A Phase I/II Study of Carfilzomib in Combination With R-CHOP (CR-CHOP) for Patients With Diffuse Large B-cell Lymphoma
Phase: PHASE1
Conditions: Contiguous Stage II Adult Diffuse Large Cell Lymphoma, Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma, Stage I Adult Diffuse Large Cell Lymphoma, Stage III Adult Diffuse Large Cell Lymphoma, Stage IV Adult Diffuse Large Cell Lymphoma
Sponsor: Case Comprehensive Cancer Center

C A S E 3 4 1 3  C R -C H O P  
                 
Pr ot oc ol Versi o n 2 0 0 9/ 0 1/ 2 0 2 3  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
          
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
C A S E 3 4 1 3  C R -C H O P  
Pr ot oc ol Versi o n   
 
 
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 1. 2. 1  Pre- cli nical dat a  
  
 1. 2. 2  Cli nical data 
  
 1. 2. 3  Cli nical p har mac o ki netics 
1. 3  R- C H O P  
  
 1. 3. 1  Pre- cli nical dat a  
  
 1. 3. 2  Cli nical data 
  
 1. 3. 3  Cli nical p har mac o ki netics 
1. 4  Rati o nale   
 
 
2. 0 
O B J E C TI V E S  
2. 1  Pri mar y O bjecti ve  ( P hase I)  
2. 2  Sec o n dar y O bj ecti ve ( P hase II)  
  
3. 0  
S T U D Y D E SI G N  
3. 1  St u d y Desi g n I ncl u di n g D ose E scalati o n /C o h orts 
3. 2  N u m ber of S u bjects 
3. 3  Re place me nt of S u bj ects  
3. 4  E x pecte d D urati o n of S u bject Partici pati o n 
 3. 4. 1  D urati o n of thera p y  
 3. 4. 2  D urati o n of f oll o w- u p 
 
4. 0  
P A TI E N T S E L E C TI O N  
4. 1  I n cl usi o n Criteria 
4. 2  E xcl usi o n Criteria  
4. 3  I n cl usi o n of W o me n a n d Mi n orities  
 
5. 0 
R E GI S T R A TI O N  
 
 
6. 0  
T R E A T M E N T P L A N  
6. 1   A ge nt A d mi nistrati o n  
 6. 1. 1 Carfilz o mi b  
 6. 1. 2  R-C H O P  
 6. 1. 3  Ac ycl o vir 
6. 2   Defi niti o n of D ose- Li miti n g T o xicit y  
6. 3  D ose Escal ati o n  
6. 4  D urati o n of T hera p y ( See Secti o n 3. 4. 1) 
6. 5  D urati o n of F oll o w- u p ( See Secti o n 3. 4. 2) 
 
7. 0 
D O S E D E L A Y S / D O S E M O DI FI C A TI O N S  
7. 1  He mat ol o gic T o xicit y  
7. 2  N o n- He mat ol o gic T o xicit y  
  
 7. 2. 1  Ne ur o pat h y 
  
 7. 2. 2  He m orr ha gi c c ystitis 
  
 7. 2. 3  He patic t o xicit y 

 
 
 
 
 
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 7. 2. 4  Rit u xi ma b h y perse nsiti vit y /i nf usi o n reacti o ns 
 7. 2. 5  N o n -He mat ol o gic t o xicit y attri b uta ble t o d o x or u bici n a n d/ or 
c ycl o p h os p ha mi de , e x cl u di n g s us pecte d ca rfilz o mi b t o xicit y, 
ne ur o pat h y, rit u xi ma b reacti o ns a n d he m orr h a gic c ystitis. 
 
8. 0 
A D V E R S E E V E N T S: LI S T A N D R E P O R TI N G R E Q UI R E M E N T S  
8. 1   A d verse E v e nts a n d P ote ntial Ris k List  
 8. 1. 1  Carfilz o mi b  
 8. 1. 2  C ycl o p h os p ha mi de 
 8. 1. 3  D o x or u bici n 
 8. 1. 4  Pe gfil grasti m  
 8. 1. 5  Pre d nis o ne 
 8. 1. 6  Rit u xi ma b  
  
       8. 1. 7  Vi ncristi ne   
  
       8. 1. 8  Ac ycl o vir 
  
       8. 1. 9 Use of c o ntr ace pti o n – Fe males  
             8. 1. 1 0 Use of c o ntrace pti o n - Mal es  
 
8. 2  Defi niti o ns  
  
 8. 2. 1  A d verse E v e nts  ( A Es) 
  
 8. 2. 2  Si g nifica nce of a n A E  
  
 8. 2. 3  Seri o us A d verse E ve nts ( S A Es) 
  
 8. 2. 4  E x pecte d ness  
  
 8. 2. 5  Attri b uti o n  
8. 3  Re p orti n g Pr oce d ures f or All A d vers e E ve nts 
8. 4  Seri o us A d verse E v e nt Re p orti n g Pr oce d ures 
  
 8. 4. 1  Re p orti n g 
  
 8. 4. 2  F D A Re p orti n g 
  
 8. 4. 3  M ulti -Ce nter Trials  
8. 5  Data Safet y T o xi cit y C o m mittee   
  
 
 
9. 0 
P H A R M A C E U TI C A L I N F O R M A TI O N  
9. 1  Carfilz o mi b  
 
9. 2  C ycl o p h os p ha mi de 
9. 3  D o x or u bici n 
9. 4  Pe gfil grasti m 
9. 5  Pre d nis o ne 
9. 6  Rit u xi ma b 
9. 7  Vi ncristi ne 
9. 8  Ac ycl o vir 
 
1 0. 0 
C O R R E L A TI V E S T U DI E S  
   
1 0. 1  Ge ne E x pr essi o n Pr ofili n g 1 0. 1. 1  Bac k gr o u n d 
      
  
         1 0. 1. 1. 1   C O O i n D L B C L defi ne d b y Ge n e E x pressi o n Pr ofili n g  

 
 
 
 
 
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         1 0. 1. 1. 2   C orrelati o n of C O O wit h cli nical o utc o mes of D L B C L  
 
 1 1. 0  
S T U D Y P A R A M E T E R S A N D C A L E N D A R  
    
     1 1. 1  St u d y Para meters  
  
  1 1. 1. 1   Scree ni n g e v al uati o n 
  
  1 1. 1. 2   Treat me nt peri o d 
    
     1 1. 2  Cale n dar  
 
 1 2. 0   
R E S P O N S E A S S E S M E N T  
               1 2. 1  A nti -t u m or Effect – H e mat ol o gic T u m ors  
  
   1 2. 1. 1   C o m plete re missi o n ( C R)  
  
   1 2. 1. 2   Partial re missi o n ( P R)  
  
   1 2. 1. 3   Sta ble d disease ( S D)  
  
   1 2. 1. 4   Pr o gressi ve disease ( P D)  
              1 2. 2  Defi niti o n of Ti me Peri o ds 
  
   1 2. 2. 1   D urati o n of res p o nse 
  
   1 2. 2. 2   Disease-free s ur vi val 
  
   1 2. 2. 3   Disease-s p ecifi c s ur vi val 
  
   1 2. 2. 4   Pr o gressi o n-free s ur vi val 
  
   1 2. 2. 5   Ti me t o pr o gressi o n 
  
   1 2. 2. 6   Ti me t o treat me nt fail ure 
              1 2. 3  Res p o nse Re vie w 
 
 1 3. 0   
R E C O R D S T O B E K E P T/ R E G U L A T O R Y C O N SI D E R A TI O N S  
      1 3. 1  Data Re p orti n g  
      1 3. 2  Re g ulat or y C o nsi derati o ns  
  
   1 3. 2. 1   Writte n i nf or m e d c o nse nt 
  
   1 3. 2. 2   S u bject data pr otecti o n 
  
   1 3. 2. 3   Rete nti o n of rec or ds 
  
   1 3. 2. 4   A u dits a n d i ns pecti o ns 
  
   1 3. 2. 5   Data saf et y a n d m o nit ori n g pla n 
1 4. 0   S T A TI S TI C A L C O N SI D E R A TI O N S  
 
R E F E R E N C E S  
 
A P P E N DI X A  
E C O G Stat us Criteria   
 
A P P E N DI X B  
I W G Res p o nse Criteria 
 
A P P E N DI X C  
S A E Tra ns mittal C o ver S heet  
 

 
 
 
 
 
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A P P E N DI X D 
C o m pre he nsi ve List of Pr ot oc ol C ha n ges 
  
  
 
  
 
  
 

 
 
 
 
 
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1. 0 
I N T R O D U C TI O N    
 
1. 1  
Diff use L ar ge B -C ell L y m p h o m a  
 
Diff use lar ge B -cell l y m p h o ma ( D L B C L) is t he m ost c o m m o n t y pe of 
l y m p h o ma.   Alt h o u g h  c o m bi nati o n  of  t he  a nti-C D 2 0  m o n ocl o nal  a nti b o d y  
rit u xi ma b wit h 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 ( R-
C H O P) us uall y res ults i n c o m plete re missi o ns, ma n y patie nts rela pse or fail t o 
res p o n d  t o  i nitial  t hera p y.   T he  1 – year  pr o gressi o n  free  s ur vi val  ( P F S)  is  
a p pr o xi matel y 8 0 % f or all patie nts treate d wit h R -C H O P   [1 ].   H o we ver, the 
heter o ge n eit y of cli nical o utc o me de pe n ds o n a n u m ber of h ost fact ors b ut ca n n ot 
be relia bl y pr e dicte d bas e d o n c o n ve nti o nal t u m or hist ol o g y.  
 
At least t w o se parate s u b gr o u ps of D L B C L base d o n cell - of-ori gi n ha ve 
bee n i de ntifie d b y  g e ne e x pressi o n pr ofili n g: t h ose deri ve d fr o m t he ger mi nal 
ce nter ( G C) a n d t h os e d eri ve d fr o m acti vate d B -cells ( A B C) [2 ].  Patie nts wit h 
D L B C L dis pla yi n g t he A B C p he n ot y pe ha ve i nferi or s ur vi val t ha n t h ose wit h t he 
G C s u bt y pe  [1 , 3 , 4 ].    S pecificall y, t he 1 -year P F S f or p atie nts wit h t he A B C 
p he n ot y pe of D L B C L is a p pr o xi matel y 6 0 %, c o m pare d t o a p pr o xi matel y 8 5 % 
f or t h ose wit h t he G C s u bt y pe [1 ]. 
 
Se veral  dia g n ostic  i m m u n o hist oc he mical  (I H C)  al g orit h ms pr o vi de 
esti mates of cell- of-ori gi n.  T he m ost wi del y use d a p pr oac h is t he Ha ns al g orit h m 
w hic h  has  reas o na ble  c o nc or da n ce  wit h  ge ne  e x pressi o n  pr ofili n g   [5 , 6 ].  
H o we ver, beca use of vari a bilit y a n d lac k of re pr o d uci bilit y f or I H C al g orit h ms t o 
pre dict cli nical  o utc o me, a  sta n dar dize d test (M O D A P L E X
®  S yste m) t o assi g n 
cell of ori gi n fr o m paraffi n  e m be d de d tiss ue is i n de vel o p me nt at t he Cle v ela n d 
Cli nic i n c olla b orati o n wit h Pri mera Dia g n ostics  [7 ].    
 
T he reas o ns f or t he differe nce i n o utc o mes b et wee n s u bt y pes of D L B C L are 
li kel y relate d t o c o nstit uti ve acti vati o n of N K-κ B p at h wa ys i n t he A B C s u b gr o u p 
of D L B C L   [8- 1 0 ]. I n a d diti o n, acti vate d N K -κ B ma y c o ntri b ute t o rit u xi ma b 
resista nce a n d ma y re pr es e nt a t hera pe utic tar get [1 1 ].  T he pr oteas o me i n hi bit ors 
b ortez o mi b a n d carfilz o mi b are a n i m p ort a nt ne w class of a ntica ncer a ge nts t hat 
ha ve si g nifica nt cli nical acti vit y i n m ulti ple m yel o ma as w ell as n o n - H o d g ki n’s 
l y m p h o ma.  Pr oteas o me i n hi bit ors li kel y act b y ma n y mec h a nis ms i ncl u di n g t he 
i n hi biti o n of p h os p h or ylate d Iκ B de gra dati o n, res ulti n g i n i n hi biti o n of N K- κ B.  
 
B ortez o mi b is F D A -a p pr o ve d f or pre vi o usl y treat e d ma ntle cell l y m p h o ma 
a n d has bee n teste d i n c o m bi nati o n wit h c he m oi m m u n ot hera p y f or D L B C L i n 
b ot h t he u pfr o nt a n d rela pse d setti n g.  I n a trial fr o m t he Nati o nal Ca ncer I nstit ute, 
b ortez o mi b was c o m bi ne d wit h d ose -a dj uste d i nf usi o nal et o p osi de, vi ncristi ne, 
d o x or u bici n, c ycl o p h os p ha mi de  a n d  pre d nis o ne  ( d ose -a dj uste d  E P O C H)  f or  
patie nts wit h rela pse d/r efract or y D L B C L  [1 2 ].  I n t his st u d y, a hi g her res p o nse 
a n d me dia n o v erall s ur vi val was o bser ve d i n t h e A B C c o m pare d t o t he G C  
s u bt y pe.  T he safet y a n d efficac y of b ortez o mi b i n c o m bi nati o n wit h R -C H O P i n 
treat me nt-naï ve l y m p h o ma patie nts was e v al uate d i n a p hase I st u d y t hat s h o we d 
t hat t his c o m bi nati o n was effecti ve a n d free of si g nifica nt si de effects.   [1 3 ]  I n 
a  se parat e  st u d y,  p atie nts  wit h  ne wl y -dia g n ose d  A B C  D L B C L  treate d  wit h  

 
 
 
 
 
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1 0  
b ortez o mi b i n c o m bi nati o n wit h R -C H O P ha d e q ui vale nt pr o gressi o n -free a n d 
o verall s ur vi val r elati ve t o t h ose wit h t he G C s u bt y pe  s u g gesti n g t hat a d diti o nal 
a nti-ca ncer acti vit y pr o vi de d b y b ortez o mi b o verca me t he hi g her ris k feat ures of 
t he A B C s u bt y pe [1 4 ]. 
 
1. 2  
C arfilz o mi b  
Carfilz o mi b is a n irre v ersi ble pr otea s o me i n hi bit or.  Pr oteas o me i n hi biti o n 
lea ds t o t he acc u m ulati o n of p ol y u bi q uiti nate d pr otei n s u bstrates wit hi n cells 
a n d t o t he selecti ve i n d ucti o n of a p o pt osis i n mali g na nt cells w hile s pari n g n o n-
mali g na nt cells.  
 
T he cli nical de vel o p me nt of carfilz o mi b has t h us far f oc use d as m o n ot hera p y 
pri maril y o n patie nts wit h rela pse d a n d refract or y m ulti ple m yel o ma ( M M)  w h o ha ve 
fe w t hera pe utic o pti o ns. I n a d diti o n, carfilz o mi b is bei n g e val uat e d as a c o m p o ne nt 
of c o m bi nati o n t hera p y wit h le nali d o mi de treat me nt i n earlier li nes of t hera p y f or 
patie nts wit h m ulti ple m yel o ma.  
 
T here is ver y l o w i nci d e nce of cli nicall y si g nifica nt ne ur o pat h y i n p atie nts 
treate d wit h carfilz o mi b, li kel y d ue t o e n ha nce d tar get selecti vit y i n viv o  [1 5 ].  A 
ma xi m u m t olerate d d ose ( M T D) of carfilz o mi b w as n ot f or mall y i de ntifie d i n p hase 
I t esti n g, s u g gesti n g t hat e n ha nce d a nti-t u m or effect wit h o ut d ose-li mite d t o xicit y 
acc o u nt f or t he cli nical acti vit y i n carfilz o mi b i n b ortez o mi b -refract or y pati e nts.   
 
O n 2 0 J ul y 2 0 1 2, K y pr olis ™ (carfilz o mi b) f or I njecti o n was a p pr o ve d u n der 
t he F o o d a n d Dr u g A d mi nistrati o n ( F D A) accelerate d a p pr o val  pr o gra m  f or t he 
treat me nt of patie nts wit h m ulti ple m yel o ma w h o ha ve recei v e d at least t w o pri or 
t hera pies,  i ncl u di n g  b ortez o mi b  a n d  a n  i m m u n o m o d ulat or y  a ge nt,  a n d  ha ve  
de m o nstrate d diseas e pr o gressi o n o n or wit hi n 6 0 da ys of c o m pleti o n of t he last 
t hera p y.  
 
1. 2. 1  Pre -cli nical D ata  
 
Carfilz o mi b (f or m erl y P R -1 7 1) is a tetra pe pti de e p o x y ket o ne-bas e d irre versi ble 
i n hi bit or  of  t he  c h y m otr y psi n-li ke  ( C T-L)  acti vit y  of  t he  2 0 S  pr oteas o me.   
Carfilz o mi b i n d uces a d ose- de pe n d e nt s u p pressi o n of pr ot eas o me C T- L acti vit y i n a 
wi de ra n ge of tiss ues ( wit h t he e xce pti o n of brai n) i n e x peri me ntal a ni mals. I n hi biti o n 
of pr oteas o me C T -L acti vit y was c o m para ble i n w h ole bl o o d a n d peri p heral bl o o d 
m o n o n uc lear cells ( P B M Cs).  
 
I n  vitr o e x peri me nts  wit h  c o nti n u o us  ( 7 2 -h o ur)  e x p os ure  t o  carfilz o mi b  
de m o nstrate p ote nt pr o -a p o pt otic acti vit y acr oss a br oa d pa nel of t u m or -deri ve d cell 
li nes i n c ult ure i ncl u di n g b ortez o mi b-resista nt t u m or cell li nes. I nc u b ati o n of t u m or 
cell li nes wit h carfilz o mi b f or as little as 1 h o ur ( mi mic ki n g i nter mitte nt i ntra ve n o us 
[I V] a d mi nistrati o n) lea ds t o ra pi d i n hi biti o n of pr oteas o me acti vit y, f oll o we d b y 
acc u m ulati o n of p ol y u bi q uiti nate d pr otei ns a n d i n d ucti o n of a p o pt otic cell deat h. 
U n der t hes e c o n diti o ns, c arfilz o mi b has little effect o n n or mal ( n o n- mali g na nt ) cells, 
w hic h c orrelat es wit h l o w i nci de nce, b ot h i n a ni mals a n d h u ma ns, of si de effects s uc h 
as m yel os u p pressi o n a n d al o pecia t hat are see n wit h ma n y a ntica ncer t hera pies.  

 
 
 
 
 
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Direct  a nti -t u m or efficac y  has  b ee n  teste d  i n  i m m u n oc o m pr o mise d  mice  
i m pla nte d wit h a variet y of t u m or cell li nes. I n a h u ma n c ol orectal a d e n ocarci n o ma 
m o del,  a d mi nistrati o n  of  carfilz o mi b  o n  a  t wi ce -wee kl y  D a y  1/ Da y  2  sc he d ule  
res ulte d i n si g nifica nt re d ucti o n i n t u m or size a n d was s u peri or t o a t wice - wee kl y 
Da y 1/ Da y 4 sc h e d ule, a n d a o nce- wee kl y d osi n g sc he d ule.  
 
N o n -cli nical re p eat-d ose t o xicit y st u dies were perf or me d i n rats a n d m o n ke ys 
usi n g 2 differe nt d ose sc h e d ules. I nitiall y, I n v esti gati o nal Ne w Dr u g (I N D) -e na bli n g 
2 8- da y  t o xicit y  st u dies  were  c o n d ucte d  usi n g  a  1 4 -da y  c y cle  wit h  carfilz o mi b  
a d mi nistere d as a n I V b ol us d ose d dail y f or 5 da ys ( o nce d ail y x 5) wee kl y f oll o we d 
b y a 9 -da y rest peri o d. S u bse q ue ntl y, I nter n ati o nal C o nfere nce o n Har m o nisati o n 
(I C H)-c o m plia nt,  Ne w  Dr u g  A p plicati o n/  Mar keti n g  A ut h orisati o n  A p plicati o n  
( N D A/ M A A)-e n a bli n g 6 -a n d 9- m o nt h c hr o nic t o xicit y st u dies i n rats a n d m o n ke ys, 
res pecti vel y, wer e c o n d u cte d usi n g a 2 8-da y sc he d ule i n w hic h carfilz o mi b was gi ve n 
dail y d osi n g f or 2 d a ys ( o nce d ail y x 2) wee kl y f or 3 wee ks f oll o we d b y a 1 2 -da y rest 
peri o d; usi n g t his sc he d ule, t he d ose- li miti n g t o xicities  
( D L Ts) w ere car dio vasc ular a n d g astr oi ntesti nal.  I n t he i nitial 2 8-da y st u dies, as well 
as i n t he c hr o ni c 6 -a n d 9-m o nt h st u dies, t o xicit y was o bser ve d i n t he gastr oi ntesti nal 
tract, b o ne marr o w, a n d p ul m o nar y a n d car di o v asc ular s yste ms. At t he ma xi m u m 
t olerate d d oses ( M T Ds) i n all st u dies, a tra nsi e nt c yclical t hr o m b oc yt o pe nia wit h o ut 
a l oss of me ga kar y oc ytes was t he m ost pr o mi ne nt he mat ol o gic t o xicit y. I m p orta ntl y, 
peri p her al ne ur o p at h y ( P N; be ha vi o ural a n d hist o pat h ol o gic ) a n d m y el os u p pressi o n 
( ne utr o pe nia a n d se vere a ne mia) w ere n ot o bser v e d. 
 
T he eff ect of a d mi nistrati o n ti me ( b ol us vs . i nf usi o n) o n t he t olera bilit y of 
carfilz o mi b was assess e d i n rats. W he n a d mi nistere d as a n I V b ol us ( < 2 0 sec o n d 
p us h), a d ose of 8 m g/ k g res ulte d i n m ortalit y i n 5 0 % of t he a ni mals a n d was 
ass ociate d wit h d ys p nea, let har g y, a n d i ncreas e d bl o o d urea nitr o ge n ( B U N) a n d 
creati ni ne ( c o nsiste nt wit h pre -re n al az ote mia) i n t he s ur vi vi n g a ni mals. A 3 0 -mi n ute 
I V i nf usi o n of t he sa me d ose was well t olerate d wit h o ut si g nifica nt si g ns of t o xicit y 
or c ha n ges i n B U N a n d creati ni ne. Pr oteas o me i n hi biti o n was e q ui vale nt bet wee n 
b ol us a n d i nf usi o n gr o u ps. 
 
1. 2. 2  Cli nical D ata 
 
T he  F D A a p pr o v al of carfilz o mi b was b ase d o n t h e res ults of t he P hase 2 P X -
1 7 1- 0 0 3- A 1 st u d y. Initial P hase 1 safet y, p har mac o ki netic ( P K ), p har mac od y na mic 
( P D), a n d d ose fi n di n g st u dies (t otal patie nts = 7 7) e xa mi ne d 2 differe nt sc h e d ules of 
carfilz o mi b a d mi nistrati o n i n patie nts wit h he mat ol o gic mali g na ncies ( M M [ n = 3 8], 
n o n- H o d g ki n  l y m p h o ma  [ N H L],  Wal d e nstr ö m  macr o gl o b uli ne mia  [ W M],  a n d  
H o d g ki n  l y m p h o ma).  St u d y  P X - 1 7 1-0 0 1,  a  d os e -escalati o n  trial,  assess e d  dail y  
d osi n g o nce dail y x 5 of carfilz o mi b wit hi n Wee k  1 of a 2 -wee k c ycl e at d ose le vels 
of 1. 2 m g/ m 2 t o 2 0 m g/ m2 f or at least 8 wee ks i n 2 9 patie nts. T he M T D was 1 5 m g/ m 2. 
D ose -Li miti n g  T o xicities ( D L Ts) w ere o bser v e d i n 2 of 5 p atie nts e nr olle d i n t he 2 0 
m g/ m 2 c o h ort: Gra de 3 f e brile ne utr o p e nia a n d Gra de 4 t hr o m b oc yt o p e nia.  
 
St u d y P X - 1 7 1-0 0 2 was prese nte d i n 2 se parate st u d y re p orts: St u d y P X - 1 7 1-
0 0 2 ( Part 1) i ncl u de d 3 7 patie nts ( 2 1 wit h M M) w h o u n der we nt se q u e ntial d ose -

 
 
 
 
 
C A S E 3 4 1 3  C R -C H O P  
Pr ot oc ol Versi o n   
 
 
1 2  
escalati o n of carfilz o mi b a d mi nistere d o n ce dail y x 2 o ver a 2 8 -da y c ycle. Alt h o u g h 
3 patie nts, eac h at a differ e nt d ose le vel e x perie nce d D L Ts (re n al fail ure, fati g ue, a n d 
h y p o xia) as defi n e d i n t h e pr ot oc ol, n o d ose le v el (t hr o u g h 2 7 m g/ m 2) met t he criteria 
f or t he M T D of carfilz o mi b. H o we ver, bas e d o n t he t otalit y of t he safet y i nf or mati o n 
a vaila ble at t hat p oi nt i n ti me, i ncl u di n g re p orts of s y m pt o ms s uc h as fe v er, c hills, 
ri g ors, or d ys p nea f oll o wi n g d osi n g i n s o me patie nts, f urt her d ose es calati o n was n ot 
p urs ue d at t hat ti me.  
 
St u d y P X - 1 7 1-0 0 2 ( Part 2) i ncl u de d 1 1 p atie nts wit h refract or y m ali g na ncies 
( 7 wit h M M) w h o recei ve d eit her si n gle-a ge nt carfilz o mi b ( 2 0 m g/ m 2 escalati n g t o 
2 7  m g/ m 2 after  C ycle  1  [ 2 0/ 2 7  m g/ m 2])  or  carfilz o mi b  ( 2 0/ 2 7  m g/ m2)  wit h  
de xa met has o ne
 ( 4 0
 m g/ w k).
 O ne
 of
 t he
 1 1
 p atie nts,
 i n
 t he
 
carfilz o mi b/ de xa m et has o ne gr o u p e x p erie n ce d a D L T of Gra de 3 li ver f u ncti o n test 
a b n or malities  (as partat e  a mi n otra nsferas e  [ A S T]  a n d  ala ni ne  a mi n otra nsferase  
[ A L T]). H o we v er, t h e pr ot oc ol-s pecifie d defi niti o n of t he M T D (i.e., a d os e i n w hic h 
= 1 7 % of p atie nts e x p erie nce d a D L T) was n ot reac he d. T heref ore, t h e re gi me n 
selecte d f or f urt her st u d y was a “ste p p e d-u p ” d osi n g sc he d ule of 2 0 m g/ m 2 i n C ycle 
1 f oll o we d b y 2 7 m g/ m 2 t hereafter (referre d t o as t he 2 0/ 2 7 m g/ m2 d ose).  
 
W hile P hase 1 st u dies were desi g ne d pri maril y t o assess safet y, efficac y was 
assesse d as a sec o n d ar y o bjecti ve i n b ot h P hase 1 st u dies a n d d ura bl e t u m or res p o nses 
meeti n g I nter n ati o nal M yel o ma W or ki n g Gr o u p (I M W G) a n d E ur o p ea n Gr o u p f or 
Bl o o d a n d Marr o w Tra ns pla ntati o n ( E B M T) criteria were o bser ve d d uri n g t his earl y 
p hase  of  testi n g.  I n  St u d y  P X - 1 7 1-0 0 1,  2  of  9  patie nts  wit h  m ulti ple  m yel o ma  
ac hie ve d a n o bjecti ve r es p o nse ( 1 partial res p o ns e [ P R], 1 mi ni mal res p o nse [ M R]) 
w hile recei vi n g carfilz o mi b 1 1 m g/ m 2 a n d 1 5 m g/ m 2, res pecti vel y. I n St u d y P X- 1 7 1-
0 0 2, prese nt e d i n St u d y Re p ort P X - 1 7 1-0 0 2 ( Part 1), res p o nses of M R or b etter w ere 
o bser ve d i n 5 of 2 1 patie nts wit h m ulti ple m yel o ma, at d oses of 1 5 m g/ m 2 ( n = 1), 2 0 
m g/ m 2 ( n = 1), a n d 2 7 m g/ m2 ( n = 3). I n St u d y P X- 1 7 1- 0 0 2, prese nte d i n St u d y Re p ort 
P X - 1 7 1-0 0 2 ( Part 2), t here were res p o nses i n 3 of 9 e val ua ble patie nts: 2 wit h P R i n 
t he
 si n gle-a ge nt
 carfilz o mi b
 gr o u p
 a n d
 1
 wit h
 a n
 M R
 i n
 t he
 
carfilz o mi b/ de xa m et has o ne gr o u p. Base d u p o n t he ke y safet y, P K/ P D, a n d effic ac y 
fi n di n gs, al o n g wit h t he o bser vati o n of > 8 0 % pr oteas o me i n hi biti o n at hi g her d ose 
le vels of carfilz o mi b, t he o nce dail y x 2 s c he d ul e at a d ose of 2 0/ 2 7 m g/ m2 was 
selecte d f or f urt her testi n g i n P hase 2.  
 
A d diti o nal  safet y  meas ures  base d  o n  i nf or m ati o n  fr o m  o n g oi n g  cli nical  
carfilz o mi b st u dies  were i nstit ute d i n later st u dies, i ncl u di n g t u m or l ysis s y n dr o me 
( T L S) pr o p h yla xis usi n g h y drati o n a n d a d mi nistrati o n of all o p uri n ol. All patie nts 
were t o r ecei v e de x a met has o ne  ( 4 m g orall y [ P O]) pri or t o eac h d os e of carfilz o mi b 
i n C ycle 1, a n d as nee de d i n s u bse q ue nt c ycles, t o miti gate p ossi ble a d verse e ve nts 
( A Es) te m p orall y ass oci ate d wit h d osi n g.  T hese A Es ma y i ncl u de e ve nts si milar t o 
c yt o ki ne releas e a n d are n ota ble f or fe ver, c hills, d ys p nea, a n d ri g ors occ urri n g m ost 
c o m m o nl y i n t he e ve ni n g f oll o wi n g t he first or s ec o n d  i nf usi o n d uri n g t he first c ycle 
of t hera p y or t he first escalati o n c ycle of t h era p y. T he re gi me n  of carfilz o mi b of 2 0/ 2 7 
m g/ m 2 o n a o nce dail y x 2 d osi n g sc he d ule, i n c o ncert wit h de xa met has o ne a n d T L S 

 
 
 
 
 
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1 3  
pr o p h yla xis, a p peare d t o per mit safe d osi n g d uri n g t he first c ycle, as  w ell as d ose -
escalati o n i n s u bse q ue nt c ycles f or p ossi ble great er efficac y.  
 
T he ke y P hase 2 st u d y of carfilz o mi b as m o n ot h era p y is St u d y P X - 1 7 1- 0 0 3, 
c o n d ucte d  i n  patie nts  wit h  rela pse d  a n d  refract or y  m ulti ple  m yel o ma  w h o  ha d  
recei v e d pri or b ortez o mi b a n d a n i m m u n o m o d ulat or y dr u g (I Mi D) a g e nt. T his st u d y 
has bee n pres e nte d i n 2 r e p orts:  St u d y re p ort P X - 1 7 1- 0 0 3 – Part 1 ( A 0) prese nte d 
t he pil ot st u d y ( n = 4 6), w hic h i ncl u de d I V carfil z o mi b a d mi nistere d at d oses of 2 0 
m g/ m 2 t hr o u g h o ut (alt h o u g h 3 patie nts c o nti n ui n g o n st u d y at t he ti me of A me n d me nt 
1 were per mitte d t o d ose-escalate t o 2 7 m g/ m 2 i n later c y cles); a n d St u d y re p ort P X-
1 7 1- 0 0 3 – Part 2 ( A 1) re p ort prese nte d t he pi v otal st u d y desi g ne d t o s u p p ort  i nitial 
U S re gistrati o n ( n = 2 6 6) w hic h i ncl u de d carfilz o mi b a d mi nistere d i n  t he ste p pe d- u p 
re gi me n ( 2 0/ 2 7 m g/ m2).  T he 2 re p orts of St u d y P X- 1 7 1-0 0 3 i ncl u de d si milar patie nt 
p o p ulati o ns, e nr olli n g patie nts  wit h a n u n met me dical nee d b y virt ue of ha vi n g bee n 
refr act or y t o t h eir last pri or re gi me n a n d ha vi n g pre vi o usl y recei ve d t he a vaila ble 
a nti-m yel o ma  t hera pies. 
  
In a d diti o n, P hase 2 St u d y P X - 1 7 1-0 0 4 pr o vi des a d diti o nal s u p p orti ve data t hat 
f urt her c h aracteri ze t he s afet y a n d efficac y pr ofile of carfilz o mi b i n patie nts w h o are 
less hea vil y pre -treat e d a n d w h o ma y n ot be refract or y. T his st u d y has bee n prese nte d 
i n 2 re p orts:  . P X- 1 7 1- 0 0 4  – Part 1 re p ort i ncl usi ve of patie nts wit h rel a pse d or 
refr act or y  m ulti ple m yel o ma  w h o  ha d  recei ve d  n o  m ore  t ha n  3  pri or  t hera pies,  
i ncl u di n g b ortez o mi b( n = 3 5), a n d . P X- 1 7 1- 0 0 4 – Part 2 re p ort i n cl usi ve of patie nts 
w h o wer e b ort ez o mi b- naï ve ( n = 1 2 7).  T o f urt her c haract erize t he d urati o n of cli nical 
be nefit,  e xte nsi o n  St u d y  P X - 1 7 1-0 1 0  was  i nitiate d  t o  all o w  patie nts  w h o  ha d  
c o m plete d ot her carfilz o mi b st u dies t o c o nti n ue t o recei ve  carfilz o mi b treat me nt, t h us 
pr o vi di n g  a d diti o nal  i nf or mati o n  o n  d urati o n  of  efficac y  a n d  o n  safet y . T o 
c haracteri ze t he safet y a n d d osi n g of carfilz o mi b i n patie nts wit h re nal i m pair me nt at  
baseli ne, P hase 2 St u d y P X - 1 7 1-0 0 5 was c o n d ucte d i n 5 0 patie nts a n d 5 c o h orts ( 3 
c o h orts of patie nts wit h decrease d creati ni ne cl eara n ce, 1 c o h ort of p atie nts wit h 
n or mal creati ni ne  cleara n ce, a n d 1 c o h ort of p atie nts o n he m o dial ysis). A carfilz o mi b 
d ose of 1 5 m g/ m 2 o n t he  o nce dail y x 2 sc he d ule w as use d f or C ycle 1, wit h t he o pti o n 
f or d ose- escalati o n t o 2 0 m g/ m2 a n d 2 7 m g/ m2 i n s u bse q ue nt c ycles, as t olerate d. 
 
St u d y P X - 1 7 1-0 0 7 is a n o n g oi n g, acti vel y e nr olli n g st u d y t hat was i nitiall y 
desi g ne d f or  patie nts wit h rela pse d s oli d t u m ors. T he st u d y was a me n de d t o i ncl u de 
t he f oll o wi n g c ha n ges: ( 1) a d diti o n of patie nts wit h rela pse d a n d refract or y m ulti ple 
m yel o ma or  l y m p h o ma; ( 2) e v al uati o n of a 3 0-mi n ute I V i nf usi o n, rat h er t ha n t he 2 
t o 1 0-mi n ute I V  i nf usi o n, of carfilz o mi b ( base d o n a ni mal st u dies s h o wi n g less 
t o xicit y wit h pr ol o n ge d i njecti o n of hi g her d oses); a n d ( 3) e val uati o n of carfilz o mi b 
i n c o m bi nati o n wit h de xa met has o ne. A me n d me nt 2 i ncl u de d a ste p wise i ncreas e i n 
carfilz o mi b d os e o n Da y 8  (i.e., a n accelerate d ste p pe d-u p re gi me n of 2 0 m g/ m 2 o n 
C ycle  1,  Da ys  1  a n d  2  o nl y,  f oll o we d  b y  i ncrease d  d ose  f or  t he  re m ai n der  of  
treat me nt),  a n d  t his  accelerate d  ste p wise  d os e  i ncrease was  mai ntai ne d  f or  
s u bse q ue nt a me n d me nts. Efficac y e n d p oi nts i ncl u de o verall res p o nse rate ( O R R), 
d urati o n of res p o nse ( D O R), pr o gressi o n free s ur vi val ( P F S), a n d ti me t o  pr o gressi o n 
( T T P). 

 
 
 
 
 
C A S E 3 4 1 3  C R -C H O P  
Pr ot oc ol Versi o n   
 
 
1 4  
 
T he pr o misi n g efficac y o bser ve d i n t he m o n ot hera p y pr o gra m s u p p orte d t he 
parallel  de v el o p me nt of carfilz o mi b i n c o m bi nati o n wit h le nali d o mi de a n d l o w- d ose 
de xa met has o ne,  bas e d o n t he h y p ot hesis t h at t his c o m bi nati o n ma y res ult i n t he 
a bilit y  t o  deli ver  o pti mize d  pr oteas o m e  i n hi biti o n  lea di n g  t o  i m pr o ve d  efficac y.  
St u d y P X - 1 7 1-0 0 6, i nitiate d i n J ul y  2 0 0 8, w as a P hase 1 b trial t o assess safet y a n d 
preli mi nar y efficac y of t he c o m bi nati o n  of carfilz o mi b, le nali d o mi de, a n d l o w - d ose 
de xa met has o ne ( 4 0 m g/ wee k) ( C R d), wit h b ot h  carfilz o mi b ( 1 5, 2 0, or 2 0/ 2 7 m g/ m 2) 
a n d le nali d o mi de ( 1 0, 1 5, 2 0, 2 5 m g) escalat e d i n se q ue ntial c o h orts i n p atie nts wit h 
rela pse d m ulti ple m yel o ma. T he pri mar y e n d p oi nt was t he M T D of b ot h carfilz o mi b 
a n d  le nali d o mi de  gi ve n  i n  c o m bi nati o n  wit h  d e xa met has o ne,  a n d  t he  sec o n dar y  
efficac y e n d p oi nts i ncl u de d O R R, D O R, P F S, a n d T T P. After a n i nteri m  safet y 
a nal ysis of 4 0 patie nts ( of a t otal of 8 4 patie nts e nr olle d), a n M T D h a d n ot bee n  
reac h e d. T h e C o h ort 6 re gi me n (carfilz o mi b 2 0/ 2 7 m g/ m2 a n d le nali d o mi de 2 5 m g 
t o get her wit h de x a met has o ne) was select e d f or t h e e x pa nsi o n p h ase of t he st u d y, a n d 
a n a d diti o nal 4 4 patie nts were e nr olle d a n d treate d.  
 
Base d o n t he res ults of t hese earl y -p h ase cli nical trials, a series of P hase 3, 
re gistrati o n e na bli n g trials was i nitiate d. Se veral P hase 3  st u dies i n patie nts wit h 
m ulti ple  m yel o ma  ha ve  bee n  c o m pleti n g  i ncl u di n g  P X - 1 7 1- 0 1 1,a  P hase  3,  
ra n d o mize d,  o pe n-l a bel, m ultice nter st u d y i n patie nts wit h rela pse d a n d refract or y 
m ulti ple m yel o ma, c o m pari n g carfilz o mi b 2 0/ 2 7 m g/ m 2 wit h a “ best s u p p orti ve care” 
re gi me n  (i.e.,  s u p p orti ve meas ures  pl us  3 0  m g  of  pre d nis ol o ne  or  6  m g  of  
de xa met has o ne  gi ve n  e ver y  ot her  da y  pl us  o pti o nal  c ycl o p h os p ha mi de),  usi n g  
si milar  eli gi bilit y  criteria  t o  t hat  prese nte d  i n  St u d y P X- 1 7 1- 0 0 3  – Part  2  ( A 1).    
Pr o gressi o n- fr ee s ur vi val was si milar bet wee n gr o u ps; o verall res p o nse rate was 
hi g her wit h carfilz o mi b ( 1 9. 1 vs 1 1. 4 %).  
 
Base d o n fi n di n gs fr o m St u d y P X - 1 7 1-0 0 6, a pi v otal re gistrati o n -e n a bli n g trial, 
St u d y 
P X - 1 7 1-0 0 9,  was  i nitiate d  c o m pari n g  C R d  vs . le nali d o mi de  pl us  
de xa met has o ne  ( R d)  i n  7 8 0  patie nts  wit h  rela pse d  m ulti ple  m yel o ma  w h o  ha ve  
recei v e d 1– 3 pri or re gi m e ns,  i ncrease d fr o m 7 0 0 patie nts i n A me n d me nt 4. St u d y 
P X - 1 7 1-0 0 9 recei ve d S pecial Pr ot oc ol  Assess m e nt ( S P A) re vi e w a n d  a gree me nt  
fr o m t he F D A i n Ja n uar y 2 0 1 0 a n d t he st u d y was i nitiate d i n J ul y 2 0 1 0 at centers i n 
t he U nite d States ( U S), Ca na da, t he E ur o p ea n U ni o n, Easter n E ur o pe, R ussia, a n d 
Israel.  Pr o gr essi o n- fr ee  s ur vi val  was  si g nifica ntl y  i m pr o ve d  wit h  carfilz o mi b  
( me dia n,  2 6. 3  m o nt hs,  vs.  1 7. 6  m o nt hs  i n  t he  c o ntr ol  gr o u p;  hazar d  rati o  f or  
pr o gressi o n or deat h, 0. 6 9; 9 5 % c o nfi de nce i nter val [ CI], 0. 5 7 t o 0. 8 3; P = 0. 0 0 0 1). 
T he me dia n o ver all s ur vi val was n ot reac he d i n eit her gr o u p at t he i nteri m a nal ysis. 
T he Ka pla n – M eier 2 4 -m o nt h o verall s ur vi val rat es were 7 3. 3 % a n d 6 5. 0 % i n t he 
carfilz o mi b a n d c o ntr ol gr o u ps, res pecti vel y ( hazar d rati o f or deat h, 0. 7 9; 9 5 % C I, 
0. 6 3 t o 0. 9 9; P = 0. 0 4). T h e rat es of o v erall res p o ns e ( partial res p o ns e or bett er) were 
8 7. 1 % a n d 6 6. 7 % i n t he carfilz o mi b a n d c o ntr ol gr o u ps, res pecti vel y ( P < 0. 0 0 1 )[1 6 ]
 
St u d y  2 0 1 1 - 0 0 3 was a  P hase  3  m ultice nter,  o pe n -la bel,  ra n d o mize d  trial  
c o m pari n g  carfilz o mi b  pl us  de xa met has o ne  ( C d)  or  b ortez o mi b  ( Velca de)  pl us  
de xa met has o ne ( V d) i n patie nts wit h  m ulti ple m yel o ma w h ose disease has rela pse d 
after at least 1, b ut n ot m ore t ha n 3 pri or  t hera p e utic re gi me ns. Bet wee n J u ne 2 0, 

 
 
 
 
 
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Pr ot oc ol Versi o n   
 
 
1 5  
2 0 1 2, a n d J u ne 3 0, 2 0 1 4, 9 2 9 patie nts were ra n d o ml y assi g ne d ( 4 6 4 t o t he carfi 
lz o mi b gr o u p; 4 6 5 t o t he b ortez o mi b gr o u p). M e dia n pr o gressi o n -free s ur vi val was 
1 8· 7 m o nt hs ( 9 5 % CI  1 5· 6 – n ot esti ma ble) i n t h e carfi lz o mi b gr o u p vers us 9· 4 
m o nt hs ( 8· 4 – 1 0· 4) i n t he b ortez o mi b gr o u p at a pre pla n ne d  i nteri m a n al ysis ( hazar d 
rati o [ H R] 0· 5 3 [ 9 5 % CI 0· 4 4– 0· 6 5]; p < 0· 0 0 0 1) [ 1 7 ].  
 
  
Si n gle-Patie nt  I N Ds  w ere  first  esta blis he d  i n  2 0 0 9  a n d  were  i nte n de d  f or  
patie nts w h o ha d  ne ver r ecei ve d carfilz o mi b a n d w h o di d n ot q ualif y f or a n y of t he 
A m ge n -s p o ns ore d cli nical  st u dies.   I n t he latter part of 2 0 0 9, after n oti n g t hat a 
n u m ber of Si n gle -Patie nt I N Ds w ere  file d, t he F D A rec o m me n d e d t hat, rat her t ha n 
c o nti n ui n g t o file i n di vi d ual Si n gle -Patie nt  I N Ds, A m ge n  s h o ul d c o nsi der pr o vi di n g 
a m ore f or malize d e x p a n de d access pr o gra m.   A n A m ge n -s p o ns ore d, C arfilz o mi b 
M ulti ple M yel o ma E x pa n de d Access Pr ot oc ol ( C -M A P)  was t heref ore a p pr o ve d a n d 
i nitiate d  i n  t he  U S  i n  J u ne  2 0 1 1,  i n  c olla b orati o n  wit h  t he M ulti ple  M yel o ma  
Researc h F o u n d ati o n ( M M R F). T his is a m ulti -ce nter, e x p a n de d access,  o pe n -la bel 
(si n gle-ar m wit h n o c o ntr ol gr o u p) st u d y of carfilz o mi b f or patie nts wit h rela pse d  a n d 
refr act or y m ulti ple m yel o ma. T he st u d y is desi g ne d t o pr o vi de access t o patie nts wit h 
rela pse d a n d refract or y disease t hat ha v e recei v e d at least 4 pri or re gi me ns a n d are 
n ot eli gi ble  f or  a n y  ot her  e nr olli n g  carfilz o mi b  st u dies,  pri or  t o  t he  p ote ntial  
c o m mercial la u nc h  of carfilz o mi b i n t he U S. T his st u d y is bei n g c o n d ucte d i n u p t o 
5 0 st u d y sites i n t he U S wit h  a ma xi m u m e nr ol me nt of 5 0 0 patie nts u n der t he c urre nt 
pr ot oc ol desi g n. 
 
A n I n vesti gat or - S p o ns ore d Trial (I S T) pr o gra m w as i nstit ute d i n 2 0 0 9 i n or der 
t o  all o w i n vesti gat ors  access  t o  carfilz o mi b  t o  c o n d uct  N o n-A m ge n -s p o ns ore d 
cli nical trials t o a ns wer  i m p orta nt q uesti o ns of cli nical rel e va nce. T h e I S T pr o gra m 
i ncl u des st u dies i n t he U S a n d E ur o pea n U ni o n ( E U) a n d aff or ds testi n g of differe nt 
c o m bi nati o n t hera pies of carfilz o mi b  wit h ot her a ge nts, ot her d oses of carfilz o mi b, 
differe nt a d mi nistrati o ns, a n d differe nt patie nt p o p ulati o ns. 
  
I n N o v e m ber 2 0 1 5, A m g e n  was  ac q uire d b y A m g e n, I nc. a n d t he I S T pr o gra m 
was tra nsiti o ne d t o t he “ N o n - A m ge n S p o ns ore d Cli nical Researc h Gr o u p ( N A S C R). 
T heref ore, i nf or mati o n re gar di n g t he dr u g s u p plier will n o w be referre d t o as A m ge n, 
n ot O n y x as descri b e d pr e vi o usl y. 
 
1. 2. 3  Cli nical P har mac o ki netics  
 
I n cli nical st u dies, carfil z o mi b d oses of 1 5 t o 3 6 m g/ m2 lea d t o a n a vera g e of 
7 7 % t o 8 6 % pr oteas o me i n hi biti o n i n w h ole bl o o d a n d P B M Cs at 1 h o ur after d osi n g.   
I n P K st u dies, carfilz o mi b is cleare d ra pi dl y, wit h a mea n ter mi nal half -life (t½ ) of 
1 5, 7, a n d = 6 0 mi n utes i n rats, m o n ke ys, a n d h u ma ns, res pecti vel y.  T he pre d o mi na nt 
meta b olites o bser ve d i n r ats, m o n ke ys, a n d h u ma ns are p e pti de fra g me nts  a n d a mi n o 
aci ds t hat are deri ve d fr o m carfilz o mi b a n d carfilz o mi b di ol, i n dicati n g t hat  pe pti dase 
clea va g e a n d  e p o xi de  h y dr ol ysis  are  t he  pri n ci pal  pat h wa ys  of  m eta b olis m  f or  
carfilz o mi b; n o n e of t hese meta b olites i n hi bit t h e acti vit y of t he 2 0 S pr oteas o me.  
H o we ver, des pite  t he ra pi d cleara nce of carfilz o mi b fr o m t he bl o o d c o m part me nt, 
pr ol o n ge d p ote nt  pr oteas o me i n hi biti o n is o bser ve d. T he p har mac o d y na mic ( P D n) 

 
 
 
 
 
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Pr ot oc ol Versi o n   
 
 
1 6  
half -life of carfilz o mi b is a p pr o xi matel y 2 4 h o urs i n rats a n d m o n ke ys, a n d = 2 4 h o urs 
i n h u ma ns. 
 
At d oses ≥ 1 5 m g/ m 2, s yste mic cleara n ce val ues o n Da y 1 of C ycle 1 ra n ge d 
fr o m 1 5 1 t o 2 6 3 L/ hr, e x cee di n g li ver bl o o d fl o w, a n d ter mi nal t ½  val ues were < 1 
h o ur. O n d a y 1 of cycle 1, a vera ge C ma x  val ues w ere 2, 5 4 6 n g/ m L a n d 3, 0 6 0 n g/ m L 
f oll o wi n g a d mi nistrati o n of 1 5 a n d 2 0 m g/ m 2, res pecti vel y. O n Da y 1 6 of C ycle 1, 
a vera g e C ma x  was 4, 5 6 4 n g/ m L  f oll o wi n g a d mi nistrati o n of 2 7 m g/ m2, i n dicati n g a 
d ose pr o p orti o nal i ncrease i n C ma x  acr oss t h e d ose ra n g e of 1 5 t o 2 7 m g/ m 2. I n 
a d diti o n, a d ose de pe n d e nt i ncrease  i n t otal e x p os ure ( A U C) was see n b et wee n 2 0 
a n d 3 6 m g/ m 2. F oll o wi n g re peate d d oses of carfilz o mi b at 1 5 a n d 2 0 m g/ m 2, A U C 
a n d t ½  were si m ilar o n Da ys 1 a n d 1 5 or 1 6 of c ycle 1, s u g gesti n g  no s yste mic 
acc u m ulati o n  of  carfilz o mi b.  A  tre n d  t o war ds  decreas e d  cleara n ce,  wit h  a 
c orres p o n di n g i ncreas e i n A U C, was o bser ve d i n fe males a n d p atie nts greater t ha n 
6 5 years  of a ge i n t he P hase 1 st u dies.  I n a p o p ulati o n P K a nal ysis ( p o ole d data fr o m 
1, 4 8 8 sa m ples  deri ve d fr o m 2 3 6 patie nts acr oss 5 st u dies), neit her ge n der n or a ge 
were i n cl u de d as  c o v ariates i n t he fi nal P K m o del; t here was n o a p pare nt effect of 
race o n e x p os ure t o carfilz o mi b.   P K data f or t he 1 5 m g/ m2 d ose was ge n erate d i n 
S t u d y P X- 1 7 1-0 0 5. P K data f or t he 2 0  m g/ m 2, 2 7 m g/ m2, a n d 3 6 m g/ m2 d oses were 
ge nerat e d i n St u d y P X- 1 7 1- 0 0 7. 
 
1. 3  
R- C H O P  
 
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  ( C H O P)  ha ve  
bee n t he m ai nsta y of tr eat me nt f or patie nts wit h a d va nce d st a ge D L B C L si nce its 
de vel o p me nt i n 1 9 7 0s. A milest o ne p hase III trial f o u n d t hat c o m ple x re gi me ns 
a d di n g  ot her  c he m ot hera p y  a ge nts  t o  C H O P,  (i.e.  m -B A C O D;  Pr o M A C E -
C yta B O M, a n d M A C O P -B) di d n ot de m o nstrate a n y si g nifica nt be n efit i n o verall 
s ur vi val ( O S), disease-free s ur vi val ( D F S), or re missi o n rate o ver C H O P [ 1 0- 1 2]. 
T he de vel o p me nt of rit u xi ma b – a m o n ocl o nal a nti b o d y tar geti n g t o C D 2 0 le d t o 
c o m bi ni n g t his a ge nt wit h c he m ot hera p y ( R- C H O P).  
 
1. 3. 1   Precli nical Data  
 
Rit u xi ma b is a ge neticall y e n gi neere d, c hi meric m uri ne/ h u ma n m o n ocl o nal 
a nti b o d y directe d a gai nst t he C D 2 0 a nti ge n f o u n d o n t he s urface of n or mal a n d 
mali g na nt pre -B a n d mat ure B cells.  T he a nti b o d y is a n I g G 1 κ i m m u n o gl o b uli n 
c o ntai ni n g m uri ne li g ht -a n d hea v y -c hai n v aria bl e re gi o n s e q ue nces a n d h u ma n 
c o nsta nt re gi o n se q ue n ces.  Rit u xi ma b is c o m p ose d of t w o hea v y c hai ns of 4 5 1 
a mi n o aci ds a n d t w o li g ht c hai ns of 2 1 3 a mi n o aci ds ( base d o n c D N A a n al ysis) a n d 
has a n a p pr o xi mate m olec ular mass of 1 4 5 k D.  Rit u xi ma b has a bi n di n g affi nit y 
f or t he C D 2 0 a nti ge n of ~ 8. 0 n M.  T here are a n u m ber of precli nical st u dies w hic h 
s u g gest  t hat  rit u xi ma b  e xerts  its  t hera pe utic  effect  b y  s o me  c o m bi nati o n  of  
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), c o m ple me nt a n d/ or direct 
cell l ysis.  D eter mi ni n g t he e x a m mec h a nis ms of acti o n of rit u xi ma b is a n acti ve 
area of i n vesti gati o n.  
 

 
 
 
 
 
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1 7  
1. 3. 2   Cli nical data  
 
Se veral se mi nal st u dies de m o nstrate d t hat t he o verall s ur vi val of patie nts wit h 
D L B C L is i m pr o ve d w he n rit u xi ma b is a d de d t o C H O P [1 6- 1 8 ].  Sta n dar d d osi n g 
or R -C H O P is 3 7 5 m g/ m 2 rit u xi ma b, 7 5 0 m g/ m2 c ycl o p h os p ha mi de, 5 0 m g/ m 2 
d o x or u bici n, a n d 2 m g vi ncristi ne all gi ve n i ntra ve n o usl y o n da ys 1 a n d 1 0 0 m g 
pre d nis o ne gi ve n or all y o n da ys 1 – 5 e ver y 2 1 d a ys f or 6 c ycl es. 
 
1. 3. 2  Cli nical P har mac o ki netics  
  
Rit u xi ma b li kel y acts s y ner gisticall y wit h c he m ot h era p y, i n w hic h cas e ha vi n g 
t hera pe utic  le v els  of  rit u xi ma b  t hr o u g h o ut  all  c ycles  of  t hera p y  s h o ul d  be  
be neficial. P har mac o ki netic st u dies of rit u xi ma b use d i n R -C H O P -1 4 sc he d ule 
s h o we d t hat rit u xi ma b le vels rise sl o wl y a n d a platea u is attai ne d o nl y after 5 c ycles 
[1 9 ].  Base d  o n  t his  o bser vati o n,  t he  Ger ma n  Hi g h  Gra de  N H L  St u d y  Gr o u p  
( D S H N H L) e val uat e d t he be nefit of i nte nsif yi n g t h e rit u xi ma b d osi n g. T his c o nce pt 
was c o m bi ne d wit h d os e i nte nsificati o n of c he m ot hera p y ( R -C H O P -1 4). I n t he 
earl y p has e of t his D E N S E R -C H O P trial, i ncrease d i nfecti o us e ve nts occ urre d, b ut 
wit h i ncreas e d s u p p orti v e care i n ter ms of pr o p h ylactic a nti micr o bials a n d P E G -
fil grasti m t he re gi me n was felt t o be s afe a n d effecti ve [2 0 ].  N o net h eless, t his 
a p pr oac h has n ot bee n g e nerall y a d o pte d.  T his li kel y reflects t he a bse n ce of data 
o n its be nefit, as w ell as t he nee d f or e xte nsi ve a nti micr o bial pr o p h yl a xis a n d 
gr o wt h fact or s u p p ort, as well as o bser ve d a n d p ote ntial e xcess t o xicit y  of t he 1 4 
da y sc he d ule. 
 
1. 4  
R ati o n ale    
 
  
 
As descri b e d a b o v e, t he a d diti o n of b ortez o mi b a p pears t o c o nfer a hi g her 
res p o nse a n d me dia n o v erall s ur vi val t o D L B C L patie nts wit h t he A BC c o m pare d 
t o t he G C s u bt y pe.  H o we ver , a hi g h i nci de n ce of ne ur o pat h y has li mite d t he 
t olera bilit y of b ortez o mi b i n c o m bi nati o n wit h R-C H O P a n d ca n res ult i n d os e 
re d ucti o ns [1 4 ].   T o f or mall y c o m pare t he b e nefit of b ortez o mi b i n c o m bi nati o n 
wit h R -C H O P, t here ha v e bee n ra n d o mize d p hase III st u dies c o m pari n g R-C H O P 
± b ortez o mi b f or D L B C L wit h t he n o n -G C s u bt y pe ( N C T 0 0 9 3 1 9 1 8 i n t he U. S. a n d 
N C T 0 1 0 4 0 8 7 1 i n E ur o pe).   
  
  
  
 
 
Beca use t he r ole of b ortez o mi b i n t he u pfr o nt ma na ge me nt of D L B C L is still 
u n k n o w n , t here is c o nsi dera ble i nterest i n e x pl ori n g t he be nefit of carfilz o mi b i n 
t his setti n g, as t his a ge nt has n o si g nifica nt d ose-li miti n g ne ur o pat h y.  If t h e p hase 
III st u dies of b ort ez o mi b s h o w n o a d va nta g e fr o m t he a d diti o n of t his a ge nt t o t he 
treat me nt of n o n-G C D L B C L , t his ma y i n dicate lac k of realizati o n of t he f ull 
p ote ntial t hera p e utic b e n efit of pr oteas o m e i n hi biti o n p ossi bl y d ue t o n e ur o pat h y -
relate d d ose re d u cti o ns.  A p ositi ve res ult s h o wi n g be nefit fr o m b ortez o mi b w o ul d 
pr o vi de pr o of of pri nci ple f or t h e use of pr oteas o me   i n hi biti o n i n D L B C L  a n d 
w o ul d s u g gest t he p ote ntial f or a n e ve n greater r ole f or carfilz o mi b.  T heref ore, 
re gar dl ess of t he o ut c o me of c urre nt p h ase III st u dies of b ortez o mi b i n t he u pfr o nt 
ma na ge me nt  f or  D L B C L,  t here  is  s o u n d rati o nal  f or  e x pl ori n g  t he  effect  of  
carfilz o mi b.    

 
 
 
 
 
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Pr ot oc ol Versi o n   
 
 
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2. 0  
O B J E C TI V E S  
 
2. 1   
Pri m ar y O bjecti ve ( P h ase I) 
T o deter mi ne t he saf et y of carfilz o mi b i n c o m bi n ati o n wit h R -C H O P ( C R -C H O P) 
i n patie nts wit h ne wl y dia g n ose d D L B C L a n d i de ntif y a rec o m me n de d p hase II 
d ose ( R P 2 D). 
 
2. 2  
Sec o n d ar y O bjecti ve s ( P h ase II) 
•  T o deter mi ne if  C R -C H O P i m pr o ves t he rates of 1- year pr o gressi o n free 
s ur vi val (P F S) a n d o verall s ur vi val ( O S) i n n o n- ger mi nal ce nter ( n o n -G C) 
D L B C L patie nts relati ve t o hist orical c o ntr ols treate d wit h R -C H O P  
•  T o deter mi ne res p o nse rates (c o m plete a n d parti al re missi o n) i n n o n- G C 
D L B C L patie nts treat e d wit h C R -C H O P a n d c o m pare t o hist orical c o ntr ols 
treate d wit h R-C H O P.  
•  Beca use  a  pr o p orti o n  ( ~ 1 0 %)  of  patie nts  classifie d  as  n o n -G C  b y  I H C  
al g orit h ms ma y n ot ha ve t he A B C s u bt y pe d of D L B C L, a n e x pl orat or y 
sec o n dar y o bjecti ve will c o m pare  t h e P F S, O S a n d res p o nse rates of t he A B C 
s u b gr o u p of patie nts wit h D L B C L as deter mi ne d b y t he Ge n e E x pressi o n 
Pr ofili n g wit h t h ose of t he o verall gr o u p of n o n- G C  D L B C L . 
 
3. 0 
S T U D Y D E SI G N  
 
3. 1  
St u d y De si g n Incl u di n g D ose Esc al ati o n/ C o h orts 
 
P h ase I 
 
•    T he pr o p ose d st u d y is a m ulti-i nstit uti o n, o pe n-la bel, p hase I/II st u d y desi g ne d t o 
e val uate t he s afet y a n d efficac y of C R - C H O P f or patie nts ne wl y dia g n ose d 
D L B C L.  Carfilz o mi b will be a d mi nistere d o n da ys 1 a n d 2 of a 2 1 d a y c ycl e wit h 
sta n dar d d ose R-C H O P f or 6 c ycles.   
•    D ose escalati o n pr ocee d e d  usi n g a sta n dar d 3 + 3  desi g n as detaile d i n t he 
Treat me nt Pla n ( Secti o n 6. 0). See sc he m a o n pa ge 4 f or details o n d ose es calati o n 
pr oce d ur es use d i n P hase I.  
P h ase II  
  F or t he p h ase II p orti o n of t he st u d y, 2 6 patie nts wit h ne wl y dia g n ose d n o n-G C 
D L B C L will be treate d wit h 6 c ycles of C R -C H O P acc or di n g t o D L 5 at 2 0  m g/ m 2 
da ys 1, 2 of c ycl e 1 f oll o we d b y  5 6 m g/ m 2 da ys 1, 2 e ver y 2 1 da ys f or c y cl es 2- 6 ( per 
ta ble a b o ve) 
•    Patie nts will be m o nit ore d f or all a d v erse e ve nts. 
•    Res p o nse will be assess e d b y P E T-C T after 6 c y cles of t hera p y  a n d o n f oll o w- u p 
acc or di n g t o m o difie d I nt er nati o nal W or ki n g Gr o u p criteria. 

 
 
 
 
 
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1 9  
3. 2  
N u m ber of S u bjects  
T he p hase I p orti o n of ot her trial e nr olle d 2 4 p atie nts i n or der t o esta blis h a n 
R P 2 D.  T he p hase II p orti o n of t he trial will e nr oll 2 6 n o n- G C D L B C L patie nts 
treate d wit h C R-C H O P wit h carfilz o mi b at tar g et d oses of D L 5, w hic h h as bee n 
f o u n d t o be well t olerat e d wit h o ut a n y D L T i n p hase I.   
 
Ass u mi n g 2 4 of t he 2 6 patie nts are e val ua ble, t his n u m ber will be a de q u ate t o 
de m o nstrate a n i m pr o ve me nt i n t he 1- year P F S fr o m 5 0 % t o 7 5 % usi n g a 
n o n para metri c (i.e., K a pla n- Meier) 2-si de d ti me-t o e ve nt ( T T E) esti mate wit h a 
si g nifica nce of 5 % a n d p o wer of 8 0 %.  . 
 
 
3. 3 
Re pl ace m e nt of S u bjects  
If a s u bject is wit h dra w n fr o m t he P hase I d ose es calati o n c o h ort f or a n y reas o n 
ot her t ha n a  D L T pri or t o c o m pleti n g t he first 2 1  da ys of  C R -C H O P  treat me nt, a 
re place me nt s u bject will be e nr olle d a n d will be assi g ne d t o t he sa me d ose le vel.  
If  a  s u bject  is  wit h dra w n  fr o m  t he  P hase  II  st u d y  f or  reas o ns  ot her  t ha n  
pr o gressi ve disease pri or t o t he c ycl e 2 assess me nts , a re place me nt s u bject ma y be 
e nr olle d as a gree d u p o n b y t he s p o ns or a n d t he i n vesti gat ors. 
 
3. 4   
E x pecte d D ur ati o n of S u bject P arti ci p ati o n  
 
3. 4. 1    D urati o n of T hera p y 
•  I n t he a bse n ce of tr eat me nt dela ys d ue t o a d verse e ve nts, treat me nt ma y 
c o nti n ue f or 6 c y cles or u ntil o ne of t he f oll o wi n g criteria a p plies: 
- Disease pr o gressi o n,  
- I nterc urre nt ill ness t hat pre ve nts f urth er a d mi nistrati o n of treat me nt,  
- T he i n vesti gat or c o nsi ders it, f or safet y reas o ns, t o be i n t he best i nterest of 
t he patie nt, 
- U nacce pta ble treat me nt relate d t o xicit y, N CI C T C A E versi o n 4. 0  Gra de 2, 
3 or 4 t h at fails t o rec o ver t o b aseli ne or < Gra de 3 i n t he a bsence of 
treat me nt wit hi n 4 wee ks, 
- A n y t o xicit y or ot her iss ue t hat ca us es a del a y of st u d y dr u g a d mi nistrati o n 
b y m ore t ha n 4 wee ks, 
- Ge ner al or s pecific c ha n ges i n t he patie nt’s c o n diti o n re n der t he patie nt 
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, 
- Patie nt decisi o n t o wit h dra w fr o m treat me nt ( partial c o nse nt) or fr o m t he 
st u d y (f ull c o nse nt), 
- Pre g na nc y d uri n g t he c o urse of t he st u d y f or a c hil d- beari n g partici pa nt 
- Deat h, or 
- S p o ns or  reser v es  t he  ri g ht  t o  te m p oraril y  s us pe n d  or  pre m at urel y  
disc o nti n ue t his st u d y. 
 

 
 
 
 
 
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Pr ot oc ol Versi o n   
 
 
2 0  
T he d ate a n d re as o n f o r disc o nti n u ati o n m ust be d oc u me nte d.  E ver y eff ort 
s h o ul d be m a de t o c o m plete t he a p pr o pri ate assess me nts.  
 
3. 4. 2  D urati o n of F oll o w U p 
Patie nts will be f oll o we d f or t o xicit y f or 3 0 da ys after treat me nt has bee n 
disc o nti n ue d or u ntil deat h, w hic he ver occ urs first. 
T he cli nical c o urse of eac h e ve nt will be f oll o we d u ntil res ol uti o n, sta bilizati o n, 
or u ntil it has bee n deter mi ne d t hat t he st u d y treat me nt or partici pati o n is n ot t he 
ca use wit h a c ut off of 2 4 m o nt hs after c o m pleti o n of t hera p y. 
Seri o us a d vers e e v e nts t hat are still o n g oi n g at t he e n d of t h e st u d y peri o d will 
necessitate f oll o w -u p t o deter mi ne t he fi nal o utc o me. A n y seri o us a d vers e e ve nt 
t hat occ urs after t he st u d y peri o d a n d is c o nsi dere d t o be p ossi bl y relate d t o t he 
st u d y treat me nt or st u d y partici pati o n will be rec or de d a n d re p orte d i m me diatel y. 
 
4. 0 
P A TI E N T S E L E C TI O N  
 
Eac h of t he criteria i n t he c hec klist t hat f oll o ws m ust be met i n or der f or a patie nt t o be 
c o nsi dere d eli gi ble f or t his st u d y.  Use t he c hec klist t o c o nfir m a patie nt’s eli gi bilit y.  
T he c hec klist m ust be c o m plete d f or eac h patie nt a n d m ust be si g ne d a n d date d b y t he 
treati n g p h ysicia n.  
 
P atie nt’s N a m e : 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
Me dic al Rec o r d # :  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
Rese arc h N urse / St u d y C o or di n at or Si g n at ure:  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _    D ate : _ _ _ _ _ _ _ _ _ _ 
 
Tre ati n g P h ysici a n [ Pri nt] :   
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
Tre ati n g P h ysici a n Si g n at ure:  _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ D ate _ _ _ _ _ _ _ _ _ _ 
 
 
4. 1 
I ncl usi o n Criteri a  
 
 
_ _ _ _ _  4. 1. 1 
Patie nts  m ust  ha ve  hist ol o gicall y  c o nfir me d  diff use  lar ge  B -cell 
l y m p h o ma ( D L B C L).  Patie nts  wit h  pre vi o usl y  dia g n ose d  i n d ole nt  
l y m p h o ma (f ollic ular l y m p h o ma a n d mar gi nal z o ne l y m p h o ma b ut n ot 
s mall l y m p h oc ytic l y m p h o ma) w h o ha ve tra nsf or me d t o D L B C L are 

 
 
 
 
 
C A S E 3 4 1 3  C R -C H O P  
Pr ot oc ol Versi o n   
 
 
2 1  
eli gi ble o nl y  if  t he y  ha ve  n ot  pre vi o usl y  bee n  treate d  f or  i n d ole nt  
l y m p h o ma.  
 
  
      4. 1. 2    Dia g n osis of hi g h gra de B -cell l y m p h o ma of n o n -ger mi nal ce nter 
s u bt y pe b y Ha ns al g orit h m as o utli ne d i n Secti o n 1 0. 1. 1. 3. 1.  
 
_ _ _ _ _  4. 1. 3   Patie nts m ust ha ve ra di o gra p hicall y meas ura ble disease . 
 
 _ _ _ _ _ 4. 1. 4 
Patie nts  ma y  ha ve  recei ve d  brief  ( < 1 5  da ys)  treat me nt  wit h  
gl uc oc ortic oi ds a n d/ or 1 c ycle of c h e m ot hera p y s uc h as R -C H O P [ or 
s o me  c o m p o ne nt(s)  t here of]  f or  t he  dia g n osis  of  B-cell  l y m p h o ma  
pr o vi de d t he y ha d all n ecessar y sta gi n g t ests p erf or me d pri or t o R -
C H O P i ncl u di n g C T a n d/ or P E T/ C T sca ns, ec h ocar di o gra m a n d b o n e 
marr o w  bi o ps y . Treat me nt  m ust  occ ur  wit hi n  6 0  da ys  pri or  t o  
e nr oll me nt.  
 
Pre vi o us treat me nt _ _ _ Y E S _ _ _ _ _ N o 
If
 Yes,
 Pleas e
 List
 Treat me nt
 a g e nts
 a n d
 dates:
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
 _ _ _ _ _  4. 1. 5   A ge > 1 8 y ears.   D osi n g or a d vers e e ve nt data are li mite d o n t he use of 
Carfilz o mi b  i n patie nts < 1 8 years of a ge, t heref ore c hil dre n are 
e xcl u de d fr o m t his st u d y.  
 
_ _ _ _ _   4. 1. 6   E C O G  Perf or ma nce stat us < 2.  Perf or ma nce Stat us of 3 will be  
acce pte d if i m pair me nt is ca use d b y D L B C L c o m plicati o ns a n d  
i m pr o ve me nt is e x pecte d o nce t hera p y is i nitiate d.  [ See A p pe n di x A].  
 
_ _ _ _ _   4. 1. 7 Patie nt m ust ha ve a de q uate he mat ol o gic, he patic, a n d re nal f u ncti o n as                        
defi ne d bel o w: 
 
 
_ _ _ _ _ 4. 1. 7. 1  He m o gl o bi n > 7. 0 g/ dl  
  
  
 
He m o gl o bi n: _ _ _ _ _ _ _ _ _ _ 
  
  
  
Date of T est: _ _ _ _ _ _ _ _ _ _ 
 
_ _ _ _ _ 4. 1. 7. 2  A bs ol ute ne utr o p hil c o u nt > 1, 5 0 0/ mc L * 
  
 
A bs ol ute ne utr o p hil c o u nt: _ _ _ _ _ _ _ _ _ 
  
 
Date of T est:  _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
_ _ _ _ _ 4. 1. 7. 3 Platele t c o u nt > 1 0 0, 0 0 0/ mc L 
  
Platelet c o u nt:  _ _ _ _ _ _ _ _ _ _  
  
Date of T est:    _ _ _ _ _ _ _ _ _ _ 
 
_ _ _ _ _ 4. 1. 7. 4 T otal bilir u bi n wit hi n n or mal i nstit uti o nal li mits  u nless d ue t o 

 
 
 
 
 
C A S E 3 4 1 3  C R -C H O P  
Pr ot oc ol Versi o n   
 
 
2 2  
Gil bert’s disease  
  
 
T otal bilir u bi n:  _ _ _ _ _ _ _ _ _ _ _ 
  
Date of T est:     _ _ _ _ _ _ _ _ _ _ _ 
 
_ _ _ _ _ 4. 1. 7. 5 A S T ( S G O T) < 2. 5 X i nstit uti o nal u p per li mit of n or mal  
  
  
  
A S T ( S G O T): _ _ _ _ _ _ _ _ _ _ _ _ 
  
  
  
Date of T est:   _ _ _ _ _ _ _ _ _ _ _ _ 
 
_ _ _ _ _ 4. 1. 7. 6 A L T ( S G P T) < 2. 5 X i nstit uti o nal u p per li mit of n or mal  
  
  
  
A L T ( S G P T):  _ _ _ _ _ _ _ _ _ _ _ 
  
  
 
Date of T est:   _ _ _ _ _ _ _ _ _ _ _ 
 
_ _ _ _ _ 4. 1. 7. 7 Creati ni ne cl eara nce > 4 5 m L/ mi n  calc ulate d b y C o c kcr oft -Ga ult  
or 2 4 h o ur c ollecti o n 
  
  
Creati ni ne cleara n ce:  _ _ _ _ _ _ _ _ _ _ 
  
 
Date o f T est:               _ _ _ _ _ _ _ _ _ _ 
 
_ _ _ _ _ 4. 1. 8   A d e q uate car diac f u ncti o n left ve ntric ular ejecti o n fracti o n ( L V E F) > 5 0 % 
as assesse d b y ec h ocar di o gra m o r M U G A ( M ulti Gate d Ac q uisiti o n Sca n).  
 
_ _ _ _ _  4. 1. 9  T he effects of Carfilz o mi b  o n t he de vel o pi n g h u ma n fet us are u n k n o w n.  
F or t his reas o n a n d beca use c he m ot hera pe utic a ge nts use d i n t his st u d y are k n o w n t o be 
terat o ge nic, w o m e n of c hil d- beari n g p ote ntial a n d me n m ust a gree t o use a d e q uate 
c o ntrace pti o n ( d o u ble barrier met h o d of birt h c o ntr ol or a bsti ne nce) 2 wee ks  pri or t o 
i nitiati o n of treat me nt, f or t he d urati o n of st u d y partici pati o n a n d f or 3 m o nt hs after 
c o m pleti n g treat me nt. S h o ul d a w o ma n bec o m e pre g na nt or s us pect t hat s he is pre g na nt 
w hile s he or her part ner is partici pati n g i n t his st u d y, s he s h o ul d i nf or m t he treati n g 
p h ysicia n i m me diatel y.   Me n m ust a gree t o refrai n fr o m s per m d o nati o n f or at least 9 0 
da ys after t h e last d ose of carfilz o mi b.   
 
 
_ _ _ _ _   4. 1. 1 0  S u bjects m ust ha ve t he a bilit y t o u n dersta n d a n d t he willi n g ness t o si g n 
a writte n i nf or me d c o nse nt d oc u me nt. 
 
_ _ _ _ _   4. 1. 1 1  I nter nati o nal Pr o g n ostic I n de x m ust be d oc u me nte d: 
 
 
E C O G perf or ma nce stat us ≥2  _ _ _ _ _  ( 1 p oi nt) 
 
  
  
  
        A ge   ≥6 0 _ _ _ _ _   ( 1 p oi nt) 
 
  
     
     ≥2  e xtra n o dal sites _ _ _ _ _  ( 1 p oi nt) 
 
  
L D H > u p per li mit of n or mal  _ _ _ _ _  ( 1 p oi nt) 
 
  
    A n n Ar b or Sta ge III or I V   _ _ _ _ _   ( 1 p oi nt) 
  
 
Is t here e vi d e nce of tra nsf or matio n fr o m i n d ole nt l y m p h o ma? _ yes _ n o 
 
 
4. 2 
E xcl usi o n Criteri a  

 
 
 
 
 
C A S E 3 4 1 3  C R -C H O P  
Pr ot oc ol Versi o n   
 
 
2 3  
 
T he prese n ce of a n y  of t h e f oll o wi n g will e xcl u de a patie nt fr o m st u d y e nr oll me nt.  
 
_ _ _ _ _   4. 2. 1    Patie nts w h o ha ve n ot rec o vere d fr o m a d verse e ve nts d ue t o a ge nts 
a d mi nistere d m ore t ha n 4 wee ks earlier.  
 
_ _ _ _ _   4. 2. 2 Patie nts w h o are recei vi n g a n y ot her i n vesti gati o n al a ge nts. 
 
_ _ _ _ _   4. 2. 3  K n o w n  C N S  i n v ol ve me nt  b y  l y m p h o ma.   Patie nts  at  hi g h  ris k  f or  
sec o n dar y  C N S  i n v ol ve me nt  b ut  wit h o ut  ne ur ol o gic  s y m pt o ms  
s us pecte d t o b e d ue t o l y m p h o ma are all o we d t o b e e nr olle d a n d recei ve 
i ntrat hecal c h e m ot hera p y  i ncl u di n g  b ut  n ot  li mite d  t o  met h otre xate,  
c ytara bi ne  a n d  gl uc o c ortic oi ds.   Patie nts  w h o  are  e nr olle d  a n d  
s u bse q ue ntl y  i de ntifie d  t o  ha ve  pat h ol o gic  c o nfir mati o n  of  C N S  
i n v ol ve me nt b y l y m p h o ma ma y be c o nti n ue d o n st u d y at t he discreti o n 
of t he pri nci pal i n vesti gat or. 
_ _ _ _ _   4. 2. 4   Hist or y of aller gic reacti o ns attri b ute d t o c o m p o u n ds of si milar 
c he mical or bi ol o gic c o m p ositi o n t o Carfilz o mi b  or ot her a g e nts ( R-
C H O P) use d i n t his st u d y. 
 
_ _ _ _ _   4. 2. 5   Acti ve c o n gesti ve heart fail ure ( Ne w Y or k Heart Ass ociati o n  
  
    
[ N Y H A] Class III t o I V), s y m pt o matic isc he mia, or c o n d ucti o n 
  
    
a b n or malities u nc o ntr olle d b y c o n ve nti o nal i nter v e nti o n or  
  
    
m y ocar dial i nfarcti o n wit hi n f o ur m o nt hs pri or t o e nr oll me nt. 
 
_ _ _ _ _   4. 2. 6   Patie nts wit h u nc o ntr olle d i nterc urre nt ill ness i ncl u di n g, b ut n ot 
li mite d t o o n g oi n g or acti ve i nfecti o n, or ps yc hi atric ill ness/s ocial 
sit uati o ns t hat w o ul d li mit c o m plia nce wit h st u d y re q uire me nts. 
 
_ _ _ _ _   4. 2. 7  Pre g na nt or breastfee di n g w o me n are e x cl u de d fr o m t his st u d y beca use 
Carfilz o mi b is a pr oteas o me i n hi bit or wit h t he p ote ntial f or terat o ge nic 
or a b ortifacie nt effects. Beca use t here is a n u n k n o w n, b ut p ote ntial ris k 
f or  a d vers e  e ve nts  i n  n ursi n g  i nfa nts  sec o n dar y  t o  treat me nt  of  t he 
m ot her wit h Carfilz o mi b , breastfee di n g s h o ul d be disc o nti n ue d if t he 
m ot her is treate d wit h Carfilz o mi b .  T hese p ote ntial ris ks ma y als o a p pl y 
t o ot her a ge nts use d i n t his st u d y.  
 
_ _ _ _ _   4. 2. 8   HI V- p ositi ve patie nts o n c o m bi nati o n a ntiretr o viral t hera p y are 
i neli gi ble beca use of t he p ote ntial f or p har mac o ki netic i nteracti o ns 
wit h Carfilz o mi b .  I n a d diti o n, t hese patie nts are at i ncreas e d ris k of 
let hal i nfecti o ns w he n treate d wit h marr o w s u p pressi ve t hera p y.  
A p pr o priate st u dies will be u n derta k e n i n patie nts recei vi n g 
c o m bi nati o n a ntiretr o viral t hera p y w he n i n dicate d. 
 

 
 
 
 
 
C A S E 3 4 1 3  C R -C H O P  
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2 4  
_ _ _ _ _   4. 2. 9  O t her mali g na ncies wit hi n t he past 3 years e xce pt f or a de q u atel y 
treate d car ci n o ma of t he cer vi x or b asal or s q ua m o us cell carci n o mas 
of t he s ki n, or l o w- ris k pr ostate ca ncer after c urati ve t hera p y, or l o w 
ris k mela n o ma if treate d wit h defi niti ve t hera p y (s uc h as e xcisi o n) a n d 
e x pecte d t o h a ve a l o w li keli h o o d of rec urre n ce.  
 
_ _ _ _ _  4. 2. 1 0  Patie nts w h o ha ve ha d m aj or s ur gical pr o ce d ures or si g nifica nt 
tra u matic i nj ur y wit hi n 2 8 da ys pri or t o st u d y treat me nt. 
  
  
 
Date of L ast Maj or S ur ger y:    
  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
  
  
  
Sc he d ule d Da y 1 of Pr ot oc ol Treat me nt:    
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
_ _ _ _ _ 4. 2. 1 1 Patie nts w h o are re p orte d t o be of direct Asia n- Pacific ( C hi na, Ja pa n,                      
Tai wa n, Si n ga p ore, Re p u blic of K orea, a n d T haila n d) a ncestr y.  
 
* wit h s p o ns or a p pr o val A N C criteria ma y b e wai ve d i n t he case of e x cessi ve disease 
i nfiltrati o n of b o ne marr o w  
 
4. 3     I ncl usi o n of W o m e n a n d Mi n orities 
B ot h me n  a n d  w o me n  are  eli gi ble  f or  t his  trial.  Mi n orities  will n ot  be  e xcl u de d,  
h o we ver, p atie nts of direct Asia n - Pacific ( C hi na, Ja pa n, Tai wa n, Si n ga p ore, Re p u blic 
of K orea, a n d T h aila n d) a ncestr y treate d wit h Carfilz o mi b are at i ncreas e d ris k of 
car di o vas c ular e ve nts a n d s h o ul d be e xcl u de d fr o m t he st u d y  t o e ns ure patie nt safet y.  
If t here ar e q uesti o ns a b o ut t he a n y i n di vi d ual patie nt’s ca n di dac y, t he case s h o ul d be 
disc usse d wit h t he Pri nci pal I n v esti gat or. 
 
 
5. 0  
R E GI S T R A TI O N  
 
All s u bjects w h o ha ve bee n c o nse nte d are t o b e re gistere d i n t he O n C ore D ata base. 
F or t h ose s u bjects w h o ar e c o nse nte d, b ut n ot e nr olle d, t he reas o n f or e x cl usi o n m ust 
be rec or de d.  
 
All s u bjects will be re gistere d t hr o u g h Cle vel a n d Cli nic a n d will be pr o vi de d a st u d y 
n u m ber b y c o ntacti n g Researc h C o or di n at or, Jac ki e T o mer (t o merj 2 @ccf. or g) , at 
2 1 6- 4 4 4- 9 8 1 4 b y s u b mitti n g t he patie nt’s c o m plete d eli gi bilit y pac ket.  
 
 

 
 
 
 
 
C A S E 3 4 1 3  C R -C H O P  
Pr ot oc ol Versi o n   
 
 
2 6  
•  Re p orte d a d vers e e ve nts a n d p ote ntial ris ks of Carfilz o mi b a n d R -C H O P 
are des cri be d i n Secti o n 8. 0. 
•  N o  i n vesti gati o nal  or  c o m mercial  a g e nts  or  t h era pies  ot her  t ha n  t h ose  
descri be d b el o w ma y be a d mi nistere d wit h t he i nt e nt t o treat t h e patie nt's 
mali g na nc y. 
•  N o i ntra- patie nt d ose escalati o n is all o we d.  
 
6. 1. 1  Carfilz o mi b  
Patie nts will recei ve Carfilz o mi b at t he d os e s pecifi e d b y t h e d ose le vel o n 
Da ys 1 a n d 2 o n a 2 1 da y c ycle . Carfilz o mi b will be a d mi nistere d I V o ver 3 0 ( +/-
1 0) mi n utes  a n d will be gi ve n after Rit u xi ma b. 
 
6. 1. 2  R- C H O P  
Use act ual wei g ht w h e n calc ulati n g s urface area.   T he start of treat me nt 
d oses f or all dr u gs ca n b e use d f or all c y cle s u nless t he B S A c h a n ges b y > 5% i n 
w hic h case d os es m ust be re -calc ulat e d.  Acet a mi n o p he n ( 6 5 0 t o 1 0 0 0 m g) P O a n d 
di p he n h y dra mi ne ( 2 5 t o 5 0 m g) P O or I V are t o b e a d mi nistere d 3 0 t o 6 0 mi n utes 
pri or t o starti n g eac h i nf usi o n of rit u xi ma b. H y dr o x yzi ne ma y b e s u bstit ute d i n 
patie nts i nt olera nt of di p he n h y dra mi ne.  Si nce tra nsie nt h y p ote nsi o n ma y occ ur 
d uri n g  rit u xi ma b  i nf usi o n,  c o nsi derati o n  s h o ul d  be  gi ve n  t o  wit h h ol di n g  a nti -
h y perte nsi ve me dicati o ns 1 2 h o urs pri or t o rit u xi ma b i nf usi o n.  A n I V b ol us of 1 
liter  n or mal  sali ne is  gi ve n  bef ore a n d  after R-C H O P  as h y drati o n t o pre ve nt  
c ycl o p h os p ha mi de-i n d uce d he m orr h a gic c ystitis. 
 
a. Pre d nis o ne 1 0 0 m g orall y da y 3 t hr o u g h 7 of s u bs e q ue nt c ycl es. 
b.  Rit u xi ma b 3 7 5 m g/ m 2 I V o n da y 2 of eac h c y cle (e ver y 2 1 da ys)  
c. C ycl o p h os p ha mi de 7 5 0 m g/ m 2 I V Da y 3 of eac h c ycle (e ver y 2 1 d a ys)  
d.  D o x or u bici n 5 0 m g/ m 2 I V Da y 3 of eac h c ycle (e ver y 2 1 da ys)  
e. Vi ncristi ne 1. 4 m g/ m 2 I V ( Ma xi m u m d ose = 2. 0 m g) D a y 3 of eac h 
c ycle ( e ver y 2 1 d a ys)  
f. Pe gfil gra sti m 6 m g S C da y 4 (e ver y 2 1 da ys).  Fil grasti m 3 0 0 or 4 8 0 
mc g I V/ S C dail y da ys 1 -1 0 ma y b e s u bstit ute d if pe gfil grasti m is n ot 
a vaila ble.O N P R O T M  is als o a n acce pta ble met h o d of a d mi nistrati o n. 
 
6. 1. 3  Ac ycl o vir 
     Patie nts will ta ke pr o p h ylactic ac ycl o vir 4 0 0 m g P O bi d be gi n ni n g o n c ycle 
1, da y 1 a n d c o nti n ui n g u ntil 6 m o nt hs after c o m pleti o n of c ycle 6. 
 
 
6. 2        Defi niti o n of D ose -Li miti n g T o xicit y   
  
Ma na ge me nt a n d d os e m o dificati o ns are o utli ne d i n Secti o n 7. 
 
 
D ose li miti n g t o xicit y will be defi ne d as a n y of t he f oll o wi n g A Es t hat o cc ur 
d uri n g c ycle 1  f or d ose l e vels - 2, -1 a n d 1 or d uri n g c ycles 1 a n d 2 f or d os e le vels 

 
 
 
 
 
C A S E 3 4 1 3  C R -C H O P  
Pr ot oc ol Versi o n   
 
 
2 7  
2- 5 of st u d y treat me nt (C R -C H O P ) wit h se verit y gra d e 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 vers e E ve nts ( C T C A E), Versi o n 4. 0:  
 
• Gra de ≥ 3 A S T/ A L T ele vati o n [e xce pti o ns ma y be ma de f or tra nsie nt (i.e., 
lasti n g < 7 Da ys) Gra de 3 ele vati o ns of A L T/ A S T i n t he prese nce of k n o w n 
li ver i n v ol ve me nt b y l y m p h o ma  a n d wit h o ut e vi de nce of ot her he p atic i nj ur y, 
if a gree d b y t he Pri nci pal I n v esti gat or; a n d/ or 
• Gra de 3 or 4 n o n-he mat ol o gic t o xicit y (e xcl u di n g fati g ue or a n ore xia lasti n g 
< 7 da ys, or Gra de 3 na usea a n d/ or v o miti n g t hat persists f or < 2 da ys f oll o wi n g 
a p pr o priate s u p p orti ve care). 
 
 
A D L T is defi ne d as a n y of t he f oll o wi n g treat me nt-relate d A E t hat occ urs d uri n g 
t he first c ycle f or d os e le v els - 2, -1, ; or first a n d s ec o n d c ycle f or d ose l e vels 2 - 5 gra d e 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 v erse E ve nts ( C T C A E), 
Versi o n 4. 0: 
 
• Gra de 4 n e utr o pe nia l asti n g ≥ 7 da ys; 
• Grade 3 or 4 ne utr o p e nia c o m plicate d b y fe ver ≥ 3 8. 0° C or i nfecti o n;  
• Gra de 4 t hr o m b o c yt o pe nia; 
• Gra de 3 t hr o m b o c yt o pe nia c o m plicate d b y he m orr ha ge; 
• Gra de 4 a ne mia. 
 
6. 3        D ose Esc al ati o n  
D ose escalati o n  is n ot a p plica ble f or P hase II. 
 
6. 4     D ur ati o n of T her a p y ( See Secti o n 3. 4. 1) 
 
 
6. 5  D ur ati o n of F oll o w- U p (see Secti o n 3. 4. 2) 
 
 
7. 0   
D O SI N G D E L A Y S / D O S E M O DI FI C A TI O N S  
All sc he d ule d v isits will ha ve a ± 3-da y wi n d o w d ue t o u na ntici pate d  or u na v oi da ble 
sc he d uli n g c o nflicts. F or he mat ol o gic or ot her t o xicit y i n t he o pi ni o n of t he treati n g 
p h ysicia n attri b uta ble t o Carfilz o mi b b ut n ot descri be d else w h ere i n t he pr ot oc ol, t he 
d ose of Carfilz o mi b ma y be re d uce d, after disc ussi o n wit h t he st u d y PI. 
 
7. 1  
He m at ol o gic T o xicit y 
O n t he da y of starti n g eac h c ycle, he m at ol o gic (a bs ol ute ne utr o p hil c o u nt, 
he m o gl o bi n a n d platelet) para met ers m ust ha ve res ol ve d t o baseli ne or gra de 1. If 
t hese criteri a are n ot met, t hera p y will be hel d b y 1 wee k i ncre me nts f or a m a xi m u m 
of 4 wee ks. If treat me nt ca n n ot be gi ve n d uri n g t hat ti me fra me t he patie nt will be 
re m o ve d fr o m st u d y. 
 
 

 
 
 
 
 
C A S E 3 4 1 3  C R -C H O P  
Pr ot oc ol Versi o n   
 
 
2 9  
d ose of c ycl o p h os p ha mi de f or o ne c y cle a n d, if t olerate d, i ncrease d t o 7 5 % of t he 
f ull d ose f or r e mai ni n g c ycles. 
 
7. 2. 3  Car diac m o nit ori n g  
Patie nts  will  be  m o nit ore d  cl oses  f or  cli nical  si g ns  a n d  s y m pt o ms  of     
h y per v ole mia,  p ul m o nar y  e de ma  or  i n dicati o ns  of  c o n gesti ve  h eart  fail ure  or  
s us pecte d car diac e ve nt. If cli nical s us pici o n arises, f urt her e val uati o n is at t he 
discreti o n  of  t he  i n vesti gat or  b ut  ma y  i ncl u de  E K G,  N -ter mi nal  pr o-brai n 
natri uretic  pe pti de  ( N T p- B N P)  meas ure me nt  a n d  p ossi bl y  ec h ocar di o gra m.  If  
car diac assess me nt r e veals si g nifica nt c h a n ges fr o m baseli ne i n car diac f u n cti o n or 
si g nifica nt  ele vati o ns  i n  N T p-B N P,  f urt her  d osi n g  wit h  ca rfilz o mi b  a n d  
d o x or u bici n ca n o nl y pr ocee d after wit h a p pr o val fr o m t he pri nci pal i n vesti gat or 
a n d t he s p o ns or.  
 
7. 2. 4  
If P R E S is s us pecte d, h ol d carfilz o mi b. C o nsi der e val uati o n wit h 
ne ur ora di ol o gical i ma gi n g, s pecificall y M RI, f or o nset of vis ual or ne ur ol o gical 
s y m pt o ms s u g gesti ve of P R E S. If P R E S is c o nfir me d, per ma ne ntl y disc o nti n ue 
carfilz o mi b. If t he dia g n osis of P R E S is e xcl u de d, carfilz o mi b a d mi nistrati o n ma y 
res u me at sa me d ose, if cli nicall y a p pr o priate. If c o n diti o n rec urs, per ma ne ntl y 
disc o nti n ue carfilz o mi b.  
 
7. 2. 5  If t hr o m b otic micr oa n gi o pat h y ( T T P/ H U S) is s us pecte d, h ol d carfilz o mi b a n d 
ma na ge per sta n dar d of care i ncl u di n g plas ma e xc ha n ge as cli nicall y a p pr o priate. 
If T M A is c o nfir m e d a n d relate d t o carfilz o mi b, p er ma ne ntl y disc o nti n ue 
carfilz o mi b. If t he dia g n osi s is e xcl u de d, carfilz o mi b ca n be restarte d at t he 
pre vi o us d ose. If t h e c o n diti o n rec urs, per m a ne ntl y disc o nti n ue carfilz o mi b. 
 
7. 2. 6  He patic T o xicit y  
If t he bilir u bi n is bet wee n 1. 5 a n d 3. 0 m g/ dl o n da y 1 of a n y c ycle 2 - 6, d o x or u bici n 
d ose will be re d uce d b y 2 5 % a n d vi ncristi ne d ose m ust be re d uce d b y 5 0 %. If t he 
he patic f u n cti o n has ret ur ne d t o n or mal b y da y 1 of t he s u bse q ue nt c y cle, f ull d oses 
will be gi ve n. If bilir u bi n is > 3. 0  m g/ dl, d o x or u bici n a n d vi ncristi ne s h o ul d dela ye d 
i n 1 wee k i ncr e me nts f or u p t o 2 w ee ks u ntil < 3. 0 m g/ dl a n d  t he n gi v e n  wit h t he 
a b o ve d ose re d ucti o ns.  If bilir u bi n re mai ns > 3. 0  m g/ dl, t he St u d y M o nit or m ust 
be c o ntacte d a n d t he St u d y PI ( or desi g nee) will be n otifie d a n d t he patie nt will b e 
disc o nti n ue d fr o m t hera p y. 
 
7. 2. 7  Rit u xi ma b H y perse nsiti vit y/I nf usi o n Reacti o ns 
Beca use rit u xi ma b is k n o w n t o ca use h y p erse nsiti vit y a n d i nf usi o n reacti o ns, it will 
be i nf use d wit h gra d uate d i ncre me ntal rates d e pe n di n g o n w het her it is bei n g gi ve n 
as a n i nitial d ose ( c ycle 1) or s u bs e q ue nt d os e ( 2 -6), per i nstit uti o nal g ui deli nes.  
As t he se verit y of i nf usi o n reacti o ns i ncrease, t h e i nf usi o n of rit u xi ma b will be 
eit her sl o we d or h el d, as i n dicate d i n t he acc o m pa n yi n g ta ble. 
 

 
 
 
 
 
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a n d g o o d uri ne fl o w d uri n g a n d after dr u g a d mi nistrati o n usi n g t he f oll o wi n g. Please 
refer t o t he pac k a ge i nsert f or a c o m plete listi n g of all t o xicities. 
 
8. 1. 3  D o x or u bici n 
 
T o xicities i ncl u de m yel os u p pressi o n, st o matitis, al o pecia, na usea a n d v o miti n g, 
a n d ac ut e a n d c hr o ni c car diac t o xicit y, ma nifest e d as arr h yt h mias or a c o n gesti ve 
car di o m y o pat h y, t he latter u nc o m m o n at t otal c u m ulati ve d oses less t ha n 5 0 0 m g/ m 2. 
T he dr u g ca uses l ocal necr osis if i nfiltrate d i nt o s u bc uta ne o us tiss ue. Please refer t o t he 
pac ka g e i nsert f or a c o m plete listi n g of all t o xicities.  
 
8. 1. 4  Pe gfil grasti m  
 
T o xicities  i ncl u de rare a n a p h ylactic reacti o ns wit h t he first d ose;  b o ne pai n at sites 
of acti ve marr o w wit h c o nti n ue d a d mi nistrati o n. L ocal reacti o ns at i njecti o n sites. 
C o nstit uti o nal s y m pt o ms, i ncrease d al kali ne p h os p hatase, L D H, uric aci d; w orse ni n g 
of  pre -e xisti n g  i nfla m mat or y  c o n diti o ns.  Please  refer  t o  t he  pac ka g e  i nsert  f or  a  
c o m plete listi n g of all t o xicities.  
 
8. 1. 5  Pre d nis o ne 
 
T o xicities  i ncl u de  i ns o m nia, a gitati o n,  pr o xi mal  m uscle  wea k ness,  gl uc ose  
i nt olera nce,  t hi n ni n g  of  s ki n,  re distri b uti o n  of  b o d y  fat,  C us hi n g oi d  facies,  
i m m u n os u p pressi o n, a n d pr o pe nsit y t o gastr oi ntesti nal ulcerati o n. Please refer t o t he 
pac ka g e i nsert f or a c o m plete listi n g of all t o xicities.  
 
8. 1. 6  Rit u xi ma b  
 
Re p orte d  a d v erse  e ve nts  i ncl u di n g  fe ver,  c hills,  hea dac he,  na usea,  v o miti n g,  
r hi nitis, ast he nia, a n d h y p ote nsi o n, occ urre d pri m aril y d uri n g rit u xi ma b i nf usi o ns a n d 
t y picall y res p o n de d t o a n i nterr u pti o n of t he i nf usi o n a n d res u m pti o n at a sl o wer rate.   
Fatal  I nf usi o n  Reacti o ns:  Se vere  a n d  fatal  car di o p ul m o nar y  e v e nts,  i ncl u di n g  
a n gi oe de ma,  h y p o xia,  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 nfar cti o n, a n d car di o ge nic s h oc k, h a ve bee n re p orte d.   Ot her reacti o ns 
i ncl u de t u m or l ysis s y n dr o me, c yt o pe ni as i ncl u di n g pr ol o n ge d pa n c yt o pe nia, marr o w 
h y p o plasia, a n d late o nset ne utr o pe nia.   T here is a n i ncrease d rate of i nfecti o us e ve nts , 
h e patitis B reacti vati o n .  Please refer t o t he pac ka ge i nsert f or a c o m plete listi n g of all 
t o xicities. 
 
8. 1. 7  Vi ncristi ne  
 
T o xicities  i ncl u de  peri p heral  ne ur o p at h y,  a ut o n o mic  ne ur o pat h y,  a n d  al o pecia.  
L ocal necr osis if i njecte d s u bc uta ne o usl y. Pleas e refer t o t he pac k a ge i nsert f or a 
c o m plete listi n g of all t o xicities.  
 
8. 1. 8  Ac ycl o vir 
  T o xicities i ncl u de ne ur ol o gic t o xicit y i ncl u di n g a gitati o n, tre m ors, deliri u m, 
hall uci nati o ns, a n d m y ocl o n us, wit h hi g her ris k i n patie nt wit h re nal i ns uffi cie nc y.  
Please ref er t o pac ka g e i nsert f or a c o m plete listi n g of all t o xicities.  

 
 
 
 
 
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8. 1. 9  Use of c o ntr ace pti o n – Fe males  
Fe males of c hil d beari n g p ote ntial s h o ul d be a d vis e d t o a v oi d b ec o mi n g pre g na nt 
w hile bei n g treate d wit h carfilz o mi b. Gi ve n t hat carfilz o mi b was clast o ge nic i n t he i n 
vitr o c hr o m os o mal a berr ati o n test i n peri p heral bl o o d l y m p h oc ytes, as a preca uti o n, 
fe males  of  c hil d beari n g  p ote ntial  a n d/ or  t heir  male  part ners  s h o ul d  use  effecti v e  
c o ntrace pti o n met h o ds or a bstai n fr o m se x ual acti vit y d uri n g a n d f or 3 0 da ys after 
treat me nt wit h carfilz o mi b. If pre g na n c y occ urs d uri n g t his ti me, patie nts s h o ul d be 
a p prise d of t he p ote ntial hazar d t o t he fet us.  
Base d o n its mec ha nis m of acti o n a n d fi n di n gs i n a ni mals, carfilz o mi b ca n ca use 
fetal har m w he n a d mi nistere d t o a pre g na nt w o m a n. Carfilz o mi b ca use d e m br y o‐fetal 
t o xicit y i n pre g na nt ra b bits at d oses t hat were l o wer t ha n i n s u bjects recei vi n g t he 
rec o m me n de d d ose. Carfilz o mi b a d mi nistere d t o pre g na nt rats a n d ra b bits d uri n g t he 
peri o d of or ga n o ge n esis was n ot terat o ge nic at d oses u p t o 2 m g/ k g/ da y i n rats or u p t o 
0. 8 m g/ k g/ da y i n ra b bits. If carfilz o mi b is use d d uri n g pre g na nc y, or if t he s u bject 
bec o mes p re g n a nt w hile ta ki n g t his dr u g, s he s h o ul d i nf or m t he i n vesti gat or or st u d y 
staff i m me diatel y. T he i n vesti gat or s h o ul d n otif y A m ge n of t he pre g na n c y a n d disc uss 
f oll o w‐u p wit h t he s u bject. It is n ot k n o w n if carfilz o mi b will re d uce t he efficac y of  
oral c o ntrace pti ves. D ue t o a n i ncrease d ris k of ve n o us t hr o m b osis ass ociate d wit h 
carfilz o mi b, s u bjects c urre ntl y usi n g oral c o ntrace pti ves or a h or m o nal met h o d of 
c o ntrace pti o n  ass ociat e d  wit h  a  ris k  of  t hr o m b osis  s h o ul d  c o nsi der  a n  alter nati ve  
met h o d of eff ecti ve c o ntr ace pti o n.  
 
8. 1. 1 0  Use of c o ntr ace pti o n – M ale s 
Males of re pr o d u cti ve p ot e ntial s h o ul d be a d vise d t o a v oi d fat h eri n g a c hil d w hile bei n g 
treate d wit h carfilz o mi b. T he p ote ntial f or carfilz o mi b t o be tra nsferre d via se me n a n d 
its effect o n s per m ar e u n k n o w n. Male s u bjects treate d wit h carfilz o mi b a n d/ or t heir 
fe male  p art ners  (if  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 or a bst ai n fr o m se x ual acti vit y w hile treate d wit h carfilz o mi b a n d f or 9 0 d a ys 
after treat me nt. If pre g n a nc y occ urs d uri n g t his ti me, patie nts s h o ul d be a p prise d of t he 
p ote ntial hazar d t o t he fet us.  
      Male  s u bjects  s h o ul d  be  a d vise d  t o  i nf or m  t he  i n vesti gat or  or  st u d y  staff  
i m me diatel y i n t he e ve nt t hat t heir fe male part ner bec o mes pre g n a nt d uri n g t he st u d y. 
U p o n  recei pt  of  t his  i nf or mati o n,  t he  i n vesti g at or  s h o ul d  n otif y  A m ge n  of  t h e  
pre g na nc y a n d disc uss f oll o w ‐u p re gar di n g t he pre g na nc y o utc o me wit h t he s u bject. 
 
8. 2  
Defi niti o ns  
 
8. 2. 1  A d verse E v e nts ( A Es)  
A n  a d verse  e ve nt  ( A E)  is  a n y  u nfa v ora ble  or  u ni nte n de d  e ve nt,  p h ysical  or  
ps yc h ol o gical, ass ociat e d wit h a researc h st u d y, w hic h ca uses har m or i nj ur y t o a 
researc h partici p a nt as a res ult of t he partici pa nt’s i n v ol ve me nt i n a researc h st u d y. T he 
e ve nt ca n i ncl u de a b n or mal la b orat or y fi n di n gs, s y m pt o ms, or disease ass ociate d wit h 
t he researc h st u d y. T h e e ve nt d oes n ot necessaril y ha ve t o ha v e a ca usal relati o ns hi p 

 
 
 
 
 
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wit h t he resear c h, a n y ris k ass ociate d wit h t he researc h, t he researc h i nter ve nti o n, or 
t he researc h assess me nts. 
A d verse e ve nts ma y b e t he res ult of t he i nter ve nti o ns a n d i nteracti o ns use d i n t he 
researc h;  t he  c ollecti o n  of  i de ntifia ble  pri vate  i nf or mati o n  i n  t he  researc h;  a n  
u n derl yi n g disease, dis or der, or c o n diti o n of t he s u bject; a n d/ or ot her circ u msta nces 
u nrela te d  t o  t he  res ear c h  or  a n y  u n derl yi n g  disease,  dis or der,  or  c o n diti o n  of  t he  
s u bject. I n ge n eral, a d verse e ve nts t hat are at least partiall y t he res ult of (a) or ( b) w o ul d 
be c o nsi dere d r elate d t o t he researc h, w h ereas a d v erse e v e nts s olel y relate d t o (c) or ( d) 
w o ul d be c o nsi der e d u nr elate d t o t he res earc h. 
 
8. 2. 2  Si g nifica nce of A Es  
E xter n al a d verse e ve nts are a d verse e ve nts e x p erie nce d b y s u bjects e nr olle d 
i n m ultice nter cli nical trials at sites ot her t h a n t he site(s) o ver w hic h t he I nstit uti o nal 
Re vie w  B oar d  has  j uris dicti o n.   I nter n al  a d verse  e ve nts  are a d vers e  e ve nts  
e x perie n ce d b y s u bjects e nr olle d at t he site(s) u n der t he I R B’s j uris dicti o n f or eit her 
m ultice nter or si n gle -ce nter researc h pr ojects. T he  si g nifica nce of A Es is use d t o 
descri be t he p atie nt/e ve nt o utc o me or acti o n crit eria ass oci ate d wit h e ve nts t hat 
p ose  a  t hreat  t o  a  patie nt’s  life  or  f u n cti o ni n g  (i.e.,  m o derate,  se v ere  or  life  
t hreate ni n g).  Base d o n t he Nati o nal Ca ncer I nstit ute G ui deli nes f or t he Ca ncer 
T h era p y Eval u ati o n Pr o gra m, se verit y ca n be defi ne d b y t he f oll o wi n g gra des of 
e ve nts:  
  
 
•  Gr a des 1 are mil d a d verse e ve nts. (e. g., mi n or e ve nt re q uiri n g n o s pecific 
me dical i nter ve nti o n; as y m pt o matic la b orat or y fi n di n gs o nl y; mar gi nal cli nical 
rele va n ce) 
 
•  Gr a des  2  are  m o derate  a d verse  e v e nts  (e. g.,  mi ni mal  i nter ve nti o n;  l ocal  
i nter ve nti o n;  n o n-i n vasi ve  i nter ve nti o n;  tra nsf usi o n;  electi ve  i nter ve nti o nal  
ra di ol o gical pr oce d ure; t hera pe utic e n d osc o p y or o perati o n). 
 
•  Gr a des 3 are se v ere a n d u n desira ble a d v erse e ve nts (e. g., si g nifica nt s y m pt o ms 
re q uiri n g  h os pitalizati o n  or  i n vasi ve  i nter ve nti o n;  tra nsf usi o n;  electi ve  
i nter ve nti o nal ra di ol o gical pr oce d ure; t hera pe utic e n d osc o p y or o perati o n). 
 
•  Gr a des 4  are life t hreate ni n g or disa bli n g a d verse e ve nts (e. g., c o m plicate d b y 
ac ute,  life-t hr eate ni n g  meta b olic  or  car di o vasc ular  c o m plicati o ns  s uc h  as  
circ ulat or y
 fail ur e,
 h e m orr ha g e,
 se psis;
 life – t hreate ni n g
 p h ysi ol o gic
 
c o nse q ue nces;  nee d  f or  i nte nsi ve  care  or  e m er ge nt  i n vasi v e  pr o ce d ure;  
e mer ge nt  i nter v e nti o nal  ra di ol o gical  pr oce d ure,  t hera pe utic  e n d os c o p y  or  
o perati o n). 
 
•  Gr a des 5 are fatal a d v ers e e ve nt res ulti n g i n deat h.    
 
 

 
 
 
 
 
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8. 2. 3  Seri o us A d verse E v e nts ( S A Es) 
•  A seri o us a d verse e v e nt ( S A E) is a n y a d verse e x perie nce occ urri n g at a n y d ose 
t hat res ults i n a n y of t he f oll o wi n g o utc o mes: 
o  Res ults i n deat h .  
o  Is a lif e-t hreate ni n g a d verse e x perie n ce.  T he ter m life-t hreate ni n g i n t he 
defi niti o n of seri o us refers t o a n a d verse e v e nt i n w hic h t he s u bject was 
at ris k of deat h at t he ti me of t he e ve nt.  It d oes n ot refer t o a n a d vers e 
e ve nt w hic h h y p ot heticall y mi g h t ha ve ca use d d eat h if it were m ore 
se vere. 
o  Re q uires  i n patie nt  h os pitalizati o n  or  pr ol o n gati o n  of  e xisti n g  
h os pitalizati o n.   A n y  a d verse  e ve nt  lea di n g  t o  h os pitalizati o n  or  
pr ol o n gati o n of h os pitalizati o n  will be c o nsi dere d as seri o us, U N L E S S 
at least o ne of t he f oll o wi n g e x pectati o ns is met:  
 T he a d missi o n res ults i n a h os pital sta y of less t ha n 1 2 h o urs O R  
 T he a d missi o n is pre -pla n ne d (i.e., electi ve  or s c h e d ule d s ur ger y 
arra n g e d pri or t o t he start of t he st u d y) O R  
 T he a d missi o n is n ot ass ociate d wit h a n a d v ers e e ve nt (e. g., 
s ocial h os pitalizati o n f or p ur p oses of res pite care. 
 H o we ver it s h o ul d be n ote d t hat i n vasi ve treat me nt d uri n g a n y 
h os pitalizati o n ma y f ulfill t he criteria of “ me dicall y i m p orta nt” 
a n d  as  s uc h  ma y  be  re p orta ble  as  a  seri o us  a d verse  e ve nt  
de pe n de nt o n  cli nical  j u d g me nt.   I n  a d diti o n  w here  l ocal  
re g ulat or y  a ut h orities  s pecificall y  re q uire  a  m ore  stri n ge nt  
defi niti o n,  t he  l ocal  re g ulati o n  ta kes  prece de nt.  Res ults   i n 
persiste nt or si g nifica nt disa bilit y/i nca pacit y .  T h e defi niti o n of 
disa bilit y  is  a  s u bsta ntial  disr u pti o n  of  a  p ers o n’s  a bilit y  t o  
c o n d uct n or mal l ife’s f u n cti o ns. 
o  Is a c o n ge nital a n o mal y / birt h defect 
o  Is a n i m p orta nt me dical e ve nt.  I m p orta nt me di cal e ve nts t hat ma y n ot 
res ult  deat h,  be  life-t hreate ni n g,  or  re q uire  h os pitalizati o n  ma y  be  
c o nsi dere d a seri o us a d v erse e x peri e nce w he n, b ase d u p o n a p pr o priate 
me dical j u d g me nt, t he y 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 his  defi niti o n.   E xa m ples  of  s uc h  me dical  e ve nts  i ncl u de  
aller gic br o nc h os p as 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 disease or dis or ders, or c o n v ulsi o ns t hat d o n ot 
res ult  i n  i n patie nt  h os pitalizati o n,  or  t he  de vel o p me nt  of  dr u g  
de pe n de n c y or dr u g a b us e.  
 
 
 

 
 
 
 
 
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8. 2. 4  E x pecte d ness  
A n e x pect e d a d verse e v e nt  is a n e ve nt pre vi o usl y k n o w n or a ntici pate d t o res ult 
fr o m  partici pati o n  i n  t he  researc h  st u d y  or  a n y  u n derl yi n g  disease,  dis or der,  or  
c o n diti o n of t he s u bject. T he e ve nt  is us uall y liste d i n t he I n vesti gat or  Br oc h ure,  
c o nse nt f or m or researc h pr ot oc ol.  
 
 
A n  u ne x pecte d  a d verse  e ve nt  is a n  a d verse  e ve nt  n ot  pre vi o usl y  k n o w n  or  
a ntici pate d t o r es ult fr o m t he researc h st u d y or a n y u n derl yi n g disease, dis or der, or 
c o n diti o n of t he s u bject.  
 
8. 2. 5  Attri b uti o n  
 
Attri b uti o n is t he relati o ns hi p bet wee n a n a d vers e e v e nt or seri o us a d vers e e v e nt 
a n d t he st u d y dr u g.  Attri b uti o n will be assi g ne d as f oll o ws: 
 
•  Defi nite – T he A E is clearl y relate d t o t he st u d y dr u g. 
•  Pr o ba ble – T he A E is li k el y relate d t o t he st u d y dr u g. 
•  P ossi ble – T he A E ma y be relate d  t o t he st u d y dr u g. 
•  U nli kel y – T he A E is d o u btf ull y relate d t o t he st u d y dr u g. 
•  U nrelate d – T h e A E is cl earl y N O T relate d  t o t he st u d y dr u g. 
 
8. 3  
Re p orti n g Pr oce d ures f or All A d verse E ve nts  
     All partici pati n g i n vesti gat ors will assess t he occ urre nce of A Es t hr o u g h o ut t he 
s u bject’s partici p ati o n i n t he st u d y.  S u bjects will be f oll o we d f or t o xicit y f or 3 0 da ys 
after tr eat me nt has b ee n disc o nti n ue d or u ntil deat h, w hic he v er o cc urs first.  T he 
cli nical c o urse of eac h e ve nt will be f oll o we d u ntil res ol uti o n, sta bilizati o n, or u ntil it 
has bee n det er mi ne d t hat t he st u d y treat me nt or partici pati o n is n ot t he ca use.  
     T he i n vesti gat or is res p o nsi ble f or e ns uri n g t hat all a d verse e ve nts o bser ve d b y t he 
i n vesti gat or or r e p orte d b y t he s u bject w hi c h occ ur after t h e s u bject h as si g ne d t he 
i nf or me d c o nse nt are f ull y rec or de d i n t he s u bject’s case re p ort f or m, s u bject’s me dical 
rec or ds, a n d/ or a n y ot h er i nstit uti o nal re q uire me nt. S o urce d oc u me ntati o n m ust be 
a vaila ble t o s u p p ort all a d verse e v e nts. 
     A  la b orat or y  test  a b n or malit y  c o nsi dere d  cli nicall y  rele v a nt  (e. g.,  ca usi n g  t he  
s u bject t o wit h dra w fr o m t he st u d y), re q uiri n g treat me nt or ca usi n g a p pare nt cli nical 
ma nifestati o ns, or j u d ge d rele v a nt b y t he i n v esti gat or, s h o ul d be re p ort e d as a n a d vers e 
e ve nt.  
     T he i n vesti gat or will pr o vi de t he f oll o wi n g f or all a d verse e ve nts: 
•  Descri pti o n of t he e v e nt 
•  Date of o nset a n d res ol uti o n 
•  Gra de of t o xicit y  
•  Attri b uti o n of relate d ness t o t he i n vesti gati o nal a ge nt 
•  Acti o n ta ke n as a res ult of t he e ve nt  
•  O utc o me of e v e nt  
 

 
 
 
 
 
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     I n  t his  st u d y,  des cri pti o ns  a n d  gra di n g  scales  f o u n d  i n  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  4. 0  a vaila ble  at  
htt p://cte p.ca ncer. g o v  will be utilize d f or A E re p orti n g.  
     I n v esti gati ve sites will re p ort a d vers e e ve nts t o t heir res pecti ve I R B acc or di n g t o t he 
l ocal I R B’s p olicies a n d pr oce d ures i n re p orti n g a d verse e v e nts. 
 
S E RI O U S 
A D V E R S E
 E V E N T
 R E P O R TI N G
 A N D
 D O C U M E N T A TI O N
 
R E Q UI R E M E N T S  
     T he I n vesti gat or -s p o ns or m ust be n otifie d of t he occ urre nce of a n y S A E wit hi n 2 4 h o urs 
of t he i n vesti gat or, desi g nee, or site pers o n n el’s k n o wle d ge of t he e v e nt. T he I n vesti gat or -
s p o ns or  is  res p o nsi ble  f or  n otif yi n g  t he  a p pr o priate  healt h  a ut h orities  ( H As),  et hics  
c o m mittees ( E Cs), a n d i n vesti gat ors, of a n y e x p e dite d, a n n u al, or ot her peri o dic safet y 
re p orts i n acc or da n ce wit h a p plica ble re g ulati o ns.  A n y safet y re p ort s u b missi o n will cr oss 
refere nce t he A m g e n  i n vesti gati o nal ne w dr u g (I N D) or cli nical trial a p pr o val ( C T A) 
n u m ber.  
     T he I n v esti gat or is als o res p o nsi ble f or n otif yi n g t he l ocal E Cs i n acc or da nce wit h l ocal 
re g ulati o ns. A d diti o nall y, t he I n v esti gat or-s p o ns or is res p o nsi ble f or re p orti n g S A Es t o 
A m ge n as descri be d  i n S A E Re p orti n g b y I n vesti gat or-s p o ns or t oA m ge n . 
 
8. 4  
Seri o us A d verse E ve nt Re p orti n g Pr oce d ures  
 
Seri o us  a d verse  e ve nts  t hat  occ ur  be gi n ni n g  wit h  t he  si g ni n g of  t he  i nf or me d  
c o nse nt f or m, d uri n g tr eat me nt, or wit hi n 3 0 da ys of t he last d ose of treat m e nt m ust be 
re p orte d t o t he Cle vel a n d Cli nic Pri nci pal I n vesti g at or.  
 
I n v esti gati ve  sites  will  re p ort  s eri o us  a d v erse  e ve nts  t o  t heir  res pecti ve  I R B  
acc or di n g t o t he l o cal  I R B’s p olicies a n d pr oce d ures i n re p orti n g seri o us a d verse  
e ve nts. 
 
  
8. 4. 1 S A E Re p orti n g b y I n vesti g at or- S p o ns or t o A m ge n  
     T he I n v esti gat or-s p o ns or m ust i nf or m A m ge n  i n writi n g b y e-mail or fa x at t he c o ntact 
i nf or mati o n liste d bel o w f or all S U S A Rs t hat are j u d ge d as reas o n a bl y relate d t o t he 
A m ge n  st u d y dr u g. Site will tra ns mit t he fi nal CI O M S of t hat e ve nt t o A m ge n  wit hi n 
t we nt y-f o ur ( 2 4) h o urs of s u b mitti n g t he re p ort t o t he a p plica ble re g ulat or y a ut h orit y. 
     F or re g ulat or y re p orti n g p ur p oses, a n e ve nt of “ Deat h, Ca use U n k n o w n ” fr o m t he st u d y 
s hall be pr ocesse d as a S U S A R.  All f or ms m ust be c o m plete d a n d pr o vi d e d t o A m ge n  i n 
E n glis h.  
     T he I n di vi d ual Case Safet y Re p ort (I C S R) ma y be referre d t o as a n i n di vi d ual safet y 
re p ort or S A E Re p ort, i ncl u di n g Pre g na nc y E x p os ure Re p orts a n d F oll o w u p Re p orts. T he 
I C S R m ust be as c o m plete as p ossi ble, at a mi ni m u m i ncl u di n g e ve nt refere nce n u m ber, 
p r ot oc ol na me a n d n u m ber, i n vesti gat or c o ntact i nf or mati o n, s pecific patie nt i de ntifiers 
(e. g., i nitials, patie nt n u m ber, dat e of birt h or a ge, or ge n der), t h e na m e of t he s us pect St u d y 
Dr u g, t he date a n d d osa ge(s) of e x p os ure, e v e nt,  t he date(s) of e v e nt,  c o u ntr y of e ve nt, 
“ Seri o us” Criteri a, Relati o ns hi p/ca usalit y of St u d y Dr u g, H os pitalizati o n hist or y f or t he 
e ve nt, E ve nt stat us/ o utc o me, Rele va nt hist or y (i ncl u di n g dia g n ostics, la b orat or y val u es, 
ra di o gra p hs, c o nc o mita nt me dicati o ns, a n d e ve nt treat me nt, a n d n arrati ve s u m mar y.  

 
 
 
 
 
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     S p o ns or s hall be res p o nsi ble f or c ollecti n g all S A Es a n d Pre g na nc y a n d Lactati o n 
E x p os ure  Re p orts  a n d  will  e xercise  c o m merciall y  reas o na ble  d ue  dili ge nce  t o  o btai n  
f oll o w-u p i nf or mati o n o n i nc o m plete S A E or Pre g na nc y a n d L actati o n E x p os ure Re p orts. 
I n t he e ve nt t hat t he C o m pa n y re q uires clarifi cati o n or f urt her i nf or mati o n o n i n di vi d ual 
S A E or Pre g na n c y a n d L actati o n E x p os ure R e p orts, C o m pa n y will n ot c o ntact n o n -part y 
i n vesti gat ors directl y, b ut will r o ute all s uc h i n q uiries t hr o u g h S p o ns or f or f or war di n g t o 
s uc h i n vesti gat or(s). S p o ns or will be res p o nsi ble t o e ns ure s uc h i n q uiries are c o m plete d 
a n d ti mel y pr o vi de d t o C o m pa n y.  
     I nf or mati o n n ot a vaila ble at t he ti me of t he i nitial re p ort (e. g., a n e n d dat e f or t he S A E, 
disc har ge  s u m mari es,  l ot  n u m bers,  rele v a nt  la b orat or y  val ues,  s ca n  d ata  a n d  a ut o ps y  
re p orts) w hic h ar e  recei ve d after t he i nitial re p ort m ust be d oc u me nte d o n a f oll o w- u p 
f or m, a n d s u b mitte d t o A m ge n  i n t he sa me ti meli n es as o utli ne d a b o v e.  S p o ns or s hall be 
res p o nsi ble f or o btai ni n g f oll o w-u p i nf or mati o n f or t he S A Es a n d de m o nstrate dili ge nce i n 
atte m pti n g t o o btai n s uc h i nf or mati o n b y, a m o n g ot her t hi n gs, mai ntai n i n g writte n rec or ds 
of s uc h atte m pts. 
     Ot her a g gre gat e a n al ysis i ncl u di n g re p orts c o nt ai ni n g safet y d ata ge n erate d d uri n g t he 
c o urse of t he st u d y is t o be s u b mitte d t o A m ge n  at t he ti me t he s p o ns or I S S s u b mits t o 
a n y b o d y  g o ver ni n g  researc h  c o n d uct  i.e.  R A,  I R B  etc.  Fi nal  st u d y  re p ort  i ncl u di n g  
u n bli n di n g data w he n a p plica ble a n d re p orts of u n a ut h orize d us e of a mar k ete d pr o d u ct t o 
be s u b mitte d t o A m ge n  at t he ti me t he s p o ns or I S S s u b mits t o a n y b o d y g o ver ni n g researc h 
c o n d uct i.e. R A, I R B etc. b ut n ot later t ha n o ne cale n dar year of st u d y c o m pleti o n.  
     S p o ns or will pr o vi de a n a n n ual I N D re p ort t o A m ge n . Re p orts c o ntai ni n g safet y dat a 
ge nerat e d d uri n g t he c o urse of t he st u d y is t o be s u b mitte d t o A m ge n  at t he ti me t he s p o ns or 
s u b mits  t o a n y b o d y  g o ver ni n g  researc h  c o n d u ct,  i.e.  re g ulat or y  a ut h orities  a n d  I R Bs.    
S p o ns or will s u p p ort rec o nciliati o n of all I C S Rs at t he e n d of t he st u d y at a mi ni m u m. 
 
Pre g n a nc y Re p orti n g b y I n vesti g at or-s p o ns or t o A m ge n   
     Re p ort Pre g na nc y a n d p ote ntial i nfa nt e x p os ure i ncl u di n g Lactati o n, wit hi n te n ( 1 0) 
cale n dar da ys of S p o ns or a war e ness. Pr o vi de t o A m ge n  t he S A E re p orts ass ociate d wit h 
pre g na nc y.  S U S A Rs ar e t o be re p orte d wit hi n t we nt y-f o ur ( 2 4) h o urs of s u b mitti n g t he 
re p ort t o t he a p plica ble r e g ulat or y a ut h orit y.  
 
Carfilz o mi b s h o ul d n ot be c har acterize d as a n a b ortifacie nt.  
 
 
T o re p ort a n S A E or ot her s afet y rel ate d i nf or m ati o n t o A m ge n ple ase 
use:  
Dr u g Safet y Re p orti n g P h o ne N u m ber:  
8 8 8- 8 1 4- 8 6 5 3 ( U. S. T oll- Free);  
8 0 5- 4 8 0- 9 2 0 5 ( T oll);  
E mail: s v g -a gs-i n- us @a m ge n.c o m.  
 
 

 
 
 
 
 
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T he S A E tr a ns mittal f or m is i ncl u de d as a n a p p e n di x at t he e n d of t he 
pr ot oc ol T he lea d st u d y c o or di nat or ( Jac kie T o mer) will be res p o nsi ble f or 
re p orti n g all S A E’s t o A m ge n. 
 
 
8. 4. 3  M ulti -Ce n ter Trials wit h Cle vela n d Cli nic I n v esti gat or as Pri nci pal I n v esti gat or 
F or m ulti -site trials w here a C le vela n d Cli nic i n vesti gat or is ser vi n g as t he Pri nci pal 
I n v esti gat or,  eac h  partici pati n g  i n vesti gat or  is  re q uire d  t o  a bi de  b y  t he  re p orti n g  
re q uire me nts set b y t he pr ot oc ol.  
Partici pati n g i n vesti gat ors m ust re p ort all s eri o us a d verse e ve nts t hat o cc ur after t h e 
s u bject  has  si g ne d  t he  i nf or me d  c o nse nt  f or m  t o  t he  C le vela n d  Cli nic Pri nci pal 
I n v esti gat or wit hi n 2 4 h o urs of dis c o ver y or n otificati o n of t he e ve nt.  I nitial seri o us 
a d verse e ve nt i nf or m ati o n a n d all a me n d me nts or a d diti o ns m ust be rec or d e d o n F D A 
F or m  3 5 0 0 A  f or  m a n d at or y  re p orti n g  ( Me d w atc h).    Rele va nt  me di cal  rec or ds  
s h o ul d be fa xe d as s o o n as t he y bec o me a vaila ble.  T he C le vela n d Cli nic Pri nci pal  
I n v esti gat or will re vi e w a n d assess t h e S A E a n d f oll o w t he re p orti n g re q uire me nts i n 
Secti o n 8. 4. 1 a n d 8. 4. 2 a n d c o m m u nicate res ults t o all  i n vesti gati o nal sites.  T he 
partici pati n g i n vesti gat or m ust pr o vi de f oll o w -u p i nf or mati o n o n t he S A E.  Re p ort 
Seri o us A d vers e E v e nts b y e m ail t o  ca ncersaei n b o x @ccf. or g  a n d C C t he S p o ns or -
I n v esti gat or hill b 2 @ccf. or g  a n d lea d st u d y c o or di nat or.  
 
 
Seri o us a d verse e ve nts o cc urri n g after c o ncl usi o n of t he st u d y A N D t h o u g ht t o be 
p ossi bl y relate d t o t he i n vesti gati o nal a ge nt will be c ollecte d a n d re p orte d wit hi n 2 4 
h o urs of disc o ver y or n otificati o n of t he e v e nt. 
Eac h  i n vesti gati ve  site  will  be  res p o nsi ble  t o  re p ort  S A Es  t hat  occ ur  at  t hat  
i nstit uti o n  t o  t heir  res pecti ve  I R B. It  is  t he  res p o nsi bilit y  of  eac h  p artici pati n g  
i n vesti gat or t o re p ort s eri o us a d vers e e v e nts t o t he st u d y s p o ns or a n d/ or ot hers as 
descri be d a b o ve  
 
 
8. 5  
D at a S afet y T o xicit y C o m mittee  
 
It  is  t he  Case  C o m pre he nsi ve  Ca n cer  Ce nter’s  Pri nci pal  I n vesti gat or’s  
res p o nsi bilit y t o e ns ure t hat A L L seri o us a d v ers e e ve nts are re p orte d t o t he Case 
C o m pre he nsi ve Ca ncer Ce nter’s D ata Safet y T o xicit y C o m mittee. T his s u b missi o n is 
si m ulta ne o us wit h t heir s u b missi o n t o t he S p o ns or or ot her Re g ulat or y b o d y. 
 
 
 
 
9. 0       P H A R M A C E U TI C A L I N F O R M A TI O N    
 
A  list  of  t he  a d vers e  e ve nts  a n d  p ote ntial  ris ks  ass ociate d  wit h  t he  
i n vesti gati o nal or c o m m ercial a ge nts a d mi nistere d i n t his st u d y ca n be f o u n d i n 
Secti o n 8.    

 
 
 
 
 
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9. 1 
C arfilz o mi b  
 
C he mic al N a m e:      
(2 S)- N- (( S)- 1-(( S)- 4- m et h yl- 1-(( R)- 2- met h yl o xira n- 2-
yl)- 1- o x o pe nta n- 2 ylcar b a m o yl)- 2- p he n ylet h yl)- 2- (( S)- 2-
( 2- m or p h oli n oacet a mi d o)- 4- p he n yl b uta n a mi d o)-
4 met h yl pe nta na mi de.  
 
Ot her N a m es:         
F or merl y referre d t o as P R - 1 7 1 
 
Cl assific ati o n:          
Pr oteas o me  I n hi bit or, A nti- ne o plastic A ge nt. 
 
M olec ul ar F or m ul a:  
C 4 0H 5 7N 5O 7 
 
C he mic al Str uct ure:   
 
 
 
 
M o de of Acti o n:      
I nhi bit or of t he c h y m otr y psi n-li ke acti vit y of t he 2 0s 
pr oteas o me  
 
Met a b olis m:     
 
 
Carfilz o mi b is ra pi dl y a n d e xte nsi vel y met a b olize d f oll o wi n g I V a d mi nistrati o n t o 
rats, m o n ke ys, a n d h u m a ns. T he pre d o mi na nt m eta b olites are p e pti de fra g me nts a n d 
t he di ol of carfilz o mi b, wit h n o u ni q ue met a b olites i de ntifie d i n h u ma ns, s u g gesti n g 
t hat  pe pti dase  clea v a ge  a n d  e p o xi de  h y dr ol ysis  are  t he  pri nci pal  p at h wa ys  of  
meta b olis m i n all t hese s pecies. T he meta b olites d o n ot i n hi bit pr oteas o me acti vit y. 
C yt oc hr o me P 4 5 0 -me diate d pat h wa ys are n ot si g nifica nt i n t he o v e rall meta b olis m of 
carfilz o mi b.  
 
Carfilz o mi b is als o ra pi dl y meta b olize d b y pe pti dases a n d e x p o xi de h y dr olases 
i n vitr o u p o n i nc u b ati o n wit h rat bl o o d a n d tiss ue h o m o ge nates d eri ve d fr o m t he l u n g, 
ki d ne y, a n d li ver, f urt her c orr o b orati n g t he e xtra he patic mec ha nis ms of m eta b olis m i n 
viv o.  
 
T he v ol u me of distri b uti o n at stea d y state ( Vss) was 0. 3 – 2 L/ k g a n d 0. 3 – 1. 1 L/ k g 
f or r ats a n d m o n ke ys, res pecti vel y. D ue t o meta b olis m i n a variet y of tiss ues a n d t he 
irre versi ble c o vale nt bi n di n g of carfilz o mi b t o t he 2 0 S pr oteas o me, t he Vss val ues ma y 
u n deresti mate  t he  e xte nt  of  tiss ue  distri b uti o n  of  carfilz o mi b.  P ote nt  pr oteas o me  

 
 
 
 
 
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4 1  
i n hi bit or y effects i n a v ariet y of tiss ues f oll o wi n g I V a d mi nistrati o n t o rats at differe nt 
d ose  le vels,  a n d  d etecti o n  of  ra di oacti vit y  i n  a  variet y  of  tiss ues  wit h  a n  I V  
a d mi nistrati o n of [ 3H- P he] -carfilz o mi b t o rats at 2 m g/ k g ( 1 2 m g/ m 2), i n dicate d ra pi d 
a n d wi de distri b uti o n of carfilz o mi b t o tiss ues, e x ce pt brai n. 
 
A n i n vitr o  pr otei n-bi n di n g st u d y usi n g e q uili bri u m dial ysis de m o nstrate d t hat 
a p pr o xi matel y 9 7 % of carfilz o mi b is b o u n d t o h u ma n plas ma pr otei ns, w hic h is si milar 
t o rats a n d m o n ke ys. C yt oc hr o me P 4 5 0 -me diate d  pat h wa ys are n ot si g nifica nt i n t he 
o verall meta b olis m of carfilz o mi b.  
 
Eli mi n ati o n  
  
E xcreti o n of [3H- P he]-carfilz o mi b was deter mi ne d b y q ua ntitati ve w h ole- b o d y 
a ut ora di o gra p h y i n r ats r ecei vi n g a si n gle I V b ol us a d mi nistrati o n of 2 m g/ k g ( 1 2 
m g/ m 2). Uri ne a n d feces acc o u nte d f or 1 4. 1 % a n d 1 8 % of t he d ose d ra di oacti vit y, 
res pecti vel y, at 1 6 8 h o urs p ost- d ose. A p pr o xi mat el y 4 4 % of t he a d mi nistere d 
ra di oacti vit y re mai ne d i n tiss ues, i n dicati n g sl o w eli mi nati o n of dr u g-deri v e d 
ra di oacti vit y, li kel y d ue t o i nc or p orati o n of 3H- p h e n ylala ni ne i nt o cell ular pr otei ns. 
E xcreti o n was als o deter mi ne d i n bile d uct-ca n n ulate d rats f oll o wi n g a si n gle I V 
b ol us a d mi nistrati o n of 2 m g/ k g. Carfilz o mi b was e xcret e d mai nl y i n t he f or m of 
meta b olites wit h less t ha n 1 % of t he d ose e xcrete d i ntact. A b o ut 5 7 % of t h e d ose was 
rec o vere d wit hi n 2 4 h o urs of d osi n g i n b ot h bile a n d uri ne sa m ples. T he li mite d 
rec o ver y was li kel y d ue t o tar get bi n di n g i n cells u na ble t o s y nt hesize ne w 
pr oteas o mes ( e. g., re d bl o o d cells [ R B Cs]) a n d pe pti dic meta b olites t hat ca n n ot be 
differe ntiat e d fr o m e n d o ge n o us c o m p o ne nts.  
 
Pr o d uct descri pti o n :   
Carfilz o mi b f or I njecti o n will be pr o vi de d as a sterile fr oze n li q ui d or l y o p hilize d 
p o w der c o ntai ni n g carfil z o mi b f or a d mi nistrati o n as a sl o w I V p us h.  B ot h t he  fr oze n a n d 
rec o nstit ute d l y o p hilize d prese ntati o ns are e q ui val e nt i n q ua ntitati ve c o m p ositi o n, w hic h 
c o nsists of 2 m g/ m L s ol uti o n of carfilz o mi b Free Base i n  1 0 m M s o di u m citrate b uffer 
( p H 3. 5) c o ntai ni n g 1 0 % ( w/ v) s ulf o b ut ylet her-β -c ycl o de xtri n ( S B E-β -C D, Ca ptis ol ® ).  
I n di vi d uall y cart o ne d si n gle- use vial c o ntai n a d ose of 6 0 m g of carfilz o mi b as a w hite t o 
off -w hite l y o p hilize d  ca k e or p o w der. Carfilz o mi b vials c o ntai n n o a nti micr o bial 
preser v ati ves a n d are i nte n de d o nl y f or si n gle use . 
 
St a bilit y:  
  
U n o pe ne d vials of carfilz o mi b are sta ble u ntil t he date i n dicate d o n t he p ac ka ge 
w he n st ore d i n t he ori gi n al pac ka g e at 2° C t o 8° C ( 3 6° F t o 4 6° F).  Retai n carfilz o mi b 
i n t he ori gi nal pac ka g e t o pr otect fr o m li g ht. T he rec o nstit ute d s ol uti o n c o ntai ns 
carfilz o mi b at a c o nce ntr ati o n of 2 m g/ m L.   W he n refri gerate d ( 2° - 8° C; 3 6° - 4 6° F) , 
t he rec o nstit ute d dr u g is sta ble f or 2 4 h o urs i n a vi al, s yri n ge or I V b a g wit h 5 % 
de xtr ose i n water ( D 5 W).  At r o o m te m perat ure ( ( 1 5° - 3 0° C, 5 9° - 8 6° C) , t hee 
rec o nstit uted dr u g is sta ble f or 4 h o urs i n a vial, s yri n ge or I V b a g i n D 5 W. 
 
R o ute of a d mi nistr ati o n :   

 
 
 
 
 
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Carfilz o mi b f or I njecti o n is a d mi nistere d as a sl o w I V p us h f or a peri o d of u p t o 
3 0 mi n utes. S u bjects s h o ul d ha ve a de di cate d li ne f or dr u g a d mi nistrati o n w he ne ver  
p ossi ble. T he li ne m ust be fl us he d wit h 2 0 cc of n or mal sali ne i m me diatel y bef ore 
a n d after dr u g a d mi nistrati o n. If a de dicate d li ne is n ot p ossi ble, t he e xisti n g i nf usi o n 
li ne m ust be fl us he d wit h a mi ni m u m of 2 0 cc of n or mal sali ne bef ore a n d after dr u g 
a d mi nistrati o n.  
  
Eac h d ose will c o nsist of Carfilz o mi b f or I njecti o n a d mi nistere d o n a m g/ m 2 
basis, a n d s h o ul d be base d o n t he s u bject’s act u al calc ulate d b o d y s urface area ( B S A) 
at baseli ne.  S u bjects wit h a B S A > 2. 2 m2 will recei ve a d ose b ase d u p o n a 2. 2 m2 
B S A.  S u bjects s h o ul d be well h y drate d pri or t o d osi n g wit h carfilz o mi b. 
 
Dr u g Pr oc ure m e nt:    
 
Carfilz o mi b will be s u p plie d f or t his st u d y b y A m ge n , I nc. 
Dr u g A cc o u nta bilit y: T h e i n vesti gat or or d esi g nate d st u d y pers o n n el are res p o nsi ble 
f or mai ntai ni n g acc ur ate dis pe nsi n g rec or ds of t he st u d y dr u g.  All st u d y dr u gs m ust be 
acc o u nte d f or, i ncl u di n g st u d y dr u g acci de ntall y or deli beratel y destr o y e d.   U n der n o 
circ u msta nces will t he i n vesti gat or all o w t he i n vesti gat i o nal dr u g t o be use d ot her t ha n 
as directe d b y t he pr ot oc ol.  If a p pr o priate, dr u g st ora ge, dr u g dis pe nsi n g, a n d dr u g 
acc o u nta bilit y ma y be dele gate d t o t he p har m ac y s ecti o n of t he i n vesti gati ve site.  
  
Dr u g Destr u cti o n: At t he c o m pleti o n of t he st u d y, t here will be a fi nal rec o nciliati o n 
of dr u g s hi p pe d, dr u g c o ns u me d, a n d dr u g re mai ni n g. T his rec o nciliati o n will be l o g ge d 
o n t he dr u g rec o nciliati o n f or m, si g ne d a n d date d. A n y discre pa n cies n ote d will be 
i n vesti gate d, res ol ve d, a n d d oc u me nte d pri or t o ret ur n or destr ucti o n of u n use d st u d y 
dr u g. Dr u g destr o y e d o n site will be d oc u me nte d i n t he st u d y files. 
 
 
 
9. 2    C ycl o p h os p h a mi de  
 
C he mic al N a m e:      
2- [ bis( 2-c hl or o et h yl)a mi n o]tetra h y dr o- 2 H- 1, 3, 2-
o xaza p h os p h ori n e 2- o xi d e m o n o h y drate.  
 
Ot her N a m es:         
C yt o xa n ™ 
 
Cl assific ati o n:          
Nitr o ge n M ustar d, A nti n e o plastic A ge nt 
 
M olec ul ar F or m ul a:  
m olec ular f or m ula C 7H 1 5Cl 7N 2O 2P• H 2O 
 
 
M o de of Acti o n:        
A n acti vate d f or m of c y cl o p h os p ha mi de, p h os p h ora mi de 
m ustar d, al k ylates or bi n ds wit h ma n y i ntracell ular 
m olec ular str uct ures, i ncl u di n g n ucleic aci ds. Its 
c yt ot o xic acti o n is pri maril y d ue t o cr oss-li n ki n g of 

 
 
 
 
 
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stra n ds of D N A a n d R N A, as well as t o i n hi biti o n of 
pr otei n s y nt hesis. 
 
Met a b olis m:     
 
A bs or pti o n:  S yste mic: Bi oa vaila bilit y: > 7 5 %  
Met a b olis m :  S yste mic: He patic  
E xcreti o n  S yste mic: Re nal, 5 t o 2 5 % u nc ha n ge d. I n dial ysis: 
c ycl o p h os p ha mi de is dial yza ble. S yste mic: Re nal: 5 t o 2 5 % u nc ha n ge d 
Eli mi n ati o n H alf Life
 
 
S yste mic : U nc ha n ge d dr u g — 3 t o 1 2 h o urs. 
S yste mic: 3 t o 1 2 h 
 
Pr o d uct descri pti o n:  w hite cr ystalli ne p o w der   
 
S ol uti o n pre p ar ati o n:  rec o nstit ute wit h N S t o i nject directl y , (i nf usi o n) diss ol ve i n 
Sterile Water f or I njecti o n, U S P ( 2 5 m L f or 5 0 0 m g, 5 0 m L f or 1 g, 1 0 0 m L f or 2 g); 
t he n dil ute i n D 5 W, 5 % de xtr ose i n 0. 9 % n or m al sali ne (D 5 N S ) or lact ate d ri n gers 
( D 5 L R or L R). 
 
St or a ge re q uire m e nts :  St ora ge at or bel o w 7 7° F ( 2 5° C) is rec o m me n de d; t his pr o d uct 
will wit hsta n d brief e x p os ure t o te m perat ures u p t o 8 6° F ( 3 0° C) b ut s h o ul d be pr otecte d 
fr o m te m perat ures a b o v e 8 6° F ( 3 0° C). 
 
St a bilit y:   Rec o nstit ute d l y o p hilize d c ycl o p h os p h a mi de is  c h e micall y a n d p h ysicall y 
sta ble f or 2 4 h o urs at r o o m te m perat ure or f or si x da ys w he n refri gerate d. 
 
R o ute of a d mi nistr ati o n :  S h ort i ntra ve n o us i nf usi o n o ver 3 0- 6 0 mi n utes. 
 
Dr u g Pr oc ure m e nt:  C ycl o p h os p ha mi de m ust be o btai ne d fr o m c o m merci al s o urces.   

 
 
 
 
 
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9. 3       D o x or u bici n 
 
C he mic al N a m e:      
1 4- H y dr o x y da u n o m yci n 
 
Ot her N a m es:         
D o x or u bici n H y dr oc hl ori de 
 
Cl assific ati o n:          
A nt hrac ycli ne, A nti ne o plastic A ge nt 
 
M olec ul ar F or m ul a:  
C 2 7H 2 9N O 1 1 
 
 
M o de of Acti o n:      
D N A i ntercalati o n 
 
Met a b olis m:     
 
A)  Distri b uti o n Sites  
  
1)  Pr otei n Bi n di n g:  7 4 % t o 7 6 %  
 
2)  Ot her Distri b uti o n  Sites  
Place nta:   Place nta c o nce ntrati o ns of d o x or u bici n were 1. 2 n m ol/ g of 
tiss ue w he n a si n gle patie nt recei ve d d o x or u bici n a b o ut 4 8 h o urs 
bef ore d eli ver y. U m bilical c or d c o n ce ntrati o ns were 0. 0 8 n m ol/ g i n t he 
sa me patie nt. 
B)  Distri b uti o n Ki netics  
 
1)  Distri b uti o n Half -Life :  5 mi n utes 
  
2)  V ol u me of Distri b uti o n:  2 0 t o 3 0 liters/ kil o gra m 
C)  Meta b olis m Sites a n d Ki netics  
  
Li ver, e xte nsi ve C ha n g es i n li ver f u ncti o n ca use d b y he pat ocell ular 
carci n o ma res ult i n ele vate d plas ma c o nce ntrati o ns of d o x or u bici n ol rat her 
t ha n d o x or u bici n [2 1 ]. 
D)  Meta b olites  
  
1)  D o x or u bici n ol, acti ve. 
  
2)  A dria m yci ne a gl yc o n es.  
 E)  Ki d ne y 
  
1)  Re nal E xcr eti o n:  5 % t o 1 2 % 
  
2)  O nl y 1 % a p pears i n t he uri ne o ver 5 da ys; less t ha n 1 % a p pears i n  
  
    t he uri ne as a gl y c o nes [2 2 ]. 
F)  Ot her  
  
( 1)  Bile, 4 0 % a n d (2)  Feces, 5 0 % [2 3 ]. 
G)  Pare nt C o m p o u n d 
 
1)  Eli mi nati o n  Half -life:  2 0 t o 4 8 h o urs.   
H)  Meta b olites:   D o x or u bici n ol, 2 0 t o 4 8 h o urs. 
 
Pr o d uct descri pti o n:   
 
D o x or u bic i n H y dr oc hl ori de I nj ecti o n is a sterile pare nteral, is ot o nic  s ol uti o n i n 
eit her si n gle d ose of m ulti- d ose vials. 
 

 
 
 
 
 
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S ol uti o n pre p ar ati o n:   
 
After rec o nstit uti o n, s ol uti o n is sta ble at r o o m te m perat ure f or 7 da ys a n d i n t he 
refri gerat or b et wee n 2 a n d 8 de grees C f or 1 5 da ys. Pr otect fr o m s u nli g ht. 
 
St or a ge re q uire m e nts :   
 
St ore p o w der at c o ntr olle d r o o m te m perat ure bet w ee n 1 5 a n d 3 0 de grees C ( 5 9 a n d 
8 6 de grees F). St ore i n ori gi nal cart o n t o pr otect fr o m li g ht. Discar d a n y u n use d p orti o n  
 
St a bilit y:   
  
 D o x or u bici n 8 m g/ 5 0 0 m L i n gl uc ose 5 % was st a ble f or 7 d a ys w he n st ore d i n 
P V C ( p ol y vi n yl c hl ori de) ba gs at 4 de grees C wit h li g ht pr otecti o n. T here w as als o n o 
l oss of d o x or u bici n w he n i nf use d via P V C i nf usi o n ba gs wit h P V C a d mi nistrati o n. 
  
D o x or u bici n 2 m g/ m L was sta ble f or u p t o 1 4 d a ys at 3 or 2 3 de grees C a n d f or a n 
a d diti o nal 2 8 da ys at 3 0 de grees C i n p orta bl e p u m p reser v oirs. 
  
D o x or u bici n was sta ble (less t ha n 1 0 % l oss of p ote nc y) f or 2 4 da ys i n 0. 9 % 
s o di u m c hl ori de st ore d at 2 5 de grees C i n P V C ( p ol y vi n yl c hl ori de) mi ni  ba gs a n d 
s yri n ges at a p H of 6. 4 7. Als o, d o x or u bici n was sta ble f or at least 4 3 da ys i n 0. 9 % 
s o di u m c hl ori de ( p H, 6. 4 7) a n d 5 % de xtr ose ( p H, 4. 3 6) at 4 a n d - 2 0 d e grees C. 
  
Alt h o u g h d o x or u bici n d oes react wit h al u mi n u m, t he reacti o n is sl o w a n d d oes 
n ot res ult i n a s u bsta ntial l oss of p ote nc y [ 2 6 3]. D o x or u bici n rec o nstit ute d wit h 0. 9 % 
s o di u m c hl ori de i njecti o n or sterile water f or i njecti o n t o a c o nce ntrati o n of 2 m g/ m L 
a n d c o m bi ne d wit h steel, plastic, or al u mi n u m was e xa mi ne d f or c ol or, p H, a n d 
p ote nc y. I n t he first 2 4 h o urs, p H c ha n g e d fr o m 4. 8 t o 4. 9 i n s ol uti o ns c o ntai ni n g 
plastic or steel. I n t he al u mi n u m -c o ntai ni n g s ol uti o n, t he p H c ha n g e d fr o m 4. 8 t o 5. 2 
a n d t he s ol uti o n c ha n ge d t o a dar ker r u b y re d. T here was n o c ha n ge i n p ote nc y i n a n y 
of t he s ol uti o ns c o ntai ni n g steel a n d al u mi n u m, res pecti vel y. N o preci pitati o n was 
n ote d; t heref or e, d o x or u bici n ma y be safel y i njecte d t hr o u g h a n al u mi n u m- h u b be d 
nee dle. H o w e ver, rec o nstit ute d d o x or u bici n s h o ul d n ot be st ore d i n s yri n ges ca p pe d 
wit h al u mi n u m - h u b be d nee dles. 
 
R o ute of a d mi nistr ati o n : 
( 1).  F or I V use o nl y; d o n ot a d mi nister I M or s u b c uta ne o usl y ( S C) 
( 2).  A d mi nister sl o wl y i nt o freel y r u n ni n g I V of S o di u m C hl ori de I njecti o n, U S P  or 
D 5 W o ver n ot less t ha n 3 t o 5 mi n utes, de pe n di n g o n t he size of t he v ei n   
a n d 
t he d osa ge; a v oi d vei ns o ver j oi nts or t h ose wit h p o or drai na g e; B utterfl y( R) 
nee dle i nsert e d  i nt o a lar ge vei n is prefera bl e. 
( 3). Care s h o ul d be ta ke n t o a v oi d e xtra vasati o n as se vere l ocal tiss ue necr osis will 
occ ur; e xtr a vasati o n ma y occ ur wit h or wit h o ut b ur ni n g or sti n gi n g, a n d e ve n if 
t here is bl o o d ret ur n o n as pirati o n of t he nee dle( 4).  If e xtra vas ati o n is s us pecte d, 
i m me diatel y st o p a d mi nistrati o n a n d restart i n a n ot her vei n; i nter mitte ntl y a p pl y 
ice t o t he site f or 1 5 mi n utes, 4 ti mes dail y f or 3 da ys. 
 
Dr u g Pr oc ure m e nt:  D o x or u bici n m ust be o btai ne d fr o m c o m mercial s o urces.   

 
 
 
 
 
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9. 4       Pe gfil gr asti m 
 
C he mic al N a m e:      
N- ( 3- h y dr o x y pr o p yl) met hi o n ylc ol o n y-sti m ulati n g fact or 
( h u ma n), 1-et h er wit h α- met h yl-ω -
h y dr o x y p ol y( o x yet h yle n e)  
 
Ot her N a m es:         
Ne ulasta ™, rec o m bi na nt met hi o n yl h u ma n gra n ul oc yte 
c ol o n y-s ti m ulati n g fact or ( G-C S F)  
 
Cl assific ati o n:           
He mat o p oietic Gr o wt h Fact or  
 
M olec ul ar F or m ul a:   
C 8 4 9H 1 3 4 8N 2 2 3O 2 4 4S 9•( C2H 4O) n 
 
 
M o de of Acti o n:       
Bi os y nt hetic he mat o p oietic a ge nt t hat affects t he 
pr oliferati o n a n d differe ntiati o n of ne utr o p hils wit hi n 
b o ne marr o w.  
 
Met a b olis m:    
Re nal.  Ne utr o p hil rece pt or bi n di n g is a n i m p orta nt fact or 
i n pe gfil grasti m cleara nce.  Ser u m cleara n ce is rel ate d t o 
t he n u m ber of circ ulati n g ne utr o p hils; ser u m 
c o nce ntrati o ns of t he dr u g decli ne ra pi dl y wit h res ol uti o n 
of ne utr o pe nia. 
 
Pr o d uct descri pti o n :   
 
P e gfil grasti m  is pr o vi de d i n a dis pe nsi n g pac k c o ntai ni n g o ne s yri n ge. 
 
S ol uti o n pre p ar ati o n:   
 
Pe gfil grasti m  is s u p plie d as a preser vati ve- free s ol uti o n c o ntai ni n g 6 m g ( 0. 6 m L) 
at a c o nce ntrati o n of 1 0 m g/ m L i n a si n gle -d ose s yri n ge wit h a 2 7 ga u g e, 1/ 2 i nc h 
nee dle wit h  a n Ultr a Safe Ò Nee dle G uar d.    
 
St or a ge re q uire m e nts :   
 
Pe gfil grasti m  s h o ul d  be  st ore d  refri g erate d  at  2°  t o  8° C  ( 3 6°  t o  4 6° F);  s yri n ges 
s h o ul d be ke pt i n t heir cart o n t o pr otect fr o m li g ht u ntil ti me of use. S ha ki n g s h o ul d be 
a v oi de d.  Bef ore i njecti o n‚ pe gfil grasti m  ma y b e all o we d t o reac h r o o m te m perat ure 
f or a ma xi m u m of  4 8 h o urs b ut s h o ul d be pr otect e d fr o m li g ht.. 
 
St a bilit y:    
 
Pe gfil grasti m  left at r o o m te m perat ure f or m ore t ha n 4 8 h o urs s h o ul d b e discar de d. 
Freezi n g s h o ul d be a v oi de d; h o we ver, if  acci de ntall y fr oze n, pe gfil grasti m s h o ul d be 
all o we d t o t ha w i n t he refri gerat or bef ore  a d mi nistrati o n. If fr oze n a s ec o n d ti me, 
pe gfil grasti m  s h o ul d be discar de d. 
 

 
 
 
 
 
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R o ute of a d mi nistr ati o n :  S u bc uta ne o us i njecti o n 
 
Dr u g Pr oc ure m e nt:  
 
Pe gfil grasti m  will be o btai ne d fr o m c o m mercial s o urces.  
 
 
9. 5        Pre d nis o ne  
 
C he mic al N a m e:      
1 7, 2 1- di h y dr o x y pre g n a- 1, 4- die ne- 3, 1 1, 2 0-tri o ne 
 
Ot her N a m es:         
N/ A  
 
Cl assific ati o n:          
A dre nal Gl uc oc ortic oi d, I m m u ne S u p pressa nt 
 
M olec ul ar F or m ul a:  
C 2 1H 2 6O 5 
 
 
M o de of Acti o n:      
Pre d nis o ne is a n a dre n oc ortical ster oi d wit h salt-retai ni n g 
pr o perties. It is a s y nt heti c gl uc oc ortic oi d a n al o g, w hic h 
is mai nl y use d f or a nti-i nfla m mat or y effects i n differe nt 
dis or ders of ma n y or g a n s yste ms. It ca uses pr of o u n d a n d 
varie d meta b olic effect s, m o difies t he i m m u ne res p o nse 
of t he b o d y t o di verse sti m uli  a n d is als o use d as 
re place me nt t hera p y f or a dre n oc ortical deficie nt p atie nts . 
 
Met a b olis m:   
 
A bs or pti o n 
A)  Bi o a v ail a bilit y  
 
1)  Oral, re g ular releas e: 9 2 %  
 Distri b uti o n  
A)  Distri b uti o n Sites  
 
1)  Pr otei n Bi n di n g 7 0 %,   T he acti ve met a b olite, 
pre d nis ol o ne, is n o nli nearl y b o u n d t o tra nsc orti n a n d 
al b u mi n . 
 
 
B)  Distri b uti o n Ki netics  
 
1))  V ol u me of Distri b uti o n 0. 4 t o 1 L/ k g 
 
 
 
Met a b olis m Sites a n d Ki netics  
 
Li ver, e xte nsi ve. 
 
a) T he li ver re d u ces t he 1 1 - o x o gr o u p of pre d nis o ne t o 
f or m t he bi ol o gicall y acti ve ster oi d, pre d nis ol o ne. 
 

 
 
 
 
 
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b)  Hist oricall y, pre d nis ol o ne has bee n rec o g ni ze d as t he 
pri mar y meta b olite of pre d nis o ne; h o we ver, s o me w or k 
has esta blis he d t hat pre d nis o ne a n d pre d nis ol o ne u n der g o 
c o m ple x re versi ble meta b olis m. After oral d oses of 
pre d nis o ne or pre d nis ol o ne, t he plas m a c o n ce ntrati o n -
ti me pr ofiles f or b ot h a ge nts are s u peri m p osa ble. 
 
 
Pr o d uct descri pti o n:    
 
A vaila ble as 1 m g, 2. 5 m g, 5 m g, 1 0 m g, 2 0 m g, a n d 5 0 m g ta blets a n d as oral 
s ol uti o n ( 5 m g/ 5 ml) 
 
S ol uti o n pre p ar ati o n:   
 
A vaila ble as  c o m merciall y -a vaila ble oral ta blets or pre- pre pare d oral s ol uti o n. 
 
St or a ge re q uire m e nts :   
 
St ore at c o ntr olle d r o o m te m perat ure at 2 5 de grees C ( 7 7 de grees F), wit h e x c ursi o n 
per mitte d bet wee n 1 5 a n d 3 0 de grees C  
( 5 9  a n d  8 6  de grees  F).  Pr otect  ta bl ets  
fr o m m oist ure.  
 
St a bilit y:   Ta blets are sta ble at r o o m te m perat ure u ntil t he date n ote d o n t he pac ka gi n g.   
 
R o ute of a d mi nistr ati o n :  Oral  
 
Dr u g Pr oc ure m e nt:  Pre d nis o ne m ust be o btai ne d fr o m c o m merci al s o urces.   
 
 
9. 6        Rit u xi m a b 
 
C he mic al N a m e:      
I D E C- C 2 B 8, C hi meric a nti- C D 2 0 m o n ocl o nal a nti b o d y, 
 
Ot her N a m es:         
Rit u xa n ™, Ma bt hera ™ 
 
Cl assific ati o n:          
M o n ocl o nal a nti b o d y, a nti ne o plastic a ge nt  
 
M olec ul ar F or m ul a:  
C 6 4 1 6H 9 8 7 4N 1 6 8 8O 1 9 8 7S 4 4 
 
 
M o de of Acti o n:      
Rit u xi ma b bi n ds wit h hi g h affi nit y t o C D 2 0- p ositi ve 
cells, perf or ms h u ma n effect or f u n cti o ns i n vitr o, a n d 
de pletes B cells i n viv o. T he F A b d o m ai 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 n cti o ns t o me diate B 
cell l ysis i n vitr o. T he bi ol o gical effect is ma nifeste d b y 

 
 
 
 
 
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B-cell de pleti o n i n peri p heral bl o o d, l y m p h n o des, a n d 
b o ne marr o w.  
 
Met a b olis m:    
N ot f ull y u n derst o o d.  G e nerall y belie v e d t o be d e gra de d 
n o ns pecificall y i n t he li ver.  
 
Pr o d uct descri pti o n:      Rit u xi ma b is a sterile, clear, c ol orless, pres er vati ve -free li q ui d 
c o nce ntrate f or i ntra ve n o us (I V) a d mi nistrati o n. 
 
S ol uti o n pre p ar ati o n:    
 
Usi n g a p pr o priate ase pti c tec h ni q ue, wit h dra w t h e necessar y a m o u nt of rit u xi ma b 
a n d dil ute t o a fi nal c o n ce ntrati o n of 1 t o 4 m g/ m L i nt o a n i nf usi o n ba g c o ntai ni n g 
eit her 0. 9 % S o di u m C hl ori de or 5 % De xtr os e i n Water. Ge ntl y i n vert t h e ba g t o mi x 
t he s ol uti o n.  Discar d a n y u n use d p orti o n left i n t he vial.  Ca uti o n s h o ul d be ta ke n 
d uri n g t he pre par ati o n of t he dr u g, as s ha ki n g ca n ca use a g gre gati o n a n d preci pitati o n 
of t he a nti b o d y. 
 
St or a ge re q uire m e nts :   
 
Rit u xi ma b  is  a  sterile,  clear,  c ol orless,  pres er v ati ve -free  li q ui d  c o nce ntrate  f or  
i ntra ve n o us  (I V)  a d mi nistrati o n.  T he  pr o d u ct  is  f or m ulate d  f or  i ntra ve n o us  
a d mi nistrati o n i n 9. 0 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 di h y drate, 
0. 7 m g/ m L p ol ys or bate 8 0, a n d Sterile Water f or I njecti o n. T he p H is a dj uste d t o 6. 5.   
 
St a bilit y:    
 
Rit u xi ma b is bi ol o gicall y a n d c he micall y sta ble at 2° C t o 8° C ( 3 6° F t o 4 6° F) a n d 
has a pr o p ose d s helf lif e sta bilit y of 3 0 m o nt hs.  O nce rec o nstit ute d i nt o I V ba gs, 
rit u xi ma b is c he micall y sta ble f or u p t o 2 4 h o urs at 2° C t o 8° C ( 3 6° F t o 4 6° F), f oll o we d 
b y u p t o 2 4 h o urs at r o o m te m perat ure ( 2 3° C).  H o we ver, si nce rit u xi ma b s ol uti o ns d o 
n ot c o ntai n preser vati ve, dil ute d s ol uti o ns s h o ul d be st ore d refri g erate d ( 2° C t o 8° C).  
N o i nc o m pati bilities bet wee n rit u xi ma b a n d p ol y vi n ylc hl ori de or p ol yet h yle ne ba gs 
h a ve  bee n  o bser v e d.   Rit u xi ma b  vials  s h o ul d  be  pr otect e d  fr o m  direct  s u nli g ht.   
Rit u xi ma b vials are i nte n de d f or si n gle use o nl y.  D o n ot use be y o n d t he e x pirati o n date 
sta m pe d o n t he cart o n. 
 
R o ute of a d mi nistr ati 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.  D o n ot 
i nf use  rit u xi ma b  C o nc urre nt l y  wit h  a n ot her  I V  s ol uti o n  or  ot her  I V  me dicati o ns.  
Pre me dicati o n,  c o nsisti n g  of  aceta mi n o p he n  6 5 0  m g  t o  1 0 0 0  m g  P O  a n d  
di p he n h y dra mi ne 2 5 t o 5 0 m g I V or P O, will be a d mi nistere d bef ore eac h i nf usi o n of 
rit u xi ma b.   Pre me dicati o n  ma y  atte n uate  i nf usi o n-relate d  e v e nts.  Si nce  tra nsie nt  
h y p ote nsi o n ma y occ ur d uri n g rit u xi ma b i nf usi o n, a nti -h y perte nsi ve me dicati o ns will 
be wit h hel d 1 2 h o urs pri or t o rit u xi ma b i nf usi o n. 
 
Rit u xi ma b  is  a d mi nistere d  i ntra ve n o usl y.  A n  i n -li ne  filter  is  n ot  re q uire d.  
A d mi nister per i nstit uti o nal g ui deli nes.  

 
 
 
 
 
C A S E 3 4 1 3  C R -C H O P  
Pr ot oc ol Versi o n   
 
 
5 0  
 
Rit u xi ma b  i nf usi o n  m ust  be  i nterr u pte d  f or  se vere  reacti o ns.   If  t he  patie nt  
e x perie n ces f e ver a n d ri g ors, t he a nti b o d y i nf usi o n is disc o nti n ue d. T he se v erit y of t he 
si de eff ects will be e val uate d. I n m ost cases, t h e i nf usi o n ca n b e res u me d at a 5 0 % 
re d ucti o n i n rate (e. g., fr o m 1 0 0 m g/ hr t o 5 0 m g/ hr) w he n s y m pt o ms ha ve c o m pletel y 
res ol ve d.  M ost patie nts w h o ha ve e x perie nce d n o n-life-t hreate ni n g i nf usi o n-relate d 
reacti o ns ha v e bee n a ble t o c o m plete t he f ull c o urs e of rit u xi ma b t hera p y.   
 
F oll o wi n g t he a nti b o d y i nf usi o n, t he i ntra ve n o us li ne s h o ul d be m ai ntai ne d f or 
me dicati o ns as n ee d e d. If t here are n o c o m plicati o ns after o ne h o ur of o bs er vati o n, t he 
i ntra ve n o us li ne ma y be disc o nti n ue d.. T he patie nt s h o ul d be treate d acc or di n g t o t he 
bes t a vaila ble l ocal practices a n d pr oce d ures. I n patie nts wit h detecta ble circ ulati n g 
l y m p h o ma cells, t he i nitial i nf usi o n rate m ust be re d uce d t o 2 5 m g/ hr; t hese patie nts 
ma y e x perie nce m ore  fr e q ue nt  a n d  se vere tra nsie nt  fe ver a n d  ri g ors, s h ort ne ss of  
breat h, a n d h y p ote nsi o n.  
 
N O T E:  I n  a d diti o n,  alter nati ve  rit u xi ma b  i nf usi o n  rates  (i.e.,  “ra pi d  rit u xi ma b  
i nf usi o n”) ca n be use d per i nstit uti o nal  g ui deli nes as l o n g as t he t otal  n u m ber of 
milli gra ms of rit u xi ma b is t he sa me a n d t hat “ra pi d i nf usi o n” is n ot a d mi nistere d wit h 
t he patie nt’s first rit u xi ma b c ycle. F urt her, a rit u xi ma b i nf usi o n ti me s h o ul d n ot be less 
t ha n 9 0 mi n utes i n d urati o n. 
 
Dr u g Pr oc ure m e nt:  Rit u xi ma b m ust be o btai ne d fr o m c o m merci al s o urces.   
 
 
9. 7       Vi ncristi ne  
 
C he mic al N a m e:      
( 3a R, 3a 1 R, 4 R, 5 S, 5a R, 1 0 b R)-met h yl 4 -acet o x y- 3a-et h yl-
9-(( 5 S, 7 S, 9 S)- 5-et h yl- 5- h y dr o x y- 9-( met h o x y car b o n yl)-
2, 4, 5, 6, 7, 8, 9, 1 0- octa h y dr o- 1 H- 3, 7- met h a n o[ 1] 
azac ycl o u n deci n o[ 5, 4- b]i n d ol- 9- yl)- 6- f or m yl- 5- h y dr o x y-
8- met h o x y- 3a, 3a 1, 4, 5, 5 a, 6, 1 1, 1 2- octa h y dr o- 1 H-
i n d olizi n o[ 8, 1-c d]car baz ole- 5-car b o x ylate 
 
Ot her N a m es:         
O nc o vi n ™ 
 
Cl assific ati o n:          
Vi nca al kal oi d, mit otic i n hi bit or, a nti ne o plastic  a ge nt 
 
M olec ul ar F or m ul a:  
C 4 6H 5 6N 4O 1 0  
 
 
M o de of Acti o n:      
Vi ncristi ne s ulfate, a n o n c ol ytic vi nca al kal oi d, has a n 
u n k n o w n mec ha nis m of acti o n, alt h o u g h it is t h o u g ht t o 
be relate d t o t he arrest of re plicati n g cells at t he 
meta p hase sta g e t hr o u g h pre ve nti o n of micr ot u b ul e 
f or mati o n i n t he mit otic s pi n dle. 
 
Met a b olis m:     
 

 
 
 
 
 
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Pr ot oc ol Versi o n   
 
 
5 1  
A bs or pti o n      Pr otei n bi n di n g: yes 
Met a b olis m      He patic; P 4 5 0 C Y P 3 A s u bfa mil y 
E xcreti o n      Fecal: a b o ut 8 0 %     Re nal: 1 0 % t o 2 0 %     
Dial yza ble: n o ( h e m o dial ysis)  
Eli mi n ati o n H alf Life      8 5 h ( 1 9 h t o 1 5 5 h) 
 
Pr o d uct descri pti o n:    
 
Vi ncristi ne s ulfate is a w hite t o off -w hite p o w der.  Eac h m L c o ntai ns vi ncristi ne 
s ulfate, 1 m g ( 1. 0 8 μ m ol); ma n nit ol, 1 0 0 m g; a n d water f or i njecti o n, qs. Acetic aci d 
a n d s o di u m acetat e ha ve bee n a d d e d f or p H c o ntr ol. T he p H of Vi n cristi ne S ulfate 
I njecti o n, U S P ra n ges fr o m 3. 5 t o 5. 5. 
 
S ol uti o n pre p ar ati o n: . 
 
Dil ute o nl y i n N S or D 5 W; d o n ot dil ute i n s ol uti o ns t hat raise or l o w er t he p H 
o utsi de t he r a n ge of 3. 5 -5. 5.   Dis pe nse wit h pr o vi de d stic ker or o v er wra p t hat states 
" F A T A L I F GI V E N I N T R A T H E C A L L Y. F O R I N T R A V E N O U S U S E O N L Y".  
 
St or a ge re q uire m e nts :  
  
 T he  r ea d y -t o-us e  s ol uti o n  s h o ul d  be  refri g erate d  d uri n g  st ora g e,  h o w e ver,  n o  
s pecific te m p erat ur e r ec o m me n dati o ns are pr o vi de d b y t he ma n ufact urer. Pr otecti o n 
fr o m li g ht has bee n rec o m me n de d.   If st ore d at r o o m te m perat ure ( 1 5 t o 3 0 de grees C) 
or i n a c o ol place ( 8 t o 1 5 de grees C), vi ncristi ne s ulfate is sta ble f or 1  m o nt h. If t he n 
refri gerate d,  t he  st a bilit y  of  vi ncristi ne  s ulfate  is  as  ori gi nall y  la bele d  b y  t he  
ma n ufact ur er ( Lill y).  
 
St a bilit y:    
 
Vi ncristi ne s ulfate i n 5 % de xtr ose i njecti o n is sta ble f or 2 4 h o urs i n b ot h glass a n d 
P V C c o ntai ners  
 
R o ute of a d mi nistr ati o n :  
 
S yri n ges s h o ul d n ot be use d f or vi ncristi ne a d mi nistrati o n. A d mi nisteri n g via a mi ni  
ba g  i nf usi o n is rec o m me n de d t o pr otect a gai nst acci de ntal i ntrat hecal a d mi nistrati o n.  
A d mi nister via free -fl o wi n g i ntra ve n o us (I V) nee dle or cat heter; i nject directl y i nt o 
vei n or i nt o t u bi n g of a r u n ni n g I V i nf usi o n wit hi n 1 mi n ute.  Vi ncristi ne is c o nsi der e d 
a vesica nt. Car e s h o ul d b e ta ke n t o a v oi d e xtra vas ati o n. 
 
Dr u g Pr oc ure m e nt:  Vi ncristi ne  m ust be o btai ne d fr o m c o m merci al s o urces.   
 
 
 
9. 8       Ac ycl o vir 
 
C he mic al N a m e:      
2- a mi n o- 1, 9- di h y dr o- 9-[( 2- h y dr o x yet h o x y) met h yl]- 6 H-
p uri n- 6- o ne 

 
 
 
 
 
C A S E 3 4 1 3  C R -C H O P  
Pr ot oc ol Versi o n   
 
 
5 2  
 
Ot her N a m es:         
Z o vira x ™ 
 
Cl assific ati o n:          
n ucle osi de a nal o g u e, a nti viral a ge nt  
 
M olec ul ar F or m ul a:  
C 8H 1 1N 5O 3  
 
 
M o de of Acti o n:      
Ac y cl o vir is c o n verte d i nt o ac ycl o- g ua n osi n e 
m o n o p h os p hate b y viral t h y mi di ne ki nase a n d f urt her 
p h os p h or ylate d i nt o t he acti ve tri p h os p hate f or m b y 
cell ular ki nases.  A c ycl o - G T P is t he n i nc or p orate d i nt o 
viral D N A  d uri n g s y nt hesis, ca usi n g pre mat ure c h ai n 
ter mi nati o n 
 
Met a b olis m:     
 
A bs or pti o n      A bs or pti o n fr o m GI tract is varia bl e a n d 
i nc o m plete; 1 0– 3 0 % of a n oral d ose ma y be a bs or be d.  9 
– 3 3 % is pr otei n b o u n d.  
Met a b olis m      Meta b olize d partiall y t o 9 -
car b o x y met h o x y met h yl g ua ni ne; a als o c o n verte d 
i ntracell ularl y i n cells i nfecte d wit h her p es vir uses t o 
ac ycl o vir tri p h os p hate  
E xcreti o n      E xcrete d pri nci pall y i n uri ne as u nc h a n ge d 
dr u g  
Eli mi n ati o n H alf Life      2. 1 – 3. 5 h o urs 
 
Pr o d uct descri pti o n:    
 
Ac ycl o vir is a w hite, cr ystalli ne p o w der.  E ac h 4 0 0-m g ta blet of Z o v ira x c o ntai ns 
4 0 0 m g of ac ycl o vir a n d t he i nacti ve i n gre die nts ma g nesi u m stearate, micr ocr ystalli ne 
cell ul ose,  p o vi d o ne,  a n d  s o di u m  starc h  gl yc olate.  Eac h  teas p o o nf ul  ( 5  m L)  of  
Z O VI R A X S us pe nsi o n c o ntai ns 2 0 0 m g of ac y cl o vir a n d t he i nacti ve i n gre die nts 
met h yl para be n  0. 1 %  a n d  pr o p yl para b e n  0. 0 2 %  (a d de d  as  pres er vati ves),  
car b o x y met h ylcell ul ose  s o di u m,  fla v or,  gl yceri n,  micr ocr ystalli ne  cell ul ose,  a n d  
s or bit ol. 
 
S ol uti o n pre p ar ati o n: . 
 
T he ma xi m u m s ol u bilit y i n water at 3 7° C is 2. 5 m g/ m L.  It is a vaila ble i n ca ps ules, 
ta blets or as a s us pe nsi o n (2 0 0 m g/ 5 ml).  
 
 
St or a ge re q uire m e nts :  
  
 Ca ps ules a n d ta blets s h o ul d be st ore d i n t i g ht, li g ht-resista nt c o ntai ners b et wee n  
1 5 – 2 5° C .  T he s us pe nsi o n s h o ul d be mai ntai ne d bet wee n 1 5 –2 5° C.  
 

 
 
 
 
 
C A S E 3 4 1 3  C R -C H O P  
Pr ot oc ol Versi o n   
 
 
5 3  
St a bilit y:   
 
Ca ps ules a n d ta blets s h o ul d be ta ke n wit hi n t he e x pirati o n date per ma n ufact urer’s 
g ui deli nes.  
 
R o ute of a d mi nistr ati o n :  
 
Orall y t wice/ da y  
 
Dr u g Pr oc ure m e nt:  Ac ycl o vir  m ust be o btai ne d fr o m c o m merci al s o urces.   
 
 
1 0. 0 
C O R R E L A T I V E / S P E CI A L S T U DI E S 
 
1 0. 1  
C orrel ati v e St u dies t o Deter mi ne Cell - of- Ori gi n ( C O O) b y t he  Ge ne 
E x pressi o n Pr ofili n g  
T he p ur p ose of t his c orrelati ve st u d y is t o assi g n C O O b y b ot h 
i m m u n o hist oc he mistr y a n d t he ge ne e x pressi o n pr ofili n g t o eac h D L B C L 
patie nt treate d wit h C R - C H O P i n or der t o pr o vi de i nsi g ht i nt o t he differe ntial 
effect of carfilz o mi b o n t he cli nical o utc o mes i ncl u di n g pr o gressi o n- free 
s ur vi val ( P F S) a n d o verall s ur vi val ( O S). 
 
1 0. 1. 1  
Bac k gr o u n d 
 
1 0. 1. 1. 1  C O O i n D L B C L as defi n e d  b y Ge ne E x pressi o n Pr ofili n g 
     L y m p h o ma classificati o n was ori gi nall y base d e xcl usi vel y o n hist ol o gic 
assess me nt of bi o ps y s peci me ns.  I m m u n o hist oc he mical (I H C) m et h o ds were 
a d de d as part of t h e Re vise d E ur o pea n- A merica n L y m p h o ma ( R E A L) a n d, 
m ore rece ntl y, t he W orl d Healt h Or ga ni zati o n ( W H O) Classificati o n sc he mas .  
I n rece nt years, it has bee n i ncreasi n gl y rec o g nize d t hat B- cell mali g na ncies ca n 
be cate g orize d b ase d o n t he cell of ori gi n ( C O O) b ase d o n t he sta ge of 
differe ntiati o n of t h e l y m p h oc yte t hat u n der g o es tra nsf or mati o n.  T hese i n cl u de 
l y m p h o ma arisi n g fr o m B-cells t hat resi de wit hi n t he l y m p h n o de ger mi nal 
ce nter ( G C) a n d are acti v el y i n v ol ve d i n i m m u n o gl o b uli n ge ne s o matic 
h y per m utati o n a n d t h ose t hat are deri ve d fr o m p ost- ger mi nal ce nter acti vate d B -
cells ( A B C) [2 4 , 2 5 ].   G e ne e x pressi o n pr ofili n g ( G E P) was t he first tec h ni q ue 
t hat c o ul d acc uratel y  stratif y D L B C L i nt o s u b-t y pes wit h differe nt o utc o mes [ 2 , 
3 ].     
      T here are w ell -descri b e d differe nces i n t he m olec ular p at h o ge nesis of eac h 
of t he t w o maj or s u bt y pes of D L B C L.  F or i nsta nce, t he G C  s u bt y pe har b ors t he 
t( 1 4; 1 8) tra nsl ocati o n i n a p pr o xi matel y 3 5 % of cases, res ulti n g i n c o nstit uti ve 
o ver- e x pressi o n  of t he a nti-a p o pt otic pr otei n Bcl- 2.  I n c o ntrast, t he 
tra nscri pti o n fact or N ucl ear Fact or Ka p p a -B ( N F- κ B ) is c o nstit uti vel y acti ve i n 
t he A B C s u bt y pe [2 6 , 2 7 ] ofte n d ue t o m utati o ns i n C A R D 1 1 or M Y D 8 8, 
c hr o nic B-cell rece pt or acti vati o n a n d i nacti vati o n of A 2 0 [ 8- 1 0 , 2 8 ]. 
 
 

 
 
 
 
 
C A S E 3 4 1 3  C R -C H O P  
Pr ot oc ol Versi o n   
 
 
5 4  
1 0. 1. 1. 2  C orrelati o n of C O O wit h cli nical o utc o mes of D L B C L  
    I n retr os pecti ve a n al ysis, D L B C L- G C patie nts i de ntifie d b y G E P ha ve 
s u peri or o ver all s ur vi val relati ve t o D L B C L -A B C w he n treat e d wit h C H O P 
( 7 6 % vs. 1 6 % 5-y ear O S, P < 0. 0 0 1) [ 2 ].  T hes e fi n di n gs ha ve bee n v ali date d i n 
s u bse q ue nt lar ger series i ncl u di n g patie nts treate d  wit h c he m ot hera p y i n 
c o m bi nati o n wit h rit u xi ma b [ 1 , 3 ].   Le nz et al.  re p orte d a seri es of 2 3 3 R-
C H O P treat me nt  patie nts w h ose t u m ors were c haracterize d usi n g G E P i n w hic h 
t he 5 year O S w as 6 0 % f or t he D L B C L- G C gr o u p c o m pare d t o a rate  of 3 9 % i n 
patie nts wit h n o n- G C  s u bt y pe ( P < 0. 0 0 1) [1 ].  Of n ote, a t hir d s u bt y pe of 
me diasti nal lar ge B-cell l y m p h o ma was f o u n d t o h a ve a m olec ular si g nat ure 
si milar t o H o d g ki n’s l y m p h o ma a n d ha d a pr o g n osis m ore si milar t o t he 
D L B C L - G C gr o u p.  
 
1 0. 1. 1. 3  Met h o ds t o pre dict C O O 
 
1 0. 1. 1. 3. 1  Ha ns a l g orit h m 
   Se veral tec h ni q u es ha v e bee n d e vel o pe d t o a p pl y I H C stai ni n g of paraffi n 
e m be d de d tiss ue t o assi g n D L B C L  t o a partic ular s u bt y pe.  The 
L y m p h o ma/ Le u ke mia M olec ular Pr ofili n g Pr oject ( L L M P P) use d se q ue nti al 
detecti o n of C D 1 0 (if p ositi ve i n ≥3 0 % of cells s u g gests G C s u bt y pe) f oll o we d 
b y B C L 6 (if < 3 0 % of cells stai n p ositi ve s u g gests n o n-G C s u bt y pe) a n d, i n 
cases of p ositi ve Bcl - 6 st ai ni n g ( ≥3 0 % of cells), M U M 1 t o differe ntiate b et wee n 
G C ) ( < 3 0 % cells) a n d n o n-G C  s u bt y pes ( ≥3 0 % of cells) [5 ].   T his is s h o w n 
sc he maticall y i n t he acc o m pa n yi n g fi g ure. T his al g orit h m of Ha ns, et al. 
s h o we d t he D L B C L-G C s u b- gr o u p t o ha ve s u peri or o verall s ur vi val relati v e t o 
t he n o n- G C B gr o u p.   
 
Fi g ure:   A p plicati o n of Ha ns Al g orit h m as Assi g n Cell of Ori gi n ( C O O) Usi n g 
I m m u n o histoc he mical (I H C) Stai ni n g  
 
 
1 0. 1. 1. 3. 2  C h oi Al g orit h m a n d Tall y Met h o d 
     Ot her al g orit h ms, i ncl u di n g t he met h o ds of C h oi, et al a n d Me yer, et al., 
i nc or p orate stai ns f or a d diti o nal pr otei ns ( G C E T 1, F o x P 1 a n d L M O 2 ) [2 9 , 3 0 ].  

 
 
 
 
 
C A S E 3 4 1 3  C R -C H O P  
Pr ot oc ol Versi o n   
 
 
5 5  
T he latter is t he s o -calle d “ Tall y” met h o d w hic h tallies t he prese nce or a bs e nce 
of pr otei ns f o u n d i n G C ( C D 1 0, G C B E T 1) or A B C ( M u m 1, F o x P 1) s u bt y pes of 
D L B C L a n d i n v o kes t he prese nce L M O 2 as “tie brea ker” t o assi g n cas es of 
e q ui v ocal sc ori n g t o t he G C gr o u p [ 3 0 ].  A n o n- G C B s u bt y pe as i de ntifie d b y 
t he Tall y met h o d was  ass ociate d wit h w orse  e ve nt -free s ur vi val ( E F S) as w ell as 
o verall s ur vi val ( O S).   B eca use of tec h ni cal diffic ulties a n d lac k of 
re pr o d uci bilit y i n t he stai ni n g f or G C E T 1 a n d F o x P 1, t he C h oi a n d Tall y 
met h o d ha ve i n her e nt li mitati o ns t hat ha ve li mite d t heir wi des prea d a d o pti o n. 
 
1 0. 1. 1. 3. 3  Re pr o d uc i bilit y of I H C Al g orit h ms 
     Alt h o u g h t he Ha ns al g orit h m is t he m ost wi del y use d I H C-bas e d tec h ni q ue 
f or deter mi ni n g C O O, it is n ot sta n dar dize d a n d dis pla ys si g nifica nt varia bilit y, 
e ve n at hi g hl y e x perie nce d ce nters.  Neit her t h e  S pa nis h Gr u p per l' Est u di dels 
Li mf o mes  de Catal u n ya i Balears ( G E L C A B)  nor t he N or dic H O V O N gr o u p 
were a ble t o vali date t he use of I H C t o pre di ct o utc o mes of patie nts wit h 
D L B C L  [3 1 , 3 2 ]. 
    T he lac k of re pr o d u ci bilit y of I H C al g orit h ms w as f urt her hi g hli g hte d b y 
t he e x perie n ce re p orte d fr o m 8 hi g hl y e x perie nce d la b orat ories t hat c o m prise d 
t he L u ne n b ur g L y m p h o ma Bi o mar ker C o ns orti u m [ 3 3 , 3 4 ].  Alt h o u g h t here was 
hi g h a gree me nt b et wee n ce nters f or stai ni n g wit h C D 2 0 a n d C D 1 0, ot her stai ns 
s uc h as Bcl- 6, M u m- 1 a n d Ki- 6 7 were hi g hl y u nrelia ble.  N o si n gle ce nter was 
i de ntifie d as c o nsiste ntl y m ore relia ble t ha n t he ot hers. 
 
 
1 0. 1. 1. 3. 4   Alter nati ve S yste m  
     Gi ve n t he p o or r e pr o d uci bilit y of I H C- b ase d a p pr oac hes t o assi g n C O O a n d t he 
c u m bers o me/e x p e nsi ve n at ure of G E P tec h ni q ue alter nati ve met h o ds f or 
deter mi ni n g C O O fr o m f or mali n-fi xe d paraffi n-e m be d de d ( F F P E) tiss ue are 
i n de vel o p me nt.   F ull details will be a me n de d t o t he C orrelati ve M et h o ds, 
Secti o n 1 0. 1. 1. 3. 5 i n t he f ut ure. 1 0. 1. 2      
 
1 0. 1. 1. 3. 5  Ne wer a p pr o ac hes 
Ne w m ulti o mics a p pr oac hes ha ve bee n de v el o pe d t o si m ulta ne o usl y st u d y t he 
i m pact of t u m or s pecific ge ne m utati o ns o n ge ne e x pressi o n a n d cli nical 
o utc o mes.  S uc h a nal ysis will be perf or me d i n c olla b orati o n wit h Dr. 
Sa n dee p Da v e at D u k e U ni versit y.  
 
Rati o nale f or A nal ysis 
See Secti o n 1 4. 0 
 
1 0. 1. 3      C ollecti o n of S peci me ns  
      Ori gi nal tiss ue bi o psies (re prese ntati ve paraffi n tiss ue bl oc k) t hat were use d 
t o esta blis h t he dia g n osis of D L B C L will be se nt t o ce ntral bi ore p osit or y f or t he 
c utti n g, wa xi n g a n d st ori n g u nstai ne d sli des. Beca use t hese tiss ues are f or mali n 

 
 
 
 
 
C A S E 3 4 1 3  C R -C H O P  
Pr ot oc ol Versi o n   
 
 
5 6  
fi xe d  a n d  par affi n  e m be d de d,  tra ns p ortati o n  of  t hese  sa m ples  at  a m bie nt  
te m perat ur e is satisfact or y. If t he tiss ue bl oc k is u na vaila ble, f or a n e x cisi o nal 
bi o ps y or lar g e i n cisi o nal bi o ps y ( > 2 c m 2 area of tiss ue):   8 u nstai n e d secti o ns o n 
c har ge d sli des (c ut at 2 -4 micr o n ) A N D 2 te n micr o n secti o ns are re q u este d.   F or 
a nee dle c or e or s mall bi o ps y ( < 2 c m 2):  8 u nstai ne d secti o ns o n c har ge d sli des 
(c ut at 2-4 micr o n) A N D 8 te n micr o n secti o ns are re q ueste d. Tiss ue bl oc ks will 
ret ur ne d  t o  t he  ori gi nati n g  site  wit hi n  3 0  b usi ness  da ys  of  recei pt  b y  t he  
bi ore p osit or y. 
 
1 0. 1. 4      Ha n dli n g of S peci me ns 
      T he cli nical i n vesti gat or or his/ her desi g nee i n c har ge of t he res earc h s u bj ect 
will  be  r es p o nsi ble  f or  ha vi n g  t he  ori gi nal  di a g n ostic  s peci me n  ( p araffi n -
e m be d de d  tiss ue  bl oc k  a n d  all  rele v a nt  re p orts  i ncl u di n g  dia g n ostic  re p ort,  
i m m u n o hist oc he mical data,  fl o w  c yt o metr y  d ata,  a n d  m olec ular  pat h ol o g y  
st u dies  ass ociate d  wit h  t he  s peci me n)  se nt  t o  t he  ce ntral  bi ore p osit or y  f or  
c ollecti o n, ha n dli n g a n d st ora ge. At t he e n d t he st u d y, t he u nstai ne d sli des will be 
batc he d b y t he bi or e p osit or y, a n d se nt t o Dr . Eri c D. Hsi, M D at Wa ke F orest 
U ni versit y f or t he cell of ori gi n ( C O O) a nal ysis utilizi n g D u o Se q:  
 
W a k e  F or est  B a ptist  M e dic al  C e nt er  
Att n:  J or d a n B o ul di n  
W a k e  R ec ei vi n g - C o m m o ns  D oc k  
1 M e dic al  C e nt er  Bl v d.  
Wi nst o n  S al e m,  N C  2 7 1 5 7  
 
C o nfir mati o n  of  t he  dia g n osis  of  D L B C L  b y  t he  C C F  de part me nt  of  
he mat o pat h ol o g y is n ot a re q uire me nt f or i ncl usi o n i n t he trial a n d will n ot be re q uire d 
f or  i nitiati o n  of  t her a p yPlease  se n d  all  c orrelati ve  sa m ples  t o  t h e  bel o w  a d dress.  
C o ntact t he lea d  
   st u d y c o or di nat or u p o n s hi p me nt. 
 
Att n: D ur ki n/ C hilt o n/ O n drej ka 
Cle vela n d Cli nic Ce ntral Bi ore p osit or y  
Pat h ol o g y a n d La b orat or y Me dici ne I nstit ute 
Cle vela n d Cli nic  
2 1 1 9 East 9 3r d. Street 
Des k L 1 5 
Cle vela n d, O H 4 4 1 0 6 
 
 
 
 
1 1. 0  
S T U D Y P A R A M E T E R S A N D C A L E N D A R  
 
1 1. 1  
St u d y P ar a m eters  

 
 
 
 
 
C A S E 3 4 1 3  C R -C H O P  
Pr ot oc ol Versi o n   
 
 
5 7  
 
1 1. 1. 1 Scree ni n g E val u ati o n   
Scree ni n g st u dies a n d e v al uati o ns will be use d t o deter mi ne t he eli gi bilit y of 
eac h s u bject f or st u d y i ncl usi o n. All e val uati o ns m ust be c o m plete d < 2 8 da ys 
pri or t o a d mi nistrati o n of pr ot oc ol t hera p y , e xce pt w here ot her wise i n dicat e d or 
-  i n t he case of patie nts w h o recei ve d 1 c y cle of R-C H O P [ or s o me 
c o m p o ne nt(s) t her e of] pri or t o st u d y e nr oll me nt, a C T a n d / or P E T/ C T, 
ec h ocar di o gra m a n d b o n e marr o w bi o ps y m ust ha ve bee n o btai n e d pri or t o 
treat me nt. T he w i n d o w f or t he a d diti o nal scree ni n g pr oce d ures ma y be e xte n de d 
f or a n a d diti o nal 1 4 da ys pri or t o i nitial S O C t hera p y. If o nl y a C T or P E T/ C T 
was c o m plete d pri or t o S O C t hera p y, as l o n g as t h ere is e vi de n ce of 
meas urea ble diseas e  a n d t u m or meas ure me nts are a vaila ble f or res p o nse 
assess me nt, t he ot her sca n ma y be o mitte d. Sca ns s h o ul d be c o m plete d wit hi n 
5 6 da ys of pre-st u d y t her a p y. 
•  I nf or me d C o nse nt 
•  De m o gra p hics 
•  Me dical Hist or y  
•  C o m plete P h ysical E xa mi nati o n  
•  Hei g ht 
•  Wei g ht  
•  Vital si g ns i ncl u di n g: bl o o d press ure, p ulse, res pirat or y rate a n d te m perat ure. 
•  C o nc urre nt Me dicati o ns Assess me nt i ncl u di n g prescri pti o n me dicati o ns, o ver-
t he-c o u nter ( O T C) me dicati o ns a n d nat ural/ her b al s u p ple me nts. 
•  E C O G Perf or ma n ce Stat us  
•  Baseli ne S y m pt o ms Assess me nt  
•  La b orat or y St u dies: 
o  C o m plete Bl o o d C o u nt ( C B C) wit h differe ntial  a n d platelets  
o  Ser u m C he mistries: al b u mi n, al kali ne p h os p hatas e, t otal bilir u bi n, 
bicar b o nate, B U N, cal ci u m, c hl ori de, creati ni ne, gl uc ose,  p otassi u m, 
t otal pr otei n, S G O T [ A S T], S G P T [ A L T], s o di u m, lactate 
de h y dr o ge nas e ( L D H) le vel, uric aci d, p h os p h or o us.  
o  Calc ulate d cr eati ni ne cleara nce will be deter mi ne d usi n g C oc kcr oft -
Ga ult f or m ula if creati ni ne a n d/ or B U N are a b n or mal.   
o  Ser u m ß- H C G f or w o m e n of c hil d beari n g p ote nti al  
o  Uri nal ysis  
o  Re m ote He patitis Pa nel  ( He patitis B S urface A nti ge n, He patitis B 
S urface A nti b o d y, He patitis B C ore A nti b o d y, He patitis C a nti b o d y)  
o  HI V testi n g  
•  E K G  
•  M U G A or ec h ocar di o gra m ( m ust be c o m plete d < 6 m o nt hs pri or t o 
a d mi nistrati o n of pr ot oc ol t hera p y) u nless t here is cli nical e vi de nce f or n e w 
car diac s y m pt o ms wit hi n peri o d of ti me si nce t he car diac assess me nt.  

 
 
 
 
 
C A S E 3 4 1 3  C R -C H O P  
Pr ot oc ol Versi o n   
 
 
5 8  
•  C T sca n of nec k, c hest, a b d o me n a n d pel vis wit h oral a n d I V c o ntrast ( n ec k 
ma y be o mitte d at discreti o n of treati n g p h ysicia n)  
•  P E T / C T sca n as baseli ne t u m or i ma gi n g assess me n t B o ne Marr o w As pirate 
a n d Bi o ps y wit h c yt o ge netics ( wit hi n 9 0 da ys of treat me nt) 
o  Ma y be o mitte d at s p o ns or discreti o n if b o ne marr o w assess me nt a n d 
FI S H ar e a v aila ble fr o m a n ot her bi o ps y t o o btai n f ull baseli ne sta gi n g  
•  Dia g n ostic bi o ps y material se nt t o Cle vela n d Cli nic f or C O O d eter mi nati o n.  
 
 
1 1. 1. 2  Treat me nt Peri o d  
I n t he cas e of patie nts w h o recei v e d 1 treat me nt of R-C H O P [ or s o me 
c o m p o ne nt(s) t her e of] pri or t o st u d y e nr oll me nt, will be gi n t he st u d y wit h C ycle 1 
st u d y treat me nt ( R- C H O P d ose 2). Patie nts s h o ul d recei v e at least 6 f ull d oses of 
R- C H O P ( bet wee n S O C a n d  st u d y treat me nt c o m bi ne d) u nless ot her wise 
s pecifie d, b ut u p o n i n vesti gat or discreti o n ma y c o m plete t he 6t h C ycle of o n-
st u d y C R- C H O P ( 7 t otal d oses).  
Patie nts first c ycle t hat i ncl u des Carfilz o mi b s h o ul d al wa ys start at 2 0 m g/ m 2 
re gar dl ess if t he y recei ve d pri or treat me nt, t he n res u me wit h 5 6 m g/ m2. 
 
Wi n d o ws 
•  Treat me nt c y cles ar e 2 1 da ys l o n g.  
•  A visit wi n d o w of ± 3 da ys is all o we d f or la bs  
•  A visit wi n d o w of ± 3 da y is all o we d f or treat me nt.  
•  A visit wi n d o w of ± 1 4 da ys is all o we d f or 6- m o nt h f oll o w- u p visits.  
 
C ycle 1, D a y 1 
•  P h ysical E xa mi nati o n  
•  Wei g ht  
•  Vital si g ns i ncl u di n g: bl o o d press ure, p ulse, res pirat or y rate a n d 
te m perat ur e. 
•  C o nc urre nt Me dicati o ns Assess me nt i ncl u di n g prescri pti o n me dicati o ns, 
o ver-t he- c o u nter ( O T C) me dicati o ns a n d nat ural/ her bal s u p ple me nts.  
•  E C O G Perf or ma n ce Stat us  
•  Baseli ne S y m pt o ms Assess me nt  
•  A d verse E v e nt E val uati o n  
•  La b orat or y St u dies: 
o  C o m plete Bl o o d C o u nt ( C B C) wit h differe ntial  a n d platelets.  
o  Ser u m C he mistries: al b u mi n, al kali ne p h os p hatas e, t otal bilir u bi n, 
bicar b o nate, B U N, cal ci u m, c hl ori de, creati ni ne, gl uc ose,  p otassi u m, 
t otal pr otei n, S G O T [ A S T], S G P T [ A L T], s o di u m, lactate 
de h y dr o ge nas e ( L D H) le vel, uric aci d, p h os p h or o us. 
•  Calc ulate d cr eati ni ne cleara nce will be deter mi ne d usi n g C oc kcr oft -G a ult 
f or m ula if cr eati ni ne a n d/ or B U N are a b n or mal.   

 
 
 
 
 
C A S E 3 4 1 3  C R -C H O P  
Pr ot oc ol Versi o n   
 
 
5 9  
•  Carfilz o mi b A d mi nistrati o n  
•  I nitiate ac ycl o vir. 
 
 
C ycle 1, D a y 2 
•  Vital si g ns i ncl u di n g: bl o o d press ure, p ulse, res pirat or y rate a n d 
te m perat ur e. 
•  Carfilz o mi b a d mi nistrati o n  
•  Rit u xi ma b a d mi nistrati o n  
•  A d verse E v e nt E val uati o n  
 
C ycle 1, D a y 3 
•  Vital si g ns i ncl u di n g: bl o o d press ure, p ulse, res pirat or y rate a n d 
te m perat ur e. 
•  C H O P a d mi nistrati o n  
 
C ycle 1, D a y 4 
•  Pe gfil grasti m a d mi nistrati o n  or O N P R O T M  weara ble de vice  
 
C ycle 1, D a y 8 - o pti o n al 
•  T he f oll o wi n g la b orat or y st u dies  ma y be perf or me d o n da y 8 per M D 
discreti o n:  
o  C o m plete Bl o o d C o u nt ( C B C) wit h differe ntial  a n d platelets  
o  Ser u m C he mistries: al b u mi n, al kali ne p h os p hatas e, t otal bilir u bi n, 
bicar b o nate, B U N, cal ci u m, c hl ori de, creati ni ne, gl uc ose,  p otassi u m, 
t otal pr otei n, S G O T [ A S T], S G P T [ A L T], s o di u m, lactate 
de h y dr o ge nas e ( L D H) le vel, uric aci d, p h os p h or o us.  
o  Calc ulate d cr eati ni ne cleara nce will be deter mi ne d usi n g C oc kcr oft -
Ga ult f or m ula if creati ni ne a n d/ or B U N are a b n or mal.   
 
C ycles 2 - 6, D a y 1 
•  P h ysical E xa mi nati o n  
•  Wei g ht  
•  Vital si g ns i ncl u di n g: bl o o d press ure, p ulse, res pirat or y rate a n d te m perat ure 
•  C o nc urre nt Me dicati o ns Assess me nt i ncl u di n g prescri pti o n me dicati o ns, o ver-
t he-c o u nter ( O T C) me dicati o ns a n d nat ural/ her b al s u p ple me nts. 
•  E C O G Perf or ma n ce Stat us  
•  A d verse e ve nt e v al uati o n 
•  La b orat or y St u dies: 
o  C o m plete Bl o o d C o u nt ( C B C) wit h differe ntial  a n d platelets  
o  Ser u m C he mistries: al b u mi n, al kali ne p h os p hatas e, t otal bilir u bi n, 
bicar b o nate, B U N, cal ci u m, c hl ori de, creati ni ne, gl uc ose,  p otassi u m, 

 
 
 
 
 
C A S E 3 4 1 3  C R -C H O P  
Pr ot oc ol Versi o n   
 
 
6 0  
t otal pr otei n, S G O T [ A S T], S G P T [ A L T], s o di u m, lactate 
de h y dr o ge nas e ( L D H) le vel, uric aci d, p h os p h or o us.  
o  Calc ulate d cr eati ni ne cleara nce will be deter mi ne d usi n g C oc kcr oft -
Ga ult f or m ula if creati ni ne a n d/ or B U N are a b n or mal.   
•  Carfilz o mi b A d mi nistrati o n   
 
C ycles 2 - 6, D a y 2 
•  Vital si g ns i ncl u di n g: bl o o d press ure, p ulse, res pirat or y rate a n d te m perat ure. 
•  Carfilz o mi b a d mi nistrati o n  
•  Rit u xi ma b a d mi nistrati o n  
 
C ycles 2 - 6, D a y 3 
•  Vital si g ns i ncl u di n g: bl o o d press ure, p ulse, res pirat or y rate a n d te m perat ure.  
•  C H O P a d mi nistrati o n  
 
C ycles 2 - 6, D a y 4 
•  Pe gfil grasti m a d mi nistrati o n  or O N P R O T M  weara ble de vice  
 
C ycles 2 - 6, D a y 8 - O pti o n al 
•  La b orat or y St u dies wit h o ut cli nical visit ma y be perf or me d o n d a y 8 at M D 
discreti o n  
o  C o m plete Bl o o d C o u nt ( C B C) wit h differe ntial  a n d platelets  
 
C ycle 3 , D a y 1 5- 2 1 
I n t he cas e of patie nts w h o recei v e d 1 c ycl e of R- C H O P [ or s o me c o m p o n e nt(s) 
t here of] pri or t o st u d y e nr oll me nt, i nteri m sca ns will be c o n d ucte d aft er 3 c ycles 
of  C R - C H O P ha ve bee n a d mi nistere d ( C 3 D 1 5- 2 1 of pr ot oc ol t hera p y) , t his 
s h o ul d be after 4 t otal r o u n ds of treat me nt f or t h ese patie nts.  
•    C T sca n of nec k, c hest, a b d o me n a n d pel vis wit h oral a n d I V c o ntrast ( n ec k   
   ma y be o mitte d at discr eti o n of treati n g p h ysicia n).  
•    P E T  sca n is o pti o nal. 
 
Off Tre at m e nt visit (t o be c o n d ucte d 4- 8 wee ks   of D a y  1 of l ast tre at m e nt 
or after c o m pleti o n of c o ns oli d ati o n r a di ati o n t her a p y) 
•  P h ysical E xa mi nati o n  
•  Wei g ht  
•  Vital si g ns i ncl u di n g: bl o o d press ure, p ulse, res pirat or y rate a n d te m perat ure. 
•  C o nc urre nt Me dicati o ns Assess me nt i ncl u di n g prescri pti o n me dicati o ns, o ver-
t he-c o u nter ( O T C) me dicati o ns a n d nat ural/ her b al s u p ple me nts. 
•  E C O G Perf or ma n ce Stat us  
•  A d verse e ve nt e v al uati o n  
•  La b orat or y St u dies: 
o  C o m plete Bl o o d C o u nt ( C B C) wit h differe ntial  a n d platelets  

 
 
 
 
 
C A S E 3 4 1 3  C R -C H O P  
Pr ot oc ol Versi o n   
 
 
6 1  
o  Ser u m C he mistries: al b u mi n, al kali ne p h os p hatas e, t otal bilir u bi n, 
bicar b o nate, B U N, cal ci u m, c hl ori de, creati ni ne, gl uc ose,  p otassi u m, 
t otal pr otei n, S G O T [ A S T], S G P T [ A L T], s o di u m, lactate 
de h y dr o ge nas e ( L D H) le vel, uric aci d, p h os p h or o us.  
o  Calc ulate d cr eati ni ne cleara nce will be deter mi ne d usi n g C oc kcr oft -
Ga ult f or m ula if creati ni ne a n d/ or B U N are a b n or mal.   
•  E K G  
•  Ec h ocar di o gra m 
•  B o ne marr o w bi o ps y ( ma y be o mitte d if scree ni n g b o ne marr o w bi o ps y w as 
ne gati ve f or i n v ol ve m e nt f or l y m p h o ma). 
•  C T sca n of nec k, c hest, a b d o me n a n d pel vis wit h oral a n d I V c o ntrast ( n ec k   
ma y be o mitte d at discreti o n of treati n g p h ysicia n) t o be o btai ne d 4- 8 wee ks 
after D a y 1 of last treat me nt c ycle.  
•  P E T sca n t o be o btai ne d bet wee n 4- 8 wee ks after da y 1 of last treat me nt c y cle . 
F or patie nts r ecei vi n g a dj u va nt or p ost-c he m ot hera p y ra diati o n treat me nt, 
P E T a n d/ or C T ca n be d eferre d u ntil after c o m pleti o n of ra diati o n.  
•  Res p o nse asses sme nt  ( See Secti o n 1 2. 0) 
 
F oll o w- U p ( hel d at a mi ni m u m of 6, 1 2 a n d 2 4 m o nt hs after D 1 of l ast 
tre at m e nt c y cle – o ne m o nt h = 3 0 d a ys or after c o m pleti o n of c o ns oli d ati o n 
r a di ati o n t her a p y) 
•  P h ysical E xa mi nati o n  
•  Wei g ht  
•  Vital si g ns i ncl u di n g: bl o o d press ure, p ulse, res pirat or y rate a n d te m perat ure. 
•  C o nc urre nt Me dicati o ns Assess me nt i ncl u di n g prescri pti o n me dicati o ns, o ver-
t he-c o u nter ( O T C) me dicati o ns a n d nat ural/ her b al s u p ple me nts. 
•  E C O G Perf or ma n ce Stat us  
•  A d verse e ve nt e v al uati o n  
•  La b orat or y St u dies: 
o  C o m plete Bl o o d C o u nt ( C B C) wit h differe ntial  a n d platelets  
o  Ser u m C he mistries: al b u mi n, al kali ne p h os p hatas e, t otal bilir u bi n, 
bicar b o nate, B U N, cal ci u m, c hl ori de, creati ni ne, gl uc ose,  p otassi u m, 
t otal pr otei n, S G O T [ A S T], S G P T [ A L T], s o di u m, lactate 
de h y dr o ge nas e ( L D H) le vel, uric aci d, p h os p h or o us.  
o  Calc ulate d cr eati ni ne cleara nce will be deter mi ne d usi n g C oc kcr oft -
Ga ult f or m ula if creati ni ne a n d/ or B U N are a b n or mal.   
•  C T nec k/c hest/a b d o me n/ pel vis ( ma y o mit nec k if n ot dee me d cli nicall y 
i n dicate d b y i n vesti gat or) 
•  Res p o nse Assess me nt  
•    Disc o nti n ue ac ycl o vir ( M o nt h 6 o nl y) 
•    E C H O  at 6 m o nt h f oll o w u p visit 
 
 

 
 
 
 
 
C A S E 3 4 1 3  C R -C H O P  
Pr ot oc ol Versi o n   
 
 
6 2  
If a patie nt pr o gr esses d uri n g treat me nt or off st u d y, t he y o nl y will o nl y be f oll o we d 
f or s ur vi val at t he a b o ve ti me p oi nts.  
 

C A S E 3 4 1 3  C R -C H O P  
                 
Pr ot oc ol Versi o n 2 0 0 9/ 0 1/ 2 0 2 3  
 
1 1. 2  
St u d y C ale n d ar  
 
 
S cree ni n g b 
               C y cl e 1  
               C y cl e 2  
                      C y cl e 3  
C ycl es 4 -6 
Off Tre at m e nt  
F oll o w -U p i 
D ay 1      
 
  
D ay 2  
D ay 3  
D ay 4  
D ay 8 n, 
D ay 1      
 
  
D ay 2  
D ay 3  
D ay 4  
D ay 8 n, 
D ay 1      
 
  
D ay 2  
D ay 3  
D ay 4  
D ay 8,  
D ay 15 -21 
D ay 1      
 
  
D ay 2  
D ay 3  
D ay 4  
D ay 8,  
I nf or me d C o n se nta 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
M e di cal Hi st ory  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
P hy sic al Exa m  
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
X 
C o n c urre nt M e d s  
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
    
 
X 
 
 
 
 
X 
X 
Vit al Si g n s  ( T, P, R, B P)  
X 
X 
X 
X 
 
 
X 
X 
X 
 
 
X 
X 
X 
 
 
 
X 
X 
X 
 
 
X 
X 
H ei g ht  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
W ei g ht  
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
X 
E C O G Perf or ma nce St at u s  
 
 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
X 
C B C  w/ Diff ere nti al  
X 
X 
 
 
 
X d 
X 
 
 
 
X d 
X 
 
 
 
X d 
 
X 
 
 
 
X d 
X 
X 
S er u m C h e mi stry c 
X 
X 
 
 
 
X c 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
X 
Uri n aly sis  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
B as eli n e Sy m pt o m s or A E e val uati o n  
 
 
 
X 
X 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
X 
E K G  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
E C H O/ M U G A e 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
B o n e m arr o w bi o ps y/a s pirat e M 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X L 
 
C T n ec k/c he st/a b d/ pel vis f 
X g 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X g 
 
 
 
 
 
X 
X j 
F D G -P E T sca n g 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
o pti onal  
 
 
 
 
 
X g 
 
R es p o n se As se ss me nt  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
ß- h C G h 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
R e m ote H e patiti s P a nel  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HI V t esti n g  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
M Ge ne ex pre ssi o n a n d m utati o n ® 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C arfilz o mi b  
 X 
X 
 
 
 
X 
X 
 
 
 
X 
X 
 
 
 
 
X 
X 
 
 
 
 
 
Rit u xi m a b  
  
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
C H O P  
  
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
P e gfil grasti m  ( or O N P R OT M) 
  
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 

 
 
 
 
 
C A S E 3 4 1 3  C R -C H O P  
Pr ot oc ol Versi o n   
 
 
6 4  
 
 
a: I nf or m e d c o n se nt m u st be si g ne d < 28  day s of st art of st u dy treat me nt .  If si g n at ure is o ut si d e t hat wi n d o w t he pati e nt s m ust eit h er i niti al a n d dat e t heir ori gi nal c o nse nt or si g n a ne w c o nse nt.  
b: Pre -st u dy H & P a n d all la bs m ust be < 28   d ay s fr o m start of treat me nt u nles s ot her wis e s p ecifi e d.  T u m or mea s ure me nts a n d ra di ol o gic e val uati o ns m ust be < 4 2 da ys fr o m st art of tre at m e nt 
u nle ss ot h er wis e s pecifi e d .    
c: C 1 D1 l a bs d o n ot hav e t o be re peat e d if b as eli n e l a bs w ere dra w n < 21 da ys pri or t o d ay 1.  All l a b s d uri n g treat me nt m u st b e c o m plet e d wit hi n 48 h o urs b ef ore t he tre at me nt da y. C he mi stry 
i n cl u de s: al b u mi n, alk ali ne p h os p hat ase, t ot al bilir u bi n, bi car b o nat e, B U N, calci u m, c hl ori d e, cre ati ni n e, gl u c os e, L D H, p h o s p h or u s, uri c a ci d, p ota ssi u m, t ot al pr ot ei n, S G O T [ A S T], S G P T [ A L T], 
s o di u m. C ycl e 1 La bs d o n ot ne e d t o be perf or m e d pri or t o da y 4 of tre at me nt.  
d . F or D os e L ev els 1 -5 o n Da y 8 ; P ha se 2 – t hi s is o nl y nec es sary p er i nv esti gat or dis creti o n 
e . M ay o bt ai n E C H O a n d/ or M U G A as ba seli ne c o nfir m ati o n of L V E F.  M ay be o btai ne d u p t o 6 m o nt h s pri or t o scree ni n g . D uri n g f oll o w-u p E C H O t o be o btai ne d at 6 m o nt h f oll o w -u p vi sit.  
f. N e ck C T m ay be o mitt e d at t h e di screti o n of t he i nv esti gat or if f elt t o  n ot be cli ni call y usef ul.  
g : All pre -st u dy a n d e n d of tre at m e nt ra di ol o gi cal eval uati o ns m ust be perf or me d b y C T Sc a n a n d F D G -P E T Sca n.  I nteri m C T  ( F D G/ P E T i s o pti o nal) m ust be o btai ne d b et w ee n da ys 15 a n d 21 of 
c ycl e 3  b ut f or mal a sse ss me nt of res p o n se will n ot be d o ne at t hi s ti m e  p oi nt .  .   Off-tre at m e nt C T s ca n a n d F D G-P E T s ca n t o b e c o m pl ete d 4 -8 we eks aft er da y 1 of l a st tre at me nt   u nl ess p atie nt 
i s u n der g oi n g c o ns oli dati o n ra di ati o n t h era py i n w hi c h ca se res p o nse as se ss m e nt st u di es ca n b e d eferre d u ntil aft er ra di ati o n..   
h . S er u m pre g na nc y te st ( W O C B P) m ust b e c o m plet e d < 72 h o urs bef ore b e gi n ni n g treat me nt.  
i:  F oll o w u p f or P D, res ol uti o n of treat m e nt rel at e d t oxi citi es, s urviv al m ust b e c o n d uct e d at a f oll o w-u p a p p oi nt me nt 4- 8 w ee ks  aft er D1 of la st treat me nt.  L o n g t er m f oll o w -u p s h o ul d b e 
c o n d uct e d at 6, 1 2, a n d 24 m o nt hs f or 2 ye ars, a n d s u bs e q ue ntl y ba se d o n dis creti o n of i n di vi d ual i n vesti g at or a n d re s ult s s h o ul d be rec or d e d o n t he a p pli c a bl e l o n g t er m f oll o w u p c ase re p ort 
f or m s. If a pati e nt pr o gres se s o n l o n g t er m f oll o w u p, o nly s urvi val dat a i s n ee d e d. 
j:  C T t o be o bt ai ne d at 6, 12, a n d 2 4 m o nt h s aft er da y 1 of l a st treat me nt.  
k   E n d  of treat m e nt b o ne marr o w bi o p sy m ay be o mitt e d if scree ni n g b o n e m arr o w bi o ps y was ne gati ve f or i n v ol ve me nt by l y m p h o m a.  
l. N ot re q uire d at scree ni n g b ut s h o ul d b e p erf or me d if t h e ge ne ex pres si o n a n d m utati o n a n aly sis at t he c o ncl usi o n of t h e st u d y 
m. B o n e m arr o w bi o psi es d o ne wit hi n 9 0  d ay s of scre e ni n g visit are a cc e pt a bl e   
n. D ay 8 a ss ess me nts are o pti o nal per M D dis creti o n  
 
 
 
 
 
 
 
 

C A S E 3 4 1 3  C R -C H O P  
                 
Pr ot oc ol Versi o n 2 0 0 9/ 0 1/ 2 0 2 3  
 
1 2. 0  
R E S P O N S E A S S E S S M E N T   
 
Alt h o u g h  res p o nse  is  n ot  t he  pri mar y  e n d p oi nt  of  t his  trial,  patie nts  wit h  
meas ura ble disease will be assesse d b y sta n d ar d criteria  bas e d u p o n t he Re vise d 
Res p o nse Criteria f or Mali g na nt L y m p h o ma  ( A p p e n di x C) [3 6 ].  All patie nts will 
be re q uir e d t o ha v e pre -treat me n F D G -P E T/ C T t, i nteri m (cycle 3 Da y 1 5- 2 1 ) C T 
sca ns a n d e n d of treat me nt res p o nse assess me nt via F D G -P E T/ C T . 
 
All pre -st u d y an d e n d of treat me nt ra di ol o gical e v al uati o ns m ust be perf or me d 
b y C T Sca n a n d F D G -P E T/ C T Sca n t o be ce ntrall y re vie we d at Cle vela n d Cli nic  
f or f or mal r es p o nse assess me nt.  I nteri m C T (i nteri m F D G-P E T/ C T is o pti o nal) 
m ust  be  o btai ne d  bet w ee n  da ys  1 5  a n d  2 1  of  c ycle  3,  b ut  f or m al  res p o nse  
assess me nt is n ot re q uire d at t his ti me  p oi nt.   Off Treat me nt F D G-P E T/ C T sca n t o 
be c o m plete d 4- 8 w ee ks  after C ycle 6, d a y 1.   
 
F or  t he  p ur p os e  of  disease  meas ure me nt  d uri n g  f oll o w -u p,  i.e.,  assessi n g  
disease pr o gressi o n aft er ac hie vi n g res p o nse, p atie nts will als o get a bas eli ne a n d 
e n d of treat me nt C T sca n.  F oll o w u p will be as per i nstit uti o nal or p h ysicia n 
practice b ut  C T sca ns m ust be o btai ne d at m o nt hs 6, 1 2 a n d 2 4 after c ycle 6, da y 1.  
  
 
 
1 2. 1 
A ntit u m or Effect  – He m at ol o gic T u m ors 
 
T he  2 0 0 7  I nter nati o nal  W or ki n g  Gr o u p  R e vise d  Res p o nse  Criteria  f or  
Mali g na nt L y m p h o ma will be use d t he f oll o wi n g cate g ories of res p o nse: C o m plete 
Res p o nse ( C R),  Partial  Res p o nse  ( P R),  Sta ble  Disease  ( S D),  Rel a pse  a n d  
Pr o gressi o n ( P D). I n t he case of sta ble disease, f oll o w -u p assess me nts m ust ha ve 
met t he S D criteria at least o nce after st u d y e ntr y at a mi ni m u m i nter val of si x 
wee ks [3 6 ]. 
 
T he f oll o wi n g g ui deli nes are t o be use d f or esta blis hi n g t u m or meas ure me nts at 
baseli ne a n d f or s u bse q u e nt c o m paris o n: 
 
•  T he si x lar gest d o mi na nt n o des or e xtra n o dal  masses m ust be i de ntifie d at 
baseli ne.  
•  If t here are 6 or f e wer n o des a n d e xtra n o d al masses, all m ust be liste d as 
d o mi na nt. 
If t here are m ore t ha n 6 i n v ol ve d n o des or e xtra n o dal masses, t he 6 lar gest 
d o mi na nt n o des or e xtra n o dal masses s h o ul d b e selecte d acc or di n g t o t he 
f oll o wi n g feat ures: 
o  n o des  s h o ul d  be  clearl y  meas ura ble  i n  at  least  t w o  per pe n dic ular  
meas ure me nts  
o  n o des s h o ul d be fr o m as dis parate re gi o ns of t he b o d y as p ossi ble 
o  n o des s h o ul d i ncl u de me diasti nal a n d retr o perit o neal areas of disease 
w he ne ver t hese sites are i n v ol ve d. 
 
•  Meas ure me nts  f or  all  d o mi na nt  n o des  a n d  e xtra n o dal  mass es  will  be  
re p orte d  at  baseli ne.   Meas ure me nts  o n  n o n-d o mi na nt  n o des  are  n ot  
re q uire d. T he l y m p h n o d es or e xtra n o d al masses s electe d f or m eas ure me nt 
s h o ul d be meas ure d i n t w o per pe n dic ular dia met ers, o ne of w hic h is t he 

 
 
 
 
 
C A S E 3 4 1 3  C R -C H O P  
Pr ot oc ol Versi o n   
 
 
6 6  
l o n gest per pe n dic ular di a meter. T he l y m p h n o des s h o ul d be meas ure d i n 
ce nti meters t o t he nearest o ne te nt h of a ce nti meter (e. g. 2. 0 c m, 2. 1c m, 2. 2 
c m, etc.)  
•  T he t w o meas ur e d dia meters of eac h l y m p h n o d e site or e xtra n o d al mass 
s h o ul d be m ulti plie d gi vi n g a pr o d u ct f or eac h n o d al site or e xtra n o dal mass. 
T he  pr o d uct  of  eac h  n o dal  site  s h o ul d  be  a d de d,  yiel di n g  t he  s u m  of  
pr o d ucts of t he dia meters ( S P D). T he S P D  will be use d i n deter mi ni n g t he 
defi niti o n of res p o nse f or t h ose w h o ha ve less t ha n a c o m plete res p o nse. 
 
1 2. 1. 1  C o m plete  Resp o nse ( C R)  
C o m plete  Res p o nse  ( C R)  C o m plete  disa p peara nce  of  all  detecta ble  cli nical  
e vi de nce of disease, a n d disease -relate d s y m pt o ms if prese nt pri or t o t hera p y. 
•  F or l y m p h o mas f or w hi c h t he F D G -P E T/ C T sca n was p ositi ve pri or t o 
t hera p y: a p ost-tr eat me nt resi d ual mass of a n y size is per mitte d as l o n g as it 
is F D G-P E T/ C T -ne g ati ve  b y i n vesti gat or assessm e nt . 
•  F or l y m p h o mas f or w hi c h t he F D G -P E T/ C T sca n was p ositi ve pri or t o 
t hera p y: a p ost-tr eat me nt resi d ual mass of a n y size is per mitte d as l o n g as it 
is F D G-P E T/ C T -ne g ati ve.  
•  If t he pretreat me nt F D G-P E T/ C T sca n was ne gati ve: all l y m p h n o des a n d 
e xtra n o dal masses m ust ha ve re gresse d o n C T t o n or mal size ( < 1. 5 c m i n 
t heir greatest tr a ns vers e dia meter f or n o des > 1. 5 c m pri or t o t hera p y). 
Pre vi o usl y i n v ol ve d n o des t hat were 1. 1 - 1. 5 c m i n t heir l o n g a xis a n d > 1. 0 
c m i n t heir s h ort a xis pri or t o treat me nt m ust ha ve decrease d t o < 1 c m i n 
t heir s h ort a xis after treat me nt. 
•  T he s plee n a n d/ or li ver, if c o nsi dere d e nlar g e d pri or t o t hera p y o n t he b asis 
of a p h ysical e xa mi nati o n or C T sca n, s h o ul d n ot be pal pa ble o n p h ysical 
e xa mi nati o n, a n d n o d ules relate d t o l y m p h o ma s h o ul d disa p pear. H o we v er, 
n o n or mal size ca n be s pecifie d beca use of t h e diffic ulties i n acc uratel y 
e val uati n g s ple nic a n d he patic size a n d i n v ol ve me nt. F or i nsta nce, a s plee n 
c o nsi dere d n or mal size ma y c o ntai n l y m p h o ma, w hereas a n e nlar g e d s plee n 
ma y n ot necessaril y refl ect t he prese n ce of l y m p h o ma, b ut variati o n s i n 
a nat o m y, bl o o d v ol u me, t he use of he mat o p oietic gr o wt h fact ors, or ot her 
ca uses.  
•  If t he b o n e marr o w w as i n v ol ve d b y l y m p h o ma pri or t o treat me nt, t he 
i nfiltrate m ust ha ve cleare d o n re p eat b o ne marr o w bi o ps y. T he bi o ps y 
sa m ple o n w hi c h t his det er mi nati o n is ma de m ust be a d e q uate ( wit h a g oal 
of > 2 0 m m u nilateral c ore). If t he sa m ple is  i n deter mi nate b y m or p h ol o g y, 
it s h o ul d be ne gati ve b y i m m u n o hist oc he mistr y. A sa m ple t hat is ne gati ve 
b y i m m u n o hist oc he mistr y b ut de m o nstrati n g a s mall p o p ulati o n of cl o nal 
l y m p h oc ytes b y fl o w c yt o metr y will be c o nsi dere d a C R u ntil data b ec o me 
a vaila ble de m o nstr ati n g a clear differe n ce i n patie nt o utc o me. 
•  N O T E:  C o m plete  Re missi o n/ u nc o nfir me d  ( C R u):  Usi n g  t he  a b o ve  
defi niti o n f or C R a n d t hat bel o w f or P R, eli mi nates t he cate g or y of C R u. 

 
 
 
 
 
C A S E 3 4 1 3  C R -C H O P  
Pr ot oc ol Versi o n   
 
 
6 7  
 
1 2. 1. 2  Partial Res p o nse ( P R)  
T he desi g nati o n of P R re q uires all of t he f oll o wi n g  
•  A > 5 0 % d ecr ease i n s u m of t he pr o d uct of t h e dia meters ( S P D) of u p t o 6 
of t he lar gest d o mi na nt n o des or e xtra n o dal masses. T hese n o des or masses 
s h o ul d be selecte d acc or di n g t o t he f oll o wi n g: (a) t he y s h o ul d be clearl y 
meas ura ble i n at least 2 per pe n dic u lar di me nsi o ns; if p ossi ble, t he y s h o ul d 
be fr o m dis parate r e gi o ns of t he b o d y; ( b) t he y s h o ul d i ncl u de me diasti nal 
a n d retr o p erit o neal areas of disease w h e ne v er t hes e sites are i n v ol ve d.  
•  N o i ncreas e i n t he size of ot her n o des, li ver or s plee n. 
•  B o ne marr o w assess me nt is irrele va nt f or deter mi nati o n of a P R if t he 
sa m ple was p ositi ve pri or t o treat me nt. H o we ver, if p ositi ve, t he cell t y pe 
s h o ul d  be  s pecifie d,  e. g.  lar ge-cell  l y m p h o ma  or  s mall  clea ve d  cell  
l y m p h o ma. 
•  N o ne w sites of diseas e.  
 
1 2. 1. 3  Sta ble Disease ( S D)  
•  Faili n g t o attai n t he criteria nee d e d f or a P R or C R, b ut n ot f ulfilli n g t h ose 
f or pr o gr essi ve disease (s ee bel o w). 
•  F or F D G -a vi d l y m p h o mas: F D G -P E T/ C T s h o ul d be p ositi ve at pri or sites 
of disease wit h n o ne w areas of i n v ol ve me nt o n t he p ost -treat me nt C T or 
F D G -P E T/ C T.  
•  F or v aria bl y F D G -a vi d  l y m p h o mas/ F D G -a vi dit y  u n k n o w n:  F or p atie nts 
wit h o ut a pretr eat me nt F D G -P E T/ C T sca n or if t he pre -treat me nt F D G-
P E T/ C T was ne g ati ve, t h ere m ust be n o c h a n ge i n t he size of t he pre vi o us 
lesi o ns o n t he p ost-treat me nt C T sca n. 
 
1 2. 1. 4  Pr o gressi ve Diseas e ( P D)  
F or deter mi nati o n of rel a pse d a n d pr o gressi ve disease, l y m p h n o des s h o ul d be 
c o nsi dere d a b n or mal if t he l o n g a xis is m ore t ha n 1. 5 c m, re gar dl ess of t he s h ort a xis. 
If a l y m p h n o de has a l o n g a xis of 1. 1 t o 1. 5 c m, it s h o ul d o nl y be c o nsi dere d 
a b n or mal if t h e s h ort a xis is m ore t ha n 1 c m. L y m p h n o des < 1 x < 1 c m will n ot be 
c o nsi dere d as a b n or mal f or rela pse or pr o gressi ve disease. Treat me nt  decisi o ns i n 
patie nts wit h pres u me d refract or y, rela pse d or pr o gressi ve disease s h o ul d n ot be ma de 
s olel y o n t he basis of a si n gle F D G- P E T/ C T sca n wit h o ut hist ol o gic c o nfir mati o n. 
•  A p pear a nce of a n y ne w l esi o n m ore t ha n 1. 5 c m i n a n y a xis d uri n g or at t he 
e n d of t hera p y, e ve n if ot her lesi o ns are d ecreasi n g i n size. I n crease d F D G 
u pta ke i n a pre vi o usl y u naffecte d site s h o ul d o nl y be c o nsi dere d rela pse d or 
pr o gressi ve  diseas e  after  c o nfir mati o n  wit h  ot her  m o dalities,  i ncl u di n g  
bi o ps y. I n patie nts wit h n o pri or hist or y of p ul m o nar y l y m p h o ma, ne w l u n g 
n o d ules i de ntifie d b y C T are m ostl y be ni g n. T h us, a t hera pe utic decisi o n 
s h o ul d  n ot  be  ma de  s olel y  o n  t he  basis  of  t he  F D G-P E T/ C T  wit h o ut  
hist ol o gic c o nfir mati o n. 

 
 
 
 
 
C A S E 3 4 1 3  C R -C H O P  
Pr ot oc ol Versi o n   
 
 
6 8  
 
•  At least a 5 0 % i n crease fr o m na dir i n t he S P D of a n y pre vi o usl y i n v ol ve d 
n o des or e xtra n o dal masses, or i n a si n gle i n v ol ve d n o de or e xtra n o dal mass, 
or  t he  size  of  ot her  lesi o ns  (e. g.  s ple nic  or  h e patic  n o d ules).  T o  b e  
c o nsi dere d pr o gressi ve disease, a l y m p h n o de or e xtra n o dal mass wit h a 
dia meter of t he s h ort a xis of less t ha n 1. 0 c m m ust i ncreas e b y > 5 0 % a n d 
t o a size of 1. 5 c m x 1. 5 c m or m ore t ha n 1. 5 c m i n t he l o n g a xis. 
 
•  At least a 5 0 % i ncr ease i n t he l o n gest dia meter of a n y si n gle pre vi o usl y 
i de ntifie d n o de or e xtra n o dal mass m ore t ha n 1 c m i n its s h ort a xis. 
 
•  Lesi o ns s h o ul d be F D G -P E T/ C T p ositi ve if t he l esi o n was F D G -P E T/ C T 
p ositi ve bef ore t hera p y u nless t he lesi o n is t o o s mall t o be detecte d wit h 
c urre nt F D G - P E T/ C T s yste ms ( < 1. 5 c m i n its l o n g a xis b y C T). 
 
•  Meas ura ble e xtra n o dal disease s h o ul d be assesse d i n a ma n ner si milar t o 
t hat f or n o dal disease. F or t hese res p o nse criteria, t he s plee n is c o nsi dere d 
n o dal disease.  Disease t hat is o nl y assessa ble (e. g., ple ural eff usi o ns, b o ne 
lesi o ns)  will  be  rec or de d  as  pres e nt  or  a bs e nt  o nl y,  u nless,  w hile  a n  
a b n or malit y is still n ote d b y i ma gi n g st u dies or p h ysical e xa mi nati o n, it is 
f o u n d t o be hist ol o gicall y ne gati ve. 
 
1 2. 2  
Defi niti o ns  of Ti m e Peri o ds  
 
1 2. 2. 1  D urati o n of res p o ns e 
T his  is  meas ure d,  o nl y  i n  res p o n ders,  fr o m  t he  d oc u me nte d  be gi n ni n g  of  
res p o nse ( C R or P R) t o t he ti me of rela ps e. 
 
1 2. 2. 2  Disease -free sur vi val  
S ur vi val is defi ne d as t he date of st u d y e ntr y t o t he date of deat h. Disease -free 
s ur vi val is meas ure d fr o m t he ti me of occ urre nce of disease-free state (e. g. t he 
a dj u va nt setti n g f oll o wi n g s ur ger y or ra di ati o n t hera p y) or attai n me nt of a c o m plete 
re missi o n) t o disease r ec urre n ce or deat h fr o m l y m p h o ma or ac ute t o xi cit y of 
treat me nt. T his defi niti o n ma y be c o m plicate d b y deat hs t hat o cc ur d uri n g t he 
f oll o w-u p peri o d t hat are u nrelate d t o t he l y m p h o ma a n d t here is c o ntr o vers y as t o 
w het her s u c h d eat hs s h o ul d be c o nsi dere d as e v e nts or ce ns ore d at t he ti me of 
oc c urr e nce. W hereas it is ofte n p ossi ble t o i de ntif y t h ose deat hs rel ate d t o t he 
l y m p h o ma, t here is t he p ote ntial f or bias i n t he attri b uti o n of deat hs. 
 
1 2. 2. 3  Disease -s p ecific s ur vi val 
Disease -s p ecific  s ur vi v al  (e. g.,  l y m p h o ma-s pecific  s ur vi val,  ca us e-s pecific 
s ur vi val) is p ote ntiall y s u bject t o bias b eca us e t he e xact ca use of deat h is n ot al wa ys 
eas y t o ascert ai n. T o mi ni mize t he ris k of bias, t he e ve nt s h o ul d be rec or de d as 
deat h fr o m l y m p h o ma, or fr o m t o xicit y fr o m t he dr u g. Deat h fr o m u n k n o w n ca uses 

 
 
 
 
 
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s h o ul d be attri b ute d t o t h e dr u g. F or certai n tri als, ti me t o ne xt l y m p h o ma treat me nt 
ma y be of i nterest, defi ne d as ti me fr o m t he e n d of pri mar y treat me nt u ntil t he 
i nitiati o n of t he ne xt t hera p y. 
 
1 2. 2. 4  Pr o gressi o n- fr ee sur vi val  
Pr o gressi o n- fr ee S ur vi val ( P F S) is defi ne d as t he ti me fr o m e ntr y o nt o st u d y 
u ntil l y m p h o ma pr o gressi o n or deat h fr o m a n y ca use. P F S refl ects t u m or gr o wt h 
a n d, t heref ore, occ urs pri or t o t he e n d p oi nt of o verall s ur vi val. I n a d diti o n, P F S is 
n ot  c o nf o u n de d  b y  t he  a d mi nistrati o n  of  s u bse q ue nt  t hera p y.  W h et her  a  
pr ol o n gati o n of P F S re prese nts direct cli nical b e nefit or a s urr o gate f or cli nical 
be nefit de pe n ds o n t he ma g nit u de of t he effect a n d t he ris k -be nefit rati o of t he 
t hera p y u n d er i n vesti gati o n. U nli ke s ur vi val, t he precise date of pr o gressi o n is 
ge nerall y u n k n o w n. It m a y be defi n e d as t he first date of d o c u me ntati o n of a ne w 
lesi o n or e nlar ge me nt of a pre vi o us lesi o n, or t he date of t he sc he d ul e d cli nic visit 
i m me diatel y  after  ra di ol o gic  assess me nt  h as  bee n  c o m plete d.  W here  t here  is  
missi n g i nf or mati o n, ce ns ori n g of t he data m a y be defi ne d as t h e last date at w hic h 
pr o gressi o n stat us was a de q uatel y assess e d or t h e first date of u nsc h e d ul e d ne w 
a nti-l y m p h o ma treat me nt. 
 
1 2. 2. 5  Ti me t o pr o gressi o n 
Ti me  t o  pr o gressi o n  ( T T P)  is  defi ne d  as  t he  ti me  fr o m  st u d y  e ntr y  u ntil  
l y m p h o ma pr o gressi o n or deat h d ue t o l y m p h o ma. I n T T P, deat hs fr o m ot her ca uses 
are  ce ns or e d  eit her  at  t he  ti me  of  deat h  or  at  a n  earlier  ti me  of  assess me nt,  
re pres e nti n g a ra n d o m patter n of l oss fr o m t he st u d y. T T P is n ot as usef ul as P F S 
u nless t he maj orit y of d eat hs o n a st u d y are u nrel ate d t o t he l y m p h o ma d u e t o t he 
efficac y of t he treat me nt a n d/ or pr ol o n ge d f oll o w u p 
 
1 2. 2. 6  Ti me t o treat me nt fail ure  
Ti me t o treat me nt fail ure (e ve nt -free s ur vi val) is meas ure d fr o m t h e ti me fr o m 
st u d y e ntr y t o a n y treat me nt fail ure i ncl u di n g disc o nti n uati o n of treat me nt f or a n y 
reas o n, s uc h as disease pr o gressi o n, t o xicit y, patie nt prefere nce, i nitiati o n of ne w 
treat me nt wit h o ut d oc u me nte d pr o gressi o n, or deat h. T his c o m p osite e n d p oi nt is 
ge nerall y n ot e n c o ura g e d b y re g ulat or y a ge nci es beca use it c o m bi nes efficac y, 
t o xicit y a n d patie nt wit h dra wal. 
 
 
1 2. 3  
Res p o nse Re vie w  
Res p o nses will be re vie we d b y t he i n vesti gat or ( PI or c o- i n vesti gat or) w h o is 
treati n g t he patie nt at eac h partici pati n g site.  Patie nts w h o ha ve bee n treat e d wit h 
3 or m or e c y cles of R -C H O P c o ntai ni n g a n y d oses of  carfilz o mi b will be a vaila ble 
f or res p o ns e assess me nt.  
 
 
 

 
 
 
 
 
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1 3. 0 
R E C O R D S T O B E K E P T  / R E G U L A T O R Y C O N SI D E R A TI O N S  
A d verse e ve nt lists, g ui deli nes, a n d i nstr ucti o ns f or A E re p orti n g ca n b e f o u n d i n 
Secti o n 8. 0 ( A d vers e E ve nts: List a n d Re p orti n g Re q uire me nts). 
 
1 3. 1 
D at a Re p orti n g  
T he O n C ore Data bas e will be utilize d, as re q uire d b y t he Case C o m pre he nsi ve 
Ca ncer Ce nter, t o pr o vi de data c ollecti o n f or b ot h accr ual e ntr y a n d trial data 
ma na ge me nt.   O n C ore is a Cli nical Trials Ma na ge me nt S yste m h o use d o n sec ure 
ser vers mai ntai ne d at Case West er n Res er ve U ni v ersit y.   O n C ore pr o perl y use d is 
c o m plia nt wit h Title 2 1 C F R Part 1 1.  Access t o data t hr o u g h O n C ore is restricte d 
b y user acc o u nts a n d assi g ne d r oles.  O nce l o g ge d i nt o t he O n C ore s yste m wit h a 
user I D a n d pass w or d, O n C ore defi nes r ol es f or e ac h us er w hic h li mits access t o 
a p pr o priate d ata. Us er i nf or mati o n a n d pass w or d ca n be o btai ne d b y c o ntacti n g t he 
O n C ore A d mi nistrat or at o nc ore-re gistrati o n @cas e.e d u. 
O n C ore is desi g ne d wit h t he ca pa bilit y f or st u d y set u p, acti vati o n, trac ki n g, 
re p orti n g, data m o nit ori n g a n d re vie w, a n d eli gi bilit y verificati o n. T his st u d y will 
utilize electr o nic Case Re p ort F or m c o m pleti o n i n t he O n C ore data b ase.  A cale n dar 
of e ve nts a n d re q uire d f or ms are a v aila ble i n O n C ore.  
 
1 3. 2 
Re g ul at or y C o nsi der ati o ns 
T he st u d y will  be  c o n d ucte d i n c o m plia nce  wit h I C H g ui deli nes  a n d wit h all  
a p plica ble f e der al (i ncl u di n g 2 1 C F R parts 5 6 & 5 0), state or l ocal la ws. 
 
1 3. 2. 1  Writte n I nf or m e d C o nse nt 
1 3. 2. 2  Pr o visi o n of writte n i nf or me d c o nse nt m ust be o btai ne d pri or t o a n y st u d y-
relate d pr o ce d ur es.  T he Pri nci pal I n v esti gat or will e ns ure t hat t he s u bject is 
gi ve n f ull a n d a de q u ate oral a n d writte n i nf or mati o n a b o ut t he nat ure, 
p ur p ose, p ossi ble ris ks a n d be n efits of t he st u d y as well as t he s u bject’s 
fi na ncial r es p o nsi bilit y.  S u bjects m ust als o be n otifie d t hat t he y are free t o 
disc o nti n ue fr o m t he st u d y at a n y ti me.  T he s u bject s h o ul d be gi ve n t he 
o p p ort u nit y t o as k q uesti o ns a n d all o we d ti me t o c o nsi der t he i nf or m ati o n 
pr o vi de d. T he ori gi nal, si g ne d writte n I nf or me d C o nse nt F or m m ust be ke pt 
wit h t he Researc h C h art i n c o nf or ma n ce wit h t he i nstit uti o n’s sta n dar d 
o perati n g pr oce d ures. A c o p y of t he si g ne d writte n I nf or me d C o nse nt F or m 
m ust be gi ve n t o t he s u bject.  
1 3. 2. 3  S u bject Data Pr otecti o n  
I n  acc or d a nce  wit h  t he  Healt h  I nf or mati o n  P ort a bilit y  a n d  Acc o u nta bilit y  Act  
( HI P A A), a s u bject m ust si g n a n a ut h orizati o n t o releas e me dical i nf or mati o n t o t he 
s p o ns or a n d/ or all o w t he s p o ns or, a re g ulat or y a ut h orit y, or I nstit uti o nal Re vie w B oar d 
access t o s u bject’s me dical i nf or mati o n t hat i n cl u des all h os pital rec or ds rele va nt t o t h e 
st u d y, i ncl u di n g s u bjects’ me dical hist or y. 

 
 
 
 
 
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T his st u d y will access electr o nic me dical rec or ds s yste ms t o o btai n me dical 
i nf or mati o n f or t he s u bjects e nr olle d t o t his st u d y. 
I n or d er t o i ns ure patie nt safet y, i n vesti gat ors a n d st u d y pers o n nel m ust ha ve u p-
t o-t he-mi n ute  healt h  i nf or mati o n  f or  s u bjects  e nr olle d  t o  t his  st u d y.   T heref ore, 
electr o nic m e dical r ec or ds m ust be utilize d t o o btai n me dical i nf or mati o n i n a ti mel y 
ma n ner .  
 
Accessi n g Electr o nic Me dical Rec or ds f or U ni versit y H os pitals ( U H)  
T he  f oll o wi n g  electr o ni c  s yste ms  will  be  use d:   I D X  pr o gra m  t o  access  
sc he d uli n g i nf or mati o n; U H P h ysicia n P ortal t o access la b res ults a n d p h ysicia n 
n otes; P C O S S LI T E as n ecessar y t o l ocate arc hi v e d me dical rec or ds; C O P A T H t o 
l ocate ar c hi ve d pat h ol o g y rec or ds; P A C S t o access ra di ol o g y i ma gi n g res ults; a n d 
M y Sec ure Car e ( S u nrise Cli nical  Ma na ger) t o  access  s o me or all  of t he a b o ve 
i nf or mati o n w he n t his a p plicati o n is f ull y f u ncti o nal.  
Access t o t hes e s yste ms is re q uire d f or t he life of t his researc h st u d y.   
I nf or mati o n o btai ne d fr o m electr o nic s yste ms will be c o pie d i nt o t he Sei d ma n 
Ca ncer  Ce nter  Cli nical  Trials  U nit  researc h  c h art  a n d/ or  pri nte d  (l a b  res ults, 
p h ysicia n n otes, etc.) a n d st ore d i n t he researc h c hart.   Res earc h c h arts are ke pt 
sec ure a n d destr o y e d acc or di n g t o U H p olic y.  
St u d y data will be o btai ne d b y t he PI, c o-i n vesti gat ors, st u d y c o or di nat or, 
a n d/ or data ma n a ger f or t his st u d y via pass w or d- pr otecte d l o gi n.  D o n na K a ne  is a 
Case Wester n Reser v e U ni versit y e m pl o yee wit h a U ni versit y H os pitals e mail 
a d dress a n d I T & S l o g o n I D a n d Pass w or d.  D o n n a Ka ne will be assessi n g E M R 
t o o btai n data re q uir e d b y t he st u d y.  All st u d y pers o n nel i n v ol ve d i n t his researc h 
will a d here t o t he U H p olicies re gar di n g c o nfi de nti alit y a n d Pr otecte d Healt h 
I nf or mati o n ( P HI).  
 
Accessi n g Electr o nic Me dical Rec or ds f or  Cle vela n d Cli nic F o u n dati o n ( C C F). 
F or Cle vel a n d Cli nic, t he electr o nic s yste ms utilize d will be E PI C, C O P A T H 
t o  l ocate  arc hi ve d  pat h ol o g y  rec or ds;  a n d  A G F A  a n d/ or  Eas y Viz  t o  access  
ra di ol o g y i ma gi n g res ults 
Access t o t hes e s yste ms is re q uire d f or t he life of t his researc h st u d y.   
I nf or mati o n  o btai ne d  fr o m  electr o nic  s yste ms  will  be  c o pie d  i nt o  t he  Ta ussi g  
Ca ncer I nstit ute researc h c hart a n d/ or pri nte d (la b res ults, p h ysicia n n otes, etc.) a n d 
st ore d  i n  t he  r esearc h  c hart.  Researc h  c harts  are  k e pt  sec ure  a n d  destr o ye d  
acc or di n g t o C C F p olic y.  
St u d y data will  be o btai ne d b y t he PI,  c o -i n v esti gat ors, st u d y c o or di nat or, 
a n d/ or data ma na g er f or t his st u d y via pass w or d -pr otecte d l o gi n.   J ac kie T o mer is 
a Cle vela n d Cli nic e m pl o yee wit h a C C F e m ail a d dress a n d I T & S l o g o n I D a n d 
Pass w or d.  J ac kie T o mer will be assessi n g E M R t o o btai n dat a re q uire d b y t he 
st u d y.  All st u d y pers o n n el i n v ol ve d i n t his res earc h will a d here t o t he C C F p olicies 
re gar di n g c o nfi de ntialit y a n d P HI.  
 

 
 
 
 
 
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1 3. 2. 4  Rete nti o n of R ec or ds  
 
T he  Pri nci pal  I n v esti gat or  of  T he  Cas e  C o m pre he nsi ve  Ca n cer  Ce nter  
s u per vises t he r ete nti o n of all d oc u me ntati o n of a d verse e ve nts, rec or ds of st u d y 
dr u g recei pt a n d dis p e nsati o n, a n d all I R B c orres p o n de nce f or as l o n g as n ee de d t o 
c o m pl y wit h nati o nal a n d i nter nati o nal re g ulati o ns. N o rec or ds will be destr o ye d 
u ntil t he Pri nci pal I n vesti gat or c o nfir ms destr u cti o n is per mitte d.  
 
1 3. 2. 5  A u dits a n d I ns p ecti o ns 
A ut h orize d r e pres e ntati ves of t he s p o ns or, a re g ul at or y a ut h orit y, a n I n d e p e n de nt 
Et hics C o m mittee (I E C) or a n I nstit uti o nal Re vie w B oar d (I R B) ma y visit t he Ce nter 
t o perf or m a u dits or i ns p ecti o ns, i ncl u di n g s o urce data verifi cati o n.  T he p ur p ose of 
a n a udit or i ns pecti o n is t o s yste maticall y a n d i n de pe n de ntl y e xa mi ne all st u d y-
relate d acti vities a n d d oc u me nts t o deter mi ne w het her t hese acti vities were 
c o n d ucte d, a n d d ata w ere rec or d e d, a n al yse d, a n d acc uratel y re p orte d acc or di n g t o t he 
pr ot oc ol, G o o d Cli n ical Practice ( G C P), g ui deli nes of t he I nter nati o nal C o nfere n ce o n 
Har m o nizati o n (I C H), a n d a n y a p plica ble re g ulat or y re q uire m e nts.  
 
1 3. 2. 6  Data Safet y a n d M o nit ori n g Pla n 
T his pr ot oc ol will a d here t o t he p olicies of t he Cas e C o m pre he nsi ve Ca n cer 
Ce nter Data a n d Safet y M o nit ori n g Pla n i n acc or da nce wit h N CI re g ulati o ns. 
 
 
1 4. 0     S T A TI S TI C A L C O N SI D E R A TI O N S  
    T he g oal of t he p hase I p orti o n of t he trial is t o defi ne a R P 2 D b y usi n g a 
sta n dar d 3 + 3 d ose escal ati o n sc he me, as o utli ne d i n secti o n 3 .  T he p hase I st u d y 
will re q uire bet w ee n 1 8 - 2 4 patie nts. 
T he p hase II p orti o n of t he trial will re q uire 2 6 p atie nts wit h n o n -G C D L B C L 
treate d wit h C R-C H O P  wit h carfilz o mi b at t he M T D t o  ac hie ve 2 4  e v al ua ble  
patie nts.  T his will all o w f or t he p ote ntial t o d e m o nstrate a n i m pr o ve me nt i n t he 1-
year P F S fr o m 5 0 % t o 7 5 % usi n g a n o n para metric (i.e., K a pla n -M eier) ti me -t o 
e ve nt ( T T E) esti mate wit h a si g nifica nce of 5 % a n d p o wer of 8 0 %.   
We esti mate t hat we will accr u e 1-2 patie nts/ m o nt h d uri n g t he p hase I p orti o n 
of t he st u d y a n d 2- 4 patie nts/ m o nt h d uri n g t he p hase II p orti o n.  Esti mate d ti me f or 
accr u al of t he p h ase II p orti o n of t he st u d y is less t ha n 2 4 m o nt hs. 
 
 

 
 
 
 
 
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1 1. 
Jazire hi, A. R., M.I. Ve g a, a n d B. B o na vi da, Devel o p me nt of rit uxi m a b -resist a nt 
ly m p h o m a  cl o nes  wit h  altere d  cell  si g n ali n g  a n d  cr oss-resist a nce  t o  
c he m ot her a py.  Ca ncer Res, 2 0 0 7. 6 7 ( 3): p. 1 2 7 0- 8 1. 
1 2. 
D u nlea v y,  K.,  S.  Pittal u ga,  M. S.  Cz ucz ma n,  et  al.,  Differe nti al  effic acy  of  
b ortez o mi b pl us c he m ot her a py wit hi n m olec ul ar s u bty pes of diff use l ar g e B -
cell ly m p h o m a.  Bl o o d, 2 0 0 9. 1 1 3 ( 2 4): p. 6 0 6 9- 7 6. 
1 3. 
Si n ha, R., J. L. Ka uf ma n, H.J. K h o ur y, Jr., et al., A p h ase 1 d ose esc al ati o n st u dy 
of  b ortez o mi b  c o m bi ne d  wit h  rit uxi m a b,  cycl o p h os p h a mi de,  d ox or u bici n,  
m o difie d vi ncristi ne, a n d pre d nis o ne f or u ntre ate d f ollic ul ar ly m p h o m a a n d 
ot her l o w- gr a de B-cell ly m p h o m as.  Ca ncer, 2 0 1 2. 1 1 8 ( 1 4): p. 3 5 3 8- 4 8. 

 
 
 
 
 
C A S E 3 4 1 3  C R -C H O P  
Pr ot oc ol Versi o n   
 
 
7 4  
1 4. 
R ua n, J., P. Marti n, R. R. F ur ma n, et al., B ortez o mi b Pl us C H O P -Rit uxi m a b f or 
Previ o usly  U ntre at e d  Diff use  L ar ge  B -Cell  Ly m p h o m a  a n d  M a ntle  Cell  
Ly m p h o m a.  J Cli n O nc ol, 2 0 1 1. 2 9 ( 6): p. 6 9 0- 7. 
1 5. 
Arast u -K a p ur, S., J. L. A n derl, M. Kra us, et al., N o n pr ote as o m al t ar gets of t he 
pr ote as o me i n hi bit ors b ortez o mi b a n d c arfilz o mi b: a li nk t o cli nic al a dverse 
eve nts. Cli n Ca ncer Res, 2 0 1 1. 1 7 ( 9): p. 2 7 3 4- 4 3. 
1 6. 
Fe u gier, P., A. Va n H o of, C. Se b ba n, et al., L o n g- ter m res ults of t he R-C H O P 
st u dy i n t he tre at me nt of el derly p atie nts wit h diff use l ar ge B-cell ly m p h o m a: a 
st u dy by t he Gr o u pe d' Et u de des Ly m p h o mes de l' A d ulte. J Cli n O nc ol, 2 0 0 5. 
2 3 ( 1 8): p. 4 1 1 7- 2 6. 
1 7. 
Pfre u n dsc h u h, M., E. K u h nt, L. Tr u m per, et al., C H O P -like c he m ot her a p y wit h 
or wit h o ut rit uxi m a b i n y o u n g p atie nts wit h g o o d -pr o g n osis diff use l ar ge - B-cell 
ly m p h o m a: 6-ye ar r es ults of a n o pe n -l a bel r a n d o mise d st u dy of t he M a b T her a 
I nter n ati o n al Tri al ( MI n T) Gr o u p. La ncet O n c ol, 2 0 1 1. 1 2 ( 1 1): p. 1 0 1 3- 2 2. 
1 8. 
Ha ber ma n n, T. M., E. A. Weller, V. A. M orris o n, et al., Rit uxi m a b -C H O P vers us 
C H O P al o ne or wit h m ai nte n a nce rit uxi m a b i n ol der p atie nts wit h diff use l ar ge 
B-cell ly m p h o m a.  J Cli n O nc ol, 2 0 0 6. 2 4 ( 1 9): p. 3 1 2 1- 7. 
1 9. 
Reiser, M. W., M. Nic ke ni g, C. Peter, N. Metz ner, B. Pfre u n dsc h u h, M, Ser u m 
levels  a n d  p h ar m ac oki n etic  of  rit uxi m a b  i n  Bi-weekly  R -C H O P  i n  el derly  
p atie nts wit h D L B C L tre ate d i n t he RI C O V E R -6 0 tri al:.  J o ur nal of Cli nical 
O nc ol o g y A S C O A n n ual Meeti n g Pr ocee di n gs Part I. , 2 0 0 6. 2 4 ( 1 8 S (J u ne 2 0 
S u p ple me nt) ): p. 7 5 3 7. 
2 0. 
Pfre u n dsc h u h, M., G. Hel d, S. Ze y nal o va, et al., I m pr ove d O utc o m e of El derly 
P o or- Pr o g n osis  D L B C L  P atie nts  wit h  6x C H O P -1 4  a n d  8  A p plic ati o ns  of  
Rit uxi m a b ( R) Give n Over A n Exte n de d Peri o d: Res ults of t he S M A R T E - R-
C H O P -1 4 Tri al of t he Ger m a n Hi g h -Gr a de N o n -H o d gki n Ly m p h o m a St u dy 
Gr o u p  ( D S H N H L)  A merica n  S ociet y  of  He mat ol o g y  A n n ual  Meeti n g  
2 0 1 1( A bstract 5 9 2). 
2 1. 
C hle b o ws ki, R. T., A. Brzec h w a -A dj u kie wi cz, A. C o w de n, et al., D ox or u bi ci n 
( 7 5  m g/ m 2)  f or  h e p at ocell ul ar  c arci n o m a:  cli nic al  a n d  p h ar m ac oki n etic  
res ults. Ca ncer Tr eat Re p, 1 9 8 4. 6 8 ( 3): p. 4 8 7- 9 1. 
2 2. 
Be nja mi n,  R. S.,  C. E.  Ri g gs,  Jr.,  a n d  N. R.  Bac h ur,  P h ar m ac o ki netics  a n d  
met a b olis m of a dri a myci n i n m a n.  Cli n P har mac ol T her, 1 9 7 3. 1 4 ( 4): p. 5 9 2-
6 0 0. 
2 3. 
Bl u m,  R. H.  a n d  S. K.  Carter,  A dri a m yci n.  A  ne w  a ntic a ncer  dr u g  wit h  
si g nific a nt cli nic al activity. A n n I nter n M e d, 1 9 7 4. 8 0 ( 2): p. 2 4 9- 5 9. 
2 4. 
L oss os,  I. S.,  A. A.  Aliza de h,  M. B.  Eise n,  et  al.,  O n g oi n g  i m m u n o gl o b uli n  
s o m atic m ut ati o n i n ger mi n al ce nter B cell-like b ut n ot i n activ ate d B cell-like 
diff use l ar ge cell ly m p h o m as.  Pr oc Natl Aca d S ci U S A, 2 0 0 0. 9 7 ( 1 8): p. 
1 0 2 0 9- 1 3. 
2 5. 
L oss os, I. S. a n d R. Le v y, M ut ati o n a n alysis of t he 5' n o nc o di n g r e g ul at ory 
re gi o n of t he B C L-6 g e n e i n n o n -H o d gki n ly m p h o m a: evi de nce f or r ec urre nt 
m ut ati o ns a n d i ntr acl o n al heter o ge neity.  Bl o o d, 2 0 0 0. 9 5 ( 4): p. 1 4 0 0- 5. 

 
 
 
 
 
C A S E 3 4 1 3  C R -C H O P  
Pr ot oc ol Versi o n   
 
 
7 5  
2 6. 
Da vis,  R. E.,  K. D.  Br o w n,  U.  Sie be nlist,  et  al.,  C o nstit utive  n ucle ar  f act or  
k a p p a B activity is re q uire d f or s urviv al of activ ate d B cell -like diff use l ar ge B 
cell ly m p h o m a cells.  J E x p Me d, 2 0 0 1. 1 9 4 ( 1 2): p. 1 8 6 1- 7 4. 
2 7. 
J ost,  P.J.  a n d  J.  R ula n d,  A berr a nt  N F -k a p p a B  si g n ali n g  i n  ly m p h o m a:  
mec h a nis ms, c o ns e q ue nces, a n d t her a pe utic i m pli c ati o ns.  Bl o o d, 2 0 0 7. 1 0 9 ( 7): 
p. 2 7 0 0- 7. 
2 8. 
Kat o, M., M. Sa na da, I. Kat o, et al., Fre q ue nt i n activ ati o n of A 2 0 i n B -cell 
ly m p h o m as. Nat ur e, 2 0 0 9. 4 5 9 ( 7 2 4 7): p. 7 1 2- 6. 
2 9. 
C h oi, W. W., D. D. Weise n b ur ger, T. C. Grei ner, et  al., A ne w i m m u n ost ai n 
al g orit h m cl assifies diff use l ar ge B -cell ly m p h o m a i nt o m olec ul ar s u bty pes wit h 
hi g h acc ur acy.  Cli n Ca ncer Res, 2 0 0 9. 1 5 ( 1 7): p. 5 4 9 4- 5 0 2. 
3 0. 
Me yer, P. N., K. F u, T. C. Grei ner, et al., I m m u n o hist oc he mic al met h o ds f or 
pre dicti n g  cell  of  ori gi n  a n d  s urviv al  i n  p atie nts  wit h  diff use  l ar ge  B-cell 
ly m p h o m a tre ate d wit h rit uxi m a b. J Cli n O nc ol, 2 0 1 1. 2 9 ( 2): p. 2 0 0- 7. 
3 1. 
G utierrez -Garcia, G., T. Car desa -Sal z ma n n, F. Cli me nt, et al., Ge ne ex pressi o n 
pr ofili n g a n d n ot i m m u n o p he n oty pic al g orit h ms pre dicts pr o g n osis i n p atie nts 
wit h diff use l ar ge B -cell ly m p h o m a tre ate d wit h i m m u n oc he m ot her a p y.  Bl o o d, 
2 0 1 1. 
3 2. 
Ra y ma n,  N.,  K. H.  La m,  B.  va n  der  H olt,  et  al.,  Pr o g n ostic  Relev a n ce  of  
I m m u n o hist oc he mic al S u bcl assific ati o n of Diff use L ar ge B-Cell Ly m p h o m a i n 
T w o Pr os pective P h as e III Cli nic al Tri als.  Cli n L y m p h o ma M yel o ma L e u k, 
2 0 1 1. 1 1 ( 1): p. 2 3- 3 2. 
3 3. 
de  J o n g,  D.,  A.  R ose n wal d,  M.  C h ha na b hai,  et  al.,  I m m u n o hist oc he mic al 
pr o g n ostic  m arkers  i n  diff use  l ar ge  B -cell  ly m p h o m a:  v ali d ati o n  of  tiss ue  
micr o arr ay as a prere q uisite f or br o a d cli nic al a p plic ati o ns --a st u dy fr o m t he 
L u ne n b ur g Ly m p h o m a Bi o m arker C o ns orti u m.  J Cli n O nc ol, 2 0 0 7. 2 5 ( 7): p. 
8 0 5- 1 2. 
3 4. 
de J o n g, D., W. Xie, A. R ose n wal d, et al., I m m u n o hist oc he mic al pr o g n ostic 
m arkers i n diff use l ar ge B-cell ly m p h o m a: v ali d ati o n of tiss ue micr o arr ay as a 
prere q uisite  f or  br o a d  cli nic al  a p plic ati o ns  ( a  st u dy  fr o m  t he  L u ne n b ur g  
Ly m p h o m a Bi o m arker C o ns orti u m).  J Cli n Pat h ol, 2 0 0 9. 6 2 ( 2): p. 1 2 8- 3 8. 
3 5. 
Wri g ht, G., B. Ta n, A. R ose n wal d, et al., A ge ne ex pressi o n -b ase d m et h o d t o 
di a g n ose cli nic ally disti nct s u b gr o u ps of diff use l ar ge B cell ly m p h o m a.  Pr oc 
Natl Aca d Sci U S A, 2 0 0 3. 1 0 0 ( 1 7): p. 9 9 9 1- 6. 
3 6. 
C hes o n, B. D., B. Pfist ner, M. E. J u wei d, et al., R evise d res p o ns e criteri a f or 
m ali g n a nt ly m p h o m a.  J Cli n O nc ol, 2 0 0 7. 2 5 ( 5): p. 5 7 9- 8 6. 
3 7. 
J u wei d,  M. E.,  G. A.  Wise ma n,  J. M.  V ose,  et  al.,  Res p o nse  assess me nt  of  
a g gressive  n o n -H o d gki n's  ly m p h o m a  by  i nte gr ate d  I nter n ati o n al  W orks h o p  
Criteri a a n d fl u ori ne - 1 8-fl u or o de oxy gl uc ose p ositr o n e missi o n t o m o gr a p hy. J 
Cli n O nc ol, 2 0 0 5. 2 3 ( 2 1): p. 4 6 5 2- 6 1. 
 
 
 
 

 
 
 
 
 
C A S E 3 4 1 3  C R -C H O P  
Pr ot oc ol Versi o n   
 
 
7 6  
A P P E N DI X A  
P E R F O R M A N C E S T A T U S C RI T E RI A  
 
 
 
E C O G Perf or m a nce St at us Sc ale  
 
Gr a de  
Descri pti o ns  
 
 
0 
 
N or mal acti vit y. F ull y acti ve, a ble t o carr y o n all 
pre -diseas e perf or ma n ce wit h o ut restricti o n.  
 
 
 
1 
 
S y m pt o ms, b ut a m b ulat or y.  Restricte d i n 
p h ysicall y stre n u o us acti vit y, b ut a m b ulat or y a n d 
a ble t o carr y o ut w or k of a li g ht or se de ntar y 
nat ure (e. g., li g ht h o use w or k, office w or k). 
 
 
 
2 
 
I n b e d < 5 0 % of t he ti me. A m b ulat or y a n d 
ca pa ble of all self -care, b ut u na ble t o carr y o ut 
a n y w or k acti vities. U p a n d a b o ut m ore t ha n 5 0 % 
of wa ki n g h o urs. 
 
 
 
3 
 
I n b e d > 5 0 % of t he ti me. Ca pa ble of o nl y 
li mite d self-care, c o nfi ne d t o be d or c hair m ore 
t ha n 5 0 % of wa ki n g h o urs. 
 
 
 
4 
 
1 0 0 % be dri d de n. C o m pletel y disa ble d. Ca n n ot 
carr y o n a n y self-care. T otall y c o nfi ne d t o be d or 
c hair.  
 
5 
 
 
Dea d.  
 
 
 
 
 
 

 
 
 
 
 
C A S E 3 4 1 3  C R -C H O P  
Pr ot oc ol Versi o n   
 
 
7 7  
A P P E N DI X B 
 
I W C R E S P O N S E C RI T E RI A ( a d a pte d fr o m [3 7 ]) 
 
 
 
 
 

 
 
 
 
 
C A S E 3 4 1 3  C R -C H O P  
Pr ot oc ol Versi o n   
 
 
7 8  
A P P E N DI X C 
 
 

 
 
 
 
 
C A S E 3 4 1 3  C R -C H O P  
Pr ot oc ol Versi o n   
 
 
7 9  
A P P E N DI X D 
 
C o m pre he nsi ve List of Pr ot oc ol C h a n ges 
 
Versi o n 1 :  9/ 6/ 2 0 1 3 
•  U p date d treat me nt cale n dar  
•  U p date d d ose le v els  
•  U p date d D L T criteria  
•  U p date d ma na g e me nt of st u d y dr u g t o xicities 
•  A d de d ac y cl o vir t o st u d y treat me nt as a nti viral pr o p h yla xis 
 
Versi o n 2 : 5/ 2 7/ 2 0 1 4 
•  A d de d m ore i nf or mati o n re gar di n g Car diac M o nit ori n g u n der t he d ose 
re d ucti o n/ d ose dela y s ecti o ns ( Secti o n 7) 
 
Versi o n 3 : 7/ 1 4/ 2 0 1 4 
•  Clarificati o n t hat Fil grasti m ma y be s u bstit ute d if pe gfil grasti m is n ot 
a vaila ble.  
•  S pecificati o n i n dicati n g t hat D L T data will be rec or der d uri n g st u d y 
c ycle 1 of tr eat me nt (  
•  A d diti o nal la b tests were re m o ve d fr o m c ycle 2 - 6, da y 8 T he i ncl u de d 
trac ke d v ersi o n of t he pr ot oc ol pr o vi des a m ore c o m pre he nsi ve vie w 
of t he re visi o ns ma de.  
 
Versi o n 4 : 1/ 5/ 2 0 1 5 
•  S pecif y w hat pr o ce d ures w o ul d occ ur o n d a y 8 a n d 9 of eac h c ycle f or 
d ose le vels 2 - 4.  
•  T he scree ni n g peri o d w as e xte n de d fr o m 1 2 d a ys t o 2 8 da ys. 
•  T he I B was u p dat e d t o i ncl u de a d diti o nal ris k i nf or mati o n. I nf or mati o n 
pre vi o usl y i n secti o n 6. 4. 8 " M yel o d ys plastic S y n dr o me a n d Ac ut e 
M yel oi d Le u ke mia ( hea di n g title a n d te xt) was re place d wit h 
" P osteri or Re versi ble E n ce p hal o pat h y S y n dr o me.  
•  U p date d ta ble a n d ass oci ate d te xt f or a d vers e dr u g reacti o ns w as als o 
a d de d. 
 
Versi o n 5 : 2/ 2 4/ 2 0 1 5 
•  Re place d I C E P L E X ter mi n ol o g y t o M O D A P L E X ter mi n ol o g y 
t hr o u g h o ut d oc u me nt - A d de d i ncl usi o n criteria 4. 1. 2 - Patie nts m ust 
ha ve ra di o gra p hicall y meas urea bl e disease – 
•  Delete d i ncl usi o n criteria 4. 1. 5 - Life e x p ecta n c y > 6 m o nt hs i n t he 
o pi ni o n of a n d d oc u me nt e d b y i n vesti gat or –  
•  U p date d Researc h C o or di nat or c o ntact i n Secti o n 5. 0 - Re gistrati o n –  

 
 
 
 
 
C A S E 3 4 1 3  C R -C H O P  
Pr ot oc ol Versi o n   
 
 
8 0  
•  A d de d D L T w or di n g a n d clarifie d i nf or mati o n f or patie nts i n d ose 
le vels > = 2 i n Secti o n 7. 1 - He mat ol o gic T o xicit y a n d i n Ta ble 5 –  
•  
U p date d Secti o n 1 0. 1. 1. 3. 4 - T he M O D A P L E X S yste m - t o a d d Qia ge n 
i nf or mati o n - U p date d Secti o n 1 0. 1. 3 - C ollecti o n of S peci me ns - c h a n gi n g 
n u m ber of secti o ns o n sli des re q ueste d, a d di n g a d diti o nal sli de i nf or mati o n, a n d 
a d de d c o ntact i nf or mati o n. - U p date d  Secti o n 1 0. 1. 4 - Ha n dli n g of S peci me ns –  
•  
A d de d i nf or mati o n a b o ut ret ur n of sli des a n d a d de d Secti o n 1 0. 1. 4. 1 - Site 
S hi p pi n g I nstr ucti o ns –  
•  
Re place d Cale n d ar a n d C ale n dar K e y i n Secti o n 1 1. 2 t o ma ke it m ore rea da ble 
a n d a d de d s u p erscri pts t o f urt her cl arif y w hic h pr o ce d ures are re q uire d f or D ose 
Le vels 2 - 6 - C orrecte d t y p o gra p hical a n d f or matti n g err ors t hr o u g h o ut t he 
d oc u me nt  
 
 
Versi o n 6 : 8/ 2 8/ 2 0 1 5 
•  
Re m o val of Dr. Bria n B ol well as list of c o -i n vesti gat ors 
•  
A d diti o n of C hrist o p her D’ A n drea as c o-i n vesti gat or 
•  
I n crease fr o m 3- m o nt h t o 6- m o nt h f or f oll o w- u p visit wi n d o w.  
•  
Vital si g ns i ncl u di n g: bl o o d press ure, p ulse, res pirat or y rate a n d te m perat ure. ( d ose 
le vels 2- 6 o nl y) 
•  
Pr ot oc ol a me n de d t o i n dicate t hat gra de 2, 3 a n d 4 ( n ot j ust gra de 3- 4 ) n o n-
he mat ol o gic t o xicit y (e xce pt fati g ue or a n ore xia l asti n g < 7 da ys or Gra d e 3 na usea 
a n d/ or v o miti n g t hat persists f or < 2 da ys f oll o wi n g a p pr o priate s u p p orti ve care or 
n o n- cli nicall y si g nifica nt gra de 3 el ectr ol yte a b n or malities t hat ha ve bee n c orrect e d) 
t hat is treat me nt-relat e d m ust ret ur n t o a gra d e 1 or better pri or t o c o nti n ui n g 
treat me nt.  I n t he case of rec urre nce of gra de 2 n o n- he mat ol o gic t o xicit y, 
c o nti n uati o n o n t he st u d y will be at t he discreti o n of t he pri nci pal i n vesti gat or.  
•  
Wi n d o w of ti me f or M U G A or ec h ocar di o gra m e xte n de d t o be wit hi n 6 m o nt hs 
pri or  t o a d mi nistrati o n of pr ot oc ol t hera p y u nless t here is cli nical e vi d e nce f or ne w 
car diac s y m pt o ms wit hi n peri o d of ti me si nce t he car diac assess me nt.  
•  
D urati o n of t her a p y m o difie d t o i n dicate t hat: “I n t he a bse nce of treat me nt d ela ys 
d ue t o a d vers e e ve nts, tr eat me nt ma y c o nti n ue f or 6 c ycles or u ntil o ne of t h e 
f oll o wi n g criteria a p plies: 
•  
U nacce pta ble tr eat me nt r elate d t o xicit y, N CI C T C A E versi o n 4. 0 Gra de 2, 3 or 
4 t hat fails t o rec o ver t o baseli ne or < Gra d e 3 i n t he a bse nce of treat me nt wit hi n 
4 wee ks].  
•  
Ster oi d pre me dicati o n cl arifie d t o i ncl u de re peat de xa met has o ne i n wit h all 
s u bseq ue nt treat me nts if i nf usi o n reacti o ns occ ur i n c ycle 1, da y 1 u nl ess bei n g 
gi ve n as part of rit u xi ma b pre- me dicati o n  

 
 
 
 
 
C A S E 3 4 1 3  C R -C H O P  
Pr ot oc ol Versi o n   
 
 
8 1  
•  E xit P E T a n d C T sca n t o be o btai ne d bet w ee n 4- 8 wee ks after c y cle 6, 
da y 1. ( n ot 4 2- 5 0 da ys) 
 
•  E xcl usi o n criteria clarifie d t o i n dicate : K n o w n C N S i n v ol ve me nt b y 
l y m p h o ma.  Patie nts at hi g h ris k f or sec o n d ar y C N S i n v ol ve me nt b ut wit h o ut 
ne ur ol o gic s y m pt o ms s us pecte d t o be d u e t o l y m p h o ma are all o we d t o be e nr olle d 
a n d recei ve i ntrat hecal c he m ot hera p y i ncl u di n g b ut n ot li mite d t o met h otre xate, 
c ytara bi ne a n d gl uc oc ortic oi ds.  Patie nts w h o are e nr olle d a n d s u bse q ue ntl y 
i de ntifie d t o ha ve pat h ol o gic c o nfir mati o n of C N S i n v ol ve me nt b y l y m p h o ma 
ma y  be c o nti n ue d o n st u d y at t he discreti o n of t he pri nci pal i n vesti gat or. 
•  A n y D L T as defi ne d i n Secti o n 6. 2 will res ult i n a d ose re d ucti o n.  I n t he 
e ve nt of da y 8 ± 1 la b orat or y testi n g re veals a n A N C < 1 0 0/ m m3, he m o gl o bi n 
< 6. 5 g/ d L, or platelets na dir < 2 5, 0 0 0/ m m 3 f or patie nts i n d ose le vel 4, carfilz o mi b 
d osi n g will be hel d o n da ys 8 a n d 9 of t he c urre nt c ycle a n d re d uce d t o o ne d ose 
le vel l o wer o n da y 1 of t he s u bse q ue nt c y cle, pr o vi de d t hat t he da y 1 para meters 
are met ( A N C ≥ 1 2 0 0/ m m 3 a n d platelets ≥ 7 5, 0 0 0/ m m 3).  S h o ul d t he patie nt 
de vel o p a r ec urre nt D L T as defi ne d i n Secti o n 6. 2, a 2 n d d ose re d u cti o n of 
carfilz o mi b will be r e q uire d.  Treat me nt ca n res u m e after all o wi n g rec o ver y t o t he 
da y 1 criteri a ass u mi n g treat me nt has n ot bee n d el a ye d f or m ore t ha n 2 w ee ks. 
Ot her wise, t he st u d y dr u gs m ust be disc o nti n ue d (see Criteria f or Disc o nti n uati o n 
of St u d y Dr u g, secti o n 3. 4. 1.) 
•  Off treat me nt visit:  C T a n d P E T sca n t o be o btai n e d bet wee n 4- 8 w ee k s 
after c ycle 6, d a y 1. F or patie nts recei vi n g a dj u va nt or p ost-c he m ot hera p y 
ra diati o n treat me nt, P E T a n d/ or C T ca n be d eferre d u ntil after c o m pleti o n of 
ra diati o n. 
•  Cale n dar u p dat e d  
•  Re p orti n g t o s p o ns or ( A m ge n) u p date d  
 
 
Versi o n 7 : 1 1/ 5/ 2 0 1 5 
•  A d de d s pecific s ecti o n i n I n cl usi o n Criteria 4. 1. 1 t o i n dicate w here t he Ha ns 
Al g orit h m is l ocate d i n t he pr ot oc ol. 
•  Re m o ve d s pecific ster oi d i nf or mati o n i n I n cl usi o n Criteria 4. 1. 3. 
•  Clarifie d  w he n  Carfilz o mi b  will  be  a d mi nistere d  i n  Secti o n  6. 1. 1  (after  
Rit u xi ma b).  
•  U p date d t he St u d y Par a meters a n d C ale n dar i n Secti o n 1 1 t o e ns ure pr o ce d ures 
are c o nsiste ntl y liste d i n eac h l ocati o n.  
•  U p date d pers o n n el w h o will access E M R f or C C F i n Secti o n 1 3. 2. 2. 
•  C orrecte d t y p os a n d f or matti n g err ors t hr o u g h o ut d oc u me nt. 
 
 

 
 
 
 
 
C A S E 3 4 1 3  C R -C H O P  
Pr ot oc ol Versi o n   
 
 
8 2  
Versi o n 8 : 4/ 1 3/ 2 0 1 6 
•  U p date d he m o gl o bi n fr o m 9. 0 g/ dl t o 7. 0 g/ dl i n secti o n 4 
•  U p date d ac ycl o vir d osi n g i n ta ble 2 
•  U p date d n urse c o ntact f or S A E re p orti n g 
•  I n crease d wi n d o w t o 1 4 da ys f or f oll o w u p visits 
 
Versi o n 9 : 5/ 1 0/ 2 0 1 6 
•  U p date d Pre d nis o ne d osi n g t o da ys 3- 7 
•  A d de d C M C t o D 8 f or d ose le vel 4 
•  U p date d st u d y cale n d ar t o i ncl u de c o n me ds a n d b aseli ne s y m pt o ms 
 
Versi o n 1 0 : 9/ 9/ 2 0 1 6 
•  U p date d Creati ni ne Cleara nce fr o m 6 0 t o 4 5 
•    Clarifie d t hat M o da ple x testi n g is n ot a re q uire m e nt f or scree ni n g 
 
   Versi o n 1 1  : 2/ 1/ 2 0 1 7  
•  A d de d N C T # t o c o ver pa ge, re m o ve d Dr. S mit h as C o-I 
•  U p date d d ose le v el 4 (carfilz o mi b)  
•  A d de d d ose le v el 5 
•  U p date d st u d y cale n d ar ( o nl y safet y la bs nee d e d f or D 8 o n d ose le vels 4 a n d 
5) 
•  Visit o n D 9 is n o l o n ger re q uire d  
•  U p date R N c o ntact f or S A E re p orti n g 
•  U p date d D L T s ecti o n t o i ncl u de d ose le vel 5 
•  Clarifie d t hat O n Pr o is acce pta ble f or pe gfil grasti m a d mi nistrati o n  
•  Re m o ve d m o da ple x testi n g  
 
Versi o n 1 2: 2/ 2 7/ 2 0 1 7 
•  T his is a n a d mi nistrati ve u p date d f or clerical err or n ote d i n pr ot oc ol a me n d me nt 
1 1.  U p dati n g  ta ble  o n  pa ges  5  a n d  2 0  t o  c orrect  err or  o n  d os e  le v el  4.  
Carfilz o mi b will be a d mi nistere d at 2 0 m g/ m 2 i n C ycle 1 f oll o we d b y 4 5 m g/ m 2 
f or c ycl es 2- 6. 
 
Versi o n 1 3 : 2/ 1/ 2 0 1 8 
•  U p dati n g R P 2 D t hr o u g h o ut pr ot oc ol  
•  Re m o vi n g d ose m o dificati o n g ui deli nes f or Vi ncristi ne, all o wi n g f or p h ysicia n 
discreti o n gi ve n fre q u e nc y of peri p heral ne ur o p at h y (secti o n 7. 2. 1 a n d T a bl e 6 -
Ma na ge me nt of Ne ur o p at h y). 
•  C ha n gi n g c o ntact f or S A E’s fr o m R N t o Re g ulat or C o or di nat or 
•  Clarif yi n g c ollecti o n a n d ha n dli n g of s peci me ns (s ecti o ns 1 0 1. 3 a n d 1 0. 1. 4) 
•  U p dati n g scree ni n g wi n d o w t o 2 8 da ys, t his was pre vi o usl y liste d i n c h a n ge 
hist or y b ut was n ot e xec ute d i n t he pr ot oc ol 

 
 
 
 
 
C A S E 3 4 1 3  C R -C H O P  
Pr ot oc ol Versi o n   
 
 
8 3  
•  A d di n g 9 0 da y wi n d o w f or scree ni n g b o ne marr o w bi o ps y 
•  Ma ki n g  i nteri m  P E T  sca n  o pti o nal  beca use  t his  is  n ot  use d  f or  disease  
assess me nt  
•  A d di n g Fl ori da as a  partici pati n g site 
•  U p dati n g  O n y x  t o  A m g e n  t hr o u g h o ut  pr ot oc ol  f or  c o nsiste nc y,  O n y x  was  
ac q uire d b y A m g e n i n 2 0 1 5. 
•  U p dati n g  S A E  re p orti n g  c o ntact  i nf or mati o n  a n d  pr o vi di n g  c o vers heet  i n  
A p pe n di x D 
 
 
Versi o n 1 4 : 4/ 1 0/ 2 0 1 8 
•  A d di n g  p h ysicia n  a n d  s p o ns or -i n vesti gat or  discreti o n  o n  d ose  re d uci n g  
Carfilz o mi b i n t he e ve nt of a n y t o xicit y. 
E xcl u di n g  patie nts  of  direct  Asia n -Pacific  ( C hi na,  Ja pa n,  Tai wa n,  Si n ga p ore,  
Re p u blic of K orea, a n d T haila n d) a ncestr y d ue t o a safet y n otice t h at was release d 
b y A m ge n 
 
Versi o n 1 5: 8/ 1/ 2 0 1 8 
•  Re m o ve d pre vi o us sta n d ar d of care pr oce d ures f or Rit u xa n a d mi nistrati o n 
•  A d de d a n E C H O at t he 6 m o nt h f oll o w u p visit 
•  U p date d secti o n o n c o ntrace pti o n use f or males a n d fe males  
 
Versi o n 1 6: 1 1/ 1 4/ 2 0 1 8 
•  Ma de Da y 8 l a bs o pti o nal 
•  A d de d R os well Par k as a s u b- site 
•  Clarifie d i ncl usi o n criteri a  
•  U p date d eli gi bilit y criteria t o i ncl u de 1 c ycle of pri or treat me nt f or D L B C L 
wit hi n 6 0 da ys of e nr oll me nt 
•  A d de d HI V t esti n g d uri n g scree ni n g 
•  A d de d a d dr ess f or c orr elati ve sa m ples  
•  U p date d S u b-te xt o n t he cale n dar t o matc h pr ot oc ol 
 
Versi o n 1 7 : 2/ 1 8/ 2 0 2 0 
•  E xcl usi o n: n o w all o ws l o w ris k, f ull y treate d mel a n o ma 
•  N o w all o ws f or s p o ns or a p pr o val f or A N C a b n or m alities d ue t o B M i nfiltrati o n  
•  Clarifie d ac y cl o vir i nc o nsista ncies: Ac ycl o vir t o start C 1 D 1  
•  Re m o ve d  s pecific  la n g ua ge  o n  rit u xi ma b  a d mi nistrati o n,  u p date d  t o  “ per  
i nstit uti o nal g ui deli nes” 
•  U p dates scree ni n g wi n d o w f or patie nts wit h S O C R -C H O P t o als o i ncl u de 
a n yt hi n g 1 4 da ys pri or t o t heir S O C R -C H O P ( d oes n ot i ncl u de t he sca ns, t h ose 
d o n’t ha ve a s p ecifie d wi n d o w) 

 
 
 
 
 
C A S E 3 4 1 3  C R -C H O P  
Pr ot oc ol Versi o n   
 
 
8 4  
•  All o ws f or eit her a C T or P E T t o be o mitte d i n p atie nts wit h S O C R -C H O P as 
l o n g as t here is e vi de nce of meas urea ble disease a n d a vaila ble T M f or res p o nse 
assess me nt  
•  B M B ca n be wai ve d b y s p o ns or if B M sta gi n g a n d FI S H are a v aila ble fr o m 
a n ot her t y pe of bi o ps y 
•  S O C R -C h o p s h o ul d be c o nsi dere d a c y cle. Patie nts s h o ul d recei ve 1 c ycle R -
C H O P, t he n 5  c ycl es of C R -C H O P. A 6t h C ycle of C R -C H O P is all o we d per 
i n vesti gat or discreti o n ( 7 t otal c ycles) 
•  I nteri m sca ns s h o ul d be d o ne  after 3 c y cles of C R-C H O P n o matter if t he y 
recei v e d  S O C  R-C H O P.  S o  f or  s o me  patie nts  sca ns  ma y  be  d o n e  4  t otal  
treat me nts. 
•  E xte n di n g sca n wi n d o w fr o m 2 8 t o 4 2 da ys f or t h os e w h o b e gi n wit h C R -C H O P  
•  E xte n di n g sca n wi n d o w t o 5 6 da ys pri or t o S O C t hera p y f or t h ose w h o be gi n 
wit h R -C H O P  
•  Re m o ve d a p pe n di x B – n o l o n ger a p plica ble  
•  Clarifie d E O T visit is 4 - 8 wee ks fr o m D 1 of last c ycle of treat me nt 
•  Clarificati o n t hat patie nts w h o pr o gress s h o ul d o nl y be f oll o we d f or s ur vi val  
 
Versi o n 1 7 : 2/ 1 1/ 2 0 2 2 
•  Re m o ve d Lisa R y bic ki 
•  Re m o ve d Dr. Eric Hsi 
•  A d de d Dr. Sar a h O n dr ej ka 
•  A d de d ge ne m utati o n a n d c o p y n u m ber a nal ysis at la b orat or y of Dr. Sa n d ee p 
Da ve at D u k e U ni versit y.