  electr ocar di o gra p hic  e vi de nce  of  ac ute  
isc he mia  or  acti ve  c o n d ucti o n  s yste m  a b n or malities. Pri or  t o  st u d y  e ntr y,  a n y  E C G  
a b n or malit y at Scree ni n g has t o be d oc u me nte d b y t h e i n vesti gat or as n ot me dicall y rele va nt.  
•  Patie nt has h y perse nsiti vit y t o b ortez o mi b, b or o n or ma n nit ol. 

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4 7  
•  Fe male s u bject is pre g na nt or breast -fee di n g.  C o nfir mati o n t hat t he s u bject is n ot pre g na nt 
m ust be esta blis he d b y a ne gati ve ser u m β -h u ma n c h ori o nic g o na d otr o pi n ( β -h C G) pre g na nc y 
test res ult o btai ne d d uri n g scree ni n g.  Pre g na nc y testi n g is n ot re q uire d f or p ost- me n o pa usal 
or s ur gicall y sterilize d w o me n.  
•  Patie nt has recei ve d ot her i n vesti gati o nal dr u gs wit h 1 4 da ys bef ore re gistrati o n 
•  Seri o us me dical or ps yc hiatric ill ness li kel y t o i nterfere wit h partici pati o n i n t his cli nical 
st u d y. 
•  Dia g n ose d or treate d f or a n ot her mali g na nc y wit hi n 3 years of  re gistrati o n, wit h t he e xce pti o n 
of c o m plete resecti o n of basal cell carci n o ma or s q ua m o us cell carci n o ma of  t he s ki n, a n i n 
sit u mali g na nc y, or l o w-ris k pr ostate ca ncer after c urati ve t hera p y.  
•  C N S i n v ol ve me nt wit h l y m p h o ma. 
•  K n o w n HI V - p ositi ve.  
•  Hist or y of disease re fract or y t o a p uri ne a nal o g ( defi ne d as re missi o n d urati o n of < 6 m o nt hs 
t o t hera p y t hat i ncl u ded fl u dara bi ne, pe nt ostati n, or cla dri bi ne).  
•  Hist or y of i nt olera nce of b ortez o mi b, b or o n, ma n nit ol, cla dri bi ne, or rit u xi ma b.  
•  Patie nt has > 1. 5 ×  U L N T otal Bilir u bi n  
•  Ra diati o n t hera p y wit hi n 3 wee ks bef ore ra n d o mizati o n. E nr oll me nt of s u bjects w h o re q uire  
c o nc urre nt ra di ot hera p y ( w hic h m ust be l ocalize d i n its fiel d size) s h o ul d be deferre d u ntil t he 
ra di ot hera p y is c o m plete d a n d 3 wee ks ha ve ela pse d si nce t he last date of t hera p y. 
 
3. 3  St u d y Tre at me nts  
3. 3. 1  Cli nic al Tri al M ateri als  
V E L C A D E ( b ortez o mi b) f or I njecti o n is a sterile l y o p hilize d p o w der f or rec o nstit uti o n a n d is 
s u p plie d  i n  vials  c o ntai ni n g  V E L C A D E  a n d  ma n nit ol  at  a  1: 1 0  rati o.   F or  e xa m ple,  vials  
c o ntai ni n g 3. 5 m g of V E L C A D E c o ntai n 3 5 m g of ma n nit ol.   
L E U S T A TI N (cla dri bi ne) f or I njecti o n is  a clear, c ol orless, sterile, preser vati ve -free, is ot o nic 
s ol uti o n. It is a vaila ble i n si n ge-use vials c o ntai ni n g 1 0 m g ( 1 m g/ m L) of cla dri bi ne. Eac h milliliter 
of L E U S T A TI N I njecti o n c o ntai ns 1 m g of t he acti ve i n gre die nt a n d 9 m g ( 0. 1 5 m E q) of s o di u m 
c hl ori de as a n i nacti ve i n gre die nt.  
Rit u xa n (rit u xi ma b) is  a  sterile,  clear,  c ol orless,  preser vati ve-free  li q ui d  c o nce ntrate  f or  
i ntra ve n o us a d mi nistrati o n. Rit u xa n is s u p plie d at a c o nce ntrati o n of 1 0 m g/ m L i n eit her 1 0 0 m g 
( 1 0 m L) or 5 0 0 m g ( 5 0 ml) si n gle- use vials. T he pr o d uct is f or m ulate d i n 9 m g/ m L s o di u m 
c hl ori de,  7. 3 5  m g/ m L  s o di u m  citrate  de h y drate,  0. 7  m g/ m L  p ol ys or bate  8 0,  a n d  Water  f or  
i njecti o n.  

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4 8  
3. 3. 2  Pre p ar ati o n, H a n dli n g, a n d St or a ge of Dr u gs 
 
V E L C A D E ( b ortez o mi b)  
Vials c o ntai ni n g l y o p hilize d V E L C A D E f or I njecti o n s h o ul d be st ore d acc or di n g t o t he la bel 
re q uire me nts.  F or t he U nite d States, st ore at U S P C o ntr olle d R o o m Te m perat ure w hic h is 2 5º C 
( 7 7º F); e xc ursi o ns per mitte d fr o m 1 5 t o 3 0º C ( 5 9 t o 8 6º F).  F or E ur o pe, d o n ot st ore a b o ve 3 0º C 
( 8 6º F).  T o date, sta bilit y data i n dicate t hat t he l y o p hilize d dr u g pr o d uct is sta ble f or at least 1 8 
m o nt hs  w he n  st ore d  u n der  t he  rec o m me n de d  c o n diti o ns.  Sta bilit y  st u dies  are  o n g oi n g,  a n d  
Mille n ni u m P har mace uticals, I nc. will n oti f y t he i n vesti gat or s h o ul d t his i nf or mati o n be re vise d 
d uri n g t he c o n d uct of t he st u d y. 
V E L C A D E is c yt ot o xic.  As wit h all c yt ot o xic dr u gs, ca uti o n is re q uire d w he n pre pari n g a n d 
ha n dli n g V E L C A D E s ol uti o ns.   C yt ot o xic dr u gs s h o ul d o nl y be ha n dle d b y staff s peciall y trai ne d 
i n t he safe ha n dli n g of s uc h pre parati o ns. T he use of gl o ves a n d ot her a p pr o priate pr otecti ve 
cl ot hi n g is rec o m me n de d.   I n case of s ki n c o ntact, was h t he affecte d area i m me diatel y a n d 
t h or o u g hl y wit h s oa p a n d water f or at least 1 5 mi n utes.  If pr o d uct c o ntacts e ye, i m me diatel y fl us h 
e ye t h or o u g hl y wit h water f or at least 1 5 mi n utes.   Al wa ys c o ntact a p h ysicia n after a n y f or m of 
b o d y c o ntact. All materials t hat ha ve bee n use d f or pre parati o n s h o ul d be dis p ose d of acc or di n g 
t o sta n dar d practices. A l o g m ust be ke pt of all dis p ose d materials. 
Dr u g is a vaila ble i n sterile, si n gle use vials c o ntai ni n g 3. 5 m g of V E L C A D E.   Eac h vial of 
V E L C A D E f or I njecti o n s h o ul d be rec o nstit ute d u n der a la mi nar fl o w bi ol o gical ca bi net ( h o o d) 
wit hi n ei g ht h o urs b ef ore d osi n g wit h 3. 5 m L of n or mal ( 0. 9 %) sali ne, S o di u m C hl ori de I njecti o n 
U S P, s o t hat t he rec o nstit ute d s ol uti o n c o ntai ns V E L C A D E at a c o nce ntrati o n of 1  m g/ m L.   Pri or 
t o rec o nstit uti o n t he vials s h o ul d re mai n i n t he cart o ns t o pr otect t he m fr o m li g ht.  Diss ol uti o n is 
c o m plete d i n a p pr o xi matel y 1 0 sec o n ds.   T he rec o nstit ute d s ol uti o n is clear a n d c ol orless, wit h a 
fi nal p H of 5 t o 6.  Rec o nstit ute d V E L C A D E s h o ul d be a d mi nistere d pr o m ptl y a n d i n n o case 
m ore t ha n 8  h o urs after rec o nstit uti o n.   All materia ls t hat ha ve bee n use d f or pre parati o n s h o ul d 
be dis p ose d of acc or di n g t o sta n dar d practices.   A l o g m ust be ke pt of all dis p ose d materials. 
Le ustati n (cla dri bi ne)  
 
L E U S T A TI N (cla dri bi ne) I njecti o n is s u p plie d as a sterile, preser vati ve -free, is ot o nic s ol uti o n 
c o ntai ni n g 1 0 m g ( 1 m g/ m L) of cla dri bi ne as 1 0 m L fille d i nt o a si n gle -use clear fli nt glass 2 0 
m L vial. Le ustati n I njecti o n is s u p plie d i n 1 0 m L ( 1 m g/ m L) si n gle -use vials ( N D C 5 9 6 7 6 - 2 0 1-
0 1) a vaila ble i n a treat me nt set (case) of se ve n vials. St ore refri gerate d 2 o t o 8oC ( 3 6 o t o 4 6oF). 
Pr otect fr o m li g ht d uri n g st ora ge.  
W he n st ore d i n refri gerate d c o n diti o ns at 2
o- 8oC ( 3 6 o- 4 6oF) pr otecte d fr o m s u nli g ht, u n o pe ne d 
vials of Le ustati n I njecti o n are sta ble u ntil t he e x pirati o n date i n dicate d o n t he pac ka g e. Freezi n g 
d oes n ot a d versel y affect t he s ol uti o n. If freezi n g occ urs, t ha w nat urall y t o r o o m te m perat ure. D O 
N O T heat or micr o wa ve. O nce t ha we d, t he vial of Le ustati n I njecti o n is sta ble u ntil t he e x pirati o n 
date if refri gerate d. D O N O T refreeze. O nce di l ute d, s ol uti o ns c o ntai ni n g Le ustati n I njecti o n 
s h o ul d be a d mi nistere d pr o m ptl y or st ore d i n t he refri gerat or ( 2 o- 8oC) f or n o m ore t ha n 8 h o urs 
pri or t o a d mi nistrati o n  

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Cla dri bi ne is a c yt ot o xic a ge nt. T he p ote ntial hazar ds ass ociate d wit h c yt ot o xic a ge nts are well 
esta blis he d a n d pr o per preca uti o ns s h o ul d be ta ke n w he n ha n dli n g, pre pari n g, a n d a d mi nisteri n g 
Le ustati n I njecti o n. T he use of dis p osa ble gl o ves a n d pr otecti ve gar me nts is rec o m me n de d. If 
Le ustati n  I njecti o n  c o ntacts  t he  s ki n  or  m uc o us  me m bra nes,  was h t he  i n v ol ve d  s urface  
i m me diatel y  wit h  c o pi o us  a m o u nts  of  water.  Se veral  g ui deli nes  o n  t his  s u bject  ha ve  bee n  
p u blis he d. T here is n o ge neral a gree me nt t hat all of t he pr oce d ures rec o m me n de d i n t he g ui deli nes 
are necessar y or a p pr o priate. All materials t hat ha ve bee n use d f or pre parati o n s h o ul d be dis p ose d 
of acc or di n g t o sta n dar d practices. A l o g m ust be ke pt of all dis p ose d materials. .  
A d mi nistrati o n: A d d t he calc ulate d d ose of Le ustati n I njecti o n t o a n i nf usi o n ba g c o ntai ni n g 5 0 0 
m L  of  0. 9 %  S o di u m  C hl ori de  I njecti o n,  U S P.  T he  use  of  5 %  de xtr ose  as  a  dil ue nt  is  n ot  
rec o m me n de d beca use of i ncrease d de gra dati o n of cla dri bi ne. A d mi xt ures of Le ustati n I njecti o n 
are c he micall y a n d p h ysicall y sta ble f or at least 2 4 h o urs at r o o m te m perat ure u n der n or mal r o o m 
fl u oresce nt li g ht i n Ba xter Viafle x®  P V C i nf usi o n c o ntai ners. Si nce li mite d c o m pati bilit y data 
are a vaila ble, a d here nce t o t he rec o m me n de d dil ue nts a n d i nf usi o n s yste ms is a d vise d. S ol uti o ns 
c o ntai ni n g Le ustati n I njecti o n s h o ul d n ot be mi xe d wit h ot her  i ntra ve n o us dr u gs or a d diti ves or 
i nf use d si m ulta ne o usl y via a c o m m o n i ntra ve n o us li ne, si nce c o m pati bilit y testi n g has n ot bee n 
perf or me d.  
 
O nce dil ute d, s ol uti o ns of Le ustati n I njecti o n s h o ul d be a d mi nistere d pr o m ptl y or st ore d i n t he 
refri gerat or ( 2o t o 8oC) f or n o m ore t ha n 8 h o urs pri or t o start of a d mi nistrati o n. Vials of Le ustati n 
I njecti o n are f or si n gle- use o nl y.  
 
Pare nteral dr u g pr o d ucts s h o ul d be i ns pecte d vis uall y f or partic ulate matter a n d disc ol orati o n pri or 
t o a d mi nistrati o n, w he ne ver s ol uti o n a n d c o ntai ner per mit. A preci pitate ma y occ ur d uri n g t he 
e x p os ure of Le ustati n I njecti o n t o l o w te m perat ures; it ma y be res ol u bilize d b y all o wi n g t he 
s ol uti o n t o war m nat urall y t o r o o m te m perat ure a n d b y s ha ki n g vi g or o usl y. D O N O T H E A T O R 
MI C R O W A V E.   
 
Rit u xa n (rit u xi ma b) 
 
F or m ulati o n:  Rit u xi ma b a nti b o d y will be pr o vi de d i n 1 0 0 m g ( 1 0 m L) a n d 5 0 0 m g ( 5 0 ml) 
p har mace utical gra de vials at a c o nce ntrati o n of 1 0 m g of pr otei n per m L (act ual c o nce ntrati o n 
s h o ul d be n ote d o n t he pr o d uct la bel).   
St ora ge a n d Sta bilit y:  Rit u xi ma b s h o ul d be st ore d at 2 - 8° C.  D o n ot freeze or st ore at r o o m 
te m perat ure.  T he pr o d uct is a pr otei n- H A N D L E G E N T L Y A N D A V OI D F O A MI N G.  T he 
a v oi da nce of f oa mi n g d uri n g pr o d uct ha n dli n g, pre parati o n a n d a d mi nistrati o n is i m p orta nt, as 
f oa mi n g ma y lea d t o t he de- nat uri n g of t he pr o d uct pr otei ns.   
Pre pare t he rit u xi ma b i nf usi o n s ol uti o n as f oll o ws: 
1. 
If a dela y i n a d mi nistrati o n of t he i nf usi o n occ urs after t he pr o d uct is pre pare d, t he pr o perl y 
i de ntifie d c o ntai ner ma y be ke pt refri gerate d at 2 - 8° C f or u p t o si x h o urs.   
2. 
Use sterile, n o n -p yr o ge nic, dis p osa ble c o ntai ners, s yri n ges, nee dles, st o pc oc ks a n d tra nsfer 
t u bi n g, etc. 

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3. 
Tra nsfer of t he rit u xi ma b fr o m t he glass vial s h o ul d be ma de b y usi n g a s uita ble sterile 
gra d uate d s yri n ge a n d lar ge ga u ge nee dle. 
4. 
Tra nsfer t he a p pr o priate a m o u nt of rit u xi ma b fr o m t he gra d uate d s yri n ge, i nt o a partiall y 
fille d I V pac k c o ntai ni n g sterile, p yr o ge n-free 0. 9 % s o di u m c hl ori de s ol uti o n, U S P (sali ne 
s ol uti o n).  T he fi nal c o nce ntrati o n of rit u xi ma b i n sali ne s ol uti o n s h o ul d be a ma xi m u m of 1 
m g/ ml.  Mi x b y i n verti n g t he ba g ge ntl y.  D O N O T U S E A V A C U U M A P P A R A T U S t o 
tra nsfer t he pr o d uct fr o m t he s yri n ge t o t he plastic ba g. 
5. 
Place a n I V a d mi nistrati o n set i nt o t he o utfl o w p ort of t he ba g  c o ntai ni n g t he i nf usi o n 
s ol uti o n. 
6. 
N O T E:  D O N O T U S E e vac uate d glass c o ntai ners w hic h re q uire ve nte d a d mi nistrati o n sets 
beca use t his ca uses f oa mi n g as air b u b bles pass t hr o u g h t he s ol uti o n.  
T he a d mi nistrati o n of rit u xi ma b will be acc o m plis he d b y sl o w I V i nf usi o n.  C A U TI O N:  D O 
N O T A D MI NI S T E R A S A N I N T R A V E N O U S P U S H O R B O L U S.  I V p u m ps s uc h as t he I M E D 
9 6 0 ma y be use d wit h t he rit u xi ma b i nf usi o n.  D O N O T I N F U S E C O N C O MI T A N T L Y wit h 
a n ot her I V s ol uti o n or I V me dicati o ns.  Pri me t he li ne wit h t he rit u xi ma b s o l uti o n s uc h t hat 
a p pr o xi matel y 3 0 m L ar e deli vere d.  T his will sat urate t he filter a n d t u bi n g.  
Dr u g a d mi nistrati o n a n d d osa ge sc he d ule 
 
C o m bi nati o n of b ortez o mi b, cla dri bi ne, a n d rit u xi ma b will be a d mi nistere d as f oll o ws:  
•  Rit u xi ma b 3 7 5 m g/ m 2 I V da y 1 
•  Cla d ri bi ne 4 m g/ m 2 I V o ver 2 h o urs da ys 1- 5  
•  B ortez o mi b 1. 3 m g/ m 2 I V da ys 1 a n d 4 
T he c o m bi nati o n will be re peate d e ver y 2 8 da ys, w hic h w o ul d c o nstit ute a c ycle, f or a ma xi m u m 
of 6 c ycles 
V E L C A D E A d mi nistrati o n  
 
V E L C A D E will be a d mi nistere d at 1. 3 m g/ m 2 o n da ys 1 a n d 4 of eac h c ycle.  
 
D r u g will be a d mi nistere 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).  Patie nts ma y be treate d o n a n o ut-patie nt basis, if p ossi ble.  T he 
p har macist will pre pare t he dr u g  u n der ase ptic c o n dit i o ns.  T he a m o u nt (i n m g) of dr u g t o be 
a d mi nistere d will be deter mi ne d base d o n b o d y s urface area.  B o d y s urface area is t o be calc ulate d 
base d o n b o d y wei g ht usi n g a sta n dar d n o m o gra m (see secti o n 8. 3 ).  T he d ose s h o ul d be calc ulate d 
o n Da y  1 of eac h c ycle; t he d ose a d mi nistere d s h o ul d re mai n t he sa me t hr o u g h o ut eac h c ycle b ut 
sh o ul d be recalc ulate d at t he start of t he ne xt c ycle.  If a patie nt e x perie nc es a n ota ble c ha n ge i n 
wei g ht (e . g., l oss or gai n of ≥8 l bs or 3. 6 k g) wit hi n a c ycle, as deter mi ne d b y a n u nsc he d ule d 
wei g ht assess me nt, t he n t he patie nt’s d ose s h o ul d be recalc u late d at t hat ti me. 
T he a p pr o priate a m o u nt of V E L C A D E will be dra w n fr o m t he i njecti o n vial a n d a d mi nistere d as 
a n i ntra ve n o us (I V) p us h o ver 3 t o 5 sec o n ds f oll o we d b y a sta n dar d sali ne fl us h or t hr o u g h a 
r u n ni n g I V li ne.  Vials are f or si n gle use a d mi nistrati o n.   

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V E L C A D E  Destr ucti o n  
F or c o m mer ciall y -la bele d V E L C A D E f or I N D-e xe m pt st u dies, please c o ntact y o ur Mille n ni u m 
Cli nical O perati o ns re prese ntati ve t o arra n ge f or ret ur n of st u d y dr u g pr oce d ures.  A n y u n use d or 
e x pire d V E L C A D E m ust be ret ur ne d t o Mi lle n ni u m.  Be s ure t o d oc u me nt dr u g ret ur n o n y o ur 
dr u g acc o u nta bilit y l o gs.  
 
Le ustati n (c la dri bi ne) a d mi nistrati o n 
 
Cla dri bi ne will be a d mi nistere d at 4 m g/ m 2 o n da ys 1 t hr o u g h 5 of eac h c ycle as a 2 - h o ur 
i ntra ve n o us  i nf usi o n. Vials  of  Le ustati n  I njecti o n  are  f or  si n gle -use  o nl y.  D r u g  will  be  
a d mi nistere 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).  Patie nts ma y be treate d o n a n o ut- patie nt basis, if p ossi ble.   
 
T he p har macist will pre pare t he dr u g u n der ase ptic c o n diti o ns.  T he a m o u nt (i n m g) of dr u g t o be 
a d mi nistere d will be deter mi ne d base d o n b o d y s urface area.  B o d y s urface area is t o be calc ulate d 
base d o n b o d y wei g ht usi n g a sta n dar d n o m o gra m (see secti o n 8. 3 ).  T he d ose s h o ul d be calc ulate d 
o n Da y 1 of eac h c ycle a n d s h o ul d be a dj uste d if t here is at least 1 0 % c ha n ge i n wei g ht.  
 
Rit u x a n (rit u xi ma b) A d mi nistrati o n  
 
Rit u xi ma b will be a d mi nistere d at 3 7 5 m g/ m 2 as a sl o w i ntra ve n o us i nf usi o n o n da y 1 of eac h 
c ycle. Dr u g will be a d mi nistere 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).  Patie nts ma y be treate d o n a n o ut-patie nt basis, if p ossi ble.  T he 
p har macist will pre pare t he dr u g u n der ase ptic c o n dit i o ns.  T he a m o u nt (i n m g) of dr u g t o be 
a d mi nistere d will be deter mi ne d base d o n b o d y s urface area.  B o d y s urface area is t o be calc ulate d 
base d o n b o d y wei g ht usi n g a sta n dar d n o m o gra m (see secti o n 8. 3 ).  T he d ose s h o ul d be calc ulate d 
o n Da y 1 of eac h c ycle a n d s h o ul d be a dj uste d if t here is at least 1 0 % c ha n ge i n wei g ht.  
 
3. 3. 4  
D ose M o dific ati o n a n d Del a y 
D ose escalati o n will n ot be all o we d i n a n y patie nt, a n d t here m ust be at least 7 2  h o urs bet wee n 
eac h d ose of V E L C A D E.   
 
Bef or e eac h c ycle , t he patie nt will be e val uate d f or p ossi ble t o xicities t hat ma y ha ve occ urre d 
after  t he  pre vi o us  c ycle(s).   T o xicities  are  t o  be  assesse d  acc or di n g  t o  t he  N CI  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), Versi o n  3. 0. 
 
D ose le vel re d ucti o ns are as f oll o ws:  
V E L C A D E:  
D ose le vel 0: 1. 3 m g/ m 2 da ys 1 a n d 4 ( baseli ne)  
D ose le vel 1: 1. 0 m g da ys 1 a n d 4  

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D ose Le vel 2: 0. 7 m g da ys 1 a n d 4 
 
Cla dri bi ne:  
D ose le vel 0: 4 m g/ m 2 da ys 1- 5 ( baseli ne)  
D ose le vel 1: 4 m g/ m 2 da ys 1- 4  
 
Rit u xi ma b: n o d ose le vel re d ucti o ns.  
He m at ol o gic t o xicities :  
 
After t he first c ycle of c o m bi nati o n c he m ot hera p y, t he s u bse q ue nt  c ycle is t o be hel d f or u p t o 2  
wee ks  ( 1 4 da ys) u ntil t he patie nt has a platelet val ue of at least 7 5 ×  1 09/ L a n d a bs ol ute ne utr o p hil 
c o u nt of at least 1. 0 ×  1 09/ L. If t he platelet val ue d oes n ot rec o ver b y t he 1 4  da ys p ost t he 
s u bse q ue nt c ycle, t he n t he patie nt will be re m o ve d fr o m t he trial.  
 
D ue t o hi g h ris k of ne utr o pe nia wit h t his re gi me n, patie nts s h o ul d  be starte d o n gra n ul oc yte 
gr o wt h fact ors pr o p h ylacticall y. Gr o wt h fact ors f or er yt hr oi d a n d me ga kar y oc ytic li nea ges are t o 
be use d as nee de d.  
 
D ose i nterr u pti o n or st u d y disc o nti n uati o n is n ot  re q uire d f or l y m p h o pe nia of a n y gra de.   
 
T hr o m b oc yt o pe ni a :  
 
Gra de 1 ( ≥ 7 5 ×  1 09/ L)    – pr ocee d wit h t hera p y ; n o d ose re d ucti o n  
Gra de 2 ( 5 0- 7 5 ×  1 09/ L)   – h ol d t hera p y u ntil c o u nt rec o ver y t o gra de 0- 1; n o d ose re d ucti o n;  
r ule o ut fact ors p ote ntiall y c o ntri b uti n g t o t hr o m b oc yt o pe nia (s uc h 
as platelet -t o xic dr u gs); 
Gra des 3 - 4 ( < 5 0 ×  1 09/ L) – 1 st e pis o de: h ol d t h era p y u ntil rec o ver y t o gra de 0- 1; r ule o ut  
fact ors p ote ntiall y c o ntri b uti n g t o t hr o m b oc yt o pe nia (s uc h as 
platelet -t o xic dr u gs); decrease cla dri bi ne b y 1 d ose le vel f or > 1 
wee k dela y ; 
         2n d e pis o de: h ol d t hera p y u ntil rec o ver y t o gra de 0-1; decrease  
V E L C A D E b y 1 d ose le vel f or > 1 wee k dela y ;  
         3r d e pis o de: disc o nti n ue t he pr ot oc ol.  
 

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Ne utr o pe ni a : 
 
Gra des 1 - 2 ( A N C ≥ 1. 0 ×  1 09/ L)   – pr ocee d wit h t hera p y; n o d ose re d ucti o n; i ncrease gr o wt h  
fact or s u p p ort if a p plica ble; 
Gra des 3 - 4 ( A N C < 1. 0 ×  1 09/ L)   – h ol d t hera p y u ntil rec o ver y t o gra de 0-2; i ncrease gr o wt h  
fact or s u p p ort if a p plica ble; decrease cla dri bi ne b y 1 d ose 
le vel  f or  > 1 wee k  dela y.  If  n o  m ore  d ose  re d ucti o ns  
p ossi ble, disc o nti n ue t he pr ot oc ol. 
A ne mi a:  
 
Gra des 1 - 2 ( H g b ≥ 8 g/ d L) – pr ocee d wit h t hera p y; n o d ose re d ucti o n; use a p pr o priate  
s u p p orti ve meas ures (s uc h as er yt hr o p oiesis s u p p orti n g a ge nts a n d 
tra nsf usi o ns); 
Gra des 3 - 4 ( H g b < 8 g/ d L) – h ol d t hera p y u ntil rec o ver y t o gra de 0-2; n o d ose re d ucti o n; use  
a p pr o priate s u p p orti ve meas ures (s uc h as er yt hr o p oiesis 
s u p p orti n g a ge nts a n d tra nsf usi o ns). If rec o ver y ti me is m ore 2 
wee ks , disc o nti n ue t he pr ot oc ol.  
N o n -he m at ol o gic t o xicities  (e xce pt ne ur o pat hic pai n a n d/ or peri p heral se ns or y ne ur o pat h y): 
 
V E L C A D E d ose m o difi cati o n:  
 
If t he patie nt e x perie nces a n y ≥ Gra de 3 n o n -he mat ol o gic t o xicit y c o nsi dere d b y t he i n vest i gat or 
t o be relate d t o V E L C A D E, t he n t hera p y is t o be hel d. 
 
V E L C A D E  is t o be hel d f or u p t o 2 wee ks u ntil t he t o xicit y ret ur ns t o Gra de 1 or better.  If, after 
t hera p y has bee n hel d, t he t o xicit y d oes n ot res ol ve, as defi ne d a b o ve, t he n t he pr ot oc ol  m ust be 
disc o nti n ue d. 
 
If t he t o xicit y res ol ves, as defi ne d a b o ve, a n d V E L C A D E is t o be restarte d, t he d ose m ust be 
re d uce d b y o ne d ose le vel. 
 
Cla dri bi ne d ose m o dificati o n:  
 
If t he patie nt e x perie nces a n y ≥Gra de 3 n o n -he mat ol o gic t o xicit y c o nsi dere d b y t he i n vest i gat or 
t o be relate d t o cla dri bi ne, t he n t hera p y is t o be hel d. 
 
Pa rtic ular atte nti o n nee ds t o be pai d t o re nal a n d ne ur ol o gical t o xicities.  
 
Cla dri bi ne is t o be hel d f or u p t o 2 wee ks u ntil t he t o xicit y ret ur ns t o Gra de 1 or better. I f, after 
t hera p y has bee n hel d, t he t o xicit y d oes n ot res ol ve, as defi ne d a b o ve, t he n t he pr ot oc ol  m ust be 
disc o nti n ue d. 
 
If t he t o xicit y res ol ves, as defi ne d a b o ve, a n d cla dri bi ne is t o be restarte d, t he d ose m ust be 
re d uce d b y o ne d ose le vel. 

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Rit u xi ma b D ose A nti b o d y M o dificati o n :   
a. Patie nts ma y e x perie nce tra nsie nt fe ver a n d ri g ors wit h i nf usi o n of rit u xi ma b.  If Gra de 3 fe ver 
( or Gra de 2 fe ver wit h ri g ors) or Gra de 2 ri g ors are n ote d, t he a nti b o d y i nf usi o n s h o ul d be 
te m p oraril y disc o nti n ue d, t he patie nt s h o ul d be o bser ve d, a n d t he se verit y of t he si de effects 
s h o ul d be e val uate d.  T he patie nt s h o ul d be treate d acc or di n g t o t he best a vaila ble l ocal 
practices a n d pr oce d ures.  F oll o wi n g o bser vati o n, w he n fe ver res ol ves t o Gra de 2 or less a n d 
ri g ors t o Gra de 1 or less, t he i nf usi o n s h o ul d be c o nti n ue d, i nitiall y, at 1/ 2 t he pre vi o us rate.  
F oll o wi n g t he a nti b o d y i nf usi o n, t he I V li ne s h o ul d be ke pt o pe n f or me dicati o ns, as nee de d.   
b. H y p ote nsi o n, br o nc h os pas m a n d a n gi oe de ma ha ve occ urre d as part of a n i nf usi o n relate d 
s y m pt o m c o m ple x.  If a Gra de 3 or greater h y perse nsiti vit y/aller gic reacti o n occ urs, a nti b o d y 
i nf usi o n s h o ul d be i nterr u pte d a n d ma y be res u me d at a 5 0 % re d ucti o n i n rate w he n s y m pt o ms 
ha ve  c o m pl etel y  res ol ve d.   Treat me nt  wit h  di p he n h y dra mi ne  a n d  aceta mi n o p he n  is  
rec o m me n de d; a d diti o nal treat me nt wit h br o nc h o dilat ors or I V sali ne ma y be use d at t he 
p h ysicia n's discreti o n.   
c. Preca uti o nar y h os pitalizati o n f or patie nts e x perie nci n g se vere i nf usi o n s y m pt o ms, w hic h d o 
n ot res ol ve after disc o nti n uati o n of t he c ycle, is rec o m me n de d.  If t here are n o c o m plicati o ns, 
t he I V li ne ma y be disc o nti n ue d after o ne h o ur of o bser vati o n.  If c o m plicati o ns occ ur d uri n g 
t he rit u xi ma b i nf usi o n, t he patie nt s h o ul d be o bser ve d f or t w o h o urs after t he c o m pleti o n of 
t he i nf usi o n.  If a patie nt e x perie nces a Gra de 3 t o xicit y t hat persists u ntil t he ne xt sc he d ule d 
i nf usi o n, t he patie nt m ust disc o nti n ue treat me nt u ntil t o xicities ha ve res ol ve d t o Gra de 2 or 
less.  If treat me nt is dela ye d f or m ore t ha n t hree wee ks, re m o ve t he patie nt fr o m pr ot oc ol 
treat me nt. 
d. T u m or L ysis S y n dr o me:  A p pr o priate me dical t hera p y s h o ul d be pr o vi de d f or patie nts w h o 
de vel o p  t u m or  l ysis  s y n dr o me.   F oll o wi n g  treat me nt  f or  a n d  res ol uti o n  of  t u m or  l ysis  
s y n dr o me,  s u bse q ue nt  rit u xi ma b  t hera p y  ma y  be  a d mi nistere d  i n  c o nj u ncti o n  wit h  
pr o p h ylactic t hera p y f or t his s y n dr o me.  C o ntact t he St u d y C o or di nat or pri or t o res u mi n g 
treat me nt i n t hese patie nts. 
e. He patitis  B  Reacti vati o n  wit h  Relate d  F ul mi na nt  He patitis  a n d  Ot her  Viral  I nfecti o ns:   
Carriers of he patitis B s h o ul d be cl osel y m o nit ore d f or cli nical a n d la b orat or y si g ns of acti ve 
H B V i nfecti o n a n d f or si g ns of he patitis t hr o u g h o ut t heir st u d y partici pati o n.  Patie nts wit h 
a n y  e vi de nce  of  acti ve  he patic  disease  or  k n o w n  H B V  i nfecti o n  s h o ul d  be  ma na ge d  as 
cli nicall y a p pr o priate a n d s h o ul d o nl y recei ve rit u xi ma b if t he y ha ve c o ntr ol of t he i nfecti o n 
a n d are a de q uatel y i nf or me d of t he ris ks.  Patie nts w h o ha ve ne ver recei ve d vacci nati o n f or 
H B V, a n d ha ve n ot ha d ser ol o gic testi n g f or H Bs A g, s h o ul d be teste d f or s urface a nti ge n 
p ositi vit y.   
I n  patie nts  w h o  de vel o p  pr o gressi ve  m ultif ocal  le u k oe nce p hal o pat h y  ( P M L),  rit u xi ma b  
s h o ul d be disc o nti n ue d a n d re d ucti o ns or disc o nti n uati o n of c o nc o mita nt i m m u n os u p pressi ve 
t hera p y  a n d  a p pr o priate  treat me nt,  i ncl u di n g  a nti viral  t hera p y,  s h o ul d  be  c o nsi dere d.  
P h ysicia ns  s h o ul d  c o nsi der  P M L  i n  a n y  patie nts  prese nti n g  wit h  ne w  o nset  ne ur ol o gic 
ma nifestati o ns, partic ularl y i n patie nts wit h s yste mic l u p us er yt he mat os us ( S L E) or l y m p h oi d 
mali g na ncies.  C o ns ultati o n wit h a ne ur ol o gist, brai n M RI, a n d l u m bar p u nc t ure s h o ul d be 

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c o nsi dere d as cli nicall y i n dicate d.  T here are n o k n o w n i nter ve nti o ns t hat ca n relia bl y pre ve nt 
P M L or a de q uatel y treat P M L if it occ urs.   
f. Se vere M uc oc uta ne o us Reacti o ns:  All patie nts o n a n d off rit u xi ma b t hera p y s h o ul d be cl osel y 
m o nit ore d  f or  si g ns  a n d  s y m pt o ms  s u g gesti ve  of  se vere  c uta ne o us  a n d  m uc oc uta ne o us  
reacti o ns.  S h o ul d t hese s y m pt o ms arise, disc o nti n ue rit u xi ma b t hera p y (if a p plica ble) a n d 
s u p p ort as cli nicall y i n dicate d.   
g. Car di o vasc ular e ve nts:  Patie nts wit h r he u mat oi d art hritis ( R A) are at i ncrease d ris k f or 
car di o vasc ular  e ve nts  c o m pare d  t o t he  ge neral  p o p ulati o n.  Patie nts  wit h  R A  s h o ul d  be  
m o nit ore d t hr o u g h o ut t he i nf usi o n, a n d rit u xi ma b s h o ul d be disc o nti n ue d i n t he e ve nt of a 
seri o us or life-t hreate ni n g car diac e ve nt.   
Patie nts w h o de vel o p cli nicall y si g nifica nt arr h yt h mias s h o ul d u n der g o car diac m o nit ori n g 
d uri n g  a n d  after  s u bse q ue nt  i nf usi o ns  of  rit u xi ma b.   Patie nts  wit h  pre -e xisti n g  car diac  
c o n diti o ns, i ncl u di n g arr h yt h mias a n d a n gi na, t hat ha ve ha d rec urre nces o f t hese e ve nts d uri n g 
rit u xi ma b t hera p y s h o ul d be m o nit ore d t hr o u g h o ut t he i nf usi o n a n d i m me diate p ost-i nf usi o n 
peri o d.  Patie nts off rit u xi ma b t hera p y s h o ul d be cl osel y m o nit ore d f or si g ns a n d s y m pt o ms 
s u g gesti ve of life-t hreate ni n g car diac e ve nts a n d s u pp orte d as cli nicall y i n dicate d.    
h. B o wel o bstr ucti o n a n d perf orati o n:  C o m plai nts of a b d o mi nal pai n, es peciall y earl y i n t he 
c o urse, s h o ul d pr o m pt a t h or o u g h dia g n ostic e val uati o n a n d a p pr o priate treat me nt.  If patie nt 
e x perie nces a b o wel o bstr ucti o n or  perf orati o n, disc o nti n ue rit u xi ma b t hera p y.  Patie nts off 
rit u xi ma b t hera p y s h o ul d be cl osel y m o nit ore d f or si g ns a n d s y m pt o ms s u g gesti ve of b o wel 
o bstr ucti o n a n d s u p p orte d as cli nicall y i n dicate d. 
i. Re nal:   Disc o nti n uati o n  of  rit u xi ma b  s h o ul d  be  c o nsi de re d  f or  t h ose  wit h  risi n g  ser u m  
creati ni ne or oli g uria.   
 
Ne ur o p at hic p ai n a n d/ or peri p her al se ns or y ne ur o p at h y : 
 
Patie nts  w h o  e x perie nce  V E L C A D E -relate d  ne ur o pat hic  pai n  a n d/ or  peri p heral  se ns or y  
ne ur o pat h y are t o be ma na ge d as prese nte d i n  Ta ble 4 Ma na g e me nt of Patie nts wit h V E L C A D E -
Relate d Ne ur o pat hic Pai n a n d/ or Peri p heral Se ns or y Ne ur o pat h y. 

Versi o n 7 :  0 8/ 1 5 / 2 0 1 7  
5 6  
T a ble 4 
 
M a n a ge me nt of P atie nts wit h V E L C A D E  Rel ate d Ne ur o p at hic P ai n  
a n d/ or Peri p her al Se ns or y or M ot or Ne ur o p at h y  
 
Rec o m me n de d D ose M o dific ati o n f or V E L C A D E  rel ate d Ne ur o p at hic P ai n a n d/ or Peri p her al Se ns or y or M ot or 
Ne ur o p at h y  
Se verit y of Peri p her al Ne ur o p at h y  
Si g ns a n d S y m pt o ms  
M o dific ati o n of D ose a n d Re gi me n  
Gra de 1 ( parest hesias , wea k ness a n d/ or l oss of refle xes)  
wit h o ut pai n or l oss of f u ncti o n  
N o acti o n  
Gra de 1 wit h pai n or Gra de 2 (i nterferi n g wit h  
f u ncti o n b ut n ot wit h acti vities of dail y li vi n g)  
Re d uce V E L C A D E t o 1. 0 m g/ m 2 
Gra de 2 wit h pai n or Gra de 3 (i nterferi n g wit h  
acti vities of dail y li vi n g)  
Wit h h ol d *  V E L C A D E t hera p y u ntil  
t o xicit y res ol ves.  
 
W he n t o xicit y res ol ves rei nitiate wit h  
a re d uc e d d ose of V E L C A D E at 0. 7  m g/ m 2.*   
Gra de 4 ( Se ns or y ne ur o pat h y w hic h is disa bli n g or m ot or 
ne ur o pat h y t hat is life t hreate ni n g or lea ds t o paral ysis )  
Disc o nti n ue V E L C A D E  
Gra di n g base d o n N CI C o m m o n Ter mi n ol o g y  Criteria C T C A E v 3. 0     
N CI C o m m o n Ter mi n ol o g y  Criteria we bsite - htt p://cte p.i nf o. ni h. g o v/re p orti n g/ctc. ht ml  
A D L = acti vities of dail y li vi n g  
* Ke y:  
Re d uce b y o ne d ose le vel:  
V E L C A D E d ose re d ucti o n fr o m 1. 3 t o 1. 0, or 1. 0 t o 0. 7 m g/ m 2/ d ose.  
Re d uce b y t w o d ose le vel s: 
V E L C A D E d ose r e d ucti o n fr o m 1. 3 or 1. 0 t o 0. 7 m g/ m 2/ d ose. 
H ol d:      
 
I nterr u pt V E L C A D E f or u p t o 2 wee ks u ntil t he t o xicit y ret ur ns t o Gra de 1 or better . 
 
T he ne ur ot o xicit y -directe d q uesti o n naire (see se cti o n 8. 6 ) is a usef ul t o ol f or deter mi ni n g t he 
prese nce  a n d  i nte nsit y  of  ne ur o pat hic  pai n  a n d/ or  peri p heral  ne ur o pat h y  fr o m  t he  patie nt’s  
pers pecti ve .   Ne ur o pat hic  s y m pt o ms  are  m ore  pr o mi ne nt  t ha n  a b n or malities  o n  t he  cli nical  
e xa mi nati o n.   After  t he  patie nt  c o m pletes  t he  ne ur ot o xicit y -directe d  q uesti o n naire,  t he  
q uesti o n naire s h o ul d be re vie we d t o assist wit h t he e val uati o n of t he o nset a n d i nte nsit y of 
peri p heral ne ur o pat h y a n d ot her ne ur ot o xicities t hat ma y p ossi bl y re q uire i nter ve nti o n or d ose 
m o dificati o n.  
 
Patie nts  wit h  mil d  he patic  i m pair me nt  ( bilir u bi n  ≤  1. 5 ×  U L N) d o n ot re q uire a starti n g d ose 
a dj ust me nt.   Please  n ote  t hat  patie nts  wit h  bilir u bi n  le vels  >  1. 5  U L N  are  e xcl u de d  fr o m  
e nr oll me nt i n t his pr ot oc ol.  If a patie nt de vel o ps m o derate or se vere he patic i m pair me nt wit h 
bilir u bi n ≥ Gra de 2 ( > 1. 5 -3. 0 X U L N) w hile o n st u d y, t he i n vesti gat or s h o ul d h ol d V E L C A D E 
u ntil t he t o xicit y ret ur ns t o < Gra de 2. Restarti n g V E L C A D E at t he ne xt l o wer d ose d le vel c o ul d 
be c o nsi dere d at t he I n vesti gat or’s discreti o n a n d f oll o wi n g e xcl usi o n of V E L C A D E -i n d uce d 
li ver i m pair me nt a n d caref ul c o nsi derati o n of li ver disease d ue t o ot her ca uses, s uc h as, b ut n ot 
li mite d t o, acti ve i nfecti o n a n d m ulti ple m yel o ma-relate d li ver disease. 
 

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5 7  
3. 3. 5  
Tre at me nt Assi g n me nt  
T his is a n o pe n -la bel trial wit h o ut ra n d o mizati o n . All patie nts will be assi g ne d t o t he sa me 
treat me nt.   
3. 3. 6  
Bli n di n g, P ac k a gi n g, a n d L a beli n g  
V E L C A D E will be s u p plie d b y Mille n n i u m P har mace uticals, I nc, i n vials as o pe n-la bel st oc k.  
B ot h t he b o x la bel a n d vial la bel 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.   
Cla dri bi ne a n d rit u xi ma b are c o m merciall y a vaila ble a n d will be la bele d as s pecifie d b y g o ver ni n g 
re g ulati o ns.  
3. 3. 7  
C o nc o mit a nt Tre at me nt  
I n vesti gat ors  s h o ul d  c o nsi der  usi n g  a nti viral  pr o p h yla xis  i n  s u bjects  bei n g  treate d  wit h  
V E L C A D E . 
Re q uire d C o nc urre nt T hera p y 
T he  f oll o wi n g  me dicati o ns/s u p p orti ve  t hera pies  are  re q uire d  d uri n g  st u d y  partici pati o n,  as  
a p plica ble: 
•  D ue t o hi g h li keli h o o d of ne utr o pe nia wit h cla dri bi ne, pr o p h ylactic use of   Ne u p o ge n, 
Ne ulasta, or Le u ki ne  is ma n dat or y  
•  P r o p h ylactic a nti bi otic t hera p y t o pre ve nt fe brile ne utr o pe nia is at t he discreti o n of t he 
treati n g p h ysicia n (e. g., ci pr ofl o xaci n, le v ofl o xaci n) 
•  P ne u m ocystis jir ovecii (c ari nii)  p ne u m o nia pr o p h yla xis is ma n dat or y ; e xact a ge nt is per 
discreti o n of t he treati n g p h ysicia n (tri met h o pri m/s ulfa met h o xaz ole is preferre d) 
•  A nti -her petic  pr o p h yla xis  is  ma n dat or y ;  e xact  a ge nt  is  per  discreti o n  of  t he  treati n g  
p h ysicia n (e. g., ac ycl o vir, valac ycl o vir, or fa mc ycl o vir)   
•  A nti -f u n gal pr o p h yla xis is n ot ma n dat or y b ut is str o n gl y e nc o ura ge d; e xact a ge nt is per 
discreti o n of t he treati n g p h ysicia n (e. g., fl uc o naz ole)  
•  Pre -me dicati o n pri or t o rit u xi ma b i nf usi o n is ma n dat or y a n d is per i nstit uti o nal g ui deli nes  
•  T o pre ve nt t u m or l ysis s y n dr o me i n patie nts wit h b ul k y t u m ors or  si g nifica nt b o ne marr o w 
or bl o o d i n v ol ve me nt, oral or I V fl ui d i nta ke i n e xcess of 2 L dail y is e nc o ura ge d d uri n g 
t hera p y.  Patie nts m ust  recei ve all o p uri n ol, d ose -a dj uste d f or re nal cleara nce, f or t he first 
t w o wee ks of t he first c ycle of pr ot oc ol t hera py.  All o p uri n ol ma y be c o nti n ue d after t he 
first t w o wee ks at p h ysicia n's discreti o n. 
•  Gr o wt h fact ors f or er yt hr oi d a n d me ga kar y oc ytic li nea ges are t o be gi ve n at t he discreti o n 
of t he treati n g p h ysicia n.  
Pr o hi bite d C o nc urre nt T hera p y 
•  A n y i n vesti gati o nal a ge nt ot her t ha n V E L C A D E, cla dri bi ne, a n d rit u xi ma b, wit hi n 1 4 
da ys of t he start of t his trial a n d t hr o u g h o ut t he d urati o n of t his trial. 

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5 8  
3. 3. 8  
Tre at me nt C o m pli a nce  
All dr u g will be a d mi nistere d 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 o r or 
i de ntifie d  s u b-i n vesti gat or(s).   T he  p har macist  will  mai ntai n  rec or ds  of  dr u g  recei pt  (if  
a p plica ble), dr u g pre parati o n, a n d dis pe nsi n g, i ncl u di n g t he a p plica ble l ot n u m bers, patie nts’ 
hei g ht, b o d y wei g ht, a n d b o d y s urface area (see secti o n 8. 3 ), a n d t otal dr u g a d mi nistere d i n 
milliliters a n d milli gra ms , a n d date a n d ti me of a d mi nistrati o n .  A n y discre pa nc y bet wee n t he 
calc ulate d d ose a n d d ose a d mi nistere d a n d t he reas o n f or t he discre pa nc y m ust be rec or de d i n t he 
s o urce d oc u me nts. 
3. 4  D ur ati o n of Tre at me nt a n d  P atie nt P artici p ati o n  
Patie nts will recei ve a ma xi m u m of 6 treat me nt c ycles. T he y w ill ha ve s h ort-ter m f oll o w-u p e ver y 
3 m o nt hs f or t w o years .  Patie nts will ha ve l o n g-ter m f oll o w- u p p h o ne calls a n n uall y u p t o 5 
years. .   
3. 5  Ter mi n ati o n of Tre at me nt a n d/ or St u d y P artici p ati o n  
Patie nts 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.  T he i n vesti gat or als o has t he ri g ht t o wit h dra w 
patie nts fr o m t he st u d y f or a n y of t he f oll o wi n g reas o ns: 
•  I nterc urre nt ill ness 
•  Occ urre nce of a n u nacce pta ble a d verse e ve nt  
•  A treat me nt c ycle dela y of m ore t ha n 2 wee ks  c o nsec uti vel y 
•  Patie nt re q uest  
•  Pr ot oc ol vi olati o ns  
•  N o n -c o m plia nce 
•  A d mi nistrati ve reas o ns  
•  Fail ure t o ret ur n f or f oll o w- u p 
•  Ge neral or s pecific c ha n ges i n t he patie nt’s c o n diti o n u nacce pta ble f or f urt her treat me nt 
i n t he j u d g me nt of t he i n vesti gat or 
•  Pr o gressi ve disease at a n y ti me  
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 St u d y visit s h o ul d be 
c o m plete d.  T he pri mar y reas o n f or a patie nt’s wit h dra wal fr o m t he st u d y is t o be rec or de d i n t he 
s o urce d oc u me nts. 
3. 6  Effic ac y,  P h ar m ac o d y n a mic/ P h ar m ac o ge n o mic / C orrel ati ve  st u dies,  a n d  S afet y  
Me as ure me nts   
3. 6. 1  C orrel ati ve St u dies   
S pecific Ai m 1 : T o i n vesti gate h u ma n Ma ntle Cell L y m p h o ma, a n d I n d ole nt L y m p h o ma utilizi n g 
a tiss ue micr oarra y ( T M A) t o de m o nstrate o ver -e x pressi o n of A ur ora A, A ur ora B, Ki- 6 7, c ycli n 
D, Bcl - 2, p h os p h or-His H 3, c -Met a n d V E G F wit h R T -P C R vali dati o n.  
O ver vie w :  
Tiss ue  micr oarra y  ( T M A)  is  a  p o werf ul  t o ol  t o  perf or m  hi g h -t hr o u g h p ut  e val uati o n  of  cell  
p he n ot y pes a n d s pecific t u m or -ass ociate d a nti ge ns w he n i nte grate d wit h i m m u n o hist oc he mical 

Versi o n 7 :  0 8/ 1 5 / 2 0 1 7  
5 9  
(I H C) stai ni n g or i n sit u h y bri dizati o n ( Wa n et al., 1 9 8 7; K o n o ne n et al., 1 9 9 8). Vali dati o n st u dies 
usi n g t u m or s peci me ns fr o m differe nt ca ncers a n d l y m p h o ma ha ve de m o nstrate d t hat T M As ca n 
acc ur atel y  re prese nt  t he  I H C  stai ni n g  res ults  of  w h ole  tiss ue  or  l y m p h  n o de  secti o ns  w he n  
m ulti ple c ores are use d ( S kacel et al., 2 0 0 2; Rassi da kis et al., 2 0 0 2). M ore o ver, t his tec h ni q ue 
facilitates t he e val uati o n of ne w bi o mar kers f or disease dia g n osis a n d pr o g n osis ( Nat k u na m et al, 
2 0 0 1). T M A p he n ot y pic st u dies of H o d g ki n's l y m p h o mas a n d B -cell n o n-H o d g ki n's l y m p h o mas 
are re p orte d b ut t he e xte nt of p ote ntial varia bilit y a m o n g o bser vers a n d met h o ds fr o m differe nt 
la b orat ories nee ds f urt her c haracterizati o n. Rece nt st u dies i n B-cell N H L s u g gest t hat t u m or 
a nti ge n  mar kers  ma y  be  use d  as  s urr o gates  f or  t he  ge ne  e x pressi o n  pr ofile  wit h e q ui vale nt 
pr o g n ostic si g nifica nce ( Nat k u na m et al, 2 0 0 1; Z u et al, 2 0 0 5). F urt her, we w o ul d li ke t o c o nfir m 
t his at t he tra nscri pt le vel b y R N A is olati o n a n d q ua ntitati ve real ti me R T-P C R. T he pr o p ose d 
T M A will be o n tiss ue retr os pecti vel y a n d/ or pr os pecti vel y c ollecte d a n d t he i nf or mati o n deri ve d 
will be utilize d as s urr o gate mar kers a n d vali date d i n t he pla n ne d P hase II trial. We pl a n t o f oc us 
o n t he hall mar ks of ca ncer k n o w n t o l y m p h o ma bi ol o g y: A ur ora ki nase A, A ur ora ki nase B, Ki -
6 7, c ycli n D, Bcl -2, p h os p h or -His H 3, c -Met a n d V E G F. T hese mar kers ca n als o be vali date d b y 
Wester n bl otti n g (if t he T M A t ur ns o ut t o be n o n -c o ncl usi ve).  
A ur ora ki nase A, a seri ne/t hre o ni ne ki nase, is i n v ol ve d i n re g ulati n g ce ntr os o me asse m bl y a n d 
c hr o m os o me se gre gati o n d uri n g mit osis. A ur ora ki nase A is k n o w n t o be o vere x presse d i n se veral 
N H L s u bt y pes  ( Ya k us hiji n et  al., 2 0 0 4)  a n d ma y be relate d t o pr ol iferati o n stat us i n M C L 
( Ca mac h o et al., 2 0 0 6). It is t h us o ur h y p ot hesis t hat A ur ora Ki nase A is res p o nsi ble f or a lar ge 
p orti o n of t he effect of pr oliferati ve si g nat ure t hat is m ost pr o g n ostic i n ma ntle cell l y m p h o ma as 
assesse d  b y  L L M P P  ( data  fr o m  R ose n wal d  et  al,  2 0 0 3,  re vie we d  b y  Dr.  Ri msza,  pers o nal  
c o m m u nicati o n). A ur ora ki nase B ma y be si milarl y si g nifica nt.   
Tiss ue Arra y C o nstr ucti o n a n d I m m u n o hist oc he mistr y 
M or p h ol o gicall y re prese ntati ve areas of all cases of l y m p h o ma o n t his st u d y will be e val uate d. 
Als o 3 t o 4 n or mal ‘reacti ve’ l y m p h n o des will be use d as c o ntr ols. I n eac h case, 3 c ores wit h a 
dia meter of 0. 6 m m will be o btai ne d fr o m 3 differe nt areas of t he tiss ue bl oc ks a n d re -e m be d de d 
i n a tiss ue micr oarra y paraffi n bl oc k usi n g a tiss ue arra yer ( Beec her I nstr u me nts, Sil ver  S pri n g, 
M D) acc or di n g t o a met h o d descri be d pre vi o usl y ( K o n o ne n et al., 1 9 9 8). 
 Serial secti o ns of t he 
paraffi n -e m be d de d l y m p h o ma tiss ue arra y  will be de paraffi nize d a n d reacte d wit h pri mar y I H C 
a nti b o d y s pecific t o mar kers liste d a b o ve Bef ore a nti b o d y i nc u bati o n, t he sli des will be pr ocesse d  
f or a nti ge n retrie val. T his will c o nsist of micr o wa vi n g t he sli des i n citrate b uffer ( 0. 1 M, p H 6. 0) 
i n a press ure c o o ker f or 2 5 mi n a n d t he n left t o c o ol. T he sli des will be i nc u ba te d wit h t he a nti b o d y 
f or 1 h o ur. Bi oti n ylate d a nti m o use/a ntira b bit sec o n dar y a nti b o dies will be a p plie d, f oll o we d b y 
stre pta vi di n- per o xi dase c o m ple x ( D A K O, Car pi nteria, C A). C ol ore d pr o d ucts will be pr o d uce d  
usi n g t he dia mi n o be nzi di ne s u bstrate. Stai ni n g reacti o ns will be sc ore d as diff use or f ocal a n d 
gra de d (fr o m 0, ne gati ve  t o 4 +, i nte nsel y p ositi ve) f or b ot h ne o plas m a n d bac k gr o u n d str o ma. 
R N A Is olati o n a n d R T- P C R  
T otal R N A will be e xtracte d fr o m all a g gressi ve B -cell N H L sa m ples utilizi n g t he R Neas y M i ni 
Kit ( Qia ge n, C A). T he a m o u nt of t otal R N A is olate d fr o m t he cells will be q ua ntifie d usi n g 
s pectr o p h ot o metric  O D 2 6 0 meas ure me nts  wit h  yiel ds  >  2 5  μ g/sa m ple.  C o ntr ol  R N A  will  be 
o btai ne d fr o m n or mal peri p heral B -cells fr o m 4 v ol u nteers ( All Cells, C A) a n d t hree s na p fr oze n 

Versi o n 7 :  0 8/ 1 5 / 2 0 1 7  
6 0  
n or mal l y m p h n o de ( U ni versit y of Ariz o na, De part me nt of Pat h ol o g y). O ne h u n dre d na n o gra ms 
of t otal R N A will be use d f or re verse tra nscri ptase ( R T) reacti o ns ( 2 0 ml t otal v ol u me) carrie d 
o ut  usi n g  S u per Scri pt  III  Plati n u m Re verse  Tra ns cri ptase  (I n vitr o ge n,  Carls ba d,  C A).   
Reacti o ns will be i nc u bate d at 4 2 0C f or 5 0 mi n utes f oll o we d b y i nc u bati o n at 3 7 0C wit h R Nase 
H f or 2 0 mi n utes.  A n O ptic o n D N A E n gi ne ( MJ Researc h, Re n o, N V) will be use d t o perf or m 
real-ti me  fl u oresce nce  detecti o n  P C R.  O ne  micr oliter  of  c D N A  pr o d uce d  fr o m  re verse  
tra nscri pti o n reacti o ns was a d de d t o 1 2. 5 μl of Plati n u m S Y B R  Gree n q P C R S u per Mi x -U D G 
(I n vitr o ge n, Carls ba d, C A), 1 μl of ge ne-s pecific or β-acti n s pecific pri mer pair (see bel o w f or 
pri mer desi g n), a n d 1 0. 5  µl of d H 2 O (fi nal v ol u me of 2 5 µl).  A m plificati o n ( 9 5 0C f or 1 5 s, 5 5 0C 
f or 3 0 s, a n d 7 20C f or 3 0 s) will be re peate d f or 4 4 c ycles. F oll o wi n g t he P C R reacti o n, a melti n g 
c ur ve assa y was perf or me d t o deter mi ne t he p urit y of t he a m plifie d pr o d uct. Data were pr o vi de d 
as a t hres h ol d c ycle val ue ( C t) f or eac h sa m ple w hic h i n dicate d t he c ycle at w hic h a statisticall y 
si g nifica nt i ncrease i n fl u oresce nce was first detecte d. T hese data were t he n n or malize d t o β-acti n, 
w hic h ser ves as a n u naffecte d c o ntr ol ge ne , f or eac h data p oi nt a n d c o m pare d t o n or mal B-cell 
c o ntr ols t o deter mi ne relati ve e x pressi o n rati os. Eac h meas ure me nt was perf or me d i n tri plicate 
a n d res ults re prese nte d as mea n + S D.  
Pri mer Desi g n  
P C R pri mers f or a b o ve ge nes will be desi g ne d usi n g Mac Vec t or ( Accelr ys, Sa n Die g o, C A) t o 
pr o d uce a m plic o ns wit h le n gt hs ra n gi n g fr o m 8 0 -2 5 0 b p t o o pti mize t he efficie nc y of q P C R.  β -
acti n pri mers fr o m Q ua nt u m R N A  β -Acti n I nter nal Sta n dar ds ( A m bi o n, A usti n, T X) will be 
use d t o n or malize t he q P C R data.  
S pecific  Ai m  2 :  T o  i n vesti gate  t he  ser u m  c yt o ki ne  pr ofile  pri or  t o  a n d  p ost  t hera p y  f or  
i de ntificati o n of pre dicti ve a n d p ote ntial pr o g n ostic mar kers of res p o nse.  
 
O ver vie w 
C yt o ki ne e x pressi o n i n patie nts wit h l y m p h o ma is d ysre g ulate d i n a s u bt y pe -s pecific wa y ( Air ol di 
et al., 2 0 0 1). We will assess t he c yt o ki ne pr ofile of all l y m p h o ma s u bt y pes pre -treat me nt a n d after 
1 c ycle of t hera p y. T he c yt o ki ne pr ofile will li kel y differ  b y l y m p h o ma s u bt y pe, ma y differ i n 
res p o n ders as c o m pare d t o n o n-res p o n ders, a n d ma y c ha n ge wit h treat me nt i n eac h l y m p h o ma 
s u bt y pe i n a u ni q ue wa y t hat w o ul d re veal u n derl yi n g bi ol o gic differe nces. I n partic ular, we will 
assess plas ma T N F -al p ha, t he re d ucti o n i n w hic h was ass ociate d wit h res p o nse t o b ortez o mi b i n 
rela pse d l y m p h o mas ( Stra uss et al., 2 0 0 6). Ot her c yt o ki nes t hat ha ve e vi de nce of si g nifica nce will 
be e x pl ore d, partic ularl y fr o m T N F a n d T G F- beta fa milies, as well as I L - 1 0 a n d I L-6.  
Ser u m C yt o ki ne Pr ofili n g  
St ore d ( - 8 0oC) or fres h patie nt ser u m sa m ples will be utilize d ( N = all patie nts a n d 4 n or mal 
v ol u nteers). Arra y sli des will be t ha we d at r o o m te m perat ure as ser u m was dil ute d 3. 5 -f ol d wit h 
1 x bl oc ki n g b uffer ( C yt o ki ne Arra y Pr ot oc ol, Ra y Bi otec h, I nc # A A H -C Y T -G 1 0 0 0). Sli des will 
be bl oc ke d wit h bl oc ki n g b uffer a n d 5 0 µ L of eac h sa m ple was h y bri dize d wit h t he sli de f or 2 
h o urs; 1 µ L i nter nal c o ntr ols will als o be a d de d.  After was hi n g, pr o vi de d bi oti n -c o nj u gate d a nti -
c yt o ki ne  a nti b o dies  will  be  dil ute d  wit h  3 0 0 µ L  of  bl oc ki n g  b uffer,  a d de d  t o  t he  sli de,  a n d  

Versi o n 7 :  0 8/ 1 5 / 2 0 1 7  
6 1  
i nc u bate d f or 2 h o urs at r o o m te m perat ure.  Was hi n g ste ps will be re peate d, f oll o we d b y a d diti o n 
of a 1: 1 5 0 0 dil uti o n of Ale xa Fl o ur 5 5 5 -c o nj u gate d stre pta vi di n a n d i nc u bate d o ver ni g ht at 4° C.  
Sli des will be was he d m ulti ple ti mes a n d rea d o n t he A x o n Ge ne Pi x usi n g t he c y 3 c ha n nel. 
A nal ysis will be c o n d ucte d usi n g t he Ra y Bi otec h a nal ysis t o ol. Res ults will be re prese nte d as 
mea n + S E as eac h sa m ple per c yt o ki ne has 3 data p oi nts.  
 
S peci al I nstr uct i o ns f or S a m ple Ac q uisiti o n f or C or oll ar y St u dies 
 
T u m or :  
1.  Paraffi n -e m be d de d pre -treat me nt s peci me n fr o m t he m ost rece nt perf or me d ( wit hi n 8 
wee ks of st u d y re gistrati o n)  t u m or bi o ps y. 1 0 u nstai ne d sli des or tiss ue bl oc k will nee d t o 
be s u b mitte d. 
 
2.  Paraffi n -e m be d de d O P TI O N A L t u m or bi o ps y s peci me n (c ollecte d wit hi n 2 da ys of C ycle 
2, da y 1. 1 0 u nstai ne d sli des or tiss ue bl oc k will nee d t o be s u b mitte d. 
 .  
Bl o o d: Peri p her al ser u m s a m ple :   
Ser u m  sa m ples ( 5 ml ser u m) are t o be c ollecte d  wit hi n 2 wee ks of st u d y re gistrati o n a n d wit hi n 2 
da ys of c ycle 2, da y 1 ( pri or t o treat me nt i nf usi o n). F or t he U Mass site, eac h ser u m sa m ple will 
be di vi de d i nt o 1 ml  ali q u ot cr yo vials a n d place d i n a  mi n us 8 0 o C. freezer f or f ut ure batc he d 
s hi p me nt. F or U A site, s u b mit re d t o p ser u m se parat or t u be at r o o m te m perat ure t o Dr. Ri msza’s 
la b ( per a p pe n di x 8. 1 1) wit hi n 2 h o urs of t he bl o o d c ollecti o n.     
 
 
S a m ple Ac q uisiti o n C ale n d ar f or C or oll ar y St u dies  
 
S A M P L E  
P R E -
S T U D Y  
WI T HI N 2 
D A Y S O F 
C Y C L E 2, 
D A Y 1  
T U M O R 1  
 
X  
 
X  
 
 
 
B L O O D 2  
X  
X  
 
 
 
1  T u m or sa m ples : Paraffi n-e m be d de d pretreat me nt  bl oc k or 1 0 u nstai ne d sli des  (fr o m m ost rece nt 
bi o ps y pr oce d ure  c ollecte d wit hi n 8 wee ks of st u d y re gistrati o n ) a n d 1 paraffi n e m be d de d bl oc k 
or 1 0 u nstai ne d sli des fr o m O P TI O N A L tiss ue bi o ps y t o be perf or me d wit hi n 2 da ys of C ycle 2, 
da y 1. 

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6 2  
2  Bl o o d sa m ples : Ser u m sa m ples ( 5 ml ser u m) are t o be c ollecte d wit hi n 2 wee ks of st u d y 
re gistrati o n a n d wit hi n 2 da ys of c ycle 2, da y 1 ( pri or t o treat me nt i nf usi o n).  
S hi p pi n g a n d H a n dli n g of St u d y S peci me ns I nstr ucti o ns  
 
S a m ples will o nl y be recei ve d M o n d a y -Fri d a y  (e xcl u di n g h oli d a ys) bet wee n 8: 0 0 a m a n d 
2: 0 0 p m M S T. 
 
A Tiss ue S u b missi o n F or m ( See A P P E N DI X 8. 1 1) m ust be c o m plete d f or eac h set of sa m ples 
c ollecte d f or a n i n di vi d ual s u bject.  
 
All s u b mitte d s peci me ns m ust be la bele d acc or di n gl y:  
 
1.  T y pe of sa m ple (ser u m,)  
2.  Ti me p oi nt of c ollecti o n (e g., C ycle 2 da y 1)  
3.  Date of s peci me n c ollecti o n  
4.  Act ual ti me of  s peci me n c ollecti o n 
5.  Pr ot oc ol I D ( U A C C/ U Mass)  
6.  S u bject’s i nitials  
7.  S u bject’s st u d y n u m ber  
 
T he Fe deral g ui deli nes f or s hi p me nt are as f oll o ws:  
 
1.  T he s peci me n  m ust be wra p pe d i n a n a bs or ba ble material.  
2.  T he s peci me n m ust be place d i n a n AI R TI G H T c o ntai ner (li ke a re -seala ble ba g).  
3.  Pac k t he re -seala ble ba g a n d s peci me n i n a St yr of oa m s hi p pi n g c o ntai ner  
4.  Pac k t he St yr of oa m s hi p pi n g c o ntai ner i n a car d b oar d b o x.  
5.  T he car d b oar d b o x m ust be mar ke d as " BI O H A Z A R D".  
 
S hi p me nt of paraffi n bl oc ks a n d sli des re q uire t he i ncl usi o n of a c ol d pac k w he n se n di n g materials 
t o Ariz o na. 
 
S hi p me nt of pr ocesse d dra w  t u bes (ser u m) re q uire s hi p me nt o n dr y ice w hic h re q uires a dr y ice 
la bel o n t he s hi p pi n g c o ntai ner a n d a MI NI M U M of 5 t o 1 0 p o u n ds of dr y ice.  
 
 
U M ass s a m ples m ay be b atc he d. C o nt act Betty Gli ns m a n n -Gi bs o n at t he Ly m p h o m a S P O R E 
Tiss ue  Service  bef ore  y o u  i nte n d  t o  s hi p  a ny  s peci me ns  t o  ass ure  pr o per  recei pt  of  t he  
s peci me ns.  
 
Se n d t o:  
Bett y Gli ns ma n n - Gi bs o n, M S 
Researc h La b orat or y of Lisa Ri m sza, M D 
U ni versit y of Ariz o na,  
De part me nt of Pat h ol o g y  
A H S C r o o m 5 2 0 8 
1 5 0 1 N. Ca m p bell A ve n ue 
T ucs o n A Z  8 5 7 2 4- 5 0 4 3 

Versi o n 7 :  0 8/ 1 5 / 2 0 1 7  
6 3  
bj gli ns m @e m ail.ariz o na.e d u 
P h o ne:  5 2 0- 6 2 6- 7 8 9 4 
Fa x:  5 2 0- 6 2 6 - 6 0 8 1 
 
 
 
 

Versi o n 7 :  0 8/ 1 5 / 2 0 1 7  
6 4  
4  A D V E R S E E V E N T S  
4. 1  Defi niti o ns  
All seri o us a d verse e ve nts ( S A Es) (re gar dless of e x pecte d ness, ca usalit y, a n d w het her 
c o m mercial or i n vesti gati o nal V E L C A D E is use d) 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).  See Secti o n 4. 2 f or t he re p orti n g of S A Es. 
T he s p o ns or- i n vesti gat or is res p o nsi ble t o meet all re g ulati o ns a n d re q uire me nts a p plica ble t o 
t he s p o ns or-i n vesti gat or. 
4. 1. 1  A d verse E ve nt Defi niti o n  
A n a d verse  e ve nt  ( A E)  is  a n y  u nt owar d  me dical  occ urre nce  i n  a  patie nt  a d mi nistere d  a  
p har mace utical pr o d uct, w hic h d oes n ot necessaril y ha ve a ca usal relati o ns hi p wit h t he treat me nt.  
A n a d verse e ve nt 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., i ncl u di n 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 t he dr u g, w het her 
or n ot it is c o nsi dere d t o be dr u g relate d.  T his i ncl u des a n y ne wl y occ urri n g e ve nt or 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 nistrati o n of dr u g. 
 
F or t his pr ot oc ol 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 s i g nifica nt c ha n ge fr o m baseli ne. 
 
4. 1. 2  Seri o us A d verse E ve nt  Defi niti o n  
A seri o us a d verse e ve nt ( S A E) is a n y a d verse e ve nt, occ urri n g at a n y d ose a n d re gar dless of 
ca usalit y t hat: 
•  Res ults i n de at h . 
•  Is life-t hre ate ni n g.  Life-t hreate ni n g mea ns t hat t he patie nt was at i m me diate ris k of deat h 
fr o m t he reacti o n as it occ urre d, i.e., it d oes n ot i ncl u de a reacti o n w hic h h y pot heticall y 
mi g ht ha ve ca use d deat h ha d it occ urre d i n a m ore se vere f or m. 
•  Re q uires  i n patie nt  h os pit aliz ati o n  or  pr ol o n g ati o n  of  e xisti n g  h os pit al iz ati o n.  
H os pitalizati o n a d missi o ns a n d/ or s ur gical o perati o ns sc he d ule d t o occ ur d uri n g t he st u d y 
peri o d, b u t pla n ne d pri or t o st u d y e ntr y are n ot c o nsi dere d A Es if t he ill ness or disease 
e xiste d bef ore t he patie nt was re gistere d i n t he trial, pr o vi de d t hat it di d n ot deteri orate 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 perf or me d earlier t ha n pla nne d).  
•  Res ults i n persiste nt or si g nific a nt i nc a p acit y  or   s u bsta ntial disr u pti o n of t he a bilit y t o 
c o n d uct n or mal life f u ncti o ns. 
•  Is a c o n ge nital a n o mal y/ birt h defect.  
•  Is a n i m p ort a nt me dic al e ve nt.  A n i m p orta nt me dical e ve nt is a n e ve nt t hat ma y n ot 
res ult i n deat h, be 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 a n 
S A E w he n, base d u p o n a p pr o priate me dical j u d g me nt, it ma y je o par dize t he patie nt or 
s u bject a n d ma y re q uire me dical or s ur gical i nter ve nti o n t o pre ve nt o ne of t he o utc o mes 
liste d i n t he defi niti o ns f or S A Es.  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 

Versi o n 7 :  0 8/ 1 5 / 2 0 1 7  
6 5  
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 nc y or dr u g a b use.   
 
Clarificati o n s h o ul d be ma de bet wee n t he ter ms “seri o us” a n d “se vere” si nce t he y A R E N O T 
s y n o n y m o us.  T he ter m “se vere” 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 (as i n mil d, m o derate, or se vere m y ocar dial i nfarcti o n); t he e ve nt itself, h o we ver, ma y be 
of relati vel y mi n or me di cal si g nifica nce (s uc h as a se vere 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 are 
us uall y ass ociate d wit h e ve nts t hat p ose a t hreat t o a patie nt’s life or f u ncti o ni n g.  A se vere a d verse 
e ve nt 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, persiste nt na usea of 
se veral h o urs d urati o n ma y be c o nsi dere d se vere na usea b ut n ot a n S A E.  O n t he ot her ha n d, a 
str o ke res ulti n g i n o nl y a mi n or de gree of disa bilit y ma y be c o nsi dere d mil d, b ut w o ul d be defi ne d 
as a n S A E  base d o n t he a b o ve n ote d criteria.  Seri o us ness ( n ot se verit 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. 
4. 2  Pr oce d ures f or A E a n d S A E Re p orti n g  
A d verse e ve nt rec or di n g will be gi n o n Da y 1 of t he first treat me nt c ycle, a n d will c o nti n ue u ntil 
3 0 da ys after t he s u bject recei ves t he last d ose of st u d y dr u g (s).  
 
All A Es will be e ntere d i n t he O nc ore data base s yste m f or s u bjects e nr olle d at t he U ni versit y of 
Ariz o na Ca ncer Ce nter  ( U A C C). All a d verse e ve nts f or eac h s u bject e nr olle d at t he U ni versit y of 
Massac h usetts Me m orial  Ca ncer Ce nter will be  e ntere d i n t he U A C C O nc ore data base  re m otel y 
b y desi g nate d st u d y staff fr o m t he U ni v ersit y of Massac h usetts Me m orial  Ca ncer Ce nter . A d verse 
e ve nt data will be s hare d bet wee n t he U A C C a n d t he U ni v ersit y of Massac h usetts Me m orial 
Ca ncer Ce nter  at least q uarterl y. T he St u d y C o or di nat or or Researc h N urse fr o m eac h i nstit uti o n 
will pri nt o ut t he a d verse e ve nt data ca pt ure f or m i n O nc ore a n d sca n t he d oc u me nt t o  t he Pri nci pal 
I n vesti gat or at eac h partici pati n g ce nter.  
 
Seri o us a d verse e ve nt ( S A E ) rec or di n g will be gi n o n Da y 1 of t he first treat me nt c ycle, a n d will 
c o nti n ue u ntil 3 0 da ys after t he s u bject recei ves t he last d ose of st u d y dr u g (s). All seri o us a d verse 
e ve nts  ( S A Es ) t hat  occ ur  at  t he  U ni versit y  of  Ariz o na  Ca ncer  Ce nter  or  t he  U ni v ersit y  of  
Massac h usetts  Me m orial  Ca ncer  Ce nter  m ust  be  re p orte d  t o  t he  pri nci pal  i n vesti gat or   a n d 
s p o ns or/i n vesti gat or, Da niel Pers k y , at 5 2 0- 6 2 6- 8 9 0 8, wit hi n 2 4 h o urs of n otificati o n of t he e ve nt, 
usi n g a st u d y s pecific  S A E f or m.   
 
T he st u d y s pecific S A E C R F  ( pr o vi de d b y Mille n ni u m-re q uest c o p y fr o m U A St u d y C o or di nat or) 
will nee d t o be c o m plete d wit h as m uc h detail as p ossi ble. Sca n t his d oc u me nt a n d pr o vi de a n y 
s u p ple me ntal d oc u me ntati o n a vaila ble (e. g., a d missi o n s u m mar y) as a P D F d oc u me nt a n d e-mail  
t o t he f oll o wi n g i n di vi d uals at t he C o or di nati n g i nstit uti o n, t he U ni versit y of Ariz o na Ca ncer 
Ce nter wit hi n 2 4 h o urs of bec o mi n g a ware t hat t he S A E has occ urre d. Pr o vi de a  fi nal re p ort wit h 
t he i n vesti gat or’s si g nat ure as s o o n as p ossi ble.  
 
St u d y C o or di nat or, L ora I ncla n, e -mail: li ncla n @azcc.ariz o na.e d u, p h o ne: ( 5 2 0) 6 9 4- 9 0 5 3. 
 
I R B C o or di nat or, R ut h Ca ña mar, e-mail: rca na mar @ uacc.ariz o na.e d u, p h o ne: ( 5 2 0) 6 2 6- 6 5 1 5. 

Versi o n 7 :  0 8/ 1 5 / 2 0 1 7  
6 6  
 
Re p orti n g t o t he U A C C  D S M B  
 
T he st u d y s pecific S A E C R F will nee d t o be c o m plete d wit h as m uc h detail as p ossi ble. Sca n t his 
d oc u me nt a n d pr o vi de a n y s u p ple me ntal d oc u me ntati o n a vaila bl e (e. g., a d missi o n s u m mar y) as a 
P D F d oc u me nt a n d e-mail  t o t he U ni versit y of Ariz o na Ca ncer Ce nter’s D S M B C o or di nat or, 
Ellee n Marti n, e -mail: ( e marti n @azcc.ariz o na.e d u ), p h o ne: ( 5 2 0) 6 2 6-4 3 8 9 wit hi n 2 4 h o urs of 
bec o mi n g a ware t hat t he S A E has occ urre d. Pr o vi de a  fi nal re p ort wit h t he i n vesti gat or’s si g nat ure 
as s o o n as p ossi ble.  
 
Re p orti n g t o t he U ni v ersit y of M ass ac h usetts Me m ori al  C a ncer Ce nter  
 
All S A Es fr o m eit her partici pati n g i nstit uti o n will be re p orte d t o Dr . E ve ns at t he U ni versit y of 
Massac h usetts M e m orial Ca ncer Ce nter via e -mail  t o A n dre w. E ve ns @ u mass me d.e d u  ( wit hi n 2 4 
h o urs of bec o mi n g a ware t hat t he S A E has occ urre d.  
 
Re p orti n g t o t he I R B  
 
S A Es m ust be re p orte d t o t heir res pecti ve i nstit uti o n’s I R B b y t he I n vesti gat or acc or di n g t o 
c urre nt p olicies a n d pr oce d ures at t he i nstit uti o n w here t he st u d y is bei n g c o n d ucte d. 
 
Re p orti n g t o Mille n ni u m  
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 yi 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.  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 first d ose of V E L C A D E u p t o a n d 
i ncl u di n g 3 0 da ys after a d mi nistrati o n of t he last d ost of V E L C A D E  A n y S A E t hat occ urs at a n y 
ti me after c o m pleti o n of V E L C A D E 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-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).  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 h e 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 he 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 diti 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 Da niel Pers k y , M. D, 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 m ust als o be re p orte d t o  Mille n ni u m P har mac o vi gila nce or desi g nee as 
s o o n as p ossi ble, b ut n o later t ha n 5 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  
Mille n ni u m P har mac o vi gila nce.   
T he s p o ns or -i n vesti gat or s h o ul d fa x t he S A E F or m wit hi n fi ve cale n dar da ys after bec o mi n g 
a ware of t he e ve nt.  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.  T he 

Versi o n 7 :  0 8/ 1 5 / 2 0 1 7  
6 7  
S A E re p ort m ust i ncl u de e ve nt ter m(s), seri o us criteria, a n d t he 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 b ot h t he i nte nsit y of t he e ve nt(s) a n d 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.  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 ble 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 or st u d y dr u g (s), 
i ncl u di n g, b ut n ot li mite d t o, tele p h o ne c o n versati o n l o gs, as s o o n as p ossi ble b ut n o later t ha n 5 
cale n 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 
Mille n ni u m P h ar m ac o vi gil a nce  
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:  
U S a n d C a n a d a  
2 4 h o ur hel pli ne:  1 -8 0 0 - 2 0 1- 8 7 2 5 
F a x:  8 8 8- 4 8 8 - 9 6 9 7 
E m ail f or S A Es if u n a ble t o f a x:  wils afet y @ p p di.c o m  
F or b ot h seri o us a n d n o n- seri o us a d verse e ve nts, t he i n vesti gat or or s u b- 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 dr u g a d mi nistrati o n.  
 
Rel ati o ns hi p  t o dr u g a d mi nistrati o n will be deter mi ne d b y t he i n vesti gat or or s u b-i n vesti gat or 
res p o n di n g yes or n o t o t he q uesti on: Is t here a reas o na ble p ossi bilit y t hat t he a d verse e ve nt is 
ass ociate d wit h t he dr u g?  
I nte nsit y f or eac h a d verse e ve nt, i ncl u di n g a n y la b a b n or malit y, will be deter mi ne d b y usi n g t he 
N CI C T C A E, versi o n 3. 0, as a g ui deli ne, w here ver p ossi ble.  T he criter ia 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 .  
 
A d diti o nall y, t he i n vesti gat or m ust i n dicate t he f oll o wi n g i nf or mati o n re gar di n g a d verse e ve nts :   
•  Date of o nset, date of res ol uti o n 
•  Fre q ue nc y of e ve nt (si n gle, i nter mitte nt, c o nti n u o us) 
•  E ve nt o utc o me (res ol ve d, o n g oi n g, deat h) 
•  Acti o n ta ke n ( n o ne, me dicati o n, ot her) 

Versi o n 7 :  0 8/ 1 5 / 2 0 1 7  
6 8  
4. 3  M o nit ori n g of A d verse E ve nts a n d Peri o d of O bser v ati o n 
A d verse e ve nts, b ot h seri o us a n d n o n -seri o us, a n d deat hs t hat occ ur d uri n g t he patie nt’s st u d y 
partici pati o n will be rec or de d i n t he s o urce d oc u me nts.  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 diti o n o r 
i nterc urre nt ill ness(es). 
 
4. 3. 1  I nteri m A n al ysis of Dr u g T o xicit y 
O nce 2 0 patie nts ha ve bee n accr ue d a n d ha ve recei ve d at least o ne f ull c ycle, t he st u d y tea m will 
re vie w all a d verse e ve nts t o deter mi ne dr u g t o xicit y.  T his a nal ysis will be d o ne b y t he Pri nci pal 
I n vesti gat or a n d re p orte d t o t he H u ma n S u bjects Pr otecti o n Pr o gra m at t he U ni versit y of Ariz o na 
i n t he f or mat of a c o nti n ui n g re vie w.   
 
If u ne x pecte d, si g nifica nt, or u nacce pta ble ris k t o patie nts has bee n deter mi ne d i n t he o pi ni o n of 
t he i n vesti gat or d uri n g t his re vie w, t his st u d y will be pre mat urel y ter mi nate d. Writte n n otificati o n 
d oc u me nti n g t he reas o n f or st u d y ter mi nati o n will be pr o vi de d t o Mille n ni u m a n d t he l ocal I R B. 
 
I n  a d diti o n  t o  o ur  o w n  re vie w,  t he  U ni versit y  of  Ariz o na  Ca ncer  Ce nter  Data  a n d  Safet y  
M o nit ori n g B oar d pla n f or Me di u m ris k st u dies will be re vie wi n g  A Es at least e ver y si x m o nt hs 
a n d t he l ocal I R B is t o recei ve S A E re p orts per i nstit uti o nal p olic y  
 
4. 4  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 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  her  treati n g  p h ysicia n  i m me diatel y  a n d  per ma ne ntl y  disc o nti n ue  dr u g   t hera p y.  
Mille n ni u m m ust als o be c o ntacte d i m me diatel y b y fa xi n g 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.  T he pre g na nc y m ust be f oll o we d 
t hr o u g h o utc o me (i.e. deli ver y, still birt h, miscarria ge) . A n S A E f or m will nee d t o be c o m plete d 
i n a d diti o n t o t his f or m. 
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 patie nt’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 
( A p pe n di x 8. 1 4) 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 (see Secti o n 
4. 2).  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 utc o me. 

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5  S T A TI S TI C A L P R O C E D U R E S  
 
5. 1  S a m ple Size Esti m ati o n  
3 9  
5. 2  R a n d o mi z ati o n a n d Str atific ati o n  
N ot a p plica ble.  
5. 3  P o p ul ati o ns f or A n al ysis 
Eli gi ble  patie nts  m ust  ha ve  o ne  of  t he  f oll o wi n g  hist ol o gies:  ma ntle  cell  l y m p h o ma,  
l y m p h o plas mac ytic l y m p h o ma ( Wal de nstr o m’s macr o gl o b uli ne mia), mar gi nal z o ne l y m p h o ma, 
s mall l y m p h oc ytic l y m p h o ma, or rela pse d f ollic ular l y m p h o ma. T he y ma y or ma y n ot ha ve bee n 
treate d f or t heir l y m p h o ma. 
5. 4  Pr oce d ures f o r H a n dli n g Missi n g, U n use d, a n d S p uri o us D at a  
5. 5  St atistic al Met h o ds  
T he pri mar y o utc o me meas ure of t his P hase II trial is pr o gressi o n -free s ur vi val ( P F S) at 2 years.  
T his will be esti mate d f or t he c o h ort a n d prese nte d al o n g wit h a p pr o priate c o nfi de nce i nter vals.  
T he Ka pla n -Meier pr o d uct -li mit met h o d will be use d t o esti mate pr o gressi o n-free s ur vi val i n t he 
prese nce of ce ns ori n g.  A 2 -year P F S of 7 0 % or m ore w o ul d be c o nsi dere d pr o misi n g, w hile a 2 -
year P F S of less t ha n 5 0 % w o ul d be disa p p oi nti n g.  T h us we w ill test w het her we ca n reject t he 
n ull h y p ot hesis of 5 0 % or less vers us t he desire d alter nati ve rate of 7 0 % or m ore.  Base d o n a n 
e xact test f or a si n gle bi n o mial pr o p orti o n at t he o ne -si de d 0. 1 0 si g nifica nce le vel, a sa m ple size 
of 3 9 patie nts w o ul d pr o vi de a p o wer of 9 0 % (i.e., ma xi m u m false ne gati ve rate of 1 0 % a n d false 
p ositi ve  rate  of  1 0 %);  t his  calc ulati o n  ass u mes  t hat  all  patie nts  w o ul d  be  f oll o we d  u ntil  
pr o gressi o n or f or at least 2 years.  All patie nts e ntere d i nt o t he trial w h o recei ve at least o ne d ose 
of treat me nt will be i ncl u de d i n t he a nal ysis.  Wit h 3 9 patie nts, t here will be greater t ha n a 9 0 % 
pr o ba bilit y of o bser vi n g a n y s pecific t y pe of a d verse e ve nt w h ose tr ue i nci de nce rate is 6 % or 
hi g her. 
5. 5. 1  I nteri m t o xicit y a n al ysis  
A n i nteri m a nal ysis f or t o xicit y will be c o n d ucte d. T he t o xicit y rate will be use d as t he e n d p oi nt 
f or t he i nteri m a nal ysis. T he 6 0 % of t o xicit y rate is u nacce pta ble w hile 4 0 % is acce pta ble. T he 
i nteri m a nal ysis will be perf or me d w he n t he first 2 0 patie nts treate d. If m ore t ha n 1 1 t o xicities are 
o bser ve d o ut of t hese i nitial 2 0 patie nts, patie nt e nr oll me nt will be disc o nti n ue d a n d t he st u d y will 
e n d. Ot her wise patie nt e nr oll me nt will c o nti n ue u ntil a t otal of 3 9 patie nts are e nr olle d.  
 

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7 0  
T he f oll o wi n g Ta ble s h o we d t he disc o nti n uati o n pr o ba bilit y w he n tr ue t o xicit y rate is gi ve n. 
  
Tr ue t oxicity 
r ate 
0. 1  
0. 2  
0. 3  
0. 4  
0. 5  
0. 6  
0. 7  
0. 8  
0. 9  
Pr o b(x ≥1 2 )   0. 0 0 0 0 0 0 1  0. 0 0 0 1  
0. 0 0 5  
0. 0 5 6 5  
0. 2 5 1 7  
0. 5 9 5 6  
0. 8 8 6 6  
0. 9 9 0 0  
0. 9 9 9 9  
 
If t he tr ue t o xicit y rate is 4 0 % a n d 6 0 %, t he n t he disc o nti n uati o n pr o ba bilit y at t he i nteri m a nal ysis 
is 5. 6 % a n d 5 9. 5 %, res pecti vel y. If 1 2 t o xicities are o bser ve d o ut of 2 0 patie nts, t here is 8 0 % 
c o nfi de nce t hat t he tr ue t o xicit y rate ≥ 5 0. 8% (l o wer b o u n d of 1 -si de d 8 0 % e xact Bi n o mial 
c o nfi de nce i nter val 
 
5. 5. 2  C orrel ati ve st u dies  
Statistical c o m p utati o ns will be perf or me d usi n g t he J M P s oft ware pac ka ge ( S A S I nstit ute I nc. 
Car y, N C). Data will be a nal yze d f or c orrelati o n bet wee n I H C sc ores a n d hist ol o g y usi n g t he 
C oc hra n- Ma ntel -Hae nszel test ( Ma ntel, 1 9 6 3 ). T his test is a varia nt of t he χ 2 -test a n d is usef ul 
f or detecti n g c orrelati o n bet wee n or dere d r o ws a n d c ol u m ns i n a fre q ue nc y ta ble. T his all o ws 
e xa mi nati o n of tre n ds t o I H C sc ores acr oss a pr o gressi o n of bi ol o gical cate g ories ( M C L Vs Ot her 
L y m p h o mas). F urt her, t he C oc hra n -Ma ntel -Hae nsz el test all o ws f or a stratifie d a nal ysis wit h o ut 
a re q uire me nt f or a lar ge sa m ple size wit hi n eac h strat u m. T his all o ws stratificati o n of t he a nal ysis 
b y sli de, w hic h c o ntr ols f or differe nces bet wee n sli des alt h o u g h o nl y 3 or 4 sc ores ma y be 
o btai ne d f or e ac h sli de. Beca use t he data are n ot n or mall y distri b ute d n o n -para metric tests will be 
use d. S pear ma n’s ρ , a n o n-para metrical c orrelati o n statistic will be use d t o meas ure t he stre n gt h 
of t he relati o ns hi p bet wee n hist ol o gic cate g or y a n d I H C sc ores. 
Statisti cal a nal yses of i nter -rater a gree me nt will be carrie d o ut usi n g t he ka p pa statistic met h o d 
( W o ols o n a n d Clar k, 2 0 0 2), w he n e val uati n g 2 raters si m ulta ne o usl y a n d als o f oc uses o n n o mi nal, 
rat her t ha n or di nal, data. If 3 raters or i nstit uti o ns, as well as ordi nal data are use d t he n a m ore 
descri pti ve a p pr oac h ca n be use d. T his ca n be e val uate d usi n g c o nc or da nce of sc ori n g base d o n 
(a) c o m plete a gree me nt a n d ( b) a gree me nt ± 1 n u merical sc ore ( 0 t o 4 +). T he n, t he perce nta ge of 
sc ores t hat were i n c o m plete a greeme nt, or i n a gree me nt wit hi n 1 n u merical sc ore, ca n c o m pare d 
a m o n g t he 3 raters or 3 i nstit uti o ns, usi n g data o n t he a vera ge res ult f or eac h of t he a nti b o dies, b y 
mea ns of a Kr us kal – Wallis test. A P- val ue < 0. 0 5 w o ul d s u g gest t hat t he 3 raters or i nstit u ti o ns 
differe d si g nifica ntl y wit h res pect t o t heir classificati o ns acr oss all a nti b o dies. All P- val ues are 2 -
taile d. 

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6  A D MI NI S T R A TI V E R E Q UI R E M E N T S  
6. 1  G o o d Cli nic al Pr actice  
T he st u d y will be c o n d ucte d i n acc or da nce wit h t he I nter nati o nal C o nfere nce o n Har m o ni zati o n 
(I C H) f or G o o d Cli nical Practice ( G C P) a n d t he a p pr o priate re g ulat or y re q uire me nt(s).  T he 
i n vesti gat or will be t h or o u g hl y fa miliar wit h t he a p pr o priate use of t he dr u g as descri be d i n t he 
pr ot oc ol  a n d  I n vesti gat or’s  Br oc h ure.   Esse ntial  cli nical  d oc u me nts  will  be  mai ntai ne d  t o  
de m o nstrate t he vali dit y of t he st u d y a n d t he i nte grit y of t he data c ollecte d.  Master files s h o ul d 
be esta blis he d at t he be gi n ni n g of t he st u d y, mai ntai ne d f or t he d urati o n of t he st u d y a n d retai ne d 
acc or di n g t o t he a p pr o priate re g ulati o ns.   
6. 2  Et hic al C o nsi der ati o ns  
T he st u d y will be c o n d ucte d i n acc or da nce wit h et hical pri nci ples f o u n de d i n t he Declarati o n of 
Helsi n ki (see secti o n 8. 5 ).  T he I R B/I E C will re vie w all a p pr o priate st u d y d oc u me ntati o n i n or der 
t o safe g uar d t he ri g hts, safet y a n d well-bei n g of t he patie nts.  T he st u d y will o nl y be c o n d ucte d at 
sites  w here  IR B/I E C  a p pr o val  has  bee n  o btai ne d.   T he  pr ot oc ol,  I n vesti gat or’s  Br oc h ure,  
i nf or me d  c o nse nt,  a d vertise me nts  (if  a p plica ble),  writte n  i nf or mati o n  gi ve n  t o  t he  patie nts  
(i ncl u di n g  diar y  car ds),  safet y  u p dates,  a n n ual  pr o gress  re p orts,  a n d  a n y  re visi o ns  t o  t hese  
d oc u me nts  will  be  pr o vi de d  t o  t he  I R B/I E C  b y  t he  i n vesti gat or.   Mille n ni u m  re q uests  t hat  
i nf or me d  c o nse nt d oc u me nts  b e  re vie we d  b y  Mille n ni u m  or  desi g nee  pri or  t o  I R B/I E C  
s u b missi o n.   
6. 3  P atie nt I nf or m ati o n a n d I nf or me d C o nse nt  
After t he st u d y has bee n f ull y e x plai ne d, writte n i nf or me d c o nse nt will be o btai ne d fr o m eit her 
t he patie nt or his/ her g uar dia n or le gal re prese ntati ve pri or t o st u d y partici pati o n.  T he met h o d of 
o btai ni n g a n d d oc u me nti n g t he i nf or me d c o nse nt a n d t he c o nte nts of t he c o nse nt will c o m pl y wit h 
I C H-G C P a n d all a p plica ble re g ulat or y re q uire me nt(s).  
6. 4  P atie nt C o nfi de nti alit y  
I n or der t o mai ntai n patie nt pri vac y, all data ca pt ure rec or ds, dr u g acc o u nta bilit y rec or ds, st u d y 
re p orts a n d c o m m u nicati o ns will i de ntif y t he patie nt b y i nitials a n d t he assi g ne d patie nt n u m ber.  
T he  i n vesti gat or  will  gra nt  m o nit or(s)  a n d  a u dit or(s)  fr o m Mille n ni u m or  its  desi g nee s a n d 
re g ulat or y a ut h orit y(ies) access t o t he patie nt’s ori gi nal me dical rec or ds f or verificati o n of data 
gat here d o n t he data ca pt ure rec or ds a n d t o a u dit t he data c ollecti o n pr ocess.  T he patie nt’s 
c o nfi de ntialit y will be mai ntai ne d a n d will n ot be ma de p u bli cl y a vaila ble t o t he e xte nt per mitte d 
b y t he a p plica ble la ws a n d re g ulati o ns.  All rec or ds, e val uati o n f or ms, a n d re p orts will be i de ntifie d 
b y  a n  i de ntificati o n  c o de  t o  mai ntai n  c o nfi de ntialit y.   A  l o g  of  patie nts'  c o des,  na mes  a n d  
a d dresses will be ke pt s e paratel y.  All rec or ds are t o be ke pt i n l oc ke d files. 
6. 5  Pr ot oc ol C o m pli a nce  
T he i n vesti gat or will c o n d uct t he st u d y i n c o m plia nce wit h t he pr ot oc ol gi ve n a p pr o val/fa v ora ble 
o pi ni o n b y t he I R B/I E C a n d t he a p pr o priate re g ulat or y a ut h orit y(ies).  C ha n ges t o t he pr ot oc ol 
will re q uire a p pr o val fr o m Mille n ni u m a n d writte n I R B/I E C a p pr o val/fa v ora ble o pi ni o n pri or t o 
i m ple me ntati o n, e xce pt w he n t he m o dificati o n is nee de d t o eli mi nate a n i m me diate hazar d(s) t o 
patie nts.  T he I R B/I E C ma y pr o vi de, if a p plica ble re g ulat or y a ut h orit y(ies) per mit, e x pe dite d 

Versi o n 7 :  0 8/ 1 5 / 2 0 1 7  
7 2  
re vie w a n d a p pr o val/fa v ora ble o pi ni o n f or mi n or c ha n ge(s) i n o n g oi n g st u dies t hat ha ve t he 
a p pr o val /fa v ora ble o pi ni o n of t he I R B/I E C. As t he c o or di nati n g ce nter, t he U A C C will be 
res p o nsi ble f or pre pari n g all pr ot oc ol a me n d me nts wit h s u m mar y of c ha n ges d oc u me nt a n d 
s u b mitti n g  t he  pr ot oc ol  a me n d me nts  t o  t he  l ocal  I R B. T he  U A  I R B  a p pr o ve d  pr ot oc ol  
a me n d me nt -relate d d oc u me nts will be distri b ute d t o all partici pati n g ce nters b y t he U A C C I R B 
C o or di nat or.   T he i n vesti gat or will s u b mit all pr ot oc ol m o dificati o ns t o Mille n ni u m a n d t he 
re g ulat or y a ut h orit y(ies) i n acc or da nce wit h t he g o ver ni n g re g ulati o ns. A n y de part ures fr o m t he 
pr ot oc ol m ust be f ull y d oc u me nte d i n t he s o urce d oc u me nts.   
 
6. 6  Re gistr ati o n Pr oce d ure  
 
All  et hical,  re g ulat or y,  tec h nical,  a n d  scie ntific  a p pr o vals  m ust  be  i n  place  bef ore  st u d y  
re gistrati o ns will be acce pte d fr o m a site.  All s u bjects will be re gistere d ce ntrall y wit h t he 
desi g nate d St u d y C o or di nat or at t he U ni versit y of Ariz o na Ca ncer Ce nter ( L ora I nc la n, B. A., 
p h o ne:  5 2 0 - 6 9 4-9 0 5 3;  fa x:  5 2 0 - 6 9 4-9 0 8 6)  pri or  t o  t he  start  of  t hera p y.  S u bjects  are  t o  be  
re gistere d fr o m  8: 0 0  a. m.  t o  5: 0 0  p. m.,  M o u ntai n  Sta n dar d  Ti me,  M o n da y  t hr o u g h  Fri da y,  
(e xcl u di n g h oli da ys). Pri or t o re gistrati o n a f ull y e xec ute d c o nse nt a n d HI P A A, re gistrati o n f or m 
a n d s u p p orti n g d oc u me ntati o n f or re vie wi n g eli gi bilit y criteria m ust be se nt t o t he re gistrati o n 
ce nter.  All  i ncl usi o n  a n d  e xcl usi o n  criteria  will  be  c o nfir me d  wit h  acc o m pa n y  s o urce  
d oc u me ntati o n t o be re vie we d b y t he St u d y C o or di nat or, L ora I ncla n at t he U ni versit y of Ariz o na  
Ca ncer Ce nter .  T he St u d y C o or di nat or will assi g n a st u d y n u m ber.   
 
A u ni q ue st u d y i de ntifier will be assi g ne d b y t he U ni versit y of Ariz o na St u d y C o or di nat or f or 
o nl y s u bjects w h o meet t he eli gi bilit y re q uire me nts a n d ha ve c o m plete d t he scree ni n g visit. T he 
u ni q ue i de ntifier f or s u bjects re gistere d at t he U ni versit y of Ariz o na  Ca ncer Ce nter will be gi n 
wit h  t he n u m ber 0 0 1. T he u ni q ue i de ntifier will be gi n wit h t he n u m ber 2 0 0 f or s u bjects re gistere d 
at t he U ni versit y of Massac h usetts Me m orial  Ca ncer Ce nter  T hese n u m bers will be iss ue d t o 
s u bjects se q ue ntiall y a n d n o s u bject i de ntificati o n n u m bers will be re-assi g ne d i n t he e ve nt t hat 
t he s u bject wit h dra ws fr o m pr ot oc ol treat me nt. 
 
T o re gister a s u bject, t h e f oll o wi n g d oc u me nts are t o be c o m plete d b y t he researc h n urse or data 
ma na ger  a n d  fa xe d  ( 5 2 0- 6 9 4- 9 0 8 6) or  e -maile d  (li ncl a n @azcc.ariz o na.e d u)  t o  t he  St u d y  
C o or di nat or, L ora I ncla n at t he U A C C:  
 
1.  C o m plete d Re gistrati o n f or m  
2.  C o m plete d Eli gi bilit y f or m  
3.  C o p y of re q uire d la b orat or y tests/ pat h ol o g y a n d sca n re p orts ( La bel wit h s u bject’s i nitials 
a n d  o bliterate  i ma ge  of  s u bject’s  na me,  a d dress,  s ocial  sec urit y  a n d  me dical  rec or d  
n u m ber) 
4.  Si g ne d patie nt c o nse nt f or m 
5.  HI P A A a ut h orizati o n f or m 
 
T he researc h n urse or data ma na ger at t he partici pati n g site will t he n call 5 2 0 - 6 9 4- 9 0 5 3; or e -mail 
li ncla n @azcc.ariz o na.e d u L ora I ncla n, t he St u d y C o or dinat or at t he U A C C t o verif y eli gi bilit y.   
T o c o m plete t he re gistrati o n pr ocess, t he C o or di nat or at t he U A C C will:  
 

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7 3  
1.  Assi g n a patie nt st u d y n u m ber re gister t he s u bject o n t he st u d y 
2.  Fa x or e- mail t he s u bject st u d y n u m ber t o t he partici pati n g site  
3.  Call t he researc h n urse or data ma na ger at t he partici pati n g site a n d ver ball y c o nfir m 
re gistrati o n. 
 
St u d y Rec or ds – D at a C ollecti o n & Rec or di n g  
All st u d y -s pecific data f or ms are t o be s u b mitte d t o t he St u d y C o or di nat or at t he U ni versit y of 
Ariz o na Ca ncer Ce nter at baseli ne (re gistrati o n), at c o m pleti o n of V C R c ycles 1 -6, a n d at t he 
f oll o w-u p i nter vals s pecifie d i n secti o n 8. 1 ( A p pe n di x), i ncl u di n g at ti me of rela pse/ pr o gressi o n, 
sec o n d mali g na nc y, or deat h.  
6. 7  St u d y D at a a n d S afet y M o nit ori n g  
T his researc h st u d y is a n i n vesti gat or-s p o ns ore d trial.  T he U ni versit y of Ariz o na Ca ncer Ce nter 
will ser ve as t he c o or di nati n g ce nter a n d t he st u d y will be m o nit ore d u n der t he a us pices of t he 
U ni versit y of Ariz o na Ca ncer Ce nter Data a n d Safet y M o nit ori n g B oar d. T his is pr o gra m has N CI 
a p pr o val a n d t he c o p y is a vaila ble u p o n re q uest. Re g ulat or y a ut h orities , t he I E C/I R B a n d/ or 
Mille n ni u m’s cli nical q ualit y ass ura nce gr o u p ma y re q uest access t o all s o urce d oc u me nts, data 
ca pt ure rec or ds, a n d ot her st u d y d oc u me ntati o n f or o n -site a u dit or i ns pecti o n.  Direct access t o 
t hese d oc u me nts m ust be g uara ntee d b y t he i n vesti gat or, w h o m ust pr o vi de s u p p ort at all ti mes 
f or t hese acti vities. 
 
T he U ni versit y of Ariz o na’s Ariz o na Ca ncer Ce nter ( U A C C) Data a n d Safet y M o nit ori n g B oar d 
( D S M B) will be t he data safet y m o nit ori n g c o mmittee of rec or d f or t he c o n d ucti o n of t his st u d y 
at t he U ni versit y of Ariz o na  Ca ncer Ce nter  a n d at t he U ni versit y of Mas sac h usetts Me m orial  
Ca ncer  Ce nter.  T he  U ni versit y  of  Massac h usetts  Me m orial  Ca ncer  Ce nter  Data  a n d  Safet y  
M o nit ori n g C o m mittee will als o be res p o nsi ble f or o versi g ht of t he data ge nerate d f or t his trial at 
t heir i nstit utio n.  At t he mi ni m u m, t he U ni v ersit y of Massac h usetts Me m orial  Ca ncer Ce nter will 
o bser ve t he Ariz o na Ca ncer Ce nter’s  Pr ot oc ol Data a n d Safet y M o nit ori n g Pla n ( Me di u m  Ris k ) 
as descri be d i n t he f oll o wi n g pa ge. 
 
R o uti ne st u d y  m o nit ori n g acti vities at t he U A C C ( pr o gress of st u d y, pr ot oc ol c o m plia nce a n d 
safet y of s u bjects) will be acc o m plis he d t hr o u g h t he U A C C Q ualit y Ass ura nce/ Q ualit y C o ntr ol 
Pr o gra m  
 
R o uti ne st u d y m o nit ori n g acti vities at t he U ni v ersit y of Massac h usetts Me m orial  Ca ncer Ce nter  
will be c o n d ucte d b y t he U ni versit y of Massac h usetts Me m orial  Ca ncer Ce nter  De part me nt staff.  
acc or di n g t o t he U A C C me di u m ris k pr ot oc ol data a n d safet y m o nit ori n g pla n.  
 
T he U ni versit y of Ariz o na Ca ncer Ce nter has a n N CI -a p pr o ve d Data a n d Safet y M o nit ori n g Pla n 
f or cli nical researc h.  Data a n d s yste ms f or partici pati n g i n t he st u d y will be m o nit ore d acc or di n g 
t o pr oce d ures o utli ne d i n t hat pla n, wit h ce ntralize d patie nt scree ni n g a n d re gistrati o n, s u b missi o n 
a n d re vie w of data, a n d i nitial verificati o n of data as s u m marize d bel o w.  
Pr ot oc ol D at a a n d S afet y M o nit ori n g Pl a n ( Me di u m Ris k)  
 
Me di u m ris k st u dies are i nte n de d t o i ncl u de all trials i n v ol vi n g t hera pe utic i nter ve nti o n(s), w hic h 

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7 4  
are n ot  desi g nate d as hi g h ris k per N CI a n d t he I N D is n ot hel d b y t he i n vesti gat or.  
 
Data a n d Safet y M o nit ori n g Pla n: 
 
1.  
I de ntific ati o n of t he D S M B o bli g ate d f or o versi g ht res p o nsi bilities: 
T he U ni versit y of Ariz o na Ca ncer Ce nter Data a n d Safet y M o nit ori n g B oar d ( D S M B) will 
pr o vi de o n g oi n g o versi g ht f or t his trial. 
 
2. 
I de ntific ati o n of t he e ntit y o bli g ate d f or r o uti ne m o nit ori n g d uties: 
R o uti ne m o nit ori n g  of t he U A C C  will be pr o vi de d b y t he Q ualit y Ass ura nce/ Q ualit y 
C o ntr ol ( Q A/ Q C) Pr o gra m t o e ns ure t hat t he i n vesti gati o n is c o n d ucte d acc or di n g t o 
pr ot oc ol desi g n a n d re g ulat or y re q uire me nts. R o uti ne m o nit ori n g of U Mass data will be 
perf or me d b y U Mass Q A/ Q C de part me n t. 
 
3. 
M o nit ori n g pr o gress a n d d at a re vie w pr ocess:  
R o uti ne m o nit ori n g of s u bject data will be c o n d ucte d at least e ver y si x m o nt hs.  
T he first r o uti ne m o nit ori n g visit will i ncl u de at a mi ni m u m:  
•  I nf or me d c o nse nt – 1 0 0 % of cases e nr olle d;  
•  S u bject eli gi bil it y - 5 0 % of cases, u p t o t w o s u bjects; 
•  Data re v ie w - 5 0 % of cases, u p t o t w o s u bjects. 
 
All s u bse q ue nt m o nit ori n g  visits will c o nsist of ra n d o ml y selecte d s u bject cases base d o n 
c urre nt  e nr oll me nt  a n d  i ncl u de  c o nti n ui n g  re vie w  of  pre vi o usl y  selecte d  cases,  as 
a p plica ble. 
 
A m o nit ori n g visit re p ort a n d f oll o w -u p letter will be c o m plete d a p pr o xi matel y wit hi n t w o 
wee ks of t he r o uti ne m o nit ori n g visit ; a c o p y will be mai ntai ne d i n t he st u d y file. A 
q uer y/fi n di n g f or m or a n electr o nic rec or d will als o be c o m plete d b y t he m o nit or t o re q uest 
a d diti o nal s o urce d oc u me ntati o n, clarificati o n, i nf or mati o n or c orrecti o ns t o t he C R F 
a n d/ or re g ulat or y rec or ds. T he Cli nical Researc h C o or di nat or or ot her a p plica ble staff 
res p o nsi ble f or t he st u d y will be gi ve n a c o p y of t his  f or m or will be n otifie d of t he 
electr o nic  rec or d  f or  res ol uti o n  of  q ueries/fi n di n gs.  T he  q uer y/fi n di n g  f or m  will  be  
mai ntai ne d wit h a c o p y of t he visit re p ort f or f oll o w -u p at t he ne xt m o nit ori n g visit. 
Electr o nic rec or ds will be a vaila ble i n t he i nstit u ti o n data base or pr o vi de d b y t he Q A/ Q C 
Pr o gra m staff.  
 
T he  Pri nci pal  I n vesti gat or  will  e ns ure  t he  acc urac y,  c o m plete ness,  le gi bilit y  a n d  
ti meli ness of t he data re p orte d i n t he Case Re p ort F or m ( C R F) or ot her acce pta ble f or mats.  
S o urce d oc u me ntati o n s u p p orti n g t he st u d y data s h o ul d i n dicate t he s u bject’s partici pati o n 
i n t he trial a n d s h o ul d d oc u me nt t he dates a n d details of st u d y pr oce d ures, a d verse e ve nts, 
a n d patie nt stat us.  
 
Case re p ort f or ms, w hi c h i ncl u de t he i ncl usi o n/e xcl usi o n criteria f or m , a d verse  e ve nt 
f or ms, seri o us a d verse e ve nt f or ms a n d Mille n ni u m Pre g na nc y f or m  s h o ul d be c o m plete d 
via t he i nstit uti o n data base or ot her acce pta ble data f or mats. Trials usi n g pa per C R Fs will 
ha ve t he data e ntere d wit h a blac k ball -p oi nt pe n or t y pe d. C orrecti o ns t o t he f or ms s h o ul d 
n ot o bsc ure t he ori gi nal e ntr y a n d s h o ul d be ma de b y stri ki n g t he i nc orrect i nf or mati o n 

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wit h a si n gle li ne. Eac h stri ke s h o ul d be acc o m pa nie d b y t he i nitials of t he c orrect or a n d 
t he c orrecti o n date. All s u bject f or ms a n d st u d y files will be st ore d i n a sec ure area li mite d 
t o a ut h orize d staff. 
 
 
N ote:  R o uti ne m o nit ori n g of re g ulat or y d oc u me nts a n d test article will be  c o n d ucte d  at  
least a n n uall y.  
 
4. 
Pr ocess  t o  i m ple me nt  st u d y  cl os ure  w he n  si g nific a nt  ris ks  or  be nefits  are  
 
i de ntifie d: 
Please refer t o Secti o n 6. 9 re gar di n g pre mat ure cl os ure.  
  
  
  
  
 
5. 
Descri pti o n of a d verse e ve nts a n d re p orti n g pr oce d ures:  
 
A D V E R S E E V E N T S   
A n a d verse e ve nt ( A E) is a n y u nt o war d me dical occ urre nce i n a patie nt or  cli nical 
i n vesti gati o n s u bject a d mi nistered a p har mace utical pr o d uct a n d t hat d oes n ot necessaril y 
ha ve a cas ual relati o ns hi p wit h t his treat me nt. A n A E ca n t heref ore be   
a n y 
u nfa v ora ble a n d u ni nte n de d si g n, s y m pt o m, or disease te m p orall y ass ociate d wit h t he use 
of  a  me dici nal  (i n vesti gati o nal)  pr o d uct,  w het her  or  n ot  relate d  t o  t he  me dici nal  
(i n vesti gati o nal) pr o d uct.  
 
A n y a n d all a d verse e ve nts will be rec or de d o n t he U M C a d verse e ve nts rec or d f or m a n d 
re vie we d b y t he Pri nci pal I n vesti gat or. 
 
All a d verse e ve nts will be classifie d usi n g eit her t h e Me d D R A ter m or N CI 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) versi o n 3. 0 a n d will a d dress: 
•  Gra de  
•  Relati o ns hi p t o st u d y dr u g( n ot relate d, u nli kel y, p ossi ble, pr o ba ble, defi nitel y)  
•  Ca usalit y  ot her  t ha n  st u d y  dr u g  ( disease  relate d,  c o nc o mita nt  me dicati o n  relate d,  
i nterc urre nt ill ness, ot her)   
•  Date of o nset, date of res ol uti o n 
•  Fre q ue nc y of e ve nt (si n gle, i nter mitte nt, c o nti n u o us) 
•  E ve nt o utc o me (res ol ve d, o n g oi n g, deat h) 
•  Acti o n ta ke n ( n o ne, hel d, d ose re d uce d, disc o nti n ue d, me dicati o n gi ve n) 
 
S E RI O U S  A D V E R S E E V E N T S  A seri o us a d verse e ve nt ( S A E) is a n y u nt o war d me dical 
occ urre nce t hat at   
a n y   
d ose:  
 
1) Res ults i n deat h;  
 
2) Is life -t hreate ni n g; 
 
3) Re q uires i n - patie nt h os pitalizati o n or pr ol o n gati o n of a n e xisti n g h os pital sta y;  
4) Res ults i n persiste nt or si g nifica nt i nca pacit y  or s u bsta ntial disr u pti o n of t he  a bilit y t o 
c o n d uct n or mal life f u ncti o ns, or: 
 
5) Is a c o n ge nital a n o mal y/ birt h defect.  
 
 N ote : A S A E ma y als o be a n i m p orta nt me dical e ve nt, i n t he vie w of t he  i n vesti gat or 
t hat re q uires me dical or s ur gical i nter ve nti o n t o pre ve nt o ne of  
t he  o utc o mes  liste d  
a b o ve.  
 

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7 6  
 All seri o us a d verse e ve nts, re gar dless of attri b uti o n, a n d a n y deat hs will be re p orte d wit hi n 
2 4 h o urs of n otificati o n of t he e ve nt t o t he s p o ns or a n d D S M B C o or di nat or. All seri o us 
a d verse e ve nts, re gar d less of attri b uti o n, a n d a n y deat hs will be re p orte d per i nstit uti o nal 
p olic y t o t he U ni versit y of Ariz o na H u ma n S u bjects Pr otecti o n Pr o gra m.   
All seri o us a d verse  e ve nts will be pr ocesse d b y t he U A C C  D S M B C o or di nat or m o nt hl y 
f or i nitial tre n d a nal ysis a n d f ull y re vie we d b y t he U A C C D S M B, e ver y si x m o nt hs. T he 
U A D S M B  c o or di nat or  will  re vie w  t he  S A E  re p orti n g  pr ocess  t o  c o nfir m  re p orti n g  
re q uire me nts are met.  
 
6.   
Pl a n f or ass uri n g d at a acc ur ac y a n d pr ot oc ol c o m pli a nce:  
R o uti ne st u d y acti vit y a n d safet y i nf or mati o n will be re p orte d t o t he D S M B e ver y si x 
m o nt hs, or m ore fre q ue ntl y if re q ueste d. T hese re p orts will i ncl u de: 
•  St u d y acti vit y, c u m ulati ve a n d f or t he peri o d u n der re vie w; 
•  Safet y ( narrati ve des cri pti o n o n n o n- seri o us a n d seri o us a d verse e ve nts); 
•  Pre deter mi ne d pr ot oc ol earl y st o p pi n g r ules f or efficac y/f utilit y;    
•  M o nit ori n g a n d pr ot oc ol c o m plia nce; 
•  C o m me nts;  
•  Attac h me nts ( A E data re vie we d b y t he PI t o c o m pile t he re p ort, S A E letters a n d 
re p orts, res ults of a n y re vie w(s), a p plica ble c orres p o n de nce wit h t he I R B or ot her 
re g ulat or y a ge ncies.  
 
  
Data, safet y a n d st u d y pr o gress will be re p orte d t o: 
•  H u ma n S u bj ects Pr otecti o n Pr o gra m (I R B)  at least a n n uall y; 
•  S p o ns or (if a p plica ble) at least e ver y si x m o nt hs. 
 
7.  
I de ntific ati o n of t he s p o ns or or f u n di n g a ge nc y, as a p plic a ble: 
T he PI will i m me diatel y n otif y; i n writi n g, t he f u n di n g a ge nc y, if a p plica ble, a n y  acti o n 
res ulti n g i n a te m p orar y or per ma ne nt s us pe nsi o n of t he st u d y. 
 
I nter nal a u dit s yste m. 
 
I nter nal a u dits ma y be perf or me d o n t his trial f oll o wi n g t he U A C C D S M pla n. A u dits will be 
i de ntifie d b y t he D S M B a n d c o n d ucte d b y a n i de ntifie d a u dit tea m. A Q A/ Q C re prese ntati ve will 
c o or di nate t he a u dit tea m f u ncti o ns a n d s u bject cases will be ra n d o ml y selecte d f or re vie w. A u dit 
res ult i nf or mati o n will be pr o vi de d t o t he PI a n d t he D S M B f or re vie w. T he f oll o wi n g st u d y 
c o m p o ne nts are re vie we d, d oc u me nte d a n d re p orte d o n: 
•  S o urce d oc u me ntati o n of s u bject eli gi bilit y 
•  A d verse e ve nts a n d seri o us a d verse e ve nts  
•  Re g ulat or y d oc u me ntati o n re vie w f or I R B c o m plia nce 
•  Dr u g acc o u nta bilit y 
•  C o m plete ness a n d q ualit y of data 
 
 
6. 8  Dr u g Acc o u nt a bilit y  
Acc o u nta bilit y f or t he dr u g at all st u d y sites is t he res p o nsi bilit y of t he pri nci pal i n vesti gat or.  T he 
i n vesti gat or will  e ns ure t hat  t he  dr u g  is  use d  o nl y  i n  acc or da nce  wit h  t his  pr ot oc ol.   Dr u g 

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7 7  
acc o u nta bilit y rec or ds i n dicati n g t he dr u g’s deli ver y date t o t he site  (if a p plica ble), i n ve nt or y at 
t he site (if a p plica ble), use b y eac h patie nt, a n d ret ur n t o Mille n ni u m or dis p osal of t he dr u g (if 
a p plica ble a n d  if a p pr o ve d b y Mille n ni u m) will be mai ntai ne d b y t he cli nical site.  Acc o u nta bilit y 
rec or ds will i ncl u de dates, q ua ntities, l ot n u m bers, e x pirati o n dates (if a p plica ble), a n d patie nt 
n u m bers.   
 
All  material  c o ntai ni n g  V E L C A D E  will  be  treate d  a n d  dis p ose d  of  as  hazar d o us  waste  i n  
acc or da nce wit h g o ver ni n g re g ulati o ns. 
6. 9  Pre m at ure Cl os ure of t he St u d y  
T his st u d y ma y be pre mat urel y ter mi nate d, if i n t he o pi ni o n of t he i n vesti gat or or Mille n ni u m, 
t here is s ufficie nt  reas o na ble ca use.  Writte n  n otificati o n  d oc u me nti n g  t he  reas o n  f or  st u d y  
ter mi nati o n will be pr o vi de d t o t he i n vesti gat or or Mille n ni u m b y t he ter mi nati n g part y.   
Circ u msta nces t hat ma y warra nt ter mi nati o n i ncl u de, b ut are n ot li mite d t o:  
•  Deter mi nati o n of u ne x pecte d, si g n ifica nt, or u nacce pta ble ris k t o patie nts 
•  Fail ure t o e nter patie nts at a n acce pta ble rate  
•  I ns ufficie nt a d here nce t o pr ot oc ol re q uire me nts 
•  I ns ufficie nt c o m plete a n d/ or e val ua ble data 
•  Pla ns t o m o dif y, s us pe n d or disc o nti n ue t he de vel o p me nt of t he dr u g 
S h o ul d t he st u d y be cl ose d pre mat urel y, all st u d y materials m ust be ret ur ne d t o Mille n ni u m. 
6. 1 0  Rec or d Rete nti o n  
T he i n vesti gat or will mai ntai n all st u d y rec or ds acc or di n g t o I C H -G C P a n d a p plica ble re g ulat or y 
re q uire me nt(s).   
 
6. 1 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 w hic h 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 Med 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 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. 
A me dicati o n err or is a pre ve nta b le e ve nt t hat i n v ol ves a n i de ntifia ble patie nt a n d t hat lea ds t o 
i na p pr o priate me dicati o n use, w hic h ma y res ult i n patie nt har m.  W hile o ver d oses a n d u n der d oses 
c o nstit ute me dicati o n err ors, d oses misse d i na d verte ntl y b y a patie nt d o n ot.  I n di vi d uals w h o 
i de ntif y a p ote ntial me dicati o n err or 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. 
F or Pr o d uct C o m plai nts or Me dicati o n Err ors,  
call Me d C o m m S ol uti o ns at  
1- 8 6 6- 8 3 5- 2 2 3 3 ( U S a n d I nter nati o nal)  
Pr o d uct  c o m plai nts  a n d  me dicati o n  err ors  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 or me dicati o n err or 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 (refer t o Secti o n 4. 2).  

Versi o n 7 :  0 8/ 1 5 / 2 0 1 7  
7 8  
 

Versi o n 7 :  0 8/ 1 5 / 2 0 1 7  
7 9  
7  R E F E R E N C E S  
1.  A da ms J, Pal o m bella VJ, Sa us ville E A, J o h ns o n J, Destree A, Lazar us D D et al. Pr oteas o me 
i n hi bit ors:  a  n o vel  class  of  p ote nt  a n d  effecti ve  a ntit u m or  a ge nts.  Ca ncer  Res  1 9 9 9;  5 9 
( 1 1): 2 6 1 5-2 2.  
2.  A gat h ocle o us A, R ule S, J o h ns o n P et al. Preli mi nar y Res ults of a  P hase I/II St u d y of Wee kl y 
or T wice Wee kl y B ortez o mi b i n C o m bi nati o n wit h Rit u xi ma b, i n Patie nts wit h F ollic ular 
L y m p h o ma, Ma ntle Cell L y m p h o ma a n d Wal de nstr o m's Macr o gl o b uli nae mia. Bl o o d 2 0 0 7; 
1 1 0 ( 1 1): 7 5 4a (a bstract 2 5 5 9). 
3.  Air ol di I, G u gliel mi n o R, G hi ott o F et al. C yt o ki ne ge ne e x pressi o n i n ne o plastic B cells fr o m 
h u ma n ma ntle cell, f ollic ular, a n d mar gi nal z o ne l y m p h o mas a n d i n t heir p ost ulate d n or mal 
c o u nter parts. Ca ncer Res 2 0 0 1; 6 1 ( 4): 1 2 8 5- 9 0. 
4.  Belc h A, K o ur o u kis C T, Cr u m p M et al. A p hase II st u d y  of b ortez o mi b i n ma ntle cell 
l y m p h o ma: t he Nati o nal Ca ncer I nstit ute of Ca na da Cli nical Trials Gr o u p trial I N D. 1 5 0. A n n 
O nc ol 2 0 0 7; 1 8 ( 1): 1 1 6- 2 1. 
5.  Bla de  J, Sa ms o n  D, Reece  D, A p perle y J, Bj or kstra n d B, Ga hrt o n G et  al. Criteria  f or 
e val uati n g disease res p o nse a n d pr o gressi o n i n patie nts wit h m ulti ple m yel o ma treate d b y 
hi g h- d ose t hera p y a n d hae m o p oietic ste m cell tra ns pla ntati o n. M yel o ma S u bc o m mittee of t he 
E B M T.  E ur o pea n  Gr o u p  f or  Bl o o d  a n d  Marr o w  Tra ns pla nt.  Br  J  Hae mat ol  1 9 9 8;  1 0 2  
( 5): 1 1 1 5- 2 3. 
6.  Ca mac h o E , Bea S, Sala verria I et al. A nal ysis of A ur ora -A a n d h M P S 1 mit otic ki nases i n 
ma ntle cell l y m p h o ma. I nt J Ca ncer 2 0 0 6; 1 1 8 ( 2): 3 5 7- 6 3. 
7.  C he n CI, K o ur o u kis C T, W hite D et al. B ortez o mi b is acti ve i n patie nts wit h u ntreate d or 
rela pse d Wal de nstr o m's macr o gl ob uli ne mia: a p hase II st u d y of t he Nati o nal Ca ncer I nstit ute 
of Ca na da Cli nical Trials Gr o u p. J Cli n O nc ol 2 0 0 7; 2 5 ( 1 2): 1 5 7 0- 5. 
8.  C hes o n B D, H or ni n g SJ, C oiffier B et al. Re p ort of a n i nter nati o nal w or ks h o p t o sta n dar dize 
res p o nse  criteria  f or  n o n- H o d g ki n's l y m p h o mas.  N CI  S p o ns ore d  I nter nati o nal  W or ki n g  
Gr o u p. J Cli n O nc ol 1 9 9 9; 1 7 ( 4): 1 2 4 4. 
9.  C hes o n B D, Pfist ner B, J u wei d M E et al. Re vise d res p o nse criteria f or mali g na nt l y m p h o ma. 
J Cli n O nc ol 2 0 0 7; 2 5 ( 5): 5 7 9- 8 6. 
1 0.  C usac k  J C,  Jr.,  Li u  R,  H o ust o n  M,  A be n dr ot h  K,  Elli ott  PJ,  A da ms  J  et  al.  E n ha nce d  
c he m ose nsiti vit y t o C P T -1 1 wit h pr oteas o me i n hi bit or P S -3 4 1: i m plicati o ns f or s yste mic 
n uclear fact or - ka p pa B i n hi biti o n. Ca ncer Res 2 0 0 1; 6 1 ( 9): 3 5 3 5- 4 0. 
1 1.  Da vis T A, Grill o -L o pez AJ, W hite C A et al. Rit u xi ma b a nti -C D 2 0 m o n ocl o nal a nti b o d y 
t hera p y i n n o n-H o d g ki n's l y m p h o ma: safet y a n d efficac y of re -treat me nt. J Cli n O nc ol 2 0 0 0; 
1 8 ( 1 7): 3 1 3 5- 4 3. 
1 2.  Da vis T A, W hite C A, Grill o -L o pez AJ et al. Si n gle- a ge nt m o n ocl o nal a nti b o d y efficac y i n 
b ul k y n o n - H o d g ki n's l y m p h o ma: res ults of a p hase II trial of rit u xi ma b. J Cli n O nc ol 1 9 9 9; 
1 7 ( 6): 1 8 5 1- 7. 
1 3.  Drac h J, Ka uf ma n n H, Pic hel ma yer O et al. B ortez o mi b, Rit u xi ma b, a n d De xa met has o n 
( B O RI D) as Sal va ge Treat me nt i n Rela pse d/ Refract or y Ma ntle Cell L y m p h o ma: S ustai ne d 
Dise ase C o ntr ol i n Patie nts Ac hie vi n g a C o m plete Re missi o n. Bl o o d 2 0 0 7; 1 1 0 ( 1 1): 7 6 0a 
(a bstract 2 5 7 8). 
1 4.  D uec hler  M, Li n ke  A, Ce b ula  B et  al. I n vitr o c yt ot o xic effect  of pr oteas o me i n hi bit or  

Versi o n 7 :  0 8/ 1 5 / 2 0 1 7  
8 0  
b ortez o mi b  i n  c o m bi nati o n  wit h  p uri ne  n ucle osi de  a nal o g ues  o n  c hr o nic  l y m p h oc ytic 
le u kae mia cells. E ur J Hae mat ol 2 0 0 5; 7 4 ( 5): 4 0 7- 1 7. 
1 5.  Este y  E H,  K urzr oc k  R,  Ka ntarjia n  H M  et  al.  Treat me nt  of  hair y  cell  le u ke mia  wit h  2 -
c hl or o de o x ya de n osi ne ( 2 - C d A). Bl o o d 1 9 9 2; 7 9 ( 4): 8 8 2- 7. 
1 6.  Fis her RI, Ber nstei n S H, Ka hl B S et al. M ultice nter p hase II st u d y of b ortez o mi b i n patie nts 
wit h rela pse d or refract or y ma ntle cell l y m p h o ma. J Cli n O nc ol 2 0 0 6; 2 4 ( 3 0): 4 8 6 7- 7 4.  
1 7.  F ora n  J M,  C u n ni n g ha m  D,  C oiffier  B  et  al.  Treat me nt  of  ma ntle -cell  l y m p h o ma  wit h  
Rit u xi ma b (c hi meric m o n ocl o nal a nti -C D 2 0 a nti b o d y): a nal ysis of fact ors ass ociate d wit h 
res p o nse. A n n O nc ol 2 0 0 0; 1 1 S u p pl 1: 1 1 7- 2 1. 
1 8.  F orst p oi nt ner R, Dre yli n g M, Re p p R et al. T he a d diti o n of rit u xi ma b t o a c o m bi nati o n of 
fl u dara bi ne, c ycl o p h os p ha mi de, mit o xa ntr o ne ( F C M) si g nifica ntl y i ncreases t he res po nse rate 
a n d pr ol o n gs s ur vi val as c o m pare d wit h F C M al o ne i n patie nts wit h rela pse d a n d refract or y 
f ollic ular  a n d  ma ntle  cell  l y m p h o mas:  res ults  of  a  pr os pecti ve  ra n d o mize d  st u d y  of  t he  
Ger ma n L o w - Gra de L y m p h o ma St u d y Gr o u p. Bl o o d 2 0 0 4; 1 0 4 ( 1 0): 3 0 6 4- 7 1. 
1 9.  F ossella F V, De V ore R, Kerr R N, Cra wf or d J, Natale R R, D u n p h y F et al. Ra n d o mize d p hase 
III trial of d oceta xel vers us vi n orel bi ne or if osfa mi de i n patie nts wit h a d va nce d n o n-s mall-
cell l u n g ca ncer pre vi o usl y treate d wit h plati n u m -c o ntai ni n g c he m ot hera p y re gi me ns. T he 
T A X 3 2 0 N o n- S mall Cell L u n g Ca ncer St u d y Gr o u p. J Cli n O nc ol 2 0 0 0; 1 8 ( 1 2): 2 3 5 4- 6 2. 
2 0.  F ossella F. D oceta xel + Cis plati n ( D C) a n d D oceta xel + Car b o plati n ( D C b) vs Vi n orel bi ne + 
Cis plati n ( V C) i n c he m ot hera p y -naï ve patie nts wit h a d va nce d a n d metast atic n o n-s mall cell 
l u n g ca ncer ( N S C L C): Res ults of a m ultice nter, ra n d o mize d p hase III st u d y. E ur o pea n J o ur nal 
of  Ca ncer,  E ur o pea n  Ca ncer  C o nfere nce,  E C C O  1 1,  2 0 0 1;  Lis b o n,  P ort u gal.  3 7(s u p pl  
6): S 1 5 4. A bstract 5 6 2  
2 1.  Fri dri k M A, Ja ger G, Kie nzer H R et al. E fficac y a n d t o xicit y of 2- C hl or o de o x ya de n osi ne 
( Cla dri bi ne)--2 h i nf usi o n f or 5 da ys --as first-li ne treat me nt f or a d va nce d l o w gra de n o n-
H o d g ki n's l y m p h o ma. E ur J Ca ncer 1 9 9 8; 3 4 ( 1 0): 1 5 6 0- 4. 
2 2.  G h o brial I M, Pa d ma na b ha n S, Ba dr os A et al. P hase II Trial of C o m bi nati o n of B ortez o mi b 
a n d Rit u xi ma b i n Rela pse d a n d/ or Refract or y Wal de nstr o m Macr o gl o b uli ne mia: Preli mi nar y 
Res ults. Bl o o d 2 0 0 7; 1 1 0 ( 1 1):(a bstract 4 4 9 4). 
2 3.  G o y A, Ber nstei n S, Ka hl B, Dj ul be g o vic B, R o berts o n M, V os S, et al. D ura ble Res p o nses 
wit h B ortez o mi b i n Patie nts wit h Rela pse d or Refract or y ma ntle Cell L y m p h o ma:  U p date d 
Ti me -t o- E ve nt A nal yses of t he M ultice nter PI N N A C L E St u d y. Bl o o d 2 0 0 7; 1 1 0: A bstract 
1 2 5. 
2 4.  G o y A, Y o u nes A, Mc La u g hli n P et al. P hase II st u d y of pr oteas o me i n hi bit or b ortez o mi b i n 
rela pse d or refract or y B-cell n o n- H o d g ki n's l y m p h o ma. J Cli n O nc ol 2 0 0 5; 2 3 ( 4): 6 6 7- 7 5. 
2 5.  Hi des hi ma T, Ric har ds o n P, C ha u ha n D, Pal o m bella VJ, Elli ott PJ, A da ms J et al. T he 
pr oteas o me  i n hi bit or  P S -3 4 1  i n hi bits  gr o wt h,  i n d uces  a p o pt osis,  a n d  o verc o mes  dr u g  
resista nce i n h u ma n m ulti ple m yel o ma cells. Ca ncer Res 2 0 0 1; 6 1 ( 7): 3 0 7 1- 6. 
2 6.  H oc hster H, Weller E, Gasc o y ne R et al. Mai nte na nce rit u xi ma b after C V P res ults i n s u peri or 
cli nical o utc o me i n a d va nce d f ollic ular l y m p h o ma ( F L): res ults of t he E 1 4 9 6 p hase III trial 
fr o m t he Easter n C o o perati ve O nc ol o g y Gr o u p a n d t he Ca ncer a n d Le u ke mia Gr o u p B. Bl o o d 
2 0 0 5; 1 0 6 ( 1 1: 3 4 9a). 
2 7.  I n war ds DJ, , Fis h ki n P A, Hill ma n D W et al. L o n g- ter m res ults of t he treat me nt of patie nts 
wit h  ma ntle  cell  l y m p h o ma  wit h  cla dri bi ne  ( 2 -C D A)  al o ne  ( 9 5 - 8 0-5 3)  or  2 -C D A  a n d  

Versi o n 7 :  0 8/ 1 5 / 2 0 1 7  
8 1  
rit u xi ma b ( N 0 1 8 9) i n t he N ort h Ce ntral Ca ncer Treat me nt Gr o u p. Ca ncer  2 0 0 8; 1 1 3( 1): 1 0 8-
1 6.  
2 8.  Ja ga n nat h S, Barl o gie B, Bere ns o n J et al. A P hase  2 st u d y of t w o d oses of b ortez o mi b i n 
rela pse d or refract or y m yel o ma. Br J Hae mat ol 2 0 0 4: 1 2 7: 1 6 5- 1 7 2 
2 9.  Karlss o n K A, Str ö m ber g M, J ö nss o n V et al. Cla dri bi ne ( C d A) Gi ves L o n ger Res p o nse 
D urati o n T ha n Fl u dara bi ne ( F) a n d Hi g h -D ose I nter mitte nt C hl ora m b ucil ( C hl) as First -Li ne 
Treat me nt of S y m pt o matic C hr o nic L y m p h oc ytic Le u ke mia ( C L L). First Res ults fr o m t he 
I nter nati o nal Ra n d o mize d P hase III Trial. Bl o o d 2 0 0 7 1 1 0 ( 1 1): 1 9 4a (a bstract 6 3 0)  
3 0.  Ka y  A C,  Sa ve n  A,  Carrera  CJ  et  al.  2 -C hl or o de o x ya de n osi ne  treat me nt  of  l o w -gra de 
l y m p h o mas. J Cli n O nc ol 1 9 9 2; 1 0 ( 3): 3 7 1- 7. 
3 1.  K o n o ne n  J,  B u be n d orf  L,  Kalli o nie mi  A  et  al.  Tiss ue  micr oarra ys  f or  hi g h -t hr o u g h p ut 
m olec ular pr ofili n g of t u m or s peci me ns. Nat Me d 1 9 9 8; 4 ( 7): 8 4 4- 7. 
3 2.  Le Bla nc R, Catle y L P, Hi des hi ma T, Le ntzsc h S, Mitsia des C S, Mitsia des N et al. Pr oteas o me 
i n hi bit or P S-3 4 1 i n hi bits h u ma n m yel o ma cell gr o wt h i n vi v o a n d pr ol o n gs s ur vi val i n a 
m uri ne m o del. Ca ncer Res 2 0 0 2; 6 2 ( 1 7): 4 9 9 6- 5 0 0 0. 
3 3.  Le nz  G,  Dre yli n g  M,  H oster  E  et  al.  I m m u n oc he m ot hera p y  wit h  rit u xi ma b  a n d  
c ycl o p h os p ha mi de, d o x or u bici n, vi ncristi ne, a n d pre d nis o ne si g nifica ntl y i m pr o ves res p o nse 
a n d ti me t o trea t me nt fail ure, b ut n ot l o n g-ter m o utc o me i n patie nts wit h pre vi o usl y u ntreate d 
ma ntle cell l y m p h o ma: res ults of a pr os pecti ve ra n d o mize d trial of t he Ger ma n L o w Gra de 
L y m p h o ma St u d y Gr o u p ( G L S G). J Cli n O nc ol 2 0 0 5; 2 3 ( 9): 1 9 8 4- 9 2. 
3 4.  Le o nar d J P, F ur ma n R R, C h e u n g Y K et al. C H O P -R + b ortez o mi b as i nitial t hera p y f or diff use 
lar ge B-cell l y m p h o ma ( D L B C L. J Cli n O nc ol 2 0 0 7; 2 5 : 1 8 S (J u ne 2 0 S u p ple me nt), A - 8 0 3 1. 
3 5.  Li g htca p E S, Mc C or mac k T A, Pie n C S, C ha u V, A da ms J, Elli ott PJ. Pr oteas o me i n hi biti o n 
meas ure me nts: cl i nical a p plicati o n. Cli n C he m 2 0 0 0; 4 6 ( 5): 6 7 3- 8 3. 
3 6.  Mal o ne y  D G,  Grill o -L o pez  AJ,  W hite  C A  et  al.  I D E C-C 2 B 8  ( Rit u xi ma b)  a nti -C D 2 0 
m o n ocl o nal a nti b o d y t hera p y i n patie nts wit h rela pse d l o w -gra de n o n -H o d g ki n's l y m p h o ma. 
Bl o o d 1 9 9 7; 9 0 ( 6): 2 1 8 8- 9 5. 
3 7.  Ma ntel N. C h i-s q uare d tests wit h o ne de gree of free d o m: E xte nsi o ns of t he Ma ntel-Hae nszel 
Pr oce d ure. J A m Stat Ass oc 1 9 6 3; 5 8: 6 9 0- 7 0 0. 
3 8.  Marc us R, I mrie K, Belc h A et al. C V P c he m ot hera p y pl us rit u xi ma b c o m pare d wit h C V P as 
first-li ne treat me nt f or a d va nce d f ollic ular ly m p h o ma. Bl o o d 2 0 0 5; 1 0 5 ( 4): 1 4 1 7- 2 3. 
3 9.  Mate os M - V, Ric har ds o n P G, Sc hla g R, K h ua ge va N K, Di m o p o ul os M A, S h pil ber g O, et al. 
B ortez o mi b  pl us  mel p hala n -pre d nis o ne  c o nti n ues  t o  de m o nstrate  a  s ur vi val  be nefit  vs  
mel p hala n -pre d nis o ne i n t he p hase III VI S T A trial  i n pre vi o usl y u ntreate d m ulti ple m yel o ma 
after 3 years' f oll o w -u p a n d e xte nsi ve s u bse q ue nt t hera p y use. Bl o o d 2 0 0 9; 1 1 4: A bstract 3 8 5 9.  
4 0.  Mc C o n ke y  DJ,  Petta wa y  C,  Elli ott  P,  A da m  J,  Pa pa n dre o u  C,  Herr ma n n  J L  et  al.  T he  
pr oteas o me as a ne w dr u g tar get i n metas tatic pr ostate ca ncer. 7t h A n n ual Ge nit o uri nar y 
O nc ol o g y C o nfere nce, 1 9 9 9; H o ust o n, T X. A bstract  
4 1.  Mc La u g hli n P, Grill o -L o pez AJ, Li n k B K et al. Rit u xi ma b c hi meric a nti -C D 2 0 m o n ocl o nal 
a nti b o d y t hera p y f or rela pse d i n d ole nt l y m p h o ma: half of patie nts res p o n d t o a f o ur -d ose 
treat me nt pr o gra m. J Cli n O nc ol 1 9 9 8; 1 6 ( 8): 2 8 2 5- 3 3. 
4 2.  Nat k u na m Y, War n ke R A, M o nt g o mer y K et al. A nal ysis of M U M 1/I R F 4 pr otei n e x pressi o n 
usi n g tiss ue micr oarra ys a n d i m m u n o hist oc he mistr y. M o d Pat h ol 2 0 0 1; 1 4 ( 7): 6 8 6- 9 4. 

Versi o n 7 :  0 8/ 1 5 / 2 0 1 7  
8 2  
4 3.  O' C o n n or  O A.  Tar ge ti n g  hist o nes  a n d  pr oteas o mes:  ne w  strate gies  f or  t he  treat me nt  of  
l y m p h o ma. J Cli n O nc ol 2 0 0 5; 2 3 ( 2 6): 6 4 2 9- 3 6. 
4 4.  O' C o n n or O A, Wri g ht J, M os k o witz C et al. P hase II cli nical e x perie nce wit h t he n o vel 
pr oteas o me i n hi bit or b ortez o mi b i n patie nts wit h i n d ole nt   n o n-H o d g ki n's l y m p h o ma a n d 
ma ntle cell l y m p h o ma. J Cli n O nc ol 2 0 0 5; 2 3 ( 4): 6 7 6- 8 4. 
4 5.  Orl o ws ki R Z, Sti nc hc o m be T E, Mitc hell B S, S hea T C, Bal d wi n A S, Sta hl S et al. P hase I 
Trial  of  t he  Pr oteas o me  I n hi bit or  P S -3 4 1  i n  Patie nts  wit h  Refract or y  He mat ol o gic  
Mali g na ncies. J Cli n O nc ol 2 0 0 2; 2 0 ( 2 2): 4 4 2 0- 7.  
4 6.  Pa pa n dre o u  C,  Dalia ni  D,  Milli ka n  R E,  T u  S,  Pa gliar o  L,  A da m  J.  P hase  I  St u d y  of  
I ntra ve n o us  (I. V.)  Pr oteas o me  I n hi bit or  P S-3 4 1  i n  Patie nts  ( Pts)  wit h  A d va nce d  
Mali g na ncies. Pr oc A m S oc Cli n O nc ol, 2 0 0 1. A bstract 3 4 0  
4 7.  Pi n k  M M,  Pie n  C S,  O na  V O,  W orla n d  P,  A da ms  J,  Ka uff ma n  M G.  P S -3 4 1  e n ha nces  
c he m ot hera pe utic effect i n h u ma n xe n o graft m o dels. Pr oc A m Ass oc Ca ncer Res, 2 0 0 2; Sa n 
Fra ncisc o, C A. A bstract 7 8 7 
4 8.  Rassi da kis G Z, J o nes D, T h o mai des A et al. A p o pt otic rate i n  peri p heral T -cell l y m p h o mas. 
A st u d y usi n g a tiss ue micr oarra y wit h vali dati o n o n f ull tiss ue secti o ns. A m J Cli n Pat h ol 
2 0 0 2; 1 1 8 ( 3): 3 2 8- 3 4. 
4 9.  Ric har ds o n P G, Barl o gie B, Bere ns o n J et al. A P hase II st u d y of B ortez o mi b i n Rela pse d, 
Refract or y M yel o ma. N E n gl J Me d 2 0 0 3; 3 4 8: 2 6 0 9- 2 6 1 7 
5 0.  Ric har ds o n  P G,  et  al.,  B ortez o mi b  or  Hi g h -D ose  De xa met has o ne  f or  Rela pse d  M ulti ple  
M yel o ma. N E n gl J Me d 2 0 0 5; 3 5 2: 2 4 8 7- 9 8.  
5 1.  Ric har ds o n et al, B ortez o mi b C o nti n ues t o De m o nstrate S u peri or Efficac y C o m pare d Wit h 
Hi g h -D ose De xa met has o ne i n Rela pse d M ulti ple M yel o ma: U p date d Res ults of t he A P E X 
Trial. Bl o o d, 2 0 0 5; 1 0 6: A bstract 2 5 4 7. 
5 2.  R o ba k T, S m ole ws ki P, Ce b ula B et al. Rit u xi ma b c o m bi ne d wit h cla dri bi ne or wit h cla dri bi ne 
a n d  c ycl o p h os p ha mi de  i n  hea vil y  pretreate d  patie nts  wit h  i n d ole nt  l y m p h o pr oliferati ve  
dis or ders a n d ma ntle cell l y m p h o ma. Ca ncer 2 0 0 6; 1 0 7 ( 7): 1 5 4 2- 5 0. 
5 3.  R ose n wal d A, Wri g ht G, Wiest ner A et al. T he pr oliferati o n ge ne e x pressi o n si g nat ure is a 
q ua ntitati ve i nte grat or of o nc o ge nic e ve nts t hat pre dicts s ur vi val i n ma ntle cell l y m p h o ma. 
Ca ncer Cell 2 0 0 3; 3 ( 2): 1 8 5- 9 7. 
5 4.  R u m mel MJ, C h o w K U, Ja ger E et al. Treat me nt of ma ntle -cell l y m p h o mas wit h i nter mitte nt 
t w o-h o ur i nf usi o n of cla dri bi ne as first -li ne t hera p y or i n first rela pse. A n n O nc ol 1 9 9 9; 1 0 
( 1): 1 1 5- 7. 
5 5.  Sa n Mi g uel J F, Sc hla g R, K h ua ge va N K, Di m o p o ul os M A, S h pil ber g O, Kr o pff M, et al. 
B ortez o mi b pl us mel p hala n a n d pre d nis o ne f or i nitial treat me nt of m ulti ple m yel o ma. N E n gl 
J Me d 2 0 0 8; 3 5 9( 9): 9 0 6- 1 7. 
5 6.  Sa ve n A, B uria n C, K ozi ol J A et al. L o n g -ter m f oll o w-u p of patie n ts wit h hair y cell le u ke mia 
after cla dri bi ne treat me nt. Bl o o d 1 9 9 8; 9 2 ( 6): 1 9 1 8- 2 6. 
5 7.  S kacel M, S kilt o n B, Petta y J D et al. Tiss ue micr oarra ys: a p o werf ul t o ol f or hi g h -t hr o u g h p ut 
a nal ysis  of  cli nical  s peci me ns:  a  re vie w  of  t he  met h o d  wit h  vali dati o n  data.  A p pl 
I m m u n o hist oc he m M ol M or p h ol 2 0 0 2; 1 0 ( 1): 1- 6. 
5 8.  S m ole ws ki  P,  D uec hler  M,  Li n ke  A  et  al.  A d diti ve  c yt ot o xic  effect  of  b ortez o mi b  i n  
c o m bi nati o n wit h a nti -C D 2 0 or a nti -C D 5 2 m o n ocl o nal a nti b o dies o n c hr o nic l y m p h oc ytic 

Versi o n 7 :  0 8/ 1 5 / 2 0 1 7  
8 3  
le u ke mia cells. Le u k Res 2 0 0 6; 3 0 ( 1 2): 1 5 2 1- 9. 
5 9.  S nell M, K oc O, Ba hlis N et al. A p hase I trial of P S -3 4 1 a n d fl u dara bi ne f or rela pse d a n d 
refract or y i n d ole nt n o n-H o d g ki n's l y m p h o ma a n d c hr o nic l y m p h oc ytic le u ke mia. J Cli n O nc ol 
2 0 0 6; 2 4 ( S u p pl 1 8): A- 7 5 8 0, 4 4 1s. 
6 0.  Stei ner P, Ne u meier H, Li g htca p E, Sa dis S, Pie n C, Pi n k M et al. A da ptati o n of H u ma n 
T u m or Cell Li nes t o P S -3 4 1. A A C R -N CI -E O R T C I nter nati o nal C o nfere nce, 2 0 0 1; Mia mi 
Beac h, F L. Mille n ni u m P har mace uticals, I nc., 7 5 Si d ne y Street, Ca m bri d ge, M A 0 2 1 3 9. 
A bstract  
6 1.  Stra uss  SJ,  Ma haraj  L,  H oare  S  et  al.  B ortez o mi b  t hera p y  i n  patie nts  wit h  rela pse d  or  
refract or y l y m p h o ma: p ote ntial c orrelati o n of i n vitr o se nsiti vit y a n d t u m or necr osis fact or 
al p ha res p o nse wit h cli nical acti vit y. J Cli n O nc ol 2 0 0 6; 2 4 ( 1 3): 2 1 0 5- 1 2. 
6 2.  Teic her B A, Ara G, Her bst R, Pal o m bella VJ, A da ms J. T he pr oteas o me i n hi bit or P S -3 4 1 i n 
ca ncer t hera p y. Cli n Ca ncer Res 1 9 9 9; 5 ( 9): 2 6 3 8- 4 5. 
6 3.  Tre o n S P, Gertz M A, Di m o p o ul os M et al. U p date o n treat me nt rec o m me n dati o ns fr o m t he 
T hir d  I nter nati o nal  W or ks h o p  o n  Wal de nstr o m's  macr o gl o b uli ne mia.  Bl o o d  2 0 0 6;  1 0 7  
( 9): 3 4 4 2- 6. 
6 4.  V E L C A D E ( b ortez o mi b) [ pac ka ge i nsert]. Ca m bri d ge, M A: Mille n ni u m P har mace uticals, 
I nc.; 2 0 0 3. 
6 5.  Wa n  W H,  F ort u na  M B,  F ur ma ns ki  P.  A  ra pi d  a n d  efficie nt  met h o d  f or  testi n g  
i m m u n o hist oc he mical reacti vit y of m o n ocl o nal a nti b o dies a gai nst m ulti ple tiss ue sa m ples 
si m ulta ne o usl y. J I m m u n ol Met h o ds 1 9 8 7; 1 0 3 ( 1): 1 2 1- 9. 
6 6.  W o ols o n R, Clar k W. Statistical met h o ds f or t he a nal ysis of bi o me dical data. I n, tra nslat or 
a n d e dit or. Ne w Y or k: J o h n Wile y a n d S o ns; 2 0 0 2; p. 2 6 3- 3 0 6. 
6 7.  Ya k us hiji n  Y,  Ha ma da  M,  Yas u ka wa  M.  T he  e x pressi o n  of  t he  a ur ora -A  ge ne  a n d  its  
si g nifica nce  wit h  t u m or ge nesis  i n  n o n-H o d g ki n's  l y m p h o ma.  Le u k  L y m p h o ma  2 0 0 4;  4 5  
( 9): 1 7 4 1- 6. 
6 8.  Zi nza ni P L. N o n -H o d g ki n's l y m p h o ma: t he e v ol vi n g r ole of p uri ne a nal o g ues. Best Pract Res 
Cli n Ha e mat ol 2 0 0 2; 1 5 ( 3): 5 0 5- 1 6. 
6 9.  Z u Y, Stei n ber g S M, Ca m p o E et al. Vali dati o n of tiss ue micr oarra y i m m u n o hist oc he mistr y 
stai ni n g a n d i nter pretati o n i n diff use lar ge B-cell l y m p h o ma. Le u k L y m p h o ma 2 0 0 5; 4 6 
( 5): 6 9 3- 7 0 1. 
 
 

Versi o n 5: 2/ 2 7/ 1 3  
8 4  
8  A P P E N DI C E S  
8. 1  St u d y Fl o w C h art  
Visits ( wee ks or da ys)  
B aseli ne  
c ycle 
1   
c ycle 
2  
c ycle 
3  
c ycle 
4  
c ycle 
5  
c ycle 
6  
Resta gi n g  
wee ks 4 -
8 after d 1 
of c ycle 6  
F oll o w -
u p #   
 
 
Wit hi n 8 
Wee ks of 
Re gistrati o n  
 
Wit hi n 4 
Wee ks of 
Re gistrati o n  
Wit hi n 2 
Wee ks of 
Re gistrati o n  
Pat h ol o gic Dia g n osis  
X  
 
 
 
 
 
 
 
 
 
 
Tiss ue Micr oarra y  sa m ple 
c ollecti o n 
X  
 
 
 
 
 
 
 
 
 
 
B o ne marr o w bi o ps y  
X  
 
 
  
  
  
  
  
  
X  (& ) 
  
C T c hest/a b d o me n/ pel vis  
 
X  
 
  
  
X p  
  
X p  
  
X  
X  
St u d y Re gistrati o n  ( k) 
 
 
X   
 
 
 
 
 
 
 
 
Hist or y/ p h ysical/ P S/ vital si g ns  
 
 
X  
 
X  
X  
X  
X  
X  
X  
X  
C B C  
 
 
X  
  
X  
X  
X  
X  
X  
X  
X  
C o m pre he nsi ve meta b olic pa nel  
( ^) 
 
 
X  
  
X  
X  
X  
X  
X  
X  
X  
He patitis B s urface a nti ge n (* ) 
 
 
X  
  
  
  
  
  
  
  
  
Ser u m Pre g na nc y  test (% ) 
 
 
X  
  
  
  
  
  
  
  
  
L D H  
 
 
X  
  
  
X p  
  
X p  
  
X  
X  
Beta 2 -micr o gl o b uli n  (* )  
 
 
X  
  
  
X  
  
X  
  
X  
X  
Ser u m s peci me n f or c yt o ki ne 
pr ofile   
 
 
X  
 
X n  
 
 
 
 
 
 
F or W M o nl y : I g M, ser u m 
visc osit y, S P E P  wit h 
i m m u n ofi xati o n 
 
 
X  
  
 
 X p  
  
 X p  
  
 X  
 X  
T o xicit y assess me nt  (i ncl u des 
F A C T/ G O G Ne ur ot o xicit y Q uesti o n naire  (!) 
 
 
  
  
X  
X  
X  
X  
X  
X  
X  
O pti o nal bi o ps y (c ycle 2, da y 1)  
 
 
  
  
X n  
  
  
  
  
  
  
*  
G o o d me dical practice  
%   
C o nfir mati o n t hat t he s u bject is n ot pre g n a nt m ust be esta blis he d b y a ne gati ve ser u m β - h u ma n c h ori o nic  
g o na d otr o pi n ( β - h C G) pre g n a nc y test res ult o btai ne d d uri n g s cree ni n g.  Pre g na n c y testi n g is n ot re q uire d  
f or p ost-me n o pa usal or s ur gicall y sterilize d w o me n.  
p   
pri or t o s tarti n g t he c ycle ( wit hi n 7 da ys) 
#   
E ver y 3 m o nt hs f or 2 years, t he n a n n uall y f or 5 ye ars. 
&   
If i n v ol ve d at dia g n osis 
n   
5 milliliters of ser u m t o be c ollecte d f or c yt o ki ne pr ofili n g a n d 1 p araffi n e m be d de d bl oc k or 1 0 u nstai ne d sli des fr o m t he o pti o nal t u m or bi o ps y t o be perf or me d  wit hi n 2 da ys of Da y 1 of C ycle 2 O N L Y 
^   
T his i ncl u des s o di u m, p otassi u m, c hl ori de, bicar b o nate, urea nitr o ge n, creati ni ne, gl uc ose, t otal pr ot ei n, al b u mi n, A S T, A L T, al kali ne p h os p hatase a n d t otal bilir u bi n 
! 
T his i ncl u des A E assess me nt as well as t he F A C T/ G O G - Ne ur ot o xicit y Q uesti o n naire 
k 
Wi t hi n 7 2 h o urs pri or t o Da y 1, C ycl e 1  

V ersi o n 7: 0 8/ 1 5/ 2 0 1 7  
8 5  
 
8. 2  K ar n ofs k y Perf or m a nce St at us Sc ale  
T he f oll o wi n g ta ble prese nts t he Kar n ofs k y perf or ma nce stat us scale 1: 
 
P oi nts  
Descri pti o n  
1 0 0  
N or mal, n o c o m plai nts, n o e vi de nce of disease  
9 0  
A ble t o carr y o n n or mal acti vit y  
8 0  
N or mal acti vit y wit h eff ort; s o me si g ns or s y m pt o ms of disease  
7 0  
Cares f or self; u na ble t o carr y o n n or mal acti vit y or t o d o acti ve w or k  
6 0  
Re q uires occasi o nal assista nce b ut is a ble t o care f or m ost of his/ her nee ds  
5 0  
Re q uires c o nsi dera ble assista nce  a n d fre q ue nt me dical care  
4 0  
Disa ble d; re q uires s pecial care a n d assista nce  
3 0  
Se verel y disa ble d; h os pitalizati o n i n dicate d.  Deat h n ot i m mi n e nt  
2 0  
Ver y sic k; h os pitalizati o n necessar y; acti ve s u p p ort treat me nt necessar y  
1 0  
M ori b u n d; fatal pr ocesses pr o gressi n g ra pi dl y  
0  
Dea d  
 
                                                 
1 
M or V, Lali berte L, M orris J N, Wie ma n n M.  T he Kar n ofs k y Perf or ma nce Stat us Scale:  a n e xa mi nati o n of its relia bilit y a n d 
vali dit y i n a researc h setti n g.  C a ncer  1 9 8 4; 5 3: 2 0 0 2- 2 0 0 7. 

V ersi o n 7: 0 8/ 1 5/ 2 0 1 7  
8 6  
 
8. 3  B o d y S urf ace Are a a n d Cre ati ni ne Cle ar a nce C alc ul ati o n s 
B o d y s urface area ( B S A) s h o ul d be calc ulate d usi n g a sta n dar d n o m o gra m t hat yiel ds t he f oll o wi n g res ults i n meters s q uare d ( m 2): 
B S A = 
3 1 3 1
)
(
)
(
l bs
Wt
i nc hes
Ht
×
 
or 
B S A = 
3 6 0 0
)
(
)
(
k g
Wt
c m
Ht
×
 
 
Creati ni ne cleara nce ( Cr Cl) ca n be calc ulate d usi n g t he C oc kr oft - Ga ult e q uati o n as f oll o ws: 
 
Cr Cl ( ml/ mi n) =  ( 1 4 0-a ge) (act ual wt i n k g)               
  
  
  
   7 2 x ser u m creati ni ne ( m g/ dl)  
F or fe males use 8 5 % of calc ulate d Cr Cl val ue.  
N ote: I n mar ke dl y o bese patie nts, t he C oc kr oft -Ga ult f or m ula will te n d t o o veresti mate t he creati ni ne cleara nce. ( A di p ose tiss ue te n ds 
t o c o ntri b ute little creati ni ne re q uiri n g re nal cleara nce.) 
 

V ersi o n 7: 0 8/ 1 5/ 2 0 1 7  
8 7  
 
8. 4  Ne w Y or k He art Ass oci ati o n Cl assific ati o n of C ar di ac Dise as e 
T he f oll o wi n g ta ble prese nts t he N Y H A classificati o n of car diac disease:  
Cl ass  
F u ncti o n al C a p acit y  
O bjecti ve Assess me nt  
I 
Patie nts wit h car diac disease b ut wit h o ut res ulti n g li mitati o ns of 
p h ysical acti vit y.  Or di nar y p h ysical acti vit y d oes n ot ca use u n d ue 
fati g ue, pal pitati o n, d ys p nea, or a n gi nal pai n. 
N o o bjecti ve e vi de nce 
of car di o vasc ular 
disease.  
II 
Patie nts wit h car diac disease res ulti n g i n sli g ht li mitati o n of p h ysical 
acti vit y.  T he y are c o mf orta ble at rest.  Or di nar y p h ysical acti vit y 
res ults i n fati g ue, pal pitati o n, d ys p nea, or a n gi nal pai n. 
O bjecti ve e vi de nce of 
mi ni mal 
car di o vasc ular disease.  
III 
Patie nts wit h car diac disease res ulti n g i n mar ke d li mitati o n of 
p h ysical acti vit y.  T he y are c o mf orta ble at rest.  Less t ha n or di nar y 
acti vit y causes fati g ue, pal pitati o n, d ys p nea, or a n gi nal pai n.  
O bjecti ve e vi de nce of 
m o deratel y se vere 
car di o vasc ular disease.  
I V 
Patie nts wit h car diac disease res ulti n g i n i na bilit y t o carr y o n a n y 
p h ysical acti vit y wit h o ut disc o mf ort.  S y m pt o ms of heart fail ure o r 
t he a n gi nal s y n dr o me ma y be prese nt e ve n at rest.  If a n y p h ysical 
acti vit y is u n derta ke n, disc o mf ort is i ncrease d.  
O bjecti ve e vi de nce of 
se vere car di o vasc ular 
disease.  
 
 
 
 
 
 
 
 
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
S o urce:  T he Criteria C o m mittee of Ne w Y or k Heart Ass ociat i o n.  N o me nclat ure a n d Criteria f or Dia g n osis of Diseases of t he Heart 
a n d Great Vessels.  9t h E d. B ost o n, M A:  Little, Br o w n & C o; 1 9 9 4: 2 5 3- 2 5 6. 

V ersi o n 7: 0 8/ 1 5/ 2 0 1 7  
8 8  
 
8. 5  Decl ar ati o n of Helsi n ki  
W orl d Me di c al Ass oci ati o n Decl ar ati o n of Helsi n ki:  
Et hical Pri nci ples f or Me dical Researc h I n v ol vi n g H u ma n S u bjects  
A d o pte d b y t he 1 8t h W M A Ge neral Asse m bl y Helsi n ki, Fi nla n d, J u ne 1 9 6 4 a n d a me n de d b y t he 2 9t h 
W M A Ge neral Asse m bl y, T o k y o, Ja pa n, Oct o ber 1 9 7 5 3 5t h W M A Ge neral Asse m bl y, Ve nice, Ital y, 
Oct o ber 1 9 8 3 4 1st W M A Ge neral Asse m bl y, H o n g K o n g, Se pte m ber 1 9 8 9 4 8t h W M A Ge neral 
Asse m bl y, S o merset West, Re p u blic of S o ut h Africa, Oct o ber 1 9 9 6 a n d t he 5 2 n d W M A Ge neral 
Asse m bl y, E di n b ur g h, Sc otla n d, Oct o ber 2 0 0 0 
A.  I N T R O D U C TI O N 
1.  T he W orl d Me dical Ass ociati o n has de vel o pe d t he Declarati o n of Helsi n ki as a state me nt of 
et hical pri nci ples t o pr o vi de g ui da nce t o p h ysicia ns a n d ot her partici pa nts i n me dical researc h 
i n v ol vi n g h u ma n s u bjects.  Me dical researc h i n v ol vi n g h u ma n s u bjects i ncl u des researc h o n 
i de ntifia ble h u ma n material or i de ntifia ble data. 
2.  It is t he d ut y of t he p h ysicia n t o pr o m ote a n d safe g uar d t he healt h of t he pe o ple.  T he p h ysicia n's 
k n o wle d ge a n d c o nscie nce are de dicate d t o t he f ulfill me nt of t his d ut y. 
3.  T he Declarati o n of Ge ne va of t he W orl d Me dical Ass ociati o n bi n ds t he p h ysicia n wit h t he w or ds, 
" T he healt h of m y patie nt will be m y first c o nsi derati o n," a n d t he I nter nati o nal C o de of Me dical 
Et hics declares t hat, " A p h ysicia n s hall act o nl y i n t he patie nt's i nterest w he n pr o vi di n g me dical 
care w hic h mi g ht ha ve t he effect of wea ke ni n g t he p h ysical a n d me ntal c o n diti o n of t he patie nt." 
4.  Me dical pr o gress is base d o n researc h w hic h ulti matel y m ust rest i n part o n e x peri me ntati o n 
i n v ol vi n g h u ma n s u bjects. 
5.  I n me dical researc h o n h u ma n s u bjects, c o nsi derati o ns relate d t o t he well-bei n g of t he h u ma n 
s u bject s h o ul d ta ke prece de nce o ver t he i nterests of scie nce a n d s ociet y. 
6.  T he pri mar y p ur p ose of me dical researc h i n v ol vi n g h u ma n s u bjects is t o i m pr o ve pr o p h ylactic, 
dia g n o stic a n d t hera pe utic pr oce d ures a n d t he u n dersta n di n g of t he eti ol o g y a n d pat h o ge nesis of 
disease.   E ve n  t he  best  pr o ve n  pr o p h ylactic,  dia g n ostic,  a n d  t hera pe utic  met h o ds  m ust  
c o nti n u o usl y be c halle n ge d t hr o u g h researc h f or t heir effecti ve ness, efficie nc y,  accessi bilit y a n d 
q ualit y. 
7.  I n c urre nt me dical practice a n d i n me dical researc h, m ost pr o p h ylactic, dia g n ostic a n d t hera pe utic 
pr oce d ures i n v ol ve ris ks a n d b ur de ns. 
8.  Me dical researc h is s u bject t o et hical sta n dar ds t hat pr o m ote res pect f or all h u ma n bei n gs a n d 
pr otect  t heir healt h a n d ri g hts.  S o me researc h p o p ulati o ns are v ul nera ble a n d nee d s pecial  
pr otecti o n.  T he partic ular nee ds of t he ec o n o micall y a n d me dicall y disa d va nta ge d m ust be 
rec o g nize d.  S pecial atte nti o n is als o re q uire d f or t h ose w h o ca n n ot gi ve or ref use c o nse nt f or 
t he msel ves, f or t h ose w ho ma y be s u bject t o gi vi n g c o nse nt u n der d uress, f or t h ose w h o will n o  
be nefit pers o nall y fr o m t he researc h a n d f or t h ose f or w h o m t he researc h is c o m bi ne d wit h care. 
9.  Researc h I n vesti gat ors s h o ul d be a ware of t he et hical, le gal a n d re g ulat or y re q uire me nts f or 
researc h  o n  h u ma n  s u bjects  i n  t heir  o w n  c o u ntries  as  well  as  a p plica ble  i nter nati o nal  
re q uire me nts.  N o nati o nal et hical, le gal or re g ulat or y re q uire me nt s h o ul d be all o we d t o re d uce 
or eli mi nate a n y of t he pr otecti o ns f or h u ma n s u bjects set f ort h i n t his Declarati o n. 

V ersi o n 7: 0 8/ 1 5/ 2 0 1 7  
8 9  
 
B.  B A SI C P RI N CI P L E S F O R A L L M E DI C A L R E S E A R C H  
1.  It is t he d ut y of t he p h ysicia n i n me dical researc h t o pr otect t he life, healt h, pri vac y, a n d di g nit y 
of t he h u ma n s u bject. 
2.  Me dical  researc h  i n v ol vi n g  h u ma n  s u bjects  m ust  c o nf or m  t o  ge nerall y  acce pte d  scie ntific  
pri nci ples, be base d o n a t h or o u g h k n o wle d ge of t he scie ntific literat ure, ot her rele va nt s o urces of 
i nf or mati o n, a n d o n a de q uate la b orat or y a n d, w here a p pr o priate, a ni mal e x peri me ntati o n. 
3.  A p p r o priate  ca uti o n  m ust  be  e xercise d  i n  t he  c o n d uct  of  researc h  w hic h  ma y  affect  t he  
e n vir o n me nt, a n d t he welfare of a ni mals use d f or researc h m ust be res pecte d.  
4.  T he desi g n a n d perf or ma nce of eac h e x peri me ntal pr oce d ure i n v ol vi n g h u ma n s u bjects s h o ul d be 
clearl y  f or m ulate d  i n  a n  e x peri me ntal  pr ot oc ol.   T his  pr ot oc ol  s h o ul d  be  s u b mitte d  f or  
c o nsi derati o n, c o m me nt, g ui da nce, a n d w here a p pr o priate, a p pr o val t o a s peciall y a p p oi nte d 
et hical re vie w c o m mittee, w hic h m ust be i n de pe n de nt of t he i n vesti gat or, t he s p o ns or or a n y ot her 
ki n d of u n d ue i nfl ue nce.  T his i n de pe n de nt c o m mittee s h o ul d be i n c o nf or mit y wit h t he la ws a n d 
re g ulati o ns of t he c o u ntr y i n w hic h t he researc h e x peri me nt is perf or me d.  T he c o m mittee has t he 
ri g ht  t o  m o nit or  o n g oi n g  trials.   T he  researc her  has  t he  o bli gati o n  t o  pr o vi de  m o nit ori n g  
i nf or mati o n t o t he c o m mittee, es peciall y a n y seri o us a d verse e ve nts.  T he researc her s h o ul d als o 
s u b mit  t o  t he  c o m mittee,  f or  re vie w,  i nf or mati o n  re gar di n g  f u n di n g,  s p o ns ors,  i nstit uti o nal  
affiliati o ns, ot her p ote ntial c o nflicts of i nterest a n d i nce nti ves f or s u bjects. 
5.  T he researc h pr ot oc ol s h o ul d al wa ys c o ntai n a state me nt of t he et hical c o nsi derati o ns i n v ol ve d 
a n d s h o ul d i n dicate t hat t here is c o m plia nce wit h t he pri nci ples e n u nciate d i n t his Declarati o n. 
6.  Me dical  researc h i n v ol vi n g h u ma n s u bjects s h o ul d be c o n d ucte d o nl y b y scie ntificall y q ualifie d 
pers o ns a n d u n der t he s u per visi o n of a cli nicall y c o m pete nt me dical pers o n.  T he res p o nsi bilit y 
f or t he h u ma n s u bject m ust al wa ys rest wit h a me dicall y q ualifie d pers o n a n d ne ver rest o n t he 
s u bject of t he researc h, e ve n t h o u g h t he s u bject has gi ve n c o nse nt. 
7.  E ver y  me dical  researc h  pr oject  i n v ol vi n g  h u ma n  s u bjects  s h o ul d  be  prece de d  b y  caref ul  
assess me nt of pre dicta ble ris ks a n d b ur de ns i n c o m paris o n wit h f oreseea ble be ne fits t o t he s u bject 
or t o ot hers.  T his d oes n ot precl u de t he partici pati o n of healt h y v ol u nteers i n me dical researc h.  
T he desi g n of all st u dies s h o ul d be p u blicl y a vaila ble. 
8.  P h ysicia ns s h o ul d a bstai n fr o m e n ga gi n g i n researc h pr ojects i n v ol vi n g h u ma n s u b jects u nless 
t he y are c o nfi de nt t hat t he ris ks i n v ol ve d ha ve bee n a de q uatel y assesse d a n d ca n be satisfact oril y 
ma na ge d.  P h ysicia ns s h o ul d cease a n y i n vesti gati o n if t he ris ks are f o u n d t o o ut wei g h t he 
p ote ntial be nefits or if t here is c o ncl usi ve pr o of of p ositi ve a n d be neficial res ults.  
9.  Me dical researc h i n v ol vi n g h u ma n s u bjects s h o ul d o nl y be c o n d ucte d if t he i m p orta nce of t he 
o bjecti ve o ut wei g hs t he i n here nt ris ks a n d b ur de ns t o t he s u bject.  T his is es peciall y i m p orta nt 
w he n t he h u ma n s u bjects are healt h y v ol u nteers. 
1 0.  Me dical researc h is o nl y j ustifie d if t here is a reas o na ble li keli h o o d t hat t he p o p ulati o ns i n w hic h 
t he researc h is carrie d o ut sta n d t o be nefit fr o m t he res ults of t he researc h. 
1 1.  T he s u bjects m ust be v ol u nteers a n d i nf or me d partici pa nts i n t he researc h pr oject. 
1 2.  T he ri g ht of researc h s u bjects t o safe g uar d t heir i nte grit y m ust al wa ys be res pecte d.  E ver y 
preca uti o n s h o ul d be ta ke n t o res pect t he pri vac y of t he s u bject, t he c o nfi de ntialit y of t he patie nt's 
i nf or mati o n a n d t o mi ni mize t he i m pact of t he st u d y o n t he s u bject's p h ysical a n d me ntal i nte grit y 

V ersi o n 7: 0 8/ 1 5/ 2 0 1 7  
9 0  
 
a n d o n t he pers o nalit y of t he s u bject. 
1 3.  I n a n y researc h o n h u ma n bei n gs, eac h p ote ntial s u bject m ust be a de q uatel y i nf or me d of t he ai ms, 
met h o ds, s o urces of f u n di n g, a n y p ossi ble c o nflicts of i nte rest, i nstit uti o nal affiliati o ns of t he 
researc her, t he a ntici pate d be nefits a n d p ote ntial ris ks of t he st u d y a n d t he disc o mf ort it ma y 
e ntail.  T he s u bject s h o ul d be i nf or me d of t he ri g ht t o a bstai n fr o m partici pati o n i n t he st u d y or t o 
wit h dra w c o nse nt t o partici pate at a n y ti me wit h o ut re prisal.  After e ns uri n g t hat t he s u bject has 
u n derst o o d t he i nf or mati o n, t he p h ysicia n s h o ul d t he n o btai n t he s u bject's freel y -gi ve n i nf or me d 
c o nse nt, prefera bl y i n writi n g.  If t he c o nse nt ca n n ot be o btai ne d i n writi n g,  t he n o n-writte n 
c o nse nt m ust be f or mall y d oc u me nte d a n d wit nesse d. 
1 4.  W he n o btai ni n g i nf or me d c o nse nt f or t he researc h pr oject t he p h ysicia n s h o ul d be partic ularl y 
ca uti o us if t he s u bject is i n a de pe n de nt relati o ns hi p wit h t he p h ysicia n or ma y c o nse nt u n der  
d uress.  I n t hat case t he i nf or me d c o nse nt s h o ul d be o btai ne d b y a well -i nf or me d p h ysicia n w h o 
is n ot e n ga ge d i n t he i n vesti gati o n a n d w h o is c o m pletel y i n de pe n de nt of t his relati o ns hi p. 
1 5.  F or a researc h s u bject w h o is le gall y i nc o m pete nt, p h ysicall y or me ntall y i nca pa ble of gi vi n g 
c o nse nt or is a le gall y i nc o m pete nt mi n or, t he i n vesti gat or m ust o btai n i nf or me d c o nse nt fr o m t he 
le gall y a ut h orize d re prese ntati ve i n acc or da nce wit h a p plica ble la w.  T hese gr o u ps s h o ul d n ot be 
i ncl u de d i n researc h u nless t he researc h is necessar y t o pr o m ote t he healt h of t he p o p ulati o n 
re prese nte d a n d t his researc h ca n n ot i nstea d be perf or me d o n le gall y c o m pete nt pers o ns. 
1 6.  W he n a s u bject dee me d le gall y i nc o m pete nt, s uc h as a mi n or c hil d, is a ble t o gi ve asse nt t o 
decisi o ns a b o ut p artici pati o n i n researc h, t he i n vesti gat or m ust o btai n t hat asse nt i n a d diti o n t o 
t he c o nse nt of t he le gall y a ut h orize d re prese ntati ve. 
1 7.  Researc h o n i n di vi d uals fr o m w h o m it is n ot p ossi ble t o o btai n c o nse nt, i ncl u di n g pr o x y or 
a d va nce c o nse nt, s h o ul d be d o ne o nl y if t he p h ysical/ me ntal c o n diti o n t hat pre ve nts o btai ni n g 
i nf or me d c o nse nt is a necessar y c haracteristic of t he researc h p o p ulati o n.  T he s pecific reas o ns 
f or i n v ol vi n g researc h s u bjects wit h a c o n diti o n t hat re n ders t he m u na ble t o gi ve i nf or me d c o nse nt 
s h o ul d  be  state d  i n  t he  e x peri me ntal  pr ot oc ol  f or  c o nsi derati o n  a n d  a p pr o val  of  t he  re vie w 
c o m mittee.  T he pr ot oc ol s h o ul d state t hat c o nse nt t o re mai n i n t he researc h s h o ul d be o btai ne d 
as s o o n as p ossi ble fr o m t he i n di vi d ual or a le gall y a ut h orize d s urr o gate. 
1 8.  B ot h a ut h ors a n d p u blis hers ha ve et hical o bli gati o ns.  I n p u blicati o n of t he res ults of researc h, t he 
i n vesti gat ors are o bli ge d t o preser ve t he acc urac y of t he res ults.  Ne gati ve as well as p ositi ve 
res ults s h o ul d be p u blis he d or ot her wise p u blicl y a vaila ble.  S o urces of f u n di n g, i nstit uti o nal 
affiliati o ns a n d a n y p ossi ble c o nflicts of i nterest s h o ul d be declare d i n t he p u blicati o n.  Re p orts 
of e x peri me ntati o n n ot i n acc or da nce wit h t he pri nci ples lai d d o w n i n t his Declarati o n s h o ul d n ot 
be acce p te d f or p u blicati o n. 
C.  A D DI TI O N A L  P RI N CI P L E S  F O R  M E DI C A L  R E S E A R C H  C O M BI N E D  WI T H  
M E DI C A L C A R E  
1.  T he p h ysicia n ma y c o m bi ne me dical researc h wit h me dical care, o nl y t o t he e xte nt t hat t he 
researc h is j ustifie d b y its p ote ntial pr o p h ylactic, dia g n ostic or t hera pe utic val ue.  W he n me dical 
researc h is c o m bi ne d wit h me dical care, a d diti o nal sta n dar ds a p pl y t o pr otect t he patie nts w h o are 
researc h s u bjects. 
2.  T he be nefits, ris ks, b ur de ns a n d effecti ve ness of a ne w met h o d s h o ul d be teste d a gai nst t h ose of 
t he best c urre nt pr o p h ylactic, dia g n ostic, a n d t hera pe utic met h o ds.  T his d oes n ot e xcl u de t he use 

V ersi o n 7: 0 8/ 1 5/ 2 0 1 7  
9 1  
 
of place b o, or n o treat me nt, i n st u dies w here n o pr o ve n pr o p h ylactic, dia g n ostic or t hera pe utic 
met h o d e xists. 
3.  At t he c o ncl usi o n of t he st u d y, e ver y patie nt e ntere d i nt o t he  st u d y s h o ul d be ass ure d of access t o 
t he best pr o ve n pr o p h ylactic, dia g n ostic a n d t hera pe utic met h o ds i de ntifie d b y t he st u d y. 
4.  T he p h ysicia n s h o ul d f ull y i nf or m t he patie nt w hic h as pects of t he care are relate d t o t he researc h.  
T he ref usal of a patie nt t o partici pate i n a st u d y m ust ne ver i nterfere wit h t he patie nt - p h ysicia n 
relati o ns hi p. 
5.  I n t he treat me nt of a patie nt, w here pr o ve n pr o p h ylactic, dia g n ostic a n d t hera pe utic met h o ds d o 
n ot e xist or ha ve bee n i neffecti ve, t he p h ysicia n, wit h i nf or me d c o nse nt fr o m t he patie nt, m ust be 
free  t o  use  u n pr o ve n  or  ne w  pr o p h ylactic,  dia g n ostic  a n d  t hera pe utic  meas ures,  if  i n  t he  
p h ysicia n's j u d g me nt it offers h o pe of sa vi n g life, re -esta blis hi n g healt h or alle viati n g s ufferi n g.  
W here p ossi ble, t hese meas ures s h o ul d be ma de t he o bject of researc h, desi g ne d t o e val uate t heir 
safet y a n d efficac y.  I n all cases, ne w i nf or mati o n s h o ul d be rec or de d a n d, w here a p pr o priate, 
p u blis he d.  T he ot her rele va nt g ui deli nes of t his Declarati o n s h o ul d be f oll o we d. 

V ersi o n 7: 0 8/ 1 5/ 2 0 1 7  
9 2  
 
8. 6  F A C T/ G O G - Ne ur ot o xicit y Q uesti o n n aire, Versi o n 4. 0 
F A C T/ G O G -Ne ur ot o xicit y Q uesti o n n aire, Versi o n 4. 0  
B y circli n g o ne ( 1) n u m ber per li ne, please i n dicate h o w tr ue eac h state me nt has bee n f or y o u 
d uri n g t he past 7 da ys. 
A D DI TI O N A L C O N C E R N S  
N ot  
at all  
A little  
bit  
S o me - 
w h at  
Q uite  
a bit  
Ver y  
m uc h  
I ha ve n u m b ness or ti n gli n g i n m y ha n ds … … … 
0  
1  
2  
3  
4  
I ha ve n u m b ness or ti n gli n g i n m y feet … … … … 
0  
1  
2  
3  
4  
I feel disc o mf ort i n m y ha n ds … … … … … … …. 
0  
1  
2  
3  
4  
I feel disc o mf ort i n m y feet … … … … … … … … 
0  
1  
2  
3  
4  
I ha ve j oi nt pai n or m uscle cra m ps … … … … …  
0  
1  
2  
3  
4  
I feel wea k all o ver … … … … … … … … … … … 
0  
1  
2  
3  
4  
I ha ve tr o u ble heari n g … … … … … … … … … … 
0  
1  
2  
3  
4  
I get a ri n gi n g or b uzzi n g i n m y ears … … … … 
0  
1  
2  
3  
4  
I ha ve tr o u ble b utt o ni n g b utt o ns … … … … … … 
0  
1  
2  
3  
4  
I ha ve tr o u ble feeli n g t he s ha pe of s mall o bjects  
w he n t he y are i n m y ha n d … … … … … … … … …  
0  
1  
2  
3  
4  
I ha ve tr o u ble wal ki n g … … … … … … … … … … 
0  
1  
2  
3  
4  
 
 
 
 
 
 
 
 
 
 
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
S o urces:  Cella D F, T uls k y D S, Gra y G, Sarafia n B, Ll o y d S, Li n n E, et al.  T he f u ncti o nal assess me nt of 
ca ncer t hera p y ( F A C T) scale:  de vel o p me nt a n d vali dati o n of t he ge neral meas ure.  J Cli n O nc ol 
1 9 9 3; 1 1( 3): 5 7 0 -7 9.  

V ersi o n 7: 0 8/ 1 5/ 2 0 1 7  
9 3  
 
8. 7 A n n Ar b or Cl assific ati o n ( AJ C C Ma n ual f or Sta gi n g of Ca ncer, 6t h e d., 2 0 0 2) 
S T A G E II  
I n v ol ve me nt of t w o or m ore l y m p h n o de re gi o ns o n t he sa me si de of t he dia p hra g m 
(II) or l ocalize d i n v ol ve me nt of a n e xtral y m p hatic or ga n or site a n d its ass ociate d 
re gi o nal l y m p h n o des (II E). 
S T A G E III  
I n v ol ve me nt of l y m p h n o de re gi o ns o n b ot h si des of t he dia p hra g m (III), w hic h ma y 
be acc o m pa nie d b y l ocalize d i n v ol ve me nt of a n ass ociate d e xtral y m p hatic or ga n or 
site (III E) or s plee n (III S) or b ot h (III S E). 
S T A G E I V  
Diff use or disse mi nate d i n v ol ve me nt of o ne or m ore e xtra l y m p hatic or ga ns wit h or 
wit h o ut  ass ociate d  l y m p h  n o de  i n v ol ve me nt,  or  is olate d  e xtral y m p hatic  or ga n  
i n v ol ve me nt wit h dista nt ( n o n-re gi o nal) n o dal i n v ol ve me nt. 
A = As y m pt o matic  
B = U ne x plai ne d fe ver ( 3 8° C), ni g ht s weats, u ne x plai ne d wei g ht l oss > 1 0 % of b o d y wei g ht o ver t he 
pre vi o us si x m o nt hs  
" B ul k y" = me diasti nal mass > 1/ 3 of t he ma xi m u m c hest dia meter (i.e., i nter nal di me nsi o n of t he 
t h oracic ca vit y meas ure d at its wi dest p oi nt per ra di o gra p h) or a n y ot her mass ≥ 1 0 c m i n ma xi m u m 
dia meter.  

V ersi o n 7: 0 8/ 1 5/ 2 0 1 7  
9 4  
 
8. 8  I nter n ati o n al W or ki n g Gr o u p Res p o nse Criteri a ( C hes o n et al, 1 9 9 9)  
R es p o nse C ate g or y  
P h ysic al 
E x a mi n ati o n  
L y m p h N o des  
L y m p h N o de 
M asses  
B o ne M arr o w  
C R (c o m plete res p o nse)  
N or mal  
N or mal  
N or mal  
N or mal  
C R u (c o m plete res p o nse, 
u nc o nfir me d)  
N or mal  
N or mal  
N or mal  
I n deter mi nate 
N or mal  
N or mal  
> 7 5 % decrease  
N or mal or 
i n deter mi nate 
P R ( partial res p o nse)  
N or mal  
N or mal  
N or mal  
P ositi ve  
N or mal  
≥5 0 % decrease  
≥5 0 % decrease  
Irrele va nt 
Decrease i n 
li ver/s plee n 
≥5 0 % decrease  
≥5 0 % decrease  
Irrele va nt 
Pr o gressi o n /rela pse 
E nlar gi n g 
li ver/s plee n, ne w sites 
Ne w or i ncrease d  
Ne w or i ncrease d  
Rea p peara nce  
If P E T sca n is als o use d f or sta gi n g, re vise d Res p o nse Criteria s h o ul d be use d ( C hes o n et al, 2 0 0 7) 

V ersi o n 7: 0 8/ 1 5/ 2 0 1 7  
9 5  
 
8. 9 U p d ate d Res p o nse Criteri a fr o m t he 3 r d I nter n ati o n al W or ks h o p o n W al der nstr o m’s 
M acr o gl o b uli ne mi a ( Tre o n et al, 2 0 0 6)  
 
Res p o nse Cate g or y  
Criteria  
C R ( C o m plete Res p o nse)    Disa p peara nce of m o n ocl o nal pr otei n b y i m m u n ofi xati o n; n o hist ol o gic e vi de nce of 
b o ne marr o w i n v ol ve me nt, res ol uti o n of a n y a de n o pat h y/ or ga n o me gal y (c o nfir me d b y 
C T sca n), or si g ns or s y m pt o ms attri b uta ble t o W M. Rec o nfir mati o n of t he C R stat us is 
re q uire d at least 6 wee ks a part wit h a sec o n d i m m u n ofi xati o n. 
P R ( Partial Res p o nse)  
At least 5 0 % re d ucti o n of ser u m m o n ocl o nal I g M c o nce ntrati o n o n pr otei n 
electr o p h oresis a n d at least 5 0 % decrease i n  a de n o pat h y/ or ga n o me gal y o n p h ysical 
e xa mi nati o n or o n C T sca n. N o ne w s y m pt o ms or si g ns of acti ve disease.  
M R ( Mi n or Res p o nse)  
At least 2 5 % b ut less t ha n 5 0 % re d ucti o n of ser u m m o n ocl o nal I g M b y pr otei n 
electr o p h oresis. N o ne w s y m pt o ms or si g ns of acti ve  disease.  
S D ( Sta ble Disease)  
A less -t ha n 2 5 % re d ucti o n a n d less-t ha n-2 5 % i ncrease of ser u m m o n ocl o nal I g M b y 
electr o p h oresis wit h o ut pr o gressi o n of a de n o pat h y/ or ga n o me gal y, c yt o pe nias, or 
cli nicall y si g nifica nt s y m pt o ms d ue t o disease a n d/ or si g ns of W M.  
P D ( Pr o gressi ve Disease)  At least 2 5 % i ncrease i n ser u m m o n ocl o nal I g M b y pr otei n electr o p h oresis c o nfir me d 
b y a sec o n d meas ure me nt or pr o gressi o n of cli nicall y si g nifica nt fi n di n gs d ue t o 
disease ( i.e., a ne mia, t hr o m b oc yt o pe nia, le uc o pe nia, b ul k y a de n opat h y/ or ga n o me gal y) 
or s y m pt o ms ( u ne x plai ne d rec urre nt fe ver of at least 3 8. 4 oC, dre nc hi n g ni g ht s weats, at 
least 1 0 % b o d y wei g ht l oss, or h y per visc osit y, ne ur o pat h y, s y m pt o matic 
cr y o gl o b uli ne mia, or a m yl oi d osis) attri b uta ble t o W M.  

V ersi o n 7: 0 8/ 1 5/ 2 0 1 7  
9 6  
 
8. 1 0  Pr ot oc ol Si g n at ure P a ge 
 
 
 
Pr ot oc ol Si g n at ure P a ge  
 
Pr ot oc ol Title : 
“ A P hase II, O pe n - La bel St u d y of B ortez o mi b ( Velca de ®), Cla dri bi ne, a n d Rit u xi ma b ( V C R) i n 
A d va nce d, Ne wl y Dia g n ose d a n d Rela pse d/ Refract or y Ma ntle Cell a n d I n d ole nt L y m p h o mas” 
 
Pr ot oc ol Versi o n/ D ate : 
A u g ust 1 5, 2 0 1 7 
 
I a gree t o c o n d uct t he st u d y as o utli ne d i n t he pr ot oc ol a n d t o c o m pl y wit h all t he ter ms a n d c o n diti o ns 
set o ut t herei n. I c o nfir m t hat I will c o n d uct t he st u d y i n acc or da nce wit h F D A a n d I C H G C P 
g ui deli nes a n d all ot her a p plica ble re g ulat or y re q uire me nts. I als o will e ns ure t hat s u b -i n vesti gat or(s) 
a n d ot her rele va nt me m bers of m y st aff ha ve access t o c o pies of t his pr ot oc ol.  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Si g nat ure of Pri nci pal I n vesti gat or     
  
  
Date of Si g nat ure 
 
 
Da niel Pers k y , M D    
  
  
 
Pri nte d N a me of Pri nci pal I n vesti gat or 
 
U ni versit y of Ariz o na Ca ncer Ce nter    
  
 
I nstit uti o n Na me 
 
 
1 5 1 5 N Ca m p bell A ve, T ucs o n, A Z 8 5 7 2 4    
 
I nstit uti o n a d dress  
 
 
 
 
 

V ersi o n 7: 0 8/ 1 5/ 2 0 1 7  
9 7  
 
A P P E N DI X 8 . 1 1 TI S S U E S U B MI S SI O N F O R M  
 
A P h a s e II, O p e n -L a b el St u d y of B ort e z o mi b ( V el c a d e ®), Cl a dri bi n e, a n d Rit u xi m a b ( V C R) i n 
A d v a n c e d, N e wl y Di a g n o s e d a n d R el a p s e d/ R efr a ct or y M a ntl e C ell a n d I n d ol e nt L y m p h o m a s  
S u bj e ct I niti al s:         S u bj e ct st u d y I D:         
D at e of S u b mi s si o n t o Ri m s z a l a b or at or y  ( M M/ D D/ Y Y Y Y):   /  /         
 
T y p e of s a m pl e a n d ti m e p oi nt c oll e ct e d  ( M M/ D D/ Y Y Y Y a n d 2 4 h o ur cl o c k f or m at) 
T u m or bl o c k pr e -st u d y:  # bl o c k s:    D at e :   /  /     Ti m e :   :   
T u m or u n st ai n e d sli d e s pr e -st u d y:  #    D at e :   /  /     Ti m e:   :   
T u m or bl o c k  C 2 D 1 : # bl o c k s:     D at e :   /  /     Ti m e:   :   
T u m or u n st ai n e d sli d e s  C 2 D 1 : #    D at e:    /  /     Ti m e:   :   
Bl o o d, s er u m, pr e st u d y: # 1 ml ali q u ot s: D at e :   /  /     Ti m e:   :    
Bl o o d, s er u m , C 2 D 1 : # 1 ml ali q u ot s: D at e :   /  /     Ti m e:   :   
* Bl o o d, fr e s h pr e st u d y: # t u b e s: D at e:   /  /     Ti m e:   :    
*Bl o o d, fr e s h C 2 D 1 :         # t u b e s: D at e :   /  /     Ti m e:   :   
 
* f or U ni v er sit y of Ari z o n a sit e o nl y 
*** writ e i n a n “ X” i n t h e b o x if bl o c k s n e e d t o b e r et ur n e d t o t h e s e n d er:    
 
C e ntr al L a b or at or y U s e O nl y  
C e ntr al L a b or at or y  I D #:     U s a bl e a s r e c ei v e d              
 
D at e s p e ci m e n ( s) r e c ei v e d:    /  /     N ot u s a bl e a s r e c ei v e d        
 
Ti m e s p e ci m e n r e c ei v e d:    :   N ot u s a bl e a s r e c ei v e d I n a d e q u at e s u b mi s si o n   
 
 
C o m me nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 

V ersi o n 7: 0 8/ 1 5/ 2 0 1 7  
9 8  
 
A P P E N DI X 8 . 1 2 S U B J E C T R E GI S T R A TI O N F O R M  
 
A P hase II, O pe n - La bel St u d y of B ortez o mi b ( Velca de ®), Cla dri bi ne, a n d Rit u xi ma b ( V C R) i n 
A d va nce d, Ne wl y Dia g n ose d a n d Rela pse d/ Refract or y Ma n tle Cell a n d I n d ole nt L y m p h o mas 
 
 
 
S u bject Re gistr ati o n D ate:  _( M M/ D D/ Y Y Y Y):   /  /      
E x pecte d St art D ate of Tre at me nt: _ _ ( M M/ D D/ Y Y Y Y):   /  /      
 
S u bject I niti als:         S u bject st u d y I D :        
 
 
* * * D O E S T HI S P A TI E N T M E E T A L L E LI GI BI LI T Y C RI T E RI A LI S T E D I N  
T H E P R O T O C O L ?      _ _ Yes  _ _ N o         
 
 
P h ysici a n: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _             Site: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
Re gistr a nt: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _              P h o ne: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
------------------------------------------------------------------------------------------------------------------------ 
 
 
C O N FI R M A TI O N O F E N R O L L M E N T  
 
 
S u bject I niti als:         S u bject st u d y I D :        
 
 
 
 
 
 
 

V ersi o n 7: 0 8/ 1 5/ 2 0 1 7  
9 9  
 
A P P E N DI X 8 . 1 3 S U B J E C T E LI GI BI LI T Y F O R M ( P a ge 1)  
 
A P hase II, O pe n - La bel St u d y of B ortez o mi b ( Velca de ®), Cla dri bi ne, a n d Rit u xi ma b ( V C R) i n 
A d va nce d, Ne wl y Dia g n ose d a n d Rela pse d/ Refract or y Ma ntle Cell a n d I n d ole nt L y m p h o mas” 
 
 
S u bject I niti als:         S u bject st u d y I D :      
 
I ncl usi o n Criteri a 
1.  V ol u ntar y writte n i nf or me d c o nse nt bef ore perf or ma nce of a n y st u d y -relate d pr oce d ure n ot 
part of n or mal 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 
s u bject at a n y ti me wit h o ut prej u dice t o f ut ure me dical care. □ 
2.  Fe male  s u bject  is  eit her  p ost -me n o pa usal  or  s ur gicall y  sterilize d  or  willi n g  t o  use  a n  
acce pta ble  met h o d  of  birt h  c o ntr ol  ( i.e.,  a  h or m o nal  c o ntrace pti ve,  i ntra-uteri ne  de vice,  
dia p hra g m wit h s per mici de, c o n d o m wit h s per mici de, or a bsti ne nce) f or t he d urati o n of t he 
st u d y. □ 
3.  Male s u bject a grees t o use a n acce pta ble met h o d f or c o ntrace pti o n f or t he d urati o n of t he 
st u d y. □ 
4.  Bi o ps y- pr o ve n  ma ntle  cell,  mar gi nal  z o ne,  l y m p h o plas mac ytic,  s mall  l y m p h oc ytic  
l y m p h o ma, or f ollic ular l y m p h o ma□ 
5.  C D 2 0 - p ositi ve disease □ 
6.  F or  patie nts  wit h  mar gi nal  z o ne,  l y m p h o plas mac ytic,  s mall  l y m p h oc ytic,  or  f ollic ular  
l y m p h o ma – at least o ne criteri o n f or i nitiati o n of treat me nt m ust be met:  
a. S y m pt o matic disease □ 
b.  C yt o pe nia relate d t o l y m p h o ma □ 
c. Le u ke mic p hase ( > 5, 0 0 0 mali g na nt l y m p h oc ytes/ µl)  □ 
d.  Mass o ver 5 c m i n greatest dia meter □ 
e. F or l y m p h o plas mac ytic l y m p h o ma: a d diti o nal treat me nt criteria are ser u m visc osit y ≥ 
4 c p, ser u m m o n ocl o nal pr otei n > 5 g/ L, c o nc urre nt pri mar y s yste mic A L a m yl oi d osis, 
c ol d a g gl uti ni n disease  □ 
7.  A ge o ver 1 8 □ 
8.  Pri or treat me nt wit h b ortez o mi b a n d/ or rit u xi ma b is acce pta ble  □ 
9.  F or f ollic ular l y m p h o ma o nl y, at least o ne pri or treat me nt  □ 
 
 

V ersi o n 7: 0 8/ 1 5/ 2 0 1 7  
1 0 0  
 
A P P E N DI X 8 . 1 3 S U B J E C T E LI GI BI LI T Y F O R M ( P a ge 2)  
 
S u bject I niti als:         S u bject st u d y I D :      
 
E xcl usi o n Criteri a 
•  Patie nt has a platelet c o u nt of < 1 0 0 ×  1 09/ L wit hi n 1 4  da ys bef ore e nr oll me nt, u nless d ue t o b o ne 
marr o w  i nfiltrati o n  wit h  l y m p h o ma,  or  d ue  t o  a ut oi m m u ne  t hr o m b oc yt o pe nia  beca use  of  
l y m p h o ma. □ 
•  Patie nt has a n a bs ol ute ne utr o p hil c o u nt of < 1. 0 ×  1 09/ L wit hi n 1 4  da ys bef ore re gistrati o n, u nless 
d ue t o b o ne marr o w i nfiltrati o n wit h l y m p h o ma. □ 
•  Patie nt has a calc ulate d or meas ure d creati ni ne cleara nce of < 2 0 m L/ mi n ute wit hi n 1 4  da ys bef ore  
re gistrati o n. ( Creati ni ne  Cleara nce  is  i n dicate d  t hr o u g h  t he  Ser u m  Creati ni ne.  If  t he  Ser u m  
Creati ni ne is a b n or mal, t he p h ysicia n ma y t he n d ue a 2 4 h o ur uri ne t o f urt her clarif y Creati ni ne 
Cleara nce. A 2 4 h o ur uri ne test is n ot re q uire d per st u d y.)  □ 
•  Patie nt has ≥ Gra d e 2 peri p heral ne ur o pat h y wit hi n 1 4 da ys bef ore  re gistrati o n. □ 
•  M y ocar dial i nfarcti o n wit hi n 6 m o nt hs pri or t o re gistrati o n or has Ne w Y or k Heart Ass ociati o n 
( N Y H A) Class III or I V heart fail ure (see secti o n 8. 4), u nc o ntr olle d a n gi na, se vere u nc o ntr olle d 
v e ntric ular arr h yt h mias, or electr ocar di o gra p hic e vi de nce of ac ute isc he mia or acti ve c o n d ucti o n 
s yste m  a b n or malities.  Pri or  t o  st u d y  e ntr y,  a n y  E C G  a b n or malit y  at  Scree ni n g  has  t o  be  
d oc u me nte d b y t he i n vesti gat or as n ot me dicall y rele va nt. □ 
•  Patie nt has h y perse nsiti vit y t o b ortez o mi b, b or o n or ma n nit ol. □ 
•  Fe male s u bject is pre g na nt or breast -fee di n g.  C o nfir mati o n t hat t he s u bject is n ot pre g na nt m ust 
be esta blis he d b y a ne gati ve ser u m β -h u ma n c h ori o nic g o na d otr o pi n ( β -h C G) pre g na nc y test 
res ult  o btai ne d d uri n g scree ni n g.  Pre g na nc y testi n g is n ot  re q uire d f or  p ost-me n o pa usal  or 
s ur gicall y sterilize d w o me n. □ 
•  Patie nt has recei ve d ot her i n vesti gati o nal dr u gs wit h 1 4 da ys bef ore re gistrati o n. □ 
•  Seri o us me dical or ps yc hiatric ill ness li kel y t o i nterfere wit h partici pati o n i n t his cli nical st u d y.  
□ 
•  Dia g n ose d or treate d f or a n ot her mali g na nc y wit hi n 3 years of re gistrati o n, wit h t he e xce pti o n of 
c o m plete resecti o n of basal cell carci n o ma or s q ua m o us cell carci n o ma of t he s ki n, a n i n sit u 
mali g na nc y, or l o w- ris k pr ostate ca ncer after c urati ve t hera p y. □ 
•  C N S i n v ol ve me nt wit h l y m p h o ma.  □ 
•  K n o w n HI V - p ositi ve. □ 
•  Hist or y of disease refract or y t o a p uri ne a nal o g ( defi ne d as re missi o n d urati o n of < 6 m o nt hs t o 
t hera p y t hat i ncl u de d fl u dara bi ne, pe nt ostati n, or cla dri bi ne). □ 
•  Hist or y of i nt olera nce of b ortez o mi b, cla dri bi ne, or rit u xi ma b.  □ 

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1 0 1  
 
A p pe n di x 8 . 1 4: Pre g n a nc y Re p orti n g F or m  
 
 
 
 
 

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1 0 2  
 
 
 
 

V ersi o n 7: 0 8/ 1 5/ 2 0 1 7  
1 0 3  
 
 
 

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1 0 4