Clinical trial NCT00980395
Conditions: Lymphoma Mantle Cell Lymphoma Indolent Lymphoma SLL
Keywords: recurrent mantle cell lymphoma stage III mantle cell lymphoma stage IV mantle cell lymphoma recurrent marginal zone lymphoma stage III marginal zone lymphoma stage IV marginal zone lymphoma Waldenstrom macroglobulinemia recurrent small lymphocytic lymphoma stage III small lymphocytic lymphoma stage IV small lymphocytic lymphoma recurrent grade 1 follicular lymphoma recurrent grade 2 follicular lymphoma recurrent grade 3 follicular lymphoma stage III grade 1 follicular lymphoma stage III grade 2 follicular lymphoma stage III grade 3 follicular lymphoma stage IV grade 1 follicular lymphoma stage IV grade 2 follicular lymphoma stage IV grade 3 follicular lymphoma extranodal marginal zone BCL mucosa assoc lymphoid tissue nodal marginal zone B Cell lymphoma splenic marginal zone lymphoma
Sponsor: University of Arizona
Start date: 2009-07-07; Completion date: 2018-08-14
Enrollment: 24 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
RATIONALE: Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cladribine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Giving bortezomib together with cladribine and rituximab may kill more cancer cells.

PURPOSE: This phase II trial is studying how well giving bortezomib together with cladribine and rituximab works in treating patients with advanced mantle cell lymphoma or indolent lymphoma.

Detailed description:
OBJECTIVES:

Primary

* Determine the 2-year progression-free survival of patients with advanced mantle cell lymphoma or indolent lymphoma treated with bortezomib, cladribine, and rituximab.

Secondary

* Determine the 2-year overall survival of patients treated with this regimen.
* Determine the complete response and overall response rate in patients treated with this regimen.
* Describe the long- and short-term toxicity of this regimen in these patients.
* Determine the prognostic importance of Aurora kinase A in patients treated with this regimen.
* Determine the cytokine profiles for each lymphoma subtype and how they change with this regimen.
* Evaluate the prognostic importance of major carcinogenic pathways using tissue microarray.

OUTLINE: Patients receive bortezomib IV on days 1 and 4, cladribine IV over 2 hours on days 1-5, and rituximab IV on day 1. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Blood samples are collected at baseline and after course 1 for cytokine profile studies. Previously collected tissue samples are obtained for analysis of Aurora kinase A and B, Ki-67, cyclin D, Bcl-2, phosphor-HisH3, c-Met, and VEGF expression by using tissue microarray (IHC staining), reverse transcriptase-PCR, and/or western blotting.

After completion of study therapy, patients are followed up every 3 months for 2 years.

Arms: arm 1: * Rituximab 375 mg/m2 IV day1
* Cladribine 4 mg/m2 IV over 2 hours days 1-5
* Bortezomib 1.3 mg/m2 IV days 1 and 4
* Repeat every 28 days for a maximum of 6 cycles
Interventions: intervention 1: rituximab intervention 2: bortezomib intervention 3: cladribine
Intervention descriptions: intervention 1: 375 mg/m2 IV Day 1. Repeat every 28 days for a maximum of 6 cycles. intervention 2: 1.3 mg/m2 IV Days 1 and 4. Repeat every 28 days for a maximum of 6 cycles. intervention 3: 4 mg/m2 IV over 2 hours Days 1-5. Repeat every 28 days for a maximum of 6 cycles.

Protocol documents:
Prot_SAP_000.pdf: 
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  
2 
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.  
 


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


Versi o n 7 :  0 8/ 1 5 / 2 0 1 7  
4 
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.  


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


Versi o n 7 :  0 8/ 1 5 / 2 0 1 7  
6 
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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7 
 
 
 
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 
 


Versi o n 7 :  0 8/ 1 5 / 2 0 1 7  
8 
A B B R E VI A TI O N S LI S T  
 


Versi o n 7 :  0 8/ 1 5 / 2 0 1 7  
9 
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  


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


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


Versi o n 7 :  0 8/ 1 5 / 2 0 1 7  
1 3  
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 


Versi o n 7 :  0 8/ 1 5 / 2 0 1 7  
1 4  
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. 


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


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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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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. 


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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  


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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.   


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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  


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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.  


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2  S T U D Y O B J E C TI V E S  
2. 1  Pri m ar y O bjecti 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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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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5 0  
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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5 1  
 
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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5 4  
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 


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


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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) 


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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 


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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 


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


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


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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  
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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) 


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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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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  
 
 
 
 


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1 0 4