Clinical trial NCT02073097
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
Start date: 2015-01-28; Completion date: 2023-06-29
Enrollment: 48 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase I/II trial studies the side effects and best dose of carfilzomib when given together with rituximab and combination chemotherapy and to see how well they work in treating patients with diffuse large B-cell lymphoma. Carfilzomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as rituximab, can block cancer growth by finding cancer cells and helping kill them. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. It is not known if carfilzomib in combination with R-CHOP is better or worse than R-CHOP alone in treating patients with diffuse large b-cell lymphoma.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the safety of carfilzomib in combination with rituximab-cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone (R-CHOP) (CR-CHOP) in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) and identify a recommended phase II dose (RP2D). (Phase I)

SECONDARY OBJECTIVES:

I. To determine if CR-CHOP improves the rates of 1-year progression free survival (PFS) and overall survival (OS) in non-germinal center (non-GC) DLBCL patients relative to historical controls treated with R-CHOP(Phase II) II. To determine response rates (complete and partial remission) in non-GC DLBCL patients treated with CR-CHOP and compare to historical controls treated with R-CHOP.

III. Because a proportion (\~10%) of patients classified as non-GC by immunohistochemical (IHC) algorithms may not have the activated B-cells (ABC) subtyped of DLBCL, an exploratory secondary objective will compare the PFS, OS and response rates of the ABC subgroup of patients with DLBCL as determined by the Gene Expression Profiling with those of the overall group of non-GC DLBCL.

OUTLINE: This is a phase I, dose-escalation study of carfilzomib followed by a phase II study.

Patients receive rituximab intravenously (IV) over at least 90 minutes, cyclophosphamide IV over 30-60 minutes, doxorubicin hydrochloride IV over 3-5 minutes, vincristine sulfate IV over 1 minute on day 1, and prednisone orally (PO) on days 1-5. Patients also receive carfilzomib IV over 30 minutes on days 1, 2, 8 and 9. Courses repeat every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and at 6, 12, and 24 months.

Arms: arm 1: Participants receive (every 21 day cycle):

* Rituximab IV over at least 90 minutes on day 2
* Carfilzomib IV over 30 minutes on days 1, and 2
* Cyclophosphamide IV over 30-60 minutes on day 3
* Doxorubicin hydrochloride IV over 3-5 minutes on day 3
* Vincristine sulfate IV over 1 minute on day 3
* Prednisone PO on days 3-7 any time
* Pegfilgrastim day 4
* Acyclovir 2x per day from cycle 1, 6 months after completion of cycle 6

Courses repeat every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Carfilzomib intervention 2: Rituximab intervention 3: Cyclophosphamide intervention 4: Doxorubicin hydrochloride intervention 5: Vincristine sulfate intervention 6: Prednisone intervention 7: Pegfilgrastim intervention 8: Acyclovir
Intervention descriptions: intervention 1: Given IV, according to dose level. Cohorts begin with dose level (DL)1, escalated in standard 3+3 design to identify a recommended phase 2 dose DL (-2) 11 mg/m2 on day 1 and 2 every 21 days, cycles 1-6

DL (-1) 15 mg/m2 on days 1 and 2 every 21 days, cycles 1-6

DL (1) 20 mg/m2 days 1,2 every 21 days, cycles 1-6

DL (2) 20 mg/m2 days 1,2 of cycle 1 followed by 27 mg/m2 days 1,2 every 21 days for cycles 2-6.

DL (3) 20 mg/m2 days 1,2 of cycle 1 followed by 36 mg/m2 days 1,2 every 21 days for cycles 2-6.

DL(4) 20 mg/m2 days 1,2 of cycle 1 followed by 45 mg/m2 days 1,2 every 21 days for cycles 2-6

DL (5) 20 mg/m2 days 1,2 of cycle 1 followed by 56 mg/m2 days 1,2 every 21 days for cycles 2-6 intervention 2: Given IV (375mg/m\^2) intervention 3: Given IV (750mg/m\^2) intervention 4: Given IV (50mg/m\^2) intervention 5: Given IV (1.4mg/m\^2) intervention 6: Given PO (100mg) intervention 7: 6 mg SC day 4 (every 21 days). Filgrastim 300 or 480 mcg IV/SC daily days 1-10 may be substituted if pegfilgrastim is not available. ONPROTM is also an acceptable method of administration. intervention 8: PO (400mg)

Protocol documents:
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Prot_SAP_002.pdf: 
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   
 
 
5  
  
 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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Pr ot oc ol Versi o n   
 
 
6  
  
 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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Pr ot oc ol Versi o n   
 
 
7  
      
  
         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  
 


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


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


 
 
 
 
 
C A S E 3 4 1 3  C R -C H O P  
Pr ot oc ol Versi o n   
 
 
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.  


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


 
 
 
 
 
C A S E 3 4 1 3  C R -C H O P  
Pr ot oc ol Versi o n   
 
 
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, 


 
 
 
 
 
C A S E 3 4 1 3  C R -C H O P  
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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Pr ot oc ol Versi o n   
 
 
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   
 
 
1 8  
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  
Pr ot oc ol Versi o n   
 
 
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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3 7  
     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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3 9  
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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4 0  
  
 
 
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.  


 
 
 
 
 
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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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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 


 
 
 
 
 
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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.  
 


 
 
 
 
 
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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 ]. 
 
 


 
 
 
 
 
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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 ].  


 
 
 
 
 
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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 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.